+

US20140356297A1 - Oral compositions for absorption of phosphorous compounds - Google Patents

Oral compositions for absorption of phosphorous compounds Download PDF

Info

Publication number
US20140356297A1
US20140356297A1 US14/462,038 US201414462038A US2014356297A1 US 20140356297 A1 US20140356297 A1 US 20140356297A1 US 201414462038 A US201414462038 A US 201414462038A US 2014356297 A1 US2014356297 A1 US 2014356297A1
Authority
US
United States
Prior art keywords
phosphorus
chewing gum
present
chitosan
composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US14/462,038
Inventor
Vincenzo Savica
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
CM&D Pharma Ltd
Original Assignee
CM&D Pharma Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=36035790&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20140356297(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by CM&D Pharma Ltd filed Critical CM&D Pharma Ltd
Priority to US14/462,038 priority Critical patent/US20140356297A1/en
Publication of US20140356297A1 publication Critical patent/US20140356297A1/en
Abandoned legal-status Critical Current

Links

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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/722—Chitin, chitosan
    • 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
    • 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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/08—Oxides; Hydroxides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/10—Carbonates; Bicarbonates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/244—Lanthanides; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A61K9/0058—Chewing gums
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to the medical, in particular the pharmaceutical field, and deals with the problem of reducing phosphorus serum level, especially in those subjects affected from hyperphosphatemia. More specifically, the present invention relates to pharmaceutical compositions to be administered by oral route capable of absorbing phosphorus compounds from fluids of the enteric tract.
  • Hyperphosphatemia is a pathologic condition due to different diseases, for example inadequate renal function, renal disease, kidney failure, in particular patients undergoing dialysis; hypoparatiroidism; osteoporosis, atherosclerosis.
  • diseases for example inadequate renal function, renal disease, kidney failure, in particular patients undergoing dialysis; hypoparatiroidism; osteoporosis, atherosclerosis.
  • Cardiovascular alterations due to calcification of vessels, myocardium and heart valves represent the major mortality and morbidity cause in uremic patients (Burke, S. K., Seminars in Nephrology, vol. 24, no 5, 403-407, 2004; Levin, N V, et al.; Seminars in Nephrology, vol. 42, no 55, 396-400, 2004).
  • Phosphorus intake occurs with food and it is very difficult to avoid it. For example, patients undergoing dialysis must eat meat, a food rich in phosphorus. On the other hand, low-protein food has a low amount of phosphorus, but its use can determine malnutrition.
  • controlling phosphorus serum levels is a necessary action for reducing cardiovascular morbidity and mortality in this kind of patients, but also can be a general health prevention in population, particularly exposed to risk of cardiovascular disease.
  • the current treatments are focused on absorbing phosphorus from food, the main source of it, by administering suitable drugs in concomitance with meals.
  • the leading therapy is represented by non-absorbed, calcium and metal-free phosphorus binders.
  • a successfully marketed drug is Sevelamer (Renagel®), based on a polyallylamine, see U.S. Pat. No. 5,496,545, U.S. Pat. No. 5,667,775, U.S. Pat. No. 6,756,363 and U.S. Pat. No. 6,562,329.
  • the inventor discovered that, in the fasting interval, considerable amounts of phosphorus are secreted in saliva, which is continuously ingested and gastric secretions, so partly nullifying the therapeutic or preventive action of the drugs taken at the meals.
  • phosphorus is recirculated in the body and contributes to maintain high serum levels, thus making difficult to achieve an effective management of the risk of cardiovascular diseases, especially in those patients particularly exposed to said risk, such as patients affected by kidney failure and/or undergoing periodical dialysis.
  • the present invention is based on the discovery that saliva and other gastric secretions contain considerable amounts of phosphorus.
  • saliva appears to be the main source of phosphorus, which is then recirculated in the body.
  • compositions of substances capable of binding phosphorus when administered during fasting periods achieve an improved treatment of hyperphosphatemia.
  • the oral compositions are characterized by a continuous slow release of the substances capable of binding phosphorus compounds.
  • the present invention comprises also an improved method for treating phosphate serum levels.
  • the present invention provides a method for treating high phosphate serum levels by administering to a subject in need of such a treatment a continuous slow-release oral composition containing a substance capable of binding phosphorus compounds during fasting periods.
  • phosphate serum levels are achieved, with immediate benefits to the patients and reduced risk of cardiovascular complications.
  • oral composition is intended as any composition which can be administered by oral route to a subject.
  • continuous slow release oral composition is intended a composition which releases in a continuous manner the active ingredient in the gastrointestinal tract, oral environment included.
  • This feature does not only covers specially designed oral compositions for the continuous slow release of an active ingredient in the gastrointestinal tract, such as for example the so-called “cronoids”, or sustained or delayed release type, but also any composition which, when retained in the mouth for a sufficient period of time, continuously releases in a slow manner the active ingredient.
  • oral composition examples include pills, lozenges, tablets, capsules, powdery compositions, solutions, suspensions, emulsions, preferably in the form of gel.
  • oral compositions such as for example, confectionery, such as candies, gummy candies, chewing gum.
  • phosphorus binding are any kind of chemical bond, such as ionic bond, covalent bond, Van der Waals interactions, chelating phenomenon.
  • phosphate binding polymers examples include those disclosed and mentioned in U.S. Pat. No. 5,496,545 and related patents.
  • the currently marketed for of these phosphate binding polymers is a polyallylamine hydrochloride (Sevelamer—Renagel®), polyallylamine carbonate, and other pharmaceutically acceptable salts thereof, a pharmaceutically acceptable salt of lanthanum, for example carbonate, alluminium hydroxide, a pharmaceutically acceptable salt of magnesium, such as acetate, carbonate, a pharmaceutically acceptable salt of calcium, such as carbonate, acetate, citrate, alginate, and a pharmaceutically acceptable salt of a ketoacid, such as mentioned in the above U.S. Pat. No.
  • polyallylamine hydrochloride is a preferred embodiment of the present invention for the class of phosphate binding polymer.
  • the most preferred embodiment of the present invention is chitosan for the class of phosphate binding polysaccharide.
  • chitosan is also used for the preparation of a medicament for the general treatment of hyperphosphatemia, including the administration of said medicament at meals, in order to absorb phosphorus compounds from food.
  • phosphorus compound any substance containing phosphorus, for example phosphate, which, when absorbed in the body affects phosphatemia by increasing it.
  • the present invention is embodied in an oral composition characterized by the slow release of a substance capable of binding phosphorus and characterized in that said substance is substantially not absorbed in the gastrointestinal tract.
  • examples of this kind of substances are aluminium hydroxide and/or magnesium hydroxide, calcium acetate, calcium carbonate.
  • substantially not absorbed in the gastrointestinal tract is intended that absorption is null or undetectable or does not increase serum phosphate level or does not involve side effects in the subject orally administered with said substance.
  • a first preferred embodiment of the present invention is an oral composition which can be retained for a long time in the mouth of the subject.
  • examples of such composition are a chewable tablet, a sachet, a mouthwash, a chewing gum, a gummy candy, a sucking tablet or candies. These compositions must be endowed with continuous slow release characteristics. Chewing gum is a more preferred embodiment, since it can be retained in the mouth for extended period, even hours.
  • This first embodiment of the present invention is advantageous since phosphate sequestration occurs in the mouth, in particular from saliva, the major source of recirculating phosphorus and once the composition has accomplished its scope, namely it has exhausted its absorbing capacity, can be directly taken out from the mouth and a new unit dose can be taken. This avoids swallowing the composition and engaging the gastrointestinal tract with the presence of a composition loaded with phosphorus, so that the subject has not to worry about a possible release of phosphorus in the gastrointestinal tract or the effective elimination of the composition.
  • a second preferred embodiment of the present invention is an oral composition which can be partly retained for a certain time in the mouth of the subject and subsequently swallowed.
  • examples of such composition is a chewable tablet, gummy candies, or candies. These compositions must be endowed with slow release characteristics.
  • This second embodiment of the present invention is advantageous since phosphorus sequestration, preferably in the form of phosphate, occurs in the mouth, in particular from saliva, the major source of recirculating phosphorus and once the composition has mostly accomplished its scope, namely it has exploited considerable part of its absorbing capacity, can be swallowed in order to continue its absorbing action through the gastrointestinal tract. This allows performing the intended treatment throughout the gastrointestinal tract with a single unit dose or a single administration of the composition.
  • This second embodiment can also be carried out by ingesting a composition according to the present invention and, after ingestion, taking a composition according to the first embodiment, retaining it in the mouth for a long time, until exhaustion of absorption capacity.
  • the two unit doses, the first one to be immediately swallowed and the second one to be retained in the mouth until exhaustion of said binding agent for a therapeutic unit can be conveniently packaged in a single therapeutic unit dose.
  • the person skilled in the art can modify the therapeutic unit by varying the number and form of the unit doses, then providing a therapeutic unit with at least one first unit dose and at least one second unit dose.
  • composition to be ingested is a powdery composition, for example a sachet containing the composition in the form of a powder.
  • Other forms of swallowable composition are well known in the art, for examples, capsules, pills, syrups, extemporary or ready-to-use solutions, suspensions, emulsions.
  • the powdery composition may be soluble, partially soluble, insoluble or resulting in a suspension or emulsion in a suitable drinkable liquid.
  • An interesting combination of the first and second embodiment is a composition that can be retained in the mouth for a certain period in the form of mouthwash and subsequently swallowed.
  • the treatment according to the present invention is carried out during fasting period.
  • the method according to the present invention can advantageously combined with the one of the state of the art, namely the administration at mealtimes of substances capable of absorbing phosphorus. In this way, a better control of phosphate serum level can be achieved.
  • the composition in particular those retained in the mouth, will be provided with detecting means signaling the complete absorption of phosphorus, namely the exhaustion of absorption capacity of the unit dose of the composition. In this way, the patient will be able to determine if and whether to discard the exhausted composition and to take another one according to medical advice.
  • a preferred embodiment of detecting means is a substance changing colour or becoming coloured in the presence of phosphorus.
  • the person skilled in the art will find in the general common knowledge information about the above detecting means in order to carry out the present invention.
  • the composition according to the present invention can be supplied with separate detecting means, in order to check phosphorus level, for example in the form of phosphate, in saliva and to determine the duration of the treatment, namely how long to retain the composition in the mouth.
  • detecting means can be found in Tobey S L, Anslyn E V; Org. Lett., 2003 Jun. 12; 5(12):2029-31.
  • a preferred pharmaceutical composition is represented by slow-release tablets containing 250, 500 or 1,000 mg of Sevelamer. These tablets will bind about 46.75 mg, 93.50 mg and 187 mg of phosphorus, respectively, deriving from salivary and gastrointestinal secretion at pH about 7.
  • the tablets are designed to be effective during diurnal and nocturnal fasting, but can be used also in different period of the day, according to medical prescription.
  • the dosage of the phosphorus-binding agent in the composition of the invention will be determined by the person skilled in the art according to standard dose finding tests. However, the dosage of the binding agent will preferably be in an amount sufficient to remove excess phosphorus with respect to physiological level. It would not be advisable to remove phosphorus in an amount such as to bring it at a level lower than physiological one, in order to avoid damage to teeth.
  • the tablet will contain at least one pharmaceutically acceptable vehicle and/or excipient.
  • vehicles and excipient are lactose anhydrous or monohydrate, povidone, microcrystalline cellulose, hydroxypropylcellulose, sodium croscaramellose, magnesium stearate, E, 171, E 172, mannitol, sodium laurylsulphate, ipromellose, methacrylic acid copolymer, macrogol, magnesium stearate, gelatine, saccharose, starch, sorbitol, mannitol, flavours, sodium saccharine, colloidal silica.
  • Tablets can be either chewed or swallowed, depending on where the desired effect of phosphorus absorption shall occur.
  • capsules containing the same or different amount of Sevelamer are designed to be effective in the same manner as the above-mentioned tablets, but mainly in the gastrointestinal tract, since they are taken and swallowed.
  • the capsule will contain at least one pharmaceutically acceptable vehicle and/or excipient and can be of the soft or rigid type.
  • vehicle and/or excipient are gelatine, titanium dioxide, sodium laurylsulphate.
  • candies and gummy candies. These candies are designed to be effective mostly in the mouth, where the saliva is secreted.
  • Candies are within the general knowledge of the person skilled in the art and the field of confectionery industry can be considered a near technical field in this case.
  • the candies will contain the active ingredient and vehicles and/or excipients of use in confectionery (see for example Food Industries Manual (24th Edition) Edited by: Ranken, M. D.; Kill, R. C.; Baker, C. G. J. ⁇ 1997 Springer-Verlag).
  • excipients are maltitol syrup, gum arabic, glycerol, aspartame, hydrogenated vegetal oil, gelatine, sorbitol, citric acid, pectin, caramel.
  • Sachets containing a soluble powder are another embodiment of the present invention and their preparation is within the normal task of a person of ordinary skill in the art.
  • vehicles and excipient examples include mannitol, sucrose, colloidal silica, methylcellulose, hydroxypropylcellulose.
  • Excipient suitable to prepare a thick solution, suspension, emulsion, or preferably a gel are also well known in the art, see for example Thickening and Gelling agents for Food, second edition by Alan Imeson).
  • a resulting gel formulation is more preferred in the embodiment of a mouthwash, which will be advantageous for patients with difficulty in chewing.
  • gelling agents examples include 70% sorbitol.
  • Suitable non-disintegrating agent will be used, such as for example waxes, paraffin, fats.
  • Continuous slow-release compositions are intended for the purposes of the present invention any one of sustained release compositions, prolonged action compositions, repeat action compositions, otherwise generally named “cronoids” (E. Ragazzi Lezioni di Tecnica Farmaceutica, Edizioni Libreria Cortina Padova, 1982).
  • differential release compositions can be prepared by means of granulates with differential coatings.
  • the active ingredient (the binding agent according to the present invention) is mixed with a suitable excipient (for example lactose, starch) and transformed into a homogeneous granulate, which is subsequently coated with a suitable material (such as lac, shellac, zein, polyacrylic resins, waxes, fats, such as cacao butter, beeswax, stearic acid, etc.).
  • a suitable material such as lac, shellac, zein, polyacrylic resins, waxes, fats, such as cacao butter, beeswax, stearic acid, etc.
  • the granules can then made up in a suitable pharmaceutical unit dose, such as capsules, tablet, multi-layered tablets.
  • the active agent is adhered on an inert granulating support (sugar, starch, etc.) and transformed in a pill or a sugar-coated pill.
  • an inert granulating support sucgar, starch, etc.
  • Multi-layered tablets in which a first layer will provide a “burst” of drug and a second or further layers will provide a continuous, slow release of drug, can be a convenient embodiment.
  • Differential disintegration granules are also a suitable embodiment of the present invention, wherein the drug is incorporated in a lipophilic excipient (cacao butter, hydrogenated oils, glyceryl stearate, beeswax, carnauba wax, saturated fatty acids, etc.) and subsequently transformed into granules, which can optionally coated with different materials according to the desired release time and site.
  • a lipophilic excipient cacao butter, hydrogenated oils, glyceryl stearate, beeswax, carnauba wax, saturated fatty acids, etc.
  • Electrode layers are also a useful alternative.
  • the active agent can also be incorporated in a suitable polymeric matrix which will gradually and continuously release it.
  • ion exchange resins can be suitably selected depending on the pH of the desired site of release (mouth, stomach, gut).
  • One possible formulation of a slow-release composition according to the present invention in the form of chewing gum comprises sorbitol, mannitol, 5% xylitol, maltitol syrup, aspartame, acesulfame k, gum base, glycerol, E320, polyalcohols, E903.
  • a slow-release composition comprises sorbitol, mannitol, 36% xylitol, maltitol syrup, sodium hydrogen carbonate, aspartame, acesulfame k, gum base, glycerol, E320, polyalcohols, E903.
  • a method for the treatment of high phosphorus serum levels, or a method for controlling phosphorus serum levels in a subject in need thereof comprises the administration of a composition according to the present invention, said composition can be directly swallowed or chewed and swallowed, followed by taking a composition according to the present invention in the form of a chewing gum and retaining it in the mouth until complete exhaustion of binding capacity of the active ingredient.
  • the chewing gum can incorporate phosphorus detecting means signalling the exhaustion of binding capacity or the chewing gum unit dose can be supplied with separate detecting means in order to periodically check phosphorus content in saliva.
  • the size of the particle comprising aluminium will be higher than 3 ⁇ m, in order to avoid intestinal absorption.
  • One exemplary tablet will comprise:
  • Sucrose powder starch, sorbitol, mannitol, flavouring agents, sodium saccharinate, magnesium stearate.
  • antiemetic or eukinetic agents can be added to or used in combination with the composition of the present invention.
  • Uremic patients have been under dialytic treatment for at least one year, mean period 8.9 ⁇ 7.3 years. All patients were in good clinical conditions.
  • Calcium and phosphorus were dosed by spectrophotometry using flex reagent cartridge by Dade Behring Inc., Newark, U.S.A. after centrifugation of the samples, while serum PTH was dosed by using Immulite 2000 intact PTH, solid phase, two site chemiluminescent enzyme labelled immunometric assay (Diagnostic Product Corporation, Los Angeles, U.S.A.).
  • cut off the upper limit of confidence intervals for mean of salivary P in controls (14.73 ml/dl)
  • 62 out of 68 subjects had a value greater than cut off.
  • test and reference (PBS) solutions were sampled for NMR analysis and added with 0.1 D 2 O.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Obesity (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Zoology (AREA)
  • Vascular Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The present invention provides medicaments useful for reducing phosphorus serum level, especially in those subjects affected from hyperphosphatemia. More specifically, the present invention relates to pharmaceutical compositions to be administered by oral route in fasting periods, in order to absorb phosphorus compounds from fluids of the enteric tract, especially from saliva.

Description

  • The present invention relates to the medical, in particular the pharmaceutical field, and deals with the problem of reducing phosphorus serum level, especially in those subjects affected from hyperphosphatemia. More specifically, the present invention relates to pharmaceutical compositions to be administered by oral route capable of absorbing phosphorus compounds from fluids of the enteric tract.
    • BACKGROUND OF THE INVENTION
  • Hyperphosphatemia is a pathologic condition due to different diseases, for example inadequate renal function, renal disease, kidney failure, in particular patients undergoing dialysis; hypoparatiroidism; osteoporosis, atherosclerosis. For a review of this problem, see U.S. Pat. No. 5,496,545 and references cited therein.
  • Cardiovascular alterations due to calcification of vessels, myocardium and heart valves represent the major mortality and morbidity cause in uremic patients (Burke, S. K., Seminars in Nephrology, vol. 24, no 5, 403-407, 2004; Levin, N V, et al.; Seminars in Nephrology, vol. 42, no 55, 396-400, 2004).
  • Most of patients undergoing dialysis or affected by chronic renal failure in conservative treatment show increased phosphorus serum levels, which are responsible of calcifications in tissues other than bone tissue and which are responsible of increased risk of cardiovascular mortality (Moe, S M, Seminars in Nephrology, vol. 24, no 5, 413-416, 2004; Eknoyan, G., et al.; Am. Kidney Dis., 42, 4, 1-204, October 2003).
  • Phosphorus intake occurs with food and it is very difficult to avoid it. For example, patients undergoing dialysis must eat meat, a food rich in phosphorus. On the other hand, low-protein food has a low amount of phosphorus, but its use can determine malnutrition.
  • It was demonstrated by scientific evidence that prevention and/or early treatment of hyperphosphoremia in uremic patients can reduce morbidity and mortality risk. Moreover, increased phosphorus serum level can stimulate higher calcium deposition in cells and bone tissue protein and enzyme synthesis and increased risk of vessel calcification (Burke, ibid.).
  • Accordingly, controlling phosphorus serum levels is a necessary action for reducing cardiovascular morbidity and mortality in this kind of patients, but also can be a general health prevention in population, particularly exposed to risk of cardiovascular disease.
  • To date, high phosphorus serum levels are treated with vitamin D or substances, which, when administered by oral route, bind phosphorus through chelating action (phosphorus binders) and eliminate it by fecal route. Although effective in their action of eliminating phosphorus, some of these substances must be avoided because of their side effects, which, in some cases can be quite severe. For example, substances containing calcium, magnesium or aluminium are avoided by those expert in the field. Lanthanum is an effective absorbing substance but its toxicity is a hamper to its use in this field.
  • The current treatments are focused on absorbing phosphorus from food, the main source of it, by administering suitable drugs in concomitance with meals.
  • The leading therapy is represented by non-absorbed, calcium and metal-free phosphorus binders. A successfully marketed drug is Sevelamer (Renagel®), based on a polyallylamine, see U.S. Pat. No. 5,496,545, U.S. Pat. No. 5,667,775, U.S. Pat. No. 6,756,363 and U.S. Pat. No. 6,562,329.
  • Current therapy is used only to limit dietary phosphorus intake by binding phosphorus content in food, but is ineffective of phosphorus serum levels and cellular content.
  • The problem of an improved treatment of high phosphorus levels is still strongly felt by those skilled in the art, especially in view of the importance of such a treatment with respect to patients affected by renal diseases, in particular uremic patients undergoing dialysis.
  • The inventor discovered that, in the fasting interval, considerable amounts of phosphorus are secreted in saliva, which is continuously ingested and gastric secretions, so partly nullifying the therapeutic or preventive action of the drugs taken at the meals.
  • By this phenomenon, phosphorus is recirculated in the body and contributes to maintain high serum levels, thus making difficult to achieve an effective management of the risk of cardiovascular diseases, especially in those patients particularly exposed to said risk, such as patients affected by kidney failure and/or undergoing periodical dialysis.
    • SUMMARY OF THE INVENTION
  • The present invention is based on the discovery that saliva and other gastric secretions contain considerable amounts of phosphorus. In particular, saliva appears to be the main source of phosphorus, which is then recirculated in the body.
  • It has now been found that oral compositions of substances capable of binding phosphorus when administered during fasting periods achieve an improved treatment of hyperphosphatemia.
  • Due to the characteristics of the improved treatment, the oral compositions are characterized by a continuous slow release of the substances capable of binding phosphorus compounds.
  • Therefore, it is an object of the present invention a continuous slow release oral composition characterized by the prolonged, continuous slow release of a substance capable of binding phosphorus compounds.
  • The present invention comprises also an improved method for treating phosphate serum levels. In particular, the present invention provides a method for treating high phosphate serum levels by administering to a subject in need of such a treatment a continuous slow-release oral composition containing a substance capable of binding phosphorus compounds during fasting periods.
  • According to the present invention, a better control of phosphate serum levels is achieved, with immediate benefits to the patients and reduced risk of cardiovascular complications.
  • This and other objects and advantages of the present invention will be disclosed in detail also by means of examples.
    • DETAILED DESCRIPTION OF THE INVENTION
  • For the purposes of the present invention, oral composition is intended as any composition which can be administered by oral route to a subject.
  • Also for the purposes of the present invention, continuous slow release oral composition is intended a composition which releases in a continuous manner the active ingredient in the gastrointestinal tract, oral environment included. This feature does not only covers specially designed oral compositions for the continuous slow release of an active ingredient in the gastrointestinal tract, such as for example the so-called “cronoids”, or sustained or delayed release type, but also any composition which, when retained in the mouth for a sufficient period of time, continuously releases in a slow manner the active ingredient.
  • Examples of oral composition are pills, lozenges, tablets, capsules, powdery compositions, solutions, suspensions, emulsions, preferably in the form of gel. According to the present invention, also some formulations pertaining to alimentary field are considered oral compositions, such as for example, confectionery, such as candies, gummy candies, chewing gum.
  • For the purposes of the present invention, as a substance capable of absorbing phosphorus compounds it is intended any substance for use as medicament which can bind phosphorus in a stable manner throughout the transit of the substance along the gastrointestinal tract until its elimination by fecal route. Examples of phosphorus binding are any kind of chemical bond, such as ionic bond, covalent bond, Van der Waals interactions, chelating phenomenon.
  • Examples of substances capable of absorbing phosphorus are phosphate binding polymers, such as those disclosed and mentioned in U.S. Pat. No. 5,496,545 and related patents. The currently marketed for of these phosphate binding polymers is a polyallylamine hydrochloride (Sevelamer—Renagel®), polyallylamine carbonate, and other pharmaceutically acceptable salts thereof, a pharmaceutically acceptable salt of lanthanum, for example carbonate, alluminium hydroxide, a pharmaceutically acceptable salt of magnesium, such as acetate, carbonate, a pharmaceutically acceptable salt of calcium, such as carbonate, acetate, citrate, alginate, and a pharmaceutically acceptable salt of a ketoacid, such as mentioned in the above U.S. Pat. No. 5,496,545; pharmaceutically acceptable anionic ion exchange resins, including those well-known with the trade mark Dowex® (styrene-divinylbenzene anion exchange resins), pharmaceutically acceptable phosphorus binding polysaccharides. Polyallylamine hydrochloride is a preferred embodiment of the present invention for the class of phosphate binding polymer. The most preferred embodiment of the present invention is chitosan for the class of phosphate binding polysaccharide.
  • In the most preferred embodiment of the present invention, chitosan is also used for the preparation of a medicament for the general treatment of hyperphosphatemia, including the administration of said medicament at meals, in order to absorb phosphorus compounds from food.
  • For the purposes of the present invention, as phosphorus compound is intended any substance containing phosphorus, for example phosphate, which, when absorbed in the body affects phosphatemia by increasing it.
  • In case of substances capable of absorbing phosphorus which can be absorbed in the gastrointestinal tract or their administration can imply side effects, the present invention is embodied in an oral composition characterized by the slow release of a substance capable of binding phosphorus and characterized in that said substance is substantially not absorbed in the gastrointestinal tract. Examples of this kind of substances are aluminium hydroxide and/or magnesium hydroxide, calcium acetate, calcium carbonate.
  • For the purposes of the present invention, as substantially not absorbed in the gastrointestinal tract is intended that absorption is null or undetectable or does not increase serum phosphate level or does not involve side effects in the subject orally administered with said substance.
  • A first preferred embodiment of the present invention is an oral composition which can be retained for a long time in the mouth of the subject. Examples of such composition are a chewable tablet, a sachet, a mouthwash, a chewing gum, a gummy candy, a sucking tablet or candies. These compositions must be endowed with continuous slow release characteristics. Chewing gum is a more preferred embodiment, since it can be retained in the mouth for extended period, even hours.
  • This first embodiment of the present invention is advantageous since phosphate sequestration occurs in the mouth, in particular from saliva, the major source of recirculating phosphorus and once the composition has accomplished its scope, namely it has exhausted its absorbing capacity, can be directly taken out from the mouth and a new unit dose can be taken. This avoids swallowing the composition and engaging the gastrointestinal tract with the presence of a composition loaded with phosphorus, so that the subject has not to worry about a possible release of phosphorus in the gastrointestinal tract or the effective elimination of the composition.
  • A second preferred embodiment of the present invention is an oral composition which can be partly retained for a certain time in the mouth of the subject and subsequently swallowed. Examples of such composition is a chewable tablet, gummy candies, or candies. These compositions must be endowed with slow release characteristics.
  • This second embodiment of the present invention is advantageous since phosphorus sequestration, preferably in the form of phosphate, occurs in the mouth, in particular from saliva, the major source of recirculating phosphorus and once the composition has mostly accomplished its scope, namely it has exploited considerable part of its absorbing capacity, can be swallowed in order to continue its absorbing action through the gastrointestinal tract. This allows performing the intended treatment throughout the gastrointestinal tract with a single unit dose or a single administration of the composition.
  • This second embodiment can also be carried out by ingesting a composition according to the present invention and, after ingestion, taking a composition according to the first embodiment, retaining it in the mouth for a long time, until exhaustion of absorption capacity. The two unit doses, the first one to be immediately swallowed and the second one to be retained in the mouth until exhaustion of said binding agent for a therapeutic unit, can be conveniently packaged in a single therapeutic unit dose. The person skilled in the art can modify the therapeutic unit by varying the number and form of the unit doses, then providing a therapeutic unit with at least one first unit dose and at least one second unit dose.
  • A preferred example of composition to be ingested is a powdery composition, for example a sachet containing the composition in the form of a powder. Other forms of swallowable composition are well known in the art, for examples, capsules, pills, syrups, extemporary or ready-to-use solutions, suspensions, emulsions. The powdery composition may be soluble, partially soluble, insoluble or resulting in a suspension or emulsion in a suitable drinkable liquid.
  • An interesting combination of the first and second embodiment is a composition that can be retained in the mouth for a certain period in the form of mouthwash and subsequently swallowed.
  • The treatment according to the present invention is carried out during fasting period. Interestingly, the method according to the present invention can advantageously combined with the one of the state of the art, namely the administration at mealtimes of substances capable of absorbing phosphorus. In this way, a better control of phosphate serum level can be achieved.
  • In another preferred embodiment of the present invention, the composition, in particular those retained in the mouth, will be provided with detecting means signaling the complete absorption of phosphorus, namely the exhaustion of absorption capacity of the unit dose of the composition. In this way, the patient will be able to determine if and whether to discard the exhausted composition and to take another one according to medical advice.
  • A preferred embodiment of detecting means is a substance changing colour or becoming coloured in the presence of phosphorus. The person skilled in the art will find in the general common knowledge information about the above detecting means in order to carry out the present invention.
  • Alternatively, the composition according to the present invention can be supplied with separate detecting means, in order to check phosphorus level, for example in the form of phosphate, in saliva and to determine the duration of the treatment, namely how long to retain the composition in the mouth. A suitable example of such detecting means can be found in Tobey S L, Anslyn E V; Org. Lett., 2003 Jun. 12; 5(12):2029-31.
  • It will be understood that the present invention is suitable for self-medication.
  • In the embodiment of the present invention wherein the phosphorus binder is Sevelamer, a preferred pharmaceutical composition is represented by slow-release tablets containing 250, 500 or 1,000 mg of Sevelamer. These tablets will bind about 46.75 mg, 93.50 mg and 187 mg of phosphorus, respectively, deriving from salivary and gastrointestinal secretion at pH about 7. The tablets are designed to be effective during diurnal and nocturnal fasting, but can be used also in different period of the day, according to medical prescription.
  • The dosage of the phosphorus-binding agent in the composition of the invention will be determined by the person skilled in the art according to standard dose finding tests. However, the dosage of the binding agent will preferably be in an amount sufficient to remove excess phosphorus with respect to physiological level. It would not be advisable to remove phosphorus in an amount such as to bring it at a level lower than physiological one, in order to avoid damage to teeth.
  • Slow-release tablets are within the general knowledge of the person skilled in the art and enabling disclosures are found in normal textbooks, such as for example Remington's Pharmaceutical Sciences, latest edition, Mack Publishing and Co.
  • A vast literature is available to the skilled person for the selection of the suitable formulation for the slow release of the active ingredient of interest, see for example U.S. Pat. No. 5,686,094 and references cited therein. U.S. Pat. No. 5,879,710 and references cited therein is an example of mucoadhesive pharmaceutical dosage form, suitable for the purposes of the present invention. U.S. Pat. No. 6,395,029 and references cited therein refer to slow release of polyanionic active ingredients, such as Sevelamer. Chewable soft gel is described in US 2004/0076664 and the references cited therein.
  • Normally, the tablet will contain at least one pharmaceutically acceptable vehicle and/or excipient. Examples of said vehicles and excipient are lactose anhydrous or monohydrate, povidone, microcrystalline cellulose, hydroxypropylcellulose, sodium croscaramellose, magnesium stearate, E, 171, E 172, mannitol, sodium laurylsulphate, ipromellose, methacrylic acid copolymer, macrogol, magnesium stearate, gelatine, saccharose, starch, sorbitol, mannitol, flavours, sodium saccharine, colloidal silica.
  • Tablets can be either chewed or swallowed, depending on where the desired effect of phosphorus absorption shall occur.
  • In the embodiment of the present invention wherein the phosphorus binder is Sevelamer, another preferred pharmaceutical composition is represented by capsules containing the same or different amount of Sevelamer. These capsules are designed to be effective in the same manner as the above-mentioned tablets, but mainly in the gastrointestinal tract, since they are taken and swallowed.
  • Slow-release capsules are within the general knowledge of the person skilled in the art and enabling disclosures are found in the same textbooks.
  • Normally, the capsule will contain at least one pharmaceutically acceptable vehicle and/or excipient and can be of the soft or rigid type. Examples of said vehicles and excipient are gelatine, titanium dioxide, sodium laurylsulphate.
  • Another embodiment of the present invention is represented by candies and gummy candies. These candies are designed to be effective mostly in the mouth, where the saliva is secreted.
  • Candies are within the general knowledge of the person skilled in the art and the field of confectionery industry can be considered a near technical field in this case.
  • Normally, the candies will contain the active ingredient and vehicles and/or excipients of use in confectionery (see for example Food Industries Manual (24th Edition) Edited by: Ranken, M. D.; Kill, R. C.; Baker, C. G. J. © 1997 Springer-Verlag). Examples of excipients are maltitol syrup, gum arabic, glycerol, aspartame, hydrogenated vegetal oil, gelatine, sorbitol, citric acid, pectin, caramel.
  • Sachets containing a soluble powder are another embodiment of the present invention and their preparation is within the normal task of a person of ordinary skill in the art.
  • Examples of vehicles and excipient are mannitol, sucrose, colloidal silica, methylcellulose, hydroxypropylcellulose. Excipient suitable to prepare a thick solution, suspension, emulsion, or preferably a gel are also well known in the art, see for example Thickening and Gelling agents for Food, second edition by Alan Imeson). A resulting gel formulation is more preferred in the embodiment of a mouthwash, which will be advantageous for patients with difficulty in chewing. Examples of gelling agents are 70% sorbitol.
  • It is within the general common knowledge that, for example tablets to be retained in the mouth until complete dissolution (for example suckable tablets) will be prepared without disintegrating agents and will have high sugar content. Suitable non-disintegrating agent will be used, such as for example waxes, paraffin, fats.
  • Continuous slow-release compositions are intended for the purposes of the present invention any one of sustained release compositions, prolonged action compositions, repeat action compositions, otherwise generally named “cronoids” (E. Ragazzi Lezioni di Tecnica Farmaceutica, Edizioni Libreria Cortina Padova, 1982).
  • Slow release compositions are manufactured according to techniques which are part of the general common knowledge.
  • For example, differential release compositions can be prepared by means of granulates with differential coatings. The active ingredient (the binding agent according to the present invention) is mixed with a suitable excipient (for example lactose, starch) and transformed into a homogeneous granulate, which is subsequently coated with a suitable material (such as lac, shellac, zein, polyacrylic resins, waxes, fats, such as cacao butter, beeswax, stearic acid, etc.). The granules can then made up in a suitable pharmaceutical unit dose, such as capsules, tablet, multi-layered tablets. Alternatively, the active agent is adhered on an inert granulating support (sugar, starch, etc.) and transformed in a pill or a sugar-coated pill. Multi-layered tablets, in which a first layer will provide a “burst” of drug and a second or further layers will provide a continuous, slow release of drug, can be a convenient embodiment. Differential disintegration granules are also a suitable embodiment of the present invention, wherein the drug is incorporated in a lipophilic excipient (cacao butter, hydrogenated oils, glyceryl stearate, beeswax, carnauba wax, saturated fatty acids, etc.) and subsequently transformed into granules, which can optionally coated with different materials according to the desired release time and site.
  • “Erodible” layers are also a useful alternative.
  • The active agent can also be incorporated in a suitable polymeric matrix which will gradually and continuously release it. For example, ion exchange resins can be suitably selected depending on the pH of the desired site of release (mouth, stomach, gut).
  • One of the best modes for carrying out the invention is represented by chewing gum, since it allows to control the permanence of the phosphorus binder agent in the mouth at patience's will.
  • As per the case of candies, chewing gum preparation is within the normal exercise of a skilled person. Just for example, U.S. Pat. No. 3,818,807 and the references cited therein teaches a chewing gum with controlled flavour release composition; see also U.S. Pat. No. 4,386,106, U.S. Pat. No. 4,515,769 and references cited therein. EP 0 427 505 and the references cited therein offer an interesting embodiment for the present invention, since a low calorie chewing gum can be attractive for patients. IE 980990 and the references cited therein provide useful information for the manufacture of a medicated chewing gum with immediate release or sustained release or both. See also WO 02/074099 and the relevant art cited.
  • One possible formulation of a slow-release composition according to the present invention in the form of chewing gum comprises sorbitol, mannitol, 5% xylitol, maltitol syrup, aspartame, acesulfame k, gum base, glycerol, E320, polyalcohols, E903.
  • Another possible formulation of a slow-release composition according to the present invention comprises sorbitol, mannitol, 36% xylitol, maltitol syrup, sodium hydrogen carbonate, aspartame, acesulfame k, gum base, glycerol, E320, polyalcohols, E903.
  • In another best embodiment of the present invention, a method for the treatment of high phosphorus serum levels, or a method for controlling phosphorus serum levels in a subject in need thereof comprises the administration of a composition according to the present invention, said composition can be directly swallowed or chewed and swallowed, followed by taking a composition according to the present invention in the form of a chewing gum and retaining it in the mouth until complete exhaustion of binding capacity of the active ingredient. The chewing gum can incorporate phosphorus detecting means signalling the exhaustion of binding capacity or the chewing gum unit dose can be supplied with separate detecting means in order to periodically check phosphorus content in saliva.
  • All the above formulations can be adopted in the general frame of the present invention, thus meaning that they can be used with a generic phosphorus binding agent suitable for human use.
  • For those binding agent whose use could imply side effects, some measures will be adopted in order to avoid or minimize the side effects.
  • For example, if aluminium hydroxide or another aluminium derivative or lanthanum carbonate or another lanthanum derivative is the binding agent, for example in the form of tablets, the size of the particle comprising aluminium will be higher than 3 μm, in order to avoid intestinal absorption.
  • One exemplary tablet will comprise:
  •
    Slow-release magnesium hydroxide 250 mg
    Slow-release aluminium hydroxide 250 mg
  • Sucrose powder, starch, sorbitol, mannitol, flavouring agents, sodium saccharinate, magnesium stearate.
  • If desired antiemetic or eukinetic agents can be added to or used in combination with the composition of the present invention.
  • The following examples further illustrate the present invention.
    • Example 1
  • Determination of Phosphorus in Saliva
  • a) Uremic patients undergoing dialytic treatment
  • 68 uremic patients (47 males and 21 females, aging 61.6±9.4) undergoing periodic bicarbonate dialysis (HD), three times weekly, using polysulphone dialyzer and 30 control healthy subjects of the same age were enrolled.
  • Uremic patients have been under dialytic treatment for at least one year, mean period 8.9±7.3 years. All patients were in good clinical conditions.
  • At the beginning of middle-week hemodialysis session, fasting patients and control subjects were subjected to blood withdrawal to dose serum phosphorus (P), calcium (Ca) and parathyroid hormone (PTH). A the same time, 2 ml of saliva samples were obtained, to dose phosphorus and calcium concentration.
  • Calcium and phosphorus were dosed by spectrophotometry using flex reagent cartridge by Dade Behring Inc., Newark, U.S.A. after centrifugation of the samples, while serum PTH was dosed by using Immulite 2000 intact PTH, solid phase, two site chemiluminescent enzyme labelled immunometric assay (Diagnostic Product Corporation, Los Angeles, U.S.A.).
  • Statistical analysis was performed as follows: salivary calcium and phosphorus, as well as the corresponding serum levels in HD patients were skewed, a logarithmic transformation was performed before analysis, and the results presented as geometric mean with 95% confidence intervals (CI). Regression analysis was used within HD patients to identify relevant relations between levels of salivary P and other parameters. To verify the association made by independent regression analysis when controlling other variables, multiple regression analysis was performed. Unpaired Student's t test was used to compare log transformed salivary P between controls and HD patients. Differences can be interpreted as the ratio of geometric means with 95% confidence intervals (CI). Upper limit of intervals for mean of salivary P was calculated in controls and a relationship for this value between controls and HD patients was established.
  • HD patients showed:
      • serum Ca 8.73 mg/dl (geometric mean)—95% CI, 8.49 to 8.98, salivary Ca 7.21 mg/dl (geometric mean)—95% CI, 6.58 to 7.91;
      • serum P 5.73±1.31 mg/dl (mean)—95% CI, 5.41 to 6.04; salivary P 30.27 mg/dl (geometric mean)—95% CI, 26.50 to 34.58.
      • PTH 5.73±143.63 pg/ml (mean)—95% CI, 110,57 to 167.69. salivary P 30.27 mg/dl (geometric mean)—95% CI, 26.50 to 34.58.
  • Controls showed:
      • salivary P 12.66±5.25 mg/dl (mean)—95% CI, 10.58 to 14.73.
  • Considering as cut off the upper limit of confidence intervals for mean of salivary P in controls (14.73 ml/dl), 62 out of 68 subjects had a value greater than cut off.
  • Salivary P was significantly correlated with serum P within HD patients (r=0.53, P<0.0001).
  • Considering that the quantity of daily salivary excretion ranges between 1,000 and 1,800 ml, it was calculated that salivary glands of the HD subjects were able to secrete a total amount of phosphate ranging from 302.7 to 544.86 ml.
  • b) Chronic renal failure patients under conservative treatment
  • 110 patients (59 males and 51 females, aging 65; 17-90) under conservative treatment, were randomly selected at dialysis unit at Papardo Hospital in Messina, Italy. Care was taken to exclude patients on treatment with drugs known to interfere with phosphorus assay. Investigation protocol included serum creatinine and phosphorus assays as well as salivary phosphorus. After overnight fasting, blood (4 ml) and saliva (2 ml) samples were withdrawn, at 8.00 a.m. Glomerulal filtration rate (GFR) was calculated according to MDRD equation [GFR (ml/min/1.73 m2)=186×(Plasma creatinine)−1.154×(Age)−0.203×(0.742 if female).
  • As salivary and serum phosphorus (P), age (yrs), GFR as well as serum creatinine values were skewed, data were log transformed before further parametric analysis was done. The results are presented as median and range. To assess possible relevant association between salivary P and demographic (age) and clinical characteristics, multiplicative regression analysis was used. To verify the associations made by univariate analysis when controlling for other variables, backward stepwise multiple regression analysis was performed. The results of the parsimonious model are shown. Differences between genders were tested by unpaired Student's t test.
  • TABLE 1
    Clinical data in 110 subjects
    Parameter Value
    Creatinine (mg/dl)  1.80 (0.50-7.60
    Serum Phosphorus  3.76 (2.30-6.80)
    Salivary Phoshorus 31.20 (10.30-95.60
    GFR (ml/min/1.73 m2* 35.77 (6.51-127.93
  • TABLE 2
    Backward stepwise multiple regression model to predict
    salivary P: final model
    Variable Coefficient b Standard Error se t P
    Constant 2.133 0.356
    Creatinine (loge mg/dl) 0.733 0.505 14.51 <0.0001
    Age (loge yr) 0.212 0.090 2.36 0.0204
    Adjusted R2 = 72.61 percent
  • Clinical data are shown in Table 1. A positive relationship (r=0.85, standard error=0.31, P<0.0001) was found between salivary P and creatinine with an index of determination (R2) of 71.5 percent. At a lesser extent, the same was true for age (r=0.45, standard error=0.52, P<0.0001). A negative association was found for GFR (r=−0.85, standard error=0.32, P<0.0001). As expected, there was a positive relationship of creatinine with both age (r=0.39, standard error=0.32, R2=15.4 percent, P<0.0001) and serum P (r=0.50, standard error 0.17, R2=24.9 percent, P<0.0001). No relationship was found between serum P and age. A prevalence of male gender was found for salivary P (P=0.002), creatinina (P=0.08) and age (P=0.002). The backward stepwise multiple regression analysis selected only creatinine and age as independent predictor of salivary P (Table 2).
    • Example 2
  • Chitosan Formulation
  • Medium and low-viscosity chitosan sequestered phosphate quantity was determined by 500 MHz High-Resolution 31P-NMR (HR-NMR) with mono-dimensional spectra acquisition at 300° K.
  • The analysis was performed according two different protocols:
      • a) studying interaction of low- and medium-viscosity chitosan
  • (FLUKA cat. 50494 and cat. 28191) and solution at different concentrations with PBS (Phosphate Buffered Saline—SIGMA), comparing the difference in phosphate amount between pure PBS and chitosan-containing PBS, in the same experimental conditions;
      • b) studying interaction of PBS with a medium-viscosity chitosan solution at different concentrations according to literature (Yong Zhang and M. Zhang, J. Biomed. Mater. Res., 2002, Dec. 5, 5, 62(3):378-86).
  • Protocol a)
  • 0.2, 1.0 and 1.5 g of low- and medium-viscosity chitosan were added to 10 ml of PBS to give 2, 10 and 15% p/v chitosan solutions.
  • Finally, solution was separated by centrifugation of residue sample.
  • 0.5 ml solution were sampled for NMR analysis and added with 0.1 D2O.
  • The results are shown in the following Table 1.
  • TABLE 1
    Concentration g/ml Medium Low
    (%) PBS PBS Chitosan PBS Chitosan
    2 1 0.87 0.13 0.99 0.10
    10 1 0.80 0.20 0.85 0.10
    15 1 0.75 0.25 0.80 0.20
  • Protocol b)
  • 1.0 and 2.0 g, respectively, of medium-viscosity chitosan were dissolved into 10 ml of 0.2 M acetic acid to give 10 and 20% p/v chitosan solutions. The obtained solutions were subsequently stirred at 50° C. for about 2 hours, in order to obtain a homogeneous polymer solution. The solution was filtered to remove air bubbles. The filtered solutions were added with 0.0931 g PBS and frozen at −20° C. to separate solids. Liquid phase was removed for NMR analysis.
  • 0.5 ml test and reference (PBS) solutions were sampled for NMR analysis and added with 0.1 D2O.
  • The results are shown in the following Table 2.
  • TABLE 1
    Medium
    Concentration g/ml Liquid
    (%) PBS phase mixture
    10 1 0.70 0.30
    20 1 0.80 0.40
  • Similar results were obtained with collagen and biocompatible polycationic polymers.

Claims (6)

1-16. (canceled)
17. A chewing gum for treating hyperphosphatemia in a subject in need thereof comprising:
(a) an effective amount of chitosan, and
(b) a pharmaceutically acceptable vehicle or excipient,
wherein the chitosan in the chewing gum, when retained in the mouth of the subject for a sufficient period of time, sequesters phosphorous compounds from the saliva of the subject and reduces salivary phosphorous levels thereby reducing recirculation of the phosphorous compounds in the body of the subject and reducing serum phosphorous levels, and the phosphorous compounds bound to the chitosan are retained within the chewing gum.
18. The chewing gum of claim 17, further comprising a gum base.
19. The chewing gum of claim 17, wherein the chewing gum further comprises sorbitol, mannitol, 5% xylitol, maltilol syrup, aspartame, acesulfame k, gum base, glycerol, butylated hydroxyanisole, polyalcohols, and carnauba wax.
20. The chewing gum of claim 17, wherein the chewing gum further comprises sorbitol, mannitol, 36% xylitol, maltilol syrup, sodium hydrogen carbonate, aspartame, acesulfame k, gum base, glycerol, butylated hydroxyanisole, polyalcohols, and carnauba wax.
21. The chewing gum of claim 17, wherein the amount of chitosan is effective to reduce the salivary phosphorous in the subject by at least 15%.
US14/462,038 2004-12-07 2014-08-18 Oral compositions for absorption of phosphorous compounds Abandoned US20140356297A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US14/462,038 US20140356297A1 (en) 2004-12-07 2014-08-18 Oral compositions for absorption of phosphorous compounds

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
IT000015A ITME20040015A1 (en) 2004-12-07 2004-12-07 CHEWING GUM, RUBBER CANDIES, TABLETS, SLOW TABLETS OF CHELANTI PHOSPHATE AND / OR PHOSPHORUS SALIVAR AND CAPSULES WITH SLOW RELEASE OF CHELANTS PHOSPHATE AND / OR PHOSPHORUS AT GASTROENTERIC LEVEL.
ITME2004A000015 2004-12-07
PCT/EP2005/056289 WO2006061336A2 (en) 2004-12-07 2005-11-29 Oral compositions for absorption of phosphorus compounds
US79204707A 2007-06-01 2007-06-01
US12/861,539 US20100316578A1 (en) 2004-12-07 2010-08-23 Oral compositions for absorption of phosphorous compounds
US14/462,038 US20140356297A1 (en) 2004-12-07 2014-08-18 Oral compositions for absorption of phosphorous compounds

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US12/861,539 Continuation US20100316578A1 (en) 2004-12-07 2010-08-23 Oral compositions for absorption of phosphorous compounds

Publications (1)

Publication Number Publication Date
US20140356297A1 true US20140356297A1 (en) 2014-12-04

Family

ID=36035790

Family Applications (4)

Application Number Title Priority Date Filing Date
US11/792,047 Expired - Fee Related US7815898B2 (en) 2004-12-07 2005-11-29 Oral compositions for absorption of phosphorus compounds
US12/861,539 Abandoned US20100316578A1 (en) 2004-12-07 2010-08-23 Oral compositions for absorption of phosphorous compounds
US12/883,498 Expired - Fee Related US8518379B2 (en) 2004-12-07 2010-09-16 Oral compositions for absorption of phosphorous compounds
US14/462,038 Abandoned US20140356297A1 (en) 2004-12-07 2014-08-18 Oral compositions for absorption of phosphorous compounds

Family Applications Before (3)

Application Number Title Priority Date Filing Date
US11/792,047 Expired - Fee Related US7815898B2 (en) 2004-12-07 2005-11-29 Oral compositions for absorption of phosphorus compounds
US12/861,539 Abandoned US20100316578A1 (en) 2004-12-07 2010-08-23 Oral compositions for absorption of phosphorous compounds
US12/883,498 Expired - Fee Related US8518379B2 (en) 2004-12-07 2010-09-16 Oral compositions for absorption of phosphorous compounds

Country Status (21)

Country Link
US (4) US7815898B2 (en)
EP (1) EP1827386B1 (en)
JP (1) JP5049135B2 (en)
KR (1) KR101283820B1 (en)
CN (1) CN101068535A (en)
AT (1) ATE481091T1 (en)
BR (1) BRPI0518517A2 (en)
CA (1) CA2587924C (en)
CY (1) CY1110985T1 (en)
DE (1) DE602005023648D1 (en)
DK (1) DK1827386T3 (en)
ES (1) ES2352957T3 (en)
HR (1) HRP20100653T1 (en)
IT (1) ITME20040015A1 (en)
MX (1) MX2007006704A (en)
PL (1) PL1827386T3 (en)
PT (1) PT1827386E (en)
RS (1) RS51507B (en)
RU (1) RU2392926C2 (en)
SI (1) SI1827386T1 (en)
WO (1) WO2006061336A2 (en)

Families Citing this family (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITME20040015A1 (en) * 2004-12-07 2005-03-07 Vincenzo Savica CHEWING GUM, RUBBER CANDIES, TABLETS, SLOW TABLETS OF CHELANTI PHOSPHATE AND / OR PHOSPHORUS SALIVAR AND CAPSULES WITH SLOW RELEASE OF CHELANTS PHOSPHATE AND / OR PHOSPHORUS AT GASTROENTERIC LEVEL.
JP2009507019A (en) 2005-09-02 2009-02-19 ジェンザイム・コーポレーション Method for removing phosphate and polymer used therein
ITRM20060204A1 (en) * 2006-04-10 2007-10-11 Vincenzo Savica PHARMACEUTICALS AND PHARMACEUTICALS FOR HYPERPROTIC HYPROPROSTICAL NORMOPROTEIC DIETS ALL HYPOPHOSPHORIC AND HYPOFOSPHORIC DRINKS
JP2009542653A (en) * 2006-07-05 2009-12-03 ジェンザイム コーポレーション Iron (II) containing therapeutic agent for hyperphosphatemia
AU2008354325A1 (en) * 2008-04-08 2009-10-15 Cypress Pharmaceutical, Inc. Phosphate-binding chitosan and uses thereof
US7943597B2 (en) * 2008-04-08 2011-05-17 Cypress Pharmaceutical, Inc. Phosphate-binding chitosan and uses thereof
US8877907B2 (en) 2010-06-07 2014-11-04 The Johns Hopkins University Molecularly imprinted polymers
US9314523B2 (en) 2010-09-21 2016-04-19 Elwha Llc Ingestible salt grabber
EP2441436A1 (en) * 2010-10-13 2012-04-18 Fresenius Medical Care Deutschland GmbH Easy to administer phosphate binder formulation
WO2012098562A2 (en) 2011-01-19 2012-07-26 Panacea Biotec Limited Liquid oral compositions of lanthanum salts
WO2012143008A1 (en) 2011-04-20 2012-10-26 Gumlink A/S Reduction of the level of free phosphorus compounds in the digestive juice
CA2833574A1 (en) * 2011-04-20 2012-10-26 Gumlink A/S Chewing gum comprising chitosan for use in reduction of the level of free phosphorus compounds in the digestive juice
PT2717896T (en) * 2011-06-08 2016-12-23 Kai Pharmaceuticals Inc THERAPEUTIC AGENTS FOR THE REGULATION OF SERUM PHOSPHORUS
CA2884062C (en) * 2012-09-04 2021-04-20 Charles Y.C. Pak Citrate-rich calcium-magnesium supplement and uses thereof
EP2983651B1 (en) 2013-04-12 2018-12-26 ExPharma Limited Compositions comprising a mixture of elastomers and chitosan and use thereof for treating disorders of phosphorous mineral metabolism
MX364785B (en) 2013-06-05 2019-05-07 Tricida Inc Proton-binding polymers for oral administration.
EP2818176A1 (en) * 2013-06-27 2014-12-31 Virbac Composition for the treatment of progressive renal diseases
CN103536977A (en) * 2013-11-04 2014-01-29 于杰 Hemoperfusion apparatus
US9744128B2 (en) 2014-06-05 2017-08-29 Mastix LLC Method for manufacturing medicated chewing gum without cooling
CA2969238C (en) 2014-12-10 2023-10-17 Tricida, Inc. Proton-binding polymers for oral administration
IL308673A (en) 2016-05-06 2024-01-01 Tricida Inc Compositions for and method of treating acid-base disorders
US10765658B2 (en) 2016-06-22 2020-09-08 Mastix LLC Oral compositions delivering therapeutically effective amounts of cannabinoids
EP3703706A4 (en) 2017-11-03 2022-04-27 Tricida Inc. COMPOSITIONS AND METHOD FOR TREATING ACID-BASE DISORDERS
CN111727037A (en) * 2017-11-29 2020-09-29 世展科技股份有限公司 Enteric-coated pharmaceutical composition and use thereof
US11273123B2 (en) 2018-07-18 2022-03-15 USpharma Ltd Chewable pharmaceutical dosage forms
CN109528764B (en) * 2018-09-30 2021-04-06 北京市中关村医院 Gel-based layered inorganic phosphorus binding agent and preparation method and application thereof

Family Cites Families (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3818807A (en) * 1972-12-06 1974-06-25 Eng Concrete Placer Inc Slurry pump piston seal
US4181718A (en) * 1975-12-29 1980-01-01 Mason Norbert S Polyanion-stabilized aluminum hydrogels
US4163777A (en) * 1977-04-29 1979-08-07 Lewis/Howe Company Controlled antacid delivery form and method of treatment therewith
US4163177A (en) * 1977-10-17 1979-07-31 Ward Derrick A Oscillation generator providing oscillations of varying amplitude
US4160820A (en) * 1977-11-28 1979-07-10 General Mills, Inc. Plaque inhibiting composition and method
US4386106A (en) * 1981-12-01 1983-05-31 Borden, Inc. Process for preparing a time delayed release flavorant and an improved flavored chewing gum composition
US4515769A (en) * 1981-12-01 1985-05-07 Borden, Inc. Encapsulated flavorant material, method for its preparation, and food and other compositions incorporating same
US4512968A (en) * 1982-11-30 1985-04-23 Lion Corporation Oral compositions
JPS61161216A (en) * 1985-01-11 1986-07-21 Teijin Ltd Sustained release drug composition using chitosan
EP0187703B1 (en) 1985-01-11 1992-08-05 Teijin Limited Sustained release preparation
JPS62132830A (en) 1985-12-05 1987-06-16 Teijin Ltd Slow-releasing medicinal drug composition
JPS63310833A (en) * 1987-06-10 1988-12-19 Nippon Medical Supply Corp Phosphorus adsorbing capsule agent
DE3936319C3 (en) 1989-11-01 1997-05-07 Bartz Volker Phosphate binder for oral administration
US5030459A (en) * 1989-11-07 1991-07-09 Warner-Lambert Company High impact mint flavor for high base chewing gum
JP2884124B2 (en) 1992-01-31 1999-04-19 鈴与株式会社 Phosphorus adsorbent
US5496545A (en) * 1993-08-11 1996-03-05 Geltex Pharmaceuticals, Inc. Phosphate-binding polymers for oral administration
GB9506126D0 (en) * 1995-03-25 1995-05-10 Johnson Matthey Plc Pharmaceutical composition and method
TW528597B (en) * 1996-03-05 2003-04-21 Mitsubishi Electric Corp Medicament for preventive and/or therapeutic treatment of hyperphosphatemia
IE980990A1 (en) * 1998-11-27 2000-05-31 Fuisz Internat Ltd Composition and Method for Medicated Chewing Gum Delivery System
DE19917705C1 (en) 1999-04-20 2000-12-28 Vitasyn Gmbh Agents for the therapy of hyperphosphataemia
US6645535B2 (en) 1999-09-02 2003-11-11 Wm. Wrigley Jr. Company Method of making coated chewing gum products containing various antacids
FI121528B (en) * 2000-10-30 2010-12-31 Biohit Oyj A pharmaceutical composition for reducing the risk of cancer by topically binding acetaldehyde in saliva, stomach or colon
US20030072841A1 (en) * 2001-03-19 2003-04-17 The Procter & Gamble Campany Polybutene containing chewing gum and confection
ITMI20012320A1 (en) * 2001-11-06 2003-05-06 Perfetti Van Melle Spa ORAL COMPOSITIONS SOLID ANTI-TARTAR AND ANTI-BACTERIAL PLATE, USEFUL AS ADJUVANTS IN DENTISTRY-STOMATOLOGICAL HYGIENE
AU2002364491A1 (en) * 2002-01-03 2003-07-30 Yissum Research Development Company Of The Hebrew University Of Jerusalem Edible compositions capable of removing oral biofilm
US7244455B2 (en) 2002-01-16 2007-07-17 Warner-Lambert Company Center-filled chewing gum containing a deliverable form of calcium
SE0302947D0 (en) * 2003-01-24 2003-11-07 Magle Ab A composition material for transmucosal delivery
ES2478258T3 (en) 2003-08-26 2014-07-21 Shire Biopharmaceuticals Holdings Ireland Limited Pharmaceutical formulation comprising lanthanum compounds
US7459502B2 (en) * 2003-11-03 2008-12-02 Ilypsa, Inc. Pharmaceutical compositions comprising crosslinked polyamine polymers
US20060177415A1 (en) * 2004-11-01 2006-08-10 Burke Steven K Once a day formulation for phosphate binders
ITME20040015A1 (en) * 2004-12-07 2005-03-07 Vincenzo Savica CHEWING GUM, RUBBER CANDIES, TABLETS, SLOW TABLETS OF CHELANTI PHOSPHATE AND / OR PHOSPHORUS SALIVAR AND CAPSULES WITH SLOW RELEASE OF CHELANTS PHOSPHATE AND / OR PHOSPHORUS AT GASTROENTERIC LEVEL.
US8323683B2 (en) * 2005-05-18 2012-12-04 Mcneil-Ppc, Inc. Flavoring of drug-containing chewing gums
US20070207206A1 (en) * 2006-03-02 2007-09-06 Rice Bronwyn C Chewable pain formula

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Langerlof et al., "The volume of saliva in the mouth before and after swallowing" Journal of Dental Research (1984) vol. 63 no. 5 pp. 618-621 *

Also Published As

Publication number Publication date
PL1827386T3 (en) 2011-05-31
SI1827386T1 (en) 2011-01-31
JP2008523022A (en) 2008-07-03
CA2587924A1 (en) 2006-06-15
ITME20040015A1 (en) 2005-03-07
DE602005023648D1 (en) 2010-10-28
RU2392926C2 (en) 2010-06-27
US20080125394A1 (en) 2008-05-29
ATE481091T1 (en) 2010-10-15
KR20070090904A (en) 2007-09-06
RS51507B (en) 2011-06-30
WO2006061336A3 (en) 2006-09-14
BRPI0518517A2 (en) 2008-11-25
DK1827386T3 (en) 2011-07-11
KR101283820B1 (en) 2013-07-15
JP5049135B2 (en) 2012-10-17
RU2007125702A (en) 2009-01-20
ES2352957T3 (en) 2011-02-24
US8518379B2 (en) 2013-08-27
US7815898B2 (en) 2010-10-19
CA2587924C (en) 2013-08-20
PT1827386E (en) 2010-12-03
WO2006061336A2 (en) 2006-06-15
MX2007006704A (en) 2008-01-16
US20100316578A1 (en) 2010-12-16
US20110002858A1 (en) 2011-01-06
EP1827386B1 (en) 2010-09-15
CN101068535A (en) 2007-11-07
CY1110985T1 (en) 2015-06-11
EP1827386A2 (en) 2007-09-05
HRP20100653T1 (en) 2011-01-31

Similar Documents

Publication Publication Date Title
US8518379B2 (en) Oral compositions for absorption of phosphorous compounds
CA2658465C (en) Liquid compositions of calcium acetate
US9402808B2 (en) Liquid oral composition of lanthanum salts
CN110200954A (en) The preparaton and its preparation and application of stomach and colon
US20130189377A1 (en) Compositions
CN114832020A (en) Pharmaceutical composition for preventing and treating child developmental disorder and preparation method thereof
WO2010005965A1 (en) Colonic purgative formulations and methods of using the same
AU2013202958B2 (en) Liquid Compositions of Calcium Acetate
ES2498918T3 (en) Liquid calcium acetate composition

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载