An industrial approach towards solid dosage development for first-in-human studies: Application of predictive science and lean principles.

Tablet development is challenging during early clinical phases of drug discovery because of dose uncertainty, limited active pharmaceutical ingredient availability, and short lead times. Here, we introduce a new framework to expedite product development using a suite of in-house and commercially available predictive tools developed through the integration of computer modelling and material-sparing characterisation methods. The strategy underpins the use of dry granulation for formulation development with guidance on scale-up and manufacturability to achieve 'First Time Right'. We present an analytical strategy based on predictive science with a focus on stability, and shelf-life related attributes to assure product quality. Thus, we provide a holistic approach towards robust, scientific product development through integrated project knowledge and risk-based approaches, delivering significant savings in both material and resources.

Simultaneous controlled iontophoretic delivery of pramipexole and rasagiline in vitro and in vivo: Transdermal polypharmacy to treat Parkinson's disease.

Effective treatment of Parkinson's disease (PD) involves administration of therapeutic agents with complementary mechanisms of action in order to replenish, sustain or substitute endogenous dopamine. The objective of this study was to investigate anodal co-iontophoresis of pramipexole (PRAM; dopamine agonist) and rasagiline (RAS; MAO-B inhibitor) in vitro and in vivo. Passive permeation of PRAM and RAS (20 mM each) across porcine skin after 6 h was 15.7 ±â€¯1.9 and 16.0 ±â€¯2.9 µg/cm2, respectively. Co-iontophoresis at 0.15, 0.3 and 0.5 mA/cm2 resulted in statistically significant increases in delivery of PRAM and RAS; at 0.5 mA/cm2, cumulative permeation of PRAM and RAS was 613.5 ±â€¯114.6 and 441.1 ±â€¯169.2 µg/cm2, respectively - corresponding to 38- and 27-fold increases over passive diffusion. Electromigration was the dominant mechanism for both molecules (>80%) and there was no effect on convective solvent flow. Statistically equivalent delivery was observed with human skin. The co-iontophoretic system showed high delivery efficiency with 29% and 35% of the applied amounts of PRAM and RAS being delivered. Preliminary pharmacokinetics studies in rats confirmed that the input rate in vivo was such that therapeutic amounts of the two drugs could be co-administered to humans by transdermal iontophoresis using reasonably sized patches and moderate current densities.

Controlled iontophoretic delivery of pramipexole: electrotransport kinetics in vitro and in vivo.

The objective of the study was to investigate the anodal iontophoretic delivery of pramipexole (PRAM), a dopamine agonist used for the treatment of Parkinson's disease, in order to determine whether therapeutic amounts of the drug could be delivered across the skin. Preliminary iontophoretic experiments were performed in vitro using porcine ear and human abdominal skin. These were followed by a pharmacokinetic study in male Wistar rats to determine the drug input rate in vivo. Stability studies revealed that after current application (0.5 mA/cm(2) for 6h), the solution concentration of PRAM was only 60.2 ± 5.3% of its initial value. However, inclusion of sodium metabisulfite (0.5%), an antioxidant, increased this to 97.2 ± 3.1%. Iontophoretic transport of PRAM across porcine skin in vitro was studied as a function of current density (0.15, 0.3, 0.5 mA/cm(2)) and concentration (10, 20, 40 mM). Increasing the current density from 0.15 to 0.3 and 0.5 mA/cm(2), resulted in 2.5- and 4-fold increases in cumulative permeation, from 309.5 ± 80.2 to 748.8 ± 148.1 and 1229.1 ± 138.6 µg/cm(2), respectively. Increasing the PRAM concentration in solution from 10 to 20 and 40 mM resulted in a 2-fold increase in cumulative permeation (816.4 ± 123.3, 1229.1 ± 138.6 and 1643.6 ± 201.3 µg/cm(2), respectively). Good linearity was observed between PRAM flux and both the applied current density (r(2)=0.98) and drug concentration in the formulation (r(2)=0.99). Co-iontophoresis of acetaminophen showed that electromigration was the dominant electrotransport mechanism (accounting for >80% of delivery) and that there was no inhibition of electroosmotic flow at any current density. Cumulative iontophoretic permeation across human and porcine skin (after 6h at 0.5 mA/cm(2)) was also shown to be statistically equivalent (1229.1 ± 138.6 and 1184.8 ± 236.4 µg/cm(2), respectively). High transport and delivery efficiencies were achieved for PRAM (up to 7% and 58%, respectively). The plasma concentration profiles obtained in the iontophoretic studies in vivo (20 mM PRAM; 0.5 mA/cm(2) for 5h) were modelled using constant and time-variant input models; the latter gave a superior quality fit. The drug input rate in vivo suggested that PRAM electrotransport rates would be sufficient for therapeutic delivery and the management of Parkinsonism.

Colloidal soft nanocarrier for transdermal delivery of dopamine agonist: ex vivo and in vivo evaluation.

Ropinirole, an antiparkinsoism dopamine agonist, is used to treat Restless Legs Syndrome. However, orally it undergoes degradation in gastrointestinal tract and extensive first pass metabolism, resulting in its poor and variable bioavailability of the commercially available oral tablets. In the present investigation, soft nanocarriers, viz., microemulsion of ropinirole with the globule size of 160.2 ± 3.87 nm and zeta potential of -4.24 mV was explored for transdermal application. Transdermal drug delivery offers benefits such as sustained therapeutic plasma levels of drugs, avoidance of first pass effect, and improved patient compliance. In comparison to the hydrogel, the developed microemulsion enhanced the drug permeation across the rat skin and porcine ear skin by 3.5 and 2 folds, respectively. Further, the developed microemulsion antagonized the catalepsy in the haloperidol-induced catalepsy rat model by 10 folds as compared to the marketed tablets. Additionally, in rotenone induced Parkinsonism rat model, the microemulsion showed improvement in the motor function by 76% whereas the oral tablet showed only 5% restoration of the normal function. Besides this, the developed formulation successfully restored the catalase and superoxide dismutase levels which were significantly reduced by rotenone administration. Overall, the in vivo studies suggested the potential of the developed transdermal microemulsion of Ropinirole as a viable alternative to marketed formulations.

Controlled iontophoretic transport of huperzine A across skin in vitro and in vivo: effect of delivery conditions and comparison of pharmacokinetic models.

The aim of this study was to investigate constant current anodal iontophoresis of Huperzine A (HupA) in vitro and in vivo and hence to evaluate the feasibility of using electrically assisted delivery to administer therapeutic amounts of the drug across the skin for the treatment of Alzheimer's disease. Preliminary experiments were performed using porcine and human skin in vitro. Stability studies demonstrated that HupA was not degraded upon exposure to epidermis or dermis for 12 h and that it was also stable in the presence of an electric current (0.5 mA · cm(-2)). Passive permeation of HupA (2 mM) was minimal (1.1 ± 0.1 µg · cm(-2)); iontophoresis at 0.15, 0.3, and 0.5 mA · cm(-2) produced 106-, 134-, and 184-fold increases in its transport across the skin. Surprisingly, despite the use of a salt bridge to isolate the formulation compartment from the anodal chamber, which contained 133 mM NaCl, iontophoresis of HupA was shown to increase linearly with its concentration (1, 2, and 4 mM in 25 mM MES, pH 5.0) (r(2) = 0.99). This was attributed to the low ratio of drug to Cl¯ (in the skin and in the receiver compartment) which competed strongly to carry current, its depletion, and to possible competition from the zwitterionic MES. Co-iontophoresis of acetaminophen confirmed that electromigration was the dominant electrotransport mechanism. Total delivery across human and porcine skin was found to be statistically equivalent (243.2 ± 33.1 and 235.6 ± 13.7 µg · cm(-2), respectively). Although the transport efficiency was ∼ 1%, the iontophoretic delivery efficiency (i.e., the fraction of the drug load delivered) was extremely high, in the range of 46-81% depending on the current density. Cumulative permeation of HupA from a Carbopol gel formulation after iontophoresis for 6 h at 0.5 mA · cm(-2) was less than that from solution (135.3 ± 25.2 and 202.9 ± 5.2 µg · cm(-2), respectively) but sufficient for therapeutic delivery. Pharmacokinetic parameters were determined in male Wistar rats in vivo (4 mM HupA; 0.5 mA · cm(-2) for 5 h with Ag/AgCl electrodes) using two-compartment models with either constant or time-variant input rates. A superior fit was obtained using the time-variant model, and the input rate in vivo was significantly greater than that in vitro. Based on these results and the known pharmacokinetics, it was estimated that therapeutic amounts of HupA could be delivered for the treatment of Alzheimer's disease using a reasonably sized patch.

Comparative in vitro and in vivo evaluation of lipid based nanocarriers of Huperzine A.

The purpose of the present investigation was to explore feasibility of nanocarrier based transdermal delivery of Huperzine A (HupA) for the treatment of Alzheimer's disease. For this investigation, microemulsion (ME), solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs) were formulated and characterized for physicochemical parameters. The pseudo-ternary phase diagrams for microemulsion region were developed using generally recognized as safe (GRAS) excipients. The SLNs and NLCs were prepared by microemulsion template technique. These nanodispersions were formulated into gels for transdermal application and evaluated for various physicochemical parameters. In vitro permeation profiles in rat skin exhibited zero-order kinetics. HupA loaded ME exhibited superior permeation than NLCs followed by SLNs and cumulative amount permeated after 24h was found to be 147.68±9.42 µg/cm(2), 129.11±32.76 µg/cm(2) and 10.74±0.68 µg/cm(2), respectively. Furthermore, optimized gels were subjected to primary skin irritation testing over a period of 48 h and were found to be safe for skin application. In vivo efficacy tested in scopolamine induced amnesia model indicated significant improvement in cognitive function in mice group treated with developed nanocarrier based formulations as compared to the control group.

Comparison of the cutaneous iontophoretic delivery of rasagiline and selegiline across porcine and human skin in vitro.

The objective was to investigate the anodal iontophoresis of the MAO-B inhibitors rasagiline (RAS) and selegiline (SEL) across porcine and human skin in vitro. Passive delivery of RAS and SEL from aqueous solution was minimal; however, increasing current density from 0.1 to 0.3 and 0.5 mA/cm(2) produced a linear increase in steady-state iontophoretic flux (J(ss,RAS)=49.1i(d)+27.9 (r(2)=0.96) and J(ss,SEL)=27.8i(d)+25.8 (r(2)=0.98)). In the absence of background electrolyte, a four-fold change in donor concentration (10, 20 and 40 mM) did not produce a statistically significant increase in cumulative permeation of either drug after iontophoresis at 0.5mA/cm(2) for 7h. Co-iontophoresis of acetaminophen confirmed that electromigration was the dominant transport mechanism for both drugs (∼90%). Total iontophoretic delivery of RAS and SEL across porcine and human skin in vitro was statistically equivalent (RAS: 1512.7 ± 163.7 and 1523.6 ± 195.9 µg/cm(2), respectively, and SEL: 1268.7 ± 231.2 and 1298.3 ± 253.3 µg/cm(2), respectively). Transport efficiencies for RAS and SEL were good (ranged from 6.81 to 8.50 and 2.86 to 3.61%, respectively). Furthermore, the delivery efficiency, i.e., the fraction of the drug in the formulation that was delivered was very high (>56% at 0.5 mA/cm(2)). Cumulative permeation of RAS and SEL from carbopol gels, potential drug reservoirs for iontophoretic systems, was 891.5 ± 148.3 and 626.6 ± 162.4 µg/cm(2), respectively; this was less than from solution and was tentatively attributed to either different partitioning or slower drug diffusion in the gel matrix. The results demonstrated that therapeutic amounts of rasagiline and selegiline could be easily delivered by transdermal iontophoresis with simple gel patches of modest surface area.

Erbium:YAG fractional laser ablation for the percutaneous delivery of intact functional therapeutic antibodies.

The physicochemical properties and stability requirements of therapeutic proteins necessitate their parenteral administration even for local therapy; however, unnecessary systemic exposure increases the risk of avoidable side-effects. The objective of this study was to use fractional laser ablation to enable the delivery of intact, functional therapeutic antibodies into the skin in vitro and in vivo. The laser-assisted delivery of Antithymocyte globulin (ATG) and Basiliximab - FDA-approved therapeutics for the induction of immunosuppression - was investigated. In vitro delivery experiments were performed using dermatomed porcine ear and human abdominal skins; an in vitro/in vivo correlation was shown using C57 BL/10 SCSnJ mice. Antibody transport was quantified by using ELISA methods developed in-house. Results showed that increasing the pore number from 300 to 450 and 900, increased total antibody delivery (sum of amounts permeated and deposited); e.g., for ATG, from 1.18±0.10 to 3.98±0.64 and 4.97±0.83 µg/cm(2), respectively - corresponding to 19.7-, 66.3- and 82.8-fold increases over the control (untreated skin). Increasing laser fluence from 22.65 to 45.3 and 135.9J/cm(2) increased total ATG delivery from 1.70±0.65 to 4.97±0.83 and 8.70±1.55 µg/cm(2), respectively. The Basiliximab results confirmed the findings with ATG. Western blot demonstrated antibody identity and integrity post-delivery; human lymphocyte cytotoxicity assays showed that ATG retained biological activity post-delivery. Immunohistochemical staining was used to visualize ATG distribution in the epidermis. Total ATG delivery across porcine ear and human abdominal skin was statistically equivalent and an excellent in vitro/in vivo correlation was observed in the murine model. Based on published data, the ATG concentrations achieved in the laser-porated human skins were in the therapeutic range for providing local immunosuppression. These results challenge the perceived limitations of transdermal delivery with respect to biopharmaceuticals and suggest that controlled laser microporation provides a less invasive, more patient-friendly "needle-less" alternative to parenteral administration for the local delivery of therapeutic antibodies.