Suppositories & Inserts Flashcards
Definition of suppositories
Solid dosage forms intended for insertion into body orifices where they melt, soften or dissolve and exert either local/systemic effects
Reasons for suppositories
- Patient may not be able to use the oral route:
- very young, old/mentally disturbed
- patients with GI tract problems
- severely debilitated (weak) - Drug is less suited for oral administration:
- GI tract side effects
- drug stability: effect of pH or enzymes
- unacceptable drug taste/smell - Parenteral route might be unstable
Advantages of suppositories
- Self administration
- Avoidance of oral and parenteral routes and their problems
- Drug causes nausea/drug restrictions
- Patient suffering from severe vomiting
- Can be targeted delivery system: localized action, get to the site at a lower dose -> reduce systemic toxicity
Disadvantages of suppositories
- Mucosal irritation
- Slow, erratic and incomplete absorption
- Diarrhea and disease states affect absorption
- Installation may trigger defecation reaction
- High cost and problems with large scale manufacturing
- Stringent storage conditions
- Development of proctitis - inflammation of the rectum
Route of administrations
Rectum, vagina and urethra
Factors affecting rectal absorption: The dosage of the drug given rectally may be greater than/less than the dose of the same drug given orally depending on:
- Physicochemical factors
- lipid-water solubility - partition coefficient
- particle size
- nature of base/release - Physiologic factors
- Colonic content
- pH/buffer capacity
- circulation route
- Part of rectum at which absorption is taking place
Physiology of rectum
Hollow with a relatively flat wall surface without villi, which secretes mucous.
Surface area of 300 cm^2
Rectal fluids are neutral - pH 7.5 without buffering capacity
Drug is usually applied at which part of the rectum
Lower part. Middle hemorrhoidal vein and inferior hemorrhoidal vein’s blood flow to lliac vein which flows to inferior vena cava (goes directly into general circulation, avoiding the liver)
Physiology of vagina
Vaginal fluids are a mixture of proteins and polysaccharides, protective mucus originate in cervix and pH is low.
Blood supply from vaginal artery and return avoids the hepatic portal system
Physiology of urethra
Short straight tube connecting the bladder to the outside; Poorly perfused by blood
Ideal suppository bases/vehicles
- Cause no irritation/inflammation - biocompatibility
- Remains solid at room temp. but melts, dissolves, softens at 37 degree celcius
- Chemically stable and inert
- Physically stable
- Melting range should be ideal for rapid solidification
- Does not affect the bioavailability of the drug
- Suitable viscosity when melted, does not leak from rectum/vagina
Classification of suppository bases
- Fatty/oleaginous - Cocoa butter, adeps solidus
- Water-soluble/water-miscible - glycerinated gelatin, polyethylene glycol
- Misc - mix of lipophilic and hydrophilic bases, mix of fatty bases and emulsifying agents
- Non-base - tablets, soft gelatin capsules
Characteristics of cocoa butter base
- Naturally occurring triglyceride
- Yellowish-white solid, mp 30-36C
- Poor water absorptive properties
- Show polymorphism (alpha - 22C, beta’ - 28-31C, beta - 34-35C, gamma - 18C)
- Beta is the most stable and desired form - mp 34-35. All forms can be converted to beta form: need beta seed crystals to get the required beta form
- Dont heat above 34.5 for long time
Disadvantages of cocoa butter base
- Insufficient contraction at cooling
- Low softening point
- Poor chemical stability
- Poor water adsorptive power
- Bad for high speed manufacture
Cocoa butter replacements
- Vegetable oils
- Wax
- Triglycerides of fatty acids
- Fatty alcohols C12- C18
Characteristic of water-soluble/water-miscible bases
May result in some irritation and dehydration as they take up water and dissolve
Examples of water-soluble/water-miscible bases
Note: these bases suppositories should be protected from moisture as they are hygroscopic
Glycerinated Gelatin - mix of glycerin and gelatin in water Polyethylene glycol (PEG) - polymers of varying MW, base properties change with MW, water-soluble: dissolve in body fluids, stable, must not store in polystyrene vials, ratio of low to high MW PEGs can be altered to prepare a base with a specific m.p., controlled release, no leaking.
Advantages of using compressed tablets (not common for rectal suppositories - low moisture environments, but becoming more popular for vaginal use)
- easier to manufacture
- more stable (storage and chemical reaction)
SPECIFIC considerations for formulation
- water
- hygroscopicity
- incompatibilities
- viscosity
- brittleness
- density
- volume contraction
- dosage replacement
- weight/volume control
Consideration for formulation
- Base selection: composition, melting behaviour, rheological properties
- Drug onset and action: quick, slow, prolonged effect
- Application and use: rectal/vaginal/urethral, systemic/local absorption
- Drug release: dissolve in rectal fluid/melt on the mucous layer
Process for drug release
- suppositories with oleaginous bases: melt -> spread
- suppositories with hydrophilic bases: dissolves in fluids -> diffuses from fluids
1. Melting and spreading
2. Sedimentation
3. Wetting
4. Dissolution
Factors to consider for drug release
- Type of base
- Solubility in water and vehicle
- Particle size
- Amount of drug
- Other additives
Drug release: Oil-soluble drug and oily base
Slow release, poor escaping tendency
Drug release: Water-soluble drug and oily base
Rapid release - preferred
Drug release: Oil soluble drug and water miscible base
Moderate release rate
Drug release: Water soluble drug and water miscible base
Rapid release- based on diffusion
How does particle size affect drug release
- Small particles -> better dissolution, less irritation, better sedimentation rate
- Suggested: 50 - 100um
How does amount of drug affect drug release
No. of particles increase -> chance of agglomerate formation increases
Density/dose replacement calculations needed if more than 100mg drug is used in 2g suppository
How does other additives affect drug release
May cause depression in the mp or cause deglomeration, which help to prevent cake formation
Ways to prepare suppositories
- Hand rolling and shaping
- Cold Compression
- Molding from a melt
Describe using hand rolling and shaping to prepare suppositories
- Weigh ingredients
- Grate cocoa butter
- Add active ingredient
- Mix thoroughly utilizing a mortar/pestle or a pill tile/spatula
- Shape into long cylinder
- Cut into desired length, rounding the tips
- Packaging and labeling
Describe using cold compression to prepare suppositories
- Base and medication mixture is forced into special molds using suppository making machines
- No heat needed
1. Mix base and other ingredients thoroughly utilizing a mortar/pestle or mechanical mixtures
2. Pressure is applied to the mold -> perfectly molded suppositories with no air bubbles (special equipment needed)
Describe using molding from a melt (fusion) to prepare suppositories
- Heat required
- Special calculations required
- Most common
1. Base material gently heated to melt
2. Active ingredients and excipients are added with mixing
3. Melt is poured into molds (slightly overfill)
4. Allow the melt to cool and congeal into suppositories
5. Trim, package and label suppositories
Considerations for the method molding from a melt
- Suppository molds: plastic, stainless steel, aluminium, bass, etc. -> understand the effect of heat and excipients on the mold
- Lubrication of mold: For mold release e.g. of lubricants: glycerinated gelatin and mineral oils
- Amount of base required: 10% extra for mold to be overfilled
- Calibration of mold
- Preparation and pouring of melt: Melt over water bath with least possible heat -> homogeneous heating, stir during pouring into chilled mold
Calibration of mold
- Prepare the molds, clean and dry cavities
- Melt sufficient suppository base to fill 6-12 molds
- Pour in the mold, cool and trim
- Remove suppositories and weigh
- Divide the total weight by the no. of blank suppositories prepared = average weight of each suppository for this particular base
- Use this weight as the calibrated value for that specific mold using that specific lot of suppository base
- Put in beaker and melt to get volume
- Calculate weight and volume of each cell
- Different bases will have different densities
When do you need to calculate for suppositories
If the active drug > 100mg for a 2g suppository weight
What if the density factor of a base is not known?
Calculate as the ratio of blank weight of the base and cocoa butter
Methods to calculate the quantity of base that active medication will occupy and the quantity of ingredients required
- Dosage replacement factor
- Density factor - Paddock method
- Occupied volume
Name some quality control tests
- Melting range test
- Liquefaction test
- Breaking test
- Softening/liquefaction temperature test
