NanoFormulation

By Gordon J.T. Tiddy, Reginald B.H. Tan

The Royal Society of Chemistry

Copyright © 2012 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-1-84973-378-6

Contents

Formulation of Nano-Bio Materials,
Formulating Nanoparticles To Achieve Oral And Intravenous Delivery Of Challenging Drugs (Keynote Lecture) Christine Vauthier, 3,
The Preparation, Optimization And Characterization Of Viral Protein Complexed Liposomes (Oral) Shailja Tiwari, Sunil K. Verma and Suresh P. Vyas, 20,
Development And In Vitro Evaluations Of A Lipid Nanoparticle Formulation Containing Tretinoin Surajit Das, Wai Kiang Ng and Reginald B.H. Tan, 38,
The Phase Behaviour Of Saturated And Unsaturated Monoglycerides And The Influence Of Triglyceride On The Aggregation In A Hydrophobic System Abdullatif Alfutimie, Robin Curtis, and Gordon J. T. Tiddy, 53,
Tamoxifen Loaded Auto-Assembled Nanoparticles For Oral Delivery: Cytotoxicity And Permeability Studies S. Barbieri, F. Sonvico, K. Bouchemal, G. Ponchel and P. Colombo, 70,
Formulation Of Gliclazide Encapsulated Chitosan Nanoparticles: In Vitro And In Vivo Evaluation Ranjith Kumar Averineni, Gopal Venkatesh Shavi, Om Prakash Ranjan, Praful Balavant Deshpande, Gurram Aravind Kumar, Usha Yogendra Nayak, Meka Sreenivasa Reddy and Nayanabhirama Udupa, 77,
Handling And Processing Of Nanopowders,
Nanocomposites Prepared By Ultrasonic Spray Pyrolysis And Their Applications (Oral) Rongbo Zheng, 89,
Sintering Studies On The Various Properties Of Barium Titanate Nanoparticles Synthesized By A Novel Technique T. Sundararajan, T. Karthi and, S. Balasivanandha Prabu, 94,
Dry Powder Nanoparticulate Formulations For Mucosal Vaccination Regina Scherließ and Simon Buske, 104,
Functionalization Of SiO2 Nanoparticles And Their Superhydrophobic Surface Coating Y. H. Sehlleier, A. Abdali, T. Hulser, H. Wiggers and C. Schulz, 113,
Influence Of The Structural Characteristics Of Silver And Gold Nanoparticles On The Surface-Enhancement Factors Of The Raman Signals From Aromatic Amines Katrina A. Smith, Ngee Sing Chong, Kiran Donthula, and Beng Guat Ooi, 121,
Processing And Stabilisation Of Nanoparticle Suspensions,
Microfluidics Reaction Technology (MRT) For Continuous Production For Nano-Formulations Of Drug Entities And Advanced Materials (Oral) T. Panagiotou, K.J. Chomistek and R.J. Fisher, 135,
Formulation And Evaluation Of Solid Lipid Nanoparticulate Gel For Antiacne Therapy Ajay Kumar, Neha Gulati, Randhir Gupta, Koshy MK and Shubhini A. Saraf, 150,
The Effect Of Formulation And Process Variables On Droplet Size Reduction Using A High-Throughput Processing Platform Vicky Riding, Daniel Harvey, Peter J. Martin and Adam J. Kowalski, 160,
Physical Chemistry At The Nanoscale,
Nanoparticles In Organic Solvents With Polymers – Stability And Consequences Upon Material Synthesis Through Spray Drying And Melt Moulding (Oral) M. Rudolph, C. Turan, S. Kirchberg, G. Ziegmann and U.A. Peuker, 177,
Thermal Investigation Of Copper-Doped-Zirconia Nanoparticles L. Mikac, M. Ivanda, G. Stefanie, S. Music, K. Furic and D. Car, 188,
Morphological Studies Of Polyaniline/TiO2 Polymer Composite N. Narsimlu, B. Kavitha, D. Srinivasu and K. Sivakumar, 194,
Bound Water Investigations On Disaccharide Based Glycolipids Seyed Mohammad, Mirzadeh Hosseini, Rauzah Hashim, Thorsten Heidelberg and Bakir A. Timimi, 205,
Smart And Functional Materials In Formulations: Coatings, Films And Tapes,
Highly-Branched Poly(N-Isopropyl Acrylamide (Keynote) Stephen Rimmer, 215,
Saxs Studies Of Poly (3-Octylthiophene) And Poly (3,3″-Dioctyl-2,2″,5’2″ Terithiophene) Polymer Thin Films K. Sivakumar, B. Kavitha, C. Wu and N. Narsimlu, 235,
Safety And Health Effects Of Nanoscale Materials: Towards Sustainable And Safe Nanomaterials,
Short-Term Exposure To Nanoparticle-Rich Diesel Engine Exhaust Causes Changes In Brain Activity But Not In Cognitive Performance In Human Volunteers (Keynote),
Anique Driessen, Bjorn Crilts, Ludo van Etten, Anica Crilts, Paul Fokkens, Flemming Cassee and Paul J.A. Borm, 243,
Nano-Sized Delivery For Agricultural Chemicals Min Zhao, Lei Liu, Robert Ehr, Tom Kalantar, Dale Schmidt, Todd Mathieson, Mike Tolley, Kerrm Yau, Steven Wensing, Qiang Zhan, Mark Zettler, Ze-Sheng Li and Dan Zweifel, 256,
Subject Index, 266,

CHAPTER 1

FORMULATING NANOPARTICLES TO ACHIEVE ORAL AND INTRAVENOUS DELIVERY OF CHALLENGING DRUGS

Christine Vauthier

1 INTRODUCTION

Existing treatments of severe diseases like cancer, severe infections and metabolic disease are limited by the general toxicity or by the low bioavailability of drugs or by both of these limitations. It has been found that associating such drugs with a carrier of colloidal size ranging from around 10 nm to several hundred nanometers was a relevant clinical approach to develop new effective and safe therapies. The benefit comes from the fact that carriers can modify the in vivo fate of the drug by changing its biodistribution. In this aim, the carrier is expected to modulate the different phases controlling drug bioavailability and biodistribution in the way it will improve the delivery to the target tissues and cells. The different processes that can be affected include absorption, distribution, metabolism and elimination when the drug is administered by the oral route or by an extravascular route. After intravenous administration, processes that need to be modulated include the distribution, the metabolism and the elimination of the drug.

The fact that carriers of colloidal size can be used to change absorption, metabolism and elimination of drugs also gives opportunity for challenging molecules to be developed. Those include new antiviral and anticancer drugs. For instance, several are small drug molecules with a low solubility in aqueous media. Others are molecules highly metabolized in biological medium. Finally, they can be part of the new generation of molecules with a very specific biological activity but unstable in biological media and incapable to cross biological barriers. A typical example of challenging small molecule is paclitaxel. It is a powerful anticancer agent widely used in clinics. However, it is a substrate of cytochrome P-450 (i.e. CYP3A4) and of the efflux pump Pgp hampering its delivery by the oral route. Those two effects greatly hamper the oral absorption of paclitaxel making this drug only administrable by parenteral routes. In addition, because this drug is a substrate of the Pgp efflux pump, treatments are rapidly inefficient due to the occurrence of a resistance to the treatment. Other molecules include peptides, proteins and nucleic acids. All these compounds are highly metabolized whatever the route of administration. They also hardly diffuse across biological barriers because of their high molecular weight and their hydrophilic characteristics.

In general, stability of drugs in biological media is well improved after association with a carrier whatever the drugs and the route of administration. Thus the most challenging goals are to improve absorption of poorly absorbed molecules by the oral route and to perfectly control the biodistribution of drugs after intravenous administration. It appears from many works that a key for the success of the approach is closely related to the adequate formulation of the carrier including a small size and suitable surface properties. The small size is mandatory to allow the drug carrier to diffuse in tissues. Regarding surface of carriers, it is in front line to interact with components of the surrounding biological medium which in turn influence the in vivo fate of the carrier. Because nanoparticles develop huge specific surface areas, there is an important contribution of surface properties of nanoparticles in the definition of their in vivo fate. Thus, to obtain a drug carrier with a specific biodistribution, a large part of formulation strategies needs to be focussed on designing its surface properties.

In practice, thanks to their size range, different colloidal systems were found suitable to be used as drug carriers. So far, a few general rules on the design and formulation strategies of their surface properties can be drawn from works aiming to obtain drug carriers with controlled in vivo fate after oral and intravenous administration. They will be discussed in the present paper based on results reported with poly(alkylcyanoacrylate) nanoparticles. These nanoparticles were the first degradable nanoparticles evaluated for intravenous and oral delivery of drugs. At present, they are a large family of drug carriers including various types of nanoparticles that were evaluated for their potential to deliver many types of drugs by different routes of administration.

2 GENERAL CONSIDERATIONS IN FORMULATION STRATEGY OF NANOPARTICLES FOR DRUG DELIVERY

A few general rules are to be considered to formulate nanoparticles designed to improve the efficacy of in vivo delivery of drugs. Although all types of carriers must be made of biocompatible material, formulation strategies greatly depend on the route of administration that will be considered for the delivery of the drug. General characteristics expected for drug carriers designed for oral and intravenous administration of drugs are summarized in table 1 together with the main known limitations compromising drug delivery by these routes of administration.

Formulating nanoparticles start by choosing suitable materials for their in vivo compatibility and degradability. Then, the formulator needs to decide which type of nanoparticles he would like to prepare between nanospheres and nanocapsules that will greatly influence the loading and releasing properties of the drug. The nanospheres occur as plain nanoparticles while nanocapsules displayed a vesicular structure. Although most of the nanoparticles developed so far were spherical, reports appeared in the literature considering non spherical nanoparticles showing that the nanoparticle shape is an additional factor influencing their fate in biological systems. Having chosen the material and the type of nanoparticles, the formulator can choose a process of preparation among a large panel of methods. Some are based on polymerization, others are based on specific preparation procedures using preformed polymers. As shown on the diagram presented in figure 1, the characteristics of the materials and the physicochemical characteristics of the drug carriers influence directly their in vivo fate. As mentioned above, nanoparticle surface is in the front line to interact with components of the surrounding biological media. It is noteworthy that, because of the submicron size of nanoparticles, the amount of surface of a given mass of nanoparticles is considerable making surface properties one of the most important parameter to control the in vivo fate of the drug carrier. Obviously, the chemical nature of the material stranding at the surface of the carrier defines the general physicochemical characteristics of the carrier surface. It also contributes to define the type of interactions with components of the surrounding medium. However, formulation of drug carriers with fully controlled in vivo fate would require that all mechanisms involved in this control will be elucidated which is not yet the case. Advances in the comprehension of phenomenon controlling the in vivo fate of nanoparticles also depends on the route of administration considered for the in vivo administration of the drug-loaded carrier. Thus specific strategies of formulations need to be applied depending on the route of administration.

3. FORMULATION OF NANOPARTICLES FOR INTRAVENOUS DELIVERY OF DRUGS

In general, when nanoparticles are designed to improve efficacy of drug administered intravenously, the aim is to achieve the delivery of the drug with a high specificity to the target cells. This implies that the in vivo fate of the nanoparticles should be perfectly controlled from the site of administration (site of injection) down to the target cells (for instance a tumor cell). These two sites are at a certain distance from each other in the body and in a different compartment.

Indeed, target cells are often located outside the blood compartment requiring that carriers cross blood vessel endothelium. Several critical steps were found decisive for the success of the delivery method (Figure 2). They need to be carefully considered while designing drug carriers to resolve specific drug delivery problem.

The following paragraph aims to explain the known critical steps that influence distribution of nanoparticles administered by intravenous injection. A polymer nanoparticle designed as a drug carrier is a man made object. Regarding the organism, it is a foreign particle which must be eliminated from the body. To achieve this aim, the organism has defence mechanisms which include opsonisation of the particle surface with serum protein, activation of the complement cascade, phagocytosis by macrophages of the mononuclear phagocyte system in charge of the elimination of foreign particles by the liver (Figure 3 particle 1). Particles recognized by the defence system are found in the liver shortly after their intravenous injection. They are called “non-stealth” nanoparticles and can serve to target drugs to the liver according to a passive targeting approach. Nanoparticles bypassing the defence systems of the organism are qualified as “stealth”. They can be transported by the blood to reach different organs and tissues while their distribution towards the liver is considerably reduced compared with that of the non-stealth nanoparticles. In this case, the second critical step corresponds to the passage of the nanoparticles through the capillary endothelium. This step is required for drug carriers to escape the blood compartment and to reach the tissue containing target cells. In general, the smaller the nanoparticles the better is the diffusion thought the endothelium. However, this greatly depends on the physiological stage of the endothelium. In most of the normal and healthy tissues, the endothelium is continuous and do not allow particles to cross over. Thus, particles remain in the blood circulation in normal and healthy tissues. In contrast, blood vessels feeding tumoral tissues are fenestrated. It is admitted that the pores of these vessels can leave a particle of a diameter bellow 100 nm to cross over although the upper limit of the particle diameter may vary with the type, size and age of the tumor. Combined with the high lymphatic drainage taking place in tumoral tissues, nanoparticles of very small size can leave the blood compartment and specifically reach tumoral tissues thanks to the enhanced permeation and retention effect (EPR) (Figure 3, particles 2). It is noteworthy that tissue of the central nervous system is extremely difficult to reach from the blood compartment because of the structure of the blood capillaries of the blood brain barrier and its high selective permeability. However, it was shown that the profile of opsonisation of certain stealth nanoparticles allowed them to be translocated into the brain tissue by a receptor mediated transport. This is a very specific transport mechanism that requires that the nanoparticles were opsonised with define apolipoproteins (Figure 3 particles 3). Thus, improved delivery of drugs can be achieved to tissue by a passive targeting of the nanoparticles. Disease tissues can be reached thanks to the combined effect of stealth properties of the nanoparticles and the EPR effect occurring at the level of the diseased tissue. To deliver drugs to the brain, stealth nanoparticles with long circulation time are requested in combination with an opsonisation with apolipoproteins.

Delivering the drug with the highest degree of specificity to the target cells requires that the drug carrier and the cells recognize each other. To achieve this aim, the drug carrier must be equipped with ligands that are able to interact specifically with the target cells. This active targeting process will allow the drug carrier to deliver its cargo only to the desired cells. More degrees of specificity may be required when the drug need to be deliver in a define compartment of the target cell or at a certain time of the cell cycle. All additional requests add to the sophistication of the drug carrier which needs to integrate all functionalities in one particle.

Obviously, strategies of formulation need to take into account the different mechanisms that control the in vivo fate of the nanoparticles. Efforts will be made in order to design the relevant nanoparticle surface in agreement with the requested biodistribution. In general, targeting drugs with nanoparticles to the liver is quite an easy task as all foreign objects from the body are naturally recognized by the defence systems of the organisms and eliminated by macrophages of the mononuclear phagocyte system including the Kuppfer cells.

Designing stealth nanoparticles which are able to distribute in define organs and tissues outside the organs of the mononuclear phagocytes system is challenging because the defence mechanisms of the body are extremely efficient and difficult to escape. As explained bellow with examples taken form the experience gained with poly(alkylcyanoacrylate) nanoparticles, several strategies were suggested to circumvent this first obstacle making possible the delivery of drugs to tumors by passive targeting.

(Continues…)Excerpted from NanoFormulation by Gordon J.T. Tiddy, Reginald B.H. Tan. Copyright © 2012 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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