`
`PRIORITY DOCUMENT
`SUBMITTED OR TRANSMITTED IN
`COMPLIANCE WITH
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`RULE 17.1(a) OR (b)
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`
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`Kongeriget Danmark
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`Patent application No.:
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`PA 2002 00092
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`Date of filing:
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`’
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`‘
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`18'January 2002
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`Applicant:
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`Novo Nordisk A/S
`Novo Allé
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`DK-2880 Bagsveerd
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`
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`This is to certify the correctness of the following information:
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`The attached photocopy is a true copy of the following information:
`
`-
`
`The specification and claims as filed with the application on the
`filing date indicated above.
`
` Patent- 09 Varemaerkestyrelsen
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`Qkonomi— og Erhvervsministeriet
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`'
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`TAASTFth> 20 November 2002
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`PATWT' ”G VARE‘WETE‘iFKNRfNfiT. EXIIIBIT 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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`WP—
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`6358.020-DK
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`Title
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`Patent- 0
`Varemar estyrelsen
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`1 8 JAN. 2002
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`MOdtaget
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`Physically stable formulation of modified GLP-1
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`5
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`10
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`Background
`Peptides are widely used in medical practice, and since they can be produced by re-
`combinant DNA technology it can be expected that their importance will increase also in the
`
`years to come.
`
`The hormones regulating insulin secretion belong to the so-called enteroinsular
`axis, designating a group of hormones, released from the gastrointestinal mucosa in 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. Many of the gastrointestinal hor-
`mones, including gastrin and secretin (cholecystokinin is not insulinotropic in man). are insu-
`linotropic, but the only physiologically important ones, those that are responsible for the in-
`cretin effect, are the glucose-dependent insulinotropic polypeptide, GIP, and glucagon-like
`peptide-1 (GLP—1). Because of its 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, GlP was
`found to be almost ineffective in NlDDM. 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 NlDDM patients. In addition, and in contrast to the other insulinotropic hor-
`mones (perhaps with the exception of secretin) it also potently inhibits gluoagon secretion.
`Because of these actions it has pronounced blood glucose lowering effects particularly in pa-
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`25
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`5
`,,
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`30
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`tients with NlDDM.
`GLP-1, a product of the proglucagon, is one of the youngest members of 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 gene is processed differently in the pancreas and in the intestine. ln the pan-
`creas, the processing leads to-the formation and parallel secretion of 1) glucagon itself, 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 sequences are buried. Glucagon seems to be the only
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`MYLAN INST. EXHIBIT 1112 PAGE 2
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`MYLAN INST. EXHIBIT 1112 PAGE 2
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`MYLAN INST. EXHIBIT 1112 PAGE 2
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`6358.020-DK
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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 much attention has been focused on the pharmacological properties of acy-
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`lated GLP—1 compounds, hitherto little is known about their physico-chemical and solution
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`structural properties. Such knowledge is a prerequisite for rational handling during e.g. pro-
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`duction, purification and formulation work and is eventually important for understanding of the
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`structural basis for the protraction mechanism.
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`GLP-1 and analogues ofGLP-1 and fragments thereof are potentially useful i.a. in the
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`treatment of type 1 and type 2 diabetes. However, solubility limitations and the low stability
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`10
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`against the actions of endogenous diaminopeptidyl peptidase limits the usefulness of these
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`compounds, and thus there still is a need for improvements in this field.
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`In WO 99/43341 are disclosed certain pharmaceutical formulations comprising GLP-1
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`having a 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-
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`tive, and a tonicity modifier, at pH 8.2 to 8.8. It is specifically stated that maintaining pH in a
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`range of about 8.2 to about 8.8 unexpectedly improves the chemical stability of the formulation.
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`In addition it is stated that the concentration of the GLP—1 molecule also plays a role in the sta-
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`bility of the formulations. in this respect it is stated that a GLP—i concentration equal to or
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`greater than 1mg/ml was physically unstable.
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`Summary of the invention
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`Human GLP—1 is a 37 amino acid residue peptide originating from preproglucagon which
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`is synthesised i.a. in the L-ceils in the distal ileum, in the pancreas and in 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 GlyBGLP-1(7-37)) designates a fragment of GLP-‘l formally de-
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`15
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`20
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`25
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`rived from GLP—1 by deleting the amino acid residues Nos. 1 to 6 and substituting the naturally
`occurring amino acid residue in position 8 (Ala) by Gly. Similarly, Lys‘“(N”—tetradecanoyl)—GLP—
`1 (7-37) designates GLP-1(7-37) wherein the s—amino group of the Lys residue in position 34 has
`been tetradecanoylated. For convenience the amino acid sequence of GLP—1 (7-37) is given
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`.30
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`below, wherein the N-terminal His is no. 7 and the C-terminai Gly is no. 37:
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`His-Ala-Glu-Gly—Thr—Phe-Thr-Ser—Asp-Val-Ser-
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`Ser-Tyr—Leu-Glu-Gly-Gln-Aia-Ala-Lys—Glu—Phe—
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`35
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`lle-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly.
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`MYLAN INST. EXHIBIT 1112 PAGE 3
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`MYLAN INST. EXHIBIT 1112 PAGE 3
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`MYLAN INST. EXHIBIT 1112 PAGE 3
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`6358.020-DK
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`Where reference in this text is made to C-terminally extended GLP—1 analogues, the amino acid
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`residue in position 38 is Arg unless otherwise indicated, the optional amino acid residue in A
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`position 39 is also Arg unless otherwise indicated and the optional amino acid residue in
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`position 40 is Asp unless othenivise indicated. Also, if a C-temiinally extended analogue extends
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`to position 41, 42, 43, 44 or 45, the amino acid sequence of this extension is as in the
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`10
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`15
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`corresponding sequence in human preproglucagon unless otherwise indicated.
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`We have discovered that certain modified GLP-1 or analogues thereof when formu-
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`lated in aqueous solution together with a buffer, are physically stable at low and high concen-
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`trations of the modified GLP-1 or analogues thereof, when kept in the pH range from about 7
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`to about 10. The present formulations are physically stable within a given shelf life period at
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`the recommended storage temperature (typically 2-3 years at 2-8°C). Furthermore, the pre-
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`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
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`thus rendering them shelf-stable and suitable for invasive (eg. injection, subcutaneous injec-
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`tion, intramuscular, intraveneous or infusion ) as well as non-invasive (eg nasal or pulmo-
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`nary, transdermal or transmucosal e.g. buccal ) means of administration. When the inventive
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`formulation comprising a GLP-1 compound was compared to the same formulation compris-
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`ing GLP-1(7-37) substituted for the GLP-1 compound, the physical stability was increased
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`considerably, and typically the shelf-life was increased from a few seconds to several
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`20
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`months in the tests used.
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`In one aspect the invention relates to a pharmaceutical formulation comprising a GLP-1
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`compound, and a buffer, wherein said GLP—1 compound is GLP-1(7-37) or an analogue
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`thereof wherein an amino acid residue of the parent peptide has a lipophilic substituent attached
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`optionally via a spacer, wherein said GLP—1 compound is present in a concentration from 0.1
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`25
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`mglml to 100 mglml. and wherein said formulation has a pH from 7.0 to 10;
`
`provided that if an isotonic agent is present and pH is 7.4 then mannitol or NaCl is not the
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`isotonic agent.
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`'
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`in another aspect the invention relates to a pharmaceutical formulation comprising
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`a GLP-1 compound. and a buffer, wherein said GLP-1 compound is GLP—1(7~37) or an ana-
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`logue thereof wherein an amino acid residue of the parent peptide has a lipophilic substituent
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`attached optionally via a spacer. wherein said GLP-1 compound is present in a concentration
`
`from 0.1 mglml or above. and wherein said formulation has a pH from 7.0 to 10.
`In a further aspect the invention relates to a pharmaceutical formulation comprising
`a GLP—1 compound. and a buffer, wherein said GLP-1 compound is GLP-1(7-37) or an ana-
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`35
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`logue thereof. wherein an amino acid residue of the parent peptide has a lipophilic substituent
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`MYLAN INST. EXHIBIT 1112 PAGE 4
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`MYLAN INST. EXHIBIT 1112 PAGE 4
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`MYLAN INST. EXHIBIT 1112 PAGE 4
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`6358.020-DK
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`attached optionally via a spacer, wherein said GLP-1 compound is present in a concentration
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`from 0.1 mglml to 100 mglml, and wherein said formulation has a pH from 7.0 to 10.
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`In a further aspect the invention relates to a method of preparing a physically stable
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`pharmaceutical formulation of a GLP-1 compound wherein said GLP-1 compound is GLP-
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`5
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`1 (7-37) or an analogue thereof, wherein an amino acid residue of the parent peptide has a
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`lipophilic substituent attached optionally via a spacer, comprising preparation of a formulation
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`containing the GLP-1 compound, and a buffer, wherein said GLP-1 compound is present in a
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`concentration from 0.1 mglml or above, and wherein said formulation has a pH from 7.0 to
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`10.
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`10
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`In a further aspect the invention relates to a method of preparing a physically stable
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`pharmaceutical formulation of a GLP-t compound wherein said GLP-1 compound is GLP-
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`1(7-37) or an analogue thereof, wherein an amino acid residue of the parent peptide has a
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`lipophilic substituent attached optionally via a spacer, comprising preparation of a formulation
`
`containing the GLP—1 compound, and a buffer, wherein said GLP-1 compound is present in a
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`15
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`concentration from 0.1 mglml to 100 mglml, 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
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`pharmaceutical formulation of a GLP—1 compound wherein said GLP-1 compound is GLP-
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`1(7-37) or an analogue thereof, wherein an amino acid residue of the parent peptide has a
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`20
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`lipophilic substituent attached optionally via a spacer, comprising preparation of a formulation
`
`containing the GLP-1 compound, and a buffer, wherein said GLP-1 compound is present in a
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`concentration from 0.1 mglml to100 mglml, and wherein said formulation has a pH from 7.0
`
`to 10; provided that if an isotonic agent is present and pH is 7.4 then mannitol or NaCl is not
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`the isotonic agent.
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`25
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`In one embodiment of the invention the pharmaceutical formulation is an aqueous
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`formulation. Such formulation is typically a solution or a suspension. In a further embodiment
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`of the invention the pharmaceutical fomtuiation is an aqueous solution.
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`.
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`In a further aspect the invention relates to a pharmaceutical formulation comprising
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`an aqueous solution of a GLP-1 compound, and a buffer, wherein said GLP-1 compound is
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`~ 30
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`GLP—1(7—37) or an analogue thereof wherein an amino acid residue of the parent peptide has a
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`lipophilic substituent attached optionally via a spacer, wherein said GLP-1 compound is pre-
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`sent in a concentration from 0.1 mglml 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
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`35
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`an aqueous solution of a GLP-1 compound, and a buffer, wherein said GLP-1 compound is
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`MYLAN INST. EXHIBIT 1112 PAGE 5
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`MYLAN INST. EXHIBIT 1112 PAGE 5
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`MYLAN INST. EXHIBIT 1112 PAGE 5
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`6358.020—DK
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`5
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`GLP—1(7—37) or an analogue thereof, wherein an amino acid residue of the parent peptide has
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`a lipophilic substituent attached optionally via a spacer. wherein said GLP—1 compound is pre-
`
`sent in a concentration from 0.1 mg/ml to 100 mglml, and wherein said formulation has a pH
`from 7.0 to 10.
`V
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`In a fUrther aspect the invention relates to a pharmaceutical formulation comprising
`an aqueous solution of a GLP-1 compound, and a buffer, wherein said GLP-1 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—i compound is pre-
`
`sent in a concentration from 0.1 mg/ml to 100 mg/ml, and wherein said formulation has a pH
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`10
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`from 7.0 to 10; provided that if an isotonic agent is present and pH is 7.4 then mannitol or
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`NaCI is not the isotonic agent.
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`15
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`20
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`in a further aspect the invention relates to a method of preparing a physically stable
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`pharmaceutical formulation of a GLP—1 compound wherein said GLP-1 compound is GLP-
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`1(7—37) or an analogue thereof, wherein an amino acid residue of the parent peptide has a 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-‘l compound is
`
`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
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`pharmaceutical formulation of a GLP-1 compound wherein said GLP-1 compound is GLP-
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`1(7-37) or an analogue thereof, wherein an amino acid residue of the parent peptide has a lipo-
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`philic substituent attached optionally via a spacer, comprising preparation of an aqueous solu-
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`tion containing the GLP-1 compound, and a buffer, wherein said GLP—1 compound is present
`
`in a concentration from 0.1 mg/ml to 100 mglml, and wherein said formulation has a pH from
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`25
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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
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`pharmaceutical formulation of‘a GLP-1 compound wherein said GLP-1 compound is GLP-
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`1(7-37) or an analogue thereof, wherein an amino acid residue of the parent peptide has a 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 compound is 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; provided that if an isotonic agent is present and pH is 7.4 then mannitol or NaCl is
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`not the isotonic agent.
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`In a further aspect the present invention relates to a method of reducing blood glu-
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`cose levels, treating diabetes type i, diabetes type II or obesity. or inhibiting gastric acid se-
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`MYLAN INST. EXHIBIT 1112 PAGE 6
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`MYLAN INST. EXHIBIT 1112 PAGE 6
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`MYLAN INST. EXHIBIT 1112 PAGE 6
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`6358.020-DK
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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 aqueous solution
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`of a GLP-1 compound, and a buffer. wherein said GLP-1 compound is GLP-1 (7-37) or an
`
`analogue thereof wherein an amino acid residue of the parent peptide has a lipophilic substitu-
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`ent attached optionally via a spacer, wherein said GLP-1 compound is present in a concen-
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`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 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 aqueous solution of a GLP-1 compound. and a buffer, wherein
`said GLP-1 compound is GLP—1(7-37) or an analogue thereof wherein an amino acid residue
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`10
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`of the parent peptide has a lipophilic substituent attached optionally via a spacer, wherein said
`
`GLP-1 compound is 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 present invention relates to a method of treating myocardial
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`15
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`infarct comprising administering to a patient in need thereof an effective amount of a phar-
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`maceutical formulation comprising an aqueous solution of a GLP-1 compound, and a buffer,
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`wherein said GLP-1 compound is GLP-1(7-37) or an analogue thereofwherein an amino acid
`
`residue of the parent peptide has a lipophilic substituent attached optionally via a spacer,
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`wherein said GLP-1 compound is present in a concentration from 0.1 mg/ml to 100 mg/ml,
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`20
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`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 (lGT) comprising administering to a patient in need thereof an effective
`
`amount of a pharmaceutical formulation comprising an aqueous solution of a GLP-1 com-
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`pound, and a buffer, wherein said GLP-1 compound is GLP—1(7-37) or an analogue thereof
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`25
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`wherein an amino acid residue of the parent peptide has a lipophilic substituent attached op-
`
`tionally via a spacer, wherein said GLP-1 compound is present in a concentration from 0.1
`
`mg/ml to 100 mglml, and wherein said formulation has a pH from 7.0 to 10.
`
`In a further aspect the present invention relates to a method of reducing body weight
`
`in a subject in need of body weight reduction comprising administering to the subject an ef-
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`‘30
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`fective amount sufficient to cause reduction in body weight for a period of time effective to
`
`produce weight loss. said time being at least 4 weeks. of a pharmaceutical formulation com-
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`prising an aqueous solution of a GLP-1 compound. and a buffer, wherein said GLP-1 com-
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`pound is GLP~1(7-37) or an analogue thereof wherein an amino acid residue of the parent
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`peptide has a lipophilic substituent attached optionally via a spacer, wherein said GLP—1 com-
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`MYLAN INST. EXHIBIT 1112 PAGE 7
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`MYLAN INST. EXHIBIT 1112 PAGE 7
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`MYLAN INST. EXHIBIT 1112 PAGE 7
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`6358.020—DK
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`7
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`pound is present in a concentration from 0.1 mglml to 100 mglml, and wherein said formula-
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`tion has a pH from 7.0 to 10.
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`The term “an effective amount" is the effective dose to be determined by a qualified
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`practitioner, who may titrate dosages to achieve the desired response. Factors for
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`consideration of dose will include potency, bioavailability. desired
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`pharmacokinetic/pharmacodynamic profiles, condition of treatment (e.g. diabetes, obesity,
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`weight loss, gastric ulcers), patient—related factors (e.g. weight, health, age, etc.), presence of
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`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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`10
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`15
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`20
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`In a further aspect the present invention relates to use of a GLP-1 compound for the
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`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 compound is present in a concentration from 0.1
`
`mg/ml to 100 mglml, and wherein said formulation has a pH from 7.0 to 10, for reducing
`
`blood glucose levels.
`
`In a further aspect the present invention relates to use of a GLP-1 compound for the
`
`preparation of a pharmaceutical formulation comprising an aqueous solution of the GLP—1
`
`compound, and a buffer, wherein said GLP-1 compound is GLP-1(7-37) or an analogue
`
`thereof wherein an amino acid residue of the parent peptide has a lipophilic substituent attached
`
`optionally via a spacer, wherein said GLP-1 compound is present in a concentration from 0.1
`
`mglml to 100 mglml, and wherein said formulation has a pH from 7.0 to 10. for treating dia-
`
`betes type I.
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`25
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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 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 compound is present in a concentration from 0.1
`
`mg/ml to 100 mglml, and wherein said formulation has a pH from 7.0 to 10, for treating dia-
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`30
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`betes type II.
`
`in a further aspect the present invention relates to use of a GLP-1 compound for the
`
`preparation of a pharmaceutical formulation comprising an aqueous solution of the GLP-1
`
`compound, and a buffer, wherein said GLP-1 compound is GLP-1(7-37) or an analogue
`
`thereof wherein an amino acid residue of the parent peptide has a lipophilic substituent attached
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`35
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`optionally via a spacer, wherein said GLP-1 compound is present in a concentration from 0.1
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`MYLAN INST. EXHIBIT 1112 PAGE 8
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`MYLAN INST. EXHIBIT 1112 PAGE 8
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`MYLAN INST. EXHIBIT 1112 PAGE 8
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`6358.020-DK
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`8
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`mglml to 100 mglml. and wherein said formulation has a pH from 7.0 to 10, for treating obe-
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`sity.
`
`.
`
`In a further aspect the present invention relates to use of a GLP-1 compound for the
`
`preparation of a pharmaceutical formulation comprising an aqueous solution of the GLP—1
`
`compound, and a buffer, wherein said GLP—1 compound is GLP—1(7—37) or an analogue
`
`thereof wherein an amino acid residue of the parent peptide has a lipophilic substituent attached
`
`optionally via a spacer, wherein said GLP-1 compound is present in a concentration from 0.1
`mglml to 100 mglml, and wherein said formulation has a pH from 7.0 to 10, for reducing body
`
`weight, typically for reducing body weight in a type 2 diabetic subject.
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`10
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`15
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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 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 compound is present in a concentration from 0.1
`
`mglml to 100 mglml, and wherein said formulation has a pH from 7.0 to 10, for treating gas-
`tric ulcers.
`
`In a further aspect the present invention relates to use of a GLP—1 compound for the
`
`preparation of a pharmaceutical formulation comprising an aqueous solution of the GLP-1
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`20
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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 has a lipophilic substituent attached
`
`optionally via a spacer, wherein said GLP-1 compound is present in a concentration from 0.1
`
`mglml to 100 mglml, and wherein said formulation has a pH from 7.0 to 10, for inhibition of
`
`apoptosis of B-cells.
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`25
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`30
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`The term “treatment" is defined as the management and care of a patient, eg. a
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`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 or intravenous in-
`
`jection by means of a syringe, optionally a pen-like syringe. Alternatively, parenteral administra-
`
`tion can be performed by means of an infusion pump. A further option is a composition which
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`may be a solution or suspension for the administration of the GLP—1 compound in the form of a
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`nasal or pulmonal spray. As a still further option, the pharmaceutical compositions containing
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`6358.020—DK
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`9
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`the GLP~1 compound of the invention can also be adapted to transdem'ral administration, e.g.
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`from a patch, optionally a iontophoretic patch, or transmucosal. e.g. bucal, administration.
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`A pharmaceutical formulation is found to be physically unstable when it exhibits tur-
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`bidity. A pharmaceutical formulation of GLP1(7-37) is found to be physically unstable as it
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`5
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`turns out to be turbid momentaneously after preparation. whereas the same pharmaceutical
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`formulation comprising a GLP—1 compound is found to be physically stable for more than 90
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`days at 5°C. Some of the present formulations are physically stable for more than 11 months
`at 5°C.
`I
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`Physical stability of the formulations is evaluated by means of visual inspection and
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`10
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`turbidity after storage of the formulation at different temperatures in top filled glass cartridges for
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`various time periods. Visual inspection of the formulations is performed in a sharp focused light
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`with a dark background. The turbidity of the formulation is characterized by a visual score rank-
`ing the degree of turbidity from 0m 3 (a formulation showing no turbidity corresponds to a visual
`score 0, and a formulation showing visual turbidity in daylight corresponds to visual score 3). A
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`15
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`formulation is classified physical unstable with respect to protein aggregation, when it shows
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`visual turbidity in daylight.
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`in one embodiment of the invention the pharmaceutical formulation comprising the
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`GLP-t compound is physically Stable for more than 12 weeks at 5°C as measured by visual
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`inspection.
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`20
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`In another embodiment of the invention the pharmaceutical formulation comprising
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`the GLP-1 compound is physically stable for more than 12 weeks at 25°C as measured by
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`visual inspection.
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`In a further embodiment of the invention the pharmaceutical formulation comprising
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`the GLP-1 compound is physically stable for more than 12 weeks at 37°C as measured by
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`25
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`visual inspection.
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`In another embodiment of the invention the formulation has a pH in the range from
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`7.5 to 10. in another embodiment of the invention the formulation has a pH in the range from
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`7.5 to 9.5. In a further embodiment of the invention the formulation has a pH in the range
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`from 7.0 to 9.5. In a further embodiment of the invention the formulation has a pH in the
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`30
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`range from 7.0 to 8.0. In a further embodiment of the invention the formulation has a pH in
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`the range from 7.5 to 8.0. in a further embodiment of the invention the formulation has a pH
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`in the range from 9.0 to 10.
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`In a further embodiment of the invention the buffer is selected from the group
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`consisting of sodium acetate, sodium carbonate, citrate, glycylglycine, histidine. glycine,
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`35
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`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 embodiment of the invention.
`In a further embodiment of the invention the GLP-1 compound is present in a
`concentration from 0.1‘mg/ml to 80mg/ml. In a further embodiment of the invention the GLP-1
`compound is present in a concentration from 1mglml to 80mglml. In a further embodiment of
`the invention the GLP-1 compound is present in a concentration from 0.1mglml to 50mglml.
`In a further embodiment of the invention the GLP-1 compound is present in a concentration
`from 1mg/ml to 50mg/ml. In a further embodiment of the invention the GLP-1 compound is
`present in a concentration from 0.1mg/ml to 20mglml. In a further embodiment of the
`invention the GLP-1 compound is present in a concentration from 1mglml to 20mg/ml. In a
`further embodiment of the invention the GLP-1 compound is present in a concentration from
`0.1mg/ml to 10mglml. In a further embodiment of the invention the GLP-1 compound is
`present in a concentration from 1 mglml to 10mg/ml. In a further embodiment of the invention
`the GLP-1 compound is present in a concentration from 0.1-5mg/ml. In a further embodiment
`of the invention the GLP-1 compound is present in a concentration from 1-5mglrnl. In a
`
`further embodiment of the invention the GLP-1 compound is present in a concentration from
`0.1-0.5mg/ml. In a further embodiment of the invention the GLP-1 compound is present in a
`concentration from 0.6-1mglml. Each one of these specific concentration ranges constitutes an
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`10
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`15
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`alternative embodiment of the invention.
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`20
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`In a further embodiment of the invention the formulation further comprises a
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`pharmaceutically acceptable preservative. In a further embodiment of the invention the
`preservative is selected from the group consisting of phenol, m-cresol, methyl p-
`hydroxybenzoate. propyl p-hydroxybenzoate, 2-phenoxyethanol, butyl p-hydroxybenzoate, 2-
`phenylethanol, benzyl alcohol, chlorobutanol, and thiomerosal, or mixtures thereof. Each one
`of these specific preservatives constitutes an alternative embodiment of the invention.
`In a further embodiment of the invention the preservative is present in a concentration
`
`from 0.1mglml to 20mg/ml. In a further embodiment of the invention the preservative is
`present in a concentration‘from 0.1mglml to 5 mglml. In a further embodiment of the
`invention the preservative is present in a concentration from 5 mglml to 10mg/ml. In a further
`embodiment of the invention the preservative is present in a concentration from 10 mglml to
`
`20mglml. Each one of these specific concentration ranges constitutes an alternative
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`25
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`‘30
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`embodiment of the invention.
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`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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`35
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`in a further embodiment of the invention the formulation further comprises an isotonic
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`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,
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`mannitol, sorbitol or glycerol), a monosaccharide (e.g. glucose or maltose), a disccharide
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`(e.g. sucrose), an amino acid
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`(e.g. L-glycine, L-histidine, arginine, lysine, isoleucine, aspartic acid, tryptophan, threonine)
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`polyethyleneglycol (e.g. PEG400), or mixtures thereof. in a further embodiment of the
`
`invention the isotonic agent is selected from the group consisting of sodium chloride,
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`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 embodiment of the invention the isotonic agent is present in a
`
`concentration from 1 mglml to 50 mglml. in a further embodiment of the invention the isotonic
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`agent is present in a concentration from 1 mglml to 7 mglml. in a further embodiment of the
`
`invention the isotonic agent is present in a concentration from 8 mglml to 16 mglml. In a
`
`further embodiment of the invention the isotonic agent is present in a concentration from 17
`
`mglml to 50mglml. Each one of these specific concentration ranges constitutes an alternative
`
`embodiment of the invention.
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`.
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`The use of an isotonic agent in pharmaceutical compositions is well-known to the
`
`skilled person. For convenience reference is made to Remington: The Science and Practice of
`
`Pharmacy, 19th edition, 1995.
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`in a further embodiment of the invention the formulation further comprises a chelating
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`agent. in a further embodiment of the invention the chelating agent is selected from salts of
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`ethlenediaminetetraacetic acid (EDTA), citric acid, and aspartic acid, and mixtures thereof.
`
`Ea