Stabilized pharmaceutically effective composition and pharmaceutical preparation comprising thereof

FIELD: medicine, pharmacology, biochemistry, pharmacy.

SUBSTANCE: invention relates to preparations reducing blood cholesterol level. Lovastatin, pravastatin, simvastatin, mevastatin, atorvastatin and their derivatives and analogs known as inhibitors of HMG-CoA-reductase are used as anti-hypercholesterolemic agents. Above mentioned active substances can be destabilized as result of effect of environment and their destruction can be accelerated in interaction with other pharmaceutical agents, such as excipients, binding agents, lubricating agents, substances promoting to slipping and disintegrating agents. Therefore, pharmaceutical components and a method for preparing a pharmaceutical preparation must be taken thoroughly to avoid above said undesirable interactions and reactions. Invention relates to inhibitor of HMG-CoA-reductase that stabilized by formation of a homogenous composition with buffer substance or an alkalinizing substance. This homogenous composition is used as an active substance in pharmaceutical preparation used for treatment of hypercholesterolemia and hyperlipidemia. Invention enhances the enhancement of stability and homogeneity of the preparation.

EFFECT: improved and valuable pharmaceutical properties of composition.

23 cl, 2 tbl, 3 dwg, 11 ex

 

This invention relates to stable inhibitor of HMG-CoA-reductase, which is used in the pharmaceutical preparation, especially suitable for the treatment of hypercholesterolemia and hyperlipemia.

More precisely, the present invention relates to stable and very homogeneous composition containing an inhibitor of HMG-CoA reductase inhibitor such as atorvastatin, pravastatin, fluvastatin and tseriwastatina or their pharmaceutically active salts, as well as to solid pharmaceutical preparations containing the above-mentioned homogeneous composition as the active substance.

Background of invention.

Lovastatin, pravastatin, simvastatin, mevastatin, atorvastatin, fluvastatin and tseriwastatina, their derivatives and analogues are known as inhibitors of HMG-CoA-reductase inhibitors and are used as antihypercholesterolemic agents. Most of them are produced by fermentation using microorganisms of different species identified as species belonging to the genus Aspergillus, Monascus, Nocardia, Amycolatopsis, Mucor or Penicillium. Some of them are produced by processing of fermentation products, including methods of chemical synthesis, for example simvastatin, or they are products of chemical synthesis, such as fluvastatin, atorvastatin and tseriwastatina.

The degree of purity of the active substance javljaetsja factor in the process of making safe and effective pharmaceutical drug. The highest possible degree of purity of this product is especially important if the pharmaceutical medication you need to take for a long time in the treatment or prevention of high cholesterol in the blood. Accumulation of impurities contained in the medicinal substances with a low degree of purity, can lead to the occurrence of side effects during treatment. In addition, impurities, which cannot be completely removed in the process of obtaining the active substance, the decomposition products formed during the impact on the final pharmaceutical product of various factors, such as temperature, moisture, low pH, carbon dioxide from air and light, can also create significant problems. Inhibitors of HMG-CoA-reductase contained in the form of salts in the final pharmaceutical drug such as atorvastatin, pravastatin, fluvastatin and tseriwastatina, is particularly sensitive to the acidic environment in which the hydroxy acid will destroy with the formation of the lactone.

In addition to the factor that the above-mentioned active substances can be destabilized under the influence of environmental factors, their decomposition can also be accelerated by interaction with other ingredients, such as fillers, binders, lubricants, substances that contribute to how the structure, dezintegriruetsja agents. Therefore, the ingredients and the method of its preparation must be chosen carefully in order to avoid the above undesirable interactions and reactions.

The stability of the active substance in the acidic environment is one of the important problems in the case of statins in the form of salts. One possible solution to the above problem is described in EP 0 336 298, where disclosed a stable pharmaceutical preparation based on pravastatin. The essential feature of this drug is to maintain an alkaline environment so that the water dispersion of a pharmaceutical product had a pH above 9, preferably about 10. In addition to the active substance pravastatin composition according to the invention includes an alkalizing agent, such as magnesium oxide, which increases the pH of the aqueous dispersion of the above drug to a value in excess of 9.0. Due to the stability of the active substance of this composition is effective. However, local alkaline environment in the place of dissolution of a pharmaceutical product may have a negative effect on the mucous membrane of the stomach it is usually acidic environment, especially due to the fact that a relatively high amount of alkalizing agent is necessary to ensure acceptable stability. This negative impact special is about obviously in the case of patients with injured mucous membrane in the stomach, where the mucous membrane per se is not able to create a sufficiently acidic environment in the stomach for proper digestion. This is especially important in the case of chronic diseases, as in the case of prevention or treatment with inhibitors of HMG-CoA-reductase.

Another approach to the creation of a stable pharmaceutical preparation described in earlier PCT application no PCT/IB99/01749, data submitted by the applicant.

The essence of the invention.

The purpose of this invention is to provide a pharmaceutical preparation containing as active substance is an inhibitor of HMG-CoA-reductase, which has excellent stability in the absence of the above disadvantages. The specific purpose is the creation of a stable active substance as such, that is, to cooking on the basis of a pharmaceutical preparation, in which the inhibitor of HMG-CoA-reductase protected from decay.

Another aim of the invention is to provide a method of producing stable inhibitor of HMG-CoA-reductase, which has excellent stability in the absence of the above disadvantages.

These and other objectives are achieved in this invention.

In accordance with this invention provides a composition comprising a homogeneous mixture of the inhibitor of HMG-CoA reductase inhibitor with a buffer substance or alkalizing substance, and this to the position obtained by cocrystallization and/or coprecipitation of the indicated inhibitor of HMG-CoA-reductase and the specified buffering agents or alkalizing substances.

Through co-crystallization and/or co-deposition of the obtained dried inhibitor of HMG-CoA reductase inhibitor is mixed with a buffer substance or alkalizing substance to obtain a very homogeneous and finely dispersed form. Suppose that the buffer substance or alkalizing substance finely dispersed around the crystals of the inhibitor of HMG-CoA-reductase, forming a protective “microenvironment”. This protective effect is much more effective than in the case of simple mixing or granulation of the original powders, even during wet mixing that takes place in the application EP-A-0 336 298. Moreover, since the inhibitor of HMG-CoA-reductase (mass) is effectively protected from the harmful effects of the environment thanks to an excellent homogeneous distribution of buffer substances or alkalizing agents, an inhibitor of HMG-COA-reductase better stored and stable during storage by itself, if it is desirable to be added to the pharmaceutical composition.

In particular, a homogeneous composition according to the invention has a high resistance to the negative effects of carbon dioxide and moisture from the air, and much more effective protection against the effect of low pH is achieved when the composition comprising the inhibitor of HMG-CoA reductase inhibitor, is entered as an active substance in Pharma is efticiency the drug.

Accordingly, this invention also provides stable pharmaceutical preparation containing the above composition as the active substance. According to this invention also provides a method of obtaining a stable inhibitor of HMG-CoA-reductase, which includes a step of crystallization and/or precipitation of the inhibitor of HMG-CoA reductase inhibitor together with a buffer substance or alkalizing agent.

A brief description of the drawings.

In Fig. 1A presents a diagram showing the increase in weight of the sample pravastatin in crystalline form and the sample lyophilized pravastatin under the action of moisture in the air. In Fig. 1B shows the corresponding difference between initial weight and weight over time.

In Fig. 2 presents a diagram showing the formation of the lactone form of pravastatin, when pravastatin was dissolved in various buffer solutions with pH in the range 7-11 (F=phosphate, C=citrate,=Borat).

In Fig. 3 presents a diagram showing the formation of various degradation products (impurities), when pravastatin was dissolved in various buffer solutions with pH in the range 7-11 (F=phosphate, C=citrate,=Borat).

A detailed description of the preferred options.

During researches, the inventors have found that there are three main causes unstable the tee in the case of a pharmaceutical product containing the active substance, and in case of loose of the active substance.

First, the active substance, as such, is very hygroscopic and it is impossible to remove all the water. This is illustrated by the following experience: 111,07 mg of pravastatin in crystalline form (prava izh) and 109,8 mg lyophilized pravastatin (prava li) was subjected to the action of moisture air. Their weight was determined at different times. The increase in weight of both samples and the difference between initial weight and weight over time is shown in Figa and 1B.

Another fact is that carbon dioxide from the air can irreversibly and reversibly bind with the active substance and can cause a decrease in pH. This is illustrated by the following experience: 5 g of sodium salt of pravastatin was dissolved in 30 ml of methanol, the pH is brought to 10 by using 3%aqueous NaOH solution. Added 40 ml of ethyl acetate, to form crystals of sodium salt of pravastatin. The crystals were filtered and dried and then placed them in three different environments: normal air, a nitrogen atmosphere, and the atmosphere of carbon dioxide. In the atmosphere of normal air and in nitrogen atmosphere the pH remained the same within 24 hours (normal air: 9,2, nitrogen: 9,5), but in the atmosphere of carbon dioxide, the pH decreased in the first two minutes from 9.2 to 6.9. After 12 minutes the pH was equal to 6.6 and after 1 hour the pH was equal to 6.5. Then the pH remained the message.

The third observation suggests that sufficient stabilization of the active substance is achieved at a pH equal to, at least, 7,0, but relatively high stability is achieved at pH of at least 8.0 in. The authors noted that at pH below 8, the formation of lactone and also increases the amount of other impurities. The presence of moisture in the air and rich in carbon dioxide to the atmosphere increases the negative effect of low pH. This is illustrated by the following experience: pravastatin was dissolved in various buffer solutions with pH in the range 7-11 (F=phosphate, C=citrate,=Borat). The formation of the lactone form of pravastatin and the formation of various degradation products (impurities) was determined after 1, 5, 13, and 28 days. The results are shown in figure 2 and 3.

According to this invention unexpectedly found that sufficient stability of the active substance, which is an inhibitor of HMG-CoA reductase inhibitor, preferably in the form of a salt, can also be achieved by the use of a pharmaceutical preparation, which does not form a noticeable alkaline medium in the aqueous dispersion. To achieve this it is important that the inhibitor of HMG-CoA-reductase was homogeneous mixture obtained through co-crystallization and/or co-precipitation with a buffer substance or alkalizing substance, skompozicii according to the invention before as the composition will be administered in pharmaceutical drug as the active substance. The composition according to the invention, which is a pharmaceutically active ingredient, may contain only the specified homogeneous crystallized together or soosazhdenie inhibitor of HMG-CoA reductase inhibitor and a buffering or alkalizing substance, but may additionally contain other components and additives, if desired.

Another unexpectedly established fact is that sufficient stability of the inhibitor of HMG-CoA reductase inhibitor in the form of a salt in mass can be achieved even in the case when the number of buffer substances or alkalizing substances, crystallized or precipitated together with an inhibitor of HMG-CoA reductase inhibitor, is small. When performing conventional stabilization described in EP-A-0 336 298, alkalizing substance added to a pharmaceutical preparation in an amount of from 1 to 75 weight. %, and in the examples, the amount of alkalizing substances per pravastatin is 33-500%.

According to this invention, the protective effect can be achieved with small amounts of a buffering agent or alkalizing substances, for example, less than 30 wt.%, preferably, this amount is 10 wt.% or less, more preferably 5 wt.% or less, and particularly 1 wt.% or men who e in relation to the number crystallized together or soosazhdenie inhibitor of HMG-CoA-reductase. The lower limit mainly depends on the environmental conditions and the type and amount of other components included in a pharmaceutical preparation, but usually to achieve the desired protective effect, at least 0.05, or 0.1 wt.% buffer substances or alkalizing substances in the calculation of the inhibitor of HMG-CoA-reductase. This addition of small amounts of buffer substances or alkalizing substances allows to avoid the negative impact of water already contained in the mass of matter, and moisture from the air, to avoid the negative effects of low pH caused by the presence of other ingredients that will be added to the pharmaceutical preparation, as well as to avoid a possible decrease in pH caused by the presence of carbon dioxide.

Accordingly, the active substance and pharmaceutical preparation according to this invention are designed to avoid negative impacts of water contained in loose bulk material and in pharmaceutical drug, to avoid the negative effect of low pH, which can be caused by other ingredients of a pharmaceutical product, and to avoid a possible decrease in pH caused by the presence of carbon dioxide.

Further, we found that the protective effect, especially resistance to the negative influence dioxide in the of Lerida, above, when the buffer substance or alkalizing substance crystallizes together or seacadets, but not when it is simply mixed with the shredding and granulation, which is assumed to be caused by a more homogeneous and fine distribution in the composition of the invention. Accordingly, the corresponding stabilizing effect can be achieved with smaller amounts of buffering or alkalizing substances.

Thus, it is possible to mix inhibitor of HMG-CoA-reductase with other ingredients, without fear that when contacting an inhibitor of HMG-CoA reductase inhibitor with acidic ingredients can be decomposed as the microenvironment inhibitor of HMG-CoA-reductase acquired weakly basic or distinctly alkaline by adding small amounts of a buffering agent or alkalizing substances. This addition of a buffer substance or alkalizing substances is also important for better manufacturability bulk composition on the basis of an inhibitor of HMG-CoA reductase inhibitor, in this case, there is no requirement to ensure that the environment did not contain carbon dioxide.

Next, we established that ensure stability and digestibility of a pharmaceutical preparation, it is preferable to adjust the pH of the composition in aqueous medium (usually represents the soup a dispersion) and the pH of the active substance (i.e. the composition containing an inhibitor of HMG-CoA-reductase).

The most acceptable stability of the active substances in drugs is achieved in the above composition, which is the active substance, which is capable of providing a pH in the range from 7 to 12 and preferably 8 to 11. The pH value is the value that is achieved by measuring the pH of the aqueous medium containing the indicated composition. In the stable pharmaceutical preparation according to this invention the alkaline pH of the active substance has a minimal effect on the pH of the drug. By creating a local environment around the active substance, which allows to achieve the high stability of the active substance decreases the negative effects of other ingredients of the pharmaceutical composition of the drug, and possible reactions between the active substance and other ingredients of the pharmaceutical composition of the drug is also difficult. Accordingly, specific composition or the active substance supported in a stable form, when the active substance capable of providing a pH in the aquatic environment in the interval from 7 to 12, preferably in the range from 8 to 11, is added to the pharmaceutical preparation.

Inhibitor of HMG-CoA reductase inhibitor, is used to obtain the composition or the active substances according to the invention is usually in the form of a salt and can the be selected from the group consisting of pravastatin, atorvastatin, fluvastatin, tseriwastatina. Because the stabilizing effect is particularly clearly expressed in these cases, an inhibitor of HMG-CoA reductase inhibitor is preferably a calcium salt of atorvastatin (atorvastatin CA) and the most preferred is the sodium salt of pravastatin (pravastatin Sodium). However, the stability can be improved according to the invention also in the case of other inhibitors of HMG-CoA-reductase.

Next will be described a method suitable for preparing the above-mentioned specific composition, including stable inhibitor of HMG-CoA-reductase. Distinctive stage is crystallization or precipitation as an inhibitor of HMG-CoA reductase inhibitor and a buffering agent or alkalizing substances from the same environment. This stage can be done as an end in the ordinary course of extraction and purification of an inhibitor of HMG-CoA-reductase, but it also can be done using the already allocated inhibitor of HMG-CoA-reductase, which has a degree of purity (IHVR), at least 98%, preferably at least 99.5%pure. First prepare a solution or dispersion of inhibitor of HMG-CoA reductase inhibitor and a buffering agent or alkalizing substances. To obtain such a solution or dispersion can be used conventional solvent or environment, for example the lower al the factual alcohols, such as methanol, ethanol, propanol and isopropyl alcohol, lower aliphatic ketones, such as acetone and methyl ethyl ketone, glycol ethers containing lower alkyl, such as methylglycol, ethylglycol, Papillion and ethyldiglycol, and bipolar aprotic solvents such as N,N-dimethylformamide (DMF), N,1M-dimethylacetamide (DMA) and dimethyl sulfoxide (DMSO), including mixtures of these solvents. Preferred are acetone and lower aliphatic alcohols, such as methanol. Then add an organic solvent in which the compounds are dissolved little or hardly or not soluble, so that the inhibitor of HMG-CoA reductase inhibitor and a buffering agent or alkalizing substance crystallized and/or co-deposited. Examples of such organic solvent include aliphatic alcohols, such as butanol, Isobutanol, amyl alcohol, hexanol, 2-ethyl-hexanol, benzyl alcohol and cyclohexanol, the highest alkylene, such as methylethylketone, methyl isobutyl ketone, cyclohexanone, esters such as methyl acetate, ethyl acetate, n-propyl-isopropyl)acetate, n-butyl and isobutyl-or vtoroy)acetate and amylacetate, ethers, such as diethyl ether and isopropyl ether, chlorinated hydrocarbons such as methylene chloride and chloroform, acetonitrile and the like, including mixtures of these is rastvoritelei. Particularly preferred as the organic solvent ethyl acetate.

the pH of the composition (active substance) is regulated preferably in the above range by using crystallized together or soosazhdenie buffer substances or alkalizing substances.

Buffer a substance or agent selected from the group consisting of salts of inorganic acids, salts of organic bases or salts of organic acids. Examples of salts of inorganic acids include sodium citrate or potassium phosphate, sodium or potassium acid phosphate, sodium or potassium, dibasic sodium phosphate, sodium carbonate, potassium, magnesium or calcium or acid carbonate of sodium, potassium, magnesium or calcium, sulfates or mixtures of such buffering agents and the like; preferred are such agents as sodium carbonate or sodium phosphate. Examples of salts of organic bases include sodium carbonate or acid carbonate aminoguanidine, carbonate or acid guanidine carbonate, carbonate or acid carbonate succinimide, carbonate or acid carbonate 1-Ada-mandelamine, N,N'-bis(2-hydroxyethyl)Ethylenediamine carbonate or acid carbonate, carbonate or acid carbonate, Tris(hydroxymethyl)aminomethane, carbonate or acid carbonate D(-)-N-methylglucamine and the like, Examples of salts of organic acids include potassium or sodium salt explicilty, citric acid, lactic acid, ascorbic acid, maleic acid, phenylacetic acid, benzoic acid, euryceros acid or the like

Alkalizing substance or agent selected from the group consisting of metal oxides, inorganic bases, organic bases of the alkaline type. Examples of metal oxides include magnesium oxide or aluminum oxide. Examples of inorganic bases include hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide, hydroxides of alkaline earth metals such as calcium hydroxide or magnesium hydroxide. Examples of organic bases include succinimide, 1-Ada-manilamen, N No. of bis(2-hydroxyethyl)Ethylenediamine, Tris(hydroxymethyl)-aminomethan, D(-)-N-methylglucamine or the like, Examples of organic acids the main character include 3-(N-morpholino)propanesulfonic acid, 4-[cyclohexylamino]-1-butanesulfonate, 4-[cyclohexylamino]-1-econsultation and alkali and alkaline earth salts of these acids, arginine, ornithine, lysine, etc.

Buffering or alkalizing substance can also be obtained in situ, for example, by adding a hydroxide of an alkali metal or alkaline earth metal in the solution and then passing carbon dioxide through the solution until the desired pH.

The composition or the active substance is about invention, described above, is then entered in the final pharmaceutical product by the conventional methods of preparation of medicines. In addition to composition (pharmaceutically active substances) according to the invention the pharmaceutical preparation according to this invention may also contain at least one component selected from the group consisting of a filler, binder, dezintegriruetsja agent, agent, promoting sliding, buffer agent; it may also contain at least one component selected from dyes, colorful paints, fragrances, adsorbents, binders and plasticizers.

Adding additional buffering or alkalizing substances to the drug can effectively improve and maintain the stability of the final composition to the action of carbon dioxide by neutralizing its acidifying effect. Any of the above-described buffering or alkalizing substances can be used for pharmaceutical preparation. In order to avoid negative effects on the mucous membrane of the stomach of a patient while taking this pharmaceutical preparation, it is preferable to use an additional buffering agent to adjust the pH of the drug, namely to obtain the pH of the solution or dispersion of a pharmaceutical product in the interval m is it 9, preferably less than 8.5, while the lower limit of the pH of a pharmaceutical product is 6, preferably 7. The number of additional buffering or alkalizing substances can be 20 wt.% or less, more preferably 10 wt.% or less based on the total weight of the tablet.

The pharmaceutical preparation according to the invention may include in addition to the inhibitor of HMG-CoA-reductase, which is sensitive to low pH, one or more fillers, such as microcrystalline cellulose, lactose, sugar, starch, modified starch, mannitol, sorbitol and other polyols, dextrin, dextran, maltodextrin, calcium carbonate, phosphate and/or acidic calcium phosphate, calcium sulfate, one or more binders, such as lactose, starches, modified starch, dextrin, dextran and maltodextrin, microcrystalline cellulose, sugar, polyethylene glycol, hydroxypropylcellulose, hypromellose, ethylcellulose, hydroxyethylcellulose, methylcellulose, carboxymethylcellulose, gelatin, gum acacia, tragakant, polyvinylpyrrolidone, magnesium silicate/aluminum, one or more dezintegriruetsja agents, such as sodium salt croscarmellose, crosslinked polyvinylpyrrolidone, crosslinked karboksimetilirovaniya starch, starches and microcrystalline cellulose, silica compound is magnesium/aluminum, polyacrylate potassium, one or more agents that facilitate the sliding, such as magnesium stearate, calcium stearate, zinc stearate, beginat calcium, sodium fumarate, talc, magnesium trisilicate, stearic acid, palmitic acid, Carnauba wax, silicon dioxide, one or more buffer agents, such as sodium citrate or potassium, sodium phosphate, dibasic sodium phosphate, calcium carbonate, acid phosphate, phosphate, calcium sulfate, sodium carbonate or magnesium, sodium ascorbate, sodium benzoate, acidic sodium carbonate or potassium lauryl sulfate, sodium or potassium or a mixture of such buffer agents.

If necessary, the drug can also include surfactants and other conventional components for solid pharmaceutical preparations such as dyes, colorful polishes, air fresheners and adsorbents. As surface-active substances can be used ionic surfactants such as sodium lauryl sulfate, or nonionic surfactants, such as various poloxamer (copolymers of polyoxyethylene and polyoxypropylene), natural or synthetic lecitine, esters sorbitan and fatty acids (such as Span®, manufactured by Atlas Chemie), esters of polyoxyethylenesorbitan and fatty acids (such as Tween®, available from Atlas Chemie), polyoxyethylene the TES gidrirovannoe castor oil such as Cremophor®, manufactured by BASF), polyoxyethylene (such as Brij manufactured by Atlas Chemie), dimethylpolysiloxane or any combination of the above-mentioned surface-active substances.

If the solid pharmaceutical preparation is prepared in the form of coated tablets, the coating can be obtained from at least one film-forming substance, such as hypromellose, hydroxypropylcellulose, at least one plasticizer, such as polyethylene glycols, dibutylsebacate, triethylcitrate and other pharmaceutical auxiliary additives used for film substances, such as pigments, fillers, etc.

Solid pharmaceutical preparations according to the present invention can be obtained, as described below:

- a mixture of active substances, fillers, binders, buffering agents, disintegrator and, if necessary, surfactants and other common when producing solid pharmaceutical ingredients homogenized using a suitable mixer. Add substance that promotes sliding, and/or lubricants and the mixture is again subjected to homogenization. The resulting mixture is pressed to tablets or filled with a mixture of capsules. If necessary, can be applied to tablet coating;

- a mixture of active substances, order the body, binder, buffering agent, disintegrator and, if necessary, surfactants and other common when producing solid pharmaceutical ingredients homogenized using suitable mixers, granularit, using a suitable solvent, such as water, ethanol, methanol, isopropyl alcohol, n-butyl alcohol, acetone, diethyl ether, ethyl acetate, isopropylacetate, methyl acetate, dichloromethane, and mixtures of these solvents, such as ethanol and acetone, methanol and acetone, dichloromethane and methanol, and mixtures thereof. The obtained granulate is dried in a suitable dryer, such as a conventional disc dryers, dryers fluidized bed, vacuum and microwave drying. To the dried granulate add substances that contribute to the slide, and/or lubricants and, if required, other conventional ingredients used in the preparation of solid pharmaceutical preparations. The resulting mixture is again subjected to homogenization and pressed into tablets or filled her capsules. Can be applied to tablet coating.

The invention is illustrated below, but in no way limited to, the following examples.

Examples.

The examples use the following devices:

System GWH GHUR: column Lichrospher, (30·4,6) mm, detector 236 nm, sample≈500 mg/l, injector 5 μl,mobile phase: 15% atsn, mobile phase b: 90% atsn, gradient 0':100% A, 3,5' 100%, the flow rate of 2.8 ml/min;

pH meter: Iskra MA 5741.

(I) Stabilization of inhibitor of HMG-CoA-reductase by adding salts of inorganic acids.

Example 1: stabilization of the sodium salt of pravastatin by adding sodium carbonate.

Sodium salt of pravastatin (I-V, 5 g) with chromatographic purity of 99.5% and a pH of 7,4(1%)/7,7(5%) was dissolved in methanol (30 ml), was added sodium carbonate (10 mg dissolved in 0.15 ml of water) and then ethyl acetate (400 ml, contains 2% water). After 1 hour, the obtained crystals were filtered off, washed with fresh ethyl acetate (50 ml) and dried at 40°C in vacuum for 6 hours. The degree of chromatographic purity of the obtained crystals (4.3 g) was 99.6 percent, and the pH was equal to 9,5(1%)/9,8(5%).

The measurement results of stability are shown in Table 1.

Example 2: stabilization of the sodium salt of pravastatin by adding acidic sodium carbonate.

Sodium salt of pravastatin (I-17226103B, 5 g) with chromatographic purity of 99.5% and a pH of 7,4(1%)/7,7(5%) was dissolved in methanol (30 ml)was added acid sodium carbonate (10 mg dissolved in 0.15 ml of water) and then ethyl acetate (400 ml, contains 2% water). After 1 hour, the obtained crystals were filtered off, washed with fresh ethyl acetate (50 ml) and dried at 40°C in vacuum for 6 hours. The degree of chromatographic clean what you obtained crystals (4.4 g) was 99.6%and and the pH was equal to 9,2 (1%)/9,6 (5%).

The measurement results of stability are shown in Table 1.

Example 3: Stabilization by adding disodium salt of acid phosphate.

Sodium salt of pravastatin (I-V, 5 g) with chromatographic purity of 99.5% and a pH of 7,4(1%)/7,7(5%) was dissolved in methanol (30 ml), was added disodium salt of acid phosphate (10 mg dissolved in 0.15 ml of water) and then ethyl acetate (400 ml, containing 2% of water). After 1 hour, the obtained crystals were filtered off, washed with fresh ethyl acetate (50 ml) and dried at 40°C in vacuum for 6 hours. The degree of chromatographic purity of the obtained crystals (4.3 g) was 99.6 percent, and the pH was equal to 8,0(1%)/8,4(5%).

The measurement results of stability are shown in Table 1.

Example 4: Stabilization by sodium hydroxide and carbon dioxide.

Sodium salt of pravastatin (I-V, 5 g) with chromatographic purity of 99.5% and a pH of 7,4(1%)/7,7(5%) was dissolved in methanol (30 ml), was added sodium hydroxide to achieve a pH of 8.3 (balance), and then ethyl acetate (400 ml, containing 2% of water). After 1 hour, the obtained crystals were filtered off, washed with fresh ethyl acetate (50 ml) and dried at 40°C in vacuum for 6 hours. The degree of chromatographic purity of the obtained crystals (4.3 g) was 99.6 percent, and the pH was equal to 7,7(1%)/8,3(5%).

The measurement results of stability are shown in Table 1./p>

(II) stabilization of the sodium salt of pravastatin by adding salts of organic bases.

Example 5: Stabilization by adding acid carbonate aminoguanidine.

Sodium salt of pravastatin (I-V, 5 g) with chromatographic purity of 99.5% and a pH of 7,4(1%)/7,7(5%) was dissolved in methanol (30 ml)was added the acid carbonate aminoguanidine (10 ml, dissolved in 1 ml of water) and then ethyl acetate (400 ml, containing 2% of water). After 1 hour, the obtained crystals were filtered off, washed with fresh ethyl acetate (50 ml) and dried at 40°C in vacuum for 6 hours.

The degree of chromatographic purity of the obtained crystals (4,2 g) was 99.6 percent, and the pH was equal to 8,1(1%)/8,8(5%).

The measurement results of stability are shown in Table 1.

(Ill) the Stabilization of the sodium salt of pravastatin by adding salts of organic acids.

Example 6: Stabilization by sodium acetate.

Sodium salt of pravastatin (I-17226103, 5 g) with chromatographic purity of 99.5% and a pH of 7,4(1%)/7,7(5%) was dissolved in methanol (30 ml), was added sodium acetate (10 ml, dissolved in 0.15 ml of water) and then ethyl acetate (400 ml, containing 2% of water). After 1 hour, the obtained crystals were filtered off, washed with fresh ethyl acetate (50 ml) and dried at 40°C in vacuum for 6 hours.

The degree of chromatographic purity of the obtained crystals (4.3 g) was 99.6 percent, and pH to be equalled what I 7,9(1%)/8,3(5%).

The measurement results of stability are shown in Table 1.

(IV) stabilization of the sodium salt of pravastatin by adding inorganic bases.

Example 7: Stabilization of magnesium oxide.

Sodium salt of pravastatin (I-V, 5 g) with chromatographic purity of 99.5% and a pH of 7,4(1%)/7,7(5%) was dissolved in methanol (30 ml)was added magnesium oxide (10 mg) and then ethyl acetate (400 ml, containing 2% of water). After 1 hour, the obtained crystals were filtered off, washed with fresh ethyl acetate (50 ml) and dried at 40°C in vacuum for 6 hours.

The degree of chromatographic purity of the obtained crystals (4.3 g) was 99.6 percent, and the pH was equal to 8,7(1%)/9,3(5%).

The measurement results of stability are shown in Table 1.

(V) stabilization of the sodium salt of pravastatin by adding an organic base.

Example 8: Stabilization of L-arginine.

Sodium salt of pravastatin (I-V, 5 g) with chromatographic purity of 99.5% and a pH of 7,4(1%)/7,7(5%) was dissolved in methanol (30 ml), was added L-arginine (10 mg dissolved in 0.15 ml of water) and then ethyl acetate (400 ml, containing 2% of water). After 1 hour, the obtained crystals were filtered off, washed with fresh ethyl acetate (50 ml) and dried at 40°C in vacuum for 6 hours.

The degree of chromatographic purity of the obtained crystals (4.3 g) was 99.6 percent, and the pH was equal to 8,9(1%)/9,3(5%).

The measurement results the Oia stability are shown in Table 1.

(VI) the Results of examples 1-8.

Table 1.

ExperienceAfter cookingAfter 1 week on the air
SampleBuffer/alkalizing-inpH(1%)pH (5%)pH(1%)pH (5%)
I 17226103BThe crude crystals7,47,77,27,6
Example 1PA2CO39,59,89,59,8
Example 2Panso39,29,69,3the 9.7
Example 3PA2NR48,08,48,08,4
Example 4NaOH/CO2,7,7 8,37,78,4
Example 5aminoguanine HCO38,18,88,28,9
Example 6CH3The N7,98,38,08,4
Example 7MgO8,79,38,89,5
Example 8L-arginine8,99,38,99,3

(VII) the Stabilization of the sodium salt of pravastatin by adding salts of organic acids of the main character.

Example 9: the Stabilization of the sodium salt of pravastatin by adding the sodium salt of 3-(N-morpholino)propanesulfonate(S).

Sodium salt of pravastatin (I-17226103, 5 g) with chromatographic purity of 99.5% and a pH of 7,4(1%)/7,7(5%) was dissolved in methanol (30 ml), was added sodium salt of 3-(N-morpholino)propanesulfonate (50 mg dissolved in 0.3 ml of water) and then ethyl acetate (400 ml, which contains 2% water). After 1 hour, the obtained crystals were filtered off, washed with fresh ethyl acetate (50 ml) and dried at 40°C in vacuum for 6 hours.

The degree of chromatographic purity of the obtained crystals (4.3 g) was 99.5%, and the pH was equal to 8,1(1%)/8,5(5%).

(VIII) the Stabilization of the sodium salt of pravastatin by adding an organic base.

Example 10: Stabilization by adding Tris(hydroxymethyl)aminomethane.

Sodium salt of pravastatin (I-17226103, 5 g) with chromatographic purity of 99.5% and a pH of 7,4(1%)/7,7(5%) was dissolved in methanol (30 ml)was added Tris(hydroxymethyl)aminomethan (50 mg dissolved in 0.4 ml of water) and then ethyl acetate (400 ml, containing 2% of water). After 1 hour, the obtained crystals were filtered off, washed with fresh ethyl acetate (50 ml) and dried at 40°C in vacuum for 6 hours.

The degree of chromatographic purity of the obtained crystals (4.3 g) was 99.6 percent, and the pH was equal to 8,0(1%)/8,3(5%).

Example 11: Stabilization by adding N,N'-bis(2-hydroxyethyl)Ethylenediamine.

Sodium salt of pravastatin (I-17226103, 5 g) with chromatographic purity of 99.5% and a pH of 7,4 (1%)/7,7 (5%) was dissolved in methanol (30 ml)was added N,N'-bis(2-hydroxyethyl)Ethylenediamine (50 mg dissolved in 0.4 ml of water) and then ethyl acetate (400 ml, containing 2% of water). After 1 hour, the obtained crystals were filtered off, washed with fresh ethyl acetate (0 ml) and dried at 40°C in vacuum for 6 hours.

The degree of chromatographic purity of the obtained crystals (4.3 g) was 99.6 percent, and the pH was equal to 8,3(1%)/8,9(5%).

(VI) the Results of examples 9-11.

Table 2.

ExperienceAfter cookingAfter 1 week on the air
SampleBuffer/alkalizing-inpH (1%)pH (5%)pH (1%)pH (5%)
 The crude crystals7,47,77,27,6
Example 9MOPS sodium salt8,18,58,18,6
Example 10Tris(hydroxymethyl)aminomethan8,08,38,08,3
Example 11N,N'-bis(2-hydroxyethyl)-Ethylenediamine8,38,98,38,8

(X) the Evaluation of the results.

The main cause of instability is an inhibitor of HMG-CoA reductase inhibitor, such as sodium salt of pravastatin in the mass is carbon dioxide from the air and the subsequent decrease in the pH value of the active substance. By decreasing the pH of the sodium salt of pravastatin into lacton the th form.

Using a variety of buffers or alkalizing agents in the process of co-precipitation and co-crystallized with an inhibitor of HMG-CoA reductase inhibitor, it is possible to obtain a very homogeneous composition as a pharmaceutically active substance, where the inhibitor of HMG-CoA reductase inhibitor is effectively protected from destabilization (see the results given in Tables 1 and 2). At the same time pH friable active substance may be communicated to the respective desired values. For example, the sodium salt of pravastatin stable, especially at pH 8-10.

In the above examples used by 0.2% of a buffering or alkalizing substances in the calculation of the sodium salt of pravastatin, but smaller or larger quantities also work efficiently.

Compositions according to this invention obtained as described above, may be incorporated in the pharmaceutical preparation in the usual quantities, for example, as described in the earlier application PCT/IB99/01749, when replacing the active substance compositions according to the invention.

1. A composition comprising a homogeneous mixture of the inhibitor of HMG-CoA reductase inhibitor with a buffer substance or alkalizing substance obtained joint crystallization and/or co-precipitation inhibitor of HMG-CoA reductase inhibitor and a buffering or alkalizing substance, and the inhibitor of HMG-CoA reductase inhibitor selected from the group including lovastatin, simvastat is h, pravastatin, atorvastatin, fluvastatin, tseriwastatina and their pharmaceutically acceptable salts.

2. The composition according to claim 1, wherein a buffering or alkalizing substance is contained in a homogeneous mixture in an amount of 10 wt.% or less based on the amount of inhibitor of HMG-CoA-reductase.

3. The composition according to claim 1, wherein a buffering or alkalizing substance is contained in a homogeneous mixture in an amount of 1 wt.% or less based on the amount of inhibitor of HMG-CoA-reductase.

4. The composition according to claim 1, characterized in that it consists only of the specified homogeneous mixture.

5. The composition according to claim 1, wherein the buffer substance is selected from the group consisting of salts of inorganic acids, salts with organic bases and salts of organic acids.

6. The composition according to claim 1, wherein the alkalizing substance selected from the group consisting of oxides of metals, inorganic bases, organic bases and organic acids the main character.

7. Composition according to any one of claims 1 to 6, characterized in that it is capable of providing a pH in the range from 7 to 12.

8. Composition according to any one of claims 1 to 6, characterized in that it is capable of providing a pH in the range from 8 to 11.

9. Composition according to any one of claims 1 to 6, characterized in that the inhibitor of HMG-CoA reductase inhibitor is in the form of salts.

11. A composition comprising a homogeneous mixture of sodium salt of pravastatin with a buffer substance or alkalizing substance obtained joint crystallization and/or coprecipitation of the specified sodium salt of pravastatin and buffering or alkalizing substances.

12. Pharmaceutical prepart, containing as active substance composition according to any one of claims 1 to 11.

13. The pharmaceutical preparation according to item 12, characterized in that it is capable of providing a pH in the range from 6 to 9.

14. The pharmaceutical preparation according to item 12, characterized in that it is capable of providing a pH in the range from 7 to 8.5.

15. The pharmaceutical preparation according to item 12, characterized in that it further comprises an additional amount of buffer substance.

16. The pharmaceutical preparation according to any one of p-15, characterized in that it additionally contains at least one ingredient selected from the group consisting of a filler, binder, dezintegriruetsja agent, substances that contribute to the slide, a buffer agent, and he may additionally contain at least one ingredient selected from dyes, colorful paints, fragrances, adsorbents, film and the plastic is of Tatarov.

17. A method of obtaining a stable inhibitor of HMG-CoA-reductase, including the stage of crystallization and/or precipitation of the inhibitor of HMG-CoA reductase inhibitor selected from the group including lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin, tseriwastatina and their pharmaceutically acceptable salts, together with a buffering or alkalizing agent.

18. The method according to claim 19, characterized in that stage of crystallization and/or precipitation includes obtaining solution containing an inhibitor of HMG-CoA reductase inhibitor and a buffering or alkalizing substances, and then adding an organic solvent to the specified solution in order to ensure crystallization and/or precipitation of inhibitor of HMG-CoA reductase inhibitor and a buffering or alkalizing substances.

19. The method according to 17 or 18, wherein the buffer substance is selected from the group consisting of salts of inorganic acids, salts with organic bases and salts of organic acids.

20. The method according to 17 or 18, wherein the alkalizing substance selected from the group consisting of oxides of metals, inorganic bases, organic bases and organic acids the main character.

21. The method according to p, characterized in that the organic solvent is ethylacetate

22. The method according to 17 or 18, characterized in that the specified HMG-CoA-reductase, used for co-crystallization and/or co-precipitation is in the form of salts.

23. The method according to item 22, wherein the inhibitor of HMG-CoA reductase inhibitor is a sodium salt of pravastatin or calcium salt of atorvastatin.



 

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