Microemulsions have gained interest from the pharmaceutical industry due to their ability to co-solubilize hydrophilic and lipophilic drugs, and to provide enhanced drug penetration. In this work, thermosensitive gelatin- and poloxamer 407-stabilized microemulsion-based gels (MBGs) were formulated using alcohol-free, low toxicity and low viscosity lecithin-based linker microemulsions. The addition of gelatin to water-rich bicontinuous microemulsions induced the formation of clear viscoelastic gels containing an oil-rich microemulsion as the gelatin seemed to dehydrate the original microemulsion. The addition of poloxamer 407 to water-continuous microemulsions produced MBGs with different gelation temperatures. High concentrations of lipophilic components in the microemulsion, particularly the oil, reduced sol-gel transition temperature, while hydrophilic components increased sol-gel transition temperature. Gelatin and poloxamer MBGs provided desirable viscoelastic properties for ophthalmic and transdermal applications with minimal impact on the transport properties of the original microemulsions.

Microemulsions have gained interest from the pharmaceutical industry due to their ability to co-solubilize hydrophilic and lipophilic drugs, and to provide enhanced drug penetration. In this work, thermosensitive gelatin- and poloxamer 407-stabilized microemulsion-based gels (MBGs) were formulated using alcohol-free, low toxicity and low viscosity lecithin-based linker microemulsions. The addition of gelatin to water-rich bicontinuous microemulsions induced the formation of clear viscoelastic gels containing an oil-rich microemulsion as the gelatin seemed to dehydrate the original microemulsion. The addition of poloxamer 407 to water-continuous microemulsions produced MBGs with different gelation temperatures. High concentrations of lipophilic components in the microemulsion, particularly the oil, reduced sol-gel transition temperature, while hydrophilic components increased sol-gel transition temperature. Gelatin and poloxamer MBGs provided desirable viscoelastic properties for ophthalmic and transdermal applications with minimal impact on the transport properties of the original microemulsions.

Transdermal drug delivery system has been limited to small and lipophilic drugs because skin has the intrinsic function to protect the body preventing entry of the external species into the body. In this thesis, two physical methods were studied to overcome the skin barrier in the controlled breakage of the skin barrier and to deliver macromolecules-based drugs through the skin; (1) polysaccharide dissolving microneedles and (2) micro thermal skin ablation. Polysaccharide dissolving microneedles system was designed to break the skin barrier in a minimized size with the mechanically poor material, to release them into skin with the dissolution of microneedles, and to deliver human growth hormone into the living hairless rats. Micro thermal skin ablation was designed to fabricate the device generating the energy impact with the basis of arc discharge, to transfer the energy impact on the skin, to remove stratum corneum selectively with three-dimensionally controlled manner, and to deliver hydrophilic macromolecules through skin.

Naltrexone (NTX) is a drug used primarily in the management of alcohol dependence and opioid dependence. Based on several drawbacks associated with the oral and injectable intramuscular dosage forms of naltrexone currently available on the market, there is substantial interest in delivering naltrexone transdermally. Although naltrexone does not permeate skin at the rate sufficient to reach therapeutic plasma concentrations in humans, novel flux enhancement methods such as microneedles help address this challenge. Earlier work in humans has demonstrated that the use of microneedles achieves plasma concentrations in the lower end of expected therapeutic values. Further flux enhancement is desired to decrease the patch area while increasing drug transport rates. In the present work, several strategies aiming at in vitro flux maximization were employed including: formulation optimization, naltrexone salt screening, and naltrexone prodrug design. While naltrexone prodrugs did not reveal any improved permeation characteristics formulation optimization through decrease in vehicle microviscosity allowed a 5-fold increase in the percutaneous transport rates, and naltrexone glycolate salt selection provided an additional 1.5-fold enhancement in flux. One of the key observations was a good correlation (R2 = 0.99) between vehicle microviscosity and drug transport rates across the microchannel pathway. This finding alone allowed for formulation optimization and, at the same time, provided a potential explanation for the low permeation of high-concentration naltrexone salts and prodrugs. In vivo studies were carried out in Yucatan minipigs using a “poke and patch” microneedle method to deliver NTX•HCl. These studies demonstrated that initial plasma concentrations spiked to 2.5 ng/ml but rapidly dropped to a plateau of below 1 ng/ml. This pharmacokinetic profile could be explained by the use of a mathematical model which identified the importance of microchannel closure kinetics on drug transport. Also, an estimate of diffusional resistance of the viable tissue associated with percutaneous NTX•HCl delivery through microchannels was obtained. Its relatively large value suggests that the effect of diffusional resistance of the dermis in vivo should not be ignored and must be accounted for in order to obtain a good in vitro-in vivo correlation.

Transdermal drug delivery (TDD) is limited by high resistance of the outer layer of the skin, namely stratum corneum which blocks any molecule that is larger than 500 Da. Research on TDD has become very active in recent years and various technologies have been developed to overcome the resistance of the stratum corneum. In particular, researchers have started to consider the possibility of combining the TDD technologies in order to achieve further increment for drug permeability. Microneedles (MNs) and sonophoresis are both promising technologies that can perform notable enhancement in drug permeation via different mechanisms and therefore give a good potential for combining with each other. We discuss the possible ways to achieve this combination as well as how this combination would increase the permeability. Some of the undeveloped (weaker) research areas of MNs and sonophoresis are also discussed in order to understand the true potential of combining the two technologies when they are developed further in the future. We propose several hypothetical combinations based on the possible mechanisms of MNs and sonophoresis.

Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Technology Author: Petr Tirala Supervisor: PharmDr. Barbora Švecová, Ph.D. Title of thesis: Formulation and (trans)dermal application of liposomes containing imiquimod Imiquimod (IMQ), a substance belonging to the class of heterocyclic imidazoquinolines, shows significant immunomodulatory effects after topical administration, which is used to treat a variety of viral and malignant diseases of the skin. IMQ is currently used in clinical practice in the form of cream Aldara® containing 5% of active substance, which is unstable and irritating and after removal from the skin IMQ poses an ecological load for the environment. The aim of this thesis was preparation of liposomes for topical administrativ containing lower - 1% amount of IMQ and evaluation of penetration of IMQ into human skin in vitro. To improve the properties of liposomes and promote patency of the active ingredient through the skin barrier to the deeper skin layers various additives were used. Permeation experiments were carried out in Franz diffusion cells on the human skin in order to create the conditions that are as physiological as possible. Amount of IMQ was determined in the uppermost layer of the skin, epidermis, dermis, acceptor phase...

Des formes galéniques spécialement étudiées permettent l'administration topique d'un médicament ou d'un actif cosmétique afin d'obtenir un effet local ou une action systémique. Les excipients présents dans la formulation, comme les tensioactifs dans les solutions micellaires, émulsions, microémulsions, nanoémulsions, nanostructures, peuvent être alors des éléments influençant la pénétration et la perméation de l'actif. L'étude de leurs effets sur la barrière cutanée peut être utile afin de choisir au mieux les différents composés de la formulation. L'objectif de cette thèse a été d'étudier l'effet de différents tensioactifs (alkylpolyglucosides, lipoaminoacides, alcools gras éthoxylés et copolymères à blocs de type Poloxamer) en solution aqueuse sur la structure et la fonction barrière de la peau, grâce à des techniques d'infrarouge à transformée de Fourier, de calorimétrie différentielle à balayage, de mesure de la perte insensible en eau et de microscopie électronique à transmission. L'objectif spécifique de ce travail a porté sur l'étude de l'absorption cutanée ex vivo de trois principes actifs de lipophilie différente (caféine, kétoprofène et progestérone) à travers un modèle de peau animale co-traitée par différents tensioactifs. Plus spécifiquement, la pénétration de la progestérone au sein des différentes couches de la peau a été étudiée compte tenu de sa lipophilie élevée limitant son passage dans les couches cutanées plus hydrophiles. A l'issue de ces travaux, nous montrons que les tensioactifs peuvent exercer non seulement des effets sur l'organisation lamellaire des lipides intercornéocytaires mais aussi sur les cornéocytes du stratum corneum (SC). Par ailleurs, ces différents résultats ont permis de définir les structures chimiques des tensioactifs favorisant l'absorption cutanée de principes actifs. Les tensioactifs anioniques comportant une chaîne aliphatique de 12 carbones augmentent sélectivement la perméation cutanée de principes actifs hydrophiles et la pénétration de principes actifs lipophiles dans les tissus cutanés. La pénétration cutanée de principes actifs est étroitement corrélée à la taille des micelles de tensioactif susceptible de s'incorporer dans les espaces intercornéocytaires du SC. Enfin, la valeur de concentration micellaire critique est une propriété physico-chimique permettant d'expliquer en partie l'effet des tensioactifs sur leur perméabilité cutanée / Dosage forms specially designed allow the topical administration of drugs or cosmetic active ingredients to obtain a local effect or a systemic action. Excipients, such as surfactants in micellar solutions, emulsions, microemulsions, nanoemulsions, nanostructures can influence the drug penetration and permeation. Understanding their effects on skin barrier is helpful in the choice of surfactant. The aim of this thesis was to study the effect of different surfactants (alkylpolyglucosides, lipoaminoacids, ethoxylated fatty alcohol and copolymers blocks) in aqueous solution on the skin barrier structure and function, using techniques like infrared Fourier transform, differential scanning calorimetry, transepidermal water loss measurement and transmission electron microscopy. The specific aim of this work focused on the ex vivo cutaneous absorption of three drugs showing different lipophilicity (caffeine, ketoprofen and progesterone) through animal skin co-treated by different surfactants. More specifically, the penetration of progesterone in the different skin layers has been studied due to its high lipophilicity limiting its permeation in the most hydrophilic layers (viable epidermis and dermis). At the outset, we showed that surfactants could provide not only an effect on lamellar organization of intercorneocyte lipids but also on the corneocytes into the stratum corneum (SC). Moreover, these different results allowed to define surfactant chemical structure increasing drug cutaneous absorption. Anionic surfactant with a C12 chain length increased significantly cutaneous permeation of hydrophilic drug and penetration of lipophilic drug into cutaneous tissue. Drug penetration is correlated with micelle size allowed its incorporation into SC intercorneocyte spaces. Finally, the value of its critical micellar concentration is a physico-chemical properties allowed to partially explain the surfactant effect on their cutaneous permeability

The use of naloxone (NAL) for opioid overdose treatment is limited mostly to parenteral (intravenous, intramuscular, and subcutaneous) or intranasal route due to significant first-pass metabolism associated with oral delivery. Injectables are painful and frequent administrations by the existing routes for patient stabilization due to the short half-life of NAL are needed. Alternative delivery systems would be beneficial if they provide a balance between sustained release properties and a comparable rapid release as is achievable with the available parenteral forms. Thus, the goal of our study is to design a clinically viable polymeric microneedle (MN) patch for NAL. MNs of varying geometric dimensions were fabricated. In vitro skin permeation data for the best-performing patch was mathematically modeled and predictions on geometric parameters for a MN patch of comparable pharmacokinetic properties to parenteral and intranasal NAL as seen in the market were determined. From these evaluations, the need to devise ways to improve flux and amount of drug released from a patch per time was identified. We explored the influence of iontophoretically driving ionized drug content in MN patches on cumulative permeation of NAL from the best-performing MN patch. To optimize the iontophoresis parameters, the influence of citrate phosphate buffer strength on drug release profile was evaluated. Also, the impact of combining iontophoresis and higher drug loading was evaluated. A reduced lag time of about 5-15 min was observed with fabricated polymeric MN patches. From the polymeric MN patch P1 loaded with 50 mg/mL of NAL, a significant drug flux of 15.09 ± 7.68 ��g/cm2/h was observed in the first 1 h (p.Increasing MN length and density (P2 and P3) made a significant difference in the amount permeated and flux (pin-vitrorelease from the best-performing patch (P3) revealed the significance of needle base diameter and needle count in improving systemic pharmacokinetics of NAL from the MN patches. With this approach, an optimized design of the patch that can reproduce the clinical pharmacokinetics of NAL obtained with commercial devices was predicted. Investigation on the influence of iontophoresis in improving flux from the P3 patch shows about a 2-fold (p

Context: Low current intensity iontophoresis treatments have shown an increase in skin perfusion over 700% from baseline potentially increasing drug clearance from the targeted area. Objective: To determine the effects of a 10-minute ice massage on subcutaneous dexamethasone sodium phosphate (Dex-P) concentration and skin perfusion during and after a 4 mA iontophoresis treatment. Design: Controlled laboratory study. Setting: Research Laboratory. Patients or Other Participants: 26 individual participants (Males = 15, Females = 11, age = 25.6 ± 4.5 y, height = 173.9 ± 8.51 cm, mass = 76.11 ± 16.84 kg). Interventions: Participants were randomly assigned into two groups: 1) Pretreatment 10-minute ice massage; and 2) no pretreatment ice massage. Treatment consisted of an 80 mA min (4 mA∙20 minutes) Dex-P iontophoresis treatment. Microdialysis probes (3 mm deep in the forearm) were used to assess Dex-P, dexamethasone (Dex), and its metabolite (Dex-met) concentrations. Skin perfusion was measured using laser Doppler flowmetry probes. Main Outcome Measures: Microdialysis samples were collected at baseline, at conclusion of treatment, and every 20 minutes posttreatment for 60 minutes. Samples were analyzed to determine Dex-total concentration ([Dex-total] = Dex-P + Dex + Dex-met). Skin perfusion was calculated as a percent change from baseline. A repeated measures ANOVA was used for Dex-total and Skin Perfusion. Results: No significant difference was found in [Dex-total] between ice and no ice treatments, (P = 0.265). A significant increase in [Dex-total] occurred over the course of the iontophoresis and posttreatment time (P <<> 0.0004). Dex-P was recovered in 15 of 21 participants with a mean concentration of 0.604 ± 0.843 g/mL. Peak skin perfusion reached 27.74 ± 47.49% and 117.39 ± 103.45% from baseline for the ice and nonice groups, respectively. Conclusions: The 10-minute ice massage prior to iontophoresis does not significantly alter the delivery of [Dex-total] through the skin. A greater [Dex-P] was recovered than previously seen with lower intensities.

No description available.