US20060106110A1 - Modified amino acid for the inhibition of platelet aggregation - Google Patents

Modified amino acid for the inhibition of platelet aggregation Download PDF

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US20060106110A1
US20060106110A1 US10/521,492 US52149205A US2006106110A1 US 20060106110 A1 US20060106110 A1 US 20060106110A1 US 52149205 A US52149205 A US 52149205A US 2006106110 A1 US2006106110 A1 US 2006106110A1
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platelet aggregation
modified amino
amino acid
cnac
pharmaceutically acceptable
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Simon Bateman
Moise Azria
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Priority to US10/521,492 priority Critical patent/US20060106110A1/en
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Priority to US12/169,184 priority patent/US20080280817A1/en
Priority to US13/327,129 priority patent/US8664211B2/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/23—Calcitonins
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/727—Heparin; Heparan
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
    • 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

Definitions

  • Platelet activation and aggregation are involved in unstable angina and acute myocardial infarction, in reocclusion following thrombolytic therapy and angioplasty, in transient ischemic attacks and in a variety of other cardiovascular disorders.
  • acute intervention such as angioplasty, or more chronically by the pathophysiological processes of atherosclerosis
  • platelets are activated to adhere to the damaged surface and to each other. This platelet activation, adherence and aggregation may lead to occlusive thrombus formation in the lumen of the blood.
  • aspirin has come into use as a prophylactic antithrombotic agent due its ability to inhibit platelet aggregation.
  • U.S. Pat. Nos. 5,773,647 ('647) and 5,866,536 ('536) describe compositions for the oral delivery of pharmacologically active agents with modified amino acids, such as N-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC), N-(10-[2-hydroxybenzoyl]aminodecanoic acid (SNAD), and N-(8-[2-hydroxybenzoyl]amino)caprylic acid (SNAC).
  • WO 00/059863 discloses the disodium salts of formula I wherein
  • modified amino acids of '647, '536 and '863 are effective inhibitors of blood platelet aggregation.
  • pharmaceutical compositions employing the modified amino acids of '647, '536 and '863 as carriers for pharmacologically active agents have the added advantage of inhibiting blood platelet aggregation.
  • the present invention provides a method of inhibiting platelet aggregation in a mammal, preferably human, comprising the administration of a platelet aggregation inhibiting amount of a modified amino acid, or a pharmaceutically acceptable salt thereof.
  • the invention provides a method of inhibiting platelet aggregation in a mammal, preferably human, comprising the administration of a pharmaceutical composition comprising a platelet aggregation inhibiting amount of a modified amino acid or pharmaceutically acceptable salt thereof.
  • the present invention provides a method of inhibiting platelet aggregation in a mammal, preferably human, receiving a pharmacologically active agent comprising the administration of a pharmaceutical composition comprising said pharmacologically active agent and a modified amino acid or a pharmaceutically acceptable salt thereof, wherein the modified amino acid or salt thereof is present in an amount effective to inhibit platelet aggregation.
  • the invention is furthermore concerned with a method of inhibiting platelet aggregation in a mammal (preferably human) comprising administering a platelet aggregation inhibiting amount of N-(-5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC), or a pharmaceutically acceptable salt thereof, to said patient.
  • a mammal preferably human
  • administering a platelet aggregation inhibiting amount of N-(-5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC), or a pharmaceutically acceptable salt thereof, to said patient.
  • the invention provides a method of inhibiting platelet aggregation in a mammal, preferably human, comprising the administration of a pharmaceutical composition comprising a platelet aggregation inhibiting amount of 5-CNAC or pharmaceutically acceptable salt thereof.
  • the invention provides a method of inhibiting platelet aggregation in a mammal, preferably human, receiving a pharmacologically active agent comprising the administration of a pharmaceutical composition comprising said pharmacologically active agent and 5-CNAC or pharmaceutically acceptable salt thereof, wherein the 5-CNAC or salt thereof is present in an amount effective to inhibit platelet aggregation.
  • the platelet aggregation inhibition activity is a function of the modified amino acid.
  • Such platelet aggregation activity is not a function of the pharmacologically active agent.
  • the invention provides a method of inhibiting platelet aggregation in a mammal receiving heparin, insulin, parathyroid hormone or calcitonin treatment, comprising administering a pharmaceutical composition comprising said heparin, insulin, parathyroid hormone or calcitonin and a modified amino acid, or pharmaceutically acceptable salt thereof, wherein the modified amino acid is present in an amount effective to inhibit platelet aggregation.
  • the invention provides a method of inhibiting platelet aggregation according to the invention, wherein the calcitonin is salmon calcitonin.
  • the invention provides a method of inhibiting platelet aggregation according to the invention, wherein the modified amino acid is present in an amount of about 25 mg to about 400 mg preferably in an amount of about 100 mg to about 200 mg.
  • the invention provides a method of inhibiting platelet aggregation according to the invention, wherein the pharmacologically active agent is present in an amount of 0.05% to 70% by weight relative to the total weight of the pharmaceutical composition.
  • the invention provides a method of inhibiting platelet aggregation in a mammal receiving heparin, insulin, parathyroid hormone or calcitonin treatment, comprising administering a pharmaceutical composition comprising said heparin, insulin, parathyroid hormone or calcitonin and 5-CNAC or pharmaceutically acceptable salt thereof, wherein the 5-CNAC is present in an amount effective to inhibit platelet aggregation.
  • the invention provides a method of inhibiting platelet aggregation according to the invention, wherein the pharmaceutical composition comprises calcitonin and 5-CNAC or a pharmaceutically acceptable salt thereof, and said mammal is human.
  • the invention provides a method of inhibiting platelet aggregation according to the invention, wherein the calcitonin is salmon calcitonin.
  • the present invention is directed to the use of a pharmaceutical composition comprising a platelet aggregation inhibiting amount of a modified amino acid, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the inhibition of platelet aggregation.
  • the invention also concerns the use of a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmacologically active agent and a modified amino acid, or pharmaceutically acceptable salt thereof, wherein the modified amino acid or salt thereof is present in an amount effective to inhibit platelet aggregation, for the manufacture of a medicament for the inhibition of platelet aggregation.
  • the invention concerns the use of a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmacologically active agent and a modified amino acid, or pharmaceutically acceptable salt thereof, wherein the modified amino acid or salt thereof is present in an amount effective to inhibit platelet aggregation for the manufacture of a medicament for the inhibition of platelet aggregation said modified amino acid being N-(-5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC), or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising a pharmacologically active agent and a modified amino acid, or pharmaceutically acceptable salt thereof, wherein the modified amino acid or salt thereof is present in an amount effective to inhibit platelet aggregation for the manufacture of a medicament for the inhibition of platelet aggregation said modified amino acid being N-(-5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC), or a pharmaceutically acceptable salt thereof.
  • the invention also concerns the use of a pharmaceutical composition
  • a pharmaceutical composition comprising heparin, insulin, parathyroid hormone or calcitonin and a modified amino acid, or pharmaceutically acceptable salt thereof, wherein the modified amino acid or salt thereof is present in an amount effective to inhibit platelet aggregation for the manufacture of a medicament for the inhibition of platelet aggregation in a mammal (preferably human) receiving heparin, insulin, parathyroid hormone (PTH) or calcitonin treatment.
  • a mammal preferably human
  • the invention concerns the use of a pharmaceutical composition according to the invention, wherein the calcitonin is salmon calcitonin.
  • the invention concerns the use of a pharmaceutical composition according to the invention, wherein the modified amino acid is present in an amount of about 25 mg to about 400 mg.
  • the invention concerns the use of a pharmaceutical composition according to the invention wherein the modified amino acid is present in an amount of about 100 mg to about 200 mg.
  • the invention concerns the use of a pharmaceutical composition according to the invention, wherein the pharmacologically active agent is present in an amount of 0.05% to 70% by weight relative to the total weight of the pharmaceutical composition.
  • the invention is also directed to the use of a pharmaceutical composition according to the invention wherein the pharmaceutical composition comprises calcitonin and 5-CNAC or a pharmaceutically acceptable salt thereof, and said mammal is human.
  • the invention is also directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a platelet aggregation inhibiting amount of a modified amino acid, or a pharmaceutically acceptable salt thereof for the inhibition of platelet aggregation.
  • the invention is furthermore directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmacologically active agent and a modified amino acid, or pharmaceutically acceptable salt thereof, wherein the modified amino acid or salt thereof is present in an amount effective to inhibit platelet aggregation for the inhibition of platelet aggregation.
  • a dose-inhibition experiment in platelet rich plasma (PRP) from 12 healthy subjects using 5 ⁇ M adenosine diphosphate (ADP) as platelet aggregation stimulator and various concentrations of 5-CNAC as platelet aggregation inhibitor was made.
  • the platelet aggregation curves for three of the individual subjects stimulated by 5 ⁇ M ADP were established.
  • a dose-inhibition experiment was made in platelet rich plasma (PRP) from 12 healthy subjects using 5 ⁇ M adenosine diphosphate (ADP) as platelet aggregation stimulator and various concentrations of 5-CNAC as platelet aggregation inhibitor. Platelet aggregation curves for three of the individual subjects stimulated by 5 ⁇ M ADP were established.
  • PRP platelet rich plasma
  • ADP adenosine diphosphate
  • a dose-inhibition experiment was made in PRP using 3 ⁇ M ADP as platelet aggregation stimulator and various concentrations of 5-CNAC as platelet aggregation inhibitor.
  • the platelet aggregation curves for two of the individual subjects stimulated by 3 ⁇ M ADP were established.
  • a dose-inhibition experiment in PRP using 2 ⁇ M ADP as platelet aggregation stimulator and various concentrations of 5-CNAC as platelet aggregation inhibitor was made.
  • the platelet aggregation curves for four of the individual subjects stimulated by 2 ⁇ M ADP were established.
  • a dose-inhibition experiment in PRP using 5 ⁇ g/mL collagen as platelet aggregation stimulator and various concentrations of 5-CNAC as platelet aggregation inhibitor was made.
  • the platelet aggregation curves for two of the individual subjects stimulated by 5 ⁇ g/mL collagen were established.
  • a dose-inhibition experiment in PRP using 2.5 ⁇ g/mL collagen as platelet aggregation stimulator and various concentrations of 5-CNAC as a platelet aggregation inhibitor was made.
  • the platelet aggregation curves for two of the individual subjects stimulated by 2.5 ⁇ g/mL collagen were established.
  • a dose-inhibition experiment in PRP using 2.0 ⁇ g/mL collagen as platelet aggregation stimulator and various concentrations of 5-CNAC as a platelet aggregation inhibitor was made.
  • the platelet aggregation curve for the subject stimulated by 2.0 ⁇ g/mL collagen were established.
  • a dose-inhibition experiment in PRP using 1 ⁇ g/mL collagen as platelet aggregation stimulator and various concentrations of 5-CNAC as a platelet aggregation inhibitor was made.
  • the platelet aggregation curves for the subjects stimulated by 1 ⁇ g/mL collagen were established.
  • a dose-inhibition experiment in PRP using 0.75 ⁇ g/mL collagen as platelet aggregation stimulator and various concentrations of 5-CNAC as a platelet aggregation inhibitor was made.
  • a dose-inhibition experiment in PRP using 0.5 ⁇ g/mL collagen as platelet aggregation stimulator and various concentrations of 5-CNAC as a platelet aggregation inhibitor inhibitor was made.
  • the platelet aggregation curves for the subjects stimulated by 0.5 ⁇ g/mL collagen were established.
  • modified amino acids useful in the present invention include any one of the 123 modified amino acids disclosed in aforementioned '536 or any one of the 193 modified amino acids described in the aforementioned '647 or any combination thereof.
  • the contents of the aforementioned '647 and '536 are hereby incorporated by reference in their entirety, especially the subject matter of the claims and corresponding working examples.
  • the modified amino acids can be the disodium salt of any of the aforementioned modified amino acids as well as ethanol solvates and hydrates thereof.
  • Suitable compounds include compounds of the following formula I wherein
  • the disodium salt may be prepared from the ethanol solvate by evaporating or drying the ethanol solvate by methods known in the art to form the anhydrous disodium salt. Drying is generally carried out at a temperature of from about 80° C. to about 120° C., preferably from about 85° C. to about 90° C., and most preferably at about 85° C. The drying step is generally performed at a pressure of 26′′ Hg or greater.
  • the anhydrous disodium salt generally contains less than about 5% by weight of ethanol and preferably less than about 2% by weight of ethanol, based on 100% total weight of anhydrous disodium salt.
  • the disodium salt of the modified amino acid can also be prepared by making a slurry of the modified amino acid in water and adding two molar equivalents of aqueous sodium hydroxide, sodium alkoxide or the like.
  • Suitable sodium alkoxides include, but are not limited to, sodium methoxide, sodium ethoxide and combinations thereof.
  • a still further method of preparing the disodium salt is by reacting the modified amino acid with one molar equivalent of sodium hydroxide to yield the disodium salt.
  • the disodium salt can be isolated as a solid by concentrating the solution containing the disodium salt to a thick paste by vacuum distillation. This paste may be dried in a vacuum oven to obtain the disodium salt of the modified amino acid as a solid.
  • the solid can also be isolated by spray drying an aqueous solution of the disodium salt.
  • modified amino acids may be prepared by methods known in the art, e.g., as mentioned above, by methods described in '647 and '536.
  • the ethanol solvates include, but are not limited to, a molecular or ionic complex of molecules or ions of ethanol solvent with molecules or ions of the disodium salt of the modified amino acid.
  • the ethanol solvate contains about one ethanol molecule or ion for every molecule of disodium salt of the modified amino acid.
  • the ethanol solvate of the disodium salt of the modified amino acid can be prepared by dissolving the modified amino acid in ethanol.
  • each gram of modified amino acid Is dissolved in from about 1 mL to about 50 mL of ethanol and generally, from about 2 mL to about 10 mL of ethanol.
  • the modified amino acid/ethanol solution is then reacted with a molar excess of a sodium containing salt, such as a monosodium containing salt, relative to modified amino acid, i.e., for every mole of modified amino acid there is more than one mole of sodium cations, yielding the ethanol solvate.
  • a sodium containing salt such as a monosodium containing salt
  • Suitable monosodium salts include, but are not limited to, sodium hydroxide; sodium alkoxides, such as sodium methoxide and sodium ethoxide; and any combination of the foregoing.
  • at least about two molar equivalents of the monosodium containing salt are added to the ethanol solution, i.e., for every mole of modified amino acid there is at least about two moles of sodium cations.
  • the reaction is performed at or below the reflux temperature of the mixture, such as at ambient temperature.
  • the ethanol solvate is then recovered by methods known is the art, such as concentration of the resulting slurry at atmospheric distillation, cooling the concentrated slurry and filtering the solid.
  • the recovered solid can then be vacuum dried to obtain the ethanol solvate.
  • the hydrates of the disodium salts of the modified amino acids may be prepared by drying the ethanol solvate to from an anhydrous disodium salt, as described above, and hydrating the anhydrous disodium salt.
  • the monohydrate of the disodium salt is formed.
  • the hydrate forms upon exposure to atmospheric moisture.
  • the hydrating step is performed at from about ambient temperature to about 50° C., preferably ambient temperature to about 30° C. and in an environment having at least 50% relative humidity.
  • the anhydrous disodium salt may be hydrated with steam.
  • the preferred modified amino acids are 5-CNAC, also known as 8-(N-2-hydroxy-5-chlorobenzoyl)aminocaprylic acid, SNAD, SNAC and their monosodium and disodium salts, ethanol solvates of their sodium salts and the monohydrates of their sodium salts and any combinations thereof.
  • the most preferred modified amino acid is the disodium salt of 5-CNAC and the monohydrate thereof.
  • the pharmacologically active agents suitable for use in the instant invention include both therapeutic as well as preventative agents.
  • the pharmacologically active agents include, but are not limited to proteins, polypeptides, hormones, polysaccharides including mixtures of muco-polysaccharides, carbohydrates, lipids and combinations thereof.
  • pharmacologically active agents include, but are not limited to the following, including synthetic, natural or recombinant sources thereof: growth hormone, including human growth hormones, recombinant human growth hormones, bovine growth hormones and porcine growth hormones; growth hormone-releasing hormones; interferons, including ⁇ , ⁇ and ⁇ -interferon; interleukin-1; interleukin-2; insulin, including porcine, bovine, human and human recombinant, optionally having counter ions including sodium, zinc, calcium and ammonium; insulin-like growth factor, including IGF-1; heparin, including unfractionated heparin, heparinoids, dermatans, chondroitins, low, very low and ultra low molecular weight heparins; calcitonin, including salmon, porcine, eel, chicken and human; erythropoietein; atrial naturetic factor; antigens; monoclonal antibodies; somatostatin; protease inhibitors; a
  • a preferred pharmacologically active agent is a pharmacologically active peptide, particularly calcitonin.
  • calcitonins have varying pharmaceutical utility and are commonly employed in the treatment of, e.g., Paget's disease, hypercalcemia and postmenopausal osteoporosis.
  • Various calcitonins, including salmon, pig and eel calcitonin are commercially available and commonly employed for the treatment of, e.g., Paget's disease, hypercalcemia of malignancy and osteoporosis.
  • the calcitonin can be any calcitonin, including natural, synthetic or recombinant sources thereof, as well as calcitonin derivatives, such as 1,7-Asu-eel calcitonin.
  • the compositions can comprise a single calcitonin or any combination of two or more calcitonins.
  • the preferred calcitonin is synthetic salmon calcitonin.
  • the calcitonins are commercially available or may be synthesized by known methods.
  • heparin heparin, insulin and PTH.
  • the amount of pharmacologically active agent is generally an amount effective to accomplish the intended purpose, e.g., a therapeutically effective amount. However, the amount can be less than that amount when a plurality of the compositions are to be administered, i.e., the total effective amount can be administered in cumulative dosage units. The amount of active agent can also be more than the effective amount when the composition provides sustained release of the pharmacologically active agent. The total amount of active agent to be used can be determined by methods known to those skilled in the art. However, because the compositions may deliver the active agent more efficiently than prior compositions, less amounts of active agent than those used in prior dosage unit forms or delivery systems can be administered to a subject while still achieving the same blood levels and/or therapeutic effects.
  • the appropriate dosage will, of course, vary depending upon, for example, the host and the nature and severity of the condition being treated. However, in general, satisfactory results will be obtained systemically at daily dosages of from about 0.5 ⁇ g/kg to about 10 ⁇ g/kg animal body weight, preferably 1 ⁇ g/kg to about 6 ⁇ g/kg body weight.
  • the pharmacologically active agent generally comprises from 0.05% to 70% by weight relative to the total weight of the overall pharmaceutical composition, preferably an amount of from 0.01% to 50% by weight, more preferably 0.3% to 30% by weight relative to the total weight of the overall pharmaceutical composition.
  • the pharmaceutical compositions for use in the present invention typically comprises a platelet-aggregation-inhibitory amount of one or more of the modified amino acids, i.e., an amount sufficient to inhibit blood platelet aggregation.
  • the modified amino acid is present in a dosage range of between about 25 mg and about 400 mg. Most preferably the modified amino acid is present in a dosage range of between about 100 mg and about 200 mg.
  • compositions for use in the present invention typically comprises a pharmaceutically active agent and a platelet-aggregation-inhibitory amount of one or more of the modified amino acids, i.e., an amount sufficient to inhibit blood platelet aggregation.
  • compositions for use in the present invention may be provided as a capsule including a soft-gel capsule, tablet, caplet or other solid oral dosage form, all of which can be prepared by methods well-known in the art.
  • compositions for use in the present invention may additionally comprise additives in amounts customarily employed including, but not limited to, a pH adjuster; a preservative; a flavorant; a taste-masking agent; a fragrance; a humectant; a tonicifier; a colorant; a surfactant; a plasticizer; a lubricant, such as magnesium stearate; a flow aid; a compression aid; a solubilizer; an excipient; a diluent, such as microcrystalline cellulose, e.g., Avicel PH 102 supplied by FMC corporation; or any combination thereof.
  • additives may include phosphate buffer salts, citric acid, glycols and other dispersing agents.
  • compositions for use in the present invention may optionally additionally comprise crospovidone, which can be any crospovidone.
  • Crospovidone is a synthetic crosslinked homopolymer of N-vinyl-2-pyrrolidone, also called 1-ethenyl-2-pyrrolidinone, having a molecular weight of 1,000,000 or more.
  • Commercially available crospovidones include Polyplasdone XL, Polyplasdone XL-10, Polyplasdone INF-10 available from ISP, Kollidon CL, available from BASF Corporation.
  • Povidone is a synthetic polymer consisting of linear 1-vinyl-2-pyrrolidinone groups having a molecular weight generally between 2,500 and 3,000,000.
  • Commercially available povidones include Kollidon K-30, Kollidon K-90F available from BASF Corporation and Plasdone K-30 and Plasdone K-29/32, available from ISP.
  • the crospovidones and povidones are commercially available. Alternatively, they may be synthesized by known processes.
  • the crospovidone, povidone or combination thereof is generally present in the compositions in an amount of from 0.5% to 50% by weight relative to the total weight of the overall pharmaceutical composition, preferably an amount of from 2% to 25%, more preferably 5% to 20% by weight relative to the total weight of the pharmaceutical composition.
  • the pharmaceutical composition may also include one or more enzyme inhibitors, such as actinonin or epiactinonin and derivatives thereof; aprotinin, Trasylol and Bowman-Birk inhibitor.
  • enzyme inhibitors such as actinonin or epiactinonin and derivatives thereof; aprotinin, Trasylol and Bowman-Birk inhibitor.
  • a transport inhibitor i.e., a ⁇ -glycoprotein, such as Ketoprofin, may be present in the compositions of the present invention.
  • the solid pharmaceutical compositions of the instant invention include a diluent, such as Avicel; and a lubricant, such as magnesium stearate.
  • a diluent such as Avicel
  • a lubricant such as magnesium stearate
  • the solid pharmaceutical compositions of the instant invention can be prepared by conventional methods, e.g., by blending a mixture of the active agent or active agents, the delivery agent and other ingredients, kneading and filling into capsules, or instead of filling into capsules, molding followed by further tableting or compression-molding to give tablets.
  • a solid dispersion may be formed by known methods followed by further processing to form a tablet or capsule.
  • the ingredients in the pharmaceutical compositions of the instant invention are homogeneously or uniformly mixed throughout the solid dosage form.
  • compositions of the present invention may be administered to deliver a pharmacologically active agent to any mammal in need thereof including, but not limited to, rodents, cows, pigs, dogs, cats and primates, particularly humans.
  • Freshly drawn venous blood from healthy volunteers is collected into 0.1 vol. mmol/L trisodium citrate. The donors have not taken any medication during two weeks prior to blood collection.
  • PRP is prepared by centrifugation of the freshly drawn blood (150 g, 15 minutes at 22° C.) and the final platelet concentration is standardized at 200 000 cell/ ⁇ L by dilution in autologous platelet-free plasma, prepared by centrifugation (1200 g, 10 minutes at 22° C.). The supernatant is collected. Samples of PRP are pre-incubated for 1 minute (22° C.) with varying concentrations of 5-CNAC in saline (stored at ⁇ 20° C.).
  • the extent of aggregation is measured by expressing the maximal difference in optical density (independent of the time after the addition of the aggregation stimulator, i.e., either ADP or collagen) and normalized taking the control curves (without 5-CNAC) as an internal standard set at 100%.
  • a dose-inhibition experiment was made in PRP from 12 healthy subjects using 5 ⁇ M ADP as the platelet aggregation stimulating agent and varying concentrations of 5-CNAC as the platelet aggregation inhibiting agent. Concentrations tested include 0.1, 1, 2, 5, 10, 25, 100, 200 and 500 ⁇ M It is seen that at increasing concentrations of 5-CNAC, inhibition of platelet aggregation becomes apparent at about 2 ⁇ M 5-CNAC or more. The aggregation curves of three individual subjects induced by 5 ⁇ M ADP were established. It is noted that 5 ⁇ M ADP stimulates maximal platelet aggregation.
  • collagen is a more potent platelet aggregation inducer.
  • Platelets are unaffected by 100 ⁇ M 5-CNAC. However, at about 1 mM 5-CNAC, inhibition of platelet aggregation becomes detectable.
  • modified amino acids of the instant invention are effective at inhibiting platelet aggregation.

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  • Hematology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US10/521,492 2002-07-17 2003-07-16 Modified amino acid for the inhibition of platelet aggregation Abandoned US20060106110A1 (en)

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US10/521,492 US20060106110A1 (en) 2002-07-17 2003-07-16 Modified amino acid for the inhibition of platelet aggregation
US12/169,184 US20080280817A1 (en) 2002-07-17 2008-07-08 Modified amino acid for the inhibition of platelet aggregation
US13/327,129 US8664211B2 (en) 2002-07-17 2011-12-15 Modified amino acid for the inhibition of platelet aggregation

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US39689802P 2002-07-17 2002-07-17
US10/521,492 US20060106110A1 (en) 2002-07-17 2003-07-16 Modified amino acid for the inhibition of platelet aggregation
PCT/EP2003/007739 WO2004006907A1 (en) 2002-07-17 2003-07-16 Modified amino acid for the inhibition of platelet aggregation

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US13/327,129 Expired - Fee Related US8664211B2 (en) 2002-07-17 2011-12-15 Modified amino acid for the inhibition of platelet aggregation

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US (3) US20060106110A1 (zh)
EP (1) EP1556027B1 (zh)
JP (1) JP4541884B2 (zh)
CN (1) CN1668290B (zh)
AT (1) ATE538782T1 (zh)
AU (1) AU2003257473A1 (zh)
BR (1) BR0312712A (zh)
CA (1) CA2492378C (zh)
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US20110207693A1 (en) * 2010-02-24 2011-08-25 Emisphere Technologies, Inc. Oral B12 Therapy
US8288360B2 (en) 2007-11-02 2012-10-16 Emisphere Technologies, Inc. Method of treating vitamin B12 deficiency
US9650673B2 (en) 2005-06-15 2017-05-16 Complete Genomics, Inc. Single molecule arrays for genetic and chemical analysis

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WO2008027958A2 (en) * 2006-08-31 2008-03-06 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
RU2504536C1 (ru) * 2012-08-20 2014-01-20 Государственное бюджетное образовательное учреждение высшего профессионального образования "Волгоградский государственный медицинский университет" Министерства здравоохранения и социального развития Российской Федерации Производное амида салициловой кислоты, обладающее антибактериальной, противогрибковой и антилизоцимной активностью

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Cited By (10)

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Publication number Priority date Publication date Assignee Title
US9650673B2 (en) 2005-06-15 2017-05-16 Complete Genomics, Inc. Single molecule arrays for genetic and chemical analysis
US9944984B2 (en) 2005-06-15 2018-04-17 Complete Genomics, Inc. High density DNA array
US10351909B2 (en) 2005-06-15 2019-07-16 Complete Genomics, Inc. DNA sequencing from high density DNA arrays using asynchronous reactions
US20080269108A1 (en) * 2005-09-19 2008-10-30 Emisphere Technologies, Inc. Crystalline forms of the Di-Sodium Salt of N-(5-Chlorosalicyloyl)-8-Aminocaprylic Acid
US8026392B2 (en) 2005-09-19 2011-09-27 Emisphere Technologies, Inc. Crystalline forms of the di-sodium salt of N-(5-Chlorosalicyloyl)-8-aminocaprylic acid
US8431736B2 (en) 2005-09-19 2013-04-30 Emisphere Technologies, Inc. Crystalline forms of the di-sodium salt of N-(5-chlorosalicyloyl)-8-aminocaprylic acid
US9238074B2 (en) 2005-09-19 2016-01-19 Emisphere Technologies, Inc. Crystalline forms of the di-sodium salt of N-(5-chlorosalicyloyl)-8-aminocaprylic acid
US8288360B2 (en) 2007-11-02 2012-10-16 Emisphere Technologies, Inc. Method of treating vitamin B12 deficiency
US8557792B2 (en) 2007-11-02 2013-10-15 Emisphere Technologies, Inc. Method of treating vitamin B12 deficiency
US20110207693A1 (en) * 2010-02-24 2011-08-25 Emisphere Technologies, Inc. Oral B12 Therapy

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ES2379949T3 (es) 2012-05-07
WO2004006907A1 (en) 2004-01-22
JP4541884B2 (ja) 2010-09-08
EP1556027B1 (en) 2011-12-28
CN1668290A (zh) 2005-09-14
US8664211B2 (en) 2014-03-04
US20120088833A1 (en) 2012-04-12
CA2492378C (en) 2011-06-14
PT1556027E (pt) 2012-04-10
BR0312712A (pt) 2005-04-26
AU2003257473A1 (en) 2004-02-02
TW200403052A (en) 2004-03-01
CA2492378A1 (en) 2004-01-22
CN1668290B (zh) 2010-04-28
EP1556027A1 (en) 2005-07-27
JP2005535670A (ja) 2005-11-24
ATE538782T1 (de) 2012-01-15
US20080280817A1 (en) 2008-11-13

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