FORMULATING FOR MICRONEEDLE DELIVERY Professor Finn Bauer
OVERVIEW Conventional microneedle strategies Change of mind set to consider systemic delivery of therapeutic agents Design & manufacture considerations Dissolving microneedles Hydrogel-forming microneedles Regulatory & clinical considerations Commercial development plan & patient benefit
CONVENTIONAL MICRONEEDLE APPLICATIONS Intradermal vaccines Local drug delivery Systemic administration of potent drugs Dissolving microneedles Coated microneedles Typically small patch sizes
EFFECTIVE IN VIVO DELIVERY OF NANOPARTICLE VACCINES Rapid Dissolvability In Situ 0 min 1 min 5 min 10 15 min min Base Plate Rhodamine-NP DAPI Rhodamine NPs Optical Coherence Tomography in vivo OVA NP or bnp 21 days i.n. Sendai Virus Infection 10 days Not vaccinated Vaccinated bnp OVA NP or bnp 7 days B16-OVA Melanoma 13 days OVA NP
Blood glucose level (% of initial) EFFECTIVE INSULIN DELIVERY IN VIVO 120 100 + 80 60 40 20 0-1 0 1 2 3 4 5 6 7 8 9 10 11 12 time (h) G20%-10 mg G20%-2.5 mg G20%-control
INDICATIONS FOR SYSTEMIC DRUG DELIVERY Potential to improve bioavailability Reduction of side-effects Sustainable drug delivery Bypass of the gastrointestinal tract Patient acceptability Patient and healthcare worker safety Co-administration of several drugs Regular patient use
CONSIDERATIONS FOR SYSTEMIC DRUG DELIVERY Most drugs are not of high potency Tens or hundreds of mg per day required Microneedle patch size Patient application Implications of repeat application Cost considerations Competitive advantages for industry Considerable benefits for patients
HIGH-LOADING DISSOLVING MICRONEEDLES 600 µm T 0 T 30 s T 5 min T 15 min Loading of 50% w/w drug Use biodegradable or low MW polymer Polymer must be good film former and have low Tg Dry slowly to promote physical stability Microneedle and patch design will influence deliverable dose Dissolution characteristics will affect duration of delivery Polymer MW and drug properties will determine whether baseplate delivery is appreciable Manufacture must be carried out in a low bioburden environment as a minimum
DELIVERY OF FIXED-DOSE COMBINATIONS IN VITRO Patch size for 24 hours delivery = 6 cm 2
Delivery of clinically-relevant doses of non-potent drugs in vivo Ibuprofen sodium (µg/ml) Occlusive backing layer Ibuprofen sodium-loaded microneedle array Adhesive foam Shaved area of rat skin Ibuprofen sodiumloaded baseplate 500 450 400 350 300 250 200 150 100 50 0 0 200 400 600 800 1000 1200 1400 1600 Time (min) Patch size for 24 hours delivery = 10 cm 2
DISSOLVING MICRONEEDLES Self-disabling Effective in vivo delivery of insulin, vaccines and nanoparticles Sustained delivery of clinically-relevant amounts of small molecule non-potent drugs in vivo Reasonable patch sizes Deposit 5-10 mg polymer per cm 2 in skin Damaged by heat/steam sterilisation Gamma sterilisation alters release profiles and may cause drug degradation or chemical binding to polymer Manufacture in a low bioburden environment
HYDROGEL-FORMING MICRONEEDLES Microneedles contain no drug themselves Drug contained in a separate drug reservoir Microneedles are chemically crosslinked Rapid uptake of skin interstitial fluid Drug diffuses through swollen microneedles Rate of drug delivery determined by crosslink density Reservoir properties can be altered to modulate drug delivery Potential for higher doses and more prolonged delivery
% original BGL IN VIVO INSULIN: DIABETIC RAT MODEL 120 100 80 60 40 20 0 0 2 4 6 8 10 12 Time (h) MN Patch
METRONIDAZOLE DELIVERY IN VIVO Patch size for 48 hours delivery = 10 cm 2
DONEPEZIL DELIVERY IN VIVO Patch size for 24 hours delivery = 30 cm 2
Ibuprofen-sodium ( g/ml) IBUPROFEN DELIVERY IN VIVO Patch size for 24 hours delivery = 30 cm 2 200 150 100 + 50 0 0 4 8 12 16 20 24 Time (h)
Bevacizumab permeation (µg) Bevacizumab concentration (ng/ml) ANTIBODY DELIVERY IN VITRO AND IN VIVO 100000 900 High dose + MN 800 700 Low dose + MN High dose Control 10000 600 1000 500 400 100 300 200 100 0 0 200 400 600 800 1000 1200 1400 Time (Minutes) 10 1 High dose Low dose IV dose 0 20 40 60 80 100 120 140 160 180 Time (hours)
HYDROGEL-FORMING MICRONEEDLES Self-disabling, but removed intact No polymer deposition in skin Sustainable in vivo delivery of insulin Delivery not limited by what can be loaded into needles themselves Delivery rate controllable by simple adjustment of hydrogel properties Sterilisable without affecting properties Selection of drug reservoir can enhance delivery of high-dose small medicines. Differing pharmacokinetic pattern for very large biomolecules: Potential for lymphatic targeting
900 m PATIENT USE 400 m 600 m
CONFIRMING CORRECT INSERTION Outcome measures With pressure indicating sensor film Consent form Red impression 600 µm Press firmly for 30 sec No preference 15% Questionnaire Microneedle patch without pressure indicating sensor film 10% Microneedle patch with pressure indicating sensor film 75%
APPLICATION OF LARGE PATCHES
SKIN APPEARANCE & BARRIER FUNCTION Skin appearance unchanged relative to control No evidence of polymer accumulation in skin Skin barrier function unchanged relative to control
IMMUNE RESPONSE No measurable increase in IgG relative to control Needle density had no detectable effect No significant difference between dissolving and hydrogelforming microneedles
INFLAMMATION No measurable increase in IL-1 relative to control Needle density had no detectable effect Low ph of Gantrez S-97 formulation had no significant impact
INFECTION No measurable increase in C-reactive protein relative to control No increases in body temperature No significant changes in weight of the animals
CONCLUSION & NEXT STEPS Microneedles have great potential for delivery of therapeutics De-risk delivery platforms in accordance with regulatory advice Develop a bridging programme applicable to any drug to be delivered Manufacturing scale-up Licensing of manufacture Clinical studies Commercialisation and patient benefit