Joseph Kushner

Scale-up model describing the impact of lubrication on tablet tensile strength.

Lubrication of 2:1 and 1:1 blends of microcrystalline cellulose and spray-dried lactose or dibasic calcium phosphate (DCP) with 0.33% or 1% magnesium stearate, as model free-flowing pharmaceutical formulations, was performed in rotary drum blenders. Blender process parameters examined in this study included type (Bin, V, and Turbula), volume (0.75-Quart to 200-L), fraction of headspace in the blender after the blend is loaded (30-70%), speed (6-202 rpm), and time (up to 225 min). Based on analysis of the experimental data, the following model for the impact of the lubrication process on tablet tensile strength at 0.85 solid fraction, TS(SF=0.85), was obtained, TS(SF=0.85)=TS(SF=0.85,0) [βexp(-γ×V(1/3)×F(headspace)×r)+(1-β)], where V is blender volume, F(headspace) is the headspace fraction, r is the number of revolutions (i.e. speed × time), TS(SF=0.85,0) is the initial tensile strength of the blend, β is the sensitivity of the blend to lubrication, and γ is the lubrication rate constant of the formulation. This model can be used to maintain tensile strength during scale-up, by ensuring that (V(1/3)F(headspace)r)(1)=(V(1/3)F(headspace)r)(2). The model also suggests that formulations with DCP are less sensitive to lubrication and more slowly lubricated than formulations with spray-dried lactose (i.e. smaller β and γ values).

Heterogeneity in Skin Treated with Low-Frequency Ultrasound

Recent experimental evidence using colored, fluorescent permeants suggests that skin treated with low-frequency sonophoresis (LFS) is perturbed in a heterogeneous manner. Macroscopic and microscopic visualization studies, topical penetration studies, transdermal permeability studies, and skin electrical resistivity measurements have shown that discrete domains, referred to as localized transport regions (LTRs), which are formed during LFS treatment of the skin, possess greatly reduced barrier properties, and therefore exhibit increased permeant skin penetration, compared to the surrounding regions of LFS-treated skin. The transformation of LTR formation from a heterogeneous to a homogeneous phenomenon has the potential benefit of increasing the maximum level of transdermal permeability or of reducing the area of skin required to deliver a desired dose of drug transdermally. Future studies, aimed at elucidating both the mechanisms of LTR formation and the limits of nondamaging formation of LTRs in the skin, are required to incorporate these proposed improvements to enhance the efficacy and practical utility of low-frequency sonophoresis.

Examining the Impact of Excipient Material Property Variation on Drug Product Quality Attributes: A Quality-By-Design Study for a Roller Compacted, Immediate Release Tablet

A quality-by-design study examining the impact of variability in excipient material properties on the quality attributes of an immediate release tablet was performed. A literature review and risk analysis identified particle size of microcrystalline cellulose (MCC), spray-dried lactose (SDL), and magnesium stearate (MgSt), and polymorph and specific surface area of MgSt as potential high-risk material properties. The following results were obtained with laboratory-scale processing equipment: (1) a 32-µm increase in d(50) (mean particle diameter) of MCC and SDL led to a ∼ 30-µm increase in blend and granulation d(50) and a statistically significant increase in the blend and granulation flow function coefficients, and (2) a 32-µm increase in d(50) of MCC and SDL, a 4.4 m(2)/g increase in the surface area, and a 19-µm decrease in the particle size of MgSt yielded an 18%-28% increase in ribbon tensile strength and tablet hardness. Confirmatory experiments with kilo-scale equipment showed impact of excipient variability on granulation particle size and tablet hardness was ∼ 50% smaller. Although the impact of these differences on overall manufacturability and performance of the tablets examined here were deemed low, the presence of statistically significant effects supports examining excipient variability as part of the design and control strategy of new drug products.

A Quality-by-Design Study for an Immediate-Release Tablet Platform: Examining the Relative Impact of Active Pharmaceutical Ingredient Properties, Processing Methods, and Excipient Variability on Drug Product Quality Attributes

The impact of filler-lubricant particle size ratio variation (3.4-41.6) on the attributes of an immediate-release tablet was compared with the impacts of the manufacturing method used (direct compression or dry granulation) and drug loading (1%, 5%, and 25%), particle size (D[4,3]: 8-114 μm), and drug type (theophylline or ibuprofen). All batches were successfully manufactured, except for direct compression of 25% drug loading of 8 μm (D[4,3]) drug, which exhibited very poor flow properties. All manufactured tablets possessed adequate quality attributes: tablet weight uniformity <4% RSD, tablet potency: 94%-105%, content uniformity <6% RSD, acceptance value ≤ 15, solid fraction: 0.82-0.86, tensile strength >1 MPa, friability ≤ 0.2% weight loss, and disintegration time < 4 min. The filler-lubricant particle size ratio exhibited the greatest impact on blend and granulation particle size and granulation flow, whereas drug property variation dominated blend flow, ribbon solid fraction, and tablet quality attributes. Although statistically significant effects were observed, the results of this study suggest that the manufacturability and performance of this immediate-release tablet formulation is robust to a broad range of variation in drug properties, both within-grade and extra-grade excipient particle size variations, and the choice of manufacturing method.

Utilizing quantitative certificate of analysis data to assess the amount of excipient lot-to-lot variability sampled during drug product development

Understanding variability in excipient physico-chemical properties is becoming an important aspect of Quality-by-Design drug product development. However, present experimental methods have only been able to study a few physico-chemical properties for a few excipient lots due to time, cost, and sample gathering considerations. An alternative analysis method is proposed here that shows how quantitative physico-chemical property data reported in vendor certificates of analysis can evaluate excipient lot-to-lot variability in a comprehensive and low cost manner. Microcrystalline cellulose, spray-dried lactose, and magnesium stearate were selected as commonly-used excipients for this demonstration. The proposed analysis method offers drug product developers several advantages over present experimental methods, including the ability to: (1) examine excipient products for manufacturing site and/or year-to-year variations, (2) quantify a domain of prior experience for each excipient by determining the percentage of excipient lots contained within a multi-dimensional ellipsoid described by the excipient lots used during drug product development, and (3) rationally select excipient lots from the vendors inventory to maximize the domain of prior experience throughout the drug development process. For cases where certificate of analysis data may contain insufficient information, drug product developers and excipient vendors should work together to identify more appropriate datasets for analysis.

Extended-Release Once-Daily Formulation of Tofacitinib: Evaluation of Pharmacokinetics Compared With Immediate-Release Tofacitinib and Impact of Food.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. An extended‐release (XR) formulation has been designed to provide a once‐daily (QD) dosing option to patients to achieve comparable pharmacokinetic (PK) parameters to the twice‐daily immediate‐release (IR) formulation. We conducted 2 randomized, open‐label, phase 1 studies in healthy volunteers. Study A characterized single‐dose and steady‐state PK of tofacitinib XR 11 mg QD and intended to demonstrate equivalence of exposure under single‐dose and steady‐state conditions to tofacitinib IR 5 mg twice daily. Study B assessed the effect of a high‐fat meal on the bioavailability of tofacitinib from the XR formulation. Safety and tolerability were monitored in both studies. In study A (N = 24), the XR and IR formulations achieved time to maximum plasma concentration at 4 hours and 0.5 hours postdose, respectively; terminal half‐life was 5.9 hours and 3.2 hours, respectively. Area under plasma concentration‐time curve (AUC) and maximum plasma concentration (Cmax) after single‐ and multiple‐dose administration were equivalent between the XR and IR formulations. In study B (N = 24), no difference in AUC was observed for fed vs fasted conditions. Cmax increased by 27% under the fed state. On repeat administration, negligible accumulation (<20%) of systemic exposures was observed for both formulations. Steady state was achieved within 48 hours of dosing with the XR formulation. Tofacitinib administration as an XR or IR formulation was generally well tolerated in these studies.

Incorporating Turbula mixers into a blending scale-up model for evaluating the effect of magnesium stearate on tablet tensile strength and bulk specific volume

Turbula bottle blenders are often used in lab-scale experiments during early-stage pharmaceutical product development. Unfortunately, applying knowledge gained with these blenders to larger-sized diffusion mixers is limited by the lack of blending models that include Turbula mixers. To address this need for lubrication blending scale-up, 2:1 blends of microcrystalline cellulose and spray-dried lactose or dibasic calcium phosphate were mixed with 1% magnesium stearate using Turbula bottle blenders, varying bottle volume, V (30-1250mL); bottle headspace fraction, F(headspace) (30-70%); and the number of blending cycles, r (24 to ∼190,000 cycles). The impact of lubrication blending on tensile strength and bulk specific volume quality attributes, QA, was modeled by:where QA(0) is initial QA value, β is sensitivity of QA to lubrication, γ is formulation-specific lubrication rate constant, and L is characteristic mixing length scale (i.e. 1.5V(1/3) for Turbula blenders, V(1/3) for simple diffusion mixers). The factor of 1.5 captures the bottle dimensions and the more complex mixing dynamics of the Turbula blender. This lubrication blending process model is valid for scale-up from 30-mL to 200-L blenders. Assessing bulk specific volume may provide a simpler, more material-sparing means for determining γ than tensile strength, since these QAs exhibited similar γ values.

Commercial scale validation of a process scale-up model for lubricant blending of pharmaceutical powders

An experimental study was conducted to verify that lubrication mixing in commercial-scale bin blenders can be described by a previously-reported lubrication blending process scale-up model. Specifically, the mixing of two placebo formulations (2:1 MCC:lactose, and 2:1 MCC:DCP) with 1% magnesium stearate in 100, 400, and 2000 L bin blenders at 30% and 70% blend fill levels for several extents of lubricant mixing was examined. The lubricated powder blends were assessed for bulk/tapped density and powder flow, as measured by Hausners ratio. The blends were then compressed into tablets and evaluated for tensile strength, friability, and disintegration. It was observed that the lubrication rate constant, γ, for tablet tensile strength and for bulk specific volume were similar. Furthermore, powder flow, as measured by Hausners ratio, improved with increased extent of lubrication. Tablet disintegration and tablet friability were both minimally affected as a result of extended lubrication for the placebos blends evaluated in this study. The results of this study confirm that the lubrication mixing model can be applied to scale-up the lubrication blending process from batches made in 30 mL bottle blenders to batches made in 2000 L bin blenders, which is a range of nearly five orders of magnitude.

Improving the hardness of dry granulated tablets containing sodium lauryl sulfate

The impact of the addition of a wetting agent, the surfactant sodium lauryl sulfate (SLS), on the tablet hardness of a dry granulated, solid oral dosage form was investigated. In three batches, SLS was added concurrently with: (1) a poorly soluble, highly hydrophobic active pharmaceutical ingredient (API) and the other excipients prior to the initial blending step, (2) magnesium stearate prior to roller compaction, or (3) magnesium stearate prior to tableting. A fourth batch, which did not contain SLS, served as a control. The maximum hardness of 100 mg, 1/4″-SRC tablets for the four batches--SLS added initially, prior to roller compaction, prior to tableting, and no SLS--were 61±3, 71±3, 89±5, and 86±3N, respectively, suggesting reduced processing of SLS improves tablet hardness by ∼50%. Dissolution of the tablets in 900 ml of simulated gastric fluid with paddles at 75 rpm showed that: (1) there was no impact on the insertion point of SLS into the process on API dissolution, and (2) that the presence of SLS improved dissolution by 5% compared to the control tablets. Adding SLS just prior to tableting can improve tablet hardness and yield similar dissolution performance relative to SLS addition prior to the initial blending step.

THU0143 Pharmacokinetics, Bioavailability and Safety of A Modified Release Once Daily Formulation of Tofacitinib in Healthy Volunteers

Background Tofacitinib is a novel, oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). The efficacy and safety of an immediate-release (IR) formulation of tofacitinib, dosed twice daily (BID), has been assessed in patients with active moderate to severe RA. To facilitate once daily (QD) dosing, a novel modified-release (MR) formulation has been designed to achieve comparability of key systemic exposure parameters. Objectives To compare the extent of exposure between a single dose of tofacitinib MR 11 mg vs an IR 2x5 mg dose in healthy volunteers (HV). Methods This was a randomised, open label, 2-way cross-over study conducted in 26 HV. Following an overnight fast, HV were randomised to receive either a single dose of MR 11 mg (MR; test) or IR 2 x 5 mg (IR; reference). Treatments were separated by a 72-hour (h) washout. Pharmacokinetic (PK) parameters were calculated using non-compartmental analyses. The primary endpoint was extent of tofacitinib exposure, measured as area under the concentration-time curve from time zero extrapolated to infinite time (AUCinf). A mixed-effects model was used to generate adjusted geometric mean ratios (MR/IR) and 90% confidence intervals (CIs). The steady-state (SS) profiles of tofacitinib MR and IR were predicted using single-dose data from this study. Results All 26 HV completed the study and were included in the analyses. The study population had a mean age of 33.6 years, a mean body weight of 77.5 kg, and was 19% female. For the MR and IR formulations, geometric mean AUCinf (ng*h/mL) was 297.5 and 286.3, respectively, resulting in an MR/IR ratio of 103.91% (90% CI: 100.49%, 107.45%). Maximum plasma concentration (Cmax; ng/mL) adjusted for formulation was 40.75 and 44.10 for MR and IR, respectively, resulting in an MR/IR ratio of 92.40% (90% CI: 84.99%, 100.45%). For both parameters, 90% CI values were wholly contained within the 80–125% range of bioequivalence. Mean terminal half-life was 5.71 h and 3.41 h for MR and IR formulations, respectively. The most common adverse events (AEs) were nausea, abdominal pain, back pain and headache. The incidence of AEs was similar between treatment groups and no serious AEs were reported. Predictions following SS dosing indicate similar time above JAK1/3 half maximal inhibitory concentration signalling thresholds and similar AUC, peak concentration and minimum concentration values between MR and IR formulations. Conclusions This study demonstrates the single dose equivalence of AUCinf and Cmax of the MR and IR formulations of tofacitinib. Single doses of both formulations were well tolerated. This novel MR formulation of tofacitinib facilitates an opportunity to enable QD dosing, while maintaining systemic drug concentrations similar to the IR formulation (administered BID). Multiple-dose studies will be conducted to confirm the predictions of the SS PK profile and demonstrate equivalence between formulations following SS dosing. Acknowledgements This study was sponsored by Pfizer Inc. Pfizer personnel were involved in protocol development and data analysis. Editorial support was provided by Claire Cridland of CMC and funded by Pfizer Inc. Disclosure of Interest : M. Lamba Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, T. Fletcher Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. Alvey Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, A. Hazra Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J. Kushner Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J. Larmann Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, T. Stock Shareholder of: Pfizer Inc, Employee of: Pfizer Inc DOI 10.1136/annrheumdis-2014-eular.1521