The fact that Palermo have never beaten Inter at the San Siro is enlightening information, and of course tells us not to back them in the betting markets to do so here! In 23 meetings between the pair, Palermo have won just three; with Inter winning 12 and eight draws. Of the 12 fixtures played there, Inter have won eight and there has been four stalemates; yep, Palermo have never beaten Inter at their San Siro home! However, they won't care too much as long as they remain outside of the bottom three after winning Serie B last season and to that end they are way above the curve. Head to Head Palermo and Inter Milan drew earlier this season. Don't let gambling become a problem in your life. Claim your FreeBet and bet live in football betting markets.
Pulmonary drug delivery Inhaled medications are commonly administered to infants and small children with asthma and cystic fibrosis. For example, obligate nose breathing is common at birth and may persist to the age of 12 months, resulting in substantial differences in the route taken for inhaled material to reach the lungs Delivery devices used in paediatric populations are the same as those used in adults although they are frequently modified by attaching a small infant or child sized mask.
There is no clinical evidence demonstrating better clinical response with or across interfaces for example, mask vs. Therefore, selection of interfaces is more dependent on age, tolerance of the device and preference of the patient. Nebulized liquids are potentially suitable for young children who cannot use metered dose inhalers MDIs and dry powder inhalers DPIs.
MDIs may be suitable for children from birth when combined with a spacer. The spacer eliminates the need for the patient to co-ordinate actuation with inhalation. A facemask is required until the child is able to manage with a mouthpiece. DPIs may be used for children from the age of 4—5 years, as minimum inspiratory flow is required. Dose adjustment for inhaled medications is typically based on body weight where extrapolation from adult doses is acceptable for children from 3 to 12 years of age For inhaled medicines it is the delivery device that controls the dosage and this is critical for paediatric populations.
However, the devices used are typically the same as those used in adults, adapted to control the dose delivered. Conclusions Paediatric formulations need to be appropriate for the child in terms of dose, convenience and acceptability to ensure compliance with the medication. There are differences in paediatric anatomy and physiology that can impact upon the performance of a drug that is different from that observed in adults.
The design of a paediatric formulation needs to take these differences in physiology into account to ensure that the pharmacokinetic profile of the drug is not compromised. This is of particular relevance to neonates and infants who are furthest in development terms from an adult.
Formulation can lead to differences in pharmacokinetic profiles for a drug, highlighting the risks associated with using off-label medicines that are manipulated to enable administration to children. Prescribers need to be aware of the consequences of manipulating medicines formulations, particularly for drugs with a narrow therapeutic index, even in extemporaneous compounding by a pharmacist where there is insufficient evidence on product quality.
The excipients used in paediatric formulations need to be appropriate for the age group — to avoid the consequences of excipient toxicity. Acceptability of medicines to paediatric patients is also of great importance in the child receiving adequate therapy. Palatable formulations are known to achieve greater compliance.
Therefore this is critical in the design of a new paediatric formulation References Gillis J, Loughlan P. Not just small adults: the metaphors of paediatrics. Arch Dis Child. Developmental anatomy and physiology of children — a practical approach: Churchill Livingstone. Forfar and Arneil's Textbook of Pediatrics. Edinburgh: Elsevier; Int J Pharm. Pediatric drugs — A review of commercially available oral formulations. J Pharm Sci. Drug delivery and formulations. Handb Exp Pharmacol.
Guideline on pharmaceutical development of medicines for paediatric use, Rev. Development of paediatric medicines: points to consider in formulation. Edginton AN, Fotaki N. Oral drug absorption in pediatric populations. In: Dressman J, Reppas C, editors. Oral Drug Absorption: Prediction and Assessment. New York: Informa Healthcare; Manipulation of drugs to achieve the required dose is intrinisic to paediatric practice but is not supported by guidelines or evidence.
BMC Pediatr. Making medicines safer for children — guidance on the use of unlicensed medicines in paediatric patients. Guidelines handbook. Guidance for industry: food-effect bioavailability and fed bioequivalence studies. In: U. Phase 1 relative bioavailability study of a prototype oral solution OS formulation of the investigational Aurora A kinase AAK inhibitor alisertib MLN in reference to a powder-in-capsule PIC formulation in patients with advanced solid tumors.
Mol Cancer Ther. Bioavailability of a pediatric amlodipine suspension. Pediatr Nephrol. Pharmacokinetic and pharmacodynamic characteristics of a new pediatric formulation of artemether-lumefantrine in African children with uncomplicated Plasmodium falciparum malaria.
Antimicrob Agents Chemother. Early clinical development of artemether-lumefantrine dispersible tablet: palatability of three flavours and bioavailability in healthy subjects. Malar J. Pharmacokinetics of two paediatric artesunate mefloquine drug formulations in the treatment of uncomplicated falciparum malaria in Gabon.
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Clin Ther. Neoimmun versus Neoral: a bioequivalence study in healthy volunteers and influence of a fat-rich meal on the bioavailability of Neoimmun. Pharmacokinetic evaluation of a new oral cyclosporine formulation. Evaluation of performance factors affecting two formulations of cyclosporine in pediatric renal transplant patients. Transplant Proc. Comparison of pharmacokinetics of Neoral and Sandimmune in stable pediatric liver transplant recipients. Liver Transpl Surg.
Oral Lyophylizate formulation of desmopressin: superior pharmacodynamics compared to tablet due to low food interaction. J Urol. Pharmacokinetics, pharmacodynamics, and comparative bioavailability of single, oral 2-mg doses of dexamethasone liquid and tablet formulations: a randomized, controlled, crossover study in healthy adult volunteers.
Pharmacokinetic comparison of orally disintegrating and conventional donepezil formulations in healthy Korean male subjects: a single-dose, randomized, open-label, 2-sequence, 2-period crossover study. A pharmacokinetic and pharmacogenetic study of efavirenz in children: dosing guidelines can result in subtherapeutic concentrations.
Antivir Ther. A randomized, open-label, 5-period, balanced crossover study to evaluate the relative bioavailability of eltrombopag powder for oral suspension PfOS and tablet formulations and the effect of a high-calcium meal on eltrombopag pharmacokinetics when administered with or 2 hours before or after PfOS. Pharmacokinetics and safety of single oral doses of emtricitabine in human immunodeficiency virus-infected children. Clinical development of an everolimus pediatric formulation: relative bioavailability, food effect, and steady-state pharmacokinetics.
J Clin Pharmacol. A single-dose, randomized, open-label, two-period crossover bioequivalence study of a fixed-dose pediatric combination of lamivudine mg, nevirapine mg, and stavudine mg tablet for oral suspension with individual liquid formulations in healthy adult male volunteers. A single-dose, randomized, open-label, two-period crossover bioequivalence study comparing a fixed-dose pediatric combination of lamivudine and stavudine tablet for oral suspension with individual liquid formulations in healthy adult male volunteers.
Pharmacokinetic and bioequivalence comparison between orally disintegrating and conventional tablet formulations of flurbiprofen: a single-dose, randomized-sequence, open-label, two-period crossover study in healthy chinese male volunteers.
Pharmacokinetics of hydroxyurea 1, mg coated breakable tablets and mg capsules in pediatric and adult patients with sickle cell disease. A single-dose, three-period, six-sequence crossover study comparing the bioavailability of solution, suspension, and enteric-coated tablets of magnesium valproate in healthy Mexican volunteers under fasting conditions.
Arch Drug Inf. Bioequivalence and pharmacokinetic comparison of two mycophenolate mofetil formulations in healthy Chinese male volunteers: an open-label, randomized-sequence, single-dose, two-way crossover study. The bioequivalence of nizatidine Axid in two extemporaneously and one commercially prepared oral liquid formulations compared with capsule. Bioequivalence assay between orally disintegrating and conventional tablet formulations in healthy volunteers. Bioavailability and pharmacokinetics of a new liquid prednisolone formulation in comparison with two commercially available liquid prednisolone products.
Curr Ther Res Clin Exp. Comparative bioavailability of propafenone after administration of a magistral suspension vs. Comparative fasting bioavailability of dispersible and conventional tablets of risperidone: a single-dose, randomized-sequence, open-label, two-period crossover study in healthy male Chinese volunteers.
Eur J Paediatr Neurol. Pharmacokinetic characteristics of a novel controlled-release sprinkle formulation of salbutamol. Eur J Drug Metab Pharmacokinet. A newly developed pediatric formulation of revatio for pediatric pulmonary arterial hypertension patients is bioequivalent to the 1X20 MG revatio commercial tablet and to the 2X10 MG sildenafil citrate clinical trial tablets in healthy adult volunteers.
Clin Pharmacol Ther. Comparison of the pharmacokinetics, safety and tolerability of two concentrations of a new liquid recombinant human growth hormone formulation versus the freeze-dried formulation. BMC Clin Pharmacol. Bioequivalence of dispersed stavudine: opened versus closed capsule dosing.
A chewable pediatric fixed-dose combination tablet of stavudine, lamivudine, and nevirapine: pharmacokinetics and safety compared with the individual liquid formulations in human immunodeficiency virus-infected children in Thailand. Pediatr Infect Dis J. Tolerability and pharmacokinetic profile of a sunitinib powder formulation in pediatric patients with refractory solid tumors: a Children's Oncology Group study.
Cancer Chemother Pharmacol. Relative bioavailability of two tacrolimus formulations: Prograf normal release and Advagraf sustained release in children with kidney transplant. Basic Clin Pharmacol Toxicol. Meeting Abstract. FI - 2, Phase I and pharmacokinetic study of topotecan administered orally once daily for 5 days for 2 consecutive weeks to pediatric patients with refractory solid tumors.
J Clin Oncol. Bioequivalence of a new liquid formulation of ursodeoxycholic acid Ursofalk suspension and Ursofalk capsules measured by plasma pharmacokinetics and biliary enrichment. Aliment Pharmacol Ther. Establishing pharmacokinetic bioequivalence of valganciclovir oral solution versus the tablet formulation. Effects of the abrupt switch from solution to modified-release granule formulation of valproate. Acta Neurol Scand. Development of fixed dose combination tablets containing zidovudine and lamivudine for paediatric applications.
Pharmacokinetics of antiretroviral drug varies with formulation in the target population of children with HIV Developing paediatric medicines:identifying the needs and recognizing the challenges. J Pharm Pharmacol. Educational Paper: formulation-related issues in pediatric clinical pharmacology.
Eur J Pediatr. Developmental pharmacology — drug disposition, action, and therapy in infants and children. N Engl J Med. Is the bitter rejection response always adaptive? Physiol Behav. The economics of pediatric formulation development for off-patent drugs.
Drug-induced oesophageal injury. Identified safety risks with splitting and crushing oral medications. J Emerg Nurs. Minitablets: new modality to deliver medicines to preschool-aged children. Acceptance of uncoated mini-tablets in young children: results from a prospective exploratory cross-over study.
Guidance for Industry. Effect of liquid volume and food intake on the absolute bioavailability of danazol, a poorly soluble drug. Eur J Pharm Sci. Effects of the quantity of water and milk ingested concomitantly with AS, a novel ester-type cephem antibiotic, on its pharmacokinetics. Int J Antimicrob Agents. A randomised comparison of oral desmopressin lyophilisate MELT and tablet formulations in children and adolescents with primary nocturnal enuresis.
Int J Clin Pract. The bad taste of medicines: overview of basic research on bitter taste. Drugs Ther Perspect. Prevalence of eye disease in early childhood and associated factors: findings from the millennium cohort study. Development of tearing in preterm and term neonates.
Arch Ophthalmol. Differences in ocular penetration of pilocarpine in rabbits of different ages. Age-related differences in ophthalmic drug disposition III. Corneal permeability of pilocarpine in rabbits. Pediatric dosing considerations in ophthalmology. J Pediatr Ophthalmol. Loss of fluorescein across the conjunctiva.
Exp Eye Res. Tear film volume and protein analysis in full-term newborn infants. Systemic side effects of ophthalmic drops. Clin Pediatr Phila ;— Ophthalmic drops causing coma in an infant. J Pediatr. Plasma timolol in glaucoma patients. Latanoprost systemic exposure in pediatric and adult patients with glaucoma: a phase 1, open-label study. Pediatric dosing considerations in ophthalmology — dosage adjustments based on aqueous humor volume ratio.
Direct measurement of ear canal volume in a pediatric population: can we explain its individual variation in terms of age and body weight? Int J Pediatr Otorhinolaryngol. An evaluation of tympanometric estimates of ear canal volume. J Speech Hear Res. Rectal anticonvulsants in seizure patients undergoing gastrointestinal surgery. J Pediatr Surg. Basic anatomical and physiological data for use in radiological protection: reference values: ICRP Publication Ann ICRP.
Despite all these limitations, our investigation showed that components of parenteral rhGH products can significantly contribute to ISP. We suggest further investigation is required for development of long acting, buffer-free, preservative-free formulations. Besides, various excipients are currently being investigated for reducing ISP which can be used as alternatives for common buffers, surfactants or preservatives in designing future rhGH formulations.
Introduction Human growth hormone hGH or somatotropin is a 22 kDa, single-chain peptide with amino acids, two disulfide bonds CysCys, CysCys , and four alpha helixes 1. Human growth hormone is produced by the somatotroph cells of the anterior pituitary gland and is released via hormonal bursts of 0.
The pulsatile secretion of GH is responsible for its metabolic and anabolic effects. Figure 1 summarizes the most important physiological functions of hGH in the human body. The extensive contribution of GH in somatic growth and maintaining hemostasis via a broad range of biochemical processes during childhood, adulthood, and adolescence, implies its importance in the management of different disorders.
Since the pituitary gland of cadavers was the only resource for obtaining hGH at that time, only children with severe GHD could receive hGH treatment. The development of recombinant hGH rhGH provided an unlimited source of hGH to meet the high demand and compensate for limited sources of the hormone. The first rhGH became available by Genentech in 4 , and large quantities of purified rhGH became accessible for the first time.
Since then, rhGH has been the focus of interest for biotech and pharmaceutical companies, and several rhGH-based biopharmaceuticals have been introduced for the management of different disorders Table 1. Growth hormone deficiency involves children and adults and can be congenital due to genetic defects or perinatal injuries or acquired due to pituitary and non-pituitary tumors, radiotherapy, or severe head injury. Recombinant growth hormone replacement therapy is a routine treatment for children and adults with GHD.
Due to the short plasma half-life of hGH 0. The most common complications associated with untreated GHD include neurological, cardiovascular, skeletal, and metabolic disorders with a higher chance of premature death 40 , Although the duration of treatment is still under debate, the treatment usually lasts for several years.
Due to the chronic nature of the condition, there is a strong demand for novel formulations with higher stability, more straightforward application, and enhanced patient convenience to improve therapeutic effectiveness via improving patient adherence. The ideal parenteral rhGH preparation should remain stable and effective during product manufacturing and storage, induce no adverse effects or immune responses, and induce minimum pain and discomfort upon injection while being easy to use.
To meet this need, different injectable formulations, delivery systems, injection devices, and routes of administration have been introduced in the last few years. Injection-site pain According to the International Association for the Study of Pain IASP definition, pain is an unpleasant experience with physiological or psychological routes, accompanying or resembling tissue damage Due to the complex nature of the phenomenon, measuring pain intensity has always been a challenge for scientists conducting clinical trials.
In this regard, three main approaches have been developed including visual analogue scale VAS , numeric rating scale NRS , and verbal rating scale VRS for measurement of pain intensity. In VAS subjects are asked to mark their pain severity on a 10 cm long line.
The markings are then converted to a numerical scale of one to Among these, NRS has shown superior compliance and sensitivity compared to the other two approaches ISP can be affected by the characteristics of the formulation or the injection device. Needle size, length, and the angle of injection are the mechanical features of injection devices determining the degree of ISP in SC injection.
Different self-injecting needle pens and needle-free devices have been developed for more straightforward injection, accurate dosing, electronic monitoring, and injection pain reduction 44 — Parenteral rhGH formulations are carefully designed preparations containing different excipients such as buffering agents phosphate, citrate, histidine, glycine, carbonate, and acetate , tonicity adjusting excipients mannitol and sodium chloride , bulking agents sugars, polyols, amino acids, and polymers , surfactants polysorbate 20 and poloxamer and preservatives antimicrobial agents and chelators.
These excipients are necessary to provide stability and maintain hGH functionality during manufacturing and storage and prevent microbial contamination. ISP can be affected by various formulation features, including concentration, osmolality, viscosity, pH, injection volume, preservatives, and buffers Patient adherence Patient adherence is a critical challenge in managing chronic conditions such as GHD that can limit the effectiveness of rhGH replacement therapy, especially during the first two years of starting the treatment Patient adherence becomes more challenging when the drug should be administered via injection.
The SC route is preferred to intramuscular IM injection for biopharmaceuticals by both patients and physicians due to lower pain, the possibility of at home-administration, and lower cost burden for patients who need to meet their physicians regularly and receive their hGH injections in medical facilities, all of which favor patient convenience For example, hGH 1. Accordingly, the available time for absorption of hGH following IM injection is not long enough to provide physiologically-relevant plasma levels by daily administration.
The longer retention time of the biopharmaceuticals at the SC injection site provides extended drug release compared to IM injection. Rapid drug absorption upon IM injection is due to the high vasculature of the muscle tissue In contrast, SC injection yielded a larger integrated hGH concentration. Patient acceptance and compliance were also significantly higher for SC injection since it was less painful.
Their results concluded that the SC route is safe, efficient, and well accepted by the patients for hGH administration The higher pain sensation associated with the IM route is related to the higher number of nerve fibers in the muscle than in SC tissue In general, water-soluble, low molecular weight, and low viscosity molecules in near-neutral pH are ideal for SC injection In addition to injection pain, ease of use is another determining factor affecting adherence to growth hormone replacement therapy However, the pain associated with frequent SC injections renders patients unwilling to adhere to their treatment, especially in children who comprise most growth hormone deficient patients According to a study by Liedert et al.
Patient convenience can be improved by reducing the injection pain or frequency or changing the administration route. The injection frequency can be reduced by using long-acting formulations with sustained rhGH release 66 — In addition, different non-invasive routes for growth hormone administration have been suggested, including intranasal, transdermal, and pulmonary 69 — For example, it has been shown that the required reconstitution of rhGH before the injection is a significant factor limiting patient compliance Liquid and freeze-dried rhGH formulations are both used for hGH replacement therapy.
According to a study by Muller et al. Their results suggest that the level of necessary reconstitution before use should be considered in the development of the formulations for improving compliance Stanhope and colleagues studied the acceptability of liquid injectable rhGH form in children with GHD for 12 weeks.
The acceptability of four different commercially available rhGH formulations Norditropin SimplexX, Humatrope, Genotropin, and Nutropin AQ was evaluated in pediatric patients with GHD in an open-label, randomized, multicenter, cross-over study for one month Viscosity, injection volume, and concentration Protein solution viscosity is an important consideration in developing liquid biopharmaceutical formulations. Injectable formulations with high viscosity often face issues of low protein stability and poor flow features.
Various features of the protein including shape, size, charge distribution, concentration, and association kinetics are involved in determining the viscosity of the solution. On the other hand, these molecular features are affected by solution conditions such as temperature, ionic strength, additives, and pH Furthermore, attractive charge-dipole, charge-charge, Van der Waals, and hydrophobic and repulsive charge-charge, and exclude volume effect forces are also involved in determining the viscosity of a protein solution However, the increase in viscosity is not always linear with regard to protein concentration The role of viscosity in ISP and its possible underlying mechanism have not been thoroughly investigated.
However, Schwarzenbach et al. Subcutaneous injection of solutions with low 1 cP and medium viscosity cP were found to be more painful compared to highly viscose cP solutions Viscosity-reducing gents such as NaCl and amino acids are commonly added to formulations as tonicity adjusting agents to reduce ISP since injection of hyper- or hypotonic parenteral formulations can induce cell shrinkage or swelling leading to increased pain Increasing NaCl concentration in 5 mM histidine buffer at pH 5.
Higher injection volumes are associated with higher ISP and the maximum volume of 2 mL per dose is recommended 1. In this regard, it has been shown that SC injection of smaller volumes of rhGH preparations is less painful and improves patient convenience 89 — In a study by Chantelau et al.
Another study evaluated the severity of pain inflicted by SC injection of different volumes of 0. The results showed that an injection volume in the range of 0. One approach to reducing the injection volume is to increase hGH concentration. However, as mentioned previously, highly concentrated hGH formulations have higher viscosity and thus a higher risk of aggregate or insoluble particulate formation, compromising product stability and safety.
Hansen and colleagues studied the effect of hGH concentration and injection volume on ISP and concluded that hGH concentration was directly associated with pain perception following SC injection. The injection volume is determined based on product concentration and dosing regimen. Hence the average dose for adults with GHD is estimated to be 0. It should be noted that the initial dose for GHD patients is gradually increased by 0.
In this case, higher injection volumes might be needed. Dosing frequency and antimicrobial preservatives Low stability and relatively short plasma half-life of rhGH demand frequent injections In addition, it has been shown that daily hGH injection has a superior growth-promoting effect compared to administering the same dose over injections per week 54 , However, it can be expected that patient non-adherence will increase with dosage frequency due to repeated ISP.
McNamara et al. Parenteral rhGH products are available as single- or multi-dose preparations. The single-dose formulations are used for a single injection in a single patient. Due to the disposable nature of these preparations, they usually do not contain antimicrobial preservatives.
On the other hand, multi-dose vials or cartridges can be used more than once and require additional preservatives to prevent microbial contamination after the first use. Antimicrobial preservatives have been associated with ISP in parenteral biopharmaceuticals, including rhGH products. Phenol, m-Cresol, and benzyl alcohol are the most commonly used preservatives in multi-dose rhGH products. According to research conducted on patients with GHD who received SC rhGH injections for one year, m-Cresol was associated with higher local pain compared to 0.
In another study, Bridges and colleagues performed a double-blinded, randomized, cross-over trial on 31 children to compare pain sensation following SC injection of rhGH formulations reconstituted with benzyl alcohol 0. Based on their results, the m-Cresol injection was more painful compared to benzyl alcohol, while no significant difference was observed between injection of 0. Subcutaneous injection of phenol 4. Similar reactions were previously reported for the m-Cresol component of commercial insulin as well Another study by Svendsen and Carstensen showed local toxic effects of high concentrations of benzyl alcohol, m-Cresol, and phenol upon 1 mL IM injection in rabbits.
Based on these data, it can be concluded that m-cresol injection induces more pain and local toxicity compared to phenol and benzyl alcohol. Another strategy for reducing the ISP is to add a local anesthetic agent to the parenteral formulation The local anesthetic effect of benzyl alcohol upon SC injection has been shown previously , According to their results, SC injection of benzyl alcohol-containing multi-dose formulation was less painful compared to the benzyl alcohol-free single-dose form In a series of three randomized, double-blinded, cross-over trials on the ISP for different QS adjuvant formulations, it was observed that the addition of benzyl alcohol 0.
It can be expected that the anesthetic effect of benzyl alcohol may be, in part, responsible for the observed lower ISP.
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