WO2008151415A1 - Combinaison destinée au traitement du diabète sucré - Google Patents

Combinaison destinée au traitement du diabète sucré Download PDF

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WO2008151415A1
WO2008151415A1 PCT/CA2008/001093 CA2008001093W WO2008151415A1 WO 2008151415 A1 WO2008151415 A1 WO 2008151415A1 CA 2008001093 W CA2008001093 W CA 2008001093W WO 2008151415 A1 WO2008151415 A1 WO 2008151415A1
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pharmaceutically acceptable
combination
acceptable salts
omeprazole
carrier
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PCT/CA2008/001093
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WO2008151415A8 (fr
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Nathan Bryson
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Nathan Bryson
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    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to drugs for the treatment of diabetes.
  • this invention relates to a particular combination drugs for the treatment of diabetes.
  • Diabetes is one of the most common endocrine diseases across all age groups and populations. In addition to the clinical morbidity and mortality, the economic cost of diabetes is huge, exceeding $90 billion per year in the US alone, and the prevalence of diabetes is expected to increase more than two-fold by the year 2010.
  • Type 1 diabetes mellitus IDDM
  • Type 2 diabetes mellitus NIDDM
  • IDDM insulin-dependent diabetes mellitus
  • NIDDM non-insulin-dependent diabetes mellitus
  • Type 1 is usually due to autoimmune destruction of the pancreatic beta cells which produce insulin. Type 1 is lethal unless treatment with exogenous insulin via injections replaces the missing hormone. About 5%-10% of North American diabetics have type 1. Possible cures include pancreas transplantation, islet cell transplantation, artificial pancreas, genetic engineering, stem cell differentiation into islets and islet cell regeneration.
  • Type 2 diabetes is associated with increasing age however there is a trend of increasing numbers of young people diagnosed with NIDDM, so-called maturity onset diabetes of the young (MODY).
  • NIDDM patients typically begin therapy by following a regimen of an optimal diet, weight reduction and exercise. Drug therapy is initiated when these measures no longer provide adequate metabolic control.
  • Initial drug therapy includes sulfonylureas that stimulate .beta.- cell insulin secretion, but also can include biguanides, . alpha. -glucosidase inhibitors, thiazolidenediones and combination therapy. It is noteworthy however that the progressive nature of the disease mechanisms operating in type 2 diabetes are difficult to control. Over 50% of all drug-treated diabetics demonstrate poor glycemic control within six years, irrespective of the drug administered. Insulin therapy is regarded by many as the last resort in the treatment of Type 2 diabetes, and there is patient resistance to the use of insulin.
  • pancreatic beta cell neoqenesis Diabetes and physiological factors associated with pancreatic beta cell neoqenesis
  • Pancreatic islets develop from endodermal stem cells that lie in the fetal ductular pancreatic endothelium, which also contains pluripotent stem cells that develop into the exocrine pancreas. Teitelman and Lee, Developmental Biology, 121 :454-466 (1987); Pictet and Rutter, Development of the embryonic endocrine pancreas, in Endocrinology, Handbook of Physiology, ed. R. O. Greep and E. B. Astwood (1972), American Physiological Society: Washington, D. C, p.25-66. Islet development proceeds through discrete developmental stages during fetal gestation which are punctuated by dramatic transitions.
  • the initial period is a protodifferentiated state which is characterized by the commitment of the pluripotent stem cells to the islet cell lineage, as manifested by the expression of insulin and glucagon by the protodifferentiated cells.
  • These protodifferentiated cells comprise a population of committed islet precursor cells which express only low levels of islet specific gene products and lack the cytodifferentiation of mature islet cells. Pictet and Rutter, supra.
  • the protodifferentiated pancreas begins a phase of rapid growth and differentiation characterized by cytodifferentiation of islet cells and a several hundred fold increase in islet specific gene expression.
  • islet formation becomes apparent as proliferating islets bud from the pancreatic ducts (nesidioblastosis). Just before birth the rate of islet growth slows, and islet neogenesis and nesidioblastosis becomes much less apparent. Concomitant with this, the islets attain a fully differentiated state with maximal levels of insulin gene expression. Therefore, similar to many organs, the completion of cellular differentiation is associated with reduced regenerative potential; the differentiated adult pancreas does not have either the same regenerative potential or proliferative capacity as the developing pancreas.
  • TGF-. alpha. transforming growth factor .alpha.
  • EGF epidermal growth factor
  • Transgenic mice over expressing TGF-. alpha, or gastrin alone did not demonstrate active islet cell growth, however mice expressing both transgenes displayed significantly increased islet cell mass (Wang et al, (1993) J Clin Invest 92: 1349-1356).
  • Bouwens and Pipeleers (1998) Diabetoligia 41 :629-633 report that there is a high proportion of budding .beta.
  • pancreatic islets Since differentiation of protodifferentiated precursors occurs during late fetal development of the pancreas, the factors regulating islet differentiation are likely to be expressed in the pancreas during this period.
  • One of the genes expressed during islet development encodes the gastrointestinal peptide, gastrin.
  • gastrin acts in the adult as a gastric hormone regulating acid secretion, the major site of gastrin expression in the fetus is the pancreatic islets. Brand and Fuller, J. Biol Chem., 263:5341-5347 (1988). Expression of gastrin in the pancreatic islets is transient. It is confined to the period when protodifferentiated islet precursors form differentiated islets.
  • pancreatic gastrin in islet development Although the significance of pancreatic gastrin in islet development is unknown, some clinical observations suggest a rule for gastrin in this islet development as follows. For example, hypergastrinemia caused by gastrin-expressing islet cell tumors and atrophic gastritis is associated with nesidioblastosis similar to that seen in differentiating fetal islets. Sacchi, et al., Virchows Archiv B, 48:261-276 (1985); and Heitz et al., Diabetes, 26:632- 642 (1977). Further, an abnormal persistence of pancreatic gastrin has been documented in a case of infantile nesidioblastosis. Hollande, et al., Gastroenterology, 71 :251-262 (1976). However, in neither observation was a causal relationship established between the nesidioblastosis and gastrin stimulation.
  • Patents US5885956, US6288301, US6558952, US6992060 provide for injectable formulations of gastrin and EGF as a method to promote beta cell neogenesis. This approach requires multiple injections, daily, over a period of several weeks. This is a complicated and painful experience, even if the theoretical outcome is potentially pancreatic regeneration, normoglycemia and normo-insulinemia in the long term.
  • TNF-alpha is an important proinflammatory cytokine.
  • Inflammatory markers such as Tumor Necrosis Factor-alpha (TNF-alpha) have been correlated to degenerative processes associated with diabetes [Nephrology Dialysis Transplantation 2006 21(12) : 3428-3434].
  • TNF-alpha Tumor Necrosis Factor-alpha
  • the autoimmune destruction of pancreatic b cells in insulin-dependent diabetes mellitus is a T cell mediated process.
  • Cytokines including TNF-alpha, released by T cells and activated macrophages are present in the inflammatory infiltrate of pancreatic islets and have a potential role in beta cell destruction.
  • cytokines have damaging effects on beta cells in vitro and are particularly potent when present in combination [Endocrinology 1999, 140: 3219]. TNF-alpha has been implicated in beta cell apoptis/death [The Journal of Immunology, 2001, 166: 4481-4489]
  • PDE inhibitors and more specifically PDE4 inhibitors, are directly involved in immunomodulation, through mechanisms that involve activation of cAMP and reduction of TNF-a production [Toxicol Lett. 2007 Jan 10;168(l): l-6; Scand J Gastroenterol. 2002 Feb;37(2) :206-14.].
  • Pentoxifylline a preferred drug for use in the combination of the invention, is a broad spectrum PDE inhibitor.
  • PDE4 inhibitors include: Rolipram, Mesembrine, Vinpocetine, Amrinone, Bucladesine, Enoximone, Milrinone, Sildenafil, Tadalafil and Vardenafil.
  • Pentoxifylline may also be used to prevent strokes, manage sickle cell disease, improve blood flow to the brain, or to treat nausea and headaches in high places (high- altitude sickness).
  • Pentoxyfylline has been shown to beneficial effects in cerebral malaria and chronic sarcoidosis [Pulmonary Rev 2001, 6,8].
  • Pentoxifylline a methylxanthine, inhibits TNF-alpha production without decreasing insulin growth factor IGF-I [Journal of Endocrinology, VoI 178, Issue 1, 101-109; Am J Respir Crit Care Med. 1999 Feb; 159(2) : 508-ll].
  • Xanthine derivatives decrease production of pro-inflammatory cytokines tumour-necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-I beta) and the de-activating cytokine interleukin-10 (IL-IO) by human leucocytes [Immunology. 1997 June; 91(2): 193-196].
  • TNF-alpha tumour-necrosis factor-alpha
  • IL-I beta interleukin-1 beta
  • IL-IO de-activating cytokine interleukin-10
  • Pentoxifylline has also been shown to aid in the prevention of the development of diabetes in rodent models [Diabetes. 1998, 47(4) : 570-5.] Research in the use of pentoxifylline in diabetes shows that this medication's anti-proteinurea action is in part associated with a decrease in the urinary TNF-alpha [J Am Soc Nephrol 16: 2119-2126, 2005].
  • the present invention relates to a new combination of drugs for treatment of diabetes.
  • This invention relates to a method for treating diabetes mellitus in an individual in need thereof by administering to the individual a composition comprising a phosphodiesterase proton-pump inhibitor and an anti-inflammatory drug is amounts sufficient to result in a diminution of one or more symptoms of diabetes, including the promotion of the differentiation of pancreatic islet precursor cells to mature insulin- secreting cells.
  • the invention also provides for a new composition and methods for treating diabetes mellitus in a patient in need thereof by administering a combination of a proton- pump inhibitor and an anti-inflammatory agent.
  • the proton-pump inhibitor in the combination therapy describes a group of drugs whose main action is pronounced and long-lasting reduction of gastric acid production. They are the most potent inhibitors of acid secretion available today. Structurally, these drugs are substituted benzimidazoles. Examples of proton-pump inhibitors include Esomeprazole, Lansoprazole, Omeprazole, Pantoprazole, Rabeprazole and Tenatoprazole.
  • the anti-inflammatory agent in the combination therapy describe a group of steroidal or non-steroidal anti-inflammatory drugs and include drugs that block one or more of the following receptors or enzymes: one or more of the five subtypes of the enzyme phosphodiesterase (PDE), cycooxygenase receptor (COX receptor), Cortisol receptor and or one or more of the cannabinoid receptors (CB).
  • PDE phosphodiesterase
  • COX receptor cycooxygenase receptor
  • Cortisol receptor Cortisol receptor
  • CB cannabinoid receptors
  • the anti- inflammatory agent in the combination therapy is a phophodiesterase inhibitor. Pentoxifylline, a xanthine derivative, with an excellent safety record over several years, is provided as an example of a broad spectrum phophodiesterase.
  • the anti-inflammatory agent in the combination therapy is specific for the phophodiesterase isoform PDE-4.
  • PDE-4 is the major cAMP-metabolizing enzyme found in inflammatory and immune cells.
  • PDE4 inhibitors have proven potential as anti ⁇ inflammatory drugs especially in airway diseases. They suppress the release of inflammatory signals, e.g., cytokines, and inhibit the production of reactive oxygen species, including an action on TNF-alpha.
  • Rolipram, or the natural product, mesembrine are examples of specific PDE-4 inhibitors.
  • the anti-inflammatory agent is a cannabinoid or endocannabinoid compound.
  • Cannabidiol is an example of a cannabinoid with anti-inflammatory properties.
  • the pharmaceutical composition comprises a therapeutically relevant dose of proton-pump inhibitor to affect an increase in serum gastrin.
  • a therapeutically relevant dose is between about 1.0 milligrams to 100.0 milligrams of a proton-pump inhibitor.
  • the pharmaceutical composition further comprises between about 1 mg and about 1000 mg of a phosphodiesterase inhibitor.
  • composition can be administered orally or by injection.
  • composition can be formulated for oral administration as a liquid or solid dosage form with immediate, slow, delayed or sustained-release characteristics.
  • the pharmaceutical compositions of the present invention are formulated as single oral dosage forms such as oral solutions, oral syrups, soft gelatin capsules, hard gelatin capsules, tablets, suspensions, capsules and sterile packaged powder including pharmaceutically-acceptable excipients.
  • the pharmaceutical composition is formulated in a sustained release carrier that causes the proton-pump inhibitor, the anti-inflammatory agent or both to be released over an extended time period following oral administration to a human patient.
  • the time period of sustained release is a period of about 2 to about 24 hours after being orally administered to the patient.
  • the composition can be formulated or combined into a drug delivery device such that sustained serum levels or therapeutic action can be maintained with reduced frequency of administration.
  • Drug delivery devices include mechanical pumps, osmotic pumps and polymer delivery devices (in-situ forming gels, patches, liposomes, microparticles, implantable rods, hydrogel implants).
  • composition of the present invention acts on a diabetic patient by increasing serum gastrin which has a number of actions including assisting in affecting differentiation of the patient's pancreatic islet precursor cells to mature insulin-secreting cells, and thereby providing newly formed pancreatic cells capable of secreting insulin in response to elevated serum glucose.
  • composition of the present invention acts on a diabetic patient by increasing TNF-alpha which reduces inflammatory cytokines and reduces overarching immune responses, which can have a detrimental effect on newly formed pancreatic cells in a diabetic patient.
  • the invention provides for methods of affecting differentiation of the patient's pancreatic islet precursor cells to mature insulin-secreting cells, while reducing destructive autoimmune responses directed at the newly differentiated cells, by increasing serum gastrin and TNF-alpha levels.
  • pancreatic islet cells that have been grown in culture to increase the number of pancreatic beta cells in the islets from pancreatic islet precursor cells; optionally the population of pancreatic beta cells or pancreatic islet precursor cells can be grown in culture for a time sufficient to expand the population of .beta. -cells prior to transplantation.
  • the methods and compositions find use in treating patients with diabetes.
  • the invention teaches how to affect an increase in serum gastrin and a decrease in serum TNF-alpha through the use of a combination of 2 oral drugs, omeprazole and pentoxyfylline, which are readily available and have excellent safety profiles.
  • the examples below are a demonstration of the invention and are not to imply limitations on the number and/or types of combinations of these classes of drugs that could be efficacious in the different forms of diabetes (Insulino-dependant type 1, insulino-resistant type 2; Alzheimer's and related neuropathies considered potentially as type 3 diabetes), nor limit the formulation possibilities that would be available to those skilled in the art.
  • compositions of the present invention can be administered either by injection or per oral.
  • oral method is preferred.
  • the active ingredients may be necessary to mill the active ingredients to provide the appropriate particle size prior to combining with the other ingredients, such as excipients. If the active compounds are substantially insoluble, they are ordinarily milled to a particle size of less than 200 mesh. If an active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • the compositions are preferably formulated in a unit dosage form, each dosage containing an effective therapeutic dose of the active ingredients.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient.
  • the active ingredients described above are typically employed at no more than about 95 weight percent of the pharmaceutical composition, more preferably no more than about 75 weight percent, with the balance being pharmaceutically inert carrier(s) and excipients.
  • the active compounds are effective over wide dosage ranges and are generally administered in pharmaceutically effective amounts. It will be understood, however, that the amount of the compounds actually administered will be determined by the potency of the combination created.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • a pharmaceutical excipient for preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • these preformulation compositions as homogeneous, it is meant that the active ingredients are dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets or capsules.
  • the pharmaceutically active ingredients, of the present invention as crystalline powders, in milled form or as tablets or capsules may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or capsule can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be coated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate as are known in the art. In this way the dose is released slowly over about 2 hours to about 24 hours.
  • the pharmaceutical composition is formulated to release both pharmaceutical agents in a sustained release manner.
  • compositions of the present invention may be incorporated for administration include aqueous solutions, suitably flavoured syrups, oil suspensions and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil as well as elixirs and similar pharmaceutical vehicles, whose pH is appropriately adjusted to maintain the stability of the components of the composition of the invention.
  • aqueous solutions suitably flavoured syrups, oil suspensions and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil as well as elixirs and similar pharmaceutical vehicles, whose pH is appropriately adjusted to maintain the stability of the components of the composition of the invention.
  • the present invention is directed to a method of treating diabetes comprising the concomitant or, alternatively, sequential administration of two components.
  • the first component of the present invention consists of a pharmaceutical composition containing as an active ingredient a proton-pump inhibitor, or a pharmaceutically acceptable salt or ester of said compound, in an amount to affect an increase in serum gastrin levels.
  • the second component consists of a pharmaceutical composition containing as an active ingredient an anti-inflammatory compound which suppresses undesirable cytokine production, and more specifically, decreases TNF-a production.
  • the amount of each component in the combination is such that the combination is therapeutically effective to treat or ameliorate a the diabetic condition.
  • the amount of each component administered according to the present method may, but does not have to be therapeutically effective by itself.
  • this invention specifically contemplates combinations wherein the amount of proton-pump inhibitor and anti-inflammatory agent in the combination is less than a therapeutically effective amount as judged by the amounts recommended in monotherapy (i.e. a "suboptimal" amount).
  • the synergistic effect results in an improved therapeutic index as compared to either agent alone while toxicity remains acceptable.
  • the active ingredients of the combination are administered to the patient in an oral unit dosage form, more preferably in capsule or tablet form.
  • administration of the combination occurs over a 21- 28 day cycle (that is, a 3 to 4 weeks cycle), which may be repeated at regular intervals or as required to improve the condition, as measured by reduced fasting serum glucose, improved glucose tolerance, improved insulin sensitivity, or a improvement of other related gluco-regulatory conditions.
  • Example 1 Omeprazole is prepared for intraperitoneal administration in 40 sodium hydroxide/sodium bicarbonate buffer (pH 8.3) in a lOmg/ml solution which is filtered 0.45- ⁇ m-pore-size just prior to use. Pentoxifylline is dissolved in sterile, pyrogen-free water to produce a stock solution at a concentration of 20mg/ml. The stock solution is passed through a 0.45- ⁇ m-pore-size filter. The drug is further diluted to the desired concentrations with sterile, pyrogen-free PBS and was used immediately.
  • PBS sodium hydroxide/sodium bicarbonate buffer
  • 3 groups of NOD mice 9 weeks of age are treated one or twice daily with IP injections with 80mg/kg of an isotonic solution of pentoxifylline, 40mg/kg of an isotonic solution of omeprazole, or a combination of both agents for a period of 28 days.
  • IP injections 80mg/kg of an isotonic solution of pentoxifylline, 40mg/kg of an isotonic solution of omeprazole, or a combination of both agents for a period of 28 days.
  • fasting glucose and HbAIc levels are lower than untreated controls and approach normo-glycemia.
  • Example 2 3 groups of NOD mice 9 weeks of age are fed chow modified by incorporation of 0.4% pentoxifylline, 0.4% omeprazole, or a combination of both agents (2% pentoxifylline + 2% mg/kg omeprazole) for a period of 28 days. At Day 30 and for 6 months post-treatment, fasting glucose and HbAIc levels are lower than untreated controls and approach normo-glycemia.
  • Example 3 3 groups of NOD mice 9 weeks of age are treated by IP injection as per example 1 with 8mg/kg rolipram alone, 100 mg/kg omeprazole alone, or a combination of both agents (8mg/kg rolipram + 100 mg/kg omeprazole) for a period of 28 days, in a manner similar to Example 1.
  • 8mg/kg rolipram alone 100 mg/kg omeprazole alone
  • a combination of both agents (8mg/kg rolipram + 100 mg/kg omeprazole) for a period of 28 days, in a manner similar to Example 1.
  • fasting glucose and HbAIc levels are lower (1-3%) than untreated controls and approach normo-glycemia.
  • Example 4 Omeprazole is granulated using water and a mixture of hydroxypropylcellulose, lactose and sodium phosphate. An enteric coating with hydroxypropylcellulose and cetyl alcohol is aplied in a fluidized bed. In a separate process Pentoxyfilline is granulated with a mixture of hydroxypropylcellulose, hydroxyethylcellulose, PEG, povidone and magnesium stearate. Both granulates are sieved and are weighed into hard gelatin capsules so as to provide 20mg Omeprazole and 200mg Pentoxifylline in a single dose unit.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention a pour objet un procédé de traitement du diabète sucré chez un individu nécessitant un traitement, comprenant l'administration à cet individu d'une composition renfermant un inhibiteur des phosphodiestérases et de la pompe à protons et un médicament anti-inflammatoire qui, lorsqu'ils sont combinés de manière efficace, favorisent la différenciation des cellules précurseurs des îlots pancréatiques en cellules matures sécrétant de l'insuline. Le procédé est exemplifié par l'administration d'oméprazole des souris non obèses diabétiques, qui stimule la sécrétion de gastrine et de pentoxifylline, entraînant une diminution de la production de la cytokine pro-inflammatoire TNF alpha.
PCT/CA2008/001093 2007-06-11 2008-06-11 Combinaison destinée au traitement du diabète sucré WO2008151415A1 (fr)

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Application Number Priority Date Filing Date Title
US94320607P 2007-06-11 2007-06-11
US60/943,206 2007-06-11
CA002600147A CA2600147A1 (fr) 2007-06-11 2007-09-05 Combinaison pour le traitement du diabete sucre
CA2,600,147 2007-09-05

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110250273A1 (en) * 2008-12-11 2011-10-13 Melford Scientific, LLC Compositions of proton pump inhibitors, kits and methods of their use to treat diabetes
CN105267160A (zh) * 2015-11-24 2016-01-27 河北智同生物制药有限公司 一种注射用长春西汀冻干制剂组合物及其制备方法
CN113069411A (zh) * 2021-04-02 2021-07-06 石家庄四药有限公司 一种己酮可可碱注射液及其制备方法
CN114869868A (zh) * 2022-04-09 2022-08-09 深圳大学 大麻二酚在制备治疗tau蛋白病和糖尿病的药中的应用

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WO2002022108A1 (fr) * 2000-09-11 2002-03-21 Andrx Corporation Formulations pharmaceutiques contenant un medicament anti-inflammatoire non steroidien et un inhibiteur de la pompe a protons
WO2004062552A2 (fr) * 2003-01-09 2004-07-29 Galephar M/F Composition pharmaceutique contenant un ains et un derive benzimidazole
WO2005076987A2 (fr) * 2004-02-10 2005-08-25 Santarus, Inc. Combinaison d'un inhibiteur de la pompe a protons, d'un tampon et d'un medicament anti-inflammatoire non steroidien
CA2624513A1 (fr) * 2005-10-05 2007-04-12 Bayer Healthcare Ag Combinaison

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WO1997025064A1 (fr) * 1996-01-08 1997-07-17 Astra Aktiebolag Formes galeniques pharmaceutiques orales comprenant un inhibiteur de pompe a protons et un anti-inflammatoire non steroidien
WO2002022108A1 (fr) * 2000-09-11 2002-03-21 Andrx Corporation Formulations pharmaceutiques contenant un medicament anti-inflammatoire non steroidien et un inhibiteur de la pompe a protons
WO2004062552A2 (fr) * 2003-01-09 2004-07-29 Galephar M/F Composition pharmaceutique contenant un ains et un derive benzimidazole
WO2005076987A2 (fr) * 2004-02-10 2005-08-25 Santarus, Inc. Combinaison d'un inhibiteur de la pompe a protons, d'un tampon et d'un medicament anti-inflammatoire non steroidien
CA2624513A1 (fr) * 2005-10-05 2007-04-12 Bayer Healthcare Ag Combinaison

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110250273A1 (en) * 2008-12-11 2011-10-13 Melford Scientific, LLC Compositions of proton pump inhibitors, kits and methods of their use to treat diabetes
CN105267160A (zh) * 2015-11-24 2016-01-27 河北智同生物制药有限公司 一种注射用长春西汀冻干制剂组合物及其制备方法
CN105267160B (zh) * 2015-11-24 2019-05-14 河北智同生物制药股份有限公司 一种注射用长春西汀冻干制剂组合物及其制备方法
CN113069411A (zh) * 2021-04-02 2021-07-06 石家庄四药有限公司 一种己酮可可碱注射液及其制备方法
CN113069411B (zh) * 2021-04-02 2022-08-09 石家庄四药有限公司 一种己酮可可碱注射液及其制备方法
CN114869868A (zh) * 2022-04-09 2022-08-09 深圳大学 大麻二酚在制备治疗tau蛋白病和糖尿病的药中的应用

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