Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1999-12-14
2001-06-12
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S464000, C424S489000, C424S493000, C424S494000
Reexamination Certificate
active
06245352
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a pharmaceutical formulation. More particularly, it relates to a new formulation of the compound tamoxifen citrate.
BACKGROUND OF THE INVENTION
Tamoxifen citrate is the non-proprietary name for the compound (Z)-2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethylamine 2-hydroxy-1,2,3-propanetricarboxylic acid. The compound is used in the treatment and prevention of breast cancer, and is believed to exert its anti-tumor effect through action as an anti-estrogen at estrogen binding sites in breast tissue. The compound and its preparation are described, for example, in U.S. Pat. No. 4,536,516.
Existing commercial formulations of tamoxifen citrate, such as NOLVADEX® (produced by Zeneca Pharmaceuticals, Wilmington Del., USA) and NOLVADEX® D (produced by Zeneca Limited, Macclesfield Cheshire, United Kingdom), contain 10 mg or 20 mg of the active ingredient, tamoxifen. Based on the results of clinical studies, it is believed that the optimum dose is 20 mg per day, which may be achieved by administering 10 mg tablets twice a day or a 20 mg tablet once a day.
Tamoxifen citrate is a compound with relatively poor solubility.
Formulations of a compound with relatively poor solubility can be relatively expensive to manufacture. Thus during manufacture, the dissolution rate of each batch of formulated compound must be tested against a dissolution specification to ensure consistency and compliance. Examples of such dissolution specifications are contained in the United States Pharmacopeia (USP) and the British Pharmacopoeia (BP). Batches that fail to pass the specification must be rejected. Formulations in which the dissolution rate of a compound is relatively close to the specification exhibit a relatively higher incidence of failed batches due to manufacturing variability. It is generally desirable to have a formulation that routinely passes the dissolution specification by a wide margin.
It is apparent that the compositions of the formulations of commercially available tamoxifen citrate vary around the world. For example, in the United States, NOLVADEX® 10 mg (produced by Zeneca Pharmaceuticals, Wilmington Del., USA) is reported in the U.S. Physicians Desk Reference, 50
th
Edition 1996 (see above) to be formulated with carboxymethylcellulose calcium, magnesium stearate, mannitol and starch. In Europe, the Italian Directory of Medicines, 1994 (OEMF spa, Via Edolo- 20125 Milano) reports that NOLVADEX® D 20 mg (produced by Zeneca Limited, Macclesfield Cheshire, United Kingdom) contains tamoxifen citrate (30.4 mg), lactose (234 mg), starch (82.2 mg), gelatin (2.2 mg), croscarmellose sodium (7.2 mg), magnesium stearate (4.0 mg), hydroxypropylmethylcellulose (5.4 mg), polyethyleneglycol (“macrogol”) (1.1 mg), and titanium dioxide (1.6 mg), the latter three ingredients presumably forming a coating for the tablet. The 10 mg formulation has half the weight of each ingredient.
BRIEF SUMMARY OF THE INVENTION
A new 20 mg tablet formulation of tamoxifen citrate has now been found which exhibits a much faster dissolution rate than either the commercial formulation of NOLVADEX® 20 mg in the USA or the commercial formulation of NOLVADEX® D 20 mg in Europe.
Accordingly, the present invention provides a pharmaceutical formulation, which comprises from 5 to 15% by weight of tamoxifen citrate and a first disintegrant which is croscarmellose sodium, the percentage by weight of croscarmellose sodium present in the formulation being chosen such that, in six 20 mg unit doses, an average of at least 65 percent by weight of the tamoxifen citrate in the formulation will dissolve within 10 minutes in 1000 mL of 0.02N hydrochloric acid at 37° C. when stirred at 100 rpm.
DETAILED DESCRIPTION OF THE INVENTION
The improved dissolution characteristics of the formulation according to the present invention are surprising, because NOLVADEX® 20 mg and NOLVADEX® D 20 mg have been found to exhibit essentially the same dissolution characteristics. Thus the presence of croscarmellose sodium in NOLVADEX® D 20 mg does not appear to confer any improved dissolution characteristics, when a comparison is made between NOLVADEX® 20 mg and NOLVADEX® D 20 mg.
The formulation may be in the form of a tablet or a capsule. Each tablet or capsule may contain, for example, 10 mg or 20 mg of tamoxifen in the form of tamoxifen citrate. Preferably it is in the form of a tablet, most preferably a 20 mg tablet.
It will be appreciated that the dissolution rate of tamoxifen citrate in a given formulation will differ according to whether the formulation is in the form of a tablet or a capsule, and depending upon how much tamoxifen citrate is present in each unit dose. For example, the tamoxifen citrate in a 10 mg tablet will dissolve faster than that in a 20 mg tablet of the same formulation.
A tablet may be un-coated or coated, for example with a conventional coating containing a colored dye, and may be of any shape, for example a disc.
As used in this specification, the term percentage by weight of an ingredient in the formulation refers to the percentage by weight of that ingredient based upon the total weight of the un-coated formulation. Thus, for example, in the Italian formulation of NOLVADEX® D 20 mg described hereinabove, the percentage by weight of croscarmellose sodium in the tablet formulation is 2%.
Preferably the percentage by weight of croscarmellose sodium present in the formulation is chosen such that at least 70 percent by weight of the tamoxifen citrate in the formulation will dissolve within 10 minutes, more preferably at least 75% by weight, especially at least 80% by weight.
The formulation preferably consists of an inter-granular component and an intra-granular component, said inter-granular component containing at least some of the croscarmellose sodium and the tamoxifen citrate. It will be appreciated that the presence of an inter-granular component and an intra-granular component results from the way in which the formulation is made, by granulating together the ingredients of the inter-granular component, and then mixing the granulated material so obtained with the ingredients of the intra-granulating material.
Preferably the inter-granular component further comprises from 5 to 15% by weight of a second disintegrant, from 55 to 75% by weight of a diluent and from 0.5 to 5% by weight of a binder, based upon the weight of the formulation.
The second disintegrant is preferably selected from starch and microcrystalline cellulose. Most preferably it is microcrystalline cellulose.
The diluent is preferably selected from lactose and mannitol. The mannitol may be powdered or granular. Preferably the mannitol is granular. It has been found that a higher percentage by weight of croscarmellose sodium may be required when powdered mannitol is used compared with when granular mannitol is used.
The binder is preferably selected from gelatin and polyvinylpyrrolidone. Most preferably it is polyvinylpyrrolidone.
The inter-granular component preferably contains from 0.75 to 2.5 percent by weight of croscarmellose sodium, based on the weight of the formulation.
Preferably the intra-granular component comprises from 5 to 15% by weight of a third disintegrant and from 0.5 to 1.5% by weight of a lubricant, based upon the total weight of the formulation.
The third disintegrant is preferably selected from starch and microcrystalline cellulose. Most preferably it is microcrystalline cellulose.
The lubricant is preferably magnesium stearate.
The intra-granular component preferably comprises from 0 to 1.5 percent by weight of croscarmellose sodium, based on the weight of the formulation.
When the second disintegrant is starch, the percent by weight of croscarmellose sodium in the formulation is preferably at least 3.0.
When the diluent is mannitol, the percent by weight of croscarmellose sodium in the formulation is preferably at least 2.0.
The formulation may further comprise a dye.
The formulation according to the invention may be prepared in a conventional manner.
Thus, the formul
Arbuthnot Gordon Nelson
Lomas Karen Klapper
Meyer Glenn Alan
Eli Lilly and Company
Hay Martin A.
Page Thurman K.
Tran S.
Voy Gilbert V.
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