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Send Orders for Reprints to [email protected] Recent Patents on Anti-Cancer Discovery, 2015, 10, 87-96 87 Understanding and Managing Oral Bioavailability: Physiological Concepts and Patents

Mohd A. Alam1,*, Fahad I. Al-Jenoobi2, Abdullah M. Al-Mohizea2 and Raisuddin Ali3

1Department of Pharmaceutics, College of , King Saud University, Riyadh, KSA; 2Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, KSA; 3Research Centre, College of Phar- macy, King Saud University, Riyadh, KSA

Received: April 24, 2014; Accepted: June 30, 2014; Revised: August 31, 2014

Abstract: Oral delivery of poorly bioavailable therapeuticals is challenging. The challenges are more serious Mohd A. Alam when physiological factors of gut such as , P-glycoprotein, permeability, pH triggered precipi- tation and degradation are responsible for poor bioavailability. P-Glycoprotein mediated multidrug resistance is on high agenda for anti-cancer . The present article compiled different methodologies used to curb these challenges of bioavailability. The concepts of poor bioavailability are illustrated along with possible management. Numerous relevant patents for bioavailability enhancement are also highlighted. Though, there is no universal approach for bioavailability enhancement, the drug related challenges are managed by altering its physicochemical characteristics or employing formulation technology, while the effects of physiological factors are minimized by using transport inhibitor or cytochrome P-450 inhibitor or or through formulation technologies (enteric coating or microenvi- ronment of pH etc.). Keywords: Bioavailability, cytochrome P-450, , P-glycoprotein, multidrug resistance, prodrug.

INTRODUCTION precipitation at changed pH, efflux pumps, etc. Numerous technical and physiological approaches have been adopted to There are numerous challenges which come in the way of manage poor bioavailability Fig. ( ). Technical approaches effective treatment of diseases. Out of these challenges, pa- 1 have been reviewed time and again [1-4]. These technical tient compliance and poor bioavailability are broadly debated approaches include: altering physicochemical properties by and investigated. Bioavailability is one of the important fac- particle size reduction, amorphization, complexation, poly- tors which determine the dose of a drug, route of administra- morphism, co-crystalization, nano-crystalization, phyto- tion, formulations and cost of drug therapy. Drugs with poor somes®, etc. and through chemical modification (salt forma- oral bioavailability are administered either at increased dose to reach therapeutic level, or as technology based formula- tion and pro-drug); developing modified release formulation such as enteric coated products, maintaining micro- tions, or with bioavailability enhancers, or their route of ad- ministration is compromised. Increased dose or dosage size environment of pH within formulation, prolonged release increases the bulk of production batch (viz. vs. liquid products, bioadhesive particles, lyophilized products (mouth dosage forms), production cost, packaging size and cost, dissolving tablets), floating systems and multi-unit particu- inventory cost, transportation, etc. The increased dose and lates. Physiological approaches include: the use of efflux dosage may also produce some adverse effects and poor pump inhibitors, inhibiting , increasing intes- compliance, respectively. The compromised routes of ad- tinal permeability, additional absorption through lymphatic ministration further augment the cost of products, for exam- system, administering drug with food, or without food etc. ple sterile products and pumps. Other routes such as buccal, Since the factors limiting oral bioavailability vary from sublingual or topical are not so feasible and their application drug to drug, so a universal bioavailability enhancing tech- is limited for improving the bioavailability. Often poor nique is not feasible. The issues for poor bioavailability have bioavailability is inherited in the drug molecules, but the been managed according to the responsible factors. For ex- physiological factors also play an important role. In proceed- ample, the and dissolution limited bioavailability ing text, attempts are made to increase the understanding of have been tackled through particle size reduction (nanoiza- bioavailability limiting factors and methods for their man- tion or micronization), chemical modification (salts or pro- agement. Factors limiting oral bioavailability include poor drugs), physical modification (amorphous, polymorphs, hy- solubility, dissolution rate, permeability, first pass or pre- drates, solvates), micelles (surfactant, polymeric), solubiliza- systemic metabolism, degradation at the site of absorption, tion, complexation (cyclodextrins, co-crystals), solid disper- sion, stearic confinement of drug molecules in polymers, *Address correspondence to this author at the Department of Pharmaceutics, additional absorption channels (viz. lymphatic system), and College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, altering absorption sites (stomach, intestine). Efflux pump Saudi Arabia; Tel: +966-1-4677192; E-mail: [email protected] inhibitors as well as drug metabolizing inhibitors

2212-3970/15 $100.00+.00 © 2015 Bentham Science Publishers 88 Recent Patents on Anti-Cancer , 2015, Vol. 10, No. 1 Alam et al.

SOLUBILITY & EFFLUX TRANSPORT DISSOLUTION FORMULATIONS P-glycoprotein inhibitors, Micronization, Nanonization, Nanoformulations, Enteric or BCRP inhibitors, MDRP Salt formation, Polymorphs, delayed release, Sustained or inhibitors Prolonged release, Amorphous form, Hydrates, Gastroretentive, Bioadhesive, , Surfactants, Mouth dissolving tablets, Soft Solubilizers, Polymeric gelatin capsules, Multi unit Micelles, Complexation, Co- particulate systems, Micro crystals, Smart crystals, environment of pH BIOAVAILABILITY Clathrates, Solid dispersions, stearic confinement of ENHANCEMENT molecules CYTOCHROM P450 ROUTE OF CYP3A, CYP1A, CYP2D, CYP2E, CYP2C etc. ADMINISTRATION Sublingual inhibitors OTHERS Food

Fig. (1). Management of poor bioavailability. have been used with poorly bioavailable substrate of efflux screening of P-gp inhibitors. Some computational ap- pump and cytochrome P450. proaches or models were proposed to predict P-gp inhibitors or substrates based on modeling, quantitative P-GLYCOPROTEIN AND CYTOCHROME P450 IN- structure-activity relationship (QSAR) analyses, and molecu- HIBITORS lar docking [9, 10]. Role of ABC efflux transporters (especially P- Cytochrome P450 (CYP) is a multigene superfamily of glycoprotein) to limit oral bioavailability and affect disposi- drug metabolizing involved in the metabolism of tion of their substrates is well established [5, 6]. Reviews most of the drugs. Absorbed drugs are majorly metabolized were written on P-glycoprotein (P-gp), multidrug resistant in liver and intestine with the help of cytochrome P450 [11, associated proteins (MRPs) and breast cancer resistance pro- 12]. The major human drug metabolizing CYP enzymes in- teins (BCRPs). Chemical composition, structure, location clude CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP1A2 and functional mechanism of efflux transporters have been and CYP2E1 [11, 12]. CYP3A4 and P-gp are expressed in discussed under these reviews [7-9]. Cytotoxic drugs such as the intestine and liver and there are reports which indicate anticancer are one of the greatest victims of P-gp and MRPs that there is a substrate overlap between the two and both are efflux, since these transporters are overexpressed on the can- believed to work concurrently for the elimination of xenobi- cer cell surface and responsible for multidrug resistance otics [8]. Some of P-gp inhibitors also modulate the function (MDR) [7, 8]. Efforts are going on to diminish the role of of drug metabolizing enzymes cytochrome P450. The use of efflux transporters for limiting , MDR and oral such P-gp inhibitors with cytochrome P450 substrates will bioavailability. One of the investigated approaches includes create another issue of and its body clear- the use of P-glycoprotein inhibitors. Several P-gp inhibitors ance [7, 13]. Therefore, investigations are underway to syn- (, antihypertensive; , breast cancer; and thesize or screen the P-gp inhibitors without having any un- cyclosporine A, immunosuppressant) were identified, but desirable clinical effect. Recently, some of such P-gp inhibi- many of them are non-selective, less potent and have their tors have been reported with minimal clinical effects [8]. P- own clinical or unwanted effects [8]. Non-therapeutic inhibi- gp substrates with low molecular weight or high permeabil- tors such as: valspodar, amdray (cyclosporine A analog) and ity and high solubility may not have significant influence of dexverapamil (R-isomer of verapamil) have been identified P-gp function. But the substrate with high molecular weight, [8]. Third generation inhibitors were developed as highly low solubility and permeability will have greater influence of specific with potent P-gp inhibitory effect. Valspodar, biri- P-gp efflux. Cheng et al. disclosed baicalein analogs to im- codar, dofequidar and elacridar inhibit P-gp along with other prove bioavailability of anti-cancer agents whose bioavail- efflux transporters, while zosuquidar and tariquidar are ability is diminished by P-glycoprotein efflux or through highly potent and only inhibit P-gp [8]. So, it is clear that CYP450 3A4 enzymes [14]. The bioavailability of a renin third generation or next generation P-gp inhibitors should be inhibitor was improved by co-administering with an efflux selective, potent and free of undesired clinical or toxic ef- protein inhibitor (PSC833) [15]. Oral bioavailability of tax- fects. In general, in vitro as well as in vivo experimental anes (prodrug or derivative of , ) in- studies are applied to assess the P-gp inhibiting potential of a creased when co-administered with P-glycoprotein inhibitors chemical substance. Since these investigations are time con- such as cyclosporin A, cyclosporin D, cyclosporin F or keto- suming, expensive and laborious, therefore there is a need to conazole [16]. P-glycoprotein inhibitors such as verapamil, develop some computational models which can reduce the , and Vitamin E-TPGS improved number of experiments, and the cost of investigations. These the bioavailability of [17]. Snoeck HJM, invented computational models will provide a way for cheap and rapid fused imidazole derivatives having multidrug resistance Physiological Factors Affecting Bioavailability Recent Patents on Anti-Cancer Drug Discovery, 2015, Vol. 10, No. 1 89 modulating properties, and their use for improving oral comprising a pharmaceutically acceptable form of bioavailability of pharmaceutical agents that are poorly ab- showed higher bioavailability when given at night compared sorbed from the gastrointestinal tract (e.g., paclitaxel) [18]. to when given in the morning without food [33]. The oral bioavailability was enhanced by using P- bioavailability of glycopyrrolate increased when adminis- glycoprotein inhibitor selected from water soluble vitamin E tered under fasted conditions [34]. Van-Buren and Rudolph, and polyethylene glycols (PEG 400, PEG 1000, PEG 1450, disclosed immune-supportive drug sparing diet, which in- PEG 4600 and PEG 8000) [19]. Azabicyclooctane, a P- creases the oral bioavailability of P450 enzymes substrates glycoprotein efflux pump inhibitor improves oral bioavail- especially imunosuppresents. This nucleotide-free diet fails ability of chemotherapeutic agents [20]. Kroin & Norman to stimulate the level of gut P450 enzymes, and synergisti- disclosed multidrug resistant modulators to increase the cally enhance the immunosuppressive by reducing bioavailability of drug in brain [21]. Benet and Wu disclosed the intestinal metabolism of drug. The disclosed diet lack the method of identifying a compound useful for increasing compounds such as purines and purine analogs. This immu- bioavailability of a drug in a mammal, by assaying the inhi- nosupportive diets include pyrimidines (cytosine, thymine, bition of P-gp transport. The methods include the measure of or uracil), or pyrimidine analogs, or compounds that may be P-gp transport inhibition in isolated cells from the gut of the metabolized into pyrimidines or pyrimidine analogs [35]. A said mammal under consideration, or in a tissue or mem- six-carbon uronate (e.g., galacturonate or glucuronate) moi- brane from the gut of the said mammal under consideration, ety is capable of complexing with iron to provide a he- or in in vivo in the gut of the said mammal, or cell growth matinic compound with high iron content and high bioavail- assays, or in vesicle assays, or in P glycoprotein ATPase ability of iron [36]. assays [22]. PRODRUG FOOD Prodrug is a therapeutically inactive substance which The concomitant administration of food may influence transformed into active moiety under in vivo conditions. oral bioavailability of drugs through complex mechanisms. Concept of prodrug is based on bio-reversible modification Foods like culinary herbs, juices, milk or milk products, fats, of active drug molecule to enhance bioavailability by im- protein and carbohydrates influence the of proving aqueous solubility (e.g. thiabendazoles) [37, 38] several drugs. Food intake affects bioavailability of drugs lipophilicity (e.g. [18F]FBAU 3',5'-dibenzoate; Paclitaxel-7- undergoing extensive pre-systemic metabolic e.g. carbonyl-cholesterol) [39], transporter-mediated absorption lipophilic bases (, ) [23]. Administra- (e.g. L-valine and L-valine-valine esters of , vala- tion of protein-rich foods increases the bioavailability of cyclovir) [40, 41] decreasing pre-systemic or first pass me- propranolol by about 50% (Label of Inderal®). Food also tabolism (e.g. valacyclovir, gly-valacyclovir, valine- modifies some physiological conditions such as pH, transit valinelopinavir) [42, 43], and through site specific delivery. time, characteristics of in vivo dissolution media, drug solu- Prodrug GS-7340 increases tenofovir bioavailability by bility, hepatic blood flow, intestinal permeability, absorption reducing its first pass liver as well as intestinal metabolism. and other physiological mechanisms etc. [24, 25]. Certain Systemic availability of GS-7340 is increased by saturating foods increase the bioavailability by inhibiting CYP- efflux transporters, facilitated by its high solubility and suf- mediated metabolism and P-gp efflux of drugs (grape juice, ficient stability in intestinal and hepatic tissue [44]. Vad- flavonoids) [25, 26]. lapudi et al. designed a conjugated prodrug of acyclovir with The bioavailability of benzhydryl piperazine containing a lipid raft (ricinoleic acid or 12-hydroxy stearicacid) and a compounds (for example: 1-(3,3-diphenylpropionyl)-4- targeting moiety (biotin). These conjugated prodrugs of acy- benzhydryl piperazine) was observed to be improved when clovir improved their efficacy at local site. The targeted lipid administered with food [27]. Bioavailability of ospemifene prodrugs biotin-ricinolic acid-acyclovir and bioting-12- (lipophilic compound) was surprisingly enhanced to a sig- hydroxy stearic acid acyclovir exhibited much higher cellular nificant level upon administration with food, while the intake accumulation than biotin-acyclovir or ricinoleic acid acy- of food did not have any positive effect on the bioavailability clovir and 12-hydroxy stearic acid-acyclovir. Both the target- of . In fact, food intake retards the absorption of ing and lipid moiety act synergistically toward cellular up- toremifene [28]. The bioavailability and peak serum concen- take [45]. The dihydropyridine and ascorbate prodrugs of tration of hepatitis C virus (‘HCV’) protease inhibitor is en- enhance their brain bioavailability and also re- hanced when administered in combination with food [29]. ported a significant decrease in gastric ulcerogenicity [46]. Bioavailability of is increased when adminis- Lu et al. reported better bioavailability of ester prodrug “ten- tered with food [30]. High fat meal increased the metaxolone ofovir dipivoxil fumarate” than marketed “tenofovir diso- Cmax by 177.5% and increased AUC (AUC0-t, AUC) by proxil fumarate” (Viread®) [47]. Ninomiya et al. synthesized 123.5% and 115.4%, respectively (SKELAXIN®, FDA la- the prodrug of tricin (anti-human cytomegalovirus) with bel). The bioavailability of balsalazide and its metabolites 5- alanine-glutamic acid. The tricin-alanine-glutamic acid con- aminosalicylic acid (5-ASA) and N-acetyl-5-ASA increased jugate exhibits enhanced in vitro permeability, stability and when administered with food [31]. The bioavailability of the oral bioavailavility in male rats [48]. The prodrug EXP3174- active form of S-[2-([[1-(2-ethylbutyl) cyclohexyl] carbonyl] pivoxil is synthesized from the major active metabolite amino) phenyl]2-methylpropanethioate increased with food “EXP3174” of . The pharmacokinetic studies of [32]. An orally administrable controlled-release composition EXP3174-pivoxil (EXP3174 = 1mg/kg) compared with 90 Recent Patents on Anti-Cancer Drug Discovery, 2015, Vol. 10, No. 1 Alam et al. losartan (as EXP3174= 5mg/kg) in rats, reveal faster absorp- 2-oxo- intermediate metabolite and subsequently tion and a 5-fold enhancement in the bioavailability of the 2-oxo-clopidogrel intermediate metabolite results in the EXP3174 (from prodrug) [49]. The prodrug approach also formation of active metabolite, a thiol derivative of clopi- improves the absorption and bioavailability of several sub- dogrel. This thiol metabolite binds rapidly and irreversibly to stances. The oral absorption of is about 60%, but platelet receptors and inhibits platelet aggregation. Fenofi- its lipophilic ester prodrugs such as pivampicillin, talampicil- brate (Tricor®, Abbott) is rapidly hydrolyzed by esterases to lin and bacampicillin showed almost complete absorption its active metabolite fenofibric acid. Tricor is indicated for [50, 51]. primary hypercholesterolemia or mixed dyslipidemia and ® The numerous orally administered prodrugs are marketed severe hypertriglyceridemia. (Vyvanse , for several benefits including bioavailability improvement. Shire LLC), a prodrug of / The information of following marketed prodrugs has been is converted to dextroamphetamine primarily in blood due to taken from their labels (patient leaflets). , a the hydrolytic activity of red blood cells. After oral admini- stration, lisdexamfetamine is rapidly absorbed from the gas- phosphate ester prodrug of amprenavir, has been marketed as ® LexivaTM (GlaxoSmithKline) for the treatment of HIV-1 trointestinal tract. Vyvanse is a central nervous system (CNS) stimulant indicated for the treatment of attention defi- infection. Fosamprenavir is rapidly hydrolyzed to am- ® prenavir by cellular phosphatases in the gut epithelium. Osel- cit hyperactivity disorder. medoxomil (Benicar , tamivir phosphate (Tamiflu®, Genentech USA Inc.) is an Daiichi Sankyo), is rapidly and completely bioactivated by ethyl ester prodrug requiring ester hydrolysis for conversion ester hydrolysis to olmesartan during absorption from the to the carboxylate active form. Oseltamivir car- gastrointestinal tract. boxylate is an inhibitor of influenza virus neuraminidase Jonckers et al. disclosed CYP450 inhibitors as pharma- affecting the release of viral particles. Oseltamivir is readily cokinetics or bioavailability boosters. These boosters can absorbed from the gastrointestinal tract after oral administra- increase at least one of the pharmacokinetic variables or tion of oseltamivir phosphate and is extensively converted bioavailability of antiviral drugs [52]. Bergamottin, principle predominantly by hepatic esterases to oseltamivir carboxy- compound in grapefruit juice increases oral bioavailability of late. After of ester prodrug, the bioavail- drug substances by inhibiting P450 3A4 enzyme in the intes- ability of oseltamivir carboxylate is increased from 5% to tine [53]. Essential oils increase the bioavailability of hydro- ® 79%. Adefovir dipivoxil (Hepsera , Gilead Sciences Inc.) is phobic pharmaceuticals (cyclosporine) by inhibiting the a diester prodrug of adefovir, which increases its oral CYP3A [54]. Gallic acid ester (Viz. Propyl gallate) increases bioavailability upto 59%. Hepsera is indicated for the treat- the bioavailability of CYP3A substrates. Gallic acid esters ment of chronic hepatitis B in patients, 12 years of age and bind CYP3A quickly and inhibit while the drug is passing older. fumarate, a water soluble pro- through the enterocyte [55, 56]. Ketoconazole was used as drug of tenofovir, is marketed under the brand name of bio-enhancer to inhibit cytochrome P450 3A and enhanced ® Viread (Gilead Sciences, Inc.). In vivo, tenofovir disoproxil oral bioavailability of cyclosporine [57]. Watkins and fumarate is converted to tenofovir, an acyclic nucleoside Schmiedlin-Ren disclosed cell culture model (Caco-2 cells) phosphonate (nucleotide) analog of 5'- for assessing oral bioavailability and drug-drug interactions monophosphate. Tenofovir disoproxil fumarate is also mar- of pharmacological agents. Model is useful for defining the keted with several combinations under brand names of Com- role of CYP3A4 in limiting the oral bioavailability and in ® ® ® ® plera , Atripla and Truvada . Valacyclovir (Valtrex , drug-drug interactions involving CYP3A4 substrates at the GlaxoSmithKline) is an L-valyl ester prodrug of the antiviral level of the intestine [58]. Flavonoids of grape fruit juice drug acyclovir. Valacyclovir hydrochloride is rapidly ab- increase the bioavailability of CYP3A substrates such as sorbed from the gastrointestinal tract and is nearly com- or [59]. Cyclic phosphoramidate pro- pletely converted to acyclovir and L-valine by first-pass in- drugs improve half-life and stability of testinal and/or hepatic metabolism. The absolute bioavail- its parent drug [60]. ability of Valtrex® is 54.5%. Valacyclovir is a representative example of prodrug that exploits carrier mediated transport. DRUG INSTABILITY AND PRECIPITATION Midodrine (ProAmatine®, Shire LLC.) is an orally acting prodrug of desglymidodrine. The deglycination of midodrine Drugs having pH dependent solubility profile may get releases the active metabolite desglymidodrine. Midodrine is precipitated when pH is changed towards its low solubility. rapidly absorbed from oral route and its absolute bioavail- Poorly water soluble basic drugs are sensitive to change of ability is 93% (measured as desglymidodrine). ProAmatine® pH and may get precipitated at basic pH in intestine; and is indicated for the treatment of symptomatic orthostatic hy- may lead to compromised or erratic bioavailability. Cinnariz- potension (OH). is a phosphate ester ine is one of the examples which showed rapid drug dissolu- prodrug of estramustine (Emcyt®, Pharmacia and Upjohn). tion at low pH, followed by precipitation at high pH [61]. After oral administration, estramustine phosphate readily Kostewicz et al. investigated in vitro precipitation of poorly dephosphorylated during absorption. Emcyt® is indicated in soluble weakly basic drugs, , BIBU 104 XX the palliative treatment of patients with metastatic and/or and BIMT 17 BS at alkaline condition [62]. In the cases of progressive carcinoma of prostate. Clopidogrel (Plavix®, highly pH dependent solubility profile (e.g., Cenicriviroc Sanofi-Aventis), is an oral prodrug and oxidized by cyto- mesylate, >100mg/mL at pH < 2 and < 0.2μg/mL at pH > 4), chromes (CYP2C19, CYP3A, CYP2B6 and CYP1A2) to a a microenvironment of suitable pH is provided in the formu- Physiological Factors Affecting Bioavailability Recent Patents on Anti-Cancer Drug Discovery, 2015, Vol. 10, No. 1 91 lation, to enhance the solubility and dissolution of drug amine oxidase-B inhibitor, used in the treatment of Parkin- within the formulation or at the surface of the formulation. son's disease) has been improved by Zydis® technology by Consequently enhanced dissolution leads to increased allowing pre-gastric absorption [72, 79]. bioavailability [63]. also crystalizes as a function ® Lyoc (Pharmalyoc) is also a lyophilization based tech- of pH [64]. L-735,524 (pH-dependent solubility, >100mg/ml nology for preparing fast dissolving tablets. The oil-in-water at pH  3.5 and 0.03mg/ml at pH 6) showed pH dependent (O/W) emulsion is directly freeze dried in blister pockets. oral absorption [65]. The proton pump inhibitors such as The Suspending agent or inert filler is added to prevent the , , etc. are acid labile sedimentation by increasing the viscosity of suspension. and preferably administered as enteric coated, which delays ® Lyoc technology enhances the bioavailability of their absorption and [66]. Acid neutralizing propiphenazone, and also reduces its Cmax to 60 min from buffer increases the oral bioavailability of epothilones, when 90 min in conventional tablet [80]. administered together. The acid neutralizer acts by reducing or avoiding the degradation, decomposition, or deactivation Some other ODT proprietary technologies are listed as: ® ® ® ® ® of epothilone by the gastrointestinal environment [67, 68]. QuickSolv , Flashtab , Lyopan , OraSolv , DuraSolv , ® ® ® ® The bioavailability of biologically active proteinaceous ma- Wowtab , AdvaTab , Frosta®, Pharmaburst , FlashDose , ® terial, oligonucleotide or analog thereof or polysaccharide is OraQuick [75]. Many of these technologies are bioequiva- increased by using bile acid salts in combination with buffer lent to the conventional oral formulations, but lyophilization capable of raising the intestinal pH 7.5-9 [69]. The bioavail- based technologies improve products performance. Numer- ® ability of orally administered acid degradable antibiotic ous ODT formulations such as Abilify Discmelt (aripipra- ® () is increased in the presence of a substance zole, Otsuka Pharmaceutical Co. Ltd.), Lamictal ODT ® that increases the intragastric pH (omeprazole). The effect (, GlaxoSmithkline), Orapred ODT (predniso- ® was found to be synergistic [70]. lone sodium phosphate, CIMA Lab Inc.), Risperdal M-Tab (, Ortho-McNeil-Janssen Pharms), Zofran ODT® TM FORMULATIONS (, Glaxosmithkline), Pepcid RPD (, Merck & Co Inc.), RybixTM ODT ( hydrochloride, Over the years, numerous formulation technologies have Victoria Pharma Inc.), Zyprexa® Zydis® (, Eli Lilly been developed to meet bioavailability challenges. Some of & Co.), Allegra® ODT (fexofenadine hydrochloride, Sanofi- them are highlighted here. Aventis), FazaClo® (, Azur Pharma International III Ltd.), Maxalt-MLT® ( benzoate, Merck & Co. MOUTH DISSOLVING TABLETS Inc.), PrevacidSoluTabTM (, Takeda Pharmaceu- TM ® Oral bioavailability may also improve by increasing ab- tical), Tovalt ODT ( tartarate, Biovail), Aricept ODT ( hydrochloride, Eisai Inc.), KemstroTM (be- sorption surface or bypassing the first-pass metabolism. Ab- ® sorption of mouth dissolving tablets starts from buccal and clofen, Schwarz Pharma), Metozolv ODT ( hydrochloride, Salix Pharm Inc.), NiravamTM (, esophageal mucosa and may improve the bioavailability of ® certain drugs [71]. Apart from conventional sublingual prod- Schwarz Pharm, CIMA Lab Inc.), and Zelapar ( ucts, the proprietary mouth dissolving technologies are also hydrochloride, Valeant Pharm) are available in US market. ® available [72-74]. Zydis is one of such technologies, based The fast onset orodispersible tablets improve the on lyophilization process. Claritin, Reditabs, Feldene Melt, bioavailability of pharmaceuticals by diminishing first pass Maxalt-MLT, Pepcid ODT, Zyprexa, Zofran ODT, Risper- effect and increased absorption of drugs from buccal and ® dal, M-Tab and Zelaper are the Zydis technology based pharyngeal regions. The fast disintegrating tablets also im- ® market products [72, 74, 75]. Zydis based tablets melt in- prove compliance in pediatric, geriatric or schizophrenic stantaneously in the mouth and are releases in the saliva. The patient [81]. The bioavailability of sufentanil was improved saliva containing drug is swallowed, allowing some drug by delivering it through buccal transmucosal route [82]. absorption at pregastric sites such as mouth, pharynx, and Bioavailability of alpha.-dihydroergocryptine in sustained- ® oesophagus [71, 72, 74]. In Zydis formulation, the drug is release delivery systems comprising combined alpha- entrapped or dissolved within lyophilized matrix of polymers dihydroergocryptine, and sustained release intelligent poly- such as dextran, gelatin, or alginate. Crystalline saccharides mer was improved [83]. A bioavailability enhanced clear such as sorbitol or , erythritol, xylitol are included microemulsion composition of cyclosporine analogues com- to impart crystallinity, hardness and elegance [76-78]. The prising Vitamin E TPGS; c) medium chain triglyceride oil; ® crystalline agent prevents collapse of amorphous Zydis d) an emulsifier; and e) ethanol is disclosed [84]. The units. Suspending or flocculating agents (e.g. natural gums) bioavailability of is improved by coating the are also added to prevent sedimentation of dispersed compo- drug on fine particulate core with polymer such as polox- ® nents. Porous and amorphous nature of Zydis products as- amer 407 [85]. Liang et al. provided an oral self-emulsifying sists fast disintegration in oral cavity. Composition including formulation of fibrate with improved bioavailability. The drug and excipients is lyophilized into shaped cavities and composition comprises fibrate ( or its derivative water is sublimated from the frozen units. Alternatively, the of mixture thereof), at least one fibrate solubilizer, at least ® drug can be loaded into readymade Zydis units by pouring one surfactant, and at least one stabilizer to prevent the crys- organic solution of drug and allowing solvent to evaporate tal growth of fibrate [86]. Liquid filled soft-gelatin capsule [71]. The bioavailability of selegeline (a selective mono- comprising polyethyle glycol, polyvinylpyrrolidone, and a 92 Recent Patents on Anti-Cancer Drug Discovery, 2015, Vol. 10, No. 1 Alam et al. surfactant; increased the bioavailability of [87]. uptake and nuclear accumulation of in MCF- The bioavailability of salmon calcitonin was enhanced by 7/ADR cells. The in vivo biodistribution also showed that making enteric coated product comprising penetration en- doxorubicin loaded mesoporous silica nanoparticles induced hancer, such as surfactants [88]. Stern disclosed a synergistic a higher accumulation of DOX in drug resistant tumors when composition comprising an acidifier (tricarboxylic organic compared with free doxorubicin [103]. Multifunctional acid e.g. citric acid) and an absorption enhancer (lauroylcar- nanoassemblies of cationic sulfate comprising nitine, acylcarnitine). The composition enhances the anionic of phosphatidylserine, significantly bioavailability of peptides (e.g. calcitonin, vasopressin) upto enhanced the cytotoxicity of vincristine sulfate to 36.5-fold 50 fold [89]. Surprisingly, the bioavailability of by increasing the cellular accumulation of vincristine sulfate was improved by using buffer systems comprising certain (12.6-fold higher) in MCF-7/Adr cells, probably by escaping water-insoluble aluminum or calcium carbonates in combi- P-gp efflux [104]. The cationic submicron emulsions of hy- nation with water-insoluble magnesium antacids [90]. droxycamptothecin efficiently deliver it into MDR cells (SGC7901/VCR cells) via electrostatic-mediated endocytosis Recently, it has been reported that nano-formulations [105]. The endosomal pH-sensitive mesoporous silica (polymeric micelles, microspheres, lipid nanocapsules, solid nanoparticles of doxorubicin overcome the P-gp mediated lipid nanoparticles, , microemulsions, self- multidrug resistance. The mesoporous silica nanoparticles microemulsifying systems etc.) of P-gp sub- may serve as an efficient nano-carrier entering cell via endo- strates can be developed to minimize or bypass its effect cytosis and bypassing the efflux pump [106]. The nanoparti- [91]. In a clinical and preclinical investigation, the oral cles of doxorubicin with polylactide-surfactant block co- bioavailability of taxanes (paclitaxel and docetaxel) was en- polymer poly(l-lactide)-vitamin E TPGS showed nuclear hanced when administered P-gp and CYP3A4 blockers such accumulation and increased cytotoxicity of doxorubicin, and as with cyclosporine or [92, 93]. The mixed polym- further decreased the activity of P-glycoprotein in drug- eric micelles comprising of pluronic copolymers and low resistant breast cancer MCF-7/ADR cells [107]. The antican- molecular weight -all-trans-retinoid acid (LHR) con- cer drug loaded nanoparticles have shown the ability to tar- jugate also improves the bioavailability of paclitaxel [94]. N- get tumors based on their unique physical and biological octyl-O-sulfate chitosan (NOSC) micelles enhance the oral properties. Numerous nanoformulations have been investi- absorption of paclitaxel in vivo and in vitro [95]. Lipid nano- gated to address P-glycoprotein. Observations of nanoformu- capsules of paclitaxel increased its bioavailability and trans- lation based strategies suggest that nanomedicinal strategies port across an intestinal barrier model. The study has re- may provide a new opportunity to overcome P-gp mediated ported an interaction between P-gp and lipid nanocapsules multidrug resistance [108-110]. transport across Caco-2 cells [96]. Bromberg et al. reported that oral administration of cytotoxics formulated with the Pluronic-PAA copolymer micelles results in enhanced drug OTHERS bioavailability. The high surface activity of the Pluronic- The essential oil of turmeric significantly enhances the PAA copolymers in water results in interactions with cell oral bioavailability (5-16 folds) of in a curcumi- membranes and suppression of the membrane pumps such as noid mixture [111]. Whey protein increased the oral P-glycoprotein [97]. Inhibition of P-glycoprotein efflux bioavailability of lipophilic active substance (lycopene) pump improved intestinal absorption and tissue distribution [112]. The bioavailability of or its esters or pre- of its substrates, while metabolism and elimination were cursors is increased by using a modulator such as reduced [98]. Numerous investigators have reported the suc- or [113]. Cerebral bioavailability of a cessful application of multifunctional nanoparticle in composition is increased by administering substantial con- multidrug resistance cases. Zhang and Li reviewed the appli- temporaneously a blood flow enhancing amount of L- cation of therapeutic nanoparticles to combat P-gp-mediated arginine [114]. The oral bioavailability of aminoalkylidene MDR. The review focuses on studies using therapeutic bisphosphonates is enhanced by making di- or tripeptide nanoparticles to counter P-gp-mediated multidrug resistance derivatives of bisphosphonates. The selected specific di in cancer therapy [99]. Multifunctional nanoparticle of pacli- and/or tripeptide derivatives of bisphosphonates are recog- taxel and 5- comprising tocopheryl polyethylene nized by the active peptide carrier transporter of the intesti- glycol 1000 succinate showed enhanced cytotoxicity [100]. nal mucosae and the prodrug is hydrolyzed into the parent The cytotoxicity of doxorubicin (DOX) was enhanced when drug by mucosal cell cytosolic enzymes [115]. Bioavailabil- encapsulated in hydrophobic core of lysine-linked di- tocopherol polyethylene glycol 2000 succinate copolymer. ity of cyclosporine, insulin, acyclovir and was The in vivo anticancer efficacy of DOX encapsulated in ly- enhanced by making intimate mixture (glassy dispersion) sine-linked di-tocopherol polyethylene glycol 2000 succinate with hydrophobically derivatized carbohydrate such as treha- copolymer was more than DOX solution [101]. Li et al. ob- lose octaacetate or trehalose octaisobutyrate [116]. The served that anticancer drug loaded LipoParticles, consisting bioavailability of phytoestrogen enhanced by administering of a dimethyldidodecylammonium bromide modified the phytoestrogen with fiber and L-glutamine. Short chain poly(lactic-co-glycolic acid) nanoparticle core surrounded by fatty acids (SCFA) are produced as a byproduct of bacterial a 1,2-dipalmitoyl-sn-glycero-3-phosphocholine shell may be fermentation from dietary fiber, in caecum. SCFA are the a promising strategy to bypass MDR [102]. The doxorubicin preferred respiratory fuels for the colonic mucosa. Therefore, loaded mesoporous silica nanoparticles increased cellular according to the present invention the combination of glu- Physiological Factors Affecting Bioavailability Recent Patents on Anti-Cancer Drug Discovery, 2015, Vol. 10, No. 1 93 tamine, fiber and a phytoestrogen provides an improved CONCLUSION metabolic environment for enterocytes and colonocytes, Challenges of bioavailability and multidrug resistance which in turn enhances the metabolism and bioavailability of have to be managed case by case, since the responsible fac- phytoestrogens [117]. The bioavailability of Ginkgo biloba tors are individualized or categorized according to drug extract (GBE) is increased when administered with polyol(s), molecules. The use of P-gp and/ or CYP inhibitors in nano- either in the concentrated paste form, diluted with edible particulate formulations of their substrates is an advanced liquid or food as an additive. The increased serum levels of idea to cope with the multidrug resistance. Combining two or gingolide A, B and bilobalide increased with polyol(s). The more approaches for the management of bioavailability and polyol(s) can be selected from xylitol, iditol, maltitol, sorbi- multidrug resistance may be a versatile idea. tol, mannitol, dulcitol, , erythritol, lactitol, glycerin, USP glycerin, food grade glycerin and propylene glycol CONFLICT OF INTEREST [118]. Aliphatic ester or ether has been used for improve- The authors confirm that this article content has no con- ment of the bioavailability of the inositol phosphate [119]. flict of interest. Piperine increases the oral bioavailability of , , , , prednisolone, cipro- ACKNOWLEDGEMENTS floxacin, and [120]. The organic carboxylic acid such as ascorbic acid or its pharmaceutically acceptable The authors acknowledge the College of Pharmacy Re- salts enhances the bioavailability of sampatrilat [121]. The search Center and the Deanship of Scientific Research in alpha- or alpha-dihydrolipoic acids have been used King Saud University for financial and logistic support. to improve the bioavailability of minerals (e.g. Zn) [122]. SUPPLEMENTARY MATERIAL The citrates and tartrates with potentiator (ascorbate or fruc- tose) improve the conjoint bioavailability of nutritional min- Supplementary material is available on the publisher's eral supplements comprising iron compounds and calcium website along with the published article. compounds [123]. Ritonavir enhances the blood level of drugs metabolized by cytochrome P450 monooxygenase REFERENCES [124]. Kozak and Kamburg disclose the use of branched [1] Alam MA, Al-Jenoobi FI, Al-Mohizea AM. Commercially chain fatty acids and derivatives thereof for the inhibition of bioavailable proprietary technologies and their marketed products. P-glycoprotein [125]. Drug Discov Today 2013; 18(19-20): 936-49. [2] Mazzaferro S, Bouchemal K, Ponchel G. 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