Targeted Intestinal Delivery of Supersaturated Itraconazole for Improved Oral Absorption

Miller, Dave A.; DiNunzio, James; Yang, Wei; McGinity, James W.; Williams, Robert O.

doi:10.1007/s11095-008-9543-1

Cited by 124 publications

(70 citation statements)

References 39 publications

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“…Miller et al (73) improved the oral absorption of itraconazole (ITZ) by the targeted intestinal delivery of the supersaturated drug formulated using HME. The amorphous solid dispersions of ITZ in Eudragit® L 100-55 containing either 20 or 40% Carbopol® 974P obtained were analyzed using DSC and XRD while the dissolution analysis was conducted using a pH change method.…”

Section: Targeted Drug Deliverymentioning

confidence: 99%

Hot-Melt Extrusion: from Theory to Application in Pharmaceutical Formulation

2015

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Abstract. Hot-melt extrusion (HME) is a promising technology for the production of new chemical entities in the developmental pipeline and for improving products already on the market. In drug discovery and development, industry estimates that more than 50% of active pharmaceutical ingredients currently used belong to the biopharmaceutical classification system II (BCS class II), which are characterized as poorly water-soluble compounds and result in formulations with low bioavailability. Therefore, there is a critical need for the pharmaceutical industry to develop formulations that will enhance the solubility and ultimately the bioavailability of these compounds. HME technology also offers an opportunity to earn intellectual property, which is evident from an increasing number of patents and publications that have included it as a novel pharmaceutical formulation technology over the past decades. This review had a threefold objective. First, it sought to provide an overview of HME principles and present detailed engineered extrusion equipment designs. Second, it included a number of published reports on the application of HME techniques that covered the fields of solid dispersions, microencapsulation, taste masking, targeted drug delivery systems, sustained release, films, nanotechnology, floating drug delivery systems, implants, and continuous manufacturing using the wet granulation process. Lastly, this review discussed the importance of using the quality by design approach in drug development, evaluated the process analytical technology used in pharmaceutical HME monitoring and control, discussed techniques used in HME, and emphasized the potential for monitoring and controlling hot-melt technology.

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Section: Targeted Drug Deliverymentioning

confidence: 99%

Hot-Melt Extrusion: from Theory to Application in Pharmaceutical Formulation

2015

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“…These polymers have historically been used as film-coating agents but have gained interest as carriers in ASDs in recent years due to their ionic characteristics that allow for targeted drug delivery along the gastrointestinal tract (58). They are commonly referred to by the trade name Eudragit® with Eudragit® E soluble at pH >5, Eudragit® L100-55 soluble at pH >5.5, Eudragit® L soluble at pH >6, and Eudragit® S soluble at pH >7.…”

Section: Polymethacrylate-based Polymersmentioning

confidence: 99%

Challenges and Strategies in Thermal Processing of Amorphous Solid Dispersions: A Review

2015

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Abstract. Thermal processing of amorphous solid dispersions continues to gain interest in the pharmaceutical industry, as evident by several recently approved commercial products. Still, a number of pharmaceutical polymer carriers exhibit thermal or viscoelastic limitations in thermal processing, especially at smaller scales. Additionally, active pharmaceutical ingredients with high melting points and/or that are thermally labile present their own specific challenges. This review will outline a number of formulation and process-driven strategies to enable thermal processing of challenging compositions. These include the use of traditional plasticizers and surfactants, temporary plasticizers utilizing sub-or supercritical carbon dioxide, designer polymers tailored for hot-melt extrusion processing, and KinetiSol® Dispersing technology. Recent case studies of each strategy will be described along with potential benefits and limitations.

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Section: Introductionmentioning

confidence: 99%

“…toxicity, safety hazards and solvent residuals make melting the method of choice despite of the potential problem of thermal degradation of drugs and carriers. Over the last decade, hot-melt extrusion (HME) has gathered renewed interest, particularly with regard to production of solid dispersions (Albers et al, 2009;Lakshman et al, 2008;Miller et al, 2008, Tian et al, 2014.Polyethylene oxide (PEO) is a semicrystalline non-ionic thermoplastic polymer exhibiting a low melting point, rapid solidification rate and low toxicity making it ideal for HME and formation of amorphous solid dispersion (Zhang and McGinity, 1999).Due to their hydrophilic character and ability to form solid dispersions, lower molecular weight PEOs have been widely used as carriers to enhance the solubility/dissolution properties of poorly soluble drugs (Li et al, 2006;Ozeki et al, 1997;Schachter et al, 2004). Melting of PEO followed by solidification upon cooling may decrease PEO crystallinity, and hence increase the amorphous PEO fraction (Prodduturi et al, 2005).…”

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confidence: 99%

The Use of Binary Polymeric Networks in Stabilizing Polyethylene Oxide Solid Dispersions

Jones

Tian

Shu

et al. 2016

Journal of Pharmaceutical Sciences

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The objective of this study was to investigate the role of amorphous domain of polyethylene oxide (PEO), a semicrystalline polymer, on the stability of drug/PEO solid dispersion. Molecular dispersion of drugs within hydrophilic low molecular weights PEOs (solid solution) has been demonstrated as a viable approach to enhance the dissolution properties and hence the oral bioavailability of poorly soluble drugs. In this system, the drug molecules are dissolved within the amorphous domain of the polymer and a miscible amorphous drug/polymer combination can result in a decrease of the polymer crystallinity, and hence increasing its amorphous fraction. This may result in increasing the drug solubility in the polymer hence affecting the stability of drug/polymer solid dispersion system. PEO is a highly crystallisable semi-crystalline polymer in natural and a rapid decrease in the amorphous fraction of the polymer may occur immediately after hot-melt extrusion resulting a forced migration of amorphous drug into nearby amorphous region. Thus, the actual concentrations of the drug within PEO solid dispersion were much higher than the concentration that we intended. Therefore, we are proposing a novel method of stabilising the amorphous drug/PEO solid dispersion by stabilising the amorphous region of PEO using another amorphous polymer. Inclusion of a miscible polymer that can increase the glass transition (Tg) of PEO (antiplasticization) or/and form strong inter-polymer interactions was used to enhance the stability of the amorphous PEO. In this study, the effects of inter-polymer interactions and miscibility between PEO and an amorphous polymer of high Tg, Eudragit ® S100, on the stability of the amorphous PEO and consequently the PEO/drug celecoxib (CX) solid dispersion was studied. Hot-melt extrusion (HME) was used to prepare different ratios of binary polymer blends of PEO/S100 (70/30, 50/50 and 30/70 w/w) and ternary solid dispersion systems containing pre-defined drug loading within the PEO/S100 polymer blends. Results from differential scanning calorimetry (DSC) and dynamic mechanical thermal analysis (DMTA) suggested a great miscibility between PEO and S100 polymer blends particularly in the 50/50 ratio. After immediately HME, single Tg was observed in all ternary systems that increase with increasing S100 amount (antiplasticization). The completely absence of PXRD crystalline Bragg's peaks also suggested the full amorphous CX/polymer solid dispersion has been produced. Upon storage, CX crystallized rapidly from the CX/PEO (30/70) system within 3 days at 40°C and 75% RH, whereas it remained stable without crystallization up to 4 weeks within CX/(PEO/S100) 30/(50/50) system. Interestingly, both the stability of the amorphous PEO and CX were greater in the ternary system containing the polymer blend at 50/50 ratio than other systems. Despite of the lower Tg of 30/(50/50) system than 30/(30/70) one, the former was more stable. This indicates that the antiplasticization effects by Eudragit ® S100 were not the ...

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Targeted Intestinal Delivery of Supersaturated Itraconazole for Improved Oral Absorption

Abstract: The results of this study strongly suggest that substantial improvements in oral antifungal therapy with ITZ can be achieved via intestinal targeting and polymeric stabilization of supersaturation.

Cited by 124 publications

References 39 publications

Hot-Melt Extrusion: from Theory to Application in Pharmaceutical Formulation

Hot-Melt Extrusion: from Theory to Application in Pharmaceutical Formulation

Challenges and Strategies in Thermal Processing of Amorphous Solid Dispersions: A Review

The Use of Binary Polymeric Networks in Stabilizing Polyethylene Oxide Solid Dispersions

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