SA93130414B1 - HMG-CoA Reductase Established Pharmaceutical Formulations Containing an HMG-CoA Reductase Inhibitor Compound - Google Patents

Abstract

Abstract: A dosage form has been discovered comprising an HMG-CoA reductase inhibitor compound such as fluvastatin sodium that is stable against change in pH related to degradation by alkaline stabilization medium capable of giving a pH of at least 8 to an aqueous solution or a dispersion. combination.

Description

. Stable Pharmaceutical Compositions Containing a NBP HMG - CoA Reductase Inhibitor Compound Full Description Background 0 | The present invention describes a pH-sensitive drug formulation that has great stability in sli storage. © Some HMG - CoA Reductase Compounds; For example, Jil SU inhibitors are useful in the treatment of hyperlipoproteinemia and atherosclerosis, and these compounds have the formula (I) OH 08 / COOM I | yq — BR -X - CH - CHa - CH 0, where 8 represents an organic moiety X - FL - CH = CH - “EVEL .

v

Jie physiologically acceptable cation represents M cation, preferably sodium or ammonium the alkali metal or ammonia cation cation. sodium potassium, especially sodium

Ju and Ali. A is less than pH and these compounds are subject to cracking when fluvastatin USAN is an example of that; A compound that includes a compound with an indication © ) “fluvastatin” The meaning of “fluvastatin sodium” sodium, which has a chemical indication, will be mentioned after that

R*, S* - (s - ) )-7- { 3-(4-fluorophenyl) -1- (1 - methyl — ethyl) - 1H-indol- 2-yl } - 3,5-dihydroxy- 6-heptenoic acid, sodium salt, { see European Patent

Application EP-A-114027 }. Yo We found that the kinetics of breaking down fluvastatin LAD by way is different as follows: pH at Ald in the fluvastatin degradation kinetics solution, YY percentage residual at fluvastatin i: after; 7 hours | .0h | dela after 8 . / 5 | i } | aA | ANY VA: | av | 0 | 1 a

YoY | ALY | ¢ Lo 0 zero : zero Lo Yes | 1 e i i H

¢ GENERAL DESCRIPTION OF THE INVENTION The instability of the aforementioned fluvastatin and, in turn: the related HMG - CoA Reductase compounds, is due to the instability of the B, §-hydroxy groups on the heptenoic acid chain (aes) and the presence of the 0© double bond of the Neutral pH to acidic pH; therefore, Jax compounds in isomerization or oxidation reactions to form: unstable aromatic compounds such as the threoisomer 'corresponding lactones and other degradation products . And to obtain acceptable dosage forms for marketing that contain 0 of that compound. That compound must be protected against pH instability. In addition, the five requirements: heat, photosensitivity, and water absorption capacity of © compounds must be observed in the manufacturing process and in the storage of dosage forms. Vo Surprisingly, it was possible to prepare formulations with a long shelf life in which at least 4 * 6 7 # of the initial volume 7 of the drug is effective after two years at # 7 Ly Fe shy and for longer periods than that. The compositions of the invention administered orally provide rapid and complete intestinal absorption of the medicinal substance. M :

Among other advantages is that the fixed formulations of the invention: can be prepared directly by JA sal techniques based on other solvents, such as wet granulation. Detailed description o This invention relates to the preparation of the pharmaceutical composition consisting of the compound HMG-CoA of the formula (I) oH OH COOM | DEET - X - CH - CHZ— CH let where R The organic moiety—CH=CH-J34 X 1. |4 represents a physiologically acceptable cation and medium Cy PFT on the introduction of a pH of at least A to a watery solution or the dispersed Phthasol 1 of the composition. - All t PRN we pack on "drug material" and 9 medium alkali S$ 8 ¢ 0 , and the alkali-denored medium is capable of stabilizing the composition by introducing at least A=pH to the aqueous solution or the dispersed solution of the composition It is preferable that the compounds of formula (T) and the alkaline medium be bonded together

: Z and combined with each other in the formulation in order to achieve dll stability of the drug. It was found that the resulting composition gives a storage period of LH for the compounds of formula (1) even in the presence of moisture or when didi e the compositions on the excipients of the drug dda ila reactive excipients with lactose. The stability of the drug substance in the formulations of the invention is at least 58 7 and typically, they form 7 AA and 49 sed Aaa at 8" permeability and even for longer periods than that.) The term 'alkaline medium' or 'base' used herein refers to one or more substances Pharmaceutical acceptable materials of A = pH at least, and preferably at least 4 to the extent of 11 M = 01 for the aqueous solution, or the dispersed solution of the composition of the invention. A on J about alfa in the composition Late water is absorbed or when water is added in small quantities to the composition The medium must be inert gs MW / º for compounds of formula (D) 0.017 can be estimated by taking the unit: dose of a formulation containing yo mg of fluvastatin or an amount of AS of another compound of formula (1) and dispersing or dissolving the formulation in 10 to 100 milliliters of water z 71 | 0

A pharmaceutically acceptable substance or substances that comprise the alkaline medium may range from slightly soluble substances: water soluble to water insoluble substances. Among Aad alkaline substances dissolved in the evening that are capable of introducing the required basicity are those that include acceptable organic carbonate salts Wy a such as sodium carbonate or potassium ¢ sodium bicarbonate or potassium hydrogen carbonate Potassium hydrogen carbonate ¢ phosphate salt selected from dibasic phosphate 0 of anhydrous sodium » potassium, calcium, or trisodium phosphate, as well as alkaline hydroxides metal hydroxides such as ¢sodium hydroxide | potassium or lithium and mixtures thereof. © Ja may fixed assemblies according to the invention on de Ze 0 of weight; Typically, from 5 to 46 7 by weight of the medicinal substance 0 ° (such as fluvastatin 0.1 “(fluvastatin to yo) 7 by weight, preferably from 1-19 7 by weight of a soluble carbonate compound such as the one chosen from Sodium bicarbonate; sodium carbonate or a mixture thereof. Among the alkali substances that are insoluble or slightly soluble in water, which give a stable alkaline medium in the compositions Ud ad on Z "7"

A

z Compounds commonly used in formulas; as hydroxide; magnesium hydroxide or oxide; lip Sean mall carbonate or aluminium; ap WISH compounds aluminum-magnesium hydroxide or carbonate such as aluminum-magnesium hydroxide

Wy, as well as the acceptable salts, hydroxide aluminum-magnesium 0 - tribasic calcium phosphate of phosphoric acid such as tribasic calcium phosphate, and mixtures thereof, in the alkali substances mentioned above; The expression 'authentically acceptable carbonate salts' means the salts of carbonates and bicarbonates

pharmaceutically acceptable inorganic compounds such as sodium bicarbonate 0 carbonate; Calcium carbonate and mixtures thereof, which are effective for intramuscular alkaline medium. Also, formulations have special storage stability such as medium 0 ' for both water-soluble alkaline excipients and excipients gp al ; Alkali insoluble in water or slightly soluble in water. The actual improvements and other advantages were achieved by using an alkaline medium comprising carbonate salt dissolved in z Pasi i ali water and carbonate salt insoluble in Water is a combination of sodium bicarbonate (or carbonate) with calcium carbonate. z x. for

Sodium bicarbonate works to neutralize the acidic aggregates in the formula in the presence of moisture that may absorb onto the molecules of the formula during storage. Calcium carbonate provides a buffering action in the buffered formulation without an apparent effect on the release of the drug upon ingestion. It was found that the carbonate salts sufficiently stabilized the substance and the drug so that preparation techniques based on Gaull water with tribasic calcium phosphate water or wet wail wet granulation could be used to prepare the compositions of the invention. The calcium carbonate can be a precipitate or a granular material 0 and preferably a precipitate. The alkaline medium is present in the compositions in sufficient quantities to make its 11m at least equal to A and preferably at least 4 to 1 | For the aqueous solution or the dispersed solution of the composition, and in general, the compositions of the invention include from 0.1 to 60 by weight (typically from 0 ne to 7 fe by weight) of the medicinal substance and from 0.1 to 61 7 0 by weight, preferably from 010 to 7 YO by weight from alkaline media. 0 The amount of dispersant used is dependent on manufacturing. For example: in tablet formulations, the amount of calcium carbonate should not exceed the amount ol for exposure to pressure z z 1 z

1 It is usually used in combination with compressible alkaline substances such as sodium bicarbonate. On the other hand, the capsules contain high levels of drug carriers capable of giving a total composition that remains free-flowing and sufficiently prepared. The solid-dose unit composition contains a ratio of carbonate z to 46:1 dissolved in water to carbonate insoluble in water

NY

?:1 to 0:7 The typical disc of the invention comprises of . By weight from calcium carbonate to sodium bicarbonate

ViYe capsule composition contains these excipients in a ratio of by weight. L 1: Ye To, in addition to the drug substance and the alkaline medium, the materials are advanced in the formulations to give the ability to prepare. filler 0 º Appropriate for use Known in the practical art (see AL ; | (49+) iw 18th ed. Remington's Pharmaceutical science ed. pp. 1678 = 1131) and includes ¢PA + iad Publisher's mark; 0 lactose and other carbohydrates - starch gelatinized; Corn starch ¢ Phosphate ( Colorcon corp ) starch 150054 1900 Lis Similar | ; cellulose ¢ dicalcium phosphate a sell disaccharide os © microcrystalline cellulose microcrystalline sodium . 1 z

1 oz mixtures thereof preferably lactose mixtures; Microcrystalline cellulose z | Microcrystalline cellulose and pregelatinized starch: A: As a result of the compressive and cracking properties of all materials; Avicela, FMC Corp. (microcrystalline cellulose) 0 and mixtures comprising microcrystalline stalks and one or more proprietary materials such as Lill pregelatinized starch are beneficial. 1 Fillers are present in formulations in amounts ranging from 1 to 16 7 by weight relative to the formulation CA ve Other base materials that may be combined with the formulation to facilitate preparation and/or to increase the resulting dosage properties ¢ include tablet binders tableting binders (such as gelatin; sugar; natural and synthetic gums such as carboxymethylcellulose ¢ methylcellulose, ¢ polyvinylpyrrolidone; 2007 1 0 — hydroxypropylmethyl-cellulose ) microcrystalline cellulose y microcrystalline cellulose and scales from the above); fragmentation materials Je) carboxymethyl cellulose crosslinked ligands croscarmellose 005106; crospovidone; Liki Sodium glycolate Sodium starch glycolate Slip facilitators Dia YL Magnesium stearate ¢ Hydrogenated vegetable oil RB Wax ARR

VY

and the like (flow agents) such as camauba wax, silicon dioxide, iron oxide and sweeteners; Coloring materials (such as iron oxide) tale such as (flavoring media) materials (aluminum lakes aluminum pigment ld oxidizing agent etc. The basic and non-acid materials used are estimated by one of the skills in the method by referring to the methods The standard and laboratory method for preparing tablets or capsules, and in general (#7 from 01 to 1), the effective amount of tablet binder ranges from 7 to © by weight; anti-adhesive materials or 1 by weight, preferably from by weight; friable materials 01 to 1# ranging from BN materials 0 0.1 lubricants to 7© materials ranging from 1° to 7# by weight Depending on the total composition. These formulations can be formulated by the known methods to provide: 101 grams leo a dose unit via top that includes 0" 0 mg + 70 mg + 6; mg etc. of the compound In the form of capsules, tablets, granules, etc.: Optionally enteric film coating materials are used for enteric coating: for tablets, granules or capsules, in order to protect them against decomposition (gad cracking) occurring prematurely of a compound the drug by the acid (those hydroxypropyl AB substances) before being absorbed into the intestine. It is ©

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« hydroxypropylmethylcellulose phthalate 55 Tela J 3. Polyvinyl acetate phthalate ¢ cellulose acetate phthalate 35 14d polyvinyl acetate phthalate aaa; Copolymer methylcellulose phthalate [copolymerized methacrylic sly; Bill m ai preferably 0 ( Rohm Phoram , Endragit® as ) methacrylic acid preferably from VY Enteric Coating Materials so that it makes the weight from 0 to 100% of the weight of the capsule ; the pill or the tablet core. 7 01 to » It is appropriate for the tablet formulations of the invention to be covered in order to protect them against moisture and light that removes color and to maintain 0 the best taste of the drug. Either the inner cover contains substances a or contains a film colorants and opacifiers suitable shading for the heart of the tablet, optionally after coating it with enteric opaque materials. The invention includes polyethylene glycol 1 polyvinyl alcohol » polyvinylpyrrolidone polyvinyl pyrrolidone hydrophilic copolymers ¢ hydroxymethyl cellulose ¢ polyvinyl alcohol » hydroxypropyleellulose propylcellulose ¢ hydroxymethylcellulose Cellulose

V¢ or similar, preferably hydroxypropylmethylcellulose. (colorcon corp , Opadry yellow ) fis hydroxypropylmethylcellulose cellulose and hydrophobic film composition materials that are used using Mnisip cellulose acetate + Ethyl cellulose as an organic carrier such as ethyl cellulose Maleic - Js aS - Polyvinyl copolymer cellulose acetate © alsakh. » polyvinyl alcohol-maleic anhydride copolymers ahydric .. The coated film is used to achieve an increase in weight per pill or by weight and preferably to achieve Z # 01 to 1 for core or tablet By an increase of it? To + # of weight. Enteric-coated membrane or its non-essential materials include polyethylene glycol such as polyethylene glycol plasticaers (e.g. polyethylene glycol 6000 001 polyethylene glycol (J 5a) diethyl phthalate J triethyleitrate < u fiw triethyl ; ; butyl phthalate glycerin ¢ propylene glycol propylene glycol ; in appropriate amounts as mentioned above for opacity butyl phthalate 0 : k die and colored materials, titanium dioxide, such as titanium dioxide | or liquid-based apparatus using ¢ methyl alcohol water and/or suitable organic solvents (such as methyl alcohol 0 71 |

Vo ¢ ( isopropyl alcohol ¢ ethyl alcohol : ethyl alcohol : ethyl ketone s ) acetone ( ketones chlorinated hydrocarbons ) ethylmethyl ketone , ( dichloroethane Dichloroethane ¢ methylene chloride methylene chloride Jia) e etc. Consider (the percentage weight a Lad composition Jas in relation to the total weight of the Turkish) as follows:

Oa la Te to 1.1 of fluvastatin compound of fluvastatin to 7/66 of the weight ('alkaline medium' 0.5 wt) and typically of 'carbonate salts' by weight (such as carbonate salts 7 Te to 21 from 0 to 68 7 by weight (such as micro cellulose 1 of all materials). For the total composition) on the following: BB "0 of (fluvastatin) HMG - CoA Reductase compound Ve: od dia) by weight 7. so by weight 'alkaline medium 7' Te to die) by weight AY to Yo from Al carbonate (and microcrystalline cellulose).

The other example of a composition according to the invention (weight in percentage of the total composition) includes a drug compound from 0 to 61 7# by weight (eg fluvastatin; calcium carbonate from © to 06 by weight; sodium bicarbonate from #, » to 01 7# by weight ee Also. From ye to “oe 7 by weight (eg gd salsa) microcrystalline cellulose (the composition of the capsule according to the invention includes (weight in percentage For the total composition (as follows: 0 drug compound from 40 to 60 # by weight) and typically from 0,5 0 to Lge by weight (such as fluvastatin) fluvastatin calcium carbonate from ©? to 46 7 by weight; sodium bicarbonate from 09 to 0 7 by weight and microcrystalline cellulose from 01 to 3 # by weight and optionally additional filler (such as pre-gelatinized starch) pregelatinized starch) in an amount from 11 to 78 7 Veo teeth Weight 1. The composition of the tablet according to the invention (weight in percentage to the total composition) includes the following: - The drug compound from 40 to 7% of the weight) as fluvastatin (fluvastatin calcium carbonate) from * to 7 01 by weight;

17 by weight and micro cellulose 7 01 sodium bicarbonate from * to : from weight. Ze to 7 © 0 of crystalline microcrystalline cellulose The fixed compositions of the invention are prepared with different techniques and processes 0 manufacturing known in | For the method, it is important in the preparation of the formulations that the drug substance be conjugated with the alkaline medium. The dry binding of these components gives a mixture and the remaining excipients (then a homogeneous mixture) and it is preferable before adding the material. The step of pressing and bonding is used to achieve the required cohesion. To obtain very stable formulas, it is preferable to use a preparation process in which the lly is attached. An aqueous or preparation process based on another solvent - 0 call alkali in the presence of a small amount of Loud drug substance with in order to give particles containing the drug with the alkali substance in the form of HMG - CoA Reductase although compounds illic inhibitors mixed So hygroscopicity sensitive to water absorption fluvastatin fluvastatin !and moisture It is not expected that a drug substance that has been sufficiently stabilized by alkaline mediation will resist cracking by these techniques. In one embodiment the drug is pulverized with an alkaline medium with water and the resulting particles are then dried. The contaminant and the 'carriers' (residual drug considered to comprise an 'external phase') are mixed (additional ©)

The aforementioned cl gy all mixed with the dry particles to produce a formulation suitable for capsules; tablets or something like that. 0 In another embodiment of the solvent-based process, which is drying in a fluid bed, a wet granulation of the drug substance is made with oo alkaline medium by known techniques such as mixing in a wet state with a quantity of slurry. After drying the resulting granules, they are combined with the remaining malt substance and other aspects (Jt), the binding material and the slip-facilitator, and then converted into tablets. Capsules or form in any form Z: Pharmacological. 1 It is important to achieve a long shelf life of the formulation in which the particles are prepared by crushing, wet granulation or other aqueous process, the Lala particles should be dried such that the weight loss on drying (L.O.D) is not more than 7 and preferably not more than JY. The drying process is carried out by tray drying or in a liquid bottom, preferably the latter. The typical drying is done at 50 1 C as the inlet temperature and less than +0 7 RH humidity in the preparation Compositions It is preferable to pass the drug substance and basic elements gad for dosage form (except for the lubricant) through date 0 of AY 56 to be crushed or granulated by wet sac wet granulated

V4. Passing the drug substance first through the sieve and then mixing with drug carriers 0 that have been sifted. Also, in addition, the dry particles or clad z are passed through a sieve of 18 to 01 in order to give smooth mixing with the other aspects. Compositions to be made into tablets are passed through a narrow jie (such as mesh #74) before being combined with the BL material and subjected to pressure; The sieving step generally requires an additional drying step and the wet particles or granules obtained by crushing or granulation process are dried to 1.0.3 from + to 8 7; Then it is passed through a vacuum 0 from 11 to 14 and then re-dried to 1.0.3 of ? To JV In the preparation method alternative to the pulverization or wet granulation techniques mentioned above the drug material with alkaline stabilization medium can be converted to powder in a lyophilizer from solution AL as an init step of the drug manufacturing process. M in US Pat. No. 774,07 contained aa all herein 2a: The typical preparation of fluvastatin sodium as sodium salts or pharmaceutically acceptable salts of HMG-CoA reductase inhibitor compounds of the invention is by hall hydrolysis | For the corresponding acetate compound such as sodium hydroxide in an ethanol © solution. Then the ethanol or any other organic side is evaporated and added. YY ¢ | z

Y. Water to the remaining side containing the drug to form an aqueous solution from which (usually after extraction with an organic solvent) is prepared by lyophilization HMG - CoA Reductase Inhibitor Compound. (Transformation into powder) Lyophilization It was found that the alkaline stabilizer dissolved in water is molasses o sodium carbonate or sodium bicarbonate or any other alkaline medium that can be added in the same original position ending 8 to side 0 or the fluvastatin compound that includes fluvastatin Jef described all; and when this aqueous side is subjected to the HMG - CoA Reductase inhibitory step on a feel tha lyophilization, 0 lyophilized drug compound can be obtained with the added alkali. A very strong mixture of the drug with the stabilizer gives stable combinations of the invention to a large extent, and this is achieved by using a weight ratio of | / . For example, 0:0000 to 1: 1 of the drug and sodium carbonate of / / , it was found The lyophilized formulation of the invention containing JUAN ve by weight of sodium carbonate is effective to give 7 10 less than a highly stable drug formulation. Z © room temperature to a temperature below the refrigeration temperature and usually in handood

mC Y with the use of a high vacuum in the order of Leda {0 °Hg or less) and then raise the temperature to room temperature or higher until the aqueous solvent is evaporated. Thus, the obtained particles are free from the solvent and include a homogeneous mixture of the drug and the stabilizer. The particles obtained can be combined with the carriers of the binder and the lubricant. All other drugs such as The material compositions of the invention obtained according to any of the aforementioned techniques can be formed into different dosage forms by known techniques and steps in the method such as conversion to 0: etc. molding tablets, capsules; granules; Or steel, as mentioned before, where the coating film composition is used. Oral and / or enteric formulation of the dosage form to give a special recovery: It is preferable to use the encapsulation film or the enteric encapsulation _ for tablets based on microcrystalline cellulose with formulation VE degree 86-00 water-based encapsulation film At a temperature of ' Any fa ian Av — 6 and the input temperature is from . Ly ta : Joo is less than the relative (RH) Leh yd) and is yy It is important to achieve high stability of the formulation that the film-coated or enteric-coated dosage form 0 is dried until the content of

JY Humidity is less than ; # It is preferable that it be less than The resulting tablet or capsule must be protected during storage against heat or light that causes oxidation, as well as against moisture contamination. Z It was found that the capsules and tablets prepared in the formulations of the invention have an attractive stability during the storage period. The dosage forms are suitable for the required use. The capsules Z Yo to 01 and the film-coated tablets of the invention have a disintegration period of 0 minutes. Enteric-coated tablets or capsules have a disintegration time in 1 minute to about > hours. Limitations Fluvastatin as well as formulations containing fluvastatin sodium

Co, the present invention covers all other sodium 1-derived compositions (1) of the formula HMG - CoA Reductase Inhibitor Compounds (15 for example in patents Jo) mentioned herein. The aforementioned compounds have been discovered and consulted in patent applications and consulted and stated (a in circulation specified herein by reference: US Patent No. 5,774,077 and European Patent No. and derivatives thereof) Patent Z indolyl dy =R)EP-A = vey vo

YV¢

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and pyrimidinyl derivatives ep (=R) pyrimidinyl — A ~ 777,856 eu indenyl indelyl (R) = 0.001,706 of that). US Patent Nos. 07:82011 piperazolyl and its derivatives (a-8 ( 5,117,100 6 ) and its derivatives and &Y¥eo, el 1) and its derivatives pymolyl pyrrol-8 ( 868471 and its derivatives); imidazolyl ddd =R) 5,004,107 m ¢ (imidazolyl indolysinyl and its derivatives - 8 (08 14LRT 1) and its derivatives azaindolyl -4 ( and its derivatives thereof); R) and its derivatives from Nllc (a cut off maphthyl tefel - 4)

LAY AY) cyclomexyl 1o:p0, 1, nen and its crackers thereof - ( 0 6 ) and its derivatives furyl furyl - R) 5,977,851 » ) and its derivatives thienyl thienyl < 8 ( kathawala 1,6. and its derivatives ) and phenylsilyl Phenylsilyl = R) 65 z VAY) 155-171 dada (Y) 11 Medical Reserch Reviews, Inc. Other compounds of formula ([) have been detected and described in ; EP-A - yy 1,0 OV ¢ and its derivatives) quinolinyl quinolinyl =R) EP-A — Ye 4,167 m J EATANAG 5 and its derivatives); European Patent No. pyrimidiny] Primidinyl-8 (and its derivatives); patent pyridazinyt pridazinyt > 2 (EP — A = 374,767 or its derivatives); pymolyl pyrrolid > 8 (EP - A= 760,778 EC No.

M z and US Patent No. 8,013,744 = (=R)EP-A imidazolyl | and its derivatives). Compounds suitable as basic active ingredients to be used in the formulations are those for which the R is selected from the indolyl ¢ pyrimidinyl indenyl pyrazolyl pyrrolyl moiety imidazolyl « indolizinyl » pyrrolopyridine « pyrazolopyridyl. pyrazolopyridine » quinolinyl ¢ phenylsilylphenyl » maphthyl » cyclohexyl 0 ¢ phenylthinyl Jud » phenylthienyl phenylfuryl ¢ the pyridazingl moiety and derivatives thereof. Compounds with formula (1) in which SIR moieties are favored by indolyl 101 pyrimidyl moieties [pyrimidiny] and indenyl moieties and their derivatives and X º CH=CH - Jd - (8). Specific examples of the detected compounds include In the patents consulted 0 above ll HMG - CoA reductase reductase compounds are considered suitable for use as active medicinal ingredients in the composition of the invention the following sodium salts or other pharmaceutically acceptable salts: Z 3R,5S-(E)-7-[4- (4-fluorophenyl)-6-(1 methylethyl)-2-dimethylaminopyrimidin- ° 5-yl]-3,5-dihydroxy-6-heptenoic acid, sodium salts; ARR

Yo erythro-(8)-7-[3-(4-fluorophenyl)-spiro[cyclopentane-1,1°-1H-inden]-2'-yl]-3,5- dihydroxy-6-heptenoic acide, sodium salt; 3R,58-(E)-7-[3-(4-fluorophenyl)-1-(1-methylethl)-indolizin-2-y1]-3,5- z dihydroxy-6-heptenoic acid, sodium salt ; 3R,58-(E)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-pyrrolo[2,3-b]pyridin- © 2513 ,S-dihydroxy-6-heptenoic acid , sodium salt; 3R,5S-(E)-7- [4~(4-fluorophenyl)-2~( 1-methylethyl)-quinolin-3-yl]-3,5- 0 dihydroxy-6-heptenoic acid, sodium salt; 3R,58-(E)-7-[1-(4-fluorophenyl)-3-(1-methylethyl)-4-oxo-1,4-dihydroquinolin- 2-y1}-3,5-dihydroxy-6- heptenoic acid, sodium salt; Va 3R,58~(E)-7-[4-(4-fluorophenyl)-6-(1-methylethyl)-3-methyl-1 H-pyrazolo[3,4-b]-3-yl]-3 ,5-dihydroxy-6-heptenoic acid, sodium salt; 3R,58-(E)-7-[3-(1-methylethyl)-5,6-diphenyl-pyridazin-4-yl]-3,5-dihydroxy-6- heptenoic acid, sodium salt; A / 3R 5S-(E)-7-[4-(-fluorophenyl)-6-(1 -methylethyl)-2-phenyl-pyrimidin-5-yl]- : - 3,5-dihydroxy-6- heptenoic acid, sodium salt; : : 3R,55~(E)-7-[4-(4-fluorophenyl)-1-(1-methylethyl)-3-phenyl-2-0x0-2,3- dihydroimidazol-5-y1]-3, 5-dihydroxy-6-heptenoic acid, sodium salt; 3R,5S-(E)-7-[4-(4-fluorophenyl)-2-(1-methylethyl)-1-ox0-1,2-dihydro-quinolin- o 3-yl]-3,5-dihydroxy -6-heptenoic acid, sodium salt; erythro~(8)-(E)-7-[4-(4-

Yy¢:

fluorophenyl)-2-(1-methylethyl)-quinolin-3-yl]-3,5-dihydroxy-6-heptenoic acid, : sodium salt; erythro-(8)-(E)-7-[ 1-(4-fluorophenyl)-3-(1-methylethyl)-pyrrolo[2,1- alJisoquinolin-2-yl]-3,5-dihydroxy-6- heptenoic acid sodium salt; erythro-(8)-(E)-7-[4-cyclopropyl-6-(4-fluorophenyl)-2-(4-methoxyphenyl) ° pyrimidin-5-y1]-3,5-dihydroxy-6-heptenoic acid sodium salt; : 3R,5S-(E)-7-[4-(4-fluorophenyl) 2 ,0-dimehylpyrimidin-5-y1]-3,5-dihydroxy-6- heptenoic acid, sodium salt; Z 3R,58-(E)-7-[4-(3,5-dimethylphenyl)-6-methyl-2-phenyl-pyrimidin-5-y1]-3,5- dihydroxy-6-heptenoic acid, sodium salt; 1 erythro-(8)-(E)-7-[3,4-bis(4-fluorophenyl)-6-(1-methylethyl)-pyridazin-5-yl} - 3,5-dihydroxy-6-heptenoic acid sodium salt; z erythro-(8)-(E)-7-[ 1-(4-fluorophenyl)-3-(1-methylethyl)-5-phenyl-1H-pyrrol-2- yl] -3,5- dihydroxy-6-heptenoic acid sodium salt; / erythro-(8)-(E)-9,9-bis(4-fluorophenyl)-3 ,5-dihydroxy-8-(1-methyl-1H-tetrazol- =~ * - 5-yl)-6, 8-nonadienoic acid sodium salt; . z erythro-(3)-(E)-3,5-dihydroxy-9,9-diphenyl-6,8-nonadienoic acid sodium salt; erythro-(8)-(E)-7-[4- (4-fluorophenyl)-1,2-bis(1-methylethyl)-3-phenylpyrrol- : y1]+3,5-dihydroxy-6-heptenoic acid , sodium salt; ° 3R,5S-(E)-7-[4,5bis (4-fluorophenyl)-2-(1-methylethyl)-1H-imidazol-1-yl]-3,5- dihydroxy-6-heptenoic acid, sodium salt; 10 a

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3R,5S8-(E)-7-[4-(4-fluorophenyl)-2,6-bis(1-methylethyl)-5-methoxymethyl-pyridin-3-yl}-3,5-dihydroxy-6-heptenoic acid, sodium salt; erythro-(6)-(E)-[4- (4-fluorophenyl)- 2-bis(1-methylethyl)-6-phenyl-pyridin-3- : yl1]-3,5-dihydroxy-6-heptenoic acid , sodium salt; erythro-(3)-(E)- [2- (4-fluorophenyl)- 4,4,6,6-tetramethyl-cyclohexen-1-y1]-3,5-©0 dihydroxy-6-heptenoic acid, sodium salt; erythro-(3)-(E)-7-[4- (4-fluorophenyl)- 2-cyclopropyl-quinolin-3-yl] 3,5- . dihydroxy-6-heptenoic acid, sodium salt; erythro-(8)-(E)-7-[4- (4-fluorophenyl)- 2-(1-methylethyl)-quinolin-3-yl] 3,5- dihydroxy-6-heptenoic acid, sodium salt; 1

Jie HMG - CoA Reductase are inhibitors (I) compounds with the formula Inhibitors of the biosynthesis of cholesterol, so they are useful in the treatment of blood sclerosis, hyperlipoproteinemia, hyperlipoproteinemia, as shown in the patent Atherosclerosis Al-Asidi “© to it before that and the consulted applications and the tucked-in cups Lad Z 0 with references. The following examples illustrate the invention in various embodiments and without any restriction. Ye

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Article (\): The fluvastatin capsule, which is administered orally, is prepared by ally, it weighs ye milligrams and has a size of a number (*), and it includes: Table: (10) Ingredient | Quantity (milligrams ) bo | Amount (mg) | | fluvastatin YY, | fluvastatin = calcium carbonate 115754 calcium bicarbonate, | 17 sodium bicarbonate Y | sodium bicarbonate, USP microcrystalline cellulose , NF' | | add Lis | pregelatinized starch 0 | pregelatinized starch, NF "gs." | purified water, USP . ° : set-asides | Amount (mg) ( | oy | | "m | Amount (mg). | -YYV,AA | microcrystalline cellulose 01, | pregelatinized starch Lis | z 0 tale , USP 1.00 talc | magnesium stearate, NF

ARE:

Yq : heavy, precipitated 4 © Avicel, PH 102, FMC Corp. 4

Starch 1500, colorcon corp. 10 + + starch 'a removed during processing' * with fluvastatin bicarbonate mg and a- mixed with fluvastatin sodium + 17.844 mg calcium carbonate » 77.76 mg microcrystalline cellulose And 70.98 milligrams of pregelatinized starch 7 for 0 minutes, then the pregelatinized starch will turn into gelatin, then mix for ? Other minutes.” 0 Josie Mixture of Add water to the mixture and mix for a while; minutes to form — 0 wet granules. Percentile as degree 50 Dryer at AA Thal C- The granules are dried

J 0.54 equals LOD heat entering it until it becomes with B Edis 01 Jan D- Dry granules are passed through / 01 for a period of microcrystalline cellulose and 1 setrasides and Tale G— all minutes. They force a pre-sifting process, then they add 10 minutes each on magnesium stearate sieve. Add 0 to the mixture and mix it for a period of “. 7 1,16 LOD The resulting composition has pH - 01. A milliliter of water gives a solution of 001 - 01 dispersing the composition in © 1 "z

Yr. E- The opaque blue capsules are filled with the composition and polished manually with salt. A minute by the paddle method Ye in 7 V0 The capsule has a specific solubility 050 paddle method a month at YA after pal Jk It was found that 4 7 of the medicine, without any light and in a resistant atmosphere, ye el a aT, with a degree of humidity.: (Y) For example, (1) can be prepared in the same way as described in the example.

Sx ln double numbered milligrams using 0 3 capsules (1). The amounts of essential elements mentioned in the 0 table (rT) Example What is fluvastatin 01 milligrams of fluvastatin capsules ‎: ;Saal) an additional 01 mg of cellulose except that it uses 0 | . Crystal Ye. (31) mL Y + fluvastatin Cli oT) The preparation of a gram tablet that is administered orally includes the following formula:

AREA

Table (1): Z) Amount (milligrams) Ingredient:

Amount (mg) 11 | fluvastatin fluvastatin ve | sodium bicarbonate, USP Sodium Bicarbonate 64 d | microcrystalline cellulose, NF microcrystalline cellulose 1 | | croscarmellose sodium, NF

Lae | eee my legs 4% Avicel PH 101 (FMC Corp.) 4 Ac-Di-Sol (FMC Corp.) 2 Kollidon 30 (BASF Corp.) / f * removed during processing : ° . Calcium carbonate fluvastatin A- passes both fluvastatin; Mix for 10851 40 minutes through a sieve croscarmellose sodium 0

ARK:

vy

Lh lak, MESH 40 Output within minutes by I + whisper: continuously for ? Minutes #0 minutes of water to the resulting mixture during mixing for a period of Gl b- to form wet granules. Aan heat The granules are dried in a liquid base dryer and in

Gl anal L.O.D becomes (—a Ly ta ian 254 equal to ital mesh Y ¢ then the granules are passed through a YAN mesh to a T equal to 0.5 .7 not more than LOD and repeated Dry it until it becomes

Yoda al zi—iymesh 14 Dry granules through a sieve 5, a: minutes. 0 mesh 0 Jie through Magnesium stearate d- Magnesium stearate is insisted. Mix with the mixture for 0 minutes

JX The resulting formula has .1.0 not more than ; . 01 #ml of water having 11m Yeo =) I dispersed the composition in 0 e<- the bright yellow colored composition was transferred to ve milliliter tablets to form the heart of a yipsine tablet A punch using a millimeter nipper 00 grams, and the composition of the hydroxypropyl cellulose covering film is used: { Yellow ", YS-1-6347-G, Colorcon corp hydroxypropylmethylcellulose o 10: A:

YY

To invert the tablet in a liquid base with a grade (10 7 aqueous suspension) at an interval to produce a tablet with an increase of Vo - Vo, an input heat equal to 0-1 in weight from .

Vo within 7 11 The resulting tablets have a specific solubility of . USP paddl 0 minutes by Badal method 0 months at 18 It was found that 7 94 of the drug remains intact after the degree of retention in the absence of light and in a moisture-proof atmosphere. 0:©[(Ja) by the same method mentioned In example (4), the preparation of milligrams where 50 fluvastatin tablets are twice as much as 0 (8) fluvastatin tablets is the amount of basic elements referred to in example (7 Ju): in the same manner as described in example (4); 0 / ml can be prepared where you use half of 01 fluvastatin fluvastatin tablets. (4) The quantities of the basic elements indicated in the example in the example ve: : : (Y) article fluvastatin fluvastatin tablet or capsule BA gait The preparation is carried out as described in any of the above examples, where the temperature at the fluidized bed in a fluidized bed is 71 |

The base is equal to F = 5 degrees Celsius and the input temperature is: on - 80 degrees Celsius; Specific Moisture Less than 50 7 with gastric sleeve formulation containing: Eudragit® (Rohm Pharma) or; Hydroxypropyl methylcellulose m veganate, hydroxypropylmethylcellulose phthalate, to sneeze an increase in weight of # 0.7 11- Article (A): The composition is prepared according to the invention as described in any of the examples mentioned above and includes 3R,5S-(E )-7-[4-(4-fluororphenyl)-6-(1 -methylethyl)-2-dimethylamino-pyrimidin- ‎5-yl]-3,5-dihydroxy-6-heptenoic acid, 01 and sodium salt as agent Active. -1 ,1'-1H-inden]-2'-yl] 3,5-dihydroxy-6-heptenoic acid.

Yo | / And sodium salt as a factor Cdl 0 ARE:

Claims (1)

Yeo | -1 1 | Pharmaceutical Composition Containing A THMG-CoA Composition (formula): OH OH . 0 | | . R-X-CH-CH;-CH-CH;-COOM I A v > that . ¢ © is an organic moiety ¢ X ° is CH=CH 1 4 is a physiologically acceptable cation of L and an alkaline medium capable of conferring a pH concentration (GH) A | eA is the lowest for an aqueous solution or to disperse the composition. . 1?-_Pharmaceutical composition comprising a compound having TL Sl as: Hamisa element No. 1 and in basic bonding with at least one Co 7 © carbonate. - Co 1 1 Pharmacist's Composition di Ga on Fluvastatin Sodium. Fluvastatin sodium oN and an acceptable alkaline medium Way a is capable of v providing a pH equal to A over CY for the Jylad ¢ | aqueous olemediate formulation. YV¢ ST | 17: D > Pharmaceutical composition according to claim No.? Whereas, Jia carbonates 7 is a mixture of water soluble Al carbonate v water soluble carbonate and water insoluble carbonate or sparingly soluble carbonate. oy is composed according to claim number ¥ where the Y alkaline medium is selected from sodium carbonate « v lie ¢ sodium bicarbonate calcium carbonate 3 ¢ and mixtures derived therefrom . 1 +- A pharmaceutical composition comprising fluvastatin sodium (1) 1 sodium Y calcium carbonate (Ys calcium carbonate) sodium carbonate or sodium bicarbonate - 1 7- Pharmaceutical composition according to claim No. 1 wherein the ratio of - water-soluble carbohydrates to water-soluble or sparingly soluble sil carbonates is of (£01 ; : ¢ to NY ~ | : D 3 A) a composition according to claim 1 comprising HMG-CoA reductase Yo in a ratio of 0 to 01 #7 by weight; z v calcium carbonate from *,” to 7#46 by weight; ¢ Sodium Picrotate 10 Yo #7 Aged Weight; 0 al z YY ° and microcrystalline cellulose at a ratio of 01 to eo | 1 of the susan. . 1 4- The LE composition of any of the above protection elements in the form of Y solid unit dosage form: 011 Pharmacist composition to be administered orally in the form of a capsule to transport Y gluvastatin sodium fluvastatin sodium which includes fluvastatin sodium v in a ratio of 0 Ge Te (A by weight); ¢ | calcium carbonate in a proportion of Yo to C56# by weight; sodium bicarbonate in a ratio of 0.9 to 01 by weight; microcrystalline cellulose 01 Ls microcrystalline cellulose to Yo by weight. These include: fluvastatin sodium in a ratio of 0.0 to 61 7# by weight; calcium carbonate in a ratio of oo 0 by weight; sodium bicarbonate in a ratio of * to Cade . 1 weight; microcrystalline cellulose in a ratio of + 0 7 to 159 7 by weight. -17 1 method for preparing a composition according to Protection Letter No. | : : a : A-17 1 method in accordance with claim No. 11 and set i Y | by co-lyophilizing lyophilization of Cl 8a and HMG-CoA reductase and alkalinity stabilizing medium, . 1 - Pharmaceutical composition Ls, of either claim 11 or ?, wherein HMG-CoA aS all 7: is a . 3R,5S~(E)-7-[4-(4-flucrophenyl)-2, 6-1 -methylethyl)-5-methoxymethyl- Y pyridin-3-yl]-3,5-dihydroxy-6 heptenoic acid, sodium salt. $ ; 7 z z z 0 l