Title of Invention	"INHALABLE PHARMACEUTICAL COMPOSITIONS CONTAINING (ENDO, SYN)-(-)-3-(3-HYDROXY-1-OXO-2-PHENYLPROPOXY)-8-METHYL-8-(1-METHYLETHYL)-8-AZONIABICYCLO [3.2.1] OCTANE SALT"
Abstract	Inhalable pharmaceutical compositions having a prolonged period of activity, characterised in that they contain the (endo, syn)-(-)-3-(3-Hydroxy-l-oxo-2-phenylpropoxy)-8-methyl-8-(l-methylethyl)-8-azoniabicyclo[3.2.1.]octane salt in an enantiomeric purity of 90 to 100% together with conventional excipients and/or carriers as herein described, wherein the (endo, syn)-(-)-3-(3-Hydroxy-l-oxo-2-phenylpropoxy)-8-methyl-8-(l-methylethyl)-8-azoniabicyclo[3.2.1.] octane salt is present in 0.005 wt.% to 0.02 wt.% of the composition optionally in conjuction with a betamimetic , an inhalable steroid or an antiallergic agent of the kind such as herein described.

Title of Invention

"INHALABLE PHARMACEUTICAL COMPOSITIONS CONTAINING (ENDO, SYN)-(-)-3-(3-HYDROXY-1-OXO-2-PHENYLPROPOXY)-8-METHYL-8-(1-METHYLETHYL)-8-AZONIABICYCLO [3.2.1] OCTANE SALT"

Abstract

Inhalable pharmaceutical compositions having a prolonged period of activity, characterised in that they contain the (endo, syn)-(-)-3-(3-Hydroxy-l-oxo-2-phenylpropoxy)-8-methyl-8-(l-methylethyl)-8-azoniabicyclo[3.2.1.]octane salt in an enantiomeric purity of 90 to 100% together with conventional excipients and/or carriers as herein described, wherein the (endo, syn)-(-)-3-(3-Hydroxy-l-oxo-2-phenylpropoxy)-8-methyl-8-(l-methylethyl)-8-azoniabicyclo[3.2.1.] octane salt is present in 0.005 wt.% to 0.02 wt.% of the composition optionally in conjuction with a betamimetic , an inhalable steroid or an antiallergic agent of the kind such as herein described.

Full Text	The present invention relates to inhalable pharmaceutical compositions containing (endo,syn)-(-)-3-(3-hydroxy-l-oxo-2-phenylpropoxy)-8-methyl-8-(l-methylethyl)-8-azoniabicyclo[3.2.1.]Octane salt The invention relates to (endo,syn)-(-)-3-(3-hydroxy-l-oxo-2-phenylpropoxy)-8-methyl-8-(1-methylethyl)-8-azoniabicyclo[3,2,1]octane salts. These compounds are useful as bronchospasmolytics with a powerful and particularly long-lasting effect. The invention further relates to the use of the salts in the manufacture of preparations for inhalation in the treatment of asthma, and a method of treating subjects in need of such treatment. The racemate of the above-mentioned compound (in the form of the bromide) is on sale under the name Ipratropium bromide as an active substance in anticholinergic drugs. It has now been found, surprisingly, that the conditions of activity of the racemate, laevorotatory and dextrorotatory enantiomers are significantly different and have major peculiarities which differ substantially from the norm. The eutomer (i.e. the enantiomer having the desired or sought activity) is the L-(-)-enantiomer. Receptor binding studies on CHO-HM receptors have shown that the L-(-)-enantiomer has approximately twice as high an affinity as the racemate. This ratio corresponds to observations which have frequently been made when comparing the effects of enantiomers and racemates. However, we have most surprisingly found in the present case that in a comparison of the eutomer with the racemate in the weight ratio 1:2, administration by inhalation to the (anaesthetised) dog exhibits not only a higher potency, but also a considerably longer duration of activity. In one aspect, therefore, we provide salts of (endo, syn)-(-)-3-(3-Hydroxy-l-oxo-2-phenylpropoxy)-8-methyl-8-(1-methylethyl)-8-azoniabicyclo[3,2,1]octane with an enantiomeric purity of 90 to 100%. The diagram shown in Figure 1 gives the percentage inhibition of bronchospasm as a function of time. The dotted line (curve B) represents the pattern for the (endo, syn)-(-)-3-(3-hydroxy-l-oxo-2-phenylpropoxy)-8-methyl-8-(1-methylethyl)-8-azoniabicyclo[3,2,1]octane and the continuous line (curve A) gives the pattern for the corresponding racemate, the hydrobromides having been used. 5 /zg of the pure L-(-)-enantiomer and, accordingly, 10 /xg of the racemate were administered. The experiment was carried out on five test animals using the pure L-enantiomer (BIIH 150 BR) whilst the racemate was administered to seven test animals. Figure 1 shows that the inhibition of acetylcholine-induced bronchospasm in the dog by the administration of the Ipratropium bromide aerosol (curve A) has reached a peak of about 55% after about 10 minutes and has fallen back to its initial level after 60 minutes. The same quantity of eutomer (curve B), as contained in the racemate, achieves a 60% inhibition after about 10 minutes and does not fall back to its starting level for 180 minutes. The half-lives measured show that the eutomer BIIH 150 BR has a duration of activity which is approximately four times longer. The eutomer is obtained in substantially pure form from the racemate by combined application of high pressure liquid chromatography and recrystallisation. The term "eutomer" for the purposes of the present invention also includes strongly concentrated products (over about 90%), preferably containing more than 95, and particularly more than 97% of the L-(-)-enantiomer. The anion corresponds to the one in the starting compound. If desired, an exchange may be carried out. The Example which follows is intended to illustrate the preparation of the L-(-)- and D-(+)-enantiomer: 18 grams of Ipratropium bromide are separated by high-pressure liquid chromatography over a Chiralcel OD column (250x20 mm) with a mobile phase composed of 600 hexane, 250 methanol, 150 ethanol and 1 saturated alcoholic NaBr solution (V:V:V:V, throughflow rate 6 ml/min., wavelength 254 nm; sensitivity 0.5 A.U.F.S, solution containing 1 g Ipratropium bromide/5 ml ethanol + 5 ml mobile phase + 2.5 ml cone, acetic acid). By repeated chromatography and recrystallisation from ethanol, the L-(-)-enantiomer, white crystals, m.p. 239-40°C (decomp.), specific rotation [a] g° = -24.06° (c = 1.014; H20), enantiomeric purity 97.4% (HPLC) and the D-(+)-enantiomer, white crystals, m.p. 238-39°C (decomp.), specific rotation [a]%° = +24.26° (c = 1.018; H2O), enantiomeric purity 98.9% (HPLC), are obtained. Elemental analyses and spectra indicate that these compounds are present. The L-(-)-eutomer in the form of the various salts, preferably the bromide, chloride or acetate salts, is suitable, by virtue of being an anticholinergic, for treating chronic obstructive bronchitis and asthma by inhalation, whilst side effects are largely excluded. According to a further aspect of the invention, therefore, we provide pharmaceutical preparations in a form suitable for inhalation which" include..'a compound of the invention, optionally: .together with pharmaceutically acceptable excipients -and/or carriers and/or, other active substances. . For use, the active substance inay,.be processed with known excipiehta and/or carriers to form conventional galenic preparations,' e. CT.. 'solutions for inhalation, suspensions in liquefied :propellant ga.ses, preparations containing liposomes or proliposomes, and powders for inhalation (optionally in capsules) for use in conventional inhalers. Accordingly, there is provided inhalable pharmaceutical compositions, having a prolonged period of activity, characterised in that they contain an (endo, syn)-(-)-3-' (3-Hydroxy-l-oxo-2;~ phenylpropoxy)-8-methyl-8-(1 ruethylethyl)-8-azoniabicyclo [3.2. 1] octane salt in an enantiomeric purity of 90 to 100% for treating diseases of the respiratory tract. Inhalable pharmaceutical compositions having a prolonged period of activity, characterised in that they contain the (endo, syn)-(-)-3-(3-Hydroxy-l-oxo-2-phenylpropoxy)-8-methyl-8-(l-methylethyl)-8-azoniabicyclo[3.2.1.]octane salt in an enantiomeric purity of 90 to 100% together with conventional excipients and/or carriers as herein described, wherein the (endo, syn)-(-)-3-(3-Hydroxy-l-oxo-2-phenylpropoxy)-8-methyl-8-(l-methylethyl)-8-azoniabicyclo[3.2.1.] octane salt is present in 0.005 wt.% to 0.02 wt.% of the composition optionally in conjuction with a betamimetic , an inhalable steroid or an antiallergic agent of the kind such as herein described. Examples of formulations (amounts given in percent by weight): 1. Metering aerosols Active substance according to the invention 0.005 Sorbitan trioleate 0.1 Monofluorotrichloromethane and difluorodichloromethane 2:3 ad 100 The suspension is transferred into a conventional aerosol container with metering valve. 50 /xl of suspension, for example, are released on each actuation. If desired, the active substance may also be present in higher doses (e.g. 0.02 wt.-%). Instead of the chlorinated propellant gases, alternative propellant gases such as TG 134a (1,1,1,2-tetra-fluoroethane) and/or TG 227 (1,1,1,2,3,3,3-hepta-fluoropropane) may also be used. 2. Powder for inhalation Micronised powdered active substance (particle size 0.5 to 7 /im) is mixed with micronised lactose and packed into hard gelatine capsules, optionally with other additives. For example, 0.01 mg of active substance and 5 mg of lactose are packed into each capsule. The powder may be inhaled using conventional inhalers, e.g. as in DE-A 3345772. 3. Solutions for inhalation Aqueous solutions of the active substance may also be used, the aerosol being produced, for example, by a device according to WO91/14468. 0.005 mg of active substance may be administered per spray dose, for example. The active substance which may be used according to the invention may advantageously also be used in conjunction with other active substances for respiratory tract therapy. (32-mimetics may be mentioned in particular; these are used in combinations with 50 - 100% of the dose for individual use. The following may be mentioned: Bambuterol Bitolterol Carbuterol Clenbuterol Fenoterol Formoterol Hexoprenaline Ibuterol Pirbuterol Procaterol Reproterol Salbutamol Salmeterol Sulfonterol Terbutaline Tulobuterol 1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2- methyl-2-butylamino]ethanol erythro-5'-hydroxy-8'-(l-hydroxy-2-isopropylaminobutyl)- 2H-1,4-benzoxazin-3-(4H)-one 1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.- butylamino)ethanol 1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2- (tert.-butylamino)ethanol. Inhalable steroids such as Budesonide, Beclomethasone (or the 17,21-dipropionate), dexamethasone-21-isonicotinate, Flunisolide and antiallergics such as disodium cromoglycate, Nedocromil, Epinastine may also be used as ingredients in the combination. These combination ingredients may also be administered in the same or smaller doses than when they are used on their own. WE CLAIM: 1. Inhalable pharmaceutical compositions having a prolonged period of activity, characterised in that they contain the (endo, syn)-(-)-3-(3-Hydroxy-l-oxo- 2-phenylpropoxy)-8-methyl-8-(l-methylethyl)-8-azoniabicyclo[3.2.1.]octane salt in an enantiomeric purity of 90 to 100% together with conventional excipients and/or carriers as herein described, wherein the (endo, syn)-(-)-3-(3-Hydroxy-l-oxo-2- phenylpropoxy)-8-methyl-8-(l-methylethyl)-8-azoniabicyclo[3.2.1.] octane salt is present in 0.005 wt.% to 0.02 wt.% of the composition optionally in conjuction with a betamimetic , an inhalable steroid or an antiallergic agent of the kind such as herein described. 2. Inhalable pharmaceutical compositions as claimed in one of claim 1 containing bromide, chloride or acetate as anion. 3. Inhalable pharmaceutical compositions as claimed in one of claims 1 to 3, wherein the betamimetic used is selected from Bambuterol Bitolterol Carbuterol Clenbuterol Fenoterol Formoterol Hexoprenalin Ibuterol Pirbuterol Procaterol Reproterol Salbutamol Salmeterol Sulfonterol Terbutalin Tulobuterol l-(2-Fluor-4-hydroxyphenyl)-2-[4-(l-benzimidazolyl)-2-methyl-2-butyl-amino]-ethanolerythro-5min-Hydroxy-8min-( 1 -hydroxy-2-isopropylaminobutyl)-2H-1,4-benzo-xazin-3-(4H)-on l-(4-Amino-3-chlor-5-trifluormethylphenyl)-2-tert.-butylamino)ethano-l l-(4-Ethoxycarbonylamino-3-cyan-5-fluorophenyl)-2-(tert. butylamino)ethanol, the steroid used is selected from Budesonide, Beclometasone (or the 17,21- Dipropionat), dexamethasone-21-isonicotinate, Flunisolide and the antiallergic agent used is selected from disodium cromoglycate, Nedocromil and Epinastine. 4. Inhalable pharmaceutical compositions substantially as herein described with reference to the foregoing examples and the drawings.

Full Text

The present invention relates to inhalable pharmaceutical compositions containing
(endo,syn)-(-)-3-(3-hydroxy-l-oxo-2-phenylpropoxy)-8-methyl-8-(l-methylethyl)-8-azoniabicyclo[3.2.1.]Octane salt

The invention relates to (endo,syn)-(-)-3-(3-hydroxy-l-oxo-2-phenylpropoxy)-8-methyl-8-(1-methylethyl)-8-azoniabicyclo[3,2,1]octane salts. These compounds are useful as bronchospasmolytics with a powerful and particularly long-lasting effect. The invention further relates to the use of the salts in the manufacture of preparations for inhalation in the treatment of asthma, and a method of treating subjects in need of such treatment.
The racemate of the above-mentioned compound (in the form of the bromide) is on sale under the name Ipratropium bromide as an active substance in anticholinergic drugs.
It has now been found, surprisingly, that the conditions of activity of the racemate, laevorotatory and dextrorotatory enantiomers are significantly different and have major peculiarities which differ substantially from the norm. The eutomer (i.e. the enantiomer having the desired or sought activity) is the L-(-)-enantiomer. Receptor binding studies on CHO-HM receptors have shown that the L-(-)-enantiomer has approximately twice as high an affinity as the racemate. This ratio corresponds to observations which have frequently been made when comparing the effects of enantiomers and racemates.
However, we have most surprisingly found in the present case that in a comparison of the eutomer with the racemate in the weight ratio 1:2, administration by inhalation to the (anaesthetised) dog exhibits not only a higher potency, but also a considerably longer

duration of activity.
In one aspect, therefore, we provide salts of (endo, syn)-(-)-3-(3-Hydroxy-l-oxo-2-phenylpropoxy)-8-methyl-8-(1-methylethyl)-8-azoniabicyclo[3,2,1]octane with an enantiomeric purity of 90 to 100%.
The diagram shown in Figure 1 gives the percentage inhibition of bronchospasm as a function of time. The dotted line (curve B) represents the pattern for the (endo, syn)-(-)-3-(3-hydroxy-l-oxo-2-phenylpropoxy)-8-methyl-8-(1-methylethyl)-8-azoniabicyclo[3,2,1]octane and the continuous line (curve A) gives the pattern for the corresponding racemate, the hydrobromides having been used. 5 /zg of the pure L-(-)-enantiomer and, accordingly, 10 /xg of the racemate were administered. The experiment was carried out on five test animals using the pure L-enantiomer (BIIH 150 BR) whilst the racemate was administered to seven test animals.
Figure 1 shows that the inhibition of acetylcholine-induced bronchospasm in the dog by the administration of the Ipratropium bromide aerosol (curve A) has reached a peak of about 55% after about 10 minutes and has fallen back to its initial level after 60 minutes. The same quantity of eutomer (curve B), as contained in the racemate, achieves a 60% inhibition after about 10 minutes and does not fall back to its starting level for 180 minutes.
The half-lives measured show that the eutomer BIIH 150 BR has a duration of activity which is approximately four times longer.
The eutomer is obtained in substantially pure form from the racemate by combined application of high pressure liquid chromatography and recrystallisation. The term

"eutomer" for the purposes of the present invention also includes strongly concentrated products (over about 90%), preferably containing more than 95, and particularly more than 97% of the L-(-)-enantiomer. The anion corresponds to the one in the starting compound. If desired, an exchange may be carried out.
The Example which follows is intended to illustrate the preparation of the L-(-)- and D-(+)-enantiomer:
18 grams of Ipratropium bromide are separated by high-pressure liquid chromatography over a Chiralcel OD column (250x20 mm) with a mobile phase composed of 600 hexane, 250 methanol, 150 ethanol and 1 saturated alcoholic NaBr solution (V:V:V:V, throughflow rate 6 ml/min., wavelength 254 nm; sensitivity 0.5 A.U.F.S, solution containing 1 g Ipratropium bromide/5 ml ethanol + 5 ml mobile phase + 2.5 ml cone, acetic acid).
By repeated chromatography and recrystallisation from ethanol, the L-(-)-enantiomer, white crystals, m.p. 239-40°C (decomp.), specific rotation [a] g° = -24.06°
(c = 1.014; H20), enantiomeric purity 97.4% (HPLC) and the D-(+)-enantiomer, white crystals, m.p. 238-39°C
(decomp.), specific rotation [a]%° = +24.26° (c = 1.018; H2O), enantiomeric purity 98.9% (HPLC), are obtained. Elemental analyses and spectra indicate that these compounds are present.
The L-(-)-eutomer in the form of the various salts, preferably the bromide, chloride or acetate salts, is suitable, by virtue of being an anticholinergic, for treating chronic obstructive bronchitis and asthma by inhalation, whilst side effects are largely excluded.
According to a further aspect of the invention, therefore, we provide pharmaceutical preparations in a

form suitable for inhalation which" include..'a compound of
the invention, optionally: .together with pharmaceutically
acceptable excipients -and/or carriers and/or, other
active substances. .
For use, the active substance inay,.be processed with known excipiehta and/or carriers to form conventional galenic preparations,' e. CT.. 'solutions for inhalation, suspensions in liquefied :propellant ga.ses, preparations containing liposomes or proliposomes, and powders for inhalation (optionally in capsules) for use in conventional inhalers.
Accordingly, there is provided inhalable pharmaceutical compositions, having a prolonged period of activity, characterised in that they contain an (endo, syn)-(-)-3-' (3-Hydroxy-l-oxo-2;~ phenylpropoxy)-8-methyl-8-(1 ruethylethyl)-8-azoniabicyclo [3.2. 1] octane salt in an enantiomeric purity of 90 to 100% for treating diseases of the respiratory tract.
Inhalable pharmaceutical compositions having a prolonged period of activity, characterised in that they contain the (endo, syn)-(-)-3-(3-Hydroxy-l-oxo-2-phenylpropoxy)-8-methyl-8-(l-methylethyl)-8-azoniabicyclo[3.2.1.]octane salt in an enantiomeric purity of 90 to 100% together with conventional excipients and/or carriers as herein described, wherein the (endo, syn)-(-)-3-(3-Hydroxy-l-oxo-2-phenylpropoxy)-8-methyl-8-(l-methylethyl)-8-azoniabicyclo[3.2.1.] octane salt is present in 0.005 wt.% to 0.02 wt.% of the composition optionally in conjuction with a betamimetic , an inhalable steroid or an antiallergic agent of the kind such as herein described.
Examples of formulations (amounts given in percent by weight):

1. Metering aerosols
Active substance according to the invention 0.005
Sorbitan trioleate 0.1
Monofluorotrichloromethane and
difluorodichloromethane 2:3 ad 100
The suspension is transferred into a conventional aerosol container with metering valve. 50 /xl of suspension, for example, are released on each actuation. If desired, the active substance may also be present in higher doses (e.g. 0.02 wt.-%).
Instead of the chlorinated propellant gases, alternative propellant gases such as TG 134a (1,1,1,2-tetra-fluoroethane) and/or TG 227 (1,1,1,2,3,3,3-hepta-fluoropropane) may also be used.
2. Powder for inhalation
Micronised powdered active substance (particle size 0.5 to 7 /im) is mixed with micronised lactose and packed into hard gelatine capsules, optionally with other additives. For example, 0.01 mg of active substance and 5 mg of lactose are packed into each capsule. The powder may be inhaled using conventional inhalers, e.g. as in DE-A 3345772.
3. Solutions for inhalation
Aqueous solutions of the active substance may also be used, the aerosol being produced, for example, by a device according to WO91/14468. 0.005 mg of active substance may be administered per spray dose, for
example.
The active substance which may be used according to the
invention may advantageously also be used in conjunction
with other active substances for respiratory tract
therapy. (32-mimetics may be mentioned in particular;
these are used in combinations with 50 - 100% of the
dose for individual use.
The following may be mentioned:
Bambuterol
Bitolterol
Carbuterol
Clenbuterol
Fenoterol
Formoterol
Hexoprenaline
Ibuterol
Pirbuterol
Procaterol
Reproterol
Salbutamol
Salmeterol
Sulfonterol
Terbutaline
Tulobuterol
1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-
methyl-2-butylamino]ethanol
erythro-5'-hydroxy-8'-(l-hydroxy-2-isopropylaminobutyl)-
2H-1,4-benzoxazin-3-(4H)-one
1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-
butylamino)ethanol
1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-
(tert.-butylamino)ethanol.
Inhalable steroids such as Budesonide, Beclomethasone (or the 17,21-dipropionate), dexamethasone-21-isonicotinate, Flunisolide and antiallergics such as disodium cromoglycate, Nedocromil, Epinastine may also be used as ingredients in the combination. These
combination ingredients may also be administered in the same or smaller doses than when they are used on their own.

WE CLAIM:
1. Inhalable pharmaceutical compositions having a prolonged period of
activity, characterised in that they contain the (endo, syn)-(-)-3-(3-Hydroxy-l-oxo-
2-phenylpropoxy)-8-methyl-8-(l-methylethyl)-8-azoniabicyclo[3.2.1.]octane salt in
an enantiomeric purity of 90 to 100% together with conventional excipients and/or
carriers as herein described, wherein the (endo, syn)-(-)-3-(3-Hydroxy-l-oxo-2-
phenylpropoxy)-8-methyl-8-(l-methylethyl)-8-azoniabicyclo[3.2.1.] octane salt is
present in 0.005 wt.% to 0.02 wt.% of the composition optionally in conjuction
with a betamimetic , an inhalable steroid or an antiallergic agent of the kind such
as herein described.
2. Inhalable pharmaceutical compositions as claimed in one of claim 1
containing bromide, chloride or acetate as anion.
3. Inhalable pharmaceutical compositions as claimed in one of claims 1 to 3,
wherein the betamimetic used is selected from
Bambuterol
Bitolterol
Carbuterol
Clenbuterol
Fenoterol
Formoterol
Hexoprenalin
Ibuterol
Pirbuterol
Procaterol
Reproterol
Salbutamol
Salmeterol
Sulfonterol
Terbutalin

Tulobuterol
l-(2-Fluor-4-hydroxyphenyl)-2-[4-(l-benzimidazolyl)-2-methyl-2-butyl-amino]-ethanolerythro-5min-Hydroxy-8min-( 1 -hydroxy-2-isopropylaminobutyl)-2H-1,4-benzo-xazin-3-(4H)-on
l-(4-Amino-3-chlor-5-trifluormethylphenyl)-2-tert.-butylamino)ethano-l
l-(4-Ethoxycarbonylamino-3-cyan-5-fluorophenyl)-2-(tert. butylamino)ethanol,
the steroid used is selected from Budesonide, Beclometasone (or the 17,21-
Dipropionat), dexamethasone-21-isonicotinate, Flunisolide and
the antiallergic agent used is selected from disodium cromoglycate, Nedocromil and Epinastine.
4. Inhalable pharmaceutical compositions substantially as herein described with reference to the foregoing examples and the drawings.

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Patent Number

220334

Indian Patent Application Number

1685/DEL/1996

PG Journal Number

30/2008

Publication Date

25-Jul-2008

Grant Date

23-May-2008

Date of Filing

30-Jul-1996

Name of Patentee

BOEHRINGER INGELHEIM KG

Applicant Address

Inventors:

#	Inventor's Name	Inventor's Address
1	GEORG SPECK
2	RICHARD REICHL
3	ROLF BANHOLZER
4	BERND DISSE

PCT International Classification Number

A61K 31/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	195 28 145.4	1995-08-01	Germany