FIELD OF THE INVENTION
The present invention relates to stable parenteral pharmaceutical compositions
comprising Bortezomib or its pharmaceutically acceptable salts or solvates thereof
and pharmaceutically acceptable stabililizing agents selected from water soluble
polymers and amino acids. The invention also provides a process for manufacturing
said stable parenteral pharmaceutical compositions.
BACKGROUND OF THE INVENTION
Bortezomib is a modified di-peptidyl boronic acid. It is a reversible inhibitor of the
chymotrypsin-like activity of the 26S proteasome in mammalian cells. Bortezomib
and related compounds are described in US Patent Nos. 5,780,454, 6,083,903,
6,297,217, 6,617,317, 6,747,150 and 7,119,080. These and all other extrinsic
materials discussed herein are incorporated by reference in their entirety. It is
believed that the boron atom in Bortezomib binds to the catalytic site of the
proteasome, ultimately leading to proteasome inhibition and reduced degradation of
pro-apoptotic factors, which in tum triggers apoptosis in treated cells.
The chemical name for Bortezomib, the monomeric boronic acid, is [(lR)-3-methyl1-[[(
2S)-I-oxo-3-phenyl-2-[(pyrazinylcarbonyl) amino] propyl] amino] butyl]
boronic acid. The solubility of Bortezomib, as the monomeric boronic acid, in water
is 3.3 to 3.8 mg/mL in a pH range of2 to 6.5. Bortezomib has the following chemical
structure (Formula I).
Bortezomib is cytotoxic to a variety of cancer cell types in vitro and causes a delay in
tumor growth in vivo in nonclinical tumor models, including multiple myeloma.
Bortezomib presently is approved for the treatment of multiple myeloma, relapsed
multiple myeloma, and mantle cell lymphoma. A variety of combination therapies
have been investigated for treating multiple myeloma, in which Bortezomib is
administered together with one or more other biologically active substances, such as
lenalidomide, dexamethasone, melphalan, prednisone, thalidomide,
cyclophosphamide, doxorubicin, vincristine, carmustine, pomalidomide, vorinostat,
tanespimycin, and perifosine. Other potential uses of Bortezomib also have been
reported, including treatment of amyloidosis.
A disadvantage that Bortezomib shares with other peptidyl boronic acids and esters is
its instability to standard conditions of purification and storage. Boronic acids and
esters tend to form anhydrides, including cyclic anhydrides referred to as "boroxines,"
during dehydration, which can make it difficult to purify the desired compound.
Boronic acids and esters also tend to oxidize in air, which can severely limit their
shelf life. Thus, Bortezomib typically is difficult to purify, to characterize and/or to
formulate into a stable therapeutic product.
Commercially, Bortezomib is sold under the tradename VELCADE@ that is approved
for use in treating various neoplastic diseases, and especially for the treatment of
relapsed multiple myeloma and mantle cell lymphoma. VELCADE® for Injection is
available for intravenous injection or subcutaneous use. Each single use vial contains
3.5 mg of Bortezomib as a sterile lyophilized powder and 35 mg mannitol, USP as
excipient. The product is provided as a mannitol boronic ester which, in reconstituted
form, consists of the mannitol ester in equilibrium with its hydrolysis product, the
monomeric boronic acid. The drug substance exists in its cyclic anhydride form as a
trimeric boroxine.
In the marketed formulation (VELCADE®) the sugar stabilization techniquethat has
been described in U.S. Patent Nos 6,713,446 and 6,958,319, is being utilized. These
patents disclose method of increasing the stability of Bortezomib by combining
boronic acid with sugars or other compounds having two or more hydroxyl groups
separated by at least two connecting atoms (C, N, S or 0). In a specific embodiment,
stable pharmaceutical compositions of boronic acid compounds are prepared by
lyophilizing an aqueous mixture comprising a boronic acid compound and a
compound having at least two hydroxyl groups, which produces a powder containing
Bortezomib, the sugar and/or an ester of Bortezomib, and the sugar, that readily
releases the boronic acid compound upon dissolution in aqueous media. The structure
ofbortezomib-mannitol ester is as follows (Formula II):
Alternative methods of increasing the stability of Bortezomib have been reported in
various publications as discussed below:
International Publication No. W02010/039762, assigned to Dr. Reddy's Laboratdries
discloses liquid formulations of Bortezomib in organic solvents such compositions
further containing ethylenetetramineacetic acid and ethylenediaminetetraacetic acid
asstabilizing agents.
International Publication No. W02010/089768, assigned to Sun Pharma discloses the
use of various solublizing agents for preparing stable parenteral formulations of
Bortezomib. More particularly, the inventors resolve the problem of stability by
preparing a composition comprising Bortezomib and tromethamine with the pH
adjusted in the range of 6.8 to 8.4.
International Publication No. W02010/114982, assigned to Cephalon discloses
lyophilized formulations of proteasome inhibitors, particularly Bortezomib, and
further discloses the use of cyclodextrins as stabilizing agents.
Also U.S. Patent No. 8,263,578 assigned to Innopharma describes a composition of
Bortezomib in a non-aqueous solvent system includ propylene glycol as predominant
component along with other ingredients such as a buffer.
It is a well known fact that formulating Bortezomib has not proven to be an easy task,
typically due to stability and solubility issues. It is apparent from all of the above
identified prior art documents that in order to prepare pharmaceutical compositions of
Bortezomib, different solvent systems and elaborated techniques (e.g cyclodextrin or
alkaline excipients) are needed. Thus, there is still the need for convenient to prepare
and stable parenteral pharmaceutical compositions of Bortezomib.
In the present invention it was surprisingly found that stable lyophilized and ready to
use injectable formulations of Bortezomib can be prepared without using sugars, but
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by using other suitable stabilizing agents instead, optionally in combination with
other pharmaceutically acceptable excipients.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a stable parenteral pharmaceutical composition
comprising Bortezomib or pharmaceutically acceptable salts or solvates thereof and
an effective amount of pharmaceutically acceptable stabilizing agents selected from
the group of water soluble polymers and amino acids. It also provides a process for
manufacturing said stable parenteral pharmaceutical compositions.
In one embodiment, the present invention provides a stable parenteral pharmaceutical
composition comprising Bortezomib or pharmaceutically acceptable salts or solvates
thereof and an effective amount of pharmaceutically acceptable stabilizing agents,
one or more suitable co-solvents along with one or more optional pharmaceutically
acceptable excipients.
Suitable water soluble polymers are selected from the group consisting of
polyvinylpyrrolidine, polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl
methylcellulose or combination thereof and the like. The water soluble polymer is
polyvinylpyrrolidine.
Suitable amino acids are selected from the group consisting of histidine, arginine,
glycine, threonine, glutamine, alanine, asparagine, serine, cysteine, leucine, lysine,
valine or combination thereof and the like.
Suitable co-solvents is selected from the group consisting of ethanol, methanol,
tertiary butanol, isopropyl alcohol, n-propanol, n-butanol, acetone, acetonitrile,
dichloromethane, dimethylsulfoxide, ethyl acetate, dimethyl carbonate, methyl ethyl
ketone, pentanol, methyl isobutyl ketone, methyl acetate, carbon tetrachloride,
dimethyl acetamide, hexafluoroacetone, chlorobutanol, acetic acid, cyclohexane,
propylene glycol, polyethylene glycol, glycerol, glycerine or combination thereof and
the like.
The other optional pharmaceutically acceptable excipients include but are not limited
to antioxidants, chelating agents, preservatives, buffers, tonicity adjuster and the like.
The pharmaceutical formulations may optionally include one or more
pharmaceutically acceptable excipients. These include but are not limited to:
Suitable antioxidants includemonothioglycerol, L-cysteine,thioglycolic acid, sodium
metabisulfite, ascorbic acid, monoethanolamine gentisate, sodium formaldehyde
sulfoxylate, sodium bisulfate and the like;
Suitable chelating agents include ethylenediamine tetraacetic acid (EDTA) and the
like;
Suitable preservatives include phenylmercuric nitrate, thiomersal, benzalkonium
chloride, benzethonium chloride, phenol, cresol, chlorobutanol and the like;
Suitable buffers include acetate, citrate, tartarate, phosphate, benzoate and
bicarbonate buffers, as well as amino acids such as glutamic acid, histidine and the
like;
Suitable tonicity agents include sodium chloride, potassium chloride, magnesium
chloride, glycerine and the like.
In a specific embodiment, the invention relates to a stable sugar free parenteral
pharmaceutical composition comprising Bortezomib or pharmaceutically acceptable
salts or solvates thereof, in the form of a lyophilized, ready to use solution and its
preparation. For example, the composition may be in the form of a solution for
injection (e.g., injectable multi dose sterile composition), in the form of a sterile
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powdered composition (e.g., lyophilized cake, powder, lyophilized powder), which
may be administered after dilution or reconstitution.
In another aspect the invention provides a process of manufacturing a stable parenteral
pharmaceutical composition of Bortezomib comprising preparing a liquid mixture
comprising Bortezomib or its pharmaceutically salts or solvates thereof, a stabilizing
agents and one or more co-solvents, which may optionally contain further
pharmaceutically acceptable excipients. Further, the liquid mixture may be subjected
to lyophilization to form a lyophilized cake or may be filled into vials to be used as a
ready to use preparation.
Lyophilized formulations of the present invention can be prepared according to
conventional freeze-drying or lyophilization techniques, including use of nitrogen
flush as the blanket on the substance to be lyophilized or using a lyophilizer. These
lyophilized compositions can be readily reconstituted by adding an aqueous solvent.
The reconstitution solvent is suitable for pharmaceutical administration. Examples of
suitable reconstitution solvents include, but are not limited to, water, saline, and
phosphate buffered saline (PBS).
In another embodiment ready-to-use preparations of Bortezomib are prepared by
dissolving Bortezomib, a suitable stabilizing agent and optionally further
pharmaceutically acceptable excipients in a suitable solvent. These can be
administered directly without any prior reconstitution step.
In another embodiment of the present invention, the pharmaceutical composition of
Bortezomib according to the present invention has a suitable pH which may range
between about 2 and about 8.
These formulations are presented as a single vial presentation containing Bortezomib
in concentrationsof 0.5 to 5 mg/ml. These pharmaceutical compositions
areadministered via intravenous or subcutaneous injection to treat patients suffering
from multiple myeloma and mantle cell lymphoma who have received at least one
prior therapy.
The vials are small, usually glass, containers that can be sealed with a suitable stopper
and seal. Other suitable primary containers are for instance, pre-filled syringes,
plastic containers, miniature screw-top jars, and any other type of container of a size
capable of holding only one unit dose of a drug.
In another embodiment of the present invention, in order to minimize oxidation of the
sensitive material headspace oxygen and/or moisture from the sealable vessel as
quickly as possible. This may be achieved by, for example, purging the sealable
container with a gas which is substantially oxygen-free, or substantially moisture
free, or substantially oxygen and moisture free. This reduces the oxygen level in the
sealable container to a level of from about 0.1% to about 10%, typically about 5% or
lower, depending on the efficiency of flushing and on how quickly the container is
sealed after flushing.
The gas used for purging the sealable container may be any appropriate inert gas
known to those in the art, the most commonly used gases being argon, helium or
nitrogen, or mixtures thereof. The most preferred inert gas is nitrogen.
Suitable means for sealing the containerinclude, for example, stoppers, caps, lids,
closures, coverings which fluidly seals the container, or the like. The means for
sealing the container are not limited to separate closures or closure devices. The
means for aseptically sealing the container include stoppers such as, for example,
stoppers that are configured to fluidly seal the opening. Suitable stoppers include
conventional medical grade stoppers that do not degrade or release significant
amounts of impurities upon exposure to the reconstituted aqueous Bortezomib
solution.
The following examples are given for the purposes of illustration only and are not
intended to limit the scope ofthe invention in any manner.
EXAMPLES
Example 1
Lyophilized Pharmaceutical Composition of Bortezomib
.....
. ,'-
.
2
3
4
5
Bortezomib
Povidone
Sodium chloride (Optional)
Acetonitrile*
Water for injection*
1mg
20mg
9mg
20%
q.s.
1mg
20mg
9mg
3.5 mg
70mg
31.5 mg
6 Nitrogen**
* Shall be removed during lyophilization process
....Nitrogen is used for blanketing in vial headspace
q.s. q.s. q.s.
The pharmaceutical composition according to Example 1 is prepared by the below
mentioned process:
(i) A suitable quantity of acetonitrile is fed into a manufacturing vessel.
(ii) Bortezomib is added to the solvent mixture in the manufacturing vessel
and then stirred.
(iii) Povidone is added to the solution in the manufacturing vessel and stirred.
10
•
·.... '.' ~. '. ~'
(iv) Ifrequired, sodium chloride is added into the mixture and stirred.
(v) The volume is then made up to 100% with water for injection.
(vi) The drug solution is filtered through a suitable 0.2 micron filter. The
filtered solution is filled into vials.
(vii) Finally the vials are half stoppered and the content is lyophilized.
(viii) The lyophilized product is reconstituted using sterile water for injection
prior to use.
Example 2
Ready to use Pharmaceutical Composition of Bortezomib
Sr. No. I~Dts Qty!mL
I Bortezomib I mg
2 Povidone 15 mg
3 Sodium chloride (Optional) 9mg
4 N,N-Dimethyl Acetamide 20%
5 Polyethylene glycol 80%
6 Nitrogen** q.s.
**Nitrogen is used for blanketing in vial headspace
The pharmaceutical composition according to Example 2 is prepared by below
mentioned process:
i) The required quantity of N, N-Dimethyl Acetamide and polyethylene glycol
mixture is fed into a manufacturing vessel and sodium chloride is dissolved in
the mixture.
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•
t\.- '.
ii) Bortezomib is added to the solvent mixture in the manufacturing vessel and
stirred.
iii) Povidone is added into the manufacturing vessel and stirred.
iv) If required, sodium chloride is added into the mixture and stirred.
v) The volume is then made up to 100% with the solvent mixture.
vi) The drug solution is filtered through a suitable 0.2 micron filter.
vii) The filtered solution is filled into vials.
viii) Finally the vials are stoppered and sealed.

We Claim:
1. A stable parenteral pharmaceutical composition comprising Bortezomib
orpharmaceutically acceptable salts or solvates thereof and an effective
amount of pharmaceutically acceptable stabilizing agents.
2. The pharmaceutical composition according to claim 1, wherein
pharmaceutically acceptable stabilizing agents are selected from the group of
water soluble polymers and amino acids.
3. The pharmaceutical composition according to claim 2, wherein the
pharmaceutically acceptable stabilizing agents is a water soluble polymer
selected from the group consisting of polyvinylpyrrolidine, polyethylene
glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose or
combinations thereof.
4. The pharmaceutical composition according to claim 3, wherein the water
soluble polymer ispolyvinylpyrrolidone.
5. The pharmaceutical composition according to claim 2, wherein the amino acid
is selected from the group consisting of histidine, arginine, glycine, threonine,
glutamine, alanine, asparagine, serine, cysteine, leucine, lysine, valine or
combinations thereof.
6. The pharmaceutical composition according to claim 1further comprising at
least one pharmaceutically acceptable co-solvent.
7. The pharmaceutical composition according to claim 6, wherein the
pharmaceutically acceptable co-solvents is selected from the group consisting
of ethanol, methanol, tertiary butanol, isopropyl alcohol, n-propanol, nbutanol,
acetone, acetonitrile, dichloromethane, dimethylsulfoxide, ethyl
acetate, dimethyl carbonate, methyl ethyl ketone, pentanol, methyl isobutyl
ketone, methyl acetate, carbon tetrachloride, dimethyl acetamide,
hexafluoroacetone, chlorobutanol, acetic acid, cyclohexane, propylene glycol,
polyethylene glycol, glycerol, glycerine or combinations thereof.
8. The pharmaceutical composition according to claim Ifurther comprising at
least one further pharmaceutically acceptable excipient.
9. The pharmaceutical composition according to claim 8, wherein the at least
one further pharmaceutically acceptable excipient is selected from the group
consisting ofantioxidants, chelating agents, preservatives, buffers and tonicity
agents.
10. A process of manufacturing stable parenteral pharmaceutical composition of
Bortezomib comprising:
(a) preparing a liquid mixture comprIsmg Bortezomib or pharmaceutically
acceptable salts or solvates thereof, a stabilizing agent, one or more cosolvents
and at least one further pharmaceutically acceptable excipient, and
(b) subjected the mixture obtained in step a) to lyophilization to form a
lyophilized cake orfilling it into vials to be used as a ready to use preparation.