Mechanistic evaluation of factors affecting compound loading into ion-exchange fibers

Donnan theory was applied to gain mechanistic understanding on the factors affecting drug loading process, compound-fiber affinity and subsequent release from fibrous ion-exchangers. Impact of initial loading solution concentration on fiber occupancy and loading efficiency of compounds were assessed experimentally and theoretically. Relative affinity towards the anion-exchange fibers was studied by dual loading of monovalent salicylic acid and either more lipophilic 3-isopropylsalicylic acid or divalent 5-hydroxyisophthalic acid. The effect of fiber framework on compound binding was evaluated separately for weakly and strongly basic fibers of similar ion-exchange capacities. The results revealed that loading into the ion-exchange fibers can be efficiently adjusted by the concentration of loading solution, leading to improved controllability of drug release from the fiber and minimised drug loss during the loading procedure. Ion-exchange fibers can be utilised successfully in simultaneous delivery of two ionic drugs, which offers a potential drug delivery system for synergistically active drugs. However, physicochemical characteristics of the drug (lipophilicity, valence) and framework of fibrous ion-exchanger affect the relative affinity of the drug towards the fiber, and should not be neglected when selecting appropriate ion-exchange fiber or optimising the external conditions during loading/release. Application of Donnan theory in modelling calculations supported precisely the experimental observations of compound loading (fiber occupancy and loading efficiency).     

Ion-exchange and iontophoresis-controlled delivery of apomorphine

The objective of this study was to test a drug delivery system that combines iontophoresis and cation-exchange fibers as drug matrices for the controlled transdermal delivery of antiparkinsonian drug apomorphine. Positively charged apomorphine was bound to the ion-exchange groups of the cation-exchange fibers until it was released by mobile counter-ions in the external solution. The release of the drug was controlled by modifying either the fiber type or the ionic composition of the external solution. Due to high affinity of apomorphine toward the ion-exchanger, a clear reduction in the in vitro transdermal fluxes from the fibers was observed compared to the respective fluxes from apomorphine solutions. Changes in the ionic composition of the donor formulations affected both the release and iontophoretic flux of the drug. Upon the application of higher co-ion concentrations or co-ions of higher valence in the donor formulation, the release from the fibers was enhanced, but the iontophoretic steady-state flux was decreased. Overall, the present study has demonstrated a promising approach using ion-exchange fibers for controlling the release and iontophoretic transdermal delivery of apomorphine.     

Fabrication and properties of capsicum extract-loaded PVA and CA nanofiber patches

The aim of this study was to prepare, characterize and evaluate electrospun polyvinyl alcohol (PVA) and cellulose acetate (CA) nanofibers loaded with capsicum extract (CE) for use in topical skin treatments. CE, 0.5, 1 or 2 wt %, was loaded into PVA and CA electrospun fiber mats. Various properties of the CE-loaded fiber mats as well as release and skin permeation were investigated. The average diameters of these fibers ranged from 251–368?nm. The release rate of capsaicin from CE-loaded as-spun PVA was faster than that of the CA fiber mats and increased as the CE content in CE-loaded as-spun PVA and CA increased. The release kinetics of the CA and PVA fibers followed the Higuchi equation. The percentages of CE that permeated the shed snake skin with PVA and CA fiber mats containing 2 wt % CE after 24?h were 60% and 20%, respectively. The results suggest a potential use of PVA and CA nanofibers being used to control skin permeation of capsicum extract. Our research suggests the potential application of CE-loaded PVA electrospun mats as transdermal drug delivery systems.     

Touch-actuated microneedle array patch for closed-loop transdermal drug delivery

To date, only approximately 20 drugs synthesized with small molecules have been approved by the FDA for use in traditional transdermal patches (TTP) owing to the extremely low permeation rate of the skin barrier for macromolecular drugs. A novel touch-actuated microneedle array patch (TMAP) was developed for transdermal delivery of liquid macromolecular drugs. TMAP is a combination of a typical TTP and a solid microneedle array (MA). High doses of liquid drug formulations, especially heat-sensitive compounds can be easily filled and stored in the drug reservoir of TMAPs. TMAP can easily penetrate the skin and automatically retract from it to create microchannels through the stratum corneum (SC) layer using touch-actuated ‘press and release’ actions for passive permeation of liquid drugs. Comparison of subcutaneous injection, TTP, solid MA, and dissolvable MA, indicated that insulin-loaded TMAP exhibited the best hypoglycemic effect on type 1 diabetic rats. A ‘closed-loop’ permeation control was also provided for on-demand insulin delivery based on feedback of blood glucose levels (BGLs). Twenty IU-insulin-loaded TMAP maintained the type 1 diabetic rats in a normoglycemic state for approximately 11.63?h, the longest therapeutic duration among all previously reported results on microneedle-based transdermal patches. TMAP possesses excellent transdermal drug delivery capabilities.     

Development and Evaluation of a Novel Drug in Adhesive Transdermal System of Levodopa and Carbidopa

Purpose

Administration of levodopa along with carbidopa increases the availability of dopamine in the mid-brain, and this combination thereby is used in the treatment of parkinsonism. However, concomitant delivery of levodopa with carbidopa in oral therapy is limited by several issues and an alternative route would be advantageous. The current study assesses the feasibility of co-administration of levodopa and carbidopa through skin using a drug in adhesive transdermal system.

Methods

Drug in adhesive transdermal system containing levodopa (5 % w/w) and carbidopa (2.5 % w/w) (1 cm² area) was fabricated and assessed for in vitro drug release, ex vivo permeation, and in vivo pharmacokinetics in rat model.

Results

In vitro dissolution profiles indicated a biphasic pattern with an initial burst effect for both levodopa and carbidopa, although the drug release rate was relatively higher for carbidopa. Ex vivo permeation studies showed higher steady-state flux for levodopa (53.77?±?6.94 μg/cm²/h) and carbidopa (23.81?±?4.06 μg/cm²/h). In vivo studies revealed that the concomitant transdermal delivery of levodopa with carbidopa significantly changed the pharmacokinetic parameters of levodopa.

Conclusions

Given the promising results, this study concludes that the transdermal delivery route could be a feasible alternative to oral therapy for the successful delivery of levodopa in Parkinson’s disorder.     

A novel method to enhance the efficiency of drug transdermal iontophoresis delivery by using complexes of drug and ion-exchange fibers

The main reason for generally low efficiency of the transdermal iontophoretic drug delivery is that the fraction of the total current contributed by the drug ions is very small. The objective of this study was to find a method to increase the fraction of the total current contributed by the drug ions so as to enhance the drug's iontophoretic delivery. Iontophoretic transport of diclofenac solution and diclofenac assisted by ion exchange materials, including ion-exchange resin, ion-exchange membrane and ion-exchange fiber, across the rat skin were investigated. Both in vitro and in vivo iontophoretic transport experiments showed the amount of diclofenac permeated across rat skin from the diclofenac-fibers was highest among those from the diclofenac simple solutions and ion exchange materials complexes. The results of this study suggested that there is an enhancement of drug across rat skin by ion-exchange fibers in ion-exchange fibers assisted iontophoresis. The present study has demonstrated the potential of a new approach using ion-exchange fibers to enhance transdermal iontophoretic transport of an ionizable drug.     

The delivery of ketoprofen from a system containing ion-exchange fibers

A postulated model for transdermal delivery using ion-exchange fibers as controlling device was designed, and the main objective of this study was to assess the rationality of the model. The release rates of ketoprofen from the carbopol-based gel vehicles containing ion-exchange fibers to which the ketoprofen had been bound have been determined across 0.22 microm microporous membrane. The fluctuation of the release rate of ketoprofen from the vehicles was much lower compared with that of simple gels, though the cumulative amount of ketoprofen delivery was less. Additional ions could increase the rate and extent of ketoprofen delivery. The iontophoretically assisted transport of ketoprofen across rat skin was also studied and found to be favorable to ketoprofen permeation. According to the tested model, the ion-layer could enhance the ketoprofen delivery and satisfactory results were achieved.     

Potential of transdermal drug delivery in Parkinson's disease

There has been a growing recognition that pulsatile stimulation of dopamine receptors may be an important mechanism in the generation of the motor fluctuations that often develop and compromise the effectiveness of long-term levodopa administration in persons with Parkinson's disease (PD). This has prompted investigation of treatment approaches that might provide more constant, and therefore physiological, dopamine receptor stimulation. Frequent levodopa administration, controlled-release levodopa preparations, inhibitors of levodopa metabolism, and duodenal, subcutaneous and even intravenous infusions of levodopa or dopamine agonists have all been employed with this goal in mind, but all have limitations. Transdermal drug delivery is a treatment approach that is not only capable of providing a constant rate of drug delivery, but is also non-invasive and relatively simple to use. However, developing a drug to be delivered transdermally for the treatment of PD has been anything but easy. Levodopa and many dopamine agonists are not sufficiently soluble to be administered via the transdermal route, and blind alleys have been encountered thus far in the investigation of suitably soluble drugs. Nevertheless, investigation continues and yet another candidate drug, rotigotine (N-0923), is currently under active investigation. Techniques designed to enhance skin permeation and thus improve the effectiveness of transdermal drug delivery are also potential sources for future treatment advances.     

Electron beam irradiation: a novel technology for the development of transdermal system of isosorbide dinitrate

The development of a transdermal delivery system for isosorbide dinitrate (ISDN) using electron beam irradiation was studied. The solid state stability of the drug to irradiation was assessed. The drug was dissolved in 2-ethylhexylacrylate (EHA)-acrylic acid (AA) system and this solution was directly irradiated on a backing membrane (Scotchpak^®1006) at different doses to get transdermal patches. The developed systems were evaluated for residual monomer content, equilibrium weight swelling ratios (EWSR), differential scanning calorimetry (DSC), weight uniformity, thickness uniformity, drug content and content uniformity, peel strength, in vitro release, skin permeation kinetics and skin irritation potential. The developed system possessed excellent adhesive properties. Increase in the irradiation doses did not have a significant effect on the peel strength values. The systems exhibited promising skin permeation kinetics and no skin irritating potential, both of which are important properties for transdermal drug delivery. The ISDN-EHA-AA system developed at an irradiation dose of 50 kGy showed a higher skin permeation profile as compared to an internationally marketed transdermal matrix system of ISDN.     

Challenges and opportunities in dermal/transdermal delivery

Transdermal drug delivery is an exciting and challenging area. There are numerous transdermal delivery systems currently available on the market. However, the transdermal market still remains limited to a narrow range of drugs. Further advances in transdermal delivery depend on the ability to overcome the challenges faced regarding the permeation and skin irritation of the drug molecules. Emergence of novel techniques for skin permeation enhancement and development of methods to lessen skin irritation would widen the transdermal market for hydrophilic compounds, macromolecules and conventional drugs for new therapeutic indications. As evident from the ongoing clinical trials of a wide variety of drugs for various clinical conditions, there is a great future for transdermal delivery of drugs.     

Hollow Fibers as an Oral Sustained-Release Delivery System

Phenylpropanolamine (PPA) bound to ion-exchange resin was encapsulated in hollow fibers made of segmented polyurethane. This system was examined as an oral sustained-release delivery system. The fibers were spun by the phase inversion process and cut into different aspect ratios (length/diameter). The U.S.P. basket dissolution method was used to evaluate the in vitro drug release kinetics and the effect of the aspect ratio on the release. For in vivo evaluation, selected fibers were orally administered to dogs in gelatin capsules. The fiber delivery system provided a sustained-release profile of plasma PPA and a longer terminal half-life when compared to an oral immediate-release formulation.     

纳米药物载体在经皮给药系统中应用的研究进展

目的介绍纳米药物载体在经皮给药系统中的应用。方法查阅国内外文献共31篇,从纳米药物载体在经皮给药系统中的应用及各自的优势和不足等方面进行综述。结果纳米药物载体具有提高药物的化学稳定性、促进药物经皮吸收、控制药物释放以及定位给药等优点,在药物的经皮吸收方面具有广阔应用前景。结论纳米药物载体为药物的经皮通透提供了新的途径和方法,但是其安全性和有效性仍需进一步研究。     

Elastic liposomes mediated transdermal delivery of an anti-hypertensive agent: propranolol hydrochloride

One major problem encountered in transdermal drug delivery is the low permeability of drugs through the skin barrier. In the present investigation ultradeformable lipid vesicles, that is, elastic liposomes were prepared incorporating propranolol hydrochloride for enhanced transdermal delivery. Elastic liposomes bearing propranolol hydrochloride were prepared by conventional rotary evaporation method and characterized for various parameters including vesicles shape and surface morphology, size and size distribution, entrapment efficiency, elasticity, turbidity, and in vitro drug release. In vitro flux, enhancement ratio (ER), and release pattern of propranolol hydrochloride were calculated for transdermal delivery. In vivo study conducted on male albino rats (Sprague Dawley) was also taken as a measure of performance of elastic liposomal, liposomal, and plain drug solution. The better permeation through the skin was confirmed by confocal laser scanning microscopy (CLSM). Results indicate that the elastic liposomal formulation for transdermal delivery of propranolol hydrochloride provides better transdermal flux, higher entrapment efficiency, ability as a self-penetration enhancer and effectiveness for transdermal delivery as compared to liposomes.     

Development and characterization of transdermal drug delivery systems for diltiazem hydrochloride

Transdermal drug delivery system of diltiazem hydrochloride was developed to obtain a prolonged controlled drug delivery. Both the matrix diffusion controlled (MDC) and membrane permeation controlled (MPC) systems were developed. The matrix diffusion controlled systems used various combinations of hydrophilic and lipophillic polymers, whereas membrane permeation controlled systems were developed using the natural polymer chitosan. The MDC systems were prepared using the cast film method and the MPC systems by an adhesive sealing technique. Both the systems were characterized for in vitro and in vivo performance. The MDC systems were characterized for physicochemical properties such as tensile strength, moisture content, and water vapor transmission. The in vitro release studies showed that the release from the matrix diffusion controlled transdermal drug delivery systems follows a nonfickian pattern and that from the membrane permeation controlled transdermal drug delivery systems follow zero-order kinetics. The release from the matrix systems increased on increasing the hydrophilic polymer concentration, but the release from the membrane systems decrease on cross-linking of the rate controlling membrane and also on addition of citric acid to the chitosan drug reservoir gel. The in vivo studies of the selected systems showed that both systems are capable of achieving the effective plasma concentration for a prolonged period of time. The MPC system achieved effective plasma concentration a little more slowly than the MDC system, but it exhibited a more steady state plasma level for 24 hr.     

Ketoconazole ion-exchange fiber complex: a novel method to reduce the individual difference of bioavailability in oral administration caused by gastric anacidity

Water insoluble faintly alkaline drugs often have potential absorption problem in gastrointestinal tract in oral administration for patients with gastric anacidity. The purpose of the present study is to develop a novel method to improve the absorption of the water insoluble faintly alkaline drug in peroral administration. This method is based on ion exchange of ion-exchange fibers. Water-insoluble faintly alkaline drug ketoconazole was used as a model drug. Ketoconazole and the active groups of the ion-exchange fibers combined into ion pairs based on the acid-base reaction. This drug carrier did not release drugs in deionized water, but in water solution containing other ions it would release the drugs into the solution by ion exchange. Confirmed by the X-ray diffraction and the differential scanning calorimetry (DSC), the ketoconazole combined onto the ion-exchange fibers was in a highly molecular level dispersed state. The improved dissolution of ketoconazole ion-exchange fiber complexes is likely to originate from this ketoconazole’s highly dispersed state. Furthermore, due to this ketoconazole’s highly dispersed state, ketoconazole ion-exchange fiber complexes significantly decreased the individual difference of absorption in oral administration of ketoconazole caused by the fluctuation of the acid degree in the gastric fluid.     

Single-layer transdermal film containing lidocaine: modulation of drug release.

We have recently described an innovative drug delivery system, a water-based and vapor permeable film intended for dermal and/or transdermal delivery. The aim of this work was to modulate the delivery of the model drug lidocaine hydrochloride from the transdermal film across rabbit ear skin. The effect of drug loading, of film-forming polymer type and content, of adhesive and plasticizer on lidocaine transport across the skin was evaluated. Additional objective was to evaluate the effect of occlusion on the kinetics of lidocaine transport, by applying an occlusive backing on the surface of the transdermal film. From the data obtained it can be concluded that the transdermal film acts as a matrix controlling drug delivery. The film-forming polymer molecular weight had a negligible effect on drug penetration, while its content was more effective. The choice of the adhesive seems to be the most important variable governing drug transport. In particular, the presence of lauric acid combined with a basic drug, such as lidocaine, can produce a relevant improvement in permeation, because of the formation of an ion pair. Concerning the kinetics, drug depletion is responsible for the declining permeation rates observed in the late times of permeation.     

Hydroxypropylmethylcellulose films for prolonged delivery of the antipsychotic drug chlorpromazine

Objectives The aim of this study was to develop transdermal films based on hydroxypropylmethylcellulose with the purpose of improving transdermal permeation of chlorpromazine hydrochloride, an antipsychotic drug used to alleviate the symptoms and signs of psychosis. Methods Hydroxypropylmethylcellulose films were prepared and evaluated for their drug content, film thickness, residual water content and bioadhesive properties. In‐vitro permeation experiments were performed in the absence and in the presence of permeation enhancers (oleic acid, polysorbate 80, or both) with the purpose of improving drug availability. Other formulative parameters, such as drug and plasticizer concentration and hydroxypropylmethylcellulose type, were investigated. Key findings Both oleic acid and polysorbate 80 had significant effect on drug permeation with respect to the control formulation. In particular films containing a mixture of oleic acid and polysorbate 80 provided the best enhancement activity for chlorpromazine. Moreover, a decrease in propylene glycol or chlorpromazine content or an increase of hydroxypropylmethylcellulose viscosity provided lower cumulative amounts of drug permeated. Conclusions The results obtained confirm that chlorpromazine permeation can be easily modulated by varying the composition of hydroxypropylmethylcellulose‐based films. These formulations could serve as candidates for transdermal delivery of antipsychotic drugs.     

Ketotifen Fumarate and Salbutamol Sulphate Combined Transdermal Patch Formulations: In vitro release and Ex vivo Permeation Studies

The present work was performed to develop and evaluate transdermal patches of combined antiasthmatic drugs (salbutamol sulphate and ketotifen fumarate). Polyvinyl alcohol membrane was used as backing membrane and eudragit RL-100 was used as matrix material to suspend the drugs in the continuous thickness of the patch. Methanol was solvent and propylene glycol was used as plasticizer. Tween 20, isopropyl myristate, eucalyptus oil, castor oil and span-20 were used as permeability enhancers. Thickness, weight variation and drug uniformity were investigated. The patch formulations were also subjected to drug release in dissolution media and permeation through rabbit skin. Effects of different enhancers were evaluated on release and permeation of drugs. F3 formulations having isopropyl myristate as permeation enhancer, showed maximum amounts of drugs release (88.11% of salbutamol sulphate and 88.33% of ketotifen fumarate) at the end of 24 h dissolution study. F3 also showed maximum permeation of both drugs (4.235 mg salbutamol sulphate and 1.057 mg ketotifen fumarate) after 24 h permeation study through rabbit skin mounted in Franz cell. The patches having no enhancer in the formulation also showed some drug release and permeation due to the presence of plasticizer. The results of the study suggested that new controlled release transdermal formulations of combined antiasthmatic drugs can be suitably developed as an alternate to conventional dosage forms.     

Enhancement of levodopa stability when complexed with β-cyclodextrin in transdermal patches

Abstract

Levodopa is a promising candidate for administration via the transdermal route because it exhibits a short plasma half-life and has a small window of absorption in the upper section of the small intestine. The aim of this study was to prepare stable levodopa transdermal patches. Both xanthan gum and Carbopol 971 polymers were selected with ethylcellulose constituting the backing layer of the prepared patches. The effect of adding β-cyclodextrin on the prepared patches was investigated. The uniformity in thickness, weight and content of the studied patches was acceptable. Physicochemical characterization revealed that there was no interaction between levodopa and the applied polymer. The results proved that levodopa precipitated as an amorphous form in carbopol patches. Controlled drug release was achieved for all the tested patches over a 6?h period. However, increased permeation was achieved for the carbopol patches. Although cyclodextrin did not enhance levodopa permeation, the stability study confirmed that levodopa stability was enhanced when complexed with β-cyclodextrin. The cumulative amount of drug released from carbopol patches is slightly higher than that of xanthan patches. The optimal stability was achieved in the carbopol/levodopa:β-cyclodextrin patch. The levodopa-β-cyclodextrin complex was successfully characterized using X-ray diffraction, NMR analysis and molecular dynamics simulations. In conclusion, carbopol/levodopa:β-cyclodextrin patches can be considered as a promising stable and effective transdermal drug-delivery system.     

Design of a transdermal delivery system for aspirin as an antithrombotic drug

Aspirin has become the gold standard to which newer antiplatelet drugs are compared for reducing risks of cardiovascular diseases, while keeping low cost. Oral aspirin has a repertoire of gastrointestinal side effects even at low doses and requires high frequent dosing because it undergoes extensive presystemic metabolism. Transdermal delivery offers an alternative route that bypasses the gut and may be more convenient and safer for aspirin delivery especially during long-term use. This study comprised formulation of aspirin in different topical bases. Release studies revealed that hydrocarbon gel allowed highest drug release. In vitro permeation studies revealed high drug permeation from hydrocarbon gel. Several chemical penetration enhancers were monitored for augmenting the permeation from this base. Combination of propylene glycol and alcohol showed maximum enhancing effect and, hence, was selected for biological investigation. The biological performance of the selected formulation was assessed by measuring the inhibition of platelet aggregation relevant to different dosage regimens aiming to minimize both drug dose and frequency of application. The results demonstrated the feasibility of successfully influencing platelet function and revealed that the drug therapeutic efficacy in transdermal delivery system is dose independent. Biological performance was re-assessed after storage and the results revealed stability and persistent therapeutic efficacy.