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Nanoparticle based drug delivery system for tuberculosis chemotherapy
Dr. Sriram Selvaraju, MBBS, MPH

Background

India’s Revised National Tuberculosis Control Program (RNTCP) recommends six months of directly observed short course chemotherapy (DOTS) comprising Rifampicin (RIF), Isoniazid (INH), Pyrazinamide (PYZ), and Ethambutol (ETB) thrice weekly for 2 months(intensive phase) followed by RIF and INH thrice weekly for a further 4 months for newly diagnosed tuberculosis patients1. The basic goals2 of anti-tuberculosis chemotherapy are to rapidly kill the actively multiplying bacilli, prevent acquired drug resistance, and sterilization of infected host tissues to prevent clinical relapse. The success and failure rate of tuberculosis treatment is dependent on the patient related factors, health system related factors and the effectiveness of the tuberculosis regimen. The non drug related factors which determine treatment outcomes include patient compliance to the treatment, under nutrition, smoking, indoor air pollution, co existing diseases like HIV and lack of effective supervision by health staff. The important problem with the current tuberculosis chemotherapy is that, when it is administered orally or intravenously, the drug is distributed throughout the body through the systemic blood circulation. A majority of molecules do not reach their targets and subsequently, stay in the body causing side effects. The drugs have short plasma half-life and rapid clearance, which limits their efficiency. To overcome the challenges3 due to anti tuberculosis drugs and improve the success rate of TB treatment, we need new tuberculosis drugs which can overcome these challenges as listed below.

Why should we have a new thinking towards the anti-tuberculosis drugs?

Though it is natural to think of developing new regimens, from 1950s till early 2012, no new drug for tuberculosis was discovered. The amount of money and time spent on finding a new drug for tuberculosis is very huge in comparison to the amount of new drugs developed. Only in December 2012 a new drug called Bedaquiline4 was approved as part of combination therapy to treat adults with pulmonary Multi-Drug Resistant Tuberculosis, but it is yet to be available in the tuberculosis control programme and the effectiveness of the drug in program conditions is to be studied. The slow rate of new drug discovery for tuberculosis conditions us to have a new thinking and new approach towards anti-tuberculosis drugs.

The alternative to discovering newer drugs for tuberculosis could be based on using modern technologies to improve the efficacy and compliance of current tuberculosis chemotherapy by changing the formulations, adding adjuvant or drug carriers and using novel drug delivery systems. Of the available technologies, nanotechnology which involves studying and working with matter on an ultra-small scale seems to provide promising solutions. Nanotechnology encompasses all areas of research where the characteristic dimensions are within the range of 1–100 nano-meters which is the scale of dimension for most components of bio molecular complexes such as microfilaments, the diameter of most globular proteins and width of a DNA double helix. It is even smaller than the wavelength of visible light and a hundred-thousandth the width of a human hair. The objective of the article is to review and summarize the potential therapeutic applications of nanoparticle based drug delivery system for tuberculosis.

What is nanoparticle? What is nanoparticle based drug delivery system for tuberculosis?

Nanoparticles are one of the many products of nanotechnology. Nanoparticles are less than about 100 nm (1 nano meter =10-9 m) in diameter that exhibit new or enhanced size-dependent properties compared with larger particles of the same material. When nanoparticles are used as drug carrier to deliver or improve the efficacy of the tuberculosis drugs then it is called as nanoparticle based drug delivery system for tuberculosis.

What are the advantages of nanoparticle based drug delivery system for tuberculosis?

  • 1. Nanoparticles have the ability to encapsulate the tuberculosis drugs within the nanoparticle matrix and protect it from hydrolytic and enzymatic degradation in the gastrointestinal tract as shown in figure 1
  • 2. By encapsulation of the drugs inside the nanoparticles, the drug metabolism and clearance by first pass metabolism is reduced.
  • 3. The important objective of nanoparticle based tuberculosis drug delivery system is to have a sustained and controlled drug release (a) above the MIC (Minimum inhibitory concentration level-orange line) and (b) well below the toxic level (rose line), so that the drugs have good bioavailability for long duration of time and no toxicities. Whereas in the conventional treatment, free tuberculosis drugs reaches the peak concentration in plasma above the toxic level to cause side effects and degrade to reaches levels below the MIC within few hours. Slow and sustained release5 (blue colour line) of nanoparticle based anti-TB drugs increases the half life and bioavailability of anti-TB drugs in plasma and target organs compared to the conventional anti-TB drugs (violet colour line) as shown in Figure 2
  • 4. The bioavailability of drugs is increased due to the bio adhesive nature of nanoparticles and by absorptive endocytosis as shown in figure 3. Due to their small size nanoparticles are able to (1) avoid opsonisation by the mononuclear phagocyte system, (2) remain in the blood circulation for a longer duration of time, (3) reaches the target organs in comparison to other traditional drug delivery systems where the drug is distributed throughout the body through the systemic blood circulation as shown in figure 4.
  • 5. They also have the advantage of encapsulating multiple drugs in the same nanoparticle which overcomes the problem of multiple drug consumption.
  • 6. They have the advantage of long shelf life compared to the conventional drugs which makes it suitable for supplying it to the peripheral health centres

To summarize, the advantages of nanoaprticle based drug delivery system for tuberculosis are listed below:

1. Few drugs to be consumed

2. Sustained and controlled drug release, leading to increased bioavailability

3. Reduced drug metabolism and slow bioactive degradation due to encapsulation

4. Less side effects compared to conventional drugs

5. More patient friendly and will increase compliance because of

? less number of doses and

? Minimal/mild side effects

6. Capacity to load or encapsulate multiple drugs (ideal for drug resistant tuberculosis)

7. Development of drug resistance will be low due to

? Few number of doses to be consumed

? Increased compliance (few doses and few drugs)

? Increased bioavailability

8. Long shelf life

What are the current evidences available for nanoparticle based tuberculosis drug delivery system?

Evidences supporting nanoparticle based drug delivery system for tuberculosis are available from animal studies conducted in mice, rat and guinea pigs. The routes of drug delivery that were tested were oral, inhalational and subcutaneous routes. (1) The efficacy, (2) Safety and toxicity of nanoparticle based drug delivery system are given below

(1) Efficacy of nanoparticle based tuberculosis drugs in different routes6

When nanoparticle based anti-tuberculosis drugs containing rifampicin, isoniazid and pyrazinamide were administered orally or through inhalation complete bacterial clearance was achieved in lungs and spleen in 5 doses given every 10th day in comparison to 46 conventional doses of anti-tuberculosis drugs given daily for achieving the same effect. When single dose of nanoparticle loaded with RIF+ INH+PYZ was administered subcutaneously in mice, therapeutic drug levels were maintained for 32 days in plasma, lungs, spleen and was able to produce sterilizing effect in lungs and spleen in comparison to 46 conventional doses of anti-tuberculosis drugs given daily for achieving the same effect.

Lectin functionalized nanoparticle based tuberculosis drugs: When the nanoparticles were functionalized using lectin and administered orally complete bacterial clearance was achieved by 3 doses fortnightly in comparison to 46 conventional doses of anti tuberculosis drugs given daily for achieving the same effect. This is due to the reason that lectins are sugar binding proteins which are usually found in fruits and vegetables we eat and they are easily recognized by the intestine. So it will absorb the lectin and in turn the nanoparticles containing the tuberculosis drugs also enter the systemic circulation. (Refer table 1 for Drug release and therapeutic efficacy of the nanoparticle-based tuberculosis drugs) anti-tuberculosis drugs for achieving the same effect.

(2) Safety and toxicity of nanoparticle based tuberculosis drugs7

No toxicity or mortality was observed on giving multiple oral doses of nanoparticle based tuberculosis drugs even on completion of sub acute (28 days) or chronic (90 days) toxicity studies based on survival, gross pathology, histopathology, biochemistry and haematology. There was no toxicity observed even at 150 times the therapeutic dose for the nanoparticle based tuberculosis drugs or drug free nanoparticle. Free drug at 40 times the therapeutic dosage level showed abnormal motor behaviour 30 minutes after administration. Toxicity and mortality was reported for free drugs starting from 80 to 150 times the therapeutic dosage levels. (Refer to table 2 for safety and toxicity profile of nanoparticle based drug delivery system for tuberculosis)

What more evidence is required for the nanoparticle based drug delivery system to reach the first in human trials?

As noted above, most of the research has been conducted in the rodents like mice, rats and guinea pigs. But before starting human clinical trials we need to experiment on a species which mimics most of the human characteristics like monkey or dog. Hence we need evidence from clinical trials in monkeys or dogs, before proceeding to the first in human trial of a nanoparticle based drug delivery system for tuberculosis.

What is the implication for the control of tuberculosis in high burden countries?

Nanoparticle based drug delivery system for tuberculosis has potential for simplifying the tuberculosis treatment with minimal number of doses and drugs, sustained drug release, good bioavailability, improved efficacy and minimal side effects compared to conventional tuberculosis chemotherapy. This will be cost saving for both the patient and the health system. Further, there is possibility of reducing the emergence of drug resistance through such a drug delivery system. Additionally, one may explore the ways to deliver the MDR-TB and XDR-TB drugs through the nanoparticle drug delivery system.

Nanoparticle based drugs currently available in the market

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3474440/pdf/ptj3710582.pdf

References

1. RNTCP ,Strategic vision for TB control for the country 2005 – 2015,

http://www.tbcindia.nic.in/pdfs/Strategic%20Vision%20for%20the%20country%202005-2015%20%20Final.pdf

2. http://cdn.intechopen.com/pdfs/28840/InTech-Old_and_new_tb_drugs_mechanisms_of_action_and_resistance.pdf

3. Rajesh Pandey, Zahoor Ahmad, Nanomedicine and experimental tuberculosis: facts, flaws, and future, Nanomedicine: Nanotechnology, Biology and Medicine, Volume 7, Issue 3, June 2011, Pages 259-272

4. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm333695.htm

5. http://www.conference2012.csir.co.za/sites/default/files/Rose_Hayeshi_FINAL.pdf

6. Lisa C du Toit, Viness Pillay* and Michael P Danckwerts, Tuberculosis chemotherapy: current drug delivery approaches, Respiratory Research 2006, 7:118

7. Pandey R, Sharma S, Khuller GK, Oral poly (lactide-co-glycolide) nanoparticle based antituberculosis drug delivery: toxicological and chemotherapeutic implications. Indian J Exp Biol. 2006 Jun;44(6):459-67.

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