Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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TIOTROPIUM CONTAINING HFC SOLUTION FORMULATIONS
This invention relates to notropium containing stable pharmaceutical solution
formulations
suitable for aerosol administration. More particularly, this invention relates
to tiotropium
containing stable pharmaceutical solution formulations suitable for aerosol
administration
wherein either an inorganic acid or an organic acid is added to the aerosol
solution
formulation which contains a tiotropium salt, preferably tiotropium bromide in
solution
with an environmentally safe hydrofluorocarbon (HFC) as a propellant, together
with an
organic compound as a cosolvent. The acid provides stability against
degradation or
decomposition of the medicament resulting largely from interaction of the
medicament
with the cosolvent and/or water present in the solution formulation.
BACKGROUND OF THE INVENTION
Tiotropium bromide is known from European Patent Application EP 418 716 A1 and
has
the following chemical structure:
H3C,N,CH3
O Br_
O
HO O
J
Tiotropium bromide is a highly effective anncholinergic with a long-lasting
activity which
can be used to treat respiratory complaints, particularly COPD (chronic
obstructive
2o pulmonary disease) and asthma. The term tiotropium refers to the free
ammonium canon.
For treating the abovementioned complaints, it is useful to administer the
active substance
by inhalation. In addition to the administration of broncholyncally active
compounds in the
form of inhalable powders containing the active substance the administration
of tiotropium
bromide can also occur in form of hydrofluorocarbon containing aerosol
solution
formulations.
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The administration of aerosol formulations of medicaments by means of
pressurized,
metered-dose inhalers (MDIs) is used widely in therapy, such as in the
treatment of
obstructive airway diseases and asthma. Compared with oral administration,
inhalation
provides more rapid onset of action while minimizing systemic side effects.
Aerosol
formulations can be administered by inhalation through the mouth or topically
by.
application to the nasal mucosa.
Formulations for aerosol administration via MDIs can be solutions or
suspensions.
Solution formulations offer the advantage of being homogeneous in nature with
the
medicament and excipient completely dissolved in the propellant vehicle.
Solution
1o formulations also obviate physical stability problems associated with
suspension
formulations and thus assure more consistent uniform dosage administration
while also
eliminating the need for surfactants.
The adr~ninistration of aerosol solution formulations via MDIs is dependent
upon the
propulsive force of the propellant system used in its manufacture.
Traditionally, the
propellant comprised a mixture of chlorofluorocarbons (CFCs) to provide the
desired
solubility, vapor pressure, and stability of the formulation. However, since
it has been
established in recent years that CFCs are environmentally harmful because they
contribute
to the depletion of the Earth's ozone layer, it is desirable to substitute
environmentally safe
hydrofluorocarbon (HFC) propellants or other non-chlorinated propellants for
environmentally harmful CFC propellants in aerosol inhalation formulations.
For example,
U.S. Patent No. 4,174,295 discloses the use of propellant systems consisting
of
combinations of HFCs, which may also contain a saturated hydrocarbon
component,
suitable for application in the fields of home products such as hair lacquers,
anti-
perspiration products, perfumes, deodorants, paints, insecticides and the
like.
It is known in the art that certain HFCs have properties suitable for use as
propellants for
the aerosol administration of medicaments. For example, published European
patent
Application No. 0 372 777 (EP089312270.5) describes the use of 1,1,1,2-
tetrafluoroethane
(HFC-134(a)) in combination with at least one "adjuvant" (a compound having a
higher
polarity than the HFC-134(a)) and a surface active agent to prepare suspension
and
3o solution formulations of medicaments suitable for administration by the
aerosol route.
Also, PCT Published Application No. W091/11496 (PCT/EP91/00178) discloses the
use of
1,1,1,2,3,3,3-heptafluoropropane (HFC-227), optionally mixed with other
propellant
components, for use in preparing suspension aerosol formulations of
medicaments.
US-A-2 868 641 and US-A-3 282 781 disclose aerosol compositions comprising a
medicament (epinephrine or isoproterenol HCl), a cosolvent, a propellant and
ascorbic acid
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as anti-oxidant. European Patent EP 673 240 B 1 proposes the addition of acids
to
medicinal aerosol formulations in order to provide for the stabilization of
the medicament.
DESCRIPTION OF THE INVENTION
The term "aerosol solution formulation" means a pharmaceutical formulation of
a
medicament suitable for aerosol administration wherein the medicament and
excipients are
completely dissolved.
The term "stabilized aerosol solution formulation" means an aerosol solution
formulation
which exhibits substantial chemical stability over time.
to
The present invention provides stabilized aerosol solution formulations
comprising a
tiotropium salt, an HFC propellant, a cosolvent, and an inorganic or an
organic acid,
characterized in that the concentration of the acid is in a range that
corresponds with a pH
range of 2.5 - 4.5 in aqueous solution.
In preferred aerosol solution formulations according to the invention the
concentration of
the acid is in a range that corresponds with a pH range of 3.0 - 4.3, more
preferred 3.5 - 4.0
in aqueous solution.
2o A small amount of water (up to about 5%, preferably up to about 3 % by
weight, ) may
also be present in the propellant/cosolvent system.
The aerosol solution formulation according to the invention preferably
contains 0.00008 to
0.4 %, preferably 0.0004 to 0.16 %, more preferably 0.0008 to 0.08 %
tiotropium. By
tiotropium is meant the free ammonium canon. In the notropium salt present in
the
formulation according to the invention the counter-ion (anion) may be
chloride, bromide,
iodide, methanesulphonate or para-toluenesulphonate. Of these anions, the
bromide is
preferred.
3o If the preferred tiotropium salt tiotropium bromide is used, the
aforementioned amounts
correspond to 0.000096 to 0.48 % tiotropium bromide, preferably 0.00048 to
0,192 %,
more preferably 0.00096 to 0.096 % tiotropium bromide.
Tiotropium bromide is, depending on the choice of reaction conditions and
solvents,
obtainable in different crystalline modifications. Most preferred according to
the invention
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are those formulations, that contain tiotropium in form of the tiotropium
bromide
monohydrate as disclosed in WO 02/30928. This tiotropium bromide monohydrate
is
characterised by an endothermic peak at 230 ~ 5°C as determined by DSC.
Accordingly, the aerosol solution formulations according to the invention
preferably
contains 0.0001 to 0.5 % tiotropium bromide monohydrate, preferably 0.000 to
0.2 %,
more preferably 0.001 to 0.1 % tiotropium bromide monohydrate.
Suitable HFC propellants are those which, when mixed with the cosolvent(s),
form a
to homogeneous propellant system in which a therapeutically effective amount
of the
medicament can be dissolved. The HFC propellant must be toxicologically safe
and must
have a vapor pressure which is suitable to enable the medicament to be
administered via a
pressurized N>DI. Additionally, the HFC propellant must be compatible with the
components of the 1V>DI device (such as containers, valves, and sealing
gaskets, etc.) which
i5 is employed to administer the medicament. Preferred HFC propellants are
1,1,1,2-
tetrafluoroethane (HFC-134(a)) and 1,1,1,2,3,3,3,-heptafluoropropane (HFC-
227). HFC-
134(a) is particularly preferred. Other examples of HFC propellants are HFC-32
(difiuoromethane), HFC-143(a) (1,1,1-trifluoroethane), HFC-134 (1,1,2,2-
tetrafluoroethane), and HFC-1~2a (1,1-difluoroethane).
2o It will be apparent to those skilled in the art that non-halogenated
hydrocarbon propellants
may be used in place of the HFC propellants in the present invention. Examples
of non-
halogenated hydrocarbons are saturated hydrocarbons, including propane, n-
butane, and
isobutane, and ethers, including diethyl ether.
It will also be apparent to those skilled in the art that, although the use of
a single HFC
25 propellant is preferred, a mixture of two or more HFC propellants, or a
mixture of at least
one HFC propellant and one or more non-CFC propellants, may be employed in the
aerosol solution formulation of the present invention.
A substantially non-aqueous HFC propellant/cosolvent system is preferred.
Water may be
present in small amounts as an impurity in the HFC propellant/cosoIvent
system, may be
3o introduced during the manufacturing process or may permeate into the system
through the
valve or valve/container seals or gaskets. If desired, small amounts of water
may be added
(up to about 5%, preferably up to about 2 % by weight) to the HFClpropellant
system, for
example, to aid in manufacturing.
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The acid in the formulations according to the invention may be any inorganic
or mineral
acid, for example, hydrochloric acid, sulfuric acid, nitric acid, or
phosphoric acid, or the
like. From the aforementioned acids hydrochloric acid is of particular
interest. The acid
may also be selected from the group of acids known to those skilled in the art
as organic
acids, which are in most cases considered to be weak acids relative to the
inorganic acids.
Representative of this group and preferred in this invention are ascorbic
acid, citric acid,
lactic acid, malic acid, benzoic acid and tartaric acid. According to this
invention, citric
acid and ascorbic acid are the most preferred organic acids.
1o The formulations according to the invention can be prepared in analogy to
methods known
in the art.
If desired, pharmaceutically acceptable excipients can be included in the
aerosol solution
formulations of the present invention. For example, a soluble surface active
agent can be
added in order to improve the performance of valve systems employed in the MDI
devices
used for the aerosol administration of the formulations. Examples of preferred
surface
active agents are sorbitan trioleate, lecithin, and isopropylmyristate. Other
suitable
lubricants are well known in the art (see, for example, Published European
Patent
Application No. 0372777 (EPO 893122705)). Other excipients are: (a)
antioxidants, for
2o example ascorbic acid and tocopherol; (b) taste masking agents, for
example, menthol,
sweeteners, and artificial or natural flavors; and (c) pressure modifying
agents, for
example, n-pentane, iso-pentane, neo-pentane, and n-hexane.
Examples of cosolvents applicable within the formulations according to the
invention are:
alcohols, for example, ethyl alcohol, isopropyl alcohol, and benzyl alcohol;
glycols for
example, propylene glycol, polyethylene glycols, polypropylene glycols, glycol
ethers, and
block copolymers of oxyethylene and oxypropylene; and other substances, fox
example,
glycerol, polyoxyethylene alcohols, polyoxtsthylene fatty acid esters, and
glycofurols (for
example glycofurol 75).
3o Examples of cosolvents that may be inert to interaction with the
medicaments) are
hydrocarbons, for example, n-propane, n-butane, isobutane, n-pentane, iso-
pentane, neo-
pentane, and n-hexane; and ethers, for example, diethyl ether.
A preferred cosolvent according to this invention is ethyl alcohol (ethanol).
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The amount of cosolvent is preferably in the range of 5 - 50% (w/w) of the
total
composition. More preferably, the amount of co-solvent in the formulation
according to the
invention is in the range of 10 - 40 % (w/w), preferably in the range of 15 -
30 %.
As mentioned hereinbefore the formulations according to the invention may
contain water
a small amount of water. One preferred embodiment of the invention pertains to
formulations that contain water in an amount of up to 5 % (w/w), preferably of
up to 3 %
(w/w). Another preferred embodiment of the invention is directed to
formulations that do
not contain any water. In these water-free formulations the amount of
cosolvent is
i0 preferably in the range of about 20 - 50% (w/w), more preferably in the
range of about 30 -
40% (w/w).
Especially in these water-free formulations the anhydrous form of tiotropium
bromide
obtainable from the tiotropium bromide monohydrate mentioned hereinbefore can
be used.
The anhydrous form is obtained from the crystalline tiotropium bromide
monohydrate
disclosed in WO 02/30928 by careful drying at more than 50°C,
preferably at 60-100°C,
most preferably at 70-100°C, under reduced pressure, preferably in a
high vacuum over a
period of 15 minutes to 24 hours, preferably 20 minutes to 12 hours, most
preferably 30
minutes to 6 hours. The term "reduced pressure" most preferably refers to a
pressure of up
to 5 x 10-2 bar, preferably 1 x 10-Z bar, most preferably 5 x 10-3 bar.
Most preferably, the abovementioned dehydration to form the anhydrate is
carned out at
about 1 x 10-3 bar or less.
Alternatively to the drying step at elevated temperature under reduced
pressure described
above, the anhydrous form may also be prepared by storing the crystalline
tiotropium
bromide monohydrate over a drying agent, preferably over dried silica gel at
ambient
temperature for a period of 12 to 96 hours, preferably 18 to 72 hours, most
preferably at
least 24 hours. The anhydrous form thus obtained should be stored more or less
dry,
depending on the particle size, to preserve its anhydrous state. In the case
of coarse crystals
of anhydrous tiotropium bromide, which may be prepared fox example as
described above,
storage at < 75 % r.h. (relative humidity) is sufficient to maintain the
anhydrous state. In
the micronised state, i.e. when the material has a much larger surface area,
water may even
be absorbed at lower humidity levels. In order to maintain the anhydrous form
in the
micronised state, it is therefore advisable to store the anhydrous form of
tiotropium
bromide over dried 'silica gel.
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The anhydrous form of tiotropium bromide was subjected to X-ray analysis which
revealed
that the crystalline anhydrous tiotropium bromide is characterised by the
elementary cells a
= 10.4336(2)A, b = 11.3297(3)A, c = 17.6332(4) ~1 and a = 90°, (3 =
105.158(2)° and y =
90° (cell volume = 2011.89(8) ~3 ). The crystalline structure of the
anhydrous form of
tiotropium bromide can be described as a layered structure. The bromide ions
are located
between the layers of tiotropium. Further details concerning the determination
of the
crystalline structure of the said anhydrous form are outlined in the
experimental part of this
patent application.
Accordingly, a further preferred embodiment of the invention is directed to a
stabilized
aerosol solution formulation comprising anhydrous tiotropium bromide
characterized by
the aforementioned parameters, an HFC propellant, a cosolvent, and an
inorganic or an
organic acid, characterized in that the concentration of the acid is in a
range that
corresponds with a pH range of 2.5 - 4.5 in aqueous solution and further
characterized in
that the formulation is free of water.
The formulations according to the invention can be administered with inhalers
known in
the art (Metered dose inhalers = MDIs).
In another aspect the invention is directed to the use of an aerosol solution
formulation as
described hereinbefore for the manufacture of a medicament for the treatment
of
respiratory complaints, particularly COPD (chronic obstructive pulmonary
disease) and
asthma.
In yet another aspect the invention is directed to a method for treatment of
respiratory
complaints, such as in particular COPD (chronic obstructive pulmonary disease)
or asthma,
characterized by the administration of an aerosol solution formulation as
described
hereinbefore.
The following Examples serve to illustrate the present invention further
without restricting
its scope to the embodiments provided hereinafter by way of example.
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I. Formulation examples
A)
B)
C)
D)
Component Concentration [ % w/w]
Tiotro iurn bromide monoh 0.02
drate
Ethanol abs. (USP) 25.0
Water ( urified, USP) 1.0
Citric acid (USP) 0.003
HFG-134a 73.977
Com onent Concentration [ % w/w]
Tiotro ium bromide monoh 0.02
drate
Ethanol abs. (USP) 20.0
A ueous HCl 0.01 mol/1 2.0
(USP)
HFC-134a 77.98
Com onent Concentration [ % w/w]
Tiotro ium bromide monohydrate 0.01
Ethanol abs. (USP) 15.0
Water ( urified, USP) 2.0
Citric acid (USP) 0.004
HFC-227 82.986
Com onent Concentration [ % w/w]
Tiotro ium bromide monoh 0.01
drate
Ethanol abs. (USP) 30.0
Water ( unified, USP) 1.0
Ascorbic acid (USP) 0.005
HFC-134a 68.985
_g_
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E)
Com onent Concentration [ % w/w]
Tiotro ium bromide (anh 0.01
drous)
Ethanol abs. (USP) 40.0
citric acid (USP) 0.004
HFC-227 59.986
The aformentioned formulations can be prepared by conventional methods known
in the
state of the art.
II. Preparation of crystalline anhydrous tiotropium bromide:
The anhydrous form is produced from the crystalline tiotropium bromide
monohydrate
(obtainable as described in WO 02/30928) by careful drying at 80 -100
°C under reduced
to pressure, preferably under a high vacuum (at about 1 x 10-3 bar or less)
over a period of at
least 30 minutes. Alternatively to the drying step at 80 -100 °C in
vacuo the anhydrous
form may also be prepared by storing over dried silica gel at ambient
temperature for a
period of at least 24 hours.
15 III. Characterisation of crystalline, anhydrous tiotropium bromide
As described hereinbefore, the crystalline anhydrous tiotropium bromide
according to the
invention may be obtained from crystalline tiotropium bromide monohydrate.
The crystalline structure of anhydrous tiotropium bromide was determined from
high-
resolution X-ray powder data (synchrotron radiation) using a real space
approach with a
20 so-called simulated annealing process. A final Rietveld analysis was
carried out to refine
the structural parameters. Table 1 contains the experimental data obtained for
crystalline,
anhydrous tiotropium bromide.
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Table 1: Experimental data relating to the crystalline structural analysis of
tiotropium
bromide (anhydrous)
formula C19H22N~4S2Br
temperature [C] 25
molecular weight 472.4
[g/mol]
space group P21/c
a [A] 10.4336(2)
0
b [A] 11.3297(3)
0
c [A] . 17.6332(4)
,!3 [] 105.158(2)
V [A3] 2011.89(8)
Z 4
calculated density 1.56
[g cm 3]
20 (range) [] 2.0 - 20
interval [20] 0.003
counting time / step3
[sec]
wavelength [A] 0.7000
The crystalline structure of the anhydrous form of tiotropium bromide can be
described as
a layered structure. The bromide ions are located between the layers of
tiotropium.
In order to clarify the structure of crystalline anhydrous tiotropium bromide
a high-
resolution X-ray powder diagram was taken at ambient temperature at the
National
Synchrotron Source (Brookhaven National Laboratory, USA) at measuring station
X3B1
(~, = 0.700 A). For this experiment a sample of crystalline tiotropium bromide
monohydrate was placed in a quartz glass capillary 0.7 mm in diameter. The
water was
eliminated by heating to 80°C in an oven under reduced pressure. - - -
The structural resolution was obtained by a so-called simulated annealing
process. The
DASH program package produced by Cambridge Crystallographic Data Center (CCDC,
Cambridge, United Kingdom) was used for this.
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Table 2 shows the atomic coordinates obtained for crystalline anhydrous
tiotropium
bromide.
Table 2: Coordinates
Atom x y z U;so
S1 1.0951(8) 0.3648(8) 0.8189(5) 0.075(9)
Sl 0.9143(9) 0.1374(8) 0.9856(5) 0.075(9)
O 0.6852(13)0.2339(6) 0.7369(6) 0.075(9)
O1 0.7389(15)0.0898(9) 0.8234(6) 0.075(9)
02 0.8211(10)0.3897(17) 0.8277(7) 0.075(9)
03 0.4975(17)0.4816(9) 0.6011(7) 0.075(9)
N 0.4025(10)0.2781(8) 0.5511(5) 0.075(9)
C 0.7509(8) 0.1885(6) 0.8038(5) 0.075(9)
C1 0.8593(7) 0.2788(5) 0.8495(4) 0.075(9)
C2 0.9924(9) 0.2533(6) 0.8225(6) 0.075(9)
C3 0.8884(9) 0.2664(7) 0.9382(4) 0.075(9)
C4 0.5848(12)0.1596(8) 0.6753(8) 0.075(9)
C5 0.4544(13)0.1929(14) 0.6809(8) 0.075(9)
C6 0.6156(13)0.1810(13) 0.5973(9) 0.075(9)
C7 0.5493(11)0.2881(11) 0.5578(6) 0.075(9)
C8 0.5869(12)0.3832(11) 0.6092(7) 0.075(9)
C9 0.4947(13)0.3902(10) 0.6575(6) 0.075(9)
C10 0.4004(10)0.2998(11) 0.6332(6) 0.075(9)
C11 0.3220(13)0.3670(13) 0.4935(6) 0.075(9)
C12 0.3450(19)0.1643(26) 0.5211(11)0.075(9)
C13 0.9184(16)0.3808(9) 0.9920(6) 0.075(9)
C-14----1-.03-13(16)0.1552(1-5)0:80-11(15)0.075(9)
- -
C15 0.9515(17)0.3374(10) 0.0501(6) 0.075(9)
C16 0.9756(18)0.2190(11) 1.0742(5) 0.075(9)
C17 1.1483(22)0.1762(18) 0.7718(24)0.075(9)
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C18 1.1860(16) 0.2800(15) 0.7768(19) 0.075(9)
BR 0.4597(4) 0.8200(15) 0.61902(25) 0.042(9)
In the above Table the "Uiso~~ values denote the isotropic temperature
factors. For
example, in single-crystal X-ray structural analysis this corresponds to the
u(eq) values.
Table 3 shows the reflexes (h,k,l indices) of the powder diagram obtained for
crystalline
anhydrous tiotropium bromide.
Table 3: Experimental data relating to the crystalline structural analysis of
anhydrous
tiotropium bromide
to
No. h k 1 24 obs.2~ talc.24 obs. -
2~ talc
1 1 0 0 8.762 8.769 -0.007
2 0 1 1 9.368 9.369 -0.001
3 -1 0 2 11.730 11.725 0.005
4 0 1 2 12.997 13.004 -0.007
5 -1 1 2 14.085 14.094 -0.009
6 1 0 2 15.271 15.275 -0.004
7 0 0 3 15.620 15.616 0.004
8 0 2 1 16.475 16.475 0.0
9 1 1 2 17.165 17.170 -0.005
2 0 0 17.588 17.591 -0.003
11 -1 ~ 2 1 18.009 18.035 -0.026
12 1 2 1 .19.33619.328 0.008
13 -2 1 2 19.596 19.600 -0.004
14 -1 0 4 20.417 20.422 -0.005
0 0 4 20.865 20.872 -0.007
-
16 2 1 1 21.150 21.145 0.005
17 -2 1 3 21.759 21.754 0.005
18 0 2 3 22.167 22.160 0.007
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19 -1 2 3 22.289 22.288 0.001
20 2 0 2 22.735 22.724 0.011
21 -2 2 1 23.163 23.159 0.004
22 -2 0 4 23.567 23.575 -0.008
23 2 1 2 24.081 24.058 0.023
24 1 0 4 24.746 24.739 0.007
25 -1 3 1 25.220 25.221 -0.001
26 1 2 3 25.359 25.365 -0.006
27 0 3 2 25.790 25.783 0.007
28 1 1 4 25.978 25.975 0.003
29 0 2 4 26.183 26.179 0.004
30 -1 3 2 26.383 26.365 0.018
31 -1 1 5 26.555 26.541 0.014
32 -3 1 2 27.024 27.021 0.003
33 3 1 0 27.688 27.680 0.008
34 -3 1 3 28.221 28.215 0.006
35 3 0 1 28.377 28.376 0.001
36 -3 0 4 29.246 29.243 0.003
37 3 1 1 29.459 29.471 -0.012
38 -1 2 5 29.906 29.900 0.006
39 -3 2 1 30.171 30.165 0.006
40 0 2 5 30.626 30.626 0.0
41 1 1 5 .30.87130.856 0.015
42 0 0 6 31.504 31.532 -0.028
43 2 1 4 31.826 31.847 -0.021
44______2_1 6.. 3-2~8~832.888 0.0
.
45 1 4 1 33.605 33.615 -0.010
46 3 0 3 34.379 34.377 0.002
47 1 0 6 35.021 35.018 0.003
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48 -4 1 1 35.513 35.503 0.01
49 1 1 6 35.934 35.930 0.004
50 -1 1 7 36.544 36.543 0.001
51 -4 1 4 37.257 37.255 0.002
52 -4 2 2 37.933 37.952 -0.019
53 4 1 1 38.258 38.264 -0.006
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