JP2006514695A - Method for enhancing the overall utilization efficiency of alendronate or other bisphosphonates by pre-dose administration of vitamin D derivatives - Google Patents

Abstract

The present invention is a method for increasing the bioavailability of bisphosphonates, wherein an effective pre-dose vitamin D derivative, such as alpha calcidol or calcitriol, is administered and, after an interval time, a therapeutic dose A method comprising administering, for example, alendronate. The invention also relates to the use of vitamin D derivatives and bisphosphonates for the manufacture of a medicament for the treatment of osteoporosis, metastatic bone disease, Paget's disease and the like.

Description

  This application claims the priority of US Provisional Patent Application Nos. 60 / 433,685 (filed December 16, 2002) and 60 / 460,206 (filed April 2, 2003), both of which are All of which are hereby incorporated by reference.

TECHNICAL FIELD The present invention relates to a recipient by administering a pre-dosage of α-calcidol (1α-hydroxyvitamin D ₃ ) to the recipient at least 6 hours prior to administering the therapeutic bisphosphonate. This relates to a method for increasing the bioavailability of bisphosphonates such as alendronate.

The present invention relates to a method for increasing the bioavailability of a bisphosphonate such as alendronate by administering a pre-dose calcitriol (1α, 25-dihydroxyvitamin D ₃ ) to a recipient, In this method, the calcitriol is delayed in release from about 3 to about 5 hours from immediate release after administration, and the therapeutic dose of bisphosphonate is administered about 6 hours or more after the pre-dose of calcitriol is administered. To do.

BACKGROUND OF THE INVENTION Treatment of osteoporosis, metastatic bone disease, and Paget's is advantageous by controlling gastric release and improving multi-dose delivery technology. Bisphosphonates, such as, for example, sodium alendronate, risedronate, etidronate, zoledronic acid and tiludronate are commonly prescribed to treat these diseases. Despite their advantages, bisphosphonates are very deficient in oral bioavailability. Alendronate has a bioavailability of less than 1%. Gert, BJ, Holland, SD, Kline, WF, Matuszewski, BK, Freeman, A., Quan, H., Lasseter, KC, Mucklow, JC, Porras, AG “Studies of The Oral Bioavailability of Alendronate,” Clinical Pharmacology & Therapeutics 1995, vol.58, pp.288-298. Its absorption is inhibited by food and beverages except for water (Id). A side effect experienced by patients taking alendronate is inflammation of the gastrointestinal epithelial mucosa (Liberman, UA, Hirsch, LJ; “Esophagitis and Alendronate” N. Engl. J. Med., 1996, vol. 335, pp.1069-70). This stimulation leads to a more serious condition. (Physicians' Desk Reference, Fosamax, Warnings.)

  Alendronate is optimally absorbed from the upper duct (duodenum and pylor) (Lin, JH “Bisphosphonates: A Review of Their Pharmacokinetic Properties” Bone, 1996, vol.18, pp.75-85; Porras, AG, Holland, SD, Gertz, BJ, “Pharmacokinetics of Alendronate,” Clin. Pharmacokinet 1999, vol. 36, pp. 315-328 .. Alendronate is optimally absorbed at a pH of about 6. Gert, BJ, Holland, SD, Kline, WF, Matuszewski, BK, Freeman, A., Quan, H., Lasseter, KC, Mucklow, JC, Porras, AG “Studies of The Oral Bioavailablity of Alendronate,” Clinical Pharmacology & Therapeutics, 1995, vol.58, pp.288-298). As discussed in commonly assigned US Pat. No. 6,476,006, by modulating the gastric release of alendronate, the drug can be prolonged into the duodenum and bulges that are part of the stomach. Can be delivered over time, resulting in increased bioavailability and thereby allowing for lower doses and less irritation.

In addition to bisphosphonate therapy, views in the treatment of osteoporosis include hormone replacement therapy and calcium replacement therapy (Kleerekoper, M., Schein, JR “Comparative Safety of Bone Remodeling Agents with A Focus on Osteoporosis Therapies,” J. Clin, Pharmacol. 2001, vol.41, p.239). An increase in the amount of calcium may improve the bone mineralization status of osteoporotic patients. Over the past 30 years, supplementing calcium with vitamin D or vitamin D derivatives such as calcitriol has been selected to treat osteoporosis problems (Cannigia, A., Vattimo, A. “Effects of 1,25 Dihydroxycholecalciferol on Calcium Absorption in Postmenopausal Osteoporosis, ”Clin, Endocrinol., 1979, vol.11, p.99; Riggs, BL, Nelson, KL“ Effect of Long Term Treatment with Calcitriol on Calcium Absorption and Mineral Metabolism in Postmenopausal Osteoporosis, J. Clin, Endocrinol. Metab. 1985, vol.61, p.457; Reid, IR, Ames, RW, Evans, MC, Gamble, GD, Sharpe, SJ “Long Term Effects of Calcium Supplementation on Bone Loss and Fracture in Post-menopausal Women, a Randomized Controlled Trial, Am. J. Med., 1995, vol.98, p.331). Calcitriol (1,25-dihydroxyvitamin D ₃ ) is a vitamin D derivative that is active in regulating the absorption of calcium from the gastrointestinal tract (Physicians' Desk Reference, Rocaltrol Oral Solution, Description). Calcitriol is a biologically active metabolite of vitamin D _3, to stimulate intestinal calcium transport (Merck Index, 13th Edition, 1643). Calcitriol is rapidly absorbed from the intestinal tract and reaches peak plasma concentrations within 3-6 hours after ingestion (Physicians' Desk Reference, Rocaltrol Oral Solution, Pharmacokinetics). Calcitriol has been used to treat calcium deficiency.

  Over the past few years, successful trials have been conducted. It was confirmed that there was a synergistic effect in using the combination therapy of calcitriol and bisphosphate (Frediani, B., Allegri, A., Bisogno, S., Marcolongo, R. “Effects of Combined Treatment with Calcitriol Plus Alendronate on Bone Mass and Bone Turnover in Postmenopausal Osteoporosis-Two Years of Continuous Treatment, ”Clin. Drug Invest. 1998, vol.15, p.223; Masud, T., Mulcahy, B., Thompson, AV , Donnolly, S., Keen, RW, Doyle, DV, Spector, TD, “Effects of Cyclical Etidronate Combined with Calcitriol Versus Cyclical Etidronate Alone on Spine and Femoral Neck Bone Mineral Density in Postmenopausal Women,” Ann. Rheum. Dis., 1998, vol.57, p.346; Malvolta, M., Zanardi, M., Veronesi, M., Ripamonti C., Gnudi, S. “Calcitriol and Alendronate Combination Treatment in Menopausal Women with Low Bone Mass,” Int. J. Tissue React. 1999, vol.21, p.51; Nuti, R., Martini, G., Giovani, S., Valenti, R. “Effect of Treatment wi th Calcitriol Combined with Low-dosage Alendronate in Involutional Osteoporosis, “Clin, Drug Invest., 2000, vol. 19, p. 56). The purpose of combination therapy is to improve treatment outcome and lower the dose of the two drugs. In these trials, the drugs are administered individually and simultaneously. International publication WO2001 / 028564 discloses a combination therapy comprising calcitriol and alendronate in a specific ratio range of the two drugs.

  While the benefits of combination therapy in the treatment of osteoporosis, metastatic bone disease and Paget's disease are recognized, and there are advances in controlled release systems for multidose medications, to fully realize the benefits of combination therapy There is a need for improved controlled release systems and improved dosing regimes for bisphosphonates and calcium transport stimulants.

SUMMARY OF THE INVENTION In one aspect, the present invention is a method for increasing the bioavailability of bisphosphonates, comprising vitamin D derivatives, particularly calcitriol, alpha-calcidol, 24,25-dihydroxyvitamin D ₃ and calcifediro. And administering a therapeutic dose of bisphosphonate, in particular alendronate, risedronate, etidronate, zoledronate, and tiludronate, after an interval time, particularly from about 6 hours to about 14 hours. A method comprising the steps of:

  In another aspect, the interval time is approximately equal to the amount of time required to reach the maximum plasma calcium level after administration of the vitamin D derivative. The present invention specifically provides a pre-dose of vitamin D derivative to be administered at bedtime and a pre-dose of bisphosphonate to be administered before meals. The interval time may be achieved by changing the time of administering the vitamin D derivative, changing the time of administering the bisphosphonate, and by using a release delay technique known in the pharmaceutical industry.

  In another aspect, the invention provides a medicament for treating osteoporosis, metastatic bone disease, and Paget's disease by administering an effective pre-dose vitamin D derivative prior to administering bisphosphonate. Related to the use of bisphosphonates for manufacturing.

  In another aspect, the present invention provides a vitamin D derivative for producing a medicament for treating osteoporosis, metastatic bone disease, and Paget's disease by administering a bisphosphonate after administering a vitamin D derivative. Related to use.

  In yet another aspect, the present invention relates to a vitamin D derivative for producing a medicament for treating osteoporosis, metastatic bone disease, and Paget's disease by administering a vitamin D derivative and bisphosphonate after an interval time. And related to the use of bisphosphonates.

Detailed Description of the Invention The present invention is a method of drug combination therapy for increasing the bioavailability of bisphosphonates, comprising administering a pre-dose calcium transport stimulator, particularly alphacalcidol, and then A method including the step of administering a bisphosphonate calcium absorption inhibitor about 6 hours or more after administration of the calcium transport stimulating substance is provided. The present invention takes advantage of the fact that calcium transport stimulators drastically reduce calcium concentration in the intestine, in addition to its confirmed benefit of increasing blood calcium. Complexation of bisphosphonate and calcium in the gut inhibits calcium absorption. In the intestine, the depletion of calcium results in improved absorption of bisphosphonates. If the bisphosphonate calcium absorption inhibitor is delivered to the upper small intestine after the vitamin D derivative, a calcium transport stimulator, is delivered, the absorption of the bisphosphonate will increase. Bisphosphonates will enter an environment where calcium is partially depleted due to the transport activity of vitamin D derivatives. Thus, this drastically reduced calcium environment allows for higher absorption of bisphosphonates, resulting in a dose reduction due to the synergistic effect of bisphosphonates and vitamin D derivatives that occur after reaching the bloodstream. In addition, the dose can be reduced.

  In one embodiment, the present invention administers an effective pre-dose of vitamin D derivative, and after about 6 hours or more, preferably from about 6 hours to about 14 hours, a therapeutic dose of bisphospho. A method is provided for increasing the bioavailability of bisphosphonates by administering an nate. In this embodiment, the preferred vitamin D derivative is alphacalcidol, and the preferred bisphosphonate is alendronate.

  In another embodiment, the present invention administers a pre-release effective dose of vitamin D derivative and after about 6 hours or more, preferably from about 6 hours to about 14 hours, a therapeutic dose of bisphospho. A method for enhancing the bioavailability of bisphosphonate by administering an nate is provided. Preferably, the release of vitamin D derivative is delayed by about 3 to 5 hours after the vitamin D derivative is administered. In this embodiment, the preferred vitamin D derivative is calcitriol and the preferred bisphosphonate is alendronate.

  As used herein, bioavailability refers to "a small degree of a dose of drug reaching its site of action or biological fluid (from which the drug accesses the site of action)", "systemic circulation" Goodman and Gilman's The Pharmalogical Basis of Therapeutics 5, 18 (Joel G. Hardman et al., McGraw Hill Pub. 10th edition, 2001). Oral bioavailability may be estimated based on secondary information (eg, urinary excretion or the amount excreted in urine without change, expressed as a percentage of the administered dose) (Id. 1918) .

  The present invention involves administering an effective pre-administered vitamin D derivative. One skilled in the art will understand that a pre-dose is a dose of vitamin D derivative that is administered prior to administering a therapeutic dose of bisphosphonate. Effective pre-administration refers to any calcium transport stimulator that results in increased intestinal absorption of bisphosphonates (compared to equal doses of bisphosphonate administered without a calcium transport stimulant). Means that it may be administered in an amount. An effective pre-dose is a vitamin D derivative dose at about 0.1 μg to about 10 μg.

Vitamin D derivatives useful in the practice of the present invention are calcium transport stimulators. Calcium transport stimulants promote calcium absorption in the intestine (Id. 1728). Vitamin D derivatives useful in the practice of the present invention are the structural analogs of the hormone vitamin D. Examples of useful vitamin D derivatives in the practice of this invention, calcitriol, alfacalcidol, 24,25 dihydric Dodo carboxymethyl vitamin D _3, and a calcifediol. In one embodiment, the preferred vitamin D derivative is alphacalcidol. A preferred dosage range for carfacalcidol is from about 0.1 μg to about 10 μg, more preferably from about 0.2 μg to about 2 μg. In other embodiments, the preferred vitamin D derivative is calcitriol. A preferred dosage range for alphacalcidol is from about 0.1 μg to about 10 μg, more preferably from about 0.2 μg to about 2 μg.

Alpha calcidol, or 1α-hydroxy vitamin D _3, is a synthetic analog of calcitriol, the hormonal form of vitamin D ₃ . Alphacalcidol stimulates intestinal calcium absorption and transport of calcium from the intestine into the bloodstream. If alphacalcidol enters the intestine, several hours must pass before blood calcium levels peak. In order to release the bisphosphonate into the minimal calcium environment, the precalcination dose of alphacalcidol should precede the administration of the bisphosphonate dose by an interval time of several hours. An interval time of several hours, for example about 6 hours to about 14 hours, allows for maximum bioavailability of the bisphosphonate.

  The greatest increase in the bioavailability of bisphosphonates is that the interval time between administration of pre-alphacalcidol and bisphosphonate doses is about 6 hours or more, preferably about 6 hours to about 14 hours, more preferably from about 6 hours to about 12 hours, and most preferably from about 6 hours to about 10 hours. This interval time allows the pre-dose of alphacalcidol to be administered between 8 pm and midnight, and the dosage of bisphosphonate is between 6 am and 10 pm (after waking up, preferably before meals) ), A convenient administration plan can be made. Such administration method enhances the bioavailability of bisphosphonate.

  Calcitriol shows maximum effect about 3 hours after administration. The present invention provides a method for improving bisphosphonate bioavailability by pre-administering calcitriol in a delayed release delivery system. The present invention relates to various vitamin D derivatives that are calcium transport stimulators by prolonging the interval time in order to maximize its effect by delaying the release of vitamin D derivatives after administration of a pre-dose vitamin D derivative. Suitable for differences in calcium depletion characteristics. When the vitamin D derivative is calcitriol, calcitriol administration is a calcitriol dosage form with enteric coatings known in the art (eg, EUDRAGIT® L, EUDRAGIT® S, cellulose acetate phthalate) For about 3 hours to about 5 hours. Such enteric coating materials are pH sensitive and can withstand prolonged contact with acidic gastrointestinal fluids. Thus, an enteric coating does not dissolve until just after passing through the stomach, but dissolves quickly in the weakly acidic to neutral environment of the small intestine. The amount of coating necessary to achieve the desired delay in the onset of drug release can be readily determined by experimentation by those skilled in the art (eg, United States Pharmacopeia, No. 26 Review./National Formulary, No. 21). Edition, 2002, <724> Drug Release, Delayed-Release (Enteric-Coated) Articles-General Drug Release Standard, pp. 2160-2161; Pharmaceutical Dosage Forms and Drug Delivery Systems, HC Ansel, LV Allen, Jr., NG Popovich (See Lippincott Williams & Wilkins, pub., 1999), Modified-Release Dosage Forms and Drug Delivery Systems, 223, 231-240).

Calcitriol, or 1α, 25-dihydroxyvitamin D ₃ is the primary active metabolite of vitamin D. Goodman and Gilman's The Pharmalogical Basis of Therapeutics, supra, at 1727. Similarly, alphacalcidol, calcitriol, has been reported to stimulate intestinal calcium absorption. With respect to calcitriol, blood calcium levels are reported to peak after about 3 to about 5 hours after calcitriol enters the intestine. In order to release bisphosphonates into the minimal calcium environment, the administration of calcitriol pre-dosage is dependent on the interval time of several hours (depending on the rate of intestinal calcium depletion) and the bistriphosphonate dosage Should be prior to administration. If calcitriol is delayed from about 3 to about 5 hours or more from immediate release after its administration, for example, about 6 to about 14 hours of an interval time of several hours allows maximum bioavailability of bisphosphonates To do.

  In one embodiment using a delayed release calcitriol pre-dose, the release of the calcitriol pre-dose is delayed from about 3 to about 5 hours after administering the pre-dose. The interval time between delayed release calcitriol pre-dose and bisphosphonate administration is about 6 hours or more, preferably about 6 hours to about 14 hours, more preferably about 6 hours to about 12 hours, and most preferred Is about 6 hours to about 10 hours. This embodiment advantageously allows the pre-calcitriol dose to be administered between 8 pm and midnight and the bisphosphonate can be administered from 6 am to 10 pm after waking up, preferably before meals. Provide a dosing schedule. This administration method increases the bioavailability of bisphosphonate. This convenient method of administration improves patient compliance.

  Embodiments of the invention include an interval time between administration of an effective pre-dose vitamin D derivative and a therapeutic dose of bisphosphonate. The interval time is expressed as T = t2−t1 (where T is the interval time, t1 is the time when the vitamin D derivative is administered, and t2 is the time when the bisphosphonate is administered). May be good. The interval time should be approximately equal to the time required for blood calcium levels to reach a maximum after administration of the vitamin D derivative. By adjusting the interval time, one skilled in the art can release the bisphosphonate to a minimal calcium environment, thereby increasing the bioavailability of the bisphosphonate.

  The present invention includes administering a therapeutic dose of bisphosphonate. The therapeutic dosage of bisphosphonate is, inter alia, the amount of bisphosphonate that treats or ameliorates osteoporosis, metastatic bone disease, Paget's disease.

  Bisphosphonates useful in the practice of the present invention are calcium absorption inhibitors. Examples of bisphosphonates useful in the practice of the present invention include alendronic acid and pharmaceutically acceptable salts thereof (hereinafter generically referred to as “alendronate”), risedronate And acceptable salts thereof (hereinafter generically referred to as “risedronate”), etidronic acid and pharmaceutically acceptable salts thereof (hereinafter generically known as “etidronate”) Zoledronic acid and pharmaceutically acceptable salts thereof (hereinafter referred to generically as “zoledronate”), and tiludronic acid and pharmaceutically acceptable salts thereof (hereinafter generically referred to as “tiludronate”). "). One skilled in the art will recognize that pharmaceutically acceptable salts can exist as solvates, eg, hydrates. One skilled in the art will recognize that these bisphosphonates may be provided as esters. Bisphosphonates may be provided in any pharmaceutically acceptable salt or acid form, with salts generally preferred because they are less membrane irritating. Alendronate is preferably provided as a monosodium salt monohydrate or trihydrate. Risedronate is preferably provided as the monosodium salt hemipentahydrate. Etidronate and tiludronate are preferably provided as hydrated or anhydrous disodium salts. Zoledronate is preferably provided as disodium salt trihydrate or trisodium salt hydrate.

  The most preferred bisphosphonate of the present invention is alendronate. A suitable therapeutic dose of alendronate is about 1 mg to 100 mg, most preferably about 10 mg to about 70 mg.

  Administration of vitamin D in a drug combination regimen may be by any means known in the art. A solid dosage form is preferred.

  Administration of bisphosphonates in drug combination regimes may be by any means known in the art. Administration by solid oral dosage form is preferred. Solid oral dosage forms are of the conventional type well known in the art (eg, Fosamax®).

  Bisphosphonates and vitamin D derivatives useful in the practice of the present invention may be manufactured into medicaments containing one or more excipients known in the art. The choice of excipient and amount to use can be readily determined based on experimentation by pharmaceutical chemists and by considering standard procedures and reference techniques in the art.

  The diluent increases the bulk of the solid pharmaceutical product and facilitates handling for patients and caregivers. Examples of the diluent include microcrystalline cellulose (for example, Avicel (registered trademark)), fine cellulose, lactose, starch, α starch, calcium carbonate, calcium sulfate, sugar, dextrin, dextrate, dextrose, dibasic calcium phosphate. Dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylate (eg Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol and tanks It is done.

  The compressed dosage form of the present invention is an excipient having functions such as serving to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include, but are not limited to, carbomers (eg, carbopol), sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, glucose, guar gum, hydrogenated vegetable oil, hydroxyethylcellulose, hydroxypropylcellulose ( For example, Klucel®), hydroxypropyl methylcellulose (HPMC) (eg, Methocel®), liquid cellulose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylate, polyvinylpyrrolidone (eg, Kollidon®) ), Plasdone®), starch, alpha starch, sodium alginate and alginic acid derivatives.

  The rate of dissolution of the compressed dosage form in the patient's stomach may be adjusted by adding a tablet disintegrant or a second super tablet disintegrant in addition to the supertablet disintegrant of the composition of the present invention. Such additional tablet disintegrating agents include, but are not limited to, alginic acid, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, colloidal silicon dioxide, sodium croalmellose (eg, Ac-Di-Sol®, Primellose® )), Crospovidone (eg, Kollidon®, Polyplasdone®), guar gum, magnesium magnesium silicate, methylcellulose, microcrystalline cellulose, potassium polacrilin, powdered cellulose, alpha starch, sodium alginate, glycol Examples include sodium acid starch (eg Explotab®) and starch.

  Glidants may be added to increase dosing accuracy and improve the flow properties of the solid composition. Excipients that can function as glidants include, but are not limited to, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, tanks and tribasic magnesium phosphate.

  When dosage forms such as tablets are prepared by compression, the composition is subject to punch pressure and pigment. Some excipients and active ingredients have a tendency to adhere to the punch and pigment surface, which causes the product to have pitting and other surface non-uniformities. A lubricant may be added to reduce the tackiness of the composition and facilitate release of the product from the dye. Lubricants include, but are not limited to, magnesium stearate, calcium stearate glycerol monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate Sodium stearyl fumarate, stearic acid, surfactant, talc, wax and zinc stearate.

  Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavorants and flavor enhancers for pharmaceutical products that may be included in the dosage forms of the present invention include, but are not limited to, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl alcohol, and Tartaric acid is mentioned.

  The dosage form may be colored using any pharmaceutically acceptable colorant to improve the appearance of the product and / or to facilitate identification of the product and unit dosage by the patient.

  Dosage forms may be usually prepared by mixing the active ingredient with any other desired excipients, dry granulation or wet granulation.

  In the dry granulation process, the active ingredients and excipients may be compressed into a lump or sheet and ground into compressed granules. The milled granules can then be compressed into a final dosage form. It is understood that the method of agglomeration or other compression, followed by comminution and recompression, makes the hydrogel, supertablet disintegrant, tannic acid, and active ingredient intergranular material the final dosage form. It will be. Alternatively, all active ingredients or excipients may be added after milling of the compressed composition, resulting in more active ingredients or excipients being granulated.

  As an alternative to dry granulation, the mixed composition may be compressed directly into the final pharmaceutical dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. Thus, the active ingredient and other desired excipients may be mixed with the composition before using direct compression tableting. In particular, such additional excipients that are very suitable for direct compression tablet molding include microcrystalline cellulose, spray dried lactose, dicalcium phosphate hydrate, and colloidal silica.

  A further alternative to dry granulation is wet granulation. The mixture of excipients is granulated by using alcohol or water and a mixture of alcohols as a granulating solvent by standard casting techniques known to those skilled in the art, followed by drying, sieving, milling and compression. And can be made into the final dosage form.

  The active ingredient may be compressed using conventional compression techniques.

  Accordingly, the present invention has been described with reference to certain preferred embodiments, which are further illustrated by the following non-limiting examples.

Example
Example 1: In-Vivo study on improving the bioavailability of alendronate:
The effect of considering the pre-administration interval of alphacalcidol in a drug combination regimen with alendronate In vitro studies in animal models, alphacalcidol in combination therapy with alendronate at various pre-administration intervals (temporal This was done to determine whether the bioavailability of alendronate increased when compared to when alendronate was administered alone.

Six female beagle dogs (about 2 years old, each weighing about 9 kg) were animal models in this study. The animals were used in each of 5 individual treatment sessions (34-42 hours, the duration of each session depends on the pre-dose test interval being measured). The same drug was administered at each treatment at the same dose. That is, alfacalcidol (ALPHA D ₃ (R), 1 [mu] g gel capsules; TEVA) is a vitamin D ₃ derivative was administered as a pre-medication and alendronate sodium (Fosalan (registered trademark), 10 mg tablets Merck, Sharp & Dohme) were bisphosphonates administered as therapeutic agents. The washout period between sessions was 7 days. The clinical status of each dog was examined within 48 hours prior to each treatment session and again after the last session. In each session, animals were dosed on an empty stomach (npo 10-12 hours). Dogs were fed a standardized diet (canned Benzo meat, 1 can, 425 g) 4 hours after the treatment dose of alendronate.

  During each session, dogs were housed in metabolic cages. Urine samples were collected from the bottom of the metabolic cage. At each round, two representative samples of urine (5 ml each) were placed in capped polyethylene vials and immediately frozen at -20 ° C. The rest of the sample was also kept frozen.

  Urine samples were analyzed by high performance liquid chromatography (HPLC) with fluorescence detection (Anapharm, Inc., Quebe).

  In each session, the pre-dose study drug alphacalcidol was administered in the morning on an empty stomach with 10-20 ml of tap water to facilitate swallowing. During the monitoring (recovery) time of each session, the dog is hydrated with 300 ml of tap water through the gastroesophageal tract each evening before the start of each test session, and 150 ml of tap water for 2 hours. Each was administered a therapeutic dose of alendronate over a maximum of 10 hours after the therapeutic administration. As above, food was fed 4 hours after the administration of alendronate.

  In the first (reference) study session, a pre-dose alpha-cardidol and a therapeutic dose of alendronate were administered simultaneously (to facilitate swallowing, 10-20 ml of tap water, immediately after the gastrointestinal tract) With 250 ml of tap water).

  In study sessions 2-5, a pre-dose of alphacalcidilol was administered with 10-20 ml of tap water. In each successive study session, after the pre-dose of alphacalcididol was administered, the therapeutic dose of alendronate was immediately followed by 10-20 ml of tap water at 1, 2, 3 or 6 hour intervals, respectively. It was administered with 250 ml of tap water via the gastrointestinal tract.

  With respect to the alphacalcidol pre-administration interval time tested, the cumulative amount of alendronate concentration in the urine was measured over 24 hours after administration of the therapeutic dose of alendronate (recovery time point (0 hour prior to alendronate administration). And again (3, 6, 9 and 24 hours after administration of alendronate).

  The results of the analysis of alendronate in urine for the five treatments are reported in Tables 1A-1E and 2. Tables 1A-1E show the results of alendronate excretion in dog urine for each experimental session. Table 2 collects the average of the total excreted alendronate as a function of the interval time between alpha-calcidol administration and alendronate administration. Table 3 collects the average of the total excreted alendronate as a function of the interval time between calcitriol and alendronate administration, performed in a separate experiment.

  The results show that the total bioavailability of alendronate is greatly increased 6 hours after administration of alfacalcidol. It will be discovered that this increase will continue if the interval time between the pre-dose of alphacalcidiol and the subsequent therapeutic dose of alendronate is increased to 8, 10 or 12 hours. Is expected. In this dog model, the bioavailability of alendronate without vitamin D derivative was about 30 μg to 50 μg. Calcitriol administered 3 hours prior to alendronate administration increased this value to 108 μg. The improvement in alendronate bioavailability is similar for the two vitamin D derivatives, calcitriol and alphacalcidol, but the optimal interval between predose administration and maximum alendronate bioavailability The time was delayed in the case of alfacalcidol. This delay can be advantageously used in designing a drug combination plan that is convenient and improves the bioavailability of alendronate.

Example 2: In vivo study for improving the bioavailability of alendronate:
Effects of changing the pre-administration interval of calcitriol in a drug combination with alendronate In vitro studies in animal models, various pre-administration intervals (temporal intervals) in combination therapy with calcitriol and alendronate Was performed to determine whether the bioavailability of calcitriol was increased when compared to when alendronate was administered alone.

Six female beagle dogs (about 2 years old, each weighing about 9 kg) were animal models in this study. The animals were used in each of 5 individual treatment sessions (lasting 22-24 hours, the duration of each session depending on the pre-dose test interval being measured). The same drug was administered at each treatment at the same dose. That is, calcitriol (ROCALTROL®, 25 μg gel capsule; ROHCE) is a vitamin D ₃ derivative administered as a pre-dose drug, and alendronate sodium (Fosamax®, 10 mg tablet, Merck, Sharp & Dohme) was a bisphosphonate administered as a therapeutic agent. There was a 7 day washout period between each session. The clinical status of each dog was known within 48 hours prior to each treatment session and examined again after the session. In each session, animals were dosed on an empty stomach (npo 10-12 hours). Dogs were fed a standardized diet (Shur-Gain, Canada, 200-250 g) 4 hours after the treatment dose of alendronate.

  During each session, dogs were housed in metabolic cages. Urine samples were collected from the bottom of the metabolic cage. At each round, two representative samples of urine (15 ml each) were placed in capped polyethylene vials and immediately frozen at -20 ° C. The rest of the sample was also kept frozen.

  Urine samples were analyzed by HPLC with fluorescence detection (Anapharm, Inc., Quebe).

  In each session, the pre-dose study drug calcitriol was administered in the morning in the fasting state with 10-20 ml of tap water to facilitate swallowing, followed by 250 ml of tap water (pH = 2.) Via the gastrointestinal tract. The water was replenished. During the monitoring (recovery) time of each session, the dogs are hydrated with 200-250 ml of tap water through the gastroesophageal tract in the evening before starting each test session, and for up to 10 hours, Alendronate was given 200-250 ml of pH-adjusted tap water every 2 hours after the therapeutic dose was administered. As above, food was fed 4 hours after the administration of alendronate.

  In the first (reference) study session, a therapeutic dose of alendronate alone was administered via the gastrointestinal tract with hydration with 250 ml of tap water adjusted to pH.

  In a second (reference) study session, a pre-dose calcitriol and a therapeutic dose of alendronate are simultaneously used to facilitate swallowing 10-20 ml of tap water, followed by 250 ml of pH-adjusted tap water and the gastrointestinal tract. Was administered via

  In the third to sixth study sessions, a pre-dose of calcitriol was administered with 10-20 ml of tap water. At each 1, 2, 3 or 6 hour interval after administration of a pre-dose of calcitriol in each successive study session, 10-20 ml of tap water followed immediately by the gastrointestinal tract at a therapeutic dose of alendronate. Administered with 250 ml of tap water.

  For each tested interval time of calcitriol, the cumulative amount of alendronate concentration in the urine was collected over a 12 hour period after administration of the therapeutic dose of alendronate, with a recovery time point (0 hour prior to administration of alendronate). And were identified again 3, 6, 9 and 24 hours after administration of alendronate.

  The results of the analysis of alendronate in urine for the five treatments are reported in Table 4. Table 4 collects the average of the total excreted alendronate as a function of interval time between calcitriol and alendronate administration.

  The results show that alendronate bioavailability is greatly increased 3 hours after calcitriol administration. The bioavailability of alendronate without vitamin D derivative in this dog model is about 30 μg to 50 μg. Calcitriol administered 3 hours prior to alendronate administration increased this value to 108 μg. By delaying the release of calcitriol pre-dose for 3-5 hours and waiting for an interval time of several hours before administering the bisphosphonate, the drug combination therapy becomes more efficient and convenient.

Example 3: In vivo study for improving the bioavailability of alendronate:
Effects of changing pre-dose in a drug combination regimen with alendronate In vitro studies in animal models, calcitriol or alphacalcidol, various pre-dose intervals (time intervals) in combination with alendronate Was performed in order to determine whether the bioavailability of alendronate was increased when compared to when alendronate was administered alone.

  The method of Example 1 was used. In this study, fosaran® alone, fosaran® with a pre-dose alpha-calcidol, at pre-administration intervals of 6, 8, and 10 hours, and fosaran® with calci Comparison was made at a pre-dose interval of 3 hours with triol. The results are shown in Table 5.

  Thus, while the invention has been described by reference to various preferred embodiments, those skilled in the art will depart from the spirit and scope of the invention as defined in the claims below. It will be understood that the exemplary embodiment changes without exception.

Claims (19)

  A method for increasing the bioavailability of a bisphosphonate comprising administering an effective pre-dose vitamin D derivative and administering a therapeutic dose of phosphonate after an interval time. How to be.   2. The method of claim 1, wherein the release of the pre-dose of the vitamin D derivative is delayed. Wherein the vitamin D derivative is calcitriol, alfacalcidol, 24,25-dihydroxyvitamin D _3, and is selected from the group consisting of calcifediol The method according to claim 1 or 2.   4. The method of claim 3, wherein the vitamin D derivative is alphacalcidiol.   4. The method of claim 3, wherein the vitamin D derivative is calcitriol.   The method according to claim 1 or 2, wherein the interval time is approximately equal to the amount of time required for blood calcium to reach a maximum after administration of the vitamin D derivative.   The method according to claim 1 or 2, wherein the interval time is about 6 hours or more.   The method of claim 6, wherein the interval time is about 6 hours to about 14 hours.   3. The method of claim 1 or 2, wherein the pre-dosage of the vitamin D derivative is from about 0.1 [mu] g to about 10 [mu] g.   The method according to any one of claims 1 to 3, wherein the bisphosphonate is selected from the group consisting of alendronate, risedronate, etidronate, zoledronate, and tiludronate.   11. The method of claim 10, wherein the bisphosphonate is alendronate.   12. The method of claim 11, wherein the dose of alendronate is about 10 mg to about 70 mg.   3. The method of claim 1 or 2, wherein the pre-dose vitamin D derivative is administered at bedtime and a predetermined dose of bisphosphonate is administered before meals.   The method according to claim 1, wherein the interval time is fasting.   3. The method of claim 2, wherein the pre-release dosage of the vitamin D derivative is a dosage form with a delayed release enteric coating.   16. The method of claim 15, wherein the release of the vitamin D derivative is delayed for about 3 to about 5 hours or more.   Bisphos for producing a medicament for the treatment of osteoporosis, metastatic bone disease, and Paget's disease comprising administering an effective pre-dose vitamin D derivative prior to administering bisphosphonate Use forphanate.   Use of a vitamin D derivative for the manufacture of a medicament for the treatment of osteoporosis, metastatic bone disease, and Paget's disease comprising administering a bisphosphonate after administering a vitamin D derivative.   Of a vitamin D derivative for the manufacture of a medicament for the treatment of osteoporosis, metastatic bone disease, and Paget's disease comprising administering a vitamin D derivative and then administering a bisphosphonate after an interval time use.