U.S. patent application number 17/531182 was filed with the patent office on 2022-03-10 for ready-to-use carfilzomib compositions.
This patent application is currently assigned to Orbicular Pharmaceutical Technologies Pvt. Ltd.. The applicant listed for this patent is Orbicular Pharmaceutical Technologies Pvt. Ltd.. Invention is credited to Raghu Kannekanti, Mailatur Sivaraman Mohan, Bhaveshkumar Vallabhbhai Patel, Hiren Patel, Mohammad Raheesh.
Application Number | 20220072085 17/531182 |
Document ID | / |
Family ID | 62978318 |
Filed Date | 2022-03-10 |
United States Patent
Application |
20220072085 |
Kind Code |
A1 |
Mohan; Mailatur Sivaraman ;
et al. |
March 10, 2022 |
Ready-To-Use Carfilzomib Compositions
Abstract
The present invention provides a stable, non-aqueous,
ready-to-use parenteral composition comprising: carfilzomib or
pharmaceutically acceptable salt thereof, acidifying agent,
optionally a surfactant, one or more solvents or co-solvents.
Inventors: |
Mohan; Mailatur Sivaraman;
(Hyderabad, IN) ; Patel; Hiren; (Hyderabad,
IN) ; Patel; Bhaveshkumar Vallabhbhai; (Hyderabad,
IN) ; Kannekanti; Raghu; (Hyderabad, IN) ;
Raheesh; Mohammad; (Hyderabad, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Orbicular Pharmaceutical Technologies Pvt. Ltd. |
Hyderabad |
|
IN |
|
|
Assignee: |
Orbicular Pharmaceutical
Technologies Pvt. Ltd.
Hyderabad
IN
|
Family ID: |
62978318 |
Appl. No.: |
17/531182 |
Filed: |
November 19, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16480561 |
Jul 24, 2019 |
11224631 |
|
|
PCT/IB2017/052359 |
Apr 25, 2017 |
|
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17531182 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 38/07 20130101;
A61K 9/0019 20130101; A61K 47/10 20130101; A61K 47/12 20130101 |
International
Class: |
A61K 38/07 20060101
A61K038/07; A61K 9/00 20060101 A61K009/00; A61K 47/10 20060101
A61K047/10; A61K 47/12 20060101 A61K047/12 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 24, 2017 |
IN |
201741002669 |
Claims
1. A composition comprising: carfilzomib or a pharmaceutically
acceptable salt thereof in a range of about 1 mg/mL to about 20
mg/mL; ethanoic acid, wherein a ratio of the ethanoic acid to the
carfilzomib is about 1:1 to about 15:1; at least one solvent;
optionally a surfactant; and optionally an anti-oxidant, wherein
the composition has pH from about 2 to about 9, wherein the
composition is stable, ready to use, and substantially
non-aqueous.
2. The composition according to claim 1, wherein the composition is
substantially free of cyclodextrin.
3. The composition according to claim 1, wherein the ratio of
ethanoic acid to carfilzomib is about 1.5:1 to about 10:1.
4. The composition according to claim 1, wherein the ethanoic acid
in the composition is in range equal to or greater than 30 mg/mL to
keep the composition stable for at least 24 hours upon
dilution.
5. The composition according to claim 1, wherein the at least one
solvent comprises at least one of an alcohol, a glycol, glycerol or
a derivative thereof, and mixtures thereof.
6. The composition according to claim 1, wherein the surfactant is
at least one of a polyoxyethylene sorbitan ester, a polyoxyethylene
polyoxypropylene copolymer, a sorbitan ester, lecithin, cremophor,
and mixtures thereof.
7. The composition according to claim 1, wherein the anti-oxidant
is at least one of monothioglycerol, alpha-tocopherol, L-cysteine,
thioglycolic acid, sodium metabisulfite, ascorbic acid, sodium
formaldehyde sulfoxylate, sodium bisulfate, butylated hydroxy
toluene, butylated hydroxy anisole, or mixtures thereof.
8. The composition according to claim 5, wherein the solvent is a
glycol which is at least one of propylene glycol, polyethylene
glycol, and mixtures thereof and the alcohol is at least one of
ethanol, butanol, t-butanol, and mixtures thereof.
9. The composition according to claim 1, wherein the pH is from
about 2 to about 9.
10. The composition according to claim 1, wherein the anti-oxidant
is alpha-tocopherol; the surfactant is a polyoxyethylene sorbitan
ester; and the solvent is glycerol, propylene glycol, polyethylene
glycol, ethanol, butanol, t-butanol, and mixtures thereof.
11. The composition according to claim 1, wherein the composition
is ready to dilute; is stable when stored at 25.degree. C., 60%
relative humidity for at least 1 month, is clear upon dilution with
a physiological solution and is stable when diluted for at least
about 24 hours.
12. The composition of claim 1, wherein the composition is
substantially free of non-volatile sugar acid.
13. A method for treating multiple myeloma and related conditions
comprising administering the composition according to claim 1 in a
parenteral dosage form.
14. A composition comprising: carfilzomib or a pharmaceutically
acceptable salt thereof; ethanoic acid; and at least one solvent,
wherein the composition is stable when stored at 25.degree. C., 60%
relative humidity for at least 1 month and the composition is ready
to use and the composition is clear upon dilution with
physiological solution and stable for at least about 24 hours.
15. The composition according to claim 14, wherein the carfilzomib
or pharmaceutically acceptable salt thereof is in a range of about
1 mg/mL to about 20 mg/mL, wherein a ratio of the ethanoic acid to
the carfilzomib is about 1:1 to about 15:1.
16. The composition according to claim 14, wherein the ethanoic
acid in the composition is in range equal to or greater than 30
mg/mL to keep the composition stable for at least 24 hours upon
dilution.
17. A method for manufacturing a composition, comprising; adding
carfilzomib to ethanol to obtain a clear solution; and adding an
acidifying agent including ethanoic acid to adjust a pH of the
clear solution in a range from 2 to 9 to form the composition,
wherein a ratio of the ethanoic acid to the carfilzomib is about
1:1 to about 15:1.
18. The method of claim 17, wherein adding carfilzomib to ethanol
further comprises: adding an additional solvent to the clear
solution, wherein the additional solvent is at least one of
propylene glycol, polyethylene glycol, polysorbate, or sorbitan
easters.
19. The method of claim 17, further comprising: adding an
anti-oxidant to the clear solution, wherein the anti-oxidant is at
least one of monothioglycerol, alpha-tocopherol, L-cysteine,
thioglycolic acid, sodium metabisulfite, ascorbic acid, sodium
formaldehyde sulfoxylate, sodium bisulfate, butylated hydroxy
toluene, butylated hydroxy anisole, and mixtures thereof.
20. The method of claim 17, further comprising: filtering the
composition; and supplying an inert gas when manufacturing the
composition.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation of U.S.
application Ser. No. 16/480,561 filed Jul. 24, 2019, which is a
national phase entry under 35 U.S.C. .sctn. 371 of International
Application No. PCT/162017/052359, filed Apr. 25, 2017, which
claims priority from India Patent Application No. 201741002669
filed Jan. 24, 2017, the disclosure of all of which are
incorporated herein by reference.
TECHNICAL FIELD
[0002] The present invention relates to a stable, non-aqueous,
ready-to-use parenteral composition comprising: carfilzomib or
pharmaceutically acceptable salt thereof, acidifying agent,
optionally a surfactant, one or more solvents.
BACKGROUND OF THE INVENTION
[0003] Carfilzomib is a peptide epoxy ketone derivative,
chemically, it is a tetra peptide epoxy ketone and an analog of
epoxomicin. Carfilzomib is commercially available as KYPROLIS.RTM.
(Carfilzomib for Injection, which is a lyophilized formulation
available as 30 mg/vial and 60 mg/vial a sterile, white to
off-white lyophilized powder and is available as a single-use vial.
Each 30 mg vial of KYPROLIS contains 30 mg of Carfilzomib, 1500 mg
sulfobutylether beta-cyclodextrin, and 28.9 mg anhydrous citric
acid, and each 60 mg vial contains 60 mg of Carfilzomib, 3000 mg
sulfobutylether beta-cyclodextrin, 57.7 mg citric acid, and sodium
hydroxide for pH adjustment (target pH 3.5).
[0004] Due to stability issues, carfilzomib containing compositions
must be lyophilized before storage and reconstituted before use.
The reconstituted solution should be diluted further. The
reconstituted or diluted compositions are not stable and must be
used within 24 hours after reconstitution. It requires initial
reconstitution, two dilutions prior to intravenous infusion and the
same needs to be carried out under aseptic conditions.
[0005] Prior to administration, the KYPROLIS.RTM. (Carfilzomib) for
Injection must first be reconstituted with 29 mL and 15 mL of
sterile water for injection, which dilutes the amount of
carfilzomib to 2 mg/mL, and then further withdraw the calculated
dose from the vial and diluted into 50 mL using 5% dextrose
Injection, USP intravenous bag.
[0006] The difficulties with the commercially available
KYPROLIS.RTM. (Carfilzomib) formulation is complex administration
process involving multiple steps. As described above, the person
administering the drug must first reconstitute the vial with
sterile water for injection and then subsequently transfer the
reconstituted solution into an intravenous bag. While
reconstituting, the medical practitioner must gently swirl and/or
invert the vial slowly for about 1 minute, or until complete
dissolution of any cake or powder occurs. The prescribing
information for KYPROLIS.RTM. (Carfilzomib) for Injection gives
clear instructions not to shake the vial to avoid foaming.
Possibility of foaming during reconstitution may pose risk of
dosing error. A further difficulty of the KYPROLIS.RTM.
(Carfilzomib) product is that the time duration from reconstitution
to administration must be completed in 24 hours. Further all the
above mentioned reconstitution steps need to be carried out in
aseptic conditions, making the process still difficult to
follow.
[0007] U.S. Pat. No. 7,737,112 discloses pharmaceutical
compositions of practically insoluble proteasome inhibitors. The
compositions disclosed in this patent utilize cyclodextrin, water
and organic solvents in order to increase the solubility and
stability of the practically insoluble proteasome inhibitors.
[0008] US patent application no. 20140073583 A1 discloses
pharmaceutical compositions comprising peptide epoxy ketone,
solvent suitable for injection selected from group consisting
ethanol, propylene glycol, polyethylene glycol and mixtures
thereof, optionally water and a non-volatile sugar acid as a
lyophilized composition. Also disclosed is a liquid composition of
carfilzomib.
[0009] WO patent publication 2015198257 A1 discloses a stable
carfilzomib injection comprising carfilzomib or pharmaceutically
acceptable salts thereof with citric acid, tertiary butyl alcohol
and water for injection to obtain lyophilized product, wherein the
said injection is free from cyclodextrin derivatives; further the
invention also discloses a ready-to-use injection comprising
carfilzomib, citric acid, dimethyl acetamide and polysorbate 80,
and the injection is free from cyclodextrin derivatives.
[0010] WO patent publication 2016170489 A1 discloses pharmaceutical
composition comprising carfilzomib or a pharmaceutically acceptable
salt thereof, at least one organic solvent such as
dimethylacetamide or propylene glycol or ethanol, and a solubilizer
such as hydroxy propyl beta-cyclodextrin (HPBCD), the composition
further comprises citric acid, wherein said composition has a water
content of less than 2.5 percent w/w.
[0011] The marketed KYPROLIS.RTM. (Carfilzomib) product has many
limitations, such as long manufacturing procedure including drug
dissolution and long lyophilization cycle to obtain the lyophilized
product. Further the lyophilized product requires multiple
dilutions and the reconstituted or diluted composition develops
frothing or foam formation, if proper care is not taken during
reconstitution. If foam is formed, then the health professional
needs to wait 5 minutes until the foam subsides from reconstituted
solution. This is a cumbersome procedure and complication to health
care professionals. Carfilzomib has low aqueous solubility and
hence considering the above drawbacks, surprisingly a stable,
ready-to-use, parenteral composition of carfilzomib has been
developed using the non-aqueous environment which overcomes the
above drawbacks. Further it does not require such cumbersome and
expensive procedures of lyophilization, multiple dilutions and
foaming.
SUMMARY OF THE INVENTION
[0012] The present invention relates to a stable, non-aqueous,
ready-to-use parenteral composition comprising: carfilzomib or
pharmaceutically acceptable salt thereof, acidifying agent,
optionally a surfactant, one or more solvents.
[0013] The composition according to above aspect, wherein the
acidifying agents include but not limited to sulphuric acid,
hydrochloric acid, hydrobromic acid, phosphoric acid, ethanoic
acid, boric acid, hydrofluoric acid, oxalic acid, nitric acid and
the like; [0014] surfactant include but not limited to
polyoxyethylene sorbitan esters (tweens), polyoxyethylene
polyoxypropylene copolymers (pluronics), sorbitan esters, lecithin,
cremophor and mixtures thereof; [0015] solvents include but not
limited to glycols such as propylene glycol, polyethylene glycol
and the like; alcohols such as ethanol, butanol, t-butanol;
glycerol or its derivatives and mixtures thereof;
[0016] Another aspect relates to a stable, non-aqueous,
ready-to-use parenteral composition comprising: [0017] i.
carfilzomib or pharmaceutically acceptable salt thereof in a
concentration range of about of 1 mg/mL to about 20 mg/mL, [0018]
ii. acidifying agent selected from ethanoic acid in a specific
ratio of about 1:1 and less than or equal to about 15:1, [0019]
iii. optionally surfactants, and [0020] iv. solvents selected from
propylene glycol, polyethylene glycol, ethanol.
[0021] The composition according to preceding claims, the
composition may comprise other excipients such as antioxidants
and/or preservatives optionally.
[0022] The composition according to according to above aspect,
wherein the ratio of ethanoic acid to carfilzomib is between about
1.5:1 to about 10:1.
[0023] The composition according to previous aspects, the
composition is free of cyclodextrins, water and non-volatile sugar
acid.
[0024] The composition according to previous aspects, wherein the
pH of the composition is from about 2 to about 9.
[0025] The non-aqueous composition according to preceding claims
for administering carfilzomib in patients in need thereof for the
treatment of multiple myeloma and related conditions.
[0026] One more aspect of the invention relates to the process for
the preparation of a composition, comprising: [0027] a) add
required quantity of ethanol in a manufacturing vessel and add
carfilzomib to it and stir to obtain a clear solution, [0028] b) to
the above vessel optionally other solvents propylene glycol or
polyethylene glycol, and optionally polysorbate or sorbitan esters
and optionally antioxidant may be added, [0029] c) adjust the pH
using suitable acidifying agent, [0030] d) filter and fill the
filtered solution into vials, stopper and seal the vials and store
the vials in suitable shipper, [0031] e) inert gas such as nitrogen
is used throughout the process to reduce the risk of oxidation of
carfilzomib.
DETAILED DESCRIPTION OF THE INVENTION
[0032] The term "composition" is intended to encompass a
combination including active ingredients and pharmaceutically
acceptable excipients, as well as any product which results,
directly or indirectly, from combination, complexation, or
aggregation of any two or more of the ingredients, or from
dissociation of one or more of the ingredients, or from other types
of reactions or interactions involving one or more of the
ingredients.
[0033] The term "formulation" or "dosage form" or "composition"
refers to finished pharmaceutical products that are suitable for
administration, including, but not limited to, injections,
parenterals, etc.
[0034] The term "excipient" or "pharmaceutically acceptable
excipient" or "adjuvant" means a component of a pharmaceutical
product that is not a pharmacologically active ingredient, such as
fillers, diluents, carrier, solvents, co-solvents, preservatives,
buffers, bulking agents, sugars, cellulose and its derivatives, pH
modifiers, antioxidants, surfactants, isotonicity agents, etc,
added to a drug to increase or aid its effect. The excipients or
adjuvants that are useful in preparing pharmaceutical compositions
are generally safe, non-toxic, and neither biologically nor
otherwise undesirable, and are acceptable for human pharmaceutical
use as well as veterinary use. The term includes one or more
excipients or adjuvants.
[0035] "Carrier" or "solvent" as used herein refers to
pharmacologically inert materials that provide a more or less fluid
matrix, suitable for topical drug administration. Carriers and
solvents herein include any such materials known in the art, which
are nontoxic and do not interact with other components of a
pharmaceutical composition or drug delivery system in a deleterious
manner. The compositions of the present invention are particularly
suitable for parenteral administration. Compositions suitable for
parenteral dosage forms such as injectable such as intravenous,
intramuscular or subcutaneous, implants and the like. Other
parenteral ingredients used in the composition are generally those
commonly used and recognized by persons skilled in the art of
parenteral formulations.
[0036] The term "Carfilzomib" includes the compound carfilzomib,
pharmaceutically acceptable salts, esters, solvates, hydrates or
polymorphs and the like thereof.
[0037] "Pharmaceutically-acceptable salts" refer to derivatives of
the disclosed compounds wherein the parent compound is modified by
making acid or base salts, solvate, hydrate and the like thereof.
Pharmaceutically-acceptable salt forms of compounds provided herein
are synthesized from the parent compound which contains a basic or
acidic moiety by conventional chemical methods.
[0038] The term "optional" or "optionally" means that the
subsequently described element, component or circumstance may or
may not be present, so that the description includes instances
where the element, component, or circumstance is included and
instances where it is not.
[0039] The term "stable" or "stability" as used herein includes
both physical and chemical stability. Stability parameters include
but not limited to potency, related substances, stable pH value and
other physico-chemical parameters.
[0040] The term "about" when used in conjunction with a numeral
here refers to a range of that numeral +/-10%, inclusive. However,
alternative concentrations are also expressly deemed suitable for
use herein.
[0041] Non-aqueous refers to the property of being free or
substantially free of water. However, this does not exclude the
presence of residual amounts of water as commonly contained in
non-aqueous organic liquids and residual amounts of water
contributed from the process of manufacturing composition, such as
trace amounts of moisture present in manufacturing vessels, tubing,
filters and the like.
[0042] Any recitation of ranges of values set forth below is merely
intended to serve as a shorthand method of referring individually
to each separate value falling within the range, unless otherwise
indicated herein, and each separate value is incorporated into the
specification as if it were individually recited herein.
Furthermore, all references, including patent applications, cited
herein are hereby incorporated by reference to the same extent as
if each reference were individually and specifically indicated to
be incorporated by reference and were set forth in its entirety
herein.
[0043] The present invention relates to a stable, non-aqueous,
carfilzomib ready-to-use, parenteral composition, wherein the
composition is free of non-volatile sugar acid, cyclodextrins and
water.
[0044] The present composition can be prepared by combining
carfilzomib, acidifying agent, and other excipients. The excipients
include solvents, pH modifiers, preservatives, antioxidants,
surfactant and the like or mixtures thereof.
[0045] The parenteral composition according to this invention
wherein, examples of solvents include but not limited to glycols
such as propylene glycol, butylene glycol, polyethylene glycol;
polyethylene glycol include polyethylene glycol 300, polyethylene
glycol 400 and the like; glycerol or its derivatives and mixtures
thereof; dioxane, trioxane and other cyclic mono-, di- and
tri-ethers, lower alkanols such as ethanol, propanol, isopropanol,
sec-butanol, t-butyl alcohol (TBA), n-butyl alcohol, ethyl acetate,
acetone, acetonitrile, ethoxy ethanol, methanol,
N-methyl-2-pyrrolidone, glycofurol, glycerol formal,
tetrahydrofurfuryl alcohol or other organic solvents and mixtures
of suitable solvents thereof or their equivalents. Solvents or
mixture or combination of solvents are used in a suitable
proportion and suitable quantity to achieve desirable effect.
Co-solvents may also be included in the present compositions and
co-solvents include, but not limited to glycols such as propylene
glycol, butylene glycol, polyethylene glycol and the like,
polyethylene glycol include polyethylene glycol 300, polyethylene
glycol 400 and the like; glycerol or its derivatives and mixtures
thereof; dioxane, trioxane and other cyclic mono-, di- and
tri-ethers, lower alkanols (such as ethanol, propanol, isopropanol,
sec-butanol, t-butyl alcohol (TBA), n-butyl alcohol, ethyl acetate,
acetone, acetonitrile, ethoxy ethanol, methanol,
N-methyl-2-pyrrolidone, glycofurol, glycerol formal,
tetrahydrofurfuryl alcohol or other organic solvents and mixtures
of suitable solvents.
[0046] In another aspect the pH of the composition plays a
significant role to keep the composition stable, pH of the present
invention is from about 2 to about 9; further pH modifications are
contemplated with suitable pH modifiers.
[0047] In one more aspect, by addition of acidifying agent to the
composition, the pH of the composition was modified between about 2
to about 9 to obtain a clear stable solution after
reconstitution.
[0048] The pH level for each pharmaceutical composition should be
selected to provide suitable solubility of the active ingredient
used therein. It is generally preferred, however, that the pH of
the compositions be suitable for injection and, therefore, will
typically be between about 2.0 and about 9.0. pH of the composition
is modified to obtain a stable non-aqueous composition using
suitable pH modifiers. pH of the present composition plays an
important role in stabilizing the composition. By addition of
acidifying agent to the composition, the pH of the composition was
modified to obtain a clear stable solution after
reconstitution.
[0049] In another aspect, the compositions are stable when the
composition is added with pH modifiers, like acidifying agents.
Examples of pH modifiers include but not limited to acidifying
agents, such as but not limited to sulphuric acid, hydrochloric
acid, phosphoric acid, ethanoic acid, boric acid, hydrofluoric
acid, hydrobromic acid, oxalic acid, nitric acid or mixtures
thereof. It is anticipated that upon addition of pH modifiers the
composition is physically and chemically more stable than without
those modifiers in the composition.
[0050] Further the composition may comprise of antioxidants and the
antioxidants used in the compositions are optional. Examples of
antioxidants include but not limited to monothioglycerol,
alpha-tocopherol, L-cysteine, thioglycolic acid, sodium
metabisulfite (SMBS), ascorbic acid, sodium formaldehyde
sulfoxylate, sodium bisulfate, butylated hydroxy toluene (BHT),
butylated hydroxy anisole (BHA) mixtures of combinations
thereof.
[0051] In another aspect composition with antioxidants
monothioglycerol, combination of butylated hydroxy toluene (BHT)
and butylated hydroxy anisole (BHA), butylated hydroxy anisole
(BHA), .alpha.-tocopherol, thioglycolic acid and composition
without antioxidants were assessed using inert gas environment
precautions. Considering the chemical stability with above
antioxidants alpha-tocopherol, BHA and thioglycolic acid were found
to be suitable in comparison with other antioxidants.
[0052] In another aspect the composition may comprise of
surfactants. Examples of surfactant include tweens, tweens include
but not limited to polyoxyethylene sorbitan esters such as
polysorbate 20 (Tween 20), polysorbate 40 (Tween 40), and
polysorbate 80 (Tween 80); polyoxyethylene polyoxypropylene
copolymers such as pluronics; sorbitan esters such as sorbitan
monostearate, sorbitan tristearate, sorbitan monolaurate and the
like, lecithin, cremophor and mixtures thereof. Surfactants in the
present compositions are optional and based on the requisite, the
surfactants may be used.
[0053] The present invention may further comprise of other suitable
excipients other than the disclosed excipients, excipients may
include preservatives such as benzyl alcohol, thiomersal, butylated
hydroxy toluene (BHT), butylated hydroxy anisole (BHA) and the like
or mixtures thereof.
[0054] The present invention relates to a stable, non-aqueous,
carfilzomib ready-to-use, parenteral composition, wherein the
composition is free of non-volatile sugar acid, cyclodextrins and
water.
[0055] The contemplated compositions are free of non-volatile sugar
acid, cyclodextrins and water. Non-volatile sugar acid include
citric acid, N-acetylneuraminic acid, N-acetyltalosaminuronic acid,
aldaric acid, aldonic acid, 3-deoxy-D-manno-oct-2-ulosonic acid,
galaturonic acid, D-galacturonic acid, glucaric acid, gluconic
acid, glucuronic acid, glucono-gamma-lactone, glyceric acid,
N-glycolylneuraminic acid, iduronic acid, isosaccharinic acid,
lactobionic acid, mucic acid, muramic acid, neuraminic acid,
pangamic acid, saccharic acid, sialic acid, threonic acid, ulosonic
acid, uronic acid, X-Gluc, xylonic acid, ascorbic acid, mixtures
thereof and other sugar acids, lactic acid, succinic acid, maleic
acid, tartaric acid, salicylic acid, benzoic acid, methanesulfonic
acid, oxalic acid, thioglycolic acid, and the like or mixtures
thereof.
[0056] Cyclodextrins include alpha-, beta-, or gamma-cyclodextrins,
beta-cyclodextrins include, hydroxy-alkyl beta-cyclodextrin,
hydroxy-propyl-beta-cyclodextrin,
sulfobutyl-ether-beta-cyclodextrin and the like. Further, the
composition is free or substantially free of water, however, this
does not exclude the presence of residual amounts of water as
commonly contained in non-aqueous organic liquids and residual
amounts of water contributed from the process of manufacturing
composition, such as trace amounts of moisture present in
manufacturing vessels, tubing, filters and the like. Therefore, the
composition may comprise trace amounts of water coming from above
process.
[0057] In another aspect the present invention relates to a stable,
non-aqueous, carfilzomib ready-to-use, parenteral composition,
wherein the composition comprises of: [0058] i) carfilzomib or its
pharmaceutically acceptable salts, solvates and hydrates thereof,
[0059] ii) acidifying agent selected from ethanoic acid in a
specific ratio of about 1:1 and less than or equal to about 15:1
[0060] iii) solvents or co-solvents selected from propylene glycol,
polyethylene glycol, ethanol, and [0061] iv. optionally
surfactants.
[0062] The non-aqueous solvent system includes, ethanol or
propylene glycol or polyethylene glycol, or a mixture of one or
more solvents, ethanol and propylene glycol; ethanol and
polyethylene glycol; propylene glycol and polyethylene glycol;
ethanol, propylene glycol and polyethylene glycol or any mixtures
or combinations thereof. The composition may also comprise
propylene glycol or polyethylene glycol, glycerol, dioxane, alcohol
and the like as co-solvents.
[0063] In another aspect, the parenteral composition accordingly
has concentration of carfilzomib between about 1 mg/mL to about 20
mg/mL; for example, between about 4 mg/mL to about 16 mg/mL and
between about 6 mg/mL to about 12 mg/mL and composition is a
ready-to-use composition.
[0064] In another aspect wherein the ratio of ethanoic acid to
carfilzomib is between about 1:1 and less than or equal to about
15:1; for example, the ratio is between about 1.5:1 to about 10:1;
further the ratio is between about 2:1 to about 8:1.
[0065] In another aspect the composition is free from
lyophilization and the composition is a ready-to-use liquid
solution, ready-to-use liquid concentrate, ready-to-dilute liquid
solution, ready-to-dilute liquid concentrate and the like. A
ready-to-use or ready-to-dilute liquid solution or liquid
concentrate is a composition that is suitable for administration
after dilution with a suitable diluent or physiological
solution.
[0066] In another embodiment, the present invention relates to a
stable, non-aqueous, ready-to-use, parenteral composition,
comprising carfilzomib or its pharmaceutically acceptable salt
thereof, ethanol, propylene glycol or derivatives, or polyethylene
glycol derivatives thereof, pH modifier, optionally antioxidants,
and optionally surfactants.
[0067] In another embodiment, the present invention relates to a
stable, non-aqueous, ready-to-use, parenteral composition,
comprising carfilzomib or its pharmaceutically acceptable salt
thereof, ethanol, propylene glycol or derivatives thereof,
polyethylene glycol 300 or polyethylene glycol 400 or derivatives
thereof, acidifying agent such as ethanoic acid, optionally
antioxidants and optionally surfactants.
[0068] In another embodiment, the present invention relates to a
stable, non-aqueous, ready-to-use, parenteral composition,
comprising carfilzomib or its pharmaceutically acceptable salt
thereof, ethanol, propylene glycol or derivatives thereof,
polyethylene glycol 300 or polyethylene glycol 400 or derivatives
thereof, ethanoic acid, optionally polysorbate 80 and optionally
thioglycolic acid or alpha-tocopherol or mixtures thereof.
[0069] In another embodiment, the present invention relates to a
stable, non-aqueous, ready-to-use, parenteral composition,
comprising carfilzomib or its pharmaceutically acceptable salt
thereof, ethanol, ethanoic acid, optionally polysorbate 80 and
optionally thioglycolic acid or alpha-tocopherol or mixtures
thereof.
[0070] In another embodiment, the present invention relates to a
stable, non-aqueous, ready-to-use, parenteral composition,
comprising carfilzomib or its pharmaceutically acceptable salt
thereof, ethanol, optionally polysorbate 80, acidifying agent and
optionally butylated hydroxy toluene or butylated hydroxy anisole,
or mixtures thereof.
[0071] In another embodiment, the present invention relates to a
stable, non-aqueous, ready-to-use, parenteral composition,
comprising carfilzomib or its pharmaceutically acceptable salt
thereof, ethanol, optionally propylene glycol and/or polyethylene
glycol 300 or polyethylene glycol 400 or derivatives thereof,
ethanoic acid, optionally polysorbate or sorbitan esters and
optionally thioglycolic acid or alpha-tocopherol.
[0072] In another embodiment, the present invention relates to a
stable, non-aqueous, ready-to-use, parenteral composition,
comprising carfilzomib or its pharmaceutically acceptable salt
thereof, ethanol, optionally propylene glycol, polyethylene glycol
300 or polyethylene glycol 400 or derivatives thereof, thioglycolic
acid or alpha-tocopherol, acidifying agent, optionally tweens or
sorbitan esters, wherein the composition is free of non-volatile
sugar acid, cyclodextrins and water.
[0073] In another embodiment, the present invention relates to a
stable, non-aqueous, ready-to-use, parenteral composition,
comprising carfilzomib or its pharmaceutically acceptable salt
thereof, ethanol, optionally alpha-tocopherol, sulphuric acid,
optionally tweens or sorbitan esters.
[0074] In another embodiment, the present invention relates to a
stable, non-aqueous, ready-to-use, parenteral composition,
comprising carfilzomib or its pharmaceutically acceptable salt
thereof, ethanol, optionally alpha-tocopherol, ethanoic acid,
optionally tweens or sorbitan esters.
[0075] In another embodiment, the present invention relates to a
stable, non-aqueous, ready-to-use, parenteral composition,
comprising carfilzomib or its pharmaceutically acceptable salt
thereof, ethanol, optionally propylene glycol, optionally
polyethylene glycol 300 or polyethylene glycol 400 or derivatives
thereof, optionally alpha-tocopherol, ethanoic acid, optionally
tweens or sorbitan esters, wherein the composition is free of
non-volatile sugar acid, cyclodextrins and water.
[0076] In another embodiment, the present invention may further
comprise of other suitable excipients to make a stable non-aqueous
composition, wherein the composition is free of non-volatile sugar
acid, cyclodextrins and water.
[0077] In another embodiment this invention discloses a process to
prepare the ready-to-use stable parenteral composition which
comprises of: [0078] a) adding required quantity of ethanol in a
manufacturing vessel and add carfilzomib to it and stir to obtain a
clear solution, [0079] b) to the above vessel optionally other
solvents propylene glycol or polyethylene glycol, and optionally
polysorbate or sorbitan esters and optionally antioxidant may be
added, [0080] c) adjusting the pH using suitable acidifying agent,
[0081] d) filtering the solution, filling the filtered solution
into vials; stoppering and sealing the vials and storing the vials
in suitable shipper, [0082] e) inert gas such as nitrogen is used
throughout the process to reduce the risk of oxidation of
carfilzomib.
[0083] Sterilization can be achieved by gamma-irradiation, e-beam,
natural light, filtration, microwave heat sterilization such as
moist heat sterilization. The sterilization may be steam
sterilization or may be heat sterilization or filtration
sterilization or a combination thereof.
[0084] In one embodiment, the present invention provides stable,
ready-to-use compositions which may be sterilized by filtration,
heat sterilization, radiation (gamma-irradiation, electron beam,
microwave) ethylene oxide sterilization and the like. Filtration is
performed through filters with pore size ranging from 0.2 .mu.m to
0.5 .mu.m.
[0085] Regardless of the particular composition, it is preferred
that the composition is packaged in a container suitable for single
or multiple-use. Such containers include an ampoule, vials, a
pre-filled syringe, an intravenous bag and the like. Multi-dose
containers may contain the carfilzomib in an amount suitable to
allow one or more distinct uses (based on the requirement to the
user). Thus, preferred multi-dose containers will be configured to
contain a volume of the composition that is suitable for multiple
and independent administrations.
[0086] Carfilzomib with or without other therapeutically active
agents may also be used in combination or prior to administering
carfilzomib composition without departing from the present
invention or to prevent side effects (e.g., hypersensitivity
reactions, gastrointestinal symptoms) associated with the
administration of the inventive compositions. These agents may
optionally be added to the compositions. Preferably the
therapeutically active agents synergistically enhance the effect of
carfilzomib. Examples of therapeutic agents that may be used in
conjunction with the pharmaceutical compositions of the present
invention include, but are not limited to alkylating agents,
antihistamines, hormonal agents, H.sub.2 antagonists, plant-derived
agents, biologic agents, thalidomides or its derivatives, steroids
or its derivatives, interleukins, interferons, cytokines,
immuno-modulating agents, monoclonal antibodies, natural product,
anticancer agents, histone deacetylase inhibitors, antiretroviral
agents, platinum-based drugs, and combinations thereof.
[0087] In one more embodiment the present invention relates to
provide a stable ready-to-use composition to treat patients in need
thereof for the treatment of multiple myeloma, lymphoma, leukemia,
carcinoma or related conditions.
[0088] To further illustrate the invention, the following examples
are provided. It is to be understood that these examples are
provided for illustrative purposes and are not to be construed as
limiting the scope of the invention. It is to be further understood
that, in the examples the functions of individual ingredients are
sometimes listed for illustration purposes.
EXAMPLES
[0089] Proposed carfilzomib compositions were developed and tested
for feasibility as semi-aqueous compositions, non-aqueous
compositions with non-volatile sugar acids, acidifying agent with
or without any excipients to check the physico-chemical parameters
and its stability. Semi-aqueous compositions were developed and
found clear as such and on dilution with physiological solution
thereby indicating physical stability, hence these compositions
were tested for chemical stability. However, semi aqueous
compositions degraded in presence of water, observed known and
unknown impurities were at higher side. Further it was understood
that composition containing aqueous portion may lead to hydrolysis,
therefore it was concluded that compositions should be free from
water. Hence non-aqueous compositions were developed and the same
are exemplified below:
Example 1: Non-Aqueous Compositions
TABLE-US-00001 [0090] NAQ1 NAQ2 NAQ3 NAQ4 NAQ5 SI. No Ingredients
Quantity (mg/mL) 1. Carfilzomib 10 10 10 10 10 2. Ascorbic acid 3
-- -- -- -- 3. Citric acid -- 10 10 -- -- 4. PEG 300 350 300 300 --
150 5. Propylene Glycol Qs to 1 mL 300 -- 150 6. Polysorbate 80 --
100 300 -- 7. Alpha-tocopherol -- -- 0.2 0.2 8. Ethanol -- Qs to 1
mL Qs to 1 mL Qs to 1 mL
Example 1: Continued
TABLE-US-00002 [0091] NAQ6 NAQ7 NAQ8 NAQ9 SI. No Ingredients
Quantity (mg/mL) 1. Carfilzomib 10 10 10 10 2. PEG 300 200 200 --
150 3. Propylene Glycol 200 200 -- 150 4. Polysorbate 80 100 300
100 300 5. Alpha-tocopherol -- 0.2 0.2 6. Sulphuric acid Qs to pH
-- -- 7. Ethanoic acid -- Qs to pH 8. Ethanol Qs to 1 mL Qs to 1 mL
Qs to 1 mL
[0092] Considering the semi-aqueous compositions results,
non-aqueous compositions were developed to check the feasibility
and stability of same.
[0093] Non-aqueous compositions NAQ1 comprising ascorbic acid were
clear as such initially and turned hazy later, hence NAQ1
compositions were discontinued from further studies. Non-aqueous
compositions NAQ2 and NAQ3 compositions comprising citric acid were
clear initially and later turned hazy, hence NAQ2 and NAQ3
compositions were discontinued from further studies. NAQ4 &
NAQ5 compositions devoid of any non-volatile sugar acid were
developed and initially the compositions were clear and slowly
developed haziness, forcing to discontinue with further
studies.
[0094] Considering above observations on clarity of drug solution,
few other compositions were developed with acidifying agent such as
sulphuric acid, ethanoic acid. NAQ6 and NAQ7 drug solution
compositions with sulphuric acid and NAQ8, NAQ9 compositions with
ethanoic acid were clear for prolonged time and hence these
compositions were considered for further studies.
Example 2: Compositions with Sulphuric Acid
TABLE-US-00003 [0095] AA1 AA2 AA3 AA4 AA5 AA6 AA7 SI. No
Ingredients Quantity (mg/mL) 1. Carfilzomib 10 10 10 10 10 10 10 2.
Propylene Glycol 150 200 200 200 -- -- -- 3. PEG 300 150 200 200
200 -- -- -- 4. Polysorbate 80 300 100 200 300 100 200 300 5.
Alpha-tocopherol 0.2 -- -- -- -- -- -- 6. Sulphuric acid Qs to pH
7. Ethanol Qs to 1 mL
TABLE-US-00004 TABLE 2 Physical Observations Physio. solution
description (mg/mL) WFI 5% dextrose Composition Description 0.2 0.5
0.2 0.5 Remarks AA1 CS CS CS CS CS Physiological solution was clear
free from particles AA2 CS LH H LH H Physiological solution turned
hazy after dilution AA3 CS LH H LH H Physiological solution was
clear for two hours after dilution with composition AA4 CS CS CS CS
CS Physiological solution was clear free from particles AA5 CS LH H
LH H Physiological solution turned hazy after dilution AA6 CS LH H
LH H Physiological solution turned hazy after dilution AA7 CS CS CS
CS CS Physiological solution was clear free from particles
[0096] CS--Clear Solution; LH--Light Hazy; H--Hazy
[0097] Considering the drug solution clarity, compositions with
sulphuric acid were developed to check the stability. Example 3
discloses that few proposed compositions containing sulphuric acid
were clear, free from the particles and the pH was recorded towards
acidic side a noteworthy indication. However physiological solution
turned hazy after dilution with few other compositions containing
less than or equal to 200 mg/mL polysorbate 80. It was confirmed
that propylene glycol and PEG 300 content in the composition had
negligible role to play. Hence AA1, AA4 and AA7 compositions were
considered for further stability studies.
Example 3--Compositions with Ethanoic Acid
TABLE-US-00005 [0098] AA8 AA9 AA10 AA11 AA12 AA13 AA14 SI. No
Ingredients Quantity (mg/mL) 1. Carfilzomib 10 10 15 10 10 10 10 2.
Polysorbate 80 -- -- -- 400 500 200 300 3. Ethanoic acid -- 150 30
10 20 30 30 4. Alpha-tocopherol -- -- -- -- -- -- 0.2 5. Ethanol Qs
to 1 mL
Example 3--Continued
TABLE-US-00006 [0099] AA15 AA16 AA17 AA18 AA19 AA20 AA21 SI. No
Ingredients Quantity (mg/mL) 1. Carfilzomib 10 10 20 20 20 10 20 2.
Polysorbate 80 400 400 -- -- -- 300 400 3. Ethanoic acid 30 50 50
100 150 30 30 4. Alpha-tocopherol -- -- -- -- -- 0.2 0.2 5. Ethanol
Qs to 1 mL
TABLE-US-00007 TABLE 3 Physical Observations Physio. solution
description (mg/mL) WFI 5% dextrose Composition Description 0.2 0.5
0.2 0.5 Remarks AA8 CS H H H H Immediately after dilution, clear
solution turned hazy AA9 CS CS CS CS CS Physiological solution was
clear free from particles after dilution AA10 CS LH H LH H
Physiological solution turned hazy after dilution AA11 CS LH H LH H
Physiological solution turned hazy after dilution AA12 CS LH H LH H
Physiological solution turned hazy after dilution AA13 CS LH H LH H
Physiological solution turned hazy after dilution AA14 CS LH H LH H
Physiological solution turned hazy after dilution AA15 CS CS CS CS
CS Physiological solution was clear free from particles after
dilution AA16 CS CS CS CS CS Physiological solution was clear free
from particles after dilution AA17 CS CS CS CS CS Physiological
solution turned hazy after dilution AA18 CS CS CS CS CS
Physiological solution turned hazy after dilution AA19 CS CS CS CS
CS Physiological solution turned hazy after dilution AA20 CS CS CS
CS CS Physiological solution was clear free from particles after
dilution AA21 CS LH H LH H Physiological solution turned hazy after
dilution
[0100] The above examples were studied for optimizing ethanoic acid
and polysorbate 80 concentration in the composition to check the
physical stability after dilution with physiological solution. From
the above observations it was accomplished that the proposed
compositions AA15 and AA16 with 10 mg/mL carfilzomib were clear and
free from the particles, even after dilution with physiological
solution. However, AA17, AA18, AA19 and AA21 compositions with 20
mg/mL carfilzomib concentration and with or without polysorbate 80
were tested and all compositions turned hazy on dilution with
physiological solution thereby endorsing physical instability.
Further AA10, 15 mg/mL concentration of carfilzomib compositions
also turned hazy, hence 15 mg/mL and 20 mg/mL compositions were
discontinued from further stability studies. Other compositions
with reduced ethanoic acid and polysorbate 80 concentration turned
hazy after dilution with physiological solution. Hence AA9, AA15,
AA16 and AA20 compositions which were clear upon dilution with
physiological solution were considered for further studies.
TABLE-US-00008 Example 4- Impact of ethanoic acid quantity on
Chemical stability EA1 EA2 EA3 EA4 EA5 EA6 SI. No Ingredients
Quantity (mg/mL) 1. Carfilzomib 10 10 10 10 10 10 2. Polysorbate 80
300 300 300 300 300 300 3. Propylene Glycol -- -- -- -- -- -- 4.
PEG 300 -- -- -- -- -- -- 5. Alpha-tocopherol 0.2 0.2 0.2 0.2 0.2
0.2 6. Ethanoic acid 150 100 50 30 20 10 7. Ethanol Qs to 1 mL
TABLE-US-00009 TABLE 4 Chemical Stability of EA1, EA2, EA3, EA4,
EA5 and EA6 compositions Parameters .fwdarw. Time EA1 EA2 EA3 EA4
EA5 EA6 Time Points (Days) Total Impurities (%) 60.degree. C. 3
days 4.1 3.78 2.81 2.66 2.22 2.1
[0101] From the above example, 6 compositions EA1, EA2, EA3, EA4,
EA5 and EA6 were tested for stability with varying concentration of
ethanoic acid at stress condition to know the stability, it was
accomplished that compositions degradation is proportional to the
quantity of ethanoic acid. Hence considering chemical stability
parameters of above compositions, it was inferred that polysorbate
80 and ethanoic acid quantity needs to be optimized in order to
stabilize the composition. Further, from the physical stability
studies, it has been concluded that AA9, AA15, AA16 and AA20
compositions were physically stable as they were clear upon
dilution with physiological solution. Therefore, considering
chemical and physical stability outcome the, below composition was
optimized.
Example 5: Optimized Composition
TABLE-US-00010 [0102] SI. No Ingredients Quantity (mg/mL) 1.
Carfilzomib 10 2. Polysorbate 80 300 3. Alpha-tocopherol 0.2 4. PEG
300 100 5. Ethanoic acid 30 6. Ethanol Qs to 1 mL
TABLE-US-00011 TABLE 5 Chemical Stability of Optimized composition
Parameters Time Total Impurities Time Points (Months) (%) T.sub.0
T.sub.0 0.06 2-8.degree. C. 1 M 0.07 25.degree. C./60 RH 1 M 0.43
40.degree. C./75 RH 1 M 1.56
[0103] Based on the physicochemical stability details, composition
of example 5 were developed to optimize quantities of ethanoic acid
required to stabilize the carfilzomib non-aqueous ready-to-use
composition. Considering the above composition stability data, it
is inferred that composition degradation is proportional to the
quantity of ethanoic acid in the composition.
[0104] Therefore, considering the above examples 1 to 5 it is
accomplished that optimum quantity of ethanoic acid and optimum
quantity of polysorbate 80 is required for both physical and
chemical stability of the non-aqueous compositions, apart from
other excipients in the compositions. Numerous trials have been
performed to determine the effect of ethanoic acid quantity on
formulation stability and parallel physical stability with
combination of surfactant, from the physical stability data it was
concluded that equal to or more than 30 mg ethanoic acid was
required to keep the diluted solution stable for at least 24 hours
or more with the help of surfactant. The observed formulation
degradation rate is directly propositional to the quantity of
ethanoic acid in the formulation. However, surfactant did not show
any significant impact on chemical stability, but played critical
role on physical stability, the minimum quantity of surfactant 300
mg is required to keep the diluted solution clear for at least 24
hours and above with the help of ethanoic acid. However, ethanoic
acid comprising compositions are comparable to each other both
physically and chemically thereby producing stable, ready-to-use,
non-aqueous compositions.
[0105] The ready-to-use compositions are stable at 2.degree. C. to
25.degree. C., and room temperature for at least 3 months.
* * * * *