Abstract:
A tablet for the controlled release of a pharmaceutically active ingredient. The tablet is in the form of coated DST&#39;s and MLDST&#39;s so that immediate release or time-delayed release can be achieved. Further, such extended release DST&#39;s and MLDST&#39;s may provide zero order or first order extended release kinetics depending on the excipients and types of pharmaceutically active ingredients in the tablet formulation. The time delay coating is made of high molecular weight water soluble polymers so that dose dumping can be minimized even when the hydrated surface of the DST and MLDST peels off. A second coating of low molecular weight water soluble polymer with a pharmaceutically active ingredient dispersed therein provides for pulsatile release.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     Not applicable. 
     STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT 
     Not applicable. 
     BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     The present invention relates to pharmaceutical dosage forms and in, particular, to a coated perforated or donut-shaped tablet for extended release of a pharmaceutically active ingredient. 
     2. Brief Description of the Related Art 
     There have been various attempts made to create extended release dosage forms for orally administering pharmaceutically active ingredients. The terms “drug” and “pharmaceutically active ingredient” are used interchangeably herein. Some dosage forms tend to release a drug at rates that do not correlate well with the needs of the patient. For example, a particular dosage form may release a large amount of a drug rapidly upon ingestion where a more constant rate of release is desirable. In other situations, varying release rates may be desirable. Additional background information on the art of controlling release rates of drugs in orally administered dosage forms is found in U.S. Pat. Nos. 5,945,125 and 6,110,500 and U.S. Published Patent Application No. US2005/0025829, the disclosures of which are incorporated herein by reference. Dosage forms typically comprise the drug; that is, the pharmaceutically active ingredient, dispersed in various excipients including polymers whose rates of dissolution are known. As the tablet is dissolved, the drug is released at a predicted rate. Coating excipients having various rates of dissolution have also been used for time delayed release of drugs. 
     Common oral extended release or pulsatile release dosage forms include tablets, caplets, and capsules containing small spherical pellets. Such dosage forms typically have the combined geometry of slabs and cylinders, which tend to produce varying release rates. Due to the shape, a cylindrical tablet does not follow zero order release kinetics. As the tablet is dissolved, the amount of surface area exposed to the dissolution medium changes, thereby changing the rate at which the dissolution occurs and thus the drug release rate decreases with drug release time. 
     When a central perforation or hole is made in an extended release tablet (donut-shaped tablet (DST)), the DST exhibits a constant drug release rate over time because a constant surface area can be radially maintained. A multi-layer DST (MLDST) can also be made as described in U.S. Published Patent Application No. US2005/0025829. 
     While constant drug release rates are desirable in certain circumstances, it is more generally desirable to be able to customize the kinetics of drug release. For example, a rapid initial release (a burst) may desirably be followed by a period of constant release. In other examples, it might be desirable to delay the release of the drug for a period of time or to release a pulse of the drug after a period of time delay or a period of constant release. 
     Hydrophilic polymers are commonly employed in extended release tablets. A problem associated with hydrophilic polymer based pharmaceutical compositions in a DST or MLDST is that these tablets can dose dump, that is, when not fully hydrated the hydrophilic polymers become very viscous and adhere to solids and biological surfaces. The surface of the tablet then peels off and the drug dosage is dumped into the patient. 
     BRIEF SUMMARY OF THE INVENTION 
     The present invention uses coated DST&#39;s and MLDST&#39;s so that immediate release or time-delayed release can be achieved. Further, such extended release DST&#39;s and MLDST&#39;s may provide zero order or first order extended release kinetics depending on the excipients and types of drugs in the tablet formulation. The coating layer for time delay is made of high molecular weight water soluble polymers so that the dose dumping can be minimized even when the hydrated surface of the DST and MLDST peels off. Low molecular weight water soluble polymer coatings having a drug dispersed therein may be employed to provide a pulsatile release of a drug. 
     These and other features and advantages of the present invention will become better understood from the following description, appended claims and accompanying drawings. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is top side perspective view of a donut-shaped tablet having a central perforation or hole as known in the prior art (DST). 
         FIG. 2  is a top side perspective view of a layered perforated tablet as known in the prior art (MLDST). 
         FIG. 3  is a top side perspective view of a coated perforated tablet according to one embodiment of the present invention, where the coating is a high molecular weight polymer without a drug dispersed in the coating. The coating is shown in partial cross section. 
         FIG. 4  is a top side perspective view of a coated layered perforated tablet accordingly to another embodiment of the present invention, where the coating is a high molecular weight water soluble polymer without a drug dispersed in the coating. The coating is shown in partial cross section. 
         FIG. 5  is a top side perspective view of a coated perforated tablet according to another embodiment of the present invention, where an inner coating comprises a high molecular weight water soluble polymer without a drug dispersed therein and an outer coating comprises a low molecular weight water soluble polymer with a drug dispersed therein. The coatings are shown in partial cross section. 
         FIG. 6  is a top side perspective view of a coated layered perforated tablet according to another embodiment of the present invention, where an inner coating comprises a high molecular weight water soluble polymer without a drug dispersed therein and an outer coating comprises a low molecular weight water soluble polymer with a drug dispersed therein. The coatings are shown in partial cross section. 
         FIG. 7  is a top side perspective view of a coated perforated tablet with sloped upper and lower surfaces according to another embodiment of the present invention, where the coating comprises a high molecular weight polymer without a drug dispersed therein. The coating is shown in partial cross section. 
         FIG. 8  is a top side perspective view of a coated perforated tablet with sloped upper and lower surfaces according to another embodiment of the present invention, where an inner coating comprises a high molecular weight water soluble polymer without a drug dispersed therein and an outer coating comprises a low molecular weight water soluble polymer with a drug dispersed therein. The coatings are shown in partial cross section. 
         FIG. 9  is a graph of the release rate of doxazosin mesylate from the embodiment of the tablet of  FIG. 3  superimposed on a graph of the release rate of a commercially-available brand of doxazosin mesylate, Cardura® XL (Pfizer Inc., New York, N.Y. USA). 
         FIG. 10  is a graph of the release rate of glipizide from the embodiment of the tablet of  FIG. 3  superimposed on a graph of the release rate of a commercially-available brand of glipizide, Glucotrol XL® (Pfizer Inc., New York, N.Y. USA). 
         FIG. 11  is a graph of the release rate of doxazosin mesylate from the embodiment of the tablet of  FIG. 4  superimposed on a graph of the release rate of a commercially-available brand of doxazosin mesylate, Cardura® XL (Pfizer Inc., New York, N.Y. USA). 
         FIG. 12  is a graph of the release rate of doxazosin mesylate from the embodiment of the tablet of  FIG. 4  superimposed on a graph of the release rate of a commercially-available brand of doxazosin mesylate, Cardura® XL (Pfizer Inc., New York, N.Y. USA). 
         FIG. 13  is a graph of the release rates of doxazosin mesylate, theophyline and diltiazem HCl from the embodiment of the tablet of  FIG. 5 . 
         FIG. 14  is a graph of the release rate of doxazosin mesylate from the embodiment of the tablet of  FIG. 6 . 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The preferred embodiments of the invention are described herein with reference to  FIGS. 1-14 . 
       FIG. 1  is top side perspective view of a perforated or donut-shaped tablet  10  having a central perforation or hole  11  as known in the prior art (DST). The perforated tablet  10  comprises a core  12  through which the hole  11  penetrates. The core  12  is defined by a surface comprising an inner radial surface  13  surrounding the hole  11 , an outer radial surface  14 , an upper lateral surface  15  extending between an upper margin of the inner radial surface and an upper margin of the outer radial surface  14  and a lower lateral surface  16  extending between a lower margin of the inner radial surface  13  and a lower margin of the outer radial surface  14 . The core  12  comprises at least one pharmaceutically active ingredient dispersed in at least one excipient. The selection of excipients allows some control in the release kinetics for the pharmaceutically active ingredient. Furthermore, it is known that perforated tablets of the type described have substantially zero order release kinetics. 
       FIG. 2  is a top side perspective view of a layered perforated tablet  20  as known in the prior art (MLDST). The layered perforated tablet  20  may comprise a plurality of layers. The character and composition of the layers may be selected for various release kinetics. For example, as described in U.S. Published Patent Application No. 2005/0025829 and shown in  FIG. 2 , an upper layer  21  and a lower layer  22  may comprise either water soluble or water insoluble polymers and an inner layer  23  may comprise a drug dispersed in an enteric polymer. Layering gives time for the tablet to hydrate to avoid dose dumping. 
       FIG. 3  is a top side perspective view of a coated perforated tablet  30  according to one embodiment of the present invention having a coating  31  of a high molecular weight polymer. The coated perforated tablet  30  has core  32  with a hole  33  extending through the core  32  as described above with reference to  FIG. 1 . The core  32  has a surface defined by an inner radial surface  34  surrounding the hole  33 , an outer radial surface  35 , an upper lateral surface  36  extending between an upper margin of the outer radial surface  35  and an upper margin of the inner radial surface  34 , and a lower lateral surface  37  extending between a lower margin of the outer radial surface  35  and a lower margin of the inner radial surface  34 . The core  32  comprises at least one pharmaceutically active ingredient dispersed in at least one excipient. The coating  31  is high molecular weight water soluble polymer substantially covering the outer radial surface  35 , the upper lateral surface  36  and the lower lateral surface  37 . The inner radial surface  34  is not covered. The coating  31  does not contain a pharmaceutically active ingredient. The high molecular weight polymer preferably has a number-average molecular weight of at least 10,000. Although the inner radial surface  34  is exposed to the dissolution medium shortly following ingestion, the coating  31  provides a time delay before the outer radial surface  35 , the upper lateral surface  36  and the lower lateral surface  37  are exposed to the dissolution medium. The amount of the time delay may be adjusted by the appropriate selection of the specific polymer, the specific number-average molecular weight and the thickness of the coating  31 . The time delay allows the tablet time to hydrate to prevent dose dumping. Furthermore, since the coating  31  does not contain a pharmaceutically active ingredient, even if the coating  31  peels off from the tablet, there will be no dose dumping. 
       FIG. 9  is a graph of the release rate of doxazosin mesylate from the embodiment of the tablet of  FIG. 3  superimposed on a graph of the release rate of a commercially-available brand of doxazosin mesylate, Cardura® XL (Pfizer Inc., New York, N.Y. USA).  FIG. 10  is a graph of the release rate of glipizide from the embodiment of the tablet of  FIG. 3  superimposed on a graph of the release rate of a commercially-available brand of glipizide, Glucotrol XL® (Pfizer Inc., New York, N.Y. USA). 
       FIG. 4  is a top side perspective view of a coated layered perforated tablet  40  accordingly to another embodiment of the present invention, where the coating  49  is a high molecular weight water soluble polymer. The embodiment of  FIG. 4  is similar to the embodiment of  FIG. 3  described above. The coated layered perforated tablet  40  of  FIG. 4  has core  41  with a hole  42  extending through the core  41 . The core  41  has a surface defined by an inner radial surface  43  surrounding the hole  42 , an outer radial surface  44 , an upper lateral surface  45  extending between an upper margin of the outer radial surface  44  and an upper margin of the inner radial surface  43 , and a lower lateral surface  46  extending between a lower margin of the outer radial surface  44  and a lower margin of the inner radial surface  43 . The core  41  comprises at least one pharmaceutically active ingredient dispersed in at least one excipient. In addition to the embodiment of  FIG. 3 , the embodiment of  FIG. 4  has an upper layer  47  and a lower layer  48  as described above with reference to  FIG. 2 . The present invention is not limited to a tablet having an upper layer and a lower layer, but to any tablet having a plurality of layers. The layered core  41  has a coating  49  of high molecular weight water soluble polymer substantially covering the outer radial surface  44 , the upper lateral surface  45  and the lower lateral surface  46 , including the upper and lower layers  47 ,  48 . The inner radial surface  43  is not covered. The coating  49  does not contain a pharmaceutically active ingredient. The high molecular weight polymer preferably has a number-average molecular weight of at least 10,000. The coating  49  provides the time delay effect discussed above. 
       FIG. 11  is a graph of the release rate of doxazosin mesylate from the embodiment of the tablet of  FIG. 4  superimposed on a graph of the release rate of a commercially-available brand of doxazosin mesylate, Cardura® XL (Pfizer Inc., New York, N.Y. USA).  FIG. 12  is a graph of the release rate of doxazosin mesylate from the embodiment of the tablet of  FIG. 4  superimposed on a graph of the release rate of a commercially-available brand of doxazosin mesylate, Cardura® XL (Pfizer Inc., New York, N.Y. USA). 
       FIG. 5  is a top side perspective view of a coated perforated tablet  50  according to another embodiment of the present invention. The embodiment of  FIG. 5  is similar to the embodiment of  FIG. 3  in having a core  51  with a hole  52  extending through the core  51 . The core  51  has a surface defined by an inner radial surface  53  surrounding the hole  52 , an outer radial surface  54 , an upper lateral surface  55  extending between an upper margin of the outer radial surface  54  and an upper margin of the inner radial surface  53 , and a lower lateral surface  56  extending between a lower margin of the outer radial surface  54  and a lower margin of the inner radial surface  53 . The core  51  comprises at least one pharmaceutically active ingredient dispersed in at least one excipient. However, rather than a single coating of high molecular weight polymer, the embodiment of  FIG. 5  has an inner coating  57  of a high molecular weight water soluble polymer and an outer coating  58  of a low molecular weight water soluble polymer. The inner coating  57  does not have a drug dispersed therein. The outer coating  58  has a drug dispersed therein. The high molecular weight polymer preferably has a number-average molecular weight of at least 10,000 and the low molecular weigh polymer preferably has a number-average molecular weight of less than 10,000. The outer coating  58  begins to dissolved and to release the pharmaceutically active ingredient upon exposure to the dissolution medium. The rate of this pulsatile release may be adjusted by the appropriate selection of the specific low molecular weight polymer, the number-average molecular and the thickness of the outer coating  58 . The inner coating  57  provides a time delay after the pulsatile release before the outer radial surface  54 , upper lateral surface  55  and lower lateral surface  56  are exposed to the dissolution medium. 
       FIG. 13  is a graph of the release rate of doxazosin mesylate, theophyline and diltiazem HCl from the embodiment of the tablet of  FIG. 5 . 
       FIG. 6  is a top side perspective view of a coated layered perforated tablet  60  according to another embodiment of the present invention. The embodiment of  FIG. 6  is a combination of the embodiments of  FIGS. 4 and 5 . The coated layered perforated tablet  60  of  FIG. 6  has core  61  with a hole  62  extending through the core  61 . The core  61  has a surface defined by an inner radial surface  63  surrounding the hole  62 , an outer radial surface  64 , an upper lateral surface  65  extending between an upper margin of the outer radial surface  64  and an upper margin of the inner radial surface  63 , and a lower lateral surface  66  extending between a lower margin of the outer radial  64  surface and a lower margin of the inner radial surface  63 . The core  61  comprises at least one pharmaceutically active ingredient dispersed in at least one excipient. In addition, the embodiment of  FIG. 6  has an upper layer  67 , a lower layer  91  and an inner layer  69  as described above with reference to  FIG. 2 . The present invention is not limited to a tablet having an upper layer  67 , a lower layer  91  and an inner layer  69 , but to any tablet having a plurality of layers. The layered cored  61  has an inner coating  68  of a high molecular weight water soluble polymer and an outer coating  92  of a low molecular weight water soluble polymer. The inner coating  68  does not have a drug dispersed therein. The outer coating  92  has a drug dispersed therein. The high molecular weight polymer preferably has a number-average molecular weight of at least 10,000 and the low molecular weigh polymer preferably has a number-average molecular weight of less than 10,000. The inner coating  68  covers substantially the outer radial surface  64 , the upper lateral surface  65  and the lower lateral surface  66  including the upper and lower layers  67 ,  91 . The inner radial surface  63  is not covered. The outer coating  92  covers substantially all of the inner coating  68  but does not cover the inner radial surface  63 . 
       FIG. 14  is a graph of the release rate of doxazosin mesylate from the embodiment of the tablet of  FIG. 6 . 
       FIG. 7  is a top side perspective view of a coated perforated tablet  70  according to another embodiment of the present invention. The embodiment of  FIG. 7  is similar to the embodiment of  FIG. 3 , but differs in that the upper lateral surface  71  slopes inwardly from the outer radial surface  72  toward the inner radial surface  73  and the lower lateral surface  74  slopes inwardly from the outer radial surface  72  toward the inner radial surface  73 . In such a tablet  70 , the release kinetics are altered since the surface area of the tablet  70  increases with time. The core  75  comprises at least one pharmaceutically active ingredient dispersed in at least one excipient. The coating  76  is high molecular weight water soluble polymer substantially covering the outer radial surface  72 , the upper lateral surface  71  and the lower lateral surface  74 . The inner radial surface  77  is not covered. The coating  76  does not contain a pharmaceutically active ingredient. The high molecular weight polymer preferably has a number-average molecular weight of at least 10,000. 
       FIG. 8  is a top side perspective view of a coated perforated tablet  80  with sloped upper and lower surfaces  81 ,  82  as described above with reference to  FIG. 7 . This embodiment of the present invention has an inner coating  83  of a high molecular weight water soluble polymer without a drug dispersed in the inner coating  83  and an outer coating  84  of a low molecular weight water soluble polymer with a drug dispersed in the outer coating  84 . 
     The present invention has been described with reference to certain preferred and alternative embodiments that are intended to be exemplary only and not limiting to the full scope of the present invention as set forth in the appended claims. For example, various combinations of the embodiments described can be employed to design a dosage form for whatever release kinetics are desired.