Injectables 1 PDF - PR5217

PR5217: Injectables 1 Associate Professor Matthias G. Wacker, PhD Department of Pharmacy | Faculty of Science [email protected] © Copyright National University of Singapore. All Rights Reserved. © Copyright National University of Singapore. All Righ...

PR5217: Injectables 1 Associate Professor Matthias G. Wacker, PhD Department of Pharmacy | Faculty of Science [email protected] © Copyright National University of Singapore. All Rights Reserved. © Copyright National University of Singapore. All Rights Reserved.  Connect to Polls Everywhere www.pollev.com/mgwacker © Copyright National University of Singapore. All Rights Reserved.  Learning Objectives How do the different administration sites of parenterals influence the performance of the drug product? What are the regulatory requirements different parenteral products must fulfill? Which excipients are used to formulate different injectables and what are their roles? How is sterility achieved in a drug product (which processes are used to sterilize liquids and solids)? © Copyright National University of Singapore. All Rights Reserved.  Written Questions in PR5217 © Copyright National University of Singapore. All Rights Reserved.  Introduction © Copyright National University of Singapore. All Rights Reserved.  Parenteral Drug Delivery Invasive treatment that usually (but not always) requires a healthcare professional. Very often used in emergency medicine to rapidly deliver the drug with an immediate onset of action. Sometimes used to formulate depot formulations of degradable and poorly permeable compounds. Very high cost of production due to the sterility requirements (clean room or closed process for all operations directly involving the product). © Copyright National University of Singapore. All Rights Reserved.  Parenteral preparations Parenteral preparations are sterile preparations intended for administration by injection, infusion or implantation into the human or animal body. Injections Infusions Concentrates Powders Implants © Copyright National University of Singapore. All Rights Reserved.  Injection Sites Intravenous administration (IV) comes Intramuscular subcutaneous intravenous intradermal with strict requirements as compared to subcutaneous (SC), or intramuscular (IM) injection. SC/IM have much higher tolerance with regards to: Particles oily liquids hypotonic or hypertonic solutions pH variations © Copyright National University of Singapore. All Rights Reserved.  Volume of Distribution Volume of distribution is a pharmacokinetic parameter indicating “presence of the drug in the blood plasma.” IV injections are commonly used to determine the volume of distribution. © Copyright National University of Singapore. All Rights Reserved.  IV Injection Case study: Liposomes © Copyright National University of Singapore. All Rights Reserved.  IV Injection Case study: Liposomes Volume of distribution of conventional doxorubicin – the drug distributes into tissue MyocetTM comprises a large amount of unbound doxorubicin. DoxilTM comprises almost no unbound doxorubicin. © Copyright National University of Singapore. All Rights Reserved. Source: Gerald Batist 2007, Cardiovasc. Toxicol (http://dx.doi.org/10.1007/s12012-007-0014-4)  Influence of Biologics ADMINISTRATION ROUTES INJECTION TYPE Oral Intramuscular Other 3% Topical Other (IM) 4% 1% Subcutaneous 3% 15% (SC) 35% Intravenous Parenteral (IV) 92% 47% © Copyright National University of Singapore. All Rights Reserved. © Copyright National University of Singapore. All Rights Reserved. Source: Li et al. 2021, J Pharm Sci (https://doi.org/10.1016/j.xphs.2021.10.031)  Pharmacokinetic profiles Plasma concentrations provide information on the extent and 30 PLASMA CONCENTRATION [ΜG/ML] rate of absorption. 25 Intravenous injection Cmax and AUC are key 20 parameters to evaluate this 15 Fast absorption effect. 10 5 Slow absorption 0 0 2 4 6 8 10 12 14 TIME [H] © Copyright National University of Singapore. All Rights Reserved.  Dissolution Poorly soluble drug at different particle sizes and resulting dissolution rates. Faster dissolution leads to faster absorption as indicated by Cmax and AUC © Copyright National University of Singapore. All Rights Reserved. Source: Ho et al. 2022, J Control Rel (https://doi.org/10.1016/j.jconrel.2021.12.011)  Subcutaneous Fluid © Copyright National University of Singapore. All Rights Reserved. Source: Torres-Teran et al. 2023, J Pharm Sci (https://doi.org/10.1016/j.ijpharm.2023.122906)  Tissue retention Molecular volume Molecular volume © Copyright National University of Singapore. All Rights Reserved. Source: Zbyszynskiet al. 2019, Nano Conv. (https://doi.org/10.1186/s40580-019-0192-3)  Lymphatic System Particles and molecules >100 nm typically do not enter the lymphatic system. Higher molecular weight molecules cannot diffuse through tissue but may still enter the lymphatic capillaries. Openings in the lymph capillaries are about 15-20 nm wide. © Copyright National University of Singapore. All Rights Reserved. Source: McLennan et al. 2005, Drug Discovery Today Tech (https://doi.org/10.1016/j.ddtec.2005.05.006)  Immune responses Anti-Drug Antibodies Formation of ADAs makes pharmacokinetics less predictable. Best strategy is to avoid ADA during preclinical evaluation of molecules. © Copyright National University of Singapore. All Rights Reserved. Source: Brunn et al. 2016, J Pharmacol. Exp. Ther. (https://doi.org/10.1124/jpet.115.229864)  Immune responses Anti-Drug Antibodies © Copyright National University of Singapore. All Rights Reserved. Source: Brey-French et al. 2021, J Pharm. Sci. (https://doi.org/10.1016/j.xphs.2021.03.027)  Injectables Advantages and Disadvantages Rapid onset of action Invasive treatment. possible. High safety requirements to Barriers to absorption lower avoid physical, chemical, and as compared to peroral route microbiological contaminations. (e.g., proteins, peptides). Long-acting formulations are Long-acting treatment (longer very challenging to develop. than peroral) possible without Sterile formulations are more “missing out a pill”. expensive to manufacture. High knowledge barrier for market competitors. © Copyright National University of Singapore. All Rights Reserved.  Preparations © Copyright National University of Singapore. All Rights Reserved.  Injections Injections are sterile solutions, emulsions or suspensions. They are prepared by dissolving, emulsifying or suspending the active substance(s) and any added excipients in Water for injections. Solutions must be clear and practically free from particles. Emulsions must not show signs of phase separation. Sediment of the suspensions must be easily redispersable. © Copyright National University of Singapore. All Rights Reserved.  Injections Multidose container Single Dose Vial Benzyl alcohol Water for Injections Water for Injections >15 mL 15 mL No Preservative preservative possible possible © Copyright National University of Singapore. All Rights Reserved.  Excipients Tonicity Sodium chloride Buffer salts (e.g., histidine, citrate, phosphate) Small molecules (e.g., dextrose, glucose, mannitol, sorbitol) Acceptable (no pain or irritation) 288 mOsmol (0.9% sodium chloride solution) ~ 225-430 mOsmol Typical range ~ 250-300 mOsmol © Copyright National University of Singapore. All Rights Reserved.  Excipients pH Buffered conditions Phosphate buffer (pKA2 = 7.2) Acetate buffer (pkA = 4.76) Citrate buffer (pKA1 = 4.76; PkA2 = 6.4) Histidine (pKA = 1.8) pH adjustment Sodium hydroxide Hydrochloric acid © Copyright National University of Singapore. All Rights Reserved.  Excipients Stabilization Physical stability Surfactants (e.g., polysorbate, poloxamer) Steric stabilizers (e.g., dextran, albumin) Chemical stability Antioxidants (e.g., ascorbic acid) Microbiological stability Preservatives (e.g., metacresol) © Copyright National University of Singapore. All Rights Reserved.  Insulin solution Zinc chloride Glycerol Metacresol Sodium hydroxide Hydrochloric acid Water for injections © Copyright National University of Singapore. All Rights Reserved.  Insulin solution Zinc chloride (Stabilizer for insulin) Glycerol (Tonicity) Metacresol (Preservative) Sodium hydroxide (pH) Hydrochloric acid (pH) Water for injections (Vehicle) © Copyright National University of Singapore. All Rights Reserved.  Infusions Infusions are sterile, aqueous solutions or emulsions with water as the continuous phase; they are usually made isotonic with blood. They are principally intended for administration in large volume. No preservatives added Solutions are practically free from particles. Emulsions show no phase separation. All infusions must be tested for pyrogens. © Copyright National University of Singapore. All Rights Reserved. © Copyright National University of Singapore. All Rights Reserved.  Concentrates for injections or infusions Concentrates for injections or infusions are sterile solutions intended for injection or infusion after dilution. They are diluted to a prescribed volume with a prescribed liquid before administration. After dilution, they comply with the requirements for injections or for infusions. © Copyright National University of Singapore. All Rights Reserved.  Antibody concentrate Polysorbate 80 sodium chloride tri-sodium citrate dihydrate Water for Injections © Copyright National University of Singapore. All Rights Reserved.  Antibody concentrate Polysorbate 80 (Stabilizer) sodium chloride (Tonicity) tri-sodium citrate dihydrate (pH / buffer) Water for Injections (Vehicle) © Copyright National University of Singapore. All Rights Reserved.  Powder for injections or infusions Powders for injections or infusions are solid, sterile substances distributed in their final containers and which, when shaken […], rapidly form either clear and practically particle-free solutions or uniform suspensions. Manufactured by freeze-drying. Contain additional excipients to facilitate the drying process. © Copyright National University of Singapore. All Rights Reserved.  Implants Implants are sterile, solid preparations of a size and shape suitable for parenteral implantation and release the active substance(s) over an extended period of time. Each dose is provided in a sterile container. Implanon (Etonorgestrel 68 mg) Core 40% ethylene vinyl acetate copolymer + etonorgestrel Membrane 100% ethylene vinyl acetate copolymer © Copyright National University of Singapore. All Rights Reserved. Source: Implanon Drug Information Sheet, Merck KGaA  Implants Hot Melt Extrusion © Copyright National University of Singapore. All Rights Reserved. www.pharma.basf.com Source: Tambe et al. 2021, J Drug Del Sci Tech (https://doi.org/10.1016/j.jddst.2021.102452)  Sterility © Copyright National University of Singapore. All Rights Reserved.  Sterility and Pyrogens Sterility and absence of pyrogens are general requirements for all injectable preparations. © Copyright National University of Singapore. All Rights Reserved.  SAL The Sterility Assurance Level (Sterility Assurance Level) indicates the probability of one viable microorganism in a certain number of drug products. It defines an acceptable safety level acceptable according to pharmacopeial standards. Common sterilization methods include: Heat sterilization methods Sterile filtration methods Aspectic production Radiation sterilization methods Chemical sterilization … © Copyright National University of Singapore. All Rights Reserved.  Sterility Testing Media for the incubation of preparations are summarized by the pharmacopeia. Filtration method refers to a method where the preparation is filtered and the filter incubated to determine microorganism counts. © Copyright National University of Singapore. All Rights Reserved.  Pyrogens © Copyright National University of Singapore. All Rights Reserved.  Sterilization Methods © Copyright National University of Singapore. All Rights Reserved.  Moist Heat Sterilization Sterilization is achieved by using dry, saturated steam under pressure. Energy input is lower as compared to dry heat but energy is transferred through evaporation (endothermic) and recondensation (exothermic). Procedure is suitable for Aqueous, thermostable solutions. Instruments, lab equipment. © Copyright National University of Singapore. All Rights Reserved.  Moist Heat Sterilization Sterilization is achieved by using dry, saturated steam under pressure. Procedure is suitable for Aqueous, thermostable solutions. Instruments, lab equipment. © Copyright National University of Singapore. All Rights Reserved.  Moist Heat Sterilization Conditions according to Ph. Eur. Temperature 121 °C Pressure 2000 hPa (2 bar) Time 15 minutes © Copyright National University of Singapore. All Rights Reserved.  Dry Heat Sterilization Energy transfer does not involve evaporation and re-condensation but a direct input of energy. Sterilization is suitable for Conditions according to Ph. Eur. Thermostable powders Temperature 180 °C Water-free, thermostable ointments Time 30 minutes Fat, oil, longer-chain alcohols with low Temperature 170 °C vapour pressure Time 60 minutes Objects (e.g. laboratory dishes) Temperature 160 °C Time 120 minutes © Copyright National University of Singapore. All Rights Reserved.  Gamma radiation © Copyright National University of Singapore. All Rights Reserved.  Summary Injectables summarize a diverse group of injection sites and preparations with differences in their biopharmaceutical characteristics. The pharmacopeia categorizes preparations by the administration route due to their tolerance for pH, particle concentration etc. Typical excipients include agents to adjust tonicity, pH and excipients to prevent physical, chemical or microbiological instability. Key requirement of injectables is sterility which can be achieved by various processes including moist heat sterilization, gamma radiation etc. © Copyright National University of Singapore. All Rights Reserved.  Thermodox® Release of doxorubicin tiggered by heat. Radiation therapy produces heat close to the ablation zone. Combined selectivity through a location-specific external trigger and a liposome that accumulates in solid tumors. © Copyright National University of Singapore. All Rights Reserved. Source: Borys and Dewhirst. 2021, Adv. Drug Del. Rev. (https://doi.org/10.1016/j.addr.2021.113985)  Thermodox® © Copyright National University of Singapore. All Rights Reserved. Source: Borys and Dewhirst. 2021, Adv. Drug Del. Rev. (https://doi.org/10.1016/j.addr.2021.113985)  Thermodox® HEAT study shows moderate improvement missing the clinical endpoint. Evaluation with different regimens (dosing or dosing- ablation interval) are ongoing. Key learning: Preclinical data often does not translate into an actual clinical advantage. © Copyright National University of Singapore. All Rights Reserved. Source: Borys and Dewhirst. 2021, Adv. Drug Del. Rev. (https://doi.org/10.1016/j.addr.2021.113985)  Questions in PR5217 Answers provided twice a week © Copyright National University of Singapore. All Rights Reserved.  Thank you! © Copyright National University of Singapore. All Rights Reserved.