WO2001013938A1

WO2001013938A1 - Medicinal composition for percutaneous/permucosal absorption

Info

Publication number: WO2001013938A1
Application number: PCT/JP2000/005740
Authority: WO
Inventors: Hiromi Hatano; Akio Kuwahara; Hitoshi Yamauchi; Masaki Hagiwara; Tadashi Ogawa
Original assignee: Daiichi Fine Chemical Co., Ltd.
Priority date: 1999-08-25
Filing date: 2000-08-25
Publication date: 2001-03-01
Also published as: AU6730500A

Abstract

A medicinal composition for percutaneous/permucosal administration which comprises (1) a peptide compound which is a compound represented by the general formula (I): Y-L-Tyr-Q-N(R?1)-CH(R2¿)-CO-X [wherein R1 represents hydrogen or C¿1-6? alkyl; R?2¿ represents optionally substituted benzyl; Q represents D-Arg or L-Arg; Y represents the two hydrogen atoms of the N-terminal amino group of L-Tyr or represents one or two substituents for the hydrogen atom(s), such as C¿1-6? alkyl or C1-6 alkylcarbonyl; and X represents -OR?5 (R5¿ is hydrogen or C¿1-6? alkyl), etc.] or a salt thereof and (2) at least one absorption accelerator selected among alcohols, higher alkanes, higher fatty acids, higher fatty acid esters, terpenes, etc.

Description

Pharmaceutical composition for transdermal and transmucosal absorption

TECHNICAL FIELD The present invention relates to a pharmaceutical composition containing a peptide compound having an analgesic action or a salt thereof as an active ingredient, and exerting a transdermal or transmucosal analgesic action. Background art

An analgesic peptide compound (also referred to as an obioide peptide) that exerts an analgesic effect via an obioid receptor to which an obioid such as morphine binds is known. Many have been proposed. Conventionally, such analgesic peptide compounds have poor oral absorbability, and have problems with side effects and profitability. Analgesic peptide compounds having both an analgesic effect and oral absorption have been proposed (for example, International Publication W095 / 24421 and International Publication W097 / 10261) and are expected to be applied to clinical applications.

On the other hand, there is known a new dosage form in which a drug is transdermally or transmucosally absorbed to control drug delivery to the systemic circulation. By administering the drug transdermally or transmucosally, pain at the time of injection can be avoided, or delay in onset of drug effect due to gastrointestinal absorption or variation in drug effect due to the first passage effect can be avoided. Since the dosage can be easily adjusted according to the onset of the drug effect, and the drug effect can be rapidly eliminated by discontinuing the drug, it is attracting attention as a safe and less burdensome method for patients.

Conventionally, products such as Flanders Tape S (Toray Eyo Co., Ltd. and Yamanouchi Pharmaceutical Co., Ltd.) and Nitrodam TTS (Nihon Ciba Geigy Co., Ltd.) have been put into practical use as transdermal therapeutic systems. For analgesic peptide compounds, the enkephalin derivative DADLE (Tyr-D-Ala-Gly-L-Phe-D-Leu-OH) In addition, it has been reported that bile salts enhance absorption through the nasal mucosa (New developments in drug delivery technology, Table 30, page 169, Toray Research Center Yuichi). Disclosure of the invention

An object of the present invention is to provide a drug for systemically administering a peptide compound transdermally or transmucosally. The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, by using a medicine containing a peptide compound represented by the following formula (I) and a specific absorption enhancer, the present invention has been made. It has been found that a peptide compound can be efficiently transdermally or transmucosally transported into the body, thereby enabling pain treatment and the like. Further, according to the method of the present invention, the analgesic action of the peptide compound can be effectively maintained. The present invention has been completed based on these findings.

That is, the present invention provides a pharmaceutical composition for transdermal or transmucosal administration, comprising the following components:

(1) General formula (I):

YL-Tyr-QN (R ')-CH ( ² )-CO- X

(In the formula,

R ¹ represents a hydrogen atom or ( ₆ alkyl group;

R ² represents a benzyl group which may have a substituent;

Q represents D-Arg or L-Arg;

Y represents two hydrogen atoms of the N-terminal amino group of Tyr or a substituent substituted by (these), and the substituent is (in the case of two, each independently) the following group:

C _1-6 alkyl group which may have an amino group,

_ClS alkyl group, which may have a carboxyl group,

It may have an amino group ( ₆ alkylcarbonyl group,

A sulfonyl group which may have an alkyl group,

A pyrimidyl group which may have a substituent,

Imidazolinyl group which may have a substituent, A group represented by the following formula:

HN2 C (R ³ )-

(In the formula, R ³ represents a hydrogen atom, a C _1-6 alkyl group, a phenyl group which may have a substituent, a hydroxyamino group which may have a substituent, or a hydrazino group which may have a substituent. Shown), and

A group represented by the following formula:

HN = C (NH-R ⁴ )-

(Wherein, R ⁴ represents a hydrogen atom, ( ₆ alkyl group, aryl group which may have a substituent, C _1-6 alkanol group which may have a substituent, or aryl carbonyl which may have a substituent. Indicates a group)

A substituent selected from

X is -OR ⁵ (wherein represents a hydrogen atom or a C _1-6 alkyl group),

-N (R ⁶ ) (R ⁷ ) (wherein, R ⁶ represents a hydrogen atom or a C _1-6 alkyl group, and R ⁷ represents a C _1-6 hydroxyalkyl group or a sulfonic acid-substituted C _1-6 alkyl group. Or R ⁶ and R ⁷ are linked together to indicate a 5- or 6-membered nitrogen-containing saturated heterocyclic group together with the nitrogen atom to which they are substituted), or

-N (R ⁸ ) -C (R ⁹ ) (R ¹⁰ ) (R ⁿ ) (wherein, R ⁸ represents a hydrogen atom, a C _1-6 alkyl group, or an aryl substituted C _1-6 alkyl group, ⁹ is a hydrogen atom, a carboxyl group, a ( ₁₆ alkoxycarbyl group, a carbamoyl group which may have a substituent, a carboxy C _1-6 alkyl group, a rubamoyl C _1-6 alkyl group which may have a substituent. , or C physician ₁₆ an alkoxy force Ruponiru C _1-6 alkyl group, R ^1G is hydrogen, C _1-6 alkyl, Amino C _1-6 aralkyl kill group, amidino C _1-6 alkyl group, Guanijino C physician _{6 represents} an alkyl group, a hydroxy C _1-6 alkyl group, a carboxy C _1-6 alkyl group, or an optionally substituted C _1-6 alkyl group, or R ⁸ and R ^1D are joined together. Represents a 5- or 6-membered carboxy-substituted nitrogen-containing saturated heterocyclic group together with the nitrogen atom substituted by R ⁸ , and R ¹¹ Represents a hydrogen atom or a C _1-6 alkyl group).

A peptide compound represented by or a salt thereof; and (2) Alcohols, higher alkanes, higher fatty acids, higher fatty acid esters, terpenes, alkyl sulfates, alkylamine oxides, pyrrolidones, inclusion compounds, bile salts, saponins , And one or more absorption enhancers selected from the group consisting of polyhydric alcohols

And a pharmaceutical composition comprising:

Preferred embodiments of the present invention include monoterpenes, saturated or unsaturated fatty acids having 6 to 18 carbon atoms, and higher fatty acid esters comprising a monohydric or polyhydric alcohol and a fatty acid having 6 to 24 carbon atoms. The above-mentioned pharmaceutical composition containing one or more selected absorption enhancers and used for transdermal administration; the absorption enhancer is selected from the group consisting of 1-menthol, d-limonene, oleic acid, and isopropyl myristate One or more selected absorption enhancers, the pharmaceutical composition for transdermal administration; higher fatty acid esters comprising a polyhydric alcohol and a fatty acid having 6 to 24 carbon atoms, cyclodextrins, Selected from the group consisting of monoterpenes, triterpenes, cholate salts, savonins, linear terpene alcohols, and dihydric or trihydric alcohols 1 Or the above-mentioned pharmaceutical composition for use in transmucosal administration comprising two or more absorption enhancers; wherein the absorption enhancer is sucrose fatty acid ester, hydroxypropyl-cyclodextrin, glycyrrhetinic acid, sodium cholate, quilasaponin The present invention provides the above pharmaceutical composition for use in transmucosal administration, which is one or more absorption enhancers selected from the group consisting of terbinol, geraniol, and propylene glycol.

From another viewpoint, a method of transdermally or transmucosally administering the above medicine to mammals including humans, and a step of transdermally or transmucosally administering the above pharmaceutical composition to mammals including humans. An analgesic method comprising the use of the compound represented by the formula (I) or a salt thereof for the production of the pharmaceutical composition is provided. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a diagram showing the transdermal absorbability of the medicament of the present invention. In the figure, LM is Toll, D-LN indicates d-limonene, OA indicates oleic acid, and IPM indicates isoprovir myristate.

FIG. 2 is a view showing the transmucosal absorbability of the medicament of the present invention. BEST MODE FOR CARRYING OUT THE INVENTION

Q represents D-Arg (D-arginine residue) or L-Arg (L-arginine residue), and R ¹ represents a hydrogen atom or a C _1-6 (C _1-6 ) alkyl group. I do. Of these, it is preferred that Q is D-Arg and R ¹ is a hydrogen atom. In the present specification, the alkyl moiety of the alkyl group or a substituent containing an alkyl moiety (for example, an alkoxy group) may be any of linear, branched, cyclic, or a combination thereof. (Examples of ₆ alkyl groups include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyclopropyl group, an n-butyl group, a sec-butyl group, a tert-butyl group, a cyclopropylmethyl group, a cyclobutyl group, Examples include an n-pentyl group, a neopentyl group, an n-hexyl group, and a cyclohexyl group.

In this specification, when a functional group is referred to as "optionally having a substituent", the functional group may have one or more optional substituents unless otherwise specified. It means that it may have. When it has two or more substituents, they may be the same or different. The position of the substituent is not limited, and may be at any substitutable site.

Although the type of the substituent is not particularly limited, a hydroxyl group, an amino group, a mercapto group, a cyano group, a carbamoyl group, a sulfamoyl group, a monoalkylamino group, a dialkylamino group, an ammonium group, an imino group, a cyano group, a nitro group, carboxyl group, a sulfonic acid group, a hydrazino group, Urei de group, halogen atom, C _1-6 alkyl groups, C _2-6 alkenyl groups, C ₂ _ ₆ alkynyl group, C _6-1. Ariru groups, C _{1 -6} alkoxy groups, C physician ₆ alkyl thio group, C _1-6 alkylsulfonyl § amino groups, C _6-1. § Li one Le sulfonyl § amino group, C _1-6 alkylcarbonyl § amino group, I mi de group, a heterocyclic group, C _fi-1. Aryloxy group, heterocyclic oxy group, C _6-1 . Arylthio group, heterocyclic thio group, C _7-1 . Aralkyl group, Heterocyclic alkyl group, c _{7-1 ()} Ararukiruokishi group, a heterocyclic Arukiruokishi group, c _2-6 alkoxycarbonyl group, C _fi _ _1Q § reel O alkoxycarbonyl group, a heterocyclic Okishi force Lupo sulfonyl group, c _{2- 6} alkylcarbonyl groups, c _6-1 . § reel carbonyl group, hetero璟Ka carbonyl group, C _2-6 alkylcarbonyl O alkoxy group, _{(-1 ()} § reel carbonyl O alkoxy group, a heterocyclic carbonyl O alkoxy group, C _2-6 alkylcarbonyl § amino group, C _6-1. § Li one Luke Ruboniruamino group, _ ₆ alkylsulfonyl group, c _6-1. § reel sulfonyl group, c _1-6 alkylsulfinyl group, c ₆ _ _{1 ()} § Li one Rusurufiniru group, c _2-6 alkylamino Cal Boniru group, c _6-10 § reel § amino group, c _1-6 alkylaminosulfonyl group, or c, and the like ₆ _ _{1 ()} § reel § amino sulfonyl group.

Further, the substituents exemplified above may be further substituted with one or more other substituents. As such an example, for example, c _1-6 hydroxyalkyl group, _ ₆ halogenation alkyl group, c _1-6 hydroxyalkyl O alkoxy group, a halogenated § Li Ichiru group, and the like halogenated alkyl group Can be. However, the substituents described above are for the purpose of illustration, and the present invention is not limited to these.

R ² represents a benzyl group which may have a substituent. Examples of the substituent on the phenyl group of the benzyl group represented by R ² include a C _1-6 alkyl group, an amino group which may have a substituent, a guanidyl group which may have a substituent, and a hydroxyl group. Can be mentioned. R ² is preferably an unsubstituted benzyl group.

Y represents two hydrogen atoms of the N-terminal amino group of L-Tyr, or a substituent in which one or two of these two hydrogen atoms have been substituted. When two hydrogen atoms are substituted, the substituents are independently selected from the above groups, which may be the same or different. As the C _1-6 alkyl group represented by Y, a methyl group, an ethyl group, an isopropyl group, a cyclopropylmethyl group and the like are preferable. Examples of the case where the C _1-6 alkyl group represented by Y has an amino group or a carboxyl group include, for example, H ₂ N-CH _2- , H ₂ N- (C¾) _2- , H00C-CH _2- , And groups such as H00C- (C) _2- . As an example of the case where the Y is C _1-G alkylcarbonyl group represented by an amino group, _{_{e.g., H 2 N- CH 2 - CO-}} , N- (CH 2) 2 -C0- , and the like. C _1-6 Examples of the sulfonyl group having an alkyl group include, for example, groups such as CH ₃ SO ₂ —.

As the pyrimidyl group and imidazolinyl group represented by Y, 2-pyrimidyl group, 2-imidazoline-2-yl group and the like can be suitably used. The pyrimidyl group or the imidazolinyl group may have a substituent, but a C _1-6 alkyl group or the like can be used as the substituent. For example, the substituted pyrimidyl group includes a 4,6-dimethyl-2-pyrimidyl group, and the substituted imidazolinyl group includes a 4-methyl-2-imidazoline-2-yl group.

As the C _1-6 alkyl group represented by R ³ , for example, a methyl group, an ethyl group, an n-propyl group and the like are preferable, and a methyl group is particularly preferable. Phenyl group represented, hydrate port Kishiamino group (H0-NH -), or hydrazino group (H ₂ N-NH-) is capable are use suitably those unsubstituted, for example, one or more Those substituted with a C _1-6 alkyl group may be used. The Ariru group R ⁴ represents can and Ageruko and phenyl group, as the Arukanoiru group and the like can be illustrated Asechiru group or Puropanoiru group, as the § Li Ichiru force Ruponiru group and the like base Nzoiru group I can do it. The phenyl group is preferably an unsubstituted phenyl group.

It is preferred that Y represents two hydrogen atoms, or one of Y is a hydrogen atom and the other is the above substituent. It is also preferred that both Y are the above substituents, for example, the same or different C _1-6 alkyl group. It is particularly preferred that the two substituents represented by y are both methyl groups.

X is ^{^{- 0R 5, -N (R 6}} ) (R 7), or ^{^{- N (R 8) - 11}} ) indicates one of. R ⁵ represents a hydrogen atom or a C _1-6 alkyl group; R ⁶ represents a hydrogen atom or a C 1- _(i alkyl group; R ⁷ is a C _1-6 hydroxyalkyl group or a sulfonic acid-substituted C _1-6 alkyl group; Although a group, hydroxyl group or sulfonic acid group may substitute on any position of the alkyl group. for example, an alkyl group in which a hydroxyl group or sulfonic acid group has been substituted with end edge is preferred. ^ and R ⁷ gar cord When they represent a 5- or 6-membered nitrogen-containing saturated heterocyclic group together with the nitrogen atom which they substitute for, the heterocyclic group may contain two or more nitrogen atoms as ring constituent atoms. In addition, hetero atoms other than nitrogen atoms (oxygen atoms, sulfur atoms, etc.) may be contained as ring constituent atoms. Examples of the heterocyclic group include a topiperazinyl group, a topyrrolidinyl group, and a topiperidinyl group.

(Examples of ₆ alkyl groups include, for example, a benzyl group. R ⁸ and R ^ll) are combined to form a 5- or 6-membered carboxy substituent together with the nitrogen atom to be substituted by R ^8. When a nitrogen-saturated heterocyclic group is used, the heterocyclic group may contain two or more nitrogen atoms as ring-constituting atoms, and a hetero atom other than a nitrogen atom (an oxygen atom, a sulfur atom, etc.) It may be included as a constituent atom. Examples of the heterocyclic group include a 2-carboxy-topyrrolidinyl group (Pro-OH) and a 3-carboxy-1-piperidinyl group. A combination in which ^ is a carboxymethyl group or a carbamoylmethyl group, and is a hydrogen atom is preferable.

The compound represented by the above formula (I) binds to L-Tyr (L-tyrosine residue) and two asymmetric carbons derived from D-Arg or L-Arg residue represented by Q, and binds to Q Asymmetric carbon derived from a phenylalanine residue which is substituted by R ⁹ and R ^1Q (except when R ^lfl represents the same substituent). The group and Y may also have one or more asymmetric carbons. Asymmetric carbons other than those present in L-Tyr, D-Arg, and L-Arg residues may be in either R- or S-configuration. As the active ingredient of the medicament of the present invention, any optically active substance, racemate, optically active substance, or any mixture of diastereoisomers may be used.

For the pharmaceutical composition of the present invention, a physiologically acceptable salt of the compound represented by the above formula (I) can be used. The kind of the salt is not particularly limited, and examples thereof include acid addition salts such as hydrochloric acid, acetate, or P-toluenesulfonate, base addition salts such as metal salts, ammonium salts, and organic amine salts, and amino acid salts. Can be used. Further, any hydrate or solvate may be used as an active ingredient of the medicament of the present invention. Furthermore, a biologically equivalent compound such as a dimer or multimer of the compound represented by the above formula (I), or a cyclic compound in which the C-terminal and the N-terminal of these compounds are bonded to each other is used. It may be used as an active ingredient of the medicament of the present invention. The production method of the compound represented by the above formula (I) is described in International Publication W095 / 24421 and International Publication W097 / 10261. In addition, the analgesic effects of these compounds are also specifically described in the above publications, so that those skilled in the art can produce the compounds included in the formula (I) according to the methods described in these publications. And its analgesic effect can be confirmed. The entire disclosure of International Publication W095 / 24421, International Publication W097 / 10261 is included as the disclosure herein.

Among the compounds represented by the formula (I), the following compounds are preferable as the active ingredient of the pharmaceutical composition of the present invention, compounds 1 and 2 are more preferable, and compound 2 is particularly preferable.

Compound 1: R ¹ is a hydrogen atom, R ² is an unsubstituted benzyl group, Q is D-Arg, Y force s One NH = C substituted on the amino group of L-Tyr (NH ₂ ) —, wherein X is —N (CH ₃ ) —CH ₂ CH ₂ C00H;

Compound 2: R ¹ is a hydrogen atom, R ² is an unsubstituted benzyl group, Q is D-Arg, and Y is a single methyl group substituted on the amino group of L-Tyr. There, X is - N (C) - compound is CH _₂ CH ₂ C00H;

Compound 3: ^One HN = C (C) in which R ¹ is a hydrogen atom, R ² is an unsubstituted benzyl group, Q is D-Arg, and Y is substituted on the amino group of Tyr - and, X is - N (CH ₃₎ - CH compound which is a _₂ CH ₂ C00H; and

Compound 4: R ¹ is a hydrogen atom, R ² is an unsubstituted benzyl group, Q is D-Arg, and Y is one methyl group substituted on the L-Tyr amino group. And X is -N (CH ₃ ) -CH ₂ CH ₂ C00 (CH ₂ ) ₇ CH ₃ .

In the pharmaceutical composition of the present invention, as absorption enhancers, alcohols, higher alkanes, higher fatty acids, higher fatty acid esters, terpenes, alkyl sulfates, alkylamine oxides, pyrrolidones, clathrates One or more substances selected from the group consisting of forming compounds, bile salts, saponins, and polyhydric alcohols are blended. Examples of alcohols include ethanol, isopropanol, decanol, and stearyl alcohol, and examples of higher alkanes include: n-Heptane, n-dodecane and the like can be mentioned. As the higher fatty acids, saturated or unsaturated fatty acids having 6 to 18 carbon atoms are preferable, and more specifically, capric acid, oleic acid, caprylic acid, lauric acid, myristic acid, or salts thereof, and the like. Can be listed.

As the higher fatty acid esters, esters of a monohydric alcohol or a polyhydric alcohol and a fatty acid having 6 to 24 carbon atoms are preferable. Examples of the ester of a monohydric alcohol and a fatty acid include force prillate, force prerate, normitate, stearate, and myristate, and more specifically, Examples include ethyl ethyl caprylate, ethyl ethyl caprate, and isopropyl myristate. Glycerin monofatty acid ester, sucrose fatty acid ester, and the like can be used as esters of polyhydric alcohol and fatty acid, and more specifically, glycerin monocaproate, glyceryl monoprillate, and monopurine. Glycerin acid, sucrose palmitate, sucrose stearate and the like can be mentioned.

Examples of terpenes include monoterpenes, chain terpene alcohols, and triterpenes. Monoterpenes include, for example, cineole, tolmenthol, mentone, d-limonene, nerolidol, and terbineol, and chain terpene alcohols include geraniol. Examples of triterpenes include glycyrrhetinic acid. Alkyl sulfates include sodium tauryl sulfate, alkylamine oxides include alkyldimethylamine oxide, and pyrrolidones include N-methyl-2-pyrrolidone. Don and the like.

Examples of the inclusion forming compounds include cyclodextrins, such as, for example, para-cyclodextrin, cyclodextrin, hydroxypropyl-/?-Cyclodextrin (HP-?-Cyclodextrin). . Bile acid salts include cholate salts, and cholate salts include cholic acid. Sodium, sodium glycocholate, sodium deoxycholate, sodium taurocholate, sodium tauroglycocholate and the like can be mentioned. Examples of saponins include kyarasaponin and tea fruit saponins.Examples of polyhydric alcohols include dihydric or trihydric alcohols, such as propylene glycol, glycerin, and butylene glycol. Can be listed. However, substances that can be used as absorption enhancers are not limited to the compounds exemplified above. The amount of the absorption promoter is not particularly limited, but is, for example, about 0.001 to 60% by weight, more preferably about 0.1 to 40% by weight, based on the weight of the composition.

As an absorption enhancer to be incorporated into a drug for transdermal absorption, for example, 1-menthol, d-limonene, oleic acid, or isopropyl myristate is suitable, and is incorporated into a drug for transmucosal absorption Absorption enhancers include, for example, sucrose fatty acid esters, hydroxypropyl-/?-Cyclodextrin, glycyrrhetinic acid, sodium cholate, quilasaponin, monoterbineol, geraniol, propylene glycol, and the like. It is suitable.

The medicament of the present invention may be provided in the form of an aqueous solution containing the compound represented by the formula (I) or a salt thereof in an amount of about 0.001 to 40% by weight based on the weight of the composition. It may be in the form of a gel or a viscous solution, or may be provided in the form of a poultice or the like. As the form of the medicament of the present invention, in the case of a composition for percutaneous absorption, for example, a solution, a cream, an ointment, a gel, a cataplasm, a positive agent, a reservoir type patch, a matrix type Patches, tapes and the like can be mentioned, and in the case of transmucosal compositions, for example, solutions, ointments, troches, sublinguals, buccal tablets, buccals, mucoadhesive preparations, etc. be able to. However, the form of the medicament of the present invention is not limited to these. When a solution is used, it is preferable to use a reservoir for holding the solution on the skin or the like.

When the medicament of the present invention is used for transmucosal administration, it is desirable that the medicament be prepared in a form applicable to mucous membranes such as the oral cavity, eyes, nasal cavity, respiratory organs, rectum, vagina, and uterus. No. Pharmaceuticals suitable for transmucosal administration include, for example, JP-A-62-195336, JP-A-3-209327, JP-B 5-22685, JP-A-6-107557, and JP-B-7-53671. Since the medicines described in JP-A-8-183741 and the like are known, the forms of the medicines described in these publications can be appropriately adopted.

According to the form of the medicament of the present invention, pharmaceutical additives usually used for the production of a medicament can be appropriately compounded. The type is not particularly limited, and examples thereof include a pH adjuster, a buffer, a tonicity agent, a preservative, a thickener, an organic solvent such as ethanol, and a surfactant. The amount is not particularly limited, and an appropriate amount can be selected depending on the form of the preparation.

When the medicament of the present invention is used as a transmucosal composition, it is preferable to incorporate a water-soluble polymer as a base. The medicament in such a form is in the form of a gel or a viscous solution. For example, the water-soluble polymer is preferably a water-soluble polymer selected from the group consisting of a neutral polymer, a cationic polymer, and an amphoteric polymer. Among these, the water-soluble polymer is formed of a neutral polymer and a cationic polymer. Water-soluble polymers selected from the group are more preferred. More specifically, examples thereof include polyvinyl alcohol, hydroxyethyl cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyacrylamide, and a copolymer of acrylamide with acrylic acid or a salt thereof. Also, when the medicament of the present invention is used as a composition for transdermal absorption, it may be preferable to mix a water-soluble polymer as a base in some cases. As the water-soluble polymer, those exemplified above are preferable. It is. The water-soluble polymer may be used in combination of two or more as a base. Example

Hereinafter, the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited to the following Examples.

Formulation Example 1: Patch for transdermal absorption

2 weight of hydroxyethyl cellulose was added to 62 weight of purified water; A liquid prepared by combining 30% by weight of propylene glycol, 5% by weight of oleic acid, and 1% by weight of Compound 2 was added, and the mixture was sufficiently stirred to obtain a gel. Next, 4.0 g of the gel obtained in this manner was combined with a support consisting of a polyethylene film in which an acryl-based pressure-sensitive adhesive was deposited on the periphery to become the pressure-sensitive adhesive surface, and a drug release layer (porous membrane). And a polyethylene terephthalate film as a release liner was attached to the pressure-sensitive adhesive surface to obtain a reservoir-type patch. Formulation Example 2: Mucoadhesive for transmucosal absorption

A mixture of 10 parts by weight of propylene glycol, 10 parts by weight of hydroxyethyl cellulose, and 20 parts by weight of ethanol was made into a paste, then 1 part by weight of compound 2 was added, and the mixture was mixed again to obtain a thickness of 120 μm. It was spread on paper separators and dried to form a drug-containing layer. Further, an ethanol solution of hydroxypropyl cellulose and castor oil was applied to one side of the drug-containing layer so as to have a thickness of 30 m, and dried to form a support layer. Thus, a two-layer laminate was obtained. This was punched out into a 10-band diameter circle to obtain a mucoadhesive preparation. Test Example 1: Transmucosal absorption test

A vertical diffusion cell (Fran ヅ -type diffusion cell, application area: 0.95 cm ² ), which circulates water at 37 ° C through the isolated mucous membrane of the mouth cavity, is sandwiched, and phosphate buffered saline (pH 7.4) 4 ml was added, and the mixture was stirred with a magnetic stirrer. 500 l of each sample was applied to one side of the donor, the solution in the receiver was sampled over time, and the drug concentration in the solution was measured by HPLC to determine the amount of drug permeating the skin. The drug used was Compound 2 acetate at a drug concentration of 2 mg / ml, the solvent used was phosphate buffered saline (PBS) and polyethylene glycol (PG), and in some tests mono-coconut oil was used. Fatty acid P0E (20) Sorbi Yun (TL-10, manufactured by Nikko Chemical) was added.

When the absorption enhancer is used, the 48-hour cumulative transmittance is as follows: glycyrrhetinic acid (5%, 0.1 PBS TL-10 containing PBS) 30.8, sodium cholate (1%,? 6) 32.2 ° quilasaponin (2.5 ° PG) 61. OL-terbineol (5, PBS) 23.4L hydroxypropyl-/?-Cyclodextrin (1 ° C 0.1% TL-10 in PBS) 41.T Sucrose palmitate (5%, PG) 77.2%, geraniol (5¾, 0.1¾ TL-10 containing PBS) 37.8%, sucrose stearate (5%, PG) 74.0¾, sucrose stearate (5%, PBS) 36.3¾, sucrose palmitin The acid ester (PBS at 5 ° C) was 28.1% and propylene glycol was 24.3%. PBS used as a control was 4. and TL-10 was 4.¾, and all of the above-mentioned absorption enhancers promoted transmucosal absorption of Compound 2. In addition, a permeation rate (10 JUL g / cm ² / hr) that could maintain the effective blood concentration of the rat (100 ng / ml) was achieved using any of the absorption enhancers. Test example 2: Transmucosal absorption test

Using the compound 2 ′ (free form) in the same manner as in Example 1 above, transmucosal absorbability for 20 hours was evaluated at a drug concentration of 2 mg / ml. The percentage of control (PBS) value (acceleration rate) when using an absorption enhancer is (1) hydroxypropyl-/?-Cyclodextrin (1%) + sucrose palmitate (1%) + PG (97.85 3.3 times, (2) hydroxypropyl-/?-Cyclodextrin (1%) + glycyrrhetinic acid (/ + PG (97.8%) 2.4 times, (3) sucrose palmitate (1) + poly-terbineol () + PG (97.8%) 2.1 times, (4) Hydroxyprovir-/?-Cyclodextrin (150 + geraniol (1%) + PG (97.8%) 2.1 times, (5) Glycyrrhetinic acid () + quilasaponin (1 %) + PG (97.8%) 2.0 times Test Example 3: Skin absorption test

After killing a hairless mouse (Hr7Kud, female, 8-10 weeks old, Kudo), the abdominal skin was immediately cut into a predetermined size, the subcutaneous fat layer was removed, and the intact skin was removed. I got Hold the skin in a cell (KH2.0 (horizontal type): effective area 0.6 cm ² , capacity 2.0 ml) previously set at 37 ° C, and place the dermis layer cell in the cell side solution 3.0 ml and the horny layer cell Fill 2.0 ml of Donna One Solution, 5% w / v% 40% Tylene glycol 400 (PEG400) solution was added to the Dona solution, and the same amount of 40% polyethylene glycol 400 was added to the receiver solution to conduct a skin permeation experiment.

Compound 1 (acetate) was used as a test drug, and 100 l of the receiver solution was collected at predetermined time intervals, and the same amount of the receiver solution was returned. Add the same volume of 0.05¾ trifluoroacetic acid to the collected sample, stir, centrifuge (15,000 rpm, 5 ° C, 15 min), quantify the supernatant by HPLC, and determine the cumulative permeation amount of the test drug. I asked. The results are shown in Figure 1. 1-Menthol (LM), d-limonene (D-LN), oleic acid (0A), and isopropylmyristate (IPM) all promoted absorption compared to the control (without absorption enhancer) . Test Example 4: Translucent absorption test

A solvent consisting of hydroxypropyl-/?-Cyclodextrin (1%) + sucrose palmitate (1%) + PG (98%) was added to 100 mg of Compound 2 (free form), and about 5 g of the administration solution was added. Obtained. Under pentovalpital anesthesia, the administration solution was placed in circular cells with a radius of 0.5 cm fixed to the left and right mucous membranes of female beagle dogs (8 months old) weighing about 10 kg, each 250〃1 (500 1 per animal) Was added and sealed with a sheet. Anesthesia was maintained by additional administration of pentobarbital until 24 hours after administration, and the administration solution in the cell was recovered 24 hours after administration, and then the inside of the cell and on the mucous membrane were washed. About 1 ml of venous blood was collected over time until 30 hours after administration, and the drug concentration in plasma obtained by centrifugation was measured. As a control, plasma was administered after subcutaneous administration of 2 mg / body of an isotonic phosphate buffer solution of compound 2 (free form) to a female Beagle dog (8 months old) weighing about 10 kg under pentobarbi anesthesia under anesthesia. Medium concentrations were measured.

The result is shown in figure 2. Compound 2 (free form) The area under the one-hour blood concentration curve after 10 m transmucosal administration and 2 mg subcutaneous administration was 1460 ng'hr / ml and 1050 ng-hr / ml, respectively. The bioavailability upon transmucosal administration, calculated from the comparison of the area under the one-hour curve, was 28%. Based on the above, Compound 2 is a peptide, but it has a high absorption from the mucous membrane and a continuous concentration of blood in the blood. Thus, an effective and continuous analgesic effect can be expected. Industrial applicability

Since the medicament of the present invention can be administered transdermally or transmucosally and exerts an excellent analgesic effect, it can improve the compliance of drug treatment in cancer pain management and improve the quality of life of patients. .

Claims

The scope of the claims

1. A pharmaceutical composition for transdermal or transmucosal administration, comprising:

(1) The following general formula (1):

YL- Tyr- Q-tUR ¹ )-CH (R ² )-CO- X

(In the formula,

R ¹ represents a hydrogen atom or a C _1-6 alkyl group;

R ² represents a benzyl group which may have a substituent;

Q represents!)-Arg or L-Arg;

Y represents two hydrogen atoms of the N-terminal amino group of L_Tyr or a substituent substituted with these (these), and the substituents are (in the case of two, each independently) the following group:

C _1-6 alkyl group which may have an amino group,

C _1-6 alkyl group which may have a carboxyl group,

C _1-6 alkylcarbonyl group which may have an amino group,

A sulfonyl group which may have an alkyl group,

A pyrimidyl group which may have a substituent,

Imidazolinyl group which may have a substituent,

A group represented by the following formula:

HN2 C (R ³ )-

A group represented by the following formula:

HN = C (NH-R ⁴ )-

(Wherein, R ⁴ is a hydrogen atom, a C _1-6 alkyl group, an aryl group which may have a substituent, a C _1-6 alkanoyl group which may have a substituent, or may have a substituent. (Indicating a carbonyl group) A substituent selected from

X is -OR ⁵ (wherein, R ⁵ represents a hydrogen atom or a C _1-6 alkyl group),

^{^{-N (R 6) (R 7}} ) ( wherein, R ⁶ represents a hydrogen atom or a C _1-6 alkyl group, R ⁷ is a _(1-6 hydroxyalkyl group or a sulfonic acid-substituted C _l-6 alkyl group Or R ⁶ and represents a 5- or 6-membered nitrogen-containing saturated heterocyclic group together with the nitrogen atom to which they are substituted), or

-N (R ⁸ ) -C (R ⁹ ) (R ^{! 0} ) (R ⁿ ) (wherein, R ⁸ represents a hydrogen atom, a C _1-6 alkyl group, or an aryl substituted C _1-6 alkyl group, R ⁹ is a hydrogen atom, a carboxyl group, a C _1-16 alkoxycarbyl group, a carbamoyl group which may have a substituent, a carboxy C _1-6 alkyl group, a rubamoyl C _1- group which may have a substituent. ₆ alkyl group, or a C _1-16 an alkoxy force carbonyl C _1-6 alkyl group, R ^1C is hydrogen, C _1-6 alkyl, Amino C _1-6 aralkyl kill group, amidino C _1-6 alkyl group , Guanijino C _1-6 alkyl group, a hydroxy C _1-6 alkyl group, a carboxy C _1-6 an alkyl group, or may have a substituent force Luba carbamoyl C _1-6 alkyl group, or R ⁸ and R ^1G represents a carboxy-substituted nitrogen-containing saturated heterocyclic group having 5 or 6 membered together with the nitrogen atom to which such connexion R ⁸ is substituted with, R ¹¹ Shows a shows a water atom or a C _1-6 alkyl group)]

A peptide compound represented by or a salt thereof; and

(2) Alcohols, higher alkanes, higher fatty acids, higher fatty acid esters, terpenes, alkyl sulfates, alkylamine oxides, pyrrolidones, clathrate forming compounds, bile salts, saponins , And one or more absorption enhancers selected from the group consisting of polyhydric alcohols

A pharmaceutical composition comprising:

2. In the general formula (I), R ′ is a hydrogen atom, ^ is an unsubstituted benzyl group, Q is D-Arg, and Y is one of the substituted amino groups of L-Tyr. A compound wherein NH = C (NH ₂ ) — and X is —N (CH ₃ ) CH ₂ CH ₂ C00H; R ¹ is a hydrogen atom, R ² is an unsubstituted benzyl group, and Q is D- Arg, a compound wherein Y is one methyl group substituted on an amino group of L-Tyr, X is -N (C¾) CH ₂ C C00H; R ¹ is a hydrogen atom, and R ² is No replacement X is -N (CH ₃ ) CH ₂ CH ₂ , where X is -N (CH ₃ ) CH ₂ CH ₂ Or a compound wherein R ¹ is a hydrogen atom, R ² is an unsubstituted benzyl group, Q is D-Arg, and Y is one methyl group substituted on the L-Tyr amino group. There, X is _{_{- N (CH 3) CH 2}} C¾C00 (CH 2) 7 CH 3 , compound, or pharmaceutical composition according to claim 1, including salts thereof.

3. In the general formula (I), R ¹ is a hydrogen atom, R ² is an unsubstituted benzyl group, and Q is! ) And -Arg, a one methyl group substituted on Amino group Y purchase Tyr, X is - N (CH ₃₎ CH according to claim 1 comprising _₂ CH ₂ C00H, compound Pharmaceutical composition.

4. The group in which the absorption enhancer is composed of monoterpenes, saturated or unsaturated fatty acids having 6 to 18 carbon atoms, and higher fatty acid esters comprising a monohydric or polyhydric alcohol and a fatty acid having 6 to 24 carbon atoms. The pharmaceutical composition according to any one of claims 1 to 3, which is one or more absorption enhancers selected from the group consisting of:

5. The medicament according to claim 4, wherein the absorption enhancer is one or more absorption enhancers selected from the group consisting of 1-menthol, d-limonene, oleic acid, and isopropyl myristate. Composition.

6. Higher fatty acid esters, cyclodextrins, monoterpenes, triterpenes, cholates, saponins, chain terpene alcohols, in which the absorption enhancer comprises a polyhydric alcohol and a fatty acid having 6 to 24 carbon atoms, and One or more absorption enhancers selected from the group consisting of divalent or trivalent alcohols, and any one of claims 1 to 3 for use in transmucosal administration 6. The pharmaceutical composition according to item 1.

7. The absorption enhancer is one or more selected from the group consisting of sucrose fatty acid esters, hydroxypropyl-5-cyclodextrin, glycyrrhetinic acid, sodium cholate, quilasaponin, hy-terbineol, geraniol, and propylene glycol. 7. The pharmaceutical composition according to claim 6, which is an absorption enhancer.

8. A method of analgesia, wherein a step of transdermally or transmucosally administering an effective amount of the pharmaceutical composition according to any one of claims 1 to 7 to mammals including humans. A method that includes

9. A compound of the formula (I) or a salt thereof according to claim 1 for the manufacture of a pharmaceutical composition according to any one of claims 1 to 7. use.