Release profiles

A dmg deHvery system is a vehicle that provides a stable environment to store an active ingredient prior to usage, and controls the release of the dmg duting usage. Typically, it is desirable for the system to be stable for a period of at least two years from the date of manufactuting. The type of release profile depends on the strategy to optimize the therapeutic effect, eg, sustained, constant, or specific temporal patterns. 

The PVFj gauge has been calibrated up to 4 GPa (Bauer, 1984) for both shock loading and release. Graham and Lee (1986) have extended these calibration studies to about 20 GPa, and have measured both a shock loading and release profile in sapphire at 12 GPa, as indicated in Fig. 3.15. 

Toxicological profiles are revised and republished as necessary, but no less than once every three years. For information regarding the update status of previously released profiles, contact ATSDR at ... 

Preliminary data are consistent with the presence of —OH groups on the surface of SDIBS." These polar surface groups can also be used to reversibly hydrogen bond dmgs onto the surface, gaining control over subsequent dmg release profiles. 

Recently, Brich and coworkers (40) reported the synthesis of lactide/glycolide polymers branched with different polyols. Polyvinyl-alcohol and dextran acetate were used to afford polymers exhibiting degradation profiles significantly different from that of linear poly-lactides. The biphasic release profile often observed with the linear polyesters was smoothened somewhat to a monophasic profile. Further, the overall degradation rate is accelerated. It was speculated that these polymers can potentially afford more uniform drug release kinetics. This potential has not yet been fully demonstrated. 

In vitro release profiles on phase II and phase III clinical supplies prepared more than 2 years apart are shown in Fig. 2. SeveT al thousand doses were prepared for the phase III trial initiated in 1988. Figure 3 shows the reproducibility of six individual batches of microspheres produced by the solvent evaporation method. Other studies have been reported with similar processes (47). 

FIGURE 2 Comparison of in vitro release profiles of phase II and phase III clinical batches of 90-day norethisterone microspheres. 

FIGURE 3 Batch-to-batch reproducibility of 90-day norethisterone microspheres as determined by in vitro release profiles. 

The in vitro release profiles of many microsphere formulations including steroids can be determined by an ethanol/water model (74). By adjusting the ethanol/water ratio in the receiving fluid, the rate and duration of release can be optimized to afford a rapid evaluation tool for developmental and quality control purposes. The model is not intended to have one-to-one correlation with in vivo results. 

These two methods produce different release profiles in vitro. Figure 5 demonstrates the release kinetics of BCNU from wafers loaded with 2.5% BCNU pressed from materials produced using these two methods. The wafers containing tritiated BCNU were placed into beakers containing 200-ml aliquots of 0.1 M phosphate buffer, pH 7.4, which were placed in a shaking water bath maintained at 37 C. The shaking rate was 20 cycles/min to avoid mechanical disruption of the wafers. The supernatant fluid was sampled periodically, and the BCNU released was determined by liquid scintillation spectrometry. The BCNU was completely released from the wafers prepared by the trituration method within the first 72 hr, whereas it took just about twice as long for the BCNU to be released from wafers... 

When norethindrone is incorporated into the matrix along with a water-soluble salt, the norethindrone release profiles shown in Fig. 

FIGURE 5 Erosion release profile for radioactive progesterone from a a mixed-substituent imidazolyl/p-methylphenoxyphosphazene polymer. 31.)... 

FIGURE 4 Release profiles of model dyes from compression-molded discs of poly(N-palmitoylhydroxyproline ester) (22). (a) Release of... 

The process of formulation for any of the above is generically the same, beginning with some form of product specification and ending with one or more formulations that meet the requirements. Correct choice of additives or excipients is paramount in the provision of efficacy, stability, and safety. For instance, the excipients may be chemically or physically incompatible with the drug or they may exhibit batchwise variability to such an extent that at the extremes of their specification they may cause failure in achieving the desired drug release profile. In addition, some excipients, especially those that are hydroscopic, may be contraindicated if the formulation is to be manufactured in tropical countries. Flence formulators must work in a design space that is multidimensional in nature and virtually impossible to conceptualize. 

Release profiles of these immunogens ean be improved through their formulation with adjuvants (Chapters 14, 15), and the immunogenieity of certain purified baeterial eomponents such as polysaccharides ean be improved by their conjugation to a carrier. 

Figure 7. In Vitro Release Profile of PHPG-Prazosin Conjugate (Loading 23.9%w/w).

In vitro release of methotrexate from the LDI based films is shown in Figure 7. The release was fast since the drug was imbedded in a thin film, in the order of 50 to 100 microns. The release profile was typical of one seen in diffusion controlled systems. The scattering of the release data was again reminiscent of the mass loss results, and the cause of that is not certain at this point... 

Iyer et al. [50] investigated the effects of roto-granulation on the performance of hydroxypropyl methylcellulose (HPMC), gelatin, and poly(-vinylpyrrolidone) (Povidone, PVP). In this process, all three binders produced similar results. However, HPMC was preferred due to prolonged drug release profiles, smaller particle size, and better content uniformity. 

In order to produce an adequate tablet formulation, certain requirements, such as sufficient mechanical strength and desired drug release profile, must be met. At times this may be a difficult task for the formulator to achieve, due to poor flow and compactibility characteristics of the powdered drug. This is of particular importance when one only has a small amount of active material to work with and cannot afford to make use of trial-and-error methods. The study of the physics of tablet compaction through the use of instrumented tableting machines (ITMs) enables the formulator to systematically evaluate his formula and make any necessary changes. 

Simple hydrodynamic analysis of the in vitro mechanism indicates that the elution concentration, in the absence of absorption, is a linear kinetic process, with a release profile that scales as the ratio of the tear production to the volume of the tear reservoir, fV/f V. Specifically ... 

Fig. 8 Comparison of time-release profiles from three different preparations of betaxolol (—) drug solution representing marketed product (--------) supension formulation (-----------) gel formulation.

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