Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
1997-08-25
2001-04-24
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S457000, C424S490000, C514S778000, C514S781000, C514S960000, C514S962000
Reexamination Certificate
active
06221390
ABSTRACT:
BACKGROUND
This invention relates to a novel pharmaceutical composition having an antihypertensive agent and an antikaliuretic agent in combination that provides effective diuretic and hypertensive properties while also being capable of resisting or reversing hypokalemia. In particular, this invention provides a novel pharmaceutical composition having hydrochlorothiazide (6-chloro-3,4-dihydro-2H-1,2,3benzothiadiazine-7-sulfonamide-1,1-dioxide) and triamterene (2,4,7-triamino-6-phenylpteridine) as active ingredients, the composition exhibiting improved dissolution and bioavailability characteristics for both active ingredients.
This invention also relates to an improved method for producing pharmaceutical compositions having two or more active ingredients which differ significantly from each other in their relative hydrophobic and/or hydrophilic and/or physiological characteristics in gastrointestinal fluid.
This invention further relates to an improved method for treating hypertensive patients with a novel pharmaceutical composition having an antihypertensive agent and an antikaliuretic agent in combination that provides effective diuretic and hypertensive properties while also being capable of resisting or reversing hypokalemia.
Currently, a pharmaceutical combination composition having 25 mg hydrochlorothiazide (6-chloro-3,4-dihydro-2H-1,2,3 benzothiadiazine -7-sulfonamide-1,1-dioxide) and 37.5 mg triamterene (2,4,7-triamino-6-phenylpteridine) is being marketed under the Dyazide® (SmithKline Beecham) label. Various granulation methods have been described for the combination pharmaceutical product.
U.S. Pat. No. 4,255,413, Rattle et al., issued Mar. 10, 1981 and U.S. Pat. No. 4,804,540, Nugent et al., issued Feb. 14, 1989 involve using a wet granulation method. This granulation method requires numerous steps, including weighing, mixing, granulation, screening the damp mass, drying, dry screening, and lubrication. Wet granulation processes need an oven or fluid bed to dry at suitable moisture content. Incomplete drying may cause processing problems and may affect stability. Several steps in this method increase the cost for producing a combination pharmaceutical combination. For example, the addition of water to the process requires additional costly validation studies and on-going testing to ensure that the water used therein is microbe and virus-free. Further, the time and energy consumed during the drying step greatly increases the costs associated with this method. Therefore, producing oral dosage forms using a wet granulation method, especially for large scale production, is costly in terms of labor, energy consumed, and time involved.
A melt granulation method incorporating polyethylene glycol (“PEG”) into the combination pharmaceutical composition has been described in U.S. Pat. No. 4,793,999, Sheth, issued on Dec. 27, 1988. This process requires heating the batch containing the active ingredients and PEG (“the content”) to at least 55° C. in order to fuse the high molecular weight PEG prior to cooling, thereby requiring special equipment such as jacketed mixer or a fluid bed coater capable of heating the content at a desirable temperature, e.g., at least 55° C. The relatively high energy requirement in the melt granulation method increases the costs associated with formulating the desired pharmaceutical composition and the heating process may contribute stability problems. In production scale, the energy requirement makes this method economically disadvantageous.
A slugging or compacting granulation has been described in U.S. Pat. Nos. 4,444,769, Blume et al., issued Apr. 24, 1984; U.S. Pat. No. 4,526,777, Blume et al., issued Jul. 2, 1985; and U.S. Pat. No. 4,547,498, Blume et al., issued Oct. 15, 1985. In this method, each active ingredient and various carriers are weighed, screened, divided into two batches, blended, screened, slugged or compacted, and comminuted using a screen. After being comminuted, the two separate batches are then mixed for final dosage formation. This compaction granulation process requires a special equipment, e.g., roller compactor, for slugging. To achieve desirable results, controlled pressure during slugging is required. For example, excessive pressure may produce hard slugs that may affect the drug release profile. This compaction granulation method requires numerous labor and time-intensive steps that increase costs associated with the formulation.
U.S. Pat. No. 4,681,765, Guley, issued Jul. 21, 1987 describes a mixed granulation method for producing combination pharmaceutical compositions. This method involves a multi-step process wherein water insensitive materials are weighed, dry mixed and wetted using water, resulting in a wet granulation. The wet granulation is then screened and dried to produce a dried granulation. The water sensitive materials are then added as a dry blend to the dried granulation, mixed, screened and blended until uniform. Several steps in this method increase the cost for producing a combination pharmaceutical combination. For example, the addition of water to the process requires additional costly validation studies and on-going testing to ensure that the water used therein is microbe and virus-free. Further, the energy consumed during the drying step greatly increases the costs associated with this method.
What is needed, therefore, is an efficient and cost-effective formulation method for producing a combination pharmaceutical composition containing hydrochlorothiazide and triamterene. The present invention satisfies this need by providing a dry mixing method for producing a hydrochlorothiazide and triamterene combination pharmaceutical composition that, surprisingly, provides acceptable bioavailability and dissolution characteristics using a more economical process.
SUMMARY
The present invention provides, in a presently preferred embodiment, a pharmaceutical composition containing both hydrochlorothiazide and triamterene, particularly in solid dosage form, with the characteristics and properties of acceptable bioavailability, with appropriate absorption of both ingredients, which permits desirable effective diuretic and antihypertensive activity while resisting or reversing hypokalemia.
It is therefore an object of the present invention to provide a safe and effective pharmaceutical composition combining hydrochlorothiazide and triamterene and which is adapted to serve as an antihypertensive and diuretic agent while resisting or reversing hypokalemic side effects.
An additional object of the present invention is to provide a dry mixing formulation method for hydrochlorothiazide and triamterene that provides acceptable bioavailability and dissolution characteristics of the combination composition and is significantly more simple and cost-effective than previously described methods. It is also an object of the present invention to provide a solid dosage unit form produced by a dry mixing formulation method. It is a further object of the present invention to provide treatment of hypertensive patients using a solid dosage unit produced by a dry mixing formulation method.
These and other objects of the present invention will become apparent from the following detailed description.
DETAILED DESCRIPTION
In a preferred embodiment of the present invention, hydrochlorothiazide (6-chloro-3,4-dihydro-2-H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide) is combined with triamterene (2,4,7-triamino-6-phenylpteridine) and non-toxic pharmaceutically acceptable carriers or other materials to produce the desired dosage form.
A preferred embodiment for the method of manufacturing the combination pharmaceutical composition of the present invention involves the steps of providing respective quantities of triamterene and hydrochlorothiazide at a weight ratio of triamterene to hydrochlorothiazide of about 1.5:1. These ingredients are dry blended together with citric acid and a nonionic surfactant. The blended product is milled and mixed with certain additional dry carrier materials or excipients including a disintegrant, a dil
Ahmed Salah U.
Naringrekar Gandha
Barr Laboratories, Inc.
Bryan Cave LLP
Criares Theodore J.
Haracz Stephen M.
Waddell Mark E.
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