FORM-2
THE PATENTS ACT, 1970
(39 OF 1970)
&
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
PARENTERAL DOSAGE FORM OF DILTIAZEM
SUN PHARMACEUTICAL INDUSTRIES LIMITED
A company incorporated under the laws of India having their office at SUN HOUSE, 201 B/1,
WESTERN EXPRESS HIGHWAY, GOREGOAN (E), MUMBAI-400063
MAHARASHTRA, INDIA.
The following specification particularly describes the invention and the manner in which it is
to be performed:
2
CROSS REFERENCE
The present patent application is a national phase of PCT application number
PCT/IB2021/058587 dated September 21, 2021 which claims priority from Indian
provisional patent application no. 202021040712 dated September 21, 2020.
5
FIELD OF THE INVENTION
The present invention relates to a parenteral dosage form of diltiazem comprising a
ready-to-infuse, stable aqueous solution of diltiazem which can be administered to a
patient in need thereof without manipulations in terms of its concentration and which is
10 stable for a prolonged period of time.
BACKGROUND OF THE INVENTION
Diltiazem is a calcium ion influx inhibitor (slow channel blocker or calcium
channel antagonist). Chemically, diltiazem hydrochloride is 1,5-benzothiazepin4(5H)one,3-(acetyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-,
15 monohydro-chloride, (+)-cis- and has the following structural formula:
Diltiazem, inhibits the influx of calcium (Ca) ions during membrane depolarization
of cardiac and vascular smooth muscle. Diltiazem hydrochloride is administered by
intravenous infusion for temporary control of rapid ventricular rate in atrial fibrillation or
20 atrial flutter and rapid conversion of paroxysmal supraventricular tachycardias (PSVT) to
sinus rhythm.
The commercially available injectable products of diltiazem are pre-concentrate
solutions which need to be diluted with a suitable diluent like dextrose or sodium chloride
solution before use. One such product by Bedford® is a diltiazem hydrochloride 5 mg/ml
25 injection solution, supplied in 5ml and 10ml vials. The step of dilution and handling
involves risk of potential calculation or dilution error as well as risk of microbiological
contamination during handling. Further, diltiazem is known to be susceptible to hydrolysis
3
and degradation in aqueous solutions. The degradation is undesirable as it results in loss of
titer of the active ingredient, and leads to formation of impurities or related compounds
which have negligible activity and are undesirable. The major pathway of degradation is odeacetylation which leads to formation of impurity “desacetyl diltiazem HCl”.
5 Thus, there is a need in the art for a stable parenteral dosage form of diltiazem,
which comprise an aqueous solution of diltiazem that is ready-to-infuse and can be
administered without any manipulation, i.e., in the pre-diluted form that can be directly
infused or injected thus eliminating the risk of any potential calculation or dilution error as
well as risk of microbiological contamination during handling and at the same time is
10 stable for a prolonged period of time. The present invention fulfills this need.
It was a surprise finding of the present inventors that presence of cyclic
oligosaccharide in parenteral dosage forms of diltiazem provides a significant stability.
The inventors have found that an aqueous solution of diltiazem is more stable in the
presence of cyclic oligosaccharides, which tend to stabilize diltiazem in aqueous solution
15 and protect it from degradation.
SUMMARY OF THE INVENTION
The present invention relates to a parenteral dosage form comprising a ready-toinfuse, stable aqueous solution comprising diltiazem or its pharmaceutically acceptable salt
and a cyclic oligosaccharide as a stabilizer.
20 In one aspect, the present relates to a parenteral dosage form comprising a readyto-infuse, stable aqueous solution comprising diltiazem or its pharmaceutically acceptable
salt, a cyclic oligosaccharide stabilizer, a pH-adjusting agent, and an alcoholic solvent.
In yet another aspect, the present invention provides a parenteral dosage form
comprising a ready-to-infuse, stable aqueous solution comprising diltiazem or its
25 pharmaceutically acceptable salt and a cyclic oligosaccharide stabilizer and in said
parenteral dosage form the level of desacetyl diltiazem or its salt impurity is not more than
10% w/w of diltiazem or its pharmaceutically acceptable salt when stored at 2-8
oC for at
least 12 months or at 25oC/40% RH for at least 6 months.
In another aspects, the present invention provides a method for controlling the level
30 of desacetyl diltiazem or its salt impurity in a ready-to-infuse parenteral dosage form of
diltiazem or its pharmaceutically acceptable salt by using a cyclic oligosaccharide
4
stabilizer, wherein in the dosage form the level of desacetyl diltiazem or its salt impurity is
not more than 6% w/w of diltiazem or its pharmaceutically acceptable salt when stored at
2-8
oC for at least 12 months or at 25oC/40% RH for at least 6 months.
DESCRIPTION OF THE INVENTION
5 As used herein, the word “a” or “plurality” before a noun represents one or more of
the particular noun.
For the terms “for example” and “such as,” and grammatical equivalences thereof,
the phrase “and without limitation” is understood to follow unless explicitly stated
otherwise. As used herein, the term “about” is meant to account for variations due to
10 experimental error. All measurements reported herein are understood to be modified by the
term “about,” whether or not the term is explicitly used, unless explicitly stated otherwise.
As used herein, the singular forms “a,” “an,” and “the” include plural referents unless the
context clearly dictates otherwise.
Unless otherwise defined, all technical and scientific terms used herein have the
15 same meaning as commonly understood by one of ordinary skill in the art to which this
invention belongs. Methods and materials are described herein for use in the present
invention; other, suitable methods and materials known in the art can also be used. The
materials, methods, and examples are illustrative only and not intended to be limiting. All
publications, patent applications, patents, and other references mentioned herein are
20 incorporated by reference in their entirety. In case of conflict, the present specification,
including definitions, will control.
The present invention provides a parenteral dosage form comprising a ready-toinfuse, stable aqueous solution comprising diltiazem or its pharmaceutically acceptable salt
and a cyclic oligosaccharide as a stabilizer.
25 The present invention relates to an aqueous solution of diltiazem that is ready-toinfuse without any manipulation, i.e., in the pre-diluted form that can be directly infused or
injected thus eliminating the risk of any potential calculation or dilution error as well as
risk of microbiological contamination during handling and at the same time is stable for a
prolonged period of time. More particularly, the invention relates to a stable, ready-to30 infuse, aqueous parenteral dosage form comprising diltiazem or its pharmaceutically
acceptable salt, a pH-adjusting agent to provide a pH in the range of 3.5 to 5.0, at least one
5
pharmaceutically acceptable stabilizer selected from a cyclic oligosaccharide and an
infusion container filled with said aqueous solution.
The term “diltiazem” as used herein includes diltiazem as well as its
pharmaceutically acceptable salts, such as diltiazem hydrochloride and other
5 pharmaceutically acceptable salts or derivative thereof.
The term “ready-to-infuse” as used herein means that the aqueous drug solution is
sterile and suitable for direct intravenous infusion or injection without manipulation, that
is, no intermediate steps of dilution, reconstitution, dispensing, sterilization, transfer,
handling or compounding are required before administration or infusion of the drug
10 solution to the patient. The aqueous drug solution can be directly administered parenterally
from the container of the dosage form. The term “ready-to-infuse” is synonymous with
“ready-to-inject” or “ready-to-administer” or “directly administering” or “direct
intravenous infusion” or “direct delivery” or ready to use. The ready-to-infuse parenteral
dosage form according to the present invention avoids the inconvenience of reconstituting
15 or diluting a lyophilized or concentrated parenteral formulation into infusion diluents prior
to infusion, as well as the risk of any potential calculation or dilution error as well as risk
of microbiological contamination during handling. Also, a ready-to-infuse parenteral
dosage form can be said to be a premixed dosage form which can be administered directly
without any dilution or mixing requirement. Moreover, diltiazem is an emergency life20 saving medicine and hence reduced time in getting the dose already in ready-to-infuse
dosage forms is advantageous and preferred. The present invention provides a stable
parenteral dosage form of diltiazem having a ready-to-infuse aqueous solution of diltiazem
that does not relate to semi-solid topical dosage forms (such as gel, hydrogel, emulgel,
paste, cream, ointment, etc.) and/or non-aqueous dosage forms that are not suitable for
25 parenteral administration.
The parenteral dosage form of the present invention is “stable”. As used herein, the
term “stable” means that the dosage form of the present invention is physically as well as
chemically stable upon storage at refrigerated conditions (2-8
oC), for prolonged period of
time, such as for at least 6 months, preferably 12 months, more preferably for 18 months to
30 24 months. The solution is also stable when stored at 25°C (room temperature condition)
for a period of at least 3 months, preferably 6 months, more preferably for 9 months to 12
months. When stored at these conditions, the aqueous solution of diltiazem or its
6
pharmaceutically acceptable salt remains chemically stable, wherein various parameters
such a drug content (assay of diltiazem) and content of related substances, i.e., known
impurities, unknown impurities and total impurity remains within specified limits.
Suitably, the assay of diltiazem remains within 90% - 110% by weight of the label claim,
5 the content of total impurities (excluding desacetyl diltiazem) remain within 1% w/w of
diltiazem hydrochloride and the content of impurity ‘desacetyl diltiazem HCl’ remains
within 10% by weight of diltiazem or its pharmaceutically acceptable salt, preferably
within 6% by weight of diltiazem hydrochloride. The impurities are expressed as % by
weight of diltiazem or its pharmaceutically acceptable salt.
10 In some embodiments, the parenteral dosage form of the present invention
comprises diltiazem HCl salt and the assay of diltiazem remains within 90% - 110% by
weight of the label claim, and the content of total impurities (excluding desacetyl diltiazem
HCl) remain within 1% w/w of diltiazem hydrochloride and the content of impurity
‘desacetyl diltiazem HCl’ remains within 10% by weight of diltiazem hydrochloride,
15 preferably within 6% by weight of diltiazem hydrochloride. The impurities are expressed
as % by weight of diltiazem hydrochloride.
The term “cyclic oligosaccharide” as used here in includes compounds with
macrocyclic ring of glucose subunits joined by α-1,4 glycosidic bonds such as
cyclodextrins. Cyclodextrins are classified as natural and derived cyclodextrins. Natural
20 cyclodextrins include three well-known industrially produced (major and minor) cyclic
oligosaccharides. The most common natural cyclodextrins are α, β, and γ consisting of 6,
7, and 8 glucopyranose units. Hydroxypropyl-β-cyclodextrin (HP-β-CD), randomly
methylated-β-cyclodextrin (RM-β-CD), and sulfobutylether-β-cyclodextrin (SBE-β-CD)
are mostly preferred for complexation.
25 The parenteral dosage form of the present invention is sterile. The term “sterile” or
“sterilized’” as used herein, means that the aqueous solution has been brought to a state of
sterility and has not been subsequently exposed to microbiological contamination, i.e., the
sterility of the solution present in the container has not been compromised. The solution
complies with the sterility requirements of the standard Pharmacopoeias, such as the
30 United States Pharmacopoeias (USP). Sterilization may be achieved by suitable techniques
such as filtration sterilization, radiation sterilization, steam sterilization and the like. In one
7
embodiment, the disclosed parenteral dosage form is subjected to sterilization by
autoclaving the dosage form at ≥ 121 °C for 15 minutes.
In one embodiment, the parenteral dosage form according to the present invention
comprises of a ready-to-infuse, stable aqueous solution comprising diltiazem or its
5 pharmaceutically acceptable salt and a cyclic oligosaccharide as a stabilizer, wherein the
cyclic oligosaccharide comprises a macrocyclic ring of glucose subunits joined by α-1,4
glycosidic bonds.
In another embodiment, the parenteral dosage form according to the present
invention comprises of a ready-to-infuse, stable aqueous solution comprising diltiazem or
10 its pharmaceutically acceptable salt and a cyclic oligosaccharide as a stabilizer, wherein
said dosage form is filled in an infusion container.
In yet another embodiment, the parenteral dosage form according to the present
invention comprises of a ready-to-infuse, stable aqueous solution comprising diltiazem or
its pharmaceutically acceptable salt and a cyclic oligosaccharide as a stabilizer filled in an
15 infusion container, wherein said infusion container is selected from an infusion bag,
perfusion bag, flexible pouch, soft bag, infusion bottle or pre-filled syringe.
In some embodiment, the disclosed stable parenteral dosage form according to the
present invention further comprises an organic solvent. In some embodiment, the organic
solvent is an alcoholic solvent.
20 In one embodiment, the parenteral dosage form comprises a ready-to-infuse, stable
aqueous solution comprising diltiazem or its pharmaceutically acceptable salt and a cyclic
oligosaccharide as a stabilizer and an alcoholic solvent.
In some embodiments, the disclosed stable parenteral dosage form comprises at
least one pharmaceutically acceptable stabilizer that is a cyclic oligosaccharide. The cyclic
25 oligosaccharide includes, but is not limited to, hydroxypropyl derivatives of cyclodextrin
(such as hydroxypropyl-β-cyclodextrin (HP-β-CD)), randomly methylated-β-cyclodextrin
(RM-β-CD), and sulfobutylether-β-cyclodextrin (SBE-β-CD). In some embodiments, the
hydroxypropyl derivative of cyclodextrin is hydroxypropyl-β-cyclodextrin (HP-β-CD). In
some embodiment of the present invention, the cyclic oligosaccharide used in the present
30 invention is hydroxypropyl-β-cyclodextrin, methylated-β-cyclodextrin (RM-β-CD) or
sulfobutylether-β-cyclodextrin (SBE-β-CD). Preferably, the cyclic oligosaccharide used in
the present invention is hydroxypropyl-β-cyclodextrin (HP-ß-CD).
8
In an embodiment of the present invention, the parenteral dosage form comprises a
ready-to-infuse, stable aqueous solution comprising diltiazem or its pharmaceutically
acceptable salt, a cyclic oligosaccharide as a stabilizer, a pH-adjusting agent, and an
alcoholic solvent.
5 In another embodiment, the parenteral dosage form comprises a ready-to-infuse,
stable aqueous solution comprising diltiazem or its pharmaceutically acceptable salt, a
cyclic oligosaccharide as a stabilizer and a pH-adjusting agent to provide a pH in the range
of about 3.5 to about 5.
In one embodiment, the parenteral dosage form comprises a ready-to-infuse, stable
10 aqueous solution comprising diltiazem or its pharmaceutically acceptable salt, a cyclic
oligosaccharide as a stabilizer, a pH-adjusting agent, and an alcoholic solvent, wherein the
cyclic oligosaccharide is selected from hydroxypropyl-β-cyclodextrin (HP-β-CD),
methylated-β-cyclodextrin (RM-β-CD) or sulfobutylether-β-cyclodextrin (SBE-β-CD).
In some embodiments according to the present invention, the cyclic
15 oligosaccharide in the parenteral dosage form is present at a concentration ranging from
about 0.1% to about 100% w/v. In one embodiment, the cyclic oligosaccharide is present
at a concentration ranging from about 0.1% to about 50% w/v. In a further embodiment,
the cyclic oligosaccharide is present at a concentration of about 5% to about 40% w/v. In
yet another embodiment, the cyclic oligosaccharide is present at a concentration of about
20 8% to about 35% w/v.
In an embodiment, the parenteral dosage form comprises a ready-to-infuse, stable
aqueous solution comprising diltiazem or its pharmaceutically acceptable salt, a cyclic
oligosaccharide as a stabilizer, a pH-adjusting agent, and an alcoholic solvent, wherein the
alcoholic solvent is ethanol or a mixture of ethanol with another co-solvent.
25 In yet another embodiment, the present invention provides a stable, ready-to-infuse,
aqueous parenteral dosage form comprising diltiazem or its pharmaceutically acceptable
salt, a pH-adjusting agent to provide a pH in the range of about 3.5 to about 5, and at least
one pharmaceutically acceptable stabilizer selected from hydroxypropyl derivatives of
cyclodextrin.
30 In a further embodiment, the present invention provides a stable, ready-to-infuse,
aqueous parenteral dosage form comprising diltiazem or its pharmaceutically acceptable
salt, a pH-adjusting agent to provide a pH in the range of about 3.5 to about 5, at least one
9
pharmaceutically acceptable stabilizer selected from hydroxypropyl derivatives of
cyclodextrin and an infusion container filled with said aqueous solution.
In yet another embodiment, the present invention provides a stable, ready-to-infuse,
aqueous parenteral dosage form comprising diltiazem or its pharmaceutically acceptable
5 salt, a pH-adjusting agent to provide a pH in the range of about 3.7 to about 4.5, at least
one pharmaceutically acceptable hydroxypropyl-β-cyclodextrin stabilizer and an infusion
container filled with said aqueous solution.
In one embodiment, the present invention provides a stable, ready-to-infuse,
aqueous parenteral dosage form comprising diltiazem or its pharmaceutically acceptable
10 salt, a pH-adjusting agent to provide a pH in the range of about 3.7 to about 4.5, at least
one pharmaceutically acceptable hydroxypropyl-β-cyclodextrin stabilizer and at least one
alcoholic solvent.
In another embodiment, the present invention provides a stable, ready-to-infuse,
aqueous parenteral dosage form comprising diltiazem or its pharmaceutically acceptable
15 salt, a pH-adjusting agent to provide a pH in the range of about 3.7 to about 4.5, at least
one pharmaceutically acceptable hydroxypropyl-β-cyclodextrin stabilizer, at least one
alcoholic solvent, and an infusion container filled with said aqueous solution.
In yet another embodiment, the present invention provides a stable, ready-to-infuse,
aqueous parenteral dosage form comprising diltiazem or its pharmaceutically acceptable
20 salt, a pH-adjusting agent to provide a pH in the range of about 3.7 to about 4.5, at least
one pharmaceutically acceptable hydroxypropyl-β-cyclodextrin stabilizer, ethanol and an
infusion container filled with said aqueous solution.
In one embodiment, hydroxypropyl-β-cyclodextrin (“HP-β-CD”) is present at a
concentration ranging from about 0.1% to about 50% w/v. In a further embodiment, HP-β25 CD is present at a concentration ranging from about 1% to about 50% w/v. In a yet further
embodiment, the concentration of HP-β-CD is from about 1% to about 10% w/v.
In some embodiment, hydroxypropyl-β-cyclodextrin is present at a concentration
of about 3.5% w/v. In another embodiment, hydroxypropyl-β-cyclodextrin is present at a
concentration of about 1% w/v.
30 In one embodiment of the present invention, the infusion container of the dosage
form is filled with an aqueous solution comprising diltiazem or its pharmaceutically
10
acceptable salt as the active ingredient. Diltiazem or its pharmaceutically acceptable salt is
present in the aqueous solution of the present invention at a concentration which allows
direct infusion of the aqueous solution to the patient without the need of further dilution. It
may be present at a concentration ranging from about 0.05 mg/ml to about 2.0 mg/ml,
5 preferably from about 0.1 mg/ml to about 2.0 mg/ml, such as for example 0.2, 0.3, 0.4, 0.5,
0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8 or 1.9 mg/ml, more preferably
from about 0.4 mg/ml to about 1.0 mg/ml. In one particular embodiment, diltiazem
hydrochloride is present in the aqueous solution in an amount of about 1.0 mg/ml.
In some embodiments, the parenteral dosage form of the present invention includes
10 the aqueous solution of diltiazem filled into infusion container which may be rigid or
flexible in nature. The volume capacity of each unit of the container may range from about
50 ml to about 500 ml. The aqueous solution may present in the infusion containers in
volumes ranging from about 50 ml to about 500 ml per infusion container, such as for
example 50 ml, 75 ml, 100 ml, 120 ml, 125 ml, 140 ml, 150 ml, 160 ml, 175 ml, 180 ml,
15 190 ml, 200 ml, 220 ml, 225 ml, 240 ml, 250 ml, 260 ml, 275 ml, 280 ml, 290 ml, 300 ml,
320 ml, 325 ml, 340 ml, 350 ml, 360 ml, 375 ml, 380 ml, 390 ml, 400 ml, 420 ml, 425 ml,
430 ml, 440 ml, 450 ml, 460 ml, 470 ml, 475 ml, 480 ml, 490 ml or 500ml. According to
preferred embodiments of the present invention, the ready-to-infuse parenteral dosage
form provides large volume containers such as infusion bags, which can accommodate a
20 volume of at least 50 ml, preferably from about 100 ml to about 500 ml of the aqueous
solution.
In another embodiment, the present invention provides a parenteral dosage form
comprising a ready-to-infuse, stable aqueous solution comprises diltiazem or its
pharmaceutical acceptable salt in a concentration range of about 0.05 to 2.0 mg/ml, a
25 cyclic oligosaccharide stabilizer in a concentration range of about 0.1 to 50% w/v, and the
pH of the solution is in range of pH 3.7 to 4.5.
In another embodiment, the present invention provides a parenteral dosage form
comprising a ready-to-infuse, stable aqueous solution comprises diltiazem or its
pharmaceutical acceptable salt in a concentration range of about 0.1 to 2.0 mg/ml, a cyclic
30 oligosaccharide stabilizer, such as hydroxypropyl-β-cyclodextrin, in a concentration range
of about 0.1 to 10% w/v, and the pH of the solution is pH 3.9.
11
In yet another embodiment, the present invention provides a parenteral dosage
form comprising a ready-to-infuse, stable aqueous solution comprises diltiazem or its
pharmaceutical salt in a concentration range of about 0.1 to 2.0 mg/ml, a cyclic
oligosaccharide, such as hydroxypropyl-β-cyclodextrin, in a concentration range of about
5 0.1 to 10% w/v, ethanol in a concentration range of about 1 to 10% w/w and the pH of the
solution is pH 3.9.
In one embodiment, the stable parenteral dosage form of the present invention
further comprises an organic solvent, preferably an alcoholic solvent. In related
embodiments, the alcoholic solvent used in present invention is ethanol and it may be
10 present in the aqueous solution of the present invention in an amount ranging from about
1.0% w/v to about 50% w/v, preferably from about 1.0% w/v to about 20.0% w/v, more
preferably from about 1.0% w/v to about 15.0% w/v, such as for example 1.0, 1.2, 1.3, 1.4,
1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5,10, 10.5, 11, 11.5, 12, 12.5, 13,
13.5, 14,14.5 or 15% w/v. In one particularly preferred embodiment, the ethanol is present
15 in the ready-to-infuse aqueous solution in an amount ranging from about 1.0% w/v to
about 5.0% w/v, preferably about 1.35% w/v. In one preferred embodiment, the aqueous
solution of the present invention comprises ethanol as a co-solvent. In another
embodiment, the aqueous solution of the present invention comprises a mixture of ethanol
and other alcohols or solvents as a co-solvent.
20 In a further embodiment, the parenteral dosage form or the ready-to-infuse aqueous
solution of the present invention further comprises other parentally acceptable excipients.
Parentally acceptable excipients that may be used include, but are not limited to, pHadjusting agents and buffers, osmogen or osmotic/tonicity adjusting agents, chelating
agents, etc. In one preferred embodiment, the dosage form is free of anti-oxidants and
25 preservatives.
In another embodiment of the present invention, various other components which
may be used in the composition according to the invention includes butylated
hydroxyanisole, butylated hydroxytoluene, ammonium sulphate, sodium metabisulfite,
edetate disodium, hydroxypropyl betadex, L-methionine, potassium phosphate monobasic,
30 anhydrous lactose, betadex sulfobutyl ether sodium, crospovidone, dextran 40, glycerin,
pentetic acid, poloxamer 188, polyethylene glycol 300, polyethylene glycol 3350,
polyethylene glycol 400, polyethylene glycol 4000, polyethylene glycol 600, povidone,
12
povidone K12, povidone K15, propylene glycol, tartaric acid (granular), L-cysteine
hydrochloride monohydrate, phosphoric acid, ammonium sulphate, propyl paraben, boric
acid, sodium metabisulfite granular, ascorbic acid, benzoic acid, benzyl alcohol, Larginine, lactic acid, methyl paraben, polyoxyl 35 castor oil (Cremophor® ELP),
5 polysorbate-80, polysorbate-20, potassium phosphate monobasic crystal, sodium
dihydrogen phosphate monohydrate, soybean oil, aspartic acid, glutamic acid and HCl.
These components may individually or combined promote the overall stability of the
formulation for long-term storage.
The pH of the aqueous solution may be adjusted in the desired range by use of a
10 pH-adjusting agent. The pH-adjusting agent includes, but is not limited to, buffering agents
known in the art. The pH-adjusting and/or buffering agents that may be used in the present
invention include, but are not limited to, citric acid, sodium citrate, sodium hydroxide,
hydrochloric acid, sulfuric acid, acetic acid, sodium acetate, tartaric acid, potassium
hydroxide and the like and mixtures thereof. In one embodiment, the pH may be auto15 adjusted in the desired range by the ingredients present in the solution of the present
invention. The pH of the solution ranges from about 3.5 to about 5, in some aspects the pH
of the solution is about 3.7 to about 4.5, such as for example 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3
or 4.4, and more preferably from about 3.7 to about 4.3.
In an embodiment, the dosage form according to present invention may be stable
20 with or without a buffer component, and may also be used as such without any additional
pH adjustment.
In one preferred embodiment, the ready-to-infuse solution of diltiazem comprises
or consists essentially of a citric acid or citrate buffer to adjust and maintain the pH in the
range of about 3.7 to about 4.5. The ready-to-infuse aqueous solution of the present
25 invention is iso-osmolar to the parenteral/plasma fluids. The tonicity adjusting agent or
osmogen that may be used may be selected from, but are not limited to, mannitol, dextrose,
sucrose, sorbitol, glycerin, glycerol, sucrose, xylitol, fructose, mannose, maltitol, inositol,
trehalose, sodium chloride, potassium chloride, calcium chloride, magnesium chloride,
inorganic salts, urea and the like and mixtures thereof. In one embodiment, the
30 osmogen/tonicity adjusting agent according to the present invention comprises dextrose,
sodium chloride, sorbitol, mannitol or ethanol.
13
In some embodiments according to the present invention, the tonicity adjusting
agent in the parenteral dosage form is present at a concentration ranging from about 0.01%
to about 50% w/v. In one embodiment, tonicity adjusting agent is present at a
concentration ranging from about 0.1% to about 35% w/v. In a further embodiment,
5 tonicity adjusting agent is present at a concentration of about 1% to about 20% w/v. In yet
another embodiment, cyclic oligosaccharide is present at a concentration of about 1% to
about 10% w/v.
In one embodiment, the present invention provides a parenteral dosage form
comprising a ready-to-infuse, stable aqueous solution comprises Diltiazem or its
10 pharmaceutical acceptable salt in a concentration range of about 0.05 to 2.0 mg/ml, a
cyclic oligosaccharide stabilizer in a concentration range of about 0.1 to 50% w/v, and the
pH of the solution is in range of pH 3.7 to 4.5, wherein when said aqueous solution is
stored at 2-8
oC for at least 12 months, the level of desacetyl diltiazem or its salt impurity is
less than 10% by weight of diltiazem or its pharmaceutically acceptable salt.
15 In another embodiment, the ready-to-infuse parenteral dosage form according to
present invention comprises diltiazem or its pharmaceutically acceptable salt and a cyclic
oligosaccharide as a stabilizer, wherein the dosage form level of desacetyl diltiazem or its
salt impurity is not more than 10% w/w of diltiazem or its pharmaceutically acceptable salt
when stored for at least 12 months at 2-8
oC.
20 In another embodiment, the ready-to-infuse parenteral dosage form according to
present invention comprises diltiazem or its pharmaceutically acceptable salt and a cyclic
oligosaccharide as a stabilizer, wherein in the dosage form the level of desacetyl diltiazem
or its salt impurity is not more than 10% w/w of diltiazem or its pharmaceutically
acceptable salt when stored for at least 6 months at 25oC/40% RH.
25 In some embodiments, the present invention provides a parenteral dosage form
comprising a ready-to-infuse, stable aqueous solution of Diltiazem or its pharmaceutical
acceptable salt, wherein in the dosage form the level of desacetyl diltiazem or its salt
impurity is less than 10% w/w, preferably less than 8% w/w, more preferably less than 6%
w/w of diltiazem or its pharmaceutically acceptable salt when stored at 2-8
oC for at least
30 12 months.
In some embodiments, the present invention provides a parenteral dosage form
comprising a ready-to-infuse, stable aqueous solution of Diltiazem or its pharmaceutical
14
acceptable salt, wherein in the dosage form the level of desacetyl diltiazem or its salt
impurity is less than 10% w/w, preferably less than 8% w/w, more preferably less than 6%
w/w of diltiazem or its pharmaceutically acceptable salt when stored at 25oC/40% RH for
at least 6 months.
5 In one embodiment, the present invention provides a method for controlling the
level of desacetyl diltiazem or its salt impurity in a ready-to-infuse parenteral dosage form
of diltiazem or its pharmaceutically acceptable salt by using a cyclic oligosaccharide
stabilizer, wherein in the dosage form the level of desacetyl diltiazem or its salt impurity is
not more than 6% w/w of diltiazem or its pharmaceutically acceptable salt when stored for
at least 12 months at 2-8 10 oC.
In one embodiment, the present invention provides a method for controlling the
level of desacetyl diltiazem or its salt impurity in a ready-to-infuse parenteral dosage form
of diltiazem or its pharmaceutically acceptable salt by using a cyclic oligosaccharide
stabilizer, wherein in the dosage form the level of desacetyl diltiazem or its salt impurity is
15 not more than 6% w/w of diltiazem or its pharmaceutically acceptable salt when stored for
at least 6 months at 25oC/40% RH.
In one embodiment, the present invention provides a parenteral dosage form
comprising a ready-to-infuse, stable aqueous solution comprises Diltiazem or its
pharmaceutical acceptable salt in a concentration range of about 0.05 to 2.0 mg/ml, a
20 cyclic oligosaccharide stabilizer in a concentration range of about 0.1 to 50% w/v, and the
pH of the solution is in range of pH 3.7 to 4.5, wherein when said aqueous solution is
stored at 25oC/40% RH for at least 6 months, the level of desacetyl diltiazem or its salt
impurity is less than 6% by weight of diltiazem or its pharmaceutically acceptable salt.
In another embodiment according to present invention, the total impurity level
25 (excluding desacetyl diltiazem HCl) in the ready-to-infuse parenteral dosage form is not
more than 1% and the desacetyl diltiazem impurity is not more than 6% w/w of diltiazem
or its pharmaceutically acceptable salt when stored at 2-8
oC for at least 12 months.
In another embodiment according to present invention, the total impurity level
(excluding desacetyl diltiazem HCl) in the ready-to-infuse parenteral dosage is not more
30 than 1% and desacetyl diltiazem impurity is not more than 6% w/w of diltiazem or its
pharmaceutically acceptable salt when stored at 25oC/40% RH for at least 6 months.
15
In one embodiment, the present invention provides a method for controlling the
level of desacetyl diltiazem or its salt impurity in a ready-to-infuse parenteral dosage form
of diltiazem or its pharmaceutically acceptable salt by using a cyclic oligosaccharide
stabilizer, wherein the cyclic oligosaccharide comprises a macrocyclic ring of glucose
5 subunits joined by α-1,4 glycosidic bonds.
In one embodiment, the present invention provides a method for controlling the
level of desacetyl diltiazem or its salt impurity in a ready-to-infuse parenteral dosage form
of diltiazem or its pharmaceutically acceptable salt by using a cyclic oligosaccharide
stabilizer, wherein the said dosage form is filled in an infusion container.
10 In some embodiments, the cyclic oligosaccharide is selected from hydroxypropylβ-cyclodextrin, methylated-β-cyclodextrin (RM-β-CD) or sulfobutylether-β-cyclodextrin
(SBE-β-CD). In a further embodiment, the cyclic oligosaccharide is hydroxypropyl-βcyclodextrin (HP-β-CD). In one embodiment, the cyclic oligosaccharide stabilizer is a
cyclodextrin.
15 In some embodiments, the present invention provides a method for controlling the
level of desacetyl diltiazem or its salt impurity in a ready-to-infuse parenteral dosage form
of diltiazem or its pharmaceutically acceptable salt by using a cyclic oligosaccharide
stabilizer and an alcoholic solvent or a mixture thereof. In one embodiment, the organic
solvent is an alcoholic solvent. In one embodiment, the alcoholic solvent is ethanol.
20 In one embodiment, the present invention provides a method for controlling the
level of desacetyl diltiazem or its salt impurity in a ready-to-infuse parenteral dosage form
of diltiazem or its pharmaceutically acceptable salt by using a cyclic oligosaccharide
stabilizer and an alcoholic solvent or a mixture thereof, wherein the method further
comprises a pH adjustment step using a suitable pH-adjusting agent to provide a pH in the
25 range of 3.5-5.
In some embodiments, the present invention provides a method for controlling the
level of desacetyl diltiazem or its salt impurity in a ready-to-infuse parenteral dosage form
of diltiazem or its pharmaceutically acceptable salt by using a cyclic oligosaccharide
stabilizer, wherein in the dosage form the level of desacetyl diltiazem or its salt impurity is
30 not more than 6% w/w of diltiazem or its pharmaceutically acceptable salt when stored for
at least 12 months at 2-8
oC and wherein said method further comprises terminally
sterilizing the dosage form by autoclaving.
16
In some embodiments, the present invention provides a method for controlling the
level of desacetyl diltiazem or its salt impurity in a ready-to-infuse parenteral dosage form
of diltiazem or its pharmaceutically acceptable salt by using a cyclic oligosaccharide
stabilizer, wherein in the dosage form the level of desacetyl diltiazem or its salt impurity is
5 not more than 6% w/w of diltiazem or its pharmaceutically acceptable salt when stored for
at least 6 months at 25oC/40% RH and wherein said method further comprises terminally
sterilizing the dosage form by autoclaving.
In one embodiment, the present invention provides the use of a cyclic
oligosaccharide stabilizer for the preparation of a ready-to-infuse, stable aqueous solution
10 of diltiazem or its pharmaceutical acceptable salt, wherein in the solution the level of
desacetyl diltiazem or its salt impurity is less than 10% w/w of diltiazem or its
pharmaceutically acceptable salt when stored for at least 12 months at 2-8
oC.
In another embodiment, the present invention provides the use of a cyclic
oligosaccharide stabilizer for the preparation of a ready-to-infuse, stable aqueous solution
15 of diltiazem or its pharmaceutical acceptable salt, wherein in the solution the level of
desacetyl diltiazem or its salt impurity is less than 10% w/w of diltiazem or its
pharmaceutically acceptable salt when stored for at least 6 months at 25oC/40% RH.
In a further embodiment, the present invention provides the use of a cyclic
oligosaccharide stabilizer for the preparation of a ready-to-infuse, stable aqueous solution
20 of diltiazem or its pharmaceutical acceptable salt, wherein in the solution the level of
desacetyl diltiazem or its salt impurity is less than 10% w/w, preferably less than 8% w/w,
more preferably less than 6% w/w of diltiazem or its pharmaceutically acceptable salt
when stored at 2-8
oC for at least 12 month.
In one further embodiment, the present invention provides the use of a cyclic
25 oligosaccharide stabilizer for the preparation of a ready-to-infuse, stable aqueous solution
of diltiazem or its pharmaceutical acceptable salt, wherein in the solution the level of
desacetyl diltiazem or its salt impurity is less than 10% w/w, preferably less than 8% w/w,
more preferably less than 6% w/w of diltiazem or its pharmaceutically acceptable salt
when stored at 25oC/40% RH for at least 6 months.
30 In yet another embodiment, the present invention provides the use of a cyclic
oligosaccharide stabilizer for the preparation of a ready-to-infuse, stable aqueous solution
of diltiazem or its pharmaceutical acceptable salt, wherein in the solution the level of
17
desacetyl diltiazem or its salt impurity is less than 10% w/w of diltiazem or its
pharmaceutically acceptable salt when stored for at least 12 months at 2-8
oC, wherein the
cyclic oligosaccharide comprises a macrocyclic ring of glucose subunits joined by α-1,4
glycosidic bonds.
5 In another embodiment, the present invention provides the use of a cyclic
oligosaccharide stabilizer for the preparation of a ready-to-infuse, stable aqueous solution
of diltiazem or its pharmaceutical acceptable salt, wherein in the solution the level of
desacetyl diltiazem or its salt impurity is less than 10% w/w of diltiazem or its
pharmaceutically acceptable salt when stored for at least 6 months at 25oC/40%RH,
10 wherein the cyclic oligosaccharide comprises a macrocyclic ring of glucose subunits
joined by α-1,4 glycosidic bonds.
In some embodiments, the cyclic oligosaccharide is selected from hydroxypropylβ-cyclodextrin, methylated-β-cyclodextrin (RM-β-CD) or sulfobutylether-β-cyclodextrin
(SBE-β-CD).
15 In one embodiment, the present invention provides the use of a cyclic
oligosaccharide stabilizer for the preparation of a ready-to-infuse, stable aqueous solution
of diltiazem or its pharmaceutical acceptable salt, wherein said solution is filled in an
infusion container.
In some embodiments, the present invention provides the use of a cyclic
20 oligosaccharide stabilizer for the preparation of a ready-to-infuse, stable aqueous solution
of diltiazem or its pharmaceutical acceptable salt, wherein in the solution the level of
desacetyl diltiazem or its salt impurity is less than 10% w/w of diltiazem or its
pharmaceutically acceptable salt when stored for at least 12 months at 2-8
oC and the cyclic
oligosaccharide stabilizer is a cyclodextrin.
25 In some embodiments, the present invention provides the use of a cyclic
oligosaccharide stabilizer for the preparation of a ready-to-infuse, stable aqueous solution
of diltiazem or its pharmaceutical acceptable salt, wherein in the solution the level of
desacetyl diltiazem or its salt impurity is less than 10% w/w of diltiazem or its
pharmaceutically acceptable salt when stored for at least 6 months at 25oC/40% RH and
30 the cyclic oligosaccharide stabilizer is a cyclodextrin.
In another embodiment, the present invention provides the use of a cyclic
oligosaccharide stabilizer for the preparation of a ready-to-infuse, stable aqueous solution
18
of diltiazem or its pharmaceutical acceptable salt, wherein in the solution the level of
desacetyl diltiazem or its salt impurity is less than 10% w/w, preferably less than 8% w/w,
more preferably less than 6% w/w of diltiazem or its pharmaceutically acceptable salt
when stored at 2-8
oC for at least 12 months.
5 In another embodiment, the present invention provides the use of a cyclic
oligosaccharide stabilizer for the preparation of a ready-to-infuse, stable aqueous solution
of diltiazem or its pharmaceutical acceptable salt, wherein in the solution the level of
desacetyl diltiazem or its salt impurity is less than 10% w/w, preferably less than 8% w/w,
more preferably less than 6% w/w of diltiazem or its pharmaceutically acceptable salt
when stored at 25 10 oC/40% RH for at least 6 months.
In some embodiments, the present invention provides the use of a cyclic
oligosaccharide stabilizer for the preparation of a ready-to-infuse, stable aqueous solution
of diltiazem or its pharmaceutical acceptable salt, wherein the method further comprises
addition of an alcoholic solvent or a mixture thereof. In one embodiment, the alcoholic
15 solvent is ethanol.
In another embodiment, the present invention provides the use of a cyclic
oligosaccharide stabilizer for the preparation of a ready-to-infuse, stable aqueous solution
of diltiazem or its pharmaceutical acceptable salt, wherein in the solution the level of
desacetyl diltiazem or its salt impurity is less than 10% w/w of diltiazem or its
pharmaceutically acceptable salt when stored for at least 12 months at 2-8 20 oC, and said
method further comprises the addition of an alcoholic solvent or a mixture thereof, and a
pH adjustment step using a suitable pH-adjusting agent to provide a pH in the range of
about 3.5 to about 5
In one further embodiment, the present invention provides the use of a cyclic
25 oligosaccharide stabilizer for the preparation of a ready-to-infuse, stable aqueous solution
of diltiazem or its pharmaceutical acceptable salt, wherein in the solution the level of
desacetyl diltiazem or its salt impurity is less than 10% w/w of diltiazem or its
pharmaceutically acceptable salt when stored for at least 6 months at 25oC/40% RH, and
said use further comprises the addition of an alcoholic solvent or a mixture thereof, and a
30 pH adjustment step using a suitable pH-adjusting agent to provide a pH in the range of
about 3.5 to about 5.
19
In one embodiment, the present invention provides the use of a cyclic
oligosaccharide stabilizer for the preparation of a ready-to-infuse, stable aqueous solution
of diltiazem or its pharmaceutical acceptable salt, wherein in the solution the level of
desacetyl diltiazem or its salt impurity is less than 10% w/w of diltiazem or its
pharmaceutically acceptable salt when stored for at least 12 months at 2-8 5
oC, and said
method further comprises terminally sterilizing the dosage form by autoclaving.
In another embodiment, the present invention provides the use of a cyclic
oligosaccharide stabilizer for the preparation of a ready-to-infuse, stable aqueous solution
of diltiazem or its pharmaceutical acceptable salt, wherein in the solution the level of
10 desacetyl diltiazem or its salt impurity is less than 10% w/w of diltiazem or its
pharmaceutically acceptable salt when stored for at least 6 months at 25oC/40% RH, and
said method further comprises terminally sterilizing the dosage form by autoclaving.
In one embodiment the present invention provides a parenteral dosage form
comprising a ready-to-infuse, stable aqueous solution comprised of diltiazem or its
15 pharmaceutically acceptable salt, wherein the level of desacetyl diltiazem or its salt
impurity is not more than 6% w/w of diltiazem or its pharmaceutically acceptable salt
when stored for at least 6 months at 25oC/40% RH.
In one embodiment, the present invention provides a parenteral dosage form
comprising a ready-to-infuse, stable aqueous solution comprised of diltiazem or its
20 pharmaceutically acceptable salt, wherein the level of desacetyl diltiazem or its salt
impurity is not more than 6% w/w of diltiazem or its pharmaceutically acceptable salt
when stored for at least 12 months at 2-8
oC.
In some embodiments, the stable, ready-to-infuse, aqueous parenteral dosage form
of the present invention is terminally sterilized.
25 In one embodiment, the stable, ready-to-infuse, aqueous parenteral dosage form of
the present invention may be terminally sterilized at temperature more than or equal to
temperature 121 °C for more than or equal to 15 minutes, or at temperature more than or
equal to 121 °C for more than 12 minutes, or at temperature more than 115 °C for more
than 8 minutes, or at temperature more than 110 °C for more than 8 minutes, or at
30 temperature not more than 110 °C for more than 8 minutes.
In some embodiments, the stable, ready-to-infuse, aqueous parenteral dosage form
of the present invention is terminally sterilized at 121°C for 15 minutes.
20
In yet another embodiment, the stable, ready-to-infuse, aqueous parenteral dosage
form of the present invention may not be terminally sterilized.
In some embodiments, the infusion container of the parenteral dosage form of the
present invention is a flexible infusion container, made up of a flexible material such as
5 plastic or any other polymeric material. In one or more embodiments, the flexible infusion
container may be an infusion bag or flexible pouch or soft bag or infusion bottle or film
and the like. In another embodiment, the infusion container is a pre-filled syringe. The
container may include one or more layers of such materials. Suitably, such materials may
include but are not limited to, polyolefin polymers, polyethylene, polypropylene; cyclo
10 olefin polymers, cyclo olefin copolymers, polypropylene based polyolefin polymers;
polycarbonates; modified polyolefin-polyethylene polymers or styrene-polyolefin based
polymers or block co-polymers thereof. Particularly, the flexible infusion container is not
impermeable in nature and possesses some permeation characteristics and the aqueous
solution of diltiazem remains in contact with these materials of the container throughout
15 the shelf life of the dosage form.
In some embodiments, the disclosed parenteral dosage form includes the aqueous
solution of diltiazem filled into an infusion container, which may be rigid or flexible in
nature.
In one embodiment, the flexible infusion containers may be made up of a material
20 comprising a polymer of cyclic olefin such as cyclooolefin homopolymer or cycloolefin
copolymer or mixture thereof. Specifically, in a particular embodiment, the container
comprises an inner layer made up of a cycloolefin polymer, a middle layer made up of
linear low density polyethylene polymer and an outer layer made up of low density
polyethylene polymer. Such containers are available commercially. and have a water
vapour transmission rate of 2 g /(m2 25 /day) when measured at (40 °C/90% relative
humidity); oxygen transmission rate of 570 ml/(m2
.24hour.atm) when measured at
(23°C/0% relative humidity) and carbon dioxide transmission rate of 3400
ml/(m2
.24hour.atm) when measured at 23°C/0% relative humidity.
In another embodiment, the flexible infusion containers may be made up of an
30 outer layer of polypropylene polymer with styrene-ethylene-butylene (SEB) block
copolymer and a middle and inner layer made up of polypropylene based polyolefin
polymer with styrene-ethylene butylene block copolymer. Such containers are available
21
commercially and have a water vapour transmission rate of 0.62 g/(m2
/day) when
measured at 23 °C/60% relative humidity; oxygen permeability of 1110
ml/(m2
.24hour.atm) when measured at 23 °C/40% relative humidity and carbon dioxide
transmission rate of 5149 ml/(m2
.24hour.atm). Alternatively, the flexible container is made
5 up of multilayer polyolefin film having layers from outside to inside made up of CPETTie-PE-Tie-EPC. These containers generally have a water vapour transmission rate of 5.0
g/(m2
/day) when measured at 38°C/100% relative humidity; oxygen transmission rate of
1315 cm3
/(m2
.24hour.atm) when measured at 73°F/0% relative humidity and carbon
dioxide transmission rate of 3945 cm3
/(m2
.24hour.atm).
10 In another embodiment, the infusion containers may include an infusion port,
which may act as an infusion connector having three assembled parts including a central
stopper made up of chlorobutyl or bromobutyl rubber (latex free); an upper breakable part
and a bottom part, both made up of polycarbonate. In one embodiment, the infusion
container contains a delivery port end for insertion of an infusion set cannula / needle. In
15 an embodiment, the infusion container/bag and the delivery port connecting to the infusion
needle form a system whereby during administration of the solution to the patient the
vacuum created by outgress of solution is accommodated by the elasticity or flexibility of
the infusion bag instead of ingress of external non-sterile air. The dosage form can
advantageously maintain the sterility of the solution until it reaches the patient.
20 In one embodiment, the flexible infusion container includes a thermally resealable
portion that is fusible in response to thermal energy, and a container body having a sealed
empty chamber in fluid communication with the resealable portion for receiving therein
the aqueous solution of the present invention. The method of filling the container includes
penetrating the resealable portion with an injection member and introducing the aqueous
25 solution of the present invention into the chamber, withdrawing the injection member
while engaging the base of the body to substantially prevent axial movement of the body,
and applying thermal energy to the resealable portion to thermally fuse the penetrated
region thereof. Such systems are elaborated in United States Patent No. 7,992,597, which
is incorporated herein by reference. Further the flexible infusion container may include a
30 chamber for receiving aqueous solution of the present invention and a thermoplastic
portion in fluid communication with the chamber. The thermoplastic portion defines a
penetrable region that is penetrable by a filling member and is heat resealable to
hermetically seal an aperture therein by applying laser radiation at a predetermined
22
wavelength and power and in a predetermined time period. Such systems are elaborated in
United States Patent No. 7,490,639, which is incorporated herein by reference.
In yet another embodiment, the flexible infusion container includes a sealed
chamber; a first penetrable septum in fluid communication with the chamber that is formed
5 of an elastic material and is penetrable by a first injection member to fill the first chamber
with the aqueous solution of the present invention there through; and a second penetrable
septum movable between first and second positions. In the first position, at least a portion
of the second septum is spaced away from the first septum to allow the injection member
to penetrate the first septum and aseptically or sterile fill the chamber with the aqueous
10 solution of the present invention there through. In the second position, the portion of the
second septum overlies and seals a resulting injection aperture in the first septum after
withdrawal of the first injection member therefrom, and is penetrable by a second injection
member to penetrate the first and second septums and withdraw the filled aqueous solution
of the present invention from the chamber and through the second injection member. Such
15 systems are elaborated in United States Patent Publication No.US20130333796, which is
incorporated herein by reference.
In one embodiment, the infusion container is rigid and is made up of a material
such as glass. Such infusion containers include infusion vials, infusion bottles, or pre-filled
syringes. However, in preferred embodiments, the container does not have a material that
20 contains borate or boron.
In another embodiment of the present invention, the container may be a pre-filled
syringe. The pre-filled syringe may be made up of a material having at least one non-glass
component. The barrel of the pre-filled syringe can preferably be made up of appropriate
plastic or polymeric material. In a preferred aspect, the syringe comprises a barrel made up
25 of cyclic olefin polymer, cyclic olefin copolymer, polypropylene, polycarbonate and the
like. The syringe may further comprise an elastomeric tip cap, made up of material such as
chloro-butyl formulation. The syringe may comprise a plunger stopper made up of rubber
material such as bromo-butyl rubber.
In some embodiments, the container may be further packaged in a secondary
30 packaging. The secondary packaging may comprise a second container such as a pouch or
overwrap or film or carton. The secondary packaging may further comprise an oxygen
scavenger. In one embodiment, the secondary packaging is designed to protect the solution
23
of diltiazem from light. In preferred embodiments, the secondary packaging pouch or film
or overwrap or carton is made up of a suitable light protective material such as aluminium.
Non-limiting examples of the material constituting secondary packaging or secondary
containers include, aluminum, various polymers and copolymers like polyamide, ethylene
5 vinyl alcohol copolymer, etc. Aluminum based containers are preferred and include
aluminium pouches, aluminium plated films, aluminium foils, aluminum laminate films,
composite aluminum films co-extruded with other polymers like polyethylene,
polypropylene, EVA, EMA, EAA, etc. In one preferred embodiment, the secondary
container is an overwrap pouch made up of composite polymer aluminium film having
10 PET, Nylon-6, aluminium foil, and CPP (polypropylene/ethylene block copolymer) from
outside to inside, the layers being either co-extruded and/or fixed using an adhesive with
the other layer. In another preferred embodiment, the secondary container is an overwrap
pouch made up of PET/NY/aluminum/oxygen absorbing layer/polyethylene. In another
preferred embodiment, the second container is an overwrap pouch made up of
15 PET/NY/aluminum/oxygen absorbing layer/polypropylene. In another preferred
embodiment, the second container is an overwrap pouch made up of
PET/NY/AL/OA/CPP. In some preferred embodiments, the dosage form may further
comprise an oxygen scavenger, which may be placed in between the infusion container
and the second overwrap container or in some embodiments, the overwrap pouch may
20 have a layer of oxygen absorbing material which acts as an oxygen scavenger, such as
fused silica bags or iron containing adsorbents like iron oxide and the like. The oxygen
scavenger or oxygen scavenging layer material may be a suitable material capable of
quickly absorbing oxygen and having good oxygen absorbing capacity and heat resistance.
Non-limiting examples of such oxygen scavenging materials include iron, silica, charcoal,
25 etc. Preferably the oxygen scavenging material is an iron based material. In one
embodiment, the oxygen scavenger may be an iron based self-reacting type or iron based
water dependent type oxygen scavenger/absorber. In one embodiment, the space between
the infusion container and secondary overwrap container or pouch is filled with an inert
gas such as nitrogen or argon.
30 In one embodiment, the present invention provides a process for the preparation of
stable, ready-to-infuse parenteral dosage form, wherein said process comprises: a) taking
water for injection in an amount of 80% of the batch size in a container; b) adding suitable
excipients including hydroxypropyl betacyclodextrin with or without an alcoholic solvent
24
to the container and mixing; c) adding and dissolving the diltiazem hydrochloride to the
above mixture; d) checking the pH of the mixture and adjusting the pH of the solution to
pH in the range of 3.5-5 by adding a suitable pH-adjusting agent, if required; e) then
adjusting the volume up to 100% using water for injection; f) filtering the above solution
5 by using 0.2 micron membrane filter, and filling the solution in a flexible infusion bag and
stoppering the bag.
In a further embodiment, the present invention provides a process for preparation
of a stable, ready-to-infuse parenteral dosage form, wherein the addition of a pH-adjusting
agent may not be required where the pH of the solution is automatically adjusted in the
10 range of pH 3.5-5.
In an embodiment, said infusion bag may be autoclaved at 121oC for 15 minutes or
may be kept unautoclaved. In another embodiment, said bag may be overwrapped using a
suitable aluminium pouch that may optionally be filled with an oxygen scavenger and/or
nitrogen gas.
15 In one embodiment, the present invention provides a method for the treatment of
atrial fibrillation, atrial flutter, or paroxysmal supraventricular tachycardia, by
administering a stable parenteral dosage form of diltiazem, which comprises a ready-toinfuse aqueous solution of diltiazem.
In another embodiment, the present invention provides the use of a stable
20 parenteral dosage form of diltiazem comprising a ready-to-infuse aqueous solution of
diltiazem for the treatment of atrial fibrillation, atrial flutter, or paroxysmal
supraventricular tachycardia.
In a further embodiment, the present invention provides a method for temporary
control of rapid ventricular rate in atrial fibrillation or atrial flutter, by using a stable
25 parenteral dosage form of diltiazem, comprising a ready-to-infuse aqueous solution of
diltiazem.
In another embodiment, the present invention provides a method for administering
a therapeutically effective amount of diltiazem to a patient in need thereof or a person
suffering from an indication where diltiazem can be administered.
30 In yet another embodiment, the present invention provides a stable, ready-to-infuse,
aqueous parenteral dosage form comprising diltiazem or its pharmaceutically acceptable
25
salt, a pH-adjusting agent to provide a pH in the range of about 3.5 to about 5, at least one
pharmaceutically acceptable stabilizer selected from a group comprised of hydroxypropyl
derivatives of cyclodextrin, for use in treatment of atrial fibrillation, atrial flutter, or
paroxysmal supraventricular tachycardia (“PSVT”).
5 In yet another embodiment, the present invention provides a stable, ready-to-infuse,
aqueous parenteral dosage form comprising diltiazem or its pharmaceutically acceptable
salt, a pH-adjusting agent to provide a pH in the range of about 3.5 to about 5, at least one
pharmaceutically acceptable stabilizer selected from a group comprised of hydroxypropyl
derivatives of cyclodextrin and an infusion container filled with said aqueous solution, for
10 use in treatment of atrial fibrillation, atrial flutter, or paroxysmal supraventricular
tachycardia.
In one embodiment, the present invention provides the use of a diltiazem
hydrochloride ready-to-infuse dosage form according to the present invention for control
of ventricular response in patients with atrial fibrillation or atrial flutter or conversion to
15 sinus rhythm in patients with PSVT.
In the context of this specification "comprising" is to be interpreted as "including".
Aspects of the invention comprising certain elements are also intended to extend to
alternative embodiments "consisting" or "consisting essentially" of the relevant elements.
Where technically appropriate, embodiments of the invention may be combined.
20 Embodiments are described herein as comprising certain features/elements. The disclosure
also extends to separate embodiments consisting or consisting essentially of said
features/elements.
Any embodiments specifically and explicitly recited herein may form the basis of a
disclaimer either alone or in combination with one or more further embodiments.
25 Hereinafter, the invention will be more specifically described by way of Examples.
The examples are not intended to limit the scope of the invention and are merely used as
illustrations.
EXAMPLES
Example 1:
30 Different exemplary batches (1A-1G) were prepared with varying concentrations of
hydroxypropyl-β-cyclodextrin. The batch manufacturing was done by initiating it with
26
80% batch size of water for injection followed by the addition of all the excipients and
addition of diltiazem hydrochloride. The compositions were adjusted to the desired pH and
the volume was made up to 100%.
Table I: Aqueous compositions of diltiazem:
Batch No
Components/
Stabilizer
1A 1B 1C 1D 1E 1F 1G
Concentration (mg/ml)
Diltiazem HCl 1 1 1 1 1 1 1
Citric Acid
monohydrate 0.15 0.15 0.15 0.15 0.15 0.15 0.15
Sodium Citrate 0.13 0.13 0.13 0.13 0.13 0.13 0.13
Sorbitol Powder 10 10 10 10 10 10 10
Dextrose Anhydrous 40 40 40 40 40 40 40
Hydroxypropyl
Betacyclodextrin 0 0.5 2 5 10 20 50
Hydrochloric acid q.s. to pH 3.9
Sodium Hydroxide q.s. to pH 3.9
Water for Injection
(WFI) q.s. to 1 ml
5
Table II: Stress stability data of different batches prepared in Table I:
Batch
No
Hydroxypropyl
beta
cyclodextrin
(mg/ml)
Desacetyl Diltiazem
HCl (%)
Acetoxy
lactum (%)
Cis(+)
hydroxy
lactum (%)
Maximum
Unknown (%)
Total
impurities*
(%)
0
7 Days
/40⁰C
Change
(Δ/7day
)
0
7 Days
/40⁰C
0
7 Days
/40⁰C
0
7 Days
/40⁰C
0
7 Days
/40⁰C
1A 0 0.04 0.60 0.56 ND ND ND ND 0.02 0.013 0.04 0.03
1B 0.5 0.04 0.55 0.51 ND ND ND ND 0.02 0.013 0.04 0.03
1C 2 0.05 0.59 0.54 ND ND ND ND 0.01 0.013 0.04 0.03
1D 5 0.03 0.67 0.64 ND ND ND ND 0.02 0.017 0.03 0.04
1E 10 0.03 0.43 0.40 ND ND ND ND 0.02 0.019 0.04 0.04
1F 20 0.03 0.40 0.37 ND ND ND ND 0.02 0.016 0.04 0.04
1G 50 0.03 0.35 0.32 ND 0.001 ND ND 0.02 0.017 0.05 0.05
Note: * Total Impurities excluding desacetyl diltiazem HCL; ND: Not Detected.
Observation: It was observed that with the increase in concentration of hydroxypropyl-βcyclodextrin (HP-β-CD), there was an improvement in stability of the formulation.
10 Particularly, the concentration of 10 mg/ml or more than 10 mg /ml showed a positive
27
effect on stability of diltiazem hydrochloride and the stability was improved as the
concentration of HP-β-CD was increased.
Example 2:
Different exemplary batches (2A-2L) were prepared with varying pH of the aqueous
5 solutions of diltiazem hydrochloride. The batch manufacturing was done by initiating it
with 80% batch size of water for injection followed by addition of all the excipients and
addition of diltiazem hydrochloride. The compositions were adjusted to the desired pH and
the volume was made up to 100%. Half of the samples from each batch were autoclaved at
121oC for 15 minutes, and remaining were kept unautoclaved.
10 Table III: Aqueous compositions of diltiazem:
Batch No
Ingredients
Concentration (mg/ml)
2A 2B 2C 2D 2E 2F 2G 2H 2I 2J 2K 2L
Diltiazem HCl 1
Ethanol 13.5
Hydroxypropyl
Betacyclodextrin 10
Hydrochloric acid q.s. q.s. q.s. q.s. q.s. q.s.
q.s
.
q.s. q.s. q.s. q.s. q.s.
Sodium Hydroxide q.s. q.s. q.s. q.s. q.s. q.s.
q.s
.
q.s. q.s. q.s. q.s. q.s.
Water for Injection
(WFI) q.s. q.s. q.s. q.s. q.s. q.s.
q.s
.
q.s. q.s. q.s. q.s. q.s.
pH 3.2 3.3 3.4 3.5 3.7 3.9 4.1 4.3 4.4 4.5 5.0 7.0
Table IV: Stress stability data of unautoclaved sample from different batches Table III:
Batch
No.
pH Desacetyl Diltiazem HCl
(%)
Acetoxy lactum
(%)
Cis(+) hydroxy
lactum (%)
Maximum
unknown (%)
Total Impurity*
(%)
0
7 Day
/ 40°C
Change
/7day 0
7 Day
/40°C 0
7 Day
/40°C 0
7 Day
/40°C 0
7 Day
/40°C
2A 3.2 0.20 0.96 0.76 ND 0.05 0.003 0.005 0.07 0.07 0.17 0.20
2B 3.3 0.18 0.88 0.70 ND ND 0.003 0.005 0.07 0.08 0.17 0.20
2C 3.4 0.15 0.73 0.58 ND ND 0.002 0.009 0.06 0.06 0.17 0.18
2D 3.5 0.15 0.67 0.52 ND 0.005 ND 0.003 0.06 0.06 0.16 0.17
2E 3.7 0.13 0.58 0.45 ND ND 0.004 0.003 0.07 0.06 0.18 0.16
2F 3.9 0.12 0.56 0.44 ND ND 0.006 0.006 0.05 0.06 0.17 0.18
2G 4.1 0.12 0.56 0.44 ND ND ND ND 0.06 0.06 0.16 0.16
2H 4.3 0.14 0.58 0.44 ND ND 0.004 0.006 0.06 0.05 0.16 0.17
2I 4.4 0.14 0.60 0.46 ND ND 0.003 0.002 0.06 0.06 0.16 0.16
28
2J 4.5 0.15 0.62 0.47 ND ND 0.003 0.005 0.06 0.05 0.17 0.16
2K 5 0.18 0.70 0.52 ND ND 0.007 ND 0.06 0.05 0.15 0.14
2L 7 5.14 9.89 4.75 ND 0.012 ND 0.003 0.07 0.20 0.17 0.31
Note: * Total Impurities excluding desacetyl diltiazem HCL; ND: Not Detected.
Table V: Stress stability data of autoclaved sample from different batches of Table III:
Batch
No. pH Desacetyl Diltiazem HCl
(%)
Acetoxy lactum
(%)
Cis(+) hydroxy
lactum (%)
Maximum
unknown (%)
Total
Impurity* (%)
0
7 Day
40°C
Change
/7day 0
7 Day
/40°C 0
7 Day
/40°C 0
7 Day
/40°C 0
7 Day
/40°C
2A 3.2 0.83 1.68 0.85 ND ND 0.002 0.005 0.07 0.05 0.16 0.17
2B 3.3 0.82 1.52 0.70 ND 0.007 0.003 0.002 0.06 0.08 0.16 0.21
2C 3.4 0.73 1.38 0.65 0.003 ND ND 0.012 0.06 0.07 0.16 0.18
2D 3.5 0.71 1.25 0.54 ND ND ND 0.004 0.07 0.06 0.16 0.17
2E 3.7 0.70 1.20 0.50 ND ND 0.004 0.008 0.07 0.06 0.17 0.19
2F 3.9 0.77 1.26 0.49 ND ND 0.007 ND 0.06 0.06 0.16 0.18
2G 4.1 0.91 1.40 0.49 ND ND 0.005 0.009 0.07 0.06 0.18 0.19
2H 4.3 1.00 1.49 0.49 ND ND 0.006 0.004 0.07 0.07 0.19 0.20
2I 4.4 1.06 1.51 0.45 0.002 ND 0.007 0.009 0.06 0.06 0.19 0.19
2J 4.5 1.09 1.58 0.49 ND ND 0.006 ND 0.07 0.05 0.19 0.16
2K 5 1.21 1.67 0.46 ND ND 0.004 0.004 0.05 0.06 0.17 0.17
2L 7 4.61 7.21 2.60 ND 0.004 ND 0.003 0.14 0.18 0.27 0.31
Note: * Total Impurities excluding desacetyl diltiazem HCL; ND: Not Detected.
5 Observation: It was observed that the pH of the solution impacted the stability of the
solution and with increase in pH, there was a gradual improvement in stability of the
aqueous solution of diltiazem according to present invention. However, at a pH above 5
may be detrimental to the stability of formulation due to possible increase in formation of a
known impurity.
10 Example 3:
Different exemplary batches (3A-3G) were prepared with varying concentrations of
various excipients for the preparation of the aqueous solutions of diltiazem hydrochloride
according to present invention. The batch manufacturing was done by initiating it with
80% batch size of water for injection as below:
15 i. a part of water for injection, 80% of the batch size was taken in a container and
suitable excipients including hydroxypropyl-β-cyclodextrin with or without alcoholic
solvent were added to the container and mixed;
29
ii. followed by adding and dissolving of diltiazem hydrochloride to the mixture of step i);
iii. checking the pH of the mixture of step ii) and adjusting the pH of the solution to pH
3.9 by adding a suitable pH-adjusting agent, if required;
iv. then the volume of the above solution of step iii) was made up to 100% using water for
5 injection;
v. filtering the above solution of step iv) using 0.2 micron membrane filter and filled in a
flexible infusion bag and stoppered.
Some of the infusion bags were autoclaved at 121oC for 15 minutes and some were kept
unautoclaved and the samples were loaded to stability study.
10 Table VI: Various aqueous compositions of diltiazem:
Batch No.
Ingredients
Concentration (mg/ml)
3A 3B 3C 3D 3E 3F 3G
Diltiazem Hydrochloride 1 1 1 1 1 1 1
Hydroxy propyl beta -
cyclodextrin 10 35 35 10 10 35 35
Ethanol - - - 13.5 13.5 13.5 13.5
Dextrose anhydrous 40 40 40 - - - -
Sorbitol 10 10 10 - - - -
Citric acid monohydrate 0.15 0.15 - 0.15 - 0.15 -
Sodium Citrate dihydrate 0.13 0.13 - 0.13 - 0.13 -
Hydrochloric acid q.s. to
adjust pH -- q.s to adjust pH --
Sodium Hydroxide q.s. to
adjust pH -- q.s to adjust pH --
pH 3.9 As such 3.9 3.9 3.9 As such 3.9
Water for Injection q.s q.s q.s q.s q.s q.s q.s
Samples from Example 3 were loaded for long term stability under refrigerated and
accelerated stability. The stability details of batch 3F & G are provided in below Tables:
Table VII: Stability data of unautoclaved samples from Table VI:
Batch
No.
Stabilit
y Cond. Stage Assay
Des.
D
Des D.
(Δ/
month)
Max.
Unk. (%)
Tot.
Imp.
Ace. L Cis. HL
Imp
3F 2-8
oC
0 99.75 0.05
0.04
0.03 0.08 ND ND
6 99.17 0.33 0.03 0.05 ND ND
12 99.56 0.55 0.03 0.06 ND ND
30
24 98.67 1.04 0.02 0.05 NA NA
25oC/
40 %
RH
0 99.75 0.05
0.38
0.03 0.08 ND ND
1 101.07 0.46 0.02 0.06 ND ND
3 98.77 1.25 0.02 0.02 ND ND
6 97.81 2.30 0.02 0.04 ND ND
12 95.91 4.65 0.02 0.06 ND ND
3G
2-8
oC
0 99.46 0.06
0.04
0.05 0.16 ND ND
6 99.41 0.32 0.05 0.17 ND ND
12 99.98 0.60 0.05 0.17 NA NA
25oC /
40% RH
0 99.46 0.06
0.39
0.05 0.16 ND ND
1 98.71 0.40 0.05 0.15 ND ND
3 98.32 1.20 0.06 0.19 0.002 ND
6 97.23 2.40 0.06 0.17 0.003 0.001
12 95.31 5.07 0.04 0.11 NA NA
Note: Des. D: desacetyl diltiazem HCl impurity; Δ/month: % Degradation rate (Δ/month);
Ace. L: acetoxy lactum impurity; Tot. Imp.*: Total Impurities (excluding desacetyl
diltiazem HCl impurity); Cis. HL Imp.: Cis (+) hydroxy lactum impurity; Max. Unk. (%):
Max. Unknown Impurities (%); NA: Not analysed
5
Table VIII: Stability data of autoclaved samples from Table VI:
Batch
No.
Stabilit
y Cond. Stage Assay Des. D Des D.
(Δ/
month)
Max.
Unk. (%)
Tot.
Imp. Ace. L Cis. HL
Imp
3F
2-8
oC
0 97.75 1.17
0.04
0.03 0.08 ND ND
6 97.67 1.38 0.03 0.07 ND ND
12 97.35 2.11 0.02 0.07 NA NA
25oC/
40 %
RH
0 97.75 1.17
0.37
0.03 0.08 ND ND
1 98.92 1.60 0.03 0.06 ND ND
3 96.44 2.33 0.02 0.04 ND ND
6 95.47 3.38 0.03 0.07 ND ND
12 94.46 5.64 0.03 0.07 ND ND
3G
2-8
oC
0 98.65 0.62
0.05
0.05 0.11 ND ND
6 97.1 0.95 0.05 0.16 0.003 0.001
12 97.59 1.19 0.05 0.16 NA NA
25oC /
40% RH
0 98.65 0.62
0.38
0.05 0.11 ND ND
1 98.07 1.00 0.05 0.14 0.002 0.002
3 98.13 1.72 0.06 0.19 0.004 0.001
6 95.54 2.91 0.05 0.16 0.003 0.002
12 94.72 5.72 0.06 0.16 NA NA
Des. D: desacetyl diltiazem HCl impurity; Δ/month: % Degradation rate (Δ/month); Ace.
L: acetoxy lactum impurity; Tot. Imp.*: Total Impurities (excluding desacetyl diltiazem
31
HCl impurity); Cis. HL Imp.: Cis (+) hydroxy lactum impurity; Max. Unk. (%): Max.
Unknown Impurities (%); NA: Not analyzed
Observation: It was observed that components of the formulation, particularly an
5 alcoholic solvent like ethanol and cyclic oligosaccharide like hydroxypropyl-βcyclodextrin, have a stabilizing effect on the overall stability of the formulation at room
temperature for at least 6 months and at 2-8
oC for at least 12 months.
Example 4:
10 Different exemplary batches (4A-4S) were prepared with varying concentrations of
various excipients for the preparation of the aqueous solutions of diltiazem hydrochloride
according to present invention. The batch manufacturing was done by initiating it with
80% batch size of water for injection followed by addition of all the excipients, adjusting
the pH if required, followed by addition of diltiazem hydrochloride and the volume was
15 made up to 100%. Some of the samples were subjected to autoclaving.
Table IX: Various aqueous compositions of diltiazem:
Batch
No.
Ingredients
Concentration (mg/ml)
4A 4B 4C 4D 4E 4F 4G 4H 4I 4J 4K 4L 4M 4N 4O 4P 4Q 4R 4S
Diltiazem
Hydrochloride 1 1 1 1 1 1
HPßCD -- 35 35 10-35 35 -- -- -- -- -- 10 -- -- --
Ethanol -- -- -- -- -- -- -- -- 13.5 --
Dex A 40 40 -- 40 -- -- 50 -- -- -- 40
Dex M -- -- 35 -- -- -- -- -- -- --
BHA -- -- -- -- -- -- -- -- -- 0.02 -- -- -- -- -- -- -- --
BHT -- -- -- -- -- -- -- -- -- -- 0.06 -- -- -- -- -- -- --
AMS -- -- -- -- -- -- -- -- -- -- -- 2 -- -- -- -- -- --
SM -- -- -- -- -- -- -- -- -- -- -- -- 1 -- -- -- -- --
EDTA -- -- -- -- -- -- -- -- -- -- -- -- -- 2 -- -- -- --
L-Methionine -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- 10 -- --
KPM -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- 2 --
NaH2PO4 -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- 2
Sorbitol 10 10 10 10 -- -- -- 50 -- -- 10
NaCl -- -- -- -- 9 9 -- -- -- -- --
Mannitol -- -- -- -- -- -- -- 50 -- --
CAM 0.15 -- -- -- -- -- -- -- -- 0.15
32
SCD 0.13 -- -- -- -- -- -- -- -- 0.13
HCL q.s. to adjust pH --
NaOH q.s. to adjust pH --
pH 3.9 As such
WFI q.s. q.s. to 1 ml
Note: HP-ß-CD: hydroxypropyl-β-cyclodextrin; SCD: sodium citrate dihydrate; CAM:
citric acid monohydrate; HCL: hydrochloric acid; NaOH: sodium hydroxide; WFI: water
for injection; NaCl: sodium chloride; NaH2PO4: dodium dihydrogen phosphate; KPM:
potassium phosphate monobasic; EDTA: disodium edetate; SM: dodium metabisulfite;
5 AMS: ammonium sulfate; BHT: butylated hydroxyl tolune; BHA: butylated hydroxyl
anisole; Dex M: dextrose monohydrate; Dex A: dextrose anhydrous.
Various samples from example 4 were loaded for stability analysis, data of samples 4A,
4B and 4C are provide in below table X and XI comparing the presence and absence of
hydroxypropyl-β-cyclodextrin in the aqueous formulations of diltiazem hydrochloride.
10 Table X: Stability data of unautoclaved samples from Table IX:
Batch
No.
Stability
Cond.
Stag
e
Assay
Des.
D
Des D.
(Δ/
month)
Max.
Unk.
(%)
Tot.
Imp.*
Ace. L Cis. HL
Imp
4A
2-8
oC
0 99.82 0.10
0.10
0.02 0.04 0.001 ND
1 100.02 0.18 0.02 0.02 ND ND
3 100.41 0.38 0.02 0.07 ND ND
6 100.74 0.73 0.02 0.05 ND ND
12 99.64 1.43 0.03 0.07 ND ND
24 99.73 2.57 0.04 0.06 NA NA
25oC/ 40
% RH
0 99.82 0.10
0.84
0.02 0.04 0.001 ND
1 99.47 1.00 0.02 0.03 ND ND
3 98.24 2.75 0.02 0.06 ND ND
6 97.46 5.12 0.02 0.06 ND 0.001
4B
2-8
oC
0 100.94 0.06
0.05
0.03 0.07 ND ND
6 102.47 0.35 0.03 0.08 ND ND
12 100.69 0.64 0.03 0.07 NA NA
25oC /
40% RH
0 100.94 0.06
0.39
0.03 0.07 ND ND
1 101.46 0.40 0.02 0.05 ND ND
3 100.36 1.21 0.02 0.07 0.001 ND
6 99.41 2.41 0.03 0.07 0.002 ND
12 93.39 5.28 0.02 0.08 NA NA
4C
2-8
oC
0 99.86 0.05
0.05
0.02 0.02 NA NA
3 100.30 0.19 0.02 0.02 NA NA
6 100.19 0.32 0.02 0.03 NA NA
12 101.40 0.65 0.01 0.01 NA NA
25oC / 0 99.86 0.05 0.45 0.02 0.02 NA NA
33
40% RH 1 100.10 0.41 0.01 0.02 NA NA
3 99.05 1.36 0.01 0.03 NA NA
6 97.76 2.69 0.02 0.04 NA NA
12 96.23 5.47 0.01 0.02 NA NA
Note: Des. D: desacetyl diltiazem HCl impurity; Δ/month: desacetyl diltiazem HCl %
Degradation rate (Δ/month); Ace. L: acetoxy lactum impurity; Tot. Imp.*: Total Impurities
(excluding desacetyl diltiazem HCl impurity); Cis. HL Imp.: Cis (+) hydroxy lactum
impurity; Max. Unk. (%): Max. Unknown Impurities (%); NA: Not analysed
5
Table XI: Stability data of autoclaved samples from Table IX:
Batch
No.
Stability
Cond.
Stag
e
Assay Des.
D
Des D.
(Δ/
month)
Max.
Unk.
(%)
Tot.
Imp.*
Ace. L Cis. HL
Imp
4A
2-8
oC
0 97.91 1.22
0.10
0.02 0.07 0.003 ND
1 97.37 1.30 0.01 0.04 ND ND
3 98.49 1.52 0.02 0.08 0.002 ND
6 99.36 1.75 0.02 0.08 0.003 0.002
12 98.19 2.41 0.03 0.10 ND ND
24 98.45 3.52 0.03 0.09 NA NA
25oC/ 40
% RH
0 97.91 1.22
0.83
0.02 0.07 0.003 ND
1 97.31 2.11 0.02 0.04 ND ND
3 96.74 3.85 0.02 0.08 0.003 ND
6 96.17 6.20 0.02 0.08 ND ND
4B
2-8
oC
0 99.91 0.70
0.05
0.02 0.06 ND ND
6 100.19 0.92 0.02 0.06 0.002 ND
12 100.61 1.25 0.02 0.07 NA NA
25oC /
40% RH
0 99.91 0.70
0.40
0.02 0.06 ND ND
1 100.28 1.13 0.03 0.08 ND ND
3 99.59 1.86 0.03 0.08 0.001 ND
6 98.16 3.14 0.03 0.08 0.002 ND
12 94.81 5.86 0.02 0.10 NA NA
4C
2-8
oC
0 99.07 0.79
0.05
0.01 0.03 NA NA
3 98.73 0.93 0.02 0.04 NA NA
6 98.10 1.07 0.01 0.05 NA NA
12 99.50 1.42 0.02 0.02 NA NA
25oC /
40% RH
0 99.07 0.79
0.45
0.01 0.03 NA NA
1 99.32 1.16 0.01 0.01 NA NA
3 97.43 2.11 0.01 0.04 NA NA
6 96.40 3.42 0.01 0.06 NA NA
12 95.51 6.21 0.02 0.03 NA NA
Note: Des. D: desacetyl diltiazem HCl impurity; Δ/month: desacetyl diltiazem HCl %
Degradation rate (Δ/month); Ace. L: acetoxy lactum impurity; Tot. Imp.*: Total Impurities
34
(excluding desacetyl diltiazem HCl impurity); Cis. HL Imp.: Cis (+) hydroxy lactum
impurity; Max. Unk. (%): Max. Unknown Impurities (%); NA: Not analysed
Observation: It was observed that the components of the formulations according to
5 present invention were stable for a prolonged period of time with cyclodextrin and various
other solvents and osmogen. Cyclodextrin containing formulations of diltiazem were
relatively found to be more stable.
35
WE CLAIM:
1. A parenteral dosage form comprising a ready-to-infuse, stable aqueous solution
comprising diltiazem or its pharmaceutically acceptable salt and a cyclic
oligosaccharide as a stabilizer.
2. The parenteral dosage form according to claim 1, wherein the cyclic
5 oligosaccharide comprises a macrocyclic ring of glucose subunits joined by α-1,4
glycosidic bonds.
3. The parenteral dosage form according to claim 1, wherein the said dosage form is
filled in an infusion container.
4. The parenteral dosage form according to claim 3, wherein said infusion container
10 is selected from an infusion bag, perfusion bag, flexible pouch, soft bag, infusion
bottle or pre-filled syringe.
5. The parenteral dosage form according to claim 1, wherein diltiazem or its
pharmaceutically acceptable salt is present in a concentration range of about 0.05
mg/ml to about 2.0 mg/ml.
15 6. The parenteral dosage form according to claim 1, wherein said aqueous solution
further comprises an alcoholic solvent at a concentration range from about 1.0%
w/v to about 50.0% w/v.
7. The parenteral dosage form of claim 1, wherein the aqueous solution is present in a
volume ranging from about 50 ml to about 500 ml per infusion container.
20 8. The parenteral dosage form of claim 1, wherein said cyclic oligosaccharide
stabilizer is a cyclodextrin.
9. The parenteral dosage form of claim 8, wherein the cyclodextrin stabilizer is
selected from hydroxypropyl-β-cyclodextrin (HP-β-CD), methylated-βcyclodextrin (RM-β-CD) or sulfobutylether-β-cyclodextrin (SBE-β-CD).
25 10. The parenteral dosage form of claim 9, wherein the cyclodextrin stabilizer is
present in a concentration range of about 0.1% to about 100% w/v, preferably
about 0.1% to about 50% w/v.
11. The parenteral dosage form of claim 3, wherein the infusion container is a flexible
or rigid container.
36
12. The parenteral dosage form of claim 1, wherein said aqueous solution further
comprises a pH-adjusting agent to provide a pH in the range of about 3.5 to about
5.
13. A parenteral dosage form comprising a ready-to-infuse, stable aqueous solution
5 comprising diltiazem or its pharmaceutically acceptable salt, a cyclic
oligosaccharide as a stabilizer, a pH-adjusting agent, and an alcoholic solvent.
14. The parenteral dosage form of claim 13, wherein the cyclic oligosaccharide
stabilizer is selected from hydroxypropyl-β-cyclodextrin (HP-β-CD), methylatedβ-cyclodextrin (RM-β-CD) or sulfobutylether-β-cyclodextrin (SBE-β-CD).
10 15. The parenteral dosage form of claim 6 or 13, wherein the alcoholic solvent is
ethanol or a mixture of ethanol with another co-solvent.
16. The parenteral dosage form according to claim 1 or 13, wherein the stable aqueous
solution comprises diltiazem or its pharmaceutical acceptable salt in a
concentration range of about 0.05 to about 2.0 mg/ml, the cyclic oligosaccharide is
15 hydroxypropyl-β-cyclodextrin in a concentration range of about 0.1 to about 50%
w/v, and the pH of the solution is in range of pH of about 3.7 to about 4.5.
17. The parenteral dosage form according to claim 16, wherein the stable aqueous
solution comprises diltiazem or its pharmaceutical acceptable salt in a
concentration range of about 0.1 to 2.0 mg/ml, the hydroxypropyl-β-cyclodextrin is
20 in a concentration range of about 0.1 to 10% w/v, and the pH of the solution is
about 3.9.
18. The parenteral dosage form according to claim 6 or 13, wherein the stable aqueous
solution comprises diltiazem or its pharmaceutical acceptable salt in a
concentration range of about 0.1 to 2.0 mg/ml, the cyclic oligosaccharide is
25 hydroxypropyl-β-cyclodextrin in a concentration range of about 0.1 to 10% w/v,
ethanol is the alcoholic solvent in a concentration range of about 1 to about 10%
w/w and the pH of the solution is about 3.9.
19. The parenteral dosage form of any of the preceding claims, wherein the level of
diltiazem desacetyl or its salt impurity is less than 10%, when said aqueous
solution is stored at 2-8 30 oC for at least 12 months.
37
20. The parenteral dosage form of any of the preceding claims, wherein the level of
diltiazem desacetyl or its salt impurity is less than 10%, when said aqueous
solution is stored at 25oC/40% RH for at least 6 months.
21. The parenteral dosage form of any of the preceding claims, wherein said dosage
5 form is terminally sterilized by autoclaving.
22. A method for treating atrial fibrillation, atrial flutter, or paroxysmal
supraventricular tachycardia, by administering a stable parenteral dosage form
according to any of the preceding claims.
23. Use of a stable parenteral dosage form according to claim 1 or 13, for the treatment
10 of atrial fibrillation, atrial flutter, or paroxysmal supraventricular tachycardia.
24. A parenteral dosage form comprising a ready-to-infuse, stable aqueous solution
comprising diltiazem or its pharmaceutically acceptable salt and a cyclic
oligosaccharide as a stabilizer, wherein in the dosage form the level of desacetyl
diltiazem or its salt impurity is not more than about 10% w/w of diltiazem or its
pharmaceutically acceptable salt when stored for at least 12 months at 2-8 15 oC.
25. A parenteral dosage form comprising a ready-to-infuse, stable aqueous solution
comprising diltiazem or its pharmaceutically acceptable salt and a cyclic
oligosaccharide as a stabilizer, wherein in the dosage form the level of desacetyl
diltiazem or its salt impurity is not more than about 10% w/w of diltiazem or its
pharmaceutically acceptable salt when stored for at least 6 months at 25 20 oC/40%
RH.
26. The parenteral dosage according to claim 24, wherein the level of desacetyl
diltiazem or its salt impurity is not more than 6% w/w of diltiazem or its
pharmaceutically acceptable salt, when stored for at least 12 months at 2-8
oC.
25 27. The parenteral dosage according to claim 25, wherein the level of desacetyl
diltiazem or its salt impurity is not more than 6% w/w of diltiazem or its
pharmaceutically acceptable salt, when stored for at least 6 months at 25oC/40%
RH.
28. The parenteral dosage according to claim 24 or 25, wherein said dosage form is
30 prepared by a process comprising of:
38
a) taking water for injection in an amount of 80% of the batch size in a
container;
b) adding suitable excipients including hydroxypropyl-β-cyclodextrin with or
without alcoholic solvent to the container and mixing;
5 c) adding and dissolving of diltiazem hydrochloride to the mixture;
d) checking the pH of the mixture and adjusting the pH of the solution to pH
in the range of about 3.5 to about 5 by adding a suitable pH-adjusting
agent, if required;
e) making up the volume to 100% using water for injection;
10 f) filtering the above solution by using a 0.2 micron membrane filter, and
filling the solution in a flexible infusion bag and stoppering the fusion bag.
29. The parenteral dosage according to claim 28, wherein the process the addition of
pH-adjusting agent may not be required where the pH of the solution is
automatically adjusted in the range of pH about 3.5 to about 5.
15 30. The parenteral dosage according to claim 28, wherein the process further
comprises optionally overwrapping the infusion bag using a suitable aluminium
pouch with an oxygen scavenger.
31. The parenteral dosage according to claim 28, wherein the process further
comprises autoclaving said fusion bag at 121oC for 15 minutes.