Pharmaceutical composition for oral administration to animals, its preparation and method of treatment of diseases associated with the secretion of acid in the stomach

 

(57) Abstract:

The invention relates to the field of veterinary medicine. Proposed oral pharmaceutical composition comprising an inhibitor of the proton pump and a gelling agent intended for the treatment of diseases associated with the secretion of acid in the stomach of animals, the method of obtaining the specified compositions and method of treatment of diseases in animals. The obtained pharmaceutical composition is stable, easy to use. 3 S. and 9 C.p. f-crystals.

The invention relates to oral pharmaceutical composition comprising a proton pump inhibitor (PP1), and is intended for treatment of diseases in animals associated with the secretion of acid in the stomach.

Inhibitors of proton pumps are strong inhibitors of acid secretion in the stomach and is used for treatment of human diseases associated with acidity of gastric juice, such as stomach ulcers and duodenal ulcers. These compounds are susceptible to degradation/transformation in acid reactions and neutral environments. Pharmaceutical compositions for oral administration to man preferably cover intersolubility coating. The criminal code is working vessels.

A peptic ulcer is a common disease in some animals, especially horses and camels. Other animals affected by the disease peptic ulcer, are, for example, dolphins, sea lions, llamas, dogs, cats and pigs. When gastroendoscopic the examination of horses were found ulcers in the mucosa with squamous epithelium, in nageleisen day in the glandular stomach and in the duodenum. The etiology of gastric ulcers and duodenal ulcers in horses remains largely unclear, however, in some cases, their appearance play an important role, obviously, stress.

It is known that anti-ulcer compounds, such as antagonists receptionof histamine-2, introduced horses several times a day orally or via gastric probe is inserted through the nasal cavity. This procedure can have a traumatic effect and require a light sedative. For such a procedure requires trained personnel.

Omeprazole and other inhibitors of proton pumps are strong inhibitors of acid secretion in the stomach of the animal. They block the production of acid in the stomach by inhibitorsinhibitors proton pumps cause profound inhibition of acid, and unlike other anti-ulcer compounds, such as H2-blockers, omeprazole can be entered once a day. In accordance with the present invention granules with intersolubility coating containing omeprazole and made in the form of a gel composition can be easily introduced into the region of the backrest language of the horse in the field, and is very well accepted by horses.

This hydrated gel containing coating intersolubility coated granules inhibitors of the proton pump, is unstable during prolonged storage at room temperature and must be made immediately before use. Currently, these compositions on sale.

Omeprazole, 5-methoxy-2-(((4-methoxy-3,5-dimethyl-2-pyridinyl) methyl)sulfinil)-1H-benzimidazole described in the European patent N 5129 as a strong inhibitor of the secretion of acid in the stomach.

Lanzoprazol, 2-[[[3-methyl-4-(2,2,2-trichoroethane)-2 - pyridyl]-methyl]sulfinil] -1H-benzimidazole described in the European patent N 174726 as a strong inhibitor of the secretion of acid in the stomach.

Pantoprazole is disclosed in the European patent N 166287 as a strong inhibitor of the secretion of acid in the stomach.

Inhibitors of proton pumps used in the compositions of the present invention are compounds of General formula 1

< / BR>
where Rarepresents a

< / BR>
< / BR>
R1and R2independently selected from hydrogen, lower alkyl, lower anissa alkoxygroup, low poroelasticity and

< / BR>
R4and R5independently selected from lower alkyl;

A represents a

< / BR>
R6and R7independently selected from hydrogen, lower alkyl, lower alkoxygroup, low forelcosure, lower foralkyl, halogen,

< / BR>
where R8is lower alkyl or lower alkoxygroup.

The term "lower alkyl" in the present invention means an alkyl group having 1-5 carbon atoms.

The term "lower alkoxygroup" in the present invention means alkoxygroup having 1-5 carbon atoms.

Examples of inhibitors of the proton pump having the formula I are the following compounds

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
Inhibitors of proton pump included in the compositions of the present invention can be used in neutral form or in the form of a basic salt such as a salt of Mg2Ca2, Na+or K+preferably the salt of Mg2or Na+. In addition, if it is valid, then the above compounds may be used in racemic form or in the form of mostly pure enantiomer.

In one embodiment, assesstimestart, for example, such as a suitable inorganic or organic water-soluble salts of potassium, calcium, magnesium or aluminum. If this mixture is to add an aqueous solution of the respective polymer compound or compounds, such as Kappa-carrageen, pectin, anionic polymers, which are known to form gels with positively charged metal ions or similar compounds, due to the interaction of ions with polymers formed pasty gel.

In another embodiment, the present invention particles covered intersolubility the floor, mixed with the appropriate ingredients. Adding low-viscosity solution of heat-sensitive polymer, such as metilgidroxiatilzelllozu (EHEC) or polyethylenepolypropylene, or similar compounds, and heating the system to a temperature of 33-35oC or above, forms a viscous paste-like gel.

In yet another embodiment of the present invention, the particles coated with intersolubility the floor, mixed with the appropriate substances in the form of gelling agents, such as dry gelling agents. As gelling agents may be IP is Apicella, the hypromellose or other similar derivatives of cellulose; fucoidan; xanthan gum; furcellaran, laminaran or similar gelling agents.

In a preferred embodiment of the present invention the inhibitor of the proton pump is omeprazole.

The number of different components of the composition may vary depending on various factors, such as the individual needs of this animal.

The amount of gelling agent may be different, but mostly it is in the range of 0.02 to 20 wt.% based on the weight of the wet gel, preferably in the range of 0.2-20 wt.%, and more preferably 0.5 to 5 wt.%.

The amount of active substance, i.e. particles covered intersolubility coating depends on the individual doses for this animal. For example, for horses the number of particles covered intersolubility coating is usually in the range of 0.1 to 20 g, and preferably 0.2 to 10 g per dose. Full final volume of gel injected horses, is in the range 5-50 ml

Other suitable substances which can be introduced into the composition, are flavorings, usually hierosolymitanum coating particles of an inhibitor of the proton pump by mixing these substances with these particles using a mixture or an ordered mixture. An ordered mixture may be obtained, for example, by adhesion of particles or by coating particles.

The mixture is covered intersolubility coating particles of an inhibitor of the proton pump with matching components dry before and after mixing up the humidity level at which the inhibitor of the proton pump is stable over a long period of time. The resulting mixture was injected into a sealed applicator, preferably in the form of a syringe.

The mixture is covered intersolubility coating of granules or tablets inhibitor of proton pumps and other components may also contain a suitable pH buffering agent, which helps to increase functional stability of the composition during its passage through the esophagus and the stomach before it reaches the small intestine, i.e., where the inhibitor of the proton pump is dissolved and absorbed. Suitable buffer substances are citric acid, tartaric acid, succinic acid, malic acid, lactic acid, benzoic acid, sorbic acid and ascorbic acid, and other substances. These substances help to reduce pH of the resulting gel to below covered camping intersolubility coating particles of an inhibitor of the proton pump and related components may also contain inert particles, for example inert granules, to facilitate mixing of the various components with particles coated with intersolubility coating. Such inert granules are, for example, granules, coated with sugar, or any other pellets that do not have adverse effects on the animal.

Granules or tablets, coated intersolubility coating can be obtained by standard methods. Omeprazole granules with intersolubility coating can be obtained, as described, for example, in the United Kingdom patent 4 786 505 (=EP 247983). Omeprazole granules or spheres with intersolubility coating preferably covers at least two coatings, one of which is an insulating coating/sublayer, and the other intersolubility the floor.

Obtaining a stable pharmaceutical composition of the present invention is carried out by introducing into a paste-like gel inhibitor of the proton pump, made in the form of granules or tablets covered with one or more coatings, one of which is intersolubility floor.

In particular, a composition in the form of a pasty gel are carried out either by 1) mixing covered, asiausa coating particles, and then adding water directly before the introduction of the animal; or by 2) mixing the coated particles with a salt containing potassium or sodium ions, and optionally a pH-buffer system, and then immediately before entering the animal with a low-viscosity aqueous solution of a gelling agent such as a polymeric compound or composition; or by (III) mixing the coated particles immediately before the introduction of the animal with a low-viscosity solution of gelling agent in the form of a thermosensitive polymer, and optionally a pH-buffer system with subsequent slight warming of the mixture.

Examples. In the following examples omeprazole granules, coated intersolubility the floor, get in accordance with Example 2, US-A 4 786 505 (=EP 247983).

Example 1. Pellets of omeprazole, covered intersolubility coating (about 600 mg) omeprazole), 7 g, xanthan gum 0.3 g mixed in the syringe. After adding 10 ml of water is formed a viscous gel.

Example 2. Pellets of omeprazole, covered intersolubility coating, 7 g, xanthan gum 0.3 g citric acid 60 mg mixed in the syringe. Adding 10 ml of water is formed in mg mixed in the syringe. Adding 10 ml of 1% aqueous solution of Kappa-Cartagena formed a viscous gel.

Example 4. Pellets of omeprazole, covered intersolubility coating, 7 g, is introduced into the syringe. After adding 10 ml of a solution of EHEC (metilgidroxiatilzelllozu), 1,25%, and lauryl sulfate sodium, 0.1%, and heat up the 35oC forms a viscous gel.

Example 5. Granules lansoprazole covered intersolubility coating (obtained in accordance with Examples 1 and 2 EP 277741 introduced into the present description by reference), 10 g, xanthan gum 0.45 g, citric acid 80, adding 15 ml of water is formed a viscous gel.

Example 6. Granules pantoprazole covered intersolubility coating (obtained in accordance with Example 2 of EP 519 365 entered into the present description by reference) (pantoprazole 1200 mg), 7G, xanthan gum 0.3 g citric acid 50 mg. adding 10 ml of water is formed a viscous gel.

The best way to implement an already known of the invention provides for the use of the composition described in Example 2.

1. Pharmaceutical composition for oral administration to animals containing dry component particles of the active substance and a gelling agent is promoting agent, moreover, as the particles of the active substance, the composition comprises an inhibitor of the proton pump in the form of dry granules or tablets covered with one or more coatings, one of which is intersolubility floor, with dry and wet components are measured so as to form a paste-like gel.

2. The pharmaceutical composition under item 1, characterized in that it further contains a pH buffering agent and/or flavoring substances.

3. The pharmaceutical composition under item 1, characterized in that it further contains a water-soluble organic or inorganic salt of potassium, calcium, magnesium or aluminum.

4. The pharmaceutical composition according to any one of paragraphs.1 to 3, characterized in that as a proton pump inhibitor contains omeprazole.

5. The pharmaceutical composition according to any one of paragraphs.1 to 3, characterized in that as a proton pump inhibitor contains lansoprazole.

6. The pharmaceutical composition according to any one of paragraphs.1 to 3, characterized in that as a proton pump inhibitor contains pantoprazole.

7. The pharmaceutical composition according to any one of paragraphs.1 to 3, characterized in that as III for oral administration to animals, includes mixing the dry component particles of the active substance with gelling agents, characterized in that the particles of active substance used inhibitor of the proton pump, is made in the form of dry granules or tablets covered with one or more coatings, one of which is intersolubility floor, which is optionally mixed with the wet component is water or an aqueous solution gallforming agent, and dry or wet components correlate well to form a paste-like gel.

9. The method according to p. 8, characterized in that the inhibitor of the proton pump perform in the form of granules or tablets, which cover at least two coatings, one of which is a sublayer, and the other is intersolubility floor.

10. The method according to any of paragraphs.8, 9, characterized in that the covered intersolubility coating dry granules or tablets proton pump inhibitor, dry gelling agent or agents optionally mixed before adding water or an aqueous solution with a pH buffer substance and/or flavoring substances to obtain a dry mixture.

11. The method according to any of the th agent and the mixture is subjected to gentle heating.

12. A method of treatment of diseases associated with the secretion of acid in the stomach, including the introduction of the animal medicinal substance, characterized in that the animal as a medicinal substance is administered physiologically active amount of a composition according to any one of paragraphs.1 to 3.

 

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