Designing Pediatric Nano-formulations Faces a slew of Obstacles: A Review

Nanotechnology is a fine tool for enhancing drug efficiency. Pediatric population dosage and pharmaceutical development remain to be challenging. Children's therapies frequently draw on the therapeutic knowledge obtained from treating adults. The pharmacokinetics and pharmaco-dynamics of children are different from those of adults, according to scientific research. Innovative technologies, like nanotechnology, may be very difficult to adopt when used with children. An optimal formulation has to be in an acceptable dose type that the pediatric patients can accommodate. Due to its complicated existence, comparatively few efforts were made, in particular to establish pediatric nano-medicines primarily to increase the solubility and stability of sparingly water-soluble liquid formulation. Though many researchers focus on developing adult medications, some new researches are been carried out to provide precision medicines to the infants. In spite of some safety issues nanotechnology has commenced an era of nano-pediatrics. The possible negative consequences and medical benefits in pediatric communities are correlated with nano-formulated drug treatment that is distinct from adults. Incentives in adult market rather than children's needs often lead to paediatric strategies. Drug kinetics design and simulation are also explored to create paediatric nano-formulation. Nano formulations play a major role in handling paediatric infectious diseases and cancer. Many studies aimed to furnish precision medicine for challenging diseases, especially liposomes are imparted Nano formulations are used in the treatment of tumours in new-borns. This article reviews the challenges faced in designing nano-paediatrics and flourishing studies involved in serving paediatric precision medicines.


Introduction
Over the past long time, nanotechnology has quickly created and has broadly connected in different areas, its huge commitment in restorative field is momentous (1) .The term "Nano-medicine" is the science and technology behind the diagnosis, treatment and Prevention of diseases using nanoscale structured materials imparted with other technologies, it also includes several areas, including drug delivery, in vivo imaging, in vitro diagnostics, biomaterials, and active inserts (2) .Globally, it occupies 5% of nanotechnology research publications.
Though Nano-medicine results in higher efficacy, improved safety and toxicological profile, the development of Nano-paediatrics is quite challenging because it's equally filled with merits and demerits Figure 1.It is essential to focus on Nano-pediatrics which enables personalized medicines for children, although there may be differential risk found in children (3,4) with an emphasis on pharmaceutical development, this article gives an overview of the present challenges and prospective opportunities related to the development of pediatric Nano-formulations.

History
Historically, the research and development in paediatric medicines were limited in progress.Although, the major focus in paediatric consideration has been growing attention to the relationship between dietary nutrients and other health outcomes, such as host defence and psychomotor development.Furthermore, the Indian drug regulatory body has recognized the necessity for paediatric regulation and the Indian Council of Medical Research has produced the National Ethical Guidelines for Biomedical Research.To address the ethical issues of performing research in children, see research involving children.Furthermore, the Indian drug paediatric control is unquestionably needed, according to regulatory authorities and the National Ethical Guidelines for Biomedical Research were developed by the Indian Council of Medical Research (5) (Table-1) addresses the ethical issues of performing research in children (6) .

Nano-Pediatrics: A Quest for Pediatric Drugs in Nano-Formulation
Children are the representatives of our future.Compromising their health has huge impact on public health.The pediatric clinical trials show the way of insufficient resource allocation.The complications involved in clinical care of children are usage of inappropriate medication, improper doses calculations and varied frequency of drug administration (7) .The safety and efficacy of medications in neonates differs from adults, this may be due to changes in developmental physiology, disease pathophysiology, or varying pharmacokinetics and pharmaco-dynamics factors (8) .Designing appropriate formulations for children with selected age categories has diminished.It is hypothesis-driven research which has to be concentrated, at present global research in pediatrics is intended to educate scientists and clinicians about pediatric formulation by establishing an International Pediatric Formulation Knowledge Platform which makes research in pediatric formulation easier worldwide (9) .Nano-tech based pediatric research is currently an area of considerable interest due to its potential application in medicines.Nano-medicines would be primarily designed for diseases that are child-specific or that display substantially higher morbidity in infants.The inhalation devices are limited for children, as they manufacture particles with large size which is incompatible with pediatric formulations, to resolve such problems smaller nanoparticles may be used (10) .
3)(14)(15)(16)(17) In early periods the process of translating medical discoveries into commercial products (e.g., biologics) usually takes decades.Nano-drugs typically improve safety more than efficacy.Academic research will still need time to be translated into clinically available products.The development of Nano-pharmaceuticals faces financial challenges despite their sales success.In the case of drugs for the same target indication, demonstrating sufficient efficacy and safety can be challenging.Some companies may not be able to afford customized instruments, equipment, or facilities or need to make stepwise investments based on incremental clinical development goals.Comparing the investment required for the development of a nanodrug involving an NCE with other forms of drug-development, the risk-return profile needs to be evaluated.Regulatory approval and development expenses for drugs approved for niche indications may not be recouped by sales.For nano-drugs, the most challenging aspect is safety and toxicity assessment of new nanomaterials.Nanoparticles that do not biodegrade readily raise concerns about their physiological effects.There are still no specific protocols to characterize Nanodrugs physico-chemically and physiologically/biologically.Interaction between nanoparticles and biological interface may affect some organs and cause other health issues.

Challenges Involved in Progress and Innovations of Designing Pediatric Nano-Formulation
The children population has different categories with varying age groups and their growth and development occurs rapidly during first 2 years approximately which shows differences in physical size, body composition, physiology, and biochemistry.Body weight increases frequently with months and body surface area (BSA) doubles during the first year.The organ systems get mature in size as well as function and proportions of body water, fat, and protein also changes (18) .Next major issue in developing pediatric formulations is the usage of excipients because the evident reveal the issues in safety and efficacy of the drugs (Table 2) (19) .Other factor includes selecting formulation with respective of age and ethics and logistics involved in conducting pediatric clinical trials (20) .

Compliance of Pediatric Nano-Formulation Related to Age
Currently, there's lack of medication developed for youngsters, the employment of improvisatory medicines could manufacture the chance of toxicity or low therapeutic dose, and after it affects the bioavailability and its stability (21) .Formulating nano-pediatrics could be a tedious method, as a result of youngsters of various age team necessities ought to be thought of.In recent times the drug medical aid for pediatric patients is recognized as a singular method, the physiological  2 .

Figure 2. Pediatric population splits into age categories
The factors to be taken into consideration are: type of formulation and the administration route due to physiological, anatomical and pharmacokinetic changes.
The exact factors include 1. Age-appropriate dosage forms.2. Facility of preparations and instructions for use for careers 3. Acceptability, 4. Choice and quantity of excipients, 5. Use of alternative delivery systems, and 6.Appropriate packaging to improve efficiency and avoid the risk of dosage inaccuracy (22,23) .
The excipients used in formulating nanopediatrics is one of the major issues in the pediatric area because it might be harmful.For example, the use of preservatives like benzyl alcohol should be handled carefully in young pediatric patients due to their metabolism [17] .Ethanol if combined with other drugs shows synergistic effects on the central nervous system.Consumption of ethanol and dextromethorphan together can cause an infant's death (24) .

Evolution and Ripening Factors Influencing Pharmacokinetics in Nano-Pediatrics
Nano-therapeutic distribution seems to be challenging in infants due to differences in body weight compared to adult, higher body water with 80 -90% and lower body fat, at 10 -15% body weight compared to 11 -20% in adult men and 16 -30% in adult women.The Pharmacokinetic of a drug administrated is determined by the absorption, distribution, metabolism, and excretion (ADME) factors in every individual.The ultimate aim of dosing regimen is to assure consistent and predictable systemic drug exposure to ensure the safety and efficacy of the drug in patients.The changes including morphological and metabolizing and transporter expression of drug may influence ADME, in infants at first 18 months (25)(26)(27) .Some of the notable factors that affect ADME are listed below 1. GI tract absorption may be affected by changes in morphology of the GI epithelium.

2.
In pediatric patients increased body fat percent may influence distribution of lipophilic drugs, 3. The drug metabolism rates may alter due to the changes in CYP450 expression 4. Development of kidney function in pediatric patients can impact in urinary excretion.
It is very hard to fix general dosing requirements due to ADME changes in pediatric growth and development (26,29) .Normally, the rates of hepatic clearance in children are found to be higher than adults which results in higher dosages by weight.The distribution and elimination of pediatric formulations may be affected by the physiological differences like increased ventilation rate, increased cardiac output, and increased body surface area to weight compared to adults (30) .The determination of doses based on a metabolic pathway of the drug and age variation of the patient is essential because the maturation of metabolic enzymes is not linear PK values are easy to predict when the elder children and adolescents physiological parameters become similar to adults (31) .

Altered Pharmacokinetic of Nano-Pediatric Formulation
The pediatric clinical pharmacology states that children are not small adults.The proper understanding of alteration in pharmacokinetic and pharmacodynamic factors along with maturing organ systems of an infant from neonates to adolescence is essential to obtain safety and accuracy in developing Nano-pediatric formulations.Bioavailability, clearance and volume of distribution are age-related factors that influence the therapeutic concentration shown (Table 3).The increased area under curve, half-life, maximum serum concentration, mean residence time and reduced clearance compared to free drug is apt for ideal nano-formulation (27,32) .

Nano Drug Delivery System in Pediatric Formulations
Nanoparticles are smaller than 5.5 nm are filtered by the kidney, whilst those between 200 and 500 nm are filtered by the spleen, as in adults; all NPs accumulate more in children's lungs, regardless of size, due to decreased airway calibre and increased breathing rate.Opsonisation may be reduced in neonates and young babies due to lower plasma protein levels.Because children have a higher cardiac output, a lower glomerular filtration rate, and a higher organ surface area to weight ratio, pharmacokinetic parameters (circulation time, area under the curve, and distribution) of NPs (100-200 nm) may be varied.Nano-particles (NPs) are active agents incorporated in the core or on the surface of the particles that can be used as delivery vehicles of genes, small sized drugs, diagnostic agents, proteins and peptides.It can alter the pharmacokinetics of drugs and leads to a different dose-response.There are different types of NPs also improve water solubility, stability and permeability of the drug and modify physicochemical properties (35) .The advantages in using leading candidates Polymeric and lipid-based NPs in pediatrics is biocompatibility biodegradability, nonimmunogenicity, non-toxicity, and High drug entrapment efficiency (36,37) .Nano-particles performance in pediatric Nano-drug development in (Figure 3) (38) . (38).

Absorption
• Neonatal period, Nano-therapeutic absorption is impaired by relatively high gastric pH, with a pH of 4.6 in the first week of life compared to a range of 1.5 to 3.5 in adults.• The gastric emptying period of neonates is raised at 75 minutes, comparison with 45 minutes of adult males and 60 minutes of adult females with liquid calories [33] .Distribution • According to proportionally higher body water, the Nano-therapy distribution is particularly impaired in infants with 80%-90% BW relative to 55%-60% BW for adults and low body fat in 10-15% BW in contrast with 11%-20% for men and 16%-30% for women [34] .

Metabolism
• The cytochrome enzymes responsible for metabolism are usually distinct between children and adult individuals and are unstable from birth to about the age of 2 years.• Children have better hepatic clearance levels than adults, due to greater dosages with respective of weight.• Because metabolic enzyme maturation is not sequential, therefore, doses must be carefully calculated depending on the metabolic mechanism of the medication and the developing age of the patients [35] .

Excretion
• During neonatal and early childhood, the removal of certain Nano-formulations is excreted in urine is impaired by the immaturity of Glomerular filtration & renal tubular secretion, which is equivalent to or greater than that found in adults [35] .

Studies of Nano-Formulation Pharmaco-kinetics in Pediatrics
While additional research into the preclinical evaluation of Nano-formulations in pediatric animals is needed, a variety of Nanoparticle formulations have been clinically tested in the pediatric population.Few examples of various clinical investigations of nano-formulation PK in children are highlighted below:

Liposomes
Liposome is widely studied nanotechnology -based formulations in pediatrics and at present there are 15 FDA approved liposomal formulations used in various cases.Liposomes are the promising carriers which were used by many researchers in developing pediatricnanoformulations especially in the case of pediatric tumours for example doxorubicin encapsulated with PEG coated liposomes approved Multi-cancer and Myeloma treatments (37) .Liposomes are a popular nanotechnology that is heavily studied as a treatment for cancer and the overview of liposomal formulations of anti-tumor treatments under clinical evaluation in children (38,39) .

Dendrimers
Dendrimers are frequently alluded to as "polymer of the 21 st century" Dendrimers are frequently branched molecules and they are highly branched three-dimensional structure with high degree of surface functionality and versatility (40) .Polyamidoamine (PAMAM) dendrimer-based therapeutic OP-101 [Dendrimer N-Acetyl-Cysteine] is currently under Phase I clinical study for evaluation of the safety, tolerability, and PK in a Nano-pediatric (41) .

Polymeric long-acting injectable
Polymeric long acting injectable (LAIs) are the clinically endorsed Nano-tech sedate conveyance frameworks which are conjugates of medicate polymers (42) .They are biodegradable drug polymers.Pegfilgrastim is a PEGylated form of leukocyte growth factor filgrastim used to treat myelosuppression due to radiation (43) .

Nano-Crystals
Nanocrystals are the most excellent choices in getting made strides bioavailability and solvency, as the measure gets the surface zone increments.They are the "clusters of atoms" and can be formulated by top-down and bottom-up technology (44) .Aprepitant is used in pediatric patient 6 months of age and older for the prevention of chemotherapyinduced nausea and vomiting (45) .

Inorganic Nanoparticles
Inorganic NPs are recent finding of Nanotech approach which is used as drug carriers, it improves drug efficacy with reduced adverse effects.They are used in pediatric Nano-formulation due to their biocompatible and non-toxic nature (46) .Ferrlecit ® is an Iron nanoparticle has a significant effect in increasing haemoglobin conc.for sustained times in paediatrics (47) .Pediatric physiology must be considered while developing NPs for children.Other Nanoparticles like gold and silver or quantum dabs have appeared guarantee.Metallic Nanoparticles show promise in cancer diagnosis and tumour growth inhibition.In addition, titanium Nanohybrids was employed to create palatable materials (31) .

Modelling and Simulation in Nano-Pediatrics
Minimum number of subjects is used in case of children for clinical trials and special attention is given in order to safeguard them from pain and sufferings.The trials should be more efficient with minimum information collected from lesser subjects; therefore model-based drug development may improve the efficacy.Types of modelling and simulation approaches involve in pediatric Nano formulations are shown on (Figure 4).

Benefits
of Model-informed drug development (MIDD) approaches in pediatric drug development (49) .Analysing factors that may impact a drug's pharmacology related to growth and Optimizing the number and duration of trials by eliminating sampling burdens associated with PK, biomarkers, and/or endpoints, as well as many other benefits and limiting unnecessary testing and avoiding incorrect dosing regimens.
Modelling & Simulation (M&S) method is a successful approach, but it has not been widely utilized in developing pediatric Nano-formulation.The applicability of M&S approaches for pediatric development nanotechnology-based formulations can be improved by creating specific models that incorporate the unique properties of nanotechnology-based formulations such as size, shape, surface chemistry, and so on.Such a strong model would be extremely useful in hastening the pediatric approval process nanotechnologybased formulations that have proven successful in adults (48) .

Approval and Growth Prospects of Nano Formulations
Since 1995, 50 Nano-Pharmaceuticals have been FDA approved and are now available for clinical use.Nano drugs are approved for a variety of indications, including cancer.FDA approval of Nano-drugs peaked between 2001 and 2005 and has declined significantly since 2006.This is probably due to the decline in investment due to the 2008 financial crisis.Most of the Nano-drugs approved to date tend to be less toxic than traditional formulations.Nano-formation versions of existing drugs under clinical development have shown promising results in terms of improved efficacy and are therefore likely to be approved by regulatory agencies.The number of FDA-approved Nanomedicines in clinical trials has steadily increased since 2007.From 2013 to 2015, most Nano-forms participated in clinical trials.This indicates that the availability of FDA-approved Nano-medicines will increase in the future.Currently, clinical trials have more anti-cancer and antibacterial Nano-medicines than any other drug class (49)(50) .

Emerging
Trends in Nano-Pediatrics-An overview of Present and Future Historically, pediatric treatments were developed by using the experience gained from adult experiments, which is still lacking in most nanotechnology platforms, no pediatric nanomedicines are approved yet.Nanomedicines that deal with diseases that affect both children and adults should be adapted to children's needs listed in (Table 4), which may require the development of different formulations, followed by clinical trials in children.Children's market fragmentation and the difficulty of pediatric clinical trials discourage researchers.Therefore, there is a limited body of literature available on this topic.But still the application of nanotechnology for treating pediatric infectious diseases and solid cancers is flourishing, from preliminary in vitro studies to preclinical and clinical trials.By using new regulatory initiatives such as the pediatric investigation plan (PIP) to promote the conduct of specific studies in children to obtain the necessary data (efficacy and toxicity, if safe to do so), pediatric medicine will be more easily approved by the FDA (67) .

Targets/ Diseases
Current Studies &Future Aspects Of Nanopediatrics Reference Brain By using nanotechnology in combination with minimally invasive administration routes, such as intranasal delivery, ARVs could be targeted to the brain and may pave the way for therapy to increase CNS function.But these developments are in their infancy and are far from clinical use.

TB
The groups of Khuller and Swai investigated the encapsulation of several anti-TB drugs within polymeric and lipid nanoparticles and assessed their effectiveness in murine TB models by the oral route.These studies were very robust because the preclinical evaluation was conducted in infected TB models.These nanomedicines are very promising to replace the current daily administration regimen with one single administration every 7-10 days.This would also facilitate the implementation of a Directly Observed Treatment, Short Course (DOTS), leading to greater adherence levels

Cardiac function
The use of liposomal doxorubicin in children was proposed to minimize cardiotoxicity (although the data are inconclusive).

58
Leukemia Cytarabine intrathecal liposomal is approved by the FDA for the prophylaxis or treatment of pediatric leukemia in the CNS 59 Malaria CDs are probably the most extensively used nanotechnology approach, especially looking at the pediatric population.They were developed by combining different nanotechnologies but only a few were specifically targeted at the pediatric population.

60,61 CANCER Cancer diagnosis
Lee and co proposed dual-mode nanoparticles for the (MRI) and fluorescence imaging of neuroblastoma expressing polysialic acids, an adhesion molecule (NCAM) on neural cells represents the characteristic marker of this tumor.

Retinoblastoma
Sahoo planned folate-changed double nutlin-3a/curcumin-stacked poly(lactide-co-glycolide) (PLGA) nanoparticles for the treatment of retinoblastoma.Kim and collaborators evaluated the section of gold nanoparticles of variable size through the blood-retinal boundary after i.v.organization.All the more as of late, Wang et al. investigated centered ultrasound to focus on the conveyance of medications to back shaft retinoblastoma with thermo-touchy medication nanocarriers that go through warming upon to 39-44 °C illumination, a boost that would set off the arrival of an epitomized drug.

Medulloblastoma
The clinical evaluation of certain investigational drugs that target the specific pathway in adult Medulloblastoma, such as vismo-degib, will eventually expand the therapeutic repertoire for children.

Ewingsarcoma
A study used poly (ethylene imine) or poly (allylamine hydrochloride) precoatednanodiamond in order to adhere siRNA to the surface.Loss of expression of the fusion gene resulted in the growth of Ewing tumor cells being completely halted and increasing apoptosis.

Rhabdomyo sarcoma
In recent works of Morita and Co-Workers, stuffed doxorubicin, and Liposomes that are sensitive to temperature were used that were heated with infrared-A radiation which pays the way to heat the tumors before i.v.Infusion of the formulation inhibits the growth of Rhabdomyosarcoma.Few researchers heated the combination of antitumoral drug stocked nanocarriers (e.g., PMs) with ultrasound localized which triggers the outbreak of the encapsulated drug and the cell membrane permeability.The clodronate liposomes and anti-VEGF combination showed beneficial effects in tumors.

65,67,69
Osteosarcoma Of all Pediatric cancers, this type concentrates the most nanotechnology research activity.This development brings added value through the use of approved pharmaceutical excipients.

Conclusion
It is obvious that the US PFI and Eu PFI suggest the application of Nano-tech-based stages of improvement of pediatric details.However, there's a need for data on how Nano-technology-based details demonstrated compelling for grown-ups can be utilized for pediatric definitions.A nano-tech analyst must too explore the continuous challenges of the restricted asserts-the pediatric populace has regularly been characterized as a "niche" populace with a little populace estimate and constrained advertise, especially in comparison to grown-ups' maladies.Generally, 27% of the world's populace is children, but pediatric trials make up as it were 17% of the overall number of trials enlisted by means of the wellbeing organization, with as were 7% of trials taking put in neonates.Industry-based subsidizing is to a great extent weighed towards grown-up's illness signs, clearing out fundamentally non-benefits organizations to support pediatric trials.The combination of this point of view with past impediments in an administrative way for Nanotechnology advancement and propensity to extrapolate from the grown-up's writing has brought about a lack of novel restorative mediations for nearly all complex infections influencing pediatric patients.In specific, depending on grown-up security and adequacy information has come about in eccentric and appalling results in children.Be that as it may, there's an expanding thrust from pediatric patients, guardians, and specialists to extend and quicken the way to interpretation for medicating definition testing in children.

Table 1 . To illustrate the ethical obstacles of implementing children research Year Prominent milestones in the timeline of pediatric health and research
1940sChronic malnutrition in infancy and childhood has long-term behavioural and health repercussions.Premature infant's rehydration is boosted using specialized formulations.