An Overview On Brain Targeting Drug Delivery System

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Abstract:-

Target delivery of drug molecules to brain is one of the most challenging research areas in pharmaceutical sciences. The blood-brain barrier (BBB) represents an insurmountable obstacle for a large number of drugs, including antibiotics,antineoplastic agents, and a variety of central nervous system (CNS)-active drugs, especiallyneuropeptides.

Therefore, various strategies have been proposed to improve the delivery of different drugs to this tissue which includesliposomes, colloidal drug carriers, micelles,chimeric peptide technology, intranasal and olfactory route of administration andnano technology. This review deals in brief about the status of the BBB, different pathologies of brain like neurodegenerative,cerebrovascular and inflammatory diseases. The first part of this article aims to review the strategies developed to circumvent the BBB and deliver drugs into the brain. The use ofnano technology andliposomes are discussed which are crucial part of this article as mainly used to target various CNS disorders. The later part of this article contains future aspects of brain drug targeting.

Keywords: -

Brain targeting technology, Colloidal drug carriers, Micelles,Liposomes,Nano Technology

Introduction:-

The global market for drugs for the central nervous system (CNS) is greatly under penetrated and would have to grow by over 500% just to be comparable to the global market for cardiovascular drugs. The principle reason for this under-development of the global brain drug market is that the great majority of drugs do not cross the brain capillary wall, which forms the blood brain barrier (BBB) in vivo. The blood-brain barrier (BBB) represents an insurmountable obstacle for a large number of drugs, including antibiotics,antineoplastic agents and a variety of central nervous system drugs (CNS)-active drugs, especiallyneuropeptides. It is located at the level of brain capillaries, where there is a convergence of different cell types; endothelial cells,pericytes,astrocytes andmicroglias (perivascular macrophages). The brain micro vessel endothelial cell (BMEC) that form the BBB, display important morphological characteristics such as the presence of tight junctions between the cells, the absence of fenestrations and a diminishedpinocytics activity, that together help to restrict the passage of compounds from the blood into the extra cellular environment of the brain. [8, 9]This barrier permits the exchange of essential gases and nutrients between the bloodstream and the brain, while blocking larger entities such as microbes, immune cells and most drugs from entering.

This barrier system is a perfectly logical arrangement, since the brain is the most sensitive and complex organ in the human body and it would not make sense for it to become the battleground of infection and immune response. This biological  demilitarization zone is enforced by an elaborate and dense network of capillary vessels that feeds the brain and removes waste products. [7, 9]Each capillary vessel is bound by a single layer of endothelial cells, connected by  tight junction , thereby making it very difficult for most molecules to exit the capillaries and permeate into the brain. Tight junctions provide significanttransendothelial electrical resistance (TEER) to BMEC and impede the penetration of potential therapeutic agents such asoligonucleosides, antibodies, peptides and proteins. Furthermore, BMEC express a variety of enzymes, bothcytosolic and on the extra cellular membrane which also contribute to the restrictive nature of the BBB. P-glycoprotein (P-gp) is also present in the luminal plasma membrane of BMEC.

This is an ATP-dependant efflux pump and a member of a family of intrinsic membrane proteins. [4, 6]P-gp is known to prevent the intracellular accumulation of an extensive variety of chemotherapeutic agents and hydrophobic compounds. Under normal conditions the BBB acts as a barrier to toxic agents and safeguards the integrity of the brain. Nevertheless, several disorders and diseases can affect the brain leading to some loss of BBB integrity. [16] The major neurological diseases affecting the brain may be categorized asneurodegerative,cerebrovascular, inflammatory (infections or autoimmune) and cancer.

Rate-limiting role of the BBB in brain drug development:-

Present-day incongruities in brain drug development are illustrated by a consideration of some of the characteristics of the CNS drug industry. Whereas 98% of all small-molecule drugs do not cross the BBB, and nearly 100% of large-molecule drugs do not cross the BBB, with some studies having co injectedPolysorbate 80, a detergent that can disrupt the BBB, with the drug as a stabilizing agent, and incorrectly attributing the detergent effects to their ownnanoparticles. In other studies, the large size of theliposomes that were used produced micro embolisms that gave a false impression of brain uptake. [1]

Brain Targeting Technology:-

The usual noninvasive approach to solving the brain drug delivery problem isto lipidize the drug, The water -soluble parts of the drugs restricts BBB transport conversion of water-soluble drug into lipid-soluble  pro drug is the traditional chemistry driven solution to the BBB problem. [15]

image

Figure 1:- Outline of a program for developing BBB drug targeting strategies derived from either chemistry based or biology-based disciplines.

Strategies for drug delivery to the brain:-

Several drugs do not have adequate physiochemical characteristics such as high lipid solubility, low molecular size and positive charge which are essential to succeed in traversing BBB.

Disruption of the BBB: -

The thought behind this approach was to break down the barrier momentarily by injectingmannitol solution into arteries in the neck. The resulting high sugar concentration in brain capillaries takes up water out of the endothelial cells, shrinking them thus opening tight junction. The effect lasts for 20-30 minute, during which time drugs diffuse freely, that would not normally cross the BBB. This method permitted the delivery of chemotherapeutic agents in patients with cerebral lymphoma, malignantglioma and disseminated CNS germ cell tumors. [4, 17]Physiological stress, transient increase in intracranial pressure, and unwanted delivery of anticancer agents to normal brain tissues are the undesired side-effects of this approach in humans.

Intraventricular / Intrathecaldelivery : -

Here using a plastic reservoir which implanted subcutaneously in the scalp and connected to the ventricles within the brain by an outlet catheter. Drug injection into the CSF is a suitable strategy for sites close to the ventricles only.

Intra nasal drug delivery: -

After nasal delivery drugs first reach the respiratory epithelium, where compounds can be absorbed into the systemic circulation by Tran cellular and Para cellular passive absorption, carrier-mediated transport, and absorption throughtrancytosis. [50, 53]When a nasal drug formulation is delivered deep and high enough into the nasal cavity, the olfactory mucosa may be reached and drug transport into the brain and/or CSF via the olfactory receptor neurons may occur. [53, 55]

Possible systems for drug delivery:-

Colloidal drug carriers:-

Colloidal drug carrier systems such asmicellar solutions, vesicle and liquid crystal dispersions, as well asnanoparticle dispersions consisting of small particles of 10 400 nm diameter show great promise as drug delivery systems. [5]The goal is to obtain systems with optimized drug loading and release properties, long shelf-life and low toxicity. The incorporated drug participates in the microstructure of the system, and may even influence it due to molecular interactions, especially if the drug possessesamphiphilic and/ormesogenic properties. [5]

image

Figure 2:-Pharmaceutical carriers

Micelles:-

Micelles formed by self-assembly ofamphiphilic block copolymers (5-50 nm) in aqueous solutions are of great interest for drug delivery applications. [4]The drugs can be physically entrapped in the core of block copolymer micelles and transported at concentrations that can exceed their intrinsic water- solubility. Moreover, the hydrophilic blocks can form hydrogen bonds with the aqueous surroundings and form a tight shell around themicellar core. As a result, the contents of the hydrophobic core are effectively protected against hydrolysis and enzymatic degradation. [7] In addition, the corona may prevent recognition by thereticuloendothelial system and therefore preliminary elimination of the micelles from the bloodstream. [9]The fact that their chemical composition, total molecular weight and block length ratios can be easily changed, which allows control of the size and morphology of the micelles.Functionalization of block copolymers with cross linkable groups can increase the stability of the corresponding micelles and improve their temporal control. [4, 7, 9]

image

Figure3:-Block copolymer micelles

Liposomes :-

Liposomes were first produced in England in 1961 by Alec D.Bangham. [17]One end of each molecule is water soluble, while the opposite end is water insoluble. Water-soluble medications added to the water were trapped inside the aggregation of the hydrophobic ends; fat-soluble medications were incorporated into thephospholipid layer. [22]
In some casesliposomes attach to cellular membranes and appear to fuse with them, releasing their or drugs into the cell. [23] In the case ofphagocytic cells, theliposomes are taken up, thephospholipid walls are acted upon by organelles calledlysosomes, and the medication is released. Liposomal delivery systems are still largely experimental; the precise mechanisms of their action in the body are under study, as are ways in which to target them to specific diseased tissues. [6, 17-20, 22-27, 56-58]

image

Figure 4:- Liposomes, Micelles,Bilayer sheet

Nano technology:-

Nanoparticulate systems for braindelivery of drugs:-

One of the possibilities to deliver drugs to the brain is the employment ofnanoparticles.Nanopartiacles are polymeric particles made of natural or artificial polymers ranging in size between about 10 and 1000 nm (1 mm) .Drugs may be bound inform of a solid solution or dispersion or be adsorbed to the surface or chemically attached. Poly (butylcyanoacrylate)nanoparticles represent the onlynanoparticles that were so far successfully used for the in vivo delivery of drugs to the brain. [8]The first drug that was de-livered to the brain usingnanoparticles was thehexapeptidedalargin (Tyr-D-Ala- Gly- Phe-Leu-Arg), aLeu-enkephalin analogue withopioid activity.

Nanoparticles andnanoformulations have already been applied as drug delivery systems with great success; andnanoparticulate drug delivery systems have still greater potential for many applications, including anti-tumors therapy, gene therapy, and AIDS therapy, radiotherapy, in the delivery of proteins, antibiotics,virostatics, and vaccines and as vesicles to pass the blood - brain barrier. [8, 9]

Nanoparticles provide massive advantages regarding drug targeting, delivery and release and, with their additional potential to combine diagnosis and therapy, emerge as one of the major tools innanomedicine. [9]The main goals are to improve their stability in the biological environment, to mediate the bio-distribution of active compounds, improve drug loading, targeting, transport, release, and interaction with biological barriers. Thecytotoxicity ofnanoparticles or their degradation products remains a major problem, and improvements in biocompatibility obviously are a main concern of future research. [10]

Nowadays nanotechnology is proved to be more efficient for enhancing drug delivery to brain. Thenanoparticles are the drug carrier system which is made from a broad number of materials such as poly (alkylcyanoacrylates) (pacas),polyacetates, polysaccharides, and copolymers. The methods of preparation ofnanoparticles, their characterization and medical application have been reviewed in details earlier (Kreuter, 1992;Barrattetal., 2001;Fattal andVauthier 2002). [8, 10]The exact mechanism ofnanoparticle transport into brain is not understood, but it is thought to depend on the particles size, material composition, and structure. In some cases it is reported to mimic molecules that would normally be transported to brain. For example,polysorbate-coatednanoparticles are thought to mimic low-density lipoprotein (LDL), allowing them to be transported across the capillary wall and into the brain by hitchingaride on the LDL receptor (Kreuter et al. 2002). [8, 10]

The nanotechnology includes;-

1) Coatednanoparticles

2)Pegylatednanoparticles

3)Solid Lipidnanoparticles (SLN)

4)Nanogels

Advantages of nanotechnology :-

1) Due to their small sizenanoparticles penetrate into even small capillaries and are taken up within cells, allowing an efficient drug accumulation at the targeted sites in the body. [10]

2) The use of biodegradable materials fornanoparticle preparation, allows sustained drug release at the targeted site after injection over a period of days or even weeks (Vinogradov et al. 2002).

Recent advances in nanotechnology:-

The research team of University of Michigan has developed a tool to diagnose and treat the most virulent forms of brain cancer. That is 20 to 200 nanometer diameternanoparticles; they dubbed Probes Encapsulated by Biologically Localized Embedding (pebbles). They designed the pebbles to carry a variety of agents on their surface, each with a unique function. The major potential advantage of using thesenanoparticles to treat cancer is of multifunctional. One target molecule immobilized on the surface could be used to help visualize the target using magnetic resonance imaging (MRI), while a third agent attached to the PEBBLE could deliver a destructive dose of drug or toxin to nearby cancer cells. All three functions can be combined in a single tiny polymerspere to make a potent weapon againstcancer.Kopelman introduced the common MRI contrast element gadolinium to the pebbles. When injected into thethe bloodstream, thenanoparticles travel their way through the bloodstream. And because they can transverse they have a targeting agent attached, the pebbles accumulate in the brain tumor enabling a clear MRI image within just a few hours. [10]

Researchers incorporated a drug calledPhotofrin along with iron oxide intonanoparticles that would target cancerous brain tumors .Photofrin is a type of photodynamic therapy (PDT), in which the drug is drawn through the blood stream to tumors cells; a special type of laser light activates the drug to attack the tumor. Iron oxide is a contrast agent used to enhance magnetic resonance imaging (MRI)

Chimeric peptide technology:-

Chimeric peptides are formed when a drug that is normally not transported through the BBB is conjugated to a brain drug-targeting vector. [11]The latter is an endogenous peptide, modified protein, orpeptidomimetic monoclonal antibody (mab) that undergoes RMT(Rapid metabolic transfer) through the BBB on endogenous receptor systems such as the insulin receptor or the tfr.Peptidomimeticmabs bind toexofacialepitopes on the BBB receptor that are removed from the endogenousligand binding site and  piggyback across the BBB on the endogenous RMT system within the BBB, In this , a drug ismonobiotinylated in parallel with the production of a vector/ avid in or a vector/streptavidin (SA) fusion protein. [11]Thebiotinylated drug is produced in one vial and the vector/avid in fusion protein is produced in another vial, and the 2 vials are mixed before administration.

Owing to the extremely high affinity of avid in or SA binding of biotin, there is instantaneous capture of thebiotinylatedneurotherapeutic agent by the vector/avid in or vector/SA fusion protein. [16]Monoclonal antibody/avid in andmab/SA fusion genes and fusion proteins are produced with genetic engineering. Brain drug delivery in rats is possible with the OX26 mousemab to the rat tfr. Brain drug delivery in humans is possible with the genetically engineeredchimeric HIRmab. The activity of the genetically engineeredchimeric HIRmab is identical to that of the originalmurine HIRmab and thechimeric antibody is avidly taken up by the primate brain. [33]The brain uptake of the HIRmab in the rhesus monkey is 2% to 4% of the injected dose which is a level of brain uptake that is 1 to 2 log orders greater than the brain uptake of aneuroactive small molecule such as morphine. [11, 16, 33]

Neuroprotection with peptide radiopharmaceuticals:-

The practice of brain imaging uses small-molecule radio chemicals that bind to monoamine or amino acid neurotransmitter systems. Whereas there are less than a dozenmonoaminergic or aminoacidergic neurotransmitter systems, there are hundreds ofpeptidergic neurotransmission systems. [40]Therefore, the use of peptide radiopharmaceuticals could greatly increase the diagnostic potential ofneuroimaging technology. [37] Potential candidates forneuroimaging include epidermal growth factor (EGF) peptide radiopharmaceuticals for the early detection of brain tumors and A_ peptide radiopharmaceuticals as a diagnostic brain scan for Alzheimer disease. Many malignantgliomas over express the EGF receptor (EGF-R) and EGF are a potential peptide radiopharmaceutical for the imaging of brain tumors. [34, 37, 40, 32]

ProteinNeurotherapeutic agent andneuroprotection in stroke:-

Virtually all small-moleculeneuroprotective agents have failed in clinical stroke trials because either (a) these molecules have unfavorable safety profiles or (b) the drugs do not cross the BBB. The therapeutic window forneuroprotection is the first 3 hours after stroke, and during this time, the BBB is intact. [45]The BBB is disrupted in later stages following stroke, but at this time, chances forneuroprotection have been lost. Therefore, if effectiveneuroprotective agents for stroke are to be developed, these molecules must have favorable safety profiles and must be able to cross the BBB. [41]A modelneurotrophin, brain-derivedneurotrophic factor (BDNF), was reformulated to enable BBB transport, and the BDNFchimeric peptide isneuroprotective following delayed intravenous administration in either regional or global brain ischemia. [35, 36, 41,42-45]

Intranasal and olfactory rout of administration:-

image

Figure 5:- The olfactory bulb, olfactory mucosa, and olfactory nerve cells in humans. [46]

Nasal transport routes:-

After nasal delivery drugs first reach the respiratory epithelium, where compounds can be absorbed into the systemic circulation utilizing the same pathways as any other epithelia in the body: Tran cellular and Para cellular passive absorption, carrier-mediated transport, and absorption throughtrancytosis. Although absorption across the respiratory epithelium is the major transport pathway for nasally-administered drugs and may represent a potentially timesaving route for the administration of certain systemic drugs delivered in cryonics medication protocols (e.g., epinephrine or vasopressin), problem of BBB-mediated exclusion of brain-therapeutic agents to be of greater immediate concern. Accordingly, the remainder of this article will deal primarily with the transport of drugs to the CNS by way of the olfactory epithelium. [46]

When a nasal drug formulation is delivered deep and high enough into the nasal cavity, the olfactory mucosa may be reached and drug transport into the brain and/or CSF via the olfactory receptor neurons may occur. The olfactory pathways may be broadly classified into two possible routes: the olfactory nerve pathway (axonal transport) and the olfactory epithelial pathway. [48]

Axonal transport is considered a slow route whereby an agent enters the olfactory neuron viaendocytotic orpinocytotic mechanisms and travels to the olfactory bulb by utilizing the sameanterograde axonal transport mechanisms the cell uses to transport endogenous substances to the brain. [53]Depending on the substance administered, axonal transport rates range from 20-400 mm/day to a slower 0.1-4 mm/day. [54]The epithelial pathway is a significantly faster route for direct nose-to-brain transfer, whereby compounds passparacellularly across the olfactory epithelium into theperineural space, which is continuous with the subarachnoid space and in direct contact with the CSF. Then the molecules can diffuse into the brain tissue or will be cleared by the CSF flow into the lymphatic vessels and subsequently into the systemic circulation. [46-55]

Factors Affecting Nasal Drug Delivery to the Brain:-

The size of the molecule is the major determinant in whether a substance will be absorbed across the nasal respiratory epithelium and/or transported along the olfactory pathway. Fisher et al. Demonstrated an almost linear relationship between the log (molecular weight) and the log (% drug absorbed) of water-soluble compounds. [51]

Other factors affecting delivery to the brain include the degree of dissociations andlipophilicity (higherlipophilicity results in better transport). Once a drug is in the brain, it can be further influenced by BBB efflux transporter systems like P-glycoprotein (P-gp). Graff and Pollack (2003), however, found that uptake into the brain was enhanced when drugs were administered in combination with the P-gp efflux inhibitor,rifampin. [48, 49]

Nose-to-Brain Research:-

Researching nose-to-brain transfer of drugs in humans must, for obvious reasons, either employ indirect visualization of drug transfer (e.g., effects on event-related-potentials), measurement of drug concentrations in the CSF during surgery, or simple monitoring of CNS effects. Such studies have clearly indicated that drugs can be delivered to the brain in this manner, but they give no clear-cut evidence regarding the role of transfer. Because of this limitation, studies of the olfactory pathway as a conduit for transmission of drugs to the CNS have mostly made use of animals having substantially different ratios of olfactory-to-respiratory epithelium than humans. [52]However, the mechanisms of transfer remain the same and are worthy of thorough investigation. To date, more than 50 drugs and drug-related compounds have been reported to reach the CNS after nasal administration in different species. [49]

A growing number of recent reports have demonstrated the effectiveness of intranasal administration ofneuroprotective agents in decreasing ischemic brain injury. For example, Ying et al. (2007) recently reported that intranasal administration of NAD+ profoundly decreased brain injury in a rat model of transient focal ischemia. Similarly, Wei et al. (2007) showed that intranasal administration of the PARG inhibitor Gallo tannin decreased ischemic brain injury in rats. Such agents are believed to provideneuroprotection by diminishing or abolishing activation of poly (ADP-ribose) polymerase-1 (PARP-1), which plays a significant role in ischemic brain damage. NAD+ was observed to reduce infarct formation by up to 86% even when administered at 2 hours after ischemic onset. Because PARP activation appears to be a downstream ischemic event, it may be worthwhile to also investigate the ability of IN (intranasal) administration of agents such asantiporters or NMDA receptor blockers to provideneuroprotection against the more upstream events of global ischemia such as membrane depolarization andexcitotoxicity. [51]

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Future aspects of brain targeting [2, 3, 12, 29, 30]:-

There are many technological challenges to be met, in developing the following techniques:

" Nano - drug delivery systems that deliver large but highly localized quantities of drugs to specific areas to be released in controlled ways;

" Controllable release profiles, especially for sensitive drugs; [1] " Materials fornanoparticles those are biocompatible and biodegradable;

" Architectures / structures, such asbiomimetic polymers,nanotubes;

" Technologies for self-assembly;

" Functions ( active drug targeting, on-command delivery , intelligent drug release devices/bioresponsive triggered systems, self-regulated delivery systems, systems interacting with the body, smart delivery); [13-15]

" Virus-like systems for intracellular delivery;

"Nanoparticles to improve devices such as implantable devices/nanochips fornanoparticle release, or multi reservoir drug delivery-chips;

" Nanoparticles for tissue engineering; e.g. For the delivery of cytokines to control cellular growth and differentiation, and stimulate regeneration; or for coating implants withnanoparticles in biodegradable polymer layers for sustained release;

" Advanced polymeric carriers for the delivery of therapeutic peptide/proteins (biopharmaceutics), And also in the development of: Combined therapy and medical imaging, for example,nanoparticles for diagnosis and manipulation during surgery (e.g. Thermotherapy with magnetic particles); [31]

" Universal formulation schemes that can be used as intravenous, intramuscular or per oral drugs

" Cell and gene targeting systems.

" User-friendly lab-on-a-chip devices for point-of-care and disease prevention and control at home.

" Devices for detecting changes in magnetic or physical properties after specific binding ofligands on paramagneticnanoparticles that can correlate with the amount ofligand.

" Better disease markers in terms of sensitivity and specificity. [38, 39]

Conclusion:-

Brain Targeting has got the attention of the many researchers due to its application in various diseases related to CNS. Only few drugs can penetrate the BBB and enters the CNS, so various systems are developed for drug delivery. It emerges that the nanotechnology and by using other routes of drug administration like intra nasal technique drug can penetrate the BBB efficiently. Further the modified colloidal particles and various modifiedliposomes enhance exposure of the BBB due to prolonged blood circulation, which favors interaction and penetration into brain endothelial cells. This system has clinical benefits like reduced drug dose, decreased side effects, non invasive routes, and more patient compliance. We still require developing a cost effective system that can be used in various CNS disorders efficiently with minimum side effect.

Acknowledgements:-

We acknowledged our Director sir DR. K. PUNDARIKAKSHUDU and also very much thankful to Professor MR. B.M.PEERZADA and Professor MR. MANISH SHAH for giving constant support.

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About Authors:

Shreeraj h. Shah

Shreeraj H. Shah
Corresponding Author: Address: Dept. of Pharmaceutics, L.J. Institute of Pharmacy, Near Nagdev-Kalyan Mandir, S.G. Highway, Makarba, Ahmedabad-382 210, Gujarat, India.

Mitesh Jayprakash Shah
E\22, Hariom Park , Opp. Gosha society, Near UDGUM school, Drive-in Road, Ahmadabad 380 054

Jitendra Ramnaresh Sharma
417, New Jashoda Nagar, b/h Phase-3, Vatwa, Ahmedabad,

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Comments

Prof. J. Vijaya Ratna's picture

Excellent handling of a very important topic. Definitely more attention must be shown to targeting brain. Diagrams are very good.

shreeraj9183's picture

THANKS A LOT MAM FOR COMPLIMENTS AND ENCOURAGEMENT

Dixon Thomas's picture

Dear Shah
you are working pretty well with publications. I appreciate your enthusiasum
DIXON THOMAS
MDCP, BELA POST
KERALA, INDIA 671321

Mr. Dixon Thomas, M. Pharm, M. S., RPh Assoc. Prof., RIPER 

 

shreeraj9183's picture

THANK YOU VERY MUCH

ks kumar upadhyayula's picture

YOUR WAY OF APPROACH TOWARDS TOPIC IS REALLY AWESOME AND THE WAY OF REPRESENTATION IS GIVING A GOOD WAY TO LEARN MORE.THE LINKS ARE MORE HELPING TO KNOW EXTRA INFORMATION.

gangadhar hari's picture

U hav choosen the right target for ur presentation.

It's really great!!!!

G Sudha Manohar's picture

Its very great to have like u people for gaining thorough knowledge.

maomer1's picture

thank you for this good work
Mohamed Abdulbagi
Sudanese pharmacist
maomer1@hotmail.com

thank you

praveengaddam's picture

nice presentation regarding BBB and targeting drugs to brain

dabhimahesh's picture

Realy nice one

Vey informative and one can collet almost information related to the from sinle source.

good job!!!!!!!!!!!!!

Dabhi Mahesh
Asst. Professor,
Department of Pharmaceutical Sciences,
Saurashtra University,
Rajkot-360 005,
GUJARAT, INDIA.

Dabhi Mahesh Department of Pharmaceutical Sciences, Saurashtra University, Rajkot-360 005, GUJARAT, INDIA.
Mayur Sojitra's picture

Very Informative article....
Mayur Sojitra
ramu's picture

thank you for this good work & nice presentation,
guntaka_rami@rediffmail.com
ramu,
Hyderabad