<p>Relationships between stresses during the drying process, particle structural and functional properties, and particle engineering by the drying process were addressed in this thesis. In the first part, the importance of the drying phase and the effect of the drying rate on the intragranular porosity of microcrystalline cellulose pellets were investigated. Differences in porosities of dried pellets could be explained by liquid-related differences in densification during convective drying rather than by differences in densification during wet agglomeration. An increased drying rate gave more porous pellets with a lower compression shear strength, and thereby stronger tablets. The next part dealt with modulation of solid-state stability and tabletting behaviour of amorphous lactose by incorporation of different polymers by spray drying. Increased content and molecular weight of poly(vinylpyrrolidone) (PVP) resulted in an increased resistance to crystallisation provoked by heat and moisture. The stabilising effect was even more evident after long-term storage. However, the glass transition temperature was almost unaffected and may, therefore, be questioned as a stability indicator for these types of materials. The presence of the polymers resulted in somewhat less deformable particles. Incorporation of PVP increased the compactability, whilst a surfactant decreased it, which could be shown to be related to differences in particle-particle adhesivity between the different particles. This thesis contributes to increased mechanistic understanding in the area of particle engineering that may lead to better prediction and optimisation of the functionality of pharmaceutical particles, which is of the utmost importance in the development and production of solid dosage forms.</p>

<p>New effective experimental techniques in medicinal chemistry and pharmacology have resulted in a vast increase in the number of pharmacologically interesting compounds. However, the number of new drugs undergoing clinical trial has not augmented at the same pace, which in part has been attributed to poor absorption of the compounds.</p><p>The main objective of this thesis was to investigate whether computer-based models devised from calculated molecular descriptors can be used to predict aqueous drug solubility, an important property influencing the absorption process. For this purpose, both experimental and computational studies were performed. A new small-scale shake flask method for experimental solubility determination of crystalline compounds was devised. This method was used to experimentally determine solubility values used for the computational model development and to investigate the pH-dependent solubility of drugs. In the computer-based studies, rapidly calculated molecular descriptors were used to predict aqueous solubility and the melting point, a solid state characteristic of importance for the solubility. To predict the absorption process, drug permeability across the intestinal epithelium was also modeled.</p><p>The results show that high quality solubility data of crystalline compounds can be obtained by the small-scale shake flask method in a microtiter plate format. The experimentally determined pH-dependent solubility profiles deviated largely from the profiles predicted by a traditionally used relationship, highlighting the risk of data extrapolation. The <i>in silico</i> solubility models identified the non-polar surface area and partitioned total surface areas as potential new molecular descriptors for solubility. General solubility models of high accuracy were obtained when combining the surface area descriptors with descriptors for electron distribution, connectivity, flexibility and polarity. The used descriptors proved to be related to the solvation of the molecule rather than to solid state properties. The surface area descriptors were also valid for permeability predictions, and the use of the solubility and permeability models in concert resulted in an excellent theoretical absorption classification. To summarize, the experimental and computational models devised in this thesis are improved absorption screening tools applicable to the lead optimization in the drug discovery process. </p>

<p>The main aim of the thesis was to explore the potential of supercritical fluid (SF) techniques in the field of drug delivery. In particular, the relatively recently developed solution-enhanced dispersion by supercritical fluids (SEDS) technology has been employed in the preparation of particles/powders. </p><p>The manufacturing, stability and bioavailability of a dosage form strongly depend on the physicochemical properties of the formulation particles. For example, dry powder inhalation (DPI) for administering drugs to the respiratory tract require particles in a narrow size range (1-5 μm) to be effective. The identification of polymorphs and control of purity are also important issues since the physicochemical properties and therapeutic effects of the alternative forms of a drug may differ substantially. Solvent-based traditional crystallisation processes provide the product that may require further down-stream processing to obtain particles for advanced drug delivery applications. This can result in unwanted changes in the physicochemical properties of the particles and thus affect the performance of the dosage form. SF processing has addressed many of the challenges in particle formation research. Among several SF technologies developed for particle processing over the last decade, the SEDS process with its specially designed co-axial nozzle with mixing chamber has resulted in improved control over the particle formation process. Carbon dioxide (CO₂) was used as the SF, because it has low critical points and is non-toxic, non-flammable and relatively inexpensive. </p><p>The initial part of the thesis concerns the formation of particles of model drugs such as hydrocortisone, budesonide and flunisolide using SEDS technology and the determination of the influence of processing conditions and solvents on particle characteristics such as size, shape and crystal structure. Particles of model drugs of differing shapes in a size range suitable for inhalation delivery were prepared. In the process, two new polymorphic forms of flunisolide were identified. This was the first report of SEDS technology being shown as a polymorph-screening tool. The remainder of the thesis deals with the development of SEDS technology for precipitating therapeutic proteins such as recombinant human growth hormone (hGH) from aqueous solutions. Powders of hGH were precipitated using SEDS without significant changes in the chemical or physical stability of the protein. The addition of sucrose to hGH in the feed solution promoted precipitation and minimised the detrimental effects of the solvent and/or the process on the physical aggregation of the protein. </p><p>In conclusion, this thesis highlights the applicability of the SEDS process in drug delivery research and advances general understanding of the particle formation phenomenon. The SEDS process may also prove to be a potential alternative technology for the precipitation of stable powders of therapeutic proteins.</p>

<p>The aim with this thesis was to study cardiovascular disease and hypertension, use of drugs and health from an epidemiological perspective. Various methods - self-rated health (SRH), health related quality of life (HRQL) - the 36-item short form questionnaire (SF-36) - and health utility measurements - the rating scale (RS) and the time-trade off (TTO) methods - were employed.</p><p>Data from the Swedish Adoption/Twin Study of Aging (SATSA) in 1984, 1987, 1990, and 1993 as well as a general population survey conducted in Uppsala County in 1995 were used.</p><p>Persons who have cardiovascular disease, both with and without drug treatment, were found to have a lower SRH as compared to others in the population. Longitudinal analyses showed that SRH was relatively stable over time among persons with cardiovascular disease. Both having a low SRH and having cardiovascular disease were associated with a higher mortality rate.</p><p>Hypertensives were found to have a lower HRQL than do others in the general population as measured by the SF-36. The lowest scoring was found in the general health perception scale (GH), whereas role emotional (RE) and mental health (MH) were the scales least affected by hypertension.</p><p>Nearly 20 percent of the antihypertensive drug users reported side effects.The pattern of side effects was similar to that reported in clinical trials. Both hypertension itself and the drug treatment were found to have an impact on the patient's health-state utility as measured by the RS. Comparative analyses showed that health utilities and psychometric quality-of-life instruments were only moderately correlated among hypertensives. </p><p>The results also showed that inequalities in HRQL were present with respect to several sociodemographic factors. </p><p>In summary, this thesis revealed that persons with cardiovascular disease and/or with hypertension experience poorer health than others in the population. The poor health may be caused both by the disease and/or the drug treatment. The results in this thesis also suggested that special attention and care should be directed to persons with cardiovascular disease and/or hypertension reporting ill health. This especially is important given that low HRQL can be a riskfactor for subsequent cardiovascular events or complications which in turn might result in higher mortality rate.</p>

The aim with this thesis was to study cardiovascular disease and hypertension, use of drugs and health from an epidemiological perspective. Various methods - self-rated health (SRH), health related quality of life (HRQL) - the 36-item short form questionnaire (SF-36) - and health utility measurements - the rating scale (RS) and the time-trade off (TTO) methods - were employed. Data from the Swedish Adoption/Twin Study of Aging (SATSA) in 1984, 1987, 1990, and 1993 as well as a general population survey conducted in Uppsala County in 1995 were used. Persons who have cardiovascular disease, both with and without drug treatment, were found to have a lower SRH as compared to others in the population. Longitudinal analyses showed that SRH was relatively stable over time among persons with cardiovascular disease. Both having a low SRH and having cardiovascular disease were associated with a higher mortality rate. Hypertensives were found to have a lower HRQL than do others in the general population as measured by the SF-36. The lowest scoring was found in the general health perception scale (GH), whereas role emotional (RE) and mental health (MH) were the scales least affected by hypertension. Nearly 20 percent of the antihypertensive drug users reported side effects.The pattern of side effects was similar to that reported in clinical trials. Both hypertension itself and the drug treatment were found to have an impact on the patient's health-state utility as measured by the RS. Comparative analyses showed that health utilities and psychometric quality-of-life instruments were only moderately correlated among hypertensives. The results also showed that inequalities in HRQL were present with respect to several sociodemographic factors. In summary, this thesis revealed that persons with cardiovascular disease and/or with hypertension experience poorer health than others in the population. The poor health may be caused both by the disease and/or the drug treatment. The results in this thesis also suggested that special attention and care should be directed to persons with cardiovascular disease and/or hypertension reporting ill health. This especially is important given that low HRQL can be a riskfactor for subsequent cardiovascular events or complications which in turn might result in higher mortality rate.

Although, pulmonary drug delivery is a well established means for targeting of drugs to the lungs for the treatment of respiratory diseases as well as for the systemic delivery of volatile anesthetic agents, drug absorption kinetics in the lung have not been subjected to extensive research. The main objective of this thesis was to investigate drug absorption characteristics of the lung barrier, using the isolated and perfused rat lung model and in vivo pharmacokinetic studies in rats. Physicochemically diverse drugs (i.e. atenolol, budesonide, cromolyn, cyanocobalamin, enalapril, enalaprilate, formoterol, imipramine, losartan, metoprolol, propranolol, talinolol, terbutaline, and the tetrapeptide TArPP) were used as model compounds. In connection to these investigations, a nebulization catheter device was successfully adapted and evaluated as a new technique for delivery of defined aerosol doses to the rat lung. In addition, a physicochemical profile of the inhaled drugs on the market worldwide during 2001 was made. The pulmonary first-order absorption rate constant and bioavailability were found to correlate to the drug lipophilicity, the molecular polar surface area, and the apparent permeability of Caco-2 cell monolayers. In contrast to the intestinal mucosa and the blood-brain barrier, the pulmonary epithelium was highly permeable to drugs with a high molecular polar surface area. Accordingly, a small hydrophilic tetrapeptide (oral bioavailability ~0.5%) showed a complete bioavailability after pulmonary delivery to rats in vivo. Regional differences in bioavailability, absorption rate, and first-pass metabolism of the peptide was demonstrated after targeted delivery to different regions of the respiratory tract in rats in vivo. The high pulmonary bioavailability of the efflux transporter substrates losartan and talinolol provides functional evidence for an insignificant role of efflux transporters such as P-glycoprotein in limiting the absorption of these drugs from the rat lung. The results of this thesis demonstrate that the lung efficiently absorbs drugs with a wide range of lipophilicity. The pulmonary route should thus be regarded as a potential alternative for administration of drugs with low oral bioavailability. In addition, drug inhalation present an opportunity to attain a more rapid onset of drug action than can be attained by the oral route.

Relationships between stresses during the drying process, particle structural and functional properties, and particle engineering by the drying process were addressed in this thesis. In the first part, the importance of the drying phase and the effect of the drying rate on the intragranular porosity of microcrystalline cellulose pellets were investigated. Differences in porosities of dried pellets could be explained by liquid-related differences in densification during convective drying rather than by differences in densification during wet agglomeration. An increased drying rate gave more porous pellets with a lower compression shear strength, and thereby stronger tablets. The next part dealt with modulation of solid-state stability and tabletting behaviour of amorphous lactose by incorporation of different polymers by spray drying. Increased content and molecular weight of poly(vinylpyrrolidone) (PVP) resulted in an increased resistance to crystallisation provoked by heat and moisture. The stabilising effect was even more evident after long-term storage. However, the glass transition temperature was almost unaffected and may, therefore, be questioned as a stability indicator for these types of materials. The presence of the polymers resulted in somewhat less deformable particles. Incorporation of PVP increased the compactability, whilst a surfactant decreased it, which could be shown to be related to differences in particle-particle adhesivity between the different particles. This thesis contributes to increased mechanistic understanding in the area of particle engineering that may lead to better prediction and optimisation of the functionality of pharmaceutical particles, which is of the utmost importance in the development and production of solid dosage forms.

New effective experimental techniques in medicinal chemistry and pharmacology have resulted in a vast increase in the number of pharmacologically interesting compounds. However, the number of new drugs undergoing clinical trial has not augmented at the same pace, which in part has been attributed to poor absorption of the compounds. The main objective of this thesis was to investigate whether computer-based models devised from calculated molecular descriptors can be used to predict aqueous drug solubility, an important property influencing the absorption process. For this purpose, both experimental and computational studies were performed. A new small-scale shake flask method for experimental solubility determination of crystalline compounds was devised. This method was used to experimentally determine solubility values used for the computational model development and to investigate the pH-dependent solubility of drugs. In the computer-based studies, rapidly calculated molecular descriptors were used to predict aqueous solubility and the melting point, a solid state characteristic of importance for the solubility. To predict the absorption process, drug permeability across the intestinal epithelium was also modeled. The results show that high quality solubility data of crystalline compounds can be obtained by the small-scale shake flask method in a microtiter plate format. The experimentally determined pH-dependent solubility profiles deviated largely from the profiles predicted by a traditionally used relationship, highlighting the risk of data extrapolation. The in silico solubility models identified the non-polar surface area and partitioned total surface areas as potential new molecular descriptors for solubility. General solubility models of high accuracy were obtained when combining the surface area descriptors with descriptors for electron distribution, connectivity, flexibility and polarity. The used descriptors proved to be related to the solvation of the molecule rather than to solid state properties. The surface area descriptors were also valid for permeability predictions, and the use of the solubility and permeability models in concert resulted in an excellent theoretical absorption classification. To summarize, the experimental and computational models devised in this thesis are improved absorption screening tools applicable to the lead optimization in the drug discovery process.

The main aim of the thesis was to explore the potential of supercritical fluid (SF) techniques in the field of drug delivery. In particular, the relatively recently developed solution-enhanced dispersion by supercritical fluids (SEDS) technology has been employed in the preparation of particles/powders. The manufacturing, stability and bioavailability of a dosage form strongly depend on the physicochemical properties of the formulation particles. For example, dry powder inhalation (DPI) for administering drugs to the respiratory tract require particles in a narrow size range (1-5 μm) to be effective. The identification of polymorphs and control of purity are also important issues since the physicochemical properties and therapeutic effects of the alternative forms of a drug may differ substantially. Solvent-based traditional crystallisation processes provide the product that may require further down-stream processing to obtain particles for advanced drug delivery applications. This can result in unwanted changes in the physicochemical properties of the particles and thus affect the performance of the dosage form. SF processing has addressed many of the challenges in particle formation research. Among several SF technologies developed for particle processing over the last decade, the SEDS process with its specially designed co-axial nozzle with mixing chamber has resulted in improved control over the particle formation process. Carbon dioxide (CO2) was used as the SF, because it has low critical points and is non-toxic, non-flammable and relatively inexpensive. The initial part of the thesis concerns the formation of particles of model drugs such as hydrocortisone, budesonide and flunisolide using SEDS technology and the determination of the influence of processing conditions and solvents on particle characteristics such as size, shape and crystal structure. Particles of model drugs of differing shapes in a size range suitable for inhalation delivery were prepared. In the process, two new polymorphic forms of flunisolide were identified. This was the first report of SEDS technology being shown as a polymorph-screening tool. The remainder of the thesis deals with the development of SEDS technology for precipitating therapeutic proteins such as recombinant human growth hormone (hGH) from aqueous solutions. Powders of hGH were precipitated using SEDS without significant changes in the chemical or physical stability of the protein. The addition of sucrose to hGH in the feed solution promoted precipitation and minimised the detrimental effects of the solvent and/or the process on the physical aggregation of the protein. In conclusion, this thesis highlights the applicability of the SEDS process in drug delivery research and advances general understanding of the particle formation phenomenon. The SEDS process may also prove to be a potential alternative technology for the precipitation of stable powders of therapeutic proteins.

<p>En ofullständig eller inaktuell dokumentation av läkemedel i Receptregistret och läkemedelslistorna kan leda till en sämre vetskap om vilka läkemedel som är aktuella att administrera samt till felmedicinering.</p><p>Syftet med denna studie är att hos patienter med diagnosen artros undersöka förekomsten av avvikelser mellan recept i Receptregistret på apotek, vårdcentralens läkemedelslista från ordinationsjournalen samt patienternas egen uppfattning om aktuell läkemedelsbehandling.</p><p>Studien genomfördes dels som registerstudie genom avstämning av journaldata på aktuella läkemedelsordinationer från Stensö Hälsocentral mot sparade recept i Receptregistret och dels som telefonintervju med patienterna om vilka recept som utgör hans/hennes aktuella ordinationer.</p><p>Av artrospatienternas recept i Receptregistret var 89 % aktuella och av artrospatiernas ordinationer i läkemedelslistorna på hälsocentralen var 69 % aktuella. Av alla artrospatienters ordinationer var det 52 % som var aktuella och som förekom i både Receptregistret och läkemedelslistorna.</p><p>Trots att studien är begränsad i storlek och att patienterna bara rekryterades från en vårdcentral indikerar resultaten att det finns betydande skillnader mellan artrospatienternas aktuella medicinering, deras läkemedelslistor på vårdcentral samt Receptregister från apotek. Genom att förbättra och göra regelbundna läkemedelsavstämningar efter ändringar i patientens läkemedelsbehandling, såväl på apotek som inom sjukvården, kan antalet avvikelser reduceras, följsamheten hos patienterna kan ökas genom att det blir lättare för dem att veta vilka läkemedel som är aktuella att administrera och medicineringsfel kan reduceras.</p> / <p>Misuse of drugs is a growing problem and a major cause of both morbidity and mortality in today's society. This may be a result of an incomplete or outdated medication history of patients and it is therefore important that all medical records are updated with the current drugs for the patient to use to prevent medication errors.</p><p>The ultimate effect of any drug therapy depends on the patient's decision to take their medicines as the doctor has prescribed, to have so-called adherence to their prescription medicines, which in turn depends in particular on the patient's knowledge of the drugs at issue. To assist the patient there are two kinds of printing, a list with the doctor’s prescriptions from the electronic patient record (EMR) and also a list from the national prescription repository (NPR) of all the saved prescriptions at pharmacies by the patient. Discrepancies may exist between what is documented in the patient's EMR and that in the pharmacy record, which both also may differ from the drugs that the patient actually is using. These discrepancies between the documents, which can both include valid and outdated prescriptions so as prescription duplicates, can cause a worsening of compliance and medication errors especially in patients with multiple drugs that may have difficult to keep track of their current drug treatment.</p><p>The aim of the study was compare the national prescription repository (NPR), the electronic medical records (EMR) and patient’s knowledge of the prescribed treatment for people with a diagnosis of osteoarthritis.</p><p>The study was conducted both as registry study by reconciliation of journal data on current drug prescriptions from a health centre (HCC) with saved recipes in the Swedish national prescription repository (NPR) and partly by telephone interview with patients about the prescriptions that represent his / her current prescriptions. The participation rate was 58 %. Twenty-nine patients with osteoarthritis were included in the study.</p><p>Of the osteoarthritis patients 89 % the recipes in the NPR were found to be valid and 11 % were outdated. Duplicates of recipes were estimated to 5 %, and double-medication occurred in 1 % of the recipes.</p><p>Of the patients' prescriptions in the medical records at the health centre 69 % were found to be valid. The outdated prescriptions were estimated to 31 % while 4 % was duplicates.</p><p>For all of the osteoarthritis patients' 247 drugs, only 52 % was valid and occurred both in the NPR and in the EMR.</p><p>There were major discrepancies between the prescriptions in the EMR, the NPR and what the patients with osteoarthritis are seeing as their current prescriptions. Through regular medical reconciliations after changes in the patients' treatment, in both health care and pharmacies, the discrepancies can be reduced, the patient can be surer of what to administrate and therefore medication errors can be reduced.</p>