WO2007125397A2 - Compositions et méthodes d'inhibition de l'acidité gastrique en utilisant des composés contenant un pont endoperoxyde - Google Patents

Compositions et méthodes d'inhibition de l'acidité gastrique en utilisant des composés contenant un pont endoperoxyde Download PDF

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WO2007125397A2
WO2007125397A2 PCT/IB2007/001078 IB2007001078W WO2007125397A2 WO 2007125397 A2 WO2007125397 A2 WO 2007125397A2 IB 2007001078 W IB2007001078 W IB 2007001078W WO 2007125397 A2 WO2007125397 A2 WO 2007125397A2
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group
gastric
endoperoxide
artesunate
ppi
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PCT/IB2007/001078
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WO2007125397A3 (fr
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Michael Marash
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Vecta, Ltd.
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Publication of WO2007125397A2 publication Critical patent/WO2007125397A2/fr
Publication of WO2007125397A3 publication Critical patent/WO2007125397A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole

Definitions

  • the present invention relates to novel oral compositions for inhibition of gastric acidity comprising endoperoxide bridge-containing compounds.
  • the present invention further relates to a method of using such compositions to reduce gastric acidity in a mammal.
  • the treatment of a wide number of pathological conditions is characterized by the need to suppress gastric acid secretion.
  • Such conditions include, but are not limited to Zollinger/Ellison syndrome (ZES), gastroesophageal reflux disease (GERD), peptic ulcer disease, duodenal ulcers, esophagitis, and the like.
  • ZES Zollinger/Ellison syndrome
  • GERD gastroesophageal reflux disease
  • peptic ulcer disease peptic ulcer disease
  • duodenal ulcers duodenal ulcers
  • esophagitis and the like.
  • Conditions such as reflux esophagitis can have serious complications and represent some of the most prevalent diseases in industrialized nations.
  • the main therapies employed in the treatment of GERD and peptic ulcer diseases include agents for reducing the stomach acidity, for example by using the histamine H 2 -receptor antagonists or proton pump inhibitors (PPIs).
  • PPIs act by inhibiting the parietal cell H + /K + ATPase proton pumps responsible for acid secretion from these cells.
  • PPIs such as omeprazole, and its pharmaceutically acceptable salts are disclosed for example in EP 05129, EP 124495 and US Patent No. 4,255,431.
  • PPI agents are acid-labile pro-drugs that are usually administered in enteric-coated granules and are weak bases. Following absorption in the small intestine, PPIs preferentially accumulate within the acidic milieu of the acid-secreting parietal cells. The acid environment within the acid milieu of parietal cells causes the conversion of the prodrugs into the active sulfenamides, which are the active agents that bind and inhibit the parietal cell If 1 YK + ATPase pumps. PPIs inhibit only activated pumps once they have fused into the membrane of the secretory canaliculus. Thus, pre-activation of parietal cells is required for the conversion of PPIs to its active protonated form and inhibition of acid secretion.
  • parietal cells The pre-activation of parietal cells is usually achieved by meal ingestion that initiates gastrin-dependent parietal cell activation. Indeed, patients are instructed to take PPI one hour prior to meal intake in order to ensure that parietal cells are activated when the PPI reaches the parietal cells via blood stream.
  • PPIs have notable limitations such as the need for meal-dependent administration of the drug, the slow onset of full pharmacological action in patients, incomplete control of nocturnal acid secretion that is associated with heartburn pain in GERD patients and inter-patient variability in pharmacokinetics that may have significant interactions with other drugs.
  • an improvement of PPI-mediated activity is a well-recognized challenge in gastroenterology.
  • Artemisinin is an anti-malarial drug isolated by Chinese scientists in 1972 from Artemisia annua L.
  • the endoperoxide moiety of artemisinin and its analogs has been found to be necessary for the anti-malarial activity, and analogs lacking this group have been found to be inactive.
  • the endoperoxide bridge undergoes reductive decomposition to form a free radical and electrophilic intermediates (Meshnick, Int. J. Parasitology, 32 (2002) 1655). It was recently proposed that artemisinin possesses its anti- parasite activity by inhibition of specific P-type ATPase (Eckstein-Ludwig et al., Nature, Vol. 424, 957).
  • artemisinin Because of the low water solubility of the natural substance artemisinin, attempts have been made to convert it to a variety of synthetic derivatives in order to improve the pharmaceutical availability.
  • Known analogs of artemisinin that have higher solubility in water are dihydroartemisinin, artemether, artesunate, arteether, propylcarbonate dihydroartemisinin and artelinic acid.
  • Artemisinin or artemisinin analogs were reported to be effective in various disorders. These include skin disorders such as psoriasis, blistering skin diseases, viral warts, and hemorrhoids (U.S. Patent No. 4,978,676).
  • U.S. Patent No. 5,219,880 discloses the use of artemisinin or artemisinin analogs in the treatment of warts, molluscum contagiosum and hemorrhoids.
  • U.S. Patent No. 5,225,427 discloses certain 10-substituted ether derivatives of dihydroartemisinin alleged to exhibit anti-malarial and anti-protozoal activity.
  • Artemisinin has been shown to be toxic to cancer cells in vitro at 20-180 ⁇ M range (Sun et al., "Antitumor Activities of 4 Derivatives of Artemisic Acid and Artemisinin B in vitro," Chung-Kuo-Yao-Li-Hsueh-Pao 13:541-543 (1992)).
  • U.S. Patent No. 5,578,637 discloses that the anticancer activity of compounds having an endoperoxide moiety such as artemisinin and its analogs, is substantially enhanced both in vitro and in vivo when administered under conditions which enhance intracellular iron concentrations.
  • WO04071506 discloses the use of Artemisinin and/or artemisinin derivatives for treating tumors induced by oncogenic viruses and for treating viral infections as well as treatment of cervical disorders associated with virus infection (e.g., cervical cancer and cervical dysplasia).
  • This publication further discloses a method of killing or inhibiting growth of cells that are infected by oncogenic viruses such as BPV, HTLV-I, herpes virus (e.g., EBV or CMV), SV40-like viruses, hepatitis virus, or adenovirus.
  • oncogenic viruses such as BPV, HTLV-I, herpes virus (e.g., EBV or CMV), SV40-like viruses, hepatitis virus, or adenovirus.
  • WO04041176 discloses the use of sesquiterpene lactone endoperoxides to treat hepatitis C infections, yellow fever, dengue fever, bovine viral diarrhea and classical swine fever.
  • Foglio et al. disclose that dihydro- epideoxyarteannuin B and deoxyartemisinin provided gastric cytoprotection by decreasing the ulcerative lesion index produced by ethanol and indomethacin in rats (Planta Med. 2002, 68 515-518).
  • compositions of the present invention comprise one or more endoperoxide- bearing compounds effective in the inhibition of gastric acidity.
  • the compositions of the present invention preferably further comprise a substituted benzimidazole H + ZK + -ATPaSe proton pump inhibitor (PPI) or H 2 blocker in order to obtain more effective reduction of gastric acidity or inhibition of gastric acid secretion.
  • PPI proton pump inhibitor
  • the endoperoxide-bearing compounds of the present invention have a sesquiterpene structure, particularly an oxygenated tricyclic sesquiterpene structure with an endoperoxide group, and preferably those which are sesquiterpene lactones or alcohols, carbonates, esters, ethers and sulfonates thereof. It will be apparent that other endoperoxide-bearing compounds may be useful for the present invention.
  • endoperoxide-bearing compounds include for example: hydroxy, hydroperoxy or peroxy derivative of a polyunsaturated fatty acid, trioxolanes, spiro and dispiro 1,2,4-trioxolanes, byciclo (3,2,2) endoperoxides, trioxanes, 3-substituted trioxanes, ozonides, 2,3 bicyclo (3.3.1) nonanes, 1,2,4-trioxanes, 1,2,4,5-tetraoxanes, terpenes and substituted terpenes.
  • the endoperoxide-bearing compound to be used in the present invention is a sesquiterpene compound, or a pharmaceutically acceptable salt thereof, according to formula (I):
  • R is -CO- or R iS -CR 1 - wherein R 1 is hydrogen, hydroxyl, alkyl, -OR 2 , -COR 2 , -COR 2 , -COOR 2 , -CO(CH 2 ) n , -COOH, -SOOR 2 , a halogen atom, an optionally substituted cycloalkyl, aryl, C-linked heteroaryl or heterocyclylalkyl group, wherein R 2 is alkyl or aryl and n is 1 to 6, or wherein R 1 is NR 1 R 2 ; where R 1 represents a hydrogen atom or an optionally substituted alkyl, alkenyl or alkynyl group; R 2 represents an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl or aralkyl group; or R 1 and R 2 together with the interjacent nitrogen atom represent an optionally substituted heterocyclic group or
  • alkyl, alkenyl or alkynyl group may be linear or branched and may contain up to 12, preferably up to , 6, and especially up to 4 carbon atoms.
  • Preferred alkyl groups are methyl, ethyl, propyl and butyl.
  • Preferred alkenyl and alkynyl groups include propenyl, butenyl, propynyl and butynyl groups.
  • an alkyl moiety forms part of another group, for example the alkyl moiety of an aralkyl group it is preferred that it contains up to 6, especially up- to 4, carbon atoms.
  • Preferred alkyl moieties are methyl and ethyl.
  • An aryl group may be any aromatic hydrocarbon group and may contain from 6 to 24, preferably 6 to 18, more preferably 6 to 16, and especially 6 to 14, carbon atoms.
  • Preferred aryl groups include phenyl, naphthyl, anthryl, phenanthryl and pyryl groups, especially a phenyl or napthyl, and particularly a phenyl, group.
  • An aralkyl group may be any alkyl group substituted by an aryl group.
  • a preferred aralkyl group contains from 7 to 30, particularly 7 to 24 and especially 7 to 18, carbon atoms, particularly preferred aralkyl groups being benzyl, naphthylmethyl, anthrylmethyl, phenanthrylmethyl and pyrylmethyl groups.
  • a particularly preferred aralkyl group is a benzyl group.
  • a cycloalkyl group may be any saturated cyclic hydrocarbon group and may contain in from 3 to 12, preferably 3 to 8, and especially 3 to 6, carbon atoms.
  • Preferred cycloalkyl groups are cyclopropyl, cyclopentyl and cyclohexyl groups.
  • a heteroaryl group may be any aromatic monocyclic or polycyclic ring system which contains at least one heteroatom.
  • a heteroaryl group is a 5-18-membered, particularly a 5- to 14-membered, and especially a 5- to 10-membered, aromatic ring system containing at least one heteroatom selected from oxygen, sulphur and nitrogen atoms.
  • Preferred heteroaryl groups include pyridyl, pyrylium, thiopyrylium, pyrrolyl, furyl, thienyl, indolinyl, isoindolinyl, indolizinyl, imidazolyl, pyridonyl, pyronyl, pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, pyridazinyl, benzofuranyl, benzoxazolyl and acridinyl groups.
  • a C-linked heteroaryl group is therefore a heteroaryl group as defined above which is linked to the tetracyclic 1,2,4-trioxane moiety of a compound of general formula I via a carbon atom in the heteroaromatic ring system.
  • a heterocyclic group may be any monocyclic or polycyclic ring system which contains at least one heteroatom and may be unsaturated or partially or fully saturated.
  • the term "heterocyclic” thus includes heteroaryl groups as defined above as well as non- aromatic heterocyclic groups.
  • a heterocyclic group is a 3- to 18-membered, particularly a 3- to 14-membered, especially a 5- to 10-membered, ring system containing at least one heteroatom selected from oxygen, sulphur and nitrogen atoms.
  • Preferred heterocyclic groups include the specific heteroaryl groups named above as well as pyranyl, piperidinyl, pyrrolidinyl, dioxanyl, piperazinyl, morpholinyl, thiomorpholinyl, morpholinosulphonyl, tetrahydroisoquinolinyl and tetrahydrofuranyl groups.
  • a heterocyclylalkyl group may be any alkyl group substituted by a heterocyclic group.
  • the heterocyclic moiety is a 3- to 18-membered, particularly a 3- to 14- membered, and especially a 5- to 10-membered, heterocyclic group as defined above and the alkyl moiety is a C 1-6 alkyl, preferably C 1-4 alkyl, and especially methyl, group.
  • An amino acid may be any .alpha.-amino acid, such as glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, cystine, methionine, aspartic acid, glutamic acid, aspargine, glutamine, lysine, hydroxylysine, arginine, histidine, phenylalanine, tyrosine, tryptophan, proline, hydroxyproline or phenylglycine, and includes both D- and L- configurations.
  • An amino acid ester may be any ester of such an amino acid, alkyl esters, particularly C 1-4 alkyl esters, being especially preferred.
  • Such preferred compounds include artemisinin; C-10 derivatives of artemisinin, dihydroartemisinin; carbonate, sulfonate, ester and ether derivatives of dihydroartemisinin, notably artemether, arteether, arteflene, artesunate, artesunate salts, dihydroartemisinin propyl carbonate, C-10 thiomorpholinyl or morpholinosulphonyl derivatives of artemisinin (artemisone), 12(beta or alpha)-
  • endoperoxide compounds may be successfully used in the disclosed method, although in a non-limiting preferred embodiment the endoperoxide compounds are those disclosed herein.
  • Pharmaceutically acceptable salts according to the present invention include the alkali or alkaline metal salts, preferably sodium or potassium, with sodium being the most preferred. Also included in the present invention are any possible conformers or isomers of the active compounds such as the alpha or beta isomers of dihydroartemisinin, artemether or arteether. Also included in the present invention are various dimers of the active compounds such as dimers of dihydroartemisinin.
  • compositions of the present invention comprise the endoperoxide-bearing compound in combination with one or more active agents for reducing gastric acid secretion or gastric acidity or for the relief of symptoms associated with heartburns or gastric ulcers as a means of further enhancing clinical efficacy.
  • active agents are for example an inhibitor of gastric acid secretion, a proton pump inhibitor (either irreversible or reversible proton pump inhibitor), an B ⁇ -blocker such as cimetidine, famotidine, nizatidine, and ranitidine, buffering agents, antacids, sucralfate, antibacterial agents, a non-steroidal anti-inflammatory (NSAID) drug or bismuth- containing compounds.
  • active agents are for example an inhibitor of gastric acid secretion, a proton pump inhibitor (either irreversible or reversible proton pump inhibitor), an B ⁇ -blocker such as cimetidine, famotidine, nizatidine, and ranitidine, buffering agents,
  • the inventors of the present invention have surprisingly found that the combination of an endoperoxide-bearing compound such as artemisinin or artesunate in combination with a PPI such as pantoprazole or omeprazole or with H 2 Blocker such as ranitidine showed better inhibition of gastric acid secretion compared to PPI, H 2 blocker or artesunate alone.
  • the active ingredients of the present invention may be formulated in a single dosage form, preferably oral dosage form, more preferably oral solid dosage form.
  • Such oral dosage forms may contain one or both of the drugs in immediate or sustained release form such as in a gastric retention form.
  • the PPI and/or H 2 blocker and the endoperoxide-bearing compound may be formulated as multi- layered tablets, suspension tablets, effervescent tablets, powder, pellets, granules, hard gelatin capsules comprising multiple beads, or soft gelatin capsules containing a lipid-based vehicle. Liquid dosage forms such as suspensions may be used as well.
  • the endoperoxide-bearing compound is combined with antacids in an effervescent tablet, fast-integrating tablet or chewable tablet which provide both immediate relief for heartburn episodes with prolonged effect on gastric acid secretion.
  • the active ingredients of the present invention might also be administered via parenteral routs of administration such as intravenous administration and subcutaneous injection, rectal administration, transdermal administration, buccal administration or nasal administration.
  • parenteral routs of administration such as intravenous administration and subcutaneous injection, rectal administration, transdermal administration, buccal administration or nasal administration.
  • the solid dosage form of the present invention is a capsule or a multi-layered tablet containing particles of both PPI and/or H 2 blocker and the endoperoxide-bearing compound.
  • the release of either PPI and/or H 2 blocker particles, the endoperoxide-bearing compound, or both PPI and/or H 2 blocker particles and the particles of the endoperoxide-bearing compound may be delayed by enteric pH-dependent release polymers or non-enteric time-dependent release polymers, such that the releasing time in the stomach is extended.
  • the active ingredients of the present invention may also be formulated in separate dosage forms.
  • the endoperoxide-bearing compound may be formulated in an oral suspension or a solid dosage form such as capsules, tablets, suspension tablets, or effervescent tablets and the PPI and/or H 2 blocker may be formulated in a separate solid dosage form, preferably capsules or tablets comprising pellets with enteric pH-dependent release polymers or non-enteric time-dependent release polymers.
  • the separate dosage forms may be provided as a kit containing pellets of the endoperoxide-bearing compound in one dosage form and pellets of PPI and/or H 2 blocker in a separate dosage form.
  • the PPI and/or H 2 blocker and the endoperoxide-bearing compound can be administered simultaneously and/or sequentially.
  • the active ingredients of the present invention may also be formulated in a dosage form suitable for parenteral administration such as intravenous administration and subcutaneous injection. It is also possible that one of the active ingredients is administered orally (such as in tablets or capsules) and the second active ingredient is administered parenterally for example by intravenous, subcutaneous or rectal administration. Although any suitable route of administration is acceptable, it is preferred to administer the compositions orally.
  • the active compounds are typically combined with a pharmaceutically acceptable carrier to form a pharmaceutical composition.
  • the pharmaceutically acceptable carrier can contain a physiologically acceptable compound that acts, for example, to stabilize the composition or to increase the absorption of the agent.
  • the present invention is directed to a method of treating a subject suffering from a disorder in which suppression of gastric acid secretion or reduction of gastric acidity is required or a disorder normally treated by suppression of gastric acid secretion.
  • the method comprises administering to the subject a pharmaceutical composition according to the present invention.
  • compositions of the present invention may be used for preventing or treating pathologies in a mammal in which inhibition of gastric acid secretion or reduction of gastric acidity is required.
  • a mammal Preferably the mammal is human.
  • the compositions of the present invention are effective both in treating the pathologies and in minimizing the risk of development of such pathologies before onset of symptoms.
  • the pharmaceutical compositions of the present invention may be used in a wide number of pathological conditions that are treated by suppression of gastric acid secretion. Such conditions include, but are not limited to Zollinger/Ellison syndrome (ZES), gastroesophageal reflux disease (GERD), esophagitis, peptic ulcer diseases, duodenal ulcers, gastritis and gastric erosions, dyspepsia, NSAJD- induced gastropathy, acute upper GI bleeding and the like.
  • ZES Zollinger/Ellison syndrome
  • GERD gastroesophageal reflux disease
  • esophagitis peptic ulcer diseases, duodenal ulcers, gastritis and gastric erosions, dyspepsia, NSAJD- induced gastropathy, acute upper GI bleeding and the like.
  • the pharmaceutical compositions of the present invention may also be used as prophylaxis or treatment for mucosal damage in patients undergoing cancer chemotherapy.
  • the compositions may be used in order to provide symptom
  • the endoperoxide-bearing compounds are formulated in a composition designed to act locally in the stomach following oral administration in order to reduce gastric acidity. Since the preferred compounds such as artemisinin or the active derivatives thereof are not soluble in the acidic conditions of the gastric fluid, it is necessary to preserve its solubility in the stomach in order to permit the active compound to act locally.
  • compositions may further comprise an agent that maintains the solubility of the endoperoxide-bearing compound in the gastric fluids.
  • agents are preferably alkaline agents or antacids that when dissolved in the gastric juice are capable of elevating the pH of the gastric fluids to a pH in which at least significant proportion of the endoperoxide-bearing compound remains soluble in the gastric fluids.
  • compositions may further comprise one or more agents that accelerate the solubility and the stability of the endoperoxide-bearing compound in aqueous environment.
  • agents are for example cyclodextrin analogs that form complexes with artemisinin or its derivatives, thereby improving the aqueous solubility of the complex and the stability of the endoperoxide bridge in aqueous environment.
  • the compositions may further comprise one or more gastric- retention agents.
  • gastric-retention agents enable the active compound to act locally in the stomach for extended time periods sufficient to induce reduction in gastric acid secretion.
  • gastric retention agents may be for example one or more polymers that swell in the stomach via the absorption of water from the gastric fluid, thereby increasing the size of the particles to promote gastric retention in the stomach.
  • the active ingredient is slowly released from the particles by diffusion or following slow erosion of the particles in the stomach.
  • the compositions of the present invention are formulated to permit systemic absorption of the endoperoxide-bearing compound in the intestine.
  • the compositions may comprise vehicle such as vegetable oil suitable for liquid formulations that increase the absorption in the intestine.
  • Figures IA and IB demonstrate the effect of artesunate, pantoprazole and the combination thereof on gastric output (Figure IA) and pH of gastric fluid in rats ( Figure IB).
  • FIGS 2 A and 2B demonstrate the effect of Artemisinin or pantoprazole on gastric output ( Figure 2A) and pH of gastric fluid ( Figure 2B).
  • Figures 3A and 3B demonstrate the dose response of artesunate on gastric output (Figure 3A) and gastric pH ( Figure 3B).
  • Figures 4A and 4B demonstrate the effect of artesunate, ranitidine and the combination thereof on gastric output ( Figure 4A) and pH of gastric fluid in rats ( Figure 4B).
  • Figures 5A and 5B demonstrate the effect of intravenous artesunate on gastric output (Figure 5A) and pH of gastric fluid ( Figure 5B).
  • Figures 6A and 6B demonstrate the effect of intravenous artesunate and/or subcutaneous indomethacin on gastric output (Figure 6A) and pH of gastric fluid ( Figure 6B).
  • Figures 7A and 7B demonstrate the effect of oral artesunate and omeprazole on gastric output (Figure 7A) and pH of gastric fluid (Figure 7B).
  • Figures 8A and 8B demonstrate the effect of oral artesunate (20 mg/kg and 40 mg/kg) and pantoprazole on gastric output (Figure 8A) and pH of gastric fluid ( Figure 8B).
  • Figures 9A and 9B demonstrate the effect of intravenous artesunate (15, 30 and 60 mg/kg) on gastric output ( Figure 9A) and pH of gastric fluid ( Figure 9B). DETAILED DESCRIPTION OF THE INVENTION
  • compositions of the present invention comprise one or more endoperoxide- bearing compounds effective in the inhibition of gastric acid secretion or reduction of gastric acidity.
  • compositions of the present invention preferably further comprise a substituted benzimidazole H + ZK + -ATPaSe proton pump inhibitor (PPI) and/or H 2 blocker in order to obtain more effective inhibition of gastric acid secretion or gastric acidity.
  • PPI proton pump inhibitor
  • the present invention relates to a composition
  • a composition comprising an endoperoxide-containing sesquiterpene compound, such as, for example, artemisinin, artesunate or an active derivative thereof.
  • an endoperoxide-containing sesquiterpene compound such as, for example, artemisinin, artesunate or an active derivative thereof.
  • artemisinin or the active derivative thereof possess its anti-acid activity via inhibition of the H + ZK + ATPase proton pump in parietal cells.
  • a similar mechanism was suggested by Eckstein-Ludwig et al (Nature, Vol. 424, 957) who showed that artemisinin possesses its anti-parasite activity by inhibition of specific P-type ATPase.
  • compounds may be employed, in general, that possess an endoperoxide group.
  • Preferred endoperoxide compounds are set forth hereinabove, although as will be apparent from the present specification that other endoperoxide-bearing compounds not specifically mentioned should also be useful.
  • compositions of the present invention may further comprise a PPI that acts as an irreversible inhibitor of the gastric H + ZK + - ATPase proton pump.
  • the PPI used in the present invention can be any substituted benzimidazole compound having H + , K + -ATPase inhibiting activity.
  • the term "PPI” shall mean any substituted benzimidazole possessing pharmacological activity as an inhibitor of H + ,K + - ATPase, including, but not limited to, omeprazole, lansoprazole, pantoprazole, rabeprazole, dontoprazole, perprazole (s-omeprazole magnesium), donprazole, ransoprazole, pariprazole, tenatoprazole and leminoprazole in neutral form or a salt form, a single enantiomer or isomer or other derivative or an alkaline salt of an enantiomer of the same.
  • gastric H + ZK + - ATPase proton pump inhibitors examples include gastric H + ZK + - ATPase proton pump inhibitors.
  • European Patent Nos. 322133 and 404322 disclose quinazoline derivatives
  • European Patent No. 259174 describes quinoline derivatives
  • WO 91/13337 and US Patent 5,750,531 disclose pyrimidine derivatives, as proton pump inhibitors.
  • Suitable proton pump inhibitors are also disclosed for example in EP-A1-174726, EP-A1-166287, GB 2 163 747 and W090/06925, W091/19711, W091/19712, W094/27988 and W095/01977.
  • any proton pump inhibitor that is activated within the acid canaliculi and inhibits the activity of the H + /K + -adenosine triphosphatase (ATPase) proton pump may be used in combination with the endoperoxide-containing compound of the present invention.
  • Particularly preferred PPIs include, but are not limited to omeprazole, esomeprazole, rabeprazole, lansoprazole, tenatoprazole and pantoprazole and derivatives or analogues thereof.
  • compositions of the present invention may further comprise an H 2 blocker.
  • H 2 blockers it is referred to herein in a broad sense and is meant to include those agents that inhibit or block the secretion of gastric acid by binding to a specific histamine receptor on the parietal cell membrane located in the stomach.
  • Exemplary of H 2 blockers contemplated by the present invention are cimetidine, ranitidine, nizatidine and famotidine.
  • H 2 blockers Histamine H 2 receptor blocking agents
  • H 2 blockers are a class of drugs which act as antagonists of the histamine H 2 receptor.
  • H 2 blockers are currently sold as prescription drugs in the United States for the treatment of medical conditions such as active duodenal ulcer, and pathological hypersecretory conditions such as Zollinger- Ellison syndrome and systemic mastocytosis.
  • Some H 2 blockers have also been approved for the prophylactic treatment of reflux esophagitis.
  • H 2 blockers are effective means of inhibiting gastric acid secretion. Such compounds have a delayed onset, generally one to two hours after ingestion, and a long duration of action.
  • Suitable H 2 blockers include, without limitation, the commercially available compounds, cimetidine (TAGAMET®, sold by SmithKline Beecham), famotidine (PEPCID®, sold by Merck, Sharp & Dohme), ranitidine (ZANTAC®, sold by Glaxo), nizatidine (AXID®, sold by Eli Lilly) as well as others reported in the literature such as etintidine, lupitidine, mifentidine, niperotidine, roxatidine, sufotidine, tuvatidine and zaltidine.
  • TAGAMET® sold by SmithKline Beecham
  • PEPCID® famotidine
  • ZANTAC® ranitidine
  • nizatidine AXID®, sold by Eli Lilly
  • compositions of the present invention optionally comprise a PPI and/or H 2 blocker in an effective amount to achieve a pharmacological effect or therapeutic improvement without undue adverse side effects.
  • a therapeutic improvement includes but is not limited to: raising of gastric pH, treatment of gastrointestinal bleeding, or improvement or elimination of symptoms.
  • the typical daily dose of the PPI varies and will depend on various factors such as the individual requirements of the patients and the disease to be treated, hi general, the daily dose of PPI will be in the range of 1-400 mg.
  • a preferred standard approximate amount of a PPI present in the composition is typically about 20-40 mg of omeprazole, about 30 mg lansoprazole, about 40 mg pantoprazole, about 20 mg rabeprazole, and the pharmacologically equivalent doses of the following PPIs: donprazole, pariprazole, dontoprazole, ransoprazole, perprazole (s-omeprazole magnesium), tenatoprazole and leminoprazole.
  • the amount included in the single dosages is believed to be in the range of 10-500 mg, more preferably 50-300 mg per dosage unit, administered, for example, 1 to 4 times per day, preferably once or twice per day.
  • compositions of the present invention may further comprise a reversible proton pump inhibitor (potassium competitive acid blockers such as AZ0865, CS526, Revaprazan and Soraprazan), sucralfate, a buffering agent, antacid, a non-steroidal anti-inflammatory (NSAID) drug and a bismuth-containing compound.
  • a reversible proton pump inhibitor such as AZ0865, CS526, Revaprazan and Soraprazan
  • sucralfate such as AZ0865, CS526, Revaprazan and Soraprazan
  • sucralfate such as AZ0865, CS526, Revaprazan and Soraprazan
  • buffering agent such as AZ0865, CS526, Revaprazan and Soraprazan
  • antacid such as AZ0865, CS526, Revaprazan and Soraprazan
  • NSAID non-steroidal anti-inflammatory
  • NSAID drugs With respect to NSAID drugs, long-term use of nonsteroidal anti-inflammatory drugs are associated with serious and sometimes fatal gastrointestinal side effects such as stomach ulcers and bleeding. At particular risk are people who take NSAIDs for a year or longer, such as for relief from the symptoms of chronic arthritis. These side effects are caused primarily by the reduction of prostaglandin formation by inhibiting the enzyme cyclooxygenase. Without being bound by theory, it is possible that artemisinin or the active derivative thereof may increase prostaglandin levels in the stomach, thus providing advantage of the combination of artemisinin or the active derivative thereof with NSAID.
  • compositions of the present invention may include one or more of the following active drugs in combination with the endoperoxide-bearing compounds: an antibacterial agent, an inhibitor of gastric acid secretion, a proton pump inhibitor (PPI), potassium- competitive acid blockers, an H 2 blocker, sucralfate, a buffering agent, antacid, an nonsteroidal anti-inflammatory (NSAID) drug and a bismuth-containing compound.
  • an antibacterial agent an inhibitor of gastric acid secretion
  • PPI proton pump inhibitor
  • potassium- competitive acid blockers an H 2 blocker
  • sucralfate a buffering agent
  • antacid antacid
  • NSAID nonsteroidal anti-inflammatory
  • compositions of the present invention may also include one or more of the following active drugs in combination with the endoperoxide-bearing compounds: mucosal protective drags (e.g., sucralfate, rebamipide, teprenone etc.), mucosal covering drags (e.g., sodium alginate, azunol preparation etc.), tissue repair accelerating drags (e.g., aceglutamide aluminum, aldioxa, gefalnate etc.), mucus production accelerating drugs (e.g., proglumide, teprenone, secretin, aldioxa etc.), mucosal microcirculation improving drugs (e.g., cetraxate hydrochloride, benexate, sulpirid etc.), prostaglandin synthesis accelerating drugs (e.g., sofalcone) and prostaglandin preparations (e.g., ornoprostil, misoprostol, enprostil etc.
  • the present invention further relates to a method of treating a subject suffering from a disorder in which suppression of gastric acid secretion or reduction of gastric acidity is required, or a disorder normally treated by suppression of gastric acid secretion.
  • the method comprises administering to the subject a pharmaceutical composition comprising one or more endoperoxide-bearing compounds as gastric acid secretion inhibitors and optionally a PPI and/or an H 2 blocker, a reversible proton pump inhibitor, sucralfate, a buffering agent, antacid, a non-steroidal anti-inflammatory (NSAID) drug and a bismuth- containing compound.
  • a pharmaceutical composition comprising one or more endoperoxide-bearing compounds as gastric acid secretion inhibitors and optionally a PPI and/or an H 2 blocker, a reversible proton pump inhibitor, sucralfate, a buffering agent, antacid, a non-steroidal anti-inflammatory (NSAID) drug and a bismut
  • compositions of the present invention may be used for preventing or treating pathologies in a mammal in which inhibition of gastric acid secretion or reducing gastric acidity is required.
  • the compositions of the present invention are effective both in treating the pathologies and in minimizing the risk of development of such pathologies before onset.
  • pathologies include for example: reflux esophagitis, gastritis, duodenitis, gastric ulcer and duodenal ulcer.
  • the compositions of the present invention may be used for treatment or prevention of other gastrointestinal disorders where gastric acid inhibitory effect is desirable, e.g.
  • NSAID nonsteroidal anti-inflammatory drags
  • GSD gastroesophageal reflux disease
  • gastrinomas in patients on nonsteroidal anti-inflammatory drags (NSAID) therapy (including low dose aspirin), in patients with Non Ulcer Dyspepsia, in patients with symptomatic gastroesophageal reflux disease (GERD), and in patients with gastrinomas.
  • NSAID nonsteroidal anti-inflammatory drags
  • GOD gastroesophageal reflux disease
  • gastrinomas gastrinomas.
  • They may also be used in patients in intensive care situations, in patients with acute upper gastrointestinal bleeding such as bleeding peptic ulcers, in patients with nonvariceal upper gastrointestinal bleeding, for prevention of stress-related mucosal bleeding, in conditions of pre-and postoperatively to prevent aspiration of gastric acid and to prevent and treat stress ulceration. Further, they may be useful in the treatment of Helicobacter infections and diseases related to these.
  • compositions of the present invention may also be used as prophylaxis or treatment for mucosal damage in patients undergoing cancer chemotherapy.
  • the compositions may be used in order to provide symptom relief and prophylaxis against upper GI ulceration in patients receiving cancer chemotherapy.
  • the compositions may be used in any other condition in which elevation of gastric pH is required such as when acid-labile drugs are administered and there is a risk that the acidic conditions in the stomach will damage the drugs.
  • the compositions of the present invention may be used in combination with any acid-labile drug in order to protect the acid- labile drug from the acidic conditions in the stomach.
  • the oral compositions may further comprise mucosal protectants, such as bismuth- containing compounds and sucralfate.
  • mucosal protectants such as bismuth-containing compounds and sucralfate.
  • Bismuth-containing compounds are well known, being used widely to treat a variety of gastrointestinal disorders such as nausea, heartburn, and diarrhea.
  • One such product is liquid Pepto-Bismol (sold by The Procter & Gamble Company). This product contains bismuth/subsalicylate and a methylcellulose/magnesium aluminum silicate suspension system.
  • Pabizol with Paregoric is a liquid suspension said to contain, in addition to opium, bismuth subsalicylate (17.0 mg/ml), aluminum magnesium silicate (8.83 mg/ml), and hydroxypropylmethylcellulose (6.7 mg/ml).
  • the oral compositions may further comprise an antibacterial agent for the treatment of ulcers associated with Helicobacter sp infection (e.g. Helicobacter pylori).
  • antibacterial agents include, for example, amoxicillin, clarithromycin or other macrolides, metronidazole and related antibiotics, tetracycline, quinolones, rifabutin or furazolidone.
  • the PPIs used in the present invention can be used in neutral form or in the form of a salt (e. g., an alkaline salt), such as for instance the Mg +2 , CA +2 , NA + , K + , or Li + salts, preferably the Mg +2 salts.
  • a salt e. g., an alkaline salt
  • the compounds can be used in racemic form or in the form of an enantiomer thereof, or salts of the racemates or the single enantiomers.
  • the H 2 blockers used in the present invention can be used in the form of specific polymorphic crystalline forms, such as Form 1 or Form 2 polymorphs of ranitidine.
  • AU PPIs are acid-labile drugs, therefore the PPI particles in the present composition are preferably formulated as pH-dependent enteric-coated granules or time-dependent release polymers in order to avoid contact with the gastric juice in the stomach.
  • suitable pH-dependent enteric-coated polymers to be used in the present invention are: cellulose acetate phthalate, hydroxypropylnethylcellulose phthalate, polyvinylacetate phthalate, methacrylic acid copolymer, shellac, hydroxypropylmethylcellulose succinate, cellulose acetate trimellitate, and mixtures of any of the foregoing.
  • a suitable commercially available enteric material, for example, is sold under the trademark Eudragit L 100-55. This coating can be spray coated onto the substrate.
  • the active ingredients of the present invention may be coated with suitable non-enteric time-dependent release coatings such as for example: film-forming compounds such as cellulosic derivatives, such as methylcellulose, hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose, and/or acrylic polymers including the non-enteric forms of the Eudragit brand polymers.
  • film-forming compounds such as cellulosic derivatives, such as methylcellulose, hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose, and/or acrylic polymers including the non-enteric forms of the Eudragit brand polymers.
  • film-forming materials such as cellulosic derivatives, such as methylcellulose, hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose, and/or acrylic polymers including the non-enteric forms of the Eudragit brand polymers.
  • HPMC hydroxypropyl methylcellulose
  • acrylic polymers including the non-enteric forms of the Eudragit brand polymers.
  • These other film forming materials generally include polyvinylpyrrolidone), Zein, ⁇ oly(ethylene glycol), poly(ethylene oxide), polyvinyl alcohol), polyvinyl acetate), and ethyl cellulose, as well as other pharmaceutically acceptable hydrophilic and hydrophobic film-forming materials.
  • These film-forming materials may be applied to the substrate cores using water as the vehicle or, alternatively, a solvent system. Hydro-alcoholic systems may also be employed to serve as a vehicle for film formation.
  • chitosan and its derivatives such as trimethylchitosan
  • water soluble polysaccharide gums such as carrageenan, fucoidan, gum ghatti, tragacanth, arabinogalactan, pectin, and xanthan
  • water-soluble salts of polysaccharide gums such as sodium alginate, sodium tragacanthin, and sodium gum ghattate
  • water-soluble hydroxyalkylcellulose wherein the alkyl member is straight or branched of 1 to 7 carbons such as hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose
  • synthetic water-soluble cellulose-based lamina formers such as methyl cellulose and its hydroxyalkyl methylcellulose cellulose derivatives such as a member selected from the group consisting of hydroxyethyl methylcellulose, hydroxypropyl methylcellulose, and hydroxybutyl
  • lamina forming materials that can be used for this purpose include polyvinylpyrrolidone), polyvinylalcohol, polyethylene oxide, a blend of gelatin and polyvinylpyrrolidone, gelatin, glucose, saccharides, povidone, copovidone, poly(vinylpyrrolidone)-poly(vinyl acetate) copolymer.
  • buffering agents to the enteric-coated formulation in order to facilitate the release of the PPI from the enteric-coated pellets, thereby enhancing the absorption of the PPI in blood.
  • a buffeing agent such as for example sodium bicarbonate may be added in an amount sufficient to provide a pH above 5 in the stomach. For example, between 300 to 2,000 mg of sodium bicarbonate may be added to the formulation. If fast absorption of PPI in blood is required, it is possible to use non-enteric PPI pellets in the present formulations, hi this case, the stability of the PPI in the stomach will be preserved due to the buffering agent that provides a pH above 5 in the stomach.
  • the active compounds used in the methods of the present invention may be administered by intravenous, parenteral, rectal, transdermal or oral means, hi preferred embodiments of the present invention, the pharmaceutical compositions are administered orally.
  • Such oral dosage forms may contain the active compound in immediate or sustained release form.
  • the endoperoxide-bearing compounds are formulated in a composition designed to act locally in the stomach following oral administration to reduce acid secretion. Since the preferred compounds such as artemisinin or the active derivatives thereof are not soluble in the acidic conditions of the gastric fluid, it is necessary to preserve its solubility in the stomach in order to permit the active compound to act locally.
  • the compositions may further comprise agents that maintain the solubility of the endoperoxide- bearing compound in the gastric fluids.
  • Such agents are preferably alkaline agents or antacids that when dissolved in the gastric juice are capable of elevating the pH of the gastric fluids to a pH in which at least significant proportion of the endoperoxide-bearing compound remains soluble in the gastric fluids.
  • Buffering agents to be used in the present invention include for example: sodium or potassium bicarbonate, magnesium oxide, hydroxide or carbonate, magnesium lactate, magnesium glucomate, aluminum hydroxide, aluminium, calcium, sodium or potassium carbonate, phosphate or citrate, di-sodium carbonate, disodium hydrogen phosphate, a mixture of aluminum glycinate and a buffer, calcium hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate, and other calcium salts. It is noted that while sodium bicarbonate dissolves easily in water, calcium carbonate is water-insoluble and is slowly soluble only in acidic environment. Therefore, calcium carbonate may be useful when sustained dissolution of the alkaline agent in the stomach is desired.
  • Examples of antacids to be used in the present invention include one or more of the following: alumina, calcium carbonate, and sodium bicarbonate; alumina and magnesia; alumina, magnesia, calcium carbonate, and simethicone; alumina, magnesia, and magnesium carbonate; alumina, magnesia, magnesium carbonate, and simethicone; alumina, magnesia, and simethicone; alumina, magnesium alginate, and magnesium carbonate; alumina and magnesium carbonate; alumina, magnesium carbonate, and simethicone; alumina, magnesium carbonate, and sodium bicarbonate; alumina and magnesium trisilicate; alumina, magnesium trisilicate, and sodium bicarbonate; alumina and simethicone; alumina and sodium bicarbonate; aluminum carbonate, basic; aluminum carbonate, basic, and simethicone; aluminum hydroxide; calcium carbonate; calcium carbonate and magnesia; calcium carbonate, magnes
  • the oral dosage forms may be in the form of tablets, capsules, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, multiparticulate formulations, syrups, elixirs, and the like.
  • Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohols, gum arabic, vegetable oils, benzyl alcohols, polyethylene glycols, gelate, carbohydrates such as lactose, amylose or starch, magnesium stearate talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidone, etc.
  • the pharmaceutical preparations can be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring
  • compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients which are suitable for the manufacture of tablets.
  • excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate.
  • the tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.
  • the present invention also includes a pharmaceutical kit, preferably an oral pharmaceutical kit.
  • the kit typically comprises as active ingredients a pharmaceutically effective amount of: (i) one or more endoperoxide-bearing compounds according to the present invention; and (ii) a substituted benzimidazole H + ZK + -ATPaSe proton pump inhibitor and/or an H 2 blocker.
  • the active ingredients are formulated in separate dosage unit forms.
  • the kit may be used to treat or prevent a disorder in a subject in which suppression of gastric acid secretion or reducing gastric acidity is required by administering to a subject the active ingredients.
  • the one or more endoperoxide-bearing compounds are typically administered simultaneously, prior to or following the administration of the PPI and/or an H 2 blocker.
  • compositions of the endoperoxide-bearing compounds of the invention generally comprise an amount of the endoperoxide compounds sufficient to suppress gastric acid secretion or to reduce gastric acidity, together with a pharmaceutically acceptable carrier.
  • the compositions are typically administered to a human or other animal subject in an amount to localize a sufficient amount of the endoperoxide-bearing compounds at the stomach to facilitate the anti-acid effect.
  • Any pharmaceutically acceptable carrier may be generally used for this purpose, provided that the carrier does not significantly interfere with the stability or bioavailability of the sesquiterpene compounds of the invention. ⁇ .
  • the particles may be formed into a packed mass for ingestion by conventional techniques.
  • the particles may be encapsulated as a "hard-filled capsule" using known encapsulating procedures and materials.
  • the encapsulating material should be highly soluble in gastric fluid so that the particles are rapidly dispersed in the stomach after the capsule is ingested.
  • the active ingredients of the present invention are packaged in compressed tablets.
  • compressed tablet generally refers to a plain, uncoated tablet for oral ingestion, prepared by a single compression or by pre-compaction tapping followed by a final compression.
  • Such solid forms can be manufactured as is well known in the art. Tablet forms can include, for example, one or more of lactose, mannitol, corn starch, potato starch, microcrystalline cellulose, acacia, gelatin, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, moistening agents, preservatives, flavoring agents, and pharmaceutically compatible carriers.
  • the manufacturing processes may employ one, or a combination of, four established methods: (1) dry mixing; (2) direct compression; (3) milling; and (4) non-aqueous granulation.
  • Such tablets may also comprise film coatings, which preferably dissolve upon oral ingestion or upon contact with diluent.
  • compositions of the present invention are formulated in compressed forms, such as suspension tablets and effervescent tablets, such that upon reaction with water or other diluents, the aqueous form of the composition is produced for oral administration.
  • compressed forms such as suspension tablets and effervescent tablets
  • aqueous form of the composition is produced for oral administration.
  • These forms are particularly useful for medicating children and the elderly and others in a way that is much more acceptable than swallowing or chewing a tablet.
  • the present pharmaceutical tablets or other solid dosage forms disintegrate the alkaline agent with minimal shaking or agitation.
  • sustained tablets refers to compressed tablets which rapidly disintegrate after they are placed in water, and are readily dispersible to form a suspension containing a precise dosage of the PPI and the parietal cell activator.
  • a disintegrant such as croscarmellose sodium may be added to the formulation.
  • the disintegrant may be blended in compressed tablet formulations either alone or in combination with microcrystalline cellulose, which is well known for its ability to improve compressibility of difficult to compress tablet materials.
  • microcrystalline cellulose alone or co-processed with other ingredients, is also a common additive for compressed tablets and is well known for its ability to improve compressibility of difficult to compress tablet materials. It is commercially available under the Avicel trademark.
  • the suspension tablet composition may, in addition to the ingredients described above, contain other ingredients often used in pharmaceutical tablets, including flavoring agents, sweetening agents, flow aids, lubricants or other common tablet adjuvants, as will be apparent to those skilled in the art.
  • Other disintegrants such as crospividone and sodium starch glycolate may be employed, although croscarmellose sodium is preferred.
  • compositions of the invention can be administered in any effective pharmaceutically acceptable form to warm blooded animals, including human and other animal subjects, e.g., oral, suppository, parenteral, or infusable dosage forms, or in any other manner effective to deliver the agents to the target tissue.
  • the route of administration will preferably be designed to optimize delivery and localization of the agents to the target tissue.
  • Compositions designed, for injection may comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, suspensions or emulsions.
  • suitable nonaqueous carriers, diluents, solvents, or vehicles include propylene glycol, polyethylene glycol, vegetable oils, such as olive oil, and injectable organic esters such as ethyl oleate.
  • compositions may also comprise adjuvants such as preserving, wetting, emulsifying, and dispensing agents. They may be sterilized, for example, by filtration through a bacteria- retaining filter, or by incorporating sterilizing agents into the compositions. They can also be manufactured in the -form of sterile solid compositions that can be dissolved or suspended in sterile water, saline, or other injectable medium prior to administration.
  • adjuvants such as preserving, wetting, emulsifying, and dispensing agents.
  • They may be sterilized, for example, by filtration through a bacteria- retaining filter, or by incorporating sterilizing agents into the compositions. They can also be manufactured in the -form of sterile solid compositions that can be dissolved or suspended in sterile water, saline, or other injectable medium prior to administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, suppositories, powders, and granules.
  • the compositions may be admixed with at least one inert diluent such as sucrose, lactose, or starch, and may additionally comprise lubricating agents, buffering agents, enteric coatings, and other components well known to those skilled in the art.
  • concentrations of the endoperoxide-containing compounds in the formulations to be applied in the practice of the present invention will generally range up to the maximally tolerated dosage, but the concentrations are not critical and may vary widely. For artemisinin and its analogs, however, best results will be obtained using formulations containing the compounds at levels of from about 0.1 to about 100 mg per kilogram of body weight per day, preferably from about 1 to about 100 mg per kilogram of body weight per day, and most preferably from about 1 to about 20 mg per kilogram of body weight per day.
  • the precise amounts employed by the attending physician will vary, of course, depending on the compound, route of administration, and physical condition of the patient and other factors.
  • the daily dosage may be administered as a single dosage or may be divided into multiple doses for administration.
  • the amount of the compound actually administered for treatment will be a therapeutically effective amount, which term is used herein to denote the amount needed to produce a substantial clinical improvement or an amount sufficient to inhibit growth of the bacteria in the subject.
  • Optimal amounts will vary with the method of administration, and will generally be in accordance with the amounts of conventional medicaments administered in the same or a similar form. Oral administration, for instance, may typically be done from once to three times a day.
  • Example 1 Artesunate is capable of reducing gastric acidity and to enhance the effect of pantoprazole on gastric acid secretion
  • the animals were then placed back into their cage for additional 3.5 hours after which the animals were sacrificed.
  • the ligature was placed around the esophagus, the stomach removed and gastric content was collected. Following centrifugation, the gastric output and the pH of the gastric juice samples was determined. Data is presented as average ⁇ SEM of gastric output (in mEq) or pH values. The number of animals was 6-8 in each experimental group.
  • Example 3 Dose response of artesunate in reducing gastric acidity secretion following administration by oral gavage
  • Example 4 Administration of artesunate in combination with ranitidine resulted in complete inhibition of gastric output
  • Example 5 Intravenous artesunate is capable of inhibiting gastric acid secretion
  • Example 6 The effect of intravenous artesunate in combination with indomethacin on gastric acid output.
  • Animals were anesthetized using anesthetic gas machine for a short period (5 minutes) that is sufficient to perform pylorus ligation and to administer artesunate (ASN, 40 mg/kg) by intravenous injection and/or indomethacin subcutaneously (INDO, 9.3 mg/kg).
  • ASN artesunate
  • INDO indomethacin subcutaneously
  • Sodium bicarbonate was administered as a placebo.
  • the animals were then placed back into their cage for additional 3.5 hours after which the animals were sacrificed and gastric content was collected.
  • indomethacin reversed the effect of artesunate in reducing gastric acid output.
  • Indometacin is a nonselective inhibitor of cyclooxygenase (COX) 1 and 2, enzymes that participate in prostaglandin synthesis from arachidonic acid.
  • COX cyclooxygenase
  • indomethacin itself led to a significant increase in gastric acid output (probably due to its inhibitory effect on the synthesis of prostaglandins).
  • Example 7 Administration of oral artesunate (45 mg/kg) in combination with omeprazole (10 mg/kg) resulted in complete inhibition of gastric output
  • pantoprazole PAN
  • FIG 8A pantoprazole (PAN) alone effectively reduced gastric output.
  • Administration of 20 mg/kg or 40 mg/kg of artesunate in combination with pantoprazole resulted in total inhibition of gastric output.
  • Figure 8B further demonstrates that treatment with a combination of artesunate and pantoprazole was much more effective in increasing the gastric pH compared to pantoprazole alone.
  • Example 9 The effect of intravenous artesunate (15, 30 and 60 mg/kg) on gastric output andpH of gastric fluid
  • Example 10 Oral formulations comprising artesunate and optionally a proton pump inhibitor (PPI) and/or ranitidine:
  • PPI proton pump inhibitor
  • Hard gelatin capsules may contain granules of artesunate in an immediate release or delayed release formulation.
  • the granules may be packed into a hard gelatin capsule in an amount corresponding to 250 mg artesunate per capsule.
  • granules of between 300 to 2,000 mg of sodium bicarbonate may be added in order to permit local activity of artesunate in the stomach.
  • Hard gelatin capsules may contain a mixed granules population of artesunate and PPI and/or ranitidine.
  • Artesunate and ranitidine granules are in an immediate release or delayed release formulation and PPI is formulated as enteric-coated granules or time- dependent release coating (delayed release).
  • Granules may be packed into a hard gelatin capsule in an amount corresponding to 40 mg PPI and/or 150 mg ranitidine and 250 mg artesunate per capsule.
  • granules of between 300 to 2,000 mg of sodium bicarbonate may be added.
  • artesunate solution is sprayed on inert beads in a fluid bed apparatus. After drying, the artesunate beads are further coated with hydroxypropyl methylcellulose (HPMC) to form the final granules.
  • HPMC hydroxypropyl methylcellulose
  • the rate of artesunate release is determined by the thickness and erosion rate of the HPMC layer. Tablets or caplets of artesunate and PPI and/or ranitidine
  • the pharmaceutical composition may be in the form of tablet or more preferably caplet.
  • the caplet contains a mixed granules population of artesunate (immediate release or delayed release, as mentioned above), enteric-coated or time-dependent release coated PPI (stable under compression pressure) and/or ranitidine and a wide variety of conventional tableting aid agents to be compressed into a caplet formulation.
  • Artesunate is granulated with a combination of Polyox WSR N60 and HPMC KlOOM. These granules are further combined with lactose and HPMC and later on compressed into mini-tabs with the ability of fast swelling into size, big enough to enable gastric retention.
  • the polymeric matrix controls the artesunate release into the stomach.
  • the artesunate mini-tabs are mixed with enteric-coated PPI and/or ranitidine pellets and filled into hard gelatin capsules. Following disintegration of the capsules gelatinic body, the PPI and/or ranitidine pellets pass though the stomach to the duodenum, where the enteric coat will dissolve. The artesunate mini-tabs remain in the stomach and slowly release their content in a controlled release gastro retentive manner. Press coated tablet of artesunate and PPI and/or ranitidine
  • the tablet's internal core is composed of artesunate combined with a mixture of hydrogels aimed for controlled release and prompt swelling of the dosage form.
  • the expanded core has gastro-retentive properties. Mixtures of gums like: xantan gum, gellan gum, together with cellulose derivatives such as sodium carboxymethylcellulose or HPMC may be applied.
  • the core is further coated with an external layer composed of enteric-coated PPI and/or ranitidine pellets (stable under compression pressure) together with appropriate filler, which disintegrates immediately after digestion and promptly releases the PPI and/or ranitidine.
  • the final product is a tablet composed of an internal controlled-release core of artesunate and an outer layer, immediate release type with the enteric-coated or time- dependent release coated PPI and/or ranitidine. Powder for oral suspension of artesunate or artesunate and PPI and/or ranitidine
  • Powder for oral suspension is comprised of artesunate or artesunate and enteric- coated or time-dependent release coated PPI granules and/or ranitidine granules.
  • Artesunate granules may be in immediate release or delayed release formulation (as mentioned above).
  • PPI are formulated as enteric-coated or time-dependent release coated granules (delayed release).
  • the composition comes in individual packets to be constituted with water. When mixed with water, powder becomes a uniform liquid suspension. Injectable preparation of artesunate
  • Artesunate liquid solution is prepared by dissolving 60 mg artesunate in 5% sodium bicarbonate and shaking vigorously till the solution becomes clear. The solution is further mixed with normal saline. To prepare a dose form for intravenous administration, the resulting solution is dispensed into sealable translucent plastic bags for use in intravenous administration of the compound.

Abstract

La présente invention concerne des compositions à utiliser dans des états pathologiques pour lesquels la réduction de l'acidité gastrique ou l'inhibition de la sécrétion d'acides gastriques est avantageuse. Les compositions comprennent un ou plusieurs composés portant des fonctions endoperoxyde qui inhibent efficacement la sécrétion d'acides gastriques ou réduisent efficacement l'acidité gastrique. Les compositions selon la présente invention comprennent en outre de préférence un inhibiteur de la pompe à protons (PPI) H+ZK+-ATPaSe ou bloqueur ffe de type benzimidazole substitué pour obtenir une réduction de l'acidité gastrique ou une inhibition de la sécrétion d'acides gastriques plus efficaces.
PCT/IB2007/001078 2006-04-27 2007-04-25 Compositions et méthodes d'inhibition de l'acidité gastrique en utilisant des composés contenant un pont endoperoxyde WO2007125397A2 (fr)

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US9623005B2 (en) 2011-06-10 2017-04-18 Queen Mary University Of London Artemisinin and its derivatives for use in the treatment of trauma haemorrhage and associated conditions
EP3269371A1 (fr) * 2011-06-10 2018-01-17 Queen Mary University of London Artémisinine et ses dérivés destinées au traitement de l'ischémie myocardique ou de la maladie coronarienne
US9949948B2 (en) 2011-06-10 2018-04-24 Queen Mary University Of London Artemisinin and its derivatives for use in the treatment of trauma haemorrhage and associated conditions
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