WO1994026110A1

WO1994026110A1 - Stable quinolone and naphthyridine premix formulations

Info

Publication number: WO1994026110A1
Application number: PCT/US1994/005316
Authority: WO
Inventors: Pramod K. Gupta; Laman A. Al-Razzak; Patricia L. Ludwig; Nishith V. Gandhi
Original assignee: Abbott Laboratories
Priority date: 1993-05-15
Filing date: 1994-05-13
Publication date: 1994-11-24
Also published as: AU6832394A; ZA943317B; IL109626A0

Abstract

Pharmaceutical compositions suitable for parenteral administration to human or veterinary patients, which comprise (a) a quinolone antimicrobial agent in aqueous solution in a concentration of between about 100 and about 300 mg/ml; (b) a first water-miscible cosolvent (preferably ethanol) in a concentration of between about 10 % and about 15 % by volume; (c) an optional second water-miscible cosolvent (preferably proplylene glycol) in a concentration of between about 25 % and about 40 % by volume; and (d) a pH-adjusting agent in a concentration sufficient to result in a composition pH of between about 9.5 and about 11.5.

Description

STABLE OUTNOLONE AND NAPHTHYRIDINE PREMIX FORMULATIONS

Field of the Invention

The present invention relates to pharmaceutical compositions, comprising quinolone- and/or naphthyridine-type antibacterial agents, which are suitable for parenteral administration to humans and animals. More particularly, the invention relates to injectable aqueous formulations of such agents, stable at high concentration, which comprise one or more cosolvents and are adjusted to a high pH.

Background of the Invention

Quinolone- and naphthyridine-3-carboxylic acid compounds (e.g., temafloxacin, ciprofloxacin, sarafloxacin and difloxacin), as well as related fused-ring compounds such as benzoxazine-6-carboxylic acids (e.g., ofloxacin) and quinobenzoxazine-, quinobenzothiazine- and pyridoacridine-5-carboxylic acids (e.g., those disclosed in WTPO International Publication No. WO 92/03136, published March

5, 1992), have been shown to be potent antimicrobial and antineoplastic agents. However, these compounds frequently have a limited solubility in water and even in parenterally acceptable cosolvent systems, where a solvent other than water is added. Stable solutions having concentrations high enough for direct use in intramuscular (IM) adminstration, or as premixes for dilution and use in intravenous (TV) adminstration, have not been described.

Consequently, in order to provide IV formulations of the above compounds (hereinafter collectively referred to as "quinolones"), approaches such as lyophilization and reconstitution have been used. These, however, sometimes result in solutions having unacceptably high counts of subvisible particle counts. Other difficulties encountered with IV preparations of quinolones include the need for counterions to improve solubility, and the occurrance of hemolysis or of veinous irritation at the site of infusion. As for IM preparations, which require greatly higher concentrations than IV formulations due to the relatively low volumes administered (ideally, less than 10 ml), suspensions of quinolones have been attempted. These, however, may provide insufficient bioavailabilty of the quinolone.

Accordingly, one object of the invention is to provide pharmaceutical compositions of quinolones having sufficiently high concentration for IM use, which also have improved long-term physical stability in solution. Another object of the present invention is to provide compositions of quinolones which, when diluted for IV use, have allowable subvisible particle counts and acceptable levels of hemolysis and veinous irritation.

Summary of the Invention

These objects are attained by the present invention, in one aspect of which are disclosed pharmaceutical compositions comprising a therapeutically effective amount of a quinolone antimicrobial agent in aqueous solution and a water-miscible cosolvent, adjusted to an alkaline pH. The adjustment of pH in these and other compositions of the invention is accomplished by the addition of a suitable amount of pH-adjusting agent such as potassium or sodium hydroxide. The cosolvent, which preferably is present in a concentration of greater than about 10% by volume (v/v), may be chosen from among ethanol, glycerol, propylene glycol and polyethylene glycol (PEG), including PEG 200, 300 and 400. The pH of these compositions is preferably greater than about 10 and, even more preferably, greater than about 10.5. In this manner, quinolone concentrations of greater than about 50, 100 or even 150 mg/ml may be maintained in stable solution for thirty days or longer, when kept at room temperature.

In a second aspect of the present invention are disclosed pharmaceutical compositions similar to those described above, but additionally comprising a second water-miscible cosolvent. Again, the second cosolvent may be ethanol, glycerol, propylene glycol or polyethylene glycol, and, ideally, one of the first and second cosolvents is present in a concentration of greater than about 10% by volume. Preferably, the pH of these compositions are greater than about 9.5 or, more preferably, greater than about 10. As before, quinolone solutions are formed which have quinolone concentrations of greater than about 50, 100 or 150 mg/ml and which remain physically stable for at least thirty days at room temperature.

In a further aspect of the present invention, pharmaceutical compositions are disclosed which comprise:

(a) a quinolone antimicrobial agent in aqueous solution in a concentration of between about 100 and about 300 mg/ml;

(b) a first water-miscible cosolvent in a concentration of between about 10% and about 15% by volume;

(c) a second water-miscible cosolvent in a concentration of between about 25% and about 40% by volume; and (d) a pH-adjusting agent in a concentration sufficient to result in a composition pH of between about 9.5 and about 1 1.5. Preferably, the pH-adjusting agent in the above compositions is present in a concentration sufficient to result in a composition pH of between about 10 and about 1 1. Also preferred are those compositions in which the first cosolvent is ethanol and the second cosolvent is propylene glycol .

Detailed Description of the Invention

The compositions of the present invention may be prepared via a number of alternative methods. In a first such method, the quinolone (in base or pharmaceutically acceptable salt form) is weighed into a suitable container and sufficient potassium or sodium hydroxide (e.g., 5-10 N) is added to provide about 1.8 to about 3.0 mEq. alkali per mEq. drug. After stirring, desired volumes of one or more cosolvents and water are added. Finally the apparent pH of the solution is adjusted with aqueous KOH or NaOH. Alternatively, the water, cosolvents and alkali may be placed in a container first and mixed; the quinolone is then added and stirred until the drug is dissolved, and the apparent pH is adjusted as before.

The compositions of the present invention are intended for parenteral administration, either directly or after dilution, to human or veterinary patients. It is anticipated that the compositions will be especially useful in the treatment of commercial livestock, as for example cattle, horses, sheep, pigs and other mammals as well as fowl such as chickens and turkeys.

The term "parenteral" as used herein refers to modes of administration other than oral (via the gastrointestinal tract) which include intravenous (TV), intramuscular (IM), intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion. For IV use (that is, when the compositions are used as a "premix"), the compositions are first diluted with a suitable diluent such as 5% dextrose in water or, more preferably, normal saline. When given IM, the compositions may be used directly. It is also anticipated that prolonged IM absorption of the compositions may be achieved by the inclusion of agents which delay absorption, such as aluminum monostearate and gelatin. Other excipients not mentioned above may be used in conjunction with the compositions of the invention. These include coating materials such as lecithin which serve to maintain proper fluidity, and surfactants/cosolubilizers such as egg phosphatide, polyoxyethylenesorbitan (e.g., TWEEN or similar), and Pluronic F-68. The compositions of the present invention may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, as for example paraben, chlorobutanol, phenol sorbic acid and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride and the like.

When the above compositions are administered, the composition volume and quinolone concentration are chosen so that a therapeutically effective amount of the drug is delivered. By "therapeutically effective amount" is meant a sufficient amount of the compound to treat microbial infection or neoplastic disease, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of such compounds and of the compositions of the present invention will be decided by the attending physician or veterinarian within the scope of sound medical or veterinary judgement The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical and veterinary arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.

The compounds, processes and uses of the present invention will be better understood in connection with the following examples, which are intended as an illustration of and not a limitation upon the scope of the invention. Where applicable either below or elsewhere in the specification, it is intended that citations to the literature are expressly incorporated by reference.

Example 1 Preparation of IM Formulations

High-concentration compositions of the present invention were prepared using temafloxacin base or hydrochloride salt. In each instance, 1 to 3 grams of temafloxacin were weighed into a glass scintillation vial and sufficient 5 or IO N KOH or NaOH was added to provide about 1.8 to 3.0 mEq. alkali per mEq. drug. After stirring the contents, desired amounts of ethanol, propylene glycol or polyethylene glycol 400, and water, were added to a final volume of about 10 ml. After further stirring, the apparent pH of the solutions was adjusted with aqueous KOH or NaOH to produce the samples described below. Initially, all samples were stored in the dark,at room temperature, in air-tight containers

Example 2 Physical Stability of IM Formulations

Certain of the above samples, prepared at 284 mg/ml concentration, were kept in disposable glass scintillation vials, in the dark and at either room temperature (RT) or

5°C, for extended periods of time and monitored for precipitation as indicated by clarity or haziness of the solution. The results, shown in Table 1 below, demonstrate the stability attainable by the high pH, cosolvent-containing compositions of the present invention.

Table 1

Stability of 284 me/ml Solutions as a Function of pH and Cosolvent or Surfactant Concentration

Propylene Ethanol Surfactant Time to Precipitate (Days)

EH Glvcol (% v/v) <% v/v) (% w/v 1° RT

10.16 20.6 10.3 0 0.08 0.08

9.22 20.6 20.6 0 1 1

9.49 20.6 20.6 0 2 2

10.51 20.6 20.6 0 4 >100

12.54 20.6 20.6 0 12 >100

10.22 20.6 20.6 0.5⁽a⁾ 7 67

9.74 20.6 20.6 1(a) 7 12

12.95 25.8 0 0 1 1

10.18 25.8 10.3 0 4 67

10.50 25.8 15.5 0 28 >100

9.60 25.8 15.5 1(b) 13 45

10.13 25.8 15.5 1(b) 9 61

9.83 30.9 0 0 1 1.5

10.09 30.9 10.3 0 4 >100

10.98 30.9 10.3 0 4 >100

1 1.28 30.9 10.3 0 4 >100

10.20 30.9 10.3 0.5⁽a⁾ 7 61

9.89 30.9 10.3 1(a) 6 13

10.32 30.9 10.3 1(a) 3 69

9.83 30.9 10.3 1(b) 7 6

10.23 30.9 10.3 1(b) 23 94

10.63 30.9 10.3 1(b) 12 >100

9.27 41.2 0 0 1 1

10.21 41.2 0 0 1 3

10.31 41.2 0 0 7 74

9.88 41.2 10.3 0 66 73

10.33 41.2 10.3 0 >125 >125

10.93 41.2 10.3 0 64 >125

9.68 51.5 0 0 8 4

10.33 51.5 0 0 37 94

12.77 51.5 0 0 78 78 Example 3 Physical Stability of IM Formulations at High Temperature

Selected formulations were stored at 90°C for seven weeks to simulate the effect of storage for two years at room temperature. One sample was 170 mg/ml temafloxacin, 41.2% v/v propylene glycol and 10.3% v/v ethanol at pH 10.4, and the other was 150 mg/ml temafloxacin, 35% v/v propylene glycol and 15% v/v ethanol at pH 10.5. At the start and end of the test period, drug potency was tested using HPLC methodology. When compared, no detectable degradation of drug was observed.

Example 4 Subvisible Particle Counts After Dilution to IV Formulation

Selected formulations were also diluted to concentrations suitable for use as IV compositions and tested for subvisible particle count In one case, a sample IM formulation of 300 mg/ml temafloxacin, 41.2% v/v propylene glycol and 10.3% v/v ethanol at pH 10.4 was diluted to 6 mg/ml and 8 mg/ml concentrations with normal saline, placed in a 100 ml partial fill glass bottle, stoppered and subjected to 25 inversions over a 10 second period. Samples were then stored at either room temperature or at 5°C before testing using a HAIC/ROYCO Model 3000 particle sizer at

10 minutes, 50 minutes, and 2, 4 and 8 hours.

The results obtained demonstrate the usefulness of the compositions of the present invention in minimizing subvisible particle counts. For all samples, counts were within acceptable BP, EP and USP limits.

Example 5 In Vitro and In Vivo Testing of IM and IV Compositions

The temafloxacin-containing compositions of the present invention were tested for bioavailability. Based on area-under-curve studies carried out in dogs, the bioavailability of a 300 mg/ml IM forumulation is substantially better than that of a suspension of similar concentration, given EM.

The compositions were also tested to determine their physiological compatibility. IM formulations were tested using the following models: (a) the amount of in vitro hemolysis produced upon mixing with whole blood; (b) a rat paw lick model, in which subplantar injection were made into the footpads of weanling rats, and licking of the injection site was used to determine pain at the injection site; and (c) the increase of creatinine phosphokinase level produced in dogs upon administration. IV formulations were tested by different models: (a) in vitro hemolysis, and (b) a rat vein irritation model, in which discoloration of rat tails was observed following infusion of samples into the tail vain.

In general, results were obtained showing compatibilities comparable to those of known commercial cosolvent-containing drug formulations, and comparing favorably to lyophilized premix formulations.

It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to active agents and formulary adjuvants useful in connection with the invention, may be made without departing from the spirit and scope thereof.

Claims

What is claimed is:

1. A pharmaceutical composition comprising a therapeutically effective amount of a quinolone antimicrobial agent in aqueous solution at alkaline pH and a water-miscible cosolvent.

2. A pharmaceutical composition according to Claim 1 wherein the cosolvent is selected from the group consisting of ethanol, glycerol, propylene glycol and polyethylene glycol and is present in a concentration of greater than 10% by volume.

3. A pharmaceutical composition according to Claim 2 wherein the pH is greater than 10.

4. A pharmaceutical composition according to Claim 2 wherein the pH is greater than 10.5.

5. A pharmaceutical composition according to Claim 2 wherein the quinolone antimicrobial agent is present in a concentration of greater than 50 mg/ml and the pH is adjusted such that the composition remains physically stable for at least thirty days at room temperature.

6. A pharmaceutical composition according to Claim 5 wherein the quinolone antimicrobial agent is present in a concentration of greater than 100 mg/ml.

7. A pharmaceutical composition according to Claim 5 wherein the quinolone antimicrobial agent is present in a concentration of greater than 150 mg/ml.

8. A pharmaceutical composition according to Claim 1 additionally comprising a second water-miscible cosolvent.

9. A pharmaceutical composition according to Claim 8 wherein the first and second cosolvents are independently selected from the group consisting of ethanol, glycerol, propylene glycol and polyethylene glycol, and at least one cosolvent is present in a concentration of greater than 10% by volume.

10. A pharmaceutical composition according to Claim 9 wherein the pH is greater than 9.5.

1 1. A pharmaceutical composition according to Claim 9 wherein the pH is greater than 10.

12. A pharmaceutical composition according to Claim 9 wherein the quinolone antimicrobial agent is present in a concentration of greater than 50 mg/ml and the pH is adjusted such that the composition remains physically stable for at least thirty days at room temperature.

13. A pharmaceutical composition according to Claim 12 wherein the quinolone antimicrobial agent is present in a concentration of greater than 100 mg/ml.

14. A pharmaceutical composition according to Claim 12 wherein the quinolone antimicrobial agent is present in a concentration of greater than 150 mg/ml.

15. A pharmaceutical composition comprising:

(a) a quinolone antimicrobial agent in aqueous solution in a concentration of between 100 and 300 mg/ml;

(b) a first water-miscible cosolvent in a concentration of between 10% and 15% by volume;

(c) a second water-miscible cosolvent in a concentration of between 25% and 40% by volume; and

(d) a pH-adjusting agent in a concentration sufficient to result in a composition pH of between 9.5 and 11.5.

16. A pharmaceutical composition according to Claim 15 wherein the pH- adjusting agent is present in a concentration sufficient to result in a composition pH of between 10 and 11.

17. A pharmaceutical composition according to Claim 16 wherein the first cosolvent is ethanol and the second cosolvent is propylene glycol.