| Title of Invention | PROCESS FOR THE PREPARATION OF CARBAPENEM ANTIBIOTIC |
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| Abstract | Abstract The present invention provides an improved process for the preparation of Ertapenem of general formula (I) or its sodium salt in amorphous form wherein R represents hydrogen or COOM and M represents hydrogen or sodium ion. |
| Full Text | Field of the Invention This invention relates to a process for the preparation carbapenem antibiotic. More particularly, the present invention provides an improved process for the preparation of Ertapenem of general formula (I) or its sodium salt in amorphous form Wif" (I) wherein R represents hydrogen or COOM and M represents hydrogen or sodium ion. Background of the Invention Ertapenem sodium is a carbapenem marketed by Merck as Invanz®, and has chemical name [4R,5S,6S]-3-[[(3S,5S)-5-[[(3-carboxyphenyl)amino] carbonyl]-3-pyrrolidinyl]-thio]-6-[(lR)-l-hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0] hept-2-ene-2-carboxylic acid. Ertapenem sodium of general formula (I) is a ip-methylcarbapenem antibiotic, and used as antibiotic agent in the treatment of moderate to severe complicated foot infection due to indicated pathogens in diabetic patients without osteomyelitis, and also useful in the treatment of pneumonia, urinary tract infections, intra-abdominal, gynecological, skin, and soft tissue infections, meningitis, septicemia and febrile Neutrogena. In view of the importance of the compound of the formula (I), several synthetic procedures to prepare the compound have been reported. US 5,478,820 and US 5,856,321 claim two different processes for preparing Ertapenem and its salt. According to US 5,478,820, disodium salt of Ertapenem was prepared by dissolving crude product in water using NaHCOs (carbon dioxide source), followed by purification using column chromatography using HP20SS® or using CHP 20P and subsequent lyophilization. According to this specification the compound of formula (I) can be formulated along with alkali metal carbonate (carbon dioxide source). US 6,504,027 provides a process for preparing Ertapenem in crystalline form which comprises deprotecting and extracting into a polar organic solution containing a crude mono-protected Ertapenem of formula CO2-X OH wherein P represents protecting group with C4.10 alcohol in the presence of an ion-pair reagent followed by adjusting the pH to 5.5, collecting and crystallizing the resultant aqueous phase to produce a crystalline compound. However this patent involves several operations and reagents. Ertapenem of general formula (I) or its sodium salt is administered as a parenteral drug. Color of the reconstituted solution is an important indicator that indicates stability of the product. The formation of intense color like dark brown, black or reddish brown indicates the presence of highly unsaturated, intensely colored impurities and/or degradation products. A significant change in color of the reconstituted solution can become a limiting factor to the shelf life of a parenteral product. In order to get rid of colored impurities, the prior art patents utilize column chromatographic techniques and extraction techniques. The prior art processes are not convenient for industrial scale-up as they involve chromatographic purification in certain stages of synthetic processes. US 7,022,841 (593/CHENP/2004) discloses a process for reducing the levels of organic solvents in a crystalline carbapenem to pharmaceutically acceptable levels; this patent indicated that the disclosed process is suitable only for crystalline solid having water content at about 13% to about 25% by passing wet nitrogen and vacuum. Further it has been indicated that the removal of residual organic solvent is difficult when the antibiotic is in amorphous form. There are several prior arts in the relevant field disclose that the use of humidified gas for the removal of residual solvent. For example, US 4,978,752 provides the method of passing humidified air to bring down the residual solvent below pharmaceutically acceptable level in the product. For example as shown in example 14 of the said patent, the content of ethanol was reduced to 100 ppm from about 10.0%. US 4,692,519 teaches a process of removing residual organic solvent by passing water vapor (moist air or moist nitrogen gas with relative humidity of not less than about 70%). JP 55-102585 teaches a method of drying penicillin, cephalosporin containing a low-boiling organic solvent with steam under reduced pressure, thereby removing the low-boiling organic solvent. Process for the preparation of formulated amorphous form of Ertapenem or its salt is described in WO02/34750A1. The process involves filtering the final formulation product using sterilizing filter into a sterilizing vial and then lyophilization to final product. Process for formulation of Ertapenem-sodium or Ertapenem-COa-adduct is provided in WO01/32172A1. The process involves sterile filtration and lyophilization. In our PCT publication WO 2008/062279 (2153/CHE/2006) we have provided an improved process for the preparation of amorphous form of Ertapenem sodium by precipitation. With our continued research for developing a process for the preparation of Ertapenem of general formula (I) or its sodium salt in amorphous form having good stability and pharmaceutically acceptable level of residual solvent, (The limit of pharmaceutically acceptable level residual solvent is provided in ICH Harmonised Tripartite guideline; see: Note for guidance on Impurities: residual solvents (CPMP/ICH/283/95)), we have identified a process, which is not only commercially viable, but involves simple sterile preparation techniques such as precipitation using organic solvent. Objective of the invention The main objective is to provide a simple and commercially viable, industrially scalable process for the preparation of compound of the formula (I) in amorphous form having good stability. Another objective is to provide a process for the preparation of amorphous form of Ertapenem of general formula (I) or its sodium salt having pharmaceutically acceptable level of residual solvent. Summary of the Invention In one aspect, the present invention provides an improved process for the preparation of Ertapenem of general formula (I) or its sodium salt wherein R represents hydrogen or COOM and M represents hydrogen or sodium ion. the said process comprising the steps of: i) obtaining solution of Ertapenem (I) or its sodium salt in water and optionally in the presence of solvent; ii) optionally adjusting the pH of step (i) solution to 5.5 to 8.5; iii) treating the solution with decolorizing agent selected from the reagent consisting of alumina, silica, clay or mixtures thereof; iv) mixing the reaction solution with an anti-solvent; v) filtering the precipitated amorphous solid, and optionally washing the solid using an organic solvent; and vi) drying the amorphous Ertapenem of general formula (I) or its sodium salt using dry gas and/or humidified gas; wherein the improvement consists of one or more of the following: i) treating the aqueous solution with decolorizing agent selected from the reagent consisting of silica, alumina, or clay; and/or ii) avoids the use of vacuum during drying step; and/or iii) maintaining the water content of amorphous form of Ertapenem of general formula (I) or its sodium salt about 2.5% to about 11.0% throughout the washing and drying process. Detailed Description "Optional" or "optionally" means that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not. Ertapenem of general formula (I) or its sodium salts includes, but not limited to, the following compounds: (H+) (Naia Further the compounds may be isolated as a mixture. In first embodiment of the present invention, the solution of Ertapenem of general formula (I) or its sodium salt in step (i) is obtained by dissolving the Ertapenem of general formula (I) or its sodium salt in water or directly from the reaction solution. In second embodiment of the present invention, the solvent used in step (i) is selected from methanol, ethanol, isopropanol, 1-propanol, acetone, tetrahydrofuran (THF), dioxane, carbonated water (Prepared by purging carbon dioxide gas in water using autoclave) and mixtures thereof. In third embodiment of the present invention the solution of Ertapenem of general formula (I) or its sodium salt is obtained by dissolving Ertapenem of general formula (I) or its sodium salt in water using buffer. The buffer used is selected from buffer such as N-morpholinoalkanesulfonic acid like, 3-(N-morpholino)propanesulfonic acid (MOPS), 3-(N-morpholino)ethanesulfonic acid (MES) 3-(N-morpholino)-2-hydroxypropanesulfonic acid (MOPSO), 3[N-tris(hydroxymethyl)methylamino]propanesulfonic acid (TAPS), and the like. The pH of the buffer solution for dissolving Ertapenem of general formula (I) or its sodium salt was adjusted between 5.5 and 8.5, preferably 5.0 and 6.0 to get monosodium. The use of buffer maintains pH of the solution medium, which minimize the degradation. In fourth embodiment of the present invention the pH of the aqueous solution optionally adjusted to about 5.5 to 8.5. The pH of aqueous solution determines the final form of Ertapenem of general formula (I) or its sodium salt. For example isolation at about pH 5.5 to 6,0 yields monosodium salt of Ertapenem, while isolation at about 7.5 pH yields disodium salt. The pH was adjusted using acids like acetic acid, formic acid, dil HCl or bases like NaOH solution, sodium bicarbonate solution and the like. In fifth embodiment of the present invention the solution of Ertapenem of general formula (I) or its sodium salt is obtained by dissolving Ertapenem of general formula (I) or its sodium salt in aqueous solution containing a base such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium hydroxide and the like. Accordingly Ertapenem monosodium dissolved using sodium bicarbonate and pH was further adjusted using NaOH to yield stable Ertapenem disodium. Likewise the pH of the aqueous solution was adjusted suitably to convert acid into sodium or one form of sodium into another form. Further the said solution is obtained directly from the reaction; the use of solution directly obtained from the reaction solution (Scheme-I illustrates the reaction) obviates the need of isolation of non-sterile Ertapenem of general formula (I) or its sodium salt and hence directly can be utilized for sterile preparation. Since Ertapenem of general formula (I) or its sodium salt being administered as injectable drug, the final drug has to be subjected to sterile micron filtration in sterile area. Scheme-1: OM O Hydrogenation P' = Protecting group P" = Hydrogen or protecting group In sixth embodiment of the present invention, the aqueous solution thus obtained was treated with decolorizing agent selected from the reagent consisting of silica, alumina, clay or mixtures thereof. Such a treatment with decolorizing agent found to be advantage in terms of increasing stability of the product. As color is one of the important indicating parameter that determines the stability of injectable drug, the conventional usage of carbon to remove color fails to yield good quality product. The color of reconstituted product is dark brown to black during the use of carbon, whereas it is pale yellow, maintained for a week at 25-30** C, during the usage of above said decolorizing agent. In seventh embodiment of the present invention the solution containing Ertapenem of general formula (I) or its sodium salt is further subjected to micron filtration into sterile area by conventional technique. In eight embodiment of the present invention, the anti-solvent used in step (iv) for precipitation of sterile Ertapenem of general formula (I) or its sodium salt is selected from ethanol, acetone, isopropyl alcohol, 1-propanol, tetrahydrofuran, acetonitrile, isopropyl ether, diethyl ether, 2-methylTHF, methyl t-butyl ether and the like or mixtures thereof. In ninth embodiment of the present invention, the organic solvent used for washing in step (v) is selected from methanol, isopropyl ether (IPE), ethyl 10 acetate, methyl acetate, ethanol, isopropyl alcohol, n-hexane, dichloromethane, diethyl ether, 2-methylTHF, methyl t-butyl ether, acetone and the like or mixtures thereof. The Ertapenem of general formula (I) or its sodium salt obtained after the precipitation and after washing is found to be amorphous in nature, and may contain higher amount of residual solvents like ethanol, iso-propanol, 1-propanol, isopropyl ether, methanol, acetone, ethyl acetate, dichloromethane (MDC), and the like. In tenth embodiment of the present invention, the Ertapenem of general formula (I) or its sodium salt thus prepared is dried using dry and/or humidified gases like air, nitrogen, carbon dioxide and the like (humidified gases are obtained by mixing with water vapour). Though US 7,022,841 teaches that the removal of residual solvent in amorphous form of Ertapenem sodium is difficult, the present invention provides amorphous Ertapenem sodium of general formula (I) or its sodium salts having water content about 2.5-11.0 % throughout the operation that permits removal of residual solvent using dry and/or humidified gas. The present invention further avoids vacuum drying technique and employs dry and/or humidified gas. The drying process involves passing dry or humidified gas through Ertapenem of general formula (I) or its sodium salt placed in a pressure filter till the desired results are obtained at -10 to 30° C, for example a Nutsche filter. The sterile sodium salt of formula (I) obtained through this process is found to be stable, free flowing, pure and could be easily handled for further filling in vials. Suitable temperature for dissolving non-sterile Ertapenem sodium is in the range of -30 to 15 °C. Precipitation was desirably carried out in the 11 temperature range of about -5 °C to 30 °C. The process provided could be conveniently followed for the preparation of non-sterile Ertapenem sodium also. In eleventh embodiment, the Ertapenem of general formula (I) or its sodium salt obtained could be optionally blended with alkali metal carbonate or bicarbonate (when R is H) or with salts like Lysine or Arginine and stored in vial under carbon dioxide atmosphere or nitrogen atmosphere. Pharmaceutical composition of Ertapenem sodium may also contain sodium citrate, sodium acetate, sodium tartrate, sodium carbonate, sodium bicarbonate, morpholinopropanesulfonic acid, or other phosphate buffers and the like and chelating agents like ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid, hydroxyethylenediaminetriacetic acid, and the like or pharmaceutically acceptable salts thereof. The final sterile compound obtained is free flowing, having good physical properties and suitable for subsequent formulation. The present invention is illustrated with the following examples, which should not be construed to limit the scope of the invention. Example-1 Preparation of sterile Ertapenem monosodium of formula (I) IR represents Hli Ertapenem monosodium (non-sterile) (40 g) was added to the cold (0-2 °C) mixture of methanol-water (200 mL each) and stirred. Activated carbon (4 g) was added and stirred. The carbon was removed by filtration and passed through micron filter, than it was added into ethanol (4 L) and stirred. The solid obtained was filtered and washed with IPE under nitrogen and dried to get sterile 12 Ertapenem sodium (27 g) in amorphous form. The color of the reconstituted product was found to be brownish yellow. Example-2 Preparation of sterile Ertapenem monosodium of formula (I) IR represents Hi: The pH of the MOPS solution in water (200 mL, 0.025 M) was adjusted to 5.0 to 6.0 using sodium hydroxide solution and then cooled to 0 to 2 °C. Ertapenem mono sodium (non-sterile) (20 g) was then added to the said buffer solution and stirred to get clear solution. To the clear solution, silica and activated carbon (2 g) were added, stirred and filtered. The filtrate was passed through micron filter and then added into ethanol (2 L) and stirred. The solid obtained was filtered, washed with methanol under nitrogen atmosphere and dried to get sterile Ertapenem sodium (27 g). The color of the reconstituted product was found to be yellow. Exampie-3 Preparation of Ertapenem disodium of formula (I) IR represepts;COOM>; To the solution of sodium bicarbonate (2.5 g in 70 mL water) Ertapenem monosodium (15 g) was added slowly at 0-5° C, by maintaining pH around 7.5 using sodium hydroxide solution. The solution obtained was subjected to carbon treatment. Filtrate containing Ertapenem disodium was added into 2500 mL of cold IPA at 0-5° C. The solid obtained was filtered washed with cold IPA followed by acetone and IPE, dried under nitrogen to yield Ertapenem disodium (sodium content: 9.2 -10.5 %; moisture content: 5-7%; pH: 7.5 - 8.0). The color of the reconstituted product was found to be brownish yellow. 13 £xample-4 Preparation of Ertapenem disodium of formula (!) {R reDreseiits;COOM>: To the solution of sodium bicarbonate (2.5 g in 70 mL water) Ertapenem monosodium (15 g) was added slowly at 0-5° C, by maintaining pH around 7.5 using sodium hydroxide solution. The solution obtained was subjected to carbon treatment and alumina and filtered. Filtrate containing Ertapenem disodium, was added into 2500 mL of cold IPA at 0-5° C. The solid obtained was filtered washed with IPA followed by acetone and IPE, dried under dry and wet nitrogen to yield Ertapenem disodium (Yield: 8-12 g; sodium content: 9.2 -10.5 %; moisture content: 5-7%; pH: 7.5 - 8.0). The color of the reconstituted product was pale yellow. ExampIe-5 Preparation of Ertapenem disodium of formula (I) R=COOM H,C H,C' Diprotected Ertapenem PNB: P-nitro protecting group H2/Pd/C NaHC03 Ertapenem disodium To a solution of sodium salt of di-protected Ertapenem (50 g) in a mixture of carbonated water (500mL), THF (100ml), DMF (25ml) and ethyl acetate (1000 mL) in autoclave, were added sodium bicarbonate (6.5 gm) and 10% Pd/carbon and subjected to hydrogenation with 8 to 10 Kg pressure at 5 - 10 °C. After completion of reaction, the reaction mass was filtered. The aqueous layer was separated, washed with ethyl acetate and the dissolved solvents in aqueous layer were removed using degassing technique. The aqueous layer was added into isopropyl alcohol (12 L) under stirring. The precipitated Ertapenem 14 disodium was filtered, washed with IPE and dried to yield amorphous form of Ertapenem disodium. The solid obtained was dissolved in water and precipitated using mixture of ethanol and methyl acetate. The solid was washed with ethanol and dried to yield Ertapenem disodium in amorphous form. The color of the reconstituted product is brownish yellow. Example-6 Preparation of Ertapenein disodium of formula (I) R=COOM To the solution of sodium salt of di-protected Ertapenem (130 g) in a mixture of carbonated water (1300mL), isopropyl alcohol (400 mL) and ethyl acetate (200 mL) in autoclave, were added sodium bicarbonate (20 gm), Pd/carbon and subjected to hydrogenation with 8 to 10 Kg pressure at 5 - 10 °C. After completion of the reaction CO2 gas was purged and the reaction mass filtered. The aqueous layer was separated, washed with ethyl acetate and the dissolved solvents in aqueous layer were removed using degassing technique. The aqueous layer was added in to isopropyl alcohol and isopropyl ether under stirring. The precipitated Ertapenem disodium was filtered, washed with IPE and ethanol and dried to yield amorphous form of Ertapenem disodium. The solid obtained (Ertapenem disodium non sterile) was dissolved in water, and treated with alumina and carbon, followed by micron filtration in to sterile area. To the filtrate, ethanol and acetone were added. The solid obtained was filtered and washed with ethanol. The precipitated amorphous form of Ertapenem disodium (having moisture content: about 1% to 11%) was slurry washed with ethanol and IPE. The solid obtained (having moisture content: about 2.5% to 6%) was dried using dry N2 gas followed by humidified N2 gas to yield amorphous Ertapenem disodium (having moisture content: about 7% to 11%) and again dried using dry N2 gas at about 5-10 °C to yield amorphous form of Ertapenem disodium having 15 moisture content (2.5-4.5%) with pharmaceutically acceptable level of residual solvent. Residual solvent before passing humidified gas: Ethanol: 3.0-5,0 %; Isopropanol: 0.5-1.0 %. Residual solvent after passing humidified gas: Ethanol: Less than 0.5 %; Isopropanol: Less than 0.5 %. The color of the reconstituted product is pale yellow. Example-7 Preparation of Ertapenein disodium of formula (I) R=COOM To the solution of sodium salt of di-protected Ertapenem (50 g) in a mixture of carbonated water (500ml), IPA (2.6ml) and ethyl acetate (20 L) in autoclave were charged sodium bicarbonate (6.5 gm) and Pd/carbon and subjected to hydrogenation with 3 to 10 Kg pressure at 5 - 10 °C. After completion of reaction CO2 gas was purged and the reaction mass was filtered.. The aqueous layer was separated, washed with ethyl acetate and was treated with activated carbon and neutral alumina, the residual solvents in aqueous layer removed using degassing technique and filtered. The aqueous layer was added into isopropyl alcohol and ethanol under stirring. The precipitated amorphous form of Ertapenem disodium (having moisture content: about 7% to 11%) was slurry washed with ethanol and IPE. The obtained solid (having moisture content: about 2.5% to 6%) was dried using dry N2 gas followed by humidified N2 gas to yield amorphous form of Ertapenem disodium (having moisture content: about 7% to 12%) and again dried using dry N2 gas at about 5- 10 °C to yield amorphous form of Ertapenem disodium having moisture content (2.5-4.5%) with pharmaceutically acceptable level of residual solvent. Residual solvent before passing humidified gas: Ethanol: 3.0-5.0 %; Isopropanol: 0.5-1.0 %. 16 Residual solvent after passing humidified gas: Ethanol: Less than 0.5 %; Isopropanol: Less than 0.5 %. Advantage of using decolorizing agent: Color of the reconstitution product: No or only a minor increase in color intensity (pale yellow to light yellow) was noted in samples kept at 25°C for one week when the above said decolorizing agent was used. In contrast to the initial color during the use of carbon was reddish brown and turned to black within a day. We claim: 1) An improved process for the preparation of amorphous form of Ertapenem of general formula (I) or its sodium salt, wherein R represents hydrogen or COOM and M represents hydrogen or sodium ion; the said process comprises the steps of: i) obtaining solution of Ertapenem of formula (I) or its sodium salt in water and optionally in the presence solvent; ii) optionally adjusting the pH of step (i) solution to 5.5 to 8.5; iii) treating the solution with decolorizing agent selected from the reagent consisting of alumina, silica, clay or mixtures thereof; iv) mixing the reaction solution with an anti-solvent; v) filtering the precipitated amorphous solid, and optionally washing the solid using an organic solvent; and vi) drying the amorphous Ertapenem of general formula (I) or its sodium salt using dry gas and/or humidified gas; wherein the improvement consists of one or more of the following: i) treating the aqueous solution containing Ertapenem (I) or its sodium salt with decolorizing agent selected from the reagent consisting of silica, alumina, or clay; and/or ii) avoids the use of vacuum during drying step; and/or iii) maintaining the water content of amorphous form Ertapenem of general formula (I) or its sodium salt from 2.5% to 11.0% from step (v) to (vi). 18 2) An improved process for the preparation of amorphous form of Ertapenem of general formula (I) or its sodium salt which comprises a) treating the solution of Ertapenem of general formula (I) or its sodium salt in water and optionally in the presence of solvent with decolorizing agent selected from the reagent consisting of alumina, silica, clay or mixtures thereof; and b) isolating Ertapenem (I) or its sodium salt. 3) A process as claimed in claim 2, wherein the decolorizing agent is alumina. 4) A process as claimed in claim 1, wherein solvent used in step (i) is selected form group comprising of methanol, ethanol, isopropanol, 1-propanol, acetone, tetrahydrofuran (THF), dioxane, carbonated water or mixtures thereof. 5) A process as claimed in claim 1, wherein anti-solvent used in step (iv) is selected from consisting of ethanol, acetone, isopropyl alcohol, tetrahydrofuran, acetonitrile, isopropyl ether, diethyl ether, 2-methylTHF, methyl t-butyl ether or mixtures thereof, 6) A process as claimed in claim 1, wherein solvent used for washing in step (v) is selected from group comprising of methanol, isopropyl ether (IPE), ethyl acetate, methyl acetate, ethanol, isopropyl alcohol, n-hexane, dichloromethane, acetone or mixture thereof. 7) A process as claimed in claim 1, wherein dry gas or humidified gas is selected from air, nitrogen, or carbon dioxide. 19 8) A process as claimed in claim 1, wherein the Ertapenem of general formula (I) or its sodium salt obtained having pharmaceutically acceptable level of residual solvent. 9) A process as claimed in claim 1 or 2, wherein the Ertapenem of general formula (I) or its sodium salt obtained having pale yellow color on reconstitution using water for injection. 10) A process as claimed in claim 1, wherein the solution of Ertapenem (I) or its sodium salt is obtained by dissolving the solution of Ertapenem (I) or its sodium salt or directly from the reaction mass. wherein R represents hydrogen or COOM and M represents hydrogen or sodium ion; the said process comprises the steps of: a) obtaining solution of Ertapenem sodium of general formula (lA) salt in water; b) treating the solution with decolorizing agent selected from the reagent consisting of alumina, silica, clay or mixtures thereof; c) mixing the reaction solution with an anti-solvent; d) filtering the precipitated amorphous solid, and optionally washing the solid using an organic solvent; and 20 e) drying the amorphous Ertapenem sodium of general formula (lA) using dry gas and/or humidified gas; wherein the improvement consists of one or more of the following: a) treating the aqueous solution containing Ertapenem sodium of general formula (lA) with decolorizing agent selected from the reagent consisting of silica, alumina, or clay; and/or b) avoids the use of vacuum during drying step; and/or c) maintaining the water content of amorphous form Ertapenem of general formula (I) or its sodium salt from 2.5% to 11.0% from step (d) to (e). |
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| Patent Number | 277942 | ||||||||||||
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| Indian Patent Application Number | 1890/CHE/2007 | ||||||||||||
| PG Journal Number | 51/2016 | ||||||||||||
| Publication Date | 09-Dec-2016 | ||||||||||||
| Grant Date | 07-Dec-2016 | ||||||||||||
| Date of Filing | 23-Aug-2007 | ||||||||||||
| Name of Patentee | HOSPIRA, INC. | ||||||||||||
| Applicant Address | 275 NORTH FIELD DRIVE, DEPT.NLEG BLDG H-1 LAKE FOREST, IL 60045 | ||||||||||||
Inventors:
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| PCT International Classification Number | C07D477/00; A61K31/397 | ||||||||||||
| PCT International Application Number | N/A | ||||||||||||
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