WO2011014781A1 - Novel oral forms of a phosphonic acid derivative - Google Patents
Novel oral forms of a phosphonic acid derivative Download PDFInfo
- Publication number
- WO2011014781A1 WO2011014781A1 PCT/US2010/043916 US2010043916W WO2011014781A1 WO 2011014781 A1 WO2011014781 A1 WO 2011014781A1 US 2010043916 W US2010043916 W US 2010043916W WO 2011014781 A1 WO2011014781 A1 WO 2011014781A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- zoledronic acid
- acid
- asparagine
- histidine
- complex
- Prior art date
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- 150000003007 phosphonic acid derivatives Chemical class 0.000 title description 2
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 claims abstract description 88
- 229960004276 zoledronic acid Drugs 0.000 claims abstract description 74
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 claims abstract description 31
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical class OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims abstract description 30
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical class OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 claims abstract description 29
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Chemical class OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims abstract description 29
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical class OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims abstract description 28
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Chemical class OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims abstract description 27
- 229960001230 asparagine Drugs 0.000 claims abstract description 18
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Chemical class OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 13
- 235000009582 asparagine Nutrition 0.000 claims abstract description 8
- 239000004475 Arginine Chemical class 0.000 claims abstract description 5
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical class NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims abstract description 5
- 229960002429 proline Drugs 0.000 claims description 26
- 229940024606 amino acid Drugs 0.000 claims description 18
- 235000001014 amino acid Nutrition 0.000 claims description 18
- 150000001413 amino acids Chemical group 0.000 claims description 18
- 229960002885 histidine Drugs 0.000 claims description 18
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 229940110377 dl- arginine Drugs 0.000 claims description 12
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims description 11
- 229930064664 L-arginine Natural products 0.000 claims description 11
- 235000014852 L-arginine Nutrition 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 229930182821 L-proline Natural products 0.000 claims description 9
- 229940122361 Bisphosphonate Drugs 0.000 claims description 8
- 150000004663 bisphosphonates Chemical class 0.000 claims description 8
- 229930024421 Adenine Natural products 0.000 claims description 7
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims description 7
- 239000004471 Glycine Substances 0.000 claims description 7
- 229960000643 adenine Drugs 0.000 claims description 7
- 229960002449 glycine Drugs 0.000 claims description 7
- 206010028980 Neoplasm Diseases 0.000 claims description 6
- 208000001132 Osteoporosis Diseases 0.000 claims description 6
- 239000006186 oral dosage form Substances 0.000 claims description 5
- 208000037147 Hypercalcaemia Diseases 0.000 claims description 4
- 208000010191 Osteitis Deformans Diseases 0.000 claims description 4
- 208000027868 Paget disease Diseases 0.000 claims description 4
- 239000003125 aqueous solvent Substances 0.000 claims description 4
- 229960003121 arginine Drugs 0.000 claims description 4
- 235000009697 arginine Nutrition 0.000 claims description 4
- 235000014304 histidine Nutrition 0.000 claims description 4
- 230000000148 hypercalcaemia Effects 0.000 claims description 4
- 208000030915 hypercalcemia disease Diseases 0.000 claims description 4
- 208000027202 mammary Paget disease Diseases 0.000 claims description 4
- 235000013930 proline Nutrition 0.000 claims description 4
- 230000006806 disease prevention Effects 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000011275 oncology therapy Methods 0.000 claims description 2
- 239000000243 solution Substances 0.000 abstract description 24
- 230000003287 optical effect Effects 0.000 abstract description 5
- 239000007864 aqueous solution Substances 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 description 14
- 239000003814 drug Substances 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 7
- 239000008186 active pharmaceutical agent Substances 0.000 description 6
- 230000035699 permeability Effects 0.000 description 6
- 238000009472 formulation Methods 0.000 description 5
- 238000011161 development Methods 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 238000001802 infusion Methods 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 description 3
- -1 two Ca2+ salts Chemical class 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N lysine Chemical compound NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 150000004684 trihydrates Chemical class 0.000 description 2
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- DCXYFEDJOCDNAF-UWTATZPHSA-N D-Asparagine Chemical class OC(=O)[C@H](N)CC(N)=O DCXYFEDJOCDNAF-UWTATZPHSA-N 0.000 description 1
- ONIBWKKTOPOVIA-SCSAIBSYSA-N D-Proline Chemical class OC(=O)[C@H]1CCCN1 ONIBWKKTOPOVIA-SCSAIBSYSA-N 0.000 description 1
- 229930028154 D-arginine Chemical class 0.000 description 1
- ODKSFYDXXFIFQN-SCSAIBSYSA-N D-arginine Chemical class OC(=O)[C@H](N)CCCNC(N)=N ODKSFYDXXFIFQN-SCSAIBSYSA-N 0.000 description 1
- 229930182846 D-asparagine Chemical class 0.000 description 1
- 229930195721 D-histidine Chemical class 0.000 description 1
- HNDVDQJCIGZPNO-RXMQYKEDSA-N D-histidine Chemical class OC(=O)[C@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-RXMQYKEDSA-N 0.000 description 1
- 229930182820 D-proline Chemical class 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 206010070840 Gastrointestinal tract irritation Diseases 0.000 description 1
- MPBVHIBUJCELCL-UHFFFAOYSA-N Ibandronate Chemical compound CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O MPBVHIBUJCELCL-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical class [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- DKJJVAGXPKPDRL-UHFFFAOYSA-N Tiludronic acid Chemical compound OP(O)(=O)C(P(O)(O)=O)SC1=CC=C(Cl)C=C1 DKJJVAGXPKPDRL-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229960004343 alendronic acid Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 229960002286 clodronic acid Drugs 0.000 description 1
- ACSIXWWBWUQEHA-UHFFFAOYSA-N clodronic acid Chemical compound OP(O)(=O)C(Cl)(Cl)P(O)(O)=O ACSIXWWBWUQEHA-UHFFFAOYSA-N 0.000 description 1
- 238000002288 cocrystallisation Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 229960005236 ibandronic acid Drugs 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 150000004667 medium chain fatty acids Chemical class 0.000 description 1
- 150000004682 monohydrates Chemical group 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- WRUUGTRCQOWXEG-UHFFFAOYSA-N pamidronate Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 description 1
- 229960003978 pamidronic acid Drugs 0.000 description 1
- 239000006201 parenteral dosage form Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229940107023 reclast Drugs 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- WPLOVIFNBMNBPD-ATHMIXSHSA-N subtilin Chemical class CC1SCC(NC2=O)C(=O)NC(CC(N)=O)C(=O)NC(C(=O)NC(CCCCN)C(=O)NC(C(C)CC)C(=O)NC(=C)C(=O)NC(CCCCN)C(O)=O)CSC(C)C2NC(=O)C(CC(C)C)NC(=O)C1NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C1NC(=O)C(=C/C)/NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C2NC(=O)CNC(=O)C3CCCN3C(=O)C(NC(=O)C3NC(=O)C(CC(C)C)NC(=O)C(=C)NC(=O)C(CCC(O)=O)NC(=O)C(NC(=O)C(CCCCN)NC(=O)C(N)CC=4C5=CC=CC=C5NC=4)CSC3)C(C)SC2)C(C)C)C(C)SC1)CC1=CC=CC=C1 WPLOVIFNBMNBPD-ATHMIXSHSA-N 0.000 description 1
- 229960005324 tiludronic acid Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 229940002005 zometa Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/401—Proline; Derivatives thereof, e.g. captopril
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4172—Imidazole-alkanecarboxylic acids, e.g. histidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6503—Five-membered rings
- C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
Definitions
- This disclosure pertains to new molecular complexes of zoledronic acid suitable for drug delivery as well as methods for their preparation and pharmaceutical compositions.
- Zoledronic acid is known as (l-hydroxy-2-imidazol-l-yl-l-phosphono-ethyl)phosphonic acid.
- Zoledronic acid is depicted by the following chemical structure:
- 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 or tumor induced hypercalcemia (TIH). It was originally developed by Novartis and marketed in a monohydrate form under the Zometa® and Reclast® brand names. Zoledronic acid was first approved in 2000 for the treatment of TIH in Canada. It was later approved for use in the US in 2001 for indications of TIH and in 2007 for osteoporosis and Paget' s disease.
- Zoledronic acid is administered as an intravenous (IV) dose of 4 mg over 15 minutes for TlH and 5 mg over 15 minutes for osteoporosis. [0041 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 many organic solvents.
- Zoledronate metal salts including Na + , Mg 2+ , Zn 2+ were reported in the monthly issued journal Drugs of the Future (Sorbera et al, 25(3), Drugs of the Future, (2000)).
- Zoledronate, zoledronic, or zoledronic salt represents the ionic form of zoledronic acid.
- a recently filed patent application (WO2008/064849 Al) from Novartis disclosed additional metal salts including two Ca 2+ salts, two Zn 2+ salts, one Mg 2+ salt, as well as a mono and trihydrate, an amorphous form, and an anhydrous form.
- the present disclosure is directed towards generating new molecular complexes of zoledronic acid that have the therapeutic efficacy of zoledronic acid but also improved aqueous solubility, rate of dissolution, and improved bioavailability.
- One aspect of the present disclosure relates to novel molecular complexes of zoledronic acid.
- the disclosure further includes methods for the preparation of such complexes.
- the disclosure further includes compositions of molecular complexes of zoledronic acid suitable for incorporation in a pharmaceutical dosage form.
- Specific molecular complexes pertaining to the disclosure include, but are not limited to, complexes of zoledronic acid with nicotinamide, adenine, glycine, and optical isomers of asparagine, histidine, argenine, and proline; D or L-asparagine, DL- asparagine, D or L-histidine, DL-histidine, D or L-arginine, DL-arginine, D or L-proline and DL- proline.
- Variants of the disclosed zoledronic acid forms in the text, including those described by the 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 invention.
- the active pharmaceutical ingredient (API) in pharmaceutical compositions can be prepared in a variety of different forms. Such compounds can be prepared so as to have a variety of different chemical forms including chemical derivatives, solvates, hydrates, cocrystal salts, etc.
- the API can also have different physical forms. For example, they may be amorphous or they may have different crystalline polymorphs or may exist in different solvated or hydrated states.
- the discovery of new forms of an API may provide the opportunity to improve the pharmacokinetic performance of a pharmaceutical product.
- pharmaceutical cocrystallization can expand the array of resources available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired
- the physical form of the API has been shown to have a substantial impact upon its physicochemical properties.
- crystalline polymorphs typically have different aqueous solubility from one another, such that a more thermodynamically stable polymorph is less soluble than a less thermodynamically stable polymorph.
- pharmaceutical polymorphs can also differ in properties such as rate of dissolution, shelf-life, bioavailability, morphology, vapor pressure, density, color, and compressibility. Accordingly, it is desirable to enhance the properties of an API by forming molecular complexes with respect to aqueous solubility, rate of dissolution, bioavailability, Cmax, Tmax, physicochemical stability, down-stream processibility (e.g. flowability compressibility, degree of brittleness, particle size manipulation), crystallization of amorphous compounds, decrease in polymorphic form diversity, toxicity, taste, production costs, and manufacturing methods.
- Novel solution complexes of zoledronic acid in the present invention could give rise to improved properties of zoledronic acid.
- a new form of zoledronic acid is particularly advantageous if it can improve the aqueous solubility and subsequent bioavailability of orally delivered zoledronic acid.
- a number of novel zoledronic acid forms have been synthesized, characterized, and disclosed herein.
- aqueous solubility of zoledronic acid is low but has been dramatically increased in this invention up to greater than 350mg/ml through creating new molecular complexes with cocrystal formers including such as nicotinamide, amino acids, and in particular with adenine, glycine, L-asparagine, DL-asparagine, L-histidine, DL- histidine, L-arginine, DL-arginine, L-proline, DL-proline.
- cocrystal formers including such as nicotinamide, amino acids, and in particular with adenine, glycine, L-asparagine, DL-asparagine, L-histidine, DL- histidine, L-arginine, DL-arginine, L-proline, DL-proline.
- a first aspect of the present invention includes aqueous solution complexes of zoledronic acid with amino acids, including but not limited to adenine, glycine, and optical isomers of asparagine, histidine, argenine and proline.
- Preferred amino acids include but are not limited to nicotinamide, adenine, glycine, L-asparagine, DL-asparagine, L-histidine, DL- histidine, L-arginine, DL-arginine, L-proline, and DL-proline suitable for coformulation in an oral dosage form, as a solution, suspension, or a solution in capsules ether incorporated in a gel structure or polymer matrix.
- These pharmaceutical formulations contain a therapeutically effective amount of at least one solution complex of zoledronic acid according to the invention and at least one pharmaceutically acceptable carrier, (also known in the art as a pharmaceutically acceptable excipient).
- the novel molecular complexes of zoledronic acid are therapeutically useful for the treatment and/or prevention of disease states associated with osteoporosis, tumor induced hypercalcemia (TIH), or Paget's disease as discussed above.
- the invention also relates to methods of treatment using novel molecular complexes of zoledronic acid of the invention or a pharmaceutical formulation containing them.
- the pharmaceutical formulations generally contain about 1% to about 99% by weight of at least one novel molecular complex of zoledronic acid of the invention and 99% to 1% by weight of a suitable pharmaceutical excipient.
- Another aspect of the invention includes improving the aqueous solubility of zoledronic acid to greater than 350mg/ml, through creating new molecular complexes with L- and DL- histidine.
- Another aspect of the invention includes improving the aqueous solubility of zoledronic acid to greater than 235mg/ml, through creating new molecular complexes with L- and DL- arginine.
- Another aspect of the invention includes improving the aqueous solubility of zoledronic acid to greater than 50mg/ml, through creating new molecular complexes with L- and DL- asparagine.
- solution complexes of zoledronic acid with amino acids Another aspect of the invention where the solution complexes of zoledronic acid with amino acids.
- Solution complexes of zoledronic acid and optical isomers of asparagine, histidine, arginine and proline; L-asparagine, DL-asparagine, L-histidine, DL-histidine, L-arginine, DL- arginine, L-proline, and DL-proline were physically stable and did not form any suspension or create precipitates when examined by the naked eye after being left standing at room temperature on the bench in screw cap vials for one year.
- Another aspect of the invention provides complexes of zoledronic acid and optical isomers of asparagine, histidine, arginine and proline; L-asparagine, DL-asparagine, L-lysine,
- Another aspect of the invention provides a method for increasing the aqueous solubility of a bisphosphonic acid or bisphosphonates by dissolving a bisphosphonic acid or
- the bisphosphonic acid may be, for example, zoledronic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, residronic acid ibandronic acid or other bisphosphonic acids known in the art.
- Example 1 Preparation of a solution of zoledronic acid :L-histidine.
- Example 2 Preparation of a solution of zoledronic:DL-histidine complex.
- Example 3 Preparation of a solution of zoledronic :L-arginine complex.
- Example 4 Preparation of a solution of zoledronic:DL-arginine complex.
- Example 5 Preparation of a solution of zoledronic:L-asparagine complex.
- Example 6 Preparation of a solution of zoledronic :DL-asparagine complex.
- Example 8 Preparation of a solution of zoledronic:DL-proline complex.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Physical Education & Sports Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Engineering & Computer Science (AREA)
- Rheumatology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
Novel solution complexes of zoledronic acid are described which give rise to improved properties of zoledronic acid. The invention includes aqueous solution and molecular complexes of zoledronic acid with and optical isomers of asparagine, histidine, arginine and proline as well as pharmaceutical complexes containing them and methods of treatment using them.
Description
NOVEL ORAL FORMS OF A PHOSPHONIC ACID DERIVATIVE
CROSS REFERENCE TO RELATED APPLICATION
[001] This application claims priority to U.S. application 61/230,234, filed July 31, 2009, which is incorporated herein by reference.
FIELD OF THE INVENTION
[002| This disclosure pertains to new molecular complexes of zoledronic acid suitable for drug delivery as well as methods for their preparation and pharmaceutical compositions.
BACKGROUND OF THE INVENTION
[003] Zoledronic acid is known as (l-hydroxy-2-imidazol-l-yl-l-phosphono-ethyl)phosphonic acid. Zoledronic acid is depicted by the following chemical structure:
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 or tumor induced hypercalcemia (TIH). It was originally developed by Novartis and marketed in a monohydrate form under the Zometa® and Reclast® brand names. Zoledronic acid was first approved in 2000 for the treatment of TIH in Canada. It was later approved for use in the US in 2001 for indications of TIH and in 2007 for osteoporosis and Paget' s disease. 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): 1099-1 105, 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 intravenous (IV) dose of 4 mg over 15 minutes for TlH and 5 mg over 15 minutes for osteoporosis.
[0041 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 many organic solvents.
[005] Various efforts have been taken to generate novel oral formulations of zoledronic acid through crystallization and metal salt formation to improve its aqueous solubility, permeability, and subsequent oral bioavailability. A crystalline trihydrate was disclosed in U.S. Patent application 2006/0178439 Al and world patent application WO2007/032808. Seven hydrated forms, an amorphous form, three monosodium salts, and eleven disodium salts with varying degrees of hydration of zoledronic acid were also disclosed in the world patent application WO2005/005447 A2. Zoledronate metal salts including Na+, Mg2+, Zn2+ were reported in the monthly issued journal Drugs of the Future (Sorbera et al, 25(3), Drugs of the Future, (2000)). Zoledronate, zoledronic, or zoledronic salt represents the ionic form of zoledronic acid. A recently filed patent application (WO2008/064849 Al) from Novartis disclosed additional metal salts including two Ca2+ salts, two Zn2+ salts, one Mg2+ salt, as well as a mono and trihydrate, an amorphous form, and an anhydrous form.
[006] The low oral bioavailability of zoledronic acid, which is <1% of the oral dose, can be attributed to poor permeability in the gastrointestinal (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 GI irritation both in the stomach and in the intestines. In some cases the irritation was so severe that medical treatment was required. Recent activity concerning the development of oral formulations has led to the use of medium chain fatty acids to enhance the drug's low permeability as disclosed in the US 2007/0134319 Al and US 2007/0196464 patent applications. Modified amino acid carriers, but not pure proteinogenic amino acids, have also been employed to improve the absorption of the drug as shown in the WO 2007/093226 Al application.
[007] In general, sparingly water soluble, provides substantial challenges for drug development of parenteral formulations due to the amount of solvent needed to dissolve the drug which could render it more suitable for infusion. Typically, the greater the volume needed to be administered parenterally to a patient, the longer the infusion time, the higher the likelihood of a vehicle- related adverse effect, the more expensive the product, and the less likelihood that the formulation will be found acceptable by the patient. By improving the aqueous solubility of the
drug the volume of solvent needed for reconstitution can therefore be dramatically reduced rendering it suitable for injection rather than infusion.
[008] Due to the fact that zoledronic acid is only available as a parenteral dosage form (infusion over at least 15 minutes) there is a clear need to develop novel forms of zoledronic acid that can be included in an oral dosage form particularly as the use of orally administered drugs are becoming more wide spread in many therapeutic areas including the treatment of cancer. The upward trend in the use of oral drugs will continue especially in light of the goal to decrease the overall cost of healthcare. Thus, there is an opportunity to create oral dosage forms of IV drugs only 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. In addition, opportunity is also provided to improve the solubility of sparingly water soluble drugs by creating molecular complexes of such drugs with standard (proteinogenic) amino acids that can subsequently be incorporated in dosage forms for a variety of drug delivery systems.
[009] The development of oral fonns of zoledronic acid to enhance the aqueous solubility or permeability has thus far been problematic. However, by using the novel approach of generating molecular complexes of zoledronic acid with standard amino acids there is an opportunity provided to improve the solubility and/or permeability resulting in a new dosage form suitable administration to humans.
SUMMARY OF THE INVENTION
[010] The present disclosure is directed towards generating new molecular complexes of zoledronic acid that have the therapeutic efficacy of zoledronic acid but also improved aqueous solubility, rate of dissolution, and improved bioavailability. One aspect of the present disclosure relates to novel molecular complexes of zoledronic acid. In addition, the disclosure further includes methods for the preparation of such complexes. The disclosure further includes compositions of molecular complexes of zoledronic acid suitable for incorporation in a pharmaceutical dosage form. Specific molecular complexes pertaining to the disclosure include, but are not limited to, complexes of zoledronic acid with nicotinamide, adenine, glycine, and optical isomers of asparagine, histidine, argenine, and proline; D or L-asparagine, DL- asparagine, D or L-histidine, DL-histidine, D or L-arginine, DL-arginine, D or L-proline and DL- proline. Variants of the disclosed zoledronic acid forms in the text, including those described by
the 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 invention.
[Oil] The foregoing and other features and advantages of the disclosed technology will become more apparent from the following detailed description. Such description is meant to be illustrative, and not limiting, of the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0121 In general, the active pharmaceutical ingredient (API) in pharmaceutical compositions can be prepared in a variety of different forms. Such compounds can be prepared so as to have a variety of different chemical forms including chemical derivatives, solvates, hydrates, cocrystal salts, etc. The API can also have different physical forms. For example, they may be amorphous or they may have different crystalline polymorphs or may exist in different solvated or hydrated states. The discovery of new forms of an API may provide the opportunity to improve the pharmacokinetic performance of a pharmaceutical product. Additionally, pharmaceutical cocrystallization can expand the array of resources available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired
characteristics.
[013] The physical form of the API has been shown to have a substantial impact upon its physicochemical properties. For example, crystalline polymorphs typically have different aqueous solubility from one another, such that a more thermodynamically stable polymorph is less soluble than a less thermodynamically stable polymorph. In addition to water solubility, pharmaceutical polymorphs can also differ in properties such as rate of dissolution, shelf-life, bioavailability, morphology, vapor pressure, density, color, and compressibility. Accordingly, it is desirable to enhance the properties of an API by forming molecular complexes with respect to aqueous solubility, rate of dissolution, bioavailability, Cmax, Tmax, physicochemical stability, down-stream processibility (e.g. flowability compressibility, degree of brittleness, particle size manipulation), crystallization of amorphous compounds, decrease in polymorphic form diversity, toxicity, taste, production costs, and manufacturing methods.
[014] During the development of drugs for oral delivery, it is frequently advantageous to have novel forms of such drug materials that possess improved properties, including increased aqueous solubility and stability. It is also desirable in general to increase the dissolution rate of
such solid forms, and potentially increase their bioavailability. This also applies to the development of novel forms of zoledronic acid which, when administered orally to a subject could achieve greater or similar bioavailabilities and pharmacokinetic (PK) profiles when compared to an IV or other formulations on a dose-for-dose basis.
[015] Novel solution complexes of zoledronic acid in 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 aqueous solubility and subsequent bioavailability of orally delivered zoledronic acid. A number of novel zoledronic acid forms have been synthesized, characterized, and disclosed herein. The aqueous solubility of zoledronic acid is low but has been dramatically increased in this invention up to greater than 350mg/ml through creating new molecular complexes with cocrystal formers including such as nicotinamide, amino acids, and in particular with adenine, glycine, L-asparagine, DL-asparagine, L-histidine, DL- histidine, L-arginine, DL-arginine, L-proline, DL-proline. The techniques and approaches set forth in the present disclosure can further be used by the person of ordinary skill in the art to prepare obvious variants thereof, said variants are considered to be part of the inventive disclosure.
[016] Accordingly, a first aspect of the present invention includes aqueous solution complexes of zoledronic acid with amino acids, including but not limited to adenine, glycine, and optical isomers of asparagine, histidine, argenine and proline. Preferred amino acids include but are not limited to nicotinamide, adenine, glycine, L-asparagine, DL-asparagine, L-histidine, DL- histidine, L-arginine, DL-arginine, L-proline, and DL-proline suitable for coformulation in an oral dosage form, as a solution, suspension, or a solution in capsules ether incorporated in a gel structure or polymer matrix. These pharmaceutical formulations contain a therapeutically effective amount of at least one solution complex of zoledronic acid according to the invention and at least one pharmaceutically acceptable carrier, (also known in the art as a pharmaceutically acceptable excipient). The novel molecular complexes of zoledronic acid are therapeutically useful for the treatment and/or prevention of disease states associated with osteoporosis, tumor induced hypercalcemia (TIH), or Paget's disease as discussed above. Accordingly, the invention also relates to methods of treatment using novel molecular complexes of zoledronic acid of the invention or a pharmaceutical formulation containing them. The pharmaceutical formulations
generally contain about 1% to about 99% by weight of at least one novel molecular complex of zoledronic acid of the invention and 99% to 1% by weight of a suitable pharmaceutical excipient.
[017] Another aspect of the invention includes improving the aqueous solubility of zoledronic acid to greater than 350mg/ml, through creating new molecular complexes with L- and DL- histidine.
[018] Another aspect of the invention includes improving the aqueous solubility of zoledronic acid to greater than 235mg/ml, through creating new molecular complexes with L- and DL- arginine.
[019] Another aspect of the invention includes improving the aqueous solubility of zoledronic acid to greater than 50mg/ml, through creating new molecular complexes with L- and DL- asparagine.
[020] Another aspect of the invention where the solution complexes of zoledronic acid with amino acids. Solution complexes of zoledronic acid and optical isomers of asparagine, histidine, arginine and proline; L-asparagine, DL-asparagine, L-histidine, DL-histidine, L-arginine, DL- arginine, L-proline, and DL-proline were physically stable and did not form any suspension or create precipitates when examined by the naked eye after being left standing at room temperature on the bench in screw cap vials for one year.
[021] Another aspect of the invention provides complexes of zoledronic acid and optical isomers of asparagine, histidine, arginine and proline; L-asparagine, DL-asparagine, L-lysine,
DL-lysine, nicotinamide, adenine, glycine, L-histidine, DL-histidine, L-arginine, DL-arginine, L- proline, and DL-proline suitable for a pharmaceutical formulation than can be delivered parenterally to the human body.
[022] Another aspect of the invention provides a method for increasing the aqueous solubility of a bisphosphonic acid or bisphosphonates by dissolving a bisphosphonic acid or
bisphosphonate in an aqueous solvent in the presence of an amino acid such as those discussed above. The bisphosphonic acid may be, for example, zoledronic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, residronic acid ibandronic acid or other bisphosphonic acids known in the art.
EXAMPLES
[023] The following examples illustrate the invention without intending to limit the scope of the invention.
[024] Zoledronic acid as a starting material used in all experiments in this disclosure was supplied by Farmkemi Limited (Wuhan Pharma Chemical Co.), China with purity of ca. 90% and was purified further via recrystallization from hot water. All other pure chemicals
(Analytical Grade) were supplied by Sigma-Aldrich and used without further purification.
[025] Example 1: Preparation of a solution of zoledronic acid :L-histidine.
[026] 17.8 mg of zoledronic acid and 9.5 mg of L-histidine were mixture and dissolved in 0.05 ml water. The solution containing the complex was stored in a screw cap vial.
[027] Example 2: Preparation of a solution of zoledronic:DL-histidine complex.
[028] 17.8 mg of zoledronic acid and 9.5 mg of DL-histidine were mixed and dissolved in 0.05 ml water. The solution containing the complex was stored in a screw cap vial for subsequent analysis and use.
[029] Example 3: Preparation of a solution of zoledronic :L-arginine complex.
[030] 35.6 mg of zoledronic acid and 21.4 mg of L-arginine were mixed and dissolved in 0.15 ml water. The solution containing the complex was stored in a screw cap vial for subsequent analysis and use.
[031] Example 4: Preparation of a solution of zoledronic:DL-arginine complex.
[032] 35.6 mg of zoledronic acid and 21.4 mg of DL-arginine were mixed and dissolved in 0.15 ml water. The solution containing the complex was stored in a screw cap vial for subsequent analysis and use.
[033] Example 5: Preparation of a solution of zoledronic:L-asparagine complex.
[034] 50 mg of zoledronic acid and 23 mg of L-asparagine were dissolved in 1 ml water. The solution containing the complex was stored in a screw cap vial for subsequent analysis and use.
[035] Example 6: Preparation of a solution of zoledronic :DL-asparagine complex.
[036] 50 mg of zoledronic acid and 26 mg of DL-asparagine monohydrate were dissolved in 1 ml water. The solution containing the complex was stored in a screw cap vial for subsequent analysis and use.
[037| Example 7: Preparation of a solution of zoledronic:L-proline complex.
[038] Approximately 11 mg of zoledronic acid and approximately 9 mg of L-proline were mixed and dissolved in 1 ml water. The solution containing the complex was stored in a screw cap vial for subsequent analysis and use.
[039] Example 8: Preparation of a solution of zoledronic:DL-proline complex.
[040] Approximately 11 mg of zoledronic acid and approximately 9 mg of DL-proline were mixed and dissolved in 1 ml water. The solution containing the complex was stored in a screw cap vial for subsequent analysis and use.
Claims
1. A solution complex of a bisphosphonic acid or bisphosphonate comprising a
bisphosphonic acid or bisphosphonate with a coformer to improve the aqueous solubility of the bisphosphonic acid or bisphosphonate.
2. A solution complex of claim 1 where the bisphosphonic acid is zoledronic acid.
3. A solution complex of claim 1 wherein the coformer is an amino acid.
4. A solution complex of claim 2 wherein the coformer is an amino acid is selected from the group consisting of glycine, adenine, asparagine, histidine, argϊnine and proline.
5. A solution complex of claim 3, wherein the amino acid is selected from the group consisting of L-asparagine, DL-asparagine, L-histidine, DL-histidine, L-arginine, DL-arginine, L-proline, and DL-proline.
6. A solution complex of claim 4, wherein the complex is:
a solution complex of zoledronic acid and L-histidine having an aqueous solubility of zoledronic acid to greater than 350 mg/ml,
a solution complex of zoledronic acid and DL-histidine having an aqueous solubility of zoledronic acid to greater than 350 mg/ml,
a solution complex of zoledronic acid and L-arginine having an aqueous solubility of zoledronic acid to greater than 235 mg/ml,
a solution complex of zoledronic acid and DL-arginine having an aqueous solubility of zoledronic acid to greater than 235 mg/ml,
a solution complex of zoledronic acid and L-asparagine having an aqueous solubility of zoledronic acid to greater than 50 mg/ml, or
a solution complex of zoledronic acid and DL-asparagine having an aqueous solubility of zoledronic acid to greater than 50 mg/ml.
7. A molecular complex of zoledronic acid comprising zoledronic acid and an amino acid selected from the group consisting of asparagine, histidine, arginine and proline.
7. A molecular complex of claim 6, wherein the amino acid is selected from the group consisting of L-asparagine, DL-asparagine, L-histidine, DL-histidine, L-arginine, DL-arginine, L-proline, and DL-proline.
8. A pharmaceutical composition comprising a complex of any one of claims 1-6 and a pharmaceutically acceptable carrier.
9. A pharmaceutical composition of claim 7, wherein the composition is a parenteral composition.
10. A pharmaceutical composition of claim 7, wherein the composition is an oral dosage form.
11. A method for the treatment and/or prevention of disease states associated with osteoporosis, tumor induced hypercalcemia (TIH), or Paget's disease comprising the step of administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition of claim 8.
12. A method for the treatment and/or prevention of disease states associated with osteoporosis, tumor induced hypercalcemia (TIH), or Paget's disease, adjuvant or neoadjuvant cancer therapies comprising the step of administering to a patient in need thereof a
therapeutically effective amount of a complex according to any one of claims 1-6.
13. A method for increasing the aqueous solubility of zoledronic acid comprising the step of: dissolving zoledronic acid in an aqueous solvent in the presence of an amino acid.
14. A method of claim 13, wherein the amino acid is selected from the group consisting of glycine, adenine, asparagine, histidine, arginine and proline.
15. A method of claim 14, wherein the amino acid is selected from the group consisting of L- asparagine, DL-asparagine, L-histidine, DL-histidine, L-arginine, DL-arginine, L-proline, and DL-proline and wherein the amino acid forms a solution complex with the zoledronic acid.
16. A method of claim 13, 14 or 15, wherein the aqueous solvent is water.
17. A method for increasing the aqueous solubility of a bisphosphonic acid or
bisphosphonate comprising the step of:
dissolving a bisphosphonic acid or bisphosphonate in an aqueous solvent in the presence of an amino acid.
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| CY20171100845T CY1119192T1 (en) | 2010-02-06 | 2017-08-07 | CRYSTAL METHOD AND BIO AVAILABILITY |
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Also Published As
| Publication number | Publication date |
|---|---|
| EP3158867B1 (en) | 2018-12-12 |
| US20150306116A1 (en) | 2015-10-29 |
| EP3158867A1 (en) | 2017-04-26 |
| EP2458996A1 (en) | 2012-06-06 |
| US9682091B2 (en) | 2017-06-20 |
| EP2458996B1 (en) | 2016-09-07 |
| EP2458996A4 (en) | 2013-02-13 |
| US20120190647A1 (en) | 2012-07-26 |
| US8980868B2 (en) | 2015-03-17 |
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