ANTECIP EXHIBIT 2021
`Grunenthal GmbH v. Antecip Bioventures II LLC
`PGR2017-00022
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`Patent Application Publication
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`Feb. 3, 2011 Sheet 1 of 39
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`

`

`US 2011/0028435 A1
`
`Feb. 3, 2011
`
`CRYSTALLIZATION METHOD AND
`BIOAVAILABILITY
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`[0001] This application claims priority to US. application
`61/230,222, filed Jul. 31, 2009; to US. application 61/288,
`036, filed Dec. 18, 2009; to US. application 61/302,110, filed
`Feb. 6, 2010; to US. application 61/312,879, filed Mar. 11,
`2010; to US. application 61/318,503, filed Mar. 29, 2010;
`and to US. application 61/359,544, filed Jun. 29, 2010; each
`of which is incorporated herein by reference.
`
`FIELD OF THE INVENTION
`
`[0002] This disclosure pertains to improvement of the
`aqueous solubility and permeability of poorly permeable and
`sparingly water soluble drug compounds through generating
`novel crystalline forms of such drugs. The novel forms
`include but are not limited to cocrystals, salts, hydrates, sol-
`vates, solvates of salts, and mixtures thereof. Methods for the
`preparation and pharmaceutical compositions suitable for
`drug delivery systems that include one or more of these new
`forms are disclosed.
`
`BACKGROUND OF THE INVENTION
`
`[0003] Many Biopharmaceutic Classification System
`(BCS) class III or IV drugs suffer from the lack ofgastrointes-
`tinal (GI) tract membrane permeability leading to poor oral
`bioavailability. Different strategies have been implemented to
`improve the permeability and subsequently the oral bioavail-
`ability of such drugs. For example, the US. patent application
`20060068010 describes a formulation method for improving
`the permeability of drugs and subsequently increasing their
`bioavailability by granulation of the physical solid mixture of
`the drug with one or more amino acids, at least one inter-
`granular hydrophilic polymer, and an additional immediate
`release excipient. Another application WO 200602009 A1
`disclosed the increase of the oral bioavailability for poorly
`permeable drugs such as bisphosphonates; risedronate as one
`of those drugs was mixed with a chelating agent such as
`ethylenediaminetetraacetate (EDTA) and other excipients to
`make an oral dosage form. Yet another application, WO
`2007093226 A1, describes a method for improving the bio-
`availability of ibandronate by generating a physical mixture
`of the drug together with a modified amino acid (acylation or
`sulphonation of the amino group with phenyl or cyclohexyl)
`and other excipients. Another application WO 2003007916
`A1 reports a gastric retention system to improve the bioavail-
`ability of a poorly permeable drug, alendronate, which was
`orally formulated with vitamin D and released an hour after
`the immediate release of vitamin D. WO 2006080780 dis-
`
`closes yet another method to improve the permeability and
`bioavailability of alendronate, a poorly permeable bisphos-
`phonate, by mixing it with a biocompatible cationic polymer
`(i.e. water soluble chitosan) with up to a 10:1 weight ratio of
`the chitosan to the drug, while the resulting mixture can be
`formulated into a solid or liquid oral dosage form. A further
`method of improving permeability of drug materials was
`discussed in the US. patent application 2007/014319 A1,
`where an oral dosage form was formulated by a powder
`mixture of a bisphosphonic acid (e.g. zoledronic acid)
`together with an inactive ingredient (either an ester of a
`medium chain fatty acid or a lipophilic polyethylene glycol
`
`Page 41
`
`ester). A similar approach was disclosed in the US application
`2007/0238707 A 1 where a medium length fatty acid or its
`derivative (6-20 carbon atom fatty acid chain) was physically
`mixed with a poorly permeable drug (e.g. zoledronic acid) in
`a capsule that was enterically coated.
`[0004] Zoledronic acid, known as (1-hydroxy-2-imidazol-
`1-yl-1-phosphono-ethyl)phosphonic acid, is depicted by the
`following chemical structure:
`
`H32
`
`HO\
`/OH
`P
`P
`HO/ \\O OéI\\O
`
`Zoledronic acid is a third generation bisphosphonate which
`far exceeds the previous generations in terms of efficacy and
`is used predominately for indications of osteoporosis, Paget’s
`disease, hypercalcemia, and inhibition of bone metastasis. It
`was originally developed by Novartis and marketed as the
`monohydrate under the brand names Zometa® and Reclast®.
`Zoledronic acid was first approved in 2000 for the treatment
`of hypercalcemia in Canada. It was later approved for use in
`the US for hypercalcemia in 2001, for multiple myeloma and
`bone metastases from solid tumors in 2002, and for
`osteoporosis and Paget’s disease in 2007. Clinical trials have
`also been conducted or are on-going exploring the use of
`zoledronic acid in neoadjuvant or adjuvant cancer therapy,
`Coleman, et al., British J Cancer 2010; 102(7):1099-1105,
`Gnant, et al., New England J. Medicine. 2009, 360 (17):679-
`691 and Davies, et al. J Clinical Oncology, 2010, 28(7s):
`Abstract 8021. Zoledronic acid is administered as an intrave-
`
`nous (IV) dose of 4 mg over 15 minutes for hypercalcemia of
`malignancy, multiple myeloma, and bone metastases from
`solid tumors, while an IV dose of 5 mg over 15 minutes is used
`for osteoporosis and Paget’s disease.
`[0005] Zoledronic acid is sparingly soluble in water and 0.1
`N HCl solution but
`is freely soluble in 0.1 N NaOH.
`Zoledronic acid is practically insoluble in various organic
`solvents.
`
`[0006] Much effort has been taken to generate novel oral
`formulations of zoledronic acid through crystallization and
`metal salt formation to improve its aqueous solubility, per-
`meability, and subsequent oral bioavailability. A crystalline
`trihydrate was disclosed in the US. Patent application 2006/
`0178439 A1 and world patent application WO2007/032808.
`Seven hydrated forms, an amorphous form, three monoso-
`dium salts, and eleven disodium salts with varying degrees of
`hydration of zoledronic acid were also disclosed in the patent
`application WO2005/005447 A2. Zoledronate metal salts
`including Na+, Mg2+, Zn2+ were reported in the journal of
`Drugs ofthe Future (Sorbera et al, 25(3), Drugs ofthe Fulure,
`(2000)). Zoledronate, zoledronic, or zoledronic salt repre-
`sents the ionic form of zoledronic acid. Patent application
`WO2008/064849 A1 from Novartis disclosed additional
`
`metal salts including two Ca2+ salts, two Zn2+ salts, one Mg2+
`salt, as well as a monohydrate, a trihydrate, an amorphous
`form, and an anhydrous form.
`[0007] According to the US Food and Drug Administration
`(FDA) Summary Basis of Approval (SBA) for zoledronic
`
`Page 41
`
`

`

`US 2011/0028435 A1
`
`Feb. 3, 2011
`
`acid, the poor oral bioavailability (approximately 1%), is
`partially due to its poor permeability in the GI tract. It was
`also noted that insoluble metal complexes were formed in the
`upper intestines, most commonly with calcium. Zoledronic
`acid has also been shown to cause severe gastric and intestinal
`irritations.
`
`[0008] All of the above attempts to improve the oral bio-
`availability ofzoledronic acidwere either focused on improv-
`ing the aqueous solubility by generating novel solid forms, or
`by mixing the drug with an inactive ingredient that has
`enhanced GI tract permeability. The improvement of aqueous
`solubility failed to improve the bioavailability of zoledronic
`acid, since the formation of insoluble zoledronate calcium
`complexes is unlikely to be prevented. On the other hand,
`powder mixtures of the poorly permeable drug with inactive
`permeability enhancers improved the bioavailability of the
`drug. This approach of mixing different materials with dif-
`ferent particle sizes and size distributions could result in a
`poor blend/physical mixture uniformity. Constituents of the
`mixture could also segregate during transportation or with
`shaking and vibration. Additionally,
`the powder blends
`require rigorous batch-to -batch consistency to ensure the uni-
`formity of the blend batches.
`[0009]
`To the best of the inventors’ knowledge, no attempt
`has been made prior to this invention towards a deliberate
`molecular design to create a molecular complex of the drug
`and additional component(s) (coformer(s)) in a single crys-
`talline structure. The benefit of such design can lead to the
`elimination of all the batch to batch blend uniformity and
`particle segregation problems that powder blends often suffer
`from. In addition, this invention simplifies the manufacturing
`of the solid dosage form (comprised of drug and excipient)
`such that the final solid dosage form is, in one embodiment, a
`powder of the molecular complex.
`[0010] Additionally,
`the resulting molecular complexes
`possess very different physicochemical properties compared
`to the parent drug, coformer or their physical mixture. These
`properties include but are not limited to melting point, ther-
`mal and electrical conductivity, aqueous solubility, rate of
`dissolution and permeability across the GI tract membrane.
`The permeability improvement could result in the enhance-
`ment of the oral bioavailability of the BCS class III and IV
`drugs. This is the first time that the concept of a molecular
`complex by design was employed to improve the permeabil-
`ity and subsequent bioavailability of a poorly permeable drug
`such as zoledronic acid. The mechanisms behind the perme-
`ability enhancement, however, are not fully understood.
`[0011] The upward trend in the use of oral drugs continues
`especially in light of the goal to decrease the overall cost of
`healthcare. Orally administered drugs are becoming more
`preferred in various therapeutic areas including cancers.
`Clearly, there is an opportunity to create oral dosage forms of
`IV drugs where oral dosage forms do not yet exist due to their
`poor aqueous solubility and/or poor permeability providing a
`clear clinical benefit
`for patients. Given the fact
`that
`zoledronic acid is only approved for IV administration, there
`is a need to develop an oral dosage form of zoledronic acid.
`By using pharmaceutically acceptable and/or approved
`coformers to hydrogen bond with zoledronic acid, novel
`molecular complexes (e.g. cocrystals, salts, solvates, and
`mixtures thereof) with improve solubility and/or permeabil-
`
`Page 42
`
`ity can be created. These novel molecular complexes could be
`used in the development ofan oral dosage form for zoledronic
`acid.
`
`SUMMARY OF THE INVENTION
`
`[0012] The present disclosure is directed towards generat-
`ing new forms of zoledronic acid, which have the therapeutic
`efficacy of zoledronic acid discussed above, with improved
`aqueous solubility, rate of dissolution, and/or improved per-
`meability and thus enhanced bioavailability. One aspect ofthe
`present disclosure includes novel molecular complexes of
`zoledronic acid that includes cocrystals, salts, and solvates
`(e.g. hydrates and mixed solvates as well as solvates of salts),
`and mixtures containing such materials. In addition, the dis-
`closure further includes methods for the preparation of such
`complexes.
`[0013] The disclosure further includes compositions of
`molecular complexes of zoledronic acid suitable for incorpo-
`ration in a pharmaceutical dosage form. Specific molecular
`complexes pertaining to the disclosure include, but are not
`limited to, complexes of zoledronic acid with sodium, ammo-
`nium, ammonia, L-lysine, DL-lysine, nicotinamide, adenine,
`and glycine. Obvious variants of the disclosed zoledronic
`acid forms in the disclosure, including those described by the
`drawings and examples, will be readily apparent to the person
`of ordinary skill in the art having the present disclosure and
`such variants are considered to be a part of the current inven-
`tion.
`
`[0014] The disclosure also includes results of an in vivo
`study ofparent (pure) zoledronic acid and selected zoledronic
`acid complexes prepared by the methods of the invention in
`rat and dog models. The drug concentrations in the rat plasma
`and dog serum samples along with the pharmacokinetic (PK)
`profiles are also included.
`[0015] The foregoing and other features and advantages of
`the disclosed technology will become more apparent from the
`following detailed description, which proceeds with refer-
`ence to the accompanying drawings. Such description is
`meant to be illustrative, but not limiting, of the invention.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`of:
`PXRD diffractograms
`shows
`1
`FIG.
`[0016]
`(A:Zoledronic acid, sodium zoledronic salt and water com-
`plex),
`(B:NaCl),
`(Z1:Zoledronic
`acid monohydrate),
`(Z3:Zoledronic acid trihydrate).
`[0017]
`FIG. 2 is an FTIR spectrum ofa complex compris-
`ing zoledronic acid, sodium zoledronic salt, and water.
`of:
`[0018]
`FIG.
`3
`shows
`PXRD diffractograms
`(C:ammonium zoledronic
`salt
`and water
`complex),
`(Z1:Zoledronic acid monohydrate), and (Z3:Zoledronic
`acid trihydrate).
`[0019]
`FIG. 4 is an FTIR spectrum of ammonium
`zoledronic salt and water complex.
`of:
`[0020]
`FIG.
`5
`shows
`PXRD diffractograms
`(D:Zoledronic, L-lysine, and water complex), (E:L-lysine),
`(Z1:Zoledronic acid monohydrate), and (Z3:Zoledronic
`acid trihydrate).
`[0021]
`FIG. 6 is an FTIR spectrum of zoledronic, L-lysine,
`and water complex.
`of:
`PXRD diffractograms
`shows
`[0022]
`FIG.
`7
`(F:zoledronic, DL-lysine, and water complex), (G:DL-
`lysine),
`(Z1:Zoledronic
`acid monohydrate),
`and
`(Z3:Zoledronic acid trihydrate).
`
`Page 42
`
`

`

`US 2011/0028435 A1
`
`Feb. 3, 2011
`
`FIG. 8 is an FTIR spectrum of zoledronic, DL-
`[0023]
`lysine, and water complex.
`of:
`PXRD diffractograms
`[0024]
`FIG.
`9
`shows
`(H:Zoledronic acid, zoledronic, DL-lysine, ethanol, and
`water complex), (G:DL-lysine), (Zl:Zoledronic acid mono-
`hydrate), (Z3:Zoledronic acid trihydrate).
`[0025]
`FIG. 10 is an FTIR spectrum of zoledronic acid,
`zoledronic, DL-lysine, ethanol, and water complex.
`of:
`[0026]
`FIG.
`11
`shows
`PXRD diffractograms
`(I:zoledronic,
`nicotinamide,
`and water
`complex),
`(J:nicotinamide), (Z1:Zoledronic acid monohydrate), and
`(Z3:Zoledronic acid trihydrate).
`[0027]
`FIG. 12 is an FTIR spectrum of zoledronic, nicoti-
`namide, and water complex.
`of:
`PXRD diffractograms
`[0028]
`FIG.
`13
`shows
`(K:Zoledronic, adenine, and water complex), (L:adenine),
`(Zl :Zoledronic acid monohydrate), (Z3 :Zoledronic acid tri-
`hydrate).
`FIG. 14 is an FTIR spectrum of zoledronic, adenine,
`[0029]
`and water complex.
`of:
`PXRD diffractograms
`shows
`[0030]
`FIG.
`15
`glycine
`complex),
`(N:glycine),
`(M:zoledronic
`and
`(Zl:Zoledronic acid monohydrate), and (Z3:Zoledronic
`acid trihydrate).
`[0031]
`FIG. 16 is an FTIR spectrum of zoledronic and
`glycine complex.
`of:
`PXRD diffractograms
`shows
`[0032]
`FIG.
`17
`(O:Zoledronic diammonia water complex), (Zl:Zoledronic
`acid monohydrate), and (Z3 :Zoledronic acid trihydrate).
`[0033]
`FIG. 18 is an FTIR spectrum ofzoledronic diammo-
`nia water complex.
`of:
`PXRD diffractograms
`shows
`[0034]
`FIG.
`19
`(P:zoledronic, DL-lysine, and water complex), (G:DL-
`lysine),
`(Zl:Zoledronic
`acid monohydrate),
`and
`(Z3:Zoledronic acid trihydrate).
`[0035]
`FIG. 20 is an FTIR spectrum of zoledronic, DL-
`lysine, and water complex.
`of:
`PXRD diffractograms
`[0036]
`FIG.
`21
`shows
`(R:Zoledronic, DL-lysine, and water complex), (G:DL-
`lysine),
`(Zl:Zoledronic
`acid monohydrate),
`and
`(Z3:Zoledronic acid trihydrate).
`[0037]
`FIG. 22 is an FTIR spectrum of zoledronic, DL-
`lysine, and water complex.
`of:
`PXRD diffractograms
`[0038]
`FIG.
`23
`shows
`(R:Zoledronic, DL-lysine, and water complex), (G:DL-
`lysine),
`(Zl:Zoledronic
`acid monohydrate),
`and
`(Z3:Zoledronic acid trihydrate).
`[0039]
`FIG. 24 is an FTIR spectrum of zoledronic, DL-
`lysine, and water complex.
`of:
`PXRD diffractograms
`[0040]
`FIG.
`25
`shows
`(Q:Zoledronic, L-lysine, and water complex), (E:L-lysine),
`(Zl:Zoledronic acid monohydrate), and (Z3:Zoledronic
`acid trihydrate).
`[0041]
`FIG. 26 is an FTIR spectrum of zoledronic,
`L-lysine, and water complex.
`[0042]
`FIG. 27 shows the 24 hr rat plasma PK profile of
`parent zoledronic acid and zoledronic acid complexes deliv-
`ered Via IV, oral, and intraduodenal (ID) routes.
`[0043]
`FIG. 28 shows the 4 hr rat plasma PK profile of
`parent zoledronic acid and zoledronic acid complexes deliv-
`ered orally.
`[0044]
`FIG. 29 shows the 4 hr rat plasma PK profile of
`parent zoledronic acid and zoledronic acid complexes deliv-
`ered ID.
`
`Page 43
`
`FIG. 30 shows the 24 hr rat plasma PK profile of
`[0045]
`parent zoledronic acid and zoledronic acid complexes deliv-
`ered by oral gavage.
`[0046]
`FIG. 31 shows the 4 hr rat plasma PK profile of
`parent zoledronic acid and zoledronic acid complexes deliv-
`ered orally.
`[0047]
`FIG. 32 shows the 4 hr rat plasma PK profile of
`parent zoledronic acid and selected zoledronic acid com-
`plexes delivered orally.
`[0048]
`FIG. 33 shows the dog serum PK profile of parent
`zoledronic acid and zoledronic acid complexes delivered IV
`and orally.
`[0049]
`FIG. 34 shows the 4 hr dog serum PK profile of
`parent zoledronic acid and zoledronic acid complexes deliv-
`ered IV and orally.
`[0050]
`FIG. 35 shows the dog serum PK profile of parent
`zoledronic acid and zoledronic acid complexes delivered IV
`and orally; enteric and non-enteric coated capsules.
`[0051]
`FIG. 36 shows the 6 hr dog serum PK profile of
`parent zoledronic acid and zoledronic acid complexes deliv-
`ered IV and orally; enteric and non-enteric coated capsules.
`[0052]
`FIG. 37 shows the dog PK data for the enteric and
`non-enteric coated hard gelatin capsules.
`[0053]
`FIG. 38 shows the 24 hr dog serum PK profile of
`zoledronic acid complexes delivered IV and orally.
`[0054]
`FIG. 39 shows the 4 hr dog serum PK profile of
`zoledronic acid complexes delivered IV and orally.
`
`DETAILED DESCRIPTION OF THE PREFERRED
`EMBODIMENTS
`
`ingredients
`active pharmaceutical
`In general,
`[0055]
`(API s) in the pharmaceutical compositions can be prepared in
`a variety of different forms including prodrugs, amorphous
`forms, solvates, hydrates, cocrystals, salts and polymorphs.
`The discovery of novel API forms may provide an opportu-
`nity to improve the performance characteristics of a pharma-
`ceutical product. Additionally, discovery of drug forms
`expands the array of resources available for designing phar-
`maceutical dosage forms with targeted release profiles or
`other desired characteristics.
`
`[0056] A specific characteristic that can be targeted
`includes the crystal form of an API. The alteration of the
`crystal form of a givenAPI would result in the modification of
`the physical properties of the target molecule. For example,
`various polymorphs of a given API exhibit different aqueous
`solubility, while the thermodynamically stable polymorph
`would exhibit a lower solubility than the meta-stable poly-
`morph. In addition, pharmaceutical polymorphs can also dif-
`fer in properties such as rate of dissolution, shelf life, bio-
`availability, morphology, vapor pressure, density, color, and
`compressibility. Accordingly, it is desirable to enhance the
`properties of anAPI by forming molecular complexes such as
`a cocrystal, a salt, a solvate or hydrate with respect to aqueous
`solubility, rate of dissolution, bioavailability, Cmax, Tmax,
`physicochemical stability, down-stream processibility (e.g.
`flowability compressibility, degree ofbrittleness, particle size
`manipulation), decrease in polymorphic form diversity, tox-
`icity, taste, production costs, and manufacturing methods.
`[0057]
`In the development of orally delivered drugs, it is
`often advantageous to have novel crystal forms of such drugs
`that possess improved properties, including increased aque-
`ous solubility and stability. In many cases, the dissolution rate
`increase of drugs is desired as it would potentially increase
`their bioavailability. This also applies to the development of
`
`Page 43
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`

`

`US 2011/0028435 A1
`
`Feb. 3, 2011
`
`novel forms of zoledronic acid which, when administered
`orally to a subject could achieve a greater or similar bioavail-
`ability and PK profile when compared to an IV or other
`formulations on a dose-for-dose basis.
`
`diffraction pattern having strong peaks at about 8.1, 13.3,
`21.5, 24.6, and 25.6102 degrees two-theta.
`[0063] The present invention provides a new crystal form of
`zoledronic acid in the form of ammonium zoledronic salt and
`
`hydrates of
`and
`solvates
`salts,
`[0058] Cocrystals,
`zoledronic acid of the present invention could give rise to
`improved properties of zoledronic acid. For example, a new
`form of zoledronic acid is particularly advantageous if it can
`improve the bioavailability of orally delivered zoledronic
`acid. A number of novel zoledronic acid forms have been
`
`synthesized, characterized, and disclosed herein. Of particu-
`lar interest are the zoledronic acid and the standard amino
`
`acids since they have indicated enhanced permeability com-
`pared with other molecular complexes ofzoledronic acid. The
`mechanism of enhanced permeability of these complexes is
`not yet understood and, while not to be bound by this expla-
`nation, it is possible that they moderate the formation of the
`insoluble Ca2+ zoledronate salt resulting in more zoledronic
`acid to be absorbed paracellularly through the tight junctions.
`It must be stressed that this is a possible mechanism of
`enhanced permeability.
`[0059]
`Schematic diagrams for zoledronic acid:amino acid
`complexes
`(a
`zoledronic
`acid:lysine
`complex and a
`zoledronic acid:glycine complex, two embodiments of the
`invention) are shown below. The diagrams show a molecular
`structure of the complex and possible interactions between
`the constituents of the complex which is different from the
`physical mix of the constituents.
`[0060]
`1. Zoledronic acid: lysine complex
`
`
`
`[0061]
`
`2. Zoledronic acid: glycine complex
`
`
`
`These represent one ofthe arrangements that molecules ofthe
`drug and the standard amino acids coformers could interact to
`form a stable complex that even when stressed thermally at
`elevated relative humidity (RH) environment have not dis-
`played any signs of deterioration or disintegration to its origi-
`nal constituents. Such stability can be attributed to the hydro-
`gen bonding (dashed line in the box) in these molecular
`complexes. When packing in a crystal structure these com-
`plexes have very different morphologies to that of its con-
`stituents or their physical mix as indicated by their powder
`X-ray diffraction (PXRD) patterns and therefore would pos-
`sess different, unpredictable physicochemical properties.
`[0062] The present invention provides a new crystal form of
`zoledronic acid in the form ofzoledronic acid, sodium zoledr-
`onate and water complex, characterized by an X-ray powder
`
`Page 44
`
`water complex, characterized by an X-ray powder diffraction
`pattern having strong peaks at about 11.0, 14.6, 15.4, 19.9,
`and 29410.2 degrees two-theta.
`[0064] The present invention provides a new crystal form of
`zoledronic acid in the form of zoledronic, L-lysine, and water
`complex, characterized by an X-ray powder diffraction pat-
`tern having strong peaks at about 9.0, 14.4, 18.1, 26.0, and
`29610.2 degrees two-theta.
`[0065] The presen