In this scientific poster, we demonstrate an optimized approach to developing oral modified-release (MR) dosage forms using the Translational Pharmaceutics platform. Download a copy now.

To demonstrate an optimized approach to developing oral modified-release (MR) dosage forms using the Translational Pharmaceutics platform. This approach uses emerging human data to inform the adjustment of formulation composition in an adaptive clinical study.

The development of MR formulations is complicated by the interplay between drug molecules, dosage form, and gastro-intestinal physiology factors. Therefore, in vitro and preclinical studies often fail to predict formulation performance in humans and in guiding the development of an optimal MR product.

This presentation highlights the use of a formulation design space, real-time manufacturing, and a flexible clinical design in overcoming the limitations described above to accelerate successful MR product development whilst maintaining regulatory and quality compliance.

Download our CRS 2021 Poster on 'Using formulation design & clinical data to optimize the development of modified release (MR) dosage forms' here.

The purpose of this study is to review the benefits of integrating product manufacturing and clinical testing to enable human PK data to inform MR composition selection in real-time, generating knowledge for future MR development (Figure 1). This platform permits the inclusion of formulation design spaces in regulatory submissions, from within which discrete compositions can be selected during the study conducted in real time.

Presented at the 24th North American ISSX Meeting, in this poster, we determine Mass Balance, Metabolite Profile and Identification and Absolute Bioavailability of Nolasiban in Healthy Female Subjects, via an integrated radiolabelled study.

This open-label study was conducted in two cohorts of six subjects. Approvals were obtained from the Medicines and Healthcare products Regulatory Agency, Ethics and the Administration of Radioactive

Download Quotient Sciences' scientific poster entitled, 'EuPFI 2021 - Development of a Novel Paediatric Belumosudil Oral Suspension'.

Belumosudil, a ROCK2 selective inhibitor, is currently in development for the treatment of immune disorders. A formulation was required suitable for a pediatric patient population aged between three months and twelve years. This development program aimed to develop a suitable, novel belumosudil oral suspension formulation using age-appropriate excipients to be used in a relative bioavailability assessment of the suspension compared to the reference adult tablet formulation. A liquid formulation enables flexible dosing by varying the dose volume according to the age and/or body weight of the patient.

Presented at the 2021 EuPFI event, the poster documents the project of a ROCK2 selective inhibitor in development for the treatment of immune disorders.

Belumosudil, a ROCK2 selective inhibitor, is currently in development for the treatment of immune disorders. An oral suspension formulation is being investigated as a possible pediatric formulation for patients aged between three months and twelve years. This study aimed to select and identify a suitable, novel belumosudil oral suspension formulation, with an optimal flavor and/or sweetener combination to improve palatability in the target population.

The study comprises a taste assessment and relative bioavailability in a two-part protocol. The initial study part (Part 1) involves a ‘sip and spit’ taste assessment to profile the taste characteristics of the API and identify a suitable flavor system which can be taken into Part 2 for a relative bioavailability assessment of the novel oral suspension compared to the reference adult oral tablet formulation.

Download our AAPS 2021 poster entitled: 'Development and Application of a PBPK Model Using Theoretical Particle Size Distribution to Describe in vivo Dissolution to Predict the Impact of Formulation Changes on Oral Bioavailability of GB001'.

GB001 is a potent and highly selective prostaglandin D2 receptor (DP2/CRTH2) antagonist investigated for the treatment of moderate to severe asthma. GB001 is an L-lysine salt thus in vivo dissolution is unlikely to conform to standard Johnson model [1] behavior using measured particle size as an input. 

A theoretical particle size distribution (T PSD) linked Physiologically Based Pharmacokinetic (PBPK) model was developed to assess the impact of drug substance, formulation or manufacturing process changes on in vivo performance of GB001 immediate release (IR) tablets in humans.

Download our scientific poster from AAPS 2021, 'Pharmaceutical and clinical performance comparisons of modified release multiparticulates and matrix tablet formulations'.

The purpose of this study is to review practical experiences of head-to-head pharmaceutical and clinical comparisons of MUPs and matrix tablet platforms to identify an optimal MR formulation.

A wide variety of formulation technologies are available to control the in vivo release profile of drugs from solid oral dosage forms, whether to achieve a target systemic pharmacokinetic (PK) profile or deliver a therapeutic to a particular anatomical site for the treatment of local gastrointestinal (GI) disease. Multiparticulate systems (MUPs) and monolithic matrix tablets are two modified release (MR) technologies commonly used for the sustained delivery of a drug over a prolonged period. There are a variety of recognized pros and cons for these approaches.

Selection of a specific MR platform and optimization of the quantitative levels of critical to performance excipients in that formulation can be challenging based on surrogate nonclinical, in vitro, or silico data, and the recognized lack of predictability of these models to performance in humans. Traditional development also means the time and cost of taking multiple options into a clinical PK study can be prohibitive.

An integrated development program with in-study protocol flexibility can enable real-time optimization of key formulation variables based on clinical data, enabling multiple technology platforms to be assessed in parallel to identify the best technology to achieve the desired target product profile (TPP).

The purpose of this study is to review practical experiences of head-to-head pharmaceutical and clinical comparisons of MUPs and matrix tablet platforms to identify an optimal MR formulation.

Download Quotient Sciences poster entitled 'EBF 2021- Analysis of Ranitidine Reference Materials Using a Six N-Nitrosamine LC-MS/MS Assay'.

We built an assay to determine six pharmaceutically relevant N-Nitrosamines in both drug substances and drug products. The analytes included in our assay were N-Nitrosodimethylamine (NDMA), N-Nitrosodiethylamine(NDEA), N-Nitroso-N-Methylaniline(NMPA), N-Nitrosodiisopropylamine(NDIPA), N-Ethyl-N-Nitroso-2-Propanamine(NIPEA) and N-Nitrosodi-n-Propylamine(NDPA). We applied our assay to determine N-nitrosamines in three different Ranitidine Reference Materials: Ranitidine Hydrochloride British Pharmacopoeia Chemical Reference Substance (BPCRS), Ranitidine Hydrochloride European Pharmacopoeia (EP) Reference Standard and Ranitidine Hydrochloride United States Pharmacopeia (USP) Reference Standard.

Download Quotient Sciences' poster, 'EBF 2021: Novel Copper Protein Speciation Method Calculating Serum Non-Ceruloplasmin Copper: A Comparative Analysis'.

• Wilson disease (WD) is an autosomal recessive disorder of copper (Cu) transport caused by mutations of the ATP7B gene
• International guidelines on the management of WD recommend serum non-ceruloplasmin-bound Cu (NCC; free Cu index) for diagnosis and therapeutic monitoring; NCC target range in WD = 50 to 150μg/L
• The current “Standard of Care” evaluation of NCC levels involves the incubation of serum with EDTA (NCC-EDTA) to chelate copper from proteins other than ceruloplasmin before ultracentrifugation
• A high molecular weight artifact binding copper from albumin retained above the 30KDa filter may result in an underestimation of true NCC
• During the conduct of an RCT (clinical trials gov: NCT03539952), the FDA highlighted the deficiencies in NCC-EDTA
• Orphalan developed and optimized a novel assay to determine NCC using copper protein speciation (NCC-CuSp) with LC-ICP-MS
• The NCC-CuSpassay is a two-step process that involves:
• Inductively coupled mass spectrometry to measure total Cu
• Liquid chromatography (LC-ICP-MS) to calculate Cp-Cu as a percentage of total Cu
• LC-ICP-MS determines Cp-Cu indirectly by the speciation of Cu-containing proteins
• There are no data in WD subjects comparing the performance of NCC-CuSpwith NCC-EDTA

We built an assay to determine six pharmaceutically relevant N-nitrosamines in both drug substances and drug products. The analytes included in our assay were N-Nitrosodimethylamine (NDMA), N-Nitrosodiethylamine (NDEA), N-Nitroso-N-Methylaniline (NMPA), N-Nitrosodiisopropylamine (NDIPA), N-Ethyl-N-Nitroso-2-Propanamine (NIPEA) and N-Nitrosodi-n-Propylamine (NDPA). We applied our assay to determine N-nitrosamines in three different Ranitidine Reference Materials: Ranitidine Hydrochloride British Pharmacopoeia Chemical Reference Substance (BPCRS), Ranitidine Hydrochloride European Pharmacopoeia (EP) Reference Standard and Ranitidine Hydrochloride United States Pharmacopeia (USP) Reference Standard.