~··
`
`PCT/DK 02/00437
`
`PRIORITY DOCUMENT
`SUBMITTED OR TRANSMITTED IN
`COMPLIANCE WITH
`RULE 17.l(a) OR (b)
`
`Kongeriget Danmark
`
`Patent application No.:
`
`PA 2001 01011
`
`Date of filing:
`
`28 June 2001
`
`REC'D 2 9 NOV 2002
`WIPO
`
`PC1
`
`Applicant:
`
`-Novo Nordisk A/S
`Novo Alie
`DK-2880 Bagsvc:erd
`This is to certify the correctness of the following information:
`' 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- og Varemrerkestyrelsen
`0konomi- og Erhvervsministeriet ·
`
`T~;ifL-.
`---=--(cid:173)
`
`PATENT- OG VAREMA:RKESTYRELSEN
`
`Karin Schlichting ✓- - - - - . :
`Head Clerk
`
`t
`~
`
`MYLAN INST. EXHIBIT 1109 PAGE 1
`
`MYLAN INST. EXHIBIT 1109 PAGE 1
`
`

`

`6358.000-DK
`
`,, .~
`
`Title
`
`Physically stable formulation of modified GLP-1
`
`1
`
`Patent-og
`Varemcerkestyrelsen
`2 8 JUNI 2001
`Modtaget
`
`Background
`Peptides are widely used in medical practice, and since they can be produced by re(cid:173)
`combinant DNA technology it can be expected that their importance will increase also in the
`years to come.
`
`s
`
`10
`
`15
`
`20
`
`25
`
`"
`
`30
`
`The hormones regulating insulin secretion belong to the so-called enteroinsular
`axis, designating a group of hormones, released from the gastrointestinal mucosa in re(cid:173)
`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(cid:173)
`mones, including gastrin and secretin (cholecystokinin is not insulinotropic in man), are insu(cid:173)
`linotropic, but the only physiologically important ones, those that are responsible for the in(cid:173)
`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(cid:173)
`tracted considerable interest among diabetologists. However, numerous investigations car(cid:173)
`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(cid:173)
`dependent diabetes mellitus (NIDDM). Furthermore, as an insulinotropic hormone, GIP was
`found to be almost ineffective in NIDDM. The other incretin hormone, GLP-1 is the most po(cid:173)
`tent insulinotropic substance known. Unlike GIP, it is surprisingly effective in stimulating insu(cid:173)
`lin secretion in NIDDM patients. In addition, and in contrast to the other insulinotropic hor(cid:173)
`mones (perhaps with the exception of secretin) it also potently inhibits glucagon secretion.
`Because of these actions it has pronounced blood glucose lowering effects particularly in pa-
`tients with NIDDM.
`GLP-1, a product of the proglucagon, is one of the youngest members of the se(cid:173)
`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. In the pan-
`creas, the processing leads .to the formation and parallel secretion of 1) glucagon itself, oc(cid:173)
`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(cid:173)
`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
`
`MYLAN INST. EXHIBIT 1109 PAGE 2
`
`MYLAN INST. EXHIBIT 1109 PAGE 2
`
`

`

`6358.000..DK
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`•
`
`35
`
`2
`
`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(cid:173)
`lated GLP-1 compounds, hitherto little is known about their physico-chemical and solution
`structural properties. Such knowledge is a prerequisite for rational handling during e.g. pro(cid:173)
`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 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 thus there still is a need for improvements in this field.
`In WO 99/43341 are disclosed certain pharmaceutical formulations comprising GLP-1
`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-
`tive, and a tonicity modifier, at pH 8.2 to 8.8. It is specifically stated that maintaining pH in a
`range of about 8.2 to about 8.8 unexpectedly improves the chemical stability of the formulation.
`In addition it is stated that the concentration of the GLP-1 molecule also plays a role in the sta(cid:173)
`bility of the formulations. In th.is respect it is stated that a GLP-1 concentration equal to or
`greater than 1 mg/ml was physically unstable.
`
`Summary of the 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 and in the brain. Processing
`of preproglucagon to give G~P-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, Gly8-GLP-1(7-37) (or GlyBGLP-1(7-37)) designates a fragment of GLP-1 formally de(cid:173)
`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, Lys34(N&•tetradecanoyl)-GLP-
`1 (7-37) designates GLP-1(7-37) wherein thee-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
`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(cid:173)
`Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe(cid:173)
`lle-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly.
`
`MYLAN INST. EXHIBIT 1109 PAGE 3
`
`MYLAN INST. EXHIBIT 1109 PAGE 3
`
`

`

`6358.000-DK
`
`3
`
`Where reference in this text is made to C-terminally extended GLP-1 analogues, the amino acid
`
`residue in position 38 is Arg unless otherwise indicated, the optional amino acid residue in
`
`position 39 is also Arg unless otherwise indicated and the optional amino acid residue in
`
`position 40 is Asp unless otherwise indicated. Also, if a C-terminally extended analogue extends
`
`5
`
`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.
`We have discovered that certain modified GLP-1 or analogues thereof when formu(cid:173)
`
`lated in aqueous solution together with a buffer, are physically stable at low and high concen(cid:173)
`
`trations of the modified GLP-1 or analogues thereof, when kept in the pH range from about 7
`
`10
`
`to about 10. The present formulations are physically stable within a given shelf life period at
`
`the recommended storage temperature (typically 2-3 years at 2-8°C). Furthermore, the pre(cid:173)
`
`sent formulations are physically stable during in-use (typically 1 month at accelerated tem(cid:173)
`
`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, subcutaneous injec-
`
`15
`
`tion, intramuscular, intraveneous or infusion ) as well as non-invasive (eg nasal or pulmo(cid:173)
`
`nary, transdermal or transmucosal e.g. buccal) means of administration. When the inventive
`
`formulation comprising a GLP-1 compound was compared to the same formulation compris(cid:173)
`
`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 seconds to several
`
`20 months in the tests used.
`
`In one aspect the invention relates to a pharmaceutical formulation comprising a GLP-1
`
`compound, and a buffer, wherein said GLP-1 compound is GLP-1 (7-37) or an analogue
`
`thereof wherein an amino acid 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
`25 mg/ml to 100 mg/ml, 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
`
`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-
`
`30
`
`logue 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 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-
`
`35
`
`logue thereof, wherein an amino acid residue of the parent peptide has a lipophilic substituent
`
`MYLAN INST. EXHIBIT 1109 PAGE 4
`
`MYLAN INST. EXHIBIT 1109 PAGE 4
`
`

`

`6358.000-DK
`
`4
`
`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 invention relates to a method of preparing a physically stable
`
`pharmaceutical formulation of a GLP-1 compound wherein said GLP-1 compound is GLP-
`
`5
`
`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 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.
`
`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 compound is present in a
`
`15
`
`concentration from 0.1 mg/ml to 100 mg/ml, and wherein said formulation has a pH from 7.0
`to 10.
`
`In a further aspect the invention relates to a method of preparing a physically stable
`
`pharmaceutical formulation of a GLP-1 compound wherein said GLP-1 compound is GLP-
`1 {7-37) or an analogue thereof, wherein an amino acid residue of the parent peptide has a
`
`20
`
`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
`
`concentration from 0.1 mg/ml to 100 mg/ml, 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 isotonic agent.
`
`25
`
`In one embodiment of the invention the pharmaceutical formulation is an aqueous
`formulation. Such formulation is typically a solution or a suspension. In a further embodiment
`of the invention the pharmaceutical formulation is an aqueous solution.
`In a further aspect the invention relates to a pharmaceutical formulation comprising
`
`an aqueous solution of a GLP-1 compound, and a buffer, wherein said GLP-1 compound is
`
`30 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 pre(cid:173)
`
`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 aspect the invention relates to a pharmaceutical formulation comprising
`
`35
`
`an aqueous solution of a GLP-1 compound, and a buffer, wherein said GLP-1 compound is
`
`MYLAN INST. EXHIBIT 1109 PAGE 5
`
`MYLAN INST. EXHIBIT 1109 PAGE 5
`
`

`

`6358.0.00-DK
`
`-~
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`5
`
`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 pre(cid:173)
`sent in a concentration from 0. J 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 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 pre(cid:173)
`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 that if 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-
`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 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
`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(cid:173)
`philic substituent attached optionally via a spacer, comprising preparation of an aqueous solu(cid:173)
`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
`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 lipo(cid:173)
`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
`7.0 to 10; provided that if an i_sotonic agent is present and pH is 7.4 then mannitol or NaCl is
`not the isotonic agent.
`In a further aspect the present invention relates to a method of reducing blood glu-
`cose levels, treating diabetes type I, diabetes type II or obesity, or inhibiting gastric acid se-
`
`MYLAN INST. EXHIBIT 1109 PAGE 6
`
`MYLAN INST. EXHIBIT 1109 PAGE 6
`
`

`

`6358.0p0-DK
`
`6
`
`5
`
`10
`
`15
`
`cretion, or inhibiting apoptosis of 13-cells, comprising administering 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 compound is GLP-1(7-37) or an
`analogue thereof wherein an amino acid residue of the parent peptide has a lipophilic substitu-
`ent attached optionally via a spacer, wherein said GLP-1 compound is present in a concen(cid:173)
`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(cid:173)
`cal formulation comprising an aqueous solution of a GLP-1 compound, and a buffer, wherein
`said GLP-1 compound is GLP-1(7-37) or an analogue thereof wherein an amino acid residue
`of the parent peptide 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
`infarct comprising administering to a patient in need thereof an effective amount of a phar(cid:173)
`maceutical 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-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 impaired
`glucose tolerance (IGT) comprising administering to a patient in need thereof an effective
`amount of a pharmaceutical formulation comprising an aqueous solution of a GLP-1 com(cid:173)
`pound, and a buffer, wherein said GLP-1 compound is GLP-1(7-37) or an analogue thereof
`25 wherein an amino acid residue of the parent peptide has a lipophilic substituent attached op(cid:173)
`tionally 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 reducing body weight
`in a subject in need of body weight reduction comprising administering to the subject an ef-
`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(cid:173)
`prising an aqueous solution of a GLP-1 compound, and a buffer, wherein said GLP-1 com(cid:173)
`pound 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 com-
`
`20
`
`30
`
`MYLAN INST. EXHIBIT 1109 PAGE 7
`
`MYLAN INST. EXHIBIT 1109 PAGE 7
`
`

`

`6358.0P0-DK
`
`7
`
`' '
`
`5
`
`10
`
`pound is present in a concentration from 0.1 mg/ml to 100 mg/ml, and wherein said formula(cid:173)
`tion has a pH from 7.0 to 10.
`The term "an effective amount" is the effective dose to be determined by a qualified
`practitioner, who may titrate dosages to achieve the desired response. Factors for
`consideration of dose will include potency, bioavailability, desired
`pharmacokinetic/pharmacodynamic profiles, condition of treatment (e.g. diabetes, obesity,
`weight loss, gastric ulcers), p~tient-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 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
`15 mg/ml to 100 mg/ml, 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
`mg/ml to 100 mg/ml, and wherein said formulation has a pH from 7.0 to 10, for treating
`diabetes type I.
`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 mg/ml, and wherein said formulation has a pH from 7.0 to 10, for treating
`diabetes type II.
`
`20
`
`25
`
`30
`
`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
`
`35
`
`MYLAN INST. EXHIBIT 1109 PAGE 8
`
`MYLAN INST. EXHIBIT 1109 PAGE 8
`
`

`

`6358.0P0-DK
`
`mg/ml to 100 mg/ml, and wherein said formulation has a pH from 7 .0 to 10, for treating obe(cid:173)
`sity.
`
`8
`
`5
`
`10
`
`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 mg/ml, 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.
`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
`15 mg/ml to 100 mg/ml, and wherein said formulation has a pH from 7 .0 to 10, for treating gas(cid:173)
`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
`compound, and a buffer, wherein said GLP-1 compound is GLP-1(7-37) or an analogue
`thereof wherein an amino aciq 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 mg/ml, and wherein said formulation has a pH from 7.0 to 10, for inhibition of
`apoptosis of f3-cells.
`The term "treatmene is defined as the management and care of a patient, e.g. a
`25 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(cid:173)
`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(cid:173)
`jection by means of a syringe, optionally a pen-like syringe. Alternatively, parenteral administra(cid:173)
`tion can be performed by means of an infusion pump. A further option is a composition which
`may be a solution or suspension for the administration of the GLP-1 compound in the form of a
`nasal or pulmonal spray. As a still further option, the pharmaceutical compositions containing
`
`20
`
`30
`
`MYLAN INST. EXHIBIT 1109 PAGE 9
`
`MYLAN INST. EXHIBIT 1109 PAGE 9
`
`

`

`6358.090-DK
`
`9
`
`the GLP-1 compound of the 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 when it exhibits tur(cid:173)
`bidity. A pharmaceutical formulation of GLP1(7-37) is found to be physically unstable as it
`turns out to be turbid momentaneously after preparation, whereas the same pharmaceutical
`formulation comprising a GLP-1 compound is found to be physically stable for more than 90
`days at 5°C. Some of the present formulations are physically stable for more than 11 months
`at 5°C.
`
`Physical stability of the formulations is evaluated by means of visual inspection and
`turbidity after storage of the formulation at different temperatures in top filled glass cartridges for
`various time periods. Visual inspection of the formulations is performed in a sharp focused light
`with a dark background. The _turbidity of the formulation is characterized by a visual score rank(cid:173)
`ing the degree of turbidity from Oto 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
`formulation is classified physical unstable with respect to protein aggregation, when it shows
`visual turbidity in daylight.
`
`5
`
`1 o
`
`15
`
`In one embodiment of the invention the pharmaceutical formulation comprising the
`GLP-1 compound is physically stable for more than 12 weeks at 5°C as measured by visual
`inspection.
`In another embodiment of the invention the pharmaceutical formulation comprising
`the GLP-1 compound is physically stable for more than 12 weeks at 25°C as measured by
`visual inspection.
`In a further embodi'T!ent of the invention the pharmaceutical formulation comprising
`the GLP-1 compound is physically stable for more than 12 weeks at 37°C as measured by
`visual inspection.
`In another embodiment of the invention the formulation has a pH in the range from
`7.5 to 10. In another embodiment of the invention the formulation has a pH in the range from
`7.5 to 9.5. In a further embodiment of the invention the formulation has a pH in the range
`from 7.0 to 9.5. In a further embodiment of the invention the formulation has a pH in the
`range from 7.0 to 8.0. In a further embodiment of the invention the formulation has a pH in
`the range from 7.5 to 8.0. In a further embodiment of the invention the formulation has a pH
`in the range from 9.0 to 10.
`In a further embodiment of the invention the buffer is selected from the group
`consisting of sodium acetate, sodium carbonate, citrate, glycylglycine, histidine, glycine,
`lysine, arginin, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium
`
`20
`
`25
`
`30
`
`35
`
`MYLAN INST. EXHIBIT 1109 PAGE 10
`
`MYLAN INST. EXHIBIT 1109 PAGE 10
`
`

`

`6358.000-DK
`
`10
`
`5
`
`10
`
`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 1 mg/ml to 80mg/ml. In a further embodiment of
`the invention the GLP-1 compound is present in a concentration from 0.1 mg/ml to 50mg/ml.
`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 0.1 mg/ml to 20mg/ml. In a further embodiment of the
`invention the GLP-1 compound is present in a concentration from 1mg/ml to 20mg/ml. In a
`further embodiment of the invention the GLP-1 compound is present in a concentration from
`0.1 mg/ml to 1 0mg/ml. In a further embodiment of the invention the GLP-1 compound is
`present in a concentration from 1 mg/ml to 1 0mg/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 1-5mg/ml. 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 0.6-1mg/ml. Each one of these specific concentration ranges constitutes an
`alternative embodim'ent of the invention.
`In a further embodiment of the invention the formulation further comprises a
`pharmaceutically acceptable preservative. In a further embodiment of the invention the
`preservative is selected from the group consisting of phenol, m-cresol, methyl p(cid:173)
`hydroxybenzoate, propyl p-hydroxybenzoate, 2-phenoxyethanol, butyl p-hydroxybenzoate, 2-
`phenylethanol, benzyl alcohol, chlorobutanol, and thiomerosal, or rr,ixtures 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 0.1 mg/ml to 20mg/ml. In a further embodiment of the invention the preservative is
`present in a concentration from 0.1 mg/ml to 5 mglml. In a further embodiment of the
`invention the preservative is present in a concentration from 5 mg/ml to 10mg/ml. In a further
`embodiment of the invention the preservative is present in a concentration from 1 O mg/ml to
`20mg/ml. Each one of these specific concentration ranges constitutes an alternative
`embodiment of the invention.
`The use of a preservative in pharmaceutical compositions is well-known to the skilled
`person. For convenience reference is made to Remington: The Science and Practice of Phar-
`35 macy, 19th edition, 1995.
`
`15
`
`20
`
`25
`
`30
`
`MYLAN INST. EXHIBIT 1109 PAGE 11
`
`MYLAN INST. EXHIBIT 1109 PAGE 11
`
`

`

`- - - - - · ·-- -·
`
`6358.000-DK
`
`11
`
`5
`
`1 o
`
`In a further embodiment of the invention the formulation further comprises an isotonic
`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. 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 embodiment of the invention the isotonic agent is selected
`from the group consisting of sodium chloride, glycerol, mannitol, glucose, sucrose, L-glycine,
`L-histidine, arginine, lysine or mixtures thereof. Each one of these specific isotonic agents
`constitutes an alternative embodiment of the invention.
`In a further embodiment of the invention the isotonic agent is present in a
`concentration from 1 mg/ml to 50 mg/ml. In a further embodiment of the invention the isotonic
`agent is present in a concentration from 1 mg/ml to 7 mg/ml. In a further embodiment of the
`invention the isotonic agent is present in a concentration from 8 mg/ml to 16 mg/ml. In a
`further embodiment of the invention the isotonic agent is present in a concentration from 17
`15 mg/ml to 50mg/ml. Each one of these specific concentration ranges constitutes an alternative
`embodiment of 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, 19th edition, 1995.
`In a further embodiment of the invention the formulation f