Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
  • A61K9/2806—Coating materials
  • A61K9/2833—Organic macromolecular compounds
  • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
  • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

• 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.
• statins or HMG-CoA reductase inhibitors
• HMG-CoA reductase inhibitors are 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.
• HMG-CoA 3-hydroxy-3-methylglutaryl- coenzyme A
• Lovastatin (MEVACOR ® ) was the first inhibitor of HMG-CoA reductase to become available for prescription in 1987.
• HMG-CoA reductase inhibitors which are natural fermentation products, mevastatin and lovastatin
• simvastatin ZOCOR ®
• pravastatin PRAVACHOL ®
• fluvastatin LESCOL ®
• atorvastatin LIPITOR ®
• cerivastatin also known as rivastatin
• 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 C 24 H 2S FNO 4 -Na, its molecular weight is 433.46 Da and its structural Formula is shown as 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.
• HMG- CoA 3-hydroxy-3-methyl-glutaryl coenzyme A
• 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).
• SR sustained release
• SR sustained release
• 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.
• 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.
• pH stabilizing agents comprising alkaline/basifying agents have generally been included as a definite requirement in formulations of the statin group of drugs.
• 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.
• a pH-stabilizing agent i.e., an alkaline/basifying agent
• 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.
• 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 present invention provides novel sustained release fluvastatin formulations which overcome the necessity of addition of an alkaline/basifying agent.
• 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.
• 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.
• 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
• alkali metal hydroxides such as sodium, potassium, or lithium hydroxide
• sustained release (SR) formulations can advantageously be formed in accordance with the present invention.
• sustained-release 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.
• 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, 37 0 C, 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.
• 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.
• GI gastrointestinal
• the composition comprises one or more excipients selected from a binder, filler, diluent, lubricant, release controller, and, a swell-controlling agent, disintegrant, and stabilizer.
• 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.
• the binder is PVP. ISP Corp. Inc.
• 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.
• MCC is selected as the most preffered filler.
• MCC can also function as a swell- controlling agent.
• 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.
• 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.
• 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.
• Diluent may be employed in amounts ranging from about 5 to 70 wt%, relative to the total weight of the said oral dosage form.
• 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.
• HEC polymers hydroxyethyl cellulosic polymer
• NATROSOL hydroxypropyl cellulose polymer
• KLUCEL hydroxypropyl cellulose polymer
• PEO polymers polyethylene oxide polymer
• 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.
• 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.
• magnesium stearate is selected as the most preferred lubricant.
• 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.
• HPMC hydroxypropylmethylcellulose
• HPMC hydroxypropylmethylcellulose
• methylcellulose ethylcellulose
• carboxymethylcellulose hydroxymethlylcellulose
• hydroxyethylcellulose generally those having a number average molecular weight in the range 10,000 to 250,000
• HPMC such as are sold by Dow Chemicals under the trade names "Methocel” and
• 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.
• 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.
• 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.
• 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.
• 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.
• fluvastatin formulations of the present invention 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.
• excipients 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.
• 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 (D 90 ) of less than 100 micron in size; more preferably D 90 is less than 20 micron in size and yet more preferably less than 10 micron.
• D 90 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.
• 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.
• 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.
• 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.
• the ingredients were formulated by wet granulation using ethanol as granulation liquid and compressed to tablets.
• the fiuvastatin sodium was amorphous, micronised material (d 90 about 4-5 micron).
• Table 2 Formulation of coating suspension for 80 mg fluvastatin SR tablet.
• Example 2 The tablets from Example 1 were coated with a coating mixture as described in Table 2.
• 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 ⁇ Locol ® ' 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.

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