Treatment Of Cardiovascular Disorders

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Solid dispersion technologies have been applied to several drug molecules that are indicated for the treatment of cardiovascular disorders. Several drugs belonging to classes of lipid lowering agents, anti-hypertensives, anti-angina, etc. demonstrate poor aqueous solubility resulting in dissolution rate limited absorption when administered orally. Hence, solid dispersion technologies have been utilized to enhance the dissolution properties of these drugs with the aim of improving in vivo drug absorption.

One such drug, fenofibrate, is a lipid lowering agent which is highly lipophilic and practically insoluble in water (0.1 mg/mL) (16). It is readily absorbed through the membranes of the GI tract, but is poorly bioavailable by oral administration due to slow and incomplete dissolution. Fenofibrate exhibits particularly low bioavailability when taken on an empty stomach (17). Sant et al. demonstrated the use of solid dispersion systems with polymeric micelles to improve the dissolution properties and enhance the oral absorption of fenofibrate (18). In this study, fenofibrate was encapsulated in a block copolymer consisting of poly(ethylene glycol) and poly(alkyl acrylate-co-methacrylic acid) by an oil-in-water emulsion method (19) and cast into films by evaporating the solvents under reduced pressure. The resulting film contained submicron particles consisting of fenofibrate dispersed within the hydrophobic acrylate blocks of the polymer micelles with the hydrophilic blocks forming an exterior shell. This delivery system exhibited pH dependant drug release as a result of the pendant carboxyl groups present on the hydrophobic chains. At pH below 4.7 these functional groups remain protonated, and hence neutrally charged promoting the formation of nanoaggregates in aqueous media by hydrophobic interaction. As the pH of the media was increased, the carboxyl groups became deprotonated rendering them anionically charged and more hydrophilic. Increased hydrophilicity of the polymer promoted deaggregation of the micellular nanoparticles followed by subsequent solubilization of the polymer leading to release of fenofibrate in a molecularly dispersed form.

This system was evaluated for in vivo drug absorption in Sprague-Dawley rats. The hypothesis tested with this study was that the pH-dependant aggregation of the nanoparticles would prevent rapid release of fenofibrate in the acidic environment of the stomach that could lead to drug precipitation and promote the release of drug in the small intestine to thereby improve bioavailability. The in vivo performance of the polymeric micelles was compared to bulk fenofibrate and a commercial formulation known as Lipidil Micro® which consisted of micronized fenofibrate with solubilization enhancers. From this study, it was determined that the polymeric micelle solid dispersion formulation exhibited the shortest Tmax, highest Cmax, and greatest AUC0 24h when compared to the bulk powder and the Lipidil Micro formulation. The relative bioavailability of the polymeric micelle formulation was observed to be 156% and 15% greater than the bulk drug and the commercial formulation, respectively. The plasma concentration versus time curve from this study is shown in Figure 1.

The use of polymeric micelles in this study illustrated an advanced solid dispersion system in which the carrier polymers where designed to

Figure 1 Plasma concentration vs. time curve of FNB after oral administration of (■) pH-sensitive self-assemblies of PEG-b-P(nBA17-co-MAA17), (•) Lipidil MicroR and (A) FNB powder to fasted Sprague-Dawley rats at a dose of 7.5mg/kg. Mean FSEM for n = 6.

form self-assembling nanoparticles by a simple O/W emulsion system, and which provided pH-dependant drug release allowing for targeted release to the small intestine. The oral delivery of fenofibrate from this unique solid dispersion system was demonstrated to provide enhanced drug absorption in vivo, and hence suggests the potential for improved treatment of hyper-lipidemia with fenofibrate.

Recently, a study conducted by Ambike et al. demonstrated improved absorption of simvastatin (SIM), a frequently prescribed cholesterol lowering agent, from solid dispersions of amorphous SIM in stabilizing excipients (20). The amorphous SIM solid dispersion particles were produced by spray drying an organic solution of the drug and poly-vinylpyrrolidone (PVP) along with Aerosil 200. Differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) confirmed that SIM was present in a predominantly amorphous state for spray dried dispersions in a 1:2:2 ratio of SIM:PVP:Aerosil 200. Tablets containing this solid dispersion formulation exhibited a substantially accelerated in vitro dissolution rate in pH 6.8 phosphate buffer. Hypolipidemic activity of the 1:2:2 SIM:PVP:Aerosil 200 solid dispersion was compared to bulk SIM in healthy Wistar rats that were administered excess coconut oil to promote hypercholesterolemia. The results of this study indicated enhanced absorption of SIM from the solid dispersion formulation over bulk SIM as the solid dispersion formulation substantially reduced total cholesterol and triglycerides while increasing HDL-cholesterol levels beyond that of the bulk powder. Hence, this study demonstrated the potential for enhanced treatment of hypercholesterolemia with SIM by formulation of the drug as an amorphous solid dispersion.

TAS-301 is a compound which is currently being developed as an antirestenosis drug for use following percutaneous transluminal coronary angioplasty. The water solubility of TAS-301 is approximately 20ng/mL, and hence the drug has been shown to be very poorly bioavailable following oral dosing to fasted rats and dogs (21). In a study by Kinoshita et al. solid dispersions of TAS-301 were produced by melt-adsorption of the drug onto porous calcium silicate known commercially as Florite® RE (FLR) (21). The melt adsorption process used to produce the dispersions was conducted by both a small-scale batch heat-treating process, and in a continuous manner by the use of a twin-screw melt extruder. The crystallinity of TAS-301 in melt adsorbed formulations with a 1:2 drug to carrier ratio was reduced to concentrations below the limits of detection of both the DSC and PXRD instruments. The authors speculated that the significant reduction in drug crystallinity may be due to hydrogen bond formation between a lone carbonyl group on the TAS-301 molecule to the sylanol group on FLR during the melt adsorption process. The apparent solubility of TAS-301 from the melt-adsorbed formulations showed an approximately 20-fold improvement over the crystalline drug. The dissolution rate of TAS-301 was also shown to increase substantially when melt adsorbed onto FLR with 100% of the drug released in 15 min compared to less than 40% released with the crystalline drug and a physical mixture.

The in vivo absorption of the drug from the 1:2 TAS-301:FLR formulation produced by melt extrusion was evaluated using beagle dogs in both the fasted and fed states. The melt adsorbed formulation was dosed in capsules and compared to the crystalline drug in both a capsule and an aqueous suspension. This study revealed that plasma concentrations of TAS-301 with the melt adsorbed formulation were higher than both the crystalline TAS-301 suspension and capsule forms under all feeding conditions. The AUC0_12hr was found to be 1.8 and 4.6 times greater with the melt-absorbed formulation than with the crystalline capsule formulation with the standard and rice-fed diets, respectively. Additionally the Cmax of the melt-adsorbed product was 2.3 and 5.1 times greater with the amorphous formulation than with the crystalline formulation with the standard and rice fed diets, respectively. This study thus demonstrated that the increase in apparent solubility and dissolution rate by formulation of TAS-301 as an amorphous solid dispersion on the porous calcium silicate carrier correlated to enhanced drug absorption in vivo. Therefore, by overcoming the solubility limitations of the drug via formulation as an amorphous solid dispersion, greater systemic absorption and hence increased efficacy of restenosis treatment with TAS-301 via oral dosing can be achieved.

Verreck et al. conducted a formulation development study for a novel microsomal triglyceride transfer protein inhibitor known as R103757 in which a cursory evaluation of prospective delivery systems revealed the potential for enhanced drug efficacy by formulation as a solid dispersion (22). An initial evaluation of the physiochemical properties of the compound indicated possible poor oral bioavailability as indicated by poor aqueous solubility (0.5 mg/mL at neutral pH) and a relatively high estimated effective human dose (1 mg/kg). A proof-of-principle study was therefore conducted to verify that R103757 exhibited solubility limited absorption by evaluating bioavailability in dogs following oral administration of a fast disintegrating tablet containing crystalline drug, a solid dispersion formulation in which R103757 and hydroxypropyl methylcellulose (HPMC) (40:60 w/w) were coated onto inert sugar beads and filled into capsules, and an oral solution containing 10% hydroxypropyl-p-cyclodextrin (HP-p-CD) which served as a reference formulation. Therefore, this study evaluated absorption of the drug in a crystalline state and an amorphous state in relation to an oral solution reference. This in vivo study confirmed the assumption of dissolution rate limited absorption for R103757 as the tablets containing crystalline drug were unable to produce quantifiable plasma concentrations of the drug, while the un-optimized solid dispersion showed quantifiable plasma levels.

Based on the result of the proof-of-principle study, the researchers concluded that a solid dispersion would likely be the most efficacious formulation for oral delivery of the drug, and hence focused on optimizing the formulation by assessing three different solid dispersion platforms: (i) film-coated sugar beads, (ii) a glass thermoplastic system (GTS) and (iii) melt extrusion. The film coated beads were produced by spraying an organic solution of the drug and HPMC (40:60 w/w) onto sugar spheres in a fluidized bed apparatus. The GTS contained R103757 (11.1%), citric acid monohydrate (55.6%), HP-p-CD (27.8%), and HPMC (5.6%) and was formed by dissolution in heated ethanol followed by evaporation of the solvent in a vacuum oven. The gel residue that remained following evaporation of the solvent was then manually formed into cylinders and placed into hard gelatin capsules. Melt extrusion was conducted with a twin screw extruder to produce a solid dispersion formulation consisting of 25% drug and 75% HPMC. The extrudates were then milled, mixed with tableting excipients, and compressed into tablets. DSC and PXRD confirmed the amorphous nature of the drug in each of these formulations while in vitro dissolution testing in 0.1NHCl demonstrated faster drug release from the melt extruded formulation over the two capsule formulations which performed similarly. The bioavailability of R103757

from these three formulations was then evaluated in a clinical trial with healthy male subjects in fed and fasted states. In the fasted state, the three solid dispersion formulations were compared to an oral solution containing 25% HP-p-CD. The results of these studies are shown in Figure 2. All of the solid dispersion platforms tested in this study exhibited relatively high bioavailability when considering that plasma concentrations for the crystalline material dosed to dogs were not quantifiable. In the fasted state, the relative bioavailability with respect to the oral solution was 27% for the film coated beads, 75% for the melt extruded tablet, and 97% for the GTS capsule. The GTS system provided greater AUC values than both the melt extruded tablets and the film coated beads in both the fed and fasted states.

In general, this study demonstrated the potential of solid dispersion systems for improving the oral bioavailability of poorly water-soluble drugs with solid state dosage forms, and how solid dispersion systems can be optimized with respect to production and formulation to provide maximum drug absorption enhancement. Specifically, this study showed that an advanced multi-component carrier system for amorphous drug provided equivalent bioavailability to an oral solution in a fasted state. This illustrates how solid dispersion systems can be tailored with respect to formulation and process technology to improve the in vivo absorption and overall therapeutic efficacy of a poorly water-soluble drug.

Dannenfelser et al. also reported the results of a formulation study involving an experimental microsomal triglyceride transfer protein inhibitor known as LAB687 (23). The compound was known to have low solubility (0.17 mg/mL) and high lipophilicity (Caco2 Papp = 6.1 x 10-4cm/min) and was previously demonstrated to be poorly bioavailable in dogs from a dry blended formulation containing crystalline drug. Therefore, the objective of this study was to assess a solid dispersion formulation with a carrier system consisting of a water soluble polymer [polyethylene glycol 3350 (PEG)]

-•- R103757 100 mg beads capsule -t- R103757 100 mg melt extrudate tablet -»- R103757 100 mg GTS capsule

Figure 2 Results of the pharmacokinetic study with 18 healthy male subjects. Comparison of the R103757 100-mg melt extrudate tablet, the 100-mg bead capsule, and the 100-mg GTS capsule under (A) fasting and (B) fed conditions.

-•- R103757 100 mg beads capsule -t- R103757 100 mg melt extrudate tablet -»- R103757 100 mg GTS capsule

Figure 2 Results of the pharmacokinetic study with 18 healthy male subjects. Comparison of the R103757 100-mg melt extrudate tablet, the 100-mg bead capsule, and the 100-mg GTS capsule under (A) fasting and (B) fed conditions.

and a surface active agent (polysorbate 80) to improve the bioavailability of LAB687. The performance of the solid dispersion system was compared to a cosolvent-surfactant solution of the drug as well as a dry blend of the micronized drug with microcrystalline cellulose (MCC). For the production of the solid dispersion formulation, LAB687 (4% w/w) was first dissolved into the molten carrier consisting of a 3:1 mixture of PEG and polysorbate 80 at 65 ± 5°C. A 500 mL aliquot of this molten solution was then filled into hard gelatin capsules to produce the final dosage form. The dry blend formulation consisted of 50% micronized drug (mean particle size 4.9 ^m) along with 49.8% MCC and 0.2% fumed silica. The cosolvent-surfactant solution contained 20 mg of drug per one milliliter of the cosolvent system which was made up of 10% propylene glycol, 45% Cremophor RH40, 35% corn oil glycerides, and 10% ethanol (w/w/w/v). An in vivo study was conducted in beagle dogs in which 50 mg of LAB687 was administered in one size 000 capsule for both the solid dispersion formulation and the dry blend formulations, and in two 00 capsules for the 20 mg/mL cosolvent surfactant solution. The results of the in vivo study are given in Table 1.

In this study, high inter-animal variability was observed with the dry blend formulation whereas the variability of the solid dispersion and cosolvent-solution was relatively low. Since the absolute bioavailability for LAB687 could not be determined, the relative bioavailabilities of each formulation were calculated based on drug absorption from the cosolvent-surfactant solution. The solid dispersion formulation showed 99.1% bioavailability with respect to the cosolvent-surfactant solution which was ten-fold greater than the dry blend formulation at 9.8%. Therefore, it was demonstrated by this study that delivering this experimental lipid lowering agent in the form of a solid dispersion substantially enhanced drug absorption in dogs, and hence suggests the potential for improved efficacy in human patients.

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