(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`11 August 2011 (11.08.2011)
`
`PCT
`
`11111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111
`
`(10) International Publication Number
`WO 2011/097269 A1
`
`(51) International Patent Classification:
`A61K 311675 (2006.01)
`C07F 9/6503 (2006.01)
`
`(21) International Application Number:
`PCT/US20ll/023427
`
`(22) International Filing Date:
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`2 Febmary20ll (02.02.2011)
`
`English
`
`English
`
`(8 l)
`
`Tampa, FL 33637 (US). WEYNA, David, R. [US/US];
`10707 N. Waterhole Place, Tampa, FL 33612 (US).
`HOUCK, Raymond [US/US]; 832 12th Street, Oakmont,
`PA 15139 (US).
`
`(74) Agent: LINDEMAN, Jeffrey, A.; J.a. Lindeman & Co.,
`Pile, 3190 Fairview Park Drive, Suite 480, Falls Chmch,
`VA 22042 (US).
`
`Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`CA,CH,CL,CN,CO,CR,CU,CZ,DE,DK,DM,DO,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
`HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP,
`KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD,
`ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI,
`NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD,
`SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR,
`TT, TZ, VA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG,
`ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ,
`TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
`EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU,
`LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK,
`SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`
`with international search report (Art. 21 (3))
`
`(30) Priority Data:
`6 February 2010 (06.02.2010)
`61/302,110
`II March 2010 (11.03 .20 10)
`61/312,8 79
`29 March 2010 (29.03.2010)
`61/318,503
`61/333,041
`10 May2010 (10.05.2010)
`10 May2010 (10.05.2010)
`61/333,028
`29 June 2010 (29.06.2010)
`61/359,544
`30 July2010 (30.07.2010)
`12/847,568
`PCT/USI0/43892 30 July2010 (30.07.2010)
`PCT/USI0/43916 30 July2010 (30.07.2010)
`61/379,814
`3 September2010 (03.09.2010)
`61/455,778
`26 October 2010 (26.10.2010)
`
`us
`us
`us
`us
`us
`us
`us
`us
`us
`us
`us
`(71) Applicant (for all designated States except US): THAR
`PHARMACEUTICALS, INC. [US/US]; 730 William
`Pitt Way, Pittsburgh, PA 15238 (US).
`
`(72)
`(75)
`
`Inventors; and
`Inventors/Applicants (for US only): HANNA, Mazen
`[GB/US]; 1451 Kensington Woods Drive, Lutz, FL
`33549 (US). SHAN, Ning [SG/US]; 14629 Grenadine
`Drive, Apt. #6, Tampa, FL 33613 (US). CHENEY, Mi(cid:173)
`randa, L. [US/US]; 15210 Amberly Drive, Apt. #631,
`
`--
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`(54) Title: CRYSTALLIZATION METHOD AND BIOAVAILABILITY
`
`(57) Abstract: Preparation and in vitro and in vivo characterization of novel forms of active pharmaceutical ingredients, suitable
`for pharmaceutical compositions in drug delivery systems for humans.
`
`Grün. Exhibit 1079
`Grünenthal v. Antecip
`PGR2017-00022
`
`

`

`wo 2011/097269
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`1
`
`PCT/US2011/023427
`
`CRYSTALLIZATION METHOD AND BIOA V AILABILITY
`
`CROSS REFERERNCE TO RELATED APPLICATIONS
`
`This application claims priority to U.S. Provisional Applications 61/302, II 0, filed 6
`
`February 2010; 611333,041, filed 10 May 2010; 61/333,028, filed 10 May 2010; 61/379,814,
`
`filed 3 September 2010; 61/455,778, filed 26 October 2010; 611312,879, filed II March 2010;
`
`61/318,503 filed 29 March 20 I 0; and 61/359,544 filed 29 June 20 I 0; to U.S. Non-Provisional
`
`Application 12/84 7 ,568, filed 30 July 20 I 0; and to PCT applications PCT IUS I 0/43916, filed
`
`30 July 2010 and PCT/US2010/043892, filed 30 July 2010; with each of above applications
`
`incorporated by reference in its entirety.
`
`FIELD OF THE INVENTION
`
`This disclosure pertains to improvement of the aqueous solubility and permeability of
`
`poorly permeable and sparingly water soluble drug compounds through generating novel
`
`crystalline fonns of such drugs. The novel forms include but are not limited to cocrystals,
`
`salts, hydrates, solvates, 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 fonns are disclosed.
`
`BACKGROUND OF THE INVENTION
`
`Many Biopharmaceutics Classification System (BCS) class III or IV drugs suffer from
`
`the lack of gastrointestinal (GI) tract membrane permeability leading to poor oral
`
`bioavailability. Different strategies have been implemented to improve the permeability and
`
`subsequently the oral bioavailability of such drugs. For example, the U.S. patent application
`
`I
`
`200600680 I 0 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 A I disclosed
`
`an increase in the oral bioavailability of poorly pem1eable bisphosphonate drugs; risedronate,
`
`an exemplary bisphosphonate, was mixed with a chelating agent such as
`
`ethylenediaminetetraacetic acid (EDT A) and other excipients to make an oral dosage form
`
`with enhanced bioavailability. In another application, WO 2007093226 describes a method
`
`for improving the bioavailability of ibandronate by generating a physical mixture of the drug
`
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`wo 2011/097269
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`PCT/US2011/023427
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`together with a modified amino acid (acylation or sulphonation of the amino group with
`
`phenyl or cyclohexyl) and other excipients. Another application, WO 2003007916 A I, reports
`
`a gastric retention system to improve the bioavailability 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 discloses yet another method to improve
`
`the permeability and bioavailability of alendronate by mixing it with a biocompatible cationic
`
`polymer (i.e. water soluble chitosan) with up to a I 0:1 weight ratio of the chitosan to the drug,
`
`while the resulting mixture can be formulated into a solid or liquid oral dosage fonn. An
`
`additional method of improving permeability of drug materials was discussed in the U.S.
`
`patent application 2007/014319 A I, where an oral dosage form was fonnulated 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 ester). A
`
`similar approach was disclosed in the US application 2007/0238707 A I where a medium
`
`chain 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.
`
`Zoledronic acid, known as ( 1-hydroxy-2-imidazol-1-yi-I-phosphono(cid:173)
`
`ethyl)phosphonic acid, is depicted by the following chemical structure:
`
`N~
`
`Ltf X
`
`_....OH
`HO,
`I~ \_\_
`HO 0 dHo
`
`(I)
`
`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 and are on-going to explore the use
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`ofzoledronic acid in neoadjuvant or adjuvant cancer therapy, Coleman, et al., British J
`
`Cancer 20 I 0; I 02(7): I 099-ll 05, Gnant, eta!., New England J Medicine. 2009, 360 (17):679-
`
`691 and Davies, et a!. J Clinical Oncology, 20 I 0, 28(7s ): Abstract 8021. Zoledronic acid is
`
`administered as an intravenous (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.
`
`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.
`
`Much effort has 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 the U.S. Patent
`
`application 2006/0178439 A I and world patent application W02007 /032808. Seven hydrated
`
`forms, an amorphous fonn, three monosodium salts, and eleven disodium salts with varying
`
`degrees of hydration ofzoledronic acid were also disclosed in the patent application
`W02005/00544 7 A2. Zoledronate metal salts including Na +, Mg2+, Zn 2+ were reported in the
`
`journal of Drugs of the Future (Sorbera eta!, Drugs ofthe Future, 2000, 25(3): 259-268).
`
`Zoledronate, zoledronic, or zoledronic salt represents the ionic fom1 of zoledronic acid. Patent
`
`application W02008/064849 AI from Novartis disclosed additional metal salts including two
`Ca2
`+ salts, two Zn 2
`+ salts, one Mg2
`
`+ salt, as well as a monohydrate, a trihydrate, an amorphous
`
`fonn, and an anhydrous form.
`
`According to the US Food and Drug Administration (FDA) Summary Basis of
`
`Approval (SBA) for zoledronic acid, the poor oral bioavailability (approximately I%), is
`
`partially due to its poor pem1eability 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.
`
`All of the above attempts to improve the oral bioavailability of zoledronic acid were
`
`either focused on improving the aqueous solubility by generating novel solid fonns, 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 ofzoledronic acid,
`
`since the fonnation 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 different particle sizes and size distributions could result in poor blend/physical
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`mixture unifom1ity. 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 uniformity of the blend batches.
`
`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 oncology. Clearly, there is an opportunity to
`
`create oral dosage fom1s of drugs with poor aqueous solubility and/or poor permeability. One
`
`such example is zoledronic acid which is only approved for intravenous administration due to
`
`its low oral bioavailability, resulting from poor permeability. By using pharmaceutically
`
`acceptable and/or approved cofonners to hydrogen or ionically bond with an API, novel
`
`molecular complexes (e.g. cocrystals, salts, solvates, and mixtures thereof) with improved
`
`solubility and/or permeability can be created. These novel molecular complexes could be used
`
`in the development of novel oral dosage forms of BCS Class III and IV drugs.
`
`SUMMARY OF THE INVENTION
`
`The present invention addresses the issue of low oral bioavailability using two
`
`approaches. The first approach represents a deliberate molecular design in the form of a
`
`molecular complex comprising drug and certain excipient(s) (coformer(s)) in a single
`
`crystalline structure. The benefit of such a design can reduce batch to batch blend unifonnity
`
`and particle segregation problems that powder blends often suffer from. In addition, this
`
`invention simplifies the manufacturing of a solid dosage fonn (comprised of drug and
`
`excipient) such that the final solid dosage form is, in one embodiment, a particulate or powder
`
`of the molecular complex. Additionally, the resulting molecular complexes possess very
`
`different physicochemical properties compared to the parent drug or coformer or the physical
`
`mixture thereof. These properties include but are not limited to melting point, thermal and
`
`electrical conductivity, aqueous solubility, rate of dissolution and permeability across the GI
`
`tract membrane. The second approach targets the issue of low permeability of BCS class III
`
`and IV drugs. The approach involves combining a low permeability drug with an amino acid
`
`which can increase penneability and subsequent oral bioavailability.
`
`The present disclosure is directed towards generating new fonns of APis, e.g.,
`
`zoledronic acid, with improved physicochemical properties, such as improved aqueous
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`PCT/US2011/023427
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`solubility, rate of dissolution, and, particularly, improved permeability resulting in enhanced
`
`bioavailability.
`
`One aspect of the present invention includes novel molecular complexes of APis (e.g.,
`
`zoledronic acid) in the form of cocrystals, salts, cocrystals of salts and solvates (including
`
`hydrates and mixed solvates) thereof. In addition, the disclosure further includes processes of
`
`making and methods for using the molecular complexes. The present invention is further
`
`directed to compositions comprising a molecular complex and additional or excess coformer,
`
`including processes of making and methods ofusing the same.
`
`The present invention is still further directed to compositions comprising BCS Class
`
`III and IV drugs and an 'additional' or 'excess' coformer. In this aspect the role of the
`
`cofonner is as a functional excipient. The additional coformer of the invention is particularly
`
`an amino acid, more particularly lysine or glycine, and more particularly lysine, wherein the
`
`coformer, particularly lysine or glycine, more particularly lysine, increases the oral
`
`bioavailability of BCS Class Ill and IV drugs.
`
`In another aspect the present invention provides for a composition comprising a
`
`molecular complex, wherein the molecular complex comprises an API and at least one
`
`coformer. In one embodiment the molecular complex is a salt. In one embodiment the salt is a
`
`crystal. In another embodiment the molecular complex is a cocrystal. In another embodiment
`
`the molecular complex is a cocrystal of a salt. In another embodiment the molecular complex
`
`is a crystalline two-component molecular complex between the API and a single coformer. In
`
`another embodiment the molecular complex is a crystalline three-component molecular
`
`complex comprising the API and the at least one coformer. In a further embodiment the
`
`crystalline three-component molecular complex consists of the API, a first coformer and a
`
`second (different) cofom1er. In a further embodiment the crystalline three-component
`
`molecular complex consists of the API, a coformer and a solvent. In a further embodiment the
`
`solvent is water.
`
`In one aspect the molar ratio of cofonner to API is about 1: 1. In another aspect the
`
`coformer is in molar excess to the API. In one embodiment the molar ratio of cofonner to API
`
`is between about 2: I and I 0: I. In another embodiment the ratio is between about 2: I and
`
`about 5: I. In another embodiment the ratio is about 2: I. In another embodiment the ratio is
`
`about 3: I. In another embodiment the ratio is about 4:1. In another embodiment the ratio is
`
`about 5: I
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`In one aspect the API is in molar excess to the coformer. In one embodiment the molar
`
`ration of API to cofonner is between about 2: I and about 10: I. In another embodiment the
`
`molar ratio is between about 2: I and about 5: I. In another embodiment the molar ratio is
`
`about 2: I. In another embodiment the molar ratio is about 3: I. In another embodiment the
`
`molar ratio is about 4:1. In another embodiment the molar ratio is about 5: I.
`
`In another aspect the composition of the present invention further comprises
`
`'additional co former' that is not in the form of a molecular complex with the API. In one
`
`embodiment the additional cofonner and the cofonner that forms a molecular complex with
`
`the API (i.e., the 'molecular complex coformer') are the same. In another embodiment the
`
`additional coformer and the molecular complex coformer are different. In another
`
`embodiment the additional cofom1er is crystalline. In another embodiment the additional
`
`co former is amorphous. In one embodiment the amount of additional co former in the
`
`composition is greater than the amount of molecular complex coformer. In another
`
`embodiment the mass ratio of the additional cofonner to the molecular complex coformer is
`
`between about 2: I to about 5000: I. In another embodiment the ratio is between about 1000: I
`
`to about 5000: I. In another embodiment the ratio is between about I 000: I to about 4000: I. In
`
`another embodiment the ratio is between about 2000: I to about 4000: l. In another
`
`embodiment the ratio is between about 1000: l to about 2000: I. In another embodiment the
`
`ratio is between about 100: I to about 2000: I. In another embodiment the ratio is between
`
`about I 00: I to about I 000: I. In another embodiment the ratio is between about I 00: I to about
`
`750: I. In another embodiment the ratio is between about 100:1 to about 500: I. In another
`
`embodiment the ratio is between about I 00: I to about 275: I. In another embodiment the ratio
`
`is between about 200: I to about 275: I. In another embodiment the ratio is between about
`
`175: I to about 275: I. In another embodiment the ratio is between about I 50: I to about 250:1.
`
`In another embodiment the ratio is between about I 00: I to about 250: I. In another
`
`embodiment the ratio is between about I 00: I to about 200: I. In another embodiment the ratio
`
`is between about 50: I to about 200: I. In another embodiment the ratio is between about 50: I
`
`to about 150: I. In another embodiment the ratio is between about 50: I to about I 00: I. In
`
`another embodiment the ratio is between about 2: I to about I 00: I. In another embodiment the
`
`ratio is between about 5: I to about I 00: I. In another embodiment the ratio is between about
`
`I 0: I to about I 00: I. In another embodiment the ratio is between about II: I to about I 00: I. In
`
`another embodiment the ratio is between about 25: I to about I 00: I. In another embodiment
`
`the ratio is between about 50: I to about I 00: I. In another embodiment the ratio is between
`
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`about 75: I to about I 00: I. In another embodiment the ratio is between about 2: I to about
`
`50: I. In another embodiment the ratio is between about 5:1 to about 50:1. In another
`
`embodiment the ratio is between about I 0: I to about 50:1. In another embodiment the ratio is
`
`between about II: I to about 50: I. In another embodiment the ratio is between about 12: I to
`
`about 50: I. In another embodiment the ratio is between about 13: I to about 50: I. In another
`
`embodiment the ratio is between about 14: I to about 50: 1. In another embodiment the ratio is
`
`between about 15: I to about 50: I. In another embodiment the ratio is between about 25: I to
`
`about 50: I. In another embodiment the ratio is between about 35: I to about 50: I. In another
`
`embodiment the ratio is at least 2: 1. In another embodiment the ratio is at least 5: I. In another
`
`embodiment the ratio is at least I 0:1. In another embodiment the ratio is at least 11: I. In
`
`another embodiment the ratio is at least 12:1. In another embodiment the ratio is at least 13: I.
`
`In another embodiment the ratio is at least 14: 1. In another embodiment the ratio is at least
`
`15: I. In another embodiment the ratio is at least 25: I. In another embodiment the ratio is at
`
`least 35: I. In another embodiment the ratio is at least 50: I. In another embodiment the ratio is
`
`at least 65: I. In another embodiment the ratio is at least 75:1. In another embodiment the ratio
`
`is at least 85:1. In another embodiment the ratio is at least 100:1. In another embodiment the
`
`ratio is at least 125: I. In another embodiment the ratio is at least 150: I. In another
`
`embodiment the ratio is at least 175:1. In another embodiment the ratio is at least 200:1. In
`
`another embodiment the ratio is at least 225: I. In another embodiment the ratio is at least
`
`250: I. I!1 another embodiment the ratio is at least 275: I. In another embodiment the ratio is at
`
`least 500:1. In another embodiment the ratio is at least 750:1. In another embodiment the ratio
`
`is at least I 00: I. In another embodiment the ratio is at least 2000: I. In another embodiment
`
`the ratio is at least 3000: I. In another embodiment the ratio is at least 4000: I.
`
`In another aspect the invention provides for a composition comprising an API and
`
`additional coformer, wherein the API is present in its free form, as a free acid or free base, or
`
`present as a salt or cocrystal with one or more coformers that are different from the additional
`
`coformer. In one embodiment the amount of additional coformer present in the composition is
`
`in excess to the amount of API present in the composition. In another embodiment the mass
`
`ratio of the additional co former to API is between about 2: I to about 5000: I. In another
`
`embodiment the ratio is between about I 000: I to about 5000: I. In another embodiment the
`
`ratio is between about I 000: 1 to about 4000: 1. In another embodiment the ratio is between
`
`about 2000: 1 to about 4000: 1. In another embodiment the ratio is between about I 000: I to
`
`about 2000: I. In another embodiment the ratio is between about I 00: I to about 2000: I. In
`
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`another embodiment the ratio is between about I 00: 1 to about I 000: I. 1n another embodiment
`
`the ratio is between about 100: I to about 750: 1. In another embodiment the ratio is between
`
`about I 00: I to about 500: I. In another embodiment the ratio is between about I 00: I to about
`
`275: I. In another embodiment the ratio is between about 200: I to about 275: I. In another
`
`embodiment the ratio is between about 175: I to about 275: I. In another embodiment the ratio
`
`is between about 150: I to about 250: I. In another embodiment the ratio is between about
`
`I 00: I to about 250: I. In another embodiment the ratio is between about I 00: I to about 200: I.
`
`In another embodiment the ratio is between about 50: I to about 200: I. In another embodiment
`
`the ratio is between about 50: 1 to about 150: 1. In another embodiment the ratio is between
`
`about 50: I to about I 00: I. In another embodiment the ratio is between about 2: I to about
`
`I 00: I. In another embodiment the ratio is between about 5: 1 to about 100: I. In another
`
`embodiment the ratio is between about 10: 1 to about 100: 1. In another embodiment the ratio
`
`is between about 11 : 1 to about 1 00: 1. In another embodiment the ratio is between about 11: 1
`
`to about I 00:1. ln another embodiment the ratio is between about 12:1 to about 100: 1. In
`
`another embodiment the ratio is between about 13: 1 to about 100: 1. In another embodiment
`
`the ratio is between about 14: 1 to about 100:1. In another embodiment the ratio is between
`
`about 15: 1 to about 100: 1. In another embodiment the ratio is between about 25: I to about
`
`100:1. In another embodiment the ratio is between about 50: 1 to about 100: 1. In another
`
`embodiment the ratio is between about 75:1 to about 100:1. In another embodiment the ratio
`
`is between about 2:1 to about 50:1. In another embodiment the ratio is between about 5:1 to
`
`about 50:1. In another embodiment the ratio is between about 10: 1 to about 50:1. In another
`
`embodiment the ratio is between about 11: 1 to about 50:1. In another embodiment the ratio is
`
`between about 12: I to about 50: I. In another embodiment the ratio is between about 13: I to
`
`about 50: I. In another embodiment the ratio is between about 14:1 to about 50:1. In another
`
`embodiment the ratio is between about 15: 1 to about 50:1. In another embodiment the ratio is
`
`between about 25: I to about 50: I. In another embodiment the ratio is between about 35: I to
`
`about 50: 1. In another embodiment the ratio is at least 2: 1. In another embodiment the ratio is
`
`at least 5: I. In another embodiment the ratio is at least 1 0: 1. In another embodiment the ratio
`
`is at least II: 1. In another embodiment the ratio is at least 12:1. In another embodiment the
`
`ratio is at least 14: 1. In another embodiment the ratio is at least 14: 1.In another embodiment
`
`the ratio is at least 15: I. In another embodiment the ratio is at least 25:1. In another
`
`embodiment the ratio is at least 35:1. In another embodiment the ratio is at least 50: I. In
`
`another embodiment the ratio is at least 65: I. In another embodiment the ratio is at least 75: I.
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`In another embodiment the ratio is at least 85: I. In another embodiment the ratio is at least
`
`100:1. In another embodiment the ratio is at least 125: 1. In another embodiment the ratio is at
`
`least 150:1. In another embodiment the ratio is at least 175:1. In another embodiment the ratio
`
`is at least 200:1. In another embodiment the ratio is at least 225: I. In another embodiment the
`
`ratio is at least 250:1. In another embodiment the ratio is at least 275:1. In another
`
`embodiment the ratio is at least 500: 1. In another embodiment the ratio is at least 750: 1. In
`
`another embodiment the ratio is at least 1 000: 1. In another embodiment the ratio is at least
`
`2000: 1. In another embodiment the ratio is at least 3000: 1. In another embodiment the ratio is
`
`at least 4000: 1.
`
`In particular embodiments the invention provides for a composition of Table 1 1.
`
`In another aspect the cofom1er of the present invention increases the oral
`
`bioavailability of the API. In one embodiment the cofom1er increases oral bioavailability of
`
`the API by at least 10%. In one embodiment the co former increases oral bioavailability of the
`
`API by at least 25%. In one embodiment the coformer increases oral bioavailability of the
`
`API by at least 75%. In one embodiment the coformer increases oral bioavailability of the
`
`API by at least two fold. In one embodiment the co former increases oral bioavailability of the
`
`API by at least three fold. In one embodiment the cofonner increases oral bioavailability of
`
`the API by at least five fold.
`
`In another aspect the co former increases the Cmax of the API. In one embodiment the
`
`co former increases Cmax of the API by at least 10%. In one embodiment the co former
`
`increases Cmax of the API by at least 25%. In one embodiment the cofonner increases Cmax of
`
`the API by at least 75%. In one embodiment the coformer increases Cmax of the API by at
`
`least two fold. In one embodiment the coformer increases Cmax of the API by at least three
`
`fold. In one embodiment the cofonner increases Cmax ofthe API by at least five fold.
`
`In another aspect the coformer reduces the time to the Tmax of the API. In one
`
`embodiment the co former reduces the time to the Tmax of the API by at least 10%. In one
`
`embodiment the co former reduces the time to the T max of the API by at least 25%. In one
`
`embodiment the coformer reduces the time to the Tmax of the API by at least 75%. In one
`
`embodiment the co former reduces the time to the Tmax of the API by at least two fold. In one
`
`embodiment the co former reduces the time to the T max of the API by at least three fold. In one
`
`embodiment the co former reduces the time to the T max of the API by at least five fold.
`
`In another aspect the coformer increases the permeability of the API in the small
`
`intestine. In one embodiment the cofonner increases the permeability of the API by at least
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`I 0%. In one embodiment the co former increases the permeability of the API by at least 25%.
`
`In one embodiment the coformer increases the permeability of the API by at least 75%. In one
`
`embodiment the coformer increases the permeability of the API by at least two fold. In one
`
`embodiment the coformer increases the permeability of the API by at least three fold. In one
`
`embodiment the cofom1er increases the penneability of the API by at least five fold.
`
`Another aspect of the present invention provides for a method of enhancing the
`
`permeability of an API comprising the step of contacting the API with a co former to form the
`
`molecular complex of the present invention.
`
`Another aspect of the present invention provides for a method of enhancing the oral
`
`bioavailability of an API comprising the step of contacting the API with a coformer to form
`
`the molecular complex of the present invention.
`
`· Another aspect of the present invention provides for a method of enhancing the
`
`permeability of an API comprising the step of combining the API with a co former to form a
`
`pharmaceutical composition of the present invention.
`
`Another aspect of the present invention provides for a method of enhancing the oral
`
`bioavailability of an API comprising the step of combining the API with a coformer to form a
`
`phan11aceutical composition ofthe present invention.
`
`In particular embodiments of the present invention, the API is abacavir, acarbose,
`
`acetazolamide, acyclovir, albuterol (salbutamol), allopurinol, amiloride, amisulpride,
`
`amlodipine, amoxicillin, amphetamine, atenolol, atropine, azathioprine, benserazide,
`
`benznidazole, camostat, captopril, cefdinir, cefotiam hexetil hydrochloride, cefprozil,
`
`cefuroxime axetil, chloramphenicol, cimetidine, ciprofloxacin, codeine, colchicine,
`
`cyclophosphamide, dapsone, dexamethasone, didanosine, diethylcarbamazine, methionine,
`
`dolasetron, doxifluridine, doxycycline, ergonovine, erythromycin ethylsuccinate, ethambutol,
`
`ethosuximide, famotidine, fluconazole, folic acid, furosemide, fursultiamine, gabapentin,
`
`glipizide, granisetron, griseofulvin, hydralazine, hydrochlorothiazide, imidapril, isoniazid,
`
`lamivudine, 1-carbocysteine, levetiracetam, levofloxacin, linezolid, lisinopril, losartan,
`
`methotrexate, methyldopa, s-methylmethionine, metoclopramide, metronidazole,
`
`moxifloxacin, nalidixic acid, nicorandil, nifurtimox, nitrofurantoin, nizatidine, nystatin,
`
`ondansetron, oseltamivir, oxcarbazepine, penicillamine, perindopril, phenobarbital,
`
`phenoxymethylpenicillin, pravastatin sodium, prednisolone, primaquine, procaterol,
`
`propylthiouracil, pseudoephedrine, pyrazinamide, pyridostigmine bromide, pyridoxine
`
`hydrochloride, ranitidine, ribavirin, riboflavin, rizatriptan, stavudine, sulfadiazine,
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`sulfamethoxazole, sultamicillin, sumatriptan, taltirelin, tegafur, tenofovir disoproxil,
`
`theophylline, thiamine, trimetazidine, trimethoprim, voglibose, zidovudine, zolmitriptan,
`
`acetylcarnitine, capecitabine, cefaclor, cefixime, cefmetazole, cefpodoxime proxetil,
`
`cefroxadine, alfoscerate, cilazapril, cimetropium bromide, diacerein, erdosteine, famciclovir,
`
`gemifloxacin, levosulpiride, nabumetone, oxiracetam, phendimetrazine, rabeprazole,
`
`roxatidine acetate, tamsulosin, terazosin, thioctic, tosufloxacin, triflusal, zaltoprofen, etidronic'
`
`acid, zoledronic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid,
`
`risedronic acid or ibandronic acid.
`
`In one aspect of the present invention the conformer is selected from the group
`
`consisting of sodium, ammonium,