Classifications

• • 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
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/365—Lactones
  • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
• • 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
  • A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
  • A61K38/46—Hydrolases (3)
  • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
  • A61K38/482—Serine endopeptidases (3.4.21)
  • A61K38/4826—Trypsin (3.4.21.4) Chymotrypsin (3.4.21.1)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
  • A61K38/46—Hydrolases (3)
  • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
  • A61K38/4873—Cysteine endopeptidases (3.4.22), e.g. stem bromelain, papain, ficin, cathepsin H
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12Y—ENZYMES
  • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
  • C12Y304/21—Serine endopeptidases (3.4.21)
  • C12Y304/21001—Chymotrypsin (3.4.21.1)
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12Y—ENZYMES
  • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
  • C12Y304/22—Cysteine endopeptidases (3.4.22)
  • C12Y304/22002—Papain (3.4.22.2)
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12Y—ENZYMES
  • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
  • C12Y304/22—Cysteine endopeptidases (3.4.22)
  • C12Y304/22033—Fruit bromelain (3.4.22.33), i.e. juice bromelain

Definitions

• This invention relates to therapeutic compositions containing certain selenium compounds. These therapeutic compositions have been found to exhibit surprising and unexpected properties in mammalian hosts. More particularly, the selenium compounds in accordance with the present invention are water soluble organic or inorganic compounds containing selenium in a form capable of being absorbed by the body tissue to be treated. Preferably, the compounds are salts containing selenium in the form of the selenite or selenate anions. In the practice of the present invention, the therapeutic compositions are formulated so that said selenium compounds are present in certain specific amounts and concentrations so that they are non-toxic yet therapeutically active.
• Selenium is one of numerous elements found in trace amounts in many foods. The selenium is present in many chemicals and often in very complex forms. Many technical studies have been carried out concerning its biological effects although the majority of the work has dealt with those adverse effects which occur by ingesting more than trace amounts of selenium-containing compounds. "
• selenium may have beneficial physiological effects on mammals. For example, it has been suggested that selenium, when ingested, reduces the rate of oxidative damage caused by chemicals, such as, for example, ozone in smog, by entering the membrances of the body's cells and protecting the contents of the cells from reacting with oxygen in a manner that damages the cells. It has also been reported that selenium may be beneficial in the treatment of heart disease by reducing or decreasing coronary vascular resistance in dogs. Other studies have suggested that some beneficial effects may arise from the use of selenium in cancer therapy.
• chemicals such as, for example, ozone in smog
• compositions have been formulated which have unexpected therapeutic and physiological properties and benefits which enable them to be easily formulated and administered to mammals, including humans.
• methods of treating mammals, including humans to reduce the severity from and to improve recovery from certain physically induced injuries to tissue caused by physical effects or irritating stimuli such as surgical operations, lacerations and burns including electrical, sun and thermal burns, etcetera.
• an organic or inorganic water soluble compound containing selenium wherein the selenium is in such a form as to be capable of being absorbed by the tissue of the host being treated, for use in treating tissue affected by one or more of incisions, lacerations, burns, infection, edema, ecchymosis, or for minimising scarring, or for .treating eye redness and irritation.
• the selenium compound is preferably a water soluble organic or inorganic selenite or selenate such as alkali metal selenites or selenates.
• the composition may be formulated for oral, injectable, topical or suppository administration.
• tablets capsules, solutions, creams and the like may be made where the selenium compound is dispersed substantially homogeneously throughout a suitable pharmaceutically acceptable carrier or vehicle in such finished dosage form.
• compositions in accordance with the present invention which contain certain selenium compounds in therapeutically effective but non-toxic dosages can be administered to mammals for the purpose of reducing the severity from and improving the recovery from physically induced damage to the host's tissue.
• physically induced damage is meant various types of damage to the tissue of a mammal. including, for example, surgical incisions, lacerations, burns, etcetera. Accompanying such damage are the likelihood of infection, edema, ecchymosis and other inflammatory responses.
• compositions of the present invention are administered prior to such physically induced damage to tissue, such as prior to surgery, an observable improvement in the patient's healing of the tissue and ' a reduced degree of infection, edema, ecchymosis and other inflammatory responses are noted.
• compositions of the preBent invention can be administered subsequent to the physically induced damage to tissue and improve the recovery of the tissue and affected areas.
• the compositions of the present invention may be applied topically to the specifically affected areas of the skin to reduce scarring, etcetera.
• the anti-inflammatory properties of the selenium compositions of this invention provide useful advantages when employed alone or with other materials utilized, for example, in pre-operative or post-operative surgical procedures.
• various compounds such as steroids have been alleged to possess anti-inflammatory properties. Included among these are, for example, cortisone and hydro-cortisone.
• the selenium compositions of this invention used alone exhibit effective anti-inflammatory properties without the detrimental side effects of some known materials which exhibit anti-inflammatory properties.
• the selenium compounds of the present invention may be combined with materials having compatible properties to form compositions exhibiting the beneficial effects of the selenium compounds, as well as enhanced beneficial effects of these other materials.
• the primary active ingredient in the therapeutic compositions of the present invention is the selenium compound or compounds.
• selenium occurs in a number varying valence forms.
• selenium compounds in which the selenium has a +4 valence usually as the selenite and selenate ions, may be utilized in the compositions of this invention.
• the preferred compounds utilized in the compositions of this invention are the water soluble alkali metal salts thereof, and particularly, the sodium and potassium salts, that is, sodium and potassium selenite and selenate.
• organic compounds of selenium may also be utilized in the compositions of this invention.
• selenium compounds of cystine and methionine as well as the aliphatic mono- and di-selenoidi-carboxylic acids having about 7 to 11 carbons in the carbon chain may be used.
• Particularly useful acids of this group include monoseleno-11, 11' - di'n-undecanoic acid, diseleno-4, 4' -di-n-valeric acid and diseleno-11, ll'-di-n-undecanamide.
• the particular organic forms of selenium compounds set forth herein are not to be considered limitative.
• Other organic selenium compounds which exhibit the desired activity and are compatible with the host and non-toxic to the host can be used in the practice of this invention.
• the selenium in the form present in the composition be capable of being absorbed by the tissue of the body to be treated. It is noted that water insoluble selenium compounds are not generally absorbed by the tissue.
• compositions of this invention can be made by mixing a suitable appropriate carrier and the selenium compound together and agitating the mixture until homogeneity is attained.
• compositions for topical administration should have generally a lower concentration of elemental selenium than compositions for other types of administrati on.
• the selenium compound can be present in such an amount so that the elemental selenium concentration of the therapeutic composition is in the order of from about 0.005 to about 2 mg per gram of the total weight of the composition. The concentration of course, depends upon the therapeutic activity desired and toxicity maximum levels.
• the daily dosage range is of the order of about 0.05 to 1.0 mg and preferably 0.5 to about 1.0 elemental selenium, it is convenient as a practical matter to formulate the composition so that about 0.5 mg to about 1.0 mg of elemental selenium is present in a given dosage amount of the composition.
• compositions of the present invention are quite stable and can be pre-mixed in the form of subsequent administration. Techniques that are recognised in the art for packaging, storing and preparing medicinal compositions for administration are . generally applicable to these compositions.
• compositions in accordance. with the present invention may be made in various physical forms for well known methods of administration.
• the composition can be in a suitable form for injectable, topical, suppository and oral administration.
• the choice of the particular carrier or vehicle and other additives present will depend upon the form desired.
• Said compositions may also be combined with other materials such as cleansing and antiseptic-type agents.
• Exemplary inert carriers or vehicles include: sugars and milk sugars, such as lactose; liquids, such as water, isotonic aqueous solutions, saline solutions and alcohol; and inert powders, creams, salves, ointments, cleansing and antiseptic agents and the like.
• Pharmaceutically active carriers or vehicles may also be used. These may include physiologically active powders, liquids, salves, creams and ointments as well as materials such as vitamins, steroids including cortisone and hydrocortisone. Other materials include proteolytic enzymes, such as those obtained from the pineapple plant and sold under the trade name of Ananase by William H. Rorer, Inc.
• proteolytic enzymes obtained from the papaya plant and sold under the trade name of Papase by Warner/Chilcott , Division of Warner-Lambert Company of Morris Plains, New Jersey, U.S.A., and others, such as animal pancreas extraqts which contain trypsin and chymotrypsin, one form of such extract being sold under the trade name of Chymoral by Armour Pharmaceutical Co. of Phoenix, Arizona, U.S.A.
• the therapeutic composition of the present invention can be prepared in dosage form as capsules, tablets, powders, syrups, oral solutions and the like.
• These orally adminstrable compositions may contain such additives as diluents, fillers, lubricants and glidants. Where they are in the form of a liquid, they should be suitably prepared so that the ingredients including the liquid pharmaceutical carrier are bland ' to the gastric mucosa.
• the therapeutic selenium compound may be dissolved in distilled or sterilized water to form a parenteral preparation, orjt can be mixed with intravenous infusions such as glucose or saline.
• selenium can be utilized in compositions suitable for topical, dermatological applications.
• the selenium compounds can be used for skin treatments and maintenance in dermatological creams, salves, and the like.
• Such compositions can be effective in treating skin irritations, certain rashes, dermatitis, eczema, acne, and pruritus.
• Such compositions also have properties making them useful in reducing the rate of cell aging due to exposure to light and oxygen which generally results in an oxidizing condition that weakens the cell membranes, thus causing the cells to deform.
• the number of damaged cells generally increases rapidly with the time of exposure to light and oxygen.
• the use of dermatological preparations containing selenium in accordance with this invention dramatically interrupts or stops such damaging effects.
• compositions of the present invention are also particularly effective in improving and accelerating the healing of tissue damaged by burns, which includes burns caused by the sun, heat, electricity, radioactive exposure and chemicals.
• selenium compositions in accordance with the invention prevent distortion or adverse bio-chemical effects in cells which are subjected to ultraviolet light which greatly damages the membrance of such cells.
• composition of the present, invention may be administered as eye drops in the form of a very dilute isotonic aqueous solution, that is, from about 0.1 mg to 0.5 mg of elemental selenium per cc solution and properly buffered to substantially neutral pH of about 6-7.
• eye drop solutions are useful in relieving eye irritation and redness caused by dust, smoke, smog, wind and sun glare, swimming, strain due to reading and television viewing or in the problems encountered in adapting to the utilization of contact lenses.
• a daily dosage of such an eye drop solution would be in the order of 1/20 to 1/5 cc.
• compositions of this invention are illustrative only and other known pharmaceutically acceptable materials can be utilized in the compositions of this invention so long as they do not react with the selenium and other active ingredients if any to destroy the identitiy thereof.
• particular carrier or vehicle chosen for use will depend upon the form of the composition needed for the particular method of adminstration and the host to receive the composition.
• the composition may be employed in the form of divided dosages when being administered whether it be in the form of a tablet, a capsule or a liquid solution.
• a particular dosage in this respect can be adminstered several times a day so long as the total amount of selenium compound does not exceed a maximum of about 1.0 mg per day.
• the composition of this invention can be made by simply mixing the selenium compound in proper proportion 'with an appropriate carrier.
• an alkali metal selenite or selenate salt in its dry form may be mechanically mixed with a powdered carrier or vehicle and shaped or pressed into tablets or encapsulated by known and art- recognized techniques.
• such salts can be dissolved in water and then mixed with a powdered .. carrier and shaped or pressed into tablets.
• liquid compositions can be prepared simply by dissolving the selenium compounds in water and using the composition in that form with recognized additives for either external or oral application.
• the materials as mixed should contain at least a 0.05 mg dosage of selenium to achieve most therapeutic benefits and may contain up to an amount conveniently combinable with the carrier to provide a daily dosage of selenium in a range of from about .05 mg to about 1.0 mg, and preferably from about 0.5 mg to about 1.0 mg.
• the stated range is generally a beneficially useful amount of selenium in accordance with this invention, it is also to be understood that this range is normally the amount given to an adult mammalian individual. However, dependent upon the weight and age of an adult mammalian host, the amount ingested by such a host may be adjusted accordingly within the stated range or somewhat outside the minimum and maximum thereof.
• the total overall amount to be ingested per day by a relatively small or young individual, for example, is preferably near the lower end of the range and for larger or older individuals, toward or in the area of the upper end of the stated range.
• a general range for daily treatment dosages again based upon the purpose of treatment and other factors of the individual, would be in the range 0.005 - 0.02 mg per kg weight of the host.
• the compositions may simply be administered orally to an adult patient or host in divided doses for several days, e.g., from 1-7 days, preceding surgery in the stated concentrations or for several days, e.g., from 1-7 days following the surgical procedure or other trauma.
• an aqueous solution of sodium selenate or sodium selenite can be made in a concentration to provide 5.0 mg of selenium and then sub-divided by dilution to provide an equivalent amount of selenium of 0.5 to 1 mg and administered in daily amounts orally or otherwise for a period of 1-5 days preceding and following surgery.
• the selenium may also be administered orally, intraveneously or subcutaneously, for example, by dissolving sodium selenate or sodium selenite in water in an amount such that one drop of the solution yields 0.33 mg of selenium.
• concentration may be based upon one drop of the solution being equal to 1/20 of a ml. More dilute and concentrated solutions may also be used.
• compositions in accordance with this invention can comprise small amounts of selenium combined with Vitamin E, wherein the Vitamin E is present in the range from about 10 I.U. to about 1000 I.U., and preferably from about 200 I.U. to about 800 I.U.
• Vitamin E is present in the range from about 10 I.U. to about 1000 I.U., and preferably from about 200 I.U. to about 800 I.U.
• the combination permits advantageous beneficial effects due to the presence of selenium with the vitamin, it being understood that in use further appropriate dilution takes place so that the daily amount of elemental selenium administered does not exceed 1.0 mg.
• the selenium can also be combined with ascorbic acid, i.e., Vitamin C and utilized in the pre-treatment of patients undergoing elective surgery. Due to the fact that some selenium does form a precipitate with the Vitamin C, an appropriate method of administration should be used to minimize this precipitation effect.
• ascorbic acid i.e., Vitamin C
• the present invention presents many advantages both in its therapeutic effects and in the ability to formulate adminstrable compositions.
• selenium When ingested, selenium is distributed to all of the cells in the body and is stored non-selectively but not uniformly, as is the case with several other elements such as chromium, iodine, and calcium.
• compositions of this invention are relatively simple to prepare.
• the water soluble sodium and potassium salts of selenium are readily available are are easily incorporated into a suitable phasmaceut- ical carrier or vehicle without the need for extraordinary and elaborate manufacturing equipnent.
• the selenium salts can be distributed in a suitable carrier and stored for long periods of time without loss of effectiveness.
• the salts can be marketed separately and simply mixed or compounded with a carrier just prior to use. Numerous other advantages of this invention will be readily apparent to those skilled in the art.
• This example is presented to illustrate the tolerance and effect of compositions of the pre'sent invention as administered to humans.
• the patient chosen for this example was 22 years old. Some four years prior to receiving the treatment in accordance with the present invention, he had undergone a rhinoplasty surgery which resulted in severe and alarming post-operative eochymosis, edema and blood red eyes.
• the rhinoplasty surgical procedure involved the fracture of the patient.'s nose and associated trauma associated with the surrounding tissues. This prior treatment and recovery of the patient acts as a control to the instant example.
• the foregoing solution was ingested in an amount daily to . yield a daily dosage of 0.65 mg per day.
• the daily dosage was continued for a period of seven days.
• On the evening of the seventh day of treatment the patient was involved in an automobile accident in which he suffered head, nose and facial injuries. This included a fracture of his nose and associated trauma to the surrounding tissue.
• the patient received emergency hospital treatment including examination and treatment by a plastic surgeon. During the course of the patient's recovery, there was no observed ecchymosis or edema of the nose, eyes or face, although trauma had been sustained as a result of the accident.
• This example illustrates the effect of orally ingesting the therapeutic composition of the present invention on the irritation of the eyes of a human patient.
• the patient was a wearer of contact lenses and for many years suffered regular inflammation and irritation due to the wearing of contact lenses.
• the patient received by oral ingestion the therapeutic composition prepared in accordance with Example 1 in an amount equivalent to a daily dosage of 0.5 mg of selenium. After a period of 5 days, the redness and inflammation that was normally present in his eyes subsided and discontinued. After his eyes reached an optimum improvement, he discontinued the ingestion of the therapeutic composition for a period of seven days. After those seven days, the patient's eyes became inflamed, red and irritated to the same extent as existed prior to the original treatment with the

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Cited By (8)

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• 1978
  • 1978-07-18 CA CA307,652A patent/CA1112164A/en not_active Expired
  • 1978-07-27 IT IT50509/78A patent/IT1107965B/it active
  • 1978-08-01 EP EP78300225A patent/EP0000670A1/de not_active Withdrawn
  • 1978-08-02 JP JP9515478A patent/JPS5459309A/ja active Pending

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