US20160081936A1 - Sustained-release formulations of colchicine and methods of using same - Google Patents

Sustained-release formulations of colchicine and methods of using same Download PDF

Info

Publication number
US20160081936A1
US20160081936A1 US14/784,596 US201414784596A US2016081936A1 US 20160081936 A1 US20160081936 A1 US 20160081936A1 US 201414784596 A US201414784596 A US 201414784596A US 2016081936 A1 US2016081936 A1 US 2016081936A1
Authority
US
United States
Prior art keywords
colchicine
formulation
disease
tablet
hours
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US14/784,596
Other languages
English (en)
Inventor
Susanne Riel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Murray and Poole Enterprises Ltd
Original Assignee
Murray and Poole Enterprises Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Murray and Poole Enterprises Ltd filed Critical Murray and Poole Enterprises Ltd
Priority to US14/784,596 priority Critical patent/US20160081936A1/en
Publication of US20160081936A1 publication Critical patent/US20160081936A1/en
Assigned to MURRAY AND POOLE ENTERPRISES LTD reassignment MURRAY AND POOLE ENTERPRISES LTD ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: RIEL, Susanne
Abandoned legal-status Critical Current

Links

Images

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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • 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
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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

  • Colchicine chemical name ( ⁇ )-N-[(7S, 12aS)-1,2,3,10-tetramethoxy-9-oxo-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]-acetamide, is an alkaloid found in extracts of Colchicum autumnale, Gloriosa superba, and other plants. It is a microtubule-disrupting agent used in the treatment of conditions that may be treated, relieved or prevented with anti-inflammatory treatment.
  • Colchicine is well recognized as a valid therapy in acute flares of gouty arthritis, familial Mediterranean fever (FMF), Behçet's disease. It has also been used to treat many inflammatory disorders prone to fibrosis. In the recent past, colchicine has been proposed to be effective in therapy in cardiovascular diseases.
  • FMF familial Mediterranean fever
  • Behçet's disease has also been used to treat many inflammatory disorders prone to fibrosis.
  • colchicine has been proposed to be effective in therapy in cardiovascular diseases.
  • colchicine could be efficient after conventional treatment failure to manage acute pericarditis (Imazio at al., Arch InternMed, 2005, 165 (17), 1987-91).
  • 84 consecutive patients with a first episode of recurrent pericarditis were randomly assigned to receive conventional treatment with aspirin alone or conventional treatment plus colchicine (1.0-2.0 mg the first day and then 0.5-1.0 mg/d for 6 months).
  • the primary end point was the recurrence rate, which was significantly decreased in the colchicine group (actuarial rates at 18 months were 24.0% vs 50.6% with conventional treatment).
  • colchicine is effective for secondary prevention of recurrent pericarditis Imazio et al., Ann. Intern. Med., 2011, 155 (7), 409-14). Colchicine has also been proposed to reduce postpericardiotomy reactions revealed as pericarditis (Imazio et al., Am. Heart J., 2011, 162 (3), 527-532; Meurin and Tabet, Arch. Cardiovasc. Dis., 2011, 104 (8-9), 425-427).
  • colchicine In another study, the effectiveness of colchicine has been shown for cardiovascular disease.
  • 532 patients with stable coronary disease receiving aspirin and/or clopidogrel (93%) and statins (95%) were randomly assigned colchicine 0.5 mg/day or no colchicine and followed for a median of 3 years (Nidorf et al., JACC, 2013, 61 (4), 404-410).
  • This study showed that colchicine 0.5 mg/day administered in addition to statins and other standard secondary prevention therapies appeared effective for the prevention of cardiovascular events in patients with stable coronary disease.
  • COLCRYS® is an immediate release formulation. Adverse effects associated with the administration of COLCRYS® include, but are not limited to, nausea, vomiting, abdominal pain, diarrhea, hair loss, weakness, nerve irritation, severe anemia, low white blood counts, and low platelets (Physicians Desk Reference, 68th ed., (2014)).
  • a process of preparing a colchicine-sustained release tablet comprising forming a granulating agent by dissolving 0.25-0.75% weight of the total composition of colchicine; adding a filling agent and a binder to Step A, and forming a wet granulation; drying the wet granulation of Step B; blending the dried granulation from Step C with a retarding agent, a filling agent, a glidant and a lubricant; and compressing the final granulation from step D into a tablet.
  • a shaped and compressed sustained release therapeutic composition comprising colchicine and excipients combined into a matrix, characterized by a long-lasting, slow and relatively regular incremental release of the colchicine upon administration, wherein the excipients include Hypromellose, and wherein the total amount of excipients is effective to bind the colchicine in a sustained release solid matrix and is no less than 99 percent of the weight of said shaped and compressed composition.
  • a shaped and compressed colchicine sustained release tablet made by wet granulating a sufficient amount of colchicine to comprise from about 0.25 to about 0.75 percent of the total composition with the excipients wherein the excipients comprise the following: lactose monohydrate from about 10 to about 80 percent of the total composition, pregelatinized starch from about 5 to about 50 percent of the total composition, Hypromellose 6 mPa*s from about 1 to about 30 percent of the total composition, purified water (q.s.), Retalac from about 5 to about 40 percent of the total composition, talc from about 0.5 to about 5 percent of the total composition, and stearic acid from about 0.5 to about 5 percent of the total composition.
  • FIG. 1 shows the dissolution profiles for colchicine sustained-release formulations containing 10%, 15% and 20%, respectively, of an exemplary retarding agent.
  • FIG. 2 shows the dissolution profiles for colchicine sustained-release formulation containing 30% of an exemplary retarding agent and tablet hardnesses of 50N and 130N, respectively.
  • FIG. 3 shows the dissolution profiles for colchicine sustained-release formulations according to FIGS. 1 and 2 .
  • FIG. 4 shows the dissolution profile for a colchicine sustained-release formulation containing 0% of an exemplary retarding agent.
  • colchicine includes colchicine or any pharmaceutically acceptable salts thereof.
  • “Pharmaceutically acceptable” means that which is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
  • “Pharmaceutically acceptable salts” includes derivatives of colchicine, wherein the colchicine is modified by making acid or base addition salts thereof, and further refers to pharmaceutically acceptable solvates, including hydrates, and co-crystals of such compounds and such salts.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid addition salts of basic residues such as amines; alkali or organic addition salts of acidic residues; and the like, and combinations comprising one or more of the foregoing salts.
  • the pharmaceutically acceptable salts include non-toxic salts and the quaternary ammonium salts of the colchicine.
  • non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; other acceptable inorganic salts include metal salts such as sodium salt, potassium salt, cesium salt, and the like; and alkaline earth metal salts, such as calcium salt, magnesium salt, and the like, and combinations comprising one or more of the foregoing salts.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
  • other acceptable inorganic salts include metal salts such as sodium salt, potassium salt, cesium salt, and the like
  • alkaline earth metal salts such as calcium salt, magnesium salt, and the like, and combinations comprising one or more of the foregoing salts.
  • Organic salts includes salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC—(CH2)n-COOH where n is 0-4, and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt, and the like; and amino acid salts such as arginate, aspara
  • “Pharmacokinetic parameters” describe the in vivo characteristics of an active agent (or a metabolite or a surrogate marker for the active agent) over time, such as plasma concentration (C), Cmax, Cn, C24, Tmax, and AUC.
  • Cmax is the measured plasma concentration of the active agent at the point of maximum, or peak, concentration.
  • Cmin is the measured plasma concentration of the active agent at the point of minimum concentration.
  • Cn is the measured plasma concentration of the active agent at about n hours after administration.
  • “C24” is the measured plasma concentration of the active agent at about 24 hours after administration.
  • Tmax refers to the time at which the measured plasma concentration of the active agent is the highest after administration of the active agent.
  • AUC is the area under the curve of a graph of the measured plasma concentration of an active agent vs. time, measured from one time point to another time point.
  • AUC0-t is the area under the curve of plasma concentration versus time from time 0 to time t, where t can be the last time point with measurable plasma concentration for an individual formulation.
  • the AUC0- ⁇ or AUC0-INF is the calculated area under the curve of plasma concentration versus time from time 0 to time infinity.
  • AUC0- ⁇ is the area under the curve of plasma concentration over the dosing interval (i.e., from time 0 to time ⁇ (tau), where tau is the length of the dosing interval.
  • Ke or Kel the terminal elimination rate constant calculated from a semi-log plot of the plasma concentration versus time curve
  • t1/2 the terminal elimination half-life, calculated as 0.693/Kel
  • CL/F denotes the apparent total body clearance after administration, calculated as Total Dose/Total AUC ⁇
  • Varea/F denotes the apparent total volume of distribution after administration, calculated as Total Dose/(Total AUC ⁇ Kel).
  • Effectiveness means the ability of an active agent administered to a patient to produce a therapeutic effect in the patient.
  • Bioavailability means the extent or rate at which an active agent is absorbed into a living system or is made available at the site of physiological activity. For active agents that are intended to be absorbed into the bloodstream, bioavailability data for a given formulation may provide an estimate of the relative fraction of the administered dose that is absorbed into the systemic circulation. “Bioavailability” can be characterized by one or more pharmacokinetic parameters.
  • a “dosage form” means a unit of administration of an active agent.
  • dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, creams, ointments, suppositories, inhalable forms, transdermal forms, and the like.
  • An “immediate release formulation” refers to a formulation that releases greater than or equal to about 80% of the pharmaceutical agent in less than or equal to about 30 min.
  • Prolonged period of time it is meant a continuous period of time of greater than about 1 hour, greater than about 4 hours, greater than about 8 hours, greater than about 12 hours, greater than about 16 hours, or up to more than about 24 hours.
  • subject or “individual” or “animal” or “patient” or “mammal,” is meant any subject, particularly a mammalian subject, for whom diagnosis, prognosis, or therapy is desired.
  • Mammalian subjects include humans, domestic animals, farm animals, and zoo, sports, or pet animals such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, cows, bears, and so on.
  • eukaryote”, “animal”, “mammal”, etc. is well known in the art and can, for example, be deduced from Wehner and Gehring (1995; Thieme Verlag).
  • animals are to be treated which are economically, agronomically or scientifically important.
  • Scientifically important organisms include, but are not limited to, mice, rats, and rabbits.
  • Non-limiting examples of agronomically important animals are sheep, cattle and pigs, while, for example, cats and dogs may be considered as economically important animals.
  • the subject/patient is a mammal; in another embodiment, the subject/patient is a human or a non-human mammal (such as, e.g., a guinea pig, a hamster, a rat, a mouse, a rabbit, a dog, a cat, a horse, a monkey, an ape, a marmoset, a baboon, a gorilla, a chimpanzee, an orang-utan, a gibbon, a sheep, cattle, or a pig); most preferably, the subject/patient is a human.
  • a non-human mammal such as, e.g., a guinea pig, a hamster, a rat, a mouse, a rabbit, a dog, a cat, a horse, a monkey, an ape, a marmoset, a baboon, a gorilla, a chimpanzee, an orang
  • colchicine used according to the present invention will be described in detail.
  • the chemical structure of colchicine (ChemID 2012) is as follows:
  • colchicine N[5,6,7,9-tetrahydro-1,2,3,10-tetratmethoxy 9-oxobenzo[a]heptalen-7-yl],(S)-acetamide; molecular formula: C 22 H 25 NO 6 ; CAS number: 64-86-8.
  • colchicine The pharmacotherapeutic mechanism of action of colchicine in diverse disorders is not fully understood, though it is known that the drug accumulates preferentially in leucocytes, particularly neutrophils which is important for its therapeutic effect.
  • Availability of tubulin is essential for several cellular functions such as mitosis. Therefore colchicine effectively functions as a “mitotic poison” or spindle poison.
  • colchicine excerpts its therapeutic effect by suppressing the acute pericardial inflammation.
  • the exact cellular and molecular mechanisms of how colchicine relieves pain and inflammation in acute pericarditis and prevents recurrences are not fully understood.
  • Colchicine in the context of the present invention can be used for the prevention and/or treatment of cardiovascular diseases and/or inflammatory diseases.
  • the present invention additionally provides a sustained release colchicine formulation for the treatment or prevention of a cardiovascular disease and/or an inflammatory disorder in a subject wherein colchicine is released from the formulation at a sustained rate along a pre-determined or desired release profile. Such release is achieved by incorporation into the formulation of an extended release component and an optional immediate release component.
  • the colchicine formulation of the present invention may be formulated in a dosage form selected from a tablet, a pill, a capsule, a caplet, a troche, a sachet, a cachet, a pouch, sprinkles, or any other form suitable for oral administration.
  • colchicine as described herein is administered in the form of a sustained release preparation.
  • Other expressions like “extended release”, “controlled release”, “modified release” or “delayed release” “preparation” or “formulation” are understood herein to have the same meaning as “sustained release preparation”.
  • Such preparations can in principal be in any form conceivable to the skilled person and include pharmaceutical forms for oral (solid, semi-solid, liquid), dermal (dermal patch), sublingual, parenteral (injection), ophthalmic (eye drops, gel or ointment) or rectal (suppository) administration, as long as a sustained release is ensured.
  • sustained release preparations encompass all pharmaceutical forms that create a steady drug release profile making the drug substance available over an extended period of time following application to the patient.
  • Such an extended period of time may be between 10, 20, 30, 40, 50 or 60 minutes and about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours.
  • Extended release may also be defined functionally as the release of over 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 99 percent (%) of colchicine after about 10, 20, 30, 40, 50 or 60 minutes and about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours.
  • Polymers and compatible mixtures thereof may be used to provide the coating for the delayed or the extended release of active ingredients, and some of their properties, include, but are not limited to: shellac, also called purified lac, a refined product obtained from the resinous secretion of an insect. This coating dissolves in media of pH >7.
  • sustained release preparations may be prepared using time release hydrophilic matrices.
  • time release hydrophilic matrices are known in the field of drug formulations.
  • one such hydrophilic matrix is hydroxypropyl methylcellulose (HPMC) or Hypromellose.
  • Hydrophilic matrices provide an initial release of the drug product in the initial phase mainly triggered by a rapid swelling of the surface of the matrix tablet, combined with an erosion process leading to an immediate release of the drug substance distributed close to the surface of the tablet. In an embodiment, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, or about 10% of the drug substance may immediately be released depending on the desired release profile.
  • At least about 20% of the drug substance may immediately be released. In another embodiment, at least about 20% of the drug substance may be released within about the first 30 minutes.
  • the term “about” or “approximately” refers to a variation of 10% from the indicated values (e.g., 50%, 45%, 40%, etc.), or in case of a range of values, means a 10% variation from both the lower and upper limits of such ranges. For instance, “about 50%” refers to a range of between 45% and 55%.
  • This gelling prevents the tablet core from dissolving and disintegrating immediately, thereby allowing the main part of the drug substances to dissolve slowly over time within in this gel structure and diffuse into solution following the rules of Fick's law.
  • the diffusion itself may be triggered in this formulation approach by the concentration of the Hypromellose and the viscosity of the formed gel, defined over the molecular weight of the Hypromellose. Therefore, drug release profiles can be modified by varying different viscosity grades of Hypromellose or mixtures thereof. All corresponding formulation and process parameters achieving the predicted release profile are common knowledge and can be adjusted using actual development technologies e.g. formulation screenings, statistical trials designs.
  • the substance responsible for sustained release of the controlled-release formulation can further mix with a binder.
  • the binder is added to increase the mechanical strength of the granules and tablets during formation.
  • Binders can be added to the formulation in different ways: (1) as a dry powder, which is mixed with other ingredients before wet agglomeration, (2) as a solution, which is used as agglomeration liquid during wet agglomeration, and is referred to as a solution binder, and (3) as a dry powder, which is mixed with the other ingredients before compaction.
  • the binder is referred to as a dry binder.
  • Solution binders are a common way of incorporating a binder into granules.
  • the binder used in the formulation is in the form of a dry powder binder.
  • binders useful for the core include hydrogenated vegetable oil, castor oil, paraffin, higher aliphatic alcohols, higher aliphatic acids, long chain fatty acids, fatty acid esters, wax-like materials such as fatty alcohols, fatty acid esters, fatty acid glycerides, hydrogenated fats, hydrocarbons, normal waxes, stearic acid, stearyl alcohol, hydrophobic and hydrophilic polymers having hydrocarbon backbones, and mixtures thereof.
  • water-soluble polymer binders include modified starch, gelatin, polyvinylpyrrolidone, cellulose derivatives (such as for example hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC)), polyvinyl alcohol and mixtures thereof.
  • the binder is HPMC.
  • the binder is Hypromellose 6 mPa*s.
  • the binder can be present in an amount of from about 1% to about 30% by weight of the formulation.
  • the sustained release formulation may include a disintegrant.
  • a disintegrant refers to an agent used in pharmaceutical preparation of tablets, which causes them to disintegrate and release their medicinal substances on contact with moisture.
  • the disintegrant may be water soluble to support the disintegrantation of a tablet in the stomach.
  • Non-limiting examples of disintegrants for use in the formulation include sucrose, lactose, in particular lactose monohydrate, trehalose, maltose, mannitol and sorbitol, croscarmellose sodium, crospovidone, alginic acid, sodium alginate, methacrylic acid DVB, cross-linked PVP, microcrystalline cellulose, polacrilin potassium, sodium starch glycolate, starch, pregelatinized starch and mixtures thereof.
  • the disintegrant is selected from microcrystalline cellulose (e.g. Avicel PH101), cross-linked polyvinylpyrrolidone (e.g. KOLLIDON® CL), cross-linked sodium carboxymethylcellulose (e.g.
  • AC-DI-SOLTM starch or starch derivatives such as sodium starch glycolate (e.g. EXPLOTAB®), or combinations with starch (e.g. PRIMOJELTM), swellable ion-exchange resins, such as AMBERLITETM IRP 88, formaldehyde-casein (e.g. ESMA SPRENGTM), and mixtures thereof.
  • starch or starch derivatives such as sodium starch glycolate (e.g. EXPLOTAB®), or combinations with starch (e.g. PRIMOJELTM), swellable ion-exchange resins, such as AMBERLITETM IRP 88, formaldehyde-casein (e.g. ESMA SPRENGTM), and mixtures thereof.
  • the sustained release formulation may include a filling agent or filler.
  • a filling agent refers to an inert substance used as filler to create desired bulk, flow properties, and compression characteristics in preparation of tablets.
  • filling agents for use in the formulation include sucrose, lactose, in particular lactose monohydrate, trehalose, maltose, mannitol and sorbitol, croscarmellose sodium, crospovidone, alginic acid, sodium alginate, methacrylic acid DVB, cross-linked PVP, microcrystalline cellulose, polacrilin potassium, sodium starch glycolate, starch, pregelatinized starch and mixtures thereof.
  • lactose monohydrate is included as a filling agent in an amount of about 10% to about 80%, preferably about 59%, by weight of the tablet.
  • pregelatinized starch is included as a filling agent in an amount of about 5% to about 50%, preferably about 7.5%, by weight of the tablet.
  • the sustained release formulation of the present invention may include a release retarding agent for maintaining a uniform release rate of the drug.
  • retarding agents include, but are not limited to, cellulose ethers, cellulose esters, acrylic acid copolymers, waxes, gums, glyceryl fatty acid esters and sucrose fatty acid esters.
  • the retarding agent is RETALAC® (Meggle), a spray agglomerated blend of 50 parts lactose monohydrate and 50 parts hypromellose.
  • the viscosity of hypromellose used herein may range from 6 mPa*s-100,000 mPa*s.
  • the viscosity of hypromellose used is 4000 mPa*s. Adjusting the amount of retarding agent in the composition may alter the release rate of the drug.
  • the retarding agent of the formulation of the present invention releases colchicine in a continuous and uniform manner and is adjusted in such a way that about 80% of the active ingredient is released in vitro in the predetermined period of time.
  • the period of time may be not more than 24 hours, not more than 16 hours, not more than 12 hours, not more than 8 hours, not more than 6 hours, not more than 4 hours, not more than 3.5 hours, or not more than 1.5 hours depending on desired attributes of the final product.
  • the release rate can vary based on whether the experiment is conducted in vitro or in vivo. Therefore, if the desired release rate is between about 1.5 to about 3.5 hours in vitro or between about 1.5 to about 6 hours in vitro, the release rate under in vivo conditions, depending on the experimental conditions, may actually be different.
  • the sustained release formulation of the present invention releases colchicine in a continuous and uniform manner in such a way that about 80% of the active ingredient is released in vitro in between about 1.5 and about 3.5 hours.
  • the sustained release formulation of the present invention may include a glidant.
  • a glidant can be used to improve powder flow properties prior to and during tableting and to reduce caking.
  • Suitable glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, talc, tribasic calcium phosphate and the like.
  • talc is included as a glidant in an amount of about 0.05% to about 5%, preferably about 1%, by weight of the tablet.
  • Non-limiting examples of lubricants useful for the core include glyceryl behenate, stearic acid, hydrogenated vegetable oils (such as hydrogenated cottonseed oil (STEROTEX®), hydrogenated soybean oil (STEROTEX® HM) and hydrogenated soybean oil & castor wax (STEROTEX® K)), stearyl alcohol, leucine, polyethylene glycol (MW 1450, suitably 4000, and higher), magnesium stearate, glyceryl monostearate, polyethylene glycol, ethylene oxide polymers (for example, available under the registered trademark CARBOWAX® from Union Carbide, Inc., Danbury, Conn.), sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine, colloidal silica, mixtures thereof and others as known in the art.
  • stearic acid is included as a lubricant in an amount of about 0.05% to about 5%,
  • coloring excipients include indigotine, cochineal carminic acid, yellow orange S, allura red AC, iron oxides, cucurmin, riboflavin, tartrazine, quinoline yellow, azorubine, amaranth, carmines, erythosine, red 2G, patented blue V, glittering blue FCF, chlorophylls, copper complexes of chlorophylls, green S, caramel, glittering black BN, carbo medicinalis vegetabilis, brown FK and HT, carotenoids, Annatto extracts, paprika extracts, lycopene, lutein, canthaxanthin, beetroot red, anthocyanes, calcium carbonate, titanium dioxide, aluminium, silver, gold or litholrubin BK or any other coloring excipient suitable for an oral administration.
  • solid carriers can be made of various component types and levels or thicknesses of coats, with or without an active ingredient. Such diverse solid carriers can be blended in a dosage form to achieve a desired performance.
  • the liquid formulations may be delivered to, and adapted for, oral, nasal, buccal, ocular, urethral, transmucosal, vaginal, topical or rectal delivery, although oral delivery is used mostly.
  • polymethacrylate acrylic polymers can be employed as coating polymers.
  • the coating is an acrylic resin lacquer used in the form of an aqueous dispersion, such as that which is commercially available from Rohm Pharma under the trade name EUDRAGIT® or from BASF under the trade name KOLLICOAT®.
  • EUDRAGIT® E100 is used as the coating polymer, which is a cationic copolymer based on dimethylaminoethyl methacrylate and neutral methacrylic esters having a average molecular weight is approximately 150,000.
  • Different coating polymers of the certain embodiments can be mixed together in any desired ratio in order to ultimately obtain a coating having a desirable drug dissolution profile.
  • compositions of the present invention can also be formulated as enteric coated delayed release oral dosage forms, i.e., as an oral dosage form of a pharmaceutical composition as described herein that uses an enteric coating to effect release in the lower gastrointestinal tract.
  • enteric coated dosage form will generally include microparticles, microgranules, micropellets or microbeads of the active ingredient and/or other composition components, which are themselves coated or uncoated.
  • the enteric coated oral dosage form may also be a capsule (coated or uncoated) containing pellets, beads or granules of the solid carrier or the composition, which are themselves coated or uncoated.
  • polystyrene-acrylic and its copolymers include: polycarbonates (linear polyesters of carbonic acid); microporous materials (bisphenol, a microporous poly(vinylchloride), micro-porous polyamides, microporous modacrylic copolymers, microporous styrene-acrylic and its copolymers); porous polysulfones, halogenated poly(vinylidene), polychloroethers, acetal polymers, polyesters prepared by esterification of a dicarboxylic acid or anhydride with an alkylene polyol, poly(alkylenesulfides), phenolics, polyesters, asymmetric porous polymers, cross-linked olefin polymers, hydrophilic microporous homopolymers, copolymers or interpolymers having a reduced bulk density, and other similar materials, poly(urethane), cross-linked chain-extended poly(urethane), poly(imides), poly(
  • Additional additives and their levels, and selection of a primary coating material or materials will depend on the following properties: pH levels at target site, desirability to make tablet pH dependent or pH independent, solubility in alcohol, resistance to dissolution and disintegration in the stomach; impermeability to gastric fluids and drug/carrier/enzyme while in the stomach; ability to dissolve or disintegrate rapidly at the target intestine site; physical and chemical stability during storage; non-toxicity; easy application as a coating (substrate friendly); and economical practicality.
  • a controlled-release tablet or capsule or the like comprises colchicine as a core coated with an immediate release layer.
  • a controlled-release double layer tablet or capsule or the like comprises a layer of sustained release and a layer of immediate release.
  • a controlled-release tablet with more than two layers comprises (i) one or two more layers of substance controlling the sustained release and (ii) one or two more layers of immediate release.
  • the composition comprising colchicine is further coated with at least one release-slowing intermediate layer of slightly soluble intermediate layer to control release of colchicine.
  • colchicine immediate release dosage forms have been used in the treatment of gout or FMF.
  • all approved pharmaceuticals containing colchicine are approved only for gout and/or FMF and are immediate release tablets.
  • Colchicine can be used in the prevention of certain other inflammatory diseases such as pericarditis, PPS and, most recently, patients with stable coronary heart diseases.
  • the difference between treatment and prevention with regard to colchicine is that in treatment, an overt disease and/or ongoing inflammation has to be treated.
  • high levels of colchicine are required, which usually goes hand in hand with unwanted side effects, most prominently gastrointestinal insults.
  • In prevention one does not have to suppress ongoing inflammation but rather suppress an outbreak of inflammation.
  • supposedly lower and steadier levels of colchicine are required and are beneficial. As described in the present invention, this is achieved by administering colchicine formulated as a sustained release preparation, as described above.
  • colchicine administered as sustained release is, e.g., a flattening of the serum level curve (lower but broader peak levels) reduces the incidence of serious adverse events related to colchicine toxicity, also in case of potential drug interactions.
  • Much of colchicine related toxicity comes from the fact that one or both of the excretion pathways (liver and kidney) is reduced in its activity, either by other drugs or by a disease (e.g. kidney insufficiency).
  • the body In the case of a slower and extended drug absorption (extended release), the body has also more time to excrete the colchicine from the system. In this case, it is less likely that colchicine levels reach toxic levels in case of defective excretion (due to drug interaction or disease).
  • administration of colchicine as sustained release is resistant to dose dumping, therefore the dissolution of the composition is not significantly influenced by alcohol.
  • colchicine does not have to go deep into the tissue (like for gout), it may be active in the blood system directly (in the vessels) where it acts on the plaques and especially on inflammatory blood cells (neutrophils). This means, less total colchicine and lower serum levels can be therapeutic. Fast and high colchicine levels, e.g., as for treating an acute gout flare can be avoided. Thus, lower levels of colchicine, e.g., about 0.1 to about 0.75 mg sustained release formulations as described above (or even less frequent doses), may be sufficient to achieve the desired clinical outcome.
  • colchicine In the normal situation, most colchicine is absorbed from the small intestine and most passes the liver (some is also excreted in the urine via kidney). There it is metabolized but quite a large proportion of colchicine goes through the liver un-metabolized. This means, it goes through the liver into the bile and from there it is excreted into the big intestine (colon). There it can be resorbed into the body again which leads to the characteristic second peak (accounts for about 50% of totally absorbed colchicine and is thought to be responsible for gastrointestinal problems, such as diarrhea). If colchicine is formulated as a sustained release preparation as described above, a slower release of colchicine results in a slower resorption.
  • Colchicine administered as sustained release in accordance with the present invention may also be beneficial for other known side/adverse effects associated with colchicine treatment/administration (the skilled person is well aware of the adverse effects that may occur upon colchicine administration or colchicine treatment).
  • administration of colchicine as sustained release, as described above results in a safety increase and safety benefit.
  • the current invention additionally encompasses a method of preparing formulations of colchicine, comprising a sustained release component, and an optional immediate release component, wherein colchicine is released from the formulation at the sustained rate along the pre-determined or desired release profile.
  • a controlled release formulation for use in oral dosage forms.
  • the formulation includes a mixture containing hypromellose as a hydrophilic matrix, which is effective to provide controlled release of a pharmaceutically active ingredient.
  • Matrix systems are well known in the art.
  • the drug is homogenously dispersed in a polymer in association with conventional excipients. This admixture is typically compressed under pressure to produce a tablet.
  • the API is released from the tablet by diffusion and erosion.
  • Matrix systems are described in detail by (i) Handbook of Pharmaceutical Controlled Release Technology, Ed. D. L. Wise, Marcel Dekker, Inc. New York, N.Y. (2000), and (ii) Treatise on Controlled Drug Delivery, Fundamentals, Optimization, Applications, Ed. A. Kydonieus, Marcel Dekker, Inc. New York, N.Y. (1992), the contents of both of which are hereby incorporated by reference.
  • the tablet surface wets and the polymer begins to partially hydrate forming an outer gel layer.
  • This outer gel layer becomes fully hydrated and begins to erode into the aqueous fluids. Water continues to permeate toward the core of the tablet permitting another gel layer to form beneath the dissolving outer gel layer.
  • These successive concentric gel layers sustain uniform release of the API by diffusion from the gel layer and exposure through tablet erosion.
  • the hypromellose when included in a compressed tablet matrix, the hypromellose provides a hydrophilic swellable structure capable of functioning as the gel layer. In this way, the drug release is controlled.
  • the colchicine formulation of the present invention can be manufactured by either wet or dry granulation of a colchicine composition, blending the resulting granulate with excipients, and then compressing the composition into tablets.
  • any equipment may be used to contact the granulating liquid with the colchicine and the excipients as long as uniform distribution of the granulating liquid is achieved.
  • small-scale production can be achieved by mixing and wetting the colchicine and the excipients in mortars or stainless steel bowls, while for larger quantities, V-blenders with intensifier bars, planetary mixers, rotary granulators, high shear granulators, and fluid-bed granulation equipment may be used.
  • the granulator is a high shear granulator.
  • a method of making a colchicine composition comprises wet granulating colchicine with pharmaceutically acceptable excipients and a granulating liquid to obtain wet granules, and mixing the granules in a next step with a second excipient to obtain a colchicine composition.
  • the pharmaceutically acceptable excipient comprises a binder and a filler.
  • the binder may be Hypromellose.
  • the filler may be lactose monohydrate and pregelatinized starch.
  • purified water is used as the granulating liquid.
  • the second excipient mixed with the granules may be a filler.
  • the filler may be lactose monohydrate.
  • the colchicine compositions can contain about 0.1 wt % to about 10 wt %, or more specifically, about 0.25 wt % to about 0.75 wt %, of colchicine, based on the total weight of the colchicine composition.
  • the method can further include mixing the colchicine composition with a glidant, a lubricant, or both to obtain a blend or compressing the blend to obtain a tablet.
  • the glidant may be Talc.
  • the lubricant may be Stearic acid.
  • the method can further include coating the tablet.
  • the wet granules are dried to obtain dried granules before mixing with a second excipient, for example a filler.
  • Wet granules can be dried by any suitable means to remove the granulating liquid and to form dried granules containing colchicine and the pharmaceutically acceptable excipient.
  • the conditions and duration of drying depend on factors such as the liquid used and the weight of the granulating particles. Examples of suitable drying methods include, but are not limited to, tray drying, forced air drying, microwave drying, vacuum drying and fluid bed drying.
  • Suitable excipients may be added extragranularly and mixed with the granules to form colchicine compositions.
  • extragranular or “extragranularly” means that the referenced material, for example, a suitable excipient, is added or has been added as a dry component after wet granulation.
  • a filler, a binder, a glidant and a lubricant are added extragranularly to the granules and mixed to form a blend.
  • the blend may be encapsulated directly into capsule shells, for example, hard gelatin shells, to form capsule formulations. Alternatively, the blend may be compressed into tablets.
  • the granules are dried granules or milled, dried granules.
  • Mixing can be carried out for a sufficient time to produce homogeneous mixtures or blends. Mixing may be accomplished by blending, stiffing, shaking, tumbling, rolling, or by any other method to achieve a homogeneous blend. In some embodiments, the components to be mixed are combined under low shear conditions in a suitable apparatus, such as a V-blender, tote blender, double cone blender or any other apparatus capable of functioning under low shear conditions.
  • a suitable apparatus such as a V-blender, tote blender, double cone blender or any other apparatus capable of functioning under low shear conditions.
  • the homogenous mixtures or blends are then compressed using any method suitable in the industry.
  • the mechanical force will define the physical properties of the tablets, especially the crushing strength of the resulting tablet.
  • the mechanical strength interacts with the initial swelling of the tablet and dilution speed of the tablet core. This effect is well known in the art and can be adjusted and controlled during the lifecycle of the product.
  • the compression strengths used may range from about 30N to about 130N. In one embodiment, the compression strength may be about 100N. In another embodiment, the compression strength may be about 100N+/ ⁇ 15N.
  • the present invention also presents a method of treatment or prevention of cardiovascular diseases and/or inflammatory disorders in a subject, comprising administering to the subject a therapeutically effective amount of a colchicine formulation of the present invention, wherein colchicine is released from the formulation at a sustained rate along a pre-determined or desired release profile.
  • the method of the current invention possesses the flexibility to selectively adjust the pharmacokinetics of the administered formulations depending on the nature of the condition and needs of the patients due to the novel design of the colchicine formulation that comprises an extended release component and an optional immediate release component, and the release profiles of both components can be selectively modified during the preparation process as described above to comply with the predetermined release profile.
  • treatment includes the application or administration of a colchicine formulation as described herein to a patient, where the patient has, or has the risk of developing a cardiovascular disease and/or an inflammatory disorder.
  • treatment is also intended to include the application or administration of a pharmaceutical composition comprising the colchicine formulation, to a patient, where the patient has, or has the risk of developing a cardiovascular disease and/or inflammatory disorder.
  • cardiovascular disease refers to any disease involving the heart and/or the vascular system (all blood vessels incl. arteries, capillaries and veins). This includes all diseases listed in chapter IX “Diseases of the circulatory system (I00-I99)” of the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) Version for 2010, by the World Health Organisation.
  • Colchicine as described herein is for use in the treatment and/or prevention of any inflammatory disorder involving the heart tissue selected from ICD-10 sections 100-199. More specifically, these include acute and recurrent pericarditis as well as post-surgical complications involving inflammation of the pericardium (Postcardiotomy syndrome, Postpericardiotomy syndrome, pericardial effusion). Other inflammatory heart diseases covered are any form of myocarditis, endocarditis and arterial fibrillation.
  • Examples are stable coronary disease, cardiovascular atherosclerosis, and atherosclerosis of the peripheral vascular system, Abdominal Aortic Aneurysm (AAA) and carotid and iliofemoral/renal atheromas (e.g. 125, 170).
  • AAA Abdominal Aortic Aneurysm
  • carotid and iliofemoral/renal atheromas e.g. 125, 170.
  • an acute cardiovascular event in a patient with stable cardiovascular disease is preferably a cardiovascular event in a patient with stable coronary disease.
  • the term “stable coronary disease” and “stable coronary heart disease” have the same meaning and are used interchangeable. Both terms include the medical condition stable coronary artery disease (SCAD). “Stable” in the context of the terms “stable cardiovascular disease”, “stable coronary disease” or “stable coronary heart disease” is defined as any conditions of diagnosed cardiovascular disease in the absence of acute cardiovascular events. Hence, e.g. stable coronary disease defines the different evolutionary phases of coronary disease, excluding the situations in, which coronary artery thrombosis dominates clinical presentation (acute coronary syndrome).
  • Cardiovascular diseases include, but are not limited to, heart diseases as described, e.g., in Robbins and Cotran, Pathologic Basis of Disease, Eighth Edition, Saunders Elsevier. Cardiovascular disease refers to a group of diseases of the circulatory system including the heart, blood and lymphatic vessels. In particular, cardiovascular disease may include vascular diseases involving atherosclerosis, plaque formation or disposition. The most common cardiovascular diseases are coronary heart disease and stroke.
  • Non-limiting examples of cardiovascular disease which may be prevented or treated according to the methods of the invention include coronary heart disease (disease of the blood vessels supplying the heart muscle), cerebrovascular disease (disease of the blood vessels supplying the brain), peripheral arterial disease (disease of blood vessels supplying the arms and legs), rheumatic heart disease (damage to the heart muscle and heart valves from rheumatic fever, caused by streptococcal bacteria), congenital heart disease (malformations of heart structure existing at birth), deep vein thrombosis and pulmonary embolism (blood clots in the leg veins, which can dislodge and move to the heart and lungs), hyperlipemia (an excessive level of blood fats, such as LDL), high blood pressure, coronary artery disease, atherosclerosis, ischemic diseases, abdominal aortic aneurism, carotid and iliofemoral/renal atheromas, heart failure, cardiac rhythm defects, arteriosclerosis, heart attack and stroke.
  • Heart attacks and strokes are usually acute events and are mainly caused by a blockage that prevents blood from flowing to the heart or brain. The most common reason for this is a build-up of fatty deposits on the inner walls of the blood vessels that supply the heart or brain. Strokes can also be caused by bleeding from a blood vessel in the brain or from blood clots.
  • colchicine can be used for the prevention of acute pericarditis, recurrent pericarditis, recurrent pericarditis in patients with a history of pericarditis, post-pericardiotomy syndrome (PPS), PPS in patients undergoing cardiac surgery, and cardiovascular events in patients with stable coronary (heart) disease (the cardiovascular events can be acute cardiovascular events).
  • PPS post-pericardiotomy syndrome
  • the cardiovascular events can be acute cardiovascular events.
  • Pericarditis is an inflammatory disease involving the pericardium, a thin double-walled fibroelastic sac, surrounding the heart. Due to inflammation, it comes to irritation and swelling of the pericardium. This causes the sac to rub against the heart which causes chest pain, the most common symptom of pericarditis. Pericarditis is the most common form if inflammatory disorder of the heart, though very rare on a population basis. Pericarditis is very heterogeneous in its origin, clinical manifestations and duration of symptoms. It can either occur as isolated clinical problem or as a manifestation of a systemic disease.
  • pericarditis is of idiopathic (spontaneous, unknown) etiology but may also occur secondary to systemic infections, acute myocardial infarction or autoimmune diseases.
  • the post-pericardiotomy syndrome (PPS) may be a troublesome complication following cardiac surgery occurring a few days to several weeks after the surgical operation.
  • the estimated incidence of the syndrome has a relatively wide range affecting from 10 to 40% of patients submitted to cardiac surgery (Prince and Cunhe, 1997, Heart Lung, 26:165).
  • Non-limiting examples of (acute) cardiovascular events are injury of the atherosclerotic wall, acute coronary syndrome, out-of-hospital cardiac arrest, or non-cardioembolic ischemic stroke. Further such events are described, e.g., in Robbins and Cotran, Pathologic Basis of Disease, Eighth Edition, Saunders Elsevier.
  • the colchicine formulation of the present invention may be used to treat inflammatory disease other than those mentioned above.
  • the inflammatory disease includes, but is not limited to, gout, familial Mediterranean fever, Behcet's disease, Age-related macular degeneration and Alzheimer's disease.
  • the colchicine formulation as described herein is useful for the treatment of various cardiovascular diseases and/or inflammatory disorders.
  • treatment of a cardiovascular disease and/or an inflammatory disorder is intended to include remediation of, improvement of, amelioration of, lessening of the severity of, or reduction in the time course of, a disease, disorder or condition, or any parameter or symptom thereof.
  • disorder disorder
  • disease disease
  • condition is to be understood as cardiovascular disease and/or inflammatory disorder as described above.
  • “amelioration” refers, without limitation, to any observable beneficial effect.
  • the colchicine formulation herein can be used to promote a positive therapeutic response with respect to the cardiovascular disease and/or inflammatory disorder.
  • a “positive therapeutic response” with respect to the cardiovascular disease and/or inflammatory disorder is intended to include an improvement in the disease can be evidenced by, for example, a delayed onset of clinical symptoms of the disease or condition, a reduction in severity of some or all clinical symptoms of the disease or condition, a slower progression of the disease or condition, an improvement in the overall health or well-being of the subject, or by other parameters well known in the art that are specific to the particular disease.
  • the colchicine formulation as described herein is useful in the prevention of various cardiovascular diseases and/or inflammatory disorders.
  • the term “prevention” is well known in the art.
  • a patient/subject suspected of being prone to suffer from a disorder or disease as defined herein may, in particular, benefit from a prevention of the disorder or disease.
  • the subject/patient may have a susceptibility or predisposition for a disorder or disease, including but not limited to hereditary predisposition.
  • Such a predisposition can be determined by standard assays, using, for example, genetic markers or phenotypic indicators.
  • a disorder or disease to be prevented in accordance with the present invention has not been diagnosed or cannot be diagnosed in the patient/subject (for example, the patient/subject does not show any clinical or pathological symptoms).
  • prevention comprises the use of compounds of the present invention before any clinical and/or pathological symptoms are diagnosed or determined or can be diagnosed or determined by the attending physician.
  • Prevention includes, without limitation, to avoid the disease or condition from occurring in patient and/or subject that may be predisposed to the disease but does not yet experience or exhibit symptoms of the disease (prophylactic treatment).
  • Colchicine according to the present invention may also be used in combination with conventional therapy for any of the diseases disclosed herein.
  • Such conventional therapies are well known in the art and the skilled person knows any such therapies.
  • Colchicine as described herein may also be used in combination with colchicine-compatible statins.
  • statins are atorvastatin (Lipitor®, Torvast®), fluvastatin (Lescol®), lovastatin (Mevacor®, Altocor®, Altoprev®), pitavastatin (Livalo®, Pitava®), pravastatin (Pravachol®, Selektine®, Lipostat®), rosuvastatin (Crestor®) and simvastatin (Zocor®, Lipex®).
  • colchicine-compatible statins are used.
  • the combination of the composition of the present invention with the colchicine-compatible statins are accomplished in connection with stable coronary heart disease.
  • statins preferably are statins which, due to the nature of their mechanism of action, metabolism and/or clearance do not, or only to a small extent, interfere with the mechanism of action, metabolism and/or clearance of colchicine and therefore show a reduced risk, severity and/or incidence of drug-related drug adverse events when given in combination with colchicine.
  • colchicine is in fixed (within the same pharmaceutical preparation) or unfixed (different pharmaceutical preparation) combination.
  • Fixed combination can mean, e.g., in a single tablet, solution, cream, capsule, gel, ointment, salve, patch, suppository or transdermal delivery system.
  • Unfixed combination as used herein is to be understood as meaning that the active ingredients/components are in more than one vehicle (e.g.
  • Each of the vehicles can contain a desired pharmaceutical composition or active component.
  • a preferred unfixed combination as described herein means that one vehicle contains colchicine, as described herein, and another vehicle contains a colchicine-compatible statin, as described herein.
  • colchicine as described herein in fixed or unfixed combination(s) encompass(es) colchicine in combination with one or more colchicine-compatible statins selected from the group consisting of atorvastatin, rosuvastatin, simvastatin and pravastatin.
  • colchicine as described herein may be used in combination with a statin and another agent, such as ezetimibe/simvastatin.
  • Colchicine as described herein may be used in combination with other drugs, e.g, which are used in medicine and are known to the skilled person (e.g. antibiotics, NSAID (non-steroidal anti-inflammatory drugs), corticosteroids).
  • Non-limiting examples for administration of the compound and or compositions according to the present invention include coated and uncoated tablets, soft gelatine capsules, hard gelatine capsules, lozenges, troches, solutions, emulsions, suspensions, syrups, elixiers, powders and granules for reconstitution, dispersible powders and granules, medicated gums, chewing tablets and effervescent tablets.
  • the composition according to the present invention can administered in any pharmaceutical form for oral (e.g. solid, semi-solid, liquid), dermal (e.g. dermal patch), sublingual, parenteral (e.g. injection), ophthalmic (e.g. eye drops, gel or ointment) or rectal (e.g. suppository) administration.
  • the composition is formulated as a tablet, capsule, suppository, dermal patch or sublingual formulation.
  • compositions used in this invention comprise pharmaceutically acceptable carriers, including, e.g., ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.
  • pharmaceutically acceptable carriers including, e.g., ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as
  • compositions used in this invention can be orally administered in an acceptable dosage form including, e.g., capsules, tablets, aqueous suspensions or solutions. Certain pharmaceutical compositions also can be administered by nasal aerosol or inhalation. Such compositions can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and/or other conventional solubilizing or dispersing agents.
  • Intravenous vehicles include sodium phosphate solutions, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils.
  • Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers, such as those based on Ringer's dextrose, and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, antioxidants, chelating agents, and inert gases and the like.
  • Parenteral formulations can be a single bolus dose, an infusion or a loading bolus dose followed with a maintenance dose. These compositions can be administered at specific fixed or variable intervals, e.g., once a day, or on an “as needed” basis.
  • composition according to the present invention may be administered in a dose range varying depending on the patient's body weight, age, gender, health condition, diet, administration time, administration method, excretion rate and disease severity.
  • the compounds of the present invention as compounds per se in their use as pharmacophores or as pharmaceutical compositions can be administered to the patient and/or subject at a suitable dose.
  • the dosage regiment will be determined by the attending physician and clinical factors. As is well known in the medical arts, dosages for any one patient depends upon many factors, including the patient's size, body surface area, age, the particular compound to be administered, sex, time and route of administration, general health, and other drugs being administered concurrently.
  • the regimen as a regular administration of the pharmaceutical composition comprising the herein defined should be, e.g., in a range as described below. Progress can be monitored by periodic assessment.
  • composition according to the present invention can be administered with a single dose or with 2, 3, 4, 5, 6, 7, 8, 9, or 10 doses, if desired.
  • the composition can be administered 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 times per day.
  • colchicine according to the present invention is administered once per day. More preferably, colchicine according to the present invention is administered once per day as a single dose.
  • composition according to the present invention can be administered regularly for long periods of time.
  • the composition can be administered regularly for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more years.
  • the composition can be administered regularly for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more months.
  • the composition can be administered regularly for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks.
  • the term “regularly” refers to administration of the composition at regular times or intervals over a period of time. For instance, the composition may be administered to a patient once daily for three years. In other embodiments, the composition may be administered to a patient once every other day for 5 years.
  • the frequency of administration may vary based on a number of factors, including, but not limited to, the severity of disease, the overall health of the patient, any additional medications the patient is taking, and whether the treatment is prophylactic or not. It should also be appreciated that the frequency of administration may be adjusted at any point.
  • the amount/concentration/dose of the composition according to the present invention can be between 0.1 mg and 5.0 mg, 0.1 mg and 2.0 mg, 0.1 mg to 1.5 mg, 0.1 mg to 1.0 mg, 0.1 mg to 0.75 mg, 0.1 mg to 0.5 mg, 0.25 mg to 5.0 mg, 0.25 mg to 2.0 mg, 0.25 mg to 1.5 mg, 0.25 mg to 1.0 mg, 0.25 mg to 0.75 mg or 0.25 mg to 0.5 mg.
  • the composition according to the present invention is administered at a daily dose of colchicine of between about 0.1 mg and about 0.75 mg or between about 0.1 mg and about 0.5 mg.
  • the amount/concentration of colchicine as used herein can be administered at the first day of administration in a higher dose (concentration/amount) compared to the administration of colchicine at the following days(s) of administration (maintenance administration/maintenance dose of administration).
  • a higher dose concentration/amount
  • such decreased dose can be started after 2, 3, 4, 5, 6, 7, 8, 9 or 10 days of initial administration of the higher dose.
  • the higher dose/amount/concentration of colchicine e.g.
  • the colchicine formulation of the present invention can be administered to a human or other animal in accordance with the aforementioned methods of treatment in an amount sufficient to produce a therapeutic effect.
  • the colchicine formulation can be administered to such human or other animal in a conventional dosage form prepared by combining the colchicine formulation of the invention with a conventional pharmaceutically acceptable carrier or diluent according to known techniques. It will be recognized by one of skill in the art that the form and character of the pharmaceutically acceptable carrier or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables.
  • terapéuticaally effective dose or amount or “effective amount” is intended an amount of the colchicine formulation that when administered brings about a positive therapeutic response with respect to treatment of a patient with a disease to be treated, e.g., an improvement in the disease can be evidenced by, for example, a delayed onset of clinical symptoms of the disease or condition, a reduction in severity of some or all clinical symptoms of the disease or condition, a slower progression of the disease or condition, an improvement in the overall health or well-being of the subject, or by other parameters well known in the art that are specific to the particular disease.
  • the invention also provides for the use of the colchicine formulation in the manufacture of a medicament for treating a subject for treating a cardiovascular disease and/or inflammatory disorder, wherein the medicament is used in a subject that has been pretreated or is concurrently being treated with at least one other therapy.
  • pretreated or “pretreatment” is intended the subject has received one or more other therapies prior to receiving the medicament comprising the colchicine formulation.
  • Pretreated or “pretreatment” includes subjects that have been treated with at least one other therapy within 2 years, within 18 months, within 1 year, within 6 months, within 2 months, within 6 weeks, within 1 month, within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, within 6 days, within 5 days, within 4 days, within 3 days, within 2 days, or even within 1 day prior to initiation of treatment with the medicament comprising the colchicine formulation.
  • current or “concomitant” is intended the subject is receiving one or more other therapies while at the same time receiving the medicament comprising the colchicine formulation. It is not necessary that the subject was a responder to pretreatment with the prior therapy or therapies or a responder to the concurrent therapy or therapies. Thus, the subject that receives the medicament comprising the colchicine formulation could have responded, or could have failed to respond, to pretreatment with the prior therapy, or to one or more of the prior therapies where pretreatment comprised multiple therapies.
  • This example illustrates a colchicine sustained release tablet.
  • the tablet uses the ingredients and concentrations shown in Table 1 below.
  • the concentrations may be altered to change certain properties of the formulations, for instance, the dissolution profile.
  • Table 2 shows the ranges for each ingredient.
  • Ingredient Range Function Colchicine 0.5-0.75 Active Pharmaceutical Ingredient (API) Lactose monohydrate 10-80 Filling Agent Pregelatinized Starch 5-50 Filling Agent Hypromellose 6 mPa*s 1-30 Binder Purified water 1 q.s. Diluent for API and Binder Lactose monohydrate 10-30 Filling Agent Retalac (Compound of 5-40 Retarding Agent Lactose monohydrate and Hypromellose 4000 mPa*s 50/50 w/w %) Talc 0.5-5 Glidant Stearic acid 50 0.5-5 Lubricant Total tablet weight 1 removed within the [mg]: process
  • the granulate is compounded with a filling agent (e.g., lactose monohydrate), a retarding agent (e.g., Retalac), and other excipients (e.g., flow enhancer, glidants and/or lubricants) to support the tablet compression process.
  • a filling agent e.g., lactose monohydrate
  • a retarding agent e.g., Retalac
  • other excipients e.g., flow enhancer, glidants and/or lubricants
  • these ingredients were placed manually through a 0.8 mm sieve and mixed with the granulate in a cube mixer (Erweka) for 10 minutes.
  • the glidant used may be Talc.
  • the lubricants used may be Stearic acid.
  • the granulate will then be blended using a suitable mixer.
  • the mechanical force will define the physical properties of the tablets, especially the crushing strength of the resulting tablet.
  • the mechanical strength interacts with the initial swelling of the tablet and dilution speed of the tablet core. This effect is well known in the art and can be adjusted and controlled during the lifecycle of the product.
  • Tableting was performed on a Korsch (EK 0) tablet press with a round tabletting tool, biconvex, 6 mm in diameter. Average tablet hardness was approximately 100N+/ ⁇ 15 N. Tablets measured about 100 mg in mass, friability was not measurable. Breaking strength and hardness were measured with a Erweka Multickeck. Friability was measured with a Erweka Friabilator and a Mettler analytical balance. The dimensions were measured using a Mitutoyo caliper.
  • the dissolution of the sustained release formulation of colchicine was measured at various time points.
  • the compositions were dissolved in 500 ml of water at 37° C. and stirred continuously over a period of 6 hours. Samples were drawn at several time points to study the kinetics of the dissolution process of the drug substance within the hydrophilic matrix system. Colchicine content in the samples was analyzed using HPLC analysis.
  • the release can be modified by both the concentration of hypromellose or by using different viscosity grades of hypromellose (e.g. 1000 mPa or 10000 mPa). In the batches tested below, the viscosity grade remained constant, however, the concentration of hypromellose 4000 mPa in the tablet was modified.
  • the dissolution profiles of the various batches are provided in Tables 4-6 and FIGS. 1-4 .
  • the dissolution profile for Batches 1-3 is summarized in Table 4 and FIG. 1 .
  • the profile for Batch 1 shows approximately a 92% release within about 30 minutes, followed by a constant release. Complete dissolution occurred after 2 hours.
  • Batch 2 shows approximately a 83% release within about 30 minutes, followed by a constant release.
  • Batch 3 shows approximately a 74% release within about 30 minutes, followed by a constant release. Complete dissolution occurred after 2 hours.
  • the dissolution profile for Batch 4 is summarized in Table 5 and FIG. 2 .
  • Batch 4A shows approximately a 30% release within about 30 minutes, followed by a constant release. Complete dissolution occurred after 6 hours.
  • Batch 4B shows approximately a 23% release within about 30 minutes, followed by a constant release. Complete dissolution occurred within 6 hours.
  • a difference in tablet hardness results in a difference in release rates.
  • FIG. 3 shows the dissolution profiles for Batches 1-4.
  • the dissolution profile for Batch 5 is summarized in Table 6 and FIG. 4 .
  • Batch 6 represents the immediate release version of the composition.
  • the profile for Batch 5 shows a 90% release within 5 minutes. Complete dissolution occurred within 2 hours.
  • the release profile of the sustained release composition can be changed to a specific or desired target release by adjusting the amount of retarding agent (i.e., Retalac) as well as tablet hardness.
  • the release depends upon a variety of factors, including erosion of the outer layer of colchicine (i.e., the immediate release portion) as well as diffusion of the inner layer of colchicine (i.e., the sustained release portion). Since the percentage of colchicine is low in the sustained release formulation and the tablets are small, this balance between erosion and diffusion is very sensitive and has to be fine-tuned to reach a very specific dissolution profile.
  • the dissolution of the sustained release formulation of colchicine in ethanol was measured at various time points.
  • the compositions were dissolved in 500 ml of three solutions, 5%, 20% and 40% ethanol, at 37° C. and stirred continuously over a period of 6 hours. Samples were drawn at several time points to study the kinetics of the dissolution process of the drug substance within the hydrophilic matrix system. Colchicine content in the samples was analyzed using HPLC analysis.
  • the therapeutic effect of the sustained release formulation containing of colchicine is evaluated in a clinical study that is a multidose, randomized, cross-over study, which will evaluate bioavailability of about 3 different 0.5 mg sustained release formulations (e.g. test product 1,2,3) of colchicine to a 0.5 mg immediate release formulation (control product), administered to healthy volunteers.
  • the primary aim of the study is to assess pharmacokinetics (PK) of test and control drug in blood as well as in neutrophils or leucocytes.
  • the primary objective of this study is to compare the pharmacokinetics of the test product vs. control product of colchicine in healthy human volunteers.
  • levels of colchicine in blood herein referred as to blood PK
  • neutrophils or leucocytes herein referred as to neutrophil PK
  • colchicine As colchicine is known to preferentially accumulate in neutrophils and inhibit many of their pro-inflammatory functions, they are thought to be a major target of colchicine therapy. Therefore it is of special interest to know whether similar concentrations of colchicine are reached in isolated neutrophils or in leukocytes which would give information on potential bioequivalence. Therefore, blood will be drawn in various time points over the course of the study to check colchicine concentrations in blood and neutrophils.
  • the study drug is administered at a single dose/day for about 8-14 days consecutive days.
  • the study consists of 24 h blood PK (high frequency data collection). Neutrophil PK is analysed in intervals that allow for conclusive determination of colchicine levels in the latter over the duration of the experiment.
  • Cycle 1 Wash out Cycle 2 Group 1 14 days 14 days 14 days Control or test 1 Test 1 or control Group 2 14 days 14 days 14 days 14 days Control or test 2 Test 2 or control Group 3 14 days 14 days 14 days Control or test 3 Test 3 or control
  • the study population consists of male healthy volunteers.
  • the patient For inclusion in the study, the patient must be 25-40 years of age; not less than 60 kg and not more than 120 kg body weight; healthy; no major competing comorbidities or contraindication to colchicine therapy; willing to provide consent and be randomized into the study.
  • Patients who meet the following criteria will be excluded: ongoing therapy with other anti-inflammatory/immunosuppressive drugs; treatment with drugs with known drug interactions with colchicine; renal/hepatic impairment; known hypersensitivity to colchicine.
  • the drug is given once a day in the morning.
  • neutrophils will be isolated or purified from raw blood from several time points. Neutrophils will be collected at the beginning the study as well as at least once at the end of the study. PK analysis includes colchicine concentrations in isolated neutrophils.
  • the LoDoCo Trial was conducted under the auspices of the Heart Research Institute of Western Australia. It was designed by the principal investigators, registered with the Australian Clinical Trial Registry (12610000293066), and received ethics approval from the Human Research Ethics Committee at Sir Charles Gairdner Hospital Perth Western Australia in July 2008. There was no external funding source.
  • the randomization sequence was computer generated, kept concealed from the investigators at all times and was managed by a research assistant who had no involvement in the evaluation or management of study patients. Once the assistant received the consent form, the patients' demographic data were entered into the data base and the investigators and patients were advised in writing of the treatment group to which the patient had been assigned. Despite electing to use the lowest dose of colchicine available, it was anticipated that a number of patients would withdraw from therapy early after randomization due to gastrointestinal side effects. In order to ensure that the requisite number of patients in the treatment arm were actually tolerant of treatment, the protocol allowed for the research assistant to assign a newly recruited patient to treatment if a patient discontinued colchicine due to side effects in the first month. Patients who were intolerant to therapy remained in the study, and were followed in the usual manner and included in the primary intention to treat analysis.
  • the ACS was characterized as being stent-related if there was evidence of significant in-stent stenosis or acute stent thrombosis.
  • Out of Hospital Cardiac Arrest was defined as either a sudden death as evidenced on the patient's death certificate, or a non-fatal out of hospital cardiac arrest, defined as a recovery from sudden collapse associated with documented asystole, ventricular tachycardia or ventricular fibrillation.
  • Noncardioembolic ischemic stroke was defined as CT or MRI proven ischemic stroke adjudged by the treating neurologist as not being due to atrial fibrillation or intracranial hemorrhage.
  • the primary efficacy outcome was the composite, ACS, fatal or non-fatal out of hospital cardiac arrest or non-cardio-embolic ischemic stroke.
  • Secondary outcomes were (a) individual components of the primary outcome, and (b) the components of ACS unrelated to stent disease.
  • the pre-specified study duration was a minimum follow up of two years in all patients. Accordingly the study was closed on May 31, 2012. During May, all living patients were contacted by phone to collect compliance and outcome data from the last date of follow-up. Final outcome data were available in all patients and no patients were lost to follow up.
  • the time-to-first-event for all outcomes is presented using a Kaplan-Meier plot.
  • the primary efficacy outcome was analyzed using a cox proportional hazards model including treatment group coded as control or colchicine.
  • the secondary outcomes were analysed similarly.
  • the primary analysis was stratified by gender, age, diagnosis of diabetes, past myocardial infarction, unstable angina, coronary bypass surgery, coronary angioplasty, and therapy with aspirin, clopidogrel or both, high dose statin therapy (defined as a dose of statin equivalent to atorvastatin of 40 mg or more), beta blockers, calcium blockers and ACE inhibitors.
  • the sustained released formulation may be administered to patient populations with different body weights. Assuming that a 0.5 mg tablet gives a certain plasma level of colchicine in average weight patients and that this particular level should be reached in every patient to achieve efficacy, one can perform PK analysis of a 0.5 mg tablet in different weight groups. It is expected that levels in blood (Cmax and AUC) in heavy patients are lower, which indicates that dose adjustments towards higher doses is necessary.
  • the primary objective of this study is to compare the pharmacokinetics of a 0.5 mg colchicine tablet in healthy human volunteers of at least 2 different body weight groups. In particular, levels of colchicine in blood will be assessed upon treatment. The hypothesis tested is that administration of an equal amount of colchicine in leads to different colchicine levels depending to body weight. Body weight and colchicine levels are inverse correlated.
  • n at least 8 subjects are selected according to body weight. If 2 groups are made, then 50% will be of low weight (e.g. below 65 kg) and 50% of high weight (e.g. above 90 kg).
  • the study drug is administered once.
  • the study consists of 24 h blood PK (high frequency data collection).
  • HPLC Physical chemistry techniques
  • immunological techniques radioimmunoassay
  • the study population consists of male healthy volunteers.
  • the patient For inclusion in the study, the patient must be 25-40 years of age; not less than 50 kg and not more than 120 kg body weight; healthy; no major competing comorbidities or contraindication to colchicine therapy; willing to provide consent and be randomized into the study.
  • Patients who meet the following criteria will be excluded: ongoing therapy with other anti-inflammatory/immunosuppressive drugs; treatment with drugs with known drug interactions with colchicine; renal/hepatic impairment; known hypersensitivity to colchicine.
  • the drug is given once in the morning of the study.
  • blood PK blood will be collected over a period of 24 h at the beginning the study in short intervals (sufficient time points to establish pharmacokinetic data, e.g: ⁇ 1, +0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 5 h, 7 h, 10 h, 12 h, 15 h and 24 h (before next application). Additional time points may be 24 h, and 72 h after drug withdrawal at the end of the study to examine the wash out phase of the drug.
  • the control drug is an IR tablet of colchicine.
  • the test drug is an SR tablet of colchicine.
  • mice The control group of mice is given a single first dose of IR colchicine in a strength which lies in the therapeutic window (the plasma level range of colchicine where a therapeutic effect can be observed. It will be determined and set arbitrary in the used laboratory animal species as a maximum level sufficiently below the LD50 and a minimum level approximately 6 fold less than the maximum level).
  • the test group is given a single first dose of SR colchicine in the same strength. Blood is drawn from both groups at time points 0.25 h, 0.5 h, 0.75 h, 1 h, and then hourly for 12 h and every 3 hours until 24 h. Simultaneously, feces are drawn from the cages of test and control animals after 3 h, 6 h, 12 h and 24 h (test and control animals must not be put in the same cages).
  • SR colchicine levels will rise more slowly and do not reach peak levels of colchicine as observed in control animals. The peak levels are observed after 3-8 h and then slowly decline. Therapeutic colchicine levels remain for at least 12 h. Due to the more complete metabolism of colchicine in the liver, enterohepatic recirculation occurs to a lesser extent and no secondary peak can be observed. As a secondary readout, feces of test and control animals are investigated to see whether enterohepatic recirculation occurs to a lesser extent in test animals than in control animals. It can be shown that the ratio of unchanged colchicine vs. metabolized colchicine is higher in control than in test animals. Thus, SR colchicine results in a more complete metabolism of colchicine in the liver.
  • the control drug is an IR tablet of colchicine.
  • the test drug is an SR tablet of colchicine.
  • mice The control group of mice is given one dose IR colchicine/day in a strength which lies in the therapeutic window (the plasma level range of colchicine where a therapeutic effect can be observed. It will be determined and set arbitrary in the used laboratory animal species as a maximum level sufficiently below the LD50 and a minimum level approximately 6 fold less than the maximum level).
  • the test group is given one dose SR colchicine/day in the same strength. Alternatively, test and control animals are given a total of two doses/day, one in the morning and one in the evening. The duration of the experiment is 2 weeks.
  • gastrointestinal adverse events e.g cramps, diarrhea etc.
  • This is evaluated in 3 ways. Daily, behaviour of the tested animals is observed with a predetermined standardized method where signs of illness are investigated. Secondly, feces are investigated daily for morphology as well as presence of apoptotic epithelial cells. Thirdly, individual animals are sacrificed at predetermined time points and the small and big intestine is investigated for histopathological signs of colchicine toxicity.
  • test and control medication consists of a SR or IR oral solid dosage form of colchicine in strength of 0.25-1 mg. A sufficiently high dose is administered to reach therapeutic levels of colchicine.
  • the tested drugs are given twice daily as indicated in Example 3, above.
  • a placebo group is included in both experimental settings. The duration of the experiment is between 2 weeks and 1 month.
US14/784,596 2013-04-16 2014-04-16 Sustained-release formulations of colchicine and methods of using same Abandoned US20160081936A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US14/784,596 US20160081936A1 (en) 2013-04-16 2014-04-16 Sustained-release formulations of colchicine and methods of using same

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US201361812514P 2013-04-16 2013-04-16
EP13194505.726 2013-11-26
EP13194505 2013-11-26
PCT/IB2014/001201 WO2014170755A2 (en) 2013-04-16 2014-04-16 Sustained-release formulations of colchicine and methods of using same
US14/784,596 US20160081936A1 (en) 2013-04-16 2014-04-16 Sustained-release formulations of colchicine and methods of using same

Publications (1)

Publication Number Publication Date
US20160081936A1 true US20160081936A1 (en) 2016-03-24

Family

ID=49683519

Family Applications (6)

Application Number Title Priority Date Filing Date
US14/784,596 Abandoned US20160081936A1 (en) 2013-04-16 2014-04-16 Sustained-release formulations of colchicine and methods of using same
US14/563,537 Active 2034-05-09 US10130585B2 (en) 2013-04-16 2014-12-08 Methods of treating and/or preventing cardiovascular disease
US14/563,503 Active US10105319B2 (en) 2013-04-16 2014-12-08 Sustained-release formulations of colchicine and methods of using same
US16/165,696 Active US10610488B2 (en) 2013-04-16 2018-10-19 Sustained-release formulations of colchicine and methods of using same
US16/594,543 Active 2035-06-28 US11648206B2 (en) 2013-04-16 2019-10-07 Sustained-release formulations of colchicine and methods of using same
US18/367,416 Pending US20230414521A1 (en) 2013-04-16 2023-09-12 Sustained-release formulations of colchicine and methods of using same

Family Applications After (5)

Application Number Title Priority Date Filing Date
US14/563,537 Active 2034-05-09 US10130585B2 (en) 2013-04-16 2014-12-08 Methods of treating and/or preventing cardiovascular disease
US14/563,503 Active US10105319B2 (en) 2013-04-16 2014-12-08 Sustained-release formulations of colchicine and methods of using same
US16/165,696 Active US10610488B2 (en) 2013-04-16 2018-10-19 Sustained-release formulations of colchicine and methods of using same
US16/594,543 Active 2035-06-28 US11648206B2 (en) 2013-04-16 2019-10-07 Sustained-release formulations of colchicine and methods of using same
US18/367,416 Pending US20230414521A1 (en) 2013-04-16 2023-09-12 Sustained-release formulations of colchicine and methods of using same

Country Status (19)

Country Link
US (6) US20160081936A1 (ja)
EP (1) EP2986280B1 (ja)
JP (1) JP6480420B2 (ja)
KR (1) KR102271048B1 (ja)
CN (1) CN105307643A (ja)
AU (3) AU2014255434B2 (ja)
BR (1) BR112015026418B1 (ja)
CA (1) CA2909370A1 (ja)
CL (1) CL2015003072A1 (ja)
EA (1) EA037375B1 (ja)
MA (1) MA38576B2 (ja)
MX (2) MX2015014656A (ja)
MY (1) MY198452A (ja)
PL (1) PL2986280T3 (ja)
PT (1) PT2986280T (ja)
SG (1) SG11201508571WA (ja)
SI (1) SI2986280T1 (ja)
WO (1) WO2014170755A2 (ja)
ZA (1) ZA201507723B (ja)

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108721265B (zh) 2012-11-02 2022-12-02 默里和普尔企业有限公司 通过给予秋水仙碱衍生物治疗或预防心血管事件
BR112015026418B1 (pt) 2013-04-16 2022-10-04 Murray And Poole Enterprises Limited Formulação de liberação prolongada de colchicina e uso da referida formulação de liberação prolongada de colchicina
EP3283063A1 (en) * 2015-04-17 2018-02-21 Murray And Poole Enterprises Limited Colchicine salicylate and uses thereof
US9907751B2 (en) * 2016-03-10 2018-03-06 RxOMEG Therapeutics LLC Composition and method of use of colchicine oral liquid
US11534421B2 (en) * 2017-06-23 2022-12-27 Nordiccan A/S Cannabinoid pouch
US10226423B1 (en) 2017-12-20 2019-03-12 RxOMEG Therapeutics LLC Colchicine drug-to-drug interactions
CA3089781A1 (en) 2018-02-02 2019-08-08 Murray & Poole Enterprises, Ltd Use of colchicine to inhibit tumor growth and metastases
CN110448527B (zh) * 2019-09-23 2021-11-26 杭州百诚医药科技股份有限公司 一种秋水仙碱口服溶液及其处方组成
KR102112456B1 (ko) 2019-11-13 2020-05-19 주식회사 에이스바이오메드 간 질환 치료용 또는 치료 효과 증진을 위한 콜히친 복합제제
CN111150702B (zh) * 2019-12-04 2021-06-22 复旦大学 一种凝胶药物缓释制剂及其制备方法与应用
KR102584738B1 (ko) 2020-01-17 2023-10-06 한국생명공학연구원 콜히친을 포함하는 피부 질환 치료용 조성물
KR20210095249A (ko) 2020-01-22 2021-08-02 주식회사 에이스바이오메드 간 질환 치료용 또는 치료 효과 증진을 위한 콜히친 복합제제
KR102150821B1 (ko) 2020-01-22 2020-09-03 주식회사 에이스바이오메드 간 질환 치료용 또는 치료 효과 증진을 위한 콜히친 복합제제
KR102177781B1 (ko) 2020-04-27 2020-11-12 주식회사 에이스바이오메드 간 질환 치료용 또는 치료 효과 증진을 위한 콜히친, 우르소데옥시콜산 및 비페닐디메틸디카르복실레이트의 복합제제
EP4262771A1 (en) * 2020-12-15 2023-10-25 Romeg Therapeutics LLC Methods and compositions for treating pericarditis
CN113476603B (zh) * 2021-07-08 2022-05-20 中南大学 一种红细胞膜包裹的磁性纳米颗粒及其制备方法和应用

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020015735A1 (en) * 1999-12-22 2002-02-07 Hedden David B. Sustained-release formulation of a cyclooxygenase-2 inhibitor
US20020169145A1 (en) * 1998-10-14 2002-11-14 Rajen Shah Sustained release pharmaceutical composition and method of releasing pharmaceutically active agent
US20090170952A1 (en) * 2007-10-05 2009-07-02 Mutual Pharmaceutical Company, Inc. Colchicine compositions and methods
CN101536990A (zh) * 2008-03-18 2009-09-23 普尔药物科技开发（深圳）有限公司 秋水仙碱胃漂浮缓释片及其制备方法
US20110207826A1 (en) * 2008-09-19 2011-08-25 Molkerei Meggle Wasserburg Gmbh & Co. Kg Lactose and cellulose-based tableting aid
US20150094323A1 (en) * 2013-04-16 2015-04-02 Murray And Poole Enterprises Limited Methods of treating and/or preventing cardiovascular disease

Family Cites Families (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3173876A (en) 1960-05-27 1965-03-16 John C Zobrist Cleaning methods and compositions
US3276586A (en) 1963-08-30 1966-10-04 Rosaen Filter Co Indicating means for fluid filters
US3546142A (en) 1967-01-19 1970-12-08 Amicon Corp Polyelectrolyte structures
US3541006A (en) 1968-07-03 1970-11-17 Amicon Corp Ultrafiltration process
US3541005A (en) 1969-02-05 1970-11-17 Amicon Corp Continuous ultrafiltration of macromolecular solutions
US4285987A (en) 1978-10-23 1981-08-25 Alza Corporation Process for manufacturing device with dispersion zone
SE9003904D0 (sv) * 1990-12-07 1990-12-07 Astra Ab Method for the manufacture of a pharmaceutical dosage form
US5171217A (en) 1991-02-28 1992-12-15 Indiana University Foundation Method for delivery of smooth muscle cell inhibitors
US7820383B2 (en) 1997-03-10 2010-10-26 Interleukin Genetics, Inc. Method for diagnosing myocardial infarction
JP2000034224A (ja) * 1998-05-11 2000-02-02 Freunt Ind Co Ltd 徐放性錠剤、その添加剤組成物及びそれらの製造方法
MXPA03008293A (es) 2001-03-13 2003-12-11 Penwest Pharmaceuticals Co Formas de dosis cronoterapeuticas.
US8853266B2 (en) 2001-12-06 2014-10-07 University Of Tennessee Research Foundation Selective androgen receptor modulators for treating diabetes
US20030144203A1 (en) 2001-12-19 2003-07-31 Voyager Pharmaceutical Corporation Methods for slowing senescence and treating and preventing diseases associated with senescence
SE0401031D0 (sv) * 2004-04-22 2004-04-22 Duocort Ab A new glucocorticoid replacement therapy
US20060045865A1 (en) 2004-08-27 2006-03-02 Spherics, Inc. Controlled regional oral delivery
US20080039408A1 (en) 2004-12-06 2008-02-14 Ronald Freudenberger Use of Oxypurinol as an Inhibitor of Anti-Neoplastic Agent-Induced Cardiotoxicity
US20060171948A1 (en) 2005-02-02 2006-08-03 Weinstein Steven P Methods of using IL-1 antagonists to reduce C-reactive protein
US20060286108A1 (en) 2005-06-16 2006-12-21 Bell Katherine A Topical compositions for the treatment of chronic wounds
CN1748671A (zh) 2005-08-30 2006-03-22 孔庆忠 含抗有丝分裂药物的缓释注射剂
CN1939290A (zh) 2005-09-29 2007-04-04 陆宪光 秋水仙碱及它的衍生物的医学用途
US20090215687A1 (en) 2005-10-21 2009-08-27 Cornell Research Foundation, Inc. Compounds for Enhancing Hypoxia Inducible Factor Activity and Methods of Use
WO2007143211A2 (en) 2006-06-02 2007-12-13 Bioseek, Inc. Methods for identifying agents and their use for the prevention of restenosis
RS51973B (en) * 2006-06-09 2012-02-29 Ucb Pharma Gmbh. STABLE PHARMACEUTICAL PRODUCTS CONTAINING FEZOTERODINE
PT103884A (pt) * 2006-11-17 2008-05-19 Astrazeneca Ab Composições de libertação prolongada e métodos para a sua preparação
WO2008131192A2 (en) 2007-04-18 2008-10-30 The Trustees Of Columbia University In The City Of New York Crystalline cholestrol and prevention of atherosclerosis
CN101485638A (zh) * 2008-01-18 2009-07-22 普尔药物科技开发（深圳）有限公司 秋水仙碱双层渗透泵控释片及其制备方法
CN101485637B (zh) * 2008-01-18 2011-03-30 普尔药物科技开发（深圳）有限公司 秋水仙碱骨架控释片或胶囊
US20090299155A1 (en) 2008-01-30 2009-12-03 Dexcom, Inc. Continuous cardiac marker sensor system
EP2262786A4 (en) 2008-04-15 2014-07-09 Takeda Pharmaceuticals Usa Inc COLCHICIN SOLIDS FORMAT, METHOD FOR THE PRODUCTION THEREOF AND METHOD FOR THEIR USE
GB0819287D0 (en) 2008-10-22 2008-11-26 Univ Bradford Compounds
CN101732274A (zh) * 2008-11-19 2010-06-16 普尔药物科技开发（深圳）有限公司 秋水仙碱双层缓释片及其制备方法
US7820681B1 (en) 2009-01-14 2010-10-26 Mutual Pharmaceutical Company, Inc. Methods for concomitant administration of colchicine and a second active agent
US8945622B2 (en) 2009-03-09 2015-02-03 Council Of Scientific And Industrial Research Sustained release composition of therapeutic agent
US20110046228A1 (en) 2009-08-20 2011-02-24 Mutual Pharmaceutical Company, Inc. Methods for administration of colchicine with grapefruit juice
US20110046227A1 (en) 2009-08-21 2011-02-24 Mutual Pharmaceutical Company, Inc. Methods for concomitant administration of colchicine and a second active agent
RU2583920C2 (ru) 2009-11-13 2016-05-10 Астразенека Аб Композиция двухслойной таблетки
EP2481411A1 (en) * 2011-01-27 2012-08-01 Ratiopharm GmbH Oral dosage forms for modified release comprising the JAK3 inhibitor tasocitinib
CA2870014A1 (en) 2012-04-13 2013-10-17 Cymabay Therapeutics, Inc. Method for treating hyperuricemia in patients with gout using halofenate or halofenic acid and an anti-inflammatory agent
CN108721265B (zh) 2012-11-02 2022-12-02 默里和普尔企业有限公司 通过给予秋水仙碱衍生物治疗或预防心血管事件
CN110148563A (zh) * 2019-05-23 2019-08-20 武汉新芯集成电路制造有限公司 一种半导体器件及其制造方法

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020169145A1 (en) * 1998-10-14 2002-11-14 Rajen Shah Sustained release pharmaceutical composition and method of releasing pharmaceutically active agent
US20020015735A1 (en) * 1999-12-22 2002-02-07 Hedden David B. Sustained-release formulation of a cyclooxygenase-2 inhibitor
US20090170952A1 (en) * 2007-10-05 2009-07-02 Mutual Pharmaceutical Company, Inc. Colchicine compositions and methods
CN101536990A (zh) * 2008-03-18 2009-09-23 普尔药物科技开发（深圳）有限公司 秋水仙碱胃漂浮缓释片及其制备方法
US20110207826A1 (en) * 2008-09-19 2011-08-25 Molkerei Meggle Wasserburg Gmbh & Co. Kg Lactose and cellulose-based tableting aid
US20150094323A1 (en) * 2013-04-16 2015-04-02 Murray And Poole Enterprises Limited Methods of treating and/or preventing cardiovascular disease
US20150094322A1 (en) * 2013-04-16 2015-04-02 Murray And Poole Enterprises Limited Sustained-release formulations of colchicine and methods of using same

Also Published As

Publication number Publication date
EP2986280B1 (en) 2021-03-17
MA38576B2 (fr) 2020-02-28
US20190054028A1 (en) 2019-02-21
KR102271048B1 (ko) 2021-06-30
SI2986280T1 (sl) 2021-08-31
AU2020294268A1 (en) 2021-01-28
US20230414521A1 (en) 2023-12-28
MA38576A1 (fr) 2017-05-31
EP2986280A2 (en) 2016-02-24
EA037375B1 (ru) 2021-03-22
WO2014170755A3 (en) 2015-02-19
CN105307643A (zh) 2016-02-03
CL2015003072A1 (es) 2016-09-23
ZA201507723B (en) 2023-05-31
WO2014170755A2 (en) 2014-10-23
PL2986280T3 (pl) 2021-10-25
AU2014255434B2 (en) 2018-11-08
AU2014255434A1 (en) 2015-11-05
MY198452A (en) 2023-08-29
US20200030240A1 (en) 2020-01-30
US10105319B2 (en) 2018-10-23
JP2016521270A (ja) 2016-07-21
PT2986280T (pt) 2021-05-07
KR20150143725A (ko) 2015-12-23
MX2015014656A (es) 2016-03-01
MX2020012310A (es) 2021-01-29
AU2019201048B2 (en) 2021-01-28
SG11201508571WA (en) 2015-11-27
BR112015026418A2 (pt) 2017-07-25
BR112015026418B1 (pt) 2022-10-04
EA201501024A1 (ru) 2016-08-31
US10610488B2 (en) 2020-04-07
US20150094323A1 (en) 2015-04-02
US20150094322A1 (en) 2015-04-02
JP6480420B2 (ja) 2019-03-13
CA2909370A1 (en) 2014-10-23
US11648206B2 (en) 2023-05-16
AU2019201048A1 (en) 2019-03-07
AU2020294268B2 (en) 2024-05-02
US10130585B2 (en) 2018-11-20

Similar Documents

Publication Publication Date Title
US11648206B2 (en) Sustained-release formulations of colchicine and methods of using same
US8007827B2 (en) Pharmaceutical dosage forms having immediate release and/or controlled release properties
US20210196682A1 (en) Pharmaceutical combination, composition and compound preparation comprising glucokinase activator and dpp-iv inhibitor, and preparation method and use thereof
JP6976946B2 (ja) 生理活性の強い、ｕｒａｔ１のインヒビターを含む医薬組成物
US8758815B2 (en) Pharmaceutical compositions comprising a combination of metformin and sitagliptin
US20100143470A1 (en) Controlled release pharmaceutical composition containing thiazides and angiotensin-ii-receptor blockers
JP6697539B2 (ja) コルヒチンの徐放性製剤およびその使用方法
US20210361582A1 (en) Colchicine salicylate derivatives and methods of treatment

Legal Events

Date Code Title Description
STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

AS Assignment

Owner name: MURRAY AND POOLE ENTERPRISES LTD, UNITED KINGDOM

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:RIEL, SUSANNE;REEL/FRAME:049373/0634

Effective date: 20190428

STPP Information on status: patent application and granting procedure in general

Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STPP Information on status: patent application and granting procedure in general

Free format text: FINAL REJECTION MAILED

STPP Information on status: patent application and granting procedure in general

Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION