• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    The present invention relates to novel solid forms of rifaximin, in particular co-crystals and co-morphs of rifaximin and a coform of the group comprising carboxylic acids, amino acids, phenolic compounds and biotin. The new solid forms of rifaximin have a different solubility than that of the polymorph rifaximin K and rifaximin. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2743719A2
    申请号:ES201930349
    申请日:2019-04-16
    公开日:2020-02-20
    发明作者:Chavez Jorge Guillermo Dominguez；Vasquez Karina Mondragon；Arroyo Héctor Senosiain
    申请人:Alparis SA De Cv；Alparis SA de CV；
    IPC主号:
    专利说明:

    [0001]
    [0002]
    [0003]
    [0004]
    [0005]
    [0006] The present invention relates to new solid forms (NFS) of Rifaximin (RFX), particularly co-crystals and co-morphs of RFX, with a coformor selected from carboxylic, nutraceutical and amino acid derivatives, as well as the respective solvates, hydrates and / or polymorphs of the new solid phase; to its use in the preparation of a composition for the treatment of conditions that require pharmacological activity against Gram-positive and Gram-negative bacteria, both aerobic and anaerobic, including a wide range of enteropathogenic bacteria.
    [0007]
    [0008]
    [0009]
    [0010] In the present invention, the new solid forms (NFS), correspond to co-crystals, coamorphs or salts, and their respective solvates and hydrates and are obtained by technical experimentation. Co-crystals and coamorphs are chemical entities with physicochemical properties different from the salts or polymorphs of the base active ingredient, and are characterized by the nature of the intermolecular interactions present between the active molecule and a second solid constituent called coformator.
    [0011]
    [0012] A co-crystal is a multicomponent crystal formed by two or more non-identical molecules and in which the two or more components of the co-crystal form a periodic crystalline network that is characterized in that the components are joined by intermolecular interactions - such as the forces of Van der Waals, n-stacks, hydrogen bonds or electrostatic interactions, but without forming covalent bonds. Similarly, a coamorph is a multicomponent amorphous solid, coamorph without a defined long-range arrangement and is composed of two or more non-identical molecules that are held together through intermolecular interactions, which provides physical and chemical stability to the amorphous phase and inhibits its tendency to crystallize.
    [0013] Rifaximin (RFX), 4-deoxy-4'-methylpyrido [1 ', 2'-1,2] imidazo- [5,4-c] -rifamycin is a synthetic intestinal anti-infective compound derived from rifampicin (see Formula 1) .
    [0014]
    [0015]
    [0016] Formula 1. Chemical structure of Rifaximin (RFX)
    [0017]
    [0018] Rifaximin has activity in Gram-positive and Gram-negative bacteria, both aerobic and anaerobic, including a wide range of enteropathogenic bacteria.
    [0019]
    [0020] Rifaximin is used as an anti-infective, for the treatment of bacterial enterocolitis resistant to symptomatic treatment in patients at risk, pseudomembranous colitis in patients resistant to vancomycin, acute diverticulitis, perioperative prophylaxis in gastrointestinal surgery and as an adjunctive therapy in hyperaemia.
    [0021]
    [0022] The absorption of rifaximin in the gastrointestinal tract is practically zero, which favors its active concentration in the intestinal lumen and feces.
    [0023]
    [0024] The New Solid Forms (NFS) of the present invention are not reported in any prior art document. Patent documents and articles related to the solid state of rifaximin (RFX) are listed below.
    [0025]
    [0026] 1. WO2005044823 (US7045620), of Alfa W., refers to alpha, beta and gamma polymorphs of RFX.
    [0027]
    [0028] 2. WO2006094662 (US8518949), of Alfa W., refers to delta polymorphs and RFX epsilon.
    [0029]
    [0030] 3. WO2009108730 (MX318780, US20100174064, US8067429), from Salix Pharmaceuticals, refers to polymorphs Q, and - l (Q, ^, a -asxa, mesylate or amorphous forms of RFX.
    [0031]
    [0032] 4. WO2010122436 (MX338334), of Alfa W., refers to a process for obtaining rifamycin derivatives.
    [0033]
    [0034] 5. WO2011153444 (MXPA2012013945, US8513275, US8815888), from Salix Pharmaceuticals, refers to the polymorph kappa, theta and co-crystal of RFX with piperazine.
    [0035]
    [0036] 6. WO2011103120 from Salix Pharmaceuticals, refers to polymorphs Q, ^, i, i-seca, i-seca ’, or B of RFX.
    [0037]
    [0038] 7. WO201215695 (MX348393, US8877770) of Clarochem, refers to an RFX crystal "k".
    [0039]
    [0040] 8. WO2012156533 (MX344858, US20140155422) by Friulchem refers to a process for preparing almost amorphous pseudocrystalline forms of RFX.
    [0041]
    [0042] 9. WO2012109605 (MX350448) of Salix Pharmaceuticals, refers to the polymorphs Mu, Pi s , Xi, Omicron.
    [0043]
    [0044] 10. US20120258166 by Alfa W., refers to amorphous RFX compositions
    [0045]
    [0046] 11. US20120196887, by Charles Darkoh, refers to compositions of RFX and bile acids.
    [0047]
    [0048] 12. WO2014006576 (MX2014015799) by Alfa W., refers to co-processed RFX and amino acids Ser, Hys, Trp, Val, Leu, Ile.
    [0049]
    [0050] 13. WO2015014984 (MXPA2016001199, CA2920080A) of Clarochem, discloses a process for preparing kappa form and crystalline form of solvated RFX.
    [0051]
    [0052] 14. Viscomi, GC, Campana M., Braga D., Crystal form of Rifaximin CrysEngComm, 2008, 10, 1074-1081.
    [0053]
    [0054] 15.Braga D., Crystal form of rifaximin CrysEngComm, 2012, 14, 6404-6411.
    [0055]
    [0056]
    [0057]
    [0058] The present invention relates to solid compounds also mentioned as new solid forms (NFS) of Rifaximin (RFX), particularly co-crystals and co-morphs of rifaximin and a coformator selected from derivatives of dicarboxylic acids and amino acids, as well as the respective solvates, hydrates and / or polymorphs of the new solid phase.
    [0059]
    [0060] The invention also relates to the use of said new solid forms for developing useful drugs as anti-infectives and / or in the treatment of conditions related to the gastrointestinal tract.
    [0061]
    [0062] In one embodiment of the present invention, co-crystalline rifaximin NFSs comprise rifaximin and a dicarboxylic acid coform of selected D-tartaric, L-tartaric, D-tartaric DL-tartaric, L-malic, DL-malic acid, succinic acid, acid oxalic, malonic acid, glutaric, azelaic, with stoichiometry ranging from 1: 1 to 3: 1 and 3: 1 to 1: 1, preferably 2: 1, 1: 1 and 1: 2. It also refers to pharmaceutical compositions comprising said co-crystals, and their use as anti-infective agents.
    [0063]
    [0064] The cocrystalline rifaximin NFS are more stable and have lower solubility than amorphous rifaximin or polymorphic rifaximin K, which impacts by decreasing its absorption and favors its concentration in the intestinal lumen and feces where it has its therapeutic effect.
    [0065]
    [0066] In another embodiment, coamorphic rifaximin NFSs comprising RFX and the D-malic acid coformor are presented.
    [0067]
    [0068] In another embodiment, crystalline rifaximin NFSs comprising RFX and the coformer L-tartaric acid, L-malic acid and D-tartaric acid.
    [0069]
    [0070] In another modality, rifaximin co-morphine NFS and a coformer selected from various amino acids are presented, including: L-Lysine (L-Lys), L-Arginine (L-Arg), L-cysteine (L-Cys), L-Histidine (His), Glycine (Gly), DL-Alanine (DL-Ala), L-phenylalanine, L-methionine, L-tyrosine and DL-tryptophan, with stoichiometry drug: coformer selected from 2: 1, 1: 1 and 1 :two. Pharmaceutical compositions containing said NFS are also presented, and their use as anti-infective agents.
    [0071]
    [0072] Coamorphic NFS of rifaximin L-Cysteine HCl monohydrate have different solubility and maintain their constant solubility for a period greater than 12 hours.
    [0073]
    [0074] In another embodiment, new solid forms of rifaximin with a nutraceutical coformer comprising at least one carboxylic group and / or a polyphenol group or phenolic compound selected from biotin, resorcinol, catechol, cumaric acid, resveratrol and trans-aconitic acid are presented. For these coformers different stoichiometries were tested, obtaining a crystalline compound with RFX and biotin with stoichiometry drug: coformator 1: 2, as well as amorphous NFS RFX: resorcinol 1: 1, RFX: catechol 1: 1, RFX: trans-aconitic acid 1 : 1, RFX: 2: 1 cumaric acid and RFX: 2: 1 resveratrol.
    [0075]
    [0076] Rifaximin (RFX) is a synthetic intestinal anti-infective agent derived from rifampin, its absorption in the gastrointestinal tract is practically nil, which favors its active concentration in the intestinal lumen and feces.
    [0077]
    [0078] RFX has various hydrogen bridge donor and acceptor groups (see Formula 1), so it is potentially capable of establishing multiple intermolecular interactions with complementary polar functional groups. The present invention presents NFS that can be co-crystals and coamorphs and salts, formed from intermolecular interactions of RFX with coformers containing carbonyl, hydroxyl and / or amino groups.
    [0079]
    [0080] During the process of obtaining the NFS you can think of a large number of combinations with the possible coformers. However, not all combinations coforming drug can establish intermolecular interactions that generate a new stable solid phase.
    [0081]
    [0082] Although there is a good knowledge of the physicochemical and chemical structure of the components that will form a new solid phase, a priori elucidation is practically impossible , from which coformers will form a co-crystal or co-morph or salts, since the interactions that determine the structure of these are relatively weak and the number of degrees of freedom of the problem is very large. For these reasons, the new solid forms presented in this document are not obvious to a person versed in the subject. The co-crystals, coamorphs, and salts of the present invention, or their respective solvates and hydrates, have shown physicochemical stability, which allows their use in the preparation of pharmaceutical compositions.
    [0083]
    [0084] In accordance with the present invention, the obtaining of co-crystalline and coamorphic NFSs is achieved by the Slurry method with the use of a minimum of solvents and in environmental conditions. This process of obtaining reduces the cost of operation of equipment for the obtaining of crystals and has a minimal impact on the environment since practically no organic solvents are used or, small amounts are used.
    [0085]
    [0086]
    [0087]
    [0088] Figures 1-23 illustrate the result of the characterization of the rifaximin NFS obtained in the present invention.
    [0089]
    [0090] Figure 1a. X-ray diffractogram of polymorph K rifaximin powders.
    [0091]
    [0092] Figure 1b X-ray diffractogram of the powder obtained from rifaximin slurry in acetonitrile.
    [0093]
    [0094] Figure 2a. X-ray diffractograms of powders of raw materials and solids obtained from slurries in acetonitrile: i) RFX, ii) RFX slurry in acetonitrile, iii) RFX: D-tartaric 2: 1, iv) RFX: D-tartaric 1 : 1, v) RFX: D-tartaric 1: 2, vi) D-tartaric acid.
    [0095] Figure 2b X-ray powder diffractograms of raw materials and solids obtained from slurries in acetonitrile: i) RFX, ii) RFX slurry in acetonitrile, iii) RFX: L-tartaric 2: 1, iv) RFX: L-tartaric 1 : 1, v) RFX: L-tartaric 1: 2, vi) L-tartaric acid.
    [0096]
    [0097] Figure 3a. X-ray powder diffractograms of raw materials and solids obtained from slurries in acetonitrile: i) RFX, ii) RFX slurry in acetonitrile, iii) RFX: D-malic 2: 1, iv) RFX: D-malic 1 : 1, v) RFX: D-malic 1: 2, vi) D-malic acid.
    [0098]
    [0099] Figure 3b of the raw materials and solids obtained from the slurries in acetonitrile: i) RFX, ii) RFX: L-malic 2: 1, iii) RFX: L-malic 1: 1, iv) RFX: L-malic 1: 2 , v) RFX slurry in acetonitrile, vi) L-malic acid.
    [0100]
    [0101] Figure 4. X-ray diffractograms of powders of raw materials and solids obtained from slurries in acetonitrile: i) Malonic acid, ii) RFX: malonic 1: 2, iii) RFX slurry in acetonitrile, iv) RFX.
    [0102]
    [0103] Figure 5. IR spectrum of: i) RFX slurry in acetonitrile, ii) RFX: 1: 2 malonic slurry in acetonitrile, iii) Malonic acid slurry in acetonitrile.
    [0104]
    [0105] Figure 6. X-ray diffractograms of powders of raw materials and solids obtained from slurries in acetonitrile: i) glutaric acid, ii) RFX: glutaric 1: 2, iii) RFX slurry in acetonitrile, iv) RFX.
    [0106]
    [0107] Figure 7. IR spectrum of: i) RFX slurry acetonitrile, ii) RFX: glutaric 1: 2 slurry in acetonitrile, iii) Glutaric acid slurry in acetonitrile.
    [0108]
    [0109] Figure 8. X-ray diffractograms of powders of raw materials and solids obtained from slurries in acetonitrile: i) Azelaic acid, ii) RFX: azelaic 1: 2, iii) RFX slurry in acetonitrile, iv) RFX.
    [0110]
    [0111] Figure 9. IR spectrum of: i) RFX slurry in acetonitrile, ii) RFX: azelaic 1: 2 slurry in acetonitrile, iii) Azelaic acid slurry in acetonitrile.
    [0112] Figure 10. Structures obtained by X-ray diffraction of monocrystals of the RFX co-crystal: D-tartaric in 2: 1 stoichiometry.
    [0113]
    [0114] Figure 11. Structures obtained by X-ray diffraction of monocrystals of the RFX co-crystal: L-malic in 2: 1 stoichiometry.
    [0115]
    [0116] Figure 12a. Calculated X-ray diffractograms of monocrystals: i) RFX: D-tartaric, and ii) RFX: L-malic.
    [0117]
    [0118] Figure 12b X-ray diffractograms. Comparison of diffractograms calculated from monocrystals, diffractograms of co-crystals experimentally obtained by slurry in acetonitrile and diffractograms of raw materials: i) RFX, ii) RFX slurry in acetonitrile, iii) RFX: D-tartaric 2: 1 calculated single crystal, iv) RFX: D-tartaric slurry 2: 1 in acetonitrile, v) RFX: L-malic 2: 1 calculated from single crystal, and vi) RFX: L-malic slurry 2: 1 in acetonitrile.
    [0119]
    [0120] Figure 13a Thermogram of DSC (line I) and TGA (line II) of the NFS RFX: L-tartaric with stoichiometry 1: 1.
    [0121]
    [0122] Figure 13b Thermogram of DSC (line I) and TGA (line II) of the NFS RFX: L-malic with 1: 1 stoichiometry.
    [0123]
    [0124] Figure 13c Thermogram of DSC (line I) and TGA (line II) of the NFS RFX: D-malic with 1: 1 stoichiometry.
    [0125]
    [0126] Figure 13d Thermogram of DSC (line I) and TGA (line II) of the NFS RFX: D-tartaric with stoichiometry 1: 1.
    [0127]
    [0128] Figure 14. Graph of the concentration obtained from the different NFS solutions with 1: 1 stoichiometry and free RFX with respect to time: RFX (^), RFX: D-malic (^), RFX: L-malic (^) , RFX: D-tartaric (A), RFX: L-tartaric (^).
    [0129] Figure 15a. X-ray powder diffractograms of raw materials and solids obtained from slurries in methanol for: i) RFX slurry in methanol, ii) RFX: L-Arg 2: 1, iii) RFX: L-Arg 1: 1, iv) RFX: L-Arg 1: 2, v) L-Arg.
    [0130]
    [0131] Figure 15b X-ray powder diffractograms of raw materials and solids obtained from slurries in methanol for: i) RFX slurry in methanol, ii) RFX: L-Cys 2: 1, iii) RFX: L-Cys 1: 1, iv) RFX: L-Cys 1: 2, v) L-Cys.
    [0132]
    [0133] Figure 15c X-ray powder diffractograms of raw materials and solids obtained from slurries in methanol for: i) RFX slurry in methanol, ii) RFX: L-Lys 2: 1, iii) RFX: L-Lys 1: 1, iv) RFX: L-Lys 1: 2, v) L-Lys.
    [0134]
    [0135] Figure 16a. Infrared (IR) spectra of the amorphous NFS and the raw materials, using L-Lysine in RFX: L-Lys 2: 1 ratio.
    [0136]
    [0137] Figure 16b IR spectra of the amorphous NFS and raw materials, using L-Lysine in RFX ratio: L-Lys 1: 1.
    [0138]
    [0139] Figure 16c IR spectra of the amorphous NFS and raw materials, using L-Arginine in RFX ratio: L-Arg 2: 1.
    [0140]
    [0141] Figure 16d IR spectra of the amorphous NFS and raw materials, using L-Arginine in RFX ratio: L-Arg 1: 2.
    [0142]
    [0143] Figure 16e IR spectra of the amorphous NFS and raw materials, using L-Arginine in RFX ratio: L-Arg 1: 1.
    [0144]
    [0145] Figure 16f. IR spectra of the amorphous NFS and raw materials, using L-Cysteine HCl monohydrate in RFX ratio: L-Cys 2: 1.
    [0146]
    [0147] Figure 16g IR spectra of the amorphous NFS and the raw materials, using L-Cysteine HCl monohydrate in RFX ratio: L-Cys 1: 1.
    [0148] Figure 16h. IR spectra of the amorphous NFS and raw materials, using L-Cysteine HCl monohydrate in RFX ratio: L-Cys 1: 2.
    [0149]
    [0150] Figure 17. Graph of the concentration obtained from the different solutions of amorphous NFS and free RFX with respect to time: RFX (■), RFX: L-Arginine 1: 1 (^), RFX: L-Arginine 2: 1 (A), RFX: L-Arginine 1: 2 (▼), RFX: L-Lysine 1: 1 (^), RFX: L-Lysine 2: 1 (^), RFX: L-Cysteine 1: 1 (► ), RFX: L-Cysteine 1: 2 (★) and RFX: L-Cysteine 2: 1 (#).
    [0151]
    [0152] Figure 18. X-ray diffractograms of raw material powders and solids obtained from acetonitrile slurries: i) RFX, ii) RFX slurry in acetonitrile, iii) RFX: Biotin 1: 2 slurry in acetonitrile, iv) Biotin slurry in acetonitrile, v) biotin.
    [0153]
    [0154] Figure 19. X-ray diffractograms of raw material powders and solids obtained from acetonitrile slurries: i) RFX, ii) RFX slurry in acetonitrile, iii) RFX: Resorcinol 1: 1 slurry in acetonitrile, iv) resorcinol slurry in acetonitrile, v) resorcinol.
    [0155]
    [0156] Figure 20. X-ray powder diffractograms of raw materials and solids obtained from slurries in acetonitrile: i) RFX, ii) RFX slurry in acetonitrile, iii) RFX: Catechol 1: 1 slurry in acetonitrile, iv) catechol slurry in acetonitrile, v) catechol.
    [0157]
    [0158] Figure 21. X-ray diffractograms of powders of the raw materials and solids obtained from the slurries in acetonitrile: i) RFX, ii) RFX slurry acetonitrile, iii) RFX: Trans-aconitic acid 1: 1 slurry in acetonitrile, iv) trans-aconitic acid acetonitrile slurry, v) trans- aconitic acid.
    [0159]
    [0160] Figure 22. X-ray diffractograms of raw material powders and solids obtained from acetonitrile slurries: i) RFX, ii) RFX slurry in acetonitrile, iii) RFX: 2: 1 coumaric acid slurry in acetonitrile, iv) acid cumurical slurry in acetonitrile, v) cumaric acid.
    [0161]
    [0162] Figure 23. X-ray powder diffractograms of raw materials and solids obtained from acetonitrile slurries: i) RFX, ii) RFX slurry in acetonitrile, iii) RFX: Resveratrol 2: 1 slurry in acetonitrile, iv) resveratrol slurry in acetonitrile, v) resveratrol.
    [0163] Due to the complexity to predict the formation of intermolecular interactions in a solid structure, the formation of an NFS and the physicochemical properties that these will present, are impossible to predict theoretically, which implies that a large number of different experiments are previously performed .
    [0164]
    [0165] Obtaining and scaling the NFS from Rifaximin (RFX) and dicarboxylic coformers.
    [0166]
    [0167] The Slurry methodology consists of making stoichiometric mixtures drug: coformator and placing them in a vial to which a few drops of solvent are added to later form a slurry supported with a magnetic stirrer.
    [0168]
    [0169] In order to obtain NFS, the methodology of slow grinding and evaporation of the solvent is also used using a vacuum assisted rotary evaporator.
    [0170]
    [0171] The monocrystals were grown by slow evaporation of 2: 1, 1: 1 and 1: 2 mixtures using acetonitrile with a few drops of water.
    [0172]
    [0173] Initially, an RFX slurry was performed only in acetonitrile to check if there was a change in the phase in the presence of the solvent.
    [0174]
    [0175] In Figures 1a and 1b it can be seen that the RFX phase changes completely in the presence of the acetonitrile solvent generating an NFS. Figure 1a shows the RFX diffractogram and Figure 1b shows the RFX slurry diffractogram in acetonitrile.
    [0176]
    [0177] Once RFX changes in the presence of solvent, the stoichiometric mixtures slurries 2: 1, 1: 1 and 1: 2 of the drug were made with D-tartaric, L-tartaric, D-malic and L-malic acids, Malonic acid, glutaric acid and azelaic acid as coformers.
    [0178]
    [0179] Each NFS is characterized by at least one of the following techniques: X-ray diffraction of powders (DRX powders), thermal analysis by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and infrared spectroscopy (IR).
    [0180]
    [0181] Figures 2a and 2b show the X-ray powder diffractograms (DRX) for RFX NFS with D-tartaric and L-tartaric acids, respectively, which exhibit new diffraction peaks at 2 theta angles, greater than 30 °.
    [0182]
    [0183] Based on these results, it can be observed that obtaining crystalline or amorphous NFS depends on the chirality of the coformer.
    [0184]
    [0185] The powder diffractograms for the RFX phases with the D-malic and L-malic acids, respectively, are shown in Figures 3a and 3b. For RFX: L-malic new diffraction peaks are observed at 2 theta angles, greater than 30 °. For RFX: D-Malic an amorphous NFS is observed. When comparing the NFS with stoichiometry 2: 1, 1: 1 and 1: 2 we can see that the positions of the bands do not coincide with each other, because coamorphic phases of different stoichiometry are being obtained. According to diffractograms, it can be assumed that the formation of a co-crystalline NFS or RFX co-morph: Málico, depends on the chirality of the coformer.
    [0186]
    [0187] Slurries of 1: 1, 1: 2 and 2: 1 mixtures were performed Rifaximin (RFX): coformer with malonic acid, glutaric acid and azelaic acid, of which resulted in NFS for the 1: 2 ratio. For these NFS, new diffraction peaks are observed in the DRX test (see figures 4, 6 and 8). IR spectra are shown in Figures 5, 7 and 9. For stoichiometric RFX ratios: NFS 1: 1 or 2: 1, amorphous phases or physical mixtures are obtained.
    [0188]
    [0189] Crystallization studies
    [0190] Slurries of 1: 1 Rifaximin (RFX) mixtures were made: coformer, once the respective phases were obtained, they were completely dissolved to allow the solution to slowly evaporate, observing the formation of crystals from which the best ones were selected for lightning diffraction studies Single crystal X (single crystal DRX).
    [0191]
    [0192] In the process of obtaining it began with RFX: coformer 1: 1 ratio, however it they obtained solid compounds with RFX: D-tartaric 2: 1 and RFX: L-malic 2: 1 (See Figures 10 and 11).
    [0193]
    [0194] Figure 10 shows the structure obtained by DRX of monocrystals of the RFX co-crystal: D-tartaric in stoichiometry 2: 1.
    [0195]
    [0196] From RFX monocrystals DRX: D-tartaric it can be seen that the conformation of the crystalline cell consists of two RFX molecules, two water molecules, three acetonitrile and one D-tartaric acid (stoichiometry 2: 1 drug : coformer). The crystalline gasket involves an n-n type interaction between the RFX naphtho-imidazole-pyridine rings, a hydrogen bridge between the amide groups and an intramolecular hydrogen bridge with a water molecule. It is important to mention the formation of this "dimer" of RFX is observed in the multiple hydrated polymorphs of RFX reported by Braga et al.
    [0197]
    [0198] The RFX co-crystalline cell: D-tartaric implies the interaction of a D-tartaric molecule with an RFX dimer and three more RFX molecules by hydrogen bridges mainly between the hydroxy of the carboxylic acid and the hydroxyl adjacent to the carboxyl; between the carbonyl of furanone and the nitrogen of the imidazole ring in the aromatic furo-naphtho-imidazol-pyridinone system of an RFX molecules of the dimer; between the hydroxy of the carboxylic acid with the carbonyl of the acetate found in the macrocyclic chain of a second RFX molecule; and finally between a hydroxyl of the D-tartaric acid with a hydroxyl group and the oxygen of the acetate of a fourth molecule of RFX. It is important to note that there is no transfer of D-tartaric acid hydrogens to rifaximin, so we can conclude that it is a co-crystal.
    [0199]
    [0200] The structures obtained by X-ray diffraction of monocrystals of the RFX: L-malic co-crystal in 2: 1 stoichiometry are shown.
    [0201]
    [0202] From the X-ray diffraction of RFX: L-malic monocrystals it can be seen that the crystalline cell of RFX-L-malic comprises a 2: 1 stoichiometry, three acetonitrile molecules and two water molecules. It presents an RFX dimer through the nn interaction between the naphtho-imidazole-pyridine rings showed the same pattern of intermolecular interactions observed in the co-crystal with D-tartaric acid; however, in the interaction established by the chain that conforms to the drug macrocycle, it was observed that a water molecule allows the interaction between two RFX chains. Finally, for the co-crystal with L-malic, the coformor is housed similarly to the structure obtained with D-tartaric acid, with the only difference that L-malic acid only interacts with an RFX dimer and two more RFX molecules , observing a decrease in the number of interactions established with respect to the co-crystal with D-tartaric. In the same way as with the RFX co-crystal: D-tartaric, the transfer of no hydrogen by L-malic acid to RFX is not observed, concluding that it is a co-crystal.
    [0203]
    [0204] Figure 12a shows a comparison of the diffractograms calculated from the crystalline structures obtained by X-ray diffraction of monocrystals of the co-crystals of: i) RFX: D-tartaric, and ii) RFX: L-malic. In both cases, stoichiometry is 2: 1. As can be seen, the calculated diffractograms show a very similar diffraction pattern, this is indicative that in both co-crystals, the intermolecular interactions that are established between the drug and the coformer and the crystalline structure that is formed for both co-crystals, are very Similar.
    [0205]
    [0206] Figure 12b shows the comparison between the calculated diffractograms, the diffractograms obtained from the acetonitrile slurries made for the 2: 1 mixtures of RFX: D-tartaric and RFX: L-malic, and the diffractograms of the raw materials used: i) RFX, ii) RFX slurry in acetonitrile, iii) RFX: D-tartaric 2: 1 calculated from single crystal, iv) RFX: D-tartaric slurry 2: 1 in acetonitrile, v) RFX: L-malic 2: 1 calculated from the single crystal, and vi) RFX: L-malic slurry 2: 1 in acetonitrile. In this figure it can be seen that the diffractograms calculated have the same diffraction pattern as the diffractograms obtained from the corresponding slurries, concluding that the 2: 1 phases of RFX: D-tartaric and RFX: L-malic were crystallized. It is interesting that, if the diffractograms of the obtained co-crystals are compared, a similarity can be observed with the diffractogram of the rifaximin acetonitrile solvate obtained by slurry, this is indicative that the crystalline structure of the acetonitrile solvate is maintained and only the molecules of the coformator are interspersed in the structure to form the co-crystal.
    [0207] 1g and 3g scaling of the NFS with 1: 1 stoichiometry
    [0208]
    [0209] RFX: L-tartaric, RFX: D-tartaric, RFX: L-malic and RFX: D-malic in stoichiometry 1: 1 were scaled from the co-crystalline or coamorphic NFS obtained, obtaining the co-crystalline phases of RFX with L-tartaric, D- tartaric and L-malic, in addition to the RFX co-morph phase: D-malic.
    [0210]
    [0211] Figures 13a-13d show thermograms of DSC, line I and TGA line II of: RFX: L-tartaric (Figure 13a), RFX: L-malic (Figure 13b), RFX: D-malic (Figure 13c) and RFX: D-tartaric (Figure 13d).
    [0212]
    [0213] From the thermal analysis by Differential Scanning Calorimetry (DSC) line I and Thermogravimetric Analysis (TGA) line II, it is observed that in the DSC thermogram there is absence of well-defined melting points for the phases that contain L-tartaric acids, D-tartaric and L-malic. This indicates that, although these phases are crystalline, they have a certain degree of disorder, which correlates with the DRX pattern where diffraction peaks are not very well defined. The melting points found for these NFS are: RFX: L-tartaric 170.1 ° C, RFX: L-malic 158.9 ° C and RFX: -D-tartaric 170.9 ° C.
    [0214]
    [0215] The RFX DSC: D-malic does not show a melting point, which is related to the loss of crystallinity, characteristic of amorphous systems, and matches the information provided by the powder DRX pattern. A loss of mass at low temperatures is observed on the TGA thermogram, indicating the loss of solvent molecules.
    [0216]
    [0217] Solubility Test
    [0218] NFS with 1: 1 stoichiometry were tested for solubility at a pH of 7.4 (0.1M sodium phosphate with 0.8% sodium lauryl sulfate) at a temperature of 37 ° C and for 1, 2, 8 and 24 hours , and were compared with the solubility of untreated RFX.
    [0219]
    [0220] In the study, saturated solutions of each solid were made in the phosphate buffer and after the established time, aliquots were taken to measure its absorbance in a UV-Vis device. The molar concentration of NFS and RFX solutions it was determined from the Lambert-Beer equation considering a molar absorptivity coefficient of 12227 L mol-1 cm-1, previously determined.
    [0221]
    [0222] Figure 14 shows a graph of the concentration obtained from the different NFS and free RFX solutions with respect to time. It is observed that, in the first hour, the solubility of the NFS is lower than RFX, mainly for the NFS RFX: L-tartaric, which shows a solubility approximately five times less than that of rifaximin. At two hours the solubility of RFX decreases unlike the NFS that are maintained in a range of concentrations similar to those obtained at the time and, this is maintained until 24 hours. At 2 hours the NFS RFX: L-tartaric has a lower solubility with respect to RFX and this situation is maintained until approximately 24 hours.
    [0223]
    [0224] It should be mentioned that the solubility results correlate with that observed by thermal analysis, where the most soluble NFS is that of RFX: D-malic which is an amorphous solid and has a lower decomposition point than the other 158.9 ° C phases. The least soluble solid phases are RFX: L-tartaric and RFX: D-tartaric that have a melting point of 170 ° C (See Figures 13a-13c).
    [0225]
    [0226] Obtaining and scaling of coamorphic phases of Rifaximin (RFX) and Amino Acids
    [0227]
    [0228] New solid phases (NFS) coamorphs were obtained starting from rifaximin and amino acid coformers. For this, the slurry technique was used by stoichiometrically mixing the drug: coformer and adding the solvent ethanol or methanol to form the slurry. The amino acids tested include L-histidine (His), Lysine (Lys), Glycine (Gly), DL-alanine (Ala), L-cysteine HCl monohydrate, L-arginine (Arg), L-phenylalanine, L-methionine, L -tyrosine and DL-tryptophan.
    [0229]
    [0230] As a result, nine amorphous NFS of RFX were obtained: amino acids with L-lysine, L-arginine and L-cysteine HCl monohydrate, in stoichiometric ratios 2: 1, 1: 1 and 1: 2, whose diffractograms are shown in Figures 15a to 15c
    [0231]
    [0232] In order to identify possible changes in the solid phase of the RFX the RFX was subjected to the same slurry conditions such as RFX: coformer. When comparing the results, it is observed that the base RFX exhibits a loss of crystallinity after being subjected to rapid evaporation, which indicates obtaining an amorphous solid.
    [0233]
    [0234] After the slurry process, we proceeded with the scaling of the NFS, resulting in eight amorphous phases: RFX: L-arginine 2: 1, 1: 1 and 1: 2; RFX: L-lysine 1: 1 and 2: 1; RFX: L-cysteine 2: 1, 1: 1 and 1: 2. The 1: 2 RFX-lysine of stoichiometry was not scalable. For the scaling of the coamorphic NFS the methodology of rapid evaporation of the solvent assisted by vacuum was used. This technique consists in dissolving a stoichiometric drug-coform composition in methanol / water. The dissolved mixtures are placed in a rotary evaporator and placed in a bath at 80 ° C for evaporation of the solvent. The mixtures are left in the bath under reduced pressure until complete evaporation of the solvent, maintaining the same conditions. Finally, the solid obtained is collected for its corresponding characterization.
    [0235]
    [0236] All amorphous NFS with L-lysine, L-arginine, L-cysteine HCl monohydrate obtained by rapid evaporation were characterized by infrared (IR) spectroscopy, as shown in Figures 16a to 16h. The amorphous NFS show a widening of the IR bands with respect to RFX and the individual coformers, such widening occurs in amorphous systems. In addition, a shift at higher and lower frequencies is observed mainly in the carbonyl band of the amino acid and RFX. Due to its overlap it is not feasible to identify the exact displacement, however, the displacement makes clear the establishment of the formation of new intermolecular interactions.
    [0237]
    [0238] Solubility tests were carried out for the NFS at a pH of 7.4 (0.1M sodium phosphate with 0.8% sodium lauryl sulfate) at a temperature of 37 ° C, for 1, 2, 8 and 24 hours, compared with the solubility of RFX base that underwent the same conditions as the RFX: coformer. For the study, saturated solutions of each solid were made in the phosphate buffer, then aliquots were taken to measure its absorbance in a UV-Visible device. The molar concentration of the NFS and RFX solutions was determined from the Lambert-Beer equation considering a molar absorptivity coefficient of 12227 L mol-1 cm-1, previously determined.
    [0239] The results of the solubility test are shown in Figure 17, where the molar concentration obtained from the different solutions of amorphous NFS and RFX with respect to time is plotted. The results show that at the time of study, the solubility of the NFS is similar to that of RFX, except for the RFX: L-cysteine 1: 1 and 1: 2 phases showing slightly higher solubility. However, at two hours the solubility of RFX decreases, unlike the new amorphous phases that remain in a similar range of concentrations as at the time. The analysis at eight hours indicates that the solubility of most amorphous phases decreases, reaching a solubility similar to RFX. For RFX: L-cysteine HCl with stoichiometry 1: 1, 1: 2 and 2: 1 in the first eight hours show a greater solubility than rifaximin. Particularly the cysteine solids HCl with stoichiometry 1: 2 and 2: 1, the solubility after eight hours remains unchanged, even up to 24 hours.
    [0240]
    [0241] Obtaining Rifaximin NFS (RFX) and Nutraceuticals
    [0242]
    [0243] New solid forms of rifaximin were obtained with a nutraceutical comprising at least one carboxylic group and / or a polyphenol group, selected from biotin, resorcinol, catechol, trans-aconitic acid, cumaric acid and resveratrol. The process of obtaining the NFS with these nutraceuticals was carried out through the slurry method using acetonitrile under environmental conditions.
    [0244]
    [0245] The stoichiometries RFX: nutraceutical 2: 1, 1: 1 and 1: 2 were tested, from which the co-crystalline NFS RFX: biotin with stoichiometry 1: 2 was achieved, as well as the co-morphic NFS RFX: Resorcinol 1: 1, RFX : 1: 1 catechol, 1: 1 RFX-trans-aconitic acid, RFX: 2: 1 cumaric acid and RFX: 2: 1 resveratrol.
    [0246]
    [0247] Figure 18 shows diffractograms of the raw materials and solids obtained from the slurries in acetonitrile: i) RFX, ii) RFX slurry in acetonitrile, iii) RFX: Biotin 1: 2 slurry in acetonitrile, iv) Biotin slurry in acetonitrile, and v ) biotin.
    [0248]
    [0249] Figures 19 to 23 show diffractograms of the coamorphic NFS obtained from rifaximin and the coformers resorcinol, catechol, aconitic acid, coumaric acid and Resveratrol
    [0250]
    [0251] Figure 19 shows X-ray diffractograms of: i) RFX, ii) RFX slurry in acetonitrile, iii) RFX: Resorcinol 1: 1 slurry in acetonitrile, iv) resorcinol slurry in acetonitrile, and v) resorcinol. Figure 20 shows X-ray diffractograms of: i) RFX, ii) RFX slurry in acetonitrile, iii) RFX: Catechol 1: 1 slurry in acetonitrile, iv) catechol slurry in acetonitrile, and v) catechol.
    [0252]
    [0253] Figure 21 shows diffractograms of: i) RFX, ii) RFX slurry acetonitrile, iii) RFX: Frans-aconitic acid 1: 1 slurry in acetonitrile, iv) frans-aconitic acid slurry acetonitrile, and v) fransitic acid.
    [0254]
    [0255] Figure 22 shows diffractograms of: i) RFX, ii) RFX slurry in acetonitrile, iii) RFX: 2: 1 slurry cumaric acid in acetonitrile, iv) slurry cumuric acid in acetonitrile, and v) cumaric acid.
    [0256]
    [0257] Figure 23 shows diffractograms of: i) RFX, ii) RFX slurry in acetonitrile, iii) RFX: Resveratrol 2: 1 slurry in acetonitrile, iv) resveratrol slurry in acetonitrile, v) resveratrol.
    [0258]
    [0259] Pharmaceutical compositions of the New Solid Phase (NFS) of Rifaximin (RFX)
    [0260]
    [0261] In one embodiment of the invention, pharmaceutical compositions comprising RFX NFSs comprising RFX and a coformor selected from dicarboxylic acid selected from D-tartaric acid, L-tartaric acid, D-malic acid and L-malic acid are presented, with RFX stoichiometry: coformor selected from 2: 1, 1: 1 and 1: 2, for use as an anti-infective agent.
    [0262]
    [0263] In another embodiment, compositions comprising RFX NFSs are presented with a coformer selected from malonic acid, glutaric acid and azelaic acid, with RFX stoichiometry: 1: 2 coformor, for use as an anti-infective agent.
    [0264]
    [0265] In another embodiment, compositions comprising the RFX co-morphic NFS and a coformor selected from Lysine (Lys), L-arginine (L-Arg) and L-cysteine HCl are presented monohydrate, with stoichiometry RFX: coformador 2: 1, 1: 1 and 1: 2, for use as an anti-infective.
    [0266]
    [0267] In another embodiment, compositions comprising the RFX NFS and the biotin coformor are presented, with RFX stoichiometry: 1: 2 coformor, for use as an anti-infective agent.
    [0268]
    [0269] In yet another embodiment, compositions comprising the RFX NFS and a coformer selected from resorcinol, catechol and aconitic acid are presented, with RFX stoichiometry: 1: 1 coformor, for use as an anti-infective.
    [0270]
    [0271] In yet another embodiment, compositions comprising the RFX NFS and a coformor selected from cumaric acid and resveratrol, with 2: 1 stoichiometry, for use as an anti-infective are presented.
    [0272]
    [0273] For the composition of tablets or capsules, the excipients or carriers comprise a diluent binding agent (20% to 70%), lubricant (3% to 7%), disintegrant (1% to 5%), non-stick slider (1% to 5 %), surfactants (1% to 5%), and a coating agent (5% to 20%).
    [0274]
    [0275] Excipients or vehicles comprise:
    [0276] • Binder diluting agent: hydroxypropylcellulose (HPC), or hydroxypropylmethylcellulose (HPMC) or polyvinylpyrrolidone (PVP).
    [0277] • Coating agent: aluminum lacquer, titanium dioxide, polyethylene glycol, HPMC, HPC, PVP.
    [0278] • Disintegrant: croscarmellose sodium, pregelatinized starch or crospovidone.
    [0279] • Non-stick slide: colloidal silicon dioxide.
    [0280] • Diluent: microcrystalline cellulose, lactose, calcium phosphate.
    [0281] • Lubricant: magnesium stearate, stearic acid, sodium stearyl fumarate. • Binding agent: hydroxypropylcellulose (HPC), polyividone,
    [0282] • Surfactant: sodium lauryl sulfate, sodium lauryl sarcosinate.
    [0283] • Vehicle: water, vehicle that evaporates during the manufacturing process.
    [0284] Example of solid oral composition in tablet or capsule
    [0285]
    [0286]
    [0287] Example of solid oral composition in tablet or capsule
    [0288]
    [0289]
    [0290]
    [0291]
    [0292] For the suspension composition, the excipients or vehicles comprise diluting, lubricating, non-stick, surfactant, plasticizer, antioxidant, opacifying, suspending agent, flavor masking, coating, sweetener, preservative or mixture thereof.
    [0293]
    [0294] Example of suspension composition
    [0295]
    [0296]
    [0297]
    [0298]
    [0299] Excipients or vehicles for suspension compositions comprise: Flavoring masks selected from: Glyceryl dipalmite, copolymer of methacrylic acid and / or sodium chloride.
    [0300] Plasticizer selected from: Dibutyl phthalate, sorbitol, vinyl agents, acrylic agents.
    [0301] Conservative selected from: Sodium benzoate, benzoic acid, potassium benzoate, calcium benzoate.
    [0302] Opacifier selected from: Titanium dioxide, titanium oxide, colloidal silicon dioxide, sorbitan esters, amide waxes, glycol esters, glycerin esters. Suspension agent selected from: xanthan gum, gum arabic, guar gum or tragacanth gum.
    [0303] Adhesive and support polymer selected from: microcrystalline cellulose, croscarmellose, polyvinylpyrrolidone.
    [0304] Sweetener selected from: sucralose, fructose, sugar or sucrose.
    [0305] Flavoring masking selected from: grape flavor, orange flavor, cherry flavor, flavor or vanilla.
    权利要求:
    Claims (18)
    [1]
    1. A solid compound formed by rifaximin and a coform of the group comprising carboxylic acids, amino acids, phenolic compounds and biotin, as well as the respective solvates, hydrates and / or polymorphs of said solid compound.
    [2]
    2. The solid compound according to claim 1, wherein the compound is crystalline and wherein the coformor is selected from D-tartaric acid, L-tartaric acid, L-malic acid, malonic acid, glutaric acid, azelaic acid and biotin.
    [3]
    3. The solid compound according to claim 1, wherein the compound is coamorphic and wherein the coformor is D-malic acid.
    [4]
    4. The solid compound according to claim 1, wherein the compound is coamorphic, the coformor is selected from Lysine (Lys), L-Arginine (L-Arg) and L-Cysteine (L-Cys) and has a drug stoichiometry: coformer between 2: 1 and 1: 2.
    [5]
    5. The solid compound according to claim 1, wherein the compound is coamorphic and the coformor is selected from frans-aconitic acid, catechol, cumaric acid, resorcinol and resveratrol.
    [6]
    6. A pharmaceutical composition comprising the compound according to any of the preceding claims and pharmaceutically acceptable excipients.
    [7]
    7. The use of the solid compound according to any one of claims 1 to 5 to produce a medicament useful in the treatment of acute and chronic infections by Gram positive and negative bacteria, diarrheal syndrome, bacterial enterocolitis, traveler's diarrhea, pseudomembranous colitis, acute diverticulitis , intestinal functional disorders associated with dysbiosis or bacterial overpopulation, in perioperative prophylaxis in gastrointestinal surgery, as an adjunct in the treatment of hepatic encephalopathy or as an adjunctive therapy in hyperammonemia.
    [8]
    8. The solid compound according to claim 2, wherein the compound is crystalline and the coformor is D-tartaric acid with stoichiometry drug: 2: 1 coformor exhibiting a DRX spectrum of powders with peaks at angle values 20 of 14.3, 19.5 and 26.4.
    [9]
    9. The solid compound according to claim 2, wherein the compound is crystalline and the coformor is D-tartaric acid with drug stoichiometry: 1: 1 coformor exhibiting a DRX spectrum of powders with spikes at angle values of 6.6, 14.1 , 19.6 and 20.4.
    [10]
    10. A solid compound according to claim 2, wherein the compound is crystalline and the coformor is D-tartaric acid with drug stoichiometry: 1: 2 coformor exhibiting a DRX spectrum of powders with spikes at angle values of 16.4, 19.0 , 22.3 and 29.5.
    [11]
    11. A solid compound according to claim 2, wherein the compound is crystalline and the coformor is L-tartaric acid with 2: 1 drug stoichiometry that exhibits a DRX spectrum of powders with spikes at angle values of 8.0, 16.5 and 17.7.
    [12]
    12. A solid compound according to claim 2, wherein the compound is crystalline and the coformor is L-tartaric acid with drug stoichiometry: 1: 1 coformor exhibiting a DRX spectrum of powders with spikes at angle values of 8.1, 12.8 and 16.6.
    [13]
    13. A solid compound according to claim 2, wherein the compound is crystalline and the coformor is L-tartaric acid with drug stoichiometry: 1: 2 coformor exhibiting a DRX spectrum of powders with peaks at angle values of 8.1, 9.3 , 25.1 and 35.9.
    [14]
    14. A solid compound according to claim 2, wherein the compound is crystalline and the coformor is L-malic acid with 2: 1 drug stoichiometry that exhibits a DRX spectrum of powders with spikes at angle values of 8.9, 14.4 , 19.4 and 20.7.
    [15]
    15. A solid compound according to claim 2, wherein the compound is crystalline and the coformor is azelaic acid with drug stoichiometry: 1: 2 coformor exhibiting a DRX spectrum of powders with spikes at values of angles 20, 7.2, 8.3 and 23.4.
    [16]
    16. A solid compound according to claim 2, wherein the compound is crystalline and the coformor is glutaric acid with drug stoichiometry: 1: 2 coformor exhibiting a DRX spectrum of powders with spikes at angle values of 8.3, 12.8, 17.2 and 18.5.
    [17]
    17. A solid compound according to claim 2, wherein the compound is crystalline and the coformor is malonic acid with 1: 2 stoichiometry that exhibits a DRX spectrum of powders with peaks at angle values of 7.7, 11.2, 12.4 and 14.7.
    [18]
    18. A solid compound according to claim 2, wherein the compound is crystalline and the coformor is biotin with 1: 2 drug stoichiometry that exhibits a DRX spectrum of powders with peaks at angle values of 18.8, 20.0 and 21.01.
    类似技术:
    公开号 | 公开日 | 专利标题
    ES2460919T3|2014-05-16|Polymorphic forms of p-hydroxybenzoate | - | -N-methyl-5- [3- | il] -4-penten-2-ammonium for the treatment of central nervous system disorders
    ES2560955T3|2016-02-23|Diamine derivative crystal and its production process
    TW200944508A|2009-11-01|Novel solid forms of bendamustine hydrochloride
    US9452157B2|2016-09-27|Pharmaceutical compositions comprising rifaximin and amino acids, preparation methods and use thereof
    US20090181990A1|2009-07-16|Stable amorphous form of pemetrexed disodium
    ES2896503T3|2022-02-24|-alpha dihydrotetrabenazine succinate salt
    ES2530423B1|2016-01-21|NEW SOLID FORMS OF TYPE 5 PHOSPHODIESTERASE INHIBITORS
    US10370406B2|2019-08-06|Salts and polymorphs of SCY-078
    US11230533B2|2022-01-25|Crystalline salts and polymorphs of a P2X3 antagonist
    ES2716420T3|2019-06-12|Crystalline eliglustat hydrochloride
    JPWO2010082531A1|2012-07-05|Activated blood coagulation factor inhibitor
    ES2743719A2|2020-02-20|NEW RIFAXIMINE SOLID PHASES |
    ES2834049T3|2021-06-16|Crystalline Eravacycline Bischloride
    ES2539236T3|2015-06-29|Otamixaban benzoic acid salt
    ES2429525T3|2013-11-15|Citrate salt of 9E-15- | -7,12,25-trioxa-19,21,24-triaza-tetracycle [18.3.1.1 | .1 | 18)] - hexacosa-1 |, 2,4,9,14,16,18 |, 20,22-nonaeno
    JP2021507927A|2021-02-25|Crystal form of barbenazintosilate and its production method and application
    WO2021126313A1|2021-06-24|Nicotine materials, methods of making same, and uses thereof
    Mortko et al.2010|Risk assessment and physicochemical characterization of a metastable dihydrate API phase for intravenous formulation development
    ES2738638T3|2020-01-24|Cabozantinib salts and their use as anticancer agents
    BR112020010135A2|2021-03-23|polymorphic forms of trimebutine maleate and method of using them
    WO2000058310A1|2000-10-05|Zolpidem salts
    JPWO2004039816A1|2006-03-02|Inorganic acid salt crystals of cephem compounds
    WO2021105779A1|2021-06-03|New solid forms of dapagliflozin
    ES2316270B1|2010-02-09|NEW CRYSTAL FORM OF MOXIFLOXACINO CHLORHYDRATE ANHYDRA FORM IV.
    同族专利:
    公开号 | 公开日
    ES2743719R1|2020-02-21|
    MX2018004788A|2019-10-21|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US20050196418A1|2004-03-04|2005-09-08|Yu Ruey J.|Bioavailability and improved delivery of alkaline pharmaceutical drugs|
    EP1727520A2|2003-12-09|2006-12-06|Medcrystalforms, Llc|Method of preparation of mixed phase co-crystals with active agents|
    ITBO20120368A1|2012-07-06|2014-01-07|Alfa Wassermann Spa|COMPOSITIONS INCLUDING RIFAXIMINA AND AMINO ACIDS, RIFAXIMINE CRYSTALS DERIVING FROM SUCH COMPOSITIONS AND THEIR USE.|
    EP3275439A1|2016-07-29|2018-01-31|Medday Pharmaceuticals|Method for treating hepatic encephalopathy|
    法律状态:
    2020-02-21| EC2A| Search report published|Ref document number: 2743719 Country of ref document: ES Kind code of ref document: R1 Effective date: 20200214 |
    2020-09-14| FA2A| Application withdrawn|Effective date: 20200908 |
    2021-01-21| NE2A| Request for restoration|Effective date: 20210115 |
    优先权:
    申请号 | 申请日 | 专利标题
    MX2018004788A|MX2018004788A|2018-04-18|2018-04-18|New rifaximin solid phases.|
    [返回顶部]