Pharmaceutical compositions

<td>REPUBLIC POLAND</td><td>(12) PATENT DESCRIPTION (19) PL (21) Application number: 356904</td><td>(11) 201 268 (13) B1</td>

<td></td><td>(22) Date of notification: April 11, 2001</td><td>(51) Int.Cl. A61K 9/20 (2006.01)</td>

<td></td><td>(86) Date and number of the international application:</td><td>A61K 31/404 (2006.01)</td>

<td></td><td>2001-04-11, PCT / EP01 / 04204</td><td>A61P 3/06 (2006.01)</td>

<td>patent Office</td><td>(87) Date and publication number of the international application:</td><td></td>

<td>Polish Republic</td><td>2001-10-25, WO01 / 78680 PCT Gazette No. 43/01</td><td></td>

Color fast pharmaceutical composition containing fluvastatin and hydroxypropyl methylcellulose and a coating

<td>(30) Priority: 2000-04-13, US, 09 / 549,222</td><td>(73) The right holder of the patent: NOVARTIS AG, Basel, CH</td>

<td>(43) Application announced: 12.07.2004 BUP 14/04</td><td>(72) Inventor (s): Oskar Kalb, Lorrach, DE Stephen Valazza, Matawan, US</td>

<td>(45) The grant of the patent was announced: March 31, 2009 WUP 03/09</td><td>(74) Representative: Łazewska Sławomira, Łazewska and Łazewski, SPÓŁKA JAWNA</td>

⁽⁵⁷⁾ The invention relates to a color-stable pharmaceutical composition containing fluvastatin and hydroxypropyl methylcellulose, and a coating in which the coating contains from 17 to 30% by weight of coloring agent, based on the total weight of the coating.

PL 201 268 B1

Description of the invention

The invention relates to a color-stable pharmaceutical composition comprising fluvastatin and hydroxypropyl methylcellulose and a coating, e.g. in the form of a prolonged release formulation.

Fluvastatin belongs to a group of medicines often referred to as HMG CoA reductase inhibitors (sometimes called 'statins'). Statins are used to lower blood cholesterol levels in patients who need it. The site of action for statins is the liver. Normal immediate-release statin forms, e.g., which release statins within 2 hours, have mild side effects due to the systemic permeation of statins. Statins appear to enter the systemic circulation when they enter the liver in relatively high concentrations over a relatively short period of time and cause "flooding of the liver and as a result some of them undergo metabolism in the first run.

Fluvastatin can be used in the form of the free acid, in the form of its ester, or in the form of its pharmaceutically acceptable salt. Such pharmaceutically acceptable salts include, for example, sodium salts, calcium salts, and ester salts. The most commonly used is the sodium derivative of fluvastatin.

Long-acting preparations called lovastatin, simvastatin and pravastatin have been proposed to prevent or reduce the side effects associated with the entry of statins into the large circulation (see EP 0 375 156).

There are several methods of preparing preparations with prolonged action. One of them is the use of certain excipients in the matrix which modify the release of the active agent dispersed in the matrix. Proposed such excipients are hydroxypropyl methylcellulose (HPMC) polymers - either alone or in combination with other substances - in long-acting formulations containing a wide range of active agents including HMG CoA reductase inhibitors, see e.g. patents US 4,369,172, US 4,357,469, US 4,226,849, and US 4,389,393. Formulations containing HPMC polymers are believed to prolong drug release because they form a dense matrix that protects or delays the ingress of gastric aqueous contents into a given drug form on contact with the aqueous environment of the stomach and thus they protect it from immediate disintegration. This gel matrix is ​​believed to be formed due to the hydration of the HPMC polymer. However, the Applicant has not found any suggestion that HPMC hydration has occurred during storage of pharmaceutical compositions, e.g., orally administered forms, containing HPMC. Moreover, whether or not there is hydration during storage, none of the above documents mentions any problems with HPMC, and in particular problems related to color instability.

The Applicant has surprisingly found that pharmaceutical compositions containing HPMC polymers, after longer storage times, e.g. after 2 years, formed gel-like areas, which areas - even more surprisingly - had an intense color. Although this discoloration made the drug forms an unsightly appearance - the surface became uneven, mottled - it did not have any impact on the safety and efficacy of the drug formulation. Nevertheless, such a speckled appearance may disturb patients and deteriorate treatment compliance.

Thus, what is needed are pharmaceutical compositions containing fluvastatin, e.g. with prolonged action, which are color-stable after prolonged storage, e.g. after storage for more than 2 years.

The subject of the invention is therefore a color-stable pharmaceutical composition containing fluvastatin and hydroxypropyl methylcellulose and a coating, characterized in that the coating contains from 17 to 30% by weight of coloring agent, based on the total weight of the coating. Preferably the pharmaceutical composition according to the invention is in a form intended for oral administration. In another preferred embodiment, the pharmaceutical composition according to the invention is in the form of granules. In yet another preferred embodiment, the pharmaceutical composition according to the invention is characterized in that it comprises compressed granules containing fluvastatin and hydroxypropyl methylcellulose, the granules having an average particle size of less than 200 micrometers. In a particularly preferred case, the pharmaceutical composition according to the invention is characterized in that the granules containing fluvastatin and hydroxypropyl methylcellulose have an average particle size of less than 200 microns.

In another preferred embodiment, the pharmaceutical composition according to the invention is characterized in that the coating contains from 22 to 25% by weight of coloring agent, based on the total weight of the coating.

PL 201 268 B1

In yet another preferred embodiment, the pharmaceutical composition according to the invention is characterized in that the coloring agent is selected from titanium dioxide and iron oxide. In a further preferred embodiment, the pharmaceutical composition according to the invention is characterized in that the coloring agent is a combination of coloring agents. In a further preferred embodiment, the pharmaceutical composition according to the invention is characterized in that the colorant is a combination of titanium dioxide and iron (II) oxide.

In a further preferred embodiment, the pharmaceutical composition according to the invention comprises hydroxypropyl methylcellulose in an amount of 15 to 50% by weight based on the total weight of the composition. In a further preferred embodiment, the pharmaceutical composition according to the invention additionally comprises a nonionic hydrophilic polymer selected from hydroxyethyl cellulose and hydroxypropyl cellulose. In another preferred embodiment, the pharmaceutical composition of the invention is characterized in that the weight ratio of hydroxypropyl methylcellulose to non-hydrophilic polymer is from about 10: 1 to 3:11. In yet another preferred embodiment, the pharmaceutical composition according to the invention is characterized in that fluvastatin is in the form of a sodium salt. In a further embodiment, the pharmaceutical composition according to the invention is made of compressed granules.

Pharmaceutical compositions according to the present invention, e.g. in the form of oral preparations, containing fluvastatin, HPMC and optionally other pharmaceutical excipients, are color stable after prolonged storage, e.g. after storage for more than 2 years.

The above term "color fastness" when used in relation to pharmaceutical compositions, e.g. in the form of oral preparations, means those pharmaceutical compositions which either do not show a spot color change as described above, or do so to an extent imperceptible to the naked eye, i.e. The change of color to speckled is so imperceptible that it cannot be seen or it can be hidden by adding one or more excipients, e.g. coloring substances.

The presence of gel-like areas can only be detected by observing the outward appearance. However, it can also be found using known analytical methods, e.g. microcalorimetric. Any heat flow can be detected by microcalorimetric methods, e.g. exothermic changes due to interaction of the media, e.g. exothermic changes due to HPMC hydration. A characteristic feature of the pharmaceutical compositions according to the present invention is the release of a significant heat flux, i.e. a heat flux above 5 μW, in particular as much as 59 μW, 9 even more particularly 19 to 59 μW for a relatively long time, e.g. for 48 hours, when tested stress at a temperature of 40 degrees Celsius and a relative humidity of 75%. The stress test may be performed in an isothermal microcalorimeter (from CSC Corporation, Provo. Utah) set to operate at 40 degrees Celsius. The pharmaceutical composition may be exposed to a relative humidity of 75%, e.g., by preparing mini-hygrostats of a sodium chloride solution inside 250 microlitre inserts in polypropylene ampoules.

As stated above, color stability can be achieved by significantly preventing or reducing the formation of HPMC gels. One way to achieve color fastness may be to reduce the humidity levels in the environment where the pharmaceutical compositions are stored. The applicant has found that the pharmaceutical compositions, e.g. in the form of oral preparations, stored at a relative humidity of not more than 75%, more preferably not more than 60%, e.g. 40 up to 60% at a temperature between 25 ° C and 40 ° C show much less tendency to change color.

The present invention therefore relates to a method of preventing or significantly reducing the formation of gels from hydrated HPMC in a pharmaceutical composition containing fluvastatin and HPMC, the method comprising the step of storing said pharmaceutical composition at a relative humidity not exceeding 75% and at a temperature between 25 ° C and 40 ° C. . Under these conditions, the granules are essentially color-stable.

The type of packaging used can also contribute to reducing the color change. Normal blister packs, eg Triplex TPX, can be used, but it is preferable to use low pressure polyethylene (HDPE) bottles. Pharmaceutical compositions, e.g. in the form of oral preparations, as described above, stored in HDPE bottles may exhibit substantially no discoloration associated with the formation of HPMC gels.

The pharmaceutical compositions according to the invention may be in any known form, e.g. powder, granules, capsules or tablets. Tablets are a preferred form of these pharmaceutical compositions.

PL 201 268 B1

The pharmaceutical compositions, e.g. in the form of oral preparations, of the present invention can be formed from a granular mass containing fluvastatin, HPMC and optionally other excipients used in pharmaceutical compositions, e.g. in the form of oral preparations, e.g. in tablets. Surprisingly, the applicant has found that the finer the average grain size of the granular mass is, the less intense the mottled color change is observed. According to the Applicant's opinion, the increase in color fastness observed as the mean particle size decreases may be due to the ability of the finer granules to form a tighter packing upon compression, thereby reducing the number and size of voids in the compacted mass. It is believed that HPMC gels form in these voids, so the smaller the number and / or size the less the possibility of gels forming.

The preferred pharmaceutical compositions are tablets formed from granules having an average granule size as determined by sieve analysis of less than about 200 microns, e.g., greater than 20 microns and less than 125 microns, more preferably 100 to 125 microns. However, a contribution to the known state of the art is the recognition of the correlation between the size of the granules and the frequency and nature of the color change. It is known that various mixtures of excipients, e.g. for different amounts of HPMC polymer, a different amount and nature of the color change may correspond, and within ranges other than those noted above, the color change may not occur or be visually imperceptible.

However, the skilled person is able to determine the appropriate size of granules for a given debonding mixture only on the basis of his experience.

The above-described granules of the pharmaceutical composition of the invention contain fluvastatin and HPMC and optionally other pharmaceutical excipients, and have an average particle size of less than 200 µm, e.g. less than 125 µm, more preferably from 100 to 125 µm.

To achieve the objectives of the present invention, the reduction of the moisture level in the environment of granules or pharmaceutical compositions, e.g. in the form of oral preparations, during storage, and fine granules as described above are used jointly or separately.

As is apparent from the definition given above, the granules and pharmaceutical compositions can be "color fast" although they may contain significant amounts of HPMC gel, such that a mottled color change would be quite pronounced were it not for the presence of a colorant to mask this color change. Thus, the pharmaceutical composition of the invention may contain HPMC gel regions and a coloring agent added in a sufficient amount to hide any mottled discoloration associated with the HPMC gel regions.

It is known that fluvastatin readily degrades when exposed to light to give distinctly colored degradation products. Although the extent of this distribution is small and does not affect the efficacy and safety of fluvastatin-containing formulations, it is preferable to use a coloring agent to hide any discoloration associated with such light degradation. Due to the fact that fluvastatin is dispersed substantially evenly throughout the granules or pharmaceutical composition, any such discoloration is quite subtle and uniform. Thus, this slight discoloration can be concealed simply by the use of conventional coloring agents in relatively small amounts. This is a favorable circumstance as the relevant authorities strictly adhere to the amount of coloring agents, e.g. iron oxides which can be used in pharmaceutical compositions. For example, in the case of iron oxide pigments, the amount of elemental iron acceptable for injection by the FDA (Federal Drug Administration) is now 5 mg / day.

Unlike the color change caused by the degradation of fluvastatin under the influence of light, the color change associated with the formation of HPMC gels is usually manifested by the appearance of discontinuous, randomly distributed areas. Such a color change is therefore usually more concentrated, and therefore more intense and motley, and as such is more difficult to hide. Thus, using conventional coloring agents used in relatively small amounts, adequate masking is not achieved.

The pharmaceutical composition according to the present invention allowed i.a. solving the above technical problem by hiding the barely perceptible mottled external appearance, and at the same time using a coloring agent, in particular iron-containing coloring agent, in as little amount as possible.

As the colorant, any known agent may be used, e.g. pigments, in particular any colorants used in pharmaceutical preparations are suitable for use in the present invention, see e.g. Handbook of Pharmaceutical Excipients, 2nd Edition.

PL 201 268 B1 (1994), Ed. Wade and Weller, pp. 130-134. Suitable coloring agents include titanium dioxide, iron (II) and (III) oxide, preferably Fe2O3, possibly in a hydrated form.

When considering the amount of coloring agent to be used per dosage unit of the drug, it should be taken into account that the maximum amount will depend on the maximum daily doses permitted by the relevant authorities and may vary within these limits depending on the number of dosage units taken during the day. , e.g., whether a drug dose is taken once or twice daily, and on the size of the particular drug dosage form. With this in mind, it is easy to determine the appropriate amount of coloring agent required to effectively hide any mottled discoloration. In a preferred embodiment of the present invention, the colorant may constitute up to 73 wt.%. coating weight, in particular 17 to 30%, e.g. 22 to 25%. The percentages mentioned relate to the total weight of the coloring agent used. The entirety of the colorant may consist of one colorant, e.g. iron (II) oxide, or it can be a combination of several agents, e.g. titanium dioxide and iron (II) oxide.

As coating materials, customary materials used for coating tablets, granules and the like can be used. Preferred coating materials are hydrophilic and are water-permeable and / or at least partially soluble in water and intestinal fluids. All coating materials are suitable for the applications related to the present invention, in particular the known flexible coatings.

The coating materials described above can be used as admixtures for other excipients known in coating formulations, for example talc or silicon dioxide, for example synthetic amorphous silicic acid of the type Syloid® (from Grace), for example SYLOID 244 FP, or wetting agents, for example the polyethylene glycols or sorbates mentioned above.

The coating materials may contain additional excipients, for example plasticizers such as e.g. Citroflex® (from Pfizer), triacetin, various phthalates, e.g. diethyl or dibutyl phthalate, mixtures of mono- and diglycerides such as Myvacet® (from Eastman), e.g. MYVACET 9-40, the aforementioned polyethylene glycols, for example with a molecular weight of about 6,000 to 8,000, and also ethylene oxide / propylene oxide block copolymers of the Pluronic® (BASF) or Syriperonic® (ICI) type, powder demoulding agents, for example magnesium trisilicate, starch or synthetic amorphous silicic acid of the type SYLOID, for example SYLOID 244 FP.

The weight of the coating used in the granules and pharmaceutical compositions of the present invention may vary within known limits, typically from about 1 to about 4 wt.%. based on the total weight of the formulation, for example about 3 wt.%.

In particularly preferred embodiments of the present invention, for the 20 mg coated tablet the coating weight is about 2 to 2.5 mg, e.g. 2.44 mg; for a 40 mg coated tablet the coating weight is about 4.5 to 5.0 mg, e.g. 4.86 mg; for an 80 mg coated tablet the coating weight is about 9.5 to 10.0 mg, e.g. 9.75 mg; and for a 160 mg coated tablet the coating weight is about 12.0 to 12.5 mg, e.g. 12.3 mg.

The granules and pharmaceutical compositions of the present invention include commercially available hydroxypropylmethylcellulose polymers that impart long-acting properties to the active agent, and include all materials cited in EP 375156, US 4,369,172, US 4,357,469, US 4,226,849 and US 4,389,393 provided herein by reference.

A preferred HPMC polymer is manufactured by Dow Corning under the trade name METHOCEL. Such an HPMC compound preferably has a degree of substitution with hydroxypropyl (HP) groups up to about 12, i.e., the HP groups constitute as much as about 12% of the HPMC functional groups. Even more preferably, in the HPMC, the HP groups make up about 7 to 12% of the functional groups, most preferably 7 to 9 percent. The dynamic viscosity index of HPMC (2% aqueous solution) is from about 100 to 100,000 mPa · s and the average molecular weight is from about 20,000 to about 170,000.

HPMC is METHOCEL K100LV, even more preferably is METHOCEL K100LVP CR, the average molecular weight of which is from about 20,000 to about 30,000. Methods for preparing such HPMC polymers are known.

The HPMC polymers can be used, for example, in amounts sufficient to provide prolonged action of fluvastatin. The term "sustained action" means the release of fluvastatin from the pharmaceutical composition over an extended period of time, e.g. over a period of more than 6 hours. In a preferred pharmaceutical composition, less than 80 wt. fluvastatin while the remaining fluvastatin is released later.

PL 201 268 B1

With more preferred compositions less than 15 wt.% Is released 0.5 hour after ingestion. of fluvastatin, 10 to 50% by weight is released within 2 hours of ingestion, and about 40 to 60% is released after 6 hours.

The preferred granules and pharmaceutical compositions of the present invention contain about 15 to about 50 wt. HPMC based on the total weight of the composition, more preferably about 20 to 40%. The weight ratio of HPMC to nonionic hydrophilic polymer (hereinafter) is preferably from about 10: 1 to about 3: 1, more preferably 7: 1 to 5: 1, most preferably 6: 1.

HPMC is a useful excipient to provide the sustained action of fluvastatin, however the applicant states that conventional sustained release formulations containing only HPMC as a release modifying excipient may however exhibit initially burst or premature release of fluvastatin. "Premature release means that shortly after ingestion of the drug, a significant amount of fluvastatin can be released, and thus the amount of active agent brought to the site of its action exceeds the value of the therapeutic dose." Although it may not affect the effectiveness of the medicinal preparation, it may cause intoxication side effects related to exceeding the therapeutic dose. The applicant has surprisingly found that premature release can be avoided or improved if the granules or pharmaceutical composition, e.g. administered orally, additionally comprises at least one non-ionic hydrophilic polymer.

The nonionic hydrophilic polymers used in the granules and pharmaceutical compositions of the present invention may be selected from the group consisting of hydroxyethyl cellulose (HEC) having an average molecular weight of 90,000 to 1,300,000, preferably from about 1,000,000 to about 1,300,000; hydroxypropyl cellulose (HPC) with an average molecular weight of 370,000 to 1,500,000, preferably 850,000 to 1,500,000, more preferably 1,000,000 to 1,200,000, and polyethylene oxide (PEO) with an average molecular weight from about 100,000 to 500,000, preferably 150,000 to 300,000, more preferably 200,000.

Examples of HEC polymers are commercially available under the tradename NATROSOL 250H or NATROSOL 250L from Hercules Incorporated, Aqualon Division. From the same company Hercules Incorporated, Aqualon Division, examples of HPC polymers are commercially available under the trade name KLUCEL or KLUCEL HXF, and examples of PEO polymers commercially available under the trade name POLYOX are manufactured by Union Carbide Corporation. Methods for the preparation of non-ionic hydrophilic polymers are known. Nonionic hydrophilic polymers may be used in the granules and pharmaceutical compositions of the present invention in amounts ranging from about 1 to about 20 wt%, preferably about 3 to 12 wt%, more preferably about 4 to 7 wt%. based on the total weight of the granules or pharmaceutical composition. The non-ionic hydrophilic polymer is present in an amount sufficient to prevent premature release of fluvastatin.

The pharmaceutical compositions of the present invention may contain other excipients to facilitate processing and / or to improve the properties of the pharmaceutical composition, including well-known tabletting excipients such as binders, e.g., gelatin, sugars, natural and artificial gums, poly (vinylpyrrolidone), disintegrants. (e.g. croscarmellose, crospovidone, sodium starch glycolate), lubricants (e.g. magnesium stearate, hydrogenated vegetable oils, carnauba wax), flow agents (e.g. silicon dioxide), anti-adherent or skid agents (e.g. talc) as well as sweeteners, fillers, flavors and antioxidants.

Fluvastatin is acid sensitive and therefore an alkaline compound is often added to provide a pH of at least about 9. Any alkaline agent effective in stabilizing formulations containing HMG-CoA reductase inhibitors can be used. It has surprisingly been found that pharmaceutical compositions containing known alkaline agents, e.g. potassium carbonate or bicarbonate, and poly (vinylpyrrolidone) and fluvastatin tend to change color during storage. This discoloration is manifested by dark spots and is different from that described above and is believed to be due to the effect of in situ formed carbonic acid on the active agent or on the excipients (carbonic acid is formed by the decomposition of carbonate or potassium bicarbonate in the presence of PVP in a humid environment) ). Like the color change associated with HPMC, this color change has no impact on the safety and efficacy of the pharmaceutical compositions and can also be hidden using the same countermeasures described above.

The structure and methods for the preparation of fluvastatin are described in EP-A-114027 and EP-A-547000, incorporated by reference to this patent application.

PL 201 268 B1

The pharmaceutical compositions of the present invention may be prepared by any known method. In the case of tablets, they may be formed by a process which forms another embodiment of the present invention and includes a step of granulating in an aqueous medium the active agent and excipients to aid tabletting under high shear stresses (shear forces).

Granules are obtained in a known manner, for example by aqueous granulation methods known in the preparation of granules by the growth or grinding method.

Forming the granules by the build-up method is carried out continuously and includes, for example, simultaneous spraying of the granulated mass with the granulation solution and drying, for example, in a drum granulator, in pan granulator, on disk granulator, in a fluidized bed, by spray drying or spray solidification. or is carried out in a batch process, for example in a fluidized bed, in a batch mixer or in a spray drum dryer.

Preference is given to methods for the preparation of granules by grinding methods which can be carried out batchwise such that first wet aggregates of the granulated mass are formed with the granulation solution, which aggregates are then ground or formed into granules of the appropriate size by known granulation methods and then these granules are dried. A suitable granulator is, for example, an Alexander granulator.

The granulation mass consists of the comminuted, preferably crushed, active ingredient and the above-described excipients. Depending on the method used, the granulation mass can be in the form of a premix or can be prepared by adding the active ingredient to mixed one or more excipients or by adding excipients to the mixed active ingredient. The wet granules are preferably dried, for example as described, by spray drying or in a fluidized bed.

Compression molding of the tablet cores is carried out on conventional tablet presses, for example eccentric tablet presses, e.g. EK-0 from Korsch, and rotary tablet presses. The tablet cores can have various shapes: round, oval, oblong, cylindrical, etc., and various sizes depending on the amount of active ingredient used.

Some examples are provided below to illustrate the invention.

Example 1

The portion of fluvastatin sodium is calculated and weighed. Potassium bicarbonate, microcrystalline cellulose, povidone, HPC and HPMC are weighed and placed in separate labeled containers. Thereafter, a 20% excess of the lot size of OPADRY Yellow, YS-1-6347-G, is placed in the labeled container. Subsequently, in the order indicated, microcrystalline cellulose, fluvastatin sodium, povidone, HPC and HPMC are transferred to a Collette Gral blender and mixed for 5 minutes with the blender driver set to slow speed with the chopper off. The resulting mixture is passed at a low speed through a screen with a mesh size of 0.8 mm using a centrifugal mill with forward knives. The screened material is then remixed in the Collette Gral mixer with the mixer driver set to slow speed and the chopper off.

Potassium bicarbonate is dissolved in purified water until a clear homogeneous solution is obtained. The sodium bicarbonate solution is then combined with the screened material and the resulting mixture is granulated in a Collette Gral mixer with the mixer driver set at high speed and the chopper set at low speed. After adding the solution, continue granulation for a period of 30 seconds with the driver set to high speed and the chopper set at low speed, and for a further period of 30 seconds with the driver set to high speed and the chopper set to high speed. The granulation mixture is then dried in a fluid bed dryer using a target inlet temperature of 50 ° C until an LOD value of 2 to 3 percent is obtained.

The dried granules are then passed through a 1.55 mm mesh screen using a spin mill with low speed rotating knives advanced. The portion of magnesium stearate is calculated and weighed according to the yield obtained after sieving through a sieve with a mesh size of 1.55 mm in relation to the theoretical amount. Thereafter, the weighed magnesium stearate is passed through a 0.25 mm sieve and mixed with the dried granules in a free fall powder mixer, and the resulting granulation mixture is discharged into a plastic lined labeled drum. Then mix8

The granulation pellet is compressed into tablets and the tablets are dust-free, passed through a metal size inspection device and stored in a plastic labeled drum.

To coat the tablets with a coating, OPADRY Yellow is mixed with a sufficient amount of purified water to obtain a 10% by weight suspension. The tablets are transferred to a pan coater and heated to 40-45 ° C. The OPADRY Yellow suspension is then added to coat the tablets by spraying until the tablet weight gain is 3% by weight. The spray coating is interrupted and the tablets are cooled by turning off the heating of the 9 pans and shaking them for a period of 5 minutes.

Example 2

The portion of fluvastatin sodium is calculated and weighed. Potassium bicarbonate, microcrystalline cellulose, povidone, HPC and HPMC are weighed and placed in separate labeled containers. Thereafter, a 20% excess to the lot size of OPADRY Yellow, OOF12953, is placed in the labeled container. Subsequently, in the order indicated, microcrystalline cellulose, fluvastatin sodium, povidone, HPC and HPMC are transferred to a Collette Gral blender and mixed for 5 minutes with the blender driver at slow speed and the chopper off. The resulting mixture is passed at medium speed through a 0.9 mm mesh screen using a Fitz Patrick mill with forward knives. The screened material is then remixed in the Collette Gral mixer with the mixer driver set to slow speed and the chopper off.

Potassium bicarbonate is dissolved in purified water until a clear homogeneous solution is obtained. The sodium bicarbonate solution is then combined with the screened material and the resulting mixture is granulated in a Collette Gral mixer with the mixer driver set at high speed and the chopper set at low speed. After adding this solution, continue granulating for a period of 30 seconds with the driver set at high speed and the chopper set at low speed, and for a further period of 30 seconds with the driver set at high speed and the chopper set at high speed. The granulation mixture is then dried in a fluid bed dryer using a target inlet temperature of 50 ° C until an LOD value of 2.5 percent to 3.5 percent is achieved.

The dried granules are then passed through a 1.5 mm mesh screen using a Fitz Patrick mill with slow speed rotating knives. The portion of magnesium stearate is calculated and weighed according to the yield obtained after sieving through a sieve with a mesh size of 1.5 mm in relation to the theoretical amount. The weighed magnesium stearate is then passed through a 1.5 mm mesh sieve using a medium speed Fitz Patrick mill and mixed with the dried granules in a free fall powder blender and the resulting granulation blend discharged into a plastic-lined, labeled drum. The granulation mixture is then compressed into tablets and the tablets are dust-free, passed through a metal size inspection device and stored in a plastic labeled drum.

To coat the tablets, OPADRY Yellow is mixed with a sufficient amount of purified water to obtain a 15% by weight suspension. The tablets are transferred to a pan coater and heated to 40-45 ° C. The OPADRY Yellow suspension is then added to coat the tablets by spraying until the tablet weight gain is 3% by weight. The spray coating is interrupted and the tablets are cooled by turning off the heating of the pans and shaking them for a period of 5 minutes.

Example 3

84.24 mg of fluvastatin sodium was combined with the following excipients as described in Examples 1 and 2 to provide the single dosage form described in Table 1:

Table 1

<td>Fluvastatin sodium derivative</td><td>84.24 mg</td>

<td> 1</td><td> 2</td>

<td>Potassium bicarbonate, USP</td><td>8.42 mg</td>

<td>Microcrystalline cellulose, NF, PH 101 (AVICEL)</td><td>111.26 mg</td>

<td>Povidone USP</td><td>4.88 mg</td>

PL 201 268 B1 cont. table 1

<td> 1</td><td> 2</td>

<td>HPC, NF (KLUCEL HXF)</td><td>16.25 mg</td>

<td>HPMC, USP (METHOCEL K 100LVP CR)</td><td>97.50 mg</td>

<td>Magnesium stearate</td><td>2.44 mg</td>

<td>FALLS Yellow</td><td>9.75 mg</td>

OPADRY Yellow (OOF12953) consisted of HPMC 2910 3cps (72 wt%); titanium dioxide (21.413 wt.%); PEG 8000 (4.0 wt.%); and yellows - iron oxide (2.587 wt.%) (24% TiO2 + FeO2 oxides).

From the formulation with the properties listed in Table 1, pharmaceutical compositions and granules were obtained which did not show any signs of a mottled discoloration.

In the case where OPADRY Yellow (OOF22737) consists of HPMC 2910 3cps (80 wt%); titanium dioxide (14.080 wt.%); PEG 8000 (4.0 wt.%); and yellow iron oxide (1.920 wt%) (16% TiO2 + FeO2 oxides), the pharmaceutical compositions showed a mottled uneven color change.