Source: http://www.google.com/patents/US6056975?ie=ISO-8859-1
Timestamp: 2015-03-05 15:13:07
Document Index: 371067022

Matched Legal Cases: ['ART                                      92', 'ART                                     88', 'ART                                      87', 'ART                                        89', 'ART                                       68', 'ART                                        61']

Patent US6056975 - Levothyroxine sodium, polysaccharide - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inAdvanced Patent SearchPatentsDisclosed are thyroid hormone preparations useful in pharmaceutical applications. These preparations are disclosed to contain thyroxine drugs in combination with an inorganic salt, a carbohydrate having a molecular weight of greater than 500, and glycine. The preparations are also disclosed to have a...http://www.google.com/patents/US6056975?utm_source=gb-gplus-sharePatent US6056975 - Levothyroxine sodium, polysaccharideAdvanced Patent SearchPublication numberUS6056975 APublication typeGrantApplication numberUS 09/156,844Publication dateMay 2, 2000Filing dateSep 18, 1998Priority dateNov 14, 1995Fee statusPaidAlso published asCA2235707A1, DE69633018D1, DE69633018T2, EP0861073A1, EP0861073B1, US5955105, WO1997017951A1Publication number09156844, 156844, US 6056975 A, US 6056975A, US-A-6056975, US6056975 A, US6056975AInventorsAmit K. Mitra, Raghunath Srinivas, Charles L. Thomas, IIIOriginal AssigneeBasf CorporationExport CitationBiBTeX, EndNote, RefManPatent Citations (13), Non-Patent Citations (2), Referenced by (8), Classifications (25), Legal Events (4) External Links: USPTO, USPTO Assignment, EspacenetLevothyroxine sodium, polysaccharide
Disclosed are thyroid hormone preparations useful in pharmaceutical applications. These preparations are disclosed to contain thyroxine drugs in combination with an inorganic salt, a carbohydrate having a molecular weight of greater than 500, and glycine. The preparations are also disclosed to have a free water content less than 4.5% by weight of the preparation. Also provided are compositions containing a reduced carbohydrate, a water soluble polysaccharide, or galactose. The preparations have improved stability wherein they are provided as being stable to the extent that substantially no potency loss is measured when the preparation is stored at 40� C. and 75% relative humidity for 3 months.
1. A stable, solid dosage form pharmaceutical preparation suitable for the treatment of thyroid disorders, said preparation comprising:an effective amount of a thryoxine drug; and a water soluble glucose polymer; said preparation being stable to the extent that substantially no potency loss is measured when the preparation is stored at 40� C. and 75% relative humidity for 3 months. 2. The preparation of claim 1, wherein the preparation is in a unit dose form.
14. Preparation of claim 1, wherein the preparation, when stored at 40� C. and 75% RH for 3 months, exhibits less than 10% by weight loss of the thyroxine drug.
______________________________________Condition     Interval % Actual (S.D.)______________________________________Initial       Initial  100.0ART                                      92.3 � (6.1)ART                                     88.1 � (2.7)ART                                      87.2 � (11.9)30� C.                            86.1 � (5.1)30� C.                           95.3 � (3.9)30� C.                            87.8 � (5.6)40� C.                            95.0 � (1.8)40� C.                           94.7 � (5.7)40� C.                           91.9 � (4.2)______________________________________
______________________________________Condition     Interval % Actual (S.D.)______________________________________Initial       Initial  97.0 � (0.4)ART                                        89.7 � (2.3)ART                                       68.3 � (1.9)ART                                        61.4 � (1.9)30� C.                              88.3 � (1.6)30� C.                             71.3 � (1.3)30� C.                             64.2 � (0.1)40� C.                              89.5 � (0.6)40� C.                             64.1 � (0.1)40� C.                             62.5 � (1.2)______________________________________
TABLE 1__________________________________________________________________________COMPOSITION OF DIRECT COMPRESSION FORMULASINGREDIENTS  24  25  26  27  28  29  30  31  32  33  34__________________________________________________________________________CROSCARMELOSE        6.500            6.500                6.500                    6.500                        6.500                            6.500                                6.500                                    6.500   1.300                                                6.500SODIUMCOLLOIDAL SILICON                0.325                      3.900                            3.9         0.332                                              0.325                                                  0.325DIOXIDEAVICEL � PH 102*                57.84                     103.322                         39.000                            103.322                                 103.322                                     122.795                                          65.78                                              63.04AVICEL � PH 112*                                                122.825GLYCINE                      83.822LEVOTHYROXINE               0.0255                  0.025                      0.025                          0.025                              0.025                                   0.025                                       0.025                                           0.025                                               0.025                                                  0.025SODIUMMAGNESIUM STEARATE,               0.650                  0.650                      0.650                          0.650                              0.650                                   0.650                                       0.650                                           0.664                                               0.650                                                  0.650NFMALTODEXTRIN     122.825                  64.99                                        66.43                                              65.0HYDROXYPROPYL-&#946;                                    0.028CYCLODEXTRINTRISODIUM PHOSPHATE                    19.500SODIUM BICARBONATE                            19.500SODIUM CARBONATE                                19.500SODIUM LAURYL                                        0.664                                              0.650SULFATETOTAL (mg per unit)           130.33              130.00                  130.33                     133.90                         130.00                             133.90                                  133.90                                      130.00                                         133.90                                             130.99__________________________________________________________________________                                                130.33 *BRAND OF MICROCRYSTALLINE CELLULOSE
Certain of the tablets of Examples 24 to 34 were subjected to stability testing. The same criteria that was used for the dry compression tablets was used in selecting tablets for stability testing. Tablets selected for stability testing were those that had good content uniformity (e.g., less 10% process loss or a relative standard deviation less than 10%), good tableting characteristics (e.g., good flow characteristics, an angle of repose greater then 42�, and good tableting). Each tablet selected for stabilt testing, having a weight of approximately 130 mg, was subjected to testing in the presence and absence of a desiccant at 30� C. (See Table 2), at 40� C. (See Table 3), and at 40� C. and 75% relative humidity (See Table 4).
TABLE 2__________________________________________________________________________STABILITY OF DIRECT COMPRESSION FORMULAS30� C. With and Without Desiccant    With Desiccant    Without Desiccant    1   2     3   6.5 1   2     3   6.5Example            Months                 Month                    Monthshs                         Month                               Months                                         Months__________________________________________________________________________Example 30 97.3     97.1         97.9, 95.3              97.1                  97.7                       97.8                           97.1, 96.7                                96.3                                    96.7        96.6              96.9    (-0.2)             (-0.6)                     (0.4))                        (+2.5)                                (-1.4)                                            (-0.6)Example 24 96.7        100.1             95.3, 92.3                       98.7                                   95.295.9        93.8              95.9    (+3.4)             (-2.9)                      (+2)                                     (-1.5)Example 34 99.8        101.9            101.0, 96.8                  95.9                       99.7                               103.7, 102.6                                  98.9        98.9              103.2    (+2.0)             (-0.9)                      (-0.1)                                (-0.1)                                     (-0.9)Example 29 99.9             100.2, 98.2                  98.6                      101.1                                99.8, 96.6                                   98.0                          98.2    (-1.1)        (-0.7)              (-1.3)  (+1.2)                          (-1.7)                                (-1.9)__________________________________________________________________________
TABLE 3______________________________________STABILITY OF DIRECT COMPRESSION FORMULASStability of Levothyroxine Sodium Tablets at 40� C.With and Without Desiccant  With Desiccant                Without DesiccantExam-        1       2     3     1     2     3ple                 Monthl                      Months                            Months                                     Months                                            Months______________________________________Exam- 99.9   101.5   97.0  95.5  101.2 97.0  97.5ple          (-1.6)              (-4.4)                                  (+1.3)                                      (+2.9)                                            (-2.4)29Exam-                                        93.8                                              96.4ple          (+1.6)              (-1.0)                                       (-2.9)                                            (-0.3)24Exam-                                        97.4                                              92.7ple          (-1.3)  (-2.3)                      (-6.7)                            (-2.1)                                  (-2.4)                                        (-7.1)34Exam-                101.2                                       92.4                                              94.6ple          (+3.9)              (-2.3)                                 (+3.3)                                      (-4.9)                                             (-2.7)30______________________________________
TABLE 4______________________________________STABILITY OF DIRECT COMPRESSION FORMULAS40� C./75% RH with Desiccant            1       2        3     6.5Example      Initial                Month                         Months                                   Months                                       Months______________________________________Example 30   97.3     101.0   97.9, 95.3                             97.0  92.4                    96.6               (-4.9)                    (-0.7)Example 24      96.7          99.1                         95.4, 93.4                                  95.8                    94.4              (-0.9)                    (-2.3)Example 34      99.8          96.5                         97.4, 94.9                                  91.2                    96.2              (-5.3)                    (-3.6)Example 29      99.9         105.2                        98.5, 96.0                                  95.6                    97.3              (-4.3)                    (-2.6)______________________________________
TABLE 5__________________________________________________________________________COMPOSITION OF WET GRANULATION FORMULAS           Example                Example                     Example                          Example                               Example                                    Example                                         Example                                              ExampleIngredient__________________________________________________________________________                                              42   35CROSCARMELLOSE SODIUM           2.62 2.6  6.500                          6.500                               6.500                                    6.500                                         9.03 6.500COLLOIDAL SILICON DIOXIDE                               3.9325                                        0.325                                            0.44                                                 0.325AVICEL � PH 102*                             19.56.86077                                    122.85                                           80.33                                                106.86AVICEL � PH 112*                               122.83GLYCINE                          103.332LEVOTHYROXINE SODIUM                    0.025     0.025                               0.0255                                   0.025                                       0.025                                            0.025                                                0.025MAGNESIUM STEARATE, NF                               0.6500                                   0.650                                        0.650                                            0.650                                                0.650MALTODEXTRIN                                         84.36PURIFIED WATER, USP                    **4.380           **4.360                              **0.005                                 **26.2                                       **26.2                                           **8.7                                                **26.2(DEIONIZED)SODIUM LAURYL SULFATE                     0.650                               0.650                                        0.650                                            0.620                                              0.65TRISODIUM PHOSPHATE                                              15.98SODIUM CARBONATE                     15.98HYDROXYPROPYL CELLULOSE                           3.93TOTAL (mg per unit)                     133.59    130.97                              133.919                                  130.98                                       175.46                                           175.46                                               130.99__________________________________________________________________________ *Brand of Microcrystalline Cellulose **Removed During Drying Process
TABLE 6__________________________________________________________________________STABILITY OF WET GRANULATION FORMULASStability of Levothyroxine Sodium Tablets at 30� C. With andWithout Desiccant    With Desiccant  Without Desiccant    1   2   3   4   1   2   3   4Example    Monthial         Months             Months                 Months                      Month                         Months                            Months                                       Months__________________________________________________________________________Example 37 106.4    100.5        107.3            102.6   102.7                        106.3                            105.8Example 42  99.4      93.3           100.5               99.5                    93.5                          98.6                               93.8Example 39  108.0     105.7          103.7              104.6                    107.4                         103.7                              107.3Example 41  101.0     104.4          100.7              100.9                  103.0                       103.3                         102.7                              103.2                                       103.4__________________________________________________________________________
TABLE 7______________________________________STABILITY OF WET GRANULATION FORMULASStability of Levothyroxine Sodium Tablets at 40� C.With and Without Desiccant  With Desiccant                Without DesiccantExam-        1       2     3     1     2     3ple                     Months               Month                        Months                               Month                                     Months                                          Months______________________________________Exam- 106.4  100.2   104.3 103.1 98.2  101.9 101.3ple37Exam-      99.4              94.3                     97.7                          95.8                                93.9                                      92.3                                            92.4ple42Exam-     108.0             105.6                    103.0                         108.0                               102.4                                     98.8                                            105.8ple39Exam-       101.8             103.4                    99.8                         102.6                               103.2                                     101.7                                           102.5ple41______________________________________
TABLE 8__________________________________________________________________________STABILITY OF WET GRANULATION FORMULASStability Levothyroxine Sodium Tablets at 40� C./75% RH With andWithout Desiccant    With Desiccant  Without Desiccant    1   2   3   4   1   2   3   4Example         Months           Month            Months                  Months                    Month                         Months                             Months                                Months__________________________________________________________________________Example 37 106.4    100.0        100.0            101.3   97.3                        101.9                            99.5Example 42   99.4       89.3          94.5              88.9                    94.1                           98.3                              92.0Example 39   108.0      103.8         89.2              107.1                    103.3                          87.9                              104.8Example 41    101.8      l04.4         102.7             101.2                   99.9                     104.4                          102.8                             102.5                                101.4__________________________________________________________________________
A number of tablets produced by dry compression in Examples 24 to 34 and by wet granulation in Examples 35 to 42 were tested for dissolution profiles. The actual 5 tablets tested represent tablets not placed on stability ("initial") and were not more than about 5 days old. A tablet was placed in a vessel containing 50 ml of distilled water or buffer and maintained at 37� C. stirred by a paddle revolving at 100 RPM. The percent of the levothyroxine sodium which dissolved in the water or, as indicated, buffer solution was measured and is reported in Tables 9, 10, 11 and 12.
______________________________________Maltodextrin:  54.3 mg (49.4%)AVICEL � PH 102:          54.3 mg (49.4%)Sodium lauryl sulfate:          0.55 mg (0.5%)Magnesium stearate:          0.55 mg (0.5%)Colloidal silicon dioxide:          0.0275 mg (0.02%)Levothyroxine sodium:          0.025, 0.100 and 0.300 mg (0.02-0.3%)______________________________________
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