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SOLUBILITY
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the reduction of crystallinity of the compound or the introduction of hydrophilic/ionizable groups. A good example of the latter is the protease inhibitor Crixivan® (indinavir) [12]. Here the introduction of an ionizable moiety (a substituted piperazin) signifi cantly increased the aqueous solubility and thereby contributed to an increase from low bioavailability for some analogs to substantial human bioavailability for the drug itself.
Despite all the progress made related to the prediction of solubility, oral bioavailability, and overall developability of drug candidates over the last 15 years, an undeniable and signifi cant trend towards a higher fraction of poorly soluble (BCS class II and IV) compounds became evident in the innovator pipeline of developmental drugs recently [13]. It has been discussed that three main factors contributed to that trend [7]:
• • •
addition of lipophilic residues to achieve an increased ligand-receptor affi nity
general broadening of the chemical space driven by the use of combinatorial chemistry, and
introduction and use of high-throughput screening.
This very trend towards candidates with potentially poor oral bioavailability might be further exacerbated by the current interest in the area of polypharmacology and the related use of framework combination methods, which are being applied towards the design of NCEs which hit multiple pharmacological targets simultaneously [14].
While one may look at the continued trend towards more lipophilic drug candidates as both counterintuitive and discouraging, one can also look at it from a diff erent perspective. The breadth of today’s pharmacological targets drives the portfolios of developmental NCEs to rather high heterogeneity. While this comes with certain challenges for the further development of the corresponding drug candidates, the opportunities for the patient likely outweigh the initial drawback. In order to fully exploit these opportunities, the application of developability methods in discovery must be complemented by additional sophisticated methods including salt or co-crystal formation (for recent reviews see [15,16]) and/ or formulation design approaches (see below) in development to minimize overall portfolio attrition and bring more valuable medicines to the patient.
Formulation/Drug Delivery System Design
In case a novel drug substance has favorable physico-chemical and biopharmaceutical properties, e.g. stability, solubility in aqueous media, permeability of biological membranes, suffi cient biological half-life for once-a-day dosing, and a broad therapeutic window, formulation scientists have a substantial array of techniques to choose from and typically focus their development activities on immediate release (IR) dosage forms, such as standard fi lm-coated tablets or hard gelatin capsules.
32 | | September/October 2013 - 15TH ANNIVERSARY ISSUE Controlled Release Dosage Forms
In case the drug at hand has a short biological half-life and/or a narrow therapeutic window, controlled release (CR) dosage forms typically will be at the center of interest of the development team, in order to allow for a reduced dosing frequency and constant plasma concentrations, which can ultimately translate into better patient adherence to the drug regimen and thus contribute to improved patient outcomes.
Since the mid-1960s, various types of CR dosage forms have already been established, including matrix-systems, microspheres, pellets, micro capsules and micro tablets, and (more recently) bio-adhesive drug delivery systems, among others [17]. The aforementioned technologies have been optimized over the years and Ambien® CR (zolpidem tartrate) is one example of several for the application of matrix CR technology. CR systems based on osmotic pressure, like single-chamber osmotic pumps, multi-chamber osmotic pumps and additional types have been established more recently [18]. Glucotrol® XL (glipizide) is an example for an osmotic pump-based system.
Orodisperible Drug Products
The need for rapid drug delivery together with the need for easy-to- swallow oral drugs in certain patient populations (including pediatric and geriatric patients) has triggered an important trend towards orodispersible tablets and fi lms. Signifi cant progress has been made over the past 15 years in this area and the term ‘orodispersible’ meanwhile has been introduced both into the United States Pharmacopeia and into the European Pharmacopeia [19]. Orodispersible tablets are typically un- coated and supposed to disperse in the oral cavity before swallowing within a timeframe of three minutes or less. A multitude of formulation and processing technologies can be applied to produce orodispersible tablets [17] as displayed in Figure 2.
Over 25 diff erent orodispersible drugs have been introduced to the market including the tablet product Zyprexa® Zydis (olanzapine) and Zuplenz® (odansentron), the fi rst prescription drug based on an orodispersible fi lm, which was approved by the FDA in 2010 [20].
Figure 2. Manufacturing of orodispersible tablets
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