• 专利附录
  • 专利说明
  • 权利要求
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  • 同族专利
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    • 专利摘要:
    COMPOSITION FOR THE TREATMENT OF CYSTIC FIBROSIS. The present invention provides compositions comprising a prostacyclin or prostacyclin analog, or a pharmaceutically acceptable salt thereof for use in preventing or treating cystic fibrosis. The invention also provides for the use of a kit comprising a prostacyclin or prostacyclin analog to treat or prevent a condition associated with cystic fibrosis in a subject.
    公开号:BR112012002578B1
    申请号:R112012002578-3
    申请日:2010-08-05
    公开日:2021-01-12
    发明作者:Michael Freissmuth；Christina Gloeckel；Xaver Koenig
    申请人:Scipharm Sàrl；
    IPC主号:
    专利说明:

    [0001] The present invention relates to compositions comprising a prostacyclin or prostacyclin analog or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of cystic fibrosis.
    [0002] [002] Cystic fibrosis (CF) is a genetic disease resulting from mutations in a 230 kb gene on chromosome 7 encoding a 1480 amino acid polypeptide known as the cystic fibrosis transmembrane conductance regulator (CFTR), which serves as a chloride in the epithelial membranes. More than 1000 mutant alleles have been identified to date. The most common mutation, ΔF508, is the elimination of a phenylalanine residue in codon 508 of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. This mutation results in a severe reduction in CFTR function, and leads to the classic phenotype of cystic fibrosis characterized by abnormalities in the functions of exocrine glands, such as increased sweat chloride, recurrent respiratory infections with bronchiectasis, and early-onset pancreatic insufficiency.
    [0003] [003] Clinically, CF is usually suspected when one or more typical phenotypic characteristics of CF are present in an individual. This could be a chronic lung disease alone or very often associated with gastrointestinal and nutritional changes (eg, pancreatic insufficiency and recurrent pancreatitis), salt loss syndromes and male urogenital anomalies (ie, obstructive azoospermia). In the human lung, thick, tenacious secretions obstruct the distal airways and submucosal glands, which express CFTR. The ductular dilatation of these glands (associated with mucus obstruction) and the thickening of airway surfaces by thick, viscous, mucopurulent debris, dominated by neutrophils, are among the pathological features of the disease. Pulmonary inflammation is another major cause of the decline in respiratory function in individuals with cystic fibrosis and may precede the onset of chronic infection. Mucinous impaction and thick concretions within the pancreatic ducts lead to chronic fibrosis, fatty gland replacement, or both, in a large subgroup of individuals with a previous diagnosis of idiopathic or alcoholic pancreatitis.
    [0004] [004] Cystic fibrosis is the most common inherited fatal disease in the Caucasian population, affecting about 4 in 10,000 children. In the United States, the average age of death increased from 8.4 years of age in 1969 to 14.3 years of age in 1998. The average age of death increased from 14 years in 1969 to 32.4 years of age in 2003 ( Cystic Fibrosis Foundation). For children born in the 1990s, the average survival is expected to be over 40 years. One of the main contributors to the significant increase in life expectancy is the improved treatment of chronic respiratory tract infections and the elimination of mucus in individuals with CF, as well as better nutrition and early diagnosis.
    [0005] [005] Loss of anion conductance of the cystic fibrosis transmembrane conductance regulator (CFTR) of apical membranes of the airway epithelium interrupts the regulation of the liquid layer of the airway surface. This leads to compromised mucociliary transport, airway infections and inflammation characteristic of cystic fibrosis (CF). The common DF508 CFTR mutation is present in at least one allele in> 90% of CF patients, and> 50% of patients are homozygous for ΔF508, the remainder being heterozygous. A central issue in CF disease is the inability of this common CFTR variant to reach the native, folded state that will leave the endoplasmic reticulum (ER) and traffic to the apical membrane of epithelial cells.
    [0006] [006] If the acquisition of the native conformation is delayed, it is believed that CFTR maintains excessive or prolonged interactions with molecular chaperones, which then target the protein for degradation by mechanisms that monitor the RE in relation to deformed or incompletely complexed proteins. Degradation associated with RE (ERAD) involves the ubiquitination of anomalous proteins and their delivery to the proteasome for digestion. If ERAD is below the rate of protein synthesis, or during treatment with proteasome inhibitors, aggregates of the mutant protein accumulate. CFTR was the first integral membrane protein in mammals to be identified as a substrate for proteasome-mediated ubiquitin degradation, and has served as a model for the growing list of protein-forming diseases, which account for a diverse set of pathological etiologies.
    [0007] [007] Essentially all CFTR ΔF508 produced by the cell are destroyed by ERAD. In addition, due to its complex folding pattern, 60-70% of the wild-type (wt) protein can be equally degraded, although this can vary between cell types. The proteolytic cleavage patterns of immature forms of wt and CFTR ΔF508 are similar, while the digestion pattern of mature wt CFTRs is different. This finding supports the concept that at least a part of the mutant CFTR retained by ER is present in an intermediate conformation that is formed along the normal CFTR fold path, as opposed to the formation of a variant protein structure. For CFTR ΔF508, this intermediate conformation cannot proceed beyond a critical step in the folding process, but this implies that CFTR ΔF508 could be rescued if it were possible to facilitate this step. A variety of experimental conditions, such as reduced temperature, incubation with chemical chaperones, or pharmacological correctors, can promote the escape of CFTR ΔF508 from the ER, generating a functional anion channel on the cell surface. In addition, the researchers reported restoring CFTR ΔF508 function by co-expressing several partial CFTR constructs or subdomains from CFT wt. However, a consensus that CFTR subdomains are effective in rescuing mutant protein is not apparent, and the mechanism of this effect remains unclear. In addition, rescue induced by CFTR fragments has been observed mainly in cells exogenously overexpressing both the CFTR fragment and the complete CFTR ΔF508.
    [0008] [008] Prostaglandin I2 (prostacyclin; epoprostenol, PGI2) is a metabolite of oxygenated arachidonic acid enzymatically formed by the sequential activities of cyclooxygenase and PGI synthase enzymes. It is produced constitutively by vascular endothelial and smooth muscle cells and is induced in inflammatory conditions in vascular and macrophage cells.
    [0009] [009] PGI2 is a potent vasodilator and antithrombotic agent, the effects of which result from binding to a single heptahelical G receptor coupled to the protein called prostanoid I (IP) 4 receptor. This receptor is coupled to Gs- and activates adenylate cyclase, resulting in an acute burst of intracellular cAMP. Since the expression of CFTR and mutant CFTR is dependent on cAMP-dependent, substances that increase intracellular levels of cAMP are of interest for the development of drugs for the treatment of CF. Most of these substances, such as forskolin, however, induce a very unspecific elevation of cAMP, which can also have very harmful effects, such as inflammation. Thus, there is an unmet need for specific cAMP promoters in the lung epithelial cells.
    [0010] [0010] Treprostinil is a potent IP receptor agonist, although its specificity for this receptor is unknown. Sprague R.S. et al. 2008, showed that Prostacyclin analogs (UT-15, Remodulin) stimulate receptor-mediated cAMP synthesis and ATP release from rabbit and human erythrocytes.
    [0011] [0011] WO 08/098196 describes the treatment of pulmonary fibrosis using Treprostinil. Pulmonary fibrosis, however, is an interstitial lung disease, which is caused by the accumulation of collagen fibers in the lung, which restricts the lung's ability to inhale air: the lung loses its conformity and increases airway resistance ( compliance = 1 / resistance). As the disease progresses, there is also an increase in vascular resistance. The site of action of Treprostinil in pulmonary fibrosis is vascularization and the interstitial space in the alveoli.
    [0012] [0012] Tissieres et al. describe studies with iloprost for the treatment of a patient with cystic fibrosis and secondary pulmonary hypertension. Aerolyzed iloprost is reported to be effective in reducing pulmonary artery pressure (The Annals of Thoracic Surgery, vol, 78, no.3, E48-E50).
    [0013] [0013] US2001 / 006979 A1 describes the use of prostacyclin derivatives such as iloprost or cicaprost for the treatment of fibrotic diseases.
    [0014] [0014] Cystic fibrosis is not related to pulmonary fibrosis, because it is a disease that originates in the bronchial epithelium. Due to the absence of CFTR, there is very little water in the mucus that covers the bronchial epithelium and, consequently, the cilia cannot move the thick mucus and the mucociliary removal is interrupted (the mucociliary removal works like a treadmill, where the lashes beat rhythmically in a concentrated manner to move the mucus back into the trachea and pharynx, from where they can be eliminated by swallowing or coughing, etc.) If mucociliary removal is interrupted, the bacteria cannot be removed from the bronchi, the bronchi are colonized by bacteria and repeated outbreaks of lung infections that destroy the lung occur. The situation can be remedied by restoring CI flows to the bronchial epithelium. Thus, in cystic fibrosis the site of action is the epithelium of the bronchial airways. The site of action is anatomically distinct (pulmonary interstitium versus bronchial airways), involves a different set of cells (fibroblasts, vascular smooth muscle cells, endothelium versus bronchial epithelial cells of absorption and secretion) and, presumably, also involves different receptors ( prostacyclin receptor vs possibly EP2 receptor).
    [0015] [0015] Currently, no cystic fibrosis treatment is available that significantly improves patients' quality of life over a long period. Therefore, it is an object of the invention to provide compositions for treatment that can increase the expression of CFTR ΔF508 and / or channel chloride function in lung epithelial cells. Brief description of the invention:
    [0016] [0016] The purpose of the invention is achieved by providing a composition comprising a prostacyclin or analog, a derivative or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of cystic fibrosis.
    [0017] [0017] According to a specific embodiment of the invention the prostacyclin analog is selected from the group of Treprostinil, Iloprost, Cisaprost or Beraprost or pharmaceutically acceptable salts thereof.
    [0018] [0018] More specifically, the Treprostinil derivative can be selected from the group of acid derivatives, prodrugs, sustained release forms, inhaled forms, oral forms, polymorphs or isomers of Treprostinil.
    [0019] [0019] The composition of the invention can be administered intravenously, inhalation, or it can be available orally selected from the group of tablets or capsules.
    [0020] [0020] Specifically, the composition comprises an effective amount of Treprostinil or its derivatives, or a pharmaceutically acceptable salt thereof that is at least 1.0 ng / kg of body weight / min.
    [0021] [0021] Furthermore, according to the present invention the use of a kit to treat or prevent a condition associated with cystic fibrosis in an individual, which includes (i) an effective amount of a prostacyclin or prostacyclin analog or derivative or a pharmaceutically acceptable salt thereof, specifically a pharmaceutically acceptable salt of Treprostinil, (ii) one or more pharmaceutically acceptable carriers and / or additives, and (iii) instructions for use in the treatment or prevention of cystic fibrosis is also provided. Figures:
    [0022] [0022] Figure 1: Accumulation of cAMP in IB3-1 cells after incubation with Treprostinil
    [0023] [0023] Figure 2: Activation of a Cl current by Treprostinil in the human bronchial epithelial cell line IB3-1 transiently expressing CFTR-wt. Detailed description of the invention
    [0024] [0024] It has been surprisingly discovered by the inventors that prostacyclin or analogs or derivatives or a pharmaceutically acceptable salt thereof can be used for the treatment of cystic fibrosis. Analogs of synthetic prostacyclin can be, for example, but are not limited to, Treprostinil, Iloprost, Cisaprost or Beraprost.
    [0025] [0025] Suitable prostacyclin derivatives include, but are not limited to, acid derivatives, prodrugs, sustained release forms, inhaled forms and oral forms of Treprostinil, Iloprost, Cisaprost or Beraprost.
    [0026] [0026] A pharmaceutically acceptable salt of prostacyclin or a prostacyclin analog of this invention can be formed between an acidic and basic group of the compound, such as a functional amino group, or a base and an acidic group of the compound, such as a functional carboxyl group. . According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt.
    [0027] [0027] Specifically, Treprostinil or its derivatives is useful according to the invention. Treprostinil can successfully improve the expression of CFTR DF508 and / or the function of the chloride channel in the epithelial cells of the lung of patients with cystic fibrosis.
    [0028] [0028] Specifically, physiologically acceptable salts of Treprostinil include salts derived from bases. Base salts include ammonium salts (such as quaternary ammonium salts), alkali metal salts, such as alkaline earth metal salts of sodium and potassium, such as calcium and magnesium, salts with organic bases, such as dicyclohexylamine and N-methyl-D-glucamine, and salts with amino acids such as arginine and lysine.
    [0029] [0029] It has been surprisingly shown that prostacyclin or analogues or derivatives thereof lead to the stimulation of cAMP production in bronchoepithelial cells. This mode of action can be through the induced activation of the IP receiver. Interestingly, the phosphodiesterase inhibitor (PDE3 inhibitor), Anagrelide, did not induce any accumulation of cAMP in experiments.
    [0030] [0030] Given this ability to stimulate the production of cAMP through the IP receptor, and the limited presence of IP receptors to a small number of cell types (such as lung epithelial cells), prostacyclin or its analog, for example For example, Treprostinil or a derivative or salt thereof could induce the expression and spread of mutant CFTR and CFTR in a specific way, it can be used for the treatment of CF.
    [0031] The present invention, therefore, also relates to a composition comprising prostacyclin or a prostacyclin analog, specifically Treprostinil or its derivatives, or a pharmaceutically acceptable salt thereof for use in the treatment of cystic fibrosis, as well as in therapies of cystic fibrosis using a prostacyclin or prostacyclin analog, specifically Treprostinil or its derivatives, or a pharmaceutically acceptable salt thereof.
    [0032] [0032] Treprostinil is a synthetic prostacyclin analog. Treprostinil is marketed as Remodulin ™. Treprostinil is a monosodium salt of acid (1R, 2R, 3aS, 9aS) - [[2,3,3a, 4,9,9a-hexahydro-2-hydroxy-1 - [(3S) -3-hydroxyoctyl] -1 / - / - benz [f] inden-5-yl] oxy] acetic.
    [0033] [0033] According to the invention, Treprostinil derivatives can be, for example, Treprostinil acid derivatives, Treprostinil prodrugs, sustained forms of Treprostinil release, inhaled forms of Treprostinil, oral forms of Treprostinil, Treprostinil polymorphs or Treprostinil isomers.
    [0034] [0034] The composition of the invention can be present in any form that can be used for administration.
    [0035] [0035] The composition of the invention can be administered as a liquid or powder. It can be administered topically, intravenously, subcutaneously, by inhalation or using a nebulizer, or in oral form available as tablets or capsules. Due to the high metabolic stability of some prostacyclin analogs like Treprostinil, or if supplied as lipid-based or pegylated forms of prostacyclins or prostacyclin analogs, the substances can also be administered as drug stores.
    [0036] [0036] Aerosol delivery of the prostacyclin analog can result in a more homogeneous distribution of the agent in a lung, so that deep delivery to the lung is achieved. Thus, the application dosage can be reduced to the sustained presence of the agent at the site of action in the lung.
    [0037] [0037] The composition can be administered with any pharmaceutically acceptable substances or vehicles or excipients, as known in the art. These can be, for example, but are not restricted to water, neutralizing agents such as NaOH, KOH, stabilizers, DMSO, saline, betaine, taurine, etc.
    [0038] [0038] The term "pharmaceutically acceptable" means approved by a federal or state government regulatory body, or listed in the USA.
    [0039] [0039] The term "vehicle" refers to a diluent, adjuvant, excipient or vehicle with which the pharmaceutical composition is administered. Saline solutions and aqueous dextrose and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions. Suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dry skimmed milk, glycerol, propylene, glycol, water , ethanol and the like. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E. W. Martin. The formulation must be selected according to the mode of administration.
    [0040] [0040] Treprostinil is of high metabolic stability, which specifically allows for administration by several routes.
    [0041] [0041] The amount of the inventive composition can be selected by any competent person, preferably the amount of prostacyclins or prostacyclin analogs or pharmaceutically acceptable salts, specifically Treprostinil is at least 1.0 ng / kg body weight / min.
    [0042] [0042] The invention further provides a kit to treat or prevent a condition associated with cystic fibrosis in an individual, which includes (i) an effective amount of a prostacyclin or prostacyclin analog or derivative or a pharmaceutically acceptable salt thereof, (ii ) one or more pharmaceutically acceptable vehicles and / or additives, and (iii) instructions for use in the treatment or prevention of cystic fibrosis.
    [0043] [0043] According to the embodiment of the invention, the kit composed of (i) an effective amount of a prostacyclin or prostacyclin analog or a pharmaceutically acceptable salt thereof, (ii) one or more pharmaceutically acceptable vehicles and / or additives , and (iii) instructions for use in the treatment or prevention of cystic fibrosis are provided for use in the treatment or prevention of a condition associated with cystic fibrosis in an individual, preferably a human.
    [0044] [0044] Such component (i) may be in a form suitable for intravenous administration, for inhalation or for oral administration. Component (i) may be in a form suitable for intravenous, inhalation or oral administration.
    [0045] [0045] More specifically, the present invention provides the use of a kit comprising i) an effective amount of Treprostinil or a pharmaceutically acceptable salt thereof, (ii) one or more pharmaceutically acceptable carriers and / or additives, and (iii) instructions for use in the treatment or prevention of cystic fibrosis in the treatment or prevention of a condition associated with cystic fibrosis in an individual, preferably a human.
    [0046] [0046] Specifically, component (i) is a pharmaceutically acceptable salt of Treprostinil.
    [0047] [0047] According to a specific modality for the use of the kit, the component (i) is in a form suitable for intravenous administration or suitable for inhalation or suitable for oral administration.
    [0048] [0048] The examples described herein are illustrative of the present invention and are not intended to be limitations thereon. Different embodiments of the present invention have been described in accordance with the present invention. Many modifications and variations can be made to the techniques described and illustrated in this document, without departing from the spirit and scope of the invention. Thus, it should be understood that the examples are illustrative only and are not limiting the scope of the invention. Examples Example 1:
    [0049] [0049] IB3-1 cells were seeded in 6-well plates (0.2 * 106 cells / well) in complete growth medium (LHC-8 + 5% FCS). The next day, the adenine nucleotide pool was metabolically marked by incubation with [3H] adenine (1µCi / well) in Dulbecco's Modified Eagle Medium (DMEM), containing adenosine deaminase (1 unit / mL) for 4h. Formation of AMP cycle was stimulated by 20 µM forskolin or the PGI-2 analogue treprostinil (Remodulin®). The test was performed in triplicate. The formation of [3H] cAMP was determined by sequential chromatography on Dowex 50WX-4 and neutral alumina columns followed by liquid scintillation counting the eluate.
    [0050] [0050] Treprostinil caused an accumulation dependent on cAMP concentration in IB3-1 cells (Fig. 1). Mei-maximal stimulation was observed in the range of 0.3 to 1 µM. Example 2:
    [0051] [0051] IB3-1 cells endogenously express only mutated CFTRΔF508, which is retained inside the cells. Using appropriate manipulations (for example, pharmacochaperones or low temperature incubations), it is possible to translocate the mutant CFTR-ΔF508 from the endoplasmic reticulum to the ER, when inserted into the cell surface, a conductance of Cl can be stimulated by the elevation of cAMP. The resulting C1 conductance, however, is small. In order to prove unequivocally that Treprostinil-induced cAMP accumulation translated into CFTR activation, we transiently expressed a GFP-tagged version of wild-type CFTR (the GFP tag allowed the identification of cells that expressed the protein on the cell surface ). As can be seen in Figure 2, Treprostinil caused a strong activation of the current induced by a depolarization of the conservation potential from -40 mV to + 60 mV. The maximum effect was delayed, that is, it was only observed after several washes of the compound. Likewise, there was also a hysteresis in the reaction when switching off, the current dropped to just baseline ~ 100 s after purification. These delayed responses reflect the (i) intervening signaling cascade (i.e., receptor-dependent Gs activation, Gccs formation-dependent cAMP activation and subsequent protein kinase A-dependent CFTR phosphorylation) and (ii) deactivation delayed increase in cAMP by phosphodiesterases. Similar delays were also seen, if the cells were stimulated with forskolin, a direct adenylyl cyclase activator, which was used as a positive control. These observations prove that Treprostinil can activate CFTR in bronchial epithelial cells. Methods:
    [0052] [0052] Electrophysiology
    [0053] [0053] Whole cell membrane clamping technique was used for the present recordings made at 22 ± 1.5 ° C, using an Axoclamp 200B membrane clamping amplifier (Axon Instruments). The pipettes had resistances between 1 and 2 Mil when filled with the recording pipet solution (composition: 110 mM CsCI, 5 mM EGTA, 2 mM MgCI2, 1 mM K2.ATP, 10 mM Hepes, pH adjusted to 7.2 with CsOH). Voltage clamping protocols and data acquisition were performed with the software pclamp 6.0 (Axon Instruments). The data was filtered at a slow pace at 2 kHz (-3 dB) and digitized at 10-20 kHz. The cells were continuously superfused with external solution (composition: 145 mM NaCI, 4.5 mM KCI, 2 mM CaCI2, 1 mM MgCI2, 5 mM glucose, 10 mM Hepes, pH adjusted to 7.4 with NaOH). When indicated, the external solution contained Treprostinil (10 µM) or forskolin (5 µM), alternation between solutions was achieved through electronically controlled pressure valves.
    [0054] [0054] Cell Culture:
    [0055] [0055] I3B-1 cells were cultured in dishes (Nunc, 3.5 cm in diameter) covered with fibronectin (10 µg / mL) of rat collagen I (30 µg / mL) and BSA 10 µg / mL) in medium LHC-8 (Gibco) containing 5% fetal bovine serum (FCS). Cells were transiently transfected with a plasmid directing the expression of GFP-labeled human wild-type CFTR using Lipofectamine plus® (Invitrogen) according to the manufacturer's instructions.
    [0056] [0056] Representative current amplitudes recorded in the whole cell membrane clamping configuration at + 60 mV. A transiently transfected IB3-1 cell expressing GFP-labeled wild-type CFTR was selected under fluorescent light and pinned for a conservation potential at -40 mV. Depolarization was induced by a voltage step to + 60 mV for 50 ms and the current amplitude was recorded. The Treprostinil wash (10 µM final concentration, TP) started at 50 s and ended in 125 s. Forskolin was purified at 275 s and removed at 375 s. The results are shown in Figure 2.
    权利要求:
    Claims (10)
    [0001]
    Use of Treprostinil or a derivative or a pharmaceutically acceptable salt thereof, characterized by the fact that it is for the preparation of a composition for the prevention or treatment of cystic fibrosis.
    [0002]
    Use, according to claim 1, characterized by the fact that the composition is for intravenous administration.
    [0003]
    Use according to claim 1, characterized by the fact that the composition is for inhalation.
    [0004]
    Use, according to claim 1, characterized by the fact that said composition is in an orally available form selected from the group of tablets or capsules.
    [0005]
    Use according to claim 1, characterized by the fact that the effective amount of Treprostinil or its derivatives, or a pharmaceutically acceptable salt thereof, is at least 1.0 ng / kg of body weight / min.
    [0006]
    Use of Treprostinil or a derivative or a pharmaceutically acceptable salt thereof, characterized by the fact that it is for the preparation of a kit to treat or prevent cystic fibrosis in an individual, which comprises (i) an effective amount of Treprostinil or a derivative, or a pharmaceutically acceptable salt thereof, (ii) one or more pharmaceutically acceptable vehicles and / or additives, and (iii) instructions for use in the treatment or prevention of cystic fibrosis.
    [0007]
    Use according to claim 6, characterized by the fact that component (i) is a pharmaceutically acceptable salt of Treprostinil.
    [0008]
    Use according to claim 6 or 7, characterized by the fact that component (i) is in a form suitable for intravenous administration.
    [0009]
    Use according to claim 6 or 7, characterized by the fact that component (i) is in a form suitable for inhalation.
    [0010]
    Use according to claim 6 or 7, characterized by the fact that component (i) is in a form suitable for oral administration.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    DE69840908D1|1997-03-14|2009-07-30|Toray Industries|COMPOSITION OF PROSTAGLANDIN I DERIVATIVES WITH DELAYED DELIVERY|
    WO2000002450A1|1998-07-08|2000-01-20|Fibrogen, Inc.|Method for treatment of fibrosis related diseases by the administration of prostacyclin derivatives|
    BR0212233A|2001-08-31|2004-10-05|Sucampo Ag|Chloride Channel Opener|
    US7550133B2|2002-11-26|2009-06-23|Alexza Pharmaceuticals, Inc.|Respiratory drug condensation aerosols and methods of making and using them|
    EP1628654B2|2003-05-22|2019-12-04|United Therapeutics Corporation|Compounds and methods for delivery of prostacyclin analogs|
    US20040265238A1|2003-06-27|2004-12-30|Imtiaz Chaudry|Inhalable formulations for treating pulmonary hypertension and methods of using same|
    US20080096915A1|2005-01-13|2008-04-24|Greenberg Traurig LLP|Compositions for the treatment of metabolic disorders|
    US7893050B2|2005-10-26|2011-02-22|Asahi Kasei Pharma Corporation|Fasudil in combination therapies for the treatment of pulmonary arterial hypertension|
    WO2007092343A2|2006-02-03|2007-08-16|Scidose Llc|Novel epoprostenol formulation and method of making thereof|
    EP2491932A3|2007-02-09|2012-12-12|United Therapeutics Corporation|Use of biomarkers for monitoring the course of treatment of a pulmonary disease upon treatment with treprostinil|CN104721825B|2009-06-12|2019-04-12|曼金德公司|With the diketopiperazine particle for determining specific surface area|
    EP2663313B1|2011-01-13|2018-08-08|SciPharm S.à r.l.|Method for enhancing engraftment of haematopoetic stem cells|
    UA113161C2|2011-02-07|2016-12-26|A COMPOSITION CONTAINING PROSTACYCLINE ANALOGUE AND PDE4 INHIBITOR FOR THE TREATMENT OF CYCLIDISIDOSIS|
    JP6542128B2|2013-01-11|2019-07-10|コルセア ファーマ インコーポレイテッド|Treprostinil Prodrugs|
    US9505737B2|2013-01-11|2016-11-29|Corsair Pharma, Inc.|Treprostinil derivative compounds and methods of using same|
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    法律状态:
    2017-10-10| B25G| Requested change of headquarter approved|Owner name: SCIPHARM SA RL (LU) |
    2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|
    2018-04-10| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2019-01-29| B07E| Notice 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 |
    2019-05-21| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|
    2020-10-27| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2021-01-12| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 10 (DEZ) ANOS CONTADOS A PARTIR DE 12/01/2021, OBSERVADAS AS CONDICOES LEGAIS. |
    2021-05-25| B16C| Correction of notification of the grant|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 05/08/2010 OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME ADI 5.529/DF |
    优先权:
    申请号 | 申请日 | 专利标题
    EP09167491|2009-08-07|
    EP09167491.1|2009-08-07|
    PCT/EP2010/061428|WO2011015630A1|2009-08-07|2010-08-05|Composition for the treatment of cystic fibrosis|
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