WO2010059733A1 - Crystalline form of linaclotide - Google Patents
Crystalline form of linaclotide Download PDFInfo
- Publication number
- WO2010059733A1 WO2010059733A1 PCT/US2009/065001 US2009065001W WO2010059733A1 WO 2010059733 A1 WO2010059733 A1 WO 2010059733A1 US 2009065001 W US2009065001 W US 2009065001W WO 2010059733 A1 WO2010059733 A1 WO 2010059733A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- linaclotide
- crystalline form
- diffraction pattern
- powder diffraction
- ray powder
- Prior art date
Links
- KXGCNMMJRFDFNR-WDRJZQOASA-N linaclotide Chemical compound C([C@H](NC(=O)[C@@H]1CSSC[C@H]2C(=O)N[C@H]3CSSC[C@H](N)C(=O)N[C@H](C(N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N2)=O)CSSC[C@H](NC(=O)[C@H](C)NC(=O)[C@@H]2CCCN2C(=O)[C@H](CC(N)=O)NC3=O)C(=O)N[C@H](C(NCC(=O)N1)=O)[C@H](O)C)C(O)=O)C1=CC=C(O)C=C1 KXGCNMMJRFDFNR-WDRJZQOASA-N 0.000 title claims abstract description 249
- 108010024409 linaclotide Proteins 0.000 title claims abstract description 249
- 229960000812 linaclotide Drugs 0.000 title claims abstract description 249
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 28
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
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- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 4
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- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 2
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/10—Peptides having 12 to 20 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/10—Laxatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
Definitions
- the present invention relates to a novel ⁇ -crystalline form of linaclotide, as well as processes for the preparation of the ⁇ -crystalline form, compositions comprising the ⁇ -crystalline form, and methods of using the ⁇ -crystalline form.
- U.S. Patent No. 7,304,036 discloses peptides that act as agonists of the guanylate cyclase C (GC-C) receptor for the treatment of gastrointestinal disorders.
- GC-C guanylate cyclase C
- One particular peptide disclosed therein is linaclotide, which consists of the following amino acid sequence: Cys Cys GIu Tyr Cys Cys Asn Pro Ala Cys Thr GIy Cys Tyr.
- U.S. Patent Nos. 7,304,036 and 7,371,727 disclose methods for the preparation of linaclotide and related peptides. The contents of U.S. Patent Nos. 7,304,036 and 7,371,727 are incorporated herein by reference, in their entirety.
- the present invention relates to a new crystalline form or polymorph of linaclotide, which has surprisingly and unexpectedly enhanced properties, such as enhanced or greater stability, as compared to amorphous linaclotide.
- a crystalline form of linaclotide may have enhanced storage stability and enhanced stability against chemical degradation as compared to amorphous linaclotide.
- the present invention relates to a novel ⁇ -crystalline form of linaclotide.
- Various methods and processes for the preparation and use of the crystalline form are also described herein.
- Figure 1 shows the X-ray powder diffraction pattern of amorphous linaclotide.
- Figure 2 shows the X-ray powder diffraction pattern of an ⁇ -crystalline form of linaclotide.
- Figure 3 shows the X-ray powder diffraction pattern of an ⁇ -crystalline form of linaclotide.
- Figure 4 shows the Fourier Transform infrared spectrum of an ⁇ -crystalline form of linaclotide.
- Figure 5 shows a differential scanning calorimetry (DSC) thermogram of an ⁇ -crystalline form of linaclotide.
- Figure 6 shows the X-ray powder diffraction pattern of an ⁇ -crystalline form of linaclotide.
- Figure 7 shows the X-ray powder diffraction pattern of an ⁇ -crystalline form of linaclotide.
- Figure 8 shows the X-ray powder diffraction pattern of an ⁇ -crystalline form of linaclotide.
- Figure 9 shows the X-ray powder diffraction pattern of an ⁇ -crystalline form of linaclotide.
- Figure 10 shows the X-ray powder diffraction pattern of an ⁇ -crystalline form of linaclotide.
- Figure 11 shows the X-ray powder diffraction pattern of an ⁇ -crystalline form of linaclotide.
- Figure 12 shows the X-ray powder diffraction pattern of an ⁇ -crystalline form of linaclotide.
- Figure 13 shows the X-ray powder diffraction pattern of an ⁇ -crystalline form of linaclotide.
- the present invention provides crystalline forms of linaclotide.
- the methods for preparation as disclosed in U.S. Patent Nos. 7,304,036 and 7,371,727 yield linaclotide in an amorphous state.
- the X-ray powder diffraction pattern of amorphous linaclotide is illustrated in Figure 1.
- the present invention relates to crystalline forms of linaclotide, specifically ⁇ -crystalline forms of linaclotide ( ⁇ form linaclotide).
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising a peak at about 6.2 +/- 0.5 degrees 2 ⁇ .
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising a peak at about 7.8 +/-0.5 degrees 2 ⁇ .
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising a peak at about 8.6 +/- 0.5 degrees 2 ⁇ .
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising a peak at about 9.7 +/- 0.5 degrees 2 ⁇ .
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising a peak at about 10.3 +/- 0.5 degrees 2 ⁇ . In certain embodiments, the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising a peak at about 11.4 +/- 0.5 degrees 2 ⁇ .
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising a peak at about 14.3 +/- 0.5 degrees 2 ⁇ .
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising a peak at about 16.0 +/- 0.5 degrees 2 ⁇ .
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising a peak at about 17.9+/- 0.5 degrees 2 ⁇ .
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising a peak at about 19.5+/- 0.5 degrees 2 ⁇ .
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising a peak at about 20.9+/- 0.5 degrees 2 ⁇ .
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising a peak at about 21.6 +/- 0.5 degrees 2 ⁇ .
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising a peak at about 22.6 +/- 0.5 degrees 2 ⁇ .
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising a peak at about 23.9+/- 0.5 degrees 2 ⁇ .
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising a peak at about 24.4 +/- 0.5 degrees 2 ⁇ .
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising a peak at about 25.2 +/- 0.5 degrees 2 ⁇ .
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising peaks at about 6.2, about 7.8, about 11.4, about 16.0, about 19.5, and at about 23.9 +/-0.5 degrees 2 ⁇ .
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising peaks at about 6.2, about 7.8, about 8.6, about 9.7, about 10.3, about 11.4, about 14.3, about 16.0, about 17.9, about 19.5, about 20.9, about 21.6, about 22.6, about 23.9, about 24.4, and at about 25.2 +/- 0.5 degrees 2 ⁇ .
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising peaks at about 6.2 and at about 7.8 +/-0.5 degrees 2 ⁇ . In exemplary embodiments, the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising peaks at about 7.8 and at about 23.9 +/-0.5 degrees 2 ⁇ . In exemplary embodiments, the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising peaks at about 6.2, about 7.8 and about 23.9 +/-0.5 degrees 2 ⁇ .
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising peaks at about 6.2, about 7.8, about 19.5 and about 23.9 +/-0.5 degrees 2 ⁇ . In exemplary embodiments, the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising peaks at about 6.2, about 7.8, about 22.6 and about 23.9 +/-0.5 degrees 2 ⁇ .
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising peaks at about 6.2, about 7.8, about 23.9 +/-0.5 degrees 2 ⁇ and optionally one or more peaks at about 19.5 +/-0.5 degrees 2 ⁇ and/or about 22.6 +/-0.5 degrees 2 ⁇ .
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising peaks at about 6.2, about 7.8, about 19.5, about 22.6 and about 23.9 +/-0.5 degrees 2 ⁇ .
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 2 or Figure 3.
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising one or more peaks as provided in Table 1. In some embodiments, the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising one or more peaks at about 5.7, about 7.7, about 23.8 +/- 0.5 degrees 2 ⁇ and optionally one or more peaks at about 7.0, about 8.5, about 9.6, about 10.2, about 11.3, about 12.6, about 13.7, about 14.3, about 15.5, about 16.4, about 17.1, about 17.9, about 18.5, about 19.4, about 20.8, about 21.5, about 22.5, about 23.1, about 24.5, about 25.5, about 26.1 , about 27.5, about 28.2, about 28.8 and/or about 29.6 +/- 0.5 degrees 2 ⁇ .
- the phrase "one or more peaks” should be understood to be inclusive of (i) crystalline forms that have XRD peaks at every peak value recited after this phrase, (ii) crystalline forms that have an XRD peak at only one of the peak values recited after this phrase, as well (iii) crystalline forms that have XRD peaks at two or more (e.g. , three or more, four or more, five or more, six or more, or even seven or more) of the peak values recited after this phrase.
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising peaks at about 5.7 and about 7.7 +/- 0.5 degrees 2 ⁇ . In some embodiments, the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising peaks at about 5.7, about 7.7 and about 23.8 +/- 0.5 degrees 2 ⁇ .
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising peaks at about 5.7, about 7.7, about 23.8 +/- 0.5 degrees 2 ⁇ and optionally one or more peaks at about 19.4 +/- 0.5 degrees 2 ⁇ and/or at about 22.5 +/- 0.5 degrees 2 ⁇ .
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising peaks at about 5.7, about 7.7, about 19.4 and about 23.8 +/- 0.5 degrees 2 ⁇ . In some embodiments, the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising peaks at about 5.7, about 7.7, about 22.5 and about 23.8 +/- 0.5 degrees 2 ⁇ . In some embodiments, the ⁇ form linaclotide is characterized by an X- ray powder diffraction pattern comprising peaks at about 5.7, about 7.7, about 19.4, about 22.5 and about 23.8 +/- 0.5 degrees 2 ⁇ .
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 6. In some embodiments, the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising one or more peaks as provided in Table 2.
- a crystalline form of linaclotide wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks at about 5.7, about 7.7 and about 23.8 +/- 0.5 degrees 2 ⁇ and optionally one or more peaks at about 6.3, about 8.4, about 9.5, about 10.5, about 11.7, about 12.4, about 13.6, about 14.7, about 15.4, about 17.0, about 17.8, about 19.6, about 20.6, about 21.3, about 22.5, about 24.4, about 25.1, about 26.5, about 27.1, about 27.7, and/or about 28.7 +/- 0.5 degrees 2 ⁇ .
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 7.
- a crystalline form of linaclotide is provided, wherein the crystalline form has an X-ray powder diffraction pattern comprising one or more peaks as provided in Table 3.
- a crystalline form of linaclotide wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks at about 5.8, about 7.7 and about 23.9 +/- 0.5 degrees 2 ⁇ and optionally one or more peaks at about 6.4, about 8.4, about 9.4, about 10.5, about 11.5, about 12.9, about 13.6, about 14.9, about 15.9, about 17.4, about 18.2, about 18.8, about 19.4, about 20.4, about 22.5, about 23.3 and/or about 25.7 +/- 0.5 degrees 2 ⁇ .
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 8.
- a crystalline form of linaclotide is provided, wherein the crystalline form has an X-ray powder diffraction pattern comprising one or more peaks as provided in Table 4.
- a crystalline form of linaclotide wherein the crystalline form has an X-ray powder diffraction pattern comprising one or more peaks at about 5.6, about 7.7, about 23.8 and optionally one or more peaks at about 8.4, about 9.5, about 10.1, about 11.0, about 11.8, about 12.2, about 14.1, about 14.9, about 15.4, about 16.3, about 17.0, about 17.8, about 18.7, about 19.4, about 20.7, about 21.5, about 22.5, about 24.4 and/or about 25.4 +/- 0.5 degrees 2 ⁇ .
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 9.
- a crystalline form of linaclotide is provided, wherein the crystalline form has an X-ray powder diffraction pattern comprising one or more peaks as provided in Table 5.
- a crystalline form of linaclotide wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks at about 7.7, about 23.8 +/- 0.5 degrees 2 ⁇ and optionally one or more peaks at about 5.6, about 9.5, about 10.1, about 11.0, about 11.8, about 12.5, about 14.1, about 14.9, about 15.9, about 17.0, about 17.8, about 19.4, about 20.2, about 20.7, about 21.1, about 21.5, about 22.5, about 23.1, about 24.4, about 25.4, and/or about 27.1 +/- 0.5 degrees 2 ⁇ .
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 10.
- a crystalline form of linaclotide is provided, wherein the crystalline form has an X-ray powder diffraction pattern comprising one or more peaks as provided in Table 6.
- a crystalline form of linaclotide wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks at about 5.6 and about 7.7 +/- 0.5 degrees 2 ⁇ and optionally one or more peaks at about 8.5, about 10.2, about 11.2, about 12.3, about 13.7, about 16.0, about 17.9, about 19.5, about 20.4, about 22.5, about 23.8 about 25.5, about 27.3, and/or about 27.6 +/- 0.5 degrees 2 ⁇ .
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 11.
- a crystalline form of linaclotide is provided, wherein the crystalline form has an X-ray powder diffraction pattern comprising one or more peaks as provided in Table 7.
- a crystalline form of linaclotide wherein the crystalline form has an X-ray powder diffraction pattern comprising one or more peaks at about 5.6, about 6.0, about 6.3, about 7.7, about 8.1, about 8.4, about 9.5, about 10.1, about 11.0, about 11.2, about 11.8, about 12.2, about 12.5, about 13.6, about 14.2, about 14.9, about 15.4, about 15.9, about 16.3, about 17.0, about 17.8, about 18.9, about 19.4, about 20.2, about 20.7, about 21.4, about 22.4, about 23.8, about 24.4 and/or about 25.4 +/- 0.5 degrees 2 ⁇ .
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 12.
- a crystalline form of linaclotide is provided, wherein the crystalline form has an X-ray powder diffraction pattern comprising one or more peaks as provided in Table 8.
- a crystalline form of linaclotide wherein the crystalline form has an X-ray powder diffraction pattern comprising one or more peaks at about 5.6, about 6.3, about 7.7, about 8.5, about 9.5, about 10.6, about 11.2, about 12.1, about 13.6, about 14.6, about 15.4, about 16.3, about 17.0, about 17.8, about 19.3, about 20.7, about 21.5, about 22.5, about 23.1 , about 23.7 and/or about 25.3 +/- 0.5 degrees 2 ⁇ .
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 13.
- a crystalline form of linaclotide is provided, wherein the crystalline form has an X-ray powder diffraction pattern comprising one or more peaks as provided in Table 9.
- a crystalline form of linaclotide wherein the crystalline form has an X-ray powder diffraction pattern comprising one or more peaks at about 5.6, about 7.0, about 7.7, about 8.4, about 9.5, about 10.1, about 11.2, about 12.4, about 13.6, about 14.6, about 15.8, about 16.6, about 18.0, about 18.9, about 19.7, about 20.7, about 21.4, about 22.4, about 23.0, about 24.1 and/or about 25.0 +/- 0.5 degrees 2 ⁇ .
- ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising peaks having d-spacing values at about 3.7, about 11.5, and about 15.5 +/- 0.5 angstroms (A). In some embodiments, ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising peaks having d-spacing values at about 3.7, about 4.5, about 11.5, and about 15.5 +/- 0.5 angstroms (A).
- the X-ray powder diffraction peaks recited herein for particular embodiments can vary by ⁇ 0.4 degrees 2 ⁇ , by ⁇ 0.3 degrees 2 ⁇ , by ⁇ 0.2 degrees 2 ⁇ , or even by ⁇ 0.1 degrees 2 ⁇ .
- a crystalline form of linaclotide is provided having an X-ray power diffraction pattern comprising peaks at about 5.7, about 7.7 and about 23.8 +/- 0.3 degrees 2 ⁇ .
- ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising peaks having d-spacing values at about 1.4, about 1.1, about 1.0, about 0.9, about 0.8, about 0.6, about 0.5 and about 0.4 +/- 3 % run.
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising d-spacing values at about 1.4, about 1.1, about 0.8, about 0.6, about 0.5 and about 0.4 +/- 3% nm.
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising a d-spacing value at about 1.4 +/- 3% nm.
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising a d-spacing value at about 1.1 +/- 3% nm.
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising a d-spacing value at about 1.0 +/- 3% nm.
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising a d-spacing value at about 0.9 +/- 3% nm.
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising a d-spacing value at about 0.8 +/- 3% nm.
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising a d-spacing value at about 0.6 +/- 3% nm.
- the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising a d-spacing value at about 0.5 +/- 3% nm. In exemplary embodiments, the ⁇ form linaclotide is characterized by an X-ray powder diffraction pattern comprising a d-spacing value at about 0.4 +/- 3% nm.
- the ⁇ form linaclotide is characterized by a Fourier Transform infrared spectrum substantially as shown in Figure 4.
- the ⁇ form linaclotide is characterized by a DSC thermogram substantially as shown in Figure 5.
- the present invention provides processes for preparing the ⁇ - crystalline forms of linaclotide described herein.
- methods for manufacturing a medicament comprising ⁇ form linaclotide that are useful in the treatment of a gastrointestinal disorder are provided.
- ⁇ form linaclotide is produced by crystallizing linaclotide to form ⁇ form linaclotide and optionally isolating the ⁇ form linaclotide.
- ⁇ form linaclotide is prepared by crystallizing linaclotide in an aqueous acid solution and optionally isolating the ⁇ -crystalline form of linaclotide.
- Any suitable aqueous acid solution can be used in this regard, such as, for example, any solution of acid in water at various strengths or concentrations.
- Such acids may include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methane sulfonic acid, phosphoric acid, acetic acid, lactic acid, p-toluene sulfonic acid, oxalic acid, glutamic acid, fumaric acid, malic acid, aspartic acid, ascorbic acid, benzoic acid, maleic acid and succinic acid.
- the aqueous acid solution is selected from hydrochloric acid, hydrobromic acid, nitric acid, methane sulfonic acid, acetic acid, lactic acid, p-toluene sulfonic acid, oxalic acid, glutamic acid, aspartic acid, ascorbic acid, benzoic acid and succinic acid.
- the ⁇ -crystalline form of linaclotide can be identified, distinguished, and separated from amorphous linaclotide in any suitable manner, such as on the basis of differences in the diffraction, thermal and/or spectroscopic properties of these different forms of linaclotide.
- suitable such methods include, for example, X-ray powder diffractometry, capillary melting point determination, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and/or spectroscopic methodologies (such as Raman spectroscopy and/or infrared (IR) spectroscopy).
- the relative intensities and positions of the peaks obtained by X-ray powder diffraction may vary depending upon, inter alia, the sample preparation technique, the sample mounting procedure, and the particular instrument employed.
- the listed X-ray powder diffraction pattern peaks for the crystalline form of linaclotide is about +/- 0.2 degrees 2 ⁇ .
- the ⁇ form linaclotide can have any desired degree of purity, relative to other substances or components in the preparation.
- the present invention provides an ⁇ -crystalline form of linaclotide that is substantially pure, such as, for example, having greater than 40%, greater than 50%, greater than 60%, greater than 70%, greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 99%, greater than 99.2%, greater than 99.4%, greater than 99.6%, greater than 99.6%, or even greater than 99.9% purity, relative to other substances or components in the preparation.
- the ⁇ form linaclotide is about 45% to 95% pure, such as, for example, about 50% to 95% pure, about 55% to 90% pure, about 60% to 95% pure, or even about 70% to 99% pure, relative to other substances or components in the preparation. In some embodiments, the ⁇ form linaclotide is about 95% to 99% pure. In some embodiments, the ⁇ form linaclotide is about 90% to 95% pure. In some embodiments, the ⁇ form linaclotide is about 85% to 90% pure. In some embodiments, the ⁇ form linaclotide is about 80% to 85% pure. In some embodiments, the ⁇ form linaclotide is about 75% to 80% pure.
- the ⁇ form linaclotide is about 70% to 75% pure. In certain embodiments, the ⁇ form linaclotide is about 65% to 70% pure. In some embodiments, the ⁇ form linaclotide is about 60% to 65% pure. In other embodiments, the ⁇ form linaclotide is about 55% to 60% pure. In yet other embodiments, the ⁇ form linaclotide is about 50% to 55% pure. In some embodiments, the ⁇ form linaclotide is about 45% to 50% pure. Compositions
- the present invention provides a composition, formulation, or dosage form that comprises ⁇ form linaclotide and optional additional components, additives and/or species, such as, for example one or more ion species that interact with linaclotide.
- Such additional components, additives, and/or species can be administered alone or as an active ingredient of the composition, formulation, or dosage form. Moreover, the additional components, additives, and/or species can be administered before, after, and/or concurrently with ⁇ form linaclotide.
- the additional components, additives, and/or species are administered separately to a patient or subject (e.g., in a separate formulation or dosage form) from the ⁇ form linaclotide.
- the optional additional components, additives, and/or species comprise an active component of the formulation.
- the optional components comprise one or more pharmaceutically-acceptable carriers and/or excipients.
- the present invention provides a composition comprising ⁇ form linaclotide and a degradation product, such as a hydrolysis product, acetylation product, a formylation product, an oxidation product, a water-mediated degradation product, and/or a deamidation product.
- a degradation product such as a hydrolysis product, acetylation product, a formylation product, an oxidation product, a water-mediated degradation product, and/or a deamidation product.
- the composition can contain any desired purity relative to hydrolysis product(s).
- the composition comprises less than about 10% by weight of hydrolysis product(s), relative to the total weight of the composition, such as, for example, less than about 7.5 wt.%, less than about 5 wt.%, or even less than about 2 wt.% of hydrolysis product(s).
- the composition comprises from about 0.05% to about 5% by weight of hydrolysis product(s).
- the composition comprises from about 0.05% to about 2% by weight of the hydrolysis product(s).
- the composition may comprise from about 0.1% to about 2% by weight of the hydrolysis product(s).
- the composition can contain any desired purity relative to acetylation product(s).
- the acetylation product may comprise less than 10% by weight of the composition.
- the acetylation product may comprise less than 7.5% by weight of the composition.
- the acetylation product may comprise less than 5% by weight of the composition.
- the acetylation product may comprise less than 2% by weight of the composition.
- the acetylation product may comprise less than 1% by weight of the composition.
- the acetylation product may comprise less than 0.5% by weight of the composition.
- the acetylation product may comprise from about 0.05% to about 5% by weight of the composition. In some embodiments, the acetylation product may comprise from about 0.05% to about 2% by weight of the composition. In other embodiments, the acetylation product may comprise from about 0.1 % to about 2% by weight of the composition. In yet other embodiments, the acetylation product may comprise from about 0.1% to about 2% by weight of the composition.
- the composition can contain any desired purity relative to formylation product(s).
- the formylation product may comprise less than 10% by weight of the composition.
- the formylation product may comprise less than 7.5% by weight of the composition.
- the formylation product may comprise less than 5% by weight of the composition.
- the formylation product may comprise less than 2% by weight of the composition.
- the formylation product may comprise from about 0.05% to about 5% by weight of the composition.
- the formylation product may comprise from about 0.05% to about 2% by weight of the composition.
- the formylation product may comprise from about 0.1% to about 2% by weight of the composition.
- the composition can contain any desired purity relative to oxidation product(s).
- the oxidation product may comprise less than 10% by weight of the composition.
- the oxidation product may comprise less than 7.5% by weight of the composition.
- the oxidation product may comprise less than 5% by weight of the composition.
- the oxidation product may comprise less than 2% by weight of the composition.
- the oxidation product may comprise from about 0.05% to about 5% by weight of the composition.
- the oxidation product may comprise from about 0.05% to about 2% by weight of the composition.
- the oxidation product may comprise from about 0.1% to about 2% by weight of the composition.
- the composition can contain any desired purity relative to water-mediated degradation product(s).
- the water- mediated degradation product(s) may comprise less than 10% by weight of the composition. In some embodiments, the water-mediated degradation product(s) may comprise less than 7.5% by weight of the composition. In some embodiments, the water- mediated degradation product(s) may comprise less than 5% by weight of the composition. In other embodiments, the water-mediated degradation product(s) may comprise less than 2% by weight of the composition. In still other embodiments, the water-mediated degradation product(s) may comprise from about 0.05% to about 5% by weight of the composition. In exemplary embodiments, the water-mediated degradation product(s) may comprise from about 0.05% to about 2% by weight of the composition. In yet other embodiments, the water-mediated degradation product(s) may comprise from about 0.1% to about 2% by weight of the composition.
- the composition can contain any desired purity relative to deamidation product(s).
- the deamidation product may comprise less than 10% by weight of the composition. In some embodiments, the deamidation product may comprise less than 7.5% by weight of the composition. In some embodiments, the deamidation product may comprise less than 5% by weight of the composition. In other embodiments, the deamidation product may comprise less than 2% by weight of the composition. In still other embodiments, the deamidation product may comprise from about 0.05% to about 5% by weight of the composition. In exemplary embodiments, the deamidation product may comprise from about 0.05% to about 2% by weight of the composition. In yet other embodiments, the deamidation product may comprise from about 0.1% to about 2% by weight of the composition.
- the invention provides a composition comprising ⁇ form linaclotide and less than 10 wt.% (such as less than 8 wt.%, less than 6 wt.%, less than 5 wt.%, less than 4 wt.%, less than 3 wt.%, less than 2 wt.%, less than 1 wt.%, less than 0.5 wt.%, or even less than 0.25 wt.%) of a combined total of a degradation product, such as a hydrolysis product, a formylation product, an oxidation product, a water-mediated degradation product, and/or a deamidation product.
- a degradation product such as a hydrolysis product, a formylation product, an oxidation product, a water-mediated degradation product, and/or a deamidation product.
- the invention provides a composition comprising ⁇ form linaclotide and less than 20 wt.% (such as less than 18 wt.%, less than 16 wt.%, less than 14 wt.%, less than 12 wt.%, less than 10 wt.%, less than 8 wt.%, less than 6 wt.%, less than 5 wt.%, less than 4 wt.%, less than 3 wt.%, less than 2 wt.%, less than 1 wt.%, less than 0.5 wt.%, or even less than 0.25 wt.%) of a combined total of a degradation product, such as a hydrolysis product, an acetylation product, a formylation product, an oxidation product, a water-mediated degradation product, and/or a deamidation product.
- a degradation product such as a hydrolysis product, an acetylation product, a formylation product, an oxidation product, a water
- the present invention provides a composition comprising ⁇ form linaclotide and multimers.
- the multimers may be formed due to disulfide linkages.
- the multimers may be formed due to non- disulfide linkages.
- the composition may contain any desired purity relative to multimers.
- the composition comprises less than about 20 wt.% of multimers, such as, for example, less than about 18 wt.%, less than about 16 wt.%, less than about 14 wt.%, less than about 12 wt.%, less than about 10 wt.%, less than about 8 wt.%, less than about 6 wt.%, less than about 5 wt.%, less than about 4 wt.%, less than about 3 wt.%, less than about 2 wt.%, less than about 1 wt.%, less than about 0.5 wt.%, or even less than about 0.1 wt.% of multimers.
- multimers such as, for example, less than about 18 wt.%, less than about 16 wt.%, less than about 14 wt.%, less than about 12 wt.%, less than about 10 wt.%, less than about 8 wt.%, less than about 6 wt.%, less than about 5
- the compositions may comprise ⁇ form linaclotide and a dimer.
- the composition comprises less than about 20 wt.% of dimers, such as, for example, less than about 18 wt.%, less than about 16 wt.%, less than about 14 wt.%, less than about 12 wt.%, less than about 10 wt.%, less than about 8 wt.%, less than about 6 wt.%, less than about 5 wt.%, less than about 4 wt.%, less than about 3 wt.%, less than about 2 wt.%, less than about 1 wt.%, less than about 0.5 wt.%, or even less than about 0.1 wt.% of dimers.
- the present invention provides a composition comprising ⁇ form linaclotide and an isomer.
- the composition comprises less than about 20 wt.% of isomers, such as, for example, less than about 18 wt.%, less than about 16 wt.%, less than about 14 wt.%, less than about 12 wt.%, less than about 10 wt.%, less than about 8 wt.%, less than about 6 wt.%, less than about 5 wt.%, less than about 4 wt.%, less than about 3 wt.%, less than about 2 wt.%, less than about 1 wt.%, less than about 0.5 wt.%, or even less than about 0.1 wt.% of isomers.
- the present invention provides a composition comprising ⁇ form linaclotide and less than about 40 wt%, such as less than about 30 wt.%, less than about 20 wt.%, less than about 15 wt.%, less than about 10 wt.%, less than about 8 wt.%, less than about 6 wt.%, less than about 5 wt.%, less than about 4 wt.%, less than about 3 wt.%, less than about 2 wt.%, less than about 1 wt.%, less than about 0.5 wt.%, less than about 0.1 wt.%, or even less than about 0.01 wt.% of amorphous linaclotide.
- the present invention provides a composition comprising between about 50:50 and 99: 1 ⁇ form linaclotide to amorphous linaclotide, such as, for example, between about 55:45 and 95:5 ⁇ form linaclotide to amorphous linaclotide, between about 60:40 and 90:10 ⁇ form linaclotide to amorphous linaclotide, between about 70:30 and 85: 15 ⁇ form linaclotide to amorphous linaclotide, or even between about 75:25 and 99:1 ⁇ form linaclotide to amorphous linaclotide.
- a composition comprising between about 50:50 and 99: 1 ⁇ form linaclotide to amorphous linaclotide, such as, for example, between about 55:45 and 95:5 ⁇ form linaclotide to amorphous linaclotide, between about 60:40 and 90:10 ⁇ form linaclotide to amorphous linaclotide,
- Formulations and preparations that comprise the ⁇ form linaclotide described herein can be prepared in any suitable manner, such as described, for example, in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (current edition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz, editors) current edition, published by Marcel Dekker, Inc., as well as Remington's Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593 (current edition).
- Administration of the present invention can be accomplished in any suitable manner according to patient needs, for example, orally, nasally, parenterally (e.g., subcutaneously, intravenously, intramuscularly, intrasternally, and/or by infusion), by inhalation, rectally, vaginally, topically, and/or by ocular administration.
- parenterally e.g., subcutaneously, intravenously, intramuscularly, intrasternally, and/or by infusion
- inhalation rectally, vaginally, topically, and/or by ocular administration.
- ⁇ form linaclotide can be administered alone or combined with various pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, starches) and excipients known in the art, including but not limited to suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorants, lubricants and the like.
- diluents such as sucrose, mannitol, lactose, starches
- excipients known in the art, including but not limited to suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorants, lubricants and the like.
- Time release capsules, tablets and gels are also advantageous in administering the compounds of the present invention.
- liquid oral dosage forms can also be used for administering ⁇ form linaclotide, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups, and elixirs.
- dosage forms can also contain suitable inert diluents known in the art such as water and suitable excipients known in the art such as preservatives, wetting agents, sweeteners, flavorants, as well as agents for emulsifying and/or suspending the compounds of the invention.
- the ⁇ form linaclotide may be injected, for example, intravenously, in the form of an isotonic sterile solution.
- Suppositories for rectal administration of ⁇ form linaclotide can be prepared by mixing the compound with a suitable excipient such as cocoa butter, salicylates and polyethylene glycols.
- a suitable excipient such as cocoa butter, salicylates and polyethylene glycols.
- the pharmaceutical composition can be in the form of creams, ointments, liniments, lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays, and drops suitable for administration to the skin, eye, ear or nose. Topical administration may also involve transdermal administration via means such as transdermal patches.
- Aerosol formulations suitable for administering via inhalation also can be made.
- the compounds according to the invention can be administered by inhalation in the form of a powder (e.g., micronized) or in the form of atomized solutions or suspensions.
- the aerosol formulation can be placed into a pressurized acceptable propellant.
- the present invention provides methods of treating gastrointestinal disorders in a patient (e.g., mammal or human) diagnosed with one or more gastrointestinal disorders (such as, for example, irritable bowel syndrome, constipation-predominant irritable bowel syndrome, chronic constipation, opioid induced constipation and/or dyspepsia), wherein the method comprises administering an effective amount of ⁇ form linaclotide (or a composition comprising said ⁇ form linaclotide and optional additional components, additives, and/or species, as described herein) to said patient.
- a patient e.g., mammal or human
- gastrointestinal disorders such as, for example, irritable bowel syndrome, constipation-predominant irritable bowel syndrome, chronic constipation, opioid induced constipation and/or dyspepsia
- ⁇ form linaclotide or a composition comprising said ⁇ form linaclotide and optional additional components, additives, and/or species, as described herein
- the methods comprise administering a pharmaceutical composition comprising ⁇ form linaclotide and a pharmaceutically acceptable carriers and/or excipients.
- the methods comprise administering a pharmaceutical composition comprising ⁇ form linaclotide and a degradation product.
- the methods comprise administering a pharmaceutical composition comprising ⁇ form linaclotide and a hydrolysis product.
- the methods comprise administering a pharmaceutical composition comprising ⁇ form linaclotide and an acetylation product. In exemplary embodiments, the methods comprise administering a pharmaceutical composition comprising ⁇ form linaclotide and an oxidation product.
- the methods comprise administering a pharmaceutical composition comprising ⁇ form linaclotide and a formylation product.
- the methods comprise administering a pharmaceutical composition comprising ⁇ form linaclotide and a deamidation product.
- the methods comprise administering a pharmaceutical composition comprising ⁇ form linaclotide and a multimer product.
- the methods comprise administering a pharmaceutical composition comprising ⁇ form linaclotide and a dimer product.
- the methods comprise administering a pharmaceutical composition comprising ⁇ form linaclotide and an isomer product.
- ⁇ form linaclotide required to achieve desired results (such as desired treatment and/or symptom relief) of a subject is dependent on several understood factors, such as the identity and severity of the disorder being treated, as well as the age, weight, etc., of the patient being treated.
- a subject or patient in whom administration of the therapeutic compound is an effective therapeutic regimen for a disease or disorder is preferably a human, but can be any animal, including a laboratory animal in the context of a clinical trial or screening or activity experiment.
- the methods, compounds and compositions of the present invention are particularly suited to administration to any animal, particularly a mammal, and including, but by no means limited to, humans, domestic animals, such as feline or canine subjects, farm animals, such as but not limited to bovine, equine, caprine, ovine, and porcine subjects, wild animals (whether in the wild or in a zoological garden), research animals, such as mice, rats, rabbits, goats, sheep, pigs, dogs, cats, etc., avian species, such as chickens, turkeys, songbirds, etc., i.e., for veterinary medical use.
- the compounds of the present invention are administered as a mono-therapy. In other embodiments, the compounds of the present invention are administered as part of a combination therapy.
- a compound of the invention may be used in combination with other drugs or therapies that are used in the treatment/prevention/suppression and/or amelioration of the diseases or conditions for which compounds of the invention are useful.
- Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the invention.
- a pharmaceutical unit dosage form containing such other drugs in addition to the compound of the invention may be employed.
- the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of invention.
- linaclotide 100 mg was added to 10 ml aqueous acid solution (for example, 0.1N hydrochloric acid). The mixture was stirred using magnetic stirrer for 30-60 minutes at room temperature. The suspension was carefully filtered into a glass container and the filtrate was stored under room temperature conditions. After a suitable formation period, the ⁇ crystalline form of linaclotide was carefully isolated, washed, dried and analyzed using powder X-ray diffractometry.
- Figure 2 shows the X-ray diffraction pattern for the ⁇ crystalline form of linaclotide.
- linaclotide 100 mg was added to 10 ml aqueous acid solution (for example, 0.1N hydrochloric acid). The mixture was stirred using magnetic stirrer for 10-60 minutes at temperature in the range of 20°C to 65 0 C. The suspension was carefully filtered into a glass container and the filtrate was stored under room temperature conditions. After a suitable formation period, the crystalline form of linaclotide was carefully isolated, washed, dried and analyzed using powder X-ray diffractometry.
- aqueous acid solution for example, 0.1N hydrochloric acid
- linaclotide 100 mg was added to 10 ml aqueous acid solution (for example, 0.1N hydrochloric acid). The mixture was stirred using magnetic stirrer for 10-60 minutes at temperature in the range of 20 0 C to 65°C. The suspension was carefully filtered into a glass container and the filtrate was stored at 4°C. After a suitable formation period, the crystalline form of linaclotide was carefully isolated, washed, dried and analyzed using powder X-ray diffractometry.
- aqueous acid solution for example, 0.1N hydrochloric acid
- linaclotide 100 mg was added to 10 ml aqueous acid solution (for example, 0.1N hydrochloric acid). The mixture was stirred using magnetic stirrer for 10-60 minutes at temperature in the range of 20°C to 65°C. The suspension was carefully filtered into a glass container. A weighed amount of a salt (for example sodium chloride) was added to the filtrate and it was stored under room temperature conditions. After a suitable formation period, the crystalline form of linaclotide was carefully isolated, washed, dried and analyzed using powder X-ray diffractometry.
- a salt for example sodium chloride
- linaclotide 100 mg was added to 10 ml aqueous acid solution (for example, 0.1N hydrochloric acid). The mixture was stirred using magnetic stirrer for 10-60 minutes at temperature in the range of 20°C to 65°C. The suspension was carefully filtered into a glass container. A weighed amount of a salt (for example sodium chloride) was added to the filtrate and it was stored at 4 0 C. After a suitable formation period, the crystalline form of linaclotide was carefully isolated, washed, dried and analyzed using powder X- ray diffractometry.
- a salt for example sodium chloride
- linaclotide 100 mg was added to 10 ml aqueous acid solution (for example, 0.1N hydrochloric acid) containing a known amount of polymer (for example, polyvinyl pyrrolidone). The mixture was shaken using an end-over-end shaker for 6-48 hours at temperature in the range of 20°C to 65°C. The suspension was carefully filtered into a glass container. A weighed amount of a salt (for example sodium chloride) was added to the filtrate and it was stored at 4°C. After a suitable formation period, the crystalline form of linaclotide was carefully isolated, washed, dried and analyzed using powder X- ray diffractometry.
- a salt for example sodium chloride
- the X-ray power diffraction patterns of the samples were determined in Example 1 using a wide-angle bench-top X-ray diffractometer (MiniFlex, Rigaku/MSC Inc., Woodlands, TX). The samples were loaded on zero background holders and exposed to CuKa radiation (3OkV x 15 mA). The instrument was operated in the step-scan mode, in increments of 0.05°2 ⁇ . The angular range was 5 to 40°2 ⁇ , and the scan rate was 0.1°2 ⁇ /min. The data collection and analyses were performed with commercially available software (JADE, version 7.1, Materials Data, Inc., Livermore, CA).
- the ⁇ -crystalline forms of linaclotide that were prepared in Examples IA- IF were prepared and analyzed in this Example using a second wide-angle bench-top X-ray diffractometer (Model D8, Bruker AXS Inc., Madison WI). A small amount of the samples was loaded on a zero background holder and exposed to CuKa radiation (4OkV x 40 mA) in the wide-angle bench-top X-ray diffractometer (Model D8, Bruker AXS Inc., Madison WI). The instrument was operated in the step-scan mode, in increments of 0.05°2 ⁇ . The angular range was 5 to 30°2 ⁇ , and the scan rate ranged from 0.05- 0.1°2 ⁇ /min. The data collection and analyses were performed with commercially available software (JADE, version 7.1, Materials Data, Inc., Livermore, CA).
- the ⁇ form linaclotide was also analyzed via Fourier Transform infrared spectroscopy by loading a small sample of the ⁇ form linaclotide (approx. 1 mg) onto a DurascopeTM diamond stage and exposing it to an IR beam in the FT-IR spectrometer using attenuated total diffuse reflectance (ATR) mode. All spectra were run at 4000 - 525 cm “1 wavenumbers, 300 scans and 2 cm " ' resolution. The Fourier Transform infrared spectrum for the ⁇ form linaclotide is shown in Figure 4.
- the ⁇ form linaclotide was also analyzed using a differential scanning calorimeter
- MDSC QlOOO TA Instruments, New Castle, DE
- the instrument was calibrated with pure samples of indium. About 2-5 mg sample was weighed in open non-hermetic aluminum pans with a cover lid and heated under dry nitrogen purge (flow rate 50 ml/min) at 10°C/min. The data was analyzed using Universal Analysis 2000 (TA instruments, New Castle, DE). The DSC thermogram of the ⁇ form linaclotide is shown in Figure 5.
- linaclotide 100 mg was mixed with 0.1N hydrochloric acid. The mixture was stirred using magnetic stirrer for 10-60 minutes at temperature in the range of 20°C to 65°C. The suspension was carefully filtered into a glass container and the filtrate was stored under room conditions. After a suitable formation period, the ⁇ crystalline form of linaclotide was carefully isolated, washed, dried and analyzed using powder X-ray diffractometry.
- Figure 6 shows the X-ray powder diffraction pattern for the crystalline form of linaclotide. Peak positions for the XRD are provided in Table 2.
- linaclotide 100 mg was mixed with 0.1N hydrochloric acid containing a known amount of polymer (for example, polyvinyl pyrrolidone). The mixture was shaken using an end-over-end shaker for 6-48 hours at temperature in the range of 20°C to 65°C. The suspension was carefully filtered into a glass container. A weighed amount of sodium chloride was added to the filtrate and it was stored at 4°C. After a suitable formation period, the ⁇ crystalline form of linaclotide was carefully isolated, washed, dried and analyzed using powder X-ray diffractometry. Figure 10 shows the X-ray powder diffraction pattern for the crystalline form of linaclotide. Peak positions for the XRD are provided in Table 6.
- polymer for example, polyvinyl pyrrolidone
- linaclotide 100 mg was mixed with 0.1N methane sulfonic acid. The mixture was stirred using magnetic stirrer for 30-60 minutes at room temperature. The suspension was carefully filtered into a glass container and the filtrate was stored under room temperature conditions. After a suitable formation period, the ⁇ crystalline form of linaclotide was carefully isolated, washed, dried and analyzed using powder X-ray diffractometry.
- Figure 12 shows the X-ray powder diffraction pattern for the crystalline form of linaclotide. Peak positions for the XRD are provided in Table 8.
- the relative chemical purity and stability of amorphous and crystalline linaclotide was studied using reverse phase high performance liquid chromatography (HPLC).
- HPLC reverse phase high performance liquid chromatography
- the chemical identification was conducted using reverse phase high performance liquid chromatography coupled with mass spectroscopy (HPLC-MS).
- HPLC-MS mass spectroscopy
- the mass spectroscopic analysis was performed at Enhance MS scan (EMS) mode with positive ionization and a scan range (m/z) of 600-1600.
- a Perkin Elmer series 200 LC instrument (Perkin Elmer, Waltham, MA) was used with a YMC Pro Cl 8 column (150mm X 3.0mm, 3 ⁇ m) (Waters Corporation, Milford, MA). The column temperature was set at 40°C while the auto sampler temperature was maintained at 4°C using a peltier tray. The injection volume was 50 ⁇ l. A gradient (0.6ml/minute) run was used comprising of two solvents; A (97.9%Water, 2% Acetonitrile, 0.1% Trifluoroacetic Acid) and B (94.9% Acetonitrile, 5% Water, 0.1% Trifluoroacetic Acid). The gradient was set according to the scheme described in Table 10. The effluent was detected at 220nm using a UV detector.
- a Perkin Elmer Series 200 LC-MS instrument (Perkin Elmer, Waltham, MA) was used with a Pursuit XR Cl 8 column (150x2mm, 3 ⁇ m). The column temperature was set at 40 0 C while the autosampler temperature was maintained at 4°C using a peltier tray. The injection volume was 5 ⁇ l. A gradient (0.25ml/minute) run was used comprising of two solvents; A (0.1% trifluoroacetic acid in water) and B (0.1% trifluoroacetic acid in acetonitrile). The gradient was set according to the scheme described in Table 11. The effluent was detected at 220nm using a UV detector. The mass spectroscopic analysis was performed at Enhance MS scan (EMS) mode with positive ionization and a scan range (m/z) of 600- 1600.
- EMS Enhance MS scan
- the precipitates prepared in Examples IA and 2 A were chemically identified as linaclotide based on HPLC-MS analysis. The purity of the precipitate was found to be in the range of 95% to 100%,
- the remaining 19.2% and 4.1% of the amorphous and ⁇ -form linaclotide respectively may comprise multimers.
- the ⁇ -crystalline form of linaclotide was found to have a substantially better stability profile than amorphous linaclotide, under the study conditions. Additionally, as is illustrated, the ⁇ -crystalline form of linaclotide had a significantly lower concentration of degradation products, as well as significantly less multimer formation.
- the ⁇ -crystalline form of linaclotide was also found to have lower concentrations of degradation products (water mediated de-amidation and hydrolysis) and non-disulfide linked multimers as compared to amorphous linaclotide after storage for three months in induction sealed 45cc high-density polyethylene bottles at 40°C/75% RH.
- acid-induced hydrolysis was pronounced in the crystalline form.
- a linaclotide hydrolysis product was prepared by transforming Asn in the 7 position to Asp (the numbering of linaclotide starts with 1 at the N-terminal Cys).
- the linaclotide hydrolysis product was synthesized using a solid phase peptide synthesis technique. The structure of the linaclotide hydrolysis product is shown below:
- the linaclotide hydrolysis product may also be prepared by other methods known in the art, e.g., by isolation from linaclotide preparations using chromatographic techniques or by recombinant expression of a nucleic acid encoding the linaclotide hydrolysis product (CCEYCCDP ACTGCY), optionally followed by oxidation of the cysteine residues to form the disulfide linkages.
- CCEYCCDP ACTGCY a nucleic acid encoding the linaclotide hydrolysis product
- the crystalline forms of linaclotide have physical properties (e.g. , stability properties) that are surprising and unexpected as compared to amorphous linaclotide and/or other crystalline forms of linaclotide.
- the crystalline forms of linaclotide may also have synergy with other active or inactive components resulting in enhanced performance characteristics or properties of pharmaceutical compositions comprising one or more crystalline forms of the present invention.
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Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
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MX2011005245A MX2011005245A (es) | 2008-11-19 | 2009-11-18 | Forma cristalina de linaclotida. |
JP2011536620A JP2012509281A (ja) | 2008-11-19 | 2009-11-18 | リナクロチドのα結晶形 |
CA2743172A CA2743172A1 (en) | 2008-11-19 | 2009-11-18 | Crystalline form of linaclotide |
EP09828173.6A EP2365821A4 (en) | 2008-11-19 | 2009-11-18 | CRYSTALLINE FORM OF LINACLOTIDE |
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US11615608P | 2008-11-19 | 2008-11-19 | |
US61/116,156 | 2008-11-19 |
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US (3) | US8222201B2 (ja) |
EP (1) | EP2365821A4 (ja) |
JP (1) | JP2012509281A (ja) |
CA (1) | CA2743172A1 (ja) |
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Cited By (2)
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WO2014118180A1 (en) | 2013-01-30 | 2014-08-07 | Sandoz Ag | Crystalline form of linaclotide |
EP4194464A1 (en) * | 2021-12-13 | 2023-06-14 | Chemi SPA | Manufacturing process for the production of linaclotide |
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EP2165707A1 (en) * | 2008-09-23 | 2010-03-24 | Genkyo Tex Sa | Pyrazolo pyridine derivatives as NADPH oxidase inhibitors |
EP2166008A1 (en) * | 2008-09-23 | 2010-03-24 | Genkyo Tex Sa | Pyrazolo pyridine derivatives as NADPH oxidase inhibitors |
CA2743172A1 (en) * | 2008-11-19 | 2010-05-27 | Forest Laboratories Holdings Limited | Crystalline form of linaclotide |
JP2016521249A (ja) * | 2012-07-12 | 2016-07-21 | フォレスト ラボラトリーズ ホールディングス リミテッド | リナクロチド組成物 |
CN104844693B (zh) * | 2015-06-10 | 2018-08-03 | 成都圣诺生物科技股份有限公司 | 一种合成利那洛肽的方法 |
EP3317292B1 (en) | 2015-07-01 | 2024-01-17 | Novetide, Ltd. | Solid state forms of linaclotide |
CN107163105B (zh) * | 2017-06-28 | 2020-12-11 | 清华大学 | 一种天然利那洛肽的结晶方法 |
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US20070010543A1 (en) * | 2005-07-01 | 2007-01-11 | Dynogen Pharmaceuticals, Inc. | Compositions and methods for treating gastrointestinal hypomotility and associated disorders |
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US7371271B2 (en) * | 2001-04-02 | 2008-05-13 | Mitsubishi Materials Pmg Corporation | Composite soft magnetic sintered material having high density and high magnetic permeability and method for preparation thereof |
SG168407A1 (en) | 2003-01-28 | 2011-02-28 | Ironwood Pharmaceuticals Inc | Methods and compositions for the treatment of gastrointestinal disorders |
US20060281682A1 (en) | 2003-01-28 | 2006-12-14 | Currie Mark G | Methods and compositions for the treatment of gastrointestinal disorders |
US7304036B2 (en) | 2003-01-28 | 2007-12-04 | Microbia, Inc. | Methods and compositions for the treatment of gastrointestinal disorders |
US7772188B2 (en) * | 2003-01-28 | 2010-08-10 | Ironwood Pharmaceuticals, Inc. | Methods and compositions for the treatment of gastrointestinal disorders |
PT1644021E (pt) | 2003-06-13 | 2013-01-30 | Ironwood Pharmaceuticals Inc | Métodos e composições para o tratamento de distúrbios gastrointestinais |
PE20090696A1 (es) * | 2007-04-20 | 2009-06-20 | Bristol Myers Squibb Co | Formas cristalinas de saxagliptina y procesos para preparar las mismas |
EP2152266A4 (en) | 2007-05-04 | 2010-07-28 | Ironwood Pharmaceuticals Inc | COMPOSITIONS AND METHODS OF TREATING DISORDERS RELATED TO SALT OR LIQUID RETENTION |
CA2743172A1 (en) * | 2008-11-19 | 2010-05-27 | Forest Laboratories Holdings Limited | Crystalline form of linaclotide |
-
2009
- 2009-11-18 CA CA2743172A patent/CA2743172A1/en not_active Abandoned
- 2009-11-18 US US12/621,272 patent/US8222201B2/en active Active
- 2009-11-18 JP JP2011536620A patent/JP2012509281A/ja active Pending
- 2009-11-18 EP EP09828173.6A patent/EP2365821A4/en not_active Withdrawn
- 2009-11-18 MX MX2011005245A patent/MX2011005245A/es active IP Right Grant
- 2009-11-18 WO PCT/US2009/065001 patent/WO2010059733A1/en active Application Filing
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2012
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US20060258593A1 (en) * | 2003-01-28 | 2006-11-16 | Currie Mark G | Methods and compositions for the treatment of gastrointestinal disorders |
US20070010543A1 (en) * | 2005-07-01 | 2007-01-11 | Dynogen Pharmaceuticals, Inc. | Compositions and methods for treating gastrointestinal hypomotility and associated disorders |
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Title |
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See also references of EP2365821A4 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014118180A1 (en) | 2013-01-30 | 2014-08-07 | Sandoz Ag | Crystalline form of linaclotide |
EP4194464A1 (en) * | 2021-12-13 | 2023-06-14 | Chemi SPA | Manufacturing process for the production of linaclotide |
WO2023110781A1 (en) * | 2021-12-13 | 2023-06-22 | Chemi Spa | Manufacturing process for the production of linaclotide |
Also Published As
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EP2365821A1 (en) | 2011-09-21 |
US8222201B2 (en) | 2012-07-17 |
JP2012509281A (ja) | 2012-04-19 |
CA2743172A1 (en) | 2010-05-27 |
MX2011005245A (es) | 2011-06-17 |
US20120214750A1 (en) | 2012-08-23 |
EP2365821A4 (en) | 2013-09-04 |
US20120309695A1 (en) | 2012-12-06 |
US8293704B2 (en) | 2012-10-23 |
US20100125056A1 (en) | 2010-05-20 |
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