L13 Drug Administration - Faculty of Life Sciences & Medicine PDF

L13 Drug administration, getting the drug to its site of action Faculty of Life Sciences & Medicine Dr Maya Thanou Drug administration; getting the drug to its site of action 5BBM0216 Pharmacy...

L13 Drug administration, getting the drug to its site of action Faculty of Life Sciences & Medicine Dr Maya Thanou Drug administration; getting the drug to its site of action 5BBM0216 Pharmacy Drug administration part 1 How to take molecules and make them into a therapy. Drug Delivery lectures handbooks Aulton's Pharmaceutics: The Design and Manufacture of Medicines, 5e by Michael E. Aulton BPharm PhD FAAPS FSP FRPharmS and Kevin M.G. Taylor BPharm PhD FRPharmS | 7 Jul 2017 Drug Delivery and Targeting: Fundamentals, Applications and Future Directions, Second Edition Paperback – 16 Aug 2016 by Anya M Hillery (Editor), Kinam Park (Editor)  Drug or Medicine Drug= Active Pharmaceutical Ingredient (API) Most likely small molecular weight (ca 300-600) organic species (synthesised by medicinal chemist) or possibly peptide or oligonucleotide (prepared by biotechnological means) Medicine = API plus excipients Excipients are materials should be inert and safe – sole function is to act as a carrier or platform for the API API = active pharmaceutical ingredient API = molecule responsible for the therapy. Generally small molecules 300-600Da/ Peptide = part of a protein Excipients – everything except therapeutic action. Drug Delivery Background – What is a therapeutic molecule/DRUG?? 2  Drug Delivery – ‘The method and route used to provide medication’ – ‘The means by which a safe and efficacious medicament is delivered in order to elicit a pre- defined clinical response’ Drug Delivery INTRODUCTION TO DRUG DELIVERY – Local vs systemic – How to get from A to B?? A B DRUG DELIVERY EFFECT Systemic administration = IV Local = topical 3  Drug Delivery Routes of delivery For all routes of delivery https://www.fda.gov/drugs/data-standards- manual-monographs/route-administration Different formulations Route of delivery determines which excipients you choose. Drug Delivery – Patient needs Elderly Toddlers Babies Chronic vs acute Severity Chronopharmacology Chronopharmacology – giving drug at right time for disease. 4  Drug Delivery – Why is drug delivery important? DRUG Therapeutic Effect Side-effects Balance therapeutic effect and adverse effects. Drug Delivery – Drug has to enter the body and distribute at the right tissue at the right time – Does swallowing the active pharmaceutical ingredient do this?? Beclometasone dipropionate E.g. beclomethasone needs to reach the nucleus, so swallowing the drug isn’t going to help with that. 5  Drug Delivery SOME COMMON PROBLEMS – ROUTE?? A drug that requires to be distributed to its active site via the systemic circulation is not orally absorbed E.g. Beclomethasone Dipropionate – Inhaler – Cream Oral administration has poor bioavailability. Drug Delivery SOME COMMON PROBLEMS – ROUTE Patient compliance is low e.g. diabetes due to non patient friendly administration Reformulate into another drug delivery device Improves therapy Reduce burden on the patient to improve compliance. 6  Drug Delivery SOME COMMON PROBLEMS – STABILITY Active Pharmaceutical Ingredient may be physically or chemically unstable Excipient stabilisation Enhances shelf-life stability Proteins degrade easily. Freeze drying is a popular method that makes the product soluble in water afterwards. Drug Delivery SOME COMMON PROBLEMS – DOSING Drug may have a short half-life Controlled or extended release may be required Reduce dosing frequency Enhances half life Controlled released has drug released at small amounts over a period of time. 7  Drug Delivery The path to drug delivery Understand the chemistry of the molecule Appreciate the pharmacology of the disease Consider the patient and the target tissue Design, manufacture and test a drug delivery system to achieve your aim i.e. provide clinical benefit for a patient Why To transfer the therapeutic at the right site To minimise the dose To minimise unwanted effects by exposure of the therapeutic to healthy tissues Package drugs in drug delivery systems. 8  Selective Drug Delivery Benefits 1) Optimise interaction of drug with its site of action at the right rate and frequency. 2) Reduce the side effects of the drug used by restricting distribution to the target sites. Paul Ehrlich Magic bullet The "magic bullet" concept comes from the fact that 19th century German chemists selectively stained tissues for histology, and in particular, selectively staining bacteria. Ehrlich was an excellent histological chemist, and invented the precursor technique to Gram staining bacteria. Ehrlich suggested that if a compound could be made that selectively targeted a disease-causing organism, then a toxin for that organism could be delivered along with the agent of selectivity. Hence, a "magic bullet" would be 1854-1915 created that killed only the organism targeted. 9  PK considerations related to drug targeting Drugs with high total clearance are good candidates Carrier –mediated transport is suitable for response sites with a relatively small blood flow The higher the rate for elimination of free drug from either central or response compartments the greater the need for targeted drug delivery To maximise targeting effect, the release of the drug from the carrier should be restricted to the response compartment Requirements Understand the biology involved in the disease processes Utilise these processes to obtain selective drug delivery, taking into the account the (patho)physiology, biochemistry and chronicity of the disease How does the disease develop e.g. how does it spread, cancer metastasis. 10  Improved Accessibility required for: Diseases of the CNS Diseases of the Immune system Cancerous states Some cardiovascular diseases Arthritic Disease Retention If drug delivered intracellularly but has high cellular permeability it can diffuse rapidly away from the site of action D D Drug must be able to get into the cell and STAY there. 11  Drug delivery and targeting systems DDTS component Purpose The “Active” Therapeutic effect The carrier system (soluble or To effect a favorable distribution of particle) the drug to protect the drug from metabolism to protect the drug from early clearance A homing mechanism or a To specifically target the drug to the homing device target cells or target tissue (passive and/or active targeting) If carrier is dissolving, then the solution will be clear. If the carrier is not dissolving, then there will be a suspension. Suspension of nanoparticles can be seen with laser. Homing system anchors drug to targeting tissue to release it. DDTS Soluble macromolecular carriers Particle carriers Antibodies or ligands with Liposomes polymers: Micelles Poly(hydroxypropylmethacrylate) Nanoparticles Poly(lysine) Microspheres Polyaspartic acid Proteins Poly (styrene co-maleic acid Solid Lipid Nanoparticles anhydride) Dendrimers Polyethylene glycol (PEG) DDTS = drug delivery targeting systems All are considered safe to be used in humans. 12  Macromolecuar carriers can take any kind of conformation in solution or in the blood. Particles are always in organized structures until they meet the target site. Factors affecting DDTS Endothelial lining if the blood circulation Anatomical location of the target (accessibility, blood supply, barriers Macrophages (MPS) mononuclear phagocytic system or Reticuloendothelial system (RES) Drugs may be attacked by macrophages. TYPES OF BLOOD CAPILLARIES Continuous capillary as found in general circulation. Subendothelial basement membrane is also continuous Fenestrated capillary (exocrine glands and pancreas). Fenestrae are sealed by membranous diaphragm. Subendothelial basement membrane is continuous Sinusoid capillary (discontinuous) as found in liver spleen, bone marrow. The endothelium containes various gaps of varying size. The subendothelial basement membrane is absent (liver) or fragmented interrupted structure (spleen, bone marrow) Bits of broken endothelium in exocrine glands. 13  Mononuclear Phagocytic system Fixed cells : macrophages in the liver (Kuppfer cells), spleen lung bone marrow and lymph nodes Mobile cells : blood monocytes and tissue macrophages MPS functions include 1. The removal and destruction of bacteria 2. The removal and destruction of denaturated proteins 3. Antigen processing and presentation 4. Storage of inert colloids 5. Assisting in cellular toxicity MPS particle clearance Particle size : 0.1-7 µm are cleared by the Kuppfer cells in the liver Particle charge : for liposomes negative and positive charged vesicles are rapidly cleared. Neutral vesicles remain longer Surface hydrophobicity: Hydrophobic particles are covered by blood proteins opsonins which help phagocytosis Therapeutic should avoid being in microsphere because otherwise they will be cleared by macrophages. Charged materials more likely to be cleared. 14  Opsonisation Opsonins stuck on surface of therapeutic particle, macrophages recuited, therapeutic drug removed. End result: phagolysosome destruction Key priority = overcome this destruction 15  Enhanced Permeation and Retention effect Normal blood vessels: tight contacts between pericytes (P) and endothelial cells (EC) P/EC ratio ~ 1/1 Tumor blood vessels: loose contacts between pericytes (P) and endothelial cells (EC) P/EC ratio 100 nm distearoylphosphatidylcholine : cholesterol: Daunorubicin 18 : 7 : 1 weight ratio DaunoXome® t 1/2 = 4.41 ± 2.33 h Daunorubicin t 1/2 = 0.77 ± 0.3 h Only formulation approved as a first line therapy of HIV-associated Kaposi’s sarcoma 25 mL Vials contain: 50 mg Clinical dose = 40mg/m2 by infusion over 60 Daunorubicin; 701 mg DSPC; 171mg min every 2 weeks cholesterol; 2.125mg sucrose; 94mg Diluted 1:1 with dextrose before use glycerine; 7 mg calcium chloride dihydrate in aqueous medium at pH 4.9-6.0 (2mg/mL Dnm) daunorubicin citrate 25  Nanoparticle structures overview 26  Nanoparticles Therapeutic Benefits Solubility – Carrier for hydrophobic entities Multifunctional capability Active and passive targeting – Ligands; size exclusion Reduced toxicity ↑ Sol ubi li ty↑ Sta bil ity↑ Spe cif ici ty= ↑ Tox ici ty↑ Ef fi cac y Schematic representation of an “extracellularly activated nanocarrier.” The nanocarrier maintains the stealth function during circulation (passive targeting). Upon arrival at the tumor sites, the nanocarriers transform to release the drug or interact with cells in a target-specific manner (active targeting). Such transformation can be triggered by the unique tumoral extracellular environment such as slightly acidic pH or a high level of proteinases Extracellularly Activated Nanocarriers: A New Paradigm of Tumor Targeted Drug Delivery Mol. Pharmaceutics, 2009, 6 (4), pp 1041–1051 27  Nanotheranostics and Image-Guided Drug Delivery: Current Concepts and Future Directions Lammers et al. Mol. Pharmaceutics, 2010, 7 (6), pp 1899–1912 Release can be activated externally. Nanodevices as a Link Between Detection, Diagnosis, and Treatment Traditional NanoBiotechnology Cancer Treatment Cancer Treatment Cancer cell Cancer cell Nanodevice Drug Imaging Reporting Detection Targeting How polymer drug conjugates work: Drug and polymer with linker that is specific to degradation enzymes that are only found in tumour cells. 28