CZ459499A3 - Process for preparing medicaments containing HMG-CoA-reductase inhibitors - Google Patents

Abstract

The present invention relates to a process for the manufacture of medicaments comprising inhibitors HMG-CoA reductase, in the form of its salts from the corresponding precursor of the active ingredient by processing with an aqueous base of the aqueous active substance solution / suspension and either containing the active ingredient the solution / suspension is then solid without isolation of the active substance the substance is sprayed immediately on the neutral excipient a Γ2 is dried in parallel or the active substance is mixed after mixing containing the appropriate binder granules with excipients and then dried.

Description

Process for the manufacture of medicaments containing HMG-CoA reductase inhibitors

Area of tangents

The invention relates to a process for the manufacture of medicaments containing HMG-CoA reductase inhibitors, in particular in the form of granules, tablets and pellets.

BACKGROUND OF THE INVENTION

It is known that HMG-CoA reductase inhibitors are used as active ingredients in medicaments for the treatment of hyperlipoproteinemia and arteriosclerosis. Most of these compounds are derived from a series of statins of formula I

OH OH

I I

RX-CH-CH ₂ -CH-CH ₂ -COOM (|) in which

R is an organic residue,

X is -CH 2 -CH 2 - or -CH = CH-, especially in (E) -form a

M represents a physiologically acceptable cation, for example from the series of alkali metal cations, preferably sodium or potassium, as well as ammonium ion.

• ··

In addition, it is known that most of the statin active ingredients are used in the form of their salts. For this purpose, the active compounds are generally prepared first in the aqueous solution from the corresponding esters or acids as a precursor by treatment with bases, and this solution is then freeze-dried to obtain the active substance itself (EP 547 000).

This method is naturally very time-consuming and cost-intensive and requires, inter alia, costs related to process monitoring, control and optimization. In addition, the lyophilization product is very difficult to handle because it exhibits very strong hygroscopic properties. This can, despite careful maintenance of climatic conditions (low air humidity) or the use of special moisture-proof packaging agents, lead to defective storage and manufacturing problems (for example, inaccuracies in weighing and deviations in the contents of the tablets by absorbing moisture in the granulate) .

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a process for the manufacture of a medicament comprising an HMG-CoA reductase inhibitor of the statin series of formula I

OH OH

I l

RX-CH-CH ₂ -CH-CH ₂ -COOM (1) wherein it represents an organic residue

· · · · · · · · · · · · · · · · · · · · · · · · ·

X is -CH 2 -CH 2 - or -CH = CH-, especially in (E) -form a

M denotes a physiologically acceptable cation, characterized in that the corresponding precursor of the active substance is first produced by treatment with an aqueous base of the active substance itself in an aqueous solution / suspension and either the active substance containing solution / suspension is then sprayed directly onto the excipient; it is simultaneously dried or, after mixing, the active ingredient-containing solution / suspension is granulated with suitable binders and excipients and then dried.

Thus, the process of the present invention describes the manufacture of medicaments without the active ingredient being isolated in its solid form, optionally as a solid substance, but directly further processed as a solution.

The overall production process is thereby greatly simplified, especially when the problematic and expensive lyofillization step for isolation of the active substance is omitted. This also means a significant improvement in the handling and safety of the manufacture of the medicinal product.

Bases which are generally used are those which contain alkali metal and alkaline earth metal ions. Preferred are hydroxides, carbonates or bicarbonates containing alkali metal or alkaline earth metal ions such as sodium, potassium, lithium, beryl, calcium or magnesium ions. Sodium hydroxide or potassium hydroxide is particularly preferred, depending on whether φ φ · φ φ φφ

- 4 φ zda zda zda zda zda zda zda zda zda zda zda zda zda zda zda zda zda zda zda zda zda zda zda zda zda zda zda zda zda zda zda zda zda zda zda zda zda zda whether the active substance is sodium or potassium.

The amount of the base is at least an equimolar amount, based on the amount of the precursor active used.

Preferred herein are the corresponding acids or esters of the formula II ° ^H OH

R X = CH-CH ₂ -CH-CH-COOR ¹ (H) or the corresponding lactones of formula III

(III) in which an organic radical is -CH 2 -CH 2 - or -CH = CH- a

R1 represents an alkyl group having 1 to 4 carbon atoms or a hydrogen atom.

Preferably, the lactones of general formula (III) are used as precursors, the actual active substances being prepared immediately in solution by cleavage of the lactone ring with a base.

• · •

Φ · ··

99 ΦΦΦ • Φ · 99

Particularly preferred is cerivastatin lactone, which is reacted in solution with sodium hydroxide to give the active ingredient cerivastatin.

The process according to the invention is suitable for the production of solid and liquid, in particular solid, dosage forms, such as powders, granules, tablets or pellets, containing the active ingredient. The powders, granules or pellets can be compressed into tablets or filled into capsules.

All conventional, pharmaceutically acceptable binders, for example polyvinylpyrrolidones, gelatin and starch and cellulose derivatives (natural or synthetic) are used as binders for granulation.

Preferably, polyvinylpyrrolidones are used, for example polyvinylpyrrolidone 25.

Other conventional excipients can be used, for example, as fillers cellulose derivatives (for example microcrystalline cellulose), sugars (for example lactose), sugar alcohols (for example mannitol and sorbitol) and inorganic fillers (for example calcium phosphates), as well as any other auxiliaries which are required for the manufacture of the medicaments of the desired properties. These include glidants (e.g. magnesium stearate), disintegrants (e.g. cross-linked polyvinylpyrrolidone and sodium carboxymethylcellulose), wetting agents (e.g. sodium lauryl sulfate), stabilizers, flavoring agents and color pigments.

Preferably, the filler used is lactose, mannitol and

- 6 microcrystalline cellulose.

The proportion of binder in the total mixture is preferably 0 to 20%, the proportion of fillers and excipients in the total mixture is preferably 70 to 99%.

The drying temperature is generally 40 to 120 ° C, preferably 60 to 100 ° C.

The process according to the invention is particularly suitable for active compounds of the formula I in which R represents optionally substituted p-Xrimidine, indole, indolizine, pyrrolo-pyridine, quinoline, dihydroquinoline, pyrazolo-pyridine, pyridazine, imidazole, pyrrolo-isoquinoline, pyridine , pyrrole and tetrazole residues.

The process according to the invention is particularly suitable for the following active compounds of the formula I:

pravastatin, sodium salt of 3R, 5S- (E) -7- [4- (4-fluoro-phenyl) -6- (1-methylethyl) -2-dimethylaminopyrimidin-5-yl] -3,5-dihydroxy-6- heptenové;

erythro- (±) - (E) -7- [3- (4-fluoro-phenyl) -spiro [cyclopentane-1,1,1-1H-inden] -2'-yl] -3,5-sodium salt -dihydroxy-6-heptenes;

3R, 5S- (E) -7- [3- (4-fluoro-phenyl) -1- (1-methylethyl) -indosilin-3-yl] -3,5-dihydroxy-6-heptenic acid, sodium salt;

sodium salt of 3R, 5S- (E) -7- [3- (4-fluoro-phenyl) -1] ·

- (1-methylethyl) -1H-pyrrolo [2,3-b] pyridin-2-yl] -3,5-dihydroxy-8-heptene;

3R, 5S- (E) -7- [4- (4-fluoro-phenyl) -2- (1-methylethyl) -quinolin-3-yl] -3,5-dihydroxy-6-heptenic acid, sodium salt;

3R, 5S- (E) -7- [1- (4-fluoro-phenyl) -3- (1-methylethyl) -4-oxo-1,4-dihydroquinolin-2-yl] -3,5-sodium salt -dihydroxy-6-heptenes;

3R, 5S- (E) -7- [4- (4-fluoro-phenyl) -6- (1-methylethyl) -3-methyl-1H-pyrazolo [3,4-b] pyridine- 5-yl] -3,5-dihydroxy-6-heptene;

3R, 5S- (E) -7- [3- (1-methylethyl) -5,6-diphenyl-pyridazin-4-yl] -3,5-dihydroxy-6-heptenic acid, sodium salt;

3R, 5S- (E) -7- [4- (4-fluoro-phenyl) -6- (1-methylethyl) -2-phenyl-pyrimidin-5-yl] -3,5-dihydroxy-6-sodium salt -heptenové;

3R, 5S- (E) -7- [4- (4-fluorophenyl) -1- (1-methylethyl) -3-phenyl-2-oxo-2,3-dihydroimidazol-5-yl] -3-sodium salt 5-dihydroxy-6-heptenes;

3R, 5S- (E) -7- [4- (4-fluorophenyl) -2- (1-methylethyl) -1-oxo-1,2-dihydroquinolin-3-yl] -3, sodium salt, 5-dihydroxy-6-heptenes;

erythro- (±) - (E) -7- [4- (4-fluorophenyl) -2- (1-methylethyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenic acid, sodium salt;

erythro- (±) - (E) -7- [1- (4-fluorophenyl) -3-pyrrolo [2,1-a] isoquinolin-2-yl] -3,5-dihydroxy-6- sodium salt heptenové;

erythro- (±) - (E) -7- [4-cyclopropyl-6- (4-fluoro-phenyl) -2- (4-methoxyphenyl) pyrimidin-5-yl] -3,5- sodium salt dihydroxy-6-heptenes;

3R, 5S- (E) -7- [4- (4-fluoro-phenyl) -2,6-dimethyl-pyrimidin-5-yl] -3,5-dihydroxy-8-heptenic acid, sodium salt;

3R, 5S- (E) -7- [4- (4-fluoro / phenyl) -6-methyl-2-phenyl-pyrimidin-5-yl] -3,5-dihydroxy-8-heptenic acid, sodium salt;

3R, 5S- (E) -7- [4- (3,5-dimethyl-phenyl) -6-methyl-2-phenyl-pyrimidin-5-yl] -3,5-dihydroxy-6-heptenic acid, sodium salt;

erythro- (±) - (E) -7- [3,4-bis- (4-fluoro / phenyl) -6- (1-methylethyl) -pyridazin-5-yl] -3,5-dihydroxy-6-sodium salt -heptenové;

erythro- (±) - (E) -7- [1- (4-fluoro-phenyl) -3- (1-methylethyl) -5-phenyl-1H-pyrrol-2-yl] -3, sodium salt, 5-dihydroxy-6-heptenes;

erythro- (±) - (E) -9,9-bis- (4-fluoro-phenyl) -3,5-dihydroxy-8 - (- 1-methyl-1H-tetrazol-5-yl) -6, sodium salt, 8-nonadiene;

erythro- (±) - (E) -3,5-dihydroxy-9,9-diphenyl-6,8-heptenic acid sodium salt;

erythro- (±) - (E) -7- [4- (4-fluoro-phenyl) -1,2-bis- (1-methylethyl) -3-phenylpyrrol-2-yl] -3,5 sodium salt -dihydroxy-6-heptenes;

Sodium salt of 3R, 5S- (E) -7- [4- (5-bis (4-fluorophenyl) -2- (1-methylethyl) -1H-imidazole)] 1-yl] -3,5-dihydroxy-6-heptene;

3R, 5S- (E) -7- [4- (4-fluorophenyl) -2,6-bis- (1-methylethyl) -5-methoxymethyl-pyridin-3-yl] -3,5-dihydroxy acid, sodium salt -6-heptenes; (cerivastatin) erythro- (±) - (E) - [4- (4-fluoro-phenyl) -2- (1-methylethyl) -6-phenyl-pyridin-3-yl] -3,5- dihydroxy-6-heptenes;

erythro- (±) - (E) - [2- (4-fluorophenyl) -4,4,6,6-tetramethyl-cyclohexen-1-yl] -3,5-dihydroxy-6-heptenic acid, sodium salt;

erythro- (±) - (E) -7- [4- (4-fluoro-phenyl) -2-cyclopropyl-quinolin-3-yl] -3,5-dihydroxy-6-heptenic acid, sodium salt;

erythro- (±) - (E) -7- [4- (4-fluorophenyl) -2- (1-methyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenic acid, sodium salt;

Particularly suitable is the process of the present invention for the sodium salt of 3R, 5S- (E) -7- [4- (4-fluoro-phenyl) -2,6-bis- (1-methylethyl) -5-methoxymethyl-pyridine-3 -yl] -3,5-dihydroxy-6-heptenoic acid.

The process described is particularly suitable when the active ingredient is used in very small amounts, for example less than 5%, in particular less than 1% (by weight of the final preparation). By further processing the solution or dropping the active ingredient suspension into a granulating liquid and subsequently coating the carrier, drug preparations can be prepared which exhibit excellent uniformity of distribution of the active ingredients. The generally known problems encountered in conventional (dry) mixing of components with strongly different proportions in the total mixture are thus eliminated in a simple manner.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

A certain amount of the cerivastatin pyridine lactone active ingredient is introduced into a suitable container. The amount of sodium hydroxide required for the quantitative reaction of cerivastatin (calculated as the molar ratio between cerivastatin pyridine lactone and sodium hydroxide), which occurs in the form of an aqueous solution (for example 2,5% (w / w)) as well as an additional calculated excess water ( for example, a 6.6-fold amount of cerivastatin pyridine lactone) was combined and added to the solid. The batch is left under suitable conditions for a certain period of time, whereby the reaction precursors to the active substance cerivastatin take place. Completeness of reaction was checked.

After the transformation was complete, the batch was filtered, and polyvinylpyrrolidone 25 and water were added. By way of example, the following composition (data [mg], based on the final mixture):

cerivastatin polyvinylpyrrolidone 25

0.1

1,8

4 4

4 4 4 4

4,444,444

4 4

444 44 44 water

q.s.

The granulation liquid thus formed is applied directly to a suitable carrier material, for example mannitol, which can be carried out by means of the prior art either by mixed granulation, for example by means of a high-speed mixer, or by fluidized bed granulation (data [mg] based on the final mixture):

mannitol

83.95.

After drying, the product is sieved and mixed.

For example, the resulting granulate can also be mixed with a lubricant (e.g. magnesium stearate) and disintegrants (e.g. cross-linked polyvinylpyrrolidone) after sieving, further processed into tablets (weight 90 mg; diameter 6 mm) and then lacquered ).

Example 2

The procedure is as in Example 1, but the liquid is not granulated to a powder carrier, but is applied to pellets in a suitable apparatus, for example in a fluidized bed apparatus.

Example 3

The procedure is as in Example 1, but the powder base is applied to a pellet containing the active substance in a suitable apparatus, for example a fluidized bed apparatus, a rotary granulator or the like.

··

Example 4

The procedure is as in Example 1, but the liquid is applied to the powdered carrier material in the powder coating to form an active-coated powder.

Example 5

The procedure is as in Examples 1 to 4, but the drug-coated powder, granules or pellets are filled into prepared capsules, for example of hard gelatin or other suitable materials.

Example 6

The procedure is as in Example 1, but the concentration of active ingredient per dosage unit is reduced to 0.01 mg or increased to 5.0 mg.

Example 7

The procedure is as in Example 1 except that a stabilizer such as sodium hydroxide is added to the granulation liquid.

Example 8

The procedure is as in Example 1, but a stabilizer such as sodium carbonate is added to the support material.

Β B B

B BB

ΒΒ ΒΒ ΒΒ ΒΒ

Β Β β · Β Β Β Β

Β Β Β Β Β Β

Β ΒΒΒΒΒ ΒΒΒ

Β Β Β Β

ΒΒ ΒΒΒΒ ΒΒ ΒΒ

Example 9

For liquid preparation (aqueous) with option, if necessary titrate pH back (adjust as alkaline after hydrolysis).

Claims (10)

CLAIMS 1. A method for the manufacture of a medicament comprising a HMG-CoA reductase inhibitor of the statin series of formula I OH OH I I RX-CH-CH ₂ -CH-CH ₂ -COOM (|) in which R is an organic residue, X is -CH 2 -CH 2 - or -CH = CH- a M stands for a pharmacologically acceptable cation, characterized in that the corresponding active ingredient is prepared by treatment with an aqueous base of the active ingredient itself in an aqueous solution / suspension, and either the solution / suspension containing active ingredient is then immediately isolated as the solid without isolation of the active substance. It is sprayed onto a neutral excipient and simultaneously dried, or after mixing the active ingredient-containing solution with suitable binders, granulated with excipients and then dried. Process according to Claim 1, characterized in that acids or esters of the general formula II are used as precursors. - 15 - OH OH 1 i i R-X-CH-CH-CH-CH-COOR • · · · · · • · · · · • · · · ······· (II) or the corresponding common lactones of formula III Λ R = X = O ^ O (lil) ve which R denotes an organic residue, X is -CH 2 -CH 2 - or -CH = CH- a R ¹ represents an alkyl group having 1 up to 4 carbon atoms or a hydrogen atom. The process according to claims 1 and 2, characterized in that sodium or potassium hydroxide is used as the base. Method according to claims 1 to 3, characterized in that polyvinylpyrrolidone, gelatin and starch and cellulose derivatives are used as binders. Method according to Claims 1 to 4, characterized in that cellulose derivatives, sugars, sugar alcohols are used as excipients. And / or inorganic fillers. The process according to claims 1 to 5, characterized in that mannitol or sorbitol is used as the excipient. Method according to claims 1 to 6, characterized in that the proportion of binder in the total mixture is 0 to 20%. Process according to Claims 1 to 7, characterized in that the proportion of binders and auxiliaries in the total mixture is 70 to 99%. Method according to claims 1 to 8, characterized in that at least an equimolar amount of base, calculated on the precursor of the active substance, is used. Method according to claims 1 to 9, characterized in that the amount of active substance is less than 5% of the total amount of the final drug form.