PS 6 F

• traditional herbal medicines


  thousands of years old, made from natural materials such as plants, flowers, seeds, berries and fungal material. consist of many substances, the actual active ingredient is unknown. usually ground ingredients, extracted using hot or cold water or water-ethanol mixtures. oral or topical usually. typically prescribed and dispensed individually by herbalisit or traditional medicine practitioner. evidence of efficacy is usually limited or non-existent, some are well studied and available in pharmacies' health food stores. AUSTL or AUSTR listed on the register.
• western medicines derived from herbal medicines


  morphine, codiene (analgesic), opium poppy juice. colchicine (anti-gout) autumn crocus
• discovery and development of drugs


  the discovery, development, testing and registration of a new drug is slow, costly, inefficient and takes 10-15 years. only 1 in 10,000 potential drugs survive the development and testing process and reach the market. typically costs 1-2 billion USD per success (the cost of one success included the costs of all the failures onlong the way to finding it)
• stages of development

  1 - drug discovery 2- pre-clinical development 3- clinical development (effect on body, safety in humans, effectiveness at treating diseases, larger scale safety and effectiveness, long-term safety) 4 - regulatory approval
• drug discovery and screening

  first - investigation of disease mechanism and relevant receptors. in vitro screening of potential chemical/biological drug candidates and selection of promising active substance for detailed investigation and possible development. active drug substance may be a natural product substance but most are produced by chemical synthesis.
• pre-clinical development / pre-formulation


  complete physiochemical characterisation of the investigative drug substance. formulation as a suitable dosage form for preliminary testing. possible structural modification to optimise solubility, stability bioavailability and pharmacological activity. overall development of a formulation suitable for humans ( capsules etc)
• clinical development / preclinical testing


  in vitro and in vivo testing of drug substance to determine pharmacokinetics (absorption, distribution, metabolism , excretion) pharmacology pharmacodynamics and safety profile (toxicology)
• quality assurance /clinical development


  optimisation of formulation for marketing, development of quality control specifications for physical, chemical and microbiological characteristics of the drug substance and the finished product to ensure their fitness for the intended use. determination of degradation profile under different conditions of packaging, temp and humidity, to establish appropriate storage conditions and shelf life (how long the produce will meet the specification for suitable use in certain conditions)
• typical drug substance specifications

  appearance (white, crystalline, odourless powder). identification (Ir and TLC, conforms to relevant standard). melting point (PhEur procedure 201-204 degrees). assay (HPLC, UV-vis, Bioassay 99-101% pr 98-102%, wider limits for bioassay). related substances (HPLC, to measure percent impurities), residual solvents (GC, percent impurities), water content (PhEur procedure NMT 0.5%) heavy metals, sulphate ash (PhEur procedure) and particle size distribution (laser diffraction)
• quality control of excipients


  excipients must comply with quality specifications that control their identity, relevant physicochemical properties, physical and chemical purity and microbiological purity. specifications are usually found in a pharmacopoeia or in the case of a novel excipient, the specifications are based on the specifications for a similar substance
• QC drug products


  identity of AI, appearance, colour, taste, physical, chemical, microbiological, organoleptic properties, assay (mean potency and delivered dose), dose uniformity, rate of dose delivery, purity (physical, chemical and microbiological)
• QC for oral liquids


  appearance: clarity, opacity and colour. odour and taste, density, viscosity, pH , identity of API, assay of API, related substance impurities/degradation products, assay of preservatives, microbial counts or sterility
• QC specifications for injections


  appearnace, identiy of actives, potency, content sufficient for required dosage, preservative concentration and efficacy, freedom from particles (solutions, emulsions), particle size distribution (suspensions), pH, sterility, freedom from endotoxins and pyrogens
• QC for semi-solids


  appearance, odour, viscosity, pH, identity of active ingredients, assay, related substance impurities/degradation products, assay of preservatives, microbial counts (water containing products)
• QC for solids


  appearance and dimesnions, identity of API, assay of API 95-105% of label claim, content uniformity (20 units within 10% +/- of mean and std <6% of mean), related substance impurities/degradation products, disintegration and dissolution rate
• stability


  drugs degrade through hydrolysis and oxidation etc. tested under various temp, moisture, air and light conditions, to determine degradation profiles and storage to maximise stability. shelf life is max 5 years, and the drug product is expected to remain high quality in storage and transport. physical changes (crystalline form, hydration, colour, absorption or loss of water), chemical changes (hydrolysis, oxidation, photolysis, geometrical or optical isomerisation (free-radicals and light), polymerisation and toxic degradation products). 0 (line) or first order (curve)
• other ways stability is lost

  chemical changes, loss of volatile constituents, loss of water, absorption of water, colour changes, solutions: crystal growth and precipitation, suspensions: crystal growth by dissolution and recrystallization (or recrystallization as a different polymorph)
• physical changes that indicated degradation


  powder: caking, clumping. capsules: change in appearance, brittle/soft shell. tablets: softening, swelling. solution: discolouration, gas-formation. suspension: caking, crystal growth. emulsion: creaming, cracking. creams: shrinkage (water evaporation), breakage of emulsion. gels: drying, separation of liquid and solid. ointments and paste: drying, granules or grittiness. suppositories: shrivelling, softening
• stability testing of drug products


  tested for stability in batches in different containers and temperature humidity conditions. accelerated: 40 degrees, 75% relative humidity. normal storage conditions: 25 degrees, 60% RH or 30 degrees and 65% RH. tested at intervals to see how the drug degrades. measures: hardness, moisture, appearance, assay, degradation and dissolution. for small percent changes assume they are linear. assign a conservative shelf life based on this
• clincial trial stages

  I: 20-100 healthy volunteers. tolerability, safety, absorption, distribution, metabolism, excretion, duration of action of dosage and potential interactions. II: 100-300 patients. effectiveness vs placebo, optimum dosage, safety at that dosage. III: 1000-3000 patients. exposed for 3-6 months. efficacy, optimum dosage, adverse effects, chronic safety, new drug compared to others, identify target population for marketing.
• registering new drugs


  drug companies submit vast amounts of data to regulatory authorities for evaluation and approval. Australia TGA. added to the ARTG and are listed or registered, AUSTL and R. scheduled by the TGA.
• post-registration control and monitoring

  phase 4. Monitoring the ongoing effects of the drug on a larger population. may lead to restriction of dosage, indications and contradictions changing and cancelling of registration. the public reports side effects or adverse effects.
• patents


  usually innovater companies take out a patent in development and only last about 20 years.
• TGA


  evaluation and registration of prescription and nonprescription medicines. regulating, inspecting, licensing and monitoring of medicine manufacturers to ensure their product is consistant and high quality. monitoring and taking action as appropriate and necessary to manage or resolve post-market quality, safety and efficacy issues, related to medicines marked in Australia. state government regulates pharmacies themselves