Drug delivery strategies for poorly water-soluble drugs: the industrial perspective

Introduction: For poorly soluble compounds, a good bioavailability is typically needed to assess the therapeutic index and the suitability of the compound for technical development. In industry, the selection of the delivery technology is not only driven by technical targets, but also by constraints, such as production costs, time required for development and the intellectual property situation. Areas covered: This review covers current developments in parenteral and oral delivery technologies and products for poorly water-soluble compounds, such as nano-suspensions, solid dispersions and liposomes. In addition, the use of biorelevant dissolution media to assess dissolution and solubility properties is described. Suggestions are also included to systematically address development hurdles typical of poorly water-soluble compounds intended for parenteral or oral administration. Expert opinion: A holistic assessment is recommended to select the appropriate delivery technology by taking into account technical as well as intellectual property considerations. Therefore, first and foremost, a comprehensive physico-chemical characterization of poorly water-soluble compounds can provide the key for a successful selection and development outcome. In this context, the identified physical form of the compound in the formulation is used as a guide for a risk–benefit assessment of the selected oral delivery technology. The potential of nano-suspensions for intravenous administration is unclear. In the case of oral administration, nano-suspensions are mainly used to improve the oral absorption characteristics of micronized formulations. The development of an in situ instantaneous solubilization method, based on stable, standardized liposomes with low toxicity, opens new avenues to solubilize poorly water-soluble compounds.

[1]  Katsuhiko Yamamoto,et al.  High-throughput cocrystal slurry screening by use of in situ Raman microscopy and multi-well plate. , 2010, International journal of pharmaceutics.

[2]  S. Balbach,et al.  Pharmaceutical evaluation of early development candidates "the 100 mg-approach". , 2004, International journal of pharmaceutics.

[3]  Martin Kuentz,et al.  Study of a Standardized Taurocholate- Lecithin Powder for Preparing the Biorelevant Media FeSSIF and FaSSIF , 2010 .

[4]  E. Masini,et al.  Histamine-releasing properties of Polysorbate 80in vitro andin vivo: correlation with its hypotensive action in the dog , 1985, Agents and Actions.

[5]  Christos Reppas,et al.  Dissolution Testing as a Prognostic Tool for Oral Drug Absorption: Immediate Release Dosage Forms , 2004, Pharmaceutical Research.

[6]  A. Fahr,et al.  Drug delivery strategies for poorly water-soluble drugs , 2007, Expert opinion on drug delivery.

[7]  R. Strickley.  Solubilizing Excipients in Oral and Injectable Formulations , 2004, Pharmaceutical Research.

[8]  W. Lorenz,et al.  Histamine release in dogs by Cremophor El® and its derivatives: Oxethylated oleic acid is the most effective constituent , 1977, Agents and Actions.

[9]  Michael Juhnke,et al.  Accelerated Formulation Development for Nanomilled Active Pharmaceutical Ingredients Using a Screening Approach , 2010 .

[10]  R. Mistry,et al.  A REVIEW: SELF EMULSIFYING DRUG DELIVERY SYSTEM , 2011 .

[11]  Shan Ren,et al.  New perspectives on lipid and surfactant based drug delivery systems for oral delivery of poorly soluble drugs , 2010, The Journal of pharmacy and pharmacology.

[12]  J. Crison,et al.  A Theoretical Basis for a Biopharmaceutic Drug Classification: The Correlation of in Vitro Drug Product Dissolution and in Vivo Bioavailability , 1995, Pharmaceutical Research.

[13]  S. Gould,et al.  2-Hydroxypropyl-beta-cyclodextrin (HP-beta-CD): a toxicology review. , 2005, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[14]  K. Amighi,et al.  Preparation and in vitro/in vivo evaluation of nano-sized crystals for dissolution rate enhancement of ucb-35440-3, a highly dosed poorly water-soluble weak base. , 2006, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[15]  Raimar Löbenberg,et al.  Dissolution Testing as a Prognostic Tool for Oral Drug Absorption: Dissolution Behavior of Glibenclamide , 2000, Pharmaceutical Research.

[16]  Jennifer B Dressman,et al.  The developability classification system: application of biopharmaceutics concepts to formulation development. , 2010, Journal of pharmaceutical sciences.

[17]  Gary Eichenbaum,et al.  Screening method to identify preclinical liquid and semi-solid formulations for low solubility compounds: miniaturization and automation of solvent casting and dissolution testing. , 2007, Journal of pharmaceutical sciences.

[18]  David S. Baker,et al.  Practical aspects of lyophilization using non-aqueous co-solvent systems. , 2002, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[19]  M. Bally,et al.  Liposomal drug delivery: recent patents and emerging opportunities. , 2007, Recent patents on drug delivery & formulation.

[20]  A. Eschalier,et al.  Study of histamine release induced by acute administration of antitumor agents in dogs , 2004, Cancer Chemotherapy and Pharmacology.

[21]  Christos Reppas,et al.  Biorelevant in vitro dissolution testing of products containing micronized or nanosized fenofibrate with a view to predicting plasma profiles. , 2011, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[22]  M. Kuentz,et al.  Oral self-emulsifying drug delivery systems, from biopharmaceutical to technical formulation aspects , 2011 .

[23]  M. Rettenmaier,et al.  Abraxane in the treatment of ovarian cancer: the absence of hypersensitivity reactions. , 2006, Gynecologic oncology.

[24]  P. van Hoogevest,et al.  Transfer of lipophilic drugs between liposomal membranes and biological interfaces: consequences for drug delivery. , 2005, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[25]  B. Kapp,et al.  Histamine release and hypotensive reactions in dogs by solubilizing agents and fatty acids: Analysis of various components in cremophor El and development of a compound with reduced toxicity , 1982, Agents and Actions.

[26]  A. Fahr,et al.  Role of phospholipids in the oral and parenteral delivery of poorly water soluble drugs , 2011 .

[27]  Elaine Merisko-Liversidge,et al.  Nanosizing for oral and parenteral drug delivery: a perspective on formulating poorly-water soluble compounds using wet media milling technology. , 2011, Advanced drug delivery reviews.

[28]  P. van Hoogevest,et al.  Lipophilic Drug Transfer Between Liposomal and Biological Membranes: What Does It Mean for Parenteral and Oral Drug Delivery? , 2006, Journal of liposome research.

[29]  M. Naidu,et al.  Polysorbate 80: a pharmacological study. , 1985, Arzneimittel-Forschung.

[30]  Alan G. E. Wilson,et al.  Development and application of a high-throughput formulation screening strategy for oral administration in drug discovery. , 2010, Future medicinal chemistry.

[31]  B. Schläppi,et al.  Preclinical safety evaluation of intravenously administered mixed micelles. , 1984, Arzneimittel-Forschung.

[32]  Jin Sun,et al.  Nanoparticle albumin-bound (NAB) technology is a promising method for anti-cancer drug delivery. , 2009, Recent patents on anti-cancer drug discovery.

[33]  W. Lorenz,et al.  Comparison of the histamine-releasing activity of cremophor El® and some of its derivatives in two experimental models: Thein vivo anaesthetized dog andin vitro rat peritoneal mast cells , 1985, Agents and Actions.

[34]  W. Lorenz,et al.  Modulation of histamine release from rat peritoneal mast cells by non-cytotoxic concentrations of the detergents Cremophor El® (oxethylated castor oil) and Triton X100. A possible explanation for unexpected adverse drug reactions? , 1986, Agents and Actions.

[35]  R. Corry,et al.  The hemodynamic effects of Cremophor-EL. , 1991, Transplantation.

[36]  G. Van den Mooter,et al.  Review: physical chemistry of solid dispersions. , 2009, The Journal of pharmacy and pharmacology.

[37]  Beate Bittner,et al.  Intravenous administration of poorly soluble new drug entities in early drug discovery: the potential impact of formulation on pharmacokinetic parameters. , 2002, Current opinion in drug discovery & development.

[38]  J. Gillespie,et al.  Food effect on the bioavailability of two distinct formulations of megestrol acetate oral suspension , 2009 .

[39]  A. Eschalier,et al.  Acute hemodynamic effects of an antitumoral agent: elliptinium. Involvement of histamine release , 1986, Agents and Actions.

[40]  J. Breitenbach,et al.  Melt-Extruded Molecular Dispersions , 2003 .

[41]  Seshadri Neervannan,et al.  Preclinical formulations for discovery and toxicology: physicochemical challenges , 2006, Expert opinion on drug metabolism & toxicology.

[42]  F. Martin,et al.  Phospholipids and Lipid-Based Formulations in Oral Drug Delivery , 2010, Pharmaceutical Research.

[43]  Charles E. Martin,et al.  Pharmaceutical Extrusion Technology , 2003 .

[44]  Thorsteinn Loftsson,et al.  Cyclodextrins as pharmaceutical solubilizers. , 2007, Advanced drug delivery reviews.

[45]  Thorsteinn Loftsson,et al.  Self-assembly of cyclodextrins: the effect of the guest molecule. , 2011, International journal of pharmaceutics.

[46]  T. Meyer,et al.  Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. , 1996, Cancer research.

[47]  Ping Li,et al.  Developing early formulations: practice and perspective. , 2007, International journal of pharmaceutics.

[48]  M. Brewster,et al.  Self-assembly of cyclodextrin complexes: aggregation of hydrocortisone/cyclodextrin complexes. , 2011, International journal of pharmaceutics.

[49]  E. Miele,et al.  Albumin-bound formulation of paclitaxel (Abraxane® ABI-007) in the treatment of breast cancer , 2009, International journal of nanomedicine.

[50]  R. Schwartz,et al.  Increased adherence of sickled and phosphatidylserine-enriched human erythrocytes to cultured human peripheral blood monocytes. , 1985, The Journal of clinical investigation.

[51]  Toshiyuki Niwa,et al.  Universal wet-milling technique to prepare oral nanosuspension focused on discovery and preclinical animal studies - Development of particle design method. , 2011, International journal of pharmaceutics.

[52]  P. Lakshmi,et al.  NANO­SUSPENSION TECHNOLOGY: A REVIEW , 2010 .

[53]  W. Tong.  Chapter 4 – Salt Screening and Selection: New Challenges and Considerations in the Modern Pharmaceutical Research and Development Paradigm , 2009 .

[54]  R. Jankowiak,et al.  Electrochemically deposited metal nanoparticles for enhancing the performance of microfluidic MEMS in biochemical analysis , 2009 .

[55]  Mark E. Davis,et al.  Cyclodextrin-based pharmaceutics: past, present and future , 2004, Nature Reviews Drug Discovery.

[56]  M. Ben-Am,et al.  Absolute Bioavailability of Imatinib (Glivec®) Orally versus Intravenous Infusion , 2004, Journal of clinical pharmacology.

[57]  S. Gould,et al.  2-Hydroxypropyl-β-cyclodextrin (HP-β-CD): A toxicology review , 2005 .

[58]  J. Dressman,et al.  In vitro-in vivo correlations for lipophilic, poorly water-soluble drugs. , 2000, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[59]  Lieven Baert,et al.  Pharmacokinetics and Disposition of Rilpivirine (TMC278) Nanosuspension as a Long-Acting Injectable Antiretroviral Formulation , 2010, Antimicrobial Agents and Chemotherapy.

[60]  F. Borek.  Liposomes in the therapy of infectious diseases and cancer: Lopez-Berestein, G. and Fidler, I.J. (Eds.), 500 pp. Alan R. Liss, New York, 1989. USD 96.00, ISBN 0-8451-2688-1 , 1990 .

[61]  Peter Van Hoogevest,et al.  Instant solubilization of poorly water-soluble drugs by in-situ loading of aqueous phospholipid dispersions suitable for parenteral administration. , 2006, PDA journal of pharmaceutical science and technology.

[62]  S. Prodduturi,et al.  Stabilization of hot-melt extrusion formulations containing solid solutions using polymer blends , 2007, AAPS PharmSciTech.

[63]  G. Liversidge,et al.  Drug particle size reduction for decreasing gastric irritancy and enhancing absorption of naproxen in rats , 1995 .

[64]  Filippos Kesisoglou,et al.  Forecasting in vivo oral absorption and food effect of micronized and nanosized aprepitant formulations in humans. , 2010, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[65]  Christos Reppas,et al.  Forecasting the In Vivo Performance of Four Low Solubility Drugs from Their In Vitro Dissolution Data , 1999, Pharmaceutical Research.

[66]  N. Kaniwa,et al.  Effect of food on the bioavailability of griseofulvin from microsize and PEG ultramicrosize (GRIS-PEG) plain tablets. , 1982, Journal of pharmacobio-dynamics.

[67]  A. Plotnick.  Lipid-based formulations of amphotericin B. , 2000, Journal of the American Veterinary Medical Association.

[68]  S. Riegelman,et al.  Pharmaceutical applications of solid dispersion systems. , 1971, Journal of pharmaceutical sciences.

[69]  D. Dolphin,et al.  Drug release characteristics of lipid based benzoporphyrin derivative. , 2003, Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques.

[70]  O. Almarsson,et al.  Combined use of crystalline salt forms and precipitation inhibitors to improve oral absorption of celecoxib from solid oral formulations. , 2007, Journal of pharmaceutical sciences.

[71]  O. Corrigan.  The biopharmaceutic drug classification and drugs administered in extended release (ER) formulations. , 1997, Advances in experimental medicine and biology.

[72]  Jing Chen,et al.  Parallel screening approach to identify solubility-enhancing formulations for improved bioavailability of a poorly water-soluble compound using milligram quantities of material. , 2007, International journal of pharmaceutics.

[73]  J. Dressman,et al.  The BCS: Where Do We Go from Here? , 2001 .

[74]  黄亚明,et al.  RxList , 2012 .

[75]  Gloria Kwei,et al.  The role of biopharmaceutics in the development of a clinical nanoparticle formulation of MK-0869: a Beagle dog model predicts improved bioavailability and diminished food effect on absorption in human. , 2004, International journal of pharmaceutics.

[76]  P. R. Veerareddy,et al.  Lipid-based formulations of amphotericin B. , 2004, Drugs of today.

[77]  K. Pathak,et al.  Porous Carriers for Controlled/Modulated Drug Delivery , 2009, Indian journal of pharmaceutical sciences.

[78]  D. Dolphin,et al.  Biodistribution of tritiated benzoporphyrin derivative (3H-BPD-MA), a new potent photosensitizer, in normal and tumor-bearing mice. , 1990, Journal of photochemistry and photobiology. B, Biology.

[79]  Brian Samas,et al.  An intravenous formulation decision tree for discovery compound formulation development. , 2003, International journal of pharmaceutics.

[80]  Wei-Guo Dai,et al.  Advanced screening assays to rapidly identify solubility-enhancing formulations: high-throughput, miniaturization and automation. , 2008, Advanced drug delivery reviews.