EP1173152A2

EP1173152A2 - Solid pharmaceutical formulations of acid-sensitive proton-pump blockers

Info

Publication number: EP1173152A2
Application number: EP00925201A
Authority: EP
Inventors: Robert Heger; Wolfgang Schrof; Jens Rieger; Rüdiger Voelkel; Jörg Breitenbach; Jürgen Zeidler; Bernd Liepold; Gunther Berndl; Rudolf Binder
Original assignee: BASF SE
Current assignee: BASF SE
Priority date: 1999-04-23
Filing date: 2000-04-11
Publication date: 2002-01-23
Also published as: CA2369951A1; WO2000064414A3; JP2002542275A; WO2000064414A2; DE19918434A1; BR0012735A

Abstract

The invention relates to a solid preparation, containing an acid-sensitive proton-pump blocker as the active substance, whereby said active substance is present in an x-ray amorphous form and is embedded in molecularly dispersed form in an auxiliary agent matrix.

Description

Solid pharmaceutical formulations of acid labile proton pump blockers

description

The present invention relates to solid preparations of an acid-labile proton pump blocker as an active substance, in which the active substance is X-ray amorphous in the form of a solid solution. The invention further relates to a method for producing such preparations.

Acid-labile proton pump blockers in the sense of this invention are, in particular, acid-labile benzimidazoles such as, for example, pantoprazole, lansoprazole, pariprazole, lemnoprazole and in particular omeprazole.

Omeprazole belongs to the so-called proton pump blocker substance class. It directly and dose-dependently inhibits the enzyme H ⁺ / K ⁺ -ATPase ("proton pump"), which is responsible for the secretion of gastric acid in the parietal cell of the stomach. Omeprazole has proven itself in the treatment of duodenal ulcer, ventricular ulcer, reflux oesophagitis and Zollinger-Ellision syndrome. Parenteral and solid oral drugs are used.

Omeprazole is absorbed in the upper duodenum, the maximum plasma concentrations being reached 1 to 3 hours after application.

Omeprazole decomposes very quickly to ineffective compounds under acidic conditions and under thermal stress. This process is associated with a brown-violet coloration of the white omeprazole powder. To prevent the undesired acid-related degradation reactions, oral omeprazole formulations must be completely protected against gastric juice so that the active ingredient can penetrate undamaged to the absorption site in the duodenum.

DE-A 1204363 describes a pharmaceutical form consisting of three different layers. The first layer is soluble in the stomach, but insoluble in the intestine. The second layer is water-soluble (regardless of pH) and the third (outer) protective layer is an enteric coating. However, a disadvantage of such a form is that it is only slowly dissolved in the intestine and therefore the active ingredient is also released only slowly becomes. In the case of omeprazole, however, a quick release formulation is needed.

EP-A 240904 describes pharmaceutical forms in which the active ingredient is embedded in a molecularly disperse form in a polymer matrix with the aid of melt extrusion. Such dosage forms are able to release the WS very quickly. A disadvantage of this form, however, is that temperature loads occur during production, which lead to degradation in the case of omeprazole.

EP-0 496 437 describes pellet cores or tablets which contain omeprazole or an alkali salt of omeprazole together with an alkaline compound and are coated with a layer of water-soluble, film-forming auxiliaries, which preferably react alkaline, and are coated with an enteric end film.

EP-A 0 239 200 describes the use of basic magnesium salts and / or basic calcium salts for stabilizing benzimidazole derivatives.

The prior art described here shows that a variety of approaches have been followed in order to provide the most suitable formulation of a proton pump blocker. Specifically, this means that a formulation is sought which has good chemical stability during storage, which prevents decomposition of the active ingredient in acid gastric juice, but at the same time releases the active ingredient as quickly as possible in an alkaline environment.

It was an object of the present invention to find a dosage form of proton pump blockers which is suitable for oral administration and which has good chemical stability when stored, which prevents decomposition of the active ingredient in acidic gastric juice and at the same time releases the active ingredient as quickly as possible in an alkaline environment .

Accordingly, solid preparations and a process for their preparation have been found in which the active substance is X-ray amorphous in the form of a molecularly disperse distribution in a polymer matrix.

In the preparations according to the invention, the acid-labile proton pump inhibitor is embedded in a molecular dispersion in a matrix consisting of one or more polymers. Suitable polymers are: gelatin such as bovine gelatin, pork gelatin or fish gelatin, starch, dextrin, pectin, gum arabic, lignin sulfonates, chitosan, polystyrene sulfonate, alginates, casein, caseinate, methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, milk powder or dextran milk, whole milk Mixtures of these protective colloids. Homo- and copolymers based on the following monomers are also suitable: ethylene oxide, propylene oxide, maleic anhydride, lactic acid, glycolic acid, oc- and β-aspartic acid, N-vinylpyrrolidone, vinyl acetate, in particular polyvinylpyrrolidone with K values according to Fikentscher from 12 to 100 and copolymers of N-vinylpyrrolidone and vinyl acetate such as VP / VAc-60/40. One of the gelatin types mentioned is particularly preferably used, in particular acidic or basic degraded gelatin with Bloom numbers in the range from 0 to 250, very particularly preferably gelatin A 100, A 200, B 100 and B 200 as well as low molecular weight, enzymatically degraded gelatin types the Bloom number 0 and molecular weights from 15000 to 25000 D such as Collagel A and Gelitasol P (from Stoess, Eberbach) and mixtures of these types of gelatin.

Gastric juice-resistant polymers based on the Eudragit ^® type are also suitable.

The preparations also contain low molecular weight surface-active compounds. As such, amphiphilic compounds or mixtures of such compounds are particularly suitable. Basically, all surfactants with an HLB value of 5 to 20 can be used. Examples of suitable surface-active substances are: esters of long-chain fatty acids with ascorbic acid, mono- and diglycerides of fatty acids and their oxyethylation products, esters of monofatty acid glycerides with acetic acid, citric acid, lactic acid or diacetyl tartaric acid, polyglycerol fatty acid esters such as e.g. the monostearate of triglycerol, sorbitan fatty acid ester, propylene glycol fatty acid ester, 2- (2 '-stearoyllactyl) lactic acid salts and lecithin. Ascorbyl palmitate is preferably used.

The amounts of the various components are chosen according to the invention so that the preparations 1 to 90% by weight, preferably 5 to 60% by weight, of active substance, 1 to 95% by weight, preferably 10 to 90% by weight , one or more polymers and 0 to 50 wt .-%, preferably 0 to 20 wt .-%, of one or more low molecular weight stabilizers. The percentages by weight relate to a dry powder. In addition, the preparations may also contain antioxidants and / or preservatives to protect the active ingredient. Suitable antioxidants or preservatives are, for example, α-tocopherol, t-butyl hydroxytoluene, t-butyl hydroxy anisole, lecithin, ethoxyquin, methyl paraben, propyl paraben, sorbic acid, sodium benzoate or ascorbyl palmitate. The antioxidants or preservatives can be present in amounts of 0 to 10% by weight, based on the total amount of the preparation.

10

The preparations may also contain plasticizers to increase the stability of the end product. Suitable plasticizers are, for example, sugar and sugar alcohols such as sucrose, glucose, lactose, invert sugar, sorbitol, mannitol, xylitol or glycerol. Lactose is preferably used as the plasticizer. The plasticizers can be contained in amounts of 0 to 50% by weight.

Other pharmaceutical auxiliaries such as binders, disintegrants, flavors, vitamins, colorings, wetting agents, additives influencing the pH value 20 (cf. H. Sucker et al., Pharmaceutical Technology, Thieme-Verlag, Stuttgart 1978) can also be obtained via the organic solvent or the aqueous phase are introduced.

25 To carry out the process according to the invention, a solution of the active substance, the polymer and, if appropriate, the further substances mentioned above is first prepared in a suitable solvent. The total solids content of the solution is between 0.5 and 40% by weight, particularly preferably between 1 and

30 20% by weight.

Suitable solvents are water, organic solvents and homogeneous mixtures of these components. Alcohols, esters, ketones 35 and acetals are preferably used for the organic solvents. In particular, methanol, ethanol, n-propanol, isopropanol or acetone are used.

When using water or aqueous solutions, the pH is adjusted to a value> 7 before the active ingredient is dissolved,

40 preferably between 8 and 10. The pH is adjusted with the aid of substances which have a pKa value of> 7. Metal hydroxides, metal carbonates, metal phosphates, metal acetates are preferably used. Sodium hydroxide, magnesium hydroxide, calcium hydroxide, ca

45 lium hydroxide, ammonium hydroxide, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium carbonate, calcium carbonate and magnesium carbonate.

The pH is preferably adjusted with ammonia water. The ammonium content of the finished dry powder is below the detection limit of ammonia (detection limit 0.1% by weight).

The solution thus prepared is transferred to a dry powder. This is e.g. possible with the help of a spraying process. The temperature at the spray head is between 70 and 130 ° C, preferably between 80 and 110 ° C.

The solution can also be converted into a dry powder using freeze drying or in a fluidized bed.

The solid omeprazole preparations according to the invention enable a faster release of active substance compared to a formulation in which the omeprazole is in crystalline form.

The solid preparations according to the invention show good chemical stability. This also applies to preparations that do not contain any detectable basic substances. Such good stability was not to be expected according to the prior art.

The solid preparations according to the invention can be produced from a liquid solution using a spray process. Temperatures occur in this process which normally lead to a degradation of the active substance. Surprisingly, such an active ingredient degradation does not occur here.

The dry powders obtained according to the invention can be filled into enteric-resistant, small intestine-soluble hard gelatin capsules or, in conventional formulations, pressed into tablets.

The preparations according to the invention can also be used for combination pharmaceutical forms, for example in combination with nonsteroidal anti-inflammatory analgesics, antibiotics such as erythromycin or clarithromycin, or with motility improvers. Examples

Production Example 1

Production of an omeprazole dry powder with an active ingredient content in the range of 30%

a) Preparation of the solution

4.8 g of gelatin A 100 are dissolved in 600 g of demineralized water at 70 ° C. with stirring. After cooling to room temperature, a further 120 g of acetone, 0.8 g of ascorbyl palmitate and 4 g of lactose are stirred into the solution. The solution is then adjusted to pH = 10 with 1 molar sodium hydroxide solution. Then 4 g of omeprazole are dissolved in the alkaline solution.

An amorphous dry powder with an omeprazole content (determined by chromatography) of 29.3% by weight was obtained by spray drying.

b) Wide-angle X-ray scattering

In Figure 1, the scatter curves of omeprazole (curve a) and dry powder (curve b) are shown according to la. The omeprazole starting material is crystalline, as evidenced by the X-ray diagram, which is distinguished by a series of sharp interferences. In contrast, the scatter curve of the dry powder shows only diffuse, broad interference maxima, which are typical for an amorphous material. The active ingredient is therefore present in the dry powder produced according to la, X-ray amorphous. This also applies to the otherwise crystalline auxiliaries lactose and ascorbyl palmitate.

c) High-resolution 13C solid-state NMR

FIG. 2 shows the high-resolution 13C solid-state NMR spectra of omeprazole (curve a) and of the dry powder (curve b) according to FIG. The pure active ingredient omeprazole shows sharp signals, as is typical for crystalline substances. In contrast, the 13C NMR spectrum of the dry powder shows strongly broadened active signals, as is typical for an amorphous material with a large number of realized conformations and random packings of the molecules. In addition to the purely spectroscopic measurements, so-called Tlrho (H) measurements with 13C detection were carried out. The exchange of spin energy between 1H cores ("spin diffusion") is used to say something about the spatial proximity of the individual components on a length scale of approx. 1 nm. Common relaxation behavior (= parallel line in the case of logarithmic plotting of the signal amplitudes vs. time) means that the structures in question are at an average distance of <1 nm, ie are molecularly mixed.

FIG. 3 shows the Tlrho (H) behavior of omeprazole (curve a) and the matrix (curve b) from preparation example la. The signal for the omeprazole comes from a signal of 126.4 ppm, which is typical for the omeprazole and is not covered by a signal from the matrix (cf. FIG. 2). The signal for the matrix originates from a signal of 172.7 ppm, which is typical for the matrix and is not covered by a signal of the omeprazole (cf. FIG. 2). It is easy to see that both lines are parallel. This course indicates the presence of a molecular mixture of active ingredient and matrix.

FIG. 3 shows the Tlrho (H) behavior of omeprazole (curve c) and the matrix (curve d) of a physical mixture of crystalline omeprazole and the same auxiliaries and the same composition as from preparation example la. The signal for the omeprazole comes from a signal of 125.3 ppm which is typical of the omeprazole and is not covered by a signal from the matrix (cf. FIG. 2).

The signal for the matrix originates from a signal of 175.7 ppm which is typical of the matrix and is not covered by a signal of the omeprazole (cf. FIG. 2). It can be clearly seen that in this case the straight lines have a different gradient. This course shows that the active ingredient and matrix are not in the form of a molecular mixture.

Preparation example 2

Preparation of the solution

0.8 g of ascorbyl palmitate and 8.8 g of Kollidon 17 PF are dissolved in a mixture of 600 g of water and 120 g of acetone at room temperature. Then with 1 molar sodium hydroxide solution Solution adjusted to pH = 10. Then 4 g of omeprazole are dissolved in the alkaline solution.

An amorphous dry powder with an omeprazole content (determined by chromatography) of 29.2% by weight was obtained by spray drying.

b) Wide-angle X-ray scattering

The scatter curves of omeprazole (curve a) and of the dry powder (curve c) according to FIG. 2a are shown in FIG. The omeprazole starting material is crystalline, as evidenced by the X-ray diagram, which is distinguished by a series of sharp interferences. In contrast, the scatter curve of the dry powder shows only diffuse, broad interference maxima, which are typical for an amorphous material. The active substance is therefore present in the dry powder produced according to 2a in an X-ray amorphous manner. This also applies to the otherwise crystalline auxiliary ascorbyl palmitate.

Preparation example 3

a) Preparation of the solution

18 g of Kollidon 17 PF are dissolved in 300 g of 25% ammoniacal solution at room temperature. Then 8 g of omeprazole are dissolved in this solution.

An amorphous dry powder with an omeprazole content (determined by chromatography) of 30.7% by weight was obtained by spray drying. The Aranσnium content in the sample was 140 ppm.

b) Wide-angle X-ray scattering

The scatter curves of omeprazole (curve a) and of the dry powder (curve d) according to FIG. 3a are shown in FIG. The omeprazole starting material is crystalline, as evidenced by the X-ray diagram, which is distinguished by a series of sharp interferences. In contrast, the scatter curve of the dry powder shows only diffuse, broad interference maxima, as are typical for an amorphous material. The active substance is therefore present in the dry powder produced according to 3a in an X-ray amorphous manner.

Preparation example 4

a) Preparation of the solution

4.8 g of fish gelatin with molecular weight fractions of 10 ³ to 10 ⁷ D are dissolved in 600 g of demineralized water at 70 ° C. with stirring. After cooling to room temperature, a further 120 g of acetone, 0.8 g of ascorbyl palmitate and 4 g of lactose are stirred into the solution with stirring. The pH is then adjusted to 9 with 25% ammoniacal solution. Then 4 g of omeprazole are dissolved in the alkaline solution.

An amorphous dry powder with an omeprazole content (determined chromatographically) of

29.5% by weight. The ammonium content in the sample was 120 ppm.

b) Wide-angle X-ray scattering

The scatter curves of omeprazole (curve a) and of the dry powder (curve e) according to FIG. 4a are shown in FIG. The omeprazole starting material is crystalline, as evidenced by the X-ray diagram, which is distinguished by a series of sharp interferences. In contrast, the scatter curve of the

Dry powder only diffuse, broad interference maxima, as are typical for an amorphous material. The active substance is therefore present in the dry powder produced according to 4a, X-ray amorphous. This also applies to the otherwise crystalline auxiliary substances lactose and ascorbyl palmitate.

Manufacture of enteric-coated capsules

70 mg spray embedding with omeprazole was carried out with 70 mg D-mannitol in a capsule size. 1 filled. The hard gelatin capsules filled in this way were coated gastro-resistant:

Coating recipe:

129.5 g Kollicoat MAE 30 DP (30%) 3.9 g PEG 6000 1.8 g PEG 400 9.1 g Talcum 114, 7 g demineralized water

The coating process was carried out in an Aeromatik Strea 1 with pelletizer insert using the following parameters:

Capsule quantity: 20 Dry temp: 30 ° C Atomizing pressure: 2 bar Blow-off pressure: 3.5 bar

Air volume: controller position 6 - 7 pump (Watson Marlow): position 5 - 9

56.9 mg of coating were applied per capsule.

Claims

claims

1. Solid preparation, containing an acid-labile proton pump blocker as the active substance, the active substance being X-ray amorphous and embedded in a molecular dispersion in an auxiliary substance matrix.

2. Preparation according to claim 1, containing as a matrix component a homo- or copolymer of N-vinylpyrrolidone.

3. Preparation according to claim 1, containing gelatin as matrix component.

4. Preparation according to one of claims 1 to 3, containing a low molecular weight surface-active compound.

5. Preparation according to claim 4, containing ascorbyl palmitate as the surface-active compound.

6. Preparation according to one of claims 1 to 5, containing an acid-labile benzimidazole as active substance.

7. Preparation according to claim 6, containing omeprazole as the active substance.

8. A process for the preparation of preparations according to any one of claims 1 to 7, characterized in that a solution of the active substance and the matrix material is prepared in water or an organic solvent and then the solvent is removed from this solution.

9. The method according to claim 8, characterized in that water is used as the solvent and the pH of the aqueous solutions is adjusted to values of> 7 with aqueous ammonia.

Sign. Solid pharmaceutical formulations of acid labile proton pump blockers

Summary

Solid preparation containing an acid-labile proton pump blocker as the active substance, the active substance being X-ray amorphous and embedded in a molecular disperse in an auxiliary matrix.