Patent Application
20070281017
The sole FIGURE is a graph depicting the release rate over time with various Mg(OH)2 levels.
The invention uses a controlled release matrix to control the release of a therapeutic ingredient. The compound can be formed into suitable solid oral dosage forms by any suitable method as is commonly known in the art. Tablets are the preferred dosage form. To obtain controlled release effects, the matrix comprises a combination of an acrylic polymer and metal hydroxide. Reliance on a controlled release coating is unnecessary.
Many conditions may benefit from the prolonged treatment effects of controlled release products. Accordingly, many therapeutically active ingredients may be used in a controlled release manner. Pain medications are perhaps most visibly effective when administered through controlled release methods. Thus, although oxycodone and its pharmaceutically active salts are preferred, many other active ingredients may be used. Morphine and its pharmaceutically acceptable salts, oxymorphone, hydromorphone, levorphanol, codeine, hydrocodone, oxycodone, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine, and other common narcotics and analgesics are non-limiting examples of such active ingredients.
Unlike prior art of sustained or controlled release products, the acrylic polymer in the present invention is used as a dry excipient, and not a sustained release coating. It is to be understood that the polymer may be present as coating, but is not necessary to achieve the desired results. The acrylic polymer is combined with the metal hydroxide into a homogeneous matrix into which the active ingredient is introduced. Surprisingly, the inventors have discovered that the rate of release of the active ingredient can be unexpectedly controlled by varying the ratio of metal hydroxide to acrylic polymer (H/P), rather than rely solely on the rate of disintegration or dissolution of the acrylic polymer. With this discovery, the amount of active ingredient and acrylic polymer may be kept constant while achieving various release rates solely through manipulation of the amount of metal hydroxide. An H/P ratio of 0.001-0.5 by weight is contemplated by the inventors. A preferred ratio of 0.002-0.1 H/P by weight has been effective, as illustrated in the figure.
The preferred acrylic polymer is methacrylate based. Most specifically, an ammonio methacrylate polymer readily available under the tradename Eudragit RSPO is preferred. As mentioned above, Eudragit is cited in the prior art for coatings. The polymer may account for a wide range of proportions in the tablet as long as the proper H/P ratio is mentioned.
Minimal amounts of magnesium hydroxide, about 0.1-5% by total tablet weight, have been found to be effective. The figure illustrates the effects of compounds prepared with 0, 1, 3, and 5% magnesium hydroxide, the preferred metal hydroxide, corresponding to 0, 0.02, 0.06, and 0.1 H/P, respectively. As shown, the rate of release of the active ingredient is greatly reduced with the addition of magnesium hydroxide which increased the ratio of metal hydroxide to acrylic polymer (H/P). Sustained dosages over 12, 18, and 24 hours or other increments are possible through manipulation of the magnesium hydroxide content. It has been surprisingly found that sub-therapeutic amount of Mg(OH)2 while used in conjunction with a given amount of acrylic polymer can vary the release profiles. Consequently, an appropriate amount of the metal hydroxide can be selected to yield the desired release rate. Other metal hydroxides, including but not limited to the group ILIA metal hydroxides, and particularly calcium hydroxide (Ca(OH)2, may also be used, although group IIA (alkaline earth) metal hydroxides are preferred.
Ultimately, the compound is shaped into a solid, oral dosage form according to known techniques. Dry granulation techniques are currently preferred, although the invention is not limited to these techniques alone. Other material including, but not limited to, binders, fillers, and gelling agents may be used in the matrix to form appropriately sized and shaped dosage forms. A matrix including only the acrylic polymer and the metal hydroxide is capable of satisfactory dosage formation, but most applications will use at least some amount of filler material. It should be appreciated that these materials are generally inert and are present mainly to aid in solid dosage (i.e. tablet) formation or other functions.
A graph plotting the percent of release versus time illustrates the effect of varying the ratio of metal hydroxide to acrylic polymer (H/P) in the compound. All tests were performed according to USP apparatus II at a speed of 50 rpm in 900 mL dissolution medium. Four test samples were prepared, each containing 10mg oxycodone as active ingredient and 50% Eudragit RSPO as the acrylic polymer. The first sample is a control without metal hydroxide. The remaining samples had 1, 3, and 5% magnesium hydroxide content by weight of the composition, corresponding to H/P ratios of 0.02, 0.06, and 0.1 by weight, respectively. The tables 1-4 below show the exemplary tablet compositions, including various additives which are commonly added as fillers, preservatives, etc.
From the above, it is readily apparent that during the tests only the amount of metal hydroxide, Mg(OH)2, was varied, with the amount of microcrystalline cellulose adjusted accordingly; all other components were equal in each sample. The microcrystalline cellulose is a well known and widely used filler material which is not used to achieve controlled release effects. This type of filler has been shown to aid in tablet formation. Accordingly, the dramatic effect on the release rates of the various compounds can only be attributed to the variation in the amount of metal hydroxide with respect to the acrylic polymer.
Referring again to the figure and Table 5, the differences in the rate of release between the various compounds become readily apparent as early as one half hour. At the half hour mark, the control sample released approximately 33% of its active ingredient compared to approximately 29 and 19% respectively for the 1% (0.02 H/P) and 3% (0.06 H/P) samples and approximately 10% in the 5% (0.1 H/P) sample. After just one hour, the control releases about 47% of its active ingredient. The 1% (0.02 H/P) sample released approximately 40% of its active ingredient after one hour. The change in the rate of release is even more dramatic in the 3% (0.06 H/P) and 5% (0.1 H/P) samples. The 3% (0.06 H/P) sample during the same time period released less than 25% of its active ingredient, while the 5% (0.1 H/P) sample released just over 10%. It is clear that manipulation of release rates is possible through controlling the amount of Mg(OH)2 while maintaining the amount of acrylic polymer in the composition.
