JP2017036215A - Angiotensin II receptor antagonist salt - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an angiotensin II receptor antagonist and a percutaneous administration formulation having excellent percutaneous absorbency.SOLUTION: The present invention provides tert-butylamine salt or diethylamine salt of an angiotensin II receptor antagonistic substance, and a percutaneous administration formulation comprising the same.SELECTED DRAWING: None

Description

  The present invention relates to a salt of an angiotensin II receptor antagonist and a preparation for transdermal administration containing the same.

  Angiotensin II Receptor Blocker (ARB) is a drug that exhibits a blood pressure lowering action by blocking the pressor substance Angiotensin II from binding to its receptor, and is widely used in clinical practice. ing. As the ARB, losartan, valsartan, candesartan cilexetil, telmisartan, olmesartan medoxomil, irbesartan, and the like are known. These administration forms of ARB are oral administration preparations represented by tablets.

  However, in oral preparations, the maximum blood concentration is reached 3 to 4 hours after normal administration, and there is a possibility that sufficient blood concentration cannot be maintained at bedtime. From this viewpoint, attempts have been made to develop a transdermal administration preparation capable of keeping the blood concentration of ARB constant for a long time (Patent Documents 1 and 2).

JP 2000-302695 A JP-T-2002-513753

However, the means described in the above-mentioned patent document has insufficient skin permeability, and an improvement thereof has been desired.
Accordingly, an object of the present invention is to improve the transdermal absorbability of ARB useful as a therapeutic agent for hypertension.

  Therefore, the present inventor manufactured various amine salts of ARB in order to improve the transdermal absorbability of ARB and examined the transdermal absorbability thereof. Among the various amine salts, tert-butylamine of ARB was studied. The present inventors have found that salts and diethylamine salts have particularly excellent transdermal absorbability and good storage stability.

  That is, the present invention provides the following [1] to [4].

[1] A tert-butylamine salt or diethylamine salt of an angiotensin II receptor antagonist.
[2] A tert-butylamine salt or diethylamine salt of candesartan, olmesartan, or irbesartan.
[3] A tert-butylamine salt or diethylamine salt of candesartan.
[4] A transdermal preparation containing the salt according to any one of [1] to [3].

  The tert-butylamine salt or diethylamine salt of ARB of the present invention is superior in transdermal absorbability and storage stability as compared with ARB-free and other salts of ARB. Therefore, a transdermal administration preparation containing a tert-butylamine salt or diethylamine salt of ARB is useful as a therapeutic agent for hypertension because the blood concentration of ARB can be kept constant for a long time.

The present invention relates to a tert-butylamine salt or a diethylamine salt of ARB, and any known ARB is included. Examples of ARB include losartan, valsartan, candesartan, telmisartan, olmesartan, irbesartan, azilsartan, etc. Among them, candesartan, olmesartan, and irbesartan are preferable, and candesartan is particularly preferable. Here, candesartan is 2-ethoxy-1-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-benzo [d] imidazole-7-carboxylic acid. Olmesartan is 4- (1-hydroxy-1-methylethyl) -2-propyl-1-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazole-5 -Carboxylic acid. Irbesartan is 2-butyl-3-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1,3-diazaspiro [4.4] non-1-ene-4- Is on.
Candesartan and olmesartan are contained as commercially available prodrugs as candesartan cilexetil and olmesartan medoxomil, respectively.

  The tert-butylamine salt or diethylamine salt of ARB can be produced, for example, by dissolving or suspending ARB in an organic solvent, adding tert-butylamine or diethylamine to this, and heating to react. Examples of the organic solvent include acetone, methanol, ethanol, tetrahydrofuran and the like. The reaction temperature is preferably room temperature to boiling point, and the reaction time is preferably 5 minutes to 1 hour. As for the addition amount of tert-butylamine or diethylamine, 1-10 mol is preferable with respect to ARB. The tert-butylamine salt or diethylamine salt of ARB can be isolated by recrystallization, various chromatographies and the like.

  The tert-butylamine salt or diethylamine salt of ARB, as shown in the Examples below, has a remarkably superior transdermal absorbability compared to the free form of ARB and other organic amine salts of ARB. As particularly useful. Moreover, the tert-butylamine salt or diethylamine salt of ARB is stable even when stored for a long period of time, and is useful as a pharmaceutical raw material. Therefore, the transdermal administration preparation containing the tert-butylamine salt or diethylamine salt of ARB is useful as a transdermal administration preparation for treating hypertension.

  Examples of the preparation for transdermal administration of the present invention include tape preparations, patch preparations, poultice preparations, ointments, cream preparations and the like, but matrix-type transdermal administration preparations are more preferable. In particular, a tape preparation, particularly a matrix-type tape preparation, is preferred because of excellent compatibility with the adhesive base and excellent cohesiveness of the adhesive layer and adhesiveness to the skin.

  The content of tert-butylamine salt or diethylamine salt of ARB in the preparation for transdermal administration is not particularly limited, but is preferably 1 to 30% by mass, more preferably 1 to 10% by mass, and particularly preferably 1 to 5% by mass. .

In the preparation for transdermal administration, in addition to tert-butylamine salt or diethylamine salt of ARB, other antihypertensive drugs such as calcium antagonists, diuretics, ACE inhibitors, β blockers, αβ blockers, α blockers Medicine etc. can be blended.
Examples of the calcium antagonist include, for example, verapamil hydrochloride, diltiazem hydrochloride, bepridil hydrochloride, clentiazem, nifedipine, nicardipine hydrochloride, felodipine, nisoldipine, cilnidipine, alanidipine, benidipine hydrochloride, manidipine hydrochloride, nilvadipine, nitrendipine, Examples include amlodipine besylate, valnidipine hydrochloride, efonidipine hydrochloride, and the like.

Examples of the diuretic include, for example, benzylhydrochlorothiazide, trichloromethiazide, methiclotiazide, ethacrynic acid, indapamide, chlorthalidone, tripamide, meticrane, mefluside, piretanide, furosemide, bumetanide, torasemide, azosemide, potassium canrenoate, spirenolactone, triamterate, Examples include acetazolamide.
Examples of the ACE inhibitor include captopril, enalapril maleate, alacepril, delapril hydrochloride, cilazapril hydrate, lisinopril hydrate, benazepril hydrochloride, imidapril hydrochloride, temocapril hydrochloride, quinapril hydrochloride, trandolapril, Perindopril erbumine.
Examples of the β-blocker include atenolol, bisoprolol fumarate, betaxolol hydrochloride, metoprolol tartrate, acebutolol hydrochloride, ceriprolol hydrochloride, nipradilol, propranolol hydrochloride, tirisolol hydrochloride, nadolol, carteolol hydrochloride, pindolol , Penbutolol sulfate, bopindolol malonate and the like.
Examples of the αβ blocker include amosulalol hydrochloride, arotinolol hydrochloride, carvedilol, labetalol hydrochloride, and bevantolol hydrochloride.
Examples of the α blocker include urapidil, terazosin hydrochloride, doxazosin mesylate, bunazosin hydrochloride, and prazosin hydrochloride.

  The form of the transdermal administration preparation of the present invention is not limited as described above, but a matrix-type transdermal administration preparation, particularly a matrix-type tape preparation is preferred. As a form of the matrix-type tape preparation, it is preferable that a drug-containing layer containing a matrix material, a drug, and, if necessary, a transdermal absorption enhancer is laminated on one surface of the support. Here, examples of the matrix material include various adhesive bases. As the adhesive base, for example, a rubber-based adhesive base, a silicone-based adhesive base, an acrylic adhesive base, a vinyl ether-based adhesive base and the like having pressure sensitivity at room temperature are used.

  The rubber-based adhesive base is not particularly limited. For example, styrene-butadiene copolymer, styrene-isoprene copolymer, styrene-isoprene-styrene block copolymer, natural rubber, synthetic isoprene rubber, Examples include polyisobutylene, polyvinyl ether, polyurethane, polyisoprene, and polybutadiene. Commercially available commercial products include Oppanol (registered trademark) series (BASF), Himol (registered trademark) series (Nippon Petroleum), Quintac (registered trademark) series (Neon Japan), Duro-tak (registered trademark) 608A, 611A (Henkel), etc. can be used.

  Although it does not specifically limit as said silicone type adhesive base, For example, silicone rubbers, such as polyorganosiloxane, etc. are mentioned. BIO-PSA (trademark registered) series (Toray Dow Corning) etc. can be used as a commercially available formulation.

  The acrylic adhesive base is not particularly limited. For example, a homopolymer having (meth) acrylic acid alkyl ester as a main monomer or a copolymer of (meth) acrylic acid alkyl ester and another copolymerizable monomer. A polymer etc. are mentioned. Here, (meth) acrylic acid means methacrylic acid or acrylic acid. Examples of the (meth) acrylic acid alkyl ester monomer include (meth) acrylic acid-2-ethylhexyl ester, (meth) acrylic acid ethyl ester, (meth) acrylic acid butyl ester, (meth) acrylic acid isobutyl ester, ( (Meth) acrylic acid hexyl ester, (meth) acrylic acid octyl ester, (meth) acrylic acid isooctyl ester, (meth) acrylic acid decyl ester, (meth) acrylic acid isodecyl ester, (meth) acrylic acid lauryl ester, ( And (meth) acrylic acid stearyl ester. Examples of the copolymerizable monomer include (meth) acrylic acid, maleic acid, fumaric acid, 2-hydroxyethyl (meth) acrylate, hydroxypropyl (meth) acrylate, acrylamide, dimethylacrylamide, diethylacrylamide, butoxymethylacrylamide, Examples thereof include ethoxymethyl acrylamide, N-vinyl-2-pyrrolidone, vinyl acetate, vinyl propionate, styrene, α-methylstyrene, vinyl chloride, acrylonitrile, ethylene, propylene, butadiene and the like.

  Furthermore, you may add a crosslinking agent to the said acrylic adhesive base as needed. The crosslinking agent is not particularly limited, and specific examples include an epoxy compound, a polyisocyanate compound, a metal chelate compound, and a metal alkoxide compound. By adding a cross-linking agent to the acrylic adhesive base, the internal cohesive force of the acrylic adhesive base is increased, so that it is possible to make it difficult for adhesive residue to occur on the skin when the patch is peeled from the skin.

  In the adhesive base layer, additives such as a plasticizer, an antioxidant and an absorption accelerator may be added within a range not impairing the effects of the present invention.

  The plasticizer is not particularly limited, and examples thereof include glycols such as ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol, polyethylene glycol, and polypropylene glycol, and fats and oils such as olive oil, castor oil, squalene, and lanolin. , Hydrocarbons such as liquid paraffin, diisopropyl adipate, diisobutyl adipate, benzyl benzoate, cetyl 2-ethylhexanoate, oleyl oleate, decyl oleate, benzyl acetate, diisopropyl sebacate, diethyl sebacate, trioleic acid Sorbitan, sorbitan tristearate, cetyl palmitate, octyldodecyl myristate, cetyl myristate, myristyl myristate, isopropyl myristate Which fatty acid esters, and the like, can be incorporated into them one or more adhesive layers.

  The antioxidant is not particularly limited. For example, a chelating agent such as sodium edetate, sodium sulfite, butylhydroxyanisole, butylhydroxytoluene, an ascorbic acid derivative such as ascorbyl tetraisopalmitate, and tocopherol acetate. And the like, and quinoline derivatives such as oxyquinoline sulfate.

  An absorption accelerator may be added to the adhesive base layer as necessary. The absorption promoter is not particularly limited. For example, alcohols such as oleyl alcohol, polyoxyethylene oleyl ether, polyethylene glycol monooleate or esters or ethers thereof; sorbitans such as sorbitan monolaurate and sorbitan monooleate Esters or ethers; phenol ethers such as polyoxyethylene nonyl phenyl ether and polyoxyethylene octyl phenyl ether; ionic interfaces such as dioctyl sodium sulfosuccinate, oleoyl sarcosine, lauryl dimethylaminoacetic acid betaine, sodium lauryl sulfate Activator: n-alkyl glucoside, n-alkyl thioglucoside, polyoxyethylene lauryl ether, dimethyl lauryl amine oxide Any nonionic surfactant; alkylmethyl sulfoxides such as dimethyl sulfoxide and decylmethyl sulfoxide; pyrrolidones such as 2-pyrrolidone, 1-methyl-2-pyrrolidone and dodecylpyrrolidone; 1-dodecylazacyclo Azacycloalkanes such as heptan-2-one and 1-geranylazacycloheptan-2-one; amines such as diisopropanolamine, triisopropanolamine, monoethanolamine, diethanolamine and triethylamine; terpenes such as menthol and cineol Is mentioned.

  As the support, the loss of the drug in the adhesive base layer can be prevented, the adhesive base layer can be protected, and the strength for imparting self-supporting property to the patch is good, and the preparation for transdermal administration is good It is desirable to have flexibility for giving a good sticking feeling.

  Such a support is not particularly limited, and examples thereof include a resin sheet, a foamed resin sheet, a nonwoven fabric, a woven fabric, a knitted fabric, an aluminum sheet, and the like. It may be made.

  Examples of the resin constituting the resin sheet include cellulose acetate, ethyl cellulose, rayon, polyethylene terephthalate, plasticized vinyl acetate-vinyl chloride copolymer, nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride, and polyurethane. , Polyethylene, polypropylene, polyvinylidene chloride and the like, and polyethylene terephthalate is preferable.

  The support is preferably one in which a polyethylene terephthalate sheet and a nonwoven fabric or a flexible resin sheet are laminated and integrated from the viewpoint of its flexibility and drug loss prevention effect, and a polyethylene terephthalate sheet and a nonwoven fabric are laminated. What is integrated is more preferable. Examples of the material constituting the nonwoven fabric include polyethylene, polypropylene, ethylene-vinyl acetate copolymer, ethylene- (meth) methyl acrylate copolymer, nylon, polyester, vinylon, SIS copolymer, SEBS copolymer. , Rayon, cotton and the like, and polyester is preferable. In addition, these materials may be used independently or 2 or more types may be used together.

  In addition, from the viewpoint of improving the adhesiveness (throwing property) between the support and the adhesive base layer, the support is formed by laminating and integrating a non-porous resin sheet made of the above material and a porous sheet. Also good. In this case, it is desirable to form the pressure-sensitive adhesive layer on the porous sheet side.

  As such a porous sheet, a sheet having improved anchoring property with the adhesive base layer is adopted. Specifically, paper, woven cloth, non-woven cloth, knitted cloth, mechanically perforated sheet Etc. Among these, paper, woven fabric, and non-woven fabric are particularly preferable from the viewpoint of handleability and the like. In the case of a nonwoven fabric, the same ones as described above can be used.

  In order to prevent drug loss in the adhesive base layer of the transdermal preparation of the present invention and to protect the adhesive base layer, the release paper is laminated and integrated on the surface of the adhesive base layer of the transdermal preparation. It is preferable to leave it.

  Examples of the release paper include resin films and paper made of polyethylene terephthalate, polyethylene, polypropylene, polyvinyl chloride, polyvinylidene chloride, and the like, and a release treatment is performed on the surface facing the adhesive layer. It is preferable. The release paper may be a single layer or a plurality of layers.

  For the purpose of improving the barrier property of the release paper, the release paper may be provided with an aluminum foil or an aluminum vapor deposition layer. Furthermore, when the release paper is made of paper, the release paper may be impregnated with a resin such as polyvinyl alcohol for the purpose of improving the barrier property of the release paper.

  Next, the manufacturing method of the transdermal administration formulation of this invention is demonstrated. The transdermal administration preparation of the present invention can be produced by a method for producing an ordinary transdermal administration preparation. For example, a base composition containing a drug is dissolved in a suitable organic solvent such as methanol or ethyl acetate, and the resulting adhesive base solution is applied onto a support, and the organic solvent is dried and removed to provide an adhesive base. It can manufacture by forming a layer and then bonding a release liner on the adhesive base layer. In addition, the adhesive base solution is coated on a release liner, the organic solvent is dried and removed to form an adhesive base layer, and then a support is bonded to the adhesive base layer. May be. In addition, in order to make the thickness of the adhesive base layer sufficient because it may be difficult to dry uniformly when thickly applying the adhesive base solution at a time when forming the adhesive base layer, You may divide and apply twice or more.

  In the case of a transdermal administration preparation of the present invention, for example, in the case of a tape preparation, if it is applied once a day, the blood concentration of ARB is stably maintained throughout the day, and a stable blood pressure lowering effect is exhibited.

  EXAMPLES Next, an Example is given and this invention is demonstrated in detail.

Example 1
(Candesartan tert-butylamine salt)
After 5.7 g of candesartan-free product was suspended in 45 mL of acetone, 5 mL of tert-butylamine was added, and the mixture was stirred for 10 minutes while heating under reflux. After cooling the reaction solution to room temperature, the solvent was distilled off under reduced pressure. Hexane 50mL was added to the obtained residue, and it stirred for 20 minutes. The precipitated crystals were collected by filtration and washed with 20 mL of hexane. The obtained crystals were dried by heating under reduced pressure at 40 ° C. for 3 hours to obtain 7.5 g of candesartan tert-butylamine salt.
Melting point: 169-172 ° C
¹ H-NMR (DMSO-d ₆ ): 1.23 (18H, s), 1.37 (3H, t, J = 7.0Hz), 4.51 (2H, q, J = 7.0Hz), 5.75 (2H, s), 6.92 -6.96 (4H, m), 6.97-7.00 (1H, m), 7.25-7.26 (1H, m), 7.27-7.32 (1H, m), 7.32-7.37 (3H, m), 7.50-7.53 (1H, m).
IR (νmax) (KBr): 3384,2981,1613,1545,1462,1381,1278,1038,761,460cm ^-1

Example 2
(Candesartan diethylamine salt)
After 499 mg of candesartan-free compound was suspended in 4 mL of acetone, 1 mL of diethylamine was added, and the mixture was stirred for 5 minutes under heating and reflux. After cooling the reaction solution to room temperature, the solvent was distilled off under reduced pressure. The obtained crystals were dried under reduced pressure at 40 ° C. for 3 hours to obtain 651 mg of candesartan diethylamine salt.
Melting point: 153-156 ° C
¹ H-NMR (DMSO-d ₆ ): 1.11 (12H, t, J = 7.0Hz), 1.38 (3H, t, J = 7.0Hz), 2.84 (8H, q, J = 7.0Hz), 4.53 (2H , q, J = 7.0Hz), 5.73 (2H, s), 6.92 (2H, d, J = 8.3Hz), 6.97 (2H, d, J = 8.3Hz), 7.00-7.03 (1H, m), 7.25 -7.27 (1H, m), 7.32-7.35 (3H, m), 7.38-7.39 (1H, m), 7.54-7.55 (1H, m).
IR (νmax) (KBr): 3422,2981,2716,2493,1616,1542,1459,1385,1353,1279,1067,1046,763,749cm ^-1

Reference example 1
(Candesartan-free body)
30 mL of methanol and 40 mL of dichloromethane were added to 10.0 g of trityl candesartan 1 methanolate and dissolved. In an ice bath, 2.7 mL of methanesulfonic acid diluted with 22 mL of methanol was slowly added dropwise and stirred for 50 minutes. 200 mL of water was added and stirred for 20 minutes in an ice bath. The precipitated crystals were collected by filtration, washed with 50 mL of water, and dried under reduced pressure at room temperature for 30 minutes. The obtained crystals were dissolved in 10 mL of DMF at 100 ° C., 290 mL of diethyl ether was added, and the mixture was stirred in an ice bath for 20 minutes. The precipitated crystals were collected by filtration and washed with 50 mL of diethyl ether. The obtained crystals were dried under reduced pressure at room temperature for 2 hours to obtain 5.8 g of candesartan-free product.
Melting point: 174-178 ° C
¹ H-NMR (DMSO-d ₆ ): 1.38 (3H, t, J = 7.0 Hz), 4.58 (2H, q, J = 7.0 Hz), 5.63 (2H, s), 6.93 (2H, d, J = 8.3Hz), 7.01 (2H, d, J = 8.3Hz), 7.16-7.20 (1H, m), 7.48-7.50 (1H, m), 7.53-7.57 (2H, m), 7.63-7.68 (3H, m ).
IR (νmax) (KBr): 3425, 2985, 1706, 1613, 1550, 1478, 1429, 1388, 1356, 1282, 1240, 1038, 760cm ^-1

Reference example 2
(Candesartan triethylamine salt)
After 504 mg of candesartan was suspended in 4 mL of acetone, 164 μL of triethylamine was added, and the mixture was stirred for 5 minutes while heating under reflux. After cooling the reaction solution to room temperature, the solvent was distilled off under reduced pressure. Hexane 20mL was added to the obtained residue, and it stirred for 7 hours. The precipitated crystals were collected by filtration and washed with 5 mL of hexane. The obtained crystals were dried under reduced pressure at room temperature for 7 hours to obtain 580 mg of candesartan triethylamine salt.
Melting point: 103-106 ° C
¹ H-NMR (DMSO-d ₆ ): 1.14 (9H, t, J = 7.0Hz), 1.40 (3H, t, J = 7.0Hz), 3.01 (8H, q, J = 7.0Hz), 4.59 (2H , q, J = 7.0Hz), 5.62 (2H, s), 6.85 (2H, d, J = 8.3Hz), 7.00 (2H, d, J = 8.3Hz), 7.13-7.16 (1H, m), 7.27 -7.33 (1H, m), 7.36-7.42 (2H, m), 7.47-7.49 (1H, m), 7.53-7.55 (1H, m), 7.61-7.63 (1H, m).
IR (νmax) (KBr): 3410,2984,2685,2497,1699,1614,1549,1476,1428,1388,1351,1280,1240,1038,762cm ^-1

Test example 1
(Permeation reagent)
First, the extracted skin (hairless mouse) was attached to a vertical diffusion cell kept at 37 ° C., and 7 mL of phosphate buffered saline (PBS, pH 7.5) was filled in the receptor phase. After standing for 1 hour, 500 μL of the sample solution was added to the stratum corneum side, and the test was started. Receptor phase PBS was collected every 2 hours up to 8 hours from the start of the test and every 4 hours thereafter up to 24 hours. After collection, the receptor phase was supplemented with the same amount of PBS. The drug concentration in the collected receptor phase PBS was measured by HPLC method, and this was plotted against time, and the 24-hour cumulative drug permeation amount per unit area (Q24: μg / cm ² ) was calculated. The skin permeation rate (Flux: μg / hr / cm ² ) was calculated from the slope of the permeation curve when the cumulative drug permeation amount reached a steady state.

(1) Table 1 shows the results when a 1% by weight equivalent amount of candesartan concentration was used as the sample solution.

  From Table 1, it was found that the tert-butylamine salt or diethylamine salt of candesartan has extremely superior transdermal absorbability compared to the free form and other organic amine salts.

Test example 2
In the same manner as in Test Example 1, olmesartan and irbesartan were examined for transdermal absorbability of tert-butylamine salt. The results are shown in Tables 2 and 3.

  From Tables 2 and 3, it was found that transdermal absorbability is improved by using olmesartan and irbesartan as tert-butylamine salts.

Test example 3
Various samples of candesartan were stored at 25 ° C., 40 ° C. and 60 ° C. for 1 to 6 months, and the purity was measured by HPLC method. The results are shown in Table 4 as relative values to the initial purity.

  From Table 4, it can be seen that the tert-butylamine salt and diethylamine salt of candesartan are excellent in long-term stability.

Claims (4)

  A tert-butylamine salt or a diethylamine salt of an angiotensin II receptor antagonist.   Tert-Butylamine salt or diethylamine salt of candesartan, olmesartan or irbesartan.   Tert-Butylamine salt or diethylamine salt of candesartan.   The transdermal administration formulation containing the salt in any one of Claims 1-3.