`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`9 January 2003 (09.01.2003)
`
`
`
`PCT
`
`(10) International Publication Number
`WO 03/002136 A2
`
`(51) International Patent Classification’:
`
`A61K 38/00
`
`Richsvej, DK-2000 Frederiksberg (DK). ENGELUND,
`Dorthe, Kot; 39 Gassehaven, DK-2840 Holte (DK).
`
`(21) International Application Number:
`
`PCT/DK02/00437
`
`(22) International Filing Date:
`
`27 June 2002 (27.06.2002)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(81) Designated States (national): AE, AG, AL, AM, AT, AU,
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU,
`CZ, DE, DK, DM, DZ, EC, EE, ES, Fl, GB, GD, GE, GH,
`GM, HR, HU,ID,IL,IN, IS, JP, KE, KG, KP, KR, KZ, LC,
`LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW,
`MX, MZ, NO, NZ, OM, PH, PL, PT, RO, RU, SD, SE, SG,
`SI, SK, SL, TJ, TM, TN, TR, TT, TZ, UA, UG, UZ, VN,
`YU, ZA, ZM, ZW.
`
`(30) Priority Data:
`PA 2001 01010
`PA 2001 01011
`PA 2001 01053
`PA 2001 01052
`PA 2002 00093
`PA 2002 00092
`
`28 June 2001 (28.06.2001) DK
`28 June 2001 (28.06.2001) DK
`4 July 2001 (04.07.2001) DK
`4 July 2001 (04.07.2001) DK
`18 January 2002 (18.01.2002) DK
`—-18 January 2002 (18.01.2002) DK
`
`(84) Designated States (regional): ARIPO patent (GH, GM,
`KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM, ZW),
`Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European patent (AT, BE, CH, CY, DE, DK, ES, FI, FR,
`GB, GR,IE, IT, LU, MC, NL, PT, SE, TR), OAPI patent
`(BE, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR,
`NE, SN, TD, TG).
`
`(71) Applicant: NOVO NORDISKA/S [DK/DK]; Novo Allé,
`DK-2880 Bagsvaerd (DK).
`
`Published:
`
`without international search report and to be republished
`upon receipt of that report
`
`Taarbaek
`st.th.
`(72) Inventors: FLINK, James, M; 76,
`Strandvej, DK-2930 Klampenborg (DK). LARSEN,Silke,
`Moller; 10, 1.mf, Ejgaardsvej, DK-2920 Charlottenlund
`(DK). JENSEN, Simon, Bjerregaard; 103A, 5.th., CLE.
`
`For two-letter codes and other abbreviations, refer to the "Guid-
`ance Notes on Codes andAbbreviations" appearing at the begin-
`ning ofeach regular issue ofthe PCT Gazette.
`
`03/002136A2
`
`(54) Title; STABLE FORMULATION OF MODIFIED GLP-1
`
`©
`S (57) Abstract: Pharmaceutical formulations of GLP-1 compounds and methods for preparation thereof.
`
`MPI EXHIBIT 1041 PAGE 1
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`MPI EXHIBIT 1041 PAGE 1
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`MPI EXHIBIT 1041 PAGE 1
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`
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`WO 03/002136
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`PCT/DK02/00437
`
`STABLE FORMULATION OF MODIFIED GLP-1
`
`1
`
`Field of the invention
`
`The present invention relates to pharmaceutical formulations comprising GLP-1
`
`compounds, uses thereof and methodsfor preparing said formulations.
`
`Backgroundof the invention
`
`Peptides are widely used in medical practice, and since they can be producedbyre-
`
`combinant DNAtechnologyit can be expected that their importancewill increase alsoin the
`
`10
`
`years to come.
`
`15
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`20
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`25
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`30
`
`The hormones regulating 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-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, numerousinvestigations 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-
`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(perhapswith 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 product of the proglucagon, is one of the youngest membersof the se-
`cretin-VIP family of peptides, but is 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 and in the intestine. In the pan-
`creas, the processing leads to the formation and parallel secretion of 1) glucagon itself, oc-
`
`MPI EXHIBIT 1041 PAGE 2
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`MPI EXHIBIT 1041 PAGE 2
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`WO 03/002136
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`PCT/DK02/00437
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`2
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`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 sequences are buried. Glucagon seemsto be the only
`biologically active product. In contrast, in the intestinal mucosa,it is glucagonthat 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 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.
`
`It is an important technical challenge to ensure prolongedstability during storage
`(shelf life) of many protein based drug products due to the inherentlability of macromole-
`cules. Hence,proteins are sensitive to both chemical and physical degradation unlike many
`small molecules. Chemical degradation involves covalent bonds, such as hydrolysis, racemi-
`zation, oxidation or crosslinking. Physical degradation involves conformational changesrela-
`tive to the native structure, which includes loss of higher order structure, aggregation, precipi-
`tation or adsorption to surfaces. GLP-1 is knownto be proneto instability due to aggregation.
`Both degradation pathways mayultimately lead to loss of biological activity of the protein
`drug.
`
`20
`
`GLP-1 and analogues of GLP-1 and fragments thereof are potentially useful i.a. in the
`treatment of 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
`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.
`
`25
`
`30
`
`35
`
`Human GLP-1is a 37 amino acid residue peptide originating from preproglucagon which
`is synthesised /.a. in the L-cells in the distal ileum, in the pancreas and in 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, Val°-GLP-1(7-37) (or Val8GLP-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 amino acid residuein position 8 (Ala) by Val. Similarly, Lys*4(N*-tetradecanoyl)-GLP-
`
`MPI EXHIBIT 1041 PAGE 3
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`WO 03/002136
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`PCT/DK02/00437
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`3
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`1(7-37) designates GLP-1(7-37) wherein the s-amino groupof the 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-terminal Gly is no. 37:
`
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-
`
`Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-
`
`{fe-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly.
`
`Where referencein 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 sequencein human preproglucagonunless otherwiseindicated.
`
`10
`
`15
`
`Summaryof the invention
`
`We have 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
`
`20
`
`10. The present formulations are physically stable within a given shelflife period at the rec-
`
`25
`
`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, intraveneousor infusion ) 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
`
`30
`
`tests used.
`
`Oneobject of the presentinvention is to provide a pharmaceutical formulation com-
`prising 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 sub-
`stituent attached optionally via a spacer, wherein said GLP-1 compoundis present in a con-
`
`35
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`MPI EXHIBIT 1041 PAGE 4
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`MPI EXHIBIT 1041 PAGE 4
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`WO 03/002136
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`PCT/DK02/00437
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`4
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`centration from 0.1 mg/ml to 100 mg/ml, and wherein said formulation has a pH from 7.0 to
`
`10;
`
`Anotherobject of the present invention is to provide a method of preparing a physi-
`
`cally stable pharmaceutical formulation of a GLP-1 compound wherein said GLP-1 com-
`
`pound is GLP-1(7-37) or an analogue thereof wherein an aminoacid residue of the parent
`
`peptide hasalipophilic substituent attached optionally via a spacer, comprising preparing 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 to 10.
`
`In one aspect of the invention the formulation contains a GLP-1 compoundin a con-
`
`centration from 1 mg/ml to 100 mg/ml.
`
`In another aspectof the invention the formulation has a pH from 7.5 to 10.
`In one embodiment the GLP-1 compoundis Arg™, Lys*°(N-e-(y-Glu(N-o-
`hexadecanoyl)))-GLP-1 (7-37).
`
`10
`
`15
`
`Description of the invention
`
`In one 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 analogue
`
`thereof wherein an aminoacid residue of the parent peptide hasa lipophilic substituent attached
`
`20
`
`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;
`
`provided thatif an isotonic agent is present and pH is 7.4 then mannitol or NaCl is 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 amino acid residue of the parent peptide hasa lipophilic substituent
`attached optionally via a spacer, wherein said GLP-1 compoundis presentin 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 agentis present and pH is 7.4 then mannitol or NaClis not the
`isotonic agent.
`
`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-
`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.
`
`25
`
`30
`
`35
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`MPI EXHIBIT 1041 PAGE 5
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`MPI EXHIBIT 1041 PAGE 5
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`WO 03/002136
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`PCT/DK02/00437
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`5
`
`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-
`logue 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 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-
`
`logue 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
`
`10
`
`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
`
`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 has a lipophilic substituent
`
`attached optionally via a spacer, wherein said GLP-1 compoundis presentin a concentration
`
`15
`
`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 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 prepararing a formulation
`
`20
`
`containing the GLP-1 compound, and a buffer, wherein said GLP-1 compoundis presentin a
`
`concentration from 0.1 mg/m! 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-
`
`25
`
`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 prepararing 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 prepararing 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
`to 10.
`
`30
`
`35
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`MPI EXHIBIT 1041 PAGE 6
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`MPI EXHIBIT 1041 PAGE 6
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`MPI EXHIBIT 1041 PAGE 6
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`
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`WO 03/002136
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`PCT/DK02/00437
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`6
`
`In a further aspect theinvention 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 aminoacid residue of the parent peptide has a
`lipophilic substituent attached optionally via a spacer, comprising preparing a formulation con-
`taining 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.
`
`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-
`
`10
`
`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 preparing a formulation con-
`
`taining the GLP-1 compound, water, 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.
`
`15
`
`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 preparing a formulation con-
`
`taining the GLP-1 compound, water, and a buffer, wherein said GLP-1 compoundis present
`
`20
`
`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 aspectthe 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
`
`25
`
`lipophilic substituent attached optionally via a spacer, comprising preparing 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.
`
`30
`
`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 preparing 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
`
`35
`
`7.0 to 10.
`
`MPI EXHIBIT 1041 PAGE 7
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`MPI EXHIBIT 1041 PAGE 7
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`MPI EXHIBIT 1041 PAGE 7
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`WO 03/002136
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`PCT/DK02/00437
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`7
`
`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 preparing a formulation con-
`
`taining the GLP-1 compound, water, 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
`
`7.5 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 compoundis GLP-
`
`10
`
`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 preparing a formulation con-
`
`taining the GLP-1 compound, water, 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
`
`7.5 to 10.
`
`15
`
`20
`
`25
`
`30
`
`35
`
`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 preparing 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
`
`7.5 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 aminoacid residue of the parent peptide has a
`lipophilic substituent attached optionally via a spacer, comprising preparing 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
`7.5 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 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 preparing a formulation con-
`taining 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
`
`MPI EXHIBIT 1041 PAGE 8
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`WO 03/002136
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`PCT/DK02/00437
`
`8
`
`to 10; providedthatif an isotonic agent is present and pH is 7.4 then mannitol or NaCl is 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
`
`lipophilic substituent attached optionally via a spacer, comprising preparing a formulation con-
`
`taining 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
`
`10
`
`isotonic agent.
`
`In one embodimentof the invention the pharmaceutical formulation is an aqueous
`
`formulation, i.e. a formulation comprising water. Such formulation is typically a solution or a
`
`suspension. Jn a further embodimentof the invention the pharmaceutical formulation is an
`
`aqueous solution. The term “aqueous formulation”is defined as a formulation comprising at
`
`least 50 %w/w water. Likewise, the term “aqueoussolution” is defined as a solution compris-
`
`ing at least 50 %w/w water, and the term “aqueous suspension’is defined as a suspension
`
`comprising at least 50 %w/w water.
`
`In another embodiment the pharmaceutical formulation is a freeze-dried formulation,
`
`whereto the physician or the patient adds the solventprior to use.
`
`20
`
`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
`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
`
`25
`
`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 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 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
`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 lipophilic substituent attached optionally via a spacer, wherein said GLP-1 compoundis pre-
`
`30
`
`35
`
`MPI EXHIBIT 1041 PAGE 9
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`MPI EXHIBIT 1041 PAGE 9
`
`MPI EXHIBIT 1041 PAGE 9
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`
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`WO 03/002136
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`PCT/DK02/00437
`
`9
`
`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 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
`
`from 7.0 to 10.
`
`In a further aspect the invention relates to a pharmaceutical formulation comprising
`
`10
`
`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; providedthat if an isotonic agent is present and pH is 7.4 then mannitol or
`
`15
`
`NaCl is not the isotonic agent.
`
`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 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
`from 7.0 to 10; provided thatif 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 hasa 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
`
`20
`
`25
`
`from 7.0 to 10.
`
`30
`
`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 aminoacid residue of the parent peptide hasalipo-
`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 1 mg/ml or above, and wherein said formulation has a pH
`from 7.0 to 10.
`
`35
`
`MPI EXHIBIT 1041 PAGE 10
`
`MPI EXHIBIT 1041 PAGE 10
`
`MPI EXHIBIT 1041 PAGE 10
`
`
`
`WO 03/002136
`
`PCT/DK02/00437
`
`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 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
`
`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-
`
`10
`
`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 aqueoussolu-
`
`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.
`
`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 fipo-
`
`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
`
`20
`
`in a conceniration 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 NaCl is
`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-
`
`25
`
`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 NaCl is
`
`30
`
`not the isotonic agent.
`In a further aspect the present invention relates to a method of reducing blood glu-
`coselevels, treating diabetes type |, diabetes typeII, obesity, or inhibiting gastric acid secre- ,
`
`tion, inhibiting apoptosis of B-cells, or stimulating the proliferation of B-cells, comprising ad-
`
`ministering to a patient in need thereof an effective amount of a pharmaceutical formulation
`
`35
`
`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
`
`MPI EXHIBIT 1041 PAGE11
`
`MPI EXHIBIT 1041 PAGE 11
`
`MPI EXHIBIT 1041 PAGE 11
`
`
`
`WO 03/002136
`
`PCT/DK02/00437
`
`11
`
`peptide has a lipophilic substituent attached optionally via a spacer, wherein said GLP-1 com-
`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.
`
`In a further aspect the present invention relates to a method of reducing blood glu-
`
`cose levels, treating diabetes type |, diabetes type Il, obesity, or inhibiting gastric acid secre-
`
`tion, inhibiting apoptosis of B-cells, or stimulating the proliferation of B-cells comprising ad-
`
`ministering to a patient in need thereof an effective amount of 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 hasa lipophilic substituent attached optionally via a spacer, wherein said GLP-1 com-
`poundis 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 gastric ulcers
`comprising administering to a patient in need thereof an effective amount of 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 prese