FORM 2
THE PATENTS ACT, 1970 (39 OF 1970) & THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION


"FORMULATION OF LANSOPRAZOLE"

We, BA RESEARCH INDIA LIMITED, of BA Research House, Opposite "Pushparaj Towers", Judges Bungalows, Bodakdev, Ahmedabad-380-054, Gujarat, India.
The following specification particularly describes the invention and the manner in which it is to performed:


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Field of the Invention
This present invention relates to a stable pharmaceutical dosage form including Lansoprazole active ingredient or pharmaceutical acceptable salt. Background of the Invention
Lansoprazole, 2-[[[3-methyl-4 (2,2,2-trifluoroethoxy)-2
pyridyl]methyl]sulfinyl]benzimidazole (marketed in the United States under the trademark PREVACID(R)), is a substituted benzimidazole that inhibits gastric acid secretion. The empirical formula of lansoprazole is C16H14F3N3O2S and the compound has a molecular weight of 369.37. Lansoprazole is an acid labile benzimidazole derivative very effective for the treatment of gastric and duodenal ulcers, gastroesophageal reflux disease, severe erosive esophagitis, Zollinger-Ellison syndrome and H-pylori eradication. However, it is well known that this compound has poor stability. In the solid state it is susceptible to heat, moisture and light, and in aqueous solution or suspension its stability decreases with decreasing pH. The degradation of lansoprazole is catalyzed by acidic reacting compounds, i.e. acidic compounds or compounds which react like acidic compounds.
Pharmaceutical preparations containing acid labile compounds have to be subcoated in order to avoid a reaction between the active ingredient and the outer acidic enteric coating which reaction -if occurring- would result in degradation, destabilization and consequently discolouration of the active ingredient.
The use of a barrier layer to protect the pharmaceutical from degradation caused by an enteric coating is well known from the prior art. Nevertheless, it is not possible to use conventional enteric coatings in a conventional way for acid labile benzimidazole compounds since decomposition takes place and the preparations become discoloured and lose the active ingredient content with time. Prior art partially avoids the above mentioned stability problem by including an alkaline salt form of the benzimidazole compound or incorporating an alkaline reacting compound (i.e. a base or compounds that react like bases, i.e. magnesium oxide, hydroxide or carbonate, aluminium hydroxide, aluminium, calcium, sodium or potassium carbonate, phosphate or citrate, composite aluminium/magnesium compounds, alkaline aminoacids, N-methyl-D-glucamine, etc.) into an enteric coated preparation. As described in US-A-4J86,505, US-A-5,232,706, EP-A-237200, EP-A-124495, US-A-5,385,739, EP-A-519144, the alkaline reacting compound may be present within or on the
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surface of the nucleus together with the benzimidazole compound. Furthermore, some authors use the alkaline reacting compound also in the composition of an isolation layer to ensure stability of these forms. It is important to note that patent US-A- 4,786,505, in its Example 1, Table 1 No.I, illustrates a formulation which is free of such alkaline reacting compound, and that according to Table 3 (No. l-II) this formulation has a rather poor stability.
Nevertheless, EP 993 830 Bl, refers to a high stability solid pharmaceutical enteric coated composition of an acid labile benzimidazole, which does not contain alkaline reacting compounds, and which comprises: a) nucleus formed by an inert core coated with a first layer consisting of the acid labile benzimidazole compound, an inert water soluble polymer selected from hydroxypropylmethylcellulose and hydroxypropylcellulose and talc; b) an inert coating disposed on said nucleus, formed by a water soluble polymer selected from hydroxypropylmethylcellulose and hydroxypropylcellulose, talc and a pigment; and c) an outer layer disposed on the previous coating comprising an enteric coating consisting of a gastric resistant polymer such as co-polymerized methacrylic acid/methacrylic acid methyl esters, a plasticizer such as triethylcitrate and talc. In this formulation talc is used as anti-tacking agent in each of the three layers.
US 2005/0129760 Al refers to oral pharmaceutical composition in the form of pellets containing a benzimidazol compound as active ingredient, comprising a) an inert core b) to which is applied a layer containing the active ingredient, c) one or more optional separating layers and d) an outer layer comprising an enteric coating. The benzimidazol compound is mixed with microcrystalline cellulose. The separating layer preferably also contains microcrystalline cellulose. Microcrystalline cellulose is known from the prior art as an excipient having different functions, e.g. diluting/binding, disintegrating, lubricant, and anti-tacking.
US 6228400 Bl discloses an orally administered pharmaceutical granule comprising a) an inert core, b) an active layer which is made from mixing a free base of benzimidazol derivative (such as omeprazole or lansoprazole) with a non-ionic surfactant and water, c) a protective coating which is made of a film forming compound, and optionally a plasticizer or excipients, and c) an enteric coating. The preferred non-ionic surfactant is Poloxamer 188 and the examples only refer to the use of said product. Poloxamer 188, is a non-ionic surfactant also known as a lubricant and anti-tacking agent.
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Objects of the invention:
It is an object of the present invention to provide a new Lansoprazole tablet formulation having suitable stability values and administrated orally.
Another object of the invention is to provide a basic filling material and a Lansoprazole tablet formulation conformable with this filler. The Lansoprazole active ingredient containing subject invention includes pharmaceutical solid dosage form core tablet, an enteric coating and a pre-coating between core tablet and enteric coating.
The core tablet includes both sodium carboxymethylcellulose as binder and isomalt as filler.
To use isomalt as filler in Lansoprazole formulation contribute the production of stable Lansoprazole formulation.
In addition using isomalt filler with sodium carboxymethylcellulose unexpectedly provides the desired core tablet strength values.
In the formulation of the subject invention, the core tablet includes also tri-basic sodium phosphate as basic material.
In the formulation of the subject invention, the core tablet includes also sodium stearil fumarate as lubricant agent.
The protective coating between core tablet and enteric coating consist of Pharmacoat 603, PVP K 25, Sepisperse AP3232; Propylene glycol.
The enteric coating" includes Eudragit, Citroflex and Simeticone Emulsion or Dimethicone Emulsion.
The preferred tablet formulation of Lansoprazole formulation is explained in Example 1.
Example 1 Lansoprazole 40 mg enteric-coated tablet formulation:

Core Tablet Amount
Lansoprazole 45.1 mg
Anhydrous tri-basic sodium phosphate 10 mg
Isomalt 56 mg
NaCMC 6mg
Crospovidone 49.5 mg
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Sodium stearil Fumarate 3.5 mg
170.1 mg
Pre-coating
Pharmacoat 603 15.85 mg
PVP K 25 0.30 mg
Propylene glycol 3.75 mg
190 mg
Enteric coating
Eudragit 45.5 mg
Simethicone 1.5 mg
The open formula of the Lansoprazole containing pharmaceutical compound is shown above and the production process is given below.
In the first step of the production, the aqueous solution of Na CMC was prepared. Some of tri-basic phosphate was added and the granulation solution was prepared (pH > 10). The Lansoprazole was transferred into the wet granulation cauldron and some of crospovidone. isomalt, anhydrous tri-basic sodium phosphate and rest of Na CMC were mixed to obtain a suitable mixture. This mixture is granulated by granulation solution in a fluidized bed. Granules were obtained and rest of crospovidone and sodium stearate fumarate were mixed and the solid mixture was made tablet by suitable tablet machine. The pre-coating process and then enteric-coating process were made respectively.
The following stability tests were performed to obtain tablets.The tablets Were placed open in boxes and the boxes were stored at 40 °C, 75 % relative humidity and at 60 °C the tablets were examined by visual observation and the results are shown below in table II.

Visual observation
Days 40 °C, 75 % relative humidity 60°C
Initially White White
5 White White
10 White White
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15 White White
20 White Pale yellow
25 White Pale yellow
30 White Pale yellow
The results obtained from the stability tests clearly show that the ancillary materials used in the Lansoprazole formulation are conformable with Lansoprazole and the formulation is stable. Pharmacokinetic study:
In vivo dissolution differences between said between the aforesaid two preparations
were demonstrated in a single dose, crossover, randomized comparative pharmacokinetic
study performed in 34 healthy volunteers.
7/ was found that
16 % subjects achieved Tmax earlier in test product compare to reference product;
68 % of subjects have higher Cmax compare to ref product
Thus, it was found that among the test population, 53 % of subjects had earlier Tmax
and higher Cmax in test product compare to reference product thereby demonstrating that the
absorption rate of the present formulation has significantly improved over the test product.
While the invention has been described by way of examples and in terms of the preferred
embodiments, it is to be understood that the invention is not limited to the disclosed
embodiments. On the contrary, it is intended to cover various modifications as would be
apparent to those skilled in the art. Therefore, the scope of the appended claims should be
accorded the broadest interpretation so as to encompass all such modifications.

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CLAIMS
1. Pharmaceutical dosage form comprising a core tablet consisting of Lansoprazole as active ingredient or an pharmaceutical acceptable salt, isomalt as filler, sodium carboxymethylcellulose as binder, at least one pharmaceutical suitable disintegrant, one basic material and one lubricant.
2. A dosage form as claimed'in claim 1 wherein said disintegrant comprises crospovidone.
3. Pharmaceutical dosage form as claimed in claim 1 or 2 including anhydrous tri- basic sodium phosphate as basic material.

4. Pharmaceutical dosage form as claimed in any preceding claim wherein said lubricant comprises sodium stearil fumarate.
5. Pharmaceutical dosage form a as claimed in any preceding claim which administrated orally.
6. Pharmaceutical dosage form as claimed in any preceding claim, which is in the tablet form.
7. Pharmaceutical dosage form as claimed in any preceding claim including enteric-coating.
8. Pharmaceutical dosage form as claimed in any preceding claim consisting of Pharmacoat 603, PVP K 25. Propylene glycol and take part between core tablet and enteric coating.
9. Use of the pharmaceutical dosage form a as claimed in any preceding claim in the manufacture of a medicine for the treatment of the a duodenal and gastric peptic ulcer, gastro-esophageal reflux disease and reflux esophagi; by the combination of two suitable antibiotics to reduce the replication of duodenal and gastric ulcer which occurs because of Helicobacter pylori.
10. A pharmaceutical formulation of Lansoprazole substantially as hereinbefore described.
Dated this the 21st day of july 2008

4 H. SUBRAMANIAM
Of Subramaniam, Nataraj & Associates Attorneys for the Applicants
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