DEVELPOMENT OF NOVEL NANOPARTICULATE DRUG DELIVERY SYSTEM ...

www.wjpps.com Vol 6, Issue 4, 2017.

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Mamta et al. World Journal of Pharmacy and Pharmaceutical Sciences

DEVELPOMENT OF NOVEL NANOPARTICULATE DRUG

DELIVERY SYSTEM OF RIFABUTIN

Kumari Mamta*1, Dr. Agrawal Amit

2, Mishra T. S.

2, Kumari Manisha

2 and

Bhawarker Swati3

*1Lakshmi Narain College of Pharmacy, Raisen, Bhopal, Madhya Pradesh, India-462044.

2Patel College of Pharmacy, Ratibad, Bhopal, Madhya Pradesh, India-462044.

3Ravishankar College of Pharmacy, Bhanpura, Bhopal, Madhya Pradesh, India-462044.

ABSTRACT

Nanotechnology has the potential to offer solutions to these current

obstacles in cancer therapies, because of its unique size and large

surface-to-volume ratios. Nanoparticles may have properties of self-

assembly, stability, specificity, drug encapsulation and

biocompatibility as a result of their material composition. The

multidisciplinary field of nanotechnology’s application for discovering

new molecules and manipulating those available naturally could be

excited in its potential to improve health care. Nanotechnology is

definitely a medical boon for diagnosis, treatment and prevention of

various diseases including cancer. It supports and ex-pands the

scientific advances in genomic and proteomics and builds on our understanding of the

molecular under-pinnings of cancer and its treatment. Encapsulation of rifabutin in Gelatin

nanoparticles enables development of the intravenous formulation of this poorly soluble anti-

tuberculosis antibiotic. After oral administration, the nanoparticle-based formulation of

rifabut in produced a 2-fold increase in bioavailability, as compared to the parent drug the

present study work on Development of Novel Nanoparticulate Drug Delivery System of

Rifabutin.

KEYWORD: Nanotechnology, Rifabutin, HPLC, methanol, Solubility, UV.

INTRODUCTION

Tuberculosishas afflicted the human race for centuries. Treatment of tuberculosis is generally

successful, except in the case of multiple-drug-resistant strains of Mycobacterium

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 6.647

Volume 6, Issue 4, 1404-1417 Research Article ISSN 2278 – 4357

*Corresponding Author

Kumari Mamta

Lakshmi Narain College

of Pharmacy, Raisen,

Bhopal, Madhya Pradesh,

India-462044.

Article Received on

30 Jan. 2017,

Revised on 19 Feb. 2017, Accepted on 12 March 2017

DOI: 10.20959/wjpps20174-8915


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tuberculosis. Rifabutin (RIF) is a first-line drug for use in the therapy of tuberculosis and is

included in the list of recommended drug regimens for treatment of latent M. Tuberculosis

infection.[1]

Modern drug carrier systems play an important role in controlled delivery of a

pharmaceutical agent to the target at a therapeutically optimal rate and dose. Among various

colloidal drug delivery systems, nanoparticles (NPs) represent a very promising approach to

this aim. NPs may be defined as being submicron colloidal systems; once in the bloodstream,

surface-nonmodified NPs (conventional NPs) are rapidly opsonized and massively cleared by

the fixed macrophages of mononuclear phagocyte system organs such as liver, lungs and

spleen. Various polymers have been used in drug delivery research, because they can

effectively deliver the drug to a target site and thus increase the therapeutic benefit, while

minimizing side effects.[2]

The best-known class of materials for controlled release is the

Gelatin. Gelatin is biocompatible polymers derived from the collagen inside animal’s skin

and bones. Nanoparticulate formulations demonstrated a higher antibacterial efficacy as

compared to the untreated control to rifabutin plain drug after oral administration.

Nanoparticles shows best stability in the refrigerated conditions.[3]

Nanoscale devices have

impacted cancer biology at three levels: early detection, tumour imaging using radiocontrast

nanoparticles or quantum dots; and drug delivery using nanovectors and hybrid

nanoparticles[4]

Hence in the present work is objected to develop Gelatin nanoparticles

containing Rifabutin.

MATERIALS AND METHODS

1. DRUG PROFILE[5-12]

Brand Names: Mycobutin

Generic Name: Rifabutin

Properties of drug Rifabutin

Mechanism of Action

Rifabutin inhibits DNA-dependent RNA polymerase in susceptible

strains of Escherichia coli and Bacillus subtilis but not in

mammalian cells. In resistant strains of E.coli, rifabutin, like

rifampin, did not inhibit this enzyme. It is not known whether

rifabutin inhibits DNA-dependent RNA polymerase in

Mycobacterium avium or in M. intracellulare which comprise M.

avium complex (MAC)[1]

Solubility in water Soluble in chloroform and methanol. Sparingly soluble in ethanol

and very slightly soluble in water (0.19 mg/ml).


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1.2. Pharmacokinetic data

Absorption

After a single oral dose administration readily absorbed from the

gastrointestinal tract. At least 53% of the orally administered rifabutin dose is

absorbed from the gastrointestinal tract

Distribution

Due to its high lipophilicity, rifabutin demonstrates a high propensity for

distribution and intracellular tissue uptake. Mean rifabutin steady-state trough

levels (Cp,minss; 24-hour post-dose) ranged from 50 to 65 ng/mL in HIV-

positive patients. Binding does not appear to be influenced by renal or hepatic

dysfunction

Metabolism

Out of the five metabolites that have been identified, 25-O-desacetyl and 31-

hydroxy are the most predominant, and show a plasma metabolite:parent area

under the curve ratio of 0.10 and 0.07, respectively. The former has an activity

equal to the parent drug and contributes up to 10% to the total antimicrobial

activity

Excretion

When taken by oral dose 53% excreted through urine as primarily metabolite.

About 30% of the dose is excreted in the feaces. Renal and biliary clearance of

unchanged drug each contribute approximately 5% to CLs/F.

Chemical Data

Chemical Formula C46H62N4O11

IUPAC name

a). 1',4-didehydro-1-deoxy-1,4-dihydro-5'-(2-methylpropyl)-1-oxorifamycin

XIV

b). (9S, 12E, 14S, 15R, 16S, 17R, 18R, 19R, 20S, 21S, 22E, 24Z)-6,16,18,20-

tetrahydroxy- 1'isobutyl-14-methoxy-7,9,15,17,19,21,25-heptamethyl-piro

[9,4(epoxypentadeca[1,11,13]trienimino)-2H-furo [2',3':7,8]naphth[1,2-

d]imidazole-2,4'-piperidine]-5,10,26-(3H,9H)-trione-16-acetate.

Molecular mass 847.02

2. METHODOLOGY

2.1 PREFORMULATION

Preformulation studies are needed to ensure the development of a stable as well as

therapeutically effective and safe dosage form. The preformulation studies, which were

performed in this project, include identification of drug, solubility analysis, partition

coefficient and drug compatibility with the lipids.

Physical Appearance[13]

The drug (Rifabutin) was obtained as a gift sample from Lupin Pharma Pvt. Ltd, Pune. The

supplied sample of rifabutin was red-voilet, crystalline, odorless, hygroscopic powder.

Melting point[14]

Melting point of rifabutin was determined by melting point apparatus and found to be

153.2°C.


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Solubility[15]

The sample was qualitatively tested for its solubility in various solvents. It was determined by

shaking 10 mg of drug sample in 10 ml of solvent (i.e., water, methanol, ethanol, ether,

chloroform, benzene etc.) in small test tubes and noted down the time require to disappear the

sample completely. Solubility profile of rifabutin is recorded in Table 1.

2.2 Determination of λmax[16]

Accurately weighed 10 mg of rifabutin was dissolved in 100 ml of methanol in a 100 ml

volumetric flask. Then, 1 ml of this stock solution was pipetted into a 10 ml volumetric flask

and volume made up to the mark with distilled water. The resulting solution was scanned

between 200-400 nm using 1700 pharmaspec schimadzu UV-visible spectrophotometer. The

λmax was found to be 275 nm (Fig. 1). The same procedure was followed for determining the

λmax in PBS (pH7.4) and sodium acetate buffer of pH 4.0 except methanol was replaced with

the respective solutions. The resulting solution was scanned between 200-400 nm using 1700

pharmaspec schimadzu UV-visible spectrophotometer. The λmax was found to be 275 nm in

these buffers also (Fig. 2 and 3).

2.3 Partition coefficient[17]

The partition behavior of drug was examined in n-octanol: water, n-octanol: PBS (7.4)

system. It was determined by taking 5 mg of drug in two separating funnels one containing

10 ml portions of n-octanol and 10 ml water and the other containing, 10 ml of n-octanol and

10 ml of PBS (pH 7.4) respectively. The separating funnels were shaken for 2 hr in a wrist

action shaker for equilibration. Two phases were separated and the amount of the drug in

aqueous phase was analyzed spectrophotometrically at 275 nm after appropriate dilution

(Table.2). The partition coefficient of the drug was calculated by using the following formula

The partition coefficient, K= Amount of drug in organic layer/ Amount of drug in aqueous

layer

2.4 DRUG-EXCIPIENT INTERACTIONS STUDIES[18]

By FTIR spectrum:- The FTIR spectrum of rifabutin should be compare with FTIR spectrum

of mixture of rifabutin and excipients used in the formulation and there should be no

interference in the peak of drug and excipients.(Fig 4).


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3. FORMULATION[19]

Nanoparticles were prepared using double desolvation method. 0.2 gm (2.0%) of gelatin was

dissolved in 10 ml water by maintaining temperature at 40±1°C. Then 10 ml acetone was

added in 10 ml gelatin solution as a desolvating agent to precipitate the high molecular mass

(HMM) gelatin. Then supernatant was discarded and the HMM was redissolved in 10 ml

distilled water under constant stirring at 1200 rpm. Then the pH of the solution was adjust to

the pH 3.0 with the help of HCl. Then the drug solution 0.1% w/w was added. The gelatin

was then desolvated again by dropwise addition of acetone under constant stirring at 1200

rpm for 30 minutes with the help of magnetic stirrer. The formed gelatin nanoparticles were

cross linked with 200µl aqueous gluteraldehyde solution (25% v/v) at room temp and the

solution was stirred for 12 hrs at 1200 rpm. The excess of gulteraldehyde was neutralized

using cysteine and the prepared nanoparticles were then sonicated for 2.0 minutes. The

particles were then purified by centrifugation at 10,000 rpm for 20 minutes and the resulting

nanoparticles were stored in refrigeration.[20]

Composition of gelatin nanoparticles

s.no. Formulation Drug :polymer Acetone Gluteraldehyde Water

code (ml) Solution(25%) (ml)

(µl)

1 NP1 2:1 20 200 20

2 NP2 2:2 20 200 20

3 NP3 2:3 20 200 20

4 NP4 2:4 20 200 20

5 NP5 2:5 20 200 20

RESULTS AND DISCUSSION

Table 1: Solubility profile of Rifabutin

S. No. Solvent Solubility

1. Water Insoluble

2. PBS (pH 7.4) Slightly soluble

3. Sodium acetate buffer(pH4.0) Slightly soluble

4. Methanol Freely soluble

5. Ethanol Sparingly soluble

6. Ether Insoluble

7. Chloroform Freely soluble

+++ = Freely soluble 1-10 parts,

+++ = Sparingly soluble 30-100 Parts

+ + = Slightly soluble 100-1000 Parts

- = Practically insoluble >10000 Parts


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Fig 1: UV scan of Rifabutin in methanol

Figs 2: UV scan of Rifabutin in PBS (pH 7.4)

Fig 3: UV Scan of Rifabutin in sodium acetate buffer (pH 4.0)


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Table 2: Partition coefficient values of rifabutin

S.No Medium Partition coefficient (n-octanol/aq. phase)

1. n-octanol : Water 3.1

2. n-octanol : PBS pH (7.4) 2.9

INTERACTION ANALYSIS OF DRUG-EXCIPIENT BY FTIR

Interaction study of Rifabutin and gelatin

Fig 4. IR of the drug Rifabutin with excipients by the FTIR instrument

EVALUATION

Particle Size and shape morphology: The morphology of gelatin nanoparticles was

determined by scanning electron microscopy (SEM). In this one drop of aqueous dispersion

was placed at the accelerating voltage of 20 KV.

SEM image of Rifabutin loaded gelatin nanoparticles

Average particle size was measured by laser particle size analyzer after dilution. Calculation

of size is given below:

Formulation code Average Particle size (nm)

NP1 880

NP2 410

NP3 740

NP4 680

NP5 580

Encapsulation Efficiency

Entrapment efficiency of nanoparticles was determined by the method proposed by

Vandervoort and Ludwing. The amount of RIF entrapped was determined by incubating the


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nanoparticle suspension (1.0 mL) in 5.0mL phosphate buffer saline (PBS, pH 7.4) for 2 h at

800rpm at 25±1◦C on a magnetic stirrer. The amount of unentrapped drug was determined

spectrophotometrically in the supernatant obtained after separation of nanoparticles by

centrifugation at 10,000g for 30 min.

Drug entrapment (%, w/w) = (Mass of the total drug −Mass of free drug) × 100/ Mass of total

drug

FORMULATION ABSORBANCE CONCENTRATION %EE AVERAGE*

CODE (µg/ml) +SD

2.224 63.57 91.54

NP1

90.75+0.79 2.099 59.87 91.93

2.795 79.21 88.79

1.595 48.74 94.54

NP2

93.51±1.08 2.031 60.94 93.27

2.213 66.28 92.73

3.405 101.35 88.93

NP3

89.29+0.64 3.621 107.16 89.51

3.647 107.92 89.43

2.961 87.49 91.13

NP4

89.86+1.24 3.461 89.71 89.66

3.753 110.72 88.81

2.795 82.36 92.05

NP5

91.28+0.64 3.072 90.49 91.24

3.303 97.26 90.56

In vitro Drug release study

10 mg of Rifabutin loaded gelatin nanoparticles were redispersed in 2.0 ml of pH 7.4 PBS

and kept in an incubator at 370C (without agitation). The supernatant obtained after

centrifugation of the suspension was collected every time for 6 hrs to determine the release of

drug. The buffer solution was changed with fresh one every time and the rifabutin

concentration in the dispersing medium was spectrophotometrically measured at 275 nm.

Results were expressed as concentration of rifabutin released in the buffer.

In-vitro release study of formulation NP1

Time √T Absorbance Amount %Cumulative Log

drug release %Cumulative

(hrs) drug remaining


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to be released

0 0 0 0 0 0

1 1 0.197 0.53 2.65 1.98

2 1.41 0.276 0.71 6.20 1.97

3 1.73 0.306 0.88 10.60 1.95

4 2 0.361 1.00 15.60 1.92

5 2.23 0.394 1.15 21.35 1.89

6 2.44 0.426 1.20 27.40 1.86

24 4.89 0.635 1.51 34.95 1.81


Time (hrs) √T Absorbance Amount %Cumulative drug

release Log

%Cumulative

drug remaining

to be released

0 0 0 0 0 0

1 1 0.217 0.620 3.10 1.98

2 1.41 0.311 0.912 7.66 1.96

3 1.73 0.435 1.260 13.96 1.93

4 2 0.578 1.580 21.89 1.89

5 2.23 0.689 1.930 31.51 1.83

6 2.44 0.748 2.190 42.46 1.75

24 4.89 0.929 2.430 54.61 1.65



Time √T Absorbance Amount %Cumulative Log %Cumulative

drug drug remaining to

(hrs) release be released

0 0 0 0 0 0


drug %Cumulative

(hrs) release drug remaining

to be released

0 0 0 0 0 0

1 1 0.148 0.494 2.47 1.98

2 1.41 0.224 0.717 6.05 1.97

3 1.73 0.261 0.826 10.18 1.95

4 2 0.338 1.052 15.44 1.92

5 2.23 0.387 1.195 21.41 1.89

6 2.44 0.415 1.277 27.79 1.85

24 4.89 0.870 2.612 40.85 1.77


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1 1 0.132 0.414 2.07 1.99

2 1.41 0.177 0.546 4.80 1.97

3 1.73 0.190 0.584 7.72 1.96

4 2 0.232 0.707 11.25 1.94

5 2.23 0.268 0.813 15.31 1.92

6 2.44 0.315 0.951 20.06 1.90

24 4.89 0.560 1.669 28.36 1.85



drug %Cumulative

(hrs) release drug remaining

to be released

0 0 0 0 0 0

1 1 0.135 0.369 1.84 1.99

2 1.41 0.186 0.518 4.43 1.98

3 1.73 0.218 0.612 7.49 1.96

4 2 0.250 0.706 11.02 1.94

5 2.23 0.301 0.855 15.29 1.92

6 2.44 0.338 0.964 20.09 1.90

24 4.89 0.596 1.720 28.69 1.85

In-vitro drug release kinetics studies of gelatin nanoparticles

STABILITY STUDIES[21]

A physical stability test was carried out to investigate the leaching of drug from gelatin

during storage. The samples were sealed in glass vials and stored at two different temperature

conditions, i.e., Refrigeration temperature (4-80C) and room temp. (37

0C) for one month and

the samples were taken after a particular time interval. The drug leakage from the

formulations was analyzed by determining its encapsulation efficiency in the same manner as

prescribed previously.

Formulation Zero order First order Highuchi’s Conclusion

code mode mode mode

Slope R2

Slope R2

Slope R2

NP1 0.00 .886 1.98 .791 0.0 .885 Follow And model

first order Higuchi’s

NP2 0.00 .887 1.98 .792. 0.0 .886 Follow first order

and Higuchi’s model

NP3 0.00 .886 1.98 .792 0.0 .886 Follow first order

and Higuchi’s model

NP4 0.00 .886 1.98 .792 0.0 .885 Follow first order and

Higuchi’s model

NP5 0.00 .887 1.98 .792 0.0 .886 Follow first order and

Higuchi’s model


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Percent encapsulation efficiency

%EE %EE %EE %EE at

Formulation Conditions at 0 at 10 at 20 30 days

codes day days days

NP1 Refrigerated 91.84 88.56 86.39 82.10

temperature

Room temperature 90.92 86.11 82.49 77.43

NP2 Refrigerated 93.79 92.11 89.97 88.84

temperature


NP3 Refrigerated 88.83 85.57 82.87 78.67

temperature


NP4 Refrigerated 89.87 88.73 84.67 81.97

temperature


NP5 Refrigerated 90.89 87.76 85.08 80.97

Temperature


The drug selected for research work is Rifabutin is a anti-tuberculae drug which inhibits

DNA- dependent RNA polymerase in susceptible strains of Escherichia coli and Bacillus

subtitles but not in mammalian cells drug sample was firstly identified for its various

pharmacopoeial tests as well as analyzed spectrophotometrically by UV result showed the

authensity and purity of drug sample. the maximum absorbance of drug was determined

by 1700 UV spectrophotometer and was found to be at 275 nm which was matched with the

standard given in pharmacopoeia Partition coefficient value of rifabutin also confirmed its

lipophilic nature as it was found to be 3.1 in n-octanol/water system and 2.9 in n-octanol/PBS

pH 7.4. Spectrophotometric method of analysis of rifabutin showed λmax at 275 nm in

methanol, PBS (pH 7.4) and sodium acetate buffer (pH 4.0). The standard curves of rifabutin

were prepared in methanol, PBS 7.4 and sodium acetate buffer pH 4.0 at λmax 275 nm and

the absorbance data obtained subjected to linear regression. The correlation coefficients were

found to be 0.9978, 0.9991and 0.9953, in methanol, PBS (pH 7.4) and sodium acetate buffer

solution (pH 4.0) respectively. Standard curve of rifabutin was prepared using different

solvents like methanol and sodium acetate buffer pH 4.0 using methanol as a cosolvent by

1700UV shimadzu spectrophotometer. The result showed that the Rifabutin follows the

Lambert beer law between the concentration range of 2-20 µg/ml.


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Drug-excipient interaction was determined by Inrfared Spectroscopy. The IR of the mixture

of drug sample and excipients was found to be within the specified range. Hence there is no

interaction between the drug sample and the excipients likely to be used in the formulation

and hence can be used in the formulation. The particle size of gelatin nanoparticles was

measured using scanning electron microscopy, that was found in the range of 10µm.

The entrapment efficiency of all gelatin nanoparticle formulations are reported. The

entrapment efficiency was found to be higher in formulation NP2 (93.5%) because of use of

gelatin with drug in equal ratio and less found in formulation NP3 (88.93%).

In-vitro release of gelatin nanoparticle formulations were done by membrane diffusion

technique. The highest % cumulative release was found in formulation NP2 (54.61%) and

lowest drug release was in formulation NP4 (28.36%). Mathematical models are commonly

used to predict the release mechanism and compare release profile. For all the formulations

(NP1 to NP5), the cumulative per cent drug release Vs time (zero order), the cumulative per

cent drug release Vs square root of time (Higuchi plot) and log cumulative per cent drug

remaining Vs time (first order) were plotted separately. In each case, r2 value was calculated

from the graph and reported. The first order release model fitting of the release data shows

that the release rate was concentration- dependent. Physical stability of gelatin nanoparticle

formulations were studied for a period of one month. The encapsulation efficiency were

determined for all gelatin nanoparticle formulations stored at different temperatures, the

results showed that proniosomal gel formulation stored at refrigerated condition (4-8⁰C) was

quite stable compared to formulation stored at room temperature.

CONCLUSION

Nanotechnology has the potential to offer solutions to these current obstacles in cancer

therapies, because of its unique size and large surface-to-volume ratios. Nanoparticles may

have properties of self-assembly, stability, specificity, drug encapsulation and

biocompatibility as a result of their material composition. The multidisciplinary field of

nanotechnology’s application for discovering new molecules and manipulating those

available naturally could be excited in its potential to improve health care. Nanotechnology is

definitely a medical boon for diagnosis, treatment and prevention of various diseases

including cancer. It supports and ex-pands the scientific advances in genomic and proteomics

and builds on our understanding of the molecular under-pinnings of cancer and its treatment.

Encapsulation of rifabutin in Gelatin nanoparticles enables development of the intravenous


1416


formulation of this poorly soluble anti-tuberculosis antibiotic. After oral administration, the

nanoparticle-based formulation of rifabutin produced a 2-fold increase in bioavailability, as

compared to the parent drug. The nanoparticles considerably improved the biodistribution

pattern of the poorly soluble anti-tuberculosis antibiotic rifabutin: encapsulation in the

nanoparticles produced two-fold increase of rifabutin bioavailability after oral administration

and enabled intravenous administration of the drug, previously unattainable. The intravenous

formulation also significantly improved rifabutin uptake in the lungs as compared to the

parent drug administered orally. Since these particles are efficiently taken up by

macrophages, the biodistribution data obtained in this study suggests that nanoparticle bound

rifabutin holds promise for the treatment of bacterial infections with predominantly

intracellular disposition of the pathogen.

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