FORMULATION AND EVALUATION OF DRY POWDER INHALERS OF BUDESONIDE FOR PULMONARY DELIVERY

About Authors:
Neethu.R.R
Uthradam
Kannayamkodu
Chenkikunnu
Kilimanoor.P.O, Trivandrum dist, Kerala 695601
neethalekshmi87@gmail.com

Abstract:
Budesonide is a corticosteroid, used in the treatment of inflammatory conditions such as asthma and COPD. The present study was undertaken with the aim to formulate and evaluate dry powder inhalers of Budesonide for pulmonary delivery. Dry powder inhalers of Budesonide were prepared using different concentrations of fine lactose and magnesium stearate by Geometric dilution method. The drug-carrrier compatibility study was carried out by FT-IR studies. A total of eleven batches were formulated and evaluated for physical appearance, average fill weight, flow properties, particle size analysis, content uniformity, moisture content and assay. In-vitro drug deposition studies were carried out by using Modified Twin Stage Impinger (TSI) apparatus. Of all eleven batches, the formulation F4, comprising of fine lactose 30% was found to be the best having comparatively higher fine particle fraction (FPF) of 25.32%. The result indicated that the amount of drug that reaches in the lung was higher for formulation F4. Further invivo safety and deposition studies on suitable animal models and human volunteers will give better insight for clinical applications of the Budesonide DPI.

REFERENCE ID: PHARMATUTOR-ART-1634

INTRODUCTION
In the search for new drug delivery, the administration of systemically acting drugs by inhalation is a promising alternative that has generated increasing interest over the past decade. Pulmonary delivery has proven especially attractive alternative to oral, transdermal, and parenteral administration for the treatment of local lung disorders including asthma, COPD and cystic fibrosis and has potential for the systemic delivery of peptides and proteins¹. All DPIs consist of a powder formulation and an inhalation device. The powder formulation is composed of a micronised drug powder, either alone or in combination with carrier particles. Since the micronised drug particles are usually highly cohesive, they are usually mixed with coarser carrier particles. This process can also promote dose uniformity of the formulations. During inhalation drug particles must detach from the carrier surface to penetrate into the respiratory airways. The detachment can occur if the forces imparted by inhalation exceed the interparticle forces between drug and carrier particles. Strong adhesion forces result in poor detachment, which in turn, lower the respirable fractions of the drug. The adhesion forces depend on physical properties of both drug and carrier particles. Therefore, the application of particles having suitable physical properties may be considered as one of the most important approaches in design of the formulation of dry powders for inhalation².   Drug targeting should reduce the dose required to achieve a desired pharmacological effect and consequently the systemic load of the drug. Although initially localized drug delivery to the lung through inhalation seems trivial, effective pulmonary therapy is rather complex and difficult to achieve. This is because for all pulmonary forms of administration (aerosols, dry powder inhalers, and nebulizers) only a certain portion of the dose is delivered directly to the lung, whereas, most will be deposited in the oropharynx and consequently swallowed .The swallowed portion of the dose, depending on the oral bioavailability of the drug, is potentially available for systemic absorption and will directly contribute to the systemic side effects of the drug. In addition, pulmonary deposited drug is often absorbed very fast from the lung or removed from the upper portion of the lung by way of the mucociliary transport mechanism. Thus, high levels of drug in the lung are difficult to maintain. On the other hand, systemically available drug (having entered through oral or pulmonary absorption) will induce systemic effects and, therefore, should be removed from circulation as efficiently as possible to achieve pulmonary selectivity. The local and systemic properties of a drug or drug delivery system are important factors in achieving pulmonary selectivity. Dry powder inhalers (DPIs) were developed as a breath actuated and environmentally friendly alternative to the MDIs. The powders are formulated by mixing cohesive micronized drug particles with larger carriers. These breath-actuated devices rely on the patient's inspiratory effort to deaggregate and subsequently inhale the drug particles. In this manner, the problems of coordinating actuation and inhalation do not exist. Powder dispersion in DPI devices is accomplished passively, by the patient's own inspiratory effort, or actively, by a component (e.g. electronic vibrator, impeller) in the DPI device, because micronized particles are difficult to deaggregate. The efficacy of passive DPI devices depends strongly on the patient’s inspiratory flow rate. This has led to the development of the more sophisticated, active DPI devices. The efficacy of inhaled medications may be affected by the patient’s age, severity of disease, and inhalation technique, as well as the specific pharmacological properties of the drug.

MATERIALS AND METHODS

Table:  List of Drug, chemicals and Excipients     

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Table: List of Instruments and Equipments

PROCEDURE FOR CALIBRATION CURVE OF BUDESONIDE⁵⁰
Accurately weighed 100 mg of Budesonide was transferred into 100 ml volumetric flask. The drug was dissolved in required quantity of Methanol and volume made up to 100 ml with Methanol. From this solution 10ml of the solution was taken and diluted up to 100 ml with Phosphate buffer pH 6.8 in standard volumetric flask to get concentration of 100 μg/ml. From the secondary stock solution 10 ml of the solution was taken and diluted up to 100 ml with Phosphate buffer pH 6.8 in standard volumetric flask to get concentration of 10 μg/ml. From the tertiary stock solution 1.0 ml, 2.0 ml, 3.0 ml, 4.0 ml, 5 ml, 6 ml, 7 ml, 8 ml, 9 ml and 10 ml of solutions were taken and transferred to 10 ml standard flask, made up the volume with Phosphate buffer pH 6.8 to get concentrations of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10μg/ml respectively. Absorbance of the solutions was measured at 246 nm using phosphate buffer pH 6.8 as blank.

STANDARD CALIBRATION CURVE OF BUDESONIDE

Table: Data for standard calibration curve in Phosphate Buffer pH 6.8

Dig:standard calibration curve for budesonide

Preparation of Dry Powder Inhalers with Coarse Lactose and Different Proportions of Fine Lactose and Magnesium Stearate

Budesonide dry powder inhaler 200μg formulations were prepared in 4g batches with 0-30% of 6 formulations of fine lactose (Lactohale 201), and 2.5-10% of 4 formulations of Magnesium Stearate with 25 mg fill weight and Lactohale 200 as Coarse Lactose (Lactohale 200) as per composition given in Table No.10

Manufacturing Process: Geometric Dilution Method
1) An accurately weighed quantity of Coarse Lactose was passed through 60# sieve and carefully placed in a polybag.
2) An accurately weighed quantity of Fine Lactose or Magnesium Stearate separately in each case was sieved through 60# sieve and added to the Coarse Lactose and mixed in geometric progress for 15 min.
3) An accurately weighed quantity of micronized Budesonide was mixed separately in each case with fine coarse lactose blend and magnesium Stearate Coarse Lactose blend in geometric progress and passed through 60# mesh and blended in polybag for 15 min.
4) The resulting blend was filled in size 3# HPMC capsule with fill weight of 25mg

Table: composition of formulation of Budesonide DPI in mg
The prepared capsules were subjected for various evaluation studies such as angle of repose,bulk density, tapped density, carr’s index, hausner’s ratio, moisture content, drug content, assay,etc.                 In vitro Deposition of dry powders for inhalation was determined using Modified Twin Stage Impinger Apparatus.

7 and 30 ml of methanol was introduced into stage 1 and stage 2 of impinger apparatus respectively. The 25 mg of formulation was loaded in to size 3# hpmc capsule and installed into Rotahaler device. Rotahaler was attached to impinger and capsule contents were released by twisting the Rotahaler. The vacuum pump was operated for 5 seconds so that a steady flow rate of 60 L/min was achieved, and the dose was released. At this time the pierced capsule content was released into the two stages of impinger apparatus. The inhaler body, capsule shells and stages 1 & 2 were separately rinsed with methanol. The rinsed liquid was collected and diluted to appropriate volume with phosphate buffer pH 6.8. The Budesonide content in each stage was determined by UV Spectrophotometric method at 246nm. The amount of drug that deposited in stage 2 of the TSI was considered as the fine particle dose (FPD). The recovered dose (RD) was defined as the total amount of drug recovered from inhaler, capsule shell, stages 1 & 2 after each actuation. The emitted dose (ED) considered being the amount that emitted from the inhalation device and capsule in to the TSI. Fine particle fraction (FPF) was the ratio of FPD to RD, which is expressed as percentage, while dispersibility was expressed as the ratio of FPD to the ED.

RESULTS

Table: various evaluation parameters

BD-bulk density,TD-tapped density,AOR-angle of repose,HR-hausner’s ratio,CI-carr’s index,CU-content uniformity,DC-drug content,SDR-size distribution range,MD-mean diameter