Flexible and precise dosing of enalapril maleate for all paediatric age groups utilizing orodispersible minitablets

Thabet, Yasmin; Walsh, Jennifer; Breitkreutz, Jörg

doi:10.1016/j.ijpharm.2018.02.037

Cited by 23 publications

(15 citation statements)

References 21 publications

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“…Investigations into novel oral dosage forms for children have indicated that formulations such as orodispersible mini-tablets or films are promising options in pediatric drug development, enabling personalized and flexible drug administration [7,32]. Dose titrations of enalapril maleate doses in the range of 0.025-4 mg were manageable with orodispersible mini-tablets of two different strengths (0.25 and 1 mg, respectively), facilitating flexible dosing for different patient groups [32]. The production of orodispersible films by means of 2D or 3D printing is considered a possibility for on-demand manufacturing of patient-specific doses [33,34].…”

Section: Main Findingsmentioning

confidence: 99%

“…It was shown that content uniformity and dose accuracy of the printed orodispersible films were at least equally good as for dose powders currently used for pediatrics. Both orodispersible mini-tablets and films dispersed in water were also suitable for administration through a nasogastric tube without causing blockage of the tube [7,32]. As enteral feeding tubes are widely used in the hospital setting, it is desirable that tests mimicking administration through feeding tubes for children are performed during drug development.…”

Section: Main Findingsmentioning

confidence: 99%

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A Focus Group Study about Oral Drug Administration Practices at Hospital Wards—Aspects to Consider in Drug Development of Age-Appropriate Formulations for Children

et al. 2020

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Oral drug administration to pediatric patients is characterized by a lack of age-appropriate drug products and the off-label use of medicines. However, drug administration practices at hospital wards is a scarcely studied subject. The aim of this study was to explore the oral drug administration practices at pediatric hospital wards, with a focus on experiences and challenges faced, methods used to mitigate existing problems, drug manipulation habits, perceptions about oral dosage forms and future needs of oral dosage forms for children. This was a qualitative study consisting of focus group discussions with physicians, nurses and clinical pharmacists in a tertiary university hospital with the objective of bringing forward a holistic view on this research topic. These healthcare professionals recognized different administration challenges that were classified as either dosage form-related or patient-related ones. A lack of depot formulations developed especially for children as well as oral pediatric dosage forms of drug substances currently available as intravenous dosage forms was recognized. The preferred oral dosage forms were oral liquids and orodispersible tablets. Patient-centered drug administration practices including factors facilitating drug administration both at hospital wards and at home after patient discharge were identified. Among all healthcare professionals, the efficient cooperation in drug prescribing and administration as well as in educating the child’s caregivers in correct administration techniques before discharge and improving the overall discharge process of patients was emphasized. This study complements the prevalent understanding that new dosage forms for children of varying ages and stages of development are still needed. It also brings a holistic view on different aspects of oral drug administration to pediatric patients and overall patient-centered drug administration practices.

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Section: Main Findingsmentioning

confidence: 99%

Section: Main Findingsmentioning

confidence: 99%

A Focus Group Study about Oral Drug Administration Practices at Hospital Wards—Aspects to Consider in Drug Development of Age-Appropriate Formulations for Children

et al. 2020

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“…When patient compliance is considered, the oral administration of liquid lipid can be associated with an unpleasant taste, which may be relevant for pediatric patients [196][197][198]. Additionally, liquid formulation makes it difficult to combine various pharmaceutical technologies such as controlled release technology.…”

Section: Development Of Su-seddss To Solid Dosage Formsmentioning

confidence: 99%

Current Status of Supersaturable Self-Emulsifying Drug Delivery Systems

Park

Kim

2020

Pharmaceutics

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Self-emulsifying drug delivery systems (SEDDSs) are a vital strategy to enhance the bioavailability (BA) of formulations of poorly water-soluble compounds. However, these formulations have certain limitations, including in vivo drug precipitation, poor in vitro in vivo correlation due to a lack of predictive in vitro tests, issues in handling of liquid formulation, and physico-chemical instability of drug and/or vehicle components. To overcome these limitations, which restrict the potential usage of such systems, the supersaturable SEDDSs (su-SEDDSs) have gained attention based on the fact that the inclusion of precipitation inhibitors (PIs) within SEDDSs helps maintain drug supersaturation after dispersion and digestion in the gastrointestinal tract. This improves the BA of drugs and reduces the variability of exposure. In addition, the formulation of solid su-SEDDSs has helped to overcome disadvantages of liquid or capsule dosage form. This review article discusses, in detail, the current status of su-SEDDSs that overcome the limitations of conventional SEDDSs. It discusses the definition and range of su-SEDDSs, the principle mechanisms underlying precipitation inhibition and enhanced in vivo absorption, drug application cases, biorelevance in vitro digestion models, and the development of liquid su-SEDDSs to solid dosage forms. This review also describes the effects of various physiological factors and the potential interactions between PIs and lipid, lipase or lipid digested products on the in vivo performance of su-SEDDSs. In particular, several considerations relating to the properties of PIs are discussed from various perspectives.Pharmaceutics 2020, 12, 365 2 of 57 intraluminal supersaturation and the biorelevance of supersaturation assays will be addressed. Finally, we will make suggestions for the successful development of su-SEDDs.There are many review articles that give useful information about the nature and application of supersaturable drug delivery systems or conventional SEDDSs. However, these reviews cover only a limited range of su-SEDDSs. Therefore, this review, which includes the current status of technology focused only on su-SEDDSs, is a valuable addition to the previous review literature because no review article currently covers such a wide range of su-SEDDSs. Conventional Solubilized SEDDSsThere has been a steady increase in the number of new drug candidates (almost 40%) that are highly hydrophobic and poorly water-soluble. The oral bioavailability of poorly water-soluble drugs is hindered by low solubility and slow dissolution in the aqueous environment of the GIT. Thus, it is a great challenge for pharmaceutical scientists to overcome the inherent slow dissolution and poor oral absorption of hydrophobic drugs [1][2][3][4]. SEDDSs have emerged as a promising approach to improving the biopharmaceutical performance of hydrophobic drugs by enhancing their bioavailability [5,6].An SEDDS is a pre-concentrate composed of a drug, oils, surfactants, and sometimes co-solvents and/or co-surfactan...

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“…The risks of ODMT administration in young children are considered to be low by EMA as presented in the EMA guideline on pharmaceutical development of medicines for paediatric use as acceptability and swallowability of 2 mm placebo minitablets have been demonstrated in over 500 children aged between 0 and 6 years without occurrence of any problems, except coughing in two children, in both cases without clinical relevance [[27], [28], [29], [30]]. The enalapril ODMTs administered in these studies will rapidly disperse in the mouth and thus the risk of choking/aspiration is considered negligible [16]. This potential risk is further mitigated by the method of administration, which includes the provision of a drink if required.…”

Section: Ethics and Disseminationmentioning

confidence: 99%

“…As part of the LENA project, a novel formulation of orodispersible minitablets (ODMT) was developed, small sized tablets (2 mm in diameter), which rapidly dissolve upon contact with water or saliva, suitable for paediatric administration [16]. Subsequently, a bioequivalence study in healthy adults was performed, showing comparable relative pharmacokinetics and drug exposure of the new ODMT and a standard tablet formulation [17].…”

Section: Introductionmentioning

confidence: 99%

Orodispersible minitablets of enalapril for use in children with heart failure (LENA): Rationale and protocol for a multicentre pharmacokinetic bridging study and follow-up safety study

Bajcetic

Dalinghaus

Breitkreutz

et al. 2019

Contemporary Clinical Trials Communications

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Introduction Treatment of paediatric heart failure is based on paradigms extensively tested in the adult population assuming similar underlying pathophysiological mechanisms. Angiotensin converting enzyme inhibitors (ACEI) like enalapril are one of the cornerstones of treatment and commonly used off-label in children. Dose recommendations have been extrapolated from adult experience, but the relationship between dose and pharmacokinetics (PK) in (young) children is insufficiently studied. Furthermore, appropriate paediatric formulations are lacking. Within the European collaborative project LENA, a novel formulation of enalapril orodispersible minitablets (ODMT), suitable for paediatric administration, will be tested in (young) children with heart failure due to either dilated cardiomyopathy or congenital heart disease in two pharmacokinetic bridging studies. Paediatric PK data of enalapril and its active metabolite enalaprilat will be obtained. In a follow-up study, the safety of enalapril ODMTs will be demonstrated in patients on long-term treatment of up to 10 months. Furthermore, additional information about pharmacodynamics (PD) and ODMT acceptability will be collected in all three studies. Methods and Analysis Phase II/III, open-label, multicentre study. Children with dilated cardiomyopathy (DCM) (n = 25; 1 month to less than 12 years) or congenital heart disease (CHD) (n = 60; 0 to less than 6 years) requiring or already on ACEI will be included. Exclusion criteria include severe heart failure precluding ACEI use, hypotension, renal impairment, hypersensitivity to ACEI. For those naïve to ACEI up-titration to an optimal dose will be performed, those already on ACEI will be switched to an expected equivalent dose of enalapril ODMT and optimised. In the first 8 weeks of treatment, a PK profile will be obtained at the first dose (ACEI naïve patients) or when an optimal dose is reached. Furthermore, population PK will be done with concentrations detected over the whole treatment period. PD and safety data will be obtained at least at 2-weeks intervals. Subsequently, an intended number of 85 patients will be followed-up up to 10 months to demonstrate long-term safety, based on the occurrence of (severe) adverse events and monitoring of vital signs and renal function. Ethics and dissemination Clinical Trial Authorisation and a favourable ethics committee opinion were obtained in all five participating countries. Results of the studies will be submitted for publication in a peer-reviewed journal. Trial registration numbers EudraCT 2015-002335-17, EudraCT 2015-002396-18, EudraCT 2015-002397-21.

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Flexible and precise dosing of enalapril maleate for all paediatric age groups utilizing orodispersible minitablets

Cited by 23 publications

References 21 publications

A Focus Group Study about Oral Drug Administration Practices at Hospital Wards—Aspects to Consider in Drug Development of Age-Appropriate Formulations for Children

A Focus Group Study about Oral Drug Administration Practices at Hospital Wards—Aspects to Consider in Drug Development of Age-Appropriate Formulations for Children

Current Status of Supersaturable Self-Emulsifying Drug Delivery Systems

Orodispersible minitablets of enalapril for use in children with heart failure (LENA): Rationale and protocol for a multicentre pharmacokinetic bridging study and follow-up safety study

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