The role of the solid state and physical properties of the carrier in adhesive mixtures for lung delivery

Abstract

Direct administration of drugs to the lung is commonly used for the treatment of local respiratory diseases, but it can also be employed to obtain a systemic effect. Besides the advantages offered in terms of higher therapeutic efficacy, this administration route raised specific drug delivery issues. In fact, to obtain a suitable bioavailability and therapeutic effect, the drug has to be efficiently deposited in the lower airways. Formulation is required to render the drug respirable. Area covered: The present paper deals with dry powders formulations, in particular it reviews the literature of the last two decades with respect to the role of the solid-state characteristics of the excipients used as carriers in adhesive mixture toward respirability of the active ingredient. Expert opinion: Many of the literature data on this topic are still not completely understood and sometimes they appear contradictory despite the intent to be complementary. More accurate and sensitive analytical methods for solid state characterization both for the drug and the carrier as well as a more systematic approach for the evaluation of the energetics of the carrier vs the drug surface is foreseen as a useful way to address some of the issues still opened in this field.

Formulation and Characterization of Pulmonary Drug Delivery Systems

“…Possible inactive excipients are: lactose, mannitol, trehalose, sucrose, sorbitol, and glucose [55]. Among them, lactose (precisely a-lactose monohydrate) is the most frequently used carrier owing to its numerous advantageous properties such as [56]: − Physico-chemical stability and compatibility (displayed with most low molecular weight drugs) − Safe toxicological profile − Availability and affordability Nonetheless, lactose possesses disadvantages as well: it cannot be administered to patients who are diabetic or lactose-intolerant since it gets ultimately swallowed by the patient, due to its impact on the oropharynx following the device actuation [56]. Due to these reasons, mannitol can be used as an alternative to lactose [57].…”

“…It is also relevant to bear in mind that an active pharmaceutical ingredient containing amino groups (proteins, weak bases) cannot be present in the same formulation as reducing sugars because it would lead to instability due to the Maillard reaction [58]. In order to overcome this, non-reducing disaccharides, nonreducing polysaccharides (trehalose and raffinose, for instance), and other sugars are being investigated as carriers [56].…”

“…In order to overcome those issues, carriers can be used. The carrier material should meet requirements such as [56,60]: − Providing bulk and ensuring flowability − Decreasing the agglomeration of the particles − Facilitating powder handling and dosing by providing a larger volume to the formulation − Helping the dispersion of the micronized drug Moreover, fine lactose particles present within an equivalent size range as the active pharmaceu-tical ingredient have been identified as an important element in order to improve the formulation performance [61]. Among the possible explanations for this phenomenon are the presence of active sites and the agglomeration of drug and fine excipients [62].…”

“…Due to the considerable size difference between the drug and its carrier, the unplanned separation of the two should be avoided, while still enabling an easy detachment of one from the other through weak enough drug-carrier interactions. Consequently, the drug delivery occurs through three steps [56]: the detachment of the active pharmaceutical ingredient from its carrier, their dispersion in the airflow, and the deposition in the respiratory tract (Figure 11). In the case of DPIs, the powder formulation is present in the capsule in an aggregated form with a size of 100-150 μm.…”

“…In adhesive drug mixtures, excipients used as carriers are considered to have a "limited" loading capacity, which makes them convenient for low drug doses. Classic drug-tocarrier ratios are 1:67.5 or 1:99 [56]. The drug quantity which can be processed is limited due to requirements for the content uniformity and stability [66].…”