Fundamentals of Pharmacy/Pharmacology Lecture 1 - Unit Introduction (PDF)

Fundamentals of Pharmacy / Pharmacology: The Science of Medicines SL12102 / SL12011 Lecture 1 – Unit introduction Dr Paul De Bank [email protected] Department of Life Sciences Outline Why study Science of Medicines?...

Fundamentals of Pharmacy / Pharmacology: The Science of Medicines SL12102 / SL12011 Lecture 1 – Unit introduction Dr Paul De Bank [email protected] Department of Life Sciences Outline Why study Science of Medicines? Pharmaceutics The medicines approval process The journey of a medicine Unit overview – MPharm & Pharmacology Teaching & learning Problem based learning Assessment Help & support Questions? Year one units Pharmacy Pharmacology SL12101: The chemistry of drugs SL12009: The chemistry of drugs (15 credits) (15 credits) SL12102: The science of medicines SL12011: The science of medicines (15 credits) (10 credits) SL12100: Health and disease SL12010: Health and disease (15 credits) (15 credits) SL12103: Preparing for professional practice 1 SL12013: Research and scientific skills for pharmacology (15 credits) (20 credits) Why study Science of Medicines? The science of medicines This Photo by Unknown Author is licensed under CC BY-NC-ND Drug discovery Safe and effective dosage form which Patient allows a therapeutic quantity of drug to reach the site of action at the right rate The chemistry of drugs Health and disease “From bench to bedside” Then: Post-marketing surveillance Life-cycle management https://www.debra.org.uk/drug-approval-process Science of medicines = PHARMACEUTICS Drug formulation – developing an appropriate dosage form accounting for physicochemical drug properties, stability, route of delivery, etc. Drug delivery systems – novel means of improving efficacy of a medicine or patient compliance, reducing side-effects, targeting drug to specific cells/tissue, etc. Biopharmaceutics – understanding the absorption, distribution, metabolism and excretion of drugs following administration and applying this to the design of dosage forms. Quality control – ensuring that standards of purity, identity, dosage and safety are met throughout the process of manufacturing a medicine. Regulatory science – according to the FDA, “…the science of developing new tools, standards, and approaches to assess the safety, efficacy, quality, and performance” of medicines. The journey of a medicine This unit will focus on the process of making a drug into a medicine and what happens to it once it has been taken by or delivered to the patient. This Photo by Unknown Author is licensed under CC BY Drug Dosage form Patient The journey of a medicine This unit will focus on the process of making a drug into a medicine and what happens to it once it has been taken by or delivered to the patient. Development of the drug delivery system taking in to account basic drug properties including: MW Lipophilicity Ionization Solubility vs pH This Photo by Unknown Author is licensed Dissolution rate under CC BY Chemical stability Particle size, crystallinity and Drug Dosage form hygroscopicity for solid drugs Compatibility with excipients and packaging materials Dosage forms This ThisPhoto Photo by Unknown Author is licensed under CC CCBY-NC-ND BY-NC-ND This ThisPhoto Photo by Unknown Author is licensed under CC CCBY-NC BY- CC NC BY-NC This Photo by Unknown Author is licensed under CC BY-SA The journey of a medicine This unit will focus on the process of making a drug into a medicine and what happens to it once it has been taken by or delivered to the patient. Effects of drug (physicochemical properties), dosage form and physiology on release and absorption This Photo by Unknown Author is licensed The organ systems involved under CC BY in the drug’s journey into, around and out of the body Dosage form Patient ADME & pharmacokinetics  Unit overview (MPharm) Semester 1: Semester 2:  Unit overview (Pharmacology) Semester 1: Semester 2: Semester 1 topics What is a medicine? Pre-formulation of solid dosage forms. Concept of medicine and dosage forms. Drug solubility and dissolution rate. Brands and generics. Role of dosage forms and excipients. Why GI structure, motility, digestion & absorption. different dosage forms? Thermodynamics. Liver anatomy and function. Physiochemical properties of small drugs. Kidney anatomy and function. Recap - Bioavailability, dissolution and Acid-base theory, pH and pKa. membrane transport. Absorption: Physiological factors affecting Electrolytes and buffers. drug absorption. Chemical kinetics and stability of dosage Absorption: Sublingual, buccal & rectal drug forms. delivery. Optimising drug properties to ensure good Absorption: Overview of absorption via oral bioavailability. different routes. Fundamental pharmaceutics Pre-formulation Organ systems ADME and pharmacokinetics Semester 2 topics Drug distribution. Liquid dosage forms: solutions. Liquid dosage forms: suspensions & Drug elimination. emulsions. Introduction to pharmacokinetics. Solid dosage forms – role of excipients. IV bolus injections. Processing of tablets. IV infusion and one-compartment model. Tablet coating and drug release. Extravascular administration. Processing of capsules. Formulation of suppositories. ADME and pharmacokinetics Formulation of solid and liquid dosage forms Learning outcomes 1. Demonstrate an understanding of what constitutes a medicine, the requirements for different dosage forms for different routes of delivery and how the production and quality of medicines is regulated. 2. Describe how the physicochemical properties of molecules and factors such as chemical kinetics and pH affect the properties of medicines and their constituent components. 3. Have detailed knowledge of the pre-formulation and formulation of solid and liquid dosage forms, including their manufacture and factors which influence their performance. 4. Demonstrate an understanding of the factors which influence the release of a drug from its dosage form and its subsequent absorption, distribution, metabolism, and elimination from the body. 5. Demonstrate how the fate and concentration of drugs in the body can be modelled and predicted using basic pharmacokinetic models. Underlined = MPharm only. See unit descriptions for SL12102 and SL12011 for more details of the units. Teaching on the unit Lectures are each timetabled for 1 hour and will be delivered as PowerPoint presentations, with the slides being made available to you via Moodle - these are not a substitute for lecture attendance! You should attempt to understand the material as it is delivered and make suitable notes. Recordings of each lecture will be made available via Panopto/Re:View and links will be provided on Moodle. Workshops are topic-specific and generally consist of a series of numerical questions for you to work through during the workshop, with the help and guidance of the relevant tutor. The workshop questions will be available via Moodle under the relevant week’s block. There are also Q&A workshops towards the end of each semester, which provide you with an opportunity to ask the teaching staff and questions you have about their topics prior to the exam periods. All workshops are ideal opportunities to ask the tutor about any concepts you’re unsure about, so please make use of them. Teaching on the unit – MPharm only There are two practical classes towards the beginning of semester two, which will allow you to contextualize some of the topics covered in semester 1 by gathering and analysing experimental data. A practical handbook will be provided to you at the start of your first practical class. The tutorials linked to this unit are concerned with your Problem Based Learning task, where you will investigate the “road-to-market” of a specific medicine. You will be supported in this by your Academic Advisor, your fellow tutees and by a paired tutorials with another tutor group. This unit will give you underpinning knowledge which will be built on throughout your degree so please make sure that you spend time to understand the materials and ask questions if you’re unsure of anything. Problem based learning (PBL) – MPharm only A learning approach which encourages you to take responsibility for your own learning by providing you with a problem that needs solving. Requires you to work together as a group to find solutions to a case study or task. Your first task, will be to examine the “road-to-market” of an approved medicine. To complete your task, you will need to retrieve, evaluate, and analyse information from different sources. More information about PBL and this specific task will be available via this unit’s Moodle page. Week 3 – PBL lecture Week 4 – PBL tutorial (single tutor group) Week 6 – Paired PBL tutorial Week 8 – PBL tutorial (single tutor group) Week 11 – PBL assessment Assessment MPharm Pharmacology Semester 1 PBL: 10% Semester 1 exam: 30% Semester 1 exam: 30% Semester 2 exam: 70% Semester 2 exam: 60% Semester 1 exam, a multi-choice question (MCQ) paper examining topics from the first semester. Semester 2 exam consisting of structured written questions which examine topics from the whole of the unit. To pass this unit, you need to achieve an aggregate mark of ≥40% across both exams. MPharm students must also pass the PBL.  Moodle Course index Block drawer Moodle Moodle Moodle Moodle Library list Help & support – unit-specific Anything about the unit or my teaching – [email protected], 5W 2.26 Don’t be afraid to ask questions – e.g., at the end of lectures and during workshops – there’s no such thing as a stupid question! Email the relevant member of staff Post a message on the unit’s Q&A forum Week 11 and Week 30/31 Q&A / revision sessions Best to deal with issues sooner rather than later! Help & support – general Your Academic Advisor Student Support Skills Centre Academic skills Maths & statistics skills Language & intercultural skills Digital skills Personal development skills Health and wellbeing skills Information for new undergraduate Life Sciences students MASH – maths and statistics help  Questions? https://www.timeshighereducation.com/blog/weirdest-questions-asked-about-your-phd Fundamentals of Pharmacy / Pharmacology: The Science of Medicines SL12102 / SL12011 Lecture 2 – What is a Medicine? Dr Paul De Bank [email protected] Department of Life Sciences  Learning objectives & overview After this lecture you should understand the concepts of: Drug delivery and absorption. Drugs, medicines, dosage forms and drug delivery systems. The medicines development pipeline and the role of science of medicines. Biopharmaceutics. Bioavailability. Pharmacokinetics and pharmacodynamics. ADME. Plasma concentration of drug versus time profiles. And how: Pharmaceutical sciences enable the right medicine/treatment to be given to the right patient at the right dose at the right time.  Drug delivery & absorption Drug absorption is the uptake of non-metabolized drug, following release from its formulation, from the site of delivery to the systemic circulation. Many routes of delivery exist: Oral Injections – intravenous, intramuscular, subcutaneous, intradermal + many more! Implants (often SC) Topical and transdermal Pulmonary (inhalation) Nasal Buccal and sublingual Ocular, otic Rectal, vaginal Involves crossing a biological barrier (or barriers) There is no absorption process in IV administration  Biopharmaceutics The ultimate aim of medicines design is to achieve the goal of getting the right drug to the right place at the right dose and at the right rate. Optimizing drug delivery involves a number of disciplines but pharmaceutics, is key to the process. Fundamental pharmaceutics – Lectures 2 to 13 What is a medicine? Concept of medicine and dosage forms. Brands and These lectures introduce you to the concept generics of biopharmaceutics, which focuses on Role of dosage forms and excipients. Why different understanding how a drug’s properties, its dosage forms? formulation, dosage, and route of Thermodynamics administration (i.e. physiology of the delivery Physicochemical properties of small drugs – site) influence its absorption, distribution, dissolution, membrane transport and diffusion, metabolism, and excretion (ADME). lipophilicity and partition coefficient Acid base theory, pH and pKa Electrolytes and buffers Rate and extent of absorption → onset, Chemical kinetics and stability of dosage forms duration and intensity of biological effect. Optimising drug properties to ensure good oral bioavailability  Drug vs medicine Drug Medicine OH O This Photo by Unknown Author is licensed under CC BY The drug is part of the medicine. https://sihaulichemicals.com/wp- content/uploads/2023/05/ibuprofen- powder-500x500-1.webp Drug = Active Pharmaceutical Ingredient (API) – the chemical moiety in a medicine which is responsible for its therapeutic effect. Some medicines have a long list of ingredients – API plus excipients. Dependent on the dosage form and desired drug release.  Dosage forms Dosage Form - the physical form (e.g. solid, semi-solid, liquids, gases) in which a medication is produced and administered. It includes the drug and any other ingredients that help deliver the medication effectively. Examples include: Tablets: Solid forms that are swallowed. Capsules: Containers, traditionally gelatin, filled with medication. Liquids: Solutions, suspensions, or emulsions taken orally or injected. Topicals: Creams, ointments, and gels applied to the skin. Inhalers: Devices that deliver medication directly to the lungs. Adapted from: Aulton's Pharmaceutics: The Design and Manufacture of Medicines: Major considerations in design of dosage forms: 1. The physicochemical properties of the drug itself. 2. Biopharmaceutical considerations, such as how the administration route of a dosage form affects the rate and extent of drug absorption into the body. 3. Therapeutic considerations of the disease state and patient to be treated, which in turn determine the most suitable type of dosage form, possible routes of administration and the most suitable duration of action and dose frequency for the drug in question.  Dosage forms and drug delivery The ultimate aim of medicines design is to achieve the goal of getting the right drug to the right place at the right dose and at the right rate. Time of onset of Dosage forms action Seconds Intravenous injections Intramuscular and subcutaneous injections, Minutes buccal tablets, aerosols, gases Short-term depot injections, solutions, Minutes to hours suspensions, powders, granules, capsules, tablets, modified-release tablets Several hours Enteric-coated formulations Days to weeks Depot injections, implants Varies Topical preparations From: Aulton's Pharmaceutics: The Design and Manufacture of Medicines  Drug delivery system (DDS) Drug Delivery System – a method or process of administering a pharmaceutical compound to achieve a therapeutic effect in humans or animals. It focuses on the technology used to deliver the drug to the target site in the body. Examples include: Controlled-release systems: Tablets or capsules designed to release the drug slowly over time. Transdermal patches: Patches applied to the skin that release medication over a prolonged period. Injectable systems: Methods like intravenous (IV) or intramuscular (IM) injections. Nanoparticles and liposomes: Advanced systems that deliver drugs at the cellular level for targeted therapy.  The medicine development pipeline Investigational new drug (IND) application New drug application P. Subhaswaraj & B. Siddhardha in Computational Approaches for Novel Therapeutic and Diagnostic Designing to Mitigate SARS-CoV-2 Infection, Academic Press, 2022, p 207-246; DOI: 10.1016/B978-0-323-91172-6.00007-8. Mean cost of getting a new molecular entity (NME) to market ~£1 billion, approx. 90% failure rate. The medicine development pipeline https://www.debra.org.uk/scientific-research-and-clinical-trials  Drug discovery and pre-clinical development Target identification and validation https://www.medicilon.com/press-events/discovery- and-optimization-of-lead-compounds/ Drug screening → hit/lead compound Lead optimization Synthesis, SAR, biological evaluation, drug-like properties (structure optimization) Formulation development Pre-formulation, formulation design and manufacture, disintegration and dissolution testing, stability testing Pharmacokinetics and toxicity BMC Neurology 2009, 9, Article number: S2; DOI: 10.1186/1471-2377-9-S1-S2 Clinical development The best drug in the world is useless if it can’t reach its site of action! Cyclical process, not linear! Formulation & drug delivery technology can optimize therapeutic outcomes. Oral delivery not always suitable – analyse delivery options.  Drug absorption in the GI tract Portal vein (and tributaries) Splenic vein (and tributaries) Superior mesenteric vein (and tributaries) Inferior mesenteric vein (and tributaries) https://teachmeanatomy.info/abdo men/vasculature/venous-drainage/  Drug absorption in the GI tract Particles in Molecules in Solid dosage form suspension solution Digestive enzymes Bacterial enzymes pH, food Efflux (e.g. P-gp) Absorption GUT EPITHELIUM BLOOD Metabolic enzymes To liver The human body cannot absorb solids! e.g. CYP3A Drugs must be in solution to be absorbed.  Drug absorption in the GI tract Some factors affecting absorption of small drugs: Effect of pH: Ionization – Henderson-Hasselbalch equation Solubility Hydrogen bonding Size Lipophilicity Lipinski’s rule of five helps predict oral absorption of drugs. N.B. Modern drug development is hindered by poor solubility of candidate drugs. Padhye, T. et al, Journal of Drug Delivery Science and Technology (2021), 61, 102178; DOI: 10.1016/j.jddst.2020.102178.  Biopharmaceutics Physicochemical properties of the drug Physical properties of the delivery system Biological effect Physiological properties of the delivery route Pharmaceutics is the science of making medicines. Biopharmaceutics is the study of the interaction of the medicine with the biological system, allowing the optimization of DDS. Biopharmaceutics includes: Chemistry – organic and physical Chemical analysis Physical tests Pre-formulation and formulation science Disintegration, liberation and dissolution tests Bioavailability studies Bioequivalence studies  Bioavailability F = Fa x Fg x Fh The bioavailability of a drug is a measure of the quantity of drug which reaches its site of action and the rate at which it gets there. Important in terms of assessing the performance of a medicine (quality of a dosage form) and for comparing different dosage forms. We need to define what we mean by the term “drug”, and we need to be able to determine the https://jnanobiotechnology.biomedcentral.c quantity of the drug at the site of action. om/articles/10.1186/s12951-021-01100-2 Fa = fraction absorbed Fg = fraction escaping gastrointestinal metabolism Fh = fraction escaping hepatic metabolism F = net oral bioavailability  Bioavailability Active parent drug Active Inactive Determining drug concentration metabolite metabolite in the systemic circulation is the generally accepted method of For most medicines, the drug is the API. measuring bioavailability – blood, serum or plasma can be used. However, this isn’t always the case e.g. pro-drugs. Appropriate for drugs which act Some metabolites may be more active than the via systemic circulation e.g. parent drug. following injection or oral delivery. May not be possible for some N.B. Technically, bioavailability – i.e. extent and rate of absorption – is not other routes, valid for IV administration as there is no absorption process. Major process affecting drug response Pharmacokinetics (PK) Pharmacodynamics (PD) What the body does to the drug What the drug does to the body Adapted from: Clarelli, F., Liang, J., Martinecz, A. et al. Multi-scale modeling of drug binding kinetics to predict drug efficacy. Cell. Mol. Life Sci. (2020), 77, 381–394; DOI: 10.1007/s00018-019-03376-y  Determinants of pharmacokinetics Liberation Absorption IV injection Distribution ADME* Metabolism Excretion * Sometimes LADME https://www.mdpi.com/1999-4923/15/4/1260 Also, LADMET  Plasma concentration vs time (oral administration) Concentration of drug in plasma, CP (µg/mL) Minimum toxic concentration (MTC)* Duration of action Cmax Therapeutic range AUC Minimum effective concentration (MEC) Tmax Time (hours) Lag time Time of onset *Maximum safe concentration  Plasma concentration vs time O N O NH NH IV Serum [NAPA] (µg/mL) Oral Time (hours) A.J. Atkinson Jr., et al. Clin Pharmacol Ther (1989), 46, 182-189  Summary It is important to fully understand the physical and chemical properties of drugs and the components within a dosage form. Combined with an understanding of the physiology at the delivery site, and the drug’s pharmacokinetics this allows us to get the right drug to the right place at the right dose and at the right rate. The rest of this unit will explore these concepts in more detail to give you an understanding of the science of medicines design. Key terms: Drug / API Medicine Absorption Biopharmaceutics Bioavailability Pharmacokinetics Pharmacodynamics Fundamentals of Pharmacy & Pharmacology: The Science of Medicines SL12102 / SL12011 Lecture 3: Concept of medicine and dosage forms, brands and generics Dr C POURZAND  Intended learning outcomes By the end of the lecture you will be able to:- Understand the nomenclature of medicinal products Explain why medicines are protected Understand research and development strategy in Pharma Industry Explain the difference between branded and generic drugs Describe the benefits and potential drawbacks of generic medicines  What is a medicine? A medicine is any product used to diagnose, cure, mitigate, treat or prevent a disease The medicinal product is the presentation of a drug in a dosage form suitable for administration to the public i.e... a formulation Drug: Also known as Active Pharmaceutical Ingredient (API) Excipient: All the other components of a formulation other than the active drug Formulation: The process in which APIs and excipients are combined to produce a medicinal product  Medicinal product nomenclature Every branded medication has 2 names: 1. The Brand name: Given by the pharmaceutical R&D company and is a registered ® name. 2. Chemical name – name for the active pharmaceutical ingredient, which is decided by an expert committee. A medication is often known by a registered brand name provided by the innovator (e.g. Zantac®, Prozac®) Medical devices and Packaging are typically trademarked ( ) Marketing and Branding is critically important in the US – the brand name can be different between EU and US (e.g. Advair® (US), Seretide® (EU)). The chemical and brand name appear on the medication label and product literature. Captain Zantac Shape and colour of Viagra was trademarked A trademark is any word, name, symbol, or design, or any combination thereof, used in commerce to identify and distinguish the goods of one manufacturer or seller from those of another and to indicate the source of the goods." Trademark generally lasts as long as the trademark is used in commerce and defended against infringement. Pantone 2567C Pantone Pantone 2587C 2573C  Branded Drugs New medicines are marketed as a branded product. Companies take out patents on each new drug they discover to regain money spent on R&D and make a profit. A standard patent last 20 years but can be extended by an additional 5 years. It takes approx. 10-15years of this period to develop, file a new drug application and obtain a marketing authorization (MA). Only the company can produce and sell the medicine to recover costs during the remaining years.  Patent vs. Marketing Life 100% % of Patent Life Remaining 75% Discovery & Pre-clinical 50% Studies Clinical Development 25% & Regulatory Marketing 0% 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Year Since Patent Approval Need to recover costs before the patent expires!  Pharmaceutical Research & Development (R&D) Industry The objective of pharmaceutical research and development is to “convert synthesised chemical compounds into candidate drugs for development” Product development involves “converting candidate drugs into dosage forms for registration and sale”  Pharmaceutical R&D Industry To be successful, research-based pharmaceutical companies must ensure that new discoveries are frequently being brought to the market. Required for market growth/shareholders and to fund the next generation of compounds. Pharmaceutical companies need a “pipeline” of new chemical entities (NCEs). Astra Zeneca Pipeline (2014) Pharmaceutical R&D companies have a mixed portfolio of products Global Distribution of Pharmaceutical Sales Medicines expenditure per person  Qvar’s generic name: Beclometasone Dipropionate Augmentin’s generic name: amoxicillin/clavulanate potassium  Blockbuster drug model A blockbuster drug is where sales reach over US $1 billion per annum. > 1/3 of the pharma market is accounted by blockbusters Search for a blockbuster is the foundation of R&D strategy. This model needs to change with advances in pharmacogenomics and personalised medicines. May fracture the market with the possibility of companies concentrating on specific ailments/therapies.  Avatar Lipitor (Pfizer) Budget $237 million Launched in 1998 International gross earning Patent protection until 2011 $3.02 billion Cost to Market: $0.5 - 1 billion International gross earning $ROI = $2.78 Billion $13.7 billion per annum $ROI ~ $100 billion ROI : Return on investment  Blockbuster drug model There were only 4 blockbuster drugs in 1992. In late 90’s blockbuster pharmaceuticals were on the verge of patent expirations while late-stage product pipelines scarce, thus shaking the foundations of an industry that was once the favorites of Wall Street. – Increased to 29 in 1998, 35 in 1999 and 44 in 2000. From 2000 to 2022, the number increased 5-fold, with a slowing of growth from 2018. However massive demand for Covid vaccines and therapeutics during pandemic accelerated the growth. Since 2000, annually ca 14 drugs became blockbusters for the first time and ca 8 lost their rank with their annual revenues falling back below $1Billion – Reasons: going generic, taken by a competitor or lost pricing power..  Examples of top Blockbusters in 2023 Comirnaty Keytruda Humira Company: Pfizer and BioNTech 2023 sales: $11.2-15.3 billion Company: AbbVie Disease: COVID-19 Company: Merck & Co. 2023 sales: $14.4 billion Before COVID, AbbVie’s Humira was 2023 sales: $25 billion Disease: Rheumatoid top-selling for 9 consecutive years. Diseases: Melanoma, non- arthritis, juvenile idiopathic In 2021, Comirnaty sales reached small cell lung cancer, head arthritis, psoriatic arthritis, $36.8 billion, being unprecedented in and neck cancer, classical ankylosing spondylitis, a single year for a pharmaceutical Hodgkin lymphoma, primary Crohn’s disease, ulcerative product. mediastinal large B-cell In 2022, the annual sales reached colitis, plaque psoriasis, lymphoma, bladder cancer, $37.8 billion by Pfizer and BioNTech hidradenitis suppurativa and which was more than double of the microsatellite instability-high uveitis. sales of their lone serious competitor or mismatch repair deficient Moderna, which sold $36 billion of its cancer, gastric cancer, Spikevax vaccine. esophageal cancer, cervical Ozempic In 2023, by transition of pandemic into cancer, liver cancer, biliary the endemic stage, sales decreased. tract cancer, Merkel cell Company: Novo Nordisk In October, Pfizer cut $9 billion from its carcinoma, kidney cancer, 2023 sales: 95.7 billion annual revenue projection Danish kroner ($14 billion) For 2024, Pfizer projects Comirnaty endometrial cancer, tumor sales reached $5 billion, being short of mutational burden-high Disease: Type 2 diabetes, cardiovascular risk reduction Wall Street’s estimate as well as the cancer, cutaneous squamous company’s own prediction that vaccine cell carcinoma, triple-negative in diabetes patients. sales would be in line with what they breast cancer were in 2023.  30 years of novel FDA approvals Annual numbers of new molecular entities (NMEs) and biologics license applications (BLAs) approved by the FDA’s Center for Drug Evaluation and Research (CDER). https://www.nature.com/articles/d41573-024-00001-x  Generic Drug Companies Generic business kicks in when a leading brand finally loses patent protection. Usually, a multiple of generic drug companies launch copycat versions of the original. Profits are much lower. Generics can become blockbusters! Loathed by the Pharma R&D Loved by Health Ministers Pharma R&D have introduced lifecycle management to increase patent protection  90’s - 00’s: The era of the Generics Population all over the World are getting older Increase in the size of the middle class Government promoting the use of generic drugs in efforts to slow down increase in health spending Increased acceptance of generic drugs by doctors, pharmacists and patients A number of blockbusters in major diseases states have lost patent protection (e.g. cardiovascular, respiratory)  What is a Generic Drug? A drug which is bioequivalent (PK and PD properties) to a leading brand name Generic medicines must be identical in dose, route of administration, safety and efficacy as the “innovator” Interchangeable with the branded drug at the pharmacy A generic name is used for the medicine (typically chemical name).  Major saving to the NHS e.g. 90-94% saving on Atorvastatin The growth of generics in the UK Number of Generic prescriptions in UK GP practices (median 83%) Worldwide Levels of Generic Penetration  Prescribing generic medicines Prescribers are encouraged to prescribe medicines by their generic name. Generic medicines are equally effective and can save up to 80% on the cost of a branded product Allow pharmacist the widest choice of products to dispense. Important if there is a shortage of a particular product.  Word of Caution In rare cases, a patient may need to stay on a branded medicine. Some examples may include: – Epilepsy medicines – slight differences in rate of absorption may cause a big difference in therapeutic effect. – Modified-release preparations – Generic equivalents may absorb differently. – Lithium – different brands may vary widely in the absorption and how the medicine becomes active. – Biological medicines – Copies of these complex medicines (called biosimilars) may not be automatically used as a substitute. Doctors need to reference the specific manufacturer.  Further resources https://www.uspharmacist.com/article/drug-patent-expirations-and-the-patent-cliff. European Medicines Agency guidance document on generic medicines and bioequivalence. https://www.ema.europa.eu/en/human-regulatory/research-development/scientific-guidelines/clinical- pharmacology-pharmacokinetics/product-specific-bioequivalence-guidance Comparator products in Bioequivalence/Therapeutic Equivalence studies https://www.gov.uk/guidance/comparator-products-in-bioequivalencetherapeutic-equivalence-studies Legal battle over Lipitor (atorvastatin) sales in UK. http://www.pharmatimes.com/news/pfizer_settles_with_teva_over_lipitor_in_uk_980269. NHS guidance on the prescribing of generic medicines in specific diseases. http://www.nhs.uk/Conditions/Medicinesinfo/Pages/Brandnamesandgenerics.aspx. Top 20 drugs by worldwide sales in 2023. The top 20 drugs by worldwide sales in 2023 | Fierce Pharma Leading pharmaceutical products by sales worldwide in 2023 https://www.statista.com/statistics/258022/top-10-pharmaceutical-products-by-global-sales-2011/ Fundamentals of Pharmacy & Pharmacology: The Science of Medicines SL12102 / SL12011 Lecture 4: Role of dosage forms and excipients. Why different dosage forms Dr C POURZAND  A Formulation Principle “The more trivial the complaint, the more demanding the consumer” There are 22 types of Nurofen on the UK market!!  The Australian federal court ruled that the company had misled consumers after it was discovered that Nurofen Back Pain, Nurofen Period Pain, Nurofen Migraine Pain and Nurofen Tension Headache are all the same pill, all containing the same active ingredient, ibuprofen lysine 342mg. In the UK, Nurofen is £2 for a packet of 16, compared to £2.85 for a packet of 12 Nurofen Tension Headache and Nurofen Migraine Pain.  How to make a medicine? Why are drugs not administered as pure substances? Need to Formulate the Dosage Form  Types of dosage forms: Definition: Dosage forms are the means by which drug molecules are delivered to sites of action within the body. What do we need in a dosage form: 1. Accurate dosing 2. Protection and Shelf-life 3. Protection from gastric juice 4. Masking taste and odour 5. Placement of drugs directly within body tissues 6. Sustained release medication. 7. Controlled release medication. 8. Insertion of drugs into body cavities 9. Use of desired vehicle for insoluble drugs  What is an excipient? “All the other components of a formulation other than the active drug” Each component requires an appropriate evaluation for safety. An excipient should be chemically and physiologically inert. People may have moral or religious problems with excipients e.g. Gelatin  Uses for excipients Aid processing of the system during manufacture and accurate dose control Control rate of absorption Protect, support or enhance stability, bioavailability or acceptability Assist in product identification Enhance any other attribute of the overall safety and effectiveness of the drug product during storage and use. Difference in in-vivo absorption is due to the Excipients used in the Formulation  Dose Control Why formulate to control dose? Aspirin tablet typically has 300 mg API Patient unlikely to be able to measure this amount Many drugs have lower doses Ethinyl estradiol - 0.01 mg or 10µg tablet Alfacalcidol – 0.001mg or 1µg capsule Difficult to manufacture - blend uniformity  Dose Equally, high dose (low potency) drugs can be a problem to formulate If drug has poor flow/compressability cannot make a tablet  Why are Ibuprofen tablets film coated? Avoiding gastric mucosal irritation- peptic and mucosal ulcers, dyspepsia, severe gastric pain and bleeding…  Taste Very subjective and difficult to quantify Many drugs extremely bitter Can be mitigated by film-coating  Types of dosage forms Dosage Forms Route of administration Physical form Oral Solid Topical Semisolid Transdermal Liquid Rectal Parenteral Vaginal Inhaled Ophthalmic Otic  Solid oral dosage forms: Tablet/Caplet A tablet is a hard, compressed medication in round, oval or square shape. Excipients include Diluents (Compressible bulking agents), binders, glidants (flow aids) and dry lubricants to ensure efficient tabletting. Disintegrants to ensure that the tablet breaks up in the GI tract. Sweeteners or film coatings for taste masking active pharmaceutical ingredients.  Solid Oral Dosage Forms 90 % of medicines are taken orally Requirements for an ideal oral solid dosage form: – drug must remain stable – drug must be bioavailable (formulation reliably releases drug in GIT) – uniform drug content (reproducible dose) – robust and resistant to disintegration during handling – easy and cost effective to mass produce – pleasant to take  Buccal and Sublingual Tablet Sublingual and buccal medications are administered by placing them in the mouth, either under the tongue (sublingual) or between the gum and the cheek (buccal). The medications dissolve rapidly and are absorbed through the mucous membranes of the mouth, where they enter into the bloodstream. Bypasses the stomach and liver. Examples  Effervescent Tablet Effervescent tablets are uncoated tablets that generally contain acid substances (citric and tartaric acids) and bicarbonates and which react rapidly in the presence of water to effervesce by releasing carbon dioxide. They are intended to be dissolved or dispersed in water before use providing: Very rapid tablet dispersion and dissolution. Pleasant tasting carbonated drink by addition of sodium saccharin (sweetener) Lubricants need to be water soluble Tablet packaging is critical for stability  Capsule A capsule is a dosage form in which a formulation is contained in a gelatin or a Hydroxypropyl methylcellulose matrix. Hard gelatin capsule Advantage: mask the unpleasant taste of its contents. The two main types of capsules are: 1. Hard-shelled capsules, which are normally used for dry, powdered ingredients, 2. Soft-shelled capsules, primarily used for oils and for active ingredients that are dissolved or suspended in oils or emulsions. Soft gelatin capsule  Oral Granules Consist of solid, dry aggregates of powder particles often supplied in single-dose sachets. Some granules are placed on the tongue and swallowed with water, others are intended to be dissolved in water before taking. Effervescent granules evolve carbon dioxide when added to water. Fast Dissolving Oral Delivery Formulations Solid dosage form that dissolves or disintegrates rapidly in oral cavity, resulting in solution or suspension without the need of water Also known as: Orodispersible tablets, melts Tablet disperses in saliva – for some drugs a portion may be absorbed from the mouth, pharynx and oesophagus as the saliva passes towards the stomach (potentially increased absorption/bioavailability) – formulations are either very porous or soft moulded matrices or compressed into tablets with very low compression force – Tablets difficult to handle - often require specialized ‘peel-off blister’ packaging  Liquid preparations Solutions Oral solutions are clear liquid preparations for oral use containing one or more APIs dissolved in a solvent. Solvents include diluted alcohol, glycerin or propylene glycol and purified water. Emulsions Oral emulsions are stabilized oil-in-water dispersions, either or both phases of which may contain dissolved solids. Suspensions Oral suspensions are liquid preparations for oral use containing one or more APIs suspended in a suitable vehicle. Liquid vehicles include purified water with cellulose derivative polymers and thickening agents (e.g. Xanthan Gum)  Liquid preparations Syrup It is a concentrated aqueous solution of a sugar. Flavored syrups are a convenient form of masking disagreeable tastes. Elixir It is pleasantly flavored clear liquid oral preparation of potent or nauseous drugs. The vehicle may contain a high proportion of ethanol in purified water and sucrose together with antimicrobial preservatives which confers the stability of the preparation.  Liquid preparations Linctus Linctuses are viscous, liquid oral preparations that are usually prescribed for the relief of cough. They usually contain a high proportion of syrup and glycerol which have a demulcent effect on the membranes of the throat. The dose volume is typically small Oral drops Oral drops are liquid preparations for oral use that are intended to be administered in small volumes with the aid of a suitable measuring device. They may be solutions, suspensions or emulsions.  Topical dosage forms Ointments Ointments are viscous, semi-solid, greasy preparations (oil 80% to 20% water) for application to the skin, rectum or nasal mucosa. The base is usually anhydrous and immiscible with skin secretions. Ointments may be used as emollients or to apply suspended or dissolved medicaments to the skin.  Topical dosage forms: Creams Creams are semi-solid emulsions, that is mixtures of oil and water. They are divided into two types: 1. Oil-in-water (O/W) creams: O/W are more comfortable and cosmetically acceptable as they are less greasy and more easily washed off using water. 2. Water-in-oil (W/O) creams: W/O creams more difficult to handle but many drugs which are incorporated into creams are hydrophobic and will be released more readily from a water-in-oil cream than an oil-in-water cream. Water-in-oil creams are also more moisturising as they provide an oily barrier which reduces water loss from the stratum corneum.  Topical dosage forms: Gels Gels are semisolid system in which a liquid phase is constrained within a 3D polymeric matrix (consisting of natural or synthetic polymer) having a high degree of physical or chemical cross-linking. They are used for medication, lubrication and some miscellaneous applications like carrier for spermicidal agents to be used intra vaginally.  Transdermal dosage forms: Patch A transdermal patch or skin patch is a medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream. An advantage of a transdermal drug delivery route over other types such as oral, topical, etc is that it provides a controlled release of the medicament into the patient. The first commercially available patch was scopolamine for motion sickness. Rectal/Vaginal dosage forms: Suppositories/Pessaries Suppositories are solid dosage forms intended for administration of medicine via the rectum, vagina (pessaries) or urethra (bougies) that melt, soften or dissolve in the body cavity. Suppositories are made by dissolving or dispersing the active ingredient(s) in a base at an elevated temperature, the mix is then poured into a mould and solidifies at room temperature. The quantity of fluid available for drug dissolution in the rectum is very small - approximately 3 ml and 100m thick layer.  Parenteral dosage forms An injection is an infusion method of putting liquid into the body, usually with a hollow needle and a syringe which is pierced through the skin to a sufficient depth for the material to be forced into the body. All requires the preparation of a sterile product Intravenous (IV) injection It is a liquid administered directly into the bloodstream via a vein. It is advantageous when a rapid onset of action is needed. 100% of drug is bioavailable Intramuscular injection It is the injection of a substance directly into a muscle. Many vaccines are administered intramuscularly. Depending on the chemical properties of the drug, the medication may either be absorbed fairly quickly or more gradually. Injection sites include the deltoid muscle of the arm, the vastus lateralis of the leg and the gluteal muscles of the buttocks.  Parenteral dosage forms Subcutaneous injections are given by injecting a fluid into the subcutis, the layer of fatty tissue directly below the dermis and epidermis. Subcutaneous injections are highly effective in administering vaccines and such medications as insulin.  Inhaled dosage forms Inhaled drug delivery is any drug or solution of drug administered by the nasal or oral respiratory tract Inhalers are prepared either as solutions, suspensions or a dry powder formulation. There is a need to deliver the drug in an aerosol form (less than 5µm)  Drug Delivery Liquid Dose inhaler Devices LDI Pressurised metered dose inhaler Dry Powder inhaler pMDI DPI Nebuliser Standard Spacers Active Passive Pneumatic Ultrasonic Inhalers Inhaler Inhalers Breath Activated Inhalers  Ophthalmic dosage forms Eye drops are saline-containing drops used as a vehicle to administer medication in the eye. Depending on the condition being treated, they may contain steroids, antihistamines or topical anesthetics. Eye drops sometimes do not have medications in them and are only lubricating and tear-replacing solutions. Ophthalmic ointments These are sterile semi-solid preparations intended for application to the conjunctiva or eyelid margin.  Otic dosage forms Ear drops - Ear drops are solutions, suspensions or emulsions of drugs that are instilled into the ear with a dropper. - It is used to treat or prevent ear infections, especially infections of the outer ear and ear canal.  References Fundamentals of Pharmacy / Pharmacology: The Science of Medicines LS12102 / LS12011 Thermodynamics Professor Duncan Craig [email protected]  CONTENTS Introduction to thermodynamics – why do pharmaceutical scientists need to know about this subject? Heat, temperature, energy and work The three laws of thermodynamics Thermodynamics in the pharmaceutical sciences  LEARNING OBJECTIVES By the end of this lecture course/workshops you should be able to Understand and manipulate the basic concepts of thermodynamics to understand real life situations Appreciate how thermodynamics informs the pharmaceutical sciences MORE INVALUABLE KNOWLEDGE AND UNDERSTANDING You will also learn Why it is a pain to tidy your room Why you burn your feet on sand on the way to the sea Why ice cream melts slowly Why you never seem to have any money These important concepts will be explored in the workshops  REFERENCE SOURCES Reading list “Physicochemical Principles of Pharmacy”; A.T. Florence & D.Attwood (3rd edition) MacMillan Press, London, 1998; chapter 3 “Martin’s Physical Pharmacy and Pharmaceutical Sciences”; P.J. Sinko, editor (6th edition) Lippincott, Williams & Wilkins, Baltimore, 2011, chapter 3 “Basic Chemical Thermodynamics”; E.B. Smith (2nd edition) Oxford University Press, Oxford, 1979  INTRODUCTION TO THERMODYNAMICS Basic Drug Drug Medicines Patient benefit science discovery disposition development Thermodynamics is an essential component of the toolbox of any scientist It also enables us to understand how drugs act on receptors, how they are distributed around the body and how we can formulate them into medicines  WHAT IS THERMODYNAMICS? Thermodynamics - the science of energy transfer Energy is the ability to perform work (see later) Generally applicable but molecularly non- specific Kinetic energy The energy of moving objects or mass (e.g. Will tell you whether a reaction or process will mechanical energy) take place but not how fast Potential energy The study of the rates associated with a Energy that is stored (e.g. nuclear energy) reaction or process is kinetics  HEAT, TEMPERATURE AND WORK What is heat and how do we measure it? Initially believed to be a physical substance (caloric), then considered to be ‘motion itself’ Now know that heat is a form of energy caused by molecular motion Heat is also considered in terms of thermal energy transfer between objects (e.g. hot water)  Temperature describes the propensity for heat to flow from one body to another Initially sensory Newton (circa 1700) developed scale (0 to 12) between water freezing and body temperature Fahrenheit (1724) – used freezing of a salt solution and body temperature with 96 divisions between the two  This led to well accepted Fahrenheit scale with 32o being melting point of ice, 98.6o being body temperature and 212o being the boiling point of water Celsius (1742) assigned freezing point of water as 0oC and the boiling point as 100oC Body temperature is 37oC For accurate work the thermodynamic temperature scale is used Zero of this scale is the zero of molecular motion (see later) Measured in Kelvins (K) whereby 0oC = 273.15K  THE CONCEPT OF WORK Work represents the transfer of energy in an ordered fashion, heat is random molecular motions Work defined by energy barrier it overcomes Both work and heat are forms of energy and are thus expressed in Joules (J) Total internal energy of Heat and work are the two system (U) ways in which energy can be added or subtracted from a system Work (W) Heat (Q) What do we mean by system? MATTER Isolated ENERGY system MATTER Closed system ENERGY MATTER Open system ENERGY An example of the interchange between heat and work Give us a sign………..  1ST LAW OF THERMODYNAMICS The algebraic sum of all energy changes in an isolated system is zero (Energy cannot be created or destroyed but merely transferred) Seven main forms of energy - electrical, gravitational, chemical, radiation, thermal, mechanical, nuclear Electrical to mechanical (motors) Gravitational to mechanical (falling weight) Thermal to radiation (lightbulb) Nuclear to thermal (atomic fission)  THE CONCEPT OF ENTHALPY The key events we are concerned with in the pharmaceutical sciences are reactions – physical or chemical These are dominated by changes in heat energy The heat energy change within a system is expressed as enthalpy (H) – expressed as a change value rather than an absolute one as that is what we measure If bonds are broken, energy is absorbed from the surroundings, H is positive (endothermic) If bonds are created, energy is lost to the surroundings, H is negative (exothermic) So which way round is the enthalpy sign? Crystallisation of a drug from the liquid to the solid state (HC) (where C stands for crystallisation) Melting of a drug (HF) (where F stands for fusion = melting) Evaporation of a volatile solvent (HV) (where V stands for vaporization)  THE 2ND AND 3RD LAWS OF THERMODYNAMICS For many years it was believed that reactions were driven by enthalpy Thought that exothermic reactions would proceed spontaneously, endothermic required energy input However, many reactions take place spontaneously even though enthalpy change may not necessarily favour this taking place For example, diffusion of a gas into a vacuum  This key parameter is entropy (S) – related to disorder and probability 2nd law – the entropy of an isolated system will either increase or stay the same but may not decrease Informally – disorder tends to increase. If a reaction will result in greater disorder then it is more likely to happen Packs of cards, bedrooms, chimneys falling down For example, protein unfolding may be endothermic (bonds being The more disorder, the more entropy broken) but may occur without (S increases - positive) further heating due to entropy  Two (equivalent) ways of looking at this – probability and molecular motion Probability – if pack of cards dropped it can form an infinite number of random piles but only a very limited number of ordered ones (cf tidying bedroom) Therefore in the course of a reaction the more random/disordered event is more likely to occur  Molecular motions - entropy is also associated with molecular motions (rotational, vibrational) that do not perform work The greater the range of these possible motions (degrees of freedom), the greater the entropy Reactions that will result in a decrease in these motions (i.e. make them more ordered) do not tend to be favoured These motions are (almost) always present and increase with increased temperature They also decrease with decreased temperature Can we come to a point when they stop altogether? See a bit later……(3 rd law)  THE CONCEPT OF HEAT CAPACITY A related concept to entropy – heat capacity This is the amount of heat to be supplied to an Material Specific object to produce a unit change in its temperature heat The SI unit of heat capacity is joule per kelvin (J/K) – capacity for ‘specific’ divide by mass at RT (J/kg. oK) This is hugely important in pharmaceutical Water 4181 engineering, but also reflects behaviour at a molecular level Copper 390 Wood 1200 Heat capacity reflects the ability to store heat energy Pyrex glass 780 Materials with higher range of molecular mobilities (degrees of freedom) can store more energy So materials with high heat capacity have higher entropy  Returning to the idea of lower temperature leads to lower entropy – will this carry on forever? No – you have to get to a state where everything stops and is perfectly ordered The 3rd law of thermodynamics – at absolute zero the entropy of a perfectly crystalline substance is zero This is -273.15oC at which all molecular motion stops The Kelvin scale is always used for thermodynamics as it is a meaningful reference point that is not system dependent  SO WILL A REACTION TAKE PLACE Wrong question – pretty much any reaction can be MADE to occur if you put enough energy in OR NOT? Right question – will a reaction take place SPONTANEOUSLY? The answer will lie in the balance between the enthalpy and the entropy Free energy (G) is the arbiter between the two The Gibbs equation G = H - TS where G is the change in free energy  Free energy is the energy availably to perform work If it is negative, then the system can perform work on the surroundings and the reaction will be spontaneous If it is positive, then the system is not able to perform work on its surroundings and the reaction will not be spontaneous Free energy is like money – you have to spend it to do the stuff you want to do It is an incredibly important concept – you will meet it with equilibrium, drug binding, drug discovery, micellization and many other processes So a spontaneous reaction is favoured by a –ve H (heat given out to surroundings) and a +ve S (system becoming more disordered) But key issue is the balance between the two – spontaneous reactions could be endothermic if entropy sufficiently positive Systems will tend to go to state of lowest free energy (bit like a bank account being emptied UNLESS you earn money, but that isn’t spontaneous…,,,,)  THERMODYNAMICS IN THE BIOSCIENCES Thermodynamics is a vital component of pharmacy, pharmacology, biochemistry, chemistry, analytical chemistry, physics, engineering and many other topics Concept of being able to understand whether something will occur or not and with what energy change underpins understanding of all reactions For pharmacy and pharmacology, thermodynamics helps us to understand how drugs behave physically, chemically and biologically  THE DRUG DISCOVERY PROCESS Solubility, partitioning and melting point are amongst the first parameters measured for a new drug – all can be interpreted in terms of thermodynamic concepts Solubility – the maximum equilibrium concentration of a drug in a given solvent (indicative of behaviour in the body) Melting point – the transition from the crystalline to the liquid state (indicative of bond strength) Partitioning – the distribution of a drug between oil and aqueous phases (indicative of permeation across biological membranes) Drug receptor interactions Drugs act via specific interactions with receptors Understanding the nature of that binding and how it may be manipulated is at the heart of pharmacology Thermodynamics provides insights into bond strengths, free energy of interactions, molecular modelling and longevity of drug-receptor interactions  THANK YOU FOR YOUR ATTENTION See you in the workshops where we will reinforce your understanding of these ideas use these concepts to understand everyday events Use these concepts to understand pharmaceutical/pharmacological principles Fundamentals of Pharmacy / Pharmacology: The Science of Medicines SL12102 / SL12011 Lecture 7 – Physicochemical Properties of Small Drugs Dr Paul De Bank [email protected] Department of Life Sciences  Learning objectives & overview After this lecture you should understand the concepts of: Drug release and dissolution. How dissolution can be described by the Noyes-Whitney equation. Drugs absorption pathways. Passive diffusion of drugs and Fick’s First Law. Diffusivity and the Stokes-Einstein equation. The application of Fick’s First Law to drug diffusion across membranes. The importance of lipophilicity. And how: How the physicochemical properties of small drugs affect their dissolution, diffusion and absorption.  Drug release from oral dosage forms For a drug to have a biological effect, it must be released (liberated) from its dosage form at the site of administration and undergo dissolution – the body can’t absorb solids. Liberation can significantly affect the drug’s bioavailability (i.e. the quantity of drug which reaches its site of action and the rate at which it gets there), and is influenced by: The dosage form, including excipients and method of manufacture. The physiology of the site of administration. Liberation usually occurs in a stepwise manner. Number of steps depends on the dosage form, but the slowest step controls the overall release rate. We’ll focus on small drug release from oral dosage forms. Tablets – coated or uncoated Capsules Suspensions or solutions  Drug release from oral dosage forms Dissolution Disintegration/ of coating Disintegration disaggregation Coated Simple Coarse Fine granules/ tablet tablet granules primary particles Drug Dissolution Drug dissolution Diffusion within tablet Drug suspension H 2O (aqueous) Tablet with insoluble, permeable coating Drug in solution  Drug dissolution Bulk dissolution medium Drug particle Drug dissolution, from crystal to liquid, involves two steps: 1. Solvation of drug molecules at the crystal surface generating a stagnant layer of drug solution (the Diffusion diffusion layer). layer 2. Drug molecules diffuse across the diffusion layer into the bulk dissolution medium (e.g. contents of the GI tract). Rate of dissolution is dependent on the slowest of these two steps. Dissolution at a constant temperature and pressure can be described by the Noyes-Whitney equation.  Drug dissolution – the Noyes-Whitney equation 𝑑𝑚 𝐷 𝐴 (𝐶𝑠 − 𝐶) = Generally, C 1 layer = stratified epithelium Functions: protection, absorption, gas exchange Specializations: keratinized layer, villi, cilia, most secrete mucus from goblet cells Drug absorption is greatly influenced by the type of epithelium and the local physiology Squamous epithelium Stratified squamous Columnar epithelium Cuboidal epithelium e.g. alveoli epithelium e.g. ductal lining e.g. nasal cavity, e.g. cornea, GI tract skin, mouth  Nasal Drug Delivery Topical delivery for treatment of allergy, congestion and infection Alternative to the oral route for systemic delivery: Avoidance of first-pass metabolism Drugs sensitive to intestinal metabolism Acid-sensitive drugs (e.g. peptides) Polar compounds with poor oral absorption Small, lipophilic drugs can diffuse through the nasal epithelium and enter the systemic circulation with bioavailability of up to 100% Passive transcellular diffusion depending on lipophilicity, ionization and size according to Fick’s first law Ease of administration (drops and sprays), particularly in the young and elderly Nasal physiology has a major impact on drug absorption  Nasal Cavity: Structure & Function Superior Frontal sinus turbinate Sphenoid sinus Volume ~20 ml Surface area ~150 cm2 Middle Internal naris turbinate High density of sub-mucosal blood Inferior supply (40 mL/min/100 g) turbinate Nasopharynx High air turbulence External naris Main function is air conditioning: Temperature (-20 to 55 °C  within 10 °C of body temp.) Humidity ( 97-98 %) Filtration Minor function is smell (olfaction) Large inter-patient variability in the internal nasal anatomy  Nasal Epithelium & Drug Deposition Pseudo-stratified columnar epithelium Initial hurdle in nasal drug delivery is deposition in the nasal cavity Large surface area due to microvilli Liquid drops spread throughout the cavity Protective mucus layer and cilia for clearance Aerosols or powders are distributed according to Mucus acts as a physical and chemical barrier to particle size drug diffusion; 1.5 to 2 litres per day!  Nose-to-Brain Drug Delivery Olfactory bulb Olfactory region Bone Bowman’s gland Olfactory nerve cells Olfactory epithelium Nerve endings Olfactory epithelium is about ~ 4 cm2 (3-5 % of total area) Effectively an area where the blood brain barrier is not present Drugs can enter the brain directly via paracellular diffusion or axonal transport through olfactory nerves Offers a promising future route for drug delivery to the CNS, including biologicals Delivery systems need to be optimized to avoid clearance  Ocular Drug Delivery Drugs administered solely for treatment of local conditions, not a viable route for systemic delivery Periocular diseases e.g.: Blepharitis (S. aureus infection of the eye lids) Conjunctivitis (infection or allergy) Keratitis (corneal clouding) Topical Delivery Possible Intraocular Delivery Required Trachoma (Chlamydia trachomatis) Dry eye Intraocular diseases e.g.: Glaucoma Age-related macular degeneration Diabetic retinopathy Infections Conjunctiva Adapted from BioRender “Anatomy of the Human Eye” template  Corneal Structure & Absorption Routes 50-100 µm thick, hydrophobic, contributes 90 % of the barrier to hydrophilic drugs and 10 % to lipophilic 600-1100 µm thick, hydrophilic connective ~2.4 cm2 (both eyes) tissue, main barrier to lipophilic drugs Corneal route: the major route for ocular drug absorption, either by transcellular (lipophilic) or paracellular (hydrophilic) diffusion Conjunctival route: drug passes through the conjunctiva and sclera, however most drug will be lost into the local capillary bed and enter the systemic circulation Adapted from Masterton, S. & Ahearne (2018) M. Exp Eye Res,177, 122-129; doi: 10.1016/j.exer.2018.08.001  Fate of Drugs Delivered to the Front of the Eye Drug Drug in Corneal or conjunctival Dose Tear Fluid absorption (10,000 litres/day Large particle burden Area of deposition related to particle size Drugs must avoid the natural defences 3 Mechanisms: inertial impaction, sedimentation or Brownian diffusion >10 µm: upper airways 7-10 µm: upper tracheo-bronchial region 2-7 µm: lower tracheo-bronchial region 0.5-2 µm: alveolar Large particles are cleared faster  The Pulmonary Epithelia & Absorption 8 µm Transcellular pathway: passive diffusion of small, lipophilic drugs through the epithelium, down a 58 µm concentration gradient. No firm evidence of significant transporters Bronchus 3-5 mm for drug uptake. Ciliated Goblet Basal Brush cell cell cell cell Paracellular pathway: passive diffusion of small, hydrophilic drugs 3 µm down a concentration gradient 10 µm Terminal bronchiole 0.5-1 mm between cells of the epithelium. Slower than transcellular. Tight 70 nm fluid junctions looser than other mucosal 0.1-0.2 µm Alveolus ~0.2 mm barriers. Advanced Drug Delivery Reviews, 19(1), 3-36 (1996); doi: 10.1016/0169-409X(95)00113-L  Factors Affecting Pulmonary Drug Absorption Mucus: Viscous layer Drug solubility important for rapid absorption 0.5-5 µm Drug size affects diffusion Interactions Varying thickness Mucociliary escalator Coughing Surface area: Large (~ 140 m2), rapid administration possible Blood supply: Large, avoids hepatic first-pass  Pulmonary Insulin Delivery Aradigm AERx System https://www.wired.com/2003/07/slideshow-breathing-new-life-into-medicine/ https://www.ondrugdelivery.com/wp- content/uploads/2018/11/Apr2006.pdf  Transdermal Drug Administration The skin is a barrier - 50 M water on the inside Traditionally, drugs applied as creams to treat local conditions Great deal of focus on transdermal drug delivery for systemic effects Accessible and plenty of it (1-2 m2) Avoids first-pass hepatic/GI metabolism Patches can deliver drugs in a controlled manner (reservoir) vs creams Good compliance, easily removed Health and Disease – Week 26 Anatomy of the Skin ~2 m2 1/3 of body’s blood supply Prevents water & nutrient loss ~1.1 mm thick 15-20 % of body mass BioRender “Anatomy of the Skin” template  The Stratum Corneum Corneocytes Intercellular lipids “Bricks and mortar” structure, ~10-30 µm thick Dead, flattened cells Inside of membrane is protein-coated Lipid rafts between the cells (liquid crystal): Ceramides, cholesterol, fatty acids Major barrier to water loss Adv Drug Deliv Rev (2021), 175, 113802 Pathways of Percutaneous Drug Penetration Transcellular Paracellular Follicular Eccrine Shunt pathways  Factors Affecting Transdermal Drug Absorption Hydration of SC – the most significant factor. Patches are occlusive so water builds up. Hydration of the SC generally increases permeability pH – 4.0 to 5.5 Age – premature babies and the elderly Injury and disease – generally reduce barrier action, even in psoriasis Site – thickness varies in different areas “Cutaneous first-pass” – oxidation, reduction, hydrolysis and conjugation (glucoronide, sulphate, methylation, glutathione)  Transdermal Delivery for Systemic Effects For potent drugs Sustained concentrations Control of delivery Reduced dosing frequency Fewer side-effects are possible Pastore, M et al. Br J Pharmacol (2015) 172(9), 2179-209; doi: 10.1111/bph.13059 Can be stopped at any time OXYTROL Transdermal Patch Oxybutynin, MW = 357  Increasing Skin Permeability - Iontophoresis LidoSiteTM Lidocaine hydrochloride, 100 mg Adrenaline bitartrate, 1.05 mg Anesthetized Area: 5 cm2 circle Onset time: 10 minutes Depth of Analgesia: 6.4mm PD after 10 mins treatment Duration of Analgesia: approximately 60 minutes  Increasing Skin Permeability - Microneedles https://www.the-scientist.com/news- opinion/opinion-an-alternative-to- Pain free delivery of drugs, including biologicals, and vaccines Wide range of types and materials injection-69165 Temporarily increase skin permeability Kim, Y-C et al Adv Drug Deliv Rev (2012), 64, 1547-1568; doi: 10.1016/j.addr.2012.04.005  Summary There are a many routes of drug delivery, with absorption greatly affected by physiology With the exception of parenteral delivery, drugs need to cross an epithelium; local physiology can greatly affect drug absorption Defence mechanisms, such as ciliated cells, and mucus can reduce drug uptake Systemic delivery of drugs is possible via a number of routes; good for potent drugs with poor oral bioavailability Drug absorption can be improved by advances in delivery systems and drug formulation