throbber
(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2005/0148497 A1
`Khan
`(43) Pub. Date:
`Jul. 7, 2005
`
`US 2005O148497A1
`
`(54) METHOD FOR ADMINISTERING GLP-1
`MOLECULES
`
`(76) Inventor: Mohammed Amin Khan, Carmel, IN
`US
`(US)
`Correspondence Address:
`EL LILLY AND COMPANY
`PATENT DIVISION
`P.O. BOX 6288
`INDIANAPOLIS, IN 46206-6288 (US)
`(21) Appl. No.:
`10/504,717
`(22) PCT Filed:
`Feb. 7, 2003
`(86) PCT No.:
`PCT/US03/03111
`
`Related U.S. Application Data
`
`(60) Provisional application No. 60/358,184, filed on Feb.
`20, 2002.
`Publication Classification
`
`(51) Int. Cl." .......................... A61K 38/26; A61K 38/17
`(52) U.S. Cl. .................................................................. 514/8
`
`(57)
`
`ABSTRACT
`
`The invention encompasses formulations that demonstrate
`the feasibility of oral absorption comprising GLP-1 com
`pounds and Specified delivery agents.
`
`MYLAN INST. EXHIBIT 1018 PAGE 1
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`

`

`US 2005/0148497 A1
`
`Jul. 7, 2005
`
`METHOD FOR ADMINISTERING GLP-1
`MOLECULES
`
`FIELD OF THE INVENTION
`0001. The present invention relates to a formulation
`useful for the oral administration comprising a glucagon-like
`peptide-1 (GLP-1) compound and a specified delivery agent.
`Oral administration of the formulations can be used to treat
`type 2 diabetes as well as a variety of other conditions.
`
`BACKGROUND OF THE INVENTION
`0002. Over the past several decades, continuous strides
`have been made to improve the treatment of diabetes mel
`litus. Approximately 90% of people with diabetes have type
`2 diabetes, also known as non-insulin dependent diabetes
`mellitus (NIDDM). Type 2 diabetics generally still make
`insulin, but the insulin cannot be used effectively by the
`body's cells. This is primarily because the amount of insulin
`produced in response to rising blood Sugar levels is not
`Sufficient to allow cells to efficiently take up glucose and
`thus, reduce blood Sugar levels.
`0003) A large body of pre-clinical and clinical research
`data Suggests that glucagon-like peptide-1 (GLP-1) com
`pounds show great promise as a treatment for type 2 diabetes
`and other conditions. GLP-1 induces numerous biological
`effects Such as Stimulating insulin Secretion, inhibiting glu
`cagon Secretion, inhibiting gastric emptying, enhancing glu
`cose utilization, and inducing weight loSS. Further, pre
`clinical Studies Suggest that GLP-1 may also act to prevent
`the B cell deterioration that occurs as the disease progresses.
`Perhaps the most salient characteristic of GLP-1 is its ability
`to Stimulate insulin Secretion without the associated risk of
`hypoglycemia that is seen when using insulin therapy or
`Some types of oral therapies that act by increasing insulin
`expression.
`0004. However, development of a GLP-1 therapeutic has
`been extremely difficult. This is primarily due to the insta
`bility of the peptide during manufacturing processes, in
`solution formulations, and in vivo. The only published
`clinical Studies employing GLP-1 compounds to treat hyper
`glycemia or other conditions involve formulating GLP-1
`compounds Such that they can be delivered by Subcutaneous
`injection or through continuous Subcutaneous infusion or
`continuous intravenous administration. Many type 2 diabet
`ics or obese patients desiring to lose weight will not be
`Willing to undertake a treatment regimen that may involve
`Several injections per day. Thus, there is a need to develop
`GLP-1 compound therapeutics that can be delivered by an
`alternative non-invasive means Such as by oral delivery.
`0005. Unfortunately, there are numerous barriers to effec
`tive oral delivery of peptides. The high acid content and
`ubiquitous digestive enzymes of the digestive tract will often
`degrade proteins and peptides before they reach the Site of
`absorption. Further, many peptides cannot effectively
`traverse the cells of the epithelial membrane in the small
`intestine to reach the bloodstream. Finally, many drugs
`become insoluble at the low pH levels encountered in the
`digestive tract and, thus, are not absorbed effectively.
`0006. The fact that GLP-1 compounds are relatively
`unstable in Solution formulations, only remain in Solution
`under a fairly narrow set of conditions, and have a relatively
`
`short in vivo half-life when administered as a Solution
`formulation, Suggested that these compounds could not be
`effectively delivered through the oral route. Thus, it was
`Surprising that GLP-1 compounds could be formulated Such
`that biologically active molecules were absorbed into the
`blood Stream after oral administration.
`0007. The present invention involves the use of specific
`delivery agent molecules that interact with GLP-1 com
`pounds in a non-covalent fashion to allow the compounds to
`croSS gut membranes and yet remain therapeutically active.
`Although the delivery agents employed in the present inven
`tion have been disclosed in a series of U.S. patents (see U.S.
`Pat. Nos. 5,541,155; 5,693,338; 5,976,569; 5,643,957;
`5,955,503; 6,100,298; 5,650,386; 5,866.536; 5,965,121;
`5,989,539; 6,001,347; 6,071,510; 5,820,881; and 6,242.495;
`see also WO 02/02509; WO 01/51454; WO 01/44.199; WO
`01/32130; WO 00/59863; WO 00/50386; WO 00/47188;
`and WO 00/40203), oral administration of formulations
`comprising GLP-1 compounds with these delivery agents
`has not been disclosed or Suggested. Further, numerous
`parameters impact whether a particular class of compounds
`can be effectively delivered in combination with one or more
`classes of delivery agents. For example, the conformation of
`the peptide, the Surface charges on the molecule under
`certain formulation conditions, the Solubility profile, the
`Stability as a formulated component, as well as Susceptibility
`to protease digestion and in Vivo Stability all influence the
`ability to deliver a compound orally.
`
`SUMMARY OF THE INVENTION
`0008. The present invention encompasses the develop
`ment of novel formulations comprising GLP-1 compounds
`and delivery agents that can be administered orally. The
`present invention provides a formulation which can be
`administered orally comprising a GLP-1 compound and a
`specified delivery agent. The GLP-1 compound can be
`native GLP-1, GLP-1 fragments, GLP-1 analogs, GLP-1
`derivatives of native, fragments, or analogs of GLP-1, and
`Exendin-3 and Exendin-4. The delivery agent is selected
`from delivery agents described in U.S. Pat. Nos. 5,541,155;
`5,693,338; 5,976.569; 5,643,957; 5,955,503; 6,100,298;
`5,650,386; 5,866.536; 5,965,121; 5,989,539, 6,001,347;
`6,071,510; 5,820,881; and 6.242,495; and WO O2/O2509;
`WO 01/51454; WO01/44.199; WOO1/32130; WO00/59863;
`WO00/50386; WO00/47188; and WO 00/40203.
`0009 Preferred GLP-1 compounds are analogs or deriva
`tives of analogs having modifications at one or more of the
`following positions: 8, 12, 16, 18, 19, 20, 22, 25, 27, 30, 33,
`and 37 and show increased potency compared with Val
`GLP-1 (7-37) OH. Preferred GLP-1 compounds are also
`described in SEO ID NO:1, SEQ ID NO:2, SEQ ID NO:3,
`SEQID NO:4, SEQID NO:5, SEQ ID NO:6, SEQ ID NO:7,
`SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID
`NO:11, SEQ ID NO:12, SEQ ID NO:13, or SEQ ID NO:14.
`More preferred GLP-1 compounds are described in com
`pounds of SEQ ID NO:2, SEQ ID NO:12, SEQ ID NO:13,
`and SEO ID NO:14.
`0010 Preferred delivery agents are described in Table 1.
`More preferred delivery agents are delivery agents corre
`sponding to numbers of Table 1 Selected from the group
`consisting of 1, 2, 4, 5, 6, 9, 10, 11, 13, 14, 15, 20, 21, 22,
`23, 24, 26, 28, 30, 31, 35, 36,38, 39, 40, 41, 42, 43, 44, 46,
`51, 52, and 54.
`
`MYLAN INST. EXHIBIT 1018 PAGE 2
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`US 2005/0148497 A1
`
`Jul. 7, 2005
`
`0.011 The present invention also encompasses a method
`of stimulating the GLP-1 receptor in a subject in need of
`Such Stimulation, Said method comprising the Step of admin
`istering to the Subject an effective amount of the oral
`formulation described herein. Subjects in need of GLP-1
`receptor Stimulation include those with non-insulin depen
`dent diabetes and obesity.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`0012. The three-letter abbreviation code for amino acids
`used in this specification conforms with the list contained in
`Table 3 of Annex C, Appendix 2 of the PCT Administrative
`Instructions and with 37 C.F.R.S 1.822(d)(1)(2000).
`0013 For purposes of the present invention as disclosed
`and described herein, the following terms and abbreviations
`are defined as follows.
`0.014. The term “formulation” as used herein refers to a
`GLP-1 compound and a specified delivery agent combined
`together which can be administered orally such that GLP-1
`compound passes through the gut into the Systemic circu
`lation and has the ability to bind to the GLP-1 receptor and
`initiate a signal transduction pathway resulting in insulino
`tropic activity. The formulation can optionally comprise
`other agents so long as the GLP-1 retains the ability to bind
`the GLP-1 receptor.
`0.015 The term “oral” as used herein refers to delivery of
`a compound by mouth Such that the compound passes
`through the Stomach, Small intestine, or large intestine into
`the Systemic circulation.
`0016. The term “GLP-1 compound” as used herein refers
`to polypeptides that include naturally occurring GLP-1
`polypeptides (GLP-1(7-37)OH and GLP-1(7-36)NH),
`GLP-1 fragments, GLP-1 analogs, GLP-1 derivatives of
`naturally occurring GLP-1 polypeptides, GLP-1 fragments,
`or GLP-1 analogs, and Exendin-3 and Exendin-4 that have
`the ability to bind to the GLP-1 receptor and initiate a signal
`transduction pathway resulting in insulinotropic activity.
`0017. The term “insulinotropic activity” refers to the
`ability to Stimulate insulin Secretion in response to elevated
`glucose levels, thereby causing glucose uptake by cells and
`decreased plasma glucose levels. For example, insulinotro
`pic activity can be determined using the method described in
`Example 1. A GLP-1 molecule has insulinotropic activity if
`islet cells secrete insulin levels in the presence of the GLP-1
`molecule above background levels.
`0018. The term “DPP IV resistant” refers to GLP-1
`molecules that have extended metabolic stability and
`improved biological activity. For example, DPP IV resis
`tance can be determined using the method described in
`Example 2. A GLP-1 molecule is DPP Iv resistant if in the
`presence of DPP IV the GLP-1 molecule has extended
`metabolic stability above that of native GLP-1. DPP IV
`resistant GLP-1 molecules can have an amino acid change at
`the DPP IV recognition site (position 8), or DPP IV resistant
`peptides can have an attached group that restricts the acces
`sibility of the DPP IV to the recognition site, or both.
`0019. A “GLP-1 fragment” is a polypeptide obtained
`after truncation of one or more amino acids from the
`N-terminus and/or C-terminus of GLP-1(7-37)OH or an
`
`analog or derivative thereof. The nomenclature used to
`describe GLP-1 (7-37)OH is also applicable to GLP-1
`fragments. For example, GLP-1(9-36)OH denotes a GLP-1
`fragment obtained by truncating two amino acids from the
`N-terminus and one amino acid from the C-terminus. The
`amino acids in the fragment are denoted by the same number
`as the corresponding amino acid in GLP-1 (7-37)OH. For
`example, the N-terminal glutamic acid in GLP-1(9-36)OH is
`at position 9, position 12 is occupied by phenylalanine; and
`position 22 is occupied by glycine, as in GLP-1 (7-37)OH.
`For GLP-1 (7-36)OH, the glycine at position 37 of GLP-1(7-
`37)OH is deleted.
`0020. A “GLP-1 analog" has sufficient homology to
`GLP-1 (7-37)OH or a fragment of GLP-1(7-37)OH such that
`the analog has insulinotropic activity. Preferably, a GLP-1
`analog has the amino acid sequence of GLP-1 (7-37)OH or
`a fragment thereof, modified So that from one, two, three,
`four or five amino acids differ from the amino acid in
`corresponding position of GLP-1 (7-37)OH or a fragment of
`GLP-1 (7-37)OH. In the nomenclature used herein to desig
`nate GLP-1 compounds, the Substituting amino acid and its
`position is indicated prior to the parent Structure. For
`example, Gluff-GLP-1(7-37)OH designates a GLP-1 com
`pound in which the glycine normally found at position 22 of
`GLP-1 (7-37)OH has been replaced with glutamic acid;
`Val-Gluff-GLP-1(7-37)OH designates a GLP-1 compound
`in which alanine normally found at position 8 and glycine
`normally found at position 22 of GLP-1 (7-37)OH have been
`replaced with valine and glutamic acid, respectively.
`0021 GLP-1 molecules also include polypeptides in
`which one or more amino acids have been added to the
`N-terminus and/or C-terminus of GLP-1 (7-37)OH, or frag
`ments or analogs thereof. It is preferred that GLP-1 mol
`ecules of this type have up to about thirty-nine amino acids.
`The amino acids in the “extended” GLP-1 molecule are
`denoted by the same number as the corresponding amino
`acid in GLP-1(7-37)OH. For example, for a GLP-1 molecule
`obtained by adding two amino acids to the N-terminus of
`GLP-1 (7-37)OH, the N-terminal amino acid is located at
`position 5; and for a GLP-1 molecule obtained by adding
`one amino acid to the C-terminus of GLP-1 (7-37)OH, the
`C-terminal amino acid is located at position 38. Thus,
`position 12 is occupied by phenylalanine and position 22 is
`occupied by glycine in both of these “extended” GLP-1
`compounds, as in GLP-1(7-37)OH. Amino acids 1-6 of an
`extended GLP-1 molecule are preferably the same as or a
`conservative Substitution of the amino acid at the corre
`sponding position of GLP-1(1-37)OH. Amino acids 38-45 of
`an extended GLP-1 molecule are preferably the same as or
`a conservative Substitution of the amino acid at the corre
`sponding position of glucagon or Exendin-4.
`0022. A “GLP-1 derivative” refers to a molecule having
`the amino acid Sequence of GLP-1, a GLP-1 fragment, or a
`GLP-1 analog, but additionally having chemical modifica
`tion of one or more of its amino acid Side groups, C-carbon
`atoms, terminal amino group, or terminal carboxylic acid
`group. A chemical modification includes, but is not limited
`to, adding chemical moieties, creating new bonds, and
`removing chemical moieties. Modifications at amino acid
`Side groups include, without limitation, acylation of lysine
`e-amino groups, N-alkylation of arginine, histidine, or
`lysine, alkylation of glutamic or aspartic carboxylic acid
`groups, and deamidation of glutamine or asparagine. Modi
`
`MYLAN INST. EXHIBIT 1018 PAGE 3
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`US 2005/0148497 A1
`
`Jul. 7, 2005
`
`fications of the terminal amino group include, without
`limitation, the des-amino, N-lower alkyl, N-di-lower alkyl,
`and N-acyl modifications. Modifications of the terminal
`carboxy group include, without limitation, the amide, lower
`alkyl amide, dialkyl amide, and lower alkyl ester modifica
`tions. Lower allyl is C-C alkyl. Furthermore, one or more
`Side groups, or terminal groups, may be protected by pro
`tective groups known to the ordinarily-skilled protein chem
`ist. The C-carbon of an amino acid may be mono- or
`dimethylated.
`0023 For the purposes of the present invention, an in
`Vitro GLP-1 receptor-signaling assay is used to determine
`whether a particular extended GLP-1 peptide will exhibit
`insulinotropic activity in vivo. Extended GLP-1 peptides
`encompassed by the present invention have an in Vitro
`potency that is not less than one-tenth the in vitro potency of
`the DPP IV resistant GLP-1 analog known as Val-GLP
`1(7-37)OH. More preferably, the extended GLP-1 peptides
`of the present invention are as potent or more potent than
`Val-GLP-1 (7-37)OH.
`0024) “In vitro potency” as used herein is the measure of
`the ability of a peptide to activate the GLP-1 receptor in a
`cell-based assay. In vitro potency is expressed as the “ECso
`which is the effective concentration of compound that results
`in 50% activity in a single dose-response experiment. For
`the purposes of the present invention, in vitro potency is
`determined using a fluorescence assay that employS HEK
`293 Aurora CRE-BLAM cells that stably express the human
`GLP-1 receptor. These HEK-293 cells have stably integrated
`a DNA vector having a cAMP response element (CRE)
`driving expression of the 3-lactamase (BLAM) gene. The
`interaction of a GLP-1 agonist with the receptor initiates a
`signal that results in activation of the cAMP response
`element and Subsequent expression of B-lactamase. The
`B-lactamase CCF2/AM Substrate that emits fluorescence
`when it is cleaved by f-lactamase (Aurora BioSciences
`Corp.) can then be added to cells that have been exposed to
`a specific amount of GLP-1 agonist to provide a measure of
`GLP-1 agonist potency. The assay is further described in
`Zlokarnik, et al. (1998) Science 279: 84-88 (See also
`Example 1). The ECso values for the compounds listed in
`example 1 were determined using the BLAM assay
`described above by generating a dose response curve using
`dilutions ranging from 0.00003 nanomolar to 30 nanomolar.
`Relative in Vitro potency values are established by running
`Val-GLP-1 (7-37)OH as a control and assigning the control
`a reference value of 1.
`0.025 The term “delivery agent” refers to molecules in
`U.S. Pat. Nos. 5,541,155; 5,693,338; 5,976,569; 5,643,957;
`5,955,503; 6,100,298; 5,650,386; 5,866.536; 5,965,121;
`5,989,539; 6,001,347; 6,071,510; 5,820,881; and 6.242,495;
`and WO 02/02509; WO 01/51454; WO 01/44.199; WO
`01/32130; WO 00/59863; WO 00/50386; WO 00/47188;
`and WO 00/40203. The delivery agents are generally
`derived from amino acids and are useful in the oral formu
`lations of the present invention., The derived amino acids
`can also be in the form of polyamino acids, and peptides. An
`amino acid is any carboxylic acid having at least one free
`amine group and includes naturally occurring and Synthetic
`amino acids. Poly amino acids are either peptides or two or
`more amino acids linked by a bond formed by other groups
`which can be linked, e.g., an ester, anhydride, or an anhy
`dride linkage. Peptides are two or more amino acids joined
`
`by a peptide bond. Peptides can vary in length from dipep
`tides with two amino acids to polypeptides with Several
`hundred amino acids. Preferred peptides include di-peptides,
`tri-peptides, tetra-peptides, and penta-peptides.
`0026 Furthermore, the delivery agents of the present
`invention are optionally in a Salt form. Examples of Salts
`include Sodium, hydrochloric acid, Sulfuric acid, phosphoric
`acid, citric acid, acetic acid, Sulfate, phosphate, chloride,
`bromide, iodide, acetate, propionate, hydrobromic acid,
`Sodium hydroxide, potassium hydroxide, ammonium
`hydroxide, and potassium carbonate.
`0027. The various oral formulations of the present inven
`tion may optionally encompass a pharmaceutically accept
`able buffer. Examples of pharmaceutically acceptable buff
`erS include phosphate bufferS Such as dibasic Sodium
`phosphate, TRIS, glycylglycine, maleate, Sodium acetate,
`Sodium citrate, Sodium tartrate, or an amino acid Such as
`glycine, histidine, lysine or arginine. Other pharmaceutically
`acceptable buffers are known in the art. Preferably, the buffer
`is Selected from the group consisting of phosphate, TRIS,
`maleate, and glycine. Even more preferably the buffer is
`TRIS.
`0028 Preferably, the TRIS concentration is between
`about 1 mM and 100 mM. Even more preferably, the
`concentration is between about 10 mM and about 50 mM,
`most preferably the buffer is about 20 mM.
`0029. The pH of the oral formulations is adjusted to
`provide Stability and to be acceptable for oral administra
`tion. Preferably, the pH is adjusted to between about 7.0 and
`about 9.0, more preferably the pH is between about 7.4 and
`8.4. Even more preferably the pH is between about 7.8 and
`8.4. Most preferably, the pH is between about 7.8 and 8.1.
`0030 The various oral formulations of the present inven
`tion may optionally encompass a Suspending agent. Some
`delivery agents require a Suspending agent due to their
`Solubility characteristics. An example of a Suspending agent
`is hydroxypropylmethylcellulose. Preferably, the final con
`centration of hydroxypropylmethylcellulose is between
`about 2% and about 10% (weight/volume). Even more
`preferably, the concentration is between about 2% and about
`5% (w/v). Most preferably the concentration is about 3.9%
`(w/v).
`0031. The oral formulations of the present invention may
`optionally comprise a coSolvent. Some delivery agents
`require coSolvents due to their Solubility characteristics.
`Examples of cosolvents include ethanol, N-methylpyrroli
`done, N,N-dimethylacetamide, N,N-dimethylformamide,
`glycofurol, ethoxydiol, propylene glycol, polyethylene gly
`col 300 and polyvinylpyrrolidone. Preferably, the final con
`centration of the cosolvents is between about 5% and about
`30% (volume/volume). Even more preferably, the concen
`tration is between about 10% and about 25% (v/v). Most
`preferably the concentration is about 20% (v/v).
`0032. The oral formulations of the present invention may
`optionally comprise a preservative. Preservative refers to a
`compound that is added to the formulation to act as an
`antimicrobial agent. Among preservatives known in the art
`as being effective and acceptable in parenteral formulations
`are phenolic preservatives, alkylparabens, benzyl alcohol,
`chlorobutanol, resorcinol, and other similar preservatives,
`and various mixtures thereof. Examples of phenolic deriva
`
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`US 2005/0148497 A1
`
`Jul. 7, 2005
`
`tives include cresols and phenol or a mixture of creSols and
`phenol. Examples of cresols include meta-creSol, ortho
`creSol, para-creSol, chlorocreSol, or mixtures thereof. Alky
`lparaben refers to a C to C alkylparaben, or mixtures
`thereof. Examples of alkylparabens include methylparaben,
`ethylparaben, propylparaben, or butylparaben. The concen
`trations must be Sufficient to maintain preservative effec
`tiveness by retarding microbial growth. Preferably, the pre
`servative is a phenol derivative. More preferably the
`preservative is a creSol. Even more preferably the preserva
`tive is meta-cresol.
`0033) A preferred concentration of a preservative in the
`final mixture is about 1.0 mg/mL to about 20.0 mg/mL.
`More preferred ranges of concentration of preservative in
`the final mixture are about 2.0 mg/mL to about 8.0 mg/mL,
`about 2.5 mg/mL to about 4.5 mg/mL and about 2.0 mg/mL
`to about 4.0 mg/mL. A most preferred concentration of
`preservative in the final mixture is about 3.0 mg/mL.
`0034. The oral formulations of the present invention may
`optionally comprise an isotonicity agent. Isotonicity agents
`refer to compounds that are tolerated physiologically and
`impart a Suitable tonicity to the formulation to prevent the
`net flow of water acroSS cell membranes. Examples of Such
`compounds include glycerin, Salts, e.g., NaCl, and Sugars,
`e.g., dextrose, mannitol, and Sucrose. These compounds are
`commonly used for Such purposes at known concentrations.
`One or more isotonicity agents may be added to adjust the
`ionic Strength or tonicity. The preferred isotonicity agent is
`NaCl. The concentration of the NaCl is preferably between
`about 10 mM and 200 mM, more preferred is between about
`50 mM and 150 mM, and most preferred is about 100 mM.
`0035. The administration compositions may alternatively
`be in the form of a Solid, Such as a tablet, capsule or particle,
`Such as a powder. Solid dosage forms may be prepared by
`mixing the solid form of the compound with the solid form
`of the active agent. Alternatively, a Solid may be obtained
`from a Solution of compound and active agent by methods
`known in the art, Such as freeze drying, precipitation,
`crystallization ad Solid dispersion.
`0.036 GLP-1 Compounds Appropriate for use in the
`Present Invention:
`0037. The GLP-1 compounds of the present invention
`can be made by a variety of methods known in the art Such
`as Solid-phase Synthetic chemistry, purification of GLP-1
`molecules from natural Sources, recombinant DNA technol
`ogy, or a combination of these methods. For example,
`methods for preparing GLP-1 peptides are described in U.S.
`Pat. Nos. 5,118,666; 5,120,712; 5,512,549; 5,977,071; and
`6,191,102.
`0.038. By custom in the art, the amino terminus of GLP
`1(7-37)OH has been assigned number residue 7, and the
`carboxy-terminus has been assigned number 37. The other
`amino acids in the polypeptide are numbered consecutively,
`as shown in SEQ ID NO:1. For example, position 12 is
`phenylalanine and position 22 is glycine.
`
`0039 The two naturally occurring truncated GLP-1 pep
`tides are represented in Formula I, SEQ ID NO:1.
`
`FORMULA I
`
`SEQ ID NO: 1
`His-Ala-Glu-Gly'-Thr-Phe-Thr-Ser-Asp-Val-Ser
`Ser-Tyr-Leu'-Glu-Gly-Gln-Ala-Ala -Lys-Glu-Phe
`Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Xaa
`
`0040 wherein:
`0041) Xaa’ is Gly, or -NH.
`0042 Preferably, a GLP-1 compound has the amino acid
`sequence of SEQ ID NO: 1 or is modified so that from one,
`two, three, four or five amino acids differ from SEQ ID NO:
`1.
`0043 A preferred group of GLP-1 compounds is com
`posed of GLP-1 analogs of Formula I (SEQ ID NO:2).
`
`FORMULA I
`
`(SEQ ID NO: 2)
`His-Xaa-Xaa-Gly-Xaa-Phe-Thr-Xaa-Asp-Xaa
`
`Xaa-Xaa-Xaa-Xaa-Xaa-Xaa’-Xaa-Xaa
`
`Xaa-Xaa’-Xaa’-Phe-Ile-Xaa-Xaa-Xaa’-Xaa
`
`Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa'-Xaa'-
`
`Xaa2-Xaa-Xaa-Xaa
`
`0044) wherein:
`0045 Xaa is Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu,
`Asp, or LyS,
`0046) Xaa is Glu, Asp, or Lys;
`0047 Xaa' is Thr, Ala, Gly, Ser, Leu, Ile, Val, Glu,
`Asp, or LyS,
`0048 Xaa' is Ser, Ala, Gly, Thr, Leu, Ile, Val, Glu,
`Asp, or LyS,
`0049 Xaa' is Val, Ala, Gly, Ser, Thr, Leu, Ile, Tyr,
`Glu, Asp, Trp, or LyS,
`0050 Xaa'7 is Ser, Ala, Gly, Thr, Leu, Ile, Val, Glu,
`Asp, or LyS,
`0051 Xaa' is Ser, Ala, Gly, Thr, Leu, Ile, Val, Glu,
`Asp, Trp, Tyr, or LyS,
`0.052 Xaa' is Tyr, Phe, Trp, Glu, Asp, Gln, or Lys;
`0.053 Xaa' is Leu, Ala, Gly, Ser, Thr, Ile, Val, Glu,
`Asp, Met, Trp, Tyr, or LyS,
`0054) Xaa' is Glu, Asp, or Lys;
`0.055 Xaa’ is Gly, Ala, Ser, Thr, Leu, Ile, Val, Glu,
`Asp, or LyS,
`0056 Xaa is Gln, ASn, Arg, Glu, Asp, or Lys;
`
`MYLAN INST. EXHIBIT 1018 PAGE 5
`
`

`

`US 2005/0148497 A1
`
`Jul. 7, 2005
`
`0057 Xaa' is Ala, Gly, Ser, Thr, Leu, Ile, Val, Arg,
`Glu, Asp, or LyS,
`0.058 Xaa is Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu,
`Asp, or LyS,
`0059) Xaa is Lys, Arg, Gln, Glu, Asp, or His;
`0060 Xaa’ is Leu, Glu, Asp, or Ly
`aa IS Leu, Qiu,
`, Or LyS,
`0061 Xaa' is Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu,
`Asp, or LyS,
`0062) Xaa' is Trp, Phe, Tyr, Glu, Asp, or Lys;
`0063 Xaa’ is Leu, Gly, Ala, Ser, Thr, Ile, Val, Glu,
`Asp, or LyS,
`0.064 Xaa is Val, Gly, Ala, Ser, Thr, Leu, Ile, Glu,
`Asp, or LyS,
`0065 Xaa" is ASn, Lys, Arg, Glu, Asp, or His;
`0.066 Xaa is Gly, Ala, Ser, Thr, Leu, Ile, Val, Glu,
`Asp, or LyS,
`0067 Xaa is Gly, Arg, Lys, Glu, Asp, or His;
`0068 Xaa’ is Pro, Gly, Ala, Ser, Thr, Leu, Ile, Val,
`Glu, Asp, or LyS, or is deleted;
`0069 Xaa is Ser, Arg, Lys, Glu, Asp, or His, or is
`deleted;
`0070 Xaa is Ser, Arg, LyS, Glu, Asp, or His, or is
`9.
`p
`deleted;
`0071) Xaa" is Gly, Asp, Glu, or Lys, or is deleted;
`0072 Xaa' is Ala, Phe, Trp, Tyr, Glu, Asp, or Lys,
`or is deleted;
`0073 Xaa' is Ser, Pro, Lys, Glu, or Asp, or is
`deleted;
`0074 Xaa' is Ser, Pro, Glu, Asp, or Lys, or is
`deleted;
`0075 Xaa' is Gly, Pro, Glu, Asp, or Lys, or is
`deleted; and
`0076) Xaa" is Ala, Ser, Val, Glu, Asp, or Lys,
`Ala-NH, Ser-NH, Val-NH, Glu-NH,
`0.077 Asp-NH, or Lys-NH, or is deleted; provided that
`when the amino acid at position 37, 38, 39, 40, 41, 42, 43,
`or 44 is deleted, then each amino acid downstream of that
`amino acid is also deleted.
`0078. It is preferred that the GLP-1 compound of formula
`I contain less than Six amino acids that differ from the
`corresponding amino acid in GLP-1 (7-37)OH or Exendin-4.
`It is more preferred that less than five amino acids differ
`from the corresponding amino acid in GLP-1(7-37)OH or
`Exendin-4. It is even more preferred that less than four
`amino acids differ from the corresponding amino acid in
`GLP-1 (7-37)OH or Exendin-4.
`0079 GLP-1 compounds of the present invention include
`derivatives of formula I Such as a C-1-6-ester, or amide, or
`C-1-6-alkylamide, or C-1-6-dialkylamide thereof. WO99/
`43706 describes derivatives of GLP-1 compounds of for
`mula I and is incorporated by reference herein in its entirety.
`
`The compounds of formula I derivatized as described in WO
`99/43706 and underivatized are encompassed by the present
`invention.
`0080. Another preferred group of GLP-1 compounds is
`composed of GLP-1 analogs of formula II (SEQ ID NO:3):
`
`FORMULA II
`
`(SEQ ID NO: 3)
`Xaa-Xaa-Xaa-Gly-Xaa-Xaa- ?-Thr-Ser-Asp-Xaa
`Ser-Xaa-Xaa'-Leu-Glu-Gly-Xaa-Xaa’-Ala-Xaa’-
`
`Xaa-Phe-Ile-Xaa-Xaa-Leu-Xaa-Xaa-Xaa
`
`Xaa-R7
`
`0081 wherein:
`0082) Xaa" is: L-histidine, D-histidine, desamino
`histidine, 2-amino-histidine, B-hydroxy-histidine,
`homohistidine, C-fluoromethyl-histidine or C.-me
`thyl-histidine;
`0083) Xaa is: Gly, Ala, Val, Leu, Ile, Ser, or Thr;
`0084. Xaa is: Thr, Ser, Arg, Lys, Trp, Phe, Tyr, Glu,
`9, ly
`p
`y
`or His;
`0085 Xaa' is: Asp, Glu, Arg, Thr, Ala, Lys, or His;
`0.086 Xaa' is: His, Trp, Phe, or Tyr;
`0.087 Xaa' is: Leu, Ser, Thr, Trp, His, Phe, Asp,
`Val, Tyr, Glu, or Ala;
`0088 Xaa' is: His, Pro, Asp, Glu, Arg, Ser, Ala, or
`p
`9.
`LyS,
`0089 Xaa' is: Gly, Asp, Glu, Gln, ASn, Lys, Arg, or
`CyS,
`0090 Xaa’ is. His, Asp, Lys, Glu, Gln, or Arg;
`0091 Xaa' is: Glu, Arg, Ala, or Lys;
`0092. Xaa’ is: Trp, Tyr, Phe, Asp, Lys, Glu, or His;
`0093 Xaa-7 is: Ala, Glu, His, Phe, Tyr, Trp, Arg, or
`LyS,
`0094) Xaa' is: Ala, Glu, Asp, Ser, or His;
`0.095 Xaa' is: Asp, Glu, Ser, Thr, Arg, Trp, or Lys;
`0096 Xaa is: Asp, Arg, Val, Lys, Ala, Gly, or Glu;
`0097 Xaa' is: Glu, Lys, or Asp;
`0.098 Xaa is: Thr, Ser, Lys, Arg, Trp, Tyr, Phe,
`Asp, Gly, Pro, His, or Glu;
`0099 Xaa is: Thr, Ser, Asp, Tip, Tyr, Phe, Arg,
`p, 11p, ly
`9.
`Glu, or His;
`0100 R is: Lys, Arg, Thr, Ser, Glu, Asp, Trp, Tyr,
`Phe, His, Gly, Gly-Pro, or is deleted.
`0101 Another preferred group of GLP-1 compounds is
`composed of GLP-1 analogs of Formula III (SEQ ID NO:4):
`
`MYLAN INST. EXHIBIT 1018 PAGE 6
`
`

`

`US 2005/0148497 A1
`
`Jul. 7, 2005
`
`FORMULA III
`
`(SEQ ID NO : 4)
`Xaa-Xaa-Glu-Gly-Xaa-Xaa'?-Thr-Ser-Asp-Xaa
`Ser-Ser-Tyr-Leu-Glu-Xaa’-Xaa-Xaa-Xaa’-Lys
`Xaa-Phe-Ile-Xaa-Trp-Leu-Xaa-Xaa-Xaa
`
`Xaa-R7
`
`0102)
`wherein:
`0103) Xaa" is: L-histidine, D-histidine, desamino
`histidine, 2-amino-histidine, B-hydroxy-histidine,
`homohistidine, C.-fluoromethylhistidine or C.-meth
`ylhistidine;
`0104 Xaa is: Gly, Ala, Val, Leu, Ile, Ser, or Thr;
`y
`0105 Xaa' is: Asp, Glu, Arg, Thr, Ala, Lys, or His;
`0106 Xaa' is: His, Trp, Phe, or Tyr;
`rp
`y
`0107 Xaa' is: Leu, Ser, Thr, Trp, His, Phe, Asp,
`Val, Glu, or Ala;
`0108) Xaa’ is: Gly, Asp, Glu, Gln, ASn, Lys, Arg, or
`CyS,
`0109) Xaa’ is: His, Asp, Lys, Glu, or Gln;
`0110. Xaa' is: Glu, His, Ala, or Lys;
`0111) Xaa is: Asp, Lys, Glu, or His;
`0112 Xaa, is: Ala, Glu, His, Phe, Tyr, Trp, Arg, or
`LyS,
`0113 Xaa is: Ala, Glu, Asp, Ser, or His;
`0114 Xaa is: Asp, Arg, Val, Lys, Ala, Gly, or Glu;
`0115 Xaa' is: Glu, Lys, or Asp;
`0116 Xaa is: Thr, Ser, Lys, Arg, Trp, Tyr, Phe,
`Asp, Gly, Pro, His, or Glu;
`0117 Xaa is: Arg, Glu, or His;
`0118 R is: Lys, Arg, Thr, Ser, Glu, Asp, Trp, Tyr,
`Phe, His, Gly, Gly-Pro, or is deleted.
`0119) Another preferred group of GLP-1 compounds is
`composed of GLP-1 analogs of Formula IV (SEQ ID NO:5):
`
`FORMULA IV
`
`(SEQ ID NO: 5)
`Xaa-Xaa-Gu-Gly-Thr-Xaa'°-Thr-Ser-Asp-Xaa-Ser
`Ser-Tyr-Leu-Glu-Xaa’?-Xaa-Ala-Ala-Zaa’-Glu-Phe
`Ile-Xaa-Trp-Leu-Val-Lys-Xaa-Arg-R
`
`0120 wherein:
`0121 Xaa" is: L-histidine, D-histidine, desamino
`histidine, 2-amino-histidine, B-hydroxy-histidine,
`homohistidine, C-fluoromethyl-histidine, or C.-me
`thyl-histidine;
`
`Xaa is: Gly, Ala, Val, Leu, Ile, Ser, Met, or
`
`0122)
`Thr;
`0123 Xaa' is: His, Trp, Phe, or Tyr;
`0124) Xaa' is: Leu, Ser, Thr, Trp, His, Phe, Asp,
`Val, Glu, or Ala;
`0125 Xaaf is: Gly, Asp, Glu, Gln, ASn, Lys, Arg, or
`CyS,
`0126 Xaa is: His, Asp, Lys, Glu, or Gln;
`0127 Xaa is: Asp, Lys, Glu, or His;
`0128) Xaa' is: Ala, Glu, Asp, Ser, or His;
`0129 Xaa is: Thr, Ser, Lys, Arg, Trp, Tyr, Phe,
`Asp, Gly, Pro, His, or Glu;
`0130 R7 is: Lys, Arg, Thr, Ser, Glu, Asp, Trp, Tyr,
`Phe, His, Gly, Gly-Pro, or is deleted.
`0131) Another preferred group of GLP-1 compounds is
`composed of GLP-1 analogs of formula V (SEQ ID NO:6):
`
`FORMUL.A W
`
`(SEQ ID NO: 6)
`Xaa-Xaa-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser
`Tyr-Leu-Glu-Xaa’-Xaa-Xaa-Ala-Lys-Glu-Phe-Ile
`Xaa-Trp-Leu-Val-Lys-Gly-Arg-R
`
`0132)
`wherein:
`0133) Xaa’ is: L-histidine, D-histidine, desamino
`histidine, 2-amino-histidine, B-hydroxy-histidine,
`homohistidine, C

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