MXPA97009906A - Use of bisphosphonates to prepare compositions to prevent loss of associated bone conterapia immunosupres - Google Patents

Abstract

The present invention relates to the use of bisphosphonates, particularly alendronate, to prepare compositions for preventing or treating bone loss associated with immunosuppressive therapy, whether the immunosuppressive therapy is not associated with a transplant

Description

USE OF BISPHOSPHONATES TO PREPARE COMPOSITIONS TO PREVENT BONE LOSS ASSOCIATED WITH IMMUNOSUPPRESSIVE THERAPY FIELD OF THE INVENTION This invention relates to the use of bisphosphonates, particularly alendronate, to prevent bone loss associated with immunosuppressive therapy, and in particular when said therapy is used in conjunction with organ transplantation.

BACKGROUND OF THE INVENTION Patients suffering from various medical conditions that require an organ or bone marrow transplant, need a variety of drugs to suppress the body's tendency to reject the organ. This usually requires the patient to become one or more agents or suppressors, such as cyclic or similar, often in combination with adrenal corticosteroids, such as rnetil predmoneone. Unfortunately, the combination of the fundamental condition, immobility or reduced mobility, and drug therapy causes these patients to experience a high degree of bone loss. In addition, some suppressive agents are being tried as therapeutic agents in the treatment of various conditions that do not necessarily involve organ transplantation, such as rheumatoid arthritis, psoriasis, inflammatory bowel disease and netrotic syndrome. These patients are also at high risk for bone loss. It would be desirable to be able to cope with or prevent bone loss in a patient receiving organ transplants or receiving immunosuppressive therapy in association with an organ transplant or other underlying medical condition.

DETAILED DESCRIPTION OF THE INVENTION It has been found in accordance with this invention that bisphosphonates can prevent and treat bone loss associated with immunosuppressant therapy when administered either in a prophylactically or therapeutically effective amount. In particular, alendronate (4-arn? No-lh? Drox? But? L? Den l, lb? S phosphonate) or a pharmaceutically effective salt thereof, can provide for and treat bone loss associated with organ transplants when administered either in a prophylactically or therapeutically effective amount. A further aspect of this invention is to prevent or treat bone loss associated with immunosuppressive therapy, regardless of whether the therapy accompanies the organ transplant by administering an effective amount of β-bisphosphonate selected from the group consisting of: alendronate, etidronate , acid (1-h? drox? -et? den-bisphosphoni co), parnidronate (3-arn? no-lh? dro? propnld? en-l, 1-diphosphonate), risedronate (2- (3-? ? r? d? ln) 1-h-droiethylidene-bisphosphonic acid), clodronate (dichloro-diene-bisphosphonic acid), thiudronate (chloro-4-femlt? omet? i iden-biefosphonic acid), ibandronic acid (1-h? drox? -3 (rnet? lpent? larn? no) -? ro? l? den-b? sphosphon? co, and pharmaceutically acceptable salts of any of the foregoing and mixtures of any of the acids and any of the salts. All of the above compounds are well known in the art, Generally, the patient who receives omepra of immune suppressants in accordance with this invention. tion will receive ciclospopna or a similar drug. In addition, the patient may also receive prednisone or another corticosteroid. As used throughout the specification and the claims, the following definitions apply: "Prophylactically effective amount" - the amount of alendronate needed to prevent or reduce the severity of bone loss related to immunosuppressant therapy, regardless of whether the Irritation suppressor therapy is accompanied by organ transplantation. "Therapeutically effective amount" - the amount of alendronate needed to treat bone loss related to immunosuppressant therapy, regardless of whether immunosuppressive therapy is accompanied by organ transplantation.

In a preferred aspect of this invention, the patient will receive alendronate. Alendronate can be prepared in accordance with any of the procedures described in U.S. Pat. 5, 019,551, 4,922,007 and the application of E.U.A. series No. 08 / 285,151, filed on August 4, 1994, each of which is incorporated herein by reference. The pharmaceutically acceptable salts of alendronate include alkali metal salts (e.g., Na, K), alkaline earth metals (eg, Ca), salts of inorganic acids, such as HCl, and salts of organic acids such as acid. citric acid and amino acids. Sodium salt forms are preferred, particularly the rnonosodium trihydrate salt form. Many of the bisphosphonate compounds of the present invention can be administered in oral dosage forms such as tablets, capsules (each of which includes sustained-release or time-regulated formulations), pills, powders, granules. , elixirs, pastes, dyes, suspensions, syrups and emulsions. Likewise, they can be administered intravenously (bolus or infusion), mtraperitoneal, subcut or inmuscular, all using forms well known to those skilled in the pharmaceutical art. An effective but non-toxic amount of the desired bisphosphonate compound can be used to prevent bone loss. The dose regimen using the claimed method is selected in accordance with a variety of factors including type, age, weight, sex and medical condition of the patient; the severity of the condition that is going to rat; the daily administration; the renal and hepatic function of the patient; and the particular compound or salt thereof. A skilled physician can easily determine and prescribe the effective amount of the drug required to prevent and / or treat bone loss. The oral doses of the present invention when the alendronate is the bisphosphonate will vary from 0.05 mg per l-g of body weight per day (rng / g / day) to about 1.0 rng / kg / day. Preferred oral doses in humans can range from total daily doses of about 2.5-50 g / day during the effective treatment period, and a preferred amount is 5, 10 or 20 rng / day. Alendronate can be administered in a single daily dose or in divided doses. It is desirable that the dose be given in the absence of food, preferably from about 30 minutes to 2 hours before the meal, such as breakfast to allow adequate absorption. In the methods of the present invention, the active ingredient is typically administered in admixture with suitable diluents, excipients or pharmaceutical carriers (collectively known herein as "carrier materials") suitably selected with respect to the intended administration form, i.e., tablets oral, capsules, elixirs, syrups and the like and consistent with conventional pharmaceutical practices. For example, for oral administration in the form of a table or capsule, the active ingredient may be combined with a non-toxic, oral pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, glucose, rilethylcellulose, magnesium stearate, rnanitol, sorbitol, croscarrnelosa sodium and the like; for oral administration in liquid form, the oral drug components can be combined with any non-toxic oral pharmaceutically acceptable inert carrier such as ethanol, glyceroi, water and the like. In addition, when desired or necessary, binders, lubricants, disintegrating agents and suitable coloring agents can also be incorporated into the mixture of active ingredients and inert carrier materials. Suitable binders may include starch, gelatin, natural sugar such as glucose, anhydrous lactose, free-flowing lactose, beta-lactose and corn sweeteners, natural and synthetic gums, such as acacia, sodium tragacanth or alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. A particularly preferred tablet formulation for alendronate is that described in the U.S. Patent. No. 5,358,941 which is incorporated herein by reference. The compounds used in the method herein can also be coupled with soluble polymers as steerable drug vehicles. Said polymers may include pol v or Lpi rrol donut, pyran copolymer, pol ihydroxypropyl methacrylamide and sirres Lares. Patients who undergo therapy with mini-suppressants can be male or female of any age. Women can be pre or post enopáus as. The following non-limiting examples < They are presented to better illustrate the invention.

EXAMPLE 1 Alendronate for prevention and treatment of bone loss induced by cyclosporine 220 men and women were enrolled in a clinical trial to evaluate the effectiveness of alendronate to prevent and treat bone loss associated with immunosuppressive therapy. All subjects were receiving an organ transplant; most were receiving a heart, lung or liver transplant. Patients are grouped randomly into 5 groups receiving either placebo, 2.5 5, 10, or 20 rng / day of alendronate for one year starting within one week after transplantation. In addition to the normal amounts of ciclopopna and steroid-such as prednisone-all patients receive 1000 mg per day of calcium and 250 IU per day of vitamin D. Mineral densities in the spine and hip are monitored, and all incidences of fractures are recorded. After one year, the patient receiving alendronate (at any dose) has a significantly higher BMD in the spine and hip than the placebo patients, and they have experienced fewer fractures. This result is observed in both strata: Those with low starting BMD can see that they earn BMD. Those whose starting BMD is not low are observed to retain BMD. In this way, alendronate prevents and treats bone loss associated with immunosuppressive therapy.

Claims (8)

NOVELTY OF THE INVENTION CLAIMS

1. - The use of a bistosphonate selected from the group consisting of: alendronate, etidronate, acid (1-h? Drox? -et? Den-bisphosphonic), parnidronate (3-arn? No-lh? Dro? Ro? Id? In -1, 1-diphosphonate), risedronate (2- (3-pr? D? L) -1-hydroxyethylidene-bisphosphon, co-clodronate (dichlorornet-i-bis-phosphonic acid), thiudronate (chloro-4-phenol acid) ? ornet? ll? den-bisphosphoni co) ibandronic acid (1-hydroxy acid-3 (rnet? lpen? larn? no) ~ prop? iden-bisphosphonium, and pharmaceutically acceptable salts of any of the foregoing, and mixtures thereof in the preparation of compositions for treating or preventing bone loss associated with immunosuppressive therapy

2. The use according to claim 1, further characterized in that the patient receives immunosuppressant therapy in association with an organ transplant

3. The use according to claim 2, further characterized in that the biophosphonate is alendronate or a pharmaceutically acceptable salt. ptable of the same.

4. The use according to claim 3, further characterized in that the alendronate is in the form of the salt of nonosodium tphidrate.

5. The use according to claim 4, further characterized in that the composition is administered to provide alendronate in a prophylactically effective amount.

6. A method according to claim 5, further characterized in that the alendronate containing the composition is administered orally.

7. A method according to claim 5, further characterized in that the alendronate containing the composition is administered to provide alendronate in a dose of 2.5 to 50 mg per day.

8. The use according to claim 7, further characterized in that the dose of alendronate is 5 rng, 10 g or 20 mg per day.