4 - Suppositories Theory Flashcards by Karlo Sison

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

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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)

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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

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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

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Soft Contact Lenses

Opthalmic controlled release drug delivery systems

Type 1 Gels

cross linked poly methacrylate

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Disintigrant for Tablet formulations

Type 1 Gels

Use Croscarmellose sodium, that SWELLS on contact with water

= cross-linked carboxymethylcellulose sodium

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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

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The taking up of liquid

WITHOUT measurable change in VOLUME

IMBIBITION

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The taking up of liquid with an INCREASE IN VOLUME

SWELLING

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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

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Reversible gel-sol (semisolid -fluid) formation with

NO CHANGE in

VOLUME or TEMPERATURE

usually triggered by SHEER FORCES

THIXOTROPY

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Desolvated gel in which the

Framework remains INTACT

both Type 1 & Type 2 gels can be desolvated to become this

XEROGELS

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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

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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

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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

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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

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Most wildley used NATURAL polymer in pharmaceutical products

HYDROPHILIC Colloid = HYDROGEL

Used as:

Soft/hard ____ capsules

Tab granulations / coatings

Emulsions / Suppositories

GELATIN

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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

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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

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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_** ## Footnote (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)** ## Footnote 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_** ## Footnote *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!** 1. **Titurate** drug into fine powder 1. add grated **cocoabutter/base** 2. **Incorporate drug** into base using pestle 3. Place **between sheets of filtered paper** 4. **kneed + roll into CYLINDER** 5. 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_ 1. **Melt the base** 1. use SLOW heating w/ cocoa butter 1. *avoid completing melting to preserve Beta polymorph seed crystals* 2. ****Add Drug** & dissolve or disperse in molten base 3. **Pour into mold** 1. allow to cool, 1. use SLOW COOLING to force crystallization as Beta polymorph

**_Fusion_** or **_Hot Melt Molding_**