巴西专利BR112017010406B1 process of carrying out high-throughput testing of high-performance liquid chromatography

专利PDF首页>>巴西专利

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:
PROCESS OF PERFORMING HIGH PRODUCTIVITY TESTING OF HIGH EFFICIENCY LIQUID CHROMATOGRAPHY The present invention features a high productivity test method of high efficiency liquid chromatography for rapid and accurate testing of large quantities of samples in the continuous manufacture of pharmaceutical compositions, such as , pharmaceutical compositions for the treatment of CFTR-mediated diseases, such as cystic fibrosis.
公开号:BR112017010406B1
申请号:R112017010406-7
申请日:2015-11-18
公开日:2021-03-09
发明作者:Eric Borsje；Henrik Torstholm Rasmussen
申请人:Vertex Pharmaceuticals Incorporated；
IPC主号:

专利说明:

TECHNICAL FIELD OF THE INVENTION
[0001] The invention relates to a process of performing high productivity tests (HTT) of high performance liquid chromatography (HPLC) useful to test quickly and precisely large quantities of samples. In one embodiment, HTT HPLC is useful for the development of process analysis techniques (PAT) for the continuous manufacture of pharmaceutical compositions. In another embodiment, the pharmaceutical compositions are for the treatment of CFTR-mediated diseases, such as cystic fibrosis and comprise one or more active pharmaceutical ingredient (API). BACKGROUND OF THE INVENTION
[0002] A common challenge for drugs approved by the FDA is the eventual lack of availability of the drug for patients in need of it. Therefore, there is a significant unmet need for the processes described for the preparation of drugs in a continuous and controlled manner, unlike the more traditional batch preparations. To achieve continuous production, PAT must be developed that accurately monitors the properties of pharmaceutical compositions without interrupting the continuity of processes. PAT, however, are spectroscopic in nature and must be correlated with references to be of any use. This correlation with references requires the execution of many samples in a timely manner using HTT HPLC techniques disclosed here. It is also anticipated that HTT HPLC can be used to test the API concentration in the final composition, just like any back-up for PAT or when PAT is not available. SUMMARY OF THE INVENTION
[0003] In one embodiment, the present invention features a high performance HPLC process comprising a) pouring containers, such as pre-weighed sample bottles into plastic bottles, such as polyethylene bottles. high density; b) add solution to each set of container and bottle using a bottle top dispenser; c) shake each set of plastic bottles, container, and solution until the sample is dissolved; d) centrifuge each set of plastic bottles, container, and solution; e) loading an aliquot of supernatant from the centrifugation step on an HPLC column; and f) executing the column with a mobile phase.
[0004] In another embodiment, the process is used to provide correlation of PAT measurement values for continuous manufacturing. In another embodiment, the process is used to measure the API concentration in the final pharmaceutical composition.
[0005] In another embodiment, the pharmaceutical composition is a tablet. In another embodiment, the tablet is for the treatment of a CFTR-mediated disease, such as cystic fibrosis (CF).
[0006] In another embodiment, the tablet comprises two APIs. In another embodiment, an API is a CF broker. In another embodiment, an API is a CF enhancer. In another embodiment, one API is a CF broker and the other API is a CF enhancer.
[0007] In another embodiment, an API is 3- (6- (l- (2,2-difluorobenzo [d] [1,3, dioxol-5-yl) cyclopropanecarboxamido) -3-methylpyridin-2-yl acid ) benzoic (Compound 1), which has the following structure:
Compound 1.
[0008] In another embodiment, an API is N- (5-hydroxy-2,4-di-tert-butyl-phenyl) -4-oxo-1H-quinoline-3-carboxamide (Compound 2), which has the following structure:
Compound 2.
[0009] In another embodiment, one API is Compound 1 and the other API is Compound 2. In another embodiment, Compound 1 is in Form I, and Compound 2 is in the form of a solid dispersion of Compound 2 substantially amorphous. BRIEF DESCRIPTION OF THE DRAWINGS
[0010] Figure 1 is a flow chart for the continuous manufacture of a Compound 1 Form I tablet and a solid dispersion of substantially amorphous Compound 2.
[0011] Figure 2 is a schematic drawing of an analytical technique (PAT) process that allowed for the continuous manufacturing process, in which in step 1) a PAT1 NIR feeder / mixer measures material attributes during the selection of raw materials ; step 2) the double screw granulator, PAT2 NIR measures the composition and BU; step 3) fluidized bed dryer, NIR PAT 3a measures uniformity of granules, LOD, forms the solid state and physical attributes of granules, PAT 3b measures laser diffraction of particle size distribution; step 4) grinding, PAT4 NIR measures the composition and BU; step 5) two feeder / mixer, PAT 5a test measures Raman and CU, PAT 5b weight, hardness, thickness; step 6) compression, PAT6 Raman measures the thickness of the coating; and step 7) coating.
[0012] Figure 3 is a schematic drawing showing a PAT Sentronics NIR line located after an extra mixer, granule mill, and granule mixer. Each probe has 7 points that cycle, sequentially, to maximize sample collection and NIR with multiplexer-NIR to ensure robust and exhaustive sampling by a powder flow controlled through optical probes.
[0013] Figure 4 is a representation of NIR that flows in powder.
[0014] Figure 5 is a Kaiser Raman spectrum Compound 1 Form I and Compound 1 Form II (Compound 1 Form II is a different polymorph disclosed in US 201131588 herein incorporated in its entirety by reference) made by pressing the tablet . The Raman Kaiser spectrometer is mounted on the Kraemer UTS tablet tester.
[0015] Figure 6 is a graph showing the good correlation between predicted and out-of-line NIR reference samples of Compound 2 granules.
[0016] Figure 7 is a series of measurements of NIR spectra of water content in samples of the granules of compound 1.
[0017] Figure 8 is a series of NIR spectra measuring a range of compositions comprising different proportions of Compound 1 Form I and a solid dispersions comprising the substantially amorphous compound 2 on the left, and the pretreated spectra on the right describes Lane A to identify Compound 1 form I and Lane B to identify amorphous Compound 2.
[0018] Figure 9 represents a calibration curve for the predicted content of Compound I of Form I versus the reference (real) content of Compound 1 Form I using partial least squares (PLS) techniques.
[0019] Figure 10 illustrates the actual results of unknown samples that comprise different contents of Compound 1 Form I (Reference Y) versus predicted content using the calibration curve, calculated from Figure 19 (predicted Y).
[0020] Figure 11 represents the percentage of transmission of a laser diffraction measurement in response to changes in line rate (flow rate) for a composition comprising Compound 1 Form I and solid dispersions comprising substantially amorphous compound 2, showing the expected reduction in percentage of transmission as the line rate of increase.
[0021] Figure 12 illustrates laser diffraction measurements of particles comprising a Form I compound and solid dispersions comprising the substantially amorphous compound at two different line rates showing that the average particle size (Dv (50) is not affected by the line rate.
[0022] Figure 13 illustrates laser diffraction measurements of particles comprising a Form 1 compound 1 and solid dispersions comprising substantially amorphous compound 2 under different processing parameters showing that particle size measurements are sensitive to such changes.
[0023] Figure 14 illustrates the predictive capabilities of analytical technology process models using Raman spectroscopy, both non-continuously and continuously, for monitoring Compound An identity solid form in a tablet.
[0024] Figure 15 illustrates the predictive capabilities of analytical technology process models using Raman spectroscopy, both non-continuously and continuously, for monitoring the identity of Compound 1 in solid form in a tablet. DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS
[0025] As used herein, "HTT" stands for High Productivity Test and "HPLC" stands for high performance liquid chromatography. The two together as in HTT HPLC refers to a high performance liquid chromatography method that can be used to quickly and precisely test a large amount of sample volume.
[0026] As used herein, the term "pharmaceutically active ingredient" or "API" refers to a biologically active compound.
[0027] As used herein, the term "PAT" means analytical technology process.
[0028] As used herein, the term "CU" represents the uniformity of the content.
[0029] As used herein, "CFTR" means regulator of the transmembrane conductance of cystic fibrosis.
[0030] As used herein, an "AF508 mutation" or "F508-del mutation" is a specific mutation within the CFTR protein. The mutation is a deletion of three nucleotides that comprise the codon for the amino acid phenylalanine at position 508, resulting in a CFTR protein that lacks this phenylalanine residue.
[0031] As used herein, a patient who is "homozygous" for a specific mutation, for example, AF508, has the same mutation in each allele.
[0032] As used herein, a patient who is "heterozygous" for a specific mutation, for example, AF508, has this mutation in one allele, and a different mutation in the other allele.
[0033] As used herein, the term "CFTR corrector" refers to a compound that increases the amount of functional CFTR protein to the cell surface, resulting in increased ion transport.
[0034] As used herein, the term "CFTR enhancer" refers to a compound that increases the activity of the CFTR protein channel located on the cell surface, resulting in increased ion transport.
[0035] The terms "solid form", "solid forms" and related terms, when used herein refer to Compound 1 or Compound 2, in a solid form particularly form in crystals, for example, amorphous states, and the like.
[0036] As used herein, the term "substantially amorphous" refers to a solid material that has little or no long-range order in the position of its molecules. For example, substantially amorphous materials have less than about 15% crystallinity (for example, less than about 10% crystallinity or less than about 5% crystallinity). It should also be noted that the term 'substantially amorphous' includes the descriptor, 'amorphous', which refers to materials that have no (0%>) crystallinity.
[0037] As used herein, the term "substantially crystalline" (as in the phrase substantially crystalline Compound 1 Form I refers to a solid material having a predominantly long gamma order at the position of its molecules. For example, substantially crystalline materials have more of about 85% crystallinity (for example, more than about 90% crystallinity, or more than about 95% crystallinity). It is also noted that the term 'substantially crystalline' includes the descriptor, 'crystalline ', which refers to materials that have 100% crystallinity.
[0038] The term "crystalline" and related terms used herein, when used to describe a substance, component, product, or form, means that the substance, or product component is substantially crystalline as determined by X-ray diffraction. . (See, for example, Remington: The Science and Practice of Pharmacy, 21 Ed, Lippincott Williams & Wilkins, Baltimore, Md (2003); The United States Pharmacopeia, 23 rd ed., 18431844 (1995)).
[0039] The term "tablet" as used herein refers to a physically discrete unit of agent suitable for the patient to be treated. In general, a compacted mixture has a higher density than that of the mixture before compacting. A dosage tablet of the invention can have almost any shape including concave and / or convex faces, rounded or angled corners, and a rounded to straight shape. In some embodiments, the tablets of the invention comprise a rounded tablet having flat faces. The tablets of the invention can be prepared by any known method of compaction and compression by those skilled in the art of producing compressed solid pharmaceutical dosage forms. In particular embodiments, the formulations provided herein can be prepared using conventional methods known to those skilled in the art in the field of pharmaceutical formulation, as described, for example, in relevant textbooks. See, for example, Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins, Baltimore, Md. (2003); Ansel et al., Pharmaceutical Dosage Forms And Drug Delivery Systems, 7th Edition, Lippincott Williams & Wilkins, (1999); The Handbook of Pharmaceutical Excipients, 4th edition, Rowe et al., Eds., American Pharmaceuticals Association (2003); Gibson, Pharmaceutical Preformulation And Formulation, CRC Press (2001), references hereby incorporated by reference in their entirety.
[0040] As used herein, an "excipient" includes both functional and non-functional ingredients in a pharmaceutical composition.
[0041] An "effective amount" or "therapeutically effective amount" of a compound of the invention can vary according to factors, such as the individual's disease state, age, and weight, and the ability of the compound of the invention to elicit a desired response in the individual. Dosage regimens can be adjusted to provide the optimal therapeutic response. An effective amount is also one in which any toxic or harmful effects (e.g., side effects) of the compound of the invention are outweighed by the therapeutically beneficial effects.
[0042] As used herein, and unless otherwise specified, the terms "therapeutically effective amount" and "effective amount" of a compound means an amount sufficient to provide a therapeutic benefit in the treatment or control of a disease or disorder, or to delay or minimize one or more symptoms associated with the disease or disorder. A "therapeutically effective amount" and "effective amount" of a compound means an amount of therapeutic agent, alone or in combination with one or more other agents, which provides a therapeutic benefit in the treatment or management of the disease or disorder. The terms "therapeutically effective amount" and "effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of a disease or disorder, or improves the therapeutic effectiveness of another therapeutic agent.
[0043] The term "substantially pure" as used in the phrase "Substance 1 Form I substantially pure" means purity greater than about 90%. In another embodiment, substantially pure refers to greater than about 95% purity. In another embodiment, substantially pure refers to greater than about 98% purity. In another embodiment, substantially pure refers to greater than about 99% purity.
[0044] With respect to Compound 1 Form I, or a solid dispersion comprising substantially amorphous Compound 2, the terms "about" and "approximately", when used in connection with the doses, amounts, or weight percent of ingredients of a composition or a dosage form, means a percentage of dose, the amount or weight that is recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, the amount or percentage by weight . Specifically, the term "about" or "approximately" means that an error is acceptable for a given value, as determined by one of ordinary skill in the art, which depends, in part, on the measured or determined value. In certain embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" means within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4 %, 3%, 2%, 1%, 0.5%, 0.1%, or 0.05% of a given value or range.
[0045] Compound 1A Form I is prepared by methods disclosed in US Patent No. 8,507,534 incorporated herein by reference in its entirety. A solid dispersion of substantially amorphous Compound 2 is prepared by methods disclosed in Published International Patent Application No. WO 2010/019239 incorporated herein by reference in its entirety. A tablet comprising Compound 1 and Compound 2 can be prepared continuously according to the flow diagram of Figure 1. THERAPEUTIC USES OF COMPOSITION
[0046] In one aspect, the invention also provides a method of treatment, decreasing the severity of, or symptomatically treating, a disease in a patient, the method comprising administering an effective amount of the pharmaceutical composition or tablet continuously prepared using PAT for the patient, preferably a mammal, in which the disease is selected from cystic fibrosis, asthma, COPD-induced chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility caused by the congenital bilateral absence of vas deferens (CBAVD), mild lung disease, idiopathic pancreatitis, bronchopulmonary aspergillosis allergy (ABPA), liver disease, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, deficiencies of type 1 lipid processing, such as familial hypercholesterolemia, chylomicronemia, abetalipoproteine mia Type 1, lysosomal storage diseases, such as I-cell disease / pseudo-Hurler, mucopolysaccharidoses, Sandhof / Tay-Sachs disease, Crigler-Najjar II type, polyiendocrinopathy / hyperinsulinemia, diabetes mellitus, Laron dwarfism, mileoperoxidase deficiency, primary hypoparathyroidism, melanoma, CDG type 1 glucanosis, congenital hyperthyroidism, imperfect osteogenesis, hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (DI), neuropphiseal DI, neprogenic DI, Charcot-Marie tooth syndrome, Perlizaeus-Neurodegenerative diseases, Merzegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, supranuclear progressive Plasy, pick's disease, various polyGlu neurological disorders such as Huntington's disease, spinocerebullar ataxia I type, spinal atrophy and muscle bulbar, pallidoluysian dentatorubal, and myotonic dystrophy, as well as spongiform encephalopathies, such as Creutzfeldt-J disease hereditary akob (due to prion protein processing defect), Fabry's disease, Straussler-Scheinker syndrome, COPD, dry eye disease, or Sjogren's disease, osteoporosis, osteopenia, bone healing and bone growth (including bone repair, bone regeneration, reducing bone resorption and increasing bone deposition), Gorham's syndrome, chloride channelopathies, such as congenital myotonia (Thomson and Becker forms), Bartter's syndrome type III, Dent's disease, hyperecplexy, epilepsy, disease lysosomal storage, Angelman syndrome, and primary ciliary dyskinesia (PCD), hereditary diseases of the structure and / or function of cilia, including PCD with situs (also known as Kartagener syndrome), without PCD situs and ciliary aplasia.
[0047] In one aspect, the invention also provides a method of treating, decreasing the severity of, or symptomatically treating a disease in a patient, which comprises preferably administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient a mammal, in which the disease is selected from generalized epilepsy with addition ferbrile seizures (+) GEFs, general epilepsy with ferbile and afferbrile seizures, congenital myotonia, paramiotonia, potassium-aggravated myotonia, periodic hyperkalemic paralysis, SQTL, SQTL / Brugada syndrome, autosomal dominant LQTS with deafness, autosomal recessive LQTS, LQTS with dysmorphic, congenital and acquired LQTS characteristics, Timothy syndrome, persistent hyperinsulinemic childhood hypoglycemia, dilated cardiomyopathy, autosomal dominant LQTS, Dent disease, osteopetrosis III, central nucleus disease, malignant hyperthermia, and catechin polymorphic tachycardia olaminergics.
[0048] In one aspect, the present invention is directed to a method of treatment, decreasing the severity of, or symptomatically treating, cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient preferably a mammal, in which the patient has the genetic mutation CFTR N1303K, ΔI507 or R560T.
[0049] In one aspect, the present invention is directed to a method of treatment, decreasing the severity of, or symptomatically treating cystic fibrosis in a patient which comprises administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, in which the patient has the CFTR G551D gene mutation. In another embodiment, the patient is homozygous in G551D. In another embodiment, the patient is heterozygous in G551D, where the other CFTR genetic mutation is any one ΔF508, G542X, N1303K, W1282X, R117H, R553X, 1717-1G-> A, 621 + 1G-> T, 2789 + 5G -> A, 3849 + 10kbC-> T, R1162X, G85E, 3120 + 1G-> A, ΔI507, 1898 + 1G-> A, 3659delC, R347P, R560T, R334W, A455E, 2184delA, or 711 + 1G-> T .
[0050] In one aspect, the present invention is directed to a method of treatment, decreasing the severity of, or symptomatically treating, cystic fibrosis in a patient which comprises administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, in which the patient has the CFTR AF508 gene mutation. In another embodiment, the patient is homozygous at AF508. In another embodiment, the patient is heterozygous at AF508, where the other CFTR gene mutation is any one from G551D, G542X, N1303K, W1282X, R117H, R553X, 1717-1G-> A, 621 + 1G-> T, 2789+ 5G-> A, 3849 + 10kbC-> T, R1162X, G85E, 3120 + 1G-> A, ΔI507, 1898 + 1G-> A, 3659delC, R347P, R560T, R334W, A455E, 2184delA, or 711 + 1G-> T.
[0051] In one aspect, the present invention is directed to a method of treatment, decreasing the severity of, or symptomatically treating, cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient , preferably a mammal, in which the patient has the CFTR gene mutation that is selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069R, R117C, D110H, R347 , R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, D1152H, 1717-1G-> A, 621 + 1G-> T, 3120 + 1G-> A, 1898+ 1G-> A, 711 + 1G-> T, 2622 + 1G-> A, 405 + 1G-> A, 406-1G-> A, 4005 + 1G-> A, 1812-1G-> A, 1525-1G -> A, 712-1G-> T, 1248 + 1G-> A, 1341 + 1G-> A, 3121-1G-> A, 4374 + 1G-> T, 3850- 1G-> A, 2789 + 5G- > A, 3849 + 10kbC-> T, 3272-26A-> G, 711 + 5G-> A, 3120G-> A, 1811 + 1.6kbA-> G, 711 + 3A-> G, 1898 + 3A-> G , 1717-8G-> A, 1342-2A-> C, 405 + 3A-> C, 1716G / A, 1811 + 1G-> C, 1898 + 5G-> T, 3850-3T-> G, IVS14b + 5G -> A, 1898 + 1G-> T, 4005 + 2T-> C and 621 + 3A-> G.
[0052] In one aspect, the present invention is directed to a method of treatment, decreasing the severity of, or symptomatically treating cystic fibrosis in a patient, comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, from preferably a mammal, in which the patient has the CFTR gene mutation that is selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V and G1069R. In one embodiment of this aspect, the invention provides a method of treatment comprising administering Compound 1 CFTR to a patient having a human CFTR mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R and S1251N. In one aspect, the present invention is directed to a method of treatment, decreasing the severity of, or symptomatically treating, cystic fibrosis in a patient, comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, in which the patient has the CFTR genetic mutation that is selected from E193K, F1052V and G1069R. In some embodiments of this aspect, the method produces a greater than 10-fold increase in chloride transport over baseline chloride transport.
[0053] In one aspect, the present invention is directed to a method of treatment, decreasing the severity of, or symptomatically treating cystic fibrosis in a patient, comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, in which the patient has the CFTR gene mutation that is selected from R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, Dl 10E, D1270N and 152H Dl. In one embodiment of this aspect, the method produces an increase in chloride transport, which is greater than or equal to 10% above the baseline of chloride transport.
[0054] In one aspect, the present invention is directed to a method of treatment, decreasing the severity of, or symptomatically treating, cystic fibrosis in a patient which comprises administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient , preferably a mammal, in which the patient has the CFTR genetic mutation that is selected from 1717-1G-> A, 621 + 1G-> T, 3120 + 1G-> A, 1898 + 1G-> A, 711 + 1G-> T, 2622 + 1G-> A, 405 + 1G-> A, 406-1G-> A, 4005 + 1G-> A, 1812-1G-> A, 1525-1G-> A, 712- 1G-> T, 1248 + 1G-> A, 1341 + 1G-> A, 3121-1G-> A, 4374 + 1G-> T, 3850-1G-> A, 2789 + 5G-> A, 3849 + 10kbC -> T, 3272-26A-> G, 711 + 5G-> A, 3120G-> A, 1811 + 1.6kbA-> G, 711 + 3A-> G, 1898 + 3A-> G, 1717-8G-> A, 1342-2A-> C, 405 + 3A-> C, 1716G / A, 1811 + 1G-> C, 1898 + 5G-> T, 3850-3T-> G, IVS14b + 5G-> A, 1898+ 1G-> T, 4005 + 2T-> C and 621 + 3A-> G G. In one aspect, the present invention is directed to a method of treatment, decreasing the severity of, or symptomatically treating cystic fibrosis in a patient who comprises administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, in which the patient has the CFTR genetic mutation that is selected from 1717-1G-> a, 181 l + 1.6kbA- > L, 2,789 + 5G-> a, 3272-26A-> G and 3849 + 10kbC-> T. In one aspect, the present invention is directed to a method of treatment, decreasing the severity of, or symptomatically treating fibrosis cystic in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, in which the patient has the CFTR genetic mutation which is selected from 2,789 + 5G-> a and 3272- 26A-> L.
[0055] In one aspect, the present invention is directed to a method of treatment, decreasing the severity of, or symptomatically treating, cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient , preferably a mammal, in which the patient has the CFTR gene mutation that is selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069R, R117C, D110H, R347 , R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, D1152H, 1717-1G-> A, 621 + 1G-> T, 3120 + 1G-> A, 1898+ 1G-> A, 711 + 1G-> T, 2622 + 1G-> A, 405 + 1G-> A, 406-1G-> A, 4005 + 1G-> A, 1812-1G-> A, 1525-1G -> A, 712-1G-> T, 1248 + 1G-> A, 1341 + 1G-> A, 3121-1G-> A, 4374 + 1G-> T, 3850- 1G-> A, 2789 + 5G- > A, 3849 + 10kbC-> T, 3272-26A-> G, 711 + 5G-> A, 3120G-> A, 1811 + 1.6kbA-> G, 711 + 3A-> G, 1898 + 3A-> G , 1717-8G-> A, 1342-2A-> C, 405 + 3A-> C, 1716G / A, 1811 + 1G-> C, 1898 + 5G-> T, 3850-3T-> G, IVS14b + 5G -> A , 1898 + 1G-> T, 4005 + 2T-> C and 621 + 3A-> G, and a human CFTR mutation selected from AF508, Rl17H, and G551D.
[0056] In one aspect, the present invention is directed to a method of treatment, decreasing the severity of, or symptomatically treating cystic fibrosis in a patient, comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, in which the patient has the CFTR gene mutation that is selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V and G1069R, and a selected human CFTR mutation from AF508, Rl17H, and G551D. In one aspect, the present invention is directed to a method of treating, decreasing the severity of, or symptomatically treating cystic fibrosis in a patient which comprises administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, in which the patient has the CFTR gene mutation that is selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R and S 125 eM, and a human CFTR mutation selected from AF508, Rl17H , and G551D. In one aspect, the present invention is directed to a method of treating, decreasing the severity of, or symptomatically treating cystic fibrosis in a patient which comprises administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, in which the patient has the CFTR genetic mutation that is selected from E193K, F1052V and G1069R, and a human CFTR mutation selected from AF508, Rl17H, and G551D. In some embodiments of this aspect, the method produces a greater than 10-fold increase in chloride transport over baseline chloride transport.
[0057] In one aspect, the present invention is directed to a method of treatment, decreasing the severity of, or symptomatically treating cystic fibrosis in a patient, comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, in which the patient has the CFTR gene mutation that is selected from R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, Dl 10E, D1270N and Dl152H, and a human CFTR mutation selected from AF508, Rl17H, and G551D. In one embodiment of this aspect, the method produces an increase in chloride transport, which is greater than or equal to 10% above the chloride transport baseline.
[0058] In one aspect, the present invention is directed to a method of treatment, decreasing the severity of, or symptomatically treating, cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient , preferably a mammal, in which the patient has the CFTR genetic mutation that is selected from 1717-1G-> A, 621 + 1G-> T, 3120 + 1G-> A, 1898 + 1G-> A, 711 + 1G-> T, 2622 + 1G-> A, 405 + 1G-> A, 406-1G-> A, 4005 + 1G-> A, 1812-1G-> A, 1525-1G-> A, 712- 1G-> T, 1248 + 1G-> A, 1341 + 1G-> A, 3121-1G-> A, 4374 + 1G-> T, 3850-1G-> A, 2789 + 5G-> A, 3849 + 10kbC -> T, 3272-26A-> G, 711 + 5G-> A, 3120G-> A, 1811 + 1.6kbA-> G, 711 + 3A-> G, 1898 + 3A-> G, 1717-8G-> A, 1342-2A-> C, 405 + 3A-> C, 1716G / A, 1811 + 1G-> C, 1898 + 5G-> T, 3850-3T-> G, IVS14b + 5G-> A, 1898+ 1G-> T, 4005 + 2T-> C and 621 + 3A-> G, and a human CFTR mutation selected from AF508, Rl17H, and G551D. In one aspect, the present invention is directed to a method of treatment, decreasing the severity of, or symptomatically treating, cystic fibrosis in a patient, comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, in which the patient has the CFTR genetic mutation that is selected from 1717-1G-> a, 181 l + 1.6kbA-> L, 2,789 + 5G-> a, 3272- 26A-> G and 3849 + 10kbC-> T, and a human CFTR mutation selected from ΔF508, R117H, and G551D. In one aspect, the present invention is directed to a method of treatment, decreasing the severity of, or symptomatically treating, cystic fibrosis in a patient, comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, in which the patient has the CFTR genetic mutation that is selected from 2,789 + 5G-> a and 3272-26A-> L, and a human CFTR mutation selected from ΔF508, R117H.
[0059] In one aspect, the present invention is directed to a method of treatment, decreasing the severity of, or symptomatically treating, cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient preferably a mammal, in which the patient has the CFTR gene mutation that is selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069R, R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, Dl lOE, D1270N, D1152H, 1717-1G-> A, 621 + 1G-> T, 3120 + 1G-> A from 1898 + 1G-> A, 711 + 1G-> T, 2622 + lg-> A, 405 + lg-> A, 406-lg-> A, 4005 + lg-> A, 1812-1G-> A, 1525 -1G-> A, 712- 1G-> T, 1248 + 1G-> A, 1341 + 1G-> A, 3121-1G-> A, 4374 + lg-> T, 3850-1G-> A, 2789 + 5G-> A, 3849 + 10kbC -> T, 3272-26A-> G, 711 + 5G-> A, 3120G-> A from 1811 + 1.6kbA-> G, 711 + 3A-> G from 1898 + 3A- > G, 1717-8G-> Um, 1342-2A-> C, 40 5 + 3A-> C, 1716G / A, 1811 + 1G-> C, 1898 + 5G-> T, 3850-3T-> L, IVS14b + 5G-> A, 1898+ 1G-> T, 4005 + 2T- > C and 621 + 3A-> L, and a human CFTR mutation selected from ΔF508, Rl17H, and G551D.
[0060] In one aspect, the present invention is directed to a method of treatment, decreasing the severity of, or symptomatically treating, cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient , preferably a mammal, in which the patient has the CFTR genetic mutation that is selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V and G1069R. In one aspect, the present invention is directed to a method of treatment, decreasing the severity of, or symptomatically treating, cystic fibrosis in a patient, comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, in which the patient has the CFTR gene mutation that is selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R and S 125 EM. In one aspect, the present invention is directed to a method of treatment, decreasing the severity of, or symptomatically treating, cystic fibrosis in a patient, comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably , a mammal, in which the patient has the CFTR gene mutation that is selected from E193K, F1052V and G1069R. In some embodiments of this aspect, the method produces a greater than 10-fold increase in chloride transport over baseline chloride transport.
[0061] In one aspect, the present invention is directed to a method of treatment, decreasing the severity of, or symptomatically treating, cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient , preferably a mammal, in which the patient has the CFTR genetic mutation that is selected from R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, Dl 10E, D1270N and 152H Dl. In one embodiment of this aspect, the method produces an increase in chloride transport, which is greater than or equal to 10% of chloride transport above the baseline.
[0062] In one aspect, the present invention is directed to a method of treatment, decreasing the severity of, or symptomatically treating, cystic fibrosis in a patient which comprises administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient , preferably a mammal, in which the patient has the CFTR genetic mutation that is selected from 1717-1G-> A, 621 + 1G-> T, 3120 + 1G-> A, 1898 + 1G-> A, 711 + 1G-> T, 2622 + 1G-> A, 405 + 1G-> A, 406-1G-> A, 4005 + 1G-> A, 1812-1G-> A, 1525-1G-> A, 712- 1G-> T, 1248 + 1G-> A, 1341 + 1G-> A, 3121-1G-> A, 4374 + 1G-> T, 3850-1G-> A, 2789 + 5G-> A, 3849 + 10kbC -> T, 3272-26A-> G, 711 + 5G-> A, 3120G-> A, 1811 + 1.6kbA-> G, 711 + 3A-> G, 1898 + 3A-> G, 1717-8G-> A, 1342-2A-> C, 405 + 3A-> C, 1716G / A, 1811 + 1G-> C, 1898 + 5G-> T, 3850-3T-> G, IVS14b + 5G-> A, 1898+ 1G-> T, 4005 + 2T-> C and 621 + 3A-> G. In one aspect, the present invention is directed to a method of treatment, decreasing the severity of, or symptomatically treating, cystic fibrosis in a patient, comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, in which the patient has the CFTR genetic mutation that is selected from 1717-1G-> a, 181 l + 1.6kbA-> L, 2,789 + 5G-> a, 3272-26A-> G and 3849 + 10kbC-> T. In one aspect, the present invention is directed to a method of treatment, decreasing the severity of, or symptomatically treating, cystic fibrosis in a patient which comprises administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, in which the patient has the CFTR genetic mutation which is selected from 2,789 + 5G-> A and 3272-26A-> G.
[0063] In one aspect, the present invention is directed to a method of treatment, decreasing the severity of, or symptomatically treating, cystic fibrosis in a patient which comprises administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient , preferably a mammal, in which the patient has the CFTR gene mutation that is selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069R, R117C, D110H, R347 , R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, D1152H, 1717-1G-> A, 621 + 1G-> T, 3120 + 1G-> A, 1898+ 1G-> A, 711 + 1G-> T, 2622 + 1G-> A, 405 + 1G-> A, 406-1G-> A, 4005 + 1G-> A, 1812-1G-> A, 1525-1G -> A, 712-1G-> T, 1248 + 1G-> A, 1341 + 1G-> A, 3121-1G-> A, 4374 + 1G-> T, 3850- 1G-> A, 2789 + 5G- > A, 3849 + 10kbC-> T, 3272-26A-> G, 711 + 5G-> A, 3120G-> A, 1811 + 1.6kbA-> G, 711 + 3A-> G, 1898 + 3A-> G , 1717-8G-> A, 1342-2A-> C, 405 + 3A-> C, 1716G / A, 1811 + 1G-> C, 1898 + 5G-> T, 3850-3T-> G, IVS14b + 5G -> A , 1898 + 1G-> T, 4005 + 2T-> C and 621 + 3A-> G, and a human CFTR mutation selected from AF508, Rl 17H, G55 and identification, and one or more mutations in the human CFTR gene selected from ΔF508, R117H and G551D.
[0064] In one aspect, the present invention is directed to a method of treatment, decreasing the severity of, or symptomatically treating, cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient , preferably a mammal, in which the patient has the CFTR genetic mutation that is selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V and G1069R, and one or more mutations in the human CFTR gene selected from ΔF508, R117H, and G55 ID. In one aspect, the present invention is directed to a method of treatment, decreasing the severity of, or symptomatically treating, cystic fibrosis in a patient, comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, in which the patient has the CFTR gene mutation that is selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R and S1251N, and one or more mutations in the human CFTR gene selected from ΔF508 , R117H, and G551D. In one aspect, the present invention is directed to a method of treatment, decreasing the severity of, or symptomatically treating, cystic fibrosis in a patient, comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, in which the patient has the CFTR gene mutation that is selected from E193K, F1052V and G1069R, and one or more human CFTR mutations selected from ΔF508, R117H, and G551D. In some embodiments of this aspect, the method produces a greater than 10-fold increase in chloride transport over baseline chloride transport.
[0065] In one aspect, the present invention is directed to a method of treatment, decreasing the severity of, or symptomatically treating, cystic fibrosis in a patient which comprises administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient , preferably a mammal, in which the patient has the CFTR genetic mutation that is selected from R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, Dl 10E, D1270N and Dl152H, and one or more mutations in the human CFTR gene selected from ΔF508, R117H, and G551D. In one embodiment of this aspect, the method produces an increase in chloride transport, which is greater than or equal to 10% of chloride transport above the baseline.
[0066] In one aspect, the present invention is directed to a method of treatment, decreasing the severity of, or symptomatically treating, cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient , preferably a mammal, in which the patient has the CFTR genetic mutation that is selected from 1717-1G-> A, 621 + 1G-> T, 3120 + 1G-> A, 1898 + 1G-> A, 711 + 1G-> T, 2622 + 1G-> A, 405 + 1G-> A, 406-1G-> A, 4005 + 1G-> A, 1812-1G-> A, 1525-1G-> A, 712- 1G-> T, 1248 + 1G-> A, 1341 + 1G-> A, 3121-1G-> A, 4374 + 1G-> T, 3850-1G-> A, 2789 + 5G-> A, 3849 + 10kbC -> T, 3272-26A-> G, 711 + 5G-> A, 3120G-> A, 1811 + 1.6kbA-> G, 711 + 3A-> G, 1898 + 3A-> G, 1717-8G-> A, 1342-2A-> C, 405 + 3A-> C, 1716G / A, 1811 + 1G-> C, 1898 + 5G-> T, 3850-3T-> G, IVS14b + 5G-> A, 1898+ 1G-> T, 4005 + 2T-> C and 621 + 3A-> G, and one or more mutations in the human CFTR gene selected from ΔF508, R117H, and G551D. In one aspect, the present invention is directed to a method of treatment, decreasing the severity of, or symptomatically treating, cystic fibrosis in a patient, comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, in which the patient has the CFTR genetic mutation that is selected from 1717-1G-> a, 181 l + 1.6kbA-> L, 2,789 + 5G-> a, 3272- 26A-> G and 3849 + 10kbC-> T, and one or more mutations in the human CFTR gene selected from ΔF508, Rl17H, and G551D. In one aspect, the present invention is directed to a method of treatment, decreasing the severity of, or symptomatically treating, cystic fibrosis in a patient, comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, in which the patient has the CFTR gene mutation that is selected from 2,789 + 5G-> a and 3272-26A-> G, and one or more mutations in the human CFTR gene selected from ΔF508, Rl17H, and G551D .
[0067] In certain embodiments, the pharmaceutically acceptable composition or tablets of the present invention comprising Compound 1 Form I and a solid dispersion of substantially amorphous Compound 2 are useful to treat, decrease the severity of, or symptomatically treat cystic fibrosis in patients who exhibit residual CFTR activity on the apical membrane of the respiratory and non-respiratory epithelium. The presence of residual CFTR activity on the epithelial surface can be easily detected using methods known in the art, for example, standard electrophysiological, biochemical, or histochemical techniques. Such methods identify CFTR activity using in vivo or ex vivo electrophysiological techniques, measurement of sweat or salivary Cl- concentrations, or ex vivo or histochemical biochemical techniques to monitor cell surface density. When using such methods, residual CFTR activity can be easily detected in heterozygous or homozygous patients for a variety of different mutations, including homozygous or heterozygous patients for the most common mutation, ΔF508, as well as other mutations, such as the mutation G551D, or the Rl17H mutation. In certain embodiments, pharmaceutically acceptable compositions or tablets comprising Compound 1 Form I and a solid dispersion comprising substantially amorphous Compound 2 are useful for treating, lessening the severity of, or symptomatically treating cystic fibrosis in patients who exhibit little or no activity of residual CFTR. In certain embodiments, pharmaceutically acceptable compositions or tablets comprising Compound 1 Form I and a solid design comprising substantially amorphous Compound 2 are useful for treating, lessening the severity of, or symptomatically treating cystic fibrosis in patients who exhibit little or no activity of residual CFTR in the apical membrane of the respiratory epithelium.
[0068] In another embodiment, the compounds and compositions of the present invention are useful for treating or alleviating the severity of cystic fibrosis in patients who have induced or increased residual CFTR activity using pharmacological methods. In another embodiment, the compounds and compositions of the present invention are useful for treating or alleviating the severity of cystic fibrosis in patients who have residual or increased CFTR activity induced using gene therapy. Such methods of increasing the amount of CFTR present on the cell surface, thereby inducing a CFTR activity hitherto absent in a patient or increasing the level of existing residual CFTR activity in a patient.
[0069] In one embodiment, the pharmaceutical compositions and tablets of the present invention comprising Compound 1 Form I and a solid dispersion comprising substantially amorphous compound 2, as described herein, are useful for treating or alleviating the severity of cystic fibrosis in patients within certain genotypes showing residual CFTR activity, for example, class I mutations (not synthesized), class II mutation (incorrect folding), class III mutations (poor regulation or gating), class IV mutations (altered conductance) or class V mutations (reduced synthesis).
[0070] In one embodiment, the pharmaceutical compositions and tablets of the present invention comprising Compound 1 Form I and a solid dispersion comprising substantially amorphous compound 2, as described herein, are useful for treating, decreasing the severity of, or symptomatically treating the cystic fibrosis in patients within certain clinical phenotypes, for example, a mild or moderate clinical phenotype, which typically correlates with the amount of residual CFTR activity in the apical membrane of the epithelium. Such phenotypes include patients who exhibit pancreatic sufficiency.
[0071] In one embodiment, the pharmaceutical compositions and tablets of the present invention comprising Compound 1 Form I and a solid dispersion comprising substantially amorphous compound 2, as described herein, are useful for treating, decreasing the severity of, or symptomatically treating the patients diagnosed with pancreatic insufficiency, idiopathic pancreatitis and congenital bilateral absence of the vas deferens, or mild lung disease in which the patient exhibits residual CFTR activity.
[0072] In one embodiment, the pharmaceutical compositions and tablets of the present invention comprising Compound 1 Form I and a solid dispersion comprising substantially amorphous compound 2, as described herein, are useful for treating, decreasing the severity of, or symptomatically treating the patients diagnosed with pancreatic insufficiency, idiopathic pancreatitis and congenital bilateral absence of the vas deferens, or mild lung disease, in which the patient has wild-type CFTR.
[0073] In addition, cystic fibrosis, modulation of CFTR activity may be beneficial for other diseases not directly caused by mutations in the CFTR gene, such as secretory diseases and other diseases mediated by folding CFTR protein. These include, but are not limited to, chronic obstructive pulmonary disease (COPD), dry eye disease, and Sjogren's syndrome. COPD is characterized by airflow limitation that is progressive and not fully reversible. The limitation of airflow is due to hypersecretion of mucus, emphysema and bronchiolitis. Wild-type or CFTR mutant activators offer a potential treatment of hypersecretion of mucus and the compromised mucociliary clearance that is common in patients with COPD. Specifically, increasing the secretion of anion through CFTR can facilitate the transport of fluid into the liquid from the surface of the airways to hydrate the mucus and optimize the viscosity of the periciliary fluid. This would lead to improved mucociliary clearance and a reduction in symptoms associated with COPD. Dry eye disease is characterized by a decrease in the production of watery tear and abnormal lipid tear film, protein and mucin profiles. There are many causes of dry eye, some of which include age, Lasik eye surgery, arthritis, medications, chemicals / thermal burns, allergies and illnesses, such as cystic fibrosis and Sjogren's syndrome. Increasing secretion of anions through CFTR would increase the transport of fluids from the corneal endothelial cells and secretory glands that surround the eye to increase corneal hydration. This would help to alleviate the symptoms associated with dry eye disease. Sjogren's syndrome is an autoimmune disease in which the immune system attacks moisture-producing glands throughout the body, including the eye, mouth, skin, respiratory tissue, liver, the vagina, and the intestine. Symptoms include dry eye, mouth, and vagina, as well as lung disease. The disease is also associated with rheumatoid arthritis, systemic lupus, systemic sclerosis, and polymypositis / dermatomyositis. Defective protein trafficking is believed to cause disease, for which treatment options are limited. Enhancers or inducers of CFTR activity can hydrate the various organs affected by the disease and to help elevate the associated symptoms.
[0074] In any part of the present patent application, where a name of a compound may not correctly describe the structure of the compound, the structure replaces the name and determines. EXAMPLES Formation of the tablet from a fully continuous wet granulation process Equipment / Process Equipment
[0075] Fully Continuous Development and Rig Launch (DLR) or a similar type of equipment. Screening
[0076] Compound 1 Form I, the solid dispersion comprising substantially amorphous Compound 2, and excipients can be dispensed in separate intermediate containers (IBCs). These materials can be tracked using a "box-by-box" screening operation. The appropriate screen sizes are 20 mesh, 40 mesh, or 60 mesh.
[0077] IBCs containing the screened Form 1 compound, the solid dispersion comprising substantially amorphous Compound 2 and excipients can be coupled to a feeder system, which can feed materials in a controlled manner, for example, using volumetric loss or gravimetric in weight feeders, in a continuous mixer. Feed rates for individual components are defined by the composition of the formulation and the overall line frequency. The line rate can be from 8 kg / h to 30 kg / h. The continuous mixer can have different blade configurations to allow proper mixing and the rotation speed of these blades can be between 80 rpm and 300 rpm. Wet granulation
[0078] A granulation solution can be prepared by dissolving 48 g of sodium lauryl sulfate and 159 g of polyvinylpyrrolidone in 1,626 g of water in a stainless steel container, using a mechanical stirrer with a stirring speed of 700 RPM. The granulation solution can be placed in a container from which the solution can be pumped into the twin-screw granulator, using a peristaltic pump with a mass flow and control meter, using a flow rate that is appropriate for the process. The mixture can be granulated using a twin screw granulator, such as the granulator that is part of the DLR. The mixture can be added to the twin screw granulator using a weight loss feeder, such as the K-Tron feeder on the DLR, with a feed rate of 8 kg / h to 24 kg / h. The twin screw granulator can be operated with a cylinder temperature of 25 degrees Celsius and a screw speed of 200-950 RPM. The granulation process can be carried out for three minutes for small batch sizes or several hours for large batch sizes. Drying
[0079] The wet granules can be fed directly into a fluid bed dryer, such as the segmented fluid bed dryer in the DLR. The final drying point can be chosen at a product temperature during discharge ranging from 40 to 55 degrees Celsius, at which point the water content of the granules can be 2.1% w / w ("Loss on drying, LOD ") or less. The drying time can be 12 minutes or shorter or longer, to reach the desired final drying point. Milling
[0080] The dried granules can be ground to reduce the size of the granules. A cone mill, such as the integrated Comil U10 Quadro can be used for this purpose. Blends
[0081] The granules can be mixed with extra-granular excipients, such as fillers and lubricants, using weight loss in feeders and a continuous mixer. The mixing speed can be 80-300 RPM. Compression
[0082] The compression mixture can be compressed into tablets, using a single station or rotary tablet press, such as the Courtoy Modul P press, which is part of the DLR system, using appropriately sized tools. The weight of the tablets for a 200 mg dose of Compound 1 Form I and 125 mg of substantially amorphous Compound 2 can be about 500 or 600 mg. Coating film
[0083] The tablets can be film coated using innovative Omega film coating equipment, which is part of the DLR system. This film coating device makes it possible to quickly coat sub-batches from 1 to 4 kg to allow continuous fabrication. Print
[0084] The film-coated tablets can be printed with a monogram on one or both tablet faces, for example with an Ackley ramp printer. PAT
[0085] The continuous process described above in one embodiment is enhanced through PAT techniques, as described in Table 1. There are 6 PAT positions, each of which includes a manual sampling port. In the sample process it can be obtained for experimental reasons, as needed, and also for the PAT maintenance model, transfer, and validation. PAT systems can be used for real-time release tests (rtrt) and can also be used in process control (IPC) and feedback / feed-forward control. Table 1

[0086] Grouping of Specifications can be done by RTRT as described in Table 2. Table 2

[0087] There is a high probability of detecting non-compliant material. For example, if the model classification criterion is set at a minimum of 95% confidence and 800 tablets are tested during batch manufacture, 40 hours of operation with a sampling rate of 1 tablet every 3 minutes, is equal to 800 tablets. Then, the probability of passing a non-compliant batch is extremely low: <(0.05) n "where n = number of samples, so the probability is <1.5 x 10-1041. Probability of not being detected of non-compliant tablets resulting from a short-term event (> 3 minutes) is as follows: 1 tablet (3 min event) ^ <0.05 (detection probability> 0.95); 2 tablets (6 minute events) ^ <0.0025 (probability of detection> 0.9975).
[0088] PAT measurements can serve as a substitute for the conventional final test directly through combining measurements to express attributes conventionally (for example, as assay, CU, dissolution, etc.). Validation can be performed using ICH Q2 as a guide. Sequential offline for the development of the online method allows the evaluation of CQAS in a way saving materials. Ultimately, RTRT will lead to ensuring product quality at a higher level of confidence than conventional testing. HTT HPLC
[0089] In one embodiment, the continuous manufacturing process of the present invention uses high productivity testing of HPLC (HTT) methods to validate samples. High-productivity HPLC test methods achieve 24 hours of sample time for at least 300 samples by improving sample preparation techniques, emphasizing generic analysis methods, using well-defined sample workflows, and automating data processing.
[0090] Sample preparation takes most of the time from an FTE and is the source of most errors. It is often overlooked during the development of the method. In one embodiment, improving sample preparation techniques comprises using disposable wide-mouthed vials. In another embodiment, improving sample preparation techniques comprises adding the entire sample vial to a disposable vial, adding diluent, stirring overnight, and centrifuging.
[0091] generic HPLC methods can be developed and validated for multiple projects. Common HPLC columns and commercial mobile phases can be used. Additional analysis improvements include standard leveraged stability and using injection overlay.
[0092] In another embodiment, HTT HPLC is used in the development of analytical process techniques as a way of correlating the spectroscopic data collected from the analytical process techniques with an absolute number.
[0093] In one embodiment, the present invention features a high performance HPLC process comprising a) pouring containers, such as one, pre-weighed sample bottles into plastic bottles, such as polyethylene bottles. high density; b) add solution to each set of container and bottle using a bottle top dispenser; c) shake the sets of plastic bottles, flasks, and solutions until the samples are dissolved; d) centrifuge the sets of plastic bottles, flasks, and solutions; e) loading an aliquot of supernatant from the centrifugation step on an HPLC column; and f) running the column with a mobile phase.
[0094] The advantage of HTT HPLC is that it can measure a large volume of samples in an accurate, accurate, and timely manner. Sample preparation uses plastic bottles as the main container that can be placed in large numbers on an agitator and then transferred directly to a centrifuge. This avoids the step of filtering the sample solution that takes longer. In addition, the size of the plastic bottle allows the sample to be added directly by simply dropping the sample container, such as a vial, into the plastic bottle. Commercially available solution dispensers can then be used to add a fixed amount of solution, thereby avoiding another time-consuming pipetting step of the solution.
[0095] Table 3 summarizes the benefits of high productivity HPLC testing compared to traditional HPLC test methods. Table 3

[0096] All publications and patents referred to in this specification are hereby incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. If the meaning of the terms in any of the patents or publications incorporated by reference conflicts with the meaning of the terms used in this specification, the meanings of the terms in this specification are intended to be control. In addition, the foregoing discussion reveals and describes merely exemplary embodiments of the invention. A person skilled in the art will easily recognize from such a discussion and from the accompanying drawings and claims, that various changes, modifications and variations can be made to it without departing from the spirit and scope of the invention as defined in the following claims.

权利要求:
Claims (4)
[0001]
1. High performance high performance liquid chromatography (HPLC) process characterized by the fact that the process comprises: a) pouring the pre-weighed sample containers into plastic bottles; b) add solution to each set of containers and bottles by means of a dispenser at the top of the bottle; c) shake a set of plastic bottles, container and solution until the sample is dissolved; d) centrifuge each set of plastic bottles, container and solution; e) loading an aliquot of supernatant from the centrifugation step under an HPLC column; and f) running the column with a mobile phase.
[0002]
2. Process according to claim 1, characterized by the fact that the containers of step a) are bottles.
[0003]
3. Process according to claim 1 or 2, characterized by the fact that the plastic bottles in step a) are high density polyethylene (HDPE) bottles.
[0004]
4. Process according to any one of claims 1 to 3, characterized by the fact that it further comprises correlating the results of the process as defined by claim 1 for measurements of process analysis techniques (PAT) for continuous manufacturing.

类似技术:

公开号 | 公开日 | 专利标题

BR112017010406B1|2021-03-09|process of carrying out high-throughput testing of high-performance liquid chromatography

JP2021165300A|2021-10-14|Methods of preparing pharmaceutical compositions for treatment of cftr mediated diseases

US20200338063A1|2020-10-29|Pharmaceutical compositions for the treatment of cftr mediated diseases

EA020783B1|2015-01-30|Pharmaceutical formulation comprising 4-[3-|-4-fluorobenzyl]-2h-phthalazin-1-one and copovidone

Shprakh2021|Formulation of somatostatin analog tablets using quality by design approach

CN105596341A|2016-05-25|Succinic acid trelagliptin solid preparation and preparation method thereof

BR112015021179B1|2021-11-30|POLYMER FOR IMPROVED PHARMACEUTICAL PERFORMANCE AND IMPROVED PROCESSABILITY, COMPOSITION COMPRISING A PHARMACEUTICAL AND A POLYMER AND METHOD FOR THE PRODUCTION OF HYDROXYPROPYLMETHYL CELLULOSE ACETATE SUCCINATE

CN107468662A|2017-12-15|One kind treats dyspeptic medicinal tablet and preparation method thereof

Shedpure et al.2011|Spectrophotometeric determination of dexrabeprazole sodium and domperidone maleate in bulk and capsule dosage form by first order derivative spectroscopy

CN109481415A|2019-03-19|A kind of Cefdinir capsule agent and preparation method thereof

同族专利:

公开号 | 公开日

SI3221692T1|2021-11-30|

EP3221692B1|2021-06-23|

US10302602B2|2019-05-28|

AU2015350049B2|2021-08-19|

ES2882656T3|2021-12-02|

PL3221692T3|2021-12-06|

HRP20211194T1|2021-10-29|

JP6494757B2|2019-04-03|

SG11201703963QA|2017-06-29|

AU2015350049A1|2017-06-08|

EP3221692A1|2017-09-27|

WO2016081556A1|2016-05-26|

MX2017006443A|2017-09-11|

JP2018502285A|2018-01-25|

DK3221692T3|2021-08-23|

RS62259B1|2021-09-30|

US20170356885A1|2017-12-14|

BR112017010406A2|2017-12-26|

KR20170084272A|2017-07-19|

RU2017120901A|2018-12-19|

CN107110831A|2017-08-29|

PT3221692T|2021-09-10|

IL252272A|2020-11-30|

HUE055423T2|2021-11-29|

RU2017120901A3|2019-04-02|

CN107110831B|2020-02-21|

CA2968130A1|2016-05-26|

RU2691136C2|2019-06-11|

IL252272D0|2017-07-31|

ZA201703531B|2019-11-27|

引用文献:

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

US3758475A|1971-07-20|1973-09-11|Sandoz Ag|Pyridopyrimidin 2 ones|

IT1226048B|1981-12-14|1990-12-10|Medea Res Srl|COMPOUNDS WITH ANTI-INFLAMMATORY ACTIVITY, PROCESS FOR THEIR PREPARATION AND RELATIVE PHARMACEUTICAL COMPOSITIONS|

EP0081756B1|1981-12-14|1985-05-15|MEDEA RESEARCH S.r.l.|New compounds with antiinflammatory and antitussive activity, process for their preparation and relative pharmaceutical compositions|

US4501729A|1982-12-13|1985-02-26|Research Corporation|Aerosolized amiloride treatment of retained pulmonary secretions|

EP0278374A3|1987-02-06|1989-03-01|Pharmatest Apparatebau Gmbh|Device for testing the release of active components by pharmaceutical products|

US5981714A|1990-03-05|1999-11-09|Genzyme Corporation|Antibodies specific for cystic fibrosis transmembrane conductance regulator and uses therefor|

JP3167762B2|1990-11-27|2001-05-21|武田薬品工業株式会社|Pyridopyridazine derivatives and uses thereof|

US5612360A|1992-06-03|1997-03-18|Eli Lilly And Company|Angiotensin II antagonists|

CA2107196A1|1992-09-29|1994-03-30|Mitsubishi Chemical Corporation|Carboxamide derivatives|

US6060024A|1993-07-14|2000-05-09|Zymark Corporation|Automatic dissolution testing system|

GB9317764D0|1993-08-26|1993-10-13|Pfizer Ltd|Therapeutic compound|

DE69416848T2|1993-10-21|1999-07-08|Searle & Co|AMIDINO DERIVATIVES AS NO-SYNTHETASE INHIBITORS|

DE4405712A1|1994-02-23|1995-08-24|Basf Ag|Substituted naphthyridines and their use|

RU2151145C1|1994-04-11|2000-06-20|Санкио Компани Лимитед|Intermediate compound for synthesis of heterocyclic compounds showing antidiabetic activity|

JP3953097B2|1994-09-27|2007-08-01|ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ|N-substituted piperidinyl bicyclic benzoate derivatives|

SI0788600T1|1994-10-28|2002-06-30|Sophion Bioscience A/S|Patch clamp apparatus and technique having high throughput and low fluid volume requirements|

US5656256A|1994-12-14|1997-08-12|The University Of North Carolina At Chapel Hill|Methods of treating lung disease by an aerosol containing benzamil or phenamil|

US5510379A|1994-12-19|1996-04-23|Warner-Lambert Company|Sulfonate ACAT inhibitors|

EP0891334A1|1996-04-03|1999-01-20|Merck & Co., Inc.|Inhibitors of farnesyl-protein transferase|

EP0984778B1|1996-08-23|2002-06-12|Agouron Pharmaceuticals, Inc.|Neuropeptide-y ligands|

CA2276081A1|1996-12-30|1998-07-09|Lekhanh O. Tran|Inhibitors of farnesyl-protein transferase|

US5948814A|1997-02-20|1999-09-07|The Curators Of The University Of Missouri|Genistein for the treatment of cystic fibrosis|

WO1998047868A1|1997-04-18|1998-10-29|Smithkline Beecham Plc|Heterocycle-containing urea derivatives as 5ht1a, 5ht1b and 5ht1d receptor antagonists|

CA2305808A1|1997-10-02|1999-04-15|Sankyo Company Limited|Amidocarboxylic acid derivatives|

WO1999041405A1|1998-02-17|1999-08-19|G.D. Searle & Co.|Process for the enzymatic resolution of lactams|

PE20000564A1|1998-06-08|2000-07-05|Schering Corp|NEUROPEPTIDE Y5 RECEPTOR ANTAGONISTS|

US6426331B1|1998-07-08|2002-07-30|Tularik Inc.|Inhibitors of STAT function|

AU770042B2|1998-12-18|2004-02-12|Bristol-Myers Squibb Pharma Company|N-ureidoalkyl-piperidines as modulators of chemokine receptor activity|

EP1157005B1|1999-02-24|2004-10-20|F. Hoffmann-La Roche Ag|3-phenylpyridine derivatives and their use as nk-1 receptor antagonists|

CZ20013046A3|1999-02-24|2002-02-13|F. Hoffmann-La Roche Ag|Phenyl and pyridinyl derivatives|

EP1394150B1|1999-02-24|2011-01-19|F. Hoffmann-La Roche AG|4-Phenylpyridine derivatives and their use as NK-1 receptor antagonists|

DE60017894T2|1999-06-04|2005-12-29|Agouron Pharmaceuticals, Inc., La Jolla|DIAMINOTHIAZOLE AND ITS USE IN THE INHIBITION OF PROTEIN KINASES|

EP1194417A1|1999-06-18|2002-04-10|Bayer Ag|Phenoxy fluoropyrimidines|

BR0008088A|1999-12-08|2002-04-09|Pharmacia Corp|Crystal form and solid form of celecoxib, pharmaceutical composition and processes for treating or preventing a cyclooxygenase-2 mediated condition or disorder in an individual and for preparing celecoxib and a crystalline form of celecoxib|

WO2001046165A2|1999-12-16|2001-06-28|Novartis Ag|N-heteroaryl-amides and their use as parasiticides|

US7122309B2|2000-01-15|2006-10-17|Avigenics, Inc.|High throughput screening assay for detecting a DNA sequence|

AU3306901A|2000-01-28|2001-08-07|Biogen Inc|Pharmaceutical compositions containing anti-beta 1 integrin compounds and uses|

WO2001056989A2|2000-02-01|2001-08-09|Cor Therapeutics, Inc.|Inhibitors of factor xa|

WO2001081317A1|2000-04-26|2001-11-01|Gliatech, Inc.|Chiral imidazoyl intermediates for the synthesis of 2--cyclopropyl derivatives|

WO2001083517A1|2000-05-03|2001-11-08|Tularik Inc.|Stat4 and stat6 binding dipeptide derivatives|

US6499984B1|2000-05-22|2002-12-31|Warner-Lambert Company|Continuous production of pharmaceutical granulation|

EP1268450A1|2000-06-01|2003-01-02|Bristol-Myers Squibb Pharma Company|Lactams substituted by cyclic succinates as inhibitors of a-beta protein production|

WO2002022608A1|2000-09-15|2002-03-21|Vertex Pharmaceuticals Incorporated|Pyrazole compounds useful as protein kinase inhibitors|

JP4272338B2|2000-09-22|2009-06-03|バイエルアクチェンゲゼルシャフト|Pyridine derivatives|

AU1137902A|2000-10-04|2002-04-15|Philadelphia Children Hospital|Compositions and methods for treatment of cystic fibrosis|

GB2367816A|2000-10-09|2002-04-17|Bayer Ag|Urea- and thiourea-containing derivatives of beta-amino acids|

WO2002034739A1|2000-10-20|2002-05-02|Merck Patent Gmbh|Chiral binaphthol derivatives|

US6884782B2|2000-11-08|2005-04-26|Amgen Inc.|STAT modulators|

DE60142921D1|2000-12-01|2010-10-07|Eisai Inc|AZAPHENANTHRIDONE DERIVATIVES AND THEIR USE AS PARP INHIBITORS|

GB0102687D0|2001-02-02|2001-03-21|Pharmacia & Upjohn Spa|Oxazolyl-pyrazole derivatives active as kinase inhibitors,process for their preparation and pharmaceutical compositions comprising them|

US6531597B2|2001-02-13|2003-03-11|Hoffmann-La Roche Inc.|Process for preparation of 2-phenyl acetic acid derivatives|

US6962674B2|2001-02-28|2005-11-08|Varian, Inc.|Dissolution test apparatus|

EP1383799A4|2001-04-10|2008-08-06|Transtech Pharma Inc|Probes, systems and methods for drug discovery|

AU2002250876B2|2001-04-23|2005-03-03|F. Hoffmann-La Roche Ag|Use of NK-1 receptor antagonists against benign prostatic hyperplasia|

EP1392302A1|2001-05-22|2004-03-03|Neurogen Corporation|5-substituted-2-arylpyridines as crf1 modulators|

US20030083345A1|2001-07-10|2003-05-01|Torsten Hoffmann|Method of treatment and/or prevention of brain, spinal or nerve injury|

US6627646B2|2001-07-17|2003-09-30|Sepracor Inc.|Norastemizole polymorphs|

WO2003007888A2|2001-07-20|2003-01-30|Adipogenix, Inc.|Fat accumulation-modulating compounds|

CA2448737C|2001-07-20|2010-06-01|Boehringer Ingelheim Ltd.|Viral polymerase inhibitors|

WO2003022852A2|2001-09-11|2003-03-20|Smithkline Beecham Corporation|Furo-and thienopyrimidine derivatives as angiogenesis inhibitors|

PA8557501A1|2001-11-12|2003-06-30|Pfizer Prod Inc|BENZAMIDA, HETEROARILAMIDA AND INVESTED AMIDAS|

JP2003155285A|2001-11-19|2003-05-27|Toray Ind Inc|Cyclic nitrogen-containing derivative|

JP2003221386A|2001-11-26|2003-08-05|Takeda Chem Ind Ltd|Bicylic derivative, method for producing the same, and use of the same|

UA84390C2|2001-12-21|2008-10-27|Ново Нордиск А/Я|Amide derivatives as glucokinase activators|

TW200307539A|2002-02-01|2003-12-16|Squibb Bristol Myers Co|Cycloalkyl inhibitors of potassium channel function|

TW200304820A|2002-03-25|2003-10-16|Avanir Pharmaceuticals|Use of benzimidazole analogs in the treatment of cell proliferation|

TW200403058A|2002-04-19|2004-03-01|Squibb Bristol Myers Co|Heterocyclo inhibitors of potassium channel function|

FR2840807B1|2002-06-12|2005-03-11|COSMETIC CARE AND / OR MAKEUP COMPOSITION, STRUCTURED BY SILICONE POLYMERS AND ORGANOGELATORS, IN RIGID FORM|

GB0221443D0|2002-09-16|2002-10-23|Glaxo Group Ltd|Pyridine derivates|

US20050215614A1|2002-10-15|2005-09-29|Rigel Pharmaceuticals, Inc.|Substituted indoles and their use as hcv inhibitors|

US7514431B2|2002-10-30|2009-04-07|Merck & Co., Inc.|Piperidinyl cyclopentyl aryl benzylamide modulators of chemokine receptor activity|

US6976384B2|2002-10-31|2005-12-20|Nanostream, Inc.|Parallel detection chromatography systems|

WO2004063179A1|2003-01-06|2004-07-29|Eli Lilly And Company|Substituted arylcyclopropylacetamides as glucokinase activators|

CA2515669A1|2003-02-10|2004-08-26|Vertex Pharmaceuticals Incorporated|Processes for the preparation of n-heteroaryl-n-aryl-amines by reacting an n-aryl carbamic acid ester with a halo-heteroaryl and analogous processes|

EP1601657A1|2003-03-12|2005-12-07|Vertex Pharmaceuticals Incorporated|Pyrazole modulators of atp-binding cassette transporters|

AT440825T|2003-06-06|2009-09-15|Vertex Pharma|PYRIMIDIN DERIVATIVES FOR USE AS MODULATORS OF ATP-BINDING CASSETTE TRANSPORTER|

EP1638505B1|2003-06-27|2012-04-25|Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc.|Amphiphilic pyridinium compounds, method of making and use thereof|

GB0315111D0|2003-06-27|2003-07-30|Cancer Rec Tech Ltd|Substituted 5-membered ring compounds and their use|

JP2005053902A|2003-07-18|2005-03-03|Nippon Nohyaku Co Ltd|Phenylpyridines, intermediate therefor, and herbicide containing the same as effective ingredient|

EP1680424A2|2003-09-05|2006-07-19|Neurogen Corporation|Heteroaryl fused pyridines, pyrazines and pyrimidines as crf1 receptor ligands|

KR20060088537A|2003-09-06|2006-08-04|버텍스 파마슈티칼스 인코포레이티드|Modulators of atp-binding cassette transporters|

US7534894B2|2003-09-25|2009-05-19|Wyeth|Biphenyloxy-acids|

US20050070718A1|2003-09-30|2005-03-31|Abbott Gmbh & Co. Kg|Heteroaryl-substituted 1,3-dihydroindol-2-one derivatives and medicaments containing them|

ZA200603515B|2003-10-08|2007-11-28|Vertex Pharma|Modulators of ATP-binding cassette transporters|

FR2861304B1|2003-10-23|2008-07-18|Univ Grenoble 1|CFTR CHANNEL MODULATORS|

GB0325956D0|2003-11-06|2003-12-10|Addex Pharmaceuticals Sa|Novel compounds|

WO2005049018A1|2003-11-14|2005-06-02|Vertex Pharmaceuticals Incorporated|Thiazoles and oxazoles useful as modulators of atp-binding cassette transporters|

WO2005049034A2|2003-11-19|2005-06-02|Glaxo Group Limited|Use of cyclooxygenase-2 selective inhibitors for the treatment of schizophrenic disorders|

ES2631362T3|2004-01-30|2017-08-30|Vertex Pharmaceuticals Incorporated|ATP binding cassette conveyor modulators|

WO2005080348A1|2004-02-19|2005-09-01|Banyu Pharmaceutical Co., Ltd.|Novel sulfone amide derivative|

ES2241496B1|2004-04-15|2006-12-01|Almirall Prodesfarma, S.A.|NEW DERIVATIVES OF PIRIDINA.|

US20080015196A1|2004-04-16|2008-01-17|Neurogen Corporation|Imidazopyrazines, Imidazopyridines, and Imidazopyrimidines as Crf1 Receptor Ligands|

US7585885B2|2004-04-22|2009-09-08|Eli Lilly And Company|Pyrrolidine derivatives useful as BACE inhibitors|

US7618978B2|2004-04-22|2009-11-17|Eli Lilly And Company|Amides as BACE inhibitors|

AU2005249154B2|2004-06-01|2011-02-10|Luminex Molecular Diagnostics, Inc.|Method of detecting cystic fibrosis associated mutations|

US8354427B2|2004-06-24|2013-01-15|Vertex Pharmaceutical Incorporated|Modulators of ATP-binding cassette transporters|

US20140343098A1|2004-06-24|2014-11-20|Vertex Pharmaceuticals Incorporated|Modulators of atp-binding cassette transporters|

MX341797B|2004-06-24|2016-09-02|Vertex Pharmaceuticals Incorporated |Modulators of atp-binding cassette transporters.|

WO2006003504A1|2004-07-01|2006-01-12|Warner-Lambert Company Llc|Preparation of pharmaceutical compositions containing nanoparticles|

AU2005269981A1|2004-07-02|2006-02-09|Bonck, John A|Tablet for pulsed delivery|

RU2416608C2|2004-08-06|2011-04-20|Оцука Фармасьютикал Ко., Лтд.|Aromatic compound|

US7977322B2|2004-08-20|2011-07-12|Vertex Pharmaceuticals Incorporated|Modulators of ATP-binding cassette transporters|

EP1794135A1|2004-09-27|2007-06-13|Amgen Inc.|Substituted heterocyclic compounds and methods of use|

AT540935T|2004-10-12|2012-01-15|Astrazeneca Ab|quinazoline derivatives|

CA2587461A1|2004-11-15|2006-05-18|Pfizer Products Inc.|Azabenzoxazoles for the treatment of cns disorders|

RS50962B|2004-12-15|2010-10-31|Dompe Pha.R.Ma S.P.A.|2-arylpropionic acid derivatives and pharmaceutical compositions containing them|

JP4790260B2|2004-12-22|2011-10-12|出光興産株式会社|Organic electroluminescence device using anthracene derivative|

AR052561A1|2005-01-25|2007-03-21|Bayer Cropscience Sa|METHOD FOR ANALYZING THE PHOSPHOROUS ACID, THE FOSETIL-AL, OR BOTH SIMULTANEOUSLY|

WO2006080884A1|2005-01-27|2006-08-03|Astrazeneca Ab|Novel biaromatic compounds, inhibitors of the p2x7-receptor|

US7888374B2|2005-01-28|2011-02-15|Abbott Laboratories|Inhibitors of c-jun N-terminal kinases|

US8242149B2|2005-03-11|2012-08-14|Vertex Pharmaceuticals Incorporated|Modulators of ATP-binding cassette transporters|

US7297700B2|2005-03-24|2007-11-20|Renovis, Inc.|Bicycloheteroaryl compounds as P2X7modulators and uses thereof|

EP1710246A1|2005-04-08|2006-10-11|Schering Aktiengesellschaft|Sulfoximine-pyrimidine Macrocycles and the salts thereof,a process for making them, and their pharmaceutical use against cancer|

AR053712A1|2005-04-18|2007-05-16|Neurogen Corp|HETEROARILOS SUBSTITUTED, ANTAGONISTS OF CB1 |

WO2006113919A2|2005-04-19|2006-10-26|Bayer Pharmaceuticals Corporation|Aryl alkyl acid derivatives for and use thereof|

GB0510139D0|2005-05-18|2005-06-22|Addex Pharmaceuticals Sa|Novel compounds B1|

US8822451B2|2005-05-24|2014-09-02|Vertex Pharmaceuticals Incorporated|Modulators of ATP-binding cassette transporters|

JP2008545744A|2005-06-02|2008-12-18|バイエル・クロツプサイエンス・アクチエンゲゼルシヤフト|Phenylalkyl-substituted heteroaryl derivatives|

JP2008543919A|2005-06-21|2008-12-04|アステックス・セラピューティクス・リミテッド|Pharmaceutical compounds|

CN2856973Y|2005-07-25|2007-01-10|中国环境科学研究院|Rotary viberator|

TW200738331A|2005-07-26|2007-10-16|Showa Denko Kk|Method for analyzing low-molecular-weight compound in sample containing water-soluble polymer and low-molecular-weight compound|

KR20080053297A|2005-08-11|2008-06-12|버텍스 파마슈티칼스 인코포레이티드|Modulators of cystic fibrosis transmembrane conductance regulator|

ES2367844T3|2005-08-11|2011-11-10|Vertex Pharmaceuticals, Inc.|MODULATORS OF THE REGULATOR OF THE TRANSMEMBRANE CONDUCTANCE OF THE CHYSICAL FIBROSIS.|

PT1928427E|2005-09-23|2010-03-01|Hoffmann La Roche|Novel dosage formulation|

KR20080064971A|2005-10-06|2008-07-10|버텍스 파마슈티칼스 인코포레이티드|Modulators of atp-binding cassette transporters|

PE20110285A1|2005-10-19|2011-06-04|Gruenenthal Chemie|SULFONAMIDOPHENYL PROPIONAMIDE DERIVATIVES AS LIGANDS OF THE VANILOID RECEPTOR SUBTYPE 1|

US20120232059A1|2005-11-08|2012-09-13|Vertex Pharmaceuticals Incorporated|Modulators of ATP-Binding Cassette Transporters|

KR20150041174A|2005-11-08|2015-04-15|버텍스 파마슈티칼스 인코포레이티드|Heterocyclic modulators of ATP-binding cassette transporters|

US7754739B2|2007-05-09|2010-07-13|Vertex Pharmaceuticals Incorporated|Modulators of CFTR|

WO2007054480A1|2005-11-08|2007-05-18|N.V. Organon|2--acetamide biaryl derivatives and their use as inhibitors of the trpv1 receptor|

WO2007067506A2|2005-12-05|2007-06-14|Smithkline Beecham Corporation|2-pyrimidinyl pyrazolopyridine erbb kinase inhibitors|

CA2634113A1|2005-12-24|2007-07-05|Vertex Pharmaceuticals Incorporated|Quinolin- 4 - one derivatives as modulators of abc transporters|

EP1974212A1|2005-12-27|2008-10-01|Vertex Pharmaceuticals Incorporated|Compounds useful in cftr assays and methods therewith|

PT3219705T|2005-12-28|2020-05-20|Vertex Pharma|Pharmaceutical compositions of the amorphous form of n-[2,4-bis-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide|

CN101395147B|2005-12-28|2013-05-29|弗特克斯药品有限公司|1- dioxol-5-yl) -n- cyclopropane- carboxamide derivatives and related compounds as modulators of ATP-binding cassette transporters for the treatment of cystic fibrosis|

US7671221B2|2005-12-28|2010-03-02|Vertex Pharmaceuticals Incorporated|Modulators of ATP-Binding Cassette transporters|

WO2007079257A2|2005-12-30|2007-07-12|Caliper Life Sciences, Inc.|Integrated dissolution processing and sample transfer system|

US7645789B2|2006-04-07|2010-01-12|Vertex Pharmaceuticals Incorporated|Indole derivatives as CFTR modulators|

NZ596889A|2006-04-07|2013-06-28|Vertex Pharma|Use of amide indole derivatives as modulators of ATP-binding cassette transporters|

US10022352B2|2006-04-07|2018-07-17|Vertex Pharmaceuticals Incorporated|Modulators of ATP-binding cassette transporters|

EP2021797B1|2006-05-12|2011-11-23|Vertex Pharmaceuticals, Inc.|Compositions of n-ý2,4-bis-5-hydroxyphenyl¨-1,4-dihydro-4-oxoquinoline-3-carboxamide|

EP1882948A2|2006-07-28|2008-01-30|Qiagen GmbH|Sample processing device|

US8563573B2|2007-11-02|2013-10-22|Vertex Pharmaceuticals Incorporated|Azaindole derivatives as CFTR modulators|

WO2008127399A2|2006-11-03|2008-10-23|Vertex Pharmaceuticals Incorporated|Azaindole derivatives as cftr modulators|

CN101206205B|2006-12-22|2011-08-10|中国科学院大连化学物理研究所|Method and isolated device for micro flux liquid chromatogram on-line large volume sample injection|

CN101209399B|2006-12-27|2010-07-28|中国科学院沈阳应用生态研究所|Reciprocating oscillation machine sample workpiece mounting and fixing device|

CN101210906A|2006-12-29|2008-07-02|电子科技大学|High throughput automated medicament screening experiment detection system|

US20080260820A1|2007-04-19|2008-10-23|Gilles Borrelly|Oral dosage formulations of protease-resistant polypeptides|

CN101687842B|2007-05-09|2013-03-06|沃泰克斯药物股份有限公司|Modulators of CFTR|

WO2008147952A1|2007-05-25|2008-12-04|Vertex Pharmaceuticals Incorporated|Modulators of cystic fibrosis transmembrane conductance regulator|

WO2009023509A2|2007-08-09|2009-02-19|Vertex Pharmaceuticals Incorporated|Therapeutic combinations useful in treating cftr related diseases|

CA2696298C|2007-08-24|2016-09-06|Vertex Pharmaceuticals Incorporated|Modulators of cystic fibrosis transmembrane conductance regulator|

DE102007042754A1|2007-09-07|2009-03-12|Bayer Healthcare Ag|Substituted 6-phenyl-nicotinic acids and their use|

JP5461405B2|2007-09-14|2014-04-02|バーテックスファーマシューティカルズインコーポレイテッド|Regulators of cystic fibrosis membrane conductance regulator|

NZ600865A|2007-09-14|2014-01-31|Vertex Pharma|Solid forms of n-[2,4-bis-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide|

FR2921657A1|2007-09-28|2009-04-03|Sanofi Aventis Sa|New nicotinamide derivatives useful for the preparation of a medicament for the treatment or prevention of cancer|

CN101952254B|2007-11-16|2012-09-05|沃泰克斯药物股份有限公司|Isoquinoline modulators of ATP-binding cassette transporters|

DE102007058718A1|2007-12-06|2009-06-10|Erweka Gmbh|Apparatus and method for the automatic release and measurement of drugs from a drug preparation|

US20100036130A1|2007-12-07|2010-02-11|Vertex Pharmaceuticals Incorporated|Processes for producing cycloalkylcarboxamido-pyridine benzoic acids|

KR20100098545A|2007-12-07|2010-09-07|버텍스 파마슈티칼스 인코포레이티드|Formulations of 3-cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid|

BRPI0821039B8|2007-12-07|2021-05-25|Vertex Pharma|solid forms of 3-cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, process for their preparation , pharmaceutical compositions comprising the same and uses|

DK2639222T3|2007-12-07|2016-10-03|Vertex Pharma|Methods for preparing cycloalkylcarboxamido-pyridinbenzoesyrer|

WO2009076593A1|2007-12-13|2009-06-18|Vertex Pharmaceuticals Incorporated|Modulators of cystic fibrosis transmembrane conductance regulator|

US20090173146A1|2008-01-07|2009-07-09|Matthias Pursch|Temperature programmed low thermal mass fast liquid chromatography analysis system|

CA2716109C|2008-02-28|2016-07-19|Vertex Pharmaceuticals Incorporated|Heteroaryl derivatives as cftr modulators|

JP5358588B2|2008-02-29|2013-12-04|ウオーターズ・テクノロジーズ・コーポレイシヨン|Chromatographic monitoring and control of multiple process streams|

PL2615085T3|2008-03-31|2016-02-29|Vertex Pharma|Pyridyl derivatives as CFTR modulators|

GB0813709D0|2008-07-26|2008-09-03|Univ Dundee|Method and product|

KR20110042356A|2008-08-13|2011-04-26|버텍스 파마슈티칼스 인코포레이티드|Pharmaceutical composition and administrations thereof|

US20100074949A1|2008-08-13|2010-03-25|William Rowe|Pharmaceutical composition and administration thereof|

US20100256184A1|2008-08-13|2010-10-07|Vertex Pharmaceuticals Incorporated|Pharmaceutical composition and administrations thereof|

EP2349223A2|2008-09-29|2011-08-03|Vertex Pharmaceuticals Incorporated|Dosage units of 3- cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid|

US20110257223A1|2008-10-23|2011-10-20|Vertex Pharmaceuticals Incorporated|Modulators of Cystic Fibrosis Transmembrane Conductance Regulator|

JP5645834B2|2008-10-23|2014-12-24|バーテックスファーマシューティカルズインコーポレイテッドＶｅｒｔｅｘＰｈａｒｍａｃｅｕｔｉｃａｌｓＩｎｃｏｒｐｏｒａｔｅｄ|Modulator of cystic fibrosis membrane conductance regulator|

DK2349263T3|2008-10-23|2014-07-21|Vertex Pharma|Modulators of the transmembrane conductance regulator for cystic fibrosis|

MX2011004374A|2008-10-23|2011-05-23|Vertex Pharma|Solid forms of n--2-phenyl)-4-oxo-5--1,4-dihydroquinoline-3- carboxamide.|

CN102203588B|2008-10-31|2015-03-18|生物梅里埃公司|Methods for separation, characterization and/or identification of microorganisms using spectroscopy|

NZ609962A|2008-11-06|2014-11-28|Vertex Pharma|Modulators of atp-binding cassette transporters|

UA104876C2|2008-11-06|2014-03-25|Вертекс Фармасьютікалз Інкорпорейтед|Modulators of atp-binding cassette transporters|

JP5699090B2|2008-12-30|2015-04-08|バーテックスファーマシューティカルズインコーポレイテッドＶｅｒｔｅｘＰｈａｒｍａｃｅｕｔｉｃａｌｓＩｎｃｏｒｐｏｒａｔｅｄ|Modulator of cystic fibrosis membrane conductance regulator|

LT2408749T|2009-03-20|2018-09-25|Vertex Pharmaceuticals Incorporated|Modulators of cystic fibrosis transmembrane conductance regulator|

KR101852173B1|2009-03-20|2018-04-27|버텍스 파마슈티칼스 인코포레이티드|Process for making modulators of cystic fibrosis transmembrane conductance regulator|

ES2441446T3|2009-05-07|2014-02-04|Gea Pharma Systems Limited|Pill production module and method for continuous pill production|

US8053866B2|2009-08-06|2011-11-08|Freescale Semiconductor, Inc.|Varactor structures|

CA2772792A1|2009-09-17|2011-03-24|Vertex Pharmaceuticals Incorporated|Process for preparing azabicyclic compounds|

BR112012008036A2|2009-10-08|2016-03-01|Ge Healthcare Ltd|chromatographic purification, optical uv flow cell, end cap for a chromatography column, chromatography column, method for operating a chromatography column, cassette device, method for operating a cassette device, purification system, and method for form an optical uv flow cell|

EP2813227A1|2009-10-22|2014-12-17|Vertex Pharmaceuticals Incorporated|Compositions for treatment of cystic fibrosis and other chronic diseases|

RU2553989C2|2009-10-23|2015-06-20|Вертекс Фармасьютикалз Инкорпорейтед|Method for obtaining modulators of cystic fibrousis transmembrane conductance regulator|

NZ599703A|2009-10-23|2014-06-27|Vertex Pharma|Solid forms of n--2-trifluoromethyl)phenyl)-4-oxo-5--1,4-dihydroquinoline-3-carboxamide|

US8802700B2|2010-12-10|2014-08-12|Vertex Pharmaceuticals Incorporated|Modulators of ATP-Binding Cassette transporters|

CN201586570U|2010-02-03|2010-09-22|兰州大学|Plastic centrifugal filtration tube|

US8471029B2|2010-03-19|2013-06-25|Vertex Pharmaceutical Incorporated|Solid forms of N-[2,4-bis-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide|

US8802868B2|2010-03-25|2014-08-12|Vertex Pharmaceuticals Incorporated|Solid forms of -1-N--1H-Indol-5-yl)-Cyclopropanecarboxamide|

MX347804B|2010-03-25|2017-05-15|Vertex Pharmaceuticals Incorporated |Solid forms of -1 -n--6-fluoro-2--1h-indol-5-yl) cyclopropanecarboxamide.|

RS54783B1|2010-04-07|2016-10-31|Vertex Pharma|Solid forms of 3- cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid|

MX364937B|2010-04-07|2019-05-15|Vertex Pharmaceuticals Incorporated Star|Pharmaceutical compositions of 3- cyclopropanecarboxamido)-3-methylpyriodin-2-yl)benzo ic acid and administration thereof.|

WO2011133751A2|2010-04-22|2011-10-27|Vertex Pharmaceuticals Incorporated|Process of producing cycloalkylcarboxamido-indole compounds|

WO2011133953A1|2010-04-22|2011-10-27|Vertex Pharmaceuticals Incorporated|Pharmaceutical compositions and administrations thereof|

CA2796646A1|2010-04-22|2011-10-27|Vertex Pharmaceuticals Incorporated|Pharmaceutical compositions and administrations thereof|

WO2011133951A1|2010-04-22|2011-10-27|Vertex Pharmaceuticals Incorporated|Pharmaceutical compositions and administrations thereof|

US8404849B2|2010-05-20|2013-03-26|Vertex Pharmaceuticals|Processes for producing modulators of cystic fibrosis transmembrane conductance regulator|

CA2798412A1|2010-05-20|2011-11-24|Vertex Pharmaceuticals Incorporated|Pharmaceutical compositions and administrations thereof|

US8563593B2|2010-06-08|2013-10-22|Vertex Pharmaceuticals Incorporated|Formulations of -1--N--6-fluoro-2--1H-indol-5-yl)cyclopropanecarboxamide|

MX2013002035A|2010-08-23|2013-03-25|Vertex Pharma|Pharmaceutical composition of -1--n--6-fluoro-2--1h-indol-5-yl) cyclopropanecarboxamide and administration therof.|

EP2608775A2|2010-08-27|2013-07-03|Vertex Pharmaceuticals Incorporated|Pharmaceutical composition and administrations thereof|

CN102058889A|2010-11-05|2011-05-18|王定豪|Dispersible tablet containing anticoagulants and application thereof|

CN102507770A|2011-10-25|2012-06-20|中国检验检疫科学研究院|High performance liquid chromatography for detecting hexachlorophene in cosmetics|

AU2012332225A1|2011-11-02|2014-05-15|Vertex Pharmaceuticals Incorporated|Use of - 5 - hydroxyphenyl] - 1, 4 - dihydro - 4 - oxoquinoline - 3 - ca rboxamide) for treating CFTR mediated diseases|

ES2622154T3|2011-11-08|2017-07-05|Vertex Pharmaceuticals Incorporated|Atp-binding cassette conveyor modulators|

PL2806859T3|2012-01-25|2019-11-29|Vertex Pharma|Formulations of 3- cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid|

AU2013226076B2|2012-02-27|2017-11-16|Vertex Pharmaceuticals Incorporated|Pharmaceutical composition and administration thereof|

US8674108B2|2012-04-20|2014-03-18|Vertex Pharmaceuticals Incorporated|Solid forms of N-[2,4-bis-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide|

JP2013253790A|2012-06-05|2013-12-19|Chube Univ|Analytical method of nivalenol|

AU2013270681A1|2012-06-08|2014-12-18|Vertex Pharmaceuticals Incorporated|Pharmaceutical compositions for the treatment of CFTR -mediated disorders|

US9012496B2|2012-07-16|2015-04-21|Vertex Pharmaceuticals Incorporated|Pharmaceutical compositions of -1--N--6-fluoro-2--1H-indol-5-yl)cyclopropanecarboxamide and administration thereof|

CN102788834B|2012-08-29|2015-06-03|浙江农林大学|Method for quickly measuring soluble sugar in fruit|

US20140092376A1|2012-10-01|2014-04-03|Momentive Performance Materials, Inc.|Container and method for in-line analysis of protein compositions|

ES2694290T3|2012-11-02|2018-12-19|Vertex Pharmaceuticals Incorporated|Pharmaceutical compositions for the treatment of diseases mediated by CFTR|

US20140127901A1|2012-11-08|2014-05-08|Taiwan Semiconductor Manufacturing Company, Ltd.|Low-k damage free integration scheme for copper interconnects|

US9636301B2|2012-12-04|2017-05-02|Arbutus Biopharma Corporation|In vitro release assay for liposome encapsulated vincristine|

US20140221424A1|2013-01-30|2014-08-07|Vertex Pharmaceuticals Incorporated|Pharmaceutical compositions for use in the treatment of cystic fibrosis|

CN103264029B|2013-05-06|2015-03-25|深圳市华星光电技术有限公司|Washing device and washing method of chromatographing sample bottles|

CN103743826B|2013-08-28|2015-12-02|合肥久诺医药科技有限公司|A kind of HPLC analytical method of Azilsartan|

CN103822976B|2013-10-15|2015-05-27|辽宁省食品药品检验所|Method for measuring 4-potassium methoxysalicylate in cosmetics|

CN110840847A|2014-04-15|2020-02-28|沃泰克斯药物股份有限公司|Pharmaceutical compositions for the treatment of cystic fibrosis transmembrane conductance regulator mediated diseases|

CN104090038B|2014-07-07|2015-09-30|黄宏南|A kind of method of Chinese caterpillar fungus polysaccharide peptide content in direct mensuration Cordyceps sinensis product|

CN104122345B|2014-07-31|2015-08-12|国家烟草质量监督检验中心|The assay method of 1,1,1-trimethylolpropane in cigarette paper using|

CN104122346B|2014-07-31|2016-03-16|国家烟草质量监督检验中心|The assay method of urea content in a kind of water base adhesive|

AU2015330923B2|2014-10-07|2020-03-12|Vertex Pharmaceuticals Incorporated|Co-crystals of modulators of cystic fibrosis transmembrane conductance regulator|

WO2016086136A1|2014-11-26|2016-06-02|Catabasis Pharmaceuticals, Inc.|Fatty acid cysteamine conjugates of cftr modulators and their use in treating medical disorders|

MA41031A|2014-11-26|2017-10-03|Catabasis Pharmaceuticals Inc|CYSTEAMINE-FATTY ACID CONJUGATES AND THEIR USE AS AUTOPHAGIC ACTIVATORS|

WO2016087665A2|2014-12-05|2016-06-09|Centre National De La Recherche Scientifique |Compounds for treating cystic fibrosis|

CA2974900A1|2015-01-26|2016-08-04|Rigel Pharmaceuticals, Inc.|Tetrazolones as carboxylic acid bioisosteres|

UY36680A|2015-05-19|2016-12-30|Glaxosmithkline Ip Dev Ltd|HETEROCYCLIC AMIDES AS QUINASA INHIBITORS|

CN105890945A|2016-04-01|2016-08-24|中国热带农业科学院分析测试中心|Ultrasonic centrifuged seepage sample injecting method for quickly measuring rapidly available potassium in soil|MX341797B|2004-06-24|2016-09-02|Vertex Pharmaceuticals Incorporated |Modulators of atp-binding cassette transporters.|

KR20150041174A|2005-11-08|2015-04-15|버텍스 파마슈티칼스 인코포레이티드|Heterocyclic modulators of ATP-binding cassette transporters|

NZ596889A|2006-04-07|2013-06-28|Vertex Pharma|Use of amide indole derivatives as modulators of ATP-binding cassette transporters|

US8802868B2|2010-03-25|2014-08-12|Vertex Pharmaceuticals Incorporated|Solid forms of -1-N--1H-Indol-5-yl)-Cyclopropanecarboxamide|

MX364937B|2010-04-07|2019-05-15|Vertex Pharmaceuticals Incorporated Star|Pharmaceutical compositions of 3- cyclopropanecarboxamido)-3-methylpyriodin-2-yl)benzo ic acid and administration thereof.|

AU2013226076B2|2012-02-27|2017-11-16|Vertex Pharmaceuticals Incorporated|Pharmaceutical composition and administration thereof|

CN110840847A|2014-04-15|2020-02-28|沃泰克斯药物股份有限公司|Pharmaceutical compositions for the treatment of cystic fibrosis transmembrane conductance regulator mediated diseases|

CA3037986A1|2016-09-30|2018-04-05|Vertex Pharmaceuticals Incorporated|Modulator of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator|

PT3551622T|2016-12-09|2020-11-12|Vertex Pharma|Modulator of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator|

WO2018227049A1|2017-06-08|2018-12-13|Vertex Pharmaceuticals Incorporated|Methods of treatment for cystic fibrosis|

EP3697774A1|2017-10-19|2020-08-26|Vertex Pharmaceuticals Incorporated|Crystalline forms and compositions of cftr modulators|

TW201944994A|2018-02-05|2019-12-01|美商維泰克斯製藥公司|Pharmaceutical compositions for treating cystic fibrosis|

WO2019161078A1|2018-02-15|2019-08-22|Vertex Pharmaceuticals Incorporated|Macrocycles as modulators of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions thereof, their use in the treatment of cycstic fibrosis, and process for making them|

法律状态:
2019-01-22| B65X| Notification of requirement for priority examination of patent application|

2019-02-12| B65Y| Grant of priority examination of the patent application (request complies with dec. 132/06 of 20061117)|

2019-02-26| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

2019-05-21| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

2019-06-11| B07A| Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]|

2019-11-12| B07A| Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]|

2020-03-10| B09B| Patent application refused [chapter 9.2 patent gazette]|

2020-06-23| B12B| Appeal against refusal [chapter 12.2 patent gazette]|

2021-03-09| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 18/11/2015, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

申请号 | 申请日 | 专利标题

US201462081181P| true| 2014-11-18|2014-11-18|

US62/081,181|2014-11-18|

PCT/US2015/061264|WO2016081556A1|2014-11-18|2015-11-18|Process of conducting high throughput testing high performance liquid chromatography|

[返回顶部]