Op­ti­miz­ing clin­i­cal out­comes for chal­leng­ing mol­e­cules with lipid-based drug de­liv­ery

Pic­tured: Op­tiShell. All im­ages cour­tesy of Catal­ent Phar­ma So­lu­tions. © 2017 Catal­ent, Inc. All rights re­served

Im­ple­ment­ing a bioavail­abil­i­ty en­hanc­ing for­mu­la­tion ap­proach can pos­i­tive­ly im­pact safe­ty, ef­fi­ca­cy, and pa­tient ad­her­ence, lead­ing to suc­cess­ful clin­i­cal out­comes.  This ar­ti­cle takes an in-depth look at how lipid-based drug de­liv­ery sys­tems (LB­DDS) can be used as a bioavail­abil­i­ty en­hanc­ing tech­nol­o­gy, as well as the soft­gel dosage form for their de­liv­ery, in or­der to achieve suc­cess­ful clin­i­cal out­comes.

Im­prov­ing Drug Ad­her­ence Rates

In gen­er­al, fol­low­ing drug ap­proval, on­ly one out of four pa­tients will ben­e­fit from a drug, large­ly due to poor ad­her­ence rates, and these rates are much high­er for chron­i­cal­ly ad­min­is­tered drugs. A 2008 study looked at drug ad­her­ence dur­ing the first 12 months of ther­a­py for 7 ma­jor med­ical con­di­tions (hy­per­ten­sion, hy­pothy­roidism, Type 2 di­a­betes, epilep­sy, hy­per­c­ho­les­terolemia, os­teo­poro­sis, and gout). The per­cent­age of pa­tients able to achieve 80% or high­er ad­her­ence rate ranged from 36.8 – 72.3%. An­oth­er study ex­am­ined the per­sis­tence rate (time from ini­ti­a­tion to dis­con­tin­u­a­tion) at 6 months for 6 drug class­es. Six month per­sis­tence ranged from 28% for over­ac­tive blad­der med­ica­tions to 66% for oral an­tidi­a­bet­ic med­ica­tions.

Kishor Wasan

“If the pa­tient isn’t tak­ing the drug prop­er­ly and on time, then it doesn’t mat­ter if it’s got a great phar­ma­co­log­ic ef­fect,” ac­cord­ing to Pro­fes­sor Kishor Wasan, Dean of the Col­lege of Phar­ma­cy and Nu­tri­tion at the Uni­ver­si­ty of Saskatchewan, Cana­da.

“It’s an im­por­tant con­cept be­cause of­ten pa­tients are tak­ing mul­ti­ple drugs, and if you give them a com­plex for­mu­la­tion or a com­plex dos­ing reg­i­men, it’s very dif­fi­cult to get com­pli­ance.” And in a clin­i­cal tri­al, that can be dis­as­trous.

One of the rea­sons that pa­tients go off their med­i­cine or don’t ad­here to a clin­i­cal tri­al  pro­to­col is be­cause they’re not get­ting the de­sired ther­a­peu­tic ef­fect.  As a re­sult, they get dis­cour­aged and quit tak­ing their med­i­cine. An­oth­er rea­son that pa­tients quit tak­ing their med­ica­tions is be­cause they ex­pe­ri­ence se­ri­ous side ef­fects.  If an en­abling for­mu­la­tion, such as a LB­DDS, can pro­vide op­ti­mal drug ex­po­sure to reach de­sired ther­a­peu­tic per­for­mance with mit­i­gat­ed side ef­fects, then the pa­tients are more like­ly to be mo­ti­vat­ed to stay on their med­ica­tion.

Am­phetericin B Case Study

Pro­fes­sor Wasan told End­points that oral lipid-based drug de­liv­ery tech­nol­o­gy can be ap­plied to new chem­i­cal en­ti­ties as well as to re­pur­pose old drugs.

As a li­po­so­mal drug de­liv­ery sci­en­tist, Wasan fo­cus­es on lipid-drug in­ter­ac­tions and how that af­fects dis­po­si­tion of drugs and me­tab­o­lism and ki­net­ics. He did his PhD work on am­pho­tericin B for the treat­ment of sys­temic fun­gal in­fec­tions and vis­cer­al leish­ma­ni­a­sis and was the prin­ci­pal in­ves­ti­ga­tor in that study.

His lab at the Uni­ver­si­ty of Saskatchewan start­ed out with li­po­so­mal drugs and moved to an oral lipid for­mu­la­tion of am­pho­tericin B for blood-borne in­fec­tions. The study gar­nered at­ten­tion from the Gates Foun­da­tion, which pro­vid­ed fund­ing for pre­clin­i­cal test­ing. The com­pound is about to start Phase I tri­als with the lipid for­mu­la­tion.

Am­pho­tericin B is a par­enter­al­ly ad­min­is­tered broad-spec­trum an­ti­fun­gal that has been on the mar­ket for more than 60 years. A lipid for­mu­la­tion of am­pho­tericin B came out in 1996 that changed the field, but it was re­nal tox­ic, and pa­tients with fun­gal in­fec­tions are of­ten AIDs pa­tients, Wasan said, and a tox­ic dose can be prob­lem­at­ic.

Wasan de­vel­oped iCO-010, a new oral lipid-based for­mu­la­tion of am­pho­tericin B that is less tox­ic. “This means you can be more ag­gres­sive in killing the fun­gal in­fec­tion be­fore you start see­ing the tox­i­c­i­ty. That’s a huge clin­i­cal ben­e­fit,” Wasan said.

It al­so means the treat­ment pe­ri­od can be short­ened, and a pa­tient could move from a two-hour in­fu­sion every day to an oral prod­uct. In the end, that saves time and mon­ey and of­fers huge lifestyle ad­van­tages to the pa­tient.

“I look at the mol­e­cule and the phys­i­cal char­ac­ter­is­tics, and I look at the cur­rent de­liv­ery method and the cur­rent bar­ri­er to bioavail­abil­i­ty. Then we can look at whether a lipid-based strat­e­gy would solve the prob­lem, and if so, which method would be the best fit,” Wasan said.

“The clin­i­cal suc­cess of lipid-based drug de­liv­ery sys­tems is large­ly due to the use of soft­gels for de­liv­ery,” he said.

Cen­tral Dog­ma of Drug Ab­sorp­tion

The cen­tral dog­ma of drug ab­sorp­tion con­sid­ers two fac­tors: the drug’s sol­u­bil­i­ty and its per­me­abil­i­ty. These two fac­tors are the cor­ner­stones of the Bio­phar­ma­ceu­tics Clas­si­fi­ca­tion Sys­tem (BCS) pro­posed by Gor­don Ami­don and the De­vel­opa­bil­i­ty Clas­si­fi­ca­tion Sys­tem (DCS) pro­posed by James But­ler and Jen­nifer Dress­man.

Ron­ak Savla

“Sol­u­bil­i­ty and per­me­abil­i­ty fac­tor in­to ab­sorp­tion and bioavail­abil­i­ty, be­cause if ei­ther is poor, it af­fects the bioavail­abil­i­ty of the drug, which in turn leads to phar­ma­co­ki­net­ic vari­abil­i­ty,” says Ron­ak Savla, Sci­en­tif­ic Af­fairs Man­ag­er at Catal­ent Phar­ma So­lu­tions and the Catal­ent Ap­plied Drug De­liv­ery In­sti­tute.

The ma­jor­i­ty of pipeline drug can­di­dates fall with­in BCS and DCS Class II, which means that they have ac­cept­able per­me­abil­i­ty but are poor­ly sol­u­bi­lized in the gas­troin­testi­nal tract. BCS and DCS Class II drugs present nu­mer­ous chal­lenges such as poor bioavail­abil­i­ty, sig­nif­i­cant sub­ject-to-sub­ject vari­abil­i­ty, ab­sorp­tion lead­ing supra or sub ther­a­peu­tic lev­els, and food ef­fects. The chal­lenges as­so­ci­at­ed with these drugs of­ten ex­tend be­yond ab­sorp­tion, and even if the drug is ab­sorbed across the gas­troin­testi­nal ep­ithe­li­um, many lipophilic mol­e­cules un­der­go ex­ten­sive first pass me­tab­o­lism by cy­tochrome P450 (CYP450) en­zymes in he­pa­to­cytes.

“The bioavail­abil­i­ty needs to be such that the right amount of ac­tive in­gre­di­ent con­sis­tent­ly gets in­to the blood­stream at the site of ac­tion to elic­it a phar­ma­co­log­i­cal re­sponse with low tox­i­c­i­ty and a fea­si­ble dos­ing reg­i­men”, says Pro­fes­sor Wasan.

Bioavail­abil­i­ty Chal­lenges As­so­ci­at­ed with Poor­ly Sol­u­ble Mol­e­cules

The ab­sorp­tion of cer­tain drugs, in­clud­ing many oral an­ti­cancer agents, may be de­creased or in­creased by the pres­ence of food. This is termed a neg­a­tive or pos­i­tive food ef­fect, re­spec­tive­ly. Poor­ly sol­u­ble drugs of­ten ex­hib­it pos­i­tive food ef­fects. Safe­ty con­cerns are am­pli­fied for drugs with a nar­row ther­a­peu­tic in­dex. If these drugs ex­pe­ri­ence a pos­i­tive food ef­fect, where­in food in­creas­es ab­sorp­tion, the drug may reach supra-ther­a­peu­tic, even tox­ic lev­els, and can re­sult in very se­ri­ous side ef­fects which are harm­ful to the pa­tient.

Jeff Browne

“This hap­pens be­cause the lipid make-up in the food, es­pe­cial­ly fol­low­ing in­ges­tion of a high fat meal, ac­tu­al­ly aid in sol­u­bi­liz­ing the drug mol­e­cule, there­by pro­mot­ing drug’s ab­sorp­tion, as it trav­els through the GI sys­tem,” ex­plained Dr. Jeff Browne, Di­rec­tor of Sci­ence & Tech­nol­o­gy at Catal­ent. “Oral an­ti­cancer agents are no­to­ri­ous for ex­pe­ri­enc­ing sig­nif­i­cant pos­i­tive food ef­fects.”

Food ef­fects have im­por­tant clin­i­cal im­pli­ca­tions: prop­er pa­tient ad­her­ence to in­struc­tions on a drug prod­uct’s la­belling re­gard­ing when to take the drug is para­mount as lack of ad­her­ence can re­sult in po­ten­tial un­der- and over-dos­ing of the med­ica­tion.  For drugs with a pos­i­tive food ef­fect, pa­tients are of­ten in­struct­ed to wait two hours af­ter eat­ing to take the drug be­cause ad­min­is­tra­tion with a high-fat meal can sig­nif­i­cant­ly in­crease drug ex­po­sure. How­ev­er, for some class­es of drug, a pos­i­tive food ef­fect can ac­tu­al­ly be an ad­van­tage and pa­tients are in­struct­ed to take the med­ica­tion with food to in­crease ex­po­sure. In this case, the ad­her­ence con­cern is that a pa­tient takes the med­ica­tion on an emp­ty stom­ach re­sult­ing in low­er ex­po­sure and there­fore a sub-ther­a­peu­tic amount of drug po­ten­tial­ly lead­ing to poor clin­i­cal out­come.

As men­tioned pre­vi­ous­ly, many oral an­ti­cancer agents ex­pe­ri­ence a pos­i­tive food ef­fect. How­ev­er these drugs are typ­i­cal­ly la­belled to be tak­en on an emp­ty stom­ach. If a pa­tient took their med­ica­tion with a meal, the pri­ma­ry con­cern would be the high­er tox­i­c­i­ty as­so­ci­at­ed with plas­ma lev­els that are above the max­i­mum ther­a­peu­tic dose. For ex­am­ple, nilo­tinib is an oral ki­nase in­hibitor known to have a sig­nif­i­cant pos­i­tive food ef­fect. Supra-ther­a­peu­tic lev­els of this drug may cause life threat­en­ing ar­rhyth­mias.

There are stud­ies in­ves­ti­gat­ing the abil­i­ty of LB­DDS to mim­ic food ef­fect. Be­cause the lipid con­tent in a LB­DDS is con­sid­er­ably less than that in a high fat meal, while a LB­DDS does have an ef­fect on a drug’s phar­ma­co­ki­net­ics, it is nor­mal­ly a low­er mag­ni­tude of ef­fect com­pared with a high fat meal.

“We looked at oral drugs for­mu­lat­ed in LB­DDS. Twen­ty-one FDA ap­proved oral drugs con­tained lan­guage about food ef­fect in their prod­uct la­bels. Eight drugs were la­belled to be tak­en with a meal. With one ex­cep­tion, these drugs cap­i­tal­ized on a pos­i­tive food ef­fect. Drugs la­belled to be tak­en with­out re­gard to food ex­pe­ri­ence ei­ther no change in their phar­ma­co­ki­net­ic pa­ra­me­ter or the mag­ni­tude of the change (in­crease of de­crease) is not clin­i­cal­ly sig­nif­i­cant to af­fect the safe­ty and ef­fi­ca­cy of the drug,” ex­plained Dr. Savla.

An­oth­er bioavail­abil­i­ty chal­lenge for poor­ly sol­u­ble drugs is they typ­i­cal­ly have greater in­tra- and in­ter-pa­tient vari­abil­i­ty, ex­pressed us­ing the mea­sure of co­ef­fi­cient of vari­abil­i­ty (CV%). In re­gards to in­tra-pa­tient vari­abil­i­ty (phar­ma­co­ki­net­ic vari­abil­i­ty with­in a sin­gle pa­tient), it is pos­si­ble that the plas­ma lev­el may fall with­in the ther­a­peu­tic win­dow one day and be sub-ther­a­peu­tic or supra-ther­a­peu­tic the fol­low­ing day. It be­comes dif­fi­cult to find a con­sis­tent dose for the pa­tient and dose titra­tion is of­ten re­quired.

“The im­muno­sup­pres­sant cy­closporine is an ex­am­ple of drug with a nar­row ther­a­peu­tic in­dex.  This drug is avail­able as two ap­proved soft­gel prod­ucts, each us­ing a dif­fer­ent lipid for­mu­la­tion. One prod­uct, Sandim­mune®, was ini­tial­ly in­tro­duced to the mar­ket as a corn oil-based for­mu­la­tion with sur­fac­tant.  The oth­er, Ne­o­ral®, was sub­se­quent­ly in­tro­duced, as a new­er glyc­eride mi­croemul­sion for­mu­la­tion. The in­tra-pa­tient vari­abil­i­ty (CV%) of the old­er Sandim­mune® prod­uct is re­port­ed to be be­tween 19-26%. The new­er Ne­o­ral® prod­uct, for­mu­lat­ed as a mi­croemul­sion, has a low­er CV% of 9-21%. The Ne­o­ral® prod­uct there­fore al­lowed clin­i­cians to bet­ter titrate the cor­rect dose for a pa­tient to main­tain a safe and ef­fec­tive plas­ma lev­el,” said Dr. Browne.

Again re­fer­ring to the Ne­o­ral® prod­uct, Pro­fes­sor Wasan in­di­cat­ed the low­er phar­ma­co­ki­net­ic vari­abil­i­ty be­tween pa­tients (in­ter-pa­tient vari­abil­i­ty) is im­por­tant be­cause physi­cians could bet­ter pre­dict phar­ma­co­log­ic re­sponse from pa­tient-to-pa­tient.

De­sign Prin­ci­ples of Lipid Based Drug De­liv­ery Sys­tems for Poor­ly Sol­u­ble Drugs

There’s not a one-size-fits-all ap­proach, or off-the-shelf LB­DDS that can be used for drug mol­e­cules. Every drug com­pound is unique and for­mu­la­tors must first un­der­stand the mol­e­cule’s phys­i­cal-chem­i­cal prop­er­ties, and im­por­tant­ly what is the like­ly rea­son for poor bioavail­abil­i­ty (poor sol­u­bil­i­ty, poor per­me­abil­i­ty, or both). On­ly then, can a LB­DDS be ra­tio­nal­ly de­signed to take in­to ac­count the spe­cif­ic drug mol­e­cule’s prop­er­ties.

Vin­cent Plas­sat

“For com­pounds ex­hibit­ing poor sol­u­bil­i­ty, we de­sign lipid for­mu­la­tions to keep the drug in so­lu­tion and pre­vent it from pre­cip­i­tat­ing out as it trav­els through the GI tract. By do­ing so we max­i­mize our chances of in­creas­ing ex­po­sure know­ing the sol­u­bi­lized form of the drug is need­ed to cross the GI mem­brane,” said Dr. Browne. “One of the big ben­e­fits of LB­DDS is the wide range of dif­fer­ent ex­cip­i­ents that the for­mu­la­tor can choose from in or­der to de­sign a lipid for­mu­la­tion that is able to sol­u­bi­lize the re­quired dose of drug pri­or to its ad­min­is­tra­tion to the pa­tient.”

“Once we sol­u­bi­lize the drug in the for­mu­la­tion, then we of­ten try to de­sign a lipid sys­tem so that it read­i­ly dis­pers­es. By in­cor­po­rat­ing dis­per­sion and di­ges­tion prop­er­ties in­to the de­sign of our lipid sys­tems, we’re of­ten able to keep the drug in so­lu­tion in the body,” says Vin­cent Plas­sat, Sci­en­tif­ic Af­fairs man­ag­er at Catal­ent.

Bioavail­abil­i­ty Chal­lenges As­so­ci­at­ed with Poor­ly Per­me­able Macro­mol­e­cules

Oral de­liv­ery of macro­mol­e­cules such as pep­tides con­tin­ues to re­ceive a lot of at­ten­tion in the phar­ma­ceu­ti­cal in­dus­try.  How­ev­er, achiev­ing ac­cept­able bioavail­abil­i­ty to pro­vide ex­po­sure lev­els for suc­cess­ful clin­i­cal out­comes is chal­leng­ing to say the least.  While pos­sess­ing rea­son­able aque­ous sol­u­bil­i­ty, the per­me­abil­i­ty of these mol­e­cules is of­ten lim­it­ed with oral bioavail­abil­i­ty of 1-2% or less.  Fac­tors that can con­tribute to poor per­me­abil­i­ty in­clude size , charge, hy­drophilic­i­ty, and mol­e­c­u­lar flex­i­bil­i­ty.  Poor­ly per­me­able com­pounds, as is the case with poor­ly sol­u­ble com­pounds, not on­ly can re­sult in low bioavail­abil­i­ty, but al­so sig­nif­i­cant vari­abil­i­ty.

De­sign Prin­ci­ples of Lipid Based Drug De­liv­ery Sys­tems for Poor­ly Per­me­able Drugs

To meet the chal­lenges posed by macro­mol­e­cules, Catal­ent’s OptiGel™ Bio tech­nol­o­gy, a LB­DDS de­liv­ered via soft­gel dose form, has been de­vel­oped in re­cent years based on nu­mer­ous ex­per­i­ments to in­crease per­me­abil­i­ty and sta­bil­i­ty of macro­mol­e­cules.

“Catal­ent’s OptiGel™ Bio tech­nol­o­gy is based on our knowl­edge around lipid-based for­mu­la­tions. This tech­nol­o­gy has al­ready been shown to hold great promise for BCS Class III com­pounds, or wa­ter sol­u­ble macro­mol­e­cules with poor per­me­abil­i­ty,” said Plas­sat.

One ap­proach en­com­passed by this tech­nol­o­gy us­es en­teric coat­ed cap­sules, which are en­gi­neered to by­pass the detri­men­tal ef­fects en­coun­tered in the stom­ach. As a re­sult, the for­mu­la­tion and mol­e­cule con­tained with­in, will be pro­tect­ed from the acidic con­di­tions of the stom­ach and sub­se­quent­ly re­leased in the in­tes­tine or the colon.

Gen­er­al speak­ing, mol­e­cules can pass through the gut wall ei­ther through the cell (tran­scel­lu­lar route) or be­tween the cells of the in­tes­tine (para­cel­lu­lar route). Some lipid for­mu­la­tions can be de­signed to im­prove per­me­abil­i­ty of the mol­e­cule through the ad­di­tion of per­me­ation en­hancers that in­crease the tran­scel­lu­lar route of ab­sorp­tion.  Oth­er lipid for­mu­la­tions in­clude per­me­ation en­hancers that pri­mar­i­ly af­fect para­cel­lu­lar trans­port by open­ing up the tight junc­tions that ex­ist be­tween cells. The char­ac­ter­is­tics of macro­mol­e­cules (size, charge, hy­drophilic­i­ty, and mol­e­c­u­lar flex­i­bil­i­ty) do not lend them to be ab­sorbed via the tran­scel­lu­lar route. An­oth­er ap­proach en­com­passed by OptiGel™ Bio tech­nol­o­gy in­creas­es the per­me­abil­i­ty of macro­mol­e­cules by tran­sient­ly open­ing up the tight junc­tions be­tween en­te­ro­cytes enough for macro­mol­e­cules to pass through. This is ac­com­plished by us­ing GRAS (gen­er­al­ly re­gard­ed as safe) ex­cip­i­ents which sim­pli­fies the lat­er reg­u­la­to­ry ap­proval path­way.

“These tight junc­tions are an evo­lu­tion­ary mech­a­nism to pre­vent any tox­ins or xeno­bi­otics from en­ter­ing the body. With these per­me­ation en­hancers, we can con­trol their ac­tiv­i­ty so they open for a cer­tain pe­ri­od of time and quick­ly close to avoid any long-term tox­i­c­i­ty,” Savla said.

Avoid the First Pass Me­tab­o­lism

De­sign­ing a lipid sys­tem that avoids the first pass me­tab­o­lism in the liv­er would add yet an­oth­er clin­i­cal ben­e­fit for pa­tients. CYP450 en­zymes in the liv­er are known to have high lev­els of ge­net­ic vari­a­tion and make it dif­fi­cult to ap­ply a uni­form dose across a di­verse pa­tient pop­u­la­tion. The end re­sult is that these drugs don’t pro­vide suf­fi­cient ex­po­sure to the pa­tient and can lead to sig­nif­i­cant vari­a­tion ei­ther with­in a giv­en pa­tient or from pa­tient to pa­tient. This al­so leads to po­ten­tial drug-drug in­ter­ac­tions in pa­tients tak­ing mul­ti­ple med­ica­tions. Pa­tients may have to stag­ger their med­ica­tion to avoid these in­ter­ac­tions. Im­prov­ing the for­mu­la­tion of these drugs through the use of LB­DDS may help mit­i­gate me­tab­o­lism.

An emerg­ing area of re­search in­ter­est as a way of mit­i­gat­ing first pass me­tab­o­lism is the de­sign of drugs and for­mu­la­tion to pro­mote lym­phat­ic up­take. The mech­a­nisms of lym­phat­ic up­take and trans­port are still un­clear. How­ev­er, what is clear, stud­ies have demon­strat­ed that through prop­er se­lec­tion of drug com­pounds and de­sign of LB­DDS, lym­phat­ic up­take of drugs can be fa­cil­i­tat­ed to avoid1st pass ef­fect in the liv­er. The po­ten­tial ad­van­tages in­clude high­er ab­sorp­tion of drugs in­to the blood stream and more uni­form dos­ing for pa­tients as well as the abil­i­ty to tar­get drugs to the lymph sys­tems for treat­ment of cer­tain can­cers and oth­er dis­ease states that maybe as­so­ci­at­ed with the lymph sys­tem.

Dosage Form Con­sid­er­a­tions for Oral Lipid-based Drug De­liv­ery Sys­tems

“Our analy­sis re­vealed that soft gelatin cap­sules or soft­gels were the most com­mon dosage form for oral­ly ad­min­is­tered LB­DDS,” said Dr. Savla. Soft­gels are com­pat­i­ble with a wide range of lipid ex­cip­i­ents and well suit­ed for LB­DDS.

Soft­gels

Pa­tients pre­fer soft­gels be­cause they can eas­i­ly swal­low soft­gel cap­sules. Soft­gels can mask the strong taste or odors of cer­tain med­ica­tions. These char­ac­ter­is­tics of the soft­gel dosage form lead to a pos­i­tive pa­tient ex­pe­ri­ence which is para­mount to achiev­ing good ad­her­ence to any med­ica­tion.

Ther­a­peu­ti­cal­ly, soft­gels for im­me­di­ate re­lease of drugs quick­ly dis­solve in the gut and re­lease the liq­uid con­tents. The soft­gel shell pro­vides an ex­cel­lent bar­ri­er to oxy­gen and the fill is her­met­i­cal­ly sealed with­out head­space to en­sure the con­tents are pro­tect­ed from the en­vi­ron­ment and the for­mu­la­tion qual­i­ty and per­for­mance char­ac­ter­is­tics are main­tained. More re­cent­ly, the en­teric coat­ing of soft­gels has been em­ployed to tar­get where in the GI the soft­gels will dis­solve and re­lease the lipid-based con­tents.

Con­clu­sion

Lipid-based drug de­liv­ery sys­tems can help over­come many of the chal­lenges posed by mol­e­cules in to­day’s phar­ma de­vel­op­ment pipelines in­clud­ing poor sol­u­bil­i­ty, poor per­me­abil­i­ty, and GI me­tab­o­lism.  These chal­lenges of­ten lead to poor bioavail­abil­i­ty as ev­i­denced by in­ad­e­quate ex­po­sure, phar­ma­co­ki­net­ic vari­abil­i­ty, and food ef­fects. LB­DDS can be ap­plied to a wide va­ri­ety of mol­e­cules, in­clud­ing macro­mol­e­cules, giv­en the ver­sa­til­i­ty they of­fer. Soft­gels are the most com­mon dosage form for oral ad­min­is­tra­tion of LB­DDS. In ad­di­tion to be­ing com­pat­i­ble with LB­DDS, soft­gels can be used for both im­me­di­ate and con­trolled or tar­get­ed re­lease ap­pli­ca­tions.  Fi­nal­ly, soft­gels are pre­ferred by pa­tients and lead to a pos­i­tive pa­tient ex­pe­ri­ence which in turn as­sures a suc­cess­ful clin­i­cal out­come.