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Plant cell culture can be used for the production of valuable secondary metabolites. Inspired by the previous studies focusing on capsaicinoid production, this study aimed for establishing plant cell cultures of Capsicum chinense to produce capsinoids. Capsinoids are non-pungent capsaicinoid analogues with potential health benefits. Another aim of this study was to determine the α-solanine content in Capsicum plants and cell cultures to ensure that no toxic amounts are formed during the cell culture. Cell cultures of non-pungent Capsicum chinense cultivars, Trinidad Pimento and Aji Dulce strain 2, were established, and the cultures were fed with intermediates, vanillin and vanillyl alcohol, to enhance the production. In addition, cell cultures of extremely pungent Trinidad Scorpion cultivar were established and they were fed with vanillyl alcohol to study if this would result in formation of capsinoids instead of capsaicinoids. A high-performance liquid chromatography (HPLC) method with UV detection was validated for determining the capsiate contents of the cell culture samples and fruit samples for comparison. To analyze the α-solanine content of the cell culture samples and leaves and flowers of three cultivars belonging to three different Capsicum species, an HPLC-UV method was validated for this purpose as well. Despite validating a sensitive and specific method for capsiate analysis, no detectable amounts of capsiate were detected in any of the cell culture samples. Cell cultures of pungent cultivars did not produce detectable amounts of capsaicinoids either. Results from analyzing the real fruit samples were in accordance with previous literature reports, and Aji Dulce fruits were found to contain higher amounts of capsiate compared to Trinidad Pimento, although having only one indoor grown Aji Dulce fruit analyzed limits the reliability. The analytical method for determining α-solanine content had problems with internal standard and specificity. This method could be used for making rough estimates about the possible α-solanine content. No hazardous amounts were detected in any of the cell culture samples. Only one sample consisting of Aji Dulce young leaves could contain α-solanine slightly above the limits set for commercial potatoes. Results with flowers of Rocoto San Pedro Orange (C. pubescens) and Aji Omnicolor (C. baccatum) were inconclusive and it couldn’t be ruled out that they might contain large amounts of α-solanine. The reason why capsinoids, or even capsaicinoids, were not detected in the cell culture samples remains unsolved, but it could be speculated that capsinoids might degrade in the cell culture environment or that selection of cultivar or cell line is critical. This study gave further proof to the previous assumptions that chili leaves are safe and should not contain notable amounts of α-solanine.

Nowadays growing number of new active pharmaceutical ingredients (API) have large molecular weight and are hydrophobic. The energy of their crystal lattice is bigger and polarity has decreased. This leads to weakened solubility and dissolution rate of the drug. These properties can be enhanced for example by amorphization. Amorphous form has the best dissolution rate in the solid state. In the amorphous form drug molecules are randomly arranged, so the energy required to dissolve molecules is lower compared to the crystalline counterpart. The disadvantage of amorphous form is that it is unstable. Amorphous form tends to crystallize. Stability of amorphous form can be enhanced by adding an adjuvant to drug product. Adjuvant is usually a polymer. Polymers prevent crystallization both by forming bonds with API molecules and by steric hindrance. The key thing in stabilizing amorphous form is good miscibility between API and polymer. They have to be mixed in a molecular level so that the polymer is able to prevent crystallization. The aim of this work was to study miscibility of drug and polymer and stability of their dispersion with different analytical methods. Amorphous dispersions were made by rotary evaporator and freeze dryer. Amorphicity was confirmed with X-ray powder diffraction (XRPD) right after preparation. Itraconazole and theophylline were the chosen molecules to be stabilized. Itraconazole was expected to be easier and theophylline more difficult to stabilize. Itraconazole was stabilized with HPMC and theophylline was stabilized with PVP. Miscibility was studied with XRPD and differential scanning calorimetry (DSC). In addition it was studied with polarized light microscope if miscibility was possible to see visually. Dispersions were kept in stressed conditions and the crystallization was analyzed with XRPD. Stability was also examined with isothermal microcalorimetry (IMC). The dispersion of itraconazole and theophylline 40/60 (w/w) was completely miscible. It was proved by linear combination of XRPD results and single glass transition temperature in DSC. Homogenic well mixed film was observed with light microscope. Phase separation was observed with other compositions. Dispersions of theophylline and PVP mixed only partly. Stability of itraconazole dispersions were better than theophylline dispersions which were mixed poorer. So miscibility was important thing considering stability. The results from isothermal microcalorimetry were similar to results from conventional stability studies. Complementary analytical methods should be used when studying miscibility so that the results are more reliable. Light microscope is one method in addition to mostly used XRPD and DSC. Analyzing light microscope photos is quite subjective but it gives an idea of miscibility. Isothermal microcalorimetry can be one option for conventional stability studies. If right conditions can be made where the crystallization is not too fast, it may be possible to predict stability with isothermal microcalorimetry.

The usage of polymer conjugation to modulate the biopharmaceutical behavior of both protein drugs as well as small molecule drugs is discussed. Emphasis has been given to polyethylene glycol (PEG) and poly[N-(2-hydroxypropyl)methacrylamide] (PHPMA) but also other polymers are looked into. Drug products on the market as well as drug candidates in clinical trials are used as examples when reviewing different polymers. The material is looked upon from a biopharmaceutical point of view. In the experimental part a polymer-drug conjugate for the treatment of ovarian cancer is synthesized and characterized. The conjugate has a HPMA polymer backbone with the anticancer drug gemcitabine attached through enzymatically labile Gly-Phe-Leu-Gly linkers. The conjugate is expected to target passively and actively to cancer tissue. The enhanced permeation and retention effect is responsible for the passive targeting, while Fab' fragments of OV-TL16 monoclonal antibodies provide the active targeting of the copolymer conjugate. In vitro cytotoxicity studies of a PHPMA-gemcitabine conjugate (without active targeting) was carried out on two ovarian cancer cell lines, A2780S and A2780AD. The IC50 values of the conjugate was shown to be 50.6 nM and 14.3 nM for A2780S and A2780AD, respectively. The corresponding IC50 values for free gemcitabine were 7.0 nM for the A2780S cell line and 3.9 nM for A2780AD cells. A preliminary in vivo efficacy study in mice with subcutaneous A2780AD tumor xenografts showed that a PHMA-gemcitabine conjugate given at a dose of 15 mg/kg (gemcitabine equivalence) was able to shrink the tumor volume by 50 % while only inducing minor body weight loss.

Actinic keratoses are premalignant skin lesions caused by sun UV-radiation. A small portion of these lesions progress into invasive squamous cell carcinoma over the years. Actinic keratoses are a growing problem in the healthcare around the world. P53 mutations are found in actinic keratosis and adjacent areas. Treatment options include surgical removal, cryotherapy, local treatment creams such as immunomodulators, and photodynamic therapy (PDT). Aminolevulenic acid (ALA) is an endogenous light-sensitizer used in PDT and methylaminolevulinate (MAL) and hexylaminolevulinate (HAL) are its esters. Either artificial light or daylight can be used as a light source in PDT. In PDT light activates the photosensitizer, which initiates a photochemical reaction and target cell destruction. The most common side effects of PDT are erythema and pain during treatment. The benefits of PDT are good cosmetic outcome and the possibility to treat large areas. In the present study 3 light-sensitizers (BF-200 ALA, MAL, HAL 0,2 % and 2 %) were tested on healthy volunteers to compare the skin irritation, pain and fluorescence caused by the treatment. Fluorescence intensity reflects PpIX production capacity. The second part of the present study was a clinical study comparing BF-200 ALA and MAL in treatment of actinic keratoses with daylight-PDT. Each patient received both light-sensitizers on opposite sides of the head and the results were evaluated 3 months after treatment. On healthy skin BF-200 ALA, MAL and HAL 2 % caused more irritation compared to HAL 0,2 %. HAL 2 % didn't differ from ALA and MAL-groups in severity of reactions, erythema or fluorescence photobleaching. In HAL-treated areas pain was smaller than in ALA- and MAL-groups. However, in lesional skin there might be differences in absorption, distribution and PpIX formation. Both BF-200 ALA and MAL were effective in daylight-PDT and there were no significant differences between the groups in either efficacy or pain caused by the treatment. Long-term follow up is still required to confirm if the results sustain.

Medical devices play a crucial role in healthcare, yet their importance is underscored by the potential for adverse events that can lead to serious consequences for patients and users. As a result, manufacturers of medical devices are required to actively monitor the safety and performance of their devices after placing them on the market. In response to incidents involving medical devices and their safety, the European Union Medical Device Regulation (MDR) came into force in May 2021, bringing more emphasis to the post-market surveillance (PMS) of medical devices. In this study, the current state of the post-market surveillance system of medical device manufacturers in Finland was investigated by conducting an online questionnaire in 2023. A total of 30 medical device companies participated in the questionnaire for a return rate of 17%. The dataset included manufacturers of different sizes, producing medical devices of all risk classes. To identify differences in the use of post-market surveillance data sources between different types of companies, the two-sided non-parametric Kruskal-Wallis-Test was used. The rest of the data was analysed using descriptive analysis. The post-market surveillance data sources with the highest reported intensity of use included customer complaints and feedback, production monitoring, and regulatory intelligence monitoring, while Post Market Clinical Follow-up and health services research were used significantly less. Significant differences between manufacturers of different device risk classes were identified for three data sources; manufacturers of higher risk class devices were found to utilize these data sources to a higher extent than manufacturers of low-risk devices. The manufacturers of medical devices seem to utilise reactive post-market surveillance data consistently to a high extent. On the other hand, the results suggest that proactive post-market surveillance methods remain underutilised despite the introduction of the MDR. Medical device manufacturers also use post-market surveillance data sources to different extents, in particular with respect to the medical device risk class. Overall, the results indicate that the MDR is bringing more emphasis on post-market surveillance, which in turn has increased the workload of medical device manufacturers.

Biologisten lääkkeiden käyttö on merkittävästi lisääntynyt 2000-luvulla, mikä on hoidollisten hyötyjen ohella lisännyt lääkekustannuksia. Vaihtokelpoisten ja halvempien biosimilaarien käyttöä on edistetty koulutuksella, lääkemääräyskäytäntöjen ohjauksella ja lainsäädännöllä. Vuosina 2024–2025 useat avoterveydenhuollossa käytettävät biologiset lääkkeet tulevat apteekissa tapahtuvan lääkevaihdon (apteekkivaihdon) piiriin. Potilaiden näkemykset biologisista lääkkeistä ovat tärkeä tutkimusaihe hoitotulosten, lääkevaihdon, rationaalisen lääkehoidon edistämisen ja lääkepolitiikan kehittämisen näkökulmista. Tutkimuksen tavoitteena oli tutkia potilaiden näkemyksiä biologisten lääkkeiden hinnoista, kustannuksista ja niiden merkityksestä. Tavoitteiden mukaiset tutkimuskysymykset liittyivät: 1) potilaiden preferenssiin lääkkeiden hoidollisesta arvosta lääkkeen hintaan verrattuna (ensisijainen tutkimuskysymys) ja yhteiskunnan lääkesäästöistä, 2) lääkkeiden hinnan merkitykseen lääkevaihdossa (potilaiden taloudellisten taustatekijöiden vaikutus ja euro-määräinen hyväksymis/maksuhalukkuus lääkevaihdossa) ja 3) potilaan oman lääkehoidon kustannettavuuteen. Tutkimus perustui Yliopiston Apteekin (YA) ja Helsingin yliopiston (HY) tammikuussa 2021 toteuttaman kyselytutkimuksen aineistoon. Kyselyyn vastasivat YA:n kanta-asiakkaat sekä Reumaliiton ja IBD- ja muut suolistosairaudet ry:n viestinnän kautta tavoitetut henkilöt. Kysely oli kohdistettu reuma-, IBD- (tulehduksellinen suolistosairaus) ja ihopsoriasispotilaille, jotka käyttivät alkuperäistä biologista lääkettä (BA), biosimilaaria (BS) tai perinteisiä pienimolekyylisiä lääkeitä (PL). Vastaajia oli yhteensä 1338 (BA-käyttäjiä 226, BS-käyttäjiä 71 ja PL-käyttäjiä 1041). Tulosmuuttujina käytettiin yksittäisiä kysymyksiä ja summamuuttujia. Lääkekäyttäjäryhmän ja muiden taustamuuttujien yhteyttä tulosmuuttujiin tutkittiin kaksi- ja monimuuttuja-analyyseillä. Suurin osa (83 %) potilaista oli sitä mieltä, että lääkkeen hinta ei saisi vaikuttaa lääkkeen valintaan biologista lääkettä määrättäessä, ja 62 %:n mielestä biosimilaarien käyttö auttaisi säästämään terveydenhuollon lääkekustannuksissa ja mahdollistaisi suuremman potilasmäärän hoidon biologisilla lääkkeillä. Potilaan taloudelliset taustatekijät eivät olleet monimuuttuja-analyysin perusteella yhteydessä näkemyksiin biologisten lääkkeiden lääkevaihdosta tai kiinnostukseen lääkevaihdosta. Jos biologisen lääkkeen hypoteettinen omavastuuhinta potilaalle olisi 600 euroa vuodessa, 14 % alkuperäisvalmisteen käyttäjistä olisi valmis vaihtamaan biosimilaariin, jos sen kustannus olisi hänelle 30 % nykyistä pienempi. Biosimilaarien käyttäjistä 38 % olisi valmis maksamaan lisää saadakseen alkuperäisvalmisteen. Biologisten lääkkeiden käyttäjillä (BA 36 % ja BS 44 %) oli ollut enemmän taloudellisia ongelmia lääkkeiden ostossa kuin perinteisten lääkkeiden käyttäjillä (25 %) (p <0,001). Potilaat suhtautuivat yleisesti myönteisesti biosimilaarien käyttöön lääkekustannusten hillitsemiseksi, mutta pitivät hoidollisia perusteita hintaa tärkeämpänä. Potilaan taloudelliset tekijät eivät olleet yhteydessä näkemyksiin lääkevaihdosta tai vaihtohalukkuuteen. Merkittävä osa potilaista on kiinnostunut vaihdosta edullisempaan biosimilaariin. Tulokset korostavat biologisiin lääkkeisiin ja lääkevaihtoon liittyvän lääkeinformaation merkitystä.

Johdanto: Terveydenhuollon tietojärjestelmiin potilaista kertyvää tieto on hyvä esimerkki massadatasta. Se muodostuu lukuisista yksittäisistä, irrallisista tapahtumista. Potilastiedon toissijaisella hyödyntämisellä tarkoitetaan tiedon käsittelyä muuta tarkoitusta kuin potilaan terveyden edistämistä ja hoitamista varten. Toisiokäytölle on tyypillistä, että pääasiallisena kiinnostuksen kohteena ei ole yksilötason tiedon hyödyntäminen, vaan isommasta potilasjoukosta saatava summatieto, josta yksilön tunnistetiedot on poistettu. Toisiokäyttö mahdollistaa potilastiedon hyödyntämisen esimerkiksi tieteellisessä tutkimuksessa ja tietojohtamisessa. Tavoite: Tutkimuksessa selvitettiin HUSin tietoaltaasta louhitun aineiston avulla, onko tietoaltaaseen tallennetun aineiston avulla mahdollista tutkia lääkehoidon turvallisuutta ja rationaalisuutta sekä selvittää, millaisessa muodossa tietoaltaan data saadaan käyttöön ja millaisia toimenpiteitä datalle tulee tehdä, jotta sitä voidaan hyödyntää potilastiedon analysoinnissa. Aineisto ja menetelmät: Massadatan hyödyntämistä pilotoitiin rekisteritutkimuksessa, jossa esimerkkinä käytettiin opioideja. Rationaalisen lääkehoidon toteutumisen tutkimiseksi määriteltiin lääkeindikaattorit eli tunnusluvut, jotka oli tarkoitettu opioidien lääkehoidon kokonaiskuvan tarkasteluun. Indikaattoreiden avulla luotiin pohja hakuparametreille ja lausekkeille, joita tietoallashaussa käytettiin. Aineisto louhittiin tietoaltaasta maaliskuussa 2020 ja se muodostui opioideja koskevista lääkemääräysmerkinnöistä, jotka oli kirjattu potilastietojärjestelmään 1.1.2015-31.12.2019. Tulokset: Tietoallashausta saatiin 321 000 potilaan opioidimääräysdataa yhteensä noin 1,73 miljoonaa riviä. Kotiutumisen yhteydessä annetut opioidireseptit rajattiin jatkoanalyysin ulkopuolelle, sillä niitä koskeva tieto ei ollut rakenteisessa muodossa. Sairaalassa annettuja säännöllisiä opioidilääkemääräyksiä koskeva aineisto oli noin 258 000 riviä. Dataa siivottiin, järjesteltiin ja validoitiin data-analyysiä varten. Toimenpiteistä huolimatta data ei soveltunut indikaattorien laskentaan. Johtopäätökset: Tietoallasaineiston käytön mahdollisuudet rationaalisen ja turvallisen lääkehoidon tutkimukseen olivat tämän tutkimuksen perusteella rajalliset. Massadata-aineiston saattaminen tutkimuksellisesti hyödynnettävään muotoon vaatii menetelmän, joka pitää sisällään useita työvaiheita ja niiden kehittäminen vaatii tietoteknistä erityisasiantuntemusta. Vaikka dataa saatiin paljon, yksittäisen potilaan opioidilääkehoidosta ei saatu kokonaiskuvaa, koska merkittävä osa datasta oli rakenteettomassa muodossa. Potilastiedon toissijaisen hyödyntämisen kannalta aineiston rakenteisen osan merkittävimmät käytön esteet liittyivät datan laatuun ja luotettavuuteen. Jotta tietoaltaasta saatava aineisto soveltuisi toisiokäyttöön tai tieteelliseen tutkimukseen, pitää sekä potilastietojärjestelmän merkintä- ja kirjaamistapoja yhtenäistää sekä data tulisi tallentaa tietoaltaaseen yhä rakenteisemmassa muodossa.

Medication safety meaning the safety of using medication is an important part of patient safety. Medication errors are the most common preventable threats of patient safety. Medication errors can occur in all stages of the medication process. Rather than blaming individuals involved in the process, incidents should be evaluated based on system thinking with an aim of identifying system and process-based weaknesses allowing errors to happen. James Reason's human error theory provides a good framework to investigate the topic from this perspective. The objective of this study was to gather information on the medication errors based on the Patient Insurance Centre 2013-2014 data of compensated medication errors. One of the aims was to identify different types of medication errors and gather information on their backgrounds and drugs involved. Another aim was to investigate the causes behind the medication errors and the views of the people involved on the contributin factors of these errors. Additionally the study aimed at identifying situations where interprofessional collaboration could have prevented medication errors from occurring. Finally the results of the study were also compared with the results of the earlier studies done using similar data. The data of the study consisted of 205 cases where medication error had caused compensated patient injury. Factors behind the errors were analyzed using descriptive statistics. The examples of most common cases were investigated more in depth through simplified root-cause analysis. Content analyses were used to gather information on the views of the people involved in errors as well as on the possibilities of preventing errors through interprofessional collaboration. The most frequent error type was omission of medication. The majority of the errors occurred in the early stages of the process when decisions on medication and treatment were done. There were altogether 250 drugs in the data out of which 98 different active ingredients were identified. Antithrombotic agents were the most common therapeutic group causing medication errors. 37% of all drugs included in data were classified as high alert medicines. More efficient use of the interprofessional collaboration could have prevented several medication errors. The number of medication errors had somewhat increased compared to earlier studies but the profiles of errors were very similar. The data of Patient Insurance Centre provides valuable information on medication errors across Finland. More accurate information on factors leading to medication errors could be obtained by improving voluntary nationwide reporting. This would make it easier to develop operating models that improve patient safety.

Suspension is nowadays the most commonly used dosage form in preclinical animal studies. However, suspension can be physically unstable and changes in particle size or crystal form of an active pharmaceutical ingredient (API) can occur during storage. Conventionally suspensions are also prepared in a mortar, and hence the quality of suspensions is operator-dependent. One of the aims in this study was to prepare suspensions using a mortar and pestle and an Ultra-turrax homogenizer to find out how the preparation method affects the particle size of suspension. A solution containing methylcellulose and Tween 80 was used as a vehicle, and five active APIs with different physico-chemical properties as model drugs. Moreover, an aim of the study was to evaluate the stability of the suspensions stored at room temperature and in the refrigerator and freezer by physical (laser diffraction, optical microscopy, X-ray powder diffraction) and chemical (high-performance liquid chromatography) methods of analysis. The aim of the study was also to assess and compare the suitability of laser diffraction and optical microscopy for the determination of partice size during preclinical studies. The suspensions prepared using a mortar and pestle and Ultra-turrax had a similar particle size in almost all cases. The particle size of API that was difficult to grind decreased significantly, also when using Ultra-turrax although the capacity used was minimum. Both prepation methods had the best repeatability of particle size when the API was easy to grind. However, Ultra-turrax could provide better homogeneity of quality than a mortar and pestle if the settings were optimized. The effect of different operators was not studied in this study. The stability of suspensions in different storage conditions was dependent on the properties of API. The particle size of all frozen suspensions decreased after two days based on laser diffraction results. Although the reason was not found from literature or supplementary tests (particle size analysis of the vehicle and pH-measurements), freezing of suspensions should be treated with caution based on this study. The crystal structures of APIs remained stabile with the exception of typical disproportionation of the API salt. Suspensions were mainly chemically stabile in all conditions, but water-solubility of API seemed to decrease stability. The micellar solubilization of drugs was also observed. The best way to determine the particle size of preclinical suspensions proved to be the combination of laser diffraction and optical microscopy images. The microscopy images confirmed the validity of the size distributions measured by laser diffraction and provided information about e.g. particle aggregation. On the other hand, optical microscopy image analysis was not suitable method for particle sizing.

The problems caused by hypromellose in sterile filtration of ophthalmic products in the pharmaceutical industry were investigated. The research project was performed at NextPharma Oy's ophthalmics manufacturing facility in Tampere during the autumn of 2020. Hypromellose is an excipient commonly used in ophthalmic products as a viscosity enhancer to prolong the contact time of the preparation on the eye surface. In the ophthalmics compounding process, hypromellose is first dispersed by slowly sprinkling it into a hot solution and thoroughly mixing, after which the solution is cooled to room temperature. During cooling, the hypromellose dissolves and gels, increasing the viscosity of the solution. Incomplete dispersion or dissolution of hypromellose during the manufacturing process can slow down the filtration rate or even clog the filter completely due to undissolved hypromellose polymer material. Hypromellose is an industrially produced cellulose derivative that often contains some amounts of unreacted cellulose and other sparingly soluble polymer particles as impurities, which can also cause problems in filtration processes. Sterile filtration is a commonly used sterilization method for ophthalmic products, in which the prepared bulk solution is filtered through a 0.1 to 0.2 µm pore size filter membrane into a sterile receiving vessel. Due to the very small pore size, sterile filters are easily clogged if the solution contains poorly dissolved material. The purpose of this work was to collect additional information on the possible causes of clogging caused by hypromellose and to determine whether the filterability of a solution containing hypromellose can be improved by optimizing the manufacturing process parameters. The design of experiments was prepared, creating a two-level full-factorial test matrix without replicates and with three centre points. Four different process parameters were used (mixing time, mixing speed, dispersion temperature, and cooling temperature). Minimum and maximum levels for the parameters were obtained in the initial tests, after which the test solutions were prepared and filtered in a randomized order according to the test matrix. The aim of the screening was to find out which parameters were affecting the filterability and what would be their optimal combination that would maximize the filtration rate and the yield of filtration. Finally, the optimized parameters were used to test different batches of hypromellose, comparing the results to previous filtration tests. Additionally, an alternative hypromellose dispersion method was tested to minimize the amount of insoluble material remained during the dispersion and cooling steps. Of the parameters tested, mixing speed was the least significant, while cooling temperature had the most effect on the filtration results. The solutions with lower cooling temperature had better filtration results, which may be due to reduced aggregation of hypromellose due to increased hydration of the polymer chains. The temperature behaviour of hypromellose solutions could be an interesting subject for further investigation. Longer mixing times and higher dispersion temperatures produced slightly better filtration results on average, but the differences were not statistically significant. Most challenging in the study was controlling the temperature and mixing of the solutions, and the retention of insoluble hypromellose material at the walls of the compounding vessel. The alternative dispersion method gave promising preliminary results, but the method still requires further testing. It would be important to also find the root cause of the filter clogging mechanism e.g., by further analysing the clogged filter membrane. The study provided additional useful information of the behaviour of hypromellose solutions in solution preparations and during sterile filtration, which has been helpful in solving production problems.