WO2007067779A2 - Methods and compositions for drug delivery enhancement - Google Patents

Abstract

A method is provided for the delivery of a therapeutic to epithelial cells through the use of a bile acid conjugated to a peptide, the peptide being ionically charged at physiological pH. The complex is well suited for oral and other forms of therapeutic administration of therapeutic drugs known in the art in order to exact systemic and/or localized effect. Intestinal epithelial cells, as well as non-epithelial cells within the gastrointestinal tract and other target cells receive with greater efficiency a charged therapeutic when delivered with an oppositely charged bile acid conjugate (BAC) through oral administration, direct injection, or infusive administrations, thereby increasing bioavailability.

Description

METHODS AND COMPOSITIONS FOR DRUG DELIVERY ENHANCEMENT

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority of U.S. Provisional Patent Application Serial No. 60/748,390 filed December 8, 2005, the contents of which are hereby incorporated by reference.

FIELD OF THE INVENTION

[0002] The invention relates in general to compositions and methods that enhance the delivery of low bioavailability therapeutics across epithelial membranes, including, for example, skin, the gastrointestinal epithelium and the bronchial epithelium, and in particular to the use of a bile acid derivative conjugate to enhance transport of the therapeutic across the target cell membrane.

BACKGROUND OF THE INVENTION

[0003] Methods for increasing drug absorption and bioavailability have garnered considerable attention for enhancing therapeutic levels of small molecule drugs (anionic, cationic or neutrally charged) to treat various mammalian diseases. In attempting to develop lower cost modes of administration that are likely to enhance patient compliance, intestinal absorption has been recognized as an attractive site for therapeutic delivery owing to the ease of access through oral or rectal routes. Oral therapy is easy to administer, generally the least expensive, and has good patient compliance for dosing. Difficulties in this method include therapeutic insolubility, and penetrating the mucus layer, which may further reduce the amount of the cellular exposure and reduce absorption efficiency. As a result, many useful drugs are limited in administration routes to intravenous or intramuscular injection.

[0004] Thus, there exists a need for improved small molecule therapeutic delivery agents capable of inducing systemic and/or local therapeutic delivery.

SUMMARY OF THE INVENTION

[0005] A compound having the formula:

RC(O)-X-Z (I) where RC(O)- is a reaction product of bile acid (5β-CHOLANIC ACID-3α, 7α, -DIOL) or a derivative of the form RCOOH and the derivative is lithocholic acid, deoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, ursocholic acid, hyocholic acid, hyodeoxycholic acid, murocholic acid, dehydrocholic acid, 7- ketodeoxycholic acid, dehydrocholic acid, diketocholanic acid, triketocholanic acid, isolithocholic acid, ketolithocholic acid, dehydrolithocholic acid, allocholanic acid, or a salt thereof;

where Z is a 1 to 50 amino acid residue chain having a net charge at physiological pH through at least 20 residue percent basic residues of arginine, lysine, or a combination thereof; at least 20 residue percent acid residues of aspartic acid, glutamic acid, or a combination thereof; or a privileged lysine containing internalization moiety of any one of SEQ ID Nos. 11-18;

where X is a nullity or has a structure prior to reaction with RCOOH of M|- B-M₂, where Mi is an amine, CH₂=CH-, iodo-, bromo-, chloro-, or N₂-; where M₂ is amine, CH₂=CH-, iodo-, bromo-, chloro-, or N₂-, carboxylate, thionyl chloride, or acid chloride; and where B is a carbon backbone of 1 to 5 amino acid residues, C₂- C i₆ alkyl, C₂-Ci₆ alkenyl, C₂-C₁₆ aryl, and C₂-Qe heteroaromatic compounds, where the heteroatom is O₅ N, or S; and

wherein the compound (I) has a net anionic or cationic charge.

[0006] The compound (I) has a net anionic or cationic charge. By associating the compound (I) with a therapeutic of an opposite ionic charge at physiological pH, the bioavailability of the therapeutic is increased. By controlling the concentration of the compound (I)₅ a micelle is formed by the compound (I) internalizing the therapeutic for delivery. A process of administration of a composition containing a compound (I) and a therapeutic is also provided.

BRIEF DESCRIPTION OF THE DRAWINGS

[0007] Fig. 1 represents octanol partition of enalaprilat with inventive compound BI l;

[0008] Fig. 2 represents in vivo plasma concentration of intestinally absorbed enalaprilat (3 mg dose) with and without an added inventive compound; [0009] Fig. 3 represents in vivo plasma concentration of intestinally absorbed enalaprilat (0.3 mg dose) with and without an added inventive compound;

[0010] Fig. 4 represents the in vivo plasma concentration of an IV dose of zanamivir (0.1 mg dose);

[0011] Fig. 5 represents in vivo plasma concentration of intestinally absorbed zanamivir (0.05 mg dose) with and without inventive compound BAC A6 (N-A6 motif of chenoxycholamide);

[0012] Fig. 6 represents in vivo plasma concentration after oral dosing of zanamivir (4 mg/kg) with and without BAC_A6 (N-A6 motif of chenoxycholamide)

(12 mg/kg) in fasted mice;

[0013] Fig. 7 represents in vivo plasma concentration after oral dosing of zanamivir (40 mg/kg) with and without B AC-A6 (N-A6 motif of chenoxycholamide)

(120 mg/kg) in fasted mice;

[0014] Fig. 8 represents in vivo plasma concentration after oral dosing of zanamivir (10 mg/kg) with and without BAC-A6 (N-A6 motif of chenoxycholamide)

(30 mg/kg) in fed mice;

[0015] Fig. 9 represents in vivo plasma concentration after oral dosing of zanamivir (10 mg/kg) at increasing levels of BAC- A6 (N-A6 motif of chenoxycholamide) in fed mice;

[0016] Fig. 10 represents sample pharmacokinetics of alendronate dosed in fasted animals at 4 mg/kg and increased plasma concentrations when dosed in the presence of BAC A6 (N-A6 motif of chenoxycholamide);

[0017] Fig. 11 represents sample pharmacokinetics of alendronate dosed in fed animals at 4 mg/kg and increased plasma concentrations when dosed in the presence of BAC A6 (N- A6 motif of chenoxycholamide);

[0018] Fig. 12 represents sample pharmacokinetics of alendronate dosed in fed animals at 0.4 mg/kg and increased plasma concentrations when dosed in the presence of BAC A6 (N-A6 motif of chenoxycholamide);

[0019] Fig. 13 illustrates absorption of alendronate in fasted mice in vivo plasma concentration is increased by BAC A6 (N- A6 motif of chenoxycholamide) in a dose responsive manner; [0020] Fig. 14 represents the area under the curve (AUC) increases corresponding in vivo plasma concentrations to increasing molar ratios of BAC A6 (N- A6 motif of chenoxycholamide); and

[0021] Fig. 15 represents the effect of increasing molar ratios of multiple BACs on methotrexate plasma concentrations in mice following oral dosing;

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] The present invention has utility in facilitating therapeutic delivery into target cells and in particular epithelial cells. The invention involves methods and products for oral, parenteral, or topical therapeutic delivery, the delivery of a therapeutic according to the present being for either systemic or localized therapy. An inventive composition is a complex with the therapeutic agent, which increases the efficiency of absorption of the therapeutic into cells relative to the bare therapeutic agent. These contain, in non-covalently bound form, one or more substances having an affinity for the therapeutic, which are capable of increasing the efficiency of absorption of the complexes into the cells. Cells of a mammalian subject, either intestinal epithelia after oral delivery, or cells in other organs after parenteral, inhalational or topical delivery, absorb the inventive composition which penetrates the cell and is distributes into the organ and/or bloodstream the therapeutic to provide a therapeutic effect. An inventive composition is optionally delivered via the intestinal lumen in a variety of ways, including through timed-release capsules, thereby obtaining a simple, noninvasive method of drug delivery for therapy. These complexes can also be delivered to other organs of the body in a variety of ways, including direct injection, infusion or topical administration. After oral delivery, the intestinal epithelial cells provide short or long term therapies for diseases illustratively including metabolic disorders, endocrine disorders, circulatory disorders, coagulation disorders, cancer, bacterial infection, eukaryotic infection, viral infection, and gastrointestinal disease.

[0023] Bile acids conjugated with peptides retain the capability of forming micellar structures, and assist the delivery of a therapeutic agent across the mucus and unstirred water layer of the intestine as well as the cutaneous barrier of the skin. A conjugated bile acid or derivative thereof is expected to solve problems of degradation or poor bioavailability of a piggybacked therapeutic to be delivered via oral or rectal administration.

[0024] As used herein, "therapeutic", synonymously described as a therapeutic agent is defined to include an organic molecular or salt thereof having a an intestinal bioavailability that is less than that of intravenous bioavailability as detailed in

Remington The Science and Practice of Pharmacy, 20^th ed. (2000) pages 1098-1126, and 1146, or an organic molecule or salt thereof in which the pharmacokinetic and or pharmacodynamic profile is altered when co administered with an inventive compound. A typical feature of an inventive therapeutic is an ionic charge at physiological pH and a monomelic molecular weight of less than 2,000 Daltons, as such dimeric through tetrameric conjugated therapeutic that exceeds the molecular weight of 2,000 Daltons is considered to be operative herein.

[0025] In a preferred embodiment administration is oral and targeted to transfect intestinal epithelial cells.

[0026] As used herein, a "subject" is defined as a mammal and illustratively includes humans, non-human primates, horses, goats, cows, sheep, pigs, dogs, cats, and rodents. The methods and compounds of the present invention are administered in therapeutically effective amounts.

[0027] As used herein, a "therapeutically effective amount" is defined to include an amount necessary to delay the onset of, inhibit the progress of, relieve the symptoms of, or reverse a condition being treated. The therapeutically effective amount is one that is less than that that produces medically unacceptable side effects.

It is appreciated that a therapeutically effective amount varies with a number of factors illustratively including subject age, condition, sex and the nature of the condition being treated. It is further appreciated that determining a therapeutically effective dose is within the knowledge of one of ordinary skill in the art.

[0028] As used herein, however, the term "amino acid chain" is intended to include at least one amino acid, and peptide mimetics.

[0029] The term "amino acid" is intended to include L- and D-form amino acids, and non-naturally occurring amino acids. , _,[0030] The therapeutic of the present invention are illustratively administered to a subject at dosage levels in the range of about 0.005-500 mg/kg/day of bile acid or derivative thereof conjugating agent combined with about 5XlO^"6 -500 mg/kg/day of therapeutic per day. The general ratio of the amount of conjugating agent to the therapeutic ranges from about 1 a molar ratio of 0.5:1-500,000:1 in the composition administered to a subject.

[0031] The absorption enhancing portion of an inventive compound is preferably a bile acid conjugated with an ionic amino acid chain linked to a bile acid steroid backbone (BAC). The bile acid moiety acts to target the therapeutic agent to the mucosal surface in the lumen of the intestine and assist in the cellular internalization of the complex. Short amino acid chains rich in arginine or lysine (cationic), or aspartic acid or glutamic acid (anionic) coupled thereto provide an affinity for opposite ionic charged therapeutic, and assist in cellular internalization of the composition. A short amino acid chains is one that contains from 1 to 50 amino acid residues of which at least 20% are one of the aforementioned residues. Typically, 1 to 50 such residues are found within an amino acid chain. It is appreciated that an amino acid chain inclusive of both cationic and anionic amino acid residues offsets the charge attributes of one another and therefore increases peptide chain length with little advantage. As such, preferably an amino acid chain includes only cationic, cationic and neutral, anionic, or anionic and neutral charge amino acid residues.

[0032] Conjugation of the amino acid chain to the bile salt yields either a cationic or anionic compound and is made through the hydroxyl groups in the 3, 7, or 12 positions of the bile acid steroid nucleus, or on the 24-carboxyl group of the bile acids.

[0033] The invention includes a bile acid conjugate (BAC), synonymously referred to as a bile acid compound having the formula:

RC(O)-X-Z (I) where RC(O)- is a reaction product of bile acid (5β-CHOLANIC ACID-3α, 7α, -DIOL) or a derivative of the form RCOOH and is lithocholic acid, deoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, ursocholic acid, hyocholic acid, hyodeoxycholic acid, murocholic acid, dehydrocholic acid, 7-ketodeoxycholic acid, dehydrocholic acid, diketocholanic acid, triketocholanic acid, isolithocholic acid, ketolithocholic acid, dehydrolithocholic acid, allocholanic acid, salts of any of the preceding or a combination of any of the preceding. Preferably, the derivative substituent forms a linkage to Z directly through the carbonyl carbon atom of RCOOH or indirectly to Z via an intermediate X linker. More preferably, the BAC has a net anionic or cationic charge. It is appreciated that in addition to the above identities for RC(O)-, a given hydrogen of R is optionally replaced with a C1-C24 alkyl to modify the lipophilicity of the resultant BAC.

[0034] The linker X is a nullity or has a structure prior to reaction with RCOOH of M1-B-M2, where the first moiety M] is reactive with the bile acid carbonyl carbon of RCOOH and a second moiety M₂ is reactive with an ionic amino acid chain Z through the Z amine, carboxyl, or a side chain moiety. Mi is an amine, CH₂=CH-, iodo-, bromo-, chloro-, or N₂-; where M₂ is amine, CH₂=CH-, iodo-, bromo-, chloro-, or N₂-, carboxylate, thionyl chloride, or acid chloride; and where B is a carbon backbone of 1 to 5 amino acid residues, C₂-C iβ alkyl, C₂-C 16 alkenyl, C₂-Qe aryl, and C₂-Ci₆ heteroaromatic compounds, where the heteroatom is O, N, or S. Substituents extending from a linker backbone are provided to modify the lipophilicity of an inventive conjugate, or tether a dye or spectroscopic marker. With the inclusion of a linker X, care should be taken to limit both the molecular weight and the hydrophilicity of the linker in order to retain the ability to cross cellular membranes. Typically, the linker moiety is reactive with the bile acid carbonyl carbon to illustratively form an amide, ether, ester, sulfonyl, or other hydrolyzable bond. The Z amino acid reactive moiety of the linker is dependent upon the amino acid moiety to be bound thereto namely, an alpha amine or carboxyl carbon and includes an amine, a carboxyl, an acid chloride, and a sulfonyl chloride. Suitable chemistries for a variety of potential reaction moieties are found in Comprehensive Organic Transformations, R.C. Larock, John Wiley & Sons 1999 and include condensation reactions between an amine and carboxylate, reductive amination with a linker ketone in the presence of a nickel catalyst and hydrogen, acid chloride reaction with a peptide amine group, and sulfonyl chloride reaction with a peptide amine group.

[0035] A substituent is optionally provided pendent from the linker backbone. The substituent illustratively includes a radioactive atom, a magnetic spectroscopically active marker and an organic dye. A radioactive atom is alternatively operative as a marker in isotope studies such as positron emission tomography, single photon emission computer tomography, radiological studies and the like. Common radio-isotopes used in medical imaging illustratively include 1231, 99mTc, and other chelated radioisotopes as detailed in U.S. 6,241,963. Spectroscopically active markers include NMR/MRI active contrast enhancing moieties known to the art such as gadolinium, as detailed in Contrast Agents 1 : Magnetic Resonance Imaging (Topics in Current Chemistry, 221) by Werner Krause, Springer Verlag, Berlin, Germany. Organic dyes, while recognized to have potentially distinct NMR/MRI signatures, are provided to yield an optically active spectroscopic signature suitable for biopsy, surgical identification, or preclinical studies of tissue treated by an inventive compound.

[0036] A linker X is provided with the proviso that any charge associated with a linker that is accounted for in the overall charge state of the bile acid (I). A non-zero length linker amino acid chain is preferably provided in instances of steric hindrance, associated with the peptide Z or to utilize a synthetic chemistry scheme where a linker X is bound to R, and then amino acid chain Z added by a peptide coupling reaction with appropriate blocking groups added to preclude side reactions; Z is a net ionic amino acid chain up to and including 50 amino acid residues long.

[0037] Cationic amino acid chains operative herein as the Z moiety in formula (I) illustratively include a single arginine residue; a 2 to 50 residue oligopeptide that contains at least 20 residue percent arginine, or at least 20 residue percent lysine; or a privileged transport sequence such as transportan or penetratin sequences. Preferably, more than 30 residue percent arginine or 30 residue percent lysine is present. Most preferably Z is less than 25 total residues in length and more than 35 residue percent arginine or 45 residue percent lysine. Z amino acid residue chains of 3 to 15 residues with at least 50 residue percent of lysine and or arginine are particularly well suited for the delivery of anionic therapeutics complexed therewith in a charge neutralizing amount. Specific examples of cationic Z moieties effective in internalizing a bile acid moiety R and a coadministered therapeutic include wholly arginine or wholly lysine oligopeptides having a length of from 1 to 12 residues, synthetic residues (RANA)_nR where n is an integer 2-5 (SEQ ID NOS. 1-4, respectively) and conventional arginine rich protein internalization proteins (M. Peitz et al. PNAS USA 2002; 99:4489-4494; D. Jo et al. Nature Biotech. 2001; 19:292- 933) such as

GRKKRRQRRRPPQ (TAT 48-60) (SEQ ID NO. 5)

GRRRRRRRRRPPQ (R9-TAT) (SEQ ID NO. 6)

TRQARRNRRRRWRERQR (HIV-I Rev 34-50) (SEQ ID NO. 7) RRRRNRTRRNRRRVR (FHV coat 35-49) (SEQ ID NO. 8)

KMTRAQRRAAARRNRWTAR (BMVgag7-25) (SEQ ID NO. 9) TRRQRTRRARRNR (HTLV-II Rex 4-16) (SEQ ID NO. 10);

privileged lysine containing protein internalization peptides (A. Muratovska et al., FEBS Let. 2004; 558:63-68) such as transportan,

LIKKALAALAKLNIKLLYGASNLTWG (SEQ ID NO- 11);

and alternative amino acid composition for transportan and its deletion analogs which maintain membrane transduction properties (Soomets et al. Biochim Biophys Acta. 2000 JuI 31;1467(l):165-76)):

GWTLNSAGYLLGKINLKALAALAKKIL (transportan) (SEQ ID NO. 12)

LNSAGYLLGKINLKALAALAKKIL (transportan7) (SEQ ID NO. 13)

GWTLNSAGYLLGKLKALAALAKKIL (transportan9) (SEQ ID NO. 14)

AGYLLGKINLKALAALAKKIL (transportanlO) (SEQ ID NO. 15) LNSAGYLLGKLKALAALAKKIL (transportanl2) (SEQ ID NO. 16); and

AGYLLGKLKALAALAKKIL (transportanH) (SEQ ID NO. 17); and penetratin RQIKIWFQNRRMKWKK (Atennapedia 43-58 - pentratin) (SEQ ID NO. 18).

[0038] As abbreviated above TAT denotes HIV-I transaction of transcription, FHV denotes flock house virus, and BMV denotes brome mosaic virus.

[0039] Cationic compounds of formula (I) are helpful in delivering anionic therapeutics. Without intending to be bound to a particular theory through micelle formation, a therapeutic is internalized within a BAC shell and protected from gastrointestinal degradation with the micelle inclusive of therapeutic having a lower net charge than the internalized therapeutic itself. Conjugation of the polyionic polypeptide chain to the bile salt is made through the hydroxyl groups in the 3, 7, or 12 positions of a bile acid steroid nucleus, or on the 24-carboxyl group of the bile acid or aforementioned bile acid derivative or via other substituent types or locations on the derivative to yield an amidyl linkage to X or Z peptides. Preferably, an amidyl linkage is present between R and the peptide tail, although it is appreciated that ether, ester, sulfonyl, of other hydrolyzable bonds are also operative herein and formed through the bile acid carboxylic acid moiety, a hydroxyl moiety extending from the tetracyclic core, and an additional core substituent or ethylenic unsaturation. ^■[0040] Anionic small molecule therapeutics represent a broad class of pharmaceuticals that are exemplary of the benefits of the present invention. By way of example, a carboxyl group imparts a negative charge that lessens bioavailability leading to higher dosing and side effects. Acid containing drugs containing carboxylic, benzoic groups found in existing drugs illustratively include 1-dopa, angiotensin-converting enzyme inhibitors such as: benazeprilat, captoprilat, enalaprilat, fosinoprilat, lisinoprilat, perindoprilat, ouinaprilat, ramiprilat, spiraprilat, trandolaprilat and moexϊprilat; cephalosporin antibiotics such as: cefaclor, cefadroxil, cefamandole, cefatrizine, cefazedone, cefazuflur, cefazolin, cefbuperazone, cefclidine, cefepime, cefetecol, cefixime, cefluprenam, cefmenoxime, cefmetazole, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotefan, cefotiam, cefoxitin, cefpimizole, cefpirome, cefoselis, cefozopran, cefpirome, cefquinome, cefpodoximc, cefroxadine, cefsulodin, cefbiramide, ceftazidime, ceftezole, ceftizoxime, ceftriaxone, cefuroxime, cephacetrile, cephalexin, cephaloglycin, cephaloridϊne, cephalosporin, cephanone, cephradine, and latamoxef; penicillins such as amoxycillin, ampicillin, apalcillin, azidocillin, azlocillin, benzylpencillin, carbenicillin, carfecillin, carindacillin, cloxacillin, cyclacillin, dicloxacillin, epicillin, flucloxacillin, hetacillin, methicillin, mezlocillin, nafcillin, oxacillin, phenethicillin, piperacillin, sulbenicllin, temocillin, and ticarcillin; carbapenems a class of beta- lactam antibiotics such as: imipenem, meropenem, ertapenem, faropenem, doripenem, danipenem/betamipron; tazobactam which inhibits the action of bacterial beta-Iactamases extending the spectrum of beta-lactam antibiotics; thrombin inhibitors such as argatroban, melagatran, and napsagatran; influenza neuraminidase inhibitors such as zanamivir, peramivir and oseltamivir; non-steroidal antiinflammatory agents such as acametacin, alclofenac, alminoprofen, aspirin acetylsalicylic acid), 4-biphenylacetic acid, bucloxic acid, carprόfen, cinchofen, cinmetacin, clometacin, clonixin, diclenofac, diflunisal, etodolac, fenbufen, fenclofenac, fenclosic acid, fenoprofen, ferobufen, flufenamic acid, flufenisal, flurbiprofm, fluprofen, flutiazin, ibufenac, ibuprofen, indomethacin, indoprofen, ketoprofen, ketorolac, lonazolac, loxoprofen, meclofenamic acid, mefenamic acid, 2-(8-methyl-10,l 1-dihydro-l l-oxodibenz[b,fjoxepin-2-yl)propionic acid, naproxen, nifluminic acid, O-(carbamoylphenoxy)acetic acid, oxoprozin, piφrofen, prodolic acid, salicylic acid, salicylsalicylic acid, sulindac, suprofen, tiaprofenic acid, tolfenamic acid, tolmetin and zopemirac; prostaglandins such as ciprostene, 16- deoxy-16-hydroxy-16-vinyl prostaglandin E₂, 6,16-dimethylprostaglandin E₂, epoprostostenol, meteneprost, nileprost, prostacyclin, prostaglandins Ei, E₂, or F_2α, and thromboxane A₂; quinolone and fluoroquinolone antibiotics such as: acrosoxacin, cinoxacin, ciprofloxacin, enoxacin, fleroxacin, flumequine, gatifloxacin, gemifloxacin, grepafloxacin, levofloxacin, lomefloxacin, moxifloxacin, naladixic acid, norfloxacin, ofloxacin, oxolinic acid, pefloxacin, pipemidic acid, piromidic acid, prulifloxacin, rufloxacin, rosoxacin, sitafloxacin, sparfloxacin, temafloxacin, and trovafloxacin; other antibiotics such as aztreonam, imipenem, meropenem, and related carbopenem antibiotics; anticonvulsants such as clorazepate, gabapentin and valproic acid; meglitinides such as: nateglinide, repaglinide, and mitiglinide; diuretics such as furosemide; statins such as: atorvastatin, cerivastatin, fluvastatin, in acid, mevastatin acid, pitavastatin, pravastatin acid, rosuvastatin and simvastatin acid; antihypertensive such as: hydralazine; antimetabolites such as: pemetrexed; calcium channel blockers such as nicardipine; bisphosphonates such as: pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, zoledronic acid etidronic acid, clodronic acid and tiludronic acid; immunosuppressive agents such as: mycophenolic acid; anticancer agents such as: etoposide phosphate, melphalan, methotrexate and pemetrexed; angiotensin II receptor antagonists such as: candesartan, telmisartan and valsartan; antifibrinolytic agents like aminocaproic acid; acetohydroxamic acid, which is prescribed to decrease urinary ammonia, and may help antibiotics to work or help with other kidney stone treatments; verteporfin, which is a medication used as photosensitizer for photodynamic treatment to eliminate the abnormal blood vessels in the eye; Liothyronine which is a thyroid hormone drug used to treat hypothyroidism; cromolyn used in an oral form to treat mastocytosis, dermatographic urticaria and ulcerative colitis; penicillamine which is used as a form of immunosuppression to treat rheumatoid arthritis and as a chelating agent in the treatment of Wilson's disease; dimercaptosuccinic acid used as a heavy metal chelating agent; ethacrynic acid which is used as a loop diuretic medication; montelukast which is an oral leukotriene receptor antagonist (LTRA) for the maintenance treatment of asthma and to relieve symptoms of seasonal allergies; misoprostol acid which is used for the treatment and prevention of stomach ulcers, to induce labor and as an abortifacient.

[0041] By way of a second example, a phosphonate or phosphate group imparts a negative charge that lessens bioavailability leading to higher dosing and side effects. Phosphate and phosphonate containing existing drugs illustratively include: antiviral compounds including adefovir, cidofovir, cyclic cidofovir, foscarnet, and tenofovir.

[0042] Anionic amino acid chains operative herein as the Z moiety in formula (I) illustratively include a single aspartic acid or glutamic acid residue, a 2-50 residue oligopeptide that contains at least 20 residue percent aspartic acid or at least 20 residue percent glutamic acid, or a combination thereof. Preferably, more than 30 residue percent aspartic acid, more than 30 residue percent glutamic acid, or combination thereof is present. Most preferably Z is less than 25 total residues in length and more than 35 residue percent aspartic acid, more than 35 residue percent glutamic acid, or combination thereof. Specific examples of anionic Z moieties effective in internalizing a bile acid or derivative thereof moiety R and a coadministered therapeutic include wholly aspartic acid or wholly glutamic acid oligopeptides having a length of from 1 to 12 residues, and synthetic residues (EANA)_nE where n is an integer 2-5 (SEQ ID NOS. 19-22, respectively). Anionic compounds of formula (I) are helpful in delivering cationic therapeutics through micelle formation, with the micelle having a lower net charge than the internalized therapeutic.

The organic small molecules positively charged therapeutics are principally delivered as salts and in particular hydrochloride salts and at physiological pH are present as cations, with the charge tending to decrease bioavailability even while increasing chemical solubility. Cationic small molecule therapeutics suitable for the delivery according to the present invention illustratively include: antacids such as magnesium hydroxide, aluminum hydroxide, and calcium carbonate; iron products such as ferrous sulfate, ferrous gluconate, ferrous fumarate, and iron-polysaccharide complex; mineral containing multivitamins; antireflux agents such as sucralfate; potassium-sparing diuretics such as amiloride, and triamterene; cardiac glycosides such as digoxin; opioid analgesics such as morphine; antiarrhythmics such as procainamide, quinidine, and quinine; histamine (H2) blockers such as ranitidine; antimicrobials such as trimethoprim, vancomycin, and gentamycin; local anesthetics such as tetracaine, and lidocaine; antipsychotics such as chlorpromazine; beta- blockers such as propranolol; antivirals such as amantadine; and sympathomimetic agents such as pseudoephedrine; neuromuscular-blocking drugs or muscle relaxants such as: atracurium, mivacuriurn and cisatracurium as well as the smooth muscle relaxant dicyclomine; selective alpha 1 antagonists such as: alfuzosin and terazosin; calcium channel blockers such as: amlodipine, verapamil and gallopamil; endothelin receptor antagonist such as: bosentan; calcimimetϊc drugs such as: cinacalcet; selective betal receptor blockers like metoprolol, propranolol, timolol and atenolol; cholinesterase reactivators such as: pralidoxime; cytotoxic/antitumor antibiotics such as: daunorubicin, doxorubicin, epirubicin, idarubicin, and mitoxantrone; topoisomerase 1 inhibitors such as irinotecan; gonadotropin-releasing hormone agonists such as leuprolide; antihypertensive agents such as: apraclonidine, clonidine, doxazosin, guanethidine, guanfacine, lofexidine, mecamylamine, methyldopa, moxonidine and prazosin; triptan drug like almotriptan, and rizatriptan; blockers of M3 muscarinic acetylcholine receptors such as: darifenacin; the amphetamine-like prescription stimulant methylphenidate; 5-HT4 agonists such as tegaserod; 5-hydroxytryptamine IB/ID (5-HT IB/ID ) receptor agonists like zolmitriptan; atypical antipsychotics such as: ziprasidone; mesylate, quinazoline alpha blockers such as doxazosin and phenoxybenzamine; drugs used to treat male erectile dysfunction such as sildenafil and the phosphodiesterase type 5 inhibitor vardenafϊl; small molecule receptor tyrosine kinase inhibitors such as sunitinib; an ti retroviral drugs such as nelfinavir; antidepressants of the selective serotonin reuptake inhibitor (SSRI) type such as sertraline; anti-diabetic drugs from the biguanide class such as metformin; serotonin 5-HT3 receptor antagonists like granisetron; orally administered antimalarial drugs used as a prophylaxis such as mefloquine; short-acting nonbenzodiazepine hypnotics such as Zolpidem;; inhibitor of phosphodiesterase-3 such as anagrelide; alpha-sympathomimetic drugs like midodrine; inhibitors of monoamine oxidase such as selegiline; ergoline-based dopamine receptor agonists like pergolide; glycopeptide antibiotics such as: vancomycin, telavancin and oritavancin; serotonin-norepinephrine reuptake inhibitors such as venlafaxine; broad spectrum glycylcycline antibiotics like tigecycline; selective estrogen receptor modulators such as: tamoxifen and 4- hydroxytamoxifen; vasodilators such as: hydralazine and dihydralazine; activators of the intracellular receptor class of the peroxisome proliferator-activated receptors such as: pioglitazone.

[0043] In use as a therapeutic delivery formulation, an inventive compound (I) is added in solution to the designed therapeutic and uptake levels of the therapeutic simulated by monitoring the partition coefficient of the therapeutic alone and in combination with a compound of formula (I). A partition coefficient monitoring technique is detailed in Example 4. In vivo optimization of the ratio of a therapeutic to compound (I) is determined by varying the ratio and monitoring blood serum levels of the therapeutic as a function of the ratio. Typically the compound (I) is present in a molar ratio of compound (I): therapeutic ranges from 0.005:1 to 500,000:1 and preferably in a ratio of from 0.05 to 50,000:1. More preferably, the molar ratio of compound (I): therapeutic ranges from 0.5:1 to 20,000:1. For a therapeutic, a molar ratio 0.1:1 to 10:1 is most preferred.

[0044] Without being intended to be limited to a particular theory, it is believed that one of the mechanisms to permit transport of highly ionized therapeutics through cell membranes requires the pairing of charged therapeutic with a compound of formula (I) having an equal but opposite charge to yield a neutral complex that can passively diffuse through the lipid membrane, synonymously described herein as ion pairing. Single charges are appreciated to often lack sufficient affinity to a therapeutic so as to increase bioavailability, and other mechanisms involving the bile salts interaction may facilitate the increase in bioavailability observed.

[0045] In the case of an anionic therapeutic at physiological pH, formulating with a compound (I) that is polycationic serves to enhance bioavailability. While the specific mechanism remains unknown, obtaining a net charge balance between the total quantity of therapeutic and compound (I) at physiological pH represents an initial estimate as to the relative quantity of compound (I) to be used.

[0046] The invention involves methods and products for oral, parenteral, mucosal, transdermal, and infusion delivery of therapeutics for both systemic and localized therapy by increasing the efficiency of absorption of a therapeutic complex with a compound of formula (I) into the cells. Cells of a mammalian subject, either intestinal epithelia after oral delivery, or cells in other organs after other forms of inventive delivery, are altered to operatively incorporate a therapeutic. These complexes also optionally are delivered to other organs of the body in a variety of ways, including direct injection or infusion. In a preferred embodiment administration is oral and targeted to transport a therapeutic into intestinal epithelial cells.

[0047] The compounds of the present invention can be administered to a patient either alone or a part of a pharmaceutical composition. The compositions can be administered to patients either orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), intracisternally, intravaginally, intreperitoneally, intravesically, locally (powders, ointments, or drops), or as a buccal or nasal spray.

[0048] Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.

[0049] These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0050] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (e) solution retarders, as for example, paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol, and glycerol monostearate, (h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.

[0051] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.

[0052] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0053] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.

[0054] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. [0055] Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.

[0056] Compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active component.

[0057] Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solution are also contemplated as being within the scope of this invention.

[0058] An inventive compound is also delivered in conjunction with an active therapeutic compound, a pharmaceutically acceptable salt, ester, amide or prodrug thereof. The therapeutic compounds are listed above in anionic and cationic forms and illustratively are active as antibiotic, a gamma or beta radiation emitting species, an anti-inflammatory, an anti tumoral, an antiviral, an antibody, a hormone, an enzyme, and antigenic peptide or protein.

[0059] The term "pharmaceutically acceptable salts, esters, amides, and prodrugs" as used herein refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term "salts" refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate and laurylsulphonate salts, and the like. These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethyl amine, ethylamine, and the like. (See, for example, S.M. Barge et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66:1-19.)

[0060] The present invention is further detailed with respect to the following non-limiting examples. While the following examples illustrate the present invention through exemplary anionic therapeutic-cationic inventive compound delivery combinations, analogs are found among cationic therapeutic-anionic inventive compound pairings. The examples presented below are intended to illustrate particular embodiments of the invention and are not intended to limit the scope of the specification, including the claims.

EXAMPLES

Example 1

Method for synthesis of bile acid conjugates (BAC)

[0061] BAC is synthesized by solid phase chemistry on a peptide synthesizer. A six L-arginine peptide is first synthesized on the resin bed using standard 9-fiuorenylmethoxycarbonyl (FMOC) chemistry. To attach the bile acid salt, an excess of chendoxycholic acid is added to the resin and allowed to react with the immobilized peptide. After conjugation, the N-hexapeptide (A6 motif in Table 1) chenoxycholamide BAC is cleaved from the resin and purified to greater than 95% purity by HPLC. Example 2

Measurement of the critical micellar concentration for bile acid conjugates (BAC) of compound I

[0062] The critical micellar concentration (CMC) of the BACs is determined using a dye solubilization method which monitored the partitioning of the dye into micelle as a function of the BAC concentration (Wang et al. Biomacromolecules 2002; 3(6): 1197-207). Briefly, serial dilutions of a 7 mg/ml solution of the BACs are made in 50 mM Tris buffer pH 8.0. 10 ul of the dye l,6-diphenyl-l,3.5-hexatriene (DPH, Sigma) (0.4 mM in methanol) is added to each ml. After overnight RT incubation in the dark, the absorbance of the samples at 356 nm is recorded. Linear regression of the data points above baseline was performed and the calculated CMC derived from the x intercept. The results for thirteen different BACs are shown in Table 1 based on a chendoxycholamide of the detailed motifs.

TABLE l

BAC CMC Measurement

Calculated

Motif A - (R-)

A3 -RRR 861.14 3.5

A4 -RRRR 1017.3 1.8

A6 -RRRRRR 1329.7 2.6

Motif B - (R-R-R-A-)

B7 -RRRARRR 1400.8 >5.0*

-RRRARRRARRR (SEQ ID

BIl NO. 26) 1940.4 1.9

MoUfC - (R-R-A-)

C5 -RRARR 1088.4 >6.4*

C8 -RRARRARR 1471.8 4.4

-RRARRARRARR (SEQ ID

CIl NO. 27) 1855.3 1.2

Motif D - (R-A-)

D3 -RAR 776.03 >9.0*

D9 -RARARARAR 1457.8 1.7

-RARARARARAR (SEQ

DIl ID NO. 28) 1685 2.5

Motif E - (R-A-W-A-) E9 -RAWARAWAR 1517.8 1.2

-RAWARAWARAWAR

E13 (SEQ ID NO. 29) 2002.3 0.8

[0063] *The CMC for three BACs D3, C5, and B7 could not be determined, and are greater than 7 mg/ml (5-9 mM for the three BACs), the highest concentration tested. The experimental range reflects the range of CMCs calculated by varying the range of data points included in the linear regression.

Example 3

Preparation of BAC/drug mixture

[0064] Typically a volume of the drug at the desired concentration in 10 mM Tris Buffer (pH 7.4) was added to a quantity of BAC solid to yield equal molar concentrations of the drug and BAC in solution. Mass spec analysis shows that the major ionic species in the BAC has a charge of +3 per BAC_A6 (N-A6 motif of chenoxycholamide) molecule (MW = 1329) under neutral pH 7.0. Thus, charge neutralization of the anionic therapeutic is expected.

Example 4

Alteration of the octanol/water partition coefficient for fluorescein and carboxylfluorescein by various BACs of Formula I

[0065] The interaction of cationic BACs with various therapeutics can be shown by determining the alterations in the partition coefficient between hydrophilic and hydrophobic liquid phases for the therapeutic. In particular, changes in the lipid solubility of the anionic fluorescent dyes carboxyfluorescein and fluorescein as model drugs are measured by dye partitioning between octanol and aqueous buffer at different pHs to determine alterations in the solubility behavior relevant to the permeability of cell membranes in vivo.

[0066] Octanol/buffer partition ratios: The ratio of concentrations of a given solute in equilibrium distribution between two immiscible solvents is termed the partition coefficient. This expression properly refers only to the distribution of a single molecular species between the two phases. Both solutes studied exist as a mixture of ionized forms within the pH range tested. Total dye concentration in the two solvent phases is measured without correction for ionization or self-association and the recommended term, "partition ratio", is used to refer to these uncorrected distributions.

[0067] Carboxyfluorescein or sodium fluorescein (both from Sigma Chemical

Co., St. Louis) is dissolved at concentrations of 10^"3 M or 10^"5 M in octanol-saturated

0.01 M Tris buffer at different pH values between 6.40 and 8.03. The aqueous dye solutions are equilibrated with equal volumes of buffer- saturated octanol by 100 inversions during 5 minutes, and the phases are separated by centrifugation. Dye concentrations are measured spectrofluorophotometrically at excitation and emission wavelengths of 485 and 512 run, respectively, with an Aminco-Bowman Ratio

Spectrofluorophotometer.

[0068] , Two methods are used to calculate partition ratios. In the first, the dye concentration in the aqueous phase is measured before (Cb) and after (C_a) partitioning and the ratio (P.R-) was obtained from the equation:

where C_OCi and C_aq are the dye concentration in the octanol and aqueous phases, respectively after equilibration, hi the second method, concentration in the octanol phase is determined by extracting the dye from octanol with an equal volume 0.1 N NaOH. Concentration in the octanol phase could not be measured directly because of the marked loss of fluorescence of both dyes in this solvent. A single base extraction of the octanol recovered 99% of the dissolved fluorescein and 99.9% of the dissolved carboxyfluorescein. Therefore, dye concentration in the first base extract is accepted as the concentration in the octanol phase and calculated the partition ratio (P .R.) from the equation:

[0069] Both methods for determining the partition ratio gave similar results when more than 10% of the initial dye concentration is removed from the aqueous phase by partitioning. When very small quantities of dye are removed, measurement of concentration differences in the aqueous phase before and after partitioning became unreliable, and only the second method is used to calculate the ratio.

[0070] Addition of the BAC compounds of Formula I increased the partitioning of the fluorescent molecules into the octanol organic phase. Likewise fluorescent- labeled peptides and oligonucleotides increased their hydrophobicity when ion paired with BAC compounds.

[0071] Representative drugs which are fluorescent and can be measured directly in phase partition experiments with BACs are provided in Table 2 in the presence of N-A6 chenoxycholamide (bile acid amidyl-A6).

TABLE 2

Representative drugs which are fluorescent and can be

measured directly in phase partition experiments with BAC

to

N)

LU

Example 5

Partitioning of BAC between buffer and octanol

[0072] Partitioning of the fluorescent compound carboxyfluorescein by a BAC of Formula I into the octanol phase of an octanol/buffer portioning system for a series of BAC compounds is determined following standard methods. An aqueous buffered solution containing 4 nmoles of carboxyfluorescein and 281 nmoles BAC is mixed with an equal volume (475 μl) of buffer saturated 1 -Octanol. The mixture is vortexed for 5 mins and the incubated at room temperature for 3 hours. The solution is centrifuged to facilitate complete phase separation and a 100 μl of aqueous material is withdrawn for fluorescent measurement. The results of such a study are presented in Table 3, where the alphanumeric references correspond to those detailed in Table 1.

TABLE 3

Octanol partitioning of Carboxyfluorescein mixed with different BAC analogs

Example 6

Intestinal administration of an anionic therapeutic cnalaprilat

[0073] Enalaprilat is administered via an open gut injection in which the therapeutic and N- A6 motif chenoxycholamide BAC absorption enhancer is injected directly into the duodenum of the intestine. Enalaprilat has a molecular weight of

348.4.

[0074] As an anionic molecule enalaprilat contains two carboxyl groups that are ionized at physiological pH in solution. Physical measurements of the BAC neutralization of anionic materials preferably using a stoichiometric excess of BAC

(on a charge basis) to neutralize the charge associated with co-mixed enalaprilat.

Without intending to be bound to a particular theory, the presence of buffer salts bound to the BAC during synthesis and purification at least partially explains this observation.

Example 7

Octanol partitioning of enalaprilat as a function of BAC concentration

[0075] Partitioning of the drug enalaprilat by increasing concentrations of the

BAC, (bile acid amidyl BI l) into the octanol phase of an octanol/buffer portioning system are summarized below. 0.3 mg/ml (100 microliters)of enalaprilat is mixed with amounts of N-BI l -motif chenoxychol amide BAC (bile acid amide of BI l motif per Table 1) ranging from 0 to 160 microliters of 5 mg/ml BAC solution (800

^■microgram max). To each solution is added 50 microliters buffer 10x (100 mM Tris

7.4), followed by the addition of 500 microliters buffer saturated 1 -octanol. The resulting two-phase mixture is vortexed 2 hours, centrifuged 5 minutes at 10,000 φm, with aqueous diluted to 1 ml. A 20 microliter aliquot is measured as shown in

Fig. 1. The experiment is repeated with N-El 3 motif ursochol amide (El 3 motif per

Table 1) and achieved results comparable to those shown in Fig. 1.

Example 8

Oral antibody delivery as an example of protein uptake

[0076] Antibodies can be delivered to the systemic circulation via the oral route.

Mouse monoclonal IgG antibodies (100 ug) specific for a synaptic vesicle protein

(SV2) are diluted into 0.5 ml PBS or PBS containing 972 μg of BAC_A6 (N-A6 motif of chenoxycholamide). Mice are orally gavaged with the above material, or the antibody in PBS is injected intraperitoneally as a control. At various time points samples of blood are obtained and the titer of the anti-SV2 antibody in the serums were determined by ELISA. Detectable levels of the anti-SV2 antibodies are detectable in the systemic circulation after oral dosing of antibodies combined with the BAC compound.

Example 9

Intestinal administration of anionic therapeutic zanamivir

[0077] Zanamivir is administered via an open gut injection in which the drug and N-A3 motif chenoxycholamide BAC absorption enhancer (A3 motif per Table 1) is injected directly into the duodenum of the intestine as shown in Fig. 9. Zanamivir has a molecular weight of 332.3. This is compared to the IV dose to determine bioavailability as the fraction absorbed as shown in Fig. 10. As an anionic molecule zanamivir contains one carboxyl group that is ionized at physiological pH in solution. Comparable results are obtained with lithocholic acid bound directly to motif D9 per Table 1, as well as for lithocholic acid amide bound to an intermediate triglycinyl linker (X of formula (I)) that is coupled to motif D3 per Table 1 (GGG- RAR lithocholamide).

Example 10

BACs enhance the bioavailability of zanamivir

[0078] Groups of mice (8 or 10) are dosed by oral gavage with a solution (0.2 ml) containing zanamivir with or without the prototype BAC analog, BAC_A6 (N- A6 motif of chenoxycholamide), at different dosing levels. The BAC:drug mixtures are incubated for 15-30 minutes at room temperature prior to dosing. At each time point, two mice are sacrificed from each group and plasma is collected by cardiac puncture. Zanamivir concentrations are determined by LC/MS/MS analysis.

[0079] The results of the data are presented in Figs 6-9. These examples demonstrate the BAC enhancement of zanamivir absorption in mice when the BAC:zanamivir complex is orally administered by gavage. The effect is evident over at least a 10-fold range in dosage level and is seen in both fed and fasted state. Further, altering the ratio of BAC to drug can significantly alter the extent of absorption. . '

[0080] Oral dosing of zanamivir (4 mg/kg) with and without BAC (12 mg/kg) in fasted mice. Fasted animals are dosed by oral gavage with zanamivir at 4 mg/kg (open circles) or Zanamivir at 4 mg/kg + 12 mg/kg BAC-A6 (filled squares) is shown in Fig. 6, with plasma zanamivir levels determined at the times indicated. Each data point represents the average of two mice. Mice dosed with the BAC:zanamivir complex show a >3 fold increase in plasma levels compared to mice dosed with Zanamivir alone. This demonstrates that the BAC enhancement effect can withstand the gastric environment and any dilution effects that normally occur with oral dosing.

[0081] Fig. 7 uses the same dosing as Fig. 6: Oral dosing of zanamivir (40 mg/kg) with and without BAC (120 mg/kg) in fasted mice. Fasted animals are dosed by oral gavage with Zanamivir at 40 mg/kg (open circles) or Zanamivir at 40 mg/kg + 120 mg/kg BAC-A6 (closed squares). Increasing the dose 10 fold to 40 mg/kg of zanamivir while maintaining the same ratio of BAC to drug (3 to 1 weight to weight) increases the plasma levels of zanamivir greater than 10-fold over that seen with zanamivir alone. In this experiment, an early time point (0.5 hours) is added to determine how rapid the absorption is. Therefore, direct comparison of C_maχ peak concentrations cannot be made. However, from these experiments, it is clear that the BAC absorption effect can be seen over at least a 10-fold range of therapeutic dosage.

[0082] Oral dosing of zanamivir (10 mg/kg) with and without BAC (30 mg/kg) in fed mice is shown in Fig. 8. Fed animals are dosed by oral gavage with zanamivir at 10 mg/kg (open circles) or Zanamivir at 10 mg/kg + 30 mg/kg BAC-A6 (closed squares), with plasma zanamivir levels determined at the times indicated. The data represent the average of two mice per data point. Fed mice are dosed by oral gavage with either zanamivir alone or in the presence of BAC at the 3:1 weight to weight ratio. The absorption enhancement by BAC occurs in the fed state, with an approximate 2.5-fold increase in serum concentrations of zanamivir at all time points examined. A diminution of the C_max and prolongation of the of the absorption and elimination phases is not uncommon in fed state studies. The results clearly show that the BAC effect is evident in the fed state.

[0083] Oral dosing of zanamivir (10 mg/kg) at increasing levels of BAC in fed mice is shown in Fig. 9. Fed animals are dosed by oral gavage with zanamivir at 10 mg/kg (open circles), zanamivir at 10 mg/kg + 30 mg/kg BAC- A6 (closed squares), and zanamivir at 10 mg/kg + 60 mg/kg BAC-A6 (closed triangles), with plasma zanamivir levels determined at the times indicated. Each data point represents the average of two mice. Increasing the BAC to drug ratio to 6:1 weight to weight, dramatically increases the plasma level of zanamivir. Peak serum concentrations of zanamivir are approximated 3-fold higher using a 3:1 w/w ratio and 8-fold higher with the higher 6:1 ratio of BAC-A6:zanamivir.

Example 11

The ability of various BAC analogs to enhance the oral bioavailability of the test drug zanamivir in mice

[0084] Oral gavage (PO) dosing solutions of delivery agent compound and zanamivir in water are prepared. The final dosing solutions are prepared by mixing the compound solution with an equal volume of zanamivir stock solution (having a concentration twice the desired final concentration) and diluting to the desired volume (0.2 ml per animal). Representative compound and zanamivir dose amounts are listed in Tables 4 and 5.

[0085] Male Swiss CFW mice 25-28 g are fasted overnight (unless indicated) and lightly anesthetized with isoflurane by inhalation prior to oral dosing. The mice are administered 0.2 ml of the dosing solution. At each time point, 4 mice are sacrificed from each group and blood is collected by cardiac puncture and plasma fractions prepared. Plasma zanamivir concentrations are quantified by LC/MS/MS analysis.

[0086] Tables 4-5 demonstrate the BAC enhancement of zanamivir absorption in mice when the BACrzanamivir complex is orally administered by gavage. The effect is evident over at least a 10-fold range in dosage level and is seen in both fed and fasted state. Further, altering the ratio of BAC to drug can significantly alter the extent of absorption. TABLE 4

Oral Gavage (Fasted Mice) Dose 1 mg/kg zanamivir, bile acid amidyl

BACs at Ix i fequal molar). Plasma samples are taken at 30 min.

Increase in

Mean Plasma Zanamivir concentration above

Concentration (ng/ml) H2O control (fold)

H2O control 55 1

A3 145 3

C8 223 4 ^"

B7 228 4

A4 458 8

DI l 575 10

A6 891 16

E9 - 1227 22

TABLE : 5

Oral Gavage (Fasted Mice) Dose 4 mg/kg Zanamivir,

BACs at Ix (equal molar). Plasma samples are taken at 30 and 60 min.

Plasma Zanamivir t Concentration

Increase above

BAC 30 min mean 60 min mean AUC 0-1 hr H2O control

Motif # arginines (ng/ml) (ng/ml) (ng/ml/hr) (fold)

H2O

Control 0 129.36 93.54 88.06 1.00

A6 6 1058.43 138.37 563.81 6.40

R6 6 241.29 373.63 214.05 2.43

A9 9 418.08 181.59 254.44 2.89

C5 4 211.96 124.82 137.19 1.56

A5 5 184.08 411.02 194.79 2.21

DI l 6 285.18 226.12 199.12 2.26

BI l 9 857.09 460.96 543.78 6.17

E9 3 169.84 379.28 179.74 2.04

E13 4 264.50 411.28 235.07 2.67

A7 7 160.86 86.46 102.04 1.16

A8 8 219.95 150.82 147.68 1.68

C8 6 414.63 189.98 254.81 2.89

CI l 8 330.98 281.19 235.79 2.68

A4 4 275.09 296.16 211.59 2.40

D9 5 950.51 177.55 519.64 5.90 Example 12

Effects of BAC analogs on alendronate oral delivery

[0087] Oral gavage (PO) dosing solutions of selected BAC and ¹⁴C labeled alendronate are prepared in water. A stock solution of alendronate is made in water.

The final dosing solutions are prepared by mixing the compound solution with an equal volume of alendronate stock solution (having a concentration twice the desired final concentration) and diluting to the desired volume (0.2 ml per animal).

[0088] Male Swiss CFW mice 25-28 g are fasted overnight (unless indicated) and lightly anesthetized with isoflurane by inhalation prior to oral dosing. The mice are administered 0.2 ml of the dosing solution. At each time point, 3-4 mice are sacrificed from each group and blood is collected by cardiac puncture and plasma fractions prepared. Plasma alendronate concentrations are quantified by scintillation counting. Representative results comparing fasted and fed animals are depicted in

Tables 6-8 and Figs. 10-15.

TABLE 6

BAC increases absorption of alendronate in fasted mice.

Alendronate to fasted animals 4 mg/kg 100 μg/dose BAC-A64x molar ratio

Ox 17.37 ng/ml/hr 4.06 fold increase 4x 70.59 ng/ml/hr

TABLE 7

BAC increases absorption of alendronate in fed mice.

Alendronate to fed animals 4 mg/kg 100 μg/dose BAC-A6 4x molar ratio

Alendronate AUC + BAC-A6 4X

molar

Ng/ml +/- S.D. AUC ng/ml +/- S.D. AUC

0.00 0.00 0.00 0.00 0.00 0.00

22.39 12.20 2.80 82.61 29.49 10.33

29.86 18.64 13.06 66.73 17.03 37.34

27.99 12.20 7.23 67.79 25.24 16.81

13.06 13.23 20.53 34.95 14.00 51.37 U)

0.93 1.62 14.00 6.35 7.41 41.31

57.62 157.15

Ox 14.40 ng/ml/hr 2.73 fold increase

4x 39.29 ng/ml/hr

TABLE 8

BAC increases absorption of alendronate in fed mice at a lower dosage.

Alendronate to fed animals 0.4 mg/kg 10 μg/dose BAC-A6 4x molar ratio

Alendronate 5.57 πg/ml/hr 1.61 fold increase

+4x molar 8.96 ng/ml/hr

bile acid

BAC-A6

Example 13

Increasing the BAC molar ratio enhances the oral bioavailability of alendronate in fasted mice.

[0089] Oral gavage (PO) dosing solutions of delivery agent compound and ¹⁴C labeled alendronate in water are prepared. An additional stock solution of alendronate is made in water. The final dosing solutions are prepared by mixing the compound solution with an equal volume of alendronate stock solution (having a concentration twice the desired final concentration) and diluting to the desired volume (0.2 ml per animal).

[0090] Male Swiss CFW mice 25-28 g are fasted overnight (unless indicated) and lightly anesthetized with isoflurane by inhalation prior to oral dosing. The mice are administered 0.2 ml of the dosing solution. At each time point, 3-4 mice are sacrificed from each group and blood is collected by cardiac puncture and plasma fractions prepared. Plasma alendronate concentrations are quantified by scintillation counting. Representative results are depicted in Table 9 and Figs. 13-14.

TABLE 9

BAC increases absorption of alendronate in fasted mice in dose response manner.

Alendronate to fasted animals 4mg/kg 100 μg/dose and (bile acid) BAC-A6 0x-4x molar ratio

+ BAC 3X molar + BAC 4X molar

+/- +/- U)

0.00 0.00 0.00 0.00 0.00 0 v4

342.04 127.29 42.75 333.02 310.40 41.6269319

328.95 108.78 83.87 350.04 45.49 85.3825137

214.39 48.60 67.92 232.73 66.90 72.8471308

166.93 64.80 47.66 234.62 10.70 58.4196146

178.38 127.29 172.66 117.31 37.46 175.968394

62.19 27.77 119.20 24.08

^",!i^: 414.87 434.244585

Ox 29.99 ng/ml/hr

Ix 124.76 ng/ml/hr

2x 148.09 ng/ml/hr

3x 207.43 ng/ml/hr

4x 217.12 ng/ml/hr

Example 14

Effects of BAC analogs on Methotrexate bioavailability following oral delivery

[0091] Groups of mice are dosed by oral gavage with a solution (0.2 ml) containing methotrexate (MTX) alone, with CDCA, or with the BACs A6 or E9, at increasing molar ratio levels. Plasma is sampled 30 min after dosing. A stock solution of MTX is made in water with NaOH added to solubilize the MTX. Final dosing solutions are prepared by mixing selected BAC solution with an equal volume of MTX stock solution (having a concentration twice the desired final concentration) and diluting to the desired volume (0.2 ml per animal).

[0092] Male Swiss CFW mice 25-28 g are fasted overnight (unless indicated) and lightly anesthetized with isoflurane by inhalation prior to oral dosing. Mice are administered 0.2 ml of the dosing solution. At each time point, 3-4 mice are sacrificed from each group and blood is collected by cardiac puncture and plasma fractions prepared. Plasma MTX concentrations are quantified by HPLC analysis. Increasing molar ratios of BACs to methotrexate increases serum drug concentrations in mice, as shown in Fig. 22 with plasma concentrations measured 30 min after gavage with 10 mg/kg MTX and Ix, 2x or 3x molar ratios of the BAC_A6 (N-A6 motif of chenoxycholamide)and BAC E9 BAC_A6 (N-E9 motif of chenoxycholamide)or with CDCA. N=3 animals per time point. Error bars indicate standard deviation. The BAC A6 at a Ix, 2x or 3x molar ratios with MTX, increases plasma serum concentration of MTX approximately 2-fold.

Example 15

Bone Deposition of alendronate after Oral Delivery

[0093] Oral gavage (PO) dosing stock solutions of delivery agent compound

(bile acid) BAC-A6 and ¹⁴C labeled alendronate in water are prepared. The final dosing solutions are prepared by mixing the compound solution with an equal volume of alendronate stock solution having a concentration twice the desired final concentration and diluting to the desired volume (0.2 ml per animal, 4 mg/kg alendronate with or without 4x molar ratio of BAC- A6).

[0094] Male Swiss CFW mice 25-28 g are fed or fasted overnight and subsequently lightly anesthetized with isoflurane by inhalation prior to oral dosing. Mice are administered 0.2 ml of the dosing solution. 24 hrs after dosing the mice are sacrificed and the tibia collected. Bone alendronate dpm are quantified after oxidation of the samples, collecting the carbon dioxide generated. The amount of ¹⁴CO₂ is quantified by scintillation counting

TABLE 11

Bone Deposition of ¹⁴C-alendronate 24 hours after oral dosing.

BAC-A6 increases the absorption and deposition in bone of alendronate after dosing in either fed and fasted animals.

mean dpm/mg

Test condition bone +/- S.D. Fold increase

Fasted Alendronate 3.92 2.39 1.0

Fasted Alendronate + BAC-A6 95.90 28.08 24.5

Fed Alendronate 9.51 6.61 1.0

Fed Alendronate + BAC-A6 38.27 16.52 4.0

Example 16

Effects of BAC_A6 on cidofovir bioavailability following oral delivery

[0095] Groups of mice are dosed by oral gavage with a solution (0.2 ml) containing cidofovir (4 mg/kg) with and without BAC_A6 (12 mg/kg) in fasted mice. Plasma is sampled 30 min after dosing. Final dosing solutions are prepared by mixing BAC solution with an equal volume of cidofovir stock solution (having a concentration twice the desired final concentration) and diluting to the desired volume (0.2 ml per animal).

[0096] Male Swiss CFW mice 25-28 g are fasted overnight, and lightly anesthetized with isoflurane by inhalation prior to oral dosing. Mice are administered 0.2 ml of the dosing solution. At each time point, 3-4 mice are sacrificed from each group and blood is collected by cardiac puncture and plasma fractions prepared. Plasma cidofovir concentrations are quantified by LC/MS/MS analysis. The BAC_A6 at a Ix molar ratio with cidofovir, increases plasma serum concentration of cidofovir approximately 2-3fold.

[0100] Patent applications and publications mentioned in the specification are indicative of the levels of those skilled in the art to which the invention pertains. These applications and publications are incorporated herein by reference to the same extent as if each individual application or publication was specifically and individually incorporated herein by reference.

[0101] The foregoing description is illustrative of particular embodiments of the invention, but is not meant to be a limitation upon the practice thereof. The following claims, including all equivalents thereof, are intended to define the scope of the invention.

[0102] What is claimed is:

Claims

1. A pharmaceutical composition for increasing bioavailability of a therapeutic in a subject comprising in combination:

the therapeutic having an ionic charge at a physiological pH; and

compound having the formula:

RC(O)-X-Z (I)

where RC(O)- is a reaction product of bile acid (5β-CHOLANIC ACID-3α, 7α, -DIOL) or a derivative of the form RCOOH and the derivative is lithocholic acid, deoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, ursocholic acid, hyocholic acid, hyodeoxycholic acid, murocholic acid, dehydrocholic acid, 7- ketodeoxycholic acid, dehydrocholic acid, diketocholanic acid, triketocholanic acid, isolithocholic acid, ketolithocholic acid, dehydrolithocholic acid, allocholanic acid, or a salt thereof;

where Z is a 1 to 50 amino acid residue chain having a net charge at physiological pH through at least 20 residue percent basic residues of arginine, lysine, or a combination thereof; at least 20 residue percent acid residues of aspartic acid, glutamic acid, or a combination thereof; or a privileged lysine containing internalization moiety of any one of SEQ ID Nos. 11-18;

where X is a nullity or has a structure prior to reaction with RCOOH of Mr B-M₂, where Mi is an amine, CH₂=CH-, iodo-, bromo-, chloro-, or N₂-; where M₂ is amine, CH₂=CH-, iodo-, bromo-, chloro-, or N₂-, carboxylate, thionyl chloride, or acid chloride; and where B is a carbon backbone of 1 to 5 amino acid residues, C₂- C16 alkyl, C₂-C₁₆ alkenyl, C₂-Cie aryl, and C₂-Ci₆ heteroaromatic compounds, where the heteroatom is O, N, or S; and the compound (I) having an ionic charge opposite that of the ionic charge of the therapeutic at the physiological pH, the compound associated with the therapeutic and present in an amount to neutralize at least in part the ionic charge.

2. The composition of claim 1, where the RCOOH is lithocholic acid, deoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, or ursocholic acid or a combination thereof.

3. The composition of claim 1 wherein Z is polycationic.

4. The composition of claim 4 wherein Z contains at least six residues.

5. The compound of claim 1 where Z contains a 3 to 12 amino acid residue chain.

6. The composition of claim 1 where Z is less than 25 total residues in length and more than 35 residue percent arginine or 45 residue percent lysine.

7. The composition of claim 1 where Z is all arginine residues.

8. The composition of claim 1 where Z is a transportan.

9. The composition of claim 1 where Z is a penetratin.

10. The composition of claim 1 where RC(O)- forms and amide bond with X or Z.

1 1. The composition of claim 10 where X has a substituent pendent from B. wherein the substituent is selected from the group consisting of: a radioactive atom, a magnetic spectroscopically active marker and an organic dye.

12. The composition of claim 1 where X is a the 1 to 5 amino acid residue chain and Z has at least 9 amino acids in the amino acid residue chain.

13. The composition of claim 1 wherein the amount of the compound present is sufficient to form a micelle around the therapeutic at the physiological pH.

14 The composition of claim 1 wherein the therapeutic is anionic.

15. The composition of claim 1 wherein the therapeutic is selected from the group consisting of 1-dopa, benazeprilat, captoprilat, enalaprilat, fosinoprilat, lisinoprilat, perindoprilat, ouinaprilat, lamiprilat, spiraprilat, trandolaprilat, moexiprilat, cefaclor, cefadroxil, cefamandole, cefatrizine, cefazedone, cefazuflur, cefazolin, cefbuperazone, cefclidine, cefepime, cefetecol, cefixime, cefluprenam, cefmenoxime, cefinetazole, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotefan, cefotiam, cefoxitin, cefpimizole, cefpirome, cefoselis, cefozopran, cefpirome, cefquinome, cefpodoximc, cefroxadine, cefsulodin, cefpiramide, ceftazidime, ceftezole, ceftizoxime, ceftriaxone, cefuroxime, cephacetrile, cephalexin, cephaloglycin, cephaloridine, cephalosporin, cephanone, cephradine, latamoxef, amoxycillin, ampicillin, apalcillin, azidocillϊn, azlocillin, benzylpencillin, carbenicillin, carfecillin, carindacillin, cloxacillin, cyclacillin, dicloxacillin, epicillin, flucloxacillin, hetacillin, methicillin, mezlocillin, nafcillin, oxacillin, phenethicillin, piperacillin, sulbeniclliπ, temocillin, ticarcillin, imipenem, meropenem, ertapenem, faropenem, doripenem, danipenem/betamipron, tazobactam, argatroban, melagatran, napsagatran, zanamivir, peramivir, oseltamivir, acametacin, alclofenac, alminoprofen, aspirin (acetylsalicylic acid), 4-biphenylacetic acid, bucloxic acid, carprofen, cinchofen, cinmetacin, clometacin, clonixin, diclenofac, diflunisal, etodolac, fenbufen, fenclofenac, fenclosic acid, fenoprofen, ferobufen, flufenamic acid, flufenisal, flurbiprofin, fluprofen, flutiazin, ibufenac, ibuprofen, indomethacin, indoprofen, ketoprofen, ketorolac, lonazolac, loxoprofen, meclofenamic acid, mefenamic acid, 2-(8-methyl-10,l 1-dihydro-l l-oxodibenz[b,fjoxepin-2-yl)propionϊc acid, naproxen, nifluminic acid, O-(carbamoylphenoxy)acetic acid, oxoprozin, pirprofen, prodolic acid, salicylic acid, salicylsalicylic acid, sulindac, suprofen, tiaprofenic acid, tolfenamic acid, tolmetin, zopemirac, ciprostene, 16-deoxy-16- hydroxy- 16- vinyl prostaglandin E₂, 6,16-dimethylprostaglandin E₂, epoprostostenol, meteneprost, nileprost, prostacyclin, prostaglandins E₁, E₂, or F_2α, thromboxane A₂, acrosoxacin, cinoxacin, ciprofloxacin, enoxacin, fleroxacin, flumequine, gatifloxacin, gemifloxacin, grepafloxacin, levofloxacin, lomefloxacin, moxifioxacin, naladixic acid, norfloxacin, ofloxacin, oxolinic acid, pefloxacin, pipemidic acid, piromidic acid, prulifloxacin, rufloxacin, rosoxacin, sitailoxacin, sparfloxacin, temafloxacin, and trovafloxacin, aztreonam, imipenem, meropenem, clorazepate, gabapentin, valproic acid, nateglinide, repaglinide, mitiglinide, furosemide, atorvastatin, cerivastatin, fluvastatin, lovastatin acid, mevastatin acid , pravastatin, pravastatin acid, rosuvastatin, simvastatin, hydralazine, pemetrexed, nicardipine, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, zoledronic acid etidronic acid, clodronic acid, tiludronic acid, mycophenolic acid, etoposide phosphate, melphalan, methotrexate, pemetrexed, candesartan, telmisartan, valsartan, aminocaproic acid, acetohydroxamic acid, verteporfin, liothyronine, cromolyn, penicillamine, dimercaptosuccinic acid, ethacrynic acid, montelukast, adefovir, cidofovir, cyclic cidofovir, foscarnet, and tenofovir.

16. The composition of claim 1 wherein the therapeutic is cationic.

17. The composition of claim 16 wherein the therapeutic is selected from the group consisting of: magnesium hydroxide, aluminum hydroxide, calcium carbonate ferrous sulfate, ferrous gluconate, ferrous fumarate, iron-polysaccharide .complex, mineral containing multivitamins, sucralfate, amiloride, triamterene, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, trimethoprim, vancomycin, gentamycin, tetracaine, lidocaine, chlorpromazine, propranolol, amantadine, pseudoephedrine: atracurium, mivacurium, cisatracurium, dicyclomine, alfuzosin, terazosin, amlodipine, verapamil, gallopamil, bosentan, cinacalcet, metoprolol, propranolol, timolol, atenolol, pralidoxime, ,daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, irinotecan; , leuprolide, apraclonidine, clonidine, doxazosin, guanethidine, guanfacine, lofexidine, mecamylamine, methyldopa, moxonidine, prazosin, almotriptan, rizatriptan, darifenacin, methylphenidate, tegaserod, zolmϊtriptan, ziprasidone; mesylate, doxazosin, phenoxybenzamine, sildenafil, vardenafil, sunitinib, nelfinavir, sertraline, metformin, granisetron, mefloquine; Zolpidem, anagrelide, midodrine, selegiline, pergolide, vancomycin, telavancin, oritavancin, venlafaxine, tigecycline, tamoxifen, 4- hydroxytamoxifen, hydralazine, dihydralazine, and pioglitazone.

18. The composition of claim 1 further comprising a pharmaceutically acceptable oral carrier.

19. A process for increasing bioavailability to a subject of a therapeutic having an ionic charge at physiological pH comprising: administering to the subject in a therapeutically effective amount the therapeutic in concert with the compound having a charge opposite the ionic charge of the therapeutic.

20. The process of claim 19, wherein said administering step is by a route selected from the group consisting of: oral, topical, nasal or inhalational administration.

21. The process of claim 19, wherein the therapeutic is delivered to a subject bloodstream for a period up to twenty-four hours.

22. The process of claim 19, wherein said administering is by parenteral administration.

23. The process of claim 19, wherein further comprising: forming a micelle of the compound of claim 1 around the therapeutic prior to said administering.

24. Use a compound of formula I for to facilitate delivery of a therapeutic to epithelial cells.

25. A process for therapeutic delivery substantially as described herein in any of the examples.