Enteric coated formulation for bisphosphonic acids and salts...

Details Enteric coated formulation for bisphosphonic acids and salts... Enteric coated formulation for bisphosphonic acids and salts...

2000-09-26

2004-01-13

Spear, James M. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Capsules

C424S461000, C424S462000, C424S463000, C424S464000, C424S465000, C424S474000, C424S480000, C424S482000, C424S494000, C424S497000

Reexamination Certificate

active

06676965

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a pharmaceutical composition, a process of preparing the pharmaceutical composition and a method of using the pharmaceutical composition. Specifically, the invention provides a pharmaceutical composition containing bisphosphonic acids or salts thereof for use in the treatment of osteoporosis and other disorders caused by the abnormal dissolution or deposition of calcium salts.
2. Background of the Invention
Methods of preparing bisphosphonic acids are set forth in U.S. Pat. No. 3,962,432; U.S. Pat. No. 4,054,598; U.S. Pat. No. 4,267,108; U.S. Pat. No. 4,327,039; U.S. Pat. No. 4,407,761; U.S. Pat. No. 4,621,077; U.S. Pat. No. 4,624,947; U.S. Pat. No. 4,746,654; U.S. Pat. No. 4,922,007; and EPO Patent Pub. No. 0,252,504. In particular, methods for the preparation of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid and 4-amino-1-hydroxy-butylidene-1,1-bisphosphonic acid monosodium salt trihydrate may be found in U.S. Pat. No. 4,407,761 and U.S. Pat. No. 4,922,007, respectively.
The pharmaceutical compositions containing the bisphosphonic acids and salts set forth in the patents listed above have the disadvantage that the active ingredients are released from the medications almost instantaneously in the upper gastrointestinal tract causing esophageal discomfort and ulceritis. Thus, the medications have to be taken on arising for the day and at least 30 minutes before the first food, beverage or medication with a full glass (200 ml) of plain water only. The patients are advised to sit upright for about 30 minutes after ingestion of the medication and until their first food of the day. Patients are instructed not to take medication at bedtime or before arising for the day. See Physician's Desk Reference (U.S.) Product Information, 1999, p. 1798.
Several problems have been noted in the preparation of tablet formulations comprising bisphosphonic acid active ingredients, and in particular with enteric coated forms of these active ingredients. For example, U.S. Pat. No. 5,431,920 points out that “standard methods for tablet formulation of bisphosphonic acids suffer from serious difficulties.” Thus, particular dry mix formulations are required when formulating tablets from these active ingredients. In addition, this same patent points out that “[e]nteric coated dosage forms can suffer from stability problems as a result of interactions between the active drug and the acidic enteric coatings.”
The present invention solves these problems by providing dosage forms of bisphosphonic acids that do not require formulation into tablets. The dosage forms of the present invention also have improved stability as compared to prior art formulations.
SUMMARY OF THE INVENTION
In summary, the invention is related to pharmaceutical compositions comprising bisphosphonic acids and salts thereof, their preparation and method of use. More specifically, the invention is related to pharmaceutical compositions comprising alendronic acid and related compounds or salts thereof surrounding an inert core, which is covered with a seal coating which is further covered with an enteric coating.
The invention provides pharmaceutical compositions for the treatment of disorders caused by the abnormal dissolution or deposition of calcium salts. The pharmaceutical compositions of the invention comprise an inert core, an active coating containing at least one bisphosphonic acid or salt thereof surrounding the inert core, a seal coating surrounding the active coating, and an enteric coating around the seal coating. Preferred bisphosphonic acids are selected from the group consisting of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, N-methyl-4-amino-1-hydroxy-butylidene-1,1-bisphosphonic acid, 4-(N,N-dimethylamino)-1-hydroxybutyl-idene-1,1-bisphosphonic acid, 3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid, 3-(N,N-dimethylamino)-1-hydroxy-propylidene-1,1-bisphosphonic acid, 1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid, and 4-(hydroxymethylene-1,1-bisphosphonic acid)-piperidine. Alendronic acid is a particularly preferred acid and alendronate sodium trihydrate is a particularly preferred salt. Other preferred salts include etidronate, clodronate, pamidronate, and ibandronate. The compositions preferably comprise from about 4% to about 40% by weight of at least one bisphosphonic acid or salt.
Typical enteric coatings for use in the invention include one or more of hydroxypropyl methylcellulose phthalate, hydroxypropyl cellulose acetyl succinate, cellulose acetate phthalate, polyvinyl acetate phthalate, and methacrylic acid-methyl methacrylate copolymers.
The active ingredient is coated onto an inert core, such as nonpareils in the form of sugar beads or sugar/starch beads, to form the active core. The composition may further contain pharmaceutically acceptable excipients, diluents, binders, solubilizers, lubricants, disintegrants, etc. In particular the active core is formed by applying an active coating to the inert core. The active coating comprises the active ingredient and may further comprise a polymer. Preferred polymers include hydroxypropyl methlcellulose, hydroxypropyl cellulose and polyvinyl pyrrolidone Compositions according to the invention may be in the form of enteric coated beads in gelatin capsules or Peltabs, and the invention further provides a process for preparing the claimed compositions in these forms. The gelatin capsules or Peltabs may themselves be coated with an enteric coating. The inventive compositions are preferentially released in the lower gastrointestinal tract upon ingestion and thus avoid the disadvantages described above for the prior art.
The invention also provides methods for the treatment of disorders caused by the abnormal dissolution or deposition of calcium salts by treating a patient in need of such treatment with a therapeutically effective amount of the inventive compositions. Disorders caused by the abnormal dissolution or deposition of calcium salts that may be treated by the compositions of the invention include osteoporosis, osteodystrophy, Paget's disease, myositis ossificans, Bechterew's disease, cholelithiasis, nephrolithiasis, urinary calculus, arteriosclerosis, arthritis, bursitis, neuritis and tetany. The compositions are particularly useful for the treatment of osteoporosis.
The above objectives and advantages of the invention are illustrative, and not exhaustive, of those which can be achieved by the invention. The examples presented herein are non-limiting. Thus, these and other objectives and advantages of the invention will be apparent from the description herein, both as embodied herein and as modified in view of any variations which will be apparent to those skilled in the art.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention provides a pharmaceutical composition comprising from about 4% to about 40% by weight of at least one 1,1-bisphosphonic acid or salt thereof as an active ingredient. The 1,1-bisphosphonic acid is preferably selected from the group consisting of:
4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;
N-methyl-4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;
4-(N,N-dimethylamino)-1-hydroxybutylidene-1,1-bisphosphonic acid;
3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid;
3-(N,N-dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid;
1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid; and
4-(hydroxymethylene-1,1-bisphosphonic acid)-piperidine.
In the present invention, the preferred active ingredient is 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, i.e. alendronic acid, and, more preferably, its monosodium salt trihydrate, alendronate sodium trihydrate. Other bisphosphonic acids or salts thereof may be used as well, including, for example, etidronate, clodronate, pamidronate or ibandronate. Suitable salts for use in the present invention may be formed with, for example, alkali metals, amines and alkanol amines. Salts may be formed by reacting th

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