How carriers affect the homogeneity and dispersibility of hydrophobic drugs?

This post by Iftikhar Khan

Corticosteroid drugs are oftenly used as a prophylaxis for asthmatic patients and the method of administration is m ore important for its proper activity. Beclomethasone dipropionate (BDP) produce s some systemic side effects like skin changes, adrenocortical suppression and cataract formation by using dry formulation. In addition, pulmonary delivery of BDP causes Candida infection. For minimising the side effect the drug formulation should be applied to the specific side of action. However, it was noticed that only 10% of the dry powder formulation reaches to the deep lung using Rotahaler, Spinhaler and Diskhaler because most of the drug deposit to the upper respiratory tract from where they swallowed  and absorbed systemically through gastrointestinal tract (GIT). So, by preparing the better formulation and drug delivery method reduces most of the side effects. And in this experiment a drug Beclomethasone dipropionate (BDP) was mixed with carrier lactose in two different forms i.e. coarse and fine lactose. The formulation of all three content as a ternary mixture was checked for their homogeneity and with the delivery of BDP. And it was found that the combination of coarse lactose with fine lactose and BDP minimise the aggregation and maximise the dispersion. However, the controlled amounts of both lactose (CL and FL) play a key role in the flowability of powder, dispersion and stability of the powder formulation.

Coarse lactose (CL) was prepared using air jet sieve and the lactose particles were collected from 63- 90 um in size after 15 minutes of shaking. Air-jet mill was used for the micronisation of fine lactose (FL) and particle less than 63 um was passed once through the jet mill. Both the sample were collected and stored at 50 C for 24 hours and then placed in dedicator over silica gel to protect it from moisture and to use for further investigation. Particle size characterization was done by using Scanning electron microscopy (SEM), where sample was placed on the stub and then coated with gold. Six formulation were prepared using CL, FL and BDP altogether with different mixing sequence and using two different ratios i.e. 64.1 : 3.4 : 1 and 65.8 : 1.7 : 1 w/w. A Turbula mixer was used for powder mixing at 90-95 rpm. In each formulation the first two components were mixed for a predetermined time (15 or 60 minutes) and than a third ingredient was added and mixed for the same time (15 or 60 minutes) for both ratios. BDP and CL in an only ratio of 67.1 : 1 was used as control.

High performance liquid chromatography (HPLC) was used for the analysis of BDP. Methanol and water (7:3) ratio was used as a mobile phase with 0.8 ml/min of flow rate and UV detector was set at 239nm. A calibration curve was prepared from standard solution between 0.1-20.0 ug/ml in range. Each formulation containing a sample of 33 + mg was taken and assayed for by HPLC for the content of BDP.

Particle size of aerosolised BDP was measured using twin stage impinger (TI), a Rotahaler was used containing 33 + mg of powder as a delivery device. A mobile phase (7 ml) was placed in each of the upper and lower parts of the twin impinger. Capsule was placed in the Rotahaler and a rubber moulded mouthpiece was used to attach Rotahaler with throat piece of the impinger. A vacuum pump was set at 60 l/min of flow rate and the dose was released for 5 seconds under these conditions and re-run for the further 7 seconds. The same procedure was repeated for 5 capsules in total for each formulation. The capsule shells, mouth piece and the Rotahaler were washed with the mobile phase to analyse it for the retained amount of drug. The samples from both upper and lower parts of TI were collected and analysed using HPLC method.

In conclusion the addition of fine lactose to the mixture of BDP with coarse lactose as a binary mixture did not affect the mixing uniformity.  The addition of BDP into the binary mixture of CL and FL (became ternary mixture) however showed a reduced in the homogeneity. And the presence of 2.5 % w/w fine lactose in the formulation exhibited an increase dispersion and deaggregation of BDP during aerosolization with an improved fine particle fraction (FPF) and fine particle dispersion (FPD). In addition, it was observed that 60 minutes mixing is better regardless of the mixing pattern of the ingredients than 15 minutes mixing.


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