Cyclodextrins in mucoadhesive microparticles containing lorazepam and risperidone

Ispitano je nastajanje inkluzijskih kompleksa lorazepama i risperidona s hidroksipropil-β-ciklodekstrinom (HP-β-CD) u otopini i u čvrstom stanju. U otopinama HP-β-CD različitih pH-vrijednostti lorazepam i risperidon stvaraju inkluzijske komplekse molarnog odnosa ciklodekstrin lijek 1:1. Nastajanje inkluzijskih kompleksa mijenja topljivost lijekova u vodi. Na stabilnost inkluzijskih kompleksa lorazepama i risperidona u otopini HP-β-CD utječe pH-vrijednost medija te prisustvo polimera (hidroksipropilmetilceluloza (HPMC) i karbomer). Inkluzijski kompleksi lorazepama i risperidona u čvrstom stanju pripremljeni su metodom sušenja raspršivanjem i karakterizirani su diferencijalnom pretražnom kalorimetrijom i infracrvenom spektroskopijom s Fourierovim transformacijama. Lorazepam, risperidon i njihovi inkluzijski kompleksi uklopljeni su u mukoadhezivne mikročestice metodom sušenja raspršivanjem. Kao mukoadhezivni polimeri korišteni su HPMC, karbomer i interpolimerni kompleks HPMC i karbomera. Oblikovane mikročestice karakterizirane su s obzirom na uklapanje djelatne tvari, raspodjelu veličina čestica, vrijednost zeta-potencijala te termoanalitičkom metodom (DSC). Mukoadhezivnost mikročestica ispitana je in situ metodom određivanja rada adhezije. Utvrđeno je da na mukoadhezivnost mikročestica utječe kemijska struktura polimera te prisustvo lijeka, dok je utjecaj HP-β-CD zanemariv. In vitro oslobađanje lorazepama i risperidona iz mikročestica ograničeno je topljivošću lijekova. Mehanizam oslobađanja lorazepama i risperidona iz mikročestica uključuje difuziju lijeka kroz izbubreni polimerni matriks te eroziju matriksa. HP-β-CD utječe na difuziju lorazepama u izbubrenom polimernom matriksu. Brzo otapanje inkluzijskog kompleksa doprinosi eroziji polimernog matriksa. Zbog toga je oslobađanje lorazepama iz mikročestica oblikovanih s HP-β-CD brže. Istim mehanizmom može se objasniti utjecaj HP-β-CD na oslobađanje risperidona iz mikročestica HPMC. Interakcija risperidona i karbomera ključna je pri oslobađanju lijeka iz mikročestica oblikovanih s karbomerom i interpolimernim kompleksom. Stoga je utjecaj HP-β-CD na oslobađanje risperidona iz mikročestica slabije izražen. Stvaranje inkluzijskih kompleksa utječe na in vitro difuzibilnost lorazepama i risperidona. Mehanizam djelovanja HP-β-CD kao promotora difuzije lijekova tumači se visokom topljivosti inkluzijskih kompleksa te utjecajem ciklodekstrina na transport lijekova kroz hidrodinamski sloj na površini polupropusne membrane. Stvaranje inkluzijskih kompleksa utječe na brzinu oslobađanja lijekova iz mikročestica, a uslijed toga rastu koncentracije lorazepama i risperidona raspoložive za difuziju. Ove karakteristike mukoadhezivnih mikročestica pružaju potencijal za nazalnu primjenu ispitivanih lijekova i njihov transport u CST i/ili tkivo mozga. Ciklodekstrini i ispitivani polimeri u mikročesticama lorazepama i risperidona mogli bi oblikovati terapijski sustav prikladan za nazalnu primjenu lijekova s učinkom na središnji živčani sustav.The inclusion complex formation of lorazepam and risperidone with HP-β-CD in solution and in solid state was investigated. In solutions of different pH values risperidone and lorazepam formed inclusion complexes with HP-β-CD. The inclusion complex formation significantly increased risperidone and lorazepam solubility. Media pH value and presence of the polymers (hydroxypropylmethyl cellulose (HPMC) and carbomer) influenced the stability of inclusion complexes. Inclusion complexes of risperidone and lorazepam in solid state were prepared by spray drying and characterised by differential scanning calorimetry (DSC) and FTIR spectroscopy. Lorazepam, risperidone and their inclusion complexes were incorporated in the mucoadhesive microparticles by spray drying. HPMC, carbomer and interpolymer complex of HPMC and carbomer were used as mucoadhesive components. Prepared microparticles were characterised by determination of drug content, particle size distribution, zeta potential measurement and DSC measurement. Mucoadhesion of the microparticles was investigated by in situ method based on adhesion work measurement. Chemical structure of the polymers and drug entrapment affected the mucoadhesion of the microparticles, while HP-β-CD effect was negligible. In vitro drug release form microparticles was limited by low water solubility of lorazepam and risperidone. The drug release mechanism included the drug diffusion through hydrated polymer matrix and matrix erosion. HP-β-CD affected the lorazepam release rate by increasing the drug solubility in swollen polymer matrix of the microparticles. HP-β-CD also promoted the matrix erosion and therefore contributed to the drug release. The same mechanism controlled the risperidone release from HPMC microparticles containing HP-β-CD. The drug-carbomer interaction limited the release of risperidone from the microparticles formulated with carbomer and interpolymer complex. Therefore, the influence of HP-β-CD on drug release from this microparticles was less pronounced. The in vitro diffusion studies were performed using standard Franz-diffusion cell. Thereby nasal absorption of the drugs was simulated. Inclusion complex formation affected lorazepam and risperidone diffusibility by increasing the drug solubility. HP-β-CD acted as a carrier of the lipophilic drugs across the hydrodynamic layer on the membrane surface and increased the drug concentration gradient over the membrane. HP-β-CD in microparticles changed the values of in vitro drug diffusion. Inclusion complex formation affected the drug release rate from the microparticles and therefore higher concentrations of lorazepam and risperidone were available for the diffusion. Above-mentioned characteristics of the mucoadhesive microparticles offer the potential for nasal application of lorazepam and risperidone and their transport to the cerebrospinal fluid and the brain. Cyclodextrins and investigated polymers in lorazepam and risperidone microparticles could formulate suitable drug delivery system for nasal application of psychoactive drugs

Analiza kiralnih lijekova kapilarnom elektroforezom

The importance of enantiomer purity control was perceived in 1960s after the Thalidomide disaster. Enantiomers can show different pharmacological efficiency, bioavailability and therapeutic indications. Very often only one enantiomer is active, while the other can have no activity whatsoever, or can even be toxic. Therefore, methods that enable separation and purity evaluation of enantiomers are very important. Most often used techniques are polarimetry, circular dichroism, roentgen diffraction and chiral chromatography. Separation techniques frequently used are high performance liquid chromatography, gas chromatography and capillary electrophoresis. Capillary electrophoresis is a very fast and cheap technique. The most often used chiral separators in capillary electrophoresis are ciclodextrins. They are cyclic oligosaharyds, composed of a-D-glucopyranoside units bound together in a ring. Topologically cyclodextrins are represented as toroids with the larger and the smaller openings of the toroid exposing to the solvent secondary and primary hydroxyl groups respectively. The exterior of the toroid is hydrophilic making it water soluble, while the interior is relatively hydrophobic. This enables the cyclodextrin to form inclusion complexes with drug molecules. One of the enantiomers forms stronger interactions with cyclodextrin then the other cyclodextrin, which ensures enantiomer separation. Enantioselective capillary electrophoretic method using cyclodextrins are used in pharmaceutical analysis, cosmetic and food industry, in forensic science and in environmental protection. In pharmaceutical analysis they are used for determination of stereochemical purity, especially when it is necessary to quantify one of the enanitomers in the presence of large quantity of other stereoisomers

Ciklodekstrini u ljekovitim oblicima

Cyclodextrins, cyclic oligosacharides, are useful pharmaceutical excipients, which have attracted widespread attention. The ground for their popularity from a pharmaceutical point of view is in their ability to change undesirable characteristics of the drugs, such as unpleasant taste, low aqueous solubility, chemical instability and improving the drug bioavailability by inclusion complex formation. Due to their biocompatibility, cyclodextrins may be used in formulations indented for different routes of drug application including oral, ocular, nasal and even parenteral route. This article outlines the importance and functionality of cyclodextrin in different dosage forms and indicates the possible directions of future development.Ciklodekstrini, ciklički oligosaharidi, predstavljaju skupinu farmaceutskih pomoćnih tvari koja je svojom multifunkcionalnošću privukla značajan interes. Temeljni razlog njihove popularnosti je u svojstvu ciklodekstrina da stvaranjem inkluzijskih kompleksa mijenjaju nepovoljne karakteristike lijekova, kao što je neugodan okus, niska topljivost u vodi i kemijska nestabilnost. Također, ciklodekstrini mogu povećati bioraspoloživost lijeka neovisno o putu primjene. Zahvaljujući biokompatibilnosti i netoksičnosti, ciklodekstrini se mogu koristiti u ljekovitim oblicima namijenjenim za različite putove primjene, uključujući oralni, okularni, nazalni te parenteralni put. Cilj ovog članka je istaknuti važnost i funkcionalnost ciklodekstrina u različitim ljekovitim pripravcima te naznačiti smjerove daljnjeg razvoja

Utjecaj kompleksacije piroksikama s ciklodekstrinima na oblikovanje gela

The aim of this work was to evaluate the role of cyclodextrins in topical drug formulations. Solid piroxicam (PX) complexes with beta-cyclodextrin (beta-CD) and randomly methylated beta-cyclodextrin (RAMEB) were prepared by freeze-drying and characterized using differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), Fourier transform infrared spectroscopy (FTIR) and near infrared spectroscopy (NIR). A physical mixture of PX and cyclodextrins was characterized by enhanced dissolution properties compared to the dissolution profile of the pure drug due to in situ complex formation. Formation of the PX-cyclodextrin inclusion complex additionally improved the drug dissolution properties. Influence of CDs on drug permeation from the water dispersion and the prepared hydroxypropyl methylcellulose (HPMC) gels was investigated. Permeation of the drug involved three consecutive processes: dissolution of the solid phase, diffusion across the swollen polymer matrix and drug permeation through the membrane. Complexation increased PX diffusion by increasing the amount of diffusible species in the donor phase. Slower drug diffusion through the HPMC matrix was the rate limiting step in the overall diffusion process. Possible interaction between the hydrophilic polymer and cyclodextrin may result in physicochemical changes, especially in a change of rheological parameters.Svrha rada bila je ispitati utjecaj kompleksacije piroksikama s ciklodekstrinima na oblikovanje pripravaka za topičku primjenu lijeka. Kompleksi piroksikama s β- i nasumično metiliranim β-ciklodekstrinom u krutom stanju pripremljeni su metodom sušenja smrzavanjem i karakterizirani su diferencijalnom pretražnom kalorimetrijom, difrakcijom X-zraka na prahu, infracrvenom spektroskopijom s Fourierovim transformacijama, te spektroskopijom u niskom infracrvenom području. Fizička smjesa lijeka s ciklodekstrinima karakterizirana je poboljšanom topljivošću u usporedbi sa čistim lijekom zbog stvaranja kompleksa in situ. Kompleksacija piroksikama sa ciklodekstrinima dodatno je poboljšala topljivost lijeka u liofiliziranom kompleksu. Ispitan je utjecaj ciklodekstrina na permeaciju lijekova iz vodenih disperzija i pripremljenih gelova s hidroksipropil metilcelulozom. Permeacija lijekova uključuje više uzastopnih procesa: otapanje krute faze, difuziju lijeka kroz izbubreni polimerni matriks, te difuziju lijeka kroz polupropusnu membranu. Kompleksacija piroksikama s ciklodekstrinima povećala je difuzibilnost lijeka uslijed porasta količine lijeka raspoloživog za difuziju. Difuzija lijeka kroz izbubreni polimerni matriks hidroksipropil metilceluloze pokazala se ključnim procesom koji određuje ukupnu difuziju lijeka. Interakcija hidrofilnog polimera s ciklodekstrinima utjecala je na fizikalno-kemijska svojstva gela, posebice na reološke parametere

Utjecaj različitih vrsta modifikacije na izvlačnu silu rotacijski zavarenih moždanika

The increasing use of modified wood justifies the intention to use it in joints made by rotary welding with dowels. Thermal modification, for example, increases the dimensional stability of wood by reducing its hygroscopicity and water absorption, but it is difficult to glue or to rotary weld due to the appearance of cracks. This can be avoided by changing the optimal welding parameters, which on the other hand directly affects the reduction of the pull-out force by more than 25 % depending on the type of the modified base. In the case of welding wooden dowels into wood modified with citric acid, the reduction in pull-out force is even greater. Due to the significant reduction, the use of this type of modification for wood welding is questionable. When citric acid modification is extended to the dowels, the dowel becomes a problem due to its lower tensile strength, which is even lower than the pull-out force of the welded dowel.Zavarivanje drva trenjem proces je kojim se spajaju dva ili više elemenata drva. Zbog trenja se stvara toplina koja omekša i rastali strukturu drva. Zavarivanje toplinski modificiranog drva zanimljivo je zbog sve veće primjene takvog drva u praksi. Toplinskom modifikacijom zbog smanjenja higroskopnosti i upijanja vode povećava se stabilnost dimenzija drva, ali zbog pojave pukotina u uzorku može biti otežano lijepljenje drva i rotacijsko zavarivanje moždanika. To se može izbjeći tako da se mijenjaju optimalni parametri zavarivanja, što izravno utječe na smanjenje izvlačne sile. Izvlačna sila moždanika zavarenoga u toplinski modificiranu podlogu smanjuje se za više od 25 %, ovisno o vrsti uzorka. Smanjenje izvlačne sile moždanika zavarenoga u drvo modificirano limunskom kiselinom čak je i veće. Zbog značajnog smanjenja izvlačne sile zavarenog moždanika upitna je primjena modifikacije limunskom kiselinom, kao i topinska modifikacija. Pri modifikaciji moždanika limunskom kiselinom vlačna je čvrstoća moždanika manja od izvlačne sile zavarenog moždanika

Utjecaj kompleksacije piroksikama s ciklodekstrinima na oblikovanje gela

The aim of this work was to evaluate the role of cyclodextrins in topical drug formulations. Solid piroxicam (PX) complexes with beta-cyclodextrin (beta-CD) and randomly methylated beta-cyclodextrin (RAMEB) were prepared by freeze-drying and characterized using differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), Fourier transform infrared spectroscopy (FTIR) and near infrared spectroscopy (NIR). A physical mixture of PX and cyclodextrins was characterized by enhanced dissolution properties compared to the dissolution profile of the pure drug due to in situ complex formation. Formation of the PX-cyclodextrin inclusion complex additionally improved the drug dissolution properties. Influence of CDs on drug permeation from the water dispersion and the prepared hydroxypropyl methylcellulose (HPMC) gels was investigated. Permeation of the drug involved three consecutive processes: dissolution of the solid phase, diffusion across the swollen polymer matrix and drug permeation through the membrane. Complexation increased PX diffusion by increasing the amount of diffusible species in the donor phase. Slower drug diffusion through the HPMC matrix was the rate limiting step in the overall diffusion process. Possible interaction between the hydrophilic polymer and cyclodextrin may result in physicochemical changes, especially in a change of rheological parameters.Svrha rada bila je ispitati utjecaj kompleksacije piroksikama s ciklodekstrinima na oblikovanje pripravaka za topičku primjenu lijeka. Kompleksi piroksikama s β- i nasumično metiliranim β-ciklodekstrinom u krutom stanju pripremljeni su metodom sušenja smrzavanjem i karakterizirani su diferencijalnom pretražnom kalorimetrijom, difrakcijom X-zraka na prahu, infracrvenom spektroskopijom s Fourierovim transformacijama, te spektroskopijom u niskom infracrvenom području. Fizička smjesa lijeka s ciklodekstrinima karakterizirana je poboljšanom topljivošću u usporedbi sa čistim lijekom zbog stvaranja kompleksa in situ. Kompleksacija piroksikama sa ciklodekstrinima dodatno je poboljšala topljivost lijeka u liofiliziranom kompleksu. Ispitan je utjecaj ciklodekstrina na permeaciju lijekova iz vodenih disperzija i pripremljenih gelova s hidroksipropil metilcelulozom. Permeacija lijekova uključuje više uzastopnih procesa: otapanje krute faze, difuziju lijeka kroz izbubreni polimerni matriks, te difuziju lijeka kroz polupropusnu membranu. Kompleksacija piroksikama s ciklodekstrinima povećala je difuzibilnost lijeka uslijed porasta količine lijeka raspoloživog za difuziju. Difuzija lijeka kroz izbubreni polimerni matriks hidroksipropil metilceluloze pokazala se ključnim procesom koji određuje ukupnu difuziju lijeka. Interakcija hidrofilnog polimera s ciklodekstrinima utjecala je na fizikalno-kemijska svojstva gela, posebice na reološke parametere

Screening of Mucoadhesive Microparticles Containing Hydroxypropyl- Beta-Cyclodextrin for the Nasal Delivery of Risperidone

Abstract: Interaction of the antipsychotic drug risperidone with hydroxypropyl-beta-cyclodextrin (HPBCD) in solution and in the solid state was studied with the aim of overcoming the limitations associated with nasal administration of low solubility drugs. Risperidone solubility studies revealed inclusion complex formation with a 1:1 stoichiometry. Low concentrations (0.1 w/v %) of hydroxypropylmethyl cellulose (HPMC) and carbomer affected risperidone solubility in water. No formation of a ternary complex was detected. The solid inclusion complex was prepared by spray drying and was characterised by thermal (DSC) and spectral (FTIR) analyses. Risperidone and the inclusion complex were loaded into microparticles by spray drying using HPMC, carbomer and HPMC/carbomer interpolymer complex (IPC) as mucoadhesive components. The microparticles were characterised with respect to drug loading, particle size distribution, thermal analysis, and zeta potential measurements. Mucoadhesive properties of the microparticles were studied by measuring the work of adhesion. Carbomer and IPC based microparticles revealed superior mucoadhesive microparticles compared to HPMC based microparticles. Drug incorporation into microparticles reduced their mucoadhesive properties, while incorporation of the cyclodextrin complex caused no additional reduction in mucoadhesion. The in vitro dissolution studies showed that formation of the inclusion complex significantly increased the risperidone dissolution rate from the microparticles, thus providing sustained drug release

In vitro dissolution/release methods for mucosal delivery systems

In vitro dissolution/release tests are an indispensable tool in the drug product development, its quality control and the regulatory approval process. Mucosal drug delivery systems are designed to provide both local and systemic drug action following ocular, nasal, oromucosal, vaginal or rectal administration. They exhibit significant differences in formulation design, physicochemical characteristics and drug release properties. Therefore it is not possible to devise a single method which would be suitable for release testing of such versatile and complex dosage forms. Different apparatuses and techniques for in vitro release testing for mucosal delivery systems considering the specific conditions at the administration site are described. In general, compendial apparatuses and methods should be used as a first approach in method development when applicable. However, to assure adequate simulation of conditions in vivo, novel biorelevant in vitro dissolution/release methods should be developed. Equipment set up, the selection of dissolution media and volume, membrane type, agitation speed, temperature, and assay analysis technique need to be carefully defined based on mucosal drug delivery system characteristics. All those parameters depend on the delivery system and physiological conditions at the site of application and may vary in a wide range, which will be discussed in details

In vitro dissolution/release methods for mucosal delivery systems

In vitro dissolution/release tests are an indispensable tool in the drug product development, its quality control and the regulatory approval process. Mucosal drug delivery systems are designed to provide both local and systemic drug action following ocular, nasal, oromucosal, vaginal or rectal administration. They exhibit significant differences in formulation design, physicochemical characteristics and drug release properties. Therefore it is not possible to devise a single method which would be suitable for release testing of such versatile and complex dosage forms. Different apparatuses and techniques for in vitro release testing for mucosal delivery systems considering the specific conditions at the administration site are described. In general, compendial apparatuses and methods should be used as a first approach in method development when applicable. However, to assure adequate simulation of conditions in vivo, novel biorelevant in vitro dissolution/release methods should be developed. Equipment set up, the selection of dissolution media and volume, membrane type, agitation speed, temperature, and assay analysis technique need to be carefully defined based on mucosal drug delivery system characteristics. All those parameters depend on the delivery system and physiological conditions at the site of application and may vary in a wide range, which will be discussed in details