WO2003051403A1 - Treatment of osteomyelitis with radiopharmaceuticals - Google Patents
Treatment of osteomyelitis with radiopharmaceuticals Download PDFInfo
- Publication number
- WO2003051403A1 WO2003051403A1 PCT/US2002/039692 US0239692W WO03051403A1 WO 2003051403 A1 WO2003051403 A1 WO 2003051403A1 US 0239692 W US0239692 W US 0239692W WO 03051403 A1 WO03051403 A1 WO 03051403A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- acid
- osteomyelitis
- ligand
- radionuclide
- bone
- Prior art date
Links
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- A61K51/0478—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group complexes from non-cyclic ligands, e.g. EDTA, MAG3
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Definitions
- This invention relates to medical uses of radiopharmaceuticals. Specifically, the present invention relates to the use of radioisotope complexes to treat osteomyelitis.
- Osteomyelitis is infection in the bones. Often, the original site of infection is elsewhere in the body, and spreads to the bone by the blood. The bone may be predisposed to infection due to a recent minor trauma that results in a blood clot or hemostasis. In children, the long bones are usually affected. In adults, the vertebrae, head, and the pelvis are most commonly affected. Bacteria or fungi are the usual organisms, but any microbe may be responsible for the infection. Pus is produced within the bone, which may result in a bone abscess.
- Chronic osteomyelitis results when the causative microbes become resistant to antimicrobial agents. This may occur due to development of cellular mechanisms to circumvent the antimicrobial agents, formation of biofilms which allow quiescent organisms to remain untouched by antimicrobial agents, death of bone tissue as a result of the lost blood supply, and other mechanisms. Chronic infection can persist for years with intermittent exacerbations. Risk factors for chronic infection are recent trauma, diabetes, hemodialysis patients, IN drug abuse, and infection with organisms that are more adept at forming biofilms or developing antimicrobial resistance. Tuberculous osteomyelitis is caused by tubercle bacilli that enter the bloodstream and settle in a bone.
- osteomyelitis primarily include pain in the bone, bone tenderness, local swelling and warmth (facial swelling), fever, nausea, general discomfort, uneasiness, or ill feeling (malaise), and drainage of pus through the skin in chronic infection. Additional symptoms include sweating, excessive chills, back pain, and low-grade swelling of the ankle, feet, or the leg.
- Osteomyelitis is diagnosed through physical examination showing bone tenderness, swelling and redness, elevated white blood cell count, elevated ESR, blood cultures that identify the causative organism, needle aspiration of vertebral space for culture, bone lesion biopsy and culture, bone scans, and drainage of a skin lesion with a sinus tract (the lesion "tunnels" under the tissues) for culture.
- the outcome of treatment for acute osteomyelitis is usually good, but when treatment of acute osteomyelitis fails the outcome of treatment for chronic osteomyelitis is worse, even with surgery.
- Chronic infection may result in bone destruction, in stiffening of joints if the infection spreads to the joints, and, in extreme cases occurring before the end of the growth period, in the shortening of a limb if the growth center is destroyed.
- Resistant chronic osteomyelitis may result in amputation and can threaten life through seeding of the microorganisms to cardiac valves, the lungs, and the brain.
- Treatment for osteomyelitis focuses on eliminating the infection and preventing the development of chronic infection.
- High-dose intravenous antibiotics are given initially. The type of antibiotics and the route of administration may later be changed depending on culture results.
- Typical lengths of treatment for acute osteomyelitis vary from 6 weeks to 6 months depending on the organism and the anatomy of the infection site.
- chronic infection surgical removal of dead bone tissue is indicated. The open space left by the removed bone tissue may be filled with bone graft or by packing material to promote the growth of new bone tissue.
- Antibiotic therapy is continued for at least 3 weeks after surgery.
- Infection of an orthopedic prosthesis requires surgical removal with debridement of the infected tissue surrounding the area. A new prosthesis may be implanted in the same operation, or delayed until the infection has resolved, depending on its severity.
- Estimates of the percentage of acute osteomyelitis cases that become chronic osteomyelitis cases vary from 10 percent to 30 percent. Once the osteomyelitis has become chronic, biofilms or abscesses usually have developed, protecting the
- the present invention is a method for the treatment of osteomyelitis comprising: providing a subject suffering from osteomyelitis and a pharmaceutical composition comprising a radionuclide; and parenterally (usually intramuscularly or intravenously) administering the composition to the patient under conditions such that the osteomyelitis is reduced.
- the present invention is a method for the treatment of osteomyelitis comprising: locally administering a composition comprising a radionuclide to a subject suffering from osteomyelitis under conditions such that the osteomyelitis is reduced.
- the present invention is a method for the treatment of osteomyelitis comprising the steps of applying a tourniquet to a subject suffering from osteomyelitis; and administering a composition comprising a radionuclide to the subject under conditions such that the osteomyelitis is reduced.
- the present invention provides improved system and methods of for the direct delivery of radiopharmaceuticals to the site of osteomyelitis.
- the present invention provides improved system and methods of for the direct delivery of radiopharmaceuticals to the site of osteomyelitis.
- the term “disease” refers to pathologies and deleterious conditions, such as infections, inflammatory responses, cancer, autoimmune, and genetic disorders.
- the term “microorganism” refers to microscopic organisms and taxonomically related macroscopic organisms within the categories of algae, bacteria, fungi (including lichens), protozoa, viruses, and subviral agents.
- the term microorganism encompasses both those organisms that are in and of themselves pathogenic to another organism (for example, animals, including humans, and plants) and those organisms that produce agents that are pathogenic to another organism, while the organism itself is not directly pathogenic or infective to the other organism.
- pathogen refers to an organism (including microorganisms) that causes disease in another organism (for example, animals and plants) by directly infecting the other organism, or by producing agents that cause disease in another organism (for example, bacteria that produce pathogenic toxins).
- osteomyelitis refers to an infection of the bone. Osteomyelitis infections are generally caused by a pathogenic microorganism (for example, a bacteria or a fungus). Osteomyelitis includes both acute and chronic (for example, persistent) bone infections.
- Systemic infection denotes infection throughout a substantial part of an organism including mechanisms of spread other than mere direct cell inoculation but rather including transport from one infected cell to additional cells either nearby or distant.
- subject suffering from osteomyelitis refers to a subject that has one or more symptoms of osteomyelitis (for example, including but not limited to, pain in the bone, bone tenderness, and swelling or warmth) or a positive diagnosis based on one or more diagnostic tests (for example, including but not limited to, a bone scan, blood culture, or culture of the infectious lesion).
- symptoms of osteomyelitis for example, including but not limited to, pain in the bone, bone tenderness, and swelling or warmth
- diagnostic tests for example, including but not limited to, a bone scan, blood culture, or culture of the infectious lesion.
- the term "subject suffering from osteomyelitis at a particular site of infection” refers to a "subject suffering from osteomyelitis” wherein the osteomyelitis has been identified as being in a particular bone or region of bone or in several particular bones or regions of bones.
- the term "such that said osteomyelitis is reduced” refers to the reduction of infection based on the lack of one or more symptoms of osteomyelitis (for example, including but not limited to, pain in the bone, bone tenderness, and swelling or warmth) or a negative diagnosis based on one or more diagnostic tests (for example, including but not limited to, a bone scan, blood culture, or culture of the infectious lesion).
- radionuclide refers to a nuclide that disintegrates with the emission of corpuscular or electromagnetic radiation.
- nuclide refers to a species of atom characterized by the charge, mass number and quantum state of its nucleus that is stable for a measurable lifetime (for example, greater than 10 "10 seconds).
- the methods of the present invention are not limited to a particular radionuclide. Any suitable radionuclide may be utilized, including but not limited to, those disclosed herein.
- pharmaceutical composition comprising a radionuclide refers to any pharmaceutically acceptable composition that comprises a radionuclide and any sterile, biocompatible pharmaceutical carrier. Pharmaceutical compounds may also include additional active agents such as, including but not limited to, ligands complexed to the radionuclides.
- pharmaceutically acceptable refers to compositions that do not substantially produce adverse allergic, immunological or other reactions when administered to a host (for example, an animal such as a human).
- pharmaceutically acceptable carrier includes any and all solvents (for example, including but not limited to, saline, buffered saline, dextrose and water), dispersion media, coatings, wetting agents (for example, sodium lauryl sulfate), isotonic and absorption delaying agents, and disintrigrants (for example, potato starch or sodium starch glycolate).
- the term "locally administering a composition comprising a radionuclide to subject suffering from osteomyelitis at said site of infection” refers to administering a pharmaceutical composition of the present invention directly to the site of osteomyelitis (for example, a limb bone).
- the term "ligand” refers to any compound capable of physically interacting with a radionuclide of the present invention.
- the radionuclide is chelated by electron donor groups of the ligand.
- any interaction that results in stable complexes when administered to a subject using the methods of the present invention is suitable.
- the term "ligand” is also not intended to be limited by the chemical nature of the compound.
- a macrocyclic or acyclic aminophosphonic acid is used as a ligand for complexing with a radionuclide of the present invention.
- cyclic compounds refers to compounds having one (that is, a monocyclic compounds) or more than one (that is, polycyclic compounds) ring of atoms.
- the term is not limited to compounds with rings containing a particular number of atoms. While most cyclic compounds contain rings with five or six atoms, rings with other numbers of atoms (for example, three, four, or twelve atoms) are also contemplated by the present invention.
- the identity of the atoms in the rings is not limited, though the atoms are usually predominantly carbon atoms.
- the rings of polycyclic compounds are adjacent to one another. However, the term "polycyclic compound” includes those compounds containing multiple rings that are not adjacent to each other.
- macrocyclic compound and “macrocycle” refer to a "cyclic compound” with a ring containing more than about eight atoms.
- heterocyclic compounds refers broadly to cyclic compounds wherein one or more of the rings contains more than one type of atom. In general, carbon represents the predominant atom, while the other atoms include, for example, nitrogen, sulfur, and oxygen. Examples of heterocyclic compounds include benzimidazole, furan, pyrrole, thiophene, and pyridine.
- parenteral administration includes all routes of administering an agent (for example, a pharmaceutical composition of the present invention) that are not through the gastrointestinal route.
- parenteral administration examples include, but are not limited to, intravenous, intra-arterial, intramuscular, local, subcutaneous, intradermal, and transcutaneous administration.
- aromatic and “aromatic compounds” refer broadly to compounds with rings of atoms having delocalized electrons.
- the monocyclic compound benzene (C 6 H 6 ) is a common aromatic compound. However, electron delocalization can occur over more than one adjacent ring (for example, naphthalene [two rings] and anthracene [three rings]).
- aromatic compounds include, but are not limited to, aromatic halides (aryl halides), aromatic heterocyclic compounds, aromatic hydrocarbons (arenes), and aromatic nitro compounds (aryl nitro compounds).
- the terms “meta substitution” and " eta position” when used in terms of substituted benzenes refer to benzene derivatives substituted at positions 1 and 3 or 1 and 5 (that is, each of the 6 carbons of the 6 membered benzene ring is numbered consecutively).
- the terms “para substitution” and “para position” when used in terms of substituted benzenes refer to benzene derivatives substituted at positions 1 and 4 of the benzene ring.
- aliphatic and aliphatic compounds refer to compounds which comprise carbon atoms in chains, rather than the ring structure of cyclic compounds.
- mixture refers to a mingling together of two or more substances without the occurrence of a reaction by which they would lose their individual properties.
- solution refers to a liquid mixture.
- aqueous solution refers to a solution that contains some water. In many instances, water serves as the diluent for solid substances to create a solution containing those substances. In other instances, solid substances are merely carried in the aqueous solution (that is, they are not dissolved therein and are a "mixture" of an aqueous solution and the non-dissolved solid substances).
- aqueous solution also refers to the combination of one or more other liquid substances with water to form a multi-component solution.
- Acylate refers to the introduction of an acyl group into a molecule, (that is, acylation).
- Bioly active refers to a molecule having the structural, regulatory, or biochemical functions of a naturally occurring molecule.
- Cell culture refers to a proliferating mass of cells that may be in either an undifferentiated or differentiated state.
- Immunologically active refers to the capability of a natural, recombinant, or synthetic polypeptide, or any oligopeptide thereof, to bind with specific antibodies and induce a specific immune response in appropriate animals or cells.
- Purified as used herein when referring to a chemical compound or molecule, indicates that the molecule is present in the substantial absence of other chemical or biological compounds of the same type.
- the term “purified” as used herein preferably means at least 95 percent by weight, more preferably at least 99.8 percent by weight, of molecules of the same type present.
- pure as used herein preferably has the same numerical limits as
- sample as used herein, is used in its broadest sense.
- a biological sample may comprise a tissue, a cell, an extract from cells, blood, serum, and other bodily fluids.
- the present invention provides methods for the treatment of osteomyelitis. Osteomyelitis is often diagnosed by a nuclear medicine bone scan using known radiopharmaceutical agents. The radiopharmaceuticals concentrate at the site of bone infection to show the presence of infection. Radiopharmaceuticals have also been used to treat bone cancers, arthritis, and to ablate bone marrow.
- the present invention provides methods for the use of radiopharmaceuticals to treat osteomyelitis.
- the methods of the present invention find use in the treatment of all forms of osteomyelitis (for example, acute or chronic infection).
- the present invention further provides delivery methods that increase the localization of the radioactivity to the bone, thus reducing the systemic radiation dose.
- the methods and compositions described below are exemplary and are not intended to limit the scope of the invention.
- One skilled in the relevant art recognizes that additional suitable radiopharmaceuticals, ligands, dosages, and treatment formulations may be substituted for those disclosed herein. I. Radiopharmaceuticals
- the present invention provides radiopharmaceuticals for the treatment of osteomyelitis.
- the invention is not limited to a particular radioisotope or ligand. Any suitable radioisotope or ligand that functions to treat osteomyelitis may be utilized, including but not limited to, those disclosed herein. Guidance for selecting and screening agents for use in the methods of the present invention are described below.
- the radiopharmaceutical compositions of the present invention comprise one or more radionuclides.
- the half-life of the radionuclides is sufficiently long to allow for localization and delivery of the complex in the bone tissue while still retaining sufficient radioactivity to kill pathogens present in the bone.
- a radionuclide having sufficient alpha or beta energy is utilized.
- the radiation can be performed with nuclides that emit radiation with relatively short path lengths before absorption (for example, beta radiation) with good microbe kill and less damage to other tissues.
- absorption for example, beta radiation
- directly targeting the radionuclide to the site of infections allows the use of a nuclide with a relatively short half life (for example, one or two days) that delivers its radiation dose quickly. This results in a higher likelihood that more of the pathogen will be killed. This is in direct contrast to the currently available methods of delivering a lower per minute dose of radiation over a longer time period that has the potential to allow more bacteria to repair any radiation damage and survive the treatment.
- radionuclides utilized in the methods of the present invention exhibit beta energy >0.5 MeN, preferably >1 MeN with an effective half- life of ⁇ 5 days, preferably ⁇ 3 days.
- Radionuclides useful in the methods and compositions of the present invention include, but are not limited to, Arsenic-77 ( 77 As), Molybdenum-99 ( 99 Mo), Rhodium-105 ( 105 Rh), Lutetium-177 ( 177 Lu), Cadmium-115 ( 115 Cd), Antimony-122 ( 122 Sb), Prometbium-149 ( 149 Pr), Osmium-193 ( 193 Os), Gold-198 ( 198 Au), Tin-117m ( 177m Sn), Strontium-89 ( 89 Sr), Thorium-200 ( 200 Th) Indium- 115 ( U5 In), Dysprosium- 165 ( 165 Dy), Lanthanum-140 ( 140 La), Ytterbium-175 ( 175 Yb), Scandium-47
- 166 Ho which emits high-energy beta particles and gamma radiation (80 KeN, 6.0 percent) useful for imaging and exhibits a half-life of 26.8 hr.
- alpha emitters such as Actinium-225 ( 225 Ac), Bismuth-212 ( 212 Bi) and Bismuth-213 ( 213 Bi) are utilized.
- the respective radionuclides can be obtained using procedures well known in the art.
- the desired radionuclide can be prepared by bombarding an appropriate target, such as a metal, metal oxide, or salt with neutrons.
- Another method of obtaining radionuclides is by bombarding nuclides with particles in a linear accelerator or cyclotron.
- Yet another way of obtaining radionuclides is to isolate them from fission product mixtures.
- the present invention is not limited to a particular method of obtaining radionuclides. Any suitable method that results in the generation of the desired radionuclide may be utilized.
- radionuclides are conjugated to pharmaceutically acceptable ligands.
- aminophosphonic acids particularly macrocyclic and acyclic aminophosphonic acids, are utilized as ligands.
- These compounds are prepared by any suitable technique. Known synthetic techniques involve reacting a compound containing at least one reactive amine hydrogen with a carbonyl compound (aldehyde or ketone) and a phosphorous acid or appropriate derivative thereof.
- the amine precursor (1,4,7,10-tetraazacyclododecane) employed in making certain of the macrocyclic aminophosphonic acids utilized in some embodiments of the present invention is a commercially available material.
- the preparation of macrocyclic aminophosphonic ligands can also be found in U.S. Patent 5,059,412. The preparation of these ligands has also been described in U.S. Patents 4,973,333, 4,882,142, 4,853,209, 4,898,724, 4,897,254, 5,587,451, 5,714,604, 5,064,633, 5,587,451, 5,066,478, 5,300,279, 5,059,412, and 5,064,633.
- ligands are selected from the group consisting of ethylenediaminetetramethylenephosphonic acid (EDTMP), diethylenetriaminepentamethylenephosphonic acid DTPMP), hydroxyethylethylenediaminetrimethylenephosphonic acid (HEEDTMP), nitrilo- trimethylenephosphonic acid (NTMP), 1, 4,7,10-tetraazacyclododecanetetra- methylenephosphonic acid (DOTMP), tris(2-aminoethyl)amine hexamethylene-phosphonic acid (TTHMP), methylene diphosphonate, hydroxymethylenediphosphonate, hydroxyethylidene diphosphonate (HEDP), and ethane- l-hydroxy-l,l-diphosphonic acid.
- ligands are macrocyclic aminophosphonic acid ligands of which 1 ,4,7, 10-tetraazacyclododecanetetramethylenephosphonic acid (DOTMP) is an example
- aminocarboxylic acids such as diethylenetriaminepentaacetic acid can also be used to deliver isotopes to bone tissue.
- aminocarboxylic acids such as diethylenetriaminepentaacetic acid
- U.S. Patent 6,231,832 teaches the delivery of Sn-117m to bone using such a chelator.
- U.S. Patent 4,897,254 teaches the uses of hydroxyethylethylenediaminetriacetic acid in combination with Sm-153 to deliver a radiation dose to bone.
- the methods and compositions of the present invention employ complexes of radionuclides and ligands.
- the complexes may be generated using any suitable method, including but not limited to, those disclosed herein.
- the radionuclide complex must be taken up preferentially by bone so that it is possible to deliver radiation to the bone with minimal exposure to other tissues such as lung, liver, bladder or kidneys.
- the radionuclide complex be rapidly cleared from the blood, thereby further reducing exposure to non-target tissues.
- the radionuclide and ligand are combined under any conditions that allow the two to form a complex.
- mixing in water at a controlled pH (the choice of pH is dependent upon the choice of ligand and radionuclide) is suitable.
- the complex is formed by chelation of the radionuclide by an electron donor group or groups that results in a stable radionuclide complex (for example, stable to the disassociation of the radionuclide from the ligand).
- 166 Ho-DOTMP is formed by adding a I66 Ho salt, such as the chloride or nitrate in aqueous HCl (0.1 - 1 N), to a sterile, evacuated vial containing at least 3 equivalents of DOTMP in aqueous base (KOH and NaOH). After stirring at a pH of 10.5, the pH is then adjusted to 7-8 by adding phosphate buffer and a stabilizing agent such as ascorbic acid. Complexation of >99 percent is generally achieved using such a method.
- a I66 Ho salt such as the chloride or nitrate in aqueous HCl (0.1 - 1 N)
- KOH and NaOH aqueous base
- phosphate buffer and a stabilizing agent such as ascorbic acid
- Radionuclide compositions described herein and physiologically acceptable salts thereof are considered equivalent.
- Physiologically acceptable salts refer to the acid addition salts of those bases which will form a salt with at least one acid group of the ligand or ligands employed and which will not cause adverse physiological effects when administered as described herein.
- Suitable bases include, but are not limited to, for example, the alkali metal and alkaline earth metal hydroxides, carbonates, and bicarbonates such as, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, sodium bicarbonate, magnesium carbonate, amine hydroxides, carbonates, and bicarbonates such as, for example, ammonium hyroxide, ammonium carbonate, or primary secondary and tertiary amine hydroxides, carbonates, and bicarbonates such as, for example, trimethyl ammonium carbonate.
- Physiologically acceptable salts can be prepared by treating the macrocyclic aminophosphonic acid with an appropriate base.
- the macrocyclic aminophosphonic acid complexes when formed at approximately a ligand to metal molar ratio of 1 : 1 to 20: 1 give biodistributions that are consistent with those exhibited by known agents that are bone-specific. The optimum ratio depends on the particular ligand utilized.
- Preferred osteomyelitic treating radionuclide compositions include 166 Ho- DOTMP, 177 Lu-DOTMP, and 153 Sm-EDTMP.
- DOTMP to are above 1, for example, from 1.5 to 3.5:1.
- the most preferred ratio is about 3.5: 1.
- Such a ratio provides adequate complexation of the radionuclide while compensating for radiolysis of the ligand.
- other acyclic aminophosphonic acid complexes can result in substantial localization of radioactivity in soft tissue (for example, liver) if large excess amounts of ligand are not used. Large excesses of ligand are undesirable since uncomplexed ligand may be toxic to the patient or may result in cardiac arrest or hypocalcemic convulsions.
- the macrocyclic aminophosphonic acid ligands are useful when large amounts of metal are required (that is, for metals that have a low specific activity).
- the macrocyclic aminophosphonic acid ligands have the ability to deposit more tolerable doses of radioactivity in the bone than is possible when using non-cyclic aminophosphonic acid ligands.
- ligands such as EDTMP
- a large excess of ligand is necessary.
- the most preferred ratio of EDTMP to Sm is 273:1.
- Aminocarboxylic acid ligands are also preferably present in large excess over radionuclide.
- pharmaceutical compositions In preferred embodiments, radionuclides and radionuclide-ligand complexes are administered as pharmaceutically acceptable compositions. A pharmaceutically acceptable means of protecting the radionuclide complex from radiolytic decay of the chelator is highly preferred.
- radioprotectants of the present invention are radio-stable anti-oxidants, compounds that either reduce the number or the activity of oxidizing radicals.
- Exemplary radio protectants that can be employed in the practice of the present invention are ascorbic acid, gentisic acid, nicotinic acid, ascorbyl palmitate, HOP(:O) H 2 , monothioglycerol, sodium formaldehyde sulfoxylate, Na 2 S 2 O 3 , SO 2 , or a reducing agent combined with BHA, BHT, pyrogallate, and tocopherol.
- Ascorbic acid is the preferred radioprotectant for use in the practice of the present invention, and can be used at 35-75 mg/ml of liquid composition. This concentration of ascorbate can provide a solution of 166 Ho-DOTMP that is stable (for example, therapeutically useful), for at least 72 hours at ambient conditions (for example, unfrozen).
- the formulations of the present invention are in the solid or preferably liquid form containing the active radionuclide complexed with the ligand.
- These formulations can be in kit form such that the chelator and radionuclide are mixed at the appropriate time prior to use in a suitable liquid carrier with the radioprotectant. Whether premixed or as a kit, the formulations usually require a pharmaceutically acceptable carrier, such as water.
- the pharmaceutical dosage forms suitable for injection or infusion can include sterile solutions, dispersions, emulsions, or microemulsions, comprising the active ingredients that are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in protective matrices such as nanoparticles or microparticles.
- the ultimate dosage form must be sterile, fluid, and stable under the conditions of manufacture and storage.
- the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycols), DMSO, and suitable mixtures thereof.
- Injectable suspensions as compositions of the present invention require a liquid suspending medium, with or without adjuvants, as a carrier.
- the suspending medium can be, for example, aqueous polyvinylpyrrolidone, inert oils such as vegetable oils or highly refined mineral oils, or aqueous carboxymethyl cellulose solutions.
- suitable physiologically acceptable adjuvants can be chosen from among thickeners such as, for example, carboxymethylcellulose, polyvinylpyrrolidone, gelatin, and the alginates.
- surfactants are also useful as suspending agents, for example, lecithin, alkylphenol, polyethylene oxide adducts, naphthalenesulfonates, alkylbenzenesulfonates, and the polyoxyethylenesorbitan esters.
- surfactants for example, lecithin, alkylphenol, polyethylene oxide adducts, naphthalenesulfonates, alkylbenzenesulfonates, and the polyoxyethylenesorbitan esters.
- Many substances that effect the hydrophobicity, density, and surface tension of the liquid suspension medium can assist in making injectable suspensions in individual cases.
- silicone antifoams, sorbitol, and sugars are all useful suspending agents.
- the present invention provides novel methods of treating osteomyelitis using radiopharmaceutical compositions.
- the compositions are delivered directly to the site of infection, thus decreasing the amount of radioactivity required to reduce infection.
- the present invention is not limited to the dosages and methods of administration described below. One skilled in the art recognizes that other suitable dosages and administration methods may be utilized in the practice of the present invention.
- the effective therapeutic amount of radionuclide composition administered to achieve elimination of osteomyelitis will vary according to factors such as the age, weight and health of the patient, the disease state being treated (for example, chronic or acute infection), the treatment regimen selected (for example, mode of administration), the amount of oxygen in the system, as well as the nature of the particular radionuclide composition to be administered. For example, less activity will be needed for radionuclides with longer half lives. The energy of the emissions will also be a factor in determining the amount of activity necessary. In some embodiments, a dose of 10 to 1000 Gy is used.
- a total dose of 20-60 Gy, most preferably 30-60 Gy, for example, 40-50 Gy of radiation is delivered to bone parenterally (for example, preferably via intramuscular injection or locally).
- the radiation exposure is reported using the Grey scale (Gy).
- One Gy is equivalent to 100 Rads.
- a rad is defined as adsorbed energy of 100 ergs per gram.
- Radioactivity measurements of the isotope in blood, urine, bone, and infected areas are used to estimate the dose to the target and non-target areas. This is translated into a therapeutic dose for the individual patient.
- a diagnostic dose of 1110-1850 MBq (30mCi to 50 mCi) of Ho-166-DOTMP is used as a diagnostic dose to determine the therapeutic dose.
- a different agent, such as Tc-99m-MDP, that has a very similar biodistribution as the therapeutic agent can be given prior to the therapeutic dose.
- Radiopharmaceuticals are administered in combination with additional agents (for example, including but not limited to, antibacterial, anti-parasitic, and antifungal agents, including those disclosed in The Physicians Desk Reference, 50th Edition, 1996).
- Useful antibiotic agents include systemic antibiotics, such as aminoglycosides, cephalosporins (for example, first, second, and third generation), macrolides (for example, erythromycins), monobactams, penicillins, quinolones, sulfonamides, and tetracyclines, including those disclosed in The Physicians Desk Reference, 50th Edition, 1996.
- antibacterial agents include 2-isocephem and oxacephem derivatives disclosed in U.S. Patent 5,919,925; pyridone carboxylic acid derivatives disclosed in U.S. Patent 5,910,498; water miscible esters of mono- and diglycerides disclosed in U.S.
- Patent 5,908,862 benzamide derivatives disclosed in U.S. Patent 5,891,890; 3-ammoniopropenyl cephalosporin compounds disclosed in U.S. Patent 5,872,249; 6-O- substituted ketolides disclosed in U.S. Patent 5,866,549; benzopyran phenol derivatives disclosed in U.S. Patent 5,861,430; pyridine derivatives disclosed in U.S. Patent 5,859,032; 2-aminothiazole derivatives disclosed in U.S. Patent 5,856,347; penem ester derivatives disclosed in U.S. Patent 5,830,889; Hpodepsipeptides disclosed in U.S. Patent 5,830,855; dibenzimidazole derivatives disclosed in U.S.
- Patent 5,824,698 alkylenediarnine derivatives disclosed in U.S. Patent 5,814,634; organic solvent-soluble mucopolysaccharides disclosed in U.S. Patent 5,783,570; arylhydrazone derivatives disclosed in U.S. Patent 5,760,063; carbapenern compounds disclosed in U.S. Patent 5,756,725; N-acylpiperazine derivatives disclosed in U.S. Patent 5,756,505; peptides disclosed in U.S. Patent 5,714,467; oxathiazines and their oxides disclosed in U.S. Patent 5,712,275; 5-amidomethyl alpha beta- saturated and -unsaturated 3 -aryl butyolactone compounds disclosed in U.S.
- Patent 5,708,169 halogenated benzene derivatives disclosed in U.S. Patent 5,919,438; sulfur- containing heterocyclic compounds disclosed in U.S. Patent 5,888,526; and oral antibacterial agents disclosed in U.S. Patent 5,707,610.
- Antifungal agents include dermatological fungicides, topical fungicides, systemic fungicides, and vaginal fungicides, including those disclosed in The Physicians Desk Reference, 50th Edition, 1996.
- antifungal agents include terpenes, sesquiterpenes, diterpenes, and triterpenes disclosed in U.S. Patent 5,917,084; sulfur- containing heterocyclic compounds disclosed in U.S. Patent 5,888,526; carbozarnides disclosed in U.S. Patent 5,888,941; phyllosilicates disclosed in U.S. Patent 5,876,738; corynrcandin derivatives disclosed in U.S. Patent 5,863,773; sordaridin derivatives disclosed in U.S.
- Patent 5,854,280 cyclohexapeptides disclosed in U.S. Patent 5,854,213; terpene compounds disclosediinU.S. Patent 5,849,956; agents derived from aspergillus furnigatus disclosed in U.S. Patent 5,873,726; inula extracts disclosed in U.S. Patent 5,837,253; hpodepsipeptides disclosed in U.S. Patent No. 5,830,855; polypeptides disclosed in U.S. Patent 5,824,874; pyrimidone derivatives disclosed in U.S. Patent 5,807,854; agents from sporomiella minimizes disclosed in U.S. Patent 5,801,172; cyclic peptides disclosed in U.S.
- Patent 5,786,325 polypeptides disclosed in U.S. Patent 5,773,696; triazoles disclosed in U.S. Patent 5,773,443; fusacandins disclosed in U.S. Patent 5,773,421; terbenzimidazoles disclosed in U.S. Patent 5,770,617; and agents obtained from hormones disclosed in U.S. Patent 5,756,472.
- the present invention contemplates the use of radiopharmaceuticals to treat . osteomyelitis in animals, including but not limited to, humans.
- the methods of the present invention are suitable to treat acute or chronic osteomyelitis in any bone.
- Suitable radiopharmaceuticals, ligands, and dosages include, but are not limited to, those described above.
- One skilled in the relevant art understands how to determine suitable compositions and dosages for a specific animal and site or extent of infection.
- the direct administration methods of the present invention provide the advantage of delivering an increased concentration of the radionuclide to the affected area and decreasing the exposure of the rest of the body. This is in contrast to systemic intravenous injection of bone agents, which results in radioactivity deposited in the entire skeletal system of the subject.
- the dose from the bone to the bone marrow is of most concern. This is especially true of radionuclides such as Ho- 166 or Y-90 that are high-energy beta emitters. If a portion of the marrow can be spared from radioactivity, then it is probable that the affected area will regenerate without putting the patient at risk.
- an arterial obstruction device such as a tourniquet
- application of one or more arterial obstruction devices to isolate portions of the skeletal system from the site of injection of the radionuclide will protect those portions of the bone marrow.
- radiopharmaceuticals are administered locally to the area of the infected bone.
- Local administration can be performed by techniques known in the art, including but are not limited to, intravenous injection, intra- arterial injection, intramuscular injection, subcutaneous injection, intraosseous injection, and transcutaneous administration.
- radiopharmaceuticals are injected intramuscularly near the site of infection.
- a tourniquet or other arterial obstruction device is placed above the area of injection in order to aid in the localization of the ' radiopharmaceuticals.
- the tourniquet is placed on the limb prior to injection and removed immediately following injection.
- the tourniquet is left in place for a short period of time following injection (for example, long enough for the radiopharmaceutical to localize to the site of infection).
- the tourniquet is left in place for greater than 2 minutes (for example, preferably 5 minutes and more preferably 10 minutes) and then removed. It is preferred that the tourniquet is left in place no greater than 60 minutes in order to avoid hypoxic damage to the tissues due to restricted blood flow.
- tourniquets are applied to one or more extremities to prevent access of the radiopharmaceutical agent to these areas.
- tourniquets are applied proximally to each leg to protect the bone marrow in the legs from exposure to the radiopharmaceutical.
- the radiopharmaceutical agent is then given intravenously into a brachial vein to be carried through the blood stream to an osteomyelitis site, for instance in the mandible or the vertebral column.
- the tourniquet is then removed after an appropriate time (less than 60 minutes but greater than 2 minutes, more preferably greater than 5 minutes, most preferably 10 minutes) after injection.
- radiopharmaceuticals are administered with additional antibacterial or fungal agents. Suitable agents include, but are not limited to, those described above.
- administration of a radiopharmaceutical agent result in the reduction of osteomyelitis (for example, as determined by a bone scan). If the infection is not sufficiently reduced or eliminated, additional doses of radiopharmaceuticals are given. Alternatively, or in combination, increased doses of radiopharmaceuticals are administered until symptoms and diagnostic tests reveal that the infection is eliminated.
- 165-Ho-nitrate targets were prepared from dissolution of holmium oxide in nitric acid followed by reduction to dryness.
- a target containing 6 mg of holmium was irradiated in a reactor for approximately 155 hours at a flux of 4.5x 10 14 n/cm 2 /s.
- the specific activity was typically in the range of 1.3 - 2 Ci/mg.
- the 166 Ho-nitrate target was dissolved in 0.3 N HCl.
- 166 Ho-chloride was supplied from the reactor in 10 ml of 0.3 N HCl.
- DOTMP 60 mg DOTMP and 168 mg NaOH was dissolved in 4 ml water and added to the 166 Ho chloride.
- the ligand to metal ratio was 3.5. The reaction mixture was allowed to mix for
- This example describes the successful treatment of osteomyelitis in rats using Ho-
- DOTMP DOTMP.
- 150 g male Sprague Dawley rats were anesthetized and prepared for surgery by shaving the left leg.
- the skin over the left tibia and fibula was opened, a hole was drilled into the bone marrow, and an 18-gauge needle was inserted into the bone marrow.
- an 18-gauge needle was inserted into the bone marrow.
- apiece of 0 surgical suture and approximately 0.1 ml of Staphylococcus aureus culture in Trypticase soy broth were introduced into the bone marrow.
- the needle was removed and the bone defect sealed with cyanoacrylate glue.
- the skin was closed with 0 surgical suture.
- the rats were followed with serial radiographs of the left leg. Lytic lesions diagnostic of osteomyelitis developed in the fibula over the next three weeks. The entire bone appeared radiolucent.
- Necropsy revealed that the tibia was eroded with only a very thin layer of bone encasing a thick fluid. Culture of the fluid grew Gram positive cocci consistent with the original
- DOTMP and EDTMP were prepared according to methods described in U.S. Patent Nos. 4,898,724 and 4,976,950.
- Ho- 166 obtained from the University of Missouri Research Reactor, Columbia Missouri, was dissolved in 0.1N HCl to yield a 6 x 10 "3 M 166 HoCl 3 solution.
- Sm-153 obtained from the University of Missouri Research Reactor, Columbia, Missouri, was dissolved in 0.1 N
- the radioactive 166 HoC13 solution was then mixed with non-radioactive 165 HoC13 solutions to prepare solutions that would have only a tracer amount of Ho.
- DOTMP 0.25 ⁇ L of the 6 x 10 "3 M 166 HoCl 3 solution was mixed with 1 mL of a 6.04 x 10 "4 M 165 HoC13 solution.
- EDTMP 0.25 ⁇ L of the 6 x 10 "3 M 166 HoCl 3 solution was mixed with 1 mL of a 4.84 x 10 "3 M 165 HoCl 3 solution.
- the radioactive 153 SmCl 3 solution was mixed with non-radioactive SmCl 3 solutions to prepare solutions that would have only a tracer amount of Sm.
- 0.25 ⁇ L of the 6 x 10 "3 M 153 SmCl 3 solution was mixed with 1 mL of a 6.06 x 10 "4 M solution of non-radioactive Sm (CH 3 COO) 3 .
- EDTMP complexes and DOTMP complexes were accomplished by the methods described in U.S. Patent Nos. 4,898,724 and 4,976,950. Following preparation of the complexes, the percentage of complexation was determined. This was accomplished by placing an aliquot of the complexation solution onto a column of swollen Sephadex C-15 cation resin and eluting with a 4:1 physiologic saline:concentrated ammonium hydroxide solution. Percentage complexation can then be determined by comparison of the counts from non-complexed metal left on the column to the total of counts from the non- complexed metal on the column and the complexed metal in the eluted solution. 4. Biodistribution studies
- Rat biodistribution studies were done on Male Sprague-Dawley rats weighing 180- 200g that had been acclimated for approximately one week prior to this study.
- Four test complexes were used, Ho-DOTMP (Example 3), Ho-EDTMP (Example 4), Sm-DOTMP (Example 5) and Sm-EDTMP (Example 6).
- the rats were placed in a restraining cage that afforded accessibility to the left hind leg and tail.
- a tie wrap tourniquet Prior to injection a tie wrap tourniquet was placed on the left hind femur above the knee to restrict blood flow. The amount of pressure induced by the tourniquet was standardized by using a tie wrap gun and was sufficient to stop arterial flow.
- Tables 1 and 2 show data as percent dose of administered radioactivity per gram of tissue. This reflects the concentration of the radioactive complex in the bone.
- Table 1 combines the data on the radioactivity found in the tibias of the rats from Examples 3 to 6 for each of the three times of tourniquet placement.
- Table 2 combines the data on the radioactivity found in the femurs of the rats from Examples 3 to 6 for the tourniquets applied for 20 minutes.
- the degree of "protection" of the bone by the tourniquet can be seen by comparison of the radioactivity in the bones on the left side ("protected" by the tourniquet for the time specified) as compared to the corresponding bones on the right side (fully exposed to the systemic, intravenous dose).
- Table 3 shows this comparison as the percentage of the concentration of radioactive complex in the unprotected bone found in the corresponding protected bone.
- the 20 minute animal data indicates high uptake of the radioactivity in bone with very little activity remaining in any soft tissue.
- Examination of Table 3 reveals that the tibias behind the tourniquets concentrated less of the radioactive bone-seeking agents than the corresponding tibias regardless of the length of time the tourniquet remained in place or the specific complex used. However, leaving the tourniquets in place for 20 minutes provided much better protection than shorter time periods. Examples 3, 4, and 5 all showed only 20 percent to 25 percent of the unprotected radioactivity concentration in the protected tibias while Example 6 (Sm-EDTMP) was less effective at 36 percent. The tourniquet was placed in the middle of the left femur.
- Examples 3 and 5 (Ho-DOTMP and Sm-DOTMP) were still able to keep the concentration of radioactivity in the 20 percent to 25 percent range in the femur.
- Examples 4 and 6 (Ho- EDTMP and Sm-EDTMP) were only able to lower the concentration of radioactivity to 40 percent to 50 percent of unprotected concentration in the femur.
Abstract
Description
Claims
Priority Applications (3)
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EP02799930A EP1458416A1 (en) | 2001-12-13 | 2002-12-11 | Treatment of osteomyelitis with radiopharmaceuticals |
JP2003552335A JP2005516933A (en) | 2001-12-13 | 2002-12-11 | Treatment of osteomyelitis with radiopharmaceuticals |
AU2002364552A AU2002364552A1 (en) | 2001-12-13 | 2002-12-11 | Treatment of osteomyelitis with radiopharmaceuticals |
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US34054501P | 2001-12-13 | 2001-12-13 | |
US34066501P | 2001-12-13 | 2001-12-13 | |
US60/340,665 | 2001-12-13 | ||
US60/340,545 | 2001-12-13 |
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WO2003051403A1 true WO2003051403A1 (en) | 2003-06-26 |
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PCT/US2002/039692 WO2003051403A1 (en) | 2001-12-13 | 2002-12-11 | Treatment of osteomyelitis with radiopharmaceuticals |
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US (1) | US7045116B2 (en) |
EP (1) | EP1458416A1 (en) |
JP (1) | JP2005516933A (en) |
AU (1) | AU2002364552A1 (en) |
WO (1) | WO2003051403A1 (en) |
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US20030118508A1 (en) | 2003-06-26 |
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US7045116B2 (en) | 2006-05-16 |
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EP1458416A1 (en) | 2004-09-22 |
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