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CH4106 > Suppositories & Inserts > Flashcards

Suppositories & Inserts Flashcards

1
Q

Definition of suppositories

A

Solid dosage forms intended for insertion into body orifices where they melt, soften or dissolve and exert either local/systemic effects

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2
Q

Reasons for suppositories

A
  1. Patient may not be able to use the oral route:
    - very young, old/mentally disturbed
    - patients with GI tract problems
    - severely debilitated (weak)
  2. Drug is less suited for oral administration:
    - GI tract side effects
    - drug stability: effect of pH or enzymes
    - unacceptable drug taste/smell
  3. Parenteral route might be unstable
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3
Q

Advantages of suppositories

A
  • 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
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4
Q

Disadvantages of suppositories

A
  • 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
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5
Q

Route of administrations

A

Rectum, vagina and urethra

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6
Q

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:

A
  1. Physicochemical factors
    - lipid-water solubility - partition coefficient
    - particle size
    - nature of base/release
  2. Physiologic factors
    - Colonic content
    - pH/buffer capacity
    - circulation route
    - Part of rectum at which absorption is taking place
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7
Q

Physiology of rectum

A

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

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8
Q

Drug is usually applied at which part of the rectum

A

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)

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9
Q

Physiology of vagina

A

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

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10
Q

Physiology of urethra

A

Short straight tube connecting the bladder to the outside; Poorly perfused by blood

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11
Q

Ideal suppository bases/vehicles

A
  • 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
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12
Q

Classification of suppository bases

A
  • 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
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13
Q

Characteristics of cocoa butter base

A
  • 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
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14
Q

Disadvantages of cocoa butter base

A
  • Insufficient contraction at cooling
  • Low softening point
  • Poor chemical stability
  • Poor water adsorptive power
  • Bad for high speed manufacture
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15
Q

Cocoa butter replacements

A
  • Vegetable oils
  • Wax
  • Triglycerides of fatty acids
  • Fatty alcohols C12- C18
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16
Q

Characteristic of water-soluble/water-miscible bases

A

May result in some irritation and dehydration as they take up water and dissolve

17
Q

Examples of water-soluble/water-miscible bases

Note: these bases suppositories should be protected from moisture as they are hygroscopic

A 
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.
18
Q

Advantages of using compressed tablets (not common for rectal suppositories - low moisture environments, but becoming more popular for vaginal use)

A
  • easier to manufacture

- more stable (storage and chemical reaction)

19
Q

SPECIFIC considerations for formulation

A
  • water
  • hygroscopicity
  • incompatibilities
  • viscosity
  • brittleness
  • density
  • volume contraction
  • dosage replacement
  • weight/volume control
20
Q

Consideration for formulation

A
  • 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
21
Q

Process for drug release

A
  • 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
22
Q

Factors to consider for drug release

A
  1. Type of base
  2. Solubility in water and vehicle
  3. Particle size
  4. Amount of drug
  5. Other additives
23
Q

Drug release: Oil-soluble drug and oily base

A

Slow release, poor escaping tendency

24
Q

Drug release: Water-soluble drug and oily base

A

Rapid release - preferred

25
Q

Drug release: Oil soluble drug and water miscible base

A

Moderate release rate

26
Q

Drug release: Water soluble drug and water miscible base

A

Rapid release- based on diffusion

27
Q

How does particle size affect drug release

A
  • Small particles -> better dissolution, less irritation, better sedimentation rate
  • Suggested: 50 - 100um
28
Q

How does amount of drug affect drug release

A

No. of particles increase -> chance of agglomerate formation increases
Density/dose replacement calculations needed if more than 100mg drug is used in 2g suppository

29
Q

How does other additives affect drug release

A

May cause depression in the mp or cause deglomeration, which help to prevent cake formation

30
Q

Ways to prepare suppositories

A
  1. Hand rolling and shaping
  2. Cold Compression
  3. Molding from a melt
31
Q

Describe using hand rolling and shaping to prepare suppositories

A
  1. Weigh ingredients
  2. Grate cocoa butter
  3. Add active ingredient
  4. Mix thoroughly utilizing a mortar/pestle or a pill tile/spatula
  5. Shape into long cylinder
  6. Cut into desired length, rounding the tips
  7. Packaging and labeling
32
Q

Describe using cold compression to prepare suppositories

A
  • 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)
33
Q

Describe using molding from a melt (fusion) to prepare suppositories

A
  • 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
34
Q

Considerations for the method molding from a melt

A
  1. Suppository molds: plastic, stainless steel, aluminium, bass, etc. -> understand the effect of heat and excipients on the mold
  2. Lubrication of mold: For mold release e.g. of lubricants: glycerinated gelatin and mineral oils
  3. Amount of base required: 10% extra for mold to be overfilled
  4. Calibration of mold
  5. Preparation and pouring of melt: Melt over water bath with least possible heat -> homogeneous heating, stir during pouring into chilled mold
35
Q

Calibration of mold

A
  1. Prepare the molds, clean and dry cavities
  2. Melt sufficient suppository base to fill 6-12 molds
  3. Pour in the mold, cool and trim
  4. Remove suppositories and weigh
  5. Divide the total weight by the no. of blank suppositories prepared = average weight of each suppository for this particular base
  6. Use this weight as the calibrated value for that specific mold using that specific lot of suppository base
  7. Put in beaker and melt to get volume
  8. Calculate weight and volume of each cell
  9. Different bases will have different densities
36
Q

When do you need to calculate for suppositories

A

If the active drug > 100mg for a 2g suppository weight

37
Q

What if the density factor of a base is not known?

A

Calculate as the ratio of blank weight of the base and cocoa butter

38
Q

Methods to calculate the quantity of base that active medication will occupy and the quantity of ingredients required

A
  1. Dosage replacement factor
  2. Density factor - Paddock method
  3. Occupied volume
39
Q

Name some quality control tests

A
  • Melting range test
  • Liquefaction test
  • Breaking test
  • Softening/liquefaction temperature test

CH4106 (18 decks)

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