What is a Medicine?
Medicine - The dosage form administered to the body. Contains a drug with non active excipients.
Directions on a label:
- Dose - Amount of drug taken on one occasion
- Frequency - How often the dose is taken
e.g Take ONE tablet (dose) TWICE daily (frequency) 20 minutes before food (other directions)
Site of action:
- Local - Drug acts in the area where it is applied e.g eye drops, skin lotions
- Systemic - Drug enters the bloodstream and can act anywhere e.g tablets, injections
Route of Administration:
- Oral - Swalllowed by mouth
- Topical - Appplied to a surface
- Parental - Injected
Therefore. Medicines contain, DRUGS (active substances), EXCIPIENTS (non-active ingredients)
Why design Medicines?
Medicines need to be effective and acceptable to the Patient.
Legal Requirements - Medicines Act 1968:
All drugs must have proven:
- Efficacy - effective for the medical condition
- Safety - safe to use by the patient
- Quality - "dose uniformity" (accurate dose of drug every time) "patient acceptability" (pleasant and easy to use) "Stability" (long shelf live) "directions" (clear instructions how to take it)
Medicines are designed for specific body sites and for specific patients (ages, diseases, lifestyles)
"Quality by Design" - Medicines must have:
- An optimum drug release rate
- Stability to chemical, physical and microbial degredation
- High patient acceptabilty and ease of use
- Be easy to manufacture as a quality product
- Uniformity- same dose every time
Design for different body sites
G I tract - pH change, enzymes, bile saltsm water availabilty, drug absorption occurs principally in small intestinre
Lung - mucocilary clearance, particle size important
Skin - excellent barrier, wide variety of skin diseases, bloodstream absorption of only tiny doses
Eye, ear, nose - sensitive to pH etc. widely different drug absorption
Vagina, womb - acidic seretions, local effects only, cyclic
Rectum - secretions, poor retention, poor absorption
Injection Sites - pH, tonicity, sterility, lack of particulates and pyrogens
Medicine design tailored to the body site is essential for patient safety and successful treatment.
How are Medicines Classified?
By type of dosage form
- Powders - powders, granules, capsules, tablets
- Liquids - solutions, suspensions, liquid emulsions
- Semi-solids - creams, ointments, gels, pastes
- Miscellaneous - suppositories, pessaries, inhalers, skin patches
By route of administration
- Topical - skin, body cavities, eye, ear, nose, rectum, vagina
- Injectable - Intravenous, Intramuscular, Subcutaneous
- Inhaled - lungs
Powder Medicines - Types
- Oral Bulk Powders - disperse spoonfuls of powder in water or milk. Way to give a large dose by mouth.
- Dusting Powders - external skin diseases e.g athletes foot
- Powders for reconstituion into a liquid - Useful when a drug is chemically unstable in water, powder dispersed in water before giving to patient, make sure it all dissolves!
Single dose powders - Sachets and wrapped powders:
- A powder mixture or granules (powder particles stuck together) containing a single dose of drugs
- Great for children, elderly and animals as they are easy to take, disperse in water or sprinkle on food
Single dose powders - Capsules
- Hard capsules - two part, hard (water-soluble e.g gelatin) polymer shell, filled with a powder mixture, easy to swallow
- Soft capsules - flexible shell of placticised polymer, used for oils, liquids, pastes (paste - concentrated powder in a liquid)
Powder Medicines - Tablets
Single dose powders - Tablets
- Single dose of compressed powder. Small, portable, convenient to take.
- Stable - no water present, coating blocks light, moisture proof packing
- Tablets differ in size, shape, colour. Printing in edible ink or embossed
- Tablets can be uncoated, sugar coated or film coated (film coated is most common, thin layer of coloured or transparent polymer)
Common Types of Tablets:
Dispersable - dissolve in water before taking, or on tongue - most rapid drug release
Immediate release - disintegrates in stomach, rapidly releasing the drug - fast
Delayed release - releases whole dose further down the GI tract - delayed, whole dose release in intestine
Extended release - slow drug release over 8 to 24 hr - prolonged axtion
Special routes - under the tongue, body cavity
Powder Medicines - Ingredients
Excipients in Bulk Powders and Sachets
- Bulking agents "Diluents" (to make/ add volume) - Sugars, sorbitol, salts, talc
- Effervsecent mixtures - citric/ fruit acids with (bi)carbonates, react to release CO2 in water - fizz
- Flavouring, Sweetening, Colours - Enumbers
- Granulating agents (binders) - polymers such as PVP and pregelled starch
- Flow aids (provide powders with the ability to flow) - collodial silicon dioxide
Ingredients in Tablets and Capsules (more complex)
- Granulating agents (binders) - binds powders together during wet granulation - polymers such as PVP
- Bulking agents "Diluents" - adds bulk - sugar, lactose, dicalcium phosphate, talc
- Compression aids - deforms under pressure, gives harder tablet - microcrystalline cellulose
- Disintegrants - swelling or wicking action, breaks up tablet in water - starch, croscarmellose
- Lubricant - helps machine eject tablet - magnesium sterate
- Flow aid - helps granule or powder flow for a more consistent fill - collodial silicon dioxide
- Tablet coat - film coat - polymers, colours, TiO2
- Capsule shell - gelatin shell, colours, TiO2
Powder Medicines - Stability Problems
Stability Problems of Powder Medicine
1. Sensitivity to moisture
- Hygroscopic- absorb moisture
- Delequescent - absorb and dissolve in it
- Efflorescent - hydrate salts that lose water of hydration
- Caking- powder sticking together due to moisture
- Flow is critical for processing and packaging. Depends on size (large particles flow better), shape, moisture, surface charge
- Add a flow aid or granulate
3. Mixing and Seperation
- An even mix is needed. Mixing depends on size, density, shape, surface moisture, static
- Unequal (size, shape and density) particles can seperate. Fine powders can agllomerate and don't mix.
- Mixtures can unmix during movement "rolling planes" can result in seperation. Pouring, mixing, vibration or transport of a mixed powder.
Powder Medicines - Mixing Solutions
It is important that the mixture does not unmix, if excipient and drug seperate, a uniform dose can't be provided
- Granulation - common in large scale manufacturing - fixes powders in space
- Ordered Mixes
- Equalise particle sizes by grinding/sieving (better than ordered mixes)
- Mix equal amounts 50:50 is most effective, geometric mixing
Granulation - To form granules
Dry granulation - mix the powders (drug, diluents, disintergrant) by "roller compaction"
Wet granulation - mix the powders (drug, diluents, disintergrant) wet the powder mixture with a solution of polymer "binder" and sieve and dry. Particles are glued together with a water soluble polymer (PVP).
Granules - Advantages
- Mixture now structured - permenant and cannot unmix
- Large size - flows well into packing machines
- Crunchy - compresses into tablets easily
Solutions - all ingredients dissolved and therefore present as single molecules within the liquid "vehicle"
Suspensions -insoluble solid particles dispersed in the liquid
Emulsions - insoluble liquid droplets dispersed in the liquid
Liquid Medicines - Types
For oral use:
- Mixture - simple formulations, vehicle is water, oreservative usually chloroform water, short shelf life, can be solutions or suspensions
- Elixir (or syrup) - more complex formulations with a longer shelf life, combination of preservatives, vehicle is often syrup, glycerol, sorbitol. If diluted the shelf life is shorter.
- Linctus - elixir for the relief of coughs and sore throats, soothing, expectorant or couch supressent action.
- Waters - simple solutions of aromatic oils usually made from concentrates, take care dispensing.
For external use:
- Lotions and applications - liquids for use on the skin, scalp or hair. Can be solutons, suspensions or emulsions. Vehicle can be water based or solvents.
- Liniment (or embrocation) - lotions for rubbing into painful joints and muscles. Vehicle can be rubefacient (makes skin red and warm)
For body cavities
- Eyedrops, eardrops, nose drops - vehicle usually water. Eyedrops must be sterile.
- Mouthwash, enema and douche
Liquid Medicines - Ingredients
The E number list lists excipients approved for foods, approved list for medicines is siilar and E numbers are used on medicine labels. Excipient classes common in liquid medicines :
- E100-199 (colours)
- E200-299 (preservatives)
- E300-399 (antioxidants, acidity regulators)
- E400-499 (thickeners, stabliziers, emulsifiers)
- E500-599 (acidity regulators (buffers), anti-caking agents)
- E600-699 (flavour enhancers)
- E700-799 (antibiotics)
- E900-1999 (miscellaneous and additional chemicals)
- Also, Vehicles, Sweeteners, Solubility enhancers
Liquid Medicines - Vehicle
Vehicle - the main liquid ingredient that the medicine is based on, the liquid in which you dissolve the drug or suspend it in.
Water BP - Water must be BP quality, BP specifies the quality of drugs and excipients used in UK medicine. Several different purities for different medicine types:
- Water from cold tap - not BP standard. Filtered and chlorinated ground/river water but not used for the preparation of medicines because dissolved salts/gas may interact with drug
- Purified/ Highly purified water (BP) - Water made by distillation, ion exchange or reverse osmosis. Used in the preparation of medicines, highly purified neede for some medicines e. g dialysis solutions. Contain low dissolved salts, gas and microbes/ endotoxins.
- Sterilised water for injections (BP) - Water produced by a specialised distillation process, ensures no microbes or endotoxins as water is sterilised.
Sweetening, Flavouring Vehicles:
- Syrup Bp, Sorboitol solution BP, glycerol BP, chloroform water BP
Other liquids - uncommon and mostly in external medicines
- Ether/alcohol in wart removers/ acne, Oils in suncreen liquids.
Liquid Medicines - Preservatives and Stablisers
Presevatives - inhibit growth of dangerous microrganisms.
- Prevent food poisoning in oral liquid
- Prevent bottle contamination and reinfection in eyedrops
- Prevent microbes degrading the medicine
- Antioxidants - reducing agent that react with dissolved oxygen or act as free radical scavengers. They prevent oxidation by being more easily oxidised than the drug or foodstuff that they are protecting. Water soluble antioxidants (Vitamin C, Sulphur dioxide, sulphites). Oil soluble antioxidants (Vitamin E, BHA, BHT) are used in formulations that contain fatty ingredients (emulsions, creams, ointments) to prevent fat oxidation "rancidity)
- Chelating agents (antioxidant synergists) - Molecules that complex with heavy metal ions in solution, reducing their ability to catalyse oxidation - so oxidation slows. E.g EDTA
Liquid Medicines - Colours
- Synthetic - thousands of synthetic dyes, commonly have an azo group (N=N may have adverse effects in asthmatics), many are toxic. A few are still safe to ingest and permitted, their use in medicines is under review as they are not essential. Others are permitted for skin use, cosmetics etc.
- Inorganic - Iron oxides (Yellow, Red, Black), Titanium oxides ( a white fine insoluble powder, opacifiant - makes films opaque to light), Betanin (purple - beetroot)
- Natural - Cochineal (beetles - deep red), Lycopene (tomatoes - red), Caramel (burnt sugar - brown), Annato (Amazonian seed pot - orange), Circumin (tumeric root - yellow)
In what forms do colours take?
- Soluble Dyes - water soluble, oil soluble, soluble in polymers
- Lakes - dyes adsorbed onto aluminum salts to make insoluble coloured powders.
- Extracts - of natural minerals
- Powdered dried foods - no toxicity testing needed
How are colours identified on labels? Several systems are in used, chemical name, E numbers (EU), FD &C (USA), Colour Index no. (worldwide), common name.
Liquid Medicines - Colours
Why are colours useful?
- Natural colours in food are often good nutritionally
- Fruit colours are natural antioxidants or are involved in body metabolism
Why are colours coloured?
- Double bonds absorb UV and visable light as electrons in the π bond jump to higher electron orbitals, colours are complex molecules with an extensively linked (conjugated) network of double bonds. Molecules with more double bonds (conjugation) absorb UV and visible light at longer wavelength.
- Toxicity - colours are not essential. EU gradual withdrawal from food/medicines.
- Azodyes - bronchostriction in asthmatics especially if apirin intolerant.
- Tartrazine - immunological sensitivity reactions.
- Natural Colours are often less chemically stable than synthetics. pH can change the colour.
Liquid Medicines - Flavours
Used to "taste mask" drugs that taste horrible making them more acceptable to the patient
Natural or Synthetic flavours can be used - get advice from "flavour houses"
Traditional Pharmacy Flavourings - widely used:
- Oils - The pure oil. Very concentrated (too strong?)
- Spirits and Tinctures - Concentrated oils/flavours in alcohol
- Concentrated Waters - Concentrated solution e.g Conc Chloroform water
- Waters - The most dilute form e.g Chloroform water, Peppermint water
- Syrups - A flavoured syrup e.g Blackcurrant syrup BP
WARNINGS - Don't get concentrated waters and waters mixed up, strength is different!
Medicinal Smelling - Often have additional activity
- Thymol, eucalyptol, menthol - decongestant, midly antiseptic
- Chloroform - common flavour and preservative
Aroma and Parfum re terms used on labels when they don't want to disclose the flavouring or scenting agents
Liquid Medicines - Flavours
Bitternes is useful as a warning and for aversion.
e.g BITREX - the bitterest material in the world
- To prevent poorly sighted people, children and animals eating or drinking dangerous things. Used in pesticides, herbicides, automotive, cleaning fluids, denatured alcohol etc
- Surgical spirit
- Anti-nail biting liquids
- Matching the bitterness of drungs in clinical trial placebos
Bitrex is the local anaesthetic Lidocaine with an added benzyl group (related structures). They both sit on the receptor one is an antagonist and one an agonist. Lidocaine kills any sense of taste whereas Bitrex is very bitter. They have opposite effects on the sensory nerves involved in taste.
Liquid Medicines - pH
pH = the concentration of H+ ions in a solution. (-log of H+ conc)
The pH range:
- Acid - pH 1-6 tastes like lemon juice
- Neutral - pH 7 - pure water. (Tap water is pH 6 slightly acidic to dissolve CO2 in water)
- Alkaline - pH 8-14 tastes soapy (because they hydrolyse fats > soap)
Why is pH so important?
- If the concentration of H+ ions is too high or low is damages our bodies, denatures our proteins, messes up biochemical reactions, kills our cells
- This is why we have detectors for pH on the tongue and in the body
Why is control of pH important in medicines?
- Drug solubility - Some drugs only dissolve in a specific pH
- Chemical stability - To prevent pH- sensitive ingredients changing/degrading
- Effectiveness of critical excipients that work at specific pH (Benzoate preservatives effective pH 2-5, aligninate thickeners only work above pH 5)
- Prevent pH shift due to dissolving atmospheric CO2 - causes a shift to acid
- Prevent stinging - eye/nose drops
Liquid Medicines - Buffers
A buffer - stablizes pH, designed to resist change in pH.
Buffers are mixtures of an acid and its salt (or a base and its salt)
Acidic Buffer: CH3COOH ⇌ CH3COO- Na+ (+H)
- If you add acidic substances (H+), H+ combines with salt and converts it into acid. So H+ removed.
- If you add basic subtances (OH-), H+ ions are released by converting acid to salt.
Common Buffers - Acetate, Citrates, Phosphates, THAM or TRIS
What is pKa?
- Ka = equilibrium contstant. pKa = -logKa
- pKa is the pH at which [salt] and [acid] are present in equal molar concentrtions.
- Buffers are effective at pH values +- 1 of their pKa
Liquid Medicines - Buffers
A level calculations
- pH = -log [H+], pOH = -log [OH-], pOH + pH= 14
Ka = [H+][A-] / [HA] (when A= salt)
- When acid mol is in excess. Acid mol - base mol (A-) = excess acid mol (HA)
- When base mol is in excess. Base mol - acid mol = excess base mol (OH-). (OH-)/ vol = [OH]
Calculating the amount of Buffer needed
Henderson Hasslebach equation
- gives the acid:salt ratio for pH you require
- pH = pKa + log [salt]/ [acid]
Van Slyke equation
- Gives the amount of buffer required to prevent a major shift in pH
- B = 2.3 CKa [H+] / (Ka + [H+]) 2
- C = total buffer concentration required
- B (Beta) = buffer capacity = amount of acid/base added/ change in pH
Liquid Medicines - Buffers
Which pH is best? -Ibruprofen oral liquid
Low pH (more H+):
- Has COOH group
- Poorly Soluble. Can't interact with water so won't dissolve.
- Aftertaste if a little dissolves
High pH (more OH-):
- Has COO-Na+ group
- Soluble - because it is ionsed and very attractive to water because of charges on O and Na.
- Tastes really horrible
A SUSPENSION will taste better than a SOLUTION
- Design our new medicine to be buffered below pH 4, this will minimize drug solubility and taste
- Use fruit flabours and colours to match the acid pH,Use aniseed/liquorice to match the acid pH
Liquid Medicines - Sweeteners
- Sugars - sucrose, glucose, fructose
- Sugar alcohols - sorbitol, malitol, xylitol, mannitol
- Simple polyols - glycerol
- Artificial Sweeteners - aspartme, sucralose
- Miscellany - starch hydrolysates (corn syrup)
Glucose (monosaccharide) > Sorbitol (sugar alcohol- no longer a ring like glucose)
Maltose (disaccharide - two glucoses)
- Sucrose (sugar) - Syrup BP vehicle. Cariogenic. 66.7% sucrose, almost a saturated solution. Preserves by dehydration - osmotic effec stops bacteria growing, sugar removed water from bacteria.
- Glycerol (simple polyols) - Glycerol BP vechicle. Dehydration preservative - same osmotic effect as sucrose.
- Sugar Alcohols - Sorbitol BP, a vehicle which is 70% sorbitol in water. Okay for diabetics, metabolised more slowly than sugar so no sudden increase in blood sugar. Non- cariogenic. Calories lower than sugars, often used in "sugar free" products.
- Synthetic - Different taste. No calories or tooth decay. Completely different ADME.
Liquid Medicines - Sweeteners
Artifical Sweeteners (synthetic):
Saccharin, Acrdulfame K, Aspartame - Chemical structures are unrelated to sugars, but the shape of molecules mean they stimulate sweetness receptors on our tongues.
Sucrose (a disaccharide sugar) > chloronated > Splenda - Artificial sugar 600x sweeter than sucrose, less is required so reduced calories.
Simple polyols (Glycols): (excipients can undergo ADME)
Glycerol BP and Propylene Glycol BP are generally regarded as safe. HOWEVER, there is a huge increase in toxicity when they are converted into Ethylene Glycol and Diethylene Glycol.
- Glycerol BP - normal part of fat breakdown, body metabolises it as food
- Ethylene Glycol - broken down into oxalic acid and glycolic acid, these metabolites are toxic to many body systems.
- Same enzymes that metabolize ethylene glycol metabolize ethanol so we can use this as treatment for poisoning. Ethanol saturated the enzymes active sites to prevent the ethylene glycol from binding and it is excreted in the urine instead.
Polymers of Ethylene Glycol are non-toxic and are widely used in medicine. They are not poisonous because ADME is different, they aren't broken down by enzymes, excreted largely unchanged, higher molecular weights so they aren't absorbed.
Liquid Medicines - Solubility enhancers
Solubility enhancers - Excipients that improve drug solubility
Solubilisers - Ampiphiles (eg surfactants) form micelles - hydrophobic centre which can dissolve ("solubilize") poorly soluble drugs.
Cyclodextrins - Accomodate "guest molecules"
Cosolvents - Salicylic acid 17%, Alcohol 18%, Ether 53% to aid solubility
There are many other stratagies for improving drug solubility:
- Optimise formulation pH for drug solubility
- Choose a soluble salt of drug
- Optimise drug crystal form
- Complex formulation
Liquid Medicines in which insoluble solids (usually drug) are dispersed as fine particles.
Vehicle - the liquid in which the particles are suspended
Suspended particles (insoluble solid) - "disperse phase"
Excipients that we have previously mentioned
Suspensions - Stability
Physical signs of instability:
- Seperation - Particles fall due to density differences, redisperse by shaking
- Caking - A cake is a high density sediment of particles, physically interlocked, difficult to redisperse
In a uniform suspension the patient gets the same dose of drug every time that they pour the medicine. If the suspension is seperated or caked, early doses wont work and later doses could overdose the patient.
How to keep suspension particles suspended?
- Shake it - If particles redisperse easily, and you can pour and accurate dose
- Thickening agents - 3 types - make vechicle thicker and stops particles from dropping
- Flocs are loose, weakly-bonded, particle aggregates
- Add a surfactant (a substance which reduces the surface tensions of a liqud) which adsorbs and adds a surface charge. Add salt to adjust the charge and you will get flocs.
- OR add a soluble polymer which adsorbs to the particle surface.
- Flocs are wealy bonded so they breakup on shaking and particles redisperse to a uniform suspension. Flocs reform on standing, this prevents caking.
Suspensions - Thickening agents
Soluble polymers - long chain molecules that thicken by entanglement and gelling - prevents movement.
- Entanglement - polymer chains are long and will entangle. Increases the viscosity.
- Gelling - Bonds or ordered structures form between the chains. These "junction zones" act as molecular cross links, making the gel stronger and more rubbery.
- Common soluble polymers - polysaccharide, cellulose ethers, gelatin (a protein), PVP (synthetic polymer)
Collodial polymers and minerals -very small plate-like particles finely dispersed in the liquid.
- They thicken by "charge dispersal". Particles are charged. Repulsion keeps particles at a distance from each other, so the whole liquid resists movement.
- Carbomer (synthetic polymer), Bentonite (clay), Veegum (mineral)
Collodial Silicon Dioxide - for gelling oils. Very small particles that form linked networks in the oil.
- Network breaks up when stirred (gel gets thinner) Reforms on standing (gel thickens). "Shear thinning behaviour". Many polymers do this eg xanthan gum.
Suspensions - Thickening agents
Properties and uses of thickening agents
1. At low concentration - Increase vehicle viscosity. keep drug particles suspended. Maintain dose uniformity in suspensions so that every dose is the same
2. At high concentration - Semi-solid "gels", transparent gel base for cosmetics and pharmaceutics
3. Thicken liquids for a greater residence time (the average of amount of time that a particle spends in a particular system) at site of action. Vehicle is thickened so stays there for longer. Examples:
- Eye drops - drug stays there for longer so eyes lubricated for longer
- Replens - Vaginal dryness
- Teething and Mouth Ulcer gels - Take care these are NOT the same. Both are local anaesthetic BUT differ in strength and drug, mouth ulcer gels contain choline salicylate which should not be given to children. (reyes syndrome)
4. Mucoadhesive dosage forms - designed to stick to mucosal surfaces for a long time. Buccal tablets that stick to gums and release drug slowly into mouth.
Liquid medicines in which one insoluble liquid is suspended as microscopic globules in another. The two liquids dont dissolve in each other (immiscible). Contains:
- External or Continuous phase - the liquid vehicle
- Internal or Disperse phase - the droplets
- Thin molecular film of emulsifying agent at the oil/water interface.
Types : Liquid emulsions - free flowing liquids, Creams - Semi-solid thick (disperse phase is often a wax).Both types can be o/w or w/o:
- o/w "Oil in Water" Milky White
- w/o "Water in Oil" Translucent
- Mulitple emulsions, droplets within droplets w/o/w or o/w/o
Types of oils
- Fixed - Vegetable oils - Triglycerides
- Mineral - Liquid Paraffin - Hydrocarbon
- Volatile (used for aroma/flavourings) - Oils from plants - Various complex structures
Emulsions - Stability
- Emulsions are inherently unstable - cannot be reformed by shaking
- Stabilised by a good emulsifying system - prevents droplet coalescence
Physical signs of instability are creaming and cracking (coalescence of droplets leading to growth and seperation of the disperse phase)
Creaming - Disperse phase droplets coalesce (increase in size) and collect near the surface.
Cracking - Phase seperation. Disperse phase forms large globules. Or seperate layer on surface. (more concentrated layer on surface than creaming)
Emulsifying agents (emulsifiers) - Amphiphiles (surfactants)
- Hydrophobic tail (dissolves in oil)
- Hydrophillic head (dissolves in water)
- Located at oil/water interfaces, molecule sits here.
Types of emulsifying agents
- Anionic (+ head) eg sodium dodecyl sulphate
- Cationic (- head) eg Cetrimide
- Non-ionic (no charge) eg Cetostreayl alcohol, cetomacrogol, polysorbate 80
Emulsifying agents are better when mixed...
- Mixed emulsions - much better than surfactants, mixture of ionic and non-ionic. Denser interfacial film, better for stabilising emulsions, widely used in creams (conc emulsions)
- Mixed emulsion - eg Emulsifying wax BP (sodium dodecyl sulphate - charged and cetostearyl alcohol - non ionic)
Polymers and proteins - Proteins have hydrophillic and hydrophobic areas and are amphiphillic, adsorb at the interface and are therefore good emulsifying agents. They can bridge between droplets and therefore act as suspending/flocculating agents.
Natural emulsifiers in food - lecithin (egg yolk) a phospholipid. Whey proteins in milk.
Stability of Emulsions
Physical - Emulsions are inherently unstable - they will seperate. Influenced by:
- Droplet size - smaller droplets = more stable, smaller droplets take longer to come together. Hand made liquid emulsions stable for 1 week, manufacture uses high sheer mixers - stable for 2 years
- Temperature - Warming or temperature fluctuation accelarates, must be stored in a cool place, freezing/thawing causes rapid seperation
- Type - w/o less stable than o/w (emulsifying agents less powerful in w/o). Creams are more stable than liquid emulsions.
- Added ingredients - If interact with emuslfiying agent, can destablise it. (cracking)
Chemical - internal oil phases are sensitive to chemical degradation.
- Internal phase has a huge surface area, increased rate of fat oxidation (rancidity), o/w less stable, in w/o, oxygen can dissolve more readily in water so can spread throughout, faster rancidity
- Oil soluble antioxidant may be needed, widely used in fatty foods
Microbiological - emulsions can growm microorganisms
- Bugs grow well in the continous water phase, use oil droplets as food. So o/w less stable.
- Temperature dependant, must be store in a cool place.
- Preservatives - aid stability but it must not interact with emulsifier or partition into the oil phase.
Emulsions - Uses
1. Oral liquid emulsions are used to administer oils by mouth
- More palatable - taste better
- Easier to administer - to feed unconscious
- More digestable - Oil as fine droplets has high surface area so is digested faster
- More effective - eg liquid paraffin is not absorbed
2. Topical emulsions - soothe itchy inflamed skin. Administer drugs topically (to body surface)
- Topical lotions (liquid- runny) and creams (semi solid - thick)
- Irritaing skin conditions - emulsion bases (no drug) are used as emollients (soothing) and antiouritics (stops itching)
- Skin infections - emulsions deliver drugs to treat parasites and fungal
- Hair lotions and shampoos - lice, dandruff
Creams are emulsions in which one phase is a semi solid or wax.
- Water is the continuous phase
- Cream can mix with wound exudates
- Feels cool as water phase evaporated
- Allows wounds to dry (needed for wound to heal)
- Used in acute conditions as not "occlusive"
- More acceptable to patients as they rub well into the skin and are less greasy than ointment.
- Oil is the continuous phase
- Oily creams
- Tend to be occlusive
- Make dry skin more supple "moisturising"
- Protect against water : nappy rash, sun/sea
Uses of creams
- Common as cosmetics
- Deliver a wide range of drugs to skin: antibiotics, antivirals, steroids, antifungals
- Used for fungal infections for damp areas
Common creams for body cavities
- Clotrimazole combi packs for vaginal thrush
- Rectal cream for haemorrhoids
Spreadable and greasy semi solids, may contain:
- dispersed powders
- small amounts of aq. liquids
Ointments with a high podwer content are called pastes
The base (vehicle) is:
- a mixture of waxes, fats and oils
- usually hydrophobic (water repellent)
Note that ointments are not usually emulsions, this is because the base is a mixture of waxes, fats and oils that all dissolve in each other (so is a uniform mixture), under a microscope you wouldn't see droplets of oils. Powders and aq. liquids (small amounts) don't usually dissolve and have to be dispersed manually in the base.
Ointments are very old - animal fats, beeswax, resin based ointments, known from many early civilisations.
Ointments - Ingredients
1. Hydrocarbons - long and medium chain alkanes. Stability - very good, chemically inert, widely used
- Hard paraffin - long chains - a hard wax
- Soft paraffin - medium chains - greasy, white and yellow available
- Liquid paraffins - short chains - liquid
2. Vegetable oils - Glyceride esters of long chain fatty acids, some unsaturated alkane bonds making them more liquid. Stability - may go "rancid" double bond oxidise and esters hydrolyse to fatty acids (smelly) Dat soluble antioxidants commonly used to slow oxidation.
- Olive, caster, arachis (peanuts) - liquid
- Coconut - solid
3. Wool Fat - The natural grease from wool. A complex micture of long chain alcohols, acids and esters of these or with sterols e.g chloesterol. Greasy. Absorbs up to 20% w/w water - useful if mixing aq. liquids into ointment. Slow oxidation. A small but significant proportion of the population react to wool fat - skin sensitivity
- Wool fat - Anhydrous Lanolin
- Wool fat with 30% water - Lanolin
4. Fatty Oils - Long chain alcohols such as stearyl and cetyl, used in combination as cetostearyl alcohol. A solid wax, an ointment stiffener. Good stability. Combinations with a surfactant eg emulsifying wax BP.
5. Wool Alcohols - long chain alcohols obtained from wool. Otherwise as for wool fat.
6.Fatty Acids - Long chain aliphatic acids e.g stearic acid (solid) oleic acid (liquid
7.Macrogolds - synthetic polumers of ethylene oxide. Dissolve in water so used in washable ointments. Good stability.
Ointments - Uses and Problems
1. Occlusives - trap sweat and water vapour under the skin to increase hydration
- Make dry skin more supple - prevents skin cracking
- Soften the Stratum Corneum
- Used in chronic dry skin orders
2. Protectives and Emollients - barrier to protect against water and wind
- Cracked Lips - e.g lip balm
- Nappy Rash - ointments, w/o creams
- Emollients - skin itching eg in eczema
- Greasy and Messy, stains clothing and not easily removed from skin
- Not for acute inflammation (oozing, red, infected), these require drying and cooling, o/w creams, aq. lotions
- If you oxxlde a wound it prevents drying however this raises skin temp and allows bacteria to grow, difficult to clean the lesions
Ear, Eye and Nose
The Nose - Nose creams and ointments, nose drops and nasal sprays for deeper penetration
The Eye -
- Eye creams and ointments - for the eyelids and glands
- Eye drops - for cornea, anterior chamber and the lens, iris and muscles is the furthest parts that drugs from eyedrops can influence
- Systemic drugs or direct injections - posterior chamber
The Ear -
- Skin topicals - external skin diseases
- Ear drops - Earwax infections
- Systemic drugs - For internal, infections, tube blockage, eardrum is a barrier to drugs
- Creams and ointments - external, areas where the surface is skin
- Drops and nasal sprays - areas they can acces, drugs can be absorbed through thin membranes but cant penetrate deeply
- Systemic therapy - for areas drops can't access, reaches the organ by diffusion from blood.
Ear, Eye and Nose - Design
Isotonic with blood and pH adjusted - important for eyes and nose - very sensitive to stinging
Irritancy tested - for all
Low cilia toxicity - Nose needs good mucociliary clearence, nose has a cilated epithelium
Vehicle - aq. for nose and eye, non aq. for ear, prevent swimmers ear
Polymer thickness - For nose and eye drops, helps retain drops at site, mucoadhesive
Preservatives - For nose and eye, prevents re-infection from the dropper tip
Sterile - no microbes - For eye, damaged eye has particular poor immune defences against infection
Rectum, Vagina and Uterus
Suppositories and Pessaries - Solid dosage forms for insertion into the R (suppositories) and V (pessaries), they melt, disintegrate or dissolve at body temperature, releasing the drug
- Wax - Hard fat BP, Macrogols (water soluble), Theobroma (cocoa fat), Melt the wax, incorporate a drug powder, pour into moulds, allow to set
- Glycerogelatin - geletin/glycerol/water, dissolve with heat, incorporate drug as a solution or powder, pour into moulds, sets to a strong transparent gel. Soluble drugs .
- Tablet - composition as for oral tablets. A compressed powder mixture.
Donut pessary - medical device, no drug. A thick ring of soft plastic used for prolapses of uterus, R , bladder.
IUDS - Medical devices used for contraception, flexible radio-opaque plastic, may contain copper metal. eg released a progesterone drug very slowly to reduce bleeding during periods
Rectum, Vagina and Uterus
Uses of Suppositories and Pessaries:
- Local effect on rectum or lower colon - laxatives, haemmorrhoids
- Systemic drug delivery - when oral dosing is not possible, bypass "first pass" liver metabolism, prolonged effect eg pain relief at night
- Pessaries - local treatment only, V infections
- V - "Douche"
- R - "Enema"
- V creams - treatment of infections
- R creams and ointments - Haemmorhoids (piles)
- Large volume infusions, 100mL to 3L bags, Fluid replacement, Parenteral nutrition - by injection
- Small volume injections
- Single injections - prefilled syringes are supplied to wards, to avoid hospital contamination
- Multidose virals - reconstituted in pharmacy sterile unit
Route of Administration - Giving by the wrong route is extremely dangerous
- IV - intravenous - vein
- IM - intramuscular - muscle
- SC - subcutaneous - under the skin
- ID - intradermal - into the dermis
- IT - intrathecal - spinal fluid
Type of dosage form:
- Depot (extended release) - liquid - oil vehicle common
- Implant (extended release) - biodegradable soluble polymer
Injectables - Design
Sterile - no microbes - prevents infection. Injecting bypasses many body defences.
No microbial waste products (pyrogens) - prevents a rise in body temperature
IV particle free (unless emulsion) - prevents clotting
Isotonic with blood - prevents stinging
pH adjusted - pH 7.4 is best, however blood is a good buffer, will tolerate a wide range pH 4-9
Preservatives - multidose injections
Irritancy - Irritant drugs can in extreme cases causes tissue damage (necrosis)
Solubilisers, Stabilisers, Cosolvents - when we need to maintain drug stability and solubility
Excipients - Non-drug ingredients in medicines and foods
- They are known to the public as additives, e-numbers, artificial ingredients, chemicals, they have bad press, lots of scare stories.
- Most damage from foods doesn't come from additives but from the high intake of fat, falt and sugar.
- Excipients in oral medicines are often the same as foods and in external medicines are often the same as cosmetics. Fewer excipients are used in medicines
- Excipients are of high quality, "Pharmacopoeial grade" each batch is tested for chemical purity
- Excipients are important in maintaining the quality and effectiveness of medicines eg chemical stability, stop microbial growth, ensure dose uniformity
- Only a few excipients have been linked with adverse reactions
As pharmacists, we should advise the public on the basis of up to date SCIENTIFIC and CLINICAL EVIDENCE , not scare stories and headlines.