FIELD OF THE INVENTION
The present invention relates to a method of making a stable pharmaceutical
composition comprising levalbuterol or its pharmaceutically acceptable salt and one
or more pharmaceutically acceptable excipients in a glass vessel or glass-lined
vessel.
BACKGROUND OF THE INVENTION
Albuterol also known as salbutamol is a p2- adrenergic antagonist and acts as a
smooth muscle relaxant. Albuterol is particularly effective as a bronchodilator in
the treatment of asthma. Albuterol contains a chiral centre and exists in two forms
i.e. (R)-albuterol, also known as levalbuterol which is as active form, and (S)-
albuterol which is considered inert. Albuterol may be supplied as a single
enantiomer or as a racemic mixture of the two enantiomers. Racemic albuterol and
racemic albuterol sulfate are commercially available as Proventil®, Ventolin® and
Vormax®. The pure (R)-enantiomer i.e. levalbuterol as its hydrochloride salt, is
commercially available as Xopenex®. The chemical name for levalbuterol
hydrochloride is (R)-a -[[(1,1-dimethylethyl) amino]methyl]-4-hydroxy-l,3-
benzenedimethanol hydrochloride and its established chemical structure is as
follows:
HO
CH2OH
As a salicylyl alcohol derivative, levalalbuterol is known to undergo oxidative
degradation to form the albuterol aldehyde, herein referred as compound D, which
is 5-(2-((l,l -dimethyl elhyl)amino)-l-hydroxyethyl)-2-hydroxybenzaldehyde and
has the following formula:
HCl
CM
E
o
LL
CD
^ ,
O
O
NKJBu
It may also undergo hydroxylation to produce 5-hydroxy albuterol.
Cfff
® Therefore, formation of degradation products in an aqueous albuterol solution limits
Q_ the shelf life during process and after storage under an ambient atmosphere.
CD
Albuterol aldehyde has an adverse effect when inhaled and hence the levels of
albuterol aldehyde in pharmaceutical formulations are stringently controlled. For
example, the FDA currently requires a levalbuterol formulation for inhalation to
contain no more than 0.05% by weight of albuterol aldehyde at the time of release
and no more than 0.08% by weight by the expiry date of the medicament. Further,
CO FDA requires that levalbuterol formulation for inhalation to contain no more than
O
0.1% by weight of 5-hydroxyalbuterol.
o
5J Any transition metal ion is able to act as an oxidising agent and can cause oxidation
JN of the active ingredient. Typically, the pharmaceutical solutions are prepared in a
{2 stainless steel mixing vessel whose surface when comes in contact with water, will
^2 leach metal ions into the composition. It has been found that the leaching of such
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CN materials from a stainless steel vessel causes oxidative degradation of the active
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<:
ingredient to form the aldehyde. Therefore, there is a need to provide stabilized
levalbuterol compositions.
One such approach of stabilization is disclosed in U.S. Pat. No. 6,451,289. This
patent aimed at to reduce levels of albuterol aldehyde after storage at 40° C for six
months using blow nitrogen gas over the solution during formulation and filling of
the solution in unit dose vials. The vials are then enclosed in an oxygenimpermeable
wrapper in a reduced oxygen atmosphere. This process is
cumbersome and it is difficult to control the level of oxygen during
manufacturing and storage. Once the protective wrapper is opened, albuterol is
exposed to ambient oxygen and degradation can occur.
US Pub. No. 2004/0110845 Al and US Pub. No. 2004/0109826 Al disclose
albuterol composition which is stabilized by incorporating a buffer and a metal
^, chelator wherein said composition contains less than 0.01% by weight
CD
U> of albuterol aldehyde after storage for at least 6 months at 40° C, or at least 18
°- months at 25° C.
J^ Sugars, such as glucose, sucrose and fructose, have been found to increase the
£ decomposition of albuterol. As a consequence, syrups containing saccharin were
O proposed in US 4,499,108.
^2 WO 2005/113481 Al discloses that albuterol is often subject to oxidation and forms
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© albuterol aldehyde. It further discloses that the solvent, co- solvent, and additives
O
are selected in such a manner that formation of the albuterol aldehyde will be equal
or less than 0.05% of the total albuterol. o
CN
CN
^ WO 2008/007099 AI discloses that in order to provide an aqueous pharmaceutical
^ formulation of albuterol which has such low levels of iron and chromium metal
ions, it is important that the initial supply of water for the aqueous solution also has
less than 12 ng/L of iron and chromium metal ions. Therefore, it teaches to purify
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£ T*D DELHI Q? 38 2 0 1 9 1 7 '-2 8 4
water by ion exchange, reverse osmosis, ultra-filtration, distillation or a
combination of techniques, upto the extent until the iron and chromium metal ion
content is less than 12 ng/L. Further, it teaches that the mixing vessel and final
container need to be composed of such a plastic material which is substantially free
of iron and chromium metal ions such as low-density polyethylene (LDPE) or a
laminate of LDPE with polyethylene terephthalate (PET).
However, recent studies show that plastic leads to contamination of stored products
by releasing harmful chemicals from the packages, especially when these products
are stored under harsh and variable temperature conditions. Furthermore, all the
prior art teaches use or selection of particular excipients in order to have a stable
composition of levalbuterol.
Therefore, there still remains a need for improved alternate methods, which avoid
or reduce the degradation of levalbuterol compositions. Accordingly, the present
inventors have discovered that the process of the present invention performs the
mixing step in a glass vessel which does not cause leaching of metal ions into the
aqueous pharmaceutical solution and thus leads to stable pharmaceutical
composition with reduced levels of 5-hydroxy albuterol and albuterol aldehyde
degradation products when stored at 40° C and NMT 25% relative humidity for 6
months.
SUMMARY OF THE INVENTION
According to main aspect, the present invention provides a process of preparing a
stable pharmaceutical composition comprising levalbuterol or its pharmaceutically
acceptable salt and one or more pharmaceutically acceptable excipients, wherein
the mixing is carried out in the glass vessel or glass-lined vessel.
According to another aspect, the present invention provides a process of preparing
a stable pharmaceutical composition comprising levalbuterol or its
pharmaceutically acceptable salt and one or more pharmaceutically acceptable
excipients, wherein the mixing is carried out in the glass vessel or glass-lined vessel
and wherein said composition is having a long shelf life with reduced levels of
albuterol aldehyde and 5-hydroxy albuterol degradation products after storage at
40° C for six months.
According to another aspect, the present invention provides a stable pharmaceutical
composition comprising levalbuterol or its pharmaceutically acceptable salt thereof
and one or more pharmaceutically acceptable excipients, wherein the one or more
pharmaceutically acceptable excipients are selected form the group comprising
tonicity agent, chelating agent, pH adjusting agent, preservative, vehicle, bulking
agent and lyoprotectants and/or combinations thereof.
According to another aspect, the present invention provides a process of preparing
a stable pharmaceutical composition comprising levalbuterol or its
pharmaceutically acceptable salt and pharmaceutically acceptable excipients
wherein said method comprises the steps of:
(a) preparing a solution comprising purified water or water for injection in glass
vessel and purging the nitrogen till dissolved oxygen reach desired level of
ppm,
(b) adding chelating agent to the solution of step (a) and stirring to form a clear
solution;
(c) optionally adding preservative to the solution of step (b);
(d) adding Levalbuterol to the solution of step (b) and stirring to form a clear
solution;
(e) adjusting the pH of the solution of step (d) if required;
(f) making the final volume of the solution using purified water or water for
injection;
(g) filtering the final solution of step (f), and filling the solution into a suitable
container.
According to another aspect, the present invention provides a process of preparing
a stable pharmaceutical composition comprising levalbuterol or a
pharmaceutically-acceptable salt thereof and one or more pharmaceutically
acceptable excipients, wherein said process is performed in a suitable glass vessel
and said composition contains no more than about 0.06 % by weight of albuterol
aldehyde and no more than about 0.08% by weight of 5-hydroxy albuterol when
stored at 40° C and NMT 25% relative humidity for 6 months.
According to another aspect, the present invention provides a process of preparing
a stable pharmaceutical composition comprising levalbuterol or a
pharmaceutically-acceptable salt thereof and one or more pharmaceutically
acceptable excipients, wherein said process is performed in a suitable glass vessel
and said composition contains no more than about 0.3% of total impurities, after
being stored for 6 months at 40° C and NMT 25% relative humidity.
According to another aspect, the present invention provides a process of preparing
a stable pharmaceutical composition comprising levalbuterol or a
pharmaceutically-acceptable salt thereof and one or more pharmaceutically
acceptable excipients, wherein said process is performed in a suitable glass vessel
and said composition contains no more than about 0.25% of total impurities, after
being stored for 6 months at 40° C and NMT 25% relative humidity.
According to another aspect, the present invention provides a stable pharmaceutical
composition comprising levalbuterol or a pharmaceutically-acceptable salt thereof
and one or more pharmaceutically acceptable excipients, wherein the composition
is having a pH in a range of about 3.3 to about 4.5.
According to another aspect, the present invention provides a stable pharmaceutical
composition comprising levalbuterol or a pharmaceutically-acceptable salt thereof
and pharmaceutically acceptable excipients which is useful for treatment or
prevention of bronchoconstrictive disorder.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a stable pharmaceutical composition of levalbuterol
or a pharmaceutically acceptable salt thereof and its manufacturing process in a
glass vessel.
Levalbuterol as mentioned herein above and herein below also comprise their
pharmaceutically acceptable salts as well as hydrates, solvates, and polymorphic
forms (crystalline or amorphous), derivatives thereof. All stereoisomer's which may
exist due to asymmetric carbons on the R substituents of the compound, including
enantiomeric and diasteromeric forms, are contemplated within the scope of this
invention. Further, it also include their enantiomeric pure forms or their racemic
mixtures.
The term "salt(s)", as employed herein, denotes acidic and/or basic salts formed
with inorganic and/or organic acids and bases. Pharmaceutically acceptable (i.e.,
non-toxic, physiologically acceptable) salts are preferred. Most preferably
hydrochloride salt.
As used herein the term "about" in reference to a numerical value means that
variations of 10% above or below the numerical value are within the range ascribed
to the specified value.
The term "total impurities" as used herein refers to any impurity including the 5-
hydroxyalbuterol, albuterol aldehyde i.e. compound D, any individual unspecified
degradation product and including A, B, C, E, F and H.
According to another embodiment of the present invention, there is provided a
stable pharmaceutical composition comprising levalbuterol or a pharmaceuticallyacceptable
salt thereof and one or more pharmaceutically acceptable excipients,
wherein the composition has total impurities less than the maximum allowed limit
as per ICH guidelines.
According to one embodiment of the present invention, there is provided a stable
pharmaceutical composition comprising levalbuterol or a pharmaceuticallyacceptable
salt thereof and one or more pharmaceutically acceptable excipients,
wherein the composition comprises from about 0.005% w/v to about 0.5% w/v
levalbuterol or its pharmaceutically acceptable salts thereof.
According to another embodiment of the present invention, there is provided a
stable pharmaceutical composition comprising levalbuterol or a pharmaceuticallyacceptable
salt thereof and one or more pharmaceutically acceptable excipients,
wherein the composition is in the form of aqueous inhalation solution or inhalation
solution concentrate.
According to another embodiment of the present invention, there is provided a
stable pharmaceutical composition comprising levalbuterol or a pharmaceuticallyacceptable
salt thereof and one or more pharmaceutically acceptable excipients,
wherein the composition is suitable for inhalation. The pharmaceutical
compositions can be in a form suitable for inhalation administration such as a sterile
solution, suspension, or emulsion in oily or aqueous vehicles.
According to another embodiment of the present invention, the pharmaceutical
composition may be in the form of a unit dose formulation or multi dose
formulation.
According to another embodiment of the present invention, the composition is filled
into a single-dose container or multi-dose container.
i -?• • ^ jt
£..*• *• - 9
According to another embodiment of the present invention, there is provided a unit
dose formulation of levalbuterol, wherein the formulation is free from
preservatives.
According to another embodiment of the present invention, the pharmaceutical
composition is in the form of ready to use composition.
According to another embodiment of the present invention, the composition as per
the present invention has a pH in the range of about 2.5 to about 5.2. Preferably,
composition has a pH in the range of about 3.3 to about 4.5.
According to another embodiment of the present invention, there is provided a
stable pharmaceutical composition comprising levalbuterol or a pharmaceuticallyacceptable
salt thereof and one or more pharmaceutically acceptable excipients,
wherein the one or more pharmaceutically acceptable excipients are selected form
the group comprising tonicity agent, chelating agent, pH adjusting agent,
preservative, vehicle, bulking agent and lyoprotectant and/or combinations thereof.
Suitable buffers may include one or more of buffers such as, for example, acetate,
citrate, phosphate, citrate-phosphate-borate buffer (Teorell-Stanhagen), phosphateacetate-
borate buffer (Britton-Robinson), tris HC1 and amino acids such as glycine,
aspartate and histidine.
Suitable pH adjusting agent include sodium hydroxide, sodium citrate/ citric acid,
sodium phosphate monobasic or sodium phosphate dibasic, hydrochloric acid,
sulphuric acid, nitric acid, sodium acetate/acetic acid, phosphoric acid, fumaric
acid, tartaric acid, maleic acid, succinic acid, ammonia solution, ammonium
carbonate, sodium borate, sodium carbonate, triethanolamine and trolamine.
Suitable chelators include EDTA or its sodium salt of EDTA, including the
disodium salt of EDTA. nitrilotriacetic acid, ethylene glycol-bis(p-aminoethyl
ether)-N,N-tetraacetic acid, ethylene glycol bis(p-aminoethyl ether)-N,N,N',N'-
tetraacetic acid (EGTA) and salts thereof, such as the disodium salt, citric acid.
Metal chelators may also be employed as their pharmaceutically acceptable
derivatives, including pharmaceutically acceptable salts, including sodium salts.
Suitable tonicity agents include propylene glycol, glycerol, propylene glycol,
sodium chloride, potassium chloride, sodium bromide, calcium chloride, mannitol,
sorbitol, dextrose, lactose, sucrose, mannose, sodium phosphate, sodium
bicarbonate, an amino acid and the like and mixtures thereof.
Suitable stabilizing or antioxidants agents include butylated hydroxyanisole
(BHA), butylated hydroxytoluene (BHT), ascorbic acid, ascorbyl palmitate, propyl
gallate, dodecyl gallate, ethyl gallate, octyl gallate, alpha tocopherol, sodium
ascorbate, sodium citrate, sodium metabisulfite, fiimaric acid, malic acid, vitamins
and vitamin esters, provitamins, ascorbic acid, vitamin E, and any pharmaceutically
compatible antioxidant known in the art, and combinations thereof.
Suitable preservative include benzalkonium chloride (BAC), benzethonium
chloride, benzoic acid, or benzoates such as sodium benzoate, sodium citrate,
benzyl alcohol, parabens (methyl, propyl, butyl), Chlorobutanol, Thimerosal or
thimerosal, acids and their pharmaceutically acceptable salts such as sorbic acid,
potassium sorbate, boric acid, borax, Sodium Perborate NaB03, salicylic acid, cetyl
pyridinium chloride, phenol, phenylethyl alcohol, phenylmercuric nitrate, and
propylparaben or combinations thereof,
Suitable vehicles include aqueous or non-aqueous solvent, present invention may
be formulated with one or a mixture of more than one pharmaceutically acceptable
solvent and is selected from, but not limited to, glycerol,. propylene glycol,
polyethylene glycol, polypropylene glycol, ethyl alcohol, isopropyl alcohol, water,
mineral oil, peanut oil, and corn oil. Pharmaceutically acceptable solvents such as
water, ethyl alcohol, isopropyl alcohol are evaporable and are usually used to
dissolve or disperse the medicament and excipients in the formulation concentrate.
Pharmaceutically acceptable reconstituting solvents such as sterile water for
injection, sterile normal saline solution, sterile phosphate buffer solution and sterile
5% dextrose solution are used for reconstitution of the dosage form of the present
invention to form a solution or a fine particle suspension of pharmaceutically active
ingredient prior to oral or nasal inhalation via a nebulizer.
According to another embodiment, the present invention provides a method of
making a stable pharmaceutical composition of levalbuterol or its pharmaceutically
acceptable salt thereof and pharmaceutically acceptable excipients wherein said
method comprises the steps of:
(a) preparing a solution comprising purified water or water for injection in glass
vessel and nitrogen is purge till dissolved oxygen reached 2ppm.
(b) adding chelating agent to the solution of step (a) and stirring to form a clear
solution;
(c) optionally adding preservative to the solution of step (b);
(d) adding Levalbuterol to the solution of step (b) and stirring to form a clear
solution;
(e) adjusting the pH of the solution of step (d) if required;
(f) making the final volume of the solution using purified water or water for
injection,
(g) filtering the final solution of step (f), and
(h) filling the solution into a suitable container.
Oxygen is displaced from water for injection by sparging with nitrogen until an
oxygen level of less than 5 ppm, preferably, 2 ppm is attained.
According to yet another embodiment, the pharmaceutical composition is prepared
in a glass vessel or a vessel lined with glassliner.
According to another embodiment, the pharmaceutical composition as per the
present invention is useful for treating bronchoconstrictive disorder which is
selected from the group comprising bronchospasm in adults, adolescents, children
6 years of age and older with reversible obstructive airway disease, asthma,
pediatric asthma, bronchial asthma, allergic asthma, occupational asthma, aspirin
sensitive asthma, exercise, induced asthma, intrinsic asthma, chronic obstructive
pulmonary disease (COPD), chronic bronchitis, cystic fibrosis and emphysema.
According to another embodiment, the present invention relates .to a stable
pharmaceutical composition comprising levalbuterol or its pharmaceutical ly
acceptable salts thereof and one or more pharmaceutically acceptable excipients,
wherein the composition optionally further comprises one or more additional
therapeutic agents. Alternatively, a compound of this invention may be
administered to a patient in need thereof in combination with the administration of
one or more other therapeutic agents.
The present invention is further illustrated by the following examples which are
provided merely to be exemplary of the invention and don't limit the scope of the
invention. Certain modifications and equivalents will be apparent to those skilled
in the art and are intended to be included within the scope of the present invention.
Example 1
Pharmaceutical composition of Levalbuterol HC1 inhalation solution
Ingredient
Levalbuterol Hydrochloride
(eq. to Levalbuterol)
Sodium Chloride
Edetate Disodium Dihydrate
Sulfuric Acid
Water for Injection
0.31 mg/3mL
0.36
(0.31)
0.63 mg/3 mL
0.63
(0-73)
1.25 mg/3 mL
1.25
(1-44)
26.7
0.33
q.s. to adjust pH to 3.3-4.5
q.s. to 3 mL
Process:
1. Collect 100% water for injection in a suitable glass vessel and purge the
nitrogen.
2. Transfer 95% of water for injection in another glass vessel and purge
nitrogen till dissolved oxygen reached 2 ppm.
3. Add EDTA dihydrate in step 2 solution and stir for 15 min or till clear
solution formed.
4. Add sodium chloride in step 3 solution and stir for 15 min or till clear
solution formed.
5. Add levalbuterol HC1 in step 4 solution and stir for 30 min or till clear
solution formed.
6. Adjust pH by using 0.1 N-sulfuric acid to pH 3.5 to 4.5 (Target 4.0).
7. Volume make up to 100% of batch size with pre-purged water for injection
of step 1.
8. Filter the bulk solution using 0.22 micron PVDF filter and hold it in a glass
O) vessel, overlay with nitrogen.
CO
Q. 9. Fill the filtered bulk solution in BFS container using BFS machine.
CD
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Note: (b) Use N2 throughout the manufacturing process and overlay with nitrogen.
(c) Parison formation and BFS ballooning to be done with high purity
CN
c nitrogen gas.
o
U-
<5 Stability Studies: The compositions prepared according to example 1 were stored
^ ,
O at 40°C and NMT 25% relative humidity for 6 months. They were tested for the
CO
o
presence of degradation products, prior to and after 6 months storage. The results
are set out in Table 1.
Table 1:
o
CN
™ Levalbuterol HC1 inhalation solution
o
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G)
2 IPO. DELHI Q? 0 8 201S 1 ? - S
M
o
Time points
Related
substance
. 5-
Hydroxyalbuterol
(RRT:0.9)
Albuterol
aldehyde
Compound D
(RRT:1.7)
Total impurity
USP
Specifi
cation
NMT
0.1%
NMT
0.08%
NMT
0.7%
Xopenex®
Initial
ND
0.02
0.18
6M
0.14
0.21
0.91
Stability condition 40°C/NMT 25%RH
1.25
mg/3mL
Initial
ND
ND
0.04
6M
0.00
0.01
0.03
0.63
mg/3mL
Initial
ND
ND
0.08
6M
0.02
0.02
0.06
0.31
mg/3mL
Initial
ND
ND
0.09
6M
0.08
0.06
0.16
*ND-not detected
The obtained stability data shows that the compositions prepared as per the present
invention result in reduced amount of 5-hydroxyalbuterol and albuterol aldehyde
impurities as well as total impurities as compared to reference listed drug i.e.
Xopenex® at initial as well as after storage for 6 months. Therefore, the present
invention provides a stable pharmaceutical composition of albuterol with an
extended shelf life.

WE CLAIM:
1. A stable pharmaceutical composition comprising levalbuterol or its
pharmaceutically acceptable salt and one or more pharmaceutically acceptable
excipients, wherein the composition is stable for at least 6 months after storage at
40° C and NMT 25% relative humidity and wherein said composition is prepared
in a glass vessel by the process comprises the steps of:
(a) preparing a solution comprising purified water or water for injection in glass
vessel and purging the nitrogen;
(b) adding chelating agent to the solution of step (a) and stirring to form a clear
solution;
(c) optionally adding preservative to the solution of step (b);
(d) adding Levalbuterol to the solution of step (b) and stirring to form a clear
solution;
(e) adjusting the pH of the solution of step (d) if required;
(f) making the final volume of the solution using purified water or water for
injection;
(g) filtering the final solution of step (f), and filling the solution into a suitable
container.
2. The stable pharmaceutical composition as claimed in claim 1, wherein said
composition contains total impurities no more than about 0.25%, after being stored
for 6 months at 40° C and NMT 25% relative humidity.
3. The stable pharmaceutical composition as claimed in claim 1, wherein said
composition contains 5-hydroxyalbuterol impurity no more than about 0.08%, after
being stored for 6 months at 40° C and NMT 25% relative humidity.
4. The stable pharmaceutical composition as claimed in claim 1, wherein said
composition contains albuterol aldehyde impurity no more than about 0.06 %, after
being stored for 6 months at 40° C and NMT 25% relative humidity.
r fs7 Q£ 2 G 1 ? 1..7 ' 2 e
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5. The stable pharmaceutical composition as claimed in claim 1, wherein the one or
more pharmaceutically acceptable excipients are selected from a group comprising
tonicity agent, chelating agent and pH adjusting agent or combinations thereof.
6. The stable pharmaceutical composition as claimed in claim 1, wherein said
composition is free of preservative.
7. The stable pharmaceutical composition as claimed in claim 1, wherein said
chelating agent is EDTA.
8. The stable pharmaceutical composition as claimed in claim 1, wherein the pH
adjusting agent is sulphuric acid.
9. The stable pharmaceutical composition as claimed in claim 1, wherein the
composition is filled into a single-dose container or multi-dose container.
10. A method of treating or preventing a bronchoconstrictive disorder, comprising
the administration of the stable pharmaceutical composition of any one of claims 1 -
9.