Abstract:
A composition which is percutaneously absorbable, including a narcotic analgesic selected from the group consisting of morphine and analogous analgesics thereof; from 1 to 20 weight percent of a percutaneous absorption accelerator comprised of one of (a) a terpene and (b) an essential oil; from 10 to 60 weight percent of a percutaneous absorption accelerating assistant comprised of one of (a) a lower alcohol having 1-5 carbon atoms, (b) water and (c) a lower glycol having 2-5 carbon atoms.

Description:
BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     The present invention relates to percutaneously absorbable formulations such as analgesics such as morphine, or its salts or bases. 
     2. Background of the Related Art 
     Narcotic analgesics such as morphine or its salts and nonnarcotic analgesics such as eptazocine have been orally administered or injected to ease postoperative and cancerous pains. 
     In the case of such injecting agents, at-home treatment is difficult because of the necessity of administration by a third person, and further medicines having short working times such as morphine are disadvantageously difficult to administer at the time of acute pain because of its increased administration frequency. 
     Oral agents, which have been developed for the purpose of simplification of administration and use, overcame some disadvantages of the injecting agents, but are not so much improved in working time, in which the migrating property and retentivity of the formulations in digestive organs are difficult to control even by pharmaceutical designs for gradual release, and the persistency has its limit. 
     Further, many cancer patients in the last stage can not have oral administration of analgesics because of vomiting and nausea which are the side effects of carcinostatic substances. 
     On the other hand, formulations applied to the skin have an expected persistency of medicinal effect of about 24 hours to 1 week for one administration, and are applicable to patients for which oral administration is not possible. 
     In general, medicines have low percutaneous absorbability, and it is the same with analgesics including morphine and its salts. 
     The main barrier to percutaneous absorption of medicines resides in a horny layer, and various accelerators have been developed as the accelerators were considered to increase the percutaneous absorbability to the lipids of the horny layer. However, the medicine permeability of the epidermis other than the horny layer becomes the barrier in simple absorption accelerators acting on the horny layer and combinations thereof, so that very excellent accelerators have not been developed yet. 
     In view of the disadvantages of the prior arts, as a result of the earnest studies on utilization of analgesics such as morphine, which were used only as injecting agents and oral agents in the past, for percutaneously absorbable type external agents such as ointment, cream, tape dressing, plaster dressing, patch dressing, and pap dressing (wet dressing), the present inventors have found and attained this invention. 
     SUMMARY OF THE INVENTION 
     The present invention can provide a percutaneously absorbable formulation by dissolving a percutaneously absorbable composition of narcotic or nonnarcotic analgesics into a base agent formed of a percutaneous absorption accelerator consisting of a terpene and/or an essential oil and a percutaneous absorption accelerating assistant consisting of a lower alcohol having 1-5 carbon atoms. 
     As the narcotic analgesics used in the present invention, morphine hydrochloride, ethylmorphine hydrochloride, morphine sulfate, cocaine hydrochloride, pethidine hydrochloride, codeine phosphate, dihydrocodeine phosphate, fentanyl citrate, sufentanil, meperidine hydrochloride and the like are used. As the nonnarcotic analgesics, eptazocine hydrobromide, buprenorphine hydrochloride, butorphanol tartrate, or other salts are used. These analgesics may be constituted by basic ones. 
     As the percutaneous absorption accelerators, hydrocarbon monoterpenes such as limonene, monoterpene alcohols such as l-menthol, terpineol and borneol, monoterpene aldehydes such as citral, monoterpene ketones such as ionone, other monoterpenes such as cineole, or essential oils containing monoterpenes such as mentha oil, peppermint oil, and eucalyptus oil are used. 
     As the percutaneous absorption accelerating assistants, lower alcohols having 1-5 carbon atoms such as methyl alcohol, ethyl alcohol, propyl alcohol, butyl alcohol, amyl alcohol, isopropyl alcohol and the like are used. 
     The blending quantities are varied depending on the kinds of medicines used, but the percutaneous absorption accelerator is preferably used in a ratio of 1-20 wt. % and the percutaneous absorption accelerating assistant in a ratio of 10-60 wt. %. 
     As other percutaneous absorption accelerators, alcohols having 8-22 carbon atoms, fatty acids having 8-22 carbon atoms, fatty acid methyl, ethyl, vinyl, n-propyl, isopropyl, propylene, n-butyl, isobutyl and buthylene esters having 8-22 carbon atoms, n-alkylpyrrolidones having 1-16 carbon atoms and/or mixtures thereof may be added. 
     Further, as other percutaneous absorption accelerating assistants, water, lower glycols having 2-20, preferably 2-5, carbon atoms such as glycerol and propylene glycol, lower ketones having 2-5 carbon atoms, or aldehyde may be added. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     FIGS. 1-11 are graphs showing the changes on standing of absorption quantities of medicines through the skin with various kinds and quantities of medicines, percutaneous absorption accelerators, and percutaneous absorption accelerating assistants related to the formulations according to the examples of the present invention and the formulations of comparative examples. 
    
    
     EFFECT 
     The percutaneous absorption accelerator in the composition physically removes the barrier ability of the horny layer of the skin and enhances the medicine permeability of the skin. 
     The percutaneous absorption accelerating assistant increases the solubility of the medicine and also medicine permeability, resulting in a remarkable improvement in absorbability of the medicine as a synergistic effect. 
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     The present invention is further illustrated in detail according to following examples. 
     EXAMPLE 1 
     Formulations as shown in Table 1 were prepared, and comparatively examined for the change on standing of skin permeating quantity by means of a skin permeation test method described below. 
     Skin Permeation Test Method 
     The abdominal extracted skin of a hairless rat (male, body weight 150 g, available from Saitama Experimental Animals) was put in a 2-chamber diffusing cell (contact area: 1.0 cm 2 ) of a skin permeation test and held at 37° C. Then, 2.5 ml of a medicine solution was put on the horny layer side, and 2.5 ml of water on the derm side. Ten diffusing cell dermic solutions were sampled and the lapse of time, and the quantities of the medicine permeated through the skin after 2, 4, 6, 8 and 10 hours were measured. The results are as shown in Table 2 and FIG. 1. 
     
                       TABLE 1______________________________________unit: w %Sample        This Invention                     Comparative ExampleComponent     1           1        2    3______________________________________Morphine hydrochloride          1           1       1     11-Menthol      5          --      --    5Ethanol       40          --      40    --Water         54          99      59    4______________________________________ 
    
     
                                           TABLE 2__________________________________________________________________________unit: μg/cm.sup.2    This Invention         Comparative Ex.                   Comparative Ex.                             Comparative Ex.Time    1         1         2         3elapsed    Mean   Deviation         Mean             Deviation                   Mean                       Deviation                             Mean                                 Deviation__________________________________________________________________________2    629   20.9  1.72             0.25  3.58                       0.52  10.2                                 3.734   1436   87.3  3.43             0.01  10.3                       1.54  49.3                                 0.126   1732   90.9  6.34             0.23  23.0                       5.59  161 10.18   1893   111   12.6             1.78  40.6                       11.4  321 20.110  --  --    17.1             3.19  73.3                       15.1  533 20.0__________________________________________________________________________ 
    
     The results showed that the formation having l-menthol selected as an absorption accelerator and ethanol as an absorption accelerating assistant has excellent percutaneous absorptivity. 
     EXAMPLE 2 
     To examine the relation of the concentration of morphine hydrochloride with skin permeativity, formations shown in Table 3 were prepared and examined on the basis of the skin permeation test. 
     
                       TABLE 3______________________________________unit: w %          This lnventionComponent        1          2     3______________________________________Morphine hydrochloride            1          10    0.011-Menthol        5           5    5Ethanol          40         40    40Water            54         45    54.99______________________________________ 
    
     As shown in FIGS. 2(a), 2(b) nd 2(c), and Table 4, the results showed that the medicine is absorbed percutaneously corresponding to the concentration of morphine hydrochloride, i.e., 0.01 W % in FIG. 2(a), 1 W % in FIG. 2(b), and 10 W % in FIG. 2(c). 
     
                                           TABLE 4__________________________________________________________________________unit: μg/cm.sup.2    This Invention           This Invention                     This InventionTime    1           2         3elapsed    Mean Deviation           Mean               Deviation                     Mean Deviation__________________________________________________________________________2    629 20.9    6256               213   8.45 0.084   1436 87.3   14399               671   17.4 0.346   1732 90.9   20323               940   27.7 1.038   1893 111    24958               1142  35.0 0.6310  --   --     18410               1580  40.4 0.88__________________________________________________________________________ 
    
     EXAMPLE 3 
     Formulations containing different kinds of percutaneous absorption accelerators were prepared as shown in Table 5, and comparatively examined for percutaneous absorbability of morphine hydrochloride in the same manner as in Example 1. 
     
                       TABLE 5______________________________________unit: w %         This InventionComponent       1          4      5______________________________________Morphine hydrochloride           1          1      11-Menthol       5          --     --Terpineol       --         5      --Peppermint oil  --         --     5Ethanol         40         40     40Water           54         54     54______________________________________ 
    
     Consequently, as shown in FIG. 3 and Table 6, excellent percutaneous absorbability was shown for every percutaneous absorption accelerator, but particularly the best was terpineol. 
     
                                           TABLE 6__________________________________________________________________________unit: μg/cm.sup.2    This Invention           This Invention                     This InventionTime    1           4         5elapsed    Mean Deviation           Mean               Deviation                     Mean Deviation__________________________________________________________________________2    629 20.9   1046               44.5   854 65.24   1436 87.3   2111               107   1766 64.76   1732 90.9   3163               226   2283 73.38   1893 111    3884               223   2662 93.810  --   --     --  --    3087 100__________________________________________________________________________ 
    
     EXAMPLE 4 
     To examine the effect of the concentration of l-menthol on the skin permeability of morphine hydrochloride from an l-menthol-ethanol-water system, formations as shown in Table 7 were prepared and examined for percutaneous absorbability. 
     
                       TABLE 7______________________________________unit: w %Sample        This Invention                       Comparative Ex.Component     6       1     7     4      5______________________________________Morphine hydrochloride         1       1      1    1      11-Menthol     2.5     5     10    1      0.1Ethanol       40      40    40    40     40Water         56.4    54    49    58     58.9______________________________________ 
    
     As shown in FIG. 4 and Table 8, the results showed that skin permeativity is excellent when the concentration of menthol is 2.5 w % or more. 
     
                                           TABLE 8__________________________________________________________________________unit: μg/cm.sup.2    This Invention         This Invention                   This Invention                             Comp. Ex. Comp. Ex.Time    1         6         7         4         5elapsed    Mean   Deviation         Mean             Deviation                   Mean                       Deviation                             Mean                                 Deviation                                       Mean                                           Deviation__________________________________________________________________________2    629   20.9   292             39.8   524                       67.1  0.0 0.0   0.0 0.04   1436   87.3   876             47.4  1164                       88.0  18.34                                 2.77  2.42                                           0.636   1732   90.9  1340             62.4  1665                       94.8  83.4                                 15.5  6.90                                           1.278   1893   111   1717             57.8  2020                       65.0  226 40.3  19.0                                           2.0210  --  --    2057             71.9  2271                       58.3  450 63.4  30.4                                           2.28__________________________________________________________________________ 
    
     EXAMPLE 5 
     To examine the effect of the concentration of ethanol, which is a percutaneous absorption accelerating assistant, on skin permeativity of morphine hydrochloride from an l-menthol-ethanol-water system, the formulations shown in Table 9 were prepared and examined for percutaneous absorbability. 
     
                       TABLE 9______________________________________unit: w %Sample         This Invention                       Comparative Ex.Component      8      1      9    6      7______________________________________Morphine hydrochloride          1      1      1    1      11-Menthol      5      5      5    5      5Ethanol        20     40     60   80     94Water          74     54     34   14     --______________________________________ 
    
     As shown in FIG. 5 and Table 10, the results showed that skin permeativity is excellent when the concentration of ethanol is 20 w % or more and less than 60 w %. 
     
                                           TABLE 10__________________________________________________________________________unit: μg/cm.sup.2    This Invention         This Invention                   This Invention                              Comp. Ex. Comp. Ex.Time    1         8         9          6         7elapsed    Mean   Deviation         Mean             Deviation                   Mean Deviation                              Mean                                  Deviation                                        Mean                                            Deviation__________________________________________________________________________2    629   20.9  45.0             4.08  15.9 2.0   0.72                                  0.7   0.76                                            0.764   1436   87.3  182 0.80  251  6.84  6.84                                  1.02  5.92                                            4.726   1732   90.9  366 18.3  688  33.6  33.6                                  0.13  25.8                                            18.68   1893   111   570 62.1  1106 226   104 0.29  66.6                                            46.310  --  --    942 87.4  --   --    --  --    --  --__________________________________________________________________________ 
    
     EXAMPLE 6 
     To examine the effect of the concentration of isopropyl alcohol (IPA), employed instead of ethanol, on skin permeativity of morphine hydrochloride from an l-menthol-alcohol-water system, the formulations shown in Table 11 were prepared and examined for percutaneous absorbability. 
     
                       TABLE 11______________________________________unit: w %          This lnventionComponent        10         11    12______________________________________Morphine hydrochloride             1          1     11-Menthol         5          5     5Ethanol          20         40    60Water            74         54    34______________________________________ 
    
     Consequently, as shown in FIG. 6 and Table 12, the skin permeativity was excellent when the concentration of isopropyl alcohol is 20 wt. % or more and less than 60 wt. % similar to the case of ethanol, and too high a concentration aggravated the absorbability. 
     
                                           TABLE 12__________________________________________________________________________unit: μg/cm.sup.2    This Invention         This Invention                   This Invention                             This InventionTime    1         10        11        12elapsed    Mean   Deviation         Mean             Deviation                   Mean                       Deviation                             Mean                                 Deviation__________________________________________________________________________2    629   20.9   229             44.4   348                       31.8  3.43                                 2.804   1436   87.3   665             94.7  1663                       75.3  75.8                                 13.06   1732   90.9  1073             145   2624                       68.2  227 32.68   1893   111   1546             184   3420                       64.1  432 48.510  --  --    1922             178   3891                       40.4  696 65.6__________________________________________________________________________ 
    
     EXAMPLE 7 
     Instead of water added as the supplement to ethanol for the percutaneous absorption accelerating assistant having an influence on skin permeativity of morphine hydrochloride from an l-menthol-alcohol-water system, glycerol was mixed as shown in Table 13, and this was comparatively examined for percutaneous absorbability. 
     As shown in FIG. 7 and Table 14, the results showed that a percutaneous absorbability similar to that for water can be held when glycerol is used. 
     
                       TABLE 13______________________________________unit: w %Sample             This InventionComponent          1       13______________________________________Morphine hydrochloride               1       11-Menthol           5       5Ethanol            40      40Water              54      --Glycerol           --      54______________________________________ 
    
     
                       TABLE 14______________________________________unit: μg/cm.sup.2   This Invention  This InventionTime    1               13elapsed Mean    Deviation   Mean   Deviation______________________________________2        629    20.9        26.8   8.404       1436    87.3        235    76.86       1732    90.9        687    1638       1893    111         1172   16910      --      --          1568   144______________________________________ 
    
     EXAMPLE 8 
     To examine the skin permeativities of other medicines to an l-menthol-ethanol-water system, formulations using fentanyl citrate (FTC), eptazocine hydrobromide (ETH), cocaine hydrochloride (CCH), and morphine hydrochloride were prepared and examined for percutaneous absorbability. 
     
                       TABLE 15______________________________________unit: w %Sample            This InventionComponent         1     14        15  16______________________________________Morphine hydrochloride             1     --        --  --FTC               --     1        --  --ETH               --    --         1  --CCH               --    --        --   11-Menthol         5      5         5   5Ethanol           40    40        40  40Water             54    54        54  54______________________________________ 
    
     As shown in FIG. 8(a), FIG. 8(b) and FIG. 8(c) and Table 16, the results showed that every formulation is excellent in skin permeativity in the 1-menthol-ethanol-water system, i.e., 
     FTC, sample 14, FIG. 8(a); 
     ETH, sample 15, FIG. 8(b), and 
     CCH, sample 16, FIG. 8(c). 
     
                                           TABLE 16__________________________________________________________________________unit: μg/cm.sup.2    This Invention         This Invention                   This Invention                             This InventionTime    1         14        15        16elapsed    Mean   Deviation         Mean             Deviation                   Mean                       Deviation                             Mean                                 Deviation__________________________________________________________________________2    629   20.9   570             19.5   586                       61.7   495                                 11.24   1436   87.3  1539             56.4  1729                       87.8  1353                                 13.76   1732   90.9  2274             66.9  2349                       57.9  2018                                 40.48   1893   111   3086             122   3095                       52.0  2549                                 14.310  --  --    3692             187   3691                       50.7  2694                                 38.1__________________________________________________________________________ 
    
     EXAMPLE 9 
     To examine the effect of different concentration of l-menthol on skin permeativity of eptazocine hydrobromide from an l-menthol-ethanol-water system, formulations as shown in Table 17 were prepared and examined for percutaneous absorbability. 
     
                       TABLE 17______________________________________unit: w %Sample      This InventionComponent   17            18     15______________________________________E.T.H.       1             1      1l-Menthol    1             2      5Ethanol     40            40     40Water       58            57     54______________________________________ 
    
     As shown in FIG. 9 and Table 18, the results showed that skin permeativity is excellent when the concentration of menthol is 1.0 wt. % or more. 
     
                                           TABLE 18__________________________________________________________________________unit: μg/cm.sup.2    This Invention           This Invention                     This InventionTime    17          18        15elapsed    Mean Deviation           Mean               Deviation                     Mean Deviation__________________________________________________________________________2   55.03    67.10  669.7               170.8 586.3                          61.704   556.3    380.3  1638               117.0 1729 87.776   1264 275.4  2063               99.52 2349 57.938   1922 223.9  2623               36.51 3095 52.0310  2407 170.8  3017               44.86 3691 50.61__________________________________________________________________________ 
    
     EXAMPLE 10 
     To examine the effect of the concentration of ethanol on skin permeativity of eptazocine hydrobromide from an l-menthol-ethanol-water system, formulations as shown in Table 19 were prepared and examined for percutaneous absorbability. 
     
                       TABLE 19______________________________________unit: w %Sample      This InventionComponent   19            20     15______________________________________E.T.H.       1             1      1l-Menthol    5             5      5Ethanol     10            20     40Water       84            73     54______________________________________ 
    
     As shown in FIG. 10 and Table 19, the results showed that skin permeativity is excellent when the concentration of ethanol is 10 wt. % or more. 
     
                                           TABLE 20__________________________________________________________________________unit: μg/cm.sup.2    This Invention          This Invention                     This InventionTime    19         20         15elapsed    Mean Deviation          Mean Deviation                     Mean Deviation__________________________________________________________________________2   9.121    9.592 97.25               14.79 586.3                          61.704   127.3    78.04 324.6               187.0 1729 87.776   393.5    207.5 1138 195.9 2349 57.938   755.6    303.4 1599 243.3 3095 52.0310  1170 276.0 2152 422.4 3691 50.61__________________________________________________________________________ 
    
     EXAMPLE 11 
     To examine the effect of concentration of eptazocine hydrobromide on skin permeativity of eptazocine hydrobromide from an l-menthol-ethanol-water system, formulations as shown in Table 21 were prepared and examined for percutaneous absorbability. 
     
                       TABLE 21______________________________________unit: w %Sample      This InventionComponent   21            22     15______________________________________E.T.H.      0.1            5      1l-Menthol   5              5      5Ethanol     40            40     40Water       54.9          50     54______________________________________ 
    
     As shown in FIG. 11 and Table 22, the results showed that skin permeativity is excellent when the concentration of eptazocine bromohydride is 1.0 wt. % or more. 
     
                                           TABLE 22__________________________________________________________________________unit: μg/cm.sup.2    This Invention           This Invention                     This InventionTime    19          20        15elapsed    Mean Deviation           Mean               Deviation                     Mean Deviation__________________________________________________________________________2   53.82    2.934   1418               586.3   586.3                          61.704   132.2    13.47   8013               328.3 1729 87.776   206.1    26.52  14273               549.4 2349 57.938   268.2    23.03  19415               103.5 3095 52.0310  311.0    27.65  23300               913.5 3691 50.61__________________________________________________________________________ 
    
     INDUSTRIAL APPLICABILITY 
     The percutaneous absorption accelerating formations according to the present invention allow the administration from the skin for medicines which could not be administered from the skin in the past by adapting monoterpenes which were only used as perfumes as percutaneous absorption accelerators and lower alcohols having 1-5 carbon atoms as skin absorption accelerating assistants, and combining them. 
     As the prevent invention is constituted for percutaneous absorption, formulations having long analgesic effects can be provided. 
     The formulations according to the present invention are suitable for at-home treatment because of their easy recipe, compared with injecting agents and oral agents, and excellent in persistency.