Critical Pharmaceuticals

[Michael Scally MD]

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.

 

[Michael Scally MD]

Intranasal Administration of Human Growth Hormone (CP024) Results in a Linear Dose Response Relationship and Induction of IGF-1 in Health Volunteers
Intranasal Administration of Human Growth Hormone (CP024) Results in a Linear Dose Response Relationship and Induction of IGF-1 in Health Volunteers -- Jordan et al. 34 (3): MON-601 -- Endocrine Reviews

Faron Jordan, PhD1, Stephen Michael Shalet, BSC,MBBS,MDFRCP2 and Gareth King, PhD3
1 Critical Pharmaceuticals Ltd, Nottingham , United Kingdom
2 Christie Hosp, Manchester , United Kingdom
3 Critical Pharmaceuticals, Nottingham ,

Introduction

All marketed formulations of human growth hormone (hGH) require subcutaneous injection and CP024 nasal growth hormone offers an attractive non-invasive route for delivery. Non-adherence to hGH therapy is estimated to be as high as 66%1,2 with 70% of patients unhappy with daily injection and 30% considering stopping treatment3. Nasal delivery provides an attractive alternative and it has been shown that children prefer nasal administration over injections4. CP024 is a dry powder formulation of hGH containing CriticalSorb™ absorption promoter. It is being developed as a treatment for GH deficiency in adults and children, is safe and well tolerated with extended stability. CriticalSorb™ is a marketed pharmaceutical excipient with an extensive toxicology package demonstrating its safety profile.

Trial Design and Results

A phase 1 study was carried out in 7 healthy volunteers to assess the tolerability, pharmacokinetics and pharmacodynamics (PD: IGF-1 induction) of 6 doses of CP024 with doses ranging from 2 - 6 mg delivered using an Aptar Pharma UDS Powder device. The objectives of the study were to measure the pharmacokinetics (PK) and dose response relationship of CP024 compared to a subcutaneous dose of 0.75 mg Omnitrope®. A PK/PD model was developed from the data. An octreotide infusion was used to suppress endogenous hGH throughout the trial.

The results showed that CP024 was well tolerated and the few adverse events observed were mild and transient similar to those observed with marketed nasal products. Powder was observed outside of the nostrils on dosing with no correlation to the dose levels administered, indicating device optimisation is required in order to achieve the full dose and optimal deposition in the nasal cavity. CP024 pharmacokinetics were highly reproducible and importantly a linear dose response with Cmax and AUC increasing in line with dose indicating that it would be possible to accurately titrate the dose and therefore IGF-1 response. IGF-1 was strongly induced and to a similar extent as a subcutaneous injection of Omnitrope. This is the first report of IGF-1 induction following intranasal administration of hGH5. CP024 is able to induce IGF-1 to a similar extent as an S.C. injection whilst having a lower systemic exposure similar to that of an endogenous profile. This may have particular benefits for overcoming insulin sensitivity seen with current treatments and the possible increase in the incidences of type 2 diabetes6, 7

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. WS. Cutfield, JGB. Derraik, AJ. Gunn, K. Reid, T. Delany. Non-Compliance with Growth Hormone Treatment in Children Is Common and Impairs Linear Growth. PLoS ONE (2011) 6(1): e16223.

3. European human growth hormone market, Frost and Sullivan Reports (2008).

4. E. Flood, S Block, M. Hall, M. Rousculp, V. Divino, S. Toback, P. Mahadevia. Children’s perceptions of influenza illness and preferences for influenza vaccine. Journal of Paediatric Healthcare, 25(3) (2011), 171-179.

5. 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.

6. WS. Cutfield, P. Wilton, H. Bennmarker. Incidence of diabetes mellitus and impaired glucose tolerance in children and adolescents receiving growth-hormone treatment. Lancet (2000); 355: 610-612.

7. J. Bell, KL. Parker, R. D, Swinford, A. R. Hoffman, T. Maneatis, and B. Lippe Long-Term Safety of Recombinant Human Growth Hormone in Children JCEM (2010) 95: 167-177;.2009-0178.

 

[bigrobbie]

Thanks as always! :thumbup: