DE20321698U1 - A medicament for increasing the bioavailability of alendronate or another bisphosphonate by administering a pre-dose of a vitamin D derivative - Google Patents

Abstract

use a bisphosphonate for the manufacture of a medicament for treatment of osteoporosis, metastatic bone disease and Paget's disease in patients receiving a biphosphonate, the Drug for administering an effective pre-dose of a vitamin D derivative prepared before administering the bisphosphonate is.

Description

These Application claims the benefit of US Provisional Patent Applications with the serial numbers. 60 / 433,685, filed December 16, 2002, and 60 / 460,206, filed April 2, 2003, both of which are hereby incorporated by reference taken in their entirety.

FIELD OF THE INVENTION

The present invention is directed to increasing the bioavailability of bisphosphonates, such as alendronate, by administering a pre-dose of alpha-cacalcidol (1α-hydroxyvitamin D ₃ ) at least six hours prior to administration of the therapeutic dose of the bisphosphonate to the recipient.

The present invention is directed to increasing the bioavailability of bisphosphonates such as alendronate by administering a pre-dose of calcitriol (1α, 25-dihydroxyvitamin D ₃ ), wherein the immediate release of calcitriol is delayed at least about three to about five hours after administration, and administering a therapeutic dose of the bisphosphonate at least about six hours after the administration of the calcitriol pre-dose to the recipient.

BACKGROUND OF THE INVENTION

The treatment of osteoporosis, metastatic bone disease and Paget's disease may benefit from improvements in gastric controlled release technology and multiple dose delivery. Bisphosphonates such as sodium alendronate, risedronate, etidronate, zoledronic acid and tiludronate are drugs commonly described to treat these disorders. Despite their advantages, bisphosphonates suffer from very poor 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, 58, 288-298 , Its absorption is inhibited by foods and drinks other than water. Id. Side effects that have occurred in patients who have taken alendronate include irritation of the upper gastrointestinal mucosa. Liberman, UA, Hirsch, LJ, "Esophagitis and Alendronate", N. Engl. J. Med., 1996, 335, 1069-70 , This irritation can lead to more severe conditions. Physicians' Desk Reference, Fosamax, Warnings.

Alendronate is best absorbed by the upper GI tract (duodenum and jejunum). Lin, JH, "Bisphosphonates: A Review of Their Pharmacokinetic Properties", Bone, 1996, 18, 75-85 ; Porras, AG, Holland, SD, Gertz, BJ, Pharmacokinetics of Alendronate, Clin. Pharmacokinet 1999, 36, 315-328 , Alendronate is best absorbed at a pH of ~ 6. 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, 58, 288-298 , As in the conventionally transmitted U.S. Patent No. 6,476,006 Controlled release of alendronate in the stomach would allow for extended provision of the drug in the duodenum and in the intestinal void and should result in improved bioavailability and thus allow for lower dosing and less irritation.

In addition to bisphosphonate therapy, options in the treatment of osteoporosis include hormone replacement therapy and calcium supplementation therapy. Kleerekoper, M., Schein, JR, "Comparative Safety of Bone Remodeling Agents with A Focus on Osteoporosis Therapies," J Clin. Pharmacol., 2001, 41, 239 , Increased calcium levels may potentially improve the state of bone mineralization in patients with osteoporosis. During the last thirty years, calcium supplementation along with vitamin D or vitamin D derivatives such as calcitriol have been ways to treat the problems of osteoporosis. Cannigia, A., Vattimo, A., "Effects of 1,25 Dihydroxycholecalciferol on Calcium Absorption in Postmenopausal Osteoporosis", Clin. Endocrinol., 1979, 11, 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, 61, 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, 98, 331 , Calcitriol (1,25-dihydroxyvitamin D ₃ ) is a vitamin D derivative which is active in regulating the absorption of calcium from the gastrointestinal tract. Physicians' Desk Reference, Rocaltrol Oral Solution, Description. Calcitriol is the biologically active metabolite of vitamin D ₃ and stimulates intestinal calcium transport. Merck Index, 13th Edition, 1643 , Calcitriol is rapidly absorbed by the intestine and reaches maximum serum levels within three to six hours after ingestion. Physicians' Desk Reference, Rocaltrol Oral Solution, Pharmacokinetics. Calcitriol is used to treat calcium deficiency.

Over the last few years, successful trials have been conducted which confirm that there is a synergistic effect when using a combined therapy of calcitriol and bisphosphonates. 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, 15, 223 ; Masud, T., Mulcahy, B., Thompson, AV, Donnolly, S., Keen, RW, Doyle, DV, Spector, TD, "Effects of Cyclic Etidronate Combined with Calcitriol Versus Cyclic Etidronate Alone on Spine and Femoral Neck Bone Mineral Density in Postmentopausal Women ", Ann. Rheum. Dis., 1998, 57, 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, 21, 51 ; Nuti, R., Martini, G., Giovani, S., Valenti, R., "Effect of Treatment with Calcitriol Combined with Low-dose Alendronate in Involutional Osteoporosis", Clin. Drug Invest., 2000, 19, 56 , The aim of the combined therapy is to improve the therapeutic results and decrease the dosage of the two drugs. In these experiments, the drugs were given separately and administered together. The International Publication WO 2001/028564 discloses a tablet containing a combination of calcitriol and alendronate in a particular ratio range of the two drugs.

Even though the benefits of combination therapy in the treatment of osteoporosis, metastatic bone disease and Paget's disease were detected and although progress in controlled release systems for multiple dose medications remains Need for an improved controlled delivery system and an improved dosage regimen for a bisphosphonate and a calcium transport stimulating agent for the benefits fully implement a combination therapy in practice.

SUMMARY OF THE INVENTION

In one embodiment, the present invention relates to the use of a bisphosphonate for the manufacture of a medicament for the treatment of osteoporosis, metastatic bone disease and Paget's disease wherein the medicament is for administering an effective pre-dose of a vitamin D derivative, especially calcitriol, alphacalcidol, 24,25- Dihydroxyvitamin D ₃ and calcifediol prior to administering the bisphosphonate, especially alendronate, risedronate, etidronate, zoledronate and tiludronate.

In Another embodiment relates to the present invention Invention the use of a vitamin D derivative for the production a drug for the treatment of osteoporosis, metastatic Bone disease and Paget's disease, the drug being used for Administering a bisphosphonate after administering the vitamin D derivative is prepared.

In Yet another embodiment relates to the present invention Invention the use of a vitamin D derivative and a bisphosphonate for the manufacture of a medicament for the treatment of osteoporosis, metastatic bone disease and Paget's disease, said the Drug for administering the vitamin D derivative and then after a time interval, in particular about 6 hours to about 14 hours, Administering the bisphosphonate is prepared.

In In another embodiment, the time interval is about equal to the amount of time the blood calcium level reaches a maximum after administering the vitamin D derivative needed. The present uses in particular provide the pre-dose of a vitamin D derivative administered at bedtime is, and the dose of a bisphosphonate, which is administered before eating becomes. The time interval is changed by changing the administration time of the vitamin D derivative, changing the time of administration of the bisphosphonate and by using the on the pharmaceutical Specialist field of known delayed release technology reached.

DETAILED DESCRIPTION THE INVENTION

The present invention provides uses for drug combination therapy for increasing the bioavailability of a bisphosphonate, wherein the described medicaments are adapted for administering a pre-dose of a calcium transport stimulating agent, especially alpha-acetidol followed by administering a bisphosphonate calcium resorption inhibitor for at least about 6 hours after the calcium transport stimulating agent has been administered. The present invention is advantageous due to the fact that a calcium transport stimulating agent depletes the intestinal calcium concentration, in addition to its perceived benefit of increasing calcium in the blood. Complexation of a bisphosphonate with calcium in the intestinal tract inhibits its absorption. The depletion of calcium results in improved absorption of the bisphosphonate in the intestine. When a bisphosphonate calcium absorption inhibitor is provided in the upper small intestine after providing a vitamin D derivative which is a calcium transport-stimulating agent, absorption of the bisphosphonate is increased. The bisphosphonate will enter an environment which is partially depleted of calcium due to the transport activity of the vitamin D derivative. Thus, this calcium-depleted environment will allow for greater absorption of the bisphosphonate, allowing for a dose reduction in addition to the dose reduction caused by the synergistic effect of the bisphosphonate and the vitamin D derivative occurring after the bloodstream has been reached.

In one embodiment, the present invention relates to the use of a bisphosphonate for the manufacture of a medicament for the treatment of osteoporosis, metastatic bone disease and Paget's disease wherein the medicament is for administering an effective pre-dose of a vitamin D derivative, especially calcitriol, alphacalcidol, 24,25- Dihydroxyvitamin D ₃ and calcifediol prior to administering the bisphosphonate, especially alendronate, risedronate, etidronate, zoledronate and tiludronate.

In Another embodiment relates to the present invention Invention the use of a vitamin D derivative for the production a drug for the treatment of osteoporosis, metastatic Bone disease and Paget's disease, taking the drug to administer a bisphosphonate after administering the vitamin D derivative is prepared.

In Yet another embodiment relates to the present invention Invention the use of a vitamin D derivative and a bisphosphonate for the manufacture of a medicament for the treatment of osteoporosis, metastatic bone disease and Paget's disease, said the Drug for administering the vitamin D derivative and then after a time interval, in particular about 6 hours to about 14 hours, Administering the bisphosphonate is prepared.

In In one embodiment, the increase in the Bioavailability of a bisphosphonate by administration an effective pre-dose of a vitamin D derivative and, at least about 6 hours later, preferably about 6 hours to about 14 hours later, administer a therapeutic dose a bisphosphonate. In this embodiment, this is preferred vitamin D derivative alphacalcidol and the preferred bisphosphonate is alendronate.

In In another embodiment, the increase takes place the bioavailability of a bisphosphonate by administration an effective pre-dose with sustained release Vitamin D derivative and, at least about 6 hours later, preferably about 6 hours to about 14 hours later, administer a therapeutic dose of a bisphosphonate. Is preferred the release of the vitamin D derivative about 3 to about 5 hours, after the vitamin D derivative has been administered, it is delayed. In this embodiment, the preferred vitamin D derivative is Calcitriol and the preferred bisphosphonate is alendronate.

As used herein, bioavailability means "the proportionate extent to which a dose of drug reaches its site of action or a biological fluid from which the drug has access to its site of action";"the proportion of drug absorbed as such in the systemic circulation" , Goodman and Gilman's The Pharmalogical Basis of Therapeutics 5, 18 (Joel G. Hardman et al., Ed., McGraw Hill Pub., 10th Edition, 2001) ). Oral bioavailability may be estimated based on secondary information (eg urinary excretion or the amount of drug excreted unchanged in the urine, expressed as a percentage of the administered dose). Id. At 1918.

The Medicaments according to the invention are prepared for the administration of an effective pre-dose of a vitamin D derivative. One skilled in the art will understand that a pre-dose is one Dose of the vitamin D derivative, which before administration of the therapeutic dose of the bisphosphonate is administered. A effective pre-dose means that stimulates calcium transport Agent can be dosed in any amount, which in an increased Intestinal absorption of the bisphosphonate results compared to a same dose of bisphosphonate, which without the calcium transport stimulant was administered. An example of an effective Pre-dose is a dose between about 0.1 μg and about 10 μg a vitamin D derivative.

The vitamin D derivatives useful in the practice of the present invention are calcium transport stimulating agents. Calcium transport stimulating agents allow the intestinal absorption of calcium. Id. At 1728. Vitamin D derivatives useful in the practice of the present invention are structural analogs of the hormone vitamin D. Examples of vitamin D derivatives useful in the practice of the present invention include calcitriol, alphacalcidol, 24 , 25-dihydroxyvitamin D ₃ and calcifediol. In one embodiment, the preferred vitamin D derivative is alphacalcidol. A preferred dose range of alphacalcidol is about 0.1 μg to about 10 μg, more preferably between about 0.2 μg to about 2 μg. In another embodiment, the preferred vitamin D derivative is calcitriol. A preferred dose range of alphacalcidol is about 0.1 μg to about 10 μg, more preferably between about 0.2 μg to about 2 μg.

Alphacalcidol, or 1α-hydroxyvitamin D ₃ , is a synthetic analogue of calcitriol, the hormonal form of vitamin D ₃ . Alphacalcidol stimulates the intestinal calcium absorption, the transport of calcium from the intestine into the bloodstream. When alpha-cacalcidol enters the intestine, several hours must elapse before the blood calcium level becomes maximum. In order to release the bisphosphonate in a minimum calcium environment, administration of the pre-dose of alphacalcidol should precede administering the bisphosphonate dose by a time interval of several hours. A time interval of several hours, z. About 6 hours to about 14 hours, allows maximum bioavailability of bisphosphonate.

The maximum increase in bisphosphonate bioavailability is observed when the time interval between administration at least the alpha-alkalocidol pre-dose and the bisphosphonate dose about 6 hours, preferably about 6 hours to about 14 hours, stronger preferably about 6 hours to about 12 hours, and the strongest preferably about 6 hours to about 10 hours. This time interval allows for a convenient dosing schedule, in which the pre-dose of Alphacalcidol between 20.00 o'clock and Midnight can be administered and the bisphosphonate dose between 6:00 am and 10:00 am the following morning, preferably before meals, can be administered. This dosing procedure increases the bioavailability of bisphosphonate.

Calcitriol shows a maximum effect about 3 hours after administration. The present invention provides a method of enhancing bisphosphonate bioavailability by predosing with calcitriol in a sustained release delivery system. The present invention accommodates differences in calcium fatigue characteristics of the various vitamin D derivatives which are calcium transport stimulating agents by extending the time interval for maximum effect of the vitamin D derivative by retarding its release after administration of the vitamin D derivative. Pre-dose. When the vitamin D derivative is calcitriol, the dose of calcitriol is between about three hours and about five hours by providing the calcitriol dosage form with an enteric coating known in the art, e.g. Eudragit ^® L, Eudragit ^® S, cellulose acetate phthalate, delayed. Such enteric coating materials are pH sensitive and can withstand prolonged contact with acidic gastric fluids. Therefore, the enteric coating does not dissolve until the stomach is left, but it simply dissolves in the middle-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 with one skilled in the art (see, e.g. United States Pharmacopeia, 26th Rev./National Formulary, 21st Edition, 2002, <724> Drug Release, Delayed Release (Enteric Coated) Articles - General Drug Release Standard, 2160-2161 ; Pharmaceutical Dosage Forms and Drug Delivery Systems, HC Ansel, LV Allen, Jr., NG Popovich (Lippincott Williams & Wilkins, Pub., 1999), Modified-Release Dosage Forms and Drug Delivery Systems, 223, 231-240 ).

Calcitriol, or 1α, 25-dihydroxyvitamin D ₃ , is a primary active metabolite of vitamin D. Goodman and Gilman's The Pharmalogical Basis of Therapeutics, supra, at 1727. It is reported that calcitriol, as well as alphacalcidol, stimulates intestinal calcium absorption. For calcitriol, it is reported that the blood calcium level is maximal at about 3 hours to about 5 hours after calcitriol has entered the intestine. To release the bisphosphonate into a minimal calcium environment, the administration of the calcitriol pre-dose should precede the administration of the bisphosphonate dose by a time interval of several hours, which depends on the rate of intestinal calcium depletion. If the immediate release of calcitriol is delayed at least about 3 to about 5 hours after its administration, a time interval of several hours, e.g. From about 6 hours to about 14 hours, maximum bioavailability of bisphosphonate.

In one embodiment, using a sustained release calcitriol pre-dose, the release of the calcitriol pre-dose is delayed about 3 hours to about 5 hours after the administration of the pre-dose. The time interval between the delayed release calcitriol pre-dose and the bisphos Phonate dose is at least about 6 hours, preferably about 6 hours at about 14 hours, more preferably about 6 hours to about 12 hours, and most preferably about 6 hours to about 10 hours. This embodiment provides a convenient dosing regimen in which the calcitriol pre-dose may be administered between 8:00 pm and midnight and the bisphosphonate dose may be administered between 6:00 am and 10:00 am the following morning, preferably before eating. This dosing procedure increases the bioavailability of bisphosphonate. The convenience of this dosing procedure improves patient compliance.

The embodiments according to the invention a time interval between administration of the effective pre-dose of the vitamin D derivative and the administration of the therapeutic Dose of bisphosphonate. The time interval can be considered T = t2 - t1 where T is the time interval, t1 is the time is to which the vitamin D derivative is administered, and t2 the Time is to which the bisphosphonate is administered. The time interval should be approximately equal to the amount of time, which the blood calcium level to Achieving a maximum after administering the vitamin D derivative needed.

By Adjusting the time interval allows one to place the bisphosphonate in an environment with minimal calcium release, with bioavailability of bisphosphonate is increased.

The Medicaments according to the invention are prepared for the administration of a therapeutic dose of bisphosphonate. A therapeutic dose of bisphosphonate is an amount of bisphosphonate which Diseases, including, but not limited to, osteoporosis, metastatic bone disease and Paget's disease, treated or relieves.

The Bisphosphonates which are in the practice of the present invention useful are calcium resorption inhibitors. Examples of bisphosphonates which are in the practice of the present invention useful include alendronic acid and pharmaceutically acceptable salts thereof (hereinafter collectively known as "alendronate"), risedronic acid and pharmaceutically acceptable salts thereof (hereinafter collectively known as "risedronate"), etidronic acid and pharmaceutically acceptable salts thereof (hereinafter collectively known as "etidronate"), zoledronic acid and pharmaceutically acceptable salts thereof (hereinafter collectively known as "zoledronate") and tiludronic acid and pharmaceutically acceptable salts thereof (hereinafter collectively known as "tiludronate") recognize that pharmaceutically acceptable salts as solvates, z. As hydrates may be present. The person skilled in the art will recognize that these bisphosphonates can also be provided as esters. The bisphosphonates may be in any pharmaceutically acceptable Salt or acid form, with salts are generally preferred since they have less membrane irritation cause. Alendronate is preferred as a monosodium salt monohydrate or trihydrate. Risedronate is preferred as a Monosodium salt hemipentahydrate provided. Etidronate and tiludronate are preferred as hydrated or anhydrous disodium salts provided. Zoledronate is preferred as a disodium salt tetrahydrate or trisodium salt hydrate.

The most preferred bisphosphonate of the present invention Invention is alendronate. The preferred therapeutic dose of Alendronate is between about 1 mg and about 100 mg, the strongest preferably between about 10 mg and about 70 mg.

The Administering the vitamin D derivative in the drug combination scheme may also be by any means known in the art. Solid oral dosage forms are preferred.

Administration of the bisphosphonate in the drug combination scheme may be by any means known in the art. Administration via a solid oral dosage form is preferred. The oral solid dosage form may be of the known in the art conventional type (z. B. Fosamax ^®).

Out the bisphosphonates and the vitamin D derivatives, which in practice of the present invention Medicines are made which one or more on the Specialty include known excipients. The selection the excipients and the amounts that can be used simply by the formulation scientist based on the Experience and consideration of standard procedures and reference work in the field.

Diluents increase the bulk of a solid pharmaceutical product and facilitate handling for the patient and caregiver. Diluents include, for example, microcrystalline Cellulose (e.g., Avicel ^®), microfine cellulose, lactose, starch, pregelatinized starch, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., Eudragit ^®), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.

Compacted dosage forms, such as those of the present invention, may include excipients whose functions include aiding the binding of the drug, and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g., Carbopol), carboxymethylcellulose sodium, dextrin, ethylcellulose, gelatin, glucose, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (z. B. Klucel ^®), hydroxypropyl methylcellulose ( HPMC) (e.g.., Methocel ^®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, polyvinylpyrrolidone (z. B. Kollidon ^®, Plasdone ^®), starch, pregelatinized starch, sodium alginate and alginate derivatives, but are not restricted to it.

The dissolution rate of a compressed dosage form in the patient's stomach can also be adjusted by the addition of a disintegrant or a secondary superdisintegant to the dosage form, in addition to the superdisintegrant of the present inventive composition. Such additional disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium (z. B. Ac-Di-Sol ^®, Primellose ^®), crospovidone (eg. B. Kollidon ^®, Polyplasdone ^®), guar gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., Explotab B. ^®) and starch, but are not limited thereto.

lubricant can improve the flow properties a solid composition and to improve the dosage accuracy be added. Excipients, which can act as lubricants, include colloidal silica, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate but are not limited to this.

If a dosage form such as a tablet made by compression becomes, a composition is a pressure of a punching tool exposed with male and female. Some excipients and agents tend to adhere to the surfaces of the punch with male and female, which can lead to that Product pore formation and other surface irregularities having. A lubricant can be added to the composition to reduce sticking and release of the product from To facilitate tools. Lubricants include magnesium stearate, Calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated Castor oil, hydrogenated vegetable oil, mineral oil, Polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, Stearic acid, surfactants, talc, Waxes and zinc stearate, but are not limited thereto.

flavorings and flavor enhancers make up the dosage form tastier for the patient. conventional Flavoring and taste improving agents for pharmaceutical products used in the dosage forms of the present invention Invention may include Maltol, vanillin, ethyl vanillin, menthol, citric acid, Fumaric acid, ethyl maltol and tartaric acid but not limited to that.

The Dosage forms may also be made using any colored pharmaceutically acceptable colorant be to improve their appearance and / or identification of the product and the unit dosage level by the patient to enable.

The Dosage form may be prepared in a conventional manner by dry blending, Dry granulation or wet granulation of the active ingredients and any other desired excipients.

at Dry granulation can be the active ingredients and excipients compressed into a piece or a sheet and then crushed into compacted granules. The compacted granules can subsequently become a final dosage form be pressed. It goes without saying that the procedures impact or roll compaction, followed by crushing and re-pressing cause the hydrogel, the Superdisintegrant, the tannic acid and the active ingredients in intragranular form the final dosage form. Alternatively, any the active ingredients or the excipients after crushing the compacted Be added to the composition, resulting in that the Active ingredient or the excipient extragranular present.

When An alternative to dry granulation may be the mixed composition using direct compression techniques directly to the pharmaceutical Final dosage form to be pressed. Direct compression produces one more uniform tablet without granules. So the active ingredients and any other desired excipient with the composition mixed before direct press tableting. Such additional Excipients, which are for a direct press tableting are particularly suitable, include microcrystalline Cellulose, spray-dried lactose, dicalcium phosphate dihydrate and colloidal silica.

A additional alternative to dry granulation is wet granulation. The mixture of excipients can be made using an alcohol or water and alcohol mixtures as a granulation solvent by standard granulation techniques known in the art granulated, followed by drying, sieving, milling and pressing to the final dosage form.

The Active ingredients can be made using conventional Pressing techniques are compacted.

Has been the invention so far with reference to certain preferred embodiments described, it will continue through the following non-limiting Examples illustrated.

EXAMPLES

EXAMPLE 1: In Vivo Study on improving the bioavailability of alendronate: effect of varying pre-dose intervals of alphacalcidol in one Drug combination scheme with alendronate.

A In vivo study on an animal model was carried out to determine if alpha-cacalcole is present at varying pre-dose intervals (Time intervals) in combination therapy with alendronate was compared to the bioavailability of alendronate the administration of alendronate alone.

Six female beagle dogs, each about 2 years old and weighing about 9 kg, were the animal models in this study. The same animals were used in each of five separate treatment sessions, each lasting 34 to 42 hours, with the duration of each session depending on the pre-dose test interval being measured. The same drugs were administered at the identical dose at each treatment, namely, Alphacalcidol (ALPHA ^® D3, 1.0 ug gel capsule; TEVA) was the vitamin D ₃ derivative, which has been administered as the pre-dose drug, and alendronate sodium ( Fosalan ^®, 10 mg tablet, Merck, Sharp & Dohme) was the bisphosphonate, which was administered as a therapeutic drug. There was a 7-day washout period between sessions. The clinical condition of each dog was checked within 48 hours before each treatment session and again after the last session. At each session, the animals were given the dose in the fasted state (npo 10 to 12 hours). The dogs were fed standard feed (canned bonzo, 1 whole can, 425 grams) five hours after the administration of the alendronate therapeutic dose.

While At each meeting, the dogs became involved in metabolism steel cages held. Urine samples were taken from the bottom of the metabolism cages won. At each rally point, two were representative Urine samples (about 5 ml each) in sealed polypropylene vials and immediately frozen at -20 ° C. The rest the sample was frozen and stored.

The Urine samples were analyzed by high performance liquid chromatography (HPLC) with Fluorescence Detection (Anapharm, Inc., Quebec, Canada) analyzed on alendronate.

at each session, the pre-dose study drug, Alphacalcidol, in the morning in the pasted state with 10 to 20 ml of tap water, administered to allow swallowing. While the observation (collection) time of each session became the Dogs having a gastroesophageal tube 300 ml tap water in the evening before the start of each test session and subsequently with 150 ml of tap water every two hours the administration of the therapeutic dose of alendronate for supplied with water for up to 10 hours. As noted above, was eating 4 hours after the administration of alendronate allows.

In the first (reference) study session, the pre-dose of alphacalcidol and the therapeutic dose of alendronate were co-administered with 10 to 20 ml of tap water to allow for swallowing. administered immediately followed by 250 ml of tap water via a gastroesophageal tube.

In The second to fifth study sessions were the pre-dose of alphacalcidol with 10 to 20 ml of tap water. In 1, 2, 3 and 6 hour intervals, respectively, after administration The pre-dose of alphacalcidol was in each of the sequential Study sessions the therapeutic dose of alendronate at 10 administered to 20 ml of tap water, followed immediately by 250 ml Tap water over a gastroesophageal tube.

For each alphacalcidol pre-dose time interval tested was the accumulated levels of alendronate in urine 24 hours after the administration of the alendronate therapeutic dose Collection times, which are at the hour 0 before the alendronate dose begin and return at 3, 6, 9, and 24 hours after the alendronate dose certainly.

The Results of analyzes of alendronate in urine for the Five treatments are shown in Tables 1A to 1E, 2 and 5 3 listed. Tables 1A to 1E give the results excretion of alendronate in canine urine for each of the Test sessions again. In Table 2 is the average of the total excreted alendronate as a function of the time interval between alpha-calcidol administration and alendronate administration compiled. Table 3 gives the average of the total excreted alendronate as a function of the time interval between calcitriol administration and alendronate administration which was performed in a separate test.

The Results showed that alendronate total bioavailability 6 hours after the administration of alphacalcidol considerably rise. It is expected that one finds that this increase will continue if the time interval between administration the pre-dose of alphacalcidol and its subsequent administration the therapeutic dose of alendronate at 8, 10 or 12 hours is increased. The alendronate bioavailability without the vitamin D derivative was 30 μg in this dog model to 50 μg. Calcitriol, which is 3 hours before alendronate administration was administered increased this value to 108 μg. The improvement in alendronate bioavailability was similar for the two vitamin D derivatives calcitriol and alphacalcidol, but the optimal time interval between administration of the pre-dose and the maximum alendronate bioavailability was in the Delayed case of alphacalcidol. This delay may be advantageous in designing a drug combination scheme with a dose regimen that is practical and bioavailability improved by alendronate.

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TABELLE 1B (Alendronat 1 Stunde nach 1-Alpha) ZUSAMMENFASSUNG DER IM URIN AUSGESCHIEDENEN ALENDRONAT-MENGE (μg) Empfänger # Zeitdauer # Entnahmezeiten (Stunde) 0,000 3,00 6,00 9,00 24,0 Gesamt 295 2 BLQ 42,05 4,71 NRV 7,58 54,34 109 2 BLQ 39,99 4,01 NRV 3,47 47,47 612 2 BLQ 39,73 4,42 4,30 4,58 53,03 648 2 1,61 109,98 9,02 7,51 8,79 136,91 005 2 BLQ BLQ BLQ BLQ BLQ 0,00 578 2 BLQ 4,87 1,82 NRV NRV 6,69 Durchshnit 49,74

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TABELLE 1C (Alendronat 2 Stunden nach 1-Alpha) ZUSAMMENFASSUNG DER IM URIN AUSGESCHIEDENEN ALENDRONAT-MENGE (μg) Empfänger # Zeitdauer # Entnahmezeiten (Stunde) 0,000 3,00 8,00 9,00 24,0 Gesamt 295 3 3,14 25,52 NRV 3,82 5,84 38132 109 3 BLQ NRV NRV 2,30 2,97 5,27 612 3 BLQ NRV 4,11 2,73 4,11 10,95 648 3 BLQ 38,98 20,58 7,32 11,28 78,16 005 3 NRV BLQ NRV NRV NRV 0,00 578 3 BLQ 16,10 9,63 1,80 NRV 27,53 Durchshnit 26,71

• BLQ: Unter der Nachweisgrenze NRV: Kein anzeigbarer Wert

TABELLE 1D (Alendronat 3 Stunden nach 1-Alpha) ZUSAMMENFASSUNG DER IM URIN AUSGESCHIEDENEN ALENDRONAT-MENGE (μg) Empfänger # Zeitdauer # Entnahmezeiten (Stunde) 0,000 3,00 6,00 9,00 24,0 Gesamt 295 4 NRV 59,51 5,68 3,87 3,97 73,03 109 4 BLQ 8105 7,04 NRV 5,06 93,15 612 4 BLQ 35,52 5,01 NRV 4,12 44,65 648 4 BLQ 47,20 7,05 5,72 NRV 59,97 005 4 BLQ 51,07 11,11 13,24 20,07 95,49 578 4 3,81 85,63 13,41 7,10 6,81 11676 Durchschnitt 80,51

• BLQ: Unter der Nachweisgrenze NRV: Kein anzeigbarer Wert

TABELLE 1E (Alendronat 6 Stunden nach 1-Alpha) ZUSAMMENFASSUNG DER IM URIN AUSGESCHIEDENEN ALENDRONAT-MENGE (μg) Empfänger # Zeitdauer # Entnahmezeiten (Stunde) 0,000 3,00 6,00 9,00 24,0 Gesamt 295 5 BLQ 65,02 31,98 6,03 7,28 110,31 109 5 BLQ 49,30 5,09 2,39 4,64 61,42 612 5 4,10 111,68 10,42 4,61 12,55 143,36 648 5 NRV 68,15 8,78 4,25 5,27 86,45 005 5 4,73 65,30 2,55 6,54 5,56 84,68 578 5 NRV 75,32 11,65 3,71 3,67 94,35 Durchschnitt 96,76

• BLQ: Unter der Nachweisgrenze NRV: Kein anzeigbarer Wert

Tabelle 2. Durchschnitt des insgesamt ausgeschiedenen Alendronats als eine Funktion des Zeitintervalls zwischen den Alphacalcidol- und Alendronat-Verabreichungen Stunden zwischen den Verabreichungen Gesamtalendronat (μg) 0 37,5 1 49,7 2 26,7 3 80,5 6 96,8 Tabelle 3. Durchschnitt des insgesamt ausgeschiedenen Alendronats als eine Funktion des Zeitintervalls zwischen den Calcitriol- und Alendronat-Verabreichungen Stunden zwischen den Verabreichungen Gesamtalendronat (μg) 0 56,9 1 56,8 2 70,0 3 108,1 6 36,0 TABLE 1A (alendronate 0 hrs after 1-alpha) SUMMARY OF URINE-DEPENDED ALENDRONATE AMOUNT (μg) receiver time Withdrawal times (hour) # # 0,000 3.00 6.00 9.00 24.0 total 295 1 BLQ NRV 6.09 NRV NRV 6.09 109 1 BLQ 27.33 4.27 BLQ 4.20 35,80 612 1 BLQ 28,01 NRV NRV 2.91 30.92 648 1 BLQ 40,99 6.90 8.45 7.02 63.36 005 1 BLQ 28.26 8.87 3.52 2.90 43.55 578 1 BLQ 25.29 13.99 2.21 3.68 45.17 Durchshnitt 37.48

• BLQ: Below detection limit NRV: No displayable value

TABLE 1B (alendronate 1 hour after 1-alpha) SUMMARY OF URIN-DEPENDED ALENDRONATE AMOUNT (μg) Receiver # Duration # Withdrawal times (hour) 0,000 3.00 6.00 9.00 24.0 total 295 2 BLQ 42.05 4.71 NRV 7.58 54.34 109 2 BLQ 39.99 4.01 NRV 3.47 47.47 612 2 BLQ 39.73 4.42 4.30 4.58 53.03 648 2 1.61 109.98 9.02 7.51 8.79 136.91 005 2 BLQ BLQ BLQ BLQ BLQ 0.00 578 2 BLQ 4.87 1.82 NRV NRV 6.69 Durchshnit 49.74

• BLQ: Below detection limit NRV: No displayable value

TABLE 1C (Alendronate 2 Hours After 1-Alpha) SUMMARY OF URIN-DEPENDED ALENDRONATE AMOUNT (μg) Receiver # Duration # Withdrawal times (hour) 0,000 3.00 8.00 9.00 24.0 total 295 3 3.14 25.52 NRV 3.82 5.84 38132 109 3 BLQ NRV NRV 2.30 2.97 5.27 612 3 BLQ NRV 4.11 2.73 4.11 10,95 648 3 BLQ 38.98 20.58 7.32 11.28 78.16 005 3 NRV BLQ NRV NRV NRV 0.00 578 3 BLQ 16.10 9.63 1.80 NRV 27.53 Durchshnit 26.71

• BLQ: Below detection limit NRV: No displayable value

TABLE 1D (Alendronate 3 Hours After 1-Alpha) SUMMARY OF URINE-DEPENDED ALENDRONATE AMOUNT (μg) Receiver # Duration # Withdrawal times (hour) 0,000 3.00 6.00 9.00 24.0 total 295 4 NRV 59.51 5.68 3.87 3.97 73.03 109 4 BLQ 8105 7.04 NRV 5.06 93.15 612 4 BLQ 35.52 5.01 NRV 4.12 44,65 648 4 BLQ 47,20 7.05 5.72 NRV 59.97 005 4 BLQ 51.07 11.11 13.24 20.07 95.49 578 4 3.81 85.63 13.41 7.10 6.81 11676 average 80.51

• BLQ: Below detection limit NRV: No displayable value

TABLE 1E (alendronate 6 hours after 1-alpha) SUMMARY OF URIN-DEPENDED ALENDRONATE AMOUNT (μg) Receiver # Duration # Withdrawal times (hour) 0,000 3.00 6.00 9.00 24.0 total 295 5 BLQ 65.02 31.98 6.03 7.28 110.31 109 5 BLQ 49,30 5.09 2.39 4.64 61.42 612 5 4.10 111.68 10.42 4.61 12.55 143.36 648 5 NRV 68.15 8.78 4.25 5.27 86.45 005 5 4.73 65,30 2.55 6.54 5.56 84.68 578 5 NRV 75.32 11.65 3.71 3.67 94.35 average 96.76

• BLQ: Below detection limit NRV: No displayable value

Table 2. Mean total excreted alendronate as a function of the time interval between alpha-calcium and alendronate administrations Hours between administrations Total alendronate (μg) 0 37.5 1 49.7 2 26.7 3 80.5 6 96.8 Table 3. Mean total excreted alendronate as a function of time interval between calcitriol and alendronate administrations Hours between administrations Total alendronate (μg) 0 56.9 1 56.8 2 70.0 3 108.1 6 36.0

EXAMPLE 2: In vivo study on improving the bioavailability of alendronate: effect of varying pre-dose intervals of calcitriol in a drug combination scheme with alendronate.

A In vivo study on an animal model was carried out to determine if calcitriol is present at varying pre-dose intervals (Time intervals) was given in a combination therapy with alendronate, the bioavailability of alendronate compared with the Increased administration of alendronate alone.

Six female beagle dogs, each about 2 years old and weighing about 9 kg, were the animal models in this study. The same animals were used in each of five separate treatment sessions, each lasting 22 to 24 hours, the duration of each session being dependent on the pre-dose test interval being measured. The same drugs were identi rule administered dosages of each treatment, namely, calcitriol (Rocaltrol ^®, 25.0 ug gel capsule, ROCHE) was the vitamin D ₃ derivative, which has been administered as the pre-dose drug, and alendronate sodium (Fosamax ^®, 10 mg tablet , Merck, Sharp & Dohme) was the bisphosphonate which was administered as the therapeutic drug. There was a 7-day washout period between sessions. The clinical condition of each dog was checked within 48 hours before each treatment session and again after the last session. At each session, the animals were given the dose in the fasted state (npo 10 to 12 hours). The dogs were fed a standardized diet (Shur-Grain, Canada, 200 to 250 grams) five hours after the administration of the alendronate therapeutic dose.

While At each meeting, the dogs became involved in metabolism steel cages held. Urine samples were taken from the bottom of the metabolism cages won. At each rally point, two were representative Urine samples (about 15 ml each) in sealed polypropylene vials and immediately frozen at -20 ° C. The rest the sample was frozen and stored.

The Urine samples were analyzed by HPLC with fluorescence detection (Anapharm, Inc., Quebec, Canada) on alendronate.

at each session, the pre-dose study drug, calcitriol, in the morning in the pasted state with 10 to 20 ml of tap water, to allow for swallowing, administered, followed from a supply of water with 250 ml of tap water (set to a pH of 2.0) via a gastroesophageal Tube. During the observation (collection) period From each session, the dogs were over a gastroesophageal Tube with 200 to 250 ml tap water (set on a pH of 2.0) the evening before the start of each test session and subsequently with 200 to 250 ml of pH adjusted tap water every two hours after the administration of the therapeutic dose supplied with water by Alendronat for up to 10 hours. As noted above, 4 hours after administration Alendronate allows eating.

In the first (reference) study session became the therapeutic dose of alendronate alone with a supply of water by administration of 250 ml pH adjusted tap water via a gastroesophageal Tube administered.

In The second (reference) study session included the predose dose of calcitriol and the therapeutic dose of alendronate concurrent with 10 up to 20 ml of tap water to allow swallowing; immediately followed by 250 ml of pH adjusted tap water a gastroesophageal tube.

In In the third to sixth study sessions, the pre-dose of Calcitriol administered with 10 to 20 ml of tap water. At intervals from 1, 2, 3 and 6 hours after administration of the pre-dose, respectively Calcitriol was used in each of the consecutive study sessions the therapeutic dose of alendronate with 10 to 20 ml of tap water immediately followed by 250 ml of tap water over one gastroesophageal tube.

For Each calcitriol pre-dose time interval tested was the cumulative one Level of urinary alendronate concentrations over 12 hours after administration of the therapeutic alendronate dose at collection times, which start with the hour 0 before the alendronate dose and again at 3, 6, 9 and 24 hours after the alendronate dose.

The Results of analyzes of alendronate in urine for the Five treatments are listed in Table 4. In Table 4 is the average of the total eliminated Alendronate as a function of the time interval between calcitriol administration and alendronate administration.

The results showed that alendronate total bioavailability increased significantly 3 hours after the administration of calcitriol. The alendronate bioavailability without the vitamin D derivative was about 30 μg to 50 μg in this dog model. Calcitriol administered 3 hours prior to alendronate administration increased this value to 108 μg. By delaying the release of the calcitriol pre-dose for 3 to 5 hours and waiting for a time interval of several hours prior to administration of the bisphosphonate, the drug combination scheme is both more effective and more practical. Table 4. Mean total excreted alendronate as a function of time interval between calcitriol and alendronate administrations Hours between administrations Total alendronate (μg) 0 56.9 1 56.8 2 70.0 3 108.1 6 36.0

EXAMPLE 3: In Vivo Study on improving the bioavailability of alendronate: effect of varying pre-doses in a drug combination scheme with alendronate.

A In vivo study on an animal model was carried out to determine if calcitriol or alphacalcidol, which are in varying Pre-dose intervals (time intervals) in a combination therapy were administered with alendronate, the bioavailability of alendronate compared to the administration of alendronate alone elevated.

The procedure of Example 1 was used. This study compared sessions Fosalan ^® alone dosage of Fosalan ^® with pre-dosing of Alphacalcidol at pre-dose intervals of 6 hours, 8 hours and 10 hours and dosage of Fosalan ^® with pre-dosing of calcitriol with a pre-dose interval of 3 hours. The results are shown in Table 5 below. Table 5: Cumulative urinary alendronate (μg) Dog no. Fosalen alone Cakitriol 3 h pre-dose Alphacalcidol 6 h pre-dose Alphacalcidol 8 h pre-dose Alphacalcidol 10 h pre-dose 205 48.84 106.68 77.78 110.49 233.93 109 65.52 73.68 44.34 90.85 48.66 612 20.67 51.48 81.69 116.53 86.74 648 83.88 138.12 77.83 95.71 192.41 005 34.06 136.86 104.74 85.29 64.46 578 61.75 222.4 69,57 77.67 12.23 average 52.5 121.5 76.0 96.1 106.4 Median 53.5 121.8 77.8 93.3 75.6 Std Dev. 22.8 60.2 19.5 14.9 87.2

Has been the invention so far with reference to various preferred embodiments the skilled person will modifications of this exemplary Recognize embodiments that are not of the spirit and from the scope of the invention as defined in the following claims is defined, deviate.

QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

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Claims (54)

Use of a bisphosphonate for the preparation a drug for the treatment of osteoporosis, metastatic Bone disease and Paget's disease in patients receiving a biphosphonate is administered, wherein the medicament for administering an effective Pre-dose of a vitamin D derivative before administering the bisphosphonate is prepared. Use according to claim 1, wherein the release the vitamin D derivative pre-dose is delayed. Use according to one of claims 1 or 2, wherein the predose of the vitamin D derivative is about 0.1 μg to about 10 μg. Use of a vitamin D derivative for the manufacture a drug for the treatment of osteoporosis, metastatic Bone disease and Paget's disease in patients receiving a bisphosphonate wherein the medicament is for administering the bisphosphonate prepared after administering the vitamin D derivative. Use of a vitamin D derivative and a bisphosphonate for the manufacture of a medicament for the treatment of osteoporosis, metastatic bone disease and Paget's disease in patients, which a bisphosphonate is administered, the drug for Administering the vitamin D derivative and then after a time interval Administering the bisphosphonate is prepared. Use according to any one of claims 1 to 5, wherein the vitamin D derivative is selected from calcitriol, alphacalcidol, 24,25-dihydroxyvitamin D ₃ and calcifediol. Use according to claim 6, wherein the vitamin D derivative Alphacalcidol is. Use according to claim 6, wherein the vitamin D derivative Calcitriol is. Use according to one of claims 5 to 7, wherein the time interval is approximately equal to the time extent, which the blood calcium level to reach a maximum after administration of the vitamin D derivative needed. Use according to claim 9, wherein the time interval at least about 6 hours. Use according to claim 9, wherein the time interval about 6 hours to about 14 hours. Use according to one of claims 1 to 5, wherein the bisphosphonate of alendronate, risedronate, etidronate, Zoledronate and tiludronate is selected. Use according to claim 12, wherein the bisphosphonate Alendronate is. Use according to claim 13, wherein the amount of alendronate is about 10 mg to about 70 mg. Use according to claim 2, wherein the pre-dose of the Vitamin D derivative is administered at bedtime and the bisphosphonate is administered before eating. Use according to claim 5, wherein the time interval is a period of fasting. Use according to claim 2, wherein the pre-dose with sustained release of the vitamin D derivative, a dosage form with an enteric coating with delayed Release is. Use according to claim 17, wherein the release of the vitamin D derivative for at least about 3 hours to about 5 hours is delayed. Use of a bisphosphonate for a Drug for the treatment of osteoporosis, metastatic bone disease and Paget's disease in patients given a biphosphonate wherein the medicament is for administering an effective pre-dose a vitamin D derivative before administering the bisphosphonate is prepared. Use according to claim 19, wherein the release the vitamin D derivative pre-dose is delayed. Use according to one of claims 19 or 20, wherein the predose of the vitamin D derivative is about 0.1 μg to about 10 μg. Use of a vitamin D derivative for a drug used to treat osteoporosis, metastatic bone disease and Paget's disease in patients given a bisphosphonate , wherein the medicament for administering the bisphosphonate after preparing the administration of the vitamin D derivative. Use of a vitamin D derivative and a bisphosphonate for a drug for the treatment of osteoporosis, metastatic Bone disease and Paget's disease in patients receiving a bisphosphonate administered, the drug being used to administer the vitamin D derivative and then after a time interval administer the bisphosphonate is prepared. Use according to any one of claims 19 to 23, wherein the vitamin D derivative is selected from calcitriol, alphacalcidol, 24,25-dihydroxyvitamin D ₃ and calcifediol. Use according to claim 24, wherein the vitamin D derivative Alphacalcidol is. Use according to claim 24, wherein the vitamin D derivative Calcitriol is. Use according to one of claims 23 to 25, where the time interval is approximately equal to the amount of time, which the blood calcium level to reach a maximum after Administering the vitamin D derivative needed. Use according to claim 27, wherein the time interval at least about 6 hours. Use according to claim 27, wherein the time interval about 6 hours to about 14 hours. Use according to one of claims 19 to 23, wherein the bisphosphonate of alendronate, risedronate, etidronate, Zoledronate and tiludronate is selected. Use according to claim 30, wherein the bisphosphonate Alendronate is. Use according to claim 31, wherein the amount of alendronate is about 10 mg to about 70 mg. Use according to claim 20, wherein the pre-dose the vitamin D derivative is administered at bedtime and the Bisphosphonate is administered before eating. Use according to claim 23, wherein the time interval is a period of fasting. Use according to claim 20, wherein the pre-dose with sustained release of the vitamin D derivative one Dosage form with an enteric coating with delayed release. Use according to claim 30, wherein the release of the vitamin D derivative for at least about 3 hours to about 5 hours is delayed. Use of a bisphosphonate containing Drug for the treatment of osteoporosis, metastatic bone disease and Paget's disease in patients receiving a biphosphonate wherein the medicament is for administering an effective pre-dose of a Vitamin D derivative prepared before administering the bisphosphonate is. Use according to claim 37, wherein the release the vitamin D derivative pre-dose is delayed. Use according to one of claims 37 or 38, wherein the pre-dose of the vitamin D derivative is about 0.1 μg to about 10 μg. Use of a medicament containing a vitamin D derivative for the treatment of Osteoporo se, metastatic bone disease and Paget's disease in patients administered a bisphosphonate, wherein the medicament is for administering the bisphosphonate after administering the vitamin D derivative. Use of a vitamin D derivative and a Bisphosphonate containing drug for the treatment of osteoporosis, metastatic bone disease and Paget's disease in patients, which a bisphosphonate is administered, the drug for Administering the vitamin D derivative and then after a time interval Administering the bisphosphonate is prepared. Use according to any one of claims 1 to 41, wherein the vitamin D derivative is selected from calcitriol, alphacalcidol, 24,25-dihydroxyvitamin D ₃ and calcifediol. Use according to claim 42, wherein the vitamin D derivative Alphacalcidol is. Use according to claim 42, wherein the vitamin D derivative Calcitriol is. Use according to one of claims 41 to 43, wherein the time interval is approximately equal to the time scale, which the blood calcium level to reach a maximum after Administering the vitamin D derivative needed. Use according to claim 45, wherein the time interval at least about 6 hours. Use according to claim 45, wherein the time interval about 6 hours to about 14 hours. Use according to one of claims 37 to 41, wherein the bisphosphonate consists of alendronate, risedronate, etidronate, Zoledronate and tiludronate is selected. Use according to claim 48, wherein the bisphosphonate Alendronate is. Use according to claim 49, wherein the amount of alendronate is about 10 mg to about 70 mg. Use according to claim 38, wherein the pre-dose the vitamin D derivative is administered at bedtime and the Bisphosphonate is administered before eating. Use according to claim 41, wherein the time interval is a period of fasting. Use according to claim 38, wherein the pre-dose with sustained release of the vitamin D derivative one Dosage form with an enteric coating with delayed release. Use according to claim 53, wherein the release of the vitamin D derivative for at least about 3 hours to about 5 hours is delayed.