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Tekoča pršila za nos sodijo v skupino kompleksnih zdravil. Izziv ne predstavlja samo svojevrsten razvojni proces farmacevtske oblike z s fizikalno spremenljivim disperznim sistemom v obliki suspenzije, emulzije ali raztopine in večkomponentnim aplikatorjem z večodmernim vsebnikom, ampak tudi nedorečene kot tudi neusklajene zahteve in pričakovanja regulatornih agencij. Doktorska disertacija zajema celovit pristop razvoja tekočega pršila za nos v obliki suspenzije. V prvi vrsti je pomembno celovito razumevanje delovanja pršila za nos in ključnih faktorjev, ki vplivajo na kakovost izdelka. Le-to lahko spremljamo z in vitro analiznimi metodami, ki nam omogočajo sprejemanje pravih odločitev tekom samega razvoja izdelka, kot tudi končno potrditev, ko z in vitro bioekvivalenčnim testiranjem potrjujemo ustrezno in ciljano kakovost izdelka. Pristop načrtovanja eksperimentov za določanje ključnih lastnosti formulacije in aplikatorja, ki vplivajo na kakovost izdelka, je predstavljen v prvem poglavju. Eksperimentalni načrt je vključeval kombinacije treh faktorjev viskoznosti suspenzije, premera šobe na pršilnem nastavku in volumna komore v odmernem mehanizmu. Merjena in vitro odziva sta bila velikost kapljic in prečni presek meglice. Na podlagi profilov izmerjenih sil tekom proženja smo ocenili tudi opravljeno delo. Z matematičnim regresijskim kvadratnim modelom smo s pomočjo površin odziva pojasnili odnos med faktorji in odzivi, in ob upoštevanju tveganj in naključnih efektov postavili kontrolno strategijo za namene napovedovanja in doseganja ciljane in vitro kakovosti zdravila. Napovedano in vitro kakovost smo preverili in uspešno potrdili z dejanskim vzorcem, izdelanim v okviru predvidene zaloge vrednosti faktorjev iz kontrolne strategije. Analizne metode, ki jih uporabljajo za merjenje in vitro kakovosti pršil za nos, povezuje z visoka stopnja variabilnosti. Metode vrednotenja morajo biti razvite na način, da sama variabilnost izdelka v največji meri prispeva k celokupni variabilnosti merjene količine. Hkrati morajo biti metode robustne, da se zmanjša vpliv in posledično prispevke naključnih faktorjev. Razvoj metode za spremljanje prečnega preseka meglice predstavlja enega izmed največjih izzivov, in je predstavljen v drugem poglavju. Najprej smo sistematično opredelili pravilno in robustno pripravo tovrstnega pršila pred analizo, ki je hkrati tudi skladna z navodili za uporabo za bolnika. Razvili smo profil avtomatičnega proženja preko določitve velikosti kapljic, kjer smo se z različnimi profili proženja na instrumentu rezultatsko približali velikosti kapljic, kot so jih generirali prostovoljci z ročnim proženjem. Določili smo preostale pogoje meritve, povezane z vizualizacijskim delom metode. Na tako zasnovani metodi smo s statističnim orodjem “Gauge repeatability and reproducibility” ovrednotili prispevke različnih faktorjev k opaženi variabilnosti metode. Določili smo pomembne faktorje, povezane s časovno komponento, bodisi časovni zamik med zaporednimi meritvami, meritve znotraj istega dneva kot tudi meritve med dnevi. Pomembne razlike so bile opažene pri testiranju istega izdelka v različnih laboratorijih. Na podlagi zaključkov statističnega vrednotenja smo uspešno postavili kontrolno strategijo različnih parametrov metode in tako zagotovili, da je skupna variabilnost v večji meri odraz kakovosti oz. variabilnosti izdelka. Predstavljen pristop vrednotenja metode je sicer uporaben za širši spekter analiznih metod farmacevtskih oblik in ne samo za pršila za nos. V tretjem poglavju smo vrednotili statistična pristopa povprečne bioekvivalence in populacijske bioekvivalence na in vitro bioekvivalenčnih parametrih velikosti kapljic in prečnega preseka meglice. Meritve smo izvedli na dobro uveljavljenem referenčnem izdelku pršila za nos. Osnova za primerjavo je bila izvedba računsko intenzivnih simulacij, ki so jasno pokazale, da oba pristopa vodita do različnih zaključkov in vitro bioekvivalenčnega preskušanja, še posebej v primeru bolj variabilnega parametra prečnega preseka meglice. Dodatno smo pokazali vpliv visoke inherentne variabilnosti parametra prečnega preseka meglice na poudarjeno asimetrično obliko krivulj moči populacijske bioekvivalence. Na podlagi naših zaključkov in zaradi vprašljive in vivo relevantnosti prečnega preseka meglice predlagamo, da se ta parameter uporablja predvsem kot orodje tekom razvoja in za zagotavljanje ustrezne kakovosti izdelka, in ne za potrebe vrednotenja bioekvivalence. Za parameter velikosti kapljic, ki je manj variabilen, smo razvili in predlagali modificiran pristop populacijske bioekvivalence, kjer se kriterij sprejemljivosti določi na podlagi primerjave referenčnega izdelka samega nase preko inovativnega računsko intenzivnega statističnega pristopa. Ključna prednost tega raziskovalnega dela je predstavitev modernih in inovativnih pristopov za stroškovno ter časovno učinkovit razvoj pršil za nos v farmacevtski industriji. Nasal spray products have been traditionally recognized as complex products, physically constituted out of a formulation system, either in form of a suspension, emulsion or a solution, and a delivery device, composed out of multiple components. Challenging development process is even harder in absence of clear and aligned quality requirements and expectations from wordlwide health regulatory bodies. This doctoral thesis presents a comprehensive approach of development of nasal spray product in a form of a suspension. First important aspect is understanding of formulation and delivery device properties, which have potential to impact quality of the product. Quality can be monitored with in vitro analytical methods. In vitro testing can be done for purposes of decisioning process during development of the product, or can be used as confirmation of suitable and targeted performance in in vitro bioequivalence studies. First chapter is devoted to Design of Experiment approach with aim of studying both formulation and delivery device properties, which have impact on quality of the product. Experimental design included combinations of three factors, viscosity of suspension, nozzle orifice diameter and shot weight. Followed responses were droplet size distribution and spray pattern obtained by in vitro tests. In addition, the amount of work needed for specific product actuation was integrated from force–displacement profiles and used as response. Results were fit to quadratic model by regression, which additionally allowed determination of second-order and interaction effects between factors. Optimized models were used to create response surfaces. Practical application of response surfaces was demonstrated by definition of optimal levels of factors based on desired performance, i.e. demonstrating a route for rational selection of specification limits of such pharmaceutical product. In vitro analytical methods used to evaluate nasal spray products are associated with a high degree of variation, and should be developed in a way that the observed total variation of results is in major part representative for product performance. Furthermore, methods should be robust to minimize contribution of random factors to the results variation. Development of spray pattern test, presented in the second chapter, is one of the most challenging. First step of the development was definition of a robust product-shaking procedure in accordance with instruction to patient. In vivo relevant actuation parameters were determined based on the comparison of the droplet size distribution results of manual actuations performed by three volunteers with those obtained by automated actuation profiles. Other method parameters related to visualisation part were determined. The final in vitro method was tested to evaluate the contribution of individual factors and interactions to the observed variance of results by using gauge repeatability and reproducibility model. It was found that the time lag between consecutive actuations significantly influences the variability of SP area, suggesting the importance of determining a recovery period. Factors time point and day were found to have the potential to impact results. Significant differences were observed when the same product was tested in different laboratories. By using this statistical approach key random factors were identified and appropriate control strategy over these factors was set to assure that assessed total results variation is representative for product performance. The same general approach is not only applicable to the development of in vitro methods for nasal spray products, but to all types of analytical testing as well. Third chapter provides insight into evaluation and comparison of average and population bioequivalence statistical approaches, using droplet size distribution and spray pattern in vitro tests. In vitro data were collected using a well-established nasal spray product on the market. Computationally intensive bootstrap simulations were used to evaluate both approaches. We concluded that both approaches can lead to different in vitro bioequivalence conclusion, especially in the case of highly variable spray pattern parameter, where pronounced asymmetric behavior of PBE empirical power curves was observed. Due to inherent high variability and unclear in vivo relevance of the spray pattern parameter, authors propose that this parameter is used as a development and quality control tool rather than for demonstration of in vitro bioequivalence. A modified PBE statistical approach is proposed for less variable droplet size distribution parameters, where acceptance criteria would be established based on comparison of reference/branded product to itself, using via innovative statistical bootstrap simulations. Most important contribution of this doctoral thesis is to provide insight into a modern and innovative approaches for time-cost efficient development of nasal spray products. |
