JPS5995212A - Base composition and pharmaceutical composition for external use - Google Patents

Abstract

PURPOSE:To provide the titled composition having improved skin permeability and transcutanous absorptivity of a drug, by compounding a nonpolar compound and a polar compound each having specific organic value, inorganic value and their ratio (based on the organic concept diagram devised by Wataru Fujiguchi). CONSTITUTION:The organic concept diagram is obtained by regarding methane as the base of all the organic compounds, assuming the other compounds as a derivative of methane, setting the specific numbers to the number of carbon atoms, substituent group, modified site, ring, etc., adding the sorces to obtain an organic value and an inorganic value, and plotting the former value on the x- axis and the latter value on the y-axis. In the above diagram, (A) one or more nonpolar compounds falling within the range defined by x=100-600, y=0-65 and y/x <=0.3 and (B) one or more polar compounds falling within the range defined by x=0-180, y=110-300 and x/y >=1, are compounded in the titled composition to increase the skin permeability and the transcutaneous absorptivity of the drug in the composition. The amount of the component (A) is 1-50wt%, preferably 5-30wt%, based on (A)+(B).

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a base composition 9 that can improve transdermal absorption of a drug,
Regarding topical pharmaceutical compositions using the base composition and methods for promoting transdermal absorption of drugs, conventionally, drugs administered to the integument have been administered locally to the integument or its lower part, such as for sterilization, disinfection, and pain. It was intended to act on the However, in recent years, attempts have been made to administer patches that have systemic effects to the skin without having to be rubbed, orally, or injected. g9
When drugs, especially systemic drugs, are administered through the skin, it is easy to maintain the drug's efficacy, and it is easy to adjust the absorption rate of the drug, so it is possible to reduce side effects caused by overdosing. Drugs are not easily metabolized by the liver due to the first-pass effect seen in oral administration, making effective use of the drug possible.
It has the advantage that even drugs that cause gastrointestinal disorders when administered orally, such as indomexin, can be administered safely.

However, since normal skin has a protective effect on the body, it generally has a property that it is difficult to absorb and permeate drugs. Therefore, even if a drug (particularly a drug intended for systemic action) is simply administered in the form of a conventional ointment, lotion, etc., it is difficult for the body to absorb the drug in an amount sufficient to produce a sufficient medicinal effect.

In view of this situation, the inventors of Zero have conducted extensive research and have obtained the following knowledge.

That is, ■The organicity value is 100 to 6 on the organic concept diagram described later.
00, the inorganic value is 0 to 65, the ratio of the inorganic value to the organic value is within the range of 0.3 or less, and the organic value is 0 to 180. A composition containing a polar compound (component B) having a ratio of 1 or more increases the skin permeability and transdermal absorption of the drug, and (2) the above composition forms a drug that can be applied to the skin. It has been found that it can be used as a base material for

The present invention was completed based on the above-mentioned new findings, and its first objective is to provide a base composition for external preparations that can enhance the skin permeability and percutaneous absorption of drugs.

A second object of the present invention is to provide a pharmaceutical composition for external use that has good skin permeability and transdermal absorption of drugs.

A third object of the present invention is to provide a method for increasing skin permeability and transdermal absorption of drugs.

That is, the present invention provides: (i) at least one type of A component and at least one type of B component;
(1) A pharmaceutical composition for external use which further contains a drug in the base composition.

In this specification, an organic conceptual diagram refers to the origin of all organic compounds as methane (CHa), and all other compounds as methane derivatives, and their carbon numbers, substituents, modified parts, rings, etc. are each fixed. Set the value of , add the scores to increase the organic value and inorganic value, and plot these values on a diagram with the organic value on the x-axis and the inorganic value on the y-axis. It is something. This organic conceptual diagram is FUJ ITA.

It was devised by Mr. At5ushi, and the details are in KUMAMOTOPHARMACEUTICAL B.
ULLETIN, No. 1, pp. 1-16 (1954), PfiARMACEU-TICAL B [JLL
ETIN, Volume 2, No. 2, pp. 168-173 (
1954), Chemistry Area, Volume 11, No. 10, 71
9-725 (1957), Fragrance Journal, No. 34, pp. 97-111 (1979), Fragrance Journal, No. 50, pp. 79-82 (198
1 year), etc. Therefore, the mechanical conceptual diagram of each compound can be easily obtained according to the methods described in these documents.

Therefore, the A component and B component used in the present invention are respectively A component region 1 on the conceptual diagram of several aircraft shown in FIG.
What is plotted within and within the B component region 2,
The mechanical value of component A is 100 (preferably 150) to 60
0 (preferably 400), the inorganic value is 0 to 65 (preferably l″160), and the ratio of the inorganic value to the organic value is 0.
3 or less (preferably 025 or less). In addition, the organic value of component B is 0 (preferably 40) to 180 (preferably 150), and the inorganic value is 110 (preferably 120) to 3.
00 (preferably 250), the ratio of the inorganic value to the organic value is 1 or more, preferably 1 to 11. More preferably 1
．． It is 3-5.

Examples of the component A include the following compounds.

(2) Straight chain, branched or cyclic aliphatic hydrocarbon having 5 to 30 carbon atoms which may be substituted with halogen: Brome and gulor are preferred as the halogen as a substituent.

The aliphatic hydrocarbon moiety has 5 carbon atoms in the case of a chain.
-30 (preferably 6-24) saturation or l or 2
An alkyl group having 2 unsaturated bonds is preferable, and in the case of a cyclic structure, a monocyclic or two-membered ring is preferable. In the case of a monocyclic ring, the number of carbon atoms is preferably 6 to 10, and it may be substituted with one or more saturated or un\CH3 saturated alkyl having 1 to 3 carbon atoms, such as methyl or -C20H2. Alternatively, two or more monocycles may be bonded via an alkylene. In the case of a two-membered ring, carbon #, lO~12 is preferred;
It may be substituted, for example with one or more lower alkyl groups such as methyl.

Specifically, n-pentane, n-hexane, n-hef'
Tan, n-octane, n-nonane, n-decane, n-undecane, n-dodecane, n-tetradecane, n-hexadecane, n-octadecane, 2-methyl-pentane,
2-methylhexane, 2,3-dimethylhexane, 2-
Methylnonane, 2,6-cyclooctano, 2,2,4,
4,6,8.8-hebutamethylnonane, pristane,
Sufsolane, light transmission paraffin, paramethane, limonene, hydrogenated product of limonene dimer, cyclohexane,
Examples include l,3-dimethylcyclohexane, cyclooctano, ingtylcyclohexane, cyclododecane, methyldecalin, decalin, octyl bromide, decyl bromide, dodecyl bromide, hexadecyl bromide, dodecyl chloride, dibromdodecano, and the like.

(2) Alcohol esters of aliphatic carboxylic acids having a total of 11 to 26 carbon atoms: The alcohol moiety is methyl alcohol, ethyl alcohol, n-propyl alcohol, -4so=propyl alcohol, n--f thyl alcohol, is.

-Butyl alcohol, 5ec-7'yl alcohol t-
Carbon 1t such as butyl alcohol, n-amyl alcohol, iso-amyl alcohol, n-hexyl alcohol, etc.
Monohydric alcohols of 1 to 6 are listed as preferred. In addition, the calci water portion has a carbon number of 1O~20
Among these fatty acids, saturated fatty acids having 12 to 18 carbon atoms are preferred. Specific examples of the ester include methyl laurate, ethyl laurate, hexyl laurate, inpropyl myristate, inpropyl palmitate, methyl stearate, and butyl stearate.

■ Mono- or diethers having carbon atoms of 1O to 24; specifically, alkyl monoethers such as dibutyl ether, dioctyl ether, dioctyl ether, didodecyl ether, methoxydodecane, and ethoxydodecane; l,8-
Examples include alicyclic ethers such as cineole, alkyl diethers such as ethyl glycol dibutyl ether, ethylene glycol dipropyl ether, and ethylene glycol dioctyl ether.

■ Ketones having 11 to 15 carbon atoms: Aliphatic ketones are preferred, such as 2-undecanone,
Examples include 3-undecanone, 4-usidecanone, 5-undecanone, 6-undecanone, 3-dodecanone, 4-dodecanone, 5-dodecanone, 2-tridecanone, 3-tridecanone, 7-tridecanone, 8-pentadecanone, 3-hexadecanone, etc. It will be done.

Examples of component B include the following compounds.

(2) Glycerin and its ester: The ester may be mono-, di- or triester, and the acid component is preferably a fatty acid having 2 to 6 carbon atoms, particularly acetic acid. Specifically, glycerin monoacetate,
Glycerin diacetate, glycerin triacetate, etc. are listed.

(2) Thioglycerol: Any of mono-, di-, or triglycerol may be used, such as α-monothioglycerol.

■ Lactic acid, its ester: The alcohol moiety in the ester has 1 to 1 carbon atoms.
The aliphatic monohydric alcohol of No. 4 is preferred.

Specific examples include lactic acid, methyl lactate, ethyl lactate, and glutyl lactate.

■ Cyclic urea: Preferably a 5- or 6-membered urea, specifically N, N'
- Dimethyl urea, ethylene urea, propylene urea, etc. are listed.

■ General formula [In the formula, J, R2, R3 and R4 are each a hydrogen atom,
Lower alkyl groups having 1 to 4 carbon atoms (methyl, ethyl, n-
Propyl, iso'7', n-butyl, etc.), nitro or acyl having 1 to 2 carbon atoms. ] A compound represented by

Specifically, urea, N-methylurea, N-ethylurea, N
-butylurea, ■, 1-dimethylurea, 1,3-dimethylurea, 1,1-diethylurea, ], ]3-diethylurea 1,1.3.3-tetramethylurea i, N-acetyl-
N'-methylurea, nitrourea, etc. are listed.

■ General formula lower alkyl (methyl, ethyl, n-propyl, 1so
-propyl, etc.), n represents an integer of 3 to 5. ] Compounds represented by: specifically 2-pyrrolidone, N-methylpyrrolidone, N
-Methylpiperidone, caprolactam, N-methylcaprolactam, etc. are listed.

■ General formula [wherein R6, R7 and R8 are hydrogen atoms, carbon & 1-3 alkyl (methyl, ethyl, n-propyl,
1so-propyl, etc.)]: Specifically, formamide, N-methylformamide,
N,N-dimethylformamide, N,N-diethylformamide, to maacetamide, N-methylacetamide.

N-dimethylacetamide, N,N-diethylacetamide, globionamide, N-methylpropionamide, N,N-dimethylpropionamide, N,N
~Diethylpropionamide, etc. are listed.

■ Alkylene glycol: Alkylene preferably has 2 to 8 carbon atoms,
Specific examples include ethylene glycol, butanediol, bentanediol, 2-methyl-2,4-bentanediol, and 2-ethyl-1,3-hexanediol.

(2) Monoalkyl ether of mono- or diethylene glycol The alkyl in the monoalkyl ether preferably has 1 to 2 carbon atoms. Specific examples include ethylene glycol monomethyl ether and ethylene glycol monoethyl ether.

■Lactone.

Specific examples include propiolactone, butyrolactone, and β-butyrolactone.

The base composition of the present invention is prepared by adding component B to component A and uniformly dissolving the mixture. The blending amount of component A is 1 to 50% by weight, preferably 5 to 30% by weight, based on the total of components A and B. Of course, the base composition may also contain pharmaceutically acceptable additives such as water.

Moreover, the external pharmaceutical composition of the present invention is prepared by blending a drug with the above-mentioned base composition.

There are no particular restrictions on the drugs to be mixed as long as they can be administered to the skin, but if the drug is intended to have a local effect on diseases of the skin or its underlying tissues, conventional topical preparations may be somewhat effective. Therefore, it is significant that the drug for the external pharmaceutical composition of the present invention is a drug that aims at systemic action.

Specifically, the drugs include benzodiazepines (e.g. diazepam, nitrazepam, flunitrazebam, lorazepam, prazepam, fludiazepam, clonazepam), diuretics [e.g. thiazides (e.g. pendroflumethiazide, polythiazide, methyclothiazide, trichlor) Methiazide, cyclopenthiand, pentylhydrochlorothiazide, hydrochlorothiazide, pumetanide) antihypertensive agents (
e.g., talonisin), antihistamines [e.g., amine ethers (e.g., diphenhydramine, carbinoxamine, diphenylbilarin), ethylenediamines (e.g., fenbenzamine), monoamines (e.g., chlorpheniramine)), nonsteroidal Anti-inflammatory agents (e.g., indomethacin, ibuprofen, ibufenac, alclofenac, diclofenac, mefenamic acid, flurbiprofen, flufenamic acid, butprofen), antineoplastic agents (e.g., 5-fluorouracil, 1-(2-tetrahydro) (5-fluorouracil, cytarabine, broxuralidine), steroidal moxibustion agents (e.g., cortisone, hydrocortisone, frednisolone, prednisone, triamcinolone, dexamethasone, betamethasone)
, anti-epileptic drugs (e.g. etosuximide), anti-arrhythmia drugs (e.g. ajmaline, brassimarin, pindolol, propranotar/L/, Ki-sin), psychiatric drugs [
e.g., clofluherol, trifluberidol, halobe IJ toll, movellon), scopolamines IJ, methylscopolamine, butylscopolamine), talolopromazine, atropobins (e.g., methylatropine bromide, methylanisotropine bromide), vasodilation agents (e.g., insorbitcinitrate, nitroglycerin, pentaerythritol tetranitrate, propanyl nitrate, diviridamol), antibiotics [e.g., tetracyclines (e.g., tetracycline, oxytetracycline, methacycline, doxycycline, methacycline): Examples include chloramphenicol, erythromycin mfx and y'fi.

The amount of the drug to be mixed may be an amount sufficient to achieve the desired medicinal effect, and it varies depending on the type of drug, the weight and condition of the patient, etc., and may be appropriately selected depending on these conditions. Generally, 0 for the total amount of A and B components.
．． The amount of O1 to 20.71i is preferably 0.2 to IO by weight.

Note that the amount of the drug to be applied can be adjusted by increasing or decreasing the area of the pharmaceutical composition applied to the skin, so it is not necessarily limited to the above-mentioned amount.

The pharmaceutical composition for external use according to the present invention can be used as it is or by adding a known pharmaceutically acceptable third acid component, and used as an external preparation such as an ointment, plaster, lotion, adhesive tape, impregnating agent, or gel. It can be administered completely. Examples of impregnating agents include those prepared by adsorbing the topical pharmaceutical composition or a composition containing known Yusan ingredients on a suitable adsorbent (gauze, P paper, porous membrane, etc.); Applied to the outer skin by fixing with adhesive tape.

Examples of the gel agent include those made into a gel using dibenzylidene rubitol (eg, Gelol D (manufactured by Shin Nihon Rika Co., Ltd.)) and spread on a support. Further, as bases for adhesive tape preparations, there may be mentioned those known per se such as acrylic copolymers, polyvinyl ether compounds, and rubber adhesive mixtures. Other external preparations can also be easily prepared by means known per se.

Hereinafter, the present invention will be explained in more detail with reference to Examples and Experimental Examples, but the present invention is not limited by these in any way.

Examples 1 to 47 [Basic prescription] (Lydiazepam 3g (2) B component
72t (3) A component 25? Using each of (2) and (3) shown in Table 1, a liquid composition with the above basic formulation was prepared by first mixing (3) with (2) and dissolving (1) in the mixture. did. B
S6: The component is solid at room temperature or does not mix uniformly with component A.
, 20% ethylene glycol mobutyl ether was used as a solubilizing agent (in this case, 31 is marked with a red stamp).

Control formulation 1 (1) Diazepam 32 (2) Ingredient B 971 Using each of the ingredients listed in the examples in Table 1 as (2), dissolve (1) in (2) and prepare the ingredients from Example 6. Except for the next group A thing old profit water.

Comparative Examples 1 to 3 (1) Diazepam 32 (2) Polar compound 721 (3) Component A 251 (2) Any one of the inorganic value, organic value, or ratio of inorganic value/organic value The above compositions were obtained in a manner similar to Examples 1 to 4'7, using polar compounds (see Table 2) whose polarity exceeds the range defined by the present invention.

Comparative Examples 4 to 6 (Lydiazepam 32 (2) Component B 722 (3) Nonpolar compound 251 (3) Any one of the inorganic value, the organic value, or the ratio of the inorganic value/organic value The above compositions were obtained by a method similar to Examples 1 to 48 using a nonpolar compound (see Table 3) in which at least one of the nonpolar compounds was outside the range defined by the present invention.

EXAMPLE The amount of drug permeated through the skin in the compositions of Examples 1 to 47, Control Formula 1, and Comparative Examples 1 to 6 was excised from rat abdominal incisions/i.
ii, and the results are shown in Tables 1, 2 and 3.
It was shown to.

The Q values in Table 11, Table 2, and Table 3 are as follows (Measurement method) Rat skin/11 was placed in a glass transmission cell, and the drug that had permeated into the physiological saline was extracted with benzene and quantified using a spectrophotometer. Note that this experiment was conducted in a sealed container.

Examples 4&~49, Experimental Example 2 (1) Diazepam 3% (2) B component O~100g (3) Ali content 100~Of Mixing ratio of B component and A component (M
A composition was prepared by preparing a mixed solution in which the quantitative ratio (quantity ratio) was varied from 100:0 to 0:100, and dissolving 3 parts of diazepam therein. The skin permeability of each composition thus obtained was measured in the same manner as in Experimental Example 1, and is shown in FIG. In Figure 2, ya is the B component alone (1
It shows the weight percent of component B relative to the total amount of drug when (lOf) is the base, and I (Example 46) is
The component is ethylene glycol monoethyl ether, the A component is hexane, and the B component in II (Example 46) is N, N, N.
' , N'-tetramethyl log, component A relates to inpropyl myristate.

Examples 50 to 60-1 Experimental Example 8 The compositions shown in Table 4 were prepared, and the amount of drug permeated through the skin in each composition was measured in the same manner as in Experimental Example 1. The results are shown in Table 4.

double bottom margin Note 1) Dimethyl sulfoxide was used instead of component B.

Note 2) Dissolve the drug in acetone and apply it to the sebum. Only in this experiment, the experiment was conducted in a non-drop container, so acetone was not used.

[Brief explanation of drawings]

Is the first one a conceptual diagram of the M machine? Figure 2 shows the skin permeability of the drug in the uninvented topical pharmaceutical composition. It shows. 1...A component area 2...B component area Diagram 2' Y-axis procedural amendment (method) % formula % 1 Indication of the incident 1980 Holder Kρ No. 205234 2 Title of the invention Base m acid compound and External Pharmaceutical Composition 3.Relationship with the person making the amendment.The entire name of Part 1 on page 1 of the specification of the patent applicant is corrected as follows. “-!I5Δ composition and external pharmaceutical composition” 73-

Claims (4)

[Claims] (1) On the unwritten organic conceptual diagram, non-organic values are in the range of 100 to 600, inorganic values are θ to 65, and the ratio of inorganic to organic values is 0.3 or less. At least one selected from polar compounds, and on the above organic conceptual diagram, the organic value is 0 to 180 and the inorganic value is 1.
10 to 300, and at least one polar compound selected from polar compounds having a ratio of inorganic value to organic value of 1 or more. Characteristic base composition for external preparations. (2) Patent M'l in which the amount of the non-polar compound blended is 1 to 50% by weight based on the total amount of the polar compound and the non-polar compound.
- A base composition according to the desired range (1). (3) On the unwritten organic conceptual diagram, an area where the organic value is 100 to 600, the inorganic value is 0 to 65, and the ratio of the inorganic value to the organic value is 0.3 or less At least one selected from non-polar compounds in 1. A pharmaceutical composition for external use, characterized in that at least 1) selected from the polar compounds falling within the above range is coated with a gold layer. (4) The external use according to claim (3), characterized in that the blending amount of the non-polar compound is 1 to 50% with respect to the total amount of the polar compound and the non-polar compound. ζ drug composition.