Phospholipids are surfactants

New mixed micellar systems based on phospholipids for the solubilization of poorly water-soluble drugs

Rupp, Christopher

In the present work the development of new mixed micelles (MM) is described, which consist to high proportions of phospholipids (PL). Bile salt / lecithin-MM have been known as the only mixed micellar system on the pharmaceutical market since the 1960s. Since then, no alternative MM system has been described which, in addition to high proportions (50%) of natural PL, uses surfactants other than bile salts. In the first part of this work it was investigated to what extent the organizational behavior of the water-insoluble, membrane-forming PL can be influenced by a combination with a suitable surfactant in such a way that MM formation is forced. By systematically selecting structurally different surfactant classes, the influence of the molecular geometry of the surfactants on the ability to solubilize the largest possible amounts of natural PL in the form of an optically clear mixed micellar solution has been investigated. In addition, structurally different PLs were examined for their suitability for the formation of MM. From literature research and the Israelachvili et al. (1970) describes the packing parameter concept (PPC) that certain structural features in the molecular structure of an amphiphilic substance lead to preferred micelle formation. A modified PPC was developed which theoretically describes the association of two different amphiphilic substances (PL + surfactant) to form MM. This transferred PPC forms the theoretical basis for the explanation of an MM formation and afterwards the different amphiphilic molecules were combined with one another. After the sucrose and polyglycerol esters were found to be two classes of surfactants that have promising structural requirements for MM formation with PL, these substances were investigated accordingly. In addition to these surfactants with the preferred structural features, other surfactant classes with different structural features have also been examined for their ability to form optically clear mixed micellar solutions with different PL. Among other things, surfactants such as the block copolymer Poloxamer 188 were used, which has a divergent molecular structure so that it does not appear in a conical geometry, for example. The newly developed MM systems should be based on saturated PL, since the aqueous systems generated in this way are more stable to oxidative changes. Transmission measurements on the different combinations of surfactants and PL made it possible to determine the turbidity in these systems, which enabled optically clear systems to be identified. With the help of dynamic light scattering (DLS) the size of the MM, micelles or other existing particles could be determined as a hydrodynamic diameter. The MM system to be developed should have a strictly monomodal particle size distribution. With the direct dispersion process, a simple production process was established and implemented that allows the production of MM without the use of organic solvents or the use of dispersing aids such as an Ultra Turrax. Classic bile salt / lecithin MM are mostly produced using organic solvents such as chloroform. The new MM system should allow large-scale production at low cost and time. The application of the transferred PPC for MM formation from two different amphiphiles was successfully implemented for the surfactants and phospholipids investigated. With this work it was possible to gain essential knowledge, which gives information about the necessary structural features of the PL and surfactants used, so that a combination results in MM formation. In this way, systems were generated which enable MM formation with high proportions of saturated (natural) PL, which has not been described in the literature so far. The combination of sucrose laurate (SL) and natural hydrogenated phosphatidylcholine (hPC) or dipalmitoylphosphatidylcholine (DPPC) in a ratio of 1: 1, even at increased concentrations above 5%, results in an optically clear solution that has a strictly monomodal particle size distribution, the average being hydrodynamic Diameter of the MM is about 20 nm. The second part of this thesis describes how the newly developed MM systems behave in the solubilization of different, poorly water-soluble drugs. The solubilization capacities of the newly developed MM systems were compared with those of known classic bile salt / lecithin MM and other systems. It could be shown that the newly developed MM systems from hPC or DPPC and SL with a mass fraction of PC of 50-60% have a significantly higher solubilization capacity for diazepam and tetrazepam than classic MM or equally concentrated polysorbates 80 or hydroxypropyl -β-cyclodextrin solutions. By developing ternary MM systems, attempts were made to improve the solubilization capacity as well as certain physicochemical properties (such as the location of the critical micelle concentration (CMC), transmission of the solutions) of the MM. With the use of small amounts of PEGylated phospholipids, a significant increase in the cloud point could be achieved. In these ternary MM systems, there was no decrease in the solubilization capacity for diazepam. Binary systems of SL and PEGylated phospholipids (50:50) enable a further increase in the solubilization capacity for diazepam. Furthermore, a new method for determining the CMC was developed, which enables a corresponding investigation of MM systems and offers several advantages over the classic methods. In this method, dilutions of PC-containing MM systems are examined using DLS technology. The water-insoluble PC molecules used in each case are only kept in solution above the CMC in the form of MM. As soon as the dilutions are appropriately low concentrated (c < cmc),="" zeigt="" eine="" präzipitation="" der="" wasserunlöslichen="" pc-moleküle="" die="" cmc="" an,="" was="" durch="" steigende="" pdi-werte="" und="" steigende="" partikelgrößen="" angezeigt="" wird.="" diese="" methode="" ermöglicht="" eine="" schnelle="" cmc-bestimmung,="" die="" wenig="" störanfällig="" ist,="" eine="" direkte="" mizellbildung="" nachweist="" und="" keine="" dritten="" indikatormoleküle="" (wie="" dph="" bei="" fluoreszenzmessungen)="" benötigt.="" ferner="" ist="" die="" stabilität="" favorisierter="" neuer="" mm-systeme="" gegenüber="" einer="" lagerungszeit="" von="" mehr="" als="" 200="" tagen,="" dem="" zusatz="" unterschiedlicher="" additiva="" sowie="" unterschiedlichen="" ph-werten="" untersucht="" worden.="" die="" stabilität="" der="" neu="" entwickelten="" mm-systeme="" ist="" im="" ph-bereich="" von="" 1-11="" gegeben,="" was="" eine="" orale="" applikation="" der="" mm="" ermöglicht,="" ohne="" dass="" diese="" im="" gastrointestinaltrakt="" zerstört="" werden.="" die="" neu="" entwickelten="" mm-systeme="" blieben="" unter="" in-vitro="" bedingungen="" im="" bereich="" von="" ph="" 1-11="" über="" weit="" mehr="" als="" 24="" stunden="" stabil.="" klassische="" gallensalz-lecithin-mm="" werden="" in="" folge="" einer="" präzipitation="" der="" sauren="" gallensalze="" zerstört,="" sobald="" der="" ph-wert="" des="" umgebenden="" milieus="" den="" pks-wert="" des="" verwendeten="" gallensalzes="" unterschreitet.="" weiterhin="" zeigten="" sich="" die="" neu="" entwickelten="" mm-system="" als="" sehr="" stabil="" gegenüber="" niedrig="" und="" hoch="" konzentrierten="" zusätzen="" der="" eingesetzten="" salze,="" zucker,="" zuckeralkohole,="" glycerol,="" strukturbrecher="" wie="" harnstoff="" oder="" nicotinamid.="" dagegen="" reagieren="" die="" systeme="" empfindlich="" gegenüber="" alkohl-zusatz.="" eine="" sehr="" effektive="" methode="" zur="" erhöhung="" der="" stabilität="" einer="" wässrigen="" zubereitung="" stellt="" die="" gefriertrocknung="" dar.="" die="" neu="" entwickelten="" mm-systeme="" ließen="" sich="" sehr="" gut="" gefriertrocknen,="" wobei="" eine="" rekonstitution="" der="" lyophilisate="" in="" wasser="" problemlos="" war,="" was="" aus="" entsprechenden="" lichtstreumessungen="" abgeleitet="" werden="" konnte.="" ebenso="" konnte="" der="" anteil="" an="" solubilisiertem="" diazepam="" wiedergefunden="" werden.="" der="" einschluss="" hydrophober="" arzneistoffe="" in="" mizellare="" oder="" mischmizellare="" systeme="" kann="" die="" stabilität="" des="" arzneistoffes="" erhöhen,="" sofern="" sich="" die="" as-moleküle="" im="" inneren="" der="" mizellen,="" geschützt="" vor="" der="" wässrigen="" phase,="" befinden="" und="" nicht="" an="" die="" oberfläche="" der="" mizellen="" adsorbiert="" vorliegen.="" strukturaufklärungen="" wurden="" an="" unbeladen="" und="" mit="" arzneistoff-beladenen="" mm="" vorgenommen,="" um="" die="" lokalisierung="" des="" hydrophoben="" arzneistoffes="" in="" den="" neu="" entwickelten="" mm-systemen="" zu="" bestimmen.="" die="" mittels="" der="" eingesetzten="" 1h-nmr-analytik="" erhaltenen="" ergebnisse="" deutet="" daraufin,="" dass="" der="" hydrophobe="" modellarzneistoff="" diazepam="" aller="" wahrscheinlichkeit="" nach="" in="" das="" innere="" der="" mm="" aufgenommen="">

Nowadays almost half of newly developed active pharmaceutical ingredients are rejected in early phase development and will never find a way to a patient because of their poor water solubility leading to bioavailability problems. Considering such arising solubility problems the development of application vehicles like mixed micelles (MM) is a challenging research topic in pharmaceutical technology. Since all known classical MM systems being introduced to the market are composed of unsaturated phosphatidylcholine and bile salts, it was the aim of this study to develop alternatively composed MM which also comprise high ratios of phosphatidylcholine (PC) but further a surfactant type that is distinct from the bile salts. A combination of a bile acid and a PC does only result in a MM formation if the applied PC types are of unsaturated origin - otherwise no MM but vesicles or PC agglomerates will occur, regardless of which type of bile salt is used. Further, a drawback of the classical MM is given by a micelle - vesicle transformation which also takes place by changing the ratio of bile salt / lecithin or the total concentration. The theoretical approach behind this work is the transfer of the packing-parameter-concept, which describes the molecular association of one amphiphilic species, to the organization behavior of two different amphiphilic species (water-insoluble phospholipid + surfactant leading to MM). Therefore the influence of the surfactant molecular geometry on the ability to form MM with phospholipids was investigated. The successful combination of a suitable water-soluble surfactant and high ratios of a suitable, natural, water-insoluble phospholipid results in an isotropically clear aqueous solution offering a strictly unimodal particle size distribution with MM showing a hydrodynamic diameter of about < 30="" nm.="" transmission="" and="" dynamic="" light="" scattering="" (dls)="" measurements="" revealed="" that="" specific="" molecular="" properties="" of="" both="" the="" surfactant-="" and="" the="" phospholipid-type="" determine="" the="" ability="" of="" those="" amphiphilic="" species="" to="" form="" mm.="" after="" testing="" a="" large="" number="" of="" different="" surfactants="" and="" different="" phospholipids,="" a="" toolbox="" with="" specific="" molecular="" conditions="" of="" both="" tested="" species,="" the="" surfactant="" and="" the="" pl,="" could="" successfully="" be="" configured.="" to="" provide="" an="" example,="" the="" surfactant="" needs="" to="" geometrically="" appear="" in="" a="" conical="" shape="" and="" a="" strictly="" defined="" breakup="" within="" its="" molecular="" geometry="" is="" required.="" here,="" the="" polar="" head="" should="" feature="" a="" high="" hydrophilicity="" which="" is="" defined="" as="" far="" as="" possible="" by="" hydroxyl-units="" instead="" of="" e.g.="" polyoxyethylenglycol="" (as="" in="" in="" the="" case="" of="" polysorbate).="" this="" large="" hydrophilic="" head="" needs="" to="" be="" explicitly="" separated="" from="" an="" absolutely="" hydrophobic="" ending="" (offering="" non="" hydrophilic="" element="" at="" all).="" laurylic="" acid="" esters="" of="" polyglycerol="" or="" sucrose,="" both="" offering="" an="" optimal="" large="" hydrophilic="" head="" region,="" which="" forces="" the="" hydrophobic="" acyl="" chains="" into="" a="" v-formation,="" led="" to="" the="" most="" benefical="" results="" regarding="" a="" formation="" with="" pl="" to="" a="" clear="" mixed="" micellar="" solution.="" it="" could="" be="" found="" that="" the="" length="" of="" the="" fatty="" acids="" within="" the="" applied="" phosphatidylcholine-type="" is="" a="" limiting="" factor="" for="" the="" formation="" of="" mm.="" it="" should="" be="" c16="" or="" c18.="" since="" the="" description="" of="" classical="" lecithin/phospholipids="" mm="" in="" the="" 1960s,="" the="" present="" work="" has="" established="" a="" way="" to="" allow="" an="" alternatively="" formation="" of="" mm="" with="" the="" benefit="" of="" using="" more="" stable="" hydrogenated="" pc-types="" and="" by="" using="" a="" class="" of="" aliphatic="" surfactants="" that="" do="" not="" belong="" to="" the="" bile="" acids.="" with="" sucrose="" laurate="" (sl)="" for="" the="" first="" time="" a="" surfactant="" was="" found="" that="" solubilizes="" up="" to="" 60%="" of="" natural="" pc="" into="" an="" optically="" clear="" solution.="" sl="" forms="" isotropically="" clear="" solutions="" with="" hydrogenated="" phosphatidylcoline="" (hpc)="" or="" dipalmitoylphosphatidylcholin="" (dppc)="" exhibiting="" a="" unimodal="" particle="" distribution="" with="" particle="" sizes="" of="" approximately="" 20="" nm,="" indicating="" mixed="" micelles,="" and="" an="" excellent="" pdi-value="" of="" 0.1,="" even="" at="" higher="" ratios="" of="" hpc="" (60%="" dppc)="" and="" over="" a="" broad="" range="" of="" total="" surfactant="" concentrations.="" in="" comparison="" to="" the="" commonly="" used="" lecithin/bile="" salt="" mm="" where="" unsaturated="" pc="" (lecithin)="" is="" required="" for="" a="" mm="" formation,="" the="" introduced="" novel="" mm="" are="" formed="" with="" saturated="" pc-types="" which="" are="" more="" stable="" against="" oxidative="" degradation.="" contrary="" to="" the="" classical="" mm,="" no="" micelle-to-vesicle-transformation="" occurred="" by="" changing="" the="" concentration="" or="" the="" ratio="" in="" the="" favourite="" developed="" mm="" system.="" the="" applied="" direct="" dispersion="" method="" is="" a="" simple="" production="" method="" for="" the="" introduced="" mm-systems="" owing="" the="" benefit="" of="" avoiding="" organic="" solvents.="" the="" present="" work="" compares="" the="" solubilization="" capacities="" of="" newly="" developed="" mm="" to="" those="" of="" classical="" lecithin/bile="" salt="" mm="" and="" different="" other="" solubilizing="" systems.="" the="" mm="" system="" with="" sl="" and="" hpc="" (50:50)="" was="" found="" to="" be="" superior="" in="" drug="" solubilization="" of="" all="" investigated="" drugs="" compared="" to="" the="" classical="" lecithin/bile="" salt="" mm.="" further,="" a="" polysorbate="" 80="" solution,="" also="" at="" 5%,="" was="" inferior="" with="" regard="" to="" solubilizing="" the="" hydrophobic="" drugs="" diazepam="" and="" tetrazepam.="" the="" mm="" sizes="" of="" the="" favorite="" developed="" mm,="" before="" and="" after="" drug="" incorporation,="" were="" analysed="" by="" dls="" to="" evaluate="" the="" influence="" of="" the="" drug="" incorporation.="" here,="" the="" particle="" sizes="" remained="" constant,="" indicating="" a="" stable="" formation="" of="" the="" solubilizate.="" further="" the="" critical="" micelle="" concentration="" (cmc)="" of="" mm="" before="" and="" after="" drug="" incorporation="" was="" analysed="" by="" three="" different="" determination="" techniques.="" in="" this="" work="" a="" new="" robust="" method="" is="" introduced="" that="" enables="" the="" cmc="" determination="" -="" unlike="" the="" classical="" surface="" tension="" measurement="" technique="" -="" by="" the="" direct="" detection="" of="" mm="" with="" hpc.="" constant="" cmc-values="" could="" be="" obtained="" regardless="" if="" diazepam="" was="" encapsulated="" within="" the="" mm="" or="" unloaded="" mm="" were="" analysed.="" long-term="" stability="" tests="" considered="" the="" novel="" mm="" system="" to="" be="" stable="" at="" least="" over="" the="" investigated="" storage="" period="" of="" 200="" days="" at="" cool="" storage="" conditions.="" a="" lyophilization="" of="" the="" empty="" and="" diazepam="" loaded="" mm="" could="" successfully="" be="" carried="" out="" leading="" again="" to="" stable="" mm="" with="" constant="" sizes="" and="" constant="" encapsulated="" drug="" amounts="" after="" reconstitution="" in="" double="" distilled="" water.="" mm="" systems="" are="" described="" to="" enhance="" the="" bioavailability="" after="" oral="" administration.="" accordingly,="" the="" stability="" of="" the="" mm="" system="" against="" ph-shifts="" has="" been="" evaluated="" and="" compared="" to="" that="" of="" classical="" bile="" salt/lecithin="" mm.="" unlike="" the="" classical="" mm="" which="" disintegrate="" at="" ph-values="" underneath="" the="" pka="" of="" the="" applied="" bile="" acid="" by="" precipitation,="" the="" introduced="" novel="" mm="" remain="" stable="" from="" ph="" 1-11="" without="" any="" fluctuation="" in="" hydrodynamic="" diameter.="" a="" 1h-nmr="" study="" suggests="" the="" solubilized="" hydrophobic="" drug="" molecules="" (diazepam)="" to="" be="" incorporated="" into="" the="" inner="" mixed="" micellar="" core="" and="" not="" being="" adsorbed="" on="" the="" outer="" shell.="" the="" new="" developed="" mm="" system="" with="" 50="" or="" 60%="" of="" well="" tolerated="" natural="" hydrogenated="" pc="" and="" sl="" seems="" to="" be="" a="" promising="" drug="" delivery="" system="" to="" enhance="" the="" bioavailability="" of="" orally="" or="" parenterally="" administrated="" hydrophobic="" drugs="" –="" not="" at="" least="" since="" it="" is="" known="" that="" pl="" in="" classical="" mm="" and="" sl="" alone="" in="" micellar="" solutions="" increase="" the="" bioavailability="" of="" different="" hydrophobic="">

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