Formulation, Optimization and Evaluation of Spray Dried Microspheres of Azithromycin Dihydrate

In the present study formulation and characterization of spray drying microspheres of azithromycin dihydrate, (prescribed extensively in solid dosage forms) in a sustained release form to overcome drug resistance, and dosing non-compliance in pediatric patients. So, the purpose of this research was to formulate sustained release microspheres of azithromycin dihydrate using chitosan as a carrier polymer, which is also a suitable polymer to mask the bitter taste of drug. Drug entrapment efficiency for azithromycin dihydrate reached to highest level of 84.8% and percentage yield to 68%. Formulated spray dried microspheres gave drug release for the initial dosing and maintenance dosing in a sustained manner for 72 hours. This gave a hope to the possibility of single dose treatment for pediatric patients. The formulated microspheres show pharmacotechnical properties in the acceptable range. KEYWORDS; Spray Dried Microspheres, Azithromycin Dihydrate, Pediatric patients. *Corresponding author MAULIK A. ACHARYA K.B.Raval College of Pharmacy, Gandhinagar-382423, Gujarat, India. Int J Pharm Bio Sci 2012 July; 3(3): (P) 131 136 This article can be downloaded from www.ijpbs.net P 132 INTRODUCTION For decades an acute or chronic illness is being clinically treated through delivery of drugs to the patients in form of some pharmaceutical dosage forms like tablets, capsules, liquids, creams, pills, aerosols, injectables, and suppositories. However, these conventional dosage forms have some drawbacks. Multiple daily dosing is inconvenient to the patient and can result in missed doses, made up doses and patient incompliance with the therapeutic regimen. When conventional immediate release dosage forms are taken on schedule and more than once daily, there are sequential therapeutically blood peaks and valley associated with taking each dose. It should be emphasized that the plasma level of a drug should be maintained with in the safe margin and effective range. For this proper and calculated doses of the drug need to be given at different time interval by conventional dosage form. To achieve and maintain the concentration of administered drug within therapeutically effective range, it is often necessary to take drug dosage several times and these results in a fluctuating drug level in plasma. Greater attention has been focused on development of sustained or controlled release drug delivery systems with concomitant recognition of the therapeutic advantages of controlled drug delivery. Controlled drug delivery systems have been introduced to overwhelm the drawback of fluctuating drug levels associated with conventional dosage forms. A variety of materials and approaches have been proposed which could be effectively used in designing and construction of systems with potential to provide predictable, precise and reproducible pattern of controlled release or even site-specific drug delivery. A sustained release system delivers the active agent at slower rate than the conventional dosage form but the release is substantially affected by external environment. Various terms like ‘smart’, intelligent’, ‘novel’, therapeutic have been assigned to controlled release systems.An ideal controlled drug delivery system is the one which delivers the drug at a predetermined rate, locally or systemically, for a specified period of time. Microencapsulation is a rapidly expanding technology. It is the process of applying relatively thin coatings to small particles of solids or droplets of liquids and dispersions. Microencapsulation provides the means of converting liquids to solids, of altering colloidal and surface properties, of providing environmental protection and of controlling the release characteristics or availability of coated materials. Many antibiotics, including macrolides and quinolones, are used incorrectly in the treatment of presumed respiratory tract infections. The use of broad-spectrum antibiotics increased considerably in the 1990s, but often this use is inappropriate. Guidelines, such as those for community-acquired pneumonia, encourage rational therapy and more prudent prescribing. There are strong links between appropriate use, compliance and resistance as well as between regimen complexity and compliance. These works provide a platform for thinking about a low dose, high-compliance drug therapy with good efficacy. Such therapy will need to be combined with programs to promote rational antibiotic use, particularly targeting inappropriate prescribing for viral infections and use of agents with a broader antimicrobial spectrum than is necessary. Azithromycin dihydrate, a macrolide antibiotic of the azalide subclass, exerts its antibacterial action by binding to the 50s ribosomal subunits of susceptible bacteria and suppressing protein synthesis. Azithromycin is an azalide antibiotic that contains a nitrogen atom in the macrolide aglycone ring. It is active in vitro against Streptococcus pneumoniae group A streptococci, Streptococcus agalactiae, Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis, and intracellular organisms such as Chlamydia, Mycoplasma, and Legionella species. Azithromycin retains the gram-positive activity of erythromycin as the result of a common mechanism of action but provides enhanced activity against gram-negative organisms. To a greater extent than other macrolides, azithromycin is concentrated in phagocytic cells Int J Pharm Bio Sci 2012 July; 3(3): (P) 131 136 This article can be downloaded from www.ijpbs.net P 133 and has shown invitro, to reduce the viability of intracellular bacteria. The pharmacokinetics of azithromycin is characterized by rapid and extensive concentration within the intracellular and interstitial compartments of tissues. High and sustained tissue antibiotic concentrations are accompanied by relatively low concentrations in serum. Given the efficacy of a one-time-dose for these common infections and the assured compliance, the hope would be that this type of regimen can help minimize the emergence of antibiotic resistance. A one-doseonly treatment is a significant advancement, giving physicians and patients an option that can effectively treat the most common respiratory tract infections, while also providing an additional benefit regarding noncompliance with therapy. The present research work was carried out with the aim to try to reduce azithromycin dosing frequency, as it is a broad spectrum antibiotic producing a resistance if given in high frequency from the childhood. So, if we can reduce the dosage frequency it will be more beneficial to all small aged respiratory tract infection patients and treat then up to older age. At the same time looking to the general child nature, such a single dosing for a treatment would lead to patient compliance, and complete treatment with appropriate dosing. MATERIALS AND METHODS Azithromycin dehydrate was collected as gift sample from Lincoln Pharmaceutical PVT. LTD., Kalol, Gujarat, India. Chitosan was collected also as a gift sample from Troikka pharmaceutical Pvt. Ltd., Ahmedabad. Acetic acid (Glacial 100%GR) was purchased from Merk Speciality PVT LTD. F. C. Reagent and Hydrochloric acid was purchased from Finar Chemicals Limited, Ahmedabad, Gujarat, India. Preparation of microspheres of chitosan and Azithromycin Chitosan microspheres were prepared by a spray drying technique. The chitosan solution to be spray dried was prepared by dissolving chitosan in water containing 0.5 %v/v acetic acid and then adding solution of Azithromycin to above solution until clear solution formed with continuous stirring up to 2 hrs with 800 rpm of top lab stirrer. Drug to Polymer ratio of 1:1 was selected for preliminary trials. The resultant solution was spray dried by using “LU-222 advanced lab spray drier (Labultima, Mumbai, India) for preparing microspheres at inlet temperature 150C, feed rate 10 ml/min and aspiration rate: 50 mBar. In the present study a 3 full factorial design was employed to study the effect of independent variables, i.e. drug: polymer ratio(X1) (1:1, 1:2, 1:3) and the concentration of Glacial acetic acid used to dissolve chitosan (X2) (0.5, 1, 1.5) on dependent variables % drug release at Q72, drug loading efficiency, mucoadhesion property, in vitro wash off test, percentage compressibility, angle of repose, percentage yield and particle size. A statistical model (equation below) incorporating interactive and polynomial terms was utilized to evaluate the responses. Y = b0 + b1X1+b2X2 + b12X1X2 + b11X1 2 + b22X2 2 Where, Y is the dependent variables, b0 is the arithmetic mean response of the nine runs, and b1 is the estimated coefficient for the factor X1. The main effects (X1 and X2) represent the average result of changing one factor at a time from its low to high value. The interaction terms (X1X2) show how the response changes when two factors are simultaneously changed. The polynomial terms (X1 2 and X2 ) are included to investigate non-linearity. Int J Pharm Bio Sci 2012 July; 3(3): (P) 131 136 This article can be downloaded from www.ijpbs.net