Solid dispersion of poorly water‐soluble drugs: Early promises, subsequent problems, and recent breakthroughs
TL;DR: Commercial use of solid dispersion systems during the past four decades has been very limited, primarily because of manufacturing difficulties and stability problems, but this has been changing in recent years because of the availability of surface-active and self-emulsifying carriers and the development of technologies to encapsulate solid dispersions directly into hard gelatin capsules as melts.
About: This article is published in Journal of Pharmaceutical Sciences.The article was published on 1999-10-01. It has received 1730 citations till now.
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TL;DR: The chemical techniques to solubilize water-insoluble drugs for oral and injection administration include pH adjustment, cosolvents, complexation, microemulsions, self-emulsifying drug delivery systems, micelles, liposomes, and emulsions.
Abstract: A review of commercially available oral and injectable solution formulations reveals that the solubilizing excipients include water-soluble organic solvents (polyethylene glycol 300, polyethylene glycol 400, ethanol, propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethylsulfoxide), non-ionic surfactants (Cremophor EL, Cremophor RH 40, Cremophor RH 60, d-alpha-tocopherol polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80, Solutol HS 15, sorbitan monooleate, poloxamer 407, Labrafil M-1944CS, Labrafil M-2125CS, Labrasol, Gellucire 44/14, Softigen 767, and mono- and di-fatty acid esters of PEG 300, 400, or 1750), water-insoluble lipids (castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil and palm seed oil), organic liquids/semi-solids (beeswax, d-alpha-tocopherol, oleic acid, medium-chain mono- and diglycerides), various cyclodextrins (alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, and sulfobutylether-beta-cyclodextrin), and phospholipids (hydrogenated soy phosphatidylcholine, distearoylphosphatidylglycerol, L-alpha-dimyristoylphosphatidylcholine, L-alpha-dimyristoylphosphatidylglycerol). The chemical techniques to solubilize water-insoluble drugs for oral and injection administration include pH adjustment, cosolvents, complexation, microemulsions, self-emulsifying drug delivery systems, micelles, liposomes, and emulsions.
1,383 citations
TL;DR: In this review, it is intended to discuss the recent advances related on the area of solid dispersions.
1,329 citations
TL;DR: NanoCrystal Technology is an attrition process wherein large micron size drug crystals are media milled in a water-based stabilizer solution and the process generates physically stable dispersions consisting of nanometer-sized drug crystals.
1,245 citations
TL;DR: The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology where required.
Abstract: Drugs with low water solubility are predisposed to low and variable oral bioavailability and, therefore, to variability in clinical response. Despite significant efforts to "design in" acceptable developability properties (including aqueous solubility) during lead optimization, approximately 40% of currently marketed compounds and most current drug development candidates remain poorly water-soluble. The fact that so many drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches that can be taken to promote apparent solubility in the gastrointestinal tract and to support drug exposure after oral administration. Here we provide a detailed commentary on the major challenges to the progression of a poorly water-soluble lead or development candidate and review the approaches and strategies that can be taken to facilitate compound progression. In particular, we address the fundamental principles that underpin the use of strategies, including pH adjustment and salt-form selection, polymorphs, cocrystals, cosolvents, surfactants, cyclodextrins, particle size reduction, amorphous solid dispersions, and lipid-based formulations. In each case, the theoretical basis for utility is described along with a detailed review of recent advances in the field. The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology (e.g., solid dispersions, lipid-based formulations, or salt forms) where required.
1,201 citations
Cites background from "Solid dispersion of poorly water‐so..."
...Alternatively, direct filling of drugcarrier melts into hard gelatin capsules has also been attempted (Serajuddin, 1999)....
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...Where drug/ carrier solubility is low and large batches are required, solvent volumes are high, resulting in significant environmental, cost, and procurement issues (Serajuddin, 1999)....
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...…dissolution and oral bioavailability for poorly water-soluble drugs was first reported by Sekiguchi and Obi in 1961 (Sekiguchi and Obi, 1961) and has been widely explored over the subsequent 50 years (Hancock and Zografi, 1997; Serajuddin, 1999; Leuner and Dressman, 2000; Newman et al., 2012)....
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...Second-generation polymeric carriers—including PVP, PEG, polymethacrylates, and HPMC (and its derivatives) —and 3rd-generation carriers including self-emulsifying and surfactant-based excipients are now considerably more common (Serajuddin, 1999; Vasconcelos et al., 2007)....
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...Emulsifiers also aid drug release by enhancing the ability of the formulation to disperse adequately on hydration (Serajuddin, 1999)....
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TL;DR: Self-emulsifying drug delivery systems (SEDDS), which are isotropic mixtures of oils, surfactants, solvents and co-solvents/surfactants, can be used for the design of formulations in order to improve the oral absorption of highly lipophilic drug compounds as discussed by the authors.
1,158 citations
References
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01 Jan 1994
TL;DR: In this paper, the authors present a list of manufacturers, product categories, and diagnostic product information, including name, product category, and identification of product categories and attributes, with a focus on medical applications.
Abstract: Section 1 Manufacturers Index...1
Section 2 Name Index...101
Section 3 Product Category Index...201
Section 4 Product Identification Section...303
Section 5 Product Information...401
Section 6 Diagnostic Product Information...2645
3,228 citations
1,883 citations
TL;DR: The amorphous state is critical in determining the solid-state physical and chemical properties of many pharmaceutical dosage forms and some of the most common methods that can be used to measure them are described.
1,864 citations
TL;DR: A comparison of the carbonyl stretching region of γ indomethacin, known to form carboxylic acid dimers, with that of amorphous indometHacin indicated that the amorphously phase exists predominantly as dimers.
Abstract: Purpose. To study the molecular structure of indomethacin-PVP amorphous solid dispersions and identify any specific interactions between the components using vibrational spectroscopy.
904 citations