Genus Mycobacterium And Tuberculosis Biology Essay

Published:

Tuberculosis is a disease scraping the human kind even in the Neolithic period. It affects one third of world population and 95 % affect the countries which are not ill equipped to meet the demand. It is microbial disease caused by Mycobacterium Tuberculosis. In 1993, the World Health Organization (WHO) declared TB to be a global public health emergency. There were an estimated 8.8 million incident cases of TB (range, 8.5 million-9.2 million) globally in 2010, 1.1 million deaths (range, 0.9 million-1.2 million) among HIV-negative cases of TB and an additional 0.35 million deaths (range, 0.32 million-0.39 million) among people who were HIV-positive (Behera, 2010). Most cases of tuberculosis evolved around South East Asia, Africa and Western Pacific regions.

Include a figure on estimated new cases of tb frm who

Similar to other developing countries, TB is still a public health problem in Malaysia despite preventive and control measures taken. The incidence rate in Malaysia has been stagnant at around 58.7 to 65.6 per 100,000 populations in the last ten years. The absolute number of new cases has been increasing from about 15,000 new cases in 2002 up to 16,665 in 2006. Sabah contributes one-third of the total cases in the country and has a notification rate for all cases of 100-200 per 100,000 people for almost a decade now. In addition, TB is the top five diseases in Malaysia that lead to Mortality (WHO).

Lady using a tablet
Lady using a tablet

Professional

Essay Writers

Lady Using Tablet

Get your grade
or your money back

using our Essay Writing Service!

Essay Writing Service

One of the greatest challenges to fight with TB epidemic is HIV epidemic. A person infected with tubercle bacillus is at risk during developing active TB in their lifetime if the immune system is not impaired. HIV/AIDS fuels the tuberculosis epidemics in many ways, such as promoting progression to active tuberculosis, increasing the risk of reactivation of latent tuberculosis infection, as well as increasing chance of tuberculosis infection once exposed to tubercle bacilli. \cite{Ngowi2009} \cite{Surname2008}.

The emergence of multidrug resistant (MDR) and extensively drug resistant (XDR) strains of mycobacterium tuberculosis raises the mortality rates of human population. WHO defines MDR TB as the bacteria become resistant to two first line drugs namely, Isoniazid and Rifampicin. MDR TB also caused by the patients attitude where they not taking the prescribed antibiotics regularly and the bacteria mutate and become resistant to drugs. In a half a million of tuberculosis cases, MDR TB has reached prevalence rate at 5 % where most of cases from India, China and Russia. In Malaysia, MDR TB cases noticed to be increase where in 2006 the number of cases increased to 42. Meanwhile, in 32 new cases found in 2008 and increased to 52 cases in 2009.

2.1.1 Genus Mycobacterium

The genus Mycobacterium consists of more than 90 species that include pathogenic or potentially pathogenic species both for humans and animals. Genus Mycobacterium is classified as an ancient genus because it is assumed that this genus was originated more than 150 million years ago. The name "myco" means fungus was given by their special characteristics to exhibit filamentous growth in liquid medium. Mycobacterium Bovis and Mycobacterium microti cause tuberculosis in animals and can be transmitted to humans. The prominent member of this genus is Mycobacterium tuberculosis which is an obligate human pathogen.

The tubercle bacilli was found by Robert Koch in 1882. In 1921, Calmette and Guerin successfully isolated a live strain of Mycobacterium bovin from cow infected with tuberculosis. The accumulated strain was known as Bacili Calmette Guerin (BCG) vaccine which used to protect humans against tuberculosis. In 1944 Streptomycin was discovered as first anti tuberculosis drug followed by a number of drugs.

The tubercle bacilli are observed as straight or slightly curved rods. The bacilli are 1-10 um in length and 0.2-0.6 um in width. Mycobacterium tuberculosis belongs to gram positive bacteria but they are difficult to stain with the gram stain method. The cells appear small red under microscopic examination. The taxonomy lineage of genus Mycobacterium is shown in Figure 1.1.

The taxonomy lineage of genus Mycobacterium is shown in figure 1.1.

Kingdom Bacteria

Phylum Actinobacteria

Class Actinobacteria

Subclass Actinobacteridae

Order Actinomycetales

Suborder Corynebacteriaceae

Family Mycobacteriaceae

Genus Mycobacterium

Species M.tuberculosis

M.africanum

M.microti

M.canetti

M.caprae

M.bovis

M.pinnipedi

2.1.3 MDR TB

Drug-resistant TB is widespread and almost found in all countries as surveyed. Multidrug-resistant tuberculosis (MDR-TB) is caused by Mycobacterium tuberculosis that is resistant to at least two of the first line drugs namely isoniazid and rifampicin which is laboratory proven. The emergence and spread of MDR-TB is a threat to people worldwide as it increasing the rate of mortality. Although, antibiotics developed in the early period (1950's) able to cure lot TB cases, but resistance to the first line TB therapies has been reported over the years.

Lady using a tablet
Lady using a tablet

Comprehensive

Writing Services

Lady Using Tablet

Plagiarism-free
Always on Time

Marked to Standard

Order Now

Fraser, A. et al., 2009. Drugs for preventing tuberculosis in people at risk of multiple- drug-resistant pulmonary tuberculosis ( Review ). Medicine, (3).

MDR-TB is often identified as a man-made tragedy because of the incomplete and inadequate treatment by patients. However, MDR-TB also can occur when someone inhales drug resistant TB germs. When the bacteria adapt to the mechanism of the main preferred drugs, then the TB changes from being common TB and becomes MDR-TB. The severity of the resistance can increase when the MDR patients not completing their medications. This severity will lead to extensively drug resistant TB (XDR-TB) where the bacteria become resistant to the second line drugs.

According to World Health Organization 2011 report, the number of new drug resistance cases increased from 1 in 2008, to 10 in 2011, while the number of countries with representative drug resistance data increased from 19 to 22. The number of high MDR-TB burden countries reports an increased in data from 4 in 2008, to 8 in 2010.

Prevention of spreading of MDR-TB can be overcome if the patients consume prescribed medicines properly as recommended by their health care provider. On the other hand, avoiding exposure to known MDR-TB patients will help to keep the problem in control.

2.1.4 Treatment of Tuberculosis

TB is curable disease because it cause by bacterial infection unlike HIV which is caused by virus infection. Bacterial infections are usually treated with antibiotics and currently there are five first line drugs namely isoniazid, rifampicin, pyrazinamide, streptomycin, and ethambutol. Other drugs that present which is in combination use of essential first line drugs are para-aminosalicylic acid, kanamycin, cycloserin and ethionamide.

The most recommended treatment for TB is directly observed treatment,short course (DOTS). It is the standard therapy to overcome TB in which implemented by World Health Organization (WHO). DOTS have been shown to reduce the drug resistance and to provide better treatment completion rates (Canadian Tuberculosis Standards 6th Edition, 2007). DOTS involve a supervised medication to the tuberculosis patient by a health care worker. The current DOTS treatment regimen is 6 months long and involves an initial 2-month treatment with 4 drugs -isoniazid, rifampicin, pyrazinamide, and ethambutol, followed by a final 4-month treatment with just isoniazid and rifampicin (Teresa et al., 2006). Although this 6-month long DOTS therapy is very effective in completely eradicating TB bacilli from the lesions, it has many side effects associated with it as well (Burman, 2010). The side effects include significant toxicity during such a long medication course, development of drug resistant strains and failure to kill latent or dormant bacilli.

The

goals of treatment are to ensure cure without relapse, to

prevent death, to impede transmission, and to prevent the

emergence of drug resistance.

List of currently used anti tuberculosis drug and their mode of action

2.1.5 Current Status of Anti tuberculosis drug

Since the control measures for TB such as Bacillus Calmette-Guérin (BCG) vaccination and chemoprophylaxis

appear to be unsatisfactory, treatment with anti-tubercular

(anti-TB) drugs becomes the only option available.

The

goals of treatment are to ensure cure without relapse, to

prevent death, to impede transmission, and to prevent the

emergence of drug resistance.

Despite the availability of several drugs and the Bacillus Calmette-Guérin (BCG) vaccine, TB

remains a major health concern worldwide, warranting the identification of new drug targets for

the design of more efficacious drugs. In 1993, the World Health Organisation (WHO) declared

TB as a global health emergency [53].

e anti-tubercular drugs currently in use are either of chemical origin, or antibiotic origin. Streptomycin was the first effective TB drug, isolated from Streptomyces griseus by Albert

Schatz and Selman Waksman in 1944, a discovery that heralded the beginning of modern TB

chemotherapy [54]. Another origin for the current drugs were the sulpha drugs, developed for

the treatment of Gram-positive bacterial infections. In 1938, sulphanilamide was found to inhibit TB infection in pigs, leading to efforts to refine the sulpha drugs for TB treatment, and

the synthesis of thiosemicarbazones, which were more effective than sulphanilamide, but were

poorer, compared to streptomycin [54]. In 1945, p-aminosalicylic acid was discovered as a TB

drug, rooting from an observation that salicylate and benzoate stimulated oxygen consumption

Lady using a tablet
Lady using a tablet

This Essay is

a Student's Work

Lady Using Tablet

This essay has been submitted by a student. This is not an example of the work written by our professional essay writers.

Examples of our work

of Mtb.

e major breakthrough was in 1952, when isoniazid was discovered. e discovery of isoniazid was based on the nicotinamide activity against Mtb in an animal model, and the reshuffling

of chemical groups in thiosemicarbazone. e nicotinamide lead also led to the discovery of

pyrazinamide in 1952. e observation that polyamines and diamines had activity against Mtb

and the subsequent synthesis of diamine analogs led to the discovery of ethambutol, in 1961. Further screening for antibiotics from soil microbes led to discovery of many other anti-tuberculosis

drugs, such as cycloserine, kanamycin and its derivative amikacin, viomycin, capreomycin, and

rifamycins and its derivative rifampicin, another popular drug for TB treatment [54].

Most of the TB drugs currently in use today were discovered during the 1950s and 1960s. e

broad-spectrum quinolones were developed in 1980s on the basis of the anti-bacterial activity of

nalidixic acid discovered in the 1960s. e quinolones, though not initially used in TB treatment,

were subsequently shown to have high activity against Mtb and have been second-line drugs for the treatment of drug-resistant TB since the late 1980s [54].

us, most of the TB drugs in current practice have been discovered by a combination of

serendipity and novel chemical modifications of an available lead compound. Given that most of

these discoveries were made decades ago, there is a pressing need for applying newer strategies

for discovery to address the serious threat posed by TB and the rise of resistant strains.

Currently, of over 20 drugs available for treating TB, four, viz. isoniazid, rifampicin, pyrazinamide, streptomycin and ethambutol, are used as front-line drugs. Injectable drugs such as

kanamycin, amikacin, capreomycin and viomycin are preferred next for treatment. Fluoroquinolones such as ciprofloxacin and ofloxacin have been found to be indispensable in the treatment

of MDR-TB. Second-line drugs, which are mainly bacteriostatic, such as p-aminosalicylic acid,

ethionamide and cycloserine, have established clinical efficacy but have more prominent side

effects [55]. Isoniazid and ethionamide are inhibitors of mycolic acid synthesis [48; 49], while

cycloserine and ethambutol inhibit synthesis of peptidoglycan [56] and cell wall arabinogalactan [57; 58] respectively, weakening the cell wall of the bacterium. Rifampicin and Amikacin

exert their pharmacological action by inhibiting bacterial RNA or protein synthesis [59-61].

Table 1.1 lists some of the current drugs available for TB, along with their targets and mechanisms of action. A comprehensive list of drugs can be found in [55]. Detailed discussions of TB

drugs and drug targets have been published earlier [54; 62]. Some of the new drug candidates

for TB, currently under clinical trials have been discussed in [63].

2.2 Drug delivery routes

Drugs may be introduced to the human body by various anatomical ways. They may be intended to for systemic effects or targeted to various organ and diseases. The choice of route of administration depends on the disease, the effect desired, and the product available. Drugs may be administered directly to the organ infected by disease and given systematically to the target organ. The various of routes of administrations are classified into following category (table 1.1).

Enteral route

Parental route

1. Oral

1. Intravascular

2. Sublingual

2.Intramuscular

3. Parental

3.Subcutaneous

4.Inhalation

In this enteral route drug is placed in gastrointestinal tract and then it absorbs in to the blood. Among the three classes under enteral route, oral drug delivery is most preferred by the patients. The reason for the preference is obvious because of ease of administration, pain free and easy to take. The absorption of the drug take place along the whole length of gastrointestinal tract and it is also cheap compared to others.

Parental means introduction of substances into the body by routes other than gastrointestinal tract but practically the term is applied to injection of substances by intravascular, intramuscular, subcutaneous and inhalation.

Figure 1 injectable route of administration

Intravascular involves administration of drug directly into the blood with the help of injection. Meanwhile, intramuscular defines that drug is given into the muscles with the aid of injection. The drug will be absorbs into the blood once it reaches the muscles. Subcutaneous drug delivery involves introduction of drug to a layer of subcutaneous fatty tissue by the use of needle. The first line anti tuberculosis drugs namely Isoniazid, streptomycin, rifampicin, ethambutol and pyrazinamide are introduced into the body by both enteral and parental routes. Table 1.2 shows route of delivery of first line anti tuberculosis drugs.

Isoniazid

Oral, intravenous, intramuscular

Streptomycin

Intraveneous and intramuscular

Rifampicin

Oral and intravaneous

Ethambutol

Oral

Pyrazinamide

Oral

2.3 Drug delivery system

A drug delivery system is defined as a formulation or a device that enable introduction of therapeutics substance in human body and increase the efficacy and safety by controlling the rate, time and place of release in body. This process includes administration of therapeutics product, release of active ingredient by the product and the subsequent transport of the active ingredient across the biological membranes to the site of action. Drug delivery system is an interface between human and the drug. It may be a formulation of the drug to administer it for therapeutics purpose or a device used to deliver the drug.

The efficiency of a drug depends on the method by which the drug is delivered to human system. Drugs will have maximum therapeutics effects at optimum concentration range and the concentration of drug above or below this optimum range can be toxic or produce no benefit at all. An efficient drug delivery system is needed, that include the approach of polymer science, pharmaceutics, bioconjugate chemistry and molecular biology.

In all drug delivery systems, the main principal is to target and kill the infected cells. The conventional therapies of tuberculosis consume longer period which is also lead to severe side effects. There is an increasing concern that resistance of antibiotics to tuberculosis. In addition, to obtain satisfactory pharmacological reaction, high dose of drug has to be applied to the patient. If a new TB treatment going to replace the already existing therapy then it should at least shorten the duration of treatment or reduce the number of dosages to be taken. Furthermore, the new drug should improve the treatment of MDR-TB or provide effective treatment against TB infection. A current approach to address the efficacy of drug treatment lies in the investigation of novel system for drug delivery. Among drug carriers one can name soluble polymers, microparticles made of insoluble or biodegradable natural and synthetic polymers, microcapsules, lipoproteins, liposomes and micelles. One of such approach is feasibility of using polymers as carriers for anti tuberculosis drug to target TB infected cells.

Polymers in dds

Polymers are macromolecules containing repeating sub-units. Polymer can control the release of a drug over a prolonged period thus avoiding repetitive dosing. Polymeric delivery systems can modify the pharmacokinetics of a drug, leading to a higher therapeutic index by decreasing the side effects. Generally, these systems are composed of a biocompatible polymer and an active pharmaceutical ingredient dispersed or covalently bound to the polymer.

Small molecular drugs enter cells by diffusion whereas macromolecules enter cells by endocytosis and the endosomes fuse with lysosomes. The membrane of lysosomes is impermeable to macromolecules. Therefore the macromolecular polymeric drug cannot escape the endo-lysosomes. The bond between the drug and the polymer must be dissolved in order for the drug to escape in to the cytoplasm.

Among all the polymers available to be used for drug delivery systems, bio degradable polymers are highly recommended. The key point of this kind of system is the removal of the carrier after the release of the active pharmaceutical ingredients. Moreover to avoid side effects when the carrier is injected, the polymer must be biocompatible. For all of these reasons, natural polymers such as polysaccharides, polypeptides, or phospholipids are generally used as building blocks for the formulations.

The term polymer therapeutics describes several classes of distinct agents, including polymeric drugs, polymer drug conjugates, polymer protein conjugates and polymeric micelles to which the drug is covalently bound and being develop as non viral vectors.

Polymer Drug Conjugate

Polymer drug conjugate is based on Ringsdorf's model which was discovered in 1975. It consists of polymer backbone, transport system, solubilizer, drug and spacer. It is prepared by conjugating the drug to a polymeric backbone via covalent linkage. Biodegradable spacer is inserted in the conjugate to ensure stability during systemic circulation and to facilitate specific enzymes or hydrolytic release of the drug. Solubilizers are classified as lipid soluble if they enhance adsorption of the drug to lipid bilayers and water solube if they maintain solubility of drug polymer conjugates causes problems for in vivo injection. The disadvantages of this carrier are that, one delivery property determined by plural components. When increasing the amount of conjugated drug per polymer chain other properties like water solubility of conjugate, drug release rate may change and effect the pharmacological activity.

Polymeric micelles are macromolecular assembly that forms from block copolymers. The drugs can be physically entrapped in the core of block copolymers micelles. The hydrophilic blocks form hydrogen bonds with the aqueous surroundings and form a tight shell around the micellar core. Thus, the contents of the hydrophobic core are protected against hydrolysis and enzymatic degradation. The chemical composition, total molecular weight and block length ratios can be easily change which allows control of the size and morphology of the micelles. The

architecture of the AB block copolymer is very simple, however, its

synthesis is more difficult than that of random polymers, where

different units are aligned on a polymer chain in a random manner. Furthermore, researchers may encounter a problem in a synthesis

of the block copolymer of a large industrial scale in a highly

reproducible manner.

The second disadvantage, specifically, for the polymeric micelle

systems is the immature technology for drug incorporation in

a physical manner. Yokoyama et al reported that physicalincorporation

efficiencies were dependent on various factors in

drug-incorporation processes. Presently, there seem to be no

universal incorporation method applicable to any polymer.

Furthermore, in some methods the drug incorporation may be

difficult on a large industrial scale, whereas the drug incorporation

is easy and efficient on a small laboratory scale.

The third disadvantage (B-1 in Table 2) is much slower extravazation

of polymeric carrier systems than that of low-molecularweight

drugs. This results from a difference in extravazation

mechanisms between polymeric carrier systems and lowmolecular-weight drugs. The polymeric systems translocate from

the bloodstream to the interstitial space of organs and tissues

through intra-cellular channels and inter-cellular junctions,

whereas the drugs permeate directly through lipid bilayer cell

membranes. Therefore, a long circulation character of the polymeric

systems is an essential requirement for delivery of a therapeutic

amount owing to compensation of the slow extravazation

with a large Area Under the Curve value that results from the long

circulation. The forth disadvantage is a risk of chronic liver toxicity.

Drugs conjugated or incorporated in the polymeric carrier systems

are metabolized in liver in a slower manner than free drug, since

access of metabolic enzymes to drugs is inhibited because of the

conjugation and incorporation. Therefore, toxic side effects of the

conjugated and incorporated drug may be exhibited for a longer

period than a case of free drug whose toxic effects can be lowered

through metabolism in a short period.

Polymer protein conjugate

Protein polymer conjugates are synthesized by conjugating a polymer chain or many polymer chains on to a protein. The site of conjugation, protein, polymer and stoichometry are important criteria when designing a protein polymer conjugate. The various methods of site specific conjugation 'grafting to' and 'grafting from' also need to be considered.

The unique catalytic and functional properties of proteins and structural property of macromolecules resulting in promising polymer protein conjugate. The conjugation studies for attaching polymers to the end group of proteins leads to the alteration in bioactivity.

Polymeric drug

To maximize the outcomes and better tailor the polymer conjugation a number of different polymers and chemical approaches being develop, yielding a selection of new structures like

Dendrimers

Dendronized polymers

Graft polymers

Block copolymers

Branched polymers

Multivalent polymers

Stars

Pic

Popular polymers that used in polymer therapeutics are categorised into three groups:

Synthetic polymers

Natural polymers

Pseudosynthetic polymers

PEG

Dextran

PGA

Poly(ethyleneimine)

Chitosan

polyamodoamines

Proteins

polyviniylalcohol

Hylaluronic acid

The studies shows that these biopolymers are effective in drug targeting, have low toxicity, improve absorption rate and prevent drug from early degradation. Moreover, polymers have unique characteristics which make them special for drug delivery studies. In general, polymers have wide range of molecular weight distribution, can interact and condense when heated and able to dissolute in various conditions. Polymers have biodegradation property where it can control by manipulating chemical or physical properties.

Natural polymers as drug carriers have advantage of easy availability and biocompatibility. Many of them have been identified and have been used as possible drugs for anticancer activity. Naturally occurring polymers such as albumin, chitin, chitosan and dextran has been successfully conjugated with known anticancer drug such as doxorubicin. In general, natural polymers being biodegradable because of their natural origin and they will be excreted from blood stream by natural catabolism. The natural polymers would allow control over the size of drug polymer and also over the functional group used for drug attachments. These groups will be modified to improve the water solubility properties of the system. Efficiency of the treatment can be increased by applying multivalency concept. In biological systems, multiple interactions are often employed to increase affinity and specificity. These multiple interactions are often much stronger than the corresponding monovalent interaction, an effect referred to as multivalency. To understand and employ this multivalent effect, synthetic organic chemistry approaches have been used to closely mimic natural multivalent systems. The use of multivalency has promising prospects for biomedical applications such as vaccines, molecular imaging and target-specific drug delivery systems. Hence, the use of natural polymers with multivalency concept is preferred and gain interest in the treatment of tuberculosis where it believes to increase the efficiency.

Chitosan

In this study chitosan was chosen because of the remarkable properties that have pave the way in biomedical and pharmaceutical fields. Chitosan is a heteropolymer consists of ß(1-4) 2-acetamido-2-deoxy-ß-D- glucopyranose (N-acetylglucosamine) and 2-amino-2-deoxy-ß-D-glucopyranose (D-glucosamine) units, randomly or block distributed throughout the biopolymer. Chitosan do not have a fixed stoichometry. It has one primary amine and two free hydroxyl groups for each monomer with a unit formula C6H11O4N. This natural biopolymer is a glucosaminoglycan and is composed of two common sugars, glucosamine and N-acetylglucosamine which are the constituents of mammalian tissue.

Pic

Chitosan is not widely present in nature and cannot be directly extracted from natural resources. Indeed, chitosan is a derivative of natural chitin. It is the second most abundant polysaccharide after cellulose but is the most abundant natural amino polysaccharide. Chitosan chemically considered analogues of cellulose, where the hydroxyl at carbon 2 been replaced by amino groups. Present day polymers are synthetic materials, their biocompatibility and biodegradability are much more limited than those of natural polymers.

Chitosan is recommended as suitable functional material, because it has excellent properties such as biocompatibility, biodegradability, non toxicity and adsorption properties. US Environmental Protection Agency acknowledge chitosan as environmentally friendly as it can be degraded by soil and water microorganism.

Chitosan refers to a family of polymers that are characterized by number of sugar units per polymer molecule which defines its molecular weight. Chitosan received much attention as a functional biopolymer for diverse applications. These functions have been revealed to be dependant not only upon their chemical structure but also the molecular size.

Chitosan is semi crystalline polymer, a weak base which is insoluble in water, alkali or aqueous solution above pH7 due to its stable and rigid crystalline structure. Chitosan is normally polydispersed and has the ability to dissolved in some inorganic and organic acid such as hydrochloric acid, phosphoric acid, succinic acid and acetic acid at certain ph value after prolong stirring. When dissolved the amino group of glucosamine are protonated to NH3+.

A wide variety of research in medical applications for chitosan and chitosan derivatives have been carried out for many years. Chitosan has been considered for pharmaceutical formulation and drug delivery applications. Chitosan is metabolized by certain human enzymes especially lysozyme and it is considered biodegradable. Chitosan polymer has also been proposed as a soluble carrier for parental drug delivery. It is also a versatile carrier for parental drug delivery. It is also a versatile carrier for biologically active species and drugs due to the presence of free amino group. Chemical modification of these groups gives to various novel biofunctional macromolecular products.

2.7.2 Polymers as Drug delivery vehicles

New approaches for TB drug treatment become essential to combat with disease, especially for patients with co infections and drug resistance. The limitation of currently available drug therapies, particularly for the treatment of diseases localized to specific organs, has led to efforts to develop alternative methods of drug administration to increase their specificity. One approach for this purpose is the use of degradable polymeric carriers for drugs which are delivered to and deposited at the site of the disease for extended periods with minimal systemic distribution of drug. The polymeric carrier is degraded and eliminated from the body shortly after the drug has been released. The polymers are divided into 3 groups:

1. Nonbiodegradable polymers - these polymers are stable in biological systems. They are mostly used as components of implantable devices for drug delivery.

2. Drug-conjugated polymers - in these the drug is attached to a water soluble polymer carrier by a cleavable bond. These polymers are less accessible to healthy tissues when compared with the diseased tissues. These conjugates can be used for drug targeting via systemic administration or by implanting them directly at the desired site of action where the drug is released by cleavage of the drug polymer bond.

3. Biodegradable polymers- these degrade under biological conditions to nontoxic products that are eliminated from the body.

An ideal drug delivery system is characterized as follows:

It should increase the bioavailability of the drug

It should provide for controlled drug delivery.

It should transport the drug intact to the site of action while avoiding the nondiseased host tissues.

The product should be stable and delivery should be maintained under various physiological variables.

A high degree of drug dispersion.

The same method should be applicable to a wide range range of drugs.

It should be easy to administer by patients.

It should be safe and reliable.

It should be cost effective.

Chitosan

The concept developed by Ringsdorf has been increase the interest in design and synthesis polymeric systems with potential drug delivery application. Although there are many polymers available commercially, but few of these polymeric systems posses properties that are suitable for drug delivery agents, such as water solubility, biocompatibility and non toxicity.

Delivery system

Advantages

Disadvantages

Micelles

Low viscosity

Small droplet size

Easy preparation

Long shelf life

Low solubilisation

Potential toxicity of surfactent

Emulsions

Small amount of surfactant

High solubility of drug into carrier

High viscosity

Instability

Short shelf life

Large droplets

Vesicle

Made from lecithin and cholesterol also present in the body

High viscosity

Difficult to prepare

Often disintegrate once administered

liposomes

Expensive

Lack of long term stability

Low pat load (encapsulation)

Possibility of new side effects

Nanoparticles

Long storage life

In vaccinations, slow degradation in the body

Limited solubility of drug

Difficult to prepare

Difficult to control size

Polymers which represents constituents are usually not bioacceptable

Dendrimers

Solubilise in water

Less filtered out from bloodstream

Tumor selectivity

Rapid release of drugs

Non selective toxicity

Limited release of loaded drug

Synthetic difficulties

Hydrogel

Environment can protect cells and other substances

Timed release of growth factors

Good transport properties

Biocompatible

Low mechanical strength

Hard to handle

Difficult to load

Sterilization

Polymers are extensively used for the delivery of an active pharmaceutical ingredient.

They can form a matrix or membrane that can control the release of a drug over

a prolonged period, thus avoiding repetitive dosing. They can also be used to

form (nano)carriers to deliver drugs, in particular poorly soluble drugs or

biotechnology-based drugs. Both systems can protect the drug from degradation.

Moreover, when the carrier is functionalized by a targeting agent, the encapsulated

drug may be selectively released inside or near a specific tissue or organ. Polymeric

delivery systems can modify the pharmacokinetics of a drug, leading to a higher

therapeutic index by decreasing the side effects and/or increasing efficacy. Several

polymeric drug delivery systems such as nanoparticles, micelles, hydrogels, or

matrices are being studied worldwide. Generally, these systems are composed of a

biocompatible polymer, degradable or not, and of an active pharmaceutical ingredient

dispersed or covalently bound to the polymer. The release of the drug usually

occurs by diffusion through the polymer, by degradation of the polymer, or by

disorganization of the supramolecular structure of the carrier.

Among all the polymers available to be used for drug delivery systems, (bio)

degradable polymers are highly recommended. Indeed, one of the key points of

this kind of system is the removal of the carrier after the release of the active

pharmaceutical ingredients. Moreover, to avoid side effects, in particular when the

carrier is injected, the polymer must be biocompatible. For all of these reasons,

natural polymers such as polysaccharides, polypeptides, or phospholipids are generally

used as building blocks for the formulations [1].

This paper will focus on chitosan and chitosan derivatives developed for

biomedical applications. In the first section, the remarkable properties of chitosan

will be exposed. The main chemical modifications used to adapt this material for

biomedical applications will be reviewed. Their applications in drug delivery

systems and tissue engineering will then be discussed.

There is now a variety of polymer-based formulations available for the immediate or controlled-release of active

pharmaceutical ingredients (APIs). These include:

Biocompatible polymers: natural polymers [albumin, chitosan, collagen, cyclodextrin, gelatine] and synthetic polymers

[poly (acrylic acid), polyacrylamide, poly (ethylene glycol)] have been used to entrap or encapsulate nucleic acids within

microspheres or nanospheres to prolong bioavailability and reduce enzymatic degradation. The maintenance of a suitable

pH environment is essential for the effcient delivery of small molecules and nucleic acids. Companies which utilise this

technology include Calando Pharmaceuticals and OctoPlus.

Biodegradable matrices:the incorporation of active ingredients into a biodegradable polymer matrix leads to the

sustained-release of small molecules and large molecules and nucleic acids localised within specific tissues. Companies

developing this technology include the Debiopharm Group, Endo Pharmaceuticals, OctoPlus, and SurModics.

Dendrimers: tree-like macromolecules containing synthetic monomers that form a branch-like structure or polymer. The

macromolecules are constructed around a simple core unit and each successive reaction introduces a new "generation" of

branching. The term dendrimer is derived from the Greek dendra, meaning tree. Dendrimers can be derived from a variety

of monomers including graphite-like dendrimers and polymers e.g. polyamidoamine, polylysine. The hollow cavities deep

within the branching structures can be loaded with nanoparticles, drugs and imaging agents. Companies leading this field

include Dendrimer Technologies and StarPharma.

Polymeric prodrugs/polymer drug conjugates:the polymer drug conjugate accumulates selectively within tumour

tissue, where it is taken up by tumour cells and the active drug released intracellularly. The uptake may be passive [taking

advantage of the enhanced permeation retention effect (EPR)], or active dependent on the nature of the backbone and

targeting ligands attached. Numerous biodegradable polymers have been designed that are pH sensitive or enzymatically

sensitive that can be conjugated to agents to render them inactive whilst in the bloodstream but once in the target cell

tissue specific peptidase can degrade the polymer to release the active agent.

This technology has been widely used in cancer therapies such as daunorubicin, doxorubicin, cisplatin and 5-fluorouracil,

where it has been shown to improve tumouricidal activity of anticancer agents and significantly increase the maximum

tolerated dose of chemotherapy in patients. Companies driving advances in these technologies include: Access Pharma,

Enzon Pharmaceuticals, Nektar Therapeutics and Samyang Pharmaceuticals.

Polymeric controlled-release delivery: A variety of polymers lend themselves to the controlled delivery of drugs due to

desirable physical properties. These properties have been harnessed in two main ways, degradation and diffusion

controlled-release due to internal or external stimuli.

Degradation controlled-release delivery:In this delivery system the drug is contained within a polymer membrane or

matrix but unlike diffusion controlled-release delivery, the polymer is designed to degrade and release the "free" drug at

specific locations within the body. The rate of polymer degradation may be stimulated by environmental conditions (pH,

temperature) and is dependent on the dissolvability of the polymer cross-linkers, the rate of hydrolysis/ionisation of water

insoluble polymers and the cleavage of the polymer. As the polymer degrades the drug is gradually released.

Diffusion controlled-release delivery: In this delivery system the drug is either suspended or dispersed within a

hydrophilic matrix derived from amino polymers, co-polymers, hydrogels or polysaccharides, also known as "monolithic"

systems, or encapsulated in a membrane derived from film-forming polymers, also known as "reservoir" systems. Water

diffuses across the membrane or into the matrix; the drug dissolves to diffuse out of the matrix or membrane. The time

taken for the water to diffuse across the membrane or within the matrix and the concentration of the drug will determine

that rate of release. Some companies have opted to combine a number of delivery platforms within a single system to

enable the controlled-release of drugs, for example, Endo Pharmaceuticals, Labopharm and Samyang Pharmaceuticals.

The application of the polymer chosen for drug development may be dependent on the drug for delivery, target tissues,

optimal pharmacokinetic profile being sought, market conditions (competition/other formulations available or under

development) and expertise of delivery specialist and/or pharmaceutical company exploring the commercialisation.

Make comparison frm journal recent advances frm drug delivery folder

2.4 Control drug delivery system

2.5 Targeted delivery systems

For targeted and controlled delivery, a number of carrier systems and homing devices are under development, such as glass like matrices, monoclonal antibodies, resealed erythrocytes, microspheres, and liposomes. There are more sophisticated systems based on molecular mechanism, nanotechnology, and gene delivery.

2.6 Novel carriers for Drug Delivery

Various novel methods of delivery have evolved since the simple administration of pills and capsules as well as injections. The novel carriers are shown in table 1.3.

Polymeric carriers for drug delivery

Collagen

Particulate drug delivery system: microspheres

Nanobiotechnology-based methods, including nanoparticles such as liposomes

Glass like sugar matrices

Resealed red blood cells

Antibody-targeted system

2.7 polymers

2.7.1 general concept

2.6 Modification of chitosan

Chitosan has high degree of crystallinity due to intra and inter hydrogen bonding that limits the accessibility of hydroxyl group to the reactant. Thus, modification in structure is necessary to convert it to other chemical product. Chitosan modification is performed by introducing a specific chemical substituent such as acetic anhydride, methyl chloride, ethylene oxide, carbon disulfide and chloro acetic acid to alter the physical and chemical structure.

The method for chemical modification of chitosan is various, depending on the reactions. A large number of chitosan derivatives have been prepared by using esterification, etherification, oxidation and other reactions such as cross linking and grafting. Chitosan derivatives such as carboxymethyl chitosan are physiologically harmless and well tolerated by the skin and mucous membranes, therefore it widely used in pharmaceutical, cosmetic and food products.

Etherification of chitosan

The introduction of ether groups into the chitosan molecule is known as etherification process. This is an inexpensive method that used in chitosan modification. The properties of chitosan ethers are defined by degree of substitution (DS) which is distinguished as the average number of hydroxyl groups substituted in a glucose unit. Commonly, etherification process involves alkalization of chitosan which is then etherified with the reagent.

The most common methods used are based on Williomson's etherification:

Chitosan-OH + R-X + NaOH Chitosan-O-R + H2O +NaX

Where R-X is an inorganic acid ester such as methyl chloride, ethyl chloride or sodium chloroacetate.

Alkali chitosan

In general, chitosan need to be converted to alkali chitosan by preswollen it and reacted with etherifying reagent such as methyl chloride. Sodium hydroxide is the most common swelling agent to use to ensure least steric hindarance of chitosan hydroxyl groups and also to give good circumstances for modification. During the preparation of alkali chitosan with sodium hydroxide, the crystalline regions of chitosan are extensively lost because of the disruption of inter molecular hydrogen bonding thus more hydroxyl group can be substituted. In carboxymethylation process, etherification efficiency depends on the diffusion and penetration of the swelling agent and etherification reagent into the chitosan structure.