A Comparative review of recently developed particulate drug carrier systems

Abstract

Particulate drug carriers include Microparticulate, nanocarriers, lipid based carriers and colloidal carriers. These are some umbrella terms under which recently many drug carrier systems are vastly developed namely niosomes, dendrimers, lipoplexes, pharmacosome, nanocrystals, nanosuspenions, ethosome and many such systems. While working on drug carriers, a pharmaceutical scientist comes through many similar sounding or synonymous terms which he might not be able to discriminate on random supervision. The literature is overwhelming with various works discussing these systems alone or together, giving their pharmaceutical significance and formulation specification and applications. But there is no such work where their basic comparison which could help a pharmaceutician to define and discriminate the wide spectrum of these carrier under one title. This review is sharply focused on elaborating the clear rationale of developing each carrier, their basic definition and intersubject comparison.

Key Words: micro,nano particulate systems, drug carriers, targeted drug delivery

Introduction

In recent years, the interest in micron and sub-micron systems (i.e.nanosystems) in pharmacy has surged. This is in part due to the advantages these systems may provide over existing systems. Designing drug delivery system is challenging in terms of targeting the drug to specific sites. Certain chemicals or therapeutic agents that show success in vitro fail to produce the same effect in the human body because of the limitation to target the designated area, as a result, high concentrations are given to patients resulting in more intense side effects. While asking for a better and more targeted drug system in therapy, a pharmaceutical scientist come across some terms very often i.e. vesicular, colloidal , noisomel,  micro particulate, nano particulate and lipid based submicron system. Depending on certain dosage form the above terms could be coined alone or in conjunction with other terms to a particular system. Dosage forms which conform themselves as surfactant spherical vesicles are often known as vesicular systems. Micron system comes range of μm and submicron in nm. Typically a colloid is an intermediates size between molecular range and coarse range. Colloidal carriers are small particles of 100-400 nm in diameter, suspended in an aqueous solution. These micro,nano,vesicular,colloidal and lipid based carriers have the advantage of easy administration and efficacy over their long residence time, better targeting etc.

The objective of present review is to clearly define the terms mentioned above, discuss the rationale or significance of these systems and present a compilation of all the dosage forms systems developed under the above mentioned terms. This review covers definition, composition, structure and functional features of all drug carriers. It will help the reader to understand the difference between different carrier systems.

Need of  Vesicular, Colloidal,Micro and Nanocarrier

Development of these carriers is a novel area of science that provides, with a new hope, the tools and technology to work at atomic, molecular and supramolecular levels leading to creation of devices and delivery systems with fundamentally new properties and functions. These carriers offer a number of advantages making it an ideal drug delivery vehicle.

1.Better drug delivery to certain stubborn or impermeable sites of body

2.Owing to their small size, chemistry and distribution these carriers have better bridged the gaps between the structure and function of biomolecules.

3.Reaching the micron or nano range with these particles, enables them to be a highly potential carriers in many biological molecules as proteins. DNA, viruses and xenobiotics.

4.Better targeting to body tissues and sites where action is required, elimination of side effects and adverse effects.

5.Owing to size, nature and chemistry, these systems give better drug permeability from biological membranes and helps in soubilization of some practically insoluble drugs and hence solve bioavailability problems of many drug.

6. It involves overlap of biotech, nanotech, and information technology, might result in many important applications in life sciences including areas of gene therapy, drug delivery, imaging, biomarkers, biosensors and novel drug discovery techniques.(1-3)

7. It also offers an attractive solution for transformation of biosystems, and provides a broad platform in several areas of bioscience.(4,5)

8. The surface properties of carriers can be modified for targeted drug delivery(6-8) for e.g. small molecules, proteins, peptides, and nucleic acids loaded nanoparticles are not recognized by immune system and efficiently targeted to particular tissue types.(9)

9. Targeted  drug carriers reduce drug toxicity and provide more efficient drug distribution.(10)

10.Drug carriers holds promise to deliver biotech drugs over various anatomic extremities of body such as blood brain barrier, branching pathways of the pulmonary system, and the tight epithelial junctions of the skin etc.

11.Drug carriers better penetrate tumors due to their leaky constitution, containing pores ranging from 100—1000 nm in diameter.

Limitation

1. Drug carriers exhibits difficulty in handling, storage, and administration because of susceptibility to aggregation.

2. It has unsuitability for less potent drugs.

3. But the key area of concern is related to its small size as nanocarriers can gain access to unintended environments with harmful consequences, e.g. it can cross the nuclear envelope of a cell and cause unintended genetic damage and mutations.(11,12)

Various Carrier Based Dosage Forms

1) Nanoparticles- Nanoparticles are roughly defined as submicron-sizedcolloidal systems (varying in size from 10 to 1000 nm), biodegradableor not.Nanospheres have a matrix likestructure, where active compounds can be firmlyadsorbed at their surface, entrapped or dissolved in the matrix.Nanocapsules have a polymeric shell and an inner core.In this case, the active substances are not only dissolved inthe core, but may also be adsorbed at their surface.(13)

2) Solid Lipid Nanoparticles (SLNs)- SLN particles made of solid lipids are  submicron colloidal carriers(50­-1000nm). These consist of a solid hydrophobic core having a monolayer of  phospholipids coating. The solid core contains drug dissolved or dispersed in the solid high melting fat matrix. The hydrophobic chains of phospholipids are embedded in the fat matrix. Depending on the type and concentration of the lipid, 0.5 to 5% emulsifier (surfactant) is added for the physical stabilization of the system. . Factors such as velocity of lipid crystallization, lipid hydrophilicity, and influence of self-emulsifying properties of the lipid on the shape of the lipid crystals (and hence the surface area) were found to affect the final size of the SLN dispersions.(15)

3) Polymeric Nanoparticles-Colloidal carriers based on biodegradable and biocompatible polymeric systems have largely influenced the controlled and targeted drug delivery concept. Nanoparticles are sub-nanosized colloidal structures composed of synthetic or semi-synthetic polymers that vary in size from 10—1000 nm. Biodegradable polymeric nanoparticles, typically consisting of polylactic acid (PLA), polyglycolic acid (PGA), polylactic- glycolic acid (PLGA), and polymethyl methacrylate (PMMA) are being investigated for the delivery of proteins, genes and DNA Polymeric nanoparticle suspensions were prepared from inert polymer resins (Eudragit RS100, and RL100) and loaded with drugs.(16)

4) Ceramic Nanoparticles -These are the nanoparticles nanoparticles made up of inorganic (ceramic) compounds such as silica, titania and alumina. Ceramic nanoparticles exist in size less than 50 nm, which helps them in evading reticuloendothelial system (RES) of body. These particles provide the complete protection to the entrapped molecules such as proteins, enzymes and drugs against the denaturizing effects of external pH and temperature as it involves no swelling and porosity changes with the change in pH.3.(17)

5) Hydrogel Nanoparticles- Hydrogel nanoparticles is another polymeric system involving the self-assembly and self aggregation of natural polymer amphiphiles such as hydrophobized polysaccharides like cholesteroyl pullulan, cholesteroyl dextran and agarose where cholesterol groups provide cross linking points in a non-covalent manner. Cross-linked hydrogel nanoparticles (PVP-NP) (35—50 nm in diameter) composed of natural polymers offers targeting to intracellular sites and good acceptability because of higher water content.(18-20)

6) Copolymerized Peptide Nanoparticles - Another modification of a polymer-based system is copolymerizedpeptide nanoparticles. It is a novel approach utilizedfor delivery of therapeutic peptides as drug–polymer conjugates in which the drug moiety is covalently bound to the carrier instead of being physically entrapped.(21)

7)Nanocrystals and Nanosuspensions-Nanocrystals are aggregates of around hundreds or thousands of molecules that combine in a crystalline form, composed of pure drug with only a thin coating comprised of surfactant or combination of surfactants. The  production technique of nanocrystals is known as ‘nanonisation’. To produce nanosuspensions, the drug powder is dispersed in an aqueous surfactant solution by high speed stirring.(12)

8) Nanotubes And Nanowires- Nanotubes and nanowires are the self-assembling sheet of atoms arranged in the form of tubes and thread-like structures of nanoscale

range. Nanostructures that have gained much attention are hollow, carbon-based cage like structures—nanotubes and fullerenes. Fullerenes are spherical structures, also known as bucky balls. Soluble derivatives of fullerenes such as C60—a soccer ball shaped arrangement of 60 carbon atoms per molecule shows promise as pharmaceutical agents. (13)

9)Functionalized Nanocarriers - The combination of functionalities of biomolecules and non-biologically derived molecular species used for special functions such as markers for research in cell, molecular biology, biosensing, bioimaging and marking of immunogenic moieties to targeted drug delivery are known as functionalized nanoparticles. Organically functionalized nanoparticles of catalytic active metals offer a high surface area and unique size dependent chemical behavior. One approach is the bioconjugate quantum dots as fluorescent biological labels. Quantum dots are crystalline clumps of several hundred atoms with an insulating outer shell of a different material. Quantum dots can be attached to the biologicals such as cells, proteins and nucleic acids.(22)

10) Nanospheres –Nanospheres are solid metrical structures with drug molecules within the matrices and/or adsorbed on the surfaces of the colloidal carriers.(23)

11) Nanocapsules-Nanocapsules are small capsules with a central core surrounded by a polymeric shell, where drug molecules may be dissolved in an oily core or  adsorbed to a surface interface.(23)

12) Liposomes-Liposomes are the microscopic vesicles composed of one or more concentric lipid bilayers, separated by water or aqueous buffer compartments with a diameter ranging from 25 nm to 100μm. According to their size, liposomes are known as Small Unilamellar Vesicles (SUV) (10-100 nm) or Large Unilamellar Vesicles (LUV) (100-3000 nm). If more than one bilayers are present, then they are referred to as Multilamellar Vesicles (MUV). Liposomes are formed when thin lipid films or lipid cakes are hydrated and stacks of liquid crystalline bilayers become fluid and swell. During agitation hydrated lipid sheets detach and self associate to form vesicles, which prevent interaction of water with the hydrocarbon core of the bilayer at the edges .(14)

13) Lipid Emulsions (LES)- Lipid emulsions are heterogenous dispersions of two immiscible liquids (oil-in-water or water-in oil) and they are subjected to various instability processes like aggregation, flocculation, coalescence and hence eventual phase separation according to the second law of thermodynamics. LE may be in the form of oil-in-water (o/w), water-in-oil (w/o), micron, submicron and double or multiple emulsions (o/w/o and w/o/w).The o/w type Les (LE) are colloidal drug carriers, which have various therapeutic applications.(24)

14) Lipid Microtubules/Microcylinders- Lipid microtubules are a self organizing system in which surfactants crystallize into tightly packed bilayers that spontaneously form cylinders of less than 1μm in diameter during a controlled cooling process.(25)

15) Lipid Microbubbles- Lipid microbubbles consist of gas filled microspheres stabilized by phospholipids , polymer or proteins and used as contrast enhancers in ultrasonic diagnostics due to the low density and high elasticity of these bubbles. These have few micron size ranges.(26)

16) Lipospheres- Lipospheres were first reported by Domb, as water dispersible solidmicro particles with a particle size between 0.2-100 μm in diameter composed of solid hydrophobic fat core stabilized by a monolayer of phospholipids molecules embedded in a microparticle surface. Lipospheres can contain a biologically active agent in the core , in the phospholipids,or a combination of two.(27)

17) Lipopolyplexes- These are assemblies, which form spontaneously between nucleic acids and polycations or cationic liposomes, and are used in transfection protocols. The shap, size distribution, and transfection capability of these complexes depends on their composition and charge ratio of nucleic acid to that of cationic lipid/polymer.(55)

18) Ethosomes - Ethosomes are noninvasive delivery carriers that enable drugs to reach the deep skin layers and/or the systemic circulation. Ethosomes contain phospholipids, alcohol (ethanol and isopropyl alcohol) in relatively high concentration and water. Unlike classical liposomes, ethosomes were shown to permeate through the stratum corneum barrier and were reported to possess significantly higher transdermal flux in comparison to liposomes. The synergistic effects of combination of phospholipids and high concentration of ethanol in vesicular formulations have been suggested to be responsible for deeper distribution and penetration in the skin lipid bilyers.(28)

19) Multicomposite Ultrathin  Capsules - The most important discovery in the  field       of supramolecular science is the development of “selfassembling ultrathin multilayered capsule”. Multicomposite ultrathin capsules are molecular assemblies of tailored architecture having layer-by-layer adsorption of oppositely charged macromolecules onto colloidal particles. Self-assembling ultrathin multilayered capsule (biomimic capsule) are multilayer films of organic compounds on solid surface and these have been studied for more than 60 years because they allow fabrication of multicomposite molecular assemblies on tailored architecture. However, both the Langmuir-Blodgelt technique and chemiosorption from solution can be used only with certain classes of molecules. An alternative approach for fabrication of multilayers by consecutive adsorption of polyanions and polycations is far more general and has been extended to other materials    such as proteins or colloids.(29)

20) Aquasomes - these are spherical 60300nm particles used for drug and antigen delivery. The particle core is composed of noncrystalline calcium phosphate or ceramic diamond, and is covered by a polyhydroxyl oligomeric film.Aquasomes  were prepared by self-assembling of hydroxyapatite by co-precipitation method and thereafter preliminary coated with polyhydroxyl oligomers (cellobiose and trehalose) and subsequently adsorbed with bovine serum albumin (BSA) as a model antigen. BSA-immobilized aquasomes were around 200 nm in diameter and spherical in shape and had approximately 20-30% BSA-loading efficiency. (56)

21) Pharmacosomes -This is the term used for pure drug vesicles formed by the amphiphilic drugs. Any drug possessing a free carboxyl group or an active hydrogen atom (–OH, NH2) can be esterified (with or without a spacer group) to the hydroxyl group of a lipid molecule, thus generating an amphiphilic prodrug. The amphiphilic prodrug is converted to pharmacosomes on dilution with water.(30)

22) Dendrimers - Dendrimers are the macromolecular compounds that consist of a series of branches around an inner core whose size and shape can be altered as desired. These represent a unique class of polymers that are fabricated from monomers using either convergent or divergent step growth polymerization. Dendrimers are made from Abn type monomers, each layer or generation of branching units doubles or triples   (n-2, n-3) the number of peripheral functional groups. Generally during dendrimer formation molecules emanate from a core and like a tree they ramify with each subsequent branching unit referred to as generation. Drug molecules can be loaded either in the interior, or can be adsorbed or attached to the surface groups. Hydrophilic dendrimers are suitable as coating agents for protection and delivery of drugs to specific sites, thus minimizing drug toxicity. The unique properties of dendrimers, such as their high degree of branching, multivalency, globular architecture and well-defined molecular weight, make them promising new scaffolds for drug delivery.(31)

23) Colloidosomes- Colloidosomes are solid microcapsules formed by the self-assembly of colloidal particles at the interface of emulsion droplets. “Colloidosomes,” are hollow, elastic shells whose permeability and elasticity can be precisely controlled.(32)

24) Niosomes-Niosomes are non-ionic surfactant vesicles and, as liposomes,are bilayered structures. Niosomes present low production cost, greater stability, andresultant ease of storage.Niosomes are chemically stable, can entrap both lipophilic and hydrophilic drugs either inaqueous layer or in vesicular membrane and present lowtoxicity because of their non-ionic nature. Other advantages include flexibility in their structural constitution, improvementof drug availability and controlled delivery at a particularsite, and, at last, niosomes are biocompatible, biodegradableand non-immunogenic. Niosomes are presentwith a range in size of 10 to 1000 nm. The colloidal drug-loaded particles consist of macromolecular materials in which drugs are dissolved, entrapped, encapsulated,and/or to which the drugs are adsorbed or attached.(33)

25) Discomes - These are defined as non-ionic surface active agents based discoidal vesicles. The discomes were relatively large in size, 12-60 microns.(34)

26) Proniosomes - These are dry formulations of surfactant-coated carrier, which can be measured out as needed and rehydrated by brief agitation in hot water. Proniosomes (and proliposomes) are normally made by spraying surfactant in organic solvent onto sorbitol powder and then evaporating the solvent. Because the sorbitol carrier is soluble in the organic solvent, it is necessary to repeat the process until the desired surfactant loading has been achieved. The surfactant coating on the carrier is very thin and hydration of this coating allows multilamellar vesicles to form as the carrier dissolves.(35)

27) Microspheres- Microspheres or protein protocells as small spherical units, for spherical particles composed of various natural and synthetic materials with diameters in the micrometer range.(36)

28) Microemulsions - Microemulsions are also termed “transparent emulsion,” “miceller emulsion,” or “swollen micellar emulsion.”  Microemulsions is defined as any multicomponent fluid made of water(or a saline solution), a hydrophobic liquid (oil), and one or several surfactants resulting in systems that are stable, isotropic, and transparent with low viscosity. Micro emulsions are thermodynamically stable colloidal dispersions of water and oil stabilized by a surfactant and, in many cases, also a cosurfactant. Micro emulsions offer an interesting and potentially quite powerful alternative carrier system for drug delivery because of their high solubilization capacity, transparency, thermodynamic stability, ease of preparation, and high diffusion and absorption rates when compared to solvent without the surfactant system(37)

29) Polymeric Micelles –These systems include amphiphilic block copolymers suchas Pluronics (polyoxyethylene polyoxypropylene block copolymers that self-associate in aqueous solution to form micelles. Polymeric micelles offer a number of advantages in terms of thermodynamic stability in physiological solution leading to their slow dissolution invivo.Because of their core–shell structure, these serve as suitable carrier for water insoluble drugs, such drugs partition in the hydrophobic core of micelles and outer hydrophilic layer aids in dispersion in aqueous media making it an appropriate candidate for intravenous administration. Nanometric size range helps micelles to evade the RES, and aids passage through endothelial cells.(38-39)

Table-1   Comparison of various features of particulate carriers

 Table 2Recent updates in drug particulate carriers

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About Authors:

Ritu Mehra Gilhotra, Vishv Priya Bhardwaj, DN Mishra

Ms Vishva Priya Bhardwaj is M Pharma (Pharmaceutics). Her area of research is Microsphere and in-situ gelling ocular drug delivery systems. She has one scientific publication and three papers presented in various national conferences.

Ms Ritu Mehra Gilhotra (M Pharma, PhD(persuing)) ,is working as an Associate Professor and Head,( Pharmaceutics), School of Pharmacy, Suresh Gyan Vihar Univerity, Jaipur and has six year experience in teaching and two year experience of research. She has 21 scientific publications, 20 papers presented in various national conferences and 01 patent (in addition). She is Editor, Asian Journal of Pharmaceutical and Clinical research and life member of APTI. Her area of research is ocular, transdermal and vesicular drug delivery systems.

Prof (Dr) DN Mishra is Dean and Ex Chairman , Department of Pharmaceutical Sciences, Guru Jambheshwar University of Science and Technology, Hisar India . Prof Mishra earned his B Pharma, M Pharma and PhD from Banaras Hindu University , Varanasi . He has a teaching and research experience of around 25 years. He has 35 national and international scientific publications and around 50 papers presented in various conferences. He is an active member of various professional bodies like APTI, IPGA, IPA and ISTE. His recent areas of research include matrix tablets, transdermal, Opthalmic and various particulate systems.