DESC:FIELD OF THE INVENTION

The present invention relates to a stable Carfilzomib injection comprising Carfilzomib or pharmaceutically acceptable salts thereof with pharmaceutically acceptable excipients that substantially increase the solubility, wherein the said injection is free from cyclodextrin derivatives. Further the present invention also relates to a process for the preparation of the stable Carfilzomib injection and methods of treatment thereof.

BACKGROUND OF THE INVENTION

Proteasome inhibitor compounds such as Bortezomib and Carfilzomib have been available as FDA approved drugs for the treatment of multiple myeloma. Carfilzomib Injection (KYPROLIS® available as 60 mg/vial) marketed by Onyx Pharms, is approved for use in patients with multiple myeloma who have received at least two prior therapies, including treatment with bortezomib and an immunomodulatory therapy and have demonstrated disease progression on or within 60 days of completion of the last therapy.

Chemically, Carfilzomib is a peptide epoxyketone compound, which is having very low solubility in water. Due to its chemical complexity and low aqueous solubility, it results into several challenges to formulate pharmaceutical compositions with desired bioavailability. The chemical structure of Carfilzomib is shown as below:

Carfilzomib is disclosed in U.S. Patent Nos. 7,232,818; 7,417,042; 7491704 and 8129346, which describe the peptide epoxyketone compounds and its use for the treatment of cancer. U.S. Patent No. 7,737,112 discloses the pharmaceutical composition comprising Carfilzomib and a substituted cyclodextrin selected from hydroxypropyl beta-cyclodextrin and sulfobutyl ether beta-cyclodextrin (SBECD).

Since Carfilzomib has low aqueous solubility, the development of a stable Carfilzomib Injection is very challenging. Further, the cost-effective accessibility and feasibility of substituted cyclodextrins limits their extensive use. Hence there exists a need to make available simple methods of formulating stable lyophilized Carfilzomib Injections with pharmaceutically acceptable excipients.

The U.S. Patent Application No. US2014/073583 describes a liquid formulation comprising (i) Carfilzomib, (ii) a water-miscible organic solvent and (iii) a non-volatile sugar acid.

Therefore, there exists the need for the development of a stable Carfilzomib Injection that substantially increases the solubility and provides the desired bioavailability. In particular, the present invention provides a stable Carfilzomib Injection as a pre-lyophilization solution that produces a stable lyophized powder. Alternatively, the present invention also provides a ready-to-use or ready-to-dilute composition.

OBJECTS OF THE INVENTION

The primary object of the present invention is to provide a stable Carfilzomib Injection comprising Carfilzomib or pharmaceutically acceptable salts thereof with pharmaceutically acceptable excipients that substantially increase the solubility and wherein the said injection is free from cyclodextrin derivatives.

Another object of the invention is to provide a stable Carfilzomib Injection comprising Carfilzomib or pharmaceutically acceptable salts thereof with at least one acid component, at least one organic solvent, optionally with other pharmaceutically acceptable excipients, and wherein the said injection is free from cyclodextrin derivatives.

Another object of the invention is to provide a process for the preparation of a stable Carfilzomib Injection, wherein the said injection is free from cyclodextrin derivatives.

Another object of the invention is to provide a stable Carfilzomib Injection for administering Carfilzomib in patients with multiple myeloma who have received at least two prior therapies, including treatment with bortezomib and an immunomodulatory therapy, and wherein the said injection is free from cyclodextrin derivatives.

SUMMARY OF THE INVENTION

In a first embodiment, the invention relates to a stable Carfilzomib Injection comprising Carfilzomib or pharmaceutically acceptable salts thereof with pharmaceutically acceptable excipients that substantially increase the solubility and wherein the said injection is free from cyclodextrin derivatives.

In another embodiment, the invention relates to a stable Carfilzomib Injection comprising Carfilzomib or pharmaceutically acceptable salts thereof with at least one acid component, at least one organic solvent, optionally with other pharmaceutically acceptable excipients, and wherein the said injection is free from cyclodextrin derivatives.

In another embodiment, the invention relates to a stable Carfilzomib Injection comprising Carfilzomib or pharmaceutically acceptable salts thereof with citric acid, tertiary butyl alcohol and water for injection.

In another embodiment, the invention relates to a stable Carfilzomib Injection comprising Carfilzomib or pharmaceutically acceptable salts thereof with tertiary butyl alcohol, acetic acid and water for injection.

In another embodiment, the invention relates to a process for the preparation of a stable Carfilzomib Injection, wherein the said injection is free from cyclodextrin derivatives.

Another object of the invention is to provide a stable Carfilzomib Injection for administering Carfilzomib in patients with multiple myeloma who have received at least two prior therapies, including treatment with bortezomib and an immunomodulatory therapy, and wherein the said injection is free from cyclodextrin derivatives.

DETAILED DESCRIPTION

The present invention relates to a stable Carfilzomib Injection comprising Carfilzomib or pharmaceutically acceptable salts thereof with pharmaceutically acceptable excipients that substantially increase the solubility and wherein the said injection is free from cyclodextrin derivatives.

The present invention relates to a stable Carfilzomib Injection comprising Carfilzomib or pharmaceutically acceptable salts thereof with at least one acid component, at least one organic solvent, optionally with other pharmaceutically acceptable excipients, and wherein the said injection is free from cyclodextrin derivatives.

The stable Carfilzomib Injection of the present invention have sufficient stability to allow storage at a commercially relevant temperature, such as between about 0.degree. C. and about 40.degree. C., for a commercially relevant period of time, such as at least one month, preferably at least one year, and most preferably at least two years. The stability can be measured using any physiochemical characterization techniques known to those skilled in the art. The stable Carfilzomib Injection of the present invention maintain their physical and chemical stability to allow storage at a commercially relevant temperature, such as 2-8.degree. C. and 25.degree. C.

The term "Injection” as used herein shall mean a pharmaceutical composition that is made under conditions such that it is suitable for parenteral administration to humans, e.g., it is made under GMP conditions and contains pharmaceutically acceptable excipients.

For the sake of the present invention, as used herein the term “stable Carfilzomib Injection” means: (i) a pre-lyophilization solution that produces a stable lyophized powder; or (ii) a pharmaceutical composition in the form of ready-to-use injection.

The stable lyophized powder of the present invention appears as white to off white lyophilized powder that can be reconstituted in less than 300 seconds and wherein the pH of the reconstituted solution is less than 6.

The stable lyophized powder of the present invention can be prepared using standard equipment as used for lyophilization or freeze-drying method. The organic solvents and water for injection are subject to evaporation during lyophilization process.

The lengthy exposure time during reconstitution process of lyophilized powder shall increase the potential for loss of potency and impurity formation due to hydrolysis. The stable Carfilzomib Injection as a pre-lyophilization solution that produces a stable lyophized powder, can be reconstituted in a time period of less than 5 minutes (i.e. 300 seconds). Preferably, the reconstitution time of the stable lyophized powder is less than 90 seconds. Further, the water content of the said lyophilized powder is less than 5%. Preferably, the water content is less than about 2%.

In another embodiment, the stable Carfilzomib Injection of the present invention can be provided as a ready-to-use injection.

The ready-to-use injection of the present invention comprises Carfilzomib or pharmaceutically acceptable salts thereof with at least one acid component, at least one organic solvent, optionally with other pharmaceutically acceptable excipients, and wherein the said injection is free from cyclodextrin derivatives.

Further, the said ready-to-use injection provides the advantage of elimination of the need for lyophilization step and thereby the need for subsequent reconstitution step.

The stable Carfilzomib Injection of the present invention as a ready-to-use injection appears as clear yellowish solution without the presence of any particulate matter, thereby the said injection maintains physical and chemical stability to allow storage at a commercially relevant temperature, such as 2-8.degree. C. and 25.degree. C.

The ready-to-use Injection can be diluted with a suitable diluent before administration. Suitable diluents include, but are not limited to, water, saline, dextrose, and water for injection.

The stable lyophized powder of Carfilzomib can also be reconstituted directly with a suitable diluent before administration. Suitable diluents include, but are not limited to, water, saline, dextrose, and water for injection.

In another embodiment, the stable Carfilzomib Injection of the present invention can be provided as a kit comprising: (i) a product vial composition comprising a stable lyophilized powder of Carfilzomib or pharmaceutically acceptable salts thereof with at least one acid component; and (ii) a diluent vial composition comprising suitable solvents, preferably Dimethylacetamide, Polysorbates or mixtures thereof. More preferably, the diluent vial comprises a mixture of Dimethylacetamide and Polysorbate 80. The diluent vial composition further optionally comprises the pharmaceutically acceptable excipients in an amount that can be determined by any person with ordinary skill in the art.

The “acid component” of the present invention includes any pharmaceutically acceptable organic or inorganic acids. The acid component includes, non-limiting examples, such as citric acid, tartaric acid, succinic acid, acetic acid, glacial acetic acid, maleic acid, phosphoric acid or combinations thereof. Preferably, the acid component is citric acid. More preferably, the acid is citric acid anhydrous.

The “organic solvent” of the present invention includes, non-limiting examples, such as dehydrated alcohol, Tertiary butyl alcohol (TBA), propylene glycol, polyethylene glycol, glycerol, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, and mixtures thereof. Preferably, the organic solvent is tertiary butyl alcohol and/or dehydrated alcohol. The amount of organic solvent in the composition can be decided by any skilled person known in the art. Preferably, the amount of organic solvent in the said composition is about 10-70% V/V, more preferably is about 30-40% V/V.

For the sake of the present invention, the term “pharmaceutically acceptable excipients” includes any suitable excipients such as buffers, bulking agents, diluents, sugars, cellulose and its derivatives, pH-adjusting agents, solubilizers, antioxidants, preservatives, surfactants, isotonicity agents, and/or lyoprotectants.

For the sake of the present invention, the term “Carfilzomib or pharmaceutically acceptable salts thereof” shall comprise of any pharmaceutically acceptable forms of Carfilzomib, including its free form (zwitter ion), and its pharmaceutically acceptable complexes, acid addition salts, base addition salts solvates, hydrates, and polymorphs.

In another embodiment, the present invention relates to a process for the preparation of a stable Carfilzomib Injection, which can be prepared either by lyophilization method and reconstituted prior to use, or as a ready-to-use injection. Lyophilization methods are well-known to a person skilled in the art.

In order to further illustrate the present invention, following examples are provided for the purpose of clarity of understanding. However, it is not intended in any way to limit the scope of the invention and it is readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made without departing from the scope of the invention.

The stable Carfilzomib Injection of the present invention as described in following examples (1 to 5) are prepared by lyophilization method. The finished product obtained by lyophilization method contains Carfilzomib as 60 mg/vial or 45 mg/vial.

Example 1: Carfilzomib Injection as a Lyophilized powder.
Product Vial Composition:
Sr. No. Ingredients mg/ml mg/ml
1 Carfilzomib 2.0 mg 6.0 mg
2 Tertiary butyl alcohol* 235.5 mg 314.0 mg
3 Citric acid anhydrous 1.92 mg 5.77 mg
4 Water for injection* q.s to 1.0 ml q.s to 1.0 ml
* Tertiary butyl alcohol (TBA) and water for injection to be evaporated during lyophilization process.

The bulk solution is prepared according to the above example to obtain 2mg/ml and 6mg/ml solution. Further, in order to obtain 60mg/vial or 45mg/vial of the lyophilized product, the equivalent amount of solution is filled in vial and subjected to lyophilization process.

To obtain 60mg/vial product, the volume of 10ml of 6mg/ml solution is filled in the vial and lyophilized. Similarly, to obtain 45mg/vial product, the volume of 7.5 ml of 6mg/ml solution is filled in vial and lyophilized.

Diluent vial composition:
Sr. No. Ingredient Quantity (mg/ml)
1. Dimethylacetamide 235.5 mg
2. Polysorbate 80 802.5 mg

Diluent vial composition is prepared by admixing Dimethylacetamide and Polysorbate 80.

The stable Carfilzomib Injection of the present invention comprises a kit comprising a product vial composition (i.e. stable lyophilized powder) and a diluent vial composition, as illustrated above.

Stability data of Carfilzomib Injection (60 mg/vial):
Sr. No Tests Specified Limits Initial 3M (25°C/60%RH)
1. Description White to off white lyophilized powder White to off white lyophilized powder White to off white lyophilized powder
2. Reconstitution time Less than 300 sec 90 sec 80 sec
3. Clarity of reconstituted solution Clear as purified water Clear as purified water Clear as purified water
4. pH of reconstituted solution Less than 6.0 5.78 5.79

The above data confirms the stability of the present invention in the form of a stable lyophilized powder as white to off white lyophilized powder that can be reconstituted in less than 300 seconds, and wherein the pH of the reconstituted solution is less than 6.

Other examples of stable Carfilzomib Injection in the form of stable lyophilized powder are as follows:

Example 2: Carfilzomib Injection as a Lyophilized powder.
Sr. No. Ingredients mg/ml
1 Carfilzomib 2.0
2 Dehydrated alcohol* 315.6
3 Citric acid anhydrous 1.923
4 Water for injection* q.s to 1.0 ml
* Dehydrated alcohol and water for injection to be evaporated during lyophilization process.

Example 3: Carfilzomib Injection as a Lyophilized powder.
Sr. No. Ingredients mg/ml
1 Carfilzomib 2.0
2 Tertiary butyl alcohol* 314.0
3 Citric acid anhydrous 1.923
4 Mannitol 6.0
5 Water for injection* q.s to 1.0 ml
* Tertiary butyl alcohol (TBA) and water for injection to be evaporated during lyophilization process.

Example 4: Carfilzomib Injection as a Lyophilized powder.
Sr. No. Ingredients mg/ml
1 Carfilzomib 2.0
2 Dehydrated alcohol* 315.6
3 Citric acid anhydrous 1.923
4 Mannitol 6.0
5 Water for injection* q.s to 1.0 ml
* Dehydrated alcohol and water for injection to be evaporated during lyophilization process.

Example 5: Carfilzomib Injection as a Lyophilized powder.
Sr. No. Ingredients mg/ml
1 Carfilzomib 2.0
2 Tertiary butyl alcohol* 314.0
3 Glacial acetic acid q.s. to adjust pH
4 Water for injection* q.s to 1.0 ml
* Tertiary butyl alcohol (TBA) and water for injection to be evaporated during lyophilization process.

The lyophilized compositions as described in Examples 2 to 5 can also be provided as a kit as illustrated in the Example 1.

Further, the stable Carfilzomib Injection of the present invention can be provided as a ready-to-use injection. Example 6 provides stable Carfilzomib Injection as Ready-to-use injection.

Example 6: Carfilzomib Ready-to-use (RTU) Injection.
Sr. No. Ingredient Quantity (mg/ml)
1 Carfilzomib 7.5
2 Citric acid anhydrous 7.211
3 Dimethyl acetamide 235.5
4 Polysorbate 80 q.s to 1.0 ml

The stable Cafilzomib Injection as Ready-to-use injection is prepared by admixing Carfilzomib and citric acid anhydrous in mixture of dimethylacetamide and Polysorbate 80.

Stability Data of Ready-to-use Injection:
Sr. No. Tests Initial 1M / (25°C/60%RH) 1M /
(2°C-8°C)
1. Description Clear yellowish solution Clear yellowish solution Clear yellowish solution
2. Clarity of solution Clear Clear Clear

The above data confirms the stability of the present invention as a ready-to-use injection, wherein the said injection maintains physical and chemical stability to allow storage at a commercially relevant temperature, such as 2-8.degree. C. and 25.degree. C.

In summary, the present invention of stable Carfilzomib Injection provides cost effective and commercially feasible solution over problems associated with the existing Carfilzomib compositions.
,CLAIMS:1. A stable Carfilzomib Injection comprising Carfilzomib or pharmaceutically acceptable salts thereof with pharmaceutically acceptable excipients that substantially increase the solubility of Carfilzomib or pharmaceutically acceptable salts thereof, wherein the said injection is free from cyclodextrin derivatives.

2. A stable Carfilzomib Injection comprising Carfilzomib or pharmaceutically acceptable salts thereof with at least one acid component, at least one organic solvent, optionally with other pharmaceutically acceptable excipients, and wherein the said injection is free from cyclodextrin derivatives.

3. The stable Carfilzomib Injection according to claim 2, wherein the acid component is selected from citric acid, tartaric acid, succinic acid, acetic acid, glacial acetic acid, maleic acid, phosphoric acid or combinations thereof.

4. The stable Carfilzomib Injection according to claim 2, wherein the organic solvent is selected from dehydrated alcohol, Tertiary butyl alcohol, propylene glycol, polyethylene glycol, glycerol, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, and mixtures thereof.

5. A stable Carfilzomib Injection comprising Carfilzomib or pharmaceutically acceptable salts thereof with citric acid, tertiary butyl alcohol and water for injection, wherein the said injection is free from cyclodextrin derivatives and wherein the said injection produces a stable lyophized powder that can be reconstituted in less than 300 seconds.

6. A stable Carfilzomib Injection comprising Carfilzomib or pharmaceutically acceptable salts thereof with acetic acid, tertiary butyl alcohol and water for injection, wherein the said injection is free from cyclodextrin derivatives and wherein the said injection produces a stable lyophized powder that can be reconstituted in less than 300 seconds.

7. A kit comprising:
(i) a product vial composition comprising a stable lyophilized powder of Carfilzomib or pharmaceutically acceptable salts thereof with citric acid; and
(ii) a diluent vial composition comprising Dimethylacetamide and Polysorbate80.

8. A stable Carfilzomib Injection comprising Carfilzomib or pharmaceutically acceptable salts thereof with citric acid, Dimethyl acetamide and Polysorbate 80, wherein the said injection is free from cyclodextrin derivatives and wherein the said injection is a ready-to-use injection.

9. A process for the preparation of a stable Carfilzomib Injection, wherein the said injection is obtained as a lyophilized powder or as a ready-to-use injection.

10. A stable Carfilzomib Injection for administering Carfilzomib in patients in need thereof for the treatment of multiple myeloma, wherein the said injection is free from cyclodextrin derivatives.