Formulation and Evaluation of Nicorandil Chewing Gum

Yashaswini P M*, Someshwara Rao B, Ranjit Kumar P, Vinod R, Suresh V Kulkarni, Ashok Kumar P.

Department of Pharmaceutics, Sree Siddaganga College of Pharmacy, B.H.Road, Tumkur-572102, Karnataka, India.

ABSTRACT:

The study was to formulate and evaluate medicated chewing gum of Nicorandil, a novel potassium channel opener used in cardiovascular diseases. The chewing gums were prepared by direct compression method using different ratio of directly compressible gum base (pharmagum-M) in order to obtain new formulation. Eight different formulations of chewing gums of Nicorandil were prepared, which contains various concentration of pharmagum M. The chewing gums which are prepared by direct compression method were characterized by pre compression characters, post compression character, buccal absorption study, drug content, and in vitro drug release studies. All the formulations gave satisfactory results in terms of pre compression characters, post compression character, buccal absorption study, drug content, and in vitro drug release. The best compression characters and in vitro drug release profile were achieved in formulations F4, F5 and F6 with a gum concentration of 84%, 86% and 88% respectively.

KEYWORDS: Chewing gum, Buccal absorption, Nicorandil, Pharmagum M, Sorbitol

INTRODUCTION:

Pharmacological Active Agents or Drugs are formulated into variety of dosage forms like Tablets, Capsules, Injectables, Inhalers, Ointments etc considering Physicochemical properties, Pharmacokinetic and Pharmacodynamic parameters and Biopharmaceutical aspects of Drugs. In addition to its confectionary role, Chewing Gum (CG) also has proven value as a delivery vehicle for pharmaceutical and nutraceutical ingredients¹. Today CG is convenient drug delivery system which is appropriate for a wide range of active substances². Many therapeutic agents are absorbed in the oral cavity. For the drugs having significant buccal absorption, dosage forms such as Lozenges, Chewable tablets and Chewing Gum permits more rapid therapeutic action compared to per-oral dosage forms³. Chewable tablets and chewing gum have been very well received by the parents for use in children with full dentition. Children in particular may consider chewing gum as a more preferred method of drug administration compared with oral liquids and tablets. The use of Medicated chewing gums is feasible in local treatment of diseases of oral cavity as well as treatment of systemic conditions. Chewing gum has been used for centuries to clean the mouth and freshen the breath⁴.

Medicated Chewing Gums are solid, single dose preparations with a base consisting mainly of gum that is intended to be chewed but not swallowed. They contain one or more active substances which are released by chewing and are intended to be used for local treatment of mouth diseases or systemic delivery after absorption through the buccal mucosa⁵. Medicated chewing gums are formulated to release the majority of their active ingredient after 20-30 minutes, but factors such as intensity of chewing and quantity of saliva produced will influence this release and the absorption from the buccal cavity.

During the chewing process, the drug contained in the gum product is released from the mass in to saliva and it could be absorbed through the oral mucosa or swallowed reaching the stomach for gastro-intestinal absorption⁶. Thus, two absorption pathways are possible to introduce the active ingredient, giving rise to a systemic effect. Drug absorbed directly, via the buccal membrane, avoids metabolism in the gastro-intestinal tract and the first pass effect of the liver, therefore it might be possible to administer a reduced dose in chewing gum compared to other oral delivery systems. Alternatively, drug released from medicated chewing gum which is not absorbed through the oral cavity membranes, will be swallowed and reach the stomach in a diluted or very dispersed form, thus being very easily available with a consequent faster on set of action. Buccal mucosa offers excellent possibilities for the delivery of suitable drugs which undergo extensive first pass metabolism⁶.

Nicorandil, a drug approved for the treatment of ischemic heartdisease, is believed to have dual properties. The intrinsicmechanism of the drug (selective activation of K⁺_ATP channelsat the sarcolemmal and mitochondrial level) allows coronaryand peripheral vasodilatation with subsequent reduction of preloadand after load. Secondly, because of the role K⁺_ATPchannels inischemic preconditioning, Nicorandil has been attributed cardio protectiveeffects⁷.

The drug has been available in Europe for years, classifiedas a new class of therapy for coronary artery disease, but failedtill now to truly penetrate on the ‘European market’.The large scaled, randomized IONA trial evaluated the efficacyof Nicorandil on top of ‘conventional’ antianginaldrugs for the treatment of stable angina pectoris⁸.

MATERIALS AND METHODS:

MATERIALS:

Nicorandil was obtained as a gift sample from Mehta pharmaceuticals, Mumbai. Pharmagum from SPI Pharma, Bangalore. Sucralose and Aerosil were given gift sample from Strides arcolab, Bangalore. Sorbitol and Vanillin were obtained from SD Fine chemicals Ltd. Mumbai. All other reagents and solvents used were of pharmaceutical or analytical grade.

METHODS:

All the ingredients were passed through sieve no.16; the sifted ingredients were weighed accurately as per the formula and kept aside. First the flavor, color and aerosil were mixed thoroughly and kept aside. The drug and pharmagum M were mixed with sorbitol. To this mixture the flavor and aerosil were added. Finally to this the weighed quantities of magnesium stearate and talc were added. The mixture was then regranulated by passing through sieve no. 16/22. 1grams of the granules were weighed and then compressed using a 14mm punch in rotary tablet punching machine.

Determination of pre compression characteristics

Evaluation of granules:

The angle of repose was measured by using funnel method¹⁰ which indicates the flow ability of the granules. Loose bulk density (LBD) and tapped bulk density (TBD)¹¹ were measured using the formula: LBD= weight of the powder/volume of the packing. TBD= weight of the powder/tapped volume of the packing. Compressibility index¹² of the granules was determined by using the formula: CI (%) = [(TBD-LBD/TBD)] ×100.The physical properties of granules were shown in Table 2.

Determination of post compression characteristics

Evaluation of tablets:

All prepared tablets were evaluated for its uniformity of weight, hardness, friability and thickness according to official methods¹³shown in Table 4 and Table 5.

Procedure for estimation of drug content:

The test cell was filled with 50ml of simulated salivary fluid. The chewing gum was placed in the equipment and the instrument was operated for a period of 60 mins at a chewing frequency of 56 strokes/ min, to ensure total release of the drug from the formulation in the simulated salivary fluid. From the dissolution medium 5 ml was withdrawn and volume was made up to 25ml with SSF and the absorbance of the resulting solution was read at 262nm.The amount of drug present in the formulation is calculated using the following equation.

Abs. 25 50

Drug Content= ------- X ----- X ---------

Slope 5 1000

Estimation of Drug Content:

Chewing gums unlike tablets cannot be assayed by the conventional method that is by crushing the tablet and weighing an accurate amount of medicament and estimating its content. For estimation of the drug content in chewing gums and for the study of drug release process from chewing gums a new apparatus (Erweka’s DRT 6 Chewing apparatus) has been designed which mimics the natural chewing actions¹⁴. (Fig.1)

Fig 1: Schematic representation of Erweka’s DRT 6 Chewing apparatus

Table 1: Formulation of Nicorandil Chewing Gum

INGREDIENTS

PHARMAGUM-M

NICORANDIL

AEROSIL

FLAVOR

SUCRALOSE

SORBITOL

MG STEARATE

TALC

78%

0.266%

0.5%

0.6%

1.5%

16.57%

0.2%

2.364%

80%

0.266%

0.5%

0.6%

1.5%

14.57%

0.2%

2.364%

82%

0.266%

0.5%

0.6%

1.5%

12.57%

0.2%

2.364%

84%

0.266%

0.5%

0.6%

1.5%

10.57%

0.2%

2.364%

86%

0.266%

0.5%

0.6%

1.5%

8.57%

0.2%

2.364%

88%

0.266%

0.5%

0.6%

1.5%

6.57%

0.2%

2.364%

90%

0.266%

0.5%

0.6%

1.5%

4.57%

0.2%

2.364%

92%

0.266%

0.5%

0.6%

1.5%

2.57%

0.2%

2.364%

In vitro drug release from the formulation:

In vitro drug release from the formulation was carried out by using Apparatus Erweka’s DRT 6 Chewing apparatus^15,16. Dissolution medium used is simulated salivary fluid pH- 6.6 at temperature 37± 0.5°C. Chewing frequency is 56 strokes min^-1. 5mlof sample is withdrawn for every 5 min and measured at 262 nm using Double beam UV Spctrophoto-meter, Labindia UV 3000⁺, Mumbai. (Fig.2)

Fig 2: Schematic diagram of the chewing chamber of in vitro chewing apparatus used

Buccal Absorption studies

100mg of the Nicorandil was dissolved in 100ml of Simulated Salivary Fluid to prepare 1mg/ml concentration solution. This is the primary stock solution. Sample preparation: 5ml of 1mg/ml solution of Nicorandil was swirled in the buccal cavity for one minute and then expelled into the beaker and check the volume of it. From this take1ml solution was dilute to 50ml using phosphate SSF to get a concentration of 20mcg/ml. The absorbance of the sample solution was read at 262 nm (n=2) ¹⁷.

Fourier Transform Infrared Spectroscopy (FTIR):

FTIR spectroscopy was used to study drug-polymer compatibility. The spectra were recorded for pure drug and drug-polymer mixtures using FTIR spectrophotometer (FTIR-8400 S, Shimadzu, Japan) with KBr pellets. The scanning range was 500-4000cm^-1.

Pre-compression characteristics:

Table 2: Pre compression characteristics of formulations F1 to F8 of Nicorandil chewing gum.

Batch no	Angle of repose (θ) (±SD)	LBD (gm/ml) (±SD)	TBD (gm/ml) (±SD)	Carr’s index (%) (±SD)
F1	24.50 ± 0.22	0.64 ± 0.04	0.78 ± 0.03	11.82 ± 0.03
F2	25.96 ± 1.03	0.68 ± 0.02	0.78 ± 0.04	12.28 ± 0.02
F3	26.18 ± 0.92	0.76 ± 0.05	0.86 ± 0.01	11.17 ± 0.05
F4	26.47 ± 1.02	0.77 ± 0.01	0.85 ± 0.02	10.48 ± 0.04
F5	26.88 ± 0.60	0.81 ± 0.04	0.90 ± 0.03	10.00 ± 0.02
F6	27.22 ± 0.59	0.84 ± 0.03	0.94 ± 0.05	10.06 ± 0.05
F7	28.82 ± 0.65	0.86 ± 0.05	0.95 ± 0.02	9.47 ± 0.05
F8	29.85 ± 0.82	0.85 ± 0.04	0.93 ± 0.05	8.60 ± 0.03

* All values are the mean of five readings ± SD

Kinetic Analysis of In vitro Drug Release Rates of Nicorandil chewing gum.

To know the mechanism of drug release from these formulations, the data were treated according to first order (log cumulative percentage of drug remaining V_S time), Higuchi’s (cumulative percentage of drug released V_Ssquare root of time), and Korsmeyer’s (log cumulative percentage of drug released V_S log time) equations along with zero order (cumulative amount of drug released V_S time) pattern.

RESULTS AND DISSCUSSION:

In the present study an attempt was made to formulate medicated chewing gum containing nicorandil using Pharmagum M as the gum base. Various formulations were analyzed for different parameters like FTIR spectroscopy, Drug content estimation, In vitro drug release profile and Model fitting studies.

In order to determine possible interaction between the drug, gum base and other ingredients used in the formulation, compatibility studies were conducted using FTIR spectroscopy. As per the Fig 5-8, there was no significant shift in the positions of the wave numbers when compared to that of the pure drug values. Thus there was no interaction between the drug and other excipients of the formulation.

As the formulation is intended to be used in the buccal cavity, buccal absorption study of the drug was conducted. The results are given in Table 4. The study showed that nicorandil has a buccal absorption of about 18.54 -18.88 %.

Different formulations were prepared and before punching of the powder mass into tablets different pre compression characteristics of the powders was studied namely Angle of repose, loose bulk density, tapped bulk density and Carr’s compressibility Index. The results of the mentioned tests are given in the Table2. The results of angle of repose and compressibility index (%) ranged from (24.50° ± 0.22 to 29.85° ± 0.82) and (10.00 ± 0.02 to 12.28 ± 0.02), respectively. The results of loose bulk density and tapped bulk density ranged from (0.64 ± 0.04 to 0.86 ± 0.05) and (0.78 ± 0.03 to 0.95 ± 0.02), respectively. The results are shown in Table 2.

After compression, different post compression parameters like Hardness, Friability, Weight variation and thickness of the formulations were determined. The results are mentioned in Table 3.

Post-compression characteristics:

Table 3: Nicorandil chewing gum properties of formulations F1 to F8.

Batch no	Hardness kg/cm²) (±SD)	Weight variation (g) (±SD)	Friability (%) (±SD)	Thickness (mm) (±SD)	Assay value(mg) (±SD)
F1	5.5 ± 0.20	1.895 ± 0.03	0.53 ± 0.10	5.36 ± 0.06	3.97 ± 1.35
F2	5.0 ± 0.14	2.876 ± 0.04	0.52 ± 0.06	5.01 ± 0.08	3.9757 ± 1.12
F3	5.0 ± 0.23	2.987 ± 0.02	0.53 ± 0.10	5.11 ± 0.04	3.9731 ± 1.01
F4	5.8 ± 0.25	2.167 ± 0.03	0.50 ± 0.06	5.04 ± 0.02	3.9673 ± 1.57
F5	6.2 ± 0.16	3.125 ± 0.04	0.46 ± 0.30	5.14 ± 0.06	3.986 ± 0.74
F6	6.2 ± 0.24	1.541 ± 0.03	0.45 ± 0.70	4.93 ± 0.03	3.9794 ± 1.19
F7	6.3 ± 0.19	2.987 ± 0.05	0.40 ± 0.50	5.03 ± 0.04	3.9742 ± 1.23
F8	6.7 ± 0.23	2.689 ± 0.03	0.41 ± 0.20	5.13 ± 0.06	3.9635 ± 1.36

* All values are the mean of five readings ± SD

The hardness was maintained between 5.5 to 6 kg/cm², resulting friability in the range of 0.40 to 0.53%. The weight variation was in the range of 1.541 ± 0.03 to 3.125 ± 0.04. The thickness of all the formulation was in the range of 4.93 to 5.36mm.

Table 4: Buccal absorption Studies of Nicorandil chewing gum.

Trial

Absorbance

Concentration

(µg)

Amount

Unabsorbed(mg)

Amount

Absorbed(mg)

% Drug Absorbed

0.3522

18.54

4.073

0.927

18.54

0.3587

18.88

4.056

0.944

18.88

The prepared formulation was analyzed for the drug content and it was found to be in the range of 3.9635 to 3.986mg of Nicorandil /chewing gum. The formulation with highest drug content was F5 with 3.986mg of Nicorandil /chewing gum and the formulation with lowest drug content was F8 with 3.963 mg of Nicorandil /chewing gum. The results are shown in Table 3.

The prepared formulations were analyzed for the in vitro drug release. The apparatus used was ‘Erweka’s DRT 6 Chewing apparatus’. The study was conducted for a period of 30 minutes using simulated salivary fluid as the dissolution medium. The chewing frequency of 56 strokes/minute was applied. The results of Cumulative drug release are given in Fig 3-4. Formulation F1 showed highest drug release of 98.611% at the end of 30 minutes and formulation F8 showed lowest drug release of 94.457% at the end of 30 minutes. The order of drug release of different formulations is as under F1>F2>F3>F4>F5>F6>F7>F8.

Fig 3: Drug release profile of F1 to F5 formulations of Nicorandil chewing gum.

Fig 4: Drug release profile of F6 to F8 formulation of Nicorandil chewing gum.

Fig 5: FT-IR spectra of pure drug Nicorandil.

Fig 6: FT-IR spectra of Pharmagum M

Table 5: Kinetic studies of the developed Nicorandil chewing gum.

Kinetic Profile of various formulations	For Zero order equation	For 1^storder equation	For Higuchi equation	For peppas Equation
Kinetic Profile of various formulations	Regression coefficient (R²)	Regression coefficient (R²)	Regression coefficient (R²)	Slope (n)	Regression coefficient (R²)
F1	0.952	0.821	0.971	0.605	0.996
F2	0.953	0.862	0.996	0.605	0.998
F3	0.954	0.900	0.998	0.620	0.998
F4	0.956	0.893	0.997	0.622	0.997
F5	0.957	0.903	0.998	0.631	0.998
F6	0.968	0.922	0.997	0.635	0.996
F7	0.962	0.876	0.995	0.660	0.997
F8	0.962	0.914	0.997	0.643	0.998

Fig 7: FT-IR Spectra of Mixture of Nicorandil + Pharmagum

Fig 8: FT-IR Spectra of final blend.

The formulations were analyzed to determine the model which best suites their drug release pattern. The regression coefficients obtained for first order kinetics were found to be (R²: 0.821 to 0.922), and with those of zero order kinetics (R²: 0.952 to 0.968), indicating that drug released from all formulation followed mixed zero order (Table 6). To evaluate drug release mechanism from the matrix tablets, plots of cumulative percentage release V_S square root of time as per Higuchi’s equation were constructed. These plots were found to be linear with all the formulations (R²: 0.971 to 0.997) indicating that the drug release from the Chewing gum was diffusion controlled. To confirm the diffusion mechanism the data were fit into korsmeyer et al’s equation. All the formulation shows good linearity (R²: 0.996 to 0.998), with the slope (n) values 0.605 to 0.660, indicating release mechanism was anomalous non-Fickian or anomalous release (0.45 < n < 0.89).

Stability studies revealed that there was no significant change in drug content and dissolution profile of chewing gum. FTIR studies revealed that there was no shift in peaks, indicating there is no interaction between Nicorandil and other ingredients used.

CONCLUSION:

Prepared formulations are evaluated for different parameters like hardness, friability, assay and in vitro drug release behavior. The analysis of release pattern was studied with the help of different pharmacokinetic models in order to determine the model which best suites the formulation’s release pattern. Among the formulations studied F4, F5 and F6 were found to have the drug release to a higher extent compared to others and at the same time they maintain their chewing gum like consistency. From this study it can be concluded that it is possible to design medicated chewing gum containing nicorandil, mainly for the treatment of angina and related conditions, where efficacy and patient compliance are of prime importance.

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Received on 22.03.2010

Accepted on 25.05.2010

Research Journal of Pharmaceutical Dosage Forms and Technology. 2(4): July-August 2010, 301-306