Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2002-09-23
2004-02-17
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S469000, C424S470000, C514S108000, C514S114000, C514S210030, C562S013000, C562S014000, C562S018000
Reexamination Certificate
active
06692764
ABSTRACT:
BACKGROUND OF THE INVENTION
The pharmaceutical industry employs various methods for compounding pharmaceutical agents in tablet formulations. In particular, wet granulation is one of the most prevalent methods. Tablets prepared by wet granulation generally require the addition of a binding agent to keep the tablet together.
A variety of bisphosphonic acids have been disclosed as being useful in the treatment and prevention of diseases involving bone resorption. Representative examples may be found in the following:
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. 4,621,077; U.S. Pat. No. 4,624,947;
U.S. Pat. No. 4,746,654; U.S. Pat. No. 4,922,077; and EPO Patent Pub. No. 0,252,504. Standard methods for tablet formulation of bisphosphonic acids, however, suffer difficulties.
Wet granulated formulations need to have an agent called a “binder,” which, in contact with water, swells or starts dissolving, forming a gel-like consistency. Traditionally, starch, starch paste, gelatin, and cellulosics such as hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone are used as binding agents in wet granulation formulations. (See, Remington's Pharmaceutical Sciences, 18th ed, (Mack Publishing Company: Easton, Pa., 1990), pp. 1635-36). Microcrystalline cellulose, such as Avicel PH101, may be employed as a binder or compression aid in compositions prepared by dry granulation formulation, but microcrystalline cellulose functions primarily as a bulking agent in wet granulation formulations because the microcrystalline cellulose loses much of its binding properties upon wetting.
The wet granulation process helps to form agglomerates of powders. These agglomerates are called “granules.” The present invention provides for a wet granulated formulation of bisphosphonic acids and process therefor wherein the tablet formulation does not contain any binder. Instead, the drug itself acts as a binder. The absence of a separate binder keeps the formulation simpler, and minimizes adverse effects that binding agents can have on dissolution. Elimination of binder also simplifies the optimization and characterization of the formulation.
DESCRIPTION OF THE INVENTION
The present invention is directed in a first embodiment to a process for the preparation of pharmaceutical compositions of bisphosphonic acids by wet granulation formulation. This process employs a blend of a bisphosphonic acid and minimal amounts of other processing aids with no binder added. This tablet formulation is prepared by:
(1) forming a powder blend of the active ingredient with diluents,
(2) wet granulating the powder blend with water to form granules,
(3) drying the granules to remove water, and
(4) compressing the lubricated granule mixture into a desired tablet form.
The shape of the tablet is not critical.
More specifically, this embodiment of the present invention concerns a process for the preparation of a tablet containing a bisphosphonic acid as an active ingredient which process comprises:
(1) forming a powder blend of the active ingredient with diluents from 3 to 25 minutes using a mixer such as a planetary or high shear granulator,
(2) wet granulating the powder blend by the addition of water while mixing over a 2 to 30 minute period to form granules,
(3) drying the granules to remove water by the use of heated air for 10 minutes to 24 hours in a dryer (fluid bed or tray type),
(4) milling the dried granules to a uniform size,
(5) adding and blending a disintegrant with the dried milled particles for 2 to 30 minutes,
(6) adding and blending a lubricant to the mixture containing the disintegrant for 30 seconds to 20 minutes, and
(7) compressing the lubricated granule mixture into a desired tablet form.
One particularly preferred process employs a high shear granulator as a mixer and comprises the steps of:
(1) forming a powder blend of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, microcrystalline cellulose, such as Avicel PH101, and lactose with a high shear granulator for 3 to 5 minutes,
(2) wet granulating the powder blend by the addition of water while mixing over a 3 to 5 minute period to form granules with the high shear granulator,
(3) drying the granules to remove water by the use of heated air by drying 10 minutes to 1 hour with a fluid bed, or 12-24 hours in a tray dryer, preferably with a fluid bed,
(4) milling the dried granules to a uniform size using a hammer type mill,
(5) adding and blending the disintegrant croscarmellose sodium NF type A with the dried milled particles for 3 to 8 minutes,
(6) adding and blending magnesium stearate lubricant to the mixture containing the croscarmellose sodium NF type A disintegrant with a ribbon blender or a planetary mixer for 3 to 8 minutes, and
(7) compressing the lubricated granule mixture into a desired tablet form, and
(8) dedusting and storing the tablets.
Another particularly preferred process employs a planetary granulator as a mixer and comprises the steps of:
(1) forming a powder blend of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, microcrystalline cellulose such as Avicel PH101, and lactose with a planetary granulator for 10 to 25 minutes,
(2) wet granulating the powder blend by the addition of water while mixing over a 3 to 10 minute period to form granules with the planetary granulator,
(3) drying the granules to remove water by the use of heated air by drying 10 minutes to 1 hour with a fluid bed, or 12-24 hours in a tray dryer, preferably with a fluid bed,
(4) milling the dried granules to a uniform size using a hammer type mill,
(5) adding and blending the disintegrant croscarmellose sodium NF type A with the dried milled particles for 3 to 8 minutes,
(6) adding and blending magnesium stearate lubricant to the mixture containing the croscarmellose sodium NF type A disintegrant with a ribbon blender or a planetary granulator for 3 to 8 minutes, and
(7) compressing the lubricated granule mixture into a desired tablet form, and
(8) dedusting and storing the tablets.
Still another particularly preferred process employs a high shear granulator as mixer, and comprises the steps of:
(1) forming a powder blend of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, microcrystalline cellulose, such as Avicel PH101, and lactose with a high shear granulator for 3 to 5 minutes,
(2) wet granulating the powder blend by the addition of water while mixing over a 3 to 5 minute period to form granules with a high shear granulator,
(3) drying the granules to remove water by the use of heated air for 10 minutes to one hour using a fluid bed dryer,
(4) milling the dried granules to a uniform size using a hammer type mill,
(5) adding and blending the disintegrant croscarmellose sodium NF type A with the dried milled particles for 3 to 8 minutes,
(6) adding and blending magnesium stearate lubricant to the mixture containing the croscarmellose sodium NF type A disintegrant with a ribbon blender for 3 to 8 minutes,
(7) compressing the lubricated granule mixture into a desired tablet form, and
(8) dedusting and storing the tablets.
Granulation is the process of adding water to a powder mixture with mixing until granules are formed. The granulation step may be varied from 2 to 30 minutes, preferably 2 to 5 minutes. The lubrication step is the process of adding lubricant to the mixture; the lubrication step may be varied from 30 seconds to 20 minutes, preferably 3 to 8 minutes.
The disclosed process may be used to prepare solid dosage forms, particularly tablets, for medicinal administration.
Preferred diluents include: lactose, microcrystalline cellulose, calcium phosphate(s), mannitol, powdered cellulose, pregelatinized starch, and other suitable diluents. Especially preferred are lactose and microcrystalline cellulose. In particular, microcrystallione cellulose NF, especially Avicel PH101, the trademarked name for microcrystalline cellulose NF manufactured by FMC Corp. is preferred.
The disintegrant may be one of several modified starches or modified cellu
Katdare Ashok V.
Kramer Kenneth A.
Beeler Nicole M.
Crane Lawrence E
Daniel Mark R.
Garcia-Rivas J. Antonio
Merck & Co. , Inc.
LandOfFree
Wet granulation formulation for bisphosphonic acids does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Wet granulation formulation for bisphosphonic acids, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Wet granulation formulation for bisphosphonic acids will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3354547