WO1997012620A1 - Procede et composition servant a traiter l'osteoporose - Google Patents

Procede et composition servant a traiter l'osteoporose Download PDF

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Publication number
WO1997012620A1
WO1997012620A1 PCT/US1996/015594 US9615594W WO9712620A1 WO 1997012620 A1 WO1997012620 A1 WO 1997012620A1 US 9615594 W US9615594 W US 9615594W WO 9712620 A1 WO9712620 A1 WO 9712620A1
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WIPO (PCT)
Prior art keywords
potassium salt
bisphosphonate
alkalinizing
administered
bone
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PCT/US1996/015594
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English (en)
Inventor
Herman L. Marder
R. Curtis Morris, Jr.
Anthony Sebastian
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The Regents Of The University Of California
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Publication date
Application filed by The Regents Of The University Of California filed Critical The Regents Of The University Of California
Priority to AU73792/96A priority Critical patent/AU7379296A/en
Publication of WO1997012620A1 publication Critical patent/WO1997012620A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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

Definitions

  • This invention concerns novel methods for treating osteoporosis in humans and more particularly, involves a method and composition for treating osteoporosis with a combination of an alkalinizing potassium salt and a bisphosphonate.
  • Osteoporosis is a metabolic bone disease characterized pathologically by an absolute decrease in the amount of bone, and clinically by increased susceptibility to fractures.
  • Riggs et al. N. En l. J. Med. (1986), 314:1676; Rusbach et al., in: Textbook of Endocrinology, Ed(s) Williams, (1981), p. 922; Riggs, in: Cecil Textbook of Medicine, Ed( ⁇ ) Wyngaarden et al., (1985), p. 1456; Riggs et al. , Am. J. Med. , (1983) , 75:899.
  • osteoporosis 7:178-208. About 20 of women in the United States suffer one or more osteoporotic fractures by age 65, and as many as 40% sustain fractures after age 65. National Research Council (U.S.) Committee on Diet and Health, "Diet and Health: Implications for Reducing Chronic Disease Risk", Chapter 23, Osteoporosis, page 615. It has previously been proposed to treat osteoporosis with anabolic agents which stimulate bone formation, e.g., fluoride, parathyroid hormone and anabolic steroids, or with antiresorptive agents which decrease bone resorption. The latter, including estrogen for hormone replacement therapy, calcitonin, calcium supplements with or without vitamin D, and bisphosphonates, are more widely used in the management of osteoporosis.
  • Inhibition of bone resorption by bisphosphonate administration not only restricts the mobilization of the inorganic cation, calcium, from bone but also restricts mobilization of the inorganic anions — carbonate, bicarbonate, phosphate, and the like — that accompany calcium.
  • Those anions supply base equivalents to the systemic circulation, which react with acids in the circulation, in effect titrating those acids and reducing the acidity of the blood and extracellular fluid.
  • base released from bone in the process of bone resorption titrates a fraction of the net amount of acid produced endogenously by metabolism of the foodstuffs in ordinary diets.
  • bisphosphonates By reducing the fraction of the daily net endogenous acid production that is neutralized by base released from bone, bisphosphonates, through their potent effect to reduce bone resorption, tend to increase the acidity of blood and lower the plasma bicarbonate concentration. In so doing, the administration of bisphosphonates may worsen the low level chronic metabolic acidosis normally present in otherwise healthy persons as a consequence of the endogenous generation of acid from acid precursors in excess of base precursors in ordinary diets.
  • Acidosis reduces the kidney's production of the calcium-solubilizing substance, citrate, Gordon, J. Clin. Invest. (1963), 42:137, and thereby fosters deposition of calcium salts within the kidney, which creates structural damage to the kidney. Ibid.
  • acidosis increases the kidney's production of ammonia, which damages the kidney by inciting inflammation and chemical injury to the kidney cells. Nath et al., Am. J. Kidney Pis. (1991) 17:654.
  • Acidosis also adversely affects the kidney by causing an abnormally high concentration of chloride in the serum (hyperchloremia) .
  • Hyperchloremia induces constriction of renal blood vessels, reducing the supply of nutrients and inducing the release of toxic chemicals.
  • exacerbation by bisphosphonates of the normally present, low-grade, diet-induced metabolic acidosis may have deleterious effects on the skeletal muscle.
  • diet-induced low-level metabolic acidosis induces wasting of nitrogen in the urine, a condition that over a long term (e.g., months or years) may result in loss of muscle mass, the major source of nitrogen in the body, and consequently, in muscle weakness. Accordingly, bisphosphonate administration in the long-term may be deleterious to muscle, reducing its mass and strength.
  • the bisphosphonates decrease bone resorption, they also substantially decrease bone formation because resorption and formation of bone are normally coupled. Consequently, the rate of bone turnover decreases, i.e., bone remodelling rates decrease. Ibid, p. 833.
  • a reduced remodeling rate restricts the repair of normally occurring microfractures which, in the long term, may weaken bone.
  • the bisphosphonates may not uniformly saturate sites in the bone. Bisphosphonate-free sites will then be subjected to increased demands, such as that of releasing skeletal base to neutralize the acids normally produced from metabolism. Over time, that could lead to skeletal instability.
  • bisphosphonates tend to inhibit mineralization of newly formed bone, and may thereby weaken bone. Safety of bisphosphonates is thus subject to compromise by misplaced patient zeal and physician error. Even at recommended doses, prolonged use (e.g., greater than 10 years) conceivably will have a similar anti-mineralization effect. It has also been proposed to administer alkalinizing potassium salts, e.g., potassium bicarbonate, in the treatment of osteoporosis. Morris et al., U.S. Patent No. 5,171,583, issued December 15, 1992 and incorporated herein by reference.
  • Such method makes use of the anti-resorptive properties of each such agent, overcoming the potential side effects of the bisphosphonates related to restriction of skeletal base mobilization, and by allowing reduced dosage of bisphosphonates, mitigating the potential adverse effects of bisphosphonates related to reduced bone turnover and impaired mineralization, to provide an improved modality for the treatment of osteoporotic conditions.
  • the present invention involves a novel method for ameliorating or preventing osteoporosis in humans afflicted with or predisposed to osteoporosis, which comprises administering the combination of the following active ingredients:
  • a pharmacologically-acceptable alkalinizing potassium salt which produces hydroxyl ions and is thereby capable of reducing the acidity (by increasing the alkalinity) of tissue fluids or urine, and which is selected from the group consisting of potassium bicarbonate and potassium salts of carboxylic acids which are metabolized to bicarbonate, and thus alkalinize, in vivo;
  • a bisphosphonate effective as a potent antiresorptive agent for bone in the treatment of osteoporosis comprising (b) a bisphosphonate effective as a potent antiresorptive agent for bone in the treatment of osteoporosis; the active ingredients being administered in amounts effective to treat osteoporosis without adversely affecting bone and acid-base homeostasis.
  • the present invention provides a more effective treatment for osteoporosis than treatments with bisphosphonates alone. It is believed that the combined treatment with potassium bicarbonate or other alkalinizing potassium salt maintains extracellular pH and plasma bicarbonate concentration, notwithstanding impaired skeletal base mobilization caused by a bisphosphonate, and thus both inhibits bone resorption and stimulates bone formation.
  • the alkalinizing potassium salts are desirably administered with food to reduce gastrointestinal irritation
  • the bisphosphonates are conventionally administered during fasting periods well in advance of meals because they are poorly absorbed from the intestine and exhibit reduced absorption in the presence of food.
  • the alkalinizing potassium salt and the bisphosphonate may be administered in a unitary dosage form designed to facilitate administration of the alkalinizing potassium salt without risk of G.I. irritation (see, for example, those dosage forms described in co-pending Marder et al. Application Serial No. 08/472,693, filed June 6, 1995), incorporated herein by reference.
  • treatment covers any treatment of osteoporotic disease, and include: (1) preventing osteoporosis from occurring in a subject who does not have osteoporosis or who has not yet been diagnosed as having it; (2) inhibiting or arresting the development of the disease; or (3) regressing or reversing the osteoporotic state.
  • normal recommended dose when used to refer to bisphosphonate, means an amount of bisphosphonate which, when administered to a human being subject to osteoporosis is effective in accomplishing one or more of the three outcomes described in the previous paragraph. Such effects may be gauged by one or more of the following chemical markers of bone resorption or formation in humans:
  • Osteocalcin is an integral protein of the organic matrix of bone synthesized by bone-forming cells (osteoblasts) during the process of bone formation. A small fraction of the newly synthesized osteocalcin escapes into the circulatory system, thus providing a blood marker of the rate of bone formation. The osteocalcin concentration increases when the rate of bone formation increases, and decreases when the rate of bone formation decreases. Brown, et al., The Lancet. May 19, 1984, p. 1091, "Serum Bone GLA-Protein: A Specific Marker For Bone Formation in Postmenopausal Osteoporosis".
  • the alkalinizing potassium salts which may be employed in accordance with the present invention are those which, when present in the body fluids, produce hydroxyl ions and are thereby capable of reducing the acidity (increasing the alkalinity) of tissue fluids or urine.
  • a number of pharmaceutically-acceptable alkalinizing potassium salts are known, several of which are set forth in Berge et al., J. Pharmaceut. Sci. (1977) 66:1, which is incorporated herein by reference. Given the disclosure herein, it will be well within the ability of one skilled in the art to select and screen pharmaceutically-acceptable alkalinizing salts for the ability to treat osteoporosis using well known methods and techniques.
  • a salt will be selected which is therapeutically effective in amounts readily achievable in humans while being relatively well tolerated. Different salts may be chosen depending on particular routes of administration and preferred modes of formulation.
  • the alkalinizing potassium salts which may be thus administered are preferably selected from the group consisting of potassium bicarbonate (KHC0 3 ) and pharmacologically acceptable, non-toxic potassium salts of carboxylic acids such as potassium gluconate (CgH j ⁇ KO ⁇ ) and potassium citrate (C € H 5 K 3 0 7 ) which are metabolized to potassium bicarbonate in vivo.
  • KHC0 3 potassium bicarbonate
  • pharmacologically acceptable, non-toxic potassium salts of carboxylic acids such as potassium gluconate (CgH j ⁇ KO ⁇ ) and potassium citrate (C € H 5 K 3 0 7 ) which are metabolized to potassium bicarbonate in vivo.
  • the use of potassium bicarbonate is particularly preferred.
  • the preparation, isolation and purification of these salts are well known to those skilled in the art, as they are commonly employed in a therapeutic setting for a variety of uses other than described herein. Specific procedures for the preparation of such salts are described in general terms in
  • bisphosphonate refers to salts or esters of bisphosphonic acid (which is an analog of pyrophosphoric acid, containing a central carbon atom rather than an oxygen atom) .
  • the bisphosphonates may have simple alkyl or halide side chains, amino side chains, or cyclic side chains. Bisphosphonates which decrease bone resorption and are useful in the practice of the present invention are disclosed, for example, in U.S. Patents Nos. 4,732,998;
  • Preferred bisphosphonates useful in the practice of this invention are non-toxic salts or esters of bisphosphonic acids of the formula:
  • R is methyl , amino, -chlorophenyl thio
  • R' is hydroxy, chloro or hydrogen; and n is an integer of from 0 to 3.
  • Particularly preferred bisphosphonates which have been found to be high potency antiresorptive agents include etidronate [ (1-hydroxyethylidene) bisphosphonate], alendronate [ (4-amino-l-hydroxybutylidene) bisphosphonate], pamidronate [ (3-amino-l-hydroxypropylidene) bisphosphonate], clodronate [ (dichloromethylene) bisphosphonate], tiludronate [([(4- chlorophenyl) thio] -methylene) bisphosphonate] and risedronate [ (l-hydroxy-2- [3-pyridinyl] -ethylidene) bisphosphonate] .
  • Administration of the pharmacologically acceptable alkalinizing potassium salt and the bisphosphonate active agents in accordance with the present invention may be in pharmaceutical compositions described hereinafter and can be via any of the accepted modes of administration for agents which are known to be useful in the treatment of osteoporosis.
  • these methods include oral, parenteral, and other modes of systemic administration. Different alkalinizing potassium salts may be admixed and simultaneously administered, or benefit may be gained in some instances by their separate, sequential administration.
  • these methods include oral, parenteral, transdermal, and other modes of systemic administration.
  • the alkalinizing potassium salt may be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, capsules, pills, powders, solutions, suspensions, or the like, preferably in unit-dosage forms suitable for administration of relatively precise dosages.
  • the bisphosphonate may be incorporated in a solid tablet, capsule or pill, preferably in unit-dosage forms suitable for administration of relatively precise dosages.
  • the unit dosage forms may also contain other active ingredients, or nontoxic auxiliary substances such as pH buffering agents and the like, for example, sorbitan monolaurate, triethanolamine, sodium acetate, triethanolamine oleate, etc.
  • the alkalinizing potassium salt agent e.g., bicarbonate
  • the alkalinizing potassium salt and bisphosphonate are administered in separate dosage forms.
  • the two drugs may thus be administered on the same schedule or on different schedules in accordance with the normal modes of administration thereof.
  • the alkalinizing potassium salt and bisphosphonate active agents may be combined in a unitary dosage form, e.g., in a tablet, capsule or pill designed to minimize if not prevent G.I. irritation by the potassium salt, thus obviating the need for their separate administration.
  • the solid combined dosage form may include conventional pharmaceutical carriers or excipients, and, in addition, may include other pharmaceutical agents.
  • the unit dosage form may be compounded with conventional nontoxic solid carriers such as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like.
  • Such compositions may contain about 50-90% of the active agents used in accordance with the present invention, preferably about 70-90%.
  • the bisphosphonate may be administered in differing amounts, and with or without cyclical dosing schedules, depending upon the particular bisphosphonate administered.
  • the preferred bisphosphonates may be administered in amounts varying from about 5 mg./day (risedronate), to 10 mg./day (alendronate), to 100 mg./day (tiludronate) , to 150 mg./day (pamidronate) to 400 mg./day (etidronate or clodronate) , amounts which have been utilized in resorption studies reported in the literature (see Francis, supra, at p. 839) .
  • the alkalinizing potassium salt should be administered in relatively high amounts, an effective dose of potassium bicarbonate, for example, being in the range of from about 30-300 mmoles (3-30 grams) per day, preferably about 60-90 mmoles per day.
  • concurrent administration of the two active agents in accordance with this invention is effective to treat osteoporosis without adverse effect on bone and acid-base homeostasis.
  • such administration may increase the efficacy of the bisphosphonate by at least about 25%, and as much as about 200% or more, relative to administration of such agent alone.
  • the bisphosphonate(s) and alkalinizing potassium salt(s) may be continuously administered on a daily basis or instead, may be administered on a cyclical basis, e.g., 14 days on, and 14 days off. It will also be appreciated by those having skill in the art that in addition to administering the active ingredients as described herein, it may be desirable to supplement the patient's calcium intake, if necessary, to maintain it at 1500 mg or more of calcium per day.
  • EXAMPLE 1 In one protocol which may be utilized in accordance with the invention employing separate bisphosphonate and alkalinizing potassium salt dosage forms, a tablet containing 10 mg. of alendronate sodium is administered to a patient one hour before breakfast and two tablets each containing 1.5 g. (15 mmoles) of potassium bicarbonate are administered to the patient concurrent with each of breakfast and dinner (equivalent to 6 grams or 60 mmoles of potassium bicarbonate per day) . This protocol is maintained for an extended period for chronic treatment of osteoporosis.
  • the present invention provides a novel method and composition which effectively treats/prevents osteoporosis in human subjects, with lower health risks and incidence of side effects than associated with the potent bisphosphonate antiresorptive agents.

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Abstract

Combinaison des agents actifs suivants dans le but de traiter l'ostéoporose: (a) sel de potassium alcalinisant acceptable en pharmacologie produisant des ions hydroxyle et, de ce fait, capable de limiter l'acidité de liquides tissulaires et de l'urine et sélectionné dans le groupe constitué par bicarbonate de potassium et par des sels de potassium d'acides carboxyliques métabolisés en bicarbonate et, devenant, par conséquent, alcalins in vivo; (b) bicarbonate efficace en tant qu'inhibiteur de la résorption osseuse dans le traitement de l'ostéoporose; les ingrédients actifs étant administrés en quantités suffisantes pour traiter l'ostéoporose sans exercer d'effets adverses sur l'os et sur l'homéostasie acide-base.
PCT/US1996/015594 1995-10-06 1996-09-27 Procede et composition servant a traiter l'osteoporose WO1997012620A1 (fr)

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AU73792/96A AU7379296A (en) 1995-10-06 1996-09-27 Method and composition for treatment of osteoporosis

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US539795P 1995-10-06 1995-10-06
US60/005,397 1995-10-06
US64903996A 1996-05-16 1996-05-16
US08/649,039 1996-05-16

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999009995A2 (fr) * 1997-08-26 1999-03-04 Unipharm Ltd. Procede de preparation de formes posologiques solides a administration par voie orale renfermant de l'acide alendronique
EP1057488A1 (fr) * 1998-12-25 2000-12-06 Toray Industries, Inc. Inhibiteurs de la production d'interleukine-6
CN111481678A (zh) * 2020-04-10 2020-08-04 浙江大学医学院附属邵逸夫医院 一种针对破骨细胞酸性封闭区的纳米材料及其制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5171583A (en) * 1988-10-21 1992-12-15 The Regents Of The University Of California Treatment of osteoporosis using potassium bicarbonate
US5496569A (en) * 1988-10-21 1996-03-05 The Regents Of The University Of California Simultaneous treatment of osteoporosis and hypertension with potassium bicarbonate

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5171583A (en) * 1988-10-21 1992-12-15 The Regents Of The University Of California Treatment of osteoporosis using potassium bicarbonate
US5496569A (en) * 1988-10-21 1996-03-05 The Regents Of The University Of California Simultaneous treatment of osteoporosis and hypertension with potassium bicarbonate

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Vol. 114, 1990 (Columbus, OH, USA), Abstract No. 114:55162, KATSUMATA, "Pharmacological Action of EHDP (Etidronate Disodium)"; & KUSURI NO CHISHIKI 1990. *
CHEMICAL ABSTRACTS, Vol. 115, 1991 (Columbus, OH, USA), Abstract No. 115:53, FITTON et al., "Pamidronate. A Review of Its Pharmacological Properties and Therapeutic Efficacy in Resorptive Bone Disease"; & DRUGS, 1991. *
CHEMICAL ABSTRACTS, Vol. 79, 1973 (Columbus, OH, USA), Abstract No. 79:61603, ELLSASSER et al., "Effect of Low Doses of Disodium Ethane-1-hydroxy-1,1-diphosphonate of Disuse Osteoporosis in the Denervated Cat Tail"; & CLIN. ORTHOP. RELAT. RES. 1973. *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999009995A2 (fr) * 1997-08-26 1999-03-04 Unipharm Ltd. Procede de preparation de formes posologiques solides a administration par voie orale renfermant de l'acide alendronique
WO1999009995A3 (fr) * 1997-08-26 1999-05-20 Unipharm Ltd Procede de preparation de formes posologiques solides a administration par voie orale renfermant de l'acide alendronique
US6465017B1 (en) 1997-08-26 2002-10-15 Unipharm Ltd. Process for the preparation of solid oral dosage forms comprising alendronic acid
EP1057488A1 (fr) * 1998-12-25 2000-12-06 Toray Industries, Inc. Inhibiteurs de la production d'interleukine-6
EP1057488A4 (fr) * 1998-12-25 2003-10-22 Toray Industries Inhibiteurs de la production d'interleukine-6
CN111481678A (zh) * 2020-04-10 2020-08-04 浙江大学医学院附属邵逸夫医院 一种针对破骨细胞酸性封闭区的纳米材料及其制备方法

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