DESC:FIELD OF INVENTION
The present invention relates to pharmaceutical composition comprising a prazole as an active ingredient and wherein the formulation exhibits dual drug release profile.
BACKGROUND OF THE INVENTION: 5
Indian patent application IN201841017811 describes prazole formulation with dual drug release profile. The same was obtained by coating a core containing the active ingredient with a two extended release polymer layers. The extended release polymers are selected from pH depended release polymer and pH independent release polymer. 10
Indian patent application IN 1551/MUM/2015 discloses a composition wherein it is prepared by coating a core containing the active ingredient with multiple layers containing release controlling polymers and a drug layer coated over the release controlling layers. Finally, an enteric coat is applied over the drug layer. U. S. Patent application No 5997903 discloses pantoprazole composition that consists of a core, 15 an intermediate layer surrounding the core and an outer gastric acid resistant layer surrounding intermediate layer.
U. S. Patent Application No 2006/165797 discloses composition comprising PPI wherein the active ingredient is present in outer coat and inner delayed release coat. The outer coat is not enteric coated and quickly dissolves in the stomach of a 20 patient immediately after ingestion (60 min).
PCT publication No. WO1999/032093 discloses solid forms of PPI comprising a core and multiple layers coated over the same to obtain the desired delayed and immediate release tablets.
3
Almost all of the existing prior art teaches the preparation of dual release prazole composition by multilayer tablet technologies. Even though progress has been made in developing multi-layered matrix tablet formulations, several issues are still being faced by formulator which includes layer separation, insufficient hardness, inaccurate individual layer weight control, and cross-contamination between the 5 layers. The Separation of each individual layer in a multi-layered tablet is a common problem and significantly impacts the quality and efficacy of the product. It can occur during the compression and/or the dissolution process. The main cause of the separation can be insufficient bonding between the adjacent layers during the tablet compression. However, this issue can be relieved by assessing the force required to 10 separate the layers of a multi-layered tablet. This might help to identify why each layer separates and to consequently take corrective action effectively. Manufacture of such a formulation and its scale-up are also challenging and a thorough understanding of tablet press design, process parameters and formulation components is required. 15
Thus there is still needs in the art for alternative formulations that overcomes the problems associated with multi-layered tablets and are stable.
OBJECTIVE
An objective of the present invention is to provide a pharmaceutical composition comprising two separate individual solid units, wherein the two individual units are 20 a solid inner core and an outer solid shell and wherein the outer solid shell is compressed over the solid inner core to form a single unit solid pharmaceutical tablet.
Another objective of the present invention is to provide a dual release enteric coated pharmaceutical composition comprising two separate individual solid units, 25 wherein the two individual units are a solid inner core and an outer solid shell and
4
wherein the outer solid shell is compressed over the solid inner core to form a single unit solid pharmaceutical tablet.
Another objective of the present invention is to provide a pharmaceutical composition wherein the composition comprises an inner solid core or an inner tablet comprising atleast 30-50% of the active ingredient and an outer shell 5 comprising atleast 30%-50% of the active ingredient wherein the outer shell is compressed on the inner solid core and wherein the composition exhibits dual drug release profile.
Another objective of the present invention is to provide a pharmaceutical composition comprising a Prazole as an active ingredient , wherein the composition 10 is composed of an inner solid core comprising about 30%-50% of the Prazole as an active ingredient and pharmaceutically acceptable excipients and an outer shell compressed into the inner solid core comprising about 30%-50% Prazole as an active ingredient and pharmaceutically acceptable excipients, wherein the composition exhibits dual drug release profile. In another embodiment prazole is a proton pump 15 inhibitors (PPI’s).
Yet another objective of the present invention is to provide a pharmaceutical composition comprising a Prazole as an active ingredient, wherein the composition is composed of an inner core (inner tablet) comprising about 30%-50% of the proton pump inhibitor and pharmaceutically acceptable excipients and an outer shell (outer 20 tablet) compressed into the inner core comprising about 30%-50% proton pump inhibitor and pharmaceutically acceptable excipients, wherein the composition exhibits dual drug release profile.
Another objective of the present invention is to provide a dual drug release pharmaceutical composition comprising a prazole as the active ingredient and 25 wherein the composition comprises an inner solid core comprising about 30% to
5
50% of the active ingredient and an outer shell comprising 30% to 50% of the active ingredient compressed on the inner shell.
Another objective of the present invention is to provide a dual drug release pharmaceutical composition comprising prazole as the active ingredient and wherein the composition comprises an inner solid core comprising about 30% to 5 50% of the active ingredient and an outer shell comprising 30% to 50% of the active ingredient and wherein the outer shell is mechanically compressed on the inner solid core.
SUMMARY:
The present invention related to a pharmaceutical composition comprising Prazole 10 as an active ingredient to provide dual drug release profile wherein composition comprises an inner solid core tablet and outer shell wherein outer shell is compressed on the inner shell.
In another embodiment, the present invention provides a composition comprising inner solid core comprising Prazole as an active ingredient and one or more 15 pharmaceutical acceptable excipients and wherein inner core is further coated with one or more seal coated and enteric coated coating.
In yet another embodiment, the present invention provides a composition comprising outer shell wherein outer shell further comprises Prazole as an active ingredient and one or more pharmaceutical acceptable excipients and wherein 20 outer shell is further coated with seal and enteric coating wherein prazole is a proton pump inhibitors (PPI’s).
In another embodiment, the outer shell is compressed over inner core to obtain a single unit solid pharmaceutical tablet
25
6
BRIEF DESCRIPTION OF FIGURES:
Figure 1 illustrate comparative figure of tablet in tablet of present invention and multi-layer technology of marketed product.
Figure 2 represents graphical representation of Plot of Mean Plasma Concentrations of Pantoprazole vs. Time for Test Product i.e. Tablet-in-Tablet formulation of present 5 invention (T) and Reference Product (R) i.e. marketed formulation.
DESCRIPTION:
The term “pharmaceutical composition” as used herein refers to delivery system in which active agents are delivered to the patients. This could be in the form of tablet, capsule, injection, liquid etc. 10
The term “pharmaceutically acceptable excipient” as used herein refers to inert substances other than active ingredients which are used in the preparation of pharmaceutical products.
The term “single unit solid pharmaceutical tablet” as used herein refers to single solid pharmaceutical dosage form containing the active medicament and 15 pharmaceutically acceptable excipients.
The term “inner solid core” or “inner tablet” as used herein refers to single solid pharmaceutical dosage form containing the active medicament and pharmaceutically acceptable excipients, and is prepared by compression of dry powder mix or granules prepared by wet granulation or dry granulation wherein the 20 granules maybe optionally coated. Suitably, the “inner core” is a compact tablet. The term “outer shell” or “outer tablet” as used herein refers to single solid pharmaceutical dosage form containing the active medicament and pharmaceutically acceptable excipients mechanically compressed over the inner solid core or inner tablet. 25
7
The term “tablet-in-tablet” as used herein refers to a single unit solid pharmaceutical composition which comprises of “inner tablet” or “inner solid core” and “an outer shell” or “the outer tablet”, wherein the outer tablet is compressed over the inner tablet.
The term “enteric coating” or “enteric coated” as used herein refers to gastro-5 resistant coating which prevents the dissolution or disintegration of oral formulation in gastric pH. Enteric coating is a basically a polymer coating which is applied to oral formulation to safely deliver drug to intestinal tract.
The term “dual release” as used herein refers to release of active agent based on pH of small intestine region. The polymers used in present invention are selected in a 10 such a way that outer shell releases drug in duodenum region while the inner core tablet releases the drug in jejunum
The term “prazole” refers to proton pump inhibitor (also known as PPI’s) which are potent inhibitors of gastric acid secretion, inhibiting it, K+- ATPase, the enzyme involved in the final step of hydrogen ion production in the parietal cells. The term 15 proton pump inhibitor includes, but is not limited to, omeprazole, lansoprazole, rabeprazole, pantoprazole and leminoprazole, including isomers, enantiomers and tautomers thereof, and alkaline salts thereof.
In an embodiment the present invention provides a pharmaceutical composition comprising an inner solid core and outer shell compressed over the inner solid core 20 and wherein the composition exhibits dual drug release profile.
In an embodiment the present invention provides a pharmaceutical composition comprising an active agent, wherein the composition is composed of an inner solid core comprising 30% to 50% active agent and an outer shell compressed over the
8
inner solid core, wherein the outer shell comprises 30% to 50% of the active agent and wherein the composition exhibits dual drug release profile.
In an embodiment the present invention provides a pharmaceutical composition comprising an active agent, wherein the composition is composed of an inner solid core and an outer shell compressed over the inner solid core. Wherein in a preferred 5 embodiment the inner solid core comprises 30% to 50% of the active ingredients and pharmaceutically acceptable excipients and wherein the outer shell comprises 30% to 50% of the active ingredient and pharmaceutically acceptable excipients.
In an another embodiment the inner solid core releases the proton pump inhibitor in jejunum region and the outer core releases the proton pump inhibitor in 10 duodenum region.
In an embodiment the present invention provides a pharmaceutical composition comprising two separate individual solid units, wherein the two individual units are a solid inner core and an outer solid shell and wherein the outer solid shell is compressed over the solid inner core to form a single unit solid pharmaceutical 15 tablet.
In an embodiment the Inner solid core of the pharmaceutical composition is composed of granules comprising the active ingredient and pharmaceutically acceptable excipient, and wherein the granules are coated with one or more layers of coating. In an embodiment the granules are compressed to form a solid inner 20 core and wherein the solid core is further coated with atleast one layer of protective coating. In an embodiment the solid shell is coated with atleast two or more layer of protective seal coating. In another embodiment the seal coated solid core are further coated with layer of coating comprising one or more enteric coated polymer.
In an embodiment prazole is a proton pump inhibitor selected from Omeprazole, 25 Esomeprazole, Lansoprazole, Rabeprazole, Pantoprazole, Dexlansoprazole or
9
pharmaceutical acceptable salt thereof. In most preferred embodiment, proton pump inhibitor is pantoprazole or Esomeprazole or acceptable salts thereof.
In a preferred embodiment the inner solid core of the pharmaceutical composition is composed of granules comprising the active ingredient and pharmaceutically acceptable excipients, wherein the granules are compressed to form a solid core and 5 wherein the solid core is further coated with atleast two or more layer of protective seal coating and wherein the seal coated inner shell are further coated with layer of enteric polymer.
In an embodiment the granules of the inner solid core are prepared by wet or dry granulation, preferably by wet granulation. In a preferred embodiment the granules 10 of the Inner solid core are prepared by wet granulating a dry mix of the active ingredient and excipient’s selected from diluent, stabilizer, disintegrant, wetting agent/surfactant, glidant. The dry mix is granulated with a binder solution, preferably an aqueous base binder solution prepared by dissolving the binding agent in solution of purified water and surfactant. The formed granules are then lubricated 15 by adding a mixture of excipients selected from Wetting agents/surfactants, glidant, lubricant and disintegrant. The lubricated granules mixture is then compressed to form the solid inner core and wherein the solid inner core is further coated with atleast two layers of protective seal coating and wherein the seal coated granules are further coated with a layer of coat comprising an enteric coat polymer. 20
In an embodiment the enteric polymer coating of the solid inner core comprises a enteric polymer selected from but not limited to hydroxypropyl methylcellulose phtalate (HMPCP), polyvinyl acetate phtalate (PVAP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), alginate, carbomer, carboxymethylcellulose, methacrylic acid copolymer (Eudragit L, Eudragit S, Acrycoat), shellac, cellulose 25 acetate phthalate (CAP), starch glycolate, polacrylin, methyl cellulose acetate
10
phtalate, hydroxypropyulcellulose acetate phthalate, cellulose acetate terephtahalate, cellulose acetate isophthalate and cellulose acetate trimellitate and wherein the enteric coated layer further comprises pharmaceutically acceptable excipient selected from plasticizer, solvent, anticaking agent, colour and opacifier.
In an embodiment the protective seal coatings of the solid inner core comprises film 5 formers selected from Akoat 512 and Akoat EC151.
In an another embodiment the inner core comprises pantoprazole sodium in an amount from 60 to 80% based on the total weight of inner core composition.
In an embodiment the Outer shell of the pharmaceutical composition is composed of granules comprising the active ingredient and pharmaceutically acceptable 10 excipients, wherein the granules are compressed over the Inner core to form a solid outer shell covering the solid inner core and wherein the solid outer shell is coated with atleast one layer of protective seal coating and wherein the seal coated outer tablet is further coated with a layer of enteric coating.
In another embodiment the outer shell is composed of granules comprising the 15 active ingredient and pharmaceutical acceptable excipients and wherein the granules are mechanically compressed over the inner solid core.
In an embodiment the granules of the outer shell are prepared by wet or dry granulation, preferably by wet granulation. In a preferred embodiment the granules of the Inner solid core are prepared by wet granulating a dry mix of the active 20 ingredient and excipient’s selected from diluent, glidant, stabilizer, disintegrant, surfactant. The dry mix is granulated with a binder solution, preferably an aqueous base binder solution prepared by dissolving the binding agent in solution of purified water and surfactant. The formed granules are then lubricated by adding a mixture of excipients selected from Wetting agents/surfactants, glidant, lubricant and 25
11
disintegrant. The lubricated granules mixture is then compressed over the solid inner core to form a solid outer shell over the inner core. And wherein the solid outer shell is further coated with atleast one layers of protective seal coating and wherein the seal coated solid outer shell are further coated with a layer of enteric coating. 5
In an another embodiment the outer shell comprises pantoprazole sodium in an amount from 5 to 15% based on the total weight of outer shell composition.
In a preferred embodiment the pharmaceutical composition of the present invention is a tablet-in-tablet composition.
In an embodiment the present invention provides a tablet-in-tablet pharmaceutical 10 composition comprising an inner tablet (inner solid core) and outer tablet (outer core) wherein the outer tablet is compressed over the inner tablet.
In an embodiment the present invention provides a tablet-in-tablet pharmaceutical composition, exhibiting dual drug release profile, comprising an active agent, wherein the composition is composed of an inner tablet (inner solid core) and an 15 outer tablet (outer shell) compressed over the inner solid core. Wherein in a preferred embodiment the inner tablet comprises 30% to 50% of the active ingredients and pharmaceutically acceptable excipients and wherein the outer tablet comprises 30% to 50% of the active ingredient and pharmaceutically acceptable excipients. 20
In an embodiment the pharmaceutically acceptable excipients are selected from diluents, binder, lubricant, buffering agents, disintegrant, enteric coated polymers, stabilizers, surfactants/wetting agents, plasticizer, anti-tacking agents, film formers.
In an embodiment the binders are selected from but not limited to microcrystalline cellulose, starch, pregelatinized starch, polyethylene glycol (PEG), sorbitol, celluloses 25
12
for example hydroxypropyl methylcellulose (HPMC); hydroxy ethylcellulose, hydroxypropyl cellulose, methylcellulose, and ethylcellulose, Polyvinylpyrrolidone (also known as polyvidone or povidone), or combination thereof.
In an embodiment diluent is selected from but not limited to selected from lactose e.g., directly compressible lactose, lactose monohydrate, lactose anhydrous, and 5 spray dried lactose; microcrystalline cellulose sugar alcohols, e.g., sorbitol, erythritol, xylitol, and mannitol, dibasic calcium or potassium phosphate, starch or combination thereof.
In an embodiment the lubricants are selected from but not limited to calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, 10 sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, hydrogenated vegetable oil, polyethylene glycol, talcum or sodium benzoate or combinations thereof.
In an embodiment the disintegrant are selected from but not limited to croscarmellose sodium, crospovidone, starch, potato starch, pregelatinized starch, 15 com starch, sodium starch glycolate, microcrystalline cellulose, low substituted hydroxypropyl cellulose or combinations thereof.
In an embodiment the stabilizers are selected from but not limited to Suitable carbonates and bicarbonates include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, 20 sodium glycine carbonate, L-lysine carbonate, and arginine carbonate or metal oxides include for example, calcium oxides, zinc oxide, magnesium oxides or combination thereof.
In an embodiment the surfactants/wetting agents are selected from group consisted of, but are not limited to polysorbate 80 (Tween 80), polysorbate 60, poloxamers 25
13
polysorbate, 40, polysorbate 20, cremophors, tyloxapols, poloxamers, benzalkonium chloride, benzethonium chloride, cetyl alcohol, carbomer, cholesterol, cocamidopropyl betaine, glyceryl monostearate, lanolin alcohols, sodium lauryl sulfate, nonoxynol 9, octoxynol 40, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 40 steate, sorbitan monolaurate, sorbitan monooleate, or a 5 combination thereof.
In an embodiment glidants are selected from but not limited to calcium phosphate tribasic, magnesium silicate, colloidal silicon dioxide, talc or combination thereof.
In an embodiment an enteric coated release polymers are selected from but not limited to hydroxypropyl methylcellulose phtalate (HMPCP), polyvinyl acetate 10 phtalate (PVAP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), alginate, carbomer, carboxymethylcellulose, methacrylic acid copolymer (Eudragit L, Eudragit S, Acrycoat), shellac, cellulose acetate phthalate (CAP), starch glycolate, polacrylin, methyl cellulose acetate phtalate, hydroxypropyulcellulose acetate phthalate, cellulose acetate terephtahalate, cellulose acetate isophthalate and 15 cellulose acetate trimellitate.
In an embodiment the plasticizers are selected from but not limited to propylene glycol, polyethylene glycol or triethyl citrate, triacetin, dibutyl sebacate, vegetable oil, lipids or a combination thereof.
In an embodiment the anti-tacking agents are silica, talcum, fumed silica, colloidal 20 silica dioxide, calcium stearate, carnauba wax, long chain fatty alcohols and waxes, such as stearic acid and stearyl alcohol, mineral oil, paraffin, micro crystalline cellulose, glycerin, propylene glycol, and polyethylene glycol.
In an embodiment the film formers are selected from but not limited to guar gum, Instacoat, Hypromellose, opadry, Povidone, hydroxypropyl cellulose, cellulose 25
14
acetate, polydextrose, Ethyl cellulose, methylcellulose, gelatin, glycerin, maltodextrin, polyvinyl alcohol (PVA), shellac, starch, Akoat 512 and Akoat EC151 or combination thereof.
In an another embodiment the present invention provides a dual release gastro resistant oral tablet-in-tablet composition comprising: 5
a) An inner core comprising:
i. Granules containing second dose of pantoprazole sodium 40 mg and;
ii. Pharmaceutical acceptable excipients selected from diluent, stabilizer, disintegrant, wetting agent, adsorbent, binder, glidant, lubricant.
Wherein the granules are compressed to form solid inner core tablet and further 10 coated with one or more seal coating and one or more enteric coating.
b) An outer shell/covering comprising:
i. First dose of pantoprazole sodium 40 mg.
ii. pharmaceutical acceptable excipients selected from stabilizers, diluents, binder, plasticizers, lubricants, surfactant, disintegrant, glidants and; 15
Wherein outer shell/covering is compressed with inner core tablet to form a single unit oral tablet and the outer shell is further coated with seal coating and enteric coating.
In an embodiment the total amount of pantoprazole sodium present in composition is 80 mg wherein “first dose” refers to amount of active ingredient release first from 20 the formulation and “second dose” refers to amount of active ingredient release after release of first dose. The present invention provides a pharmaceutical composition comprising an outer covering having first dose of pantoprazole sodium 40 mg which releases first followed by the release of second dose of pantoprazole sodium 40 mg from inner core. 25
15
In an embodiment the dosage strength of active ingredient present in inner core and outer shell is 1:1.
In an another embodiment the present composition exhibits dual drug release profile and wherein the distribution of active ingredient in the inner solid core and the outer solid shell is in the ratio of 1:1. 5
In an embodiment the cumulative percentage releases of pantoprazole sodium from the tablets shows that less than 4% of drug releases in acidic medium; less than 45% of drug releases in pH equivalent to duodenum while more than 90% drug releases in pH equivalent to jejunum.
While the invention has been described with respect to specific composition which 10 include presently preferred modes of carrying out the invention, those skilled in the art will appreciate that there are numerous variations and permutations of the above described embodiments that fall within the spirit and scope of the invention. It should be understood that the invention is not limited in its application to the details of construction and arrangements of the components set forth herein. 15
EXAMPLES
The present invention is described in detail with reference to the examples given below. The examples are provided just to illustrate the invention and therefore, should not be construed to limit the scope of the invention.
Example 1: 20
Inner core/tablet – Composition details for Pantoprazole Gastro resistant tablets 40 mg (Core Tablet)
S. No.
Ingredients
%age
Function Core comprising 40 mg of Pantoprazole sodium
16
DRY MIX
1.
Pantoprazole Sodium
70.98 (eq. 40 mg)
Active
2.
Starch (maize)
1.67
Diluent
3.
Sodium Carbonate
5.30
Stabilizer
4.
Sodium Starch Glycolate
3.78
Disintegrant
5.
Sodium Lauryl Sulphate
0.76
Wetting agent
6.
Colloidal Silicon Dioxide
0.38
Adsorbent
BINDER
7.
HPMC- E 5
0.83
Binder
8.
Polysorbate 80 (Tween 80)
1.52
Wetting agent
9.
Purified Water
Qs
Solvent
LUBRICATION
10.
Sodium Lauryl Sulphate
2.27
Wetting agent
11.
Colloidal Silicon Dioxide
0.76
Glidant
12.
Magnesium Stearate
1.14
Lubricant
13.
Talcum
1.52
Lubricant
14.
Crosspovidone
9.09
Disintegrant
Total
100%
COATING
SEAL COATING 1
15.
Instacoat sol IC-S-1643
--
Film Former
16.
Iso Propyl Alcohol
--
Solvent
17.
Methylene Chloride
--
Solvent
SEAL COATING 2
18.
Opadry Clear 1R 7006
--
Film Former
17
19.
Iso Propyl Alcohol
--
Solvent
20.
Methylene Chloride
--
Solvent
ENTERIC COATED LAYER
PART-A
21.
Acrycoat S 100
--
Enteric coated polymer
22.
Tri ethyl Citrate
--
Plasticizer
23.
Isopropyl Alcohol
--
Solvent
24.
Purified Water
--
Solvent
PART-B
25.
Talcum
--
Anticaking agent
26.
Col Iron Oxide Of (Ferric Oxide) Red
--
Colour
27.
Titanium Dioxide
--
Opacifier
28.
P.E.G. 6000
--
Plasticizer
29.
Isopropyl Alcohol
--
Solvent
30.
Purified Water
--
Solvent
31.
Acetone
--
Solvent
Outer tablet/shell - Composition for Pantoprazole Gastro resistant tablets 40 mg (Outer Tablet)
S. No.
Ingredients
%age
Function Outer tablet comprising 80 mg of tablet
DRY MIX
1.
Pantoprazole Sodium
8.22 (eq. 40 mg)
Active
2.
Sodium bicarbonate
7.02
Stabilizer
18
3.
Mannitol
21.64
Diluent
4.
Starch (maize)
20.07
Diluent
5.
Light Magnesium Oxide
22.81
Stabilizer
BINDER
6.
Polyvinyl Pyrrolidone (PVPK 30)
1.76
Binder
7.
P.E.G. 400
0.31
Plasticizer
8.
Purified Water
--
Solvent
LUBRICATION
9.
Magnesium Stearate
0.84
Lubricant
10.
Sodium Starch glycolate
2.63
Surfactant
11.
Crospovidone
3.51
Disintegrant
12.
Talcum
0.84
Lubricant
13.
Colloidal Silicon Dioxide
1.05
Glidant
14.
Starch (maize)
6.14
Diluent
15.
Sodium bicarbonate
3.16
Stabilizer
Coating materials (Seal Coating)
16.
Akoat 512
--
Film Former
17.
Purified Water
--
Solvent
Coating materials (Enteric Coating)
18.
Akoat EC-155
--
Film Former
19.
Col. Iron Oxide (Ferric Oxide) Yellow
--
Colour
20.
Purified Water
--
Solvent
19
Example 3- A process of preparation of Pantaprazole gastro resistant tablet following steps:
Step 1- Preparation of inner solid core (or inner tablet) comprising pantoprazole sodium 40 mg:
All the ingredients used in table 1 were accurately weighed and dispensed in stores 5 under RLAF. Pantaprazole sodium 40 mg along with starch, sodium lauryl sulphate, sodium starch glycolate, colloidal silicon dioxide and sodium carbonate were sifted double polyethylene bags lined HDPE containers. All the sifted materials were sifted in RMG for 10 minutes at slow Impeller speed with Chopper off. Sufficient amount of Polysorbate 80 and HPMC-E5 were dissolved in purified water and was stirred till 10 a transparent binder solution was obtained. The prepared binder solution was slowly added in the premix materials over a period of 02-03 minutes with impeller ON & chopper OFF in a rapid mix granulator (RMG). Purified water was added as per the requirements for 05-08 minutes till to obtained dough like consistency.
The wet mass was then passed through a multi mill at slow speed and knives 15 forward using 8.0 mm screen and wet coarse granules were collected in FBD bowl. The wet coarse granules were dried in the FBD initially through air drying for 10 minutes then at temperature between 60°C -70°C (with intermittent raking after every 20 minutes for 5 minutes) and outlet temperature 40-45°C for 30-35 minutes or till the value of moisture content obtained between LOD 2.0% - 3.5% w/w at 20 80°C.
The dried granules were sifted through sieve #24 fitted with mechanical sifter and retained granules were passed through multi mill at medium speed and knives forward using 1.0 mm screen. the milled granules were again sifted through sieve #24 fitted with mechanical sifter. 25
20
The lubricant materials - Sodium Lauryl Sulphate, Colloidal Silicon Dioxide, Magnesium stearate, Talcum, Crospovidone were sifted in Vibro sifter using sieve #40. The sifted granules and sifted lubricated materials except magnesium stearate were charged into the Rotocube Mixer/Octagonal Blender /V Blender for 10 minutes at 12 RPM ± 1 RPM. Then Magnesium stearate was added and was mixed for 05 5 minutes at 12 RPM ± 1 RPM. After lubrication, the granules were compressed in Tablet Compression Machine using punch set of 5.0 mm, round, Concave & Plain to obtain uncoated core tablets.
The uncoated core tablet was now subjected to 2 layers of protective Seal coating coating: 10
Seal Coating-1 solution preparation: - Coating materials: Instacoat Sol IC-S-1643, Methylene Chloride, Isopropyl Alcohol were taken in SS Container & Colloid Mill and the uncoated tablet was than subjected to the first layer of protective seal coating
Seal Coating-2 solution preparation: - Coating materials: Opadry Clear 1R7006, Methylene Chloride and Isopropyl Alcohol were taken in SS Container & Colloid Mill 15 and the seal coated tablet obtain in step 11 a, was again coated with the second layer of protective seal coating
The seal coated inner solid core was then subjected to a layer of Enteric coat.
Preparation of enteric coating solution:
PART A: 20
Step 1-Acrycoat S-100 was dissolved in Isopropyl alcohol.
Step 2- Triethyl citrate was added in purified water.
Step 3- Step 2 was added in step 1.
PART B:
21
Step 1- Col. Iron Oxide (Ferric Oxide USNF) Red, Talcum & Titanium Dioxide were dissolved in Isopropyl alcohol.
Step 2- PEG-6000 was dissolved in purified water.
Step 3- Step 2 was added in step 1.
Step 4- acetone was added in a solution obtained in step 3. 5
Step 5-Add solution obtained in PART-A into Part-B
Step 6-The solution was then passed through colloidal mill and this solution was passed through 200# muslin cloth.
The enteric coated pantoprazole 40 mg was than examined for in-process tests.
Step 2- Preparation of outer solid shell (or outer tablet) granules of comprising 10 Pantoprazole sodium 40 mg:
Dispensing of raw material: All the ingredients used in table 2 were accurately weighed and dispensed in stores under RLAF. Sifting of API & excipients: Pantaprazole sodium 40 mg along with sodium bicarbonate, mannitol, starch, light magnesium oxide were sifted double polyethylene bags lined HDPE containers. All 15 the sifted materials were sifted in RMG for 10 minutes at slow Impeller speed with Chopper off. Dissolve PEG 400 and polyvinyl pyrrolidone (PVPK 30) were dissolved in purified water in a clean SS container and was stirred till a transparent binder solution was obtained. The prepared binder solution was slowly added in premix materials over a period of 02-03 minutes with impeller ON & chopper OFF in a rapid 20 mix granulator (RMG). Purified water was added as per the requirements for 05-08 minutes till to obtained dough like consistency.
The wet mass was passed through a multi mill at slow speed and knives forward using 8.0 mm screen and wet coarse granules were collected in FBD bowl. The wet coarse granules were dried in the FBD initially through air drying for 10 minutes then 25
22
at temperature between 60°C -70°C (with intermittent raking after every 20 minutes for 5 minutes) and outlet temperature 40-45°C for 30-35 minutes or till the value of moisture content obtained between LOD 2.0% - 3.5% w/w at 105°C.
The dried granules were sifted through sieve #20 fitted with mechanical sifter and retained granules were passed through multi mill at medium speed and knives 5 forward using 1.5 mm screen. the milled granules were again sifted through sieve #20 fitted with mechanical sifter.
Sodium starch glycolate, Colloidal Silicon Dioxide, Magnesium stearate, Talcum, Crospovidone, starch, sodium bicarbonate were sifted in Vibro sifter using sieve #40. The sifted granules and sifted lubricated materials except magnesium stearate were 10 charged into the Octagonal Blender V Blender for 10 minutes at 12 RPM ± 1 RPM. Then Magnesium stearate was added and was mixed for 05 minutes at 12 RPM ± 1 RPM.
Step 3- Preparation of Dual release 80 mg gastro resistant tablet:
The outer shell (or outer tablet) granules obtained in Step-2 were compressed over 15 the inner core tablet of pantoprazole sodium obtained in Step-1 to obtain uncoated solid single unit tablet, by using punch set of 11.00 mm, round, Concave, upper punch plain & lower punch plain.
Step 4-Seal Coating of uncoated dual release 80 mg gastro resistant tablet:
The formulation obtained from step 3 is further coated with seal coating in a SS 20 container and colloid mill with Akoat-512 and purified water.
Step 5- Enteric coating of sealed coated tablet:
The seal coated tablets obtain in step-4 were further coated with Akoat EC-155, Col. Iron Oxide (Ferric Oxide) Yellow, Purified Water in a SS container and colloid mill
23
The enteric coated tablets were than examined for in-process checks and packed in suitable packaging.
Example 4- Dissolution profile of the pharmaceutical composition
The dual release gastric resistant tablets prepared as per example 1-2 of present study were subjected to dissolution study. The in vitro release study was performed 5 in acidic buffer, phosphate buffer and tris buffer, the cumulative percentage releases of pantoprazole sodium from the tablets shows that less than 4% of drug releases in acidic medium; less than 45% of drug releases in pH equivalent to duodenum while more than 90% drug releases in pH equivalent to jejunum.
From the dissolution study it was observed that only small amount of pantoprazole 10 sodium releases in acidic media (pH similar to stomach), therefore the drug remains intact and stable in gastric media while major portion of pantoprazole sodium releases in pH equivalent to duodenum) and mostly in pH equivalent to jejunum) thus exhibiting dual release of formulation of present invention.
Example 5- Pharmacokinetic Studies: 15
To monitor the safety and tolerability of dual release pantoprazole sodium gastro-resistant tablet of the present invention, single dose of 80mg of tablet was administered orally to healthy, adult, human subjects under fasting conditions.
Number of subject: Twenty-four (24) healthy, adult, human subjects were dosed in the study. 20
Dose Administration: The human subjects were fasted overnight at least 10.00 hours and one tablet was administered orally to each subject while in sitting position with approximately 240mL of water in each period, followed by a thorough mouth check to ensure that the drug has been swallowed.
24
Sampling Schedule: Twenty-three (23) blood samples were collected from each subject and 05 mL blood sample was take out at 0.33, 0.67, 1.00, 1.33, 1.67, 2.00, 2.33, 2.67, 3.00, 3.33, 3.67, 4.00, 4.50, 5.00, 5.50, 6.00, 7.00, 8.00, 10.00, 12.00, 16.00 and 24.00 hours’ post-dose. Pre-dose (0.00 hours) blood sample of 05 mL was taken not more than one hour prior to dosing in each period. 5
Pharmacokinetic Parameters: estimated plasma concentration-time profiles of Pantoprazole was calculated with following pharmacokinetic parameters was calculated using SAS (SAS Institute Inc., U.S.A.) version 9.4 or higher.
Primary parameters: Cmax, AUC0-t and AUC0-8
Secondary parameters: tmax, t½, kel and AUC_%Extrap_obs, 10
Variable
Mean
SD
Minimum
Median
Maximum
CV%
Cmax (ng/mL)
3172.821
1047.9064
1909.285
2988.2065
5622.898
33.028
Tmax (hr)
2.840
0.8061
1.33
2.84
5.00
28.380
AUC0-t (ng.hr/mL)
13623.168
5104.0311
6671.998
11560.898
30600.738
37.466
AUC0-8 (ng.hr/mL)
13754.649
5143.0602
6800.065
11664.002
30976.240
37.391
Kel (hr-1)
0.237
0.0827
0.087
0.257
0.398
34.873
t1/2 (hr)
3.482
1.8251
1.740
2.700
7.940
52.413
AUC_%Extrap_obs
1.008
0.5785
0.330
0.875
2.800
57.372
The tablet–in-tablet formulation of the subject invention was able to achieve a Cmax, Tmax and AUC which were non-inferior to the existing alternative formulation existing in the market.
25
Example 6 – Comparative pharmacokinetic data against marketed reference product.
A comparative pharmacokinetic study was conducted, to compare the rate and extent of absorption of Pantoprazole Tablet of the present invention against a marketed multilayer formulation (Ref product 1) as represented in Fig 1. 5
The objective of the study were- To compare the rate and extent of absorption of Pantoprazole tablets as per the present invention (Test product 1) against a marketed multilayer formulation (Ref product 1) as represented Fig 2.
Methodology: Clinical personnel explained all study related procedures, duration, dates and timings, information on the study treatments and confidentiality of the 10 subject’s data clearly to the subjects during the informed consent procedures. Subjects who signed the consent form and showed their willingness to participate in the study were enrolled. Subjects who were eligible when assessed against the inclusion and exclusion criteria and who were found to be healthy on physical examination with laboratory investigation values within reference limits were 15 considered for admission to study. Treatments were allocated to subjects as per the randomization schedule generated using statistical techniques with SAS version 9.4. Blood samples were drawn before dosing (0.00 hour) and up to 24.00 hour after dosing in each period. Plasma concentrations of Pantoprazole were analyzed using LC-MS/MS method. Statistical analysis was performed to assess bioequivalence 20 between the pharmacokinetic parameters of test and reference formulation using SAS version 9.4.
Number of Subjects- 24
25
26
Pharmacokinetic parameters:
Employing the estimated plasma concentration-time profiles of Pantoprazole, the following pharmacokinetic parameters were calculated
Primary pharmacokinetic parameters: Cmax, AUC0-t and AUC0-8
Secondary pharmacokinetic parameters: tmax, t1/2, kel and AUC_%Extrap_obs 5
Statistical analysis of the pharmacokinetic parameters were performed using SAS version 9.4.
Fig 2 provides the Linear plot of mean plasma concentration of Test Product 1(as indicated by red line) and Ref Product 1 (as indicated by blue line). From the figure it can be observed that 90% confidence intervals of the differences of least squares 10 means for the Ln-transformed pharmacokinetic parameters Cmax, AUC0-t and AUC0-8 of Pantoprazole is within the bioequivalence acceptance limits of 80.00-125.00%
Hence it was concluded that the Test product 1 was bioequivalent or non-inferior to the ref product 1 with respect to rate and extent of absorption.
No serious or life-threatening adverse events were reported during the course of 15 the study. The Test product 1 was found to be safe and tolerable in healthy, adult, human subjects under fasting conditions.
Example-7
Inner core/tablet – Composition details for Esomeprazole Gastro resistant tablets 40 mg (Core Tablet) 20
S. No.
Ingredients
%age
Function Core comprising 40 mg of Pantoprazole sodium
DRY MIX
1.
Esomeprazole Magnesium Trihydrate
71.60 (eq. 40 mg)
Active
2.
Starch (maize)
1.66
Diluent
27
3.
Sodium Carbonate
4.70
Stabilizer
4.
Sodium Starch Glycolate
3.80
Disintegrant
5.
Sodium Lauryl Sulphate
0.75
Wetting agent
6.
Colloidal Silicon Dioxide
0.38
Adsorbent
BINDER
7.
HPMC- E 5
0.85
Binder
8.
Polysorbate 80 (Tween 80)
1.52
Wetting agent
9.
Purified Water
Qs
Solvent
LUBRICATION
10.
Sodium Lauryl Sulphate
2.27
Wetting agent
11.
Colloidal Silicon Dioxide
0.75
Glidant
12.
Magnesium Stearate
1.13
Lubricant
13.
Talcum
1.50
Lubricant
14.
Crosspovidone
9.09
Disintegrant
Total
100%
COATING
SEAL COATING 1
15.
Instacoat sol IC-S-1643
--
Film Former
16.
Iso Propyl Alcohol
--
Solvent
17.
Methylene Chloride
--
Solvent
SEAL COATING 2
18.
Opadry Clear 1R 7006
--
Film Former
19.
Iso Propyl Alcohol
--
Solvent
20.
Methylene Chloride
--
Solvent
ENTERIC COATED LAYER
PART-A
21.
Acrycoat S 100
--
Enteric coated polymer
22.
Tri ethyl Citrate
--
Plasticizer
23.
Isopropyl Alcohol
--
Solvent
24.
Purified Water
--
Solvent
PART-B
25.
Talcum
--
Anticaking agent
26.
Col Iron Oxide Of (Ferric Oxide) Red
--
Colour
27.
Titanium Dioxide
--
Opacifier
28.
P.E.G. 6000
--
Plasticizer
29.
Isopropyl Alcohol
--
Solvent
30.
Purified Water
--
Solvent
31.
Acetone
--
Solvent
28
Outer tablet/shell - Composition for Esomeprazole Gastro resistant tablets 40 mg (Outer Tablet)
S. No.
Ingredients
%age
Function Outer tablet comprising 40 mg of tablet
DRY MIX
1.
Pantoprazole Sodium
8.30 (eq. 40 mg)
Active
2.
Sodium bicarbonate
7.02
Stabilizer
3.
Mannitol
21.65
Diluent
4.
Starch (maize)
20.00
Diluent
5.
Light Magnesium Oxide
22.75
Stabilizer
BINDER
6.
Polyvinyl Pyrrolidone (PVPK 30)
1.75
Binder
7.
P.E.G. 400
0.32
Plasticizer
8.
Purified Water
--
Solvent
LUBRICATION
9.
Magnesium Stearate
0.86
Lubricant
10.
Sodium Starch glycolate
2.62
disintegrant
11.
Crospovidone
3.52
Disintegrant
12.
Talcum
0.86
Lubricant
13.
Colloidal Silicon Dioxide
1.05
Glidant
14.
Starch (maize)
6.15
Diluent
15.
Sodium bicarbonate
3.15
Stabilizer
Coating materials (Seal Coating)
16.
Akoat 512
--
Film Former
17.
Purified Water
--
Solvent
Coating materials (Enteric Coating)
18.
Akoat EC-155
--
Film Former
19.
Col. Iron Oxide (Ferric Oxide) Yellow
--
Colour
20.
Purified Water
--
Solvent

,CLAIMS:1. A pharmaceutical composition comprising:
a) an inner solid core composed of granules comprising a proton pump inhibitor and pharmaceutically acceptable excipients and wherein the granules are 5 compressed to form the inner solid core
b) an outer shell, composed of granules comprising a proton pump inhibitor and pharmaceutically acceptable excipients.
wherein the inner solid core releases the proton pump inhibitor in jejunum region and the outer core releases the proton pump inhibitor in duodenum region. 10
and wherein the outer shell is compressed over the inner solid core to form a single unit solid pharmaceutical tablet.
2. The pharmaceutical composition as claimed in claim 1 wherein the outer solid core is mechanically compressed over the inner solid core to form a single unit solid pharmaceutical tablet. 15
3. The inner solid core as claimed in claim 1 is further coated with atleast two layer of protective seal coating and at-least one layer of enteric coating.
4. The outer solid shell as claimed in claim 1 is coated with atleast one layer of protective seal coating and a layer of enteric coating
5. The protective seal coating as claimed in claim 3 and 4 are composed of film 20 former and solvent
6. The enteric coating as claimed in claim 3 and 4 is composed of enteric coated polymer, plasticizer and solvent.
7. A process for preparation of the pharmaceutical composition as claimed in claim 1, comprising – 25
a) Preparation of granules for the inner solid core
b) Compression of the granules of step (a) to form inner solid core
30
c) Coating of the inner solid core of step (a) with atleast two layers of protective seal coating
d) Coating of the protective seal coated inner solid core of step (c) with atleast one layer enteric coating
e) Preparation of granules for the outer solid shell 5
f) Compression of the granules of step (e) over the inner solid core of step (d) to form the outer solid shell
g) Coating of the outer solid shell with atleast one layer of protective seal coating
h) Coating of the protective seal coated outer shell with atleast one layer of 10 enteric coating.
8. The active ingredient as claimed in any of the above claims is selected from proton pump inhibitors wherein proton pump inhibitors are omeprazole, lansoprazole, rabeprazole, pantoprazole, leminoprazole and Esomeprazole including isomers, enantiomers and tautomers thereof or pharmaceutically 15 acceptable salts thereof.
9. The active ingredient as claimed in any of the above claims is Pantoprazole or Esomeprazole or pharmaceutically acceptable salts thereof.
10. The dosage strength of active ingredient as claimed in any of the above claim present in inner core and outer shell is 1:1. 20
11. The pharmaceutical excipients as claimed in any of the above claims are selected from one or more Diluent, stabilizer, Disintegrant, Wetting agent, Adsorbent, Binder, Glidant, Lubricant, Disintegrant, Film former, Solvent, Enteric coated polymer, Plasticizer, Anti-caking agent, Colorant, Opacifier.
12. The pharmaceutical composition as claimed in any of the above claim 25 exhibits dual drug release profile and wherein the distribution of active
31
ingredient in the inner solid core and the outer solid shell is in the ratio of 1:1.
13. The pharmaceutical composition as claimed in any of the above claims is a tablet-in-tablet composition.
14. A tablet-in-tablet pharmaceutical composition comprising an inner solid core (inner tablet) and an outer shell (outer tablet), wherein the outer shell is compressed over the inner solid core to form a single unit solid pharmaceutical tablet and wherein the tablet-in-tablet composition exhibits dual drug release profile.
15. A tablet-in-tablet as claimed in any of the above claim wherein the cumulative percentage releases of pantoprazole sodium from the tablets shows that less than 4% of drug releases in acidic medium; less than 45% of drug releases in pH equivalent to duodenum while more than 90% drug releases in pH equivalent to jejunum.

Dated this 18th day of November 2022
For Akums Drugs & Pharmaceutical Ltd.
Siddhartha Dulakakhoria
(Authorized Signatory)