Patent Application
20070281016
The sole FIGURE is a graph depicting the release rate over time with various surfactant 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 surfactant. 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 controlled 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 surfactant 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 surfactant to acrylic polymer, 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 surfactant in the controlled release matrix. A ratio of surfactant to acrylic polymer (S/P) of approximately 0.005-0.5 by weight is contemplated by the inventors. A preferred ratio of approximately 0.02-0.2 by weight has been effective.
The preferred acrylic polymer is methacrylate based. Most specifically, an ammonio methacrylate polymer readily available under the tradename Eudragit RSPO is preferred. As discussed 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 S/P ratio is mentioned.
Any surfactants may be used. Preferably, anionic surfactant is used. Most preferably, the surfactant is sodium lauryl sulfate. Minimal amounts of sodium lauryl sulfate, about 1-5% by total tablet weight, have been found to be effective. The amount of surfactant for a given amount of polymer is preferably selected based upon the desired release rate. The FIGURE illustrates the effects of compounds prepared with 0, 1, 3, and 5% sodium lauryl sulfate, corresponding to 0.02, 0.06, and 0.1 S/P respectively. As shown, the rate of release of the active ingredient is greatly reduced as the S/P ratio increases. Controlled dosages over 12, 18, and 24 hours or other increments are possible through manipulation of the S/P ratio.
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 surfactant is capable of satisfactory dosage formation without the use of these additional materials, but most applications will use at least some amount of filler material. It should be appreciated that these materials are inert and generally 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 sodium lauryl sulfate concentration 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 at 150 mg each. Each contained approximately 10 mg oxycodone hydrochloride as the active ingredient and Eudragit RSPO as the acrylic polymer at 50% by weight of the composition. The first sample is a control without surfactant. The remaining samples had 1, 3, and 5% sodium lauryl sulfate (SLS), by weight of the composition, as the surfactant, corresponding to surfactant/polymer ratios (S/P) of 0.02, 0.06, and 0.1, respectively. The tables below show the various 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 surfactant, sodium lauryl sulfate 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 surfactant with respect to the acrylic polymer.
Referring again to the FIGURE, the differences in the rate of release between the various compounds become readily apparent as early as one half hour where the control sample released approximately 33% of its active ingredient compared to approximately 28%, 24%, and 17% respectively for the 1% (0.02 S/P), 3% (0.06 S/P), and 5% (0.1 S/P) samples. After three hours, the control releases about 80% of its active ingredient. The SLS containing samples exhibit a nearly congruent path compared to the control, shifted due to increased controlled release effects. The 1% (0.02 S/P) and 3% (0.06 S/P) sample released approximately 70 and 60% of their active ingredients, respectively, after three hours. The change in the rate of release is even more dramatic in the 5% (0.1 S/P) sample, and released less than 40% of its active ingredient in the same period. It is clear that manipulation of release rates is possible through controlling the ratio of SLS to polymer in the composition.
