CN1829528A - Compositions comprising gastrin compounds and their use in diabetes - Google Patents

Compositions comprising gastrin compounds and their use in diabetes Download PDF

Info

Publication number
CN1829528A
CN1829528A CNA200480022042XA CN200480022042A CN1829528A CN 1829528 A CN1829528 A CN 1829528A CN A200480022042X A CNA200480022042X A CN A200480022042XA CN 200480022042 A CN200480022042 A CN 200480022042A CN 1829528 A CN1829528 A CN 1829528A
Authority
CN
China
Prior art keywords
weeks
compositions
treatment
gastrin
beneficial effect
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CNA200480022042XA
Other languages
Chinese (zh)
Inventor
A·克鲁兹
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Waratah Pharmaceuticals Inc
Skyepharma Canada Inc
Original Assignee
RTP Pharma Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/US2003/016660 external-priority patent/WO2003100024A2/en
Application filed by RTP Pharma Inc filed Critical RTP Pharma Inc
Publication of CN1829528A publication Critical patent/CN1829528A/en
Pending legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/2207—Gastrins; Cholecystokinins [CCK]
    • 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

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Diabetes (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Endocrinology (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Obesity (AREA)
  • Zoology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hematology (AREA)
  • Emergency Medicine (AREA)
  • Organic Chemistry (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

The invention relates generally to novel compositions and methods comprising a gastrin compound. The compositions and methods provide beneficial effects, in particular sustained beneficial effects, in the treatment of diabetes.

Description

Comprise the compositions of gastrin compounds and the application in diabetes thereof
Invention field
The present invention relates to compositions and the method that comprises gastrin compounds widely, and uses thereof.
Background of invention
Gastrin relevant with other somatomedin with the growth of fetal pancreas (Brand andFuller, J.Biol.Chem.263:5341-5347).Gastrin is expressed in the islets of langerhans of fetus momently and this expression is limited to the period that original differentiated islet precursor forms differentiated islet.When also not knowing the importance that the pancreas gastrin is expressed in the islets of langerhans, have been noted that being accompanied by nesidioblastosis pancreas gastrin raises.Especially, verified in baby's nesidioblastosis pancreas gastrin lasting unusually people such as (, Gastroenterology, 71:251-262,1976) Hollande and the too much disease of gastrin express islet cell tumor by gastrin and caused.Similar also relevant (people such as Sacchi, Virchows Archiv B, 48:261-276,1985) seen in atrophic gastritis and the differentiated fetal islets of langerhans with nesidioblastosis.Yet, in two kinds of observed results, do not have a kind of accidental contact to be based upon between nesidioblastosis and the gastrin stimulation.
Any reference material that this paper quoted does not allow to provide as the present invention prior art references.
Summary of the invention
The invention provides a kind of compositions, especially a kind of pharmaceutical composition comprises one or more can provide beneficial effect in diabetes and the treatment of its complication gastrin compounds.
An aspect the invention provides a kind of pharmaceutical composition, and comprising provides beneficial effect after one or more are treated, the gastrin compounds of especially lasting beneficial effect.The beneficial effect that a kind of compositions of the present invention provides can comprise the increase of absorption, distribution, metabolism and/or the elimination of gastrin compounds.A kind of compositions can possess the bioavailability (absorbing faster and higher) of increase or the effect of enhanced treatment, especially persistent beneficial effect are provided.
The present invention also provides a kind of and has been used for to patient's administration to provide the pharmaceutical composition of beneficial effect, especially persistent beneficial effect, the pharmaceutically useful carrier, adjuvant or the excipient that comprise a kind of gastrin compounds and choose wantonly.
The present invention also provides a kind of pharmaceutical composition that is used for the treatment of disease or disease, comprises to be present in the gastrin compounds that the treatment of lasting beneficial effect effective dose is provided in pharmaceutically useful carrier, adjuvant or the excipient.
In one embodiment, provide a kind of pharmaceutical composition that comprises gastrin compounds, this pharmaceutical composition is suitable for giving individual to provide persistent beneficial effect with treatment disease or disease.In a preferred embodiment, said composition is a kind of dosage form that individual back produces about euglycemia level that gives, and this approximately normal blood sugar level continues for some time after treatment stops.
In another embodiment, the present invention relates to a kind of liquid medicine dosage form that comprises gastrin compounds or its officinal salt, and relate to the freeze-dried pharmaceutical formulation that to recombinate and stablize and be suitable for the suspension of parenteral admistration to prepare.
In a specific embodiment, the present invention relates to a kind of Aquo-composition that comprises the gastrin compounds that is suitable for supplying with persistent beneficial effect.The present invention also provides a kind of gastrin compounds that lasting beneficial effect is provided or aqueous compositions medicine of its officinal salt and at least a solubilizing agent of comprising.
The present invention relates to be included in treatment disease or disease and especially provide beneficial effect in the diabetes, the compositions of the gastrin compounds of especially lasting beneficial effect.
On the other hand, the present invention relates to a kind of compositions, the gastrin compounds that comprises effective dose is used to induce islets of langerhans precursor propagation to be the mature insulin secretory cell of recruitment, especially after giving gastrin compounds in one lasting period.The propagation of islets of langerhans precursor can be induced in external or body.Said composition can be that dosage is used to induce the islets of langerhans precursor to be induced to differentiate into the mature insulin secretory cell effectively.Said composition may reside in pharmaceutically useful carrier, adjuvant or excipient.
The present invention provides a kind of preparation to stablize the important business method for compositions again, and said composition comprises the gastrin compounds that is suitable for providing beneficial effect after one or more are treated, especially persistent beneficial effect.A kind of method of mixing one or more gastrin compounds and a kind of pharmaceutically useful carrier, adjuvant or excipient that comprises, especially effectively a kind of pharmaceutically useful carrier, adjuvant or the excipient of physically stable gastrin compounds.After the preparation of compositions, they can be placed the disease of proper container and labelled labeled for treatment.For the administration of the present composition, such labelling comprises dosage, frequency and method.
The present invention expects that also the compositions that comprises at least a gastrin compounds is used for preventing and/or treating the application of disease and/or disease medicament in preparation.The present invention provides the application of pharmaceutical composition of the present invention in preventing and/or treating the preparation of disease and/or disease medicament in addition.This medicine provides useful effect after the treatment, especially persistent beneficial effect.
The invention provides a kind of method that is used for the treatment of and/or prevents individual disease and/or disease, comprise that one or more gastrin compounds that give this individual treatment effective dose are to provide beneficial effect.The invention provides a kind of therapeutic scheme on the one hand, this therapeutic scheme produces persistent beneficial effect after the treatment.
The present invention has unique application in preventing and/or treating diabetes.Thereby, the present invention relates to a kind of Therapeutic Method, comprise one or more gastrin compounds for the treatment of effective dose, the individuality that this chemical compound has diabetic symptom produces beneficial effect, especially persistent beneficial effect.In one embodiment, persistent beneficial effect is by one or more following being confirmed: (a) the C-peptide generates and increases; (b) the pancreas insulin generates and increases; And/or (c) approximately normal blood sugar level.
In one embodiment, the invention provides a kind of method that is used to prevent and/or treat I type or type ii diabetes, comprise of the present invention a kind of compositions for the treatment of effective dose.
In an other embodiment, the invention provides a kind of being used for comprises of the present invention a kind of compositions for the treatment of effective dose suffering I type or type ii diabetes individuality to improve disease and/or progression of disease or obtaining disease and/or the method in light stage of disease.
The present invention relates to a kind of progress that glucose tolerance reduces or non-insulin demand type ii diabetes of postponing to the method that the insulin requirements type ii diabetes changes, comprise of the present invention a kind of compositions for the treatment of effective dose.
The present invention also relates to a kind of method that increases individual insulin synthesis ability, comprise of the present invention a kind of compositions for the treatment of effective dose.
In embodiments of the present invention, individuality does not make insulinize.
The invention provides a kind of medicine box, comprise one or more gastrin compounds of the present invention or pharmaceutical composition.In one aspect, the invention provides the medicine box that is used to prevent and/or treat diabetes, contain the compositions, container and the operation instructions that comprise one or more gastrin compounds.The compositions of this medicine box can further comprise pharmaceutically useful carrier, adjuvant or excipient.
From following drawings and detailed description, various aspects of the present invention, feature and superiority are conspicuous to those people that are good in this area.
Description of drawings
The present invention may be better understood with reference to these accompanying drawings:
Fig. 1 is the bar chart that shows with E1 (1 μ g/Kg/ days I.P.14) or the nearest onset diabetes NOD mice therapeutic outcome of G1 (3g/Kg/ days I.P.14 days) treatment.Shown (the fasting blood glucose level (mM) of FBG＞6.6mM) of the 0th day and onset diabetes after 35 days.
Fig. 2 and the same of Fig. 1 description are to show the therapeutic outcome bar chart for the treatment of nearest onset diabetes NOD Mus with E1 or G1.Pancreas insulin content (μ g/pancreas) is the vehicle that shows separately onset diabetes and the 35th day.Stop treatment after 14 days.
Fig. 3 shows to monitor morbidity diabetes NOD Mus 8 all results' string diagram recently, comprises the initial 18 day course of treatment of using gastrin.Shown at the 0th week and each all fasting blood glucose level (mM) thereafter.
Fig. 4 is that demonstration reduces chronic diabetes insulin dependency NOD Mus fasting blood glucose level with the G1 therapeutic scheme and prevents insulin treatment to stop dead chart after 14 days.
The detailed description of embodiment
Vocabulary
The numerical range of this paper terminal point narration has comprised and has been included in all numerical value and marks (for example: 1 to 5 comprises 1,1.5,2,2.75,3,3.90,4 and 5) in this scope.Also can be understood as all numerical value and its mark can be by term " " pact " mean 0.1-50%, 5-50% or the 10-40%, the especially 10-20% that add or deduct institute's referential data, more preferably 10% or 15%.Further, can understand like this, unless this paper clearly indication in addition, " " " and, for example: mention that a kind of compositions contains the " mixture of compound.
Chemical compound described herein can comprise one or more asymmetric centers and can produce the form of enantiomer, diastereomer and other stereoisomers, and it can be defined as R or S type according to spatial chemistry.Therefore, the present invention includes all possible like this diastereomers and enantiomer and their racemic modification and the pure form of optically-active.Optical activity (R)-and (S)-isomer can be used the synthon or the chiral reagent of chirality or use traditional method to decompose preparation.Unless otherwise, when chemical compound described herein comprised the geometric asymmetry center, this chemical compound comprised E and two kinds of geometric isomers of A simultaneously.All tautomeric forms all are included in the scope of the present invention.
Term described herein " " " " refers to comprise a kind of animal of homoiothermic animal, mammal for example, and it is suffered from or under a cloudly will or just be partial to a kind of disease or disease.Mammal comprises any member of nonrestrictive Mammalia.Usually, this term is meant the people.This term also comprises breeds the domestic animal that is used for food or regards house pet, comprises horse, milch cow, sheep, poultry, fish, pig, cat and zoo animal, goat, ape (for example: gorilla or chimpanzee) and rodent for example mouse and mice.This paper uses method expection prevention and the therapeutic use on main body/individuality/individuality.Described hereinly be used for the treatment of the people that the typical main body of scheme comprises susceptible, suffers or suffered disease or disease.A kind of main body is a diabetic individual in the embodiment of the present invention.
Term " does not influence the effectiveness of active component or active and main body do not had toxicity.Carrier, adjuvant or excipient comprise diluent, binding agent, adhesive, lubricant, disintegrating agent, filler, wetting agent or emulsifying agent, pH buffer agent and in order to prepare the necessary other materials such as absorbent of a kind of unique combination thing.The example of carrier etc. includes but not limited to saline, buffer saline, glucose, water, glycerol, ethanol and its mixture.Being used for these media of active substance and the purposes of reagent is being known in the art.
" close in the chemical compound of use.The example of officinal salt comprises sodium, calcium, ammonium, hydrated ferric oxide., 2-aminopropane., triethylamine, 2-ethamine, 2-ethylamino-, ethanol, histidine, procarine and carboxyl potassium salt and semicarbazide hydrochloride.Phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, mesylate (mesylate) and tosilate (toluene fulfonate) that amino other pharmaceutically useful salt are hydrobromate, sulfate, disulfate, phosphate, acetate, oxalates, hydrophosphate, dihydro.
Term "/or treatment " is meant before and after disease or disease incidence and gives main body a kind of compositions of the present invention.Therapeutic scheme may be carried out a kind of acute or chronic approach." pharmacology and/or therapeutics effect and the pharmacokinetics character and the biological activity that improve.In embodiments of the invention, beneficial effect includes but not limited to following: the islets of langerhans inflammation alleviate or disappearance, progression of disease slow down or prevention, survival rate increase or disease or treatment of conditions or recovery.
In one embodiment, beneficial effect can be by one or more following proofs: (a) fasting blood glucose level reduces, especially when blood sugar level during greater than 7-10mM; (b) the hemoglobin glycosylation reduces; (c) serum insulin concentration raises; (d) pancreas insulin product or content increase; And/or (e) prevention of progression of disease.In a specific embodiment, this beneficial effect comprise (a) and (b) and (c) or (a), (c) and (d).
In a preferred embodiment, this beneficial effect is one " really ", and this beneficial effect stops the back in treatment and continues a prolongation period.Beneficial effect can continue at least about 2 to 4 weeks, 2 to 5 weeks, 3 to 5 weeks, 2 to 6 weeks, 2 to 8 weeks, 2 to 10 weeks, 2 to 12 weeks, 2 to 14 weeks, 2 to 16 weeks, 2 to 20 weeks, 2 to 24 weeks, 2 thoughtful Decembers or 2 thoughtful 18 months extended periods after the treatment.The period that beneficial effect continues may be relevant with the persistent period and the minute of treatment.Individual may be periodically or seriality ground continuously treatment approximately or at least about 2 to 4 weeks, 2 to 6 weeks, 2 to 8 weeks, 2 to 10 weeks, 2 to 12 weeks, 2 to 14 weeks, 2 to 16 weeks, 2 thoughtful 6 months, 2 all to 12 months, 2 thoughtful 18 months.One section persistent beneficial effect can be shown as a back increase and the about normal or low blood sugar level that prolongs increase, pancreas insulin product or the content of one or more C-peptide prods in the period of treatment.
Comparing with the effect of not using this chemical compound, is a statistically evident effect according to this beneficial effect of statistical analysis to the gastrin compounds effect." " Chang Butong's " effect or level can show as and be more or less than standard level.In embodiments of the invention, compare with the effect that does not have gastrin compounds, this difference may exceed or hang down 1.5,2,3,4,5 or 6 times.
" (for example: gastrin compounds) maybe can produce the consumption or the dosage of the present composition of beneficial effect, especially one or more persistent beneficial effects of one or more expectations.The treatment effective dose of material can cause the reaction of expectation according to morbid state, age, sex and body weight and this material such as individuality in individuality factors vary such as ability.Can regulate dosage to provide best therapeutic effect (for example: the beneficial effect that continues).For example: can give every day several divided doses or according to the treatment situation urgency correspondingly reduce dosage.
" or " polypeptide with same amino acid order.Such natural sequence polypeptide can separate from nature maybe and can make by reorganization or synthesis mode.This term comprises clearly by a polypeptide and blocks naturally or secrete, comprise take place naturally variant form polypeptide variants (for example: selectively montage formation or splice variant) and spontaneous allelic variant.
Term " 70-80%, about especially at least 85%, more preferably at least about 90%, the polypeptide of about at least 95% amino acid sequence identity most preferably, especially with any SEQ ID Nos.1 to 5 in sequence recognition have 70-80%, 85%, 95%, 98% or 99% amino acid sequence identity at least.Such variant comprises, for example: the N-of polypeptide total length or C-be terminal to be increased or delete one or more amino acid residues or comprise the mature sequence of the variant SEQ ID NOs:1 to 5 that obtains from other kinds, but does not comprise the natural sequence polypeptide.
The homogeneity percentage rate of two aminoacid sequences or two nucleotide sequences is defined as the percentage ratio that amino acid residue in this candidate sequence or nucleotide are equivalent to amino acid residue in polypeptide or the nucleotide sequence.Collating sequence and introduce gaps after, in case of necessity in order to obtain the sequence homogeneity of largest percentage, and do not consider the part of any conservative substitution as this sequence homogeneity.Being used for measuring aminoacid or the percentile datum line of nucleotide sequence homogeneity can for example obtain in multiple traditional method: use disclosed obtainable computer software to comprise GCG program package (people such as Devereux J., Nucleic Acids Research 12 (1): 387,1984); BLASTP, BLASTN, and FASTA (Atschul, people J.Molec.Biol.215:403-410 such as S.F., 1990).Blast program can obtain (BLAST Manual, Altschul, people NCBI NLM NIH Bethesda such as S., Md.20894 publicly from NCBI and other sources; Altschul, people J.Mol.Biol.215:403-410 such as S., 1990).Those skilled in the art can determine to be used for the suitable parameter of measuring basis line, comprise any algorithm that will obtain the maximum datum line of sequence total length that this quilt compares.The method that is used for measuring homogeneity and similarity is all compiled the obtainable computer program the public.
" basic sour residue replaces, one or more amino acid residues of parent polypeptide transform, one or more amino acid residues of parent polypeptide have been removed and/or one or more amino acid residue is added to polypeptide on this parent peptide.Such addition, replacement, cancellation and/or conversion can at the N-end or C-be terminal or in this parent polypeptide, or their combination.
Can will suddenly change by standard method and introduce in the polypeptide, for example: site-directed mutagenesis and PCR mediated mutagenesis.Conservative substitution can occur on the non essential amino acid residue of one or more predictions.″
The amino acid residue of similar side chain is replaced.The aminoacid that has a similar side chain be known in the art comprise have basic side chain aminoacid (for example: lysine, arginine, histidine), acid side-chain (for example: aspartic acid, glutamic acid), uncharged polar side chain (for example: glycine, aspartic acid, glutamic acid, serine, threonine, tyrosine and cysteine), nonpolar side chain (for example: alanine, valine, leucine, Iso, proline, tryptophan), β-side chain (for example: threonine, valine, Iso), and aromatic side chain (for example: tyrosine, phenylalanine, tryptophan, histidine).Sudden change can also be introduced in the middle of part or all of natural sequence, for example randomly: pass through saturation mutagenesis.Being accompanied by the mutation variant polypeptide can be by recombinant expressed.
" base has passed through chemical modification.Chemical modification comprises to be added chemical part, produce new key and eliminates chemical part.Polypeptide can be by chemical modification, for example: the formation of alkanisation, acyl groupization, glycosylation, pegylation, ester, deacylated tRNA amine or amic formation.
" the selected polypeptide that operably is connected with heterologous polypeptide of (preferred biologic activity) (for example: a polypeptide except this selected polypeptide)." this selected polypeptide and this allogenic polypeptide are structure endomixis each other within fusion rotein, term.This heterologous polypeptide can be fused to the N-end or the C-end of a selected polypeptide.The method that can pass through the recombinant DNA of standard produces chimeric and fused protein.
" thing, its completely or partially, directly or indirectly, strengthen, induce, imitate or improve in other respects the activity of gastrin or gastrin/cck receptor.Especially, can use the completely or partially related and/or activation gastrin/cck receptor of a gastrin compounds.Gastrin/cck receptor comprises the receptor relevant with gastrin.
More of the present invention during use, gastrin compounds can be relevant with gastrin/CGK receptor, link together, and is influential or the ligand of stimulation arranged.Gastrin compounds can be selected, is a kind of suitable IC that has 50Peptide or non-peptide micromolecule, for example: the about IC of 0.7nM 50Record (referring to people such as Singh (1995) J.) Biol.Chem.270:8429-8438 by method known in the field, with people (1995) J.Biol.Chem.270:5019-5023 such as Kopin in-vitro cell growth mensuration has been described, receptors bind is measured people (1995) J.Biol.Chem.270:5019-5023 such as people (1995) J.Biol.Chem.270:8429-8438 such as being described in Singh and Kopin).
" sheet, analog are (for example: mutein), derivant, hypotype, variant, chimeric polyeptides, the polypeptide with sequence homogeneity, peptide mimics and its pharmaceutically useful salt and active metabolite and prodrug.This term comprises the various ways of gastrin especially, preprogastrin, progastrin, for example gastrin-34 (big gastrin), gastrin 17 (little gastrin), gastrin 8 (miniature gastrin), pentagastrin, tetra gastrin and segment, analog and its derivant.
The sequence of gastrin comprises that big gastrin-34 (people such as Bonato, 1986, Life Science39:959) and little gastrin-17 (people (1966) Nature 209:583 such as Bentley) all are presented in the middle of the SEQ ID NOs.1 to 5.Big gastrin-34 is the expansion of little gastrin-17 at an aminoacid sequence of N-end in essence.Big gastrin cracking in vivo discharges gastrin-17.Glp is a pyroglutamic acid at the N-end, and it is a kind of natural cyclisation form of glutamic acid.In multiple embodiments, when cysteine or lysine added to gastrin with pyroglutamic acid terminal, this pyroglutamic acid was replaced by glutamic acid, or this pyroglutamic acid is by cancellation.Further, shown in this paper SEQ ID NOs:1 to 4, gastrin-34 and gastrin-17 can have methionine or leucine at 15.Gastrin compounds can be Sulfated or non-sulfuric acidization.[referring to J.H.Walsh, " Gastrin " in Gut Peptides:Biochemistry and Physiology, ed.J.H.Walsh and G.J.Dockray, Raven Press Ltd., New York, 1994 summaries] about gastrin
Gastrin compounds also comprises active analogue thereof, segment and other variants, for example share amino acid sequence identity, for example: share 60%, 70%, 80%, 90%, 95%, 98% or 99% sequence homogeneity with endogenous mammal gastrin or natural sequence gastrin.
The example that can be used for gastrin compounds of the present invention comprises and is disclosed in United States Patent (USP) 6,288, the chemical compound in 301.More of the present invention during use, gastrin compounds for example can be selected from the peptide of gastrin-receptor or non-peptide agonists or partial agonist: A71378 people such as (, Am.J.Physiol.258 (4Pt1): G648,1990) Lin.In of the present invention other were used, gastrin compounds can be gastrin/cck receptor ligand, included but not limited to gastrin compounds described herein or such as the cholecystokinin (CCK) of CCK 58, CCK 33, CCK 22, CCK 12 and CCK 8; Or the like.
Gastrin compounds also comprises the similar bioactive peptide that can increase the excretory material of endogenous gastrin, cholecystokinin or come from tissue storage.Example is secretion of stomach release peptide, gastric acid inhibitory and the omeprazole that increases blood plasma gastrin level, increase the soybean trypsin inhibitor that CCK stimulates and stimulate the gastrin secretion and not with the bonded gastrin releasing peptide of gastrin-receptor.
Can prepare gastrin compounds with conventional method.For example: can be synthetic and economically preparation such as the little gastrin form of gastrin 17 by peptide, and synthetic peptide is commercially availabie.Especially, can use in the known method of protein chemistry and synthesize gastrin compounds by chemosynthesis, for example: solid phase synthesis (Merrifield, 1964, synthetic (Houbenweyl J.m.Chem.Assoc.85:2149-2154) or in homogeneity solution, 1987, Methods of Organic Chemistry, ed.E.Wansch, Vol.15I andII, Thieme, Stuttgart).Can use manual procedures or automatization to finish this synthesizes.Can carry out synthesizing automatically, for example: use AppliedBiosystems431A peptide synthesizer (Perkin Elmer).
Gastrin compounds can be by recombinant method preparation known in those skilled in the art.Therefore, the present invention expects nucleotide sequence and a kind of host cell that comprises the nucleotide sequence that is used for the gastrin compounds preparation of coding gastrin compounds and optional controlling element.
Gastrin compounds also can obtain from the source of commerce.For example: (New Jersey, the U.S. can obtain to have methionine or leucine SHG 17 at 15 from Bachem AGBubendorf (Switzerland) and Research Plus Inc.
" the eukaryotic host cell that comprises the gastrin compounds nucleotide sequence.For example: this polypeptide can be expressed in bacterial cell for example in E. coliform, bacillus or Streptonzyces, insect cell (adopting baculovirus), yeast cells or the mammalian cell.Other host cells that are fit to can be at Goeddel, GeneExpression Technology:Methods inEnzymology 185, and AcademicPress finds among the San Diego, CA (1991).Also can select a kind of host cell, it adjusts an expression of inserting nucleotide sequence, modifies (for example: glycosylation or phosphorylation) and (for example: cracking) this polypeptide processes in a kind of mode of needs.Host system or cell line can be selected to have and special be used for proteinic translation post-treatment and modification with its specific structure.For the stable expression of protein extended high rate rate, the cell line and the host system of can design stability ground expressing this gene outcome.
" because of having the factor of regulating action in expressing, for example: promoter or enhancer, a large amount of suitable media and the promoter that are used to produce recombination structure coding gastrin compounds are well known to a person skilled in the art and are commercially availabie.Illustrate carrier below.Bacteroidal: pBs, phagescript, PsiX174, pBluescript SK, pBs KS, pNH8a, pNH16a, pNH18a, pNH46a (stratagene); PTrc99A, pKK223-3, pKK233-3, pDR540, pRIT5 (pharmacia).Eukaryotic: pWLneo, pSV2cat, pOG44, PXTL pSG (stratagene) pSVK3, pBPV, pMSG, pSVL (pharmacia).Just as herein defined " " be meant that free polynucleotide within carrier or cell express this polypeptide with a kind of regulatory factor in the mode that becomes to have the host cell of this polynucleotide that are connected/regulatory factor sequence by transfection.Regulation and control unit can be basic or bring out the regulator site of transcribing, for example: the position of inducing the adjusting that the insulin factor transcribes by the concentration of glucose of increase in the born of the same parents.
"/or disease ", " " disease.Term used herein " tangible symptom, comprise experimental animal model and comprise human I type and type ii diabetes, diabetes starting stage and with insulin reduce or blood sugar level slightly to raise be the prediabetic symptom of feature." individuality of sugar level performance, and/or demonstrate and be easy to suffer from diabetes or the symptom relevant with the family history genetic predisposition, or once suffered from diabetes or related indication individuality and ill again risk with regard to the obesity of type ii diabetes with before comprising.
" excretory ability to produce or to increase the absorbtivity of cell to glucose, reduces serum glucose or blood sugar level.Method known in the field can be used for measuring insulinotropic activity.For example: can measure gastrin-receptor bonding activity with method in external and the body, receptor activation effect (referring to the method for describing in EP 619,322 patents of authorizing people such as Gelfand and the United States Patent (USP) 5,120,712) and insulin or C-peptide level.If islet cells excreting insulin under the situation of this chemical compound or compositions existence surpasses basic horizontal or lacks gastrin compounds or composition levels, chemical compound described herein or compositions have insulinotropic activity.
" born of the same parents, islets of langerhans precursor or beta cell, it may have or not have the characteristic of the stem cell that has the ability of duplicating in unlimited mode.
Compositions and method
The present invention relates to utilize one or more gastrin compounds that beneficial effect is provided, especially enhanced beneficial effect, the more preferably compositions of persistent beneficial effect and method.
In one embodiment, disease wherein or symptom are diabetes, the lasting beneficial effect of compositions or therapeutic scheme of the present invention can be shown as one or more be selected from following:
A) after the individuality that has a diabetic symptom gave gastrin compounds, the pancreas insulin level raise with respect to the level that does not have gastrin compounds.Preferably, this chemical compound is bringing out about at least rising of 0.05%, 0.1%, 0.5%, 1%, 2%, 5%, 10%, 15%, 20%, 30%, 33%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 95% or 99% on the body pancreas insulin level one by one.
B) have the reduction or the disappearance of islets of langerhans inflammatory symptom after the individual administration of diabetic symptom.
C) reduce with respect to the blood sugar level of in not using the individuality that has diabetic symptom of gastrin compounds, measuring.Preferably, this chemical compound brings out about at least 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% blood sugar level reduction.Most preferably, this chemical compound produces approximately or approaches the blood sugar level of the common level of a normal individual.
D) glucose tolerance improves, and especially, improves at least approximately 5-95%, 10-90%, 10-80%, 10-70%, 10-60% in glucose tolerance.
E) raise with respect to the C-peptide level of in not using the individuality that has diabetic symptom of gastrin compounds, measuring.Preferably, it is about at least 0.05%, 0.1%, 0.5%, 1%, 2%, 5%, 10%, 15%, 20%, 30%, 33%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 95% that this chemical compound causes, or 99% C-peptide level raises.
F) blood sugar level is approximately normally kept one period prolonged period, especially at least 1 week, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 20 weeks, 24 weeks, 30 weeks, 40 weeks, 52 weeks, or 78 weeks, more preferably 2 to 4 weeks, 2 to 5 weeks, 3 to 5 weeks, 2 to 6 weeks, 2 to 8 weeks, 2 to 10 weeks, 2 to 12 weeks, 2 to 16 weeks, 2 to 20 weeks, 2 to 24 weeks, 2 weeks arrived December, or 2 weeks to 18 month.
G) reduce, prevent or slow down the speed of the progression of disease in the diabetic individual.
H) reduction or the serious hyperglycemia of prevent diabetes symptom and the progress of ketoacidosis.
I) survival rate that has a diabetic symptom individuality raises.
J) reduce the injection of insulin/absorption demand that passes to few 10-90%, 10-80%, 10-70%, 1060%, 10-50%, 10-40%, 10-30% or 10-20%.
One or more such beneficial effects can be at diabetic individual or disease model, for example: show in NO (NOD) mice that has a diabetic symptom.
Can select gastrin compounds to be used for the special application of the present invention according to one or more following properties: with the binding ability of gastrin-receptor; Cause transduction genetic approach signal and produce propagation and/or differentiation beta cell or insulinotropic active ability; Reduce the ability of glucose level; Insulinotropic activity; The stimulation of beta cell breeding/differentiation; And/or in the conventional method that people use, half-life at least 5 minutes to 24 hours the body, preferred 2 to 10 hours or 2 to 8 hours.
Can select pharmaceutical composition of the present invention and method, it has persistent beneficial effect, preferred statistically evident persistent beneficial effect.In one embodiment, provide a kind of pharmaceutical composition to comprise and be selected from following a kind of gastrin compounds: gastrin 17 and its analog and derivant, preferably had 17 amino acids residues at the in succession SHG I of a leucine residue of 5 of amino acid/11s with statistically evident lasting beneficial effect.In a kind of specific embodiment, provide the pharmaceutical composition that comprises gastrin-17 (leucine) with statistically evident beneficial effect.
The present invention has expected that compositions of the present invention is used to prevent and/or improves disease seriousness, symptom and/or disease and/or the disease purposes of generating period again.The present invention has expected that also the use present composition or therapeutic scheme prevent and/or treat mammiferous symptom and/or disease.Especially, the invention provides the method and composition that improves that uses gastrin compounds to be used for the lasting therapeutic scheme of diabetes.The invention provides a kind of compositions that comprises gastrin compounds in one embodiment, said composition has obtained bigger usefulness, effectiveness and effectiveness.This bigger usefulness can show by the glucose tolerance that improves the serious diabetic individual in the treatment, and this therapeutic scheme is stopping to treat the lasting improvement that produces blood sugar level in the diabetic individual of back and up-to-date morbidity.The glucose tolerance that this paper describes the compositions generation improves and can observe by using low gastrin dosage, for example: be lower than the dosage of 1-50 μ g/kg body weight, especially 1-30 μ g/kg body weight.
The bigger usefulness of gastrin therapeutic scheme of the present invention and effectiveness have been improved the treatment ratio of therapeutic scheme, have reduced disadvantageous side effect and toxicity.Even therapeutic scheme is to finish long after at the β cytoclasis just to begin, method of the present invention also improves the effectiveness that secular diabetes are improved.
Though do not wish by special mechanism combination, the β cell mass increase of using the gastrin doctor smelting improvement aspect glucose tolerance afterwards can cause β cell regeneration and follow.According to morphometry, histologic analysis can show that use gastrin therapeutic scheme has excited β cell regeneration to follow the increase of β cell mass.These can be confirmed by the increase of pancreas insulin content on the biochemistry.The β cell mass that increases can also cause the increase that insulin secretion is measured in the blood flow, and it can show by the increase of circulation C-peptide in the blood plasma.
Permanent effectively pancreatic cell regeneration can give according to the present invention to obtain after gastrin compounds of the present invention or the compositions.The gastrin compounds compositions gives in the individual body with propagation and/or the differentiation that reaches islet cells or gives cell in vitro to be used for transplanting.Can use the method known in those skilled in the art that comprises recombination method that gastrin compounds is introduced cell.For example: chimeric insulin promoter-gastrin fusion gene can be in vivo or the external pancreatic cell that is incorporated into to express one or more gastrin compounds.
The present invention relates to a kind of method that is used for stem cell or CFU-GM to insulin secretory cell development and differentiation, comprise with a kind of gastrin compounds for the treatment of effective dose of the present invention or compositions contacting stem cell or CFU-GM or in order to the gastrin compounds or the compositions of the q.s of breeding and differentiated stem cells or CFU-GM.Stem cell can be available from managing in islets of langerhans, umbilical cord, embryo or stem cell.Compare with not using the gastrin compounds compositions, breeding is very different with the persistent period with the consumption of differentiation.In one embodiment, stem cell or CFU-GM contact with gastrin compounds or compositions in culture medium.In another embodiment, stem cell or CFU-GM contact with gastrin compounds or compositions in individual body.Gastrin compounds or compositions can stem cell transplantation before the individuality, during and administration afterwards, with breeding in long one period with break up individual intravital stem cell.This method can comprise in addition and gives a kind of immunosuppressant.
On the one hand, the invention provides a kind of method that is used for the treatment of diabetes, comprise after the administration in long one period enough differentiated islet precursors effectively to the gastrin compounds of mature insulin secretory cell amount by providing a kind of.The gastrin compounds of said composition can be administered systemically in the physiology acceptable carrier, especially injection, preferred intravenous injection.Selectively, gastrin compounds can be expressed in position, has in the external or body of the nucleic acid of one or more coding gastrin compounds to transform the islets of langerhans precursor in the expression structure carrier that provides the cell internalizing compound to express.The nucleic acid of coding gastrin compounds can be included in the expression structure that comprises preprogastrin peptide precursor coded sequence, then expresses and is processed into gastrin.This expression structure can comprise controlling element.
The present invention also relates to induce the regeneration of individual islets of langerhans, make islets of langerhans precursor and the propagation that is enough to increase and prolong individual islets of langerhans precursor induce the gastrin compounds of the present invention or the compositions of the regenerated amount of islets of langerhans thereby comprise.On the one hand, the invention provides a kind of method that is used to excite the individual beta-cell proliferation that continues, comprise the of the present invention a kind of gastrin compounds or the compositions for the treatment of effective dose.In one embodiment, the invention provides a kind of interior method that increases individual beta cell quantity and/or size that is used to continue for some time, comprise the of the present invention a kind of gastrin compounds or the compositions for the treatment of effective dose.
The reproducibility differentiation of multipotency pancreas precursor, for example: the pancreatic duct cell differentiation that can use gastrin compounds to obtain a prolonging period is mature insulin-secretory cell, compositions as herein described and method are used for treatment of diabetes, the diabetes of especially firm onset, and give gastrin compounds or compositions by therapeutics, this chemical compound or compositions are to be administered systemically, or in pancreas expressed in situ.
The invention provides the method that is used in the individuality treatment diabetes of needs treatment, by giving a kind of compositions that enough makes individual islets of langerhans precursor be divided into ripe islets of langerhans-secretory cell lastingly and/or stimulate the gastrin compounds of the amount that has the islet cells insulin synthesis now that includes.Said composition can be administered systemically or expressed in situ, comprise a kind of nucleic acid by host cell and be configured in a kind of expression vector, wherein this nucleic acid is configured in and comprises a kind of coded sequence that is used for gastrin compounds in the islets of langerhans precursor, transcribes and translational control element function.
On the one hand, the invention provides a kind of method that is used in the individuality treatment diabetes of needs treatment, this method comprises and gives this individuality a kind of compositions that said composition provides is enough to produce the gastrin compounds that the islets of langerhans precursor is divided into the amount of mature insulin-secretory cell lastingly.On the other hand, the invention provides a kind of insulin dependency diabetes that are used for the treatment of, especially the I type or the method at diabetes initial stage give a kind of gastrin compounds that breaks up the regeneration amount of diabetes mammal with comprising optimum decision system and continue the plain secretory cell quantity in the island of functional glucose responding ground increase in the pancreas in one period after stimulating islets of langerhans regeneration causing administration.
The present invention expected a kind of in a persistent period expansion be transplanted to the method for the intravital islet function β of diabetic individual cell concentration, this method comprises gastrin compounds or the compositions that gives individual a kind of treatment effective dose of the present invention.
One embodiment of the invention provide a kind of method that is used to prevent and/or treat diabetes, this method comprises a kind of compositions of mammal that needs treatment, said composition comprises the administration metapedes to increase the gastrin compounds of insulin secretory cell in one persistent period in mammalian body, prevents and/or treats diabetes with this.Said composition is to be administered systemically.This mammal is the diabetes mammals, for example: this mammal had got the diabetes of 1% time in its life-span, and this gastrin compounds provides with the amount that is enough to induce the islets of langerhans precursor to be divided into the insulin secretory cell of glucose responding in persistent one period.
Another embodiment of the invention provides a kind of method that is used to prevent and/or treat diabetes, this method comprises a kind of compositions of mammal that needs treatment, said composition comprises the gastrin compounds of administration metapedes with the amount of the amount that increases islets of langerhans precursor differentiation in the islet tissue in one persistent period and process, prevents and/or treats diabetes with this.
On the other hand, the invention provides a kind of method that prevents and/or treats diabetes, this method comprises a kind of compositions of mammal that needs treatment, said composition comprises the administration metapedes to increase the gastrin compounds of the amount of insulin secretion β cell quantity in the mammalian body in one persistent period, determine the regenerated quantity of islets of langerhans, prevent and/or treat diabetes with this.The regenerated quantity of islets of langerhans can be by following one or more parametric measurements: blood sugar level, serum glucose, blood glycosylation hematochrome, islet cells quantity, serum insulin and insulin content.Give said composition and reduced the blood sugar level of chemically examining before the compositions with respect to giving.Reduced at a persistent time durations with respect to the intravital glycosylation hemochrome concentration of the mammal that gives to chemically examine before the compositions.Raise at a persistent time durations with respect to the intravital serum insulin concentration of mammal that gives to chemically examine before the compositions.Raise at a persistent time durations with respect to the intravital pancreas insulin concentration of the mammal that gives to chemically examine before the compositions.
Advance on the one hand, the invention provides a kind of regenerated method of islets of langerhans that in mammalian body, is used to induce, this method comprises and gives mammal a kind of compositions, said composition is enough to increase the amount of islets of langerhans precursor differentiation in the islet tissue and the gastrin compounds of the amount of time in containing after the administration during persistent a period of time, induces islets of langerhans regeneration with this.These cells can be for cellulous.These cells are delivered to mammal in the mode of system.
Advance on the one hand, the invention provides the method that is used for inducing in the zooblast islets of langerhans regenerative therapy in a kind of lasting period, the nucleotide sequence that comprises the coding gastrin compounds on making cell and being operably connected to controlling element contacts, for example: the insulin promoter receptor agents, for example, the metallothioneins promoter, for example, cell is sexual cell, or cell is the homologous cell of In vitro culture.
The present invention has expected based on the Therapeutic Method of cell, uses gastrin compounds of the present invention or compositions of the present invention.Therefore, the present invention has expected and comprises and use gastrin compounds of the present invention or combination treatment cell, or treat mammal explant islet tissue and induce mammiferous cell or islet tissue to provide the method for beneficial effect, especially persistent beneficial effect.Referring to PCT/CA03/33595 about common cultivation with based on the description of the Therapeutic Method of cell.
A kind of method that is used for the treatment of main body disease described herein or symptom, comprise that some cell in vitro contact with gastrin compounds of the present invention or compositions, randomly cultivate these cells, need the individuality of treatment to provide useful effect, especially persistent beneficial effect in these cells.
In the embodiment based on the Therapeutic Method of cell, cell is the islets of langerhans vessel cell, and being used for the chemical compound of this method or the amount of compositions effectively increases insulin secretory cell amount in the individual body in a persistent period.This cell is homologous (for example: come from individuals with same), or comes from other individualities of identical type, or comes from variety classes.
The present invention also expects a kind of method for the treatment of individual diabetes, comprises that the gastrin compounds of the present invention being transplanted to a kind of islets of langerhans goods in the individual body and treating effective dose or compositions are to provide beneficial effect, especially persistent beneficial effect.
The present invention also relates to a kind of support islet cells or precursor cultured method, there are this cell of cultivation down in the gastrin compounds of the present invention or the compositions that include the amount that is enough to lasting these cell culture.With respect to the cell culture that not this chemical compound or compositions exist, these cells can continue to cultivate at very long time durations.Cultured cell in the presence of gastrin compounds of the present invention or compositions is in the preparation of the cell that is used for transplanting and keep very useful.
The method and composition that is used for treating at the individuality of needs treatment diabetes by islet cells in the implantation diabetic individual body also is provided, and this islet cells exposure is cultivated the gastrin compounds of q.s to increase the quantity of beta Cell of islet in the islets of langerhans in persistent period.Randomly, beta Cell of islet ground quantity can be cultivated growth in a period of time, is enough to expansion and transplants preceding P-cell ground quantity.
Another embodiment of the invention provides a kind of method that is used for the treatment of diabetes, this method comprises: contact with the compositions that comprises the gastrin compounds that is enough to increase islets of langerhans precursor propagation and insulin secretory cell quantity at the external cell that makes, cell after contacting to the mammal that needs this to produce beneficial effect, especially persistent beneficial effect.Cell can be homologous.Said composition provides with the amount that is enough to influence differentiation of stem cells, for example: influence that the islets of langerhans precursor is divided into mature insulin secretion islet cells in the islets of langerhans.Said composition provides with the amount that is enough to increase pancreatic stem cell propagation, and for example: the islets of langerhans precursor is in over a long time.Stem cell can be available from islet tissue or non--islet tissue, for example liver or bone marrow.
The invention provides a kind of method for the treatment of disease or disease, comprise the individual administration that the compositions of gastrin compounds or any aforementioned claim is treated needs together with a large amount of cells, thereby beneficial effect, preferred persistent beneficial effect are provided.On the one hand, the invention provides that a kind of to be used to expand with differentiated stem cells be the method for insulin secretory cell in the diabetic individual cell, this method comprises to be implanted cell individuality and gives a kind of compositions, said composition contains the gastrin compounds of effective dose to produce beneficial effect, especially persistent beneficial effect.For example: the cell of implantation is available from the mankind, for example: available from people's islets of langerhans, and people's liver, people's bone marrow, people's umbilical cord, or people's embryos.Can be by such as being injected directly into organ, for example: be expelled to islets of langerhans, kidney, perhaps the approach of liver is implanted this cell individual.Selectively, implanting cell can be by intravenous injection, for example: be expelled to portal vein or hepatic vein.In specific embodiment, implant the preceding compositions external treatment that contains gastrin compounds that uses earlier of cell.
The present invention comprises that also compositions of the present invention and one or more other therapeutic agents unite the purposes of use, include but not limited to immunosuppressant (for example: rapamycin, Ciclosporin A, ISAtx247 and FK506) appetrol, antidiabetic drug, appetite stimulator medicine, antihypertensive, treat and/or prevent by disease or disease cause or with the General Medicine of medicament, the especially diabetes of the complication of disease or disease association and obesity, anti--nauseant, anticephalalgic and treatment or prevention side effect.
The present invention expects that also the compositions that comprises at least a gastrin compounds is used for providing beneficial effect, the application in the medicine of especially persistent beneficial effect in treatment disease or disease in preparation.
In one embodiment, at least a gastrin compounds that the present invention relates to treat effective dose is used for application in treatment disease or disease provide in the medicine of beneficial effect, especially persistent beneficial effect in preparation.
In one embodiment, the invention provides gastrin compounds and be used for increasing the application of β cell quantity in the individual body in (preferably continuing to increase) treatment back and/or big or small medicine in preparation.
In another embodiment, the invention provides the application of gastrin compounds medicine of Beta cell proliferation after preparation is used for stimulating (the preferred stimulation that prolongs) treatment.
In another embodiment, the invention provides gastrin compounds is used for prolonging or treating lastingly the medicine of I type or type ii diabetes in preparation application.
The present invention also provides gastrin compounds of the present invention or pharmaceutical composition to be used for providing beneficial effect in treatment disease or disease the application in the medicine of preferred lasting beneficial effect in preparation.
The treatment effectiveness of the present composition and method and toxicity can be measured by the standard pharmaceutical process in cell culture or the laboratory animal, for example: by counting statistics mathematic(al) parameter ED for example 50(half is treated effective dosage) or LD 50(the lethal dosage of half).Therapeutic index is the dosage rate of effective and toxic action, and it can pass through ED 50/ D 50Express.Pharmaceutical composition shows that big therapeutic index is preferred.
Method of the present invention can further be measured one or more following labels: β cell mass, the quantity of insulin secretion sexual cell and the glucose response of insulin secretion sexual cell that blood glucose, serum glucose, blood glycosylated hemoglobin, pancreatic beta cell group, serum insulin, pancreas insulin level, form are determined.
Administration
Gastrin compounds of the present invention can contact with site of action in individuality or the patient body to produce beneficial effect, the mode administration of especially lasting beneficial effect by any activating agent that causes with compositions.This active component can be in different time points with the administration simultaneously or sequentially of any order, to produce the beneficial effect of expectation, preferred persistent beneficial effect.Gastrin compounds of the present invention and compositions can be made the form that continues release, are used for the part and are administered systemically.Selection can be so that the effect optimization of the present composition and Therapeutic Method be to provide the form of medication and the route of administration of beneficial effect, especially persistent beneficial effect, and this is within skilled practitioners or veterinary's limit of power.
The method of parenteral includes, but are not limited to transdermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal and oral cavity route administration.Chemical compound can any administration easily, and for example infusion or single fast injection see through epithelium or mucocutaneous layer (for example oral mucosa, rectum and intestinal mucosa etc.) absorbs, can be with other bioactive ingredients administration.Preferred route of administration is to be administered systemically, for example subcutaneous injection.For parenteral, chemical compound described herein and compositions can be with the normal saline with proper pH value, PBS or other suitable buffer administrations.Slow releasing preparation also can be used for one or both therapeutic agents.
Compositions can peroral dosage form administration, for example tablet, capsule (comprising slow release or controlled release form separately), pill, powder, granule, elixir, tincture, suspensoid, syrup and Emulsion.They also can intravenous (single fast injection or infusion), the form administration of intraperitoneal, subcutaneous or intramuscular, and the dosage form of being utilized all is that the those of ordinary skill of pharmaceutical field is known.The present composition can use suitable intranasal excipient via the part, or comes by the intranasal administration via transdermal route, for example uses conventional transdermal patch.The dosage rule of using the transdermal delivery system administration is to continue medication to be better than intermittently administration in whole dosage regimen process.
Dosage regimen of the present invention can change to some extent according to known facts, the for example method of the pharmacodynamic profile of medicament and administration and approach, the frequency of individual race, age, or sex, health status, medical condition and body weight, the nature and extent of symptom, classification, the treatment of the disease of treatment simultaneously, route of administration, individual hepatic and renal function, and desired effects.
Therapeutic dose of the present invention (this dosage is for treating the specific patient's condition or disease so that effect to be provided, and especially persistent beneficial effect is effective) will depend on the character of the patient's condition or disease, can determine with standard clinical techniques.The exact dose that adopts in the preparation also depends on the order of severity of route of administration and the patient's condition or disease, should determine according to judgement and each individual situation of practitioner.Carry out the conventional determining that the blood plasma level of insulin or C-peptide and glucose or glucose excite the empty stomach level of (glucose challenges) with a kind of ordinary skill of this area.
The suitable dose scope of administration is that beneficial effect preferably is provided, especially persistent beneficial effect.The normally about 0.01 μ g of dosage range is to the every kg body weight of about 500 μ g gastrin compounds every day, for example about 0.01 μ g to about 1 μ g/kg, about 0.1 μ g/kg to about 10 μ g/kg or about 1 μ g/kg to about 50 μ g/kg.
Another aspect of the present invention provides the pharmaceutical composition that contains 0.1-30,0.1-40,0.1-50 and g/kg/ days gastrin compounds of 0.1-60 μ.
Special example of the present invention provides persistent beneficial effect, and the dosage range of gastrin compounds administration is 1-30 μ g/kg body weight, especially 3-30 μ g/kg body weight, more particularly 5-20 μ g/kg body weight.
Compositions of the present invention or treatment can comprise at least a gastrin compounds of unit dose, to provide beneficial effect, especially persistent beneficial effect." unit dose " refers to single single dose just, it can be used individuality, and can handle easily and pack, it is physics and chemically stable unit dose, comprises the mixture of such a activating agent or activating agent and one or more solids or liquid pharmacy adjuvant, carrier or excipient.
On the one hand, provide to comprise and treated effectively the not pharmaceutical composition of the gastrin compounds of optimal dose, it is for continuing for some time the interior glucose level that reduces or reduce, and increase Beta cell proliferation or differentiation are effective after perhaps treating.
On the other hand, provide improved pharmaceutical composition, it comprises the effectively gastrin compounds of optimised quantity not of treatment, and is and treats the especially form of diabetes of the disease or the patient's condition for a long time or fast.
On the one hand, the invention provides the pharmaceutical composition that comprises 30-3000,100-3000,100-6000,1000-6000,2000-6000 and the every single dose of 3000-6000 μ g gastrin compounds.
Can use compositions of the present invention or preparation periodically or continuously approximately or about at least 2 weeks to 4 weeks, 2 weeks to 6 weeks, 2 weeks to 8 weeks, 2 weeks to 10 weeks, 2 weeks to 12 weeks, 2 weeks to 14 weeks, 2 weeks to 16 weeks, 2 weeks to 6 month, 2 weeks to 12 month or 2 weeks to 18 month to individuality.Can use present composition one or many every day, especially 1 or 2 every day.
The present composition or its part comprise usually based on the form of medication of expection and suitable pharmaceutically useful carrier, adjuvant and the excipient that make one's options, this and consistent with the pharmacy practice of routine.
Suitable pharmaceutical carriers, adjuvant and excipient are described in the standard body of Remington ' sPharmaceutical Sciences (Mack publishing company).Example for the oral administration of capsule or tablet form, active component can combine with oral, nontoxic pharmaceutically useful inert carrier, for example lactose, starch, sucrose, methylcellulose, magnesium stearate, glucose, calcium sulfate, dicalcium phosphate, mannitol and sorbitol etc.For the oral administration of liquid form, drug component can combine with any oral, nontoxic pharmaceutically useful inert carrier, for example ethanol, G ﹠ W etc.Suitable adhesive (for example gelatin, starch, corn sweetener, natural sugar comprise glucose, natural and synthetic natural gum and wax), lubricant (for example enuatrol, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate and sodium chloride), disintegrating agent (for example starch, methylcellulose, agar, bentonite and xanthan gum), flavoring agent and coloring agent also can combine with compositions or its component.Compositions as herein described can also comprise wetting agent or emulsifying agent, perhaps the pH buffer agent.
Compositions can be liquid solution, suspensoid, Emulsion, tablet, pill, capsule, slow releasing preparation or powder.Can with conventional binding agent and carrier for example triglyceride compositions is made suppository.Oral formulations can comprise standard vector, for example the mannitol of pharmaceutical grade, lactose, starch, magnesium stearate, saccharin sodium, cellulose, magnesium carbonate etc.Various delivery systems are known, can be used for compositions of the present invention is carried out administration, for example are encapsulated in liposome, microgranule and the microcapsule etc.
An aspect of of the present present invention, compositions have about pH value of 7 to 10.
The parenteral preparation of the present composition can comprise aqueous solution, syrup, aqueous or oiliness suspensoid and contain edible oil such as the Emulsion of Oleum Gossypii semen, Oleum Cocois or Oleum Arachidis hypogaeae semen.The dispersant or the suspending agent that can be used for aqueous suspension comprise synthetic or natural natural gum such as tragakanta, alginate, arabic gum, glucosan, sodium carboxymethyl cellulose, gelatin, methylcellulose and polyvinylpyrrolidone.
The compositions of parenteral can comprise aseptic aqueous or non-aqueous solvent, for example water, isotonic saline solution, etc. ooze glucose solution, buffer or be convenient to be used for the treatment of other solvent of activating agent parenteral.The compositions that expection is used for parenteral also can comprise conventional additives, for example for example antioxidant such as methyl hydroxybenzoate or similar additive of stabilizing agent, buffer agent or antiseptic.
In an example, according to conventional methods compositions herein is made and be suitable for subcutaneous or intravenous carries out administration to provide beneficial effect, the pharmaceutical composition of especially persistent beneficial effect to the mankind.Typically, compositions subcutaneous or intravenous administration the aqueous buffer solution solution that is sterile isotonic.Necessary, compositions also can comprise solubilizing agent and local anesthetic, to alleviate the pain of injection site.Usually, the composition that is provided is by respectively or mixed be packaged into unit dosage form, for example, for example in ampoule or the capsule (sachette), also indicates for example amount of activating agent at hermetically sealed container as exsiccant freeze-dried powder or water-free concentrate packaging.When compositions will be carried out the infusion administration, can provide the ampoule of sterile water for injection or injection normal saline, so that composition can be by mixed before administration.
Compositions of the present invention can be made into the form of neutral form or salt.Pharmaceutically useful salt comprises those salt that form with free amine group, for example derived from those salt of hydrochloric acid, phosphoric acid, acetic acid, oxalic acid, tartaric acid etc., and those salt that form with free carboxy, for example derived from those salt of sodium, potassium, ammonium, calcium, hydrated ferric oxide., 2-aminopropane., triethylamine, 2-ethylaminoethanol, histidine, procaine etc.
An example is, the pharmaceutical composition (for example tablet, capsule, powder or powdery form) of solid form is provided, and it comprises crystalline or unbodied gastrin compounds.
Another example is, the pharmaceutical composition (for example tablet, capsule, powder or powdery form) of solid form is provided, and it comprises crystalline or unbodied gastrin compounds.
Another example is, the present invention relates to comprise the liquid pharmaceutical formulation of the pharmaceutically useful salt of gastrin compounds, also relates to freeze-dried pharmaceutical formulation, and it can be by reconstruct to provide stable and suspensoid that be suitable for parenteral.
Special example is, the present invention relates to comprise the waterborne compositions of the pharmaceutically useful salt of gastrin compounds, and the solvent system that produces solubilization.
The present invention also provides the medicine of the aqueous formulation of the pharmaceutically useful salt that comprises gastrin compounds and at least a solubilizing agent.
Compositions of the present invention can for example be held back filter by antibacterial and filter, add biocide, irradiation compositions or heating combination in compositions by following method sterilization.Perhaps, chemical compound of the present invention that is provided or compositions can be aseptic solid preparations, freeze-dried powder for example, and it is easy to be dissolved in the aseptic solvent before being about to use.
Except preparation described herein, compositions also can be made into depot formulation.This durative action preparation can be by implanting (for example subcutaneous or intramuscular) or intramuscular injection administration.Therefore, for example, this part can with suitable polymeric material or hydrophobic material (for example making the Emulsion of acceptable oil), perhaps ion exchange resin carries out preparation together, perhaps makes slightly molten derivant, for example makes slightly molten salt.
Compositions of the present invention and component thereof can comprise the soluble polymer as target medicine carrier.
Prepare after the pharmaceutical preparation, they can be placed proper container, and the labelling disease for the treatment of.For the administration of the present composition, this labelling will the amount of comprising, frequency and medication.
An example of the present invention is, provides to comprise one or morely one or more are housed provide beneficial effect, the drug packages or the medicine box of the container of the pharmaceutical composition composition of the present invention of especially persistent beneficial effect.This container is incidental can be various writing materials, operation instructions for example, or being used for the points for attention of production, use or the sale of standard pharmaceutical preparation or biological product by government organs' prescribed form, these points for attention have reflected the permission of government organs for production, use or the sale of human product.
Another example of the present invention provides medicine box.On the one hand, medicine box comprises gastrin compounds or pharmaceutical composition.Medicine box is a kind of packing, and dress contains the container of the present composition in it, also interior dress carries out administration with compositions to individuality description.
Via specific embodiment the present invention will be described in more detail.The following example that is provided is the purpose that is used to describe in detail, does not attempt to limit by any way the present invention.Those skilled in the art will discern multiple nonessential parameter at an easy rate, and these parameters can change or revise to produce essentially identical result.
Embodiment
Embodiment 1
Gastrin or EGF are to the fasting glucose of the NOD mice of diabetes outbreak recently and the influence of pancreas insulin content
The purpose of this experiment is to measure independent gastrin (G1) or EGF (E1) whether can improve the diabetic conditions of the NOD mice of onset diabetes recently.
(Germanton NY) buys non-obese diabetes (NOD) female mice of suffering from chronic insulin-dependent diabetes from Taconic.Mice is carried out stable breeding, and under the environment of no cause of disease, feed, look after according to the requirement of the relevant the care of animal guide of Canadian committee.The diabetes progress of monitoring NOD mice (fasting glucose, FBG＞6.6mmol/l).After the diabetes outbreak, mice is handled according to following method: (i) excipient (V)-saline phosphate buffer (n=4), (ii) E1 (E) 1 μ g/kg/ days, i.p. administration, (n=5) once a day, administration 14 days, (iii) G1 (G) 3 μ g/kg/ days, i.p. administration, (n=5) once a day, administration 14 days.Mice is not accepted the insulin substitution therapy.Monitoring fasting blood glucose level and pancreas insulin level.E1 is 51 amino acid whose EGF analog; G1 is the gastrin analog, and it has identical length with natural gastrin, but at the 15th an amino acid whose change is arranged.
35 days later fasting glucose (FBG) levels of the control animal that excipient is handled double.The value that the animal FBG level that E1 or G1 handle writes down during with diabetes outbreaks (the 0th day) is close, although the disease progression of this animal model (for example the carrying out property destruction of islet cells).Referring to Fig. 1.The new life of the islet cells that EGF or gastrin stimulate has compensated the destruction of these cells.Also measured the pancreas insulin level of all animals in addition.Because the destruction of beta cell, the pancreas insulin level of the matched group that excipient is handled reduced at the 35th day, and the animal that E1 or G1 handle has then shown the pancreas insulin level that significantly improves with respect to pretreatment values.Referring to Fig. 2.The result of this research proves, after the diabetes outbreak recently of NOD mice, short-term (14 days) with E1 or G1 handle can the prevent diabetes situation deterioration, and after treatment stops, can also continuing to improve the pancreas insulin content at least 3 weeks.
Embodiment 2
Gastrin is to the long lasting effect of the fasting glucose of the NOD mice of diabetes outbreak recently
The purpose of this experiment is whether the treatment of determining gastrin can produce secular improvement to the diabetic conditions of the NOD mice of onset diabetes recently.(Germanton NY) buys the NOD mice from Taconic.Mice is carried out stable breeding, and under the environment of no cause of disease, feed, look after according to the requirement of the relevant the care of animal guide of Canadian committee.
After initial 18 days, monitor fasting glucose (FBG) at least 8 weeks of level of non-obese diabetes (NOD) mice with 3 μ g/kg/ days gastrins processing at the very start from treatment.Also monitor the control group mice that excipient is handled.
Fasting glucose (FBG) level of the control animal that excipient is handled increases in time.After stopping treatment, the FBG level of the animal that gastrin is handled reduced at least 5 weeks with respect to control animal.Referring to Fig. 3.After the result of this research proved that treatment stops, the processing of gastrin had reduced at least 5 weeks of fasting blood glucose level of NOD mice.
Embodiment 3
Gastrin is to the dose dependent influence of the fasting glucose of the NOD mice that suffers from chronic insulin-dependent diabetes
Purpose:
Determine whether gastrin (G1) can prevent the development of serious hyperglycemia and suffer from the death of the NOD mice of chronic insulin-dependent diabetes.
Method:
The NOD mice that suffers from chronic insulin-dependent diabetes and continue to carry out insulinize is divided into different treatment groups, carries out following processing: (i) excipient (n=4), (ii) G1 1 μ g/kg/ days, i.p. administration, twice of every day (n=4), administration 28 days, (iii) G1 5 μ g/kg/ days, i.p. administration, twice of every day (n=4), administration 28 days, (iv) G1 10 μ g/kg/ days, i.p. administration, twice of every day (n=4), administration 28 days.Begin to treat and stopped insulinize in back 14 days with G1.G1 is 17 amino acid whose gastrin analog, and it and natural gastrin molecule have equal length, but at the 15th an amino acid whose variation are arranged.
Result and conclusion:
From the 0th day to the 14th day, to carry out in the animal of insulinize continuing, the fasting glucose of all treatment groups (FBG) the level all level with the 0th day record is close, and except the group for the treatment of with 10 μ g/kg/ days G1, the FBG of this group demonstrates reduction.At the 28th day, insulinize stopped back 14 days, and all animals of vehicle group die from diabetic ketoacidosis (DKA), the injection of insulin because these mices place one's entire reliance upon.Yet, with all mices all also survivals after stopping 2 weeks of insulinize of G1 treatment.The fasting blood glucose level of the mice of 1 μ g/kg/ days G1 treatment keeps improving, but has obtained the fasting blood glucose level of corresponding reduction with G1 (being the respectively 5 and 10 μ g/kg/ days) treatment that increases dosage.Referring to Fig. 4.These data show, under the situation of insulinize not, the treatment of gastrin can significantly improve the control to the glucose of chronic insulin-dependent diabetes NOD mice.
Instantiation described herein scope of the present invention without limits, because these examples only are intended to illustrate one aspect of the present invention, the example of any function equivalence all within the scope of the present invention.Really, except those changes that show and describe, it seems that from top description and accompanying drawing various changes of the present invention all will be conspicuous for a person skilled in the art herein.Such change all is intended to drop within the scope of additional claim.
All publications, patent and the patent publications that this paper relates to all is incorporated herein by reference by the full text of same degree, just pointed out especially and individually and will be incorporated herein by reference in full as the independent publication of each piece, patent or patent publications.Any list of references cited herein is not all admitted to provide as prior art of the present invention.
Sequence table
Sequence table
<110>WARATAH?PHARMACEUTICALS，INC.
CRUZ，ANTONIO
＜120〉comprise the compositions and the method for gastrin compounds
<130>1336-3-WO
<140>PCT/CA2004/000769
<141>2004-05-27
<150>PCT/US03/16660
<151>2003-05-27
<160>5
<170>PatentIn?version?3.3
<210>1
<211>34
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic peptide
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=pyroglutamic acid
<400>1
Xaa?Leu?Gly?Pro?Gln?Gly?Pro?Pro?His?Leu?Val?Ala?Asp?Pro?Ser?Lys
1 5 10 15
Lys?Gln?Gly?Pro?Trp?Leu?Glu?Glu?Glu?Glu?Glu?Ala?Tyr?Gly?Trp?Met
20 25 30
Asp?Phe
<210>2
<211>34
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic peptide
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=pyroglutamic acid
<400>2
Xaa?Leu?Gly?Pro?Gln?Gly?Pro?Pro?His?Leu?Val?Ala?Asp?Pro?Ser?Lys
1 5 10 15
Lys?Gln?Gly?Pro?Trp?Leu?Glu?Glu?Glu?Glu?Glu?Ala?Tyr?Gly?Trp?Leu
20 25 30
Asp?Phe
<210>3
<211>17
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic peptide
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=pyroglutamic acid
<400>3
Xaa?Gly?Pro?Trp?Leu?Glu?Glu?Glu?Glu?Glu?Ala?Tyr?Gly?Trp?Met?Asp
1 5 10 15
Phe
<210>4
<211>17
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic peptide
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=pyroglutamic acid
<400>4
Xaa?Gly?Pro?Trp?Leu?Glu?Glu?Glu?Glu?Glu?Ala?Tyr?Gly?Trp?Leu?Asp
1 5 10 15
Phe
<210>5
<211>101
<212>PRT
＜213〉mankind
<300>
<308>P01350
<309>2004-06-15
<313>(1)..(101)
<400>5
Met?Gln?Arg?Leu?Cys?Val?Tyr?Val?Leu?Ile?Phe?Ala?Leu?Ala?Leu?Ala
1 5 10 15
Ala?Phe?Ser?Glu?Ala?Ser?Trp?Lys?Pro?Arg?Ser?Gln?Gln?Pro?Asp?Ala
20 25 30
Pro?Leu?Gly?Thr?Gly?Ala?Asn?Arg?Asp?Leu?Glu?Leu?Pro?Trp?Leu?Glu
35 40 45
Gln?Gln?Gly?Pro?Ala?Ser?His?His?Arg?Arg?Gln?Leu?Gly?Pro?Gln?Gly
50 55 60
Pro?Pro?His?Leu?Val?Ala?Asp?Pro?Ser?Lys?Lys?Gln?Gly?Pro?Trp?Leu
65 70 75 80
Glu?Glu?Glu?Glu?Glu?Ala?Tyr?Gly?Trp?Met?Asp?Phe?Gly?Arg?Arg?Ser
85 90 95
Ala?Glu?Asp?Glu?Asn
100

Claims (41)

1. pharmaceutical composition, described compositions comprises the gastrin compounds that lasting beneficial effect is provided and pharmaceutically suitable carrier, adjuvant or the excipient for the treatment of effective dose.
2. pharmaceutical composition according to claim 1, described compositions are that the form that continues the euglycemia level of an elongated segment time after the administration is provided in diabetic individual.
3. according to the described pharmaceutical composition of aforementioned arbitrary claim, wherein said compositions comprises the gastrin compounds for the treatment of effective dose, and is to be used to have individuality long-term of these needs or the form of treatment fast.
4. according to the described pharmaceutical composition of aforementioned arbitrary claim, described compositions comprises about 0.1 to 20 or 0.1 to 30 μ g/kg/ days gastrin compounds, especially 3-30 μ g/kg/ days.
5. according to the described pharmaceutical composition of aforementioned arbitrary claim, wherein said beneficial effect is following one or more: the progression of disease that alleviates or disappear, slow down of islets of langerhans inflammation, survival rate increase or the minimizing of diabetic symptom or related complication.
6. according to the described compositions of aforementioned arbitrary claim, beneficial effect wherein is persistent beneficial effect, and it stops the time period that the back continues a prolongation in treatment.
7. pharmaceutical composition according to claim 6, wherein said beneficial effect continued after treatment approximately or at least about 2 weeks to 4 weeks, 2 weeks to 5 weeks, 3 weeks to 5 weeks, 2 weeks to 6 weeks, 2 weeks to 8 weeks, 2 weeks to 10 weeks, 2 weeks to 12 weeks, 2 weeks to 16 weeks, 2 weeks to 20 weeks, 2 weeks to 24 weeks, 2 weeks to 12 month or 2 weeks to 18 month.
8. the C-peptide of time expand generated after pharmaceutical composition according to claim 7, wherein said lasting beneficial effect can show as and treat increases, the pancreas insulin generates increase and about normal or low blood sugar level.
9. according to the described pharmaceutical composition of aforementioned arbitrary claim, wherein for the effect of gastrin compounds with lack the statistical analysis that effect that gastrin compounds exists is compared, persistent beneficial effect is that statistics is significant.
10. according to the described pharmaceutical composition of aforementioned arbitrary claim, wherein said persistent beneficial effect increases the pancreas insulin level at least about 0.05%, 0.1%, 0.5%, 1%, 2%, 5%, 10%, 15%, 20%, 30%, 33%, 35%, 40%, 45% or 50%.
11. according to the described pharmaceutical composition of aforementioned arbitrary claim, wherein said lasting beneficial effect is reduced to less about 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% with blood sugar level.
12. according to the described pharmaceutical composition of aforementioned arbitrary claim, to be treatment back reduce at least about blood sugar level in the period in 2 weeks to 4 weeks, 2 weeks to 5 weeks, 3 weeks to 5 weeks, 2 weeks to 6 weeks, 2 weeks to 8 weeks, 2 weeks to 10 weeks, 2 weeks to 12 weeks, 2 weeks to 16 weeks, 2 weeks to 20 weeks, 2 weeks to 24 weeks, 2 weeks to 12 month or 2 weeks to 18 month wherein said persistent beneficial effect.
13. a method that is used for the treatment of individual diabetes comprises that at least a gastrin compounds that gives this individual treatment effective dose is to provide persistent beneficial effect.
14. a Therapeutic Method comprises at least a gastrin compounds that gives the individual treatment effective dose, has wherein produced the lasting beneficial effect of at least a diabetic symptom for the administration with diabetic symptom individuality.
15. method for preparing stable pharmaceutical composition, said composition comprises gastrin compounds, and physically stable gastrin compounds and being suitable for provides the beneficial effect of treatment diabetes, pharmaceutically suitable carrier, adjuvant or the excipient of preferred lasting beneficial effect effectively.
16. a method for the treatment of diabetes comprises the individual administration to the needs treatment of the compositions of the treatment gastrin compounds of effective dose or any aforementioned claim, thereby beneficial effect, preferred persistent beneficial effect is provided.
17. a method for the treatment of diabetes comprises the individual administration that the compositions of gastrin compounds or any aforementioned claim is treated needs together with a large amount of cells, thereby beneficial effect, preferred persistent beneficial effect is provided.
18. a method for the treatment of diabetic individual is included in and external the compositions of a large amount of cells with gastrin compounds or any aforementioned claim is contacted, cultured cell randomly, and with the individual administration of this cell to the needs treatment.
19. induce the regenerated method of individual islets of langerhans for one kind, thereby comprise that islets of langerhans precursor and the prolongation that is enough to provide individual islets of langerhans precursor are strengthened cultivation effect induces the gastrin compounds of the regenerated amount of islets of langerhans or the compositions of any aforementioned claim to contact.
20. a method of for a long time stem cell being expanded and is divided into insulin secretory cell comprises stem cell is contacted with the gastrin compounds of effective dose or the compositions of any aforementioned claim.
21. a method for the treatment of diabetes, this method comprise that the administration to needs treatments comprises the compositions of gastrin compounds, use with the quantity that is enough to for a long time to increase the β cell of mammiferous secretion pancreas insulin, thereby treat diabetes.
22. method for the treatment of diabetes, this method comprises that the administration to the needs treatment comprises the compositions of gastrin compounds, using with the enhanced amount of prolongation of islets of langerhans precursor propagation that pancreatic tissue is provided using the gastrin compounds metapedes, thus the treatment diabetes.
23. method for the treatment of diabetes, this method comprises that the administration to the needs treatment comprises the compositions of gastrin compounds, prolong the amount that increases with the cell quantity that is enough to provide mammiferous secretion pancreas insulin, and measure the regenerated amount of islets of langerhans, thus the treatment diabetes.
24. the method for claim 23, wherein the regenerated amount of islets of langerhans is to measure by the parameter that is selected from the definite β cell mass of blood glucose, serum glucose, blood glycosylated hemoglobin, pancreatic beta cell group, serum insulin, pancreas insulin content and form.
25. the method for claim 23 is wherein compared with using the blood glucose of being measured before the compositions, has reduced blood glucose after using compositions in the time that prolongs.
26. the method for claim 25 is wherein compared with using the blood glucose of being measured before the compositions, uses compositions blood glucose has been reduced by 50%.
27. the method for claim 23 is wherein compared with the mammiferous glycosylated hemoglobin of the contrast of not using compositions, glycosylated hemoglobin concentration reduced in the time that prolongs.
28. the method for claim 23 is wherein compared with using the mammalian blood serum insulin concentration of being measured before the compositions, change of serum C-peptide insulin concentration improved in the time that prolongs.
29. the method for claim 23 is wherein compared with using the mammalian pancreas insulin concentration of being measured before the compositions, the pancreas insulin concentration improved in the time that prolongs.
30. the method for claim 23, wherein cell is a pancreatic ductal cell.
31. the method for claim 23, wherein gastrin compounds is to be enough to causing that pancreas islets of langerhans precursor prolongs the amount that is divided into glucose reactivity insulin secreted islet cells and provides.
32. the method for claim 23, wherein gastrin compounds is to be enough to causing that pancreas islets of langerhans precursor prolongs the amount that is divided into glucose reactivity insulin secreted islet cells and provides.
33. the method for claim 23, wherein compositions prolongs the amount be divided into mature insulin secreted islet cells and provides to be enough to influence pancreas islets of langerhans precursor in the pancreatic tissue.
34. the method for claim 23, wherein compositions is to be enough to the providing enhanced amount of prolongation of pancreas islets of langerhans precursor propagation to provide.
35. induce the regenerated method of mammalian pancreas islets of langerhans for one kind, this method comprises the compositions that comprises gastrin compounds to administration, the enhanced amount of prolongation with the islets of langerhans precursor propagation that is enough to provide pancreatic tissue is used, thereby induces the regeneration of pancreas islets of langerhans.
36. one kind is used for inducing the regenerated method of islets of langerhans mammal, this method comprises uses the compositions that comprises gastrin compounds, uses to be enough to the producing amount that increases on the β cell quantity of persistent secretion islets of langerhans insulin in mammal.
37. a method that is used for inducing at zooblast the treatment of islets of langerhans reproducibility comprises this cell is contacted with the nucleotide sequence that operably is connected to the coding gastrin compounds on the controlling element, thereby causes the lasting beneficial effect of this gastrin compounds.
38. the compositions of the gastrin compounds of a dosage that comprises the mature insulin secreted cell that effectively to induce the lasting propagation of islets of langerhans precursor to become recruitment.
39. its dosage is enough to induce the islets of langerhans precursor to be divided into the compositions of the claim 38 of mature insulin secreted cell.
40. the compositions that comprises at least a gastrin compounds is used for treating lastingly the application of the medicine of diabetes in preparation.
41. the medicine box of the described compositions of aforementioned arbitrary claim.
CNA200480022042XA 2003-05-27 2004-05-27 Compositions comprising gastrin compounds and their use in diabetes Pending CN1829528A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
USPCT/US03/16660 2003-05-27
PCT/US2003/016660 WO2003100024A2 (en) 2002-05-24 2003-05-27 Treatment for diabetes

Publications (1)

Publication Number Publication Date
CN1829528A true CN1829528A (en) 2006-09-06

Family

ID=33488788

Family Applications (1)

Application Number Title Priority Date Filing Date
CNA200480022042XA Pending CN1829528A (en) 2003-05-27 2004-05-27 Compositions comprising gastrin compounds and their use in diabetes

Country Status (11)

Country Link
EP (1) EP1648495A2 (en)
JP (1) JP2007513059A (en)
CN (1) CN1829528A (en)
AU (1) AU2004243541A1 (en)
BR (1) BRPI0410710A (en)
CA (1) CA2527186A1 (en)
MX (1) MXPA05012605A (en)
NO (1) NO20055582L (en)
PL (1) PL379145A1 (en)
RU (1) RU2005140518A (en)
WO (1) WO2004105780A2 (en)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20040064605A (en) 2001-01-12 2004-07-19 와라타 파마수티컬즈, 인크. Compositions for inducing islet neogenesis, containing gastrin/cck receptor ligands and egf receptor ligands
EP1837031B1 (en) 2002-06-07 2009-10-14 Waratah Pharmaceuticals, Inc. Compositions and methods for treating diabetes
ATE445407T1 (en) 2002-06-07 2009-10-15 Waratah Pharmaceuticals Inc METHODS AND COMPOSITIONS TO TREAT DIABETES
AU2005207870B2 (en) * 2004-01-30 2010-08-19 Waratah Pharmaceuticals, Inc. The combined use of GLP-1 agonists and gastrin for regulating blood glucose levels
WO2008106779A1 (en) * 2007-03-02 2008-09-12 Waratah Pharmaceuticals Inc. Gastrin compound for diabetes treatment

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6558952B1 (en) * 1992-12-14 2003-05-06 Waratah Pharmaceuticals, Inc. Treatment for diabetes
JPH09511384A (en) * 1994-01-24 1997-11-18 リサーチ トライアングル ファーマシューティカルズ リミテッド Treatment of juvenile diabetes
KR20040064605A (en) * 2001-01-12 2004-07-19 와라타 파마수티컬즈, 인크. Compositions for inducing islet neogenesis, containing gastrin/cck receptor ligands and egf receptor ligands
CA2501677A1 (en) * 2002-10-22 2004-05-06 Waratah Pharmaceuticals, Inc. Treatment of diabetes

Also Published As

Publication number Publication date
AU2004243541A1 (en) 2004-12-09
EP1648495A2 (en) 2006-04-26
WO2004105780A3 (en) 2005-01-20
BRPI0410710A (en) 2006-06-13
PL379145A1 (en) 2006-07-24
NO20055582D0 (en) 2005-11-25
RU2005140518A (en) 2007-07-10
NO20055582L (en) 2006-02-27
CA2527186A1 (en) 2004-12-09
JP2007513059A (en) 2007-05-24
WO2004105780A2 (en) 2004-12-09
MXPA05012605A (en) 2006-02-22

Similar Documents

Publication Publication Date Title
CN1268391C (en) Use of GLP-1 analogs and derivatives administered peripherally in regulation of obesity
CN1243770C (en) Neurotrophic growth factor
CN1501809A (en) Chronic treatment regimen using glucagon-like insulinotropic peptides
CN1283997A (en) Keratinocyte growth factor-2 formulations
CN1703424A (en) GLP-1 derivatives and transmicosal absorption preparations thereof
CN1468258A (en) Glucagon-like peptide-1 analogs
CN1622822A (en) Medicinal compositions containing ghrelin
CN1229357A (en) Method of inhibiting fibrosis with growth inhibition excitant
CN1589279A (en) Peptides effective in the treatment of tumors and other conditions requiring the removal or destruction of cells
US20090117102A1 (en) Methods and compositions using CD3 agonists
CN101035806A (en) Amylin family polypeptide-6 (AFP-6) analogs and methods of making and using them
CN1688340A (en) Methods and compositions for modulating T helper (TH) cell development and function
CN109996557A (en) As peptides GLP1/ glucagon/GIP receptor stimulating agent noval chemical compound
CN1582301A (en) Peptides effective in the treatment of tumors and other conditions requiring the removal or destruction of cells
CN1179106A (en) Recombinant human alpha-fetoprotein and uses thereof
CN1264307A (en) Method of enhancing function of upper gastrointestinal tract
CN1829528A (en) Compositions comprising gastrin compounds and their use in diabetes
CN1917898A (en) Biologically active substance of a vasoactive intestinal peptide for treating interstitial lung infections
CN1799624A (en) chromatin peptide for blocking human HIF-1 alpha gene and regulating network downstream related gene
CN1190437A (en) Bone stimulating factor
CN1802170A (en) Therapies for chronic inflammatory demyelinating polyneuropathy using interferon-beta
CN1257187C (en) Calreticulin-tumor necrosis factor correlated apoptosis inducing ligand fusion protein and its prepn and use
CN1893970A (en) Beta-amyloid-analogue-cell epitop vaccine
CN1056537C (en) A pharmaceutical formulation
CN1875104A (en) Anti-angiogenic peptides from the N-terminus of endostatin

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C02 Deemed withdrawal of patent application after publication (patent law 2001)
WD01 Invention patent application deemed withdrawn after publication