Pharmaceutical compositions containing an inhibitor of hmg reductase

 

(57) Abstract:

The invention relates to pharmaceutical compositions containing the inhibitor nm g COA reductase (E.)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino] pyrimidine-5-yl]-(3R, 5S)-3,5-dihydroxide-6-envoy acid or its pharmaceutically acceptable salt as an active ingredient. The composition also contains trehosnovnoy phosphate salt in which the cation is multivalent. Preferably Tihonova phosphate salt is rejonowy calcium phosphate. The composition remains stable over a long period of time. 4 C. and 17 C.p. f-crystals.

The invention relates to pharmaceutical compositions and more specifically to pharmaceutical compositions containing (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methyl-sulfonyl)amino] pyrimidine-5-yl] -(3R,5S)-3,5-dihydroxide-6-envoy acid or its pharmaceutically acceptable salt (hereinafter called "Agent"), in particular sodium and calcium salts, especially calcium salt, bis[(E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino] -pyrimidine-5-yl] -(3R, 5S)-3,5-dihydroxide-6-ene acid]calcium salt (formula I below).

The Agent opened the Katsia 0521471, and in Bioorganic and Medical Chemistry(1997), 5(2), 437-444, and is useful in the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis.

The problem with the Agent, is that in certain conditions it undergoes decomposition. This makes it difficult to obtain a product, and the provision of pharmaceutical compositions with an adequate shelf life. The main formed by the decomposition products are the corresponding (3R,5S) lactone (hereinafter referred to as "lactone") and oxidation products (hereinafter referred to as "B2"), in which the hydroxy-group adjacent to the carbon-carbon double bond is oxidized to the ketone functional group.

It is therefore important to find a pharmaceutical Agent composition that remains stable over a long period of time. Also preferably, this composition had good fluidity for ease of processing it in a single dosage form for oral administration, such as tablets, and good characteristics disintegration and solubility during processing into tablets for oral administration and that these tablets could have different strength characteristics. It is also desirable that such pills are a good size, about the droxy-6-heptenophos acid, which are inhibitors of HMG COA reductase, are disclosed in UK patent 2262229. These compositions require the presence of an alkaline environment (such as a carbonate or bicarbonate), is able to bring the pH of an aqueous solution or dispersion of the composition, at least up to 8.

Now they had found a new pharmaceutical composition of the Agent, which has the pre-emptive properties and which solves one or more problems associated with obtaining the composition of the Agent.

Accordingly, the first aspect of the present invention relates to a pharmaceutical composition containing the Agent and trehosnovnoy phosphate salt in which the cation is multivalent.

The second aspect of the present invention relates to the use of trehosnovnoy phosphate salt in which the cation is multivalent, for stabilization Agent.

Tihonova phosphate salt in which the cation is multivalent, includes, for example, trehosnovnoy calcium phosphate, trehosnovnoy phosphate magnesium and trehosnovnoy phosphate of aluminum. Trehosnovnoy calcium phosphate is particularly preferred.

The ratio trehosnovnoy phosphate salt and Agent in the pharmaceutical compo is 1:10 to 10:1 by weight, and more specifically from 1:5 to 10:1 by weight.

Preferably the pharmaceutical composition according to the invention is prepared in the form of dosage forms for oral administration such as tablets. Therefore, another aspect of the present invention relates to pharmaceutical compositions containing the Agent, trehosnovnoy phosphate salt in which the cation is multivalent, and one or more fillers, bonding agents, disintegrants (leavening agents), or lubricants. Another aspect of the present invention relates to pharmaceutical compositions for oral administration containing the Agent, one or more fillers, one or more binding substances, one or more of disintegrants, one or more lubricants and trehosnovnoy phosphate salt in which the cation is multivalent.

Suitable fillers include, for example, lactose, sugar, starches, modified starches, mannitol, sorbitol, inorganic salts, cellulose derivatives (e.g. microcrystalline cellulose, cellulose, calcium sulphate, xylitol and lactic.

Suitable binders include, for example, polyvinylpyrrolidone, lactose-based wax, microcrystalline cellulose, methylcellulose, carboxymethyl cellulose, hypromellose, hydroxyethyl cellulose, hydroxypropylcellulose, copolyvidone, gelatin and sodium alginate.

Suitable disintegrant include, for example, sodium croscarmelose, crosspovidone, polyvinylpyrrolidone, sodium starch glycolate, corn starch, microcrystalline cellulose, hypromellose and hydroxypropylcellulose.

Suitable lubricants include, for example, magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, Carnauba wax, hydrogenated vegetable oil, mineral oil, polyethylene glycols and sodium fumarate.

Additional conventional excipients that may be added include preservatives, stabilizers, antioxidants that contribute to the yield condition additives on the basis of silicon dioxide, substances that prevent adhesion, or substance that promotes sliding.

Other suitable fillers, binders, disintegrant, lubricants and additional excipients that may be used are described in Handbook of Pharmaceutic: Tablets Volume 1, 2ndEdition, Lieberman, Herbert A., et al., 1989; Modern Pharmaceutics, Banker, Gilbert and Rhodes, Christopher T, 1979; and Remington's Pharmaceutical Sciences, 15thEdition, 1975.

Typically the Agent is present in amount ranging from 1 to 50% and preferably from 1 to 20 wt.% (especially from 2 to 15%) of the composition.

Typically Tihonova phosphate salt, such as trehosnovnoy calcium phosphate present in amounts ranging from 1 to 50%, for example from 1 to 25%, such as from 1 to 20%, and especially from 5 to 18 wt.%.

Typically one or more fillers are present in an amount of from 30 to 90 wt.%.

Typically one or more binding substances are present in quantities of from 2 to 90 wt.%.

Typically one or more of disintegrant present in an amount of from 2 to 10 wt.% and especially from 4 to 6 wt.%.

It will be clear that a specific excipient can perform a role as a binder, and filler or binder, filler and disintegrant. Typically the combined amount of filler, binder and disintegrant is, for example, 70-90 wt.% song.

Typically one or more lubricants are present in an amount of from 0.5 to 3 wt.% and especially 1 to 2 wt.%.

The preferred composition is selected from lactose, mannitol, microcrystalline cellulose, povidone, crosspovidone, nachrichtentechnische and magnesium stearate. Preferred individual compositions according to the invention include, for example, the compositions containing the Agent, trehosnovnoy calcium phosphate, microcrystalline cellulose, lactose, matrikamantra, bottled hydroxytoluene and magnesium stearate; compositions containing an Agent, povidone, trehosnovnoy calcium phosphate, microcrystalline cellulose, mannitol, matrikamantra, bottled hydroxytoluene and magnesium stearate; compositions containing an Agent trehosnovnoy calcium phosphate, crosspovidone, microcrystalline cellulose, lactose and magnesium stearate, and the composition containing the Agent, povidone, trehosnovnoy calcium phosphate, microcrystalline cellulose, lactose, matrikamantra, magnesium stearate and bottled hydroxytrol. If you use lactose and microcrystalline cellulose, they are preferably present in a weight ratio of from about 1:1 to 3:1.

Compositions of the present invention, which are of particular interest include, for example, specific variants of the embodiments presented below in the accompanying examples.

The pharmacy is primarily known from the prior art, for example, by dry mixing of the components. For example, the Agent trehosnovnoy phosphate salt (e.g., trehosnovnoy calcium phosphate), one or more fillers, one or more binding agents and one or more disintegrants, as well as other excipients, if desired, are mixed together. The components of the mixture before mixing or the mixture can pass through a sieve, for example, with openings 400-700 mesh. Then added to the mixture lubricating substance that can pass through a sieve, and mixing continued until a homogeneous mixture. The mixture is then pressed into tablets. Alternatively, you can use the method of wet granulation. For example, the Agent trehosnovnoy phosphate salt, one or more fillers, one or more binding substances and a part of disintegrant, as well as other excipients, if desired, are mixed together, for example, using a granulator, and powdery mixture granularit using a small amount of purified water. The granulate is dried and passed through a mill. The rest of disintegrant and lubricating substance is added to the crushed granulated mixture, and after the Pach is W dry mixing and wet granulation, including the order of addition of components and their sifting through a sieve and mix before pressing into tablets in accordance with principles well known in the prior art.

Then the tablets can be coated, for example, by spraying in the form of a composition of the film is water-based. The coating can include, for example, lactose, hypromellose, triacetin, titanium dioxide and iron oxide. The combination of ingredients of the coating are commercially available, for example, such as described in the examples below. The coating can be, for example, 0.5 to 10 wt.% the composition of the tablets, in particular 1 to 6%, and preferably 2-3%. Coatings containing iron oxide are especially preferred because they reduce the rate of formation of products of fotorazlozheniya Agent.

Another aspect of the present invention relates to a method for producing a stable pharmaceutical composition, which comprises mixing the Agent with trehosnovnoy phosphate salt in which the cation is multivalent. Another aspect of the present invention relates to a method for producing a stable pharmaceutical composition, which includes an introduction tsuu Agent.

The following pharmaceutical compositions in which the Agent is a calcium salt of formula I, are intended only to illustrate the invention and are in no way to limit.

Example 1

Agent, mg - 2,50

Trehosnovnoy calcium phosphate, mg - 20,0

Microcrystalline cellulose, mg and 47.0

Monohydrate lactose, mg and 47.0

Matrikamantra, mg - 3,00

Bottled hydroxytoluene, mg - 0,05

Magnesium stearate, mg - 1,00

Agent, microcrystalline cellulose, lactose monohydrate, matrikamantra, trehosnovnoy calcium phosphate and bottled hydroxytoluene were mixed together for 10 minutes magnesium Stearate was sifted through sieve #40 mesh (425 μm) was added to the mixture and mixing continued for another 3 minutes Obtained homogeneous mixture was pressed into tablets.

Tablets were stored at 70oC/80% relative humidity during the week. A week later it was discovered that there were only 0,11% wt./wt. the oxidation product B2 and only 0,50% wt./wt. the lactone. For comparison, a similar composition in which 20.0 mg trehosnovnogo calcium phosphate was changed to 20.0 mg dibasic calcium phosphate was formed to 0.23 wt.%. /Mac. B2 and 15,61% wt./wt. varnish>/BR>Microcrystalline cellulose, mg and 47.0

Mannitol, mg and 47.0

Matrikamantra, mg - 3,00

Bottled hydroxytoluene, mg - 0,05

Magnesium stearate, mg - 1,00

Agent, povidone, mannitol, microcrystalline cellulose, bottled hydroxytoluene, trehosnovnoy calcium phosphate and matrikamantra (in quantities above) were mixed together for 5 to 60 minutes magnesium Stearate was sifted through sieve #40 mesh (425 μm) was added to the mixture and mixing continued for another 3 minutes Obtained homogeneous mixture was pressed into tablets. On the compressed tablets were coated by spraying them in the pan for coating a mixture of hydroxypropylmethylcellulose, polyethylene glycol 400, titanium dioxide and iron oxide (commercially available under the name Spectrablend from the company Warner-Jenkinson) and water. The increase of mass due to the coating ranged from 1 to 6% wt./wt. and preferably from 2 to 3% wt./wt.

Tablets were stored at 70oC/80% relative humidity during the week. A week later it was discovered that there were only 0,06%, wt./wt. the oxidation product B2 and only 2,22% wt./wt. the lactone.

Example 3

Agent, mg - 2,60

Crosspovidone, mg - 3,75

Trejon is/BR> Magnesium stearate, mg - 0,94

Agent and crosspovidone were mixed together for 5 min, and the mixture was passed through a sieve with openings of 400-700 microns. Then through a sieve missed a small portion of the microcrystalline cellulose. Sifted through a sieve material was mixed with other ingredients (except lubricants) for 10 min Stearate was passed through sieve #40 mesh (425 μm) was added to the mixture, and the mixture was mixed for another 3 minutes Obtained homogeneous mixture was pressed into tablets. On the compressed tablets were coated by spraying them in the pan for coating a mixture of lactose monohydrate, hydroxypropylmethylcellulose, triacetin and iron oxide (commercially available under the name Opadry from Colorcon) and water. The increase of mass due to the coating ranged from 1 to 6% wt./wt. and preferably from 2 to 3% wt./wt.

Tablets were stored at 70oC/80% relative humidity during the week. A week later it was discovered that there were only 0.19 percent wt./wt. the oxidation product B2 and only 2,71% wt./wt. the lactone.

Example 4

Agent, mg - 2,50

Povidone, mg - 2,50

Trehosnovnoy calcium phosphate, mg - 20,0

Microcrystalline C is - ,00

Bottled hydroxytoluene, mg - 0,05

Part trehosnovnogo calcium phosphate and bottled hydroxytrol was mixed for 30 s in the bag. Agent, povidone, the rest of trehosnovnogo calcium phosphate, microcrystalline cellulose, lactose monohydrate, the mixture trehosnovnogo calcium phosphate/bottled hydroxytoluene and part of nachrichtentechnische was mixed in a granulator for 30 sec. Powder mixture was granulated using purified water for 1 min at a speed of adding 70 mg/pill/min. the mixture was Granulated and dried in a fluidized bed dryer at 50oWith up until loss on drying was less than 2% wt./wt. Dried granulated mixture was passed through a mill (for example, Comil). Crushed granular and the rest of nachrichtentechnische was mixed for approximately 5 minutes, the magnesium Stearate was passed through sieve #40 mesh (425 μm) was added to the mixture and mixing continued for another 3 minutes Obtained homogeneous mixture was pressed into tablets.

Tablets were stored at 70oC/80% relative humidity during the week. A week later it was discovered that there were only 0.23 percent wt./wt. the oxidation product B2 and that is was changed to 20.0 mg dibasic calcium phosphate, was formed to 0.19 wt.%. /Mac. B2 and 28,15% wt./wt. the lactone.

in

1. Pharmaceutical composition comprising an inhibitor of HMG COA reductase(E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl (methyl-sulfonyl)amino] -pyrimidine-5-yl] -(3R, 5S)-3,5-dihydroxide-6-envoy acid or its pharmaceutically acceptable salt as an active ingredient and trehosnovnoy phosphate salt in which the cation is multivalent.

2. The pharmaceutical composition under item 1, in which trehosnovnoy phosphate salt in which the cation is multivalent, choose from trehosnovnogo calcium phosphate, trehosnovnogo phosphate magnesium and trehosnovnogo phosphate of aluminum.

3. The pharmaceutical composition under item 1 or 2, in which Tihonova phosphate salt in which the cation is multivalent, is trehosnovnoy calcium phosphate.

4. The pharmaceutical composition according to any one of paragraphs.1-3, in which the ratio trehosnovnoy phosphate salt and the active ingredient is in the range from 1:80 to 50:1 by weight.

5. The pharmaceutical composition according to any one of the preceding paragraphs, optionally containing one or more fillers, bonding agents, disintegrants or MCA is HMG COA reductase - (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino] pyrimidine-5-yl] -(3R,5S)-3,5-dihydroxide-6-envoy acid or its pharmaceutically acceptable salt as an active ingredient, one or more fillers, one or more binding substances, one or more of disintegrants, one or more lubricants and trehosnovnoy phosphate salt in which the cation is multivalent.

7. The pharmaceutical composition according to p. 6, in which the active ingredient is present in an amount of from 1 to 80 wt.% song.

8. The pharmaceutical composition under item 6 or 7, in which Tihonova phosphate salt is present in amount from 1 to 50 wt.% song.

9. The pharmaceutical composition according to paragraphs.6, 7, or 8, in which the filler is present in an amount of from 30 to 90 wt.% song.

10. The pharmaceutical composition according to any one of paragraphs.6-9, in which the binder is present in an amount of from 2 to 90 wt.% song.

11. The pharmaceutical composition according to any one of paragraphs.6-10, in which disintegrant is present in an amount of from 2 to 10 wt.% song.

12. The pharmaceutical composition according to any one of paragraphs.6-11, in which the lubricating substance is constituted�)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino] pyrimidine-5-yl] -(3R, 5S)-3,5-dihydroxide-6-envoy acid or its pharmaceutically acceptable salt as an active ingredient, trehosnovnoy calcium phosphate, microcrystalline cellulose, lactose, matrikamantra, bottled hydroxytoluene and magnesium stearate.

14. The pharmaceutical composition according to p. 6, containing (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino] pyrimidine-5-yl] -(3R, 5S)-3,5-dihydroxide-6-envoy acid or its pharmaceutically acceptable salt as an active ingredient, trehosnovnoy calcium phosphate, povidone, microcrystalline cellulose, mannitol, matrikamantra, bottled hydroxytoluene and magnesium stearate.

15. The pharmaceutical composition according to p. 6, containing (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino] pyrimidine-5-yl] -(3R, 5S)-3,5-dihydroxide-6-envoy acid or its pharmaceutically acceptable salt as an active ingredient, trehosnovnoy calcium phosphate, crosspovidone, microcrystalline cellulose, lactose and magnesium stearate.

16. The pharmaceutical composition according to p. 6, containing (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino] pyrimidine-5-yl] -(3R, 5S)-3,5-dihydroxide-6-envoy acid or its farmatsevticheskiy cellulose, lactose, matrikamantra, bottled hydroxytoluene and magnesium stearate.

17. The pharmaceutical composition according to any one of the preceding paragraphs, in which the active ingredient is a calcium salt of (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl (methylsulphonyl)amino] pyrimidine-5-yl]-(3R,5S)-3,5-dihydroxide-6-ene acid.

18. Application trehosnovnoy phosphate salt in which the cation is multivalent, to stabilize the inhibitor of HMG COA reductase connection (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)-amino] pyrimidine-5-yl]-(3R,5S)-3,5-dihydroxide-6-ene acid or its pharmaceutically acceptable salt.

19. Application under item 18, where trehosnovnoy phosphate salt in which the cation is multivalent, choose from trehosnovnogo calcium phosphate, trehosnovnogo phosphate magnesium and trehosnovnogo phosphate of aluminum.

20. Application under item 18 or 19, where Tihonova phosphate salt in which the cation is multivalent, is trehosnovnoy calcium phosphate.

21. A method of obtaining a stabilized pharmaceutical composition, comprising an introduction trehosnovnoy phosphate salt in which the cation is mnogovalentnym-2-[methyl(methylsulphonyl)amino] -pyrimidine-5-yl]-(3R,5S)-3,5-dihydroxide-6-envoy acid or its pharmaceutically acceptable salt.

 

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