Provider: - Institution: - Data provided by Europeana Collections- Quality by design concept represents systematic approach to pharmaceutical product development which consists of assessment, ...improvement of formulation and process understanding and optimization by combined use of previous knowledge, risk analysis and experimental work. Spray drying technology has found its use in pharmaceutical industry thanks to process simplicity and flexibility, as a single-step process in which liquid is transferred into powder with properties easily controlable by process variables manipulation. Understanding how changes in process parameters can influence the physicochemical properties of resulting product, is especially important in production of solid dosage forms where assurance of predictions and control of performance are the main goals. Main goal of this research is spray drying understanding improvement through process characterization and modelling performed by quality by design concept. The research consists of two sections with following goals: spray drying process development as technology suitable for providing homogeneous powders and subsequently, dose uniformity of low-dose drug substances (model substance naratriptan hydrochloride); and spray drying process development in production of powders with poorly soluble drug substances (model substances voriconazole and aripiprazole). The research is also dealing with examination of potential use of two beta-cyclodextrin derivatives: 2- hydroxypropyl-beta-cyclodextrin (HPBCD) and 2-O-methyl-beta-cyclodextrin (2-O-MBCD) for the purpose of solubility and dissolution improvement of selected model substances. Within the development process, according to quality target product profile for powder as a intermediate product, critical product quality attributes were identified, and then critical quality attributes for input parameters (material properties, process parameters) were defined and their functional relationships with critical product quality attributes were determined. In first section of research, effects of spray drying process parameters (inlet air temperature, pump speed, aspirator, feed concentration) on process and powder characteristics (production yield, moisture content and mean particle size) were examined. In the second section of research solubility studies with poorly soluble substances and cyclodextrins were conducted, as well as molecular docking simulations, and characterisation of spray dried drug:CD powders was performed. For selected formulation with aripiprazole and HPBCD, spray drying process characterisation and modelling was performed. Effects of spray drying process parameters (inlet air temperature, pump speed, feed concentration) on process and powder characteristics (production yield and moisture content) were examined. Design of experiments, response surface methodology (RSM) and artificial neural networks multilayer perceptron (MLP) were used in process characterisation and modelling. Fractional factorial design (24-1) applied as a screening method enabled examined parameters significance assessment, based on which parameter aspirator was excluded from further study. Use of central composite design (CCD), RSM and MLP helped in spray drying process characterisation and modelling for formulations with all threee model drug substances, and significant models were developed (p-value<0.05). RSM results analysis resulted in definition of functional relationships between input parameters and monitored responses. In case of naratriptan hydrochloride and aripiprazole formulation, observations were similar. Parameter that had the greates influence on each investigated response was pump speed. In case of naratriptan hydrochloride second order polynome was obtained only for moisture content, for which interaction between inlet air temperature and feed concentration was the only statistically significant interaction. Result analysis for aripiprazole formulation did not show any statistically significant interaction between the parameters, and only for yield second order polynomial equation were obtained which described quadratic effect of pump speed. With both model substances, models developed by MLP which considers monitored responses simultaneously, had better predictability expressed as correlation between predicted and experimental results, because MLP has the ability to better model nonlinear, intricate systems in comparison to RSM. For powder with naratriptan hydrochloride following correlation coefficients were obtained: for yield R2 MLP1=0.898, R2 RSM1=0.842; moisture content R2 MLP1=0.642, R2 RSM1=0.550; mean particle size R2 MLP1=0.779, R2 RSM1=0.712 and outlet air temperature R2 MLP1=0.933, R2 RSM1=0.862. For powder with aripiprazole following results were obtained: for yield R2 MLP1=0.854, R2 RSM1=0.846; moisture content R2 MLP1=0.886, R2 RSM1=0.871; outlet air temperature R2 MLP1=0.893, R2 RSM1=0.899. By investigation of new ways in combining RSM and MLP, for the purpose of lowering the necessary number of practically executed experiments, potential of MLP use for completion of the data set defined by a experimental design necessary for RSM application, was recognized. For powder with naratriptan hydrochloride following correlation coefficients were obtained: for yield R2 RSM2=0.828; outlet air temperature R2 RSM2=0.786. For powder with aripiprazole following results were obtained: for yield R2 RSM2a=0.828, R2 RSM2b=0.338; moisture content R2 RSM2a=0.783, R2 RSM2b=0.656; outlet air temperature R2 RSM2a=0.856, R2 RSM2b=0.737. Model with better predictability was RSM2a, which was the result of using MLP2a neural network with better performance for CCD data completion. Namely, in case of powder with aripiprazole, in data completion two neural networks were used, which had the different predictability performance (MLP2a and MLP2b models). Obtained results confirmed the assumption that by design of experiments (DOE) data of better quality can be provided because they render models which are better describing the system and result in more accurate predictions. However, it is important that the MLP use is robust enough. Also, potential of DOE based modelling was recognized for decoding the black-box nature of neural networks predictions (determination of significance and relationships between factors). Predictions of MLP1 model (best R2) for all the experiments within CCD, were processed by RSM and models RSM3 were developed. For powders with naratriptan hydrochloride following correlation coefficients were obtained: for yield R2=0.994; moisture content R2=0.961; outlet air temperature R2=0.916. For powder with aripiprazole following results were obtained: for yield R2=0.931; moisture content R2=0.920; outlet air temperature R2=0.941. This approach in process modelling enabled determination of relationships between factors and responses which are much more complicated than RSM1 models indicated, which could be the reason for better predictability of MLP1 model. It has been concluded that by combined application of RSM and MLP benefits of both methodologies are gained, therefore process understanding improvement was achieved. By application of desirability approach numerical optimization of process parameters for 25% solutions was performed, with requirement for maximizing the yield while minimizing the moisture content in powder. By using the RSM1 models developed separately for each drug substance, optimal process parameters were defined for powder with naratriptan hydrochloride: pump speed 10% and inlet air temperature 190°C, and for powder with aripiprazole: pump speed 10% and inlet air temperature 180°C. Experiments were executed under these process parameters and results obtained for yield, moisture content and outlet air temperature were similar to predicted values for both formulations. Only in case of aripiprazole, there was a slightly bigger difference in predicted and observed yield, which was explained by a larger value obtained for Lack of fit. Spray dried powders characterisation of formulations with all three model substances revealed a certain similarities between the powders. Spray dried products stored under mild ambient conditions during prolonged time period (6-12 months), were all without the presence of crystalline drug (absence of characteristic peaks on DSC thermograms and FTIR spectra), indicating relatively good physical stability of formulations. As expected, on laboratory spray drying device, powder with small particles, and voluminous powder of poor flowability were obtained. However, on pilot and industrial scale devices, due to larger drying chamber and the ability for efficient drying of larger droplets and larger particle production, significant improvement in resulting powders can be expected. Particle visualization was performed by scanning electron microscopy. Photomicrographs are showing that particles are spherically shaped, with surface from smooth to shriveled, and presence of hollow particles was also observed. In case of naratriptan hydrochloride as a low-dose model drug substance it has been shown that powder of good content uniformity can be obtained (RSD 0.23%). In second section of research, before the selection of formulation for process modelling was made, examination of cyclodextrin effect on drug solubilization was performed with both poorly soluble drug substances, and drug:CD spray dried powders were characterized. According to solubility study with voriconazole, 2-O-MBCD was found to be more efficient solubilizer than HPBCD, while in case of aripiprazole complexation resulted in similar solubility improvement with both CD. These conclusions were confirmed by factorial experimental design studies. Aripiprazole solubilization capacity was more pH and ionic composition dependent than it was influenced by CD type, and maximal solubilization was achieved in citrate buffer pH 3.0. By phase-so
Provider: - Institution: University of Zagreb. Faculty of Pharmacy and Biochemistry. Department of pharmaceutical technology. - Data provided by Europeana Collections- Nesanica je jedan od najčešćih ...poremećaja spavanja koji zahvaća oko 30% odrasle populacije, a značajno je
češći kod starije populacije i psihičkih bolesnika. Zahvaljujući svojim farmakološkim svojstvima, zaleplon je hipnotik
izbora za kratkotrajno liječenje nesanice. Međutim, slaba topljivost i razgradnja u jetri ograničavaju mu oralnu
bioraspoloživost na samo 30%. Stoga je cilj ovog rada pripremom inkluzijskih kompleksa s ciklodekstrinima
poboljšati topljivost lijeka u vodi, a uklapanjem u oblik s kontroliranim oslobađanjem razviti novi terapijski sustav
koji bi mogao značajno unaprijediti terapijsku učinkovitost ovog lijeka.
Spektrofluorimetrijska i solubilizacijska ispitivanja su pokazala da β-ciklodekstrin sa zaleplonom stvara
komplekse prikladne stabilnosti, no topljivost nastalog kompleksa je ograničena. Od kemijski modificiranih derivata,
nasumično metilirani β-ciklodekstrin se pokazao najprikladnijim, dok je topljivost i stabilnost inkluzijskih kompleksa
zaleplona sa sulfobutil-β-ciklodekstrinom i hidroksipropil-β-ciklodekstrinom nešto niža. Nastajanje inkuzijskih
kompleksa s navedenim derivatima ciklodekstrina je potvrđeno primjenom 1H NMR spektroskopije, a određena je i
njihova struktura. Sustav karakterizira istovremeno prisustvo dva načina vezanja. Prvi, dominantni način uključuje
inkluziju fenilnog prstena molekule zaleplona u centralnu šupljinu molekule ciklodekstrina, a drugi inkluziju
pirazolo1,5-a pirimidinskog prstena molekule lijeka, dok je nastajanje kompleksa višeg reda isključeno.
Termodinamička ispitivanja su pokazala da je nastajanje kompleksa zaleplona s β-ciklodekstrinom i njegovim
metiliranim i hidroksipropiliranim derivatima entalpijom uvjetovani proces, dok je kompleksiranje lijeka sa sulfobutil-
β-ciklodekstrinom entropijom vođen proces. U oba slučaja riječ je o spontanom procesu.
Dodatkom hipromeloze je značajno povećan solubilizacijski potencijal metiliranog β-ciklodekstrina uslijed
nastajanja ternarnih kompleksa lijek-ciklodekstrin-polimer, dok hidrofilni polimeri nisu utjecali na topljivost i
stabilnost kompleksa zaleplona s β-ciklodekstrinom. Binarni i ternarni kompleksi zaleplona s navedenim
ciklodekstrinima i hidrofilnim polimerima u čvrstom stanju pripremljeni su tehnikom sušenja raspršivanjem.
Diferencijalna pretražna kalorimetrija, difrakcija rentgenskih zraka na prašku te pretražna elektronska mikroskopija su
pokazale djelomičnu amorfizaciju lijeka u binarnim i ternarnim kompleksima s β-ciklodekstrinom, dok su kompleksi s
metiliranim-β-ciklodekstrinom bili u potpunosti amorfne strukture. Binarni kompleksi s metiliranim-β-
ciklodekstrinom te ternarni kompleksi s metiliranim-β-ciklodekstrinom i hipromelozom bili su najučinkovitiji u
povećanju topljivosti zaleplona u odnosu na ostale komplekse. Korištenjem manitola kao topljivog punila te ternarnog
kompleksa zaleplona s metiliranim β-ciklodekstrinom i hipromelozom pripremljene su tablete koje omogućuju
oslobađanje doze lijeka u samo 5 minuta, osiguravajući brz početak djelovanja lijeka. Topljivi kompleksi zaleplona s u
vodi topljivim, polimernim derivatom ciklodekstrina su pripremljeni i tehnikom mljevenja u vibracijskim
mikromlinovima. Nakon 90 minuta mljevenja pri frekvenciji od 24 Hz dobiven je amorfni produkt koji otapanjem u
vodi prelazi u inkluzijski kompleks, što je dokazano 1H-NMR spektroskopijom.
Primjenom tehnike sušenja raspršivanjem pripremljene su mikrosfere s pH ovisnim oslobađanjem zaleplona
kao novi terapijski sustav za liječenje nesanice koju karakterizira prerano buđenje te nemogućnost naknadnog
usnivanja. Matriks koji sadrži 80% Eudragita S100 i 20% glicerolmonostearata pokazao se optimalnim u sprječavanju
neželjenog oslobađanja lijeka pri nižim pH-vrijednostima medija, dok je uklapanjem 50% doze lijeka u obliku
inkluzijskog kompleksa s metiliranim β-ciklodekstrinom osigurano potpuno oslobađanje lijeka u umjetnom crijevnom
mediju, kinetikom nultog reda (k0=155 μg/min).- Insomnia is one of the most common sleep disorders affecting about 30% of adult population, while its
prevalence is even higher among elderly and psychiatric patients. Pharmacological properties makes zaleplon the drug
of choice for the short term treatment of insomnia, but its low aqueous solubility and intensive metabolism in liver are
reducing its oral bioavailability to only 30%. Therefore, the aim of this work was to improve aqueous solubility of
zaleplon through inclusion complexation and to develop a novel drug delivery system able to enhance its therapeutical
efficiency.
Spectrofluorimetric and phase solubility studies showed that parent β-cyclodextrin forms stable inclusion
complexes with zaleplon, but aqueous solubility of the complexes formed was limited. Among chemically modified β-
cyclodextrin derivatives, randomly methylated derivative was the most efficient, while the solubility and stability of
zaleplon complexes with sulphobutyl- and hydroxypropyl-β-cyclodextrin was less pronounced. The inclusion complex
formation in all cases was confirmed by 1H-NMR spectroscopy. The structure of the complexes formed was
characterised by the presence of two different binding modes which existed simultaneously in the solution. The first
and the dominant one occurs through inclusion of phenyl moiety of the drug into central cavity of cyclodextrin
molecule, while the other involves the inclusion of the pyrazolo1,5-apyrimidine ring of the drug. The formation of
higher order complexes was not demonstrated. Thermodynamic studies showed that complexation of zaleplon with β-
cyclodextrin and its randomly methylated and hydroxypropylated derivatives was enthalpy driven, while entropy
driven complexation was observed in case of sulphobutyl-β-cyclodextrin. In all cases, inclusion complex formation
was a spontaneous process.
Addition of hypromellose enhanced significantly the solubilising and complexing potential of randomly
methylated β-cyclodextrin due to ternary complex formation, while hydrophilic polymers had no effect on solubility
and stability of zaleplon complexes with parent β-cyclodextrin. Binary and ternary zaleplon complexes with
cyclodextrins and polymers tested were prepared by spray-drying. Differential scanning calorimetry, X-ray powder
diffractometry and scanning electron microscopy showed only partial drug amorphization of the drug in binary and
ternary complexes with β-cyclodextrin, while all complexes with randomly methylated β-cyclodextrin were
completely amorphous. The inclusion complex formation in spray-dried products was confirmed by the solid state
NMR. Binary and ternary complexes with randomly methylated β-cyclodextrin and hypromellose were the most
efficient in increasing the dissolution rate of zaleplon. The use of mannitol as a soluble filler and ternary inclusion
complex with randomly methylated β-cyclodextrin and hypromellose allowed formulation of tablets which released
the complete drug dose in 5 minutes, providing fast onset of drug action. Highly soluble zaleplon complexes with
soluble, polymeric β-cyclodextrin derivative were also prepared by co-grinding in high energy vibrational micromill.
Co-grinding at frequency of 24 Hz resulted in an amorphous product which is readily soluble in water, forming
inclusion complexes as demonstrated by 1H-NMR spectroscopy.
Spray-drying technique was used to prepare pH-responsive zaleplon microspheres with delayed release
properties as a novel drug delivery system for treatment of specific type of insomnia characterised with premature
awaking and inability to fall asleep again. Matrix containing 80% of Eudragit S100 and 20% of glycerol monostearate
was demonstrated to be optimal, preventing the drug release at high pH-values. The incorporation of 50% of the drug
dose in form of binary inclusion complex with randomly methylated β-cyclodextrin ensured complete drug release in
simulated intestinal media, with the zero-order release rate (k0=155 μg/min).- All metadata published by Europeana are available free of restriction under the Creative Commons CC0 1.0 Universal Public Domain Dedication. However, Europeana requests that you actively acknowledge and give attribution to all metadata sources including Europeana
U ovom revijalnom radu opisana su fizičko-kemijska svojstva ciklodekstrina, različiti načini njihove primjene te mehanizmi oslobađanja ljekovitih tvari iz kompleksa s ciklodekstrinima (razrjeđenje, ...kompetitivna zamjena, vezanje na proteine, promjena ionske jakosti i temperature te unos ljekovite tvari u tkivo). Opisana je uporaba ciklodekstrina i ograničenja uporabe u različitim sustavima za isporuku lijekova za nazalnu, oftalmičku, transdermalnu, rektalnu te detaljno za peroralnu primjenu. Mnogobrojna istraživanja su potvrdila da su ciklodekstrini korisni sastojci pripravaka za različite načine primjene jer povećavaju vodotopljivost, stabilnost i bioraspoloživost ljekovite tvari, a smanjuju njenu iritabilnost.
Istražen je proces proizvodnje ciklodekstrina iz škroba pomoću ciklodekstrin glukanotransferaze iz bakterije Bacillus megaterium. Pomoću optimalno uređenog plana i metode odzivnih površina istražen ...je utjecaj koncentracije škroba i enzima na proizvodnju ciklodekstrina. Izrađeni su matematički modeli koji opisuju proces u dva područja varijacija nezavisnih varijabla koja se preklapaju. Modeli su upotrijebljeni za određivanje optimalnih vrijednosti varijabla. Povećanjem koncentracije škroba povećala se količina nastalog β-ciklodekstrina, a smanjio prinos. Optimalna koncentracija škroba bila je 50 mg/mL. Kritična je koncentracija ciklodekstrin glukanotransferaze, prijeko potrebna za maksimalnu proizvodnju β-ciklodekstrina, bila 2 U/g. Utvrđeni su faktori koji limitiraju potpunu konverziju škroba u ciklodekstrine i ustanovljeno je da produkti reakcije znatno inhibiraju aktivnost enzima. Dokazano je da ciklodekstrin glukanotransferaze može razgraditi velike koncentracije β-ciklodekstrina i transformirati ga u različite tipove ciklodekstrina. Djelovanjem enzima nastaju α-, β- i γ-ciklodekstrini u različitim omjerima, ovisno o dužini trajanja procesa.
Sugamadeks je novi lijek za reverziju neuromuskularnog bloka. Po kemijskoj građi on je alfa-ciklodekstrin s lipofilnom unutrašnjom stranom molekule koja omogućuje stvaranje stabilnih kompleksa, tzv. ...enkapsulaciju molekula mišićnih relaksatora, napose rokuronija. Fizička enkapsulacija novi je mehanizam eliminacije relaksatora s mjesta njegova učinka. Ona omogućuje brzu i potpunu reverziju dubokog i plitkog neuromuskularnog bloka ovisnu o primijenjenoj dozi. Sugamadeks nema neželjenih kolinergičkih muskarinskih nuspojava koje se opažaju nakon primjene inhibitora kolinesteraze neostigmina i edrofonija kao što su bradikardija, hipersalivacija i abdominalne boli. Nakon primjene prilagođene doze sugamadeksa učinak rokuronija može biti kratak kao i učinak sukcinilkolina. Ovo je osobito važno u situacijama kada se bolesnik ne može intubirati niti ventilirati ili kada je kirurški zahvat nepredviđeno brzo završen. Kliničke studije na većem broju bolesnika pokazat će omjer koristi i rizika njegove primjene u skupinama osjetljivih bolesnika, osobito može li sugamadeks smanjiti učestalost poslijeoperacijskih respiracijskih komplikacija.
