Somatropin intranasal - Critical PharmaceuticalsThe stanozolol injection reviews of an improved, efficacious human GH hGH product administered by a noninjectable route of delivery nasall as the nasal route zyzz masteron highly desirable. We have developed a novel nasal hGH product CP that showed excellent nasal absorption somattopin 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 Somatropin nasal spray in man. The objective of the study was to assess the pharmacokinetics, somatropin nasal spray, and tolerability of CP compared with sprsy sc hGH injection. This was a single-center, nonrandomized placebo-controlled, somatropin nasal spray, five-way crossover study in eight healthy volunteers. The study was carried out at somatropin nasal spray contract research organization, Quotient Bioresearch. Eight healthy male volunteers, given an iv infusion of octreotide to suppress meditech stanozolol reviews endogenous GH secretion somatropin nasal spray the study period, participated in the study.
Are HGH sprays, growth hormone pills and patches real?
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 CP 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.
The objective of the study was to assess the pharmacokinetics, pharmacodynamics, and tolerability of CP compared with a sc hGH injection. This was a single-center, nonrandomized placebo-controlled, open-label, five-way crossover study in eight healthy volunteers.
The study was carried out at a contract research organization, Quotient Bioresearch. 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 No volunteers were withdrawn due to side effects.
No serious adverse events were reported and no subjects withdrawn from study due to the treatment. After the nasal administration of CP, 3-fold higher hGH blood levels were obtained as compared with hGH nasal control. CP 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.
The study indicates that CP 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. When human GH hGH , isolated from the pituitaries of human cadavers, was first used to treat GH deficiency in children, it was injected im three times a week, primarily due to the scarcity of supply 1.
The availability of recombinant hGH in the mids not only avoided the iatrogenic risk of transmission of Creutzfeldt-Jakob disease but also allowed an increase in production of the hormone and hence made possible the investigation of alternative treatment regimens.
Because sc injections are less painful than im injections and are easier to self-administer, this became the preferred route of administration in children and adults, eventually by means of the easy-to-use pen-type delivery devices eg, Novo Nordisk Norditropin FlexPro Pen; Eli Lilly Humatrope Pen. Despite having a very different pharmacokinetic profile to that found after im injection, the efficacy after the sc administration of hGH was shown to have increased, and interestingly, neither route of administration produces a pharmacokinetic profile equivalent to the endogenous hGH profile in healthy volunteers 2 , 3.
Since that time, with the aim of developing formulations that might further increase efficacy, increase patient compliance and persistence, or reduce side effects, investigators have evaluated the administration of hGH via the iv, oral, pulmonary, transdermal, and nasal routes 2 , 4 , — 8. Also, numerous sustained-release formulations have been investigated, with two reaching the market 9 , Despite these efforts and the significant advances achieved in drug delivery over the last few decades, hGH replacement therapy still requires administration via injection, usually on a daily basis.
As might be expected, adherence to hGH replacement therapy is correlated to efficacy, and missing as little as one injection per week has been shown to significantly reduce the growth rate in children 15 , The development of improved efficacious hGH products administered via alternative routes of delivery is therefore highly desirable.
The nasal route of drug delivery is particularly attractive due to the favorable environment in the nasal cavity for drug absorption the pH and paucity of enzymes, its abundant blood supply, and absorptive mucosa and the relative ease with which nasal sprays can be administered The pharmacokinetics of nasal administration of hGH has been evaluated in volunteers and in patients using absorption enhancers to improve absorption across the nasal mucosa 20 , — However, pharmacodynamic studies in patients using nasally administered hGH did not induce increased levels of IGF-1, and hence, these formulations were considered therapeutically inactive 4.
We recently discovered a novel absorption enhancer, CriticalSorb Solutol HS15, BASF , that promotes the transepithelial transport of coformulated proteins and peptides across the nasal membrane. This resulted in the development of a dry powder nasal formulation of hGH CP A variety of species has been shown to express GH and GH receptors in multiple tissues in the central nervous system such as the thalamus, hypothalamus, pituitary, and hippocampus, which implicates a role for GH signaling in the development and maintenance of neural tissue as well as cognition and memory 24 Furthermore, the regulation of GH synthesis and secretion is complex and involves modulation by both central and peripherally derived modulators 25 We hypothesized that the proximity of the pituitary gland and its blood supply to the site of absorption, the potential for direct nose to brain delivery of hGH with the possibly of reaching hGH receptors in the brain, and the potential for a more physiologically equivalent hGH plasma profile 26 , 27 could make the nasal route of delivery particularly promising for GH replacement therapy.
After the completion of a preclinical safety assessment package on both CriticalSorb and CP, the current studies evaluated the safety and tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of CP in healthy volunteers. Recombinant hGH was supplied by Sandoz. Omnitrope and octreotide Sun Pharmaceuticals were supplied through a local hospital pharmacy. The study was a single-center, nonrandomized, placebo-controlled, open-label, five-way crossover study in eight healthy male volunteers designed to assess the pharmacokinetics, pharmacodynamics, and tolerability of the CP formulation 5 mg hGH in each nostril compared with a sc injection of 1 mg Omnitrope and 5 mg hGH administered in each nostril formulated as a simple solution.
Furthermore, the effect of a dosing schedule as with either one or two daily doses was also investigated. The study subjects were healthy male volunteers aged 22—50 years, with a body mass index of Safety blood samples and urinalysis samples were taken before drug administration as a baseline and prior to discharge on each period.
On admission to the clinical unit, subjects were tested for drugs of abuse, breath alcohol, and carbon monoxide. Electrocardiogram and vital signs were assessed 1 hour before dosing and at 1, 2, 4, 12 and 24 hours after the dose. Blood samples were taken at various time points throughout the study as follows below. Venous blood samples were withdrawn via an in-dwelling cannula or by venipuncture for analysis of hGH and IGF-1 at various time points before and after the dose.
IGF-1 concentrations were measured before the dose at 30 minutes and 1, 3, 6, 12, and 24 hours after each dose. For regimen E the following time schedule was used for hGH sampling: For the second dose the following time schedule was used: IGF-1 concentrations were measured for the first dose at predose 30 minutes, 1.
The analysis of the PK data for bioavailability of nasal hGH relative to the sc injection was assessed using the following PK parameters: Eight white male subjects were enrolled in the study mean age The mean BMI was No subjects withdrew from the study. All subjects who were dosed with CP were included in the PK and PD analysis and the safety and tolerability evaluation.
During the study, no serious adverse events AEs were reported, and no subject was withdrawn from the study due to the treatments. A total of nine AEs were assessed as due to local nasal irritation and related to CP, all of which were transient and were assessed as mild in severity Table 1.
Of these, only one subject reported five of the AEs and overall the most common were rhinorrhea and sensation of pressure in the nose three AEs reported by two subjects for each. There were no clinically significant findings in the clinical laboratory measurements, vital signs assessments, electrocardiogram recordings, or physical examinations. CP was administered as two different formulations A and B at a dose of 5 mg per nostril once daily compared with the same hGH dose administered nasally as a simple solution without the CriticalSorb absorption enhancer and 1 mg hGH sc.
CP B was also administered twice a day separated by 7 hours. On at least 10 occasions, a reflux of powder was seen emitted out of the nostrils on dosing and hence in these volunteers the nasal formulation was not fully delivered into the nasal cavity. Therefore, the relative bioavailability of CP is likely to be an underestimate of the true bioavailability.
After the sc administration of 1 mg hGH, the median time to maximum serum concentration T max was 5. The variability in the pharmacokinetics after the intranasal administration of hGH was similar to that observed after the sc injection the C max coefficients of variation were When CP B was dosed twice daily, the PK profile of CP after the first dose was similar to the second dose as well as similar to the single-dose administration regimen.
This is important because it indicates that on repeated dosing, pharmacokinetics and consequently PD will be reproducible. There was no significant difference between the IGF-1 levels achieved after a sc injection and CP at 10 hours after the dosing.
IGF-1 levels with time after administration of CP once and twice daily compared with sc injection and intranasal hGH control. For each volunteer the difference in the minimum IGF-1 concentration at the start of treatment and C max maximum IGF-1 concentration after treatment was determined and the values plotted in Figure 3 for each volunteer for each treatment regimen.
When hGH was administered nasally without CriticalSorb, no IGF-1 inductions occurred and levels continually fell throughout the hour period, as shown by the fall in IGF-1 concentrations. Difference between the minimum IGF-1 concentration at start of treatment shaded bar and maximum IGF-1 concentrations after treatment solid bar for each subject after treatment by regimens A—E x-axis IGF-1 concentration [nanograms per milliliter].
The CriticalSorb absorption vehicle and hGH nasal formulations were well tolerated, with any local nasal irritation being mild and transient. As a nasal spray, the nasal administration of hGH has the advantage of not having side effects associated with hGH injections, including pain, injection site reactions, inflammation, bruising, and lipoatrophy. Lack of pain, needle free, and safety all scored high in patient surveys 29 , 30 , and nasal delivery of hGH is therefore likely to be preferred by patients.
Previous attempts to deliver hGH intranasally reported that the formulations were less well tolerated with frequent reports of pain, itching, burning, stinging, and an unpleasant taste 4 , 20 , 22 , These side effects almost certainly resulted from the absorption enhancers used sodium taurodihydrofusidate and dipalmitoyl phosphatidylcholine , causing irritation. Importantly, the nasal hGH formulation containing CriticalSorb also induced IGF-1, with the levels obtained after twice-daily nasal dosing being the same not significantly different as for a sc injection of the hGH up to 19 hours after the first administration.
For example, Laursen et al 4 reported the bioavailability and bioactivity of nasal GH 0. Intriguingly, given the lower hGH exposure observed after dosing with CP compared with the sc injection, it appears that for a given plasma level of hGH, intranasal dosing results in a greater induction of IGF-1 compared with a sc injection.
This could be due to the hGH plasma profile more closely resembling the endogenous pattern of GH secretion in healthy individuals. Endogenous GH is stored and secreted from the anterior pituitary gland in a pulsatile fashion throughout the day, each burst lasting 2—4 hours and the largest peak occurring just after the onset of sleep 3.
The pharmacokinetics observed after the nasal administration of CP are reminiscent of these endogenous bursts, with elevated levels lasting approximately 4 hours. The effect of pulsatile GH on the growth rate of hypophysectomized rats has been explored by different researchers using iv injections of hGH.
The studies suggested that frequent GH pulsative administration was superior to infrequent delivery or continuous infusion in terms of promotion of bone growth or body weight 32 , 33 and increased serum IGF-1 The results were found in two similar studies in which the total dose was changed from being administered three times weekly im to daily administration by sc injection 36 , A study evaluating the effect of a pulsatile vs continuous iv administration of hGH in GH-deficient patients 38 found that eight boluses given at 3 h intervals starting at 8: Serum IGF-1 levels have been correlated with the achieved growth rate after GH replacement therapy 39 , Achieving the same IGF-1 induction with lower serum GH levels has the potential to maintain efficacy of treatment while reducing the risk of side effects due to the direct actions of hGH.
In particular, given the increasing incidence of diabetes, there is increasing concern of GH's effects on insulin sensitivity Indeed, an analysis of data from the Pharmacia KIGS postmarketing surveillance database found an increased incidence of diabetes in children treated with GH replacement therapy In conclusion, we have developed a nasal spray formulation of hGH able to induce IGF-1 levels to a similar extent as that observed after sc injection.
Because nasal sprays are pain free and relatively simple to administer, CP could be an attractive treatment option for patients, particularly children and needle-phobic patients, but in addition, because a similar PD effect is possible with lower systemic hGH exposure, there could be less potential for insulin insensitivity.
Current address for T. Current address for L. Current address for F. The other authors have nothing to disclose. National Center for Biotechnology Information , U. J Clin Endocrinol Metab. Published online Oct 1. Critical Pharmaceuticals Ltd A. Address all correspondence and requests for reprints to: Received Nov 19; Accepted Sep Copyright for this article is retained by the author s.
Study design The study was a single-center, nonrandomized, placebo-controlled, open-label, five-way crossover study in eight healthy male volunteers designed to assess the pharmacokinetics, pharmacodynamics, and tolerability of the CP formulation 5 mg hGH in each nostril compared with a sc injection of 1 mg Omnitrope and 5 mg hGH administered in each nostril formulated as a simple solution.
The following five regimens were administered: CP CriticalSorb powder prototype nasal formulation 2, containing 5 mg hGH in a mg dose, administered as a single spray in each nostril twice a day using an Aptar UDS powder device, the two dosing occasions separated by 7 hours.