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 "DELAYED RELEASE FORMULATION OF LANSOPRAZOLE"

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


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Field of the Invention
The present invention relates to oral pharmaceutical compositions in pellet or tablet form for combined use of Lansoprazole with an antimicrobially-active ingredient for the treatment of disorders caused by Helicobacter. Background of the Invention
Lansoprazole, 2-[[[3-methyl-4 (2,2.2-trifluoroethoxy)-2-
pyridyl]rnethyl]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 C16H14N3O2S 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-4,786,505, 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 surface of the nucleus together with the benzimidazole compound. Furthermore, some
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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.l, 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 microcrystall ine cellulose. Microcrystalline cellulose is known from the prior art as an excipient having different functions, e.g. diluting/binding, disintegrating, lubricant, and anti-tack ing.
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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SUMMARY OF THE INVENTION
The action of an antimicrobially-active ingredient on Helicobacter surprisingly is enhanced by administering Lansoprazole in slow-release dosage form (extended release form). It must be regarded as particularly surprising that, in addition, administration of the slow-release Lansoprazole results in the onset of action taking place significantly faster than on administration in a form without retarding such release. The duration of treatment until Helicobacter is eradicated is shortened, saving considerable amounts of antibiotic and acid inhibitor.
The invention thus relates to oral pharmaceutical compositions in pellet or tablet form for combined use of Lansoprazole with an antimicrobial ly-active ingredient for treatment of disorders caused by Helicobacter, wherein Lansoprazole is present at least partly in slow-release form.
The invention also relates to an oral pharmaceutical composition in pellet or tablet form for acid-labile irreversible proton pump inhibitors comprising an alkaline pellet or tablet core, at least one release-slowing, release-controlling intermediate layer and an outer enteric layer which is soluble in the small intestine, wherein the intermediate layer for the pharmaceutical composition is formed from a water-insoluble film former, the film former being applied from anhydrous solution or aqueous dispersion. DETAILED DESCRIPTION
Examples of suitable antimicrobially-active ingredients (active against Helicobacter and, in particular, against Helicobacter pylori) are enumerated in European Patent Application EP-A 0282131. These active ingredients include, for example, bismuth salts (such as bismuth subcitrate or bismuth subsalicylate), sulfonamides, nitrofurans (such as nitrofiirazone, nitrofurantoin or furazolidone), metronidazole, tinidazole, nimorazole or antibiotics. Examples of antibiotics which may be mentioned in this connection are, arranged according to particular classes of active ingredient: aminoglycosides, such as gentamicin, neomycin, kanamycin, amikacin or streptomycin; macrolides, such as erythromycin, azithromycin, clarithromycin, clindamycin or rifampicin; penicillins, such as penicillin G, penicillin V, ampicillin, mezlocillin or amoxicillin; polypeptides, such as bacitracin or polymyxin; tetracyclines, such as tetracycline, chlorotetracycline, oxytetracycline, minocycline or doxycycline; carbapenems, such as imipenem, loracarbef, meropenem or panipenem; cephalosporins, such as cefalexin, cefoxitin, cefuroxime axetil, cefotaxime, cefpodoxim proxetil, cefaclor, cefadroxil or cephalothin; gyrase inhibitors, such as ciprofloxacin, norfloxacin, ofloxacin or pefloxacin, or other different antibiotics, such as chloramphenicol.
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Particularly worth of mention in this connection is also the conjoint administration of Lansoprazole with a plurality of antimicrobially-active ingredients, for example with a combination of bismuth salt and/or tetracycline with metronidazole, or with the combination of amoxicillin or clarithromycin with metronidazole.
Antimicrobially-active ingredients which may be emphasized are erythromycin, azithromycin, clarithromycin, clindamycin, rifampicin, ampicillin, mezlocillin, amoxicillin, tetracycline, minocycline, doxycycline, imipenem, meropenem, cefalexin, cefuroxime axetil, cefpodoxime proxetil, cefaclor, cefadroxil, ciprofloxacin, norfloxacin, ofloxacin and pefloxacin.
Clarithromycin and amoxicillin may be mentioned as antimicrobially-active ingredients which should be particularly emphasized.
Combined administration means, for the purpose of the present invention, fixed and, in particular, free combinations, i.e. either slow-release Lansoprazole and the antimicrobially-active ingredient are present together in one dosage unit, or slow-release Lansoprazole and antimicrobially-active ingredient, which are present in separate dosage units, are administered in direct succession or at a relatively large time interval; a relatively large time interval means a time span up to a maximum of 24 hours. For use as separate dosage units, these are preferably made available together in one pack. For example, the two dosage units are packed together in blister packs which are designed with regard to the relative arrangement of the two dosage units with respect to one another, the inscription and/or coloring in a manner known per se so that the time for taking the individual components (dosage regimen) of the two dosage units are evident to a patient.
A dosage unit means, in particular, a medicinal dosage form in which slowing of
Lansoprazole release is achieved with as few problems as possible. This includes, in
particular, tablets, coated tablets or pellets, and microtablets in capsules, with the dosage
form advantageously being designed so that the two active-ingredient components
(Lansoprazole on the one hand and antimicrobially-active ingredient on the other hand) are
released, or made available effectively for the body, in such a way that an optima] active
ingredient profile, and thus action profile, is achieved.
It is possible to use (for retarding release) various types and degrees of retardation so that a Lansoprazole plasma level, which persists as long as possible and is sufficient for raising pH, is ensured.
The pharmaceutical formulation of the antimicrobially-active ingredient is carried out as is familiar per se to the skilled worker for the individual active ingredient.
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Rapid release of part of the Lansoprazole and extending release of another part can be achieved, for example, also by layered tablets or multilayer tablets, in which case part of the Lansoprazole is present in an outer coating in a form without retarding its release; this is followed by another coating containing the antimicrobially-active ingredient and then the core with the Lansoprazole, whose release is extended in a suitable manner.
The details of how to achieve slowing of or extending release are familiar to the skilled worker on the basis of his expert knowledge. The skilled worker is likewise familiar with suitable ancillary substances and vehicles for the required dosage forms (pharmaceutical formulations). Besides solvents, tablet auxiliary substances and other active ingredient excipients it is possible to use. for example, tablet-coating compositions, plasticizers, antioxidants, preservatives, dyes, etc. Where incompatibilities between the active ingredients or between the active ingredients and ancillary substances are expected, suitable separating layers are provided where appropriate (for example in layered or multi-layer tablets).
The dosage of the active ingredients depends greatly on the nature of the antimicrobially-active ingredients used. A typical dosage for Lansoprazole can be regarded as being a daily dose of from about 0.01 to about 20, preferably from 0.05 to 5, in particular from 0.1 to 1.5, mg/kg of body weight, where appropriate in the form of a plurality of single doses. Penicillins, such as amoxicillin, are administered in a daily dose of from about 5 to 40, preferably from 10 to 20, mg/kg of body weight.
Because of a great tendency to decompose in a neutral and, in particular, acidic environment, which also results in highly colored decomposition products, for oral compositions, it is necessary on the one hand to keep Lansoprazole in an alkaline environment and, on the other hand, to protect it from exposure to acids. It is generally known to coat tablets or pellets which contain an acid-labile active ingredient with an enteric coating which, after passage through the stomach, rapidly dissolves in the alkaline medium in the intestine. In the case of Lansoprazole, which is very acid-labile, it is necessary to process it in the tablet core or in pellets in the form of its alkaline salts, for example as sodium salts, or together with alkaline substances. Since the substances suitable for enteric coatings contain free carboxyl groups, a problem arises when the enteric coating is partly or even completely dissolved from the inside because of the alkaline medium in the interior, and the free carboxyl groups promote decomposition of the active ingredients. It is therefore necessary to provide a sealing intermediate layer (subcoating) between the enteric coating and the alkaline tablet core. EP-A 0244380 proposes to coat cores which contain the active ingredient together with alkaline compounds or as alkaline salt with at least one layer, which is soluble in water
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or rapidly disintegrates in water, of nonacidic, inert pharmaceutically-acceptable substance before the enteric layer is applied.
The intermediate layer or intermediate layers act as pH-buffering zones in which hydrogen ions, which diffuse in from the outside, are able to react with the hy.droxyl ions which diffuse out of the alkaline core. In order to increase the buffer capacity of the intermediate layer, it is proposed to incorporate buffer substance into the intermediate layer(s). It is possible in practice by this method to obtain rather stable compositions. However, relatively thick intermediate layers are required to prevent the unsightly discoloration which occurs even on only slight decomposition. In addition, considerable effort must be made to avoid traces of moisture during manufacture. It is a further aim within the scope of the present invention to provide an oral pharmaceutical composition with delayed and controlled release of active ingredients in pellet or tablet form for Lansoprazole, which is distinguished by great resistance to decomposition and discoloration of the active ingredient caused by moisture and other effects.
This aim is particularly advantageously achieved by providing at least one release-slowing intermediate layer of water-insoluble film former, which at the same time represents a barrier for mutual interactions between the active ingredient with an alkaline reaction and the enteric coating with an acidic reaction.
In this connection, film formers are regarded as insoluble in water when they cannot be dissolved in water without further additions (organic solvents, detergents, alkalizing substances, etc.).
The slowing of release can be achieved, for example, by a semipermeable membrane, as disclosed in numerous patents (e.g. EP B 0185331).
The details of how to achieve slowing of release are familiar to the skilled worker on the basis of his expert knowledge. The skilled worker is likewise familiar with suitable ancillary substances and vehicles for the required dosage forms (pharmaceutical formulations). Besides solvents, tablet ancillary substances and other active ingredient excipients it is possible to use, for example, tablet-coating compositions, plasticizers, antioxidants, preservatives, dyes, etc. Where incompatibilities between the active ingredients or between the active ingredients and ancillary substances are expected, suitable separating layers are provided where appropriate.
The oral pharmaceutical compositions according to the invention are distinguished from the prior art by controlled release of active ingredients and increased stability. It is particularly advantageous to keep the intermediate layer (which controls the release of active ingredients) very thin (between 20 and 80, preferably between 40 60, .mu.m), which leads to
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a considerable saving of material and shorter processing times. The insolubility of the intermediate layer in water means that the application of the enteric layer in the form of aqueous suspensions is not critical because there can be no dissolution of the intermediate layer. Furthermore, oral pharmaceutical compositions with a considerably smoother surface are obtained, which not only leads to a better visual appearance but also technically simplifies an imprinting process for tablets.
For a basic reaction of the pellet or tablet core it is mixed (where required increase in pH is not achieved simply by using an active-ingredient salt) with an inorganic base. Mention may be made in this connection of, for example, the pharmacologically-suitable alkali-metal, alkaline-earth-metal or earth-metal salts of weak acids and the pharmacologically-suitable hydroxides and oxides of alkaline-earth and earth metals. Sodium carbonate may be mentioned as a base to be emphasized by way of example.
Besides filler and binder, other ancillary substances, in particular lubricants and nonstick agents, and tablet disintegrants, are used in the manufacture of the tablet cores. A suitable binder is, in particular, polyvinylpyrrolidone in various degrees of polymerization. Examples of lubricants and nonstick agents which may be mentioned are higher fatty acids and their alkali-metal and alkaline-earth-metal salts, such as calcium stearate. Suitable tablet disintegrants are, in particular, chemically inert agents. Tablet disintegrants which may be mentioned as preferred are crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcelluloses and sodium starch glycolate.
Examples of film-forming polymers which can be used in the water-insoluble release-slowing intermediate layer(s) (to be applied to the pellet or tablet core) include ethylcellulose, polyvinyl acetate, Eudragit.RTM. RS, Eudragit.RTM. RL, etc. The release rate can be controlled not only by incorporating therein suitable water-soluble pore formers, such as PEG, lactose, mannitol, sorbitol, HPMC, etc., but also by the thickness of the coating layer applied.
The solvents or dispersants used for the release-controlling polymer dispersion are non-aqueous organic solvents, such as alcohols, ketones or halogenated hydrocarbons or mixtures of such solvents.
It is possible in a similar way to use osmotic systems with semipermeable membranes of cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, as known in the art to control the release of active ingredients. These can be coated with aqueous dispersions of enteric lacquers without changing release rate.
Examples of suitable polymers for the enteric coating are methacrylic acid/methyl methacrylate copolymer or methacrylic acid/ethyl methacrylate copolymers (Eudragit.RTM.
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L) or cellulose derivatives, such as carboxymethylethylcellulose (CMEC, Duodcel), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HP50, HPSS), hydroxypropylmethylcellulose acetate succinate (HPMCAS) or polyvinyl acetate phthalate, to which it is also possible to add, if desired, plasticizer (such as propylene glycol) and/or other additives and ancillary substances (e.g. buffers, bases, such as, preferably, aluminum hydroxide, or pigments).
The layers are applied in conventional ways using equipment customary for these purposes. EXAMPLES
The following formulation examples explain the invention in detail without restriction it. Example 1 Tablets:
I. Production of Uncoated Core:

SI.
No. Ingredient Amount
i) Lansoprazole 45 mg
ii) Sodium carbonate 10
iii) Mannitol 20
iv) EPMC 20
v) HPMC 9
vi) Calcium stearate 2.2
106.2 mg
The compound (i) is mixed with one part of (ii), (iii) and (iv) above. The remainder of (ii) and (iii) is added to the clear aqueous solution of (v), and the pH is adjusted to >10 with (ii). This solution is used for fluidized bed granulation. The remainder of (iv) and (vi) is added to the dried granules, and the granules are compressed in a suitable tabletting machine.
II. Release-Slowing Layer

SI. No. Ingredient Amount
vii) Ethyl cellulose 9.9 mg
viii) Lactose 2.42 mg
ix) Propylene glycol 1.0 mg
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x) Ammonia 0.85
14.17 mg
Compound (vii) is dissolved in 165 ml of isopropanol to prepare solution (A). A fine suspension of (viii) in 165 ml of isopropanol is prepared using a rotor-stator agitator, and subsequently (ix) and (x) are stirred in using a suitable agitator to prepare suspension (B). The solution (A) and the suspension (B) are combined.
The tablet cores obtained from I are coated to an adequate layer thickness with the suspension obtained above in suitable apparatus.
III. Enteric Coating:
xi) Eudragit 13.64 mg
xii) Triethyl citrate 1.36 mg
15.00 mg
Compound (xi) is diluted with 140 ml of water, and (m) is added. The resulting dispersion is screened before processing. The dispersion from III is sprayed onto the presealed cores obtained from II in suitable equipment.
Example 2
Tablets:
I. Production of the Uncoated Core:
Production of the cores took place as in Example I point I.
II. Release-Slowing Layer:

SI. No. Ingredient Amount
vii) Polyvinyl acetate 9.15 mg
viii) Lactose 2.3 mg
ix) Propylene glycol 0.8 mg
x) Ammonia 0.8 mg
13.05 mg
Compound (vii) is dissolved in 150 ml of 1:1 acetone/chloroform mixture to prepare a
solution (A).
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A fine dispersion of (viii) in 150 ml of 1:1 acetone/chloroform mixture is prepared using a
rotor-stator agitator, and subsequently (ix) and (x) are stirred in using a suitable agitator to
prepare a suspension (B). Solution (A) and suspension (B) are combined.
The tablet cores obtained in I are coated to a sufficient layer thickness with the suspension
obtained above in suitable apparatus.
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.
It was found that
- 23 % subjects achieved Tmax earlier in test product compare to reference product;
- 39 % of subjects have higher Cmax compare to ref product
Thus, it was found that among the test population, 20 % 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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We claim:
1. An oral pharmaceutical composition in pellet or tablet form with delayed and controlled release of active ingredient, comprising an acid-labile irreversible proton pump inhibitor other than Lansoprazole, and wherein the composition comprises an alkaline pellet or tablet core, at least one intermediate layer controlling release of active ingredient and an outer enteric layer which is soluble in the small intestine.
2. A process for producing an oral pharmaceutical composition in pellet or tablet form for lansoprazole, as active ingredient, which comprises a) incorporating the active ingredient as an alkaline salt and/or with addition of an alkaline substance in a pellet or tablet core, b) applying thereto at least one release-slowing intermediate layer comprising a water-insoluble, release-slowing film former and c) subsequently applying an outer enteric layer which is soluble in the small intestine.
3. A process as claimed in claim 2, wherein the water-insoluble, release-slowing film former for the intermediate layer is applied in solution or dispersion form.
4. An oral pharmaceutical composition as claimed in claim 1, wherein the acid-labile irreversible proton pump inhibitor is Lansoprazole.
5. An oral pharmaceutical composition in pellet or tablet form with delayed and controlled release of active ingredient and comprising an acid-labile irreversible proton pump inhibitor other than Lansoprazole, and wherein part of the proton pump inhibitor is in a controlled (extended) release form and part of the proton pump inhibitor is in a form without retarding its release (rapid release form).
6. An oral pharmaceutical composition as claimed in claim 1, wherein at least one intermediate layer is formed from a water-insoluble, re lease-slowing film former.
7. An oral pharmaceutical composition as claimed in claim 6, wherein the film former is one which has been applied from a solution or dispersion.
8. An oral pharmaceutical composition as claimed in claim 6, wherein the intermediate layer contains, as water-insoluble, release-slowing film former, ethylcellulose or polyvinyl alcohol.
9. An oral pharmaceutical composition as claimed in claim 6, wherein the outer enteric layer, which is soluble in the small intestine, comprises methacrylic acid/methyl methacrylate copolymer or methacrylic acid/ethyl methacrylate copolymer.
10. Use of the pharmaceutical dosage form according to claim 1 or 9, in the manufacture of a medicine for the treatment of duodenal and gastric peptic ulcer, gastroesophageal 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.
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BA_formul_008_comp] 11. A pharmaceutical formulation of Lansoprazole as is hereinbefore described.

Dated this the 21st day of july2008


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

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