Nasal Administration and Plasma Pharmacokinetics of Parathyroid Hormone Peptide PTH 1-34 for the Treatment of Osteoporosis.

Nasal delivery of large peptides such as parathyroid 1-34 (PTH 1-34) can benefit from a permeation enhancer to promote absorption across the nasal mucosa into the bloodstream. Previously, we have published an encouraging bioavailability (78%), relative to subcutaneous injection in a small animal preclinical model, for a liquid nasal spray formulation containing the permeation enhancer polyethylene glycol (15)-hydroxystearate (Solutol® HS15). We report here the plasma pharmacokinetics of PTH 1-34 in healthy human volunteers receiving the liquid nasal spray formulation containing Solutol® HS15. For comparison, data for a commercially manufactured teriparatide formulation delivered via subcutaneous injection pen are also presented. Tc-99m-DTPA gamma scintigraphy monitored the deposition of the nasal spray in the nasal cavity and clearance via the inferior meatus and nasopharynx. The 50% clearance time was 17.8 min (minimum 10.9, maximum 74.3 min). For PTH 1-34, mean plasma Cmax of 5 pg/mL and 253 pg/mL were obtained for the nasal spray and subcutaneous injection respectively; relative bioavailability of the nasal spray was ≤1%. Subsequently, we investigated the pharmacokinetics of the liquid nasal spray formulation as well as a dry powder nasal formulation also containing Solutol® HS15 in a crossover study in an established ovine model. In this preclinical model, the relative bioavailability of liquid and powder nasal formulations was 1.4% and 1.0% respectively. The absolute bioavailability of subcutaneously administered PTH 1-34 (mean 77%, range 55-108%) in sheep was in agreement with published human data for teriparatide (up to 95%). These findings have important implications in the search for alternative routes of administration of peptides for the treatment of osteoporosis, and in terms of improving translation from animal models to humans.

In vitro and preclinical assessment of an intranasal spray formulation of parathyroid hormone PTH 1-34 for the treatment of osteoporosis.

Osteoporosis treatment with PTH 1-34 injections significantly reduces the incidence of bone fracture. Potential further reductions in fracture rate should be observed through nasal spray delivery to address the poor compliance associated with patient dislike of repeated PTH 1-34 subcutaneous injections. In vitro human osteoblast-like Saos-2 cell intracellular cAMP levels were used to define PTH 1-34 nasal spray formulation bioactivity. The chemically synthesised PTH 1-34 had an EC50 of 0.76nM. Absorption enhancers polyethylene glycol (15)-hydroxystearate (Solutol® HS15), poloxamer 407, chitosan or sodium hyaluronate did not diminish the bioactivity of PTH 1-34 within an in vitro cell culture model (p >0.05). We also demonstrated the effectiveness of the transmucosal absorption enhancer Solutol® HS15 in a nasal spray formulation using a preclinical pharmacokinetic model. In Sprague-Dawley rats without the absorption enhancer the uptake of PTH 1-34 into the blood via intranasal delivery produced a Cmax of 2.1±0.5ng/ml compared to 13.7±1.6ng/ml with Solutol® HS15 enhancer (p=0.016) and a Cmax14.8±8ng/ml in subcutaneous injections. Together these data illustrate that the nasal spray formulation bioactivity in vitro is not affected by the nasal spray absorption enhancers investigated, and the Solutol® HS15 nasal spray formulation had an equivalent pharmacokinetic profile to subcutaneous injection in the rat model. The Solutol® HS15 formulation therefore demonstrated potential as a PTH 1-34 nasal spray formulation for the treatment of osteoporosis.

Intranasal Human Growth Hormone (hGH) Induces IGF-1 Levels Comparable With Subcutaneous Injection With Lower Systemic Exposure to hGH in Healthy Volunteers.

CONTEXT: The development of an improved, efficacious human GH (hGH) product administered by a noninjectable route of delivery such as the nasal route is highly desirable. We have developed a novel nasal hGH product (CP024) that showed excellent nasal absorption in animal models; however, the translation of these results into the clinical setting is essential because past attempts to develop such formulations by other groups have been unable to induce IGF-1 in man. OBJECTIVE: The objective of the study was to assess the pharmacokinetics, pharmacodynamics, and tolerability of CP024 compared with a sc hGH injection. DESIGN: This was a single-center, nonrandomized placebo-controlled, open-label, five-way crossover study in eight healthy volunteers. SETTING: The study was carried out at a contract research organization, Quotient Bioresearch. VOLUNTEERS: Eight healthy male volunteers, given an iv infusion of octreotide to suppress the endogenous GH secretion during the study period, participated in the study. No volunteers were withdrawn due to side effects. MAIN OUTCOME MEASURES: Measurement of hGH and IGF-1 levels and tolerability of the drug product was performed. RESULTS: No serious adverse events were reported and no subjects withdrawn from study due to the treatment. After the nasal administration of CP024, 3-fold higher hGH blood levels were obtained as compared with hGH nasal control. The relative bioavailability was about 3%. CP024 (given twice daily) induced a significant increase in IGF-1 levels up to 19 hours after administration, with no significant difference to those obtained after the sc injection of hGH. CONCLUSIONS: The study indicates that CP024 is a promising candidate for an efficacious nasal product for the treatment of GH deficiency due to induction of IGF-1 similar to that after a sc injection, despite the lower plasma hGH concentration obtained. A dose-response study is needed to evaluate the optimal nasal dose.

Mechanism of mucosal permeability enhancement of CriticalSorb® (Solutol® HS15) investigated in vitro in cell cultures.

PURPOSE: CriticalSorb™, with the principal component Solutol® HS15, is a novel mucosal drug delivery system demonstrated to improve the bioavailability of selected biotherapeutics. The intention of this study is to elucidate mechanism(s) responsible for the enhancement of trans-mucosal absorption of biological drugs by Solutol® HS15. METHODS: Micelle size and CMC of Solutol® HS15 were determined in biologically relevant media. Polarised airway Calu-3 cell layers were used to measure the permeability of a panel of biological drugs, and to assess changes in TEER, tight junction and F-actin morphology. The rate of cell endocytosis was measured in vitro in the presence of Solutol® HS15 using a membrane probe, FM 2-10. RESULTS: This work initially confirms surfactant-like behaviour of Solutol® HS15 in aqueous media, while subsequent experiments demonstrate that the effect of Solutol® HS15 on epithelial tight junctions is different from a 'classical' tight junction opening agent and illustrate the effect of Solutol® HS15 on the cell membrane (endocytosis rate) and F-actin cytoskeleton. CONCLUSION: Solutol® HS15 is the principle component of CriticalSorb™ that has shown an enhancement in permeability of medium sized biological drugs across epithelia. This study suggests that its mechanism of action arises primarily from effects on the cell membrane and consequent impacts on the cell cytoskeleton in terms of actin organisation and tight junction opening.

CriticalSorb™: enabling systemic delivery of macromolecules via the nasal route.

Systemic delivery of proteins via the nasal route has to date been limited by their poor absorption across the nasal mucosa, and the less than optimal tolerability of known permeation enhancers. We have recently developed a highly effective nasal delivery system (CriticalSorb™) based on Solutol HS15. Extensive toxicology studies have shown CriticalSorb™ to be very well tolerated, non-toxic and non-irritant. Cell culture and ex vivo-isolated tissue studies have shown it to promote transport of molecules mainly via transcellular but also to some extent, via paracellular routes. Pharmacokinetic/pharmacodynamic studies in rats, rabbits, non-human primates and recently in man have demonstrated significantly enhanced systemic delivery of nasally administered proteins including insulin (~6 kDa) and human growth hormone (~22 kDa), and pharmacodynamics similar to those after subcutaneous injection. CriticalSorb™ therefore opens up the possibility of developing nasal spray formulations for macromolecules such as proteins.

CriticalSorb: a novel efficient nasal delivery system for human growth hormone based on Solutol HS15.

The absorption enhancing efficiency of CriticalSorb for human growth hormone (MW 22 kDa) was investigated in the conscious rat model. The principle absorption enhancing component of CriticalSorb, Solutol HS15, comprises polyglycol mono- and di-esters of 12-hydroxystearic acid combined with free polyethylene glycol. When administering hGH nasally in rats with increasing concentrations of Solutol HS15, it was found that for a 10%w/v solution formulation a bioavailability of 49% was obtained in the first 2h after administration. Furthermore it was shown that the most effective ratio of Solutol HS15 to hGH was 4:1 on a mg to mg basis. Histopathology studies in rats after 5 days repeated nasal administration showed that Solutol HS15 had no toxic effect on the nasal mucosa. These results have been confirmed in a 6 month repeat nasal toxicity study in rats. It can be concluded that the principle absorption enhancing component of CriticalSorb - Solutol HS15 - is a potent and non- toxic nasal absorption enhancer that warrants further development.