Intravesical compositions

Abstract

The present invention provides a pharmaceutical composition for intravesical administration, in particular for use in the treatment of urinary bladder disorders.

Description

[0001] Intravesical Compositions

[0002] Field of the Invention

[0003] The present invention relates to a pharmaceutical composition for intravesical administration, in particular for use in the treatment of urinary bladder disorders.

[0004] Background

[0005] The treatment of urinary bladder disorders with an active pharmaceutical ingredient (API) can be carried out via the systemic route, i.e. by oral or intravenous administration of a suitable formulation of an API. Alternatively, a formulation of an API can be administered intravesically, i.e. by instillation through the urethra to the bladder. On the one hand, the latter route of administration has the benefit of allowing the API to directly contact the bladder inner surface, without systemic exposure of the body to the API. On the other hand, the intrinsic properties of the bladder pose unique challenges in developing effective intravesical therapies (cf. L. Douglass et al., Bladder Cancer 2 (2016) 285-292). In particular, intravesical APIs are constantly diluted by urine and are regularly removed from the bladder by voiding.

[0006] For increasing the dwell time of APIs inside the bladder, intravesical drug delivery devices have been developed in the prior art that are implanted in the bladder, left in place and release API over an extended period of time. This increases the amount of time over which the bladder mucosa is exposed to the API. The device can be made of a biodegradable polymer incorporating the API. Upon intravesical implantation, the polymer device will stay in the bladder, degrade over time and gradually release API, thus maintaining a constant exposure of the bladder inner surface to the API.

[0007] Another intravesical technology is the use of nanocarriers for optimized targeted drug delivery. Nanocarriers can be liposome nanocarriers in which spherical vesicles composed of phospholipid layers surround a core which contains an API. The liposomes are believed to increase the solubility and stability of the API in urine. Yet another intravesical technology is based on the use of so-called reverse thermosensitive (RT) hydrogels for allowing to increase the dwell time of intravesical APIs. These polymer hydrogels are in the liquid state at low temperature (below the body temperature), yet solidify into a gel at higher temperatures, in particular when approaching or reaching body temperature. When an API is incorporated in the hydrogel, the resulting liquid formulation can be administered through the urethra to the bladder using a catheter. Upon reaching the bladder and assuming body temperature, the formulation will change its aggregate state from liquid to solid, forming a solidified gel reservoir which may optionally coat and adhere to the bladder inner surface, allowing to slowly release the API from the gel and increasing the drug dwell time. See US 2022 / 0118096 Al and US 9,950,069 B2. Commercial products based on RT hydrogels, such as JELMYTO (Urogen Pharma, Inc.), have gelling temperatures (gelation points) of less than 20°C, e.g., 19°C. Therefore, they require cooling to be liquid at the time of administration. In addition, they exhibit limited storage stability and are provided in the form of a kit separately comprising lyophilized API in one vial and gel for reconstitution in another vial.

[0008] A particular API useful in the treatment of bladder disorders such as urinary tract cancer, bladder cancer and upper tract urothelial carcinoma is gemcitabine. Gemcitabine is a pro-drug and pyrimidine antimetabolite that is metabolized intracellularly to active diphosphate and triphosphate nucleosides. It inhibits DNA synthesis by inhibiting DNA polymerase and ribonucleotide reductase. It also induces apoptosis and is primarily active against cells in the S-phase of DNA synthesis. Gemcitabine is typically instilled over 1 to 2 hours once or twice a week for several weeks at doses typically ranging from 500 to 2000 mg in up to 100 ml of saline. It is known that such formulations are voided from the bladder before full efficacy is achieved. Gemcitabine as API may be supplemented with docetaxel, a plant-derived taxane and semi-synthetic analogue of paclitaxel, that hinders the ability of cancer cells to replicate by interfering with microtubule structures inside the cells.

[0009] Despite the advances in the prior art regarding the intravesical instillation of APIs into the bladder, there is an ongoing need to improve the delivery of intravesical therapies, in particular maintaining a constant drug concentration in the bladder over time, with a ready to use formulation that is storage stable without the need for specific precautions.

[0010] Summary of the Invention

[0011] In accordance with the present invention, a pharmaceutical composition is provided that is a liquid at room temperature, but gets converted into a gel at body temperature. The composition provides for the controlled and sustained release of API in the bladder upon intravesical administration, based on formulating the API in a specific reverse thermosensitive hydrogel.

[0012] In a first aspect, the present invention provides a pharmaceutical composition for intravesical administration, comprising

[0013] (a) an effective amount of gemcitabine or a pharmaceutically acceptable acid addition salt thereof, optionally in combination with an effective amount of docetaxel,

[0014] (b) 25.0 to 35.0 wt.% of ethylene oxide / propylene oxide triblock copolymers consisting of

[0015] (b-1) 50 to 70 wt.% of poloxamer 407 and

[0016] (b-2) 30 to 50 wt.% of poloxamer 188,

[0017] (c) optionally 0.2 to 2.0 wt.% of viscosity adjusting agent, and

[0018] (d) a pharmaceutically acceptable buffer solution.

[0019] In a second aspect, the present invention provides a pharmaceutical composition as defined in the first aspect of the invention for use in the treatment of urinary tract cancer, bladder cancer, or upper tract urothelial carcinoma, in particular non-muscle invasive bladder cancer.

[0020] In a third aspect, the present invention provides a method of treating urinary tract cancer, bladder cancer, or upper tract urothelial carcinoma, in particular non-muscle invasive bladder cancer, the method comprising administering a therapeutically effective amount of the pharmaceutical composition as defined in the first aspect of the invention through the urethra to the bladder of a patient in need thereof.

[0021] Brief Description of the Drawings

[0022] Fig. 1 illustrates the viscosity (cP) at 37.0±0.1°C for the compositions described in Table 1.

[0023] Fig. 2 illustrates the viscosity (cP) at 25.0±0.5°C for the compositions described in Table 1.

[0024] Fig. 3 illustrates the gelling onset temperature (°C) for the compositions described in Table 1.

[0025] Fig. 4 illustrates the percentage of related substances for the composition of Example 1 described in Table 1.

[0026] Fig. 5 illustrates the percentage of related substances for the composition of Example 2 described in Table 1.

[0027] Fig. 6 illustrates the percentage of related substances for the composition of Example 6 described in Table 1.

[0028] Fig. 7 illustrates the viscosity (cP) at 37.0±0.1°C for the compositions described in Table 2.

[0029] Fig. 8 illustrates the viscosity (cP) at 25.0±0.5°C for the compositions described in Table 2.

[0030] Fig. 9 illustrates the gelling onset temperature (°C) for the compositions described in

[0031] Table 2. Detailed Description of the Invention

[0032] Throughout the specification and claims, the following definitions apply:

[0033] • The terms "active pharmaceutical ingredient" (API), "active ingredient" or "pharmaceutically active ingredient", and “drug" will be used interchangeably.

[0034] • The terms "pharmaceutical composition", "composition", "pharmaceutical formulation" and "formulation" will be used interchangeably.

[0035] • The terms “disorder” and “condition” or "medical condition” will be used interchangeably.

[0036] • Room temperature refers to a temperature of 25.0±0.5°C.

[0037] • Body temperature refers to a temperature of 37.0±0.1°C.

[0038] • Unless specified otherwise, all percentages are given herein as weight per weight (w / w), based on the total weight of the product concerned.

[0039] Active Pharmaceutical Ingredient (API) (a)

[0040] The API (a) used in the present invention is gemcitabine or a pharmaceutically acceptable acid addition salt thereof, optionally in combination with docetaxel.

[0041] In one embodiment of the present invention, the pharmaceutical composition comprises 0.5 to 2.5 wt.% of gemcitabine or a pharmaceutically acceptable acid addition salt thereof, optionally in combination with 0.04 to 0.10 wt.% of docetaxel.

[0042] In one embodiment of the present invention, the pharmaceutically acceptable salt of gemcitabine used in the pharmaceutical composition is the hydrochloride salt, gemcitabine hydrochloride.

[0043] The pharmaceutical composition of the present invention preferably contains no API other than gemcitabine (or a pharmaceutically acceptable acid addition salt thereof) and optionally docetaxel. Ethylene Oxide / Propylene Oxide Triblock Copolymer (b)

[0044] The pharmaceutical composition of the present invention uses a particular combination of specific ethylene oxide / propylene oxide triblock copolymers (b) for accomplishing the desired reverse thermosensitive characteristics. One part (b-1) of the copolymer (b) is constituted by poloxamer 407, and another part (b-2) of the copolymer (b) is constituted by poloxamer 188.

[0045] Poloxamers are nonionic triblock copolymers composed of a central hydrophobic block of polypropylene oxide) (PPO) flanked by two hydrophilic blocks of polyethylene oxide) (PEO). Poloxamers are also known by the trade names Pluronic, Kolliphor and Synperonic. The length of the polymer blocks can be customized, thus modifying and adjusting the poloxamer properties. Poloxamers are commonly abbreviated by the letter P followed by three digits, wherein the first two digits multiplied by 100 give the approximate molecular mass of the PPO content, and the last digit multiplied by 10 gives the percentage of the PEO content. This convention is also used forthe naming of Kolliphor products, whereas the Pluronic and Synperonic products use a different coding scheme: Here, the abbreviation starts with a letter to define the physical form at 20°C (L = liquid, P = paste, F = flake (solid)) followed by two or three digits. The first digit in a two-digit number, or the first two digits in a three-digit number, multiplied by 300 indicate(s) the approximate molecular mass of the PPO content, and the last digit multiplied by 10 gives the percentage of the PEO content.

[0046] The pharmaceutical composition of the present invention comprises poloxamer 407 (b-1) (corresponding to Pluronic F127) and poloxamer 188 (b-2) (corresponding to Pluronic F68) in a total amount of from 25.0 to 35.0 wt.%. In one embodiment, the proportion of ethylene oxide / propylene oxide triblock copolymers (b) is 27.0 to 33.0 wt.%, preferably 27.5 to 28.5 wt.%., even more preferably about 28.0 wt.%.

[0047] The ethylene oxide / propylene oxide triblock copolymers consist of 50 to 70 wt.% of poloxamer 407 (b-1) and 30 to 50 wt.% of poloxamer 188 (b-2). In one embodiment, the ethylene oxide / propylene oxide triblock copolymers consist of 50 to 60 wt.% of poloxamer 407 (b-1) and 40 to 50 wt.% of poloxamer 188 (b-2), preferably 52 to 55 wt.% of poloxamer 407 (b-1) and 45 to 48 wt.% of poloxamer 188 (b-2), more preferably about 54 wt.% of poloxamer 407 (b-1) and about 46 wt.% of poloxamer 188 (b-2).

[0048] Viscosity Adjusting Agent (c)

[0049] The pharmaceutical composition of the present invention optionally further comprises (c) viscosity adjusting agent. In one embodiment, the viscosity adjusting agent is one or both selected from the group consisting of sodium carboxymethyl cellulose and sodium hyaluronate. Preferably, the total proportion of the viscosity adjusting agent is 0.2 to 2.0 wt.%, more preferably 0.2 to 1.5 wt.%, even more preferably 0.5 to 1.0 wt.%. In one embodiment, the viscosity adjusting agent optionally contained in the pharmaceutical composition of the present invention is sodium carboxymethyl cellulose in an amount of up to 1.5 wt.%, preferably from 0.5 to 1.5 wt.%, or sodium hyaluronate in an amount of up to 1.0 wt.%, preferably from 0.2 to 1.0 wt.%. In one embodiment, the pharmaceutical composition of the present invention does not contain viscosity adjusting agent other than sodium carboxymethyl cellulose and sodium hyaluronate, in particular it does not contain hydroxypropylmethyl cellulose (HPMC) and polyethylene glycol (PEG), more particularly it does not contain HPMC and PEG 400.

[0050] Sodium carboxymethyl cellulose and sodium hyaluronate can impart mucoadhesive properties to the pharmaceutical composition. In other words, they can enhance the adhesion of the composition to the inner surface of the bladder, once the composition has been administered by intravesical administration through the urethra. The enhanced adhesion subsequently contributes to an increased dwell time of the composition inside the bladder, concomitantly improving the desired sustained release of the API. In addition, sodium carboxymethyl cellulose and sodium hyaluronate act as agents for adjusting the viscosity of the pharmaceutical composition. Carboxymethyl cellulose (CMC) is a water-soluble cellulose derivative with carboxymethyl (-CH2-COOH) groups substituting the hydrogen atoms of one or more of the three hydroxyl groups of each glucose units of the cellulose backbone. Owing to the carboxymethyl groups, CMC forms salts with cationic ions, in particular alkali metal ions such as sodium ions. The number of glucose units in a CMC molecule determines the degree of polymerization (DP). A glucose unit contains three hydroxyl groups, and the average number of hydroxyl groups substituted per glucose unit with a carboxymethyl group represents the degree of substitution (DS).

[0051] In one embodiment, sodium carboxymethyl cellulose used in the pharmaceutical composition has a molecular weight from 49,000 to 725,000 and a degree of substitution from 0.6 to 1.0, more preferably 0.65 to 0.9.

[0052] Pharmaceutically Acceptable Buffer Solution (d)

[0053] The aqueous component of the pharmaceutical composition of the present invention is a pharmaceutically acceptable buffer solution. The term buffer solution as used herein refers to an aqueous solution of one or more buffering agents, used in combination with a strong acid or base.

[0054] In one embodiment, the buffering agent of the pharmaceutically acceptable buffer solution is potassium dihydrogen phosphate, combined with sodium hydroxide as a strong base.

[0055] In one embodiment, the concentration of the buffering agent in the pharmaceutical composition is from 0.01 to 1.0 M, preferably 0.02 to 0.1 M, more preferably about 0.02 M (M = mol / liter).

[0056] Generally, the pharmaceutically acceptable buffer solution is selected to adjust the pH of the composition as needed. In one embodiment, the buffer solution provides the composition with a pH in the range of from 7.0 to 8.0, preferably about pH 7.5, determined at 25.0°C. The pH of the buffer solution and other aqueous solutions mentioned herein, including the pharmaceutical composition of the present invention, is generally determined at 25.0°C, using a pH meter. Approximately 4-5 mL of the sample is taken in a suitable test tube or glass beaker. The pH of the solution is measured by dipping the electrode in the test tube or glass beaker carefully without touching the bottom and sides of either of them. The value is noted as pH of the solution.

[0057] Other Components

[0058] The pharmaceutical composition of the present invention may additionally contain one or more pharmaceutically acceptable excipients other than the components (a), (b), (c) and (d), such as stabilizers, diluents, pH adjusting agents, colorants, other preservatives, etc., provided they do not prevent achieving the objects of the invention.

[0059] In particular, acid or base may be added for adjusting the pH of the composition. Examples of suitable pH adjusting agents include organic or inorganic bases selected from meglumine, sodium hydroxide (NaOH), and sodium bicarbonate. In one embodiment, sodium hydroxide (NaOH) is used as a pH adjusting agent.

[0060] In one embodiment, the pharmaceutical composition additionally contains a solubilizer. In particular, such a solubilizer may be used when the API is gemcitabine (or gemcitabine hydrochloride) in combination with docetaxel. The solubilizer may be selected from polysorbate 80, polysorbate 20, glycerin, Span 20, PEG 300 and ethanol. The solubilizer may be used in a total amount of from 0.2 to 1.50 wt.%.

[0061] Preferably, the pharmaceutical composition does not contain any component other than components (a), (b), (c) and (d) as defined above and in the appended claims.

[0062] Pharmaceutical Composition of the First Aspect of the Invention

[0063] The pharmaceutical composition of the first aspect of the invention comprises components (a) to (d) as defined above and in the appended claims. In particular, the following embodiments of the pharmaceutical composition are envisaged by the present invention in terms of proportions of components (a) to (d):

[0064] Embodiment (1)

[0065] (a) 0.6 to 2.5 wt.%

[0066] (b) 27.0 to 33.0 wt.%, consisting of

[0067] (b-1) 50 to 60 wt.%

[0068] (b-2) 40 to 50 wt% of

[0069] (c) 0 to 1.5 wt.%

[0070] (d) providing a pH of from 7.0 to 8.0 at 25.0°C

[0071] Embodiment (2)

[0072] (a) 1.25 to 2.5 wt.%

[0073] (b) 28.0 to 33.0 wt.%, consisting of

[0074] (b-1) 54 to 64 wt.%

[0075] (b-2) 36 to 46 wt.%

[0076] (c) 0 to 1.5 wt.% of sodium CMC

[0077] (d) providing a pH of from 7.0 to 8.0 at 25.0°C

[0078] Embodiment (3)

[0079] (a) 1.25 to 2.5 wt.%

[0080] (b) 28.0 to 33.0 wt.%, consisting of

[0081] (b-1) 54 to 64 wt.%

[0082] (b-2) 36 to 46 wt.%

[0083] (c) 0 to 1.0 wt.% of sodium hyaluronate

[0084] (d) providing a pH of from 7.0 to 8.0 at 25.0°C Embodiment (4)

[0085] (a) about 1.25 wt.%

[0086] (b) about 28.0 wt.%, consisting of

[0087] (b-1) about 64 wt.%

[0088] (b-2) about 36 wt.%

[0089] (c) 0.5 to 1.5 wt.% of sodium CMC

[0090] (d) providing a pH of about 7.5 at 25.0°C

[0091] Embodiment (5)

[0092] (a) about 1.25 wt.%

[0093] (b) about 28.0 wt.%, consisting of

[0094] (b-1) about 64 wt.%

[0095] (b-2) about 36 wt.%

[0096] (c) 0.2 to 1.0 wt.% of sodium hyaluronate

[0097] (d) providing a pH of about 7.5 at 25.0°C

[0098] Embodiment (6)

[0099] (a) about 1.25 wt.%

[0100] (b) about 33.0 wt.%, consisting of

[0101] (b-1) about 54 wt.%

[0102] (b-2) about 46 wt.%

[0103] (c) 0.5 to 1.5 wt.% of sodium CMC

[0104] (d) providing a pH of about 7.5 at 25.0°C

[0105] Embodiment (7)

[0106] (a) about 1.25 wt. %

[0107] (b) about 33.0 wt.%, consisting of

[0108] (b-1) about 54 wt.%

[0109] (b-2) about 46 wt.%

[0110] (c) 0.2 to 1.0 wt.% of sodium hyaluronate

[0111] (d) providing a pH of about 7.5 at 25.0°C Embodiment (8)

[0112] (a) about 2.5 wt.%

[0113] (b) about 33.0 wt.%, consisting of

[0114] (b-1) about 54 wt.%

[0115] (b-2) about 46 wt.%

[0116] (c) 0.5 to 1.5 wt.% of sodium CMC

[0117] (d) providing a pH of about 7.5 at 25.0°C

[0118] Embodiment (9)

[0119] (a) about 2.5 wt. %

[0120] (b) about 33.0 wt.%, consisting of

[0121] (b-1) about 54 wt.%

[0122] (b-2) about 46 wt.%

[0123] (c) 0.2 to 1.0 wt.% of sodium hyaluronate

[0124] (d) providing a pH of about 7.5 at 25.0°C

[0125] In one embodiment of the present invention, the pharmaceutical composition is a reverse thermosensitive (RT) hydrogel. A RT hydrogel performs the function of a matrix material capable of supporting and releasing API over an extended period of time (sustained release). It has reverse thermosensitive characteristics, also known as thermoreversible characteristics, in that it is liquid at lower temperature and solidifies in the form of a gel at higher temperature. More particularly, the expression "reverse thermosensitive" as used herein refers to a property where the hydrogel is a liquid at least at a temperature of 25.0±0.5°C (room temperature), yet converts into a gel when heated to a temperature of 37.0±0.1°C (body temperature).

[0126] Viscosity

[0127] In one embodiment, the pharmaceutical composition of the present invention has a viscosity of less than 5,000 cP at 25.0±0.5°C and a viscosity of greater than 50,000 cP at 37.0±0.1°C. Preferably, the viscosity at 25.0±0.5°C is less than 1,000 cP, and the viscosity at 37.0±0.1°C is greater than 60,000 cP. More preferably, the viscosity at 25.0±0.5°C is less than 700 cP, and the viscosity at 37.0±0.1°C is greater than 65,000 cP.

[0128] The viscosity of the composition at the specified temperature is determined as follows:

[0129] 1. Viscosity measurement at 37.0±0.1°C

[0130] For the viscosity measurement at 37.0±0.1°C, an Anton Paar rotational viscometer (Visco QC 300H) with PTD 100 (Cone-Plate measuring system) was used. Spindle CP51 was attached to the system and the temperature was set. Gently 5 mL of sample was taken in the measuring cup. The measuring cup was mounted inside the PTD 100 heating tube using clamping bracket. The test was run at a run time of 5 minutes for each test. The viscosity value was recorded from the system and reported for interpretation.

[0131] 2. Viscosity measurement at 25.0±0.5°C

[0132] For the viscosity measurement at 25.0±0.5°C, a Brookfield viscometer (DV-II Plus Pro) with Rheocalc software was used. Gently around lOmL of sample was added in the sample holder, by taking care to avoid air bubbles. Carefully a spindle SC4-18 was inserted in the sample solution and the test was run. The soak time was 3 min and the run time was 5 min for the test of the sample. The shear was kept at 0.5 / s and 4 / s during the soak and run time of the sample. The viscosity value was recorded from the system and reported for interpretation.

[0133] Gelling Onset Temperature

[0134] In one embodiment, the pharmaceutical composition of the present invention has a gelling onset temperature of between 20.0 and 35.0°C. Preferably, the gelling onset temperature is in the range of 23.0 to 34.0°C. More preferably, the gelling onset temperature is in the range of 24.0 to 33.0°C. The gelling onset temperature of the composition is determined by using a TA Rheometer (Discovery HR 10) with TRIOS software. After initial calibration with 40mm parallel plate geometry, the rheometer was set for test initiation. The rheometer base plate temperature was set to 15°C and slowly about 1 mL sample was added from a syringe on the plate. The geometry gap was set, and the test was started. On completion of the test, the gelling onset temperature was recorded by the software.

[0135] Stability

[0136] In one embodiment, the pharmaceutical composition of the present invention is stable at 25.0°C for at least 30 days, preferably for at least 90 days, more preferably for at least 180 days. The stability of the composition is determined using the HPLC based related substance method as described in US pharmacopeia (USP43-NF38 - 2094). The following parameters were used in the method.

[0137] 1. Analytical Column (Stationary Phase): Agilent Zorbax SB C8, 250 x 4.6 mm, 5p with guard column C8, 4.0 x 2.0 mm.

[0138] 2. Mobile phase: A: 2.5 pH phosphate Buffer, B: Methanol

[0139] 3. Run time: 30 min

[0140] The related substances estimated along with their relative retention time and acceptance criteria are as given below:

[0141] * NMT = Not more than; Imp. = Impurity; Hig. Unk. = Highest Unknown

[0142] Generally, the thermoreversible characteristics, the viscosity and the gelling onset temperature of the pharmaceutical composition of the present invention can be adjusted by means of the identity and proportions of the components (a) to (d) as disclosed herein. Use according to the Second Aspect of the Invention and Method of Treatment according to the Third Aspect of the Invention

[0143] The pharmaceutical composition of the present invention is suitably used in the treatment of urinary tract cancer, bladder cancer, or upper tract urothelial carcinoma, in particular non-muscle invasive bladder cancer.

[0144] In a method of treating urinary tract cancer, bladder cancer, or upper tract urothelial carcinoma, in particular non-muscle invasive bladder cancer, a therapeutically effective amount of the pharmaceutical composition of the present invention is administered through the urethra to the bladder of a patient in need thereof.

[0145] The pharmaceutical composition is normally administered intravesically by using a syringe and a catheter. At the time of administration, the temperature of the pharmaceutical composition should be below the gelling onset temperature of the composition, for example at 25.0±0.5°C (room temperature), thus providing a syringeable liquid, i.e. a liquid that can be passed through a syringe with connected catheter. Generally, owing to its inherent properties, the composition of the present invention has the benefit of not requiring cooling prior to administration. The composition will pass through the catheter into the bladder as a liquid. When the composition assumes body temperature, it solidifies and forms a gel that includes the API. Owing to its mucoadhesive characteristics, the gel can stick to the inner surface (mucosa) of the bladder, so that the composition cannot be excreted from the bladder by voiding. Instead, it will release API in a sustained manner over hours, days or weeks.

[0146] Experimental Section

[0147] The present invention is further described in the following examples, which are not in any way intended to limit the scope of the invention as defined in the claims.

[0148] Materials

[0149] Gemcitabine hydrochloride (API)

[0150] Docetaxel (API) • Poloxamer 407 (P407; F127)

[0151] • Poloxamer 188 (P188; F68)

[0152] • Sodium carboxymethyl cellulose (NaCMC)

[0153] • Potassium dihydrogen phosphate (KH2PO4)

[0154] • Sodium hydroxide (NaOH)

[0155] • Sodium hyaluronate

[0156] • Sulfobutylether-P-Cyclodextrin (SBECD)

[0157] • Hydroxypropyl- P-Cyclodextrin (HP-|3-CD)

[0158] • Water for injection (WFI)

[0159] Manufacturing process:

[0160] Step 1: Phosphate buffer solution of pH 8 was prepared by dissolving potassium dihydrogen phosphate and sodium hydroxide in water for injection.

[0161] Step 2: Poloxamer 407 and poloxamer 188 were added to phosphate buffer solution prepared in step 1 and allowed for soaking and wetting to form a clear mixture.

[0162] Step 3: Sodium carboxymethyl cellulose or sodium hyaluronate was added to the polymer mixture prepared in step 2 to form a homogeneous mixture.

[0163] Step 4: Gemcitabine hydrochloride was added to the homogeneous polymer mixture prepared in step 3 to form a homogenous mixture.

[0164] Step 5: Sodium hydroxide solution was added to the homogenous mixture prepared in step 4 to adjust pH to 7.5.

[0165] Step 6: Final weight was adjusted by addition of phosphate buffer solution and mixed using overhead stirrer to get a homogeneous mixture.

[0166] Step 7: The homogenous mixture was filled in glass vials and sealed with rubber stopper and aluminum seal.

[0167] Step 8: Product in glass vials was sterilized by autoclave at 121°C temperature, 1 bar pressure for 15 minutes time to obtain the pharmaceutical composition.

[0168] Examples 1 to 9

[0169] The pharmaceutical compositions were prepared in accordance with the above manufacturing process to provide Examples 1 to 9 as summarized in Table 1 below. Table 1: Liquid compositions of gemcitabine

[0170] Comparative Examples 1 to 3

[0171] The pharmaceutical compositions were prepared in accordance with the above manufacturing process to provides Comparative Examples 1 to 3 as summarized in Table 2 below.

[0172] Table 2: Liquid compositions of gemcitabine Examples 10 to 12: Liquid compositions of gemcitabine and docetaxel

[0173] The pharmaceutical compositions were prepared in accordance with the below manufacturing process to provide Examples 10 to 12 as summarized in Table 2 below.

[0174] Manufacturing Process:

[0175] 1. Sulfobutylether-P-Cyclodextrin (SBECD) and Hydroxypropyl- P-Cyclodextrin were mixed in water for injection to obtain a solution.

[0176] 2. Polyethylene glycol and povidone were dissolved in alcohol followed by addition of docetaxel and mixed thoroughly to obtain a solution.

[0177] 3. The solutions obtained in step 1 and step 2 were mixed thoroughly.

[0178] 4. In another beaker Phosphate buffer solution of pH 8 was prepared by dissolving potassium dihydrogen phosphate and sodium hydroxide in water for injection.

[0179] 5. Poloxamer 407 and poloxamer 188 were added to phosphate buffer solution prepared in step 4 and allowed for soaking and wetting to form a clear solution.

[0180] 6. Gemcitabine hydrochloride was added to the homogeneous polymer mixture prepared in step 5 to form a clear solution.

[0181] 7. Solution obtained in step 3 was mixed thoroughly with solution from step 6.

[0182] 8. Final weight was adjusted by addition of water for injection and the solution was filled in glass vials and sealed with rubber stopper and aluminum seal.

[0183] Table 2: Liquid compositions of gemcitabine and docetaxel

[0184] Physicochemical Properties

[0185] The viscosity (cP) at 37.0±0.1°C and viscosity (cP) at 25.0±0.5°C of the formulations of Examples 1 to 9 and Comparative Examples 1 to 3 were studied and are represented in Fig. 1 and 2. The gelling onset temperature (°C) of the formulations of Examples 1 to 9 and Comparative Examples 1 to 3 were studied and are represented in Fig. 3.

[0186] The viscosity (cP) at 37.0±0.1°C and viscosity (cP) at 25.0±0.5°C of the formulations of Examples 10 to 12 were studied and are represented in Fig. 7 and 8. The gelling onset temperature (°C) of the formulations of Examples 10 to 12 are represented in Fig. 9.

[0187] Examples 1-12 all reach a viscosity above 50,000 cP at 37.0±0.1°C (i.e. in the body), whereas the comparative examples do not reach the desired viscosity at 37.0±0.1°C.

[0188] Storage Stability

[0189] The storage stability of the compositions of Example 1, 2 and 6 was determined over three months and is summarized in Fig. 4, Fig. 5 and Fig. 6. These examples tested were within the specification limit of related substances across the stability conditions for three months.

Claims

Claims1. A pharmaceutical composition for intravesical administration, comprising(a) an effective amount of gemcitabine or a pharmaceutically acceptable acid addition salt thereof, optionally in combination with an effective amount of docetaxel,(b) 25.0 to 35.0 wt.% of ethylene oxide / propylene oxide triblock copolymers consisting of(b-1) 50 to 70 wt.% of poloxamer 407 and(b-2) 30 to 50 wt.% of poloxamer 188,(c) optionally 0.2 to 2.0 wt.% of viscosity adjusting agent, and(d) a pharmaceutically acceptable buffer solution.

2. The pharmaceutical composition according to claim 1, comprising 27.0 to 33.0 wt.%, preferably 27.5 to 28.5 wt.%., even more preferably about 28.0 wt.% of (b) ethylene oxide / propylene oxide triblock copolymers.

3. The pharmaceutical composition according to claim 1 or 2, wherein the ethylene oxide / propylene oxide triblock copolymers consist of 50 to 60 wt.% of poloxamer 407 (b-1) and 40 to 50 wt.% of poloxamer 188 (b-2), preferably 52 to 55 wt.% of poloxamer 407 (b-1) and 45 to 48 wt.% of poloxamer 188 (b-2), more preferably about 54 wt.% of poloxamer 407 (b-1) and about 46 wt.% of poloxamer 188 (b-2).

4. The pharmaceutical composition according to any one of claims 1 to 3, comprising 0.2 to 2.0 wt.% of viscosity adjusting agent (c), preferably 0.5 to 1.5 wt.% of sodium carboxymethyl cellulose or 0.2 to 1.0 wt.% of sodium hyaluronate.

5. The pharmaceutical composition according to any one of claims 1 to 4, comprising 0.5 to 2.5 wt.% of (a) gemcitabine or a pharmaceutically acceptable acid addition salt thereof, optionally in combination with 0.04 to 0.10 wt.% of docetaxel.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the pharmaceutically acceptable acid addition salt of gemcitabine is the hydrochloride salt.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein a buffering agent of the pharmaceutically acceptable buffer solution (d) is potassium dihydrogen phosphate, combined with sodium hydroxide.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the pharmaceutically acceptable buffer solution (d) provides the composition with a pH in the range of from 7.0 to 8.0, preferably about pH 7.5, at 25.0°C.

9. The pharmaceutical composition according to any one of claims 1 to 8, which does not contain any further viscosity adjusting agent, in particular no hydroxypropylmethyl cellulose and polyethylene glycol 400.

10. The pharmaceutical composition according to any one of claims 1 to 9, which is a reverse thermosensitive hydrogel.

11. The pharmaceutical composition according to any one of claims 1 to 10, having a viscosity of less than 5,000 cP at 25.0°C and a viscosity of greater than 50,000 cP-s at 37.0°C.

12. The pharmaceutical composition according to any one of claims 1 to 11, having a gelling onset temperature of between 20.0 and 35.0°C.

13. The pharmaceutical composition according to any one of claims 1 to 12, which is stable at 25.0°C for at least 30 days.

14. The pharmaceutical composition according to any one of claims 1 to 13 for use in the treatment of urinary tract cancer, bladder cancer, or upper tract urothelial carcinoma, in particular non-muscle invasive bladder cancer.

15. A method of treating urinary tract cancer, bladder cancer, or upper tract urothelial carcinoma, in particular non-muscle invasive bladder cancer, the method comprising administering a therapeutically effective amount of the pharmaceutical composition according to any one of claims 1 to 13 through the urethra to the bladder of a patient in need thereof.

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