DESCRIPTION
FIELD OF THE INVENTION
The present invention is related to a formulation used in the management of GERD (Gastro
Esophageal Reflux Disease). Further, the present invention is related to a long acting
formulation containing proton pump inhibitor (PPI). Further, the present invention is related to a
long acting formulation containing a proton pump inhibitor and prokinetic agent.
BACKGROUND OF THE INVENTION
Generally the Proton Pump Inhibitor is taken once daily in the morning with empty stomach so
as to improve the bioavailability. However, the Proton Pump inhibitor often works only for 16-18
hours thus leading to chances of nocturnal acidity. Although, various formulation available in the
prior art formulated the sustained release or extended release formulations of PPI , however
none of them is able to provide the action for 24 hours due to typical chemical nature of the PPI.
Proton pump inhibitors (or "PPIs") are a class of pharmaceutical compounds that inhibit gastric
acid secretions by inhibiting H+/K+ adenosine triphosphate, an enzyme present in parietal cells
found in the gastric lining of the stomach. H+/K+ adenosine triphosphate is variously referred to
as an "acid pump" or "proton pump" and examples of PPI's include Rabeprazole,
Esomeprazole, lansoprazole, omeprazole, and pantoprazole. PPIs rapidly degrade in acidic
environments and therefore, dosage forms containing PPIs generally are designed to protect
the PPI from the acidic environment of the stomach. Specifically, such dosage forms are
designed such that a single dose of the PPI is released in the upper small intestine where the
PPI can be absorbed. PPI are metabolized in the parietal cells to produce active sulfonamide
metabolites that inactivate the proton pump thus reducing the hydrogen ion secretion.
LHI 1 7 - 0 4 - 2 0 17 17 : 5
PPIs bind to cysteine 813, resulting in covalent inhibition of the enzyme via formation of
disulphide that stabilizes the enzyme in the E2 conformation. Several salient features required
for the activity are
a) The weak basicity of the compounds (pka » 4), allowing them to accumulate in the acid space
adjacent to their site of action,
b) The sulphoxides undergoes Smile's rearrangement to form spiro intermediate,
c) The active thiophillic group binds to thiol group of enzymes and generates disulphide bridges
to cause enzyme inactivation.
The protonation in the pyridine nitrogen initiates the formation of spiro intermediate and then
sulfenamide. This sulphenamide binds covalently to sulfhydryl groups of cysteines of proton
pump. The introduction of methyl group in the 6 position of the pyridine ring of the sulfinyl
benzimidazole makes the compound more stable in acid medium, prevents the formation of
spiro intermediate and supports the suggested mechanism. The anti-oxidant defence protein
hemeoxygenase (HO-1) is a target of PPIs in both endothelial and gastric epithelial cells. HO-1
induction might account for the gastro-protective effects of PPIs independently of acid inhibition.
The therapeutic effect of PPIs does not directly correlate with serum concentrations of these
drugs. Although, the therapeutic effect of these drugs is longer, however some patients may
experience nocturnal acidity. Thus, there might be some acidity during the night.
For PPIs, once the plasma concentration is more than 100ng/ml, a therapeutic response is
obtained. Further, the maximum therapeutic response is obtained at the plasma concentration
greater than 250mg/ml. Peak plasma concentrations for PPIs typically occur within 1-3 hours
after ingestion, and the half-life of such drugs is generally short, usually less than 2 hours.
US 20100086572 provides for a continuous release dosage form (which is referred to as
"dosage forms") comprising a continuous release dosage form, which releases PPI in a first
release portion directly to the gastric mucosa and a second release portion to provide for
sustained plasma levels resulting in increased therapeutic efficacy.
CA 2570916 provides dosage forms (variously referred to as "formulations") comprising a PPI
that is released from the dosage form as a first and a second dose. Each dose of PPI is present
in an amount sufficient to raise the plasma levels of the PPIto at least 100 ng/ml.
US 20080003281 discloses oral solid pharmaceutical dosage form comprising an acid sensitive
proton pump inhibitor (PPI) as single active drug, releasing the PPI in two separate pulses, one
immediate and one delayed. The PPI is formulated into a core material in the form of tablets,
which are coated i.a. with a combination of a delay release modifying layer and a lag time
controlling layer that together achieves beneficial release properties. The tablets are further
provided with an enteric coating layer. The application also relates to processes for preparing
the dosage forms as well as their use in the treatment of gastrointestinal diseases.
CN 101305995 relates to a compound preparation containing domperidone and pantoprazole
sodium, and a preparation method. In the compound preparation, the domperidone comprises a
sustained-release part and an immediate-release part, and the pantoprazole sodium is a
common release component. The invention discloses a preparation method of the compound
preparation.
674/MUM/2004 relates to stable pharmaceutical composition of rabeprazole sodium in a form of
enteric coated pellets, either alone or in combination with one or more prokinetic agent,
preferably mosapride in a form of sustained release tablets, in a single unit dosage form, which
provides enhanced bioavailability of rabeprazole. Present invention also discloses process for
preparation of said pharmaceutical formulation.
L H I 1 7 - 8 4 - 2 0 1 7 1 7 : 3
None of the above formulations uses the lag time concept with sustained release formulation.
Thus there is need of a formulation that uses the lag time concept along with sustained release
action so as to provide a formulation the effect of which last for 24 hours.
OBJECTIVE OF THE INVENTION
The object of the present invention is to provide a formulation that effectively reduces nocturnal
acidity.
Another object of the present invention is to provide a formulation that is effective for 24 hours.
Yet another object of the present invention is to provide a formulation that uses a time lag
concept.
Another object of the present invention is to provide a formulation that provides a time lag and
sustained release action simultaneously.
Another object of the present invention is to prepare a formulation of PPI and Domperidone
which is effective for 24 hours.
Another object of the present invention is to provide a formulation which effectively manages
Gastro Esophageal Reflux Disease (GERD) for longer period.
DETAILED DESCRIPTION OF THE INVENTION
PPI are the mainstay treatment for acidity and an important component in the treatment of
GERD. Although PPI are considered to follow once-a-day treatment regimen, however, in many
cases they are not effective throughout the day and thus not ensuring proper protection form
acidity for full day, leading to nocturnal acidity.
Hence the present invention provides a formulation with a dosing regimen that fills the gaps
identified in the prior art. Further, the lag time concept and the modified release concept have
been simultaneously used in the present formulation.
The formulation is prepared in such a manner that the first part of the formulation is immediately
release in the intestine and attaches to its receptors thereby immediately relief from acidity.
Further, the other part will release in a sustained manner after a pre determined lag time so as
to assure that all of the PPI releasing from the formulation attaches to its receptor and almost no
PPI excreted out from the body without giving its effect. Further, the formulation will work for an
extended period of time.
The dosage form may include but not limited to tablets, capsules, tablet in capsules, pellets in
capsules or pellets & tablets in capsule.
The PPI or Proton Pump Inhibitor includes the pharmaceutical acceptable salts and also
includes salts, esters, ethers, polymorphs, metabolites, pure form, isomers, mixtures of isomers,
and complexes.
The Proton pump inhibitor includes, but not limited to, pantoprazole, rabeprazole, omeprazole,
esomeprazole, lansoprazole etc.
In a preferred embodiment, the proton pump inhibitor is omeprazole.
The prokinetic agent includes, but not limited to, domperidone, levosulpiride, mosapride,
cisapride etc.
In a preferred embodiment, the prokinetic is domperidone.
In a preferred formulation, the actives consist of Omeprazole and domperidone. The formulation
is in capsule dosage form. In this formulation, there are 4 tablets in a capsule. One tablet of
Omeprazole Enteric coated for relatively immediate action, one tablet of Omeprazole Enteric
coated sustained release which provides action for longer duration, one tablet of domperidone
immediate release and the 4th tablet consists of domperidone sustained release.
D L H I 1 7 - 0 . 4 - 2 0 1 7 17 :
In another preferred formulation, the actives consist of Omeprazole and domperidone. The
formulation is in capsule dosage form. In this formulation, there are 2 tablets and pellets in a
capsule. One tablet of Omeprazole Enteric coated for relatively immediate action, one tablet of
Omeprazole Enteric coated sustained release which provides action for longer duration, and the
pellets contain sustained release domperidone.
According to another preferred formulation, 3 tablets are placed in a capsule in which one tablet
is enteric coated omeprazole, one tablet enteric coated sustained release tablet and one tablet
consists of sustained release domperidone.
The sustained release tablet of PPI in the embodiments is prepared in such a manner so as to
provide the effect on proton pump inhibitor
The particles of the present invention may comprise, in addition to the active substances, also
excipients such as fillers, binders, disintegrants, glidants and lubricants.
Suitable fillers are microcrystalline cellulose, powdered cellulose, lactose, starch, pregelatinized
starch, sucrose, glucose, mannitol, sorbitol, calcium phosphate, calcium hydrogen phosphate,
aluminium silicate, sodium chloride, potassium chloride, calcium carbonate, calcium sulfate,
dextrates, dextrin, maltodextrin, glycerol palmitostearate, hydrogenated vegetable oil, kaolin,
magnesium carbonate, magnesium oxide, polymethacrylates, talc and others, preferably
microcrystalline cellulose and lactose. Suitable binders are starch, pregelatinized starch, gelatin,
sodium carboxymethylcellulose, polyvinylpyrrolidone, alginic acid, sodium alginate, acacia,
carbomer, dextrin, ethylcellulose, guar gum, hydrogenated vegetable oil, methylcellulose,
hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, glucose syrup,
magnesium aluminium silicate, maltodextrin, polymethacrylates, zein, preferably hydroxypropyl
cellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone.
i :LHI. 17 - 8 4 - 2 0 1 7 1 7 : 35
Suitable disintegrants are starch, pregelatinized starch, sodium starch glycolate, sodium
carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, calcium
carboxymethylcellulose, methylcellulose, microcrystalline cellulose, powdered cellulose,
potassium polacrilinin, cross-linked polyvinylpyrrolidone, alginic acid, sodium alginate, colloidal
silicon dioxide, guar gum, magnesium aluminium silicate and others, preferably sodium starch
glycolate, cross-linked sodium carboxymethylcellulose and cross-linked polyvinylpyrrolidone.
Suitable glidants are magnesium stearate, calcium stearate, aluminium stearate, stearic acid,
palmitic acid, cetanol, stearol, polyethylene glycol of different molecular weights, magnesium
trisilicate, calcium phosphate, colloidal silicon dioxide, talc, powdered cellulose, starch and
others, preferably colloidal silicon dioxide.
Suitable lubricants are steraic acid, calcium, magnesium, zinc or aluminium stearate,
siliconized talc, glycerol monostearate, glycerol palmitostearate, hydrogenated castor oil,
hydrogenated vegetable oil, mineral oil, light mineral oil, polyethylene glycol, sodium benzoate,
sodium lauryl sulfate, sodium stearyl fumarate, talc and others. Preferred lubricants are
magnesium and calcium stearate, and stearic acid.
The formed particles of the present invention have good flow and compressible properties.
Formed particles of the invention may optionally be coated with a release controlling coating or
with a protective coating. The coating may be prepared from polymer or nonpolymer
substances. Suitable polymers that may be used are hydroxypropyl cellulose, hydroxypropyl
methylcellulose, methylcellulose, ethylcellulose, hydroxyethyl cellulose, sodium
carboxymethylcellulose, cellulose phthalate acetate, polyvinyl acetate phthalate, hydroxymethyl
cellulose phthalate, polyvinyl alcohol, methylhydroxyethyl cellulose, polymers of acrylic and
methacrylic acid, maltodextrin and others. Nonpolymer substances that may be used are
carnauba wax, cetyl alcohol, sucrose, glucose, shellac and others. The coating may optionally
PO DELHI; 17-04-2017 17:35
comprise other coating agents conventionally used in coating such as fillers, e.g. talc, lactose,
polysaccharides and others, plasticizers, e.g. dibutyl sebacate, triethyl citrate, polyethylene
glycol, adipic acid, coconut oil, oleic acid and others, colourants, e.g. titanium dioxide, lakes,
pigments and others, antioxidants and others.
The modified release tablet of PPI will have a lag time of not less than 2 hours preferably 3
hours relative to the immediate release tablet. The dissolution profile of the modified release
tablet is managed in such a manner that the effect lasts for 24 hours.
The preferred embodiment can be developed, but not limited to, in the following manner:
A) Manufacturing Omeprazole Enteric coated Tablet
1) The following ingredients were weighed:
S.NO. INGREDIENTS QUANTITY (gm)
Dry Mixing Materials
1
2
3
4
5
6
Omeprazole Magnesium
eq. to Omeprazole
Pregelatinised starch
Sodium Carbonate
Dibasic calcium Phosphate
Starch
Sodium Starch Glycolate
572.615
147.50
50.00
225.00
150.00
150.00
Binding Materials
7
8
Hydroxy Propyl Cellulose
Purified Water
25.00
650.00 ml
Lubrication Materials
9
10
11
12
13
Magnesium stearate
Sodium starch glycolate
Talcum
Croscarmellose Sodium
Colloidal Silicon dioxide
25.00
225.00
5.00
62.50
12.50
Coating Materials
For Seal coating
1
2
Akoat512
Purified water
80
560.00 ml
For Enteric coating
1
2
3
Akoat EC-151
Col. Indigo Caramine Lake
Purified water
248.00
4.50
1700.00 ml
L H I 1 . 7 - 0 4 - 2 0 1 7 17:
2) SIFTING
The materials were sifted with suitable sieves
S.NO
1
2
3
4
5
6
INGREDIENTS
Omeprazole Magnesium
eq. to Omeprazole
Pregelatinised starch
Sodium Carbonate
Dibasic calcium Phosphate
Starch
Sodium Starch Glycolate
SIEVE NO
#30
#40
#40
#40
#100
#40
3) DRY MIXING
Transfer sifted Omeprazole magnesium, Pregelatinised Starch, Sodium Carbonate, Dibasic
calcium phosphate, starch and sodium starch glycolate in to RMG and mix at slow speed of
impeller for 10 minutes.
4) BINDER PREPARATION
Dissolve HPC 25 gm in 400 ml Purified water and stir well to get a clear solution.
5) WET MIXING
Pour the binder of step 4 in the RMG containing dried mixed material at slow speed of impeller
for 5 minutes. After addition of Binder, mixing was continue at slow speed of Impeller and
Chopper for about 3 minutes. Add additional quantity 250 ml of Purified water and again mixed
for 2 minute at impeller slow to get the desired granules.
6) WET MILLING
Pass the wet mass using sieve #8.
7) DRYING
Dry the wet milled material in FBD at inlet temperature 60°-65°C for the time 40 minutes to get
moisture content between 2,5% to 3.5 % w/w.
8) SIFTING
P O D E L H I 1 7 - 0 4 - 2 0 1 7 1 7 : 35
Sift the dried granules sieve #24.
9) MILLING
Mill the sieve tops using multimill with 1 mm screen. Sift the milled material through #24 sieve.
10) LUBRICATION
a) Sift the material:
b)
S.NO
1
2
3
4
5
COMPOSITION
Magnesium stearate
Sodium starch glycolate
Talcum
Croscarmellose Sodium
Colloidal Silicon dioxide
SEIVE NO
#40
#40
#40
#40
#40
ransfer the sized and dried granules of step 8 and 9 and sifted lubricants except Magnesium
stearate into cleaned V blender and blend for 10 minutes at approximately 12 RPM.
c) Then add Magnesium stearate Batch to step b and blend for 5 minutes at 12 RPM
11) COMPRESSION
The material obtained in step 10 was compressed to form tablets.
12) COATING
The tablets were undergone seal coating followed by enteric coating.
B) Manufacturing Omeprazole Extended Release Enteric coated Tablet
1) The following ingredients were weighed:
S.NO.
Dry Mixing Materials
1
2
3
4
5
Binding Materials
7
8
Lubrication Materials
9
10
Coating Materials
INGREDIENTS
Omeprazole Magnesium
eq. to Omeprazole
Sodium Carbonate
MCC
Dibasic calcium Phosphate
Methocel
Polyvinyl pyrrolidone
Isopropyl Alcohol
Magnesium stearate
Colloidal Silicon dioxide
QUANTITY (gm)
572.615
75.00
281.40
338.00
195.00
18.00
750.00 ml
25.00
15.00
- 2 0 1 7 . 1 7 :3
For Seal coating
1
2
Akoat512
Purified water
50
300.00 ml
For Enteric coating
1
2
3
4
5
6
7
AcrycoatS-100
Triethyl citrate
Talcum
Col. Red Oxide of Iron
Acetone
Isopropyl Alcohol
Purified water
141.00
14.00
71.00
3.00
1027.00
1200.00
96.50
2) SIFTING
The materials were sifted with suitable sieves.
S.NO.
1
2
3
4
5
INGREDIENTS
Omeprazole Magnesium eq. to Omeprazole
Sodium Carbonate
MCC
Dibasic calcium Phosphate
Methocel
Sieve
#30
#40
#40
#40
#40
3) DRY MIXING
Transfer the sifted materials of Step 2 into RMG and mix at slow speed of impeller for 10
minutes.
4) BINDER PREPARATION
Dissolve polyvinyl pyrrolidone 18.00 gm in 400.00 ml of Isopropyl alcohol and stir well to get a
clear solution.
5) WET MIXING
Pour the binder of step 4 in the RMG containing dried mixed material at slow speed of impeller
for 3.0 minutes. After addition of binder, mixing was continue at slow speed of impeller and
chopper for about 2.0 minutes. Add additional quantity 350.00 ml of Isopropyl alcohol and again
mixed for 2 minutes at impeller slow to get desired granules.
6) WET MILLING
PO DELHI. 17-04-2017 17:
Pass the wet mass using sieve #8.
7) DRYING
Air dry the wet milled material for 5 minutes in FBD then dry at inlet temperature 45-50°C for the
time 30 minutes to get moisture content between 3.0 to 3.5% w/w.
8)-SIFTING
Sift the dried granules through 24 sieve.
9) MILLING
Mill the sieve tops using multimill with 1.0 mm screen (Knife forward and slow speed). Sift the
milled material through 24 mesh.
10) LUBRICATION
a) Sift the material as per the sieve size mentioned in the below material:
S.NO
1
2
Ingredients
Magnesium stearate
Colloidal Silicon dioxide
Sieve Number
#40
#40
b) Transfer the sized and dried granules of step 8&9 and sifted lubricants as Colloidal Silicon
dioxide into a cleaned V Blender and blend for 10 minutes at 12 RPM.
c) Then add Magnesium stearate Batch to step b and blend for 5 minutes at 12 RPM.
11) COMPRESSION
The granules obtained were compressed to form a tablet.
12) COATING
a) Seal Coating:
Take Akoat-512 50 gm in 300 ml of purified water and colloid for 30 minutes in colloid mill then
sieve with 200 nylon mesh. The end product is used for seal coating the tablets.
L K I 1 7 - 8 4 - 2 . 0 1 7 1 7 :3
b) Enteric coating
i) Take Acetone 1027 gm, Isopropyl alcohol 1027 gm and purified water 96.50 gm in container.
ii) In half quantity of above solvent mixture, 3 gm Iron oxide was added and and colloid for 5
minutes.
iii) After 5 minutes in this solution add Acrycoat S-100 and mixed for 45 minutes.
iv) To other half quantity, Triethyl citrate 14 gm and Talcum 71 gm was added and mixed for 15
minutes.
v) Solutions obtained from step iii and step iv are mixed and colloid for 10 minutes.
vi) The end product is used for coating the tablets obtained after seal coating in step 12.
C) Manufacturing Domperidone Sustained Release Tablet
1) The following ingredients were weighed:
S.NO.
1
2
3
4
INGREDIENTS
Domperidone
MCC
Methocel K-4M
MethocelK-100LV
QUANTITY (gm)
757.637
992.00
475.00
150.00
Binding Materials
5
6
Polyvinyl pyrrolidone
Isopropyl Alcohol
100.00
1700.00 ml
Lubrication Materials
7
8
Magnesium stearate
Colloidal Silicon dioxide
13.00
13.00
Coating Materials
1
2
3
Akoat512
Col. Indigo Caramine Lake
Purified water
70.00
4.00
450.00 ml
The materials were sifted with suitable sieves.
S.NO.
1
2
3
4
INGREDIENTS
Domperidone
MCC
Methocel K-4M
Methocel K-100 LV
QUANTITY (gm)
757.637
992.00
475.00
150.00
Sieved Number
#40
#40
#40
#40
3) DRY MIXING
DELHI 1 7 - 0 4 - 2 0 1 7 1 7 :3
Transfer the sifted materials of Step 2 into RMG and mix at slow speed of impeller for 10
minutes.
4) BINDER PREPARATION
Dissolve polyvinyl pyrrolidone 100.00 gm in 1000.00 ml of Isopropyl alcohol and stir well to get a
clear solution.
5) WET MIXING
Pour the binder of step 4 in the RMG containing dried mixed material at slow speed of impeller
for 5.0 minutes. After addition of binder, mixing was continue at slow speed of impeller and
chopper for about 3.0 minutes. Add additional quantity 700.00 ml of Isopropyl alcohol and again
mixed for 2 minutes at impeller slow to get desired granules.
6) WET MILLING
Pass the wet mass using sieve #8.
7) DRYING
Air dry the wet milled material for 5 minutes in FBD then dry at inlet temperature 45-50°C for the
time 30 minutes to get moisture content between 2.5 to 3.5% w/w.
8) SIFTING
Sift the dried granules through 24 sieve.
9) MILLING
Mill the sieve tops using multimill with 1.0 mm screen (Knife forward and slow speed). Sift the
milled material through 24 mesh.
10) LUBRICATION
a) Sift the material as per the sieve size mentioned in the below table:
S.NO
1
2
Ingredients
Magnesium stearate
Colloidal Silicon dioxide
Sieve Number
#40
#40
b) Transfer the sized and dried granules of step 8&9 and sifted lubricants as Colloidal Silicon
dioxide into a cleaned octagonal Blender and blend for 10 minutes.
c) Then add Magnesium stearate Batch to step b and blend for 5 minutes.
11) COMPRESSION
The granules obtained were compressed to form a tablet.
12) COATING
i) Take Col. Indigo Caramine Lake 4.0 gm dissolved in purified water 450 ml gm and colloid for 5
minutes in colloid mill.
ii) After that add 70.00 gm Akoat-512 in it.
iii) Further, colloid the solution in colloidal mill for 25.00 minutes.
iv) Filter the coating solution through 200 nylon mesh and use the solution for film coating.
The tablets so obtained with the above processes are put in the capsules to get the novel
formulation.
On dissolution of the above novel formulation, the time lag in initiation of the release of
omeprazole immediate release enteric coated and Omperazole sustained release enteric
coated was found to be 3 hours.

CLAIMS
We claim:
1) A long acting pharmaceutical formulation for the management of GERD and related
symptoms comprising an acid-release inhibitor.
2) The acid release inhibitor as claimed in claim 1 can be selected from Proton pump inhibitors
or H2 receptor antagonist.
3) Formulation claimed in claim 1 further comprises prokinetic agent preferably domperidone.
4) The proton pump inhibitors as claimed in claim 2 can be selected from Dexlansoprazole,
Esomeprazole, llaprazole, Lansoprazole, Omeprazole, Pantoprazole, Rabeprazole,
Tenatoprazole and Timoprazole.
5) H2 Antagonist as claimed in claim 2 can be selected from Cimetidine, Famotidine, Lafutidine,
Ranitidine and Roxatidine.
6) The formulation claimed in claim 1 may have multiple release profile of acid release inhibitor
wherein first release is immediate and the second release is sustained.
7) The immediate and sustained release profile as claimed in claim 5 may have the time gap of
not less than 2 hours more preferably 3 hours, between initiations of release.
8) The formulation as claimed in claim 1 may be pellets in capsule, Tablets in capsule or Tablets
and pellets in capsule.
9) Formulation claimed in claim 3 preferably contains 1 tablet of immediate release enteric
coated omeprazole, 1 tablet of sustained release enteric coated omeprazole and 1 tablet of
sustained release domperidone.