WO2002009728A1 - Procedes servant a prevenir ou a traiter des maladies et des etats au moyen de glucides complexes - Google Patents

Procedes servant a prevenir ou a traiter des maladies et des etats au moyen de glucides complexes Download PDF

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Publication number
WO2002009728A1
WO2002009728A1 PCT/US2001/041473 US0141473W WO0209728A1 WO 2002009728 A1 WO2002009728 A1 WO 2002009728A1 US 0141473 W US0141473 W US 0141473W WO 0209728 A1 WO0209728 A1 WO 0209728A1
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WIPO (PCT)
Prior art keywords
cascade
effective amount
sodium hyaluronate
treat
complex carbohydrates
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PCT/US2001/041473
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English (en)
Inventor
Harold G. Brown
Karen K. Brown
Carol A. Cooper
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Dermal Research Laboratories, Inc.
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Application filed by Dermal Research Laboratories, Inc. filed Critical Dermal Research Laboratories, Inc.
Priority to AU2001281368A priority Critical patent/AU2001281368B2/en
Priority to AU8136801A priority patent/AU8136801A/xx
Priority to US10/343,240 priority patent/US7879824B2/en
Priority to NZ524076A priority patent/NZ524076A/en
Priority to EP01959852A priority patent/EP1311276A4/fr
Priority to CA2417867A priority patent/CA2417867C/fr
Publication of WO2002009728A1 publication Critical patent/WO2002009728A1/fr
Priority to US13/006,975 priority patent/US8367642B2/en

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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
    • A61K31/70—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
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • 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
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • 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
    • A61K31/737—Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate

Definitions

  • the invention relates to novel uses for a composition of matter comprising complex carbohydrates preferably as the sole active ingredient, applied topically, orally, mucosally or parenterally to prevent or treat diseases and conditions associated with allergies or the adhesion, metastatic or coronary cascades. Also disclosed are methods of preventing and treating the above-mentioned diseases and conditions by administering the complex carbohydrates of the present invention. Additionally, this invention describes novel uses for a composition of matter comprising at least one complex carbohydrate and at least one transdermal or transmucosal carrier useful for effecting transdermal or transmucosal migration resulting in topical or mucosal delivery of macromolecules, through the skin or mucous membranes of mammals and into the bloodstream.
  • complex carbohydrates are defined as any polymer comprising more than two sugar moieties and include such classes of compounds as polysaccharides and oligosaccharides.
  • Polysaccharides include mucopolysaccharides and mannans whereas oligosaccharides are comprised of branched polysaccharides such as sialylated sugars including milk sugars.
  • the key milk sugars (also called hexaoses) incorporated in the general class of complex carbohydrates are difucosyllacto-N- hexaose a and b, Disialyl-monofucosyllacto-N-hexaose and monofucosyllacto-N-hexsaose I, II, and II (obtainable from Oxford Glycosystems, Inc.).
  • glycosaminoglycans that can be obtained from numerous sources ⁇ e.g. rooster combs, trachea, umbilical cords, skin, articular fluids and certain bacteria such as Streptococci spp) . Most glycosaminoglycans
  • glycosaminoglycans are composed of repeating sugars such as n-acetylglucosamine, glucuronic acid and n-acetyl galactosamine (these are known as non-sulfated glycosaminoglycans). If such glycosaminoglycans contain sulfur groups they are known as sulfated glycosaminoglycans .
  • Heparin, hyaluronic acid and chondroitin sulfate are the most studied mucopolysaccharides. Heparin has been used for a number of years as an anticoagulant. Hyaluronic acid has been used therapeutically since the 1970s as a replacement for the vitreous humor of the eye post surgery and, more recently, as replacement for joint fluid in arthritic joints. The mode of action for hyaluronic acid injected directly into joints for treatment of arthritis has been proposed to be lubrication and replacement of the degraded joint fluid with highly viscous hyaluronic acid. High molecular weight (>750,000 daltons) and high viscosity have been reported to be critical for this use. (For purposes of this patent, all molecular weights are expressed as daltons . The unit designation will not be added hereinafter. )
  • chondroitin sulfate or polysulfated glycosaminoglycan (known by its commercial name as ADEQUAN ® ) could be injected intramuscularly for reduction of pain and inflammation associated with arthrosis of horses.
  • ADEQUAN ® polysulfated glycosaminoglycan
  • chondroitin sulfate had developed into a popular nutritional supplement being used extensively to treat joint problems. Such treatment requires oral doses between 1000 and 3000 mg/day for humans. Even with these high doses (>15mg/Kg) , relief from joint pain often takes 6- 9 months .
  • the adhesion cascade was first described in the early 1990s. In a summary by Adams and Shaw (The Lancet, 343, Apr. 2, 1994) the adhesion cascade is supposed to describe the mechanism by which pain and swelling are produced post trauma. It is divided into four sequential steps of tethering, triggering, strong adhesion and motility. Tethering interactions are mediated by a family of three lectin-like carbohydrate-binding molecules (selectins) . These interactions are strong enough to cause the leukocytes to roll along the blood vessel walls to the site of trauma instead of flowing freely through such vessels as they would in a non-traumatized state.
  • the triggering response is stimulated by factors such as cytokines stimulated by a traumatic event and mediated by adhesion molecules called integrins.
  • Integrins by themselves, do not bind well to epithelium. However, when activated, integrins promote strong adhesion of the leukocyte to the epithelial surface.
  • Leukocytes bind to the epithelial cells via their receptor sites such as CD44, CD31, etc. By a mechanism of attachment and detachment the leukocytes are guided to the site of trauma. At the site of trauma the adhesion to the blood vessel wall becomes stronger and the interaction of these integrins with their ligands on the surface of the leukocytes are responsible for cessation of movement and flattening of the leukocyte.
  • VCAM-1 and LFA-1 and other such integrins allow leukocytes to pass between endothelial cell junctions and into the tissue that has been traumatized. Collection of leukocytes at the site of trauma produces inflammation which is then followed by pain or other sequelae.
  • the metastatic cascade is very similar to the adhesion cascade. It has been proposed that tumor cells of all types contain CD44 receptor sites on their surface. These CD44 receptor sites appear to be involved in metastasis functioning similar to the receptor sites on leukocytes tethering the tumor cells to the blood vessel wall and providing the motility necessary for movement from one site to another in the mammalian body.
  • CD44 and tumor cells/cancer teaches that hyaluronic acid or hyaluronan actually stimulates metastasis (Eur. J. Cancer, 1999, March; 35 (3), 473-480).
  • a coronary cascade has recently been described in the Harvard Health Letter (December 1999, pg. 4-5) and SCIENCE vol:285, 23 July, 1999, pg 595-599).
  • This cascade describes a new mechanism to explain the development of heart disease and stroke.
  • Unstable plaques are the problem plaques because they are "swarming with T cells and macrophages" that are responding to a site of trauma and triggering the adhesion cascade resulting in inflammation. It is the "swarming T cells and macrophages” that make these plaques unstable.
  • the T cells are described as sending macrophages a signal to release a protein called tissue factor which "spills out and encounters circulating blood, attracting platelets and triggering formation of a clot that quickly blocks up the artery”.
  • complex carbohydrates of the present invention could be administered topically, orally, mucosally or parenterally, in low doses, to prevent and treat diseases and conditions associated with allergies, the adhesion cascade, the metastatic cascade and the coronary cascade described herein.
  • Figure 1 is a graph demonstrating the effect of treating an adult suffering with Attention Deficit Disorder with various formulations of hyaluronic acid.
  • Figure 2 is a graph demonstrating the effect of treating a 9 year old child suffering from Attention Deficit Hyperactivity Disorder with hyaluronic acid.
  • the present invention relates to a method of preventing and treating diseases and conditions associated with allergies, autoimmunity, the adhesion cascade, the metastatic cascade or the coronary cascade comprising administering (i) at least one complex carbohydrate as the sole active ingredient, or (ii) at least one pharmaceutical composition which comprises as an active ingredient a pharmacologically effective amount of at least one low purity or cosmetic grade complex carbohydrate selected from the group consisting of oligosaccharides, sialylated oligosaccharides, polysaccharides and glycosaminoglycans, and an effective amount of at least one transdermal or transmucosal carrier (e.g. essential oil) in an amount effective to deliver the complex carbohydrate into the blood stream.
  • a transdermal or transmucosal carrier e.g. essential oil
  • the present invention relates to using complex carbohydrates, including but not limited to mucopolysaccharides and glycosaminoglycans, to bind to the receptor sites on leukocytes (e.g. CD44 and CD31) blocking their ability to tether to the blood vessel walls, inhibiting the motility to the site of trauma thus reducing the pain, swelling and other sequelae associated therewith (interrupting the adhesion cascade) .
  • leukocytes e.g. CD44 and CD31
  • the present invention teaches that complex carbohydrate molecules, including but not limited to mucopolysaccharides and glycosaminoglycans, bind to the receptor sites on tumor cells blocking their ability to tether to the blood vessel walls and inhibit the tumor motility which, in turn, inhibits the potential for metastasis.
  • compositions of the present invention inhibit the macrophages from swarming to a site of irritation or trauma on a blood vessel wall wherein said macrophages would normally accumulate producing the unstable plaques described previously, thus preventing and treating heart disease and stroke. Additionally, the compositions of the present invention inhibit the T-cell and macrophage "swarming" thus blocking the release of the tissue factor (referred to previously) and preventing cardiac events caused by said ruptured plaques.
  • allergies and allergy-related diseases diseases associated with the bodies' adverse reactions to stimuli such as foods, inhalants and drugs wherein said adverse reactions include but not limited to Attention Deficit Disease, Attention Deficit Hyperactivity Disease, interstitial cystitis, autism, migraines, asthma, Turret's Syndrome, fibromyalgia, anaphylaxis, rhinitis, sinusitis and inflammation providing the environment for yeast infections, bacterial infections or virus infections and autoimmune diseases wherein the bodies' macrophages attack its own body tissues and organs producing diseases including but not limited to rheumatoid and osteoarthritis, Lupus Erythematosis, multiple sclerosis, polymyositis, muscular dystrophy, Diabetes, and potentially Alzheimer' s Disease, are associated by a mechanism similar to the adhesion cascade.
  • CD44, CD31, RHAMM and other similar receptors are involved in producing the allergic reaction and the autoimmune response. Again, the binding of complex carbohydrates to these receptor sites inhibit the reaction and/or response. Therefore, allergies, allergy-related diseases and autoimmune diseases respond to treatment by oral, mucosal, topical and parenteral administration of complex carbohydrates as described herein.
  • the complex carbohydrates of this invention can be used to prevent and/or treat Alzheimer's Disease.
  • Another explanation for the development of dementia and Alzheimer' s Disease is that an amyloid protein is produced in the brain resulting in the formation of amyloid plaques that lead to neuronal degeneration.
  • the neuronal degradation is associated with diseases related to various types of dementia including but not limited to Alzheimer's Disease. Since it is known that CD44 is present in significant amounts on neuronal cells in the brain, the complex carbohydrates of the present invention bind to CD44 and/or other receptor sites in the brain and inhibit the formation of such amyloid plaques.
  • the invention relates to a composition of matter comprising complex carbohydrates preferably as the sole active ingredient, applied topically, orally, mucosally or parenterally to prevent and treat diseases and conditions associated with allergies, autoimmunity, and the adhesion, metastatic or coronary cascades.
  • complex carbohydrates preferably as the sole active ingredient, applied topically, orally, mucosally or parenterally to prevent and treat diseases and conditions associated with allergies, autoimmunity, and the adhesion, metastatic or coronary cascades.
  • the compositions described in U.S. Patent 5,888,984 and in PCT/US00/02328 may also be utilized in the methods of the present invention.
  • this invention describes a composition of matter comprising at least one complex carbohydrate and at least one transdermal or transmucosal carrier useful for effecting transdermal or transmucosal migration of said complex carbohydrate, resulting in topical or mucosal delivery of said molecules, through the skin or mucous membranes of mammals and into the bloodstream in order to prevent or treat the diseases and conditions associated with allergic reactions, the adhesion cascade the metastatic cascade or the coronary cascade.
  • Transdermal carriers are those compounds that allow molecules, including macromolecules to pass through the skin and into the blood stream of mammals.
  • Transmucosal carriers are those compounds that allow molecules including macromolecules to pass through the mucous membranes and into the blood stream of mammals.
  • a patch or bandage can be embedded with the complex carbohydrates of the present invention so as to extend delivery of the molecules and/or provide slow release over several days.
  • the complex carbohydrates of the present invention in bandages, they can be used without the presence of transdermal or transmucosal carriers with open wounds, or containing said carriers when used to treat closed wounds or reduce scarring or scar tissue.
  • This invention further describes a method of preventing and treating diseases and conditions of mammals associated with allergies, autoimmunity, the adhesion cascade, the metastatic cascade or the coronary cascade comprising administering a composition of complex carbohydrates topically, orally, mucosally or parenterally preferably on a repeated basis (e.g. 2 times per day, preferably 4 times per day, and most preferably 8 times per day, or simply "as needed") .
  • this invention describes a mechanism by which inflammation, including diseases and conditions associated therewith, tumor growth, tumor metastasis, allergies and allergy-related diseases, autoimmune diseases, coronary diseases and central nervous system diseases can be prevented or treated by administering complex carbohydrates topically, orally, mucosally, or parenterally.
  • this invention describes the prevention and treatment of numerous diseases and conditions including but not limited to arthritis (osteoarthritis and rheumatoid arthritis), gastritis, stomach or intestinal ulcers, colitis, esophagitis, bronchitis, the common cold, rhinitis, sore throat, tonsillitis, tendonitis, fibromyalgia, chronic fatigue syndrome, interstitial cystitis, polymyositis, autism, Lupus Erythematosis, headaches including migraines, pancreatitis, anaphylaxis, vaginitis, hemorrhoids, sunburn, heat burns, temporomandibular joint (TMJ) condition, gingivitis, dental caries, dental pain, post surgical pain, menstrual pain, extremity cramps, pre and post partum pain, itching associated with allergies and hypersensitivity (e.g. poison ivy, oak and sumac and eczema) , asthma, emphyse
  • ADHD fibromyalgia
  • Turret's Syndrome Multiple Sclerosis
  • ALS Amyotrophic Lateral Sclerosis
  • Lou Gehrig' s Disease Lou Gehrig' s Disease
  • Parkinson's Disease high blood pressure, heart disease, heart attack, vasculitis, stroke, increased degradation of spinal nerves post spinal cord injury, head or brain trauma post injury, adhesion formation post surgery or chemotherapy, scar formation post surgery, non-healing wounds, decubutis ulcers, irritation of nerve bundles (e.g.
  • dementia including but not limited to Alzheimer's disease, Human Immunodeficiency Virus infection (HIV) , yeast infections, bacterial infections, viral infections, encephalitis, epilepsy, meningitis, peripheral neuropathy, Creuztfeldt-Jacob Disease, Bell's Palsy, cognitive disorder, cancer, Diabetes, skin problems such as acne, lick granulomas, hot spots, psoriasis, rashes, wrinkles, and even hair loss.
  • HAV Human Immunodeficiency Virus infection
  • yeast infections bacterial infections
  • viral infections encephalitis
  • epilepsy meningitis
  • peripheral neuropathy Creuztfeldt-Jacob Disease
  • Bell's Palsy cognitive disorder
  • Such prevention and treatment are accomplished by topically, orally, mucosally or parenterally applying complex carbohydrates of the present invention to mammals in an amount and number of applications so as to be effective in preventing and treating the target disease or condition. It is understood that such prevention or treatment results in blockage of receptor sites
  • This invention describes novel uses for a composition of matter comprising at least one complex carbohydrate that is applied topically, orally, mucosally or parenterally to prevent and/or treat diseases and conditions associated with allergies, autoimmunity, the adhesion cascade, the metastatic cascade or the coronary cascade.
  • the invention also encompasses novel uses for a composition comprising at least one complex carbohydrate and at least one transdermal or transmucosal carrier.
  • the invention also preferably encompasses novel uses for a composition of matter comprising complex carbohydrates as the sole active ingredient. Further, the compositions disclosed in U.S.
  • Patent 5,888,984 and in PCT/US00/02328 may also be utilized in the methods of the present invention. More specifically, the present invention is directed to a method of preventing and treating diseases and conditions associated with allergies, autoimmunity, the adhesion cascade, the metastatic cascade and the coronary cascade comprising administering said complex carbohydrates to the affected mammal topically, orally, mucosally or parenterally.
  • a significant feature of this invention is that the complex carbohydrates are preferably administered in a low dose.
  • low dose is meant from 0.000001 mg/kg to 150 mg/kg, preferably from 0.001 mg/kg to 100 mg/kg and more preferably from 0.01 mg/kg to 20 mg/kg.
  • the invention also describes a method for reducing the sequelae of trauma in irritated or inflamed tissue of mammals by the topical or mucosal application of a mixture of a transdermal or transmucosal carrier and one or more complex carbohydrates or mixtures thereof. The composition described is applied directly on or over the traumatized site or on a mucous membrane.
  • the invention describes a method for reducing the sequelae of trauma in irritated or inflamed tissue of mammals by topical, oral, mucosal or parenteral application of a complex carbohydrate of the present invention or mixture thereof as the only active ingredient.
  • trauma is meant an event that produces an adverse effect on a mammal.
  • sequelae of trauma is meant the pain, swelling, inflammation, adhesion formation, nerve damage, nerve sensitivity and any other physiological change that results from trauma .
  • Macromolecules as used herein means any molecule with a molecular weight >1000 daltons (Da) .
  • Mammals as used herein includes but is not limited to humans, dogs, cats, horses, cattle, swine, rabbits, guinea pigs, mice.
  • Topical administration as used herein means application to the dermis anywhere on the mammal, including into the ear canal.
  • Mucosal administration as used herein means application to any mucous membrane of a mammal. Mucous membranes include but are not limited to the mouth, gums, nasal passage, throat, vagina and the rectum.
  • Transdermal means transfer of molecules, including macromolecules through the skin of mammals so that the complex carbohydrates may act systemically .
  • Transmucosal means transfer of molecules, including macromolecules through the mucous membranes of mammals so that the complex carbohydrates may act systemically.
  • Diseases preventable and treatable by the present invention include but are not limited to tonsillitis, the common cold, pancreatitis, ulcerative colitis, stomach or intestinal ulcers, cold sores, Lupus Erythematosis, Parkinson's Disease, osteoarthritis, degenerative arthritis, rheumatoid arthritis, polymyositis, Amyotrophic Lateral Sclerosis (ALS) or Lou Gehrig' s Disease, multiple sclerosis, Creutzfeldt-Jakob Disease heart disease, heart attack, vasculitis, stroke, Alzheimer's disease, asthma, emphysema, allergy-related diseases, Human Immunodeficiency Virus
  • HAV HAV disease
  • yeast infections yeast infections
  • bacterial infections bacterial infections
  • encephalitis epilepsy
  • meningitis peripheral neuropathy
  • Bell's Palsey Cerebral Palsey
  • Conditions preventable and treatable by the above-described complex carbohydrates include but are not limited to ulcers, gastritis, esophagitis, bronchitis, sore throat, tendonitis / fibromyalgia, headaches including migraines, vaginitis, anaphylaxis, hemorrhoids, sunburn, heat burns, temporomandibular joint (TMJ) condition, dental caries, dental pain, gingivitis, post surgical pain, menstrual pain, cramps, pre and post partum pain, interstitial cystitis, itching associated with allergies and hypersensitivity (poison ivy) , pain associated with insect bites or stings, Attention Deficit Disorder, Attention Deficit Hyperactivity Disorder (ADHD), Turret's Syndrome
  • Particularly amenable conditions or diseases targeted for such prevention or treatment include but are not limited to irritated or inflamed muscles, cramped muscles, inflamed tendons, inflamed nerves or nerve bundles (e.g. inflamed ganglion, lick granulomas, trigger points, fibromyalgia) , swollen and painful joints, inflamed bladder (interstitial cystitis) bruised tissue, tired feet, allergic conditions of the skin, other allergic conditions (e.g.
  • psoriasis chronic fatigue syndrome
  • open wounds decubitis ulcers
  • burns sunburns
  • inflamed stomach or intestinal lining gastritis, colitis, ulcers
  • dental problems inflamed bronchi or esophagial lining
  • adhesions formed after surgery trauma or chemotherapy, pain post surgery, dental work or injury
  • plaques formed on veins or arteries leading to heart disease and stroke inflammation associated with Alzheimer's Disease, Multiple Sclerosis, amylotropic lateral sclerosis (ALS) , head or brain trauma, degration of the spinal cord post spinal cord injury, tumor formation and tumor metastasis.
  • ALS amylotropic lateral sclerosis
  • a significant advantage of this invention is that pharmaceutical grade complex carbohydrates are not required for topical, oral or mucosal application.
  • the invention preferably uses cosmetic or food grade (e.g. low purity) complex carbohydrates for these applications.
  • complex carbohydrates can be obtained from any source as long as the source is not contaminated with undesirable adventitious agents (disease-producing viruses, bacteria, fungi, parasites, etc.).
  • Such low purity complex carbohydrates such as mucopolysaccharides may be contaminated with up to 20% wt/vol proteins, 15% wt/vol nucleic acids, 1% wt/vol teichoic acids, 5% wt/vol lipids, fractions of hyaluronic acid ⁇ 30,000 (defined as reactive by both Balazs in U.S.
  • compositions of the immediate invention will cause reactions when injected into monkey eyes or joints of horses but will not cause reactions when applied to the skin of mammals or when delivered orally or mucosally to such mammals. Because the low purity pharmaceutical compositions of this invention are applied topically, orally or mucosally, these contaminants produce no adverse reactions (e.g. irritation or blistering of skin). Additionally, if one must select and use only certain molecular weight ranges of hyaluronic acid or salts thereof, the cost would be prohibitive. In fact, the presence of multiple molecular weight fractions in compositions of the immediate invention is preferable for efficacy.
  • the formulations of this invention can include preservatives allowable in foods or topical preparations. Allowable preservatives include but are not limited to methyl and propyl parabens, propylene glycol, ethylenediamine tetraacetic acid (EDTA) , sorbitol, ascorbic acid, sorbate and sorbic acid, benzoic acid, and any other acceptable preservative, including mixtures thereof.
  • Allowable preservatives include but are not limited to methyl and propyl parabens, propylene glycol, ethylenediamine tetraacetic acid (EDTA) , sorbitol, ascorbic acid, sorbate and sorbic acid, benzoic acid, and any other acceptable preservative, including mixtures thereof.
  • complex carbohydrates are effective in formulations of this invention.
  • complex carbohydrates with a molecular weight of ⁇ 1,000, 1,000 to 30,000, 100,000-500,000, >1, 000, 000 or >4, 000, 000 have proven to be effective. It has been found that complex carbohydrates, especially glycosaminoglycans with lower molecular weights (e.g. ⁇ 30,000) act more quickly than those with high molecular weights (e.g. >1, 000, 000).
  • glycosaminoglycans especially sodium hyaluronate, salts or derivatives thereof (also called hyaluronic acid or hyaluronan) with a molecular weight average below 300,000 Da.
  • the high molecular weight glycosaminoglycans provide a longer-lasting effect.
  • the latter macromolecules are broken down by enzymes in the body (hyaluronidase) to smaller molecules that are active in binding or stimulate production of increased amounts of lower molecular weight hyaluronic acid by the mammals' own body.
  • the preferred formulation for most treatments includes a mixture of low and high molecular weight complex carbohydrates. It has been noted by the inventors that the optimum molecular weight for treatment of allergies, allergy-related diseases and conditions, asthma, ADD and ADHD is between 30,000 and 500,000 Da, preferably between 100,000 and 300,000. It has been determined that very high molecular weight (>4 X 10 6 ) is essentially ineffective for treatment of the above .
  • complex carbohydrates useful in combination with transdermal or transmucosal carriers for direct topical or mucosal application on sites of trauma or to be absorbed therein may be of any type already recognized as useful for parenteral treatment.
  • complex carbohydrates including polysaccharides, glycosaminoglycans or their derivatives that bind to leukocyte receptor sites and/or bind to selectins, integrins, or any other receptor sites that are involved with the mechanisms by which leukocytes move to sites of trauma or that enable metastasis of tumors and that, when bound, serve to inhibit any of the steps of the adhesion cascade, allergy or autoimmune mechanisms, the metastatic cascade, or the coronary cascade would be useful in such pharmaceutical compositions.
  • Such compounds may be obtained from any source. They can be extracted from rooster combs (U.S. Pat. No. 4,141,973), produced by fermentation of bacteria (U.S. Pat. No. 4,782,046), or extracted from trachea, skin, umbilical cords, etc. and need only be pure enough to be used as a cosmetic in that they do not cause reactions when administered topically, orally or mucosally.
  • These molecules include but are not limited to polysaccharides, glycosaminoglycans such as hyaluronic acids and derivatives or salts thereof (Genzyme, Lifecore Biomedicals, Meiji Seika Kaisha, Ltd.), chondroitin sulfates A, B, or C or their derivatives (SIGMA Chemical Company) , keratan sulfate and derivatives thereof (SIGMA Chemical Company) , heparin or heparin sulfate and derivatives thereof (SIGMA Chemical Company, Rhone Poulenc Rorer Pharmaceuticals) , dermatan sulfate and derivatives thereof (SIGMA Chemical Company) and certain sialylated sugars such as trifucosyllacto-N-hexaose and sialyl Lewis x (Oxford Glycosystems) .
  • the sources listed are exemplary only and not limitations of the invention.
  • the preferred complex carbohydrates of this invention are mucopolysaccharides (glycosaminoglycans) including hyaluronic acid and salts, sulfates or derivatives thereof, chondroitin sulfate and polysulfated forms, salts or derivatives thereof, sialyl Lewis x and salts or derivatives thereof, heparin and sulfates, salts or derivatives thereof, dermatan, and sulfates, salts or derivatives thereof, keratin and salts, sulfates and derivatives thereof, as well as combinations of the above.
  • mucopolysaccharides glycosaminoglycans
  • mucopolysaccharides including hyaluronic acid and salts, sulfates or derivatives thereof, chondroitin sulfate and polysulfated forms, salts or derivatives thereof, sialyl Lewis x and salts or derivatives thereof, heparin and sulf
  • the most preferred complex carbohydrates are hyaluronic acid including salts, sulfates or derivatives thereof, chondroitin sulfate including polysulfated forms, low molecular weight heparin including salts, sulfates and derivatives thereof and sialyl Lewis x including salts and derivatives thereof and combinations thereof.
  • At least two different molecular weight ranges of complex carbohydrates be included in the composition. At least one should be from a low molecular weight range ⁇ from 1000 to ⁇ 50,000 (e.g. 49,000) ⁇ and the other one or more should be from a higher molecular weight range (from 100,000 to 500,000 or >1, 000, 000).
  • Such complex carbohydrates may or may not be a mixture of two or more different types of complex carbohydrates.
  • one complex carbohydrate providing the high molecular weight moiety could be selected from the group consisting of glycosaminoglycans such as hyaluronic acid and another complex carbohydrate in the same pharmaceutical composition providing the low molecular weight moiety could be a second polysaccharide or a sialylated sugar selected from the group consisting of chondroitin sulfate, keratan sulfate, heparin, heparin sulfate, dermatan sulfate, acemannan, sialyl Lewis x , and hexaoses.
  • heparin When heparin is used, it is advantageous to use low molecular weight heparin as it has been demonstrated to be free of anti-coagulant activity. However, high molecular weight heparin will be broken down to low molecular weight heparin when administered orally or mucosally.
  • a more preferred embodiment of this invention comprises a mixture of at least two glycosaminoglycans.
  • One of the glycosaminoglycans would be of a low molecular weight range ( ⁇ 30,000).
  • the second glycosaminoglycan would be of a high molecular weight (>500,000 Da).
  • the most preferred embodiment of this invention comprises a mixture of two or more molecular weight ranges of hyaluronic acid or salts or derivatives thereof, such as sulfates, acetates, phosphates, methylates and nitrates.
  • Said composition comprises for instance, a hyaluronic acid or salt or derivative thereof with a molecular weight of ⁇ 100,000 Da combined with a hyaluronic acid or salt or derivative thereof which has a molecular weight >1, 000, 000 Da.
  • Routes of administration of the complex carbohydrates of the present invention include parenteral (discussed below) , topical whereby the compounds may or may not be combined with transdermal carriers including but not limited to essential oils; oral whereby the compounds may or may not be mixed with transmucosal carriers including but not limited to essential oils or other transmucosal carriers, coated with protective oral delivery materials such as hydrogels, carbopols, etc., or delivered orally without a coating wherein the complex carbohydrates are the sole active ingredient, mucosally wherein the complex carbohydrates are the sole active ingredients or parenterally.
  • parenteral discussed below
  • topical whereby the compounds may or may not be combined with transdermal carriers including but not limited to essential oils
  • oral whereby the compounds may or may not be mixed with transmucosal carriers including but not limited to essential oils or other transmucosal carriers, coated with protective oral delivery materials such as hydrogels, carbopols, etc., or delivered orally without a coating wherein the complex carbohydrates are the sole active ingredient, mu
  • mucosal delivery includes but is not limited to application of the compounds to the mucous membranes of the nose, eyes, mouth, throat, gums, tonsils, eyes, esophagus, stomach, colon, rectum, vagina, or any other mucous membrane.
  • complex carbohydrates used for parenteral administration to mammals must be pure enough to be injected safely without causing adverse local or systemic effects and of a viscosity allowing ease of injection.
  • the preferred viscosity is that which is safe to administer without stimulating an adverse effect in a mammal.
  • the intravenous route would require a lower viscosity than other parenteral routes of administration. For instance, a viscosity of 500 centipois should not cause problems. A preferred viscosity is less than 200 centipois.
  • pharmaceutical grade complex carbohydrates may be necessary.
  • Parenteral injections may be administered intramuscularly (IM) , intravenously IV) , subcutaneously (SC) , intradermally (ID) , intraparitoneally (IP) and/or injected into tumors.
  • the parenteral formulation of the present invention may be in an aqueous form as a liquid or gel that is safe when injected IM, SC, IV, ID, IP, or by any other route of administration.
  • This formulation must be purer and be of a pharmaceutical grade.
  • a pharmaceutical grade is meant that it should be sterile, contain ⁇ 3% protein (w/w) , ⁇ 5 ⁇ g/mL nucleic acids as measured by UV absorbance at 260nm, ⁇ 0.5 EU/mL endotoxin as measured by LAL, ⁇ 80 ppm (w/w) iron and ⁇ 1.0 ppm heavy metals.
  • the most effective injectable formulation would contain mucopolysaccharides or glycosaminoglycans, more specifically, low molecular weight heparin, hyaluronic acid of all molecular weights, chondroitin sulfate, dermatan sulfate and/or keratin sulfate. If hyaluronic acid is used, the viscosity must be at a level acceptable to be injected by the route chosen without causing adverse reactions. For instance, high viscosity hyaluronic acid >1000 centipoise would not be injected intravenously whereas it could be injected subcutaneously or intramuscularly. Low viscosity hyaluronic acid ⁇ 500 centipoise could be injected intravenously, subcutaneously or intramuscularly.
  • Administration of complex carbohydrates by the parenteral routes of administration has been found to be particularly effective in the treatment of any type of inflammation, pain, nerve damage, nerve sensitivity, autoimmunity and/or itching which is associated with the adhesion cascade, tumors associated with the metastatic cascade and development of heart diseases and stroke associated with the coronary cascade described earlier.
  • This route of administration is preferable for treatment of pain post surgery or dental procedures, treatment for various types of cancer wherein patients cannot ingest food or liquids, treatment of degenerative muscle and joint diseases including the treatment of Multiple Sclerosis, ALS, osteoarthritis, rheumatoid arthritis-, or post partum pain. It is also useful for treatment of spinal cord injuries, treatment of heart attacks and stroke (e.g.
  • heart disease due to high blood pressure and stroke treatment of pain and swelling and/or fractures resulting from athletic injuries, treatment of inflammation and pain associated with bursitis, reduction of inflammation (edema) in extremities resulting from diabetes, reduction of inflammation and pain in association with interstitial cystitis, treatment of decubitus ulcers resulting from poor circulation by diabetic patients or bedridden patients, treatment of inflammation and itching of skin resulting from severe allergic reactions such as poison ivy and insect bites/stings, treatment of sever ADD, ADHD or autism, treatment of anaphylaxis, treatment of polymyositis, treatment of inflammation and pain associated with tendonitis, treatment of inflammatory skin conditions such as severe acne or psoriasis and treatment of burns or sunburn.
  • treatment may include both parenteral injection and oral, mucosal or topical application of one or more complex carbohydrates .
  • complex carbohydrates As indicated earlier, the most recent theories to explain heart attacks and stroke involves the eruption of unstable plaques which have been found to be infiltrated with T-cells and macrophages thus linking these disease syndromes to the adhesion cascade.
  • heart disease high blood pressure, heart attacks and stroke
  • hyaluronic acid, chondroitin sulfate, heparin sulfate, low molecular weight heparin, keratin sulfate or dermatan sulfate, including salts or derivatives thereof can be taken daily as a preventative for heart disease and stroke.
  • amounts from lmg/day to 20 mg/day are used to prevent heart disease and stroke. This could be administered orally or mucosally.
  • Acute disease, including heart attacks could be treated by parenteral injection of the complex carbohydrates of the present invention.
  • a mixture of hyaluronic acid and chondroitin sulfate could be administered daily for prevention of heart disease and stroke.
  • the daily dose would preferably be less than a total of 100 mg. Repeated low doses have been demonstrated to be between 0.0001 mg and 100 mg.
  • transdermal or transmucosal carriers can be added to enhance the penetration of the complex carbohydrates through the skin or mucous membranes.
  • Transdermal and transmucosal carriers include but are not limited to essential oils, polymer blends containing low density polyethylene copolymer or ethylene and 1-butene, 1-hexene, or 1-octene and a linear low density polyethylene copolymer, chemical esters, salicylates, dimethyl sulfoxide (DMSO) and glycocholates . It is preferred that very low concentrations of essential oils be used to orally or mucosally deliver the complex carbohydrates of the present invention, including the macromolecules, through mucous membranes and, consequently, into the blood stream.
  • essential oils include but are not limited to essential oils, polymer blends containing low density polyethylene copolymer or ethylene and 1-butene, 1-hexene, or 1-octene and a linear low density polyethylene copolymer, chemical esters, salicylates, dimethyl s
  • compositions of the present invention utilize slightly higher concentrations of essential oils. These range from 0.05% to 5.0%, preferably from 0.5% to 3.0%.
  • the essential oils of the present invention may be either natural or synthetic and may be obtained from any source.
  • Natural Eucalyptus Oil, Rosemary Oil, Pine Needle Oil, Tea Tree Oil, Sage Oil, Jojoba Oil, Cinnamon Oil, Anise Oil, Lemon Oil, Lime Oil, Orange Oil, Peppermint Oil, Spearmint Oil, Wintergreen Oil, Clove Leaf Oil, Almond Oil, White Pine Oil, Camphor Oil, Cardamon Oil, Cedar Leaf Oil, Sweet Birch Oil and many others can be purchased from Lorrann Oils.
  • Synthetic Wintergreen Oil, Anise Oil, Fir Tree Oil, Rose Oil and Camphor Oil can be obtained from the same source. Menthol and derivatives thereof can be obtained from SIGMA Chemical Company. The purity of these essential oils is of little concern as long as they meet the requirements for a food or cosmetic and do not produce adverse reactions when applied to the skin of mammals.
  • An example of an animal-derived essential oil is EMU oil, extracted from the skin of the EMU.
  • a complex carbohydrate with a natural or synthetic essential oil should be adequate to form an emulsion, suspension, solution, cream or ointment at the time of application.
  • a liquid formulation will not be effective if the oil is separated from the aqueous phase.
  • a suspension or solution that may be resuspended by shaking prior to application is acceptable for use.
  • Any cream or ointment base that does not interfere with the effectiveness of the active ingredients may be included in the formulation. Therefore, one embodiment of this invention is a cream base containing at least one complex carbohydrate and at least one essential oil.
  • Another embodiment is an ointment base containing at least one complex carbohydrate and at least one essential oil.
  • One preferred embodiment is a liquid or gel formulation in an aqueous base that contains at least one complex carbohydrate and at least one essential oil.
  • a significant advantage of this liquid formulation is that the preparation is not greasy or oily, does not leave a greasy or oily film on the skin and does not leave a lingering odor on the skin.
  • the most preferred embodiment is a liquid or gel formulation in an aqueous base that contains at least one complex carbohydrate as the sole active ingredient.
  • the complex carbohydrates of the present invention can also be prepared as a solid and incorporated into bandages. Preferably a 1% solution is used. It can be embedded into the bandage material remaining moist, or dried. It can also be formulated into a solid polymer by addition of cross- linking agents . The latter may be applied to open wounds or to scars to assist with the healing process and/or reduce scar formation.
  • the treatment of irritated or inflamed mammalian tissue by direct topical application requires a dose or total dose regimen effective to reduce or alleviate the results of the trauma. It is preferred to administer at least about 0.000001 mg/Kg of body weight of each ingredient over the site of trauma at least once per day or as often as necessary.
  • the components of this formulation are naturally-occurring substances and are safe when applied topically. There is no inherent upper limit to the tolerable dose. However, as in all medicinal treatments it is prudent to use no more than is necessary to achieve the desired effect. It has been noted that more intense inflammation and pain require more dose applications for relief. A dose of 100 mg/Kg of body weight has been used safely and could serve as an upper limit for use. Similar dose regimens are recommended for wound healing whereas the pharmaceutical composition is applied on the wound until adequate promotion of granulation of the wound has occurred and healing is complete .
  • a convenient topical application formulation is a combination of one or more complex carbohydrates such as polysaccharides, oligosaccharides, or glycosaminoglycans at a total concentration of between 0.1% and 5% wt/vol. These can be used without a transdermal carrier or with a transdermal carrier including one or more essential oils. If essential oils are used, they are preferably combined with the complex carbohydrates at a total concentration of between 0.5% and 20% vol/vol with the remainder of the formulation being made up of a liquid, cream or ointment base.
  • the liquid base may be aqueous.
  • a preferred embodiment of the topical formulation is a combination of one or more glycosaminoglycans at a total concentration of between 0.1% and 5% wt/vol with one or more essential oils at a total concentration of between 0.5% and 5% vol/vol with the remainder of the formulation being a cream, ointment or aqueous base.
  • a more preferred embodiment of the invention is a combination of equal amounts of two or more molecular weight ranges of glycosaminoglycans (one below 30,000 and one above 500,000) at a combined concentration of between 0.5% and 3.0% wt/vol with two or more essential oils having a total concentration of between 0.5% and 5.0% vol/vol with the remainder of the formulation being an aqueous, cream or ointment base.
  • the most preferred embodiment of the topical formulation is a combination of hyaluronic acid (sodium hyaluronate or hyaluronan) with a molecular weight ⁇ 30,000 with hyaluronic acid with a molecular weight between 100,000 and 500,000 or >750,000 at a total hyaluronic acid concentration of between 0.5% and 3.0% wt/vol and an essential oil selected from the group comprising Rosemary Oil, Tea Tree Oil, Wintergreen Oil, Eucalyptus Oil, Menthol and Camphor at a concentration of between 1.0% and 3.0% vol/vol with the remainder of the formulation being DI water.
  • hyaluronic acid sodium hyaluronate or hyaluronan
  • an essential oil selected from the group comprising Rosemary Oil, Tea Tree Oil, Wintergreen Oil, Eucalyptus Oil, Menthol and Camphor at a concentration of between 1.0% and 3.0% vol/vol with the remainder of the formulation being DI water.
  • Preferred complex carbohydrates include heparin, preferably low molecular weight, hyaluronic acid, chondroitin sulfate, dermatan sulfate, keratan sulfate, and acemannan (active ingredient of Aloe Vera) .
  • Preferred essential oils include Tea Tree Oil, Rosemary Oil, Eucalyptus Oil, Wintergreen Oil, Sage Oil, Jojoba Oil, White Pine Oil, Camphor Oil, Cinnamon oil, Oil of Clove, Spearmint Oil, Peppermint Oil, EMU Oil and Menthol.
  • the oral and mucosal formulations of the present invention include any of the complex carbohydrates listed above, alone or in combinations, whereby the formulation is administered as a form selected from the group consisting of a liquid, an emulsion, a suspension, a cream, an ointment, a gel, a foam, a spray, a solid, a powder and a gum.
  • liquid or solid could be added to a drink or drink mix, to food, be a part of a soft drink or any other type of carbonated drink, a supplement drink, used as a mouthwash, or added to a mouthwash, as a toothpaste, as a gargle, as a spray, added to a vaporizer, as a liquid center of a gum or throat lozenge, added to a food, cookie or treat, or used in any other way so as to retain the effectiveness of the complex carbohydrate.
  • a gel form can include a gel applied by mouth, to the gums, to the tongue, under the tongue, to the eyes, to the nose, to the vaginal area or vagina, or to the rectum.
  • a foam could be added to wounds, to the mouth, to the gums, to the vagina or any other mucous membrane.
  • a solid can be incorporated into food, treats such as candy or treats for animals, a chewing gum, a dissolvable gum, a lozenge, capsules, tablets, dissolvable tablets, suppositories, a bandage and any other form that would not damage the effectiveness of the complex carbohydrates or the essential oils, if used in the formulation.
  • Other additives may be added to said oral formulations to improve taste and palatability or enhance the flavor.
  • treats for horses may include sugar, flavorings such as apple or peppermint or a liquid or gel may be applied to a sugar cube, food or other treat.
  • Treats for dogs may include liver, apple, peppermint, yeast or any other palatable flavoring.
  • the same formulations as mentioned for oral use can be used for mucosal delivery of the complex carbohydrates. The only limitation is that the formulation remain in contact with a mucosal surface for a period of at least 2 to 10 seconds .
  • the complex carbohydrates may be added to foods that are then baked, it is preferred to add the complex carbohydrates to the surface of the food after baking is complete. This retains the greatest activity.
  • the complex carbohydrates of the present invention may be added to nutritional supplements to enhance their effectiveness.
  • a mixture of complex carbohydrates and zinc, zinc gluconate, zinc gluconate glycine could be used for more effective treatment of sore throat and colds.
  • a mixture of the complex carbohydrates of this invention and capsicum may produce an even more effective treatment for joint pain and swelling.
  • Addition of vitamins, minerals and other nutritional additives may produce enhancement of the nutritional activity by the complex carbohydrates.
  • the complex carbohydrates of this invention can be used to prevent and/or treat Alzheimer's Disease.
  • hyaluronic acid, salts or derivatives thereof could be administered daily as a preventative for Alzheimer's Disease. Amounts from lmg/day to 20 mg/day should prevent the degradation apparent in Alzheimer's Disease. This could be taken orally. Preferably, it would be taken mucosally. Acute Alzheimer's Disease could be treated by parenteral injection. Alternately, a mixture of hyaluronic acid and chondroitin sulfate could be administered daily for prevention or treatment of Alzheimer's Disease. Again, the daily dose would preferably be less than a total of 100 mg .
  • Paralysis resulting from spinal cord injuries may be prevented or treated effectively using the complex carbohydrates of this invention.
  • the medication since the patient may not be able to take an oral medication, the medication may be administered mucosally using suppositories
  • IM IM
  • SC IM
  • IV IM
  • SC parenterally
  • injecting IM IM
  • SC parenterally
  • the dose may need to be higher, in the range of 20 to 1,000 mg per day.
  • Drugs to assist repair of nerves would preferably be administered concurrently.
  • EXAMPLE 1 An 18 year old female suffered from chronic fibromyalgia localized in the face and neck. This condition had existed for approximately 5 years. There was nothing that provided relief for her condition. Prior to use of the compositions of the present invention, she had taken pain relievers, acupuncture, and numerous other procedures to treat her condition. None had provided substantial relief without severe side effects. She was given a formulation containing a mixture of high and low molecular weight 1% sodium hyaluronate. This formulation was prepared from hyaluronic acid powder obtained from Collaborative Laboratories, Inc. which was made up to a 1% solution in deionized, distilled water. One half 'of the final 1% solution was removed and its molecular weight was broken down by alkaline hydrolysis.
  • the pH was adjusted to between 11 and 14 using ION NaOH. Then the solution was heated while mixing at a temperature between 37° and 50 °C. When a molecular weight of between 10,000 and 50,000 was obtained as measured by viscosity (Brookfield Viscometer) , the pH was adjusted back to neutral (between 6.0 and 7.0). The final mixture was then prepared by combining 1 liter of this low molecular weight preparation with 1 liter of the original 1% solution (high molecular weight of > 1 X 10 6 ) of sodium hyaluronate. The patient was instructed to take this formulation orally, holding the liquid in the mouth for several seconds to allow mucosal adsorption before swallowing it. She took 10 mg two times per day (AM and PM) .
  • ADHD Attention Deficit Hyperactivity Disorder
  • Turret's Syndrome A 9 year old male suffering from severe Attention Deficit Hyperactivity Disorder (ADHD) complicated by Turret's Syndrome, who was being treated by diet control with little success, was given a sample of the mixture used in EXAMPLE 1. This treatment was not complicated by concurrent treatment with drugs such as Ritalin as his parents were adverse to using this medication. Therefore, any response observed was related to the use of the complex carbohydrates of the present invention. He took 10 mg in the morning and 10 mg in the evening, using the solution as a mouthwash (holding it in his mouth for about 10 to 20 seconds and then swallowing) . His parents kept very strict records of his activity and noted that his Turret's Syndrome was fully controlled and he suffered no tics while taking the sodium hyaluronate.
  • ADHD Attention Deficit Hyperactivity Disorder
  • the sodium hyaluronate gel was prepared by adding sodium hyaluronate (Collaborative Laboratories, Inc) to deionized, distilled water to a 1% concentration.
  • Preservatives selected from methyl paraben (0.17%), propylparaben (0.025%) and propylene glycol (10%) were added to maintain sterility of the liquid preparation.
  • the pH of this preparation was between 6 and 8 and the preparation had a molecular weight of >1, 000, 000.
  • the gel was being applied directly on the tongue by dropper bottle. Both went on vacation together and spent most of 5 days in the bright sun in a boat. They did not use a sun blocker. Each previous year both had suffered severe discomfort from sunburn after the first day's exposure. This time, at the end of the 5 days, both noted that they were not sunburned, had suffered no discomfort and were developing a nice tan. It is concluded that the preparation of this invention prevented sunburn, allowing tanning to occur.
  • the formulation of this invention was able to control the pain associated with cervical disc degeneration and osteoarthritis. All such conditions are associated with the adhesion cascade, confirming that diseases and conditions associated therewith are preventable or treatable by the complex carbohydrates of the present invention.
  • EXAMPLE 4 A 60 year old male suffering from colon cancer had been unable to tolerate his colostomy and demanded that his surgeon remove the colostomy and reconnect his colon. He refused chemotherapy. He was given a formulation of 1% sodium hyaluronate (Collaborative Laboratories, Inc) which was prepared with a mixture of molecular weights of hyaluronate (as described in EXAMPLE 1) . When he began taking the hyaluronate preparation, his CEA was 70.1. He has taken the hyaluronate at a dose of 10 mg three times per day mucosally and after 6 months of treatment his CEA has dropped to 4.1. He has taken no other treatments.
  • This treatment of cancer demonstrates the successful use of the complex carbohydrates of the present invention to treat a disease associated with the metatastic cascade. The polymyositis that was successfully treated in this example was thought to represent treatment of a disease associated with the adhesion cascade or autoimmune disease.
  • the subject adult was a 48 year old female who had suffered all her life with attention deficit disorder (ADD) .
  • ADD attention deficit disorder
  • ⁇ 30,000 low molecular weight sodium hyaluronate
  • I'm having longer periods of well being, energy and clear thinking. Each week I have seen a progression of positive responses. This is the first time I have been able to define periods of allergic reaction. I can observe when reactions start and end. I'm not using nasal spray (Flonase) in the morning when I wake up or, especially before I go to bed. Before starting the oral formulation, I had to use this spray before bedtime or I would wake up in the middle of the night, coughing and choking with a lot of phlegm. I am able to start and finish projects. I have even been able to work crossword puzzles - something that I could never even look at prior to treatment. My quality of life is far superior than ever before. I have been offered a real job at an advertising agency.
  • Figure 1 plots the response of this patient while taking the compositions of the present invention. It is based on the patient's own description of her average daily activities and reactions. The scale runs from a -30 (a reaction in which the patient responded in a manner wherein she was unable to function or . focus on any activity) to +30 (energy, clear-thinking, able to focus, feel great). If there were no significant negative or positive responses during a day, the reaction rate was recorded as 0.
  • this patient was provided with a high molecular weight (>1, 000.000) oral hyaluronate formulation.
  • Her family reported an immediate lack of response that continued during the time when she continued to take this formulation. She was unable to work or drive a car during this period of time. After 9 days on the high molecular weight formulation she was switched to a formulation that contained a mixture of molecular weights of hyaluronate (as described in EXAMPLE 1) .
  • This formulation was prepared by mixing 3 parts of low molecular weight ( ⁇ 30,000) with 1 part of high molecular weight (>1, 000, 000) . She demonstrated an immediate positive response that has continued. She has reported that whereas while taking the low molecular weight hyaluronate she felt extremely energetic and capable of doing anything and everything, when she ate or was exposed to something that caused her significant problems, she suffered from extreme "crashes". These "crashes" were observed by the inventor and would be described as a catatonic state in which this patient did not respond. She sat and stared into space or fell asleep. While taking the mixed molecular weight hyaluronate, she was not experiencing "highs” or "crashes”.
  • the patient from EXAMPLE 5 did experience 2 anaphylactic reactions after eating certain foods containing corn syrup or being exposed to mold. During such reactions she would become catatonic and collapse. After the first such reaction, a pharmaceutical grade low molecular weight sodium hyaluronate (approximately 350,000 MW) was administered intramuscularly. She was observed for her response. Within 10 minutes she became conscious and was able to speak haltingly. She was unable to focus well on the conversation. Within 30 minutes she appeared normal and was able to carry on a coherent, intelligent conversation. She had no idea what had happened.
  • EXAMPLE 7 The subject child was a 9 year old male who has suffered with ADHD all his life. He had demonstrated learning disabilities compounded with behavioral problems. He was described as unable to focus, did not read, write or draw. Additionally, his- behavior was such that he could not socialize with other children or with adults. When in contact with other children he was unable to play, often became angered and caused physical harm to others. He had been under treatment by several physicians, psychologists and allergists all his life but none were able to help his condition. The allergists determined that he had allergies to most all foods, dust, molds, soaps and just about everything in his environment. At one time he was prescribed Ritalin daily.
  • This boy attended a special school in which his Teachers reported his daily activity to his parents so that they could try to monitor his eating habits. They provided a daily numerical score. A score of 100 was excellent. This child averaged daily scores of 0 to 10, at best. This child was placed on the low molecular weight oral glycosaminoglycan, sodium hyaluronate. A dose of 20-30 mg BID was applied orally in food or drinks. It was added to rice milk for breakfast and made into icing for cookies for snacks as he was not cooperative enough to take it on his own. His response was monitored by using the numerical score provided by his teachers and averaging it with a numerical score of his behavior at home provided by his parents. The child responded positively within a few days.
  • glycosaminoglycans of the present invention can treat ADHD very effectively. Any route of, administration may produce similar effects. In the most severe cases, the treatment would begin with a parenteral injection followed by oral or mucosal daily doses.
  • EXAMPLE 8 The patient was a 37 year old female who had suffered from interstitial cystitis for eight years. She had seen many doctors and been to Mayo Clinic to seek treatment that could provide her with relief. This condition presents as a constant pain in the bladder that produces "excruciating pain” and a sensation of an intense need to urinate (urgency) . It appears to be caused by inflammation of the lining of the bladder. Cysts or sores develop that are irritated by the urine in the bladder. Since the bladder cannot empty, there is constant irritation and constant pain. A recent theory is that the irritation is produced by allergic reactions to certain foods or drinks and by sexual intercourse. This patient had been to all types of physicians and even to the Mayo Clinic to obtain relief from her pain.
  • EXAMPLE 9 A 49 year old female who was diagnosed with Lupus Erythematosis 24 years ago, presented with an acute outbreak of the disease. Her face was covered with eruptions as was the skin on her forearms. She was also feeling very tired and complained of general joint pain. She was provided with a sodium hyaluronate preparation with a molecular weight of ⁇ 30,000. She was instructed to initially take 10 to 20 mg of the liquid TID. She reported that after taking the first dose, the eruptions on her face began "drying up”. By the third dose the eruptions were significantly reduced and beginning to heal. Within 3 days, the eruptions had essentially disappeared. This patient has been treated with the composition of the present invention for a period of 8 months without a recrudescence of the disease. She also reported that the constant aching and pain in her joints had disappeared and she felt 100% improvement.
  • Lupus Erythematosis is known to be an autoimmune disease. Therefore, the complex carbohydrate compositions of the present are able to successfully treat said autoimmune disease.
  • This dog was injected with 10 mg of sodium hyaluronate having a molecular weight ranging from 30,000 to 400,000 (1.0 mL intramuscularly - equivalent to 10 mg) .
  • the open wound began to heal.
  • This injection was followed up with topical application of a low molecular weight hyaluronic acid prepared by making a 1% (wt/vol) solution of hyaluronic acid (Medex Ltd) containing 1% Wintergreen Oil (Loranne Oil) , 1% Spearmint Oil (Loranne Oil) and 0.5% Peppermint Oil (Loranne Oil).
  • the topical formulation was applied at least two times per day. Over a period of 2 months the lick granuloma healed completely and the swelling reduced to a diameter of 3 inches. The dog has not ' licked this area since treatment began. Therefore, the complex carbohydrates of the present invention are able to successfully treat lick granulomas (a previously untreatable condition of dogs) and eliminate the cause of the lick
  • Dogs often develop areas on their skin that become irritated and that they lick until the area is raw and oozing. Often these areas become infected with normal flora (bacteria) on the skin. Additionally, the hair around the area is usually either licked off or sloughs off. These areas are termed "hot spots". They are extremely difficult to treat and are thought to be caused by allergies to foods or environmental stimuli. Treatment generally includes cortisone by injection or by mouth followed by antibiotics (oral or topical) to treat the complication of bacterial infection. Three dogs with severe hot spots were treated with the complex carbohydrates of the present invention. Dog #1 had a large hot spot on the top of the head (diameter 3 X 2 inches) and smaller ones around the muzzle area. Dog #2 had a large hot spot on its back just in front of the tail.
  • the weight of the two patients were 155 lbs and 128 lbs, respectively. Therefore, the doses administered were 0.07 mg/Kg and 0.09 mg/Kg. This provided relief (within 15 minutes). However, the relief lasted only 1-3 hours.
  • the patients reported that they had to take the chondroitin Sulfate solution three to five times per day to obtain successful treatment. After two months of this regimen, the patients were given a mixture of the 5% chondroitin sulfate and 1% high molecular weight hyaluronic acid. They were instructed to take this as often as necessary. Each reported that this product was effective when taken only 2 times per day and the effect lasted from 8 to 10 hours for the Lupus patient and for the interstitial cystitis patient.
  • Sodium hyaluronate having a molecular weight range of between 10,000 and 2 million was formulated so that it could be used as a scar reduction patch.
  • the formulation was prepared as follows: To 50 mL of 1% sodium hyaluronate (Medex Ltd) was added 7 grams of alphy-hydroxy acid. The solution was mixed until a clear solution was produced. Then 20 mL of USP Glycerol was added and this was mixed to homogeniety. Finally, 1% sodium hyaluronate was added to QS the volume to a total of 100 mL. After the final HA addition, the solution thickened and was spread evenly on the bottom of a petri dish.
  • the solidified HA was cut into a shape slightly larger than the scar. It was applied over the scar and held in place by applying an ace bandage. Approximately 1/2 of the scar was left untreated so as to serve as a control. The Bandage was allowed to remain over the scar for a period of 2 weeks. Intermittently, the HA patch was removed and the scar was cleaned. If the solidified HA patch dried out, it was moistened slightly with water and reapplied. After only two weeks of application the raised scar tissue (adhesion) had essentially disappeared. This demonstrates that scar reduction can be accomplished by use of the complex carbohydrates of the present invention.
  • gauze was soaked in 1% sodium hyaluronate having a molecular weight range from 30,000 to 500,000 and allowed to dry.
  • This HA-containing gauze was applied to open wounds of the following types: 1) a rug burn produced by sliding on artificial turf on a football field; 2) a surgical wound resulting from a hip replacement; and 3) a cut finger resulting from a piece of broken glass.
  • the bandages were kept on the wounds until they were healed well enough to remain uncovered. It was reported that the rug burn was healed within 3 days. This compared with a 2 week healing period normally experienced by this patient. The surgical wound healed within 5 days, again almost 10 days sooner than expected. The cut fingei was healed within 3 days. The conclusion was that a glycosaminoglycan is very effective in stimulating wound healing when incorporated into gauze and used as a bandage.

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Abstract

L'invention concerne un procédé de prévention et de traitement de maladies et d'états pathologiques associés à des allergies, à l'auto-immunité, à la cascade d'adhérences ou aux cascades métastatiques ou coronaires, ce qui consiste à administrer (i) au moins un glucide complexe en tant qu'ingrédient actif unique ou (ii) au moins une composition pharmaceutique contenant en tant qu'ingrédient actif une quantité efficace sur le plan pharmacologique d'au moins un glucide complexe de pureté limitée ou de grade cosmétique sélectionné dans le groupe constitué par des oligosaccharides, des oligosaccharides sialylés, des polysaccharides et des glucosaminoglycanes, ainsi qu'une quantité efficace d'au moins un véhicule transdermique, ou pouvant traverser la muqueuse, et suffisante pour introduire dans la circulation sanguine le glucide complexe.
PCT/US2001/041473 2000-07-31 2001-07-31 Procedes servant a prevenir ou a traiter des maladies et des etats au moyen de glucides complexes WO2002009728A1 (fr)

Priority Applications (7)

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AU2001281368A AU2001281368B2 (en) 2000-07-31 2001-07-31 Methods of preventing or treating diseases and conditions using complex carbohydrates
AU8136801A AU8136801A (en) 2000-07-31 2001-07-31 Methods of preventing or treating diseases and conditions using complex carbohydrates
US10/343,240 US7879824B2 (en) 2001-07-31 2001-07-31 Methods of preventing or treating diseases and conditions using complex carbohydrates
NZ524076A NZ524076A (en) 2000-07-31 2001-07-31 Preventing or treating diseases associated with allergies, autoimmunity and adhesion, metastatic and coronary cascades using complex carbohydrates, in particular hyaluronic acid
EP01959852A EP1311276A4 (fr) 2000-07-31 2001-07-31 Procedes servant a prevenir ou a traiter des maladies et des etats au moyen de glucides complexes
CA2417867A CA2417867C (fr) 2000-07-31 2001-07-31 Procedes servant a prevenir ou a traiter des maladies et des etats au moyen de glucides complexes
US13/006,975 US8367642B2 (en) 2000-07-31 2011-01-14 Methods of preventing or treating diseases and conditions using complex carbohydrates

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WO2002060471A2 (fr) * 2001-01-30 2002-08-08 Ich Productions Limited Ligands des proteines tyrosine phosphatases de type recepteur
EP1393749A1 (fr) * 2002-08-30 2004-03-03 Petrigni, Giuseppe Préparation pharmaceutique en forme colloidale pour le traitement des maladies de la peau, comprenant de l' acide hyluronique
US6709682B2 (en) 1996-03-08 2004-03-23 In Clover, Inc. Product and method for treating joint disorders in vertebrates
EP1407776A1 (fr) * 2002-10-10 2004-04-14 Giuseppe Petrigni Une composition pharmaceutique colloide comprenant des biopolymères d'acide hyaluronique pour le traitement des maladies respiratoires
WO2004073584A3 (fr) * 2003-02-19 2005-01-27 Stellar Internat Inc Traitement de la cystite au moyen d'une forte dose de sulfate de chondroitine
EP1611893A1 (fr) * 2003-03-25 2006-01-04 Seikagaku Corporation Remede contre une lesion nerveuse
WO2007131546A1 (fr) * 2006-05-11 2007-11-22 Sandra Gobbo Mélanges binaires d'acide hyaluronique et utilisation thérapeutique de ceux-ci
WO2008071245A1 (fr) * 2006-12-12 2008-06-19 Farco-Pharma Gmbh Préparation pharmaceutique pour le traitement de pathologies inflammatoires du système urogénital
EP1999159A2 (fr) * 2006-03-25 2008-12-10 Romano Development Inc. Procede d'isolement et de stabilisation d'aminoglycanes de faible masse moleculaire provenant de coquilles d' oeufs sous forme de dechets
WO2009138843A1 (fr) * 2008-05-13 2009-11-19 Hertek S.A. Utilisation orale de glycosaminoglycanes et compositions correspondantes
EP2292243A1 (fr) * 2009-08-14 2011-03-09 Holy Stone Healthcare Co.,Ltd. Mélange d'acide hyaluronique pour traiter et empêcher les maladies intestinales inflammatoires
WO2012175813A1 (fr) 2011-06-21 2012-12-27 Turun Yliopisto Oligosaccharides multivalents de type mannoses [bêta)-1-2-liés comme composés immunostimulateurs et leurs utilisations
AU2010202941B2 (en) * 2009-08-14 2013-05-09 Holy Stone Healthcare Co., Ltd. Mixture of hyaluronic acid for treating and preventing peptic ulcer and duodenal ulcer
US8519008B2 (en) 2003-01-22 2013-08-27 Purina Animal Nutrition Llc Method and composition for improving the health of young monogastric mammals
US20150366978A1 (en) * 2013-01-25 2015-12-24 Gnosis S.P.A. Compositions Containing Chondroitin Sulphate, Proteolytic Enzymes and Sulphydryl Compounds for Improving the Bioavailability of Chondroitin Sulphate
US9241953B2 (en) 2008-05-13 2016-01-26 Apharm S.R.L. Glycosaminoglycan oral use and compositions
CN107303271A (zh) * 2016-04-25 2017-10-31 惠觅宙 一种含有小分子透明质酸的注射液及其用途
WO2017186088A1 (fr) * 2016-04-25 2017-11-02 惠觅宙 Utilisation d'un fragment d'acide hyaluronique à petites molécules
EP2563376B1 (fr) * 2010-04-30 2017-11-22 Ayawane Composition dermatologique à base d'huile d'argan et d'acide hyaluronique
EP2034956B1 (fr) 2006-05-26 2018-03-21 Altergon S.A. Compositions comprenant des glycosaminoglycanes de faible viscosité et utilisation de ladite composition dans le traitement de la cystite chronique
CN108721320A (zh) * 2017-04-24 2018-11-02 惠觅宙 小分子透明质酸片段的应用

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CA3161344A1 (fr) * 2019-12-13 2021-06-17 Felix Polyak Complexes comprenant un polymere de glucide et un principe actif et leurs procedes de preparation

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Cited By (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6709682B2 (en) 1996-03-08 2004-03-23 In Clover, Inc. Product and method for treating joint disorders in vertebrates
WO2002060471A2 (fr) * 2001-01-30 2002-08-08 Ich Productions Limited Ligands des proteines tyrosine phosphatases de type recepteur
WO2002060471A3 (fr) * 2001-01-30 2007-11-01 Ich Productions Ltd Ligands des proteines tyrosine phosphatases de type recepteur
EP1393749A1 (fr) * 2002-08-30 2004-03-03 Petrigni, Giuseppe Préparation pharmaceutique en forme colloidale pour le traitement des maladies de la peau, comprenant de l' acide hyluronique
EP1407776A1 (fr) * 2002-10-10 2004-04-14 Giuseppe Petrigni Une composition pharmaceutique colloide comprenant des biopolymères d'acide hyaluronique pour le traitement des maladies respiratoires
US10172376B2 (en) 2003-01-22 2019-01-08 Purina Animal Nutrition Llc Methods for feeding sows and for improving the health of young piglets
US11452303B2 (en) 2003-01-22 2022-09-27 Purina Animal Nutrition Llc Methods for feeding sows and for improving the health of young piglets
US8519008B2 (en) 2003-01-22 2013-08-27 Purina Animal Nutrition Llc Method and composition for improving the health of young monogastric mammals
US9433232B2 (en) 2003-01-22 2016-09-06 Purina Animal Nutrition Llc Methods for feeding sows and for improving the health of young piglets
US9078457B2 (en) 2003-01-22 2015-07-14 Purina Animal Nutrition Llc Method and composition for improving the health of young monogastric mammals
US10980250B2 (en) 2003-01-22 2021-04-20 Purina Animal Nutrition Llc Methods for feeding sows and for improving the health of young piglets
US7772210B2 (en) 2003-02-19 2010-08-10 Stellar Pharmaceuticals Inc. Cystitis treatment with high dose chondroitin sulfate
AU2004212650B2 (en) * 2003-02-19 2009-07-23 Stellar Pharmaceuticals Inc. Cystitis treatment with high dose chondroitin sulfate
EP2857024A1 (fr) * 2003-02-19 2015-04-08 Tribute Pharmaceuticals Canada Inc. Traitement de la cystite avec une forte dose de sulfate de chondroitine
US8778908B2 (en) 2003-02-19 2014-07-15 Stellar International Inc. Cystitis treatment with high dose chondroitin sulfate
US8084441B2 (en) 2003-02-19 2011-12-27 Stellar Pharmaceuticals, Inc. Cystitis treatment with high dose chondroitin sulfate
US8334276B2 (en) 2003-02-19 2012-12-18 Stellar Pharmaceuticals Inc. Cystitis treatment with high dose chondroitin sulfate
WO2004073584A3 (fr) * 2003-02-19 2005-01-27 Stellar Internat Inc Traitement de la cystite au moyen d'une forte dose de sulfate de chondroitine
US7511026B2 (en) 2003-03-25 2009-03-31 Seikagaku Corporation Therapeutic agent for nerve damage
AU2004224510B2 (en) * 2003-03-25 2009-12-03 Seikagaku Corporation Remedy for nerve damage
EP1611893A4 (fr) * 2003-03-25 2007-05-16 Seikagaku Kogyo Co Ltd Remede contre une lesion nerveuse
EP1611893A1 (fr) * 2003-03-25 2006-01-04 Seikagaku Corporation Remede contre une lesion nerveuse
EP1999159A4 (fr) * 2006-03-25 2010-09-29 Romano Dev Inc Procede d'isolement et de stabilisation d'aminoglycanes de faible masse moleculaire provenant de coquilles d' oeufs sous forme de dechets
EP1999159A2 (fr) * 2006-03-25 2008-12-10 Romano Development Inc. Procede d'isolement et de stabilisation d'aminoglycanes de faible masse moleculaire provenant de coquilles d' oeufs sous forme de dechets
EA014469B1 (ru) * 2006-05-11 2010-12-30 Сандра Гоббо Бинарные смеси гиалуроновой кислоты и их терапевтическое применение
WO2007131546A1 (fr) * 2006-05-11 2007-11-22 Sandra Gobbo Mélanges binaires d'acide hyaluronique et utilisation thérapeutique de ceux-ci
EP2034956B2 (fr) † 2006-05-26 2023-06-28 Altergon S.A. Compositions comprenant des glycosaminoglycanes de faible viscosité et utilisation de ladite composition dans le traitement de la cystite chronique
EP2034956B1 (fr) 2006-05-26 2018-03-21 Altergon S.A. Compositions comprenant des glycosaminoglycanes de faible viscosité et utilisation de ladite composition dans le traitement de la cystite chronique
WO2008071245A1 (fr) * 2006-12-12 2008-06-19 Farco-Pharma Gmbh Préparation pharmaceutique pour le traitement de pathologies inflammatoires du système urogénital
EP2581090A1 (fr) * 2008-05-13 2013-04-17 Apharm S.r.l. Compositions et usage oral de glycosaminoglycane
EA018333B1 (ru) * 2008-05-13 2013-07-30 Афарм С.Р.Л. Применение гликозаминогликанов для перорального введения и композиции гликозаминогликанов
US8735373B2 (en) 2008-05-13 2014-05-27 Apharm S.R.L. Glycosaminoglycan oral use and compositions
US9241953B2 (en) 2008-05-13 2016-01-26 Apharm S.R.L. Glycosaminoglycan oral use and compositions
WO2009138843A1 (fr) * 2008-05-13 2009-11-19 Hertek S.A. Utilisation orale de glycosaminoglycanes et compositions correspondantes
AU2010202941B2 (en) * 2009-08-14 2013-05-09 Holy Stone Healthcare Co., Ltd. Mixture of hyaluronic acid for treating and preventing peptic ulcer and duodenal ulcer
EP3842046A1 (fr) * 2009-08-14 2021-06-30 Holy Stone Healthcare Co.,Ltd. Mélange d'acide hyaluronique permettant de traiter et d'empêcher les maladies intestinales inflammatoires
EP2292243A1 (fr) * 2009-08-14 2011-03-09 Holy Stone Healthcare Co.,Ltd. Mélange d'acide hyaluronique pour traiter et empêcher les maladies intestinales inflammatoires
AU2010212350B2 (en) * 2009-08-14 2013-02-07 Holy Stone Healthcare Co., Ltd. Mixture of hyaluronic acid for treating and preventing inflammatory bowel disease
EP2289522B1 (fr) * 2009-08-14 2019-09-25 Holy Stone Healthcare Co.,Ltd. Utilisation d'acide hyaluronique pour le traitement d'ulcères gastro-duodénaux
KR101476802B1 (ko) * 2009-08-14 2014-12-26 홀리스톤 헬스케어 코포레이션 리미티드 염증성 장질환 치료 및 예방용 약학 조성물
EP2563376B1 (fr) * 2010-04-30 2017-11-22 Ayawane Composition dermatologique à base d'huile d'argan et d'acide hyaluronique
US9221861B2 (en) 2011-06-21 2015-12-29 Abo Akademi University Multivalent [beta]-1-2-linked mannose oligosaccharides as immunostimulatory compounds and uses thereof
WO2012175813A1 (fr) 2011-06-21 2012-12-27 Turun Yliopisto Oligosaccharides multivalents de type mannoses [bêta)-1-2-liés comme composés immunostimulateurs et leurs utilisations
US20150366978A1 (en) * 2013-01-25 2015-12-24 Gnosis S.P.A. Compositions Containing Chondroitin Sulphate, Proteolytic Enzymes and Sulphydryl Compounds for Improving the Bioavailability of Chondroitin Sulphate
WO2017186088A1 (fr) * 2016-04-25 2017-11-02 惠觅宙 Utilisation d'un fragment d'acide hyaluronique à petites molécules
AU2017255833B2 (en) * 2016-04-25 2022-09-01 Mizhou Hui Application of small-molecule hyaluronic acid fragment
CN107303271A (zh) * 2016-04-25 2017-10-31 惠觅宙 一种含有小分子透明质酸的注射液及其用途
CN108721320A (zh) * 2017-04-24 2018-11-02 惠觅宙 小分子透明质酸片段的应用

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CA2417867A1 (fr) 2002-02-27
EP1311276A1 (fr) 2003-05-21
NZ533078A (en) 2006-11-30
CA2417867C (fr) 2012-09-11
EP1311276A4 (fr) 2007-09-12
AU2001281368B2 (en) 2005-07-28
AU8136801A (en) 2002-02-13
NZ524076A (en) 2004-07-30

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