Formulation and Evaluation of Antihypertensive Microparticulate Drug Delivery System

 

S. M. Sarode1*, M. K. Kale2, G. S. Talele3 and G. Vidyasagar1

1Veerayatan Institute of Pharmacy, Bhuj, Gujarat

2K.Y.D.S.C.T’s College of Pharmacy, Sakegaon (M.S.)

3J.Z.M.D.S. College of Pharmacy, Mamurabad.

 

ABSTRACT:

The phenomenon of absorption via a limited part of the GI tract has been termed the "narrow absorption window", once the dosage form passes the absorption window, the drug will be neither bioavailable nor effective. In extreme cases, drugs, e.g. methyldopa, Captopril,  that are insufficiently absorbed due to narrow absorption cannot be delivered entirely, and are either given by a parentral route, or the development of such medication, which is otherwise safe and effective, is stopped altogether. Diltiazem HCL is a calcium channel blocker widely used for the treatment of angina pectoris, arrhythmias and hypertension. Its short biological half life and thus frequent administration (usually three to four times a day) makes it a potential candidate for CR: SR preparations. It has a short plasma half life of about 3 hours. Diltiazem HCL microspheres were prepared by chemical cross linking method. The microspheres were spherical, discrete and free-flowing. Encapsulation efficiency was found to be 95.62 %. Diltiazem HCL release from microspheres was slow and diffusion controlled. Good liner relationships were observed between percent coat and release rate of the microspheres.

 

KEYWORDS: Microencapsulation, controlled release, Chitosan

 

INTRODUCTION:

Oral route is most convenient and commonly employed route of drug administration. The preferred route for the administration of most drugs is via the gastrointestinal tract most drugs are well absorbed from throughout the entire intestinal tract, but some compounds, usually those which are polar in nature, are poorly absorbed from the large intestine. For such drugs, the main area from which absorption occurs is the small intestine. For last so many decades conventional dosage forms, like tablets, capsules, pills, powders, parenteral preparations, solutions, emulsions, suspensions, creams, ointments and aerosols are used in the treatment of acute or chronic diseases. Even today these immediate release formulations can be considered as primary pharmaceutical product commonly seen in market. When such a conventional dosage form is administrated, the concentration of such drug in systemic circulation gradually rises to attend a therapeutic range and this concentration is maintained for some time and finally decreases to sub therapeutic value rendering the drug pharmacological inactive. Also the therapeutic window of many drugs is limited by their short circulating half-life and absorption via a defined segment of the intestine. Such pharmacokinetic limitations lead in many cases to frequent dosing of these medications to achieve the required therapeutic effect. This results in "pill burden" and consequently, decreased patient compliance2,12,14.

 

Epidemiologic studies have also shown that there is a substantial increase in the rate of acute myocardial infarction, ischemic stroke, and sudden death in the early morning period, especially during the first 4 hours after awakening. In addition, studies of older Japanese patients with systolic hypertension suggest that there is an important relationship between steep increases in the early morning BP and higher incidence of stroke and ischemic brain lesions3,11.

 

MATERIALS AND METHOD:

Chitosan was provided by Mahtani Chitosan Pvt. Ltd, Veraval.Diltiazem HCl was provided by Astron research Pvt Ltd., Baroda.

 

Preparation of microspheres:

Chitosan 4% w/v solution was prepared in 5% v/v acetic acid in which Diltiazem HCl (100 mg) was dissolved. This was then dispersed in 150ml (1:1) heavy and light liquid paraffin containing dioctyl sodium sulphosuccinate (0.2% w/v). While dispersing the stirring rate was kept constant at 1000 rpm. Glutaraldehyde was then added. Initially, 2ml. of aq. 25% glutaraldehyde was added to the liquid paraffin before adding the drug polymer dispersion. Then after 30 min and 60 mins. 2ml each of 25 % glutaraldehyde was added and stirring was continued for total of 2 hrs. The liquid paraffin was decanted; the microspheres were filtered, washed with n- hexane to remove traces of oil and ice then with water to remove excess of glutaraldehyde. The collected microspheres were air dried4,10.

 

Evaluation of microspheres:

Drug Content:

Accurately weighed microspheres (100mg) were crushed in glass mortar-pestle and the powdered microspheres were suspended in 20ml of simulated gastric fluid (pH 1.2).After 24 hours the solution was filtered using Whattman filter paper. Of this 1 ml of the filtrate was taken and diluted to 10 ml. The absorbance was measured at 239 nm. 5

 

Fig no. 1

Dissolution Studies

The dissolution studies were performed using Dissolution Apparatus USP Type II (Rotating Paddle Model no. DA-3). using simulated gastric fluid (pH1.2) – 900 mL hrs and at 100 rpm at temp 37 ºC ± 0.50C. During dissolution study 5 mL aliquot was withdrawn at different time intervals of 1 to 12 hrs and same was replaced with equal volume of fresh medium. The withdrawn samples were filtered through Whatman filter paper no.42 and absorbances were measured at 239 nm for simulated gastric fluid. 7,9

 

Cumulative percent drug dissolved of batch

S.N

Time in hrs

% Cumulative drug release

1

0

0

2

1

17.89±1.729

3

2

22.26±1.585

4

3

31.37±1.620

5

4

39.48±2.184

6

5

43.11±2.062

7

6

50.62±1.176

8

7

68.91±2.024

9

8

72.00±1.688

10

9

78.65±1.462

11

10

82.19±1.109

12

11

89.93±1.582

13

12

94.61±0.939

*Represents mean ± S.D   (n=3)

 

DSC Study:

This study was performed at Sophisticated Analytical Instrument Facility, Indian institute of technology, Powai, Mumbai. For the structural, crystal and physical state characterization of Diltiazem HCL DSC studies were performed for pure drug, pure Chitosan and microspheres.  The DSC study was carried out with Mettler DSC 30S, Mettler Toledo India Pvt. Ltd., Switzerland, using crucible Al 40µL, at of 100C /min heating rate, under nitrogen environment. The temperature range used was 0 –3000C. 6

 

Surface morphology:

This study was performed at SAIF Department, IIT, Powai, Mumbai by Scanning Electron Microscopy (SEM) using JSM 6380 A(JOEL, Japan).The microspheres were coated with Platinum by ion sputtering using Autofine coater JFC-1600 (JOEL, Japan) The microspheres were kept on the sample holder and the scanning electron micrographs were taken. 13

 

Determination of particle size

The particle size was determined using stage micrometer. The diameters of about 275 microspheres were measured and the average particle size determined. 8,7

 

RESULTS AND DISCUSSIONS:

Drug Content:

Good drug loading was achieved for the different formulation. Some drug was lost to the external phase during preparation and recovery.

 

The results also indicate that the loading efficiency in the microspheres depends upon the preparation conditions. The incorporation efficiency of drug appeared to be low at all cross linking densities. The highest drug % entrapment was observed for the batch (95.62%).

 

Dissolution Studies:

The release profile of Diltiazem HCL IP from the different formulation of the chitosan microspheres are shown in Fig. No.2. The data clearly indicate the drug release can effectively be controlled by varying the cross linking density of the microspheres.

 

Fig. no.2: In-vitro release profile of Diltiazem HCL from formulation

 

The concentration of chitosan used in the microspheres preparation can modify the release behavior of the drug from the produced microspheres. When a more concentrated polymer solution was initially employed for synthesis of the microspheres, the drug was more effectively entrapped into the polymer matrix, but it resulted in slow release rate, but when lower concentration of chitosan was used the higher release rate was observed in the formulation.

 

The batche showed remarkably sustained release of drugs. From batch the release rate was extended upto 12 hrs; wherein in the 1st phase, during first five hours about 39.48% of drug was released from the chitosan microspheres. Following this in second phase remaining amount (upto94.61%) of drug released slowly upto12 hrs, and the concentration of drug released remained in therapeutics range for 15 hrs. The remaining batches showed the sustained release of the drug, but as release rate was very low the whole amount of drug was not released.

 

DSC Study:

The DSC studies showed that there was a shift in endotherm in Diltiazem HCL loaded chitosan microspheres. In pure Diltiazem HCL the endotherm was observed at 212ºC, which indicate the melting of the drug. The peak for the drug was reduced to 210ْC when the DSC of the microspheres was performed indicating that the drug was entrapped in the chitosan microspheres. Results are shown in Fig. No. 3.

 

Fig No.3

 

SEM:

From the SEM photography it was observed the formulated optimized microspheres (DZ-4) were found to be spherical shaped with heterogeneous size distribution having rough surface morphology. Results are shown in Fig. No. 4.

 

Fig No.4

Particle Size:

All the microspheres Ranged between 400-500 μm in diameter. It has be seen that mean particle size was significantly affected by amount of polymer.The results for the particle size analysis are shown in Fig. No.5 .

 

 

Fig No.5

ACKNOWLEDGEMENTS:

Authors are thankful to I.I.T. Powai for SEM and DSC Studies.

 

REFERENCES:

1.        Illum L., Ping H. Gastro Retentive Controlled Release Microspheres for Improved Drug Delivery. US Patent 424145(2001).

2.        Brahmankar D. M., Jaiswal S. B.. (Eds); Biopharmaceutics and Pharmacokinetics A Treatise; I Edn: Vallbh Prakashan, Delhi 100034: 1995; 39-59, 335-357;

3.        Lachman Leon, Liberman Herbert, A. Kanig, L. Joseph. The Theory and Practice of Industrial Pharmacy, 3rd  Edn , 1991; 430-456.

4.        Stanley, D.S., Formulation Strategies for Absorption Windows, Drug Discovery Today, 2005; 10(4), 249-257.

5.        Akbuga J, Durmaz G, Preparation and Evaluation of Crosslinked Chitosan Microspheres Containing Furosemide, Int. J. Pharm. ,1994; 111, 217–222.

6.        Gutierrez Rocca J, Omidian H., Shah K. Progresses in Gastroretentive Drug Deliver y Systems, Pharmatech, 2003; 152-156.

7.        Shinde A J. Gastroretentive Drug Delivery System: An Overview, http//: www. Pharmainfo.net.

8.        Bardonnet P L, Faivre V, Pugh W J. Piffaretti, J. C., Falson, F. Gastroretentive Dosage Forms: Overview and Special case of Helicobacter pylori, J. Control. Release , 2006;111,  1 – 18

9.        Hwang S J, Park H, Park K. “Gastric Retentive Drug Delivery Systems.” Crit. Rev. Ther.Drug Carrier Syst. , 1998; 15, 243–284.

10.     Grubel P. Gastric Emptying of Non-Digestible Solids in the Fasted Dog., J.Pharm.Sci., 1987; 76, 117 –122.

11.     Nishioka Y, Kyotani S, Masui H, Okamura M, Miyazaki M, Okazaki K, Ohnishi S, Yamamoto Y, Ito K. Preparation and Release Characteristics of Cisplatin Albumin Microspheres Containing Chitin and Treated with Chitosan. Chem. Pharm. Bull. , 1989; (Tokyo) 37, 3074–3077.

12.     Gilles P, Juan I. Specific and Non-Specific Bioadhesive Particulate Systems for Oral Delivery to the Gastrointestinal Tract, Advanced Drug Delivery Reviews, 1998; 34, 191–219.

13.     Sinha V R, Singla A K, Wadhawan S, Kaushik R., Kumria R, Bansal K, Dhawan S . Chitosan Microspheres as a Potential Carrier for Drugs Int. J. of Pharma, 2004,274, 1–33.

14.     Spenlehauer Gilles, Veillard Michel, Verrechia Thierry. Microspheres, Process for Their Preparation and Their Use, US Patent 6120805.

 

 

Received on 10.04.2010

Accepted on 13.05.2010        

© A&V Publication all right reserved

Research Journal of Pharmaceutical Dosage Forms and Technology. 2(3): May-June 2010, 237-240