Human Growth Hormone Delivery with a Microneedle Transdermal System: Preclinical Formulation, Stability, Delivery and PK of Therapeutically Relevant Doses.

This study evaluated the feasibility of coating formulated recombinant human growth hormone (rhGH) on a titanium microneedle transdermal delivery system, Zosano Pharma (ZP)-hGH, and assessed preclinical patch delivery performance. Formulation rheology and surface activity were assessed by viscometry and contact angle measurement. rhGH liquid formulation was coated onto titanium microneedles by dip-coating and drying. The stability of coated rhGH was determined by size exclusion chromatography-high performance liquid chromatography (SEC-HPLC). Preclinical delivery and pharmacokinetic studies were conducted in female hairless guinea pigs (HGP) using rhGH coated microneedle patches at 0.5 and 1 mg doses and compared to Norditropin® a commercially approved rhGH subcutaneous injection. Studies demonstrated successful rhGH formulation development and coating on microneedle arrays. The ZP-hGH patches remained stable at 40 °C for six months with no significant change in % aggregates. Pharmacokinetic studies showed that the rhGH-coated microneedle patches, delivered with high efficiency and the doses delivered indicated linearity with average Tmax of 30 min. The absolute bioavailability of the microneedle rhGH patches was similar to subcutaneous Norditropin® injections. These results suggest that ZP-transdermal microneedle patch delivery of rhGH is feasible and may offer an effective and patient-friendly alternative to currently marketed rhGH injectables.

Erythropoietin-coated ZP-microneedle transdermal system: preclinical formulation, stability, and delivery.

PURPOSE: To evaluate the feasibility of coating formulated recombinant human erythropoietin alfa (EPO) on a titanium microneedle transdermal delivery system, ZP-EPO, and assess preclinical patch delivery performance. METHODS: Formulation rheology and surface activity were assessed by viscometry and contact angle measurement. EPO liquid formulation was coated onto titanium microneedles by dip-coating and drying. Stability of coated EPO was assessed by SEC-HPLC, CZE and potency assay. Preclinical in vivo delivery and pharmacokinetic studies were conducted in rats with EPO-coated microneedle patches and compared to subcutaneous EPO injection. RESULTS: Studies demonstrated successful EPO formulation development and coating on microneedle arrays. ZP-EPO patch was stable at 25°C for at least 3 months with no significant change in % aggregates, isoforms, or potency. Preclinical studies in rats showed the ZP-EPO microneedle patches, coated with 750 IU to 22,000 IU, delivered with high efficiency (75-90%) with a linear dose response. PK profile was similar to subcutaneous injection of commercial EPO. CONCLUSIONS: Results suggest transdermal microneedle patch delivery of EPO is feasible and may offer an efficient, dose-adjustable, patient-friendly alternative to current intravenous or subcutaneous routes of administration.

Parathyroid hormone (1-34)-coated microneedle patch system: clinical pharmacokinetics and pharmacodynamics for treatment of osteoporosis.

OBJECTIVES: To evaluate the clinical PK/PD of PTH(1-34) delivered by a novel transdermal drug-coated microneedle patch system (ZP-PTH) for the treatment of osteoporosis. METHODS: Phase 1 PK studies evaluated the effect of site of administration, patch wear time and dose in normal volunteers, ages 40-85 yrs. Phase 2 was conducted in post-menopausal women with osteoporosis to determine the patch dose response compared to placebo patch and FORTEO® injection. RESULTS: Phase 1 ZP-PTH patch delivery demonstrated a rapid PTH plasma pulse profile with T(max) 3 times shorter and apparent T(1/2) 2 times shorter than FORTEO®. In Phase 2, ZP-PTH 20, 30 and 40 µg doses showed a proportional increase in plasma PTH AUC. Inter-subject and intra-subject AUC variability was similar for all patch doses and comparable to injection. All patch doses produced a significant increase in spine bone mineral density. Unexpectedly, ZP-PTH also produced an early increase in hip bone mineral density, an effect not observed with the injection. CONCLUSIONS: These studies suggest that this novel ZP-PTH patch system can deliver a consistent and therapeutically relevant PTH PK profile. Based on encouraging Phase 2 safety and efficacy data, the program is advancing into a pivotal Phase 3 clinical study.

Effect of transdermal teriparatide administration on bone mineral density in postmenopausal women.

CONTEXT: Treatment of osteoporosis with an anabolic agent, teriparatide [human PTH 1-34 (TPTD)], is effective in reducing incident fractures, but patient resistance to daily sc injections has limited its use. A novel transdermal patch, providing a rapid, pulse delivery of TPTD, may provide a desirable alternative. OBJECTIVE: The aim of the study was to determine the safety and efficacy of a novel transdermal TPTD patch compared to placebo patch and sc TPTD 20-microg injection in postmenopausal women with osteoporosis. DESIGN: Our study consisted of 6-month, randomized, placebo-controlled, positive control, multidose daily administration. PATIENTS: We enrolled 165 postmenopausal women (mean age, 64 yr) with osteoporosis. INTERVENTIONS: A TPTD patch with a 20-, 30-, or 40-microg dose or a placebo patch was self-administered daily for 30-min wear time, or 20 microg of TPTD was injected daily. OUTCOMES: The primary efficacy measure was mean percentage change in lumbar spine bone mineral density (BMD) from baseline at 6 months. RESULTS: TPTD delivered by transdermal patch significantly increased lumbar spine BMD vs. placebo patch in a dose-dependent manner at 6 months (P < 0.001). TPTD 40-microg patch increased total hip BMD compared to both placebo patch and TPTD injection (P < 0.05). Bone turnover markers (procollagen type I N-terminal propeptide and C-terminal cross-linked telopeptide of type I collagen) increased from baseline in a dose-dependent manner in all treatment groups and were all significantly different from placebo patch (P < 0.001). All treatments were well tolerated, and no prolonged hypercalcemia was observed. CONCLUSION: Transdermal patch delivery of TPTD in postmenopausal women with osteoporosis for 6 months is safe and effective in increasing lumbar spine and total hip BMD.

Demonstrated solid-state stability of parathyroid hormone PTH(1-34) coated on a novel transdermal microprojection delivery system.

PURPOSE: This study assessed conditions necessary for at least a 2-year, ambient temperature storage stability of the peptide parathyroid hormone 1-34, or PTH(1-34), coated on a novel transdermal microprojection delivery system, or ZP-PTH. METHODS: Liquid coating characterization of high concentration PTH(1-34) formulations (>20% w/w) was assessed by viscosity and contact angle measurements along with RP-HPLC and SEC-HPLC. Solid-state coating morphology of PTH(1-34) on microprojection arrays was determined by SEM, and stability on storage was assessed after dissolution and testing with stability indicating assays. Internal vapor analysis was performed to detect and quantify volatile organics released by patch components into the headspace inside the final package. RESULTS: Aggregation and oxidation were the primary degradation mechanisms for solid-state PTH(1-34) in this transdermal delivery system. Although these two degradation pathways can be retarded by appropriate stabilizers and use of foil pouch packaging (nitrogen purged and desiccant), the solid-state drug formulation's compatibility with patch components, particularly the plastic retainer ring, surprisingly dictated PTH(1-34) stability. Internal vapor analysis demonstrated that PTH(1-34) was particularly vulnerable to vapors such as moisture, oxygen, and outgassed formaldehyde, and each of these volatiles played a unique and significant role in PTH(1-34)'s degradation mechanism. CONCLUSIONS: Identifying degradation mechanisms of volatile compounds on solid-state PTH(1-34) peptide stability allowed for the rationale for selection of final formulation, system components and packaging conditions. A >2-yr, ambient temperature storage stability was demonstrated for solid-state drug coated on a novel transdermal microprojection delivery system. This system was successfully tested in a Phase 2 clinical trial for the treatment of post-menopausal women with osteoporosis.

Effect of delivery parameters on immunization to ovalbumin following intracutaneous administration by a coated microneedle array patch system.

Immunization to the model antigen ovalbumin was investigated using a novel intracutaneous delivery system consisting of antigen-coated microneedle arrays. The influence of the following parameters on the resulting immune responses was investigated: depth of vaccine delivery, dose of vaccine delivered, density of microneedles on the array, and area of application. The immune response was found to be dose dependent, and mostly independent of depth of delivery, density of microneedles, or area of application. Our studies show that the shortest, most tolerable microneedle arrays can be used for achieving consistent and high antibody titers. Overall, the microneedle array proves to be a very versatile delivery technology, allowing easy and reproducible antigen delivery to skin for efficient vaccination without the use of a needle and syringe.

Macroflux microprojection array patch technology: a new and efficient approach for intracutaneous immunization.

PURPOSE: We evaluated the Macroflux microprojection array patch technology as a novel system for intracutaneous delivery of protein antigens. METHODS: Macroflux microprojection array systems (330-microm micro-projection length, 190 microprojections/cm2, 1- and 2-cm2 area) were coated with a model protein antigen, ovalbumin (OVA), to produce a dry-film coating. After system application, microprojection penetration depth, OVA delivery, and comparative immune responses were evaluated in a hairless guinea pig model. RESULTS: Macroflux microprojections penetrated into hairless guinea pig skin at an average depth of 100 microm with no projections deeper than 300 microm. Doses of I to 80 microg of OVA were delivered via 1- or 2-cm2 systems by varying the coating solution concentration and wearing time. Delivery rates were as high as 20 microg in 5 s. In a prime and boost dose immune response study, OVA-coated Macroflux was most comparable to equivalent doses injected intradermally. Higher antibody titers were observed when OVA was administered with the microprojection array or intradermally at low doses (1 and 5 microg). Macroflux administration at 1- and 5-microg doses gave immune responses up to 50-fold greater than that observed after the same subcutaneous or intramuscular dose. Dry coating an adjuvant, glucosaminyl muramyl dipeptide, with OVA on the Macroflux resulted in augmented antibody responses. CONCLUSIONS: Macroflux skin patch technology provides rapid and reproducible intracutaneous administration of dry-coated antigen. The depth of skin penetration targets skin immune cells; the quantity of antigen delivered can be controlled by formulation, patch wearing time, and system size. This novel needle-free patch technology may ultimately have broad applications for a wide variety of therapeutic vaccines to improve efficacy and convenience of use.