Novel Topical Ophthalmic Formulations for Management of Glaucoma

Purpose

Preparation of topical ophthalmic formulations containing brimonidine-loaded nanoparticles prepared from various biodegradable polymers—PCL, PLA and PLGA—for sustained release of brimonidine as a once daily regimen for management of glaucoma.

Methods

Nanoparticles were prepared using spontaneous emulsification solvent diffusion method then characterized regarding their particle size, zeta potential, morphology and drug contents. Brimonidine-loaded nanoparticles were incorporated into eye drops, temperature-triggered in situ gelling system and preformed gel and characterized regarding their pH, viscosity, uniformity of drug contents, in vitro release study, in vitro cytotoxicity and in vivo intraocular pressure (IOP) lowering effects.

Results

The results of optimized brimonidine-loaded PCL-, PLGA- and PLA-NPs respectively, are: particle sizes of 117.33?±?4.58 nm, 125.67?±?5.15 nm and 131.67?±?3.79 nm; zeta potentials of ?18.5?±?2.87 mV, ?21.82?±?2.7 mV and ?28.11?±?2.21 mV; and encapsulation efficiencies of 77.97?±?1.38%, 68.65?±?3.35% and 73.52?±?2.92%. TEM analyses revealed that all NPs have spherical shapes with dense core and distinct coat. In vitro release data showed a sustained release without any burst effect with Higuchi non-Fickian diffusion mechanism. Cytotoxicity studies revealed that all formulations are non-toxic. Also all formulations possessed a sustained IOP lowering effect compared to Alphagan® P eye drops.

Conclusions

Our formulations showed prolonged management of glaucoma that should meet with better patient compliance as a once-daily formulation.     

Validation of Anatomical Models to Study Aerosol Deposition in Human Nasal Cavities

Purpose

Intranasal deposition of aerosols is often studied using in vitro nasal cavity models. However, the relevance of these models to predict in vivo human deposition has not been validated. This study compared in vivo nasal aerosol deposition and in vitro deposition in a human plastinated head model (NC1) and its replica constructed from CT-scan (NC2).

Methods

Two nebulizers (Atomisor Sonique® and Easynose®) were used to administer a 5.6 μm aerosol of ^99mTc-DTPA to seven healthy volunteers and to the nasal models. Aerosol deposition was quantified by γ-scintigraphy in the nasal, upper nasal cavity and maxillary sinus (MS) regions. The distribution of aerosol deposition was determined along three nasal cavity axes (x, y and z).

Results

There was no significant difference regarding aerosol deposition between the volunteers and NC1. Aerosol deposition was significantly lower in NC2 than in volunteers regarding nasal region (p?<?0.05) but was similar for the upper nasal cavity and MS regions. Mean aerosol distribution for NC1 came within the standard deviation (SD) of in vivo distribution, whereas that of NC2 was outside the in vivo SD for x and y axes.

Conclusions

In conclusion, nasal models can be used to predict aerosol deposition produced by nebulizers, but their performance depends on their design.     

Lipid-based Formulations for Danazol Containing a Digestible Surfactant,Labrafil M2125CS: <Emphasis Type="BoldItalic">In Vivo</Emphasis> Bioavailability and Dynamic <Emphasis Type="BoldItalic">In Vitro</Emphasis> Lipolysis

Purpose

To evaluate the use of Labrafil® M2125CS as a lipid vehicle for danazol. Further, the possibility of predicting the in vivo behavior with a dynamic in vitro lipolysis model was evaluated.

Methods

Danazol (28 mg/kg) was administered orally to rats in four formulations: an aqueous suspension, two suspensions in Labrafil® M2125CS (1 and 2 ml/kg) and a solution in Labrafil® M2125CS (4 ml/kg).

Results

The obtained absolute bioavailabilities of danazol were 1.5?±?0.8%; 7.1?±?0.6%; 13.6?±?1.4% and 13.3?±?3.4% for the aqueous suspension, 1, 2 and 4 ml Labrafil® M2125CS per kg respectively. Thus administration of danazol with Labrafil® M2125CS resulted in up to a ninefold increase in the bioavailability, and the bioavailability was dependent on the Labrafil® M2125CS dose. In vitro lipolysis of the formulations was able to predict the rank order of the bioavailability from the formulations, but not the absorption profile of the in vivo study.

Conclusions

The bioavailability of danazol increased when Labrafil® M2125CS was used as a vehicle, both when danazol was suspended and solubilized in the vehicle. The dynamic in vitro lipolysis model could be used to rank the bioavailabilities of the in vivo data.

     

Potential of a Cyclone Prototype Spacer to Improve In Vitro Dry Powder Delivery

Purpose

Low inspiratory force in patients with lung disease is associated with poor deagglomeration and high throat deposition when using dry powder inhalers (DPIs). The potential of two reverse flow cyclone prototypes as spacers for commercial carrier-based DPIs was investigated.

Methods

Cyclohaler®, Accuhaler® and Easyhaler® were tested with and without the spacers between 30 and 60 Lmin^?1. Deposition of particles in the next generation impactor and within the devices was determined by high performance liquid chromatography.

Results

Reduced induction port deposition of the emitted particles from the cyclones was observed due to the high retention of the drug within the spacers (e.g. salbutamol sulphate (SS): 67.89?±?6.51% at 30 Lmin^?1 in Cheng 1). Fine particle fractions of aerosol as emitted from the cyclones were substantially higher than the DPIs alone. Moreover, the aerodynamic diameters of particles emitted from the cyclones were halved compared to the DPIs alone (e.g. SS from the Cyclohaler® at 4 kPa: 1.08?±?0.05 μm vs. 3.00?±?0.12 μm, with and without Cheng 2, respectively) and unaltered with increased flow rates.

Conclusion

This work has shown the potential of employing a cyclone spacer for commercial carrier-based DPIs to improve inhaled drug delivery.     

Oral Delivery of Low Molecular Weight Heparin by Polyaminomethacrylate Coacervates

Purpose

Oral bioavailability of low molecular weight heparin (LMWH) can be achieved by several advanced drug delivery approaches. Here, a new preparation method for coacervates (CAs) using non-toxic polyethylene glycol derivates was developed.

Methods

LMWH were coacervated with polyaminomethacrylates (Eudragit® RL or RS) using polyethylene glycol (PEG) derivatives as non-toxic solvents. CAs were analyzed for their physicochemical properties and pharmacokinetic parameters were determined for different formulations in rabbits.

Results

CAs from both polymer types using various PEGs were of irregular shape and had particle sizes of around 40 μm, encapsulation efficiencies of >90%, and complete LMWH in vitro release was obtained within 2 h. In vivo, oral Absorption at doses of 300 IU/kg was rather low (F?<?2.5%) while dose increase resulted in a maximum at 600 IU/kg (F_RL: 6.0?±?1.2%; F_RS: 5.8?±?2.5%) and 1,200 IU/kg did not result in higher bioavailability (F_RL: 4.6?±?0.4%; F_RS: 4.1?±?0.8%). CAs were applicable to various LMWH types where the oral availability decreased in the order fondaparinux>enoxaparin>nadroparin>certoparin depending mainly on the molecular weight.

Conclusions

CAs prepared by an organic solvent-free method allowed the oral delivery of LMWHs. The therapeutic efficiency and the simple and solvent-free manufacturing process underlines the high potential of this new preparation method.     

In Vitro and In Vivo Characterisation of PEG-Lipid-Based Micellar Complexes of Salmon Calcitonin for Pulmonary Delivery

Purpose

To investigate DSPE-PEG₂₀₀₀-based micellar formulations of salmon calcitonin (sCT) for their ability to improve pulmonary delivery.

Methods

Micelles were characterised by DLS and ³¹P-NMR spectroscopy. Stability against sCT degrading peptidases, trypsin, ??-chymotrypsin and neutrophil elastase as well as their influence on transepithelial absorption was investigated in vitro. In vivo perfomance of sCT micelles was studied in an experimental model of intratracheal aerosolisation into rats.

Results

Micelles with a mean hydrodynamic diameter of 12?nm spontaneously assembled, when a total concentration of 0.02?mM of PEG-lipid and sCT (at 1:1 molar ratio) was exceeded. Nuclear magnetic resonance confirmed the presence of small micellar structures. The micellar formulation showed increased stability against enzymatic digestion. In vitro studies also showed that sCT micelles were able to enhance transepithelial absorption. Data obtained from in vivo experiments provided evidence of significantly (P?AUC _inf and a relative bioavailability of 160?±?55% when compared to plain sCT solution.

Conclusions

The herein described PEG-lipid micelles are promising carriers for enhanced pulmonary delivery of sCT.     

Cumulative Organic Anion Transporter-Mediated Drug-Drug Interaction Potential of Multiple Components in Salvia Miltiorrhiza (Danshen) Preparations

Purpose

To evaluate organic anion transporter-mediated drug-drug interaction (DDI) potential for individual active components of Danshen (Salvia miltiorrhiza) vs. combinations using in vitro and in silico approaches.

Methods

Inhibition profiles for single Danshen components and combinations were generated in stably-expressing human (h)OAT1 and hOAT3 cells. Plasma concentration-time profiles for compounds were estimated from in vivo human data using an i.v. two-compartment model (with first-order elimination). The cumulative DDI index was proposed as an indicator of DDI potential for combination products. This index was used to evaluate the DDI potential for Danshen injectables from 16 different manufacturers and 14 different lots from a single manufacturer.

Results

The cumulative DDI index predicted in vivo inhibition potentials, 82% (hOAT1) and 74% (hOAT3), comparable with those observed in vitro, 72?±?7% (hOAT1) and 81?±?10% (hOAT3), for Danshen component combinations. Using simulated unbound C_max values, a wide range in cumulative DDI index between manufacturers, and between lots, was predicted. Many products exhibited a cumulative DDI index?>?1 (50% inhibition).

Conclusions

Danshen injectables will likely exhibit strong potential to inhibit hOAT1 and hOAT3 function in vivo. The proposed cumulative DDI index might improve prediction of DDI potential of herbal medicines or pharmaceutical preparations containing multiple components.     

Clinical Potential of a Silk Sericin-Releasing Bioactive Wound Dressing for the Treatment of Split-Thickness Skin Graft Donor Sites

Purpose

An ethyl alcohol-precipitated silk sericin/PVA scaffold that controlled the release of silk sericin was previously developed and applied for the treatment of full-thickness wounds in rats and demonstrated efficient healing. In this study, we aimed to further evaluate the clinical potential of this scaffold, hereafter called “silk sericin-releasing wound dressing”, for the treatment of split-thickness skin graft donor sites by comparison with the clinically available wound dressing known as “Bactigras®”.

Methods

In vitro characterization and in vivo evaluation for safety of the wound dressings were performed. A clinical trial of the wound dressings was conducted according to standard protocols.

Results

The sericin released from the wound dressing was not toxic to HaCat human keratinocytes. A peel test indicated that the silk sericin-releasing wound dressing was less adhesive than Bactigras®, potentially reducing trauma and the risk of repeated injury upon removal. There was no evidence of skin irritation upon treatment with either wound dressing. When tested in patients with split-thickness skin graft donor sites, the wounds treated with the silk sericin-releasing wound dressing exhibited complete healing at 12?±?5.0 days, whereas those treated with Bactigras® were completely healed at 14?±?5.2 days (p?=?1.99?×?10^?4). In addition, treatment with the silk sericin-releasing wound dressing significantly reduced pain compared with Bactigras® particularly during the first 4 postoperative days (p?=?2.70?×?10^?5 on day 1).

Conclusion

We introduce this novel silk sericin-releasing wound dressing as an alternative treatment for split-thickness skin graft donor sites.     

Intravaginal Flux Controlled Pump for Sustained Release of Macromolecules

Purpose

To design a flux controlled pump (FCP) capable of 30-day, controlled release of macromolecules to the vaginal mucosa.

Methods

The FCP is composed of a single chamber fabricated from a rigid thermoplastic with orifices and encloses a pellet of water-swellable polymer containing the drug substance. We performed testing both in vitro and in rabbits. To ensure vaginal retention in the rabbit, we designed and attached an oval shape-memory polyether urethane retainer to the FCP allowing for long-term intravaginal evaluation of a solid dosage form without invasive surgical implantation.

Results

The orifices and swelling properties of the polymer pellet control water entry for polymer hydration and expansion, and subsequent extrusion of the drug-containing gel from the orifice. A FCP device containing a pellet composed of hydroxypropyl cellulose compounded with a model macromolecule, achieved controlled in vitro release for 30 days with an average release rate of 24?±?2 μg/day (mean ± SD) and range of 16 to 42 μg/day. We observed a slightly lower average release rate in vivo of 20?±?0.6 μg/day (mean?±?SD).

Conclusions

The size of the orifice and nature of the swelling polymer controls the hydration rate and thereby macromolecule release rate and duration from this FCP.     

Fucosylated Multiwalled Carbon Nanotubes for Kupffer Cells Targeting for the Treatment of Cytokine-Induced Liver Damage

Purpose

To develop, characterize and exploring the sulfasalazine loaded fucoyslated multi walled carbon nanotubes for Kupffer cell targeting for effective management of cytokine-induce liver damage.

Methods

Sulfasalazine was loaded into the fucosylated MWCNTs after subsequential functionalization (carboxylation, acylation and amidation) using dialysis membrane technique. The in vitro, in vivo studies were performed on macrophages J 774 cell line for Kupffer cells targeting for the treatment of cytokine-induced liver damage.

Results

The loading of SSZ into SSZ-FUCO-MWCNTs was 87.77?±?0.11% (n?=?3). Sustained release was obtained from SSZ-FUCO-MWCNTs, with 89.12?±?0.71% of SSZ released into medium at 48th hr. SSZ-FUCO-MWCNTs showed the 9.01?±?0.23% hemolysis was drastically reduced from 21.62?±?0.24% SSZMWCNTs 21.62?±?0.24%. In SRB assay, SSZ-FUCO-MWCNTs showed more cytotoxicity than raw and SSZ-MWCNTs. In cytokine assay, SSZ- FUCO-MWCNTs exhibited significantly higher inhibition of IL-12 p40 secretion. In Western blot assay, SSZ-FUCO-MWCNTs significantly inhibit NF-κB activation.

Conclusion

The results suggested that the SSZ-FUCO-MWCNTs may be useful nano-carriers for targeted delivery to Kupffer cells in the treatment of cytokine-induced liver damage.     

Acid-Responsive Polymeric Nanocarriers for Topical Adapalene Delivery

Purpose

The acne skin is characteristic of a relatively lower pH microenvironment compared to the healthy skin. The aim of this work was to utilize such pH discrepancy as a site-specific trigger for on-demand topical adapalene delivery.

Methods

The anti-acne agent, adapalene, was encapsulated in acid-responsive polymer (Eudragit® EPO) nanocarriers via nanoprecipitation. The nanocarriers were characterized in terms of particle size, surface morphology, drug-carrier interaction, drug release and permeation.

Results

Adapalene experienced a rapid release at pH 4.0 in contrast to that at pH 5.0 and 6.0. The permeation study using silicone membrane revealed a significant higher drug flux from the nanocarrier (6.5?±?0.6 μg.cm^?2.h^?1) in comparison to that (3.9?±?0.4 μg.cm^?2.h^?1) in the control vehicle (Transcutol®). The in vitro pig skin tape stripping study showed that at 24 h post dose-application the nanocarrier delivered the same amount of drug to the stratum corneum as the positive control vehicle did.

Conclusions

The acid-responsive nanocarriers hold promise for efficient adapalene delivery and thus improved acne therapy. Figure

pH liable nanocarriers enhance the adapalene delivery to acne skin.     

In Vitro,In Vivo,and In Silico Evaluation of the Bioresponsive Behavior of an Intelligent Intraocular Implant

Purpose

An autofeedback complex polymeric platform was used in the design of an intelligent intraocular implant—the I³—using stimuli-responsive polymers, producing a smart release system capable of delivering therapeutic levels of an anti-inflammatory agent (indomethacin) and antibiotic (ciprofloxacin) for posterior segment disorders of the eye in response to inflammation.

Methods

Physicochemical and physicomechanical analysis of the I³ was undertaken to explicate the highly crosslinked make-up and ‘on-off’ inflammation-responsive performance of the I³. In addition, energetic profiles for important complexation reactions were generated using Molecular Mechanics Energy Relationships by exploring the spatial disposition of energy minimized molecular structures. Furthermore, preliminary in vivo determination of the inflammation-responsiveness of the I³ was ascertained following implantation in the normal and inflamed rabbit eye.

Results

In silico modeling simulating a pathological inflammatory intraocular state highlighted the interaction potential of hydroxyl radicals with the selected polysaccharides comprising the I³. The intricately crosslinked polymeric system forming the I³ thus responded at an innate level predicted by its molecular make-up to inflammatory conditions as indicated by the results of the drug release studies, rheological analysis, magnetic resonance imaging and scanning electron microscopic imaging. In vivo drug release analysis demonstrated indomethacin levels of 0.749?±?0.126 μg/mL and 1.168?±?0.186 μg/mL, and ciprofloxacin levels of 1.181?±?0.150 μg/mL and 6.653?±?0.605 μg/mL in the normal and inflamed eye, respectively.

Conclusions

Extensive in vitro, molecular, and in vivo characterization therefore highlighted successful inflammation-responsiveness of the I³. The I³ is a proposed step forward from other described ocular systems owing to its combined bioresponsive, nano-enabled architecture.     

Development and In Vitro-In Vivo Evaluation of Polymeric Implants for Continuous Systemic Delivery of Curcumin

Purpose

The introduction of curcumin into clinics is hindered by its low water solubility and poor bioavailability. To overcome these limitations, we developed curcumin implants using poly (??-caprolactone) as the polymeric matrix.

Methods

Implants were prepared by melt-extrusion method; in vitro drug release was optimized for effects of polymer composition, drug load, surface area and water-soluble additives. Implants were also tested under in vivo conditions for cumulative curcumin release, and liver concentration was correlated with its efficacy to modulate selected xenobiotic-metabolizing enzymes (CYP1A1 and GSTM).

Results

Drug release from implants followed biphasic release pattern with Higuchi kinetics and was proportional to the surface area of implants. Drug release increased proportionately from 2 to 10% (w/w) drug load, and incorporation of 10% (w/w) of water-soluble additives (F-68, PEG 8000 and cyclodextrin) did not significantly alter the drug release. In vivo drug release was found to be ??1.8 times higher than in vitro release. Curcumin was detected at 60?±?20 ng/g in the liver after four days of implantation and was almost constant (8?C15 ng/g) for up to 35 days. This time-dependent drop in curcumin level was found to be due to induction of CYP1A1 and GSTM (??) enzymes which led to increased metabolism of curcumin.

Conclusion

Our data showed that these implants were able to release curcumin for long duration and to modulate liver phase I and phase II enzymes, demonstrating curcumin??s biological efficacy delivered via this delivery system.     

A Rifapentine-Containing Inhaled Triple Antibiotic Formulation for Rapid Treatment of Tubercular Infection

Purpose

The potential for rifapentine-containing oral therapeutic regimens to significantly shorten the current six-month anti-tubercular treatment regimen is confounded by high plasma protein binding of rifapentine. Inhaled aerosol delivery of rifapentine, a more potent anti-tubercular antibiotic drug, in combination with other first-line antibiotics may overcome this limitation to deliver a high drug dose at the pulmonary site of infection.

Methods

A formulation consisting of rifapentine, moxifloxacin and pyrazinamide, with and without leucine, was prepared by spray-drying. This formulation was assessed for its physico-chemical properties, in vitro aerosol performance and antimicrobial activity.

Results

The antibiotic powders, with and without leucine, had similar median aerodynamic diameters of 2.58?±?0.08 μm and 2.51?±?0.06 μm, with a relatively high fine particle fraction of 55.5?±?1.9% and 63.6?±?2.0%, respectively. Although the powders were mostly amorphous, some crystalline peaks associated with the δ polymorph for the spray-dried crystalline pyrazinamide were identified.

Conclusions

Stabilisation of the powder with 10% w/w leucine and protection from moisture ingress was found to be necessary to prevent overt crystallisation of pyrazinamide after long-term storage. In vitro biological assays indicated antimicrobial activity was retained after spray-drying. Murine pharmacokinetic studies are currently underway.     

Lack of association between SLCO1B1 polymorphism and the lipid-lowering effects of atorvastatin and simvastatin in Chinese individuals

Purpose

There is significant inter-individual variability in the lipid-lowering effects of atorvastatin and simvastatin. Our goal was to investigate the impact of SLCO1B1 genetic polymorphism on the lipid-lowering effects of atorvastatin and simvastatin.

Methods

We recruited 363 unrelated hyperlipidemic patients with the CYP3A4*1/*1, CYP3A5*1/*1, and CYP3AP1*1/*1 genotypes: 189 of these were treated with atorvastatin and 174 were treated with simvastatin as a single-agent therapy (20 mg?day^?1 orally) for 4 weeks. The genotyping of SLCO1B1 c.521T?>?C (p.V174A, OATP-C*5) was performed with allele-specific polymerase chain reaction (AS-PCR), and PCR restriction fragment length polymorphism (RFLP) was performed to detect the carriers of SLCO1B1 c.388A?>?G (p.N130D, OATP-C*1b). Serum triglyceride (TGs), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels were determined before and after treatment.

Results

The frequencies of the SLCO1B1 521T?>?C and 388A?>?G variant alleles in Chinese hyperlipidemic patients were found to be 16.2% and 72.1% respectively. After treatment with 20 mg simvastatin or atorvastatin daily for 4 weeks, TC, TG, and LDL-C concentrations were lower than at baseline, on average, by 18.1?±?3.7%, 25.8?±?9.7%, 27.7?±?5.4% in the simvastatin-treated group, and 17.5?±?3.7%, 22.6?±?8.6%, 27.5?±?5.5% in the atorvastatin-treated group respectively, and the mean relative reduction in serum HDL cholesterol did not reach statistical significance (?1.0?±?10.9%, 0.5?±?9.3%). However, no significant differences were observed in the lipid-lowering effects of atorvastatin and simvastatin between subjects with different SLCO1B1 genotypes.

Conclusion

The SLCO1B1 521T?>?C and 388A?>?G variants were found to be relatively common in Chinese patients with essential hyperlipidemia. These frequencies were found to be similar to those observed in healthy Chinese and Japanese individuals, but significantly different from Caucasians and blacks. SLCO1B1 521T?>?C and 388A?>?G polymorphisms may not be associated with the lipid-lowering effects of atorvastatin and simvastatin.     

Influence of Suspension Stabilisers on the Delivery of Protein-Loaded Porous Poly (DL-Lactide-co-Glycolide) (PLGA) Microparticles via Pressurised Metered Dose Inhaler (pMDI)

Purpose

This work investigates the feasibility of delivering large (≈ 25 μm) porous poly (lactide-co-glycolide) (PLGA) microparticles containing a model protein via pressurised metered dose inhaler (pMDI).

Methods

Porous PLGA microparticles were prepared by modified double emulsion method as pMDI suspension based systems containing suspension stabilisers in 1,1,1,2,3,3,3-heptafluoropropane (HFA 227). Physical suspension stability was assessed by visual and optical suspension techniques. Aerosolisation characteristics were investigated using aerosol particle sizing, dose delivery through the valve (DTV) and shot weight.

Results

An optimum concentration of suspensions stabiliser was required to achieve physical pMDI suspension stability; values of; 0.0075%w/w PVP K30 or 0.075%w/w PEG 300 were required. Formulations that exhibited good physical stability also showed optimum aerosolisation characteristics. When employing 0.0075% PVP K30 DTV at the start and end of can life was 98.11(±10.01) % and 75.06 (±7.01) % respectively verses values of 37.39 (±11.12) % and 5.57 (±1.72) % without the inclusion of PVP K30.

Conclusion

Porous PLGA microparticles show potential as macromolecule/protein carrier and also to target lower regions of the lungs when prepared as pMDI suspension formulations in HFA 227 using suspension stabilisers to achieve consistent dose delivery through the life of the pMDI, however, inter-relationship between the device and the formulation need to be considered to achieve suitable respiratory delivery.     

SPECT-CT Comparison of Lung Deposition using a System combining a Vibrating-mesh Nebulizer with a Valved Holding Chamber and a Conventional Jet Nebulizer: a Randomized Cross-over Study

Purpose

To compare in vivo the total and regional pulmonary deposition of aerosol particles generated by a new system combining a vibrating-mesh nebulizer with a specific valved holding chamber and constant-output jet nebulizer connected to a corrugated tube.

Methods

Cross-over study comparing aerosol delivery to the lungs using two nebulizers in 6 healthy male subjects: a vibrating-mesh nebulizer combined with a valved holding chamber (Aerogen Ultra®, Aerogen Ltd., Galway, Ireland) and a jet nebulizer connected to a corrugated tube (Opti-Mist Plus Nebulizer®, ConvaTec, Bridgewater, NJ). Nebulizers were filled with diethylenetriaminepentaacetic acid labelled with technetium-99 m (^99mTc-DTPA, 2 mCi/4 mL). Pulmonary deposition of ^99mTc-DTPA was measured by single-photon emission computed tomography combined with a low dose CT-scan (SPECT-CT).

Results

Pulmonary aerosol deposition from SPECT-CT analysis was six times increased with the vibrating-mesh nebulizer as compared to the jet nebulizer (34.1?±?6.0% versus 5.2?±?1.1%, p?<?0.001). However, aerosol penetration expressed as the three-dimensional normalized ratio of the outer and the inner regions of the lungs was similar between both nebulizers.

Conclusions

This study demonstrated the high superiority of the new system combining a vibrating-mesh nebulizer with a valved holding chamber to deliver nebulized particles into the lungs as comparted to a constant-output jet nebulizer with a corrugated tube.

     

Assessment of the Lateral Diffusion and Penetration of Topically Applied Drugs in Humans Using a Novel Concentric Tape Stripping Design

Purpose

To determine the extent of lateral spread and stratum corneum (SC) penetration of caffeine (CAF), hydrocortisone (HC) and ibuprofen (IBU) using a novel concentric tape stripping technique.

Method

Ethanolic solutions of CAF, HC or IBU were applied to the forearm of 8 volunteers. At various time points, 10 successive layers of SC were removed by stripping with tapes perforated into concentric rings and analysed for drug concentration and mass of SC protein. In vitro permeation studies assessed the percutaneous absorption of these compounds across human skin.

Results

CAF and IBU showed significant lateral spreading across the SC while HC formed a drug depot at the site of application. Relative to the applied dose, the in vivo recovery of all compounds from the combined 10 strips at 3?mins ranged between 83.0 and 92.9?% and decreased to between 64.5 and 66.9?% at 3?h. IBU recovery further decreased to 47.7?±?5.6?% at 6?h, correlating with greater in vitro penetration relative to CAF and HC.

Conclusion

Drug concentration decreased with increased lateral distance from the application site. The lower recovery of IBU in the upper tape strip regions compared to CAF and HC may be a consequence of greater penetration into the SC with time.     

The Optimization of an Intravaginal Ring Releasing Progesterone Using a Mathematical Model

Purpose

Progering® is the only intravaginal ring intended for contraception therapies during lactation. It is made of silicone and releases progesterone through the vaginal walls. However, some drawbacks have been reported in the use of silicone. Therefore, ethylene vinyl acetate copolymer (EVA) was tested in order to replace it.

Methods

EVA rings were produced by a hot-melt extrusion procedure. Swelling and degradation assays of these matrices were conducted in different mixtures of ethanol/water. Solubility and partition coefficient of progesterone were measured, together with the initial hormone load and characteristic dimensions. A mathematical model was used to design an EVA ring that releases the hormone at specific rate.

Results

An EVA ring releasing progesterone in vitro at about 12.05?±?8.91 mg day^?1 was successfully designed. This rate of release is similar to that observed for Progering®. In addition, it was observed that as the initial hormone load or ring dimension increases, the rate of release also increases. Also, the device lifetime was extended with a rise in the initial amount of hormone load.

Conclusions

EVA rings could be designed to release progesterone in vitro at a rate of 12.05?±?8.91 mg day^?1. This ring would be used in contraception therapies during lactation. The use of EVA in this field could have initially several advantages: less initial and residual hormone content in rings, no need for additional steps of curing or crosslinking, less manufacturing time and costs, and the possibility to recycle the used rings.     

In Vitro Cell Integrated Impactor Deposition Methodology for the Study of Aerodynamically Relevant Size Fractions from Commercial Pressurised Metered Dose Inhalers

Purpose

The purpose of this study was to present a modified Andersen cascade impactor (ACI) as a platform to evaluate the deposition and subsequent transport of aerosol micropaticles across airway epithelial cells.

Methods

The impaction plate of an ACI was modified to accommodate up to eight Snapwells. Aerodynamic particle size distribution of the modified ACI was investigated with two commercially available formulations of Ventolin® (salbutamol sulphate) and QVAR® (beclomethasone dipropionate). Deposition and transport of these drug microparticles across sub-bronchial epithelial Calu-3 cells were also studied.

Results

The modified ACI demonstrated reproducible deposition patterns of the commercially available pressurised metered dose inhalers compared to the standard ACI. Furthermore, the Calu-3 cells could be placed in different stages of the modified ACI. No significant effect was observed among the transport rate of different particle sizes deposited on Calu-3 cells within the range of 3.3 to 0.4 μm.

Conclusions

The use of the cell compatible ACI to assess the fate of microparticles after deposition on the respiratory epithelia may allow for better understanding of deposited microparticles in vivo.