Microneedle Patches for Vaccine Stabilization and Enhanced Immunization. Anne Moore

Transcription

1 Microneedle Patches for Vaccine Stabilization and Enhanced Immunization Anne Moore University College Cork, Ireland

2 Issues with Current Vaccine Distribution Vaccine Potency Cost

3 Current Immunization Programme Issues: Summary HIGH COST: Vaccines and cold packs stored in cold chain LOW VOLUME: Deployment of new vaccines constrained by lack of cold chain volume; e.g., rotavirus. Heat/cold sensitivity of different vaccines: correct storage in the right place is critical The last mile; potential for controlled temperature conditions. High rates of vaccine wastage Discard vaccine vials open at the end of a session. Open a 10 dose vial even if only 1 child comes to the session to avoid missed opportunities

4 Immunization Costs: Unsustainable Gandhi et al., Vaccine 31S (2013) B137 B148 Lydon et al., Vaccine (2008) 26, 6706

5 ImmuPatch: Solutions to Vaccination Obstacles For Healthcare systems: Stability; eliminate cold chain & permit stockpiling Eliminate training costs (easy to administer) Eliminate reconstitution Eliminate needlesticks Single dose Reduced logistics cost For the manufacturer: Integrated into manufacturing process; alternative fill finish Reduced COGs (must be low cost fabrication method) Potential for dose-sparing Courtesy of WHO For the User: Self-administered? Minimal pain.

6 Development History 1 st Generation: Silicon MN (solid & hollow) 2 nd Generation: Coated MN Film-coated (top) Spray-coated (bottom) 3rd Generation: Dissolvable MN Laminate Layered MN (method 1; top) Horizontal MN (method 2: bottom) FITC loaded trehalose CMC + Glyceri CMC + Glycerin Drug 1 Drug 2

7 Formulation Considerations Characteristic Safe for skin administration Known & uniform distribution Standard processing conditions - Previously included in an injected product or implant in body. Uses off the shelf equipment Can be used in a GMP environment Can be scaled up to a commerical scale Formulation and equipment can work together. Maintain stability of vaccine under storage conditions Retain ability to penetrate skin after storage Dissolution profile under storage conditions - Long term 40 o C in hermetically sealed vials - Short term 1 hour after removal from packaging (40C/75% RH) - Mechanical testing

8 Coated microneedles Screen polymer and process parameters in combination on flat silicon disks Taguchi design of experiments (6 variables 2 levels, 8 runs per polymer, polymer 2 levels ) McGrath, M.G. et al (2011) Int. J. Pharm. 415(1-2)

9 Coated microneedles; Film coating McGrath, M.G. et al (2011) Int. J. Pharm. 415(1-2)

10 Coated microneedles Dip coating; doesn t work for these MN Correct parameters: vaccine localised around MN, not spread on base Vrdoljak. et al (2011) J Control Release (1):34-42

11 Coated microneedles; Delivers live vaccines No vaccine AdV5 expressing b-gal MVA expressing b-gal Vrdoljak. et al (2011) J Control Release (1):34-42

12 Microneedles delivered vaccine; Skewed T cell responses %CD i.d. Microneedle Patch Flat Patch IFN+TNF+ TNF+ IFN+ MN-mediated delivery of MVA-PbCSP induced a higher proportion of TNF+CD8+ T cells compared to id delivery Vrdoljak. et al (2011) J Control Release (1):34-42

13 Dissolvable Microneedles targeted to epidermis or upper dermis Dissolvable Microneedles (DMN): Apply patch to skin, microneedles penetrate past the stratum corneum, then dissolve Typically µm height for DMN (epidermis & dermis) Stratum Corneum ( 10µm) Epidermis (50-100mm) Dermis (1-3mm)

14 Dissolvable Microneedle Fabrication Atomised Spray Technique Figure 1 CMC CMC Silicon CMC + Glycerol CMC + Glycerol McGrath, M.G., et al. (2014) Eur J Pharm Biopharm.;86(2):200-11

15 Comparison of Dissolvable Microneedle Fabrication Methods Conventional Dissolvable Microneedle Fabrication Methods mould Apply excess formulated vaccine to mould Vacuum/centrifuge Dispense into pores on (pre-treated) mould Dispenser Formulated vaccine mould Remove excess, add to original formulation Dry the formulation in mould Dry the formulation in mould Remove microneedles from mould with tape Remove microneedles from mould Vrdoljak, J Control Release Mar 10;225:

16 Dissolvable ImmuPatch Unique Production process: Simple Water is the only waste material No vaccine is lost or re-used: improved GMP transfer. Scalable Vaccine formulation can be concentrated to needle tip or to different microneedles Continuous, automated fabrication system for fast, costeffective manufacture Excipients: Safe, Stabilise and Strengthen Stabilises drug/vaccine in dry form outside of cold chain. Fast dissolution of microneedle for vaccines Sufficient mechanical strength to penetrate into skin Already approved for injectable products 1cm 0.25 mm Adhesive tape Result: Stable, potent vaccine-loaded microneedles Drug 1 Drug 2

17 Dissolvable ImmuPatch Dissolvable microneedles composed of live virus expressing b- galactosidase was administered to ex vivo porcine skin. All microneedles penetrated and delivered virus (blue areas) Fabrication process does not destroy sensitive material (live virus successfully infects the skin & expresses b-gal) Intradermal injection of live virus expressing b-galactosidase using needle-and-syringe

18 WHO s 26 vaccine preventable diseases Bacteria: Common Paediatric Diphtheria Group A, C meningococcal infections Hib Others: Pertussis Pneumococcal infections Tetanus Tuberculosis Anthrax Cholera Typhoid fever (S. typhi) Virus Common Paediatric Measles Mumps Rubella Poliomyelitis Varicella: chickenpox & shingles Rotavirus Seasonal: Influenza Adolescent/adult/Travellers HPV: Cervical cancer Yellow fever Japanese encephalitis Rabies Hepatitis A, Hep B Smallpox

19 Dissolvable ImmuPatch: Alum-based subunit vaccines Preliminary DMN (dissolvable microneedle) patch is equivalent to SC (subcutaneous) administration * 5.0 * * Endpoint titre (Log 10 ) day 34 day 56, 3wks post boost Prime Boost 2.0 TT (high dose) SC - TT (low dose) SC TT-alum SC TT (low dose) DMN TT-alum DMN Olivia Flynn

20 H 3 H A (m g ) H 1 H A (m g ) H 1 H A (m g ) Dissolvable ImmuPatch: Enhanced Vaccine Stability Influenza vaccine Antigen (2011/12) in ImmuPatch is stable at 45C and 75% RH for at least 6 months and is significantly more stable than current, liquid formulation H1N1 HA L iq u id (1 5 m g /d o s e ) D M N (3 m g /d o s e ) 3 2 * * D a y M o n th 1 8 H3N2 HA TIV: Trivalent inactivated Influenza Vaccine:, 2011/12 A/California/7/2009 (H1N1) A/ A/Perth/16/2009 (H3N2) B/Brisbane/60/ D a y Vrdoljak, J Control Release Mar 10;225:

21 Dissolvable ImmuPatch: Immunogenicity in mice: TIV Dose sparing (3μg or 0.375μg) Anti H1 HA Endpoint (Log 10) * H1N ** * 20% DMN 2.5%DMN 20% IM 2.5% IM Anti-H3 HA Endpoint (Log 10) *** H3N ** * 20% DMN 2.5%DMN 20% IM 2.5% IM Day post prime Day post prime TIV: Trivalent inactivated Influenza Vaccine:, 2011/12 A/California/7/2009 (H1N1) A/ A/Perth/16/2009 (H3N2) B/Brisbane/60/2008 Vrdoljak, J Control Release Mar 10;225:

22 Dissolvable ImmuPatch: Broader Immunity: TIV Chimeric Pseudotype Particle Assay H 5 V ie tn a m / H 1 S th C a ro lin a / H 1 1 h e a d / H 1 s ta lk * H IC * 0 From: Rino Rappuoli F1000 Med Reports 2011, 0.3 m g d 2 8 D M N 0.3 m g d 2 8 IM 0.3 m g d 5 6 D M N 0.3 m g d 5 6 IM Vrdoljak, J Control Release Mar 10;225: Nigel Temperton, U. Kent

23 Recombinant Adenovirus Vectors as Vaccine Delivery Platforms Prophylactic & Therapeutic Attenuated Recombinant Vaccines for Replication incompetent; in vivo Ag factory Approx 100nm in size. Very homogenous particles Highly immunogenic; Ab & T cell Stability AdHu5; pre-existing immunity may reduce efficacy; overcome with alternative human or chimp serotypes prevents repeated use Insert size limitations. Malaria, HIV, TB Influenza, HBV, HCV Tumours Ebola virus Liquid vaccine stored at -80C

24 DMN: Ad stability: Accelerated Conditions K in e tic A d titr e (ifu /m l) D M N 4 0 C D M N 2 5 C L iq u id 4 0 C W e e k Ad in DMN are stable up to at least 12 weeks. Ad in liquid has degraded by week 12

25 Silicon MN: Skewed Antibody Response to the Ad-encoded Antigen Ratio of Ab titre to Antigen versus AdHu5 at day 50 post-prime Carey et al., Sci Reports : 6154

26 A n ti-v e c to r E n d p o in t (lo g 1 0 ) % p a ra s ite m ia % p a ra s ite m ia % p a ra s ite m ia A n ti-m S P E n d p o in t (lo g 1 0 ) % p a ra s ite m ia % p a ra s ite m ia Si-MN overcome anti-vector immunity & enhance vaccine efficacy A Ab responses to malaria antigen Efficacy * * * * * * d 3 5 d 5 4 d 7 4 A d /A d ID /ID : 3 / D a y A d /M ID /ID 5 / B 2.0 ID - ID ID ID M N M N ID M N M N P r im e B o o s t Ab responses to adenovirus vector * * * * A d /A d M N / M N : 3 / D a y N a iv e : 0 / D a y * * * d 3 5 d 5 4 d A d /A d M N / ID : 6 / ID - ID ID ID M N M N ID M N M N P r im e B o o s t D a y Carey et al., Scientific Reports, 2014

27 Why is ImmuPatch different to ID? ID ImmuPatch MVA-RFP, ex vivo porcine skin Carey et al., Scientific Reports, 2014

28 ImmuPatch: Non-inflammatory AdV Priming Skin IL-1 Skin TNF 2deltaCT * ID MN Naive 2deltaCT ** ** * ID MN Naive Time Time Skin IL-10 Skin type I IFN 2deltaCT * ID MN Naive ** 2deltaCT * ID MN Naive * Time Carey et al., Sci Reports : Time

29 ImmuPatch: Non-inflammatory AdV Priming 2deltaCT ** LN IL-1 ID MN Naive 2deltaCT LN TNF 0.04 * ID MN 0.03 Naive ** 0.1 ** Time Time 2deltaCT ** LN IL-10 ID MN Naive 2deltaCT ** LN Type I IFNb ** ID MN Naive $ Time Carey et al., Sci Reports : Time

30 Translation of MN manufacturing to large scale; HOW? Conventional Dissolvable Microneedle Fabrication Methods mould Apply excess formulated vaccine to mould Vacuum/centrifuge Dispense into pores on (pre-treated) mould Dispenser Formulated vaccine mould Remove excess, add to original formulation Dry the formulation in mould Dry the formulation in mould Remove microneedles from mould with tape Remove microneedles from mould Vrdoljak, J Control Release Mar 10;225:

31 Dissolvable Microneedle Fabrication Formulation A: Physical Parameters 1 Unstable droplet formation Formulation B: Physical Parameters 2 Stable droplet formation Formulation A Physical Parameters 1 Stable droplet formation Manipulation of meniscus formation Allen et al., Int J Pharm Mar 16;500(1-2):1-10

32 issolvable Microneedle Fabrication Control of formulation volume dispensing and drug/vaccine position Sugar/polymer + Congo red Sugar +congo red Allen et al., Int J Pharm Mar 16;500(1-2):1-10

33 H A A /C a lifo rn ia C o n c. (u g /m l) Dissolvable Microneedle Fabrication Effect of dispensing parameters on Hemagglutinin H1 A/California/7/2009 integrity C o n t r o l 3 0 V / H z 5 0 V / H z 8 0 V / H z 3 0 V /5 0 H z 3 0 V / H z Allen et al., Int J Pharm Mar 16;500(1-2):1-10

34 Dissolvable Microneedle Physical Stability Need to balance fast dissolution in vivo with no dissolution in environment. Dissolvable microneedles are composed of hydrophilic materials with large surface area in contact with atmosphere following unpacking before application

35 Change In Mass (%) Target RH (%) Change In Mass (%) Target RH (%) Dissolvable Microneedle Physical Stability DVS Trehalose DMN Method 1 DVS Trehalose DMN Method % dm 70% 60% 80% % 60% 80% Time/mins DVS - The Sorption Particular 0 DVS - The Time/mins Particular Method 1 Recrystallisation event detected 60% RH Method 2 Recrystallisation event detected 80% RH

36 Solid state form and location of drug: Drug Stability in Individual Microneedles Drug- loaded DMN dried method 1 Drug-loaded DMN dried method 2 No difference was observed between the drug in the DMN (irrespective of the drying conditions) and the drug raw material.

37 Formulation Considerations Be aware of regulatory status of your formulation. Need experimental design to select formulation in conjunction with processing parameters. Formulation can be optimised but also processing parameters; important to consider both! Process parameters should be considered in relation to what is sensible. Need analytical methodology to deal with 3D micron devices. Fabrication process is critical to final structure, distribution, form need to study actual products. Need to consider interaction with backing layers, dissolution methodology and in vivo delivery. Need to address challenge of fast dissolution and environmental physical stability.

38 Vaccine-loaded MN; New Frontiers Manufacturing Translation: Nano-fluidics and biologics that will be used clinically, not as IVD. Assaying solid state biological in a 3D format. Clinical translation; will they be better than current needleand-syringe? Utility of their use? Complexity introduced by adjuvants. Alum, o/w etc? Limit to live and inactivated whole vaccines? Push and Pull; Adopted by manufacturer; practically all vaccines administered with a needle and syringe. Desired for by healthcare providers and vaccinees. Regulatory definitions

39 Core Researchers Anto Vrdoljak Marie McGrath John Carey Timmy Doody Caroline O Sullivan Kate Dillane Sonja Vucen Evin Allen Olivia Flynn Joanne McCaffrey Cristina Walter Agnese Donadei Abina Crean, Conor O Mahony Collaborators Simon Draper, Jenner Institute, University of Oxford Nigel Temperton U. Kent National Immunisation Office Brenda Corcoran Michael McAuliffe Cork institute of Technology