POT/OK 02/00437
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`PRIORITY DOCUMENT
`SUBMITTED OR TRANSMITTED IN
`COMPLIANCE WITH
`RULE 17.1(a) OR (b)
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`
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`Patent application No.:
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`PA 2001 01052
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`Date offiling:
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`04 July 2001
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`Applicant:
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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 copyof the following information:
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`The specification and claims as filed with the application on the
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`-
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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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`TAASTRUP 20 November 2002
`“A
`a“
`a" 7
`for Yeman —s
`bS MUMEGL
`—_————
`arin’Schiichting
`Head Cierk
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`PATENT- OG VAREMAERKESTYRELSEN
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`6358.010-DK
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`Title
`Physically stable formulation of modified GLP-1
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`>
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`oO
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`Ctagey
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`Background
`Peptides are widely used in medical practice, and since they can be produced by re-
`combinant DNAtechnologyit can be expectedthattheir importancewill increase also in the
`years to come.
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`The hormones regulating insulin secretion helong 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 ofinsulin. The enhancing effect on insulin secretion, the so-called incretin
`effect, is probably essential for a normal glucosetolerance. Manyofthe 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 considerableinterest amongdiabetologists. However, numerous investigations car-
`ried out during the following years clearly indicated that a defective secretion of GIP was not
`involved in the pathogenesisofinsulin dependent diabetes mellitus (IDDM)or noninsulin-
`dependent diabetes mellitus (NIDDM). Furthermore, as an insulinotropic hormone, GIP was
`20_found to be almost ineffective 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 NIDDM patients. In addition, and in contrast to the otherinsulinotropic hor-
`mones (perhaps with the exception of secretin)it also potently inhibits glucagon secretion.
`Because of these actionsit has Pronounced blood glucose lowering effects particularly in pa-
`tients with NIDDM.
`GLP-1, a product of the proglucagon,is one ofthe youngest membersof the se-
`cretin-VIP family of peptides, butis already established as an important gut hormone with
`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 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
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`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.
`While muchattention has been focused on the pharmacological properties of acy-
`lated GLP-1 compounds,hithertolittle is known about their 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 understanding of the
`Structural basis for the protraction mechanism.
`GLP-1 and analogues of GLP-1 and fragments thereof are potentially usefulia.in the
`treatmentof type 1 and type 2diabetes. However,solubility limitations and the low stability
`against the actions of endogenous diaminopeptidy! peptidaselimits the usefulness of these
`compounds, and thustherestill is a need for improvementsin this field.
`In WO 99/43341 are disclosed certain pharmaceutical formulations comprising GLP-1
`havinga lipophilic substituent. All of the disclosed formulations are maintained at PH 7.4.
`In WO 00/37098 are 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 ina
`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 alsoplays 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 i.a. in the L-cells in the distal ileum, in the pancreas andin the brain. Processing
`of preproglucagonto 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 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 aminoacid residues Nos. 1 to 6 and substituting the naturally
`occurring aminoacid residuein position 8 (Ala) by Gly. Similarly, Lys*4(N°-tetradecanoyl)-GLP-
`1(7-37) designates GLP-1 (7-37) wherein the e-amino group ofthe Lys residuein position 34 has
`beentetradecanoylated. 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-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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`Wherereferencein 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 discoveredthat certain modified GLP-1 or analogues thereof when formu-
`lated in aqueoussolution together with 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 recommendedstorage 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-
`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,intraveneousorinfusion ) as well as non-invasive (eg nasalor pulmo-
`nary, transdermal ortransmucosal e.g. buccal ) meansof administration. When the inventive
`formulation comprising a GLP-1 compound was comparedto the same formulation compris-
`ing GLP-1(7-37) substituted for the GLP-1 compound,the physical stability was increased
`considerably, and typically the shelf-life was increased from a few secondsto several
`monthsin the tests used.
`In one aspectthe invention relates to a pharmaceutical formulation comprising a GLP-1
`compound, and a buffer, wherein said GLP-1 compoundis GLP-1(7-37) or an analogue
`thereofwherein an aminoacid 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/mi 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 another 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-
`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
`from 0.1 mg/ml or above, and wherein said formulation has a pH from 7.0 to 10.
`in a further aspectthe invention relates to a pharmaceutical formulation comprising
`a GLP-1 compound, anda buffer, wherein said GLP-1 compound is GLP-1(7-37) or an ana-
`logue thereof, wherein an amino acid residue of the parent peptide 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/mi 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 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 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.
`
`In a further aspect the invention relates to a method of preparing a physicaily stable
`pharmaceutical formulation of a GLP-1 compound 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, 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 agentis present and PH is 7.4 then mannitol or NaClis not
`the isotonic agent.
`In one embodimentofthe invention the pharmaceutical formulation is an aqueous
`formulation. Such formulationis typically a solution or a suspension.In a further embodiment
`of the invention the pharmaceutical formulation is an aqueoussolution.
`In a further aspect the inventionrelates 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 analoguethereof 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
`7.0 to 10.
`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
`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, and a buffer, wherein said GLP-1 compoundis
`GLP-1(7-37) or an analoguethereof, 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; provided thatif an isotonic agentis present and pHis 7.4 then mannitolor
`NaClis not the isotonic agent.
`In a furtheraspectthe 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 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
`presentin 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-4 compound wherein said GLP-1 compound is GLP-
`1(7-37) or an analogue thereof, wherein an amino acid residue ofthe parent peptide has a lipo-
`philic substituent attached optionally via a spacer, comprising preparation of an aqueoussolu-
`tion containing the GLP-1 compound, and a buffer, wherein said GLP-1 compoundis present
`in a concentration from 0.1 mg/mlto 100 mg/ml, 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 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 ofthe parent peptide has a lipo-
`. philic substituent attached optionally via a spacer, comprising preparation of an aqueoussolu-
`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; providedthatif an isotonic agentis present and pHis 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 type Il 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 ofthe parent peptide hasa lipophilic substitu-
`ent attached optionally via a spacer, wherein said GLP-1 compoundis present in a concen-
`tration from 0.1 mg/ml to 100 mg/mI, and wherein said formulation has a PH from 7.0 to 10.
`In a further aspect the presentinvention relates to a method of treating gastric ulcers
`comprising administering to a patient in need thereofan effective amountof a 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 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 method of treating myocardial
`infarct comprising administering to a patient in need thereof an effective amount of 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 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 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 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 aminoacid residue of the Parent peptide hasa lipophilic substituent attached op-
`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 body weight
`in a subjectin 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 amino acid residue ofthe parent
`peptide hasa lipophilic substituent attached optionally via a spacer, wherein said GLP-1 com-
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`poundis present in a concentration from 0.1 mg/ml to 100 mg/ml, and wherein said formula-
`tion has a pH from 7.0 to 10.
`Theterm “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,
`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
`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 aqueoussolution of the GLP-1
`compound,and a buffer, wherein said GLP-1 compoundis GLP-1(7-37) or an analogue
`thereof wherein an amino acidresidue 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,for reducing
`blood glucoselevels.
`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-14 compound is 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 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
`diabetes typeI.
`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 compound is GLP-1(7-37) or an analogue
`thereof wherein an amino acid residue ofthe 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
`diabetestypeIl.
`In a further aspectthe 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 residueof the parent peptide has a 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.
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`In a further aspect the present invention relates to use of a GLP-1 compound for 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 amino acid residue of the parentpeptide 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 pHfrom 7.0 to 10, for reducing body
`weight, typically for reducing body weightin a type 2 diabetic subject.
`In a further aspectthe presentinvention 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
`thereofwherein an amino acid residue ofthe parentpeptide 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 pHfrom 7.0 to 10,for treating gas-
`tric ulcers.
`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 ofthe parent peptide hasa lipophilic substituent attached
`optionally via a spacer, wherein said GLP-1 compoundis presentin a concentration from 0.1
`mg/mi to 100 mg/ml, and wherein said formulation has a pH from 7.0 to 10,forinhibition of
`apoptosis of B-cells.
`The term “treatment” is defined as the managementandcare of a patient, e.g. a
`mammal, in particular a human,for the purpose of combating the disease, condition, or disorder
`andincludes the administration of a GLP-1 compoundto prevent the onset of the symptoms or
`complications,or alleviating the sympiomsor 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 or intravenousin-
`jection by meansof a syringe, optionally a pen-like syringe. Alternatively, parenteral administra-
`tion can be performed by meansofan infusion pump.A further option is a composition which
`may be a solution or suspensionfor the administration of the GLP-1 compoundin the form of a
`nasal or pulmonalspray.Asastill further option, the pharmaceutical compositions containing
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`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 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 atdifferent temperaturesin topfilled glass cartridges for
`various time periods. Visual inspection of the formulationsis performedin a sharp focusedlight
`with a dark background. The turbidity 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 visual turbidity in daylight correspondsto 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 measured by 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 embodimentofthe invention the formulation has a pHin the range from
`7.5 to 10. In another embodimentofthe invention the formulation has a pHin the range from
`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 embodimentofthe invention the formulation hasa pHin the
`range from 7.0 to 8.0. In a further embodimentofthe invention the formulation has a pH in
`the rangefrom 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 embodimentofthe 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
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`6358.010-DK
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`10
`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 0.1mg/ml to 80mg/ml. In a further embodimentofthe invention the GLP-1
`compoundis presentin a concentration from 1mg/ml to 80mg/mi. In a further embodiment of
`the invention the GLP-1 compoundis present in a concentration from 0.1mg/ml to 50mg/ml.
`In a further embodimentofthe invention the GLP-1 compoundis present in a concentration
`from img/ml to 50mg/ml. In a further embodiment of the invention the GLP-1 compoundis
`presentin a concentration from 0.1 mg/ml to 20mg/ml. In a further embodiment of 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 presentin a concentration from
`0.1mg/ml to 10mg/ml. in a further embodimentofthe invention the GLP-1 compoundis
`present in a concentration from img/mlto 1Omg/mi. In a further embodimentofthe invention
`the GLP-1 compoundis present in a concentration from 0.1-5mg/mi. In a further embodiment
`of the invention the GLP-1 compoundis presentin a concentration from 1-5mg/ml. Ina
`further embodimentof the invention the GLP-1 compoundis presentin a concentration from
`0.1-0.5mg/ml. In a further embodimentofthe invention the GLP-1 compoundis presentin a
`concentration from 0.6-img/ml. Each one of these specific concentration ranges constitutes an
`alternative embodiment of the invention.
`In a further embodimentof the 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-hydroxybenzoate, 2-phenoxyethanol, butyl p-hydroxybenzoate, 2-
`phenylethanol, benzy| alcohol, chlorobutanol, and thiomerosal, or mixtures thereof. Each one
`of these specific preservatives constitutes an alternative embodimentof the invention.
`In a further embodimentof the invention the preservative is present in a concentration
`from 0.1mg/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 embodimentof the
`invention the preservative is present in a concentration from 5 mg/ml to 10mg/mi. In a further
`embodimentof the invention the preservative is presentin a concentration from 10 mg/mlto
`20mg/ml. Each oneof these specific concentration rangesconstitutes an alternative
`embodimentof the invention.
`The use ofa preservative in pharmaceutical compositions is well-known to the skilled
`person. For conveniencereference is made to Remington: The Science and Practice ofPhar-
`macy, 19" edition, 1995.
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`In a further embodiment of the invention the formulation further comprises an isotonic
`agent. In a further embodimentof the invention the isotonic agent is selected from the group
`consisting of a salt (e.g. sodium chloride), a polyhydric alcohol (e.g. mannitol, sorbitol or
`glycerol), a monosaccharide (e.g. glucose), a disccharide (e.g. sucrose), or an amino 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 agent is present ina
`concentration from 1 mg/ml to 50 mg/ml.In a further embodimentof the invention the isotonic
`agentis present in a concentration from 1 mg/ml to 7 mg/m. In a further embodimentof the
`invention the isotonic agent is 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 oneof these specific concentration ranges constitutes an alternative
`embodimentof the invention.
`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 agentis selected from salts of
`ethlenediaminetetraacetic acid (EDTA), citric acid, and aspartic acid, and mixtures thereof,
`Each oneof these specific chelating agents constitutes an alternative embodimentof the
`invention.
`
`In a further embodimentof the invention the chelating agentis presentin a
`concentration from 0.1mg/ml to 5mg/ml. In a further embodimentof the invention the
`chelating agentis presentin a concentration from 0.4mg/ml to 2mg/ml. In a further
`embodimentofthe invention the chelating agentis present in a concentration from 2mg/mlto
`5mg/mi.
`
`The use of a chelating agent in pharmaceutical compositionsis 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 embodimentofthe inven