Abstract:
The invention is a controlled release composition comprising a therapeutic amount of an active ingredient in a controlled release matrix. The matrix comprises a combination of a pharmaceutically acceptable acrylic polymer and a metal hydroxide. The amount of metal hydroxide, relative to a given amount of acrylic polymer, is selected for and corresponds to a pre-determined release rate for said active ingredient. The compound is preferably used to provide controlled release dosage of oxycodone through a matrix of ammonio methacrylic polymer and magnesium hydroxide.

Description:
BACKGROUND OF THE INVENTION 
       [0001]    1. Field of the Invention 
         [0002]    The present invention relates to a controlled release therapeutic compound employing a controlled release matrix including acrylic polymer and a metal hydroxide. More particularly, the invention relates to a compound wherein the rate of release of an active ingredient is determined by the ratio of metal hydroxide to acrylic polymer in the compound. Most particularly, the invention relates to a controlled release compound incorporating a therapeutic agent into a controlled release matrix including ammonio methacrylic polymer and magnesium hydroxide. 
         [0003]    2. Description of the Related Art 
         [0004]    Many medical conditions are best treated by administration of a pharmaceutical in such a way as to sustain its action over an extended period of time. Many delivery systems have been developed over time for providing such treatments. These products have become known as sustained release, controlled release, time release, etc. Each of these designations is nearly synonymous with the others. The term controlled release is used herein for convenience, and is not intended to be distinguished from the other terms in the art. Regardless of the term, the concept behind each as used herein is prolonged delivery of active ingredient over time via an oral dosage form. 
         [0005]    Controlled release preparations provide a longer duration of pharmacological response after administration than is ordinarily experienced after the administration of an immediate release dosage form. Such extended periods of response provide for many inherent therapeutic benefits that are not achieved with short acting, immediate release products. This kind of pharmaceutical administration can be useful for treating chronic pain, such as that associated with rheumatic or arthritic conditions. Controlled-release dosage forms can also be used beneficially in the administration of a variety of drugs whose sustained action is important to their efficacy in treating many conditions. 
         [0006]    Many physiological factors influence both the gastrointestinal transit time and the release of a drug from a controlled release dosage form, and thus influence the uptake of the drug of the patient&#39;s system. Ideally, such controlled-release dosage forms should release the active pharmaceutical ingredient at a controlled rate such that the amount of active pharmaceutical ingredient which is available in the body to treat the condition is maintained at a relatively constant and desired level over an extended period of time. That is, it is desirable that the active pharmaceutical ingredient be released at a reproducible, predictable rate. 
         [0007]    Many controlled release formulations are known in the art. Included among these are specially coated beads or pellets, coated tablets, and ion exchange resins, wherein the slow release of the active drug is brought about through selective breakdown of, or permeation through, the coating of the preparation or through formulation with a special matrix to effect the release of the drug. 
         [0008]    Several controlled release products incorporate fast-release and slow-release components. The combination allows for quick entry of active ingredient during initial treatment periods, while permitting a sustaining effect through later release during subsequent hours. Multiple, alternative layers of coatings and medicine, as well as coated and uncoated medicaments have been used to create this effect. 
         [0009]    Some controlled release products use specially designed excipient matrices, which determine the rate of release. Special cellulose-derived matrices have been developed for this purpose. Specifically, plasticized ethylcellulose materials have been found to be effective. The specific composition and structure of these materials exhibit desired properties for the controlled release of the desired therapeutic agent. Other types of controlled release mechanisms are also known. 
         [0010]    In the case of controlled release coatings, often a polymeric material, such as acrylic polymer, is used to coat a tablet or other dosage form. The particular polymer used has a disintegration of dissolution factor associated with it, correlating to the controlled rate of release of the therapeutic agent. Another benefit of these coatings is their ability to mask undesirable medicinal tastes. In some cases, the acrylic polymer has been blended into the excipient material as filler material in addition to use as the controlled release coating. 
         [0011]    Metal hydroxides have been used for their therapeutic effects in treating various ailments. Among these, magnesium hydroxide has been used as a laxative and as an anti-diarrheal. The use of metal hydroxides until now, particularly Mg(OH) 2 , has been limited to its use as a therapeutic agent. However, heretofore there has been no teaching of a controlled release formulation providing a pharmacologically active ingredient in a novel excipient matrix combining suitable proportions of an acrylic polymer and metal hydroxide for controlling release rates of such as active ingredient. 
       SUMMARY OF THE INVENTION 
       [0012]    A controlled release composition consists of a therapeutic amount of an active ingredient in a controlled release matrix. The matrix comprises a combination of a pharmaceutically acceptable acrylic polymer and metal hydroxide. The amount of metal hydroxide, relative to the amount of acrylic polymer, is selected for and corresponds to a pre-determined release rate for said active ingredient. The compound is preferably used to provide controlled release dosages of oxycodone through a matrix of ammonio methacrylic polymer and magnesium hydroxide. 
     
     
       BRIEF DESCRIPTION OF THE DRAWING 
         [0013]    The sole FIGURE is a graph depicting the release rate over time with various Mg(OH) 2  levels. 
       
    
    
     DETAILED DESCRIPTION 
       [0014]    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. 
         [0015]    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. 
         [0016]    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. 
         [0017]    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. 
         [0018]    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. 
         [0019]    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. 
         [0020]    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  10 mg 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. 
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 Oxycodone Hydrochloride Extended Release Tablets, 10 mg, H/P = 0 
               
             
          
           
               
                   
                   
                 Quantity 
                 Quantity 
               
               
                   
                 Excipients 
                 mg/tablet 
                 (%) 
               
               
                   
                   
               
             
          
           
               
                   
                 Oxycodone Hydrochloride 
                 10 
                 6.7%   
               
               
                   
                 Microcrystalline Cellulose 
                 48.5 
                 32.3%   
               
               
                   
                 Ammonio Methacrylate Copolymer 
                 75 
                 50%  
               
               
                   
                 Collodial Silicon Dioxide 
                 3 
                 2% 
               
               
                   
                 Magnesium Hydroxide 
                 0 
                 0% 
               
               
                   
                 Povidone 
                 7.5 
                 5% 
               
               
                   
                 Stearic Acid 
                 3 
                 2% 
               
               
                   
                 Magnesium Stearate 
                 3 
                 2% 
               
               
                   
                 Tablet Weight 
                 150 
                 100%  
               
               
                   
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 Oxycodone Hydrochloride Extended Release Tablets, 10 mg, H/P = .02 
               
             
          
           
               
                   
                   
                 Quantity 
                 Quantity 
               
               
                   
                 Excipients 
                 mg/tablet 
                 (%) 
               
               
                   
                   
               
             
          
           
               
                   
                 Oxycodone Hydrochloride 
                 10 
                 67%  
               
               
                   
                 Microcrystalline Cellulose 
                 47 
                 31.3%   
               
               
                   
                 Ammonio Methacrylate Copolymer 
                 75 
                 50%  
               
               
                   
                 Collodial Silicon Dioxide 
                 3 
                 2% 
               
               
                   
                 Magnesium Hydroxide 
                 1.5 
                 1% 
               
               
                   
                 Povidone 
                 7.5 
                 5% 
               
               
                   
                 Stearic Acid 
                 3 
                 2% 
               
               
                   
                 Magnesium Stearate 
                 13 
                 2% 
               
               
                   
                 Tablet Weight 
                 150 
                 100%  
               
               
                   
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                 Oxycodone Hydrochloride Extended Release Tablets, 10 mg, H/P = .06 
               
             
          
           
               
                   
                   
                 Quantity 
                 Quantity 
               
               
                   
                 Excipients 
                 mg/tablet 
                 (%) 
               
               
                   
                   
               
             
          
           
               
                   
                 Oxycodone Hydrochloride 
                 10 
                 67%  
               
               
                   
                 Microcrystalline Cellulose 
                 44 
                 29.3%   
               
               
                   
                 Ammonio Methacrylate Copolymer 
                 75 
                 50%  
               
               
                   
                 Collodial Silicon Dioxide 
                 3 
                 2% 
               
               
                   
                 Magnesium Hydroxide 
                 4.5 
                 3% 
               
               
                   
                 Povidone 
                 7.5 
                 5% 
               
               
                   
                 Stearic Acid 
                 3 
                 2% 
               
               
                   
                 Magnesium Stearate 
                 3 
                 2% 
               
               
                   
                 Tablet Weight 
                 150 
                 100%  
               
               
                   
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 4 
               
             
             
               
                   
               
               
                 Oxycodone Hydrochloride Extended Release Tablets, 10 mg, H/P = .1 
               
             
          
           
               
                   
                   
                 Quantity 
                 Quantity 
               
               
                   
                 Excipients 
                 mg/tablet 
                 (%) 
               
               
                   
                   
               
             
          
           
               
                   
                 Oxycodone Hydrochloride 
                 10 
                 6.7%   
               
               
                   
                 Microcrystalline Cellulose 
                 41.0 
                 32.3%   
               
               
                   
                 Ammonio Methacrylate Copolymer 
                 75 
                 50%  
               
               
                   
                 Collodial Silicon Dioxide 
                 3 
                 2% 
               
               
                   
                 Magnesium Hydroxide 
                 7.5 
                 5% 
               
               
                   
                 Povidone 
                 7.5 
                 5% 
               
               
                   
                 Stearic Acid 
                 3 
                 2% 
               
               
                   
                 Magnesium Stearate 
                 3 
                 2% 
               
               
                   
                 Tablet Weight 
                 150 
                 100%  
               
               
                   
                   
               
             
          
         
       
     
         [0021]    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. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 5 
               
             
             
               
                   
               
               
                 Release Profile of formulations from Tables 1–4 
               
             
          
           
               
                 Time 
                 0% Mg(OH) 2 , 
                 1% Mg(OH) 2 , 
                 3% Mg(OH) 2 , 
                 5% Mg(OH) 2 , 
               
               
                 (hr) 
                 H/P = 0 
                 H/P = 0.02 
                 H/P = 0.06 
                 H/P = 0.1 
               
               
                   
               
             
          
           
               
                 0.5 
                 33 
                 29 
                 19 
                 10 
               
               
                 1 
                 47 
                 40 
                 21 
                 11 
               
               
                 2 
                 66 
                 54 
                 25 
                 13 
               
               
                 3 
                 79 
                 64 
                 27 
                 15 
               
               
                 4 
                 88 
                 71 
                 29 
                 16 
               
               
                 5 
                 94 
                 76 
                 31 
                 18 
               
               
                 6 
                 98 
                 79 
                 33 
                 19 
               
               
                 8 
                 102 
                 83 
                 35 
                 21 
               
               
                 10 
                 103 
                 85 
                 37 
                 23 
               
               
                 12 
                 104 
                 87 
                 39 
                 25 
               
               
                   
               
             
          
         
       
     
         [0022]    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.