Patent Application
20240082253
The presented invention relates to a lyophilized pharmaceutical formulation comprising:
The presented invention relates to a lyophilized pharmaceutical formulation comprising:
The copanlisib salt is preferably hydrochloride salt or dihydrochloride salt or hydrogen phosphate salt or malate salt.
The formulation optionally comprises glycine. The ratio between the bulking agent selected from trehalose or lactose and glycine can be between 2:5 to 5:2 (parts by weight), said ratios of excipients being calculated on the anhydrous basis and the sum of the parts by weight of the sugar component and glycine is 7.
Glycine as Tg′-modifier (glass transition temperature modifier) capable of modifying a sufficiently Tg′ of the pharmaceutical solution to higher temperatures and therefore improves the economy of process for preparation of the formulation.
The weight ratio between the copanlisib salt and the bulking agent can be between 1:2 and 1:2.5, preferably between 1:2.1 and 1:2.3. In the case both the bulking agent and glycine are used, the weight ratio between copanlisib or a salt thereof and sum of the bulking agent and glycine can be between 1:2 and 1:2.5, preferably between 1:2.2 and 1:2.4.
The bulking agent selected from lactose or trehalose can be used either in an anhydrous form or in a hydrated form. Trehalose is preferably used as trehalose dihydrate, lactose is preferably used as lactose monohydrate.
It has been surprisingly found that the use of lactose or trehalose provides better stability than other bulking agents disclosed in the prior art. Comparative trials have been performed against mannitol and glycine among others bulking agents, the results are disclosed in Examples 1 to 8.
In comparison with the formulation disclosed in WO2019/048527, the formulation of the presented invention has following advantages:
The presented invention further relates to a pharmaceutical solution comprising:
The pharmaceutical solution further optionally comprises glycine.
The concentration of copanlisib salt thereof in the solution is preferably 30 mg/ml (calculated on copanlisib as a base). The salt of copanlisib is preferably hydrochloride salt or dihydrochloride salt or hydrogen phosphate salt or malate salt. In a preferred embodiment of the invention the copanlisib salt is formed in situ during the manufacturing process by contacting copanlisib with an acid in the solvent.
The bulking agent selected from lactose or trehalose can be used either in an anhydrous form or in a hydrated form. Trehalose is preferably used as trehalose dihydrate, lactose is preferably used as lactose monohydrate.
The weight ratio between copanlisib salt and the bulking agent (calculated as anhydrous form) can be between 1:2 and 1:2.5, preferably between 1:2.1 and 1:2.3. The concentration of trehalose (calculated as anhydrous form) in the pharmaceutical solution can be between 62.5 mg/ml and 72.5 mg/ml, preferably it is 67.5 mg/ml. The concentration of lactose (calculated as anhydrous form) in the pharmaceutical solution can be between 58.5 mg/ml and 68.5 mg/ml, preferably it is 63.2 mg/ml.
In the case glycine is used the ratio between the bulking agent and glycine can be between 2:5 to 5:2 (parts by weight), said ratios of excipients being calculated on the anhydrous basis and the sum of the parts by weight of the sugar component and glycine is 7 and the weight ratio between copanlisib or a salt thereof and the sum of the bulking agent and glycine can be between 1:2 and 1:2.5, preferably between 1:2.2 and 1:2.4. The concentration of trehalose (calculated as anhydrous form) or lactose (calculated as anhydrous form) in the pharmaceutical solution can be between 20 mg/ml and 70 mg/ml. The concentration of glycine in the pharmaceutical solution can be between 30 mg/ml and 60 mg/ml, preferably it is between 40 mg/ml and 50 mg/ml.
The solvent is preferably water, more preferably water for injection.
pH of the solution can be adjusted for example 2 M aqueous sodium hydroxide solution. Preferably, pH of the solution is adjusted to pH greater than 5.5, preferably to pH between 5.5 and 5.7.
The pharmaceutical solution can be further processed to a lyophilized dosage forms suitable for parenteral administration after reconstitution.
It has been surprisingly found that the stability of the prepared solutions remains unchanged for at least 72 hours, which is particularly advantageous for the industrial production of injectable dosage forms. The tested solutions remained clear and without precipitation for the indicated time. Also, the stability of the drug products prepared according to examples shows a significant improvement in terms of purity compared to the formulations disclosed in WO2019/048527 as is presented in Example 7.
The presented invention further relates to a process for preparation of lyophilized pharmaceutical formulation comprising:
The process steps are preferably performed under a protective atmosphere, for example using nitrogen or argon. The salt can be selected from copanlisib salt with hydrochloric acid or phosphoric acid (H3PO4) or malic acid. The suitable solvent is preferably water. pH of the solution is preferably adjusted to pH between 5.5 and 5.7. The formulation can optionally comprising glycine.
In a preferred embodiment of the invention the copanlisib salt is prepared “in situ” by contacting copanlisib base with an acid in the solvent. In the preferred embodiment of the invention the of lyophilized pharmaceutical formulation comprising:
The pharmaceutical formulation can optionally comprising glycine. The process steps are preferably performed under a protective atmosphere, for example using nitrogen or argon. The concentration of copanlisib base in the solvent is preferably 30 mg/ml. The acid can be selected form hydrochloric acid or phosphoric acid (H3PO4) or malic acid. The acid can be added in a form of a solution of the acid in the suitable solvent. The molar ratio between copanlisib base and the hydrochloric acid can be between 1:2 and 1:2.4. The molar ratio between copanlisib and phosphoric acid (H3PO4) or malic acid can be between 1:1 and 1:1.3. The mixture is then stirred for between 10 and 60 minutes to obtain a solution. For the preparation of said salts “in situ”, it is advantageous to use the corresponding acids, i.e. hydrochloric acid or malic acid or phosphoric acid (H3PO4) in an excess of 10% with respect to their stoichiometric amount needed to form the salt. The benefit of this process is the surprising simplicity of the process and economic advantage, where the “in situ” preparation eliminates yield losses due to salt isolation by crystallization or precipitation, further material handling such as separation drying and subsequent characterization. It is generally known that each crystallization step can reduce the yield by 10 to 30% (w/w).
The suitable solvent is preferably water. pH of the solution is preferably adjusted to pH higher than 5.5, more preferably to pH between 5.5 and 5.7, advantageously with sodium hydroxide water solution (for example 2 M solution).
The pharmaceutical solution for lyophilization preferably contains:
The concentration of the bulking agent in the pharmaceutical solution is preferably:
In the case glycine is optionally used, the concentration of bulking agent trehalose or lactose is preferably between 20 mg/ml and 30 mg/ml (calculated on trehalose anhydrous form or lactose anhydrous form) and the ratio between the bulking agent and glycine can be between 2:5 to 5:2 (parts by weight), said ratios of excipients being calculated on the anhydrous basis and the sum of the parts by weight of the sugar component and glycine is 7.
The prepared pharmaceutical solution can be further processed to lyophilized injectable dosage forms as described in Examples or by a process comprising:
After reconstitution, for example in saline solution, the lyophilized formulation according to presented invention can be used for treatment conditions treatable by copanlisib or a salt thereof.
The invention will be further illustrated by the following examples.
2000 mg of Mannitol was mixed with 1152 mg of copanlisib dihydrochloride, 92 mg of citric acid anhydrous and 23 mL water for injection (WFI). The mixture was sonicated for 60 seconds. Pale yellow solution was formed. pH of the solution was then adjusted using 2 M NaOH to pH 4.58. Volume was made up to 25 mL with WFI.
Solution was filtered using a 0.22-micron syringe filter (PVDF), filled into ISO 6R vials and semi-stoppered with two leg stoppers. Filling dose was 1.71 ml per vial, overfill corresponds with 8.4 mg of Copanlisib base.
In order to obtain the product without any risks of the cake collapse or any chemical degradation, the lyophilization process was conducted at the conservative parameters presented in the WO2019/048527.
Thus, filled vials were loaded in in the lyophilization chamber and lyophilized using Epsilon 2-6D according to following program:
In the end of the lyophilization process vials were closed under vacuum directly into the lyophilization chamber.
Prepared vials (after lyophilization) were put on stability study at 40° C./75% R.H. Stability study results are presented in following table. Purity was determined by HPLC (Waters Alliance) with UV detection. Physical parameters were evaluated using method according to Ph. Eur. (pH, color, clarity).
After reconstitution with 4.4 ml of saline (0.9% NaCl), concentration of formed solution is 15 mg/ml of Copanlisib base.
Stability study results (storage conditions 40° C./75% R.H.)
3746.2 mg of trehalose dihydrate was mixed with 1728 mg of copanlisib dihydrochloride and 45 mL water for injection (WFI). The mixture was sonicated for 60 seconds. Pale yellow solution was formed.
pH of the solution was then adjusted using 2 M NaOH to pH 5.57. Volume was made up to 50 mL with WFI.
Solution was filtered using a 0.22-micron syringe filter (PVDF), filled into ISO 6R vials and semi-stoppered with two leg stoppers. Filling dose was 2.28 ml per vial, overfill corresponds with 8.4 mg of Copanlisib base.
Filled vials were loaded in in the lyophilization chamber and lyophilized using Epsilon 2-6D according to following program:
In the end of the lyophilization process vials were closed under vacuum directly into the lyophilization chamber.
Prepared vials were put on stability study at 40° C./75% R.H. Purity was determined by HPLC (Waters Alliance) with UV detection. Physical parameters were evaluated using method according to Ph. Eur. (pH, color, clarity).
After reconstitution with 4.4 ml of saline (0.9% NaCl), concentration of formed solution is 15 mg/ml of Copanlisib base.
Stability study results (storage conditions 40° C./75% R.H.)
3507.6 mg of lactose monohydrate was mixed with 1728 mg of copanlisib dihydrochloride and 40 mL water for injection (WFI), sonicated for 4 minutes. Pale yellow solution was formed.
pH of the solution was then adjusted using 2 M NaOH to pH 5.69. Volume was made up to 50 mL with WFI.
Solution was filtered using a 0.22-micron syringe filter (PVDF), filled into ISO 6R vials and semi-stoppered with two leg stoppers. Filling dose was 2.28 ml per vial, overfill corresponds with 8.4 mg of Copanlisib base.
Filled vials were loaded in in the lyophilization chamber and lyophilized using Epsilon 2-6D according to following program:
In the end of the lyophilization process vials were closed under vacuum directly into the lyophilization chamber.
Prepared vials were put on stability study at 40° C./75% R.H. Stability study results are presented in following table. Purity was determined by HPLC (Waters Alliance) with UV detection. Physical parameters were evaluated using method according to Ph. Eur. (pH, color, clarity).
After reconstitution with 4.4 ml of saline (0.9% NaCl), concentration of formed solution is 15 mg/ml of Copanlisib base.
Stability study results (storage conditions 40° C./75% R.H.)
Composition of pharmaceutical solutions:
Example 4A: 1728 mg of copanlisib dihydrochloride were mixed with 3500 mg of glycine and 30 ml of water for injection (WFI) previously bubbled with nitrogen for 20 minutes. The mixture was stirred for 15 min at 400 rpm until dissolution. Yellow solution was formed.
pH of the solution was then adjusted using 2 M NaOH to pH 5.60. Volume was made up to 50 mL with WFI. pH of the solution was 5.45, therefore pH was readjusted by 2 M NaOH solution to pH 5.60.
Solution was filtered using a 0.22-micron syringe filter (PVDF), filled into ISO 6R vials and semi-stoppered with two leg stoppers. Filling dose was 2.28 ml per vial, overfill corresponds with 8.4 mg of Copanlisib base.
The pharmaceutical solution was analyzed after filtration and after 72 hours of storages at 5° C. Purity was determined by HPLC (Waters Alliance) with UV detection. No precipitation was seen in the pharmaceutical solution.
Example 4B: 1728 mg of copanlisib dihydrochloride was mixed with 2500 mg of glycine, 1110 mg of trehalose dihydrate and 30 ml of water for injection (WFI) previously bubbled with nitrogen for 20 minutes. The mixture was stirred at 400 rpm for 15 minutes until dissolution. Yellow solution was formed.
pH of the solution was then adjusted using 2 M NaOH to pH 5.61. Volume was made up to 50 mL with WFI. pH was readjusted by 2 M NaOH solution to 5.60.
Solution was filtered using a 0.22-micron syringe filter (PVDF), filled into ISO 6R vials and semi-stoppered with two leg stoppers. Filling dose was 2.28 ml per vial, overfill corresponds with 8.4 mg of Copanlisib base.
The pharmaceutical solution was analyzed after filtration and after 72 hours of storages at 5° C. Purity was determined by HPLC (Waters Alliance) with UV detection. No precipitation was seen in the pharmaceutical solution.
Example 4C: 1728 mg of copanlisib dihydrochloride was mixed with 2500 mg of glycine, 1050 mg of lactose monohydrate and 30 ml of water for injection (WFI) previously bubbled with nitrogen for 20 minutes. The mixture was stirred at 400 rpm for 15 minutes until dissolution. Yellow solution was formed.
pH of the solution was then adjusted using 2 M NaOH to pH 5.60. Volume was made up to 50 mL with WFI. pH was readjusted by 2 M NaOH solution to 5.57.
Solution was filtered using a 0.22-micron syringe filter (PVDF), filled into ISO 6R vials and semi-stoppered with two leg stoppers. Filling dose was 2.28 ml per vial, overfill corresponds with 8.4 mg of Copanlisib base.
The pharmaceutical solution was analyzed after filtration and after 72 hours of storages at 5° C. Purity was determined by HPLC (Waters Alliance) with UV detection. No precipitation was seen in the pharmaceutical solution.
Vials prepared according to Examples 4A, 4B and 4C were loaded in in the lyophilization chamber and lyophilized using Epsilon 2-6D) according to following program:
In the end of the lyophilization process vials were closed under vacuum directly into the lyophilization chamber.
Prepared vials were put on stability study at 40° C./75% R.H. Stability study results are presented in following table. Purity was determined by HPLC (Waters Alliance) with UV detection. Physical parameters were evaluated using method according to Ph. Eur. (pH, color, clarity).
After reconstitution with 4.4 ml of saline (0.9% NaCl), concentration of formed solution is 15 mg/ml of Copanlisib base.
Composition of pharmaceutical solutions:
Example 5A: 1500 mg of copanlisib base was mixed with 3500 mg of Glycine and 20 mL of water for injection (WFI). 5 ml Phosphoric acid (H3PO4) in form of diluted solution (88 mg/ml in water) was added and the mixture was stirred for 15 minutes at 400 rpm until dissolution. Yellow solution was formed.
pH of the solution was then adjusted using 2 M NaOH to pH 5.63. Volume was made up to 50 mL with WFI, pH was not changed.
Solution was filtered using a 0.22-micron syringe filter (PES), filled into ISO 6R vials and semi-stoppered with two leg stoppers. Filling dose was 2.28 ml per vial, overfill corresponds with 8.4 mg of Copanlisib base.
The pharmaceutical solution was analyzed after filtration and after 72 hours of storages at 5° C. Purity was determined by HPLC (Waters Alliance) with UV detection. No precipitation was seen in the pharmaceutical solution.
Example 5B: 1500 mg of copanlisib base was mixed with 2500 mg of Glycine, 1110 mg of trehalose dihydrate and 20 mL of water for injection (WFI). 5 ml of Phosphoric acid in form of diluted solution (88 mg/ml in water) was added. The mixture was stirred for 15 minutes at 400 rpm until dissolution. Yellow solution was formed. pH of the solution was then adjusted using 2 M NaOH to pH 5.67. Volume was made up to 50 mL with WFI.
Solution was filtered using a 0.22-micron syringe filter (PES), filled into ISO 6R vials and semi-stoppered with two leg stoppers. Filling dose was 2.28 ml per vial, overfill corresponds with 8.4 mg of Copanlisib base.
The pharmaceutical solution was analyzed after filtration and after 72 hours of storages at 5° C. Purity was determined by HPLC (Waters Alliance) with UV detection. No precipitation was seen in the pharmaceutical solution.
Example 5C: 1500 mg of Copanlisib base was mixed with 2500 mg of Glycine, 1050 mg of Lactose monohydrate and 20 mL of water for injection (WFI). 5 ml of Phosphoric acid in form of diluted solution (88 mg/ml in water) was added and the mixture stirred for 15 minutes at 400 rpm until dissolution. Yellow solution was formed.
pH of the solution was then adjusted using 2 M NaOH to pH 5.63. Volume was made up to 50 mL with WFI.
Solution was filtered using a 0.22-micron syringe filter (PES), filled into ISO 6R vials and semi-stoppered with two leg stoppers. Filling dose was 2.28 ml per vial, overfill corresponds with 8.4 mg of Copanlisib base.
The pharmaceutical solution was analyzed after filtration and after 72 hours of storages at 5° C. Purity was determined by HPLC (Waters Alliance) with UV detection. No precipitation was seen in the pharmaceutical solution.
Vials prepared according to Examples 5A, 5B and 5C were loaded in the lyophilization chamber and lyophilized using Christ Epsilon 2-6D according to following program:
In the end of the lyophilization process vials were closed under vacuum directly into the lyophilization chamber.
Prepared vials were put on stability study at 40° C./75% R.H. Stability study results are presented in following table. Purity was determined by HPLC (Waters Alliance) with UV detection. Physical parameters were evaluated using method according to Ph. Eur. (pH, color, clarity).
After reconstitution with 4.4 ml of saline (0.9% NaCl), concentration of formed solution is 15 mg/ml of Copanlisib base.
Example 5A Glycine: Stability study results (storage conditions 40° C./75% R.H.)
Composition of pharmaceutical solutions:
Example 6A: 1500 mg of Copanlisib base was mixed with 3500 mg of Glycine and 20 mL of water for injection (WFI). 5 ml of Malic acid in form of diluted solution (97 mg/ml in water) was added and the mixture stirred for 15 minutes at 400 rpm until dissolution. Yellow solution was formed.
pH of the solution was then adjusted using 2 M NaOH to pH 5.63. Volume was made up to 50 mL with WFI. pH was readjusted by 2 M NaOH solution to 5.61.
Solution was filtered using a 0.22-micron syringe filter (PES), filled into ISO 6R vials and semi-stoppered with two leg stoppers. Filling dose was 2.28 ml per vial, overfill corresponds with 8.4 mg of Copanlisib base.
The pharmaceutical solution was analyzed after filtration and after 72 hours of storages at 5° C. Purity was determined by HPLC (Waters Alliance) with UV detection. No precipitation was seen in the pharmaceutical solution.
Example 6B: 1500 mg of copanlisib base was mixed with 2500 mg of Glycine, 1110 mg of Trehalose dihydrate and 20 mL of water for injection (WFI). 5 ml of Malic acid in form of diluted solution (97 mg/ml in water) was added and the mixture was stirred for 15 minutes at 400 rpm until dissolution. Pale yellow solution was formed.
pH of the solution was then adjusted using 2 M NaOH to pH 5.64. Volume was made up to 50 mL with WFI.
Solution was filtered using a 0.22-micron syringe filter (PES), filled into ISO 6R vials and semi-stoppered with two leg stoppers. Filling dose was 2.28 ml per vial, overfill corresponds with 8.4 mg of Copanlisib base.
The pharmaceutical solution was analyzed after filtration and after 72 hours of storages at 5° C. Purity was determined by HPLC (Waters Alliance) with UV detection. No precipitation was seen in the pharmaceutical solution.
Example 6C: 1500 mg of Copanlisib base was mixed with 2500 mg of Glycine, 1050 mg of Lactose monohydrate and 20 mL of water for injection (WFI). 5 ml of Malic acid in form of diluted solution (97 mg/ml in water) was added and the mixture stirred for 15 minutes at 400 rpm until dissolution. Pale yellow solution was formed.
pH of the solution was then adjusted using 2 M NaOH to pH 5.67. Volume was made up to 50 mL with WFI.
Solution was filtered using a 0.22-micron syringe filter (PES), filled into ISO 6R vials and semi-stoppered with two leg stoppers. Filling dose was 2.28 ml per vial, overfill corresponds with 8.4 mg of Copanlisib base.
The pharmaceutical solution was analyzed after filtration and after 72 hours of storages at 5° C. Purity was determined by HPLC (Waters Alliance) with UV detection. No precipitation was seen in the pharmaceutical solution.
Vials prepared according to Examples 6A, 6B and 6C were loaded in in the lyophilization chamber and lyophilized using Christ Epsilon 2-6D) according to following program:
In the end of the lyophilization process vials were closed under vacuum directly into the lyophilization chamber.
Prepared vials were put on stability study at 40° C./75% R.H. Stability study results are presented in following table. Purity was determined by HPLC (Waters Alliance) with UV detection. Physical parameters were evaluated using method according to Ph. Eur. (pH, color, clarity).
After reconstitution with 4.4 ml of saline (0.9% NaCl), concentration of formed solution is 15 mg/ml of Copanlisib base.
Example 6A Glycine: Stability study results (storage conditions 40° C./75% R.H.)
Example 6B Trehalose+Glycine: Stability study results (storage conditions 40° C./75% R.H.)
Example 6C Lactose+Glycine: Stability study results (storage conditions 40° C./75% R.H.)
Composition of pharmaceutical solutions:
Example 7A: 1500 mg of copanlisib base was mixed with 2000 mg of Glycine, 1665 mg of Trehalose dihydrate and 20 mL of water for injection (WFI). 5 ml of Phosphoric acid (H3PO4) in form of diluted solution (88 mg/ml in water) was added and the mixture was stirred for 15 minutes at 400 rpm until dissolution. Yellow solution was formed.
pH of the solution was then adjusted using 2 M NaOH to pH 5.64. Volume was made up to 50 mL with WFI.
Solution was filtered using a 0.22-micron syringe filter (PES), filled into ISO 6R vials and semi-stoppered with two leg stoppers. Filling dose was 2.28 ml per vial, overfill corresponds with 8.4 mg of Copanlisib base.
The pharmaceutical solution was analyzed after filtration and after 72 hours of storages at 5° C. Purity was determined by HPLC (Waters Alliance) with UV detection. No precipitation was seen in the pharmaceutical solution.
Example 7B: 1500 mg of copanlisib base was mixed with 2000 mg of Glycine, 1575 mg of Lactose and 20 mL of water for injection (WFI). 5 ml of Phosphoric acid in form of diluted solution (88 mg/ml in water) was added and the mixture was stirred for 15 minutes at 400 rpm until dissolution. Yellow solution was formed. pH of the solution was then adjusted using 2 M NaOH to pH 5.66. Volume was made up to 50 mL with WFI.
Solution was filtered using a 0.22-micron syringe filter (PES), filled into ISO 6R vials and semi-stoppered with two leg stoppers. Filling dose was 2.28 ml per vial, overfill corresponds with 8.4 mg of Copanlisib base.
The pharmaceutical solution was analyzed after filtration and after 72 hours of storages at 5° C. Purity was determined by HPLC (Waters Alliance) with UV detection. No precipitation was seen in the pharmaceutical solution.
Vials prepared according to 7A and 7B were loaded in in the lyophilization chamber and lyophilized using Christ Epsilon 2-6D according to following program:
In the end of the lyophilization process vials were closed under vacuum directly into the lyophilization chamber.
Prepared vials were put on stability study at 40° C./75% R.H. Stability study results are presented in following table. Purity was determined by HPLC (Waters Alliance) with UV detection. Physical parameters were evaluated using method according to Ph. Eur. (pH, color, clarity).
After reconstitution with 4.4 ml of saline (0.9% NaCl), concentration of formed solution is 15 mg/ml of Copanlisib base.
Example 7A Trehalose+Glycine: Stability study results (storage conditions 40° C./75% R.H.)
Example 7B Lactose+Glycine: Stability study results (storage conditions 40° C./75% R.H.)
Composition of pharmaceutical solutions:
Example 8A: 1500 mg of copanlisib base was mixed with 2000 mg of Glycine and 1665 mg of trehalose dihydrate and 20 mL of water for injection (WFI). 5 ml of Malic acid in form of diluted solution (97 mg/ml in water) was added and the mixture was stirred for 15 minutes at 400 rpm until dissolution. Pale yellow solution was formed. pH of the solution was then adjusted using 2 M NaOH to pH 5.68. Volume was made up to 50 mL with WFI.
Solution was filtered using a 0.22-micron syringe filter (PES), filled into ISO 6R vials and semi-stoppered with two leg stoppers. Filling dose was 2.28 ml per vial, overfill corresponds with 8.4 mg of Copanlisib base.
The pharmaceutical solution was analyzed after filtration and after 72 hours of storages at 5° C. Purity was determined by HPLC (Waters Alliance) with UV detection. No precipitation was seen in the pharmaceutical solution.
Example 8B: 1500 mg of Copanlisib base was mixed with 2000 mg of Glycine, 1575 mg of Lactose monohydrate and 20 mL of water for injection (WFI). 5 ml of Malic acid in form of diluted solution (97 mg/ml in water) was added and the mixture was stirred for 15 minutes at 400 rpm until dissolution. Pale yellow solution was formed.
pH of the solution was then adjusted using 2 M NaOH to pH 5.71. Volume was made up to 50 mL with WFI.
Solution was filtered using a 0.22-micron syringe filter (PES), filled into ISO 6R vials and semi-stoppered with two leg stoppers. Filling dose was 2.28 ml per vial, overfill corresponds with 8.4 mg of Copanlisib base.
The pharmaceutical solution was analyzed after filtration and after 72 hours of storages at 5° C. Purity was determined by HPLC (Waters Alliance) with UV detection. No precipitation was seen in the pharmaceutical solution.
Vials prepared according to 8A and 8B were loaded in in the lyophilization chamber and lyophilized using Christ Epsilon 2-6D according to following program:
In the end of the lyophilization process vials were closed under vacuum directly into the lyophilization chamber.
Prepared vials were put on stability study at 40° C./75% R.H. Stability study results are presented in following table. Purity was determined by HPLC (Waters Alliance) with UV detection. Physical parameters were evaluated using method according to Ph. Eur. (pH, color, clarity).
After reconstitution with 4.4 ml of saline (0.9% NaCl), concentration of formed solution is 15 mg/ml of Copanlisib base.
Example 8A Trehalose+Glycine: Stability study results (storage conditions 40° C./75% R.H.)
Example 8B Lactose+Glycine: Stability study results (storage conditions 40° C./75% R.H.)
In drawing 1 the stability data of lyophilized formulations comprising copanlisib or a salt thereof and a bulking agent selected from trehalose or lactose and optionally glycine are depicted.
It can be concluded that stability (expressed as the change of sum of impurities in time) of lyophilized formulation according to presented invention (EX 2, EX 3, EX 4B, EX 4C, EX 5B, EX 5C, EX 6B, EX 6C) is significantly better that the stability of lyophilized formulation prepared according to prior art WO2019/048527 (Example 1, Replica in the chart).
In drawing 2 stabilities of formulations comprising only glycine and combination of glycine and trehalose or lactose are depicted.
It can be concluded that stabilities of formulation comprising glycine only (EX 5A, EX 6A) are much worse that stabilities of formulation comprising glycine and trehalose or lactose (EX 5B, EX 5C, EX 6B, EX 6C).
| Number | Date | Country | Kind |
|---|---|---|---|
| 21166992.4 | Apr 2021 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2022/058763 | 4/1/2022 | WO |
