Patent Document

This application is a division of application Ser. No. 08/104,150, filed on Aug. 11, 1993, now abandoned, which is a 371 of PCT/US92/10773 filed Dec. 18, 1992. 
    
    
     BACKGROUND OF THE INVENTION 
     In general, it is preferable that medicines are easy to swallow and in the administrational form of small volume or quantity. In addition, it is desirable that their ingredients are uniformly distributed and they are administered efficiently, e.g., in a high concentration. Encapsulation can satisfy such purposes as discussed in a Japanese patent application titled &#34;Simplified Encapsulation of Medicines,&#34; which has been published in the Japanese Unexamined Patent Gazette No. 1-502185. 
     This Gazette discloses a specific solvent solution system that is to be encapsulated and composed of an ionizable medicine, hydroxide ions or hydrogen ions enough to enhance the solubility of said medicine, and a specified amount of water and polyethylene glycol (PEG). 
     However, this solvent system using PEG can cause a local reaction due to existing hydroxide ions depending on the properties of other components in the capsule. As the result, an ester may be produced and, thereby, may cause the purity of the encapsulated contents to be lowered. 
     The inventors of the present invention have earnestly investigated the purity deterioration of the solute component (medicine) due to its reaction with the solvent and found that polyoxyethylene sorbitan fatty acid ester (hereafter, abbreviated POSE) is a solvent useful for preventing the deterioration of purity, and have reached the present invention. 
     1. Field of the Invention 
     The present invention relates to a solvent system that includes a highly concentrated acidic medicine, the solubility of which is enhanced by partial ionization of said medicine. 
     This solvent system is used by being enclosed in soft gels (soft elastic gelatin capsules) or hard gelatin shells. 
     2. Outline of the Invention 
     The present invention relates to a high concentration solvent system to be enclosed in capsules, said system being composed of 
     a) 10-80% by weight acidic medicine, 
     b) 0.1-1.0 mole hydroxide ions for one mole of said medicine, and 
     c) 1-20% by weight water 
     included in POSE, the mean molecular weight of said POSE being 600-3000. 
     SUMMARY OF THE INVENTION 
     Hereafter, the present invention will be explained in detail. 
     a) Ibuprofen, Naproxen, Indomethacin, Acetaminophen, etc. may be exemplified as among the acidic medicines to be used in this invention. 
     Said acidic medicine is selectively used in the range of about 10-80% by weight for the amount of POSE in consideration of the kind of acidic medicine used. The use of the medicine in the region under or over said range is less advantageous because the system may become too low in concentration in the former while it may become inhomogeneous, causing the crystallization of the acidic medicine in the form of insoluble substances in the latter. 
     b) In the present invention, about 0.1-1.0 mole hydroxide ions is used for each molar equivalent of said acidic medicine. 
     Hydroxide ions originated, for example, from sodium and/or potassium hydroxide, are used together with water. Use of hydroxide ions in the concentration under or over the above-mentioned range is less advantageous because the acidic medicine may not be dissolved in the former, causing an inhomogeneous phase system and, on the other hand, the gelatin constituting the shell of capsules tends to be hydrolyzed in the latter, causing leaking capsules 
     c) in the present invention, about 1-20% by weight water is included in POSE. If the water content is lower than about 1% by weight, the ionization of the acidic medicine might be incomplete though it depends on the nature of the medicine used, making the desired solubility unattainable. On the other hand, if the water content is more than about 20% by weight, the capsule containing such water may be softened and impractical. 
     In the present invention, this water can be added directly to the POSE or the acidic medicine; otherwise it can be added to the hydroxide to be used in order to obtain an aqueous solution of alkaline hydroxide, which is afterwards added to the POSE. 
     In the present invention, POSEs with mean molecular weights of approximately 600-3000 are preferably used. Such POSEs are well known, for example, under the trade name of Tween (Atlas Powder Co.) and are easily available in the market. Specific POSEs useful in the present invention include: 
     TWEEN 20 ethylene oxide condensate of sorbitanmonolaurate 
     TWEEN 21 ethylene oxide condensate of sorbitanmonolaurate 
     TWEEN 40 ethylene oxide condensate of sorbitanmonopalmitate 
     TWEEN 60 ethylene oxide condensate of sorbitanmonostearate 
     TWEEN 61 ethylene oxide condensate of sorbitanmonostearate 
     TWEEN 65 ethylene oxide condensate of sorbitantristearate 
     TWEEN 80 ethylene oxide condensate of sorbitanmonooleate 
     TWEEN 81 ethylene oxide condensate of sorbitanmonooleate 
     TWEEN 85 ethylene oxide condensate of sorbitantrioleate 
     Effects of the Invention 
     The effects of the present invention may be listed as follows: 
     a) The solubility of acidic medicine can be increased by about 4-400%. 
     b) The chemical stability of the included medicine is higher than that in the case where PEG is used as the primary solvent. 
     c) When filled in capsules, the capsule contents can be reduced in volume. 
     d) No deteriorative effects are inflicted on the shell of capsules. 
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     Some embodiments will be described with emphasis laid on the contrast with PEG so as to explain the present invention in further detail. 
    
    
     EXAMPLE 1 
     10 g each of Ibuprofen and Naproxen, both acidic medicines, was partially neutralized with a potassium hydroxide solution in PEG 400 and polyoxyethylene sorbitan fatty acid easter (&#34;polysorbate&#34; in Japanese Pharmacopcia; trade name: TWEEN) and the solubilities of these medicines were measured. 
     It is possible as shown in Table 1 to increase the solubility of the medicine. 
     
                       TABLE 1______________________________________                   TWEEN 80 (This      PEG 400 (Control)                   Invention            Solubil-         Solubil-  Unit Dose ity       Capsule                             ity    CapsuleMedicine  (mg)      (%)       Size   (%)    Size______________________________________Ibuprofen  150       25        11     75     4Naproxen  100       15        18     55     4______________________________________ 
    
     EXAMPLE 2 
     Ibuprofen in various polyoxyethylene sorbitan fatty acid ester solutions (TWEEN) was partially neutralized with an alkaline solution and preserved at 105° C. for 44 hours. The amount of ester produced between the acidic medicine and the solvent and the content of the remaining Ibuprofen were measured and compared with those in the case where PEG is used instead of POSE. 
     It is shown in Table 2 that the formation rate of ester can be made lower than that in the case where PEG is used as solvent. 
     
                                           TABLE 2__________________________________________________________________________   Control Sample  This Invention   A   B   C   D   E   F   G   H__________________________________________________________________________Ibuprofen   200 200 200 200 200 200 200 200PEG 400 250 125 125 0   0   0   0   0PEG 1500   0   125 0   125 0   0   0   0TWEEN 20   0   0   0   0   250 0   0   0TWEEN 40   0   0   0   0   0   250 0   0TWEEN 60   0   0   0   0   0   0   250 0TWEEN 80   0   0   0   0   0   0   0   250Propylene Glycol   0   0   125 125 0   0   0   0NaOH    12  12  12  12  12  12  12  12Pufified Water   51  51  51  51  51  51  51  51Total Content   513 513 513 513 513 513 513 513(mg)Alkali n/e   0.29       0.29           0.29               0.29                   0.29                       0.29                           0.29                               0.29   after       after           after               after                   after                       after                           after                               after   treated       treated           treated               treated                   treated                       treated                           treated                               treat-                               edPEG Ester (%)   8.5 7.5 2.8 1.4 ND  ND  ND  NDPG Ester (%)   ND  ND  13.1               11.2                   ND  ND  ND  NDIbuprofen (%)   90.5       90.3           83.0               85.7                   93.8                       94.0                           94.1                               94.8__________________________________________________________________________ After Treated . . . Value determined after preserved at 105° C. fo 44 hours ND: Not Detected 
    
     EXAMPLE 3 
     Naproxen in various polyoxyethylene sorbitan fatty acid ester solutions was partially neutralized with an alkaline solution and preserved at 105° C. for 44 hours. The amount of ester produced between the acidic medicine and the solvent and the content of the remaining Naproxen were measured to be compared with those in the case where PEG is used. 
     It is shown in Table 3 that the formation rate of ester can be made lower than that in the case where PEG is used as solvent. 
     
                                           TABLE 3__________________________________________________________________________     Control Samples                  This Invention     I  J  K   L  M   N  O    P__________________________________________________________________________Naproxen  100        100           100 100                  100 100                         100  100PEG 600   168        0  0   0  0   0  0    0PEG 400   0  168           166 168                  0   0  0    0TWEEN 20  0  0  0   0  209 0  0    0TWEEN 40  0  0  0   0  0   209                         0    0TWEEN 60  0  0  0   0  0   0  209  0TWEEN 80  0  0  0   0  0   0  0    209KOH       11 12 0   12 12  12 12   12NaOH      0  0  8   0  0   0  0    0Purified Water     11 12 17  12 12  12 12   12Total Content (mg)     290        292           291 292                  333 333                         333  333Alkali n/e     0.47        0.49           0.47               0.49                  0.49                      0.49                         0.49 0.49     after        after           after               after                  after                      after                         after                              after     treat-        treat-           treat-               treat-                  treat-                      treat-                         treated                              treat-     ed ed ed  ed ed  ed      edPEG Ester (%)     4.6        7.4           6.1 5.1                  ND  ND ND   NDNaproxen (%)     95.4        92.6           93.9               93.9                  97.4                      98.1                         98.3 98.5__________________________________________________________________________ After Treated . . . Value determined after preserved at 105° C. fo 44 hours ND: Not Detected 
    
     EXAMPLE 4 
     Ibuprofen dissolved separate in three kinds of solvents--two kinds of polyoxyethylene sorbitan fatty acid ester (TWEEN 20 and TWEEN 80) and polyethylene glycol--was partially neutralized (0.3-0.4 m/e) with alkaline solutions and the obtained solutions were encapsulated into soft capsules whose shell films are made of 100 parts gelatin, 35 parts glycerin and 15 parts sorbitol using a rotary soft-capsule filling machine, producing each capsule whose fill weight is approximately 390 mg. 
     It was found in these capsules preserved at 40° C. for 6 months that the formation rate of ester is lower in the capsules filled with POSE than in those filled with PEG. 
     
                                           TABLE 4__________________________________________________________________________   No 1       No 2          No 3              No 4                 No 5                     No 6                        No 7                            No 8                               No 9__________________________________________________________________________FormulationIbuprofen   155 155          155 155                 155 155                        155 155                               155PEG 400 95  95 95  95 171 95 95  0  0PEG 1500   95  95 95  95 19  0  0   0  0TWEEN 20   0   0  0   0  0   95 0   190                               0TWEEN 80   0   0  0   0  0   0  95  0  190NaOH    9   0  9   0  9   9  9   0  0KOH     0   13 0   13 0   0  0   13 13Fill Quantity   385 389          385 389                 385 385                        385 389                               389(ag)Stability TestResults (%)1 month 50° C.   91.0       94.1          97.4              96.8                 95.5                     96.1                        97.3                            99.8                               101.33 mths Room   96.7       94.8          98.1              97.4                 98.1                     99.3                        98.7                            99.5                               99.4Temp.3 months 40° C.   94.8       94.8          94.8              94.8                 94.2                     96.7                        96.8                            98.2                               98.16 mths Room   96.7       96.1          95.5              94.8                 95.5                     99.3                        96.1                            99.9                               100.6Temp.6 months 40° C.   92.8       93.5          92.9              91.6                 89.7                     92.8                        95.5                            97.2                               97.4Change in Ester Formation with Time (%)Amount of esterafter preservedat 40° C. for 3mthsGlycerin Ester   2.1 2.3          2.1 2.1                 2.1 2.4                        1.8 1.8                               1.7PBG Ester   1.7 1.7          1.8 1.6                 1.8 1.1                        1.1 0.0                               0.0Amount of esterafter preservedat 40° C. for 6monthsGlycerin Ester   2.1 2.5          2.1 2.1                 2.1 2.5                        1.8 1.8                               1.8PBG Ester   1.1 1.6          1.9 1.8                 1.8 1.5                        1.5 0.0                               0.0__________________________________________________________________________ 
    
     EXAMPLE 5 
     Naproxen separately dissolved in three kinds of solvents--two kinds of POSE (TWEEN 20, TWEEN 80) and PEG--was partially neutralized with alkaline solutions and the obtained solutions were encapsulated into soft capsules whose shell films are made of 100 parts gelatin, 30 parts glycerin and 15 parts sorbitol using a rotary soft-capsule filling machine, producing each capsule whose fill weight is approximately 574 mg. 
     It was found in these capsules preserved for 4 months at 40° C. that the formation rate of ester is lower in the capsules filled with POSE than those in PEG. 
     
                       TABLE 5______________________________________       No 1   No 2    No 3     No 4______________________________________FormulationNaproxen      200      200     200    200PEG 400       330      165     0      0PEG 1500      0        165     0      0TWEEN 20      0        0       330    0TWEEN 80      0        0       0      330KOH           22       22      22     13Purified Water         22       22      22     31Fill Quantity (mg)         574      574     574    574Results ofStability Test (%)1 mth    50° C.             98.3     98.5  99.1   99.33 mths   Room     99.6     99.5  99.9   99.9    Temp.3 mths   40° C.             98.9     99.1  99.6   99.76 mths   Room     99.8     99.3  99.7   99.7    Temp.6 mths   40° C.             97.3     97.6  98.9   99.2______________________________________

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