Classifications

• • 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
  • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
  • A61K33/10—Carbonates; Bicarbonates
• • 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
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
  • A61K31/716—Glucans
  • A61K31/722—Chitin, chitosan
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  • 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
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • 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
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
  • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• the present invention relates to a composition of matter comprising calcium carbonate dispersed finely with organic matter consisting essentially of chitin and polypeptide. Pharmaceutical uses of said composition of matter are provided.
• WO 2005/115414 disclosed an orally-administrable composition comprising stable amorphous calcium carbonate and its use in treating bone disorders.
• the present invention aims at a composition of matter comprising calcium carbonate dispersed in a lesser part of organic matter consisting of chitin and polypeptide.
• the present invention provides a composition of matter, comprising 100 weight parts (wp) of calcium carbonate mixed finely with from 10 to 30 wp of organic matter comprising from 90 to 99 wt % chitin and from 1 to 10 wt % polypeptide.
• Said composition of matter may further comprise up to 40 wp of inorganic salts other than calcium carbonate (CaCO 3 ) and up to 30 wp of moisture per 100 wp of CaCO 3 .
• said composition of matter originates from crustacean gastrolith.
• said composition of matter originates from artificial mixture of CaCO 3 , chitin, and polypeptide (Pp).
• Said composition preferably comprises 100 wp of CaCO 3 and from 15 to 25 wp of organic matter essentially consisting of chitin and polypeptide, which organic matter comprises from about 95 to 99 wt % chitin and from 1 to 5 wt % polypeptide.
• Said other salts are preferably selected from salts comprising magnesium, calcium, potassium, strontium, sodium, phosphate, sulfate, carbonate, chloride, bromide, and fluoride, of course with the proviso that said salts do not simultaneously comprise calcium and carbonate, so as not to increase the desired calcium carbonate amount.
• the invention is further directed to a pharmaceutical formulation for oral administration comprising the composition of matter described above.
• Said pharmaceutical formulation comprises calcium carbonate (CaCO 3 ) finely mixed with an organic matter essentially consisting of chitin and polypeptide (Pp), wherein said organic matter and said CaCO 3 are present in a ratio of from 1/10 to 3/10, and said Pp and said chitin are present in a ratio of from 1/100 to 1/10, for treating conditions associated with calcium metabolism or calcium signaling.
• said pharmaceutical formulation originates from crustacean gastrolith.
• said pharmaceutical formulation originates from artificial mixture of CaCO 3 , chitin, and Pp.
• Said pharmaceutical formulation comprises CaCO 3 finely dispersed or mixed with an organic matter (Om) essentially consisting of chitin and Pp, wherein said organic matter and said CaCO 3 are present in a ratio of from 1/10 to 3/10, and said Pp and chitin are present in a ratio of from 1/100 to 1/10, for treating conditions selected from the group consisting of pain, proliferative diseases, neurological disorders, immunologic disorders, cardiovascular diseases, pulmonary diseases, nutritional disorders, reproductive disorders, musculoskeletal disorders, and dental problems.
• Said treating may comprise mitigating the symptoms of the diseases.
• Said proliferative disease is selected from sarcomas, carcinomas, lymphomas and melanomas.
• Said carcinoma is preferably breast carcinoma or bronchogenic carcinoma.
• Said treating may comprise shrinking tumors, stopping their growth, or slowing down or inhibiting the cell proliferation in the tumors.
• Said pain may be selected from postoperative pain, pain after injury, pain associated with cancer, and neuropathic pain.
• Said neurologic disorder may be selected from demyelinating diseases, dementias, and movement disorders; said disorders being, for example, multiple sclerosis, Alzheimer's disease, Parkinson's disease, or other degenerative disease.
• Said condition may comprise a bone or bone marrow disorder, such as fracture or osteoporosis.
• a composition of the invention is used for treating a neurodegenerative disorder.
• the invention relates to the use of a composition of matter according to the invention as a medicament.
• the invention also relates to the use of the composition of matter in the manufacture of a medicament for treating cancer, or neurodegenerative disorders, or bone disorders and injuries.
• a novel method of treating cancer comprising orally administering a composition of matter containing an organic matter finely mixed with CaCO 3 , said organic matter essentially consisting of chitin and Pp, wherein said organic matter and CaCO 3 are present in a ratio of from 1/10 to 3/10, and wherein said Pp and chitin are present in a ratio of from 1/100 to 1/10.
• a novel method of treating a degenerative disorder comprising orally administering a composition of matter containing an organic matter finely mixed with CaCO 3 , said organic matter essentially consisting of chitin and Pp, wherein said organic matter and CaCO 3 are present in a ratio of from 1/10 to 3/10, and wherein said Pp and chitin are present in a ratio of from 1/100 to 1/10.
• a method for managing pain comprising orally administering a composition of matter containing an organic matter (Om) finely mixed with CaCO 3 , said Om essentially consisting of chitin and Pp, wherein said organic matter and CaCO 3 are present in a ratio of from 1/10 to 3/10, and wherein said Pp and chitin are present in a ratio of from 1/100 to 1/10, preferably from 1/100 to 1/20.
• Om organic matter
• a method for treating a bone disorder or injury comprising orally administering a composition of matter containing an organic matter finely mixed with CaCO 3 , said organic matter essentially consisting of chitin and Pp, wherein said organic matter and CaCO 3 are present in a ratio of from 1/10 to 3/10, and wherein said Pp and chitin are present in a ratio of from 1/100 to 1/10.
• said composition according to the invention is administered orally in daily doses of from about 0.5 to about 5 g.
• the invention is directed to a method of preparing the composition of matter comprising 100 weight parts (wp) of calcium carbonate mixed finely with from 10 to 30 wp of organic matter comprising from 90 to 99 wt % chitin and from 1 to 10 wt % polypeptide, which method comprises i) providing a material containing CaCO 3 and organic matter (Om), wherein the mass ratio Om/CaCO 3 is between 1/10 and 3/10, and wherein said Om consists essentially of chitin and Pp, the mass ratio Pp/chitin being between 1/100 and 1/10; ii) homogenizing the mixture if necessary, and iii) adjusting water content in the mixture to be from 10 to 30 wp per 100 wp CaCO 3 .
• said material containing CaCO 3 and Om in above step i) is obtained from biological source.
• said material containing CaCO 3 and Om in step i) is an artificial mixture of the components.
• Said biological source may be an organ or a body part of a crustacean, preferably selected from decapods.
• Said method of the invention comprises the steps of i) providing a material containing CaCO 3 , and Om consisting essentially of chitin and Pp, wherein the mass ratio Om/CaCO 3 is between 1/10 and 3/10, and the mass ratio Pp/chitin is between 1/100 and 1/10; optionally adjusting water content in the mixture up to 30 wp per 100 wp CaCO 3 ; iii) optionally adjusting the content of inorganic salts other than CaCO 3 in the mixture up to 40 wp per 100 wp of CaCO 3 ; and iv) homogenizing the mixture to obtain a fine dispersion.
• Said embodiment employing a biological source may comprise the steps of i) selecting crayfish, monitoring and optionally inducing the formation of gastrolith; harvesting developed gastroliths; iii) drying said gastroliths in hot air until only about 20 parts of water per 100 parts of CaCO 3 is retained; and iv) grinding said dried gastroliths.
• Said embodiment employing an artificial mixture may comprise, in one possible procedure but without being limited to it, the steps of i) dispersing calcium hydroxide in water; ii) optionally admixing sodium and/or potassium phosphate; iii) saturating the dispersion with carbon dioxide while adding chitin and polypeptide; iv) centrifuging the suspension; v) discarding a part of the supernatant; and vi) drying the part of the dispersion containing the sediment until only about 20 parts of water per 100 parts of CaCO 3 is retained.
• composition of matter comprising 100 weight parts (wp) of calcium carbonate mixed with about 20 wp of organic matter consisting of chitin and a lesser amount of polypeptide, when orally administered to patients suffering from proliferative or neurodegenerative diseases, has a surprisingly positive effect on the course of the disease.
• a composition originating from crustacean gastrolith comprising per 100 wp of calcium carbonate about 20 wp of organic matter consisting of chitin and polypeptide, and which further contained about 30 wp of additional inorganic salts and 20 wp of moisture, exhibited healing or mitigating effects in the patients with proliferative disorders.
• a daily dose of 1.5 g of the above said gastrolith-based composition led to dramatic effects on the patients' state.
• the pain decrease was reported by the patients, and in continued treatments, the changes included improved blood tests and remissions of the metastatic tumors.
• patients suffering from advanced Alzheimer's disease (AD) exhibited improvements when being daily administered around 1 g of the said composition, wherein the benign effects included improved cognitive abilities and increased physical activity, and further included mitigation effects on the patients suffering from chronic pains, particularly bone pains.
• AD Alzheimer's disease
• composition of matter according to the invention has been found to mitigate pains in a diverse group of conditions, comprising bone weakening and injuries, the subjectively improved state of the patients being accompanied by impressive laboratory findings.
• the invention thus relates to a composition of matter comprising 100 weight parts (wp) of calcium carbonate mixed with from 10 to 30 wp of organic matter consisting of chitin and polypeptide, and to the use of said composition in managing chronic pain and in treating conditions comprising chronic pain.
• the composition of the invention additionally contributes to healing the underlying causative factor, such as a proliferative disease, or to mitigating the accompanying main disorder, such as Alzheimer disease.
• an important role of calcium in the regulation of all bodily functions must be taken into consideration.
• Calcium forms up to 5% of the solids in the human body, and beside structural functions in the bones, it has many important regulatory and signaling functions, as indicated by, in view of its total amount incredibly low, intracellular calcium ion concentrations of about 10 ⁇ 7 M.
• Calcium ions being an intracellular signal transducer, participate in controlling muscle contraction, releasing neurotransmitters, secreting hormones, regulating cell motility and mitosis, and affecting gene expression. Calcium signaling stands at the beginning of the life when participating at the egg fertilization, and it stands at its end when the cells die of apoptotic death.
• chitin and polypeptide there are from 10 to 30 weight parts of chitin and polypeptide per 100 weight parts of calcium carbonate, and it can be hardly assessed how the finely admixed organic component affects the behavior of administered calcium.
• chitin and protein molecules may exhibit occlusive effects on amorphous micro particles or on microcrystals of calcium carbonate, or they may show chelating effects, and the types of eventual interactions will change also according to the changing pH and the presence of digestion factors along the tract, wherein various materials may possibly bind calcium ions, including, for example, bile acids, proteins originating from the administered composition, proteins originating in the body, etc.
• Chitin may have additional effects, as indicated in various reports showing biological activities of chitin, an example being US 2004/0234614, which describes an immunomodulating effect of inhaled chitin particles.
• surprising benign activity of the composition according to the invention may result from concurrent effects of the fine dispersion of inorganic calcium and organic macromolecules, of the mixture of chitin and polypeptide molecules interspersed with amorphous or microcrystalline calcium carbonate, and of the consistence of chitin interwoven in an inorganic/organic web of calcium carbonate with polypeptide.
• the materials of the invention may be other factors contributing to the final effects of the materials of the invention, but, however theoretically interesting they are, the mutual interactions of the components, their description, or the involved mechanisms are, of course, not a part of the invention.
• composition of matter according to the invention comprises calcium carbonate homogeneously mixed, and finely dispersed, with an organic matter consisting of chitin and polypeptide.
• an organic matter consisting of chitin and polypeptide.
• CaCO 3 calcium carbonate
• chitin an oligosaccharide or polysaccharide of any origin comprising [1-4]- ⁇ -linked N-acetyl-D-glucosamine
• protein or “polypeptide” is used in connection with the composition of the invention, the intended meaning is any polypeptide or any mixture of polypeptides that is pharmaceutically acceptable for oral administration.
• composition of matter of the invention comprises chitin and polypeptide in a total amount of from 10 to 30 weight parts per 100 weight parts of calcium carbonate, and in a ratio of polypeptide/chitin of from 0.01 to 0.1, preferably said total amount is from 15 to 25 wp, and said ratio is from 0.01 to 0.05.
• the composition of matter according to the invention may further comprise inorganic salts other than calcium carbonate in an amount of up to 40 wp per 100 wp of calcium carbonate, and moisture in an amount of up to 30 wp per 100 wp of calcium carbonate.
• the invention is also directed to a pharmaceutical formulation comprising a composition of matter defined above.
• the pharmaceutical formulation of the invention comprises CaCO 3 , chitin and polypeptide in a total amount of from 10 to 30 wp per 100 wp of said CaCO 3 , water up to 30 wt per 100 wp, and may further comprise additional inorganic salts, as well as components used in pharmaceutical formulations to provide a desired consistency, such as a carrier, binding agent, or diluent, provided that the component is inert and in no way affects the chemical or physical properties of the active components that are relevant for their therapeutic activities.
• a filler or “filler”.
• composition of matter according to the invention is pressed into tablets without any filler.
• additional pharmaceutically active agent may be present in a formulation according to the invention, for specific indications, wherein said additional agent may be selected, for example, from antiviral, antifungal, antibacterial, antiseptic, anti-inflammatory or immunomodulatory, antineoplastic, and analgesic agents.
• the invention provides a composition of matter comprising CaCO 3 finely mixed with chitin and polypeptide for use as a pharmaceutical.
• the ratio of the organic matter to calcium carbonate in said composition of matter is between 10 to 30 wp organic matter per 100 wp CaCO 3 , wherein said composition of matter comprises water up to 30 wt per 100 wp CaCO 3 , and may further comprise additional inorganic salts up to 40 wp per 100 wp of CaCO 3 .
• the invention provides a composition of matter for treating a proliferative disease selected from sarcomas, carcinomas, lymphomas and melanomas.
• a proliferative disease selected from sarcomas, carcinomas, lymphomas and melanomas.
• the current treatments available for bronchogenic carcinoma include surgery, radiation therapy, and chemotherapy. While being the leading cause of cancer death among men (32%) and women (25%) [The Merck Manual of Diagnosis and Therapy, 17 th Ed., 1999], the said condition has a poor prognosis, and a really urgent need is felt for additional treatments which would improve the prospects, or, at least, mitigate the most distressing symptoms, including pains. Frequently found symptoms comprise bone pains.
• Cancer pain syndromes may be caused by tumors invading bone or soft tissues, compressing or infiltrating nerves, or obstructing a hollow viscus, or they may follow therapy.
• the composition of matter according to the invention was demonstrated to improve the state of patients with lung cancer. Furthermore, the composition according to the invention was found to mitigate bone pain associated with the proliferative diseases.
• composition originating from crustacean gastrolith comprising CaCO 3 finely mixed with chitin and polypeptide, wherein the ratio of the organic matter to calcium carbonate in said composition was about 20 wp pf the organic matter per 100 wp CaCO 3 , said matter consisting essentially of chitin and protein and further containing about 30 wp of inorganic salts and about 20 wp of moisture per 100 wp CaCO 3 , was found to cause tumors shrinkage at a daily dose of 0.5-2.0 g.
• breast carcinomas afflicting one woman in eight. Although showing a better prognosis than lung cancer, many complications frequently appear, including drug toxicity and adverse effects, wherein some women do not respond to standard therapies.
• the treatment may include surgery, radiation therapy, and chemotherapy, eventually accompanied by endocrine therapy.
• breast cancers require that more treatment elements be simultaneously or subsequently employed.
• combination regimens should be used.
• palliative treatment is usually necessary, as well as treatments of secondary problems, which problems may comprise trauma, intoxication, post-radiation symptoms, secondary infections, etc. If metastases develop, the current treatments offer an increase of median survival only by 3 to 6 months.
• a composition of matter according to the invention was demonstrated to improve the state of patients with breast cancer metastasized to other organs, wherein the improvements included shrinkage of the tumors, increase of the bone mass, renewal of nail growth after the radiation therapy, improved laboratory blood values.
• a composition of matter according to the invention originating from crustacean gastrolith, comprising CaCO 3 finely mixed with chitin and polypeptide, wherein the ratio of the organic matter to calcium carbonate in said composition was about 20 wp of the organic matter per 100 wp CaCO 3 , said matter consisting essentially of chitin and protein and further containing about 20 wp water about 30 wp inorganic salts per 100 wp CaCO 3 , was shown to be very effective in amounts up to 2.0 g daily.
• the administration of a composition of the invention surprisingly affects simultaneously a variety of diagnostic parameters and symptoms, including the pain—which is alleviated.
• composition of the invention may remarkably contribute even in these cases, since it promotes bone healing. Furthermore, since the composition of the invention was found to have palliative effects, and especially alleviating effects on bone pains, in a variety of disorders, it will be very helpful also in the complex treatments of breast cancers, in which many analgesics have adverse effects, and some are inefficient.
• a composition of matter for treating a neurological disorder, such as pain, and dementia or other neurodegenerative disorders.
• a neurological disorder such as pain, and dementia or other neurodegenerative disorders.
• An example of dementia is Alzheimer disease, of which occurrence above the age of 60 increases nearly linearly with the increasing age, accounting for more than 65% of the dementias in the elderly [Ibid.]. No effective treatments are known against the disease that gradually destroys cognitive functions and finally leads to severe complications and restrictions in physical activities.
• the composition of matter according to the invention comprising CaCO 3 dispersed in an organic matter consisting essentially of chitin and polypeptide, wherein the ratio of the organic matter to calcium carbonate in said composition is between 10 and 30 wp of the organic matter per 100 wp CaCO 3 was found to mitigate the symptoms of Alzheimer's disease.
• a composition originating from crustacean gastrolith comprising CaCO 3 finely mixed with organic matter consisting essentially of chitin and polypeptide, wherein the ratio of the organic matter to calcium carbonate in said composition was about 20 wp of the organic matter per 100 wp CaCO 3 , and further containing about 20 wp water and about 30 wp inorganic salts per 100 wp CaCO 3 , was found to mitigate the symptoms of Alzheimer's disease in patients who were administered a daily dose of from 0.8 to 1.5 g, the benign effects including improved cognitive abilities and increased physical activity; and, importantly, in patients with chronic pains, palliative effects of said composition was observed.
• Neurological disorders include pain. Pain is sometimes a symptom of a well defined underlying disease or cause, such as cancer or postoperative pain, and sometimes it is a problem occurring without a clear reason, such as neuropathic pain. Chronic pain may develop, for example, after injury.
• the existing treatments include administration of analgesics, antidepressants, or anesthetics, which may be, however, inefficient or may have adverse effects, and therefore new treatments are needed.
• the composition of matter according to the invention mitigated pain in diverse cases, and therefore are believed to be a non-harmful alternative for pain managing. Calcium carbonate finely mixed with organic matter consisting essentially of chitin and polypeptide may hardly present a toxic challenge, when orally administered.
• a gastrolith-derived composition according to the invention in which the ratio of the organic matter to calcium carbonate in said composition is about 20 wp of the organic matter per 100 wp CaCO 3 , further containing about 20 wp water and 30 wp inorganic salts, was found to alleviate pain in patients with different diagnostic states, particularly bone pain, when administered at several daily doses (within a week) of about 1-1.5 g (depending on the weight and age of the patient).
• a composition of matter for treating a bone or bone marrow disorder, including fracture or osteoporosis.
• the bone formation in humans surpasses or equals bone resorption till the age of about 45 years, followed by a period of the net loss of about 0.5% per year; women may experience up to tenfold higher rate of bone loss during several years after menopause.
• the patients often suffer from pain in the bones or muscles, fractures may develop. Consumption of 1 to 1.5 g calcium daily is recommended.
• composition of matter according to the invention comprising CaCO 3 finely mixed with organic matter, consisting essentially of chitin and polypeptide dispersed in CaCO 3 , wherein the ratio of the organic matter to calcium carbonate in said composition of from 10 to 30 wp of the organic matter per 100 wp CaCO 3 was found to improve the state of patients suffering from osteoporosis.
• a composition originating from crustacean gastrolith comprising CaCO 3 finely mixed with organic matter consisting essentially of chitin and polypeptide, wherein the ratio of the organic matter to calcium carbonate in said composition was about 20 wp of the organic matter per 100 wp CaCO 3 , and further containing about 20 wp water and about 30 wp inorganic salts, was found to mitigate the osteoporosis symptoms when administered at a daily dose of about 0.5 g; bone loss was stopped, while 1.5 g led to improvements comprising the increase of the bone density measured in the spine.
• the composition of the invention accelerated healing of bone fractures.
• the invention provides a method of treating a condition selected from the group consisting of proliferative diseases, neurological diseases, bone disorders, and chronic pain, which method comprises administering a therapeutic amount of a composition of matter consisting of calcium carbonate, chitin and polypeptide, wherein the mass ratio of the organic matter to calcium carbonate is from 1/10 to 3/10, and the mass ratio of polypeptide to chitin is from 1/100 to 1/10.
• said composition further comprises water in an amount of up to 30 weight parts and inorganic salts in an amount of up to 40 weight parts per 100 parts of CaCO 3 .
• the composition is preferably administered in one dose every day during a period sufficient for achieving an improvement of symptoms or healing of underlying causes associated with said condition.
• the present invention provides a means for treating or mitigating a disorder associated with calcium metabolism, or calcium signaling.
• the conditions implicated with calcium metabolism or signaling comprise immunologic and proliferative, neurological, cardiovascular and pulmonary, nutritional, musculoskeletal, and dental problems.
• Said proliferative conditions include cancers; and said treating or mitigating may comprise shrinking a tumor or preventing the proliferation of carcinogenic cells in said tumor.
• Said neurological conditions include neurodegenerative demyelinating diseases, such as MS, and dementias, such as AD, and movement disorders, such as Parkinson's disease.
• composition of matter for oral administration The toxicity measurements confirmed the safety of the composition of matter for oral administration.
• Therapeutic daily doses of from 0.5 g to 2 g of the compositions have been found useful in specific cases, but in view of the low toxicity, the doses may be increased when needed, as a skilled person will appreciate.
• the invention relates to a composition of matter, and the use thereof in the preparation of a medicament, mimicking certain features of the composition of crustacean gastrolith, comprising calcium carbonate finely mixed or dispersed with an organic matter which essentially consists of chitin and polypeptide (Pp), wherein the mass ratio (chitin+Pp)/CaCO 3 is between 1/10 and 3/10, and the mass ratio Pp/chitin is between 1/100 and 1/10, preferably between 1/100 and 1/20.
• the composition of the invention may comprise moisture up to about 30 mass parts per 100 mass parts of CaCO 3 , and it may further comprise inorganic salts other than calcium carbonate up to about 40 mass parts per 100 mass parts of CaCO 3 .
• said CaCO 3 is essentially amorphous.
• Said other salts may comprise, for example, cations selected from magnesium, potassium, strontium, and sodium, and anions selected from carbonate, phosphate, sulfate, chloride, bromide, and fluoride; the terms anion and cation are used to simply describe the salt composition, without implying anything about the solubility of the salts. If said calcium carbonate is amorphous, the analytical indications, IR and X-ray, as disclosed in WO 2005/115414 are obtained. It is known that some salts, such as phosphates, may support the amorphous state of calcium carbonate.
• Said composition of the invention may be prepared by homogenizing a mixture containing 100 weight parts of calcium carbonate, and from 10 to 30 weight parts of organic matter consisting essentially of chitin and polypeptide, optionally further including in said mixture up to 30 weight parts of water and up to 40 parts of pharmaceutically acceptable inorganic salts other than CaCO 3 , wherein said homogenizing achieves fine dispersion of all components, the calcium carbonate preferably appearing as amorphous or microcrystalline.
• said composition of the invention may be obtained from biological source, for example from crustacean which in certain organs or body parts contain calcium carbonate and said organic matter.
• Said crustaceans preferably include the order of decapods, represented, for example, by crayfish.
• Said body part may comprise gastrolith or parts of exoskeleton, preferably of a crayfish, for example Cherax quadricarinatus.
• the invention provides a method of preparing a composition of matter comprising calcium carbonate finely mixed or dispersed with an organic matter (Om) which essentially consists of chitin and Pp, comprising i) providing a material containing CaCO 3 , chitin, and Pp, wherein the mass ratio Om/CaCO 3 is between 1/10 and 3/10, and the mass ratio Pp/chitin is between 1/100 and 1/10; optionally adjusting water content in the mixture up to 30 wp per 100 wp CaCO 3 ; optionally adjusting the content of inorganic salts other than CaCO 3 in the mixture up to 40 wp per 100 wp of CaCO 3 ; iv) homogenizing the mixture to obtain a fine dispersion.
• Om organic matter
• Said homogenizing may comprise stirring, grinding, or milling.
• Said water adjusting may include drying at higher temperatures or at lower air pressures.
• said method of the invention comprises selecting crayfish and monitoring, and optionally inducing, the formation of gastrolith, harvesting developed gastroliths, drying them in hot air, and grinding, thereby to obtain the composition of the invention.
• said method of the invention comprises dispersing calcium hydroxide in water, optionally with smaller amounts of sodium and/or potassium phosphate, and saturating the suspension with carbon dioxide while adding chitin and polypeptide, centrifuging the suspension, and drying the sediments with a part of the supernatant, thereby to obtain the composition of the invention.
• a skilled person can calculate the amounts of the components so as to obtain the desired ratios.
• Said polypeptide may be selected from soluble and insoluble proteins, acceptable for oral administration.
• Gastroliths of Cherax quadricarinatus were prepared as described [WO 2005/115414]. Dried gastroliths containing about 20 parts of water per 100 parts of CaCO 3 were ground to yield a composition of matter according to the invention, denoted CM1 hereinafter. Pharmaceutical formulation according to the invention were obtained by pressing CM1 into tablets according to the methods already described [Ibid].
• CM1 The toxicity of CM1 was determined on rats (Harlan Biotech Israel, Rehovot). A daily dose of 65 mg CM1 per 1 kg body weight caused no mortality, or any noticeable clinical signs, and all laboratory values were normal during the whole period of 14 days.
• CM2 a composition of matter according to the invention
• the calcium additive was stopped after starting the treatment with a composition according to the invention.
• CM1 Four patients suffering from osteoporosis, age 55-78 years were daily administered tablets of CM1. One patient was receiving a daily dose of 0.5 g during four months with no changes in her situation. Other patient, receiving 1.5 g daily for 5 weeks, showed increase in bone density (the results were compared to the situation 4 years ago before osteoporosis). One patient (72 years old) was receiving 0.8 g daily for 2 months, and 1.5 g daily for 2 months. The bone density measured in the spine increased substantially (up to 13% in several regions of the bone). An improvement in the activity of thyroid gland was reported in one of the patients.
• CM1 Three patients, afflicted with several types of bone fractures comprising pelvis, back and foot (man age 40), leg (age 9), finger ( woman age 40) respectively, were administered tablets CM1 for up to two weeks.
• the finger broken in two regions was treated for a week to a full healing.
• Pelvis, back and foot fractures in one wounded patient took six weeks to full recovery when taking 1.5 g daily for two weeks from the second week, whereas the initial estimation by the doctors of the recovery time was up to about six months.
• the patient with a broken leg took 0.5 g CM1 daily and experienced pain reduction within tree days, and full recovery after a week (estimated by the doctors to take three weeks).
• mice Five groups of rats, each consisting of five females, were fed on normal granular food.
• the animals in groups (1) and (2) were ovarectomized at the age of one month, the animals in group (3) were only incised to open abdomen without ovarectomy—to serve as a control group.
• group (1) received food enriched with 1.2 wt % dried gastrolith
• group (2) received food enriched with the corresponding amount of crystalline calcium carbonate
• group (3) received non-enriched food.
• the animals were sacrificed six weeks after the operation.
• the following parameters were checked: total body weight; blood values, including calcium, phosphate, estradiol; mass of femur and tibia after the animals' sacrifice; femur and tibia histology; the mass of femur and tibia ashes (800° C., 12 hours); and Ca and Mg contents in the ashes.

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