TFF tech­nology for pul­monary drugs

Inhal­able med­ica­tion is essen­tial with lung dis­eases. But not every active ingre­dient can be processed into a res­pirable med­ica­tion. Now, a new thin film freezing (TFF) process devel­oped by the Uni­ver­sity of Texas at Austin can tame even dif­fi­cult sub­stances. The US com­pa­nies TFF Phar­ma­ceu­ti­cals and Experic are col­lab­o­rating on new powder for­mu­la­tions and processes for encap­su­lating TFF inhal­able powders.

Anyone who has ever tried to pour the con­tents of a saucepan into a narrow bottle opening will have a rough idea of the effi­ciency of oral delivery of many pul­monary drugs. Fre­quently, only around ten per­cent of the active ingre­di­ents reach their target. One of the rea­sons for this is the poor sol­u­bility of many drugs in water. This makes it dif­fi­cult for the body to absorb the active ingre­di­ents, reducing effi­ciency. Delivery through dry powder inhalers is much more effi­cient and tar­geted, explains John Koleng, Vice Pres­i­dent of Product Devel­op­ment and Man­u­fac­turing at TFF Phar­ma­ceu­ti­cals. “The patient takes a deep breath, and the tiny par­ti­cles of the engi­neered powder con­taining the active sub­stance directly reach the deep pul­monary tis­sues without major loss. This only works with fine pow­ders whose par­ti­cles are aero­dy­nam­i­cally smaller than about five microm­e­ters. This rules out many highly effec­tive sub­stances from the start.” Researchers at the Uni­ver­sity of Texas at Austin have suc­ceeded in iden­ti­fying a solu­tion to this problem. They devel­oped a tech­nology which con­verts a coarse powder into a light and res­pirable one. TFF Phar­ma­ceu­ti­cals has secured a license for the patented thin film freezing process technology.

“With TFF tech­nology, a coarse powder can be con­verted into a light and res­pirable one.”John J. Koleng, Ph.D., R.Ph.
Vice Pres­i­dent of Product Devel­op­ment and Manufacturing 
at TFF Pharmaceuticals

Frozen and conditioned

“Thin film freezing is a par­ticle engi­neering process,” explains Koleng. “We dis­solve the drug in a sol­vent and then drop the liquid onto a stain­less-steel drum cooled with liquid nitrogen, where the droplets are rapidly frozen. The frozen product is then freeze-dried to remove the sol­vent thus yielding the TFF powder.” At the end of the process, the orig­i­nally coarse and com­pact powder has been con­verted to brittle matrix par­ti­cles that are highly porous, have a large sur­face area and a low bulk den­sity. After con­di­tioning, the result is a fine powder. This way, a dry powder inhaler is used to deliver up to 75 % of the active ingre­dient to the lungs where it is intended to act.

Since the begin­ning of 2019, the US com­pany Experic has been offering con­tract ser­vices for the man­u­fac­turing, pack­aging, labeling and global logis­tics of clin­ical trial mate­rials and spe­cialty com­mer­cial sup­plies. Experic is focused on the small, mid­size, and spe­cialty phar­ma­ceu­tical customer.

Lever­aging common potential

TFF Phar­ma­ceu­ti­cals works closely with Harro Höfliger and its partner, Experic, in eval­u­ating TFF man­u­fac­tured pow­ders and their sub­se­quent encap­su­la­tion for use with a dry powder inhaler. Experic is a con­tract man­u­fac­turing and devel­op­ment orga­ni­za­tion that man­u­fac­tures and pack­ages clin­ical trial mate­rials and spe­cialty sup­plies pri­marily for small, medium and spe­cialty phar­ma­ceu­tical cus­tomers. ­Justin ­Lacombe, Chief ­Sci­en­tific Officer at Experic, explains: “As a CDMO partner, we man­u­fac­ture pow­ders for TFF ­Phar­ma­ceu­ti­cals and carry out tests with our Harro ­Höfliger filling machines. In this way we can test for­mu­la­tions for com­pat­i­bility with the encap­su­la­tion machines at an early stage of devel­op­ment. This sup­ports early suc­cess with ini­tial clin­ical man­u­fac­turing and facil­i­tates feed­back that enables suc­cessful scale-up.”

“As a CDMO partner, we man­u­fac­ture TFF pow­ders and carry out filling tests with our Harro Höfliger machines.”Justin Lacombe, Ph.D.
Chief Sci­en­tific Officer at Experic

Infi­nite possibilities

The thin film freezing par­ticle engi­neering process has a lot of poten­tial, and TFF Phar­ma­ceu­ti­cals and ­Experic are working together to develop new appli­ca­tions. One of these is TFF Phar­ma­ceu­ti­cals’ inhaled tacrolimus product, cur­rently in Phase 2 trials. Tacrolimus is a nat­ural com­pound that acts as an immuno­sup­pres­sant. Inhaled tacrolimus is being studied as an alter­na­tive to oral tacrolimus for lung trans­plant patients where direct to lung delivery could poten­tially main­tain the effi­cacy of the oral therapy while reducing side effects and drug-drug inter­ac­tions. How­ever, TFF devel­opers are not just looking at repur­posing existing drugs.

Koleng explains that around one third of the most impor­tant drugs avail­able world­wide are dif­fi­cult to dis­solve in water and that thin film freezing tech­nology is suit­able for many of them, as well as for com­bi­na­tion ther­a­pies and the growing seg­ment of bio­logics. “Inhal­able pow­ders are the future,” he says, adding: “They can be accu­rately mea­sured, don’t require cold chain storage and dis­tri­b­u­tion, and are sig­nif­i­cantly easier to ­handle than sterile syringes. We can give them a boost with TFF technology.”

How thin film freezing works:

1. For­mu­la­tion:

The thin film freezing process involves first com­bining a drug or drugs in a liquid car­rier system, which can include agents designed to pro­mote dis­per­sion and avoid aggre­ga­tion, as well as excip­i­ents to pro­mote delivery to the target site.

2. Freezing:

Con­trolled freezing the liquid mate­rial on the sur­face of a cryo­genic drum results in brittle matrix par­ti­cles: highly porous, large sur­face area, low-den­sity particles.

3. Drying:

The frozen sol­vent is then removed by sub­li­ma­tion to yield a dry powder mate­rial that can be aerosolized to facil­i­tate delivery to the lungs, nose, eyes and top­i­cally through the skin.

4. Fin­ishing:

The brittle matrix par­ti­cles are then fur­ther processed to facil­i­tate cre­ation of the final dosage form for the tar­geted route of administration.

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Photos: Experic, Avector/Adobe Stock