Drug Delivery
the pharmacology induced by the biopharmaceuti- cal in both humans and the candidate preclinical safety species is therefore required, and studies should only be performed in appropriate species. This may mean that a single species approach is sufficient and there are many examples of biophar- maceuticals which received subsequent regulatory approval following evaluation in a single species. Due to the strong emphasis on pharmacology, non-clinical safety programmes in early-stage development are product specific and unless the biopharmaceutical has a chemical modification, may omit some studies that are routinely found in NCE preclinical safety work packages, such as genetic toxicology studies. Moreover, for most bio- pharmaceuticals, safety pharmacology end-points are undertaken on a risk-based approach and are often incorporated into the design of pivotal repeat-dose toxicity studies in pre-clinical research, with investigations in a single species commonly being acceptable. Depending on the mechanism of action of a specific biopharmaceutical, respiratory safety pharmacology may need to be supplemented with investigations of other systems that may be targeted such as the central nervous system. The feasibility of such investigations requires very care- ful consideration, especially with reference to the selected pharmacologically relevant species.
Inhaled biopharmaceutical formulations and devices
Inhaled drugs that have progressed through discov- ery and into development tend to be formulated in one of two ways; either as liquid formulations, where treatments are commonly administered in a hospital environment or with the assistance of an experienced carer, or as a powder, which is gener- ally acknowledged to be more efficient, stable and convenient for patients.
For powders, crystalline forms are more thermo- dynamically stable and typically more chemically stable than amorphous material. However, amor- phous powders are more common than crystalline as they have the ability to wrap round but amor- phous powders are very hygroscopic requiring careful handling and stabilisation, for example from dehydration, thermal, shear, oxidation, light and pH. Particle engineering techniques such as lyophilisation, spray drying or vacuum foam dry- ing are often used in preference to traditional man- ufacturing techniques such as micronisation as they aid with these stability considerations and ensure structural integrity of the biopharmaceuti- cal. The added advantage with these particle engi- neering techniques is they offer control with parti-
56
cle density, size, morphology and surface character- istics in order to enhance both the particle popula- tion aerodynamic characteristics and preserve the biopharmaceutical chemical structure when formu- lated with excipients. Various excipients that have been used include mannitol, trehalose, sucrose, leucine, reflinose, tween-20, sodium chloride, saccharide, surfactant, sodium citrate and citric acid. Importantly, if a novel excipient is required for the formulation then it may be necessary to perform a safety assessment of the excipient alone as well as in the final drug product.
Most biopharmaceuticals show good aqueous solubility for liquid formulations. Nonetheless, liq- uid formulations can have limits with viscosity, ionic strength and surface tension which will impact output and drug concentration. Similarly to powder, excipients are added to pro- vide a viable formulation. Common excipients and functions are shown in Table 1.
It is not essential to use the nebuliser device pro- posed for clinical studies for pivotal GLP toxicolo- gy studies. Often this not practical or feasible as the generation characteristics of the clinical device are not suitable for delivery of the test material to the non-clinical species in question (eg the need to generate smaller aerosol particle sizes for delivery to rodents) or compromised output as it is impor- tant to maximise the delivery of active drug by selecting the most appropriate device(s) as there are a number of device types, each associated with their own advantages and disadvantages. Device compatibility is crucially important. Though Pressurised Metered Dose Inhalers (pMDI) formulations are not easily compatible with biopharmaceutical drugs due to the inherent temperature, pressure and excipient aspects, in some cases there may be viable approaches to sta- bilise the drug product. An alternative approach to nebulisers and pMDIs are soft mist devices, which provide a pMDI-like dosing experience with an aqueous solution product. However, one of the drawbacks with these delivery products is the requirement for high concentrations, as well as the forces involved in delivering the formulation, which may prove incompatible for drug products where large doses are needed.
In contrast to MDIs, which require the patient to co-ordinate breathing-in with actuating the dose by hand, dry powder inhalers (DPIs) generally require little or no hand-breath co-ordination, and they can deliver quite high payloads with a quicker dosing time than nebulisers. However, additional pre-formulation, formulation and device screening
Drug Discovery World Winter 2017/18
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72
