U.S. patent application number 13/352043 was filed with the patent office on 2012-05-10 for low viscosity, highly flocculated triamcinolone acetonide suspensions for intravitreal injection.
This patent application is currently assigned to Alcon Research, Ltd.. Invention is credited to Bhagwati P. Kabra, Ruma Sarkar.
Application Number | 20120115829 13/352043 |
Document ID | / |
Family ID | 40548758 |
Filed Date | 2012-05-10 |
United States Patent
Application |
20120115829 |
Kind Code |
A1 |
Kabra; Bhagwati P. ; et
al. |
May 10, 2012 |
Low Viscosity, Highly Flocculated Triamcinolone Acetonide
Suspensions for Intravitreal Injection
Abstract
Triamcinolone acetonide suspension compositions are disclosed.
The suspension compositions have a relatively low viscosity and are
easy to extrude through a 27- or 30-gauge needle but are highly
flocculated and easily redispersed. The compositions are
particularly suitable for intravitreal injection.
Inventors: |
Kabra; Bhagwati P.; (Euless,
TX) ; Sarkar; Ruma; (Fort Worth, TX) |
Assignee: |
Alcon Research, Ltd.
Fort Worth
TX
|
Family ID: |
40548758 |
Appl. No.: |
13/352043 |
Filed: |
January 17, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12401168 |
Mar 10, 2009 |
8128960 |
|
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13352043 |
|
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61035459 |
Mar 11, 2008 |
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Current U.S.
Class: |
514/174 ;
514/252.19 |
Current CPC
Class: |
A61P 27/00 20180101;
A61K 47/34 20130101; A61P 27/02 20180101; A61K 31/58 20130101; A61K
9/0048 20130101; A61K 9/10 20130101; Y10S 514/913 20130101; Y10S
514/912 20130101 |
Class at
Publication: |
514/174 ;
514/252.19 |
International
Class: |
A61K 31/58 20060101
A61K031/58; A61P 27/02 20060101 A61P027/02; A61K 31/496 20060101
A61K031/496 |
Claims
1. An aqueous suspension composition particularly suited for
injection into the eye, wherein the suspension composition does not
contain a preservative, has a pH from 6-7.5, a viscosity of 2-12
cps, and a Degree of Flocculation greater than 5, and wherein the
suspension composition consists essentially of: a) 3.5-4.5% (w/v)
triamcinolone acetonide having a mean volume diameter of 3-10
.mu.m; b) 0.45-0.55% (w/v) sodium carboxymethylcellulose; c)
0.002-0.02% (w/v) polysorbate 80; d) one or more pharmaceutically
acceptable chloride salts as tonicity-adjusting agents in a total
amount sufficient to cause the suspension composition to have an
osmolality from 250-350 mOsm; e) a buffering agent: f) water for
injection; and g) optionally a pH-adjusting agent to adjust the pH
to 6-7.5.
2. The suspension composition of claim 1 wherein the suspension
composition has a Degree of Flocculation greater than 6.
3. The suspension composition of claim 2 wherein the suspension
composition has a Degree of Flocculation greater than 7.
4. The suspension composition of claim 1 wherein the concentration
of triamcinolone acetonide is 4% (w/v).
5. The suspension composition of claim 1 wherein the sodium
carboxymethylcellulose has a molecular weight such that a 2% (w/v)
solution of the sodium carboxymethylcellulose in water at
25.degree. C. has a viscosity of 25-50 cps.
6. The suspension composition of claim 1 wherein the concentration
of sodium carboxymethylcellulose is 0.5% (w/v).
7. The suspension composition of claim 1 wherein the concentration
of polysorbate 80 is 0.01-0.02% (w/v).
8. The suspension composition of claim 7 wherein the concentration
of polysorbate 80 is 0.015% (w/v).
9. The suspension composition of claim 1 wherein the suspension
composition comprises sodium chloride, potassium chloride, calcium
chloride, and magnesium chloride.
10. The suspension composition of claim 9 wherein the suspension
composition comprises 0.4-0.6% (w/v) sodium chloride, 0.05-0.1%
(w/v) potassium chloride, 0.04-0.06% (w/v) calcium chloride, and
0.01-0.04% (w/v) magnesium chloride.
11. The suspension composition of claim 1 wherein the buffering
agent comprises sodium acetate and sodium citrate.
12. The suspension composition of claim 1 wherein the suspension
composition has a viscosity of 2-9 cps.
13. The suspension composition of claim 12 wherein the suspension
composition has a viscosity of 2-8 cps.
14. An aqueous suspension composition particularly suited for
injection into the eye, wherein the suspension composition does not
contain a preservative, has a pH from 6-7.9, a viscosity of 2-12
cps, and a Degree of Flocculation greater than 5, and wherein the
suspension composition consists essentially of: a) 0.5 to 8.0%
(w/v) of a poorly soluble drug, wherein the drug has a mean volume
diameter of 3-10 .mu.m; b) 0.45-0.55% (w/v) sodium
carboxymethylcellulose; c) 0.002-0.02% (w/v) polysorbate 80 or
tyloxapol; d) one or more pharmaceutically acceptable chloride
salts as tonicity-adjusting agents; e) water for injection; f)
optionally a buffering agent; and g) optionally a pH-adjusting
agent to adjust the pH to 6-7.9.
15. The suspension composition of claim 14 wherein the poorly
soluble drug is selected from the group consisting of drugs for
treating macular edema; drugs for treating retinal vein occlusion;
drugs for treating geographic atrophy; drugs for treating dry age
related macular degeneration; and drugs for treating wet age
related macular degeneration.
16. The suspension composition of claim 14 wherein the poorly
soluble drug is tandospirone.
17. The suspension composition of claim 14 where the suspension
composition comprises polysorbate 80.
18. A method of treating an ophthalmic disorder comprising
administering by intravitreal injection a suspension composition
consisting essentially of: a) 0.5 to 8.0% (w/v) of a poorly soluble
drug, wherein the drug has a mean volume diameter of 3-10 .mu.m; b)
0.45-0.55% (w/v) sodium carboxymethylcellulose; c) 0.002-0.02%
(w/v) polysorbate 80 or tyloxapol; d) one or more pharmaceutically
acceptable chloride salts as tonicity-adjusting agents; e) water
for injection; f) optionally a buffering agent; and g) optionally a
pH-adjusting agent to adjust the pH to 6-7.9.
19. The method of claim 18 wherein the suspension composition
comprises polysorbate 80.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to injectable formulations
used for treating diseases or conditions of the eye. More
particularly, the present invention relates to suspension
formulations that have a low viscosity and are highly (i.e.
loosely) flocculated. The suspension formulations comprise the
steroid triamcinolone or other poorly soluble drug compound.
BACKGROUND OF THE INVENTION
[0002] Injectable compositions containing triamcinolone acetonide
have been available for many years. Commercial products include
Kenalog.RTM.-10 Injection (triamcinolone acetonide injectable
suspension, USP) and Kenalog.RTM.-40 Injection (triamcinolone
acetonide injectable suspension, USP), which are marketed by
Bristol-Myers Squibb Co. These products contain 10 mg/ml or 40
mg/ml of triamcinolone acetonide, respectively. According to its
package insert, Kenalog-40 Injection is approved for certain
intramuscular and intra-articular uses. Where oral therapy is not
feasible or is temporarily undesirable in the judgment of the
physician, Kenalog-40 Injection is indicated for intramuscular use
in certain cases for endocrine disorders, rheumatic disorders,
collagen diseases, dermatologic diseases, allergic states,
ophthalmic diseases, gastrointestinal diseases, respiratory
diseases, hematologic disorders, neoplastic diseases, and edematous
state. The specific approved ophthalmic indication is "[s]evere
chronic allergic and inflammatory processes involving the eye, such
as: herpes zoster ophthalmicus; iritis; iridocyclitis;
chorioretinitis; diffuse posterior uveitis and choroiditis; optic
neuritis; sympathetic ophthalmia; and anterior segment
inflammation. Kenalog-40 Injection is indicated for intra-articular
or intrabursal administration, and for injection into tendon
sheaths, as adjunctive therapy for short-term administration (to
tide the patient over an acute episode or exacerbation) in the
following conditions: synovitis of osteoarthritis; rheumatoid
arthritis; acute and subacute bursitis; acute gouty arthritis;
epicondylitis; acute nonspecific tenosynovitis; and posttraumatic
osteoarthritis.
[0003] Recently, the use of Kenalog.RTM.-40 Injection to treat
diabetic macular edema, has been growing more common. In this use,
the product is injected into the vitreous of patients suffering
from diabetic macular edema. In some cases, the product is
processed by the physician or pharmacy in an attempt to remove the
preservative that is present in the Kenalog-40 Injection
formulation supplied by Bristol-Myers Squib Co. (i.e., benzyl
alcohol) because the preservative may be irritating to the vitreous
and tissues in the posterior segment of the eye. Additionally, the
commercially available product must be used immediately after it is
shaken to avoid settling; the package insert reads as follows:
"After withdrawal [from the shaken product vial], inject without
delay to prevent settling in the syringe."
[0004] What is needed is an improved triamcinolone acetonide
suspension composition that is suitable for injection into the eye,
does not settle rapidly, and can be easily injected through a small
needle that offers the potential for a self-sealing puncture wound
(e.g., 27-gauge or 30-gauge).
SUMMARY OF THE INVENTION
[0005] The present invention provides improved triamcinolone
acetonide suspension compositions that are particularly suited for
injection into the eye. The improved aqueous suspension
compositions have excellent settling characteristics, are easily
resuspended with gentle-shaking, are preservative-free, and are
capable of being smoothly and easily injected through 30-gauge
needles. In addition, the suspension compositions of the present
invention can be terminally sterilized by autoclaving. The
suspension compositions are also suitable for poorly soluble drugs
other than triamcinolone,
[0006] Among other factors, the present invention is based on the
finding that a suspension composition of triamcinolone acetonide
that has improved settling characteristics relative to the
currently available Kenalog-40 Injection triamcinolone acetonide
composition can be obtained. The present invention is also based on
the finding that a triamcinolone acetonide suspension composition
containing a relatively low amount of surfactant has superior
flocculation properties, relative to the currently available
Kenalog-40 Injection composition, while still being both easily
processed during manufacturing, transfer and filling operations,
and easily extruded through a 27-gauge to 30-gauge needle.
DETAILED DESCRIPTION OF THE INVENTION
[0007] Unless indicated otherwise, all ingredient amounts are
expressed on a weight/volume percent basis.
[0008] In a preferred embodiment, the aqueous suspension
compositions of the present invention consist essentially of
triamcinolone acetonide, carboxymethylcellulose, polysorbate 80, a
pharmaceutically-acceptable tonicity-adjusting chloride salt, a
buffering agent and water for injection.
[0009] Triamcinolone acetonide is a steroid that can be made by
known methods and is commercially available in micronized forms.
The triamcinolone acetonide should be sized so that mean volume
diameter is 3-10 .mu.m. Sizing techniques, such as ball-milling,
are known and can be used to attain these particle size and
distribution requirements. The suspension compositions of the
present invention contain from 35-45 mg/ml (3.5-4.5%) of
triamcinolone acetonide, preferably 40 mg/ml (4.0%) of
triamcinolone acetonide.
[0010] In addition to triamcinolone acetonide, the suspension
compositions of the present invention contain 0.45-0.55% sodium
carboxymethylcellulose ("CMC"). Preferably, the compositions
contain 0.5% CMC. CMC is commercially available from a variety of
sources in different grades. For example, low (7LF PH), medium (7MF
PH) and high (7HF PH) viscosity grades of CMC are available from
Hercules Inc. The CMC ingredient included in the compositions of
the present invention is preferably a low viscosity grade, such
that the viscosity of a 2% solution of the CMC in water at
25.degree. C. is 25-50 cps. (as measured using a Brookfield LVT
viscometer with a CP-42 spindle at 60 rpm).
[0011] The compositions of the present invention have a viscosity
of 2-12 cps, preferably 2-9 cps, and most preferably 2-8 cps. They
settle slowly and resuspend readily. This relatively low viscosity
ensures that the product is easily processed during manufacturing,
transfer and filling operations, and is easily extruded through
27-gauge or 30-gauge needles.
[0012] Generally, pharmaceutical suspension compositions contain a
surfactant to wet and disperse drug particles, and the amount of
surfactant used is generally greater than the amount needed to
fully wet the individual particles because such an excess helps
make the particles easy to disperse. However, it can be extremely
difficult to achieve a high degree of flocculation.
[0013] The amount of polysorbate 80 used in Kenalog-40 is 0.04%.
However, it was found that if the surfactant concentration is
significantly lower, e.g., 0.015%, the particles form loose
floccules, thereby resulting in a high degree of flocculation. The
low viscosity and high degree of flocculation of the compositions
of the present invention ensures that they redisperse or resuspend
easily upon gentle shaking. The compositions of the present
invention therefore contain a reduced concentration of surfactant,
relative to Kenalog-40. More specifically, the compositions of the
present invention contain 0.002-0.02% polysorbate 80. Preferably,
the compositions contain 0.01-0.02% polysorbate 80, and most
preferably the compositions contain 0.015% polysorbate 80.
[0014] As used herein, "Degree of Flocculation" means the ratio of
final sediment volume (i.e., as a percentage of the total volume)
to particle concentration. For example, a suspension with a 4%
particle (drug) concentration and a final sediment volume of 8%
would have a Degree of Flocculation of 2. Similarly, a suspension
composition with a 4% particle concentration and a final sediment
volume of 20% would have a Degree of Flocculation of 5, and the
same composition with a final sediment volume of 40% would have a
Degree of Flocculation of 10.
[0015] The final sediment volume is the sediment volume (i.e.,
percentage of total volume) after prolonged room-temperature
storage and does not significantly change with additional storage
time. The final sediment volume can be reached quickly for low
viscosity suspensions, e.g. in several hours to a few days, but it
can take days or weeks to reach final sediment volume for medium to
high viscosity systems.
[0016] Sediment volume can be determined as follows: place 10 mL of
the suspension composition in a 10 mL graduated cylinder and record
the sediment volume as a function of time. For example, if the
sediment is up to 1 mL mark on the graduated cylinder, it
represents a sediment volume of 10%. If this does not change
significantly with additional storage time, then it is used as
final sediment volume.
[0017] The compositions of the present invention have a Degree of
Flocculation greater than 5, preferably greater than 6, and most
preferably greater than 7.
[0018] The compositions of the present invention also comprise one
or more pharmaceutically acceptable chloride salts as
tonicity-adjusting agents. The most preferred chloride salt is
sodium chloride. Preferably, the compositions comprise more than
one chloride salt. In a most preferred embodiment, the compositions
comprise sodium chloride, potassium chloride, calcium chloride, and
magnesium chloride. The tonicity-adjusting agents are present in a
total amount sufficient to provide the compositions of the present
invention with an osmolality of 250-350 mOsm. In one embodiment,
the compositions comprise 0.4-0.6% sodium chloride, 0.05-0.1%
potassium chloride, 0.04-0.06% calcium chloride, and 0.01-0.04%
magnesium chloride.
[0019] If necessary, the suspension compositions of the present
invention also contain a pH-adjusting agent, such as NaOH or HCl to
adjust the pH of the compositions to pH 6-7.5. The suspension
compositions contain a pharmaceutically acceptable buffering agent
to maintain the pH of the compositions within the range of 6-7.5.
Suitable buffering agents include sodium acetate and sodium
citrate. Preferably, the compositions contain a combination of
sodium acetate and sodium citrate.
[0020] The suspension compositions of the present invention are
preferably packaged in unit dose containers, such as glass or
plastic vials. The suspension compositions can also be packaged in
pre-filled syringes or cartridges.
[0021] As used herein, injection "into the posterior segment of the
eye" includes, but is not limited to, injection into the vitreous
body, injection into or beneath the sclera, and injection external
to the vitreous and beneath the Tenon's capsule.
[0022] In one embodiment, the present invention relates to a method
of treating macular edema including but not limited to diabetic
macular edema, or retinal vein occlusion, including central and
branch retinal vein occlusions, comprising injecting into the
posterior segment of the eye the suspension composition described
above. In another embodiment, the present invention relates to a
method of treating post-surgical inflammation comprising injecting
into the anterior segment of the eye the suspension composition
described above. In still another embodiment, the present invention
relates to a method of treating an ophthalmic disease or condition
in the posterior segment of the eye, including but not limited to
macular degeneration, comprising injecting into the posterior
segment of the eye the suspension composition described above. For
these embodiments in which a disease or condition of the eye is
treated, the compositions of the present invention are preferably
injected (e.g., into the vitreous or other locations in the
posterior segment of the eye, or into the anterior chamber) so as
to deliver an initial dose of 4 mg of triamcinolone acetonide
(e.g., 100 microliters of 40 mg/mL suspension composition), with
subsequent dosage as needed over the course of treatment.
[0023] In yet another embodiment, the present invention relates to
a method of enhancing visualization of the vitreous during
vitrectomy procedures. In this embodiment, the composition of the
present invention is administered intravitreally so as to deliver 1
to 4 mg of triamcinolone acetonide (e.g., 25-100 microliters of 40
mg/mL suspension composition).
[0024] In another embodiment, the present invention relates to
suspension compositions of poorly soluble drugs other than
triamcinolone. As used herein, a "poorly soluble drug" is a drug
that has a solubility at 22.degree. C. of less than 1 mg/mL at pH
7.5 in phosphate buffered saline. The suspension compositions
consist essentially of the poorly soluble drug compound,
carboxymethylcellulose, polysorbate 80 or tyloxapol, a
pharmaceutically-acceptable tonicity-adjusting chloride salt,
optionally a buffering agent, optionally a pH-adjusting agent, and
water for injection. The suspension compositions have a pH from
6-7.9, a viscosity of 2-12 cps, and a Degree of Flocculation
greater than 5. Preferably, the suspension compositions consist
essentially of: [0025] a) 0.5 to 8.0% (w/v) of a poorly soluble
drug, wherein the drug has a mean volume diameter of 3-10 .mu.m;
[0026] b) 0.45-0.55% (w/v) sodium carboxymethylcellulose; [0027] c)
0.002-0.02% (w/v) polysorbate 80 or tyloxapol; [0028] d) one or
more pharmaceutically acceptable chloride salts as
tonicity-adjusting agents; [0029] e) water for injection; [0030] f)
optionally a buffering agent; and [0031] g) optionally a
pH-adjusting agent to adjust the pH to 6-7.9.
[0032] The preferred concentration of polysorbate 80 or tyloxapol
is 0.002-0.01% for compositions with a poorly soluble drug compound
concentration ranging from 0.5-2%. The preferred concentration of
polysorbate 80 or tyloxapol is 0.01-0.02% for compositions with
poorly soluble drug compound concentration ranging from 2-8%.
[0033] In one embodiment, poorly soluble drugs may be drugs for
treating macular edema, retinal vein occlusion, geographic atrophy,
dry age related macular degeneration, or wet age related macular
degeneration. One example of such a poorly soluble drug is
tandospirone.
[0034] The present invention also relates to a method of treating
an ophthalmic disorder comprising administering by intravitreal
injection a suspension composition consisting essentially of:
[0035] a) 0.5 to 8.0% (w/v) of a poorly soluble drug, wherein the
drug has a mean volume diameter of 3-10 .mu.m; [0036] b) 0.45-0.55%
(w/v) sodium carboxymethylcellulose; [0037] c) 0.002-0.02% (w/v)
polysorbate 80 or tyloxapol; [0038] d) one or more pharmaceutically
acceptable chloride salts as tonicity-adjusting agents; [0039] e)
water for injection; [0040] f) optionally a buffering agent; and
[0041] g) optionally a pH-adjusting agent to adjust the pH to
6-7.9.
[0042] Certain embodiments of the invention are illustrated in the
following examples.
Example 1
[0043] The composition of Kenalog.RTM.-40 is shown in Table 1.1
below. It contains 4% triamcinolone acetonide and 0.04% polysorbate
80. The viscosity of this suspension is about 14 cps.
[0044] The particle size data for several lots was measured by
laser light diffraction (Microtrac.RTM. S3000) and is shown in
Table 1.2. The median particle size of the various lots of
Kenalog-40 ranged from 13 to 22 .mu.m.
[0045] The force required to extrude the Kenalog.RTM.-40 suspension
through a one-half inch 30 gauge needle attached to a 1 mL
tuberculin syringe is provided in Table 1.3. The results show that
Kenlaog-40 suspension plugged the 30 gauge needle. The force
required was quite variable and high. The plugging of the needle is
due to the large particle size of this suspension.
[0046] The Kenalog.RTM.-40 suspension composition was determined to
have a final sediment volume of about 14% and therefore has a
Degree of Flocculation of 3.5. Thus, this suspension is only
lightly flocculated, relative to the suspension compositions of the
present invention.
TABLE-US-00001 TABLE 1.1 KENALOG-40 Composition KENALOG-40
Component W/V% Triamcinolone 4 Acetonide Carboxymethyl- 0.75
cellulose Sodium Polysorbate 80 0.04 Benzyl Alcohol 0.99 Sodium
Chloride 0.75 Sodium Hydroxide 5.0 to 7.5 and/or Hydrochloric Acid
Water for Injection qs to 100%
TABLE-US-00002 TABLE 1.2 Particle Size Data for Six Lots of
KENALOG-40, measured using Microtrac Manufacturer Particle Size
Particle Size Particle Size Lot Number (.mu.m) .times. .sub.10
(.mu.m) .times. .sub.50 (.mu.m) .times. .sub.90 (Expiration Date)
(by Microtrac) (by Microtrac) (by Microtrac) 5L01206 5.0 20.2 50.0
(October 2007) 6B19016 3.5 13.6 38.6 (February 2008) 6D16625 4.3
21.1 57.4 (April 2008) 6F11285 3.4 13.6 40.9 (April 2008) 6F15845
5.6 21.7 54.0 (April 2008) 6D18800 4.2 15.7 41.6 (April 2008)
TABLE-US-00003 TABLE 1.3 Extrusion Force Data For Kenalog-40 (1 mL
Tuberculin Syringe with 30 GA .times. 1/2'' needle) Average Load
lbs force Formulation (Standard Maximum Load Description Deviation)
lbs force Kenalog 40 5.33 10.2 (Plugged in mg/mL (4.457) 4 out of
10 lot 6F11285 samples) Ex April 2008
Example 2
[0047] Triamcinolone acetonide suspensions with different
concentrations of polysorbate 80 but without CMC were prepared as
shown in Table 2.1. The mean volume particle size of the
triamcinolone acetonide substance used in these compositions was
5-6 .mu.m (measured using a Microtrac.RTM. S3000 instrument).
[0048] A settling study was carried out on these formulations by
placing 10 mL samples of each of them in separate 10 mL graduated
cylinders and recording sediment volume as a function of time.
Kenalog.RTM.-40 was studied as a control. The results are provided
in Table 2.2. These results show that 4% triamcinolone formulations
with polysorbate 80 concentrations less than 0.02% have high final
sediment volumes. For these compositions, the sediment volume
stabilized within a day and did not change for 7 days. The Degree
of Flocculation for these samples ranged from 9.5 to 13.5,
indicating that the compositions are highly flocculated. However,
the formulations with a polysorbate 80 concentration of 0.02% and
higher formed a compact sediment layer at the bottom of the
graduated cylinder. The sediment volume in those cases was less
than 10% and the Degree of Flocculation was around 2. Thus,
formulations with a polysorbate 80 concentration 0.02% are not
highly flocculated.
TABLE-US-00004 TABLE 2.1 Composition of Triamcinolone Acetonide
Suspension without Viscosity Agents Used in the Settling Study
Composition A B C D E F Triamcinolone 4% 4% 4% 4% 4% 4% Acetonide
Polysorbate 80 0.002% 0.005% 0.01% 0.015% 0.02% 0.025% Sodium
Chloride 0.64% 0.64% 0.64% 0.64% 0.64% 0.64% Potassium Chloride
0.075% 0.075% 0.075% 0.075% 0.075% 0.075% Calcium Chloride 0.048%
0.048% 0.048% 0.048% 0.048% 0.048% (Dihydrate) Magnesium Chloride
0.03% 0.03% 0.03% 0.03% 0.03% 0.03% (Hexahydrate) Sodium Acetate
0.39% 0.39% 0.39% 0.39% 0.39% 0.39% (Trihydrate) Sodium Citrate
0.17% 0.17% 0.17% 0.17% 0.17% 0.17% (Dihydrate) Sodium Hydroxide
Adjust Adjust Adjust Adjust Adjust Adjust and/or pH pH pH pH pH pH
Hydrochloric Acid to 6.8 to 6.8 to 6.8 to 6.8 to 6.8 to 6.8 Water
for Injection qs to qs to qs to qs to qs to qs to 100% 100% 100%
100% 100% 100%
TABLE-US-00005 TABLE 2.2 Settling Study of Kenalog-40 and
Triamcinolone Acetonide Suspension without CMC at different
polysorbate 80 concentrations Settling Phase in each 10 mL
Volumetric Cylinder Time Point (Sedimentation Volume %) Composition
Kenalog-40 A B C D E F Polysorbate 80 0.04% 0.002% 0.005% 0.01%
0.015% 0.02% 0.025% Initial (0 mins) Homogenous: Homogenous:
Homogenous: Homogenous: Homogenous: Homogenous: Homogenous: 10 mL
10 mL 10 mL 10 mL 10 mL 10 mL 10 mL 1 Hour Sediment: Sediment:
Sediment: Sediment: Sediment: Sediment: Sediment: 7.4 mL (74%) 5.2
mL (52%) 5.4 mL (54%) 5.2 mL (52%) 3.8 mL (38%) 7.4 mL (74%) 7.2 mL
(72%) 2 Hours Sediment: Sediment: Sediment: Sediment: Sediment:
Sediment: Sediment: 5.0 mL (50%) 5.2 mL (52%) 5.4 mL (54%) 5.2 mL
(52%) 3.8 mL (38%) 4.8 mL (48%) 4.2 mL (42%) 4 Hours Sediment:
Sediment: Sediment: Sediment: Sediment: Sediment: Sediment: 1.4 mL
(14%) 5.2 mL (52%) 5.4 mL (54%) 5.2 mL (52%) 3.8 mL (38%) 1.0 mL
(10%) 1.0 mL (10%) 6 Hours Sediment: Sediment: Sediment: Sediment:
Sediment: Sediment: Sediment: 1.4 mL (14%) 5.0 mL (50%) 5.4 mL
(54%) 5.2 mL (52%) 4.0 mL (40%) 0.8 mL (8%) 0.8 mL (8%) 1 Day
Sediment: Sediment: Sediment: Sediment: Sediment: Sediment:
Sediment: 1.4 mL (14%) 5.0 mL (50%) 5.4 mL (54%) 5.2 mL (52%) 4.0
mL (40%) 0.8 mL (8%) 0.8 mL (8%) 2 Days Sediment: Sediment:
Sediment: Sediment: Sediment: Sediment: Sediment: 1.4 mL (14%) 5.0
mL (50%) 5.4 mL (54%) 5.2 mL (52%) 3.8 mL (38%) 0.8 mL (8%) 0.8 mL
(8%) 5 Days Sediment: Sediment: Sediment: Sediment: Sediment:
Sediment: Sediment: 1.4 mL (14%) 5.0 mL (50%) 5.4 mL (54%) 5.2 mL
(52%) 3.8 mL (38%) 0.8 mL (8%) 0.8 mL (8%) 7 Days Sediment:
Sediment: Sediment: Sediment: Sediment: Sediment: Sediment: 1.4 mL
(14%) 5.0 mL (50%) 5.4 mL (54%) 5.2 mL (52%) 3.8 mL (38%) 0.8 mL
(8%) 0.8 mL (8%) Degree of 3.5 12.5 13.5 13 9.5 2 2
Flocculation
Example 3
[0049] Compositions of 4% triamcinolone acetonide suspensions with
0.015% polysorbate 80 and different concentrations of CMC are
described in Table 3.1 below. The mean volume particle size of the
triamcinolone acetonide substance used in these compositions was
5-6 .mu.m (measured using a Microtrac.RTM. S3000 instrument).
[0050] A settling study was carried out on these formulations by
placing 10 mL samples of each of them in separate 10 mL graduated
cylinders and recording sediment volume as a function of time. The
results are provided in Table 3.2. The Degree of Flocculation in
every case is >10. Thus, these compositions are representative
examples of the highly flocculated compositions of the present
invention.
TABLE-US-00006 TABLE 3.1 Compositions of Triamcinolone Injection
With CMC Composition G H I J Triamcinolone 4% 4% 4% 4% Polysorbate
80 0.015% 0.015% 0.015% 0.015% Carboxymethylcellulose 0% 0.25% 0.5%
0.75% sodium (7LFPH) Sodium Chloride 0.64% 0.64% 0.64% 0.64%
Potassium Chloride 0.075% 0.075% 0.075% 0.075% Calcium Chloride
(Dihydrate) 0.048% 0.048% 0.048% 0.048% Magnesium Chloride 0.03%
0.03% 0.03% 0.03% (Hexahydrate) Sodium Acetate (Trihydrate) 0.39%
0.39% 0.39% 0.39% Sodium Citrate (Dihydrate) 0.17% 0.17% 0.17%
0.17% Sodium Hydroxide and/or Adjust pH Adjust pH Adjust pH Adjust
pH Hydrochloric Acid to 6.8 to 6.8 to 6.8 to 6.8 Water for
Injection qs to 100% qs to 100% qs to 100% qs to 100%
TABLE-US-00007 TABLE 3.2 Settling Study of Triamcinolone Acetonide
Suspensions with 0.015% Polysorbate 80 at different CMC
concentrations Settling Phase in each 10 mL Volumetric Cylinder
Time Point (Sedimentation Volume %) Composition G H I J Polysorbate
80 0.015% 0.015% 0.015% 0.015% Concentration Carboxymethyl 0% 0.25%
0.5% 0.75% Cellulose Sodium, 7LFPH concentration Initial Homo-
Homo- Homo- Homo- (0 minutes) genous: genous: genous: genous: 10 mL
10 mL 10 mL 10 mL 5 minutes Sediment: Sediment: Sediment: Sediment:
0 9.0 mL (90%) 9.8 mL (98%) 9.9 mL (99%) 10 minutes Sediment:
Sediment: Sediment: Sediment: 8.2 mL (82%) 9.8 mL (98%) 9.6 mL
(96%) 9.8 mL (98%) 20 minutes Sediment: Sediment: Sediment:
Sediment: 6.4 mL (64%) 9.0 mL (90%) 9.2 mL (92%) 9.6 mL (96%) 30
minutes Sediment: Sediment: Sediment: Sediment: 6.4 mL (64%) 8.2 mL
(82%) 9.0 mL (90%) 9.3 mL (93%) 21 hours Sediment: Sediment:
Sediment: Sediment: 4.8 mL (48%) 5.6 mL (56%) 5.2 mL (52%) 5.4 mL
(54%) 24 hours Sediment: Sediment: Sediment: Sediment: 4.8 mL (48%)
5.6 mL (56%) 5.4 mL (54%) 5.2 mL (52%) Degree of 12 14 13.5 13
Flocculation
Example 4
[0051] A suspension composition representative of the compositions
of this invention is described in Table 4.1 below. This formulation
has 4% triamcinolone acetonide and 0.015% polysorbate 80. The
viscosity of this formulation is about 5 cps. (Brookfield LVT
viscometer using a CP-42 spindle at 60 rpm.)
[0052] The particle size measurement of a representative lot of
this composition is provided in Table 4.2 (measurements were made
using a Microtrac.RTM. S3000 instrument). The median particle size
is 5.6 .mu.m.
[0053] The force required to extrude this composition through a
one-half inch 30 gauge needle attached to 1 mL tuberculin syringe
is provided in Table 4.3. The results show that the required force
was much smaller than that for Kenlaog-40 suspension (see Example
1, Table 1.3). In this case, there was no plugging of the 30 gauge
needle.
[0054] A settling study of the type described in Example 2 was also
performed and Composition K had a Degree of Flocculation of about
13, indicating it is a highly flocculated composition.
TABLE-US-00008 TABLE 4.1 Composition of Triamcinolone Acetonide
Injection Composition Component K mg/mL Triamcinolone 4.0 40
Acetonide Polysorbate 80 0.015 0.15 Carboxymethyl- 0.5 5.0
cellulose Sodium Sodium Chloride 0.55 5.5 Potassium Chloride 0.075
0.75 Calcium Chloride 0.048 0.48 (Dihydrate) Magnesium Chloride
0.03 0.3 (Hexahydrate) Sodium Acetate 0.39 3.9 (Trihydrate) Sodium
Citrate 0.17 1.7 (Dihydrate) Sodium Hydroxide Adjust pH to Adjust
pH and/or approx. 6.8 to approx. Hydrochloric Acid 6.8 Water for
Injection Qs to 100% qs to 1 mL
TABLE-US-00009 TABLE 4.2 Particle Size Data for a Representative
Lot of Triamcinolone Acetonide Suspension FID 110300 Particle Size
Particle Size Particle Size (pm) .times. .sub.10 (.mu.m) .times.
.sub.50 (.mu.m) .times. .sub.90 Composition (by Microtrac) (by
Microtrac) (by Microtrac) K 1.6 5.6 10.8
TABLE-US-00010 TABLE 4.3 Extrusion Force Data For Triamcinolone
Acetonide Sterile Suspension (1 mL Tuberculin Syringe with 30 GA
.times. 1/2'' needle) Average Load lbs force Maximum Load
Composition (Standard Deviation) lbs force K 0.55 1.1 (no plugging
(0.205) occurred)
Example 5
[0055] Compositions of 1% and 8% tandospirone suspensions are
provided in Table 5.1 below.
TABLE-US-00011 TABLE 5.1 Tandospione Suspension Compositions
Composition Composition Component M N Tandospirone 1.0 8.0
Polysorbate 80 or 0.005 0.02 Tyloxapol Carboxymethyl- 0.5 0.5
cellulose Sodium Sodium Chloride 0.8 0.8 Dibasic Sodium 0.25 0.25
Phosphate Dodecahydrate Sodium Hydroxide Qs to approx. Qs to
approx. and/or 7.5 .+-. 0.2 7.5 .+-. 0.2 Hydrochloric Acid Water
for Injection Qs to 100% Qs to 100%
* * * * *