WO1991017751A1 - Compositions de gallium administrables par voie orale et procedes de traitement les utilisant - Google Patents

Compositions de gallium administrables par voie orale et procedes de traitement les utilisant Download PDF

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Publication number
WO1991017751A1
WO1991017751A1 PCT/US1991/003599 US9103599W WO9117751A1 WO 1991017751 A1 WO1991017751 A1 WO 1991017751A1 US 9103599 W US9103599 W US 9103599W WO 9117751 A1 WO9117751 A1 WO 9117751A1
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gallium
composition
complex
treatment
intestine
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PCT/US1991/003599
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English (en)
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Mahendra Shah
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Fujisawa, Inc.
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Publication of WO1991017751A1 publication Critical patent/WO1991017751A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • 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
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • 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
    • A61K47/545—Heterocyclic compounds

Definitions

  • the present invention relates to the field of pharmaceuticals, generally, and in particular to pharmaceutical compositions containing gallium and their use in the treatment of bone calcium disorders, the treatment of certain cancerous condition:--, and the diagnosis of various conditions through the use of radiodiagnostic techniques.
  • Gallium is a metal which belongs to the Group Ilia elements of the periodic table. By mechanisms which are still uncertain, radioactive gallium salts are known to accumulate in certain tumors. 67-Gallium citrate has been used for diagnostic purposes in patients with bone infections and malignant diseases. In 1952, King et al., (Arch. Int. Med. 90:785 (1952)) first showed that injections of highly radioactive gallium caused tumor regression in cancer patients.
  • U.S. Patent No. 4,303,636 discloses a method of cancer treatment which uses radioactive 67-gallium, as a cytotoxic agent.
  • Non-radioactive salts of gallium and other Group Ilia metals were first evaluated for their anticancer activity in 1971 and gallium was found to be the most potent and least toxic element for reducing the size of animal tumors.
  • Gallium nitrate entered into clinical trials as a cytotoxic anticancer agent in 1976.
  • Gallium has been known for many years to be useful in the treatment of calcium bone disorders.
  • U.S. Patent No. 4,529,593 teaches the use of pharmaceutically acceptable gallium salts to reduce the excessive loss of bone calcium. That patent specifically teaches the use of gallium to prevent or treat disorders associated with extensive loss of calcium from bone in humans by administering to the individual a pharmaceutically acceptable gallium compound.
  • disorders which may be thus prevented or treated are hypercalce ia. osteopeni , osteoporosis, bone ⁇ esrruction due to metastasis from malignant tumors, and hyperparathyroidism.
  • Gallium salts which are disclosed to be of use include the nitrate, citrate, and halide, preferably the chloride, carbonate, acetate, tartrate, oxalate, oxide or hydrated oxide.
  • gallium citrate 67-Ga For the non-invading nuclear medical diagnosis of cancer or tumor, there is ordinarily used gallium citrate 67-Ga.
  • gallium citrate 67-Ga For example, in U.S. Patent No. 4,479,913 there is described an apparatus and method for diagnosing ocular cancer in which the radiation level produced in each eye is measured after the administration of a tumor-localizing radiopharmaceutical, such as gallium-67. Determination of a malignancy is based on the detection of increased radioactive uptake in the area of the tumor.
  • the active compound typically has been administered intravenously.
  • the oral administration of the gallium compounds discussed therein no effective means of oral administration has heretofore been employed.
  • U.S. Patent No. 4,596,710 relates to the application of gallium chloride as drug particularly useful for the treatment of malignant tumors, and to the pharmaceutical compositions purportedly intended for oral administration
  • the anti-tumoral effect of gallium chloride in female dogs having spontaneous malignant tumors of the breast is disclosed.
  • the gallium chloride was administered in the form of drinkable ampoules.
  • the use of gallium chloride in the treatment of malignant tumors of the genital tracts, administered by the oral route is disclosed.
  • acceptance of the oral administration of gallium chloride for such treatment has not existed. It is not known if that has been due to problems with the oral administration of the gallium chloride or due to other reasons. In any event, the oral administration of gallium chloride has not, to date, become an acceptable means of treatment of malignant tumors.
  • gallium can be readily administered orally for use in the treatment of bone calcium disorders, for chemotherapeutic purposes and for radiographic imaging.
  • certain gallium compounds are used for the first time in such pharmaceutical applications by protecting the compositions from dissociation in the stomach while allowing for their release in the intestines.
  • gallium complexes can be absorbed in adequate pharmaceutical doses provided that such complexes are protected from destruction in the stomach and are formulated to be released in the intestine.
  • gallium compositions of the present invention thus provide for ease of administration, because they may be administered orally, whereas gallium compositions used previously in similar applications have typically required intravenous or intramuscular administration.
  • the compounds have the potential to penetrate into regions of the body which were inaccessible to the previously employed gallium compounds.
  • the gallium compounds of use comprise the gallium complexes of 3-hydroxy-4-pyrone or of a 3-hydroxy-4-pyrone in which one or more of the hydrogen atoms attached to ring carbon atoms are replaced by a hydrocarbon group of 1 to 6 carbon atoms.
  • the present invention particularly relates in part to the pharmacologic use in humans and animals of the aforementioned pharmaceutically acceptable gallium compositions in non-nephrotoxic amounts to inhibit resorption of calcium from bone in patients with hypercalcemia, bone fragility or other disorders associated with abnormally increased calcium resorption, by administering to a patient suffering from one of those conditions a therapeutically effective amount of such a compound.
  • the gallium compounds may also be used to treat disorders associated with extensive loss of calcium from bone in a human by administering to the patient a therapeutically effective amount of one of the aforementioned gallium compositions.
  • the present invention provides a method for the treatment of malignant tumors, particularly tumors of the breast and the genital tracts, by administering a therapeutically effective amount of one of the aforementioned gallium compositions.
  • the gallium compounds may be used as radiodiagnostic agents to detect the presence of tumors and the like, by administering such compositions to an individual and then determining if the gallium has been selectively bound to a localized region of the body, signifying the possible presence of a tumor.
  • the present invention relates to the use of compositions comprising certain gallium compounds in several pharmaceutical applications.
  • the compounds employed in the present invention are of particular interest because of their ability to be usefully absorbed into a patient's bloodstream and distributed throughout the body, after oral administration.
  • gallium compounds have been employed in the same or similar applications, but have been hindered by the need to administer the compounds through intravenous injection, or the like.
  • the ability of the gallium compositions of the present invention to be usefully administered orally stems in part from the chemical composition of the ligands which are complexed with the gallium.
  • the hydroxypyrones providing ligands which may be used in complexes according to the present invention all have the general formula (I) , and those of particular interest also have the specific formula (II) or (III) :
  • R is a hydrocarbon group containing from about 1 to about 6 carbon atoms.
  • the hydrocarbon groups may optionally contain heterologous atoms, such as oxygen, sulfur, or the like and may thus include functional groups such as esters, ethers, ketones, and the like.
  • R represents an aliphatic group, most preferably an alkyl group, for example methyl, ethyl, n-propyl isopropyl or butyl.
  • n may be 0, l, 2 or 3
  • the substituted 3-hydroxy-4-pyrones may carry more than one type of hydrocarbon group but this is not usual and, indeed, substitution by one rather than two or three hydrocarbon groups is preferred.
  • the R group represents an aliphatic hydrocarbon group, the same may be cyclic or acyclic, having a branched chain or especially a straight chain in the latter case, and may be unsaturated or especially saturated. Groups of from 1 to 4 carbon atoms and particularly of 1 to 3 carbon atoms are of most interest.
  • Alkyl groups are preferred, for example cyclic groups such as cyclopropyl and especially cyclohexyl, but more particularly preferred are acyclic-alkyl groups such as n-propyl and isopropyl, and especially ethyl and methyl.
  • the gallium complexes are conveniently prepared by the reaction of the hydroxypyrone and gallium ions, the latter conveniently being derived from a gallium salt, particularly a gallium halide and especially gallium chloride.
  • the reaction is conveniently effected in a suitable mutual solvent and water may often be used for this purpose.
  • an aqueous/organic solvent mixture may be used or an organic solvent, for example ethanol, methanol or chloroform and mixtures of these solvents together and/or with water where appropriate.
  • methanol or especially ethanol may be used where it is desired to effect the separation of at least a major part of a by-product such as sodium chloride by precipitation while the gallium complex is retained in solution.
  • Reaction to form the gallium complex is generally rapid and will usually have proceeded substantially to completion after 5 minutes at about 20° C, although a longer reaction time may be used if necessary.
  • the reaction mixture may conveniently be evaporated on a rotary evaporator or freeze dried to yield the solid gallium complex. This may, if desired, be crystallized from a suitable solvent, for example water, an alcohol such as ethanol, or a solvent mixture, including mixtures containing an ether.
  • hydroxypyrones such as maltol
  • a convenient starting material in many instances consists of pyromeconic acid which is readily obtainable by the decarboxylation of meconic acid.
  • pyromeconic acid may be reacted with an aldehyde to insert a 1-hydroxyalkyl group at the 2-position, which group may then be reduced to produce a
  • the present invention relates in part to the pharmacologic use in humans and animals of the aforementioned pharmaceutically acceptable gallium compounds in non-nephrotoxic amounts to treat bone calcium disorders.
  • the gallium compounds are used to inhibit resorption of calcium from bone in patients with hyper ⁇ alcemia, bone fragility or other disorders associated with abnormally increased calcium resorption, by administering to a patient suffering from one of those conditions a therapeutically effective amount of such a compound.
  • the gallium compounds are used to prevent extensive loss of calcium from bone in a human by administering to the patient a therapeutically effective amount of one of the aforementioned gallium compounds.
  • the gallium complexes used in the treatment of such disorders are made with nonradioactive gallium.
  • the compositions are administered orally in sufficient therapeutic quantity to effectively treat the disease.
  • the quantities administered will be sufficient to maintain a serum blood level in the patient of from about 0.1 to about 5.0 micrograms of gallium per ml of blood, preferably from about 0.5 to about 2.0 micrograms of gallium per ml of blood.
  • Such blood levels may be achieve by administering from about 0.1 to about 20 grams of gallium per day to the patient.
  • the gallium complexes of the present invention are employed wherein the gallium may or may not be radioactive, such as gallium-67.
  • the gallium may or may not be radioactive, such as gallium-67.
  • the complexes have the ability to reach areas previously unaccessible to other gallium compositions.
  • the complexes used in accordance with the present invention may permeate the blood-brain barrier, making them useful for the treatment of tumorous conditions of the brain.
  • the gallium complexes of the present invention may be used as radiodiagnostic agents to detect the presence of tumors and the like.
  • the complexes for such a purpose, is made with radioactive gallium (gallium- 67) .
  • the complexes are administered to an individual and then a determination is made as to whether such compounds have been selectively bound to a localized region of the body, signifying the possible presence of a tumor.
  • the gallium complexes may be useful in the detection of tumorous conditions of the brain.
  • the method of detecting localized concentrations of radioactivity is well known in the art.
  • one type of apparatus and method used to detect ocular tumors is described in U.S. patent no. 4,448,763. After administering the gallium-67 complex, the radiation level in both eyes are measured and compared.
  • the quantity of gallium complex administered for the purpose of radiodiagnostically determining the presence of a tumor is not critical. Typically from about 100 mg to about 1000 mg of gallium is administered for such purposes. Because the gallium has been found to preferentially bind to. tumorous cells, a localized concentration of radiation after the gallium complex has been allowed to distribute throughout the body, may be indicative of a tumorous condition.
  • indium competes with gallium for blood and soft tissue binding sites, yet does not compete for gallium binding sites in tumors. Therefore, in accordance with the present invention, it is also contemplated that the gallium complexes used in accordance with the present invention may be administered with indium, as taught in the aforementioned U.S. Patent No. 4,448,763, which is hereby incorporated by reference. As taught in that patent, the indium may be administered before, concurrent with, or after the administration of the gallium complexes of the present invention.
  • Indium may therefore be used as an adjunct in both the use of gallium complexes to treat cancerous conditions, and in the use of the gallium complexes as radiodiagnostic agents.
  • the gallium complexes may be formulated for use as pharmaceuticals by a variety of methods. Where desired, more than one hydroxypyrone gallium complex as described above may be present in the pharmaceutical composition.
  • compositions incorporating a liquid diluent may be used for oral administration, it is preferred to use compositions incorporating a solid carrier, for example a conventional solid carrier material such as starch, lactose, dextrin or magnesium stearate.
  • a solid carrier for example a conventional solid carrier material such as starch, lactose, dextrin or magnesium stearate.
  • the gallium complex will of course be present in such a preferred composition in solid form, which form is accordingly a preferred one for the complex, and such a solid composition may conveniently be presented as some type of formed composition, for example as tablets, capsules (including spansules) , etc.
  • One of several approaches may be employed to avoid or reduce exposure of the gallium complex to the acidic conditions of the stomach and to allow the release of the gallium compounds in the intestine.
  • Such approaches may involve various types of controlled release system, ranging from one, which may for example be based on a polymer, which simply provides a delayed release of the complex with time, through a system which is resistant to dissociation under acidic conditions, for example by the use of buffering, to a system which and is biased towards release under conditions such as prevail in the small intestine, for example a pH sensitive system which is stabilized towards a pH of 1 to 3 such as prevails in the stomach but not one of 7 to 9 such as prevails in the small intestine. Since the pH of the stomach is higher after a meal, it may be advantageous, whatever method of formulation is used, to administer the gallium complexes at such a time.
  • a particularly convenient approach to a controlled release composition involves encapsulating the gallium complex by a material which is resistant to dissociation in the stomach but which is adapted towards dissociation in the small intestine (or possibly, if the dissociation is slow, in the large intestine) .
  • Such encapsulation may be achieved with liposomes, phospholipids generally being resistant to dissociation under acidic conditions.
  • the liposomally entrapped complexes can therefore survive the acid environment of the stomach without dissociating.
  • the pancreatic enzymes On entry into the small intestine, the pancreatic enzymes rapidly destroy the phospholipid-dependent structure of the liposomes thereby releasing the complex. Liposome disruption is further facilitated by the presence of bile salts.
  • One particular method of encapsulation involves the use of gelatine capsules coated with a cellulose acetate phthalate/diethylphthalate layer.
  • This coating protects the gelatin capsule from the action of water under the acid conditions of the stomach where the coating is protonated and therefore stable.
  • the coating is however destabilized under the neutral/alkaline conditions of the intestine where it is not protonated, thereby allowing water to act on the gelatin.
  • Once released in the intestine the rate of permeation of the intestine wall by the water soluble complex is relatively constant irrespective of the position within the intestine, i.e. whether in the jejunum, ileum or large intestine.
  • Other examples of methods of formulation which may be used include the use of polymeric hydrogel formulations which do not actually encapsulate the gallium complex but which are resistant to dissociation under acidic conditions.
  • a second approach to countering the effect of the acidic conditions prevailing in the stomach involves formulation of the complex in the pharmaceutical composition together with the metal-free hydroxypyrone from which it is derived.
  • the dissociation of the complex involves various equilibria between the complex, and the metal-free compound, so that the presence of the latter will inhibit this dissociation.
  • Any proportion of the free compound can be advantageous in this context but little further advantage accrues from increasing the proportion beyond a certain level.
  • a preferred range for the molar proportion of the free compound present in compositions according to the present invention is thus from 0 to 100 moles of free hydroxypyrone:1 mole of gallium complex.
  • a proportion of up to no more than 20, 30 or 50 moles:1 mole is used with a lower level of 0.5, 1 or
  • liquid compositions are of interest in certain particular instances. It is often desirable to produce liquid compositions containing a higher concentration than is readily obtainable with a purely aqueous composition or indeed one containing organic solvents such as simple monohydric alcohols. It has been found that this may be done by the use of solvents containing two or more hydroxy groups or a hydroxy and an ether group, especially of glycols or glycol ethers, either in admixture with water or, for better solubilization, alone.
  • glycol ethers of particular interest are the mono-ethers containing as an etherifying group an aliphatic hydrocarbon group of l to 6 carbon atoms as described above, for example a methyl group, such a glycol mono-ether being methyl ethylene glycol. In general, however, the glycols themselves are preferred.
  • glycols examples include the simple dihydroxy alkanes such as ethylene glycol as well as those more complex compounds comprising two hydroxy groups attached to a chain containing both carbon and oxygen atoms, such as triethylene glycol, tetraethylene glycol and polyethylene glycol, for example, of 4,000 daltons molecular weight. Triethylene glycol and especially tetraethylene glycol are of particular interest in view of their very low toxicity. By using such glycols and glycol ethers it is possible to increase solubility for many complexes to 10 to 20 mg/ml.
  • gallium compound may administered topically in an intra-oral formulation comprising, for example, a highly concentrated rinse, gel, or other pharmaceutically acceptable carrier for the local treatment of periodontal disease.
  • compositions may be formulated in unit dosage form, i.e. in the form of discrete portions containing a unit dose, or a multiple or sub-unit dose. While the dosage of hydroxypyrone gallium complex given will depend on various factors, including the particular compound which is employed in the composition, it may be stated by way of guidance that maintenance at a satisfactory level of the amount of gallium present in the human body for the treatment purposes described previously, will often be achieved using a daily dosage, in terms of the gallium content of the compound, which lies in a range from about 0.1 to 100 mg and often in a range from 0.5 to 10 mg, for example 1 or 2 mg. However, it will be appreciated that it may be appropriate under certain circumstances to give daily dosages either below or above these levels.
  • the aim should be to provide the amount of gallium required by the patient without administering any undue excess and the properties of the pharmaceutical compositions according to the present invention are particularly suited to the achievement of this aim.
  • the concentration of gallium in the pharmaceutical composition in the form of the hydroxypyrone complex may vary quite widely, for example over a range from about 0.001 to about 20% w/w. However, it is more usual for the concentration to exceed 0.01% w/w and it may often exceed 0.05 or 0.1% w/w, while a more usual limit for the upper end of the range is about 13% w/w.
  • a common range of concentration is 0.05 to 5% w/w, for example 0.2 to 0.5, 1 or 2% w/w.
  • EXAMPLE l - Preparation of Gallium Maltol Enteric Coated Capsule A preparation of gallium maltol in admixture with maltol (containing 1 part by weight of gallium to 10 parts by weight of maltol) is obtained by the addition of a IM ethanolic solution of gallium chloride to a methylene chloride solution of the appropriate amount of maltol, followed after 5 minutes at 20° C. by treatment with a 10 molar excess of solid solution carbonate, stirring for 10 minutes, filtration and evaporation of the solvents.
  • the resulting solid gallium maltol preparation is divided into 50 mg quantities and added to standard gelatine capsules (16 x 5 mm) , each capsule containing 5 mg of gallium.
  • the capsules are then coated with • a cellulose acetate phthalate/diethylphthalate layer (6 mg coat per cm 2 of capsule surface) in a small scale procedure analogous to the procedure described by Jones, ibid.
  • a proportion of the capsules are treated to add a second similar coating.
  • S--h capsules are resistant to dissociation in the stomach but will undergo dissociation in the intestine. Thus, when treated at 37° C.
  • the singly coated capsules are typically stable for 30 minutes but in Krebs Ringer bicarbonate solution (pH 7.4) at 37° C. they dissociate to release the gallium complex within 1 minute.
  • the doubly coated capsules are typically stable at pH 2.0 for 20 hours, again dissociating within l minute at pH 7.4.
  • the phospholipid may be varied among egg yolk phosphatidyl chlorine, dimyristoyl phosphatidylcholine and dipalmitoyl phosphatidylcholine together with a preparation of cholesterol varying from 0 to 1 moles of cholesterol per mole of phospholipid.
  • Liposomes produced by either method are resistant to dissociation in the stomach but will undergo dissociation in the intestine.
  • Gallium maltol complex was administered to laboratory rats, (1) intravenously, (2) directly to the intestine, or (3) into the stomach.
  • the proximal region of the duodenum was ligated (double ligation, 1 cm apart at the pylorous) under anesthesia.
  • an aqueous solution of gallium maltol complex was injected, intravenously, into the duodenum (below the ligation) , or into the stomach (above the ligation) .
  • serial blood samples for serum preparation were collected primarily from the tail vein. The samples were taken 0.5, 0.75, 1.0, 2.0, 3.0, and 4.0 hours after administration of the dose.
  • the apparent oral bioavailability was calculated based upon the following formula wherein AUC means "area under the plasma concentration v. time curve from zero time to 4 hours post- dose.”
  • Figure l shows the results of the serum sampling, in terms of the concentration of the gallium in the blood.
  • introduction directly into the intestine achieved a blood serum level essentially identical to that achieved • through intravenous injection.
  • the introduction directly into the stomach, without ligation, provided the nest highest level of serum availability, as the gallium complex under such conditions could pass, in part, into the intestine.
  • This comparative performance is shown graphically in Figure 2.
  • Table I contains the numerical data calculated for the foregoing experiment for each laboratory rat studied and Table II contains the summary data for each rat grouping, based upon the route of administration

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Abstract

Compositions de gallium administrables par voie orale comprenant un complexe de gallium dans lequel chaque ligand est fourni par le même composé ou un composé différent sélectionné dans le groupe composé de 3-hydroxy-4-pyrones dans lequel un ou plusieurs des atomes d'hydrogène fixés aux atomes de carbone cyclique sont facultativement remplacés par un groupe hydrocarbure contenant 1 à 6 atomes de carbone, ladite composition inhibant la dissociation du complexe de gallium dans l'estomac tout en permettant une libération dudit complexe de gallium dans l'intestin. On utilise les compositions dans le traitement de troubles calciques osseux, à des fins chimiothérapeutiques et en imagerie radiographique.
PCT/US1991/003599 1990-05-24 1991-05-22 Compositions de gallium administrables par voie orale et procedes de traitement les utilisant WO1991017751A1 (fr)

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EP0959889A1 (fr) * 1996-07-30 1999-12-01 BERNSTEIN, Lawrence Richard Procedes et compositions permettant d'inhiber la proliferation de keratinocytes
WO2005070465A2 (fr) * 2004-01-14 2005-08-04 Gilead Sciences, Inc. Dispersions a base de lipides utiles dans l'administration de medicaments
US7354952B2 (en) 2005-11-04 2008-04-08 Genta Incorporated Pharmaceutical gallium compositions and methods
US8168214B2 (en) 2006-11-09 2012-05-01 Bernstein Lawrence R Local administration of gallium compositions to treat pain
US9492551B2 (en) 2005-10-27 2016-11-15 Lawrence R. Bernstein Orally administrable gallium compositions and methods of use

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US5883088A (en) * 1989-11-22 1999-03-16 Bernstein; Lawrence Richard Solid dosage forms for the oral administration of gallium
US5968922A (en) * 1989-11-22 1999-10-19 Bernstein; Lawrence Richard Gallium complexes of 3-hydroxy-4-pyrones to treat or prevent hypercalcemia
US5981518A (en) * 1989-11-22 1999-11-09 Bernstein; Lawrence Richard Gallium complexes of 3-hydroxy-4-pyrones to treat or prevent calcium homeostasis disorders
US5998397A (en) * 1989-11-22 1999-12-07 Bernstein; Lawrence Richard Gallium complexes of 3-Hydroxy-4-pyrones to treat or prevent bone disease
US6004951A (en) * 1989-11-22 1999-12-21 Bernstein; Lawrence Richard Administration of gallium complexes of 3-hydroxy-4-pyrones to provide physiologically active gallium levels in a mammalian individual
US6048851A (en) * 1989-11-22 2000-04-11 Bernstein; Lawrence Richard Solid pharmaceutical compositions for the oral administration of gallium
WO1993009776A1 (fr) * 1991-11-12 1993-05-27 Lawrence Richard Bernstein Compositions pharmaceutiques comprenant des complexes au gallium de 3-hydroxy-4-pyrones
US5470873A (en) * 1992-11-23 1995-11-28 University Technologies International, Inc. Diabetes prevention and treatment using gamma-pyrones
US5298525A (en) * 1992-11-23 1994-03-29 University Technologies International, Inc. Diabetes prevention and treatment
EP0959889A1 (fr) * 1996-07-30 1999-12-01 BERNSTEIN, Lawrence Richard Procedes et compositions permettant d'inhiber la proliferation de keratinocytes
EP0959889A4 (fr) * 1996-07-30 2000-08-16 Lawrence Richard Bernstein Procedes et compositions permettant d'inhiber la proliferation de keratinocytes
WO2005070465A2 (fr) * 2004-01-14 2005-08-04 Gilead Sciences, Inc. Dispersions a base de lipides utiles dans l'administration de medicaments
WO2005070465A3 (fr) * 2004-01-14 2006-04-13 Gilead Sciences Inc Dispersions a base de lipides utiles dans l'administration de medicaments
EP2384744A1 (fr) * 2004-01-14 2011-11-09 Gilead Sciences, Inc. Dispersions à base de lipides utiles pour l'administration de médicaments
US9492551B2 (en) 2005-10-27 2016-11-15 Lawrence R. Bernstein Orally administrable gallium compositions and methods of use
US7354952B2 (en) 2005-11-04 2008-04-08 Genta Incorporated Pharmaceutical gallium compositions and methods
US7456215B2 (en) 2005-11-04 2008-11-25 Genta Incorporated Pharmaceutical gallium compositions and methods
US7842724B2 (en) 2005-11-04 2010-11-30 Genta Incorporated Pharmaceutical gallium compositions and methods
US8168214B2 (en) 2006-11-09 2012-05-01 Bernstein Lawrence R Local administration of gallium compositions to treat pain
US9517198B2 (en) 2006-11-09 2016-12-13 Lawrence R. Bernstein Local administration of gallium compositions to treat pain

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