Design and Evaluation of Nimesulide Lozenges for Pediatrics

 

Mohd. Yousuf Ali*¹, Md. Shamim Qureshi¹, Md. Hamed¹, Byasabhusan Das¹ and K. Purushotham Rao²

¹Dept. of Pharmaceutics, Anwarul Uloom College of Pharmacy, New Mallepally, Hyderabad 500001, India.²Dept. of Pharmaceutics, HKE Society’s College of Pharmacy, Gulbarga-585105, Karnataka, India

*Corresponding Author E-mail: drsmileforu_433@yahoo.com

ABSTRACT:

Most of the illnesses are associated with fevers, headache and body aches and it is very difficult for parents to manage pediatric patients to administer the drug dosage forms. In the present investigation, an attempt has been made to formulate medicated sugar based tablet lozenges for kids using Nimesulide as model drug, which is commonly used analgesic and anti-pyretic. There are many dosage forms available in the market but still there is a need for new dosage form which acts effectively. So the present investigation has been taken up to design, prepare and evaluate hard candy based medicated tablet lozenges to meet the need of improved action dosage form. All the formulations prepared were subjected to various physico- chemical parameters such as hardness, drug content uniformity, weight variation, moisture content etc. The prepared formulations have a hardness of 9-12 Kg/cm², not gritty, mouth feel freshness taste. Stability studies of selected formulations were also carried out at 37^oC and 45^oC for a period of six months. Formulations were tested for drug excipient interactions subjecting to IR Spectral analysis. In-vitro drug dissolution studies showed 97.62% for F₀ formulation in 15 Minutes and 85.04% for F₁ formulation release of drug in 30 minutes. The hard boiled candy lozenges can provide an attractive alternative formulation in the treatment of pain and fever in pediatrics.

 

 

INTRODUCTION:

Many Pediatric patients express difficulty in swallowing tablets and hard gelatin capsules, tending to non-compliance and ineffective therapy. Recent advance in novel drug delivery systems (NDDS) aim to enhance safety and efficacy of drug molecules by formulating a convenient dosage form for administration and to achieve better patient compliance. One such approach is hard boiled candy Lozenges. Advantages of this drug delivery system includes patient compliance, convenience and comfortness for efficient treatment include low dose, immediate Onset of action, reduced dosage regimen and economic¹. Nimesulide is a non-steroidal anti-inflammatory drug of the sulfoanilide class with the analgesic and antipyretic properties². It was selected as drug candidate, as it is not available in such dosage form. Objective of the present work was to develop such a NDDS for Nimesulide by heating and congealing method for the treatment of pain and fever.

 

MATERIALS AND METHODS:

Nimesulide was gift sample from M/s Alkem Pvt. Ltd., Mumbai, Mucoadhesive polymer carboxy methyl cellulose sodium salt was gift sample from SD fine chemicals Pvt. Sucrose (SD Fine Chemicals Pvt. Ltd., Mumbai), Citric acid (CDH Pvt. Ltd., Mumbai), Color (Loba Chemicals Pvt. Ltd., Mumbai) were also used. All the other ingredients used were of Analytical grade. The desired quantity of sugar was dissolved in water by heating and stirring in a copper kettle until complete sugar was dissolved. Corn syrup was added when the cooking temperature reaches 110ºC. Cooking was then continued to 145 – 154.4ºC, till the syrupy base becomes thick. The finished cooked syrup (154.4ºC) is then placed in vacuum chamber which is maintained at 274 mm Hg for about 30 minutes to remove the traces of water molecules and to give plasticity to the base prepared.  The candy base was then transferred to a water-jacketed stainless steel cooling table of 214 ft. for the mixing operation. This mixing was done manually and during the mixing cycle, the temperature of candy base (154.4ºC) was brought to 90ºC to form a solidified mass. A hydrogenated vegetable oil-based lubricant is spread onto the table surface to alleviate this condition. At this stage the drug, mucoadhesive polymers, citric acid, other excipients such as color and favoring agents were added manually and mixed thoroughly. Then this solidified mass was placed between the rollers of the batch former. The rollers move in a counter rotating pattern that rolls the batch backward and forward so as not to distort any portion of the solidified mass in the batch former to form a rope size in shape. The diameter of the mass rope as it leaves the lower end of the former is adjusted by a hand wheel. The thickness of the rope was determined by the diameter of the size rollers and the gap between rollers. The candy rope is fed into a final set of sizing rollers was discharged from the batch former and rope sizer and from there into the rotating dies head furnished with plungers and guiding cams for the stamping and formation of the individual lozenges. Multiple belt conveyors pass as the formed lozenges into the drying chamber. Hot air was blown over the product (lozenges) in the drying chamber which was rotated is at a temperature of 15-20^oC, at a velocity of 1500-3000 ft/mins as the lozenges passed from the cooling belts. Then the dried lozenges is then taken in other container and lubricated with oils. So that prepared Lozenges should not stick to each other. The prepared nimesulide lozenges were packed with the help of machine called Maksom double twist wrapper³.

 

Evaluation of Tablet Lozenges:

Twenty tablets were selected at random and weighed individually. The individual tablet weights were compared with the average weight for the determination of weight variation⁴. Hardness of the tablets was determined by using Monsanto hardness tester. For the drug content uniformity, five tablets were weighed and powered in a mortar. From this; powder equivalent to 100mg. of drug was taken in a 100ml. volumetric flask. It was extracted with 20ml. of phosphate buffer at pH 6.7 for filtrate was make up to mark with phosphate buffer solution. Further appropriate dilutions were made and the absorbance was measured at 205nm for Nimesulide against blank. The drug content was calculated using the standard calibration curve. The mean percent drug content was calculated as an average of three determinations. For determination of in-vitro dissolution time, USP XXIII Dissolution test apparatus was used by taking 100 ml of pH 6.7 phosphate buffer in 250ml beaker, Tablet Lozenge was placed in rotating basket at a speed of 100 rpm and temperature 37±1ºC was maintained. 5 ml aliquots were withdrawn at 5, 10, 15, 20, 25 and 30 minutes intervals, after each withdrawal of a sample an equal volume of dissolution medium was added to the dissolution vessel.  The filtered samples were diluted and analyzed spectrophotometrically at 205nm. The FT-IR spectra of Nimesulide and its formulations were obtained in order to rule out drug- carrier interactions.

 

Dissolution study⁵:

In-vitro dissolution of nimesulide tablet lozenges was studied in USP XXIII Dissolution test apparatus by taking 100 ml of pH 6.7 phosphate buffer in 250ml beaker, Tablet lozenge was placed in rotating basket at a speed of 100 rpm and temperature 37±1ºC was maintained. 5 ml aliquots were withdrawn at 5, 10, 15, 20, 25 and 30 minutes intervals, after each withdrawal of a sample an equal volume of dissolution medium was added to the dissolution vessel.  The filtered samples were diluted and analyzed spectrophotometrically at 205nm.

Table No. 1: Working formulae to prepare Nimesulide Tablet Lozenges

Sl. No.	Ingredient	Formulations
		Without hydrocolloids (F0)	With Na CMC (F1)
1.	Sugar	680 gms	675 gms
2.	Liquid Glucose	286 gms	281 gms
3.	Drug (Nimesulide)*	17 gms	17 gms
4.	Sodium CMC (1%)	--	10 gms
5.	Citric Acid	10 gms	10 gms
6.	Flavoring Agent	6.7 gms	6.7 gms
7.	Colouring Agent	0.3 gms	0.3 gms
	Total Weight	1 Kg (1000 gms)	1 Kg (1000gms)

* Each tablet lozenges contains 50 mg of nimesulide, contains weight of 3 gms.

 

Stability studies:

Short term stability studies on the promising formulation F₁ (Lozenges containing carboxy methyl cellulose sodium salt) were carried out by storing the tablets at 37^oC and 45^oC over a period of 3 weeks period. At intervals of one week, the tablets were visually examined for any physical changes in drug content and hardness.

 

Figure No. 1: Comparative studies of Nimesulide Lozenges with and without hydrocolloid (F₀ and F₁,)

 

Moisture content determination:

The moisture content for all the formulations (F₀ and F₁) was determined and results were shown in Table No.3

 

RESULTS AND DISCUSSION:

Medicated tablets lozenges of nimesulide were prepared by using heat and congealing method using mucoadhesive polymer such as sodium hydroxyl methyl cellulose while citric acid, sweetening agent and favoring agent were also used according to analytic grade. A control formulation F₀ and formulation F₁ were designed.

 

The hardness of the tablet lozenges prepared was 11.5 Kg/cm² without hydrocolloids and 11.8 Kg/cm² with Sodium carboxyl methyl cellulose shown in table no 2. The Weight Variation of the Tablet Lozenges was not more than 5% shown in table no 2. Drug content was found to be within 95% to 105%, which is within acceptable limits shown in table no 2.

 

 

Table No. 2: Physicochemical Parameters of the Nimesulide Tablet Lozenges

Sl. No.	Parameters	Standard Limits	Formulations prepared
			Without hydrocolloids* (F0)	With Na CMC* (F1)
1.	Hardness (kg/cm²)	--	11.5	11.8
2.	Weight variation (mg)	>250 mg – 5%	3.303 ± 0.165 gms	3.331 ± 0.166 gms
3.	Thickness (mm)	--	14.01	14.02
4.	Drug content (mg)	95 – 105%	98.6 ± 0.216	99.3 ± 0.123
5.	Diameter (mm)	--	17.41	17.42

* Each reading is a mean of three replicates.

 

Table No. 3: Moisture Content of Tablet Lozenges of Nimesulide for Different Time Intervals

Sl. No.	Date	Without added hydrocolloids* (F0)	With Sodium CMC *(F1)
1.	01.07.2007	1.2469	1.6232
2.	01.10.2007	1.2505	1.6281
3.	10.01.2008	1.2524	1.7253

* Each reading is a mean of three replicates, standard limits 0.9 - 2.0%

 

 

In vitro dissolution studies on the formulation F₀ (Control) and formulation with sodium carboxy methyl cellulose (F₁) were carried out in pH 6.7 phosphate buffer. The data reveals that, the drug dissolution studies for formulation F₀ indicated that in 15 minutes time 97.62% of the drug was dissolved and the drug dissolution studies for formulation F₁ indicated that in 30 minutes time 85.04% of the drug was dissolved, shown in table no 4.

 

Table No. 4: Comparative In-vitro drug release studies of all prepared Tablet Lozenges

Time (min.)	Formulations prepared
	Without hydrocolloids*(F0)	With Na CMC* (F1)
5	28.11	15.64
10	59.60	48.15
15	97.62	59.00
20	--	69.70
25	--	74.65
30	--	85.04

* Each reading three is a mean replicates.

 

The formulations F₀ (without hydrocolloid), F₁ (with Na CMC) were subjected to moisture content determination. The results shown that the formulations were within limits, shown in tablet no 3.

 

IR spectroscopic studies indicated that the drug is compatible with all the excipients. The IR spectrum of F₁ showed that all the characteristic peaks of nimesulide pure drug, thus confirming that no interaction of drug occurred with the components of the formulation. Short term stability studies of the above formulation indicated that there were no significant changes in drug content and hardness at the end of three periods.

 

REFERENCES:

1.       Herbert A., Lieberman and Lachman L. Pharmaceutical dosage forms-tablets series. Marcel Dekker. 2^nd Edn. 1981: Vol I: 339-467.

2.       The Merck Index, “Nimesulide Drug profile”, 13^th Edn. 1174: (2001).

3.       Herbert A., Lieberman and Lachman L. Pharmaceutical dosage forms-tablets series. Medicated Lozenges, Marcel Dekker. 2^nd Edn. 1981: Vol I: 459-487

4.       Maryadele J., O’Neil and Ann Smith. Merck Index, Merck Research Laboratories, 13th Edn.2001:10.

5.       Manoj K., Roop K.K and Agarwal S.P., Formulation of choline salicylate as lozenge tablet for improved delivery to oral cavity. Indian Journal of Pharmaceutical Sciences May-June 2000.p.233

 

 

Received on 01.02.2010       Modified on 28.02.2010

Accepted on 20.03.2010      © RJPT All right reserved