Formulation Strategy for Low Absorption Window Antihypertensive Agent

 

Ankit A. Kharia*¹, S.N. Hiremath², A.K. Singhai³, L.K. Omray⁴ and G.R Godge⁵

¹Oriental College of Pharmacy, Thakral Nagar. Bhopal-462021, India        

²PRES’S College of Pharmacy. Chincholi, Nashik-422101, India 

³Lakshmi Narayan College of Pharmacy, Bhoapl-462021, India    ⁴Sagar Institute of Pharmaceutical Sciences, Sagar-470 228, India             

⁵PDVVPF’S College of Pharmacy, Ahmednagar- 414001, India

*Corresponding Author E-mail: ankitanandkharia@yahoo.co.in

ABSTRACT:

An attempt was made to design and evaluate hydrodynamically balanced systems (HBS) of Diltiazem HCl hydrochloride using Locust bean gum and Methocel K4M as the polymers. All tablets contained an effervescent base consisting of sodium bicarbonate and citric acid. The tablets were prepared by direct compression method. All the designed nine batches of formulations were evaluated for hardness, friability, weight variation, drug content uniformity, swelling index, in vitro buoyancy, and drug release pattern. Estimation of diltiazem HCl in the prepared HBS was carried out by extracting drug with 0.1N HCl and analyzed at 236.4 nm spectrophotometricaly. All formulations had floating lag time below 3 minutes and constantly floated on dissolution medium for more than 24 hours. These studies indicate that the proper balance between Locust bean gum and Methocel K4M can produce a desired drug dissolution profile. The proposed formulation showed good physicochemical properties, good stability and controlled drug release pattern, thereby improving the bioavailability of the drug.

 

 

INTRODUCTION:

Oral delivery of drug is the most preferable route of drug delivery due to the ease of administration, patient compliance and flexibility in formulation, etc¹. Conventional drug delivery systems achieve as well as maintain the drug concentration within the therapeutically effective range needed for treatment only when taken several times a day. This results significant fluctuations in drug levels². Furthermore, an important factor, which may adversely affect the performance of an oral controlled drug delivery system, is that the dosage form may be rapidly transported from the more absorption regions to the regions where the drug is not well absorbed. Extended release dosage forms with prolonged residence time in stomach are highly desirable for drugs that are locally active in the stomach, that have an absorption window in the stomach or in upper part of small intestine, that are unstable in the intestinal or colonic environment and/or low solubility at high pH values³. These include floating drug delivery systems, swelling and expanding systems, polymeric bioadhesive systems, high-density systems, and other delayed gastric emptying devices⁴.

 

During the last decade, many studies have been performed concerning the sustained release dosage form of drugs, which have aimed at the prolongation of gastric emptying time (GET). The GET has been reported to be from 2 to 6 hours in humans in the fed state². Accordingly, when a sustained release dosage form is administered orally, sufficient bioavailability and prolongation of the effective plasma level occasionally cannot be obtained. Also reflected in the recent scientific patent literature, an increased interest in novel dosage forms which possesses not only a mechanism for controlled release of the drug but also controlled gastrointestinal (GI) transit time exists today in academic and industrial research groups⁵.

 

Diltiazem HCl hydrochloride (DTZ) is a calcium channel blocker belonging to the benzothiazepine family. It is widely prescribed for the treatment of hypertension and angina⁶. Bioavailability of DTZ is 30% to 40% owing to an important first pass metabolism^6-8. It has an elimination half-life of 3.5 hours and has an absorption window in the upper intestinal tract^7,8. Efficacy of the administered dose may get diminished due to incomplete drug release from the device above the absorption window⁹. Therefore, it is considered as a suitable candidate for the design of a hydrodynamically balanced system with a view to improve its oral bioavailability.

 

 

In the present work, an attempt has been made to formulate HBS of diltiazem HCl using HPMC and Locust bean gum¹⁰ in order to deliver the drug at a controlled rate to its absorption site so that its oral bioavailability can be enhanced.

 

MATERIALS AND METHODS:

Materials

Diltiazem HCl and Locust bean gum were received as a gift sample from Modern Labs (Indore, India). Methocel K4M was received as a gift sample from Colorcon Asia Pvt Ltd (Goa, India).  Microcrystalline cellulose was received as a gift sample from Motiff Labs (Goa, India). Citric acid and sodium bicarbonate were purchased from S. D. Fine Chemicals (Mumbai, India). All other ingredients were of laboratory grade.

 

Methods

Preparation of Diltiazem HBS

All the tablets were prepared by direct compression method. DTZ (180 mg) was mixed with the required quantities of polymer blend, sodium bicarbonate (10%), citric acid and MCC by geometric mixing. The powder blend was then lubricated with magnesium stearate (1%) and talc (1%) and compressed on a 10-station rotary tablet machine (Rimek, Ahmedabad, India) using a 12-mm standard flat-face punch. The tablets were round and flat faced; size, average diameter of 12 ± 0.1 mm and thickness of 4.5 ± 0.2 mm; and hardness, range of 5 to 6 kg/cm2.

 

Evaluation of Diltiazem HBS

All the batches of formulations were evaluated for hardness, friability, weight variation, drug content uniformity, in vitro buoyancy, swelling index, and drug release pattern.

 

Hardness and Friability Test

The crushing strength (Kg/cm²) of tablets was determined by using Monsanto type hardness tester¹¹. In all the cases, means of three replicate determinations were taken. Friability was determined by weighing 20 tablets after dusting, placing them in the friabilator (Roche Friabilator) and rotating the plastic cylinder vertically at 25 rpm for 4 min¹². After dusting, the total remaining weight of the tablets was recorded and the percent friability (PF) was calculated using following formula

 

% Friability = (Weight_{initial weightl} – Weight_final weight) X 100

          Weight_{initial weight}

 

Uniformity of weight and drug content

Uniformity of weight was determined by dusting of each tablet and placing in the electronic balance¹² (Shimadzu BL-220H). The weight data from the tablets were analyzed for sample mean and percent deviation. Uniformity of drug content was determined by taking 10 tablets in a glass mortar and powdered; 100 mg of this powder was placed in a 100 mL stoppered conical flask.  The drug was extracted with 0.1N HCl with vigorous shaking on a mechanical gyratory shaker (100 rpm) for 5 hours and filtered into 50 mL volumetric flask through cotton wool and filtrate was made up to the mark by passing more 0.1N HCl through filter, further appropriate dilution were made and absorbance was measured at 236.4 nm¹³ using 0.1N HCl as blank solution by UV-Visible double beam spectrophotometer (Pharmaspec UV-1700 Shimadzu)

 

In vitro Buoyancy studies

The in vitro buoyancy was characterized by floating lag time and total floating time. The test was performed using a USP 23 type-2 dissolution test apparatus (Electrolab) using 900 mL of 0.1N HCl at paddle rotation of 100 rpm at 37ºC ± 0.5ºC. The time required for the tablet to rise to the surface of the dissolution medium and the duration of time the tablet constantly floated on the dissolution medium were noted as floating lag time and floating time⁴, respectively.

 

Swelling Index

The individual tablets were weighted accurately and kept in 50 ml of water.  Tablets were taken out carefully after 60 minutes, blotted with filter paper to remove the water present on the surface and weighed accurately.  Percentage swelling index (SI) was calculated by using the formula¹⁴

 

             SI = Wet weight – Dry Weight) X 100

                                     Dry weight

 

In- vitro dissolution studies

In vitro dissolution studies of HBS of diltiazem HCl were carried out in USP 23 type 2 dissolution test apparatus (Electrolab), employing a paddle stirrer at 100 rpm using 900 mL of 0.1N HCl at 37ºC ± 0.5ºC as dissolution medium. One tablet was used in each test. At predetermined time intervals 5 mL of the samples were withdrawn by means of a syringe fitted with a prefilter. The volume withdrawn at each interval was replaced with same quantity of fresh dissolution medium maintained at 37 ºC ± 0.5 °C.  The samples were analyzed for drug release by measuring the absorbance at 236.4 nm using UV-Visible double beam spectrophotometer ((Pharmaspec UV-1700 Shimadzu) after suitable dilutions.

 

Kinetic modeling of drug release

The dissolution profile of all the batches was fitted to zero-order^15,16, first-order^15,16, Higuchi¹⁷ and Korsemeyer-peppas¹⁸ models to ascertain the kinetic modeling of drug release.

 

RESULTS AND DISCUSSION:

In the present work, HBS of diltiazem HCl were prepared by using natural polymer (Locust bean gum) and Methocel K4M at different drug to polymer ratio along with a gas-generating agent, sodium bicarbonate. The composition of various formulations is shown in table no.1

 

The prepared HBS tablets were evaluated for hardness, friability, uniformity of weight, uniformity of drug content, swelling index, floating lag time, in vitro floating time, in vitro dissolution, short-term stability and drug-polymer interaction. The evaluation data is shown in table no. 2.

The hardness of the prepared HBS of diltiazem HCl was found to be in the range of 5.10 to 6.00 Kg/cm².  The friability of all tablets was less than 1% i.e., in the range of 0.25 to 0.76%.  The percentage deviation from the mean weights of all the batches of prepared HBS was found to be within the prescribed limits. The low values of standard deviation indicate uniform drug content in all the batches prepared as shown in table no.2.

 

Figure-1: In vitro drug release studies of F1 to F9 formulations

 

Figure-2: Cumulative percent drug released Vs square root of time (Higuchi’s plots) of F1 to F9 formulations

 

Figure-3: Log cumulative percent drug released Vs Log time (Peppas plots) of F1 to F9 formulations

The swelling index of formulations F₁ to F₉ were found to be in the range of 39.54 – 72.34.  The swelling index was found to be highest for F₇.  The swelling index of the formulation increases with an increase in the concentration of Locust bean gum. The swelling index values are shown in table no. 2.

 

In vitro floating studies were performed by placing tablets in USP 23 type 2 dissolution test apparatus containing 900 mL of 0.1N HCl maintained at a temperature of 37ºC ± 0.5ºC.  The floating lag time and floating time was noted visually. When an optimum concentration of gas generating agent sodium bicarbonate (10% of total weight of formulation) was used, the floating lag time was found to be in between 0.4 – 3.88 minutes with a floating time of 24 hours. It was observed that the floating lag time of formulation F₉ was maximum which may be due to high drug polymer ratio among all formulations.

 

In vitro drug release studies were performed using USP 23 type 2 dissolution test apparatus at 100 rpm using 900 mL of 0.1N HCl maintained at 37ºC ± 0.5ºC as the dissolution medium. Cumulative percent drug release of F₁ to F₉ formulations in 12 hours were found to be in the range of 58.54 to 100.34%. Formulation F2 containing Locust bean gum 25mg and Methocel K4M 50mg showed promising dissolution parameters (t50% = 2.15 hours, t70% = 5.5 hours and t90% = 8.73 hours) with desired floating properties. From the dissolution data as shown in table no. 6, it is evident that as the proportion of Methocel K4M or Locust bean gum in polymer blend increases their decrease in the release rate of drug and cumulative percentage drug release in 12 hours. From the result it was clear that the release rate was higher for formulation containing low level of Methocel K4M or Locust bean gum compared with other formulations containing higher level. This may be owing to the release retarding effect of Methocel K4M and Locust bean gum at higher concentration because drug may have entrapped within a polymer matrix causing a decrease in the rate of drug release. The results of in vitro drug release pattern were plotted in fig.1. 

 

Drug Release Kinetics

In vitro dissolution data of HBS was subject to goodness of fit test by linear regression analysis according to zero-order, first-order, Higuchi and Korsemeyer-peppas model to ascertain the mechanism of drug release.  The results of linear regression analysis including regression coefficients are summarized in table no. 3 and plots shown in figure 1 to 3.

It was observed from the above data that all formulations have displayed zero order release kinetics (r values in the range of 0.986 to 1). The values of r for Higuchi’s equation of formulation was found to be in the range of 0.965 to 1, which shows that the data fitted well to Higuchi’s square root of time equation confirming the release followed diffusion mechanism. Kinetic data also treated for Peppas equation, the slope (n) values ranges from 0.454 to 0.775 that shows non-Fickian diffusion mechanism. The kinetic data of formulation F1 to F9 is tabulated in table no 3.

Table 1. Formula for F1 to F9 Formulations

Ingredients (mg)	F1	F2	F3	F4	F5	F6	F7	F8	F9
Diltiazem HCl	180	180	180	180	180	180	180	180	180
Locust bean gum (X1)	25	25	25	50	50	50	75	75	75
Methocel K4M (X2)	25	50	75	25	50	75	25	50	75
MCC	50	50	50	50	50	50	50	50	50
NaHCO3 (10%)	30.5	33.1	35.7	33.2	35.7	38.3	35.7	38.3	41.3
Citric acid	12.5	13	13.5	13	13.5	14	13.5	14	14.5
Mg. stearate (1% )	6.4	6.6	6.6	6.6	6.6	7.1	6.6	7.1	7.4
Talc (1%)	6.4	6.6	6.6	6.6	6.6	7.1	6.6	7.1	7.4

MCC, Micro Crystalline Cellulose: NaHCO_3, Sodium bicarbonate

 

Table 2. Evaluation of F1 to F9 formulations

Formulation Code	Mean Hardness Kg/ cm²	Friability % W/W	Average Weight (mg)	Mean Drug Content % ±SD	Swelling Index ±SD	Floating Lag Time (min)	Floating time (hrs)
F1	5.90	0.45	333.7	97.91±1.85	39.54±0.2	0.43	24
F2	5.50	0.48	363.8	99.31±1.43	43.54±1.3	0.41	24
F3	5.60	0.25	390.5	97.99±2.05	49.66±2.2	2.34	24
F4	5.10	0.76	362.5	100.66±1.35	52.43±1.4	0.98	24
F5	6.00	0.45	393.2	98.62±1.02	50.75±1.2	1.53	24
F6	5.30	0.67	420.4	100.45±2.05	48.76±0.7	1.34	24
F7	5.10	0.54	390.3	97.61±1.65	72.34±1.3	2.35	24
F8	5.50	0.36	421.4	98.98±1.46	68.83±2.5	1.06	24
F9	6.00	0.53	446.3	97.56±2.06	62.56±2.5	3.88	24

 

Table 3. Regression Analysis Data of F1 to F9 Formulations of Diltiazem HCl

Batch		Zero Order	First Order	Higuchi’s Equation	Peppas Equation
	r	1	-1	1	1
F1	a	69.32	2.654	55.43	1.96
	b	12.36	-1.423	31.54	0.454
	r	0.978	-0.927	0.994	0.994
F2	a	33.54	2.234	5.954	1.645
	b	5.976	-0.124	28.321	0.465
	r	0.998	-0.986	0.978	0.978
F3	a	19.432	2.213	0.887	1.345
	b	4.432	-0.041	22.564	0.543
	r	0.989	-0.924	0.992	0.956
F4	a	61.534	2.034	43.324	1.698
	b	3.342	-0.104	12.435	0.456
	r	0.998	-0.946	0.976	0.554
F5	a	29.32	1.943	5.044	1.534
	b	4.956	-0.083	24.082	0.645
	r	0.995	-0.995	0.997	0.997
F6	a	12.99	1.965	-7.032	1.143
	b	4.345	-0.033	18.546	0.764
	r	0.999	-0.992	0.986	0.979
F7	a	15.534	1.964	-5.875	1.243
	b	5.546	0.050	23.546	0.656
	r	0.986	-0.958	0.965	0.965
F8	a	8.554	1.998	-5.102	1.123
	b	5.456	-0.036	22.324	0.645
	r	0.987	-0.993	-0.996	0.967
F9	a	9.345	1.965	-10.837	0.953
	b	5.654	-0.031	20.232	0.775

r, correlation coefficient; a, Intercept; b, Slope

 

 

CONCLUSION:

This study concludes that hydrophilic polymer such as Methocel and Locust bean gum plays an important role for the formulation of HBS. As the amount of the polymer in the formulations increases, the drug release rate decreases. The proposed formulations followed Higuchi’s kinetics while the drug release mechanism was found to be anomalous type, controlled by diffusion through the swollen matrix. Both the polymers can be used in combination and do not interact with the drug. On the basis of evaluation parameters, the proposed formulation containing may be used once a day administration in the management of chronic heart diseases such as angina and hypertension. 

Table 4. Dissolution Parameters for F1 to F9 Formulations

Batch Code	t50% (hours)	t70% (hours)	t90% (hours)	Cumulative percent drug release in 12 hours
F1	0.55	0.76	1.43	100.34
F2	2.15	5.50	8.73	100.12
F3	6.65	10.73	>12	76.45
F4	0.47	2.45	8.72	98.65
F5	3.96	7.43	10.05	95.30
F6	8.42	13.87	>12	62.00
F7	4.61	7.21	9.32	71.00
F8	8.71	13.92	>12	65.34
F9	9.31	15.75	>12	58.54

t_50%, t_70% and t_90%  are time taken to release of drug from factorial formulations ie 50%, 70% and 90% respectively.

 

ACKNOWLEDGEMENT:

The authors would like to thank Modern laboratories, Indore, India for providing funding support for this project.

 

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Received on 16.09.2009          Modified on 19.11.2009

Accepted on 12.12.2009         © RJPT All right reserved