WO2009009622A2 - Compositions pharmaceutiques contenant du attm, procédés pour obtenir et conserver le cuivre à un état ciblé et stable et pour prévenir et traiter des maladies du système central nerveux liées au cuivre - Google Patents

Compositions pharmaceutiques contenant du attm, procédés pour obtenir et conserver le cuivre à un état ciblé et stable et pour prévenir et traiter des maladies du système central nerveux liées au cuivre Download PDF

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Publication number
WO2009009622A2
WO2009009622A2 PCT/US2008/069567 US2008069567W WO2009009622A2 WO 2009009622 A2 WO2009009622 A2 WO 2009009622A2 US 2008069567 W US2008069567 W US 2008069567W WO 2009009622 A2 WO2009009622 A2 WO 2009009622A2
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WIPO (PCT)
Prior art keywords
formulation
microns
particles
attm
weight
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PCT/US2008/069567
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English (en)
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WO2009009622A3 (fr
Inventor
Steve H. Kanzer
John S. Althaus
Charles L. Bisgaier
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Pipex Pharmaceuticals, Inc.
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Publication of WO2009009622A2 publication Critical patent/WO2009009622A2/fr
Publication of WO2009009622A3 publication Critical patent/WO2009009622A3/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
    • A61K31/28—Compounds containing heavy metals
    • A61K31/305—Mercury compounds
    • A61K31/31—Mercury compounds containing nitrogen
    • 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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/485—Inorganic compounds

Definitions

  • the present invention relates to pharmaceutical products and methods for treating excessive metal buildup or metal malabsorption in animals and humans.
  • Copper is a trace element that is essential to life. Despite its essentiality, however, copper also is an extremely reactive oxidative species that has the potential to be very toxic to cells, proteins, and organ systems such as the liver, brain and vasculature.
  • the present invention includes ammonium tetrathromolybdate (ATTM) formulations having targeted particle sizes, usually in the 150-700 micron range, which are useful as pharmaceutical compositions.
  • APM ammonium tetrathromolybdate
  • the present invention also includes a two-part pill, tablet or capsule, wherein one part contains zinc and is intended to release in the gastrointestinal tract of a human or other animal, and the other part contains a copper chelator and is intended to chelate copper only after the zinc has induced metallotheionein production in the gastrointestinal tract.
  • the two part delivery system constitutes a kit, wherein the zinc-containing component first initiates metallothioneins and subsequently a copper complexing or chelating agent is subsequently added to the kit. This would allow the copper complexing/chelating agent to bind excess copper that is not blocked from absorption by the zinc induced MT.
  • kits may exist of the two components initially, whereby the direct copper binding component is eventually removed, tapered in dose, or continued at a markedly reduced dose.
  • This type of kit would allow the zinc component to induce MT to high levels during the early part of treatment, and limit exposure of the copper complexing/chelating agent during the later stage of therapy.
  • the present invention also includes a tablet, pill or capsule comprising zinc, preferably a zinc-cysteine complex, that dissolves or disintegrates at different rates in different locations of the gastrointestinal tract of a human or other animal, so as to optimize induction of matrix metallotheionein in the gastrointestinal tract to efficiently block the potential absorption of copper that may be contained in the gastrointestinal tract.
  • zinc preferably a zinc-cysteine complex
  • the present invention also includes a method of treating Alzheimer's disease in a subject comprising administration of a composition which protects the subject from exposure to soluble forms of copper contained in ingestible substances including but not limited to drinking fluids; the composition can comprise zinc, and preferably a zinc- cysteine complex.
  • the present invention also includes a pharmaceutically acceptable formulation suitable for human or other animal use that contains less than 120 mg of tetrathiomolybdate, optionally less than lOOmg, less than 80mg, less than 60mg, less than 40mg, less than 20mg, less than lOmg or less than 5mg, for example. This dosing can be taken daily, for example.
  • the present invention also includes a method of treating disease in a subject which comprises administration of a dose of a thiomolybdate of between 2 mg to 20 mg.
  • the dose will likely be between 5 and 140 mg/day.
  • the dose form could be given as oral, IV, IP, subcutaneously.
  • Oral doses should be administered with meals, away from meals and in some cases a combination of dose regimens with and without meals.
  • the present invention also includes a method of treating a CNS (Central Nervous System) disease in a human or animal which comprises administration of agent capable of stabilizing, controlling and/or reducing free copper levels in the serum;
  • the agent can comprise pegalated forms of superoxide dismutase or liposomal, depo injection or other sustained release forms of copper complexing agents selected from the group consisting of superoxide dismutase, ceruloplasmin, metallothionein, transferrin, amyloid beta, apoe4 and CCS (Copper Chaperon for SODl (Superoxide Dismutase I)).
  • the present invention also includes a pharmaceutical composition suitable for oral administration in a human or animal that containing thiomolybdate crystals of an individual weight of approximately 0.3 to 0.5 micrograms.
  • the present invention also includes a pharmaceutical composition
  • a pharmaceutical composition comprising an immediate release capsule or portion of a capsule containing thiomolybdate crystals, particles, microparticles, enterically coated microparticles, alone or in combination, capable of binding copper contained in food as well as copper endogenously secreted into the jejunum and intestines via the bile.
  • a method of treating Wilson's disease in a patient comprises administration of an oral dosage form of this composition.
  • the Wilson's disease can be neurologically presenting Wilson's disease.
  • a thiomolybdate is administered to a patient in need thereof orally three times per day with meals and three times a day away from meals.
  • the thiomolybdate administered orally with meals can be swallowed substantially within the first fifteen minutes of the first bite of the meal, or partway through the meal, preferably about halfway through the meal.
  • the thiomolybdate administered orally with meals can be swallowed substantially within the first fifteen minutes of the first bite of the meal, or about halfway through the meal.
  • the present invention also includes a capsule containing a thiomolybdate suitable for oral administration in a human or an animal and immediate release in the stomach wherein the capsule has a water content of approximately 6% or less; preferably, the capsule comprises a material selected from the group of methyl cellulose, hydroxylpropyl methyl cellulose, carrageenan, polyesters, poly(nonhalogenated hydrocarbons), poly(halogenated hydrocarbons), poly(halogenated polyethers), polymers formed from dienes, poly(higher alkylene oxides), polyamides, polysiloxanes, polysilanes, poly(acrylonitriles), poly(lower alkylene oxides), acrylate polymers, polyacrylic acids and alternating copolymers, poly(ethylene terephthalate), poly(butylene terephthalate), poly(trimethylene terephthalate), poly(ethylene naphthalate), polyethylene, polypropylene, polystyrene, polyisobutylene, polymethylpen
  • Fig. 1 is a plot of the dissolution profile of an ammonium tetrathromolybdate
  • Fig. 2 is a plot of ATTM formulations tested at room temperature and ambient humidity; Conditions were Mono (monohydrate lactose), Anydrous (anhydrous lactose, Quali (methyl cellulose capsules), Air (air atmosphere) and N2 (nitrogen atmosphere) in accordance with Example 14 hereof.
  • Fig. 3 is a plot of the particle size distribution, as determined by sieving and then weight of the two ATTM lots used in the clinical trials (Clinical trial lots) for the treatment of the initial neurological presentation of Wilson's Disease. The treatment in both trials resulted in a 96 percent stabilization or improvement in neurologic function.
  • the particle size distribution and weight of an additional synthesized lot is shown(New Lot). This lot is typical of newly synthesized ATTM lots in that they have a particle size distribution larger than material used in the clinical trials and therefore is not suitable for uniform commercial production of capsules each containing about 20 mg ATTM (New Lot).
  • Fig. 4. Is a plot of uniformity of fill for capsules made with a milled new lot of ATTM blended with excipients.
  • Large particle size ATTM was milled and then subject to a particle size sieve to isolate particles between 150- 700 microns, which were then blended with excipients in a commercial V-blender under argon and filled into hydroxylpropyl methyl cellulose capsules using a commercial Macofar capsule filling machine such that each capsule should contain approximately 20 mg of ATTM.
  • Approximately 60,000 capsules were prepared and 9 to 11 samples were taken from the first, middle and last third of the production run.
  • Capsule samples taken were assayed for ATTM content and uniformity of fill by dissolving the content of the sample capsules in 5mM phosphate buffer, pH 7.0 and measuring the absorption at 467 nm. Capsules from the first, middle and end of the process were all shown to contain + 3 percent of the targeted 20mg of ATTM per capsule.
  • Fig. 5 Comparison of dissolution properties of hand-filled ATTM to scale prepared capsules.
  • ATTM lots and formulation thereof were used to hand fill capsules.
  • capsules prepared in a commercial process test run, using milled and sieved ATTM, were assessed for dissolution. Dissolution at pH 7.0 was tested for hand- filled gelatin capsules containing ATTM from the clinical trial supply (approximately 20mg) and lactose monohydrate (approximately 280mg) or hydroxypropyl methyl cellulose capsules containing milled and sieved ATTM (approximately 20 mg) and lactose monohydrate (approximately 280mg).
  • hydroxypropyl methyl cellulose capsules were filled by a commercial process and contained roller milled then sieved (about 150-700 micron particles) ATTM (approximately 20mg), lactose monohydrate (approximately 268mg), cabosil (approximately 6mg), and glycerol stearate (approximately 6mg).
  • the three types of capsules were subject to dissolution at pH 7.0. At pH 7.0 nearly all of the ATTM was recovered in solution (great than about 95 percent) hydroxypropyl methyl cellulose capsules were filled by a commercial process and contained roller milled then sieved (about 150-700 micron particles) ATTM
  • the content of the gelatin capsules were essentially completely in solution within 5 minutes, while the ATTM content of the HPMC capsules were essentially completely in solution within 30 minutes upon the initiation of the experiment.
  • Example 1 Four cohorts of patients of 12 or more patients each, one cohort with late onset Alzheimer's disease, one cohort with late onset Parkinson's disease, one cohort of normal elderly patients that are age matched to the Alzheimer's and Parkinson's cohort and one cohort of normal patients aged 20 to 40 are administered equal amounts of distilled or tap water containing the isotope Cu .
  • Serial serum samples are obtained at time zero and every 20 minutes over the course of 2 hours and then periodically up to 24 hours. Serum samples are fractionated in three or more affinity columns or affinity beads that have binding specificity for either ceruloplasmin, albumin and one or more other copper binding proteins, such as, homocysteine, and apoE.
  • the affinity columns or affinity beads are subsequently separately washed with distilled water and the eluted solution of each is measured and quantified for total radioactivity by means of standard protocols measuring total radioactivity indicating the total amount of Cu present in such elution on an absolute and related on a percentage basis to both the total solution volume as well as quantity of ceruloplasmin, albumin or other proteins.
  • the results show both a higher average level of peak Cu levels and AUC of Cu in the albumin and other protein elutions in the Alzheimer's and Parkinson's patients compared to aged matched controls and young patients, as well as when age matched controls are compared to younger patients.
  • the size of the tetrathiomolybdate crystals are controlled to provide selected, sustained or delayed release in the stomach and the intestines.
  • Crystal size may be controlled through controlled crystal growth, or by milling as described below.
  • larger tetrathiomolybdate crystals for example, ammonia tetrathiomolybdate pass through the stomach essentially unchanged and dissolve in the gut, while smaller crystals dissolve in the stomach.
  • sustained release in relation can be achieved by providing a mixture of crystals of varying sizes. For example, a mixture comprising crystals of 50-100 microns and 200-500 microns or crystals of about 150 -700 microns may be provided, in a single capsule.
  • An object of the present invention includes oral nutriceutical formulations that contain elemental molybednum and sulphur. Upon administration and dissolution in the stomach or rumen such formulations would combine in the low pH environment of the stomach or rumen and form thiomolybdates capable of complexing free copper in the gastrointestinal tract and systemic circulation much like ammonium tetrathiomolybdate. While such formulations would be expected to be far less reliable in terms of dosing, they might have the advantages as natural products pursuant to the Dietary Health Supplement and Education Act (DSHEA).
  • DSHEA Dietary Health Supplement and Education Act
  • stable copper isotope Cu and the radioactive copper isotope Cu are utilized as the active copper ingredient to permit copper balance and treatment effect to be evaluated and adjusted on an individual basis.
  • Such studies may be conducted by sampling serum, CSF fluid, stool, or urine, or by biopsy. Such information provides a useful diagnostic method to evaluate the effects of other therapeutic approaches, such as therapies to improve hepatic excretion of copper as well as copper chelators.
  • Example 11 Controlled dietary copper supplementation.
  • Copper, copper salts or copper bound to low molecular weight amino acids is dissolved in a solution of dried or evaporated milk, dried whey, dried milk lipids, or dried milk proteins or other natural copper binding proteins.
  • the resulting mixture of copper bound complexes may be dried and formulated as a pill or tablet.
  • the dried copper bound complexes are formulated in a pill or capsule together with zinc.
  • the pill or tablet is formulated utilizing gastrorententive forms of zinc, enteric coated zinc and/or sustained release zinc such that the copper bound complexes are released into the gastrointestinal tract ahead of the zinc.
  • the copper bound complexes are digested in the GI and absorbed by enterocytes where they are processed intracellularly with metallothionein and/or transcuprein, whereupon such metallothionein and/or transcuprien bound copper enters the liver and is taken up for processing and incorporation into ceruloplasmin and then either released into the serum, retained in the liver or excreted into the bile.
  • the later passing zinc is absorbed in the enterocytes, thereby upregulating metallothionein, which serves to block subsequent absorption of solubilized copper (free or loosely bound copper such as copper- containing tap water or other liquids that would otherwise pass into the hepatic circulation upon water flux without proper processing by the enterocyte and enter the hepatic circulation bound to albumin).
  • solubilized copper free or loosely bound copper such as copper- containing tap water or other liquids that would otherwise pass into the hepatic circulation upon water flux without proper processing by the enterocyte and enter the hepatic circulation bound to albumin.
  • Example 13 Dissolution of ATTM as a Capsulated Formulation Introduction: We performed a dissolution experiment using a capsule containing 20 mg of ammonium tetrathiomolybdate plus excipient. ATTM crystals used were 500 microns or smaller. No ATTM was recovered in the gastric dissolution medium at any time. After, 3 hours of dissolution, insoluble black particles released from the capsule were found suspended in solution. After neutralization of the gastric media to pH 9, these black particles solubilized resulting in about 10% of ATTM being recovered. Summary:
  • the ATTM used was separated from larger ATTM by passing it through a 500 micron sizing sieve.
  • the capsule contained approximately 20 mg of ATTM and 180 mg of excipient. Dissolution Conditions
  • the amount of ATTM remaining was about 10% of the ATTM present in the capsule.
  • Ammonium tetrathiomolybdate formulated capsules were studied for stability. Various conditions and capsule types (gelatin Galliport capsules and QualiCaps, hydroxypropyl methyl cellulose capsules)were examined. The best formulation was found when QualiCaps capsules (low moisture hydroxypropyl methylcellulose) were used, nitrogen was used as the storage atmosphere and the excipient included lactose monohydrate. Summary:
  • ATTM was completely stable after 8-Weeks when stored at room temperture and ambient relative humidity. At 24 weeks the ATTM were still highly stable for most conditions with the exception of anhydrous lactose monohydrate in gelatin capsules stored under nitrogen or air. 2. ATTM was 60% to 90% stable after 8-Weeks when stored at 40 0 C and 70% relative humidity. As stability tests were extended to 24 weeks under these stressed conditions stability decreased.
  • Lactose monohydrate was better than lactose anhydrous (3 of 4 cases)
  • ATTM predominantly from a single lot stored at low temperature and an inert atmosphere was used to conduct clinical trials for the neurological presentation of Wilson's Disease. This lot was subsequently subject to characterization of particle size analysis using molecule sieves (Figure 3).
  • the ATTM was shown to consist of a distribution by weight of particles size predominantly between approximately > 125 to 700 microns as shown in Figure 3. Additional lots of ATTM were prepared and were shown to consist of particles larger than those used in clinical trials. A lot typical of the newer preparation is also shown in Figure 3. These lots contained particles much larger than used in the clinical trial lot. The presence of large particles without further formulation is not appropriate to allow consistent and uniform fill of commercial capsules in that the variation in weight between capsules would be greatly influenced by the large particles.
  • Each ATTM capsule used in the clinical trial contained about 20 mg of active ingredient comprised of ATTM particles with about 2 mg of particles of ⁇ 125 microns, about 5.8 mg of particles of about 250-500 microns, about 10 mg of particles of about 250-500 microns, about 1.6 mg of particles of about 500-700 microns, and about 0.6 mg of particles greater than 700 microns (Figure 3).
  • the unique size distribution of the ATTM crystals allows for a very effective treatment for the initial neurological presentation of Wilsons 's disease.
  • hydroxypropyl methyl cellulose capsules were filled by a commercial process and contained roller milled then sieved (about 150-700 micron particles) ATTM (approximately 20mg), lactose monohydrate (approximately 268mg), cabosil (approximately 6mg), and glycerol stearate (approximately 6mg).
  • ATTM approximately 20mg
  • lactose monohydrate approximately 268mg
  • cabosil approximately 6mg
  • glycerol stearate approximately 6mg
  • hydroxypropyl methyl cellulose capsules were filled by a commercial process and contained roller milled then sieved (about 150-700 micron particles) ATTM (approximately 20mg), lactose monohydrate (approximately 268mg), cabosil (approximately 6mg), and glycerol stearate (approximately 6mg) hydroxypropyl methyl cellulose capsules were filled by a commercial process and contained roller milled then sieved (about 150-700 micron particles) ATTM (approximately 20mg), lactose monohydrate (approximately 268mg), cabosil (approximately 6mg), and glycerol stearate (approximately 6mg) at the end of 3 hour from all capsules tested.
  • the content of the gelatin capsules were essentially completely in solution within 5 minutes, while the ATTM content of the HPMC capsules were essentially completely in solution within 30 minutes upon the initiation of the experiment.
  • the hydroxypropyl methyl cellulose capsules filled by the commercial process and contained roller milled then sieved (about 150-700 micron particles) ATTM (approximately 20mg), lactose monohydrate (approximately 268mg), cabosil (approximately 6mg), and glycerol stearate (approximately 6mg) were also subject to dissolution initiated at gastric pH (pH 1.1) and neutralized after 2 hours.

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  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
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  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract

L'invention concerne des compositions pharmaceutiques comprenant une formulation à libération prolongée d'un agent qui induit une malabsorption du cuivre chez un animal ou l'homme. Les compositions pharmaceutiques comprennent, de préférence, des formulations de tétrathromolybdate d'ammonium (ATTM) ayant des tailles de particules ciblées, de préférence, dans la plage de 150 à 700 microns.
PCT/US2008/069567 2007-07-09 2008-07-09 Compositions pharmaceutiques contenant du attm, procédés pour obtenir et conserver le cuivre à un état ciblé et stable et pour prévenir et traiter des maladies du système central nerveux liées au cuivre WO2009009622A2 (fr)

Applications Claiming Priority (2)

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US94868107P 2007-07-09 2007-07-09
US60/948,681 2007-07-09

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WO2009009622A2 true WO2009009622A2 (fr) 2009-01-15
WO2009009622A3 WO2009009622A3 (fr) 2009-02-26

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000013712A2 (fr) * 1998-09-04 2000-03-16 The Regents Of The University Of Michigan Methodes et compositions pour la prevention ou le traitement du cancer
WO2004009072A2 (fr) * 2002-07-23 2004-01-29 The Regents Of The University Of Michigan Tetrapropylammonium tetrathiomolybdate et composes associes pour therapies anti-angiogeniques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000013712A2 (fr) * 1998-09-04 2000-03-16 The Regents Of The University Of Michigan Methodes et compositions pour la prevention ou le traitement du cancer
WO2004009072A2 (fr) * 2002-07-23 2004-01-29 The Regents Of The University Of Michigan Tetrapropylammonium tetrathiomolybdate et composes associes pour therapies anti-angiogeniques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PARK KH ET AL: 'Inhibition kinetics of mushroom tyrosinase by copper-chelating ammonium tetrathiomolybdate' BIO CHEMICA ET BIOPHYSICA ACTA. GENERAL SUBJECTS vol. 1726, no. 1, 2005, pages 115 - 120, XP005130387 *

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