FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"FORMULATIONS OF DOMPERIDONE AND PANTOPRAZOLE
2. APPLICANT
(a) NAME: MEDLEY PHARMACEUTICALS LIMITED
(b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956
(c) ADDRESS: Medley House, D-2, MIDC Area, Street No. 16,
Andheri (East), Mumbai-400 093, Maharashtra, India
3.PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

Technical field:
The present invention relates to a composition comprising two pharmaceutical^ active ingredients, namely domperidone and pantoprazole along with other pharmaceutically acceptable ingredients for the effective treatment of gastrointestinal symptoms such as hyperacidity, nausea and others. More particularly the present invention relates to an oral bilayered composition comprising domperidone and pantoprazole.
Background and prior art:
The chemical name of Domperidone is 5-cholro-l-[l-[3-(2,3-dihydro-2-oxo-lH-benzimidazol-l-yl)propyl]-4-piperidinyl]-l,3-dihydro-2H-benzimidazol-2-one. Domperidone is used to increase the contractions of the stomach and bowel, to treat nausea and vomiting caused by other drugs and to control the GI symptoms associated with the use of dopamine agonists used to treat Parkinson's disease, etc. Domperidone is also referred to as a prokinetic agent. Domperidone acts as a competitive antagonist at dopamine D2 receptors. Dopamine is responsible for inhibiting gastrointestinal motility and reduction of gastric and oesophageal sphincter tone and inhibition of gastro-duodenal co-ordination. Domperidone reverses these effects. Further, Domperidone acts on the chemoreceptor trigger zone, which lies outside the blood brain barrier and therefore also has an anti emetic activity.
Domperidone is available under prescription as tablets for the treatment of functional dyspepsia at doses of up to 80 mg per day or as tablets, suspensions or suppositories for the treatment of emesis (in nausea or vomiting) at oral doses of up to 120 mg per day. Pharmaceutically acceptable salts, e.g. the maleate salt of domperidone may be used instead of domperidone itself.
Pantoprazole is a substituted benzimidazole, 5-(difluoromethoxy) - 2- [[(3, 4- dimethoxy-2- pyridinyl) methyl] sulfinyl] -1 H- benzimidazole sesquihydrate.
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Pantoprazole is used to treat gastroesophageal reflux disease (GERD), a condition in which backward flow of acid from the stomach causes heartburn and injury of the food pipe (esophagus). It is also used to treat conditions where the stomach produces too much acid, such as Zollinger-Ellison syndrome. Pantoprazole is in a class of medications called proton-pump inhibitors. It works by decreasing the amount of acid made in the stomach.
The usual dose for the treatment of peptic ulcer or GERD is the equivalent of 40 mg of pantoprazole once daily.
Domperidone is first disclosed in US4066772 as compounds of the class of 1-(benzazolyalkyl) piperidine derivatives useful as antiemetic agents.
Pantoprazole is first disclosed in EP166287 and US4758579 as an anti ulcerative.
FR2845914 discloses an antiemetic tablet that disintegrates rapidly in the mouth comprising of at least one each of active agent namely metopimazine, metoclopramide, domperidone, dimenhydrinate, diphenhydramine or meclozine.
CN1449757 discloses an orally disintegrating tablet preparation of Domperidone.
CN1456148 discloses a pharmaceutical composition comprising domperidone, metoclopramide etc. for treating constipation.
RU2192848 discloses an antiemetic remedy, containing domperidone as active component
US6319514 describes a pharmaceutical composition comprising domperidone and a NSAID for treatment of acute migraine attacks.
WO0021534 discloses a combination of ibuprofen, lysine and domperidone for treating and/or preventing migraine, migraine-associated nausea and vomiting and headache with nausea following overindulgence.
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US5814339 discloses a film coated tablet comprising as active ingredients, paracetamol and domperidone, and a process for preparing such tablets.
JP11079994 discloses a nasal drop comprising domperidone.
GB2313309 discloses a pharmaceutical composition comprising a combination of NSAID, narcotic (Codeine) with domperidone for migraine attacks.
NZ281236 discloses a film-coated tablet composition comprising paracetamol and domperidone.
The prior art does not disclose a composition combining the two active ingredients, domperidone and pantoprazole.
Objective of this invention:
The objective of the invention is to provide relief from gastrointestinal symptoms associated with the use of various drugs including dopamine agonists to treat Parkinson's disease by combining domperidone and pantoprazole as an oral bilayered composition. The gastrointestinal symptoms include inhibition of gastrointestinal motility, reduction of gastric and oesphageal sphincter tone, inhibition of gastroduodenal co-ordination, nausea and vomiting which can be reversed by domperidone. Other gastrointestinal symptoms include gastroesophageal reflux disease in which backward flow of acid from the stomach causes heartburn and injury to oesophagus and excess secretion of acid by stomach. These symptoms are reversed by pantoprazole.
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Summary of the invention:
The present invention provides a pharmaceutical composition as a bilayered tablet dosage form comprising Domperidone and Pantoprazole for controlling GI tract symptoms such as nausea, vomiting and GERD associated with use of dopamine agonists in Parkinson's disease. The said bi-layered tablet comprises Domperidone in a sustained release form and Pantoprazole in a conventional dosage release form prepared with the aid of various pharmaceutically acceptable excipients by conventional process.
Detailed Description of the Invention:
According to the present invention, there is provided a process for preparing the
composition comprising mixing 30 mg Domperidone, 20-50 mg microcrystalline
cellulose, 5-25 mg HPMC K-4 5-25 mg HPMC K-15(dry) and passing through a mesh;
Dissolving binders such as 1-10 mg HPMC E-5 in isopropyl alcohol (q.s.) and purified
water and granulating the abovementioned dry blend;
Drying the granulates till NMT 2% moisture and passing through a mesh, milling the
over sized granules and again passing through a mesh;.
Mixing the lubricants, 0.5-0.8 mg Purified Talc, 0.5-5.0 mg Magnesium Stearate and
0.25-0.35 mg Ponceau 4R and passing through a mesh;
Mixing the granules with the above mentioned mixture of lubricants and 0.5-8.0 mg
HPMC K-4 and 5.0 - 25 mg HPMC K-15 and compressing at 110.0-123.0 mg in a
bilayer tablet.
According to the present invention, there is provided a process for preparing the composition comprising mixing Pantoprazole, 2.5-4.5 mg Sodium Carbonate, 78.0-82.0 mg Mannitol, 5.0-7.0 mg Crospovidone and 0.2-0.3 mg Quinoline Yellow after passing through a mesh;
Dissolving binders such as 0.2-15.0 mg Methocel E-5 in purified water and granulating the abovementioned dry blend;
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Drying the granulates till NMT 1.5% moisture and passing through a mesh, milling the over sized granules and again passing through a mesh;
Mixing the lubricants, 4.0-6.0 mg Calcium stearate and 4.5-7.0 mg Crospovidone and 11.0-12.5 mg Mannitol and passing through a mesh. Mixing the granules with the above mentioned mixture of lubricants and compressing at 153.0-168.0 mg in a bilayer tablet. Further pre-coating the tablet with 5.0-25.0 mg Eudragit L-100 with plasticizer and opaciflier, seal coating comprising 1.5-5.0 mg HPMC E5 with plasticizer, opacifier and colour and finally coating a final coat comprising 5.0-25.0 mg Eudragit L-100, with plasticizer, opacifier and colour.
Example:
Brief description of tables
Table 1 relates to the item-wise quantities in the Domperidone layer of the tablet
Table 2 relates to the item-wise quantities in the Pantoprazole layer
Table 3 relates to the item-wise quantities in the coating
Table 1

Sr. No. Item Quantity/tablet (in %) Preferred embodiment (in mg)
01 Domperidone BP 20-30 30.0
02 Microcrystalline Cellulose IP 30-40 40.0
03 HPMC K-4 USP 8-9 10.0
04 HPMC K-15 USP 12-14 15.0
05 HPMC E-5 USP 3-5 5.0
06 Isopropyl alcohol* LP. qs qs
07 Purified Water* IP qs qs
08 Ponceau 4R IH 0.2-0.3 0.3
09 HPMC K-4 USP 2-4 4.0
10 HPMC K-15 USP 5-6 6.0
11 Purified Talc IP 2-5 3.0
12 Magnesium Stearate IP 0.5-2 1.0

Sr. No. Item Quantity/tablet (in %)
01 Pantoprazole Sodium Sesquihydrate M/RM/82 25-35
02 Mannitol-25 (Extra fine grade) USP 45-55
03 Sodium Carbonate Anhydrous BP 1-3
04 Crosspovidone USP/NF 3-5
05 Quinoline Yellow ws IH 0.1-0.2
06 Methocel E5 USP 0.1-1
07 Purified Water IP* qs
08 Mannitol-25(Extra fine grade) USP 7-8
09 Crosspovidone USP/NF 2-5
10 Calcium Stearate BP 2-4

Sr.No. Item Quantity/tablet (in %) Preferred embodiment (in mg)
01 Eudragit L-l00 USP 40-50 16.0
02 Isopropyl alcohol* IP qs qs
03 Acetone* IP qs qs
04 Dibutyl phthalate IP 9-10 6.0
05 Purified Talc IP 15-20 6.0
06 Hydroxy propyl methyl Cellulose E-5 (Colorcon) IP 8-10 3.2
07 Methylene Chloride*M/RM/32 qs qs
08 Polyethylene Glycol 6000 IP 6-7 2.4
09 Titanium dioxide IP 9-12 3.8
31 Yellow iron oxide 2-3 0.9

The preferred embodiment is performed by the following process:
I) Preparation of Domperidone granules
Domperidone, Microcrystalline Cellulose, HPMC K4, and HPMC K 15 are passed
through suitable
mesh sieve and are mixed in a Planetary mixer,
HPMC E-5 is added to Isopropyl Alcohol under stirring, further to it Purified
Water is added till a uniform translucent paste is formed,
The dry mixed material is granulated using binder solution of HPMC-5 in a planetary
mixer set at high speed, The granules formed are dried at 60±5°C in a fluid bed drier till
loss on drying is below 1.5% and the granules are sifted through appropriate mesh sieve,
The lubricants are passed through appropriate mesh sieve and are mixed geometrically
with the granules in a blender.
II) Preparation of Pantoprazole granules
Pantoprazole Sodium Sesquihydrate, Mannitol-25, Sodium Carbonate Anhydrous,
Crosspovidone and QuinolineYellow are passed through a suitable mesh sieve and mixed
in a Planetary mixer at slow speed,
Methocel E-5 is dissolved in Demineralised water under stirring till uniform
translucent mass is formed,
The dry material is granulated with the binder of Methocel E-5 solution in the
planetary mixer at high speed,
The granules are dried in fluid bed drier at 55±5°C.
The semi dried granules are passed through appropriate mesh sieve and are dried till
moisture content is 1.5%.
The lubricants are mixed, sifted through appropriated mesh sieve and are geometrically
mixed with granules.
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III) Compression
Compress the two granules formed as a bilayered tablet on a tabletting machine controlling tabletting parameters such as tablet weight, diameter, thickness and hardness.
IV) Coating
Coating is carried out in three stages :
1. Precoating
2. Seal coating
3. Final coating
A lacquer solution is prepared comprising Eudragit-L-100 is prepared and Dibutyl phthalate and Talc in Isopropyl alcohol and water. Precoating is carried out by coating the tablets with precoating solution comprising lacquer solution and Talc in Isopropyl alcohol and Acetone controlling coating process parameters such as pan rpm, spray rate, air temperature and bed temperature,
The tablets obtained after precoating are seal coated with seal coating solution comprising HPMC E-5, Talc, PEG-6000 and colour in Isopropyl alcohol, Methylene chloride and water controlling coating process parameters such as pan rpm, spray rate, air temperature and bed temperature,
The tablets after seal coating are finally coataed with a final coating solution comprising lacquer solution, Talc, Titanium dioxide, PEG 6000 and colour in Isopropyl alcohol, Acetone and water controlling coating process parameters such as pan rpm, spray rate, air temperature and bed temperature.
While the present invention is described above in connection with preferred or illustrative embodiment, this embodiment is not intended to be exhaustive or limiting of the invention. Rather, the invention is intended to cover all alternatives, modifications and equivalents included within scope, as defined by appended claims.
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We Claim:
1. Bilayered tablet compositions for controlling GI tract symptoms and side-effects associated with use of dopamine agonists in Parkinson's disease, comprising the active ingredients Pantoprazole as Pantoprazole Sodium Sesquihydrate and Domperidone in the form of base and pharmaceutically acceptable excipients such as fillers, binders, release modifying agents, solvents, lubricants, glidants, film-formers, plasticizers and various colouring agents.
2. Tablet formulations as in claim 1 wherein one layer of the said bilayer tablet consists of Domperidone in sustained release form and the second layer of the said bilayer tablet consists of Pantoprazole in conventional dosage release form.
3. Tablet formulations as claimed in claims 1 and 2 wherein sustained release of Domperidone is achieved using cellulose polymers as release modifying agents, wherein the cellulose polymers are selected from Carbopol, Xanthan Gum particularly Hydroxypropylmethyl cellulose and its various grades, more particularly HPMC K-4 in the range of 5-25 mg, and HPMC K-15 in the range of 5-25 mg.
4. Tablet formulations as claimed in claim 1 wherein the binders are selected from PEG 6000, P V P K 30 particularly Hydroxy propylmethyl cellulose, more particularly HPMC E-5 in the range of 1-10 mg in Domperidone layer and Methocel E-5 in the range of 0.2-15.0 mg in Pantoprazole layer.

5. Tablet formulations as claimed in claim 1 wherein the fillers are selected from Starch, Lactose and Avicel particularly Microcrystalline cellulose in the range of 20-50 mg in Domperidone layer and Mannitol, Crospovidone and Sodium Carbonate in the ranges of 78.0-82.0 mg, 5.0-7.0 mg, 2.5-4.5 mg respectively in Pantoprazole layer.
6. Tablet formulations as claimed in claim 1 wherein lubricants and glidants are selected from Stearic Acid, Cocoa butter particularly Purified Talc in the range of 0.8-0.8 mg and Magnesium stearate in the range of 0.5-5.0 mg in Domperidone layer and Calcium stearate in the range of 4.0-6.0 mg in Pantoprazole layer.
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7. Tablet formulations as claimed in claim 1 wherein the said tablet is enteric coated, wherein enteric coating agents are selected from Cellulose acetate phthalate and Hydroxypropyl methyl cellulose, particularly polymethylmethacrylic acid esters (Eudragit) in the range of 5.0-25.0 mg.
8. Tablet formulations as in claims 1 to 7 wherein the final form of the tablet is in film coated form wherein film coating agents are selected from Hydroxypropylmethyl cellulose, PV P K 30 particularly Hydroxypropylmethyl cellulose, HPMC E5 in the range of 1.5-5.0 mg.
9. Tablet formulations as claimed in claims 1 to 8 wherein the plasticizer used in film coating and enteric coating are selected from Carboxyl acetate phthalate, particularly Dibutyl phthalate.
10. Tablet formulations as claimed in claim 1 wherein Hydroxypropylmethyl cellulose and its various grades are used in granulation stage as binder cum release modifying agent and in lubrication stage as release modifying agent.
11. Tablet formulations as substantially described herein with reference to the
foregoing example.

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Abstract
The invention discloses a bilayered tablet composition comprising Domperidone in sustained release dosage form and Pantoprazole in conventional release dosage form for the effective treatment of gastro-intestinal symptoms related to the treatment of Parkinson's disease with dopamine agonists.