U.S. patent application number 17/154516 was filed with the patent office on 2021-07-29 for phenylephrine hydrochloride compositions and containers.
This patent application is currently assigned to Nevakar Inc.. The applicant listed for this patent is Nevakar Inc.. Invention is credited to Tushar Hingorani, Harshil H. Jain, Reema Ajitkumar Puri, Kumaresh Soppimath.
Application Number | 20210228507 17/154516 |
Document ID | / |
Family ID | 1000005504466 |
Filed Date | 2021-07-29 |
United States Patent
Application |
20210228507 |
Kind Code |
A1 |
Puri; Reema Ajitkumar ; et
al. |
July 29, 2021 |
Phenylephrine Hydrochloride Compositions and Containers
Abstract
A ready-to-administer antioxidant free phenylephrine
compositions has improved stability and is optionally free of metal
chelating agents. Contemplated compositions are preferably packaged
into a flexible polymer bag and maintain degradation of the
phenylephrine at remarkably low levels, even over extended storage
periods.
Inventors: |
Puri; Reema Ajitkumar;
(Hillsborough, NJ) ; Jain; Harshil H.; (Monmouth
Junction, NJ) ; Hingorani; Tushar; (Bridgewater,
NJ) ; Soppimath; Kumaresh; (Skillman, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Nevakar Inc. |
Bridgewater |
NJ |
US |
|
|
Assignee: |
Nevakar Inc.
Bridgewater
NJ
|
Family ID: |
1000005504466 |
Appl. No.: |
17/154516 |
Filed: |
January 21, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62964457 |
Jan 22, 2020 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/183 20130101;
A61K 47/12 20130101; B65B 3/003 20130101; B65D 75/38 20130101; A61K
47/02 20130101; A61K 31/137 20130101; A61K 9/0019 20130101; B65D
81/266 20130101 |
International
Class: |
A61K 31/137 20060101
A61K031/137; A61K 47/12 20060101 A61K047/12; A61K 47/18 20060101
A61K047/18; A61K 47/02 20060101 A61K047/02; A61K 9/00 20060101
A61K009/00; B65D 81/26 20060101 B65D081/26; B65D 75/38 20060101
B65D075/38; B65B 3/00 20060101 B65B003/00 |
Claims
1. A ready-to-administer sterile antioxidant free phenylephrine
composition, comprising: phenylephrine or salt thereof at a
concentration of equal or less than 0.4 mg/ml; an acetate buffer,
wherein the composition has a pH of between 4.5 and 5.5; and an
optional metal ion chelator; wherein no more than 0.5% degradation
products are formed from degradation of the phenylephrine upon
storage of the phenylephrine composition over a period of at least
six months at 25.degree. C.
2. The composition of claim 1, wherein the phenylephrine or salt
thereof is present in the composition at a concentration of about
0.04 mg/ml.
3. The composition of claim 1, wherein the phenylephrine or salt
thereof is present in the composition at a concentration of about
0.08 mg/ml.
4. The composition of claim 1, wherein the phenylephrine or salt
thereof is present in the composition at a concentration of about
0.16 mg/ml.
5. The composition of claim 1, wherein the phenylephrine or salt
thereof is present in the composition at a concentration of about
0.4 mg/ml.
6. The composition of claim 1, wherein the acetate buffer has a
concentration of equal or less than 5 mM.
7. The composition of claim 1, wherein the composition has a pH of
about 5.0.
8. The composition of claim 1, wherein the composition is packaged
in a flexible polymer bag, wherein the flexible polymer bag is
further packaged in a metallized pouch that optionally contains an
oxygen scavenger
9. The composition of claim 1, further comprising a tonicity agent
selected from the group consisting of sodium chloride, glycerol,
thioglycerol, mannitol, lactose, and dextrose.
10. The composition of claim 1, comprising the metal ion chelator,
wherein the metal ion chelator is ethylene diamine tetra acetic
acid (EDTA), and wherein the metal ion chelator is present in an
amount of equal or less than 10 mcg/mL.
11. A method of manufacturing a ready-to-administer sterile
antioxidant free phenylephrine composition, comprising: formulating
a buffered liquid including phenylephrine or salt thereof; wherein
the buffered composition comprises an acetate buffer and has a pH
of between 4.5 and 5.5, and optionally further comprises a metal
ion chelator; wherein the phenylephrine or salt thereof is present
in the buffered liquid at a concentration of equal or less than 0.4
mg/ml; and terminally sterilizing the liquid composition; wherein
no more than 0.25% degradation products are formed from degradation
of the phenylephrine upon storage of the phenylephrine composition
over a period of at least six months at 25.degree. C.
12. The method of claim 11, wherein the buffered liquid comprises
water for injection.
13. The method of claim 11, wherein the acetate buffer has a
concentration of equal or less than 5 mM.
14. The method of claim 11, wherein the composition has a pH of
about 5.0.
15. The method of claim 11, further comprising a step of packaging
the composition into a flexible polymer bag and packaging the
flexible polymer bag into a metallized pouch that optionally
contains an oxygen scavenger.
16. The method of claim 11, wherein the composition comprises the
metal ion chelator, wherein the metal ion chelator is ethylene
diamine tetra acetic acid (EDTA), and wherein the metal ion
chelator is present in an amount of equal or less than 10
mcg/mL.
17. The method of claim 11, wherein the composition further
comprises a tonicity agent selected from the group consisting of
sodium chloride, glycerol, thioglycerol, mannitol, lactose, and
dextrose.
18. The method of claim 11 wherein terminally sterilizing the
liquid composition comprises autoclaving the liquid
composition.
19. A ready-to-administer sterile antioxidant free phenylephrine
composition, essentially consisting of: phenylephrine or salt
thereof at a concentration of between about 0.04 mg/ml and about
0.4 mg/ml; an acetate buffer, wherein the composition has a pH of
between 4.5 and 5.5; and an optional metal ion chelator, wherein
the optional metal ion chelator is present in an amount of equal or
less than 10 .mu.g/mL; wherein no more than 0.5% degradation
products are formed from degradation of the phenylephrine upon
storage of the phenylephrine composition over a period of at least
six months at 25.degree. C.
20. The composition of claim 19, wherein phenylephrine or salt
thereof is present at a concentration of about 0.04 mg/ml, or at a
concentration of about 0.08 mg/ml, or at a concentration of about
0.16 mg/ml, or at a concentration of about 0.4 mg/ml.
Description
[0001] This application claims priority to our co-pending US
Provisional Patent Application with the Ser. No. 62/964,457, which
was filed Jan. 22, 2020, which is incorporated by reference
herein.
FIELD OF THE INVENTION
[0002] The field of the invention pharmaceutical compositions and
methods, and particularly as they relate to stable, sterile and
ready-to-administer antioxidant free phenylephrine compositions,
uses, and methods of manufacturing and packaging same.
BACKGROUND OF THE INVENTION
[0003] The background description includes information that may be
useful in understanding the present disclosure. It is not an
admission that any of the information provided herein is prior art
or relevant to the presently claimed invention, or that any
publication specifically or implicitly referenced is prior art.
[0004] All publications and patent applications herein are
incorporated by reference to the same extent as if each individual
publication or patent application were specifically and
individually indicated to be incorporated by reference. Where a
definition or use of a term in an incorporated reference is
inconsistent or contrary to the definition of that term provided
herein, the definition of that term provided herein applies and the
definition of that term in the reference does not apply.
[0005] Phenylephrine hydrochloride as shown below is an
.alpha.-adrenergic receptor agonist, used primarily as a
decongestant, as an agent to dilate the pupil, and to increase
blood pressure in adults with clinically important hypotension
resulting primarily from vasodilation, in such settings as septic
shock or anesthesia.
##STR00001##
[0006] Interaction of phenylephrine with .alpha..sub.1-adrenergic
receptors on vascular smooth muscle cells causes activation of the
cells and results in vasoconstriction. Following intravenous
administration of phenylephrine hydrochloride, increases in
systolic and diastolic blood pressures, mean arterial blood
pressure, and total peripheral vascular resistance are observed.
The onset of blood pressure increase following an intravenous bolus
of phenylephrine hydrochloride is rapid, typically within minutes.
As blood pressure increases following intravenous administration,
vagal activity also increases, resulting in reflex bradycardia.
Phenylephrine has activity on most vascular beds, including renal,
pulmonary, and splanchnic arteries.
[0007] Phenylephrine is available as an over-the-counter nasal
decongestant, either alone or in combination with other cold
remedies. Intravenous phenylephrine has been available and marketed
for several decades. In ophthalmology, ophthalmic preparations
(e.g., eye drops) of phenylephrine or phenylephrine combinations
have been used to induce mydriasis, as a provocative test for
angle-closure glaucoma, and as an adjunct in the treatment of
anterior uveitis and secondary glaucoma.
[0008] Pharmacokinetics for phenylephrine following intravenous
administration follows a 2-compartment model with rapid
distribution (.alpha.-phase half-life <5 min) from the central
compartment to peripheral tissues and end organs. Phenylephrine is
extensively metabolized by the liver (primarily by monoamine
oxidase and sulfotransferase), with only 12% of the dose excreted
unchanged in the urine. The primary metabolic pathway is
deamination by monoamine oxidase, forming the major metabolite,
3-hydroxymandelic acid. Following i.v. administration,
phenylephrine and its metabolites are primarily eliminated in the
urine. These metabolites are inactive with respect to
.alpha..sub.1- and .alpha..sub.2-adrenergic receptors.
[0009] Phenylephrine hydrochloride is very soluble in water, freely
soluble in ethanol, and insoluble in chloroform and ethyl ether.
Phenylephrine hydrochloride is sensitive to light. Phenylephrine
has been reported to be stable below pH 7.3, above pH 7, the
degradation occurs on the side chain with loss of secondary amine
function, and the phenolic group remains stable.
[0010] Currently, phenylephrine hydrochloride for intravenous use
is marketed as Phenylephrine hydrochloride solution, 10 mg/mL, USP
solution concentrate by West Ward Pharmaceuticals. It is available
as a concentrate (10 mg/mL) as a single-dose 1 mL vial (10 mg of
phenylephrine hydrochloride per vial), Phenylephrine hydrochloride
solution is a clear colorless, sterile, non-pyrogenic solution for
intravenous use and must be diluted before administration as an
intravenous bolus or continuous intravenous infusion. Each mL
contains phenylephrine hydrochloride 10 mg, sodium chloride 3.5 mg,
sodium citrate dihydrate 4 mg, citric acid monohydrate 1 mg, and
sodium metabisulfite 2 mg in water for injection. The pH is
adjusted with sodium hydroxide/or hydrochloric acid if necessary,
to a pH range of 3.0 to 6.5.
[0011] The concentrate must be diluted prior to use and requires
personnel intervention, there is a possibility of microbial
contamination or dilution error. Even more significantly, the
diluted solution should not be held for more than 4 hours at room
temperature or for more than 24 hours under refrigerated
condition.
[0012] Thus, even though various phenylephrine hydrochloride
formulations are known in the art, extended stability at low and
ready-to-use concentrations is problematic. In addition, presence
of metabisulfite in known compositions may lead to undesirable side
effects in at least some subjects. Consequently, there is a need
for improved stable, low concentration, ready-to-administer
antioxidant free phenylephrine hydrochloride formulations, and
methods of manufacturing and storing the same.
SUMMARY OF THE INVENTION
[0013] The present inventive subject matter is directed to various
phenylephrine formulations in an aqueous solution that are
antioxidant free and that enhance or preserve the chemical
stability of phenylephrine at low (especially at ready-to-use)
concentrations and consequently extend the product shelf life of
such ready-to-use products with little to no degradation products
formed from phenylephrine after storage at ambient temperatures
over extended periods (e.g., at least 6 months). Advantageously,
contemplated compositions are sterile, and in some cases will also
not include a metal ion chelator.
[0014] In one aspect of the inventive subject matter, the inventors
contemplate a ready-to-administer sterile antioxidant free
phenylephrine composition that includes phenylephrine at a
concentration of equal or less than 0.4 mg/ml, an optional metal
ion chelator, and an acetate buffer, wherein the composition has a
pH of between 4.5 and 5.5. Advantageously no more than 0.5%
degradation products are formed from degradation of the
phenylephrine upon storage of the phenylephrine composition over a
period of at least six months at 25.degree. C.
[0015] In some embodiments, the phenylephrine is present in the
composition at a concentration of about 0.04 mg/ml, or at a
concentration of about 0.08 mg/ml, or at a concentration of about
0.16 mg/ml, or at a concentration of about 0.4 mg/ml or at a
concentration of 0.8 mg/mL. Typically, but not necessarily, the
acetate buffer has a concentration of equal or less than 5 mM,
and/or the composition has a pH of about 5.0.
[0016] In further embodiments, contemplated compositions comprise a
tonicity agent (e.g., sodium chloride, glycerol, thioglycerol,
mannitol, lactose, or dextrose), and/or include the metal ion
chelator. Suitable metal ion chelators especially include ethylene
diamine tetra acetic acid (EDTA), and it is generally preferred
that metal ion chelator is present in an amount of equal or less
than 10 .mu.g/mL.
[0017] Where desired, the composition may be packaged in a flexible
polymer bag, which may in turn be further packaged into a
metallized pouch that may or may not include an oxygen
scavenger.
[0018] For example, contemplated ready-to-administer sterile
antioxidant free phenylephrine composition may essentially consist
of phenylephrine at a concentration of between about 0.04 mg/ml and
about 0.4 mg/ml, an acetate buffer, wherein the composition has a
pH of between 4.5 and 5.5 (e.g., about 5.0), and an optional metal
ion chelator and an isotonicity adjusting agent. As noted, before,
no more than 0.15% degradation products are typically formed from
degradation of the phenylephrine upon storage of the phenylephrine
composition over a period of at least six months at 25.degree.
C.
[0019] In further examples, phenylephrine is present at a
concentration of about 0.04 mg/ml, or about 0.08 mg/ml, or about
0.16 mg/ml, or about 0.4 mg/ml. Where a metal ion chelator is
included, it is generally preferred that the metal ion chelator is
present in an amount of equal or less than 10 .mu.g/mL.
[0020] In another aspect of the inventive subject matter, the
inventors also contemplate a method of manufacturing a
ready-to-administer sterile antioxidant free phenylephrine
composition that will include a step of formulating a buffered
liquid including phenylephrine or salts thereof. Most typically,
the buffered composition comprises an acetate buffer and has a pH
of between 4.5 and 5.5, and optionally further comprises a metal
ion chelator, and it is preferred that in such methods the
phenylephrine is present in the buffered liquid at a concentration
of equal or less than 0.4 mg/ml. As will be appreciated,
contemplated methods further include a step of terminally
sterilizing the liquid composition. Advantageously no more than
0.15% degradation products are formed from degradation of the
phenylephrine upon storage of the so prepared phenylephrine
composition over a period of at least six months at 25.degree.
C.
[0021] Suitable phenylephrine concentrations in such methods
include about 0.04 mg/ml, about 0.08 mg/ml, about 0.16 mg/ml, and
about 0.4 mg/ml. It is further preferred that the acetate buffer
has a concentration of equal or less than 5 mM, and/or that the
composition has a pH of about 5.0. Where the composition comprises
the metal ion chelator, it is generally preferred that the metal
ion chelator is ethylene diamine tetra acetic acid (EDTA), and/or
that the metal ion chelator is present in an amount of equal or
less than 10 .mu.g/mL. In further aspects of contemplated
compositions, the composition further comprises a tonicity agent
such as sodium chloride, glycerol, thioglycerol, mannitol, lactose,
and dextrose.
[0022] Most typically, terminal sterilization will include a step
of filling the liquid solution in a primary bag (such as a flexible
polymer bag with a stopper), followed by placing the filled primary
bag in a metallized pouch that optionally contains an oxygen
scavenger and are sealed. Methods presented herein may include
autoclaving the liquid contained in the sealed secondary bag (which
may optionally contain an oxygen scavenger).
[0023] In yet another aspect of the inventive subject matter, the
inventors also contemplate a method of increasing blood pressure in
an individual that includes a step of administering the
ready-to-inject phenylephrine composition presented herein. For
example, the ready-to-inject phenylephrine composition may be
administered as a bolus to thereby deliver between 40-100 .mu.g
phenylephrine, and/or may be administered as a continuous
intravenous infusion to thereby deliver between 10 and 40 .mu.g/min
phenylephrine. Most typically, the ready-to-inject phenylephrine
composition is administered without further dilution.
[0024] Various objects, features, aspects, and advantages will
become more apparent from the following detailed description of
preferred embodiments, along with the accompanying drawing in which
like numerals represent like components.
BRIEF DESCRIPTION OF THE DRAWING
[0025] FIG. 1 is an exemplary illustration of oxidative degradation
of phenylephrine.
[0026] FIG. 2 is an exemplary illustration of pH dependent
cyclization of phenylephrine.
[0027] FIG. 3 is an exemplary illustration of aldehyde dependent
phenolic cyclization of phenylephrine.
[0028] FIG. 4 is an exemplary illustration of furan dependent
phenolic cyclization of phenylephrine
[0029] FIG. 5 is an exemplary flow chart depicting a manufacturing
process for phenylephrine compositions contemplated herein.
DETAILED DESCRIPTION
[0030] The inventors have now discovered that stable aqueous and
ready-to-use aqueous pharmaceutical formulations of phenylephrine
or its pharmaceutically acceptable salts can be prepared in a
conceptually simple and effective manner. Advantageously, such
formulations are antioxidant free, may or may not include a metal
ion chelator, have a phenylephrine concentration of between 40-400
mcg/mL, and more preferably between 10-100 mcg/mL, and have a
physiologically desirable pH of between 4.5 and 5.5. As used
herein, the term "phenylephrine" should be interpreted broadly to
include pharmaceutically acceptable salts and prodrugs thereof.
[0031] Unexpectedly, and in spite of the known instability of
low-concentration phenylephrine formulations, the inventors
discovered that phenylephrine compositions could be prepared that
contain phenylephrine or salts thereof at a concentration suitable
for direct administration (i.e., without the need for dilution
prior to administration) and that could be stored over months
without significant degradation. Moreover, the inventors also
surprisingly found that storage stability of phenylephrine was
significantly affected by the choice of buffering agent, especially
at low concentrations of phenylephrine as is shown in more detail
below. In particular, where acetate was used as a buffering agent,
stability of low concentration phenylephrine was significantly
increased as compared to a citrate or tartrate buffer with
everything else being equal. Moreover, contemplated compositions
were also thermally stable and thus allowed for terminal
sterilization.
[0032] In one aspect of the inventive subject matter, the inventive
subject matter is directed to a stable aqueous pharmaceutical
preparation of phenylephrine or its pharmaceutically acceptable
salts in a ready-to-use form where the pharmaceutical preparation
is sterile and packaged in a polymeric (preferably flexible) bag
for infusion or in a blow-fill-seal (BFS) container. Particularly
preferred formulations are ready-to-administer, anti-oxidant free
phenylephrine infusion formulations that include phenylephrine
hydrochloride at low concentrations, such as about 0.04 mg/ml, or
about 0.08 mg/ml, or about 0.16 mg/ml, or about 0.4 mg/ml, and have
a pH of between 3.0-6.0, preferably between 4.5-6.0, and more
preferably between 4.5-5.5 (e.g., about 5.0). As is also shown in
more detail below, such formulations may contain a metal ion
chelating agent or may be chelating agent free and an isotonicity
adjusting agent such as dextrose or sodium chloride, more
preferably sodium chloride.
[0033] In this context, it should be recognized that while
phenylephrine is stable as a solid, it will readily degrade in an
aqueous solution following various complex and distinct degradation
mechanisms, which at least in part will depend on the particular
pH. The inventors generated predicted ionization constants using
known algorithms (Chemicalize, commercially available program from
ChemAxon) and exemplary results are shown immediately below. Here,
the strongest acidic pKa (pKa: 9.07) is seen on the phenolic
hydroxyl group, while the strongest basic pKa (pKa: 9.69) is on the
amine functionality.
##STR00002##
[0034] As will be readily appreciated, the different ionization
stages of phenylephrine are dependent on the pH of the solution in
which phenylephrine is present. Thus, phenylephrine can be present
in aqueous solutions in neutral (unionized) form, in cationic form,
anionic form (single or double negative charge), or in zwitterionic
form. As should also be appreciated, the ionization state of
phenylephrine will influence the rate and type of degradation.
Among other degradation mechanisms, phenylephrine can undergo
degradation via oxidation, pH dependent cyclization, aldehyde
dependent phenolic cyclization, and furan dependent cyclization.
Notably, phenylephrine is not subject to racemization as a function
of pH, and phenylephrine is optically stable in solutions at pH 3.0
and pH 6.0.
[0035] Oxidative degradation of phenylephrine occurs through the
oxidation of the phenolic and secondary alcohol moieties, with the
liberation of four hydrogens. This mechanism then produces the
corresponding quinone, and the degradation of ketone (PHE Deg. 1,
with an MW of 179 Da), and further oxidation of the secondary amine
to the corresponding nitrone takes place to yield the second
degradation (PHE Deg.2, with an MW of 195 Da) as shown in FIG. 1. A
pH dependent cyclization of phenylephrine has been shown to proceed
via a pH dependent pathway. Around pH 7, degradation of
phenylephrine involves the side chain with loss of the secondary
amine function under retention of the phenolic group. The
decomposition products have not been identified but
5-hydroxy-N-methyl indoxyl has been proposed as is shown in FIG.
2.
[0036] Phenylephrine also degrades in the presence of formaldehyde
as shown in FIG. 3 in an aldehyde dependent phenolic cyclization.
Here, cyclization is a very fast reaction within a wide pH range.
This reaction sequence is also known as a "phenolic cyclization"
and typically leads to formation of tetrahydroisoquinolines (THQs).
In FIG. 3 the degradation product Imp 1 corresponds to
4,6-dihydroxyN-methyl-1,2,3,4-tetrahydroisoquinoline, and the
degradation product Imp 4 corresponded to
4,8-dihydroxy-N-methyl-1,2,3,4-tetrahydroisoquinoline. FIG. 4
depicts yet another degradation mechanism of phenylephrine, a furan
dependent cyclization. Here, formation of Imp 3 and Imp 5 are
attributable to reaction of phenylephrine with a furan. It is known
that the primary sources of thermally produced furan and its
derivatives (such as 5-HMF) are saccharides. The highest potential
to produce 5-HMF upon thermal treatment has glucose, originating
from saccharose hydrolysis, for example, during autoclaving.
Similarly, in another reaction sequence (phenolic cyclization),
there is the possibility of condensation of 5-HMF with
phenylephrine, thereby forming
1-[5-(hydroxymethyl)-2-furyl]-2-methyl-1,2,3,4-tetrahydroisochinolin-4,8--
diol (4,8-THQ-HMF) and
1-[5-(hydroxymethyl)-2-furyl]-2-methyl-1,2,3,4-tetrahydroisochinolin-4,6--
diol (4,6-THQ-HMF) as also shown in FIG. 4.
[0037] Despite the various degradation routes, and as is described
in more detail below, contemplated aqueous pharmaceutical
preparation of phenylephrine hydrochloride in a ready-to-use form
were remarkably stable at room temperature (e.g., 25.degree. C.,
60% relative humidity). Degradation products from the degradation
of phenylephrine in solution remained within acceptable limits
(e.g., less than 10 wt %, less than 5 wt %, less than 2 wt %, less
than 1 wt %, less than 0.7 wt %, less than 0.6 wt %, less than 0.5
wt %, less than 0.4 wt %, less than 0.3 wt %, less than 0.2 wt %,
less than 0.1 wt %) over long term storage (e.g., at least 1 month,
at least 2 months, at least 3 months, at least 6 months, at least 9
months, at least 12 months, at least 18 months). Therefore, the
phenylephrine formulations of the inventive subject matter can be
provided in a ready-to-use form to avoid the inconvenience and time
associated with diluting a concentrated small volume phenylephrine
parenteral formulation into infusion diluents prior to infusion.
Thus, the ready-to-use formulations also eliminate microbial
contamination risks and calculation errors associated with
dilution.
[0038] For example, exemplary contemplated formulations may contain
phenylephrine hydrochloride as the active ingredient at a
concentration of 40 mcg/mL, 80 mcg/mL, 160 mcg/mL, or 400 mcg/mL as
indicated in Table 1 below. These solutions may contain glacial
acetic acid as a buffering agent, optionally ethylene diamine tetra
acetic acid (EDTA) as a metal chelator, sodium chloride for
isotonicity and water for injection as a vehicle. Hydrochloric
acid/sodium hydroxide are used as pH adjusting agents, and the
resulting solutions are then filled in a 250 mL non-PVC IV bag and
terminally sterilized. Following sterilization, the IV bag can be
placed in an aluminum overwrap which may or may not include an
oxygen scavenger. Alternatively, the resulting solution can be
filled in a 250 mL non-PVC IV bag and then placed in a secondary
packaging (such as metallized pouch with or without oxygen
scavenger, optionally flushed with an inert gas such as nitrogen)
and then terminally sterilized.
TABLE-US-00001 TABLE 1 Ingredient Quantity (mg/mL) Phenylephrine
0.04 0.08 0.16 0.4 Hydrochloride Sodium chloride 8.46 8.46 8.46
8.46 Glacial Acetic Acid 0.3 0.3 0.3 0.3 EDTA (Titriplex III) 0.01
0.01 0.01 0.01 Hydrochloric q.s. to pH 5.0 q.s. to pH 5.0 q.s. to
pH 5.0 q.s. to pH 5.0 acid/ sodium hydroxide Water q.s. to 1.0 mL
q.s. to 1.0 mL q.s. to 1.0 mL q.s. to 1.0 mL
[0039] However, it should be appreciated that contemplated
formulations can be prepared in a range of concentrations commonly
required by medical practitioners for emergency restoration of
blood pressure in cases of anesthesia, among other suitable uses.
For example, phenylephrine can be present in contemplated
formulations at a concentration of between 0.001 to 0.2% w/v, or
between 0.001 to 0.01% w/v, or between 0.004 to 0.04% w/v, etc.
Therefore, contemplated phenylephrine concentrations are 10-50
mcg/mL, 30-70 mcg/mL, 50-100 mcg/mL, 75-150 mcg/mL, 100-200 mcg/mL,
300-500 mcg/mL, 400-700 mcg/mL, 500-1,000 mcg/mL, and even higher.
Of course, it should also be appreciated that phenylephrine may be
present as a non-salt or in a salt form, and all pharmaceutically
acceptable salts are deemed suitable for use herein. Therefore,
suitable salt forms include phenylephrine hydrochloride,
phenylephrine hydrobromide, etc.
[0040] Some contemplated formulations will include phenylephrine
hydrochloride and a vehicle without preservatives, and particularly
without anti-oxidants and/or metal ion chelating agents, while in
other aspects contemplated formulations will include at least one
excipient. Regardless of the particular form of preparation,
contemplated formulations may further include stabilizing agents,
buffer components, and isotonicity adjusting agents.
[0041] For example, tonicity agents, such as sodium chloride,
glycerol, thioglycerol, mannitol, lactose, dextrose and the like
can be included in some contemplated compositions. The amount of
tonicity adjusting agent used can be adjusted to obtain osmolality
of the formulations in the range of 260 to 340 mOsm/kg. An
osmometer can be used to check and adjust the amount of tonicity
adjusting agent to be added to obtain the desired osmolality.
Additionally, or alternatively, contemplated formulations may
include further pharmaceutically acceptable excipients, and
especially buffers, and any reasonable mixture thereof. Among other
choices, contemplated buffers include buffer systems in which an
organic or inorganic acid and a corresponding salt form the buffer
system as well as amphoteric compounds (e.g., HEPES, MES, etc.).
Most typically, the buffer will be a pharmaceutically acceptable
buffer that is present at a relatively low concentration.
[0042] For example, suitable buffers include acetate buffers,
citrate buffers, and tartrate buffers. However, and as is described
in more detail below, the inventors surprisingly discovered that
particularly at relatively low concentrations (e.g., equal or less
than 400 mcg/mL, equal or less than 200 mcg/mL, equal or less than
100 mcg/mL, equal or less than 70 mcg/mL, equal or less than 40
mcg/mL, equal or less than 20 mcg/mL, equal or less than 10 mcg/mL)
of phenylephrine, not all buffers provided equal stability to the
phenylephrine. Indeed, at increasingly lower concentrations (e.g.,
equal or less than 100 mcg/mL, equal or less than 70 mcg/mL, equal
or less than 40 mcg/mL, equal or less than 20 mcg/mL, equal or less
than 10 mcg/mL) of phenylephrine, the choice of buffer had an
increasingly significant impact on stability of phenylephrine,
especially at a lower concentration.
[0043] This effect was pronounced at relatively low concentrations
of the buffering agents, and typical low concentrations include
equal or less than 20 mM, equal or less than 10 mM, equal or less
than 5 mM, equal or less than 3 mM, or equal or less than 20 mM as
is demonstrated in more detail below. Therefore, in especially
preferred aspects of the inventive subject matter, the buffer is
acetate buffer at a strength of equal or less than 5 mM, or equal
or less than 5 mM, particularly where the phenylephrine
concentration is equal or less than 100 mcg/mL, equal or less than
70 mcg/mL, equal or less than 40 mcg/mL, equal or less than 20
mcg/mL, equal or less than 10 mcg/mL.
[0044] In this context, it should be appreciated that contemplated
compositions are ready-to-administer formulations and that the
administered volume will typically be relatively large (e.g., at
least 10 mL or at least 50 mL, or at least 100 mL, or at least 200
mL, or at least 300 mL, or at least 400 mL, or at least 500 mL).
Consequently, the buffer strength must be relatively low so as to
avoid adverse effects of adding substantial quantities of buffer to
the circulation of an individual. Notably, the inventors discovered
that a desirable pH range can be achieved at a low buffer
concentration that afforded phenylephrine stability over extended
storage.
[0045] It should further be appreciated that depending on the
particular ingredients, the pH of the formulation may vary.
However, it is generally preferred that the pH of the formulations
is suitable for injection and will typically be between 3.0 and
7.0, more typically between 4.7 and 6.0. For example, contemplated
pH ranges will be between 4.5-5.0, or between 4.7-5.2, or between
4.9-5.4, or between 5.1-5.6, or between 5.3-5.8, or between
5.5-6.0, or between 5.7-6.2, or between 5.9-6.4, or between
6.1-6.4, or between 6.3-6.6, or between 6.5-6.8, or between
6.7-7.0. Thus, suitable pH may be 4.0, or 4.1, or 4.2, or 4.3, or
4.4, or 4.5, or 4.6, or 4.7, or 4.8, or 4.9, or 5.0, or 5.1, or
5.2, or 5.3, or 5.4, or 5.5, or 5.6, or 5.7, or 5.8, or 5.9, or 6.0
(each +/-0.2 pH units). As will be readily appreciated, the pH can
be maintained using any suitable buffer system, and all buffer
systems with buffer capacity in the above noted pH values/ranges
are deemed appropriate for use herein.
[0046] In at least some embodiments, contemplated formulations may
also include one or more chelating agents, and particularly metal
ion chelators. For example, suitable chelators include various
bicarboxylic acids, tricarboxylic acids, and aminopolycarboxylic
acids such as ethylenediaminetetraacetic acid (EDTA), ethylene
glycol-bis(.beta.-aminoethyl ether)-N,N,N',N'-tetraacetic acid
(EGTA), and penta(carboxymethyl)diethylenetriamine (DTPA), and
salts and hydrates thereof. While not limiting to the inventive
subject matter, it is contemplated that the metal ion chelators
will slow down both the baseline and metal ion-stimulated oxidation
of phenylephrine. Remarkably, the inventors unexpectedly observed
that the desirable effect of the chelators was observable at
relatively low concentrations of the chelators. For example,
reduction of the baseline and metal ion-stimulated autoxidation of
Phenylephrine was observed at chelator concentrations of between 1
.mu.g/ml and 10 .mu.g/ml as is shown in more detail below.
Therefore, metal ion chelators can be included at concentrations of
between 1 .mu.g/ml and 10 .mu.g/ml, or between 5 .mu.g/ml and 20
.mu.g/ml, or between 20 .mu.g/ml and 50 .mu.g/ml, or between 50
.mu.g/ml and 100 .mu.g/ml. The term "metal ion chelator" as used
herein refers to multi-dentate compounds that complex metal cations
and that have no other significant physiological role (e.g.,
metabolite) in a mammal. Therefore, EDTA is deemed a metal ion
chelator whereas citrate or tartrate are not deemed a metal
chelator.
[0047] For the purpose of improving the stability of aqueous
formulation of phenylephrine or hydrochloride salt thereof, which
are susceptible to oxidation, the action of the oxygen can be
reduced or even prevented by eliminating or neutralizing oxygen.
Optional inert gas sparging (by bubbling/purging the solution with
nitrogen and/or any other inert gas such as argon, helium, freons,
xenon) can be carried out during any of the manufacturing steps. In
one example, an aqueous solution was purged with an inert gas under
the reduced pressure. The injectable solutions of the inventive
subject matter may have a particularly low content of oxygen
dissolved in the solvent water, typically less than 4 ppm less, or
than 2 ppm, or more preferably less than 1 ppm. A chelating agent
can be dissolved in the solution for injection, followed by
addition of sodium chloride. As will be readily appreciated,
further modifications in the generalized process can be made as
known to the person skilled in the art.
[0048] In yet further contemplated aspects, it should be
appreciated that desirable stability can be achieved with
contemplated compositions in the absence of a chelator and/or an
antioxidant. Such is particularly beneficial where chelators would
have an otherwise undesirable effect and/or where side effects for
antioxidants should be reduced or avoided. Thus, and viewed from a
different perspective, contemplated compositions can be prepared
without addition of EDTA and/or sulfites.
[0049] With respect to sterilization it is noted that the bulk
solutions can be filtered through a 0.22 micron filter, and filled
into a polyethylene, polypropylene or low-density polyethylene
containers in a blow-fill-seal process. BFS is a form of advanced
aseptic manufacturing wherein the container is formed, filled, and
sealed in one continuous, automated system not requiring human
intervention. The process begins with the extrusion of plastic
granules in the form of a hot hollow pipe of molten plastic called
a parison. The next step is the blow molding of the container with
an open top through which the container is filled--all while the
plastic remains hot and in a molten state. Once filled, the
container is hermetically sealed and cooled. The blow-fill seal
process can take several seconds, and contemplated
ready-to-administer compositions advantageously are formulated to
withstand the temperature and pressure requirements without
substantial degradation of phenylephrine (e.g., less than 10 wt %,
less than 5 wt %, less than 2 wt %, less than 1 wt %, less than 0.7
wt %, less than 0.6 wt %, less than 0.5 wt %, less than 0.4 wt %,
less than 0.3 wt %, less than 0.2 wt %, less than 0.1 wt %
degradation) over long term storage (e.g., at least 1 month, at
least 2 months, at least 3 months, at least 6 months, at least 9
months, at least 12 months, at least 18 months). Under the
conditions tested, the assays indicated that if water for
injections contained between 0.1 to 8.4 ppm of dissolved oxygen
preferably less than 5 ppm, preferably less than 2 ppm, preferably
less than 1 ppm, and the residual oxygen content into the primary
packaging was between 0.01 to 20%, preferably less than 10%,
preferably less than 5%, preferably less than 1%, such conditions
assisted in improving the stability of phenylephrine hydrochloride.
Thus, reduction of dissolved oxygen with inert gas as described
above is deemed suitable for such processes as well.
[0050] Once the phenylephrine formulations are filled in large
volume polymeric, semi-permeable infusion containers manufactured
via BFS technology and or flexible IV bags, the containers can
optionally be layered or covered with a secondary packaging system
including an aluminum pouch and/or other oxygen scavenger. For
example, the BFS containers can further be sealed in an oxygen and
moisture barrier blister packaging. The blister packaging can
comprise one or more layers, and the one or more layers can include
aluminum foil or other oxygen absorber having an oxygen
transmission rate (OTR) between 0.0005 to 5.00 cc/100 in.sup.2/24
hrs. Additionally or alternatively, one or more oxygen absorbers
(metal or metal free, organic material) can be incorporated into
any portion of the BFS container, the secondary packaging system,
or between the two (e.g., between the BFS container and the
multi-layer packaging) such that the oxygen absorber removes at
least a portion of oxygen from the air surrounding said
oxygen-sensitive drug.
[0051] It should further be appreciated that contemplated
formulations will be sterilized, and all known manners of
sterilization are deemed suitable for use herein, including
filtration through a 0.22 micron filter, heat sterilization,
radiation (e.g., gamma, electron beam, microwave), and/or ethylene
oxide sterilization to render the formulations sterile.
[0052] The optimum therapeutically effective amount of a drug is
the amount of the drug in the composition that will yield the most
effective results in terms of efficacy of treatment in a given
subject. This amount can vary depending upon a variety of factors,
including but not limited to the physiological condition of the
subject (including age, sex, disease type and stage, general
physical condition, responsiveness to a given dosage, and type of
medication), the nature of the pharmaceutically acceptable carrier
or carriers in the formulation, and the route of administration.
One skilled in the clinical and pharmacological arts will be able
to determine a therapeutically effective amount through routine
experimentation, for instance, by monitoring a subject's response
to administration of a compound and adjusting the dosage
accordingly. For additional guidance, see Remington: The Science
and Practice of Pharmacy (Gennaro ed. 20th edition, Williams &
Wilkins Pa., USA) (2000). Moreover, and depending on the particular
purpose, it should also be recognized that contemplated
compositions may be combined (in vivo, or in a therapeutic
formulation or administration regimen) with at least one other
therapeutically active agent to additively or synergistically
provide a therapeutic or prophylactic effect.
[0053] In further contemplated aspects, it should be appreciated
that the phenylephrine formulations presented herein can be
prepared in a variety of methods, and all manners of production are
deemed suitable for use herein. For example, in one embodiment as
also schematically depicted in FIG. 5, water for injection is used
as the carrier and is admixed with a desired quantity of EDTA until
completely dissolved, to which then sodium chloride as tonicity
agent is added. Once the sodium chloride is completely dissolved,
acetic acid is added in a desired amount and allowed to completely
dissolve after which phenylephrine hydrochloride is compounded into
the so prepared solution. The pH is then adjusted to pH 5.0 +/-0.2
using pH adjusting agents such as hydrochloric acid or sodium
hydroxide and the so prepared solution is brought to the desired
final volume using water for injection. Upon final pH correction,
the solution is filtered through a 0.22 micron filter and filled
into suitable containers such as polymeric (e.g., polypropylene)
flexible bags at a desired volume (e.g., 250 mL). The bags are then
sealed and placed into a metallized overwrap as secondary
container. Preferably, an oxygen scavenger is included into the
space between the metallized overwrap and the inner container, the
space is optionally flushed with an inert gas, and once the
overwrap is sealed, the sealed bags are subjected to terminal
sterilization using an autoclaving process. Sterilization can also
be performed using processes other than autoclaving such as gamma
irradiation e-beam sterilization, etc. However, autoclaving is
typically preferred.
EXAMPLES
[0054] The following examples are provided for illustrative
purposes only and should not be interpreted as limiting the present
invention. Unless noted otherwise, all quantities indicated in %
are weight percent following the general analytical protocol as
indicated below.
[0055] Analytical protocol: phenylephrine hydrochloride (PEP) assay
is performed using an isocratic reversed-phase HPLC-UV method.
Biphenyl-modified core-shell silica particles are used as a
stationary phase for chromatographic analysis using Kinetex.RTM.
2.6 .mu.m Biphenyl LC Column, 4.6.times.50 mm, 2.6 .mu.m. The
mobile phase is a methanol-water mixture containing .about.0.1%
o-phosphoric acid (3:97 v/v Methanol). Quantitation of PEP is
accomplished by comparing corresponding peak areas from the sample
solution chromatogram and the Phenylephrine Hydrochloride Reference
Standard (RS) solution.
[0056] Related substances: Determination of PEP related compounds
is performed using a linear-gradient reversed-phase HPLC-UV method.
Biphenyl-modified core-shell silica particles are used as
stationary phase for chromatographic analysis using Kinetex.RTM.
Biphenyl LC Column, 4.6.times.150 mm, 2.6 .mu.m. The mobile phase
is prepared by online mixing of water with methanol with both
solvents containing orthophosphoric acid. Related compounds are
defined by their relative retention times (RRT). Quantitation of
the related compounds is accomplished by comparing the
corresponding peak areas from the Sample Solution chromatogram to
the PEP peak area from the Phenylephrine Hydrochloride Reference
Standard (RS) solution chromatogram. Relative response factors are
used to correct for chemical structure effects on chromatographic
responses.
[0057] As already mentioned above, the ionization behavior of
phenylephrine and salts thereof in aqueous solution is fairly
complex, with pKa values of about 9.07, 9.69 and greater than 14.
These values correspond to ionization of the first phenolic group,
amine group, and the benzylic hydroxyl group, respectively. In view
of these data, it is therefore contemplated that pH values of less
than 6.0 should be employed to prevent phenylephrine cyclization
reaction. To that end and to verify pH ranges of between pH 5.0 and
6.0, the stability of exemplary phenylephrine HCl solution at 160
mcg/mL was tested at two different pH values, pH 5.0 and 6.0.
[0058] To determine the optimum pH, a pH-dependent stability study
was conducted only at accelerated condition of 80.degree. C.
Phenylephrine hydrochloride solution, 400 mcg/mL was screened at
five different pH conditions: 4.0, 4.5, 5.0, 5.5 and 6.0, and the
compositions are shown in Table 2. Drug product was filled in 100
mL IV bags and terminally sterilized at 121.degree. C. for 15
minutes. The IV bag was overwrapped with an aluminum overwrap with
an oxygen scavenger. The initial time point was analyzed prior to
and post terminal sterilization. Result are presented in Tables
3-7. The total impurities observed were lowest at pH 4.0 after 3
weeks at 80 C, 10-15% lower than at pH 4.5. There was no
significant difference between the data at pH 4.5 and 5.0. Higher
levels of total impurities were observed at pH 5.5 and 6.0. Since
the product will be administered without dilution by intravenous
route, though pH 4.0 formulation showed 10-15% less total
impurities, pH 5.0 was selected to avoid any tolerability
issues.
TABLE-US-00002 TABLE 2 Table 2: Composition of Phenylephrine
Hydrochloride Solution, 400 mcg/mL at different pH conditions
Quantity (mg/mL) Ingredient Lot # 12136-A Lot # 12136-B Lot #
12136-C Lot # 12136-D Lot # 12136-E Phenylephrine HCl 0.4 0.4 0.4
0.4 0.4 EDTA 0.01 0.01 0.01 0.01 0.01 Citric Acid 1.05 1.05 1.05
1.05 1.05 Sodium Chloride 8.45 8.45 8.45 8.45 8.45 10N NaOH/6N HCl
q.s. to pH 4.0 q.s. to pH 4.5 q.s. to pH 5.0 q.s. to pH 5.5 q.s. to
pH 6.0 Water q.s. to 1.0 mL q.s. to 1.0 mL q.s. to 1.0 mL q.s. to
1.0 mL q.s. to 1.0 mL
TABLE-US-00003 TABLE 3 Table 3: Stability of Phenylephrine
Hydrochloride Solution, 400 mcg/mL at pH 4.0 in citrate buffer.
Storage Condition T0 T0 80.degree. C. Time Point
(Pre-Sterilization) (Autoclaved) 3 days (Autoclaved) 3 weeks
(Autoclaved) Appearance CCS CCS CCS CCS pH 4.02 3.96 3.97 4.04
Assay (%) 101.2 101.7 101.5 102.8 Related Unknown.sub.(RRT) NR NR
NR.sub.(0.70) 0.29.sub.(0.66) Compounds (%) 0.05.sub.(0.73)
0.19.sub.(0.70) 0.07.sub.(2.63) 0.15.sub.(1.55) 0.07.sub.(2.25)
0.05.sub.(1.69) 0.06.sub.(1.80) NR.sub.(1.85) 0.11.sub.(2.21) Total
Impurities NR NR 0.19 0.85 (%) CCS--Clear colorless solution;
NR--Not Reported (<0.05%)
TABLE-US-00004 TABLE 4 Table 4: Stability of Phenylephrine
Hydrochloride Solution, 400 mcg/mL at pH 4.5 in citrate buffer.
Storage Condition T0 T0 80.degree. C. Time Point
(Pre-Sterilization) (Autoclave) 3 days 3 weeks Appearance CCS CCS
CCS CCS pH 4.52 4.44 4.46 4.54 Assay (%) 101.8 102.5 101.4 101.7
Related Unknown.sub.(RRT) NR NR NR 0.27.sub.(0.66) Compounds (%)
0.26.sub.(0.70) 0.14.sub.(1.55) 0.05.sub.(1.69) 0.08.sub.(1.80)
0.06.sub.(1.85) NR.sub.(1.90) 0.14.sub.(2.21) Total Impurities NR
NR NR 1.00 (%) CCS--Clear colorless solution; NR--Not Reported
(<0.05%)
TABLE-US-00005 TABLE 5 Table 5: Stability of Phenylephrine
Hydrochloride Solution, 400 mcg/mL at pH 5.0 in citrate buffer.
Storage Condition T0 T0 80.degree. C. Time Point
(Pre-Sterilization) (Autoclave) 3 days 3 weeks Appearance CCS CCS
CCS CCS pH 5.01 4.98 4.98 4.98 Assay (%) 102.2 101.5 100.7 102.8
Related Unknown.sub.(RRT) NR NR NR 0.28.sub.(0.66) Compounds
0.27.sub.(0.70) (%) 0.10.sub.(1.55) NR.sub.(1.60) 0.06.sub.(1.69)
0.07.sub.(1.80) 0.05.sub.(1.85) 0.11.sub.(2.21) Total Impurities NR
NR NR 0.94 (%) CCS--Clear colorless solution; NR--Not Reported
(<0.05%)
TABLE-US-00006 TABLE 6 Table 6: Stability of Phenylephrine
Hydrochloride Solution, 400 mcg/mL at pH 5.5 in citrate buffer.
Storage Condition T0 T0 80.degree. C. Time Point
(Pre-Sterilization) (Autoclave) 3 days 3 weeks Appearance CCS CCS
CCS CCS pH 5.55 5.47 5.46 5.53 Assay (%) 101.6 101.5 101.8 102.8
Related Unknown.sub.(RRT) NR NR NR 0.49.sub.(0.66) Compounds (%)
0.24.sub.(0.70) 0.08.sub.(1.55) 0.05.sub.(1.60) 0.07.sub.(1.69)
0.08.sub.(1.80) 0.05.sub.(1.85) 0.12.sub.(2.21) NR.sub.(2.90)
0.06.sub.(3.20) 0.05.sub.(4.13) Total Impurities (%) NR NR NR 1.29
CCS--Clear colorless solution; NR--Not Reported (<0.05%)
TABLE-US-00007 TABLE 7 Table 7: Stability of Phenylephrine
Hydrochloride Solution, 400 mcg/mL at pH 6.0 in citrate buffer.
Storage Condition T0 T0 80.degree. C. Time Point
(Pre-Sterilization) (Autoclave) 3 days 3 weeks Appearance CCS CCS
CCS CCS pH 5.99 5.97 5.97 6.00 Assay (%) 101.4 100.9 100.4 102.7
Related Unknown (RRT) NR NR NR.sub.(1.73) 0.50.sub.(0.66) Compounds
(%) NR.sub.(1.80) 0.12.sub.(0.70) 0.19.sub.(1.94) NR.sub.(1.60)
0.07.sub.(1.69) 0.08.sub.(1.80) 0.05.sub.(1.85) 0.39.sub.(1.90)
0.12.sub.(2.21) 0.21.sub.(2.90) 0.09.sub.(3.20) NR.sub.(4.13) Total
Impurities NR NR 0.19 1.63 (%) CCS--Clear colorless solution;
NR--Not Reported (<0.05%)
[0059] Selection of buffering agent: Based on the pH screening
study, a pH of 5.0 was selected as the target pH. Since
phenylephrine hydrochloride does not have a pKa within one unit of
pH 5.0, a buffering agent was necessary to maintain the pH of the
drug product over the shelf-life.
[0060] A buffering agent is a weak acid or base used to maintain
the pH of a solution near a chosen value after the addition of
another acid or base. That is, the function of a buffering agent is
to prevent a rapid change in pH when acids or bases are added to
the solution. Buffer concentration and buffer selection play an
important role in maintaining the pH of the product. It is
generally advised to choose a buffering agent whose pKa is close to
the pH of the product. Citric acid (pKa--3.1, 4.7, and 6.4),
tartaric acid (pKa--2.98, 4.34) and acetic acid (pKa--4.76) were
chosen as buffering agents for the stability study.
[0061] Stability of Phenylephrine hydrochloride solution, 400
mcg/mL was tested in 5 mM citrate acid, acetic acid and tartaric
acid at two different conditions (60.degree. C. and 80.degree.).
The composition for the study is presented in Table 8. The drug
product was filled in 100 mL IV bags and sterilized at 121.degree.
C. for 15 minutes. Bags were overwrapped with an aluminum overwrap
with an oxygen scavenger. Samples were tested for appearance, pH,
color change, assay, and related substances at different time
points. Based on the data, it was observed that the degradation of
Phenylephrine hydrochloride was the least in acetic acid followed
by citric acid and tartaric acid at 60.degree. C. at 3 weeks.
Hence, acetic was chosen as the primary buffer and citric acid was
chosen as a back-up buffer to in the next study to determine effect
of buffer concentration. Exemplary results are presented in Tables
9-11.
TABLE-US-00008 TABLE 8 Table 8: Composition of Phenylephrine
Hydrochloride Solution, 400 mcg/mL with different buffers Quantity
(mg/mL) Lot # 12206 Lot # 12207 Lot # 12208 Ingredient (5 mM
Citrate buffer) (5 mM Acetate buffer) (5 mM Tartrate buffer)
Phenylephrine HCl 0.4 0.4 0.4 Acetic Acid -- 0.3 -- Citric Acid
1.05 -- -- Tartaric Acid -- -- 0.75 Sodium Chloride 8.55 8.3 8.17
10N NaOH/6N HCl q.s. to pH 5.0 q.s. to pH 5.0 q.s. to pH 5.0 Water
q.s. to 1.0 mL q.s. to 1.0 mL q.s. to 1.0 mL
TABLE-US-00009 TABLE 9 Table 9: Stability of Phenylephrine
Hydrochloride Solution, 400 mcg/mL in 5 mM Citrate buffer at pH
5.0. Storage Condition 60.degree. C. 80.degree. C. Time Point
Initial Day 4 1 week 3 week Day 4 1 week 3 week Appearance CCS CCS
CCS CCS CCS CCS CCS pH 5.01 5.00 4.99 4.96 5.01 4.99 4.97 Assay (%)
99.2 98.8 99.0 98.8 99.1 98.7 100.1 Impurity C NR NR NR 0.11 NR NR
0.10 Impurity E NR NR NR NR NR NR 0.16 Impurity F NR NR NR 0.06 NR
NR NR Related Unknown.sub.(RRT) NR.sub.(0.61) NR.sub.(0.61)
NR.sub.(1.80) NR.sub.(0.90) NR.sub.(0.70) NR.sub.(1.69) .sup.
0.32.sub.(0.70) Compounds .sup. 0.09.sub.(0.70) NR.sub.(0.70) .sup.
0.05.sub.(0.70) .sup. 0.23.sub.(1.16) .sup. 0.07.sub.(4.13)
NR.sub.(1.80) .sup. 0.1.sub.(1.55) (%) NR.sub.(1.69) .sup.
0.09.sub.(4.13) NR.sub.(1.23) NR.sub.(1.85) .sup. 0.18.sub.(1.60)
NR.sub.(1.80) .sup. 0.28.sub.(1.60) .sup. 0.14.sub.(0.70)
NR.sub.(1.69) .sup. 0.07.sub.(2.21) NR.sub.(1.69) .sup.
0.06.sub.(2.21) .sup. 0.06.sub.(1.83) .sup. 0.07.sub.(4.13)
NR.sub.(1.83) NR.sub.(1.85) NR.sub.(1.85) .sup. 0.07.sub.(2.21)
NR.sub.(1.90) .sup. 0.05.sub.(4.13) .sup. 0.16.sub.(2.21) .sup.
0.05.sub.(2.53) Total 0.23 0.09 0.05 0.89 0.07 0.20 1.04 Impurities
(%) CCS--Clear colorless solution; NR--Not Reported (<0.05%)
TABLE-US-00010 TABLE 10 Table 10: Stability of Phenylephrine
Hydrochloride Solution, 400 mcg/mL in 5 mM acetate buffer at pH
5.0. Storage Condition 60.degree. C. 80.degree. C. Time Point
Initial Day 4 1 week 3 week Day 4 1 week 3 week Appearance CCS CCS
CCS CCS CCS CCS CCS pH 5.02 5.02 4.99 4.98 5.04 5.00 5.00 Assay (%)
101.5 99.7 101.5 101.8 100.5 100.8 102.8 Impurity C NR NR NR 0.12
NR NR 0.13 Impurity E NR NR NR NR NR NR 0.12 Related
Unknown.sub.(RRT) NR NR NR.sub.(2.21) NR.sub.(0.90, 1.22; 1.55)
NR.sub.(2.21,) NR.sub.(1.55) .sup. 0.10.sub.(1.16) Compounds .sup.
0.09.sub.(4.13) .sup. 0.08.sub.(1.60) NR.sub.(2.76) NR.sub.(1.69)
.sup. 0.17.sub.(1.60) (%) .sup. 0.12.sub.(1.73) .sup.
0.05.sub.(4.13) NR.sub.(1.80) NR.sub.(1.69, 1.83) NR.sub.(1.83)
NR.sub.(1.85) .sup. 0.05.sub.(1.85) NR.sub.(1.85) .sup.
0.07.sub.(2.21) NR.sub.(1.90) .sup. 0.09.sub.(2.21) .sup.
0.23.sub.(2.21) NR.sub.(2.76) .sup. 0.1.sub.(3.20) NR.sub.(4.13)
Total (%) NR NR 0.09 0.41 0.05 0.07 0.90 CCS--Clear colorless
solution; NR--Not Reported (<0.05%)
TABLE-US-00011 TABLE 11 Table 11: Stability of Phenylephrine
Hydrochloride Solution, 400 mcg/mL in 5 mM tartrate buffer at pH
5.0. Storage Condition 60.degree. C. 80.degree. C. Time Point
Initial Day 4 1 week 3 week Day 4 1 week 3 week Appearance CCS CCS
CCS CCS CCS CCS CCS pH 5.02 5.02 5.03 5.03 5.08 5.04 5.02 Assay (%)
98.9 NT 98.7 99.1 98.3 98.8 99.1 Impurity C NR NT NR 0.15 NR NR
0.08 Impurity D NR NT NR 0.08 NR NR NR Impurity E NR NT NR NR 0.05
NR NR Related Unknown.sub.(RRT) NR NT NR .sup. 0.22.sub.(0.70)
NR.sub.(1.73) .sup. 0.05.sub.(1.60) .sup. 0.10.sub.(1.16) Compounds
.sup. 0.19.sub.(1.55) NR.sub.(1.80) NR.sub.(1.69) .sup.
0.06.sub.(1.23) (%) NR.sub.(1.80) NR.sub.(1.88) NR.sub.(1.80)
NR.sub.(1.55) .sup. 0.12.sub.(1.85) .sup. 0.10.sub.(2.21)
NR.sub.(1.85) NR.sub.(1.60) .sup. 0.11.sub.(2.21) .sup.
0.10.sub.(2.53) .sup. 0.08.sub.(2.21) .sup. 0.07.sub.(1.69) .sup.
0.19.sub.(2.25) NR.sub.(2.76) NR.sub.(2.53) .sup. 0.05.sub.(1.83)
NR.sub.(3.20) .sup. 0.12.sub.(2.21) NR.sub.(3.38) .sup.
0.06.sub.(3.20) .sup. 0.10.sub.(4.13) Total (%) NR NT NR 1.16 0.25
0.13 0.62 CCS--Clear colorless solution; NR--Not Reported
(<0.05%), NT--Not Tested
[0062] Buffer Concentration: Stability of phenylephrine
hydrochloride was determined at 1 mM and 2 mM citrate buffer and
compared to stability of 5 mM acetate buffer. Stability of
phenylephrine hydrochloride solution was bracketed at 40 mcg/mL and
400 mcg/mL. The formulation compositions for the study are shown in
Table 12. Drug product was filled in 100 mL IV bag and terminally
sterilized at 121.degree. C. for 15 minutes. The sterilized bag was
then encased in an aluminum overwrap with an oxygen scavenger.
Stability testing was carried out at 25.degree. C./60% RH and
40.degree. C./75% RH. The samples were tested for appearance, pH,
dissolved oxygen, color change, assay and related substances at
different time points. Based on the results, it was observed that
phenylephrine hydrochloride was more stable in 5 mM acetic acid
than in 1 mM and 2 mM citric acid at the same pH as can be seen
from the results in Tables 13-18.
TABLE-US-00012 TABLE 12 Table 12: Compositions of Phenylephrine
Hydrochloride Solution, 40 mcg/mL and 400 mcg/mL in acetate and
citrate buffer. Quantity (mg/mL) 5 mM Acetate Buffer 1 mM Citrate 2
mM Citrate Ingredients Lot # 12323 Lot # 12322 Lot # 12457 Lot #
12382 Lot # 12458 Lot # 12381 Phenylephrine HCl 0.04 0.4 0.04 0.4
0.04 0.4 Glacial acetic acid 0.3 0.3 -- -- -- -- Citric acid -- --
0.21 0.21 0.42 0.42 Sodium Chloride 8.46 8.30 8.73 8.57 8.70 8.54
10N NaOH/6N HCl q.s to pH 5.0 q.s to pH 5.0 q.s to pH 5.0 q.s to pH
5.0 q.s to pH 5.0 q.s to pH 5.0 Water q.s. 1.0 mL q.s. 1.0 mL q.s.
1.0 mL q.s. 1.0 mL q.s. 1.0 mL q.s. 1.0 mL
TABLE-US-00013 TABLE 13 Table 13: Stability of Phenylephrine
Hydrochloride Solution, 40 mcg/mL in 5 mM acetate buffer at pH 5.0.
Storage Condition 25.degree. C. .+-. 2.degree. C./60% RH .+-. 5% RH
40 .+-. 2.degree. C./75 .+-. 5% RH Time Point Initial 1 M 2 M 3 M 6
M 1 M 2 M 3 M 6 M Appearance CCS CCS CCS CCS CCS CCS CCS CCS CCS
Assay (%) 100.4 100.5 101.5 102.4 101.3 100.6 101.5 102.9 101.9
Dissolved oxygen NT 1.24 1.53 1.84 1.21 1.50 0.89 1.72 2.15 (ppm)
pH NT 5.00 5.00 5.04 5.01 5.03 5.00 5.04 5.08 Impurity C* NR NR NR
NR NR NR NR NR 0.07 Impurity F** NR 0.09 NR 0.1 0.12 0.11 NR 0.06
0.08 Related Unknown.sub.(RRT) NR .sup. 0.06.sub.(1.45) .sup.
0.07.sub.(0.73) .sup. 0.06.sub.(1.53) NR .sup. 0.06.sub.(1.45) NR
NR.sub.(1.70) .sup. 0.06.sub.(1.70) Substance NR.sub.(2.00)
NR.sub.(3.16) NR.sub.(1.60) NR.sub.(1.86) .sup. 0.06.sub.(1.9) (%)
NR.sub.(2.60) .sup. 0.06.sub.(2.40) NR.sub.(1.95) .sup.
0.36.sub.(2.42) NR.sub.(2.84) .sup. 0.07.sub.(2.64) NR.sub.(2.0)
.sup. 0.07.sub.(2.82) NR.sub.(3.60) NR.sub.(1.53) .sup.
0.10.sub.(3.58) Total (%) NR 0.15 0.07 0.16 0.12 0.30 NR 0.07 0.34
*Impurity F - 2-Methyl-1,2,3,4-tetrahydroisoquinoline-4,8-diol;
**Impurity C- 1-(3-Hydroxyphenyl)-2-(methylamino)ethan-1-one
hydrochloride (Phenylephrone - phenylephrine related compound);
CCS--Clear colorless solution; NR--Not Reported (<0.05%);
NT--Not tested
TABLE-US-00014 TABLE 14 Table 14: Stability of Phenylephrine
Hydrochloride Solution, 400 mcg/mL in 5 mM acetate buffer at pH
5.0. Storage Condition 25.degree. C. .+-. 2.degree. C./60% RH .+-.
5% RH 40 .+-. 2.degree. C./75 .+-. 5% RH Time Point Initial 1 M 2 M
3 M 6 M 1 M 2 M 3 M 6 M Appearance CCS CCS CCS CCS CCS CCS CCS CCS
CCS Assay (%) 99.5 101.2 100.4 102.8 101.0 100.9 100.6 102.2 100.6
Dissolved oxygen (ppm) N/A 0.98 1.05 1.76 1.46 1.18 1.03 1.83 1.77
pH N/A 5.03 5.05 5.06 4.99 5.05 5.05 5.05 5.01 Impurity F* NR NR NR
NR NR NR NR NR NR Related Unknown.sub.(RRT) NR NR NR NR NR NR NR
NR.sub.(1.86) NR Substance NR.sub.(2.0) (%) NR.sub.(3.0) Total (%)
NR NR NR NR NR NR NR NR NR *Impurity
F-2-Methyl-1,2,3,4-tetrahydroisoquinoline-4, 8-diol; CCS--Clear
colorless solution; NR--Not Reported (<0.05%).
TABLE-US-00015 TABLE 15 Table 15: Stability of Phenylephrine
Hydrochloride Solution, 40 mcg/mL in 1 mM citrate buffer at pH 5.0.
Storage Condition 25.degree. C. .+-. 2.degree. C./60% RH .+-. 5% RH
40 .+-. 2.degree. C./75 .+-. 5% RH Time Point Initial 1 Month 2
Month 3 Month 6 Month 1 Month 2 Month 3 Month 6 Month Appearance
CCS CCS CCS CCS CCS CCS CCS CCS CCS Assay (%) 100.4 100.1 100.9
100.8 102.5 100.1 100.9 101.0 102.5 Dissolved oxygen (ppm) NT 1.5
1.38 1.68 1.58 1.24 2.81 1.18 1.41 pH NT 5.01 5.02 5.02 5.08 5.04
5.01 5.01 5.1 Impurity F NR NR NR NR 0.26 0.14 NR NR 0.28 Impurity
C NR NR NR NR 0.19 NR NR NR 0.2 Impurity G NR NR NR NR 0.07 NR NR
NR 0.07 Related Unknown.sub.(RRT) NR .sup. 0.05.sub.(0.73) NR
NR.sub.(1.60) NR .sup. 0.11.sub.(0.60) NR .sup. 0.17.sub.(2.60)
.sup. 0.29.sub.(9.18) Compounds NR.sub.(2.68) NR.sub.(0.80) .sup.
0.21.sub.(1.60) (%) .sup. 0.05.sub.(1.75) .sup. 0.25.sub.(1.75)
.sup. 0.05.sub.(2.68) NR.sub.(2.68) NR.sub.(1.85) NR.sub.(2.0)
NR.sub.(2.1) NR.sub.(2.85) Total (%) NR 0.05 NR NR 0.8 0.30 NR 0.63
NR CCS--Clear colorless solution; NR--Not Reported (0.05%), NT--Not
Tested
TABLE-US-00016 TABLE 16 Table 16: Stability of Phenylephrine
Hydrochloride Solution, 400 mcg/mL in 1 mM citrate buffer at pH
5.0. Storage Condition 25.degree. C. .+-. 2.degree. C./60% RH .+-.
5% RH 40 .+-. 2.degree. C./75 .+-. 5% RH Time Point Initial 1 Month
2 Month 3 Month 6 Month 1 Month 2 Month 3 Month 6 Month Appearance
CCS CCS CCS CCS CCS CCS CCS CCS CCS Assay (%) 100.6 99.6 100.7
101.5 100.0 100.0 101.5 102.8 102.7 Dissolved oxygen NT 1.34 2.00
2.18 7.06 1.79 1.28 1.7 1.09 (ppm) pH NT 5.05 4.98 5.03 4.95 5.05
4.99 5.03 4.96 Impurity F NR NR NR NR 0.06 NR NR NR NR Impurity C
NR NR NR NR 0.07 NR NR NR NR Impurity G NR NR NR NR 0.08 NR NR NR
NR Related Unknown.sub.(RRT) NR NR NR NR .sup. 0.32.sub.(0.49) NR
NR NR.sub.(1.70) NR Compounds .sup. 0.12.sub.(0.78) NR.sub.(1.86)
(%) .sup. 0.35.sub.(1.78) NR.sub.(1.95) .sup. 0.06.sub.(1.96)
NR.sub.(2.0) .sup. 0.09.sub.(2.82) .sup. 0.03.sub.(3.57) Total (%)
NR NR NR NR 0.97 NR NR NR NR CCS--Clear colorless solution; NR--Not
Reported (<0.05%), NT--Not Tested
TABLE-US-00017 TABLE 17 Table 17: Stability of Phenylephrine
Hydrochloride Solution, 40 mcg/mL in 2 mM citrate buffer at pH 5.0.
Storage Condition 25.degree. C. .+-. 2.degree. C./ 40 .+-.
2.degree. C./ 60% RH .+-. 5% RH 75 .+-. 5% RH 1 2 3 6 1 2 3 6 Time
Point Initial Month Month Month Month Month Month Month Month
Appearance CCS CCS CCS CCS CCS CCS CCS CCS CCS Assay (%) 100.2
100.2 100.9 101.0 102.4 100.0 101.0 101.4 101.8 Dissolved oxygen NT
1.18 4.97 1.67 4.96 0.98 4.95 1.62 2.25 (ppm) pH NT 4.99 1.75 4.98
1.52 5.00 1.9 4.98 5.07 Impurity F 0.10 NR NR NR 0.12 0.11 NR NR
0.08 Impurity C NR NR NR NR 0.10 NR NR NR 0.07 Impurity G NR NR NR
NR NR NR NR NR 0.03 Related Unknown.sub.(RRT) .sup. 0.07.sub.(0.70)
NR.sub.(0.73) NR .sup. 0.06.sub.(1.60) NR .sup. 0.11.sub.(1.60) NR
.sup. 0.15.sub.(2.6) .sup. 0.29.sub.(2.42) Compounds NR.sub.(0.73)
NR.sub.(3.0) .sup. 0.05.sub.(1.75) .sup. 0.05.sub.(0.73) .sup.
0.05.sub.(1.60) .sup. 0.07.sub.(2.82) (%) NR.sub.(1.45)
NR.sub.(2.60) NR.sub.(1.80) .sup. 0.05.sub.(1.75) .sup.
0.11.sub.(3.57) .sup. 0.07.sub.(3.60) NR.sub.(2.68) .sup.
0.05.sub.(2.68) NR.sub.(1.80) .sup. 0.28.sub.(9.18) NR.sub.(3.0)
NR.sub.(2.68) NR.sub.(1.7) Total (%) 0.24 NR NR 0.11 0.22 0.32 NR
0.25 0.68 CCS--Clear colorless solution; NR--Not Reported
(<0.05%), NT--Not Tested
TABLE-US-00018 TABLE 18 Table 18: Stability of Phenylephrine
Hydrochloride Solution, 400 mcg/mL in 2 mM citrate buffer at pH
5.0. Storage Condition 25.degree. C. .+-. 2.degree. C./ 40 .+-.
2.degree. C./ 60% RH .+-. 5% RH 75 .+-. 5% RH 1 2 3 6 1 2 3 6 Time
Point Initial Month Month Month Month Month Month Month Month
Appearance CCS CCS CCS CCS CCS CCS CCS CCS CCS Assay (%) 100.9
100.8 101.2 101.9 102.4 100.7 102.2 102.0 101.6 Dissolved oxygen NT
1.35 2.04 2.51 1.67 1.48 1.84 1.92 1.09 (ppm) pH NT 5.08 4.98 5.04
4.95 5.06 4.99 5.05 4.97 Impurity F NR NR NR NR NR NR NR NR NR
Related Unknown.sub.(RRT) NR NR.sub.(3.44) NR NR NR NR NR
NR.sub.(1.86) NR Compounds NR.sub.(1.95) (%) Total NR NR NR NR NR
NR NR NR NR Impurities (%) CCS--Clear colorless solution; NR--Not
Reported (<0.05%), NT--Not Tested
[0063] The above studies to screen the types of buffer and their
optimum concentration were all conducted by filling the formulation
in 100 mL polypropylene bags from Technoflex. These polypropylene
bags were part of the primary packaging component of the product.
The filled bags (primary packaging) were further packaged into an
aluminum overwrap pouch with an oxygen scavenger (secondary
packaging). According to literature studies and data from initial
studies suggested that phenylephrine hydrochloride was
comparatively stable to oxidative degradation to its
sympathomimetic amine counterparts. Hence, a study was conducted to
evaluate the necessity of oxygen scavenger to product
stability.
[0064] Stability of Phenylephrine hydrochloride solution, 40 mcg/mL
and 400 mcg/mL were tested at 1 mM, 2 mM and 5 mM acetate buffer
with secondary aluminum overwrap without an oxygen scavenger. The
samples as shown in Table 19 were tested for appearance, pH, assay,
and related substances at different time points. Based on the
results shown in Tables 20-25, it was observed that the formulation
with 5 mM acetate buffer was more stable and had less degradation
compared to 1 mM and 2 mM acetate buffer.
TABLE-US-00019 TABLE 19 Table 19: Composition of Phenylephrine
Hydrochloride solution (40 mcg/mL and 400 mcg/mL) for secondary
packaging evaluation Quantity (mg/mL) 5 mM Acetate buffer 1 mM
Acetate buffer 2 mM Acetate buffer Ingredients Lot #12857 Lot
#12849 Lot #12943 Lot #12968 Lot #12944 Lot #12969 Phenylephrine
HCl 0.04 0.4 0.04 0.4 0.04 0.4 Glacial acetic acid 0.3 0.3 0.06
0.06 0.12 0.12 Sodium Chloride 8.46 8.46 8.73 8.3 8.46 8.3 10N
NaOH/6N HCl q.s to pH 5.0 q.s to pH 5.0 q.s to pH 5.0 q.s to pH 5.0
q.s to pH 5.0 q.s to pH 5.0 Water q.s. 1 mL q.s. 1 mL q.s. 1 mL
q.s. 1 mL q.s. 1 mL q.s. 1 mL
TABLE-US-00020 TABLE 20 Table 20: Stability of Phenylephrine
Hydrochloride solution, 40 mcg/mL in 5 mM acetate buffer with
aluminum overwrap. Time point 1 Month 3 Month 6 Month 40 .+-.
25.degree. C. .+-. 40 .+-. 25.degree. C. .+-. 40 .+-. 2.degree. C./
2.degree. C./ 2.degree. C./ 2.degree. C./ 2.degree. C./ 3 Weeks 75
.+-. 60% RH .+-. 75 .+-. 60% RH .+-. 75 .+-. Storage Condition
Initial 60.degree. C. 5% RH 5% RH 5% RH 5% RH 5% RH Appearance CCS
CCS CCS CCS CCS CCS CCS Assay (%) 100.4 102.2 100.8 101.7 101.4
101.4 101.0 pH 4.91 5.12 4.91 4.93 4.9 4.88 4.89 Impurity F NR NR
0.08 0.08 0.08 0.06 0.14 Impurity C NR NR NR 0.07 0.1 NR 0.09
Related Unknown.sub.(RRT) NR .sup. 0.05.sub.(1.45) .sup.
0.05.sub.(3.0) NR NR NR NR Substance .sup. 0.05.sub.(2.0) (%)
NR.sub.(3.0) Total (%) NR 0.05 0.13 0.15 0.18 0.06 0.23 CCS--Clear
colorless solution; NR--Not Reported (<0.05%), NT--Not
Tested
TABLE-US-00021 TABLE 21 Table 21: Stability of Phenylephrine
Hydrochloride solution, 400 mcg/mL in 5 mM acetate buffer with
aluminum overwrap. Time point 1 Month 3 Month 6 Month 40 .+-.
25.degree. C. .+-. 40 .+-. 25.degree. C. .+-. 40 .+-. 2.degree. C./
2.degree. C./ 2.degree. C./ 2.degree. C./ 2.degree. C./ 3 Weeks 75
.+-. 60% RH .+-. 75 .+-. 60% RH .+-. 75 .+-. Storage Condition
Initial 60.degree. C. 5% RH 5% RH 5% RH 5% RH 5% RH Appearance CCS
CCS CCS CCS CCS CCS CCS Assay (%) 99.1 102.2 99.7 102.5 101.5 100.2
99.2 pH 5.02 4.99 5.02 5.01 5.03 4.99 5.02 Impurity F NR NR NR NR
NR NR 0.09 Related Unknown.sub.(RRT) NR NR 0.08 .sup.
0.08.sub.(1.37) NR NR NR Substance (%) Total (%) NR NR 0.08 0.08 NR
NR 0.09 CCS--Clear colorless solution; NR--Not Reported
(<0.05%), NT--Not Tested.
TABLE-US-00022 TABLE 22 Table 22: Stability of Phenylephrine
Hydrochloride Solution, 40 mcg/mL in 1 mM acetate buffer with
aluminum overwrap. Storage Condition 40 .+-. 2.degree. C./
60.degree. C. 75 .+-. 5% RH 2 Weeks 1 Month 3 Month Time Point
Initial S NS N NS N NS N Appearance CCS CCS BCS BCS BCS BCS BCS BCS
Assay (%) 100.2 101.9 46.8 43.1 99.5 97.6 69.7 57.5 pH 4.9 4.9 4.68
4.88 4.87 4.86 4.75 4.7 IMP C NR NR 2.12 1.93 0.19 0.35 1.97 1.9
IMP F 0.05 0.08 5.05 4.61 0.28 0.54 2.74 2.87 IMP G NR NR 0.09 0.08
NR NR 0.06 0.08 IMP D NR NR 0.09 NR NR NR NR NR IMP A NR NR NR NR
NR NR 0.06 0.08 Related Unknown.sub.(RRT) 0.07 0.17 0.27 0.37 0.2
0.94 0.2 0.27 Substance (3.0) (9.181) (1.451) (1.451) (1.78) (1.78)
(0.488) (0.488) (%) 0.26 0.32 0.09 0.15 0.09 0.16 (1.597) (1.597)
(1.965) (1.965) (0.53) (0.53) 0.09 0.13 0.13 0.13 0.08 0.14 (1.654)
(1.654) (3.037) (3.037) (0.784) (0.784) 0.1 0.12 0.06 0.11 0.14
(3.588) (3.588) (3.076) (0.888) (0.888) 0.13 0.09 0.07 0.07 (5.67)
(3.719) (1.231) (1.192) 0.09 0.09 0.07 0.1 (5.828) (5.67) (1.376)
(1.231) 1.31 0.07 2.9 0.06 (6.426) (5.828) (1.78) (1.376) 0.56 2.1
1.07 0.06 (6.875) (6.426) (1.965) (1.704) 0.12 0.83 0.09 2.08
(7.007) (6.875) (2.021) (1.78) 0.31 0.13 0.12 1.18 (7.152) (7.007)
(2.059) (1.965) 0.08 0.49 0.06 0.18 (7.49) (7.152) (2.334) (2.021)
0.12 0.15 0.07 0.1 (7.771) (7.49) (2.347) (2.059) 0.16 0.14 0.08
0.09 (8.411) (7.771) (2.48) (2.347) 0.22 0.11 0.07 0.08 (9.181)
(7.982) (2.667) (2.48) 0.33 0.21 0.73 0.06 (9.959) (8.411) (2.825)
(2.625) 0.09 0.28 0.14 0.1 (10.525) (9.181) (3.037) (2.667) 0.1
0.41 0.11 1.33 (10.657) (9.959) (3.076) (2.825) 1.4 0.1 0.17 0.08
(11.736) (10.525) (IMP 9) (3.037) 0.1 0.22 (10.657) (3.076) 1.44
0.07 (11.736) (3.188) 0.3 (2.68) Total 0.12 0.25 13.11 14.27 0.88
2.17 11.08 11.77 Impurities (%) Storage Condition 25.degree. C.
.+-. 2.degree. C./ 60% RH .+-. 5% RH 1 Month 3 Month Time Point NS
N NS N Appearance CCS CCS CCS CCS Assay (%) 100.6 100.8 100.1 100.6
pH 4.89 4.9 4.87 4.87 IMP C 0.07 0.08 0.1 0.08 IMP F 0.11 0.12 0.16
0.14 IMP G NR NR NR NR IMP D NR NR NR NR IMP A NR NR NR NR Related
Unknown.sub.(RRT) 0.1 0.08 0.12 0.1 Substance (1.78) (1.78) (1.78)
(1.78) (%) 0.09 0.11 0.14 0.13 (3.037) (3.037) (3.037) (3.037) 0.06
(3.578) Total 0.37 0.46 0.51 0.45 Impurities (%) BCS: Brown colored
solution; CCS--Clear colorless solution; NR--Not Reported
(<0.05%), NT--Not Tested. S--Aluminum overwrap with GLS 100 MBC;
NS--Aluminum overwrap with no scavenger; N--No secondary
overwrap.
TABLE-US-00023 TABLE 23 Table 23: Stability of Phenylephrine
Hydrochloride Solution, (400 mcg/mL) in 1 mM acetate buffer with
aluminum overwrap. Storage Condition 40 .+-. 2.degree. C./
25.degree. C. .+-. 2.degree. C./ 60.degree. C. 75 .+-. 5% RH 60% RH
.+-. 5% RH 2 Weeks 1 Month 3 Month 1 Month 3 Month Time Point
Initial S NS N NS N NS N NS N NS N Appearance CCS CCS CCS CCS CCS
CCS CCS CCS CCS CCS CCS CCS Assay (%) 100.0 NT NT NT 100.4 102.1
95.7 99.2 102.5 101.7 102.0 104 pH 4.94 4.96 4.98 4.96 4.93 4.93
4.93 4.94 4.96 4.93 4.93 4.92 Related Unknown.sub.(RRT) NR NT NT NT
NR NR NR NR NR NR NR NR Substance Total (%) NR NR NR NR NR NR NR NR
NR NR NR NR (%) CCS--Clear colorless solution; NR--Not Reported
(<0.05%), NT--Not Tested. S--Aluminum overwrap with GLS 100 MBC;
NS--Aluminum overwrap with no scavenger; N--No secondary
overwrap
TABLE-US-00024 TABLE 24 Table 24: Stability of Phenylephrine
Hydrochloride Solution, 40 mcg/mL in 2 mM acetate buffer with
aluminum overwrap. Storage Condition 40 .+-. 2.degree. C./
60.degree. C. 75 .+-. 5% RH 2 Weeks 1 Month 3 Month Time Point
Initial S NS N NS N NS N Appearance CCS CCS CCS CCS CCS CCS CCS CCS
Assay (%) 100.4 98.8 100.8 103 100.3 100.6 97.7 97.3 pH 4.87 4.88
4.9 4.87 4.89 4.88 4.85 4.84 IMP C NR 0.63 0.11 0.14 0.15 0.13 0.34
0.38 IMP F NR 1.55 0.33 0.38 0.18 0.17 0.52 0.59 IMP G NR 0.09 NR
NR NR NR NR NR Related Unknown.sub.(RRT) NR .sup. 0.07.sub.(5.67)
.sup. 0.21.sub.(9.18) NR .sup. 0.07.sub.(1.78) .sup.
0.09.sub.(1.78) .sup. 0.24.sub.(1.78) .sup. 0.41.sub.(1.78)
Substance .sup. 0.3.sub.(7.49) .sup. 0.06.sub.(3.58) .sup.
0.14.sub.(1.97) .sup. 0.18.sub.(1.97) (%) .sup. 0.21.sub.(9.18)
.sup. 0.08.sub.(2.42) .sup. 0.12.sub.(2.83) .sup. 0.08.sub.(2.83)
Total NR 2.86 0.65 0.51 0.45 0.40 1.41 1.68 Impurities (%) Storage
Condition 25.degree. C. .+-. 2.degree. C./ 60% RH .+-. 5% RH 1
Month 3 Month Time Point NS N NS N Appearance CCS CCS CCS CCS Assay
(%) 100.9 101 100.5 100.9 pH 4.88 4.86 4.85 4.85 IMP C 0.08 0.06
0.08 0.07 IMP F 0.08 0.07 0.09 0.08 IMP G NR NR NR NR Related
Unknown.sub.(RRT) .sup. 0.06.sub.(3.578) NR .sup. 0.08.sub.(1.78)
.sup. 0.11.sub.(1.78) Substance (%) Total 0.21 0.13 0.24 0.27
Impurities (%) CCS--Clear colorless solution; NR--Not Reported
(0.05%), NT--Not Tested; S--Aluminum overwrap with GLS 100 MBC;
NS--Aluminum overwrap with no scavenger; N--No secondary
overwrap
TABLE-US-00025 TABLE 25 Table 25: Stability of Phenylephrine
Hydrochloride Solution, 400 mcg/mL in 2 mM acetate buffer with
aluminum overwrap Storage Condition 40 .+-. 2.degree. C./
60.degree. C. 75 .+-. 5% RH 2 Weeks 1 Month 3 Month Time Point
Initial S NS N NS N NS N Appearance CCS CCS BCS BCS BCS BCS BCS BCS
Assay (%) 99.5 NT NT NT 102.8 102.3 95.4 94.7 IMP C NR NT NT NT NR
NR 0.2 0.22 IMP F NR NT NT NT NR 0.08 0.34 0.34 IMP A NR NT NT NT
NR NR 0.06 0.07 pH 4.89 4.99 4.75 4.74 4.95 4.95 4.77 4.76 Related
Unknown.sub.(RRT) NR NT NT NT .sup. 0.08.sub.(1.78) .sup.
0.16.sub.(1.78) .sup. 0.12.sub.(0.488) .sup. 0.12.sub.(0.49)
Substance .sup. 0.21.sub.(1.78) .sup. 0.07.sub.(1.38) (%) .sup.
0.1.sub.(1.965) .sup. 0.24.sub.(1.78) .sup. 0.3.sub.(2.825) .sup.
0.09.sub.(1.97) .sup. 0.08.sub.(2.68) .sup. 0.32.sub.(2.83) .sup.
0.06.sub.(3.08) .sup. 0.1.sub.(2.68) Total NR NT NT NT 0.08 0.24
1.42 1.63 Impurities (%) Storage Condition 25.degree. C. .+-.
2.degree. C./ 60% RH .+-. 5% RH 1 Month 3 Month Time Point NS N NS
N Appearance CCS CCS CCS CCS Assay (%) 102.1 104.4 101.6 96.2 IMP C
NR NR NR NR IMP F NR NR NR NR IMP A NR NR NR NR pH 4.95 4.96 4.93
4.9 Related Unknown.sub.(RRT) NR .sup. 0.06.sub.(1.38) NR NR
Substance (%) Total NR 0.06 NR NR Impurities (%) BCS: Brown colored
solution; CCS--Clear colorless solution; NR--Not Reported
(<0.05%), NT--Not Tested; S--Aluminum overwrap with GLS 100 MBC;
NS--Aluminum overwrap with no scavenger; N--No secondary
overwrap
[0065] Selection of metal ion chelator: Citric acid, ascorbic acid,
tartaric acid and edetate disodium (EDTA) are commonly used
chelating agents for parenteral drug products. Citric acid or
ascorbic acid have very weak association constants compared to
EDTA. Addition of these acids to the formulation would also lead to
more acidic pH values. Thus, EDTA (0.01%) was screened during the
initial experiments as potential metal chelator to improve
stability of the solution. However, based on the results and
mechanism of degradation, it was determined that there was no need
of any chelating agents.
[0066] However, based on later performed stainless steel and bulk
hold compatibility studies, it was observed that for lower strength
(40 mcg/mL) formulations, there was a metal-initiated oxidative
impurity (RRT .about.2.0) observed as early as 24 hours (0.06%) of
the bulk hold in the stainless steel container (316L) (see results
in Table 26), which grew over time to 0.31% at 120 hrs. However, in
the highest strength, 400 mcg/mL, this impurity was not observed
till 96 hrs (see results in Table 27). The study was then repeated
by incorporating EDTA in the formulation (10 mcg/mL), and it was
observed that no impurities above the reporting threshold
(>0.05%) were found at least until 48 hrs for the lowest
strength, 40 mcg/mL (see results in Table 28). For the highest
strength, 400 mcg/mL, no impurity above the reporting threshold
(>0.05%) was observed till 96 hrs (see results in Table 29).
TABLE-US-00026 TABLE 26 Table 26: Results for Stainless-Steel
(316L) compatibility and Bulk Hold study of Phenylephrine
Hydrochloride Solution, 40 mcg/mL without EDTA Product Lot #13158
(pH 5.0), 40 mcg/mL Time Point Initial 24 HRS 48 HRS 72 HRS Samples
C T C T C T C Appearance CCS CCS CCS CCS CCS CCS CCS Assay (%)
101.3 100.6 100.6 99.5 99.7 99.0 101.3 pH 4.93 4.98 5.06 5.02 5.04
5.02 5.03 S-Form 0.04 NT NT NT 0.05 0.04 0.05 Color L* 100 100 100
100 100 99 100 a* 0 0 0 0 0 0 0 b* 0 0 0 0 0.1 0.1 0.1 Related
Unknown.sub.(RRT) NR.sub.(2.25) NR.sub.(2.25) NR.sub.(2.25) .sup.
0.06.sub.(2.0) NR .sup. 0.11.sub.(2.0) NR Substance Total NR NR NR
0.06 NR 0.11 NR (%) Impurities (%) Time Point 72 HRS 96 HRS 120 HRS
Samples T C T C T Appearance CCS CCS CCS CCS CCS Assay (%) 101.6
102.5 102.2 102.5 102.4 pH 5.04 5.08 5.03 5.08 6.07 S-Form 0.06 NT
NT 0.03 NT Color L* 99.9 99.8 100 100 100 a* 0.1 -0.1 0 0 0 b* 0.2
-0.1 0 0.1 0.1 Related Unknown.sub.(RRT) .sup. 0.16.sub.(2.0)
NR.sub.(2.25) .sup. 0.09.sub.(1.46) NR .sup. 0.31.sub.(2.0)
Substance .sup. 0.21.sub.(2.0) .sup. 0.06.sub.(1.46) (%)
NR.sub.(3.60) .sup. 0.05.sub.(4.0) Total 0.16 NR 0.21 NR 0.37
Impurities (%) C--Control; T--Test; CCS--Clear colorless solution;
NR--Not Reported (<0.05%), NT--Not Tested.
TABLE-US-00027 TABLE 27 Table 27: Results for Stainless-Steel
(316L) compatibility and Bulk Hold study of Phenylephrine
Hydrochloride Solution, 400 mcg/mL without EDTA Product Lot #13158
(pH 5.0), Phenylephrine Hydrochloride Solution, 400 mcg/mL Time
Point Initial 24 HRS 48 HRS 72 HRS 96 HRS 120 HRS Samples C T C T C
T C T C T C T Appearance CCS CCS CCS CCS CCS CCS CCS CCS CCS CCS
CCS CCS Assay (%) 100 99.5 100.2 100.3 100.8 100.8 100.3 100.1 102
101.6 100.4 100.8 pH 5.08 5.05 4.93 4.95 4.96 4.96 4.97 5.01 4.96
4.95 4.98 4.94 S-Form 0.06 0.04 0.06 NT NT 0.05 0.05 0.05 0.06 NT
0.07 NT Color L* 100.1 100.3 100.3 100.3 100.3 100.3 100.3 100.2
100 100 100 99.9 a* 0 0 0 0 0 0 0 0 0 0.1 0 0.1 b* 0 0 -0.1 -0.1
0.1 -0.1 -0.1 0 0 0 0 0.1 Unknown.sub.(RRT) NR NR NR NR NR
NR.sub.(2.0) NR NR.sub.(2.0) NR.sub.(2.25) NR.sub.(2.0) NR .sup.
0.12.sub.(2.0) NR.sub.(2.25) NR.sub.(3.50) NR.sub.(5.46)
NR.sub.(2.25) NR.sub.(3.53) Related Total NR NR NR NR NR NR NR NR
NR NR NR 0.12 Substance Impurities (%) (%) C--Control T--Test;
CCS--Clear colorless solution; NR--Not Reported (0.05%), NT--Not
Tested
TABLE-US-00028 TABLE 28 Table 28: Results for Stainless-Steel
(316L) compatibility and Bulk Hold study of Phenylephrine
Hydrochloride Solution, 40 mcg/mL with 10 mcg/mL EDTA Product Lot
#13661 (pH 5.0), 40 mcg/mL with 10 mcg/mL EDTA Time Point Initial
24 HRS 48 HRS 72 HRS Samples C T C T C T C T Appearance CCS CCS CCS
CCS CCS CCS CCS CCS Assay (%) 100.3 101.1 100.9 99.9 100.8 100.4
100.9 99.8 pH 5.01 5.0 5.0 5.02 4.97 4.98 5.01 5.01 Impurity F NR
NR NR NR NR NR NR NR Related Unknown.sub.(RRT) NR NR NR
NR.sub.(0.85) NR NR NR .sup. 0.07.sub.(0.85) Compounds .sup.
0.05.sub.(0.85) NR.sub.(1.20) (%) NR.sub.(1.68) Total NR NR NR NR
NR NR NR 0.07 Impurities (%) Time Point 96 HRS 168 HRS Samples C T
C T Appearance CCS CCS CCS CCS Assay (%) 100.6 100.1 100 98.8 pH
4.97 5.01 5.01 4.99 Impurity F NR 0.05 NR 0.13 Related
Unknown.sub.(RRT) NR .sup. 0.10.sub.(0.62) NR .sup. 0.32.sub.(0.85)
Compounds .sup. 0.13.sub.0.85) .sup. 0.11.sub.(1.2) (%) .sup.
0.06.sub.(1.68) .sup. 0.21.sub.(1.68) Total NR 0.18 NR 0.78
Impurities (%) C--Control T--Test; CCS--Clear colorless
solution;--NR--Not Reported (<0.05%), NT--Not Tested
TABLE-US-00029 TABLE 29 Table 29: Results for Stainless-Steel
(316L) compatibility and Bulk Hold study of Phenylephrine
Hydrochloride Solution, 400 mcg/mL with 10 mcg/mL EDTA Product Lot
#13661 (pH 5.0), 400 mcg/mL with 10 mcg/mL EDTA Time Point Initial
24 HRS 48 HRS 72 HRS Samples C T C T C T C T Appearance CCS CCS CCS
CCS CCS CCS CCS CCS Assay (%) 100.2 100.6 100 100.5 99.9 100.3 99.9
100.5 pH 5.02 5.01 5.03 5.0 5.01 5.02 5.03 5.06 Related
Unknown.sub.(RRT) NR NR NR NR NR NR NR NR Compounds Total NR NR NR
NR NR NR NR NR (%) Impurities (%) Time Point 96 HRS 168 HRS Samples
C T C T Appearance CCS CCS CCS CCS Assay (%) 100.5 101.4 100.9
100.1 pH 5.05 5.02 5.03 5.01 Related Unknown.sub.(RRT) NR
NR.sub.(0.85) NR .sup. 0.08.sub.(0.85) Compounds NR.sub.(0.60) (%)
NR.sub.(1.68) Total NR NR NR 0.08 Impurities (%) C--Control;
T--Test; CCS--Clear colorless solution; NR--Not Reported (0.05%),
NT--Not Tested.
[0067] An accelerated stability study (at 60.degree. C.) was also
conducted with formulations containing 10 mcg/mL EDTA in the
formulation. Based on the accelerated stability results as shown in
Tables 30-31, no significant change in the impurity profile was
observed with formulation containing 10 mcg/mL EDTA based on the 4
weeks data.
TABLE-US-00030 TABLE 30 Table 30: Stability results of
Phenylephrine HCl, 40 mcg/mL in 5 mM acetate buffer and 10 mcg/mL
EDTA. Storage Condition 40 .+-. 2.degree. C./ 60.degree. C. 75 .+-.
5% RH Time Point Initial 1 Week 2 Week 3 Week 4 Week 1 M Packaging
S NS S NS S NS S NS S NS S NS Appearance CCS CCS CCS CCS CCS CCS
CCS CCS CCS CCS CCS CCS Assay (%) 100.6 99.5 100.7 101.6 102.3
102.4 100.7 99.6 101 102.5 101.8 102.4 pH 5.03 4.96 5 4.98 4.93
4.93 4.96 4.96 5.02 4.99 5.04 4.95 DO 1.15 8.71 1.16 10.45 2.75
5.77 1.24 6.34 1.28 6.12 0.89 6.05 Impurity F NR NR NR 0.05 0.05
0.07 0.07 0.06 0.07 0.08 NR NR Related Unknown.sub.(RRT)
NR.sub.(1.20) NR.sub.(1.20) NR.sub.(1.20) NR.sub.(1.20)
NR.sub.(1.20) NR.sub.(1.20) NR.sub.(1.20) NR.sub.(1.20)
NR.sub.(1.20) NR.sub.(1.20) NR.sub.(1.20) NR.sub.(1.20) Substance
NR.sub.(1.90) (%) Total NR NR NR 0.05 0.05 0.07 0.07 0.06 0.06 0.08
NR NR Impurities (%) S--Aluminum overwrap with Scavenger, NS--Clear
overwrap with no scavenger; CCS--Clear colorless solution; NR--Not
Reported (<0.05%), NT--Not Tested
TABLE-US-00031 TABLE 31 Table 31: Stability results of
Phenylephrine HCl, 400 mcg/mL in 5 mM acetate buffer and 10 mcg/mL
EDTA Storage Condition 40 .+-. 2.degree. C./ 60.degree. C. 75 .+-.
5% RH Time Point Initial 1 Week 2 Week 3 Week 4 Week 1 M Packaging
S NS S NS S NS S NS S NS S NS Appearance CCS CCS CCS CCS CCS CCS
CCS CCS CCS CCS CCS CCS Assay (%) 98.9 98.3 101.2 101.2 100.9 101.6
99.9 100.5 99.8 100.7 0.79 6.26 pH 4.97 4.95 5.03 5.02 5 4.99 4.98
5.02 5.06 5.06 5.02 5.02 DO 1.34 10.65 1.19 8.73 1.21 5.94 1.73
6.05 1.39 NT 99.9 101.4 Impurity F NR NR NR NR NR NR NR NR NR NR NR
NR Related Unknown.sub.(RRT) NR NR NR NR NR NR NR NR NR.sub.(1.20)
NR.sub.(1.20) NR NR Substance Total NR NR NR NR NR NR NR NR NR NR
NR NR (%) Impurities (%) S--Aluminum overwrap with Scavenger,
NS--Clear overwrap with no scavenger; CCS--Clear colorless
solution; NR--Not Reported (<0.05%), NT--Not Tested
[0068] As used herein, the term "administering" a pharmaceutical
composition or drug refers to both direct and indirect
administration of the pharmaceutical composition or drug, wherein
direct administration of the pharmaceutical composition or drug is
typically performed by a health care professional (e.g., physician,
nurse, etc.), and wherein indirect administration includes a step
of providing or making available the pharmaceutical composition or
drug to the health care professional for direct administration
(e.g., via injection, infusion, oral delivery, topical delivery,
etc.). It should further be noted that the terms "prognosing" or
"predicting" a condition, a susceptibility for development of a
disease, or a response to an intended treatment is meant to cover
the act of predicting or the prediction (but not treatment or
diagnosis of) the condition, susceptibility and/or response,
including the rate of progression, improvement, and/or duration of
the condition in a subject.
[0069] The recitation of ranges of values herein is merely intended
to serve as a shorthand method of referring individually to each
separate value falling within the range. Unless otherwise indicated
herein, each individual value is incorporated into the
specification as if it were individually recited herein. All
methods described herein can be performed in any suitable order
unless otherwise indicated herein or otherwise clearly contradicted
by context. The use of any and all examples, or exemplary language
(e.g., "such as") provided with respect to certain embodiments
herein is intended merely to better illuminate the full scope of
the present disclosure, and does not pose a limitation on the scope
of the invention otherwise claimed. No language in the
specification should be construed as indicating any non-claimed
element essential to the practice of the claimed invention.
[0070] It should be apparent to those skilled in the art that many
more modifications besides those already described are possible
without departing from the full scope of the concepts disclosed
herein. The disclosed subject matter, therefore, is not to be
restricted except in the scope of the appended claims. Moreover, in
interpreting both the specification and the claims, all terms
should be interpreted in the broadest possible manner consistent
with the context. In particular, the terms "comprises" and
"comprising" should be interpreted as referring to elements,
components, or steps in a non-exclusive manner, indicating that the
referenced elements, components, or steps may be present, or
utilized, or combined with other elements, components, or steps
that are not expressly referenced. Where the specification claims
refers to at least one of something selected from the group
consisting of A, B, C . . . and N, the text should be interpreted
as requiring only one element from the group, not A plus N, or B
plus N, etc.
* * * * *