Note: Descriptions are shown in the official language in which they were submitted.
CA 02388614 2002-04-23
1
PHARMACEUTICAL AGENT PREPARATIONS
The present invention relates to solid dosage forms of an active
pharmaceutical ingredient in which a physical mixture of at least
two preparations of the active ingredient which differ in
relation to the physical state of the active ingredient is
present. The invention further relates to dosage forms which,
comprise a third preparation differing in relation to the
physical state of the active ingredient.
Great problems concerning the bioavailability of dosage forms
arise with a whole, series of very effective active pharmaceutical
ingredients, especially when uniform blood plasma concentrations
are wanted, but.excessively high blood plasma levels must be
avoided, because of the severe side effects, during long-term
therapy. This applies for example to many immunosuppressants, HIV
therapeutic agents or CNS-active substances.
Cyclosporines, a series of nonpolar, cyclic oligopeptides, are
distinguished by their immunosuppressant effect. Of them,
cyclosporine A in particular has attained therapeutic
significance, consists of 11 amino acids and is obtained by
fermentation.
Although cyclosporine formulations have been developed both for
oral and for intravenous use, it is preferred to administer
cyclosporine orally because it ensures better patient compliance.
However, cyclosporine A is quite large, with a molecular weight
of 1202 g/mol, and is very lipophilic, which is also manifested
by a very low solubility in water (<0.004% m/V). Owing to a
certain solubility in oils such as olive oil, and in ethanol, it
has been possible to develop emulsion concentrates which on oral
administration lead to a bioavailability of about 30$, although
this is relatively variable (cf. R.H. Miiller et al. in
"Pharmazeutische Technologies Moderne Arzneiformen",
Wissenschaftliche Verlagsgesellschaft, Stuttgart, 1997, pp.
118-125).
Oral forms currently available on the market are accordingly
either emulsion concentrates for administration as solutions or
microemulsions used to fill capsules. In both cases, solvents
such as ethanol and/or oil are employed to stabilize the
cyclosporine.
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0050/50838
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However, the biolavailability may be subject to great variations
in the range from 10 to 60$. These variations are connected with
the pharmaceutical form and the state of the preparation in the
gastrointestinal tract. In addition, the natural digestion of
fats has a significant influence on the absorption of
cyclosporine administered orally.
WO 97/07787 also describes cyclosporine formulations which,
beside the active ingredient, comprise an alkanolic solvent such
as ethanol or propylene glycol, and a nonionic polyoxyalkylene
derivative as surface-active substance.
However, such forms have the disadvantage firstly that they
contain solvents, especially ethanol, and secondly that the
cyclosporine tends to recrystallize at low temperatures, which is
a problem in relation to storage stability. This is because such
precipitates are very substantially unabsorbed so that a uniform
bioavailability is not ensured in some circumstances.
EP-A 425 892 discloses a method for improving the bioavailability
of active pharmaceutical ingredients with peptide bonds, wherein
a solution of the active ingredient in a water-miscible organic
solvent is rapidly mixed with an aqueous colloid so that the
active ingredient precipitates in colloidal form.
WO 93/10767 describes oral administration forms for
pharmaceutical peptides in which the pharmaceutical is
incorporated into a gelatin matrix in such a way that the
colloidal particles which form have a neutral charge. However,
the disadvantage of such forms is their tendency to flocculation.
It is also known, for example, from EP-A 240 904, that molecular
dispersions of an active ingredient in a polymer matrix can be
obtained by melt extrusion.
It is an object of the present invention to find dosage forms
suitable for oral administration of active ingredients of low
bioavailability, such as, for example, cyclosporine, which
contain no solvents and are comparable in their bioavailability
to microemulsions.
We have found that this object is achieved by the dosage forms
defined at the outset, in which the active ingredient is present
in the form of a physical mixture of at least two preparations of
the active ingredient which differ in relation to the physical
state of the active ingredient. Pharmaceutical forms in which a
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005/50838 CA 02388614 2002-04-23
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third physically different form of the active ingredient is
additionally present have also been found.
According to the invention, the active ingredient is present in a
first preparation (component 1) in the form of solid, X-ray
amorphous particles colloidally dispersed in a matrix of a
polymeric coating material. In a second preparation (component
2), the active ingredient is present as a molecular dispersion in
an excipient matrix. In a third, physically different form
(component 3), the active ingredient is present in the form of
crystalline particles.
.The dosage form according to the invention is suitable in
principle for all active ingredients of low solubility in water
and low bioavailability, but especially for cyclosporine.
It is possible according to the invention to process all
cyclosporines, but cyclosporine A is preferred. Cyclosporine A
has a melting point of 148 to 151~C and is employed as a colorless
crystalline substance.
In component 1, the active ingredient is colloidally embedded in
the form of X-ray amorphous particles in a coating matrix
consisting of one or more polymeric stabilizers. Suitable
polymeric stabilizers are swellable protective colloids such as,
for example, bovine, porcine or fish gelatin, starch, dextrin,
pectin, gum arabic, ligninsulfonates, chitosan,
polystyrenesulfonate, alginates,' caseine, caseinate,
methylcellulose, carboxymethylcellulose, hydroxypropylcellulose,
milk powder, dextran, whole milk or skimmed milk or mixtures of
these protective colloids. Also suitable are homo- and copolymers
based on the following monomers: ethylene oxide, propylene oxide,
acrylic acid, malefic anhydride, lactic acid, N-vinylpyrrolidone,
vinyl acetate, a- and ~i-aspartic acid. One of said gelatin types
is particularly preferably employed, in particular acid- or
base-degraded gelatin with Bloom numbers in the range from 0
to 250, very particularly preferably gelatin A 100, A 200, H 100
and B 200, and low molecular weight, enzymatically degraded
gelatin types with Bloom number 0 and molecular weights of from
15,000 to 25,000 D, such as, for example, Collagel A and
Gelitasol P (from Stoess, Eberbach), and mixtures of these
gelatin types.
These preparations additionally comprise low molecular weight
surface-active compounds. Particularly suitable as such are
amphiphilic compounds or mixtures of such compounds. Suitable in
principle are all surfactants with an HLB of from 5 to 20.
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Examples of suitable surface-active substances are: esters of
long-chain fatty acids with ascorbic acid, mono- and diglycerides
of fatty acids and their ethoxylation products, esters of fatty
acid monoglycerides with acetic acid, citric acid, lactic acid or
diacetyltartaric acid, polyglycerol fatty acid esters such as,
for example, the monostearate of triglycerol, sorbitan fatty acid
esters, propylene glycol fatty acid esters,
2-(2-stearoyllactyl)lactic acid salts and lecithin. Ascorbyl
palmitate is preferably employed.
Id
The amounts of the various components are chosen according to the
invention so that the preparations comprise from 0.1 to 70~ by
weight, preferably 1 to 40~ by weight, of active ingredient, from
I to 80~ by weight, preferably 10 to 60$ by weight, of one or
more polymeric stabilizers and from 0 to 50~ by weight,
preferably 0.5 to 20$ by weight, of one or more low molecular
weight stabilizers. The percentages by weight are based on a dry
powder.
To produce the first formulation, firstly a solution of the
active ingredient in a suitable solvent is prepared, solution
meaning in this connection a true solution or a melt emulsion.
Suitable solvents are organic, water-miscible solvents which are
volatile and thermally stable and contain only carbon, hydrogen,
nitrogen and oxygen. They are expediently at least 10~ by weight
miscible with water and have a boiling point below 200~C and/or
have fewer than 10 carbon atoms. Corresponding alcohols, esters,
ketones and acetals are preferred. In particular, ethanol,
n-propanol, isopropanol, 1,2-butanediol 1-methyl ether,
1,2-propanediol 1-n-propyl ether or acetone is used.
In one embodiment of the invention, a solution of the active
ingredient is prepared by dissolving the latter in the chosen
solvent at temperatures in the range preferably of from 20 to
150°C, within a period of less than 120 seconds, it being possible
where appropriate to operate under a gage pressure of up to 100
bar, preferably 30 bar.
In a further preferred embodiment, the active ingredient solution
is prepared by heating the mixture of active ingredient and
solvent within a period of less than 10 seconds above the melting
point of the active ingredient to 150 to 240~G, it being possible
where appropriate to operate under a gage pressure of up to 100
bar, preferably 30 bar.
0050/50838
CA 02388614 2002-04-23
The concentration of the active ingredient solution prepared in
this way is generally from 10 to 500 g of active ingredient per
1 kg of solvent. In a preferred embodiment of the process, the
low molecular weight stabilizer is added directly to the active
5 ingredient solution.
In a process step which follows this, the active ingredient
solution is mixed with an aqueous solution of the polymeric
coating material. The concentration of the solution of the
polymeric coating material is from 0.1 to 200 g/1, preferably 1
to 100 g/1.
In order to obtain particle sizes as small as possible in the
mixing step, it is advisable for the mechanical energy input to
be high when mixing the active ingredient solution with the
solution of the coating material. Such an energy_input can take
place, for example, by vigorous stirring or shaking in a suitable
apparatus, or by injecting the two components as a powerful jet
into a mixing chamber so that vigorous mixing occurs.
The mixing step can be carried out discontinuously or,
preferably, continuously. The mixing step results in the active
ingredient being precipitated in the form of solid, X-ray
amorphous particles. The colloidal suspension obtained in this
way can be converted in a manner known per se into a dry powder,
for example by spray drying, freeze drying or fluidized-bed
drying.
The procedure for producing the preparations according to the
invention is to adjust the pH of the solution of the coating
material, in particular of gelatin, and of a solution of the
active ingredient so that the active ingredient particles which
are forming do not develop a neutral charge, i.e. the pH of the
gelatin solution must not be adjusted to a value such that a
stage of neutral charge is set up when the particles form. The
particles are preferably produced at pH values above 7.
The average diameter of the solid active ingredient particles in
the matrix of the polymeric coating material is from 20 to
1000 nm, preferably 100 to 600 nm. The spherical active
ingredient particles are completely X-ray amorphous. X-ray
amorphous means in this connection the absence of crystal
interferences in X-ray powder diagrams (cf. H.P. Klug, L.E.
Alexander, "X-Ray Diffraction procedures for Polycrystalline and
Amorphous Materials", John Wiley, New York, 1959). The active
005/50838 CA 02388614 2002-04-23
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ingredient particles are distinguished by having a negative
charge after redispersion in aqueous medium at a pH above 5.
In the second formulation, the active ingredient is in the form
of a molecular dispersion in an excipient matrix. Such molecular
dispersions of an active ingredient in a matrix are also referred
to as "solid solutions" (cf. Chiou and Riegelman, J. Pharm. Sci.,
60, 1281-1300). Such solid solutions can be produced by the
solution process by dissolving the active ingredient together
with the components forming the excipient matrix in a suitable
solvent, and then removing the solvent. Examples of suitable
solvents are water, ethanol, isopropanol, acetone, chlorinated
hydrocarbons such as methylene chloride or chloroform,
tetrahydrofuran, toluene or methyl ethyl ketone. The solvent is
normally evaporated off in vacuo.
Such solid solutions can also be produced by the melt process
where the active ingredient and the starting materials forming
the excipient matrix are intimately mixed while molten. The
process is preferably carried out without addition of solvents.
The melt process is carried out in a kneader or screw extruder.
Examples of suitable kneaders are those supplied by Haake or
Farrell.
The melt is preferably produced in a screw extruder, particularly
preferably a twin screw extruder with and without kneading disks
or similar mixing elements. Co-rotating twin screw extruders are
particularly preferred.
Depending on the composition, processing generally takes place at
temperatures of from 40 to 260~C, preferably 50 to 200~C.
The starting materials can be fed into the extruder or kneader
singly or as premix. Addition preferably takes place in the form
of powdered or granulated premixes. Thus, the liquid or oily
surface-active substance can be previously mixed with another
starting material to give free-flowing granules. Addition of the
surface-active substance in liquid form, for example via liquid
pumps, which are preferably heated in the case of semisolid
substances, is likewise possible.
It is also possible first to dissolve the active ingredient in
the surface-active substance, and then to granulate this mixture
with the polymer. In this case, the active ingredient itself must
not melt.
0050/50838 CA 02388614 2002-04-23
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In the case of temperature-sensitive active ingredients it may
also be advisable first to melt the other starting materials and
only then to add the active ingredient.
The starting materials are accordingly processed together to give
a melt which is processed to a homogeneous composition by input
of mechanical energy, in particular in the form of shear forces.
The homogeneous melt is then extruded through a die or a breaker
plate and shaped. This can take place by cutting off the
extrudate by conventional techniques, for example with the aid of
rotating knives or by compressed air cutting off, resulting in
pellets or granules. It is further possible for the shaping to
take place as described in EP-A 240 906, by the extrudate being
passed between two counter-rotating calender rolls and being
directly shaped to tablets. The melt can likewise be discharged
through the open head and, after solidification, where
appropriate also ground or further processed by suitable
granulating equipment such as rolls or compacting units.
Examples of suitable matrix formers which the second formulations
can contain are melt-processable water-soluble or water-swellable
polymers. Water-soluble means that at least 1 g of the polymer
dissolves in 10 ml of water at 25~C. Water-swellable means that
the water uptake at 25~C and 75$ relative humidity is more than 1~
by weight, without the polymer dissolving.
Examples of suitable polymers are homo- and copolymers of
N-vinylpyrrolidone with Fikentscher K values of from 19 to 100. A
suitable comonomer is, in particular, vinyl acetate, as is vinyl
propionate, vinylcaprolactam or vinylimidazole.
Likewise suitable are cellulose derivatives, for example
hydroxyalkylcelluloses such as hydroxypropylcellulose,
alkylcelluloses or alkylhydroxyalkylcelluloses such as
hydroxypropylmethylcelluloses.
Additionally suitable are polyethylene glycols with molecular
weights of from 1500 to 10 million D or
polyoxyethylene/polyoxypropylene block copolymers.
It is, of course, also possible to employ mixtures of said
polymers.
Also suitable as matrix formers are sugar alcohols such as
erythritol, isomalt, mannitol, sorbitol, xylitol or mixtures of
such sugar alcohols.
0050/50838 CA 02388614 2002-04-23
The matrix may also contain pharmaceutically acceptable
excipients such as bulking agents, lubricants, mold release
agents, flow regulators, plasticizers, dyes, flavorings and/or
stabilizers in the amounts customary for this purpose.
In a further embodiment of the invention, the active ingredient
dosage forms may comprise a third formulation (component 3). The
active ingredient is present in this formulation in the form of
particles, the active ingredient in the particles having a
crystallinity of at least 20$. The crystallinity refers to the
proportion of active substance which is not in amorphous form.
The active ingredient can also be present in component 3 in
different crystal modifications.
The active ingredient is present in this formulation in
particular as pure crystalline substance without further
excipients. The particles have average diameters in the range
from 0.05 to 200 dun, preferably 0.1 to 50 Eun. The crystalline
particles can be obtained from crude crystalline product by
grinding processes known per se. Examples of suitable grinding
processes are dry or wet grinding. Examples of suitable apparatus
are ball mills, pinned disk mills or air jet mills.
The dosage forms according to the invention are obtained by
physically mixing components 1, 2 and 3. The total amount of
active ingredient in component 1 is preferably in the range from
10 to 70~ by weight, particularly preferably from 20 to 60$ by
weight, in component 2 is preferably in the range from 10 to 70$
by weight, particularly preferably from 20 to 60~ by weight, and
in component 3 is preferably in the range from 0 to 30~ by
weight. The physical properties of the individual components are
unchanged after the mixing.
The physical mixtures according to the invention of two or three
preparations of the active ingredient in each of which the active
ingredient is present in a different physical form can be
employed in all oral drug forms suitable for this purpose. Thus,
for example, they can be packed into hard or soft gelatin
capsules or be compressed to tablets under conditions known per
se.
Surprisingly, the dosage forms according to the invention have
bioavailabilities which are higher than those of the individual
components. Such a synergistic effect was unexpected for the
skilled worker.
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The results of a study on dogs prove the good bioavailability of
the dosage form by comparison with a product on the market.
Production Example 1
Production of an active ingredient dry powder with an active
ingredient content in the region of 10~ by weight
a) Production of the micronisate
3 g of cyclosporine A were stirred into a solution of 0.6 g
of ascorbyl palmitate in 36 g of isopropanol at 25°C,
resulting in a clear solution.
To precipitate the cyclosporine A in colloidal form, this
solution was fed at 25°C into a mixing chamber. It was there
mixed with 537 g of an aqueous solution of 14.4 g gelatin B
100 Hloom and 12.6 g of lactose in deionized water which has
been adjusted to pH 9.2 with 1 N NaOH. The pressure
throughout the process was limited to 30 bar. After mixing, a
colloidal dispersion of cyclosporine A was obtained with a
cloudy white appearance.
The average particle size was determined by quasielastic
light scattering to be 256 nm with a variance of 31~.
Fraunhofer diffraction was used to determine the average of
the volume distribution to be D(4,3) - 0.62 N,m with a fine
content of the distribution of 99.2$ <1.22 ~.m.
b) Drying of dispersion a) to give a nanoparticulate dry powder
Spray drying of the product la) afforded a nanoparticulate
dry powder. The active ingredient content in the powder was
determined by chromatography to be 9.95 by weight. The dry
powder dissolves in drinking water to form a cloudy white
dispersion (hydrosol).
Production Example 2
Production of a cyclosporine dry powder with an active ingredient
content in the region of 15~ by weight
a) Production of the micronisate
3 g of cyclosporine A were stirred into a solution of 0.6 g
of ascorbyl palmitate in 18 g of isopropanol and 18 g of
deionized water at 25°C. Dissolving was completed by heating
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D~r~~~ ,r~a~3$ CA 02388614 2002-04-23
l
in a heat exchanger. The cyclosporine solution remained in
the heat exchanger for 90 sec, the temperature not exceeding
135°C.
To precipitate the cyclosporine A in colloidal form, this
solution was fed at 135°C into a mixing chamber. It was there
mixed with 393.9 g of an aqueous solution of 9.2 g gelatin A
100 Bloom and 6.1 g of lactose in deionized water which has
been adjusted to pH 9.2 with 1 N NaOH. In order to prevent
evaporation of the water, the pressure throughout the process
was limited to 30 bar. After mixing, a colloidal dispersion
of cyclosporine A was obtained with a cloudy white
appearance.
The average particle size was determined by quasielastic
light scattering to be 285 nm with a variance of 48~.
Fraunhofer diffraction was used to determine the average of
the volume distribution to be D(4,3) = 0.62 ~,m with a fine
content of the distribution of 99.8$ <1.22 ~,m.
b) Drying of dispersion 2a) to give a dry powder
Spray drying of the dispersion resulted in a nanoparticulate
dry powder. The active ingredient content in the dry powder
was determined by chromatography to be 15.9$ by weight. The
dry powder dissolves in drinking water to form a cloudy white
dispersion.
The average particle size immediately after redispersion was
determined by quasielastic light scattering to be 376 nm with
a variance of 38~. Fraunhofer diffraction was used to
determine the average of the volume distribution to be D(4,3)
- 0.77 N.m with a fine content of the distribution of 84.7
<1.22 ~,m.
Freeze drying the product resulted in a nanoparticulate dry
powder. The active ingredient content in the powder was
determined by chromatography to be 16.1$ by weight
cyclosporine. The dry powder dissolved in drinking water to
give a cloudy white hydrosol.
The average particle size immediately after redispersion was
determined by quasielastic light scattering to be 388 nm with
a variance of 32$. Fraunhofer diffraction was used to
determine the average of the volume distribution to be D(4,3)
a
CA 02388614 2002-04-23
0050/50838
11
- 0.79 ~m with a fine content of the distribution of 82.4
< 1. 2 2 dun .
35
Production Example 3
5
A colloidal dispersion of cyclosporine A was produced from 4.5 g
of cyclosporine A, 0.9 g of ascorbyl palmitate, 9.6 g of gelatin
A 100 Bloom and 7.2 g of lactose in analogy to Example 2a).
10 The average particle size was determined by quasielastic light
scattering to be 280 nm with a variance of 21~. Fraunhofer
diffraction was used to determine the average of the volume
distribution to be D(4,3) = 0.62 N.m with a fine content of the
distribution of 99.2% <1.22 Vim.
b) Drying of dispersion 3a) to give a nanoparticulate dry powder
Spray drying resulted in a nanoparticulate dry powder with a
cyclosporine A content (determined by chromatography) of
19.9$ by weight. The dry powder dissolved in drinking water
to form a cloudy white dispersion (hydrosol).
The average particle size immediately after redispersion was
determined by quasielastic light scattering to be 377 nm with
a variance of 45~. Fraunhofer diffraction was used to
determine the average of the volume distribution to be D(4,3)
- 0.62 ~,m with a fine content of the distribution of 83.3$
<1.22 ~.ttt.
Production Example 4
A preparation was produced employing fish gelatin with molecular
weight contents of from 103 to 10~ D as coating matrix material in
analogy to Production Example 3.
Production Example 5
Production of a solid solution of cyclosporine by melt extrusion
Production took place in a Werner & Pfleiderer ZKS30 twin screw
extruder with an output of 2 kg/hour. The still plastic extrudate
was shaped by calendering as described in EP-A 240 906. A mixture
of 65~ by weight of a polyvinylpyrrolidone with K value 12, 15$
by weight of poloxamer 407 and 20$ by weight of cyclosporine was
processed.
005~~50838 CA 02388614 2002-04-23
a
12
Temperature of the sections: 50, 88, 128, 131, 127, 126~C;
Die: 120~C.
The calendered forms were ground using an air jet mill so that
95~ of the particles had a diameter <10 Eun.
Production Example 6
A mixture of 80~ by weight of a copolymer of 60$ by weight of
N-vinylpyrrolidone and 40% by weight of vinyl acetate, and 20~ by
weight of cyclosporine was processed in analogy.to Example 5.
Temperature of the sections: 55, 110, 140, 137, 136, 141~C;
Die: 140~C.
Pharmacokinetic properties of the formulations
Blood level kinetics in dogs: General method
Cyclosporine was administered in the appropriate preparation,
either orally as solid form or by gavage in the case of liquid
forms, to beagle dogs with a weight in the range from 8 to 12 kg.
Liquid forms were given 50 ml of water, washing down with a
further 50 ml of water. Solid forms were administered without
water. Feed was withdrawn from the animals 16 h before
administration of the substance, and feeding was renewed 4 h
after administration of the substance. Blood was taken in
heparinized vessels from the jugular vein or the Vena cephalica
antebrachii of the dogs before administration of the substance
and at intervals up to 32 h. The blood was deep-frozen and stored
at -20~C until the analytical workup. The blood levels were
determined by a validated, internally standardized GC-MS method.
Form 1 (for comparison):
Sandimmun Optoral, capsule, 100 mg of active ingredient
Form 2:
Dry powder from Production Example 2, active ingredient dose
100 mg; administration as hydrosol
Form 3:
Extrudate from Production Example 5, active ingredient dose
100 mg; administration as tablet
005/50838 ~ CA 02388614 2002-04-23
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Form 4:
Combination of dry powder from Example 2 and extrudate from
Example 5, active ingredient dose in the dry powder 50 mg and in
the extrudate 50 mg
Areas under the curves of the blood levels and relative
bioavailability
Table
Form 1 (Sandimmun Optoral)
Para- Dog Dog Dog Dog Dog Dog Mean Median
meter 1 2 3 4 5 6
15tmax 2.0 2.0 2.0 1.0 2.0 2.0 2.0
Cmax 1030.0 1062.0 865.0 387.0 1799.0 869.0 1002.0 949.5
AUC 5781.8 6487.8 6497.0 2403.67892.2 7047.8 6018.4 6492.4
AUC/ 734.7 855.9 759.9 288.5 947.4 846.1 738.8 803.0
dose
BA $ 99 116 103 39 128 114 100 I00
AUC: Area under the curve
BA: Bioavailability
tmax: (h]
Cmax: [ng/ml]
Form 2
Para- Dog Dog Dog Dog Dog Dog Mean Median
1 2 3 4 5 6
meter
~1
tmax 2.0 1.0 2.0 1.0 2.0 2.0 1.7 2.0
Cmax 488.0 821.0 783.0 985.0 737.0 1088.0 817.0 802.0
AUC 2441.5 3519.8 3712.8 4094.83117.0 4964.5 3641.7 3616.3
AUC/
290.5 423.9 427.0 458.6 349.1 585.8 424.0 429.9
dose
BA 49 73 72 77 59 98 71 72
%
Form 3
para- Dog Dog Dog Dog Dog Dog Mean Median
1 2 3 4 5 6
meter
tmax 3.0 2.0 1.0 1.0 2.0 2.0 2.0 1.9
Cmax 692.0 738.0 772.0 1065.0525.0 481.0 715.0 712.6
AUC 2870.5 2830.3 2758.0 3597.31899.0 2003.0 2794.1 2678.9
AUC/ 413.4 441.5 402.7 478.4 341.8 310.5 408.0 399.5
dose
BA 69 74 68 80 57 52 67 68
$
0050/50838
CA 02388614 2002-04-23
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Form 4
Para- Dog Dog Dog Dog Dog Dog Mean Median
meter 1 2 3 4 5 6
tmax 2.0 2.0 0.5 1.0 1.0 1.0 1.0
Cmax 1132.01314.0 6024.0 1013.0 894.0 1579.0 1992.7 1223.0
AUC 4292.05214.3 11519.53931.3 3271.05189.3 5569.5 4740.6
AUC/ 510.7 641.4 1324.7 440.3 366.4 612.3 649.3 561.5
dose
BA $ 86 108 222 74 61 103 109 94
20
30
40
