Ultrasound-assisted surface engineering of pharmaceutical powders

Effective processing of powdered particles can facilitate powder handling and result in better drug product performance, which is of great importance in the pharmaceutical industry where the majority of active pharmaceutical ingredients (APIs) are delivered as solid dosage forms. The purpose of this work was to develop a new ultrasound-assisted method for particle surface modification and thin-coating of pharmaceutical powders. The ultrasound was used to produce an aqueous mist with or without a coating agent. By using the proposed technique, it was possible to decrease the interparticular interactions and improve rheological properties of poorly-flowing water-soluble powders by aqueous smoothing of the rough surfaces of irregular particles. In turn, hydrophilic polymer thin-coating of a hydrophobic substance diminished the triboelectrostatic charge transfer and improved the flowability of highly cohesive powder. To determine the coating efficiency of the technique, the bioactive molecule β-galactosidase was layered onto the surface of powdered lactose particles. Enzyme-treated materials were analysed by assaying the quantity of the reaction product generated during enzymatic cleavage of the milk sugar. A near-linear increase in the thickness of the drug layer was obtained during progressive treatment. Using the enzyme coating procedure, it was confirmed that the ultrasound-assisted technique is suitable for processing labile protein materials. In addition, this pre-treatment of milk sugar could be used to improve utilization of lactose-containing formulations for populations suffering from severe lactose intolerance. Furthermore, the applicability of the thin-coating technique for improving homogeneity of low-dose solid dosage forms was shown. The carrier particles coated with API gave rise to uniform distribution of the drug within the powder. The mixture remained homogeneous during further tabletting, whereas the reference physical powder mixture was subject to segregation. In conclusion, ultrasound-assisted surface engineering of pharmaceutical powders can be effective technology for improving formulation and performance of solid dosage forms such as dry powder inhalers (DPI) and direct compression products.Jauhepartikkelien pintakäsittelyn avulla voidaan parantaa lääkevalmistuksessa käytettävien kiinteiden lääke- ja apuaineiden käsiteltävyyttä, prosessoitavuutta ja vaikutusta lopputuottessa/ elimistössä. Tämän väitöskirjatutkimuksen tavoitteena oli kehittää uusi ultraääntä hyväksikäyttävä nesteen sumutusmenetelmä, jonka avulla olisi mahdollisuutta muokata/pinnoittaa erilaisia jauhemaisia lääke- ja apuaineita siten, että niiden jatkoprosessoitavuus ja viime kädessä myös lääkevalmisteen laatu paranisivat. Tutkimuksessa ultraääntä on käytetty muodostamaan vesi-höyrysumua joko päällystysaineen kanssa tai ilman sitä. Väitöskirjatyössä kehitetyn uuden jauheenkäsittelytekniikan avulla oli mahdollista muokata huonosti valuvien ja karkeapintaisten jauhepartikkelien (mm. tiamiinihydrokloridi ja laktoosi) pintoja suoraan veden avulla ja vähentää niiden välistä kontaktipinta-alaa. Tämä puolestaan vähensi jauhepartikkelien välistä vuorovaikutusta (koheesiota) ja paransi ko. jauhemassan valuvuutta. Lisäksi menetelmän avulla voitiin päällystää suoraan hienojakoista lääkeainetta (ibuprofeenia) hydroxypropyylimetyylselluloosa (HPMC) -polymeerin muodostamalla ohuella kalvolla. Tuloksena lääkeaineen jauhepartikkeleiden valuvuus parani. Yllä mainitulla ultraääniavusteisella sumutustekniikalla onnistuttiin pinnoittamaan myös laktoosijauhetta maitosokeria pilkkovalla bioaktiivisella β-galaktosidaasientsyymillä. Laktoosin nanopäällystyminen ja tutkitun ultraääniavusteisen tekniikan tehokkuus selvitettiin ensyymi-tuotteen konsentraatiomääritysten avulla. Ensyymipinnoituksella vahvistettiin, että työssä kehitetty menetelmä sopii myös labiilin proteinimateriaalin käsittelemiseksi. Lisäksi tämän tyyppisellä maitosokerin esikäsittelyllä voitaisiin lisätä laktoosia sisältävien lääkevalmisteiden käyttöä laktoosi-intoleransista kärsivillä ihmisillä. Ultraääniavusteista tekniikkaa käytettiin myös lääkeapuaineen jauhepartikkeleiden päällystämi-seen parantamaan pieniannoksisten tablettivalmisteiden annostarkkuutta. Tabletit valmistettiin mikrokiteisesta selluloosasta, jonka partikkelit oli ennen puristusprosessia päällystetty malliaineen (riboflaviininatriumfosfaatti) vesiliuoksella. Käsittelyn tuloksena tablettien paino ja annoksen jakelutarkkuus oli selkeästi parempi kuin fysikaalisesta binääriseoksesta puristetun referenssi-tabletin vastaavat laatuominaisuudet. Yhteenvetona jauheiden pintojen hallittu muokkaus ultraääniavusteisesti antaa lupaavan mahdollisuuden jatkossa parantaa kiinteiden lääkemuotojen (kuten esimerkiksi jauheinhalaatio-valmisteiden ja suorapuristeisten tablettien) prosessoitavuutta ja vaikutusta elimistössä

Impact of Drug Load and Polymer Molecular Weight on the 3D Microstructure of Printed Tablets

This study investigates the influence of drug load and polymer molecular weight on the structure of tablets three-dimensionally (3D) printed from the binary mixture of prednisolone and hydroxypropyl methylcellulose (HPMC). Three different HPMC grades, (AFFINISOLTM HPMC HME 15LV, 90 Da (HPMC 15LV); 100LV, 180 Da (HPMC 100LV); 4M, 500 Da (HPMC 4M)), which are suitable for hot-melt extrusion (HME), were used in this study. HME was used to fabricate feedstock material, i.e., filaments, at the lowest possible extrusion temperature. Filaments of the three HPMC grades were prepared to contain 2.5, 5, 10 and 20 % (w/w) prednisolone. The thermal degradation of the filaments was studied with thermogravimetric analysis, while solid-state properties of the drug-loaded filaments were assessed with the use of X-ray powder diffraction. Prednisolone in the freshly extruded filaments was determined to be amorphous for drug loads up to 10%. It remained physically stable for at least 6 months of storage, except for the filament containing 10% drug with HPMC 15LV, where recrystallization of prednisolone was detected. Fused deposition modeling was utilized to print honeycomb-shaped tablets from the HME filaments of HPMC 15LV and 100LV. The structural characteristics of the tablets were evaluated using X-ray microcomputed tomography, specifically porosity and size of structural elements were investigated. The tablets printed from HPMC 15LV possessed in general lower total porosity and pores of smaller size than tablets printed from the HPMC 100LV. The studied drug loads were shown to have minor effect on the total porosity of the tablets, though the lower the drug load was, the higher the variance of porosity along the height of the tablet was observed. It was found that tablets printed with HPMC 15LV showed higher structural similarity with the virtually designed model than tablets printed from HPMC 100LV. These findings highlight the relevance of the drug load and polymer molecular weight on the microstructure and structural properties of 3D printed tablets

Rapid interferometric imaging of printed drug laden multilayer structures

Peer reviewe

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

Peer reviewe

Data-enriched edible pharmaceuticals (DEEPs) : Patients' preferences, perceptions, and acceptability of new dosage forms and their digital aspects – An interview study

Background In the field of pharmaceuticals, there is a shift away from the traditional “one-size-fits-all” concept to a more patient-centered one. A potential approach to obtain personalized medicine is with printed Data-Enriched Edible Pharmaceuticals (DEEPs). DEEPs that are printed in the pattern of QR codes contain both the patient-tailored dose and data that can be used to give patients personalized drug information and combat counterfeit medicines. Objectives The study aims to explore patients' preferences, perceptions, and acceptability of DEEPs, and the digital aspects of them. Methods Thirteen participants, living in Denmark, were interviewed twice using a semi-structured approach. Interviews were conducted face-to-face or via video calls. The interviews were transcribed, translated, and analyzed using thematic coding analysis. Results The participants found it useful to participate in the design of their own medicine. The orodispersible nature of DEEPs and the possibility to select color, embedded images, flavors, and physical dimensions of DEEPs were considered beneficial for patients' adherence. Patients' personal preferences, convenience, and aesthetics were the main drivers for their favored design of DEEPs. The acceptability of digital healthcare in connection to DEEPs was found to be related to the participants' level of digital literacy. Conclusions The participants generally had a positive attitude towards DEEPs and the digital aspects of them. However, to accept digital healthcare in connection to DEEPs, it should be adaptable and easy to use for everyone. The combination of digital healthcare and on-demand fabricated DEEPs could potentially contribute to higher patient adherence and safety in the future