Intranasal Administration of Human Growth Hormone Critical Pharmaceuticals - Delivering Advanced Therapeutics - Critical Pharmaceuticals - is a Nottingham UK-based clinical stage biotechnology company developing a pipeline of unique biological drug products utilizing its proprietary drug delivery technologies. Critical Pharmaceuticals lead product is a nasal formulation of human growth hormone that has significant advantages over existing daily injectable products and has shown equivalent bioactivity to a subcutaneous injection of marketed product in a Phase 1 clinical trial. CP024 Nasal Growth Hormone (hGH / Somatropin) - Critical Pharmaceuticals Jordan FM, Illum L, Shalet S, King G, Lewis AL. Intranasal Administration of Human Growth Hormone (CP024) and Induction of igf-1 in Healthy Volunteers. Intranasal Administration of Human Growth Hormone (CP024) and Induction of IGF-1 in Healthy Volunteers -- Jordan et al. 33 (3): OR30-3 -- Endocrine Reviews Rationale - Patient adherence to growth hormone replacement therapy is estimated to be as low as 36-49%1 with 70% of patients unhappy with daily injection and 30% considering stopping treatment (Frost & Sullivan). Efficacy is related to treatment adherence (Acerin 2007) and consequently suboptimal adherence reduces efficacy and increases healthcare costs. All of the presently available marketed formulations of growth hormone require subcutaneous injection and an intranasally delivered formulation that increases patient convenience and ease of use should increase adherence and treatment success. Nasal Human Growth Hormone Formulations - CriticalSorb™ is an advanced nasal delivery system that facilitates the absorption of macromolecules across biological membranes. We have used this technology to develop CP024, a nasal spray formulation of human growth hormone (hGH), able to achieve bioavailabilities of 20-43% relative to subcutaneous injection in rats, rabbits and cynomolgus monkeys, which is higher than any previously reported2,3. These formulations have been shown to be well tolerated in a 14 day repeat intranasal dose toxicity study. CriticalSorb™ itself is already used in a number of marketed products for oral and intravenous administration and was shown to be well tolerated in a six month repeat intranasal dose toxicity study. Furthermore, the nasal application of growth hormone provides peak plasma levels over a period of 2-3 hours similar to that expected with endogenous growth hormone secretion in children. A Phase 1 study was carried out to evaluate the bioavailability and bioactivity of two CP024 formulations administered intranasally to healthy volunteers relative to a subcutaneous injection of Omnitrope®. Trial Design and Results - Single centre, open label, five-way crossover in eight healthy volunteers. Endogenous GH secretion was suppressed by an infusion of octreotide. The results showed that CriticalSorb significantly and reproducibly enhanced the absorption of hGH across the nasal mucosa after intranasal administration. The formulations were also well tolerated with highly reproducible pharmacokinetics. More importantly however, IGF-1 was strongly induced and the induction was similar to that seen after a subcutaneous injection of Omnitrope®. This is the first report of IGF-1 induction following intranasal administration of hGH4. A second trial is underway to investigate the dose response relationship for CP024 and IGF-1 induction. 1. F. Haverkamp, L. Johansson, H. Dumas, S. Langham, M. Tauber, D. Veimo, F. Chiarelli. Observations of nonadherence to recombinant human growth hormone therapy in clinical practice. Clin Ther, 30(2) (2008) 307-316. 2. H.R. Costantino, L. Illum, G. Brandt, P.H. Johnson, S.C. Quay, Intranasal delivery: Physicochemical and therapeutic aspects, Int. J. Pharm. 337 (2007) 1-24. 3. Y.H. Cheng, A.M. Dyer, I. Jabbal-Gill, M. Hinchcliffe, R. Nankervis, A. Smith, P. Watts. Intranasal delivery of recombinant human growth hormone (somatropin) in sheep using chitosan-based powder formulations. Eur J Pharm Sci. 2005 Sep;26(1):9-15. 4. T. Laursen, B. Grandjean, J.O.L. Jørgensen, J.S. Christiansen. Bioavailability and bioactivity of three different doses of nasal growth hormone (GH) administered to GH-deficient patients: comparison with intravenous and subcutaneous administration. Eur J Endocrinol (1996) 135: 309-15. Illum L, Jordan F, Lewis AL. CriticalSorb: a novel efficient nasal delivery system for human growth hormone based on Solutol HS15. J Control Release 2012;162(1):194-200. ScienceDirect.com - Journal of Controlled Release - 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.