Types of Complex Formulations

Transcription

1 Types of Complex Formulations Johannes Stanta on behalf of the EBF EBF Focus Workshop New Modalities and Novel Concepts in Bioanalysis Altis Grand Hotel, Lisbon - 15 to 16 May

2 What are complex formulations and why do we use them? Improve therapeutic index Different approach for drug transportation into body Safely achieve its desired therapeutic effect Complex Formulations Prolong exposure Change the biodistribution May provide improved targeting 2

3 What are complex formulations and why do we use them? Different approach for drug Pro-drugs transportation into body Improve therapeutic index Prolong exposure Complex Formulations Nanoforms e.g. Liposomes, dendrimers, nanoparticles, exosomes May provide improved targeting Safely achieve its desired therapeutic effect Change the biodistribution 3

4 Pro-Drugs versus Active drugs 4

5 Classification of Pro-drugs Type Bioactivation site Tissue location of bioactivation Examples Therapeutic target tissues/cells Fluorouracil Type I Intracellular Metabolic tissues (liver, GI mucosal cell, lung etc.) Codeine GI fluids Oxyphenisatin Type II Extracellular Systemic circulation and other extracellular fluid compartments Acetylsalicylate Therapeutic target tissues/cells ADEPTs 5

6 Carbon Nanotubes Size (nm) Characteristics Applications diameter and length Single layer or multiple layer. Remarkable strength and unique electrical properties (conducting, semi conducting, or insulating) Functionalisation enhanced solubility, penetration to cell cytoplasm and to nucleus. Carrier for gene delivery, peptide delivery 6

7 Dendrimer Size (nm) Characteristics Applications <10 Highly branched, nearly monodisperse polymer system produced by controlled polymerization; three main parts: core, branch and surface Long circulatory, controlled delivery of bioactives, targeted delivery of bioactives to macrophages, liver targeting 7

8 Liposome Size (nm) Characteristics Applications Phospholipid vesicles, biocompatible, versatile, good entrapment efficiency Long circulatory, offer passive and active delivery of gene, protein, peptide and various other 8

9 Metallic nanoparticles Size (nm) Characteristics Applications <100 Gold and silver, iron, zinc, copper and titanium. Very small size resulting in high surface area available for functionalization. Stable, persistent and reactive. Drug and gene delivery, thermal ablation and radiotherapy enhancement Au Ag Fe Zn Cu Ti 9

10 Silica nanoparticles Size (nm) Characteristics Applications <100 Very large surface area of the pores allows the particles to be filled with a drug or a cytotoxin. Drug and gene delivery and radiotherapy enhancement Rosenholm et al., Nanoscale, 2010, 2,

11 Previous work by the EBF Ø Open Symposium 2017 Workshop Does the use of novel / targeted drug delivery systems have an impact on bioanalytical strategies? Analytical strategies Amount and type of validation Impact of multicomponent measurements Test item, formulation understanding 11

12 Get substantial information from formulation department Use experience from challenges with prodrugs Think Scientifically Understand Limitations ISR for constantly leaking vehicle will never work Validations for released drug should include released QCs Include QCs that represent critical steps for collection and preparation Show control where you can Characterise to the best of your ability 12

13 Survey: What EBF community is currently doing? Ø 53 replies Working on novel formulations: Ø 43% Pharma vs 68% CRO 13

14 Type of formulation Liposomes Nanoparticles Exosomes Dendrimer Prodrugs 14

15 Type of formulation Liposomes Nanoparticles Exosomes Dendrimer Prodrugs 15

16 How many projects have you supported? CRO Pharma >

17 Involvement in the characterisation of formulation? Yes 16% No 84% 17

18 Request by health authority to measure exposure to formulation components? Yes, by FDA MHRA EMA No 89% 18

19 What is being validated? Pro-drug Always pro-drug and active drug Nanoform 100% total drug 77% Total & released drug 23% Total, released and encapsulated NB 7 companies measure free, only 3 of these validate the assay 19

20 Resource requirement 250 %Resource compared to Standard Minimum Average Maximum

21 Draft Regulation FDA Dec 2017 Drug Products, Including Biological Products, that Contain Nanomaterials Parent drug and major active metabolites, measured in the appropriate biologic matrices. Total, free, and nanomaterial-associated drug should be measured separately or indirectly derived. The concentrations of free parent drug and major active metabolite(s) may be low. The use of validated, specific, and highly sensitive methods is recommended. 21

22 Regulation EMA April 2018 Liposome Drug Products Chemistry, Manufacturing, and Controls; Human Pharmacokinetics and Bioavailability; and Labeling Documentation Guidance for Industry You should use validated bioanalytical methods when evaluating the pharmacokinetics and bioavailability of the liposome-contained and free drug substance (drug released from the liposome). 22

23 What can we conclude from the survey? Ø Overall 55% companies are working on novel formulation projects Ø Overall number of projects per company is generally small (2-5 projects) Ø Not many bioanalysis groups are involved in formulation characterisation Ø Pro-drug and active drug measurement using validated methods is common practice Ø All companies measure total for nanoform in regulatory studies Ø ¼ companies measure total, released and encapsulated with validated methods Ø Typically more resources are required for complex formulation bioanalysis 23

24 Ø Amanda Wilson Ø Fred van Heuveln Ø Magnus Knutsson Ø Susanne Pihl Acknowledgment 24

25 Questions? 25