AU2013201203B2 - Sns-595 and methods of using the same - Google Patents

Abstract

A pharmaceutical composition comprising (+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4 (methylamino)- I -pyrrolidinyl]-4-oxo- 1 -(2-thiazolyl)- 1,8-naphthyridine-3-carboxylic acid and 5 an acid, wherein the pH of the composition is in the range 2 to 3 5 when measured in an aqueous solution O'.name-

Description

AUSTRALIA Patents Act COMPLETE SPECIFICATION (ORIGINAL) Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority Related Art: Name of Applicant: Sunesis Pharmaceuticals, Inc. Actual Inventor(s): Daniel C. Adelman, Jeffrey A. Silverman Address for Service and Correspondence: PHILLIPS ORMONDE FITZPATRICK Patent and Trade Mark Attorney!; 367 Collins Street Melbourne 3000 AUSTRALIA Invention Title: SNS-595 AND METHODS OF USING THE SAME Our Ref: 964059 POF Code: 125692/478999 The following statement is a full description of this invention, including the best method of performing it known to applicant(s): -1la SNS-595 AND METHODS OF USING THE SAME The present application is a divisional application from Australian patent No. 2011201277, which in turn is a divisional application from Australian patent application No. 2005222622, the entire contents of which are incorporated herei:1 by this reference. SNS-595 is novel naphthyridine cytotoxic agent that was previously known as AG-7352 (see e.g., Tsuzuki et al., Tetrahedron-Asymmetry 12: 1793-1799 (2001) and U.S. Patent No. 5,817,669). The chemical name of SNS-595 is (+)-1,4-dihydro-7.[(3S,4S)-3-methoxy-4 (methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazoyl)-1,8-naphthyr'idine-3-carboxylic acid and has the structure shown below C0 2 1' H I I H H N N N CH36 The present invention relates to pharmaceutical compositi-ms and methods of using SNS 595 to treat cancer. The discussion of documents, acts, materials, devices, articles and the like is included in this specification solely for the purpose of providing a context for the present invention. It is not suggested or represented that any or all of these matters formed part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this application. Where the terms "comprise", "comprises", "comprised" or "comprising" are used in this specification (including the claims) they are to be interpreted as specifying the presence of the stated features, integers, steps or components, but not precluding the presence of one or more other features, integers, steps or components, or group thereof. DESCRIPTION OF THE FIGURES Figure 1 depicts the plasma concentrations of SNS-595 over time among the various patient cohorts.

lb SUMMARY OF THE INVENTION One aspect of the present invention provides a pharmaceutical composition comprising (+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-l (2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid and an acid, wherein the pH of the composition is in the range 2 to 3.5 when measured in an aqueous solution. Another aspect provides an aqueous pharmaceutical composition comprising ab:ut 100 mg of (+)-1,4 dihydro-7-[(3 S,4S)-3-methoxy-4-(methylamino)- I -pyrrolidinyl] -5 4-oxo-I-(2-thiazolyl)-1,8 naphthyridine-3-carboxylic acid per 10 mL of the composition, about 450 mg of sorbitol per 10 mL of the composition and an acid, wherein the pH of the composition is in the range of 2.3 to 2.7. Another aspect provides a pharmaceutical composition prepared as a lyophilized powder comprising (+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4 oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid and an acid, wherein the lyophilized powder is suitable for reconstitution in sterile water to obtain a composition with a pH in the range 2 to 3.5 when measured in an aqueous solution in which the (+)-1,4-dihydro-7-[(3S,4S) 3-methoxy-4-(methylamino)-1 -pyrrolidinyl]-4-oxo--I (2-thiazolyel)-1,8-naphthyridine-3 carboxylic acid is present in an amount of 10 mg per mL. DETAILED DESCRIPTION In one aspect of the present invention, pharmaceutical composition is provided comprising: a) SNS-595 and b) an acid in an aqueous solution wherein the pH of the solution is 2-3.5. A. used herein, a numerical range is intended to be inclusive. For example, the range of pH 2-3.5 includes both pH 2 and pH 3.5. In one embodiment, the pH of the composition is 2-3. In another embodiment, the pH of the composition is 2.3-2.7. As used herein, an aqueous solution i; a liquid comprising water. Suitable examples of acids include both organic and inorganic acids such as acetic acid, ascorbic acid, benzene-sulfonic acid, ethanesulfonic acid, glycol acid, hydrogen chloride, 2 hydrogen bromide, hydroxyethanesulfonic acid, lactic acid, ma eic acid, methanesulfonic acid, proprionic acid, succinic acid, sulfuric acid, trifluoroacetic acid, and toluenesulfonic acid. In one embodiment, the acid is hydrochloric acid, methanesulfonic acid or lactic acid. In another embodiment, the acid is methanesulfonic acid. 5 In another embodiment, the pharmaceutical composition further comprises a tonicity agent. Suitable examples of a tonicity agent include amino acids (e.g., alanine and glycine), electrolytes (e.g., sodium chloride and potassium chloride), monosaccharides (e.g. glucose or galactose), disaccharides (e.g. sucrose) and hexahydric alcohols (e.g., mannitol and sorbitol). In 10 another embodiment, the tonicity agent is sodium chloride, glucose, mannitol, or sorbitol. In another embodiment, the tonicity agent is a hexahydric alcohol. In another embodiment, the tonicity agent is sorbitol. SNS-595 is a cytotoxic agent for the treatment of cancer. The types of cancers that can 15 be treated using the inventive methods include but are not limited to: bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer r), esophageal cancer, head and neck cancer, leukemia, liver cancer, lung cancer (both small cell and non-small cell), lymphoma, melanoma, myeloma, neuroblastorna, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), 20 stomach cancer, testicular cancer, thyroid cancer, and uterine cancer. In another aspect of the invention, a method of using SNS-595 to treat a human cancer is provided. The method comprises administering to a patient on the basis of body surface area, a dose of 10 mg/m 2 -150 mg/m 2 of SNS-595. Body surface area calculations can be calculated for 25 example, with the Mosteller formula wherein: BSA (m 2 )= square root of [(height (cm) x weight (kg)/3600]. In another embodiment, the dose is 10 mg/m 2 -100 mg/m 2 . In another embodiment, the dose is 30 mg/m 2 -75 mg/m 2 . In another embodiment, the dose is 40 mg/m 2 -80 mg/m 2 . In another embodiment, the dose is 50 mg/m 2 -90 mg/m 2 . 30 In another embodiment the dose is 20 mg/m 2 -30 mg/m 2 . In another embodiment the dose is 25 mg/m 2 -35 mg/m 2 . In another embodiment the dose is 40 Ig/m 2 -50 mg/m 2 . In another embodiment the dose is 45 mg/m 2 -55 mg/m 2 . In another embociment the dose is 50 mg/m 2 -60 3 mg/m 2 . In another embodiment the dose is 55 mg/m 2 -65 mg/m 2 . In another embodiment the dose is 60 mg/m2-70 mg/m2. In another embodiment the dose is 65 mg/m 2 -75 mg/m 2 . In another embodiment the dose is 70 mg/m 2 -80 mg/m 2 . In another embodiment the dose is 75 mg/m2_ 85mg/m 2 . In another embodiment the dose is 80 mg/m 2 -90 mg/in 2 . In another embodiment the 5 dose is 85 mg/m 2 -95 mg/m 2 . In another embodiment the dose is 90 mg/m 2 -100 mg/m 2 . In another embodiment the dose is 95 mg/m 2 -105 mg/m 2 . In another embodiment the dose is 100 mg/m 2 -1 10 mg/m 2 . In another embodiment the dosc is 105 mg/m 2 - 115 mg/m 2 . In another embodiment the dose is 110 mg/m 2 -120 mg/m 2 . In another embodiment the dose is 115 10 mg/m 2 -125 mg/m 2 . In another embodiment the dose is 120 mg/ n 2 -130 mg/m 2 . In another embodiment the dose is 125 mg/m 2 - 135 mg/rn 2 . In another embodiment the dose is 130 mg/m2_ 140 mg/m 2 . In another embodiment the dose is 135 mg/m2-145 mg/m 2 . In another embodiment the dose is 140 mg/m 2 -150 mg/m 2 . 15 The administered dose of SNS-595 can be delivered simultaneously (e.g. a single bolus injection) or over a 24-hour period (e.g., continuous infusion over time or divided bolus doses over time) and is repeated until the patient experiences stable disease or regression, or until the patient experiences disease progression or unacceptable toxicity For example, stable disease for solid tumors generally means that the perpendicular diameter of measurable lesions has not 20 increased by 25% or more from the last measurement. See e.g., Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines, Journal of the National Cancer Institute 92(3): 205-216 (2000). Stable disease or lack thereof is determined by methods known in the art such as evaluation of patient symptoms, physical examination, visualization of the tumor that has been imaged using X-ray, CAT, PET, or MRI scan and other commonly accepted evaluation 25 modalities. The administered dose of SNS-595 can be expressed in units other than as mg/m 2 . For example, doses can be expressed as mg/kg. One of ordinary skill in the art would readily know how to convert doses from mg/m 2 to mg/kg to given either the height or weight of a subject or 30 both (see e.g., http:///wwwfda.gov/cder/cancer/animalframe.htni). For example, a dose of 10 mg/m 2 -150 mg/m 2 for a 65 kg human is approximately equal to 0.26 mg/kg-3.95 mg/kg.

4 In another aspect of the present invention, SNS-595 is aihministered according to a dosing schedule. In one embodiment, the method comprises: i) administering a dose of 10 mg/n-150 mg/m 2 of SNS-595 to a patient; ii) waiting a period of at least one day where the sub ject is not administered any 5 SNS-595; iii) administering another dose of 10 mg/m 2 -150 mg/in 2 of SNS-595 to the patient; and, repeating steps ii)-iii) a plurality of times. 10 For example, if the waiting period were 6 days, then the initial dose of SNS-595 is administered on Day 1 (step i); the waiting period is six days (step ii); and the following dose of SNS-595 is administered on Day 8 (step iii). Other exemplary time periods include 2 days, 3 days, 13 days, 20 days, and 27 days. In another embodiment, the waiting period is at least 2 days and steps ii) through iii) are repeated at least three times. In another embodiment, the waiting 15 period is at least 3 days and steps ii) through iii) are repeated at least five times. In another embodiment, the waiting period is at least 3 days and steps ii) through iii) are repeated at least three times. In another embodiment, the waiting period is at least 3 days and steps ii) through iii) are repeated at least five times. In another embodiment, the wailing period is at least 6 days and steps ii) through iii) are repeated at least three times. In another embodiment, the waiting period 20 is at least 6 days and steps ii) through iii) are repeated at least five times. In another embodiment, the waiting period is at least 20 days and steps ii) trough iii) are repeated at least three times. In another embodiment, the waiting period is at least 20 days and steps ii) through iii) are repeated at least five times. In another embodiment, the waiting period is at least 27 days and steps ii) through iii) are repeated at least three times. In another embodiment, the waiting 25 period is at least 27 days and steps ii) through iii) are repeated at least five times. In another embodiment, the dosing method comprises administering a weekly dose of SNS-595 to a subject. In another embodiment, the dosing method comprises administering a dose of SNS-595 to a subject every two weeks. In another embodiment, the dosing method 30 comprises administering a dose of SNS-595 to a subject every tl-ree weeks. In another embodiment, the dosing method comprises administering a dose of SNS-595 to a subject every four weeks.

5 In another embodiment, the dosing method comprises a c'ycle wherein the cycle comprises administering a dose of SNS-595 to a subject every week for three weeks followed by a period of at least two weeks where no SNS-595 is administered to said subject and wherein the cycle is repeated a plurality of times. In another embodiment, the period where no SNS-595 is 5 administered is two weeks. In another embodiment, the period where no SNS-595 is administered is three weeks. In another aspect of the invention, a method of treating a solid tumor is provided. The method comprises: 10 i) administering a dose of 10 mg/m 2 -100 mg/m 2 of SNS-595 to a patient; ii) waiting a period of at least six days where the sub ject is not administered any SNS-595; iii) administering another dose of 10 mg/m 2 -100 mg/m n2 of SNS-595 to the patient; and, 15 iv) repeating steps ii)-iii) a plurality of times. In another aspect of the invention, a method of treating a hematologic cancer such as leukemias and lymphomas is provided. The method comprises: i) administering a dose of 60 mg/m 2 -1 50 mg/m 2 of SNS-595 to a patient; 20 ii) waiting a period of at least two days where the subject is not administered any SNS-595; iii) administering another dose of 60 mg/m 2 -150 mg/mn 2 of SNS-595 to the patient; and, iv) repeating steps ii)-iii) a plurality of times. 25 In another aspect of the present invention, a method is provided supportive care to patients being treated with SNS-595. The method comprises: a) administering to a patient a dose of 10 mg/m 2 -150 mg/m 2 of SNS-595 and b) administering a therapeutically effective amount of a supportive care agent. 30 The supportive care agent is any substance that prevents .r manages an adverse effect from SNS-595 treatment and is administered according to the appropriate dosing regimen for that substance. For example, different supportive care agents for treating nausea have different 6 dosing regimen. While some are administered prophylactically, others are co-administered with SNS-595 while still others are administered after the administration of SNS-595. Illustrative examples of supportive care agents their doses and dosing regimens are found in The Physician's Desk Reference. 5 In one embodiment, the supportive care agent is an antieinetic. Illustrative examples of antiemetics include but are not limited to phenothiazines, butyrophenones, benzodiazapines, corticosteroids, serotonin antagonists, cannabinoids, and NKi receptor antagonists. Examples of phenothiazine antiemetics include prochlorperazine and trimethcbenzamide. An example of a 10 butyrophenone antiemetic is haloperidol. An example of a benzodiazapine antiemetic is lorazepam. An example of a corticosteroid antiemetic is dexamethasone. Examples of a serotonin antagonist antiemetic include ondansetron, granisetron, and dolasetron. An example of a cannabinoid antiemetic is dronabinol. An example of an NK1 receptor antagonist is aprepitant. 15 In another embodiment, the antiemetic is prochlorperazirne. In another embodiment, the antiemetic is prochlorperazine and the therapeutically effective -mount is 10 mg. In another embodiment, the antiemetic is prochlorperazine and the therapeutically effective amount is an oral dose of 10 mg before the administration of SNS-595. In another embodiment, the antiemetic is prochlorperazine and the therapeutically effective amount is an oral dose of 10 mg 20 every four to six hours as needed after the administration of SNS-595. In another embodiment, the antiemetic is dexamethasone. In another embodiment, the antiemetic is dexamethasone and the therapeutically effective amount is at least 4 mg. In another embodiment, the antiemetic is dexamethasone and the therapeut cally effective amount is an oral 25 dose of 4 mg before the administration of SNS-595. In another 'embodiment, the antiemetic is dexamethasone and the therapeutically effective amount is an or al dose of 8 mg before the administration of SNS-595. In another embodiment, the antiemotic is dexamethasone and the therapeutically effective amount is an intravenous dose of betwe en about 10 mg and about 20 mg before the administration of SNS-595. In another embodiment, the antiemetic is dexamethasone 30 and the therapeutically effective amount is an oral dose of 4 mg every six to twelve hours as needed after the administration of SNS-595.

7 In another embodiment, the antiemetic is lorazepain. In another embodiment, the antiemetic is lorazepam and the therapeutically effective amount is 1 mg. In another embodiment, the antiemetic is lorazepam and the therapeutically effective amount is an oral dose of 1 mg before the administration of SNS-595. In another embodiment, the antiemetic is 5 lorazepam and the therapeutically effective amount is an intravenous dose of I mg before the administration of SNS-595. In another embodiment, the antiemetic is lorazepam and the therapeutically effective amount is an oral dose of 1 mg every fo-ir to six hours as needed after the administration of SNS-595. 10 In another embodiment, the antiemetic is dolasetron. In another embodiment, the antiemetic is dolasetron and the therapeutically effective amount is 100 mg. In another embodiment, the antiemetic is dolasetron and the therapeutically effective amount is an oral dose of 100 mg before the administration of SNS-595. In another embodiment, the antiemetic is dolasetron and the therapeutically effective amount is an intravenous dose of 100 mg before the 15 administration of SNS-595. In another embodiment, the antiemetic is ondansetron. In another embodiment, the antiemetic is ondansetron and the therapeutically effective amount is at least 10 mg. In another embodiment, the antiemetic is ondansetron and the therapeutical y effective amount is an 20 intravenous dose of 10 mg before the administration of SNS-595. In another embodiment, the antiemetic is ondansetron and the therapeutically effective anoniat is an intravenous dose of 32 mg before the administration of SNS-595. In another embodiment, the antiemetic is granisetron. In another embodiment, the 25 antiemetic is granisetron and the therapeutically effective amoun t is 10 jig/kg. In another embodiment, the antiemetic is granisetron and the therapeutically effective amount is an intravenous dose of 10 pg/kg before the administration of SNS-595. In another embodiment, the antiemetic is granisetron and the therapeutically effective amount is at least 1 mg. In another embodiment, the antiemetic is granisetron and the therapeutically effective amount is an oral 30 dose of 1 mg before the administration of SNS-595. In another embodiment, the antiemetic is granisetron and the therapeutically effective amount is an oral dc-se of 2 mg before the administration of SNS-595.

8 In another embodiment, the antiemetic is aprepitant. In another embodiment, the antiemetic is aprepitant and the therapeutically effective amount is at least 80 mg. In another embodiment, the antiemetic is aprepitant and the therapeutically effective amount is an oral dose of 125 mg before the administration of SNS-595. In another embodiment, the antiemetic is 5 aprepitant and the therapeutically effective amount is a daily oral dose of 80 mg for at least two days after the administration of SNS-595. In another embodiment, the supportive care agent is a he matopoietic agent. A hematopoietic agent is a molecule that stimulates hematopoiesis. Illustrative examples of 10 hematopoietic agents include but are not limited to granulocyte ';olony stimulating factor (G CSF), granulocyte macrophage colony stimulating factor (GM-CSF), erythropoietin and erythropoiesis stimulating protein, and derivatives thereof. Examples of G-CSF include but are not limited to filgrastim and its derivatives including pegfilgrastim. An example of GM-CSF includes sargramostim. An example of erythropoietin is epoetir. alfa. An example of 15 erythropoiesis stimulating protein is darbepoetin alfa. In another embodiment, the hematopoietic agent is G-CSF. In another embodiment, the hematopoietic agent is filgrastim. In another embodiment, the -ematopoietic agent is filgrastim and the therapeutically effective amount is at least 4 pig/kg. In another embodiment, the 20 hematopoietic agent is filgrastim and the therapeutically effective amount is a daily dose of at least 4 pig/kg for at least 7 days after the administration of SNS-595. In another embodiment, the hematopoietic agent is filgrastim and the therapeutically effective amount is a daily subcutaneous dose of between about 4 pg/kg and about 8 pg/kg for at least 7 (lays starting from the third day after the administration of SNS-595. In another embodiment, tL.e hematopoietic agent is 25 filgrastim and the therapeutically effective amount is a daily subcutaneous dose of between about 4 pg/kg and about 10 pg/kg for at least 14 days starting from the third day after the administration of SNS-595. In another embodiment, the hematopoietic agent is pegfi lgrastim. In another 30 embodiment, the hematopoictic agent is pegfilgrastim and the therapeutically effective amount is 6 mg. In another embodiment, the hematopoietic agent is pegfi:.grastim and the therapeutically effective amount is a daily subcutaneous dose of 6 mg after the administration of SNS-595. In another embodiment, the hematopoietic agent is pegfilgrastim and the therapeutically effective 9 amount is 100 pg/kg. In another embodiment, the hematopoiet c agent is pegfilgrastim and the therapeutically effective amount is a daily dose of 100 Ag/kg after the administration of SNS 595. 5 In another embodiment, the hematopoietic agent is GM-CSF. In another embodiment, the hematopoietic agent is sargramostim. In another embodimei nt, the hematopoietic agent is sargramostim and the therapeutically effective amount is 250 yg /m 2 . In another embodiment, the hematopoietic agent is sargramostim and the therapeutically effective amount is a daily intravenous or subcutaneous dose of 250 pg/m 2 . In another emt odiment, the hematopoietic 10 agent is sargramostim and the therapeutically effective amount is a daily intravenous or subcutaneous dose of 250 yg/m 2 as needed starting from the third day after the administration of SNS-595. In another embodiment, the hematopoietic agent is sergramostim and the therapeutically effective amount is a daily intravenous or subculaneous dose of 250 gg/m 2 as needed starting from the tenth day after the administration of SNS-595. 15 In another embodiment, the hematopoietic agent is erythropoietin. In another embodiment, the hematopoietic agent is epoetin alfa. In another embodiment, the hematopoietic agent is epoetin alfa and the therapeutically effective amount is at least 150 units/kg. In another embodiment, the hematopoietic agent is epoetin alfa and the the rapeutically effective amount is 20 an intravenous or subcutaneous dose of 150 units/kg three times a week after the administration of SNS-595. In another embodiment, the hematopoictic agent is epoetin alfa and the therapeutically effective amount is an intravenous or subcutaneous dose of 300 units/kg three times a week after the administration of SNS-595. In another embodiment, the hematopoietic agent is epoetin alfa and the therapeutically effective amount is 40,000 units. In another 25 embodiment, the hematopoietic agent is epoetin alfa and the therapeutically effective amount is a weekly dose of 40,000 units after the administration of SNS-59:i. In another embodiment, the hematopoietic agent is eryt1-ropoiesis stimulating protein. In another embodiment, the hematopoietic agent is darbepoetin alla. In another embodiment, the 30 hematopoietic agent is darbepoetin alfa and the therapeutically ;ffective amount is between about 1.5 pg/kg and about 4.5 pg/kg. In another embodiment, tae hematopoietic agent is darbepoetin alfa and the therapeutically effective amount is a w weekly dose of between about 1.5 Ag/kg and about 4.5 sg/kg.

10 All cited references are incorporated herein by reference. EXAMPLE 1 Pharmaceutical composition suitable for injection or intravenous infusion 5 Acidic compositions (< pH 4) provided the appropriate balance of increased solubility of SNS-595 and desirable pharmaceutical properties (e.g. increaseI patient comfort by causing less irritation at the delivery site). An illustrative example of a suita ble composition comprises: 10 mg SNS-595 per mL of aqueous solution of 4.5% sorbitol that is adjusted to pH 2.5 with methanesulfonic acid. One protocol for making such a solution includes the following for 10 making a 100mg/lOmL presentation: 100 mg of SNS-595 and 450 mg D-sorbitol are added to distilled water; the volume is brought up to a volume of 10 mL; and the pH of the resulting solution is adjusted to 2.5 with methanesulfonic acid. The resulting composition is also suitable for lyophilization. The lyophilized form is then reconstituted with sterile water to the appropriate concentration prior to use. 15 EXAMPLE 2 Pharmacokinetics of SNS-595 in cancer patients SNS-595 was administered to enrolled patients for up to six cycles. A cycle is defined as a three-week period, with SNS-595 administered on the first day of each cycle (day 0), followed 20 by at least 21 days of observation. SNS-595 was administered 10 cohorts of at least 3 patients and dose escalation occurred by sequential cohort. Doses of SNS-595 were linear with AUCoo and its pharmacokinetic properties were remarkably consistent anong patients in the same cohort. Figure 1 depicts the plasma concentrations of SNS-595 over time among the various patient cohorts and Table 1 shows the pharmacokinetic parameters derived there from. 25 11 Table 1 HL (hr) CO (ngmL) Cmax AUClast AUCINFobs CI~c bs Vazobs Vssobs MRTINF_obs ((Ig/m2)L (ng/ml.) (hWnglmL) (hznglmL) (L/ml inkg) (Lg) (Lg) (hr) 3 16.27 152.28 138.80 750.08 1139.55 1.11 1.55 144 21.96 SD 4.871 82282 80.566 87.622 263 0.3-8 0.297 0.277 6.836 a 20.69 376.69 347.00 2400.00 2900.29 0.71 128 1.24 29.05 SD 0.327 243.598 214.96 170.556 245.84 0.113 0.295 0.218 1.15 12 17.61 2888.66 224607 5395.53 8329.18 0.71 1.17 1.07 23.67 SD .896 1302.71 1065.145 292.281 181.804 0.1:8 0.28 0.184 5.021 24 16.14 2924A8 270.33 11133.03 12655.32 0.83 1.15 1.06 21.65 SD 2601 2884.702 2573.02 46B.453 851.458 0.116 0.124 0.16 5.21 48 21.32 1984.82 2888.00 21098.63 27347.56 0.93 1.57 1.48 28.90 SD 6.32 189.677 2379.809 9405.348 14382.787 0.* 0.7 0A7 8.91 60 17.63 4797.47 4537.80 28112.17 33816.18 0.83 1.20 1.08 23.71 So 4.15 2215.20 1947.89 9127.12 13081.44 0.3;2 0.37 0.218 8.93

Claims (28)

1. A pharmaceutical composition comprising (+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4 (methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid and an acid, wherein the pH of the composition is in the range 2 to 3.5 when measured in an aqueous solution

2. The pharmaceutical composition of claim 1 in which the (+)-1,4-dihydro-5 7 [(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8 naphthyridine-3-carboxylic acid is present in an amount of 10 mg per mL.

3. The pharmaceutical composition of claim 1 further comprising water.

4. The pharmaceutical composition of claim 1, wherein the pH of the composition is in the range 2 to 3.

5. The pharmaceutical composition of claim 1, wherein the pH of the composition is in the range 2.3 to 2.7 when measured in aqueous solution.

6. The pharmaceutical composition of any one of claims 1 to 5, wherein the acid is hydrogen chloride, hydrogen bromide or sulfuric acid.

7. The pharmaceutical composition of any one of claims 1 to 6 further comprising a tonicity agent, wherein the tonicity agent is selected from the group consisting of amino acids, electrolytes, monosaccharides, disaccharides, and hexahydric alcohols.

8. The pharmaceutical composition of claim 7, wherein the tonicity agent comprises sorbitol.

9. The pharmaceutical composition of claim 8 further comprising sorbitol in an amount of 45 mg per ml.

10. The pharmaceutical composition of any one of claims 1 to 9, wherein the pH of the composition is about 2.5 when measured in aqueous solution.

11. A powder comprising the composition of claim 1.

12. An aqueous pharmaceutical composition comprising about 100 mg of (+)-1,4 dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-5 4-oxo-1-(2-thiazolyl)-1,8 naphthyridine-3-carboxylic acid per 10 mL of the composition, about 450 mg of sorbitol per 10 mL of the composition and an acid, wherein the pH of the composition is in the range of 2.3 to 2.7.

13. The pharmaceutical composition of claim 1, wherein the composition comprises about 100 mg of (+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4 oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid and about 450 mg of sorbitol per 10 mL of the composition. 13

14. The pharmaceutical composition of claim 13, wherein the pH is about 2.5.

15. A lyophilized powder comprising the composition of claim 1.

16. A pharmaceutical composition prepared as a lyophilized powder comprising (+) 1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo- 1-(2-thiazolyl)- 1,8 naphthyridine-3-carboxylic acid and an acid, wherein the lyophilized powder is suitable for reconstitution in sterile water to obtain a composition with a pH in the range 2 to 3.5 when measured in an aqueous solution in which the (+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4 (methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid is present in an amount of 10 mg per mL.

17. An aqueous pharmaceutical composition comprising about 10 mg/mL of (+)-1,4 dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8 naphthyridine-3-carboxylic acid, about 45 mg/mL of sorbitol, and sufficient acid to render the pH of the composition in the range 2.3 to 2.7.

18. An aqueous pharmaceutical composition comprising about 10 mg/mL of (+)-1,4 dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8 naphthyridine-3-carboxylic acid, about 45 mg/mL of sorbitol, and sufficient acid to render the pH of the composition about 2.5.

19. An aqueous pharmaceutical composition comprising about 100 mg of (+)-1,4 dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8 naphthyridine-3-carboxylic acid per 10 mL of the composition, about 450 mg of sorbitol per 10 mL of the composition, and an acid, wherein the pH of the composition is in the range of 2 to 3.5.

20. An aqueous pharmaceutical composition comprising about 10 mg/mL of (+)-1,4 dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8 naphthyridine-3-carboxylic acid, about 45 mg/mL of sorbitol, and sufficient acid to render the pH of the composition about 2.5.

21. The pharmaceutical composition of claim 1 that is formulated for intravenous administration.

22. A product formed by a process of contacting about 100 mg of (+)-1,4-dihydro-7 [(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8 naphthyridine-3-carboxylic acid per 10 mL of the product, about 450 mg of sorbitol per 10 mL of the product and an acid, wherein the pH of the product is in the range of 2.3 to 2.7. 14

23. A product formed by a process of contacting about 10 mg/mL of (+)-1,4-dihydro-7 [(3S,4S)-3-methoxy-4-(methylamino)- 1 -pyrrolidinyl] -4-oxo- 1-(2-thiazolyl)- 1,8 naphthyridine-3-carboxylic acid, about 45 mg/mL of sorbitol, and sufficient acid to render the pH of the product in the range of 2.3 to 2.7.

24. The pharmaceutical composition of any one of claims 1 to 21 for use in treating cancer.

25. The pharmaceutical composition of claim 24 for use in treating ovarian cancer, breast cancer, or leukemia.

26. An aqueous pharmaceutical composition comprising about 10 mg/mL of (+)-1,4 dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8 naphthyridine-3-carboxylic acid, and sufficient acid to render the pH of the composition in the range 2.3 to 2.7.

27. An aqueous pharmaceutical composition comprising about 10 mg/mL of (+)-1,4 dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8 naphthyridine-3-carboxylic acid, and sufficient acid to render the pH of the composition 2.5.

28. The pharmaceutical composition of claim 1 or claim 16; or the aqueous pharmaceutical composition of any one of claims 12, 17, 18, 19, 20, 26 and 27; substantially as hereinbefore defined, with reference to any of the Examples.