Pain Management

Ibuprofen is one of the most commonly used non-steroidal anti-inflammatory drugs (NSAID) for the management of mild to moderate pain. It is very

Table 1 Mean Pharmacokinetic Parameters and Relative Bioavailabilities for the Three Formulation Approaches

Treatment: dose, formulation

(ng-h/mL)

Frel (%)

50 mg, cosolvent-surfactant solution

1-2 1160

6960

100.0

50 mg, solid dispersion

1-2 803

6900

99.1

50 mg, dry blend (micronized drug)

1 128

681

9.8

slightly soluble in water (50 mg/mL) but highly permeable through physiological membranes (24). The bioavailability of ibuprofen from conventional dosage forms is typically high with approximately 80% of an oral dose absorbed from the GI tract (25). Although it is well absorbed, the onset of action of ibuprofen can be somewhat delayed due to its poor aqueous solubility. Since rapid onset of action is preferred with anti-inflammatory agents, overcoming the solubility limitations of the drug could improve the efficacy of ibuprofen and the management of acute pain. In a recent clinical study conducted by Klueglich et al. a solid dispersion technology known as Meltrex® was evaluated for improving pain therapy with ibuprofen by accelerating the onset of therapeutic action (26). Hot-melt extrusion is the basis of the Meltrex technology, and the process is used primarily to produce drug delivery systems that contain the active ingredient in a more readily soluble form (27). For this study, the Meltrex system was utilized to produce a molecular dispersion of ibuprofen in a hydrophilic polymer matrix such that the dissolution rate of the drug becomes dependant on the dissolution rate of the polymer matrix rather than the drug itself (28). Hence, by eliminating the solubility constraints that impede the dissolution rate of ibuprofen, it was hypothesized that the drug would be more readily absorbed following oral administration and the time to onset of therapeutic action would be reduced.

In a clinical study with healthy male subjects, the Meltrex ibuprofen formulation was compared to a traditional ibuprofen tablet as well as a tablet containing a chemical derivative of ibuprofen, ibuprofen lysinate. This derivative of ibuprofen has shown improved solubility, rate of absorption, and faster relief of pain over conventional ibuprofen (29). The ibuprofen plasma concentration versus time profile from this study can be seen in Figure 3. These results demonstrated the bioequivalence of the Meltrex formulation and the ibuprofen lysinate formulation based on AUC0-m, Cmax, and tmax. In the fasted state, the pharmacokinetic profile of the extrudate formulation was found to differ from the traditional ibuprofen tablet in that the Cmax was 20% greater and the tmax occurred almost one hour earlier, yet the total AUC was approximately equal. Therefore, total ibuprofen exposure between the extrudate and traditional ibuprofen formulations was equivalent; however, absorption was much more rapid with the extrudate formulation. The authors therefore concluded that since the pharmacological effect of ibuprofen has been shown to be correlated with serum concentrations these in vivo results suggest that a more rapid onset of action was achieved with the extrudate formulation. This study demonstrated that formulation of ibuprofen as a molecular dispersion by the Meltrex technology successfully overcomes the solubility limitations of ibuprofen to provide more rapid absorption following oral administration than conventional ibuprofen tablets, and hence presumably allows for faster onset of therapeutic action.

Figure 3 Geometric mean Ibuprofen plasma concentrations following single oral administration of a 400-mg ibuprofen extrudate (square), lysinate (triangle), and regular (diamond) tablet under fed (filled) and fasted (open) conditions, respectively.

ABT-963 is a selective COX-2 inhibitor that is used for the treatment of pain and inflammation (30). The compound is very poorly water-soluble with a saturation solubility of 16 mg/mL in water at 25°C. A preliminary pharmacokinetic study in dogs conducted by Chen et al. revealed that the bioavailability ABT-963 was 24% from capsules containing the bulk drug, and absorption was determined to be dissolution rate limited (31). This preliminary pharmacokinetic evaluation prompted these researchers to evaluate a solid dispersion system as a potential solution to overcoming the solubility limitations of the compound that restricted its oral bioavailability. Hence, a melt method was adopted in which ATB-963 was dispersed in molten Pluronic F-68. Pluronic F-68 is a water soluble, non-ionic, surface active copolymer which has been used extensively in pharmaceutical preparations as a solubilizing agent and in solid dispersion systems to improve the solubility of active agents (32-34). In solubility studies performed by Chen et al. it was found that Pluronic F-68 had a substantial solubilizing effect on ABT-963, and therefore was selected as the carrier for the solid dispersion. The use of DSC and PXRD confirmed that the drug was in a crystalline state following production of the solid dispersions for all drug loadings. The presence of an active ingredient in a crystalline state is less common in solid dispersion formulations than the amorphous counterpart because for many drugs the thermodynamic stability of the crystal lattice is the primary obstacle to improving the drug's dissolution properties. However, with respect to stability, a crystalline dispersion would be preferred as amorphous solid dispersions are often thermodynamically metastable, and thus drug recrystallization and a corresponding decrease in dissolution rate can occur on storage. This example of ABT-963 as a crystalline solid dispersion in Pluronic F-68 is therefore unique as it was shown by dissolution testing to provide substantial improvement in the dissolution rate of the drug without a morphological change.

The Pluronic F-68 dispersion and a conventional immediate release (IR) wet granulation formulation were dosed to dogs in capsules with a solution of the drug in PEG 400 as a reference. The plasma concentration versus time curve from this study is shown below in Figure 4, and the PK parameters are shown in Table 2. The results of this in vivo study demonstrated that the ATB-963 solid dispersion formulation provided comparable drug plasma concentrations to the PEG 400 solution with a relative bioavailability of 94.1%. The traditional immediate release granulation formulation was found to have a much lower relative bioavailability of 46.5%. Additionally, the solid dispersion formulation was found to produce less inter-subject variability than the IR formulation. The increased plasma concentration implies improved therapeutic action with the solid dispersion formulation over the IR formulation. Hence, this study exemplifies the use of a crystalline solid dispersion system to improve

Figure 4 Plasma concentration of ABT-963 following oral administration of PEG solution and capsule formulations to fasted dogs.

Figure 4 Plasma concentration of ABT-963 following oral administration of PEG solution and capsule formulations to fasted dogs.

Table 2 Pharmacokinetic Parameters of ABT-963 after Oral Dosing of 50-mg ABT-963 in Capsules and PEG Solution in Fasted Dogs

Table 2 Pharmacokinetic Parameters of ABT-963 after Oral Dosing of 50-mg ABT-963 in Capsules and PEG Solution in Fasted Dogs

C

T

AUC

AUC/D

BAa

Formulation

(Hg/ml)

(h)

(Hg-h/ml)

( M-g ' h/ml/mg/kg)

(% relative)

IR capsule

1.86 ± 1.28

2.1 ± 1.1

34.2±25.6

8.1 ±5.3

46.5 ±27.2

Solid dispersion13

3.62± 1.00

5.2 ± 5.8

64.6 ±19.2

16.0 ±4.1

94.1 ±20.0C

PEG solution

4.00±0.88

3.2±5.0

70.1 ±11.5

17.0±2.4

a Bioavailability relative to PEG solution.

b Cnax and AUC of the solid dispersion formulation were normalized from 40 mg dose to 50 mg dose. "Significantly different between the IT and solid dispersion formulations (P<0.05).

a Bioavailability relative to PEG solution.

b Cnax and AUC of the solid dispersion formulation were normalized from 40 mg dose to 50 mg dose. "Significantly different between the IT and solid dispersion formulations (P<0.05).

the dissolution properties and oral absorption of a poorly water-soluble NSAID, ultimately resulting in improved management of acute pain.

Indomethacin (IND) is another example of an NSAID which has shown improved efficacy by formulation as a solid dispersion. Chowdary and Babu utilized a solvent evaporation technique to produce amorphous dispersions of indomethacin with hydroxypropyl cellulose-SL (HPC-SL), HPMC, and hydroxyethyl cellulose (HEC) (35). All formulations showed substantial improvement in dissolution rate, with the greatest improvement being with the HPC-SL formulation. In vivo studies were conducted in healthy fasted human volunteers with the IND-HPC-SL and IND-HPMC solid dispersion formulations using bulk IND as a reference. The results of this study demonstrated that faster absorption and higher serum levels were achieved with the solid dispersion formulations. The mean absorption rate constants (ka) and AUC0-3hr values for the IND, IND-HPMC, and IND-HPC-SL doses were 0.5159, 0.6879, 0.9016 h-1 and 1.72, 2.02, 2.44 |ig-h/mL; respectively. However, the AUC0_M values were similar for all formulations indicating that total IND exposure was similar for each formulation. Therefore, as with the ibuprofen solid dispersion system, formulation of IND as an amorphous dispersion in cellulosic polymers did not enhance overall bioavailability, but rather accelerated the onset of therapeutic action. A good correlation was found between the in vitro dissolution results and in vivo absorption as the IND-HPC-SL formulation exhibited the most rapid dissolution rate and had the greatest ka value. This result further confirmed that the onset of therapeutic action of IND is dissolution rate limited. Therefore, this study indicated that the efficacy of orally administered IND in treating acute pain or inflammation is improved by formulation as a solid dispersion owing to an accelerated rate of absorption.

Piroxicam is another drug from the family of NSAIDs that is classified as a BCS class II drug. Oral piroxicam is typically indicated for treatment of osteoarthritis and rheumatoid arthritis and not for analgesia owing to slow and gradual absorption with a long elimination half-life (36). This pharmacokinetic profile provides prolonged therapeutic action; however, the onset of anti-inflammatory or analgesic action is delayed. Therefore, as with the previously discussed NSAIDs, treatment of acute pain and inflammation with piroxicam could be improved by formulating the drug in a manner that accelerates drug dissolution and promotes rapid absorption.

Yuksel et al. evaluated a solid dispersion of piroxicam in a carrier system composed of Gelucire 44/14 and Labrasol (37). The dispersion was produced by a melt method in which piroxicam was stirred into the molten carrier system and subsequently the molten dispersion was filled into hard gelatin capsules. The solid dispersion system of piroxicam was comparatively evaluated against bulk piroxicam and a commercially available tablet containing piroxicam-p-cyclodextrin complexes for in vitro drug release and in vivo absorption. Dissolution tests were conducted in various media and while the bulk piroxicam showed pH-dependant and incomplete dissolution, the solid dispersion formulation provided rapid dissolution of piroxicam (85% in 30 min) irrespective of pH. The commercial tablet also showed substantial improvement in the dissolution properties of piroxicam; however, some pH-dependence was found with a reduction in release rate at pH 4.5. The in vivo performance of these three piroxicam formulations was evaluated in healthy human volunteers. An equivalent of 20 mg of piroxicam was dosed to each subject with the bulk drug and solid dispersion dosed in hard gelatin capsules. This study revealed that the solid dispersion formulation provided the greatest maximum concentration (2.64 mg/mL) in the shortest time-to-peak (82.5 min), followed by the commercial tablet (2.44 mg/mL, 120 min) and the bulk drug (0.999 mg/mL, 144 min). These results indicated that the solid dispersion and commercial tablet formulations performed substantially better than the bulk drug with respect to rate and extent of absorption, with the solid dispersion formulation providing greater acceleration of absorption than the commercial tablet. With respect to overall absorption, the solid dispersion and commercial tablet formulations showed statistically equivalent total AUC values which were over two-fold greater than that of the bulk drug. Thus, in this case, the advanced formulation designs were able to improve the initial rate and extent of absorption, as well as total exposure over that of the bulk drug.

The studies discussed above illustrate how the use of solid dispersion formulation technologies can improve drug therapy for the management of acute pain and inflammation with BCS class II NSAIDs. In the studies reviewed, it was repeatedly demonstrated that poorly soluble drugs can be rendered more soluble via solid dispersion systems by the individual or synergistic effects of particle size reduction, morphology alteration, and improved particle wetting properties by intimate association with hydro-philic carrier systems. It is by these modifications that dissolution rates of the above mentioned NSAIDs can be dramatically improved. Since the absorption of these drugs form the GI tract is primarily limited by the rate at which they enter solution in the gastrointestinal lumen, solid dispersion systems directly promote absorption of these drugs by accelerating their dissolution rates. For acute pain management, accelerated absorption relates directly to the onset of therapeutic action, and hence solid dispersion formulations appear to provide more therapeutically effective oral doses of BCS class II NSAIDs than traditional formulations.

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