4 research outputs found
Lipid-based systems as promising approach for enhancing the bioavailability of poorly water-soluble drugs
Low oral bioavailability as a consequence of low water solubility of drugs is a growing challenge to the development of new pharmaceutical products. One of the most popular approaches of oral bioavailability and solubility enhancement is the utilization of lipid-based drug delivery systems. Their use in product development is growing due to the versatility of pharmaceutical lipid excipients and drug formulations, and their compatibility with liquid, semi-solid, and solid dosage forms. Lipid formulations, such as self-emulsifying (SEDDS), self-microemulsifying SMEDDS) and self-nanoemulsifying drug delivery systems (SNEDDS) were explored in many studies as an efficient approach for improving the bioavailability and dissolution rate of poorly water-soluble drugs. One of the greatest advantages of incorporating poorly soluble drugs into such formulations is their spontaneous emulsification and formation of an emulsion, microemulsion or nanoemusion in aqueous media. This review article focuses on the following topics. First, it presents a classification overview of lipid-based drug delivery systems and mechanisms involved in improving the solubility and bioavailability of poorly water-soluble drugs. Second, the article reviews components of lipid-based drug delivery systems for oral use with their characteristics. Third, it brings a detailed description of SEDDS, SMEDDS and SNEDDS, which are very often misused in literature, with special emphasis on the comparison between microemulsions and nanoemulsions
Evaluation of colloidal systems with lecithin for dermal application of ascorbyl palmitate
Solubilisation of poorly soluble drug with self-microemulsifying delivery systems incorporated into solid dosage forms
Topnost zdravilne učinkovine (ZU) je eden izmed najbolj pomembnih parametrov, s katerim zagotavljamo terapevtsko koncentracijo ZU v sistemskem krvnem obtoku. Ker pa je kar 40 – 70 % na novo odkritih ZU slabo vodotopnih, je razvoj učinkovitih peroralnih farmacevstkih oblik (FO) ključnega pomena. Slabo vodotopne ZU po peroralni aplikaciji izkazujejo namreč omejeno (nižjo) biološko uporabnost (BU) in visoko inter- ter intraindividulano variabilnost. Med sodobnejše pristope solubilizacije slabo vodotopnih ZU sodijo na lipidih osnovani samo-(mikro)emulgirajoči sistemi (S(M)ES), ki po peroralni aplikaciji v stiku s fiziološkim medijem pod vplivom peristaltičnega gibanja gastrointestinalnega trakta hitro in spontano tvorijo optično transparentne in termodinamsko stabilne mikroemulzije (ME) tipa O/V, znotraj katerih ostane ZU raztopljena celoten čas prehoda prebavnega trakta. Na tržišču so danes dostopne samo FO, ki temeljijo na vgradnji tekočih SMES – npr. s tekočim SMES napolnjene mehke želatinske kapsule. Pri izdelavi slednjih pa se srečujemo s problemi kompatibilnosti in stabilnosti ter visokimi proizvodnimi stroški. Prav zato potekajo številne raziskave s ciljem združitve prednosti SMES in trdnih FO. Namen doktorskega dela je zato solubilizacija slabo topne ZU s SMES vgrajenimi v trdne FO. V uvodu doktorske naloge smo se osredotočili na SMES in kritičen pregled metod za izdelavo trdnih SMES. Podrobneje smo opisali metodo sušenja z razprševanjem, ki smo jo kot metodo izbora tudi uporabili v našem eksperimentalnem delu. V Poglavju 1 pa smo na podlagi literaturnega pregleda podrobno predstavili na lipidih osnovane dostavne sisteme (angl. Lipid Based Drug Delivery Systems, LBDDS) ter pripravili razširjeno primerjavo med ME in nanoemulzijami (NE), saj je to področje tudi v literaturi še izrazito terminološko neenotno in neusklajeno. Eksperimentalno delo doktorske disertacije smo razdelili na tri dele. V prvem delu (Poglavje 2) smo se osredotočili na razvoj in vrednotenje SMES, izdelanega na osnovi površinsko aktivne snovi (PAS) Gelucire® 44/14. Cilj razvoja SMES je bil izbrati formulacijo, ki bo izkazovala samo-mikroemulgirajoče lastnosti (velikost kapljic ME < 100 nm) in zagotavljala maksimalno količino vgrajene ZU pri minimalni koncentraciji izbranih PAS. Na podlagi rezultatov študije topnosti modelne ZU naproksena v izbranih pomožnih snoveh in izdelanih (psevdo)trikomponentnih diagramov, se je kot najbolj optimalna izkazala formulacija s 60 % oljne faze (Miglyol 812®1: PeceolTM 2 =1:1) ter 40 % emulgatorske faze (Gelucire® 44/141: Solutol® HS 152 =1:1), ki tvori po dispergiranju 39,9±0.1 nm velike kapljice in v njej lahko solubiliziramo (raztopimo) 6% m/m naproksena glede na tekoči SMES. Pri vrednotenju samo-mikroemulgirajočih lastnosti SMES smo ugotovili, da solubilizirana ZU še zmanjša velikost kapljic ME, kar je posledica dobre topnosti naproksena v emulgatorski fazi in dodatne ukrivljenosti emulgatorskega filma. Z in vitro testom sproščanja pa smo preverili vpliv SMES na solubilizacijo oz. hitrost raztapljanja ZU in potrdili hipotezo, da z vgradnjo naproksena v SMES signifikantno izboljšamo tako obseg sproščanja kot tudi hitrost raztapljanja naproksena. V drugem delu doktorske naloge smo s ciljem združitve prednosti na lipidih osnovanih sistemov in trdnih FO razviti tekoči SMES pretvorili v trdno FO z različnimi metodamit.j. polnjenje v kapsule, sušenje z razprševanjem, adsorpcija na trdne nosilce in granuliranje s talinami, pri čemer smo uporabili različne nosilce, primerne za posamezno metodo (Poglavje 4). Metode smo primerjalno vrednotili in kot metodo izbora za izdelavo trdnih SMES, na podlagi samo-(mikro)emulgirajočih lastnosti nastalih prahov, izbrali metodo sušenja z razprševanjem, kjer smo kot nosilec uporabili maltodekstrin (MD). Na podlagi načrta eksperimentov (DoE) smo s popolnim 2-nivojskim – 3-faktorskim (23) načrtom vrednotili vpliv procesnih parametrov metode sušenja z razprševanjem na samo-(mikro)emulgirajoče lastnosti (velikost kapljic in porazdelitev le-teh) in izkoristek procesa. Na podlagi statističnega vrednotenja smo ocenili, da ima tlak razprševanja največji in signifikanten vpliv (z negativnim predznakom) na samo-(mikro)emulgirajoče lastnosti prahov. Na porazdelitev velikosti kapljic (PDI) poleg tlaka razprševanja signifikantno vpliva tudi pretok oz. hitrost črpanja disperzije za razprševanje (antagonistični učinek). Z eksperimentalnim delom smo potrdili hipotezo, da z DoE lahko optimiziramo tvorbo trdnega SMES. Na podlagi DoE smo definirali nastavitve ključnih procesnih parametrov ter v odvisnosti od teh izbrali tudi optimalno sestavo disperzije za razprševanje in izdelali trdne SMES z vgrajeno ZU. Potrdili smo, da smo tudi s pretvorbo SMES ohranili samo-mikroemulgirajoče lastnosti formulacije in povečali topnost in hitrost raztapljanja naproksena. Trdni SMES izkazuje nižjo hitrost raztapljanja v primerjavi s tekočim SMES (najprej se mora raztopiti trdni nosilec MD, v katerem so ujete kapljice tekočega SMES), ZU pa se sprosti v enakem obsegu, kar je lahko rezultat spontane tvorbe ME. Nadalje smo v Poglavju 3 preverili vpliv nosilca in koncentracije vgrajene ZU na ključne lastnosti SMES. Ugotovili smo, da koncentracija ZU in izbran nosilec vplivata tako na samo-mikroemulgirajoče in morfološke lastnosti trdnih SMES ter na učinkovitost enkapsuliranja kot tudi na profil raztapljanja ZU. Dodatno ZU v prenasičeni koncentraciji vpliva tudi na kristaliničnost vgrajene ZU. V tretjem delu disertacije smo se osredotočili na izdelalvo samo(mikro)emulgirajočih tablet in minitablet s ciljem preveriti hipotezo, da z DoE lahko optimiziramo tvorbo trdnega SMES in izdelamo tablete in minitablete z ohranjenimi samo(mikro)emulgirajočimi lastnostmi in izboljšano topnostjo naproksena (Poglavje 4). Tablete in minitablete smo izdelali iz trdnih SMES, izdelanih z metodo sušenja z razprševanjem, na osnovi MD in naproksenom v dveh koncentracijah (6% m/m in 18% m/m glede na tekoči SMES). Ugotovili smo, da tako tablete kot minitablete ne izkazujejo samo-mikroemulgirajočih lastnosti, temveč po redispergiranju tvorijo emulzije. Kljub temu pa še vedno izkazujejo izboljšano topnost in hitrost raztapljanja v SMES vgrajenega naproksena v primerjavi s samo ZU. Rezultati pričujoče doktorske disertacije bodo prispevali k boljšemu razumevanju vpliva različnih metod, nosilcev in koncentracije vgrajene ZU na samo-(mikro)emulgirajoče in morfološke lastnost trdnih SMES. Z izbiro ustreznega nosilca lahko dosežemo tako pospešeno kot upočasnjeno sproščanje ZU iz trdnega SMES s povečano hitrostjo raztapljanja in obsegom sproščanja glede na samo ZU. Vključitev DoE za definiranje procesnih parametrov metode za izdelavo samo-mikroemulgirajočih prahov in uporaba metode Ramanskega mapiranja, kot novosti za preučevanje trdnih SMES, nam omogoča poglobljeno študijo razumevanja in tudi načrtovanja trdnih SMES s ciljnimi fizikalno-kemijskimi in biofarmacevtskimi lastnostmi produkta in s tem podpira tehnološko konkurenčnost sistemov SMES za solubilizacijo slabo topnih ZU.Solubility of a drug is one of the most important parameters by which a therapeutic concentration of a drug is ensured in the systemic bloodstream. However, because 40 to 70% of newly developed drugs are poorly water soluble, the development of effective drug delivery systems is crucial. After oral administration, poorly water-soluble drugs show limited bioavailability and high inter- and intraindividual variability.
One modern approach for the solubilization of poorly water-soluble drugs is lipid-based self-microemulsifying drug-delivery systems (SMEDDS), which in physiological media spontaneously form optically transparent and thermodynamically stable o/w microemulsions (ME), containing drug already dissolved. Only liquid SMEDDS formulations in the form of hard and soft gelatin capsules are available on the market. Their production is limited by compatibility and stability problems and high production costs. This is why several studies are ongoing with a view to combining the advantages of SMEDDS formulations and solid dosage forms. Therefore, this doctoral dissertation focuses on the solubilization of a poorly water-soluble drug with a SMEDDS formulation incorporated into solid dosage forms. The introduction to the dissertation focuses on SMEDDS formulation and provides a critical overview of methods for solid SMEDDS preparation. The spray-drying method, which was also used in the experimental work, is described in greater detail. Chapter 1 reviews lipid-based drug delivery systems (LBDDS). An extended comparison is made between ME and nanoemulsions (NE) due to the discrepancy in the literature using these terms. The first part of the dissertation (Chapter 2) focuses on the development and evaluation of liquid SMEDDS based on the Gelucire® 44/14 surfactant. The aim was to select a formulation that shows self-microemulsifying properties (mean droplet size of ME after dilution < 100 nm) and is able to solubilize the highest amount of the model drug (i.e., naproxen) using a minimal concentration of selected surfactants. Based on a solubility study of naproxen in selected excipients and construction of (pseudo)ternary diagrams, the most promising formulation consisted of a 60% w/w oil phase Miglyol 812®1:PeceolTM 2 = 1:1) and a 40% w/w surfactant/co-surfactant (S/co-S) mixture (Gelucire® 44/143:Solutol® HS 154 = 1:1). This composition was able to solubilize 6% w/w of naproxen and form droplets of 39.9 ± 0.1 nm upon dilution. The effect of incorporated naproxen on self-microemulsifying properties was observed. This is attributed to the good solubility of naproxen in a S/co-S mixture, promoting greater curvature of the surfactant film and consequently reducing the ME droplet size. In order to evaluate the effect of SMEDDS on dissolution profiles, an in vitro dissolution study was performed. The results obtained confirmed the prediction that incorporating naproxen into the SMEDDS formulation significantly improves its extent and dissolution rate. The aim of the second part of the dissertation was to combine the advantages of LBDDS and solid dosage forms. Thus, the developed liquid SMEDDS is transformed into a solid dosage form by using different solidification techniques: filling into hard gelatin capsules, spray drying, adsorption onto solid carriers, and melt granulation, and using a suitable solid carrier for each method (Chapter 4). The solidification techniques were comparatively evaluated with regard to the self-microemulsifying properties of the powders obtained. Based on these results, spray-drying techniques in combination with maltodextrin (MD) as a solid carrier were selected for further experimental work. After this, design of experiments (DoE) on the spray-drying process using MD was performed using a three-factor, two-level full factorial design (23) in order to evaluate the influence of process parameters on self-microemulsifying properties (mean droplet size after reconstitution and PDI) of the powders obtained and the yield of the process. Based on the results, the spraying pressure and pump speed had a major and significant influence on mean droplet size and PDI, exhibited an antagonistic effect. The results obtained confirmed the prediction that DoE can optimize formation of solid SMEDDS. The settings of key spray-drying process parameters were defined based on DoE. Based on these, optimal composition of the dispersion for spray drying was also selected and naproxen-loaded solid SMEDDS were prepared. The obtained results confirmed that, with the transformation of liquid to solid SMEDDS, self-microemulsifying properties were preserved and an enhanced solubility and dissolution rate of naproxen was achieved. Namely, solid SMEDDS show a lower dissolution rate of naproxen in comparison to liquid SMEDDS (first the solid carrier MD needs to be dissolved, in which droplets of liquid SMEDDS are entrapped), but the incorporated drug is release to the same extent, which is the result of spontaneous ME formation. Chapter 3 also examines the influence of a solid carrier and the concentration of the incorporated drug on key characteristics of SMEDDS formulation. The results obtained showed that drug concentration and the type of carrier used influenced the self-microemulsiufying and morphological properties of solid SMEDDS. In addition, an influence on the degree of encapsulation and dissolution profile was observed. Moreover, the supersaturated concentration of the incorporated drug also influenced its physical properties. The third part of the dissertation focuses on preparing self-(micro)emulsifying tablets and minitablets, with the aim of verifying the prediction that by using DoE it is possible to optimize a solid SMEDDS formation and prepare tablets and minitablets with preserved self-microemulsifying properties and enhanced naproxen solubility (Chapter 4). Tablets and minitablets were prepared from spray-dried solid SMEDDS containing naproxen in two different concentrations (6% and 18% w/w). The results obtained showed that tablets and minitablets do not exhibit self-microemulsifying properties after reconstitution, but they do form emulsions. Nevertheless, they still show enhanced solubility and dissolution rate of naproxen incorporated into a SMEDDS formulation in comparison to pure drug. The results of this dissertation will contribute to a better understanding of the influence of various solidification methods, solid carriers, and incorporated drug concentration on self-microemulsifying and morphological properties of solid SMEDDS. By selecting an appropriate solid carrier, both immediate and modified drug release from solid SMEDDS may be achieved with an improved dissolution rate and extent of drug release in comparison to pure drug. The implementation of DoE for defining the process parameters of the method for self-microemulsifying powder preparation and the Raman mapping method, which is an innovation in studying solid SMEDDS, make it possible to study the issue in depth and to formulate solid SMEDDS for the target physicochemical and biopharmaceutical properties of the final product. This supports the technological competiveness of SMEDDS formulations for solubilization of poorly water-soluble drugs