Browsing by Subject "Pharmaceutical technology"

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  • Kainulainen, Saila (Helsingin yliopisto, 2020)
    The solubility of a poorly water-soluble drug can be improved by converting the crystalline drug into an amorphous form. However, the amorphous form is metastable due to the higher energy state and recrystallization may occur during storage and dissolution. The amorphous form can be stabilized by forming an amorphous solid dispersion (ASD), where the drug molecules are dispersed to the solid medium, e.g. hydrophilic polymer. One preparation method for amorphous solid dispersions is spray drying, where a solution containing a drug and polymer is converted into small droplets in a drying chamber, in which the solvent evaporates in a hot gas stream and solid particles are formed. The aim of this study was to investigate whether an ASD of a poorly water-soluble drug can be prepared by spray drying using 20:80 (V/V) ethanol-water mixture as a solvent in a feed solution. Indomethacin (γ-polymorph) was used as a model drug and polyvinylpyrrolidone vinyl acetate (PVPVA) as a polymer. The aim was to find a suitable formulation where the drug is in the amorphous form after spray drying and remains in the amorphous form during storage. The ratios of the drug to polymer in the spray-dried formulations were 1:4, 1:6, 1:8, 1:10, 1:12 and 1:16. The study also examined whether a change in one process parameter, pump feed rate, affects the amorphous nature and stability of the resulting spray-dried solid dispersions. Two different pump feed rates, a higher 30% and a lower 15%, were used in the study. X-ray powder diffraction (XRPD) was used to characterize the solid-state of the spray-dried formulations. XRPD measurements were performed immediately after spray drying and on selected time points during storage. Formulations 1:10 at 30% feed rate, 1:12 at both feed rates and 1:16 at 30% feed rate were amorphous after spray drying. In 1:12 (30%) and 1:16 (30%) formulations indomethacin remained in amorphous form over the study periods (22 and 56 days, respectively). In other formulations, indomethacin was found to be in crystalline α-form immediately after spray drying or recrystallization to the α-form occurred during storage. The interaction between indomethacin and PVPVA was studied by surface plasmon resonance spectroscopy (SPR). The aim of the SPR measurements was to understand the interaction between these substances in the feed solution used in spray drying. PVPVA solutions of various concentrations (1%, 0.5%, 0.1% and 0.01%) were injected to the surface of the gold sensor coated with crystalline γ-indomethacin, and the changes in the SPR signal responses were monitored during the interaction. The same measurements were also performed on a pure gold sensor without indomethacin. An interaction between indomethacin and PVPVA can be observed, and based on the measurements, a polymer layer with a thickness of about 1 nm was formed on the surface of the indomethacin sensor regardless of the concentration of the polymer solution. Thus, even a small amount of polymer in solution is sufficient to cover the indomethacin crystals. This may also occur in the feed solution during spray drying, but further studies with SPR are still needed, especially with amorphous indomethacin. This study showed that an ASD of indomethacin and PVPVA can be successfully prepared by spray drying using an aqueous feed solution. Spray-dried 1:12 and 1:16 formulations at a higher pump feed rate were found to be stable enough for further studies. If the spray-dried material is further formulated into a pharmaceutical product, indomethacin must remain in amorphous form throughout the shelf-life of the product to maintain the improved solubility.
  • Veijanen, Terhi (Helsingin yliopisto, 2020)
    Granulation is used to improve the flowability of pharmaceutical powders, reduce the amount of fines and increase the density of the material. Roller compaction has shown growing interest in recent years and it is used ever more frequently in pharmaceutical industry. Roller compaction has many superior qualities compared to wet granulation such as good control of process and absence of moisture and heat in the process. It is also cost effective compared to traditional granulation methods. New APIs are often sensitive to moisture. Therefore traditional granulation methods cannot be used. In the roller compaction process powder mixture is fed between two counter-rotating rolls where the compaction occurs and ribbon is formed. After compaction the ribbon is crushed into granules of desired size. The aim of this study was to find out how the mixture ratio of plastic and brittle material affects the physical properties of roller compacted ribbons such as the strength and stiffness of the ribbons and the structure of the ribbon surface. The materials used were microcrystalline cellulose and dicalsiumphosphate. Nine powder mixtures of 0 to 40 w-% of dicalsiumphosphate were prepared after which the mixtures were roller compacted with the same compactor parameters. Two methods were developed to study the above mentioned characteristics of the ribbons. For the stiffness and strength studies a 3-point bending method was developed for Lloyd material tester. For the surface structure characteristics of ribbons a measurement set up for FlashSizer 3D image analysis device was designed. Bending tests for the ribbons were performed in two different directions. For each batch of ribbons a slope of the linear area and maximum point of bending curves were defined, which represent the stiffness and strength of the ribbons accordingly. Also Young’s modulus and tensile strength were calculated, which are characteristics of a given material. In addition area under curve, which represents the work done to break the ribbon, was calculated. The strength and stiffness of the ribbons decreased with the increasing amount of dicalsiumphosphate. A clear trend was observed. Also Young’s modulus, tensile strength and AUC decreased accordingly. The increase of dicalciumphosphate led to diminished compactibility of the powder mixtures. The compaction force was probably not high enough to fragment the dicalsiumphosphate particles. The ribbons showed higher strength and stiffness when the bending was done perpendicularly ie. across the ribbon width compared to parallel measurements. Also relative standard deviations were smaller in this measurement set up. The 3-point bending method could not mostly distinguish between adjacent formulations from each other but when the difference in the amount of dicalsiumphosphate increased to 10-20 w-% statistically significant differences were observed in most of the calculated values. The surface structure of the ribbons differed between formulations when evaluated visually. Ribbons with less dicalsiumphosphate had a surface structure that followed the knurled pattern of the compactor rolls better.
  • Järvelä, Jasper (Helsingin yliopisto, 2021)
    Lääketieteen kehittyessä yksilöllisen lääkehoidon tarpeeseen on kiinnitetty enemmän huomiota kuin aikaisemmin ja etenkin lapsille lääkkeiden tarkka annostelu on erityisen tärkeää. Kaupallisilla valmisteilla tarpeeksi pienet annokset eivät usein ole mahdollisia eikä tablettien puolittaminen takaa tarkkaa lääkkeiden annostelua. 3D-tulostamista on ajateltu mahdollisena vaihtoehtona ex tempore -lääkkeiden tuotantoon ja sen mahdollisuuksia on tutkittu laajalti viime vuosien aikana. Tämän tutkimuksen tavoitteena on selvittää, miten ekstruusiomenetelmällä tulostetut varfariinikalvot vertautuvat sairaala-apteekin käyttämiin varfariiniannosjauheisiin, sekä olisiko kyseistä menetelmää mahdollista hyödyntää sairaala-apteekeissa. Tutkimuksessa valmistettiin puolikiinteän aineen ekstruusiolla 0,1 mg:n, 0,5 mg:n ja 2 mg:n varfariinikalvoja, jotka kuivattiin 85 ℃:ssa valmistusprosessin nopeuttamiseksi. Kalvoja verrattiin saman vahvuisiin varfariinia sisältäviin sairaala-apteekin valmistamiin annosjauheisiin. Kalvoissa käytettiin hydroksipropyylimetyyliselluloosaa kalvonmuodostaja-aineena ja glyserolia tuomaan plastisuutta. Annosjauheet koostuivat kaupallisesta 5 mg:n Marevan-valmisteesta ja täyteaineena käytetystä laktoosista. Molemmista lääkevalmisteista mitattiin liukenemisnopeus ja annosyksiköiden yhdenmukaisuus. Molempien valmisteiden toimivuus nenä-mahaletkussa tutkittiin myös, sillä kalvojen on tärkeää soveltua erilaisille potilasryhmille. Kalvot olivat kovia, mikä aiheutti niiden hitaan liukenemisen. Puolikiinteän aineen valmistus ja tulostuksen toteuttaminen tavoitteiden mukaisesti osoittautui oletettua vaikeammaksi. Kalvoissa mitattiin annosjauheita tasaisempi lääkeainepitoisuus. Molempien lääkevalmisteiden kohdalla huomattiin, että kaikki varfariini ei pääse nenä-mahaletkujen läpi. Tärkein huomio oli, että hyvin yksinkertaisella formulaatiolla on mahdollista tuottaa lupaavia lääkevalmisteita. Tämä tutkimus esittelee syitä, joiden vuoksi 3D-tulostusta on hyvä tutkia mahdollisena ex tempore -valmistuksen menetelmänä.
  • Holopainen, Emmi (Helsingin yliopisto, 2021)
    Lääkkeen elinkaaren aikana on useita toimijoita, ja matka lääkkeen valmistuksesta käyttöön Suomessa on kirjallisuuden perusteella pitkä ja monimutkainen. Lisäksi lääkevalmisteita on lukuisia erilaisia. Vaikka lääkepakkausten materiaalit ja materiaalivaatimukset tunnetaan suhteellisen hyvin esimerkiksi lääkkeiden myyntilupien tuomien vaatimusten takia, on kvantitatiivista tietoa eri materiaalivirroista lääkepakkausten elinkaaren aikana vain vähän tietoa. Tämän tutkimuksen tavoitteena oli tutkia kuinka paljon ja millaista pakkausmateriaalia lääkevalmisteen elinkaaren aikana syntyy, ja miten ympäristöasiat on huomioitu lääkepakkausten elinkaaren aikaisissa materiaalivirroissa. Lisäksi pyrittiin löytämään ehdotuksia materiaalivirtojen kehittämiseksi sekä selvittämään, miten kuluttajaa tulisi ohjeistaa lääkepakkausten kierrätyksestä. Tutkimusmenetelmäksi valittiin teemahaastattelu. Toukokuun ja joulukuun välisenä aikana vuonna 2020 aineistoksi muodostui viisi puolistrukturoitua teemahaastattelua ja kaksi kirjallista vastausta. Aineisto analysoitiin aineistolähtöisellä sisällönanalyysillä. Tutkimustulosten perusteella lääkevalmisteiden elinkaaren aikana syntyviä materiaalivirtoja ei tunneta vielä kunnolla. Tutkimuksessa korostui apteekin rooli lääkkeitä jakavana toimijana sekä lääkejätteen kerääjänä. Tukkuliiketoiminnan havaittiin keskittyneen kahdelle suurelle toimijalle Suomessa. Esteinä materiaalivirtojen kehittämiselle nähtiin kankeat myyntilupakäytännöt, jotka tekevät varsinkin pitkään markkinoilla olleiden lääkevalmisteiden pakkausmateriaalimuutokset hankaliksi. Myyntilupaprosessi koettiin kalliiksi, mikä estää esimerkiksi vain sairaala-apteekkeihin tarkoitettujen pakkausten tarjoamisen markkinoille. Muita haasteita olivat esimerkiksi ympäristönäkökulman ja potilasturvallisuuden väliset ristiriidat. Lääkkeiden myyntilupa ei vaadi ohjeistamaan kuluttajaa pakkausmateriaalien kierrätyksessä. Tutkimuksen mukaan lääketeollisuudessa on mietitty, voisiko pakkauksen kierrätyksen mainita pakkausselosteessa ilman myyntilupaprosessin läpikäyntiä. Tulisi kuitenkin tutkia, olisiko merkinnällä vaikutusta lääkepakkausten kierrätykseen. Toinen huomio lääkepakkausten kierrättämisessä on se, ovatko esimerkiksi primääripakkaukset turvallisia kierrätyksen kannalta. Jatkotutkimusta tarvitaan lisää. Tämä Pro gradu on tehty SUDDEN-hankkeen viitekehyksessä, yhteistyössä Suomen ympäristökeskuksen kanssa. SUDDEN-hanke pyrkii löytämään ratkaisuja lääkkeiden elinkaaren aikana syntyvien ympäristöhaittojen vähentämiseksi ja edistämään kestävää lääketeollisuutta.
  • Lifländer, Rami (Helsingin yliopisto, 2020)
    Throughout the history, there has been a wide selection of drugs developed for therapy of cardiovascular diseases (CVD). Despite a broad spectrum of different therapeutic strategies to deaccelerate and try to reverse the progression of cardiovascular diseases has been achieved, only a modest amelioration of the health of the CVD patients was achieved, as the mortality remains high by being the cause of nearly one in every three deaths yearly, myocardial infarction being involved in majority of these cases. Novel solutions are being studied to overcome this problem, one of them being nanoparticles, which may provide potential solution by carrying drugs to the desired location. Microfluidics technique may further improve the properties of nanoparticles, being a platform that allows the production of homogenous and repeatable batches that are non-dependent by the operator using it. In this thesis, it is described how microfluidics-based preparation of spermine-functionalised acetalated dextran nanoparticles co-loaded with a trisubstituted isoxazole and curcumin perform in physicochemical and in vitro experiments, in order to evaluate their potential in the application of ischemic myocardial injury therapy.
  • Kontola, Sandra (Helsingfors universitet, 2018)
    Flowability is an important powder character and, despite decades of research, there are still issues in finding a suitable measurement method. Common challenges are sample size and methodology’s suitability for cohesive powders due to their ability to form vault structures. Powder flowability properties depend strongly on particle features such as size and shape. As particles are in contact with other particles and materials, they receive electric charge and form bonds. In addition to these variables, the gravity and shear stress affect the powder. A combination of all these determine the powder properties such as flowability. Besides the particle properties, process and preservation conditions and especially humidity affects the powder properties significantly. Hence, the powder’s flow behavior varies in different conditions. There are several measurement devices available but none of them is able to yield intrinsic values. Reliability of the measurements presents another challenge as the measured values cannot be directly compared with published literature. Moreover, the flow measurement of cohesive powders is either impossible or extremely difficult with the devices currently available and the sample size needs to be sufficient. Hence, there is a need for new devices, which measure powder flow easily in small-scale. Small sample size is important especially when developing new, expensive drugs since their properties need to be explored in order to develop a new formulation. The aim of the empirical study was to develop a device, which measures particularly the flowability of cohesive powders in small-scale. A ground for the study was a device developed at University of Helsinki, which measures powder flowability by utilizing horizontal movement. In addition, the device breaks the problematic vault formation of cohesive powders by jolts. In the study a cuvette, which utilizes the horizontal movement and measures the powder flow, was developed. Flowability tests were run with five powders – Acetaminophen, Pharmatose 80M, Pharmatose 200M, Emcompress®, Avicel PH-101, Avicel PH-102, Avicel PH-200 and Maize Starch. The results were promising and the device was capable of classifying the powders by their flowabilities but more research is still needed.
  • Novakovic, Dunja (2020)
    Active pharmaceutical ingredients can assume a diverse spectrum of solid-state forms. These forms differ in properties that are of utmost importance for pharmaceutical performance, such as solubility, dissolution rate and bioavailability. Thus, selection of a suitable solid-state form is highly important, particularly for the growing number of poorly water-soluble drug molecules. The amorphous (i.e. non-crystalline) form offers an often much needed solubility advantage at the price of thermodynamic physical instability and possible recrystallization. As the number of poorly water-soluble molecules in drug development is growing, so is the interest in the amorphous form and strategies for its stabilization. Formation of amorphous polymeric solid dispersions is the most common answer. However, issues with recrystallization, particularly at the surface, still remain, as well as high polymeric loadings. The importance of differentiating between the surface and bulk properties of pharmaceutical materials is becoming increasingly recognized. Processes such as dissolution or chemical reactions with surrounding materials start from surfaces. For drugs in the amorphous form, inevitable recrystallization starts at the surface. This transformed (partly) crystalline surface thus dictates dissolution (or lack thereof), as well as other properties relevant for manufacturing, shelf-life or administration. This is why understanding, monitoring and manipulating superficial phenomena is of such importance. Most established solid-state analytical methods show no or limited surface specificity. Nonlinear imaging (sum frequency generation (SFG) and coherent anti-Stokes Raman scattering (CARS)) are relatively new solid-state and surface specific methods. Moreover, as imaging methods, they can visualize solid-state distribution at the surface. Therefore, this thesis utilized novel nonlinear imaging approaches to better understand surface solid-state behavior. Further, the importance of surfaces in the crystallization, stabilization and dissolution of amorphous drugs was investigated. The first part of the thesis established surface and solid-state specific non-linear imaging methods capable of distinguishing multiple solid state forms. SFG imaging proved to be an excellent tool in detecting low levels of surface crystallization (undetectable with other analytical methods employed), in particular amorphous transformation to a single crystalline solid-state form. Additionally, multimodal nonlinear imaging (SFG and CARS modalities, each with their own benefits) was used for the first time in pharmaceutical samples to simultaneously differentiate up to three different solid-state forms. The second part of the thesis compared surface versus bulk crystallization and investigated surface crystallization (change in the solid-state form) during storage, as one of the key indicators of pharmaceutical performance. Both the cross-sectional SFG imaging of compressed powders, as well as the SEM morphology of continuous particle tablets allowed visualization of the surface-biased crystallization during storage. Further, the addition of different excipients physically mixed with the drug affected the crystallization of the amorphous drug in the bulk, however, their inability to stabilize the crystallization at the surface was demonstrated. In contrast, thin polymer coatings were successful in delaying the onset of surface crystallization at high humidity and elevated temperature during storage. The final part of the thesis investigated the implications of storage-induced surface crystallization and its stabilization with polymer coatings on pharmaceutical performance during dissolution, as a further necessary step in drug development. It was shown that different extents and natures of surface crystallinity affect drug dissolution. Multimodal nonlinear imaging revealed up to five solid-state forms simultaneously present at the surface, and aided the interpretation of the dissolution profiles. The initial dissolution rates of the short-term stored polymer coated samples were equivalent to those of the unaged uncoated samples. In summary, this thesis demonstrated the importance of surface solid-state properties, and their surface-specific analysis, for understanding the pharmaceutical performance of amorphous formulations during storage and dissolution. With further developments in amorphous drug formulations, the interest in surface crystallization and its prevention in the future will likely increase, together with the demand for surface-specific solid-state analysis. Altogether, it can be expected that in the future the understanding and utilization of surface phenomena will evolve from superficial to comprehensive.
  • Espo, Erika (Helsingin yliopisto, 2021)
    Nowadays, targetability studies usually require sample modifications and quite often, examination requires the use of directed light in harmful wavelengths. The surface plasmon resonance (SPR) technique does not need either of those actions. With SPR technology, the targetability of biomolecules can be studied in real-time and without any additional labels. The SPR response is received by measuring the change in surface plasmon resonance conditions due to refractive index changes caused by material interactions in the vicinity of a metal sensor surface. In the present study, the targetability of neonatal Fc receptor (FcRn) was studied by SPR. FcRn-mediated targetability studies were performed against protein A and human colorectal adenocarcinoma (Caco-2) immobilized on SPR sensors. The aim of the study was to confirm the FcRn targetability with bare Fc-fragment and Fc-fragment modified nanoparticles (NPs) designed for oral drug delivery. The NPs consisted of a core porous silicon (PSi) particle, entrapped into a lignin capsule, and finally functionalized with the FcRn-targeting ligand. Results confirmed the binding efficacy of bare Fc-fragment with protein A at pH 6.5, which was the critical pH value for preserving the lignin capsule around the PSi NPs. The cell-based SPR response was significantly higher for FcRn-targeted NPs when compared with non-functionalized NPs. According to these results, FcRn-mediated transcytosis emerges with great potential for oral drug delivery via Fc-functionalized NPs.