Issue link: https://www.e-digitaleditions.com/i/1481142
Inhalation OctOber 2022 27 the downside was an absence of a confirmatory taste signal. A great deal of research effort has been put into the preparation of the active ingredient for inhalation. Some of the processes can impart substantial elec- trostatic energy to the particle that can influence its subsequent behavior and create inconsistency. Research has focused on processes that can produce small particles that are consistent, have low intrin- sic energy and are readily aerosolizable. As various active drugs have different physico-chemical proper- ties, this is a major challenge: "particle engineering" techniques, such as co-suspension low-density phos- pholipid particles, have been added to traditional milling technology methods. 17-19 Dose storage, moisture protection and metering It is critical that powders remain dry throughout their storage life. Some capsule-based products may require blister over-packaging to retain their dry state. Reservoir devices are usually foil-packed for the same reason. Individual blister product packs may be made of foil or plastic, with considerable attention paid to correct sealing. DPIs, therefore, have individ- ual filling technology requirements based on the con- straints of, for example, blister-strip size, orientation, fill weight, and format for loading into the DPI. e filling technology tends to be "made-to-measure," requiring bespoke filling lines. is is distinct from pMDIs (and capsule DPIs) where the filling technol- ogy is standard. In summary, individual dry powder dose-metering can take place in the factory in the case of capsules or blister devices but will take place in situ for reservoir devices. De-aggregative processes In order to deliver the medication effectively, the effort of inhalation must lift the powder from the device and separate the active medicinal particles from any carrier or agglomeration, so that the fine particles (diameter < 6 µm) may transit the oro- pharynx into the airways. ere are a number of ways to achieve this: first, turbulent energy can be created to empty the formulation from the dose location; second, the formulation can encounter obstacles that cause the active to separate from the carrier. Processes that involve vortices, accelerative forces and physical impact may all have a role. A consequence of these processes is that DPIs have a resistance to air flow. A patient will typically use a forceful, fast, deep inhalation maneuver. 20 ere has been considerable debate over whether a higher resistance may engender a longer inhala- tion effort or whether a lower resistance may feel easier. 21 is aspect sets DPIs apart from nebulizers and pMDIs that typically have very low resistance used carrier as it is safe, well tolerated, improves flow properties, and can be used as a taste signal. To pro- vide the high standards of consistency required for pharmaceutical use, lactose manufacturers have had to innovate and invest. 11 It had been thought that the first use of inhaled lactose as an inert carrier for powdered drugs was the Aero- halor; in terms of modern pharmaceutics, this cer- tainly appears to be correct. ere are, however, 19th century references to the use of sugar of milk or milk- sugar (saccharum lactis or lactose monohydrate). e Lesser Writings 12 of Samuel Hahnemann (1755- 1843), the founder of homeopathy, are clear regard- ing use of sugar of milk: "[it] is not a medicinal ingredient, it is a mere vehicle and recipient for the simple medicinal substance of the homoeopathic practitioner …" [from 1825]. Hahnemann further describes administration via olfaction of a phial of homeopathic powders diluted with sugar of milk [from 1827]. By 1858, a book detailing the unsci- entific basis for homeopathy 13 cited Hahnemann: "should both nostrils be stopped up by coryza or polypus, the patient should inhale by mouth, hold- ing the orifice of the phial betwixt his lips." It would seem, therefore, that if olfaction was not feasible, then inhalation of inert lactose powder (plus homeo- pathic substance) was recommended. During the intervening years, the early pioneers of powder inhalation (Trousseau, Burow, Ebert) were using sugar of milk to give powders "suffi- cient body." 4 It is fascinating to read Ebert's descrip- tion: "So minutely does the sugar of milk divide the nitrate, that if even a small portion of the powder only reach[es] the larynx, it will still contain the nitrate," and "… the patient is desired to draw in air rapidly and forcibly …." 14 It is apparent that the basics of dry powder inhalation—a large mass of inert carrier and a forceful inhalation—were known 170 years ago. Lactose can be manufactured to different sizes and, in some cases, optimum flow may be helped by a mix- ture of lactose types. e lactose carrier is separated from the active particle during the course of inhala- tion by de-aggregative processes that include turbu- lence and tortuous airways. 11 Because the carrier is diametrically too large to pass into the airways, it is deposited in the mouth and is used as a convenient confirmatory taste signal. Alternative carriers and additives have been used: mannitol, magnesium stea- rate as an aid to flow and with moisture control prop- erties, 13 and sodium cromoglycate—which has high moisture uptake properties—as a sacrificial moisture control component. 15 High levels of safety are para- mount for these carrier substances. Non-carrier approaches have also been used, for example, spheronization of drug into soft aggre- gates in early Turbuhaler ® (Astra) formulations, 16 permitting pure drug substance to be supplied, but