Introduction To Nanoparticulate Systems

Published Date: 02 Nov 2017

Drug delivery research is clearly moving from the micro- to the nano size scale. Nanotechnology is therefore emerging as a field in medicine that is expected to elicit significant therapeutic benefits. The development of effective nano delivery systems capable of carrying a drug specifically and safely to a desired site of action is one of the most challenging tasks of pharmaceutical formulation investigators. They are attempting to reformulate and add new indications to the existing blockbuster drugs to maintain positive scientific outcomes and therapeutic breakthroughs1.

During last two decades, considerable attention has been given to the development of novel drug delivery systems (NDDS). The rational for control drug delivery is to alter the pharmacokinetics and pharmacodynamics of drug substance in order to improve the therapeutic efficacy and safety. Besides more traditional matrix or reservoir drug delivery systems, colloidal drug delivery system has gained in more popularity2. Colloidal drug delivery systems offer a number of advantages over conventional dosage forms. Due to their small particle size, colloidal preparations lend themselves to parenteral preparations and may be useful as sustain release injections for the delivery to a specific organ or target site3. The major colloidal drug delivery systems include liposome and nanoparticles2.

The nano delivery systems mainly include nanoemulsions, lipid or polymeric nanoparticles, and liposomes. Nanoemulsions are primarily used as vehicles of lipophilic drugs following intravenous administration. On the other hand, the ultimate objective of the other nanodelivery systems is to alter the normal biofate of potent drug molecules in the body following their intravenous administration to markedly improve their efficacy and reduce their potential intrinsic severe adverse effects4.

Ongoing efforts are being made to develop polymeric nanocarriers capable of delivering active molecules specifically to the intended target organ. This approach involves modifying the pharmacokinetic profile of various therapeutic classes of drugs through their incorporation into nanodelivery systems. These site-specific delivery systems allow an effective drug concentration to be maintained for a longer interval in the target tissue and result in decreased adverse effects associated with lower plasma concentrations in the peripheral blood. Thus, drug targeting has evolved as the most desirable but elusive goal in the science of drug nanodelivery1.

Drug targeting offers enormous advantages but is highly challenging and extremely complicated. Increased knowledge on the cellular internalization mechanisms of the nanocarriers is crucial for improving their efficacy, site-specific delivery, and intracellular targeting. Optimal pharmacological responses require both spatial placement of the drug molecules and temporal control at the site of action. Many hurdles still need to be overcome through intensive efforts and concentrated interdisciplinary scientific collaborations to reach the desired goals1. There are various techniques to prepare drug-loaded nanoparticles, the selection of which depends on the physicochemical properties of the bioactive molecule and the polymer4. The nanoparticulate drug delivery field is complex and requires considerable interdisciplinary knowledge1.

Pharmaceutical nanoparticles are submicron-sized, colloidal vehicles that carry drugs to the target or release drugs in a controlled way in the body. After preparation, nanoparticles are usually dispersed in liquid. Such a system can be administered to humans for example by injection, by the oral route, or used in ointments and ocular products. Alternatively, nanoparticles can be dried to a powder, which allows pulmonary delivery or further processing to tablets or capsules5.

In drug delivery, nanoparticles should readily be biocompatible (not harmful for humans) and biodegradable (deteriorate and expulse in the body conditions). These properties, as well as targeting and controlled release, can be affected by nanoparticle material selection and by surface modification. Materials such as synthetic polymers, proteins or other natural macromolecules are used in the preparation of nanoparticles. To process these materials into nanoparticles, a variety of preparation techniques exist ranging from polymerization of monomers to different polymer deposition methods5.

Nanoparticles in pharmaceutical applications have gained plenty of research attention during recent decades. Although the research concerning formulation of nanoparticles into drug delivery devices has been extensive, only a few polymeric nanoparticulate products have reached the market. Among the drugs used in nanoparticle formulations, particularly cancer therapeutics is widely studied because the formulation might reduce toxicity of the drug while improving efficacy of the treatment. In addition to drug molecules, other candidates to be encapsulated in or coupled with nanoparticles include macromolecules like proteins, peptides and genes (nucleic acids). These kinds of molecules tend to be inactivated in the body by enzymatic degradation. In terms of controlled release, nanoparticles provide protection against the body conditions resulting in sustained release and maintenance of bioactivity before the drug reaches the target5.

After intravenous administration, nanosized particles are mainly taken up by the macrophages of the mononuclear phagocyte system (MPS) and, thus, can be localized in the liver, spleen and lungs. By modifying particle surface, e.g., by coating, defense mechanisms of the body can be avoided to some extent leading to longer circulation times of nanoparticles in the blood5.

Tailored coating also enables another promising application of nanoparticles: drug delivery across the blood-brain barrier (BBB). From the intestine, after oral administration, intracellular uptake may occur and prior to that, the nanoparticles can adhere to the mucosa (bioadhesion) and thus improve pharmacokinetics of the drug. As a summary of the above mentioned facts, the benefits of nanoparticles include protection of the encapsulated pharmaceutical substance, improved efficacy, fewer adverse effects, controlled release and drug targeting. Correspondingly, potential active substances in nanoparticle formulations could be expensive molecules applicable in small amounts. At the present time, several successful laboratory scale nanoparticulate drug targeting systems are available and some processes have been scaled up4,5.

1.1. HISTORY

Nanotechnology is an emerging and dynamic field. It is multidisciplinary in nature. Several ancient practices have been developing nanoparticles through the traditional processes but they were not identified as nanosystems /nanoparticles. Ayurveda, the ancient traditional system of medicine in India has described several "Bhasmas" which have particles with sizes in nano range and have been used traditionally1.

Nanotechnology has immense applications in almost all the fields of science and human life. As generally acknowledged, the modern nanotechnology originated in 1959. However, the actual term "nanotechnology" was not coined until 1974 by NorioTaniguchi from japan1,6. First polymer nanoparticles for pharmaceutical application were prepared in the late 1960’s and early 1970’s7,9. Since the last two decades, studies have particularly focused on the stealth-type carriers which are undetectable by mononuclear phagocytes system (MPS). These stealth nanoparticles have shown a prolonged half-life in the blood. Such long-circulating nanoparticles are supposed to be able to directly target tumors located outside the MPS regions8.

1.2. DEFINITION

Nanoparticles are colloidal polymeric particles of size below 1µm with a therapeutic agent either dispersed in polymeric matrix or encapsulated in polymer1,5. The term "polymeric nanoparticle" encompasses nanospheres and nanocapsules. Nanospheres are defined as a polymeric matrix in which the drug is uniformly dispersed and nanocapsules are described as a polymeric membrane that surrounds the drug in the matrix core as seen in Fig: 14.

Figure: 1 Structure of the polymeric nanospheres and nanocapsules4

Depending on the type of material or carrier used, four broad classes of nanoparticles are recognized as4:

Polymeric nanoparticles

Lipid based nanoparticles

Metal based nanoparticles and

Biological nanoparticles.

1.3. ADVANTAGES

Nanoparticles have received considerable attention over the past 20 years due to their advantages compared to other drug delivery systems4. The advantages of using nanoparticles for drug delivery result from two main basic properties such as small size and use of biodegradable materials.

These advantages include4,10:

Targeted delivery of drugs to the specific site to minimize toxicity.

Improved bioavailability by reducing fluctuations in therapeutic ranges.

Improved stability of drugs against enzymatic degradation.

Sustained and controlled release effect that reduces dosing frequency with improved patience compliance.

The ease of administering through various routes including oral, nasal, pulmonary, intraocular, parenteral and transdermal.

The small particle size also reduces potential irritant reactions at the injection site.

1.3.1. Advantages over Microparticles4

They have higher intracellular uptake compared to micro particles.

They are better suited for I.V. delivery since the smallest blood capillaries in the body is about 5-6 μm.

1.3.2. Advantages over Liposomes4

They have better stability in biological fluids and during storage.

Their preparation is more amenable to scale-up.

They have the unique ability to create a controlled release product.

1.4. LIMITATIONS OF NANOPARTICLES

The science and knowledge that the scientific community has today about nanotechnology and its potential versatile applications are based only on the research work done in the laboratories. The major limitations and technological hurdles faced by nanotechnology and its applications in the field of drug delivery should be addressed.

The major limitations include10:

As nanoparticles have larger surface area when compared to their volume, friction and clumping of the nanoparticles into a larger structure is inevitable, which may affect their function as a drug delivery system.

In addition, small particle size and large surface area readily result in limited drug loading and burst release.

Due to their minute size, these drug carriers can be cleared away from the body by the body’s excretory pathways. When these are not excreted, larger nanoparticles can accumulate in vital organs, causing toxicity leading to organ failure.

Once the nanoparticles are administered into the human body, they should be controlled by an external control, preventing them from causing adverse effects.

These drug delivery technologies are in various stages of research and development. 1.5. MATERIALS USED FOR PREPARATION OF NANOPARTICLES

Nanoparticles can be prepared from a variety of materials such as metals (silver, gold, platinum, silicon), as well as polymers and lipids. Researchers have developed virus based nanoparticles for tissue-specific targeting and imaging agents in vivo4. Polymeric nanoparticles made from natural and synthetic polymers have received the majority of attention due to higher stability and the opportunity for further surface nanoengineering. They can be tailor-made to achieve both controlled drug release and disease specific localization by tuning the polymer characteristics and surface chemistry11. Biodegradable polymers are advantageous in many ways over other materials for use in drug delivery systems such as nanoparticles. By selecting the appropriate polymer type, molecular weight, and copolymer blend ratio, the degradation/erosion rate of the nanoparticles can be controlled to achieve the desired type and rate of release of the encapsulated drug1.

Polymeric materials can be classified broadly as natural polymers and synthetic polymers. The selection of materials for preparing nanoparticles depends upon consideration of the following factors4,10

Size and surface characteristics of the particle desired.

Aqueous solubility and stability of drugs or active ingredients.

Degree of biodegradability, biocompatibility and toxicity.

Drug release profile desired.

Antigenicity of the polymer.

A wide range of synthetic and natural polymers available for nanoparticle formation, but their biocompatibility and biodegradability are the major limiting factors for their use in the drug delivery area. Synthetic polymers, on the other hand, offer better reproducibility of the chemical characteristics of the synthesized nanoparticles as compared to the natural polymers12.

Most widely used materials for preparing nanoparticles in drug delivery were given in the table: 1.

Table: 1Most widely used polymers for preparing nanoparticles in drug delivery4

Material

Full name

Abbreviation or commercial names

Synthetic homopolymers

Poly lactide

PLA

Poly (lactide-co-glycoloide)

PLGA

Poly(epsilon-caprolactone)

PCL

Poly (isobutylcyanoacrylate)

PIBCA

Poly (isohexylecyanoacrylate)

PIHCA

Poly (n-butylcyanoacrylate)

PBCA

Poly(acrylate) and poly(methacrylate)

Eudragit

Natural polymers

Chitosan

Alginate

Gelatin

Albumin

Copolymers

Poly (lactide)-poly (ethyleneglycol)

PLA-PEG

Poly(lactide-co-glycolide)poly(ethyleneglycol)

PLGA-PEG

Poly(epsilon-caprolactone) poly(ethyleneglycol)

PCL-PEG

Poly(hexadecylcyanoacrylate-co- poly(ethyleneglycol) cyanoacrylate)

Poly(HDCA- PEGCA)

Colloid stabilizers

Dextran

PluronicF68

F68

Poly(vinyl alcohol)

PVA

Tween20 and Tween80

The utility of a nanoparticle delivery system is dependent upon the bio acceptability of the carrier polymer, which, inturn, is affected by the particle size and physicochemical properties of the polymer. Ultimately, the bioacceptability of the polymer, physicochemical properties of the drug, and the therapeutic goal will influence the final choice of the appropriate polymer, particle size, and the manufacturing method. Based on the manufacturing method for the nanoparticles, drug molecules can be either dissolved in a liquid core or dispersed within a dense polymeric matrix, resulting in nanocapsules or nanospheres1.

1.5.1. Biodegradable Polymers Used In the Fabrication of Nanoparticles

Biodegradable polymers are advantageous in many ways over other materials used in drug delivery systems such as nanoparticles1. By selecting the appropriate polymer type, molecular weight, and copolymer blend ratio, the degradation/ erosion rate of the nanoparticles can be controlled to achieve the desired type and rate of release of the encapsulated drug1. The common biodegradable polymers used in drug delivery include1, 5.

Polyesters, such as lactide and glycolide copolymers, polycaprolactones, poly(-hydroxybutyrates),

Polyamides, which includes natural polymers such as collagen, gelatin, and albumin, and semisynthetic pseudo-poly(amino acids) such as poly(N-palmitoyl hydroxyproline ester),

Polyurethanes,

Polyphosphazenes,

Polyorthoesters,

Polyanhydrides and Poly (alkyl cyanoacrylates).