Oral input form based medications pantoprazole

 

(57) Abstract:

Usage: in the pharmaceutical industry, for oral administration of drugs on the basis of pantoprazole. The inventive oral input in form of granules or tablets made from the kernel, the water-soluble intermediate layer and the outer layer resistant to gastric juice. In the tablet core comprises a biologically active substance pantoprazole mixed with buffer inorganic compound of a basic nature, preferably with sodium carbonate as a binder is polyvinylpyrrolidone and/or hypromellose, as the filler is mannitol. The pellet contains pantoprazole and polyvinylpyrrolidone, and/or hydroxypropylmethylcellulose. 5 C.p. f-crystals.

The invention relates to oral forms of administration of medicinal products on the basis of pantoprazole.

In European patent application EP-A-244380 described oral introduction to cyclotouring biologically active substances from the class of H+/K+-ATPase-inhibitor with pyridylmethylamine-1H-benzimidazole-structure, which are the core, intermediate layer and is resistant to gastric juice outer layer. In European Pat what entiteled "Omeprazole".

In the forms of introduction, mentioned in the European patent applications EP-A-244 380 and EP-A-247 983, for cyclotouring biologically active substances stabilization is achieved, in particular as a result of additive bases to the nucleus and, thus, higher values of pH: to achieve sufficient stability during storage should be, however, as when receiving, and storing and complied with certain conditions that only with difficulty can be adjusted in accordance with the optimal Galanova composition and hassle-free storage of stock. Thus, in EP-A-247 983 says that for long-term stability during storage is essential that the water content in the form of an introduction, containing a biologically active substance omeprazole /resistant to gastric juice, coated tablets, capsules and granules); is kept low and is preferably not more than 1.5 wt. In accordance with this final packaging with beads coated with resistant to gastric juice sheath, packaged in capsules of hard gelatin with dehumidifiers that reduce the water content in the gelatin shells so that the water content of the pellets does not exceed 1.5 wt.major, contributes to mass, extrudable for the manufacture of cores of the granules was not enough plastic in order then this extrudate was possible to give the rounded shape of spherical particles. Moreover formed body has a cylindrical shape, which at later stages covering sheath at the ends get less thick layers of varnish and therefore these places do not have the required resistance towards gastric juice and, in addition, not reliably protects the core from resistant to gastric juice layer in the membrane, which is essential for stability.

These stability problems also appear in the case, if you try to prepare H+/K+-ATPase-inhibitor pantoprazole /Prop.INN for connecting 5-/deformedarse/-2//3,4-dimethoxy-2-pyridyl/methyl-sulfonyl/-1H-benzimidazole/ thus, as described in European patent applications EP-A-244 380 and EP-A-247 983.

Unexpectedly found that the refusal of certain fillers and binders are often used as auxiliary materials, how they are to obtain cores of the granules or tablets in the European patent application is the EU ETS are in particular lactose, microcrystalline cellulose and hydroxypropylcellulose.

The subject of this invention is, therefore, a drug that contains the active substance pantoprazole, oral input, resistant to gastric juice, in the form of granules or tablets, which consists of a core granules or tablets with the main reaction, one or more inert, water-soluble intermediate layer (intermediate layer) and is resistant to gastric juice of the outer layer and which is characterized by the fact that the kernel along with pantoprazole and/or along with the salt of pantoprazole as a binder contains polyvinylpyrrolidone and/or hypromellose and optionally additionally as an inert filler is mannitol.

For the main reaction, the nucleus of granules or tablets to him (if you do not achieve the desired increase in pH) in the application of salts of biologically active substances add inorganic base. It should be called, for example, pharmacologically compatible salts of alkali metals, salts of alkaline earth metal or earth metal salt of a weak acid and pharmacologically compatible hydroxide and oxide deliciosamente sodium.

Along with filler and binder in the manufacture of tablets with the kernel used more and other auxiliary materials, in particular substances which impart lubricity (tablets), and lubrication, as well as a means of breaking the tablets.

As substances which impart lubricity (tablets) and grease should be called, for example, calcium salts of higher fatty acid series, such as calcium stearate.

As a means for tearing tablets are considered especially chemically indifferent means. As the preferred means for tearing tablets should be called polyvinylpyrrolidone, forming a cross connection (for example, Crosspovidone).

Relative to the intermediate layer (s) are soluble in water, which is applied on the core granules or tablets, reference is made to such water-soluble layers as they are applied before applying resistant to gastric juice layers, or as they are described, for example, in the patent DE-01 05 39 151. As a film polymers used for the intermediate layer include, for example, hypromellose and/or polyvinylpyrrolidon, which, if desired, can be added plasticizers (as proprerly">

Any outer layers that are resistant to gastric juice, can be used, well-known specialist on the basis of his special knowledge. Mainly used to avoid organic solvents and because the proposed kernel has no sensitivity to water, known from the prior art) water dispersion of the respective polymers that are resistant to gastric juice, as, for example, copolymerized methacrylic acid (methyl ester of methacrylic acid copolymerized) optionally, adding a plasticizer (for example, tritylated).

Biologically active substance pantoprazole is known from European patent 166 287. As salts of pantoprazole should mention mentioned in the European patent 166 287 salt, for example, the preferred salt is the sodium salt.

The use of mannitol as the sole filler for tablets requires the use of an appropriate binder, which should give the core a sufficient hardness. When the polyvinylpyrrolidone used for the manufacture of cores as a binder, it is, in particular, about the product with higher mol.m. (about 300,000 to 400,000). As a preferred polyvinylpyrrolidone thought differs in comparison with the known from the prior art form of introduction to other H+/K+-ATPase-moderators with pyridylmethylamine-1H-benzimidazole-structure so that the water content beyond 1.5 wt. at the core of the tablet, does not change color (decomposition) of biologically active substances. Thus, the higher the residual moisture of the grains (for example, 5 to 8 wt.) also get a stable tablet.

Granules can be obtained by applying the preliminary isolation by sucrose-starter-granule and the subsequent application of the 30% isopropanolamide solution of biologically active substances with hydroxyethylmethylcellulose as binders.

Applying an insulating layer can be carried out analogously to the tablets using the respective dispersions (for example, Opadry). Coating resistant to gastric juice coating is similar to the method steps described for tablets.

Another object of the invention is a method of obtaining a proposed according to the invention medicines in the form of granules or tablets, which differs in that get proposed according to the invention the core, cover one or more intermediate, water-soluble job explain more in detail the invention, not limiting it.

I. Tablets

1. Tablet core consisting of the following substances, mg:

a) pantoprazole-Na-sesquihydrate 45,1

b) sodium carbonate 10,0

c) mannitol 42,7

d) crosspovidone 50,0

e) 90 PVP (Povidone) 4,0

f) calcium stearate 3,2 155,0

a) is mixed with part of the substances listed under (b), (c) and (d). The residue (b) and (c) served in a transparent aqueous solution specified under (e), and regulate to obtain a pH value of > 10. With this solution carry out granulation in the fluidized bed. In the dried granulate is added the remainder of (d) and (f), and the granulate is formed on an appropriate machine for the manufacture of tablets.

II. Preliminary isolation (intermediate layer), mg:

g) HPMC 2910, 3 cps 15,83

h) PVP 25 0,32

(i) titanium dioxide 0,28

j) LB iron oxide yellow 100E 172 0,025

k) propylene glycol 3,54 20,00

The total weight of the pre-insulated cores 175,00 mg

g) is dissolved in water and add substance specified under (h), and also dissolve /A/. i) and j) are suspended using a suitable stirrer in the water /In/. A and b are mixed. After adding k) the suspension is filtered immediately before further processing, in which obtained under p. I core tablets in soy to gastric juice, mg:

l) Eudragit-L30D 13,64

m) Triethylcitrate 1,36 15,00

The total weight for each film-coated tablet, resistant to gastric juice, 190,00 mg

l) diluted with water and add m). The dispersion is passed through a sieve before being processed.

On pre-insulated cores obtained under p. II, in the appropriate equipment to produce a coating of a substance specified in paragraph III.

2. Granules

1. Starter-granules, g:

a) sucrose pellets (0.7 to 0.85 mm) 950,0

b) hypromellose 50,0

a) are sprayed with an aqueous solution (b) in the fluidized bed (way of Wurster).

II. Active granules

c) pantoprazole-Na-sesquihydrate, g: 403,0

d) hypromellose 40,3

c) and d) are dissolved successively in 30% isopropanol and sprayed up to 900 g, obtained under p. I starter granules in the fluidized bed (way of Wurster).

III. Preliminary isolation (intermediate layer)

The coating carried out similarly to the method steps specified for tablets in the vessel (boiler) or in the fluidized bed.

IV. Coating resistant to gastric juice.

The coating carried out similarly to the method steps, OPV capsules of the appropriate size (for example, 1).

1. Oral input, resistant to gastric juice form of the medicinal product, which is an inhibitor of gastric juice, in the form of granules or tablets, consisting of a core comprising a biologically active substance from the class of benzimidazole derivatives in a mixture with one or more buffer inorganic compounds of basic character or a physiologically compatible salt of a derivative of benzimidazole, optionally in a mixture with the specified buffer compound, at least one binder and optionally a filler and other additives target, one or more inert water-soluble intermediate layer surrounding this core, and the outer layer resistant to gastric juice, characterized in that the core as biologically active substances from the class of derivatives of benzimidazole contains pantoprazole, as a binder, polyvinylpyrrolidone and/or hypromellose, if necessary, the filler is mannitol.

2. Form under item 1 in the form of tablets, wherein the core as the binder contains polyvinylpyrrolidone and/or hypromellose, as well as fill will win polyvinylpyrrolidone and/or hypromellose.

4. Form according to any one of paragraphs.1 to 3, characterized in that the core as the physiologically compatible salts of biologically active substances from the class of derivatives of benzimidazole contains pantoprazole sodium.

5. Form according to any one of paragraphs.1 to 4, characterized in that the core as a buffer inorganic compounds of basic character contains one or more compounds selected from the group comprising salts of sodium, potassium, calcium, magnesium, aluminum and weak acids, hydroxides of calcium, magnesium and aluminum, oxides of calcium and magnesium.

6. Form according to any one of paragraphs. 1 to 5, characterized in that the core as a buffer inorganic compounds the main character contains sodium carbonate.

 

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