PET/OK.02/00437
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`Reco29 NOV 2002
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`Kongeriget Danmark
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`ae
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`Patent application No.:
`Dateoffiling:
`Applicant:
`—
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`PA 2001 01053
`04 July 2001
`_ Novo Nordisk A/S
`Novo Allé*
`DK-2880 Bagsveerd
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`t
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`!
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`PRIORITY DOCUMENT
`SUBMITTED ORTRANSMITTED IN
`COMPLIANCE WITH
`RULE 17.1(a) OR (b)
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`This is to certify the correctnessof the following information:
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`The attached photocopyis a true copyof the following information:
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`-
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`The specification and claims asfiled with the application on the
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`filing date indicated above. Patent- og Varemzerkestyrelsen
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`@konomi- og Erhvervsministeriet
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`
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`Head Clerk
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`6300.010-DK
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`Title
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`1
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`Patent- og
`Varemzerkestyrelsen
`04 JULI 2001
`Modtaget
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`Physically stable formulation of modified GLP-1
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`Background
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`Peptides are widely used in medical practice, and since they can be producedbyre-
`combinant DNAtechnology it can be expected that their importancewill increase alsoin the
`years to come.
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`The hormonesregulating insulin secretion belong to the so-called enteroinsular
`axis, designating a group of hormones, released from the gastrointestinal mucosain re-
`sponse to the presence and absorption of nutrients in the gut, which promote an early and
`potentiated release of insulin. The enhancing effect on insulin secretion, the so-called incretin
`effect, is probably essential for a normal glucose tolerance. Manyof the gastrointestinal hor-
`mones,including gastrin and secretin (cholecystokinin is not insulinotropic in man), are insu-
`linotropic, but the only physiologically important ones, those that are responsible for the in-
`cretin effect, are the glucose-dependent insulinotropic polypeptide, GIP, and glucagon-like
`peptide-1 (GLP-1). Becauseofits insulinotropic effect, GIP, isolated in 1973 immediately at-
`tracted considerable interest among diabetologists. However, numerous investigations car-
`ried out during the following years clearly indicated that a defective secretion of GIP was not
`involved in the pathogenesis ofinsulin dependent diabetes mellitus (IDDM) or non insulin-
`dependentdiabetes mellitus (NIDDM). Furthermore, as an insulinotropic hormone, GIP was
`found to be almostineffective in NIDDM. The otherincretin hormone, GLP-1 is the most po-
`tent insulinotropic substance known. Unlike GIP,it is surprisingly effective in stimulating insu-
`lin secretion in NIDDM patients. In addition, and in contrast to the other insulinotropic hor-
`mones(perhaps with the exception of secretin) it also potently inhibits glucagon secretion.
`Because of these actions it has pronounced blood glucose lowering effects particularly in pa-
`tients with NIDDM.
`GLP-1, a product of the proglucagon,is one of the youngest membersofthe se-
`cretin-VIP family of peptides, but is already established as an important gut hormone with
`regulatory function in glucose: metabolism andgastrointestinal secretion and metabolism.
`The glucagon geneis processed differently in the pancreasandin the intestine. In the pan-
`creas, the processing leads to the formation and parallel secretion of 1) glucagonitself, oc-
`cupying positions 33-61 of proglucagon (PG); 2) an N-terminal peptide of 30 amino acids
`(PG (1-30)) often called glicentin-related pancreatic peptide, GRPP; 3) a hexapeptide corre-
`sponding to PG (64-69); 4) and,finally, the so-called major proglucagon fragment (PG (72-
`158)), in which the two glucagon-like sequencesare buried. Glucagon seemsto be the only
`biologically active product. In contrast, in the intestinal mucosa,it is glucagonthatis buried in
`a larger molecule, while the two glucagon-like peptides are formed separately.
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`While muchattention has been focused on the pharmacological properties of acy-
`lated GLP-7 compounds, hithertolittle is known about their physico-chemical and solution
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`structural properties. Such knowledgeis a prerequisite for rational handling during e.g. pro-
`duction, purification and formulation work and is eventually important for understanding of the
`structural basis for the protraction mechanism.
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`GLP-1 and analogues of GLP-1 and fragments thereof are potentially usefuli.a. in the
`treatmentof type 1 and type 2 diabetes. However, solubility limitations and the low stability
`against the actions of endogenous diaminopeptidyl peptidase limits the usefulness of these
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`compounds, and thustherestill is a need for improvementsin thisfield.
`In WO 99/43341 are disclosed certain pharmaceutical formulations comprising GLP-1
`havingalipophilic substituent. All of the disclosed formulations are maintained at pH 7.4.
`In WO 00/37098are disclosed shelf-stable formulations comprising GLP-1, a preserva-
`tive, and a tonicity modifier, at pH 8.2 to 8.8.It is specifically stated that maintaining pH in a
`range of about 8.2 to about 8.8 unexpectedly improves the chemical stability of the formulation.
`In addition it is stated that the concentration of the GLP-1 molecule also plays a role in the sta-
`bility of the formulations.In this respectit is stated that a GLP-1 concentration equal to or
`greater than 1mg/ml was physically unstable.
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`Summary ofthe invention
`Human GLP-1 is a 37 amino acid residue peptide originating from preproglucagon which
`is synthesised /.a. in the L-cells in the distal ileum, in the pancreas andin the brain. Processing
`of preproglucagon to give GLP-1(7-36)amide, GLP-1(7-37) and GLP-2 occurs mainlyin the L-
`cells. A simple system is used to describe fragments and analoguesofthis peptide. Thus, for
`example, Gly*-GLP-1(7-37) (or Gly8GLP-1 (7-37)) designates a fragment of GLP-1 formally de-
`rived from GLP-1 by deleting the amino acid residues Nos. 1 to 6 and substituting the naturally
`occurring aminoacid residuein position 8 (Ala) by Gly. Similarly, Lys*“(N*°-tetradecanoyl)-GLP-
`1(7-37) designates GLP-1(7-37) wherein the e-amino groupof the Lys residuein position 34 has
`been tetradecanoylated. For convenience the amino acid sequence of GLP-1 (7-37)is given
`below, wherein the N-terminalHis is no. 7 and the C-terminal Gly is no. 37:
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`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-
`Ser-Tyr-Leu-Glu-Gly-Gin-Ala-Ala-Lys-Glu-Phe-
`lle-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly,
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`Where referencein this text is made to C-terminally extended GLP-1 analogues, the aminoacid
`residue in position 38 is Arg unless otherwise indicated, the optional amino acid residue in
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`position 39 is also Arg unless otherwise indicated and the optional amino acid residue in
`position 40 is Asp unless otherwise indicated.Also,if a C-terminally extended analogue extends
`to position 41, 42, 43, 44 or 45, the amino acid sequence of this extension is as in the
`corresponding sequence in human preprogiucagon unless otherwiseindicated.
`Wehave discovered that certain modified GLP-1 or analogues thereof when formu-
`lated in aqueous solution together with a buffer, are physically stable at high concentrations
`of the modified GLP-1 or analogues thereof, when kept in the pH range from about 7 to about
`10. The present formulations are physically stable within a given shelf life period at the rec-
`ommended storage temperature (typically 2-3 years at 2-8°C). Furthermore, the present for-
`mulations are physically stable during in-use (typically 1 month at accelerated temperatures
`e.g. 25°C or 37°C). The formulations of the invention are also chemically stable thus render-
`ing them shelf-stable and suitable for invasive (eg. injection, subcutaneousinjection,intra-
`muscular, intraveneousorinfusion ) as well as non-invasive (eg nasal or pulmonary,trans-
`dermal or transmucosal e.g. buccal ) means of administration. When the inventive formula-
`tion comprising a GLP-1 compound was compared to the same formulation comprising GLP-
`1(7-37) substituted for the GLP-1 compound,the physical stability was increased considera-
`bly, and typically the shelf-life was increased from a few seconds to several monthsin the
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`tests used.
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`In one aspectthe invention relates to a pharmaceutical formulation comprising a GLP-1
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`compound, and a buffer, wherein said GLP-1 compound is GLP-1(7-37) or an analogue
`thereof wherein an aminoacid residue of the parent peptide has a lipophilic substituent attached
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`optionally via a spacer, wherein said GLP-1 compoundis presentin a concentration from 1
`mg/ml to 100 mg/m!, and wherein said formulation has a pH from 7.0 to 10;
`provided thatif an isotonic agent is present and pH is 7.4 then mannitol or NaCl is not the
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`isotonic agent.
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`In another aspectthe invention relates to a pharmaceutical formulation comprising
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`a GLP-1 compound, and a buffer, wherein said GLP-1 compound is GLP-1(7-37) or an ana-
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`logue thereof wherein an amino acid residue of the parent peptide hasalipophilic substituent
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`attached optionally via a spacer, wherein said GLP-1 compoundis present in a concentration
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`from 1 mg/ml or above, and wherein said formulation has a pH from 7.0 to 10.
`In a further aspect the invention relates to a pharmaceutical formulation comprising
`a GLP-1 compound, and a buffer, wherein said GLP-1 compound is GLP-1(7-37) or an ana-
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`logue thereof, wherein an amino acid residue of the parent peptide hasa lipophilic substituent
`attached optionally via a spacer, wherein said GLP-1 compoundis present in a concentration
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`from 1 mg/ml to 100 mg/m, and wherein said formulation has a pH from 7.0 to 10.
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`In a further aspect the invention relates to a method of preparing a physically stable
`pharmaceutical formulation of a GLP-1 compound wherein said GLP-1 compoundis GLP-
`1(7-37) or an analogue thereof, wherein an amino acid residue of the parent peptide has a
`lipophilic substituent attached optionally via a spacer, comprising preparation of a formulation
`containing the GLP-1 compound, and a buffer, wherein said GLP-1 compoundis present in a
`concentration from 1 mg/ml or above, and wherein said formulation has a pH from 7.0 to 10.
`In a further aspect the invention relates to a method of preparing a physically stable
`pharmaceutical formulation of a GLP-1 compound wherein said GLP-1 compound is GLP-
`1(7-37) or an analogue thereof, wherein an amino acid residue of the parent peptide has a
`lipophilic substituent attached optionally via a spacer, comprising preparation of a formulation
`containing the GLP-1 compound, and a buffer, wherein said GLP-1 compoundis present in a
`concentration from 1 mg/ml to 100 mg/ml, and wherein said formulation has a pH from 7.0 to
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`10.
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`In a further aspect the invention relates to a method of preparing a physically stable
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`pharmaceutical formulation of a GLP-1 compound wherein said GLP-1 compound is GLP-
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`1(7-37) or an analogue thereof, wherein an amino acid residue of the parent peptide has a
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`lipophilic substituent attached optionally via a spacer, comprising preparation of a formulation
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`containing the GLP-1 compound, and a buffer, wherein said GLP-1 compoundis presentin a
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`concentration from 1 mg/ml to 100 mg/ml, and wherein said formulation has a pH from 7.0 to
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`10; provided thatif an isotonic agent is present and pH is 7.4 then mannitol or NaClis not the
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`isotonic agent.
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`In one embodimentof the invention the pharmaceutical formulation is an aqueous
`formulation. Such formulation is typically a solution or a suspension. In a further embodiment
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`of the invention the pharmaceutical formulation is an aqueous solution.
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`In a further aspect the invention relates to a pharmaceutical formulation comprising
`an aqueoussolution of a GLP-1 compound, and a buffer, wherein said GLP-1 compoundis
`GLP-1(7-37) or an analogue thereof wherein an amino acid residue of the parent peptide has a
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`lipophilic substituent attached optionally via a spacer, wherein said GLP-1 compoundis pre-
`sent in a concentration from 1 mg/mlor above, and wherein said formulation has a pH from
`7.0 to 10.
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`In a further aspectthe invention relates to a pharmaceutical formulation comprising
`an aqueoussolution of a GLP-1 compound, and a buffer, wherein said GLP-1 compoundis
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`GLP-1(7-37) or an analogue thereof, wherein an amino acid residue of the parent peptide has
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`a lipophilic substituent attached optionally via a spacer, wherein said GLP-1 compoundis pre-
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`sent in a concentration from 1 mg/ml to 100 mg/ml, and wherein said formulation has a pH
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`from 7.0 to 10.
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`ss)
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`In a further aspect the invention relates to a pharmaceutical formulation comprising
`an aqueous solution of a GLP-1 compound, and a buffer, wherein said GLP-1 compoundis
`GLP-1(7-37) or an analogue thereof, wherein an amino acid residue of the parent peptide has
`a lipophilic substituent attached optionally via a spacer, wherein said GLP-1 compoundis pre-
`sent in a concentration from 1 mg/ml to 100 mg/ml, and wherein said formulation has a pH
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`from 7.0 to 10; provided thatif an isotonic agent is present and pH is 7.4 then mannitol or
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`NaClis not the isotonic agent.
`
`In a further aspect the invention relates to a method of preparing a physically stable
`pharmaceutical formulation of a GLP-1 compound wherein said GLP-1 compound is GLP-
`1(7-37) or an analoguethereof, wherein an amino acid residue of the parent peptide hasa lipo-
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`philic substituent attached optionally via a spacer, comprising preparation of an aqueous
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`solution containing the GLP-1 compound,and a buffer, wherein said GLP-1 compoundis
`present in a concentration from 1 mg/mlor above, and wherein said formulation has a pH
`from 7.0 to 10.
`
`In a further aspect the invention relates to a method of preparing a physically stable
`pharmaceutical formulation of a GLP-1 compound wherein said GLP-1 compound is GLP-
`
`1(7-37) or an analogue thereof, wherein an amino acid residue of the parent peptide hasa lipo-
`philic substituent attached optionally via a spacer, comprising preparation of an aqueous solu-
`tion containing the GLP-1 compound, and a buffer, wherein said GLP-1 compoundis present
`in a concentration from 4 mg/ml to 100 mg/ml, and wherein said formulation has a pH from
`7.0 to 10.
`
`In a further aspect the invention relates to a method of preparing a physically stable
`pharmaceutical formulation of a GLP-1 compound wherein said GLP-1 compound is GLP-
`1(7-37) or an analogue thereof, wherein an amino acid residue of the parent peptide hasa lipo-
`philic substituent attached optionally via a spacer, comprising preparation of an aqueous solu-
`tion containing the GLP-1 compound, and a buffer, wherein said GLP-1 compoundis present
`in a concentration from 1 mg/ml to 100 mg/ml, and wherein said formulation has a pH from
`7.0 to 10; provided thatif an isotonic agent is present and pH is 7.4 then mannitol or NaClis
`not the isotonic agent.
`In a further aspect the presentinvention relates to a method of reducing blood glu-
`coselevels, treating diabetes type |, diabetes typeIl or obesity, or inhibiting gastric acid se-
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`cretion, or inhibiting apoptosis of B-cells, comprising administering to a patient in need
`thereof an effective amount of a pharmaceutical formulation comprising an aqueoussolution
`of a GLP-1 compound,and a buffer, wherein said GLP-1 compound is GLP-1(7-37) or an
`analogue thereof wherein an amino acid residue of the parent peptide has a lipophilic substitu-
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`ent attached optionally via a spacer, wherein said GLP-1 compoundis present in a concen-
`tration from 1 mg/ml to 100 mg/ml, and wherein said formulation has a pH from 7.0 to 10.
`In a further aspect the present invention relates to a methodoftreating gastric ulcers
`comprising administering to a patient in need thereof an effective amountof a pharmaceuti-
`cal formulation comprising an aqueous solution of a GLP-1 compound,and a buffer, wherein
`said GLP-1 compound is GLP-1(7-37) or an analogue thereof wherein an amino acid residue
`of the parent peptide hasalipophilic substituent attached optionally via a spacer, wherein said
`GLP-1 compoundis present in a concentration from 1 mg/ml to 100 mg/ml, and wherein said
`formulation has a pH from 7.0 to 10.
`In a further aspect the present invention relates to a method oftreating myocardial
`infarct comprising administering to a patient in need thereof an effective amountof a phar-
`maceutical formulation comprising an aqueoussolution of a GLP-1 compound,and a buffer,
`wherein said GLP-1 compound is GLP-1(7-37) or an analogue thereof wherein an amino acid
`residue of the parent peptide hasa lipophilic substituent attached optionally via a spacer,
`wherein said GLP-1 compoundis present in a concentration from 1 mg/ml to 100 mg/ml, and
`wherein said formulation has a pH from 7.0 to 10.
`In a further aspect the present invention relates to a method of treating impaired
`glucose tolerance (IGT) comprising administering to a patient in need thereof an effective
`amount of a pharmaceutical formulation comprising an aqueous solution of a GLP-1 com-
`pound, and a buffer, wherein said GLP-1 compound is GLP-1(7-37) or an analogue thereof
`wherein an amino acid residue of the parent peptide hasa lipophilic substituent attached op-
`tionally via a spacer, wherein said GLP-1 compoundis present in a concentration from 1
`mg/ml to 100 mg/ml, and wherein said formulation has a pH from 7.0 to 10.
`In a further aspect the present invention relates to a method of reducing body weight
`in a subject in need of body weight reduction comprising administering to the subject an ef-
`fective amountsufficient to cause reduction in body weightfor a period of time effective to
`produce weightloss, said time being at least 4 weeks, of a pharmaceutical formulation com-
`prising an aqueoussolution of a GLP-1 compound, and a buffer, wherein said GLP-1 com-
`pound is GLP-1(7-37) or an analogue thereof wherein an aminoacid residue of the parent
`peptide hasa lipophilic substituent attached optionally via a spacer, wherein said GLP-1 com-
`poundis presentin a concentration from 1 mg/ml to 100 mg/ml, and wherein said formulation
`has a pH from 7.0 to 10.
`The term “an effective amount” is the effective dose to be determined by a qualified
`practitioner, who maytitrate dosages to achieve the desired response. Factors for
`consideration of dosewill include potency, bioavailability, desired
`pharmacokinetic/pharmacodynamicprofiles, condition of treatment (e.g. diabetes, obesity,
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`weightloss, gastric ulcers), patient-related factors (e.g. weight, health, age, etc.), presence of
`co-administered medications(e.g.insulin), time of administration, or other factors known to a
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`medical practitioner.
`in a further aspect the present invention relates to use of a GLP-1 compoundfor the
`preparation of a pharmaceutical formulation comprising an aqueous solution of the GLP-1
`compound,and a buffer, wherein said GLP-1 compoundis GLP-1 (7-37) or an analogue
`thereof wherein an amino acid residue of the parent peptide hasa lipophilic substituent attached
`optionally via a spacer, wherein said GLP-1 compoundis present in a concentration from 1
`mg/ml to 100 mg/ml, and wherein said formulation has a pH from 7.0 to 10, for reducing
`blood glucoselevels.
`In a further aspect the presentinvention relates to use of aGLP-1 compound for the
`preparation of a pharmaceutical formulation comprising an aqueoussolution of the GLP-1
`compound, and a buffer, wherein said GLP-1 compound is GLP-1(7-37) or an analogue
`thereof wherein an aminoacid residue of the parent peptide hasa lipophilic substituent attached
`optionally via a spacer, wherein said GLP-1 compoundis present in a concentration from 4
`mg/ml to 100 mg/ml, and wherein said formulation has a pH from 7.0 to 10,for treating dia-
`betes typeI.
`In a further aspect the presentinvention relates to use of a GLP-1 compoundforthe
`preparation of a pharmaceutical formulation comprising an aqueous solution of the GLP-1
`compound,and a buffer, wherein said GLP-1 compound is GLP-1(7-37) or an analogue
`thereof wherein an aminoacid residue of the parent peptide hasa lipophilic substituent attached
`optionally via a spacer, wherein said GLP-1 compoundis present in a concentration from 1
`.
`mg/ml to 100 mg/mi, and wherein said formulation has a pH from 7.0 to 10, for treating dia-
`betes typeII.
`In a further aspect the present invention relates to use of a GLP-1 compoundforthe
`preparation of a pharmaceutical formulation comprising an aqueoussolution of the GLP-1
`compound, and a buffer, wherein said GLP-1 compound is GLP-1(7-37) or an analogue
`thereof wherein an aminoacid residue of the parent peptide hasa lipophilic substituent attached
`optionally via a spacer, wherein said GLP-1 compoundis present in a concentration from 1
`mg/ml to 100 mg/ml, and wherein said formulation has a pH from 7.0 to 10, for treating obe-
`sity.
`
`In a further aspect the presentinvention relates to use of a GLP-1 compoundfor the
`preparation of a pharmaceutical formulation comprising an aqueoussolution of the GLP-1
`compound, and a buffer, wherein said GLP-1 compoundis GLP-1(7-37) or an analogue
`thereof wherein an aminoacid residue of the parent peptide hasa lipophilic substituent attached
`optionally via a spacer, wherein said GLP-1 compoundis present in a concentration from 1
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`mg/ml to 100 mg/ml, and wherein said formulation has a pH from 7.0 to 10, for reducing body
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`weighi, typically for reducing body weight in a type 2 diabetic subject.
`In a further aspect the present invention relates to use of a GLP-1 compoundfor the
`preparation of a pharmaceutical formulation comprising an aqueous solution of the GLP-1
`compound, and a buffer, wherein said GLP-1 compound is GLP-1(7-37) or an analogue
`thereof wherein an amino acid residueof the parent peptide hasalipophilic substituent attached
`optionally via a spacer, wherein said GLP-1 compoundis present in a concentration from 1
`
`mg/ml to 100 mg/ml, and wherein said formulation has a pH from 7.0 to 10, for treating gas-
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`tric ulcers.
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`In a further aspect the present invention relates to use of a GLP-1 compoundforthe
`preparation of a pharmaceutical formulation comprising an aqueoussolution of the GLP-1
`compound, and a buffer, wherein said GLP-1 compound is GLP-1(7-37) or an analogue
`thereof wherein an aminoacid residue of the parent peptide hasa lipophilic substituent attached
`optionally via a spacer, wherein said GLP-1 compoundis present in a concentration from 1
`mg/ml to 100 mg/ml, and wherein said formulation has a pH from 7.0 to 10, for inhibition of
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`apoptosis of B-cells.
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`The term “treatment” is defined as the management andcare of a patient, e.g. a
`mammal, in particular a human, for the purpose of combating the disease, condition, or disorder
`and includes the administration of a GLP-1 compoundto prevent the onset of the symptoms or
`complications, or alleviating the symptoms or complications, or eliminating the disease, condi-
`tion, or disorder. Pharmaceutical compositions containing a GLP-1 compound according to the
`present invention may be administered parenterally to patients in need of such a treatment.
`Parenteral administration may be performed by subcutaneous, intramuscularor intravenousin-
`jection by meansof a syringe, optionally a pen-like syringe. Alternatively, parenteral administra-
`tion can be performed by meansof an infusion pump.A further option is a composition which
`may be a solution or suspension for the administration of the GLP-1 compoundin the form of a
`nasal or pulmonalspray. Asa still further option, the pharmaceutical compositions containing
`the GLP-1 compoundofthe invention can also be adapted to transdermal administration, e.g.
`from a patch,optionally a iontophoretic patch, or transmucosal, e.g. bucal, administration.
`A pharmaceutical formulation is found to be physically unstable whenit exhibits tur-
`bidity. A pharmaceutical formulation of GLP1(7-37) is found to be physically unstableasit
`turns out to be turbid momentaneously after preparation, whereas the same pharmaceutical
`formulation comprising a GLP-1 compoundis found to be physically stable for more than 90
`days at 5°C, Someof the presentformulations are physically stable for more than 11 months
`at 5°C,
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`Physicalstability of the formulations is evaluated by meansofvisual inspection and
`turbidity after storage of the formulation at different temperaturesin topfilled glass cartridges for
`various time periods. Visual inspection of the formulations is performed in a sharp focusedlight
`with a dark background. Theturbidity of the formulation is characterized by a visual score rank-
`ing the degreeofturbidity from 0 to 3 (a formulation showing noturbidity correspondsto a visual
`score 0, and a formulation showing visualturbidity in daylight corresponds to visual score 3). A
`formulation is classified physical unstable with respect to protein aggregation, whenit shows
`visualturbidity in daylight.
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`In one embodimentof the invention the pharmaceutical formulation comprising the
`GLP-1 compoundis physically stable for more than 12 weeks at 5°C as measuredbyvisual
`inspection.
`In another embodimentof the invention the pharmaceutical formulation comprising
`the GLP-1 compoundis physically stable for more than 12 weeks at 25°C as measured by
`visual inspection.
`In a further embodiment of the invention the pharmaceutical formulation comprising
`the GLP-1 compoundis physically stable for more than 12 weeks at 37°C as measured by
`visual inspection.
`In another embodimentof the invention the formulation has a pHin the range from
`7.5 to 10. In another embodimentof the invention the formulation has a pH in the range from
`7.5 to 9.5. In a further embodimentof the invention the formulation has a PH in the range
`from 7.0 to 9.5. In a further embodimentofthe invention the formulation has a pH in the
`range from 7.0 to 8.0. In a further embodimentof the invention the formulation has a pHin
`the range from 7.5 to 8.0. In a further embodimentof the invention the formulation has a pH
`in the range from 9.0 to 10.
`In a further embodimentof the invention the buffer is selected from the group
`consisting of sodium acetate, sodium carbonate, citrate, glycylglycine, histidine, glycine,
`lysine, arginin, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium
`phosphate, and tris(hydroxymethyl)-aminomethan, or mixtures thereof. Each oneof these
`specific buffers constitutes an alternative embodimentof the invention.
`In a further embodimentof the invention the GLP-1 compoundis presentin a
`concentration from 1mg/mlto.80mg/mi. In a further embodiment of the invention the GLP-1
`compoundis presentin a concentration from {mg/ml to 50mg/ml. In a further embodiment of
`the invention the GLP-1 compoundis present in a concentration from 1img/ml to 20mg/mi. In
`a further embodimentof the invention the GLP-1 compoundis present in a concentration
`from 1mg/ml to 10mg/ml. In a further embodimentof the invention the GLP-1 compoundis
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`presentin a concentration from 1-5mg/ml. Each one of these specific concentration ranges
`constitutes an alternative embodimentof the invention.
`
`in a further embodimentof the invention the formulation further comprises a
`pharmaceutically acceptable preservative. In a further embodimentof the invention the
`
`preservative is selected from the group consisting of phenol, m-cresol, methyl p-
`hydroxybenzoate, propyl p-hydroxybenzoate, 2-phenoxyethanol, butyl p-hydroxybenzoate, 2-
`phenylethanol, benzyl alcohol, chlorobutanol, and thiomerosal, or mixtures thereof. Each one
`
`of these specific preservativesconstitutes an alternative embodimentof the invention.
`In a further embodimentof the invention the preservative is present in a concentration
`from 0.1mg/mi to 20mg/ml. In a further embodimentof the invention the preservativeis
`present in a concentration from 0.1mg/ml to 5 mg/ml. In a further embodimentof the
`invention the preservative is present in a concentration from 5 mg/ml to 10mg/ml. In a further
`embodimentof the invention the preservative is present in a concentration from 10 mg/ml to
`20mg/ml. Each oneof these specific concentration ranges constitutes an alternative
`embodimentof the invention.
`
`The use of a preservative in pharmaceutical compositions is well-knownto the skilled
`person. For convenience reference is made to Remington: The Science and Practice of Phar-
`macy, 19" edition, 1995.
`In a further embodiment of the invention the formulation further comprises an isotonic
`agent. In a further embodimentofthe invention the isotonic agentis selected from the group
`consisting of a salt (¢.g. sodium chloride), a polyhydric alcohol (e.g. mannitol, sorbitol or
`glycerol), a monosaccharide (e.g. glucose), a disccharide (e.g. sucrose), or an amine acid
`(e.g. L-glycine, L-histidine, arginine, lysine, isoleucine, aspartic acid, tryptophan, threonine ),
`or mixtures thereof. In a further embodimentof the invention the isotonic agentis selected
`from the group consisting of sodium chloride, glycerol, mannitol, glucose, sucrose, L-glycine,
`L-histidine, arginine, lysine or mixtures thereof. Each one of these specific isotonic agents
`constitutes an alternative embodimentof the invention.
`In a further embodimentof the invention the isotonic agentis presentin a
`concentration from 1 mg/ml to 50 mg/ml. In a further embodimentofthe invention the isotonic
`agentis present in a concentration from 1 mg/ml to 7 mg/ml. In a further embodimentofthe
`invention the isotonic agentis present in a concentration from 8 mg/ml to 16 mg/ml. Ina
`further embodimentof the invention the isotonic agentis present in a concentration from 17
`mg/ml to 50mg/mi. Each oneof these specific concentration ranges constitutes an alternative
`embodimentof the invention.
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`The use of an isotonic agent in pharmaceutical compositions is well-known to the
`
`skilled person. For convenience reference is made to Remington: The Science and Practice of
`Pharmacy, 19" edition, 1995.
`In a further embodimentof the invention the formulation further comprises a chelating
`agent. In a further embodimentof the invention the chelating agent is selected from salts of
`
`ethlenediaminetetraacetic acid (EDTA), citric acid, and aspartic acid, and mixtures thereof.
`
`Each one of these specific chelating agents constitutes an alternative embodimentof the
`
`invention.
`
`In a further embodimentof the invention the chelating agent is present in a
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`concentration from 0.1mg/ml to S5mg/ml. In a further embodiment of the invention the
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`chelating agentis present in a concentration from 0.1mg/ml to 2mg/ml. In a further
`embodimentofthe invention the chelating agent is present in a concentration from 2mg/mIto
`5mg/ml.
`
`The use of a chelating agent in pharmaceutical compositions is well-knownto the
`skilled person. For convenience reference is made to Remington: The Science and Practice of
`Pharmacy, 19" edition, 1995.-
`In a further embodimentof the invention the formulation further comprises a stabiliser
`selected from the group of high molecular weight polymers or low molecular compounds.In a
`further embodimentof the invention the stabilizer is selected from polyethylene glycol (e.g.
`PEG 3350), polyvinylalcohol (PVA), polyvinylpyrrolidone, carboxymethylcellulose, different
`salts (e.g. sodium chloride), L-glycine, L-histidine, arginine, lysine, isoleucine, aspartic acid,
`tryptophan,threonine and mixtures thereof. Each oneof these specific stabilizers constitutes
`an alternative embodimentof the invention.
`
`In a further embodiment ofthe invention the high molecular weight polymeris pre-
`sent in a concentration from 0.1mg/mi to 50mg/ml. In a further embodimentof the invention
`the high molecular weight polymeris present in a concentration from 0.1mg/ml to 5mg/ml. In
`a further embodime