Title of Invention

"A LIQUID PHARMACEUTICAL FORMULATION CONTAINING A QUINOXALINE-2-ONE- DERIVATIVE OR A PHARNMACEEUTICAL SALT THEREOF FOR THE TRANS-TYMPANIC OR INTRA-TRANSTYMPANIC ADMINISTRATION"

Abstract A liquid pharmaceutical formulation, for the trans-tympanic or intra-transtympanic administration, characterized in that the formulation contains   a   quinoxalin   2-one   derivative   of   the   formula in which Rl and R2, independently of one another, are hydrogen, methyl-, ethyl-, propyl- or butyl- groups, or Rl and R2 together form a cyclo-alkyl compound, R3 is methoxy-, ethoxy-, hydroxy-, hydrogen, Cl-C4-alkyl- or halogen; and n = 1,2 or 3;or a pharmaceutical^ acceptable salt of the aforesaid derivatives; and, in addition, containing between 1:2 and 1:500. of a compound that acts as a permeability accelerator or carrier of the kind such as herein described in respect of the afore-mentioned quinoxalin-2-one derivatives; optionally in combination with a pharmaceutically acceptable solvent of the kind such as herein described.
Full Text The present invention relates to a liquid pharmaceutical formulation containing a quinoxaline-2-one-deiivative or a pharnmaceeutical salt thereof for the trans-tympanic or jritra-transtympanic administration.
The invention concerns a pharmaceutical foimafatioh as well as the use of this formulation for the treatment especially of inner ear diseases..
Quinoxaline-2-one derivatives have been known since the 60'sor early 70's as active pharmaceutical compounds. An important representative of the quinoxaliner2-one derivatives is Caroverin (= non-proprietary Same) whose correct chemical name is 1-diethylanimoemyl-3-(p-methoxyben2yl)-l,2dirrydro-qumoxaHne-2-one.
EP-A-0 542 689 describes the use of quinqxline-2-one derivatives for the production of, effective pharmaceutical, neuro-protective cttmp@unds for the treatment of nsuro-toxicities and functional disturbances of the central aei«Hi$ system. According to EP-A-Q 542 689, Caroverin is especially useful in the treatmeigt of cochlear post-synaptic tinnitus. The previously described, pharmaceutically effective of cochlear post-synaptic tinnitus, the patient-was- adroinistered between 70 and 150 mg of Caroverin dissolved in 100 ml of physiological saline, intravenously.
WO 99/66931 proposes the use of quinoxal|n#derivatives for the treatment of diseases ,• caused by the presence of free-radicals of celfeoxygen metabolism, for stimulation of nerve cell synthesis and for antagonizing glutamate teeejtors, etc. According to WO 99/66931, the quinoxaline derivates referred to can be administered by any known method, especially oral, trans-dermal, topical and parenteral, altMugfathe intra-venous route is preferred. The topical administration of Caroverin in the form of an ointment has been described for the alleviation of sun injuries as well as of skin inflammation caused by oxidation. For these indications, it is a matter of treating superficially aad locally with the active medication, which need not necessarily penetrate the blood circulation systemfbr the activity to be effective. In the example of its use mentioned in WO 99/66931, Caroverin was administered once or more frequently to the patient intravenously in relatively high doses. The dosage used was between 160 mg to 1000 mg per day. For many indications, the degree of effectiveness of Caroverin was strongly dependent on the dosage given, and was
only satisfactoiy at high doses. For example, to achieve a neuro-regenerative effect, it was necessary to administer higher doses of Caroverin
In view of the very high doses required, the specialists did not previously consider the administration of Caroverin by a trans-dermal route, since with trans-dermal administration, it is well known that only relatively small active amounts may be introduced into the blood stream. Trials undertaken by the inventor have shown also that Caroverin only has a limited permeability through, the skin.
In addition, new trials by the inventor have shown that Caroverin is not indicated for the treatment of all forms of tinnitus. Apart from cochlear post-synaptic tinnitus, which, according to EP 0 542 689, is treatable by infusion of Caroverin, it has been observed that a muscular tinnitus (also known as myognathic tinnitus) is not responsive to the intravenous administration of Caroverin. Muscular or myognathic tinnitus is identified by imparting an electrical charge to the chewing musculature, whereby the intensity and frequency of the symptoms of tinnitus can be altered. Myognathic tinnitus can substantially be caused to disappear when the tendon bundles of the middle ear musculature that operates the chain of auditory ossicles are surgically sectioned (tenotomy). The precise mechanism involved in this effect is still unclear.
Morbus Meniere, named after the French doptor of the same name, is a relatively rare disease, the symptoms of which are turning-giddiness, ringing in the ears and noise-sensitive hearing deficiency. The disease appears from time to time, and is usually accompanied by severe nausea and vomiting. After some time, a pan-cochlear loss of hearing develops. At the present time, the recommended medical therapies for Morbus Meniere are highly unsatisfactory.
It is, therefore, an object of this invention, to irfake available an improved pharmaceutical preparation or formulation for the treatment of inner ear diseases. An object of this ' • invention is to provide an improved formulation that can also be administered by the patient himself. Yet another object is to make available a medicine and/or a pharmaceutical formulation for the treatment also of the so-called muscular or myognathic
tinnitus, Morbus Meniere, labyrinthine vertigo and impairment of hearing, especially such associated with speech comprehension deficiency.
According to the present invention, the object is achieved by means of a pharmaceutical formulation, especially for trans-tympanic or intra-transtympanic administration, that contains a quinoxalin-2-one derivative of the formula
(Formula Removed)
in which R1 and R2, independently of one another, are hydrogen, methyl-, ethyl-, propyl- or, butyl-, or Rl and R2 together form a cyclo-alkyl compound.. R3 is methoxy, ethoxy, hydroxy, hydrogen, C1-C4 alkyl or halogen; and n = 1, 2 or 3, or a pharmaceutically compatible salt of the aforesaid derivatives; and, - , further containing an active amount of a compound which, with reference to the above-mentioned quinoxalin-2-one derivatives , works a$ a permeability accelerator or carrier in respect of the afore-mentioned quinoxdin-2-one derivatives; as well as, if required, a pharmaceutically compatible solvent.
The inventor was surprised to discover that, with the help of a suitable permeability accelerator, or activator, and carrier system, respectively, a formulation could be identified that could provide trans-tympanic administration, and that was already highly effective with low dosages. This result was completely unexpected since it ha.d been necessary to administer relatively high doses of quinoxalin-2-orie derivatives intravenously in the case of the abovementioned indications. Therefore, it cduld not have been expected that the quinoxalin-2-one derivatives together with a suitable permeability accelerator or earner system were already effective at much lower dosages when the novel formulation was applied through the tympanum.
sodium carbonate. N-[(l-nbutyl-4-ptpericlyl)methyl]indole-3-carboxamide is prepared by coupling N-(l-nbutyl-4-piperidyl)methyIamine with a indole-3-carboxylic acid.
An alternative process for preparing SB 207266-A has now been discovered which involves the use of the N-(l-n butyl-4-piperidyl)methylamine intermediate at a later stage in the process thus resulting in an increased yield of SB 207266-A relative to the amount of this intermediate, which is relatively expensive to produce.
Accordingly, the present invention provides a process for the preparation of SB 207266 or a pharmaceutically acqeptable salt thereof, which process comprises the reaction of of N-(l-nbutyl-4-piperidyl)methylamine with a compound of formula (A):
(Formula Removed)
wherein R is alkyl, such as methyl or ethyl.
The compound of formula (A) wherein R is methyl is methyl 3,4-dihydro-2#-(l,3]-oxazino[3,2-a]indole-10-carboxylate.
The conditions and reagents for this reaction are similar to those described in the literature.
Preferably, the reaction is catalysed by an aluminium or lithium based catalyst, More preferably, the catalyst is trimethylalummium.
A mixture of the amine and ester in ft suitable solvent (eg toluene) is treated with a solution of trimethylaluminium in toiOene or hexanes at ambient temperature. The resulting solution is then heated, preferably to reflux (112 °C ) for about four hours until the reaction is complete. The reaction is cooled to about 70°C and quenched by cautious addition of aqueous sodium hydroxide solution. The aqueous layer is separated and the mixture washed once more with caustic and twice with water, maintaining the temperature at about 70°C. The product is isolated as described in the attached Example.
Alternative catalysts include NaH7Et2Al which isiused in a similar way to AlMe3.
BuLi is also suitable but is used at lower temperatures and requires two equivalents of the base and two equivalents of the amine.
Especially effective are the quinoxaiin-2-one? derivatives in which the Rl and R2 substituents are an ethyl group, where n = 2, aad in which R3 is a methoxy group, so that the molecule is l-diethylaminoethyl-3-(p-me1hoxybenzyl)-l,2-dihydro-quinoxalin-2-one (non-proprietary name: Caroverin) or a pharmaceutically compatible salt thereof, Furthermore, quinoxalm-2-one derivatives are also effective in which the Rl and R2 subsituents are an ethyl group where n = 2, attd R3 is a hydroxy group, so that the molecule is l-diethylammoethyl-3-(p-hydroxybenzyl)-l,2-dmydrorquinoxalin-2"One or a pharmaceutically compatible salt thereof.
Advantageously, the permeability accelerator used in the formulation is one of the following compounds: dimethyl sulphoxide, ;mono*glyceride, ethyl- or methyl-palmitic acid ester, fatty acids, fatty acid esters, fatty acid alcohols, substituted dialkyl fatty acids having 8 to 14 carbon atoms, N-methyl pyrrolidone, N-methyl-2-pyrroIidone oleic acid, propylene glycol, diethylene glycol, the mono-alkyt ether or carboxy-methyl ether of polyethylene glycol, propylene glycol fatty acid ester, lauryl acetate, N.N-dialkyl lauramide, histamine, a dialkyl lauramide/dimethyl formaoride mixture, dimethyl acetamide,. N,N-diethyl-m-toluamide, ethylene glycol monomethyl ether, isopropyl myristate,.isopropyl palmitate, propylene glycol and oleic acid or oleyl alcohol, 2-pyrrolidone and dimethyl formamide, lauric acid, linoleic acid, lauryl acetate, sodium oleate, glycerine rcono-oleate, urea, 1-bisabolol. Also possible is the use of a combination of 2 or more of the aforementioned permeability accelerators.
In a preferred formulation, the permeability accelerator used is at least dimethyl sulphoxide or propylene glycol. It has been shown that dimethyl sulphoxide is a good solvent and, surprisingly, a good permeability accelerator for quinoxalin-2-one derivatives, especially for Caroverin. Furthermore, dimethyl sulphoxide can be added in fairly high : concentrations. The content by weight of dimethyl sulphoxide in the.formulation preferably comprises between 5 and 50%, but can also be higher. Advantageously, the formulation contains, together with dimethyl mlphoxide, at least another second permeability accelerator. This can be a member of the above-mentioned group.;of permeability accelerators. By the addition of at leest one further permeability accelerator, the content by weight of dimethyl sulphoxide can be correspondingly reduced. In this way, the risk is reduced that the administration of the formulation causes skin irritation.
Preferably, the second permeability accelerator is a glycol compound such, for example, as an ethylene- and/or propylene glycol compound.
Advantageously, the ratio by weight of quinoxalin-2-one derivative to the permeability accelerator is between 1:2 and 1:500, preferably between 1:20 and 1:100. As the solvent, for example, glycerine* or another physiologically eompatible compound, such as water, can be used.
An advantageous formulation uses a nanoemulsion or liposomes, which contain the said quinoxalon-2-one compound according to Formula (I), as the permeation accelerator or carrier. Expediently, the nanoemulsion or the liposomes contain a membrane-forming molecule and a coemulsifier besides the said quinaxalon-2-one derivatives.
Substances which make it. possible to form two-layer systems (sorcalled "bilayers") are
preferably used as the membrane-forming molectile. A phospholipid is preferably used as
the membrane-forming molecule. It may be, a hydrogenated or partially hydrogenated
phospholipid. A naturally or artificially produced lecithin is preferably used. The latter
may, for example, be obtained from soy beans of hen's eggs. ^Examples of phospholipids
are phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol,
phosphatidylinositol, phosphatidylserme and sphingomyelin. The acyl chain may be either saturated or unsaturated, and may have from 12 to 22, preferably from 14 to 18 C atoms. Other liposome-forming membrane lipids sfcch as glycolipids, ceraniides, gangliosides and cerebrosides may be used instead of, or partially instead of, phospholipids.
The lipids may be derived from natural plant, animal or: microbiological sources, synthetically produced or partially synthetically produced, inclusive of monoacyl phospholipids derived from polyethylene glycol (PEG), for example pegylated monoacyl phosphatidylethanolamine.
According to a particularly preferred embodiment^ a phospholipid of the formula.
(Formula Removed)
R1 denotes C10-C20 acyl;
R2 denotes hydrogen or C10-C20 acyl
R3 denotes hydrogen, 2-trimethylamino-l-ethyl, 2-amino-l-ethyl, unsubstituted Q-Cs
alkyl or C1-C5 alkyl substituted with one or more Carboxyl, hydroxy or amino groups; the
inositol or glyceryl group, or salts of these compounds,
is used as the membrane-forming molecule.
The C10-C20 acyl is preferably a straight-stained C1o-C2 A phospholipid of Formula (II) in which R3 denotes 2-trimethylamino-l -ethyl is referred
to by the trivial name lecithin, and a phospholipid of Formula (II) in which R3 denotes.2-
-amino-1-ethyl is referred to by the trivial name cephalin. For example, naturally occurring
cephalin or lecithin having different or identical acyl groups, or mixtures thereof, are
suitable. '- •. -
The membrane-forming component is preferably used in a concentration of about 0.1 to 30% by weight, expressed in terms of the total weight of membrane-forming component; emulsifier and active substance.
One of the following coemulsifiers, or an etmusifter mixture of two or more of the coemulsifiers listed below, may be used as the emulsifier:
Alkali metal, ammonium and aminium salts ©f fatty acids, for example lithium, sodium,
potassium, ammonium, triethylamine, ethanolamftie, diethanolamine or triethanolamine
salts. Sodium, potassium or ammonium (NR1R2R3) salts are preferred, R1, R2 and R3
independently of one another denoting hydrogen, C1-C4 alkyl orC1-C4 hydroxyalkyl.
Alkyl sulfates such as, for example, sodium dodeeyl sulphate.
Salts of bile acid, for example sodium cholate, sodium glycocholate and sodium
taurocholate;
partial fatty acid esters of sorbitan, for example sofbitan monolaurate;
sugar esters, for example sucrose monolaurate;
fatty acid partial glycerides, for example lauric acid mohoglyceride;
polyglycerol esters of fatty acids;
propylene glycol esters of fatty acids;
lactic acid esters of fatty acids, for example sodium stearoyl-lactyl-2-lactate;
proteins, for example casein.
Emulsifiers of the polyoxyetfaylene type are more particularly preferred. Examples of such, emulsifiers are:
polyethoxylated sorbitan fatty acid esters, for example polysorbate 80;
polyethoxylated vitamin E derivates, fbr example vitamin E polyethylene glycol
1000 succinate;
polyethoxylated fatty acid partial glycerMes, for example diethylene glycol
monostearate;
polyethoxylated carbohydrates;
block polymers of ethylene oxide and propylene oxide, for example poloxamer
188.
The emulsifier is advantageously present in the formulation at a concentration of about 1 to about 50% by weight, expressed in terms of the total weight of the membrane-forming component, the emulsifier and the activ.e substance. The quinoxalin-2-one compound is -, present in the formulation at a concentration of about 0.1 to 70%'by weight, expressed in
terms of the total weight of the components (membrane-fonning component, emulsifier and quinoxalin-2-one compound).
The subject of the present invention also comprise! the use of a quinoxalin-2-one . derivative of the formula
(Formula Removed)
in which Rl and R2, independently of one another, are hydrogen, methyl-, ethyl-, propyl-
or butyl-, or Rl and R2 together form a cyclo-alkji compound;
R3 is the methoxy, ethoxy, hydroxy, hydrogen* a C1-C4 allcyl or halogenatom, and n = 1, 2
or 3; '
or a pharmaceutically compatible salt of the affere-^ientioned quinoxalin-2-one compound;
and
an effective amount of a compound that is a permeability accelerator, also in the form of a
suitable carrier like a nanoemulsion or liposontes, ai respect of the above-mentioned
quinoxalin-2-one derivatives for the manufacture of a pharmaceutical formulation that can
be administered through the tympanum for the treatment of inner-ear diseases. Preferably,
Caroverin or a salt compound of Caroverin is used in the formulation, Salt compounds
have the advantage that they are more readily soluble in divers solvents.
A further subject of the present invention is fh« use, in accordance with the Claims 30 to 37, for the treatment of the hitherto unknown Indications, such as the treatment of myognathic tinnitus, Morbus Meniere, labyrinthine vertigo or speech discrimination impediments together with hearing impediments. These are new indications for quinoxalin-2-one derivatives and, in particular, for Caroverin. For the aforementioned indications the quinoxalin-2-one derivatives can be used also in accordance with a known form of adminisfration like, e.g. intravenous injection. Preferably, the qtunoxalin-2-one . derivatives, however, are administered in a formulation together with a. permeability
accelerator or in a carrier system in the form of liposomes or a nanoemulsion according to the above description.
The formulation according to the invention is joefgjably administered in aliquid,form. Aqueous formulations as well as non aqueous ones can be used.' Advantageously the viscosity of the formulation is between 5000 and 25000 rhPas (milli-Pascal per second), preferably between 15000 and 20000 mPas, so that a longer period of administration of the active ingredient into the inner ear is achieved, Tfte part by weight of quinoxalin-2-one derivative used is preferably between about 0*5% and 12%.
The treatment of a patient takes place as follows: An absorbable material such, for example, as a wick of about 2 mm diameter and 2 to 3 cm in length is soaked with the inventive formulation. The soaked wick is then inserted into the ear so that it lies against the tympanic membrane. Depending on the c©ncentration of the solution used, the therapy lasts between 3 and 24 hours. Depending on fie condition of the disease, the above described treatment is continued by the addjtienal administration of a specific number of drops of the active formulation, such, for example, as 3 — 4 drops every second day.
In the case where the formulation is a nanoexnulsian, the formulation can also be appiied directly onto tympanum.
Alternatively, the formulation can also be administered intra-trans-tympanically. For this form of administration of active substances, a cansla or drainage tubule that reaches into the middle ear, is used and tire active substances afe administered via the drainage tubule.
Examples of the Formulation
Three examples of the non-aqueous formulations are as follows:
Example 1 j&campie 2
0.5% of Caroverin 0,5% of Caroverin
20% of dimethyl sulphoxide 20% of dimethyl sulphoxide
30% of propylene glycol 30% of propylene glycol
50% of glycerine §0% of gel
Example 3 jBxanfflle 4
10% of Caroverin hydrochloride 1 % of Caroverin
20% of dimethyl sulphoxide 1% of acetone
'30% of propylene glycol f®& of propylene glycol
40% of glycerine
The viscosity of the different trial solutions (formulations) is, preferably, between 5000 and 25000 mPas, more preferably between ! 5000■*- 20000rnPas.
The following example is of an aqueous forrnulatibn with a thickening agent:
Example 5
1 % of Caroverin hydrochloride
20% of dimethyl sulphoxide
30% of propylene glycol
48% of water
1% of thickening agent (PVM/MA decadierie cross-polymer).
The viscosity of the solution is preferably increased by the addition of a thickening agent, so that, duiing the drop-wise administration of th$ solution mto the outer auditoiy meatus the solution stays as long as possible on the tympanic membrane without running out. Because of the good adhesion of the formulation en the tympanic membrane, a long lasting administration of the active ingredient into fhe inner ear is ensured.
Preparation of a nanoemulsion / liposomes
In order to produce the formulation, the ermilsifier and the quinoxalm-2-one compound are mixed to form a homogenous liquid phase, qptionally while heating. The phospholipid is dissolved in this phase, optionally with the aid of a solubility promoter, for example ethanol. This results in a homogenous solution, It may then be diluted with water to the intended concentration of active substance.



We claim:
1. A liquid pharmaceutical formulation, for the trans-tympanic or intra-transtympanic administration, characterized in that the formulation contains a quinoxalin 2-orie derivative of the formula
(Formula Removed)
in which Rl and R2, independently of one another, are hydrogen, methyl-, ethyl-, propyl- or butyl- groups, or Rl and R2 together form a cyclo-alkyl compound, R3 is methoxy-, ethoxy-, hydroxy-, hydrogen, Cl-C4-alkyl- or halogen; and n = 1, 2 or 3;
or a pharmaceutically acceptable salt of the aforesaid derivatives; and, in addition, containing between 1:2 arid 1:500 of a compound that acts as a permeability accelerator or carrier of the kind such as herein described in respect of the afore-mentioned quinoxalin-2-one derivatives; optionally in combination with a pharmaceuticalry acceptable solvent of the kind such as herein described.
2. A liquid pharmaceutical formulation as claimed in claim 1, wherein Rl and R2 are ethyl groups; n=2, and R3 is a methoxy group, so that the molecule is 1 -diethylaminoethyl-3-(p-methoxybenzyl)-1,2-dihydro-quinoxalin-2-one(INN: Caroverin), or a pharmaceutically acceptable salt of quinoxalin-2-one derivative.
3. A liquid pharmaceutical formulation as claimed in Claim 1, wherein Rl and R2 are ethyl groups; n=2; and R3is a hydroxy group, so that the molecule is l-diethylarriinoethyl-3-(p-hydroxy-benzyl)-l,2-dihydro-quinoxaline-2~one or a pharmaceutically acceptable salt of quinoxalin-2-one derivative.
4. A liquid pharmaceutical formulation as claimed in any one of the claims 1 to 3, wherein the formulation may comprises a combination of two or more permeability accelerator.
5. A liquid pharmaceutical formulation as claimed in any one of the claims 1 to 4, wherein the permeability accelerator used at least contains dimethyl sulphoxide or propylene glycol,
6. A liquid pharmaceutical formulation as claimed in any one of the claims 1 to 5, wherein the part by weight of dimethyl sulphoxide in the formulation is between 5 and 50%.
7. A liquid pharmaceutical formulation as claimed in any one of the claims 1 to 6, wherein the permeation accelerator or carrier comprises at least one of the following compounds: Dimethyl sulphoxide, monoglyceride, ethyl- or methyl- palmitic acid ester, fatty acids, fatty acid esters, fatty acid alcohols, substituted dialkyl fatty acids having 8 to 14 carbon atoms, N-methyl-pyrrdlidorie, N-methyl-2-pyrrolidone, oleic acid, propylene glycol, diethylene glycol, the mono-alkyl ether or carboxy-methyl ether of polyethylene glycol, propylene glycol fatty acid ester, lauryl acetate, N,N-dialkyl lauramide, N,N-dialkyl lauramide/dimethyl formamide mixture, dimethyl acetamide, N,N-diethyl-m-toluamide, histamine, ethylene glycol monomethyl ether, isopropyl myristate, isopropyl palmitate, propylene glycol and oleic acid or oleic alcohol, 2-pyrrol|done and dimethyl formamide, lauric acid, linoleic acid, lauryl acetate, sodium oleate, glycerine mono-oleate, urea and 1-bisabolol, nanoemulsion or liposomes.
8. A liquid pharmaceutical formulation as claimed in any one of the claims 1 to 7, wherein at least one further, second permeability accelerator is contained in combination with dimethyl sulphoxide.
9. A liquid pharmaceutical formulation as claimed in any one of the Claims 1 to 8, wherein the second permeability accelerator is a glycol compound.
10. A liquid pharmaceutical formulation as claimed in Claim 8 or 9, wherein the second permeability accelerator is ethylene- or propylene glycol.
11. A liquid pharmaceutical formulation as claimed in any one of the Claims 1 to 10 wherein the ratio by weight of the quinoxaline-2-one derivative to the permeability accelerator is between 1:2 and 1:500, preferably between 1:20 and 1:100.
12. A liquid pharmaceutically formulation as claimed in any one of claims 1 to 11, wherein the ratio by weight of the quinoxalin-2-one derivative to the permeability accelerator is between 1:22 and 1:50 glycerine and/or water are used as the solvent.
13. A liquid pharmaceutical^ formulation as claimed in any one of the claims 1 to 12, wherein the viscosity of the formulation is between 5000 and 25000 mPas (milliPascal), preferably between 15000 and 20000 mPas.
14. A liquid pharmaceutically fofmwlation as claimed in claim 14, wherein the nanoemulsion or the Mposomes contain the following compounds besides the said quinoxajon -2-one compound:
a membrane-forming molecule and a coemulsifier.


Documents:

346-delnp-2005-abstract.pdf

346-delnp-2005-Assignment-(30-03-2012).pdf

346-delnp-2005-claims-(cancelled).pdf

346-DELNP-2005-Claims.pdf

346-delnp-2005-complete specification(as files).pdf

346-delnp-2005-complete specification(granted).pdf

346-delnp-2005-Correspondence Others-(30-03-2012).pdf

346-delnp-2005-correspondence-others.pdf

346-delnp-2005-correspondence-po.pdf

346-DELNP-2005-Description (Complete).pdf

346-delnp-2005-form-1.pdf

346-delnp-2005-Form-16-(30-03-2012).pdf

346-delnp-2005-form-18.pdf

346-DELNP-2005-Form-2.pdf

346-delnp-2005-form-3.pdf

346-delnp-2005-form-5.pdf

346-delnp-2005-form-9.pdf

346-delnp-2005-gpa.pdf

346-delnp-2005-pct-101.pdf

346-delnp-2005-pct-210.pdf

346-delnp-2005-pct-301.pdf

346-delnp-2005-pct-304.pdf

346-delnp-2005-pct-332.pdf

346-delnp-2005-pct-408.pdf

346-delnp-2005-petition-137.pdf

346-delnp-2005-petition-138.pdf

abstract.jpg


Patent Number 246214
Indian Patent Application Number 346/DELNP/2005
PG Journal Number 08/2011
Publication Date 25-Feb-2011
Grant Date 21-Feb-2011
Date of Filing 31-Jan-2005
Name of Patentee PHAFAG AG
Applicant Address GEWERBEWEG 143,9486 SCHAANWALD,PRINCIPALITY OF LIECHTENSTEIN
Inventors:
# Inventor's Name Inventor's Address
1 WERNER BIEBERSCHULTE GRASGARTEN 505,9492 ESCHEN,PRINCIPALITY OF LIECHTENSTEIN.
2 KLAS EHRENBERGER GUNTHERGASSE 1,1090 VIENNA,AUSTRIA
PCT International Classification Number A61K 9/08
PCT International Application Number PCT/CH2003/000523
PCT International Filing date 2003-07-30
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 1357/02 2002-07-31 Switzerland