Pharmaceutical formulation

The present invention relates to 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.degree. C. when stirred at 100 rpm.

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.RTM. (produced by Zeneca Pharmaceuticals, Wilmington Del., USA)
 and NOLVADEX.RTM. 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.RTM. 10 mg (produced by Zeneca Pharmaceuticals,
 Wilmington Del., USA) is reported in the U.S. Physicians Desk Reference,
 50.sup.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.RTM. 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.RTM. 20 mg in the USA or the commercial
 formulation of NOLVADEX.RTM. 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.degree. 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.RTM. 20 mg and
 NOLVADEX.RTM. D 20 mg have been found to exhibit essentially the same
 dissolution characteristics. Thus the presence of croscarmellose sodium in
 NOLVADEX.RTM. D 20 mg does not appear to confer any improved dissolution
 characteristics, when a comparison is made between NOLVADEX.RTM. 20 mg and
 NOLVADEX.RTM. 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.RTM. 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 formulation may be prepared by mixing the ingredients, then
 compressing them into a tablet or filling them into a capsule. A tablet
 may then, if desired, be coated. It will be appreciated that the
 dissolution rate of a given formulation may decline if the tablet is
 compressed to an excessive hardness.
 According to another aspect, therefore, the present invention provides a
 process for manufacturing a pharmaceutical formulation of tamoxifen
 citrate, which comprises formulating 5 to 15% by weight of tamoxifen
 citrate with 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.degree. C. when stirred at 100 rpm.
 The preferred formulation comprising an inter-granular component and an
 intra-granular component may be prepared 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. Conveniently, the ingredients of the
 inter-granular component are granulated using a solvent such as water. The
 resultant granules are then dried, for example using a fluid bed drier,
 and then passed through a screen, for example of 1270 micron. It has been
 found that the screen size and the form of the screen holes minimally
 influence the dissolution rate of the eventual tablet. The screened
 material is then blended with the ingredients of the intra-granular
 component, for example using a tumble blender, and the resultant mixture
 is pressed into a tablet mold or filled into a capsule. Optionally the
 tablet formulation is then provided with a non-performance aesthetic
 coating.

The following Examples illustrate the invention.
 In each Example, the formulations were made following essentially the
 following procedure:
 The ingredients of the inter-granular mixture were mixed with purified
 water in a Niro Fielder PP-1, High Shear Mixer with a Masterflex console
 Peristaltic Pump and Head, then dried in a Niro Fielder MP-1 fluid bed
 drier, measuring water content using a Computrac Moisture Analyzer, and
 milled using a Quadro comil, model 197S with screen 2A 050 G 037 19 136
 (1270 micron). The resultant inter-granular mixture was then blended with
 the components of the intra-granular mixture using a P-K Twinshell Tumble
 Blender, and the resultant blend was compressed into tablets using a Key
 International DB-16 Rotary Press.
 If desired, the tablet formulation may then be coated.
 It will be appreciated that instead of compressing the formulation mixture
 into a tablet, it could have been filled into a capsule.
 EXAMPLE 1
 250 mg Tablets Containing 20 mg Tamoxifen as Tamoxifen Citrate