throbber
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`(12)
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`TEPZZ_687Z_9B_T
`EP 1 687 019 B1
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`(11)
`
`EUROPEAN PATENT SPECIFICATION
`
`(45) Date of publication and mention
`of the grant of the patent:
`22.11.2017 Bulletin 2017/47
`
`(21) Application number: 04797453.0
`
`(22) Date of filing: 18.11.2004
`
`(51) Int Cl.:
`A61K 9/00 (2006.01)
`A61K 38/28 (2006.01)
`A61K 47/18 (2017.01)
`A61K 47/26 (2006.01)
`
`A61K 38/26 (2006.01)
`A61K 47/10 (2017.01)
`A61K 47/20 (2006.01)
`
`(86) International application number:
`PCT/DK2004/000792
`
`(87) International publication number:
`WO 2005/049061 (02.06.2005 Gazette 2005/22)
`
`(54) PROPYLENE GLYCOL-CONTAINING PEPTIDE FORMULATIONS WHICH ARE OPTIMAL FOR
`PRODUCTION AND FOR USE IN INJECTION DEVICES
`
`FÜR DIE HERSTELLUNG UND VERWENDUNG IN INJEKTIONSVORRICHTUNGEN OPTIMALE
`PROPYLENGLYKOL ENHALTENDE PEPTIDFORMULIERUNGEN
`
`FORMULATIONS PEPTIDIQUES A BASE DE PROPYLENE GLYCOL OPTIMALES POUR LA
`PRODUCTION ET L’UTILISATION DANS DES DISPOSITIFS D’INJECTION
`
`(84) Designated Contracting States:
`AT BE BG CH CY CZ DE DK EE ES FI FR GB GR
`HU IE IS IT LI LU MC NL PL PT RO SE SI SK TR
`
`(30) Priority: 20.11.2003 DK 200301719
`
`(43) Date of publication of application:
`09.08.2006 Bulletin 2006/32
`
`(60) Divisional application:
`11157594.0 / 2 394 656
`17196501.5
`
`(73) Proprietor: NOVO NORDISK A/S
`2880 Bagsværd (DK)
`
`(72) Inventors:
`• PEDERSEN, Tina Bjeldskov
`DK-2750 Ballerup (DK)
`• BONDE, Claude
`DK-2800 Lyngby (DK)
`• ENGELUND, Dorthe Kot
`DK-2840 Holte (DK)
`
`(56) References cited:
`WO-A-92/19260
`WO-A-95/05848
`WO-A-95/22560
`WO-A-02/067989
`WO-A-2005/046716
`US-A1- 2002 151 467
`
`WO-A-93/23010
`WO-A-95/13825
`WO-A-99/16417
`WO-A-03/013589
`US-A- 5 206 219
`
`• SINGH, SOMNATH ET AL: "Effect of polyols on
`the conformational stability and biological
`activity of a model protein lysozyme" AAPS
`PHARMSCITECH , 4(3), 334-342 CODEN:
`AAPHFZ; ISSN: 1522-1059 URL:
`HTTP://WWW.AAPSPHARMSCITECH.ORG/PT04
`03/PT0 40342/PT040342.PDF, October 2003
`(2003-10), XP002342618
`• PRIDAL L ET AL: "ABSORPTION OF
`GLUCAGON-LIKE PEPTIDE-1 CAN BE
`PROTRACTED BY ZINC OR PROTAMINE",
`INTERNATIONAL JOURNAL OF
`PHARMACEUTICS, ELSEVIER BV, NL, vol. 136, 1
`January 1996 (1996-01-01), pages 53-59,
`XP002938824, ISSN: 0378-5173, DOI:
`10.1016/0378-5173(95)04480-9
`
`(74) Representative: Nielsen, Lars Balzer et al
`Novo Nordisk A/S
`Corporate Patents
`Novo Allée
`2880 Bagsvaerd (DK)
`
`Remarks:
`The file contains technical information submitted after
`the application was filed and not included in this
`specification
`
`Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent
`Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the
`Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been
`paid. (Art. 99(1) European Patent Convention).
`
`Printed by Jouve, 75001 PARIS (FR)
`
`EP1 687 019B1
`
`Novo Nordisk A/S Ex. 2005, P. 1
`Fresenius Kabi v. Novo Nordisk
`IPR2022-00657
`
`

`

`EP 1 687 019 B1
`
`Description
`
`FIELD OF THE INVENTION
`
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`[0001] The present invention relates to pharmaceutical formulations comprising the peptide Arg34, Lys26(N-ε-(γ-Glu(N-
`α-hexadecanoyl)))-GLP-1(7-37) and propylene glycol.
`
`BACKGROUND OF THE INVENTION
`
`[0002] 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
`production equipment and in the final product. Such deposits increase the need to clean the filling equipment during
`production of the formulation and this results in reduced production capability. In addition, such deposits may also result
`in reduced yield of the final product since vials/cartridges containing 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.
`[0003] Accordingly, it is desirable to identify an alternative isotonic agent to mannitol for inclusion in peptide-containing
`formulations and in particular, for inclusion in peptide formulations which are administered by injection. PRIDAL L ET
`AL: "ABSORPTION OF GLUCAGON-LIKE PEPTIDE-1 CAN BE PROTRACTED BY ZINC OR PROTAMINE",INTER-
`NATIONAL JOURNAL OF PHARMACEUTICS, ELSEVIER BV, NL, vol. 136, 1 January 1996 (1996-01-01), discloses
`a composition comprising GLP-1 (7-36) amide in combination with disodium phosphate and an isotonic agent glycerol
`at pH about 7 (pH= 6.9).
`
`25
`
`SUMMARY OF THE INVENTION
`
`30
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`35
`
`[0004] The present inventors have discovered that peptide formulations containing propylene glycol at certain con-
`centrations 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 (eg. injection, subcutaneous injection, intramuscular,
`intraveneous or infusion) as well as non-invasive (eg nasal, oral, pulmonary, transdermal or transmucosal e.g. buccal)
`means of administration.
`[0005] The present invention therefore relates to a pharmaceutical formulation comprising the peptide Arg34, Lys26(N-
`ε-(γ-Glu(N-α-hexadecanoyl)))-GLP-1(7-37) and propylene glycol, where the propylene glycol is present in a concentration
`of 1-100 mg/ml and the pH of the formulation is from 7-10. In a preferred embodiment, the pharmaceutical formulations
`of the invention further contain a buffer and a preservative.
`The present invention is defined in the appended claims. Subject matters which are not encompassed by the scope of
`the claims do not form part of the present invention.
`
`40
`
`BRIEF DESCRIPTION OF THE FIGURES
`
`[0006]
`
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`Figure 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 buffer), mannitol, sorbitol, xylitol, sucrose
`or glycerol as the isotonic agent with the far right slide containing mannitol with peptide Arg34, Lys26(Nε-(γ-Glu(Nα-hex-
`adecanoyl)))-GLP-1(7-37).
`
`Figure 2 shows light microscopy pictures of from left to right, some of the dried droplets of placebo formulations
`containing mannitol, arginin, inositol or glycerol as the isotonic agent.
`
`Figure 3 shows light microscopy pictures of clogged needles dosed with placebo formulations containing myoinositol,
`maltose or glycerol as the isotonic agent.
`
`Figure 4 shows light microscopy pictures of deposits on needles dosed with placebo formulations containing glycine,
`lactose or mannitol as the isotonic agent.
`
`Figure 5 shows filling equipment after 24 hours simulated filling with Arg34, Lys26(Nε-(γ-Glu(Nα-hexadecanoyl)))-GLP-
`
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`1(7-37) medium containing myo-inositol.
`
`EP 1 687 019 B1
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`Figure 6 shows deposits on filling equipment after 24 hours simulated filling with a mannitol-containing placebo
`formulation.
`
`Figure 7 shows deposits on needles dosed with mannitol (top panel) and propylene glycol (bottom panel)-containing
`Arg34, Lys26(Nε-(γ-Glu(Nα-hexadecanoyl)))-GLP-1(7-37) formulations.
`
`DESCRIPTION OF THE INVENTION
`
`[0007] The present invention relates to a pharmaceutical formulation comprising the peptide Arg34, Lys26(N-ε-(γ-Glu(N-
`α-hexadecanoyl)))-GLP-1(7-37) and propylene 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.
`[0008] The pharmaceutical formulations of the invention are found to be optimal for production because they exhibit
`reduced deposits in production equipment relative to formulations containing other isotonicity agents as measured by
`the simulated filling studies described in the Examples. In addition, 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.
`[0009] The peptide to be included in the formulation of the invention is a GLP-1 agonist as defined in the present
`claims where "a GLP-1 agonist" is understood to refer to a peptide which fully or partially activates the human GLP-1
`receptor. In a preferred embodiment, the "GLP-1 agonist" is a peptide as defined in the present claims that binds to a
`GLP-1 receptor, preferably with an affinity constant (KD) or a potency (EC50) of below 1 mM, e.g. below 100 nM as
`measured by methods known in the art (see e.g. WO 98/08871) and exhibits insulinotropic activity, where insulinotropic
`activity may be measured in vivo or in vitro assays 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.
`[0010] The GLP-1 agonist is Arg34, Lys26(Nε-(γ-Glu(Nα-hexadecanoyl)))-GLP-1(7-37).
`[0011] The GLP-1 agonist is present in a concentration from 0.1 mg/ml to 100 mg/ml, more preferably in a concentration
`from 0.1 mg/ml to 50 mg/ml, and most preferably in a concentration of from 0.1 mg/ml to 10 mg/ml.
`[0012]
`In one embodiment, the final concentration of propylene glycol in the formulations of the invention is from 1 to
`50 mg/ml.
`[0013]
`In another embodiment, the final concentration of propylene glycol in the formulations of the invention is from
`5 to 25 mg/ml.
`[0014]
`In yet another embodiment, the final concentration of propylene glycol in the formulations of the invention is
`from 8 to 16 mg/ml.
`[0015]
`In yet a further embodiment, the final concentration of propylene glycol in the formulations of the invention is
`from 13 to 15 mg/ml.
`[0016]
`In still another embodiment, the final concentration of propylene glycol in the formulations of the invention is
`from 13.5 to 14.5 mg/ml.
`[0017]
`In another embodiment of the invention, the formulation has a pH in the range from 7.0 to 9.5.
`[0018]
`In a further embodiment of the invention, the formulation has a pH in the range from 7.0 to 8.0.
`[0019]
`In yet a further embodiment of the invention, the formulation has a pH in the range from 7.2 to 8.0.
`[0020]
`In a further embodiment of the invention, the formulation has a pH in the range from 7.0 to 8.3.
`[0021]
`In yet a further embodiment of the invention, the formulation has a pH in the range from 7.3 to 8.3.
`[0022]
`In a preferred embodiment of the invention, the formulations contain, in addition to a peptide and propylene
`glycol, a buffer and/or a preservative.
`[0023] Where a buffer is to be included in the formulations of the invention, the buffer is selected from the group
`consisting of sodium acetate, sodium carbonate, citrate, glycylglycine, histidine, glycine, lysine, arginin, sodium dihy-
`drogen phosphate, disodium hydrogen phosphate, sodium phosphate, and tris(hydroxymethyl)-aminomethan, or mix-
`tures thereof. Each one of these specific buffers constitutes an alternative embodiment of the invention. In a preferred
`embodiment of the invention the buffer is glycylglycine, sodium dihydrogen phosphate, disodium hydrogen phosphate,
`sodium phosphate or mixtures thereof.
`[0024] Where a pharmaceutically acceptable preservative is to be included in the formulations of the invention, the
`preservative is selected from the group consisting of phenol, m-cresol, methyl p-hydroxybenzoate, propyl p-hydroxy-
`benzoate, 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 preferred embodiment of the invention the preservative is phenol or m-cresol.
`[0025]
`In a further embodiment of the invention the preservative is present in a concentration from 0.1 mg/ml to 50
`mg/ml, more preferably in a concentration from 0.1 mg/ml to 25 mg/ml, and most preferably in a concentration from 0.1
`
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`EP 1 687 019 B1
`
`mg/ml to 10 mg/ml.
`[0026] 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 Pharmacy, 19th edition, 1995.
`[0027]
`In a further embodiment of the invention the formulation may further comprise a chelating agent where the
`chelating agent may be selected from salts of ethlenediaminetetraacetic acid (EDTA), citric acid, and aspartic acid, and
`mixtures thereof. Each one of these specific chelating agents constitutes an alternative embodiment of the invention.
`[0028]
`In a further embodiment of the invention the chelating agent is present in a concentration from 0.1 mg/ml to
`5mg/ml. In a further embodiment of the invention the chelating agent is present in a concentration from 0.1mg/ml to
`2mg/ml. In a further embodiment of the invention the chelating agent is present in a concentration from 2mg/ml to 5mg/ml.
`[0029] The use of a chelating 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.
`[0030]
`In a further embodiment of the invention the formulation may further comprise a stabiliser selected from the
`group of high molecular weight polymers or low molecular compounds where such stabilizers include polyethylene glycol
`(e.g. PEG 3350), polyvinylalcohol (PVA), polyvinylpyrrolidone, carboxymethylcellulose, different salts (e.g. sodium chlo-
`ride), L-glycine, L-histidine, imidazole, arginine, lysine, isoleucine, aspartic acid, tryptophan, threonine and mixtures
`thereof. Each one of these specific stabilizers constitutes an alternative embodiment of the invention. In a preferred
`embodiment of the invention the stabiliser is selected from the group consisting of L-histidine, imidazole and arginine.
`[0031]
`In a further embodiment of the invention the high molecular weight polymer is present in a concentration from
`0.1mg/ml to 50mg/ml. In a further embodiment of the invention the high molecular weight polymer is present in a con-
`centration from 0.1mg/ml to 5mg/ml. In a further embodiment of the invention the high molecular weight polymer is
`present in a concentration from 5mg/ml to 10mg/ml. In a further embodiment of the invention the high molecular weight
`polymer is present in a concentration from 0mg/ml to 20mg/ml. In a further embodiment of the invention the high molecular
`weight polymer is present in a concentration from 20mg/ml to 30mg/ml. In a further embodiment of the invention the
`high molecular weight polymer is present in a concentration from 30mg/ml to 50mg/ml.
`[0032]
`In a further embodiment of the invention the low molecular weight compound is present in a concentration from
`0.1mg/ml to 50mg/ml. In a further embodiment of the invention the low molecular weight compound is present in a
`concentration from 0.1mg/ml to 5mg/ml. In a further embodiment of the invention the low molecular weight compound
`is present in a concentration from 5mg/ml to 10mg/ml. In a further embodiment of the invention the low molecular weight
`compound is present in a concentration from 10mg/ml to 20mg/ml. In a further embodiment of the invention the low
`molecular weight compound is present in a concentration from 20mg/ml to 30mg/ml. In a further embodiment of the
`invention the low molecular weight compound is present in a concentration from 30mg/ml to 50mg/ml.
`[0033] The use of a stabilizer 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.
`[0034]
`In a further embodiment of the invention the formulation of the invention may further comprise a surfactant
`where a surfactant may be selected from a detergent, ethoxylated castor oil, polyglycolyzed glycerides, acetylated
`monoglycerides, sorbitan fatty acid esters, poloxamers, such as 188 and 407, polyoxyethylene sorbitan fatty acid esters,
`polyoxyethylene derivatives such as alkylated and alkoxylated derivatives (tweens, e.g. Tween-20, or Tween-80),
`monoglycerides or ethoxylated derivatives thereof, diglycerides or polyoxyethylene derivatives thereof, glycerol, cholic
`acid or derivatives thereof, lecithins, alcohols and phospholipids, glycerophospholipids (lecithins, kephalins, phosphatidyl
`serine), glyceroglycolipids (galactopyransoide), sphingophospholipids (sphingomyelin), and sphingoglycolipids (cera-
`mides, gangliosides), DSS (docusate sodium, docusate calcium, docusate potassium, SDS (sodium dodecyl sulfate or
`sodium lauryl sulfate), dipalmitoyl phosphatidic acid, sodium caprylate, bile acids and salts thereof and glycine or taurine
`conjugates, ursodeoxycholic acid, sodium cholate, sodium deoxycholate, sodium taurocholate, sodium glycocholate, N-
`Hexadecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate, anionic (alkyl-aryl-sulphonates) monovalent surfactants,
`palmitoyl lysophosphatidyl-L-serine, lysophospholipids (e.g. 1-acyl-sn-glycero-3-phosphate esters of ethanolamine,
`choline, serine or threonine), alkyl, alkoxyl (alkyl ester), alkoxy (alkyl ether)-derivatives of lysophosphatidyl and phos-
`phatidylcholines, e.g. lauroyl and myristoyl derivatives of lysophosphatidylcholine, dipalmitoylphosphatidylcholine, and
`modifications of the polar head group, that is cholines, ethanolamines, phosphatidic acid, serines, threonines, glycerol,
`inositol, and the postively charged DODAC, DOTMA, DCP, BISHOP, lysophosphatidylserine and lysophosphatidylthre-
`onine, zwitterionic surfactants (e.g. N-alkyl-N,N-dimethylammonio-1-propanesulfonates, 3-cholamido-1-propyldimethy-
`lammonio-1-propanesulfonate, dodecylphosphocholine, myristoyl lysophosphatidylcholine, hen egg lysolecithin), cati-
`onic surfactants (quarternary ammonium bases) (e.g. cetyltrimethylammonium bromide, cetylpyridinium chloride), non-
`ionic surfactants, polyethyleneoxide/polypropyleneoxide block copolymers (Pluronics/Tetronics, Triton X-100, Dodecyl
`β-D-glucopyranoside) or polymeric surfactants (Tween-40, Tween-80, Brij-35), fusidic acid derivatives- (e.g. sodium
`tauro-dihydrofusidate etc.), long-chain fatty acids and salts thereof C6-C12 (eg. oleic acid and caprylic acid), acylcarnitines
`and derivatives, Nα-acylated derivatives of lysine, arginine or histidine, or side-chain acylated derivatives of lysine or
`arginine, Nα-acylated derivatives of dipeptides comprising any combination of lysine, arginine or histidine and a neutral
`or acidic amino acid, Nα-acylated derivative of a tripeptide comprising any combination of a neutral amino acid and two
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`EP 1 687 019 B1
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`charged amino acids, or the surfactant may be selected from the group of imidazoline derivatives, or mixtures thereof.
`Each one of these specific surfactants constitutes an alternative embodiment of the invention.
`[0035] The use of a surfactant 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.
`[0036] The formulations of the invention may be prepared by conventional techniques, e.g. as described in Remington’s
`Pharmaceutical Sciences, 1985 or in Remington: The Science and Practice of Pharmacy, 19th edition, 1995, where
`such conventional techniques of the pharmaceutical industry involve dissolving and mixing the ingredients as appropriate
`to give the desired end product..
`[0037] As mentioned above, in a preferred embodiment, the formulations of the invention-contain, in addition to a
`peptide and propylene glycol, a buffer and/or a preservative.
`[0038] As the formulations of the invention are optimal for production and for use in injection devices since they exhibit
`reduced deposits of production equipment and reduced clogging of injection devices, the above methods of production
`can be used to produce peptide formulations suitable for use in production and/or for use in injection devices.
`[0039] The formulations of the invention are suitable for administration to a mammal, preferably a human. The route
`of administration of the formulations of the invention may be any route which effectively transports the peptide contained
`in the formulation to the appropriate or desired site of action, such as oral, nasal, buccal, pulmonal, transdermal or
`parenteral.
`[0040] Due to the ability of propylene glycol to reduce clogging of injection devices when compared to other isotonic
`agents and to mannitol in particular, in a preferred embodiment, the formulations of the invention are to be administered
`parenterally to a patient in need thereof. Parenteral administration may be performed by subcutaneous, intramuscular
`or intravenous injection by means of a syringe, optionally a pen-like syringe. Alternatively, parenteral administration can
`be performed by means of an infusion pump.
`[0041] A further option is a composition which may be a powder or a liquid for the administration of the formulation in
`the form of a nasal or pulmonal spray. As a still further option, the formulation can also be administered transdermally,
`e.g. from a patch, optionally a iontophoretic patch, or transmucosally, e.g. bucally. The above-mentioned possible ways
`to administer the formulations of the invention are not to be considered as limiting the scope of the invention.
`[0042] The following examples illustrate various aspects of the invention but are in no way intended to limit the scope
`thereof.
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`EXAMPLES
`
`EXAMPLE 1
`
`Simulated filling experiments, drop and clogging tests of replacement candidates for mannitol
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`35
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`[0043] As laboratory experiments have shown that with regards to clogging of needles and deposits on needles,
`formulations without peptide ("placebo") give the same conclusions as formulations with peptide at 0.3-5.0 mg/ml, the
`screening studies in Example 1 have been done using placebo except where indicated otherwise.
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`Preparation of Formulations With Different Isotonic Agents
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`[0044] Preservative (5.5 mg/ml phenol) and buffer 1.24 mg/ml disodium hydrogen phosphate, dihydrate) were dissolved
`in water and the isotonic agent was added while stirring. pH was adjusted to pH 7.9 using Sodium Hydroxide and/or
`Hydrochloric acid. Finally, the formulation was filtered through a 0.22 mm filter. The isotonic agents tested in each
`formulation and their concntrations are shown in Table 1.
`
`Table 1 Composition of the tested formulations
`
`Formulation no.
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`Tonicity modifier
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`Glucose monohydrate (38.0 mg/ml)
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`Laktose monohydrate (65.0 mg/ml)
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`Maltose (67.2 mg/ml)
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`Glycine (15.1 mg/ml)
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`Polyethylenglycol 400 (77.5 mg/ml)
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`L-arginin (24.6 mg/ml)
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`(continued)
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`Formulation no.
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`Tonicity modifier
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`Myo-Inositol (35.2 mg/ml)
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`Propylene glycol (13.7 mg/ml)
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`Dimethylsulfon (18 mg/ml)
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`Mannitol (35.9 mg/ml)
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`Sorbitol (39.5 mg/ml)
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`Xylitol (39.5 mg/ml)
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`Sucrose (79.1 mg/ml
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`Glycerol (16 mg/ml)
`
`Osmolarity
`
`[0045] The osmolarity of the different placebo formulations was determined and the results are shown in Table 2.
`[0046] An isotonic solution has an osmolarity of around 0.286 osmol/L. As can be seen from Table 2 three of the
`formulations (PEG 400, sucrose and xylitol) are more than 20% from being isotonic (0.229-0.343 osmol/l), however for
`these kind of experiments the osmolarity is not expected to influence the results, though, the tonicity of the formulations
`should be adjusted in future experiments.
`
`Table 2. The measured osmolarity of the formulations
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`Formulation no.
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`Isotonic agent
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`Osmolarity
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`Glucose monohvdrate (38.0 mg/ml)
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`Laktose monohydrate (65.0 mg/ml)
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`Maltose (67.2 mg/ml)
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`Glycine (15.1 mg/ml)
`
`Polyethylenglykol 400 (77.5 mg/ml)
`
`L-arginin(24.6 mg/ml)
`
`Myo-Inositol (35.2 mg/ml)
`
`Propylene glycol (13.7 mg/ml)
`
`Dimethylsulfon (18 mg/ml)
`
`Mannitol (35.9 mg/ml)
`
`Sorbitol (39.5 mg/ml)
`
`Xylitol (39.5 mg/ml)
`
`Sucrose (79.1 mg/ml
`
`Glycerol (16 mg/ml)
`
`0.315
`
`0.283
`
`0.306
`
`0.286
`
`0.370
`
`0.318
`
`0.285
`
`0.268
`
`0.274
`
`0.284
`
`0.310
`
`0.351
`
`0.346
`
`0.262
`
`Drop test
`
`[0047] A droplet of each formulation is placed on a microscope slide and let to dry. The deposit is visually examined
`by eye and light microscope.
`[0048] A photograph of the dried droplets of some of the formulations is shown in Figure 1. In this figure it is clearly
`observed that mannitol cause deposits on the microscope slide when let to dry. No deposits were observed for sorbitol,
`xylitol, sucrose and glycerol. The droplet on the far right (Form 1) contains mannitol and Arg34, Lys26(Nε-(γ-Glu(Nα-hex-
`adecanoyl)))-GLP-1(7-37).
`[0049]
`In Figure 2, the candidates causing the most deposits on the microscope slide are shown. For comparison
`glycerol, which does not cause deposits, is shown (mannitol, arginine, inositol).
`
`6
`
`Novo Nordisk A/S Ex. 2005, P. 6
`Fresenius Kabi v. Novo Nordisk
`IPR2022-00657
`
`

`

`Clogging test
`
`EP 1 687 019 B1
`
`[0050]
`In this test 10 NovoPens® 1.5 ml mounted with NovoFine 30® G (G 30 needle) were tested for each formulation,
`5 of them placed in upright and 5 in horizontal position. The Pensystems were stored at room temperature in between
`testing. Each day the needle was examined for deposits and an air shot was performed prior to injection into a tissue.
`Degree of resistance and clogging, if any, was noted. Injections were made on a daily basis with the same needle, and
`this was done for 9 working days for all the formulations.
`[0051] The results from the clogging test are shown in Table 3.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`7
`
`Novo Nordisk A/S Ex. 2005, P. 7
`Fresenius Kabi v. Novo Nordisk
`IPR2022-00657
`
`

`

`EP 1 687 019 B1
`
`needle)
`31 (2 at
`
`needle)
`1 (5 at
`
`needle)
`31 (2 at
`needle)
`(1 at
`
`47
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`1
`
`43
`
`on needle
`Deposits
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`21
`
`0
`
`3
`
`2
`
`0
`
`0
`
`0
`
`0
`
`1
`
`0
`
`0
`
`1
`
`0
`
`1
`
`0
`
`0
`
`0
`
`5
`
`16 (6 at needle)
`
`1 (2 at needle)
`
`16 (7 at needle)
`
`5
`
`4
`
`9
`
`6
`
`3 (2 at needle)
`
`12 (5 at needle)
`
`0
`
`1
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`6
`
`needle
`
`needle top
`
`needle
`
`Gel-like drop on
`
`Dried drop at
`
`5
`
`10
`
`15
`
`20
`
`25
`
`0
`
`0
`
`4
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`2
`
`5
`
`2
`
`7
`
`8
`
`10
`
`9
`
`8
`
`11
`
`0
`
`0
`
`0
`
`0
`
`1
`
`2
`
`0
`
`0
`
`0
`
`1
`
`44
`
`35
`
`41
`
`32
`
`20
`
`12
`
`21
`
`14
`
`26
`
`25
`
`20
`
`23
`
`13
`
`10
`
`laktose (90)
`
`maltose (90)
`
`glycine (90)
`
`Glucose (90)
`
`Myoinositol (90)
`
`sorbitol (90)
`
`Dimethyls ulfon (90)
`
`Xylitol (90)
`
`arginin (90)
`
`PEG 400 (90)
`
`Propylene glycol (90)
`
`Sucrose (90)
`
`Glycerol (90)
`
`Mannitol (90)
`
`8
`
`Clogged
`
`resistance
`
`Resistance
`
`resistance
`
`observations)
`
`Drop at top of
`Table 3 Clogging test in NovoPen 1.5 using 30G NovoFine
`
`Much
`
`Some
`
`Isotonic agent (no. of
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`Novo Nordisk A/S Ex. 2005, P. 8
`Fresenius Kabi v. Novo Nordisk
`IPR2022-00657
`
`

`

`EP 1 687 019 B1
`
`[0052]
`In Table 3 and in Figure 3 it was observed that inositol and maltose clogged the needle. For comparison glycerol
`which does not clog the needle is shown in Figure 3. In Figure 4, and in Table 3, it was observed that formulations
`containing glycine, lactose and mannitol gave rise to a lot of deposits on the needle. For glycine, the deposits were a
`droplet deposited down the needle, whereas for lactose and mannitol the deposits occurred at the top of the needle.
`
`Simulated filling
`
`[0053]
`1 L of each formulation was subjected to a simulated filling experiment which lasted for 24 hours. After 24 hours
`the filling equipment was inspected for the presence of deposits.
`[0054] Based on the results from the simulated filling studies (data not shown), the placebo formulations can be divided
`into three categories. 1. Those isotonic agents that do not cause deposits on the filling equipment: Xylitol, glycerol,
`glucose monohydrate, maltose, PEG 400 and propylene glycol. 2. Those isotonic agent that cause few deposits and
`have superior filling properties compared to mannitol: Sorbitol, sucrose and glycine. 3. Those isotonic agent that are
`comparable or worse than mannitol: Mannitol, lactose monohydrate, arginin, myo-inositol and dimethylsulfon.
`
`Conclusion
`
`[0055]
`In the simulated filling experiment xylitol, glycerol, glucose, maltose, PEG 400, propylene glycol, sorbitol, sucrose
`and glycine were found to be suitable replacements candidates for mannitol. However, as glucose is a reducing sac-
`charide, and therefore is able to initiate unwanted degradation in the formulation, this tonicity modifier is ruled out.
`Furthermore, maltose is ruled out due to clogging of needles. This leads to the following candidates: glycerol, xylitol,
`sorbitol, sucrose, glycine, propylene glycol and PEG 400, which are found to have suitable properties as replacements
`candidates for mannitol in peptide formulations with regards to drop test, clogging of needles and simulated filling.
`[0056] However, on the basis of the following considerations, propylene glycol was chosen as the isotonic agent over
`the other candidates to be further investigated in head to head comparison studies with mannitol:
`
`a. propylene glycol was observed to have no influence on the physical and chemical stability of Arg34, Lys26(Nε-(γ-
`Glu(Nα-hexadecanoyl)))-GLP-1(7-37)-containing formulations;
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`b. propylene glycol was observed to have no influence on antimicrobial preservative testing; and
`
`c. use of propylene glycol would no require that further toxicity studies be tested
`
`EXAMPLE 2
`
`35
`
`40
`
`45
`
`50
`
`55
`
`Comparison Of Mannitol and Propylene Glycol-Containing Placebo Formulations In Simulated Filling Studies
`and Simulated Use Studies
`
`Preparation of Formulations
`
`[0057] Preservative and buffer were dissolved in water and the isotonic agent was added while stirring. pH was adjusted
`to the aimed pH using Sodium Hydroxide and/or Hydrochloric acid. Finally, the formulation was filtered through a 0.22
`mm filter. The compositions of the formulations were as follows:
`
`Disodium hydrogen phosphate, dihydrate:
`Phenol:
`Propylene glycol or mannitol:
`Water for Injection:
`pH: 7.90
`
`1.42 mg/ml
`5.5 mg/ml
`13.7 or 35.9 mg/ml
`up to 1.0 ml.
`
`Simulated Filling Study
`
`[0058] A simulated filling study lasting 24 hours was performed as described in Example 1 and after 24 hours, the
`filling equipment was inspected for the presence of deposits. No deposits were observed on the filling equipment for the
`propylene glycol formulation. By comparison, after 24 hours, a lot of deposits were observed on the filling equipment for
`the mannitol formulation (see Figure 6).
`
`9
`
`Novo Nordisk A/S Ex. 2005, P. 9
`Fresenius Kabi v. Novo Nordisk
`IPR2022-00657
`
`

`

`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`Simulated In Use Study
`
`EP 1 687 019 B1
`
`[0059] For the simulated in use study, a clogging test was conducted as described in Example 1. The same needle
`was used during the study period of ten working days and each day, the needle was inspected for the presence of
`deposits. Figure 7 shows photographs of needles dosed with the propylene glycol (top panel) or mannitol (bottom panel)
`containing formulations. Deposits on the needle were observed in 48% of the cases when mannitol was used as an
`isotonic agent whereas no deposits were observed when propylene glycol was used as the isotonic agent.
`
`Example 3
`
`Comparison of Propylene Glycol to Mannitol In Arg34, Lys26(Nε-(γ-Glu(Nα-hexadecanoyl)))-GLP-1(7-37) Contain-
`ing Formulations
`
`Preparation of Formulations
`
`[0060] Preservative, isotonic agent (mannitol or propylene glycol) and buffer were dissolved in water and pH was
`adjusted to the desired pH. Arg34, Lys26(Nε-(γ-Glu(Nα-hexadecanoyl)))-GLP-1(7-37) was dissolved in water while stirring
`slowly. The two solutions were then mixed and pH adjusted to the desired pH using sodium hydroxide and/or hydrochloric
`acid. Finally, the formulation was filtered through a 0.22 mm filter. The compositions of the formulations were as follows:
`
`Arg34, Lys26(Nε-(γ-Glu(Nα-hexadecanoyl)))-GLP-1(7-37) (6.25 mg/ml),
`Disodium hydrogen phosphate, dihydrate (1.42 mg/ml),
`Phenol (5.5 mg/ml),
`mannitol or propylene glycol (35.9 or 14.0 mg/ml),

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