Note: Descriptions are shown in the official language in which they were submitted.
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STANNSOPORFIN COMPOSITIONS AND ADMINISTRATION
TECHNICAL FIELD
Tin (IV) mesoporphyrin IX dichloride, or stannsoporfin,
is a mesoporphyrin chemical compound having the following
structure:
0
OH
Na' Sn~a N
N
OH
O
Stannsoporfin has been proposed for use, for example, as
a medicament in the treatment of various diseases including,
for example, psoriasis (U.S. Patent No. 4,782,049 to Kappas et
al.) and infant jaundice (for example, in U.S. Patent
Nos. 4,684,637, 4,657,902 and 4,692,440). Stannsoporfin is
also known to inhibit heme metabolism in mammals, to control
the rate of tryptophan metabolism in mammals, and to increase
the rate at which heme is excreted by mammals (U.S. Patent
Nos. 4,657,902 and 4,692,440).
Processes for obtaining stannsoporfin are known in the
art. Protoporphyrin IX iron (III) chloride or hemin, of the
structural formula:
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2
0
OH
Cl-- Fe'~/N
N
OH
O
is commonly used as starting material. The hemin is generally
hydrogenated to form an intermediate mesoporphyrin IX
dihydrochloride, which is subsequently subjected to tin
insertion, yielding stannsoporfin. Methods for making
stannsoporfin are disclosed in United States Patent No.
6,818,763 and United States Patent Application Serial No.
10/812,156, filed on March 29, 2004, the contents of both of
which are incorporated herein by reference.
. One way of administering stannsoporfin is by an
injectable solution. Although stannsoporfin has been provided
in aqueous solutions in the past, it has been found that in
stannsoporfin solutions having higher concentrations, the
stannsoporfin does not adequately dissolve in the
solution. It would be desirable to provide compositions, drug
products and methods of manufacture that can include higher
concentrations of stannsoporfin. It would further be
desirable to provide compositions and drug products that
include stannsoporfin that are stable and have an acceptable
shelf life.
DISCLOSURE OF THE INVENTION
One aspect of the present invention is directed towards a
pharmaceutical composition or drug product comprising
stannsoporfin in an aqueous solution, wherein the
concentration of stannsoporfin in the solution is at least
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about 4 mg/ml, preferably at least about 4.5 mg/ml, and more
preferably at least about 5 mg/ml. In one embodiment a
preferred range of stannsoporfin concentration is between
about 5-40 mg/ml, including concentrations of 10 mg/ml, 15
mg/ml, 20 mg/ml, 25 mg/ml, 30 mg/ml, 35 mg/ml and 40 mg/ml.
According to one embodiment, the composition or drug
product has a physiological osmolarity. According to another
embodiment, the composition or drug product is stable at room
temperature for at least about one month. In other
embodiments, the composition or drug product is stable at room
temperature up to at least about two months, in still other
embodiments, the solution or drug product is stable at room
temperature up to at least about three months, and in other
embodiments, the solution or drug product is stable at room
temperature up to at least about six months. As used herein,
room temperature includes, but is not limited to temperatures
between about 68 F and 77 F.
Another aspect of the present invention is directed
towards a drug product including a stannsoporfin solution,
wherein the drug product includes a single dose of
stannsoporfin in solution. In certain embodiments, the
solution may further comprise a base, an acid and a buffering
agent.
Another aspect of the present invention is directed
towards a method of making a pharmaceutical composition
comprising a stannsoporfin aqueous solution, wherein
stannsoporfin is mixed with a buffering agent. The
stannsoporfin is then dissolved through the addition of a base
which preferably raises the pH to at least about 10. After
the stannsoporfin has completely dissolved, the pH is then
lowered within a physiological pH range by the addition of an
acid so that it can be administered to a patient. As used
herein, physiological pH range refers to a pH range of less
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than about 8. According to one or more embodiments as used
herein, physiological pH range means a pH between about 7.2
and 7.9, and more preferably, a physiological pH means a pH
between about 7.4 and 7.9.
Another aspect of this invention is directed towards a
method of making a drug product comprising an aqueous solution
of stannsoporfin in a concentration of at least about 4.5
mg/ml. Still another aspect of the invention pertains to
treatment of hyperbilirubinemia utilizing the compositions and
drug products disclosed herein.
BEST MODE FOR CARRYING OUT THE INVENTION
It is to be appreciated that the various process
parameters described herein (by way of example only,
temperature, time, and pressure) are approximations and may be
varied, and certain steps may be performed in different
order. Before describing several exemplary embodiments of the
invention, it is to be understood that the invention is not
limited to the details of construction or process steps set
forth in the following description. The invention is capable
of other embodiments and of being practiced or carried out in
various ways.
In overview, one or more embodiments relate to
compositions, drug products and methods of treatment using
stannsoporfin. As used herein, tin (IV) mesoporphyrin IX
dichloride includes tin 4+ mesoporphyrin IX dichloride and
stannsoporfin. Tin (IV) mesoporphyrin IX dichloride can be
obtained according to a variety of methods, for example,
through the methods disclosed in United States Patent No.
6,818,763, and co-pending United States Patent Application
Serial No. 10/812,156 (Publication No. 20040210048), which are
incorporated herein by reference. However, it should be
understood that other methods can be used to produce
mesoporphyrin halides such as tin mesoporphyrin IX dichloride,
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and the present invention is not limited to a particular
method of mesoporphyrin production.
For example, a two-stage hydrogenation process can be
used to prepare tin mesoporphyrin. In the first stage, a
5 reaction mixture of hemin and a hydrogenation catalyst are
subjected to a first elevated temperature for a first period
of time. The first stage temperature can be in the range of
about 85-95 C and the period of time is at least about one
hour, for example, between about 1-3 hours.
In the second stage of hydrogenation, the reaction
mixture is cooled to a second temperature for a second period
of time. For example, the second temperature can be in a
range of about 45-50 C and hydrogenated for a second period of
time of about 3-6 hours, in order to convert substantially all
hemin (protoporphyrin IX iron (III) chloride) to mesoporphyrin
IX formate. This second stage can also be conducted in the
presence of formic acid. The same catalyst may be used as in
the first step described above, so that the two stages of the
process may be conducted in the same reactor. Optionally, a
further charge of hydrogen may be supplied to the reactor
prior to commencing the second stage. In some situations, the
second hydrogenation stage increases the yield of the
mesoporphyrin IX formate, while reducing the amount of
impurities in the final metal mesoporphyrin halide. (See the
following Figure).
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6
0 0
aH a H
FR Pd/C /
H MJCZzH
Famic acid H
CH
CH
1
o 0
By the method described above, the mesoporphyrin IX
intermediate compound in the present invention is not isolated
as a dihydrochloride, but rather as a formate salt. It will
be understood, of course, that other processes can be used for
the preparation of tin (IV) mesoporphyrin intermediates.
The mesoporphyrin IX formate may be isolated from a
formic acid solution by the addition of a solvent such as
ether or another organic solvent, leading directly to the
mesoporphyrin IX formate intermediate, which is further
subjected to drying. Ethers such as, for example, methyl
tert-butyl ether, diethyl ether or di-isopropyl ether, among
others, may be used.
According to the process described above, less solvent is
required compared to other processes, and such smaller volumes
allow for less filter time to obtain the intermediate. Ratios
of the amount of hemin to the amount of solvent of about 1:10
to about 1:20 may be used. In addition, the filtration and
washings of the mesoporphyrin IX formate are rapid. After
drying, a crude intermediate formate is obtained, in high
yields (about 80-95%) and its purity, established by HPLC, is
about or above 97%.
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The insertion of metal into mesoporphyrin IX formate to
obtain metal mesoporphyrin halide is described below with
specific reference to tin, to prepare stannsoporfin.
The insertion of tin into mesoporphyrin IX formate is
utilized to create tin mesoporphyrin. To create tin
mesoporphyrin, mesoporphyrin IX formate is subjected to
heating with a tin (II) carrier in an acid such as acetic
acid, buffered with an acetate ion, in the presence of an
oxidant, at reflux. Tin (II) carriers such as tin (II)
halides or tin (II) acetate can be used. Suitable acetate
counter ions include ammonium, sodium or potassium ions.
Oxidants such as oxygen from air or in pure form as well as
hydrogen peroxide can also be used. Mesoporphyrin IX formate
can be subjected to heating with tin (II) chloride in acetic
acid, buffered with ammonium acetate, and the reaction is
conducted in the presence of air, at reflux. During this
process, tin mesoporphyrin dichloride is isolated from the
reaction mixture by the addition of water, followed by
filtration to provide a filter cake. Prior to drying at about
90-100 C, the filter cake is triturated into hot, dilute
hydrochloric acid, for example, at a concentration of about
0.1N-6N, at about 90-100 C. The crude, substantially pure tin
mesoporphyrin chloride (crude tin (IV) mesoporphyrin IX
dichloride) is obtained with a yield of about 75-95% and a
purity of about 95%, as judged by HPLC analysis. (See the
following Figure).
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0
O
OH OH
SnC12,NH4OAc,OZ N N CI, N
Sn
H 2HC02H G
N N~ N \
OH OH
O
O
The tin mesoporphyrin IX dichloride obtained by the
above-described process may be further purified by dissolving
the product in an aqueous inorganic base solution, for
example, dilute ammonium hydroxide, followed by treatment with
charcoal. The product is then re-precipitated by addition to
an acid solution, such as acetic acid, hydrochloric acid or a
mixture thereof. The above dissolving, charcoal treatment and
re-precipitation steps may be repeated a number of times,
typically about 1-3 times in order to ensure the desired
purity. Prior to drying, the cake is triturated in hot,
dilute hydrochloric acid of a concentration of about 0.1N-6N,
at a temperature of about 90-100 C, in order to remove any
residual ammonium salts. The tin mesoporphyrin chloride
product (tin (IV) mesoporphyrin IX dichloride or
stannsoporfin) is obtained in a yield of about 50-70%, with an
HPLC purity of about or greater than 97%.
The process described above may also be performed to
produce substantially pure or pharmaceutical quality tin
mesoporphyrin chloride (tin (IV) mesoporphyrin IX dichloride
or stannsoporfin) in large scale quantities, such as
quantities exceeding about 0.1kg through and including
multiple kilogram amounts, by slight modifications of the
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above procedure, such as increased reaction or drying times as
appropriate based upon the increase in scale of the starting
reactants. Temperature and pressure times likewise can be
modified as needed. The tin mesoporphyrin chloride product
(tin (IV) mesoporphyrin IX dichloride or stannsoporfin) is
obtained in the large scale production process in a yield of
about 60-90%, with an HPLC purity of about 97%.
Alternatively, the stannsoporfin can be obtained by the
methods disclosed in co-pending and United States Patent
Application Serial No. 10/812,156, filed on March 29, 2004,
the entire contents of which is incorporated herein by
reference. In overview, stannsoporfin can be produced by
isolating a mesoporphyrin formate and converting the
mesoporphyrin formate to a tin mesoporphyrin halide. The
mesoporphyrin formate can be converted directly to a metal
mesoporphyrin halide, or alternatively, the mesoporphyrin
formate can first be converted to mesoporphyrin
dihydrochloride and the mesoporphyrin dihydrochloride can then
be converted to the metal mesoporphyrin halide.
The compositions of the present invention can be prepared
and administered in a wide variety of parenteral dosage forms.
Thus, the compositions of the present invention can be
administered by injection, that is, intravenously,
intramuscularly, intrathecally, intracutaneously,
subcutaneously, intraduodenally, or intraperitoneally.
Additionally, the compositions of the present invention can be
administered transdermally.
Liquid form preparations can include solutions,
suspensions, and emulsions, for example, water or water
propylene glycol solutions. For parenteral injection, liquid
preparations can be formulated in solution in aqueous
solutions as described herein.
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The pharmaceutical preparation is preferably in unit
dosage form. In such form, the preparation is subdivided into
unit doses containing appropriate quantities of the active
component. The unit dosage form can be a packaged
5 preparation, the package containing discrete quantities of
preparation, such as packeted in vials or ampules.
The quantity of active component in a unit dose
preparation may be varied or adjusted from about 0.1 to about
50 mg, preferably 0.1 to about 40 mg, and more preferably 0.1
10 to about 20 mg according to the particular application and the
potency of the active component and size of the patient. The
composition can, if desired, also contain other compatible
therapeutic agents.
In therapeutic use as agents for treating neonatal
hyperbilirubinemia, the compounds utilized in the
pharmaceutical methods of this invention are administered at
the initial dosage of about 0.1 mg to about 20 mg per kilogram
body weight (IM) daily. Specific exemplary embodiments
involve the use of about 0.5 mg to about 6 mg per kilogram
body weight (IM) for the treatment of neonatal
hyperbilirubinemia. The dosages, however, may be varied
depending upon the requirements of the patient, the severity
of the condition being treated and the compound being
employed. Determination of the proper dosage for a particular
situation is within the skill of the art. In one embodiment,
generally, treatment is initiated with smaller dosages which
are less than the optimum dose of the compound. Thereafter,
the dosage is increased by small increments until the optimum
effect under the circumstance is reached.
One aspect of the present invention is directed towards a
pharmaceutical composition that comprises stannsoporfin, where
it is in an aqueous solution and the concentration of
stannsoporfin in the solution is between about 4.5 and 40
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mg/ml, and preferably between about 4.5 and 25 mg/ml. In one
or more embodiments, the components of the stannsoporfin
composition comprise an acid, a base and a buffering agent
mixed in an aqueous solution. The composition is preferably
sterile and has a physiological osmolarlity. The compositions
or drug products are preferably packaged in amber glass vials.
The pharmaceutical composition containing stannsoporfin
can be a component of a drug product, wherein the product is
contained in a single dose unit. According to one embodiment,
a single dose unit includes at least about 0.5 ml of solution,
and more preferably, at least about 1 ml of solution.
The solution may be provided in a drug product form by
containing the solution in a suitable container such as an
ampule or vial. According to certain embodiments, the
solution is stable and has a shelf life of at least about 3
months. In other embodiments, the solution has a shelf life
of at least about 6 months.
Another aspect of this invention is directed towards a
method of making a pharmaceutical composition comprising large
quantities of stannsoporfin. In one or more embodiments, the
stannsoporfin is present in an amount of at least about 4.5
mg/ml. In an exemplary embodiment, a pre-determined amount of
stannsoporfin is mixed with a buffering agent in aqueous
solution. There are numerous buffers which may be suitable
for creating the pharmaceutical composition. Examples of such
buffers include: an alkali earth metal buffering agent, a
calcium buffering agent, a magnesium buffering agent, an
aluminum buffering agent, sodium bicarbonate, potassium
bicarbonate, magnesium hydroxide, magnesium lactate, magnesium
gluconate, magnesium oxide, magnesium aluminate, magnesium
carbonate, magnesium silicate, magnesium citrate, aluminum
hydroxide, aluminum hydroxide/magnesium carbonate, aluminum
hydroxide/sodium bicarbonate coprecipitate, aluminum
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glycinate, aluminum magnesium hydroxide, aluminum phosphate,
sodium citrate, calcium citrate, sodium tartrate, sodium
acetate, sodium carbonate, sodium polyphosphate, sodium
dihydrogen phosphate, potassium pyrophosphate, sodium
polyphosphate, potassium pyrophosphate, disodium
hydrogenphosphate, tribasic sodium phosphate dodecahydrate,
dipotassium hydrogen phosphate, trisodium phosphate,
tripotassium phosphate, potassium carbonate, potassium
metaphosphate, calcium acetate, calcium glycerophosphate,
calcium chloride, calcium hydroxide, calcium lactate, calcium
carbonate, calcium gluconate, calcium bicarbonate, sodium
phosphate, potassium phosphate, calcium phosphate, magnesium
phosphate, potassium citrate, trihydroxymethylaminomethane, an
amino acid, an acid salt of an amino acid, and an alkali salt
of an amino acid, and combinations of the foregoing. The
buffer used should be able to be used in a concentration
effective to raise the pH of the solution to about 10 or
above, when base is added to the solution. In addition, the
buffer must be pharmaceutically acceptable.
According to one or more embodiments, the method of
making a pharmaceutical composition further comprises
adjusting the pH of the solution to a pH of at least about 10
to facilitate dissolution of the stannsoporfin in the
solution. This can be accomplished through the addition of a
strong base to the solution. Strong bases with low pKb values
facilitate the dissolution of large quantities of
stannsoporfin. The base used in this method can be any
pharmaceutically acceptable strong base such as a metal
hydroxide or other hydroxide bases. Presently preferred bases
include pharmaceutically acceptable Group I and Group II metal
hydroxides. Sodium hydroxide has been demonstrated to be
suitable. Other suitable bases may include potassium
hydroxide, calcium hydroxide, ammonium hydroxide, tetraethyl
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ammonium hydroxide, 10% ethanolamine or magnesium hydroxide.
The base should be pharmaceutically acceptable and effective
to raise the pH of the solution to about 10 or above.
According to one or more embodiments of the method of the
invention the pH of the solution is adjusted to a pH range of
less than 8, for example between about 7.2 and 7.9, more
preferably to a pH of between about 7.4 to 7.9. This can be
accomplished through the addition of a pharmaceutically
effective strong acid in a dilute concentration to the
solution corresponding to the base used to raise the pH. One
example of suitable acid is 0.3 N. hydrochloric acid. Other
suitable acids may include niric acid, perchloric acid or
hydroiodic acid. In preferred embodiments, the pH range of the
stannsoporfin solution should be in a form that can be
administered so the pH range is preferably between about 7.4
and 7.9.
Another aspect of this invention is directed towards a
method of lowering bilirubin levels in a mammal comprising
parenterally administering a stannsoporfin solution that has a
concentration of stannsoporfin greater than 4.5 mg/ml. While
the intended recipients of this medication to treat
hyperbilirubinemia are humans, particularly infants, the
stannsoporfin solution may also be effective in other mammals.
Another aspect of this invention is directed towards a
method of making a drug product comprised of an aqueous
solution of stannsoporfin in a concentration of at least about
4.5 mg/ml. This aqueous solution can further comprise an
acid, a base and a buffering agent. One way in which this
aqueous solution can be packaged is in a vial. Preferably,
the vial is a Type 1 amber glass tubing vial to protect the
composition from light. According to one or more embodiments,
the drug product is stable and has a shelf life of at least
about 1 month, and preferably at least about 3 months. In
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other embodiments, the product has a shelf life of at least
about 6 months at room temperature.
In certain embodiments, the drug product or compositions
exhibits a physiological osmolarity. As used herein, the
phrase "physiological osmolarity" means the drug product or
composition, when administered to a patient does not cause
irritation or an adverse reaction. Previous formulations did
not exhibit a physiological osmolarity, and administration of
the composition caused irritation to the patient. A suitable
range for the osmolarity according to certain embodiments is
between about 270 and 328 mOsmol/L, and more preferably
between about 280-300 mOsmol/L osmolarity.
Exemplary embodiments of the invention will be further
described for illustrative purposes with reference to the
following non-limiting examples.
EXAMPLE 1
PREPARATION OF AN AQUEOUS SOLUTION OF STANNSOPORFIN
A desired volume of the batch for the solution was
determined. The amount of stannsoporfin required for the
batch was calculated and recorded. The quantities of base
(for example, iN sodium hydroxide, NaOH) and acid (for
example, 0.3N hydrochloric acid, HC1) required for adjusting
the pH of the batch were calculated and recorded. The
projected final weight of the solution batch based on the
components and based on the theoretical density of the
stannsoporfin injection was calculated and recorded.
An empty mixing vessel was purged with nitrogen NF for a
minimum of 15 minutes. Purging continued throughout the
formulation process. Water for injection was added to the
vessel. The temperature of the mixing vessel was measured and
adjusted to between about 15 C to 30 C. The mixing vessel was
maintained within this temperature range throughout the
process. Mixing began at 400 to 600 rpm, and the mixing was
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maintained at this rate throughout the process. A buffering
agent (for example, tribasic sodium phosphate dodecahydrate)
was added and the solution was mixed for 30 to 35 minutes,
until the buffering agent completely dissolved. Stannsoporfin
5 was added to the mixing vessel. The contents of the vessel
were now mixed for approximately 30 to 35 minutes. A 10 ml
sample of the bulk solution was withdrawn and its pH was
measured. If the pH was below about 10, small increments of
1N sodium hydroxide solution was added to aid in the
10 dissolution of the stannsoporfin.
The pH was increased to above about 10 and any amount of
added sodium hydroxide was recorded. The solution was then
observed to determine if the stannsoporfin was dissolved. The
contents of the vessel were mixed for approximately 30 to 35
15 minutes. Another 10 ml sample of the bulk solution was
withdrawn, and its pH was measured.
If the pH was above about 8, it was adjusted downwards by
adding small increments of 0.3N hydrochloric acid solution.
Any amount of acid added was recorded. The amount of water
for injection to add to obtain the final weight of the
solution was determined. The water for injection was added
until the final weight of the solution was reached. The
contents of the vessel were then mixed for - 45 to 50 minutes.
A 10 ml sample was withdrawn and its final pH was recorded.
The final weight of the solution was also measured.
EXAMPLE 2
A STANNSPORFIN SOLUTION
A 23 L stannsoporfin solution was prepared in accordance
with Example 1 including the following components:
Component Amount/ml Amount/23L
Stannsoporfin 0.020g 460.Og
Tribasic Sodium Phosphate Dodecahydrate,
ACS 0.017g 391.Og
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Sodium Hydroxide NF (iN solution) 0.090ml 2.OL
Hydrochloric Acid NF
(0.3N solution) 0.090ml 2.OL
Water for Injection USP qs to 1.Oml qs to 23.0L
Nitrogen NF qs headspace qs headspace
EXAMPLE 3
STANNSOPORFIN SOLUTION STABILITY TESTS
Samples produced in accordance with EXAMPLES 1 and 2 were
subjected to stability testing as follows. The stability
samples were stored at 3 conditions (4 C 2 C, 25 C 2 C/60o
5%RH and, 40 C 2 C/75o 5%RH) , and were monitored as
follows: 4 C 2 C for 0, 3, 6, 9, 12, 18, 24, 36, 48, and 60
months; 25 C 2 C/60 0 5%RH for 0, 3, 6, 9, 12, 18, 24, 36,
48, and 60 months; 40 C 2 C/75o 5%RH 0, 1, 2, 3, 4, 5, and
6 months. At the indicated time intervals for each storage
condition, the stability samples were tested for appearance,
assay, purity, pH, identification, and sterility. Appearance,
Peak Purity [by diode array detector (DAD)], Identity (UV),
and sterility according to USP were satisfactory at each test
point, unless otherwise indicated. Sterility testing was
performed initially and at 12 and 24 months.
Limits:
pH: 7.4 to 8.0
Volume in Container: Not less than 1.5 ml per vial withdrawable.
Particulate Matter (USP G877>):
NMT 6,000 parts ? 10 pm per vial.
NMT 600 parts ? 25 um per vial.
NMT= Not More Than
Assay: 95.0% to 105.0% of label
Impurities (total): NMT 3%
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Sterility (USP <71>): Sterile
Bacterial Endotoxins (USP <85>): Contains NMT 0.7 EU/mg of
Stannsoporfin Injection
EU= Endotoxin Units
All measured parameters were within acceptable limits.
EXAMPLE 4
OSMOLARITY OF A STANNSOPORFIN SOLUTION
A formulation was prepared in accordance with the having the
following components therein:
Component Amount/ml Amount/25ml
1. Stannsoporfin 20.02 mg 500.5 mg
2. Tribasic Sodium Phosphate
Dodecahydrate, ACS 16.0 mg 400.2 mg
3. Reverse Osmosis Water Q.S. to 19 ml
75% of
Final Vol.
4. Sodium Hydroxide NF (1N solution) titrate to 500 pl
pH > 10
5. Hydrochloric Acid NF (0.3N solution) titrate to
pH 7.4-7.8 900 }sl
6. Reverse Osmosis Water Q.S. to
Final volume
Components 1, 2 and 3 were mixed together, and then component
4 was added to titrate the solution to a pH of about 10.56.
Component 5 was then added to titrate the solution to a pH of
7.62. Water was added Q.S. to volume.
Osmolality was measured using a Wescore 5500 Vapor Pressure
Osmometer. Prior to measuring the osmolality of the samples,
the osmometer was calibrated using osmolality standards of 290
mmol/kg, 1000 mmol/kg and 100 mmol/kg. The osmolality values
were 255, 252 and 256 mmol/kg, and the average value was 254
mmol/kg.
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EXAMPLE 5
OSMOLARITY OF A STANNSOPORFIN SOLUTION
A formulation was prepared having the following components
therein:
Component Amount/ml Amount/25m1
1. Stannsoporfin 20.03 mg 500.7 mg
2. Tribasic Sodium Phosphate
Dodecahydrate, ACS 17.0 mg 425 mg
3. Reverse Osmosis Water Q.S. to 19 ml
75% of
Final Vol.
4. Sodium Hydroxide NF (1N solution) titrate to 1 ml
pH > 10
5. Hydrochloric Acid NF (0.3N solution) titrate to
pH 7.4-7.8 1 ml
6. Reverse Osmosis Water Q.S. to
Final volume
Components 1, 2 and 3 were mixed together, and then component
4 was added to titrate the solution to a pH of about 10.56.
Component 5 was then added to titrate the solution to a pH of
7.62. Water was added Q.S. to volume.
Osmolality was measured using a Wescore 5500 Vapor Pressure
Osmometer. Prior to measuring the osmolality of the samples,
the osmometer was calibrated using osmolality standards of 290
mmol/kg, 1000 mmol/kg and 100 mmol/kg. The osmolality values
were 292, 289 and 284 mmol/kg, and the average value was 288
mmol/kg.
EXAMPLE 6
URINARY EXCRETION OF STANNSOPORFIN SOLUTIONS
Urinary excretion of two stannsoporfin formulations
differing in osmolarity was measured as a marker of drug
absorption from the muscle compartment into the central
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circulatory compartment. Forty mg of a prior art formulation
having a non-physiological osmolarity of 400 mOsmol/L or a
formulation having a physiological osmolarity of 270-328
mOsmol/L prepared according to the present invention were
administered intramuscularly to healthy adult volunteers. Urine
samples were collected up to 48 hrs after administration and
excreted tin mesoporphyrin measured fluorometrically and
expressed as % of dose administered.
Formulation Prior Art Present Invention
Osmolarity (mOsmol/L) 400 270-328
Urine Excretion (% of 0.20-0.38 0.79-8.35
Dose)
No urinary tin mesoporphyrin was detected after 24 hrs
following administration of the non-physiologic stannsoporfin
formulation, whereas urinary tin mesoporphyrin was detected in
urine up to and including 48 hrs following administration of the
physiologic stannsoporfin formulation. The data suggest greater
drug absorption of stannsoporfin into the circulatory system
from the formulation having a physiologic osmolarity as compared
to the formulation that is somewhat hyperosmolar, thereby
indicating an increase the drug's bioavailablity.
While the foregoing is directed to various embodiments of
the present invention, other and further embodiments of the
invention may be devised without departing from the basic
scope thereof, and the scope thereof is determined by the
claims that follow.
