Nasal Drug Delivery System Biology Essay

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Now nasal drug delivery system has been recognised as very promising route for delivery of therapeutic compounds. The objective of the study was to prepare and evaluate mucoadhesive microspheres of antimigrain drug (zolmitriptan) in combination with chitosan for nasal administration. Microspheres of zolmitriptan-chitosan were prepared by the emulsification-crosslinking method with a potential application as drug carriers for nasal administration by insufflation. The microspheres were characterised in terms of morphology (scanning electron microscopy, SEM), drug content, swelling index, particle size (laser diffraction method) and thermal behaviour (differential scanning calorimetry, DSC), powder X-ray diffraction (PXRD) and Fourier transform infra-red spectroscopy (FT-IR). The drug release profiles were investigated by in vitro drug release in pH 6.8 phosphate buffer. In the formulation containing 90% (w/w) chitosan, the drug was molecularly dispersed. FT-IR studies showed that the bands corresponding to intermolecular hydrogen bonding were broader and more diffuse when zolmitriptan was amorphous. The drug was chemically stable with a 95-103% loading in the microparticles. The microspheres had median particle size of 37.9±2.5µ irrespective of the formulation. The mucoadhesive microspheres of chitosan containing zolmitriptan drug were prepared and evaluated successfully for nasal administration. Microspheres prepared by emulsification-crosslinking method had potential application as drug carrier for nasal administration by insufflations.

Key Words: zolmitriptan, chitosan, mucoadhesive, nasal delivery, emulsification-crosslinking method.

Introduction

Recently, carrier technology offers an intelligent approach for drug delivery by entrapping the drug into a carrier such as microspheres, nanoparticles and liposomes which changes the release and absorption characteristics of the drug. The microparticulate delivery systems are considered as a reliable means to deliver the drug to the target site with specificity, if modified, and to maintain the desired concentration at the site of interest without untoward effects. Microspheres constitute an important part of these particulate drug delivery systems by virtue of their small size and efficient carrier characteristics [1-4]. The use of microsphere-based therapy allows drug release to be carefully tailored to the specific treatment site through the choice and formulation of various drug-polymer combinations. The total dose of medication and the kinetics of release are the variables, which can be manipulated to achieve the desired result. Using innovative microencapsulation technologies, and by varying the polymer ratios, molecular weight of the polymer, etc., microspheres can be developed into an optimal drug delivery system which will provide the desired release profile. Microsphere based systems may increase the life span of the drug encapsulated and control the release of the drugs. Being small in size, microspheres have large surface to volume ratios and can be used for controlled release of insoluble drugs [5]. Particle size of microspheres is an important parameter in the preparation of various dosage forms of drugs which are administered by various routes like oral, parenteral, topical, etc. Also, by simply changing the size of microspheres, it is possible to achieve localization of microspheres in a particular organ or tissue [6]. The nasal route has gained tremendous attention for systemic drug delivery by many researchers within the last few decades due to its great potential utility for drug delivery. Nasal drug delivery also offers the convenience and safety of being noninvasive. In addition, nasal drug administration results in quick onset of action as compared to oral, sublingual and transdermal administrations [7].

Zolmitriptan, 4S-4-({3-[2-(dimethylamino)ethyl]-1H-indol-5-yl}methyl)-1,3-oxazolidin-2-one, is a second generation triptan prescribed for patients with migraine attacks, with or without anaura, and cluster headaches. It has a selective action on serotonin (5-HT1B/1D) receptors and is very effective in reducing migraine symptoms, including pain, nausea, and photo- or phonophobia [8]. It is currently available as a conventional tablet, an oral disintegrating tablet and a nasal spray (2.5mg and 5mg per dose). The nasal dose is claimed to be absorbed rapidly, with detectable plasma zolmitriptan concentrations within 2min after administration. In contrast, plasma zolmitriptan concentrations are generally not detected until 15-20 min after administration of a tablet formulation [9]. Patients with migraine generally suffer from nausea and vomiting; oral treatment can therefore be inconvenient or could fail [10]. The absolute bioavailability of zolmitriptan is up to 40% for both oral and nasal dosage forms [11]. The faster clearance of the drug from the nasal cavity could explain the low bioavailability for the nasal formulation. The purpose of this study was to include chitosan (a mucoadhesive polymer) in the preparation of zolmitriptan nasal microspheres, using an emulsification-crosslinking method, with the ultimate intent of enhancing the bioavailability of the nasal zolmitriptan formulation by improving the residual time of the drug in the nose. To the best of our knowledge, microspheres of zolmitriptan for nasal application have not previously been prepared and characterised; nor is a solid-state analysis of pure zolmitriptan available in the open literature. Microspheres of zolmitriptan and chitosans (various molecular weights and types) were prepared using a emulsification-crosslinking method. The proportion (%, w/w) of polymer in the formulations was also varied. The effect of formulation variables on the physicochemical and solid-state properties, as well as the dissolution behaviour of the powders, was studied.

Material and methods

Materials

Zolmitriptan (batch number 070701) was purchased from Dr.Reddy's laboratory, Hyderbad, India. Chitosan was a gift sample from Colorcon Asia Pvt. Ltd., Goa, India and used without any modification and purification. Liquid paraffin (light and heavy), glutaraldehyde (25% aqueous solution) (GA), and hexane were purchased from S.D. Fine Chemicals, Mumbai, India. Dioctyl sodium sulfosuccinate (DOSS) was procured from Wilson Laboratories, Mumbai, India. All other chemicals and reagents used in the study were of analytical grade.

Preparation of chitosan microspheres

Mucoadhesive microspheres of chitosan were prepared by simple w/o emulsification-crosslinking process using liquid paraffin (heavy and light, 1:1) as external phase [12,13]. Chitosan was dissolved in 2% aqueous acetic acid solution containing drug i.e. zolmitriptan by continuously stirring until a homogeneous solution was obtained. This solution was added slowly to liquid paraffin (heavy and light, 1:1) containig 0.2% (w/v) of DOSS as stabilizing agent under constant stirring at for 15 min using a propellant stirrer (Remi, Mumbai, India) at different rpm. To this w/o emulsion, GA was added slowly and stirring was continued for 2 h. The hardened microspheres were separated by vacuum filtration and washed several times with hexane to remove oil. Finally, microspheres were washed with distilled water to remove unreacted GA. The microspheres were air dried for 24 h and then stored in vacuum desiccator until further use.

Preparation of amorphous zolmitriptan

Melt-cool on a hot plate

Crystalline zolmitriptan was heated on aluminium foil at 140-C on a laboratory hot plate until it melted and the product was allowed to cool to room temperature. The glassy material was then gently ground with a mortar and pestle and stored in a desiccators over silica gel at −15 -C. This was used as the amorphous zolmitriptan reference.

Differential scanning calorimetry (DSC)

Crystalline zolmitriptan (3-5 mg) was heated to 142 -C under dry N2 purge in a crimped aluminium pan, held for 30 s to guarantee complete melting, and rapidly cooled to −70 -C. The heating and cooling rates were 20-C/min.

Microsphere characterization

Morphology

Scanning electron microscopy and energy dispersive X-ray spectrometry (SEM/EDS)

The microsphere shape and surface were evaluated by scanning electron microscopy (SEM). The observations were made with a scanning electron microscope (JSM 5610 LV, Jeol Datum Ltd., Japan). The samples were mounted directly onto the SEM sample holder using double-sided sticking tape and images were recorded at the required magnification at the acceleration voltage of 5 kV. The elemental analysis of the microspheres was determined by energy dispersive X-ray spectrometry after the SEM procedure. The X-ray spectrum was conducted with 10 keV in EDS procedure. The X-ray spectrum was then used for semi quantitative analysis through the elemental percentage mode of the standardless approach.[6]

Drug content

The content of zolmitriptan in the microparticles (referred to as 'drug load') was determined using the HPLC method as described in the previous section. Samples of dry powder formulations (2-3 mg) were dissolved in 15.0 ml of 0.25% (v/v) acetic acid and the resulting solution was analysed using HPLC. The drug content in the microparticles was expressed as a percentage of the nominal load.

Swelling index

The equilibrium water uptake of the microspheres was determined by measuring the extent of swelling of the matrix in phosphate buffer pH 6.2. To ensure complete equilibration, microspheres were allowed to swell for 12 h. The excess surface adhered liquid drops were removed by blotting with soft tissue papers and the swollen microspheres were weighed to an accuracy of 0.01mg using an electronic microbalance (Mettler AE 163, Switzerland). The microspheres were then dried in an oven at 60 -C for 3 h until there was no change in the dried mass of the microspheres. The % equilibrium water uptake was calculated as:

% Water uptake = Weight of swollen microspheres−Weight of dry microspheres -100

Weight of dry microspheres

Particle size analysis

The mean particle size of the microspheres was measured using optical microscope (Olympus CX31). The microscope was equipped with the software Magnus pro 3.0 and Olympus master through a camera [14].

Differential scanning calorimetry (DSC)

The thermal behaviour of the microparticles was studied using a Thermal Advantage DSC Q1000 (TA Instrument) equipped with a refrigerated cooling system. The instrument had been calibrated for temperature and enthalpy using indium. The standard/conventional DSC method was used to determine the melting temperature (Tm) and the heat of fusion (_H) of crystalline zolmitriptan. The drug (1-3 mg) was accurately weighed into non-hermetic aluminium pans and crimped. The samples were scanned from 25 to 160 -C at a heating rate of 10 -C/ min under continuous nitrogen purge (50 ml/min). The amorphous samples were characterised by temperature modulated differential scanning calorimetry (TMDSC). Samples (3-10mg) were accurately weighed into non-hermetic aluminium pans and crimped, then scanned at 15-300 -C at a heating rate of 4-C/min (modulation amplitude 1-C, modulation period 60 s) under continuous nitrogen purge (50 ml/min). The glass transition temperature (Tg) at inflection.

Powder X-ray diffraction (PXRD)

PXRD patterns for various dry powder formulations were collected using a Siemens D5000 powder diffractometer with Cu K_ radiation (1.54056 Å). The tube voltage and amperage were set at 40 kV and 40mA, respectively. The divergence slit and antiscattering slit settings were variable for the illumination on the 20mm sample size. Each sample was scanned between 5 and 50- in 2_with a step size of 0.02-. The measurement time per step was 3.2 s. The instrument was previously calibrated using a silicon standard.

FT-IR spectroscopy

The IR spectra for the powders were recorded on a Bruker IFS 113V equipped with DTGS detectors, using the DRIFT (Diffuse Reflectance Infrared Fourier Transform) technique, with well dried KBr as diluent. A total of 100 scans was collected over the range of 4000-400 cm−1 and at a resolution of 4 cm−1 for each sample. Data were analysed using OPUS software. Some samples were measured in triplicate to assure reproducibility of the results.

In vitro dissolution study

An in vitro dissolution test was carried out using a modified USP II dissolution apparatus (automatic dissolution test equipment PTWS 610, Pharma Test, Germany). Accurately weighted powdered samples corresponding to 5mg (2.5mg in the case of the 90% w/w polymer) were placed directly on a basket (5_mmesh), which was rotated at 100 rpm. Phosphate buffer (900ml, pH= 6.8, 37 -C) was used as dissolution medium. The sampleswere withdrawn periodically using a sampling probe (assembled with a 10-_m filter) and measured online using a Cecil CE 3021 UV detector at a wavelength of 222nm. The solutions were returned to the test vessels after measurement. The data were analysed with WinDiss-PTFC software. Dissolution tests were performed at least in triplicate.

Statistical analysis

The data were statistically analysed using the Minitab® Software version [11]. Two-way analysis of variance (ANOVA) was tested and p < 0.05 was accepted as significant.

Results and discussion

Morphology

SEM pictures of microparticles are shown in Fig. 1. Visual examination of the SEM pictures indicated that the microparticles of chitosans were spherical with varied surface roughness. Similarly, all the zolmitriptan-chitosan microparticles were spherical, irrespective of chitosan proportion.

Drug content

HPLC analysis of the powders indicated that the zolmitriptan was chemically stable during the emulsification-crosslinking process. The proportion of drug loaded in the microparticles ranged from94 to 105% (Table 2). Statistical analysis of these data indicated no significant differences between formulations prepared at various rpm and different proportions of polymer (two-way ANOVA: p > 0.05). [15]

Swelling index

The % equilibrium water uptake of the microspheres was ranged from 124% to 232%. This may be due to the formation of a rigid network structure at higher concentration of crosslinking. Hence, the crosslinking of microspheres has a great influence on the equilibrium water uptake [16].

Particle size analysis

The particle size data for various powders are presented in Table 2. The particles of these powders appear to be smaller in SEM pictures, it may be inappropriate to directly correlate with the measured mean particle size distribution using laser diffraction due to variable aggregation behaviour of the particles in LD. All formulations had similar particle size distributions (SPAN) (two-way ANOVA: p > 0.05) (Table 2). It is commonly understood that particles greater than 10_m in diameter are more likely to be effectively deposited in the nasal cavity. However, the physiological function of the nose is to filter the inspired air and prevent particles from entering the lungs, and particles larger than 0.5_mhave been collected in the nose [17]. Accordingly, the microparticles of zolmitriptan prepared in this study are suitable for nasal administration. Furthermore, it is the combined particle properties, such as size distribution, shape, and density that determine the site and amount of powder deposition in the nasal cavity [18]. The true densities of the powders are presented in Table 2. The densities of the microparticles prepared from different proportions of chitosans did not differ significantly (two-way ANOVA: p > 0.05).

Differential scanning calorimetry (DSC)

DSC thermograms of crystalline and amorphous zolmitriptan (prepared using the melt-cool method and in the DSC) are shown in Fig. 3. The DSC curve for crystalline zolmitriptan displays a single endothermic peak (Tmax) = 138.2±0.4 -C and the heat of fusion (_H) = 120.4±2.6 J g−1, attributed to the melting of crystalline zolmitriptan. The Tg values for amorphous zolmitriptan prepared on a hot plate and in the DSC (heat-cool-heat) were around 48.7 and 50.2 -C, respectively (dry Tg) (Table 3). This indicates that the method of preparat ion of amorphous zolmitriptan had no effect on the Tg. No thermal events were observed when amorphous zolmitriptan was heated past the Tg.

Powder X-ray diffraction (PXRD)

The PXRD patterns for the samples are presented in Fig. 3. Raw zolmitriptan showed several characteristic peaks at 2_ angles 13.9-, 15.5-, 19.3-, 22.1-, and 24.0-, indicating that the material was crystalline (Fig. 3). The PXRD pattern of crystalline zolmitriptan was in agreement with a previously reported pattern [19]. Zolmitriptan prepared on a hot plate and chitosan (chitosan base) formulations (proportion of chitosan) showed diffuse halo patterns, demonstrating its amorphous nature. This result is in agreement with the finding in the TMDSC study.

FT-IR spectroscopy

Fig.4a shows IR spectra for the crystalline and amorphous forms of zolmitriptan. The spectral differences between the two solid forms were evident. The IR spectrum for amorphous form showed non-specific broadening of absorption bands. These spectral differences between solid forms could be attributed to the variations in the hydrogen bonding patterns. The -C O stretching vibration band at around 1733cm−1 for crystalline zolmitriptan was shifted to 1743 cm−1 (higher wave number or lower frequency); this was associated with band broadening (Fig.4b). Furthermore, the N-H stretching vibration band at 3346cm−1 was broadened for the amorphous drug (Fig.4c). These spectral changes indicate the alteration of hydrogen bonding patterns in the amorphous form [20].

In vitro dissolution study

The dissolution profiles for amorphous (ground samples prepared by the heat-cool method) and crystalline zolmitriptan ('as is') were similar: 100% dissolved in approximately 35min. Fig.5 shows the dissolution profiles of the emulsified-crosslincked formulations containing various proportions of the polymer. The dissolution or release rate of zolmitriptan from the microparticles was decreased as the proportion of polymer increased, as indicated by the slope of the dissolution profiles. The time to reach maximum solution concentration (Tmax) for formulations with chitosan was within 60 min. The release of drug from the polymer microparticles was controlled by the formation of a gel which slowed diffusion of the drug across the viscous boundary layer close to the dissolving surface and/or slowed crystallization of the amorphous drug (lower solubility) as a result of supersaturation in the boundary layer [21]. Since the dissolution rate of crystalline zolmitriptan was the same as that of the amorphous form, it is reasonable to suggest that the prolonged release was the result of the gel formation. Thorough mixing of the drug with the chitosans (glassy solid solution) and the development of interactions between them may also have played a role in controlling the release of drug from the formulations. Chitosans have previously been shown to control the release of highly soluble drugs [22]

Conclusions

Emulsification-crosslinking is a suitable technique for preparing spherical microparticles of zolmitriptan and chitosan with a narrow particle size range and high drug loading. The powders were chemically stable during processing and amorphous in nature. The proportion of chitosan affected the extent of zolmitriptan dispersion in the chitosan matrix. A mixture of glassy solid solution and amorphous glassy emulsion occurred in formulations containing 30-70% (w/w) polymer and a glassy solid solution occurred in the formulation containing 90% (w/w) polymer. Hydrogen bonds were formed between the carbonyl stretching of zolmitriptan and the amino group of the chitosans. The proportion and the molecular weight of the chitosan both affected drug release. The presence of a chitosan controlled the release of zolmitriptan from microparticles in which the drug was dispersed at a molecular level. These interesting formulations deserve further characterisation in terms of long term stability, mucoadhesive characteristics, ex vivo/in vivo tissue permeation, and possibly in vivo studies in the future.

Acknowledgements

Authors are thankful to Amol S Amritkar, Bhim B Pawar, IPE, Boradi, Maharashtra; for their valuable suggestions during writing this research article. We are also grateful to Institute of Pharmaceutical Education, Boradi, MS. INDIA for providing the required facilities for this work.

Table.1. Formula.

Code

Chitosan

Drug

GA

rpm

Drug entrapment efficiency

Microspheres

F1

30

70

25%

1000

90

Very irregular

F2

50

50

25%

1000

80

Very irregular

F3

70

30

25%

1000

75

Very irregular

F4

90

10

25%

1000

65

Very irregular

F5

30

70

25%

1200

97

Spherical free flowing

F6

50

50

25%

1200

87

Spherical free flowing

F7

70

30

25%

1200

80

Spherical free flowing

F8

90

10

25%

1200

76

Spherical free flowing

F9

30

70

25%

1400

93

Spherical free flowing

F10

50

50

25%

1400

84

Spherical free flowing

F11

70

30

25%

1400

77

Spherical free flowing

F12

90

10

25%

1400

70

Spherical free flowing

Table 2

Various physical properties of powders. Data presented is the mean of three determinations (n = 3). ±S.D. = standard deviation; NA= not applicable.

Formulation ID

Drug loading (%)

Volume-weighted mean particle size (_m)

Particle size distribution (SPAN)

True density (g/ml)

F1

101.1±0.6

7.4 ± 0.5

1.4 ± 0.1

1.2 ± 0.0

F2

96.8±1.0

3.7 ± 0.4

1.1 ± 0.0

1.3 ± 0.0

F3

98.1±0.7

2.6 ± 0.0

1.5 ± 0.1

1.4 ± 0.0

F4

102.2±0.3

3.8 ± 0.0

2.5 ± 0.0

1.2 ± 0.0

F5

105.5±1.4

7.0 ± 0.8

1.2 ± 0.2

1.2 ± 0.0

F6

93.9±0.7

4.4 ± 0.0

1.0 ± 0.1

1.3 ± 0.0

F7

100.6±1.4

3.0 ± 0.0

2.0 ± 0.0

1.4 ± 0.0

F8

99.6±2.6

3.6 ± 0.0

2.4 ± 0.0

0.8 ± 0.0

F9

99.1±1.6

9.4 ± 1.1

5.0 ± 0.8

1.3 ± 0.0

F10

101.2±0.5

3.8 ± 0.1

1.2 ± 0.1

1.3 ± 0.0

F11

101.0±1.1

2.7 ± 0.1

1.6 ± 0.1

1.4 ± 0.0

F12

97.9±2.0

2.7 ± 0.0

1.32 ± 0.1

1.4 ± 0.0

Table 3

Glass transition temperature (Tg) for amorphous zolmitriptan and chitosans. Data presented is the mean of three determinations (n = 3).

Material

Tg (-C)

Zolmitriptan (dry Tg)

50.2 ± 0.3

Zolmitriptan (hot plate method)

48.7 ± 0.7

Chitosn base

130.2 ± 1.0

Table 4. dissolution profile of batches.

Time

F1

F2

F3

F4

F5

F6

F7

F8

F9

F10

F11

F12

0

0

0

0

0

0

0

0

0

0

0

0

0

20

76

77

74

72

85

83

80

76

84

80

79

78

40

92

94

92

91

99

98

96

95

94

95

96

95

60

95

96

94

93

99

99

97

97

96

97

98

96

80

97

98

96

97

100

99

99

98

98

98

99

98

100

98

99

98

99

100

100

99

99

100

99

99

100

FIGURES

C:\Users\MSI\Desktop\SEM photograps.jpg

C:\Users\MSI\Desktop\DSC thermograms.jpg

C:\Users\MSI\Desktop\PXRD.jpg

C:\Users\MSI\Desktop\FTIR.jpg

C:\Users\MSI\Desktop\disolution profile of zolmitriptan.jpg

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