Nanofibrillar cellulose for encapsulation and release of pharmaceuticals

The main role of excipients is to ensure the safety and efficacy of the whole pharmaceutical formulation throughout its shelf-life and administration. Formulation design and development as well as material testing are the key components for successful drug delivery. This is becoming increasingly complicated as new active pharmaceutical ingredients typically have poor solubility and/or bioavailability. Due to this, there is an ever increasing need to explore new excipients and material combinations as innovative formulation solutions are required. Furthermore, modified release formulations are needed to control the release rates and to adjust the desired therapeutic effects, raising even more demand for effective formulations. The main aim of this thesis was to evaluate the performance of plant based materials nanofibrillar cellulose (NFC) and anionic carboxylated nanofibrillar cellulose (ANFC) as pharmaceutical excipients for modified release formulations and bioadhesive films. These materials are widely available from renewable sources; biocompatible with relatively low toxicity combined with high mechanical strength and large surface area available for encapsulation. NFC and ANFC, together with HFBII protein, were used as emulsion stabilizers for encapsulation and release of poorly water-soluble drugs. The synergistic stabilization mechanism achieved with these biopolymers improved emulsions stability with extremely low concentrations. In another study, ANFC hydrogels were evaluated as matrix reservoirs for diffusion controlled drug release. Their rheological and drug release properties were shown to be preserved after freeze-drying and reconstruction. The ANFC hydrogels controlled the release kinetics of small molecular weight drugs moderately, whereas significant control was obtained in the case of large proteins. In a comparative study, three new grades of microcrystalline cellulose (MCC) hydrogels were evaluated for diffusion controlled drug release. MCC matrices efficiently controlled the release of both large and small compounds, indicating great potential for drug release applications in a similar manner to the ANFC hydrogels. Bioadhesive NFC and ANFC based films were prepared by incorporating bioadhesive polymers mucin, pectin and chitosan into the film structure. The bioadhesive properties of the films combined with good mechanical and hydration properties, together with low toxicity makes them a feasible option for buccal drug delivery applications. In conclusion, NFC and ANFC were shown to be versatile excipients applicable for several types of dosage forms. In the future, it is seen that these materials may be used systematically as functional excipients for modified release dosage form.Apuaineiden tärkein tehtävä on varmistaa farmaseuttisen formulaation turvallisuus ja tehokkuus säilytyksestä annosteluun asti. Formulaation suunnittelu ja kehittäminen sekä materiaalien testaus ovat keskeisiä tekijöitä onnistuneessa lääkkeen annostelussa. Uudet farmaseuttiset yhdisteet ovat kuitenkin tyypillisesti hyvin niukkaliukoisia ja/tai niiden biologinen hyötyosuus on huono, mikä hankaloittaa formulointia. Tästä syystä uusia apuaineita ja materiaaliyhdisteitä on tutkittava, jotta löydettäisiin innovatiivisia ratkaisuja formulointiongelmiin. Lisäksi formulaatioilla voidaan säädellä vapautumisnopeutta ja terapeuttisia vaikutuksia, joka entisestään lisää tehokkaiden formulaatioiden kysyntää. Tämän tutkimuksen tavoitteena oli arvioida kasviperäisten materiaalien, nanofibrilloidun selluloosan (NFC) ja anionisen karboksyloidun nanofibrilloidun selluloosan (ANFC) suorituskykyä farmaseuttisina apuaineina säätövalmisteissa ja bioadhesiivisissa kalvoissa. Nämä materiaalit ovat bioyhteensopivia, helposti saatavilla uusiutuvista luonnonlähteistä ja niiden mekaaninen lujuus sekä pinta-ala ovat suuret. Lisäksi NFC ja ANFC eivät ole toksisia, joten niitä voidaan hyödyntää lääkeaineiden kapseloinnissa. HFBII proteiinia käytettiin NFC:n ja ANFC:n kanssa emulsio-stabilisaattoreina niukkaliukoisten lääkeaineiden kapseloinnissa ja vapauttamisessa. Näiden biopolymeerien synergistinen vaikutus tehosti emulsioiden stabiilisuutta jo erittäin alhaisilla pitoisuuksilla. Toisessa tutkimuksessa, ANFC:n vaikutusta arvioitiin lääkeaineiden varastoitumista ja diffundoitumista hydrogeelimatriisissa. ANFC hydrogeeli sääteli pienten molekyylien vapautumiskinetiikkaa kohtuullisesti, kun taas suurten proteiinien vapautumista merkittävästi. Lisäksi kylmäkuivattujen hydrogeelien reologiset ominaisuudet voitiin säilyttää uudelleen hydratoimisen jälkeen. Kolmannessa tutkimuksessa verrattiin kolmea uutta eri mikrokiteistä selluloosalaatua (MCC) ja niiden kykyä säädellä lääkeaineiden vapautumista. MCC matriisien todettiin säätelevän tehokkaasti sekä pienien että suurien molekyylien vapautumista. Näiden tutkimusten perusteella sekä ANFC että uudet MCC:t ovat potentiaalisia materiaaleja säätövalmisteiden formuloinnissa. Lisäksi tässä työssä valmistettiin bioadhesiivisia NFC ja ANFC kalvoja, yhdistämällä niihin bioadhesiivisia polymeerejä (pektiini, musiini ja kitosaani). Bioadhesiivisten kalvojen mekaaniset ominaisuudet, bioyhteensopivuus, bioadhesiivisuus ja hydrataatio-ominaisuudet mahdollistavat niiden käytön bukkaalisina lääkevalmisteina. NFC ja ANFC toimivat erittäin monipuolisina apuaineina useille eri lääkemuodoille. Tulevaisuudessa näitä materiaalija voidaan käyttää systemaattisesti funktionaalisina apuaineina säätövalmisteissa

Casein-poly(acrylic acid) nanoparticles as controlled delivery vehicles

Casein based formulations are promising materials for controlled drug release. Caseins are the major milk proteins, and their biocompatibility, low toxicity and natural metabolism in physiological systems make caseins extremely suitable materials for pharmaceutical formulations. Polyelectrolyte complex nanoparticles can be prepared under very mild conditions, and they are stable in the gastrointestinal tract, which makes them suitable carrier materials for oral delivery and controlled release of peptide and protein drugs. Aim of this work was to synthesize casein-poly(acrylic acid) polyelectrolyte complex nanoparticles in different mass ratios, and to study the release profile of a model compound rhodamine 6G from these nanoparticles. The casein shell of the nanoparticles was crosslinked with two different crosslinkers, because the objective was to study the effect of surface modification on size of nanoparticles as well as on the release profile of the model compound. The goal was to achieve controlled release of the model compound by modifying the thickness and the density of the casein shell structure. Size and size distribution of nanoparticles was studied by dynamic light scattering. Surface charge was studied by electrophoretic mobility measurements. Morphology was characterized with electron microscopy, and the effect of the casein shell thickness on the release of rhodamine 6G was studied with dialysis method. The synthesized nanoparticles had spherical morphology, but the size distribution was wide. The release of rhodamine 6G was slower from the nanoparticles when compared to the release of reference free rhodamine 6G, but the effect of casein shell thickness on the release of loaded rhodamine 6G remained partially unclear. However, it seems possible to achieve controlled release of encapsulated compounds from casein-poly(acrylic acid) nanoparticles with optimal surface modification in the future.Kaseiineihin perustuvat formulaatiot ovat lupaavia materiaaleja lääkeaineiden säädeltyyn vapauttamiseen. Kaseiinit ovat maidon pääproteiineja, ja niiden bioyhteensopivuus, alhainen toksisuus ja luonnollinen metabolia fysiologisissa systeemeissä tekevät kaseiineista erittäin sopivia materiaaleja farmaseuttisiin formulaatioihin. Polyelektrolyytti kompleksi nanopartikkeleita voidaan valmistaa hyvin miedoissa olosuhteissa ja ne ovat stabiileja ruoansulatuskanavassa, jonka vuoksi ne sopivat oraaliseen annosteluun kantajamateriaaleiksi peptidi ja proteiini lääkkeiden säädeltyyn vapautukseen. Työn tarkoituksena oli syntetisoida kaseiini-polyakryylihappo polyelektrolyytti kompleksi nanopartikkeleita eri massasuhteilla, ja tutkia malliaineena toimivan rodamiini 6G:n vapautumisprofiilia näistä nanopartikkeleista. Nanopartikkelien kaseiinikuori ristisilloitettiin kahdella erilaisella ristisilloittajalla, koska haluttiin tutkia pinnan muokkauksen vaikutusta nanopartikkelien kokoon ja malliaineen vapautumisprofiiliin. Tavoitteena oli saavuttaa malliaineen säädelty vapautuminen muokkaamalla kaseiinikuoren paksuutta ja tiiviyttä. Nanopartikkelien kokoa ja kokojakaumaa tutkittiin dynaamisella valonsironnalla. Pinnan varausta tutkittiin nanopartikkelien elektroforeettisen liikkuvuuden mittauksella. Morfologiaa tutkittiin elektronimikroskopialla, ja kaseiinikuoren paksuuden vaikutusta rodamiini 6G:n vapautumiseen tutkittiin dialyysimetodilla. Syntetisoidut nanopartikkelit olivat muodoltaan pyöreitä, mutta kokojakauma oli suuri. Rodamiini 6G:n vapautuminen nanopartikkeleista oli hitaampaa kuin referenssinä käytetyn vapaan rodamiini 6G:n vapautuminen, mutta kaseiinikuoren paksuuden vaikutus nanopartikkeleihin ladatun rodamiini 6G:n vapautumiseen jäi osittain epäselväksi. Optimaalisella pinnan muokkauksella lienee kuitenkin mahdollista saavuttaa säädelty vapautumisprofiili kaseiini-polyakryylihappo nanopartikkeleihin ladatuille yhdisteille tulevaisuudessa

Hydrophobin-nanofibrillated cellulose stabilized emulsions for encapsulation and release of BCS class II drugs

The purpose of this study was to construct biopolymer-based oil-in-water emulsion formulations for encapsulation and release of poorly water soluble model compounds naproxen and ibuprofen. Class II hydrophobin protein HFBII from Trichoderma reesei was used as a surfactant to stabilize the oil/water interfaces of the emulsion droplets in the continuous aqueous phase. Nanofibrillated cellulose (NFC) was used as a viscosity modifier to further stabilize the emulsions and encapsulate protein coated oil droplets in NFC fiber network. The potential of both native and oxidized NFC were studied for this purpose. Various emulsion formulations were prepared and the abilities of different formulations to control the drug release rate of naproxen and ibuprofen, used as model compounds, were evaluated. The optimal formulation for sustained drug release consisted of 0.01% of drug, 0.1% HFBII, 0.15% oxidized NFC, 10% soybean oil and 90% water phase. By comparison, the use of native NFC in combination with HFBII resulted in an immediate drug release for both of the compounds. The results indicate that these NFC originated biopolymers are suitable for pharmaceutical emulsion formulations. The native and oxidized NFC grades can be used as emulsion stabilizers in sustained and immediate drug release applications. Furthermore, stabilization of the emulsions was achieved with low concentrations of both HFBII and NFC, which may be an advantage when compared to surfactant concentrations of conventional excipients traditionally used in pharmaceutical emulsion formulations. (C) 2017 Elsevier B.V. All rights reserved.Peer reviewe

Effects of nanofibrillated cellulose hydrogels on adipose tissue extract and hepatocellular carcinoma cell spheroids in freeze-drying

The aim of this study was to evaluate the effects of two nanofibrillated cellulose (NFC) hydrogels on two human derivatives during freeze-drying. Native NFC hydrogel is a suitable platform to culture 3D cell spheroids and a hydrogel processed further, called anionic NFC (ANFC) hydrogel, is an excellent platform for controlled release of proteins. Moreover, it has been shown to be compatible with freeze-drying when correct lyoprotectants are implemented. Freeze-drying is a method, where substance is first frozen, and then vacuum dried trough sublimation of water in order to achieve dry matter without the loss of the original three-dimensional structures. The first chosen human derivative was adipose tissue extract (ATE) which is a cell-free growth factor-rich preparation capable of promoting growth of regenerative cells. The release of growth factors from the freeze-dried mixture of ATE and ANFC was compared to that of non-freeze-dried control mixtures. The release profiles remained at the same level after freeze-drying. The second derivative was hepatocellular carcinoma (HepG2) cell spheroids which were evaluated before and after freeze-drying. The 3D structure of the HepG2 cell spheroids was preserved and the spheroids retained 18% of their metabolic activity after rehydration. However, the freeze-dried and rehydrated HepG2 cell spheroids did not proliferate and the cell membrane was damaged by fusion and formation of crystals.Peer reviewe

Multisensorisen huoneen rakentaminen erityistä tukea tarvitseville lapsille ja nuorille

Palokas, Heli & Paukkonen, Mari. Multisensorisen huoneen rakentaminen erityistä tukea tarvitseville lapsille ja nuorille. Kevät 2018, 53 s., 21 liitettä. Diakonia-ammattikorkeakoulu, hoitotyön koulutusohjelma, sairaanhoitaja (AMK). Tämän opinnäytetyön tarkoituksena oli rakentaa multisensorinen huone erityistä tukea tarvitsevien lasten ja nuorten avohuollon yksikköön. Tavoitteena oli tarjota vaihtoehtoinen tai muita menetelmiä tukeva hoitomenetelmä kehitysvammaisten lasten ja nuorten hoitotyössä. Toiminnallisessa opinnäytetyössä tutkimme näyttöön perustuvaa tietoa, jonka avulla pyrimme argumentoimaan menetelmän hyötyjä kohderyhmämme asiakkaille. Tuomalla uusia näkökulmia hoitotyöhön toivomme lisäävämme vaihtoehtoisten hoitomenetelmien näkyvyyttä sekä kehittävämme hoidon laadukkuutta. Rakensimme multisensorisen huoneen Juniorikodin tiloihin, joka on Rinnekoti-Säätiön erityistä tukea tarvitsevien lasten ja nuorten avohuollon yksikkö. Opin-näytetyön teoriaosassa kerrotaan yhteistyökumppanista, autismikirjosta, huoneen rakentamisen prosessista sekä menetelmää käsittelevistä tutkimuksista ja koetuista hyödyistä. Opinnäytetyö on tehty tuottamisprosessia noudattaen, ja sen produktio valmistui syksyllä 2017. Rakensimme multisensorisen huoneen, jonka lopputulos on esteettinen ja ehjä kokonaisuus, sekä lisä Juniorikodin toiminnassa. Prosessilla saavutettiin opinnäytetyön tavoite, joka oli luoda erityistä tukea tarvitseville lapsille ympäristö, josta he voivat hyötyä sekä saada voimaannuttavia kokemuksia.Palokas, Heli & Paukkonen, Mari. Building a Multi-Sensory room to children and adolescents with special needs. Spring 2018, 53 p., 21 appendices. Language: Finnish. Diaconia University of Applied Sciences, Degree Programme in Nursing, Option in Nursing, Registered Nurse. The purpose of this study was to build a Multi-Sensory room for children and adolescents with special needs in a non-institutional healthcare unit. The aim was to provide an alternative or a supportive treatment method for children and ado-lescents with intellectual disabilities. In this functional thesis, evidence-based in-formation is provided to argue for benefits of the method in the healthcare of the target audience. A Multi-Sensory room was built in the premises of Juniorikoti, which is a non-institutional healthcare unit for children and adolescents with special needs founded by the Rinnekoti Foundation. The thesis addresses datum about our co-operation partner as well as autism spectrum disorders, the process of building a Multi-Sensory room and the methodological studies and proven benefits. The thesis was written in accordance with the production process and the product was completed in the autumn of 2017. In the building of the multisensory room, aesthetics and intact design, as well the functions of Juniorikoti were taken into consideration. The process reached the goal, which was to create an environ-ment for children with special needs, from which they could benefit and gain em-powering experiences. By introducing new perspectives in non-institutional healthcare, we hope to increase the visibility of alternative treatment methods and to improve the quality of nursing. Keywords: Non-institutional healthcare, Snoezelen, Multi-Sensory, sensory room, autism spectrum disorder

Entangled and colloidally stable microcrystalline cellulose matrices in controlled drug release

Drug release from a new type of matrix material consisting of partially fibrillated microcrystalline cellulose was investigated. A mechanical treatment of novel AaltoCell T cellulose microcrystals caused partial opening of the nanofibrillary structure of the cellulose particles and entanglement of individual particles led into formation of an elastic network of microcrystalline cellulose. The rheological properties of the stable hydrogel-like materials were characterised by shear rheometry. Model compounds metronidazole and lysozyme were successfully employed in drug release experiments carried out by delignified (bleached) and lignin-containing matrices. The viscosity as well as the lignin-content played a role in the release dynamics of the drugs. Microcrystalline AaltoCell T was proven as high-performing material for diffusion controlled release of the chosen model compounds and can be seen as a safe and economical alternative for novel matrix materials such as nanocellulose or cellulose derivatives.Peer reviewe

Nanofibrillar cellulose hydrogels and reconstructed hydrogels as matrices for controlled drug release

Concentrated 3% and 6.5% anionic nanofibrillar cellulose (ANFC) hydrogels were introduced as matrix reservoirs for controlled delivery applications of small molecules and proteins. A further aim was to study how the freeze-drying and subsequent rehydration of ANFC hydrogel affects the rheological properties and drug release of selected model compounds from the reconstructed hydrogels. It was demonstrated that the 3% and 6.5% ANFC hydrogels can be freeze-dried with suitable excipients into highly porous aerogel structures and redispersed back into the hydrogel form without significant change in the rheological properties. Freeze-drying did not affect the drug release properties from redispersed ANFC hydrogels, indicating that these systems could be stored in the dry form and only redispersed when needed. For large molecules, the diffusion coefficients were significantly smaller when higher ANFC fiber content was used, indicating that the amount of ANFC fibers in the hydrogel can be used to control the release rate. The release of small molecules was controlled with the ANFC fiber content only to a moderate extent. The results indicate that ANFC hydrogel can be used for controlled delivery of several types of molecules and that the hydrogel can be successfully freeze-dried and redispersed.Peer reviewe

Pectin and Mucin Enhance the Bioadhesion of Drug Loaded Nanofibrillated Cellulose Films

Purpose Bioadhesion is an important property of biological membranes, that can be utilized in pharmaceutical and biomedical applications. In this study, we have fabricated mucoadhesive drug releasing films with bio-based, non-toxic and biodegradable polymers that do not require chemical modifications. Methods Nanofibrillar cellulose and anionic type nanofibrillar cellulose were used as film forming materials with known mucoadhesive components mucin, pectin and chitosan as functional bioadhesion enhancers. Different polymer combinations were investigated to study the adhesiveness, solid state characteristics, film morphology, swelling, mechanical properties, drug release with the model compound metronidazole and in vitro cytotoxicity using TR146 cells to model buccal epithelium. Results SEM revealed lamellar structures within the films, which had a thickness ranging 40-240 mu m depending on the film polymer composition. All bioadhesive components were non-toxic and showed high adhesiveness. Rapid drug release was observed, as 60-80% of the total amount of metronidazole was released in 30 min depending on the film formulation. Conclusions The liquid molding used was a straightforward and simple method to produce drug releasing highly mucoadhesive films, which could be utilized in treating local oral diseases, such as periodontitis. All materials used were natural biodegradable polymers from renewable sources, which are generally regarded as safe.Peer reviewe