Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

• the present invention relates to a pharmaceutical preparation comprising, as an active ingredient, a substance selected from the group consisting of the above-mentioned argininamides, salts thereof, and hydrates thereof.
• R 1 represents a (2R, 4R) 14-alkyl-2-functional lipoxypiperidino group
• R 2 represents a phenyl group or a condensed polycyclic compound residue defined below.
• R 2 may have one or more substituents selected from a lower alkyl group, a lower alkoxy group and an amino group substituted with a lower alkyl group.
• the benzene ring is bonded to the thio atom of the sulfonyl group in the above general formula (I), and the benzene ring may be a heterocyclic ring or another heterocyclic ring.
• the substances selected from the group are known as compounds having antithrombin activity. Is (JP 56_ 15267, JP Sho 55 -33499, JP- ⁇ Pi JP 56 - 92213 JP).
• argato mouth van ((2R, 4R) — 1— [N 2 — ((RS) _3_methyl-1,2,3,4—tetrahydro8-quinoline sulfonyl) 1 L-arginyl] 1 4— Methyl-2 -Piperidinecarboxylic acid 'hydrate, a generic name, is a drug marketed under the trade name Novastan (registered trademark, Mitsubishi Pharma Corporation).
• the argininamides represented by the general formula (1), argatroban are poorly soluble in water, and the preparations currently marketed in Japan are prepared as 2 OmL ampules.
• a method of preparing a high-concentration argatroban solution using high-concentration alcohols represented by high-concentration ethanol (Japanese Patent Application Laid-Open No. H11-317277) is also known. Injectable preparations marketed in the United States are filled in 2.5 mL vials, but dissolve 25 O mg of argatroban using a high concentration of ethanol. Use of a high concentration of ethanol may cause undesirable effects due to ethanol, such as suppression of vasodilatory and central effects, so when using as an additive, the amount of ethanol should be as small as possible. Is desirably reduced. Disclosure of the invention
• an object of the present invention is to affect a pharmaceutical preparation containing the above argininamides as an active ingredient, which is highly convenient in a medical field. It is also an object of the present invention to provide a pharmaceutical preparation that is highly safe, has excellent storage stability, and is easy to manufacture.
• the active ingredient is a substance selected from the group consisting of argininamides represented by the general formula (I), salts thereof, and hydrates thereof, at a concentration of lmg / mL or more,
• the present invention provides the following pharmaceutical preparations.
• An active ingredient a substance selected from the group consisting of argininamides represented by the following general formula (I), salts thereof, and hydrates thereof, at a concentration of 1 mg / mL or more, about 10 mg Zm L
• Pharmaceutical preparations in the form of a solution containing the following solution (however, the solution is a solution containing at least water), and the solution is filled in a container of about 1 mL or more and about 2 OmL or less.
• R 1 represents a (2R, 4R) 14-alkyl-4-carboxypiperidino group
• R 2 represents a phenyl group or a condensed polycyclic compound residue as defined below.
• R 2 may have one or more substituents selected from a lower alkyl group, a lower alkoxy group and an amino group substituted with a lower alkyl group.
• the cyclic compound residue is a condensed polycyclic compound residue containing a benzene ring, wherein the benzene ring is bonded to the thio atom of the sulfonyl group in the general formula (I), and the benzene ring is a heterocyclic ring.
• the other ring which may be condensed represents a residue having a total number of carbon atoms of 7 to 14 constituting the ring of the polycyclic compound residue
• R 1 in the general formula (I) is a (2R, 4R) -14-methyl-2-carboxypiperidino group, and R 2 is a 3-methyl-1,2,3,4-tetrahydro-18-quinolyl group
• any one of the above (1) to (6) including a solution containing about 5 mg / mL of a substance selected from the group consisting of the arginine amides, salts thereof, and hydrates thereof; Pharmaceutical preparation of Claim.
• the pharmaceutical preparation according to any one of the viscosity of the solution is about 35. 8 s at a shear rate of _1 about 15 mPa ⁇ s one 1 or less at 25 ° C (1) (8).
• the active ingredient is a substance selected from the group consisting of argininamides represented by the following general formula (I), salts thereof, and hydrates thereof, at a concentration of 1 mg Zni L or more and about 1 Omg ZmL or less. in containing, pharmaceutical composition comprising about 1 5 mPa at about 35. 8 s-1 shear speed viscosity at 25 ° C, s is one less than one solution (although the solution is a solution containing at least water) object. ... (
• R 1 represents a (2R, 4R) _4-monoalkyl-2-carboxypiperidino group
• R 2 represents a phenyl group or a condensed polycyclic compound residue defined below.
• R 2 may have one or more substituents selected from a lower alkyl group, a lower alkoxy group and an amino group substituted with a lower alkyl group
• the fused polycyclic compound residue is a benzene ring
• the benzene ring is bonded to the thio atom of the sulfonyl group in the general formula (I), and the benzene ring has another ring which may be a heterocyclic ring. Condensed to indicate a residue having a total number of carbon atoms of 7 to 14 constituting the ring of the polymorphic compound residue
• R 1 is a (2R, 4R) -14-methyl-2-carboxypiperidino group
• R 2 is 3-methyl-1,2,3,4-tetrahydro-1-8—
• a pharmaceutical composition comprising:
• composition according to any one of the above (49) to (52), wherein the monohydric alcohol and the solubilizing agent are not more than about 25% (w / v) in a solution. includes a valence alcohol, and pharmaceutical compositions consisting of a solution p H is about 4 to about 7.
• FIG. 1 is a graph showing the relationship between sorbitol concentration and viscosity in Example 4.
• FIG. 2 is a view showing an HPLC chart of Example 5.
• FIG. 3 is a graph showing the relationship between the pH of the pharmaceutical preparation of Example 6 and the production of related substances.
• a solution having a capacity of about 1 mL or more and about 20 mL or less is filled with a solution, and the solution is an arginine represented by the above general formula (1) as an active ingredient.
• R 1 represents a (2R, 4R) 14-alkyl-12-carboxypyridino group.
• the alkyl refers to a C1-C5 lower alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group or a butyl group.
• R 2 represents a phenyl group or a condensed polycyclic compound residue as defined below.
• the condensed polycyclic compound residue is a condensed polycyclic compound residue containing a benzene ring, wherein the benzene ring is bonded to the ⁇ atom of the sulfonyl group in the general formula (I), and Is fused with another ring which may be a heterocyclic ring, and the total number of carbon atoms constituting the ring of the polycyclic compound residue is 7 to 14.
• the fused polycyclic compound residue is a bicyclic compound residue or a tricyclic compound residue.
• the bicyclic compound residue is preferably a group in which a 5- or 6-membered ring is fused to a benzene ring, and the 5- or 6-membered ring may be a heterocyclic ring.
• the tricyclic compound residue is preferably a group in which another 5- or 6-membered ring is fused to a 5- or 6-membered ring, and the 5- or 6-membered ring may be a heterocyclic ring.
• Heterocycles constituting the above heterocycle The atom is, for example, an oxygen atom, a nitrogen atom, or an io atom.
• R 2 may be substituted with one or more groups selected from the group consisting of a lower alkyl group, a lower alkoxy group, and an amino group substituted with a lower alkyl group.
• a lower alkyl group for example, a C1-C5 alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, or a tert-butyl group, and as a lower alkoxy group, for example,
• Examples of the C1-C5 alkoxy group such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, or a butoxy group, and an amino group substituted with a lower alkyl group include, for example, the lower alkyl group described above.
• an alkylamino group or a dialkylamino group substituted with a group for example, the lower alkyl group
• condensed polycyclic compound residue represented by R 2 examples include an anthryl group, a phenanthryl group, a benzofuranyl group, a dibenzothenyl group, a phenoxachel group, a quinolyl group, a carbazolyl group, an ataridinyl group, and a phenazinyl group.
• the benzene ring of the polycyclic compound residue and the ⁇ atom of the sulfonyl group in the general formula (I) are bonded, but the bonding position on the benzene ring is not particularly limited. Les ,.
• Specific compounds included in the arginine amides include the following compounds.
• the arginine amides include isomers such as optical isomers and diastereomers, and any of these may be used as the arginine amides. A mixture of sexes may be used. 'The above argininamides can be easily produced according to the method described in JP-A-56-15267,' JP-A-55-33499, or JP-A-10-101649. is there.
• the arginine amides of the present invention may form addition salts with various inorganic or organic acids or inorganic bases or organic bases according to the method described in JP-A-56-15267. Can be.
• the pharmaceutical preparation of the present invention is preferably used as an injection. When used as an injection, it can be diluted at the time of use. Also, drops can be prepared at the time of use using the pharmaceutical preparation of the present invention.
• an infusion can be prepared by adding the pharmaceutical preparation of the present invention to an infusion. Alternatively, it can be used by adding it to the dialysate during dialysis.
• the container used for filling the pharmaceutical preparation of the present invention may have a capacity of about ImL or more and about 2 OmL or less, and the shape and material are not particularly limited.
• the capacity of the container is preferably about 1 OmL or less, and about 2 mL is most preferable.
• the pharmaceutical preparation of the present invention contains the active ingredient argininamide represented by the general formula (I) at a concentration of about ImgZmL or more and about 1 Omg / mL or less, preferably about 5 mg / mL. Is the concentration of The weight of arginine amides contained in the container is preferably about 1 Omg.
• the container is preferably a glass ampoule.
• the pharmaceutical preparation of the present invention may be prepared by, for example, sucking a solution from a pharmaceutical preparation in a form filled in an ampoule into a syringe, and then mixing the solution with an infusion to prepare an infusion. It is desirable to include a solution that is easily sucked.
• a pharmaceutical preparation it is preferable that the viscosity of the solution is about 35. 8 s-1 at a shear rate of about 1 5MPa- s one 1 or less at 25 ° C, particularly preferably, the viscosity of the solution 25 ° C About 71. In 6 s-1 of shear rate of about 1 OmPa ⁇ s- 1 or less at.
• the viscosity can be measured using a rotational viscometer (type B) at 25 ° C as shown in the examples described later.
• the solution contained in the pharmaceutical composition of the present invention contains at least water, but does not exclude the presence of other solvents.
• the solution preferably contains at least 30% (w / v) water. More preferably, it is a solution containing 35% to 55% (w / v) of water.
• composition of a solution in which arginine amides are dissolved at a concentration of about lmg / mL or more and about 1 Omg / mL or less is not particularly limited, and various compositions are possible.
• An example of a preferred formulation is a formulation in which a monohydric alcohol is added for dissolving arginine amides.
• the monohydric alcohol any pharmaceutically acceptable one such as methanol and ethanol can be used.
• the concentration in the solution should be no more than about 25% (w / v), preferably no more than 20% (w / v), taking into account the central depressing action caused by ethanol. Is preferred. It is more preferably from 10% to 25% (w / v), further preferably from 10% to 20% (w / v), and most preferably from 15% to 20% (w / v).
• polyhydric alcohol When the amount of monohydric alcohol is reduced in consideration of safety, polyhydric alcohol can be added as a dissolution aid.
• polyhydric alcohol means a dihydric or higher alcohol, but is used as a concept that does not include saccharides.
• any pharmaceutically acceptable one can be used.
• dihydric or trihydric polyhydric alcohols are preferable, and glycerin is particularly preferable.
• Polyhydric alcohol content is not particularly limited, but about 30%
• Saccharides can be used in the pharmaceutical preparation or the pharmaceutical composition of the present invention.
• the saccharides include saccharides such as glucose and fructose, and xylitol and the like. Sugar alcohols such as sorbitol can be mentioned. Of these, sorbitol is preferred.
• the use of saccharides may increase the viscosity of the solution, and it is generally not preferable to add a large amount of saccharides. Therefore, the pharmaceutical preparation of the present invention preferably does not contain a large amount of saccharide, and the saccharide content is, for example, about 30% (w / v) or less, and preferably 25% (w / v) or less. preferable. It is also preferable that the saccharides are not substantially contained.
• the pharmaceutical preparation of the present invention can be prepared by dissolving argininamides in a solution containing the above-mentioned monohydric alcohols and the like. Polyhydric alcohols and / or saccharides can be added to the solution as needed. In dissolving, the order and conditions are not particularly limited, but arginine amides are first dissolved in monohydric alcohols or a mixture of monohydric alcohol and polyhydric alcohol and Z or saccharide, and then water is added. It is preferable to additionally prepare.
• the pharmaceutical preparation of the present invention is a stable preparation in which the generation of substances other than the active ingredient is substantially suppressed after heat sterilization. More preferably, it is a preparation in which the amount of substances other than the active ingredient (individually decomposed products) is suppressed to about 0.2% or less when stored at 40 ° C for 6 months after heat sterilization. . Whether or not the preparation is a pharmaceutical preparation in which production other than the active ingredient is substantially suppressed can be easily confirmed by analyzing the solution after heat sterilization by HPLC, as described in Examples below.
• the heat sterilization is not particularly limited as long as it can ensure the safety as a medicine, but usually, heat sterilization at 121 ° C for 20 minutes and a substance having the same effect can be used. .
• the substance (individual decomposition product) other than the active ingredient of the present invention includes a decomposition product derived from the active ingredient and other unknown compounds.
• the active ingredient is argatropane
• the following main decomposition products (decomposition products i) and other unknown compounds are included as substances other than the active ingredients.
• the above solution containing argininamides was prepared, and the pH of the solution was adjusted before heat sterilization Pharmaceutical formulations can be mentioned.
• the pH of the solution is preferably from about 4 to about 7, more preferably from about 5 to about 7. Adjustment of pH can be performed using a usual pH adjuster.
• a pH adjuster such as hydrochloric acid or sodium hydroxide can be used.
• the pharmaceutical preparation of the present invention can be prepared by heat sterilization.
• the pharmaceutical composition provided by the present invention comprises, as an active ingredient, a substance selected from the group consisting of the arginine amides represented by the general formula (I), salts thereof, and hydrates thereof.
• a pharmaceutical composition comprising: The pharmaceutical composition is preferably filled in a container having a capacity of about 1 mg / mL or more and about 2 Omg / mL or less, but the capacity of the container is not limited to the above.
• Argatroban used in the following examples It is manufactured according to the method described in Japanese Patent Application Laid-Open No. H10-10-149. The viscosities shown below were measured under the following conditions.
• Measuring device B-type viscometer (Manufacturer: Tokimec Co., Ltd., Publisher: Toki Sangyo Co., Ltd.)
• Rotational speed 60 rpm (Based on the instruction manual, measure at 30 rpm for 1 OmPa ⁇ s 1 or more, shear rate is 60 rpm: 71.58 s—30 rpm: 3 5.7.9 s- 1 )
• Example 1
• Tables 2 and 3 show the viscosity of each formulation and the stability when stored at 4 ° C for 24 hours.
• compositions containing argatroban at a concentration of about 5 mg / ml were obtained, and these pharmaceutical compositions had a viscous suction viscosity in a syringe and had good stability.
• a pharmaceutical composition containing 5 mg / ml of argatroban was prepared in the same manner for the formulation shown in Table 4 (in Table 4, the concentration of argatroban is shown in mg / ml). Ethanol and concentrated glycerin concentrations are shown as 0 / o ( W / V )).
• Table 4 shows the viscosity of each formulation.
• a pharmaceutical composition containing argatroban at a concentration of about 5 mg / ml was obtained, and these pharmaceutical compositions had a viscosity that facilitated inhalation into syringes.
• composition 9 1 0 1 1 1 1 2 1 3 1 4
• the temperature of the thermostat was reset to 25 ° C, and stirring was continued. After 24 hours, 1 ml of the suspension was collected and filtered through a 0.45 / m membrane filter to obtain a sample for HPLC.
• Example 2 In the same manner as in Example 2, a solution having the following composition was prepared, and the viscosity was measured. The results are shown in Table 6 (in the table, the solubility is shown in mg / ml and the prescribed concentration is shown in w / v%). Table 6
• Example 5 a pharmaceutical composition having the formulation shown in Table 7 below was prepared (in the table, the concentrations of ethanol and glycerin are shown by% (w / v)). The viscosity when 0 to 40% (% by weight) was added was measured. The concentration of Argato mouth bun is S mg Zm1. The results are shown in Figure 1. The results in Fig. 1 showed that the viscosity of the solution was significantly affected by the sorbitol concentration. Table 7 Example 5
• UV absorption photometer (measuring wavelength: 254 nm)
• Glycerin 450 g was placed in a 1 L beaker and stirred, and ethanol (150 g) was added and mixed with stirring.
• Argatroban 5 g was added to the mixture, and the mixture was heated and dissolved as needed.
• 380 g of distilled water for injection was added and mixed with stirring. Adjust the pH to about 4, 4.5, 5, 5.5, 6, 6.7, or 7.5 by adding 0.024 mol / L hydrochloric acid or 0.025 mol / L sodium hydroxide to the resulting solution, and add distilled water for injection. The total amount was set to 1.
• UV absorption photometer (measurement wavelength: 259 nm)
• Mobile phase Adjust the pH to 5.0 by adding ammonia TS to diluted acetic acid (100) (1 ⁇ 400). To 550 mL of this solution, add 450 mL of methanol.
• Flow rate Adjust so that the retention time of the first eluting peak of the two peaks of argatroban is about 50 minutes.
• Area measurement range A range of about 1.4 times the retention time of the peak eluting out of the two peaks of argatroban after the solvent peak Table 9
• Example 11 a pharmaceutical composition shown as “comparative composition” in Table 11 below, and a pharmaceutical composition described in Example 6 of JP-A No. A formulation known as “known composition”) and a product marketed in the United States under the trade name Argatropan
• “Operability from syringe” refers to the operability when aspirating a solution into a 10 ml syringe when 21G (gauge) is used as a needle (required finger force and finger / palm). (Load applied to). Since further the operability decreases when using a needle thin 22G and 23G than 21 G, the viscosity of the pharmaceutical composition as lOmPa ⁇ s one 1 or less, is preferably as low as possible viscosity.
• novel pharmaceutical preparations and pharmaceutical compositions comprising as an active ingredient a substance selected from the group consisting of the above-mentioned argininamides, salts thereof, and hydrates thereof.
• ADVANTAGE OF THE INVENTION The pharmaceutical formulation and pharmaceutical composition of this invention have the advantage that the convenience and safety in a medical field are high, the storage stability is good, and it can be manufactured more easily.

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• 2004
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