WO2010006451A1 - Forme galénique contenant une statine - Google Patents

Forme galénique contenant une statine Download PDF

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Publication number
WO2010006451A1
WO2010006451A1 PCT/CA2009/001031 CA2009001031W WO2010006451A1 WO 2010006451 A1 WO2010006451 A1 WO 2010006451A1 CA 2009001031 W CA2009001031 W CA 2009001031W WO 2010006451 A1 WO2010006451 A1 WO 2010006451A1
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WIPO (PCT)
Prior art keywords
dosage form
pharmaceutically acceptable
stable
present
statin
Prior art date
Application number
PCT/CA2009/001031
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English (en)
Inventor
Mathew Philip
Naresh Talwar
Shruti Bhat
Original Assignee
Pharmascience Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pharmascience Inc. filed Critical Pharmascience Inc.
Priority to CA2730665A priority Critical patent/CA2730665C/fr
Publication of WO2010006451A1 publication Critical patent/WO2010006451A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics

Definitions

  • the present invention relates to a novel dosage form, a process for the manufacturing the same, as well as the composition of the novel dosage form. More specifically, the present invention relates to a dosage form comprising rosuvastatin calcium as a pharmaceutically acceptable active ingredient
  • Rosuvastatin calcium is a synthetic lipid- lowering agent for oral administration.
  • the chemical name for rosuvastatin calcium is bis[(E)-7-[4 ⁇ (4-fluoro ⁇ henyl)-6-isopropyl-2-[methyl(memyIsulfonyl)amino] pyrimidtr>5- yl] (3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt. It has the following structural formula:
  • Rosuvastatin calcium belongs to the class of medications known as "statins", which are known to inhibit the 3-hydroxy-3-methyl-glutaryl-coenzyme A (“HMG-CoA”) reductase e n zyme. HMG-CoA reductase is involved in regulating cholesterol levels. Statins are used along with changes to diet and exercise to help control the amount of cholesterol produced by the body. Rosuvastatin calcium can help a person's body decrease low- dens i ty l i poprotein (LDL) cholesterol (i.e. bad cholesterol) and triglyceride levels; i ncrease high-density lipoprotein (HDL) cholesterol ⁇ i.e.
  • LDL low- dens i ty l i poprotein
  • HDL high-density lipoprotein
  • This ratio represents the balance between good and bad cholesterol Rosuvastatin calcium is indicated as an adjunct to diet, at least equivalent to the Adult Treatment Panel IH (ATP m TLC diet), for the reduction of elevated total cholesterol, (Total-Q, LDL-C, Apolipoprotein B ("ApoB”), the Total-C/HDL-C ratio and triglycerides and for increasing HDL-C; in hyperlipidemic and dyslipidemic conditions, when response to diet and exercise alone has been inadequate including: primary hypercholesterolemia (Type IIa including heterozygous familial hypercholesterolemia and severe non-familial hypercholesterolemia), combined (mixed) dyslipidemia (Type lib), homozygous familial hypercholesterolemia where rosuvastatin calcium is used either alone or as an adjunct to diet and other lipid lowering treatment such as apheresis.
  • Type IIa including heterozygous familial hypercholesterolemia and severe non-familial hypercholesterolemia
  • Type lib
  • Rosuvastatin calcium is also known to be a synthetic, enantiomerically pure lipid- lowering agent. It is a selective, potent and competitive inhibitor of HMG-CoA reductase. This enzyme catalyses the conversion of HMG-CoA to mevalonate, which is an early and rate-Iimiting step in cholesterol biosynthesis. Studies have also shown that rosuvastatin calcium lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver by increasing the number of hepatic LDL receptors on the cell-surface for enhanced uptake and catabolism of LDL. Additionally, rosuvastatin calcium inhibits the hepatic synthesis of very low density lipoprotein (VLDL), thereby reducing the total number of VLDL and LDL particles.
  • VLDL very low density lipoprotein
  • rosuvastatin According to Canadian Patent No. 2,429,263 (issued March 17, 2009 to AstraZeneca), rosuvastatin, and pharmaceutically acceptable salts of rosuvastatin, can be used in the treatment of heterozygous familial hypercholesterolemia. According to Canadian Patent Application No. 2,560,167 (filed April 25, 2005 by Alcon, Inc.), statins can also be used for the treatment of ocular hypertension and glaucoma.
  • Canadian Patent Application No. 2,450,820 (filed August 16, 2002 by Teva Pharmaceutical Industries Ltd.) is directed to processes for preparing a calcium salt of a statin from an ester derivative or protected ester derivative of the statin by using calcium hydroxide,
  • Canadian Patent Application No. 2,537,962 relates to two polymorphic forms of bis[(E)- 7-[4-(4-fluorophenyl) ⁇ isopropyl-2-[methyl(methylsulfonyl)ar ⁇ uno]py ⁇ iinidin-5-yI]- (3R,5S)-3,5-dihydroxyhept-6-enok: acid] calcium salt processes for making them and their use as HMG Co-A reductase inhibitors.
  • United States Patent No. 7,241,800 (issued July 10, 2007 to Mai De Ltd.) relates to anhydrous amorphous forms of rosuvastatin calcium, fluvastatin sodium and pitavastatin calcium, as well as to processes for their preparation, to pharmaceutical compositions containing them and to methods of treatment using the same.
  • a problem associated with the chemical compound rosuvastatin is that it readily undergoes degradation under certain conditions such as exposure to atmospheric conditions (i.e. humidity, oxygen, air and light), thereby significantly reducing the storage life of any pharmaceutical compositions containing rosuvastatin or its salts, such as rosuvastatin calcium.
  • This degradation problem is referred to in Canadian Patent Nos. 2,313,783 and 2,315,141 (both invented by N.A. Wiggins and J.R. Creekmore and issued to AstraZeneca).
  • the major degradation products formed are the corresponding (3R,5S) lactone and an oxidation product in which the hydroxyl group adjacent to the carbon-carbon double bond is oxidized to a ketone functionality.
  • Canadian Patent No. 2,313,783 discloses the use of a tribasic phosphate salt in which the cation is multivalent to provide stability to the composition, thereby avoiding degradation.
  • Canadian Patent No. 2,315,141 discloses the use of an inorganic salt in which the cation is multivalent for stabilizing the rosuvastatin calcium structure.
  • Canadian Patent Application No. 2,543,716 discloses formulations comprising therapeutically effective amounts of at least one acid- stable, carrier-mediated transport statin, at least one poorly water-soluble, carrier- mediated transport statin, or at least one large molecular weight, carrier-mediated transport statin, such as atorvastatin and rosuvastatin, or a pharmaceutically acceptable salt thereof, and methods of their use.
  • the second group of ingredients inhibit the formation of lactones consists of corn starch, mannitol, hydroxypropyl cellulose, and hypromellose.
  • the rosuvastatin calcium formulations of the prior art require the use of stabilizing agents, for example, inorganic salts in which the cation is multivalent, such as tribasic calcium phosphate, and some ingredients which specifically prevent degradation. Usage of stabilizing agents inherently renders the manufacturing process more costly due to the use of additional pharmaceutical e ⁇ cipients, and which, in turn, consumes more time.
  • a novel stable pharmaceutical dosage form containing a statin that is substantially free of stabilizing agents, said dosage form comprising a statin combined with the following pharmaceutically acceptable ex ⁇ pients: colloidal silicon dioxide, microcrystalline cellulose, and lactose monohydrate.
  • the colloidal silicon dioxide is present in an amount ranging from 0.5 to 1.5 %
  • the microcrystalline cellulose is present in an amount ranging from 25 to 35%
  • lactose monohydrate is present in an amount ranging from 50 to 70% by weight of the dosage form.
  • the statin is rosuvastatin or a pharmaceutically acceptable salt thereof. More preferably, the statin is rosuvastatin calcmm.
  • a rosuvastatin dosage form that allows a single daily administration with a prolonged effect, simplified production and is cost effective.
  • a process for manufacturing the novel dosage form in another aspect of the present invention, there is provided a process for manufacturing the novel dosage form.
  • the manufacturing process of the present invention is simple and less time consuming.
  • the dosage forms according to the present invention substantially decrease the formation of lactone or oxidation degradation products in comparison to the commercially available dosage form containing rosuvastatin, hence they present greater stability than what was achieved in the Crestor® product
  • the pharmaceutically active substance is a statin, for example, rosuvastatin.
  • statin for example, rosuvastatin.
  • rosuvastatin includes all optical isomers, racemic mixtures and the like of the compound and all pharmaceutically acceptable salts, amides, prodrugs and analogs thereof.
  • a "pharmaceutically acceptable salt” or a “pharmaceutically acceptable ester” of the compound as provided herein is a salt or ester which is not biologically or otherwise undesirable.
  • a pharmaceutically acceptable salt of rosuvastatin is, for example, rosuvastatin calcium.
  • an effective amount or “pharmaceutically effective amount” of an active agent are meant to be a nontoxic but sufficient amount of the active agent to provide the desired therapeutic effect
  • the exact amount required will vary from subject to subject, depending on age, general condition of the subject, the severity of the condition being treated, and the particular active agent administered, and the like. Thus, it is not possible to specify an exact “effective amount”; however, an appropriate “effective” amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
  • the typical daily dosage of rosuvastatin calcium is in the range of about 5 mg to about 100 mg.
  • excipient refers to a generally pharmaceutically inactive or inert substance used as a diluent or vehicle for a drug.
  • a pharmaceutically acceptable excipient includes a "pharmaceutically acceptable carrier".
  • tablets, troches, pills, capsules, and the like may contain excipients including binders, such as gum tragacanth, acacia, corn starch or gelatin; a disintegrating agent such as corn starch, potato starch, algin ⁇ c acid; and a lubricant such as magnesium stearate.
  • Capsules may contain additional excipients such as a liquid carrier.
  • pharmaceutically acceptable carrier a carrier comprised of a material that is not biologically or otherwise undesirable, i.e., the material may be administered to an individual along with the selected active agent without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.
  • agent is used generically herein to refer to any components present in the pharmaceutical formulations other than the active agent or agents, and thus includes diluents, binders, lubricants, disintegrants, fillers, colouring agents, wetting or emulsifying agents, pH buffering agents, preservatives, and the like.
  • substantially free is intended to mean that the present invention does not contain any specific amount of stabilizing agent that is sufficient to stabilize the active substance, formulation or end product .
  • stabilizing agent refers to any substance or a mixture of substances, which when in contact with the active agent in appropriate quantities, will improve the physical and chemical characteristics of the active agent.
  • the expression "dosage form” may consist of granules, spheroids, beads, pellets, capsules, tablets or any other suitable unit
  • the dosage form is preferably a tablet
  • the present invention relates to a novel stable pharmaceutical dosage form containing a statin, wherein the dosage form is substantially free of stabilizing agents, said dosage form comprising a statin combined with at least the following pharmaceutically acceptable excipients: colloidal silicon dioxide, microcrystalline cellulose, and lactose monohydrate.
  • a tablet composition is made of several components, such as for example at least one pharmaceutically acceptable active substance (e.g. a statin, rosuvastatin or pharmaceutically acceptable salt thereof) combined with at least one pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable substance is combined with at least three pharmaceutically acceptable excipients, being colloidal silicon dioxide, microcrystalline cellulose, and lactose monohydrate.
  • statins include statins.
  • Suitable statins include, for example, atorvastatin, cerivastatin, fmvastatin, Iovastatin, mevastatin, pitavastarin, pravastatin, rosuvastatin and simvastatin. Rosuvastatin and salts thereof are particularly preferred pharmaceutically acceptable active agents, and rosuvastatin calcium is the most preferred.
  • the pharmaceutically acceptable active agent could be co-administered with another active agent known to a person skilled in the art, such as, for example, simvastatin could be coadministered with ezetimibe (Vytorin®), lovastatin with niacin (Advicor®), and atorvastatin with amlodipine (Caduet®).
  • another active agent known to a person skilled in the art, such as, for example, simvastatin could be coadministered with ezetimibe (Vytorin®), lovastatin with niacin (Advicor®), and atorvastatin with amlodipine (Caduet®).
  • Each of the active agents in the individual tablets may be in the form of a pharmaceutically acceptable salt, ester, amide, prodrug or other derivative or analog, including active agents modified by appending one or more appropriate functionalities to enhance selected biological properties. Such modifications are known in me art and/ or are described in the pertinent texts and literature.
  • the pharmaceutically acceptable active substance of the present invention is combined with three pharmaceutically acceptable excipients, being colloidal silicon dioxide, microcrystalline cellulose, and lactose monohydrate.
  • the dosage forms of the present invention may include additional pharmaceutically acceptable excipients, such as diluents, djsintegrants, binders, lubricants, glidants, and the like.
  • Diluents are typically necessary to increase the bulk of a tablet so that a practical size is provided for compression.
  • Suitable diluents include, foi example, lactose, spray dried lactose, ⁇ -Iactose, ⁇ -lactose, Tabletose®, various grades of Pharmatose®, Microtose®, Fast Flow®, sorbitol, microcrystalline cellulose, various grades of Avicel®, Vivacel®, Vivapui®, powdered cellulose, kaolin, starch, hydrolyzed starches, pregelatinized starch, alumina, sucrose, dextrins, dextrose, fructose, maltodextrins, and the like.
  • Disintegrants are used to facilitate tablet disintegration or "breakup" after administration, and are generally starches, days, cellulose and cellulose derivatives, alginic acid or alginates, gums, crospovidone, polarci ⁇ lin potassium, sodium starch glycollate, pregelatinized starch, and the like.
  • Binders are used to impart cohesive qualities to a tablet formulation, and thus ensure that a tablet remains intact after compression.
  • Suitable binder materials include, but are not limited, to starch (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums (e.g., acacia, tragacanth, sodium alginate, celluloses, and Veegum), and synthetic polymers such as polymethacrylates and polyvinylpyrrolidone (povidone), ethylcellulose, hydroxyethyl cellulose, hydroxypropylmethylcellulose (HPMC), methylcellulose, polyethylene oxide, and the like.
  • starch including corn starch and pregelatinized starch
  • gelatin including sucrose, glucose, dextrose, lactose and sorbitol
  • sugars including sucrose, glucose, dextrose, lacto
  • Lubricants are used to facilitate tablet manufacture.
  • suitable lubricants include magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, and polyethylene glycol, talc, stearic acid (chemically designated as octadecanoic acid, C 18 H 36 O 2 ), zinc stearate, sodium stearyl fumerate, calcium stearate, and light mineral oil.
  • the lubricants are preferably present at no more than approximately 0.5 to 2.5 wt. % relative to tablet weight.
  • Suitable glidants include colloidal silicon dioxide, silicon dioxide (SiO 2 ) (Aerosil®), magnesium silicate, starch, talc, magnesium brisilicate, etc. Colloidal silicon dioxides are also known to function as an absorbent, anti-caking agent, emulsion stabilizer; glidant; suspending agent; and tablet disintegrant
  • the dosage forms may also contain minor amounts of nontoxic auxiliary substances such as antioxidants, for example, ascorbic acid, ascorbyl palmitate, butylated hydr ⁇ xyl anisole, butylated hydroxyl toulene, potassium meta bisulfite, propyl gallate, sodium thiosulfate, tocopherol, tocopherol acetate, tocopherol hemisuccinate, TPGS or other tocopherol derivatives, hypophosphorous add, fumaric acid, monothioglycerol; coloring agents, flavouring agents, surface active agents, such as for example, sodium lauryl sulfate, poly oxyethylene sorbitan fatty add esters (Tween® series), Myrj® series, Solutol® HS, poly oxyethylene alkyl ethers (Byrj® series), poly oxyethylene, castor oil derivatives, polyoxyethylene stearates, sorbitan esters (i.e.
  • antioxidants for example, ascorbic acid
  • sorbitan fatty acid esters poloxamers
  • sucrose fatly acid ester vitamin E TPGS
  • polyethylene glycol fatty acid esters wetting or emulsifying agents
  • buffering agents including for example, citric add, sodium dtrate, dilute HCl, sodium hydroxide, fumaric add, tartaric acid, malic acid, succinic acid, preservatives, such as methyl and propyl parabens, BKC, thiomersal, and the like.
  • buffering agents including for example, citric add, sodium dtrate, dilute HCl, sodium hydroxide, fumaric add, tartaric acid, malic acid, succinic acid, preservatives, such as methyl and propyl parabens, BKC, thiomersal, and the like.
  • citric add sodium dtrate
  • dilute HCl sodium hydroxide
  • fumaric add tartaric acid
  • malic acid malic acid
  • succinic acid preserv
  • the coating composition of the present invention can be made of several components.
  • the coating composition can include a coating agent, alone or in combination with any other pharmaceutically acceptable exdpient such as a film forming polymer, anti-tack ⁇ ng agents, glidants, diluents, lubricants, plastidzers, additives, surface active agents, and solvents.
  • the coating composition of an embodiment of t ⁇ ie present invention can comprise a coating agent, such as Opadry II®, manufactured by Colorcon.
  • the end product can further be coated with a non-functional or top coat so as to improve the appearance of the dosage form, such as a tablet.
  • a non-functional or top coat so as to improve the appearance of the dosage form, such as a tablet.
  • conventional coating procedures and equipment may be used to coat the dosage units (the drug-containing tablets, beads or particles).
  • novel drug dosage forms of die present invention are to be administered orally to a mammal and can be used to administer rosuvastatin calcium, to treat or prevent a variety of disorders, conditions and diseases.
  • administration of rosuvastatin calcium may be carried out in order to treat any disorder, condition or disease for which rosuvastatin calcium is generally indicated.
  • disorders, conditions and diseases include those described m the background of the present invention.
  • the typical daily dose is in the range of approximately 5 mg to 100 mg, preferably 5 mg to 60 mg, and more preferably 40 mg.
  • the exact dosage regimen will depend on a number of factors, including age, the general condition of the patient, the particular condition or disorder being treated, the severity of the patient's condition or disorder, and the like.
  • a standard dose of 10 mg for oral administration, once daily, is recommended in most patients.
  • Step 1 - rosuvastatin calcium and portion of lactose monohydrate (10.0 g) are blended together and screened through 420 ⁇ m mesh (blend #1).
  • Step 2 Aerosil, microcrystalline cellulose (Avicel®) and crospovidone are screened through 420 ⁇ m and blended with blend #1 for 1 minute to form blend #2.
  • Step 3 the remaining portion of lactose monohydrate is screened through 600 ⁇ m mesh and blended with blend #2 for 1 to 2 minutes to form blend #3.
  • Step 4 - magnesium stearate is screened through 420 ⁇ m mesh (425 ⁇ m) and is then blended with blend # 3 for several minutes (Le. 1-2 minutes) to form the final blend.
  • Step 5 - the final blend is compressed using a rotary press, so as to form, for example, tablets.
  • the resulting tablets are then coated with, for example Opadry ⁇ ® (from Colorcon) to a weight gain of 2% to 3.0% w/w.
  • the coating process can be performed with conventional coating equipment, for example O'HARA Lab CoatTM.
  • Step 1 - rosuvastatin calcium and portion of lactose monohydrate (10.0 g) are blended together and screened through 420 ⁇ m mesh (blend #1).
  • Step 2 Aerosil microcrystalline cellulose (Avicel®) and crospovidone are screened through 420 ⁇ m and blended with blend #1 for 1 minute to form blend #2.
  • Step 3 the remaining portion of lactose monohydrate is screened through 600 ⁇ m mesh and blended with blend #2 for 1 to 2 minutes to form blend #3.
  • Step 4 - magnesium stearate is screened through 420 ⁇ m mesh (425 ⁇ m) and is then blended with blend # 3 for several minutes (i.e.1-2 minutes) to form the final blend.
  • Step 5 - the final blend is compressed using a rotary press, so as to form, for example, tablets.
  • the resulting tablets are then coated with, for example Opadry ⁇ ® (from Colorcon) to a weight gain of 2% to 3.0% w/w.
  • the coating process can be performed with conventional coating equipment, for example O'HARA Lab CoatTM.
  • Step 1 Rosuvastatin calcium and microcrystailine cellulose (Avicel®101) are blended together in a V blender for 3 minutes and screened through 225-250 ⁇ m mesh (blend #1).
  • Step 2 Aerosil, microcrystalline cellulose (Avicel®102) and crospovidone are blended together in a V-blender for 3 minutes and screened through 1000-1200 ⁇ m mesh to form blend #2.
  • Step 3 lactose monohydrate is screened through 1000-1200 ⁇ m mesh and blended with blend # 1 and blend #2 for 21 minutes in a Bin Blender to form blend #3.
  • Step 4 Magnesium stearate is screened through 420 ⁇ m mesh and is then blended with blend # 3 foi 3 minutes in a Bin Blender to form, the final blend.
  • Step 5 - the final blend is compressed using a rotary press, so as to form, for example, tablets.
  • the resulting tablets are then coated with, for example Opadry H® (from Colorcon) to a weight gain of 2% to 3.0% w/w.
  • the coating process can be performed with conventional coating equipment, for example O'HARA Lab CoatTM.
  • the process for manufacturing ihe novel dosage form according to the present invention generally comprises:
  • a statin with the following pharmaceutically acceptable excipients: colloidal silicon dioxide, microcrystalline cellulose, and lactose monohydrate so as to form a blend;
  • a third step of applying a coating composition optionally, a third step of applying a coating composition.
  • Direct compression of powder is a preferred manufacturing technique.
  • other dosage forms can be envisaged; though fo ⁇ the purposes of the present invention, the tablet form is preferred.
  • the dosage form, fof example a tablet, of the present invention was subjected to accelerated stability studies as per ICH guideline conditions in their primary packaging.
  • a primary packaging includes tablets packed in high-density polyethylene (HDPE) packs with a desiccant and further induction sealed and also in blister packs.
  • HDPE high-density polyethylene
  • One (1) month and three (3) months stability studies were conducted and tested for degradation,
  • a comparative study of the stability results for the composition of the present invention versus compositions stabilized with tribasic calcium phosphate (i.e. Crestor) are provided in the following tables.
  • the dosage forms according to the present invention substantially avoids the formation of lactone or oxidation degradation products in comparison to the commercially available dosage form containing rosuvastatin calcium, presenting greater stability than what was achieved in the Crestor® product.
  • the level of degradation of the active pharmaceutical ingredient in HDPE packs and blister packs is approximately the same, with 0.16% of the oxidation product and 0.09% of the lactone detected in the HDPE packs versus 0,06% of the oxidation product and 0.13% of the lactone in the blister packs after 3 months storage at 40°C and 75% relative humidity.
  • composition (or formulation) of the present invention is stable without the addition of any stabilizers.
  • the major degradation products being the lactone and the keto-acid (oxidation product), are well controlled.

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Abstract

La présente invention concerne une nouvelle forme galénique pharmaceutique stable qui contient une statine et des procédés pour préparer de telles formes galéniques, la forme galénique étant pratiquement exempte d'agents de stabilisation et la statine étant combinée aux excipients de qualité pharmaceutique suivants : du dioxyde de silicium colloïdal, de la cellulose microcristalline et du monohydrate de lactose.
PCT/CA2009/001031 2008-07-15 2009-07-14 Forme galénique contenant une statine WO2010006451A1 (fr)

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CA2730665A CA2730665C (fr) 2008-07-15 2009-07-14 Forme galenique contenant une statine

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CA2,637,977 2008-07-15
CA002637977A CA2637977A1 (fr) 2008-07-15 2008-07-15 Forme pharmaceutique contenant une statine

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010140992A1 (fr) * 2009-06-03 2010-12-09 Mahmut Bilgic Compositions pharmaceutiques stables contenant du calcium rosuvastatine
US20140328936A1 (en) * 2011-12-08 2014-11-06 Hexal Ag Novel pharmaceutical statin composition
CN105796518A (zh) * 2016-04-08 2016-07-27 山东省中医药研究院 一种黄独素b分散片及其制备方法
CN113143882A (zh) * 2021-04-30 2021-07-23 海南通用三洋药业有限公司 一种瑞舒伐他汀钙胶囊的制备方法和瑞舒伐他汀钙胶囊

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CA2465621A1 (fr) * 2003-06-12 2004-12-12 Warner-Lambert Company Llc Compositions pharmaceutiques d'atorvastatine
WO2006054308A2 (fr) * 2004-11-22 2006-05-26 Dexcel Pharma Technologies Ltd. Formulations d'atorvastatine stables
EP1923057A1 (fr) * 2005-11-21 2008-05-21 Teva Pharmaceutical Industries Ltd Formule pharmaceutique atorvastanine
US20080138429A1 (en) * 2003-02-12 2008-06-12 Vlasta Humar Coated Particles and Pharmaceutical Dosage Forms

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US20080138429A1 (en) * 2003-02-12 2008-06-12 Vlasta Humar Coated Particles and Pharmaceutical Dosage Forms
CA2465621A1 (fr) * 2003-06-12 2004-12-12 Warner-Lambert Company Llc Compositions pharmaceutiques d'atorvastatine
WO2006054308A2 (fr) * 2004-11-22 2006-05-26 Dexcel Pharma Technologies Ltd. Formulations d'atorvastatine stables
EP1923057A1 (fr) * 2005-11-21 2008-05-21 Teva Pharmaceutical Industries Ltd Formule pharmaceutique atorvastanine

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WO2010140992A1 (fr) * 2009-06-03 2010-12-09 Mahmut Bilgic Compositions pharmaceutiques stables contenant du calcium rosuvastatine
US20140328936A1 (en) * 2011-12-08 2014-11-06 Hexal Ag Novel pharmaceutical statin composition
US9717707B2 (en) * 2011-12-08 2017-08-01 Hexal Ag Pharmaceutical statin composition
CN105796518A (zh) * 2016-04-08 2016-07-27 山东省中医药研究院 一种黄独素b分散片及其制备方法
CN113143882A (zh) * 2021-04-30 2021-07-23 海南通用三洋药业有限公司 一种瑞舒伐他汀钙胶囊的制备方法和瑞舒伐他汀钙胶囊

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