The preferred method for the administration of most drugs is via the oral route as conventional compressed tablet or dry-filled capsule formulations. However, there are a growing number of drugs and candidate drug compounds whose inherent solubility and permeability characteristics result in unacceptably low bioavailability when delivered from conventional oral formulations. Many times, standard manipulations aimed at enhancing bioavailability through improvements in the drug solubility or dissolution rate, such as particle size-reduction, or salt or crystal form selection, are either ineffective or do not enhance absorption sufficiently to make these traditional approaches viable options. In such instances, lipid-based formulations may offer an opportunity to enhance bio-availability through processes that impact physicochemical, and occasionally physiologic, mechanisms controlling drug absorption. Efforts to develop tablet formulations containing sufficient quantities of lipid and surfactant excipients to solubilize a poorly water-soluble drug have met with limited success due to the tendency for these excipients to compromise the physical integrity and mechanical strength of conventional compressed tablets. However, most lipid-based formulations are compatible with either hard gelatin capsule (HGC) or soft gelatin capsule (SGC) shells, which allow the development of commercially viable oral dosage forms. The dynamic nature of fully or partially-solubilized drugs in lipid formulations, however, requires careful control of manufacturing, packaging, and handling conditions to maintain the physical and chemical stability of drug and excipients alike, thereby ensuring consistent product performance.
EXCIPIENT SELECTION: GENERAL CONSIDERATIONS
The relationship between in vitro solubility in aqueous media and in vivo drug absorption is well established (1) and the most common reason that lipid excipients are considered for use in an oral formulation is to enhance drug bioavailability resulting from low aqueous solubility (2,3). However, lipid-based formulations can also improve drug absorption through inhibition of P-glycoprotein-mediated efflux (4,5), enhanced lymphatic drug transport and concomitant reduction of hepatic first pass metabolism (6-8), or through prolongation of gastrointestinal transit time, thereby allowing greater time for drug dissolution and absorption to occur (9). Lipid-based formulations have also proven useful in preparing stable formulations of moisture sensitive drugs (10).
The initial objective in excipient screening is to identify excipients or excipient combinations in which the drug has maximal solubility, with the objective of finding a formulation in which the entire drug dose can be solubilized in the fill volume of a single oral capsule of acceptable size. The selected drug concentration for the final formulation should be somewhat less than the maximum solubility in the chosen excipient mixture over the anticipated range of processing and storage temperatures to safeguard against precipitation of the drug. In instances where the drug dose cannot be fully solubilized in the fill volume of a single capsule, the formulator may choose to deliver the drug as a partially solubilized lipid suspension. In addition to simple lipid solution formulations, emulsions (11), self-emulsifying drug delivery systems (SEDDS) and self micro-emulsifying drug delivery systems (SMEDDS) (discussed in detail in Chapter 5), are combinations of lipids, surfactants, and cosurfactants, that have found application for enhancing and normalizing drug absorption (12-14).
Developing a viable lipid based oral drug formulation with acceptable performance characteristics requires the formulator to maintain the solubility and stability of the drug in an excipient blend that does not adversely interact with the capsule (15). Unexpected precipitation of the drug in the dosage form may result from a number of factors, including insufficient solubility in the excipient matrix, loss of a volatile solubilizing excipient (e.g., ethanol), changes in storage temperature, or migration of water into the formulation from the capsule shell or the environment. In addition, the potential dehydrating effects of some excipients on HGCs can lead to loss of moisture and brittleness or fracture of the capsule shell, which can sometimes be remedied by using SGC, which contain higher levels of plasticizers (propylene glycol, sorbitol, and glycerol) and water.
The low hygroscopicity of the thermo-softening excipients not only makes them particularly compatible with HGC, but also frequently yields final products that are relatively resistant to moisture-induced drug precipitation (16). These excipients are available within a range of melting points and hydrophile-lipophile balance (HLB) values and provide the formulator with latitude for creating specific drug release characteristics in the final product. Examples of these excipients include the Gelucire® and Capmul® lines of derivatized glyceride excipients from Gattefosse and Abitec respectively, and the Cremophor® or Solutol® lines of polyoxyl castor oil and polyethylene glycol derivatives, respectively, from BASF Corporation. These excipients exist as waxy solids or semisolids at typical ambient temperatures and require melting prior to capsule filling; this limits their use to HGC that tolerate temperatures up to 70°C. In addition to being relatively nonhygroscopic, and therefore compatible with HGC shells, the high viscosity of thermo-softening excipients obviates the need for capsule sealing operations, which are required to prevent leakage when using formulations that are liquid at ambient temperatures. For those compounds intended to remain completely solubilized (in the semi solid matrix) at ambient temperatures it is important to develop a quantitative sense of the potential for in situ precipitation or crystallization upon cooling and storage. Direct determination of drug solubility in the congealed excipient matrix is challenging for obvious reasons; however, a solubility estimate may be obtained by back-extrapolation from drug solubility values determined at a series of temperatures at which the excipient is molten. Alternatively, the physical state of the drug in the congealed matrix can be confirmed by using a combination of analytical techniques, including X-ray diffraction, microscopy (polarized light or hot stage) and thermal analysis [Differential Scanning Calorimetry (DSC) or modulated DSC], which together can identify eutectic mixtures, two phase systems, and glassy states of a drug substance (17). For example, correlating the visual changes in the crystalline form of a formulated drug observed during hot stage microscopy with the quantitative thermal events recorded during DSC analysis can be useful for defining the drug solubility range and physical state in the excipient matrix. In addition to physical characterization, the chemical stability of the drug in the molten excipient matrix should be determined over the time and temperature ranges to which the drug will be exposed during manufacturing operations.
When developing formulations using thermo-softening excipients, it is essential to characterize and control the physical state of the excipient matrix, which can crystallize upon congealing. In order to destroy any preformed crystalline structure and to ensure homogeneous dispersion of the multiple components contained in these excipients (e.g., the lauryl macrogolglycerides), the excipient manufacturers recommend liquefying the entire contents of the bulk container by heating to 10°C
above the nominal melting temperature followed by thorough mixing prior to use in formulating. Removal and use of portions of bulk containers prior to the melting and mixing step is not recommended and may produce final products, which vary in physical and performance characteristics. Most manufacturers recommend that a given batch of excipient be exposed to no more than three or four melting/cooling cycles to minimize thermally-induced accumulation of peroxides or free fatty acids, which can catalyze drug degradation. For this reason, it is a good practice for the scientist to divide the melted and mixed bulk excipient material into a number of smaller aliquots to support formulation development activities.
The crystalline forms of these excipients that control drug solubilization and release characteristics, are influenced by the thermal history acquired during the product handling and processing procedures (18,19), which if not adequately controlled, will lead to variation in the product in vitro dissolution profile and possibly, in vivo performance. The crystalline form of the excipient matrix can be controlled through postmanufacturing annealing or by careful and consistent control of the congealing process (20). Annealing that involves holding the final product at a controlled, elevated temperature for a predetermined period of time, is used to accelerate conversion of a thermo-softening excipient to its most stable crystalline form. The annealing time may range from a period of several hours to several days, with the duration inversely related to the annealing temperature. For example, the conversion of Gelucire 50/13 to its stable ft crystalline form, requires several months at 25°C, but can be driven to completion in less than two days by annealing at 40°C (21).
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