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Thinking beyond the Tablet – Enabling Formulation Development for non-oral routes Liping Zhou Ipsen BioSciences Routes of Drug Delivery the preferred route Factors governing the choice of route: 2 • Local vs. systemic effect • Drug properties (physical & chemical) • Drug metabolism • Rapidity of the desired response • Rate & extent of absorption from various routes • Accuracy of the dosage • Convenience and patient centricity Routes of Drug Delivery EFFECTS LOCAL SYSTEMIC Internal Oral Sublingual (buccal) Rectal 3 Parenteral Injections (IV/IM/SC/ID…) Inhalational transdermal Intranasal Ocular Mucosal-throat Vaginal Inner-ear Inhalational Transdermal Intrathecal …… Routes of Drug Delivery 4 What can we do beyond oral routes? Drug properties Medical needs Route of administration Case examples: Suitable delivery devices -- sustained release of peptide drugs -- device-aid controlled release 5 Example#1: PEPTIDE FORMULATION DEVELOPMENT FOR SUSTAINED RELEASE 6 Why Peptides? Craik et al., Chem Biol Drug Des., 2013, 81(1):136-47. 7 What is a peptide? It is not a large small molecule: It is not a small protein: Molecular weight >>500 Amorphous Many are amphiphilic Tendency to self aggregate Surface activity Maximum instability Number of residues is usually less than 50 Lack of organized tertiary or higher order structure Some amount of secondary structure, likely to be metastable Fluxional behavior. There may be rapid inter-conversion of many metastable conformations Less common motifs, such as 310 helices (in comparison with a-helices) Side chains are fully solvent exposed – subject to degradation Challenging to formulate! 8 Why Peptides? 40-49 With sustained release form 30-39 Glatiramer (COPAXONE) Leuprolide (LUPRON) (9-mer) 20-29 1-9 Goserelin (ZOLADEX) (10-mer) Octreotide (SANDOSTATIN) (8-mer cycl.) Teriparatide (FORTEO) (34-mer) 10-19 Exenatide (BYETTA) (39-mer) Triptorelin (DECAPETYL) (10-mer) Desmopressin (9-mer cycl.) Size distributions of peptide drugs on the market in 2010 (in terms of amino acid numbers) Bivalirudin (ANGIOMAX) (20-mer) Eptifibatide (INTEGRILIN) (6-mer cycl.) Calcitonin (MIACALCIN) (32-mer) Craik et al., Chem Biol Drug Des., 2013, 81(1):136-47. Lanreotide (SOMATULINE) (8-mer cycl.) Enfuvirtide (FUZEON) (36-mer) 0 500 1000 1500 2000 2500 3000 3500 Worlwide Sales (US $ Millions) Global annual sales of major peptide drugs Peptide Therapeutics Foundation, 2010, “Development Trends for Peptide Therapeutics“ Routes of delivery of marketed peptide products (PharmacircleTM) 9 Lews AL, Richard J; Ther. Deliv. (2015), 6, 149-163 Sustained Release of Peptide Drugs Micro particulates Depot injections PLGA based rod implants In situ gel formation due to peptide self assembly Thermo gelling system Polymer-tocopherol conjugate based depot FluidCrystal (naturally occurring polar lipids) self-assembly system Device-aid release control Other emerging technologies 10 Polymer micro-particle design PLGA: poly lactic and glycolic acids copolymer Mitragotri et. al., Nature Reviews/Drug Discovery, 2014, 13, 655 11 Example: SOM230 Pasireotide (SOM230) is a cyclohexapeptide. For chronic disease, bid SC injections may not be convenient Long-acting release (LAR) was achieved by less soluble salt form with biodegradable polymers – once-monthly IM administration Drug release rate is controlled in LAR with less peak-to-trough fluctuation than sc injections, thereby minimizing adverse effects “Burst effect” Dietrich et. al., Eur J Endo (2012), 166, 821 12 Effect of particle size on particle disposition Particulates do not across most epithelial or endothelial cells Particulates greater than 10mm do not redistribute from an IM depot Particulates greater than 0.2mm do not leave the vascular system (except via endocytosis) 13 Depot injections PLGA based rod implants In situ gel formation due to peptide self assembly Thermo gelling system Polymer-tocopherol conjugate based depot FluidCrystal (naturally occurring polar lipids) self-assembly system carrier API 14 compliance Example: PLGA based rod implant – Goserelin acetate carrier API SC administration of PLGA biodegradable implant (rod) Ready-to-use drug product Stable peptide/polymer One-month and three-month implants available 15 http://my-journal-entries.blogspot.com/2007/11/attended-urologists-surgery-in-st.html compliance Example: liquid based implant – Eligard carrier API compliance Ease of administration The liquid drug product solidifies in the body and slowly releases the drug over time as the polymer is degraded by normal biological processes 16 http://www.medscape.org/viewarticle/438957_4 carrier Physical Stability of Peptides API Jorgense et. al., Expert opin. Drug deliv. (2009), 6(11),1219 17 compliance carrier Physical Stability of Peptides API compliance Colloidal Stability How strong are API-API interactions? Interfacial Stability Does exposure to interfaces cause damage? All 3 aspects are closely related They are linked to immunogenicity* Conformational Stability Is the 3-D structure maintained? * (1) Wang et al., Int J Pharm, 2012, 431, 1-11; (2) Ratanji et al., J Immunotox, 2014, 11, 99-109; (3) den Engelsman et al., Pharm Res, 2011, 28, 920-933 18 carrier Physical Stability of Peptides API compliance Aggregates are complex entities Aggregates can be caused by: Impurities Stress Batch to batch variation formulation Different manufacturing procedures Not all aggregates are the same: The aggregates exist as an aggregate mixture, rather than a single form The size of the aggregates can be very small (not readily detectable) to be in the subvisible range Aggregates may not have a consistent profile through product lifecycle: The time to reach thermodynamic stable stage varies. 19 carrier Sustained Release of somatuline Nanofabrication by molecular self-assembly 20 API compliance Extended release Sustained release Autogel Suspension of PLGA micro particle monthly 10-14 days SC IM Pre-filled syringe Powder in a vial + solvent in a vial Re-constitution required prior to injection WFI + acetic acid (for pH adjustment) Mannitol Carmellose Sodium Polysorbate 80 Sustained Release of somatostatin analogues Nanofabrication by molecular self-assembly Spontaneously self-assemble into mono-disperse nanotubes. Pouget et. al., JACS (2010), 132, 4230 21 Peptide Aggregation Degarelix – mechanism of fibrillation The gelling process is mainly influenced by the concentration of degarelix, time, temperature, salt content and proteins. http://www.researchgate.ne t/profile/Gregoire_Schwach /publications 22 Peptide Aggregation Sustained release of degarelix via gel formation Degarelix, a potent peptide self-depoting GnRH receptor blocker FDA approval: Dec 24, 2008; EMA approval: Feb 19, 2009 Polarization microscopy schematic illustration After administration, in contact with body fluids such as plasma, degarelix spontaneously forms a gel (naturally forming prolong-release form) http://www.researchgate.net/profile/Gregoire_Schwach/publications 23 Peptide Aggregation Sustained release of degarelix via gel formation Long acting of the degarelix depot Gradual release of monomeric functional analogs at termini controlled & slow release No apparent toxicity to dermal cells observed http://www.researchgate.net/profile/Gregoire_Schwach/publications 24 Peptide Aggregation Case example: changes caused by fluorescent tag ID Peptide A Sequence 30 AA Solubility 1mg/mL in water 25 Peptide B TAMRA-Peptide A 1mg/mL in DMSO Peptide Aggregation Case example: changes caused by fluorescent tag Data collected using SECMALS Mn=8.8X104 (22-23mer) 10 times higher concentration used for un-tagged peptide (5 mg/mL vs. 0.5 mg/mL); Mn=5.6X104 Aggregation observed with the tagged peptide only Solid line: LS signal Dotted line: calculated molar mass Red: Peptide B (tagged peptide) Blue: Peptide A 26 Peptide Aggregation Case example: changes caused by fluorescent tag Peptide A Peptide B Rh=4.02±0.25nm Rh <0.5nm Data from QELS Size of the aggregate determined 27 Peptide Aggregation Case example: concentration dependent aggregation Peptide C: a 39 aa peptide with lipid at the N-terminal 1 mg/mL in PBS 0.1 mg/mL in PBS 0.01 mg/mL in PBS & PBS control Data from DLS Aggregation is concentration dependent Aggregates are not necessarily uniform; multiple forms can co-exist 28 Example#2: DEVICE-AID DRUG DELIVERY 29 Novel Delivery & Patient Centricity Convenient & personalized Insulin 30 Delivery Devices – controlled release External pump Infusion pumps used in hospital settings delivering aqueous solutions via existing IV lines MiniMed-Medtronic SC insulin infusion Pump + bio-sensor + electronics: Enabling the delivery of the right dose at the right time Implantable pump 31 Duros (Alza) osmotic pump Viadur leuprolide acetate implant, 12 months dose Telemedicine: Chip based delivery API stability at 37C over dosing period is required Limited internal volume: ~150uL; high drug concentration Titanium tube administered by a trocar / minor surgery; remove through minor incision Release rates are independent of agent properties or environmental conditions A self-contained hermeticallysealed device that can store 100’s of therapeutic dose. Chips are communicated with over a special frequency Drug administration or dose change is controlled with a code; cells are opened individually Bidirectional communications link between the chip and the receiver enables the update of information including dose delivery, battery life etc. Delivery Devices – controlled release • Evaluation of the Duros (Alza) osmotic pump in rodent study API #1 API #2 Poor PK outcome Decreased API release rate due to chemical degradation Constant release of the API within the required time-frame 32 Delivery Devices – controlled release • Evaluation of the Duros (Alza) osmotic pump in rodent study API#3 33 • No major chemical degradation found within the 7-day period. • Temperature dependent gelling has been identified – current formulation is not suitable for osmotic pump. Nose-to-Brain Drug Delivery Classical devices for local and systemic delivery. Devices often commercially established, fulfilling regulatory requirements; however limited ability of nose-to-brain delivery. Nasal spray pumps Single dose Multiple dose Pressurized Advanced http://www.impelneuropharma.com/pod-technology/ 34 Innovative device designed for nose-to-brain delivery. Device has not established commercially and fulfilment for regulatory requirements is needed. Alternative (POD) Nose-to-Brain Drug Delivery Impel Neuropharma’s Pressurized Olfactory Device (POD) for nose-to-brain peptide delivery, bypassing BBB. Delivery of MAG3 (a technetium-99m labeled 3-aa peptide) with POD: POD administration led to significantly higher MAG3 signal in all brain regions examined. The POD device technology results in greater than 50 % deposition of drug in the olfactory region of the nasal cavity, whereas standard devices deposit < 5 %. http://www.impelneuropharma.com/pod-technology/ 35 Conclusions Non-oral routes provide alternatives to improve patient centricity and quality of life. Innovative technologies made the non-oral deliveries of drugs more convenient, and/or more effective. Early consideration of drug delivery strategy can improve the compatibility of new drug products. Enabling formulation development is essential to optimize the efficacy and safety profiles for each API Understanding the benefits and limitations of each delivery systems to enable the design for delivery. 36 IPSEN Bioscience, Inc. 650 East Kendall, Cambridge, MA