US20140018398A1 - Otamixaban formulations with improved stability - Google Patents
Otamixaban formulations with improved stability Download PDFInfo
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- US20140018398A1 US20140018398A1 US14/008,343 US201214008343A US2014018398A1 US 20140018398 A1 US20140018398 A1 US 20140018398A1 US 201214008343 A US201214008343 A US 201214008343A US 2014018398 A1 US2014018398 A1 US 2014018398A1
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- PFGVNLZDWRZPJW-XESZBRCGSA-N COC(=O)C(CC1=CC(C(=N)N)=CC=C1)[C@@H](C)NC(=O)C1=CC=C(C2=CC=[N+]([O-])C=C2)C=C1 Chemical compound COC(=O)C(CC1=CC(C(=N)N)=CC=C1)[C@@H](C)NC(=O)C1=CC=C(C2=CC=[N+]([O-])C=C2)C=C1 PFGVNLZDWRZPJW-XESZBRCGSA-N 0.000 description 1
- OJOKVVILBSUTSB-OPAMFIHVSA-N COC(=O)[C@H](CC1=CC(C(N)=O)=CC=C1)[C@@H](C)NC(=O)C1=CC=C(C2=CC=[N+]([O-])C=C2)C=C1 Chemical compound COC(=O)[C@H](CC1=CC(C(N)=O)=CC=C1)[C@@H](C)NC(=O)C1=CC=C(C2=CC=[N+]([O-])C=C2)C=C1 OJOKVVILBSUTSB-OPAMFIHVSA-N 0.000 description 1
- UINHDROFOVENTH-QVKFZJNVSA-N C[C@@H](NC(=O)C1=CC=C(C2=CC=[N+]([O-])C=C2)C=C1)[C@@H](CC1=CC(C(=N)N)=CC=C1)C(=O)O Chemical compound C[C@@H](NC(=O)C1=CC=C(C2=CC=[N+]([O-])C=C2)C=C1)[C@@H](CC1=CC(C(=N)N)=CC=C1)C(=O)O UINHDROFOVENTH-QVKFZJNVSA-N 0.000 description 1
- PLMYNNRPMDSPCH-XRKZMFMDSA-I I[V](I)I.I[V]I.[C-]#[N+]C1=CC=CC(CC(C(=O)OC)[C@@H](C)NC(=O)C2=CC=C(C3=CC=NC=C3)C=C2)=C1.[C-]#[N+]C1=CC=CC(CC(C(=O)OC)[C@@H](C)NC(=O)C2=CC=C(C3=CC=[N+]([O-])C=C3)C=C2)=C1 Chemical compound I[V](I)I.I[V]I.[C-]#[N+]C1=CC=CC(CC(C(=O)OC)[C@@H](C)NC(=O)C2=CC=C(C3=CC=NC=C3)C=C2)=C1.[C-]#[N+]C1=CC=CC(CC(C(=O)OC)[C@@H](C)NC(=O)C2=CC=C(C3=CC=[N+]([O-])C=C3)C=C2)=C1 PLMYNNRPMDSPCH-XRKZMFMDSA-I 0.000 description 1
- FNXSXMRWRPIPCW-GBWXFZKJSA-K I[V]I.O=C(O)C1=CC=C(C2=CC=NC=C2)C=C1.O=C(O)C1=CC=CC=C1.[C-]#[N+]C1=CC=CC(CC(C(=O)OC)[C@@H](C)N)=C1.[C-]#[N+]C1=CC=CC(CC(C(=O)OC)[C@@H](C)NC(=O)C2=CC=C(C3=CC=NC=C3)C=C2)=C1.[V].[V]I Chemical compound I[V]I.O=C(O)C1=CC=C(C2=CC=NC=C2)C=C1.O=C(O)C1=CC=CC=C1.[C-]#[N+]C1=CC=CC(CC(C(=O)OC)[C@@H](C)N)=C1.[C-]#[N+]C1=CC=CC(CC(C(=O)OC)[C@@H](C)NC(=O)C2=CC=C(C3=CC=NC=C3)C=C2)=C1.[V].[V]I FNXSXMRWRPIPCW-GBWXFZKJSA-K 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4425—Pyridinium derivatives, e.g. pralidoxime, pyridostigmine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- the present invention relates to pharmaceutical compositions comprising methyl (2R,3R)-2- ⁇ 3-[amino(imino)methyl]benzyl ⁇ -3- ⁇ [4-(1-oxidopyridin-4-yl)benzoyl]amino ⁇ butanoate or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable acidic reacting compound or to an aqueous solution or dispersion of said to composition, as well as a process for the preparation of the same, methods of using said compositions to treat subjects suffering from conditions which can be ameliorated by the administration of an inhibitor of Factor Xa.
- Methyl (2R,3R)-2- ⁇ 3-[amino(imino)methyl]benzyl ⁇ -3- ⁇ [4-(1-oxidopyridin-4-yl)benzoyl]amino ⁇ butanoate (CAS number 193153-04-7) has the international nonproprietary name Otamixaban and shows the structure illustrated in Formula I:
- Factor Xa is the penultimate enzyme in the coagulation cascade.
- Factor Xa (fXa) is a critical serine protease situated at the confluence of the intrinsic and extrinsic pathways of the blood coagulation cascade.
- FXa catalyses the conversion of prothrombin to thrombin via the prothrombinase complex. Its singular role in thrombin generation, coupled with its potentiating effects on clot formation render it an attractive
- Both free factor Xa and factor Xa assembled in the prothrombinase complex are inhibited by Otamixaban.
- Factor Xa inhibition is obtained by direct complex formation between the inhibitor and the enzyme and is therefore independent of the plasma co-factor antithrombin III.
- Effective factor Xa inhibition is achieved by administering the compound either by continuous intravenous infusion, bolus intravenous administration or any other parenteral route such that it achieves the desired effect of preventing the factor Xa induced formation of thrombin from prothrombin.
- Otamixaban is highly efficacious in rodent, canine and porcine models of thrombosis.
- Otamixaban induces dose-dependent, rapid direct factor Xa inhibition in patients with stable coronary artery disease who are taking their usual comedication, some of whom have mild renal impairment (Hinder et al., Clinical Pharmacology and Therapeutics, Vol. 80, No. 6, 2006, pages 691-702).
- the other of said degradants is (2R,3R)-2-(3-Carbamoyl-benzyl)-3-[4-(1-oxy-pyridin-4-yl) benzoylamino]-butyric acid methyl ester and has the structure illustrated in Formula III:
- It is an object of the present invention to find a long term stable pharmaceutical composition for methyl (2R,3R)-2- ⁇ 3-[amino(imino)methyl]benzyl ⁇ -3- ⁇ [4-(1-oxidopyridin-4-yl)benzoyl]amino ⁇ butanoate which does not have the disadvantages of increased concentrations of (2R,3R)-2-(3-Carbamimidoyl-benzyl)-3-[4-(1-oxy-pyridin-4-yl) benzoylamino]-butyric acid or (2R,3R)-2-(3-Carbamoyl-benzyl)-3-[4-(1-oxy-pyridin-4-yl) benzoylamino]-butyric acid methyl ester which occur during terminal sterilization or long term storage.
- liquid pharmaceutical compositions for methyl (2R,3R)-2- ⁇ 3-[amino(imino)methyl]benzyl ⁇ -3- ⁇ [4-(1-oxidopyridin-4-yl)benzoyl]amino ⁇ butanoate or a pharmaceutically acceptable salt thereof with a pH below 5 are advantageous with respect to limiting the increase in both (2R,3R)-2-(3-Carbamimidoyl-benzyl)-3-[4-(1-oxy-pyridin-4-yl) benzoylamino]-butyric acid and (2R,3R)-2-(3-Carbamoyl-benzyl)-3-[4-(1-oxy-pyridin-4-yl) benzoylamino]-butyric acid methyl ester, influenced oppositely by autoclaving or long term storage.
- a pH below 5 provides the clear advantage of the pharmaceutical compositions according to the invention which are (i) long term stable pharmaceutical compositions and (II) sterile injection solutions by autoclavation (steam sterilization), which is a simple, economic and safe method for sterilization.
- the present invention provides a pharmaceutical composition of methyl (2R,3R)-2- ⁇ 3-[amino(imino)methyl]benzyl ⁇ -3- ⁇ [4-(1-oxidopyridin-4-yl)benzoyl]amino ⁇ butanoate or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable acidic reacting compound.
- the present invention provides also a sterile pharmaceutical composition of methyl (2R,3R)-2- ⁇ 3-[amino(imino)methyl]benzyl ⁇ -3- ⁇ [4-(1-oxidopyridin-4-yl)benzoyl]amino ⁇ butanoate or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable acidic reacting compound.
- the present invention provides a pharmaceutical composition of methyl (2R,3R)-2- ⁇ 3-[amino(imino)methyl]benzyl ⁇ -3- ⁇ [4-(1 -oxidopyridin-4-yl)benzoyl]amino ⁇ butanoate or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable acidic reacting compound.
- “Pharmaceutically acceptable acidic reacting compound” refer to a non-toxic compound capable of imparting a pH below 5 to an aqueous solution or dispersion of methyl (2R,3R)-2- ⁇ 3-[amino(imino)methyl]benzyl ⁇ -3- ⁇ [4-(1-oxidopyridin-4-yl)benzoyl]amino ⁇ butanoate or a pharmaceutically acceptable salt thereof.
- Illustrative acidic reacting compounds are citric acid, acetic acid, glycolic acid, adipic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, glucuronic acid, fumaric acid, malic acid, tartaric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, hyaluronic acid, acetyl salicylic acid, or mineral acids such as hydrochloride acid or salts of mineral acids such as potassium dihydrogen phosphate or amino acids like glycine and its salts or a mixture of one or more of said acidic reacting compounds.
- the acidic reacting compound is citric acid.
- a pharmaceutically acceptable acidic reacting compound for imparting a pH below 5 to an aqueous solution or dispersion of methyl (2R,3R)-2- ⁇ 3-[amino(imino)methyl]benzyl ⁇ -3- ⁇ [4-(1-oxidopyridin-4-yl)benzoyl]amino ⁇ butanoate or a pharmaceutically acceptable salt thereof depends on the respective compound and can be determined by a person skilled in the art by e.g.
- Buffer solution is an aqueous solution consisting of a mixture of a weak acid and its conjugate base or a weak base and its conjugate acid. It has the property that the pH of the solution changes very little when a small amount of strong acid or base is added to it. Buffer solutions are used as a means of keeping pH at a nearly constant value in a wide variety of chemical applications.
- Degradant refers to any drug-based materials generated after the preparation of the pharmaceutical composition according to the invention. Analysis of impurities and degradants is done using reverse phase HPLC techniques on samples as is known in the art.
- Freeze-drying also known as “lyophilization” refers to a dehydration process. Freeze-drying works by freezing the material and then reducing the surrounding pressure and adding enough heat to allow the frozen water in the material to sublime directly from the solid phase to the gas phase.
- i. v. refers to intravenous injection or infusion and is the giving of liquid substances directly into a vein.
- the word intravenous simply means “within a vein”.
- Long term refers to 1 to 3 months.
- Long term storage refers to storage of a pharmaceutical composition for 1 to 3 months at 40° C. and 75% relative humidity.
- “Very long term” refers to 3 to 6 months.
- “Very long term storage” refers to storage of a pharmaceutical composition for 3 to 6 months at 40° C. and 75% relative humidity.
- mL refers to the milliliter, defined as one-thousandth of a liter, and also often referred to by the SI derived unit name cubic centimeter.
- non-ST elevation myocardial infarction refers to the definition of Myocardial Infarction based on ACC/AHA, ESC and WHF consensus; see also Guidelines for the diagnosis and treatment of non-ST segment elevation acute coronary syndromes; Eur Heart J, 2007, 28(13): 1598-1660.
- Normal saline or “isotonic saline” refers to an aqueous solution of 0.9% of sodium chloride, having an osmolarity of about 308 mOsmol/L, which shows about the same osmolarity as blood plasma.
- “Otamixaban” refers to the international nonproprietary name for methyl (2R,3R)-2- ⁇ 3-[amino(imino)methyl]benzyl ⁇ -3- ⁇ [4-(1-oxidopyridin-4-yl)benzoyl]amino ⁇ butanoate.
- “Patient” means primates such as humans or a warm blooded animal, such as for example rat, mice, dogs, cats or guinea pigs.
- Phathological condition refers to diseases, disorders or conditions in a patient, particularly those in which Factor Xa may play a role.
- pH is a measure of the acidity or basicity of a solution. It approximates but is not equal to p[H], the negative logarithm (base 10) of the molar concentration of dissolved hydrogen ions (H + ).
- pH determination in a solid pharmaceutical composition according to the invention is performed by suspending or dissolving a sample containing about 1 mg of Otamixaban of said pharmaceutical composition in about 1 mL of purified water. The pH of the supernatant is determined with a pH meter or by a pH indicator. pH can be measured using either pH indicators such as phenolphthaleine—in form of solution or pH strips—or using potentiometric method. Strips are very useful when 0.2 to 0.5 pH unit accuracy is requested.
- pH meter is the only way to go.
- Potential of the pH electrode depends on the activities of hydronium ions. This dependence is described by Nernst equation, thus once the potential has been measured the activity can be calculated. As a first approximation activity is identical to the ions concentration.
- pH meter is a device used for potentiometric pH measurements. pH meter is nothing else but precise voltmeter, connected to the pH electrode, and scaled in such a way that it displays not the measured potential, but already the pH value.
- “Pharmaceutically acceptable salt” is any acid salt of the base compound methyl (2R,3R)-2- ⁇ 3-[amino(imino)methyl]benzyl ⁇ -3- ⁇ [4-(1-oxidopyridin-4-yl)benzoyl]amino ⁇ butanoate which is able to be administered in pharmaceutical compositions for preclinical and clinical use.
- Illustrative inorganic acids which form suitable salts include mineral acids, such as hydrochloric acid, phosphoric acid and sulfamic acid; and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, benzoate, amino acids and the like.
- the acid addition salt is derived from a mineral acid, with hydrochloric acid being preferred.
- RH refers to relative humidity; the relative humidity of an air-water mixture is defined as the ratio of the partial pressure of water vapor in the mixture to the saturated vapor pressure of water at a prescribed temperature.
- “Sterilization” refers to any process that effectively kills or eliminates transmissible agents such as fungi, bacteria, viruses or spore forms from the pharmaceutical composition. Sterilization can be achieved e.g. through application of heat, chemicals, irradiation, high pressure or filtration or a combination thereof.
- Steam sterilization refers to a widely-used method for heat sterilization in an autoclave. Autoclaves commonly use steam heated to 121° C. to 134° C. To achieve sterility, an effective holding time of at least 15 minutes at 121° C. or 3 minutes at 134° C. is required. Proper autoclave treatment will inactivate all fungi, bacteria, viruses and also bacterial spores, which can be quite resistant.
- “Sterilization through filtration” refers to a method generally used for liquids that would be damaged by heat, irradiation or chemical sterilization. A filter with pore size 0.2 ⁇ m will effectively remove bacteria. If viruses must also be removed, a much smaller pore size around 20 nm is needed.
- “Therapeutically effective amount” means an amount of the compound, which is effective in treating the named disorder or condition.
- “Tonicity” means a measure of the osmotic pressure (as defined by the water potential of the two solutions) of two solutions which are separated by a semi permeable membrane. It is commonly used when describing the response of living cells immersed in an external solution. Like osmotic pressure, tonicity is influenced only by the solutes that cannot cross the membrane, as only these exert an osmotic pressure. Solutes able to freely cross the membrane do not affect tonicity because they will after some time be in equal concentrations on both sides of the membrane.
- Treat” or “treating” means any treatment, including, but not limited to, alleviating symptoms, eliminating the causation of the symptoms either on a temporary or permanent basis, or preventing or slowing the appearance of symptoms and progression of the named disorder or condition.
- acidic reacting compounds are organic acids such as citric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, hyaluronic acid, acetyl salicylic acid, cinnamic acid, salicyclic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid and sulfonic acids such as methanesulfonic acid and 2-hydroxyethanesulfonic acid or its salts or a mixture of one or more of said organic acids and its salts.
- organic acids such as citric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid,
- acidic reacting compounds are mineral acids such as hydrochloride acid or phosphoric acid or salts of mineral acids such as potassium dihydrogen phosphate, or amino acids and its salts or a mixture of one or more of said mineral acids or amino acids and its salts.
- the acidic reacting compound is citric acid or sodium citrate or a mixture thereof.
- an acidic reacting compound to Otamixaban creates a pH from about pH 3 to about pH 4.5, or from about pH 3.7 to about pH 4.3, about pH 3.8 to about pH 4.3, or from about pH 4.0 to about pH 4.2 or of about pH 4.0 in the pharmaceutical composition according to the invention.
- the pH determination is performed after taken a sample from said pharmaceutical composition. The pH is determined with a pH meter or by a pH indicator.
- the invention relates to an aqueous pharmaceutical composition containing from 0.8 mg/mL to 30 mg/mL (2R,3R)-2- ⁇ 3-[amino(imino) methyl]benzyl ⁇ -3- ⁇ [4-(1-oxidopyridin-4-yl)benzoyl]amino ⁇ butanoate, or from 0.9 mg/mL to 26 mg/mL, or from 0.9 mg/mL to 6 mg/mL.
- the invention relates to an aqueous pharmaceutical composition containing from 2.0 mg/mL to 30 mg/mL (2R,3R)-2- ⁇ 3-[amino(imino)methyl]benzyl ⁇ -3- ⁇ [4-(1-oxidopyridin-4-yl)benzoyl]amino ⁇ butanoate, or from 2.0 mg/mL to 25 mg/mL, or from 16 mg/mL to 25 mg/mL or from 3.0 mg/mL to 6 mg/m L.
- the invention relates to an aqueous pharmaceutical composition wherein a buffer solution is used as an acidic reacting compound which is capable of imparting a pH below 5.0 to an aqueous solution or dispersion of the composition of methyl (2R,3R)-2- ⁇ 3-[amino(imino)methyl]benzyl ⁇ -3- ⁇ [4-(1-oxidopyridin-4-yl)benzoyl]amino ⁇ butanoate or a pharmaceutically acceptable salt thereof.
- a buffer solution is used as an acidic reacting compound which is capable of imparting a pH below 5.0 to an aqueous solution or dispersion of the composition of methyl (2R,3R)-2- ⁇ 3-[amino(imino)methyl]benzyl ⁇ -3- ⁇ [4-(1-oxidopyridin-4-yl)benzoyl]amino ⁇ butanoate or a pharmaceutically acceptable salt thereof.
- a buffer solution to Otamixaban creates a pH from about pH 3 to about pH 5.0, or from about pH 3 to about pH 4.7, or from about pH 3.5 to about pH 4.6 or from about pH 3.6 to about pH 4.3, from about pH 3.6 to about pH 4.2, or from about pH 3.6 to about pH 4.1 in the aqueous pharmaceutical composition.
- suitable buffers contain buffering substances such as citric acid and its sodium or potassium salt, phosphoric acid and its sodium or potassium salt or hydrogen phosphate, or dibasic sodium phosphate, acetic acid and its sodium salt, lactic acid and its salts, succinic acid and its salts, tartaric acid and its salts, ascorbic acid and its salts, aspartic acid and its salts, benzoic acid and its salts, adipic acid and its salts, glucuronic acid and its salts, or mineral acids such as hydrochloride acid or salts, amino acids and its salts like glycine or serine or mixtures of such buffering substances.
- Preferred examples are mixtures of citric acid and sodium citrate. Examples of such mixtures are citric acid with sodium citrate (monosodium citrate, di-sodium citrate) and citric acid or potassium dihydrogen phosphate and hydrogen phosphate.
- the concentration of the buffer solution which creates a pH below 5.0 in an aqueous pharmaceutical composition is from 1 mMol/L to 1000 mMol/L or from 20 mMol to 25 mMol, or from 4 mMol to 6 mMol.
- additional tonicity adjuster could be added to the liquid pharmaceutical preparation according to the invention to receive a solution showing an osmolarity from 260 mOsmol/L to 350 mOsmol/L or of about 308 mOsmol/L, which has about the same or similar osmolarity as blood plasma.
- tonicity adjuster are salts such as sodium chloride or sugars like glucose or sugar alcohols like mannitol. In case of sterilization by autoclaving salts or sugar alcohols such as mannitol are preferred.
- concentration for salts can be from 0 mg/mL to 20 mg/mL, dependent on the concentration of Otamixaban and of the acidic reacting compound.
- concentration for glucose or sugar alcohols like mannitol can be from 0 mg/mL to about 60 mg/mL, dependent on the concentration of Otamixaban and of the acidic reacting compound.
- the tonicity of the whole solution shall not exceed and osmolarity from 260 mOsmol/L to 350 mOsmol/L.
- Aqueous pharmaceutical compositions according to the invention may be prepared by incorporating methyl (2R,3R)-2- ⁇ 3-[amino(imino)methyl]benzyl ⁇ -3- ⁇ [4-(1-oxidopyridin-4-yl)benzoyl]amino ⁇ butanoate or a pharmaceutically acceptable salt thereof, and an acidic reacting compound in the respective required amounts, in water with various of the other ingredients enumerated herein, as required, followed by mixture for an appropriate time.
- the invention relates to a sterile pharmaceutical composition of methyl (2R,3R)-2- ⁇ 3-[amino(imino)methyl]benzyl ⁇ -3- ⁇ [4-(1-oxidopyridin-4-yl)benzoyl]amino ⁇ butanoate or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable acidic reacting compound in an aqueous solution or a dispersion of the composition.
- the invention relates to a sterile aqueous pharmaceutical composition of methyl (2R,3R)-2- ⁇ 3-[amino(imino)methyl]benzyl ⁇ -3- ⁇ [4-(1-oxidopyridin-4-yl)benzoyl]amino ⁇ butanoate or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable acidic reacting compound and water at a pH below 5.0 or a dispersion of the composition.
- Sterile pharmaceutical composition can be prepared by sterilization the pharmaceutical composition according to the invention.
- Sterilization refers to any process that effectively kills or eliminates transmissible agents such as fungi, bacteria, viruses or spore forms from the pharmaceutical composition. Sterilization can be achieved through application of heat, chemicals, irradiation, high pressure or filtration.
- Steam sterilization is a preferred method of sterilization and refers to method for heat sterilization in an autoclave. Autoclaves commonly use steam heated to 121° C. to 134° C. To achieve sterility, a holding time of at least 15 minutes at 121° C. or 3 minutes at 134° C. is required. Additional sterilizing time may be required for liquids and instruments if the vials with the solution or powder are additionally packed in layers of cloth, as they may take longer to reach the required temperature.
- Sterile liquid pharmaceutical composition according to the invention may be prepared by incorporating methyl (2R,3R)-2- ⁇ 3-[amino(imino)methyl]benzyl ⁇ -3- ⁇ [4-(1-oxidopyridin-4-yl)benzoyl]amino ⁇ butanoate or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable acidic reacting compound, in the required amounts, in water, and optionally with various of the other ingredients enumerated herein, as required, followed by sterilization. Sterilization can be achieved through application of heat, chemicals, irradiation, high pressure or filtration.
- dispersions may be prepared by incorporating the sterilized methyl (2R,3R)-2- ⁇ 3-[amino(imino)methyl]benzyl ⁇ -3- ⁇ [4-(1-oxidopyridin-4-yl)benzoyl]amino ⁇ butanoate or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable acidic reacting compound into a sterile vehicle which contains the dispersion medium and the other ingredients enumerated herein.
- Powders for injections or infusions are solid, sterile substances or mixtures of substances including methyl (2R,3R)-2- ⁇ 3-[amino(imino)methyl]benzyl ⁇ -3- ⁇ [4-(1-oxidopyridin-4-yl)benzoyl]amino ⁇ butanoate and a pharmaceutically acceptable acidic reacting compound, distributed in their final containers and which, when shaken with the prescribed volume of a prescribed sterile liquid rapidly form clear and practically particle-free solutions. After dissolution, they comply with the requirements for injections or for infusions.
- the mixing of the substances can be carried out using any of the mixing techniques known in the art.
- Freeze-dried products for parenteral use are considered as powders for injections or infusions.
- the Otamixaban and a pharmaceutically acceptable acidic reacting compound and optionally further components of the pharmaceutical composition according to the invention can be mixed as powders.
- This mixing can be carried out using any of the mixing techniques known in the art.
- the mixing is preferably carried out using a high shear mixer, V-blender (or other twin-shell blender), bin blender or Turbula mixer-shaker. Blending is typically carried out for sufficient time to assure complete mixing. Once the blend is made the solid form is prepared by procedures known in the art.
- the preferred methods of preparation may include vacuum drying and the freeze drying technique which may yield a powder of the methyl (2R,3R)-2- ⁇ 3-[amino(imino)methyl]benzyl ⁇ -3- ⁇ [4-(1-oxidopyridin-4-yl)benzoyl]amino ⁇ butanoate or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable acidic reacting compound and optionally plus any additional ingredients enumerated herein such as from the previously sterile-filtered solution or steam sterilized solution thereof.
- Sterilization of the prepared powder can be achieved through application of heat, chemicals or irradiation. Steam sterilization is a preferred method of sterilization and refers to method for heat sterilization in an autoclave. The powder is sterilized in an appropriate vial or vehicle.
- the sterile powder can be stored until a sterile injectable solution is prepared by adding a pre-sterilized appropriate solvent such as water followed by mixing of the composition. It is also possible to add a pre-sterilized appropriate solvent and store the prepared liquid pharmaceutical composition.
- the invention relates to an aqueous pharmaceutical composition for injection containing a maximum impurity level of (2R,3R)-2-(3-Carbamimidoyl-benzyl)-3-[4-(1-oxy-pyridin-4-yl)benzoylamino]-butyric acid that does not exceed about 8.0% after long term storage.
- the maximum impurity level of (2R,3R)-2-(3-Carbamimidoyl-benzyl)-3[4-(1-oxy-pyridin-4-yl) benzoylamino]-butyric acid is from 0.3% to 4.0%, or from 0.4% to 3.0%, or from 0.4% to 1.8%, or from 0.4% to 0.8%, or from 0.43% to 0.7%.
- the invention relates to an aqueous pharmaceutical composition for injection containing a maximum impurity level of (2R,3R)-2-(3-Carbamoyl-benzyl)-3-[4-(1-oxy-pyridin-4-yl)benzoylamino]-butyric acid methyl ester that does not exceed about 5.0% after long term storage.
- the maximum impurity level of (2R,3R)-2-(3-Carbamoyl-benzyl)-3-[4-(1-oxy-pyridin-4-yl) benzoylamino]-butyric acid methyl ester is from 0.7% to 4.5%, or from 0.8% to 4.0%, or from 0.9% to 3.5%, or from 1.2% to 2.2%, or from 1.4% to 2.0%.
- the invention relates to an aqueous pharmaceutical composition for injection containing a maximum total impurity level that does not exceed about 13%.
- the total impurity level is from 1.0% to 8.5%, or from 1.1% to 8.0%, or from 1.3% to 6.0%, or from 1.6% to 4.0%, or from 1.8% to 3.5%.
- the relative amounts of methyl (2R,3R)-2- ⁇ 3-[amino(imino)methyl]benzyl ⁇ -3- ⁇ [4-(1-oxidopyridin-4-yl)benzoyl]amino ⁇ butanoate and acid counterion in its salts may vary and depends, for example, on the particular acid selected and the methods employed in preparing the salts.
- the salts of the present invention comprise about one equivalent of acid for about each equivalent of methyl (2R,3R)-2- ⁇ 3-[amino(imino)methyl]benzyl ⁇ -3- ⁇ [4-(1-oxidopyridin-4-yl)benzoyl]amino ⁇ butanoate.
- the acid addition salts of (methyl (2R,3R)-2- ⁇ 3-[amino(imino)methyl]benzyl ⁇ -3- ⁇ [4-(1-oxidopyridin-4-yl)benzoyl]amino ⁇ butanoate may be prepared by dissolving the free base in aqueous or aqueous-alcohol solution or other suitable solvents containing the appropriate acid or to which the appropriate acid is added, and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt may separate directly and/or may be obtained by concentration of the solution.
- compositions of the present invention may be useful in inhibiting Factor Xa. Accordingly, the present invention provides methods for the treatment or prevention of a pathological condition that may be capable of being modulated by inhibiting production of Factor Xa.
- pathological conditions examples include, for example, acute myocardial infarction (AMI), non-ST elevation myocardial infarction, unstable angina, thromboembolism, acute vessel closure associated with thrombolytic therapy, percutaneous transluminal coronary angioplasty (PTCA), transient ischemic attacks, stroke, intermittent claudication, and restenosis.
- AMI acute myocardial infarction
- non-ST elevation myocardial infarction unstable angina
- thromboembolism acute vessel closure associated with thrombolytic therapy
- PTCA percutaneous transluminal coronary angioplasty
- transient ischemic attacks stroke, intermittent claudication, and restenosis.
- compositions described herein thus may be useful for, inter alia, inhibiting blood coagulation by virtue of their general ability to inhibit the penultimate enzyme in the coagulation cascade, Factor Xa, rather than thrombin.
- compositions within the scope of the present invention may exhibit marked pharmacological activities according to tests described in the literature, including in vivo tests and in vitro tests, the latter of which are believed to correlate to pharmacological activity in humans and other mammals.
- both free Factor Xa and Factor Xa assembled in the prothrombinase complex (Factor Xa, Factor Va, calcium and phospholipid) may be inhibited.
- Factor Xa inhibition may be obtained by direct complex formation between the inhibitor and the enzyme and is therefore independent of the plasma co-factor antithrombin III.
- Effective Factor Xa inhibition may be achieved by administering the pharmaceutical composition according to the invention by continuous intravenous infusion, bolus intravenous administration or any other suitable route such that it may achieve the desired effect of preventing the Factor Xa induced formation of thrombin from prothrombin.
- Factor Xa inhibitors may be useful in the treatment or prevention of other diseases in which the generation of thrombin may play a pathologic role.
- thrombin has been proposed to contribute to the morbidity and mortality of such chronic and degenerative diseases as arthritis, cancer, atherosclerosis and Alzheimer's disease by virtue of its ability to regulate many different cell types through specific cleavage and activation of a cell surface thrombin receptor. Inhibition of Factor Xa may effectively block thrombin generation and therefore neutralize any pathologic effects of thrombin on various cell types.
- the injectable aqueous pharmaceutical composition may be delivered intravenously in a specific dosage form.
- Said dosage form may be delivered in an intravenous infusion dose.
- suitable infusion doses of methyl (2R,3R)-2- ⁇ 3-[amino(imino)methyl]benzyl ⁇ -3- ⁇ [4-(1-oxidopyridin-4-yl)benzoyl]amino ⁇ butanoate may range from 0.07 mg/Kg body weight/h to 0.14 mg/Kg body weight/h. Further suitable doses may range from 0.08 mg/Kg body weight/h to 0.12 mg/Kg body weight/h. Said dosage form may also be delivered in an intravenous bolus dose.
- suitable infusion doses of methyl (2R,3R)-2- ⁇ 3-[amino(imino)methyl]benzyl ⁇ -3- ⁇ [4-(1-oxidopyridin-4-yl)benzoyl]amino ⁇ butanoate may range from 0.07 mg/Kg body weight to 0.14 mg/Kg body weight.
- a suitable dose balancing patient safety and efficacy will be a dose close to 0.1 mg/kg body weight/h after i.v. bolus of approximately 0.08 mg/kg body weight.
- Said injectable dosage form may be administrated with other drug products such as glycoprotein IIb/IIa inhibitors, unfractionated heparin, low molecular weight heparins, enoxaparin, or clopidogrel.
- said injectable dosage form may be combined with blood thinners including, but not limited to, coumadin, warfarin, or aspirin.
- Liquid injectable pharmaceutical compositions according to the invention may be prepared by incorporating methyl (2R,3R)-2- ⁇ 3-[amino(imino)methyl]benzyl ⁇ -3- ⁇ [4-(1-oxidopyridin-4-yl)benzoyl]amino ⁇ butanoate or a pharmaceutically acceptable salt thereof and an acidic reacting compound or buffer in the required amounts, in water, with optionally various of the other ingredients enumerated herein, as required, followed by mixing for an appropriate time.
- Liquid pharmaceutical compositions may also contain other components routinely utilized in formulating pharmaceutical compositions.
- One example of such components is lecithin.
- Its use in compositions of the invention as an emulsifying agent may range from about 0.05 to about 1% by weight, and all combinations and subcombinations of ranges and specific amounts therein. More preferably, emulsifying agents may be employed in an amount of from about 0.1 to about 0.5% by weight.
- Other examples of components that may be used are antimicrobial preservatives, such as benzoic acid or parabens; suspending agents, such as Polysorbate 80. The selection of such optional components and their level of use in the compositions of the invention is within the level of skill in the art and will be even better appreciated from the working examples provided hereinafter.
- water, a suitable oil, saline, and glycols, such as propylene glycol or polyethylene glycols may be suitable solvents for liquid pharmaceutical compositions.
- suitable solutions for liquid pharmaceutical compositions may be prepared by dissolving methyl (2R,3R)-2- ⁇ 3-[amino(imino)methyl]benzyl ⁇ -3- ⁇ [4-(1-oxidopyridin-4-yl)benzoyl]amino ⁇ butanoate or a pharmaceutically acceptable salt thereof and an acidic reacting compound in the solvent and, if necessary, adding buffering substances.
- Anti-oxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid either alone or combined, may be additionally added.
- Sodium EDTA may also be employed.
- a parenteral composition suitable for administration by injection may be prepared by stirring from 1 mg to 30 mg/mL by weight of methyl (2R,3R)-2- ⁇ 3-[amino(imino)methyl]benzyl ⁇ -3- ⁇ [4-(1-oxidopyridin-4-yl)benzoyl]amino ⁇ butanoate, or a pharmaceutically acceptable salt thereof, in 1 mL to 200 mL of water and adding under mixing from 2 mg/mL to 4 mg mL by weight of sodium citrate and from 2 mg/mL to 4 mg/mL of citric acid monohydrate and 5 mg/mL to 8 mg/mL sodium chloride. Finally the pH is adjusted to pH 4 by the addition of sodium hydroxide or hydrochloric acid.
- the prepared solution is filtered and filled in an appropriate vial.
- the solution and the vial are sterilized by steam sterilization in an autoclave.
- Autoclaves commonly use steam heated to 121° C. to 134° C. To achieve sterility, a holding time of at least 15 minutes can be used.
- TsOH is p-Toluenesulfonic acid with the formula CH 3 C 6 H 4 SO 3 H.
- TsOH refers to the monohydrate.
- Compound (IV) 100.0 g
- THF anhydrous tetrahydrofuran
- the resulting suspension was cooled down to ⁇ 20 ⁇ 3° C. and lithium hexamethyldisilazide (LiHMDS) (475.6 grams, 1.3 M solution in THF) was added over 55 minutes and stirred for 20 minutes at ⁇ 20 ⁇ 3° C.
- LiHMDS lithium hexamethyldisilazide
- the liquid pharmaceutical composition was prepared as follows:
- the pH value was adjusted using sodium hydroxide solution (e.g. 1 M sodium hydroxide) or hydrochloric acid, diluted (e.g. 1 M hydrochloric acid). Water for injection was added to adjust the final weight.
- sodium hydroxide solution e.g. 1 M sodium hydroxide
- hydrochloric acid e.g. 1 M hydrochloric acid
- Solution from step II was filtered using a sterilized membrane filter (e.g. polyvinylidene difluoride, polyether sulfone or polyamide) having a nominal pore size of 0.2 ⁇ m.
- a sterilized membrane filter e.g. polyvinylidene difluoride, polyether sulfone or polyamide
- injection vials were then closed with sterilized flip-off caps with inserted sealing discs or with injection stoppers and flanged caps with tear-off lids.
- the filtration equipment (as a part of the equipment with direct product contact), the injection stoppers, and the flip-off caps with inserted sealing discs were sterilized by steam, e.g. ⁇ 121° C. for at least 15 minutes (Ph.Eur./USP).
- composition of the liquid pharmaceutical composition prepared is given in Table 1:
- Liquid pharmaceutical compositions were prepared containing 1 mg/mL Otamixaban as described in Example 5. The appropriate pH value was adjusted by using sodium hydroxide solution (1 M sodium hydroxide) or diluted hydrochloric acid (1 M hydrochloric acid).
- the terminal sterilization was carried out in an autoclave at standard conditions of ⁇ 15 min./ ⁇ +121° C.
- the gradient may be shortened for the analysis of the standards and the system suitability tests (not for blank!) in the following way:
- Liquid pharmaceutical compositions were prepared containing 1, 5 or 50 mg/mL Otamixaban as described in Example 5.
- the appropriate pH value was adjusted by using sodium hydroxide solution (1 M sodium hydroxide) or diluted hydrochloric acid (1 M hydrochloric acid).
- Liquid pharmaceutical compositions were prepared containing 1 mg/mL Otamixaban as described in Example 5. The appropriate pH value was adjusted by using sodium hydroxide solution (1 M sodium hydroxide) or diluted hydrochloric acid (1 M hydrochloric acid). The prepared vials were autoclaved one time and were stored at 40° C. and 75% RH (relative humidity).
- Liquid pharmaceutical compositions were prepared containing 1 mg/mL Otamixaban basically as described in Example 5. Instead of citric acid monohydrate and sodium citrate dihydrate as used in Example 5, tartaric acid, succinic acid, malic acid and phosphoric acid were used at a level of 22.8 mMol/L. For comparison, samples without acidic reacting compound were included also. The appropriate pH value was adjusted in all samples (including also the “without” samples) by using sodium hydroxide solution (1 M sodium hydroxide) or diluted hydrochloric acid (1 M hydrochloric acid). The prepared vials were autoclaved once and were stored at 40° C. and 75% RH (relative humidity).
- the terminal sterilization was carried out in an autoclave at standard conditions of ⁇ 15 min./ ⁇ +121° C.
- Liquid pharmaceutical compositions were prepared containing 1 mg/mL Otamixaban as described in Example 9. Citric acid was used at a level of 22.8 mmol/L. The appropriate pH value was adjusted by using sodium hydroxide solution (1 M sodium hydroxide) or diluted hydrochloric acid (1 M hydrochloric acid). The prepared vials were autoclaved once and were stored at 40° C. and 75% RH (relative humidity).
- Liquid pharmaceutical compositions were prepared containing 1 mg/mL Otamixaban basically as described in Example 5. Instead of citric acid monohydrate and sodium citrate dihydrate as used in Example 5, tartaric acid, succinic acid, malic acid, citric acid and phosphoric acid were used at a level of 22.8 mMol/L. For comparison, samples without acidic reacting compound were included also. The appropriate pH value was adjusted by using sodium hydroxide solution (1 M sodium hydroxide) or diluted hydrochloric acid (1 M hydrochloric acid). The prepared vials were autoclaved once and twice by terminal sterilization. The terminal sterilization was carried out in an autoclave at standard conditions of ⁇ 15 min./ ⁇ +121° C.
- the levels for Formula III are higher than for Formula II and increase in a about linear dependency from the number of autoclaving.
- the levels of impurity for Formula II and Formula III depend on the pH of the tested liquid pharmaceutical composition and are independent on the used acidic reacting compound.
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US15/265,191 US9993464B2 (en) | 2011-03-29 | 2016-09-14 | Otamixaban formulations with improved stability |
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US14/008,343 US20140018398A1 (en) | 2011-03-29 | 2012-03-27 | Otamixaban formulations with improved stability |
PCT/EP2012/055361 WO2012130819A1 (fr) | 2011-03-29 | 2012-03-27 | Formulations d'otamixaban ayant une stabilité améliorée |
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EP (1) | EP2691075A1 (fr) |
JP (1) | JP5993933B2 (fr) |
KR (1) | KR101844623B1 (fr) |
CN (1) | CN103561723B (fr) |
AR (1) | AR085580A1 (fr) |
AU (1) | AU2012234323A1 (fr) |
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CA (1) | CA2830962C (fr) |
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EA (1) | EA025572B1 (fr) |
IL (1) | IL228573A (fr) |
MA (1) | MA35050B1 (fr) |
MX (1) | MX342324B (fr) |
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US20160079828A1 (en) * | 2013-07-03 | 2016-03-17 | Schaeffler Technologies AG & Co. KG | Bearing arrangement in an electric motor |
US9993464B2 (en) | 2011-03-29 | 2018-06-12 | Sanofi | Otamixaban formulations with improved stability |
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SG11201505953TA (en) | 2013-01-31 | 2015-08-28 | Vertex Pharma | Pyridone amides as modulators of sodium channels |
CA3073127A1 (fr) | 2017-08-16 | 2019-02-21 | Merck Patent Gmbh | Lyophilisats stables comprenant de l'acide 5,10-methylene-(6r)-tetrahydrofolique et un acide dicarboxylique |
CN109010273B (zh) * | 2018-10-08 | 2021-03-19 | 中国药科大学 | 一种阿哌沙班纳米混悬剂及其制备方法 |
CN113384526A (zh) * | 2021-08-03 | 2021-09-14 | 合肥医工医药股份有限公司 | 一种稳定的阿哌沙班口服溶液制剂及其制备方法 |
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EP1500393A1 (fr) | 1992-11-27 | 2005-01-26 | Mayne Pharma (USA) Inc. | Composition injectable de taxol |
SK284507B6 (sk) | 1996-01-02 | 2005-05-05 | Aventis Pharmaceuticals Inc. | Substituované N-[(aminoiminometyl)fenyl]propylamid alebo N-[(aminometyl)fenyl]propylamid, farmaceutický prostriedok s jeho obsahom a použitie |
US6080767A (en) | 1996-01-02 | 2000-06-27 | Aventis Pharmaceuticals Products Inc. | Substituted n-[(aminoiminomethyl or aminomethyl)phenyl]propyl amides |
GB0108903D0 (en) * | 2000-10-05 | 2001-05-30 | Aventis Pharm Prod Inc | Novel crystalline forms of a factor Xa inhibitor |
US20050059719A1 (en) * | 2003-09-16 | 2005-03-17 | Badawy Sherif Ibrahim Farag | Solid dosage formulation containing a Factor Xa inhibitor and method |
FR2863891B1 (fr) * | 2003-12-23 | 2006-03-24 | Pf Medicament | Composition pharmaceutique de vinflunine destinee a une administration parentale, procede de preparation et utilisation |
AU2010277725B2 (en) * | 2009-07-29 | 2016-08-18 | Sanofi | Otamixaban for treatment of elderly and renal impaired non-ST elevation myocardial infarction patients |
US20140018398A1 (en) | 2011-03-29 | 2014-01-16 | Sanofi | Otamixaban formulations with improved stability |
CN103562183B (zh) | 2011-03-29 | 2015-12-23 | 赛诺菲 | 奥米沙班的苯甲酸盐 |
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- 2012-03-27 EP EP12710516.1A patent/EP2691075A1/fr not_active Withdrawn
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9993464B2 (en) | 2011-03-29 | 2018-06-12 | Sanofi | Otamixaban formulations with improved stability |
US20160079828A1 (en) * | 2013-07-03 | 2016-03-17 | Schaeffler Technologies AG & Co. KG | Bearing arrangement in an electric motor |
Also Published As
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CN103561723B (zh) | 2016-04-20 |
CA2830962C (fr) | 2019-06-18 |
MA35050B1 (fr) | 2014-04-03 |
IL228573A0 (en) | 2013-12-31 |
KR20140019818A (ko) | 2014-02-17 |
CO6801755A2 (es) | 2013-11-29 |
EP2691075A1 (fr) | 2014-02-05 |
JP5993933B2 (ja) | 2016-09-14 |
EA025572B1 (ru) | 2017-01-30 |
BR112013024801A2 (pt) | 2016-12-20 |
AU2012234323A1 (en) | 2013-10-17 |
US20170224668A1 (en) | 2017-08-10 |
WO2012130819A1 (fr) | 2012-10-04 |
CA2830962A1 (fr) | 2012-10-04 |
US20120252852A1 (en) | 2012-10-04 |
MX342324B (es) | 2016-09-23 |
SG193932A1 (en) | 2013-11-29 |
KR101844623B1 (ko) | 2018-04-02 |
US9993464B2 (en) | 2018-06-12 |
CN103561723A (zh) | 2014-02-05 |
IL228573A (en) | 2017-12-31 |
AR085580A1 (es) | 2013-10-09 |
EA201391406A1 (ru) | 2014-02-28 |
JP2014509621A (ja) | 2014-04-21 |
NZ616180A (en) | 2015-10-30 |
MX2013011260A (es) | 2014-03-27 |
UY33975A (es) | 2012-10-31 |
ZA201308061B (en) | 2015-01-28 |
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