JPS63135331A - Pyridonecarboxylic acid preparation - Google Patents

Abstract

PURPOSE:To obtain the titled preparation having suppressed tendency of generation of insoluble foreign material with time and useful as an antibacterial agent, by filling a solution of a specific acid addition salt of a pyridonecarboxylic acid in a container having silicone-coated inner surface. CONSTITUTION:A solution of an acid addition salt of a pyridonecarboxylic acid having antibacterial activity, capable of forming an acid addition salt and expressed by formula [R is (lower alkyl-substituted) 1-piperazinyl, amino or 1-pyrrolidinyl, etc., substituted with lower alkylamino, etc.; A is N or C-X (X is H or halogen); B is N, C-X or together with R1 form a 5-6-membered ring; Y is H, amino, etc.; R1 is alkyl, cycloalkyl, etc.] is filled in a container having silicone-coated inner surface to obtain the objective pyridonecarboxylic acid preparation. The compound of formula is e.g. a pyrido[2,3-d]pyrimidine derivative wherein both A and B are N or a 1,8-naphthyridine derivative wherein A is C-X and B is N.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to a liquid pharmaceutical formulation that does not generate insoluble foreign matter. More specifically, the present invention provides pyrido/carbo/l! The present invention relates to a pharmaceutical formulation filled with a solution of an acid addition salt of i. In addition, in this specification-1), pyrido/carbo/acid refers to a carboxyl group at the 3-position and an oxo-1&'i: 1,4-dihydropyridine at the 4-position as its partial skeleton. means a compound.

PRIOR ART AND PROBLEMS TO BE SOLVED Pyridonecarboxylic acid is widely known as an extremely excellent antibacterial agent against not only Durum-positive bacteria but also Durum-negative bacteria.

Pyridone carb/acid can also be administered orally or parenterally (particularly by injection) as a solution, but such solutions generate insoluble foreign matter over time.

Since the insoluble foreign matter does not contain one gold Ii atom derived from glass, it is considered to be some kind of modified product of pyridonecarboxylic acid, rather than 7 lakes derived from the glass container. The generation of such insoluble foreign substances not only gives a sense of anxiety to the user, but also can sometimes cause serious side effects. Therefore, it is strongly desired to suppress the generation of non-H foreign substances.

Regarding the solubilization of pyridonecarboxylic acid, it is known that, for example, adding an acid to its lactate (Japanese Patent Application Laid-Open No. 0F-180771) or adding an excess base (Japanese Patent Application Laid-Open No. 0F-180771) There is. However, adding an acid or base will drastically increase or decrease f) II of the solution, which may accelerate the decomposition of pyridone carboxylic acid,
It may generate flakes from glass containers, cause strong local irritation or hemolysis in the case of injections, or change the liquid properties (p 1) of other infusions (weakly acidic) in the case of infusions. It may cause unexpected problems.

Additionally, drugs are commonly solubilized using various additives. Such additives include, for example, antioxidants such as ascorbic acid and sodium bisulfite; solubility aids such as jetanolamine; I', D T
Complexing agents such as A4 sodium and citric acid; Warming agents such as sodium phosphate; Glucose.

Isotonic agents such as sorbitol and sodium chloride; surfactants such as hardened Himanura; organic solvents such as glycerin and propylene glycol. However, such additives could not effectively suppress the generation of insoluble foreign substances in pyridone carboxylic acid solutions. Furthermore, 1) nitrogen exchange in the container space had no effect on the generation of insoluble foreign matter.

As a result of further investigation, the present inventors found that a solution of an acid addition salt of pyridonecarboxylic acid was filled in a container covered with silicone.
), the present invention was completed based on the finding that the generation of insoluble foreign substances over time can be effectively suppressed.

Conventional technology regarding combinations of drugs and containers includes:
For example, a vacuum vial containing a specific Cefa r1 sporin J'Ω body (Japanese Patent Application Laid-Open No. 1983-18014), y
Eye drops containing drugs such as scorbic acid in a polyester container (Special υ (1982-21014)), formulations in which high-concentration fibrinogen is dispensed into a syringe and frozen (Special [Special
IT+ 1982-90508), Comprehensive bikumi/drug for intravenous injection divided into three containers (Japanese Patent Application Laid-Open No. 58-1) 04
13) A package made by filling an oxygen-impermeable container with eleuthero (Japanese Patent Application Laid-Open No. 2004-204720)
etc. are known. However, these documents do not disclose anything about the combination of pyrido/carbo/acid and container, as well as silicone-coated containers.

Means for Solving the Problems The present invention provides pyridonecarboxylic acid, which is prepared by filling a container with a silicon corrugated inner surface with a solution of an acid addition salt of pyridonecarbo/acid that can inhibit antibacterial activity and form an acid addition salt. A flash in the formulation.

The drug to be loaded in the present invention has antibacterial activity.
Any pyrido/carboxylic heptacid that can form an acid addition salt can be used. Acid addition salt form +J12L t! )
The pyridonecarboxylic acid may be any compound having a basic substituent such as a 1-piperazinyl group.More specifically, an acid addition salt of pyridonecarboxylic acid represented by the following general formula is used.

(In the formula, R may be substituted with a lower alkyl group 1
- means a piperazinyl group, or an amine 7) person,
1-pyrrolidinyl J substituted with 7 lower alkyl amide groups, ami/lower alkyl group or lower alkyl amide/lower alkyl Jλ! The 1-pyrrolidinyl group may be further substituted with a lower alkyl group or a halogen atom. A means Nt or C-X. B means N or C-X, or may form 5 to 60 rings together with R1. X here represents a hydrogen atom or a halogen atom. Y means a hydrogen atom, amino 1A or a halogen atom. R1 means a lower alkyl group or a lower cis-alkyl group, or phenyl W optionally substituted with a

In the above general formula, A and B are both N, IJ
)' [2,3-dl Pi IJ Mi
'? 7 Derivatives JQ, 1,8-naphthyridine derivatives in which A is C-x and B is N, A and 0
are both C-X, and IN and R1 form a 5-6n ring, for example, pyrido[1,2,
3-d c ] [1,4]benzoxazine J J
Q-form and the like are included, and specific examples include the following compounds.

5.8-Dihydro1j-8-ethyl-2-(l-piverazinyl)-5-oxopyrido[2,3-d]pyrimidine-
6-carbo/acid 1-edi-G-fluor'-1,/I-dihydro-4
-oxo-7-4-piperazinyl)-1,8-naphthyridine-3-carboxylic acid 7-(3-amino-1-pyrrolidinyl)-■-ethyl(i-fluoro0-1,4-dihydro n-4- Oquino 1,8-naphthyridi/-3-carboxylic acid 7-(3-amino-1-pyrrolidinyl)-1-nk-6-fluoro-J,4-dihydro-4-okino 1.8- naphthyridi/-3-carbo/acid 1-cyclop[1-biru-6-fluoro'+-7-(3-methylami/-!-pyrrolidinyl)-4-dihydro-4
-Oxo-1,8-naphthyridine-3-carbo/acid 1-cis 1-propyl-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxo-1,8-
naphthyridi/-3-carboxylic acid 7-(cis-3-amino/
Methyl-4-rinn rJ-i-pyrrolidinyl)-1-cyclopropyl-8-7)korj-1,/l-dihydro 0
-4- Oh, ton! , 8-naphthyridi7-3-carboxylic acid 7-(3-amino-1-pyrrolidinyl)-1-(2,
4-difluorophenyl)-6-fluorojJ-J, 4-
1-Ethyl-6-fluoro-7-(1-piperazinyl) 4-oxo-1,8-naphthyridine-3-carboxylate
-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7-(3-amino-1-pyrrolidinyl) = 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-
Oxoquinoline-3-carpono-1-cyclopropyl-6
-Fluoro-7=(1-piperazinyl)-1,4-dihydro-4-occhibutonolino-3-carboxylic acid 5-amino-1-cyclopropyl-7-(3-ethylaminomethyl-1-pyrrolidinyl)-6,8 -difluoro-1,4-dihydro-4-okinki/su/-3-carboxylic acid 1-cyclopropyl-7-(3-ethylaminomethyl-
1-pyrrolidinyl)-5,e,8-)refluoro r+ −
1-ethyl-6,8-difluoro-7-(3-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate)
9-fluoro-3-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid
0-(4-methyl-1-piperazinyl)-7-oxo-
2,3-dihydro0-7H-pyrido[1,2,3-d
The acid addition salt of [1,4]be]7zuoxazine-6-carboxylic acid pyridonecarbo/ is hydrochloric acid.

1/l ftft, inorganic acids such as phosphoric acid; acetic acid,
Lactic acid, succinic acid, meta/sulfo7 acid, malate/acid, malo7 f@.

Organic acids such as gluco/acids include those formed from acids such as amino acids such as aspartic acid and glutamic acid, and usually include hydrochloride and methanesulfonate.

Further, the container used in the present invention may be of any TT quality as long as it is coated with silicone, but it is usually made of glass. Container formats are vials, ampoules, or oral liquids, 1 eye drop, 1 ohm.

These include bottles for eardrops or intravenous drips, and are sometimes colored.

The solvent is generally water, but may also be a physiologically acceptable solvent.
It may also be an organic solvent such as fillet/glycol or a mixture of organic solvent and water.

The preparation of the present invention can be prepared by dissolving the acid addition salt of pyridone carboxylic acid in a solvent, or by suspending or dissolving the pyridone carboxylic acid in a solvent and adding equimolar amount of the acid to the solution, if desired. 52 can be easily prepared by adding and dissolving an auxiliary agent and filling it into a predetermined container. In the case of injections and drips, sterilization using a membrane filter and heat sterilization are further performed. The concentration of pyridonecarboxylic acid in the solution varies depending on the type, but is between 0.2 and 50 m
ff/■l, and the liquid property of the solution is P
II in the range of 3 to 8.5, preferably 4.0 to 5.5. A buffering agent 9 can be added as an auxiliary agent if desired.
There are tonicity agents, non-1+IF agents, etc.

Although the pyridonecarboxylic acid preparation of the present invention obtained by heating does not contain any special additives to suppress the generation of insoluble foreign substances, there is virtually no generation of insoluble foreign substances even when left at 60°C for one month. It is not recognized as such. As described above, the pyridone carboxylic acid preparation of the present invention meets the demand for suppressing the use of additives as much as possible.

■Body side Next, the present invention will be explained in more detail with reference to Examples.

Example 1 Acid addition salt of formulation pyrido 7carbo/acid' 1
．． 095 g sorbitol
5g7IQJ distilled water
Appropriate amount 100 ■i '7-(cis-3-amitumedel-4-chloro-1-pi[1ridinyl)-i7 cloprovir-6-fluoroU-no 1,4-dihydro0-4-okine-1.8- Naphthyridine 7-3-no Jrubo/acid hydrochloric acid 4 J: Juice Q of acid addition salt of pyridonecarboxylic acid and sorbitol
Dissolve in a portion of distilled water. After adding the remaining Han distilled water, it is filtered with a membrane filter (0,221) m). 10-e portions of this solution are filled into silicone-coated colorless ampules or unsilicone-treated colorless ampoules (control), melted shut, and autoclaved at +20'C for 20 minutes.

Foreign body inspection Insoluble foreign body inspection is performed according to 1) Insoluble foreign body inspection method for injections (meat limit inspection) described in the Revised Japanese Mulberry Pharmacopoeia and I
I I A C light shielding type automatic particle! The number of particles was measured using a method (instrumental inspection) using a water pump (Pacific Scientific Co., Ltd.).

The results are shown below.

Table 1 Test for insoluble foreign substances 1 +; Foreign substances that are easily detected 1; Foreign substances not detected ” Number of particles with a diameter of 5 μm or more/ml When using a container covered with silicone as shown in Table 1 The generation of insoluble foreign matter is extremely effectively suppressed.

Claims (8)

[Claims] (1) A pyridone carboxylic acid preparation prepared by filling a container with a silicone-coated inner surface with a solution of an acid addition salt of pyridone carboxylic acid that has antibacterial activity and can form an acid addition salt. (2) The pyridonecarboxylic acid preparation according to claim 1, wherein the pyridonecarboxylic acid is a compound represented by the following general formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R is a lower alkyl group) May be substituted 1
- means a piperazinyl group, or a 1-pyrrolidinyl group substituted with an amino group, a lower alkylamino group, an amino lower alkyl group, or a lower alkylamino lower alkyl group, and the 1-pyrrolidinyl group is further a lower alkyl group. Alternatively, it may be substituted with a halogen atom. A means N or C-X. B means N or C-X, or may form a 5- to 6-membered ring together with R_1. X here means a hydrogen atom or a halogen atom. Y means a hydrogen atom, an amino group or a halogen atom. R_1 means a lower alkyl group or a lower cycloalkyl group, or a phenyl group optionally substituted with a halogen atom). (3) The pyridonecarboxylic acid preparation according to claim 1 or 2, wherein the pyridonecarboxylic acid is a compound having a pyrido[2,3-d]pyrimidine skeleton. (4) Claim 1 or 2, wherein the pyridonecarboxylic acid is a compound having a 1,8-naphthyridine skeleton.
The pyridone carboxylic acid preparation described in Section 1. (5) The pyridonecarboxylic acid preparation according to claim 1 or 2, wherein the pyridonecarboxylic acid is a compound having a quinoline skeleton. (6) Pyridonecarboxylic acid is pyrido[1,2,3-dc
] [1,4] The pyridonecarboxylic acid preparation according to claim 1 or 2, which is a compound having a benzoxazine skeleton. (7) The pyridonecarboxylic acid preparation according to claim 1, wherein the acid addition salt is a hydrochloride. (8) The pyridonecarboxylic acid preparation according to claim 1, wherein the material of the container is glass. (9) The pyridone carboxylic acid preparation according to claim 8, wherein the container is a bottle for oral liquid medicine, a bottle for eye drops, a bottle for nasal drops, a bottle for ear drops, a bottle for drip, a vial, or an ampoule.