POT/DK 02/00437
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`PRIORITY DOCUMENT |
`SUBMITTED OR TRANSMITTED IN |
`COMPLIANCE WITH
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`RULE17.1(a) OR (b)
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`Kongeriget Danmark
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`Patent application No.:
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`Date offiling:
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`Applicant:
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`PA 2002 00092
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`18January 2002
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`Novo Nordisk A/S
`Novo Allé
`DK-2880 Bagsveerd
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`This is to certify the correctness of the following information:
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`The attached photocopyis a true copy of the following information:
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`-
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`The specification and claims asfiled with the application on the
`filing date indicated above.
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`°
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`Patent- og Varemzerkestyrelsen
`@konomi- og Erhvervsministeriet
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`TAASTRUP 20 November 2002
`oe
`ae
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`(oF Karin 86 fishinCi
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`Head Clerk
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`PATENT: 0G VAREMNVEHHEANYENST. EXHIBIT 1112 PAGE 1
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`MYLAN INST. EXHIBIT 1112 PAGE 1
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`MYLAN INST. EXHIBIT 1112 PAGE 1
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`aARERR SK
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`6358.020-DK
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`Title
`Physically stable formulation of modified GLP-1
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`Patent- 0
`Varemzerkestyrelsen
`128 JAN. 2002
`Modtaget
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`Background
`Peptides are widely used in medical practice, and since they can be producedbyre-
`combinant DNAtechnologyit can be expectedthat their importance will increase also in the
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`years to come.
`The hormones regulating insulin secretion belongto the so-called enteroinsular
`axis, designating a group of hormones,released from the gastrointestinal mucosa in re-
`sponseto the presence and absorption of nutrients in the gut, which promote an early and
`potentiated release ofinsulin. 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-
`inotropic, but the only physiologically important ones, those that are responsible forthe in-
`cretin effect, are the glucose-dependentinsulinotropic 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 of insulin dependent diabetes mellitus (IDDM)or non insulin-
`dependent diabetes mellitus (NIDDM). Furthermore, as an insulinotropic hormone, GIP was
`found to be almostineffective in NIDDM. The other incretin hormone, GLP-1 is the most po-
`tent insulinotropic substance known. Unlike GIP,it is surprisingly effective in stimulating insu-
`lin secretion in NIDDMpatients. In addition, and in contrast to the other insulinotropic hor-
`mones(perhaps with the exception of secretin)it also potently inhibits glucagon secretion.
`Becauseof these actions it has pronounced blood glucose lowering effects particularly in pa-
`tients with NIDDM.
`GLP-1, a productof the proglucagon,is one of the youngest membersof the se-
`cretin-VIP family of peptides, but is already established as an important gut hormonewith
`regulatory function in glucose metabolism and gastrointestinal secretion and metabolism.
`The glucagon geneis processeddifferently in the pancreas andin the intestine. In the pan-
`creas, the processing leadsto-the formation andparallel 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 sequencesareburied. Glucagon seemsto be the only
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`biologically active product. In contrast,in the intestinal mucosa,it is glucagon that is buried in
`a larger molecule, while the two glucagon-like peptides are formed separately.
`While muchattention has been focused on the pharmacological properties of acy-
`lated GLP-1 compounds,hithertolittle is known abouttheir physico-chemical and solution
`structural properties. Such knowledgeis a prerequisite for rational handling during e.g. pro-
`duction, purification and formulation work and is eventually important for understandingof the
`structural basis for the protraction mechanism.
`GLP-1 and analogues of GLP-1 and fragmentsthereof are potentially useful /.a. in the
`treatmentof type 1 and type 2 diabetes. However, solubility limitations and the low stability
`against the actions of endogenous diaminopeptidyl peptidaselimits the usefulness of these
`compounds,andthus therestill 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 chemicalstability of the formulation.
`In additionit is stated that the concentration of the GLP-1 molecule also playsa rolein the sta-
`bility of the formulations.In this respectit is stated that a GLP-1 concentration equalto 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 i.a.in the L-cells in the distalileum,in the pancreas andin the brain. Processing
`of preproglucagon to give GLP-1(7-36)amide, GLP-1(7-37) and GLP-2 occurs mainly in the L-
`cells. A simple system is used to describe fragments and analogues of this 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 aminoacid 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 s-amino group ofthe Lys residue in position 34 has
`been tetradecanoylated. For convenience the amino acid sequence of GLP-1 (7-37) is given
`below, wherein the N-terminal His is no. 7 and the C-terminalGly 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-
`lte-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly.
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`Where reference in this text is made to C-terminally extended GLP-1 analogues, the amino acid
`residue in position 38 is Arg unless otherwise indicated, the optional amino acid residue in -
`position 39 is also Arg unless otherwise indicated and the optional amino acid residue in
`position 40 is Asp unless otherwiseindicated.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 preproglucagon unless otherwise indicated.
`Wehave discovered that certain modified GLP-1 or analogues thereof when formu-
`lated in aqueoussolution togetherwith a buffer, are physically stable at low and high concen-
`trations 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 shelflife period at
`the recommended storage temperature(typically 2-3 years at 2-8°C). Furthermore,the pre-
`sent formulations are physically stable during in-use (typically 1 month at accelerated tem-
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`peratures e.g. 25°C or 37°C). The formulations of the invention are also chemically stable
`thus rendering them shelf-stable and suitable for invasive (eg. injection, subcutaneousinjec-
`tion, intramuscular, intraveneousor infusion ) as well as non-invasive (eg nasal or pulmo-
`nary, transdermal or transmucosal e.g. buccal ) means of administration. When the inventive
`formulation comprising a GLP-1 compound was compared to the same formulation compris-
`ing GLP-1(7-37) substituted for the GLP-1 compound, the physicalstability was increased
`considerably, and typically the shelf-life was increased from a few secondsto several
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`monthsin the tests used.
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`In one 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 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 0.1
`mg/ml to 100 mg/ml, and wherein said formulation has a pH from 7.0 to 10;
`providedthatif an isotonic agentis present and pHis 7.4 then mannitol or NaClis not the
`isotonic agent.
`In another aspectthe 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-
`logue 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 0.1 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-4(7-37) or an ana-
`logue thereof, wherein an amino acid residueof the parentpeptide hasa lipophilic substituent
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`attached optionally via a spacer, wherein said GLP-1 compoundis present in a concentration
`from 0.1 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 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 presentin a
`concentration from 0.1 mg/ml or above, 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
`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 0.1 mg/ml to 100 mg/ml, and wherein said formulation has a pH from 7.0
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`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 presentin a
`concentration from 0.1 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 one embodimentof the invention the pharmaceutical formulation is an aqueous
`formulation. Such formulation is typically a solution or a suspension.In.a further embodiment
`of the invention the pharmaceutical formulation is an aqueous solution.
`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 aminoacid 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 0.1 mg/ml or above, and wherein said formulation has a pH from
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`7.0 to 10.
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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
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`GLP-1(7-37) or an analogue thereof, wherein an aminoacid 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 0.1 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 pharmaceutical formulation comprising
`an aqueoussolution of a GLP-1 compound, anda 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 0.1 mg/ml to 100 mg/ml, and wherein said formulation has a pH
`from 7.0 to 10; providedthatif an isotonic agent is present and pHis 7.4 then mannitol or
`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 compoundis GLP-
`1(7-37) or an analogue thereof, wherein an amino acid residue of the parent peptide has a lipo-
`philic substituent attached optionally via a spacer, comprising preparation of an aqueous
`solution containing the GLP-1 compound,and a buffer, wherein said GLP-1 compoundis
`present in a concentration from 0.1 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 analoguethereof, wherein an aminoacid 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 0.1 mg/ml to 100 mg/ml, and wherein said formulation has a pH from
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`7.0 to 10.
`In a further aspect the invention relates to a method of preparing a physically stable
`pharmaceutical formulation ofa 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 0.1 mg/ml to 100 mg/ml, and wherein said formulation has a pH from
`7.0 to 10; provided thatif an isotonic agentis present and pHis 7.4 then mannitol or NaClis
`not the isotonic agent.
`In a further aspect the present invention relates to a method of reducing blood glu-
`coselevels, treating diabetes type 1, diabetes type II 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 hasa lipophilic substitu-
`ent attachedoptionally via a spacer, wherein said GLP-1 compoundis present in a concen-
`tration from 0.1 mg/ml to 100 mg/ml, and wherein said formulation has a pH from 7.0 to 10.
`In a further aspect the presentinvention relates to a method oftreating gastric ulcers
`comprising administering to a patient in need thereof an effective amountofa pharmaceuti-
`cal 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 substituent attached optionally via a spacer, wherein said
`GLP-1 compoundis presentin a concentration from 0.1 mg/ml to 100 mg/ml, and wherein
`said formulation has a pH from 7.0 to 10.
`in a further aspectthe presentinvention 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 thereofwherein an amino acid
`residue of the parent peptide hasa lipophilic substituent attached optionally via a spacer,
`wherein said GLP-1 compoundis presentin a concentration from 0.1 mg/ml to 100 mg/ml,
`and wherein said formulation has a pH from 7.0 to 10.
`In a further aspect the presentinvention relates to a methodoftreating impaired
`glucose tolerance (IGT) comprising administering to a patient in need thereof an effective
`amountof a pharmaceutical formulation comprising an aqueoussolution 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 hasalipophilic substituent attached op-
`25
`tionally via a spacer, wherein said GLP-1 compoundis present in a concentration from 0.1
`mg/ml to 100 mg/ml, and wherein said formulation has a pH from 7.0 to 10.
`In a further aspect the presentinvention relates to a method of reducing bedy weight
`in a subject in need of body weight reduction comprising administering to the subject an ef-
`fective amountsufficient to cause reduction in body weight for 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-
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`poundis presentin a concentration from 0.1 mg/ml to 100 mg/ml, and wherein said formula-
`tion 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 dose will include potency, bioavailability, desired
`pharmacokinetic/pharmacodynamicprofiles, condition of treatment (e.g. diabetes, obesity,
`weight loss, 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.
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`In a further aspect the present invention relates to use of a GLP-1 compoundfor the
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`preparation of a pharmaceutical formulation comprising an aqueoussolution of the 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 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 0.1
`mg/ml to 100 mg/ml, and wherein said formulation has a pH from 7.0 to 10, for reducing
`blood glucoselevels.
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`In a further aspect the present invention 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 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 presentin a concentration from 0.1
`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 present invention 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 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 0.1
`mg/ml to 100 mg/ml, and wherein said formulation has a pH from 7.0 to 10,for treating dia-
`betestypeIl.
`
`In a further aspect the present invention 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 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 0.1
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`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 present invention 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 amino acid residue of the parent peptide has a lipophilic substituent attached
`optionally via a spacer, wherein said GLP-1 compoundis present in a concentration from 0.1
`mg/ml to 100 mg/ml, and wherein said formulation has a pH from 7.0 to 10, for reducing body
`weight, typically for reducing body weightin 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 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 0.1
`mg/ml to 100 mg/ml, and wherein said formulation has a pH from 7.0 to 10,for treating gas-
`tric ulcers.
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`In a further aspect the present invention 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 compound is GLP-1(7-37) or an analogue
`thereof wherein an aminoacid residueof the parent peptide hasa lipophilic substituent attached
`optionally via a spacer, wherein said GLP-1 compoundis presentin a concentration from 0.1
`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.
`The term “treatment” is defined as the managementand care 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 compound to 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, intramuscular orintravenousin-
`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 suspensionfor the administration of the GLP-1 compound in the form of a
`nasalor pulmonalspray.Asa still further option, the pharmaceutical compositions containing
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`the GLP-1 compoundofthe invention can also be adapted to transdermaladministration,e.g.
`from a patch, optionally a iontophoretic patch, or transmucosal, €.g. bucal, administration.
`A pharmaceutical formulation is found to be physically unstable whenit exhibits tur-
`bidity. A pharmaceutical formulation of GLP 1(7-37) is found to be physically unstable asit
`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 present formulations 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 formulationsis performed in a sharp focusedlight
`with a dark background.Theturbidity of the formulation is characterized by a visual score rank-
`ing the degreeofturbidity from 0to 3 (a formulation showingnoturbidity correspondsto a visual
`score 0, and a formulation showingvisualturbidity in daylight correspondsto visual score 3). A
`formulationis classified physical unstable with respectto protein aggregation, whenit shows
`visual turbidity in daylight.
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`In one embodiment ofthe invention the pharmaceutical formulation comprising the
`GLP-1 compoundis physically stable for more than 12 weeks at 5°C as measuredby visual
`inspection.
`In another embodimentofthe 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 embodimentof 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 pH in the range from
`
`7.5 to 10. In another embodimentof the invention the formulation has a pH in the range from
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`7.5 to 9.5. In a further embodimentofthe invention the formulation has a pH in the range
`from 7.0 to 9.5. In a further embodimentof the invention the formulation has a pHin 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, glycyiglycine, histidine, glycine,
`lysine, arginin, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium
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`phosphate, and tris(hydroxymethyl)-aminomethan, or mixtures thereof. Each one of these
`specific buffers constitutes an alternative embodimentof the invention.
`In a further embodimentof the invention the GLP-1 compoundis present ina
`concentration from 0.1mg/ml to 80mg/ml. In a further embodimentof the invention the GLP-1
`compoundis present in a concentration from 4mg/ml to 80mg/ml. In a further embodiment of
`the invention the GLP-1 compound is present in a concentration from 0.1mg/ml to 50mg/mi.
`In a further embodimentof the invention the GLP-1 compoundis present in a concentration
`from 1mg/ml to 50mg/mi. In a further embodimentof the invention the GLP-1 compoundis
`presentin a concentration from 0.1mg/mito 20mg/ml. In a further embodimentof the
`invention the GLP-1 compoundis present in a concentration from img/ml to 20mg/mi. In a
`further embodimentof the invention the GLP-1 compoundis present in a concentration from
`0.1mg/ml to 10mg/ml. In a further embodimentof the invention the GLP-1 compoundis
`presentin a concentration from 1mg/mlto 10mg/ml. In a further embodimentof the invention
`the GLP-1 compoundis presentin a concentration from 0.1-5mg/ml. In a further embodiment
`of the invention the GLP-1 compoundis presentin a concentration from 1-5mg/mi. Ina
`further embodimentof the invention the GLP-1 compoundis present in a concentration from
`0.1-0.5mg/ml. In a further embodimentof the invention the GLP-1 compoundis presentin a
`concentration from 0.6-1mg/ml. Each oneofthese specific concentration ranges constitutes an
`alternative embodimentof the invention.
`In a further embodimentofthe invention the formulation further comprises a
`pharmaceutically acceptable preservative. In a further embodimentofthe invention the
`preservative is selected from the group consisting of phenol, m-cresol, methyl p-
`hydroxybenzoate, propyl p-hydroxybenzoaie, 2-phenoxyethanol, butyl p-hydroxybenzoate, 2-
`phenylethanol, benzyl alcohol, chlorobutanol, and thiomerosal, or mixtures thereof. Each one
`of these specific preservatives constitutes an alternative embodiment of the invention.
`In a further embodimentof the invention the preservative is present in a concentration
`from 0.img/ml to 20mg/ml. In a further embodimentof the invention the preservative is
`presentin a concentration from 0.1mg/ml to 5 mg/ml. In a further embodiment of 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 presentin a concentration from 10 mg/ml to
`20mg/ml. Each one of these specific concentration ranges constitutes an alternative
`embodimentof the invention.
`The use of a preservative in pharmaceutical compositions is well-known to the skilled
`person. For convenience reference is made to Remington: The Science and Practice ofPhar-
`macy, 19" edition, 1995.
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`In a further embodimentof the invention the formulation further comprises an lsotonic
`agent. in a further embodiment of the invention the isotonic agent is selected from the group
`consisting of a salt (e.g. sodium chloride), a polyhydric alcohol(e.g. propyleneglycol, xylitol,
`mannitol, sorbitol or glycerol), a monosaccharide (e.g. glucose or maltose), a disccharide
`
`(e.g. sucrose), an amino acid
`(e.g. L-glycine, L-histidine, arginine,lysine, isoleucine, aspartic acid, tryptophan, threonine )
`polyethyleneglycol (e.g. PEG400), or mixtures thereof. In a further embodimentof the
`invention the isotonic agent is 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 embodiment of
`the invention.
`|
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`In a further embodimentof the invention the isotonic agentis present in a
`concentration from 1 mg/m! to 50 mg/m. In a further embodimentof the invention the isotonic
`agentis present in a concentration from 1 mg/ml to 7 mg/ml. In a further embodimentof the
`
`invention the isotonic agentis present in a concentration from 8 mg/ml to 16 mg/ml. Ina
`further embodimentof the invention the isotonic agent is present in a concentration from 17
`mg/ml to 50mg/ml. Each one of these specific concentration ranges constitutes an alternative
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`embodimentof the invention.
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`.
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`The use of an isotonic agent in pharmaceutical compositions is well-known to the
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`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 agentis 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
`concentration from 0.1mg/ml to S5mg/ml. In a further embodimentof the invention the
`chelating agentis present in a concentration from 0.1mg/ml to 2mg/ml. In a further
`embodimentof the invention the chelating agent is presentin a concentration from 2mg/mlto
`5mg/ml.
`
`The Use of a chelating 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.
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