I 1111111111111111 11111 111111111111111 111111111111111 IIIII IIIIII IIII IIII IIII
`US008114833B2
`
`c12) United States Patent
`Pedersen et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,114,833 B2
`*Feb.14,2012
`
`(54) PROPYLENE GLYCOL-CONTAINING
`PEPTIDE FORMULATIONS WHICH ARE
`OPTIMAL FOR PRODUCTION AND FOR USE
`IN INJECTION DEVICES
`
`(75)
`
`Inventors: Tina Bjeldskov Pedersen, Smorum
`(DK); Claude Bonde, Lyngby (DK);
`Dorthe Kot Engelund, Holte (DK)
`
`(73) Assignee: Novo NordiskA/S, Bagsvaerd (DK)
`
`( *) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 663 days.
`
`This patent is subject to a terminal dis(cid:173)
`claimer.
`
`(21) Appl. No.: 11/435,977
`
`(22) Filed:
`
`May 17, 2006
`
`(65)
`
`Prior Publication Data
`
`US 2007/0010424Al
`
`Jan. 11, 2007
`
`Related U.S. Application Data
`
`application
`of
`(63) Continuation
`PCT/DK2004/000792, filed on Nov. 18, 2004.
`
`No.
`
`(60) Provisional application No. 60/524,653, filed on Nov.
`24, 2003.
`
`(30)
`
`Foreign Application Priority Data
`
`Nov. 20, 2003
`
`(DK) ................................. 2003 01719
`
`(51)
`
`Int. Cl.
`A61K 38/26
`(2006.01)
`(52) U.S. Cl. ............................................ 514/2; 530/308
`(58) Field of Classification Search ........................ None
`See application file for complete search history.
`
`(56)
`
`References Cited
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`
`Primary Examiner - Christina Bradley
`(74) Attorney, Agent, or Firm - Michael J. Brignati
`
`ABSTRACT
`(57)
`The present invention relates to pharmaceutical formulations
`comprising a peptide and propylene glycol, to methods of
`preparing such formulations, and to uses of such formulations
`in the treatment of diseases and conditions for which use of
`the peptide contained in such formulations is indicated. The
`present invention further relates to methods for reducing the
`clogging ofinjection devices by a peptide formulation and for
`reducing deposits on production equipment during produc(cid:173)
`tion of a peptide formulation.
`
`31 Claims, 7 Drawing Sheets
`
`Novo Nordisk Exhibit 2011
`Dr. Reddy's Laboratories v. Novo Nordisk A/S
`IPR2024-00009
`Page 00001
`
`

`

`US 8,114,833 B2
`Page 2
`
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`OTHER PUBLICATIONS
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`Non-Final Office Action mailed Dec. 9, 2009 in U.S. Appl. No.
`12/184,531 filed Aug. 1, 2008 by Mortensen et al.
`Sigma, Custom Peptide Synthesis, 2004, pp. 1-2, http://www.
`SIGMA-GENOSYS.COM/PEPTIDE DESIGN.ASP.
`Bailey et al. The Kinetics of Enzyme-Catalysed Reactions Biochemi(cid:173)
`cal Engineering Fundamentals, 2nd Ed., pp. 129-148 (1986).
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`glycerol.html), Printed Aug. 04, 2009.
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`Strasbourg.
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`Aggregation Before During and After Purification, Analytical Bio(cid:173)
`chemistry, 2003, 223-231, vol. 316, Academic Press.
`Shinotesuto, Patent Abstracts of Japan, of JPlO 101696.
`Skovgaard et al., "Using Evolutionary Information and Ancestral
`Sequences to Understand the Sequence-Function Relationship in
`GLP-1 Agonists," J. Mo!. Bio., 2006, vol. 363, p. 977-988.
`Tsoka et al, Selective Flocculation Ands Precipitation for the
`Improvement of Virus-Like Particle Recovery From Yeast
`Homogenate, Biotechnol Prog. vol. 16(4), pp. 661-7 (2000).
`Non-Final Office Action in U.S.Appl. No.10/185,923, Filed June 27,
`2002, Inventors: Funk et al. Sent Mar. 10, 2006.
`
`Non-Final Office Action in U.S. Appl. No. 10/185,923, Filed Jun. 27,
`2002, Inventors: Flink et al. Sent Oct. 9, 2007.
`Non-Final Office Action in U.S. Appl. No. 11/786,095, Filed Apr.
`11,2007, Inventors: Funk et al. Sent Feb. 24, 2009.
`Non-Final Office Action in U.S.Appl. No. 12/343,722, Filed Dec. 24,
`2008, Inventors: Funk et al. Sent May 22, 2009.
`Non-Final Office Action in U.S.Appl. No. 10/719,601, Filed Nov. 21,
`2003, Inventors: Markussen et al. Sent Mar. 4, 2005.
`Non-Final Office Action in U.S. Appl. No. 11/220,266, Filed Sep. 6,
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`Non-Final Office Action in U.S. Appl. No. 11/290,634, Filed Nov. 30,
`2005, Inventors: Juul-Mortensen et al. Sent Jun. 30, 2008.
`Non-Final Office Action in U.S. Appl. No. 11/290,634, Filed Nov. 30,
`2005, Inventors: Juul-Mortensen et al. Sent Nov. 9, 2007.
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`
`Novo Nordisk Exhibit 2011
`Dr. Reddy's Laboratories v. Novo Nordisk A/S
`IPR2024-00009
`Page 00002
`
`

`

`US 8,114,833 B2
`Page 3
`
`European Pharmacopoeia, 3rd Edition, 2.2.3, 1997, pp. 17-8, Council
`of Europe-Strasbourg.
`Frokjaer & Hovgaard, Pharmaceutical Formulation Development of,
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`Dated Nov. 1, 2010 from Patent EP1412384.
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`Journal of Medicinal Chemistry, 2000, vol. 43, pp. 1664-9.
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`Mack Publishing Co., Remington's Pharmaceutical Sciences, 16th
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`Edition, 1990, Chapter 84, pp. 1545-50.
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`the Pharmaceutical Sciences, 1983, 3rd Edition, p. 232.
`
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`the Pharmaceutical Sciences, 1983, 3rd Edition, p. 323.
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`Villanueva Penacarril M.L. Potent Glycognic Effect ofGlp-1(7-36)
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`vol. 42, pp. 4-26.
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`vol. 1, 2nd Edition, p. 20.
`
`* cited by examiner
`
`Novo Nordisk Exhibit 2011
`Dr. Reddy's Laboratories v. Novo Nordisk A/S
`IPR2024-00009
`Page 00003
`
`

`

`U.S. Patent
`
`Feb.14,2012
`
`Sheet 1 of 7
`
`US 8,114,833 B2
`
`FIGURE 1
`
`Novo Nordisk Exhibit 2011
`Dr. Reddy's Laboratories v. Novo Nordisk A/S
`IPR2024-00009
`Page 00004
`
`

`

`U.S. Patent
`
`Feb.14,2012
`
`Sheet 2 of 7
`
`US 8,114,833 B2
`
`r
`
`FIGURE 2
`
`,
`
`fr~~~;· ........
`
`.-:•t:':
`
`...
`
`7
`
`Mannitol
`
`Argi-
`
`lnosi-
`
`Glyce-
`
`Novo Nordisk Exhibit 2011
`Dr. Reddy's Laboratories v. Novo Nordisk A/S
`IPR2024-00009
`Page 00005
`
`

`

`U.S. Patent
`
`Feb. 14,2012
`
`Sheet 3 of 7
`
`US 8,114,833 B2
`
`FIGURE 3
`
`Myo-inositol
`
`Maltose
`
`Glycerol
`
`Novo Nordisk Exhibit 2011
`Dr. Reddy's Laboratories v. Novo Nordisk A/S
`IPR2024-00009
`Page 00006
`
`

`

`U.S. Patent
`
`Feb.14,2012
`
`Sheet 4 of 7
`
`US 8,114,833 B2
`
`FIGURE 4
`
`Glycine
`
`Lactose
`
`Mannitol
`
`Novo Nordisk Exhibit 2011
`Dr. Reddy's Laboratories v. Novo Nordisk A/S
`IPR2024-00009
`Page 00007
`
`

`

`U.S. Patent
`
`Feb.14,2012
`
`Sheet 5 of 7
`
`US 8,114,833 B2
`
`FIGURES
`
`Novo Nordisk Exhibit 2011
`Dr. Reddy's Laboratories v. Novo Nordisk A/S
`IPR2024-00009
`Page 00008
`
`

`

`U.S. Patent
`
`Feb.14,2012
`
`Sheet 6 of 7
`
`US 8,114,833 B2
`
`FIGURE 6
`
`Novo Nordisk Exhibit 2011
`Dr. Reddy's Laboratories v. Novo Nordisk A/S
`IPR2024-00009
`Page 00009
`
`

`

`U.S. Patent
`
`Feb.14,2012
`
`Sheet 7 of 7
`
`US 8,114,833 B2
`
`FIGURE 7
`
`Novo Nordisk Exhibit 2011
`Dr. Reddy's Laboratories v. Novo Nordisk A/S
`IPR2024-00009
`Page 00010
`
`

`

`US 8,114,833 B2
`
`1
`PROPYLENE GLYCOL-CONTAINING
`PEPTIDE FORMULATIONS WHICH ARE
`OPTIMAL FOR PRODUCTION AND FOR USE
`IN INJECTION DEVICES
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`This Application is a continuation of International Appli(cid:173)
`cation serial no. PCT/DK2004/000792 filed Nov. 18, 2004 10
`and claims priority from U.S. application Ser. No. 60/524,653
`filed Nov. 24, 2003 and from DanishApplication serial no. PA
`2003 01719 filed Nov. 20, 2003.
`
`FIELD OF THE INVENTION
`
`2
`preferred embodiment, the pharmaceutical formulations of
`the invention further contain a buffer and a preservative.
`The present invention also relates to methods for producing
`the pharmaceutical formulations of the invention.
`In one embodiment, the method for preparing a peptide
`formulation comprises:
`a) preparing a first solution by dissolving preservative,
`propylene glycol and buffer in water;
`b) preparing a second solution by dissolving the peptide in
`water;
`c) mixing the first and second solutions; and
`d) adjusting the pH of the mixture inc) to the desired pH.
`In another embodiment, the method for preparing a peptide
`15 formulation comprises:
`a) preparing a first solution by dissolving preservative and
`buffer in water;
`b) adding propylene glycol to the first solution;
`c) mixing the first solution with a second solution contain(cid:173)
`ing peptide dissolved in water; and
`d) adjusting the pH of the mixture inc) to the desired pH.
`In yet another embodiment, the method for preparing a
`peptide formulation comprises:
`a) preparing a solution by dissolving preservative, buffer
`and propylene glycol in water;
`b) adding the peptide to the solution of step a); and
`c) adjusting the pH of the solution of step b) to the desired
`pH.
`The present invention further relates to methods oftreat-
`30 ment using the pharmaceutical formulations of the invention
`where the compositions are administered in an amount effec(cid:173)
`tive to combat the disease, condition, or disorder for which
`administration of the peptide contained in the formulation is
`indicated.
`In addition the present invention also relates to a method
`for reducing deposits on production equipment during pro(cid:173)
`duction of a peptide formulation, where the method com(cid:173)
`prises replacing the isotonicity agent previously utilized in
`said formulation with propylene glycol at a concentration of
`between 1-100 mg/ml.
`In one embodiment, the reduction in deposits on the pro(cid:173)
`duction equipment during production by the propylene gly(cid:173)
`col-containing formulation relative to that observed for the
`formulation containing the previously utilized isotonicity
`45 agent is measured by a simulated filling experiment.
`The present invention also relates to a method for reducing
`deposits in the final product during production of a peptide
`formulation, where the method comprises replacing the iso(cid:173)
`tonicity agent previously utilized in said formulation with
`50 propylene glycol at a concentration of between 1-100 mg/ml.
`In one embodiment, the reduction in deposits in the final
`product is measured by a reduction in the number of vials
`and/or cartridges of the propylene glycol-containing formu(cid:173)
`lation that must be discarded due to deposits relative to num-
`55 ber of vials and/or cartridges of the formulation containing
`the previously utilized isotonicity agent that must be dis(cid:173)
`carded due to deposits.
`The present invention further relates to a method for reduc(cid:173)
`ing the clogging of injection devices by a peptide formula-
`60 tion, where the method comprises replacing the isotonicity
`agent previously utilized in said formulation with propylene
`glycol at a concentration of between 1-100 mg/ml.
`In one embodiment, the reduction in clogging of the injec(cid:173)
`tion device by the propylene glycol-containing formulation
`65 relative to that observed for the formulation containing the
`previously utilized isotonicity agent is measured in a simu(cid:173)
`lated in use study.
`
`The present invention relates to pharmaceutical formula(cid:173)
`tions comprising a peptide and propylene glycol, to methods
`of preparing such formulations, and to uses of such formula- 20
`tions in the treatment of diseases and conditions for which use
`of the peptide contained in such formulations is indicated.
`The present invention further relates to methods for reducing
`the clogging of injection devices by a peptide formulation and
`for reducing deposits on production equipment during pro- 25
`duction of a peptide formulation.
`
`BACKGROUND OF THE INVENTION
`
`The inclusion of isotonicity agents in peptide-containing
`pharmaceutical formulations is widely known and one of the
`more common isotonic agents used in such formulations is
`mannitol. However, the present inventors have observed that
`mannitol causes problems during the production of peptide
`formulations as it crystallizes resulting in deposits in the 35
`production equipment and in the final product. Such deposits
`increase the need to clean the filling equipment during pro(cid:173)
`duction of the formulation and this results in reduced produc(cid:173)
`tion capability. In addition, such deposits may also result in
`reduced yield of the final product since vials/cartridges con- 40
`taining the peptide formulation may need to be discarded if
`particles are present. Finally, the present inventors have
`observed that in peptide formulations to be administered by
`injection, the presence of mannitol results in clogging of
`injection devices.
`Accordingly, it is desirable to identify an alternative iso(cid:173)
`tonic agent to marmitol for inclusion in peptide-containing
`formulations and in particular, for inclusion in peptide for(cid:173)
`mulations which are administered by injection.
`
`SUMMARY OF THE INVENTION
`
`The present inventors have discovered that peptide formu(cid:173)
`lations containing propylene glycol at certain concentrations
`exhibit reduced deposits in production equipment and in the
`final product and also exhibit reduced clogging of injection
`devices. The present compositions may be formulated with
`any peptide and are also physically and chemically stable thus
`rendering them shelf-stable and suitable for invasive ( e.g.
`injection, subcutaneous injection, intramuscular, intravenous
`or infusion) as well as non-invasive (e.g. nasal, oral, pulmo(cid:173)
`nary, transdermal or transmucosal e.g. buccal) means of
`administration.
`The present invention therefore relates to a pharmaceutical
`formulation comprising a peptide and propylene glycol,
`where the propylene glycol is present in a concentration of
`1-lO0mg/ml and the pH of the formulation is from 7-10. In a
`
`Novo Nordisk Exhibit 2011
`Dr. Reddy's Laboratories v. Novo Nordisk A/S
`IPR2024-00009
`Page 00011
`
`

`

`3
`BRIEF DESCRIPTION OF THE FIGURES
`
`US 8,114,833 B2
`
`20
`
`4
`thereof where each of these peptides constitutes an alternative
`embodiment of the present invention.
`In the present application, the designation "an analogue" is
`used to designate a peptide wherein one or more amino acid
`residues of the parent peptide have been substituted by
`another amino acid residue and/or wherein one or more
`amino acid residues of the parent peptide have been deleted
`and/or wherein one or more amino acid residues have been
`added to the parent peptide. Such addition can take place
`either at the N-terminal end or at the C-terminal end of the
`parent peptide or both. Typically "an analogue" is a peptide
`wherein 6 or less amino acids have been substituted and/or
`added and/or deleted from the parent peptide, more prefer-
`15 ably a peptide wherein 3 or less amino acids have been sub(cid:173)
`stituted and/or added and/or deleted from the parent peptide,
`and most preferably, a peptide wherein one amino acid has
`been substituted and/or added and/or deleted from the parent
`peptide.
`In the present application, "a derivative" is used to desig(cid:173)
`nate a peptide or analogue thereof which is chemically modi(cid:173)
`fied by introducing an organic substituent e.g. ester, alkyl or
`lipophilic functionalities, on one or more amino acid residues
`of the peptide or analogue thereof.
`In one embodiment, the peptide to be included in the for-
`mulation of the invention is a GLP-1 agonist where "a GLP-1
`agonist" is understood to refer to any peptide which fully or
`partially activates the human GLP-1 receptor. In a preferred
`embodiment, the "GLP-1 agonist" is any peptide that binds to
`30 a GLP-1 receptor, preferably with an affinity constant (Kn) or
`a potency (EC50 ) of below 1 µM, e.g. below 100 nM as
`measured by methods known in the art (see e.g. WO
`98/08871) and exhibits insulinotropic activity, where insuli(cid:173)
`notropic activity may be measured in vivo or in vitro assays
`35 known to those of ordinary skill in the art. For example, the
`GLP-1 agonist may be administered to an animal and the
`insulin concentration measured over time.
`Methods for identifying GLP-1 agonists are described in
`WO 93/19175 (Novo NordiskA/S) and examples of suitable
`40 GLP-1 analogues and derivatives which can be used accord(cid:173)
`ing to the present invention includes those referred to in WO
`99/43705 (Novo NordiskA/S), WO 99/43706 (Novo Nordisk
`A/S), WO 99/43707 (Novo Nordisk A/S), WO 98/08871
`(analogues with lipophilic substituent) and in WO 02/46227
`45 (analogues fused to serum albumin or to Fe portion of an
`Ig).(Novo NordiskA/S), WO 99/43708 (Novo NordiskA/S),
`WO 99/43341 (Novo NordiskA/S), WO 87/06941 (The Gen(cid:173)
`eral Hospital Corporation), WO 90/11296 (The General Hos(cid:173)
`pital Corporation), WO 91/11457 (Buckley et al.), WO
`50 98/43658 (Eli Lilly & Co.), EP 0708179-A2 (Eli Lilly & Co.),
`EP 0699686-A2 (Eli Lilly & Co.), WO 01/98331 (Eli Lilly &
`Co).
`In one embodiment, the GLP-1 agonist is selected from the
`group consisting of GLP-1(7-36)-amide, GLP-1(7-37), a
`55 GLP-1(7-36)-amide analogue, a GLP-1(7-37) analogue, or a
`derivative of any of these.
`In one embodiment, the GLP-1 agonist is a derivative of
`GLP-1(7-36)-amide, GLP-1(7-37), a GLP-1(7-36)-amide
`analogue or a GLP-1(7-37) analogue, which comprises a
`60 lipophilic substituent.
`In this embodiment of the invention, the GLP-1 derivative
`preferably has three lipophilic substituents, more preferably
`two lipophilic substituents, and most preferably one lipo(cid:173)
`philic substituent attached to the parent peptide (ie GLP-1 (7-
`65 36)-amide, GLP-1(7-37), a GLP-1(7-36)-amide analogue or
`a GLP-1(7-37) analogue), where each lipophilic substituent
`(s) preferably has 4-40 carbon atoms, more preferably 8-30
`
`FIG.1 shows a photograph of dried droplets on microscope
`slides of from left to right, placebo (no peptide) formulations
`containing no isotonic agent ( e only water, preservative and 5
`buffer), mannitol, sorbitol, xylitol, sucrose or glycerol as the
`isotonic agent with the far right slide containing mannitol
`with peptide Arg34
`, Lys 26(W-(y-Glu(N"'-hexadecanoyl)))(cid:173)
`GLP-1(7-37).
`FIG. 2 shows light microscopy pictures of from left to 10
`right, some of the dried droplets of placebo formulations
`containing mannitol, arginin, inositol or glycerol as the iso(cid:173)
`tonic agent.
`FIG. 3 shows light microscopy pictures of clogged needles
`dosed with placebo formulations containing myoinositol,
`maltose or glycerol as the isotonic agent.
`FIG. 4 shows light microscopy pictures of deposits on
`needles dosed with placebo formulations containing glycine,
`lactose or mannitol as the isotonic agent.
`FIG. 5 shows filling equipment after 24 hours simulated
`, Lys 26(NE-(y-Glu(N"'-hexadecanoyl)))(cid:173)
`filling with Arg34
`GLP-1(7-37) medium containing myo-inositol.
`FIG. 6 shows deposits on filling equipment after 24 hours
`simulated filling with a mannitol-containing placebo formu- 25
`lation.
`FIG. 7 shows deposits on needles dosed withmannitol (top
`panel) and propylene glycol (bottom panel)-containing
`Arg34
`, Lys 26(NE -(y-Glu(N"'-hexadecanoyl) ))-GLP-1 (7-37)
`formulations.
`
`DESCRIPTION OF THE INVENTION
`
`The present invention relates to a pharmaceutical formula(cid:173)
`tion comprising a peptide or a mixture of peptides and pro(cid:173)
`pylene glycol where the final concentration of propylene
`glycol in the formulation is 1-100 mg/ml and the pH of the
`formulation is in the range of from 7-10.
`The pharmaceutical formulations of the invention are
`found to be optimal for production because they exhibit
`reduced deposits in production equipment relative to formu(cid:173)
`lations containing other isotonicity agents as measured by the
`simulated filling studies described in the Examples. In addi(cid:173)
`tion, the pharmaceutical formulations of the invention are
`found to be optimal for use in injection devices because they
`exhibit reduced clogging of the injection devices relative to
`formulations containing other isotonicity agents as measured
`by the simulated in use studies described in the Examples.
`The formulations of the present invention may be formu(cid:173)
`lated with any peptide where examples of such peptides
`include, but are not limited to, glucagon, human growth hor(cid:173)
`mone (hGH), insulin, aprotinin, FactorVII, tissue plasmino(cid:173)
`gen activator (TPA), FactorVIIa, FFR-FactorVIIa, hepari(cid:173)
`nase, ACTH, Heparin Binding Protein, corticotropin(cid:173)
`releasing factor, angio-tensin, calcitonin, glucagon-like
`peptide-I, glucagon-like peptide-2, insulin-like growth fac(cid:173)
`tor-I, insulin-like growth factor-2, fibroblast growth factors,
`gastric inhibitory peptide, growth hormone-releasing factor,
`pituitary adenylate cyclase activating peptide, secretin,
`enterogastrin, somatostatin, somatomedin, parathyroid hor(cid:173)
`mone, thrombopoietin, erythropoietin, hypothalamic releas(cid:173)
`ing factors, prolactin, thyroid stimulating hormones, endor(cid:173)
`phins, enkephalins, vasopressin, oxytocin, opiods, DPP IV,
`interlenkins,
`immunoglobulins, complement
`inhibitors,
`serine protease inhibitors, cytokines, cytokine receptors,
`PDGF, tumor necrosis factors, tumor necrosis factors recep(cid:173)
`tors, growth factors and analogues as well as derivatives
`
`Novo Nordisk Exhibit 2011
`Dr. Reddy's Laboratories v. Novo Nordisk A/S
`IPR2024-00009
`Page 00012
`
`

`

`US 8,114,833 B2
`
`5
`
`6
`acid residue or di peptide spacer forms an amide bond with a
`carboxyl group of the lipophilic substituent.
`Preferred spacers are lysyl, glutamyl, asparagyl, glycyl,
`beta-alanyl and gamma-aminobutanoyl, each of which con(cid:173)
`stitutes an individual embodiment. Most preferred spacers are
`glutamyl and beta-alanyl. When the spacer is Lys, Glu or Asp,
`the carboxyl group thereof may form an amide bond with an
`amino group of the amino acid residue, and the amino group
`thereof may form an amide bond with a carboxyl group of the
`lipophilic substituent. When Lys is used as the spacer, a
`further spacer may in some instances be inserted between the
`E-amino group of Lys and the lipophilic substituent. In one
`embodiment, such a further spacer is succinic acid which
`forms an amide bond with the E-amino group ofLys and with
`an amino group present in the lipophilic substituent. In
`another embodiment such a further spacer is Glu or Asp
`which forms an amide bond with the E-amino group of Lys
`and another amide bond with a carboxyl group present in the
`lipophilic substituent, that is, the lipophilic substituent is a
`NE-acylated lysine residue.
`In another embodiment, the spacer is an unbranched alkane
`a,w-dicarboxylic acid group having from 1 to 7 methylene
`groups, which spacer forms a bridge between an amino group
`of the parent peptide and an amino group of the lipophilic
`substituent. Preferably, the spacer is succinic acid.
`In a further embodiment, the lipophilic substituent with the
`attached spacer is a group of the formula CH3 (CH2 )PNH(cid:173)
`CO(CH2 )qCO-, wherein p is an integer from 8 to 33, pref(cid:173)
`erably from 12 to 28 and q is an integer from 1 to 6, preferably
`2.
`
`,
`
`5
`carbon atoms, even more preferably 8-25 carbon atoms, even
`more preferably 12-25 carbon atoms, and most preferably
`14-18 carbon atoms.
`In one embodiment, the lipophilic substituent comprises a
`partially or completely hydrogenated cyclopentanophenath-
`rene skeleton.
`In another embodiment, the lipophilic substituent is a
`straight-chain or branched alkyl group.
`In yet another embodiment, the lipophilic substituent is an
`acyl group of a straight-chain or branched fatty acid. Prefer- 10
`ably, the lipophilic substituent is an acyl group having the
`formula CH3 (CH2 )nCO-, wherein n is an integer from 4 to
`38, preferably an integer from 12 to 38, and most preferably
`is CH3 (CH2 ) 12CO-, CH3 (CH2 ) 14CO-,CH3 (CH2 ) 16CO-,
`CH3 (CH2 ) 1sCO-, CH3 (CH2 ) 20CO-
`and CH3 (CH2 ) 15
`22CO-. In a more preferred embodiment, the lipophilic sub(cid:173)
`stituent is tetradecanoyl. In a most preferred embodiment, the
`lipophilic substituent is hexadecanoyl.
`In a further embodiment of the present invention, the lipo(cid:173)
`philic substituent has a group which is negatively charged 20
`such as a carboxylic acid group. For example, the lipophilic
`substituent may be an acyl group of a straight-chain or
`branched alkane a, w-dicarboxylic acid of the formula H OOC
`(CH2)mCO-, wherein m is an integer from 4 to 38, prefer(cid:173)
`ably an integer from 12 to 38, and most preferably is HOOC 25
`(CH2 ) 14CO-, HOOC(CH2 ) 16CO-, HOOC(CH2 ) 1sCO-,
`HOOC(CH2 ) 20CO- or HOOC(CH2 )nCO-.
`In the GLP-1 derivatives of the invention, the lipophilic
`substituent(s) contain a functional group which can be
`attached to one of the following functional groups of an 30
`amino acid of the parent GLP-1 peptide:
`(a) the amino group attached to the alpha-carbon of the
`N-terminal amino acid,
`(b) the carboxy group attached to the alpha-carbon of the
`C-terminal amino acid,
`( c) the epsilon-amino group of any Lys residue,
`( d) the carboxy group of the R group of any Asp and Glu
`residue,
`( e) the hydroxy group of the R group of any Tyr, Ser and
`Thr residue,
`(f) the amino group of the R group of any Trp, Asn, Gin,
`Arg, and His residue, or
`(g) the thiol group of the R group of any Cys residue.
`In one embodiment, a lipophilic substituent is attached to
`the carboxy group of the R group of any Asp and Glu residue. 45
`In another embodiment, a lipophilic substituent is attached
`to the carboxy group attached to the alpha-carbon of the
`C-terminal amino acid.
`In a most preferred embodiment, a lipophilic substituent is
`attached to the epsilon-amino group of any Lys residue.
`In a preferred embodiment of the invention, the