Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • C07K14/575—Hormones
  • C07K14/605—Glucagons
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides

Definitions

• the present invention relates to a pharmaceutical composition comprising a GLP-2 derivative of improved solubility and/or stability, and to a method for improving the solubility and/or stability of GLP-2 or a fragment or an analogue thereof.
• Peptides are widely used in medical practice, and since they can be produced by recombinant DNA technology it can be expected that their importance will increase also in the years to come. When native peptides or analogues thereof are used in therapy it is generally found that they have a high clearance. A high clearance of a therapeutic agent is inconvenient in cases where it is desired to maintain a high blood level thereof over a prolonged period of time since repeated administrations will then be necessary.
• peptides which have a high clearance are: ACTH, corticotropin-releasing factor, angiotensin, calcitonin, insulin, glucagon, glu- cagon-like peptide-1 , glucagon-like peptide-2, insulin-like growth factor-1 , insulin-like growth factor-2, gastric inhibitory peptide, growth hormone-releasing factor, pituitary adenylate cyclase activating peptide, secretin, enterogastrin, somatostatin, somatotropin, somatomedin, parathyroid hormone, thrombopoietin, erythropoietin, hypothalamic releasing factors, prolactin, thyroid stimulating hormones, endorphins, enkephalins, vasopressin, oxytocin, opiods and analogues thereof, superoxide dismutase, interferon, asparaginase, arginase, arginine deamina
• GLP-2 and other preproglucagon fragments are given La. by Schmidt et al. (Diabetologia 28 704-707 (1985). Little is known about the physical chemical properties of GLP-2 but GLP-2 is expected, like GLP-1 , to be a highly flexible and unstable molecule. GLP-2 and fragments thereof and analogues of GLP-2 and fragments thereof are potentially useful La. in regulation of appetite and in the treatment of small bowel syndrome. However, the high clearance limits the usefulness of these compounds, and thus there still is a need for improvements in this field. We recently found that derivatisation of this relatively small and very flexible molecule resulted in compounds whose plasma profile were highly protracted and still had retained activity (PCT application No. DK97/00360).
• Preproglucagon from which GLP-2 originates, is synthesized a. in the L-cells in the distal ille- um, in the pancreas and in the brain. Processing of preproglucagon to give GLP-1 and GLP-2 occurs mainly in the L-cells.
• GLP-2 is a 33 amino acid residue peptide possibly in some tissue expended to 34 amino acid residues.
• a simple system is used to describe fragments, analogues and derivatives of GLP-2.
• Lys 20 GLP-2(1-33) designates a fragment of GLP-2 formally derived from GLP-2 by deleting the amino acid residues No. 34 and substituting the naturally occurring amino acid residue in position 20 (Arg) by Lys.
• Arg 30 Lys 35 (N ⁇ -tetradecanoyl)GLP-2(1-35) designates a derivative of a GLP-2 analogue formally derived from GLP-2 by C-terminal addition of a Lys residue, exchange of the naturally occurring amino acid residue in position 30 (Lys) with an Arg residue and tetradecanoylation of the ⁇ - amino group of the Lys residue in position 35.
• GLP-2 derivatives that are found to be very protracted.
• GLP-2 and GLP-2 analogues are molecules to which no defined solution structure can be ascribed
• CD Circular Dichroism
• CD can be used to show that the GLP-2 derivatives have a certain partially structured conformation independent of their concentration.
• an increase in the helix content is seen with increasing concentration, from 10-15% to 30-35% (at 500 ⁇ M concentration) in parallel with peptide self-association.
• the helix content remains constant above 30% at concentrations of 10 ⁇ M.
• the aggregated structured conformation is an inherent property of the derivative present in water or dilute aqueous buffer without the need for any additional structure-inducing components.
• the CD signal is proportional to the average content of ⁇ -helix in the peptides, i.e., a CD value of -1 corresponds to 10% ⁇ - helix content under these conditions.
• the present invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising a GLP-2 derivative which has a helix content as measured by CD at 222 nm in H 2 O at 22 ⁇ 2 °C exceeding 25%, preferably in the range of 25% to 50%, at a peptide concentration of about 10 ⁇ M.
• the size of the partially helical, micelle-like aggregates may be estimated by size-exclusion chromatography.
• the apparent (critical micelle concentrations) CMC's of the peptides may be estimated from the concentration dependent fluorescence in the presence of appropriate dyes (e.g. Brito, . & Vaz, W. (1986) Anal. Biochem. 152, 250-255).
• the derivatives have a partially structured micellar-like aggregate conformation in aqueous solutions makes them more soluble and stable in solution as compared to the native peptide.
• the increased solubility and stability can be seen by comparing the solubility after 9 days of standing for a derivative and normal GLP-2(1-34) in a pharmaceutical formulation, e.g. 5 mM phosphate buffer, pH 6.9 added 0.1 M NaCI.
• an analogue is used to designate a peptide wherein one or more amino acid residues of the parent peptide have been substituted by another amino acid residue and/or wherein one or more amino acid residues of the parent peptide have been deleted and/or wherein one or more amino acid residues have been added to the parent peptide. Such addition can take place either at the N-terminal end or at the C-terminal end of the parent peptide or both.
• derivative is used in the present text to designate a peptide in which one or more of the amino acid residues of the parent peptide have been chemically modified, e.g. by alkylati- on, acylation, ester formation or amide formation.
• GLP-2 derivative is used in the present text to designate a derivative of GLP-2 or an analogue thereof.
• the parent peptide from which such a derivative is formally derived is in some places referred to as the "GLP-2 moiety" of the derivative.
• the present invention relates to pharmaceutical composition accor- ding to claim 1 , wherein the concentration of GLP-2 derivative is not less than 0.5 mg/ml, preferably not less than about 5 mg/ml, more preferred not less than about 10 mg/ml and, preferably, not more than about 100 mg/ml.
• composition of the invention preferably comprises a GLP-2 derivative whe- rein at least one amino acid residue of the parent peptide has a lipophilic substituent attached. More preferred are compositions comprising a GLP-2 derivative having a lipophilic substituent which is attached to any one of the amino acid residues in 20-34, preferably 30-34, most preferred 30.
• composition according to the invention preferably further comprises one or more of the following substances:
• an isotonic agent preferably selected from the group consisting of sodium chloride, mannitol and glycerol;
• a preservative preferably selected from the group consisting of phenol, m-cresol, methyl p- hydroxybenzoate, butyl p-hydroxybenzoate and benzyl alcohol;
• a buffer preferably selected from the group consisting of sodium acetate, citrate, glycylgly- cine, histidine, 2-phenylethanol and sodium phosphate;
• the pharmaceutical composition of the invention comprises a GLP- 2 derivative wherein the lipophilic substituent comprises from 4 to 40 carbon atoms, preferably from 8 to 25 carbon atoms.
• the lipophilic substituent is preferably attached to an amino acid residue in such a way that a carboxyl group of the lipophilic substituent forms an amide bond with an amino group of the amino acid residue, or, the lipophilic substituent is attached to an amino acid residue in such a way that an amino group of the lipophilic substituent forms an amide bond with a carboxyl group of the amino acid residue.
• composition according to the invention compri- ses a GLP-2 derivative wherein the lipophilic substituent is attached to the parent peptide by means of a spacer.
• the spacer is preferably, in one embodiment, an unbranched alkane ⁇ , ⁇ -dicarboxylic acid group having from 1 to 7 methylene groups, preferably two methylene groups, which form a bridge between an amino group of the parent peptide and an amino group of the lipophilic sub- stituent.
• the spacer is preferably, in another embodiment, an amino acid residue except Cys, or a di- peptide such as Gly-Lys or any unbranched alkane ⁇ , ⁇ -aminoacid having from 1 to 7 methylene groups, preferably 2-4 methylene groups, which form a bridge between an amino group of the parent peptide and an amino group of the lipophilic substituent.
• a di- peptide such as Gly-Lys or any unbranched alkane ⁇ , ⁇ -aminoacid having from 1 to 7 methylene groups, preferably 2-4 methylene groups, which form a bridge between an amino group of the parent peptide and an amino group of the lipophilic substituent.
• the lipophilic substituent comprises a partially or completely hydro- genated cyclopentanophenathrene skeleton.
• the lipophilic substituent is a straight-chain or branched alkyl group.
• the lipophilic substituent is preferably the acyl group of a straight-chain or branched fatty acid, the acyl group more preferably being:
• CH 3 (CH 2 ) n CO- wherein n is 4 to 38, preferably CH 3 (CH 2 ) 6 CO-, CH 3 (CH 2 ) 8 CO-, CH 3 (CH 2 ) 10 CO-, CH 3 (CH 2 ) 12 CO-, CH 3 (CH 2 ) 14 CO-, CH 3 (CH 2 ) 16 CO-, CH 3 (CH 2 ) 18 CO-, CH 3 (CH 2 ) 20 CO- and CH 3 (CH 2 ) 22 CO-; or
• an acyl group of a straight-chain or branched alkane ⁇ , ⁇ -dicarboxylic acid or • selected from the group comprising HOOC(CH 2 ) m CO-, wherein m is from 4 to 38, preferably from 4 to 24, more preferred selected from the group comprising HOOC(CH 2 ) 14 CO-, HOOC(CH 2 ) 16 CO-, HOOC(CH 2 ) 18 CO-, HOOC(CH 2 ) 20 CO- and HOOC(CH 2 ) 22 CO-.
• the lipophilic substituent is a group of the formula CH 3 (CH 2 ) p ((CH 2 ) q COOH)CHNH-CO(CH 2 ) 2 CO-, wherein p and q are integers and p+q is an integer of from 8 to 33, preferably from 12 to 28.
• the lipophilic substituent is a group of the formula CH 3 (CH 2 ) r CO-NHCH(COOH)(CH 2 ) 2 CO-, wherein r is an integer of from 10 to 24.
• the lipophilic substituent is a group of the formula CH 3 (CH 2 ) s CO-NHCH((CH 2 ) 2 COOH)CO-, wherein s is an integer of from 8 to 24.
• the lipophilic substituent is a group of the formula -NHCH(COOH)(CH 2 ) 4 NH-CO(CH 2 ) u CH 3 , wherein u is an integer of from 8 to 18.
• the lipophilic substituent is a group of the formula -NHCH(COOH)(CH 2 ) 4 NH-COCH((CH 2 ) 2 COOH)NH-CO(CH 2 ) w CH 3 , wherein w is an integer of from 10 to 16.
• the lipophilic substituent is a group of the formula -NHCH(COOH)(CH 2 ) 4 NH-CO(CH 2 ) 2 CH(COOH)NH-CO(CH 2 ) x CH 3 , wherein x is an integer of from 10 to 16.
• the lipophilic substituent is a group of the formula -NHCH(COOH)(CH 2 ) 4 NH-CO(CH 2 ) 2 CH(COOH)NH-CO(CH 2 ) y CH 3 , wherein y is zero or an integer of from 1 to 22.
• the pharmaceutical composition according to the invention comprises a GLP-2 derivative wherein the parent peptide is selected from the group comprising GLP- 2(1-30); GLP-2(1-31); GLP-2(1-32); GLP-2(1-33); GLP-2(1-34) and GLP-2(1-35).
• the pharmaceutical composition according to the invention comprises a GLP-2 derivative wherein the parent peptide has the following amino acid sequence: X 1 HX 2 DGSFSDEMNTX 3 LDX 4 LAX 5 X 6 DFINWLX 7 X 8 TKITDX 9
• X 1 is NH 2 , DFPEEVAIVEELGRR, DFPEEVTIVEELGRR, DFPEEVNIVEELRRR, or a fragment thereof, X 2 is Ala or Gly,
• the pharmaceutical composition according to the invention preferably comprises a GLP-2 deri- vative wherein a total of up to fifteen, preferably up to ten, more preferably up to six, amino a- cid residues have been exchanged with any ⁇ -amino acid residue which can be coded for by the genetic code.
• the parent peptide is most preferably selected from the group comprising:
• the pharmaceutical composition of the present invention comprises a GLP-2 derivative which is selected from the group comprising
• Lys 20 (N ⁇ -tetradecanoyl)GLP-2(1-33);
• Lys z 30 bis(N ⁇ -tetradecanoyl)GLP-2(1-33);
• Lys 20 (N ⁇ -tetradecanoyl)Arg 30 GLP-2(1-33);
• the present invention furthermore relates to a method for improving the solubility and/or stability of GLP-2 or a fragment or an analogue thereof, characterised in that a lipophilic substituent is introduced on any one of the amino acid residues of the parent peptide.
• the lipophilic substituent is preferably introduced on any one of the amino acid residues in position 20-34, preferably 30-34, most preferred 30.
• the lipophilic substituent preferably comprises from 4 to 40 carbon atoms, more preferably from 8 to 25 carbon atoms.
• the lipophilic substituent is the acyl group of a straight-chain or branched fatty acid; preferably selected from the group comprising CH 3 (CH 2 ) n CO-, wherein n is 4 to 38, preferably CH 3 (CH 2 ) 6 CO-, CH 3 (CH 2 ) 8 CO-, CH 3 (CH 2 ) 10 CO-, CH 3 (CH 2 ) 12 CO-, CH 3 (CH 2 ) 14 CO-, CH 3 (CH 2 ) 16 CO-, CH 3 (CH 2 ) 18 CO-, CH 3 (CH 2 ) 20 CO- and CH 3 (CH 2 ) 22 CO-.
• the GLP-2 parent peptide is preferably GLP-2(1-30); GLP-2(1-31); GLP-2(1-32); GLP-2(1-33); GLP-2(1-34) and GLP-2(1-35).
• the lipophilic substituent attached to the GLP-2 moiety preferably comprises 4-40 carbon atoms, in particular 8- 25 carbon atoms.
• the lipophilic substituent may be attached to an amino group of the GLP-2 moiety by means of a carboxyl group of the lipophilic substituent which forms an amide bond with an amino group of the amino acid to which it is attached.
• the lipophilic substituent may be attached to said amino acid in such a way that an amino group of the lipophilic substituent forms an amide bond with a carboxyl group of the amino acid.
• the lipophililic substituent may be linked to the GLP-2 moiety via an ester bond.
• the ester can be formed either by reaction between a carboxyl group of the GLP-2 moiety and a hydroxyl group of the substituent-to-be or by reaction between a hydroxyl group of the GLP-2 moiety and a carboxyl group of the substituent-to-be.
• the lipophilic substituent can be an alkyl group which is introduced into a primary amino group of the GLP-2 moiety.
• the lipophilic substituent is attached to the GLP- 2 moiety by means of a spacer in such a way that a carboxyl group of the spacer forms an amide bond with an amino group of the GLP-2 moiety.
• suitable spacers are suc- cinic acid, Lys, Glu or Asp, or a dipeptide such as Gly-Lys.
• the spacer is succinic acid, one carboxyl group thereof may form an amide bond with an amino group of the amino acid residue, and the other carboxyl group thereof may form an amide bond with an amino group of the lipophilic substituent.
• the spacer is Lys, Glu or Asp
• the carboxyl group thereof may form an amide bond with an amino group of the amino acid residue
• the amino group thereof may form an amide bond with a carboxyl group of the lipophilic substituent.
• a further spacer may in some instances be inserted between the ⁇ -amino group of Lys and the lipophilic substituent.
• such a further spacer is succinic acid which forms an amide bond with the ⁇ -amino group of Lys and with an amino group present in the lipophilic substituent.
• such a further spacer is Glu or Asp which forms an amide bond with the ⁇ -amino group of Lys and another amide bond with a carboxyl group present in the lipophilic substituent, that is, the lipophilic substituent is a N ⁇ -acylated lysine residue.
• the lipophilic substituent has a group which can be negatively charged.
• One preferred group which can be negatively charged is a carboxylic acid group.
• the parent peptide can be produced by a method which comprises culturing a host cell containing a DNA sequence encoding the peptide and capable of expressing the peptide in a suitable nutrient medium under conditions permitting the expression of the peptide, after which the resulting peptide is recovered from the culture.
• the medium used to culture the cells may be any conventional medium suitable for growing the host cells, such as minimal or complex media containing appropriate supplements. Suitable media are available from commercial suppliers or may be prepared according to published re- cipes (e.g. in catalogues of the American Type Culture Collection).
• the peptide produced by the cells may then be recovered from the culture medium by conventional procedures including separating the host cells from the medium by centrifugation or filtration, precipitating the prote- inaceous components of the supernatant or filtrate by means of a salt, e.g. ammonium sulphate, purification by a variety of chromatographic procedures, e.g. ion exchange chromato- graphy, gelfiltration chromatography, affinity chromatography, or the like, dependent on the type of peptide in question.
• a salt e.g. ammonium sulphate
• the DNA sequence encoding the parent peptide may suitably be of genomic or cDNA origin, for instance obtained by preparing a genomic or cDNA library and screening for DNA sequen- ces coding for all or part of the peptide by hybridisation using synthetic oligonucleotide probes in accordance with standard techniques (see, for example, Sambrook, J, Fritsch, EF and Ma- niatis, T, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, New York, 1989).
• the DNA sequence encoding the peptide may also be prepared synthetically by established standard methods, e.g.
• the DNA sequence may also be prepared by polyme- rase chain reaction using specific primers, for instance as described in US 4,683,202 or Saiki et a/., Science 239 (1988), 487 - 491.
• the DNA sequence may be inserted into any vector which may conveniently be subjected to recombinant DNA procedures, and the choice of vector will often depend on the host cell into which it is to be introduced.
• the vector may be an autonomously replicating vector, i.e. a vector which exists as an extrachromosomal entity, the replication of which is independent of chromosomal replication, e.g. a plasmid.
• the vector may be one which, when in- troduced into a host cell, is integrated into the host cell genome and replicated together with the chromosome(s) into which it has been integrated.
• the vector is preferably an expression vector in which the DNA sequence encoding the peptide is operably linked to additional segments required for transcription of the DNA, such as a pro- moter.
• the promoter may be any DNA sequence which shows transcriptional activity in the host cell of choice and may be derived from genes encoding proteins either homologous or heterologous to the host cell. Examples of suitable promoters for directing the transcription of the DNA encoding the peptide of the invention in a variety of host cells are well known in the art, cf. for instance Sambrook et a/., supra.
• the DNA sequence encoding the peptide may also, if necessary, be operably connected to a suitable terminator, polyadenylation signals, transcriptional enhancer sequences, and translati- onal enhancer sequences.
• the recombinant vector of the invention may further comprise a DNA sequence enabling the vector to replicate in the host cell in question.
• the vector may also comprise a selectable marker, e.g. a gene the product of which complements a defect in the host cell or one which confers resistance to a drug, e.g. ampicillin, kana- mycin, tetracyclin, chloramphenicol, neomycin, hygromycin or methotrexate.
• a selectable marker e.g. a gene the product of which complements a defect in the host cell or one which confers resistance to a drug, e.g. ampicillin, kana- mycin, tetracyclin, chloramphenicol, neomycin, hygromycin or methotrexate.
• a secretory signal sequence (also known as a leader sequence, prepro sequence or pre sequence) may be provided in the recombinant vector.
• the secretory signal sequence is joined to the DNA sequence encoding the peptide in the correct reading frame.
• Secretory signal sequ- ences are commonly positioned 5' to the DNA sequence encoding the peptide.
• the secretory signal sequence may be that normally associated with the peptide or may be from a gene encoding another secreted protein.
• the host cell into which the DNA sequence or the recombinant vector is introduced may be any cell which is capable of producing the present peptide and includes bacteria, yeast, fungi and higher eukaryotic cells.
• suitable host cells well known and used in the art are, without limitation, E. coli, Saccharomyces cerevisiae, or mammalian BHK or CHO cell lines.
• the GLP-2 derivatives of the invention can be prepared by introducing the lipophilic substituent into the parent GLP-2 or GLP-2 analogue using methods known perse, see for example WO 95/07931 , the contents of which is hereby incorporated in its entirety by reference.
• N ⁇ -acylation of a Lys residue can be carried out by using an activated amide of the acyl group to be introduced as the acylating agent, e.g. the amide with benzot azole.
• the acylation is carried out in a polar solvent in the presence of a base.
• compositions containing a GLP-2 derivative according to the present invention may be administered parenterally or orally to patients in need of such a treatment.
• Parenteral administration may be performed by subcutaneous, intramuscular or intravenous injection by means of a syringe, optionally a pen-like syringe.
• parenteral administration can be performed by means of an infusion pump.
• a further option is a composition which may be a powder or a liquid for the administration of the GLP-2 derivative in the form of a nasal or pul- monal spray.
• the pharmaceutical compositions containing a the GLP-2 derivatives of the invention can also be adapted to transdermal administration, e.g. from a patch, optionally a iontophoretic patch, or transmucosal, e.g. bucal, administration.
• compositions containing a GLP-2 derivative of the present invention may be prepared by conventional techniques, e.g. as described in Remington's Pharmaceutical Sciences, 1985 or in Remington: The Science and Practice of Pharmacy, 19 th edition, 1995.
• the injectable compositions of the GLP-2 derivative of the invention can be prepared using the conventional techniques of the pharmaceutical industry which involves dissolving and mixing the ingredients as appropriate to give the desired end product.
• the GLP-2 derivative is dissolved in an amount of water which is somewhat less than the final volume of the composition to be prepared.
• An isotonic agent, a preservative and a buffer is added as required and the pH value of the solution is adjusted - if necessary - using an acid, e.g. hydrochloric acid, or a base, e.g. aqueous sodium hydroxide as needed.
• the volume of the solution is adjusted with water to give the desired concentration of the ingredients.
• composition for nasal administration of certain peptides may, for example, be prepared as described in European Patent No. 272097 (to Novo Nordisk A/S) or in WO 93/18785.
• the pharmaceutical compositions containing a GLP-2 derivative is provided in the form of a composition suitable for administration by injection.
• a composition can either be an injectable solution ready for use or it can be an amount of a solid composition, e.g. a lyophilised product, which has to be dissolved in a solvent before it can be injected.
• the injectable solution preferably contains not less than about 0.5 mg/ml, preferably not less than about 5 mg/ml, more preferred not less than about 10 mg/ml of the GLP-2 derivative and, preferably, not more than about 100 mg/ml of the GLP-2 derivative.
• compositions containing a GLP-2 derivative of this invention can be used in the treatment of various diseases, including obesity, small bowel syndrome, Crohn's disease, ileitis, intestinal inflammation, gastric and duodenal ulceration, inflammatory bowel disease (IBD) and intestinal cancer damage therapy.
• diseases including obesity, small bowel syndrome, Crohn's disease, ileitis, intestinal inflammation, gastric and duodenal ulceration, inflammatory bowel disease (IBD) and intestinal cancer damage therapy.
• IBD inflammatory bowel disease
• the particular GLP-2 derivative to be used and the optimal dose level for any patient will depend on the disease to be treated and on a variety of factors including the efficacy of the specific peptide derivative employed, the age, body weight, physical activity, and diet of the patient, on a possible combination with other drugs, and on the severity of the case. It is recommended that the dosage of the GLP-2 derivative of this invention be determined for each individual patient by those skilled in the art.
• the title compound (0.1 mg, 1.8 %) was isolated, and the product was analysed by PDMS.
• the m/z value for the protonated molecular ion was found to be 4107.8 ⁇ 3.
• the resulting molecular weight is thus 4106.8 ⁇ 3 amu (theoretical value 4106 amu).

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• 1999
  • 1999-02-25 JP JP2000533156A patent/JP2002504527A/ja active Pending
  • 1999-02-25 EP EP99907325A patent/EP1060192A2/de not_active Withdrawn
  • 1999-02-25 WO PCT/DK1999/000080 patent/WO1999043361A1/en not_active Application Discontinuation
  • 1999-02-25 AU AU27128/99A patent/AU2712899A/en not_active Abandoned

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