2009

• Dr. Blaesi was accepted to the PhD program in Mechanical Engineering at MIT.

• He started working towards his PhD.

2010

• Dr. Blaesi joined the Novartis-MIT Center for Continuous Manufacturing to conduct his doctoral research.

• He was given the thesis topic of designing a new injection-molding machine for more economical manufacture of pharmaceutical solid dosage forms (tablets).

2012

• Dr. Blaesi and Dr. Saka met for the first time. They connected immediately, and from then on met almost daily for several hours to discuss Dr. Blaesi’s research.

• Dr. Blaesi and Dr. Saka soon concluded that injection molding produces dosage forms with minimally-porous microstructure, which is substantially different from the microstructure of the common powder-based, porous tablets.

Schematic microstructures of (a) particulate and (b) minimally-porous dosage forms. Schematic from A.H. Blaesi, Ph.D. thesis.

• As result, they started to mathematically model dissolution and drug release of minimally-porous solids.

• They concluded that minimally-porous solids generally dissolve by surface erosion. If the thickness of the solid is large, the dissolution time is large, too.

• As a result, a minimally-porous dosage form with the thickness of a conventional tablet may not release drug within 30 minutes of immersing in a dissolution fluid, the most relevant requirement of conventional tablets.

Schematic of the dissolution of a minimally-porous solid. Molecules of the solid dissolve into the dissolution fluid, and are convected away within a concentration boundary layer of thickness, δ_c. As a result, the solid erodes. If the thickness of the solid is large, the erosion (or dissolution) time is long. Schematic from A.H. Blaesi, Ph.D. thesis.

• Excited by this observation, Dr. Blaesi became interested in how the manufacturing process affects the dosage form’s microstructure, and its dissolution (or drug release) rate.

• He left the Novartis-MIT Center for Continous Manufacturing to pursue his doctoral thesis independently on this topic with Dr. Saka.

2013

• Dr. Blaesi and Dr. Saka concluded that dosage forms produced by solidification of a liquid (or melt) should consist of a skeletal structure (or framework) to assure that drug can be released rapidly.

• As a result, foamed (or “cellular”) dosage forms comprising gas-filled cells (voids) surrounded by thin walls of drug and excipient were considered. It was hypothesized that if the cells are open, dissolution fluid would percolate the structure, and the dosage form would dissolve rapidly.



Schematic microstructure of a cellular solid with drug-filled walls and air-filled cells or voids. The drug-filled walls comprise an excipient matrix (gray) and drug particles (black). Because some walls are removed, the cells are connected, or open, allowing dissolution fluid to percolate through upon immersion. Schematic from A.H. Blaesi, Ph.D. thesis.

• It was further hypothesized that such structures could be economically manufactured by introducing a blowing agent in a molding process.

2014

• First patent application was filed on polymeric cellular dosage forms for immediate drug release.

• Dr. Blaesi graduated from MIT and joined the laboratory of the late Dr. Warren M. Zapol at the Massachusetts General Hospital, Harvard Medical School, to work on the production and delivery of nitric oxide to the lungs.

• Nonetheless, Dr. Blaesi and Dr. Saka continued their collaboration.

• To produce and test tablets with skeletal microstructure, Dr. Blaesi set up a small “laboratory” in his studio apartment in Cambridge, USA.

• Polymeric cellular dosage forms were produced by injecting gas bubbles into a melt, and solidifying the foamed melt.

Schematic of the process to produce polymeric cellular dosage forms. Adapted from A.H. Blaesi and Nannaji Saka, Continuous manufacture of polymeric cellular dosage forms, Chem. Eng. J. 2016.

Fabrication of experimental polymeric cellular dosage forms. Image adapted from results published in A.H. Blaesi and Nannaji Saka, Continuous manufacture of polymeric cellular dosage forms, Chem. Eng. J. 2016.

2015

• First paper was published on polymeric cellular dosage forms for immediate drug release.

• It was shown that structures with open cells could be produced if the volume fraction of cells was sufficiently large.

• Such open-cell structures dissolve and release drug rapidly (in just a few minutes).

Scanning electron micrographs of (a) unfoamed (minimally-porous) structure, (b) closed-cell structure, (c) and (d) partially open-cell structure, (e) and (f) open-cell structure. Data from A.H. Blaesi, N. Saka, Melt-processed polymeric cellular dosage forms for immediate drug release, J. Control. Rel. 220 (2015) 397-405.

Disintegration of melt-processed dosage forms in a dissolution fluid: (top) unfoamed and (bottom) φv = 0.55. Data from A.H. Blaesi, N. Saka, Melt-processed polymeric cellular dosage forms for immediate drug release, J. Control. Rel. 220 (2015) 397-405.

Drug amount released versus time after immersing selected cellular dosage forms in a stirred dissolution fluid. Data from A.H. Blaesi, N. Saka, Melt-processed polymeric cellular dosage forms for immediate drug release, J. Control. Rel. 220 (2015) 397-405.

• The process of producing open cells, however, relied on the coalescence of gas bubbles in the melt, which is difficult to control.

• As a result, microstructures comprising other 3-dimensional structural frameworks were considered.

• Fibrous dosage forms with cross-ply structure appeared particularly promising. The inter-fiber space is open at any volume fraction of fibers. Moreover, both the fiber radius and the inter-fiber spacing are precisely controlled.

Microstructure of a fibrous dosage form: (a) isometric view of fiber stacking, (b) top view, and (c) front and side view. Schematic from A.H. Blaesi, N. Saka, 3D-micro-patterned fibrous dosage forms for immediate drug release, Mater. Sci. Eng. C 84 (2018) 218-229.

2016

• As a result, Dr. Blaesi and Dr. Saka developed a new 3D-printing process for depositing drug-containing fibers that were plasticized by either dissolution of excipient in a solvent or by melting on a movable platform.

• This enabled fabrication of tablets with precisely controlled fiber radius and inter-fiber spacing.

• The first tests of the fibrous dosage forms were indeed encouraging. They released drug rapidly, and the manufacturing process was simple, too.

  

  Schematic of wet 3D-micro-patterning process for manufacturing fibrous dosage forms. A mixture of solid drug and solid polymeric excipient particles at a predetermined drug-to-excipient mass ratio is filled in a syringe at point A. By controlled displacement of the piston, the powder mixture is fed through a hopper into an extruder at B. The solid granules are then transported forward from B to C by the rotating screw. At point C a solvent, the other input, is added to the mixture, solvating the excipient and forming a plasticized mass in the extruder. The extruder drives the plasticized mass through a converging die to E, and through a cylindrical nozzle thereafter. The fibrous extrudate is then 3D-micro-patterned to a dosage form at F. Finally, the wet fibrous structure is dried to form a solid fibrous dosage form. Schematic from A.H. Blaesi, N. Saka, Fibrous dosage forms by wet 3D-micro-patterning: Process design, manufacture, and drug release rate, Eur. J. Pharm. Biopharm. 130 (2018) 345-358.

  

  Photograph of the apparatus for continuous manufacture of 3D-micro-patterned fibrous dosage forms by a melt process: (a) motor, (b) syringe pump, (c) hopper, (d) extrusion screw and barrel, (e) heater, (f) infrared lamp, (g) extruder nozzle exit, (h) deposited fiber bed, (i) supply channels for cooling fluid, and (j) x-y-z stage. Image from A.H. Blaesi, N. Saka, 3D-micro-patterned fibrous dosage forms for immediate drug release, Mater. Sci. Eng. C 84 (2018) 218-229.

  

  Photograph of the manufacture of a fibrous dosage form by patterning the fibrous extrudate. Image from A.H. Blaesi, N. Saka, Fibrous dosage forms by wet 3D-micro-patterning: Process design, manufacture, and drug release rate, Eur. J. Pharm. Biopharm. 130 (2018) 345-358.

  

  Scanning electron micrographs of dosage forms: (a) top view and (b) front view of fibrous dosage form with R0/λ0 = 0.14 (φs = 0.22); (c) top view and (d) front view of fibrous dosage form with R0/λ0 = 0.27 (φs = 0.43); (e) top view and (f) front view of fibrous dosage form with R0/λ0 = 0.39 (φs = 0.61), and (g) section of minimally-porous solid. The R0/λ0 and φs values are average quantities derived directly from the SEM images. Images from A.H. Blaesi, N. Saka, 3D-micro-patterned fibrous dosage forms for immediate drug release, Mater. Sci. Eng. C 84 (2018) 218-229.

  

  Fraction of drug dissolved versus time after immersing fibrous and non-porous dosage forms in a stirred dissolution fluid. Data from A.H. Blaesi, N. Saka, 3D-micro-patterned fibrous dosage forms for immediate drug release, Mater. Sci. Eng. C 84 (2018) 218-229.

• Enzian Pharmaceutics was incorporated as a collective society in Switzerland.

• First patent was filed on fibrous dosage forms for immediate drug release.

• Dr. Blaesi left the Massachusetts General Hospital at Harvard Medical School to work solely on independent research with Dr. Saka.

2017

• Enzian Pharmaceutics was incorporated as a C-corporation in Delaware.

• First two papers on fibrous dosage forms for immediate drug release were accepted.

• Moreover, while producing and testing various tablet compositions and microstructures at home, Dr. Blaesi found that some tablets did not dissolve rapidly as all others. Rather, they expanded due to water absorption and formed an expanded viscous gel that released drug slowly.

• Amazed by this “new” behaviour, Dr. Blaesi thought about how such tablets could be used. The unexpanded solid tablet certainly was small enough to be swallowable and pass through the oesophagus into the stomach. But after expansion the expanded viscous gel would perhaps be too large to pass through the pylorus into the small intestine. The idea of using the technology for gastroretentive dosage forms was born.

Images of the top view of an expandable fibrous dosage form at various times after immersing in a dissolution fluid. A.H. Blaesi, N. Saka, Expandable fibrous dosage forms for prolonged drug delivery, Mater. Sci. Eng. C 120 (2021) 110144.

2018

• First patent was filed on expandable fibrous dosage forms.

• The expandable fibrous dosage forms were optimized by including a strengthening excipient in the fibers.

• The strengthening excipient stabilized the expanded viscous gel.

Images of an expandable fibrous dosage form with strengthening excipient after immersing in a dissolution fluid. Data from A.H. Blaesi, N. Saka, Expandable, dual-excipient fibrous dosage forms for prolonged delivery of sparingly-soluble drugs, Int. J. Pharm. 615 (2022) 120396.

2019

• First paper on expandable fibrous dosage forms was accepted.

2020

• First patent on expandable fibrous dosage forms with strengthening excipient was filed.

• Enzian Pharmaceutics was incorporated as a corporation (Aktiengesellschaft) in Switzerland.

• Expandable fibrous dosage forms were further optimized.

• It was shown that the optimized expandable fibrous dosage forms exhibit prolonged gastric residence time in dogs.

Position and shape of an Enzian dosage form after administering to a dog. The images were obtained by biplanar fluoroscopy. They show the abdomen in lateral projection (cranial left, caudal right). Image from A.H. Blaesi, D. Kümmerlen, H. Richter, N. Saka, Mechanical strength and gastric residence time of expandable fibrous dosage forms, Int. J. Pharm. 613 (2022) 120792.

2021

• Prolonged gastric residence by the optimized expandable fibrous dosage forms was demonstrated on pigs.

2022

• The expandable fibrous dosage forms were further optimized to release cancer drugs at a controlled rate.

• The concept was validated on dogs for the first time using a sparingly-soluble tyrosine kinase inhibitor as drug.

2023

• The design, theoretical modeling, and experimental validation of gastroretentive fibrous dosage forms for prolonged delivery of sparingly-soluble tyrosine kinase inhibitors was accepted for publication as a four-paper series.

• Prolonged gastric residence by expandable fibrous dosage forms was demonstrated for the first time on a human.

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