U.S. patent application number 13/756731 was filed with the patent office on 2013-06-06 for oral suspension of prednisolone acetate.
This patent application is currently assigned to Taro Pharmaceuticals North America, Inc.. The applicant listed for this patent is Taro Pharmaceuticals North America, Inc.. Invention is credited to Satish Asotra, Shen Gao, Avraham Yacobi.
Application Number | 20130143853 13/756731 |
Document ID | / |
Family ID | 37727875 |
Filed Date | 2013-06-06 |
United States Patent
Application |
20130143853 |
Kind Code |
A1 |
Asotra; Satish ; et
al. |
June 6, 2013 |
ORAL SUSPENSION OF PREDNISOLONE ACETATE
Abstract
The present invention relates to novel oral suspension
formulation comprising prednisolone acetate, a pharmaceutically
acceptable vehicle and a thickening agent. The present invention
further provides a method of treating patients in need of
prednisolone with the novel formulation.
Inventors: |
Asotra; Satish; (Brampton,
CA) ; Gao; Shen; (Bolton, CA) ; Yacobi;
Avraham; (Englewood, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Taro Pharmaceuticals North America, Inc.; |
Grand Cayman |
|
KY |
|
|
Assignee: |
Taro Pharmaceuticals North America,
Inc.
Grand Cayman
KY
|
Family ID: |
37727875 |
Appl. No.: |
13/756731 |
Filed: |
February 1, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13483273 |
May 30, 2012 |
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13756731 |
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12870144 |
Aug 27, 2010 |
8206727 |
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13483273 |
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11457197 |
Jul 13, 2006 |
7799331 |
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12870144 |
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60705370 |
Aug 4, 2005 |
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Current U.S.
Class: |
514/179 |
Current CPC
Class: |
A61P 7/00 20180101; A61P
19/02 20180101; A61P 37/08 20180101; A61P 3/00 20180101; A61P 29/00
20180101; A61P 5/00 20180101; A61P 35/00 20180101; A61P 25/00
20180101; A61K 31/57 20130101; A61K 9/0053 20130101; A61P 7/10
20180101; A61P 1/00 20180101; A61K 9/10 20130101; A61P 11/00
20180101; A61P 37/02 20180101; A61P 17/00 20180101; A61K 9/0095
20130101 |
Class at
Publication: |
514/179 |
International
Class: |
A61K 9/00 20060101
A61K009/00 |
Claims
1-23. (canceled)
24. A pharmaceutical composition comprising a pharmaceutically
effective amount of fine milled prednisolone acetate particles
dispersed in suspension in the composition, wherein the composition
is suitable for oral delivery and comprises a thickening agent and
a wetting agent.
25. The composition of claim 24, wherein the prednisolone acetate
remains dispersed in the suspension without agitation during the
shelf life of the composition and has a crystalline stability such
that the prednisolone particles stay within a target particle size
range over time.
26. The composition of claim 24, wherein the composition is
spill-resistant.
27. The composition of claim 24, wherein the pH is between about
4.0 and about 5.9.
28. The composition of claim 24, wherein the pH is between about
4.6 and about 5.4.
29. The composition of claim 24, wherein the composition comprises
components that are mutually compatible.
30. The composition of claim 24, wherein the composition is
storage-stable.
31. The composition of claim 24, wherein the thickening agent is a
carbomer.
32. The composition of claim 24, wherein the wetting agent is a
poloxamer.
33. The composition of claim 24, wherein the composition comprises
an aqueous vehicle.
34. The pharmaceutical composition of claim 24, wherein the
composition, when administered to humans, exhibits pharmacokinetic
parameters within the 80-125% confidence interval, with a
statistical power of at least 80%, of one or more of the following
values: a. C.sub.max of 176.27 ng/mL; b. T.sub.max of 1.00 hour; c.
AUC.sub.T of 812.39 ngh/mL; d. AUC.sub..infin. of 846.53 ngh/mL; e.
K.sub.el of 0.2629 hr.sup.-1; and f. T.sub.1/2el of 2.66 hours.
35. The pharmaceutical composition of claim 24, comprising from
about 0.5 mg/mL to about 5 mg/mL of prednisolone acetate.
36. The pharmaceutical composition of claim 24, comprising from
about 0.5 mg/mL to about 5 mg/mL of prednisolone acetate, water,
glycerin, sorbitol in an amount up to about 20% (w/w), propylene
glycol in an amount up to about 20% (w/w), wetting agent in an
amount up to about 3% (w/w) and a thickening agent in an amount up
to about 1% (w/w).
37. The pharmaceutical composition of claim 24, comprising: a. from
about 5 mg/5 mL to about 15 mg/5 mL prednisolone acetate; b. 0.1%
poloxamer 188; c. 50% glycerin; d. 5% sorbitol crystalline; e. 5%
propylene glycol; f. 0.065% edetate disodium; g. 0.2% sucralose; h.
carbomer in an amount up to about 1%; i. 0.04% butylparaben; and j.
sodium hydroxide.
38. The pharmaceutical composition of claim 24, wherein the
composition exhibits an in vitro dissolution profile of about 82%
to about 85% released after about 15 minutes, about 93% to about
95% released after about 30 minutes, about 95% to about 97%
released after about 45 minutes and about 96% to about 97% released
after about 60 minutes.
39. A method for treating a patient in need of prednisolone,
comprising the step of orally administering a therapeutically
effective amount of the pharmaceutical composition of claim 24.
40. The method of claim 39, wherein the patient is suffering from a
medical condition selected from the group consisting of endocrine
disorders, rheumatic disorders, collagen diseases, dermatologic
diseases, allergic states, respiratory diseases, hematologic
disorders, neoplastic diseases, edema, gastrointestinal diseases
and nervous diseases.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit under 35 U.S.C.
.sctn.119(e) of the U.S. Provisional Application No. 60/705,370
filed Aug. 4, 2005, the disclosure of which is incorporated by
reference in its entirety herein.
BACKGROUND OF THE INVENTION
[0002] The invention relates to a pharmaceutical formulation for
oral administration comprising an effective amount of prednisolone
acetate in a pharmaceutically acceptable, aqueous,
suspension-stabilizing vehicle.
[0003] Corticosteroids are used to treat patients with inflammatory
and immune diseases. Prednisolone is a corticosteroid that has been
formulated into capsules, tablets and liquid preparations for oral
delivery. The base form of prednisolone and the salt form,
prednisolone sodium phosphate, are commercially available in oral
liquid formulations. However, the bitter taste of the commercial
compositions is described extensively in the medical literature and
contributes to poor patient compliance with medical instructions
for the use of the drug. U.S. Pat. No. 4,448,774 describes aqueous
solutions comprising a steroid selected from the group of
prednisolone, prednisolone sodium phosphate, prednisone and methyl
prednisolone. The solution described in the patent is described as
being preferable to previously known formulations because no
alcoholic solvent is required and it is not a suspension.
Suspensions of prednisolone are reported to be problematic because
they are not stable and over time the active agent settles out of
the formulation and gives variable dosage amounts. U.S. Pat. No.
5,763,449 describes the use of a combination of three well known
taste masking agents to achieve a pleasant tasting liquid
pharmaceutical composition. Prednisolone and prednisolone sodium
phosphate are disclosed as bitter tasting drugs that may be used in
the formulation.
[0004] Another form of prednisolone, prednisolone acetate, is
commonly used to for medicinal purposes. However, because of its
poor aqueous solubility, prednisolone acetate is used in topical,
parenteral and opthamalogical formulations, not oral formulations.
The use of the acetate form could provide a taste advantage because
it is insoluble in the aqueous environment of the mouth, and
therefore prevents the interaction of the bitter-tasting molecules
of the prednisolone with the taste buds.
[0005] The present disclosure is to a novel, organoleptic, oral,
liquid suspension of prednisolone acetate that is an improvement
over previously disclosed and commercialized oral prednisolone
dosage forms.
SUMMARY OF THE INVENTION
[0006] The present invention is to a pharmaceutical composition for
oral delivery comprising a pharmaceutically effective amount of
prednisolone acetate, pharmaceutically acceptable vehicle and a
thickening agent. The present composition contains between about
0.5 mg/mL to about 7 mg/mL of prednisolone acetate. More preferably
the concentration of prednisolone acetate is between about 1 mg/mL
to about 5 mg/mL. The most preferred compositions of the present
invention will deliver 5 mg/5 mL prednisolone acetate or 15 mg/5 mL
prednisolone acetate.
[0007] The inventive formulation has prednisolone acetate dispersed
in an oral formulation comprising a vehicle and a thickening agent.
The aqueous vehicle may be comprised of glycerin, and the preferred
thickening agent is carbomer.
[0008] The prednisolone acetate of the present invention is within
a fine range of particle size. The median particle size of the
prednisolone acetate is between about 1 .mu.m to 30 .mu.m,
particularly between about 5 .mu.m to 10 .mu.m, and more
particularly between 6 .mu.m to 8 .mu.m. Ninety percent of the
prednisolone acetate in the inventive composition has a median
particle size of greater than 1 .mu.m and less than 30 .mu.m.
[0009] The inventive composition further comprises pharmaceutically
acceptable excipients. The excipients include wetting agents,
spreading agents, stabilizers, sweeteners and flavoring agents. The
inventive composition is organoleptically pleasing.
[0010] The novel formulation has a pH of between about 4.0 to about
5.9, more preferably of between about 4.6 to about 5.4, most
preferably 4.8 to 5.2.
[0011] The inventive composition is comprised of from about 29 to
about 64% water (w/w), up to about 50% glycerin (w/w), up to about
20% sorbitol (w/w), up to about 10% propylene glycol (w/w), up to
about 3% surfactant (w/w) and up to about 1% of a thickening agent
(w/w).
[0012] The pharmaceutical composition of the invention comprises
the following ingredients a) 0.1% poloxamer 188; b) 50% glycerin;
c) 5% sorbitol crystalline; d) 5% propylene glycol; e) 0.065%
disodium edetate; f) 0.2% sucralose; g) 0.44% carbomer; h) 0.04%
butylparaben; and i) sodium hydroxide to a pH of s between about
4.8 to about 5.2.
[0013] The inventive formulation may be used to treat a patient in
need of an effective amount of the active pharmaceutical vehicle,
prednisolone.
[0014] Among the medical conditions that may be treated by the
formulation of the present invention are endocrine disorders,
rheumatic disorders, collagen diseases, dermatologic diseases,
allergic states, respiratory diseases, hemaologic disorders,
neoplastic diseases, edema, gastrointestinal diseases or nervous
diseases using an effective amount of the orally delivered
prednisolone acetate composition.
DETAILED DESCRIPTION OF THE INVENTION
[0015] In describing embodiments of the present invention, specific
terminology is employed for the sake of clarity. However, the
invention is not intended to be limited to the specific terminology
so selected. It is to be understood that each specific element
includes all technical equivalents, which operate in a similar
manner to accomplish a similar purpose. The above-described
embodiments of the invention may be modified or varied, and
elements added or omitted, without departing from the invention, as
appreciated by those skilled in the art in light of the above
teachings. Each reference cited herein is incorporated by reference
as if each were individually incorporated by reference.
[0016] The formulation of the present invention is a palatable,
oral formulation of prednisolone acetate. Prednisolone acetate has
been used in ophthalmic and parenteral medicinal products, but has
not previously been used in oral liquid preparations. Prednisolone
acetate is practically insoluble in water. The low solubility
presents a formulary challenge during product development of an
aqueous liquid oral preparation. However, the use of the acetate
form provides a taste advantage because the active does not
dissolve in the aqueous environment of the mouth, and therefore
prevents the interaction of the bitter-tasting molecules of the
prednisolone with the taste buds.
[0017] The present invention is an aqueous suspension having a
thickening component and a vehicle, or carrier, component and may
include other pharmaceutically acceptable excipients. The vehicle
is pharmaceutically acceptable, aqueous and suspension-stabilizing.
Prednisolone acetate is evenly dispersed in the semi-solid aqueous
vehicle. The suspension has a homogeneity so that the active
ingredient is uniformly dispersed but undissovled in the vehicle.
The formulation consists of mutually compatible components at room
temperature. The suspension has a crystalline stability in that the
prednisolone particles stay within a target particle size range
over time.
[0018] The vehicle component serves as the external phase of the
suspensions. The vehicle may be comprised of water, glycerin,
propylene glycol and mixtures thereof. The vehicle component may
contain glycerin up to about 50%. The vehicle may also comprise
propylene glycol up to about 20% or from about 3% to about 10%.
Purified water comprises the bulk of the vehicle component
comprising from about 29% to about 64% of the formulation.
[0019] Purified water makes up the bulk of the vehicle component,
comprising from about 29% to 64% (w/w) of the formulation. Water
concentration can be less than about 50% (w/w) or even less than
about 43% (w/w).
[0020] Thickening agents are pharmaceutically acceptable excipients
that add a desired viscosity and flow to a formulation. Carbomers
are synthetic high molecular weight polymers of acrylic acid. In
one embodiment, carbomer 943P (Carbopol 974P) has been found to be
a suitable thickening, or gelling agent, providing good sensory
appeal and texture. The rheology of the carbomer provides for a
high yield value, low shear thinning quality, in non-thixotropic
liquid formulations.
[0021] The viscosity of the carbomer gel is pH dependent. Carbomer
gels exhibit maximum viscosity at about pH 7.0. More acidic or
basic pH's will cause the carbomer to lose viscosity. However,
prednisolone acetate is most stable at slightly acidic pH's, and
will degrade to undesirable breakdown products at the higher pH. At
neutral pH's, prednisolone acetate will undergo oxidation and
hydrolysis and form undesirable and less active degradation
products. At a pH of 4.6 to 5.4, prednisolone acetate is stable in
the formulation and the carbomer may retain its viscosity. The
carbomer comprises up to about 1% (w/w) of the inventive
formulation. In particular, we have found that the carbomer of the
inventive formulation should be between about 0.40% to about 0.50%,
more particularly, about 0.40% to about 0.48%.
[0022] The oral formulation of prednisolone acetate is a
spill-resistant formulation. Spill resistant oral formulations are
more extensively described in, for example, U.S. Pat. Nos.
6,071,253, and 6,102,254, herein incorporated by reference.
[0023] The pharmaceutical suspension comprising of the invention
has prednisolone acetate uniformly dispersed in an aqueous vehicle,
the active ingredient remaining in suspension without agitation
during the product shelf-life. The shelf life may be up to about
six, twelve, eighteen, twenty-four months, thirty months, or
thirty-six months. The suspension has antimicrobial activity, is
pharmaceutically effective and meets applicable regulatory
requirements as would be understood by a person of ordinary skill.
The viscosity may be about 5,000 to about 15,000 cps, about 5,000
to about 14,800 cps, about 9,000 to about 11,000 cps, or about
9,500 to about 10,500 cps. In inventive pharmaceutical suspensions
there is no crystalline growth during a heat-cool study for three
days at a temperature range of about 8.degree. C. to about
45.degree. C. The active ingredient particles may be crystals that
neither dissolve or grow substantially when the sample is heated
e.g. to 45.degree. C. and cooled to room temperature
repeatedly.
[0024] The formulation is dosed by volume, and specific gravity
values were used to estimate the prednisolone acetate concentration
in the composition. The 5 mg/mL dose was calculated, based on
specific gravity to be 0.097% (w/w), which is equivalent to 0.087%
(w/w) of the prednisolone base form. The 15 mg/mL dose was
calculated to be about 0.293% (w/w), which is equivalent to 0.262%
of prednisolone base form.
[0025] The particle size of the active pharmaceutical ingredient
may have important effects on the bioavailability of a formulation.
Smaller particle sizes have increased surface area and will
dissolve faster than larger particles. However, decreasing the
particle size may cause some agglomeration of the particles, and
the increased surface area can result in faster degradation of the
compound due to oxidation and hydrolysis. In the inventive
formulation, a fine particle size was found to achieve the desired
bioavailabilty. The prednisolone acetate of the inventive
formulation has a median particle size of approximately from about
1 .mu.m to about 30 .mu.m, more preferably about 5 .mu.m to about
20 .mu.m, most preferably from about 6 .mu.m to about 8 .mu.m. The
particle size may be achieved using such methods air-jet milling,
ball milling, mortar milling or any other method known in the art
for decreasing particle size, For example, the prednisolone acetate
particles of the disclosed formulation were micronized using a
stainless steel, air-jet mill with a grinding chamber diameter of
four inches (Sturtevant, Hanover, Mass., U.S.A., model no.
SDM-4.)
[0026] The size of the particles may be measured using a light
scattering device, sedimentation methods, centrifugal force
measurements, or any method known to one skilled in the art. By
means of an example, the Matersizer 2000 manufactured by Malvern
Instruments, Ltd., Malvern U.K., may be used to measure the
particle size.
[0027] Pharmaceutical excipients are pharmaceutically acceptable
ingredients that are essential constituents of virtually all
pharmaceutical products. Excipients serve many purposes in the
formulation process. The inventive pharmaceutical suspensions may
comprise at least one additional component selected from the group
consisting of excipients, surface active agents, dispersing agents,
sweetening agents, flavoring agents, coloring agents,
preservatives, oily vehicles, solvents, suspending agents,
dispersing agents, wetting agents, emulsifying agents, demulcents,
buffers, salts, spreading agents, antioxidants, antibiotics,
antifungal agents and stabilizing agents.
[0028] Spreading agents may be added to the vehicle component.
Polyols, such as malitol, mannitol, polyethylene glycol and
sorbitol may be added to the vehicle components to adjust the
spreadability in the spoon bowl upon pouring. The present
embodiment may contain sorbitol, in a concentration of less than
5%.
[0029] The suspensions of the present invention may also contain
Edetate Disodium (EDTA). EDTA is a chelating agent that forms a
stable water-soluble complex with alkaline earth and heavy metal
ions. It is useful as an antioxidant synergist, sequestering metal
ions that might otherwise catalyze autoxidation reactions. EDTA may
also have synergistic effects as an antimicrobial when used in
combination with other preservatives (Handbook of Pharmaceutical
Excipients 4.sup.th Ed.).
[0030] The suspension formulations may require a crystal
conditioning surfactant, i.e. a wetting agent. The hydrophobic
properties of prednisolone acetate may benefit from a wetting agent
to disperse the steroid in the formulation. A concentration of from
about 0.05% to about 0.5% poloxamer 188 was found to be effective
at wetting the prednisolone acetate without excessive foaming and
dispersion of the suspension.
[0031] The present formulation is an improvement over previously
described prednisolone suspensions because the ingredient remains
suspended indefinitely, without agitation; that is without stirring
or shaking. The dispensed dose is always uniform over the shelf
life of the product. The formulation of the invention can not be
shaken easily, so the particles remain suspended without
shaking.
[0032] The suspension has antimicrobial activity. Propylparaben (up
to about 0.04%) and butylparaben (0.018% to about 0.18%) are
suitable. Other antimicrobial excipients may also be used. These
suspensions are alcohol-free.
[0033] The organoleptic ingredients improve the taste and
appearance and do not negatively affect the suspension stability.
The organoleptic agents in the following examples include coloring
and flavoring agents, sweeteners and masking agents.
[0034] Mutual compatibility of the components means that the
components do not separate in preparation and storage for up to the
equivalent of two years at room temperature (as indicated by three
month intervals of accelerated stability testing at 40.degree.
centigrade and at 75% relative humidity). Storage stability means
that the materials do not lose their desirable properties during
storage for the same period. Preferred compositions do not exhibit
a drop in viscosity of more than 50% or an increase in viscosity of
more than 100% during that period.
[0035] The following examples further illustrate the invention, but
should not be construed as limiting the invention in any
manner.
Example 1
[0036] The prednisolone acetate oral suspension was formulated to
contain the following ingredients:
TABLE-US-00001 TABLE I Composition of Oral Prednisolone Acetate
Suspension 5 mg/5 mL INGREDIENTS (w/w %) 15 mg/mL Prednisolone
Acetate 0.097 0.293 Poloxamer 188 0.1 0.1 Glycerin 50 50 Sorbitol
Crystalline 5 5 Propylene Glycol 5 5 Edetate Disodium 0.065 0.065
Sucralose 0.2 0.2 Artificial Cherry Flavor 0.15 0.15 Bell Flavor
Masking Agent 0.2 0.2 Carbomer 934 0.44 0.44 Butylparaben 0.04 0.04
Purified water to 100% to 100% NaOH pH 4.6-5.4 pH 4.6-5.4
Example 2
[0037] Comparison of different Prednisolone Actives for Sensory
Evaluation: A small sample of volunteers compared the different
formulations of prednisolone for taste and flavor. Results are
given in Table 2.
TABLE-US-00002 TABLE 2 Sensory Perception following different
samples of Prednisolone Formulations Product Description Initial
Taste After Taste Commercially Available Slightly sweet,
Persistent, very bitter Prednisolone 5 mg/5 ml intense wild cherry
Commercially Available Moderately sweet, Delayed moderately
Prednisolone sodium mild raspberry bitter unpleasant taste
phosphate 5 mg./5 ml persists for long time Taro Prednisolone
Phosphate Pleasantly sweet, Delayed slightly bitter, Experimental
Syrup 5 mg/ cherry flavored Intensity increases 5 mL with time
Prednisolone Acetate Pleasantly sweet, No bitterness perceived
Suspension 5 mg/mL cherry flavored
Example 3
[0038] pH Screen Stability
[0039] Stability testing was performed on 1.0 kg portions of a 5.0
kg experimental batch of 5 mg/5 mL prednisolone acetate. NaOH was
added to the portions to give various pH values (Batch A-E) and
packaged in 4 ounce amber PETG bottles. The samples were left at
the environmentally stressed conditions of 40.degree. centigrade or
50.degree. centigrade for one month. HPLC methods were used to
measure the percent of prednisolone acetate retained in the bottle.
The control sample used was a 5 mg/15 mL prednisolone acetate
suspension exposed at to room temperature and sampled after 4
months. The data is summarized in Table 3.
[0040] As demonstrated by the results shown in Table 3, in the pH
range of 5.0 to 6.2, the micronized prednisolone acetate is more
stable at the lower pH values.
TABLE-US-00003 TABLE 3 Stability of Prednisolone Acetate Oral
Suspension (varying pH) Batch (%) Prednisolone (%) Prednisolone (%)
Prednisolone No. pH Acetate.sup.1 (RT) Acetate.sup.1 (40.degree.
C.) Acetatel.sup.1 (50.degree. C.) A 5.02 96.7 96.7 95.2 B 5.39
96.1 96.1 93.0 C 5.71 95.4 95.4 81.7 D 5.90 92.8 92.8 44.3 E 6.22
87.3 87.3 67.4
Example 4
[0041] Suspension Dissolution
[0042] Dissolution tests are a qualitative tool that provides
information about the biological availability of a drug
formulation. Experimentally, suspension formulations are considered
to disintegrate equivalently to tablet formulations, therefore
dissolution testing is done comparing suspensions to tablets. A
standard dissolution test (USP Apparatus 2 (paddle)) was followed
to compare the prednisolone acetate suspension to a commercially
available 5 mg tablet of prednisolone. As shown in FIG. 1, the
dissolution curves of the suspensions were very similar to the
dissolution curve for the tablet following a 15 minute period.
TABLE-US-00004 TABLE 4 Dissolution of Prednisolone Acetate
Suspensions v. Prednisolone Tablets Prednisolone Acetate
Prednisolone Suspension Tablets TIME 15 mg/5 ml 5 mg/5 ml 5 mg 5 48
45 69 15 85 82 93 30 95 93 96 45 97 95 98 60 97 96 98
Example 5
[0043] Twenty three volunteers (male and female non- or ex-smokers)
were orally administered a single 5 mg dose of prednisolone in the
morning after a ten hour overnight fast. The study design was a
randomized, 6-sequence, 3-period, crossover design. Either 5 mL of
a 5 mg/mL prednisolone acetate suspension, or one 5 mg tablet of a
commercially available product, was administered. Blood samples
were taken at determined intervals. Pharmacokinetic parameters used
to evaluate and compare the relative bioavailability, and therefore
bioequivalence, of the two formulations of prednisolone after a
single oral dose administration under fasting conditions were
C.sub.max, AUC.sub.T, AUC.sub..infin., K.sub.el and T.sub.1/2el.
[0044] C.sub.max--Maximum Concentration. [0045] AUC.sub.T--Area
under the Concentration-time Curve Using the Trapezoidal Method to
the Last Measurable Concentration; [0046] AUC.sub..infin.--Area
under the Concentration-time Curve extrapolated to infinity; [0047]
K.sub.ej--Elimination Rate Constant; [0048] T.sub.1/2el--Terminal
Half-Life. to Bioequivalence was determined using the 90%
confidence interval for the exponential of the difference between
the tablet and the suspension. The test met the 80.00-125%
confidence interval limits with a statistical power of at least
80%.
TABLE-US-00005 [0048] TABLE 5 Bioequivalency: Prednisolone 5 mg/5
mL Suspension versus 5 mg/5 mL Syrup versus 5 mg Tablets Following
a 5 mg administration/Fasting State (100% prelims N = 23/23)
Prednisolone 5 mg/ml Prednisolone 5 mg Suspension Tablet
Coefficient Coefficient of of PARAMETER MEAN Variation MEAN
Variation C.sub.max (ng/mL) 160.90 15.8 176.27 18.7 T.sub.max
(hours) 1.33 41.6 1.00 33.2 AUC.sub.T (ng h/mL) 821.73 20.2 812.39
17.7 AUC.sub..infin. (ng h/mL) 852.23 19.6 846.53 17.1 K.sub.el
(hour.sup.-1) 0.2681 13.4 0.2629 9.7 T.sub.1/2el (hours) 2.63 12.6
2.66 10.0 For Tmax, the median is presented.
[0049] In describing embodiments of the present invention, specific
terminology is employed for the sake of clarity. However, the
invention is not intended to be limited to the specific terminology
so selected. It is to be understood that each specific element
includes all technical equivalents, which operate in a similar
manner to accomplish a similar purpose. The above-described
embodiments of the invention may be modified or varied, and
elements added or omitted, without departing from the invention, as
appreciated by those skilled in the art in light of the above
teachings. Each reference cited herein is incorporated by reference
as if each were individually incorporated by reference.
* * * * *