REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No. 17/405,772, filed Aug. 18, 2021, which is a continuation of U.S. patent application Ser. No. 16/425,580, filed May 29, 2019, which is a continuation of U.S. patent application Ser. No. 15/042,886, filed Feb. 12, 2016, which is a continuation of U.S. patent application Ser. No. 13/105,513, filed May 11, 2011, which is a continuation of International Application No. PCT/US2009/064220, filed Nov. 12, 2009, which claims the benefit U.S. Provisional Application No. 61/199,253, filed Nov. 15, 2008, the entire disclosures of each of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical compositions comprising a quinolone carboxylic acid derivative antimicrobial compound and a cyclodextrin. These compositions have improved solubility, stability, and tolerability. These compositions are useful for intravenous administration for treating, preventing, or reducing the risk of infection.

BACKGROUND

An appropriate pharmaceutical carrier system is generally a requirement for the safe and effective delivery of a pharmaceutical drug active. The entire pharmaceutical composition, i.e., the pharmaceutical drug active formulated in a pharmaceutical carrier, can affect the bioavailability and also the pharmacokinetics and pharmacodynamics of the drug active. It is therefore important that a pharmaceutical composition be carefully developed and manufactured to deliver the desired pharmaceutical drug active in a safe and effective manner.

The delivery of antimicrobial agents for treating or preventing microbial infections can present special challenges. To provide therapeutic efficacy, it is generally desired that the antimicrobial agent be administered to the patient to achieve systemic concentrations in the bloodstream or target organs above a minimum inhibitory concentration (MIC) for a sufficient time against the particular microbial organism or organisms being targeted. Consequently, an antimicrobial agent that otherwise exhibits an effective antimicrobial profile in vitro can be ineffective, or even harmful, unless properly formulated for in vivo administration.

The challenge of developing suitable antimicrobial compositions is further complicated for the development of liquid formulations for parenteral administration, such as intravenous administration. Intravenous delivery of a drug active is an important route of administration where the drug cannot be administered orally or by other means, for example where a patient is unconscious, or seriously ill, and cannot otherwise take the drug orally. Although not the case with the pyridine carboxylic acid antimicrobial agents of the present invention, many drugs cannot be delivererd orally because of low oral bioavailability or low oral toleration. The development of suitable compositions for intravenous administration often pose many and often complex challenges including balancing the interplay of, solubility of the drug active, chemical and physical stability of the composition, and toleration of the composition upon infusion. In addition to solubility, stability, and toleration, other considerations include ease of manufacture of the composition, convenience of storing the composition, and ease of reconstitution of the composition, e.g., in the case of compositions which are in the form of dry powders or lyophils designed for reconstitution prior to administration.

Solubility of the pharmaceutical drug active is an important consideration, if not the primary consideration, for a product intended for intravenous administration because without sufficient solubility, the pharmaceutical drug active might not be suitable for intravenous administration. Also, limitations on the volume of an intravenous formulation that can be safely and conveniently administered will further constrain the parameters for developing a practical formulation. If the pharmaceutical drug active cannot be solubilized at a practical level, then it might not even be possible to develop an intravenous formulation of the drug.

Stability of a pharmaceutical composition is another important consideration. A pharmaceutical composition must have sufficient chemical and physical stability such that the potency of the pharmaceutical drug active is maintained above a required level and the integrity of the overall formulation is maintained to enable safe administration. It is important that the formation of potentially harmful degredants and byproducts is minimized.

Tolerability of a pharmaceutical composition is yet another important consideration, because an intravenous formulation should not irritate or damage the blood vessels and surrounding tissue of the patient. Furthermore, the composition should not cause undue venous intoleration or undue discomfort during administration, or alternatively should reduce venous intoleration or discomfort.

A pharmaceutical composition should have sufficient efficacy. A pharmaceutical composition should also have sufficient chemical and physical stability to enable administration to a patient. A pharmaceutical composition should also maintain the potency of the drug active over a useful length of time. Potency of a drug active in a pharmaceutical composition can be maintained, for example, by keeping the concentration or level of the drug active constant, or nearly constant, in the composition over time.

Therefore, the present invention addresses the foregoing and other needs.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a powder X-ray diffraction pattern of crystalline D-glucitol, 1-deoxy-1-(methylamino)-, 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-h-ydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylate (salt).

FIG. 2 shows a powder X-ray diffraction pattern of crystalline D-glucitol, 1-deoxy-1-(methylamino)-, 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-h-ydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylate trihydrate (salt).

SUMMARY OF THE INVENTION

The present invention relates to antimicrobial compositions and more specifically compositions of quinolone carboxylic acid derivatives. The present invention relates to a pharmaceutical composition comprising a quinolone carboxylic acid derivative or a pharmaceutically acceptable salt or ester thereof, and a cyclodextrin selected from the group consisting of an alpha-cyclodextrin, a beta-cyclodextrin, a gamma-cyclodextrin, and mixtures thereof. These compositions have improved solubility of the drug active, improved chemical and physical stability, i.e. improved stability of the drug active and of the overall composition, and improved tolerability for intravenous administration or injection. These compositions are useful for intravenous administration or injection, for treating, preventing, or reducing the risk of infection.

In one aspect, the invention relates to a pharmaceutical composition which prior to mixing comprises (a) a quinolone carboxylic acid derivative or a pharmaceutically acceptable salt or ester thereof, and (b) a cyclodextrin.

In one aspect, the invention relates to a pharmaceutical composition comprising (a) a quinolone carboxylic acid derivative or a pharmaceutically acceptable salt or ester thereof, an (b) a cyclodextrin.

In one aspect, the invention relates to a pharmaceutical composition comprising an inclusion complex, said inclusion complex comprising (a) a quinolone carboxylic acid derivative or a pharmaceutically acceptable salt or ester thereof, and (b) a cyclodextrin.

In one aspect, the invention relates to a pharmaceutical composition comprising (a) an inclusion complex, said inclusion complex further comprising (i) a quinolone carboxylic acid derivative or a pharmaceutically acceptable salt or ester thereof, and (ii) a cyclodextrin; and (b) a chelating agent.

In one aspect, the invention relates to a pharmaceutical composition comprising (that is in the form of) an aqueous solution.

In one aspect, the invention relates to a pharmaceutical composition comprising (that is in the form of) a dry mixture. In one aspect, the invention relates to a pharmaceutical composition wherein said dry mixture is a lyophile. In one aspect, the invention relates to a pharmaceutical composition wherein said dry mixture is made by lyophylization. In one aspect, the invention relates to a pharmaceutical composition wherein said dry mixture or lyophile is reconstituted. In one aspect, the invention relates to a pharmaceutical composition wherein said pharmaceutical composition is diluted.

In one aspect, the invention relates to a pharmaceutical composition wherein said cyclodextrin is selected from the group consisting of alpha-cyclodextrins, beta-cyclodextrins, gamma-cyclodextrins, and mixtures thereof. In one aspect, the invention relates to a pharmaceutical composition said cyclodextrin is selected from the group consisting of beta-cyclodextrins, gamma-cyclodextrins, and mixtures thereof. In one aspect, the invention relates to a pharmaceutical composition wherein said cyclodextrin is a beta-cyclodextrin.

In one aspect, the invention relates to a pharmaceutical composition wherein said cyclodextrin is a beta-cyclodextrin selected from the group consisting of a beta-cyclodextrin ether, a beta-cyclodextrin ester, and mixtures thereof. In one aspect, the invention relates to a pharmaceutical composition wherein said cyclodextrin is a hydroxyalkyl-beta-cyclodextrin. In one aspect, the invention relates to a pharmaceutical composition wherein said hydroxyalkyl-beta-cyclodextrin is a hydroxypropyl-beta-cyclodextrin.

In one aspect, the invention relates to a pharmaceutical composition wherein said cyclodextrin is a beta-cyclodextrin corresponding to the following formula (3) (beta-cyclodextrin)-OR (3) in which the residues R are hydrogen or hydroxyalkyl groups and part of the residues R may optionally be alkyl groups, the beta-cyclodextrin ether having a water-solubility of more than 1.8 g in 100 ml water. In one aspect, the invention relates to a pharmaceutical composition wherein R is selected from the group consisting of hydroxyethyl, hydroxypropyl, dihydroxypropyl, methyl, or ethyl.

In one aspect, the invention relates to a pharmaceutical composition wherein said R group is hydroxypropyl. In one aspect, the invention relates to a pharmaceutical composition wherein said hydroxypropyl beta-cyclodextrin has a molecular substitution per anhydro glucose unit of about 0.86 to about 1.14. In one aspect, the invention relates to a pharmaceutical composition wherein said hydroxyl-propyl beta-cyclodextrin has a molecular substitution per anhydro glucose unit of about 0.59 to about 0.73.

In one aspect, the invention relates to a pharmaceutical composition wherein said hydroxypropyl beta-cyclodextrin corresponds to the CAS Registry Number 128446-35-5.

In one aspect, the invention relates to a pharmaceutical composition wherein said cyclodextrin is a sulfoalkyl ether cyclodextrin derivative of Formula 1

[Image Omitted]

wherein n is 4, 5 or 6;

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈and R₉in Formula 1 are each, independently, O⁻ or a O—(C_2-6alkylene)- SO₃⁻ group, and at least one of R₁and R₂is, independently, said O—(C_2-6alkylene)-SO₃⁻ group; and S₁, S₂, S₃, S₄, S₅, S₆, S₇, S₈and S₉are each, independently, a pharmaceutically acceptable cation, and wherein said composition shows an absence of underivatized cyclodextrin as measured by thin-layer chromatography. In one aspect, R₁, R₂and R₃are each, independently, said O—(C_2-6-alkylene)-SO₃⁻ group. In one aspect, at least one of R₁, R₂and R₃is, independently, a O—(CH₂)_m—SO₃⁻ group, wherein m is 2, 3, 4, 5 or 6. In one aspect, R₁, R₂and R₃are each, independently a O—(CH₂)_m—SO₃⁻ group, wherein m is 3 or 4. In one aspect, R₄, R₆and R₈is, independently, said O—(C_2-6-alkylene)-SO₃⁻ group; and R₅, R₇and R₉are each −O⁻. In one aspect, R₄, R₆and R₈is, independently, said O—(C_2-6-alkylene)-SO₃⁻ group; and R₅, R₇and R₉are each −O⁻. In one aspect, R₄, R₆and R₈are each a —O—(C_2-6-alkylene)-SO₃-group; and R₅, R₇and R₉are each —O⁻. In one aspect, S₁, S₂, S₃, S₄, S₅, S₆, S₇, S₈and S₉are each, independently, H⁺, L⁺, Na⁺, K⁺, Ca⁺², Mg⁺², or ammonium.

In one aspect, the invention relates to a pharmaceutical composition wherein said sulfoalkyl ether cyclodextrin is sulfobutyl ether beta-cyclodextrin. In one aspect, said sulfoalkyl ether beta-cyclodextrin corresponds to the CAS Registry Number 194615-04-8.

In one aspect, the invention relates to a pharmaceutical composition wherein said cyclodextrin is a gamma-cyclodextrin.

In one aspect, the invention relates to a pharmaceutical composition wherein said quinolone carboxylic acid derivative corresponds to the following structure of Formula 2

[Image Omitted]

wherein R¹represents a hydrogen atom or a carboxyl protective group; R²represents a hydroxyl group, a lower alkoxy group, or a substituted or unsubstituted amino group; R³represents a hydrogen atom or a halogen atom; R⁴represents a hydrogen atom or a halogen atom; R⁵represents a halogen atom or an optionally substituted saturated cyclic amino group; R⁶represents a hydrogen atom, a halogen atom, a nitro group, or an optionally protected amino group; X, Y and Z may be the same or different and respectively represent a nitrogen atom, —CH═ or —CR⁷═ (wherein R⁷represents a lower alkyl group, a halogen atom, or a cyano group), with the proviso that at least one of X, Y and Z represent a nitrogen atom, and W represents a nitrogen atom or —CR⁸═ (wherein R⁸represents a hydrogen atom, a halogen atom, or a lower alkyl group); with the proviso that R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, W, X, Y, and Z as defined in this claim are defined with respect to Formula 2, or a pharmaceutically acceptable salt or ester thereof. In one aspect, when R¹represents a hydrogen atom, R²represents an amino group, R³and R⁴represent a fluorine atom, R⁶represents a hydrogen atom, X represents a nitrogen atom, Y represents —CR⁷═ (wherein R⁷represents a fluorine atom), Z represents —CH═, and W is —CR⁸═ (wherein R⁸represents a chlorine atom), then R⁵is not a 3-hydroxyazetidine-1-yl group, or a pharmaceutically acceptable salt or ester thereof.

In one aspect, the invention relates to a pharmaceutical composition wherein said quinolone carboxylic acid derivative corresponds to the following compound (A)

[Image Omitted]

or a pharmaceutically acceptable salt or ester thereof.

In one aspect, the invention relates to a pharmaceutical composition wherein said quinolone carboxylic acid derivative is a D-glucitol, 1-deoxy-1-(methylamino)-, 1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6-fluoro-1,4- dihydro-7-(3-hydroxy-1-azetidinyl)-4-oxo-3-quinolinecarboxylate (salt).

In one aspect, the invention relates to a pharmaceutical composition wherein said quinolone carboxylic acid derivative is a crystalline D-glucitol, 1-deoxy-1-(methylamino)-, 1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6-fluoro- 1,4-dihydro-7-(3-hydroxy-1-azetidinyl)-4-oxo-3-quinolinecarboxylate (salt) characterized, when measured at about 25° C. with Cu—Ka radiation, by the powder diffraction pattern shown in FIG. 1.

In one aspect, the invention relates to a pharmaceutical composition wherein said quinolone carboxylic acid derivative is D-glucitol, 1-deoxy-1-(methylamino)-, 1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6-fluoro-1,4- dihydro-7-(3-hydroxy-1-azetidinyl)-4-oxo-3-quinolinecarboxylate trihydrate (salt).

In one aspect, the invention relates to a pharmaceutical composition wherein said quinolone carboxylic acid derivative is crystalline D-glucitol, 1-deoxy-1-(methylamino)-, 1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxy-1-azetidinyl)-4-oxo-3-quinolinecarboxylate trihydrate (salt), characterized, when measured at about 25° C. with Cu—Ka radiation, by the powder diffraction pattern shown in FIG. 2.

In one aspect, the invention relates to a pharmaceutical composition wherein said chelating agent is EDTA or a salt thereof. In one aspect, said chelating agent is an EDTA salt selected from the group consisting of a sodium salt, a potassium salt, a calcium salt, a magnesium salt, and mixtures thereof. In one aspect, said chelating agent is disodium EDTA.

In one aspect, the invention relates to a pharmaceutical composition further comprising a polyhydroxyamine compound. In one aspect, said polyhydroxyamine compound is meglumine.

In one aspect, the invention relates to a pharmaceutical composition wherein said quinolone carboxylic acid derivative has a measurable improvement in solubility compared to the quinolone carboxylic acid derivative in water. In one aspect, said quinolone carboxylic acid derivative has a solubility of at least about 1 mg/ml at 25° C. In one aspect, said quinolone carboxylic acid derivative has a solubility of at least about 2 mg/ml at 25° C. In one aspect, quinolone carboxylic acid derivative has a solubility of at least about 3 mg/ml at 25° C. In one aspect, said quinolone carboxylic acid derivative has a solubility of at least about 5 mg/ml at 25° C. In one aspect, said quinolone carboxylic acid derivative has a solubility of at least about 10 mg/ml at 25° C. In one aspect, said quinolone carboxylic acid derivative has a solubility of at least about 15 mg/ml at 25° C. In one aspect, said quinolone carboxylic acid derivative has a solubility of at least about 20 mg/ml at 25° C. In one aspect, said quinolone carboxylic acid derivative has a solubility of at least about 25 mg/ml at 25° C. In one aspect, said quinolone carboxylic acid derivative has a solubility of at least about 30 mg/ml at 25° C.

In one aspect, the invention relates to a pharmaceutical composition which has improved stability.

In one aspect, the invention relates to a pharmaceutical composition having improved stability as measured by at least one of the following parameters:

- (a) the composition maintains a pH within about 10% of its initial pH, or
- (b) the composition retains at least about 90%, or at least 95%, of the initial amount of the quinolone carboxylic acid derivative, or
- (c) the composition does not form a precipitate such that per unit container, the compositions has 6000 or less particles of 10 microns or greater and has 600 or less particles of 25 microns or greater as measured using a standard light obscuration particle test as described in USP Section 788 on Particulate Matter in Injections.

In one aspect, the invention any of the parameters (a), (b), or (c) are determined at least 30, 69, 90, 180 days, or one year after the composition has been allowed to stand at room temperature, during that time.

In one aspect, the invention relates to a pharmaceutical composition wherein said composition provides a measurable enhancement in venous toleration. In one aspect, said venous toleration is measured in a rat tail infusion model. In one aspect, said composition can be infused in a rat tail infusion model for at least one hour at the rate of 10 ml/kg/hr. In one aspect, the invention relates to a pharmaceutical composition according to claim 65 wherein said composition can be infused on a least two, three, four, or five consecutive days in a rat tail infusion model for at least one hour at the rate of 10 ml/kg/hr.

In one aspect, the invention relates to a pharmaceutical composition according wherein said quinolone carboxylic acid derivative has a measurable improvement in solubility compared to the quinolone carboxylic acid derivative in water, and/or the composition has improved stability, and/or the composition provides a measurable enhancement in venous toleration.