Novel composition containing an acid-labile Esomeprazole and process for
its preparation
Field of Invention:
The present invention relates to compositions comprising an acid labile (-)-enantiomer of omeprazole and a process for preparation thereof
Baclcground of Invention:
The compound 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)- methyl]sulfmyl]- IH-benzimidazole, having the generic name omeprazole, and therapeutically acceptable salts thereof, are described in EP 5129. The specific alkaline salts of omeprazole are described in EP 124 495. Omeprazole is effective as a gastric acid secretion inhibitor, and is useful as an antiulcer agent. In a more general sense, omeprazole may be used for prevention and treatment of gastric-acid related diseases in mammals and especially in man, including e.g. reflux esophagitis, gastritis, duodenitis, gastric ulcer and duodenal ulcer. Furthermore, omeprazole may be used for treatment of other gastrointestinal disorders where gastric acid inhibitory effect is desirable e.g. in patients on NSAID therapy, in patients with Non Ulcer Dyspepsia, in patients with symptomatic gastro-esophageal reflux disease (GERD), and in patients with gastrinomas.
Omeprazole belongs to the benzimidazole category, almost all of benzimidazole derivates are susceptible to degradation/transformation in acidic reacting and neutral media. The degradation is catalyzed by acidic reacting compounds and the benzimidazoles (proton pump inhibitor) are usually stabilized by using alkaline reacting compounds. In respect to the stability properties of the benzimidazole compounds mentioned above, it is obvious that their oral solid dosage form must be protected from contact with the acidic reacting gastric juice and the acdve substance must be transferred intact form to that part of the gastrointestinal tract where pH is less acidic, neutral or alkaline and where rapid absorption of the pharmaceutically active substance, i.e., the benzimidazole derivative, can occur.

U.S. Pat. Nos. 4,628,098; 4,853,230; 5,689,333; 5,045,321; 5,093,132; 5,433,959; teach various stabilizing agents for the these benzimidazole derivatives in the core tablets. These references also show that such compounds are stable in the presence of basic inorganic salts of magnesium, calcium, potassium and sodium. The stability is further consolidated by separating the acid labile benzimidazoles from the acidic components of the enteric coat by an intermediate coating.
U.S. Pat. No. 6,013,281 also discloses that a separating layer is formed in situ by direct application of an acidic enteric material on to the alkaline core containing the benzimidazoles (Proton pump inhibitor).
Omeprazole is a sulfoxide and a chiral compound, wherein the sulfur atom being the stereogenic center. Thus, omeprazole is a racemic mixture of its two single enantiomers, the (+)-enantiomer of omeprazole and the (-)-enantiomer of omeprazole. The absolute configurations of the enantiomers of omeprazole have been determined by an X-ray study of an N-alkylated derivative of the (+)-enantiomer in neutral form. The (+)-enantiomer of the neutral form and the (-)-enantiomer of the neutral form were found to have the R and S configuration, respectively. The conditions for the optical rotation measurement for each of the compounds mentioned above are described in WO 94/27988,
Lindberge et el. In US Patent 5877192, describes that omeprazole exhibits polymorphic metabolism, i.e. a few individuals (3% among the Caucasian populations and 15-20% among Orientals) metabolise omeprazole slowly (slow metabolisers) compared to the rest of the population (rapid metabolisers). Slow metabolisers of omeprazole will obtain higher than the average plasma concentrations of the drug. The inhibition of gastric acid secretion is correlated to the area under the plasma concentration versus time curve (AUG). Thus the patent teaches one of the enantiomers of omeprazole, referred to as the (-)-enantiomer of omeprazole, or a pharmaceutically acceptable salt thereof, provides increased average plasma levels (AUG) upon administration of the same doses of the (-)-enantiomer of omeprazole compared to those of racemic omeprazole, the said enantiomer possess an improved antisecretory effect and a better clinical effect.
In light of abovesaid consideration, Lindberg et al. tried to obtain compounds with improved pharmacokinetic and metabolic properties that will give an improved therapeutic profile such

as a lower degree of interindividual variation, Lindberg et al in US Patent 5,714,504 provides such compounds, which are novel salts of single enantiomers of Omeprazole, more preferably provides pure crystalline enantiomeric salts of omeprazole and methods for the preparation thereof. The patent suggests optically pure crystalline enantiomeric magnesium salt of omeprazole is a preferred salt of (-)-enantiomer of Omeprazole. Prior art teaches the use and preparation of novel salts of single enantiomers of Omeprazole, for improved pharmacokinetic and metabolic properties that will give an improved therapeutic profile such as a lower degree of interindividual variation.
US patent 504 also states that, "single enantiomers of omeprazole have hitherto only been obtained as syrups and not as crystalline products. The salts defined by the present invention are easy to obtain by means of the novel specific method according to one aspect of the invention of preparing the single enantiomers of omeprazole. In contrast to the neutral forms the salts can be obtained as crystalline products."
Hence (-)-enantiomer of Omeprazole is difficult to handle and incorporate in solid dosage form due to its nature and stability, (-)-enantiomer of Omeprazole is very unstable compared to the salt of (-)-enantiomer of Omeprazole. In accoradance with the said invention, we have used single enantiomers of Omeprazole i.e. (-)-enantiomer of Omeprazole as an active ingredient,that exists as a solid, without converting it to the salt forms as of mentioned in the patent 504 and developed a stable pharmaceufical composition consisting of single enantiomers of Omeprazole. The (-)-enantiomer of Omeprazole has been stabilized in a unique way; moreover there is no specific reference of such stabilization and further its incorporation in the pharmaceutical composition.
Our co-pending Indian patent application 340/MAS/2003, which is hereby incorporated by reference, discloses a method for the preparation of solid premix consisting the (-)-enantiomer of Omeprazole in combination with some pharmaceutically acceptable excipients. Hereinafter the said premix of (-)-enantiomer of Omeprazole has been interchangeably used as esomeprazole base premix or esomeprazole premix.
Objective of Invention:
Objective of present invention is to develop a pharmaceutical composition comprising single enantiomers of Omeprazole.

is a mixture comprising esomeprazole, mannitol and meglumine. The esomeprazole premix, thus utiHzed in the invention is yellow colored fine powder, wherein 90% of plurality of particles has particle size not more than 100 microns. Esomeprazole premix thus mentioned above consists of esomeprazole base 30 to 60%, sugar alcohol 30 to 60% and stabihser varying from Ito 10% of total weight of premix, any variation made in the quantities of components of premix should be under the scope of this invention.
Furthermore the core of said invention comprises esomeprazole premix mixed uniformly with pharmaceutically acceptable excipients comprising inert filler, alkaline agent, surface active agent, disintegrant, stabilizer, binder, lubricants and flow improvers.
The filler of said invention preferably consist of water soluble substances such as mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol, lactose. The surface active agent may be any pharmaceutically acceptable, non toxic surfactant. A suitable surfactants include one or more sodium lauryl sulfate, docusate sodium, poloxamer, polyoxyethylene stearates, polyoxyethelene sorbitol esters of fatty acid. The binder may be pharmaceutically acceptable binder, preferably one or more from the group comprising Povidone, Methylcellulose, Hydroxypropyl methylcellulose. Ethyl cellulose, Hydroxyethyl cellulose, Hydroxypropyl cellulose, Starch. The Pharmaceutically acceptable alkaline substance may be any pharmaceutically acceptable, non toxic substance from a group, which includes basic inorganic salts not limited to magnesium oxide, magnesium hydroxide or carbonate, aluminium hydroxide, aluminium, calcium, sodium or potassium carbonate, phosphate or citrate.
The disintegrant may consist of one or more pharmaceutically acceptable disintegrant from the group comprising Crospovidone, Croscarmellose sodium. Sodium starch glycolate, Polacrillin sodium, Polacrillin potassium, Croscarmellose calcium, low substituted Hydroxypropyl cellulose. Starch, Pregelatinised starch and the like.
The core of said invention is prepared by homogenously mixing the esomeprazole premix and additives mentioned hereinabove, further the powder mixture is then formulated into small beads, pellets, granules, fine granules, minitablets or tablets, hard gelatine or soft gelatine capsules by conventional pharmaceutical procedures.
Separating layer:
The alkaline reacting cores containing an acid labile compound must be separated from the enteric coating polymer(s) containing free carboxyl groups, which otherwise causes

degradation/discoloration of the acid labile compound during the coating process or during storage.
The separating layer(s) can be applied to the core pellets or tablets by conventional coating procedures in a suitable coating pan or in fluidized bed apparatus using water and/or conventional organic solvents for the coating solution. In contrast to the available prior art references describing water soluble or slightly water soluble subcoats in pharmaceutical compositions comprising proton pump inhibitor, we have used water insoluble subcoat. The scope of this invention also includes water soluble subcoats. In the case of tablets another method to apply the coating can be performed by the drycoating technique. The outer, separating layer, may consists of pharmaceutically acceptable, water soluble or in water rapidly disintegrating tablet excipients. Ordinary plasticizers, pigments, titanium dioxide talc and other additives may also be included into the separating layer. In the case of gelatin capsules the gelatin capsule itself serves as separating layer. The quantity of subcoat of said invention may vary from 0.3% to 6%, preferably 0.5 to 4.0%, more preferably 1-3 % of the total weight of core.
Water insoluble subcoat or an intermediate coating material used herein includes Zein. Zein a subcoating material used in an invention, available commercially as Zein F4000, Zein 6000 is basically a prolamine obtained from com. Zein is a granular, straw to pale yellow colored amorphous powder or fine flakes and has characteristic odor and bland taste. Zein was Generally Recognized As Sate (GRAS) by USFDA in March 1985.
Chemically Zein is a protein derivative which comprises Glutamine (21.4%), Leucine (19.3%), Proline (9.0%), Alanine (8.3%) as a major amino acids components. Zein does not contain lysine or tryptophan.
Zein is practically insoluble in acetone, ethyl and water but soluble in aqueous alcohol solutions, aqueous acetone solutions (60-80% v/v). Zein's insolubility in water at acidic pH is due to high proportion of hydrocarbon group side chains, and high percentage of amide groups present with a relatively low amount of carboxylic acid groups. Solubility of zein improves as the pH approaches to alkalinity. In another embodiment of the invention, Zein can be combined with at least one enteric coating polymer soluble in intestinal pH but insoluble in water. The enteric coating polymer of subcoat constitutes about 0.5 to 20%, preferably 5-15%, more preferably 5-10% of the total subcoat.

Enteric coating layer:
The enteric coating layer is applied on to the sub-coated cores by conventional coating techniques such as, for instance, pan coating or fluidized bed coating using solutions of polymers in water and/or suitable organic solvents or by using latex suspensions of said polymers. As enteric coating polymers can be used, for example, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, co-polymerized methacrylic acid/methacrylic acid methyl esters such as, for instance, compounds known under the trade name Eudragit.RTM. L 12,5 or Eudragit.RTM. L 100, (Rohm Pharma) or similar compounds used to obtain enteric coatings. Solution of Eudragit- L-100-55 in Isopropyl alcohol is the preferred enteric coating solution. The enteric coating can also be applied using water-based polymer dispersions, e.g. Aquateric (FMC Corporation), Eudragit.RTM. L 100-55 (Rohm Pharma), Coating CE 5142 (BASF). The enteric coating layer can optionally contain a pharmaceutically acceptable plasticizer such as, for instance, cetanol, triacetin, citric acid esters such as, for instance, those known under the trade name Citroflex.RTM. (Pfizer) phthalic acid esters, dibutyl succinate or similar plasticizers.
The amount of plasticizer is usually optimized for each enteric coating polymer(s) and is usually in the range of 1-20% of the enteric coating polymer(s). Dispersants such as talc, colorants and pigments may also be included into the enteric coating layer. The weight of enteric coat appHed in a said invention is 1-12%, preferably 2-10 % and more preferably 4-8%) of the weight of core of tablet
Final Dosage Forms :
The final dosage form may be an enteric coated tablet or capsule or in the case of enteric coated pellets, pellets dispensed in hard gelatin capsules or sachets or pellets formulated into tablets.
Process:
A process for the manufacture of the oral dosage form first comprises a preparation of core consisting esomeprazole premix and further coating the core with the separating layer and then with the enteric coating layer.

Following are given few examples of stable Esomeprazole, which do not limits the scope of an invention and only presented here to show how the invention be carried out. The examples represent preferred embodiments of the invention. Example I.

* Composition of esomeprazole premix:
Esomeprazole 40mg, mannitol 3 mg and meglumine 37 mg
Process: Core of tablet was prepared by mixing esomeprazole premix with all ingredients from 2 to 11, further blend was directly compressed over tablet compression machine, it was further coated with solution of zein prepared in 90% of isopropyl alchol and 10% purified water. Subcoated tablets were then enteric coated with Eudragit L 100-55 dissolved in isopropyl alcohol. Finally enteric coated tablets were film coated Opadry Pink. The final product of esomeprazole thus prepared was stored at accelerated stability conditions (40°C Temp/ 75% Humidity) for 1 month, 2 months, and 3 months. All samples were analysed for the presence of compound known to result from the decomposition of

esomeprazole (termed as an impurity). The total impurity determined after completion of 3 months was found to be less than 3.0%. Example II.

* Composition of esomeprazole premix:
Esomeprazole 40mg, mannitol 3 mg and meglumine 37 mg
Process: Core of tablet was prepared by mixing esomeprazole premix with all ingredients from 2 to 11, further blend was directly compressed over tablet compression machine, it was further coated with solution of HPMC. Subcoated tablets were then enteric coated with Eudragit L 100-55 dissolved in isopropyl alcohol. Finally enteric coated tablets were film coated Opadry Pink.
The final product of esomeprazole thus prepared was stored at accelerated stability conditions (40°C Temp/ 75% Humidity) for 1 month, 2 months, and 3 months. All samples were analysed for the presence of compound known to result from the decomposition of

esomeprazole (termed as an impurity). The total impurity determined after completion of 3 months was found to be less than 3.0%.
Although the invention has been described in a preferred form with a certain degree of particularity, it is understood that the present disclosure of the preferred form has been made only by way of example, and that numerous changes in the details of construction and combination and arrangement of procedures and parts may be made without departing from the spirit and scope of the invention as hereinafter claimed. It is intended that the patent shall cover by suitable expression in the appended claims, whatever features of patentable novelty exist in the invention disclosed.

We claim:
1) A pharmaceutical composition comprising:
a) a core comprising premix of (-) enantiomer of omeprazole
b) one or more layers of subcoat and
c) an enteric coating layer surrounding said subcoating layer.

2) A premix of (-) enantiomer of omeprazole, comprising (-) enantiomer of omeprazole and atleast one stabilizer.
3) A premix of claim 2, further comprises water soluble pharmaceutically acceptable filler.
4) A premix of claim 2, wherein stabilizer is selected from group comprising meglumine lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, and procaine,
5) A premix of claim 2, wherein stabilizer is meglumine.
6) A premix of claim 3, wherein water soluble pharmaceutically acceptable filler is sugar , sugar derivative or sugar alcohol.

7) A premix of claim 6, wherein water soluble pharmaceutically acceptable fillers are mannitol, xylitol, erythritol.
8) A premix comprising (-) enantiomer of omeprazole, meglumine and mannitol
9) A premix of claim 3, comprising about 20 to 70% of (-) enantiomer of omeprazole to the total weight of premix.

10) A pharmaceutical composition of claim 1, wherein subcoat is water insoluble or water soluble.
11) A pharmaceutical composition of claim 10, wherein water insoluble subcoat is zein.
12) A water insoluble subcoat of zein of claim 11, wherein zein is about 1 to about 6% of weight of a core comprising premix of (-) enantiomer of omeprazole

13) A pharmaceutical composition of claim 10, the water soluble subcoat comprises
hyroxypropyl methylcellulose, hyroxypropyl cellulose or polyvinyl-pyrrolidone.
14) A water soluble subcoat of claim 13, wherein water soluble subcoat is about 2 to about 10
% of weight of a core comprising premix of (-) enantiomer of omeprazole
15) A pharmaceutical composition of claim 1, wherein the enteric coating comprises
hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, co-polymerized
methacrylic acid/methacrylic acid methyl ester or polyvinyl acetate phthalate, optionally
containing a plasticizer.
16) An enteric coat of f claim 15, wherein enteric coat is about 5 to about 15 % of weight of
a core comprising premix of (-) enantiomer of omeprazole
17) Process for the preparation of an oral pharmaceutical composition, comprising a
preparation of a core consisting a premix of (-) enantiomer of omeprazole and
pharmaceutically acceptable excipients, further coating the cores with one or more subcoating
layers and finally the subcoated cores are coated with an enteric coating layer.