Development of Naratriptan Hydrochloride In-Situ Nasal Gel

 

Nikita S. Malekar1*, Sheetal B. Gondkar1, Bhushan A. Bhairav1, Pinak S. Paralkar2,

Ravindra B. Saudagar 3

1Department of Quality Assurance Techniques, KCT’S, Ravindra Gambhirrao Sapkal College of Pharmacy, Anjaneri, Nashik 422213, Maharashtra , India

2Department of Pharmaceutics , KCT’S, Ravindra Gambhirrao Sapkal College of Pharmacy, Anjaneri,

Nashik 422213, Maharashtra, India

3Department of  Pharmaceutical Chemistry, KCT’S, Ravindra Gambhirrao College of Pharmacy, Anjaneri,

Nashik 422213, Maharashtra, India

*Corresponding Author E-mail:  nikitamalekarresearch @gmail.com

 

ABSTRACT:

Development of pH sensitive Naratriptan Hydrochloride in-situ nasal gel was aimed to improve absorption. In the present research work mixture of Carbopol-934 and Xanthan Gum were used to benefit pH sensitive gelation property. Different formulation were prepared  by different concentrations of Carbopol-934 and Xanthan Gum .In this formulation the release profile depend on the concentration of Carbopol-934 and Xanthan Gum. These formulations were evaluated for parameters like pH, drug content, viscosity, mucoadhesive strength, gel strength, in-vitro drug release, and drug  and excipients compatability. A 32 factorial design was applied to see the effect of various Carbopol-934 (X1) and Xanthan gum (X2) on the various models to a certain kinetic of drug release. Regression analysis and analysis of variance were performed for dependent variables. The study indicates that the formulation was effective in providing in-vitro release of drug and the mucoadhesive formulation. The objective of this study was to formulate a intranasal gel for drug targeting directly to brain via olfactory lobe pathway.

 

KEYWORDS:  Anti-migraine, Carbopol-934, Xanthan Gum , In-Situ Gelling System , pH sensitive.

 

 


INTRODUCTION:

Now adays many drugs have better systemic bioavailability through nasal route as compared to oral administration. The nose is also considered an attractive route for needle-free vaccination and for systemic drug delivery, especially when rapid absorption and effect are desired. The nasal delivery is a feasible alternative to oral or parenteral administration for some drug because of the high permeability of the nasal epithelium, rapid drug absorption across this membrane and evidence of first pass metabolism.

 

Prolonged drug delivery can be achieved by various new dosage forms like in-situ gel. In-situ forming polymeric formulation is drug delivery system that is in sol form before administration in the body, but once administered, undergoes gelation in-situ to form a gel. In-situ nasal drug delivery system is the type of mucoadhesive drug delivery system. Now aday’s in-situ gel has been used as vehicle for the drug delivery of the drug for both local treatment and systemic effect. In-situ nasal gel drug delivery system is advantageous over the conventional drug delivery system like sustained and prolonged release of drug, reduced frequency of administration, improved patient compliance and comfort.1,3

 

Migraine is a condition, in which a person experiences tremendous headache. Generally, this headache affects only one side of the head. Migraine attacks are more common to those people who take too much of stress or are work alcoholic. In such people, the blood flow in the brain muscles drops, as results of too much load, squeezing the arteries. When the person suddenly relaxes, these tight brain muscles expand, stretching the blood vessel walls. The blood pumped with each heart beat then, pushes the vessel further, causing immense pain. Though the exact cause of migraine has not been identified, there are number of factors that can trigger the severe headache.2

 

MATERIALS AND METHODS:

Materials

Naratriptan Hydrochloride was obtained as gift sample from DANO Pharmaceuticals, Mumbai; Xanthan Gum was obtained as a gift sample from Signet chemicals and Carbopol-934 was obtained from Loba chemicals, Mumbai. Polyethylene Glycol, Bezalkonium Chloride and Triethanolamine used were AR Grade.

Physicochemical Studies:

Drug Solubility Study:

The solubility of Naratriptan Hydrochloride was checked in solvents like distilled water, methanol and phosphate buffer etc

 

Determination of λmax of the drug:

The UV spectrum of Naratriptan Hydrochloride was obtained using UV-visible spectrophotometer Jasco V630.Accurately weighed 10 mg of the drug was dissolved in sufficient quantity of water and volume made up to 10 ml. The stock solution was diluted to obtain a concentration of 100 µg/ml. 1 ml of aliquot was withdrawn and  volume was made up to 10 ml using water to obtain the concentration of 10 µg/ml. The resultant solution was scanned from 200 to 400 nm and the spectrum was recorded to obtain the value of maximum wavelength.

 


 

Figure 1: UV-visible spectrum of Naratriptan Hydrochloride in Distilled Water

 

Figure 2: Infra-red spectrum of Naratriptan Hydrochloride

 


Infra-Red Spectrum:

FTIR study was carried on pure drug, drug samples kept for 1 month at 400C .The infrared absorption spectrum of Naratriptan Hydrochloride was recorded over the wave number 4000 to 400 cm-1 using Fourier Transform Infrared Spectrophotometer (Bruker Eco -ATR).


 

Figure 3: Infra-red spectrum of drug with polymer.

 

Table 1: Interpretation of Infra-red spectrum of drug and polymer

Sr. no

 

Functional group

Peaks

Pure Drug

Pure Drug+ Carbopol +Xanthan Gum

Stranded Frequency (cm-1)

1

Ar. N-H( Strtech)

Yes

Yes

3500-3800

2

Ar. C-H ( Strtech)

Yes

Yes

3000-3300

3

N-H  (Stretch)

Yes

Yes

2500-2200

4

S=O ( Easter)

Yes

Yes

1350-1450

5

Ar. –N (Stretch)

Yes

Yes

1250-1360

6

C-N ( Stretch))

Yes

Yes

1030-1230

7

S-OR (Ester)

Yes

Yes

700-900

8

C-H                      (Out of Plane)

Yes

Yes

730-770

 


Method 4, 5

The formulations were prepared by cold method. The drug containing water, gelling polymer and mucoadhesive polymers were hydrated separately in calculated amount of distilled water at room temperature and cooled and stored at 4˚C. Both polymeric solutions were mixed slowly on ice bath; Preservative was added slowly with continuous stirring in polymer solution. Both solution (Drug and Polymer) were mixed with each other by gentle stirring. The final dispersion was then stored in a refrigerator until clear solution was obtained. Different formulizes of gel were prepared by using ingredients mentioned in (Table -1).In this formulation concentration of Carbopol-934 was ranged between 0.1 to 0.3% ,  concentration of Xanthan Gum in between 0.1 to 0.2% . Drug was dissolved in mixture of distilled water and PEG; both the polymers were hydrated separately. Solution was kept at room temperature over night. Preservative was added in polymeric solution. Mixing of drug and polymeric solution was done at cold condition.


 

Table 2: 32 Factorial Design Used For Preparation of Formulations

              Formulation code

 

Ingredient (%)     

 

F1

 

 

F2

 

 

F3

 

 

F4

 

 

F5

 

 

F6

 

 

F7

 

 

F8

 

 

F9

 

Naratriptan Hydrochloride 

3.5

3.5

3.5

3.5

3.5

3.5

3.5

3.5

3.5

Carbopol 934

0.1

0.2

0.3

0.1

0.2

0.3

0.1

0.2

0.3

Xanthan Gum

0.1

0.1

0.1

0.15

0.15

0.15

0.2

0.2

0.2

PEG 400

1

1

1

1

1

1

1

1

1

Benzalkonium chloride

0.01

0.01

0.01

0.01

0.01

0.01

0.01

0.01

0.01

Triethanolamine

q.s

q.s

q.s

q.s

q.s

q.s

q.s

q.s

q.s

Purified water ml (q.s)

100

100

100

100

100

100

100

100

100

 


 

EVALUATION OF NASAL GEL

Physical parameter

Clarity

The formulations were visually checked for the clarity.

 

pH

pH of each formulation was determined by using Digital pH meter (Digital pH meter 335). This was previously calibrated by pH 4 and pH 7. The pH values were recorded immediately after preparation.

Rheological study 6, 7

Viscosity

The rheological properties of gels were determined by the Brookfield viscometer; type DV-II + PRO using spindle no LV-3 (63). Viscosity of the formulations was taken at two different pH i.e. at respective pH  and pH 7.4 with varying shear rate.

 

Measurement of Gelling capacity 8, 9                                 

The gelling capacities of formulations were determined by placing 1 drop of the prepared formulations into a vial containing 2 mL of SNF freshly prepared. Gelation was assessed visually and noting the time for gelation.

 

Measurement of the gel strength 10, 11

A sample of 25 mL of the gel was put in a 50 mL graduated cylinder. A weight of 14.33 g was placed on the gel surface. The gel strength, which is an indication for the ophthalmic gel at physiological temperature, was determined by the time in seconds required by the weight to penetrate 5 cm into the gel.  All measurements were performed in triplicate (n=3). The apparatus used for measuring gel strength at  respective pH and pH 7.4

 

Mucoadhesive Strength 12                        

“Detachment Stress is the force required to detach the two surfaces of mucosa when a formulation/gel is placed in between them”. The detachment stress was measured by using a modified analytical balance.

 

Drug Content

1ml of prepared formulation was dissolved in 100 ml of water; 1 ml of this solution was diluted up to 10 ml. This solution was measured for absorbance using UV- visible spectrophotometer at 282 nm and % drug content was determined.

In-vitro Drug Release Study 14, 15

In-vitro release study of the formulated in-situ gel was carried out by using diffusion cell through goat nasal mucosa. Diffusion cell with inner diameter 1.4cm was used for the study. The formulation 1 ml were placed in donor compartment and Freshly prepared 100 ml simulated nasal electrolyte solution (sodium chloride 0.745gm, potassium chloride 0.129 gm, calcium chloride dehydrated 0.005gm, distilled water q.s. 100ml) in receptor compartment. Goat nasal mucosa was mounted in between donor and receptor compartment. The position of the donor compartment was adjusted so that goat nasal mucosa just touches the diffusion medium. The whole assembly was placed on the thermostatically controlled magnetic stirrer. The temperature of the medium was maintained at 37°C ± 0.5°C. 2ml of sample is withdrawn from receiver compartment after 30 min, 1, 2, 3, 4, 5, 6, 7 and 8 hrs and same volume of fresh medium is replaced. The withdrawn samples was diluted to 10ml in a volumetric flask with water and analyzed by UV spectrophotometer at 282nm.

 

RESULT AND DISCUSSION

Clarity:

On careful visual inspection against dark and white background, all the prepared nasal gel formulations were found to be free from, suspended particulate matter. All the formulations were found to be clear.

pH :

The pH of all formulations from F1 to F9 was found to be in the range of 6.0 to 6.4 pH values of formulation shown in Table 2

 


 

Table 3: Evaluation Parameters

Formulation code

Observed pH (±S.D.)

Gel strength (sec) (±S.D.)

Detachment Force (N) (±S.D.)

Drug content (%) (±S.D.)

Cumulative Drug

Release (%) (±S.D.)

F1

6.1± 0.2

0.49  ± 0.01

0.04251 ± 0.005

95.28±0.03

95.84

F2

6.4 ± 0.4

0.71 ± 0.03

0.07194 ± 0.12

95.85±0.34

95.79

F3

6.2 ± 0.3

0.94 ± 0.03

0.03989 ± 0.005

95.07±0.59

95.32

F4

6.0± 0.2

0.56± 0.017

0.1569 ± 0.005

97.8±0.17

96.88

F5

6.1 ± 0.2

0.78 ± 0.02

0.08829 ± 0.0097

99.3±1.10

99.22

F6

6.2± 0.2

1.15± 0.003

0.1206  ± 0.005

101.4±0.22

94.02

F7

6.0 ± 0.2

0.65± 0.004

0.06213 ± 0.0006

97.1±2.60

96.92

F8

6.1 ± 0.1

0.85± 0.03

0.09156 ± 0.0057

99.53±0.87

98.44

F9

6.4 ± 0.0

1.28± 0.03

0.1536± 0.022

97.99±0.32

91.68

 


Gel Strength:

The gel strength was found to be affected by concentrations of gelling and mucoadhesive polymers. Optimal mucoadhesive gel must have suitable gel strength so as to be administered easily and can be retained at nasal mucosal region without leakage after administration. Gel strength of all formulations showed comparable results as that of viscosity results.

 

Drug content:

The percentage drug content of all prepared nasal formulations was found to be in the range of 95.07-101.04%. Therefore uniformity of content was observed in all formulation.

 

Mucoadhesive strength:

Bioadhesive force means the force with which gels bind to nasal mucosa. Greater mucoadhesion is indicative of prolonged residence time of a gel and thus prevents its drainage from nose cavity. The mucoadhesion force increased significantly as the concentration of mucoadhesion polymers increased. The Detachment force was determined for nasal gels. Results of this test indicate that the variable Carbopol and Xanthum gum both are having effect on Mucoadhesive strength.

 

Viscosity:

The viscosities of formulations at respective pH and at pH 7.4 are shown in Table- 4 and Table -5. The viscosities of formulation at respective pH and at pH 7.4 are shown in  figure-4 and figure-5.Viscosity v/s rpm plots for all formulations shows decrease in viscosity as shear rate (rpm) was increased which indicate that gel has the pseudo plastic flow. As pH was increased the increased in viscosity was observed. Concentration of Carbopol was a major factor affecting viscosity of formulations. In combination with Xanthan Gum , Carbopol has shown considerable increases viscosity when concentration of Xanthan Gum is 0.15% w/v to 0.2%w/v.

 


 

Table 4: Viscosity of formulations

RPM

Viscosity (cp) of Formulations

Formulation Code

F1

F2

F3

F4

F5

F6

F7

F8

F9

5

410.5

458.3

568.1

430.1

460.1

612.3

455.5

462.3

730.2

10

250.3

309.9

352.1

265.1

295.5

398.2

272.9

270.2

435.1

15

175.2

289.1

298.3

198.3

 265.3

312.5

210.2

210.3

348.1

20

157.1

230.2

267.1

178.2

240.1

278.3

184.3

185.2

282.1

25

130.2

210.2

232.5

164.2

220.2

240.3

174.1

162.3

245.1

30

110.1

160.1

178.1

121.3

175.1

228.3

130.1

135.2

230.2

 

Figure 4 : Viscosity profile of formulations

 

Table 5: Viscosity of formulations at pH 7.4

 

 

 

RPM

Viscosity (cp) at pH7.4

Formulation code

F1

F2

F3

F4

F5

F6

F7

F8

F9

5

458.1

488.5

523.1

467.2

490.2

750.2

485.2

493.2

854.2

10

298.1

320.2

408.5

325.1

348.3

435.1

328.1

356.2

682.1

15

223.8

230.8

385.4

235.3

310.1

420.5

250.3

256.1

575.2

20

178.2

203.1

298.5

185.5

285.8

327.8

198.3

225.3

450.1

25

156.7

197.3

246.3

160.2

268.5

267.3

175.2

210.3

387.1

30

103.1

152.1

233.3

110.8

223.1

240.3

123.5

184.3

257.3

 

Figure 5: Viscosity profile of formulations at pH 7.4

 


In-vitro Drug Release:

The result tells us that, out of the nine formulations maximum release after 8hrs was found for F5 formulation. This indicates release of 99.22% drug available for antimigraine activity of the drug. F5 formulation showed steady state release up to 8hrs which also indicates that this formulation would show good contact with biological membrane.


 

Figure 6: In-vitro drug release of formulation

 


Optimization:13

A 32 full factorial design was selected and the 2 factors were evaluated at 3 levels, respectively. The percentage of Carbopol (X1) and Xanthan Gum (X2) were selected as independent variables and the dependent variable was % drug release. The data obtained were treated using Design expert version 8.0.4.1 software and analyzed statistically using analysis of variance (ANOVA). The data were also subjected to 3-D response surface

 

methodology to study the interaction of Carbopol (X1) and Xanthan Gum (X2) on dependent variable. (Table no.35) Shows ANOVA for the dependent variable % drug release. The values of X1 and X2 were found to be significant at p <0.05, hence confirmed the significant effect of both the variables on the selected responses. From this data optimum concentration of Carbopol 0.2%w/v and Xanthan Gum 0.15 %w/v was found.   


 

Figure 7: Surface response plot showing effect of Carbopol and Xanthan Gum on drug release.

 


Release Kinetics:

In the present study, the drug release was analyzed to study the kinetics of drug release mechanism. The results showed that the factorial design batches followed zero order.

 

Table 6: Drug Release kinetics for optimized batch

Sr.no

Model fitting

R2 Value

1.

Zero Order

0.994

 

CONCLUSION:

In-vitro study suggested that such formulation can be an alternative route to the conventional dosage form of Naratriptan Hydrochloride and it can also be part replacement therapy to the conventional oral administration of Naratriptan Hydrochloride. This Naratriptan Hydrochloride nasal in-situ gel formulation fulfills all necessary parameters required for nasal mucosal use. This optimized formulation having improved viscosity and better mucoadhesive property may improve the bioavaibility of nasal administration.

 

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Received on 02.07.2016             Modified on 22.08.2016

Accepted on 18.08.2016           © RJPT All right reserved

Research J. Pharm. and Tech. 2017; 10(4): 979-985.

DOI: 10.5958/0974-360X.2017.00178.0