Pharmaceutical formulation comprising a 2-...

Details Pharmaceutical formulation comprising a 2-... Pharmaceutical formulation comprising a 2-...

2000-09-19

2002-05-21

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

C424S457000, C424S458000, C424S456000, C424S489000, C424S498000

Reexamination Certificate

active

06391342

ABSTRACT:

The present invention relates to an oral pharmaceutical formulation comprising a 2-[[(2-pyridinyl)methyl]sulfinyl]benzimidazole having anti-ulcer activity as active ingredient, and a process for the preparation of such formulation.
2-[[(2-pyridinyl)methyl]sulfinyl]benzimidazoles having anti-ulcer activity is a well-known group of compounds which have been extensively described in the literature, and a substantive number of patents and patent applications have been directed to such compounds, to processes for their preparation and to formulations containing them as active ingredient.
The compounds prepared according to our international patent application No. PCT/DK98/00058 are examples of such compounds, viz the 2-[[(2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole derivatives of the general formula I
wherein
R
2
represents H, OCH
3
, OCHF
2
or CF
3
,
R
3
represents H, CH
3
or OCH
3
,
R
4
represents H, OCH
3
, OCH
2
CF
3
or halo, such as Cl, Er or F, and
R
5
represents H, CH
3
or OCH
3
, and salts thereof.
Specific examples are the compounds, 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole (omeprazole), 2-[[[4-(2,2,2-trifluoroethoxy)-3-methyl-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole (lansoprazole), 2-[[(2-pyridinyl)methyl]-sulfinyl]-1H-benzimidazole (timoprazole) and 5-di-fluoromethoxy-2- [[(3,4-dimethoxy-2-pyridinyl)methyl]-sulfinyl]-1H-benzimidazole (pantoprazole), among which omeprazole, lansoprozole and pantoprazole are presently being marketed in Denmark as gastric acid secretion inhibiting agents, e.g. for the treatment and prophylaxis of gastric and duodenal ulcers, reflux oesophagitis and Zollinger-Ellison's syndrome.
In the following the invention will be explained with particular reference to omeprazole, however it should be understood, that the invention is not limited to an omeprazole containing formulation.
As is known in the art, omeprazole is sensible to acids, but very soluble in alkaline solutions and only slightly soluble in water. Furthermore, omeprazole is known to be sensible to humidity, heat, light and organic solvents.
Consequently oral formulations of omeprazole and other 2-[[(2-pyridinyl)methyl]sulfinyl]benzimidazoles have been provided with an enteric coating for protection of the active ingredient against degradation by the gastric acid in the stomach and release of the active ingredient in the proximal part of the small intestine.
An oral formulation of omeprazole based on pellets provided with an enteric coating, and results of bio-availability tests carried out with such pellet formulation is described in Scand. J. Gastroenterol., 1985, 20 (suppl. 108), pp. 113-120, Pilbrandt {dot over (A)}. and Cederberg C., “Development of an oral formulation of omeprazole”. However, the stability of this type of formulation is not satisfactory, and degradation of the omeprazole is observed, among others due to the acidic nature of the enteric coating.
In an attempt to improve the stability of omeprazole, certain alkaline salts of omeprazole have been prepared, cf. EP 0 124 495 A. Similarly, EP 0 237 200 B1, EP 0 423 748 B1 and EP 0 446 961 B1, the two later being based on divisional applications of the former, use basic inorganic salts of magnesium and/or calcium to improve the stability of 2-[[(2-pyridinyl)methyl]sulfinyl]benzimidazoles having anti-ulcer activity.
However, it has also been described that when such alkaline cores are provided with an enteric coating of a conventional enteric coating polymer such as, e.g., cellulose acetate phthalate, water from the gastric juice may diffuse through the coating while the dosage form resides in the stomach and dissolve the core partially in the close proximity of the enteric coating. Here it will form an alkaline solution which will attack the enteric coating from the inside and eventually dissolve it.
In order to solve this problem EP 0 247 983 B1 and EP 0 496 437 B1, the later being based on a divisional application of the former, suggest providing enteric coated small alkaline reacting cores, which as the active component contains omeprazole together with an alkaline reacting compound, or an alkaline salt of omeprazole optionally together with an alkaline reacting compound, with a subcoating comprised of one or more inert reacting subcoating layers comprising tablet excipients which are soluble or rapidly disintegrating in water, or polymeric, water-soluble, film-forming compounds, optionally containing pH-buffering alkaline compounds. The subcoating separates the alkaline reacting cores from the enteric coating. Hydroxypropyl methylcellulose, hydroxypropyl cellulose and polyvinyl-pyrrolidone are mentioned as examples of materials for the subcoating.
Corresponding formulations based on other acid labile benzimidazoles are disclosed in EP 0 244 380 B1.
According to WO 96/24338 a water soluble separating layer comprising a water soluble salt of an enteric coating polymer is formed in situ between an alkaline reacting core material containing a proton pump inhibitor, such as omeprazole, lansoprazole or pantoprazole, and an enteric coating. The alkaline reacting core may be prepared in different ways, such as by preparation of granules or tablets including the active substance and the alkaline reacting compound(s) or by application of a layer including the active substance and the alkaline reacting compounds) to preformed seeds.
WO 94/02140 describes an enteric pharmaceutical composition comprising a core containing an anti-ulcer agent, such as omeprazole or lansoprazole, an undercoating of one or two layers and an enteric coating, wherein the core and/or the undercoating comprises aluminium hydroxide.sodium bicarbonate coprecipitate optionally in mixture with a buffer, or a mixture of one of the following with a buffer: aluminium glycinate, an amino acid, an acid salt of an amino acid and an alkali salt of an amino acid, as a stabilizer, the buffers used being capable of controlling the pH of the mixtures to 8-9.
ES 2 024 993 describes an oral pharmaceutical composition comprising a core including omeprazole or an alkaline salt thereof in combination with a basic compound, a first coating made from an inert water soluble excipient and a second basic compound, and a second coating being an enteric coating. As examples of basic compounds which may be included in the composition, sodium, potassium, magnesium, calcium, aluminium and dihydroxy aluminium salts of amino acids or a pyridine carboxylic acid are mentioned. Furthermore the known anti-ulcer agents ranitidine and famotidine are mentioned as examples of the basic compounds which may be added to the core.
EP 0 277 741 A1 describes a method for producing spherical granules having a core being coated with spraying powder containing a drug and low substituted hydroxypropyl cellulose while being sprayed with an aqueous binder, such as a 1% (w/v) solution of hydroxypropyl cellulose. By the process spherical granules being excellent in hardness and disintegration are said to be obtained. The coated cores may be coated with further coatings; sustained release coatings, gastric coatings and enteric coatings being mentioned as examples. Benzimidazoles having anti-ulcer activity are mentioned as examples of the drug and in Examples 1 and 10 lansoprazole is used as the drug. However, it is noted that in both examples, lansoprazole is utilized in combination with a very substantive amount of the alkaline stabilizer, magnesium carbonate.
WO 96/23500 describes an oral pharmaceutical formulation containing a benzimidazole compound, which is labile in acid medium, e.g. omeprazole and lansoprazole, which is obtained by coating inert cores with a first layer containing the benzimidazole compound, a water-soluble inert polymer such as hydroxypropyl methylcellulose or hydroxypropyl cellulose, and pharmaceutically acceptable excipients having

Affiliated with

Also associated with

Rating

Pharmaceutical formulation comprising a 2-... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Pharmaceutical formulation comprising a 2-..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Pharmaceutical formulation comprising a 2-... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2819547