Disposition of 14C-Quinelorane in Dogs Following Oral or Intravenous Dosing and Transdermal Patch Application

A transdermal patch was developed to circumvent the emesis associated with the oral and intravenous administration of a dopamine agonist, quinelorane, to dogs.

Approximate steady-state plasma concentrations were achieved following the daily application of a transdermal patch for 7 days. Each dog received between 0.1 and 0.2 mg/kg per day from the transdermal patch.

At steady-state conditions, dogs received either a single oral dose of ¹⁴C-quinelorane at 0.1 mg/kg, a bolus intravenous dose of 0.03 mg/kg or had a transdermal patch containing the radioactive free base, ¹⁴C-quinelorane, applied to their abdomens for 24 hours; the approximate dose was 0.18 mg/kg.

The plasma pharmacokinetics were measured by liquid scintillation counting and ELISA.

The systemic bioavailability of quinelorane, as measured by the ELISA, was 30%, indicative of first-pass metabolism.

The radioactive urinary metabolite profile was similar for all three routes of administration. Principal entities in the urine were quinelorane, the N-despropyl- and the hydroxy-lactam- metabolites, accounting for 29, 25 and 3% of the dose, respectively. The major route of excretion of radioactivity was via. the urine, irrespective of the route by which the drug was administered.     

Silicone adhesive,a better matrix for tolterodine patches—a research based on in vitro/in vivo studies

Objective: To design and optimize a drug-in-adhesive (DIA) type transdermal patch for tolterodine (TOL) based on acrylic and silicone matrixes.

Methods: Initial in vitro studies were conducted to optimize the formulations. Two types of adhesive matrixes, drug loading, and enhancers were evaluated on the TOL transport across rabbit skin. For in vivo studies, patches were administered to rabbit abdominal skin. Pharmacokinetic assessments were performed based on plasma level of TOL up to 28?h for acrylic patch and 52?h for silicone patch after topical application.

Results: The final formulation of acrylic adhesive type patch consisted of 10% TOL (w/w) and 5.8?×?10^?4 mol isopropyl myristate (IPM) and 2.9?×?10^?4 mol Span 80 in per unit gram (mol/g) of adhesive, while 2.5% TOL (w/w) and 2.9?×?10^?4 mol/g IPM for silicone adhesive type patch. Comparison of the pharmacokinetic parameters between two types of patches showed that the steady-state concentration of silicone type patch was 2-fold higher than that of acrylic type patch being 0.97?mg/L versus 0.49?mg/L, and the absolute bioavailability was 27.5% for silicone type patch and 6.3% for acrylic type patch, respectively. In addition, the prediction of in vivo drug level from the in vitro permeation data of silicone adhesive formulation was in good agreement with actual observed concentration data in rabbits.

Conclusion: These results indicate that the silicone type of TOL patch is an appropriate delivery system for the treatment of overactive bladder (OAB).     

Formulation study of a patch containing propranolol by design of experiments

Objective: To evaluate the feasibility of a transdermal patch containing propranolol (PR).

Method: Skin penetration enhancers (SPEs) able to improve the skin permeability of PR were selected and a quality by design approach was applied to the development of the patch by a 2⁴ full factorial design. The permeation profile of PR from the formulations was assessed in in vitro permeation studies performed by using Franz diffusion cells and human epidermis as membrane. Finally, skin irritation was evaluated by the Draize test.

Results: N-methyl pyrrolidone (NMP) resulted as the best SPE: in addition, the critical factors influencing the PR diffusion through the human epidermis when loaded in the patch resulted in the matrix thickness (X₁, p?=?0.0957) and PR content (X₃, p?=?0.0004) which improved the flux; conversely, NMP lacked its enhancement effect when loaded in the patch and the increase in its concentration (X₄, p?=?0.006) affected the drug permeation through human epidermis. The flux of optimal formulation was 12.7?μg/cm²/h. On the basis of the steady-state concentration and clearance of PR, the estimated patch surface was 100–120 cm², since the activity of PR is related to its Senantiomer and no in vivo bioconversion occurs.

Conclusion: A patch containing (S)-PR was prepared and the (S)-PR flux (13.3?μg/cm²/h) permitted to confirm the suitability of a transdermal administration of PR. In particular, the use of a 50?μm thick methacrylic matrix containing 8% (S)-PR and 15% NMP can allow to develop a patch non-irritating to the skin, in order to ensure a constant permeation flux of PR over 48?h.     

Safety studies on intravenous infusion of a potent angiogenesis inhibitor: taurocholate-conjugated low molecular weight heparin derivative LHT7 in preclinical models

Context: As a class of angiogenesis inhibitors, heparin conjugates have shown significant effectiveness in several studies.

Objectives: The purpose of our current study is to evaluate the effectiveness and safety of infusing the conjugate of low molecular weight heparin and taurocholate (LHT7), which has been developed as a potent angiogenesis inhibitor.

Methods: To evaluate its safety, the method of intravenous infusion was compared with its i.v. bolus administration. Intravenous infusion was administered at a rate of 400?μl/min/kg of body weight for 30?min. Pharmacokinetic (PK) analysis, organ accumulation, and plasma concentration profiles of LHT7 were measured. The anticancer effect of LHT7 was evaluated in murine and human xenograft models, and preclinical studies were performed in SD rats and beagle dogs.

Results: The results of the PK studies showed reduced organ accumulation in mice and the AUC_(0–96?h) (area under the curve) was increased up to 1485?±?125?h?×?μg/ml. The efficacy, at dose 1?mg/kg/2 d was higher for i.v. infusion than for i.v. bolus administration in both murine and human cancer models. The preclinical studies showed the safety dose of LHT7 is less than 20?mg/kg in SD rats and in the next safety analysis in beagle dogs showed that there were no organ-specific adverse effects in higher doses, such as, 12?mg/kg. LHT7 showed sustained effects with minimized adverse events when administered through i.v. infusion.

Conclusions: LHT7 (i.v. infusion) could be safely used for further clinical development as a multi-targeting anti-angiogenic agent.     

Transdermal Nicotine Delivery Systems: Multi-institutional Cooperative Bioequivalence Studies

Abstract

Nicotine transdermal delivery systems (nicotine-TDSs) have been evaluated clinically and found to provide effective assistance to smokers in smoking cessation with minimal occurrence of withdrawal symptoms. However, substantial skin reactions have been reported with the four nicotine-TDSs marketed recently. To reduce the skin reactions, a new type of nicotine-TDS has been recently developed. In vitro skin permeation studies demonstrated that this nicotine-TDS yields a constant skin permeation profile with a rate of permeation across the human cadaver skin comparable to the steady-state permeation rates attained by Habitrol? and Nicoderm® systems. Clinical studies completed in two ethnic groups have demonstrated that this newly-developed nicotine-TDS is clinically effective and has yielded minimal skin irritation. As part of technical transfer program, a clinical study was initiated in 18 non-obese non-smoking Taiwanese, using Latin-square design, to compare the systemic bioavailability and pharmacokinetic profile of nicotine delivered transdermally from the nicotine-TDSs fabricated at technology licensee (Sintong nicotine-TDS) in comparison with that from the technology developer (TBS nicotine-TDS), using one marketed nicotine-TDS (Habitrol? system) as the reference product. In vitro release and skin permeation studies of nicotine from the nicotine-TDSs manufactured at both licensor and licensee were found similar in kinetic profiles and comparable in rates. Since the patch size of these nicotine-TDSs studied was smaller than the marketed product used (10 cm² for both Sintong and TBS nicotine-TDSs, versus 20 cm² for Habitrol? system), the daily doses of nicotine delivered to the volunteers are equivalent between Sintong and TBS nicotine-TDSs [9.58 (± 2.23) vs. 8.76 (± 1.88) mg/day/patch] but are lower than that from Habitrol? system [15.13 (± 4.05) mg/day/patch]. Thus, for the statistical analysis of the pharmacokinetic parameters obtained need to be corrected for the difference in patch size and daily nicotine dose delivered. The results of statistical analysis suggested that Sintong and TBS nicotine-TDSs are bioequivalent to Habitrol? system.     

Formulation optimization of a drug in adhesive transdermal analgesic patch

Abstract

Context: Conventional pain management approaches have limitations such as gastrointestinal side effects, frequent dosing, and difficulties in swallowing medications. Hence, to overcome these limitations, we developed a transdermal analgesic patch.

Objective: This study was designed to formulate a drug in adhesive transdermal patch with codeine (CDB) and acetaminophen (APAP) that may potentially treat moderate pain in children.

Materials and methods: Three analgesic drugs hydrocodone bitartrate, CDB and APAP were screened by a slide crystallization study using polarized light microscope and their permeation profiles were studied using vertical Franz diffusion cells across porcine ear skin, dermatomed human skin and epidermis for 24?h, and the samples were quantified by high performance liquid chromatography. Patches used for permeation studies were prepared by dissolving sub-saturation concentration of the drug(s) in adhesive (with/without 5% w/w oleic acid [OA]), cast with a film casting knife.

Results and discussion: Among the three drugs screened, CDB demonstrated the best permeation profile (660.21?µg/cm²), and shortest lag time (4.35?±?0.01?h), and hence was chosen for patch studies. The highest concentration of CDB in the patch at which drug does not crystallize was determined as 40% of its saturation solubility (Cs) and that of APAP was determined as 200% of its Cs. CDB standalone patch delivered 105.48?µg/cm² of CDB, while the CDB–APAP combination patch with 5% w/w OA delivered 151.40?µg/cm² CDB and 58.12?µg/cm² APAP in 24?h.

Conclusion: Drug-in-adhesive patches using CDB and APAP were developed for infants and children. Addition of OA enhanced solubility and permeation of drugs.     

Magnetophoresis in combination with chemical enhancers for transdermal drug delivery

Purpose: The objective of the present work was to investigate the effect of combination of a novel physical permeation enhancement technique, magnetophoresis with chemical permeation enhancers on the transdermal delivery of drugs.

Methods: The in vitro drug transport studies were carried out across the freshly excised abdominal skin of Sprague-Dawley rats using transdermal patch systems (magnetophoretic and non-magnetophoretic) of lidocaine hydrochloride (LH). LH gel prepared using hydroxypropyl methylcellulose (HPMC) was spread over the magnets as a thin layer. To investigate the effect of chemical permeation enhancers, menthol, dimethyl sulfoxide, sodium lauryl sulfate and urea (5% w/v) were incorporated in the gels prior to loading on the patch system.

Results: The flux of lidocaine from magnetophoretic patch was ~3-fold higher (3.07?±?0.43 µg/cm²/h) than that of the control (non-magnetophoretic patch) (0.94?±?0.13 µg/cm²/h). Incorporation of chemical permeation enhancers in the gel enhanced the magnetophoretic delivery flux by ~4 to 7-fold.

Conclusions: The enhancement factor due to combination of chemical permeation enhancer was additive and not synergistic. Mechanistic studies indicated that magnetophoresis mediated drug delivery enhancement was via appendageal pathway.     

Fabrication and characterization of matrix type transdermal patches loaded with tizanidine hydrochloride: potential sustained release delivery system

Abstract

Objective: This study was designed to optimize and develop matrix type transdermal drug delivery system (TDDS) containing tizanidine hydrochloride (TZH) using different polymers by solvent evaporation method.

Significance: A strong need exists for the development of transdermal patch having improved bioavailability at the site of action with fewer side effects at off-target organs.

Methods: The patches were physically characterized by texture analysis (color, flexibility, smoothness, transparency, and homogeneity), in vitro dissolution test and FTIR analysis. Furthermore, functional properties essential for TDDS, in vitro percentage of moisture content, percentage of water uptake, in vitro permeation by following different kinetic models, in vivo drug content estimation and skin irritation were determined using rabbit skin.

Results: The optimized patches were soft, of uniform texture and thickness as well as pliable in nature. Novel transdermal patch showed ideal characteristics in terms of moisture content and water uptake. FTIR analysis confirmed no interaction between TZH and cellulose acetate phthalate (CAP). The patch showed sustained release of the drug which increased the availability of short acting TZH at the site of action. The patch also showed its biocompatibility to the in vivo model of rabbit skin.

Conclusions: The results demonstrated that topically applied transdermal patch will be a potential medicated sustain release patch for muscle pain which will improve patient compliance.     

Development of a daphnetin transdermal patch using chemical enhancer strategy: insights of the enhancement effect of Transcutol P and the assessment of pharmacodynamics

Objective: The aim of this study was to develop a drug-in-adhesive patch for transdermal delivery of daphnetin (DA), which is a coumarin derivative in Girald Daphne, and to investigate the role of Transcutol P (TP) in the release and percutaneous permeation processes of DA.

Methods: Backing films, permeation enhancers and enhancer content in the transdermal patch were investigated through in vitro experiments using rat skin. Anti-inflammatory and analgesic effects of the optimized formulation were evaluated using the adjuvant arthritis model and the pain model induced by acetic acid, respectively. In addition, the enhancement effect of TP was investigated using differential scanning calorimetry (DSC), FTIR, and molecular dynamic simulation.

Results: The optimal formulation, composed of DURO-TAK^® 87-2852, CoTran^TM 9680, 1% DA, and 10% TP showed anti-inflammatory and analgesic effects. It was found that TP only promoted the release process of DA from its transdermal patch. Furthermore, the decrease of interaction between drug and pressure sensitive adhesive (PSA) as well as the improvement of PSA mobility due to TP addition were the main factors that enhanced the release of DA from patch.

Conclusions: This study successfully used TP to develop a DA patch with good anti-inflammatory and analgesic effects, proving that TP promotes the release of DA by reducing the interaction between DA and PSA and increasing the mobility of PSA.     

Cannabidiol bioavailability after nasal and transdermal application: effect of permeation enhancers

Context: The nonpsychoactive cannabinoid, cannabidiol (CBD), has great potential for the treatment of chronic and ‘breakthrough’ pain that may occur in certain conditions like cancer. To fulfill this goal, suitable noninvasive drug delivery systems need to be developed for CBD. Chronic pain relief can be best achieved through the transdermal route, whereas ‘breakthrough’ pain can be best alleviated with intranasal (IN) delivery. Combining IN and transdermal delivery for CBD may serve to provide patient needs-driven treatment in the form of a nonaddictive nonopioid therapy. Objective: Herein we have evaluated the IN and transdermal delivery of CBD with and without permeation enhancers. Materials and Methods: In vivo studies in rats and guinea pigs were carried out to assess nasal and transdermal permeation, respectively. Results: CBD was absorbed intranasally within 10 minutes with a bioavailability of 34–46%, except with 100% polyethylene glycol formulation in rats. Bioavailability did not improve with enhancers. The steady-state plasma concentration of CBD in guinea pigs after transdermal gel application was 6.3 ± 2.1 ng/mL, which was attained at 15.5 ± 11.7 hours. The achievement of a significant steady-state plasma concentration indicates that CBD is useful for chronic pain treatment through this route of administration. The steady-state concentration increased by 3.7-fold in the presence of enhancer. A good in vitro and in vivo correlation existed for transdermal studies. Conclusion: The results of this study indicated that CBD could be successfully delivered through the IN and transdermal routes.     

Pharmacokinetic evaluation of differential drug release formulations of rabeprazole in dogs

Objectives: To develop novel dual release prototype capsule formulations of rabeprazole and evaluation of pharmacokinetic properties relative to the reference product (Aciphex^®) in Beagle dogs.

Methods: The dual release prototype formulations of rabeprazole were developed by preparing optimized mini-tablets core which was subsequently coated with barrier/enteric coating using standard excipients. Both novel prototype formulations were subjected for in vitro release and assay by HPLC-UV to assess long term stability. Single dose pharmacokinetic study used a single sequence three treatments crossover design. In Periods 1 and 2, four dogs received oral 20?mg dose of two prototype formulations. In Period 3, all dogs received a 20?mg oral dose of Aciphex^® reference product. There was a 1-week washout time between two successive periods. A quantitative analysis of rabeprazole/sulfide metabolite in plasma samples was performed using a validated LC-MS/MS assay and PK parameters were estimated by non-compartmental analysis.

Results: The stability of the prototype formulations was confirmed over a period of 24 months with an acceptable assay and dissolution data. One of the novel prototype formulations showed 70% oral bioavailability relative to the reference product. Despite a 30% reduced bioavailability, this showed 1?h delay in peak concentration, longer plasma residence time of rabeprazole (up to 12?h) and longer apparent elimination half-life.

Conclusions: The use of a canine model has enabled the selection of a novel dual-release prototype formulation of rabeprazole for further clinical development.     

Controlled Transdermal Mucolytic Delivery System: In Vivo Performance

Abstract

A multicomponent transdermal bromhexine delivering system was developed. The drug permeation across the human cadavar skin from either sexes was determined and found to be dependent on age, sex and site of skin. The system that could control the the delivery of the drug to allow it to permeate across the skin at a rate that is required to achieve the therapeutic concentration was selected and chosen for in vivo performance evaluation. Prior to in human volunteers availability testing the designed system was evaluated in rabbits and the system exhibiting desirable performance was redesigned for evaluation in human volunteers.T.P.S_o system delivering 1.991±0.116 mg bromhexine/cm² hr with a 453 μg/cm² priming dose was tested in human volunteers and found to maintain bromhexine blood level at or around peak plasma level for 20–24 hrs. The study reveals that bromhexine holds potential for transdermal delivery with a need of further clinical and pharmacodynamic studies.     

Enhanced Release of Drugs from Silicone Elastomers: (IV) Subcutaneous Controlled Release of Indomethacin and in Vivo/In Vitro Correlations

Abstract

The subcutaneous controlled release of indomethacin from implants was studied. The subderraal implants were prepared from silicone elastomers containing various levels of glycerol. The in vitro and in vivo releases of indomethacin were observed to follow a matrix diffusion-control mechanism. The release flux of indomethacin was enhanced when glycerol was incorporated into the silicone elastomers. An in vivo/in vivo correlation coefficient of 0.85 (< 0.05) was obtained for implants containing up to 20% (w/w) of glycerol. The survival rates on the ninth day post-implantation were determined to be 20, 65, and 100%, respectively, for the mice receiving implants containing 20, 10, and 0% glycerol. An LD₅₀ dose of 34 mg/kg was assessed for the subcutaneous controlled administration of indomethacin in CD-1 mice, which is not significantly different from the intraperitoneal LD₅₀ of 28 mg/kg and the intravenous LD₅₀ of 40 mg/kg.     

Simultaneous Estradiol and Levonorgestrel Transdermal Delivery from a 7-day Patch: In Vitro and In Vivo Drug Deliveries of Three Formulations

ABSTRACT

A new drug-in-adhesive transdermal patch was developed to deliver both estradiol and levonorgestrel through the skin over a 7-day period, but at different rates. This report elucidates the in vitro and in vivo biopharmaceutical studies that were necessary during the development of this product. Three test patches had to be manufactured, all delivering estradiol at the same rate, but delivering levonorgestrel at three different rates so that a levonorgestrel dose response could be studied in the clinic. An in vitro hairless mouse skin model (HMS) using modified Franz diffusion cells was used to select the test products delivering levonorgestrel in the order of 1:2:3. HMS experiments also demonstrated that the presence of estradiol did not affect the flux of levonorgestrel. Two in vivo studies in postmenopausal women showed that at steady state (four weeks of once-weekly dosing) the three test products all delivered estradiol at comparable rates. Similarly, the levonorgestrel deliveries for the three test products were in the order expected. The target fluxes of both drugs were achieved in these three test products by varying the drug loads and patch size. That this approach was successful is evidence of the value of using the HMS penetration experiments in transdermal product development and should provide useful insights for other formulations having to develop complex systems. One of the test products is now marketed as Climara Pro^TM.     

In Vitro and In Vivo Percutaneous Absorption Studies of Ketotifen Patches

Abstract

The purpose of the study is to develop a suitable transdermal delivery system for ketotifen. The physicochemical properties and skin penetration of ketotifen were evaluated for the optimization of the method of patch preparation. The distribution coefficients of ketotifen were determined in octanol/phosphate buffer systems, the partition coefficient and pka value of ketotifen were obtained as 120 and 6.73, respectively. In vitro skin penetration of ketotifen solution was determined at 35°C in the Valia-Chien diffusion cell by using the abdominal skin of nude mouse. The results showed that ketotifen had an optimal skin permeability at pH 7.5. In addition, ketotifen had higher rate of penetration through stripped skin, it was suggested that the main barrier for percutaneous absorption of ketotifen is stratum corneum. Ketotifen patch was fabricated in a stainless mold containing Eudragit S-100 and PEG 400. Other components, tween, span and fatty acids were also incorporated into the patch as penetration enhancers. For animal study, a patch with area of 30 cm² was applied on the dorsal skin of rabbit. The plasma level, after 10 hrs administration were reached 60 ng/mL and maintained a constant level. The results proposed that ketotifen was successfully absorbed through the skin from the applied patch.     

The Effects of Formulation Variables on Iontophoretic Transdermal Delivery of Leuprolide to Humans

Abstract

Feasibility of applying iontophoresis to facilitate the transdermal permeation of leuprolide acetate was investigated. Because of the complexity of the factors involved in the process of iontophoresis, theoretical predictions of the combination effects from formulation variables are difficult. This study incorporated the formulation variables, drug levels and buffer concentrations, in a device prepared by Drug Delivery System, Inc., to assess the feasibility for leuprolide delivery.

Steady state serum leuprolide concentrations were achieved within 30 minutes of patch application, and were maintained for the duration of the study period. An increase in LH levels was observed for each formulation. The serum leuprolide concentrations were higher with lower drug concentration and more dilute buffer solutions. Increasing drug concentration in the patch appeared to inhibit delivery of leuprolide. A mean steady state serum concentration, 0.8 ng/ml, was achieved by a formulation composed of 10 mg/ml leuprolide acetate and 0.05 M acetate buffer at pH 5.0. Competitive reaction of ions possibly involved in the delivery mechanism will be discussed.     

Scopolamine Sublingual Spray: An Alternative Route of Delivery for the Treatment of Motion Sickness

ABSTRACT

The purpose of this study was to develop a sublingual drug delivery spray formulation of scopolamine hydrobromide (L-(-)-hyoscine hydrobromide) and to determine the absolute bioavailability of scopolamine hydrobromide following sublingual delivery and to investigate the effect of a bioadhesive on the pharmacokinetic parameters of this drug in a rabbit model. Rabbits received a single scopolamine free base equivalent sublingual dose of 100 μg/kg and this was compared to intravenous administration of the drug. Blood samples were collected at different time points, and plasma scopolamine concentrations were determined using a new sensitive and specific LC/MS analytical method which utilized electrospray ionization detection. The bioavailability of sublingual scopolamine was determined by comparing plasma concentrations after sublingual spray delivery with equivalent intravenous doses. Following delivery of the sublingual spray dose, the average C_max was 1024.4 ± 177 ng/mL, and the AUC value was found to be 61067.6 ± 9605 ng.min/mL. Relative to the intravenous dose (100% bioavailability), the bioavailability was 79.8% after sublingual spray administration. The addition of 2% chitosan, a bio-adhesive material and an absorption enhancer, showed a significant improvement in scopolamine sublingual absorption (p < 0.05) was observed. Considering the limitations of delivering scopolamine orally or transdermally to patients who experience motion sickness, the sublingual route of administration using a spray delivery dosage form, is a potential alternative modality for the prevention of nausea and vomiting associated with motion sickness.     

The Effects of Pressure-Sensitive Adhesives and Solubilizers on the Skin Permeation of Testosterone from a Matrix-Type Transdermal Delivery System

ABSTRACT

Matrix-type transdermal delivery systems of testosterone (TS) were formulated with three different pressure-sensitive adhesives (PSA). The effects of PSA, skin permeation enhancers, and solubilizers on the rat skin permeation rate of TS were systematically investigated. Without a solubilizer, the skin permeation rate of TS reached its maximum value when only 2% of TS was loaded in the matrix and the crystal formation in the matrix was very rapid and severe. Two surfactants differing in their hydrophile–lipophile balance (HLB) number were, therefore, considered. Span 80, which was of the lower HLB number, was more effective than Tween 80 in increasing the solubility, and thereby increasing the permeation rate of TS. Moreover, the concentrations of both the solubilizer and the skin permeation enhancer affected the skin permeation rate. Thus, the highest skin permeation rate (4.14 µg/cm²/hr) was achieved when 2% TS was loaded in DuroTak® 87-2516 together with 10% Span 80 and 3% dodecylamine, the permeation enhancer. In vivo study showed that the application of an experimental patch on rat abdominal skin resulted in a prompt and significantly higher plasma concentration of TS than that of a commercial product (Testoderm®) designed to apply on the scrotal skin. The area under the curve (AUC) increased linearly as the loading dose of TS increased up to 6%. Thus, based on these results, a non-scrotal matrix-type transdermal delivery system of TS could be developed.     

In Vitro Evaluation of the Release of Albuterol Sulfate from Polymer Gels: Effect of Fatty Acids on Drug Transport Across Biological Membranes

ABSTRACT

In this investigation, the diffusion of the beta₂ agonist albuterol sulfate (ABS) across several membranes (cellulose, hairless mouse skin, human cadaver skin) from polymer gels was studied, and the effects of several fatty acids on drug permeation through skin were evaluated. The results were then used to predict whether transdermal delivery would be appropriate for ABS. All in vitro release studies were carried out at 37°C using modified Franz diffusion cells. In preliminary studies, ABS release through cellulose membranes was studied from two polymeric gels, Klucel® (hydroxypropylcellulose) and Methocel® (hydroxypropylmethylcellulose). Three polymer concentrations were used for each gel (0.5%, 1.0%, and 1.5%). From these experiments, Klucel 0.5% was selected as the optimal formulation to study ABS diffusion across hairless mouse skin. Experiments were conducted to evaluate the effects of capric acid, lauric acid, and myristic acid as penetration enhancers. The results suggested that lauric acid preferentially enhanced ABS diffusion compared to the other fatty acids studied, and follow-up studies were done to evaluate the release through human cadaver skin from a donor containing 2% ABS and lauric acid in 0.5% Klucel®. These experiments showed that a 2:1 (lauric acid:ABS) molar ratio gave the best ABS release rates. The release rate across human cadaver skin declined slowly over 24 hr, and an average flux over 24 hr of ?0.09 mg/hr cm² was measured. Using this value as a steady-state flux, extrapolations predicted that transdermal delivery can be used to maintain therapeutic ABS plasma levels (6–14 ng/mL) for extended periods. The results of this research suggest that ABS is a good candidate for transdermal drug delivery.     

Physicochemical stability,pharmacokinetic, and biodistribution evaluation of paclitaxel solid dispersion prepared using supercritical antisolvent process

Aim: To investigate the physicochemical stability, pharmacokinetics (PK), and biodistribution of paclitaxel (PTX) from paclitaxel solid dispersion (PSD) prepared by supercritical antisolvent (SAS) process.

Methods: Physicochemical stability was performed in accelerated (40°C 70?±?5% RH) and stress (60°C) storage conditions for a period of 6 months and 4 weeks, respectively. PK and biodistribution studies were performed in rats following i.v. administration of PTX equivalent to 6 and 12?mg/kg formulations.

Results: Physical stability of PSD showed excellent stability with no recrystallization of the amorphous form. Chemical stability of PSD in terms of % PTX remaining was 98.2?±?0.6% at 6 months and 97.9?±?0.3% at 4 weeks of accelerated and stress conditions, respectively. The PK study showed a nonlinear increase in AUC with increasing dose, that is, 100% increase in dose (from 6 to 12?mg/kg) resulted in 405.90% increase in AUC. Unlike PK study, the organ distribution study of PTX from PSD showed linear relationship with dose escalation. The order of organ distribution of PTX from highest to lowest for both PSD and Taxol^® was liver>kidney>lung>brain.

Conclusions: This study demonstrated excellent physicochemical stability with insight information on the PK and biodistribution of PTX from PSD prepared by SAS process.