PERCUTANEOUSLY ABSORBABLE COMPOSITION OF MORPHINE HYDROCHLORIDE

Abstract: A percutaneously absorbable preparation comprising a narcotic analgesic of a low percutaneous absorbability such as morphine hydrochloride or sulfate, a nonnarcotic analgesic such as eptazocine hydrobromide, a percutaneous absorption promoter, and a percutaneous absorption promoter aid.

Description: Technical Field The present invention relates to percutaneously absorbable morphine hydrochloride compositions. Background Art Narcotic analgesics such as morphine or its salts and non-narcotic 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 their increased administration frequency. Oral agents, which have been developed for the purpose of simplification of administration and use, overcome some disadvantages of the injecting agents, but are not so much improved in working time, in that the migrating property and retentivity of the formations in digestive organs are difficult to control even by pharmaceutical designs for gradual release, and the persistency has its limit. Further, many cancerated 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, skin applying formulations have expectable persistency of medicinal effect for about 24 hours to 1 week by one administration, and are applicable to patients impossible of oral administration. 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 the horny layer of the epidermis, and various accelerators which 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 art, 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. EP-A-0147146 discloses a percutaneously absorbable composition comprising at least one systemically active, water soluble or solubilizable drug (eg conjugated estrogens, etodolac or estradiol), a percutaneous transfer enhancing amount (eg about 4-16% by weight) of menthol and at least one pharmaceutically acceptable solvent (inter alia, glycerin, propylene glycol, isopropanol and ethanol) for the drug. EP-A-0093563 discloses a percutaneously absorbable composition comprising indomethacin, 0.3 - 10% by weight of at least one solubilizer selected from C 10 terpenoids (inter alia, menthol and terpineol) and C 10 phenols, and a solvent (inter alia, alcohols such as ethanol and propanol and mixed alcohol-water systems). Disclosure of the Invention According to one aspect of the present invention, there is provided a percutaneously absorbable composition comprising an analgesic and means for enhancing percutaneous absorption of the analgesic, characterised in that said analgesic is morphine hydrochloride, said means comprises 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, and water, said percutaneous absorption accelerator is used in a ratio of 1-20 wt%, and said percutaneous absorption accelerating assistant is used in a ratio of 10-60 wt%. According to a further aspect of the present invention, there is provided a method of manufacturing a percutaneously absorbable composition, comprising mixing an analgesic with means for enhancing percutaneous absorption of the analgesic, characterised in that said analgesic is morphine hydrochloride, said means comprises 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, and water, said percutaneous absorption accelerator is used in a ratio of 1-20 wt%, and said percutaneous absorption accelerating assistant is used in a ratio of 10-60 wt%. 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. Further, as other percutaneous absorption accelerating assistants, water, lower glycols having 2-20 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 1-7 are graphs showing the changes on standing of absorption quantities of morphine hydrochloride through the skin with various kinds and quantities of 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 physcially removes the barrier ability of the horny layer of the skin and enhances the permeability of the skin towards morphine hydrochloride. The percutaneous absorption accelerating assistant increases the solubility of the morphine hydrochloride and also the permeability of the latter, resulting in a remarkable improvement in absorbability of the morphine hydrochloride as an synergistic effect. Optimum Conditions to Practise the Invention 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 on 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 150g, available from Saitama Experimental Animals) was put in a 2-chamber diffusing cell (contact area: 1.0 cm 2 ) of skin permeation test as held at 37°C, 2.5 ml of a medicine solution is put on the horny layer side, and 2.5 ml of water on the derm side. Ten diffusing cell dermic solutions are sampled on 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. unit: µg/cm 2 Time elapsed This Invention 1 Comparative Ex. 1 Comparative Ex. 2 Comparative Ex. 3 Mean Deviation Mean Deviation Mean Deviation Mean Deviation 2 629 20.9 1.72 0.25 3.58 0.52 10.2 3.73 4 1436 87.3 3.43 0.01 10.3 1.54 49.3 0.12 6 1732 90.9 6.34 0.23 23.0 5.59 161 10.1 8 1893 111 12.6 1.78 40.6 11.4 321 20.1 10 - - 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. unit: w% Component This Invention 1 2 3 Morphine hydrochloride 1 10 0.01 1-Menthol 5 5 5 Ethanol 40 40 40 Water 54 45 54.99 As shown in Fig. 2 and Table 4, the results showed the medicine is absorbed percutaneously corresponding to the concentration of morphine hydrochloride. unit: µg/cm 2 Time elapsed This Invention 1 This Invention 2 This Invention 3 Mean Deviation Mean Deviation Mean Deviation 2 629 20.9 6256 213 8.45 0.08 4 1436 87.3 14399 671 17.4 0.34 6 1732 90.9 20323 940 27.7 1.03 8 1893 111 24958 1142 35.0 0.63 10 - - 28410 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. unit: w% Component This Invention 1 4 5 Morphine hydrochloride 1 1 1 1-Menthol 5 - - Terpineol - 5 - Peppermint oil - - 5 Ethanol 40 40 40 Water 54 54 54 Consequently, as shown in Fig. 3 and Table 6, excellent percutaneous absorbability was shown in every percutaneous absorption accelerator, but particularly the best in terpineol. unit: µg/cm 2 Time elapsed This Invention 1 This Invention 4 This Invention 5 Mean Deviation Mean Deviation Mean Deviation 2 629 20.9 1046 44.5 854 65.2 4 1436 87.3 2111 107 1766 64.7 6 1732 90.9 3163 226 2283 73.3 8 1893 111 3884 223 2662 93.8 10 - - - - 3087 100 Example 4 To examine the effect of the concentration of ℓ-menthol on skin permeability of morphine hydrochloride from ℓ-menthol-ethanol-water system, formations as shown in Table 7 were prepared and examined for percutaneous absorbability. 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. unit: µg/cm 2 Time elapsed This Invention 1 This Invention 6 This Invention 7 Comp.Ex. 4 Comp. Ex. 5 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 0.0 4 1436 87.3 876 47.4 1164 88.0 18.4 2.77 2.42 0.63 6 1732 90.9 1340 62.4 1665 94.8 83.4 15.5 6.90 1.27 8 1893 111 1717 57.8 2020 65.0 226 40.3 19.0 2.02 10 - - 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 ℓ-menthol-ethanol-water system, formations shown in Table 9 were prepared and examined for percutaneous absorbability. 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%. unit: µg/cm 2 Time elapsed This Invention 1 This Invention 8 This Invention 9 Comp. Ex. 6 Comp. Ex. 7 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 0.76 4 1436 87.3 182 0.80 251 6.84 6.84 1.02 5.92 4.72 6 1732 90.9 366 18.3 688 33.6 33.6 0.13 25.8 18.6 8 1893 111 570 62.1 1106 226 104 0.29 66.6 46.3 10 - - 942 87.4 - - - - - - Example 6 To examine the effect of the concentration of isopropyl alcohol (IPA) adapted instead of ethanol on skin permeativity of morphine hydrochloride from ℓ-menthol-alcohol-water system, formations shown in Table 11 were prepared and examined for percutaneous absorbability. 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.% similarly to the case of ethanol, and too much high concentration rather aggravated the absorbability. unit: µg/cm 2 Time elapsed This Invention 1 This Invention 10 This Invention 11 This Invention 12 Mean Deviation Mean Deviation Mean Deviation Mean Deviation 2 629 20.9 229 44.4 348 31.8 3.43 2.80 4 1436 87.3 665 94.7 1663 75.3 75.8 13.0 6 1732 90.9 1073 145 2624 68.2 227 32.6 8 1893 111 1546 184 3420 64.1 432 48.5 10 - - 1922 178 3891 40.4 .696 65.6 Example 7 Instead of the water added as the supplement of ethanol of the percutaneous absorption accelerating assistant having an influence on skin permeativity of morphine hydrochloride from 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 the percutaneous absorbability similar to the case of water can be held when glycerol is used. unit: µg/cm 2 Time elapsed This Invention 1 This Invention 13 Mean Deviation Mean Deviation 2 629 20.9 26.8 8.40 4 1436 87.3 235 76.8 6 1732 90.9 687 163 8 1893 111 1172 169 10 - - 1568 144 Industrial Applicability The percutaneous absorption accelerating formations according to the present invention allow the administration from the skin for morphine hydrochloride 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 has a constitution for percutaneous absorption, formations having long analgesic effects can be provided. The formations 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.

Claims: Claims for the following Contracting States : AT, BE, CH, DE, DK, FR, GB, IT, LI, LU, NL, SE A percutaneously absorbable composition comprising an analgesic and means for enhancing percutaneous absorption of the analgesic, characterised in that said analgesic is morphine hydrochloride, said means comprises 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, and water, said percutaneous absorption accelerator is used in a ratio of 1-20 wt%, and said percutaneous absorption accelerating assistant is used in a ratio of 10-60 wt%. A percutaneously absorbable composition according to claim 1, wherein the percutaneous absorption accelerator is a monoterpene or an essential oil containing a monoterpene. A percutaneously absorbable composition according to claim 1, wherein the percutaneous absorption accelerating assistant is any one or more of methyl alcohol, ethyl alcohol, propyl alcohol, butyl alcohol, amyl alcohol and ispropyl alcohol. A percutaneously absorbable composition according to claim 1, wherein any one of lower glycols having 2 to 20 carbon atoms, lower ketones having 2 to 5 carbon atoms and aldehydes are added as other percutaneous absorption accelerating assistants. A method of manufacturing a percutaneously absorbable composition, comprising mixing an analgesic with means for enhancing percutaneous absorption of the analgesic, characterised in that said analgesic is morphine hydrochloride, said means comprises 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, and water, said percutaneous absorption accelerator is used in a ratio of 1-20 wt%, and said percutaneous absorption accelerating assistant is used in a ratio of 10-60 wt%. Claims for the following Contracting State : ES A method of manufacturing a percutaneously absorbable composition, comprising mixing an analgesic with means for enhancing percutaneous absorption of the analgesic, characterised in that said analgesic is morphine hydrochloride, said means comprises 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, and water, said percutaneous absorption accelerator is used in a ratio of 1-20 wt%, and said percutaneous absorption accelerating assistant is used in a ratio of 10-60 wt%. A method according to claim 1, wherein the percutaneous absorption accelerator is a monoterpene or an essential oil containing a monoterpene. A method according to claim 1, wherein the percutaneous absorption accelerating assistant is any one or more of methyl alcohol, ethyl alcohol, propyl alcohol, butyl alcohol, amyl alcohol and ispropyl alcohol. A method according to claim 1, wherein any one of lower glycols having 2 to 20 carbon atoms, lower ketones having 2 to 5 carbon atoms and aldehydes are added as other percutaneous absorption accelerating assistants.

Inventors: KOBAYASHI KOUJI, KUSANO HISASHI, MORIMOTO YASUNORI, SUGIBAYASHI KENJI, KOBAYASHI, KOUJI, KUSANO, HISASHI, MORIMOTO, YASUNORI, SUGIBAYASHI, KENJI, KOBAYASHI, KOUJI, TOKO YAKUHIN KOGYO, KUSANO, HISASHI, 19-304, NISHIAGEO, MORIMOTO, YASUNORI, 7-22, NISHISAKADO 4-CHOME, SUGIBAYASHI, KENJI, 9-22, NISHISAKADO 4-CHOME
Applicants: MORIMOTO YASUNORI, MORIMOTO, YASUNORI
Application year: 1991
Main classification: A61K47
IPC codes: A61K45, A61K9, A61K31, A61K47