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Journal Article•DOI•

State of the art of nanocrystals--special features, production, nanotoxicology aspects and intracellular delivery

Rainer H. Müller1, Sven Gohla, Cornelia M. Keck2, Cornelia M. Keck1, Cornelia M. Keck3 •
Free University of Berlin1, University of Applied Sciences, Kaiserslautern2, Universiti Putra Malaysia3
01 May 2011-European Journal of Pharmaceutics and Biopharmaceutics (Elsevier)-Vol. 78, Iss: 1, pp 1-9
TL;DR: Drug nanocrystals are the latest, broadly introduced nanoparticulate carrier to the pharmaceutical market from the year 2000 onwards and the effect of size, degradability versus biopersistency and intracellular uptake are discussed, classifying the nanocry crystals in the low/non-risk group.
About: This article is published in European Journal of Pharmaceutics and Biopharmaceutics.The article was published on 2011-05-01 and is currently open access. It has received 559 citations till now.

Summary (1 min read)

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Summary

  • Drug nanocrystals are the latest, broadly introduced nanoparticulate carrier to the pharmaceutical market from the year 2000 onwards.
  • The special features of nanocrystals for the delivery of poorly soluble drugs are briefly reviewed (saturation solubility, dissolution velocity, adhesiveness).
  • The industrially relevant bottom up and top down production technologies (pearl milling, high pressure homogenization, combination technologies) are presented.
  • As nanotoxicological aspects, the effect of size, degradability versus biopersistency and intracellular uptake are discussed, classifying the nanocrystals in the low/non-risk group.
  • Intracellular uptake plays a minor or no role for dermal and oral nanocrystals, but it plays a key role for intravenously injected nanocrystals (e.g. nevirapine, paclitaxel, itraconazole).
  • Uptake by the macrophages of the mononuclear phagocytic system (MPS, liver spleen) can modify/optimize blood profiles via prolonged release from the MPS , but also target toxicity by too high organ concentrations and thus cause nanotoxicity.
  • The balance in the competitive intracellular uptake by MPS and the target cells (e.g. blood–brain barrier) decides about therapeutic efficiency.
  • The concept of “differential protein adsorption” to modulate this balance is shown for its applicability to nanocrystals for intracellular delivery to the cells of the blood–brain barrier .

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Citations
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Journal Article•DOI•
Strategies to Address Low Drug Solubility in Discovery and Development

[...]

Hywel David Williams1, Natalie L. Trevaskis, Susan A. Charman, Ravi Mysore Shanker2, William N. Charman, Colin W. Pouton, Christopher J.H. Porter •
Monash University1, Pfizer2
01 Jan 2013-Pharmacological Reviews
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 "State of the art of nanocrystals--s..."

  • ...SLN formulations also provide opportunities for targeted therapies; however, these lie beyond the scope of this review [see Muller et al. (2011b) and Joshi and Müller (2009) for details]....

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  • ...…use of modified nanosuspension formulations to form the basis of targeted or site-specific delivery systems in a manner analogous to that of liposomes or nanoparticles is outside the scope of the current article but has been addressed elsewhere (Vonarbourg et al., 2006; Muller et al., 2011a)....

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  • ...SLNs can be manufactured in large scale using high-pressure homogenization (Muller et al., 2011b)....

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  • ...In addition, SLN formulations may be used to facilitate parenteral delivery of poorly water-soluble drugs (Wissing et al., 2004; Reddy et al., 2005; Muller et al., 2011b) and in a manner analogous to nanocrystal suspensions (see Section IX), aqueous dispersions may be lyophilized for convenient…...

    [...]

  • ...Solid lipid nanoparticles (SLNs) consist of a lipidic core that is solid at both room temperature and physiologic temperatures, and a surfactant-stabilized outer surface (Mehnert and Mader, 2001; Bummer, 2004; Muller et al., 2011b)....

    [...]

Journal Article•DOI•
Nanomedicine: Principles, properties, and regulatory issues

[...]

Sara Soares1, João Sousa1, Alberto A. C. C. Pais1, Carla Vitorino1•
University of Coimbra1
20 Aug 2018-Frontiers in Chemistry
TL;DR: The introduction of nanomedicines in the pharmaceutical market, and all the controversy associated to basic concepts related to these nanosystems, and the numerous methodologies applied for enhanced knowledge are reviewed.
Abstract: Several scientific areas have benefited significantly from the introduction of nanotechnology and the respective evolution. This is especially noteworthy in the development of new drug substances and products. This review focuses on the introduction of nanomedicines in the pharmaceutical market, and all the controversy associated to basic concepts related to these nanosystems, and the numerous methodologies applied for enhanced knowledge. Due to the properties conferred by the nanoscale, the challenges for nanotechnology implementation, specifically in the pharmaceutical development of new drug products and respective regulatory issues are critically discussed, mainly focused on the European Union context. Finally, issues pertaining to the current applications and future developments are presented.

397 citations

Cites background from "State of the art of nanocrystals--s..."

  • ...The superoxide dismutase converts superoxide anion into hydrogen peroxide and catalase, in contrast, converts it into water and molecular oxygen (Nel et al., 2006; Arora et al., 2012; Azhdarzadeh et al., 2015)....

    [...]

  • ...The free radicals will induce oxidative stress and interact with the fatty acids in the membranes of the cell (Nel et al., 2006; Arora et al., 2012; Azhdarzadeh et al., 2015)....

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  • ...Distinct physiological outcomes are possible due to the different pathways for cell injury after the interaction between nanomaterials and cells and tissues (Nel et al., 2006; Arora et al., 2012; Azhdarzadeh et al., 2015)....

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Journal Article•DOI•
Mucoadhesive polymers in the design of nano-drug delivery systems for administration by non-parenteral routes: A review

[...]

Alejandro Sosnik1, José Neves2, Bruno Sarmento2•
Technion – Israel Institute of Technology1, University of Porto2
01 Dec 2014-Progress in Polymer Science
TL;DR: The benefit of the incorporation of mucoadhesive polymers into the structure of these innovative pharmaceutical products to prolong their residence time in the administration site and the release of the drug cargo will be discussed with focus in the developments of the last decade.

388 citations

Journal Article•DOI•
Bottom-up approaches for preparing drug nanocrystals: formulations and factors affecting particle size.

[...]

Biswadip Sinha1, Rainer H. Müller1, Jan P. Möschwitzer1•
Free University of Berlin1
30 Aug 2013-International Journal of Pharmaceutics
TL;DR: The bottom-up approach has not yet been established as a successful commercial technology, however, it has the potential to produce small size drug nanocrystals with less energy demanding processes.

378 citations

Cites background from "State of the art of nanocrystals--s..."

  • ...…the fact that particles with this size range get new 182 physical properties, and their permeation through various biological barriers improves 183 (Muller et al., 2011).184 Several review articles are already available in the fields that focus on various aspects 185 of top-down production method…...

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Journal Article•DOI•
Nanotoxicology applied to solid lipid nanoparticles and nanostructured lipid carriers - a systematic review of in vitro data.

[...]

Slavomira Doktorovova1, Eliana B. Souto1, Amélia M. Silva1•
University of Trás-os-Montes and Alto Douro1
01 May 2014-European Journal of Pharmaceutics and Biopharmaceutics
TL;DR: This review collected the available data from cytotoxicity, oxidative stress and hemocompatibility studies in vitro and analysed their outcomes and provided a summary of the availableData in a form of reference table.

328 citations

References
More filters
Journal Article•DOI•
A Theoretical Basis for a Biopharmaceutic Drug Classification: The Correlation of in Vitro Drug Product Dissolution and in Vivo Bioavailability

[...]

Gordon L. Amidon1, Hans Lennernäs2, Vinod P. Shah, John R. Crison•
University of Michigan1, Uppsala University2
01 Mar 1995-Pharmaceutical Research
TL;DR: A biopharmaceutics drug classification scheme for correlating in vitro drug product dissolution and in vivo bioavailability is proposed based on recognizing that drug dissolution and gastrointestinal permeability are the fundamental parameters controlling rate and extent of drug absorption.
Abstract: A biopharmaceutics drug classification scheme for correlating in vitro drug product dissolution and in vivo bioavailability is proposed based on recognizing that drug dissolution and gastrointestinal permeability are the fundamental parameters controlling rate and extent of drug absorption. This analysis uses a transport model and human permeability results for estimating in vivo drug absorption to illustrate the primary importance of solubility and permeability on drug absorption. The fundamental parameters which define oral drug absorption in humans resulting from this analysis are discussed and used as a basis for this classification scheme. These Biopharmaceutic Drug Classes are defined as: Case 1. High solubility-high permeability drugs, Case 2. Low solubility-high permeability drugs, Case 3. High solubility-low permeability drugs, and Case 4. Low solubility-low permeability drugs. Based on this classification scheme, suggestions are made for setting standards for in vitro drug dissolution testing methodology which will correlate with the in vivo process. This methodology must be based on the physiological and physical chemical properties controlling drug absorption. This analysis points out conditions under which no in vitro-in vivo correlation may be expected e.g. rapidly dissolving low permeability drugs. Furthermore, it is suggested for example that for very rapidly dissolving high solubility drugs, e.g. 85% dissolution in less than 15 minutes, a simple one point dissolution test, is all that may be needed to insure bioavailability. For slowly dissolving drugs a dissolution profile is required with multiple time points in systems which would include low pH, physiological pH, and surfactants and the in vitro conditions should mimic the in vivo processes. This classification scheme provides a basis for establishing in vitro-in vivo correlations and for estimating the absorption of drugs based on the fundamental dissolution and permeability properties of physiologic importance.

5,049 citations

"State of the art of nanocrystals--s..." refers background in this paper

  • ...By combining the size related risks with the risks derived from persistency, a nanotoxicological classification system (NCS), similar to the BCS after Amidon, is proposed in this article....

    [...]

  • ...The oral bioavailability of poorly soluble drugs can be increased when it is limited by their dissolution velocity and too low solubility (class II drugs of the biopharmaceutical classification system (BCS) after Amidon [18])....

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Journal Article•DOI•
Nanosuspensions in drug delivery

[...]

Barrett E. Rabinow1•
Baxter International1
01 Sep 2004-Nature Reviews Drug Discovery
TL;DR: Water insolubility issues of the past have provoked a paradigm change, which now offers novel solutions for innovative drugs of the future, and additional pharmacokinetic benefits of the drugs so formulated have come to be appreciated.
Abstract: A surprisingly large proportion of new drug candidates emerging from drug discovery programmes are water insoluble, and therefore poorly bioavailable, leading to abandoned development efforts. These so-called 'brickdust' candidates can now be rescued by formulating them into crystalline nanosuspensions. In the process of overcoming issues involving solubility, additional pharmacokinetic benefits of the drugs so formulated have come to be appreciated. As such, insolubility issues of the past have provoked a paradigm change, which now offers novel solutions for innovative drugs of the future.

1,388 citations

"State of the art of nanocrystals--s..." refers background in this paper

  • ...Drug nanocrystals are particles made from 100% drug; typically, they are stabilized by surfactants or polymeric steric stabilizers [1,2]....

    [...]

Journal Article•DOI•
Nanosizing: a formulation approach for poorly-water-soluble compounds.

[...]

Elaine Merisko-Liversidge, Gary Liversidge, Eugene R. Cooper
01 Feb 2003-European Journal of Pharmaceutical Sciences
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

"State of the art of nanocrystals--s..." refers methods in this paper

  • ...A low energy milling process is the pearl mill (bead mill), the technology developed by Liversidge and co-workers [28,29], being the NanoCrystal technology of élan (prev....

    [...]

Patent•
Surface modified drug nanoparticles

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Liversidge Gary G, Cundy Kenneth C, John F. Bishop, Czekai David A
20 Jan 1992
TL;DR: In this article, the authors describe methods for the preparation of such particles and dispersions containing the particles and demonstrate that such particles exhibit unexpected bioavailability and are useful in methods of treating mammals.
Abstract: Dispersible particles consisting essentially of a crystalline drug substance having a surface modifier adsorbed on the surface thereof in an amount sufficient to maintain an effective average particle size of less than about 400 nm, methods for the preparation of such particles and dispersions containing the particles. Pharmaceutical compositions containing the particles exhibit unexpected bioavailability and are useful in methods of treating mammals.

1,214 citations

Journal Article•DOI•
Cyclodextrins in drug delivery: an updated review.

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Rajeswari Challa1, Alka Ahuja1, Javed Ali1, Roop K. Khar1•
Hamdard University1
14 Oct 2005-Aaps Pharmscitech
TL;DR: Cyclodextrins, because of their continuing ability to find several novel applications in drug delivery, are expected to solve many problems associated with the delivery of different novel drugs through different delivery routes.
Abstract: The purpose of this review is to discuss and summarize some of the interesting findings and applications of cyclodextrins (CDs) and their derivatives in different areas of drug delivery, particularly in protein and peptide drug delivery and gene delivery. The article highlights important CD applications in the design of various novel delivery systems like liposomes, microspheres, microcapsules, and nanoparticles. In addition to their well-known effects on drug solubility and dissolution, bioavailability, safety, and stability, their use as excipients in drug formulation are also discussed in this article. The article also focuses on various factors influencing inclusion complex formation because an understanding of the same is necessary for proper handling of these versatile materials. Some important considerations in selecting CDs in drug formulation such as their commercial availability, regulatory status, and patent status are also summarized. CDs, because of their continuing ability to find several novel applications in drug delivery, are expected to solve many problems associated with the delivery of different novel drugs through different delivery routes.

1,135 citations

Related Papers (5)
Nanosuspensions in drug delivery

[...]

01 Sep 2004-Nature Reviews Drug Discovery
Barrett E. Rabinow
Drug nanocrystals of poorly soluble drugs produced by high pressure homogenisation

[...]

01 Jan 2006-European Journal of Pharmaceutics and Biopharmaceutics
Cornelia M. Keck, Rainer H. Müller
Nanocrystal technology, drug delivery and clinical applications

[...]

12 Sep 2008-International Journal of Nanomedicine
Jens-Uwe A. H. Junghanns, Rainer H. Müller
Nanosizing: a formulation approach for poorly-water-soluble compounds.

[...]

01 Feb 2003-European Journal of Pharmaceutical Sciences
Elaine Merisko-Liversidge, Gary Liversidge, Eugene R. Cooper
Nanosizing--oral formulation development and biopharmaceutical evaluation.

[...]

30 Jul 2007-Advanced Drug Delivery Reviews
Filippos Kesisoglou, Santipharp Panmai, Yunhui Wu
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Q1. What are the contributions in this paper?

Drug nanocrystals are the latest, broadly introduced nanoparticulate carrier to the pharmaceutical market from the year 2000 onwards. As nanotoxicological aspects, the effect of size, degradability versus biopersistency and intracellular uptake are discussed, classifying the nanocrystals in the low/non-risk group.