CA2161683C - Veterinary composition containing a proton pump inhibitor - Google Patents
Veterinary composition containing a proton pump inhibitor Download PDFInfo
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- CA2161683C CA2161683C CA002161683A CA2161683A CA2161683C CA 2161683 C CA2161683 C CA 2161683C CA 002161683 A CA002161683 A CA 002161683A CA 2161683 A CA2161683 A CA 2161683A CA 2161683 C CA2161683 C CA 2161683C
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Abstract
A stable, oral pharmaceutical composition comprising a proton pump inhibitor and a gelling agent designed for the treatment of gastric acid related diseases in animals, the process for preparation of the composition and the use thereof.
Description
21fi168~
"'O 94/25070 PCT/SE94/00368 Veterinary composition containing a proton pump inhibitor.
Technical Field The invention relates to an oral pharmaceutical composition comprising a proton pump inhibitor (PPI) and is designed for the treatment of gastric acid related diseases in animals.
Background of the Invention Proton pump inhibitors are potent inhibitors of gastric acid secretion and are used for the treatment of gastric acid related diseases in humans, such as for instance gastric and duodenal ulcers. These substances are susceptible to degradation/transformation in acid reacting and neutral media. Pharmaceutical formulations for oral administration to humans are preferably enteric-coated.
These formulations are sensitive to moisture and must be stored in well-closed, tight containers during long-term storage.
Peptic ulcer diseases are common also in some animals, especially in horses and camels. Other animals of interest for treatment of peptic ulcer diseases are for example dolphins, sea-lions, llamas, dogs, cats and pigs. By gastro-endoscopic evaluation of horses, ulcers have been found in the squamous mucosa, the non glandular fundus, the glandular stomach and the duodenum. The aetiology of gastro-duodenal ulcers in the equine species is mainly unknown but stress appears to play an important role in some cases.
Anti-ulcer compounds such as for instance histamine-2-receptor antagonists have reportedly been administered several times a day to horses by oral or naso-gastric tubes. This procedure can be traumatic and may require light sedation of the horse. Trained persons are required for the administration.
WO 94/25070 216 ~. ~ ~ ~
Z
Omeprazole and other proton pump inhibitors are potent inhibitors of gastric acid secretion in animals. They block the production of gastric acid by inhibition of H+K+-ATPase, the enzyme responsible for the production of hydrogen ions in the parietal cells. The proton pump inhibitors cause profound acid suppression and unlike most other anti-ulcer compounds such as for instance the H2-blockers, omeprazole can be given once daily. According to the present invention enteric-coated beads containing omeprazole in a gel formulation can easily be applied onto the dorsal part of the tongue of the horse during field conditions and is well accepted by the horses.
Such a moist gel comprising enteric-coated beads of proton pump inhibitors is not stable during long-term storage at room temperature and must be prepared ex tempore. To-day there exist no such formulation on the market.
Omeprazole, 5-methoxy-2(((4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)sulfinyl)-1 H-benzimidazole, is disclosed in European patent no S 129 as a potent inhibitor of gastric acid secretion.
Lansoprazole, 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole, is disclosed in European patent no 174 726 as a potent inhibitor of gastric acid secretion.
Pantoprazole is disclosed in European patent no 166 287 as a potent inhibitor of gastric acid secretion.
Leminoprazole is disclosed in UK patent no 2 163 747.
2a Summary of the Invention In one aspect, the invention provides a pharmaceutical composition, for oral administration to an animal, comprising a proton pump inhibitor in the form of beads or tablets, wherein the beads or tablets are coated with one or more coatings and wherein at least one coating is an enteric-coating, wherein the proton pump inhibitor in the form of beads or tablets is incorporated into a paste-like gel, wherein the proton pump inhibitor has the general formula (I) N
A
Ra S O~~ (I) NH
wherein Ra is a group of the formula:
' N or O w N
N ~CH2R4 R5 wherein: R1 and R3 are independently selected from the group consisting of a hydrogen atom, a halogen atom, C1_Salkyl and C1_Salkoxy, R2 is selected from the group consisting of a hydrogen atom, C1-5alkyl, C1-5alkoxy, C1-Salkoxy-C1_Salkoxy, C1_Sfluoroalkoxy and O
and N
2b R4 and RS are independently C1_Salkyl; and A is a group of the formula /~ \
' ~ or S
R~ N \
wherein: R6 and R' are independently selected from the group consisting of a hydrogen atom, a halogen atom, C1_Salkyl, C1_Sfluoroalkyl, C1_Salkoxy, Cl_Sfluoroalkoxy, O N
and / -0 , C R
wherein R$ is C1_Salkyl or C1_Salkoxy. Preferably, the beads or tablets are coated with at least two coatings one of which is a subcoat and the other of which is an enteric-coating. The pharmaceutical composition may be adapted for oral administration to a horse. In one embodiment, the composition comprises a component which comprises dry enteric-coated beads or tablets as defined above, which component on addition of water or an aqueous solution gives a paste-like gel; and the component may further comprise a dry constituent. In a further embodiment, the composition may comprise a component which comprises dry enteric-coated beads or tablets as defined above, and further comprising a dry gelling agent, which component on the addition of water or an aqueous solution gives a paste-like gel; the component may further comprise a pH-buffering agent, a flavouring substance or a mixture thereof. The dry enteric-coated beads or tables and dry gelling agent may be mixed to form a dry mixture before the addition of water or the aqueous 2c solution; and the dry enteric-coated beads or tablets, the dry gelling agent, and the pH-buffering agent, the flavouring substance or a mixture thereof may be mixed to form a dry mixture before the addition of water or the aqueous solution. The mixture may be an ordered mixture.
In a further embodiment, the composition may comprise a first component which comprises dry enteric-coated beads or tablets as defined above, and further comprising a water soluble, organic or inorganic salt of potassium, calcium, magnesium or aluminium, and a second component which comprises an aqueous solution of a gelling agent, which first and second components when mixed give a paste-like gel; and the first component may further comprise a pH-buffering agent, a flavouring substance or a mixture thereof. In a further embodiment, the composition may comprise a first component which comprises dry enteric-coated beads or tables as defined above, and a second component which comprises an aqueous solution of a temperature sensitive gelling agent, which first and second components when mixed and subjected to gentle heating give a paste-like gel; and the first component may further comprise a dry pH-buffering agent, a flavouring substance or a mixture thereof. Preferably, the proton pump inhibitor is omerprazole, lansoprazole, pantoprazole or leminoprazole.
In a further aspect, the invention provides: a stable pharmaceutical composition, for oral administration to an animal, in the form of a kit of components comprising a first component comprising dry enteric-coated beads or tablets as defined above, and a second component comprising a dry constituent, which first and second components on addition of water or an aqueous solution give a paste-like gel; or a stable pharmaceutical composition, for oral administration to an animal, in the form of a kit comprising 2d a first component which comprises dry enteric-coated beads or tablets as defined above, and a water soluble, organic or inorganic salt of potassium, calcium, magnesium or aluminium, and a second component which comprises a dry gelling agent, which first and second components when mixed in the presence of water or an aqueous solution give a paste-like gel; and the first component may further comprise a pH-buffering agent, a flavouring substance or a mixture thereof. In this aspect, the invention also provides a stable pharmaceutical composition, for oral administration to an animal, in the form of a kit comprising a first component which comprises dry enteric-coated beads or tablets as defined above, and a second component which comprises a temperature sensitive gelling agent, which first and second components when mixed in the presence of water or an aqueous solution and subjected to gentle heating give a paste-like gel; and the first component may further comprise a dry pH-buffering agent, a flavouring substance or a mixture thereof.
Preferably, the composition in its entirety or parts thereof is dispensed into an applicator in the form of a syringe.
The invention also provides a process for preparing a pharmaceutical composition as defined above, which process comprises incorporating the proton pump inhibitor in the form of beads or tablets which are coated with one or more coatings one of which is an enteric-coating, into a paste-like gel.
The invention also provides use of a composition as defined above in the preparation of an active dosage form for the treatment of a gastric acid related disease in an 2e animal; or for the treatment of a gastric acid related disease in an animal.
The invention also provides a commercial package comprising a composition as defined above and associated therewith instructions for the use thereof in the treatment of a gastric acid related disease in an animal.
Detailed description of the Invention The present invention provides oral pharmaceutical compositions for easy administration to horses and other animals. The proton pump inhibitor is in the form of dry particles, such as beads or tablets, which are coated with one or more coatings one of Which is an enteric-coating.
The beads or tablets can be prepared by compaction, crystalisation, applying a solution or suspension of the proton pump inhibitor onto inert cores, extrusion and sPheronisation or similar processes. The enteric-coated beads or tablets are mixed with dry gelling agent(s), such as for instance xanthan gum, guar gum, locust bean gum, tragacanth, modified cellulose derivatives or similar gel forming compounds. When water is added to this mixture a paste-like gel is formed. The gel is for example applied dorsally at the tongue'of the animal such as a horse with a suitable applicator.
Proton pump inhibitors used in the compositions of the invention are compounds of the general formula I
N
A
-~NH
3a wherein R is a Rz Ra ' ~ CH2- or , .~~_ N
/ \Rs R1 and R3 are independently selected from hydrogen, lower alkyl, lower alkoxy WO 94/25070 PCTlSE94100368 and halogen, R2 is selected from hydrogen, lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy, lower fluoralkoxy and O
N
R4 and RS are independently selected from lower alkyl, A is s w / \
' ~ ~ or R~ N
R6 and R~ are independently selected from hydrogen, lower alkyl, lower alkoxy, lower fluoroalkoxy, lower fluoroalkyl, halogen, s C R ~ ~O
wherein Rg is lower alkyl or lower alkoxy.
Lower alkyl in the present invention means an alkyl group having 1-5 carbon atoms.
Lower alkoxy in the present invention means an alkoxy group having 1-5 carbon atoms.
v0 94/25070 ~~ ~j ~~ PCT/SE94I00368 Examples of proton pump inhibitors according to formula I are I
CH2 S-~NH / Omeprazole O ~N \
N CH IS ~ / Lanzoprazole NH
O
N CH II ~ \
S~ I /
NH Pantoprazole CH2' CH2 OCH3 C H2~
O \
C H2 S --~ I /
NH
\CH2 IS--lNH I /
- N Lerninoprazole i H2 CH
O
CH2 S ~NH
The proton pump inhibitors used in the compositions of the invention may be used in neutral form or in the form of a basic salt, such as for instance the Mg2+, Ca2+, Na+, or K+ salts, preferably the Mg2+ of Na+ salts. Further where applicable, a compound listed above may be used in racemic form or in the form of a substantially pure enantiomer.
In one embodiment of the invention the enteric-coated particles are mixed with suitable substances, such as for instance suitable inorganic or organic water soluble salts of potassium, calcium, magnesium or aluminium. When a water solution of a suitable polymeric compound or compounds, such as for instance kappa-carrageenan, pectin, anionic polymers known to give gels with positively charged metal ions, or similar compounds, is added to the mixture a paste-like gel is formed through the interaction of the ions with the polymers.
In another embodiment of the invention the enteric-coated particles are mixed with 'O 94~Li070 ~~ PCT/SE94/00368 suitable constituents. When a low-viscous solution of a temperature-sensitive polymer, such as for instance ethylhydroxyethylcellulose (EHEC) or polyethylenepolypropylene glycols or similar substances, is added and the system is warmed to temperatures of 33-35°C or higher a viscous paste-like gel is formed.
In still another embodiment of the invention the enteric-coated particles are mixed with suitable substances in the form of gelforming agents, such as dry gelling agent. As gelforming agents can be used for example acacia, agar, alginic acid, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose or other similar cellulose derivatives, fucoidan, xanthan gum, furcellaran, laminaran or similar gelforming agents.
In a preferred embodiment of the invention the proton pump inhibitor is omeprazole.
The amount of the different components of the composition can vary and will depend on various factors such as for example the individual requirement of the animal treated.
The amount of gelforming agent can vary but is within the range 0.02-20% by weight calculated on the amount of wet gel, preferably in the range of 0.2-20%
and especially 0.5-5% by weight.
The amount of active substance, i.e. the enteric-coated particles, depends on the individual dosages for the animal. For example the amount of enteric-coated particles is usually in the range of 0.1-20 grams, preferably 0.2-10 grams per dosage for horses. The total volume of the final gel given to horses is in the range of 5-50 ml.
Other suitable substances which may be incorporated in the composition are flavouring substances known in the pharmaceutical field.
'lbe suitable substances may be added to the enteric-coated proton pump inhibitor particles by mixing the different substances with the enteric-coated particles to a mixture or an ordered mixture. An ordered mixture may be produced for example by particle adhesion or coating processes.
'The mixtures of enteric-coated proton pump inhibitor particles and the suitable constituents are dried before or after mixing to a moisture level where the proton pump inhibitor has a good long-term stability. The mixture is preferably dispensed into a tight applicator preferably in the form of a syringe.
The mixture of the enteric-coated proton pump inhibitor beads or tablets and other constituents can also comprise a suitable pH-buffering substance which will improve the functional stability of the formulation during its transport through the oesophagus and stomach before it reaches the small intestine where the proton pump inhibitor is dissolved and absorbed. Suitable buffering substances are citric acid, tartaric acid, succinic acid, malic acid, lactic acid, benzoic acid, sorbic acid and ascorbic acid and other substances. Such substances will decrease the pH-value of the gel produced to a value below 5.5, thus protecting the enteric coating of the beads or tablets.
Further the mixture of the enteric coated proton pump inhibitor particles and suitable constituents may also comprise inert particles, such as inert beads to facilitate the mixing of the different constituents with the enteric-coated particles.
Such inert beads are for example beads of coated suger or any other kind of beads not harmful to the animal.
Enteric coated beads or tablets can be prepared by conventional methods.
Enteric-coated pellets of omeprazole can for instance be prepared as described in the US
Patent No. 4,786,505 (=EP 247983), Such enteric coated pelleu or beads of omeprazole are preferably coated with at least two coatings one of which is an isolation coating/subcoat and the other is an enteric coating.
'11~e preparation of a stable pharmaceutical composition according to the invention is performed by incorporating a proton pump inhibitor in the form of beads or tablets, which are coated with one ore more coatings one of which is an enteric-ooating, into a paste-like gel.
More particular, the preparation of a formulation in the form of a paste-like gel is performed by either n mixing the coated particles of the proton pump inhibitor with a dry gelling agent and optionally a pH-buffering system protecting the coated particles whereafter water is added ex tempore, just prior to administration 1C to the animal, or II) mixing the coated particles with a potassium or calcium ion containing salt and optionally a pH-buffering system and thereafter ex tempore, just prior to administration to the animal, with a low-viscous water solution of a gelling agent such as a polymer compound or compounds or by III) mixing the coated particles ex tempore, just prior to administration to the animal, with a low-viscous solution of a gelling agent in the form of temperature-sensitive polymer and optionally with a pH-buffering system and then subjecting the mixture to gentle heating.
Examples The omeprazole enteric-coated pellets in the examples below arc prepared according to example 2 of US-A 4,786,505 (=EP 247983).
Example 1 Omeprazole enteric-coated pellets 7 g (corresponding to about 600 mg of omepraiole) Xanthan gum 0.3 g are mixed in a syringe.
When 10 ml of water are added a viscous gel is formed.
Example 2 Omeprazole enteric-coated pellets 7 g Xanthan gum 0.3 g Citric acid 60 mg 5 are mixed in a syringe.
When 10 ml of water are added a viscous gel is formed.
Exam le Omeprazole enteric-coated pellets 7 g 10 Potassium chloride ' 30 mg are mixed in a syringe.
When 10 ml of a l~k solution of kappa-carrageenan arc added a viscous gel is fornxd.
Examvle 4 Omeprazole enteric-coated pellets _ 7 g are dispensed into a syringe.
When 10 ml of a solution of EHEC (ethylhydroxyechylcellulose) 1.2596 and sodium lauryl sulphate O.l~c are added and warmed to 35°C a viscous gel is formed.
Examflle 5 Lansoprazole enteric-coated pellets 10 g (prepared according to examples l and 2 of EP 277 741, oorTesponding to lansoprazole --900 mg) Xanthan gum 0.45 g Citric acid 80 mg When 15 ml of water are added a viscous gel is formed.
Example 6 Pantoprazole enteric-coated pellets 7 g (prepared according to example 2 of EP 519 365, corresponding to pantoprazole --1200 mg) Xanthan gum 0.3 g Citric acid 50 mg When 10 ml of water are added a viscous gel is formed.
The best mode of carrying out tt ~ invention known at present is to use the composition described in Example 2.
"'O 94/25070 PCT/SE94/00368 Veterinary composition containing a proton pump inhibitor.
Technical Field The invention relates to an oral pharmaceutical composition comprising a proton pump inhibitor (PPI) and is designed for the treatment of gastric acid related diseases in animals.
Background of the Invention Proton pump inhibitors are potent inhibitors of gastric acid secretion and are used for the treatment of gastric acid related diseases in humans, such as for instance gastric and duodenal ulcers. These substances are susceptible to degradation/transformation in acid reacting and neutral media. Pharmaceutical formulations for oral administration to humans are preferably enteric-coated.
These formulations are sensitive to moisture and must be stored in well-closed, tight containers during long-term storage.
Peptic ulcer diseases are common also in some animals, especially in horses and camels. Other animals of interest for treatment of peptic ulcer diseases are for example dolphins, sea-lions, llamas, dogs, cats and pigs. By gastro-endoscopic evaluation of horses, ulcers have been found in the squamous mucosa, the non glandular fundus, the glandular stomach and the duodenum. The aetiology of gastro-duodenal ulcers in the equine species is mainly unknown but stress appears to play an important role in some cases.
Anti-ulcer compounds such as for instance histamine-2-receptor antagonists have reportedly been administered several times a day to horses by oral or naso-gastric tubes. This procedure can be traumatic and may require light sedation of the horse. Trained persons are required for the administration.
WO 94/25070 216 ~. ~ ~ ~
Z
Omeprazole and other proton pump inhibitors are potent inhibitors of gastric acid secretion in animals. They block the production of gastric acid by inhibition of H+K+-ATPase, the enzyme responsible for the production of hydrogen ions in the parietal cells. The proton pump inhibitors cause profound acid suppression and unlike most other anti-ulcer compounds such as for instance the H2-blockers, omeprazole can be given once daily. According to the present invention enteric-coated beads containing omeprazole in a gel formulation can easily be applied onto the dorsal part of the tongue of the horse during field conditions and is well accepted by the horses.
Such a moist gel comprising enteric-coated beads of proton pump inhibitors is not stable during long-term storage at room temperature and must be prepared ex tempore. To-day there exist no such formulation on the market.
Omeprazole, 5-methoxy-2(((4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)sulfinyl)-1 H-benzimidazole, is disclosed in European patent no S 129 as a potent inhibitor of gastric acid secretion.
Lansoprazole, 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole, is disclosed in European patent no 174 726 as a potent inhibitor of gastric acid secretion.
Pantoprazole is disclosed in European patent no 166 287 as a potent inhibitor of gastric acid secretion.
Leminoprazole is disclosed in UK patent no 2 163 747.
2a Summary of the Invention In one aspect, the invention provides a pharmaceutical composition, for oral administration to an animal, comprising a proton pump inhibitor in the form of beads or tablets, wherein the beads or tablets are coated with one or more coatings and wherein at least one coating is an enteric-coating, wherein the proton pump inhibitor in the form of beads or tablets is incorporated into a paste-like gel, wherein the proton pump inhibitor has the general formula (I) N
A
Ra S O~~ (I) NH
wherein Ra is a group of the formula:
' N or O w N
N ~CH2R4 R5 wherein: R1 and R3 are independently selected from the group consisting of a hydrogen atom, a halogen atom, C1_Salkyl and C1_Salkoxy, R2 is selected from the group consisting of a hydrogen atom, C1-5alkyl, C1-5alkoxy, C1-Salkoxy-C1_Salkoxy, C1_Sfluoroalkoxy and O
and N
2b R4 and RS are independently C1_Salkyl; and A is a group of the formula /~ \
' ~ or S
R~ N \
wherein: R6 and R' are independently selected from the group consisting of a hydrogen atom, a halogen atom, C1_Salkyl, C1_Sfluoroalkyl, C1_Salkoxy, Cl_Sfluoroalkoxy, O N
and / -0 , C R
wherein R$ is C1_Salkyl or C1_Salkoxy. Preferably, the beads or tablets are coated with at least two coatings one of which is a subcoat and the other of which is an enteric-coating. The pharmaceutical composition may be adapted for oral administration to a horse. In one embodiment, the composition comprises a component which comprises dry enteric-coated beads or tablets as defined above, which component on addition of water or an aqueous solution gives a paste-like gel; and the component may further comprise a dry constituent. In a further embodiment, the composition may comprise a component which comprises dry enteric-coated beads or tablets as defined above, and further comprising a dry gelling agent, which component on the addition of water or an aqueous solution gives a paste-like gel; the component may further comprise a pH-buffering agent, a flavouring substance or a mixture thereof. The dry enteric-coated beads or tables and dry gelling agent may be mixed to form a dry mixture before the addition of water or the aqueous 2c solution; and the dry enteric-coated beads or tablets, the dry gelling agent, and the pH-buffering agent, the flavouring substance or a mixture thereof may be mixed to form a dry mixture before the addition of water or the aqueous solution. The mixture may be an ordered mixture.
In a further embodiment, the composition may comprise a first component which comprises dry enteric-coated beads or tablets as defined above, and further comprising a water soluble, organic or inorganic salt of potassium, calcium, magnesium or aluminium, and a second component which comprises an aqueous solution of a gelling agent, which first and second components when mixed give a paste-like gel; and the first component may further comprise a pH-buffering agent, a flavouring substance or a mixture thereof. In a further embodiment, the composition may comprise a first component which comprises dry enteric-coated beads or tables as defined above, and a second component which comprises an aqueous solution of a temperature sensitive gelling agent, which first and second components when mixed and subjected to gentle heating give a paste-like gel; and the first component may further comprise a dry pH-buffering agent, a flavouring substance or a mixture thereof. Preferably, the proton pump inhibitor is omerprazole, lansoprazole, pantoprazole or leminoprazole.
In a further aspect, the invention provides: a stable pharmaceutical composition, for oral administration to an animal, in the form of a kit of components comprising a first component comprising dry enteric-coated beads or tablets as defined above, and a second component comprising a dry constituent, which first and second components on addition of water or an aqueous solution give a paste-like gel; or a stable pharmaceutical composition, for oral administration to an animal, in the form of a kit comprising 2d a first component which comprises dry enteric-coated beads or tablets as defined above, and a water soluble, organic or inorganic salt of potassium, calcium, magnesium or aluminium, and a second component which comprises a dry gelling agent, which first and second components when mixed in the presence of water or an aqueous solution give a paste-like gel; and the first component may further comprise a pH-buffering agent, a flavouring substance or a mixture thereof. In this aspect, the invention also provides a stable pharmaceutical composition, for oral administration to an animal, in the form of a kit comprising a first component which comprises dry enteric-coated beads or tablets as defined above, and a second component which comprises a temperature sensitive gelling agent, which first and second components when mixed in the presence of water or an aqueous solution and subjected to gentle heating give a paste-like gel; and the first component may further comprise a dry pH-buffering agent, a flavouring substance or a mixture thereof.
Preferably, the composition in its entirety or parts thereof is dispensed into an applicator in the form of a syringe.
The invention also provides a process for preparing a pharmaceutical composition as defined above, which process comprises incorporating the proton pump inhibitor in the form of beads or tablets which are coated with one or more coatings one of which is an enteric-coating, into a paste-like gel.
The invention also provides use of a composition as defined above in the preparation of an active dosage form for the treatment of a gastric acid related disease in an 2e animal; or for the treatment of a gastric acid related disease in an animal.
The invention also provides a commercial package comprising a composition as defined above and associated therewith instructions for the use thereof in the treatment of a gastric acid related disease in an animal.
Detailed description of the Invention The present invention provides oral pharmaceutical compositions for easy administration to horses and other animals. The proton pump inhibitor is in the form of dry particles, such as beads or tablets, which are coated with one or more coatings one of Which is an enteric-coating.
The beads or tablets can be prepared by compaction, crystalisation, applying a solution or suspension of the proton pump inhibitor onto inert cores, extrusion and sPheronisation or similar processes. The enteric-coated beads or tablets are mixed with dry gelling agent(s), such as for instance xanthan gum, guar gum, locust bean gum, tragacanth, modified cellulose derivatives or similar gel forming compounds. When water is added to this mixture a paste-like gel is formed. The gel is for example applied dorsally at the tongue'of the animal such as a horse with a suitable applicator.
Proton pump inhibitors used in the compositions of the invention are compounds of the general formula I
N
A
-~NH
3a wherein R is a Rz Ra ' ~ CH2- or , .~~_ N
/ \Rs R1 and R3 are independently selected from hydrogen, lower alkyl, lower alkoxy WO 94/25070 PCTlSE94100368 and halogen, R2 is selected from hydrogen, lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy, lower fluoralkoxy and O
N
R4 and RS are independently selected from lower alkyl, A is s w / \
' ~ ~ or R~ N
R6 and R~ are independently selected from hydrogen, lower alkyl, lower alkoxy, lower fluoroalkoxy, lower fluoroalkyl, halogen, s C R ~ ~O
wherein Rg is lower alkyl or lower alkoxy.
Lower alkyl in the present invention means an alkyl group having 1-5 carbon atoms.
Lower alkoxy in the present invention means an alkoxy group having 1-5 carbon atoms.
v0 94/25070 ~~ ~j ~~ PCT/SE94I00368 Examples of proton pump inhibitors according to formula I are I
CH2 S-~NH / Omeprazole O ~N \
N CH IS ~ / Lanzoprazole NH
O
N CH II ~ \
S~ I /
NH Pantoprazole CH2' CH2 OCH3 C H2~
O \
C H2 S --~ I /
NH
\CH2 IS--lNH I /
- N Lerninoprazole i H2 CH
O
CH2 S ~NH
The proton pump inhibitors used in the compositions of the invention may be used in neutral form or in the form of a basic salt, such as for instance the Mg2+, Ca2+, Na+, or K+ salts, preferably the Mg2+ of Na+ salts. Further where applicable, a compound listed above may be used in racemic form or in the form of a substantially pure enantiomer.
In one embodiment of the invention the enteric-coated particles are mixed with suitable substances, such as for instance suitable inorganic or organic water soluble salts of potassium, calcium, magnesium or aluminium. When a water solution of a suitable polymeric compound or compounds, such as for instance kappa-carrageenan, pectin, anionic polymers known to give gels with positively charged metal ions, or similar compounds, is added to the mixture a paste-like gel is formed through the interaction of the ions with the polymers.
In another embodiment of the invention the enteric-coated particles are mixed with 'O 94~Li070 ~~ PCT/SE94/00368 suitable constituents. When a low-viscous solution of a temperature-sensitive polymer, such as for instance ethylhydroxyethylcellulose (EHEC) or polyethylenepolypropylene glycols or similar substances, is added and the system is warmed to temperatures of 33-35°C or higher a viscous paste-like gel is formed.
In still another embodiment of the invention the enteric-coated particles are mixed with suitable substances in the form of gelforming agents, such as dry gelling agent. As gelforming agents can be used for example acacia, agar, alginic acid, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose or other similar cellulose derivatives, fucoidan, xanthan gum, furcellaran, laminaran or similar gelforming agents.
In a preferred embodiment of the invention the proton pump inhibitor is omeprazole.
The amount of the different components of the composition can vary and will depend on various factors such as for example the individual requirement of the animal treated.
The amount of gelforming agent can vary but is within the range 0.02-20% by weight calculated on the amount of wet gel, preferably in the range of 0.2-20%
and especially 0.5-5% by weight.
The amount of active substance, i.e. the enteric-coated particles, depends on the individual dosages for the animal. For example the amount of enteric-coated particles is usually in the range of 0.1-20 grams, preferably 0.2-10 grams per dosage for horses. The total volume of the final gel given to horses is in the range of 5-50 ml.
Other suitable substances which may be incorporated in the composition are flavouring substances known in the pharmaceutical field.
'lbe suitable substances may be added to the enteric-coated proton pump inhibitor particles by mixing the different substances with the enteric-coated particles to a mixture or an ordered mixture. An ordered mixture may be produced for example by particle adhesion or coating processes.
'The mixtures of enteric-coated proton pump inhibitor particles and the suitable constituents are dried before or after mixing to a moisture level where the proton pump inhibitor has a good long-term stability. The mixture is preferably dispensed into a tight applicator preferably in the form of a syringe.
The mixture of the enteric-coated proton pump inhibitor beads or tablets and other constituents can also comprise a suitable pH-buffering substance which will improve the functional stability of the formulation during its transport through the oesophagus and stomach before it reaches the small intestine where the proton pump inhibitor is dissolved and absorbed. Suitable buffering substances are citric acid, tartaric acid, succinic acid, malic acid, lactic acid, benzoic acid, sorbic acid and ascorbic acid and other substances. Such substances will decrease the pH-value of the gel produced to a value below 5.5, thus protecting the enteric coating of the beads or tablets.
Further the mixture of the enteric coated proton pump inhibitor particles and suitable constituents may also comprise inert particles, such as inert beads to facilitate the mixing of the different constituents with the enteric-coated particles.
Such inert beads are for example beads of coated suger or any other kind of beads not harmful to the animal.
Enteric coated beads or tablets can be prepared by conventional methods.
Enteric-coated pellets of omeprazole can for instance be prepared as described in the US
Patent No. 4,786,505 (=EP 247983), Such enteric coated pelleu or beads of omeprazole are preferably coated with at least two coatings one of which is an isolation coating/subcoat and the other is an enteric coating.
'11~e preparation of a stable pharmaceutical composition according to the invention is performed by incorporating a proton pump inhibitor in the form of beads or tablets, which are coated with one ore more coatings one of which is an enteric-ooating, into a paste-like gel.
More particular, the preparation of a formulation in the form of a paste-like gel is performed by either n mixing the coated particles of the proton pump inhibitor with a dry gelling agent and optionally a pH-buffering system protecting the coated particles whereafter water is added ex tempore, just prior to administration 1C to the animal, or II) mixing the coated particles with a potassium or calcium ion containing salt and optionally a pH-buffering system and thereafter ex tempore, just prior to administration to the animal, with a low-viscous water solution of a gelling agent such as a polymer compound or compounds or by III) mixing the coated particles ex tempore, just prior to administration to the animal, with a low-viscous solution of a gelling agent in the form of temperature-sensitive polymer and optionally with a pH-buffering system and then subjecting the mixture to gentle heating.
Examples The omeprazole enteric-coated pellets in the examples below arc prepared according to example 2 of US-A 4,786,505 (=EP 247983).
Example 1 Omeprazole enteric-coated pellets 7 g (corresponding to about 600 mg of omepraiole) Xanthan gum 0.3 g are mixed in a syringe.
When 10 ml of water are added a viscous gel is formed.
Example 2 Omeprazole enteric-coated pellets 7 g Xanthan gum 0.3 g Citric acid 60 mg 5 are mixed in a syringe.
When 10 ml of water are added a viscous gel is formed.
Exam le Omeprazole enteric-coated pellets 7 g 10 Potassium chloride ' 30 mg are mixed in a syringe.
When 10 ml of a l~k solution of kappa-carrageenan arc added a viscous gel is fornxd.
Examvle 4 Omeprazole enteric-coated pellets _ 7 g are dispensed into a syringe.
When 10 ml of a solution of EHEC (ethylhydroxyechylcellulose) 1.2596 and sodium lauryl sulphate O.l~c are added and warmed to 35°C a viscous gel is formed.
Examflle 5 Lansoprazole enteric-coated pellets 10 g (prepared according to examples l and 2 of EP 277 741, oorTesponding to lansoprazole --900 mg) Xanthan gum 0.45 g Citric acid 80 mg When 15 ml of water are added a viscous gel is formed.
Example 6 Pantoprazole enteric-coated pellets 7 g (prepared according to example 2 of EP 519 365, corresponding to pantoprazole --1200 mg) Xanthan gum 0.3 g Citric acid 50 mg When 10 ml of water are added a viscous gel is formed.
The best mode of carrying out tt ~ invention known at present is to use the composition described in Example 2.
Claims (29)
1. A pharmaceutical composition, for oral administration to an animal, comprising a proton pump inhibitor in the form of beads or tablets, wherein the beads or tablets are coated with one or more coatings and wherein at least one coating is an enteric-coating, wherein the proton pump inhibitor in the form of beads or tablets is incorporated into a paste-like gel, wherein the proton pump inhibitor has the general formula (I):
wherein R a is a group of the formula:
wherein:
R1 and R3 are independently selected from the group consisting of a hydrogen atom, a halogen atom, C1-5alkyl and C1-5alkoxy, R2 is selected from the group consisting of a hydrogen atom, C1-5alkyl, C1-5alkoxy, C1-5alkoxy-C1-5alkoxy, C1-5fluoroalkoxy and R4 and R5 are independently C1-5alkyl; and A is a group of the formula:
wherein:
R6 and R7 are independently selected from the group consisting of a hydrogen atom, a halogen atom, C1-5alkyl, C1-5fluoroalkyl, C1-5alkoxy, C1-5fluoroalkoxy, wherein R8 is C1-5alkyl or C1-5alkoxy.
wherein R a is a group of the formula:
wherein:
R1 and R3 are independently selected from the group consisting of a hydrogen atom, a halogen atom, C1-5alkyl and C1-5alkoxy, R2 is selected from the group consisting of a hydrogen atom, C1-5alkyl, C1-5alkoxy, C1-5alkoxy-C1-5alkoxy, C1-5fluoroalkoxy and R4 and R5 are independently C1-5alkyl; and A is a group of the formula:
wherein:
R6 and R7 are independently selected from the group consisting of a hydrogen atom, a halogen atom, C1-5alkyl, C1-5fluoroalkyl, C1-5alkoxy, C1-5fluoroalkoxy, wherein R8 is C1-5alkyl or C1-5alkoxy.
2. A pharmaceutical composition according to claim 1, wherein the proton pump inhibitor is:
3. A pharmaceutical composition according to claim 1 or 2, wherein the beads or tablets are coated with at least two coatings one of which is a subcoat and the other of which is an enteric-coating.
4. A pharmaceutical composition according to claim 1, 2 or 3, wherein the pharmaceutical composition is adapted for oral administration to a horse.
5. A pharmaceutical composition according to any one of claims 1 to 3, wherein the composition comprises a component which comprises dry enteric-coated beads or tablets as defined in any one of claims 1 to 3, which component on addition of water or an aqueous solution gives a paste-like gel.
6. A pharmaceutical composition according to claim 5, wherein the component further comprises a dry constituent.
7. A pharmaceutical composition according to any one of claims 1 to 3, comprising a component which comprises dry enteric-coated beads or tablets as defined in any one of claims 1 to 3, and further comprising a dry gelling agent, which component on the addition of water or an aqueous solution gives a paste-like gel.
8. A pharmaceutical composition according to claim 7, wherein the component further comprises a pH-buffering agent, a flavouring substance or a mixture thereof.
9. A pharmaceutical composition according to claim 7 wherein the dry enteric-coated beads or tables and dry gelling agent are mixed to form a dry mixture before the addition of water or the aqueous solution.
10. A pharmaceutical composition according to claim 8, wherein the dry enteric-coated beads or tablets, the dry gelling agent, and the pH-buffering agent, the flavouring substance or a mixture thereof are mixed to form a dry mixture before the addition of water or the aqueous solution.
11. A pharmaceutical composition according to claim 9 or 10, wherein the mixture is an ordered mixture.
12. A pharmaceutical composition according to any one of claims 1 to 3, comprising a first component which comprises dry enteric-coated beads or tablets as defined in any one of claims 1 to 3, and further comprising a water soluble, organic or inorganic salt of potassium, calcium, magnesium or aluminium, and a second component which comprises an aqueous solution of a gelling agent, which first and second components when mixed give a paste-like gel.
13. A pharmaceutical composition according to claim 12, wherein the first component further comprises a pH-buffering agent, a flavouring substance or a mixture thereof.
14. A pharmaceutical composition according to any one of claims 1 to 3, comprising a first component which comprises dry enteric-coated beads or tables as defined in any one of claims 1 to 3, and a second component which comprises an aqueous solution of a temperature sensitive gelling agent, which first and second components when mixed and subjected to gentle heating give a paste-like gel.
15. A pharmaceutical composition according to claim 14, wherein the first component further comprises a dry pH-buffering agent, a flavouring substance or a mixture thereof.
16. A pharmaceutical composition according to any one of claims 1 to 15, wherein the proton pump inhibitor is omerprazole.
17. A pharmaceutical composition according to any one of claims 1 to 15, wherein the proton pump inhibitor is lansoprazole.
18. A pharmaceutical composition according to any one of claims 1 to 15, wherein the proton pump inhibitor is pantoprazole.
19. A pharmaceutical composition according to any one of claims 1 to 15, wherein the proton pump inhibitor is leminoprazole.
20. A stable pharmaceutical composition, for oral administration to an animal, in the form of a kit of components comprising a first component comprising dry enteric-coated beads or tablets as defined in any one of claims 1 to 3, and a second component comprising a dry constituent, which first and second components on addition of water or an aqueous solution give a paste-like gel.
21. A stable pharmaceutical composition, for oral administration to an animal, in the form of a kit comprising a first component which comprises dry enteric-coated beads or tablets as defined in any one of claims 1 to 3, and a water soluble, organic or inorganic salt of potassium, calcium, magnesium or aluminium, and a second component which comprises a dry gelling agent, which first and second components when mixed in the presence of water or an aqueous solution give a paste-like gel.
22. A pharmaceutical composition according to claim 21, wherein the first component further comprises a pH-buffering agent, a flavouring substance or a mixture thereof.
23. A stable pharmaceutical composition, for oral administration to an animal, in the form of a kit comprising a first component which comprises dry enteric-coated beads or tablets as defined in any one of claims 1 to 3, and a second component which comprises a temperature sensitive gelling agent, which first and second components when mixed in the presence of water or an aqueous solution and subjected to gentle heating give a paste-like gel.
24. A pharmaceutical composition according to claim 23, wherein the first component further comprises a dry pH-buffering agent, a flavouring substance or a mixture thereof.
25. A pharmaceutical composition according to any one of claims 1 to 24, wherein the composition in its entirety or parts thereof is dispensed into an applicator in the form of a syringe.
26. A process for preparing a pharmaceutical composition according to any one of claims 1 to 3, which process comprises incorporating the proton pump inhibitor in the form of beads or tablets which are coated with one or more coatings one of which is an enteric-coating, into a paste-like gel.
27. Use of a composition according to any one of claims 1 to 25 in the preparation of an active dosage form for the treatment of a gastric acid related disease in an animal.
28. Use of a composition according to any one of claims 1 to 25 for the treatment of a gastric acid related disease in an animal.
29. A commercial package comprising a composition according to any one of claims 1 to 25, and associated therewith instructions for the use thereof in the treatment of a gastric acid related disease in an animal.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE19939301489A SE9301489D0 (en) | 1993-04-30 | 1993-04-30 | VETERINARY COMPOSITION |
| SE9301489-2 | 1993-04-30 | ||
| PCT/SE1994/000368 WO1994025070A1 (en) | 1993-04-30 | 1994-04-26 | Veterinary composition containing a proton pump inhibitor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2161683A1 CA2161683A1 (en) | 1994-11-10 |
| CA2161683C true CA2161683C (en) | 2005-11-22 |
Family
ID=35474745
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002161683A Expired - Fee Related CA2161683C (en) | 1993-04-30 | 1994-04-26 | Veterinary composition containing a proton pump inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2161683C (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018065953A1 (en) * | 2016-10-06 | 2018-04-12 | Jubilant Generics Limited | Pharmaceutical suspension dosage form of benzimidazole compounds and process of preparation thereof |
-
1994
- 1994-04-26 CA CA002161683A patent/CA2161683C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CA2161683A1 (en) | 1994-11-10 |
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