They are classified according to: Singh GN Jul 5 To: Formulation approaches to pediatric oral drug delivery: The state-based authority responsible for manufacture, distribution, and sale of drugs; drugs are required to have a state license before they are marketed. Development of paediatric medicines:
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Dosing accuracy is highly determined by the volume to be measured and the type of dosing device. A minimum volume for accurate dosing with an oral syringe, measuring spoon or cup is yet to be defined. Oral liquid medicines, for example, tramadol, clonazepam, may be marketed as drops for children of different ages. Their main benefits include a low dosing volume, ease of swallowing and dosing flexibility.
However, drops require careful consideration when dosing is critical in view of the risk of drop size variation and counting errors. Oral formulations may be designed in a form that is solid upon manufacture, yet liquid upon administration to the child, for example, dispersible tablets, effervescent tablets and granules for oral solution.
Easy swallowing may also be achieved by orodispersible formulations such as orodispersible tablets, granules and lyophilisates. Oral solid formulations are commonly manufactured as powders, granules, capsules or tablets. Granules can be coated in order to modify the release or to mask the taste of the active substance. Powders and granules are easy to swallow for infants and preschool children, yet children may not like their mouth feel.
Moreover, clinical evidence indicates that powders and granules are commonly given with food or drink to ease swallowing even when the joint intake of the medicine with food or drink is not part of the marketing authorisation, that is, not recommended in the user instruction. Capsules can be either soft or hard. Hard capsules can be filled with powder or coated granules.
They are normally intended for direct swallowing, however some may be opened and their contents given as such. Some may be opened as well, however this practice is more likely to impact bioavailability. Tablets can be either coated or uncoated and for immediate or modified gastroresistant, extended, prolonged release. Immediate tablets can be manufactured as chewing tablets to enable easy swallowing.
Otherwise, tablets are intended to be swallowed intact. Nevertheless, immediate tablets can be chewed, crumbled or crushed without any relevant impact on the medicine's stability and bioavailability, although taste may be significantly deteriorated. The latter is more likely with immediate tablets that have a film-coating for taste masking. Modified release tablets can be achieved through different principles.
When achieved through a dedicated coating of the tablet or an osmotic pump system, it is evident that the tablet must be swallowed intact. If the modified release character is based on coated granules, the effect of chewing and crumbling may be less drastic; however in the majority of cases there is still a need to take these formulations intact. In any case, these tablets should not be crushed to powder.
So far, immediate and modified release tablets are rarely developed for use in infants and preschool children as historic opinions suggest that young children cannot swallow tablets intact. Actually, the tablets were even better accepted than 0. Tablets of different sizes. From left to right: Novel types of oral solid dosage forms are increasingly being investigated to realise safe and effective medications that are also more easy to use by children, parents and caregivers, for example, orodispersible mini-tablets, pulptablets, pellets, oral dispersible films, oral gels and medicated nipple-shield.
This dosage form combines the advantages of the manufacture of a solid formulation, such as limited need for harmful excipients, good stability and good portability, with easy swallowing by the child, while at the same time limiting the risk of spillage. Orodispersible films consist of a water-dissolving polymer that adheres to the mucosa upon contact with the saliva. Oral administration is realised by swallowing medicated saliva.
Orodispersible films may also be intended for oromucosal use. Another approach to oral administration in children is provided by Bar-Shalom. The author indicates a need for a flexible formulation that is acceptable to children of any age and health status. He proposes an automated compounding concept consisting of a pulp-like carrier, microencapsulated drug and a dispensing robot by which a pharmacy can deliver any dose upon request.
However, the application of such an approach may require rethinking of commonly applied clinical, regulatory and marketing principles. Excipients form the major constituent of the majority of medicines. They serve different functions as, for example, filler, binder, desintegrans, preservative, antioxidant, sweetener, taste masker, colouring agent and coating agent. Excipients are anticipated to have no pharmacological action.
However, it is increasingly recognised that excipients may exert a different safety profile in children due to the immaturity of their organ and body systems. Thus, excipients that are safe for use in adults and older children may not necessarily be so when used in younger children. The database provides an easy searchable tool of the pharmacology, toxicology and safety data of a selected group of excipients as published in peer-reviewed journals, government reports and other databases.
The discussion focuses on a specific set of excipients that are known for or have been associated with increased harm in humans, for example, benzalkonium chloride, benzoic acid and benzoates, benzylalcohol, cyclodextrins, ethanol and propylene glycol. Good pharmaceutical development implies that the selection of a paediatric medicine is based on an integrated approach balancing, for example, the advantages and disadvantages of the different routes of administration and formulation options including the safety of excipients, usability, manufacturability, cost and patient access figure 2.
Such comparison is especially important in case of multiple medication use and when interchanging medicines upon drug shortages, altered reimbursement rules or transitions of care. The relevant product information can be obtained from the open access databases of the European regulatory authorities or paediatric formularies. The system is commonly used by industry to support formulation changes, whereas bioequivalence studies may be waived for class I drugs.
However, it is increasingly acknowledged that the BCS testing conditions are not appropriate to young children, for example, because of a change in the ratio between paediatric dose and gastric volumes over growth. In fact, Batchelor et al 49 showed that drugs may shift to another class in the BCS when the testing conditions are altered to better reflect child physiology.
As a consequence, they considered that there is a need for an age-specific BCS system to support paediatric formulation development. Child acceptability involves the overall ability and willingness of the child to use a medicine as intended. Adequate user acceptability and drug adherence are key to safe and effective paediatric pharmacotherapy. Therefore, these aspects require due consideration during paediatric drug development, prescriptions and pharmacovigilance.
When drug administration causes problems, healthcare professionals or caregivers may decide to manipulate the dosage form or to give medicines with food or drink, even when this is not recommended in the user information. Safe and effective paediatric pharmacotherapy requires careful consideration of selecting the type of drug, a suitable dose and an age-appropriate formulation, and the younger the child, the more the attention that is required.
The lack of knowledge on the pharmaceutical development and production of medicines for the youngest children has been identified as a barrier to essential medicines. Recent global incentives and funding opportunities have resulted in increased research in this domain and in an integrated approach to formulation development. Key aspects involve the development of novel dosage forms such as mini-tablets and orodispersible formulations, the safety of excipients, child acceptability and the importance of suitable dosing devices.
The acquired knowledge is useful to formulation scientists as well as to doctors, pharmacists and caregivers when prescribing, compounding, dispensing or administering medicines to children. Contributors This manuscript has been drafted by DAvR-N following the publication of her thesis on child-friendly medicines: All four co-authors have carefully read and commented on the draft manuscript and have agreed to the final manuscript as currently submitted. Disclaimer The opinions in this article are not intended to reflect the opinions of the MEB or EMA or any of its working parties or committees.
Register a new account? Forgot your user name or password? Search for this keyword. Latest content Current issue Archive Authors About. Log in via Institution. Safe and effective pharmacotherapy in infants and preschool children: Abstract Safe and effective paediatric pharmacotherapy requires careful evaluation of the type of drug substance, the necessary dose and the age-appropriateness of the formulation. Oral formulations Oral administration may be directed at a systemic effect following absorption, or at a local effect in the gastrointestinal tract.
View inline View popup. Oral liquid formulations Oral liquid formulations such as solutions and suspensions are commonly given to young children because they are easy to swallow. Formulations that are swallowed as a liquid or pulp Oral formulations may be designed in a form that is solid upon manufacture, yet liquid upon administration to the child, for example, dispersible tablets, effervescent tablets and granules for oral solution.
Oral solid formulations Oral solid formulations are commonly manufactured as powders, granules, capsules or tablets. Novel approaches to paediatric formulation development Novel types of oral solid dosage forms are increasingly being investigated to realise safe and effective medications that are also more easy to use by children, parents and caregivers, for example, orodispersible mini-tablets, pulptablets, pellets, oral dispersible films, oral gels and medicated nipple-shield.
Excipients Excipients form the major constituent of the majority of medicines. Well-designed paediatric formulations Good pharmaceutical development implies that the selection of a paediatric medicine is based on an integrated approach balancing, for example, the advantages and disadvantages of the different routes of administration and formulation options including the safety of excipients, usability, manufacturability, cost and patient access figure 2. Formulation acceptability Child acceptability involves the overall ability and willingness of the child to use a medicine as intended.
Conclusion Safe and effective paediatric pharmacotherapy requires careful consideration of selecting the type of drug, a suitable dose and an age-appropriate formulation, and the younger the child, the more the attention that is required. The availability and age-appropriateness of medicines authorized for children in The Netherlands. Br J Clin Pharmacol ; Adverse drug reactions and off-label and unlicensed medicines in children: BMC Med ; What does the food and drug administration safety and innovation act mean for you?
Ocul Surf ; Adv Drug Deliv Rev ; In the latter, while both drugs may be indicated, separate dose adjustments cannot be easily undertaken. The matter remains unresolved. Concerns about regulatory capacity and rigour led to an examination in of the CDSCO by the Department-Related Parliamentary Standing Committee on Health and Family Welfare, one of over 20 standing committees consisting of members of Parliament and established by the Parliament of India to undertake specialist parliamentary work [ 6 ].
In , it issued its report the 59th Report [ 6 ]. This report highlighted multiple deficiencies in the approval processes of the CDSCO, noting that these were compounded by understaffing, a lack of appropriate skills, and inadequate infrastructure. This is in violation of rules though till May , there was some ambiguity on powers of the State Drug Authorities in this respect.
However the end result is that many FDCs in the market have not been tested for efficacy and safety. This can put patients at risk. Section 9 of [ 6 ]. The committee also noted that multiple FDCs available in India had been rejected by regulators in Europe, North America, and Australia, while others never had approval applications submitted outside India Section 7 of [ 6 ]. The report, however, provided no systematic examination of regulatory or drug utilisation data to support its complaints.
To our knowledge, this is the first empiric study into the concerns described about FDCs by the 59th Report. It examines the regulation and use in India of oral FDCs in four therapeutic areas: The law, passed under British colonial rule, placed responsibility for imports on central government, with the states being responsible for manufacture, distribution, and sale. This was followed in by the requirement for prior central approval for manufacture, along with an obligation on state license applicants to produce evidence that the drug had been approved S4 and S5 Texts.
FDCs were not specifically mentioned, but they were regarded as new drugs, with recorded central approvals for FDC formulations dating continuously from Increased central control of drug regulation has occurred incrementally ever since, whilst the states have retained their licensing powers over the manufacturing and sale of most drugs. Part XA included and includes requirements for pre-manufacturing central approval before a state manufacturing license is granted and for license applicants to produce evidence of that approval, whilst expressly including FDCs in the definition of a new drug and setting out specific data submission requirements for FDCs.
Those FDCs therefore required central approval prior to manufacturing under Rules B or C, and applicants had to submit evidence to state authorities of that prior approval. This is reflected in the heading of Rule D: In , the rules were amended again to impose the legal duty on the CDSCO to be satisfied when approving new drugs for import or manufacture that they are safe and effective.
The 59th Report Section 9. We identified no ambiguity in the rules. Rules 69 6 and 75 6 are not relevant to determining that question, but they imposed an additional requirement of producing evidence of approval in favour of the applicant. The requirement in effect lapsed after 4 y from either the date of the first approval or, if earlier, from the date of the inclusion of the FDC in the Indian Pharmacopoeia. For 4 y after approval, or after inclusion in the Indian Pharmacopoeia if earlier, companies wanting to market new drugs—including FDCs—must obtain approval of their own formulation from the CDSCO.
We aimed to determine if evidence existed to support the concerns of the 59th Report. This was an ecologic study of FDC approvals in India. It included a time-trend analysis of FDC sales volumes — in each of the four therapeutic areas of study, with a cross-sectional examination of the — data to determine the contributions to FDC product numbers and sales volumes of CDSCO-approved and-unapproved formulations. Using publicly accessible records available from the CDSCO for the period —, we collated information on FDC approvals granted annually in each area [ 16 ].
The CDSCO listed approvals chronologically in a portable document format pdf that included the drugs comprising individual FDC formulations, indication, and the date of approval. Relevant information was extracted into an Excel spreadsheet. We focussed on original formulation approval, that is, the first approval granted for the drug combination in the FDC being examined.
No information was available publicly on the clinical evidence that was provided to support approvals. In the Indian legal documents, the terms used are as follows: The board established under Section 5 of the Drugs and Cosmetics Act, , to advise the central and state governments on technical matters arising out of the administration of the act. The finished FDC as manufactured and named or branded by a pharmaceutical company. Multiple companies may choose to manufacture FDCs of the same formulation.
FDCs made by different pharmaceutical companies are given brand names to distinguish them from FDCs of the same formulation made by other companies. The state-based authority responsible for manufacture, distribution, and sale of drugs; drugs are required to have a state license before they are marketed. We determined for each therapeutic area the numbers of FDC formulations and branded products marketed, and we undertook a time-trend analysis of annual sales volumes over 5 y, — Data were obtained from PharmaTrac, a commercial database comprising monthly audits of pharmaceutical product sales through multiple supply routes some 5, pharmaceutical companies, 18, distributers and stockists, and 32, sub-stockists to over , retailers, hospitals, and dispensing doctors in 23 regions of India [ 20 ].
The sampling data are projected to estimate national sales totals. They include generic and branded product names, manufacturers, sales volumes and value, and date of market launch. Value is reported in rupees; we used current exchange rates to report in US dollars. We examined monthly data available for the 5-y period November —October There was a large amount of data; in presenting the results, we focus on the most recent mo period, November —October S1 Table includes the individual formulation and product data for each of the 5 y examined.
We searched the PharmaTrac database according to therapy and treatment group in the first instance. For each therapeutic area, we identified the FDC formulations and extracted into Excel worksheets the product, volume, and value data. We summed the monthly data to obtain mo volumes and values for the 5-y period November —October The database was additionally searched using the individual drug names of NSAIDs, oral anti-diabetic drugs, anti-depressants, benzodiazepines, and anti-psychotics.
Searches were conducted in duplicate, with discrepancies resolved by re-searching and agreement. While some older formulations had become obsolete by — e. In each therapeutic area, more new original formulations were launched on the market after 1 May than before Table 1. All the formulations available in the UK and US in each therapeutic area were approved by the respective regulators.
Individual formulations gave rise to multiple branded products. On average, the ratio of formulations to products was around 1: Overall, unapproved formulations gave rise to substantial proportions of branded products for all groups except metformin FDCs: Metformin FDCs are expressed as a percent of total oral diabetes drugs. Numerator and denominator data are included in S3 Table. Overall, across the four therapeutic areas, approved and unapproved formulations contributed varying proportions of FDC sales volumes: Sales values followed generally similar patterns.
Fig 1 summarises the proportions of formulations and products on the market and sales volumes and value in — arising in each therapeutic area from unapproved formulations. In contrast, of the sales volume arising from formulations marketed after 1 May 1, Most frequently, these were NSAID combinations with muscle relaxants chlorzoxazone, dicyclomine, drotaverine, thiocolchicoside, tizanidine, tolperisone or proteolytic enzymes serratiopeptidase, trypsin-chymotrypsin.
There were also combinations with misoprostol, tranexamic acid, and sumatriptan S2 Table. The most popular FDCs were dual combinations with sulfonylureas glimepiride, glipizide, gliclazide, glibenclamide and a triple combination with glimepiride and pioglitazone Table 2. Benzodiazepine with tricyclic antidepressant combinations accounted for Among the most popular FDCs, dozens of branded products were available, most with sales recorded in — Table 3.
Of ten formulations on the market, three accounted for CDSCO approval preceded the marketing date in all cases. Seven formulations included trihexyphenidyl benzhexol. No anti-psychotic formulations were listed. Multiple formulations, most without CDSCO approval, included drugs banned, restricted, or never approved internationally owing to adverse effects Table 5 [ 23 — 29 ].
Sales volumes were generally high. In three of the four areas examined, there were more unapproved formulations on the market than approved formulations. Many millions of doses were sold of FDCs that included drugs restricted, banned, or never approved in other countries owing to their association with serious adverse events including fatality. This occurred despite the legal need since for a new drug to have been approved before manufacture, including an FDC meeting the applicable legal test see Box 1.
In our analysis of the data in four therapeutic areas, we found no notable differences in the overall proportion of centrally approved formulations after 1 May compared with before. In our detailed analysis of the national rules S1 Text , we found no ambiguity relating to the question of whether an FDC needed central approval prior to manufacture. Clearly, however, the legal test until needed to be interpreted in order to determine its application to FDCs, and practice appears to have varied, as presumably approval was sought for some FDCs but not for others.
Numerous FDCs were marketed before the CDSCO approval date, suggesting that in some cases state licenses permitting manufacturing and sale were obtained first and approval sought retrospectively. However, state drug authority records to confirm this were unavailable. NSAIDs are among the most widely used drugs internationally. Indeed, some anti-psychotic FDCs were potentially lethal.
Tricyclic antidepressants, benzodiazepines, and antipsychotic medicines are independently associated with increased risk of falls, especially among older patients [ 30 ]. Nevertheless, FDCs comprising these sedating classes in single formulations were sold in considerable volumes. Since , the CDSCO is obliged to be satisfied as to the safety and effectiveness of products approved. The grounds for approval are not published, but the regulator acknowledges having approved some new drugs without clinical data Section 7 of [ 6 ] [ 31 , 32 ].
Many formulations being sold without approval contravene FDC development guidance on basic pharmacological parameters [ 8 , 33 ]. Pharmacovigilance in India is at an early stage and adverse event reporting rates are very low, so the absence of adverse event reports offers no reassurance of the safety of such formulations Sections 8 and 12 of [ 6 ] [ 34 — 36 ].
The study has limitations. We relied on publicly available records for central approvals and commercial sales records to determine the formulations marketed, the market launch dates, and the sales volumes. These sources were not compiled in order to support research, and they cannot be independently verified. Nevertheless, they are nationwide datasets that permit informative examination of data relevant to complaints about regulation and use in India of FDCs.
The sales data reflect mainly private out-of-pocket prescription spending. Sales through hospitals and dispensing doctors may include government-subsidised drugs, but we could not confirm this. Notwithstanding the limitations of the sales data and the absence of systematic central regulatory and state licensing records, this study substantiates the complaints of the 59th Report in demonstrating that regulatory problems in India extend well beyond widely publicised concerns about manufacturing standards.
FDCs were sold in large volumes. There was no FDC dispensing recorded in the other therapeutic areas [ 38 ]. Problematic production and use in India of FDCs will not be rectified without addressing the contributing causes. Price control has been evaded by including these drugs in FDC formulations [ 39 , 40 ] though amendments in the National Pharmaceutical Pricing Policy may prevent this [ 41 ]. However, price control could also be evaded by manufacturing SDFs of different strength to those on the National List of Essential Medicines of India [ 39 ], and the evasion argument does not explain why prescribers prefer FDCs.
Neither does it explain the large numbers of FDC products on the market. The Drugs Controller General India DCG[I] requested that states ask manufacturers to prove the safety and efficacy of their FDCs licensed without central approval within a period of 18 mo January [ 42 ], policy guidelines for approval of FDCs were published June [ 43 ], and the Chaudhury committee made recommendations on new drugs, clinical trials, and banning of drugs July [ 44 ].
Legislative underpinning for the mo safety and efficacy review, however, was lacking, and following industry lobbying, the DCG I excluded from it FDCs licensed before 21 September June [ 45 ]. In our view, significant factors contributing to the large number of FDCs on the market include structural problems with provisions of the Drugs and Cosmetics Rules, , stemming partly from the aged Drugs and Cosmetics Act, , and amendments to the rules [ 47 ].
The Drugs and Cosmetics Amendment Bill introduced in Parliament in and the proposed version put out for 12 d of consultation by the Ministry of Health and Family Welfare on 31 December are not aimed at these issues [ 48 , 49 ]. Withdrawal from the market should be staged, prioritising FDCs that include drugs banned or unapproved internationally and potentially most likely to harm patients. Approved FDC formulations containing drugs that have been withdrawn or restricted by other regulators should be reviewed with the intention of applying similar restrictions in India unless a strong evidence base dictates otherwise.Apple — WWDC 2017 Keynote