Nanobased Drug Delivery System: A Review

 

Selvakumar Kalimuthu and  AV Yadav*

Biopharmaceutics Research Group,Govt. College of Pharmacy Karad - 415124, Maharashtra, India

*Corresponding Author E-mail:  selvamph@yahoo.com

 

ABSTRACT

Nanoscience and nanotechnology are the emerging area in recent years, particularly in drug discovery and development process. Nanotechnology has wide variety of applications in pharmaceutical sciences. The major applications of nanotechnology are development of dosage forms that may have better efficacy than conventional dosage forms. Nanocrystals are used to improve the pharmacokinetic properties such as solubility and permeability. Nanoparticles are used to target the drug at specific site of the body or tissue. Various technologies which are used to fabricate the nano based drug delivery systems are reviewed.

 

KEY WORDS:     Nanocrystals, Bioavailability, dosage form, poorly soluble drugs

 


INTRODUCTION:

Nanoscience and nanotechnology are the emerging area in recent years, particularly in drug discovery and development process. Nanotechnology is defined as the science and engineering carried out in the nanoscale that is 10-9 meters. In last two decades, research began developing the ability to manipulate the matter at the level of single atom and a small group of atoms and to characterize the properties of the materials and the systems at the scale. Nanostructures have the different physical properties than that of its bulk form1. Nanotechnology has wide variety of applications in pharmaceutical sciences. The major applications of nanotechnology are development of dosage forms that may have better efficacy than conventional dosage forms.

 

Total expenditure for developing a new molecule for therapeutic use is approximately $1 billion and it requires an average of twelve years. Drug discovery research is a highly risky business and chances for failure are more after investing substantial money and time. Many reasons are suggested for lack of productivity, including more stringent and tight regulatory environment2.

 

Advent of High Through Put (HTP) screening, combinatorial chemistry and bioinformatics provided a large number of potential molecules for therapeutic use.

 

These molecules show promising pharmacodynamic effect, whereas the pharmacokinetic properties of such molecules may be unfavorable. It is estimated that more than 60% of drug molecules being identified through combinatorial screening are either poorly soluble or poorly permeable and

40% of drug molecules available in the market suffer from the similar disadvantage3. Drug solubility and permeability are the two important parameters, which determine the bioavailability and hence therapeutic efficacy4.   In this background, in addition to synthesis of new molecules, optimization of existing molecules for better clinical outcome   by overcoming the poor physicochemical property through formulation approach is a lucrative and economical way. Formulation approach reduces the risk and cost associated with new drug discovery; at the same time it allows the market exclusivity. Nano based formulation improves both the solubility and permeability; thereby it improves the bioavailability and hence therapeutic efficacy5.

 

Nano based formulations are classified as nanocrystalline particles or nanocrystals and nanoparticles. Nanocrystals are used to improve the pharmacokinetic properties such as solubility and permeability6. Nanoparticles are used to target the drug at specific site of the body or tissue. Drug nanocrystals are nanoparticles being composed of 100% drug without any polymeric matrix material. According to the definition of nanoparticles mean particle size is below 1 μm. Nanocrystals are formulated for both oral and non-oral administration7. There are several production techniques to produce nanocrystals. Basically, one can differentiate between top down and bottom up technologies. The bottom up technologies starts from the molecules, which are dissolved in suitable solvent system and it is precipitated in nano range by adding anti solvent. The top down technologies is based on disintegration methods by means of various types of wet milling methods. In precipitation technology, the drug is dissolved in a solvent and this solution is added to the non-solvent. Addition of non-solvent is necessary to yield a very fine product by passing the Oswald’s Mier area. The basic advantages of precipitation technique are the use of simple and low cost equipment, and scaling up is relatively easy by using the static blender or micromixers. However, there are some basic problems associated with precipitation techniques. The particles produced need to retain their size after precipitation; growth of particles is to be avoided. To sum up, bottom up technologies are not widely used in industry to produce drug nanocrystals. Now days, top down technologies involving various milling techniques are more frequently used. There are two basic disintegration technologies for production of drug nanocrystals known as Pearl/Ball milling and high-pressure homogenization. In pearl milling, the drug macro suspension is filled into a milling container containing milling pear (e. g glass, zinc oxide or special polymer). The pearl are moved by stirrer, the drug is ground to nano crystals in between pearls. The general problem of pear milling is potential problem of erosion of material from the milling pearls leading to product contamination8

 

The second most frequently used disintegration method is milling by high-pressure homogenization. Dispersions (emulsion or suspension) are accelerated and passed through a very thin gap with an extremely high velocity prior to entering the gap, the suspension contained in a cylinder with relatively large diameter compared to the width of the gap. According to the law of Bernoulli, the flow volume of the liquid in a closed system per cross section is constant. That means the reduction in diameter leads to a tremendous increase in the dynamic pressure and simultaneously a decrease of static pressure when the liquid is in homogeniser gap. A liquid boils when its vapor pressure is equal to the air/static pressure of the environment. In the gap, static pressure drops below the vapor pressure of the liquid at room temperature. Consequently, the liquid starts boiling, form gas bubbles which implode after leaving the homogenization gap and being again under normal air pressure conditions9,10. The cavitation was considered as the determining factor. Some of the patented technologies are given in Table No. 01. A number of dosage forms are developed based on the nanotechnology and their clinical phases are given in Table No. 02.

 

NANOTECHNOLOGY:

Drug delivery system:

Nanobased drug delivery systems have gained more importance in recent years, because of it applicability in break throughing technology. Advent of molecular biology, combinatorial chemistry and high throughput screening provided lots of class II and class IV compounds, which pose either solubility or permeability related problems. Tissue permeability determines the targetability   of a drug or dosage form13. Nanoparticles because of its altered physicochemical property are widely used to target the drug molecule on particular tissue or organ, without producing more toxicity to host cell, when compared to plain drug14. Another important applicability of Nanotechnology in drug delivery system is to combat the solubility related problems of poorly soluble drug by enhancing inherent surface area of the molecule15. These sections of review discuss the technologies and its applicability in drug and dosage form delivery development.

 

Nanosizing for poorly soluble drugs: 

It is estimated that 40 % or more active substances being identified through combinatorial chemistry are poorly soluble in nature. Most of invitro screening procedures of newly identified chemical entity are screened using DMSO as a solvent. When these molecules are formulated using conventional methods, the performance of the drug in pre-clinical screen is oftentimes erratic and highly variable16. A limiting factor for invivo performance of poorly water soluble drugs, following oral administration, is their resistance to being wetted by and dissolved into the fluid in gastrointestinal tract. Increasing the dissolution rate of poorly water-soluble drugs is thus important in optimizing the bioavailability of dosage form. Over last 10 years, Nanoparticles engineering has been developed and reported for their pharmaceutical applications. In this approach, poorly water-soluble compounds are formulated as nanometer sized drug particles17. Nanocrystals are wisely used to improve the solubility of drug by improving effective surface area and wettability1.

 

Narrow ranges of techniques are available to produce drug nanocrystals; Disintegration followed by particle size reduction into nano range is called on Top down technology. Drug nanocrystals are formulated in a liquid dispersion medium by using various types of milling techniques by a high-pressure homogenization18, 19. These drug nanocrystals are stabilized using surfactant or polymer. Oral administration is possible as a suspension. However, more patient friendly dosage forms such as tablets and capsules can be prepared by converting suspension into solid dosage form. Because of their small size, the nanosuspension can be injected parentrally, especially intravenously. Intravenously administered dosage form provides 100% bioavailability. The bottom up technology starts from the molecular levels that are dissolved and precipitated them by adding the solvent to non-solvent20.

 

Table: 1 Overview of the technologies and patent application on which the various homogenization processes are based11

Nanocrystal

Company

Patent/patent application No

NanomorphTM

Novartis

GB 22 69 536  GB 22 00 048

Hydrosol

Soligs/Abbott

D 19637517

NanocrystalTM

élan Nano Systems

US 5145684

DissoCubes®

SkyePharma

US 5858410

Nanopure

PharmaSol

PCT/EP00/0635

NANOEDGETM

Baxter

US 6884436

 

Table:2 Overview of drugs being presently in different clinical phases12

Drug

Indication

Drug delivery company

Pharma company

Route

Status

Paclitaxel

Anti cancer

American BioSci.

American PP*

IV

Phase III

Undisclosed

Anti-infective

Baxter  NANOEDGE

Undisclosed

Oral

Phase II

Undisclosed

Anti cancer

Baxter  NANOEDGE

Undisclosed

Oral

Phase I

Rapamune

Immuno-suppressant

Élan  Nanosystems

Wyeth

Oral

Marketed

Emend

Anti-emetic

Élan Nanosystems

Merck

Oral

Marketed

Cytokin inhibitor

Crohn’s Diseases

Élan Nanosystems

CytokinPharmSci

Oral

Phase II

Diagnostic

Imaging agent

Élan Nanosystems

Photogen

IV

Phase I/II

Thymectacin

Anti cancer

Élan Nanosystems

NewBiotics

IV

Phase I/II

Fenofibrate

Lipid lowering

Skye-Pharma

Undisclosed

Oral

Phase I

Busulfan

Anti cancer

Skye-Pharma

Supergen

Intrathecal

Phase I

Budesonide

Asthma

Élan Nanosystems

Sheffield

Pulmonary

Phase I

Silver

Eczema

NUCRYST

Self developed

Topical

Phase I

Calcium phosphate

Vaccine adjuvant

BioSante

Self developed

Oral

Phase I

Insulin

Diabetes

BioSante

Self developed

Oral

Phase I

*PP – Pharmaceutical partners 


 


Precipitation techniques:

Precipitation technology is one of the scalable processes, in which drug nano crystals are prepared from its solvent upon addition of non-solvent. Nonionic polymer or surfactant can be used as a stabilizer. True. H. Rogger21 et al in 2004 invented a scalable controlled precipitation process to enhance the dissolution rate of drugs. Danazole and Naproxen were selected as a model drug; both drugs showed enhanced dissolution than drug particles. Basically the drug is dissolved in a solvent and this solution is added to a non-solvent. Addition of the solvent to the non-solvent is necessary to yield a very fine product bypassing Oswald Mier area. NanomorphTM, a nanocrystalline product developed by Soliys/Abbot, Hydrosol by Suckar and other nano based drug crystals, which are produced by precipitation method were patented in US and Europe22. In the case of NanomorphTM, amorphous drug nanocrystals are produced to further enhance dissolution velocity and solubility. There are number of advantages in precipitation techniques such as relatively simple, low cost and scalability. However, there are few problems associated with precipitation technique. The particle needs to be retain their size after precipitation. In case of a special crystalline state is given to the particles matrix, this state needs to be maintained during the shelf life of the product to avoid a decrease in bioavailability. The techniques are not widely used in drug nanocrystals preparation.

 

Top down technology:

The basic principle behind the top down technology is disintegration of drug micro-particles into nano level. Various milling techniques are widely used to prepare the drug nanoparticles from macro-particles suspension or coarse suspension. There are two basic disintegration technologies for drug nanocrystals known as pearl/ball milling and high-pressure homogenization. Drug macro suspension is filled in to milling container containing milling pearls. The pearls are moved by a stirrer, the drug is ground to nanocrystals in between pearls. Erosion of pearl material is one of the regulatory related issues for both oral and parental drug product approval. The second most

 

frequently used disintegration method is milling by high-pressure homogenization. There are two different types of homogenizers widely used in industry it includes microfluidisation and piston-gap homogeniser23.

 

Microfluidisation is a jet stream principle; the suspension is accelerated and allowed to pass with high velocity in ‘Z’ type chamber or Y type chamber. The change in the direction of its flow leads to collision of particles leading to disintegration of particles into nano level. The basic disadvantage of microfluidisation technique is more number of cycles required to get nanocrystals.

 

Piston-gap homogenizer:

The basic principle for obtaining Nanosuspension is cavitation force created in high-pressure homogenization. A favorable concentration of surfactant solution is prepared in suitable solvent. Drug is dispersed in aqueous surfactant solution. The obtained macro suspension is passed through a high-pressure homogenization typically 1500 bar and three to ten up to a maximum 20 passes. In general jet-milling process is prepared to make a fine nanosuspension. The resulting suspension is passed through 25micrometer orifice at 1500 bar pressure. High velocity of suspension leads dynamic fluid pressure that increase with decrease in static pressure.  Reduction in static pressure leads to boiling of water at room temperature; cavitation is formed while water starts bubbling, Cavitation force breaks the micro particles in to nanoparticles24.

 

Table: 3

Advantages of Nanoparticles

v  Controlled and sustained mode of drug release

v  Passive and Active drug targeting

v  Long-depot preparation

v  Site specific targeting

v  Intracellular targeting

v  Drug stabilization in both invitro/invivo environment

 

Nanoparticles:

Nanoparticles are defined as particulate dispersions or solid particles of polymeric materials in which drug is embedded or encapsulated in a uniform manner. Usual size range of nanopolymeric particles is 10 – 1000nm. Nanocapsules are vesicular system in which the drug is confined to a cavity surrounded by a unique polymer membrane, while nanospheres are matrix system in which the drug is physically and uniformly dispersed. In recent year, biodegradable polymeric nanoparticles are used as potential drug delivery devices because of their ability to target a particular organ, as carrier of DNA in gene therapy25, and their ability to deliver protein, peptide and genes. The main applications of nanoparticles are tumor targeting and vaccine adjuvant. A major goal in designing such devices, using nanoparticles as a delivery system, is to achieve the controlled release of pharmacologically active agent to the specific site of action at the therapeutically optimal rate and dosage regimen. Though liposomes have been used as potential carriers with unique advantages like protecting drugs from degradation, target the drug to the site of action and reduce the toxicity or side effects, development work is limited due to inherent problem such as low encapsulation efficiency, rapid leakage of water soluble drug in presence of biological components26.

 

In spite of the several advantages, Nanoparticles have limitations such as smaller particle size and lower surface area can lead to particle aggregation, making physical handling of nanoparticles difficult in liquid and dry form. Drug loading is another important issue, which affect the reproducibility and performances of nanoparticles27. Complete removal of toxic cross-linking agents and surfactants is essential to avoid the excipient related toxicity28. Advantages of nanoparticles are given in table no: 03.

 

Preparation of nanoparticles:

A successful application of nanoparticles in drug delivery depends on the polymer in which drug is to be loaded. Varieties of polymeric materials are used to fabricate the nanoparticles, which include proteins, polysaccharides, semi-synthetic and synthetic polymers29. Selection of polymer material will be based on their physicochemical property, compatibility with drug, biodegradability and immunogenity. Most of the polymers available till today lack any one of the above-mentioned property. Synthetic polymers are widely preferred to fabricate nanoparticles. Microbial load, variability in quality and immunogenic properties are the unfavorable factors for nanoparticle preparation. However, the final selection of nanoparticulate matrix is based on many factors including size of the nanoparticles required, inherent properties of the drug like solubility and stability, surface characteristics such as charge and permeability, degree of biodegradability, biocompatibility and toxicity, drug release profile and antigenicity of the final product30

 

The selection of the appropriate method in the preparation of nanoparticles depends on the physicochemical properties of the polymer and drug to be loaded. A preparation technique determines the inner structure of the nanoparticles. There are two types of inner structure, commonly known as matrix type and reservoir type. The drug can be entrapped within the reservoir or the matrix or otherwise be adsorbed on the surface of the nanoparticles. Various methods of preparation of nanoparticles are listed in the table no: 4

 

Characterization of Nanoparticles

Essential Characterization for Nanocrystals/ Nano suspensions is

  1. Particle size and size distribution
  2. Particle morphology
  3. Surface properties
  4. Crystalline state
  5. Saturation solubility and Dissolution velocity
  6. Bio-interaction

 

APPLICATION OF NANOTECHNOLOGY IN DRUG DELIVERY:

Recent advances in medicinal and synthetic chemistry provided a wide variety of large molecular lipophilic compounds for therapeutic use. Conventional drug delivery system fails to deliver such potential drug candidates properly. A poor pharmacokinetic property such as solubility, poor permeability and high molecular charge often creates a challenging task to a formulation scientist. Wide ranges of technologies are available to combat the poor pharmacokinetic properties. These techniques include redesigning of the molecule, pro-drugs, salt formation and formulation strategies. In that formulation development is an easy and lucrative way to improve the pharmacokinetics of the drug molecule. Low cost, developmental time and liberated regulatory requirements are the positive factors, so that pharmaceutical companies are investing substantial money in this field. A wide variety of novel technologies, including molecular dispersions, micronization, micro emulsion, and lipid based dosage forms and nanoparticles are available to improve the efficacy of a molecule31. More recently nanoparticles gained more importance because of its modified and favorable physicochemical properties than their bulk form. Nanocrystals and nanoparticles are widely used to improve the bioavailability and to formulate a controlled release dosage form, respectively. One of the very interesting properties of nanoparticles is its altered tissue distribution thereby enabling tissue selective drug delivery and reduces the toxicity-associated problem.

 

Table: 4

Preparation techniques

1.      Amphiphilic macromolecules Cross-linking

§  Heat cross-linking

§  Chemical cross-linking

2.      Polymerization based methods

§  Polymerization of monomers

§  Emulsion polymerization

§  Dispersion polymerization

§  Interfacial condensation

§  Interfacial complexation

3.      Polymer precipitation methods

§  Solvent extraction method

§  Solvent displacement method

§  Salting out

 

Bioavailability enhancement:

Therapeutic efficacy of any dosage form for systemic activity depends on its bioavailability. Bioavailability is rate limited by two commonly known factors such as drug dissolution and drug permeation. Drug dissolution is the major rate-determining step for poorly water-soluble drugs. Dissolution velocity enhancement can be achieved by various techniques such as particle size reduction, usage of proper polymorphism, salt formation, solubilization and so on. A lucrative particle size reduction technology is nanosizing in which drug crystals are reduced to sub-micron level; as it offers enormous surface area for drug solubilization in gastrointestinal fluid. Current literature review states that orally administered non-disintegrable nanoparticles are as such up taken by gastrointestinal epithelium. More over solid lipid nanoparticles have altered pathway of drug absorption by lymphatic uptake, thereby it prevents the pre-systemic metabolism and hence it improves the bioavailability32. Various controlled release nanoparticulate systems were tried in past. These controlled release nanoparticles release the drug in pre-programmed manner and offers uniform plasma drug concentration without fluctuation for the prolonged period of time33.

 

Applicability on parentral drug delivery is also appreciable. Formulation and development of parentral dosage form for poorly soluble drugs is a challenging task. Solubilization of the drug in most of the acceptable solvent is limited for example paclitaxel. Paclitaxel, the first of a new class of microtubule stabilizing agent was not a chance discovery but was the outcome by investigation of over 12000 natural compounds for anti-tumor activity. Paclitaxel is poorly soluble in an aqueous medium and can be dissolved in toxic organic solvents. Paclitaxel is currently formulated in a vehicle composed of 1:1 blend of cremophor EL and ethanol, which is diluted with 5-20 folds of normal saline or dextrose solution (5-10%) for administration34. The amount of cremophor required to solubilise the paclitaxel is more (50% v/v) and hence it produce toxicity. Wide variety of approaches were used in past, including co-solvency, emulsification, micellization, liposome formulation, cyclodextrin and nanocrystals. Nano crystal based paclitaxel intravenous formulation is developed by American Biosciences and the drug product is currently in phase III studies in U. S35.

 

Drug targeting:

Targeting of drugs offers enormous advantages but is equally challenging. Better understanding of the physiological barriers, which a drug needs to overcome, should enable the pharmaceutical scientist to develop successful design of targeted drug delivery systems. Better appreciation of molecular biology, advances in polymer chemistry and their interaction with nanotechnology has brought renaissances on the field of drug delivery, where by nanosized drug delivery system are emerging as a panacea for the global quest of drug targeting. Various nanobased drug carriers such as liposomes, nanoparticles, solid lipid nanoparticles, polymeric micelles and polymer conjugates are used to target the drug molecule in specific tissue or organ. Liposomes can be used to deliver immunomodulators, cytotoxic and antimicrobial agents to the

 

macrophages by means of passive targeting. The rapid uptake and accumulation of liposomes in tumor cells has been proposed to be a reason for reduced plasma level and toxicity of various chemotherapeutic efficacies. Two such formulations are currently commercially available Daunosome TM liposome loaded with Daunorubicin and Doxil TM based on doxorubicin. These formulations have an extended circulating time by virtue of their small size and sterically stabilized surfaces. Selective uptake of unmodified liposomes by the phagocytic walls has also been exploited in intracellular delivery of antimicrobial agents thereby increasing therapeutic index and decreasing toxicity subsequently36.

 

Nanoparticles

Nanoparticles constitute a versatile drug delivery system, which can potentially overcome physiological barriers, and guide the drug to specific cells or intracellular compartments either by passive or ligand mediated targeting approaches. It also allows controlling the release pattern of drug and sustaining drug levels for a long time by approximately selecting the polymeric carriers. Like all colloidal drug carriers system, Nanoparticles are rapidly opsonized and cleared by the macrophages of RES. Thus, intravenously injected nanoparticles are mostly (90%) preferred for drug administration. This characteristic bio-distribution is of special benefit for targeting drugs to macrophage and has been employed for chemotherapy of RES localized tumors. The RES uptake of nanoparticle depends on the particle size, surface charge and surface hydrophilicity. Particles less than 100 nm, with hydrophilic surface charges undergo relatively less opsonization and clearance on the blood and allows long circulating nanoparticles or sterically stabilized nanoparticles. The formulation approach for surface modification of nanoparticles with polysorbate is known to result in greater transport of nanoparticles across the blood brain barrier37. Polysorbates on the surface of nanoparticles act as anchor for apolipoprotein E, which adsorbs on the nanoparticles.

 

Polymeric Micelles:

Amphiphilic copolymers self assemble in an aqueous medium to form spherical colloidal nanoparticles called polymeric micelles. Polymeric micelles have been proposed as novel carrier system in drug targeting due to their increased loading capacities, stability in physiological conditions and the possibility of engineering the core shell architecture for different applications. The sizes of polymeric micelles are usually less than 100 nm and their hydrophilic surface is of crucial importance in overcoming the major obstacle in drug targeting the RES uptake. The PEG/PLA block copolymers having amino/ sachharide and functional groups have been prepared. Such a micelles with peptide/ sugar moieties on the surface can be used to target the specific peptide receptors on cell surface for cell specific targeting of drugs. Stability of micelles is another critical factor for effective drug delivery invivo. The micelles must dissociate to release the entrapped drug at the target site38.

 

Polymer drug conjugates:           

Polymer drug conjugates were developed in order to improve the cell specificity of low molecular weight anti-cancer drugs, to effectively target the tumor cells. Conjugation of polymeric carriers to low molecular weight drugs is to bring the drastic change in the pharmacokinetic disposition of drugs at both whole body and the cellular levels. These conjugates allow passive drug targeting of tumors and their long circulation time in blood stream39. The drug clinically tested polymer-drug conjugate bearing a targeting ligand is galactosamine directed HPMA- tetrapeptidyl-doxorubicin. The system is designed for treatment of liver cancer by targeting the asialoglycoproteins receptors on hepatocytes.  Doxorubicin concentration was found to be 12-50 folds higher in hepatoma tissue than could be achieved by free drug40.

 

NANOTECHNOLOGY FOR FUTURE MOLECULES:

Advent of molecular biology and human genomic sequencing provided a wide variety of potent molecule for therapeutic use.  A number of synthetic procedure offered potent molecules for therapeutic use. While designing a new molecule for any specific indication, consideration made for achieving the optimized pharmacodynamic effects, but this approach frequently results poor pharmacokinetic properties along with potential toxicity.  Nanobased pharmaceuticals not only improve the pharmacokinetic property and also reduce the toxic incidence of dosage form by enhancing tissue selectivity.  Future technology for designing of molecules for therapeutic use may be based on highly specified target sites such as gene, intracellular components and or bit of specific protein molecules. In such a case nano based drug delivery technology is the wonderful tool to achieve the optimized tissue drug concentration and also retain the drug concentration in particular tissue for the prolonged period of time. The number of protein and peptide molecules for therapeutic use is sharply increasing in recent years. Chemistry and biology of protein molecules are entirely different from the conventional synthetic molecules. Protein and peptides are having very little stability in both Invitro and invivo environment. Bioavailability of protein molecules are rate limited by its large molecular size and enzymatic instability in invivo circumstances41.Nanobased drug delivery system for protein and peptide molecules not only improves its stability in invivo environment and also increases the tissue permeability. The effective drug delivery of protein and peptide molecules may be achieved by designing suitable dosage form based on nanotechnology42.

 

CONCLUSION:

Nanodrug delivery system can be considered as a universal formulation approach for poorly soluble drugs. The successful implementation of nanocrystal technology to a chemical entity is primarily driven by solubility properties of the drug and hence can be readily applied to various classes of compounds. Nanoparticles have been developed

 

as an important strategy to deliver conventional drugs, recombinant proteins, vaccines and more recently nucleotides. Nanodrug delivery systems modify the kinetics, body distribution and drug release of an associated drug

 

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Received on 20.10.2008           Modified on 20.11.2008

Accepted on 24.12.2008          © RJPT All right reserved

Research J. Pharm. and Tech. 2(1): Jan.-Mar. 2009; Page 21-27