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DEVELOPMENT AND CHARACTERISATION OF MEDICATED CHEWING GUM CONTAINING INDOMETHACIN IP


Sarath chandran C*, Mrs. Neethu , Vipin K V
Academy of Pharmaceutical Sciences, Pariyaram Medical College Pariyaram, India

Abstract

The chewing gum may be considered as an excellent mode of drug delivery. The medicated chewing gums containing various drug moieties are tried and approved by the regulatory bodies for their safe use in human beings. The medicated chewing gum containing Indomethacin IP was developed using the conventional process and subjected for various characterisation studies. The developed product was as good as confectionary chewing gums. The drug loading capacity of medicated chewing gum during the investigation was satisfactory.

The in-vitro drug release profile of developed medicated chewing gum was evaluated at different chewing frequencies. The study suggested that, at higher chewing frequency of 60 cyc/minutes delivers better drug release profile. The drug release from conventional capsule of Indomethacin IP was compared against the developed formulation. The developed medicated chewing gum had better in-vitro drug release profile at all chewing frequencies in comparison with capsule. The products were stable throughout the period of investigation.

Key words: chewing, gum, medicated, Indomethacin IP, frequency.

Introduction

Chewing gum (CG) is a pleasure that almost everyone enjoys and is a habit practiced by children as well as adults in many countries. Research studies had shown that CG may keep the people awake, alert and tension free. The use of chewing gum may improve both episodic and working memory. In addition to confectionary role, CG has proved its potential as a drug delivery tool through oral mucosa. Oral mucosa has rich blood supply and it offer permeability for many drugs which makes this route as an attractive alternative for drug administration. The presence of saliva in mouth helps for the drug permeation across moist membrane which occurs much more readily than across non-mucous membranes. Chewing gums containing medicinal products are termed as medicated chewing gums (MCG). MCG has history for about a century. It was reported that in 50 AD, the Greeks sweetened their breath and cleansed their teeth using mastiche, a resin from the bark if mastic tree. The present generation of MCG is having potential to administer drugs either locally or systemically through oral route1,2.

The medicated chewing gums are defined by European Pharmacopeia and the guidelines for pharmaceutical dosage forms issued in 1991 by the committee for medicinal products for human use as “ solid single dose preparations with a base consisting mainly of gum that are intended to be chewed but not to be swallowed, proving a slow steady release of medicine contained. The first MCG was launched in year 1924 in USA with a brand name of Aspergum®. A MCG, that is intended to be chewed for a certain period of time may effectively deliver the drug or combination of drugs. MCG’s are not swallowed and the remaining mass after chewing is discarded. During the chewing process, the drug incorporated in the formulation is released in to the saliva. The released portion of the drug/s has two fates; either may be absorbed through oral mucosa or may reach the stomach for GI absorption. As a result of continuous chewing, the drug which reaches the stomach for GI absorption is available as small particles, thus it may undergo rapid dissolution and absorption. The drugs causing side effects such as GI disturbances and irritation may possibly be formulated as MCG since it may reduce the intensity of these side effects. The absorption of drug drugs from oral mucosa may overcome the premature drug degradation due to enzyme activity and pH of the gastro intestinal tract and it may provide rapid onset of action by the entry of drug in to systemic circulation through jugular vein. In fact both these process may occur simultaneously; hence MCG may offer both local and systemic effect1,2,3.

There are plenty of commercially available MCG approved by USFDA. Some of the leading brands are listed in the table (Table No.1)

Table No. 1: Marketed brands of medicated chewing gums approved by USFDA

Brand Name Drug/ API  Indication  Manufacturer 
Niconette® Nicotin Smoking cessation Glaxo Smithklim
Nicotinell® Nicotin Smoking cessation Novartis
Niquitin® Nicotin Smoking cessation Glaxo Smithklim
Fluorette® Fluride Dental caries Fertin Pharma
Vitaflo CHX® Chlorhexidine Gingivitis and Plaque Fertin Pharma
Stay Alert® Caffeine Antibacterial Stay Alert Safety Service Inc.
Travvell® Dimenhydrinate Motion sickness Asta Medica

The MCG not only offers clinical benefits, but also an attractive, discrete and efficient drug delivery system. The MCG is believed to manifest its position as convenient and advantageous drug delivery system as it meets the high quality standards of pharmaceutical industry and also deliver active ingredients in effective, safe and economical manner. The possibilities of MCG as drug delivery tool must be explored in treating various disease conditions. Indomethacin IP is a hetero aryl acetic acid analogue of NSAID with anti-inflammatory, analgesic and anti-pyretic activity. Even though Indomethacin IP is a potential NSAID, but it is reported with excess stomach acid secretion, stomach cramp, diarrhoea, water retention and even rupture in the wall of stomach as well as intestine.

These side effects are persistent with all the solid dosage forms developed with Indomethacin IP. The MCG may be one of the better alternatives to minimise these reported side effects with maximizing the therapeutic benefits. This investigation is made to explore the possibilities to develop a successful MCG of Indomethacin IP (MCGI) as a formulation with faster onset of action, improved release profile and reduced side effects. The developed MCGI may reduce the severity of GI side effects caused by the drug and improve the patient comfort4,5.

Materials AND METHODS

Formulation of medicated chewing gum of Indomethacin IP (MCGI)

The MCGI was developed as per the composition listed in the table (Table No.2). The powdered drug and excipients were sifted through sieve no. 40 and accurately weighed. The gum base taken in china dish was melted at 70o C. The drug, glycerol and soya lecithin were added in to the gum base and stirred thoroughly until it became a uniform mass. The flavouring and colouring agents were added in the last stage. The resultant mixture was cooled, rolled, and cut in to pieces to produce sticks of MCG6,7.

Table 2: Composition of medicated chewing gum of Indomethacin IP (MCGI)

Sl. No Ingredients Quantity
1 Indomethacin IP 100 mg
2 Chewing gum base 2 gm
3 Glycerol 0.2 ml
4 Soya lecithin 0.2 ml
5 Peppermint q.s
6 Amaranth q.s

 

General appearance and physical parameters

The colour, odour, consistency and weight of the developed MCGI was evaluated and reported. The consistency was tested using Monsanto hardness tester and weight was measured using calibrated digital balance6,7.

Estimation of drug content

The developed MCGI was crushed with a 40 ml phosphate buffer solution (PBS) of Ph 6.8 in a mortar using a pestle for about 30 minutes. From this solution, sample was withdrawn and absorbance was measured at 317 nm6,7.

In- vitro drug release profile

The in-vitro dissolution study for MCGI was performed using a specially designed in-house dissolution apparatus, which may mimic the normal mastication process of humans (Fig No.1).

Fig 1: In-vitro dissolution study apparatus for MCGI

The developed MCGI was kept in cylindrical vessel containing PBS of Ph 6.8. The cylinder was placed in between movable piston and base plate. The piston was moved at fixed frequency ie, 30, 40, 50 and 60 cyc/ minutes. During the trials, 1 ml of sample was withdrawn every 5 minutes for duration 60 minutes.The sink condition was maintained throughout the study. The samples with drawn were measured for drug content by using UV Spectrophotometric method at 317 nm. A comparative study of developed MCGI was made against a marketed sample of Indomethacin IP capsule using a type- I dissolution apparatus. The resulted data’s were evaluated and compared for their drug release profile6,7,8.

Stability studies for developed MCGI

An accelerated stability study for developed MCGI was carried out as per ICH guidelines with necessary modifications. The MCGI was exposed at different temperature conditions of 4±2o C, 30±2o C and 45±2o C for a period of 45 days. The MCGI was tested for consistency, colour, odour and drug content6,7.

Results and discussions

The preformulation studies like determination of melting point, percentage loss on drying and drug- excipient interactions were performed using drug and gum base. The melting point for Indomethacin IP was measured at 160oC and it complies with IP standards. The percentage loss on drying was 0.2%, which was within IP limits9. The FTIR studies were carried out to confirm the possibilities for interactions between Indomethacin IP and confectionary gum base. The wave lengths were similar for spectrum obtained in case of pure Indomethacin IP, confectionary gum base and physical mixture of both. The study confirmed the compatibility of drug and excipient, selected for formulation development.

The MCGI for this investigation was prepared using the conventional production process or melting process. MCG’s are formed by the aggregation of water- insoluble phase, known as gum base and rest of the ingredients. To provide visual appearance for the developed product, sufficient quantity of amaranth was added. Since mint flavour is the preferred for CG products, peppermint oil was used as flavouring agent. Both ingredients were added in the last stage of production process to retain their stability. The presence of glycerol and soya lecithin maintains the softness of the developed MCG throughout the shelf life10,11. The developed MCGI was packed in aluminium foil and used for further investigations (Fig No2).

Fig 2: Formulated medicated chewing gum of Indomethacin IP

The developed MCGI was evaluated physical consistency, colour, odour, drug content, in-vitro dissolution pattern and stability. The red colour induced by amaranth was giving good visual appearance for the developed MCGI. The hardness measured using Monsanto hardness apparatus suggested soft nature of the product, which may be comparable with commercially available confectionary CG. The optimised concentration of glycerine and soya lecithin may be the reason behind softness of developed MCGI. The odour of the MCGI was minty as peppermint was added as flavouring agent.  The average drug content available in the developed MCGI was 80.2%. The high content measured support the ability of medicated chewing gums to retain maximum possible concentration of incorporated drug moiety12,13. For the success of any pharmaceutical formulation, the percentage drug content plays a key role.

The in- vitro drug release studies of developed MCGI was performed using specially designed instrument in pharmaceutics department, which may mimic the normal chewing process by human beings. The instrument was operated at different chewing frequencies i.e. 30, 40, 50 and 60 cyc/ minutes. The influence of chewing frequencies on the drug release pattern from a MCG may be critical and must be evaluated. The percentage drug release after 30 minutes of study at 30 cyc/ minutes frequency was 73.78±0.03.Which increased to 78.4±0.10, 82.52±0.21 and 89.77±0.04 respectively for 40, 50 and 60 cyc/ minutes at the end of 30 minutes of dissolution study. (Table No.3)

Table 3: In-vitro drug release profile of MCGI at different chewing frequencies

SI. No Time % Drug released in different chewing frequencies
30 cyc/minutes 40 cyc/minutes 50 cyc/minutes 60 cyc/minutes
1 0

 

0.00 0.00 0.00 0.00
2 5

 

24.13±0.01 28.58±0.03 31.88±0.13 32.3±0.02
3 10

 

32.53±0.02 33.93±0.20 53.09±0.21 41.63±0.02
4 15

 

42.97±0.03 50.26±0.30 53.74±0.12 61.7±0.02
5 20

 

53.82±0.01 62.98±0.17 64.56±0.23 75.94±0.03
6 25

 

62.49±0.02 74.66±0.20 74.64±0.28 83.4±0.02
7 30

 

73.78±0.03 78.4±0.10 82.52±0.21 89.77±0.04

When chewing frequency was increased, the percentage drug released from the MCGI significantly increased. Hence it may be important to apply effective chewing to get the full benefit of medicated chewing gums. The proper direction for usage may be provided to the patients and physicians through printed leaf lets or demonstration. This may ensure complete drug release of drug from developed medicated chewing gum and also deliver better therapeutic response for the patient14.

To substantiate the benefit of formulating Indomethacin IP as a medicated chewing gum, in- vitro dissolution study of conventional capsule of Indomethacin IP was carried out. The result was compared with the percentage drug release profile obtained with MCGI under different chewing frequencies. The maximum percentage drug release obtained for MCGI was 89.77±0.04 at the end of 30 minutes of study, which was significantly higher than 62.15±0.15% of drug released from conventional capsule. The in-vitro dissolution study performed in all the selected chewing frequencies showed better percentage drug release than that of conventional capsule of Indomethacin IP (Fig No.3). This may suggest the possibility of medicated chewing gum as a better drug delivery tool10,11,12.

Fig 3: Comparison of drug release profile between MCGI and capsule

The developed medicated chewing gum of Indomethacin IP was able to maintain its physicochemical integrity throughout the period of stability study. The evaluated parameters such as colour, odour, consistency and drug content remained stable. Hence, it may be suggested that, medicated chewing gum is one of the stable and effective option to deliver Indomethacin IP for management of pain and inflammation.

Summary and Conclusion

The data obtained from the investigation strongly suggested that medicated chewing gum of Indomethacin IP may provide local and systemic delivery of drug with a faster on set of action than existing oral formulation of the drug. The developed medicated chewing gum was able to release maximum amount of drug incorporated. Based on literature review and data obtained during the investigation, it may be concluded that medicated chewing gum of Indomethacin IP may be a effective, safe and stable oral formulation which may be convenient as well as economical for the patient population. The extensive clinical investigations may be performed on the developed formulation to substantiate its claim in terms of clinical efficacy.

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