Nanofibrillar cellulose in drug delivery

The choice of proper excipients is one of the key factors for successful formulation of pharmaceutical dosage forms. Increasing number of new therapeutic compounds suffers from poor solubility and/or bioavailability, creating a challenge from the drug formulation point of view. Problems have also been encountered in attempts to formulate biological drugs such as peptides and proteins, considering their sensitivity towards certain production processes and routes of administration. In both cases the choice of the right excipient(s) is essential to provide particular processability and development of systems with desirable drug delivery kinetics. The aim of this work was to evaluate pharmaceutical applications of nanofibrillar cellulose (NFC), a renewable, biodegradable and widely available plant based material, as a potential excipient in the production of pharmaceutical dosage forms. Initially, tablets with immediate drug release were manufactured by methods of direct compression and compression after wet granulation using spray dried NFC as a filler material. Addition of NFC improved the flow properties of commercially available and widely used microcrystalline cellulose. The main focus of the thesis was to evaluate NFC material for long-term sustained drug release purposes. This goal was successfully achieved by two approaches: 1) by setting up a spray drying method for the production of drug loaded NFC microparticles, and 2) by developing a simple three-step method for the production of drug loaded NFC films with matrix structures. Both systems were able to sustain the drug release over long periods of time ranging from two months for the spray dried microparticles up to over three months for the films. The drug release kinetics were system and drug dependent, reaching, in several cases, zero order drug release kinetics. The final part of the thesis work focused on studying the interactions between small molecular weight drugs, peptides and proteins with the NFC fibers. The purpose of this study was to further clarify and fully understand the mechanisms behind the successful performance of NFC as drug release controlling material. Binding of drugs to NFC due to the electrostatic interactions was observed. This kind of knowledge is beneficial when choosing the proper drug/excipient combination for the formulation process. In conclusion, NFC was shown to be a versatile excipient for the production of pharmaceutical dosage forms, while the comprehensive evaluation of the full potential of NFC in pharmaceutical applications warrants further experiments in the future.Lääkkeenkehityksessä sopivien apuaineiden valinta on ratkaisevan tärkeää. Varsinkin, koska monet uudet terapeuttiset aineet ovat niukkaliukoisia tai muuten vaikeasti annosteltavia. Erityisen vaativaa on biologisten lääkkeiden kuten proteiinien ja peptidien formulointi tehokkaiksi lääkevalmisteiksi. Apuaineet on valittava siten, että lopputuote on helposti valmistettavissa ja vapauttaa lääkettä sovelluskohteen vaatimalla erityisellä nopeudella. Tässä työssä tutkittiin nanokuituista selluloosaa ja sen soveltuvuutta farmaseuttiseksi apuaineeksi. Nanokuituinen selluloosa on uusiutuva, biohajoava, uusi biomateriaali, jota voidaan eristää suurissa määrissä kasviperäisesti massasta. Siitä voidaan valmistaa uusia erittäin huokoisia mutta kestäviä matriiseja, joiden soveltuvuutta lääkeformulaatioissa tutkittiin eri tavoin. Tablettien suorapuristuksessa nanokuituista selluloosaa käytettiin täyteaineena. Ennen käyttöä selluloosa ensin sumukuivattiin ja märkägranuloitiin sopivaksi jauheeksi. Saadut virtausominaisuudet olivat verrannollisia tai jopa parempia kuin kaupallisesti saatavilla olevalla mikrokiteisellä selluloosalla. Työn pääasiallinen tutkimuskohde oli selvittää nanokuituisen selluloosan soveltuvuutta apuaineeksi pitkitetyssä lääkkeenvapautuksessa. Siitä valmistettiin huokoisia mikropartikkeleita sumukuivaamalla sekä lääkkeellä ladattuja kalvoja työn aikana kehitetyllä kolmivaiheisella menetelmällä. Molemmat lähestymistavat onnistuneesti pitkittivät lääkevapautusta; mikropartikkeleista vapautuminen jatkui noin kuukauden ajan ja kalvoista jopa kolmen kuukauden ajan. Vapautumiskinetiikka riippui valmistemuodosta ja käytetystä lääkeaineesta, mutta noudatti monessa tapauksessa nollannen kertaluvun kinetiikkaa. Tarkemmissa tutkimuksissa sähköstaattinen vuorovaikutus osoittautui lääkeaineiden ja selluloosakuitujen pääasialliseksi sitoutumismekanismiksi. Toisaalta nanokuituverkoston todettiin hidastavan jopa pienmolekyylien diffuusiota n. kymmenesosaan vapaasta diffuusiosta. Tällainen perustieto on tärkeää tulevien lääkevalmisteiden suunnittelussa, jotta voidaan valita sopiva apuaine ja sen määrä. Nanokuituinen selluloosa osoittautui joustavaksi ja monipuoliseksi apuaineeksi farmaseuttisten lääkemuotojen tuotannossa. On odotettavaa, että tulevaisuudessa tällä uudelle materiaalille löytyy vielä runsaasti uusia käyttökohteita farmaseuttisissa sovelluksissa

Inhibitory activity of the isoflavone Biochanin A on intracellular bacteria of genus Chlamydia and initial development of a buccal formulation

Peer reviewe

Spray-dried cellulose nanofibers as novel tablet excipient

The purpose of this study was to evaluate the potential of cellulose nanofibers (also referred as microfibrillated cellulose, nanocellulose, nanofibrillated, or nanofibrillar cellulose) as novel tabletting material. For this purpose, physical and mechanical properties of spray-dried cellulose nanofibers (CNF) were examined, and results were compared to those of two commercial grades of microcrystalline cellulose (MCC), Avicel PH101 and Avicel PH102, which are the most commonly and widely used direct compression excipients. Chemically, MCC and CNF are almost identical, but their physical characteristics, like mechanical properties and surface-to-volume ratio, differ remarkably. The novel material was characterized with respect to bulk and tapped as well as true density, moisture content, and flow properties. Tablets made of CNF powder and its mixtures with MCC with or without paracetamol as model compound were produced by direct compression and after wet granulation. The tensile strength of the tablets made in a series of applied pressures was determined, and yield pressure values were calculated from the measurements. With CNF, both wet granulation and direct compression were successful. During tablet compression, CNF particles were less prone to permanent deformation and had less pronounced ductile characteristics. Disintegration and dissolution studies showed slightly faster drug release from direct compression tablets with CNF, while wet granulated systems did not have any significant difference

Supersaturated lipid-based drug delivery systems–exploring impact of lipid composition type and drug properties on supersaturability and physical stability

Objective: The objective of the current study was to systematically investigate the impact of lipid composition on the ability to design supersaturated lipid-based drug delivery systems (sLBDDS) using three model drugs with different physico-chemical properties. Significance: This study expands the list of investigated sLBDDS by using alternative vehicle compositions relative to current literature. Methods & Results: Drug supersaturation was thermally-induced based on previously reported methods and was successfully achieved for celecoxib and cinnarizine. For the novel drug, JNJ-2A, a lower supersaturation potential was observed for the tested LBDDS. For celecoxib and cinnarizine, crystalline precipitate was observed for some sLBDDS upon storage at 25 °C/65%RH, particularly for medium chain sLBDDS (celecoxib) and long chain sLBDDS (cinnarizine). The greater risk of precipitation observed for celecoxib and cinnarizine, particularly at higher apparent degree of supersaturation (aDS) may be related to their higher crystallization tendency as determined by differential scanning calorimetry. Conclusions: In conclusion, the potential for supersaturation in LBDDS, and the risk of precipitation, was found to be highly drug dependent. The apparent degree of supersaturation was considered a major factor impacting the ability to maintain drug supersaturation upon storage

Toward simplified oral lipid-based drug delivery using mono-/di-glycerides as single component excipients

Objective: This study aimed to systematically explore compositional effects for a series of lipid systems, on the in vitro drug solubilization and in vivo bioavailability of three poorly water-soluble drugs with different physico-chemical properties. Significance: While many lipid-based drug products have successfully reached the market, there is still a level of uncertainty on the design guidelines for such drug products with limited understanding on the influence of composition on in vitro and in vivo performance. Methods and Results: Lipid-based drug delivery systems were prepared using either single excipient systems based on partially digested triglycerides (i.e. mono- and/or di-glycerides) or increasingly complex systems by incorporating surfactants and/or triglycerides. These lipid systems were evaluated for both in vitro and in vivo behavior. Results indicated that simple single component long chain lipid systems are more beneficial for the absorption of the weak acid celecoxib and the weak base cinnarizine compared to equivalent single component medium chain lipid systems. Similarly, a two-component system produced by incorporating small amount of hydrophilic surfactant yields similar overall pharmacokinetic effects. The lipid drug delivery systems based on medium chain lipid excipients improved the in vivo exposure of the neutral drug JNJ-2A. The higher in vivo bioavailability of long chain lipid systems compared to medium chain lipid systems was in agreement with in vitro dilution and dispersion studies for celecoxib and cinnarizine. Conclusions: The present study demonstrated the benefits of using mono-/di-glycerides as single component excipients in LBDDS to streamline formulation screening and improve oral bioavailability for the three tested poorly water-soluble drugs