Suppositories and displacement value calcs

What are the ways people can take suppositories?

Rectal, vaginal or urethral drug delivery

• Systemically - far from contact (flagyl, indomectacin)

• Locally - site of contact

What are the advantages of suppositories?

• Bypass 1st pass metabolism

• Faster onset (local)

• Enhanced absorption (due to bypassing)

• Higher bioavailability (due to bypassing)

• Avoid taste issues (paeds)

Why are suppositories used rectally?

• Solid unit dosage form suitably shaped for insertion

• Melt when warmed to body temp

• Dissolve when in contact with mucous secretions

  • Base can have a local action

    • Anusol, bisacodyl, protosedyl

How long can you keep suppositories?

3 months

What is the formulation of suppositories?

Nominal weight range for moulds

• Infant - 1g

• Child - 2g

• Adult - 4g

• Drug content from 0.1% - 40 %

• Other excipients

• Viscosity modifiers

• Surface active agents

What are the 2 types of bases?

Fatty/oleaginous

• Melt at body temp (oily)

• Semi-synthetic fatty vehicles (adeps solidus)

Water soluble or miscible

• Disperse in rectal cavity

• Glycerinated gelatin and PEGs used

• Mainly for laxative purposes

What are the properties for an ideal base?

• Solid at room temp

• Melt at body temp

  • Water soluble form of the drug dispersed in a fatty base

• Release the drug

• Non-toxic and non-irritant

• Stable on storage

• Compatible with drug

• Capable of being moulded and easily removed

What is the difference between a high and low solubility base?

Very soluble base = low drug release

Low solubility base = drug deposits onto mucosal surface

What happens after the suspension has been inserted?

What are the 2 ways suppositories prepared?

Moulding from a molten mass (most common)

• The base is melted and the drug added

• Poured into moulds and allowed to cool

• Suppositories removed and wrapped

Cold compression (less uniform)

• Ingredients combined by thorough mixing into a paste

• Then forced into moulds

What is the displacement value?

The number of parts by weight of the drug which displace one part by weight of theobroma oil

b. no paracetamol

What are semi-solids?

• Dermatological vehicles for topical application and transdermal delivery

What does the skkin do?

• Regulates heat and water loss

• Acts as a barrier to noxious chemicals and MOs

• 3 layers

  • Hypodermis

  • Dermis

  • Epidermis layers

Describe the hypodermis

Subcutaneous fat layer

• Insulates the body

• Protects against shock

• Source of energy

• Contains blood vessels and nerves

Describe the dermis

• 3-5 mm thick

• For support (collagen) and elasticity (elastin)

• Extensive vasculature

• Regulates temp

• Delivers oxygen and nutrients around the body

• Removes toxins and waste

Describe the epidermis layers

• 0.1-0.2 mm thick

• Protection

• Cell renewal after 4 week lifespan

• Avascular

  • No blood vessels

What are the main advantages and disadvantages of transdermal deliver?

Advantages:

• Simple removal of dose

• Avoids the GI tract and liver (first pass) metabolism

• Lower dose needed

• Avoids multi dosing as the drug action lasts longer

Disadvantages:

• Skin barrier limits absorption

• Not for all types of drugs

• Irritation and sensitisation

• Different for all races, ages and environments

Why do drugs target the skin surface?

To generate a protective layer/attack bacteria and fungi

• Protective films/sunscreens to avoid moisture loss

• Topical antibiotics, antiseptics and deodorants to kill MOs

Why do drugs target the stratum corneum?

To improve emollience by raising water content

• Stimulates sloughing 

  • Removing dead cells

Why do drugs target the viable epidermis and dermis?

Can treat diseases

• Steroid

• Non- steroidal anti-inflammatory agents

• Anaesthetic drugs to relieve pain (mainly local effect)

• Anti-histamines to alleviate itches

Why do drugs target the skin appendages?

Hair follicles and sweat glands

• Shunt routes that bypass stratum corneum

• High permeability

• Low surface area (0.1% of total)

• Antiperspirant to reduce hyperhidrosis of sweat glands

• Barium sulphides as depilatories (hair removal creams)

 

Why do drugs target systemically?

Low delivery efficiency so limited

• Patches decrease pill usage but only 10mg a day so less drug

• Hyoscine for travel sickness

• Clonidine for hypertension

• Nicotine for smoking

• Fentanyl for pain

What are the 3 different routes of absorption?

1 - Transepidermal (most common)

• Intercellular

  • Between cells

  • Predominant route

• Transcellular

  • Across membranes

What are the optimal drug characteristics?

• Small MW ( <500 daltons)

• Lipophilic (logP ~ 2)

• Low melting point (good solubility)

• Hydrogen bonds interact with lipid polar head groups in skin

• pKa in unionised form

 

Ficks first law of diffusion

Absorption model

Membrane diffusion

Octanol-water partition coefficient

Potts and Guy

Calculation summary

What is the pH partition hypothesis?

Unionised partition into lipid membranes

• Transdermal absorption of weak electrolytes favours the unionised form

Examples of semi solids

• Liquid Preparations

• Gels (Jellies)

• Powders

• Ointments

  • Hydrocarbon, fats and fixed oils, silicones, absorption, emulsifying, water soluble

• Creams (emulsions for topical administration)

  • Water-in-oil, Oil-in-water

• Pastes

Features of creams

Prone to MO contamination

• Aqueous cream BP

• Dimethicone cream BP

Describe cream o/w emulsions

• As continuous phase evaporates the conc of water soluble drug increases

• Deposits liquid and moisturisers onto skin

• Needs mixed emulsifiers - surfactants and fatty acids

Describe cream w/o emulsions

Describe ointments

Dispersion/dissolution of a medicament into an ointment base

The base depends on:

• Size of application (occlusion)

• Rate of drug release (solubility and diffusion)

• Drug stability (hydrolysis reduced in hydrophobic base)

• Rheology (effect of drug inclusion)

Describe HC bases

Hard, soft liquid paraffin

• Diff consistencies depending on temps

• Bad solvents

Properties:

• Form thick, occlusive films

• Sticky feel

Describe silicone bases

• Dimethicone and dimethyl polysiloxanes

• Water repellent if ST is ↓

  • Protects against water soluble irritants

    • Nappy rash, bedsore, colostomy discharge

Describe absorption bases

• Less occlusive that HCs (weaker barrier for water loss)

• Not emulsified so water has to be absorbed with low HLB surfactants to form w/o

  • Wool alcohol ointment BP

• W/O absorb more water (hydrous wool fat BP)

Describe emulsifying bases

Anhydrous bases containing o/w emulsifying agents

• Water miscible

• Washable

• Self emulsifying

Describe water soluble bases

Mixtures of high and low MW polyethylene glycols (macrogols carbowaxes)

• Non greasy, soften and melts into skin

• Doesn’t incorporate large volumes of aq solutions

• Reduces the anti microbial activity of methyl and propyl p

What is the difference in stability between creams and ointments?

Ointments have a longer shelf life (3 months vs 28 days)

• Ointments are less prone to hydrolysis

• No susceptible to microbial contamination

• Little to no water phase

• More thermodynamically stable

• More homogeneous and stable

  • As they’re hydrophobic

• Less phase separation or drying out

Creams are aq so they have less chemical stability so need a preservative

• Water promotes hydrolysis and oxidation (degradation of active ingredients)

What are pastes?

Up to 50% of powder is dispersed into ointment base (Zn, talc, starch)

• Localises the action of irritants (dithranol) or staining materials (coal tar)

• Forms opaque films (sun block)

What are gels?

Semi solid system where there an interaction between colloidal particles in a liquid, type 1 and type 2

Can be based on:

• Dispersed solids

• Hydrophilic polymers

What are hydrogels?

Type 1 gels

Covalent interactions mediated by cross-linkers

• Doesn’t flow when there’s stress

• Able absorb lot of water

• Wound dressings and sustained release implants

Describe type 2 gels

Most common gel type

• Weak bonds

• Stress leads to junction zones (reversible destruction)

• Pseudoplastics

What are excipient and physical types of permeability enhancements?

Excipients:

• Alcohol

• Sulfoxides

• Azone

• Surfactants (improves diffusion and K)

Physicals:

• Needles

• Disadvantages:

  • Pain

  • Physiological fear

  • Infection risk

What are the minimally invasive methods for enhancing permeability?

• Tape stripping

• Suction ablation

• Iontophoresis

• Electroporation

• Sonophoresis

• High velocity particles

• Laser assisted delivery

• Microneedles

What is tape stripping?

The adhesive removes layers of stratum corneum

• Uncontrolled but hydration helps

What is suction ablation?

 Removal of stratum corneum by suction blister formation

• Vacuum is applied to selected area

• Drug delivery can happen straight to stratum lucidum

What is iontophoresis?

Transfer of charged substances using an electric field

• Enlarges range of drug candidates (polar and charged)

• More drug candidates as it acts in molecules themselves

What is electroporation?

Large voltage treatment to make transient hydrophilic pores

• Pores aren't permanent

• Allows things to get through when needed

10us - 100ms lasting

What is sonophoresis?

Formation and collapse (cavitation) of gas bubbles

• Uses ultrasonic energy

• Temp elevation

What are high velocity particles?

Compressed gas shoots fine particles through the skin

• Used for macromolecules (vaccines)

• Drug can be coated in particles

Describe laser assisted delivery

Ablative - high energy forms pores

Optoacoustic - stress wave transiently increases permeability

• Well controlled

• Hydrophilic and lipophilic drugs

What are microneedles used for?

Piercing upper epidermis

• Can be hollow or solid

What are coated and polymeric microneedles?

Coated microneedles – usually stainless steel arrays coated with a formulation containing drug

 

Polymeric microneedles – higher resilience, can provide improved drug-release pattern because of the polymer's degradation and dissolving capabilities