Formulation and Evaluation of Isradipine Buccal Tablets

 

Vijaya Kumar Bontha¹*, Buchi Babu Pabbu¹, Garrepally Prasad¹, Shashi Ravi Suman Rudrangi², Swathi Chilukala¹, Samatha Rudrangi³

[1]Department of Pharmaceutics, Jangaon Institute of Pharmaceutical Sciences, Kakatiya University,

Yeshwanthapur, Jangaon-506167, Andhra Pradesh, India

2Department of Pharmaceutical Sciences, School of Science, University of Greenwich, Chatham Maritime,

Kent, United Kingdom ME4 4TB

³Department of Pharmaceutics, Talla Padmavathi College of Pharmacy, Kakatiya University, Urus,

Kareemabad-506002, Andhra Pradesh, India

 

ABSTRACT:

The aim of this study was to develop effective bioadhesive buccal tablets of Isradipine. Isradipine is a dihydropyridine-class calcium channel antagonist. It binds to calcium channels with high affinity and specificity and inhibits calcium flux into cardiac and smooth muscle. It was selected as a model drug due to its extensive first-pass metabolism and low oral bioavailability (15-24%). Buccal tablets of Isradipine were prepared by direct compression method using bioadhesive polymers Carbopol 934P, Sodium alginate, Methocel K4M, and Hydroxy ethyl cellulose in various combinations and concentrations. The prepared tablets were evaluated by various parameters like weight variation, hardness, thickness uniformity, surface pH, swelling studies and Ex-vivo bioadhesive strength. The tablets were evaluated for in vitro release in pH 6.8 phosphate buffer for 8 hr in USP XXIV standard dissolution apparatus. In order to determine the mode of release, the data was subjected to Korsmeyer-Peppas diffusion model. The optimized formulations followed non-fickian release mechanism. The formulations F10, F14 and F18 exhibited good controlled release profile when compared with other formulations. FTIR spectral studies showed that there were no interactions between the drug and excipients. The present study concludes that buccal delivery of Isradipine tablets can be good way to bypass the first pass metabolism.  Further the efficacy of the developed formulations has to be assessed by pharmacokinetic studies in humans.

 

 

INTRODUCTION:

Oral route is possibly the most preferred route of drug delivery to the patient and the clinician alike. Nevertheless, the peroral administration of drugs has its own disadvantages like hepatic first pass metabolism and enzymatic degradation within the GI tract. As a result other absorptive mucosae are considered as potential sites for drug administration.¹

 

Buccal mucosa is richly vascularised and more accessible for the administration and removal of a dosage form. Buccal drug delivery involves the administration of drug via the buccal mucosa (the lining of cheek) to the systemic circulation via internal jugular vein. ^2-4Harsh environmental factors that exist in oral delivery of a drug are circumvented by buccal delivery.

 

Buccal delivery offers various advantages over peroral administration for systemic drug delivery.  It avoids acid hydrolysis in the gastrointestinal (GI) tract and bypassing the first-pass effect, and, depending on the particular drug, a better enzymatic flora for drug absorption.^{3, 5}

 

Isradipine is a water insoluble calcium channel blocker approved for the treatment of angina pectoris and hypertension. It undergoes significant first-pass metabolism and low oral bio-availability (15-24%).⁶The fast releasing buccal drug delivery systems release the drug without delay and produce immediate relief. The immediate release of drug can be achieved by preparing the buccal dosage form. Buccal delivery of Isradipine bypasses hepatic first pass metabolism and is expected to produce the similar effect (as that of oral route) at lower doses.^{7, 8}

 

MATERIALS:

Isradipine was received as gift sample from Matrix Laboratories Limited (Hyderabad, India). Hydroxy propyl methyl cellulose and hydroxy ethyl cellulose were generously gifted by Aurobindo Pharma limited (Hyderabad, India). Carbopol, sodium alginate, lactose, magnesium stearate and talc were purchased from SD Fine Chemicals (Mumbai, India). All the polymers received were of pharmaceutical grade and were used as received. Other materials and solvents used were of analytical grade.

 

METHODOLOGY:

1. Characterization of Isradipine:

UV spectroscopic study (Determination of l max): ⁹

Preparation of phosphate buffer pH 6.8: 

Accurately measured 50 ml of 0.2 M Potassium dihydrogen phosphate was taken in a 200 ml volumetric flask and 22.4 ml of 0.2 M NaOH was added to that, and then water was added to make up the volume.

 

Preparation of stock solution:

100 mg of Isradipine was accurately weighed and transferred to a 100 ml volumetric flask. It was dissolved in sufficient amount of phosphate buffer pH 6.8 and volume was made upto 100ml with distilled water. Exactly 4 ml of the stock solution was pipetted out and was diluted to 100ml with distilled water. The resulting solution was 40 mg/ml. The spectrum was recorded in the range of 200-400 nm. The wavelength of maximum absorption was found to be 332 nm.

 

Preparation of standard solution of Isradipine:

A standard solution was prepared by dissolving 100 mg of Isradipine in 100ml of phosphate buffer pH 6.8 It was further diluted with phosphate buffer pH 6.8 to get the solutions in the concentration range of 5,10,15,…..40 mg/ml. The absorbance values were determined at 332 nm. A graph of absorbance Vs concentration was plotted from the data.

 

2. Preformulation Studies

Preparation of Powder Blends:

All the ingredients were weighed accurately and passed through sieve no.100. Then all the ingredients were mixed according to decreasing order of their weight. The prepared powder blend was subjected to various parameters as follows.

 

 

Evaluation of Powder Blends:

The Preformulation studies of the powder blends of drug, polymer, lactose and other excipients were done by calculating Bulk density, Tapped density, Angle of repose and Carr’s index (% compressibility). ^10-13

 

3. Formulation of Bioadhesive Tablets 

Formulation of Preliminary Batches:  

To study the release pattern of Isradipine from each polymer the preliminary batches of Isradipine were prepared by using Sodium alginate, carbopol 934p, HEC, HPMC at different ratio. The bioadhesive tablets were prepared with selected polymers by direct compression on 8 station tablet compression machine using 10 mm punch. Accurately weighed quantities of drug and other ingredients viz. Sodium alginate, carbopol 934p, HEC, HPMC K4M, Lactose, and Magnesium stearate were mixed by triturating in a glass mortar-pestle. The blend was directly compressed at weight of 150 mg using flat-faced 10 mm diameter punch. The compositions of the formulation batches containing different polymers in various ratios are specified in Table 1 the on trial and error basis.

 

The evaluation of tablets was done according to procedures given in the standard books mention below:

To achieve objective of the work i.e. to produce fast onset of action and to enable patient terminate the therapy tablet must release the drug fast and it must be intact i.e. it should not undergo erosion for sufficient period of time (4-8 hour) to terminate therapy. But the formulation containing only one polymer should not achieve the both objectives. Formulation containing HEC release the drug fast but tablet undergoes erosion and the formulation containing CP 934 P intact for sufficient time but they extend the release of drug. Therefore to achieve objective combination of two or more polymer should be prepared. Therefore again 12 formulations were prepared and the evaluation was done as similar of previous batches.

 

Formulation of Mucoadhesive Tablets containing combination of polymers: 

To achieve the objective of the work i.e. to produce quick onset of action and to enable patient to terminate the therapy, tablet must release the drug quickly and it must be intact during the therapy and hence the formulations containing combination of the polymers were prepared. Table 2 shows the formulations containing combination of polymers.

 

Table 1: The composition of formulation containing drug to polymer ratio (1:1and 1:2)

Ingredients	Formulations
	F1	F2	F3	F4	F5	F6	F7	F8
Drug (mg)	10	10	10	10	10	10	10	10
Carbopol 934p (mg)	10	20	-	-	-	-	-	-
Na.alginate (mg)	-	-	10	20	-	-	-	-
HPMC K4M (mg)	-	-	-	-	10	20	-	-
HEC (mg)	-	-	-	-	-	-	10	20
Lactose (mg)	126	116	126	116	126	116	126	116
Mag. Stearate %	2	2	2	2	2	2	2	2
Talc %	2	2	2	2	2	2	2	2

Table 2: The formulations containing combination of polymers

Ingredients	Formulations
	F9	F10	F11	F12	F13	F14	F15	F16	F17	F18	F19	F20
Drug (mg)	10	10	10	10	10	10	10	10	10	10	10	10
Carbopol 934p (mg)	30	30	30	30	30	30	30	30	-	-	-	-
Na.alginate (mg)	-	-	-	-	-	-	-	-	30	30	30	30
HPMC K4M (mg)	10	20	30	40	-	-	-	-	10	20	30	40
HEC (mg)	-	-	-	-	10	20	30	40	-	-	-	-
Lactose (mg)	96	86	76	66	96	86	76	66	96	86	76	66
Mag. Stearate (mg)	2	2	2	2	2	2	2	2	2	2	2	2
Talc (mg)	2	2	2	2	2	2	2	2	2	2	2	2

 

Evaluation of Tablets: ^14-16

The formulated tablets were evaluated for Thickness, Hardness, Weight variation, Friability, Surface pH, Swelling index, Bioadhesion strength and in-vitro drug release and average values were calculated.

 

Ex-vivo mucoadhesion studies:

Porcine buccal mucosa was used as the model membrane. It was obtained from slaughterhouse. The underlying buccal tissues were separated and washed thoroughly with phosphate buffer solution pH 6.8.

 

Fabrication of the test assembly:

For in-vitro study, an apparatus was designed for determination of mucoadhesive force. The working of balance formed the basis of the fabricated mucoadhesion test apparatus. The glass vial was fixed to one side of the balance. The Porcine buccal mucosa was tied to this glass vial. The other glass vial was attached to the base of the balance within the bigger size bottle which is filled with phosphate buffer pH 6.8 to maintain the mucosa in moist condition during the study. The balance was balanced at this position by placing weight to the right side pan. The tablet was moistening in the phosphate buffer pH 6.8 and it was placed in between this two vials and press by finger slightly to stuck tablet to the buccal mucosa Then water was added into the right side pan containing beaker from the burette at a constant rate of 100 drops per minute.

 

Measurement of adhesion force: The tablet to be tested was stuck on the mucosal surface. A preload of 50 g was placed on the clamp for 5 minutes (preload time) to establish adhesion bonding between tablet and mucosa. The preload and preload time were kept constant for all the formulations. After completion of the preload time, preload was removed, and water was then added into the beaker from the burette at a constant rate of 100 drops per minute. The addition of water was stopped when tablet was detached from the porcine buccal mucosa. The weight of water required to detach an Isradipine tablet from buccal mucosa was noted as Mucoadhesion strength, and these experiments were repeated with fresh mucosa in an identical manner (three tablets) ^{17, 18, 19}

 

In-vitro drug release studies:

Standard USP dissolution apparatus was used to study the in-vitro release profiles using rotating paddle method. In-vitro release study of buccoadhesive tablets of Isradipine was carried out using USP type II apparatus (Paddle method) at 100 rpm. To study the drug release from only one side of tablets, the glasses were used. For this purpose, keep the melted wax on the each glass, and before solidification, the tablet was placed in the semisolid wax so that drug could be released only from upper face of tablet. Medium used for the release rate study was 900 ml phosphate buffer solution pH 6.8. During the course of study the assembly was maintained at 37 ± 0.2^oC. The sample was withdrawn; 5 ml at time interval of 30 minutes, 1, 2, upto 8 hours and replaced with 5 ml of fresh dissolution method. The amount of drug released was determined spectrophotometrically at 332 nm.

 

Fourier transform infrared (FTIR) spectroscopy:

The FTIR samples (Isradipine, and optimized formulations) were obtained, using Perkin Elmer FTIR system Spectrum BX series (Beaconsfield, Buckinghamshire, UK), in the frequency range of 4000–550 cm^-1 at 4 cm^-1 resolution. The technique used very small amount of each sample which directly loaded into the system. Spectrum BX series software version 2.19 was used to determine peak positions.

 

RESULTS AND DISCUSSIONS:

1.       UV Spectral Analysis of Isradipine

 

Figure 1: UV spectra of Isradipine in phosphate buffer pH 6.8

 

The UV spectrum of Isradipine (Fig 1) indicates the value for λ_max as 332 nm. in phosphate buffer pH 6.8 Isradipine exhibited  λ_max value in phosphate buffer pH 6.8 Hence, phosphate buffer pH 6.8 can be used as dissolution medium for its estimation.

1.1 Preparation of Standard Curve:                      

Table 3: Calibration curve of Isradipine in phosphate buffer pH 6.8

Sr. No.	Concentration (µg/ml)	Absorbance
1.	0	0
2	5	0.127
3.	10	0.245
4.	15	0.358
5.	20	0.476
6.	25	0.594
7.	30	0.705
8.	35	0.822
9	40	0.947

 

Isradipine showed maximum absorption at wavelength 332 nm in phosphate buffer pH 6.8. An absorbance Vs. Concentration graph was plotted. Table 3 displays the absorbance and concentration values.  Calibration curve (Fig 2) was done by taking absorption of diluted stock solutions at wavelength 332 nm.

 

2.  Evaluations of Buccoadhesive Tablets

2.1. For Powder blend: The physical parameters of the powder blends for the formulation F1-F20 were shown in the Table 4.

 

 

Table 4: Physical parameters of powder blend for F1-F20

Formulations	Angle of Repose(0)	Bulk Density(g/ml)* (± SD)	Tapped Density(g/ml)* (± SD)	Carr’s Index
F1	27.25	0.591±0.03	0.721±0.04	18.03
F2	28.12	0.685±0.02	0.873±0.04	21.53
F3	28.36	0.778±0.05	0.898±0.03	13.36
F4	29.46	0.998±0.03	1.108±0.04	13.46
F5	30.06	0.678±0.02	0.789±0.03	14.06
F6	29.45	0.781±0.04	0.898±0.04	13.02
F7	26.52	0.864±0.09	0.103±0.03	13.33
F8	29.76	0.961±0.01	1.108±0.09	13.26
F9	28.8	0.61±0.02	0.70±0.04	12.51
F10	28.1	0.66±0.01	0.80±0.05	12.69
F11	28.36	0.63±0.02	0.73±0.07	13.69
F12	29.46	0.61±0.07	0.73±0.03	17.56
F13	24.5	0.65±0.04	0.70±0.09	6.69
F14	23.8	0.67±0.02	0.70±0.06	6.33
F15	24.3	0.71±0.01	0.75±0.04	5.48
F16	22.4	0.61±0.06	0.70±0.03	5.94
F17	27.25	0.63±0.04	0.74±0.02	14.86
F18	28.12	0.65±0.05	0.76±0.04	14.48
F19	28.5	0.70±0.06	0.85±0.06	17.37
F20	28.5	0.70±0.09	0.86±0.04	17.85

 * n=3

 

2. 2. For Buccoadhesive Tablets

2.2.1. Physical parameters of buccoadhesive tablets:

Table 5: Physical parameters of buccoadhesive tablet

*n=3 and for avg. weight n=20

 

Figure 2: Calibration curve of Isradipine in phosphate buffer pH 6.8

 

The physical parameters of the buccal tablets for the formulation F1-F20 were shown in the Table 5.Diameter of all tablets were found to be 10.120.02 mm. The formulations containing Carbopol 934p was found to be thicker than other formulations. The thickness of all the formulations was found to be in the range of 2.65 – 2.80 mm. All the formulations show the hardness in the range of 3 – 4.6 kg/cm². Maximum hardness found in formulation containing Carbopol 934p and minimum with Sodium alginate. All the formulations also complies the test for weight variation. The % friability shown by all the formulations was found to be in the range of 0.70-0.85. Friability for all the formulation shown less than 0.90% which is in the acceptable limits which indicates formulations have good mechanical strength.

.

2.2.2 Uniformity of Content:

All the formulations complies the test for uniformity of content as it found to be within the limit of 97%-101%. The results of content uniformity (Table 6) shows all the formulations comply with those prescribed in the Indian pharmacopeia

 

Table 6: Uniformity of content for buccoadhesive tablet

  * n=10

 

Table 7 depicts the swelling studies of the tablets. The rate and extent of swelling increased with an increasing concentration of polymer in the formulation. The formulation F2 containing Carbopol 934p shows the highest swelling rate it is hydrophilic in nature and absorbs solution rapidly.  The maximum swelling was attained at the 5 to 6 hrs after that tablet starts to erode slowly. All the formulations were eroded within 6 hours except F2 formulation. The formulations F9 to F12 containing combination of Carbopol 934p and HPMC K4M as both the polymers are hydrophilic in nature and absorb solution rapidly.  The maximum swelling was attained at the 5 to 6 hrs after that tablet starts to erode slowly.  The maximum swelling index was observed in formulation F13 to F16 containing Carbopol 934p and HEC shows the high swelling index value and the formulation loses its shape slightly due to erosion of HEC.  The maximum swelling was attained at the 4 to 6 hrs after that tablet starts to erode slowly. The formulations F17 to F20 containing combination of sodium alginate and HPMC K4M as both the polymers are hydrophilic in nature and absorb solution rapidly.  The maximum swelling was attained at the 5 to 6 hrs after that tablet starts to erode slowly.

 

2.2.3. Swelling Studies

Table 7: Swelling studies of the formulations

Formulation	Time (hours)
	0	1/2	1	2	3	4	5	6	7	8
F1	0	53.37	84.28	102.26	128.2	147.56	150.3	-	-	-
F2	0	75.49	122.37	149.39	181.3	219.49	228.4	227.3	224.3	222.4
F3	0	66.83	93.86	107.76	113.8	113.40	-	-	-	-
F4	0	87.66	111.94	134.17	149.6	149.16	-	-	-	-
F5	0	65.43	68.78	66.87	64.89	-	-	-	-	-
F6	0	85.13	98.54	125.78	127.5	126.4	123.5	-	-	-
F7	0	47.58	99.55	145.46	169.8	178.96	-	-	-	-
F8	0	78.63	91.33	104.16	126.2	154.16	156.6	156.8	-	-
F9	0	23.3	52	78.7	99.3	118	124.6	85.3	75.3	62.6
F10	0	30.1	42.6	79.3	113.3	120.1	133.3	140.1	156.6	160.1
F11	0	30.1	56.6	73.3	111.3	127.3	143.3	153.3	164	168.6
F12	0	34.6	50.6	76.6	114.1	123.3	143.3	166.6	192.6	203.3
F13	0	26.6	48.1	93.3	146.6	300.1	246.6	218.1	200.6	183.3
F14	0	63.3	93.3	113.3	150.1	197.3	233.3	217.3	166.6	149.3
F15	0	43.3	53.3	99.3	126.1	186.1	216.6	242.6	262.6	275.3
F16	0	48.1	63.3	102.6	128.6	141.3	160.1	237.3	259.3	324.3
F17	0	63.3	93.3	106.6	146.6	176.1	160.1	141.3	140.1	124.6
F18	0	54.6	86.1	102.6	134.1	153.3	166.1	200.1	176.1	163.3
F19	0	54.1	78.1	119.3	138.6	158.6	154.1	186.6	194.6	200.1
F20	0	52.6	100.6	118.1	134.1	160.6	167.3	176.1	186.1	206.6

Table 8: Effects of polymers on Mucoadhesive strength, Mucoadhesive force and Mucoadhesion time

* ⁿ⁼³

 

2.2.4 Bioadhesion studies and Mucoadhesion time of tablets

The values of the mucoadhesive strength of buccal tablets are given in table 8. It was observed that bioadhesive force was decreased in polymers according to following order Carbopol 934p > sodium alginate > HEC > HPMC K4 M.

 

The values of the mucoadhesive strength of isradipine buccal tablets are given in table 8. The bioadhesive characters were found to be affected by the nature and proportions of the bioadhesive polymers used in the formulations. In all the formulations, as the polymer mixture concentration increased, the mucoadhesion was increased. The results obtained from the bioadhesion study shows that the formulation F9 to F12 containing Carbopol  934p and HPMC K4M shows the required bioadhesion force and mucoadhesion time . This might be due to ionization of  Carbopol 934p at salivary pH which leads to improved attachment of the device to mucosal surface.  The formulations F13 to F16 containing Carbopol 934p with the combination of other polymers HEC shows the maximum bioadhesive force and mucoadhesion time. The formulations F17 to F20 exhibit the decrease in adhesion force than other formulations as using another polymer such as Na. alginate.

 

The high bioadhesive strength of carbopol 934P may be due to the formation of secondary bioadhesion bonds with mucin and interpenetration of polymeric chains in the interfacial region, while the other polymers like sodium alginate undergo superficial bioadhesion The bioadhesion force and mucoadhesion time of formulations containing different polymer were decreased in the following order of polymer used. Carbopol 934p > Na. Alginate.  Bioadhesive strength exhibited by the optimize tablets can be considered satisfactory for maintaining them in the oral cavity for 8 hrs.

 

2.2.5. In-vitro Drug Release Study

Four different polymers-Carbopol 934p, sodium alginate, HEC, HPMC K4M were selected and dosage forms were prepared and their individual drug release profiles were evaluated. It was observed that as the percentage of polymer increased, the amount of drug released was decreased. This may be structural reorganization of hydrophilic polymer. When the polymer is exposed to aqueous medium, it undergoes hydration and chain relaxation to form viscous gelatinous layer. The thick viscous gel layer hinders the drug diffusion into aqueous medium. In vitro dissolution study of formulations F1 to F8 was done. All were failed in extending the release of drug, formulations were undergoes to erosion rapidly. However formulation F2 exhibited the extended drug release i.e. 99.60% after 7 hour.

 

Increase in concentration of HPMC K4M might result in increase in gel strength of the polymer. The thick viscous gel layer hinders the release of Isradipine from buccoadhesive tablets. The drug release was governed by the amount of matrix forming polymers.

 

F9 to F12 were prepared with carbopol 934p and HPMC K4M.  F9 released the drug completely within 6 hours. The percent of drug release from formulations F10, F11 and F12 was 101.82%, 94.16%, 88.82 % in 8 h respectively; this was considered due to different polymer concentrations in all the four formulations. In polymer mixture of all formulations HPMC K4M concentration was used increasingly from F9 to F12, where as concentrations carbopol 934p were maintained constantly in formulations F9 to F12, respectively. Among the F9 to F12, F10 exhibited the desired drug release within 8hrs.

 

The F13 to F17 formulations were prepared with carbopol 934p and HEC. F13 released the drug completely (100%) within 6 hours.  The percent drug release from formulations F14, F15, F16 was found to be 101.2%, 98.6% and 93.9 %in 8 h respectively. F14 obtained the desired drug release profile and In-vivo Mucoadhesion time.

 

Formulations F17 to F20 containing sodium alginate and HPMC K4M ,the percentage of drug release from formulations F18,F19 and F20 was 101.8%,101.8% and 91.28%  in 8h respectively. Formulation F17 unable to sustain the drug release for desired period of time, it releases the 100.89% within the 6 hrs. From the %drug release profiles of all the formulations, the F18 shows the desired drug release (101.82%) within 8 hrs. The cumulative drug release profiles of the formulations were shown in the tables 9-12.

 

 

 

 

 

Optimized formulations

The optimized formulation are F10 with  Carbapol 934p and HPMCK4M was showing better results ,F14 containing the Carbapol 934p and HEC,F18 containing the sodium alginate and HPMCK4M.

 

Drug release mechanism

The mechanism of release for the optimized formulations (Fig 3-Fig 8) was determined by fitting dissolution data in to different kinetic models viz. Zero-order, First-order, Higuchi, and Korsmeyer-Peppas corresponding to the release data of formulations. For most of the formulations the R² value of Korsmeyer-Peppas and Higuchi model is very near to 1 than the R² values of other kinetic models.  Thus it can be said that the drug release follows Korsmeyer-Peppas and Higuchi model mechanism.

 

 

Table 9: Cumulative % drug release of preliminary batches buccoadhesive tablets

Time	Formulations
	F1	F2	F3	F4	F5	F6	F7	F8
1	54.669	45.32	63.81	53.81	64.75	55.044	55.87	43.37
2	72.136	57.13	74.07	60.86	78.13	63.818	83.24	65.24
3	83.871	67.75	87.22	68.75	86.40	74.073	99.46	78.94
4	99.134	74.61	98.93	77.17	99.14	87.220	-	99.44
5	-	80.29	-	87.70	-	98.938	-	-
6	-	89.90	-	98.17	-	-	-	-
7	-	99.60	-	-	-	-	-	-
8	-	-	-	-	-	-	-	-

 

Table 10: Cumulative % drug release from formulations F9 to F12

 

Table 11: Cumulative % drug release from formulations F13 to F16

Time	Formulation
	F13	F14	F15	F16
1	55.70 ± 0.23	52.430±1.21	45.352±1.63	38.41 ± 0.54
2	70.66 ± 0.59	60.090±0.56	53.721±0.23	43.68 ± 0.36
3	80.66 ± 0.67	69.840±0.31	64.033±0.56	48.88 ±  0.71
4	86.43 ± 0.59	78.749±0.36	73.667±0.68	52.75 ± 0.97
5	94.84 ± 0.54	86.809±0.59	79.818±0.61	67.95 ± 0.71
6	100.89 ±0.36	94.632±0.51	87.732±0.34	75.39 ± 0.48
7	-	98.952±0.75	94.164±0.54	86.40 ± 1.29
8	-	101.28 ±1.01	98.633±0.89	93.91 ± 0.23

 

Table 12: Cumulative % drug release from formulations F17 to F20

Time	Formulation
	F17	F18	F19	F20
1	55.70 ± 0.23	47.33 ± 1.63	44.38 ± 1.36	37.02 ±  2.84
2	70.66 ± 0.59	58.68 ± 1.48	52.91 ± 0.23	49.26 ±  0.36
3	80.66 ± 0.67	67.41 ± 2.34	63.99 ± 1.28	58.05 ±  1.28
4	94.84 ± 0.54	74.44 ± 1.07	70.79 ± 1.29	67.27 ±  1.51
5	100.89 ±0.36	81.18 ± 0.36	79.70 ± 0.23	73.50 ±  0.71
6	-	87. 70 ± 0.23	88.82 ± 0.48	81.18 ± 0.36
7	-	93.91 ± 0.23	95.70 ± 0.23	87. 70 ± 0.23
8	-	101.82 ± 0.48	101.82 ± 0.48	91.28 ±1.01

 

Figure  3: % Drug Release from  Formulations F1-F4	Figure  4: % Drug Release from Formulations F5-F8
Figure  5: % Drug released from formulations F13 to F16   Figure 7: % Drug released from formulations F17 to F20	Figure 6: % Drug released from formulations F9 to F12   Figure 8: Cumulative % drug release of optimized formulations

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 13: Mechanism of in vitro release

Fourier transform infrared (FTIR) spectroscopy studies:

The pure drug (Fig 9) and the optimized formulations F10, F14, F18 (Fig 10, 11 and 12 respectively) were subjected to FTIR studies. The results showed that there is no interaction between the drug and excipients.

 

 

Figure 9: FTIR of Isradipine pure drug

 

FTIR of optimized formulation F10

 

Figure 10: FTIR of optimized formulation F10

 

FTIR of optimized formulation F14

 

Figure 11: FTIR of optimized formulation F14

 

FTIR of optimized formulation F18

 

Figure 12: FTIR of optimized formulation F18

 

ACKNOWLEDGEMENTS:

We would like to express our deepest gratitude towards Prof. Stephen. R. Wicks, University of Greenwich, U.K., Prof. D. Rambhau and Prof. Shashank Apte, Natco Research Centre, Hyderabad for their noble guidance throughout the project.

 

CONCLUSION:

Buccal tablet of Isradipine can be formulated as an approach to avoid the first pass metabolism and thereby improve its bioavailability. Formulated tablets gave satisfactory results for various evaluation parameters like hardness, weight variation, content uniformity, swelling studies, mucoadhesion studies and in vitro drug release. The polymer combination of carbopol 934p and HPMC K4M, carbopol 934p and HEC, sodium alginate and HPMC K4M gave the satisfactory results in terms of drug release, mucoadhesive performance, physicochemical properties and surface pH. Formulations F10, F14 and F18 gave better controlled drug release in comparison to the other formulations. The drug release from above formulation followed zero order profile and the mechanism of drug release from floating tablets followed Non-Fickian diffusion. Drug–excipients interaction of optimized formulations was determined by using FTIR studies. In this analysis drug–excipients compatibility interactions were not observed.

 

REFERENCES:

1.    Pfister, W.R. and Ghosh, T.K., Intraoral Delivery Systems: An Overview, Current Status, and Future Trends. In: Swarbrick   J. Editor. Drug Delivery to the Oral Cavity Molecules to Market. CRC press: New York; 2005. p. 2-40

2.       Ketousetuo Kuotsu, A.K. Bandyopadhyay., Buccal Mucosa as a Route for Systemic Drug Delivery: A review. J. Pharm.    Phamaceut. Sci. 1998; 1: 15-30

3.       Shojaei  A. H., Buccal Mucosa as a route for Systemic Drug Delivery: A Review, J Pharm Pharm Sci., 1998, 1(1), 15-30

4.       Miller N.S., Johnston T. P., The use of mucoadhesive polymers in buccal drug delivery, Advanced Drug Delivery Reviews  2005, 57, 1666–1691

5.       Kok Khiang Peh and Choy Fun Wong. Polymeric films as vehicle forbuccal delivery: Swelling, mechanical, and bioadhesive properties. J Pharm Pharm Sci. 1999; 2, 2: 53-61

6.       Rathbone  M,  Drummond  B,  and  Tucker  I:  Oral  cavity  as  a  site for systemic drug delivery. Adv Drug Del Rev. 1994    3:1-22

7.       Williams AD  and  Lemke  LT:  Foye’s  Principles  of  Medicinal Chemistry. Fifth edition. Philadelphia. LippincottWilliams and Wilkins; 2002; p. 555

8.       Senel S, Kremer M, Nagy K and Squier C: Delivery of Bioactive Peptides and  Proteins  Across  Oral  (Buccal)  Mucosa   Current Pharm Biotech. 2001; 2:175-186

9.       Indian Pharmacopoeia, Controller of Publication, Delhi, Vol. I, 2007; 735-736

10.    United States of Pharmacopoeia XXIV NF 27, United States of Pharmacopoeial Convention, Rockville, 2007; 660-672

11.    Wells, J., Pharmaceutical preformulation: The physical properties of drug substances. In: Aulton, M.E., Pharmaceutics-The science of dosage form design, 2nd ed. Churchill Livingstone; 2002. p. 133-34

12.    Benker, G.S., Anderson, N.R., Tablets. In: Lachman, L., Lieberman, H.A., Kanig, J.L.. The theory and practice of       industrial pharmacy, 3rd ed. Varghese Publishing House; 1987. p. 297-299

13.    Sinko, P.J., Martin’s physical pharmacy and pharmaceutical sciences, 5th ed. Lippincott Williams and Wilkins; 2006 p      557,558

14.    Benker, G.S., Anderson, N.R., Tablets. In: Lachman, L., Lieberman, H.A., Kanig, J.L., The theory and practice of       industrial pharmacy, 3rd ed. Varghese Publishing House; 1987. p. 300

15.    Indian Pharmacopoeia. Govt. of India. Ministry of Health and Family Welfare, Published by The Indian Pharmacopoeia      commission, Ghaziabad. Vol 1, 2007. 477-478

16.    Park, C.R. and Munday, D.L., Development and evaluation of a biphasic buccal adhesive tablet for nicotine replacement       therapy. Int. J. Pharm. 2002; 237: 397-404

17.    Gupta, A., Garg, S., Khar, R.K., Mucoadhesive buccal drug delivery sys-tem – A review. Indian Drugs. 1992; 29(13):  586-593

18.    Vamshi vishnu yamsani,Ramesh Gannu, Chandrasekhar Kolli1m. Bhanoji Rao, Madhusudan rao Yamsani., Studies on        buccoadhesive tablets of Terbutaline sulphate. Indian J. Pharm. Sci. 2008; 505-510

19.    Niazi, S.K., Handbook of Bioequivalence testing. Vol.171. Informa health care, New York, 2007; p. 538,539

 

 

Received on 08.07.2012       Modified on 10.08.2012

Accepted on 12.08.2012      © RJPT All right reserved