14 Characterization of Microcapsules Containing Naltrexone
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or Naltrexone Pamoate CURT THIES Department of Chemical Engineering, Washington University, St. Louis, Mo. 63130
Introduction The concept of long-acting injectable drug formulations has intrigued pharmaceutical scientists for some time. One way to prepare the desired formulations i s to synthesize drug-filled microcapsules that can be injected. The coating material used to form such capsules must not only provide controlled drug release, but also be biocompatible and bioabsorbable. These requirements severely r e s t r i c t the number of acceptable coating materials. However, one promising material i s d1-poly(lactic acid)(d1-PLA). I n i t i a l results of efforts to develop injectable microcapsules with d1-PLA as the coating material focused on cyclazocine, a narcotic antagonist (1). More recent work has focused upon the use of d1-PLA to encapsulate naltrexone free base (NFB), also a narcotic antagonist, and naltrexone pamoate (NP), the pamoate salt of naltrexone free base. This paper describes some of the properties of selected NFB and NP microcapsule samples. Experimental Microcapsules containing NFB or NP were prepared with d1poly(lactic acid) supplied by Dr. Donald Wise of Dynatech R/D CO., Cambridge, Mass. The capsules contained 33 wt. % NFB or 50 wt.% NP. Several capsule fractions were isolated from each capsule batch by sieving. For each capsule fraction, the smaller number given represents the size of the rectangular screen opening which retained the microcapsule, whereas the larger number represents the size of the rectangular screen opening through which the capsules passed. In vitro release properties of the capsules were evaluated at 37°C i n pH 7.4 phosphate buffer. A l l evaluations were carried out i n a rotating bottle apparatus (40 rpm) manufactured by Ernest Menold, Lester, Pa. The test samples consisted of 15 mg of capsules suspended i n 75 ml of buffer. Concentration of
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In Controlled Release Polymeric Formulations; Paul, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1976.
Downloaded by UNIV OF CALIFORNIA SAN DIEGO on December 4, 2015 | http://pubs.acs.org Publication Date: June 1, 1976 | doi: 10.1021/bk-1976-0033.ch014
14.
THiES
Microcapsules
Containing
Naltrexone
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naltrexone in the extracting solution was established spectrophotometrically by using the 282 nm band characteristic of naltrexone. Evaluation of microcapsules containing NP was complicated by non-stoichiometric diffusion of naltrexone and pamoic acid from such capsules. Pamoic acid has an absorbance maximum at 288 nm. NP release curves based on changes i n magnitude of this peak were constructed. However, NP capsules which released their payload over a prolonged period did not release naltrexone free base and pamoic acid i n a 1:1 molecular ratio. For this reason, extracts from such NP capsules were acidified to pH 2.0 with HC1. This precipitated nearly a l l of the pamoic acid, so the concentration of naltrexone l e f t i n solution could be established from i t s absorption maximum at 282 nm. Controls containing only pamoic acid were treated similarly i n order to determine the amount of pamoic acid remaining i n solution at pH 2.0. This contribution to the 282 nm maximum of naltrexone was then subtracted from a l l actual test runs i n order to give corrected values of the amount of naltrexone released by the capsules. Release data have been plotted as mg NFB or mg NP released by 15 mg capsules as a function of extraction time. Results and Discussion Figures 1 and 2 contain i n vitro release data for capsules isolated from representative NFB and NP encapsulation runs. Figure 1 shows that the NFB capsules being evaluated release -50% of their payload within the f i r s t few hours of extraction; the remaining NFB i s leached out over a three week period. After the f i r s t surge of NFB release, NFB extraction from the capsules i s essentially zero order. The relatively large amount of NFB released by the capsules i n i t i a l l y i s attributed to rapid and essentially complete release of NFB from capsules that have gross defects in their walls. The solubility of NFB i n pH 7.4 buffer at 37°C i s -450 mg/100 ml. This does not suffice to classify NFB as a highly water-soluble drug. Nevertheless, the solubility i s sufficiently great to ensure rapid and complete removal of NFB from defective
