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WO2005123098A2 - Procede pour prevenir les effets secondaires gastro-intestinaux d'un medicament ou d'un aliment - Google Patents

Procede pour prevenir les effets secondaires gastro-intestinaux d'un medicament ou d'un aliment Download PDF

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Publication number
WO2005123098A2
WO2005123098A2 PCT/DK2005/000405 DK2005000405W WO2005123098A2 WO 2005123098 A2 WO2005123098 A2 WO 2005123098A2 DK 2005000405 W DK2005000405 W DK 2005000405W WO 2005123098 A2 WO2005123098 A2 WO 2005123098A2
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Prior art keywords
strontium
acid
day
dosed
range corresponding
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WO2005123098A3 (fr
Inventor
Stephan Christgau
Christian Hansen
Henrik Nilsson
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Osteologix AS
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Osteologix AS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • 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
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents

Definitions

  • the present invention relates to methods of alleviating or preventing potential GI side effects of a pharmaceutical product intended for oral administration or a food product by the administration of a strontium salt.
  • GI side effects may include epigastric/abdominal pain, nausea, vomiting, diarrhea, dyspepsia, bloating, flatulence, anorexia, mucosal erosions and/or inflammation (esophagitis, gastritis, duodenitis, enteritis), gastrointestinal hemorrhage including hematemesis, melena and hematochezia, (peptic) ulcerations and GI strictures.
  • GI side effects have been demonstrated for numerous drug classes such as non-steroidal anti-inflammatory drugs (NSAIDs), bisphosphonates, disease modifying anti-rheumatic drugs (DMARDs), glucocorticoids, cytostatic agents and others, that are used in used in treatment/prevention of malignant disease and others.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • DMARDs disease modifying anti-rheumatic drugs
  • glucocorticoids glucocorticoids
  • cytostatic agents cytostatic agents
  • COX-1 cyclo-oxygenase 1
  • NSAIDs such as mixed COX1/COX2 inhibitors or more specific inhibitors of COX2 are used extensively for the management of acute and chronic pain, which is encountered in a wade range of diseases and conditions.
  • Pain may be the symptom responsible for most physician visits, and pain is fundamental to medicine and in defining the well-being of individuals.
  • pain remains extremely difficult to define and quantify and the etiology of pain remains elusive.
  • many psychological and psychosocial factors are related to adjustment to persistent pain.
  • Non-steroidal anti-inflammatory drugs comprise a heterogeneous group of compounds with an ability to reduce inflammatory signaling molecules such as prostaglandin synthesis and cyclo-oxygenase enzymes.
  • NSAIDs are associated with significant side effects such as a gastrointestinal and cardiovascular complications.
  • Conventional NSAIDs e.g. ibuprofen or naproxen, inhibit both isoforms of the cyclo- oxygenase enzyme i.e. COX-1 and COX-2 with almost equal potency. Inhibition of COX-1 is thought to be principally responsible for the gastrointestinal adverse effects of NSAIDs.
  • COX-2 specific inhibitors e.g.
  • rofecoxib, celecoxib and valdecoxib were developed with aim of reducing GI related effects of the drug and block predominantly the COX-2 isoform, whilst the COX-1 isoform is largely spared.
  • the so-called COX-2 inhibitors are not absolutely specific for this isoform of cyclooxygenase, they mere have a preference such as e.g. a 10 fold higher affinity for the COX-2 isoform compared to the COX-1 isoform, and thus they are able to inhibit the Gl-protective COX-1 enzyme to some extent.
  • the analgesic e.g. an NSAID
  • the analgesic may be administered prophylactically before the operation and continued dosing of said NSAID, following a regular schedule in order to minimize pain and inflammation.
  • Patients benefit from receiving optimal NSAID doses, and in some cases very high doses of these analgesic agents are required to efficiently relieve the pain.
  • the dosing of palliative agents are of paramount importance, and since many of the NSAIDs are effective in reducing/preventing/alleviating pain, they reduce the need for opioids, but they are associated with a number of deleterious side-effects, of which the well documented gastrointestinal (GI) irritation is one of the more serious ones.
  • GI gastrointestinal
  • OA OA
  • A neurogenic pain (pain resulting from damage to the peripheral nerves or to the central nervous system itself), psychogenic pain (pain not due to past disease or injury or any visible sign of damage inside or outside the nervous system), e.g. fibromyalgia and whiplash syndrome
  • NSAIDs a very large systemic burden of NSAIDs can be required to obtain a required palliative effect. Consequently the GI side effects associated with long term NSAID therapy becomes a significant source of morbidity and even mortality in the clinical management of these conditions.
  • Bisphosphonates strongly decreases osteoclast-mediated bone resorption and are therefore now used extensively in the treatment of patients with metabolic bone diseases characterized by elevated bone turnover such as osteoporosis and Paget's disease.
  • metabolic bone diseases characterized by elevated bone turnover
  • increased focus have been directed to their adverse effects in the gastrointestinal tract, especially esophageal injury and gastroduodenal ulceration.
  • These side effects may significantly limit the use of these agents, as a required prophylactic use of a bisphosphonate in order to prevent a condition such as osteoporosis would entail the administration of said bisphosphonate to an otherwise healthy subject, who would be prone to treatment withdrawal if apparent GI complications/symptoms are associated with the treatment.
  • GI side effects represent one of the most common reasons for withdrawal and non-compliance to bisphosphonate treatments.
  • Bisphosphonates containing an amino group/nitrogen atom in its side chain may exert a direct cytotoxic effect on stomach epithelial cells by inhibiting a key enzyme of the mevalonate pathway responsible for protein prenylation. This is a key cellular process in most cells, and most in vitro studies with epithelial cells shows a significant cytotoxic potential of amino-bisphosphonates.
  • Alendronate and risedronate are the most commonly used orally administered drugs of this type, but newer bisphosphonates such as ibandronate and zoledronate are now being introduced into clinical practice. These compounds all contain a nitrogen atom in their side-chains, which may be especially prone to confer a propensity for GI side effects as outlined above. Shortly after the introduction of alendronate, numerous reports of erosive esophagitis and ulceration appeared. This was thought to be due to contact injury and reflux of acidified alendronate (alendronic acid) into the distal esophagus. Appropriate dosing instructions were subsequently devised, which alleviated this problem to some extent, but was of little effect in those patients with preexisting reflux disease or motility disorders of the esophagus.
  • Cytostatic and cytotoxic agents comprise a very heterogeneous group of compounds. Nevertheless, a common site of side effects of this group of therapeutically and/or prophylactically active substances is the GI tract. Common side effects include mucositis (often with ulcerations), such as stomatitis, glossitis, esophagitis and intestinal lesions. [Mitchell EP. Gastrointestinal toxicity of chemotherapeutic agents. Semin Oncol 1993; 19: 566-79. Kennedy L & Diamond J. Assessment and management of chemotherapy- induced mucositis in children.
  • Ulcerative stomatitis is often related to a direct toxic effect on the mucosa, but can also be related to drug-induced neutropenia. Furthermore, anorexia, nausea, vomiting, diarrhea and intestinal lesions and perforations can be seen, and can even be fatal in some instances; such as e.g. have been described with methotrexate or fluorouracil (FU) treatment.
  • methotrexate or fluorouracil (FU) treatment methotrexate or fluorouracil (FU) treatment.
  • FU fluorouracil
  • Systemically administered glucocorticoids may induce gastrointestinal side effects, including peptic ulcers, gastrointestinal hemorrhage and perforation.
  • Risk factors include the total corticosteroid dose, as well as a previous history of peptic ulceration, advanced malignant disease and concurrent use of NSAIDs. [Ellershaw JE and Kelly MJ. Corticosteroids and peptic ulceration. Palliat. Med.1994: 8(4): 313-9.]
  • strontium ranelate has the ability to provide relief for gastro-duodenal pain.
  • this reference does not disclose the potential of strontium containing compounds such as an inorganic or organic salt of strontium to ameliorate GI toxicity and/or side effects associated with many conventional drugs.
  • this previous patent does not disclose the pharmaceutical use of a strontium containing product for protection of the stomach epithelial cells.
  • the present invention we disclose methods of alleviating or preventing potential GI side effects of a pharmaceutical product intended for oral administration by co-administering with said pharmaceutical product a strontium salt.
  • the present invention relates particularly to the unexpected ability of ionic strontium to protect gastric epithelial cells from damaging effects of other pharmaceutical compounds.
  • beneficial properties of strontium-containing compounds such as inorganic or organic strontium salts are applicable to all pharmaceutical drug classes known to induce GI side effects.
  • the Gl-protective properties of strontium are suitable for preventing GI side-effects which can be associated with the intake of many food and drink items, such as certain soft drinks (i.e. coca cola®), fermented food products, food products containing high levels of carboxylic acids e.g. lactic acid, citric acid, amino acids and food items containing high levels of inorganic acids such as phosphoric acid, hydrochloric acid, sulphoric acid and nitric acid.
  • the excellent safety and toxicology profile of strontium enable an administration of high doses of this ion, i.e. more than 1 g daily, such as more than 2 g daily or more than 3 g daily, and thus a strontium compound according to the invention can be added in sufficient amount to prevent ameliorate GI related side effects of a food product used in even relatively high quantities.
  • a strontium salt for a use according to the invention should preferentially be water soluble, and in one embodiment of the present invention, the pH of an aqueous solution of a strontium salt according to the invention has a pH of more than 10.
  • Di- carboxyllic salts of strontium such as strontium malonate, strontium succinate, strontium oxalate, strontium fumarate, strontium aspartate and strontium glutamate may be especially suited for a pharmaceutical use according to the invention.
  • strontium salts having a water-solubility of at least about 1 g/l and at the most about 100 g/l, which is a range well suited for ensuring the complete solubility of the strontium ion in the stomach.
  • strontium salts in general including both highly soluble (i.e. with solubilities above 100 g/l) and poorly soluble (i.e. with solubilities below 1 g/l) as well strontium salts with intermediate solubility are contemplated to be suitable for use in the present context.
  • Such strontium salts are e.g.
  • amino acid salts strontium glutamate and strontium aspartate; strontium malonate; strontium pyruvate, strontium maleate and strontium succinate are not meant to limit the scope of the invention in any way, and a pharmaceutical composition according to the present invention may be manufactured with many different strontium salts comprising both inorganic and organic counter-ions to the strontium ion.
  • the inorganic acid for making strontium salts may be selected from the group consisting of boric acid, bromous acid, chloric acid, diphosphoric acid, disulfuric acid, dithionic acid, dithionous acid, fulminic acid, hydrazoic acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, hydrogen sulfide, hypophosphoric acid, hypophosphorous acid, iodic acid, iodous acid, metaboric acid, metaphosphoric acid, metaphosphorous acid, metasilicic acid, nitrous acid, orthophosphoric acid, orthophosphorous acid, orthosilicic acid, phosphoric acid, phosphinic acid, phosphonic acid, pyrophosphorous acid, selenic acid, sulfonic acid, thiocyanic acid and thiosulfuric acid.
  • the organic acid may be selected from the group consisting of C 2 H 5 COOH,
  • the present invention is not limited to the above-mentioned specific examples of suitable salts, but merely to the general applicability of water-soluble salts of strontium.
  • Some of the known strontium salts e.g. strontium chloride and strontium hydroxide
  • strontium salts may be used in the combination treatment of the invention.
  • the water-solubility of the strontium salt is at the most about 200 g/l such as, e.g.
  • the most about 150 g/l at the most about 100 g/l, at the most about 75 g/l, at the most about 50 g/l, at the most about 25 g/l, at the most about 10 g/l, at the most about 5 g/l, at the most about 2.5 g/l, or at the most about 1 g/l at room temperature (20-25 °C).
  • a strontium salt having a water-solubility of at the most about 1 g/l e.g. strontium citrate, strontium carbonate, strontium ranelate, strontium oxalate or strontium hydrogen phosphate
  • the present inventors have shown that it is possible to delay the appearance of the peak concentration, i.e. the active substance itself may contribute to a delayed release of the strontium ion. This may provide a therapeutic benefit when administered in combination with another pharmaceutical substance with the propensity to induce GI damage as defined in the present invention.
  • the strontium salt for use according to the invention may be water soluble, having a water solubility of at least 1 g/l, such as, e.g., at least 5 g/l, at least 10 g/l, at least 20 g/l, at least 30 g/l, at least 40 g/l, at least 50 g/l, at least 60 g/l, at least 70 g/l, at least 80 g/l, at least 90 g/l or at least 100 g/l measured at room temperature, i.e. a temperature of 20-25°C.
  • a more water soluble organic strontium salt comprising an anion with one or more carboxyl-groups may provide significant physiological benefits for a medical use according to the invention.
  • the present invention can be carried out by combining in one pharmaceutical composition a strontium compound in combination with one or more other drug products associated with a GI side effect.
  • a strontium compound in combination with one or more other drug products associated with a GI side effect.
  • Such combinations may be administered separately to a subject in need thereof, or they may be given in combination formulated in the same pharmaceutical dosage unit.
  • Pharmaceutical compositions comprising an effective amount of a strontium containing compound according to the invention and another pharmaceutical product associated with an increased risk or susceptibility to induce a GI side effect may conveniently be formulated with suitable carrier or diluent.
  • Such compositions are preferably in the form of an oral dosage unit or parenteral dosage unit.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a) a strontium-containing compound and b) one or more further active substances associated with an increased risk or susceptibility to induce a GI side effect together with one or more physiologically acceptable excipients, wherein the strontium compound a) and the one or more active substances b) may be chosen among the compounds and substances mentioned above.
  • the invention may be carried with a pharmaceutical compound consisting of a strontium salt of a pharmaceutically active anions associated with a GI side effect as specified above, such as an NSAID, a bisphosphonate or a cytotoxic agent.
  • a pharmaceutical compound consisting of a strontium salt of a pharmaceutically active anions associated with a GI side effect as specified above, such as an NSAID, a bisphosphonate or a cytotoxic agent.
  • physiologically acceptable excipients may be a therapeutically inert substance or carrier.
  • the carrier may take a wide variety of forms depending on the desired dosage form and administration route.
  • the pharmaceutically acceptable excipients may also be e.g. fillers, binders, disintegrants, diluents, glidants, solvents, emulsifying agents, suspending agents, stabilizers, enhancers, flavors, colors, pH adjusting agents, retarding agents, wetting agents, surface active agents, preservatives, antioxidants etc. Details can be found in pharmaceutical handbooks such as, e.g., Remington's Pharmaceutical Science or Pharmaceutical Excipient Handbook.
  • the compounds with which the invention is concerned may also be prepared for administration by any route consistent with their pharmacokinetic properties. Especially an oral administration of one or more pharmaceutical compounds according to the invention is relevant, as this is a likely administration route where GI side effects are encountered.
  • the orally administrable compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical, or sterile parenteral solutions or suspensions.
  • Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrrolidone; fillers for example lactose, sugar, carboxy-methyl cellulose, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate or magnesium stearate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan mono- oleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or coloring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats
  • emulsifying agents for example lecithin, sorbitan mono- oleate, or acacia
  • non-aqueous vehicles which may include edible oils
  • almond oil fractionated coconut oil
  • oily esters such as glycerine,
  • the solid composition may be in the form of tablets such as, e.g. conventional tablets, effervescent tablets, coated tablets, melt tablets or sublingual tablets, pellets, powders, granules, granulates, particulate material, solid dispersions or solid solutions.
  • the pharmaceutical composition may be in the form of a tablet.
  • the tablet may be coated with a coating that enables release of at least part of the salt in the proximal part of the small intestine, such as e.g.
  • the duodenum and/or the proximal jejunum such as at least 50% w/w, at least 60% w/w, at least 65% w/w, at least 70% w/w, at least 80% w/w or at least 90% w/w of the total amount of the salt contained in the tablet.
  • the tablet may have a shape that makes it easy and convenient for a patient to swallow.
  • the tablet may thus e.g. have a rounded or a rod-like shape without any sharp edges.
  • the tablet may be designed to be divided in two or more parts.
  • a strontium compound may simply be added to the food product. This can be done in a variety of different ways, employing common techniques used in the manufacture and/or processing of food and drinks. In principle, a strontium compound can be added to a food item in need thereof either in the primary or secondary processing.
  • Primary processing is the conversion of raw food materials to foods that can be eaten or to ingredients that are used to make edible food products. At its simplest it can be seen as: washing, milling, trimming, squeezing, peeling, ageing and butchery, shelling and chopping.
  • Secondary processing is the conversion of raw ingredients, i.e. the products of primary processing, to edible food products. These procedures may involve one or more of the following: mixing, heating, enrobing, cooling, extruding, drying, layering/dividing, aerating, forming/moulding and fortifying.
  • a strontium compound such as a strontium salt
  • a gastrointestinal (GI) side effects may include epigastric/abdominal pain, nausea, vomiting, diarrhea, dyspepsia, bloating, flatulence, anorexia, mucosal erosions and/or inflammation (esophagitis, gastritis, duodenitis, enteritis, colonitis), gastrointestinal hemorrhage including hematemesis, melena and hematochezia, (peptic) ulcerations and GI strictures.
  • a reduction of GI related side effects is intended to denote a decrease in severity and/or incidence among a given treated patient population
  • a reduction in GI related side effects according to this definition could thus be construed as a substantial reduction in incidence of any of the GI side effect listed above, such as at least a 10% reduction in incidence or more preferably at least 20 % reduction in incidence or even more preferable a more than 30 % reduction in incidence.
  • a reduction in GI related side effect can also be expressed as a substantial reduction in severity in any of the GI side effects listed above, such as reduction in severity and/or size of an ulcer, mucosal erosion, gastrointestinal hemorrhage including hematemesis, melena and hematochezia, (peptic) ulcerations and GI strictures or a reduction in severity and/or frequency of vomiting, diarrhea, nausea, epigastric/abdominal pain, bloating, flatulence and anorexia.
  • Chrohn's disease means an inflammatory condition in the small intestine. It usually occurs in the lower part of the intestine, but can affect any part of the digestive tract, including the mouth, stomach and large intestine. The symptoms of the disease include abdominal pain and frequent bowel movements. Chrohn's disease manifests itself because the inflammation of the intestine causes blockage in the intestine. The disease can also result in sores and ulcers. Digestive problems also occur, as nutrients are unable to be absorbed. This adds to the general GI problems associated with the disease.
  • osteoarthritis or "OA” means a type of arthritis that is caused by breakdown of cartilage with eventual loss of the cartilage of the joints. The condition may manifest itself in one or only a few joints or it may present as a systemic deterioration of multiple joints.
  • Cartilage is a protein substance that serves as a "cushion” between the bones of the joints.
  • Osteoarthritis is also known as degenerative arthritis or "arthrosis”.
  • OA is not considered an inflammatory disease, there may be both systemic and/or local elevations in inflammatory activity, which may play a role in OA pathogenesis.
  • DMOAD Disease Modifying anti-OsteoArthritis Drug
  • DMOAD Disease Modifying anti-OsteoArthritis Drug
  • glucocorticoids Another group of compounds associated with increased risk of GI side effects are the glucocorticoids. These steroid hormones belong to the subgroup of hormones collectively known as corticosteroids. There are two main types of corticosteroids: mieralcorticoids and glucocorticoids. Mineralcorticoids like aldosterone are responsible for the maintenance of salt and fluid balance in the body. Glucocorticoids like cortisol and cortisone affect metabolism and inhibit inflammation. Common glucocorticoids include prednisone, dexamethasone, and hydrocortisone but a number of other synthetic glucocorticoids are used in clinical practice.
  • NSAID's non-steroidal antiinflammatory agents
  • molecules such as enolic acis such as piroxicam, tenoxicam and meloxicam, heteroaryl acetic acids such as diclofenac, tolmetin, ketorolac, misoprostol and zomepirac; Indole and indene acetic acids such as indomethacin, mefenamic acid, sulindac and etodolac; Para-amino phenol derivates such as phenacetin and acetaminophen; propionic acids including naproxen, flurbiprofen, fenoprofen, oxaprozin, carprofen, ketoprofen and ibuprofen; fenamates including mefenamic acid, meclofenamate and flufenamic acid; alkanones such as nabumetome; pyrazolone
  • valdecoxib (tradename BEXTRA® by Pharmacia & Upjohn Company, North Peapack, New Jersey), etoricoxib (tradename ARCOXIA® by Merck & Co., Inc., Whitehouse Station, New Jersey), lumiracoxib (tradename PREXIGE® by Novartis AG, Basel, Switzerland), parecoxib, and rofecoxib (tradename VIOXX® by Merck & Co., Inc., Whitehouse Station, New Jersey), deracoxib (tradename DERAMAXX® by Novartis AG, Basel, Switzerland).
  • cytotoxic agents used in e.g. chemotherapy of a malignant disease. More than 100 chemotherapeutic drugs are currently used to treat different cancers, and many more are in different stages of development, making this a very diverse and heterogeneous group of compounds. Furthermore, cytotoxic agents are often given in combination with surgery and radiotherapy treatments and patients are usually given more than one drug to provide a more effective treatment and reduce the chance of chemo-resistance. These cytotoxic agents usually work by directly binding to the tumor and induce apoptosis of cancer cells.
  • cytotoxic agents when administered by the oral route to a mammal in need thereof, may mediate a similar effect on cells of the stomach and intestinal epithelia, and thus they may with advantage be given in combination with a strontium compound to ameliorate such side effects.
  • the following list of common cytotoxic agents are provided to indicate the type of agents with potential medical use as claimed in this invention, but the list is not meant to limit the scope of the invention.
  • cytotoxic treatments comprise the following agents: paclitaxel (Taxol), docetaxel (Taxotere), carboplatin (Paraplatin), cisplatin (Platinol), oxaliplatin (Eloxatine), gemcitabine (Gemzar), irinotecan (Camptosar), capecitabine (Xeloda), doxorubicin (Adriamycin), epirubicin (Ellence), cyclophosphamide (Cytoxan), etoposide (Vepesid), vinorelbine (Navelbine), fludarabine (Fludara), mitoxantrone (Novantrone), procarbazine (Natulan, Matulane), vinblastine (Velben, Velban, Velsar), mitomycin (Mutamycin), vindesine (Eldesine), vincrestine (Oncovin, Vincasar, Vincrex), teniposide
  • composition containing alendronate and a strontium compound
  • Alendronate and strontium malonate, lactose and cornstarch are blended to uniformity.
  • the cornstarch for paste is suspended in 200 ml of water and heated with stirring to form a paste.
  • the paste is used to granulate the mixed powders (wet granulation).
  • the wet granules are passed through a number 8 hand screen and dried at 80°C. After drying, the granules are lubricated with 1 % magnesium stearate and pressed into a tablet.
  • Such tablets can be administered to a human subject in need thereof, such as an OA or RA patient, from one to two times daily
  • Example 2 Pharmaceutical composition containing methotrexate and a strontium compound
  • Example 3 Pharmaceutical composition containing naproxen and a strontium compound
  • the tablets are prepared as described in Example 1.
  • Example 4 Pharmaceutical composition containing celecoxib and a strontium compound
  • the tablets are prepared as described in Example 1.
  • Example 5 Treatment with strontium malonate and naproxen The aim of this experiment is to evaluate palliative effects as well as the presence of GI side effects in two groups of patients treated with either a combination of a strontium compound and naproxen alone.
  • the palliative treatment regiments are given to patients with a clinical diagnosis of mild to moderate OA.
  • the patients are selected to comprise OA patients with a clinical diagnosis of OA at either the hip and/or knee joints with a well defined clinical presentation of the disease. Pain and function of the patients are evaluated with a standardized scoring system (WOMAC score) at the initiation of the study and after 2, 4 and 6 weeks.
  • the presence of gastric irritations, including ulcers is determined by upper endoscopic examinations performed at baseline and at study termination. The response in the treated patients is compared to the response in a similar placebo treated group.
  • the study cohort consists of patients above 50 years of age (mean about 59 years) with OA of the medial femoro-tibial compartment and/or the hip diagnosed according to the clinical and radiological criteria of the American College of Rheumatology.
  • the patients are recruited at a clinic of osteoarthritic rehabilitation.
  • the severity of their disease corresponds to grade 2 or 3 on the Kellgreen and Lawrence scoring scale, with average disease duration of about 5 years. They are divided in two groups equally sized treated with either 200 mg naproxen and 1200 mg strontium malonate or 200 mg naproxen alone for six weeks.
  • Urine samples are obtained at baseline and after 12 month as second morning void samples without dietary restrictions.
  • the primary outcome measures in the trial are the presence of upper GI damage determined by endoscopic examination. As secondary endpoints the presence of disease symptoms is assessed by the Western Ontario and McMasters Universities osteoarthritis index (WOMAC, VA 3.0 version) performed bi-weekly. As a secondary outcome measures biomarkers of bone and cartilage turnover is measured.
  • urine samples are obtained at baseline and after 2 and 6 weeks and measured for the presence of cartilage degradation products using the CartiLaps assay specific for C-telopeptide fragments of articular cartilage derived collagen type II, and the urine CrossLaps ELISA (CTX-I) specific for osteoclast generated degradation products of bone matrix type I collagen.
  • CTX-I I measurements are obtained at baseline and after 2 and 6 weeks and measured for the presence of cartilage degradation products using the CartiLaps assay specific for C-telopeptide fragments of articular cartilage derived collagen type II, and the urine CrossLaps ELISA (CTX-I) specific for osteoclast generated degradation products of bone matrix type I
  • Urinary levels of collagen type II C-telopeptide fragments are measured by the CartiLaps ELISA assay.
  • the assay uses a highly specific monoclonal antibody MAbF46 specific for a 6-amino acid epitope (EKGPDP) derived from the collagen type II C-telopeptide.
  • EKGPDP 6-amino acid epitope
  • the assay is performed essentially as described by the manufacturer (Nordic Bioscience, Herlev, Denmark). All samples are measured in duplicates. All samples from one individual are measured in the same ELISA plate and two control samples are included on each ELISA plate. Average intra- and inter- assay CV is determined. Three genuine control samples are included on each microtitre plate and if measurements deviate more than +20% from the predetermined values the plate is re- measured.
  • the study demonstrates if the combination strontium and naproxen prevent the occurrence of GI side-effect observed in human subjects when administering naproxen alone.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Hospice & Palliative Care (AREA)
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  • Nutrition Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

L'invention concerne des procédés pour atténuer, réduire et/ou prévenir les effets secondaires gastro-intestinaux induits par une substance pharmaceutique active sur le plan thérapeutique et/ou prophylactique ou par un produit alimentaire chez un animal, y compris un mammifère, le procédé comprenant l'administration d'un ou plusieurs composés contenant du strontium. L'invention concerne des procédés dans lesquels une substance active dans la thérapie et/ou la prévention ou un produit alimentaire associé à des effets secondaires gastro-intestinaux ou responsable de ces effets est administré avec un ou plusieurs composés contenant du strontium.
PCT/DK2005/000405 2004-06-17 2005-06-17 Procede pour prevenir les effets secondaires gastro-intestinaux d'un medicament ou d'un aliment Ceased WO2005123098A2 (fr)

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DKPA200400949 2004-06-17

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WO2005123098A3 WO2005123098A3 (fr) 2006-07-06

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006089546A1 (fr) * 2005-02-28 2006-08-31 Osteologix A/S Comprimés comprenant une charge élevée de strontium
US7595342B2 (en) 2003-05-07 2009-09-29 Osteologix A/S Water-soluble strontium salts for use in treatment of cartilage and/or bone conditions
EP2530068A1 (fr) 2011-05-31 2012-12-05 Lacer, S.A. Nouveaux sels de strontium, leur synthèse et leur utilisation dans le traitement de l'ostéoporose
US8609616B2 (en) 2004-02-26 2013-12-17 Osteologix A/S Strontium-containing compounds for use in the prevention or treatment of necrotic bone conditions

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB241266A (en) * 1924-07-14 1925-10-14 Knoll & Co Chem Fab Improvements in the manufacture of double compounds of dimethylxanthines, earth alkali and salicylic acid
FR2846558B1 (fr) * 2002-11-05 2006-07-14 Servier Lab Utilisation du sel distrontique de l'acide 2-n,n-di(carboxymethyl)amino-3-cyano-4-carboxymethyl- thiophene-5-carboxylique pour l'obtention de medicaments destines au traitement des douleurs gastro-duodenales

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7595342B2 (en) 2003-05-07 2009-09-29 Osteologix A/S Water-soluble strontium salts for use in treatment of cartilage and/or bone conditions
US8609616B2 (en) 2004-02-26 2013-12-17 Osteologix A/S Strontium-containing compounds for use in the prevention or treatment of necrotic bone conditions
WO2006089546A1 (fr) * 2005-02-28 2006-08-31 Osteologix A/S Comprimés comprenant une charge élevée de strontium
EP2530068A1 (fr) 2011-05-31 2012-12-05 Lacer, S.A. Nouveaux sels de strontium, leur synthèse et leur utilisation dans le traitement de l'ostéoporose
WO2012163563A1 (fr) 2011-05-31 2012-12-06 Lacer, S.A. Nouveaux sels de strontium, leur synthèse et utilisation dans le traitement de l'ostéoporose

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Publication number Publication date
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