|Year : 2011 | Volume
| Issue : 2 | Page : 103-109
Nanoparticles in drug delivery system
Department of Pharmacy, Oman Medical College, Oman
|Date of Submission||18-Apr-2011|
|Date of Acceptance||29-May-2011|
|Date of Web Publication||23-Aug-2011|
A R Mullaicharam
Department of Pharmacy, Oman Medical College, P.O. Box 620, Postal Code: 130, Azaiba, Muscat
Source of Support: None, Conflict of Interest: None
| Abstract|| |
The pharmaceutical field has long been a model for industry, creating best practices in Research and Development, manufacturing, marketing and other disciplines. As such, it also has recorded historic levels of profitability. But an evolving marketplace, changing regulatory standards, increased manufacturing costs and a number of other factors have begun exerting pressure on pharmaceutical producers. One of the bright spots for the industry is nanoparticles technologies, which offer seemingly unlimited potential to help solve health problems and thus grow the pharmaceutical business. In recent years, various nanotechnology platforms in the area of medical biology, including both diagnostics and therapy, have gained remarkable attention. This paper explores the potential success of these particles in the clinic, which relies on consideration of important parameters such as nanoparticles fabrication strategies, their physical properties, drug loading efficiencies, drug release potential, and various therapeutic applications.
Keywords: Drug delivery, nanotechnology in healthcare, preparation and evaluation methods
|How to cite this article:|
Mullaicharam A R. Nanoparticles in drug delivery system. Int J Nutr Pharmacol Neurol Dis 2011;1:103-9
| Introduction|| |
An essential requirement of modern drug is the controlled delivery of drug or an active substance to the site of action in the body in an optimal concentration versus time profile. One attempt to achieve this goal is the development of colloidal drug carrier known as nanoparticles (NPs)  . NPs are solid colloidal particles ranging in size from 10 to 1000 nm (1 ΅m) in which the active principle (drug or biologically active material) is dissolved, entrapped, adsorbed and/or attached to the carrier material. 
The concept of using NPs as a vehicle for drug delivery was first developed by Speiser and coworkers in the late 1960s and 1970s. , Nanomaterials are at the leading edge of the rapidly developing field of nanotechnology. Nanotechnology can be used as a drug carrier for a large number of drugs such as antibiotics, antineoplastic agents and a variety of drugs, especially neuropeptides. Furthermore, nanosize carriers of molecules such as vitamin D and vitamin A have potential applications in dermatology and cosmetics.
Research into the rational delivery and targeting of pharmaceutical, therapeutic and diagnostic agents is at the forefront of projects in nanomedicine . This involves the identification of precise targets related to specific clinical conditions and the choke of appropriate nanocarriers to achieve the required response, minimizing the side effects.
At present, one of the most attractive areas of research in drug delivery is the design of nanomedicine consisting of nanosystems that are able to deliver drugs to the right place. Furthermore, by modifying the surface characteristics of NPs by coating them with substances such as surfactants, it is possible to enhance the delivery of NPs to the spleen relative to the liver. 
| Benefits of Nanotechnology in Healthcare|| |
- Targeted delivery of ingredients to a particular cell type or receptor
- Therapeutic effect lasts longer due to extended release of ingredients
- Capable of heat triggered local release
- Useful to diagnose various diseases
- Enhanced bioavailability of ingredients
- Enhanced stability of ingredients
- Prolonged shelf life
- Fill the tiny holes in teeth
- To minimize the side effects of drugs
- Nanodevices reduce the intrusiveness and increase patient comfort
In addition to newly formulated drugs, NPs can, in many cases, be applied to reformulations to:
- Improve the efficacy of the current drugs that underperform;
- Make many viable many compounds that never made it through trial phase to the market;
- Improve efficacy or limit side effects of older drugs now off the market or off patent, allowing them to be re-introduced; and
- Change the method of drug delivery to improve customer acceptance or reduce manufacturing costs.
All common delivery vehicles - oral, injection, transdermal, transmucosal, ocular, pulmonary and implant - can effectively use NPs in their formulation. The technology offers numerous potential advantages that may apply in some or all of these delivery forms. These advantages include, but are not limited to, a number of functionalities depending on the drug's specific application and performance goals:
- Prolong circulation in the blood;
- Accumulate in the pathological area;
- Enhance water or lipid solubility;
- Respond to local stimuli, such as changes in pH, temperature or light;
- Penetrate anatomical features such as cell walls, blood vessels, stomach epithelium and blood-brain barrier; and
- Selectively target specific cell types.
Numerous studies show that particles less than 100 μm in size have greater absorption and delivery efficiency in the gastrointestinal, pulmonary and vascular systems, and similar dermal penetration characteristics. This could prove particularly beneficial to BCS class II, III and IV active pharmaceutical ingredients, which typically have low solubility and/or low permeability. A drug is considered to have low solubility at 0.1 mg/L. Industry analysts estimate that about 10% of drugs currently in the market have poor solubility.
Nanodelivery has shown tremendous promise in targeting drugs at tumors. Tumor microvasculature typically contains pores of 100-1000 nm diameter, while healthy heart, brain and lung tissue is 10 nm or less. So, by manufacturing NP-based drug molecules between 75 and 900 nm, researchers and manufacturers have been able to create compounds that selectively target only the malignant tissue.
Recent research with the anticancer drug doxorubicin has shown it to be more effective on cancerous tumors when delivered via NPs than through traditional delivery mechanisms. 
| Preparation of Nanoparticles|| |
Numerous methods exist for the manufacture of NPs, allowing extensive modulation of their structure, composition and physiochemical properties. The choice of preparation method essentially depends on the raw materials intended to be used and on the solubility characteristics of active compound to be associated with the particles. Regarding the raw material, criteria such as biocompatibility, the degradation behavior, choice of administrative route, desired release profile of the drug and finally the type of biomedical application determine its selection. The most important milestones in development of nanoparticulate systems are summarized in [Table 1].
The methods for preparing NPs from preformed polymers can be classified into four categories:
- Salting out
- Solvent displacement and
- Emulsification diffusion.
It is worth nothing that although all the methods enable the preparation of nanospheres, only solvent displacement and more recently, the emulsification diffusion technique have enabled the preparation of nanocapsules.
Emulsion - evaporation
This technique is based on a patent of Vanderhoff et al. The polymer is dissolved generally in a chlorinated solvent (CH 2 CI 2 , CHCI 3 ) and emulsified in an aqueous phase containing surfactant. , The most common surfactants used for this type of preparation are polysorbates, poloxamers and sodium dodecyl sulfates. Emulsification can be achieved by mechanical stirring, sonication,  or micro fluidization (high-pressure homogenization through narrow channels).  The organic solvent is then removed and pressure is reduced under these conditions; the organic solvent diffuses into aqueous phase and is progressively evaporated.
The salting out technique was introduced and patented by Bindschaedler et al.,, and Ibrahim et al . In this method, toxic solvents are avoided. Here, acetone is used which can be easily removed by cross-flow filtration in the final stage.
The preparation method consists of adding, under mechanical stirring, an electrolyte-saturated solution containing a hydrocolloid, generally Poly Vinyl Alcohol (PVA), as a stabilizing and viscosity increasing agent to an acetone solution of polymer. This PVA is compatible with several electrolytes.  The saturated aqueous solution prevents acetone from diffusing into water by a salting out process. After the preparation of an O/W emulsion, sufficient water or an aqueous solution of Poly Ethylene Glycol is added to allow the complete diffusion of acetone into the aqueous phase, thus inducing the formation of nanospheres. ,
This technique was first described and patented by Fessi et al. In this process, polymer, drug and optionally lipophilic stabilizer (e.g. phospholipids) are dissolved in a semi-polar water miscible solvent, such as acetone or ethanol. The solution is then poured under magnetic stirring into a non-solvent (usually water containing surfactant) which leads to the preparation of nanospheres.
This method is a modification of salting out procedure. It was first described and patented by Leroux et al., wherein large amounts of salts in aqueous phase are avoided to eliminate problems of compatibility. Here, partially water soluble solvent is used, which is previously saturated in water to ensure the thermodynamic equilibrium. Polymer is dissolved in the water-saturated solvent containing stabilizer and the organic phase is emulsified under agitation. The subsequent addition of water leads to diffusion into the external phase, which in turn forms NPs.
Carriers in preparation of nanoparticles 
The polymers used for the preparation of NPs) are either amphiphilic macromolecules, obtained from natural sources, hydrophobic polymers or synthesized chemically. Some of these polymers were originally investigated for bio-medical applications, and consequently, for their safety and bio-degradation.
Various natural hydrophilic and synthetic hydrophobic polymers are used for the preparation of NPs. But natural hydrophilic polymers have certain disadvantages such as batch-to-batch reproducibility, the specific conditions for their degradation and potential anti genicity.
Polymers can be synthesized before or during NP preparation. The first group includes polyesters and the second group includes poly(alkyl cyanoacrylates) (PACA).
The safety of the polyesters is clearly illustrated by the fact that some formulations based on these polymers have been approved for human use. All these polymers will eventually be interesting, relative to their safety, for the design of nanoparticulate drug carriers. Other criteria, such as preparation conditions of nanospheres, drug-polymer compatibility, expected drug release behavior, and the final purpose of the formulation (i.e. route of administration) should be taken into account for the final choice of the polymer carrier.
[Table 2],[Table 3],[Table 4] illustrate the polymers used for the preparation of NPs and nanocapsules.
|Table 3: Various synthetic polymers used for the preparation of nanoparticles|
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Physico-chemical and biological considerations in preparation of nanoparticles 
Choice of materials and methods
This mainly depends on the property of the drug to be associated with the NP carrier. The choice of continuous phase that is opposite in its lipophilicity/hydrophobicity to the drug enhances the absorption of the drug to the NP carrier, thus increasing the payload. NPs may have a very short life in the body.
Albumin or short-chain poly cyanoacrylate NPs have moderate degradation and elimination rate.
Long-chain polycyanocrylates have longer degradation rate.
Polymetha crylate NPs have a very long life in the body.
They are spherical particles of nontoxic polymeric material with entrapped bioactive material.
It is generally associated with porosity and drug partitioning with the carrier.
The release of drugs from NPs in aqueous media is rapid. Hence, NPs should not be stored in aqueous media.
No adverse reactions have been reported.
| Physicochemical Characterization|| |
As any other dosage form intended to be used in medicine, nanoparticulate formulations are usually characterized in terms of size, morphology, drug content and in vitro drug release. A wide range of techniques are available for the physicochemical characterization of NPs and are listed in [Table 5]. Detailed description of each technique can be obtained from references. ,
|Table 5: Principle techniques for physicochemical characterization of nanoparticles|
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Interaction of biodegradable nanoparticles with blood components and cell membranes
On exposure to blood, colloidal carriers become coated with plasma proteins. Some of these proteins are involved in the attachment of the NPs to the membrane of mononuclear phagocytic cells and thus regulate the elimination of the carrier. The protein responsible for these activities is known as opsonins, which are of two types, viz., specific and non-specific, based on whether they interact with specific receptors on microphages or not. NPs coated with specific surfactants (polyxamers) are prone to less interaction with plasma proteins. A simple approach to evaluate the protection offered by coating agent is to measure the zeta potential of coated and non-coated NPs in biological fluids. The low zeta potential indicates no interactions with blood proteins. The total amount of adsorbed proteins can also be directly quantified by spectrophotometric methods or densitometry on electorphorectic gel.
Drug loading into NPs is very important with regard to its release characteristics. Generally, increase in the drug loading leads to acceleration of the drug release. However, in particular cases, increase in the drug loading may also slow down the release. This can be explained by possible drug crystallization inside the nanospheres. In this case, the drug must dissolve prior to diffusing, which slows down the release.
The precise drug content determination can be a problem due to colloidal nature of the drug carried. However, the method of choice is separation of the particles by ultracentrifugation followed by quantitative analysis of the drug after dissolving the pelleted pelleted polymer. The drug content can be determined in the supernatant or the filtrate.
The following methods have been used for the determination of in vitro release of drug from NPs:
- Using diffusion cells with artificial or biological membrane
- Using dialysis bag
- Reverse dialysis sac technique
- Centrifugal ultrafiltration technique
The dissolution media that can be used is a buffer solution of a required pH The drug release is found to occur by any one of the following mechanisms:
- Desorption of surface bound drug
- Diffusion through the matrix or the polymer wall
- Combined erosion and diffusion
| Conclusions|| |
NPs are one of the promising drug delivery systems, which can be of potential use in controlling and targeting drug delivery as shown in [Table 6].  It is a frontier area of future scientific and technological development. Significant efforts have been made on surface engineering of nanoparticulate carriers to overcome various biological barriers and target specific tissue sites. NPs are used for parenteral, oral, ocular and transdermal applications as well as in cosmetics and hair care technologies, sustained release formulations and as a carrier for radio nucleotides in nuclear medicine. Design principles of these NPs, including nanoemulsions, dendrimers, nano-gold, liposomes, drug-carrier conjugates, antibody-drug complexes, and magnetic NPs, are primarily based on unique assemblies of synthetic, natural, or biological components, including but not limited to synthetic polymers, metal ions, oils, and lipids as their building blocks. 
Poor drug encapsulation efficiency and rapid release of the encapsulated drug limit the use of NPs in biomedical applications involving water-soluble drugs. This can be overcome by preparation of a novel surfactant-polymer drug delivery carrier demonstrating sustained release of water-soluble drugs. 
Patients using ophthalmic drops have to face frequent dosing schedules and difficult drop instillation. Therefore, a long-lasting pilocarpineloaded chitosan (CS)/Carbopol NP ophthalmic formulation was developed. 
The potential nanotechnology in the field of pharmaceutical biotechnology will positively affect medical and pharmaceutical science in all areas. Improved diagnostics will allow not only working with point-of-care devices close to the patients, but also to combine diagnostic and therapeutic actions in a nanoscaled drug delivery system. 
As nanotechnology continues to evolve, so also will its application in pharmacology and related biological health applications. Ongoing research points toward nanotechnology's benefits outweighing potential drawbacks in the majority of applications in which it has been studied. Oncological uses seem to hold early promise, but researchers have only scratched the surface. Nanoproduct research across virtually all biomedical fields is yielding important strides forward.
There is no one nanotechnological solution, just as there is no one NP to solve every application challenge. Matching technologies to challenges will continue to demand intense research. New NP production techniques and equipment will aid in furthering discovery of pharmaceutical drugs. 
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]