Medicines Design (BPH)

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  • Created by: Louise
  • Created on: 18-12-14 12:12

What is a Medicine?

Drug - The pure active chemical

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) STRUCTURE 

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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 must be designed for different body areas, for specific body sites (must be designed to be effective in these areas). Medicines must also be designed for different patients; ages, diseases, physiologies, expectations, 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
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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.

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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

  • Oral
  • Topical - skin, body cavities, eye, ear, nose, rectum, ******
  • Injectable - Intravenous, Intramuscular, Subcutaneous 
  • Inhaled - lungs
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Powder Medicines - Types

Bulk Powders:

  • 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)
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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

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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
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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

2. Flow

  • 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. 
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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

Possible solutions:

  • 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
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Liquid Medicines - Types

  1. Solutions - all ingredients dissolved and therefore present as single molecules within the liquid "vehicle"
  2. Suspensions -insoluble solid particles dispersed in the liquid
  3. Emulsions - insoluble liquid dropletsdispersed in the liquid

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
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Liquid Medicines - Ingredients

Excipient classes common in liquid medicines

  • Vehicles
  • Preservatives 
  • Colours
  • Flavours
  • Buffers
  • Sweeteners
  • Solubility enhancers
  • Thickening agents
  • Emulsifying agents

The E number list lists excipients approved for foods, approved list for medicines is siilar and E numbers are used on medicine labels.

  • E100-199 (colours)
  • E200-299 (preservatives)
  • E300-399 (antioxidants, acidity regulators)
  • E400-499 (thickeners, stabliziers, emulsifiers)
  • E500-599 (acidity regulators, anti-caking agents)
  • E600-699 (flavour enhancers)
  • E700-799 (antibiotics)
  • E900-1999 (miscellaneous and additional chemicals)
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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.
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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

Stabilisers

  1. 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)
  2. 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
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Liquid Medicines - Colours

  1. 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.
  2. Inorganic - Iron oxides (Yellow, Red, Black), Titanium oxides ( a white fine insoluble powder, opacifiant - makes films opaque to light), Betanin (purple - beetroot)
  3. 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. 

Why are colours useful?

  • Appearance
  • Natural colours in food are often good nutritionally 
  • Fruit colours are natural antioxidants or are involved in body metabolism
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Liquid Medicines - Colours

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.

Other issues

  • Toxicity - colours are not essential. EU gradual withdrawal from food/medicines, UK food standards agency suggested the same.
  • Azodyes - bronchostriction in asthmatics especially if apirin intolerant.
  • Tartrazine - immunological sensitivity reactions.
  • Natural Colours are often less chemically stable than synthetics. Changing pH can change the colour (ionise)
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Liquid Medicines - Colours

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.

Other issues

  • Toxicity - colours are not essential. EU gradual withdrawal from food/medicines, UK food standards agency suggested the same.
  • Azodyes - bronchostriction in asthmatics especially if apirin intolerant.
  • Tartrazine - immunological sensitivity reactions.
  • Natural Colours are often less chemically stable than synthetics. Changing pH can change the colour (ionise)
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