WO2008102379A1

WO2008102379A1 - Stable sustained release formulations of fluvastatin

Info

Publication number: WO2008102379A1
Application number: PCT/IS2008/000006
Authority: WO
Inventors: Fjalar Johannsson
Original assignee: Actavis Group Ptc Ehf.
Priority date: 2007-02-19
Filing date: 2008-02-19
Publication date: 2008-08-28
Also published as: IS8612A; EP2124904A1

Abstract

The invention provides stable solid sustained release pharmaceutical formulations of fluvastatin, which formulation do not need to include a pH-stabilising agent. The formulations can preferably contain amorphous, micronised material. Sustained release formulations are disclosed with excellent dissolution profiles. Preferred formulations include formulations of fluvastatin sodium.

Description

Stable sustained release formulations of fluvastatin

FIELD OF INVENTION

The present invention relates to stable solid sustained release oral pharmaceutical formulations comprising fluvastatin as an active ingredient, or a pharmaceutically acceptable salt, hydrate or solvate thereof, which exhibits excellent stability without any necessity to add an alkaline pH- stabilizing agent in the formulation. Preferred formulations comprise the active ingredient in amorphous form, which formulations are surprisingly stable.

TECHNICAL BACKGROUND AND PRIOR ART

The class of drugs called statins (or HMG-CoA reductase inhibitors) is currently the most therapeutically effective drugs available for lowering cholesterol levels in people with or at risk for cardiovascular disease. These agents are competitive inhibitors of 3-hydroxy-3-methylglutaryl- coenzyme A (HMG-CoA) reductase, the enzyme catalyzing the early rate-limiting step in cholesterol biosynthesis, conversion of HMG-CoA to mevalonate.

Lovastatin (MEVACOR^®) was the first inhibitor of HMG-CoA reductase to become available for prescription in 1987. In addition to the HMG-CoA reductase inhibitors which are natural fermentation products, mevastatin and lovastatin, there are now a variety of semi-synthetic and totally synthetic variants, including simvastatin (ZOCOR^®), pravastatin (PRAVACHOL^®), fluvastatin (LESCOL^®), atorvastatin (LIPITOR^®), cerivastatin (also known as rivastatin) and nisvastatin (also known as NK-104).

Fluvastatin sodium is the generic name for the compound R*,S*-(E)-(±)-7-[3-(4-fluorophenyl)-l- (l-methyl-ethyl)-lH-indol-2-yl]-3,5-dihydroxy-6-heptenoic acid monosodium salt. The empirical Formula is C₂₄H_2SFNO₄-Na, its molecular weight is 433.46 Da and its structural Formula is shown as Formula I:

Formula I This molecular entity is the first entirely synthetic 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG- CoA) reductase inhibitor, and is in part structurally distinct from the fungal derivatives of this therapeutic class.

Fluvastatin undergoes first pass metabolism, which begins to show non-linear kinetics (competitive inhibition) at doses higher than 20 mg and result in higher than expected systemic concentrations at higher dosages. Although fluvastatin undergoes extensive metabolism, only the parent drug, fluvastatin, is the active moiety and its metabolites are not considered to be active. Fluvastatin has a short elimination life (1.5-2 hours); therefore, accumulation of fluvastatin is unlikely after chronic dosing with the immediate release (IR) product. The approved IR dose of Lescol® is 20-80 mg per day. Usually, doses at or below 40 mg are taken once a day at bedtime. Doses of 80 mg are to be taken in divided dosages (40 mg twice a day). Although Lescol® has been well tolerated, some adverse events (AEs) such as elevation in transaminase levels, headache, and dyspepsia have been reported. In order to increase the tolerability and reduce the occurrences of adverse events, a sustained release (SR) formulation of fluvastatin has been developed, marketed as Lescol^® SR 80. The SR formulation delivers fluvastatin at a slower rate than the conventional IR form, thus reducing the first pass saturation resulting in lower systemic exposure, that in turn should allow for a high dosage with increased efficacy and tolerability of fluvastatin.

Sustained release formulations are generally more difficult to prepare and many criteria must be fulfilled in order to obtain a satisfactory product. Several methods of providing sustained release (SR) formulations have been proposed in the art. Generally, these devices may be characterized as either diffusion controlled systems, osmotic dispensing devices, dissolution controlled matrices, or erodible/degradable matrices. One such means is to use certain excipients in a matrix which modifies the release of an active agent dispersed within said matrix. Hydroxypropyl methyl cellulose (HPMC) polymers have been suggested as release-modifying excipients; either alone or in combination with other materials, in SR formulations for use with a wide variety of active agents. Some formulations with HMG CoA reductase inhibitors are disclosed in U.S. Patent No. 4,369,172. Other formulations are proposed e.g. in published patent applications US 2007/0031493, US 2005/0203186, WO 2006/105643, WO 2006/071077, and WO 2005/097194.

It is thought that formulations containing HPMC polymers prolong drug release by forming a gelatinous matrix upon exposure to the aqueous medium of the stomach which prevents or delays ingress of the aqueous medium of the stomach into the dosage form and thereby preventing its rapid disintegration. The gel matrix is thought to form as a result of hydration of the HPMC polymer.

EP 547000 Bl describes that fluvastatin sodium is extremely susceptible to degradation at pH below about 8. The suggested solution is to provide compositions comprising the drug substance and an alkaline medium, which is capable of imparting a pH of at least 8 to an aqueous solution or dispersion of the composition. It is pointed out in EP 547000 Bl that, in addition to the pH sensitivity, the heat and light sensitivity, as well as the hygroscopicity, of fluvastatin sodium impose particular requirements on the manufacture and storage of pharmaceutical dosage forms of fluvastatin sodium.

In the related literature and known prior art formulations, "pH stabilizing agents", comprising alkaline/basifying agents have generally been included as a definite requirement in formulations of the statin group of drugs.

It will be greatly appreciated to provide alternative economical sustained release formulations of fluvastatin, which is a very useful drug for widespread and serious medical indications associated with elevated cholesterol levels.

SUMMARY OF THE INVENTION

The invention provides novel sustained release formulations of fluvastatin based on amorphous material, which formulations are stable and economical, and provide reproducible and desired release profiles.

The present inventor has surprisingly found that stable formulations of fluvastatin can be obtained without using a pH-stabilizing agent, i.e., an alkaline/basifying agent, contrary to what has been taught in the art. The inventor was able to formulate fluvastatin formulations having a prolonged shelf life, and sufficient stability under the extreme conditions that the product may be exposed to such as non-optimal pH, light, humidity, heat, pressure, etc., and with the possibility of being provided in less sophisticated and expensive packages than used for currently marketed formulations.

Contrary to what was expected, the amorphous form of the active ingredient proved particularly suitable in stable sustained release formulations. Amorphous material is typically simpler and more economical to manufacture but can suffer from stability problems. Crystallised material as a general rule has a lower enthalpy and thus is found more stable, consequently, for sensitive materials such as fluvastatin, crystallised forms have dominated the pharmaceutical market. Method to produce amorphous fluvastatin are known in the art, see e.g. WO 2006/109147, but commercially useful formulations have to applicant's knowledge not been successfully made.

The present invention relates to stable solid sustained release oral pharmaceutical formulations comprising fluvastatin, or a pharmaceutically acceptable salt, hydrate or solvate thereof, which exhibit excellent stability without any necessity to add pH-stabilizing alkaline/basifying agent in the formulation.

The details of the present invention together with illustrative examples as well as experimental findings are given below. DETAILED DESCRIPTION OF THE INVENTION

As is mentioned above, the present invention provides novel sustained release fluvastatin formulations which overcome the necessity of addition of an alkaline/basifying agent. The term "alkaline/basifying agent" in this context refers to an agent which would impart a pH of 8 or higher in an aqueous solution or suspension of the formulation, that is, such agent would impart a pH of at least 8 in the microenvironment of particles of said formulation whether any other excipient and/or the active ingredient of the formulation are dissolved or not. The phrase "not containing an alkaline/basifying agent" as used herein means that the formulation does not contain a pH-lowering effective amount of such agent.

Among such alkaline/basifying agents which have been suggested in the prior art as the necessary alkaline/basifying agent are certain pharmaceutically acceptable inorganic carbonate salts such as sodium or potassium carbonate, sodium bicarbonate, or potassium hydrogen carbonate; phosphate salts selected from, e.g., anhydrous sodium, potassium or calcium dibasic phosphate, or trisodium phosphate; as well as alkali metal hydroxides such as sodium, potassium, or lithium hydroxide; and mixtures of the foregoing. Consequently, the present invention provides fluvastatin formulations without any of the above ingredients in a pH-lowering amount.

It will be appreciated that sustained release (SR) formulations can advantageously be formed in accordance with the present invention.

As used herein, "sustained-release" (SR) means that the pharmaceutically active agent is released from the dosage form over an extended period of time, as compared to a dosage form of the same drug in a matrix that quickly and readily dissolves.

As plasma concentration release profiles for the same formulation may vary between different patient groups as well as between individual patients, a suitable and reproducible way to assess the active ingredient release from a pharmaceutical formulation is to measure the dissolution of the formulation in a well defined test. The preferred formulations of the present invention have a dissolution profile when tested in a standard paddle dissolution bath test ("apparatus 2" according to USP 29 and Eur. Pharmacopoeia 5th ed., 50 rounds per min. in 900 mL phosphate buffer, 37⁰C, pH 6.8), such that 18-45% of the fluvastatin compound is released within 6 hours, 35-66% of the compound is released within 12 hours, and no less than 70% of the compound is released within 24 hours. In particular, such dissolutions profiles can advantageously be obtained with formulations of fluvastatin or a salt thereof such fluvastatin sodium, prepared in accordance with the present invention.

One aspect of the present invention provides a sustained release formulation of fluvastatin using hydroxyethylcellulose (which does not need to be modified or derivatised), including formulations of fluvastatin sodium, which have the desired dissolution profiles as described above. These formulations may suitably comprise in the range of 5-35 wt% of hydroxyethyl cellulose, such as in the range of about 10-30 wt%, including about 10 wt%, 15 wt%, 20 wt%, 25 wt% and 30 wt%. The sustained release formulations of the invention can suitably be prepared from micronised material. Said formulations preferably comprise said fluvastatin sodiummaterial in micronised form as described herein,.

The formulation of the invention can provide essentially complete absorption of the active substance in the gastrointestinal (GI) tract including the lower GI tract and the colon, providing an increased blood concentration, relative to that resulting from the administration of an equivalent dosage of conventional immediate release formulations.

According to a preferred embodiment, the composition comprises one or more excipients selected from a binder, filler, diluent, lubricant, release controller, and, a swell-controlling agent, disintegrant, and stabilizer. Preferably, a binder is selected from the group consisting of polyvinyl pyrrolidone (povidone or PVP), hydroxypropyl cellulose (HPC); hydroxypropylmethyl cellulose (HPMC); methyl cellulose, ethyl cellulose, acacia gum, pregelatinized starch, sodium alginate, glucose, polyethylene oxide, dextrin or other binders. According to preferred embodiments, the binder is PVP. ISP Corp. Inc. manufactures several different forms of the povidone under the trade name of Plasdone^® which are compatible with a wide range of materials as demonstrated by their tolerance to pH changes and salts. Plasdone^® K-29/32 polymer is generally regarded as the universal binder for wet granulation process as its intermediate molecular weight results in high binding capacity and low solution viscosity for ease of processing. Average molecular weights of typical Plasdones, i.e., K-12, C-15, K-25, K-29/32, K90D are 4,000; 10,000; 34,000; 58,000; 1,300,000, respectively. Binder is employed in a total amount of about 0.5 to 10 wt%, preferably from about 1 to about 5 wt%, relative to the total weight of the said oral dosage form.

Suitable fillers include one or more of starch, pregelatinized starch, wheat starch, corn starch, lactose, sucrose, glucose, sorbitol, dextrates, dextrins, dextrose, fructose, mannitol, sorbitol, carboxymethylcellulose calcium, microcrystalline cellulose (MCC), powdered cellulose, sodium chloride and mixtures thereof. According to preferred embodiments, MCC is selected as the most preffered filler. In the present formulation, MCC can also function as a swell- controlling agent. Among the other water insoluble polymers such as starch, gelatin, collagen and polyacrylic acid that are the good candidates for controlling the rate of penetration of surrounding fluid into the core, MCC products from FMC Corp. are preferred. FMC Corp. offers different commercially available forms under the trade name of Avicel^® pH-101, Avicel^® pH-102 and Avicel^® pH-103, having the mean particle size of 50, 100 and 50 micron, respectively. Filler may be employed in amounts ranging from about 5 to 45 percent and preferably, from about 15 to about 25 percent by weight, relative to the total weight of the said oral dosage form.

In pharmaceutical preparations including the formulations of the present invention, mannitol is primarily used as diluent in tablet formulations, due to low hygroscopicity and high chemical stability. It is of particular value since it is not hygroscopic and may thus be used with moisture sensitive active ingredients. Mannitol may be used in direct compression tablet applications, for which the granular and spray-dried forms are available, or in wet granulations. Granulations containing mannitol also have the advantage of being dried easily. Mannitol is stable in the dry state and in aqueous solutions in which mannitol is not attacked by dilute acids or bases, nor by atmospheric oxygen. Among the commercially available options; it can be obtained from Roquette Pharma under the tradename of PEARLITOL^® 160 C, 50 C and 25 C having the mean diameters of 160, 50 and 25 micron, respectively. Diluent may be employed in amounts ranging from about 5 to 70 wt%, relative to the total weight of the said oral dosage form.

A substantial amount of statins, particularly, fluvastatin may be released in a short period of time after ingestion such that the amount of active agent delivered to the site of action is above the desired therapeutic level. Whereas this may not have any consequence for the efficacy of the drug substance there may be resultant toxic side effects associated with the greater than therapeutic dose.

The premature release may be avoided or ameliorated in accordance with the present invention in preferred embodiments where the formulation comprises at least one non-ionic hydrophilic polymer. Useful polymers of this type include in particular hydroxyethyl cellulosic polymer (HEC polymers) which are commercially available from Hercules Incorporated, Aqualon Division under the tradename NATROSOL 's, and of hydroxypropyl cellulose polymer (HPC polymers), which are also available from Hercules Incorporation, Aqualon Division under the tradename KLUCEL's, and of polyethylene oxide polymer (PEO polymers) which are available from Union Carbide Corporation under the tradename POLYOX's. The non-ionic hydrophilic polymers may be employed in oral dosage forms according to the invention in amounts ranging from about 1 to about 40% by weight, preferably about 5 to 20% by weight, relative to the total weight of the said oral dosage form. Preferably, HEC with a molecular weight of 1,000,000 to 1,300,000 are employed.

Suitable lubricants include one or more of magnesium stearate, sodium stearyl fumarate, stearic acid, colloidal anhydrous silica, synthetic aluminum silicate, magnesium oxide, calcium stearate, talc, hydrogenated castor oil, and mixtures thereof. Lubricant in the amounts varying from about 0.1% to about 4% by weight, preferably from about 0.5 % to about 2% by weight, relative to the total weight of the said oral dosage form, may be used. According to the most preferred embodiments, magnesium stearate is selected as the most preferred lubricant.

Optionally, disintegrants such as sodium starch glycolate, crospovidone, low-substituted HPC, and others; glidants such as silicon oxide and others can also be employed in the formulation. In one aspect the present invention provides a solid pharmaceutical composition for release of active substance into a desired aqueous environment, contains an outer layer (coating) surrounding a core, wherein the core generally comprises the active ingredient. The coating layer will generally comprise from about 1% to 10 % by weight, relative to the total weight of the said oral dosage form. Said coating layer preferably includes one or more of the following excipients; plasticizer, water swellable polymer, and color agent. The plasticizer may be present in an amount varying from about 0.1% to about 30% by weight, preferably from about 5% to about 20% by weight, relative to the total weight of the of the coating layer of the said drug. The plasticizer may be selected from one or more of the group consisting of glycerine, triethyl acetate, triacetin, stearic acid, sorbitol, diethyl phthalate, dibutyl phthalate, propylene glycol, polyethylene glycol (PEG) and others. PEG is selected as the preferred plasticizers with an average molecular weight (MW_avg) varying from 190 to 9000. More preferably, PEG with an MW_avg varying from 4800 to 7000 is employed.

Water-swellable polymers which may be utilised in a coating layer or optionally in a core of the oral dosage form of the present invention may be selected from the group including one or more of hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose, methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxymethlylcellulose, hydroxyethylcellulose, generally those having a number average molecular weight in the range 10,000 to 250,000, such as cellulose ethers, for example HPMC such as are sold by Dow Chemicals under the trade names "Methocel" and "Opadry" (sold by Colorcon). Preferably the water swellable polymer is HPMC. Among the commercially available ones such as "Methocel" E5, E6, E15, E50-LV, K15M, KlOOM and E4M, and "Opadry" OY- S-7251. The water swellable polymer is preferably present in the coating composition in amounts ranging from 0% to 80% relative to the total weight of the coating of the said oral dosage form.

Suitable colorant include any approved agents by the EMEA and FDA in an amount less than the maximum allowable quantities for oral pharmaceutical use, including titanium oxide and yellow iron oxide or their mixture. Color agent is ranging from about 1% to 50% by weight, relative to the total weight of the coating layer of the said oral dosage form.

It has been disclosed earlier that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to crystalline forms (Konne T., Chem. Pharm. Bull., 38, 2003 (1990)). For some therapeutic indications one bioavailability pattern may be favored over another. The amorphous form of cefuroxime axetil is good example of a compound exhibiting higher bioavailability than the crystalline forms. For atorvastatin calcium, which is a member of the statin drugs and structurally somewhat similar to fluvastatin, it has been found that its crystalline forms are less readily soluble than the amorphous form, which may cause problems in the bioavailability of atorvastatin in the body.

Therefore, different forms (i.e. different polymorphs or amorphous vs. crystal material) cannot generally be exchanged for one another in otherwise similar formulations without carefully assessing whether the clinical profile of the formulation is affected. In the majority of the cases, amorphous forms dissolve faster than crystalline forms of the same compounds due to the less availability of the stabilizing intermolecular attractive forces which thus need not be overcome for the compound to dissolve, so that dissolution rate is not retarded. This is generally not desired for sustained release formulations. On the other hand, generally speaking, amorphous form of a compound is more hygroscopic than its crystalline form, and therefore the amorphous form of relatively unstable compounds are generally less stable than crystallised forms.

It has surprisingly been found that the fluvastatin formulations of the present invention, including formulations of fluvastatin sodium such as further described herein, can advantageoulsy comprise amorphous material. Such formulations with the preferred excipients as desribed herein can be readily formulated into tablets and show excellent stability and quite satisfactory bioavailability and disolution profiles, comparable to those of clinically approved prior art formulations of the same active ingredient in crystallised form.

In this invention, in the preferred formulation of fluvastatin, selection of the excipients, their quantity in the formulation (and in certain embodiments the core and coating layers) are optimized, and preferably also together with the particle size of the active ingredient so that almost identical release profiles with that of the originally clinically approved product were achieved. In the preferred embodiment, excipients were employed directly without any further size reduction step, i.e used in the commercially available sizes, while the active ingredient is preferably employed in amorphous form and in micronized sizes, that means having a particle size (D₉₀) of less than 100 micron in size; more preferably D₉₀ is less than 20 micron in size and yet more preferably less than 10 micron. The term D₉₀ refers to the particle size which at least 90% of the particles are below.

Micronised material is generally more sensitive to degradation, as the surface to volume ration is higher than for larger particles, exposing more surface to environmental factors. Micronised material can however provide advantages in terms of homogeneous distribution of the material in a drug matrix. Tableting properties may be quite different.

It is believed that in the present invention, micronized fluvastatin particles are packaged in between the larger excipient particles (roughly, 50- 120 micron in sizes) reducing the interparticle void space. The polymeric matrix that is surrounding the micronized particles functions in such a way that proper release rates are attained once the solids are exposed to the surrounding fluid medium. In other words, using the Fluvastatin in amorphous form, especially at a reduced particle sizes is believed to be offering fine dispersion of the active ingredient with the excipients that allows the fine and homogeneous dispersion of the drug into the polymer matrix.

Bioerodible devices represent a form of sustained release formulations for which it is complex to derive at and define mathematically the mechanism of dissolution. Complexity of the system arises from the fact that as the polymer dissolves, the diffusional path length for the drug may change. This usually results in a moving-boundary diffusion system. Zero-order release can occur only if surface erosion occurs and surface area does not change with time. The disadvantage of this system is that release kinetics are often hard to control, since many factors affecting both the drug and the polymer must be considered. The present invention has come up with very satisfactory sustained release formulations for fiuvastatin of this kind. Dissolution tests have shown very positive results.

Stable pharmaceutical compositions may be prepared by processes known in the prior art including, for example, by comminuting, mixing, granulation (wet and dry), melting, sizing, kneading, drying, molding, immersing, coating, compression (dry or direct), etc. The coating may be carried out by known conventional methods. The coating may be applied one or more of the excipients or their mixture or mixtures with the active ingredient. Coating may be applied more than once and may be carried out, optionally in different sequences of the manufacturing stages, after blending with one or more pharmaceutically acceptable excipients. Spray coating in a coating pan or fluidized bed technique may be employed. The amount of coating agent and the carrier vehicle vary upon the type of formulation and mode of administration, and are readily discernible to those of ordinary skill in the art. Suitable solvents used include one or more of ethanol, methanol, methylene chloride, acetone, propyl alcohol, isopropyl alcohol, butyl alcohol, trichloroethane, ethylformamide, water and mixtures thereof.

EXAMPLES The following examples are illustrative of the present invention and should not be considered as limiting the scope of the invention.

Example 1: Tablet formulation

Table 1. Formulations of 80 mg fiuvastatin SR tablet.

Formulation: I II III

Amount Amount Amount

Ingredients (mg) (mg) (mg)

Magnesium stearate 4,20 4,20 4,20

Povidone 10,50 10,50 10,50

Microcrystalline cellulose 68,67 68,67 68,67

Hydroxyethyl cellulose 35,00 52,50 70,00

Mannitol 147,15 129,65 112,15

Fluvastadium sodium 84,48 84,48 84,48

Total tablet core 350,00 350,00 350,00

The ingredients were formulated by wet granulation using ethanol as granulation liquid and compressed to tablets. The fiuvastatin sodium was amorphous, micronised material (d₉₀ about 4-5 micron). Table 2. Formulation of coating suspension for 80 mg fluvastatin SR tablet.

Coating

HPMC 6,04

Macrogol 1,45

Yellow iron oxide 0,60

Titanium dioxide 2,41

Coating weight 10,50

Total tablet weight 360,50

The tablets from Example 1 were coated with a coating mixture as described in Table 2.

Example 2: Biostudy

In order to assess the bioavailability of the formulations of the invention, a preferred embodiment formulation of the invention, 80 mg SR fluvastatin tablet formulation developed in this study as described in Example 1 (Formulation II) and coated as described in Example 2, was tested against innovator's 80 mg SR fluvastatin tablet (marketed under the trade name of ^λLocol^®' in Germany). A comparative, randomized, single-dose, 2-way crossover bioavailability study was carried out both under fed and fasted conditions with 154 and 48 volunteers respectively.

The 80% confidence intervals of the ratios of LSM derived from the analyses of the In- transformed pharmacokinetic parameters, AUC₀-_t, AUC_inf , C_maχ and T_max for fluvastatin in plasma were found to be within the 80-125% acceptable range under both fed and fasted states.

Example 3: Stability Tests

In Table 3, six-months stability test results that were carried out at 40⁰C & 75% relative humidity (RH), using 100,000 tablets of 80 mg Fluvastatin SR tablets prepared in accordance to the invention described in Example 1 (Formulation II) and coated as described in Example 2, that are maintained in al/al, blister; duma plastic container with desiccant and in brown glass bottles with desiccant ; while in Table 4, stability tests results for the innovator's 80 mg Fluvastatin SR tablets of the innovator, ^λLocol^®' were carried out at the identical conditions with those of given in Table 3, which are maintained in al/al blister are given for comparison purposes for three batches.

These results show that 96 to 97.9% of the fluvastatin remains in the product without undergoing any significant degradation reaction, which is comparable to the comparative product which yields a 96.9 to 98% remaining quantity of fluvastatin. In terms of total impurity formation; the products developed in this invention showed a total impurity level, varying between 0.35 to 0.36 at zero time; and showed only a very negligible increase that is varying between 0.35 to 0.73 after 6 months; the same value has increased from 0.39 at time zero to 0.63 after 6 months for the innovator's product which reveals that product developed in this invention remained stable over 6 months and showed very little variation from packing to packing. Among the three packings, al/al blister offers the most preferred selection as far as cost, ease of handling and by being less sophisticated and having less risk of exposing the dosage form to further environmental risks such as bottles or containers do, in which the remaining tablets might expose upon opening the tabs.

Table 3. Six-months stability results that were carried out at 40°C & 75%RH, using 100,000 tablets of 80 mg Fluvastatin SR tablets (Formulation II of Example 1).

Table 4. Six-months stability results that were carried out at the identical conditions with those of described above for Table 3 for the innovator's 80 mg Fluvastatin SR tablets (Locol ®)

Claims

1. A solid orally administrable sustained release pharmaceutical formulation comprising as active ingredient fluvastatin or a pharmaceutically acceptable salt, hydrate or solvate thereof and a pharmaceutically acceptable excipient, wherein said active ingredient is in amorphous form.

2. The formulation of claim 1, with the provisio that excipients of said formulation do not contain a pH-stabilising agent.

3. The formulation of claim 2 which formulation does not contain a pH-stabilising agent from the group of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium hydrogen carbonate, anhydrous sodium phosphate, potassium phosphate, calcium dibasic phosphate, trisodium phosphate, sodium hydroxide, potassium hydroxide, and lithium hydroxide; or any mixture of those.

4. The formulation of claim 1 wherein the fluvastatin or pharmaceutically acceptable salt, hydrate or solvate thereof is in the form of micronised particles.

5. The formulation of claim 4, wherein said micronised particles have a D₉₀ particle size of less than 100 micron.

6. The formulation of claim 4, wherein said micronised particles have a D₉₀ particle size of less than 20 micron.

7. The formulation of claim 4, wherein said micronised particles have a D₉₀ particle size of less than 10 micron.

8. The formulation of claim 4, wherein said micronised particles have a D₉₀ particle size of less than 5 micron.

9. The formulation of any of the preceding claims, comprising the sodium salt of fluvastatin.

10. The formulation of any of the preceding claims wherein said formulation comprises a core and a coating layer, wherein said core comprises said fluvastatin active ingredient or pharmaceutically acceptable salt, hydrate or solvate thereof.

11. The formulation of any of the preceding claims wherein said formulation comprises in the range of about 5% to about 65% by weight of fluvastatin or pharmaceutically acceptable salt, hydrate or solvate thereof.

12. The formulation of claim 11, wherein said formulation comprises in the range of about 10% to about 30% by weight of fluvastatin or said pharmaceutically acceptable salt, hydrate or solvate thereof.

13. The formulation of any of the preceding claims comprising one or more of the excipients selected from the group consisting of a binder, a filler, a diluent, a lubricant, a release controller, a disintegrant and a stabilizer.

14. The formulation of claim 13 comprising a binder selected from the group consisting of polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, ethyl cellulose, acacia gum, pregelatinized starch, sodium alginate, glucose, polyethylene oxide, wheat starch, corn starch, lactose, sucrose, glucose, sorbitol, dextrates, dextrins, dextrose, fructose, mannitol, and sorbitol.

15. The formulation of claim 13 comprising a filler selected from the group consisting of starch, pregelatinized starch, wheat starch, corn starch, lactose, sucrose, glucose, sorbitol, dextrates, dextrins, dextrose, fructose, mannitol, sorbitol, calcium phosphate, calcium sulfate, carboxymethylcellulose calcium, microcrystalline cellulose (MCC), powdered cellulose, sodium chloride and mixtures thereof.

16. The formulation of claim 13 comprising a lubricant selected from one or more of magnesium stearate, sodium stearyl fumarate, stearic acid, colloidal anhydrous silica, synthetic aluminium silicate, calcium stearate, talc and hydrogenated castor oil.

17. The formulation of any of the preceding claims, comprising a release controller selected from non-ionic hydrophilic polymers including hydroxyethylcellulose (HEC), hydroxypropylcellulose and polyethyleneoxide.

18. The formulation of claim 17 which comprises hydroxyethylcellulose (HEC).

19. The formulation of claim 18 comprising in the range of about 5-35 wt% of hydroxyethyl cellulose.

20. The formulation of any of the preceding claims, which formulation exhibits a dissolution profile such that in the range of 18 to 45 % of the fluvastatin compound is dissolved in

6 hours, the test being performed using a paddle dissolution bath, (apparatus 2 according to USP 29 and Eur. Pharmacopoeia 5th ed.) 50 rounds per min. in 900 ml_ phosphate buffer, pH 6.8 at 37⁰C.

21. The formulation of any of the preceding claims wherein the formulation exhibits a dissolution profile such that in the range of 35-66% of the fluvastatin compound is dissolved in 12 hours and no less than 70% of the fluvastatin is dissolved in 24 hours, in the dissolution test described in claim 19.

22. The formulation of claim 10, wherein said core comprises fluvastatin sodium, mannitol, microcrystalline cellulose, hydroxyethylcellulose, polyvinyl pyrrolidone, and magnesium stearate.