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WO1996021440A1 - Procedes pour accroitre la biodisponibilite d'agents ayant une activite biologique - Google Patents

Procedes pour accroitre la biodisponibilite d'agents ayant une activite biologique Download PDF

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Publication number
WO1996021440A1
WO1996021440A1 PCT/US1995/016161 US9516161W WO9621440A1 WO 1996021440 A1 WO1996021440 A1 WO 1996021440A1 US 9516161 W US9516161 W US 9516161W WO 9621440 A1 WO9621440 A1 WO 9621440A1
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Prior art keywords
compound
phosphate
inositol
groups
therapeutic
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PCT/US1995/016161
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English (en)
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WO1996021440A9 (fr
Inventor
Harry N. Antoniades
Marc D'alarcao
Helion Povoa
Original Assignee
Alpha-Therapeutics, Inc.
Trustees Of Tufts College
ANTONIADES, Nicholas, H.
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Application filed by Alpha-Therapeutics, Inc., Trustees Of Tufts College, ANTONIADES, Nicholas, H. filed Critical Alpha-Therapeutics, Inc.
Priority to AU45159/96A priority Critical patent/AU4515996A/en
Publication of WO1996021440A1 publication Critical patent/WO1996021440A1/fr
Publication of WO1996021440A9 publication Critical patent/WO1996021440A9/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/548—Phosphates or phosphonates, e.g. bone-seeking
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/6552—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring
    • C07F9/65522—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring condensed with carbocyclic rings or carbocyclic ring systems

Definitions

  • a potential medicinal agent may exhibit desirable in vitro and in vivo biological activity, yet not be therapeutically useful because of low absorption, poor solubility, or inability to reach the appropriate target site in a concentration sufficient for effectiveness. Poor bioavailability may result from one or more of such characteristics.
  • Flavonoids are an example of compounds with desirable biological activities whose use as therapeutic agents is limited by poor bioavailability. Flavonoids are flavone (2-phenylchrome; 2- phenyl- -benzopyrene; 2-phenyl-l, 4-benzopyron) derivatives constituting a class of naturally occurring molecules isolated from various plants.
  • flavonoids include apigenin (4', 5-7-trihydroxyflavone) ; genistein (4', 5, 7, trihydroxy-isoflavone) ; guercetin (3, 3 ' , 4', 5-7 pentahydroxy-flavone) ; rutin (guercetin-3-rutinoside) ; conjugated forms such as guercetin pentaacetate, and guercetin 3-D-galactoside; and phenolic and lipophilic poly ethoxylated flavonoids, such as nobiletin and tangeretin (Kandaswa i et. al (1991) Cancer Lett. 56:147-52). Examples of naturally occurring flavonoids are shown in Figure 1.
  • the isoflavonoid genistein is a potent, and specific inhibitor of tryosine protein kinases (Akiyama et al. (1987) J. Biol. Chem. 262; 5592-5595.
  • This in vivo study confirmed previous data in cell culture which demonstrated the inhibitory effects of other flavonoids such as guercetin, on the proliferation of human leukemic cells in culture, including human leukemic cell line K562 (Hoffman et al. (1988) Brit. J. Cancer 59: 347-348); acute myeloid and lymphoid leukemia progenitors (Larocca et al. (1991) Brit. J. Haematol.
  • Flavonoids are relatively insoluble in water. Pharmokinetic studies in humans suggest that less than 1% of orally administered guercetin (4 grams) was absorbed unchanged (Gugler et al. (1975) Eur. J. Clin. Pharmacol. 9:229).
  • camptothecin into a water soluble form (1 mg/ml H20) by first modifying the molecule through the attachment of a hydroxyl group at position 9 or 10
  • the invention features methods for enhancing the bioavailability of therapeutic compounds.
  • a conjugate is formed by covalently attaching to the agent a chemical moiety which is highly bioavailable, resulting in increased bioavailability of the agent.
  • a linker element As shown in our examples given below we were capable of conjugating the native, unmodified hydroxyl groups of therapeutic agents to moieties via a linker element, a process yielding molecules of high water solubility ( ⁇ 100mg/ml H20 vs. lmg/ml H20 for the alkylated camptothecin) , and retaining full biologic activity.
  • agent or “potential medicinal agent” is meant a compound having desirable in vitro and/or in vivo biological activity in experimental animals which could potentially be used in the treatment of a disease or malignancy.
  • the agent is a flavonoid or flavonoid derivative.
  • the agent is a nonflavonoid.
  • bioavailability is meant the extent at which an agent is water soluble and therefore injectable, or capable of trespassing the intestinal wall so that it can be absorbed into a living system or is made available at the site of physiological action.
  • An increase in bioavailability means that a larger amount of the administered agent reaches a relevant target site.
  • the chemical moiety is meant a compound possessing high bioavailability and which confers enhanced bioavailibity to an agent as a conjugate.
  • the chemical moiety to be covalently attached to the agent will vary depending on the specific agent used.
  • the chemical moiety increased bioavailabity to an agent is inositol phosphate.
  • inositol phosphate is meant inositol having one or more phosphate groups, including mono- phosphorylated inositol, di-phosphorylated inositol, or poly-phosphorylated inositol.
  • conjugate is meant a synthetic chimeric molecule formed by a covalent bond or bonds between a chemical moiety and a potential medicinal agent, or between a chemical moiety, a linking element. and the agent molecule.
  • the potential medicinal agent possesses enhanced bioavailability relative to the unconjugated agent.
  • the increased bioavailability of an agent results from an increase in its solubility in a biological fluid. Solubility of the agent in the desired medium results from modifying the polarity of the agent. Accordingly, in one aspect, the bioavailability of an agent is increased by covalent attachment of a chemical moiety that alters the polarity of the agent, increasing its solubility in the desired medium.
  • a third method of increasing the bioavailability of an agent is to effectively increase the concentration of the agent at the target cell.
  • the bioavailability of an agent is increased by covalent binding to a chemical moiety which binds a specific target cell.
  • the resulting conjugate binds the target cell, increasing the concentration of the agent at the target cell.
  • the chemical moiety is actively transported into the target cell.
  • the resulting conjugate is transported into the target cell, resulting in delivery of the bound agent to the target cell.
  • An example of a chemical moiety actively transported into a target cell is inositol phosphate, which is transported into cells having an active inositol phosphate transport system.
  • the conjugate may be formed by direct covalent attachment to a chemical moiety to the agent, or by indirect attachment to a chemical moiety via a linking element.
  • linking element is meant a chemical element connecting the agent and chemical moiety.
  • the linking element is a carbon chain having between 1 to 5 carbons in length and having one or more reactive moieties such that other groups may be attached to the linking element.
  • the linking element may increase the aqueous or lipid solubility of the agent.
  • the linking element may function to enhance the bioavailability of the agent or may be utilized to facilitate conjugate synthesis.
  • the linking element is succinate.
  • the linking element connects multiple agent molecules to a cell targeting chemical moiety, this increasing the effective concentration of the agent at the target site.
  • the invention encompasses various methods for attachment of the chemical moiety to the potential medicinal agent.
  • a conjugate is formed by attachment of inositol phosphate to a flavonoid molecule.
  • the conjugate is formed by attachment of inositol phosphate to a flavonoid through the phosphate group of the inositol (for example, see Fig. 3A) .
  • the molecules are coupled via a linking element through the phosphate linkage (for example, see Fig. 3B) .
  • the molecules are coupled via a linking element at a position on the inositol other than the phosphorylated position (for examples, see Figs. 3C and 3D) .
  • the invention features flavonoid-inositol phosphate conjugates where the conjugated flavonoid has enhanced bioavailability relative to the unconjugated flavonoid, resulting from improved water-solubility and/or cellular delivery.
  • Inositol phosphate may be conjugated to flavonoids through a covalent bond or series of covalent bonds between inositol phosphate and one or more hydroxyl and/or amino residues of the flavonoid.
  • the flavonoids useful in this invention may be naturally occurring or synthetic.
  • the therapeutic agent is covalently bound to a phosphonate, and preferably to a bisphosphonate, through a linking element.
  • Said bisphosphonate may include, but is not limited to, alendronate, pamidronate, etidronate, clodromate, tiludronate, ibandronate or residronate ( Figure 4 ) . Additional examples of bisphosphonate structures are given in Shinoda et al. (1983) Calcified Tissue International, Springer Verlag, 35: 87-99.
  • Bisphosphonates have been used in the treatment of several clinical conditions, namely ectopic calcification, ectopic bone formation, Paget's disease, osteoporosis and increased osteolysis of malignant origin (Dunn et al. (1994) Drugs and Aging 5: 446-474; Licata
  • Bisphosphonates may be conjugated to a flavonoid or to a nonpeptide nonflavonoid therapeutic agent having one or more hydroxyl groups and/or one or more amino groups.
  • the bisphosphonates and the therapeutic compounds are coupled via a linking element at a position on the bisphosphonate other than the phosphorylated one(s) .
  • Conjugation of therapeutic agents of low water solubility to bisphosphonates may increase their bioavailability by increasing both their water solubility and their localized delivery to bone. This is desirable in the treatment of osteosarcomas when the agent is cytotoxic for human malignant osteosarcoma cells.
  • apigenin, guercetin, and camptothecin exhibit strong antiproliferative effects on primary human osteosarcoma cells in culture.
  • Agents conjugated to bisphosphonate which are capable of inhibiting tyrosine protein kinases, such as flavonoids (Hagiwaza ewt. al. (1977) ibid; Grazian et. al. (1983) ibid; Akiyama et. al.
  • osteoporotic lesions may be delivered by the bisphosphonates to osteoporotic lesions in the bones of human patients with osteoporosis. Inhibition of tyrosine kinase activity in osteoclasts at the site of osteoporotic lesions may result in a decrease activity of bone resorption which is promoted by osteoclasts. Osteoclast proliferation has been shown to be sensitive to tyrosine kinase activity C. Hall et al. (1994) Bioch. Bioph. Res. Commun., 199: 1237-1244; Yoneda et al. (1993) J. Clin. Invest., 91: 2791-2795; Lowe et al. (1993) Proc. Nat'1. Acad. sci. USA, 90: 4485-4489.
  • CD19-receptor of the leukemic cells may be used to increase the water solubility and site delivery of other non-flavonoid compounds.
  • the solubility of a compound in water may be increased by formation of a conjugate between a chemical moiety and a non-flavonoid compound having one or more hydroxyl groups and/or one or more amino groups.
  • the conjugate of the invention may be administered to a patient in a number of ways known to the art, including, intravenous, parenteral, intranasal, oral, topical, transdermal, and subcutaneous sustained release injectable implant formulations.
  • Formulations may be prepared by any of the techniques known in the pharmaceutical arts. Such techniques are described, for example in Remington's Pharmaceutical Sciences ((1980)
  • Formulations for parenteral administration may contain common excipient such as sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated napthalenes, and others of similar nature.
  • polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated napthalenes, and others of similar nature.
  • biocompatible, biodegradable lactate polymers, lactate/glycoside copolymers, or polyoxethylene-polyoxy-propylene copolymers may be useful excipient to control the release of the conjugate of the invention.
  • Other potentially useful parenteral delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.
  • Formulations for administration by inhalation may contain excipient such as, for example, lactose.
  • Inhalation formulas may be aqueous solutions containing excipient such as, for example, polyoxyethylene 9-lauryl ether, glycocholate and deoxycholate, or they may be oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasal.
  • Compositions for parenteral administration may also include glycocholate for buccal administration, or cikic acid for vaginal administration.
  • Topical administration may utilize slow releasing patches.
  • Fig. 2 provides examples of the chemical structures of active synthetic flavonoids.
  • Fig. 3 is a diagram illustrating four methods for the synthetic coupling of inositol phosphate to a flavonoid derivative.
  • Fig. 3A shows coupling of the components through the phosphate group.
  • Fig. 3B shows coupling via a linking element through the phosphate linkage.
  • Figs. 3C and 3D show coupling via a linking element at a position on the inositol other than the phosphorylated one(s) ..
  • Fig. 4 contains examples of bisphosphonates.
  • Fig. 5 and Fig. 6 are synthetic pathways for preparation of a phosphoinositol-succinate linked quercetin.
  • Fig. 7 is a synthetic pathway for preparation of a phosphoinositol-succinate linked apigenin.
  • Fig. 8 is a synthetic pathway for preparation of e phosphoinositol-succinate linked genistein.
  • Fig. 9 is a synthetic pathway for preparation of an inositol phosphate linked regioselectively to quercetin via a glycerol linker.
  • Fig. 10 is a synthetic pathway for preparation of a phosphoinositol quercetin linked through the phosphate group.
  • Fig. 11 Antiproliferative activity of quercetin and phosphoinositol-succinate linked quercetin on a primary human adenocarcinoma cell line (SW 480) in culture.
  • the biologic activity of the water- soluble conjugated quercetin (6c) is similar to that of unconjugated guercetin. In all biologic studies the unconjugated guercetin was dissolved in dimethylsulfoxide (DMSO) .
  • DMSO dimethylsulfoxide
  • Fig. 12 Antiproliferative activity of quercetin and phosphoinositol-succinate linked quercetin on a primary human osteosarcoma cell line (MG 63) in culture.
  • the biologic activity of the water-soluble conjugated quercetin (6c) is similar to that of unconjugated quercetin.
  • Fig.13 A bisphosphonate-coupled flavonoid.
  • the invention features methods for increasing the bioavailability of a potential medicinal agent such that the agent becomes therapeutically useful.
  • the methods of the invention are particularly useful with a biologically active agent whose therapeutic use is limited by low bioavailability.
  • the invention may be used with any agent for which increased bioavailability is desired.
  • the bioavailability of any agent may be low due to a variety of factors, including low solubility and/or low rate of transport to its target cell.
  • the bioavailability of an agent may be low due to its inability to reach an effective concentration at the site of the target cell.
  • the invention provides methods for overcoming these problems, thus increasing the medicinal usefulness of a variety of biologically active agents.
  • flavonoid derivatives have antiproliferative effects on malignant cells in vitro and in experimental animals in vivo. Their therapeutic use is precluded, however, by their poor water solubility.
  • the present invention provides for increasing the water solubility of the therapeutic agents.
  • the methods of the invention may also be used to increase the cellular delivery of any agent by allowing the agent to be actively transported into cells by the cell membrane inositol phosphate transport system. (See, Saltiel and Sorbara-Cazan (1987) Biochem. Biophys. Res. Commun. 149:1084-1092).
  • Bisphosphonate-linked flavonoid and nonflavonoid therapeutic compounds may be delivered to bone lesions of patients with osteosarcomas or osteoporosis.
  • the methods of the invention are preferably used with agents having biological activates which would be useful in the treatment of diseases, such as the antiiproliferative effect of flavonoid in tumors, leukemia, and nonmalignant proliferative disorders such as psoriasis.
  • flavonoid is meant any flavone molecule containing one or more hydroxyl groups and/or one or more amino groups.
  • a linking element at a position on the inositol other than the phosphorylated one(s) (for examples, see Figs. 3C and 3D) .
  • Each synthetic method of the invention may be varied in the position(s) of attachment to the inositol and the flavonoid, in the number and position of phosphate groups, in the length and chemical nature of the linking unit, in the flavonoid derivative coupled, and in the inositol isomer used (e.g., myo- or chiro-, etc.).
  • Linking elements include succinate diester, 4-hydroxybutyrate ester phosphate diester, and glycerol diester.
  • flavonoids are conjugated to inositol-2 phosphate via a succinate linker.
  • suitable linkers include alkyl chains, mono or poly alcohol units, mono- or polyether units, thioethers, mono- or polyester units, mono- or polyamine units, mono- or polysulfates, mono- or polyarenes, mono- or polyphosphates, mono- or polyamides, peptides, mono- or polysulfides, mono- or polysaccharide, or a combination of these structures.
  • the invention is shown herein in what is considered to be the most practical and preferred embodiments.
  • Example 1 Preparation of (quercetin-5-yl) (myo-inositol-2- phosphate-1-yl) succinate.
  • Compound 6c (quercetin-5-yl) (myo-inositol-2-phosphate-l-yl) succinate) may be prepared as illustrated in Figs. 5 and 6. 3,4,5,6-Tetra-benzyl-l-(1,1,1,-trichloroethylchloro- formyl)-Myo inositol.
  • reaction mixture was then cooled to -42-C (MeCN/C02) and 2.1 ml of 1 M 85% MCPBA in CH2C12 was added. The ice bath was immediately removed and the reaction mixture allowed to warm to room temperature. After ten minutes, 5 ml of 0.1 M NH4 HC03 buffer (Ph 7.87) and 5 ml of 10% Na2S204 were added. The crude reaction mixture was extracted with
  • An inositol-phosphate-quercetin derivatives may be prepared as shown in Fig. 10. Generally, 3,4,5,6-tetrabenzyl yo-inositol is treated with benzyl bis(disopropylamino-phosphoramidite followed by a peracid to produce the 1,2-cyclic phosphate. Subsequently, the cyclic phosphate is coupled with guercetin (or a protected quercetin) , which after catalytic hydrogenation produces the desired compounds.
  • Fig. 9 illustrates a synthetic pathway to a coupled guercetin with a glycerol linker.
  • 3,4,5,6- tetrabenzyl myo-inositol is treated with allyl bromide, then phosphorylated.
  • the peracid generates concomitantly an epoxide at the allyl group.
  • Subsequent treatment with a protected quercetin, followed by deprotection provides the product.
  • Biologic Activity of Water-Soluble Conjugated Flavonoids was determined in vitro in cultures of a primary human colon adenocarcinoma cell line (SW 480) , and a human osteosarcoma cell line (MG-63) .
  • SW 480 primary human colon adenocarcinoma cell line
  • MG-63 human osteosarcoma cell line
  • the malignant cells were plated in 24-well culture plates, and their population was measured after 6 or 9 days of culture in the presence or absence of the test material.
  • the unconjugated flavonoid was dissolved in dimethylsulfoxide (DMSO) and then diluted to the desired concentration with the culture media.
  • DMSO dimethylsulfoxide
  • the water-soluble conjugated flavonoid was dissolved in a minimum volume of distilled water and diluted to the desired concentration with the culture media.

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Abstract

Procédés pour augmenter la biodisponibilité d'un agent médicinal potentiel non peptidique par liaison covalente à une fraction chimique formant un conjugué à la biodisponibilité et à la solubilité dans l'eau accrues par rapport à l'agent non conjugué. Lesdits agents médicinaux incluent des composés flavonoïdes et non flavonoïdes ayant une activité biologique, dont la solubilité dans l'eau et la biodisponibilité sont accrues par liaison covalente à des fractions comprenant des molécules de phosphate d'inositol et de bis-phosphonate.
PCT/US1995/016161 1995-01-09 1995-12-08 Procedes pour accroitre la biodisponibilite d'agents ayant une activite biologique WO1996021440A1 (fr)

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AU45159/96A AU4515996A (en) 1995-01-09 1995-12-08 Methods for increasing the bioavailability of biological active agents

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US37020895A 1995-01-09 1995-01-09
US08/370,208 1995-01-09
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