Percutaneously absorbable compositions of morphine or analogous analgesics of morphine

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.sup.2) of a skin permeation test and held at 37.degree. 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: .mu.g/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: .mu.g/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: .mu.g/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: .mu.g/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: .mu.g/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: .mu.g/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: .mu.g/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: .mu.g/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: .mu.g/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: .mu.g/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: .mu.g/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.

Claims

1. A composition which is percutaneously absorbable, comprising:

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.

2. The composition according to claim 1, wherein the percutaneous absorption accelerator is one of (a) a monoterpene and (b) an essential oil containing a monoterpene.

3. The composition according to claim 2, wherein the percutaneous absorption accelerator is a monoterpene and is one of (a) 1-menthol and (b) terpineol.

4. The composition according to claim 3, wherein the percutaneous absorption accelerating assistant is at least one lower alcohol having 1-5 carbon atoms selected from the group consisting essentially of methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, or amyl alcohol.

5. The composition according to claim 2, wherein the percutaneous absorption accelerator is an essential oil containing a monoterpene and is one of (a) mentha oil and (b) peppermint oil.

6. The composition according to claim 5, wherein the percutaneous absorption accelerating assistant is at least one lower alcohol having 1-5 carbon atoms selected from the group consisting essentially of methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, and amyl alcohol.

7. The composition according to claim 2, wherein the percutaneous absorption accelerating assistant is at least one lower alcohol having 1-5 carbon atoms selected from the group consisting essentially of methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, and amyl alcohol.

8. The composition according to claim 1, wherein the percutaneous absorption accelerating assistant is at least one lower alcohol having 1-5 carbon atoms selected from the group consisting essentially of methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, or amyl alcohol.

9. The composition according to claim 1, wherein the analogous analgesics of morphine include salts of morphine and bases of morphine.

10. The composition according to claim 9, wherein the analogous analgesics of morphine are selected from the group consisting essentially or morphine hydrochloride, ethyl morphine hydrochloride, and morphine sulfate.