Development of innovative release strategies

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109 When a mixture of 5% of the hydrochloride and 15% of the base is used instead of pure base, the maximum piston force is slightly decreased. In numbers, 1.2 kN and 3.3 kN are required instead of 1.6 kN and 3.6 kN for RG 502 and RG 502 H, respectively. This can probably be attributed to the ball bearing effect of the hydrochloride that was discussed earlier ( V, 1.1).

Figure 64 ǀ Influence of different drug blends (fraction of oxybutynin hydrochloride + fraction of oxybutynin base = 20% of the total implant mass) on the implant diameter.

The implants consisted of 80% of RG 502 or RG 502 H and 20% of oxybutynin. Extrusion was performed using the standard program at 75 °C (mean ± standard deviation, n = 2).

Figure 64 displays the development of the implant diameters with increasing amounts of oxybutynin hydrochloride in the drug blends. For the most part, a connection to the maximum piston force can be established. The diameters, for example, were found to be greater for implants based on RG 502 H instead of RG 502. In addition, the strand thickness increases with the hydrochloride content. An exception is only formed for the corner points which represent pure base and pure hydrochloride. In the beginning, when the hydrochloride to base ratio is increased from 0:1 to 1:3, the strand diameter increases as well although the maximum piston force turned out to slightly decrease. An inverse effect becomes obvious as soon as pure hydrochloride is used instead of a drug blend consisting of 19% of the salt and 1% of the base. The maximum piston force was shown to increase while the implant diameter became smaller. This phenomenon cannot be explained so far.

Hence, it necessitates further investigations.

Figure 65 gives an overview of the in vitro release profiles that were obtained for the different drug blends. As can be seen, the combination of oxybutynin hydrochloride and oxybutynin base in one and

0,5 0,7 0,9 1,1 1,3

0 5 10 15 20

diameter [mm]

fraction of oxybutynin hydrochloride [%]

RG 502 RG 502 H

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the same implant is an innovative tool for precisely controlling drug release from PLGA matrices.

Even 1% of the base instead of the hydrochloride is enough to significantly alter the release characteristics. That way, every conceivable profile that ranges in between the limits given by the release of the pure drug substances can be realized. Dependent on the intended purpose, this might be much more effective than the replacement of the polymer. However, when the latter is combined with the use of different drug blends, a wide range of release profiles can be covered. The lag phase that refers to the release from RG 502-based systems, for example, can be shifted from 1 d to 14 d,

Figure 65 ǀ In vitro drug release from implants consisting of 80% of the polymer and 20% of a drug blend made from oxybutynin hydrochloride and oxybutynin base in 0.1 M phosphate buffer pH 6.0 at 37 °C (mean ± standard deviation, n = 3). Top: RG 502. Bottom: RG 502 H.

0 20 40 60 80 100

0 5 10 15 20 25 30

cumulative oxybutynin release [%]

time [d]

0% hydrochloride, 20% base 5% hydrochloride, 15% base 10% hydrochloride, 10% base 15% hydrochloride, 5% base 19% hydrochloride, 1% base 20% hydrochloride, 0% base

0 20 40 60 80 100

0 5 10 15 20 25 30

cumulative oxybutynin release [%]

time [d]

0% hydrochloride, 20% base 5% hydrochloride, 15% base 10% hydrochloride, 10% base 15% hydrochloride, 5% base 19% hydrochloride, 1% base 20% hydrochloride, 0% base

111 dependent on the composition of the drug blend. Higher hydrochloride to base ratios lead to more prolonged lag phases. Additionally, the increase of the release rates at the beginning of the erosion phase is more pronounced for implants with higher base contents. The drug release is finally completed between 21 d and 39 d (data not shown). For RG 502 H-based implants, similar results were found although the limits given by the pure drug substances were narrower.

If the release kinetics are compared to the results that were achieved for the maximum piston forces ( Figure 63), a correlation seems to be given. With increasing hydrochloride content, the maximum piston force increases as well. At the same time, the release becomes slower. This might be explained by the fact that the implants are of a higher density, that way decreasing the water uptake into the matrix. However, calculation of the rod densities revealed no significant differences.

Implants consisting of 80% of RG 502 and 20% of oxybutynin base, for example, had a density of 1.32 mg/mm³ ± 0.03 mg/mm³ whereas 1.34 mg/mm³ ± 0.01 mg/mm³ were obtained for their salt-containing counterparts. This leads to the conclusion that the maximum piston force does not influence the release rates.

INFO BOX #5

How is it possible to determine the content of the hydrochloride and the base at the same time?

As soon as the drug substances are dissolved, it is no longer possible to distinguish between the hydrochloride and the base. This is the reason why one and the same HPLC method can be used for the determination of the concentration.

In this thesis, a standard curve referring to oxybutynin hydrochloride was prepared. By means of the molecular weights of both APIs, this line through the origin was translated to the corresponding base. That way, two factors - the slopes - were obtained that allowed for the conversion of the peak areas into the concentration of either the hydrochloride or the base.

When drug blends were investigated, it was necessary to convert these factors once more. For example, the correction factor for a 3:1 mixture of oxybutynin hydrochloride and oxybutynin base was calculated as follows: factor_blend . 5 factorhydrochloride + .25 factor_base.

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