L3 - Drug delivery mechanism .pdf

DRUG DELIVERY MECHANISMS Pierce Kavanagh [email protected] Lab 2.63, Trinity Centre, Saint James’s Hospital 1  Learning objectives Explore the molecular basis of drug delivery – Log P Look at the effects th...

DRUG DELIVERY MECHANISMS Pierce Kavanagh [email protected] Lab 2.63, Trinity Centre, Saint James’s Hospital 1  Learning objectives Explore the molecular basis of drug delivery – Log P Look at the effects that formulation has on drug delivery – oral dosage as an example Explore some novel drug delivery technologies 2  Factors influencing drug delivery Molecular structure – medicinal chemistry Product formulation – pharmaceutics Route of administration - pharmacokinetics 3 At a molecular level Drug absorption and Log P Categorizing drugs – acids and bases pH and Log P 4  Drug absorption - oral Drug absorption is controlled by the epithelial cell layer. Intestinal epithelium is the major barrier Intestine for orally administered drugs. Drug The transcellular pathway is an important route for drug absorption. Drug molecules partition into cell membranes (lipid bilayer) Apical at the apical side (mucosa) to enter the membrane cytoplasmic domain. The drug molecules partition into another cell membrane at the basolateral side and onwards to systemic circulation. Transport is typically passive (energy independent) and follows a concentration Epithelial gradient (high to low) - simple diffusion cell though the phospholipid bilayer. Basolateral membrane This process is suited to small lipophilic compounds as molecules must penetrate 5 the phospholipid bilayer.  Lipophilic and hydrophilic Lipophilic (hydrophobic) substances that dissolve well in lipids/non-polar solvents. Hydrophilic substances that dissolve well in water/polar solvents. Like dissolves like - lipophilic molecules tend to penetrate a cell membrane due to their solubility in the lipid bilayer Lipophilic molecules tend to penetrate a cell Very lipophilic compounds membrane may (diffuse be retained through the lipidin the cell membrane bilayer) Hydrophilic Lipophilic Very lipophilic ≀≀≀ Lipid bilayer ≀≀≀≀≀ ≀≀≀≀ ≀ ≀≀≀ 6 How do we measure a drug’s lipophilicity? We can simulate the absorption process by shaking the drug with an immiscible mixture of a lipophilic solvent (octanol, ‘the lipid bilayer’) and a hydrophilic solvent (water, ‘extracellular/cytoplasmic fluid’). Measure the concentrations of the drug in each layer. The distribution of the drug between the two layers can then be calculated. This distribution is an indicator of the drug’s lipophilicity e.g. if all of the drug is in the octanol phase then it is very lipophilic. 7  Partition coefficient and Log P We express the distribution as follows [Drug]octanol Partition Coefficient, P = [ ] = concentration [Drug]water This is expressed as a log value [Drug]octanol Log P= Log10 (Partition Coefficient) = Log10 [Drug]water The higher the Log P value, the more lipophilic the drug i.e. more of the drug dissolves in the octanol phase (oil). The lower the Log P value, the more hydrophilic the drug i.e. more of the drug dissolves in the water phase. 8  Calculating Log P [Drug]octanol = 0 mg/mL [Drug]octanol = 0.8 mg/mL octanol octanol Equal volumes Before shaking After shaking water water [Drug]water = 1.0 mg/mL [Drug]water = 0.2 mg/mL P = [Drug]octanol = 0.8 mg/mL = 4 [Drug]water 0.2 mg/mL Log P = Log10 (4) = 0.602 9  Log P values – drug absorption Optimal Log P values for gastrointestinal absorption by passive diffusion (oral drugs) range from 0 to 3 Very high Log P - bioaccumulation e.g. polychlorinated biphenyls (PCBs), Log P > 5 It should be noted Log P values reported for a drug in the literature may be variable. This can be due to experimental variation Log P values can be calculated mathematically. Different methods give different values. Lipinski's rules - rules of thumb that indicate the likelihood of a compound being pharmacologically active No more than 5 hydrogen bond donors No more than 10 hydrogen bond acceptors Molecular mass less than 500 Da 10 Partition coefficient not greater than 5 An example of how Log P is altered by molecular modification - anticholinergics a permantant N N O O O O OH OH 3-Quinuclidinyl benzilate Clidinium (bromide) Hallucinogen/incapacitating agent Therapeutic agent – antispasmodic – - centrally acting abdominal cramps, irritable bowel syndrome Log P -0.65 ALOGPS Log P -1.1 ChemAxon 11  Categorizing drugs Most drugs ionise to some extent (weak acids or bases) and the pH of the medium will have a profound effect on Log P (the pH dependent version is known as Log D) and thus absorption. Ionized compounds are less lipophilic. We can categorize compounds as acidic, basic (and neutral). Basic functional groups: amines (–NH2, NHR, NR2). Acidic functional groups: carboxylic acids (-CO2H), sulphonic acids (-SO3H), phenols (Ar-OH). Ibuprofen Lignocaine - H + Carboxylic acid - acidic Amine - basic 12  pH and Log P (Log D for ionizable compounds) Let’s look at her an acid (HA). It ionizes to some extent in water. much mon is measures car HA + H2O H3O+ + A- [H3O+][A-] # Ka (dissociation constant) = - [HA] To make it more manageable, the dissociation constant is normally expressed as a log value (pKa) pKa = - log10(Ka) = - log10 [A ][H3O ] - + [HA] pKa is a measure of the strength of an acid (ionizability) If the pH is 1 unit more or less than the pKa value, then the drug is 91 % ionized Ibuprofen or 91 % unionized respectively. OH O O O Log D In general, an ionized drug has a lower Log D value (less lipophilic) than its unionized form and thus absorption will pH 13 be affected by pH The pKa for a basic drug (B) is expressed for deprotonation of its conjugate acid. & BH+ + H2O H 3 O+ + B Ank, H + Lignocaine Increasingly lipophilic 100 90 80 70 60 % ionized 50 40 30 20 10 0 0 2 4 6 8 10 12 14 BH+ pH Excel B MarvinSketch (https://chemaxon.com/marvin) 14 Routes of administration and formulations Routes of administration Constituents of a formulation – oral dosage as an example Bioequivalence Oral dosage – factors affecting absorption 15  Routes of administration & Ank A Comprehensive Map of FDA-Approved Pharmaceutical Products. Pharmaceutics. 2018 Dec 6;10(4). Hao Zhong, Ging Chan, Yuanjia Hu, Hao Hu , Defang Ouyang Oral delivery is a very common route of administration (RoA) Self-administered, patient centred, cheap, absorption along whole GI tract, controlled release of drugs Affected by product formulation 16  Formulation - pharmaceutics An oral pharmaceutical product such as a tablet contains a number of ingredients, each of which may affect drug absorption Active Pharmaceutical Ingredient (API) – The morphology of the API (its physical state e.g., crystalline or amorphous) and particle size may affect bioavailability (i.e., how much is absorbed). Excipients – Fillers, bulking agents and ingredients added to facilitate the manufacturing process e.g., tablet release agents/lubricants such as magnesium stearate. The dosages of many drugs are quite small (milligrams) and it would be impossible to 17 administer them without a carrier.  Bioequivalence A bioequivalence study compares the bioavailability of a drug (i.e. how much is absorbed) for two or more products. The absorption of a drug from different formulations, containing the same amount of active ingredient, may be different due to the drug release kinetics. Administration studies are performed individually on each of the comparable products. Plasma/serum drug concentrations following administration are used to calculate the pharmacokinetic parameters which are then compared. Crossover study Enrollment R Product A Wash-out Product B R Randomization (5 half lives) 18 and cross-over  Oral - factors affecting absorption Drug solubility – rate and extent of dissolution of compound in GI tract – type of salt e.g., hydrochloride, sulphate etc. for basic drugs. API Log P – lipophilicity. Very lipophilic compounds may not dissolve in biofluids. Particle shape and size/surface area of drug (the smaller the particle size the greater the surface area and thus more exposure to the surrounding medium) The degree of solvation/hydration (e.g. water molecules associated with the drug in a hydrate form will affect its intermolecular interactions) In vivo drug (chemical) stability Gastrointestinal pH (pKa of drug) 19  Controlling the release of a drug Excipients may interact with the drug molecule e.g. through ionic, hydrogen bonding or other intermolecular forces such as van der Waals. These interactions will control the release of an active constituent. For example, cyclodextrin is a cyclic oligosaccharide which can from inclusion (host- guest) complexes with drugs. Inclusion Cyclodextrin complex Self-assembly Drug molecule This can be tethered to a polymer backbone 20 Some novel technologies Passive targeting – a pro-drug Active targeting Deuterium analogs (bioisosterism) 21  Passive targeting Exploit differences between target tissue and other tissues to deliver drugs selectively. For example, in tumours, rapid cell [O2] proliferation, altered metabolism, and abnormal blood vessels result in reduced transport of oxygen. The tumour cells become hypoxic. The oxygen difference between the tumour and surrounding normal tissues can be exploited to target drug delivery. A drug may be activated at low oxygen levels e.g., by chemical reduction. This can then, for example, act as a DNA alkylating agent (cytotoxic). pH activation can also be used. 22  Passive targeting – an example - Cl Anka Adenine N NH2 N N N N NH2 N Cl N N N-3 R R R R N N N N O O O O hypoxia NO2 NH2 NH NH2 A B C Pro-drug Active drug DNA alkylation Chem Soc Rev. 2019 Feb 4;48(3):771-813. Hypoxia-targeted Drug Delivery. Amit - cytotoxic Sharma , Jonathan F Arambula, Seyoung Koo, Rajesh Kumar, Hardev Singh, Jonathan L Sessler, Jong Seung Kim, doi: 10.1039/c8cs00304a. A pro-drug is a compound that becomes pharmacologically active through metabolism. Under hypoxic conditions, the nitro group (NO2) in the pro-drug (A) is reduced to an amino group (NH2). The resulting molecule (B) will then form an active DNA alkylating agent (C). This attacks the N-3 position of adenine in DNA. 23  Active targeting The drug is conjugated to an antibody that is recognized specifically in the tissue of interest. For example, an antibody directed against a tumour-associated antigen could be used to target an anticancer drug to malignant tissues. A polymer may be used to link the drug to the antibody. The drug may be attached via an acid-labile bond, and selectively released in the acidic environment of the tumour. Produce antibody against H+ tissue specific antigen Y H+ +H+ H Y Conjugate drug polymer Y complex to antibody 24  Deuterium analogs – an example Ivacaftor is used in the treatment of cystic fibrosis. It is metabolized by oxidation of the tert-butyl group. Replace hydrogen atoms with deuterium atoms (a non-radioactive isotope of hydrogen) at the site of metabolism. Bioisosterism Jan OH (bioisosteric replacement) hydrogen OH CH3 CH3 CH3 CH3 O O CH3 O O CExchange an atom or of a H2 OH N N group of atoms with an alternative, broadly similar, H H N atom or group of atoms. N H H Create a new molecule OH D C CD3 3 deuterium OH D C CD3 3 OH with similar biological O O C O O CD3 D2 N H N H properties to the parent N H N H compound. ivacaftor hydroxy metabolite A carbon-deuterium bond is stronger than a carbon-hydrogen bond slower rate of metabolism – improved pharmacokinetics lower doses improved efficacy, safety, tolerability 25 alternative metabolic pathways may reduce toxicity Chemistry Capital https://www.youtube.com/watch?v=dSyan8L2IJI 26