INTRODUCTION:

Oral route is the most preferred route for better patient compliance and straight forward administration. Medicated oral jellies are the most attractive dosage forms for patients and can be ingested without water. It is different dosage form to solid and liquid dosage forms. The oral medicated jellies are manufactured by heating method using various kinds of polymer with different concentration. As most of the pharmaceutical drugs give a bitter taste so, taste masking is an important parameter in designing the dosage form and it is mainly done by adding sweetener and flavors.

But in the case of preparation of dosage form for migraine aspartame cannot be used as a sweetener as aspartame may trigger the migraine attacks. Various evaluation parameters are conducted like stability study, viscosity, in-vitro drug release, drug content.

Migraine is an interminable neurological disorder characterized by perennial moderate to acute headaches usually in association with a various number of autonomic nervous system symptoms. A migraine is a grievous, painful headache that is often preceded or lead by sensory warning signs such as flashes of light, blind spots, twinge in the arms and legs, nausea, vomiting, and increased sensitivity response to light and sound. The torturous pain that migraines bring can last for hours or even days.

Zolmitriptan (4S)-4-([3-(2-[dimethylamine] ethyl)-1Hindol-5-yl] methyl)-2-oxazolidinone, is a white to almost white powder highly soluble in water (20mg/ml). It is a BCS (biopharmaceutics classification system) class-3 drug with high solubility and low porousness. It has a pKa value of 9.52. Zolmitriptan is a second-generation triptan prescribed for patients with severe migraine attacks, with or while not an undertone and cluster headaches. It has a selective action on 5-hydroxytryptamine (5-HT1B/1D) receptors and it's terribly effective in reducing headache symptoms, as well as pain, nausea and icon or acoustic phobia. It is presently on the market as a standard pill, an oral disintegrating tablet and a nasal spray (2.5mg and 5 mg/dose). The drawbacks of current oral Zolmitriptan therapies area unit slow onset of action and low bioavailability (about 40%). Zolmitriptan undergoes highly hepatic first pass metabolism and to solve the problems of hepatic first pass metabolism oral jellies were prepared. Several works have been done on Zolmitriptan to improve its bioavailability since it has high first pass metabolism

Advantages:

1. It can be administer easily i.e., anywhere, anytime as it is easy to handle and doesn’t require water.

2. Therapeutic action of drug can be terminated by spitting it before complete ingestion of medicated jelly.

3. It can also be used for systemic delivery of drugs, which are prone to metabolism in the gut wall or liver.

4. Moreover the drugs that are liberated and swallowed from medicated jelly, will reach the gastrointestinal tract either in dissolved or suspended form in saliva and hence it will be easily available.

5. Delivery of therapeutic agent to systemic circulation through the oral mucosa can help to overcome the problems related to difference in drug release and retention times.

6. It serves as ideal method of drug delivery for dysphasia patients as it reduces the risk of aspiration.

Disadvantages:

1. As it is aqueous based preparation it needs appropriate packaging to maintain stability of drugs in various environment.

2. It may lead to unpleasant taste if not formulated appropriately.

MATERIALS AND METHOD:

Zolmitriptan Hydrochloride was procured from Yarrow Chem., Mumbai, Chitosan hydrochloride was procured from Loba Chem, Sorbitol and Propylene Glycol was procured from S.D Fine, Mumbai. All other ingredients were of analytical grade.

FT-IR Study of the Drugs and Excipients⁵:

Infra-red spectra matching approach was used for the detection of any possible chemical reaction between the drug and the excipients. A physical mixture (1:1) of drug and polymer was prepared and mixed with suitable quantity of potassium bromide. About 100mg of this mixture was compressed to form a transparent pellet using a hydraulic press at 2 tons’ pressure. It was scanned from 4000 to 150 cm-1 in FT-IR spectrophotometer. The IR spectrum of the physical mixture was compared with those of pure drug and excipients and matching was done to detect any appearance of disappearance of peaks.

Standard Calibration Curve of Zolmitriptan Hydrochloride:

A UV absorption maximum was determined by scanning 10µg/ml solution of Zolmitriptan hydrochloride in phosphate buffer of pH 6.8, at 226nm by using UV-visible spectrophotometer. Further a representative spectrum was drawn of Zolmitriptan hydrochloride in phosphate buffer of pH 6.8.

Formulation of Oral Jelly:

In a 50ml beaker required amount of propylene glycol was taken and warmed then the required amount of pure drug Zolmitriptan hydrochloride was added and stirred well on a magnetic stirrer until the drug gets completely dissolved and cool it at room temperature. Weight the required amount of chitosan hydrochloride and mix it with triethanolamine and keep it as it is for 30min until it forms a jelly. In another beaker take the required amount of sucralose and dissolve it in sufficient amount of distilled water and add the flavoring and coloring agents. Now mix the drug solution in the polymer solution and the sucralose solution also in the polymer solution to form a jelly. This formulation was carried out with different concentrations.

Table 1: Formulation of Oral Jelly

Ingredients	FJ1	FJ2	FJ3	FJ4	FJ5	FJ6
Zolmitriptan Hydrochloride	5mg	5mg	5mg	5mg	5mg	5mg
Sucralose	30mg	30mg	30mg	30mg	30mg	30mg
Propylene Glycol	2715mg	2712.5	2710	2707.5	2705	2702.5
Triethanolamine	30mg	30mg	30mg	30mg	30mg	30mg
Chitosan Hydrochloride	5mg	7.5mg	10mg	12.5mg	15mg	17.5mg
Sorbitol	2200mg	2200mg	2200mg	2200mg	2200mg	2200mg
Mix Fruit Flavor	1ml	1ml	1ml	1ml	1ml	1ml
Sunset Yellow	1ml	1ml	1ml	1ml	1ml	1ml

Evaluation Parameters:

Appearance:

The prepared jelly was inspected visually for clarity, color, texture and presence of any particulate materials. The test is important regarding patient compliance and acceptance.

Determination of pH⁶:

The pH of aqueous solutions of the prepared jellies was checked by using a calibrated digital pH meter at constant temperature. For the purpose 1g of the weighed formulation was dispersed in 100ml of distilled water and the pH was noted. The standard pH of the jelly was 7.5-8.1

Determination of Viscosity:

Viscosity of the jelly was measured by using (LV) Brookfield viscometer (Dial type). As the system is non-Newtonian spindle no. 4 was used. Viscosity was measured for the fixed time 2min at 1.5rpm.

Factor = 4 M

M = 1000

Viscosity = Dial reading x factor

The viscosity was calculated by following relation.

Viscosity in centipoises = Dial reading × Factor

(The factor in above calculation is found in factor finding data chart provided by the manufacturer of Brookfield Viscometer).

Drug Content⁷:

The prepared jelly was tested for drug content uniformity by UV-Spectrophotometric method. Each sample was placed in 10ml volumetric flask and diluted with Phosphate buffer 6.8 up to 10ml and sonicated in a Sonicator for about 10min and then removed and filtered. The absorbance of the solution was measured at 223nm using UV/visible spectrophotometer. The percentage drug content was determined.

In-vitro Dissolution Study^8-9:

The in-vitro drug release study was carried out in the USP apparatus II (Paddle). The RPM was fixed at 50RPM. The medium was chosen phosphate buffer of pH 6.8. The time for the dissolution study was 45min i.e. in every 5min the sample was removed and then the fresh medium was filled in it to maintain the sink condition. The absorbance’s of the samples withdrawn were analyzed on the U.V Spectrophotometer to calculate the % Cumulative Drug Release.

Order of Release Study^10-15:

All the release data was fitted into various kinetic models like, zero order, first order, higuchi, and Korsmeyer-Peppas, in order to find out order and mechanism of drug release from oral jelly. Determined the order of release of drug from the selected batch of oral jelly by graphical method from the dissolution data, a graph was plotted with % drug release remaining Vs time to find out zero order release. % drug release Vs square root of time to find out higuchi diffusion mechanism and log % of cumulative drug release Vs log of time to find out korsmeyer-peppas’s.

The value of ‘n’ gives an indication of the release mechanism; when n = 1, the release rate is independent of time (zero-order) (case II transport), n = 0.5 for Fickian diffusion and when 0.5 < n <1.0, diffusion and non-Fickian transport are implicated. Lastly, when n > 1.0 super case II transport is apparent.

Stability Study^16-20:

The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity, light and enables recommended Storage conditions, re-test periods and shelf lives to be established. In the present study, stability studies were carried out at Room Temperature (25°C + 2°C / 60 % RH ± 5%) and Accelerated testing(40°C ± 2°C / 75 % RH ± 5%) for 3 months for the optimized formulation. The optimized formulation was analyzed for the Physical Appearance, Drug Content, pH and Dissolution Study.

RESULTS AND DISCUSSIONS:

FT-IR Study of the Drugs and Excipients:

The FT-IR study reveals that there were no chemical or physical interactions between the drugs and the excipients.

Standard Calibration Curve of Zolmitriptan Hydrochloride:

The maximum absorption (i.e. λmax) of Zolmitriptan hydrochloride in phosphate buffer of pH 6.8 was found to be 223nm. The linear equation was found to be = 0.064x + 0.009and the r²value was found to be 0.998 respectively.

Figure 3: Standard Calibration Curve of Zolmitriptan Hydrochloride

Evaluation Parameters:

Table No.2: Evaluation Parameters of the Prepared Jelly

Formulation	Appearance	pH	Drug Content (%)	Viscosity (CPS)
FJ1	Transparent and smooth	7.5	98.15	273600
FJ2	Transparent and smooth	7.6	98.53	351234
FJ3	Opaque and smooth	7.0	98.40	542335
FJ4	Opaque and smooth	7.6	97.10	335435
FJ5	Opaque and smooth	8.1	99.90	294520
FJ6	Transparent and smooth	7.7	98.02	482355

In-vitro Dissolution Study:

Table No.3: In-vitro Dissolution Study (% Cumulative Drug Release)

Time (min)	% Cumulative Drug Release
Time (min)	FJ1	FJ2	FJ3	FJ4	FJ5	FJ6
0	0	0	0	0	0	0
10	59.60%	66.9%	70.29%	76.1%	83.3%	77.38%
15	60%	68.6%	71.63%	77.2%	85.7%	81.9%
20	62.2%	69.5%	72.50%	78.3%	89.9%	88.0%
30	63.6%	70.3%	73.61%	79.1%	91.0%	91.1%
45	64.7%	71.8%	75.0%	81.0%	95.4%	93.8%

Figure 4: % Cumulative Drug Release

Figure 5: %Cumulative Drug Release of the Marketed Formulation.

Figure 6: Comparative in-vitro study of FJ5 and Marketed Formulation

Kinetics Study:

Table No.4: Model Fitting Data for In-vitro Releases Kinetic Parameters of Oral Jelly.

Formulation	Zero Order	First Order	Higuchi Diffusion	Korsmeyer – Peppas	Best Fit Model	Value of n	Mechanism of Release
FJ1	0.947	0.949	0.984	0.926	First Order	0.067	Fickian release
FJ2	0.854	0.909	0.930	0.902	First Order	0.061	Fickian release
FJ3	0.836	0.85	0.903	0.997	First Order	0.062	Fickian release
FJ4	0.981	0.985	0.992	0.957	First Order	0.030	Fickian release
FJ5	0.927	0.968	0.957	0.971	First Order	0.052	Fickian release
FJ6	0.849	0.934	0.913	0.951	First Order	0.134	Fickian release

Stability Studies:

Table No.5: Stability Study of FJ5 Formulation at Room Temperature

Room Temperature (25°C + 2°C/60 % RH ± 5%)	Appearance	Drug Content (%)	pH
0 Day	Opaque and Smooth	99.9	8.1
15 Day	Opaque and Smooth	99.9	8.1
30 Day	Opaque and Smooth	99.9	8.1
45 Day	Opaque and Smooth	99.9	8.0
60 Day	Opaque and Smooth	99.81	8.0
75 Day	Opaque and Smooth	99.8	7.8
90 Day	Opaque and Smooth	99.76	7.8

Table No.6: Stability Study of FJ5 Formulation at Accelerated Study

Accelerated testing (40°C ± 2°C / 75 % RH ± 5%)	Appearance	Drug Content (%)	pH
0 Day	Opaque and Smooth	99.9	8.1
15 Day	Opaque and Smooth	99.9	8.1
30 Day	Opaque and Smooth	99.9	8.1
45 Day	Opaque and Smooth	99.8	8.1
60 Day	Opaque and Smooth	99.8	8.1
75 Day	Opaque and Smooth	99.75	7.9
90 Day	Opaque and Smooth	99.72	7.6

CONCLUSION:

The results of the present study demonstrated that delivery of Zolmitriptan hydrochloride oral jelly could be beneficial to improve the drug release from the dosage form. Zolmitriptan Hydrochloride is recommend in therapy of migraine and available as tablets form. Owing to only 40%bioavailability of Zolmitriptan hydrochloride may not control the migraine effectively. Focusing on this in the present study an attempt was made to develop oral jelly of Zolmitriptan hydrochloride using chitosan hydrochloride with different concentration as a jelling agent. In FTIR spectra there is no disappearance of peak present in drug and physical mixture it shows the compatibility of drug and polymer. The result of physico-chemical parameter such as pH, appearance, texture and viscosity shows that all formulation were within standard limit and as compare to other formulations FJ5 is considered as best in their characteristics. In-vitro dissolution study results of all were formulations shows immediate release and it varied according to the concentration of Chitosan Hydrochloride. The percentage release of drug increased at higher concentration of polymer. The result of drug content estimation show andconcentration of drug was higher in FJ5this indicates the influence of polymer. The FJ5 formulation was compared with the drug release with the marketed formulation and it was seen that in 45 min 83.3% of the drug gets releases in the jelly while in the marketed formulation only 49.5% of the drug is released. The observed results were fitted with release kinetics and it shows all the formulation obeys first order release with Fickian mechanism. Stability study was performed for the best formulation at room temperature as well as the accelerated testing and the result indicates that the prepared jelly was highly stable during its storage. Thus it was concluded among the all formulation FJ5 having better release characteristics due to the higher concentration of chitosan hydrochloride and which shows that the oral jelly can be a better alternative from the tablet dosage form and it could be beneficial to improve the bioavailability of Zolmitriptan hydrochloride.

REFERENCE:

1. Aminoff, Roger P. Simon, David A. Greenberg, Michael J. Clinical neurology (7 ed.). New York, N.Y: Lange Medical Books/McGraw-Hill. (2009) pp. 85–88.

2. Malviya VR, Pande SD, Road CKN. Preparation ad Evaluation of Zolmitriptan Hydrochloride Lozenge. J Pharma Res. 2019;8(8):624-629.

3. Malviya VR, Tawar MG. Preparation and Evaluation of Oral Dispersible Strips of Teneligliptin Hydrobromide for Treatment of Diabetes Mellitus. International Journal of Pharmaceutical Sciences and Nanotechnology. 2020 Jan 31;13(1):4745-52.

4. Raja Manali M, Dhiren P, Oral medicated jelly: a recent advancement in formulation, An International Journal of Pharmaceutical Sciences, 2016; 7(2):13-20.

5. Malviya V, Thakur Y, Gudadhe SS, Tawar M. Formulation and evaluation of natural gum based fast dissolving tablet of Meclizine hydrochloride by using 3 factorial design 2. Asian Journal of Pharmacy and Pharmacology. 2020;6(2):94-100.

6. Raut S, Uplanchiwar V, Bhadoria S, Gahane A, Jain SK, Patil S. Comparative evaluation of zidovudine loaded hydrogels and emulgels. Research Journal of Pharmacy and Technology. 2012;5(1):41-5.

7. Malviya VR, Pande SD, Bobade NN. Preparation and Evaluation of Sustained Release Beads of Zolmitriptan Hydrochloride. Research Journal of Pharmacy and Technology. 2019;12(12):5972-6.

8. Kumar L. An Overview on Preparation and Evaluation of Microparticulated Intra-Vaginal Gel. Research Journal of Pharmacy and Technology. 2009;2(1):48-51.

9. Shah RR, Magdum CS, Wadkar KA, Naikwade NS. Fluconazole topical microemulsion: preparation and evaluation. Research Journal of Pharmacy and Technology. 2009;2(2):353-7.

10. Shete AS, Mohite VL, Yadav AV. Preparation and Evaluation of Mucilage of Ocimum Basilicum as a Gelling Agent. Research Journal of Pharmacy and Technology. 2008;1(3):201-3.

11. Yadav AV, Urade MN. Preparation and evaluation of chitosan containing mucoadhesive buccal films of venlafaxine hydrochloride. Research Journal of Pharmacy and Technology. 2010;3(4):1213-7.

12. Begum SA, Sree VP, Anusha V, Veronica ZK, Sree PV, Prameela K, Nazeema MD, Padmalatha K. Formulation and evaluation of pediatric oral soft jellies of salbutamol sulphate. Research Journal of Pharmacy and Technology. 2018;11(11):4939-45.

13. Charyulu RN, Devi PP, Jose J, Shetty AV. Formulation and evaluation of mucoadhesive oral gel containing miconazole nitrate for oral candidiasis. Research Journal of Pharmacy and Technology. 2013;6(11):1251-7.

14. Kumar R, Jose J, Mahin MM, Raut R, Masurkar S, Swamy VB. Formulation and Evaluation of Gels from Gum of Cissus refescence. Research Journal of Pharmacy and Technology. 2012;5(3):415-23.

15. Malviya V, Manekar S. Design, Development and Evaluation of Aceclofenac and Curcumin Agglomerates by Crystallo Co-Agglomeration Technique. Research Journal of Pharmacy and Technology. 2021 Mar 1;14(3):1535-41.

16. Malviya V. Preparation and Evaluation of Emulsomes as a Drug Delivery System for Bifonazole. Indian Journal of Pharmaceutical Education and Research. 2021 Jan 1;55(1):86-94.

17. Singh S. Drug Stability Testing and Shelf-life Determination According to International Guidelines. Pharm. Technol. 1999; 23:68-88

18. Singh S, Bakshi M. Development of stability-indicating assay methods-A critical review. J. Pharm. Biomed. Anal. 2002; 28:1011-1040.

19. Malviya V, Pande S. Development and Evaluation of Fast dissolving Film of Fluoxetine hydrochloride. Research Journal of Pharmacy and Technology. 2021 Oct 31;14(10):5345-50.

20. Malviya V, Ladhake V, Gajbiye K, Satao J, Tawar M. Design and Characterization of Phase Transition System of Zolmitriptan Hydrochloride for Nasal Drug Delivery System. International Journal of Pharmaceutical Sciences and Nanotechnology. 2020 May 31;13(3):4942-51.

Received on 23.10.2021 Modified on 27.01.2022

Res. J. Pharma. Dosage Forms and Tech.2022; 14(2):139-144.

DOI: 10.52711/0975-4377.2022.00022