JPH0315632B2 - - Google Patents

Description

[Detailed description of the invention]

Pharmaceutical drugs are generally most conveniently administered to humans by the oral route. Accordingly, stable oral dosage forms such as tablets, capsules and oral liquids are most commonly manufactured. In these types of oral dosage forms, the solubility of the active ingredients contained is generally not a problem. Absorption is facilitated by the longer time the substance remains in the gastrointestinal tract and by the general digestive process. Of course, extremely poorly soluble substances are only slowly absorbed when administered orally, and a portion of the administered drug may be excreted, so that the desired drug effect cannot be fully exerted. Methods for improving the solubility of such substances must therefore be applied to produce effective oral dosage forms. One such method known to those skilled in the art is to prepare soluble salts of drugs. In many cases oral routes of administration are not available or preferred. For example, when treating microbial infections in humans, parenteral routes of administration are often preferred, and indeed necessary. For example, intravenous administration is often used to quickly obtain high blood concentrations of certain antimicrobial agents. Slow intravenous infusions may also be used to maintain specific blood levels over extended periods of time. Intramuscular and intravenous injections can also be used to treat frail or unconscious pediatric patients. The characteristics of the active ingredient necessary to produce a stable parenteral dosage form or to produce a stable dosage form that can be made into a parenteral dosage form immediately before use are such that the same active ingredient are different from those required for oral dosage forms containing Thus, for parenteral formulations, the active ingredient must itself have at least the following characteristics, or it must be converted into a derivative (eg, a salt) having such characteristics: (a) A pH that is compatible with blood and muscle tissue and does not damage cell structures, preferably about PH4-8.
High solubility in water. (b) Stability in solution, preferably at room temperature and in the presence of air. (c) be derivatized with a reagent (ie, an acid or base) that is relatively non-toxic and acceptable for drug-modulating effects; (d) Derivatization reagents should be relatively inexpensive. (e) The derivative should be easily produced and produce a stable form upon lyophilization. (f) The derivative should be compatible with and sufficiently soluble in standard parenteral solutions for convenient administration. Two new antibacterial agents have recently been reported. For example, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid (hereinafter referred to as "Compound A" in some cases)
The antibacterial effect of ``Antimicrobial Agent''
and Chemotherapy” Vol. 17, pp. 103-108 (1980
) and “Antimicrobial Agents and
Chemotherapy, Vol. 19, pp. 188-189 (1981)
and are incorporated herein by reference. 1-ethyl-6-fluoro-1,
The antibacterial activity of 4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid (hereinafter sometimes referred to as "Compound B") has been reported in "Current Chemotherapy and
Infectious Disease, Proceedings of the
11th International Congress of Chemotherapy
and the 19th Interscience Conference on
Antimicrobial Agents and Chemotherapy” Volume 1, Page 451 (American Society for Microbiology, published in 1980)
, which is incorporated herein by reference. Compound A is also described in US Pat. No. 4,146,719, which is incorporated herein by reference. The compound is amphoteric and does not have a high degree of water solubility. The patent only discloses the production of the hydrochloride salt. For reasons discussed below, this salt, like many other salts of Compound A prepared from various acids and bases, is unsuitable for preparing parenteral dosage forms containing Compound A. be. It would therefore be beneficial and advantageous to provide derivatives of Compound A having the above characteristics in order to be able to prepare useful parenteral dosage forms. Compound B as the hydrochloride salt is described in British Patent Application No.
Produced in Example 1 of No. 2034698. Dosage form is not listed. Compound B is also described in European Patent Application No. 9425, which is incorporated herein by reference. Compound B is amphoteric and does not have a high degree of water solubility. The patent specifically states that compound B
Salts of ``can be formed from a variety of inorganic and organic acids, and examples of suitable acids include hydrochloric acid, acetic acid,
lactic acid, succinic acid, lactobionic acid and methanesulfonic acid, particularly preferred salts are hydrochloride or methanesulfonate. The patent also states that oxalic acid can be used to make salts.
For reasons discussed below, these salts and many other salts made from various acids and bases are unsuitable for preparing useful parenteral dosage forms containing Compound B. Regarding the use of compound B, European patent application no. It is described that they can be used in the form of pharmaceutical preparations containing them by mixing with agents. The patent goes on to state that the pharmaceutical formulations may be powders, granules, tablets, ointments, suppositories, creams, capsules, etc. Additionally, all in vivo test methods reported in that patent, Examples B-G, use the oral route of administration. The few dosage form preparation examples, Examples H and J, are for oral dosage forms (capsules and tablets, respectively). It can be assumed that these inventors recognized that useful parenteral dosage forms could not be readily prepared from Compound B. This is because the manufacture and use of these important dosage forms is neither taught nor discussed therein. It would therefore be beneficial and advantageous to provide derivatives of compound B having the above characteristics for the preparation of useful parenteral dosage forms. In a general aspect relating to compounds, the present invention relates to compounds of structural formula C (wherein X is N or CH and Z is galacturonic acid, aspartic acid, gluconic acid or glutamic acid). In a first subsection relating to compounds, the present invention relates to compounds of structural formula D (However, in the formula, Z is galacturonic acid, aspartic acid, gluconic acid or glutamic acid)
In a second sub-category relating to compounds, the present invention relates to compounds having the structural formula E (where Z is galacturonic acid, aspartic acid, gluconic acid or glutamic acid). In a first specific aspect relating to compounds, the invention provides 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,
8-naphthyridine-3-carboxylic acid galacturonate. In a second specific aspect regarding compounds, the invention provides 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,
8-naphthyridine-3-carboxylic acid aspartate. In a third specific aspect relating to compounds, the invention provides 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,
8-naphthyridine-3-carboxylic acid gluconate. In a fourth specific aspect regarding compounds, the present invention provides 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,
8-naphthyridine-3-carboxylic acid glutamate. In a fifth specific aspect relating to compounds, the invention provides 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-
Located in quinoline carboxylic acid galacturonate. In a sixth specific aspect relating to compounds, the invention provides 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-
Located in quinoline carboxylic acid aspartate. In a seventh specific aspect relating to compounds, the invention provides 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-
Found in quinoline carboxylic acid gluconate. In an eighth specific aspect relating to compounds, the invention provides 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-
Located in quinoline carboxylic acid glutamate. In general aspects relating to pharmaceutical compositions, the present invention provides a compound of structural formula C in combination with a pharmaceutically acceptable carrier. wherein X is N or CH and Z is galacturonic acid, aspartic acid, gluconic acid, or glutamic acid. In a first sub-subsection relating to pharmaceutical compositions, the present invention provides compounds of structural formula D in combination with a pharmaceutically acceptable carrier. (However, in the formula, Z is galacturonic acid, aspartic acid, gluconic acid or glutamic acid)
An antibacterial pharmaceutical composition comprising a compound having the following properties: In a second subsection relating to pharmaceutical compositions, the present invention provides compounds of structural formula E in combination with a pharmaceutically acceptable carrier. (However, in the formula, Z is galacturonic acid, aspartic acid, gluconic acid or glutamic acid)
An antibacterial pharmaceutical composition comprising a compound having the following properties: In a third sub-paragraph relating to pharmaceutical compositions, the present invention provides compounds of structural formula C in combination with a pharmaceutically acceptable carrier. wherein X is N or CH and Z is galacturonic acid, aspartic acid, gluconic acid or glutamic acid. In a general aspect relating to pharmaceutical methods, the present invention relates to a compound of structural formula C (wherein X is N or CH and Z is galacturonic acid, aspartic acid, gluconic acid or glutamic acid) to a mammal such as: , a method for treating a mammal suffering from a bacterial infection. In a first subsection relating to pharmaceutical methods, the present invention provides compounds of structural formula C in combination with a pharmaceutically acceptable carrier. (wherein X is N or CH and Z is galacturonic acid, aspartic acid, gluconic acid or glutamic acid) in a mammal such as: A method of treating a mammal suffering from a bacterial infection, the method comprising administering to a mammal a bacterial infection. In a second sub-subsection relating to pharmaceutical methods, the present invention provides compounds of structural formula C in combination with a pharmaceutically acceptable parenteral carrier. (wherein X is N or CH and Z is galacturonic acid, aspartic acid, gluconic acid or glutamic acid) in a mammal such as: A method for parenterally treating a mammal suffering from a bacterial infection, the method comprising administering parenterally to a mammal suffering from a bacterial infection. In terms of chemical methods, the present invention relates to structural formula (wherein X is defined below) with an acid of formula Z as defined below. wherein X is N or CH and Z is galacturonic acid, aspartic acid, gluconic acid or glutamic acid. Compound A i.e. 1-ethyl-6-fluoro-
1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid was prepared as described in U.S. Pat. No. 4,146,719.
Alternatively, they can be produced by obvious modifications of the methods described therein. Compound B i.e. 1-ethyl-6-fluoro-
1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid as described in European Patent Application No. 9425 or as described therein. It can be produced by obvious modifications of the method described above. Compounds A and B are converted into their corresponding acid addition salts by treatment with organic and inorganic acids in known manner. For example, compounds A and B can be treated in solution or suspension with the desired acids in the same or different solvents. Suitable solvents or solvent mixtures can be readily selected by those skilled in the art, and the preferred solvent of the present invention is water. When preparing the salt in water, a suspension of compound A or B in water is stirred with the selected acid dissolved or suspended in the water. The mixture can be briefly warmed to increase solvent content and aid salt formation. For example, the suspension can be heated to about 60°C and then returned to room temperature with stirring.
When producing gluconate salts, it has been found to be particularly convenient to produce gluconic acid in situ from gluconate delta-lactone. For example, delta lactone gluconate is compound A.
Or add to the aqueous suspension of B and stir at room temperature for about 20 hours. Brief heating of this mixture to about 60°C will reduce the time required for complete salt formation to about 3 hours. Modifications to this method to optimize salt formation are readily available to those skilled in the art. Compounds A and B can be mixed with approximately equimolar amounts of salt-forming reagent, or an excess of salt-forming reagent can be used if desired. Salts can be recovered by standard methods such as lyophilization. The salt can then be purified by recrystallization if desired. As used herein, "galacturonic acid", "galacturonate", "aspartic acid",
The terms "aspartate", "glutamate", "glutamate", "gucconate", "gluconate" and "delta-lactone gluconate" include the respective isomers of those reagents as well as their respective isomers. A mixture of bodies shall be included. The invention therefore contemplates, for example, the use of D, L and DL mixtures of the abovementioned salt-forming reagents. Preferred forms are the naturally occurring forms (L form for amino acids and D form for gluconic acid, delta lactone gluconate and galacturonic acid). The compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. The solvated forms, generally with pharmaceutically acceptable solvents such as water, ethanol, etc., are equivalent to the unsolvated forms for purposes of this invention. Preferred salts of compounds A and B for purposes of this invention are the pharmaceutically acceptable salts and are the galacturonate, aspartate, glutamate and gluconate salts. Gluconate is the most preferred salt and is particularly preferred when prepared from D-gluconic acid generated in situ from D-gluconate delta-lactone. In research on a number of pharmaceutically acceptable acid and base addition salts prepared from Compounds A and B, the preferred salts described above, particularly the gluconate salts, have been found to be useful parenteral dosage forms containing Compounds A and B. It was recognized that it has the characteristics necessary for manufacturing. The utility of these special salts for preparing parenteral dosage forms from compounds A and B was surprising and could not have been predicted from the prior art. For example, one skilled in the art would have appreciated that useful parenteral dosage forms containing Compounds A and B could be prepared from the acid addition salts disclosed in the prior art literature. Surprisingly, this is not the case, and particularly surprisingly in the case of the present invention, the use of the common hydrochloride salt for preparing parenteral dosage forms from both compounds A and B is Excluded. The table below provides a collection of solubility and PH data that identifies the majority of pharmaceutically acceptable salts prepared from Compounds A and B that contain these compounds. This indicates that it cannot be used to manufacture oral dosage forms.

【table】

[Table] The data listed in the table were obtained by the following solubility screening test procedure. Calculated amount of Compound A for the chosen concentration
Alternatively, weigh Compound B into a volumetric flask. Equimolar amounts of the acid, amino acid or base to be coupled are added either as a solution or by dry weight. Deionized water is added up to volume to achieve the pre-selected concentration. All flasks are sonicated for 15 minutes, left at room temperature for 30 minutes, and then passed through a fine glass filter. After measuring the pH of the liquid, dilute it appropriately with 0.1N hydrochloric acid to obtain an appropriate concentration for measuring the ultraviolet absorption spectrum. Standard IV (for intravenous administration) 10-fold dilution of the initial solution
Make a solution. The appearance of these dilutions is observed for precipitate formation (results of dilution experiments are given in the table below). Initial experiments in solubility screening were performed to prepare solutions containing Compound A or B at a final concentration of approximately 25 mg/ml. Those acids or bases that did not solubilize sufficient material to reach this concentration are not considered useful. The acid or base determined to be useful is then used to produce a solution containing at least 150 mg/ml of Compound A or B. Additionally, these more concentrated solutions having a PH of about 4 to about 8 are believed to have successfully passed this screening test. The unexpected characteristics of the salts prepared from compounds A and B are evident in view of the results reported in the table. These characteristics are considered with respect to the necessary conditions (a-f) outlined above to produce useful parenteral dosage forms. For example, the hydrochloride of compound A has adequate solubility but an unusable PH, whereas the hydrochloride of compound B not only has inadequate solubility but also has an unusable PH. have. The methanesulfonate and isethionate salts of compounds A and B have good solubility but are unsatisfactory with respect to PH. The same is true for both salts prepared from L-cysteic acid. Although the acetate salts of both Compounds A and B are considered useful, they cannot be successfully lyophilized and thus have limited utility. Based on the data in the table, these lactate salts are considered useful. However, lactic acid cannot be consistently obtained in currently available commercial forms and in satisfactory grades and is therefore not useful. The choline and sodium salts are excluded based on the PH of their respective solutions. Useful salts have therefore been found to be galacturonate, aspartate, glutamate and gluconate. The table further corroborates the results of the table, but is presented with a focus on the use of selected lyophilized and crystallized salts.

Tables and Tables relate to salts in solution for standard intravenous administration.

【table】

【table】

【table】

[Table] The compounds of the present invention include Staphylococcus, Streptococcus, Haemophilus, Neisseria, Clostridium, Enterobacter, Escherichia, It is useful in treating diseases caused by microorganisms of the genera Klebsiella, Proteus, Providencia, Pseudomonas and Serratia. Although the salts of the invention can be administered orally, it is preferred that they are administered parenterally;
The dosage is then adjusted according to the needs and tolerance of the individual patient. Of the various parenteral routes, the intravenous route is most preferred. The usual dosage range for a 70Kg patient is about 70mg per day to about
Up to 21g (1mg to 300mg per kg of body weight per day)
and preferably 210mg to 6.3g (1
3 mg to 90 mg per kg body weight per day), optionally administered in divided doses. It is demonstrated in the following table that the compounds of the invention have antibacterial activity both in vitro and in vivo when tested using standard methods.

[Table] A 〓0.1 0.1
0.2 〓0.1
Asparagus 0.1 〓0.1
0.2 〓0.1
Ginate Glutami 〓0.1 〓0.1
0.1 0.1
Gluconate salt 0.2 〓0.1
0.2 〓0.1
acid salt

Galact 0.1 〓0.1
0.1 〓0.1
uronic acid
salt

[Table] Asparagus 〓0.1
0.8 〓0.1
Ginate Glutami 0.1
1.6 〓0.1
Gluconate salt 0.2
1.6 0.2
Acid acid galacto 0.1
0.8 〓0.1
uronic acid salt

[Table] Acid acid
Galact 1.6
1.6 0.8
uronic acid salt
a Based on the content of compound A.

[Table] Asparagus 0.2 〓0.1
0.1 〓0.1
Ginate Glutami 0.2 〓0.1
0.2 0.1
Gluconate salt 0.4 0.1
0.2 0.2
acid salt

[Table] Glutami 0.2
1.6 〓0.1
phosphate
Glucon 0.8
1.6 0.4
acid salt

[Table] Phosphate
Glucon 3.1
3.1 3.1
acid salt
a Based on the content of compound B.

【table】

【table】

【table】

[Method A]

1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8
-Naphthyridine-3-carboxylic acid sesquihydrate
A suspension of 1.39 g (4 mmol), 712 mg (4 mmol) of D-gluconate δ-lactone and 30 ml of water is stirred at room temperature for 2 hours. The suspension at 55-60℃
Warm briefly to and continue stirring at room temperature for 1 hour. Insoluble material is removed and the liquid is lyophilized. The solid content was dissolved in 4 ml of water and 24 ml of absolute ethanol.
Crystallize from ml solution. The crystals are filtered, washed with absolute ethanol and ether, and dried to yield 1.08 g of product (mp 165-167°C (decomposed)). [α] ²³ _D +4.8° (c2, water). Analysis shows that the sample contains 0.7 moles of water per mole of compound. [Method B] 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8
-Naphthyridine-3-carboxylic acid sesquihydrate
A suspension of 2.78 g (8 mmol), 1.21 ml (2.8 mmol) of a 2.34N commercial D-gluconic acid solution and 60 ml of water is stirred at room temperature. After 12 hours, addition of 2.7 ml (6.3 mmol) of a commercial solution of D-gluconic acid in water gives a yellow solution within 5 minutes. The solution is clarified and the liquid is lyophilized. Dissolve the solids in approximately 10 ml of water and 40 ml of absolute ethanol.
Crystallize from ml solution. The crystals were stirred at room temperature for 4 hours, filtered, washed with absolute ethanol and ether, and dried to yield 3.97 g [m.
p.164-165° (decomposition)] is obtained. [α] ²³ _D +4.9°
(c2, water). The sample contains approximately 1 mol of water per mole of compound.
Analysis shows that it contains mol. Example 7 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-
Quinolinecarboxylic acid D-gluconate [Method A] 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid monohydrate 2.7g ( 8 mmol), 1.43 g (8 mmol) of D-gluconic acid δ-lactone and 60 ml of water are stirred at room temperature for 19.5 hours. The solution is clarified by filtration and the liquid is lyophilized. The solid is crystallized from a solution of approximately 10 ml of water and 50 ml of absolute ethanol.
The crystals were filtered, washed with absolute ethanol and ether, and dried to yield 3.56 g [m.
p.171-172℃ (decomposition)] is obtained. [α] ²³ _D +5.1°
(c2, water). The sample contains 0.1 water per mole of compound.
Analysis shows that it contains mol and is slightly hygroscopic. [Method B] 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid monohydrate 0.98 g (2.9 mmol), 1.17 ND- in water 2.48 ml (2.9 mmol) gluconic acid (obtained by diluting the commercial solution)
and 20 ml of water are stirred at room temperature for 2 hours.
The yellow solution is clarified by filtration and the liquid is lyophilized. The solid is crystallized from a solution of about 4 ml of water and 17 ml of absolute ethanol. The crystals are filtered, washed with absolute ethanol and ether, and dried to give 1.35 g of product (mp 165-168° (decomposed)) as crystals. [α] ²³ _D +5.7° (c2,
water). Analysis shows that the sample contains approximately 0.2 moles of water per mole of compound. D-gluconate salts made from commercial gluconic acid solutions (see Examples 6B and 7B) were found to have lower decomposition points than the corresponding salts made using D-gluconate delta-lactone. It was done. Gluconate salts made from commercial D-gluconate solutions are also more deeply colored (resulting in darker solutions) than the corresponding salts made using D-gluconate delta-lactone. Therefore, the production of gluconate using delta lactone D-gluconate is the preferred method of the present invention. Example 8 Lyophilized injectable formulation 22.6 g of compound B as sesquihydrate, 23.2 g of D-gluconate δ-lactone are added to 250 ml of water for injection, briefly heated to 55° C. and stirred for 3 hours. At the same time, cool to room temperature. The resulting solution is filtered through a 0.2 μ strainer, 4.8-5.2 ml of solution is filled into sterile vials, and lyophilized. Approximately 50 vials are obtained, each containing approximately 645 mg of Compound D as the gluconate salt and approximately 245 mg of excess gluconic acid. In addition to 22.6 g of compound B as a sesquihydrate, 12.2 g of D-gluconate δ-lactone and 250 ml of water for injection,
Heat briefly to 55° and stir for 3 hours while cooling to room temperature. The resulting solution is filtered through a 0.2 μ strainer, 4.8-5.2 ml of solution is filled into sterile vials, and lyophilized. Approximately 50 vials are obtained, each containing approximately 645 mg of Compound D as the gluconate salt. Add 21.9 g of compound A as a monohydrate and 23.2 g of D-gluconate δ-lactone to 250 ml of water for injection.
Briefly heat to 55° C. and stir for 3 hours while returning to room temperature. The resulting solution is filtered through a 0.2 μ strainer, 4.8-5.2 ml of solution is filled into sterile vials, and lyophilized. Approximately 50 vials are obtained, each containing approximately 645 mg of Compound E as the gluconate salt and approximately 245 mg of excess gluconic acid. Add 21.9 g of compound A as a monohydrate and 23.2 g of D-gluconate δ-lactone to 250 ml of water for injection.
Briefly heat to 55°C and stir for about 3 hours, after which time the temperature returns to room temperature. The resulting solution is filtered through a 0.2 μ strainer, 4.8-5.2 ml of solution is filled into sterile vials, and lyophilized. Approximately 50 vials are obtained, each containing approximately 645 mg of Compound E as the gluconate salt. Example 9 Injection Solution A solution is prepared as described in Example 8 from 22.6 g of Compound B sesquihydrate and 23.2 g of D-gluconate delta-lactone in 250 ml of water for injection. Pour approximately 5 ml of the resulting solution into 50 sterile ampoules.
Fill each book and seal. A solution is prepared as described in Example 8 from 21.9 g of Compound A monohydrate, 23.2 g of D-gluconate delta lactone in 250 ml of water for injection. Approximately 5 ml of the resulting solution is filled into 50 sterile ampoules each and sealed. Example 10 Capsules [Compound D as gluconate 100 mg, 250 mg,
or capsules containing 500 mg] Compound D (as gluconate) 500 g Lactose (United States Pharmacopoeia, anhydrous) Adequate amount or 200 g Stelotex powder HM 5 g Compound D as gluconate and lactose in twin powders with a strong stirring bar Mix in a shell mixer. Mix by rolling for 2 minutes, then stir with a strong stirring rod.
Mix for 1 minute, then tumble again for 1 minute. Next, a part of the mixture is mixed with Stelotesque powder,
Pass through a #30 sieve and add to the rest of the mixture. Then mix the mixed ingredients for 1 minute,
Mix with a strong stir bar for 30 seconds and tumble for an additional minute. Mixture into capsules of appropriate size
Filling 141 mg, 352.5 mg or 705 mg yields capsules containing 100 mg, 250 mg and 500 mg, respectively. [Capsules containing 100 mg, 250 mg or 500 mg of Compound E as gluconate] Compound E (as gluconate) 500 g Lactose (United States Pharmacopoeia, anhydrous) as appropriate or 200 g Stelotex powder HM 5 g Mix as above, and 100mg when filled,
Capsules containing 250mg and 500mg are produced. Example 11 Tablet [Tablet containing 100 mg, 250 mg or 500 mg of Compound D as gluconate] Compound D (as gluconate) 500 g Corn starch NF 200.0 g Microcrystalline cellulose 46.0 g Stelotex powder HM 4.0 g Purified water Add appropriate amount or 300.0 ml corn starch, cellulose and Compound D as gluconate together to a planetary mixer and mix for 2 minutes. Add water to this mixture and mix for 1 minute. The resulting mixture is spread on a tray and dried in a hot air oven at 50° C. until the moisture level is 1-2%. This dry mixture is then poured into a Fitzmill.
Grind and pass through #RH2B sieve at medium speed.
The steroidex powder is added to the grinding mixture and the whole is mixed by drum rotation for 5 minutes. 150 each of the total mixture using a suitably sized punch
Compressed tablets of 100 mg, 250 mg or
Contains 500mg of active ingredient. Tablets are prepared from Compound E as the gluconate salt in a similar manner. Example 12 Suppositories Compound as gluconate per 3g suppositories
Suppositories containing 250 mg, 500 mg or 1000 mg of D were formulated as follows. Compound D (as gluconate)
250mg 500mg 1000mg Polyethylene glycol 1540
1925mg 1750mg 1400mg Polyethylene glycol 8000
825mg 750mg 600mg Polyethylene glycol 1540 and polyethylene glycol 8000 are melted together at 60°C and compound D as the gluconate salt is dissolved in the melt. The whole is placed in a mold at 25°C to produce a suitable suppository.

Claims (1)

[Claims] 1 Structural formula C wherein X is N or CH and Z is galacturonic acid, aspartic acid, gluconic acid, or glutamic acid. 2 Structural formula D (However, in the formula, Z is galacturonic acid, aspartic acid, gluconic acid or glutamic acid)
A compound according to claim 1 having the following. 3 Structural formula E (However, in the formula, Z is galacturonic acid, aspartic acid, gluconic acid or glutamic acid)
A compound according to claim 1 having the following. 4 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,
The compound according to claim 1, which is 8-naphthyridine-3-carboxylic acid galacturonate. 5 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,
The compound according to claim 1, which is 8-naphthyridine-3-carboxylic acid aspartate. 6 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,
The compound according to claim 1, which is 8-naphthyridine-3-carboxylic acid gluconate. 7 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,
The compound according to claim 1, which is 8-naphthyridine-3-carboxylic acid glutamate. 8 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-
The compound according to claim 1, which is quinolinecarboxylic acid galacturonate. 9 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-
The compound according to claim 1, which is quinolinecarboxylic acid aspartate. 10 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3
- The compound according to claim 1, which is quinoline carboxylic acid gluconate. 11 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3
- The compound according to claim 1, which is quinolinecarboxylic acid glutamate. 12 Structural formula C wherein X is N or CH and Z is galacturonic acid, aspartic acid, gluconic acid, or glutamic acid. 13. The pharmaceutical composition according to claim 12, which is combined with a pharmaceutically acceptable carrier. 14 Structural formula D in combination with a pharmaceutically acceptable carrier (However, in the formula, Z is galacturonic acid, aspartic acid, gluconic acid or glutamic acid)
Claim 13 containing a compound having
Antibacterial pharmaceutical compositions as described in Section. 15 Structural formula E in combination with a pharmaceutically acceptable carrier (However, in the formula, Z is galacturonic acid, aspartic acid, gluconic acid or glutamic acid)
Claim 13 containing a compound having
Antibacterial pharmaceutical compositions as described in Section. 16. A pharmaceutical composition according to claim 12 for parenteral use. 17 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-
The pharmaceutical composition according to claim 12, containing 1,8-naphthyridine-3-carboxylic acid gluconate. 18. A pharmaceutical composition according to claim 17 for parenteral use. 19 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3
- The pharmaceutical composition according to claim 12, containing quinoline carboxylic acid gluconate. 20. A pharmaceutical composition according to claim 19 for parenteral use. 21 Structural formula (wherein X is as defined below) with an acid of formula Z as defined below. (wherein X is N or CH and Z is galacturonic acid, aspartic acid, gluconic acid or glutamic acid).