FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 43)
TITLE OF THE INVENTION:
"D-RABEPRAZOLE COMPOSITION"
APPLICANT:
(a) NAME: TITAN LABORATORIES PRIVATE LIMITED
(b) NATIONALITY: An Indian Company Incorporated Under The Companies Act, 1956
(c) ADDRESS: 102, Titan House, 60 Feet Road, Ghatkopar (E),
Mumbai: 400077, Maharashtra, India.
PREAMBLE TO THE DESCRIPTION: COMPLETE
The following specification particularly describes the invention and the manner in which it is to be performed.

Field of Invention:
The present invention relates to a novel acid-stable pharmaceutical formulation for D-rabeprazole. More specifically, the present invention relates to a novel stable formulation for D-enantiomer of rabeprazole containing a primary amine as stabilizing agent and process for manufacturing thereof.
Background of Invention:
Rabeprazole and its enantiomers, specifically D-enantiomer have been conventionally used for treatment of erosive or ulcerative gastro-esophageal reflux disease (GERD) or heartburn, as commonly known. Rabeprazole is a Proton pump inhibitor first disclosed in US5045552 assigned to Takeda. D-rabeprazole, chemically known as (D)-2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl]sulfinyl]-lH-benzimidazole is a benzimidazole type anti-ulcer drug.
Currently rabeprazole is marketed as AchipHex, which is a racemic mixture of both (R) and (S) form of rabeprazole. The purified D-rabeprazole, is marketed by Emcure in India as Dexpure. The efficacy of D-rabeprazole compared to rabeprazole has been proven by Pai et al in their article titled "Randomized, double-blind, comparative study of D-rabeprazole 10 mg versus rabeprazole 20 mg in the treatment of gastroesophageal reflux disease" published in World J Gastroenterol 2007 August 14; 13(30): 4100-4102.
The stability of D-rabeprazole is often poor especially in acidic pH. Hence, it is imperative to maintain the microenvironment at an alkaline pH, most preferably

around 8-10. This has been conventionally achieved by adding a component which maintains the pH in this particular range. These additional components are, mostly, alkaline metal salts, more preferably Na- Ca- and Mg-salts selected form carbonates, oxides, hydroxides etc.
It is also a common knowledge that most of enteric polymers have an acidic pH. Hence, to maintain alkaline microenvironment generally a seal coat has to be superseded over the drug layer, in case of core coat pellets or tablets. Seal coat is generally made of polymers like modified cellulosic polymers etc.
As reported in EP1755566 that benzimidazole compounds have poor stability when exposed to acidic conditions. The stability is reported to decrease with decreasing pH. For example, the half-life of an aqueous esomeprazole composition at a pH of 6.5 is reported to be of the order of about 18 hours whereas the half-life at a pH of 4 is reported to be of the order of about 10 minutes. The stability of benzimidazole compounds also has been reported to decrease with high heat and moisture.
EP1755566 further reports that benzimidazole compounds are acid labile. As such, they are generally designed as enteric coated dosage forms in order to avoid degradation of the active pharmaceutical ingredient (API) at the low pH found in the stomach.
However, because enteric coatings are generally comprised of acidic compounds, direct covering of the benzimidazole compounds with these types of coatings has

been reported to cause degradation and decomposition of the active pharmaceutical ingredient, causing the active pharmaceutical ingredient preparation to undergo discoloration and to lose its active ingredient content over time.
An attempt to address this stability was disclosed in US .2005214371, assigned to Di Capua, Simona et al, which discusses a pharmaceutical formulation comprising a) an inner core coated with the acid labile drug; b) a first intermediate coating devoid of an alkaline stabilizing agent and the benzimidazole compound; c) a second intermediate coating comprising an alkaline stabilizing agent; and, d) an outer enteric layer. In US '371 the alkalizing agents used are magnesium carbonate, magnesium oxide, sodium hydroxide and organic base.
The overall processes for manufacturing these formulations are lengthy and expensive. Hence there is a need to develop less expensive approaches for achieving the desired stability results. Further, the inert core which is in direct contact with drug, may possibly lead to acidic microenvironment.
Primary amines are known to have alkaline pH; this property can be utilized for maintaining the microenvironment around drug in alkaline pH.
Customarily, Trihydroxymethylaminomethane (THAM), a primary amine, has been used as buffer in biotechnology and biochemistry. Trihydroxymethylaminomethane has been known to buffer the alkaline range of pH, that is, from 7.0 - 9.0. Trihydroxymethylaminomethane is much less costlier as compared to other

buffering agents. Furthermore, Trihydroxymethylaminomethane is oftentimes used as an alternative for sodium carbonate for treatment for metabolic acidosis, so it can be suggested that Trihydroxymethylaminomethane can also function as an antacid, thereby showing improved therapeutic effect.
In view of the buffering functionality of Trihydroxymethylaminomethane and overall cost reduction of process, as such and further, based on the fact that D-rabeprazole requires an alkaline pH to be stable, the inventors propose a novel acid-stable pharmaceutical formulation comprising Trihydroxymethylaminomethane as buffering agent.
Summary of Invention:
Accordingly, the present invention relates to a novel acid-stable pharmaceutical formulation for oral administration of D-rabeprazole consisting of Trihydroxymethylaminomethane as buffering agent or stabilizer for maintaining the alkaline conditions required for stabilizing, whereby the drug layer is further coated with a layer of Trihydroxymethylaminomethane
In an aspect of invention the Trihydroxymethylaminomethane layer functions as a barrier coat to protect D-rabeprazole from the acidic enteric polymer. It, further, buffers acidic environment contributed by the inert core and also maintains alkaline conditions in the drug suspension.
In an aspect, the invention provides pellets comprising;

a) Inert core seeds;
b) the said seeds are coated with a layer of Trihydroxymethylaminomethane optionally along with polymer;
c) the said alkali coated seeds are then layered with drug layer comprising Trihydroxymethylaminomethane and drug, optionally along with polymer;
d) the drug layer is further coated with an layer of Trihydroxymethylaminomethane, optionally comprising a primary amine and
e) finally the alkaline drug pellets are finally coated with a enteric coat, which may or may not comprise primary amine
In another aspect, the invention provides drug pellets comprising;
a) Inert core seeds, optionally hardened;
b) a drug coat made up of drug mixed with a primary amine and optionally a binder or excipients;
c) the drug layer is further coated with an layer of Trihydroxymethylaminomethane, and
d) enteric coat, which may optionally comprise a primary amine.
In a further aspect, ratio of Trihydroxymethylaminomethane in each layer may be in equimolar ratio or any other suitable ratio.
In another aspect, the suspension comprising the drug may be formulated with any suspension grade Avicel or the like.

Brief Description of Drawings:
Fig. 1 illustrates the pellets formed by the invention.
Detailed Description of Drawings:
The appended Fig. 1 illustrates the pellet 1. Said pellet comprises of an inert core 11, which can be selected from microcrystalline cellulose beads, starch beads, sugar beads, inert organic or inorganic material beads, or any other beadlets or commercially available non-peril seeds, granules, particles and micropellets.
The inert core 11, can, optionally, be an extruded - spheronized core. The extruded-spheronized core essentially would comprise of the active, that is, Dexrabeprazole and a pharmaceutically acceptable excipient such as microcrystalline cellulose. Said core 11 is substantially devoid of any alkalizing agent, such as Trihydroxymethylaminornethane.
Core 11, can optionally be hardened by techniques known for the purpose in art.
The core 11 is further coated with a Trihydroxymethylaminornethane layer 12. The layer 12 has dual functions. Firstly, being substantially made of only Trihydroxymethylaminornethane it serves to provide an alkaline microenvironment for stabilizing the active, that is, Dexrabeprazole, which, as known in art, requires an alkaline microenvironment. Secondly, being disposed in between the inert core 11 and drug layer 13 serves to avoid any chemical interaction between drug and core, in

an event that the core has any acidic moieties. This layer is substantially free of any pharmaceutically functioning excipients.
Trihydroxymethylaminomethane layer 12 is further coated with the drug layer 13. Drug layer 13 essentially comprises of drug Dexrabeprazole, and a primary amine. The rationale for mixing a primary amine lays in the fact that dexrabeprazole is an acid labile drug, that is, at acidic pH dexrabeprazole undergoes degradation thereby reducing its efficacy. The addition of primary amine, which is indigenously basic in nature helps in reducing the acid degradation of active. This layer can further comprise any additional excipients, if needed.
Drug layer 13 is further coated with yet another Trihydroxymethylaminomethane layer 14 as barrier layer. The layer disposed herein has a sole function of not allowing any chance reaction of the acidic groups of the enteric coating polymer which might lead to degradation of the active. The layer 14 might also function in maintaining alkaline microenvironment for bettering the stability of the drug.
Finally, the entire pellet with layers 11,12,13 and 14 is overcoated with a layer 15, which essentially comprises of a polymer which is known in art for showing enteric characteristic, that is, the a polymer which does not dissolve in acidic pH of around 1 - 2, which is generally observed in gastric sac but dissolves instantly at alkaline pH of the intestine. The necessity of this layer is that, benzimidazoles are generally not stable in the gastric sac, it is imperative that the drug be absolved in intestine

from where it is readily absorbed and are effective in blocking the H+/K+ Proton pumps.
Detailed Description of Invention:
The invention will now be described in details with reference to preferred and optional embodiment, with a view of clearer understanding of the invention and to rule out ambiguity, if any.
For purpose of this invention "drug" or "active" or "D-rabeprazole" or "dexrabeprazole" are used interchangeably. All there terms relate to the d-isomer or d-enantiomer of drug rabeprazole. The said isomer is marketed in India by Emcure under brand name Dexpure® or as Dirab® by Hetero Drugs.
For the purpose of this invention "alkali coated seeds" relates to the seeds coated with a primary amine. With reference to Fig. 1, an alkali coated seed would comprise an inert core 11 together with Trihydroxymethylaminomethane layer 12.
For the purpose of this invention term "alkaline drug pellet" relates to the alkali coated seeds having a drug layer supersede with a layer of primary amine. With reference to Fig. 1, alkaline drug pellet would comprise of alkali coated seed alongwith drug layer 13
As already known from various scientific literatures and general practice in pharmaceutical industry, D-rabeprazole is highly unstable under acidic pH which is

generally witnessed in gastric sac. It is also known that essentially all enteric coated polymers produce acidic microenvironment in pellets or tablets. Owing to maintenance of alkaline microenvironment in a range of 7.0 to 12.0, generally, an alkalizing agent is added which are essentially salts of alkaline metals like Na, Ca or Mg. However, most of these salts are costly and in effect increase the overall cost of production.
Trihydroxymethylaminornethane, as already mentioned, is comparatively cheaper than the alkaline salts, as well as shows a certain degree of antacid activity. Therefore, in an embodiment, the invention provides a pharmaceutical formulation comprising a stable combination of D-rabeprazole and Trihydroxymethylaminornethane having pH in range of 7.0 to 12.0.
In an embodiment, the inner inert core or seed core is made of any conventional material used as seeds, including but not limited to water soluble or insoluble seed selected from microcrystalline cellulose beads, starch beads, sugar beads, inert organic or inorganic material beads, or any other beadlets or commercially available non-peril seeds, granules, particles and micropellets.
The seeds can, optionally be hardened with any hardening polymers selected from but not limited to hydroxypropylmethyl cellulose, hydroxyl propyl cellulose, hydroxyl ethyl cellulose, croscarmellose cellulose or any commercially available cellulose derivate, alginate derivatives or gums, including, but not limited to guar gum, tamarind gum, acacia gum, okra gum, hibiscus gum.

The inner core seeds, optionally hardened, are firstly coated with a primary coat of primary amine, preferably Trihydroxymethylarninornethane. The said primary amine can optionally be mixed with a film-forming polymers selected from, but not limited to, hydroxypropylmethyl cellulose, hydroxyl propyl cellulose, hydroxyl ethyl cellulose, croscarmellose cellulose or any commercially available cellulose derivate, alginate derivatives or natural or synthetic gums, including, but not limited to guar gum, tamarind gum, acacia gum, okra gum, hibiscus gum, karaya gum, veegum, khaya gum, aloe mucilage, albizia gum, locust bean gum, honey locust gum, psyllium mucilage, chestnut gum, tara gum, hakea gum, konjac glucomannan, mimosa mucilage, hupu gum, fenugreek mucilage, and resins and tannins. The said coated seeds are termed as "alkali coated seeds" for the purpose of this description.
The core may, optionally comprise microcrystalline cellulose blended with drug and spheronized to form a seed core which can replace the inert seed cores, resulting in further reduction of manufacturing cost.
The alkali coated seeds are then layered with a drug coat. The said drug coat essentially comprises of drug mixed with primary amine. The said primary amine may be the same as- or different than primary amine used for purpose of coating the inner core or seed core.

The alkaline drug pellets can serve as a starting material for different dosage forms; for example, when granules are used they can form the starting materials for dry suspensions.
In a preferred embodiment, the primary amine used for coating the inner core or seed core is Trihydroxymethylaminomethane.
The hence formed drug pellet is further coated with Trihydroxymethylaminomethane devoid of any other excipient having any function. This layer functions as a barrier layer which protects the drug from acidic enteric coat which may be applied over this layer. The pellet hence formed is termed as "alkaline drug pellet".
The Trihydroxymethylaminomethane coated alkaline drug pellet, as above, is then further coated with an enteric polymer. The enteric polymer can be selected from, but not limited to, hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, hydroxypropylmethyl cellulose acetate succinate, methacrylic acid copolymers, polyvinyl pyrrolidone phthalate etc.
In a preferred embodiment of the invention, firstly, the inner core is coated with Trihydroxymethylaminomethane. Secondly, a second coat will be the drug layer comprising of the drug suspension. The said suspension comprises drug, Trihydroxymethylaminomethane and microcrystalline cellulose of suspension, preferably Avicel 591 or 611. Thirdly, a third layer of the

Trihydroxymethylaminomethane alone or along with polymer, preferably hydroxypropyl cellulose. Finally, a fourth layer comprising the enteric coat is applied over the Trihydroxymethylaminomethane layer. The said enteric coating material is preferable, hydroxypropyl methylcellulose acetate succinate, LF grade or any methacrylic acid copolymers , hydroxypropyl methyl cellulose phthalate or S-100.
In an embodiment, the invention provides an acid-stable pharmaceutical formulation comprising dexrabeprazole and a primary amine. Said primary amine is Trihydroxymethylaminomethane {THAM). The formulation of invention is a pellet formulation, preferably a layered pellet formulation. Said layered pellet formulation comprises:
a. an inert core;
b. a primary coat of Trihydroxymethylaminomethane;
c. a drug coat may optionally comprise a primary amine and
d. a barrier layer
e. an enteric coat
In formulation, as above, the inert core is alkalized with THAM. Further, the barrier coat comprises only THAM without any functional excipients and primary coat may or may not contain any pharmaceutically functional excipients and the drug coat comprises drug admixed with THAM.

The invention is further illustrated by the following example but should not be
construed as limiting the scope of the invention in any way.
Table 1
Formulation: Dexrabeprazole EC pellets 6% w/w

Ingredient Std. Qty Rationale
Seal coat on NPS
HPMC E-5 30.0 Binder
THAM 121.1 Stabilizer
Water 1000.0 * Solvent
NPS(25-30 #) 600.0 Core
Drug Coating on seal coated NPS
Dexrabeprazole Na 18.25 Active
HPMC E5 6.30 Binder
MgO 9.40 Anti-caking agent
NPS(seai coated 25-30#) 100.00 Core
THAM 36.3 Stabilizer
Purified Water q.s. *Solvent
Seal Coating of drug loaded pellets
HPMC E5 12.00 Binder
MgO 1.50 Anti-caking agent
PG Sugar 7.33 Suspending agent, Viscosity increasing agent
Ti02 0.48 Opacifier
THAM 12.14 Stabilizer
Purified water q.s. ""Solvent
Drug loaded pellets 100.00 Active
Enteric Coating of drug loaded and fu rther seal coated pellets
Eudragit L 30 D 83.34 Polymer
NaOH 0.2 Alkalizing agent
Tween 80 0.82 Surfactant, wetting agent
Purified Talc 6.0 Anti-caking agent, glidant
Titanium Dioxide 0.82 Opacifier
Triethyl Citrate 2.50 Plasticizer

Purified Water 57.6 * Solvent
Seal coated drug loaded pellets 100.00 Active
Procedure:
1. Seal coating of NPS
1. Dissolve THAM in purified water .Check pH and adjust with cone. HC1 if required.
2. Dissolve HPMC E5 in above solution of step 1 under stirring to obtain a clear solution.
3. Load the NPS into the FBC bowl and pre heat the same and then start the coating the NPS.
4. Continue the coating and dry the coated pellets. Use these seal coated pellets for drug loading.
Drug loading:
1. Take sufficient quantity of water in SS container. Dissolve THAM in the purified water .Further dissolve Dexrabeprazole, HPMC E-5 in order.
2. Disperse MgO in above solution and stir.
3. Load the Seal coated NPS in FBC bowl and start drug loading and continue till the entire solution is used to achieve the required drug load.
4. Dry the drug loaded pellets.
Seal coating of drug loaded pellets:
1. Take specified quantity of purified water in SS container. Dissolve THAM, HPMC E -5 and PG sugar in specified order.
2. Disperse MgO and Titanium Dioxide in above solution and stir for 10 min. Filter the solution.
3. Load the Drug loaded pellets in FBC and start seal coating using solution of step 2.
4. On completion further dry the pellets in FBP.

Enteric coating of drug loaded and further seal coated pellets:
1. Take half quantity of specified quantity of Purified water, into this dissolve NaOH, Tween 80 and Triethyl Citrate.
2. Take remaining quantity of water into this disperse Eudragit L 30 D.
3. Add solution of step 2 into step 1.
4. Add specified quantity of talc into above step.
5. Finally disperse Titanium Dioxide in above step solution and stir till it gets dispersed. Filter the solution.
6. Load the Seal Coated drug loaded pellets in FBP and start Enteric Coating using the above solution of step 5.
7. On completion dry the pellets in FBP maintaining inlet temp around 45° C.
8. Additional coating may be required to obtain results.
9. Sieve the product through the required sieve.
The enteric coating of the seal coated drug loaded pellets of step (iii) can also be achieved using HPMC phthalate or S100 as depicted in Table la. Table la

Enteric Coating of drug loaded and further seal coated pellets
Ingredients Composition 1 Composition 2
HPMC Phthalate 55 18.00 - Polymer
S100 - 2.0 Polymer
Cetyl Alcohol 2.0 Surfactant, wetting agent
Triethyl Citrate 2.0 0.50 Plasticizer
Isopropyl alcohol 110.00 50.00 * Solvent
Acetone 220.00 100.00 *Solvent
Seal coated drug loaded pellets 100.00 100.00 Active
*A11 solvents gets evaporated during processing.

We Claim,
1. An acid stable pharmaceutical formulation comprising dexrabeprazole and a
primary amine.
2. The acid-stable pharmaceutical formulation as claimed in claim 1, wherein the primary amine is Trihydroxymethylaminomethane (THAM),
3. The acid-stable pharmaceutical formulation as claimed in Claims 1 and 2 is a pellet formulation.
4. The acid-stable pharmaceutical formulation as claimed in Claim 3 is a layered pellet formulation comprising:
a. an inert core;
b. a primary coat of Trihydroxymethylaminomethane;
c. a drug coat may optionally comprise a primary amine
d. a barrier layer
e. an enteric coat
wherein, the drug may be mixed with same or different primary amine as used in
the primary coat,
and,
wherein the inert core is alkalized by Trihydroxymethylaminomethane
5. The acid-stable pharmaceutical formulation as claimed in Claim 4, wherein
the barrier layer comprises Trihydroxymethylaminomethane without any
functional excipients.

6. The acid-stable pharmaceutical formulation as claimed in Claim 4, wherein the primary coat may or may not contain any pharmaceutically functional excipients.
7. The acid-stable pharmaceutical formulation as claimed in Claim 4, wherein the drug coat comprises Trihydroxymethylaminomethane admixed with drug.