Op­ti­miz­ing Oral Drug De­liv­ery us­ing Zy­dis® Oral­ly Dis­in­te­grat­ing Tablet Tech­nol­o­gy to Ad­dress Pa­tient Chal­lenges

KEY POINTS

• Pa­tients pre­fer oral dos­ing, but swal­low­ing tablets can be a chal­lenge for many pa­tients.
• The Zy­dis® oral­ly dis­in­te­grat­ing tablet (ODT) plat­form ad­dress­es chal­lenges as­so­ci­at­ed with oral dos­ing, ex­pand­ing ben­e­fits for pa­tients and op­tions for health­care providers.
• A strong growth tra­jec­to­ry is ex­pect­ed for ODTs giv­en ther­a­peu­tic in­no­va­tion and con­tin­ued tech­nol­o­gy de­vel­op­ment.

Many pa­tients pre­fer con­ven­tion­al tablets for the ad­min­is­tra­tion of med­ica­tions, but some geri­atric and pe­di­atric pa­tients and those with al­tered men­tal sta­tus and phys­i­cal im­pair­ments find swal­low­ing tablets to be dif­fi­cult. Oral­ly dis­in­te­grat­ing tablets (ODTs), which dis­solve com­plete­ly with­out chew­ing or suck­ing, of­fer a pa­tient-friend­ly dosage form for the ad­min­is­tra­tion of small-mol­e­cule drugs, pep­tides and pro­teins. With the po­ten­tial for mul­ti­ple sites of drug ab­sorp­tion, of­ten faster on­set ac­tion for the ac­tive phar­ma­ceu­ti­cal in­gre­di­ent (API), and po­ten­tial­ly greater bioavail­abil­i­ty, ODTs are an at­trac­tive op­tion for drug de­vel­op­ers con­sid­er­ing first-to-mar­ket for­mu­la­tions or prod­uct line ex­ten­sions of ex­ist­ing drugs with com­pat­i­ble API. In this re­port, we look at how in­no­va­tion in the in­dus­try-lead­ing Zy­dis ODT plat­form is ex­pand­ing oral for­mu­la­tion op­tions and bring­ing ben­e­fits to pa­tients.

ODT TECH­NOL­O­GY OF­FERS MUL­TI­PLE PA­TIENT BEN­E­FITS

ODTs of­fer sev­er­al key ad­van­tages over oth­er dosage forms. Their rapid dis­in­te­gra­tion im­proves the oral drug de­liv­ery ex­pe­ri­ence for many pa­tients from young chil­dren to se­niors to pa­tients suf­fer­ing from dys­pha­gia.

Zy­dis ODT for­mu­la­tions are ide­al for:

• Acute con­di­tions where treat­ment is re­quired “on the go”
• Pa­tients ex­pe­ri­enc­ing nau­sea and vom­it­ing
• Pa­tients with liq­uids re­stric­tions
• Pe­di­atric pa­tients who have not learned to swal­low tra­di­tion­al tablets

Ad­di­tion­al­ly, the in­stant dis­per­sion of the tablets in the mouth pre­vents pa­tient “cheek­ing”—hold­ing tablets in the cheek for lat­er dis­pos­al or redi­rec­tion—of­fer­ing par­tic­u­lar ben­e­fit where com­pli­ance may be re­sist­ed, such as psy­chi­atric pa­tients or ad­dic­tion treat­ments ad­min­is­tered un­der su­per­vi­sion. “Every time I in­tro­duce some­one to Zy­dis ODT, they are blown away by the speed with which it dis­pers­es—con­sis­tent­ly less than three sec­onds,” said Ralph Gos­den, Head of Prod­uct De­vel­op­ment at Catal­ent, the ex­perts in Zy­dis tech­nol­o­gy.

Such ease of use, com­bined with im­proved mouth­feel, and taste mask­ing of bit­ter APIs can help to make it eas­i­er for pa­tients to stick with their dos­ing reg­i­men. And stronger pa­tient com­pli­ance may ul­ti­mate­ly trans­late to im­proved clin­i­cal out­comes—a win for every­one.

ZY­DIS FUNC­TION­AL­I­TY

Used in the first com­mer­cial ODT to re­ceive U.S. FDA ap­proval, the Zy­dis ODT plat­form has a long his­to­ry of in­no­va­tion. This fam­i­ly of pro­pri­etary tech­nolo­gies of­fers a range of ca­pa­bil­i­ties, with three tar­get­ed for­mu­la­tions. Zy­dis ODT tech­nol­o­gy can be uti­lized for the de­liv­ery of small mol­e­cule APIs, pep­tides and al­ler­gens. The Zy­dis ODT is a unique freeze-dried dosage form that dis­pers­es with­in three sec­onds, with­out the need for wa­ter, and is ide­al for the de­liv­ery of small mol­e­cules whether tar­get­ing pre-gas­tric or gas­troin­testi­nal ab­sorp­tion. Zy­dis Ul­tra tech­nol­o­gy of­fers en­hanced taste-mask­ing ca­pa­bil­i­ties, in­creased drug load­ing and the po­ten­tial for func­tion­al coat­ing, while main­tain­ing the fast dis­per­sion char­ac­ter­is­tics of Zy­dis ODT.

Zy­dis Bio tech­nol­o­gy al­lows for the buc­cal or sub-lin­gual (oro­mu­cos­al) de­liv­ery of large-mol­e­cule pep­tides and al­ler­gens. It is al­so unique­ly po­si­tioned as a vac­cine dosage form, as the man­u­fac­tur­ing process pre­serves vac­cine sta­bil­i­ty and al­lows for long-term stor­age and shelf life. Zy­dis ODT rapid dis­in­te­gra­tion and API re­lease are ide­al for sub­lin­gual vac­cine ap­pli­ca­tions. To­geth­er, these at­trib­ut­es of­fer many ad­van­tages for the po­ten­tial oral de­liv­ery of vac­cines, such as ease of de­liv­ery and cost—im­por­tant con­sid­er­a­tions for those fo­cused on pa­tient safe­ty, pub­lic health and sup­ply chain is­sues.

With Zy­dis ODT and Zy­dis Bio, there ex­ists the po­ten­tial for pre-gas­tric ab­sorp­tion, where the drug is ab­sorbed oro­mu­cos­al­ly in­to sys­temic cir­cu­la­tion. This chan­nel avoids first pass me­tab­o­lism and gas­troin­testi­nal degra­da­tion, there­by po­ten­tial­ly trans­lat­ing to low­er dos­es and a re­duc­tion in the for­ma­tion of metabo­lites and im­prov­ing a drug’s safe­ty pro­file. Catal­ent is cur­rent­ly en­gaged in a pro­gram with As­ton Uni­ver­si­ty, U.K., to cre­ate a pre­dic­tive tool to de­ter­mine op­ti­mum lev­els of ab­sorp­tion en­hancer to boost pre-gas­tric ab­sorp­tion.

IS ODT THE RIGHT FIT?

ODTs are ap­pro­pri­ate for a wide range of ther­a­peu­tic ar­eas, from al­ler­gy and gas­troin­testi­nal treat­ments to an­ti-psy­chot­ic med­i­cines and an­ti-de­pres­sants. New prod­ucts can ben­e­fit from the out­set, while ex­ist­ing prod­ucts can be re­for­mu­lat­ed as an ODT for line ex­ten­sions and dif­fer­en­ti­a­tion for a val­ued brand. Fea­si­bil­i­ty eval­u­a­tions are an im­por­tant first step for de­vel­op­ers con­sid­er­ing ODTs, as the API must be suit­able for oral ad­min­is­tra­tion. Some class­es of drugs may be re­strict­ed from ODT de­vel­op­ment due to their re­quire­ment for spe­cif­ic han­dling fa­cil­i­ties. Oth­er­wise, the suit­abil­i­ty of an API for ODT for­mu­la­tion re­lates to its physic­o­chem­i­cal prop­er­ties and tar­get prod­uct pro­file.

The Zy­dis re­search and de­vel­op­ment team ful­ly char­ac­ter­izes each API and as­so­ci­at­ed Zy­dis for­mu­la­tions through­out the de­vel­op­ment process to mit­i­gate po­ten­tial pit­falls and pro­vide a ro­bust da­ta pack­age in sup­port of reg­u­la­to­ry fil­ings. This process in­cludes:

• Con­sid­er­a­tion of the rel­e­vant API char­ac­ter­is­tics iden­ti­fied dur­ing the tech­ni­cal eval­u­a­tion of im­por­tant pre­for­mu­la­tion da­ta, sol­u­bil­i­ty and aque­ous sta­bil­i­ty fac­tors
• Con­sid­er­a­tion of dose, lipophilic­i­ty, and mol­e­c­u­lar weight, es­pe­cial­ly when tar­get­ing oro­mu­cos­al drug ab­sorp­tion
• Cre­ation of a range of pro­to­type for­mu­la­tions pre­pared un­der dif­fer­ent pro­cess­ing con­di­tions
• Use of an­a­lyt­i­cal tech­niques to de­ter­mine the com­pat­i­bil­i­ty of a can­di­date API with the Zy­dis tech­nol­o­gy
• Short-term ac­cel­er­at­ed phys­i­cal sta­bil­i­ty stud­ies

Cer­tain med­ica­tions have char­ac­ter­is­tics that are chal­leng­ing for ODT tech­nol­o­gy. For ex­am­ple, high-dose for­mu­la­tions and ex­treme­ly bit­ter API’s have pre­vi­ous­ly pre­sent­ed dif­fi­cul­ties. Zy­dis Ul­tra helps to ad­dress these chal­lenges by al­low­ing for im­proved taste mask­ing so that, through a spe­cial­ized coat­ing process, a high­er amount of API can be in­cor­po­rat­ed in­to the rapid­ly dis­pers­ing tablet.

THE ZY­DIS MAN­U­FAC­TUR­ING PROCESS

For those APIs de­ter­mined to be com­pat­i­ble with Zy­dis ODT tech­nol­o­gy, the man­u­fac­tur­ing process is well de­fined and scal­able, con­sist­ing of four main steps:

• Mix­ing of the API and ap­pro­pri­ate ex­cip­i­ents to form a so­lu­tion or sus­pen­sion
• Pre­cise­ly fill­ing the liq­uid in­to pre­formed blis­ters be­fore freez­ing the mix­ture
• Freeze-dry­ing to re­move the wa­ter and cre­ate a sol­id, dis­persible tablet
• Seal­ing of the blis­ters to pro­tect the dosage form from light and mois­ture

The lyophiliza­tion process re­sults in a porous, mois­ture-pen­e­tra­ble prod­uct sur­face. Unit dos­ing the liq­uid mix al­lows for pre­cise con­trol of the tablet’s size and weight, en­sur­ing dose uni­for­mi­ty. The ex­cip­i­ents and man­u­fac­tur­ing process work to­geth­er to cre­ate the rapid dis­in­te­gra­tion prop­er­ties of Zy­dis ODTs.

The process for Zy­dis Ul­tra, which ef­fec­tive­ly taste masks most bit­ter APIs, dif­fers in that the API must be poly­mer-coat­ed in an acoustic mix­er be­fore it is in­cor­po­rat­ed in­to the Zy­dis ma­trix. For­mu­la­tion strate­gies such as use of fla­vors, sweet­en­ers and ion ex­change resins are ef­fec­tive when the API is mod­er­ate­ly to rea­son­ably bit­ter, but poor taste can re­main for ex­treme­ly bit­ter com­pounds. The acoustic coat­ing tech­nol­o­gy em­ployed to cre­ate Zy­dis Ul­tra pro­vides a bar­ri­er around each drug par­ti­cle to en­sure that the bit­ter taste does not break through. The poly­mer coat­ing pro­vides ef­fec­tive pro­tec­tion in the aque­ous en­vi­ron­ment of the mouth, but is quick­ly re­moved in the gas­troin­testi­nal tract, en­sur­ing that bioavail­abil­i­ty is main­tained ver­sus con­ven­tion­al oral de­liv­ery meth­ods.

Bi­o­log­i­cal mol­e­cules are of­ten less sta­ble than their small-mol­e­cule API coun­ter­parts. Zy­dis Bio there­fore us­es poly­mers ca­pa­ble of main­tain­ing a low so­lu­tion vis­cos­i­ty at low tem­per­a­tures, al­low­ing the prod­uct sus­pen­sion to be dis­pensed in­to the blis­ter pock­ets while main­tain­ing sta­bil­i­ty.

ZY­DIS TECH­NOL­O­GY AT WORK: MAK­ING IM­MUNOTHER­A­PY CON­VE­NIENT

Us­ing its Zy­dis ODT tech­nol­o­gy, Catal­ent sup­port­ed Den­mark-based ALK-Abel­lo A/S (ALK) in the for­mu­la­tion, de­vel­op­ment and man­u­fac­tur­ing of ALK’s sub­lin­gual im­munother­a­py (SLIT) tablets for the treat­ment of res­pi­ra­to­ry al­ler­gies. An al­ter­na­tive to reg­u­lar sub­cu­ta­neous in­jec­tions, which need to be ad­min­is­tered by a clin­i­cian, the SLIT tablets of­fer pa­tients ex­tra­or­di­nary con­ve­nience by de­liv­er­ing sol­u­bi­lized al­ler­gens to im­mune cells em­bed­ded with­in the mu­cosae un­der the tongue. The freeze-dried tablet tech­nol­o­gy ef­fec­tive­ly en­cap­su­lates the al­ler­gens with­out im­pact­ing their sta­bil­i­ty, then rapid­ly re­leas­es and sol­u­bi­lizes them with a small amount of sali­va.

Prod­uct test re­sults were com­pelling: “In vit­ro eval­u­a­tions of Zy­dis ODT en­cap­su­lat­ed al­ler­gens show[ed] the tablet dis­in­te­grates with­in one sec­ond, sol­u­bi­lizes the al­ler­gens in a lim­it­ed vol­ume of flu­ids and re­leas­es all its con­tent with­in 15-30 sec­onds.”¹,² By con­trast, com­pressed sub­lin­gual tablets lagged, tak­ing 31 sec­onds to dis­solve, and re­leased on­ly 8.7 per­cent of al­ler­gens af­ter one minute, with par­tic­u­lates left be­hind.

ALK’s Ex­ec­u­tive Vice Pres­i­dent of R&D Hen­rik Ja­co­bi cred­its Zy­dis ODT as a ma­jor con­trib­u­tor to the suc­cess of his com­pa­ny’s SLIT treat­ments: “Fast-dis­solv­ing tech­nol­o­gy is used across ALK’s SLIT tablet range, which has de­liv­ered con­sis­tent­ly strong re­sults through­out its clin­i­cal de­vel­op­ment. We be­lieve that the tablet for­mu­la­tion tech­nol­o­gy is an im­por­tant fac­tor in this suc­cess.”

STRONG GROWTH PROSPECTS FOR ODTs  

Lever­ag­ing 25 years of re­search, de­vel­op­ment and pro­duc­tion, the Zy­dis plat­form con­tin­ues to over­come chal­lenges as­so­ci­at­ed with oral dos­ing, and to ex­pand ben­e­fits for pa­tients, and op­tions for health­care providers. “As new treat­ments are iden­ti­fied for ex­ist­ing and new­ly char­ac­ter­ized in­di­ca­tions, I be­lieve that ODTs will con­tin­ue to fea­ture strong­ly across the range be­cause of the spe­cif­ic pa­tient ben­e­fits of­fered,” said Dr. Su­san Ban­bury, Head of Zy­dis For­mu­la­tion at Catal­ent.

With well-es­tab­lished and read­i­ly scal­able man­u­fac­tur­ing process­es, ODTs present a sig­nif­i­cant op­por­tu­ni­ty to ben­e­fit many more pa­tients with rapid­ly dis­solv­ing oral for­mu­la­tions. With new class­es of ther­a­peu­tic en­ti­ties, the Zy­dis ODT for­mu­la­tion and process may al­so of­fer cer­tain tech­ni­cal ad­van­tages such as low tem­per­a­ture pro­cess­ing and en­hanced prod­uct sta­bil­i­ty. “The com­bi­na­tion of ther­a­peu­tic in­no­va­tion and con­tin­ued ODT tech­nol­o­gy de­vel­op­ment means a bright fu­ture for Zy­dis ODTs,” added Dr. Ban­bury.For more in­for­ma­tion, vis­it https://www.catal­ent.com/oral-dose/oral-tech­nolo­gies/oral­ly-dis­in­te­grat­ing-tablets/ or con­tact:

• Su­san Ban­bury, PhD Head of Zy­dis For­mu­la­tion at Catal­ent: su­san.ban­bury@catal­ent.com
• Ralph Gos­den, BSc MSc Head of Prod­uct De­vel­op­ment at Catal­ent: ralph.gos­den@catal­ent.com

Ref­er­ences:

¹Angkaw­init­wong U, Shar­ma G, Khaw P, Broc­chi­ni S, Williams G. Sol­id-state pro­tein for­mu­la­tions. Ther De­liv. 2015;6(1):59-82.

²Lund K, Ki­to H, Skyds­gaard M, Nakaza­wa H, Ohashi-Doi K, Law­ton S. The Im­por­tance of Tablet For­mu­la­tion on Al­ler­gen Re­lease Ki­net­ics. Clin Ther. 2019 Mar 15.