EP1758594A1 - Combinaison pour inhiber la resorption osseuse comprenant un bisphosponate (alendronate) et une vitamine d (cholecalciferol) - Google Patents

Combinaison pour inhiber la resorption osseuse comprenant un bisphosponate (alendronate) et une vitamine d (cholecalciferol)

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Publication number
EP1758594A1
EP1758594A1 EP04776045A EP04776045A EP1758594A1 EP 1758594 A1 EP1758594 A1 EP 1758594A1 EP 04776045 A EP04776045 A EP 04776045A EP 04776045 A EP04776045 A EP 04776045A EP 1758594 A1 EP1758594 A1 EP 1758594A1
Authority
EP
European Patent Office
Prior art keywords
vitamin
cholecalciferol
alendronate
pharmaceutical composition
bisphosphonate
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.)
Withdrawn
Application number
EP04776045A
Other languages
German (de)
English (en)
Inventor
Anastasia G. Daifotis
Andrew Denker
Craig Ikeda
Bogdan K. Matuszewski
Sid Mazel
Arturo G. Porras
Art Santora
Randal Alan Seburg
Limin Zhu
John Yates
John D. Kirsch
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.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
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Filing date
Publication date
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP1758594A1 publication Critical patent/EP1758594A1/fr
Withdrawn legal-status Critical Current

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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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • 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
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/69—Boron compounds
    • 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
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to compositions comprising a bisphosphonate compound and a vitamin D compound.
  • the present invention also relates to methods of using such compositions for example to treat, reduce, inhibit or prevent abnormal bone resorption in mammals.
  • the present invention further relates to methods of making bisphosphonate and vitamin D compositions.
  • osteoporosis is a systemic skeletal disease characterized by a low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Osteoporosis is becoming a worldwide pandemic, with marked increases in its occurrence coinciding with the worldwide increase of longevity.
  • a principal cell type responsible for bone reso ⁇ tion is the multinucleated cell called the osteoclast.
  • Bisphosphonates are well known as selective inhibitors of osteoclastic bone reso ⁇ tion.
  • Bisphosphonates are believed to bind to hydroxyapatite in bone and to inhibit the bone reso ⁇ tive activity of osteoclasts through their intracellular action. See, e.g., H. Fleisch, Bisphosphonates In Bone Disease, From The Laboratory To The Patient, 4th Edition, Academic Press (2000). It has also been reported that bisphosphonates bind to bone and then are released into the reso ⁇ tion lacuna during reso ⁇ tion. After this they are taken up by the osteoclast, and subsequently inhibit the enzyme farnesyl diphosphate synthase.
  • This intracellular action in turn prevents the isoprenylation (farnesylation and geranylgeranylation) of GTPases, signaling proteins that attach to membrane vesicles.
  • the family of geranylgeranylated small GTPases include those that direct the formation of the ruffled border- the organelle of active bone reso ⁇ tion. See A.A. Reszka and G.A. Rodan, "Bisphosphonate Mechanism of Action,” Curr Rheumatol Rep. 5(l):65-74 (February, 2003). Bisphosphonates are understood to be useful in preventing bone loss associated with a number of conditions.
  • bisphosphonates are known to be useful in the prevention of bone loss and in the treatment of diseases such as, but not limited to, osteoporosis, osteopenia, metastatic bone disease, multiple myeloma, periodontal disease, tooth loss, hype ⁇ arathyroidism, rheumatoid arthritis, Paget's disease, osteonecrosis, osteoarthritis, periprosthetic bone loss or osteolysis, and hypercalcemia of malignancy. All of these conditions are characterized by bone loss, resulting from an imbalance between bone reso ⁇ tion - i.e., breakdown - and bone formation.
  • diseases such as, but not limited to, osteoporosis, osteopenia, metastatic bone disease, multiple myeloma, periodontal disease, tooth loss, hype ⁇ arathyroidism, rheumatoid arthritis, Paget's disease, osteonecrosis, osteoarthritis, periprosthetic bone loss or osteolysis, and hypercalcemia of malignancy. All
  • Alendronate sodium is one of the most potent bisphosphonates currently available, and does not impair bone mineralization at doses which maximally inhibit bone reso ⁇ tion. It has also been found that the increase in bone mineral density observed with the administration of alendronate is positively associated with a decrease in vertebral and non-vertebral (including the hip) fractures, a decrease in spinal deformity and a retention of height. This indicates that when administered for a substantial period of time, alendronate decreases bone turnover acting positively to produce a strengthened bone. Alendronate sodium is approved in more than 90 countries for the treatment of osteoporosis in postmenopausal women.
  • Alendronate sodium is also approved for the treatment of osteoporosis in men, glucocorticoid-induced osteoporosis, and Paget's disease of bone.
  • Other bisphosphonates such as ibandronate, minodronate, pamidronate, risedronate, tiludronate and zoledronate, have many properties in common with alendronate, including high potency as inhibitors of osteoclastic bone reso ⁇ tion.
  • bisphosphonates are poorly absorbed (on the order of about 1%) from the gastrointestinal tract. See, e.g., B.J.
  • intravenous administration is costly and inconvenient, especially when the subject must be given an intravenous infusion lasting several hours on repeated occasions.
  • intravenous administration of bisphosphonates is associated with acute renal injury if administered too rapidly.
  • oral administration of the bisphosphonate is desired, higher doses may be administered to compensate for the low bioavailability from the gastrointestinal tract.
  • Bisphosphonate therapy has been associated with hypocalcaemia.
  • the early inhibition of bone reso ⁇ tion can induce a decrease in serum calcium, which occurs within hours, days or weeks of the start of treatment.
  • the serum calcium decrease can persist for many weeks to months following the initiation of treatment and can be prominent in subjects having a deficiency in vitamin D.
  • the hypocalcaemia response to bisphosphonate therapy can occasionally be severe enough to be symptomatic and warrant clinical intervention, particularly in patients with hypoparathyroidism (See, e.g., Vasikaran, S.D., Ed., Bisphosphonates: An Overview with Special Reference to Alendronate, Ann. Clin. Biochem. (2001) 38: 608-623).
  • Vitamin D is required for normal calcium abso ⁇ tion.
  • adequate vitamin D and calcium intake is desirable for subjects using bisphosphonates.
  • Adequate vitamin D levels become even more important when calcium needs are elevated due to the net influx of calcium into bone that occurs as a result of bisphosphonate therapy during effective osteoporosis treatment.
  • adequate vitamin D and calcium intake is desirable for subjects using bisphosphonates.
  • Vitamin D compounds comprise a group of fat soluble secosteriods that are found in very few foods naturally, and they are photosynthesized in the skin of vertebrates by the action of solar UV radiation.
  • vitamin D may come in several forms, the most physiologically relevant forms are vitamin D 3 (cholecalciferol) and vitamin D 2 (ergocalciferol).
  • the latter is formed when the yeast and plant sterol, ergosterol, is exposed to UV radiation, while the former originates from 7-dehydrocholesterol and is synthesized in the skin.
  • the metabolic pathway for vitamin D 3 and vitamin D 2 is similar, and their biological efficacy in humans is similar, their main function being the maintenance of serum calcium and phosphorous concentrations within normal ranges.
  • Vitamin D 3 is the obligate precursor of the hormone calcitriol (also called 1 ,25-dihydroxycholecalciferol or 1,25-dihydroxy vitamin D 3 ), whose principal action is to enhance the ability of the small intestine to absorb calcium, and retain phosphate from the diet.
  • the hormone-like metabolite of ergocalciferol is 1 ,25-dihydroxy ergocalciferol (1,25- dihydroxyvitamin D 2 ).
  • parathyroid hormone (PTH) along with the hormonal metabolite of vitamin D 3 , calcitriol, mobilizes monocytic stem cells in the bone marrow to become mature osteoclasts.
  • cholecalciferol and ergocalciferol are biologically inactive precursors of the hydroxylated biologically active metabolites of vitamin D. Because vitamin D is lipid soluble, it may be stored in fat tissues in the body or metabolized to the principal storage metabolite 25-hydroxyvitamin D and stored in other organs. The 25-hydroxyvitamin D is transported in blood plasma and metabolized by the body when needed. Specifically, as shown in the example of cholecalciferol in FIG.
  • 1, 7-dehydrocholesterol in the skin converts to pre-vitamin D 3 (an iso er of vitamin D 3 , not shown in FIG. 1) upon exposure to sunlight, and then to vitamin D 3 (cholecalciferol). Cholecalciferol is then metabolized in the liver to form 25-hydroxycholecalciferol, also known as 25- hydroxy vitamin D 3 , and this is further metabolized in the kidney to the hormonal form 1,25- dihydroxycholecalciferol, also known as calcitriol.
  • other metabolites of vitamin D include l ⁇ -hydroxy vitamin D, 24,25 dihydroxy vitamin D, and l ⁇ , 24,25- trihydroxy vitamin D.
  • vitamin D both D 2 and D 3
  • D 2 and D 3 A primary biological function of vitamin D (both D 2 and D 3 ) is to help maintain calcium homeostasis by increasing the intestine's efficiency in absorbing dietary calcium. It helps to ensure that the amount of calcium absorbed is adequate to maintain blood calcium in the normal range and adequate to maintain skeletal mineralization.
  • Adequate vitamin D intake facilitates intestinal abso ⁇ tion of calcium, and plays an important role in regulating calcium metabolism and in the mineralization of the skeleton. Vitamin D insufficiency and deficiency are recognized as causes of metabolic bone disease in adults.
  • Vitamin D insufficiency is characterized by the impairment of calcium and phosphate abso ⁇ tion but no impairment of normal bone mineralization and is typically associated with a serum 25- hydroxy vitamin D level between about ⁇ 9 to about 30 ng/mL.
  • Vitamin D deficiency is characterized by severely impaired calcium abso ⁇ tion, secondary hype ⁇ arathyroidism, hypophosphatemia, low or low normal blood calcium, and impaired bone mineralization. Serum 25-hydroxy vitamin D levels are usually about ⁇ 9 ng/mL.
  • Vitamin D insufficiency and deficiency result in increased parathyroid hormone (PTH), which in turn causes increased osteoclastic activity, urinary phosphate loss and calcium mobilization from bone.
  • PTH parathyroid hormone
  • vitamin D insufficiency is thought to be an important cause of gradual bone loss.
  • the histological picture may either be one of osteomalacia, osteoporosis or a combination of the two.
  • the prevalence of vitamin D insufficiency and deficiency creates a need for additional vitamin D intake in the patient populations prone to, or suffering from, conditions such as osteoporosis or osteopenia and in the subjects undergoing bisphosphonate therapy for these conditions.
  • vitamin D insufficiency In subjects undergoing bisphosphonate therapy, and in particular those subjects with inadequate dietary calcium intake or inadequate calcium abso ⁇ tion, there is a need for adequate vitamin D to facilitate bone formation and mineralization, while minimizing the potential for or occurrence of vitamin D insufficiency.
  • Some form of increasing vitamin D intake is often used in clinical trials of bone reso ⁇ tion compounds and recommended on product labels and in product package circulars.
  • approximately 30% of the osteoporotic patients in, for example, the United States have some degree of vitamin D insufficiency and prevalence increases with age.
  • subjects taking oral bisphosphonates and requiring vitamin D are advised to take two separate products at two different times. Vitamin D formulations are most commonly taken daily, while bisphosphonates may be administered daily, weekly, monthly or at longer intervals.
  • vitamin D cannot be taken simultaneously with bisphosphonates, simply due to the fact that bisphosphonate abso ⁇ tion is so poor, and that most bisphosphonate oral dosage regimens require a 30 minute time interval between ingestion of the bisphosphonate and other substances (including but not limited to vitamin D).
  • patient compliance with dosing regimens that require a separate administration of a vitamin D compound at some time interval either before or after bisphosphonate administration is not high. (Some bisphosphonate compounds require administration prior to ingestion of foods, and therefore any vitamin D administration would have to occur at some, time interval after bisphosphonate administration).
  • vitamin D can also be administered in the form of a multi-vitamin, in the United States, for example, many over-the-counter oral vitamin D formulations are not sold in the dosage units required for dosing less frequently than daily.
  • a bisphosphonate and vitamin D product to provide an amount of vitamin D nutrition to facilitate normal bone formation and mineralization in subjects undergoing bisphosphonate therapy.
  • a bisphosphonate and a vitamin D combination for oral administration according to a continuous dosing schedule at dosing intervals less frequent than daily dosing and more frequent than dosing at 6 months or longer intervals.
  • a single product comprising vitamin D and a bisphosphonate, suitable for once-weekly dosing, to increase the convenience of vitamin D intake and to increase patient compliance with recommended vitamin D nutrition during bisphosphonate therapy.
  • methods of preparing and administering such vitamin D/bisphosphonate compositions are also preparing and administering such vitamin D/bisphosphonate compositions.
  • the present invention provides pharmaceutical compositions comprising a bisphosphonate compound and a vitamin D compound.
  • embodiments of the present invention include pharmaceutical compositions comprising a bisphosphonate compound, or pharmaceutically acceptable salts, derivatives or hydrates of the bisphosphonate, or mixtures thereof, and a vitamin D compound, such as a pharmaceutical grade vitamin D compound.
  • the vitamin D compound comprises cholecalciferol.
  • the bisphosphonate comprises, for example, alendronate, a pharmaceutically acceptable salt of alendronate (for example, sodium, potassium, calcium, magnesium, or ammonium, or a hydrate of any of those salts), such as alendronate monosodium, alendronate monosodium monohydrate, or alendronate monosodium trihydrate.
  • the pharmaceutical composition comprises cholecalciferol and alendronate monosodium trihydrate. (See FIG. 2)
  • Compositions of the present invention may be in the form of compressed, coated or uncoated tablets, capsules, elixirs, emulsions, or other acceptable dosage forms.
  • the bisphosphonate (or pharmaceutically effective salts, derivatives or hydrates thereof, or mixtures thereof) is present in pharmaceutically effective amounts, for example from about 0.05 mg to about 1120 mg.
  • the vitamin D compound is present in pharmaceutically effective amounts, for example from about 100 IU to about 60,000 IU of a vitamin D compound (40 IU of vitamin D has a mass of approximately 1 microgram).
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising from about 100 IU to 36,000 IU of a vitamin D compound, and from about 5 mg to about 560 mg, on a bisphosphonic acid active basis, of a bisphosphonate, pharmaceutically acceptable salts, derivatives or hydrates thereof, or mixtures thereof.
  • the present invention relates to a pharmaceutical composition comprising from about 100 IU to 28,000 IU of a vitamin D compound, and from about 5 mg to about 280 mg, on a bisphosphonic acid active basis, of the bisphosphonate, pharmaceutically acceptable salts, derivatives or hydrates thereof, or mixtures thereof.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising from about 100 IU to 8,400 IU of a vitamin D compound, and from about 5 mg to about 280 mg, on a bisphosphonic acid active basis, of the bisphosphonate, pharmaceutically acceptable salts, derivatives or hydrates thereof, or mixtures thereof.
  • the present invention relates to a pharmaceutical composition comprising from about 100 IU to 5,600 IU of a vitamin D compound, and from about 5 mg to about 280 mg, on a bisphosphonic acid active basis, of the bisphosphonate, pharmaceutically acceptable salts, derivatives or hydrates thereof, or mixtures thereof.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising from about 100 IU to 4,200 IU of a vitamin D compound, and from about 5 mg to about 280 mg, on a bisphosphonic acid active basis, of the bisphosphonate, pharmaceutically acceptable salts, derivatives or hydrates thereof, or mixtures thereof.
  • An embodiment of the present invention is a pharmaceutical composition comprising about 2,800 IU of a vitamin D and about 70 mg, on an bisphosphonic acid active basis, of a bisphosphonate or pharmaceutically acceptable salts, derivatives or hydrates of a bisphosphonate, or mixtures thereof.
  • An embodiment of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising about 2,800 IU of cholecalciferol and about 70 mg, on an alendronic acid active basis, of alendronate or pharmaceutically acceptable salts, derivatives or hydrates of alendronate, or mixtures thereof.
  • the cholecalcifeol is pharmaceutical grade.
  • An example of a composition of the present invention is a tablet comprising alendronate sodium, cholecalciferol or cholecalciferol granules containing an appropriate equivalent amount of cholecalciferol and additional excipients, such as suitable fillers, diluents, binders, lubricants, glidants, disintegrants and the like.
  • composition of the present invention is a tablet comprising alendronate sodium, cholecalciferol or cholecalciferol granules containing an appropriate equivalent amount of cholecalciferol, lactose, lactose anhydrous, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate.
  • Compositions of the present invention may be formulated to meet various purity and stability criteria, for example, to comprise less than 1% by weight of each isomer of cholecalciferol (relative to total cholecalciferol), after storage for 24 months at about ⁇ 30 °C and about ⁇ 30 % relative humidity.
  • compositions of the present invention may also be formulated to comprise less than about 5% total degradants of cholecalciferol after storage for 24 months at about ⁇ 30 °C and about ⁇ 30 % relative humidity.
  • the effect that environmental humidity may have on the purity and stability of the composition can be eliminated by using appropriate packaging, such as aluminum foil blister packs or HDPE bottles with dessicant.
  • the present invention encompasses methods of manufacturing compositions and dosage forms disclosed in this specification, as well as products made according to those methods.
  • An embodiment of such a method comprises preparing a powder blend comprising a bisphosphonate, such as alendronate, compacting the powder blend to form a mixture, milling and blending the mixture with a vitamin D compound to form a final granule blend, and compressing the final granule blend, for example, to form tablets.
  • the final granule blend may be lubricated before it is compressed.
  • the powder blend comprises alendronate, colloidal silicon dioxide, lactose anhydrose, microcrystalline cellulose, croscarmellose sodium and magnesium stearate.
  • the roller compacting of the powder blend forms compacted ribbons, which may be milled, blended with cholecalciferol granules, lubricated, and compressed into a solid dosage form.
  • the advantages of the methods of manufacturing of the present invention include increased stability of the vitamin D compound in a bisphosphonate/vitamin D composition, as well as increased uniformity of the particle size of the individual compounds used in the compositions of the present invention.
  • the alendronate powder blend may be pre-blended with one or more of the excipients first, blended with the rest of the excipients, and then roller compacted.
  • bisphosphonate granules such as, for example alendronate granules
  • methods of manufacturing bisphosphonate granules include but are not limited to, slugging, as well as wet granulation methods. If the bisphosphonate granules are manufactured using slugging, then the bisphosphonate (such as alendronate) powder blend may be compressed into a non-ribbon compact and then milled into granules, which may then be blended with a vitamin D compound to form a granule blend, which may then be compressed into a solid dosage form (e.g., a tablet).
  • a solid dosage form e.g., a tablet
  • the bisphosphonate and all of the excipients may be wet granulated with a granulating liquid (e.g., water), then dried, milled, blended with a vitamin D compound, and processed to a final dosage form (e.g., a tablet).
  • a direct blend method can also be employed by blending the bisphosphonate, all of the excipients, and the vitamin D compound together and then compressing into a tablet or encapsulting into a capsule or other solid dosage forms. Further description of possible methods for manufacturing the bisphosphonate granule are described in U.S. Patent 5,358,941; U.S. Patent 5,882,656 and PCT Publication WO 95/29679.
  • Metabolic bone diseases include, but are not limited to, osteoporosis, post-menopausal osteoporosis, steroid-induced osteoporosis, male osteoporosis, other disease-induced osteoporosis, idiopathic osteoporosis, and glucocorticoid-induced osteoporosis.
  • the present invention also encompasses methods for preventing, reducing, inhibiting or treating osteoporosis, conditions associated with osteoporosis, and other diseases and conditions associated with abnormal bone resorption.
  • Such other diseases and conditions may include, as further examples, metastatic bone disease, hypercalcemia of malignancy, periprosthetic osteolysis, inflammatory arthritis, and other diseases and conditions identified herein in a human or other mammal.
  • the present invention relates to a method for eliciting a disease modifying effect on an arthritic condition in a mammal which comprises administering to the mammal a therapeutically effective amount of a vitamin D/bisphosphonate composition.
  • the present invention also relates to methods for eliciting a disease modifying effect on subchondral bone sclerosis, preventing osteophyte formation or progression and preventing joint destruction in a mammal, which comprise administering to the mammal a therapeutically effective amount of a vitamin D/bisphosphonate composition.
  • the present invention also encompasses a method for reducing the risk of bone fractures in a mammal which comprises administering a unit dosage of the vitamin D/bisphosphonate composition.
  • Embodiments of such methods encompass administering the compositions of the present invention to mammals, including humans. Such compositions may be administered at intervals of once- weekly, bi-weekly, monthly, twice-monthly, and bi-monthly.
  • compositions of the present invention during bisphosphonate therapy while minimizing the occurrence of or potential for the complications associated with vitamin D insufficiency.
  • compositions and methods of the present invention may be useful in mammals identified as having or being susceptible to vitamin D insufficiency or deficiency, or desiring adequate amounts of vitamin D.
  • once-weekly dosing to treat osteoporosis or another disease or condition associated with abnormal bone reso ⁇ tion and to minimize the risk or complications from vitamin D insufficiency is maintained on a continuous schedule until the desired therapeutic effect is achieved.
  • An embodiment of the methods of the present invention includes administering once weekly, to a mammal suffering from osteoporosis, a tablet comprising about 2,800 IU cholecalciferol and about 70 mg alendronate or pharmaceutically acceptable salts, derivatives or hydrates of alendronate, or mixtures thereof.
  • the therapeutic effect of once- weekly administration of the vitamin D compound of a composition of the present invention is substantially similar to the therapeutic effect of a recommended daily dosage of vitamin D, for example, 400 IU, 600 IU or 800 IU vitamin D daily.
  • the present invention additionally encompasses methods for measuring cholecalciferol in the pharmaceutical compositions (e.g , stability) comprising cholecalciferol and a bisphosphonate.
  • An embodiment of such a method comprises extracting cholecalciferol from such a composition into a first solution to form a second solution, separating a sample containing cholecalciferol from the second solution, and detecting an amount of the cholecalciferol in the sample, for example, using reverse-phase high performance liquid chromatography.
  • Embodiments of such methods provide increased measurement sensitivity and may advantageously be used with compositions of the present invention to distinguish between cholecalciferol and pre-cholecalciferol, or between isomers of cholecalciferol and pre- cholecalciferol, or to detect cholecalciferol or pre-cholecalciferol ester adducts.
  • the present invention further encompasses methods for measuring cholecalciferol in plasma after administration of the bisphosphonate/cholecalciferol compositions of the present invention.
  • An embodiment of such a method comprises administering to a mammal a composition comprising alendronate and cholecalciferol, obtaining from the mammal a plasma sample, extracting the cholecalciferol from the plasma sample to form a first solution, reacting the cholecalciferol in the first solution with a dienophile to form one or more diels-alder addition products of cholecalciferol, separating the diels-alder addition products of cholecalciferol using high performance liquid chromatography (HPLC) separation, and detecting an amount of cholecalciferol in the sample using mass spectroscopy.
  • HPLC high performance liquid chromatography
  • Embodiments of such methods provide an increased measurement sensitivity and may advantageously be used with the compositions of the present invention, for example, to measure the pharmacokinetic effects of administration of the compositions of the present invention.
  • the present invention also provides methods of measuring the pharmacokinetic effect over time of administering the compositions of the present invention, including, for example, as reflected by the total urinary excretion, area under the serum-concentration-versus-time curve (AUC), steady state maximum plasma concentration (C ⁇ K ), time of C m ⁇ (T ⁇ ), and plasma concentration median apparent half-life (t ) 2 ) of a tablet comprising about 70 mg alendronate and about 2,800 IU cholecalciferol.
  • AUC serum-concentration-versus-time curve
  • C ⁇ K steady state maximum plasma concentration
  • T ⁇ time of C m ⁇
  • t plasma concentration median apparent half-life
  • the present invention can comprise, consist of, or consist essentially of the essential as well as optional ingredients, components, steps and methods described or claimed herein. Further features, advantages and embodiments of the invention, its nature and various advantages, will become more apparent from the following detailed description, and from practice of the invention.
  • FIG. 1 depicts the metabolism of vitamin D 3 .
  • FIG. 2 depicts the chemical structures of cholecalciferol and alendronate monosodium trihydrate.
  • FIG. 3 depicts the chemical structures of vitamin D 2 and of vitamin D 3 .
  • FIG. 4 shows a schematic diagram summarizing an embodiment of a method of preparing compositions of the present invention.
  • FIG. 5 depicts thermal and photochemical isomerizations and transesterifications of vitamin D 3 .
  • FIG. 6 shows the results of a radiolabel study of vitamin D 3 degradation.
  • abnormal bone reso ⁇ tion means a degree of bone reso ⁇ tion that exceeds the degree of bone formation, either locally, or in the skeleton as a whole, or alternatively, can be associated with the formation of bone having an abnormal structure.
  • "Arthritic condition” or “arthritic conditions” refers to a disease wherein lesions, some of which are inflammatory, are confined to the joints or any inflammatory conditions of the joints, most notably rheumatoid arthritis. (Academic Press Dictionary of Science Technology; Academic Press; 1st edition, January 15, 1992). An arthritic condition can be caused by inflammation, trauma or infection.
  • compositions of the present invention are also useful, alone or in combination, to treat or prevent arthritic conditions or symptoms/diseases involving arthritis, such as amyloidosis; ankylosing spodylitis; bacterial arthritis; basic calcium phosphate crystal deposition disease; Behcet's disease; bursitis and tendinitis; CPPD deposition disease; calcific tendonitis; ca ⁇ al tunnel syndrome; Ehlers-Danlos syndrome; enteropathic arthritis; Felty's syndrome; fibromyalgia; gout; fungal arthritis; hemoglobinopathy; hemophilic arthropathy; hypertrophic osteoarthropathy; infectious arthritis; inflammatory bowel disease; juvenile arthritis; juvenile rheumatoid arthritis; lupus erythematosus; lyme disease; marfan syndrome; mixed connective tissue disease; multicentric reticulohistocytosis, myopathies; myositis; osteoarthritis; osteonecrosis; osteonecros
  • osteoarthritis is a connective tissue disease, with pathology arising from mechanical insult-induced articular cartilage degeneration, subchondral bone remodeling and limited synoviticc inflammation response.
  • the net outcome of these activities is joint deformity secondary to erosion of articular cartilage, peri-articular endochondral ossification osteophytosis, subchondral bone sclerosis and cyst formation.
  • Oettmeier, R., and K. Abendroth, 1989 "Osteoarthritis and bone: osteologic types of osteoarthritis of the hip," Skeletal Radiol.
  • An embodiment of the present invention encompasses the treatment, reduction, inhibition or prevention of an arthritic condition which comprises administering a therapeutically effective amount of a composition of the present invention.
  • Another embodiment is the treatment, reduction, inhibition or prevention of osteoarthritis which comprises administering a therapeutically effective amount of a composition of the present invention.
  • bisphosphonate as used herein, corresponds to the chemical formula:
  • R ⁇ is independently selected from the group consisting of H, OH, and Cl
  • R 2 is independently selected from CH 3 , Cl, CH 2 CH 2 NH 2 , (CH 2 ) 3 NH 2 , CH 2 -3-pyridyl, CH 2 -S-phenyl-Cl, CH 2 CH 2 N(CH 3 )(pentyl), CH 2 -imidazole, CH 2 -2-imidazo-pyridinyl, N-(cycloheptyl), CH 2 CH(CH 3 ) 2 , (CH 2 ) 5 NH 2 , and CH 2 -l-pyrrolidinyl, and combinations thereof.
  • Ri is OH and R 2 is a 3-aminopropyl moiety, so that the resulting compound is a 4-amino-l- hydroxybutylidene- 1,1 -bisphosphonate, i.e., alendronate.
  • Pharmaceutically acceptable salts, derivatives, and hydrates of the bisphosphonates are also encompassed by the compounds and methods of the present invention.
  • Non-limiting examples of salts include those selected from the group consisting alkali metal, alkaline metal, ammonium, and mono-, di-, tri-, or tetra-C C 3 o-alkyl-substituted ammonium, including sodium, potassium, calcium, magnesium, and ammonium salts.
  • Non-limiting examples of derivatives include those selected from the group consisting of esters and amides. Also encompassed within the scope of the present invention are the various hydrates and other solvates of bisphosphonates, and pharmaceutically acceptable salts thereof. Also encompassed within the scope of the present invention are hydrates of alendronate, including but not limited to, hydrates with water content between about one to twelve percent, and their crystalline forms. Non-limiting examples of hydrates of alendronate and other bisphosphonates include the monohydrate, dihydrate, trihydrate, hemihydrate, 1/4 hydrate, 1/3 hydrate, 2/3 hydrate, 3/4 hydrate, 5/4 hydrate, 4/3 hydrate, and 3/2 hydrate.
  • Non-limiting examples of bisphosphonates useful in the present invention include the following: Alendronic acid, 4-amino-l-hydroxybutylidene- 1,1 -bisphosphonic acid.
  • Alendronate also known as alendronate sodium or monosodium trihydrate, or by the trademark FOSAMAX®
  • FOSAMAX® 4-amino-l-hydroxybutylidene- 1,1 -bisphosphonic acid monosodium trihydrate.
  • Cycloheptylaminomethylene- 1,1 -bisphosphonic acid YM 175, Yamanouchi (incadronate or cimadronate), as described, for example, in U.S. Patent 4,970,335, to Isomura et al., issued November 13, 1990.
  • 1,1-dichloromethylene- 1,1 -diphosphonic acid clodronic acid
  • disodium salt clodronate, Procter and Gamble
  • the bisphosphonate is selected from the group consisting of alendronate, pharmaceutically acceptable salts, derivatives and hydrates thereof, and mixtures thereof.
  • the pharmaceutically acceptable salt of alendronate may be selected from the group consisting of the sodium, potassium, calcium, magnesium, and ammonium salt of alendronate, and may be alendronate monosodium or a hydrate thereof, including for example alendronate sodium monohydrate or alendronate sodium trihydrate.
  • the compositions of the present invention comprise alendronate sodium (monosodium salt of 4-amino-l-hy droxybuty lidene- 1, 1-bisphosphate), which is a member of the nitrogen-containing bisphosphonate class of drugs.
  • bisphosphonate and “bisphosphonates,” as used herein in referring to the therapeutic agents of the present invention, are meant to also encompass diphosphonates, bisphosphonic acids, and diphosphonic acids, as well as salts, derivatives and hydrates ⁇ t these materials.
  • the use of a specific nomenclature in referring to the bisphosphonate or bisphosphonates is not meant to limit the scope of the present invention, unless specifically indicated. Because of the mixed nomenclature currently in use by those of ordinary skill in the art, reference to a specific weight or percentage of a bisphosphonate compound in the present invention is on an acid active weight basis, unless indicated otherwise herein.
  • Bisphosphonate doses calculated on the basis of their salt, derivative or hydrate forms are included within the dosage ranges of the present invention on the basis of their bisphosphonic acid active weights. Additionally, the doses of all hydrate forms of alendronate are calculated on the basis of the alendronic acid active weight. For instance, the doses of the monohydrate, trihydrate, hemihydrate and all other hydrate forms of alendronate and its salts, are calculated on the basis of their alendronic acid active weights.
  • the phrase "about 70 mg of a bone reso ⁇ tion inhibiting bisphosphonate selected from the group consisting of alendronate, pharmaceutically acceptable salts, derivatives and hydrates thereof, and mixtures thereof, on an alendronic acid active weight basis” means that the amount of the bisphosphonate compound selected is calculated based on 70 mg of alendronic acid.
  • bisphosphonic acid and
  • alendronic acid include the related bisphosphonic acid forms, pharmaceutically acceptable salt forms and equilibrium mixtures of these. The terms include crystalline, hydrated crystalline, and amo ⁇ hous forms of alendronic acid and pharmaceutically acceptable salts thereof.
  • alendronic acid specifically includes, but is not limited to, anhydrous alendronate monosodium, alendronate monosodium hemihydrate, alendronate monosodium monohydrate, alendronate monosodium trihydrate, anhydrous alendronate dipotassium, and alendronate dipotassium pentahydrate. Alendronate monosodium monohydrate and other crystalline forms of alendronate sodium are disclosed in U.S. Patent No. 6,281,381.
  • Potassium salts of alendronic acid, and hydrates thereof, are disclosed in International Patent Publication WO 99/20635. While it is conventional to dose and calculate the dosages of bisphosphonates on the basis of bisphosphonic acid active weight, bisphosphonate dosages can be calculated and administered based on other salt or hydrate forms. For example, dosages of the bisphosphonate risedronate are calculated based on the weight of the anhydrous risedronate sodium salt. According to the Physician's Desk Reference (55 th Edition, page 2664, (2001)), for example, each tablet of risedronate contains the equivalent of 5 mg or 30 mg of anhydrous risedronate sodium, in the form of the hemi-pentahydrate with small amounts of monohydrate.
  • cholecalciferol granules refers to the granules that contain cholecalciferol and may also contain pre-vitamin D 3 , isomers of vitamin D 3 , transesterfied vitamin D 3 or its isomers and/or additional excipients.
  • continuous schedule or “continuous dosing schedule,” as used herein, mean that the dosing regimen is repeated until the desired therapeutic effect is achieved.
  • the continuous schedule or continuous dosing schedule is distinguished from cyclical or intermittent administration.
  • Dry Vitamin D 3 100 granules refers to Dry Vitamin D 3 100, Gelatin Coated, Pharmaceutical Grade granules which are sold commercially by BASF.
  • generalized bone loss means bone loss at multiple skeletal sites or throughout the skeletal system.
  • localized bone loss means bone loss at one or more specific, defined skeletal sites.
  • human in need of treatment means human in need of prevention
  • human in need thereof and “human at risk thereof,” as used herein, refer to a human in need of treatment for a disease condition, in need of prevention, mitigation, inhibition or reduction of a disease condition, or at risk of developing a disease condition, as determined by a clinician or researcher.
  • IU as used herein, means International Units. It is customary to use International Units (IU) when stating the potency and dosage of vitamin D.
  • IU International Unit
  • nce-weekly dosing means that a unit dosage, for example a unit dosage of bisphosphonate and a vitamin D compound, is administered once a week, i.e., once during a seven-day period, preferably on the same day of each week. In the once- weekly dosing regimen, the unit dosage is generally administered about every seven days.
  • a non-limiting example of a once-weekly dosing regimen would entail the administration of a unit dosage of the bisphosphonate and a vitamin D compound every Sunday.
  • a unit dosage for once-weekly administration is not administered on consecutive days, but the once-weekly dosing regimen can include a dosing regimen in which unit dosages are administered on two consecutive days falling within two different weekly periods.
  • "Osteophyte” as used herein refers to newly formed bony structures located at the joint margins, and their occurrence is strongly associated with the late stage of osteoarthritis progression. The current hypothesis is that osteophytes originate from activated periosteum leading to new cartilaginous outgrowths that eventually turns into bone by the process of endochondral bone formation.
  • “Pharmaceutically acceptable” as used herein with reference to salts, esters, hydrates and derivates of a bisphosphonate (such as alendronate) means that the salts, derivatives or hydrates of the bisphosphonate has the same general pharmacological properties as the free acid form from which they are derived and are acceptable from a toxicity viewpoint.
  • pharmaceutically effective amount means that amount of a compound, for example a bisphosphonate compound or a vitamin D compound, that will elicit a desired therapeutic effect or response when administered in accordance with a treatment regimen.
  • a pharmaceutically effective amount of bisphosphonate is an amount administered according to a treatment regimen that is sufficient to elicit prevention, reduction, inhibition or treatment of abnormal bone reso ⁇ tion, for instance.
  • pharmaceutical grade means of a sufficient quality and potency so as to conform to applicable United States Pharmacopoeia (USP) and European Pharmacopoeia (Ph. Eur.) compendial requirements. While at this time there is no USP monograph for a formulated vitamin D 3 product, an applicable Ph.Eur. monograph has been published.
  • a "pharmaceutical grade” cholecalciferol for example, generally is of a superior grade than the vitamin D commonly used in nutritional supplements.
  • preventing, inhibiting, reducing or treating include addressing abnormal bone reso ⁇ tion (and the resultant physiological conditions - e.g. , osteoporosis) through the direct or indirect alteration of osteoclast formation or activity, and encompass prevention, inhibition, reduction or treatment of bone loss, especially the inhibition of removal of existing bone either from the mineral phase and/or the organic matrix phase, through direct or indirect alteration of osteoclast formation or activity.
  • These terms also mean addressing other disease states or conditions in such fashion as to promote relief from the disease or condition.
  • the term "until the desired therapeutic effect is achieved,” as used herein, means that a composition, for example, a bisphosphonate and cholecalciferol composition, is administered according to a chosen dosage schedule, or a course of therapy is followed, up to the time that the clinical or medical effect sought for the disease or condition is observed by the clinician or researcher.
  • the bisphosphonate compound may be continuously administered until the desired change in bone mass or structure is observed. In such instances, achieving an increase in bone mass, preventing further reduction in bone mass or replacing abnormal bone structure with more normal bone structure, are among the desired objectives.
  • the bisphosphonate compound may be continuously administered for as long as necessary to prevent the undesired condition.
  • Non- limiting examples of administration periods can range from about 2 weeks to the remaining life span of the mammal.
  • administration periods can range from about 2 weeks to the remaining life span of the human, preferably from about 2 weeks to about 40 years, more preferably from about 1 month to about 35 years, more preferably from about 6 months to about 30 years, and most preferably from about 1 year to about 20 years.
  • vitamin D as used herein, means both vitamin D 2 and vitamin D 3 which have the chemical structures shown in FIG. 3.
  • vitamin D compound means vitamin D (ergocalciferol) and vitamin D 3 (cholecalciferol), 7-dehydrochlosterol and pre-vitamin D and pre-vitamin D 3 , as well as isomers of or esters of any of 7-dehydrocholesterol, vitamin D 2 , vitamin D 3 , pre-vitamin D 2 , or pre-vitamin D 3 , or mixtures thereof.
  • vitamin D 2 and vitamin D 3 are at equilibrium with their respective pre-vitamin isomers, although that equilibrium is shifted in favor of vitamin D 2 and vitamin D 3 .
  • vitamin D compound does not include metabolites of vitamin D, such as, for example, 25-hydroxycholecalciferol or calcitriol or their analogs, nor does the term include the active hormone calcitriol or its analogs.
  • vitamin D 3 and cholecalciferol are used interchangeably herein, unless expressly otherwise indicated.
  • the present invention provides compositions comprising a bisphosphonate, or pharmaceutically acceptable salts, derivatives or hydrates of the bisphosphonate, or mixtures thereof, and a vitamin D compound.
  • the bisphosphonate compound is selected from alendronate sodium, alendronate sodium monohydrate or alendronate sodium trihydrate, and the vitamin D compound is cholecalciferol.
  • the precise dosage of the bisphosphonate and the vitamin D compound will vary with the dosing schedule, the oral potency of the particular bisphosphonate chosen, the age, size, sex and condition of the mammal or human, the nature and severity of the disorder to be treated, and other relevant medical and physical factors.
  • a precise pharmaceutically effective amount cannot be specified in advance, but can be readily determined by the caregiver or clinician. Appropriate amounts can be determined by routine experimentation from animal models and human clinical studies.
  • a pharmaceutically effect amount of bisphosphonate is chosen according to a continuous dosing schedule until the desired therapeutic effect is achieved.
  • an effective oral dose of bisphosphonate is typically from about 0.0001 mg/kg to about 100 mg/kg body weight and preferably about 0.0005 to about 20 mg/kg of body weight for a 75 kg subject.
  • an appropriate amount of the vitamin D compound is chosen to provide adequate vitamin D nutrition during the dosing interval without interfering with the bisphosphonate's ability to obtain a bone reso ⁇ tion inhibiting effect.
  • an amount of the vitamin D compound comprises from about 100 IU to about 60,000 IU.
  • an oral amount of the vitamin D compound in embodiments of the present invention include, but are not limited to, dosages of 700, 1,400 IU, 2,800 IU, 4,200 IU, 5600 IU, 7,000 IU, 8,400 IU, 14,000 IU, 28,000 IU, 36,000 IU and 60,000 IU of the vitamin D compound.
  • an oral pharmaceutically effective amount of alendronate typically comprises from about 0.05 mg to about 1 120 mg of the alendronate compound, on an alendronic acid weight basis.
  • an oral pharmaceutically effective amount of alendronate in embodiments of the present invention include, but are not limited to, dosages of about 2.5 mg, 5 mg, 8.75 mg, 10 mg, 17.5 mg, 35 mg, 40 mg, 70 mg, 140 mg, 280 mg, 560, and 1 120 mg of alendronate, each on an alendronic acid weight basis.
  • a bisphosphonate and vitamin D composition of the present invention is typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers, suitably selected with respect to a dosage form for oral administration.
  • suitable pharmaceutical diluents, excipients, or carriers suitably selected with respect to a dosage form for oral administration.
  • oral dosage forms include tablets (including compressed, coated or uncoated), capsules (each of which includes sustained release or timed release formulations), hard or soft gelatin capsules, pellets, pills, powders, granules, elixirs, tinctures, slurries, effervescent compositions, films, sterile solutions or suspensions, syrups and emulsions and the like.
  • compositions may also be administered in intravenous (bolus or infusion), intraperitoneal, topical (e.g., ocular eyedrop), intranasal, inhaled, subcutaneous, intramuscular or transdermal (e.g. , patch) form, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories all using forms well known to those of ordinary skill in the pharmaceutical arts.
  • An effective but non-toxic amount of the compositions desired can be employed.
  • the compositions are intended for oral, parenteral, intranasal, sublingual, or rectal administration, or for administration by inhalation or insufflation.
  • compositions according to the invention can conveniently be effected by methods known from the art, for example, as described in Remington's Pharmaceutical Sciences. 17* ed., 1995.
  • the active ingredients can be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, croscarmellose sodium and the like;
  • oral administration in liquid form e.g., elixirs, syrups, slurries, emulsions, suspensions, solutions, and effervescent compositions
  • the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • suitable binders can include but are not limited to starch, gelatin, natural sugars such as glucose, anhydrous lactose, free-flow lactose, beta-lactose, and corn sweeteners, natural and synthetic gums, such as acacia. guar, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, and the like.
  • Lubricants used in these dosage forms can include but are not limited to sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Suitable disintegrants may be one of several modified starches or modified cellulose polymers, including crosscarmellose sodium.
  • Diluents, which may be used as compression aids include, but are not limited to, lactose, dicalcium phosphate, cellulose, microcrystalline cellulose, and the like.
  • Glidants which improve the flow characteristics of a powder mixture, may also be utilized in the present invention. Examples of glidants include, but are not limited to, colloidal silican dioxide, talc, and the like.
  • compositions used in the present method can also be coupled with soluble polymers as targetable drug carriers.
  • soluble polymers can include but are not limited to polyvinylpyrrolidone, pyran copolymer, polyhydroxylpropyl-methacrylamide, and the like. Additional excipients, such as those described in U.S. Patent 5,358,941; U.S. Patent 5,882,656 and PCT Publication WO 95/29679, may also be utilized.
  • An embodiment of the present invention is a 80 mg to 1500 mg tablet including about 0.5% to about 90% alendronate sodium by weight, about 1% to about 70% cholecalciferol granule by weight (equivalent to about 0.0005% to about 20% cholecalciferol by weight), about 10% to about 80% lactose anhydrous by weight, about 5% to about 50% microcrystalline cellulose by weight, about 0.1 % to about 5% colloidal silicon dioxide by weight, about 0.5% to about 10% croscarmellose sodium by weight, and about 0.5% to about 5% magnesium stearate by weight.
  • the weight range of Dry Vitamin D 3 100 granules is to ensure 2800 IU potency in each tablet because the granule contains a potency range of 100,000 IU to 110,000 IU vitamin D 3 per gram.
  • the quantity of lactose anhydrous is adjusted according to the amount of Dry Vitamin D 3 100 granules added to the tablet in order to maintain a final tablet weight of 325 mg.
  • Other non-limiting examples of oral compositions of the present invention comprising a bisphosphonate compound, such as alendronate, and a vitamin D compound, are described herein, including in the Examples below.
  • the Dry Vitamin D 3 100 granules contain about 100,000 IU vitamin D 3 per one gram of granule weight.
  • 28 mg of Dry Vitamin D 3 100 granules contains about 2800 IU of vitamin D 3 , which is the equivalent of about 70 ⁇ g vitamin D 3 .
  • Bisphosphonate/vitamin D compositions of the present invention may be administered at intervals of once-weekly, bi-weekly, monthly, twice monthly, and bi-monthly.
  • an oral pharmaceutically effective amount of alendronate comprises from about 0.05 mg to about 1120 mg of the alendronate compound, on an alendronic acid active weight basis.
  • Embodiments of the present invention providing a weekly oral pharmaceutically effective amount of alendronate include, but are not limited to, unit dosages which are useful for preventing osteoporosis comprising a vitamin D compound and from about 35 mg to about 70 mg of the alendronate compound; a unit dosage which is useful for treating osteoporosis comprising a vitamin D compound and about 70 mg of the alendronate compound; a unit dosage which is useful for treating Paget's disease comprising a vitamin D compound and about 280 mg of the alendronate compound; and a unit dosage which is useful for treating metastatic bone disease comprising a vitamin D compound and about 280 mg of the alendronate compound.
  • a pharmaceutically effective amount of a vitamin D compound in a bisphosphonate/vitamin D composition of the present invention comprises from about 100 IU to about 60,000 IU of vitamin D.
  • the composition comprises from about 100 IU to about 5,600 IU of a vitamin D compound, and a pharmaceutically effective amount of alendronate, pharmaceutically acceptable salts, derivatives or hydrates of alendronate, or mixtures thereof.
  • the pharmaceutically acceptable amount of alendronate comprises from about 0.05 mg to about 1 120 mg, on an alendronic acid active basis, of alendronate, pharmaceutically acceptable salts, derivatives or hydrates of alendronate or mixtures thereof.
  • a pharmaceutically effective amount of a vitamin D compound in a bisphosphonate/vitamin D composition of the present invention comprises from about 100 IU to about 60,000 IU of vitamin D.
  • the composition comprises from about 100 IU to about 8,400 IU of a vitamin D compound, and a pharmaceutically effective amount of alendronate, pharmaceutically acceptable salts, derivatives or hydrates of alendronate, or mixtures thereof.
  • the pharmaceutically acceptable amount of alendronate comprises from about 0.05 mg to about 1120 mg, on an alendronic acid active basis, of alendronate, pharmaceutically acceptable salts, derivatives or hydrates of alendronate or mixtures thereof.
  • a pharmaceutically effective amount of a vitamin D compound in a bisphosphonate/vitamin D composition of the present invention comprises from about 100 IU to about 36,000 IU of vitamin D.
  • the composition comprises from about 100 IU to about 11,200 IU of a vitamin D compound, and a pharmaceutically effective amount of alendronate, pharmaceutically acceptable salts, derivatives or hydrates of alendronate, or mixtures thereof.
  • the pharmaceutically acceptable amount of alendronate comprises from about 0.05 mg to about 1120 mg, on an alendronic acid active basis, of alendronate, pharmaceutically acceptable salts, derivatives or hydrates of alendronate or mixtures thereof.
  • the present invention also encompasses methods for preventing, reducing, inhibiting and treating diseases and conditions associated with abnormal bone reso ⁇ tion, such as osteoporosis.
  • a person suffering from osteoporosis i.e., has a bone mineral density (BMD) which is at least about two or two and one-half standard deviations below the norm of pre-menopausal women, would be a candidate for administration of a composition of the present invention according to a method of the present invention.
  • BMD bone mineral density
  • vitamin D 3 administered in a once-weekly dose up to seven or more times than the amounts that would be given on a daily basis, can be simultaneously co-administered with a bisphosphonate, such as alendronate, without adversely affecting the bioavailability of the bisphosphonate. See, e.g., Example 7.
  • a bisphosphonate such as alendronate
  • the methods of the present invention do not have disadvantages of current methods of treatment which require cumbersome, irregular, or complicated dosing regimens to provide adequate vitamin D during bisphosphonate therapy.
  • composition of the present invention such as a composition comprising a bisphosphonate compound, for example alendronate, and a vitamin D compound, would be effective for all of the indications for which compositions comprising alendronate or other bisphosphonates without a vitamin D compound are effective.
  • the methods and compositions of the present invention are useful for reducing or inhibiting bone reso ⁇ tion, and for treating, reducing, inhibiting or preventing abnormal bone reso ⁇ tion, and conditions associated therewith.
  • Compositions of the present invention can thus be used in humans and other animals to increase bone mass and to prevent, inhibit, reduce and treat the following conditions and disease states: bone loss; osteoporosis, including but not limited to, post-menopausal osteoporosis, steroid-induced osteoporosis, male osteoporosis, disease-induced osteoporosis, idiopathic osteoporosis, and glucocorticoid-induced osteoporosis; osteonecrosis, Paget's disease; osteoarthritis; rheumatoid arthritis, other arthritic conditions, abnormally increased bone turnover; localized bone loss associated with periprosthetic bone loss or osteolysis; bone fractures; metastatic bone disease; Gaucher's disease; avascular necrosis; polyostotic fibrous dysplasia; Charcot's joint; parasitic disorders; osteogenesis imperfecta; homocystinuria; lysinuric protein intolerance; Turner's syndrome; immobilization; fibr
  • the present invention relates to the use of a composition of the instant invention for the preparation of a medicament useful in the treatment, reduction, inhibition or prevention of an arthritic condition.
  • the present invention also relates to the use of a composition of the instant invention and an agent selected from androgen receptor modulator; an inhibitor of osteoclast proton ATPase; an inhibitor of HMG-CoA reductase; an osteoblast anabolic agent; calcitonin; Vitamin K2 or a pharmaceutically acceptable salts and mixtures thereof, for the preparation of a medicament useful in the treatment of an arthritic condition.
  • the arthritic condition is amyloidosis; ankylosing spodylitis; bacterial arthritis; basic calcium phosphate crystal deposition disease; Behcet's disease; bursitis and tendinitis; CPPD deposition disease; calcific tendonitis; ca ⁇ al tunnel syndrome; Ehlers-Danlos syndrome; enteropathic arthritis; Felty's syndrome; fibromyalgia; gout; fungal arthritis; hemoglobinopathy; hemophilic arthropathy; hypertrophic osteoarthropathy; infectious arthritis; inflammatory bowel disease; juvenile arthritis; juvenile rheumatoid arthritis; lupus erythematosus; lyme disease; marfan syndrome; mixed connective tissue disease; multicentric reticulohistocytosis, myopathies; myositis; osteoarthritis; osteonecrosis; osteonecrosischondrodystrophy; polyarteritis; polymyalgia rhe
  • An embodiment of the invention is a method of treating, reducing, inhibiting or preventing the progression of osteoarthritis in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a composition of the instant invention.
  • osteoarthritis is accompanied with a well-defined changes in the joints, including erosion of the articular cartilage surface, peri-articular endochondral ossification/osteophytosis, and subchondral bony sclerosis and cyst formation. See Oettmeier R, Abendroth, K, "Osteoarthritis and bone: osteologic types of osteoarthritis of the hip," Skeletal Radiol. 1989; 18: 165-74.
  • Another embodiment of the invention is a method of treating, reducing, inhibiting or preventing rheumatoid arthritic conditions in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a composition of the instant invention.
  • a composition of the instant invention It is known in the literature that progressive destruction of the periarticular bone is a major cause of joint dysfunction and disability in patients with rheumatoid arthritis. See Goldring SR, " Pathogenesis of bone erosions in rheumatoid arthritis" Curr. Opin. Rheumatol. 2002; 14: 406-10.
  • generalized bone loss is a major cause of morbility associated with severe rheumatoid arthritis.
  • compositions of the present invention comprising a bisphosphonate compound and a vitamin D compound can be used to treat, reduce, inhibit or prevent the bone loss associated with rheumatoid arthritis and other osteoarthritic conditions. More generally, it is believed that bisphosphonates can be given in the same formulation with vitamin D without adversely affecting the bioavailability of the bisphosphonate. Furthermore, it is believed that lower doses of vitamin D and higher doses of vitamin D can be given in the same formulation with bisphosphonates without affecting their bioavailability. As an example, a once-weekly dosage of 2800 IU vitamin D is believed to be effective when administered in combination with a bisphosphonate in the compositions of the present invention.
  • vitamin D 2 can be used in place of vitamin D 3 with similar results as those found for vitamin D 3 .
  • administration of a vitamin D compound in the same formulation with a bisphosphonate compound eliminates the separate dosing requirements of vitamin D during bisphosphonate treatment and provides vitamin D nutrition without adversely affecting the bioavailability and efficacy of the bisphosphonate.
  • Patients would benefit from the vitamin D and bisphosphonate combination because it provides additional vitamin D nutrition to facilitate normal bone formation and mineralization and to enhance the efficacy of bisphosphonate treatment. From patient lifestyle and compliance standpoints, the methods of the present invention would also be more convenient than daily or cyclic dosing regimens for bisphosphonates with additional daily vitamin D administration.
  • alendronate could potentially penetrate into the stratum basale of the stratified squamous epithelium (e.g., via its own penetration or via penetration into a site of local injury caused by abrasive food or other agent), it could cause an inhibition of keratinocyte growth, as suggested by its effects on keratinocyte growth in vitro. See, A. A. Reszka et al., Mol. Pharmacol., 2001 ;59(2): 193-202. Suppression of growth could slow the process of epithelial repair, thus leading to local irritation or ulceration.
  • vitamin D/bisphosphonate composition is useful for the prevention or treatment of sway. Additionally, it is believed that a vitamin D/bisphosphonate composition is useful for reducing falls. It is believed that a vitamin D/bisphosphonate composition will increase muscle strength, improve neuromuscular function, reduce body sway and improve physical function in elderly people.
  • vitamin D receptors have been identified in muscle tissue and muscle weakness, limb pain and impaired physical function are well recognized manifestations of severe vitamin D deficiency.
  • a number of prospective, randomized, intervention studies demonstrated the efficacy of vitamin D to improve musculoskeltal function and reduce fall risk.
  • Treatment with vitamin D, and calcium has been shown to reduce the incidence of non- vertebral fractures and to reduce postural sway and possibly the incidence of falls. See J.K. Dhesi et al., Age and Aging 2002;31 :267-271. Additionally, it has been demonstrated that the number of falls in elderly community-dwelling patients can be significantly reduced by treatment with alfacalcidol (1-alfa-hydroxy vitamin D 3 ), and minimal calcium intake. See L.
  • the present invention also provides for the use of a composition comprised of a vitamin D compound and a bisphosphonate compound comprising a pharmaceutically effective amount of at least one bisphosphonate, or a pharmaceutically acceptable salt, derivative or hydrate of the bisphosphonate, or mixtures thereof, and one or more active ingredients for the manufacture of a medicament for the treatment, reduction, inhibition or prevention, in mammals such as humans, of the conditions and disease states identified above.
  • the methods and compositions of the present invention can also comprise a histamine H2 receptor blocker (/ e. , antagonist) and/or a proton pump inhibitor, which are well known therapeutic agents for increasing gastric pH. See, e.g., L.J.
  • histamine H2 receptor blocker and/or a proton pump inhibitor can help to minimize adverse gastrointestinal effects.
  • the histamine H2 receptor blocker and/or proton pump inhibitor is administered from about 30 minutes to about 24 hours prior, or from about 30 minutes prior to about 12 hours prior, to the administration of the bisphosphonate and vitamin D composition.
  • histamine H2 receptor blocker and/or proton pump inhibitor will depend upon the particular compound selected and factors associated with the mammal to be treated, i.e., size, health, etc.
  • histamine H2 receptor blockers and/or proton pump inhibitors include those selected from the group consisting of cimetidine, famotidine, nizatidine, ranitidine, omprazole, and lansoprazole.
  • the present invention further encompasses methods of manufacturing compositions of the present invention, including for example pharmaceutical compositions comprising a bisphosphonate compound and a vitamin D compound.
  • a method for preparing an alendronate- cholecalciferol formulation comprises: preparing a powder blend comprising alendronate; compacting the powder blend to form an alendronate mixture; milling and blending the alendronate mixture with cholecalciferol granules to form a blend; and lubricating and compressing the blend.
  • a method for preparing an alendronate-cholecalciferol solid dosage form comprises: blending alendronate, colloidal silicon dioxide, lactose anhydrous, microcrystalline cellulose, and croscarmellose sodium to form a pre-blend; blending the pre-blend and magnesium stearate to form a first lubricated mixture; roller compacting the first lubricated mixture to form compacted ribbons; milling the compacted ribbons to form a lubricated blend; blending the lubricated blend with cholecalciferol granules to form a second lubricated mixture; and compressing the second lubricated mixture into the solid dosage form.
  • the composition is made by a process comprising roller compacting an alendronate sodium formulation to form a ribbon, milling of the ribbon produced from the roller compaction step and then blending with the extragranular addition of the vitamin D 3 formulation.
  • this formulation and process results in a product which satisfies regulatory requirements for product release and stability of both alendronate and vitamin D 3 . As shown in FIG.
  • a pre-blend of colloidal silicon dioxide, lactose anhydrous, and alendronate sodium is prepared.
  • the pre-blend is then blended with microcrystalline cellulose and croscarmellose sodium.
  • magnesium stearate is added to form a lubricated mixture.
  • the lubricated mixture is passed through a roller compactor and the compacted ribbons are milled, as indicated at step 304.
  • FIG. 1 In the embodiment depicted in FIG.
  • vitamin D 3 granules containing about 2800 IU (or the equivalent of about 70 ⁇ g) of vitamin D 3 are then added and blended with the milled granules, with the vitamin D 3 granule charge quantitity adjusted based on both incoming granule assay and the yield from the roller compaction/milling step.
  • the resulting mixture is then compressed at step 306 to form tablets and the compressed tablets are de-dusted.
  • the resulting tablets may be packaged in suitable packaging, including for example moisture-proof and light-tight blister packs or bottles.
  • Vitamin D 3 (cholecalciferol) and vitamin D 2 (ergocalciferol) are water insoluble, hydrophobic compounds with a melting point of about 84 °C and about 115 °C, respectively. These compounds are also highly prone to oxidation and are photolabile, breaking down into various degradation products. Vitamin D granule is also prone to segregation. The stability of vitamin D is thus affected by the extent and nature of processing as well as the storage conditions (e.g , exposure to light, high temperatures, and high relative humidity) of the vitamin D/bisphosphonate compositions. As a result, the desire to include vitamin D in the compositions of the present invention presents a particular challenge insofar as developing methods of manufacturing and storing vitamin D-containing compositions is concerned.
  • vitamin D/bisphosphonate compositions that have been formulated so as to reduce the degradation of the vitamin D, both during processing and during storage. There is also a need for methods of manufacturing such stable compositions. In addition, there is a need to develop methods of detecting or measuring the degradation of vitamin D in vitamin D- containing compositions, such as those of the present invention. In addition, because the level of a particular vitamin D degradant may be very small (on the order of nanograms), there is a need to develop methods of measuring or detecting degradation of vitamin D in vitamin-D containing compositions, such as those of the present invention, having a limit of quantitation (LOQ) sufficient to detect the amounts of vitamin D degradants.
  • LOQ limit of quantitation
  • the present invention also provides methods of manufacturing compositions comprising a bisphosphonate compound and a vitamin D compound that minimizes the loss of the vitamin D compound during manufacture.
  • the temperature during the manufacturing process is less than or equal to about 35 °C.
  • the temperature is between about 20 °C to about 30 °C.
  • the relative humidity during the manufacturing process is less than or equal to about 60% RH. In another embodiment, the relative humidity is between about 20% to about 40%.
  • controls may be placed on the starting moisture levels of not only the vitamin D components of the formulation, but also on any excipients that may be present.
  • the relative humidity is between about 25% to about 35%.
  • the present invention also encompasses methods of manufacture that comprise an additional drying step.
  • the compositions of the instant invention may be manufactured under different conditions (temperature and/or relative humidity) as described above, and the moisture content of the manufactured composition may be reduced by drying the composition.
  • the drying may involve drying (with, for example, heat) the compositions of the present invention after the solid dosage form has been created.
  • the drying may involve film coating of a solid dosage forms (e.g., tablets) of the compositions of the present invention.
  • the drying may also involve packaging the compositions of the present invention with appropriate amounts of dessicants or other moieties to reduce moisture content.
  • the drying may involve storing the compositions of the present invention in storage forms that reduce moisture and or light (e.g., aluminum blister packs, moisture-proof bottles).
  • vitamin D compounds used as a starting material may include a free flowing, stabilized granules of vitamin D.
  • the vitamin D granules used as a starting material in manufacturing methods of the present invention are Dry Vitamin D 3 100, Gelatin Coated, Pharmaceutical Grade, sold by BASF.
  • the particles of vitamin D are dissolved in medium chain triglycerides in droplets of 1-2 ⁇ m embedded in a starch-coated matrix of gelatin and sucrose.
  • the dissolved vitamin D can then be stabilized with t-butylhydroxytoluene (BHT).
  • BHT t-butylhydroxytoluene
  • the vitamin D granules contain sodium aluminum silicate as a flow aid.
  • the amount of vitamin D added to the composition may be need to be adjusted based the source of vitamin D and/or the potency of the vitamin D being added. For example, if Dry Vitamin D 3
  • the granules may have different potencies (e.g., 100,000 IU/g or 105,000 IU/g or 1 10,000 IU/g) which would require one to adjust the amount of granules added to the composition in order to achieve 2800 IU, or 5600 IU, of vitamin D in the composition.
  • the vitamin D contained in an embodiment of the present invention conforms to the acceptance criteria of the Ph. Eur. Cholecalciferol Concentrate (Powder Form) monograph. While at this time there is no USP monograph for a formulated vitamin D 3 product, an applicable Ph.Eur. monograph has been published.
  • the inactive ingredients in the compositions of the vitamin D compounds used in embodiments of compositions of the present invention are either compendial or food grade materials.
  • the alendronate used as a starting material is compendial grade alendronate sodium monohydrate, or compendial grade alendronate sodium trihydrate, obtained from Merck & Co., Inc.
  • commercially available vitamin D granules can possibly be used in the compositions of the present invention, such as those available from Roche, BASF, or Solvay.
  • kits for conveniently and effectively carrying out the methods in accordance with the present invention.
  • kits are especially suited for the delivery of solid oral forms such as tablets or capsules and in embodiments include a number of unit dosages a card having the dosages oriented in the order of their intended use.
  • An example of such a kit is a "blister pack.”
  • Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms.
  • a memory aid can be provided, for example in the form of numbers, letters, or other markings or with a calendar insert, designating the days in the treatment schedule in which the dosages can be administered.
  • placebo dosages or calcium or dietary supplements, either in a form similar to or distinct from the bisphosphonate and vitamin D unit dosages, can be included to provide a kit in which a dosage is taken every day.
  • these agents can be included as part of the kit.
  • the present invention also provides a detection method that was developed in order to measure the degradation products of the vitamin D 3 compounds of the present invention. Specifically.
  • ⁇ method of measuring the degradation of the pharmaceutical composition may comprise extracting the cholecalciferol from the composition into a first solution to form a second solution, separating a sample containing cholecalciferol from the second solution, and detecting the amount of cholecalciferol in the sample by subjecting the sample to reverse-phase HPLC separation.
  • the detection method of the present invention is carried out to detect about 2800 IU to about 5600 IU cholecalciferol per pharmaceutical composition. Additionally, the detection method has a limit of quantitation (LOQ) of cholecalciferol of less than about 9 ng/mL cholecalciferol.
  • the method utilizes a first solution which comprises water, alcohol, acetonitrile or mixtures thereof.
  • the first solution contains about 5% water and about 95% methanol.
  • An exemplary sample preparation may be extracted of 15 tablets containing 2800 IU of vitamin D each into about 50 mL of about 5% water and about 95% methanol.
  • the resulting solution may be stirred for about 10 minutes, sonicated for about 30 minutes, and then stirred for an additional 3 hours.
  • the separating of the samples may be carried out by centrifugation, which can be from about 5,000 ⁇ m to about 15,000 ⁇ m.
  • the column is a Phenomenex Phenosphere 8 ⁇ A ODS (1) column (150 x 4.6 mm, 3 ⁇ m), and the injection volume is 100 ⁇ L.
  • the samples are eluted down the column and then detected.
  • a 65-minute gradient may be used.
  • a detection wavelength of about 260 nm to about 265 nm may also be used.
  • the detecting step is accomplished at a reverse-phase HPLC column temperature of about 25°C.
  • a sample tray temperature of about 5°C may be used.
  • the detecting step comprises reverse-phase HPLC separation using an eluant of about 99% acetonitrile and about 1% of 0.025% phosphoric acid.
  • the reverse-phase HPLC column that may be used in the methods of the present invention include columns that are either only partially endcapped or not endcapped.
  • the endcapping process reduces the free silanol groups on the stationary phase, therefore, it affects the separation between pre-vitamin D and vitamin D peaks.
  • Attempts to use endcapped columns were unsuccessful in providing a peak resolution that was sufficient for the assay method of the present invention because any degradate eluting between the two actives would not be resolved and quantitated.
  • a vitamin D 3 isomer (0.96RRT) was observed as eluting between two actives found in the formulation. More method development using other endcapped columns all showed limited resolution between pre-vitamin D 3 and vitamin D 3 peaks.
  • a column with higher carbon loading has more C lg stationary phase; therefore, it interacts more strongly with the esters and retains the esters on the column for a longer period of time. Accordingly, in an embodiment of the methods of the present invention, a HPLC column having less than about 10% carbon loading may be used. Using a column with lower carbon loading reduced the interaction between the stationary phase and the esters, resulting in earlier elution of these peaks. Results showed that, for example, using a Platinum EPS C lg column with low carbon loading (5%), all esters were eluted before
  • both pre-vitamin D and vitamin D peaks can be quantitated to calculate the total amount of vitamin D in a sample.
  • the methods of the present invention are sufficiently sensitive and selective, with a sample of about 2800 IU cholecalciferol, to distinguish between cholecalciferol, pre-cholecalciferol, and their isomers, and to detect one or more cholecalciferol ester adducts, or one or more pre-cholecalciferol ester adducts.
  • Three types of potential vitamin D 3 degradation products have been observed in stability studies for the pharmaceutical compositions of the present invention, which are described below (including in Example 6).
  • the tablet composition that was studied comprises about 91.4 mg alendronate sodium, about 26.7 mg cholecalciferol granules, about 131.0 mg microcrystalline cellulose, about 62.4 mg lactose anhydrous, about 9.7 mg croscarmellose sodium, about 0.8 mg colloidal silicon dioxide, and about 3.1 mg magnesium stearate.
  • the structure of vitamin D 3 includes a conjugated triene, which undergoes a variety of thermal and photochemical isomerizations.
  • vitamin D 3 Five vitamin D 3 isomers have been identified in exemplary pharmaceutical compositions of the present invention (in this example, using vitamin D 3 (cholecalciferol)): pre-vitamin D 3 , trans-vitamin D 3 , and three additional isomers at 0.78RRT, 0.96RRT and 1.09RRT (which is a measure of retention time of the compound by high performance liquid chromatography (HPLC) as described below). Structures for some of these vitamin D 3 isomers are shown in FIG. 5. Structural conclusions are based on UV, MS, and in some cases NMR spectroscopy. Vitamin D and its isomer pre-vitamin D are known to interconvert thermally by a sigmatropic 1 ,7-hydrogen shift.
  • vitamin D assays when reported conventionally comprise the sum of both species. This is consistent with both USP and Ph.Eur. monographs for vitamin D 3 containing products, for example. Available stability data indicate that none of the other isomers will approach the ICH qualification threshold of 1.0% by weight at 24 months, stored at 25°C/60%RH in appropriate packages.
  • the most prominent degradation products appear to be vitamin D 3 esters formed by transesterification reactions of vitamin D 3 with the medium chain triglycerides (MCT) in the vitamin D 3 granules used in the compositions of the present invention. Structures for some of these vitamin D 3 ester adducts are also shown in FIG. 5. The predominant species correspond to n-octanoate (C 8 ) and n- decanoate (C 10 ) esters of vitamin D 3 .
  • the pre-vitamin D 3 ester adducts can be generated either by reaction of pre-vitamin D 3 with the triglycerides in the vitamin D 3 compound or by thermal conversion from the vitamin D 3 esters.
  • vitamin D can undergo autoxidation through induction by a free radical initiator or spontaneously in solid or solution phase to form a variety of products, some of which have been identified.
  • Representative characterization of vitamin D degradation (and, specifically, vitamin D 3 in this instance) in embodiments of compositions of the present invention confirms the autoxidative lability of vitamin D 3 in which vitamin D 3 was converted to an oil or amo ⁇ hous solid and exposed to temperatures from 20-40°C.
  • HPLC analysis showed extensive destruction of vitamin D 3 and the appearance of many unresolved degradation products exhibiting very low ultraviolet (UV) abso ⁇ tion. At longer exposure times, these abso ⁇ tions continued to decrease as further reaction occurred.
  • UV ultraviolet
  • Tritium labeled vitamin D 3 was utilized as a means of tracking degraded vitamin D 3 , independent of changes in UV abso ⁇ tion characteristics.
  • the radiolabeled vitamin D 3 was inco ⁇ orated into a formulation that modeled the vitamin D granules used in embodiments of compositions of the present invention, and was then analyzed for stability.
  • the antioxidant level in the model formulation was at a reduced level from antioxidant levels considered desirable for commercial formulations, in order to ensure that degradation occurred within a reasonable timeframe.
  • Samples were analyzed after 14 weeks at 40°C/75%RH and 70°C using liquid scintillation counting (LSC) and reverse-phase high performance liquid chromatography (RP-HPLC) with simultaneous UV and online radiodetection.
  • LSC liquid scintillation counting
  • RP-HPLC reverse-phase high performance liquid chromatography
  • the present invention also includes methods of measuring the pharmacokinetic parameters in mammals upon the administration of the compositions of the present invention.
  • the pharmacokinetic parameters that may be measured include, for example, total urinary excretion, urinary excretion, area under the serum-concentration-versus-time curve (AUC), steady state maximum plasma concentration (C max ), time of C max (T max ), and serum concentration median apparent half-life (t ⁇ 2 ) of a tablet, such as, for example, a tablet comprising about 70 mg alendronate and about 2,800 IU cholecalciferol.
  • compositions and methods of the present invention produce pharmaceutically effective levels of alendronate and cholecalciferol in the body (the latter as demonstrated by comparison to recommended daily amounts of a vitamin D compound in the compositions and methods of the present invention).
  • the present invention includes methods of measuring cholecalciferol in human serum after administration of a pharmaceutical composition comprising alendronate and cholecalciferol, the method comprising: (1 ) administering to a human a composition comprising alendronate and cholecalciferol; (2) obtaining from the human a plasma sample; (3) extracting the cholecalciferol from the plasma sample to form a first solution; (4) reacting the cholecalciferol in the first solution with a dienophile to form one or more diels-alder addition products of cholecalciferol; (5) separating the diels-alder addition products of cholecalciferol using high performance liquid chromatography (HPLC) separation; and (6) detecting an amount of cholecalciferol in the sample using mass spectroscopy.
  • HPLC high performance liquid chromatography
  • the dienophile comprises 4-phenyl- 1,2,4- triazoline-3,5-dione (P-TADO or PTAD).
  • the detecting step may be conducted in a positive ionization mode using a heated nebulizer probe, and may further comprise adding a deuterated internal standard cholecalciferol to each human plasma sample, and extracting, reacting, separating, and detecting the deuterated internal standard cholecalciferol along with the sample cholecalciferol.
  • This method has a limit of quantitation (LOQ) of cholecalciferol of less than about 0.5 ng/mL cholecalciferol when 1 mL of plasma is measured.
  • LOQ limit of quantitation
  • An embodiment of the present invention is a vitamin D/bisphosphonate composition wherein a plot of serum concentration of a mammal over 120 hours after administration of the composition yields at least one of the following: a least-squares (LS) mean AUC(o- ⁇ 2 o hr ) of cholecalciferol of about 296.4 ng.h/mL, wherein the pharmacokinetic parameters have been measured without taking into account baseline cholecalciferol serum concentrations; a least-squares (LS) mean AUC(o.
  • the composition comprises a bisphosphonate and cholecalciferol wherein a plot of plasma concentration a mammal over 120 hours after administration of the composition yields at least 5.
  • a least-squares (LS) mean for steady state maximum plasma concentration (C max ) of over 120 hours of about 5.9 ng/mL wherein the pharmacokinetic parameters have been measured without taking into account baseline cholecalciferol serum concentrations
  • a least-squares (LS) mean for steady state maximum plasma concentration (C max ) of about 4.0 ng/mL wherein the pharmacokinetic parameters have been measured by taking into account baseline cholecalcif
  • the0 composition has a plasma concentration median apparent half-life (t ⁇ / 2 ) of the cholecalciferol of the composition in mammals that is about 23.8 hours, and the pharmacokinetic parameters have been measured by taking into account baseline cholecalciferol serum concentrations using a subtraction of estimated baseline cholecalciferol procedure.
  • t ⁇ / 2 plasma concentration median apparent half-life
  • a 70 mg alendronate/2800 IU vitamin D 3 combination tablet according to the present invention was shown to be bioequivalent to a 70 mg alendronate tablet with respect to alendronate bioavailability; (2) the bioavailability of vitamin D 3 in the 70 mg alendronate/2800 IU vitamin D 3 combination tablet and in a tablet containing 2800 IU vitamin D 3 (without alendronate) was5 shown to be similar, and (3) a 70 mg alendronate/2800 IU vitamin D 3 combination tablet according to the present invention was shown to be generally well tolerated.
  • a finished drug product is a combination tablet containing alendronate sodium (about 70 mg anhydrous free acid equivalent) and vitamin D 3 (about 2800 I.U. (about 70 ⁇ g)), with ingredients identified in Table 1-1. All of the excipients are compendial and were selected to achieve maximum physical and chemical stability. Table 1-1
  • tablets comprising other relative weights of alendronate, on an alendronic acid active basis are prepared including, but not limited to, about 2.5 mg, 5 mg, 8.75 mg, 17.5 mg, 70 mg, 140 mg, 280 mg, 560 mg, or 1 120 mg per tablet.
  • tablets comprising other relative weights of vitamin D 3 per unit dosage are prepared including, but not limited to, about 1,400, 2,800, 5,600, 7,000 IU, 8,400 IU, 14,000 IU, 28,000, or 36,000 IU per tablet. Such tablets may be administered at intervals ranging from once-weekly to bi-monthly.
  • a composition comprising a bisphosphonate and vitamin D may be prepared using mixing and formulation techniques as described in this specification.
  • a composition containing about 35 mg of alendronate, on an alendronic acid active basis, and about 5,600 IU of vitamin D 3 may be prepared using the following relative weights of ingredients.
  • Granule contains approximately 100,000 IU per one gram; therefore 56 mg of the granule is equivalent to about 5600 IU.
  • the resulting dosage forms are used in accordance with the methods of the present invention for preventing, inhibiting, reducing or treating osteoporosis, for example.
  • dosage forms comprising other relative weights of alendronate, on an alendronic acid active basis are prepared including, but not limited to, about 2.5 mg, 5 mg, 8.75 mg, 17.5 mg, 70 mg, 140 mg, 280 mg, 560 mg, or 1120 mg per tablet.
  • dosage forms comprising other relative weights of vitamin D 3 per unit dosage are prepared including, but not limited to, about 1,400, 2,800, 5,600, 7,000 IU, 8,400 IU, 14,000 IU, 28,000, or 36,000 IU per dosage form. Such dosage forms may be administered at intervals ranging from once-weekly to bi-monthly. These dosage forms may be, for example, tablets or capsules
  • tablets comprising other relative weights of alendronate, on an alendronic acid active basis are prepared including, but not limited to, about 2.5 mg, 5 mg, 8.75 mg, 17.5 mg, 70 mg, 140 mg, 280 mg, 560 mg, or 1 120 mg per tablet.
  • tablets comprising other relative weights of vitamin D 3 per unit dosage are prepared including, but not limited to, about 1,400, 2,800, 5,600, 7,000 IU, 8,400 IU, 14,000 IU, 28,000, or 36,000 IU per tablet. Such tablets may be administered at intervals ranging from once-weekly to bi-monthly.
  • Vitamin D 3 Pulpose Form
  • vitamin D 3 cholecalciferol
  • a two-period, crossover, study in 14 healthy, nonpregnant women and men, aged 18 to 85 was conducted. Subjects received one alendronate 70-mg tablet in each period. A single dose of vitamin D 3 5600 IU was coadministered with the alendronate tablet in one of the two periods, based on a computer-generated patient allocation schedule.
  • the vitamin D 3 powder was reconstituted in 60 mL of plain tap water and administered to the subject with the alendronate tablet (Treatment A).
  • the vitamin D 3 bottle was rinsed and filled with 60 mL of plain tap water 3 times, each then administered to the subject. Therefore, a total volume of 240 mL of plain tap water was administered with the vitamin D 3 .
  • a 240-mL volume of plain tap water was administered with the dose (Treatment B). At least a 14-day washout separated each period.
  • the treatment schematic and allocation are in Table 4- 1.
  • Composition (per bottle): Dry vitamin D 3 Type 100 CWS/HP 51.96 mg f Equivalent to 5600 IU.
  • Urine specimens for alendronate assay were collected for pharmacokinetic analyses over the following intervals: -2 to 0 hour predose, 0 to 8 hours postdose, 8 to 24 hours postdose, and 24 to 36 hours postdose.
  • the urine collection obtained over the 2-hour period just prior to study drug administration provided a baseline alendronate determination.
  • All urine specimens were collected in preweighed polypropylene containers.
  • For the 0- to 8-, 8- to 24-, and 24- to 36-hour postdose urine collections 12.5 grams of boric acid were added to the containers as a preservative at the beginning of the timed interval. At the end of each timed collection interval, the entire urine collection was weighed, the specific gravity measured, and the net volume determined.
  • the urine specimen was acidified in situ.
  • the analytical method for the determination of alendronate in human urine involved 3 distinct operations: (1) isolation of the analyte and an internal standard (pamidronate) from urine, (2) formation of strongly fluorescent derivatives, and (3) HPLC separation and fluorescence detection of the resulting derivatives.
  • Alendronate and the internal standard were co-precipitated from urine with naturally present phosphates by the addition of calcium chloride and sodium hydroxide.
  • DEA anion-exchange diethylamine
  • Alendronate was eluted from the DEA cartridge by a solution of 0.20 M sodium citrate and 0.20 M sodium phosphate dibasic (adjusted to pH 9). Alendronate was derived with 2,3-naphthalenedicarboxyaldehyde in the presence of N-acetyl-D- penicillamine at room temperature. The derivative was then applied to a non-silica-based polymeric column composed of the copolymer of styrene and divinyl benzene. The mobile phase was initially composed of 85% 0.025 M sodium citrate, 0.025 M sodium phosphate dibasic (pH 6.95), and 15% acetonitrile at a flow rate of 1 mL/min.
  • IU vitamin D 3 and the 70-mg alendronate tablet alone was performed using an analysis of variance (ANOVA) model suitable for a 2-period, crossover design.
  • the ANOVA model contained factors for sequence, subject (sequence), period, and treatment. Total urinary excretion was log-transformed. Results from the Shapiro- Wilk test for normality, along with plots of residuals from the model, did not suggest any departure from the assumptions of the ANOVA model.
  • a 95% Cl was computed, based upon the t-distribution, for the GMR for total urinary excretion.
  • the posterior probability that the true GMR is above the clinically important bound of 0.50 was also calculated.
  • One subject was dropped from the above analysis since this particular subject had urinary alendronate concentrations for all 3 collection intervals (0 to 8, 8 to 24, and 24 to 36 hours) below limit of quantification for both treatments. Due to a slight imbalance in the ordering of the treatment sequences, the least-squares means for the total urinary excretion are reported. The data from that subject was excluded from analysis. The least-square means were obtained by back-transformation from the ANOVA model.
  • Table 4-5 displays the total urinary excretion of alendronate as a 70-mg alendronate tablet plus vitamin D 3 and the 70-mg alendronate tablet for each subject. Summary statistics along with the GMR, with its corresponding 95% Cl, for total urinary excretion of alendronate are in Table 4-6. The least-squares geometric mean for total urinary excretion was 183.61 for the 70-mg alendronate tablet plus 5600 IU vitamin D 3 and 157.97 ⁇ g for the 70-mg alendronate tablet alone.
  • Vitamin D 3 (Contained in an Alendronate/Vitamin D Tablet) on Alendronate Abso ⁇ tion
  • fourteen healthy adult subjects (6 men, 8 women, ages 33 - 61 yr.) were administered single 70-mg tablets of alendronate, without vitamin D 3 , and together with a powdered dose of vitamin D 3 , (5600 IU) suspended in 240 mL of water. This study was of an open, randomized, crossover two-way design.
  • the pu ⁇ ose of the study was to obtain a preliminary estimate of the relative bioavailability of alendronate following a 70-mg tablet administered with vitamin D 3 , relative to alendronate administered without vitamin D 3 .
  • Alendronate was administered orally as a 70-mg tablet in each of the two periods. In one period, the tablet was administered with vitamin D 3 powder reconstituted in plain tap water and in the alternate period the tablet was taken alone with plain tap water.
  • Urine was collected for two hours preceding and 36 hours following each dose of alendronate for analytical determination of excreted alendronate. Relative bioavailability was estimated based on total urinary recovery of alendronate over the 36 hours post-dose.
  • Urinary recovery of alendronate following the dose of 70-mg alendronate without vitamin D 3 was 202 ⁇ g with a 90% Cl of (126 ⁇ g, 279 ⁇ g), recoveries following the 70-mg dose administered together with vitamin D 3 , averaged 238 ⁇ g with a 90% Cl of (159 ⁇ g, 316 ⁇ g).
  • the geometric mean ratio (90% Cl) was estimated at 1.18 (0.80, 1.74).
  • Vitamin D 3 and Alendronate The stability of a composition of the invention in the form of a combination tablet containing alendronate sodium (70 mg anhydrous free acid equivalent) and vitamin D 3 (2800 I.U./70 ⁇ g) has been studied.
  • Table 6-1 contains a the tablet composition of an embodiment of an alendronate/vitamin D combination tablet. All of the excipients are compendial grade and were selected to achieve maximum physical and chemical stability.
  • the alendronate assay and dissolution methods may employ reversed-phase HPLC with pre-column 9-fluorenylmethyl chloroformate (FMOC) derivatization, similar to methods already reported for FOSAMAX ® tablets.
  • the vitamin D 3 assay and degradates method may also be a reversed-phase, gradient HPLC method (RP-HPLC) capable of resolving and quantitating vitamin D 3 and multiple potential degradation products of vitamin D 3 .
  • the vitamin D 3 content uniformity and dissolution assays also employ reversed-phase HPLC.
  • the dissolution method may use a surfactant medium (1% SDS) due to the poor aqueous solubility of vitamin D 3 Due to the low vitamin D 3 potency (70 ⁇ g) of the combination tablet, one may use three tablets to 500 mL of medium to obtain a suitable signal. Fifty-two weeks of assay and degradate data are provided below for a batch of the combination tablets stored at 30°C/65%RH and 40°C/75%RH (See Tables 6-2 and 6-3). These data demonstrate the acceptable stability of an embodiment of a compositions of the present invention, although the data generated do indicate that there is slight degradation of vitamin D 3 . Greater degradation is found at higher temperatures in the aluminum blisters and the HDPE bottles without desiccant. Table 6-2: Summary of Vitamin D 3 Stability Assay Results: Alendronate Sodium 70 m Vitamin D 2800 I.U. Combination Tablets
  • Table 6-3 Summary of Vitamin D 3 Degradation Stability Results: Alendronate Sodium 70 mg/Vitamin D 3 2800 I.U. Combination Tablets Foil to Foil Aluminum Blister
  • Part I included Treatments A and B
  • Part II included Treatments A and C.
  • Treatments consisted of the following: Treatment A - single dose of a 70 mg alendronate/2800 IU vitamin D 3 combination tablet according to Table 7-3 below; Treatment B - single dose of a 70 mg alendronate tablet according to Table 7-2 below; Treatment C - a single dose of a 2800 IU vitamin D tablet (containing placebo excipients to replace alendronate) according to Table 7-4 below.
  • urine was collected starting 2 hours prior to, and over the 36 hours following, dose administration in each period for determination of total urinary excretion of alendronate.
  • Part II blood samples were collected for serum vitamin D 3 determination in each period at -24, -18, -12, and -6 hours predose, at 0 hour (just prior to drug administration), and at selected times over the 120 hours following dose administration.
  • Part I of the study evaluated the bioequi valence of alendronate in the 70 mg alendronate/2800 IU vitamin D 3 combination tablet according to Table 7-3 below, and a 70-mg alendronate tablet according to Table 7-2 below.
  • Part II of the study evaluated serum pharmacokinetics (AUCo- ⁇ o hx , C max ) of vitamin D 3 obtained following administration of the 70 mg alendronate/2800 IU vitamin D 3 combination tablet and the 2800 IU vitamin D 3 tablet.
  • the 2800 IU vitamin D 3 tablet contained 2800 IU vitamin D 3 and the inactive excipients in the alendronate/vitamin D 3 combination tablet.
  • the primary pharmacokinetic parameter in Part I was total urinary excretion of alendronate from 0 to 36 hours following oral-dose administration. Determination of total urinary excretion of alendronate was consistent with previous studies characterizing the oral bioavailability of alendronate through urinary excretion, since plasma concentrations following oral administration are low and difficult to detect.
  • the primary pharmacokinetic parameters in Part II were AUC 0 .i 20hr and C max of vitamin D 3 .
  • Serum vitamin D 3 concentrations for 24 hours prior to study drug administration were collected to provide an indication of the behavior of endogenous levels of vitamin D 3 over 24 hours in a controlled environment. Since vitamin D 3 is synthesized in the skin via exposure to ultraviolet light, subjects were housed in the study unit and not exposed to direct sunlight during the duration of the pharmacokinetic-sampling periods (e.g., for 144 hours, from 24 hours pre-dose until 120 hours postdose).
  • Subjects were required to wear sunblock (SPF 45) and limit sun exposure throughout the entire study including the washout period. Subjects were also restricted from eating foods known to be high in vitamin D 3 (e.g. , salmon, herring, mackerel, cod, tuna fish, swordfish oysters, and sardines) as well as foods known to be supplemented with vitamin D 3 (e.g., certain cereals, fortified milk and some yogurts).
  • Vitamin D 3 e.g., salmon, herring, mackerel, cod, tuna fish, swordfish oysters, and sardines
  • Each subject in Part I received a single oral dose of 70 mg alendronate/2800 IU vitamin D 3 combination tablet and a single oral dose of 70 mg alendronate in a randomized, crossover fashion.
  • Subjects in Part II received a single oral dose of 70 mg alendronate/2800 IU vitamin D 3 combination tablet and a single oral dose of a 2800 IU vitamin D 3 tablet in a randomized crossover fashion.
  • Doses were administered with 240 mL of plain tap water following an overnight fast (except water), beginning at 2100 hours the evening prior to dosing.
  • Subjects were instructed not to lie down and to remain upright (at least at a 45° angle, sitting or standing) between drug administration and the defined meal.
  • Subjects fasted until the standard meal, which was administered at 2 hours post-dose.
  • the procedures for administration of the alendronate/vitamin D 3 combination tablet were the same as those for alendronate.
  • the compositions administered in the study are as set forth in the tables 7-1 through 7-4 below: Table 7-1 Clinical Supplies
  • the area under the serum concentration-versus-time curve from 0 to 120 hours postdose was calculated using the unadjusted concentrations of vitamin D 3 (C,) by the trapezoidal method to the last sample collection.
  • Samples with concentrations lower than the assay's limit of quantitation (LOQ) were assigned a value of zero for calculation pu ⁇ oses.
  • Maximum observed concentrations (C max ) and time of C max (T max ) were obtained by inspection of the measured concentrations of vitamin D 3 in serum and the actual recorded times of sample collection.
  • Concentration profiles of vitamin D 3 in serum were also measured in three different ways, two of which account for baseline vitamin D 3 serum concentrations in the manner discussed in below.
  • AUCo-i20hr, Cmax and Tma were calculated in the same manner.
  • the bioavailability of the 70 mg alendronate tablet/2800 IU vitamin D 3 combination tablet relative to the 70 mg alendronate alone tablet was estimated using the GMR for the total urinary excretion of alendronate from the alendronate/vitamin D 3 combination tablet versus the 70-mg alendronate-alone tablet.
  • the relative bioavailability of the 70 mg alendronate/2800 IU vitamin D 3 combination tablet with respect to 2800-IU vitamin D 3 tablet alone was estimated using the GMR (alendronate plus vitamin D 3 /vitamin D 3 alone) for AUCo.i20hr and Cmax-
  • the vitamin D 3 single-dose pharmacokinetics following the administration of 70 mg alendronate/2800 IU vitamin D 3 combination tablet and 2800 IU vitamin D 3 tablet were compared using three different approaches. In the first approach, the vitamin D 3 pharmacokinetics for endogenous vitamin D 3 serum concentrations were compared following the administration of the two treatments.
  • the vitamin D 3 single-dose pharmacokinetics (AUC 0 . ⁇ 2 o hr and C ma ⁇ ) for endogenous vitamin D 3 serum concentrations following the ' administration of 70 mg alendronate/2800 IU vitamin D 3 combination tablet and 2800 IU vitamin D 3 tablet were compared using an ANOVA model appropriate for a 2-period, crossover design. Appropriate transformations were used on the pharmacokinetic parameters (i.e., log-transformation for AUC 0 .i20hr, C ma , ranks for T max , and inverse for apparent ⁇ ). Back-transformed summary statistics and inferential results were reported. The assumptions of the ANOVA model were tested for normality.
  • C, C, + Cj 4- Ae ⁇ kd l ' ⁇ '- ) + Be 'k “ ( "' i " ) -(A + B)e ' ⁇ ( ' ⁇ '” « )
  • t time relative to dose administration
  • C m Slope of predicted baseline
  • A, B, k d , e i and k a are parameters of a two-compartment model with first order abso ⁇ tion and t ⁇ ag is the individual delay in abso ⁇ tion following oral administration of vitamin D 3 .
  • Pharmacokinetic parameters measured using this method (AUCo-nohr, Cma , Tma ) were calculated in the same manner as described using the first measurement method. Summary statistics for total urinary excretion of alendronate over 36 hours are presented in Table 7-5 below.
  • the LS means for total urinary excretion of alendronate were 197.5 and 191.9 ⁇ g for the 70 mg alendronate/2800 IU vitamin D 3 combination tablet and 70-mg alendronate-alone tablet, respectively.
  • the GMR and corresponding 90% Cl for the total urinary excretion of alendronate was 1.03 (0.91, 1.17).
  • the 90% Cl fell within the pre-specified bioequivalence bounds of (0.80, 1.25).
  • the LS means for vitamin D 3 AUC 0 .i20hr (not considering endogenous vitamin D 3 serum concentrations) were 296.4 and 337.9 ng h/mL for the 70 mg alendronate/2800 IU vitamin D 3 combination tablet and 2800 IU vitamin D 3 tablet, respectively (Table 7- 6).
  • the AUCo-i 20hr GMR (alendronate plus vitamin D 3 combination tablet/vitamin D 3 tablet) was 0.88, with a 90% Cl of (0.81 , 0.95).
  • Table 7-8 displays the results of statistical analysis for the vitamin D 3 T max , obtained from serum profiles not considering endogenous vitamin D 3 serum concentrations.
  • the median T max for vitamin D 3 with and without alendronate was 12.0 and 9.0 hours, respectively. No significant between- treatment difference was observed (p-value>0.200).
  • the LS means for vitamin D 3 AUC 0 . ⁇ 2 ohr were 297.5 and 336.7 ng h/mL for 70 mg alendronate/2800 IU vitamin D 3 combination tablet and 2800 IU vitamin D 3 tablet, respectively (Table 7- 9).
  • the AUCo-i20hr GMR (alendronate plus vitamin D 3 combination tablet/vitamin D 3 tablet) was 0.88, with a 90% Cl of (0.82, 0.95).
  • the LS means C max of vitamin D 3 were 5.9 and 6.6 ng/mL for 70 mg alendronate/2800 IU vitamin D 3 combination tablet and 2800-IU vitamin D 3 tablet, respectively, as shown in Table 7- 10 below.
  • the C max GMR 70 mg alendronate/2800 IU vitamin D 3 combination tablet 2800 IU vitamin D 3 tablet
  • the 90% Cl for AUC 0 -i20hr and Cmax GMR with pre-dose vitamin D 3 concentration at time 0 as a covariate, fell within the pre-specified bioequivalence bounds of (0.80, 1.25).
  • the LS means C max of vitamin D 3 measured using model-based vitamin D 3 baseline concentrations, were 4.0 and 4.6 ng/mL for the 70 mg alendronate/2800 IU vitamin D 3 combination tablet and 2800 IU vitamin D 3 tablet, respectively, as shown in Table 7-12.
  • the C ma GMR 70 mg alendronate/2800 IU vitamin D 3 combination tablet/2800 IU vitamin D 3 tablet
  • the 90% Cl for C ⁇ GMR measured using model-based vitamin D 3 baseline concentrations fell within the pre-specified bioequivalence bounds of (0.80, 1.25).
  • Table 7-13 displays the results of statistical analysis for vitamin D 3 T max obtained from profiles measured using model-based baseline vitamin D 3 concentrations. The median T max for vitamin D 3 with or without alendronate was 12.0 and 9.0 hours, respectively. No significant between-treatment difference was observed (p-value>0.200).
  • EXAMPLE 8 Degradation Detection Method A method has been developed for the composite assay of vitamin D 3 in combination alendronate/vitamin D 3 tablets (70 mg alendronate/2800 IU vitamin D 3 ). Vitamin D 3 is extracted from 15 tablets in about 50 mL of 5% water/ 95% methanol diluent. The solution is stirred for 10 minutes, sonicated for 30 minutes, and stirred for an additional 3 hours. Samples are centrifuged and 100 ⁇ L of the supernatant are injected onto a Phenomenex Phenosphere 8 ⁇ A ODS (1) column (150 x 4.6 mm, 3 ⁇ m) for reversed phase HPLC analysis.
  • the method is a 65-minute gradient method with a detection wavelength at 265 nm. Both pre-vitamin D 3 and vitamin D 3 peaks are quantitated and summed to calculate the total amount of vitamin D 3 in the sample.
  • the method was validated for satisfactory specificity, linearity, recovery, precision, reproducibility, solution stability, sensitivity, and robustness.
  • the limit of quantitation was determined by injecting different concentrations of vitamin D 3 solution and selecting the lowest concentration with a signal-to-noise ratio above 10.
  • the LOQ was determined as about 9 ng/mL (injection volume 100 ⁇ L), which is 0.04% of the method concentration with an average signal-to-noise ratio of 11.1 for ten replicate determinations.
  • Alendronate and vitamin D tablets or other solid dosageformulations containing about 70 mg of alendronate, on an alendronic acid active basis, and about 5,600 IU of vitamin D may be prepared. (See Examples 1, 2, and 3).
  • the tablets or other solid dosage formulations may be orally administered to a subject once-weekly, i.e., preferably about once every seven days (for example, every Sunday), for a period of at least one year.
  • This method of administration is expected to be useful and convenient for treating or preventing osteoporosis while providing vitamin D nutrition.
  • This method is also expected to be useful for improving subject acceptance and compliance, and ensuring that all subjects taking a bisphosphonate receive adequate vitamin D nutrition.
  • alendronate and vitamin D tablets or other solid dosage formulations containing about 70 mg of alendronate, on an alendronic acid active basis, and about 2,800 IU of vitamin D may be prepared.
  • the tablets or other solid dosage formulations may be orally administered to a subject once-weekly, / ' . e. , preferably about once every seven days (for example, every Sunday), for a period of at least one year.
  • This method of administration is expected to be useful and convenient for treating or preventing osteoporosis while providing vitamin D nutrition.
  • This method is also expected to be useful for improving subject acceptance and compliance, and ensuring that all subjects taking a bisphosphonate receive adequate vitamin D nutrition.
  • alendronate and vitamin D tablets or other solid dosage formulations containing about 35 mg to about 70 mg of alendronate, on an alendronic acid active basis, and 2,800 IU of vitamin D may be prepared.
  • the tablets or other solid dosage formulations may be orally administered to a human subject once- weekly, i.e., preferably about once every seven days (for example, every Sunday), for a period of at least one year.
  • This method of administration is expected to be useful and convenient for treating or preventing osteoporosis while providing vitamin D nutrition.
  • This method is also expected to be useful for improving subject acceptance and compliance, and ensuring that all subjects taking a bisphosphonate receive adequate vitamin D nutrition.
  • Alendronate and vitamin D tablets or other solid dosage.formulations containing about 280 mg of alendronate, on an alendronic acid active basis, and about 5,600 IU of vitamin D may be prepared. (See, e.g., Examples 2 and 3).
  • the tablets or other solid dosage.formulations may be orally administered to a subject once- weekly, i.e., preferably about once every seven days (for example, every Sunday), for a period of at least one to six months. This method of administration is expected to be useful and convenient for treating Paget's disease while providing vitamin D nutrition. This method is also expected to be useful for improving subject acceptance and compliance, and ensuring that all subjects taking a bisphosphonate receive adequate vitamin D nutrition.
  • alendronate and vitamin D tablets or other solid dosage.formulations containing about 280 mg of alendronate, on an alendronic acid active basis, and about 2,800 IU of vitamin D may be prepared. (See, e.g., Example 3).
  • the tablets or other solid dosage.formulations may be orally administered to a subject once-weekly, i.e., preferably about once every seven days (for example, every Sunday), for a period of at least one to six months.
  • This method of administration is expected to be useful and convenient for treating Paget's disease while providing vitamin D nutrition.
  • This method is also expected to be useful for improving subject acceptance and compliance, and ensuring that all subjects taking a bisphosphonate receive adequate vitamin D nutrition.
  • Alendronate and vitamin D tablets or other solid dosage formulations containing about 280 mg of alendronate, on an alendronic acid active basis, and 5,600 IU or 2,800 IU of vitamin D may be prepared.
  • the tablets or other solid dosage formulations may be orally administered to a subject once-weekly, i.e., preferably about once every seven days (for example, every Sunday). This method of administration is expected to be useful and convenient for treating metastatic bone disease while providing vitamin D nutrition. This method is also expected to be useful for improving subject acceptance and compliance, and ensuring that all subjects taking a bisphosphonate receive adequate vitamin D nutrition.

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Abstract

L'invention concerne des compositions et des procédés pour prévenir, inhiber, réduire et traiter des états et des troubles associés à une résorption osseuse anormale chez les mammifères, y compris, par exemple, l'ostéoporose. Dans certains modes de réalisation, les compositions contiennent une quantité pharmaceutiquement efficace d'alendronate et de vitamine D3 pour un dosage hebdomadaire. Des compositions et des procédés de l'invention fournissent un apport de vitamine D durant le traitement au bisphosphonate pour promouvoir la formation et la minéralisation osseuses normales, tout en minimisant l'occurrence ou l'éventualité de complications associées à l'insuffisance en vitamine D, telle que l'hypocalcémie et l'ostéomalacie. La présente invention porte également sur des procédés pour produire les compositions de la présente invention, pour mesurer la stabilité et la dégradation de ces compositions, et pour mesurer les niveaux de plasma sanguins de la vitamine D.
EP04776045A 2004-05-19 2004-05-19 Combinaison pour inhiber la resorption osseuse comprenant un bisphosponate (alendronate) et une vitamine d (cholecalciferol) Withdrawn EP1758594A1 (fr)

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US7745226B2 (en) 2005-04-06 2010-06-29 Quest Diagnostics Investments Incorporated Methods for detecting vitamin D metabolites
KR100822133B1 (ko) * 2006-11-06 2008-04-15 한미약품 주식회사 비타민 ｄ 또는 이의 유도체의 고체분산체 및비스포스포네이트를 포함하는, 골다공증 예방 또는 치료용복합제제
US20100179110A1 (en) 2006-12-20 2010-07-15 Mostafa Akbarieh Composition Containing a Bisphosphonic Acid in Combination with Vitamin D
JP2010513475A (ja) * 2006-12-20 2010-04-30 ランドシュタイナー サイエンティフィック エッセ アー デ シー ヴイ リセドロネートおよびビタミンｄ組成物
CN101444521B (zh) * 2007-11-26 2012-07-04 信谊药厂 包含阿仑膦酸钠和胆维丁的药物制剂
US7972868B2 (en) 2007-11-28 2011-07-05 Quest Diagnostics Investments Incorporated Methods for detecting dihydroxyvitamin D metabolites by mass spectrometry
KR101102364B1 (ko) * 2009-09-18 2012-01-03 한림제약(주) 비스포스포네이트 유도체 및 고용량의 콜레칼시페롤을 포함하는 약학 조성물
US7977117B2 (en) 2009-12-03 2011-07-12 Quest Diagnostics Investments Incorprated Vitamin D metabolite determination utilizing mass spectrometry following derivatization
CA2783797C (fr) 2009-12-11 2021-06-08 Quest Diagnostics Investments Incorporated Determination par spectrometrie de masse de vitamine d non metabolisee, non derivee
CA2783708C (fr) 2009-12-11 2018-09-18 Quest Diagnostics Investments Incorporated Spectrometrie de masse de composes steroidiens dans des echantillons multiplexes
CN102210697B (zh) * 2010-04-02 2013-05-22 秦引林 用于治疗代谢性骨病的药物组合
KR101230178B1 (ko) * 2010-06-10 2013-02-06 주식회사 네비팜 골다공증 예방 또는 치료용 조성물 및 이의 제조방법
WO2016065052A1 (fr) 2014-10-22 2016-04-28 Extend Biosciences, Inc. Conjugués insuline vitamine d
EP3220961B1 (fr) 2014-10-22 2023-07-05 Extend Biosciences, Inc. Conjugués de vitamine d thérapeutiques
US11450405B2 (en) * 2018-10-18 2022-09-20 Fresenius Medical Care Holdings, Inc. Techniques for modeling parathyroid gland functionality and calcimimetic drug activity
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