Category: Formulation and Quality
Purpose: A capsule-based inhalation system is very common for drug delivery to the lungs. It is loaded with a hard capsule containing a micronized powder formulation of drug prior to inhalation. The capsule is punctured, opened or cut within the device to release the internal contents upon inspiration (1).
During a deep breath sequence, aerosolization of powder takes place. The active drug particles detach from the carrier particle surface enabling deposition into the lower respiratory tract. This powder de-agglomeration is a key component to successful drug delivery, along with the shear fluid dynamic which may be enhanced by turbulence (2). Hard capsules within the inhalation device contribute in creating this turbulence by rapid rotation inside the inhaler.
The question arises, "Which type of capsule, HPMC (hydroxypropyl methylcellulose) or gelatin, is optimal for an adequate delivery of aerosolized powder into the lungs??
To assess the aerodynamic performance of Salmeterol-Fluticasone inhalation formulation in both capsule types, accelerated stability studies were performed. Filled capsules were exposed to 40°C / 75% RH for six months and evaluated at different time intervals.
Methods: Salmeterol Xinafoate (100 mcg) with Fluticasone Propionate (200 mcg) at a fill weight of 25 mg was filled into HPMC and Gelatin capsules. These filled capsules were placed on a six month accelerated stability program at 40°C / 75% RH. Testing took place on the initial sample, and after accelerated conditions at one, two, three, and six-month intervals. The packaging was the same as the marketed product in India, SEROFLO Rotacaps, manufactured by Cipla. Primary packaging consisted of an HDPE bottle (30 count) with a secondary corrugated box.
A single pin capsule puncturing device (Lupihaler) was used for performance evaluation of the inhalation blend on Fine Particle Distribution (% FPD) and Drug Retention (% DR). Internal lubrication during the capsule manufacturing process for both the capsule types was constant. The drugs in the formulation were evaluated to ascertain if any differences in the aerodynamic performance could be attributed to the capsule type.
Results: The results indicate different capsules have a direct impact on the aerodynamic performance of the same inhalation formulation. The stability study of six months gave variable results as shown in Figures 1A and 1B.
Fine particle sizes in the range of 1-5 µm are most efficiently absorbed throughout the entire surface area of the lungs. Larger particle sizes may deposit in the pharynx or the many branches throughout the pulmonary pathway and not reach the entire alveolar region. Particles less than 1 µm can be expelled in the normal breath sequence. Higher fine particle distribution yielded better drug deposition and efficient absorption. The % FPD as seen in Figure 1A was higher in HPMC capsules as compared to gelatin capsules up to the six months accelerated stability conditions. At the sixth month there was a significant difference between the % FPD in HPMC and gelatin capsules.
% DR in Figure 1B clearly illustrates that lowest percent drug retention was seen in HPMC. During the period of six months, the drug retention for HPMC capsules was not more than 1%. Conversely, gelatin capsules showed drug retention of up to 5% and 7%, for Salmeterol and Fluticasone, respectively.
Conclusion: The study to evaluate the aerodynamic performance of Salmeterol-Fluticasone inhalation blend in HPMC and gelatin capsules was successfully performed for a period of six months at 40°C / 75% RH.
Apart from the difference in capsule raw material composition, the inherent moisture content of both capsules can contribute to the results. HPMC capsules contain around 3-8% of moisture, whereas gelatin contain 13-16%. The force of attraction between the drug and carrier particle can be affected by this moisture content. This could be one of the reasons for the vast difference in % DR values of HPMC and gelatin capsules. A lower than optimum moisture content in gelatin capsules may lead to brittleness (as the water is removed from the capsule shell by the moisture sensitive fill) which can also impact the aerodynamic performance. HPMC capsules have lower static force, and it could be an additional factor for lower drug retention. The % FPD demonstrates HPMC capsules have better aerosolization properties. HPMC capsules performed better than gelatin capsule regarding aerodynamic properties for Salmeterol-Fluticasone inhalation formulation.
1. Capsules Based Inhalers: An Effective Alternative in Inhalation Delivery, Fernando D, The Healthcare Packaging Products Magazine, 2016; (64):66-68
2.The Science Behind Capsule-Based Dry Powder Inhalation Technology, Fernando D, Justin K and Jnanadeva B, On Drug Delivery, 2017; 11(80):4-8.
Fernando Diez– Scientific Business Development Manager, ACG Europe, Corby, England, United Kingdom
Sanjay Powale– Mumbai, Maharashtra, India
Anita Solanki– Mumbai, Maharashtra, India
Jnanadeva Bhat– Mumbai, Maharashtra, India
Dorene Almeida– Mumbai, Maharashtra, India