Development and Evaluation of Hard Candy Lozenges Containing Roxithromycin for Treatment of Oral Infection

Surbhi Choursiya, Arpana Indurkhya

Sri Aurobindo Institute of Pharmacy, Indore.

*Corresponding Author E-mail: Drx.surbhichoursiya@gmail.com, indurkhyarpana@gmail.com

ABSTRACT:

The objective of the present study was to developed and evaluate of the hard candy lozenges containing roxithromycin for the treatment of oral bacterial infection. The mouth of human body provides non-shedding surfaces (teeth) for natural microbial colonization. These can the accumulation of large masses of bacteria and their products at stagnant sites. Dental plaque and gingivitis are some of this type of conditions, which can develop due to microbial accumulation on teeth and mouth ulcers are small, painful sores on the inside lining of the mouth. In this current study, Roxithromycin macrolide category wide spectrum antibacterial drug was selected as a drug because the existing market product of Roxithromycin is not available in the form of lozenges that can deliver the drug from the oral cavity. In the present investigation, taste is one of the most important parameters of oral formulations so β-Cyclodextrin is used as a good taste masking agent for bitter drug and also enhances the solubility of the drug. Hard candy lozenges were formulated by heating and Congealing technique with exicipients like sucrose, Isomalt, Glycerin, citric acid, flavor and color and evaluated for organoleptic properties the test like diameter, thickness, weight variation, hardness, friability, mouth dissolving time, and % drug content. The Optimized formulation of Roxithromycin Hard candy lozenges (H₆) were sweet in taste, smooth in texture and having a diameter 13.708±0.00 mm, thickness 7.704±0.00 mm, hardness is 11±1kg/cm2 and drug content uniformity is 97±0.02%. The weight variation and friability of lozenges (H₆) was passed as per IP and mouth dissolving time is found at 25±2 min. In vitro dissolution study for roxithromycin hard candy lozenges lozenge was performed in pH 6.8 phosphate buffers wherein 95% of the drug was released within 30 min.

KEYWORDS: Roxithromycin, Lozenges, Hard Candy Lozenges, Beta-Cyclodextrin agent, Oral infections.

INTRODUCTION:

Oral drug delivery is the most preferred and simplest means as the oral route provides a maximum active surface area of all drug delivery system for administration of various drugs. The oral route of drug administration has been widely used for both conventional as well as novel drug delivery.^[1,2]

The lozenges are solid medicated, flavored and sweetened base dosage forms intended to be sucked and hold in the mouth or pharynx to treat local irritation, mouth or pharynx infection. Lozenges are one of the very popular and better innovative dosage form and oral confectionary products. It is a potentially useful for means of administration drugs either locally or systematically through the oral cavity. The reasons for this preference because of the easy to administered for the geriatric and pediatric patient, and widespread acceptance by patients. The development of new drug delivery systems for existing drug with an improved efficacy, avoid first pass hepatic metabolism, no need of water intake, and increase bioavailability together with reduced dosing frequency to minimum side effects.^{[3,4,5, 6,7]}

Oral infection is a common public health problem. They can affect the tongue dorsum, lateral sides of tongue, buccal epithelium, hard palate, soft palate, supragingival plaque of tooth surfaces, subgingival plaque.^[8,9]

The antimicrobial drug is used to treat the oral infection. Roxithromycin macrolide category wide spectrum antibacterial drug that inhibits bacterial protein biosynthesis by binding reversibly to the subunit 50S of the bacterial ribosome, thereby inhibiting translocation of peptidyl-tRNA. This action is mainly bacteriostatic at low concentrations, but can also be bactericidal in high concentrations. Roxithromycin is very slightly soluble in water and bitter in taste so inclusion Complexation techniques are used to reduce of unpleasant taste, improving patient compliance and better therapeutics efficacy.^[10,11,12]

MATERIALS AND METHODS:

Materials:

Roxithromycin was received as a gift sample from Century Pharmaceuticals Limited, Vadodara, India. Sucrose, Isomalt. glycerin, citric acid, menthol, peppermint and β Cyclodextrin were of used as an analytical grade.

Methodology:

Pre-formulation studies:

Standardization of Roxithromycin by UV–Vis Spectrophotometric:

Standard Calibration of Roxithromycin in 6.8 Phosphate buffer:

Accurately weighed 50mg of Roxithromycin was transferred in 50ml of volumetric flask and then 2ml of methanol was added to dissolve the drug and volume was made up to the mark by 6.8 pH phosphate buffer to get the concentration of 1000μg/ml. The further dilution of 5, 10, 15, 20, and 25μg/ml were prepared from the stock solution and absorbance was taken at 219nm. The UV spectrum of Roxithromycin is shown in Fig.1.

Fig.1: UV spectrum of Roxithromycin in Phosphate buffer in pH 6.8

Table 1: Optical characteristics of Roxithromycin

Parameters	Values
Absorption Maxima (nm)	219
Beer’s range (μg/ml)	5-25 µg/ml
Regression equation (y)*	y = mx+c
Slope (m)	0.030
Intercept (c)	0.018
Correlation coefficient(R^2)	0.998

Table 2: Calibration Curve of Roxithromycin in Phosphate buffer in pH 6.8

Concentration	Absorbance Mean ±S.D. (n=3)
0	0.000 ± 0.000
5	0.184 ± 0.002
10	0.329 ± 0.001
15	0.474 ± 0.004
20	0.619 ± 0.001
25	0.764 ± 0.003

Fig. 2: Calibration Curve of Roxithromycin in Phosphate buffer in pH 6.8

Preparation of taste masking Roxithromycin by inclusion Complexation techniques:

By Solvent Evaporation Method:

In this method separately aqueous solution of β-CD (1:1) and an alcoholic solution of Roxithromycin were prepared then mixing of both solutions to get molecular dispersion of Roxithromycin and complexing agents and finally evaporating the solvent under vacuum to obtain solid powdered inclusion compound. The solid powdered was dried and pulverized and passed through mesh (#) 80 and stored in desiccators for further study.

Formulation of Hard Candy Lozenges^[13-15]:

Hard candy lozenges are mixtures of sugar and other carbohydrates in an amorphous or glassy state. They can also be regarded as solid syrups of sugars. The moisture content and weight of hard candy lozenge should be between 0.5 to 1.5% and 1.5-4.5g respectively. These should undergo a slow and uniform dissolution or erosion over 5-10min., and should not be disintegrate. The temperature requirements for their preparation of hard candy lozenges is usually high hence, heat labile materials cannot be incorporated in them.

Advantages:

It can be given to those patients who have difficulty in swallowing.

Easy to administer to geriatric and pediatric population.

Improved patient compliance.

Method of Preparation of Roxithromycin Hard lozenges:

By heating and congealing technique:

In this method firstly sugar syrup was prepared by dissolved sucrose and isomalt in water and heating temp. 100°C for 30 min. to form a clear viscous solution. Then roxithromycin complex, color, flavor and preservatives were added in syrup solution for heating temp 100°c. Then this syrup was poured into prelubricated mould of desired shape and size to form hard candy lozenges.

Table 3: Composition of Roxithromycin Hard Candy lozenges

Ingredients	H1	H2	H3	H4	H5	H6
Drug: βCD complex	75mg	75mg	75mg	75mg	75mg	75mg
Sucrose	200mg	180 mg	175 mg	150 mg	125 mg	100 mg
Isomalt	700mg	720mg	725mg	750mg	775mg	800mg
Glycerine	0.1ml	0.1ml	0.1ml	0.1ml	0.1ml	0.1ml
Citric Acid	500 mg	500 mg	500 mg	500 mg	500 mg	500 mg
Methyl Parabean	5 mg	5 mg	5mg	5 mg	5 mg	5 mg
Peppermint	q.s.	q.s.	q.s.	q.s.	q.s.	q.s.
Coloring Agent	q.s.	q.s.	q.s.	q.s.	q.s.	q.s.
Water	q.s.	q.s.	q.s.	q.s.	q.s.	q.s.
Total	1500 mg	1500 mg	1500 mg	1500 mg	1500 mg	1500 mg

Optimized formula:

Table 4: Optimized formula of hard candy lozenges

Ingredients	H6 (Each lozenges)
Drug: βCD complex	75mg
Sucrose	100 mg
Isomalt	800mg
Glycerine	0.1ml
Citric Acid	500 mg
Methyl Parabean	5 mg
Peppermint	q.s.
Coloring Agent	q.s.
Water	q.s.
Total	1500 mg

Evaluation of Hard Candy Lozenges of Roxithromycin:

The prepared Lozenges were evaluated for following official and unofficial parameters like organoleptic test, hardness, thickness, diameter, weight variation, friability, mouth dissolving time, drug content and in vitro dissolution studies etc.

Orgnoleptic test:

Orgnoleptic properties were evaluated as manually for prepared hard candy Lozenges of Roxithromycin.

Table 5: Orgnoleptic examination of prepared Hard candy lozenges

Parameters	Result
Shape	Spherical
Color	Light yellow
Texture	Smooth
Taste	Sweet

Diameter and Thickness:

The diameter and thickness were measured by using Vernier caliper. The hard candy lozenges dimensions are a very important factor in their manufacture. The three lozenges were selected randomly from the formulation, and then thickness and diameter were measured.

Table 6: Evaluation of lozenges for diameter and thickness

Evaluation Parameter	Result (Mean ± SD) (n=3)
Diameter	14.708 ± 0.00 mm
Thickness	7.504 ± 0.00 mm

Hardness:

The hardness of ten hard lozenges was determined by using Monsanto Hardness tester. Mean and standard deviation were computed and reported. It is expressed in kg/cm². The average hardness for lozenges is calculated and presented with standard deviation and observation reading mentioned in below table.

Table 7: Evaluation of lozenges for Hardness

Evaluation Parameter	Result (Mean ± SD) (n =5)
Hardness	11 ± 1 kg/cm^2

Weight Variation Test:

Twenty lozenges from the formulation were randomly selected and weighed together the tablets were then weighed individually. The batch passes the test for weight variation test if not more than two of the individual lozenge weight deviates from the average weight by more than the percentage according to IP limits shown in table.

Table 8: Weight variation limit according to IP

Average weight of Tablet (mg)	% Deviation
Less than 80	10
80-250	7.5
More than 250	5

Friability:

Friability was determined by using a Roche friabilator. 10 lozenges were weighed and placed in the Roche friabilator and all the parameters set on the friabilator. The apparatus was rotated at 25rpm (100 rotations) for 4 minutes. After revolutions the lozenges were deducted and weighed again. The maximum mean weight loss samples are not more than 1.0 %. The percentage friability was measured using the formula:

              W₀ -W

% F =----------------  × 100

                W₀

and observation reading mentioned in below table

Where,  

% F = Friability in percentage,

W₀ = Initial weight of lozenges

W = Final weight of lozenges after revolution

Table 9: Evaluation of Hard candy lozenges for Friability

Evaluation Parameter	Result (Mean ± SD)
Friability	0.023 ± 0.2% (Pass)

Mouth Dissolving Time:

The time taken by the lozenges to dissolve completely was determined by USP disintegration apparatus, where lozenges were placed in each tube of the apparatus and time taken for the lozenges to dissolve completely was noted by using 900ml phosphate buffer of pH 6.8 at 37 ⁰c. This test was done in triplicate. The average dissolving time for lozenges was calculated and presented with standard deviation.

Table 10: Evaluation of lozenges for Mouth Dissolving Time

Evaluation Parameter	(Mean ± SD) (n=3)
Mouth Dissolving Time	25 ± 2 min.

Drug Content:

Lozenges were powdered and dissolved in small volume of methanol in 50ml volumetric flask and volume make upto 50ml of Phosphate buffer at pH 6.8. From this solution 1ml taken and diluted with Phosphate buffer at pH 6.8 in 50ml volumetric flasks then sonicated for 30 min then filtered using filter paper. The absorbance of this solution was measured at 219nm using appropriate blank. The drug content of Roxithromycin lozenges was calculated using calibration curve and observation reading mentioned in below table.

Table 11: Evaluation of lozenges for Drug contents in lozenges

Evaluation Parameter	% Drug content (Mean ± SD) (n=3)
Drug Content	97 ± 0.020

RESULTS AND DISCUSSION:

In Vitro Dissolution Study:

Dissolution study was carried out in 900ml of the dissolution medium (Phosphate buffer of pH 6.8) was placed in the vessels of the dissolution apparatus USP (type II). The dissolution medium was equilibrated to 37 ±0.5°C, and the paddle speed set to 50 revolutions per minute. Lozenges were placed in each of the vessels of the dissolution apparatus and operated at the specified rate. At specified time intervals of 5, 10, 15, 20, 25 and 30 min 5ml samples were withdrawn from dissolution medium and 5ml of fresh dissolution medium was added to the beaker. The vessel was kept covered for the duration of the test and the temperature of the medium maintained at 37±0.5°C at all times. The withdrawn samples were filtered and diluted upto 10ml phosphate buffer of pH 6.8 in volumetric flask. The diluted filtrates were analyzed by UV spectrophotometer at a wavelength of 219nm using a phosphate buffer of pH 6.8 as blank solution. Using the equation obtained from the calibration curve, the concentration of Roxithromycin in samples taken at time, 5, 10, 15, 20, 25, and 30 min were calculated the percentage drug release. A plot of percentage drug release against time was established.

Dissolution Conditions:

Dissolution Apparatus: USP type II (Paddle)

Model: Model-TDT 6P, Electro lab, Mumbai

Stirrer: Paddle type.

Dissolution media quantity: 900 ml

Dissolution media: pH 6.8 (Phosphate buffer)

Temperature: 37±0.5^oC

Paddle RPM: 50

Sampling intervals: 5, 10, 15, 20, 25 and 30 min.

Table12: Dissolution profile of Hard candy lozenges

S.  No	Time (min)	Cumulative percent drug dissolved (n=3)
		Set 1	Set 2	Set 3	(Mean ± SD)
1	5	47.23	51.13	48.03	48.79 ± 0.068
2	10	65.95	64.55	65.03	65.17 ± 0.067
3	15	71.01	72.59	71.76	71.78 ± 0.060
4	20	83.81	85.81	85.11	83.91 ± 0.133
5	25	93.95	92.11	93.81	93.27 ± 0.057
6	30	95.58	94.60	95.17	95.08 ± 0.0379

From above table and figure of In vitro dissolution for lozenge was found that in pH 6.8 phosphate buffer 95 % drug was released within 30 min.

CONCLUSION:

In present research work is the formulation and Evaluation of hard candy lozenges for oral bacterial infection can be successfully developed with Roxithromycin complex of β Cyclodextrin is good taste masking and also enhance the solubility of drug. It can be concluded that developed lozenge formulation proves to be were beneficial for local infection. Due to easy administrations and also improve the patient compliance. The lozenge onset of action could also be increased. The developed formulation can be used for treatment of local infection especially in case of pediatrics and geriatrics patients and those who can’t swallow the drug.

ACKNOWLEDGMENT:

Authors are thankful to our Director of College S.C. Chaturvedi, Head of Department Mrs. Arpana Indurkhya, Faculty of Pharmacy in Sri Aurobindo Institute of Pharmacy, Indore for extending laboratory and instrumental facilities to carry out the work. I would also like to thank provide as a gift sample from Century Pharmaceuticals Limited, Vadodra, India in complete me research work successfully.

REFERENCES:

1. Meghwal M, Goswami TK. Chemical Composition, Nutritional, Medicinal and Functional Properties of Black Pepper: A Review. Open Acc Sci Rep. 2012; 1:1-5.

2. Paul M, ESCMID Guideline for the Management of Acute Sore Throat, 2012; 18: ESCMID, 1-18.

3. Maheshwari Rachana, Jain Vikas, Ansari Rehana et al. A Review on lozenges. Journal Home Page www.bbbulletin.org. 2013; 1(1): 35-43.

4. Munot M., Sharma Neha, Gujar N. Kishore. Orodental Delivery Systems. International Journal of Pharm. and Pharmaceutical Science. 2013; 5(3):1-10.

5. Maheshwari R, Jain V, Ansari R, Mahajan SC, Joshi G. A review on lozenges. BBB, 2013; 1-9.

6. Shinde SG, Kadam V, Kapse GR, Jadhav SB, Zameeruddin, Bharkad VB. A review on lozenges. IAJPR, 2014; 4(2): 567-570

7. Pothu R and Yamsani MR. Lozenges formulation and evaluation: A review. IJAPR. 2014; 1: 290-294.

8. Shinde Satish G, Kadam Vaishali, Kapse G.R.et al. A Review on lozenges. Indo American Journal of Pharmaceutical Research. 2014; 4(1): 566-571.

9. Pundir Suchitra, Verma Abhay, Murari Lal. A Review on lozenges. Journal der Pharma. Forschung. 2014; 2(1): 1-10.

10. Stephen O. Majekodunmi. A Review on Lozenges. American Journal of Medicine and Medical Sciences. 2015; 5(2): 99-104.

11. Adavelly Manasa, Amma Venu, Velpula Rajeshwari. Formulation and Evaluation of Cetrizine Lozenges. International Journal of Innovative Pharmaceutical Sciences and Research. 2017; 5 (10): 93-103.

12. Mishra Kamlendra, Kutubuddin Tasneem, Jain Vikas et al. Formulation and Evaluation of Herbal Lozenges. Research Journal of Drug Delivery and Therapeutics. 2017; 7(7): 1124-1129.

13. Mayuri J. Chandrawanshi, R. S. Sakhare, Dr. Shivappa N. Nagoba  et al.  A Review on Medicated Lozenges. World Journal of Pharmaceutical Research. 2018; 8 (2): 396-412.

14. Pokale Apurva D., Dr. K Shrikant. Tillooand et al. Medicated Chewable Lozenges: A Review. International Journal of Recent Scientific Research. 2019; 10(4): 32071-32076.

15. Chaudhari V Punam, Chaudhari Nirma G., Chaudhari Pooja S. et al. Formulation and Evaluation of Medicated candy Containing albendazole For Pediatric Indian Journal of Drugs. 2019; 7(2): 73-80.

Received on 26.04.2020       Modified on 19.05.2020

Accepted on 15.06.2020      ©Asian Pharma Press All Right Reserved

Asian J. Pharm. Ana. 2020; 10(3):150-154.  

DOI: 10.5958/2231-5675.2020.00027.7