Browsing by Subject "Teollisuusfarmasia"

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  • Mikkola, Vilhelmiina (Helsingfors universitet, 2015)
    Organogels refer to gels whose liquid phase is composed of an organic solvent instead of water. Compared to hydrogels it is estimated that oil based organogels, alias oleogels, are able to improve the solubility and bioavailability of the poorly water-soluble drugs and also to promote the stability of the easily water-degradable drugs. Furthermore, it has been estimated that compared to fluid oil based products organogels are able, especially in veterinary medicine, to facilitate the administration of the drugs and other nutritive substances by guaranteeing more precise and more stable administration platform. The purpose of this work was to develop and to optimize the composition and the manufacturing process of the organogel based nutritional product for pets. Fish oil and solid active pharmaceutical ingredients were used as active components of the nutritional product but in addition for operating as a source of fatty acids fish oil also functioned as a liquid phase of the organogel formulation. In this work the fish oils were thickened with colloidal silicon dioxide. In addition to the silica different surface active agents; krill oil, lecithin or tocopherol; were also added to some of the formulations in order to enhance the gelation property of the colloidal silicon dioxide. Systematic design of experiments was utilized in the planning of the organogel formulation test series. Two different silicon dioxide grades and seven different surface active agents were used in this work. The three-dimensional structure of the organogel samples were examined by Cryo-TEM. The rheological properties of the organogel formulations were determined by dynamic rotation rheometer one week and 3 months after the preparation of the organogel samples. On the basis of the observations that were done in this work, certain levels of krill oil and lecithin grades Phosal® 35 SB, Phosal® 53 MCT and Phosal® 75 SA were able to enhance the gelation property of the silica-fish oil mixtures compared to the formulations that contained only plain silica or silica-tocopherol mixtures. Especially krill oil was found to be able to enhance the thickening effect of the silica-fish oil mixtures even when small concentrations and low shear rates were used whereas either high silica contents or high shear rates were needed to thicken the pure fish oil-silica mixtures. Although krill oil and lecithin grades Phosal® 35 SB, Phosal® 53 MCT and Phosal® 75 SA were, in certain concentration levels, able to enhance the thickening effect of the silica-based fish oil mixtures the predemands of the paste-like consistency, solidity and 2 years stability time were not fulfilled as desired. On the basis of the observations that were done in the pre-tests, it is however possible that either by using different krill oil and fish oil combinations or by using higher shear methods it could be possible to form the desired, stiff, paste-like, stable organogels at least with the help of krill oil and colloidal silicon dioxide.
  • Neuvonen, Janina (Helsingfors universitet, 2019)
    Flowability of powders is in critical role when manufacturing the most popular dosage forms, tablets and capsules, of pharmaceutical industry. Re-formulation is expensive and time-consuming, so it is important to determine powder flow properties at the initial stage of drug development prior to tabletting and encapsulation processes. There are many different methods, like shear cell, flow through an orifice and bulk and tapped density, to examine powder flowability. Despite the methods, the most reliable means of examining powder flowability is often empirical. In early stages of drug development, it would be good to have faster, more reliable and cheaper methods to examine powder flowability. FT4 Powder Rheometer is a relatively new flowability characterization technique. The aim of this study is to find out whether the library created using the FT4 Powder Rheometer methods makes it possible to characterize the rheological properties of solids in the early stages of drug development. In addition, the aim is to investigate whether FT4 Powder Rheometer methods can predict the success of masses in tableting and encapsulation processes. The information gained from the research can be used in the future, for example, in continuous processes, because flowability plays an important role, especially in the supply of raw materials to the process, which is the most important division of continuous processes. To the library were selected for particle size and shape 15 different types of material. These materials were subjected to five different FT4 Powder Rheometer basic test methods. In addition, the particle size and shape of the materials and the flow through an orifice and the bulk and tapped density were determined to support the results of the powder rheometer. The principal component analysis was used to process the results. As the tablet and capsule masses examined, the masses of a previous study were utilized. Those masses were tableted and encapsulated in that previous study. These tablet and capsule masses contain a variable amount of cohesive drug substance. FT4 Powder Rheometer methods provide more complex information about materials and their behaviour than conventional flowability test methods. From the powder rheometer parameters pressure drop, compressibility and specific energy distinguish the cohesive and the non-cohesive materials, because the cohesive materials with these parameters obtain clearly higher values than non-cohesive materials. Additionally, the cohesion of FT4 Powder Rheometer shear cell test mainly distinguishes highly cohesive materials from other materials. The flow rate index makes it possible to separate the materials to which the change in flow rate particularly affects. Fluidizing materials, due to the air flow, are distinguished by the aeration test. Avicel PH-102 could be used as a rough limit value for well and poorly flowing materials in the created library (excluding the aeration and shear cell test). Stability index -, flow rate index -, specific energy -, pressure drop -, and compressibility-results of the FT4 Powder Rheometer correlated to the proportional proportion of the cohesive drug in the mixture. These parameters could possibly be used to distinguish mixtures containing the cohesive material. Additionally, specific energy, compressibility, pressure drop, basic flowability energy, stability index and flow rate index correlated with the weight variation of the tablets. With these parameters one could possibly assess the tabletability of the mixtures. A much larger library is needed to evaluate and predict the rheological properties of new materials. FT4 Powder Rheometer can possibly be used to predict the tableting success of tablet and capsule masses. This would be interesting to look more extensively, for example as part of a library. Additionally, it would be good to investigate whether the results of powder rheometer correlate to continuous production.
  • Naukkarinen, Noora (Helsingfors universitet, 2013)
    The pet medication industry is growing but there are still challenges especially in feline medication. Palatable flavours, efficient taste masking technologies and easily administrable dosage forms are needed to facilitate feline medication. Based on the literature review, there is only little information about cat's preference to individual flavours. The methods for palatability testing should be improved to achieve reliable results. Most common taste masking technologies are flavouring and tablet coating. In experimental section different flavours for taste masking were studied. Five main flavours were selected: phenylalanine, leucine and methionine as possibly good flavours and arginine and denatonium benzoate as bad flavours. In preformulation experiments tableting characteristics, thermal behaviour and crystal structure of flavours were analysed. The aim was also to study their possible incompatibilities with tablet excipients. The main compatilibility study method was X-ray powder diffraction (XRPD), but differential scanning calorimetry (DSC) was also used. Excipient povidone (PVP) was incompatible with nearly all of the main flavours. The use of lactose as an excipient was excluded because of the risk of the Maillard reaction. In tableting studies a tablet mass containing microcrystalline cellulose (MCC), calcium hydrogen phosphate dihydrate, mannitol, hydroxypropyl cellulose (HPC), crospovidone, talc and sodium stearyl fumarate was produced. Minitablets of diameter 3 mm without any flavours were compressed. Also minitablets with flavours phenylalanine and denatonium benzoate were compressed. Minitablets complied with the European Pharmacopoeia tests for uniformity of mass, disintegration and friability. However, characterization and handling of minitablets was found to be challenging due to very small size of the tablets. Minitablets are a promising technology for facilitating feline medication in the future.
  • Räntilä, Sanna (Helsingfors universitet, 2010)
    The purpose of this study was to describe cat owners' problems that relate to cat medication, especially from the drug formulation point of view. Oral, topical, eye and ear administration routes were included into study. There are few compliance and palatability studies made for cats and dogs in Finland and abroad, but this kind of descriptive study relating different drug formulation has never been done before. This study was carried out as Internet survey questionnaire study and it was addressed to cat owners who visited in academic veterinary hospital for small animals and those municipal and private veterinary offices that were randomized into the study. Additionally, the survey study was addressed to cat owners who had medicated their cats during January-March 2010. Those cat owners were contacted through Internet discussion sites. In the veterinary offices the office staff selected the proper candidates for the study and distributed invitations to participate. For distributing invitations the main criteria was that the cat owner received veterinary medication prescription or got directions for using some medication in cat. 59 answers were received in the study and 84 % of all formulation were administered via oral route. The products were antimicrobial and paracite medicines, cardiovascular and anti-inflammatory medicines. Based on the study results most of the problems were related to oral and ear administration routes. Cat showed low compliance and unwillingness to take pills and capsules because of the unpleasant smell, taste and mouth feel of the product. Tablet and capsule form medicines caused problems to the owners, because it was often necessary to adjust the dose by splitting and cutting half the tablet. This made it difficult for owners to follow given medication instructions. The consistency of liquid medicine forms was described sticky and package material thick and stiff. Because of these factors cat owners had difficulties to evaluate the amount of drops to administer to cats ear or eye and the amount remaining in the medicine bottle. According to the study results there is a need for palatable and easily administered medicines that will be taken readily by cats. It should also be possible to adjust to dose as described. The survey questionnaire is a convenient study method for descriptive purposes and it should be carefully considered what kind of sampling method to use and how to carry out the sampling in practice.
  • Taipale, Heidi (Helsingin yliopisto, 2020)
    The national legislation, based on EU Directive 93/42, has regulated the high-risk medical devices in Europe to this day. It requires that in order to enter the market, the device must be safe, suitable for the intended use and acceptable in performance. The demonstration of clinical efficacy is not required. The information on which clinical evidence is based, is not publicly available, as clinical evaluation data and the results of a clinical trial are not required as a condition of market access in Europe. This has given the opportunity for manufacturers for faster and more cost-effective pathway to bring the medical devices to market in Europe. This has boosted the activity of device industry in Europe. However, the weaknesses of European legislation are considered to be one of the reasons caused the large-scale device scandals (lack of safety and effectiveness) in the early 2000s. As a result, a new EU Regulation 2027/745 on medical devices has been created and will enter into force in all Member States in May 2021. The aim of this study was to create an overview of the clinical evidence on high-risk medical devices marketed in Europe and how the issue has been investigated. A systematic literature review was used as the method in this study. The challenge was that there was lack of material available on the subject in question. This is probably due to the limited availability on clinical information of marketed devices, as a public database (Eudamed) does not exist yet in Europe and the device manufacturer may not publish the results of clinical studies. This issue has been investigated by using some reimbursement assessment decisions could be found from few European countries. The level of clinical evidence of devices in the United States has been extensively investigated. Medical devices marketed in Europe have been submitted for registration to United States, so information on European devices can be found in United States public sources. This information will provide a stronger insight of the level of clinical evidence regarding the devices marketed in Europe and thus the publication has been justified to be included in this study. According to the information obtained from this study, the clinical evidence of high-risk medical devices is mostly incomplete and of poor quality. This has negative effects on physicians making treatment decisions, patients using the devices, as well as device manufacturers. Clinical trial methods do not fully comply with the gold standard and the use of other methods is not clearly justified. The requirements for new devices will be significantly tightened and the clinical evidence of already approved devices will need to be updated due to the new device regulation. Clinical data will be publicly available in Eudamed database in the near future. Guidance from Notified Bodies and Authorities regarding alternative methods for clinical trials expected to be also clarified. New requirements of clinical evidence will increase manufacturer´s costs. It may also be the case that, clinical evidence updates of current devices cannot be implemented from a safety point of view. It is likely that important devices will exit the European market and the industry will suffer. An agreement should be reached together with authorities and industry to ensure self-sufficient European device manufacturing and the promptly availability of vital devices for patients.
  • Suominen, Riina (Helsingin yliopisto, 2022)
    COVID-19 pandemic has caused a global crisis and its effects have also been reflected to pharmaceutical supply in Finland. At the beginning of the crisis the effects were especially evident in the consumption of self-medication analgesics, prescription drugs and drugs related to respiratory diseases. In a global crisis, collaboration between the public, private and third sector is becoming increasingly important, and it is important to consider how to develop the capacity for collaboration between organizations in different sectors during a pandemic. The purpose of this study was to find out how the cross-sector collaboration between the public, private and third sector of the pharmaceutical supply in Finland was organized in the crisis caused by the COVID-19 pandemic, what was the role of the cross-sector collaboration and how the preparedness and crisis management of the drug supply could be improved. The study was conducted as a semi-structured interview survey and the interviewees were selected to cover the various sectors of Finnish pharmaceutical care as well as possible. The analysis was performed by the Gioia method and thematic design. Based on the study the organization of cross-sector collaboration was both operator- and authority-oriented and the legislation and environment in the drug supply created the framework for the crisis management. Both the authorities and the advocacy organizations can be described as having acted as hubs for organization. There was no clear crisis organization in drug supply, but different actors were involved in the crisis management at different stages of the crisis. The role of collaboration was emphasized in the sharing of information and resources and in joint solution of problems. The collaboration enabled foresight and preparedness, a focus on core tasks and crisis management, and mutual benefit. Lessons learned from the COVID-19 pandemic include the need to increase and intensify collaboration, increase crisis plans and crisis training, update the system of security of supply and mandatory reserve supplies, increase self-sufficiency, and increase overall governance. Cross-sectoral collaboration was seen as useful in crisis management of the crisis in the drug supply chain. The collaboration promotes the formation of a common picture of the situation and the flow of information from the field to decision-makers. Comparing the results of this study with the literature it can be said that the results partially support the previous literature. However, crisis management of the pharmaceutical supply chain from the organization of cross-sectoral collaboration point of view has not been studied in the past.
  • Ylä-Outinen, Saija (Helsingfors universitet, 2011)
    Ksylitolilla on edulliset käyttöominaisuudet. Edullisista käyttöominaisuuksista huolimatta ksylitolin käyttö lääkevalmisteiden apuaineena on vähäistä. Viime vuosina lääketeollisuudessa on kuitenkin lisääntynyt kiinnostus ksylitoliin ja muihin sokerialkoholeihin. Kirjallisuudesta löytyy vain vähän tietoa ksylitolin puristuvuudesta ja sen soveltuvuudesta tablettien täyteaineeksi. Tässä työssä karakterisoitiin erilaisten ksylitolilaatujen ominaisuuksia ja niiden soveltuvuutta suorapuristuksella valmistettavien tablettien täyteaineeksi. Materiaaleina käytettiin kolmea rakeistettua ksylitolia ja kahta jauhemaista ksylitolia. Ksylitolilaaduista tutkittiin ominaisuudet, joilla on vaikutusta materiaalin puristumiseen. Tutkittavat ominaisuudet olivat kaato- ja tärytiheys, todellinen tiheys, partikkelikoko ja partikkelikokojakauma ja valuvuus. Kirjallisuuden perusteella ksylitoli on lievästi hygroskooppinen, joten tässä työssä tutkittiin myös ksylitolin hygroskooppisuus eri olosuhteissa. Työssä tutkittiin ksylitolin puristuvuutta yksin ja yhdessä huonosti puristuvan lääkeaineen, parasetamolin, kanssa. Eri ksylitolilaatujen puristumista tutkittiin eri-kokoisilla painimilla. Ksylitoli on hyvin soveltuva apuaine myös lapsille tarkoitettuihin lääkevalmisteisiin ja siten tutkittiin myös oliko ksylitolista mahdollista puristaa minitabletteja. Minitablettien käyttö tulevaisuudessa lasten annostelumuotona tulee todennäköisesti lisääntymään. Rakeistetut ksylitolilaadut puristuivat tämän tutkimuksen perusteella suhteellisen hyvin. Jauhemaiset ksylitolit puristuivat huonosti. Syynä näiden huonoon puristuvuuteen oli liian suuri partikkelikoko ja partikkelikokojakauma, joka esti partikkelien välisten sidosten muodostumista. Parasetamoli heikensi huomattavasti kaikkien ksylitolilaatujen puristuvuutta. Ksylitoli ei siis yksinään pysty kumoamaan parasetamolin huonoa puristuvuutta, vaan formulaatioon tarvittaisiin ksylitolin lisäksi jokin yleisesti tablettien suorapuristuksessa käytettävä täyteaine. Tämän tutkimuksen perusteella ksylitoli on hygroskooppinen, mutta vasta suhteellisen kosteuden ollessa hyvin korkea (95 %). Siten ksylitolin hygroskooppisuus ei ole haitaksi ajatellen ksylitolia sisältävien valmisteiden valmistusta tai säilytystä.
  • Koskela, Jaana (Helsingfors universitet, 2015)
    Mechanofusion is a dry coating method in which the high shear forces cause a mechanochemical reaction between the processed particles. With the approach it is possible to improve flowability of a host cohesive powder when the guest particle forming the coating is magnesium stearate. Applying mechanofusion in tablet formulations could make poor flowing large dose drug substances suitable for direct compression. However, it is well known that magnesium stearate decreases mechanical strength of the tablets and prolongs disintegration and dissolution time of tablets. A previous study, however, showed that it is possible to compress tablets from a formulation dry coated with magnesium stearate without reducing the dissolution rate. Dry coating with magnesium stearate and its effect on a plastic material, known to be sensitive for the negative effects of magnesium stearate, has not been studied previously. The aim of the study was to examine the effect of mechanical dry coating with magnesium stearate on the physical qualities and compression behaviour of a plastic material. The effect was studied by dry coating four grades of microcrystalline cellulose with different magnesium stearatecon centrations. The approach was to find an optimum between the flowability and compressibility of the powders by using different process parameters. Microcrystalline cellulose with median particle size of 23 and 78 µm were also mechanofused without magnesium stearate in order to examine whether mechanofusion itself has an effect on the properties of microcrystalline cellulose. Pure raw materials and Turbula-mixed magnesium stearate and microcrystalline cellulose blends were studied as references. Dry coating with magnesium stearate improved the flow properties of microcrystalline cellulose with D50 value less than 78 µm. Powders with D50 value greater than 144 µm, however, break down under the shear during the process and hence their flow properties were decreased. This suggests, that mechanofusion as a process is more suitable for the small particle size microcrystalline cellulose powders which, based on the results, can withstand the high-shear forces better. Mechanofusion of plain microcrystalline cellulose (D50 78 µm) revealed that the moisture content of the powder increased and stronger tablets could be compressed. Mechanofusion may cause changes to the microstructure of microcrystalline cellulose particles and to its ability to adsorb moisture. Dry coating with magnesium stearate was very effective even with short processing times and relatively low blade speeds, and it was challenging to compress hard tablets from the mechanofused mixtures. Plastic material was found to be sensitive for the negative effects of magnesium stearate, and better flow properties of a mechanofused powder resulted in weaker compressed tablets.
  • Siirola, Outi (Helsingfors universitet, 2013)
    There aren't always available suitable authorized drug products for different age and different weight pediatric patients. Hospital pharmacies have to prepare suitable doses and dosage form for these very young patients extemporaneously. In Finland oral powders are usually used in pediatric medication. In previous studies it has been found that part of drug dose sticks to paper of oral powder and the patient doesn't get the entire intended dose. It is suggested that hard capsules may be better dosage form than oral powders, because capsules have smaller area than oral powders, where the powder can stick. The aim of this study was to examine, whether warfarin- and spironolactone capsules prepared by hospital pharmacy meet European Pharmacopeia standards of uniformity of content. Capsules were compounded from commercial tablets and capsulated by Feton-capsulating device. In this study capsules manufactured with automatic capsule filling device attached to analytical balance, oral powders and capsules prepared from pure drug substance were also compared to capsules compounded from tablets. The three month stability of compounded capsules was also examined. In hospital pharmacy many different strengths are compounded from same drug substance, ordered by physician. Ordered strengths can be nearly identical, but whether the small differences in concentration can possibly be prepared in hospital pharmacy is unknown. From both drug substances two strengths with small difference in concentration were prepared and it was studied if statistically significant difference exists. The drug concentrations of preparations were measured by high performance chromatography (HPLC). Aqualab-water activity meter was used to study water activity of samples during the stability testing. Content uniformities of all capsule batches complied with test specified in the European Pharmacopeia.The drug concentrations of capsules were significantly lower than target concentrations. With these drug substances no difference, between the drug concentration of oral powder and capsules, was found. According to this study oral powders can be replaced by capsules. Warfarin and spironolactone capsules remain at least three months, when storaged in room temperature. Warfarin capsules can be prepared accuracy of 0,1 mg and spironolactone capsules accuracy of 0,5 mg.
  • Itämö, Satu (Helsingfors universitet, 2018)
    Marketing authorized pharmaceutical preparations that are aimed at adult use cause problems both in administration and when dosing. Over and underdosing are the most common medication errors in pediatric population. Only a fraction of medicinal products are clinically tested and evaluated for pediatric use. Children should have the right for the best achievable health, medical care and rehabilitation. The aim of this study was to determine problematic pharmaceutical preparations, formulations or excipients experienced by healthcare professionals. The another aim of this study was to comprise (?) the view of healthcare professionals about 3D-printed medicinal products by using the collected data. By using the data, the problems, challenges, targets for development and other suggestions regarding pediatric medication were identified. New 3D printed medicines suitable for children can be developed by using the observations of this study. The study was carried out as semi-structured interview. Frameworks of the themes were structured by using the subjects of a recently made semi-structured questionnaire. The semi-structured interview was carried out as a group-interview, where the participants were presented open questions according to the themes structured before. According to the study results, the prejudices of the interviewees towards the new technology were mainly positive. The adjustability of the printed medicine by the means of the patient was most highlighted property in the interviews. Accoring to the experiences of the interviewees’, the most suitable pharmaceutical preparations used are liquid preparations such as oral liquids or suspensions. When using solid oral formulations, the age of the patient was not seen as significant. The most common reason for compounding the preparation was the wrong size of the product or dose. The varying availability of pharmaceutical preparations was seen as delaying factor at the start of the medical treatment. In the interview the pharmacists recognized the most common excipients causing adverse events. The different roles of the occupational groups were identified according to their work duties.
  • Nordberg, Antti (Helsingfors universitet, 2011)
    Nearly one fourth of new medicinal molecules are biopharmaceutical (protein, antibody or nucleic acid derivative) based. However, the administration of these compounds is not always that straightforward due to the fragile nature of aforementioned domains in GI-tract. In addition, these molecules often exhibit poor bioavailability when administered orally. As a result, parenteral administration is commonly preferred. In addition, shelf-life of these molecules in aqueous environments is poor, unless stored in low temperatures. Another approach is to bring these molecules to anhydrous form via lyophilization resulting in enhanced stability during storage. Proteins cannot most commonly be freeze dried by themselves so some kind of excipients are nearly always necessary. Disaccharides are commonly utilized excipients in freeze-dried formulations since they provide a rigid glassy matrix to maintain the native conformation of the protein domain. They also act as "sink"-agents, which basically mean that they can absorb some moisture from the environment and still help to protect the API itself to retain its activity and therefore offer a way to robust formulation. The aim of the present study was to investigate how four amorphous disaccharides (cellobiose, melibiose, sucrose and trehalose) behave when they are brought to different relative humidity levels. At first, solutions of each disaccharide were prepared, filled into scintillation vials and freeze dried. Initial information on how the moisture induced transformations take place, the lyophilized amorphous disaccharide cakes were placed in vacuum desiccators containing different relative humidity levels for defined period, after which selected analyzing methods were utilized to further examine the occurred transformations. Affinity to crystallization, water sorption of the disaccharides, the effect of moisture on glass transition and crystallization temperature were studied. In addition FT-IR microscopy was utilized to map the moisture distribution on a piece of lyophilized cake. Observations made during the experiments backed up the data mentioned in a previous study: melibiose and trehalose were shown to be superior over sucrose and cellobiose what comes to the ability to withstand elevated humidity and temperature, and to avoid crystallization with pharmaceutically relevant moisture contents. The difference was made evident with every utilized analyzing method. In addition, melibiose showed interesting anomalies during DVS runs, which were absent with other amorphous disaccharides. Particularly fascinating was the observation made with polarized light microscope, which revealed a possible small-scale crystallization that cannot be observed with XRPD. As a result, a suggestion can safely be made that a robust formulation is most likely obtained by utilizing either melibiose or trehalose as a stabilizing agent for biopharmaceutical freeze-dried formulations. On the other hand, more experiments should be conducted to obtain more accurate information on why these disaccharides have better tolerance for elevating humidities than others.
  • Sinnemaa, Olivia (Helsingin yliopisto, 2022)
    The package leaflet (PL) is a technical document sheet included in medicine packages to provide guidance on safety and rational use of medicines for the user. The EU is increasingly encouraging the adoption of digital product information, which in time should be seen as the basic medicine information. The outdated package leaflet has for a long time been criticized by both patients and pharmaceutical operators. As a result, it is important to map the perspectives of various pharmaceutical operators on the electronic package leaflet. The aim of the study was to gain broader knowledge and deeper understanding of what opportunities and challenges the electronic package leaflet entails from the perspective of different pharmaceutical operators, and whether there are differences between opinions of the pharmaceutical operators. The study also sought to find out how the electronic package leaflet compared with the printed current leaflet from an environmental perspective. The study was conducted as a questionnaire e-survey, whose target groups were companies in the pharmaceutical industry, The Finnish Medical Agency (Fimea) and hospital pharmacies / departmental pharmacists. The material was collected over a three-week period in April 2022. The data was analysed both quantitatively and qualitatively. Based on the results of the study, it emerged that 55 experts, broadly across the pharmaceutical field, took part in the study. According to the pharmaceutical operators, the main opportunities of the electronic package leaflet were its ease of use and environmental friendliness. Patient safety, which is always a focal point when discussing medicines, would also increase as the users would have access to the most up-to-date medicine information (75 %, n = 41). In addition, the QR code on the medicine packages could be utilized when introducing ePL. The challenges, however, mainly concerned the user's lack of internet connectivity and incompetence in the use of e-services. Although pharmaceutical operators are of different opinion on the electronic package leaflet, it is highlighted that the majority of respondents (69 %, n = 38) believe that ePL would be an improvement and a more environmentally friendly alternative than the current printed leaflet. The study shown that there are differences in the perspectives on ePL between different pharmaceutical operators. The varying opinions on the electronic package leaflet depends on the respondent's position in the pharmaceutical sector. Despite the disagreement, the majority believe that ePL would be a positive development and a prerequisite for achieving the challenges of the future.
  • Kuosmanen, Hanna (Helsingin yliopisto, 2022)
    More and more drugs for the treatment of lung cancer are entering the market with limited research evidence and high cost. However, health care resources are limited. To provide rationale and sustainable treatment for all patients, the need for health technology assessments has increased. International value frameworks with varying uses, structures, and components have also been developed to help assess the value of drug therapies. The purpose of the study is to illustrate how physicians, authorities, and pharmaceutical industry experts define the value and the effectiveness of drug therapy. The study also aims to chart the attitudes of health care professionals towards international value assessment frameworks and to describe the current challenges in health technology assessments focusing on lung cancer therapy. In addition, the purpose of the study is to evaluate the importance of therapeutic and economic evaluation of lung cancer therapies. The research material includes interviews with physicians (n=2), authorities (n=3), and pharmaceutical industry experts (n=5). The interviews were conducted as an individual (n=8) and pair interviews (n=1). The interview method used was a semi-structured thematic interview. The interviews were analyzed by using inductive and abductive content analysis and theming. The theoretical framework in the study was related to the challenges of assessing the therapeutic and economic value of pharmacotherapies. According to the study, the value and effectiveness of drug therapy are determined in a varied and perspective-dependent manner. The value of drug therapy can be divided into three dimensions, which were therapeutic, social, and economic impact. Treatment’s effectiveness was primarily determined by the health benefits gained and by the effects the therapy has on patients, society and care pathways. Based on the data, the current challenges of the therapeutic and economic evaluation of pharmacotherapies are related to the implementation methods and criteria of evaluation and decision-making, resources, cooperation needs, scientific evidence, ethics, the structure of the health care system and legislation. Based on the results, physicians, authorities, and pharmaceutical industry experts have different opinions of the need for cooperation. The interviewees also evaluated differently the status of the current development activities and the importance of international evaluations. There were also differences in the opinions on how important the therapeutic and economic evaluation of lung cancer therapies was considered. If the importance was considered low, the importance of the evaluations was expected to increase only after the refinement of treatment recommendations and guidelines. According to the data, the international value frameworks are not actively used in Finland and their significance will be considered insignificant in the future as well. The usefulness of the value frameworks was primarily limited due to structural factors, the assessment of reliability and the current evaluation system in Finland. The benefits of the value frameworks were primarily related to the coherence of the evaluation process, easing the evaluation process and improving patient equality.
  • Niittymäki, Johanna (Helsingfors universitet, 2017)
    There are many challenges in use of dosage forms in medication of elderly people. Especially swallowing of solid dosage forms can be difficult. Dosage forms are often altered to enhance drug intake. Medication adherence is a major contributor to the success of therapy. Adherence is a multidimensional phenomenon which is also affected by properties of medicinal product. Theoretical framework of this thesis is World Health Organization's multidimensional adherence model. Only few studies exist on how properties of dosage forms affect to the success of medical treatment of elderly. The aim of this study was to find out what kind of difficulties related to dosage forms occur in medical treatment of elderly people living in nursing homes. Future goal is to develop dosage forms better suited to elderly and hence improve their medication adherence. This study consisted of interviews and e-survey. This study was carried out in six nursing homes where 322 elderly residents fulfilled the inclusion criteria of the study. Nurses (n = 48) were interviewed to explore their views on difficulties related to dosage forms. Other difficulties in use of dosage forms were also surveyed as well as frequency of tablet crushing. Difficulties in use of dosage forms on the medical treatment of the elderly were gathered in the e-survey. Also, the need to crush tablets and open capsules was surveyed as well as need to split tablets to obtain the dose needed. Difficulties in use of dosage forms are common in medical treatment of elderly people. Majority of the interviewed nurses has encountered these difficulties at least few times a week. The most common problematic dosage form was the tablet. About half of the nurses named the big size of tablets and capsules as the most important difficulty in the use of current oral or peroral dosage forms. Over half of the nurses have crushed or given crushed drug daily. The most common reason for dosage form altering was the big size of the medicinal product. Majority of the nurses has often encountered also other than dosage form related difficulties of which the most common challenges are related to suspiciousness. In e-survey, nurses submitted entries regarding 111 elder people. Most cases were related to splitting of a tablet to obtain the desired drug dose. Tablet crushing was reported for little less than one-fifth of the elderly people. Both the splitting and crushing entries were distributed over multiple different medicinal products. Some other difficulties related to dosage forms were reported for less than one-tenth of the elderly people. Based on this study more appropriate dosage forms should be developed for the medical treatment of elderly people. Oral solutions, orodispersible tablets as well as transdermal patches all have advantages. Pharmaceutical research and development can facilitate medical treatment of elderly people and hence improve their medication adherence by introducing more appropriate dosage forms.
  • Rantanen, Heta (Helsingin yliopisto, 2020)
    Iäkkäiden määrän lisääntyminen aiheuttaa tarpeen kehittää ja tutkia uusia lääkkeitä sekä lääkemuotoja entistä enemmän. Iän tuomat fysiologiset muutokset sekä useat sairaudet voivat aiheuttaa ongelmia perinteisten lääkkeiden annostelussa. Annosteluongelmien ratkaiseminen lääkemuodon muokkaamisella voi kuitenkin aiheuttaa riskin lääkitysturvallisuudelle. Tämän pro gradu -tutkielman tarkoituksena oli tutkia iäkkäitä potilaita hoitavien lääkäreiden kohtaamia lääkemuotoihin liittyviä ongelmia. Tutkimuksen avulla pyrittiin selvittämään, kohtaavatko lääkärit hoitotyössä lääkemuotojen aiheuttamia ongelmia, ja minkälaisia ongelmia lääkärit kohtaavat. Lisäksi lääkäreiden haastatteluissa esiinnousseita teemoja verrattiin hoitajien kolmen päivän seurantajakson aikana verkkokyselylomakkeelle kirjaamiin lääkemuotoihin liittyviin käytännön ongelmiin, joita käytännön hoitotyössä palveluasumisen yksiköissä ilmeni aiemmin toteutetussa tutkimuksessa. Tutkimuksessa haastateltiin viittä lääkäriä, joilla oli kokemusta iäkkäiden lääkehoidosta. Lääkärit etsittiin tutkimukseen mukaan sosiaalisen median kautta hakuilmoituksella. Puolistrukturoidut haastattelut nauhoitettiin ja litteroinnin jälkeen niiden analysoinnissa käytettiin aineistolähtöistä sisällönanalyysiä. Tabletteihin liittyviksi ongelmiksi lääkärit mainitsivat niiden ison koon ja pintaominaisuudet, joiden vuoksi niiden nieleminen vaikeutuu. Muita ongelmia olivat tablettien tunnistettavuus, jakouurteen puute sekä sopivien vahvuuksien puute, vaikkakin yleisesti lääkäreiden mielestä eri vahvuuksia on tarpeeksi markkinoilla. Kapseleiden ongelmiksi lääkärit mainitsivat myös ison koon sekä epäselvyyden siitä, saako kapselia avata vai ei. Oraaliliuosten ongelmiksi koettiin paha maku, liian laimeat vahvuudet, lasku- ja mittaamisvirheen riski sekä sekaantumisen vaara. Lääkelaastarit jakoivat mielipiteitä, mutta niiden ongelmiksi lueteltiin muun muassa iho-oireet ja laastarin irtoaminen. Yleisesti lääkärit eivät olleet tablettien murskaamisen kannalla, mutta jokainen haastatelluista lääkäreistä totesi murskaamisen olevan joissakin tilanteissa ainoa vaihtoehto. Lisäksi lääkärit luettelivat useita lääkemuotoihin liittymättömiä ongelmia, jotka liittyivät sekä potilaaseen mutta myös terveydenhuoltojärjestelmään. Jotta lääkemuotoihin liittyviä ongelmia voitaisiin vähentää, tulisi iäkkäiden kohdalla aina arvioida lääkehoito säännöllisesti. Arvioinnin perusteella iäkkäälle voitaisiin valita hänelle parhaiten sopivat lääkemuodot ja huolehtia siitä, ettei tarpeettomia valmisteita ole käytössä. Lääketeollisuuden ja lääkeviranomaisten vastuulla on edistää lääkkeiden kehitystä ja uusien innovaatioiden tuomista markkinoille. Käytännössä lääketeollisuus voi helpottaa terveydenhuollon ammattilaisten työtä tuottamalla selkeitä lääkeinformaatiotekstejä, joilla voisi esimerkiksi helpottaa murskaamispäätöksen tekemistä.
  • Horelli, Mari (Helsingfors universitet, 2015)
    The purpose of this qualitative material thesis was to describe and summarize the pharmaceutical industry of pharmaceutical company Orion Oyj years between 1899 and 1998 in form of historical study. Previous publications concerning Orion's history have not had precisely industrial point of view. The study is mostly arranged by pharmaceutical forms and additionally some Orion's pharmaceutical products are displayed exemplary and their characters are analyzed. Also development of excipients and package materials are examined briefly. The notices of development of Orion's industrial pharmacy are constantly put into perspective by comparing it to the international industrial pharmacy. Analysis begins in 1899 due to the first finnish pharmaceutical company establishment which also had influences on the starting points of Orion. The study ends in 1998 because of Finland's associaton of European Union in 1995 which also had influences on the Orion's business. The material of the study consist of Orion's public documents including among others Orion's personnel journals, product indexes, sheets, history books and the other produced material of Orion. The material was gathered in the archive of Orion in Espoo during some weeks between October 2013 and Juny 2014. The material of Orion was compared to scientific literature in order to emphasize their worldwide influence. The most of the scientific reference material includes articles but some industrial pharmacy handbooks have been also used because of difficulties of having historical articles. According to the hypothesis the significance of Orion's pharmaceutical industry was minor on the scale of international pharmaceutical industry. The contacts to the foreign industrial countries and compliance with the guidelines of FDA and European Pharmacopoeia were on focus in Orion's aim to accompany international development of industrial pharmacy. One of the important themes in Orion's business was the transform from multi industry to the special industry which was supported by rationalization of production introduced in 1950's. In the context of quality control there have been many projects put in practise especially in 1960's and 1970's, for example the GMP-guidelines introduction, the trading licence system of the pharmaceuticals and the renovations of all the production rooms.Though the pioner of the industrial pharmacy, The United States, was in the quality control even several decades in advance of Finland and consequently Orion. Orion's major products were in the company's program with a licence system. Maybe the most considerable efforts have been made to advance conventional tablet production for example by enhancing equipment and process conditions. Contrary to conventional tablets pharmaceutical formulations like patches and soft capsules have been in Orion's program mainly to complete the company's selection.Some pharmaceutical forms were possible to produce in Orion quite early, for example vaccinations since 1940's and sterile eye drop producing since 1950's. In the last decades of this study, 1980's and 1990's, Orion was focused on the projects like Easyhaler and some own brand name drugs.
  • Kiljunen, Sanna (Helsingin yliopisto, 2021)
    The objective of this research has been to investigate the management of alerts of Medicines Verification Systems in Europe. Verification of medicines according to Falsified Medicines Directive (FMD) came into force 9.2.2019. There is no standardized tool or system for the management of alerts, every Medicines Verification Organisation and manufacturer have had to find their own ways to manage the alerts. The research has been performed as a theme survey via questionnaire that has been sent to Medicines Verification Organisations in 30 European countries. Information to the questions of the questionnaire has also been gathered from the Internet pages that are mainly maintained by the Medicines Verification Organisations. This kind of method triangulation has been used in order to improve the reliability of the research. Answering rate of the survey was 17 %. By including the information gathered by method triangulation the overall yield percent of information in this study was 45 %. The information received via the questionnaire did not contradict with the public information. As conclusion, marketing authorization holders have been registered as users of the National Medicines Verification Systems or they have signed a contract with Medicines Verification Organisations. Marketing authorization holders are paying the costs of the Medicines Verification Systems. Penalties of FMD non-compliance are in use in part of the European countries. In the beginning of the implementation of the Medicines Verification System there has been stabilization periods in use which have already ended in half of the European countries. National competent authority is informed about system alerts typically in case of suspected falsification. In half of the European countries there is a separate computerized alert management system in use. Marketing authorization holder usually has access to the system. In some of the countries it is possible to integrate the system to the own serialization system of the marketing authorization holder. In six European countries there has been set a specific time for the alert investigation of the marketing authorization holder. Based on the results of this research the alert management system that covers the whole Europe that European Medicines Verification Organization is planning would really be needed. One common computerized system and common rules would ease up the alert management of all the stakeholders of the medicines verification.
  • Yliniemelä-Sipari, Sanna (Helsingin yliopisto, 2022)
    Tämän tutkimuksen päätavoitteena oli selvittää Bayer Oy:n Turun tuotantolaitoksella käytettävän CAPA-prosessin kehittämiskohteita. Tutkimuksessa pyrittiin erityisesti selvittämään, kuinka korjaavien ja ehkäisevien toimenpiteiden eli CAPA-toimenpiteiden toteuttamista voidaan tehostaa ja mitkä tekijät vaikeuttavat aikataulussa pysymistä. Lisäksi tavoitteena oli etsiä syitä myös sille, miksi juurisyyanalyysi ja todellisten juurisyiden löytäminen koetaan haastavaksi. Tutkimusmenetelmänä käytettiin puolistrukturoitua teemahaastattelua, johon valittiin tavoitteellisella otannalla 10 tuotantolaitoksella työskentelevää asiantuntijaa. Haastattelut toteutettiin videohaastatteluina etäyhteyden kautta. Aineiston laadullinen analyysi tehtiin deduktiivisesti ATLAS.ti -ohjelmaa apuna käyttäen. Tutkimuksen tulosten perusteella CAPA-prosessin kehittämiskohteet voidaan jakaa neljään pääkategoriaan: suunnittelu ja resurssit, järjestelmä, koulutus sekä yhteistyö ja merkitys. Keskeiseksi kehittämiskohteeksi nostettiin selvitys- ja toteuttamisvaiheiden suunnittelu, niiden toteutumisen seuranta sekä riittävien resurssien (aika, henkilöstö) varmistaminen. Lisäksi sähköistä Dev@com-dokumentointijärjestelmää tulisi kehittää niin, että se tukee CAPA-prosessin eri vaiheita ja on helppokäyttöinen sekä yhteinen kaikille CAPA-tapauksille. Juurisyyanalyysissä hyödynnettävien menetelmien ja työkalujen käyttöön toivottaisiin lisäkoulutusta, jonka lisäksi CAPA-prosessin tavoitteita tulisi selventää. Myös yhteistyön lisääminen yli osastorajojen ja vastuun jakaminen useammalle henkilölle koettiin tärkeiksi keinoiksi kehittää CAPA-prosessia ja lisätä sen merkitystä eri työtasoilla ja koko tuotantolaitoksella. Tutkimuksen tulokset ovat linjassa kirjallisuudessa esitettyjen havaintojen ja mielipiteiden kanssa ja siten mahdollisesti yleistettävissä muihin lääkeyrityksiin tai lääkinnällisiä laitteita valmistaviin yrityksiin. Yleistettävyyttä voitaisiin parantaa vielä laajentamalla tutkimusta muihin lääkeyrityksiin. Tämä tutkimus on yksi ensimmäisistä julkaistuista laadullisista tutkimuksista, jossa saatiin hyödyllistä tietoa siitä, mikä auttaa lääkeyrityksiä tehostamaan CAPA-prosessia ja tukemaan toiminnan jatkuvaa parantamista.
  • Harju, Helena (Helsingfors universitet, 2010)
    Immunoglobulin G is very unstable and that is why it is very challenging to formulate and process it. Because of the unstability, IgG is vulnerable to changes in pH, heat and mechanical stress. Exposure to these stresses makes IgG aggregate more easily and lose its biological activity. To restore stability, IgG is formulated to a solid product from which it can be regenerated. With TFF (Tangential Flow Filtration) IgG can be purified from other components. The filtration is based on a half-permeable membrane which permeates the other components except for the IgG. The filtration pressure is the force which keeps the liquid flowing. It is important to control this pressure, too high or too low pressure will damage the IgG. IgG can also be protected with polysorbate which is a surfactant going to the protein/liquid interface and therefore stabilizing IgG. IgG does not stay stable in liquid very long so it has to be lyophilized to improve its process- and storage stability. Lyophilization is a long and energy consuming process. Optimisation of the process is therefore essential to save time and resources. First IgG is freezed to produce ice. Primary drying is the second step, sublimation will change ice to water vapor. Secondary drying is based on water desorption, that way residual water is removed from the lyophilizate. The drying process is carried out altering shelf temperature on which the samples are placed. Chamber pressure is also an important factor in IgG stabilisation. These factors have their impact on IgG stability. Also adding disaccharide, trehalose, in the formulation increases the stability of IgG. The purpose of this work was to optimise both the filtration and lyophilisation process so that IgG would remain as stable as possible. During preliminary testing the results showed that magnetic stirring prior to filtration will damage the IgG, showing aggregation and less biological activity. Aggregation was measured with DLS and biological activity with ELISA. Changes in the secondary structure after lyophilisation were measured with CD. The actual filtration tests were carried out using three different filtration pressures and two different polysorbate 20 concentrations, and water. The results showed that IgG is most stable in 1,25 bar filtration pressure and 0,01 % polysorbate concentration. There was less aggregation and more biological activity. The filtration tests proved to be challenging because there were several parameters that were difficult to control. The same challenge was faced when analysing the results. Lyophilisation tests were carried out using three different pressures during primary drying and three different heating rates during secondary drying. The analysis methods were the same as during filtration tests. In addition, the IgG secondary structure changes were under investigation. The lyophilisation tests showed that trehalose clearly protects the IgG. Visually lyophilised samples which contained trehalose were mechanically more stable than those which did not contain trehalose. The analysis showed that the pressure of 60 mTorr and low heating rate (5 °C/h) resulted in better stability of IgG, aggregation was lower and biological activity higher. During lyophilisation no changes in the secondary structure was seen in CD. This was possibly due to lack of sensitivity of the analysis method.
  • Nuolimo, Sirpa (Helsingfors universitet, 2016)
    Tavoitteet. Työn tavoitteena oli pyrkiä selvittämään, kuinka lääkevalmisteiden ja CE-merkittyjen terveydenhuollon laitteiden ja tarvikkeiden välinen rekisteröintiprosessi ja rekisteröinnin käytännön työ eroavat toisistaan. Hakemusprosessien ja dokumentaation erojen tutkiminen viranomaisvaatimusten ja työn käytännön suorittamisen näkökulmista katsottiin tärkeäksi, jotta on mahdollista vertailla lääkevalmisteiden ja laitteiden välisiä rekisteröintiprosesseja kokonaisuutena sekä tarkastella valmisteen rekisteröintistatuksen vaikutusta rekisteröinnistä vastaavien henkilöiden työmäärään, ajankäyttöön ja työtehtävien sisältöön. Menetelmät. Tutkimus suoritettiin sähköisen kyselytutkimuksen avulla, joka lähetettiin Suomessa toimiville lääkkeiden myyntiluvan haltijoille ja CE-merkittyjen terveydenhuollon laitteiden ja tarvikkeiden rekisteröinnistä vastaaville valmistajille. Kyselytutkimus toteutettiin Helsingin yliopiston verkkolomaketyökalulla, jota hyväksikäyttäen rakennettiin kyselytutkimuksen runko, kerättiin vastausaineisto sekä käsiteltiin tutkimusaineistoa raportointivalmiiksi. Kysymysten sisältö määriteltiin rekisteröinnin jäsenjärjestön julkaisemiin urakuvauksiin sekä yritysten työpaikkailmoitusten työnkuvauksiin perustuen. Kyselytutkimuksen tekninen ja sisällöllinen toimivuus testattiin pilotoinnin avulla. Vastausaineiston sisältöanalyysi suoritettiin kvantitatiivisten tutkimusmenetelmien keinoin. Tulokset ja johtopäätökset. Lääkevalmisteiden ja CE-merkittyjen terveydenhuollon laitteiden ja tarvikkeiden rekisteröintiprosessit eroavat toisistaan merkittävimmin hakemusprosessien rakenteen ja viranomaistoiminaan osalta, vaikkakin molemmilla sektoreilla perimmäinen tavoite on sama; osoittaa valmisteen teho ja turvallisuus sille aiotussa käyttötarkoituksessa. Hakemusrakenteiden ja viranomaistoiminnan erojen voidaan nähdä olevan perustekijät, joista johtuvat muut rekisteröintityötä ja dokumentaatiovaatimuksia erottavat tekijät, myös käytännön tasolla. Kyselytutkimuksen vastausaineiston perusteella merkittävimmin käytännön työssä vaikuttavat erot liittyivät rekisteröintityön osuuteen kokonaistyöajasta, hallinnollisten tehtävien osuuteen sekä työn sisällön aiheuttamiin vaatimuksiin. Lääkerekisteröintityötä tekevien rekisteröintityön osuus kokonaistyöajasta ja hallinnollisen työn osuus rekisteröintityöstä oli laiterekisteröintityötä tekeviä merkittävästi suurempi. Työn sisällön asettamat vaatimuserot näkyivät muun muassa lääkerekisteröintityössä vastaajien enemmistön farmaseuttisena koulutustaustana ja laiterekisteröintityössä teknisenä koulutustaustana. Kaiken kaikkiaan työssä havaitut erot vaikuttaisivat rekisteröintistrategisesti suosivan valintaa CE-merkityksi lääkinnälliseksi laitteeksi sellaisissa rajatapaustilanteissa, joissa valmiste on mahdollista rekisteröidä joko lääkkeeksi tai lääkinnälliseksi laitteeksi.