DESC:FIELD OF INVENTION:
The present invention relates to pharmaceutical composition more particularly tablet-in-tablet pharmaceutical formulations comprising Proton pump inhibitor and Prokinetic agents. The invention also relates to processes of preparing such compositions. 5
BACKGROUND:
The combination of proton pump inhibitors(PPIs) with Prokinetic agents is a well-known therapy in patients suffering from gastro-oesophageal reflux disease (GERD), acidity or heartburn. The combination of two different drugs act in two different mechanisms and generally have greater efficacy than monotherapy, reduces pill 10 burden and is patient compliant.
Marketed formulation like Rablet D Capsule SR is a hard gelatin capsule comprising Rabeprazole as enteric coated pellets and Domperidone as sustained release pellets; ESOLEAF-DSR is a hard gelatin Capsule comprising esomeprazole magnesium tablet, Domperidone as 10mg immediate release tablet and as 20 mg sustained release 15 tablet.
The existed marketed formulations are generally available as pellets or mini-tablets filled in a hard gelatin capsule, however the process of preparing these formulations are time consuming and added extra cost to the formulation. Capsule formulations may require more careful consideration of the compatibility of active ingredients with 20 the capsule shell material and the encapsulation process. Encapsulation processes can be more complex and time-consuming compared to tablet compression or direct compression techniques. Capsules may be more susceptible to moisture and oxygen permeation, potentially impacting the stability of the active ingredients. Capsules may
3
be more expensive to manufacture compared to tablets, primarily due to the added costs associated with encapsulation processes and capsule shell materials.
Thus there still need in art to develop a solid oral formulation which doesn¡¦t required additional manufacturing steps, additional cost and labor. The inventors of the present invention are able to formulate a composition which provides multiple 5 releases of active agents in a single dosage form without the need of formulating separate entities.
SUMMARY OF THE INVENTION:
The present invention provides an alternative formulation to overcome the problems associated with marketed formulation. The present invention provides a novel drug 10 delivery system which are designed to provide triple release profile to maintain pharmacologically effective drug concentrations over a longer period of time with a single daily dose.
The novel drug delivery system of present invention is a unique tablet-in-tablet formulation which provides immediate effect as well as sustained effect without using 15 multiple process steps and avoiding use of gelatin, having better drug content uniformity, safe, efficacious and is well tolerated.
The tablet-in-tablet formulation of present invention are designed where outer portion contains Prokinetic agents in dual release profile in bi-layered structure and inner core tablets contains proton pump inhibitors providing delayed release of drug. 20
BRIEF DESCRIPTION OF DRAWINGS:
Figure.1 is an image illustrating the composition of bilayer tablet in tablet
4
DETAILED DESCRIPTION OF INVENTION:
Those skilled in the art will be aware that the present disclosure is subject to variations and modifications other than those specifically described. It is to be understood that the present disclosure includes all such variations and modifications. The disclosure also includes all such compositions, components of the composition, referred to or 5 indicated in this specification, individually or collectively and all combinations of any or more of such components or composition.
Definitions
For convenience, before further description of the present disclosure, certain terms employed in the specification, and examples are collected here. These definitions 10 should be read in the light of the remainder of the disclosure and understood as by a person of skill in the art. The terms used herein have their meanings recognized and known to those of skill in the art, however, for convenience and completeness, particular terms and their meanings are set forth below.
The articles ¡§a¡¨, ¡§an¡¨ and ¡§the¡¨ are used to refer to one or to more than one (i.e., to 15 at least one) of the grammatical object of the article.
The terms ¡§comprise¡¨ and ¡§comprising¡¨ are used in the inclusive, open sense, meaning that additional elements may be included. It is not intended to be construed as ¡§consists of only¡¨.
Throughout this specification, unless the context requires otherwise the word 20 ¡§comprise¡¨, and variations such as ¡§comprises¡¨ and ¡§comprising¡¨, will be understood to imply the inclusion of a stated element or step or group of element or steps but not the exclusion of any other element or step or group of element or steps.
The term ¡§including¡¨ is used to mean ¡§including but not limited to¡¨. ¡§Including¡¨ and 25 ¡§including but not limited to¡¨ are used interchangeably.
5
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the disclosure, the preferred methods, and materials are now described. All publications mentioned 5 herein are incorporated herein by reference.
The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purposes of exemplification only. Functionally equivalent products and processes are clearly within the scope of the 10 disclosure, as described herein.
The term ¡§pharmaceutical composition¡¨ 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.
The term ¡§pharmaceutically acceptable excipient¡¨ refers to inert substances other 15 than active ingredients which are used in the preparation of pharmaceutical products.
The term ¡§excipients¡¨ as used herein means a component of a pharmaceutical product that is not an active ingredient. The excipients that are useful in preparing a pharmaceutical composition are generally safe and non-toxic.
The term ¡§inner solid core¡¨ or ¡§inner tablet¡¨ as used herein refers to single solid 20 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 granules maybe optionally coated. Suitably, the ¡§inner core¡¨ is a compact tablet.
6
The term ¡§single unit solid pharmaceutical tablet¡¨ as used herein refers to pharmaceutical dosage form containing the active medicament and pharmaceutically acceptable excipients.
The term ¡§outer shell¡¨ or ¡§outer tablet¡¨ as used herein refers to single solid pharmaceutical dosage form containing the active medicament and pharmaceutically 5 acceptable excipients mechanically compressed over the inner solid core or inner tablet.
The term ¡§enteric coating¡¨ or ¡§enteric coated¡¨ as used herein refers to gastro-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 10 formulation to safely deliver drug to intestinal tract.
The term ¡§dual release¡¨ as used herein refers to immediate release and delayed release action of prokinetic agents.
The term ¡§proton pump inhibitors¡¨ or ¡§PPIs¡¨ refers to potent inhibitors of gastric acid secretion, inhibiting it, K+- ATPase, the enzyme involved in the final step of hydrogen 15 ion production in the parietal cells. The term 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.
The term ¡§prokinetic agents¡¨ refers to active agents which helps in controlling acid 20 reflux by improving gastrointestinal motility and causes the contents of stomach to empty faster.
The term ¡§tablet-in-tablet¡¨ refers to a single dosage form comprising an inner core tablet and outer shell tablet wherein outer shell tablet is compressed over inner core
7
tablet completely and uniformly surrounding the inner core tablet to obtain ¡§tablet-in-tablet¡¨.
The term ¡§bilayer¡¨ refers to outer part of the tablet which is arranged into two separate layer wherein one layer shows immediate release of prokinetic agents and other layer shows sustained release. 5
Figure 1 is an image showing the bilayer tablet in tablet formulation of present invention. The bilayer tablet in tablet comprises an outer tablet 30 having bilayer arrangement wherein bilayer is an immediate release layer of prokinetic agents 10 and sustained release layer 20 of prokinetic agent wherein inner tablet 4 have delayed release proton pump inhibitors. 10
The present invention provides a pharmaceutical composition comprising combinations of proton pump inhibitors (PPIs) and prokinetic agents as active ingredients in a single unit dosage form wherein the composition of the present invention is an alternative of existed marketed products.
The existed marketed products such as Pan-D capsule PR is hard gelatin capsule 15 contains Pantoprazole sodium as gastro-resistant pellets and Domperidone as prolonged release pellets; Pantop-D SR Capsule is a hard gelatin capsule contains two resistant pantoprazole and Domperidone as sustained release pellets. However, the marketed products¡¦ manufacturing technology is a time consuming and laborious process therefore the inventors of the present invention have developed a stable 20 formulation which provide a single unit dosage form comprising combinations of PPIs and prokinetic agents which is less time consuming and cost efficient as compared to prior art formulation.
8
The present invention provides a multi-action single dosage unit formulation comprising fixed dose combinations of PPIs and prokinetic agents wherein the present invention is a tablet-in-tablet formulation.
In an embodiment the tablet-in-tablet formulation of the present invention can be used in treatment of acid related ingestion, hurt burn, gastroesophageal reflux 5 disease (acid reflux) and Peptic ulcer disease.
In an embodiment the present invention provides a tablet-in-tablet composition comprising PPIs and prokinetic agents wherein the formulation comprises an inner tablet comprising PPIs and an outer shell or coat surrounding the inner tablet which is compressed onto the inner tablet. 10
The present invention provides tablet-in-tablet composition comprising:
a. an enteric coated inner tablet wherein the inner tablet comprises of one or more pharmaceutically active agent, and wherein the inner tablet exhibits delayed drug release profile.
b. an outer tablet wherein the outer tablet is compressed over the inner tablet, 15 completely surrounding the inner tablet, wherein the outer tablet is a bilayer tablet composed of sustained release layer and an immediate release layer and wherein the sustained release layer and immediate release layer comprises same or different pharmaceutically active ingredients.
In an another embodiment outer tablet of present invention has a bi-layer structure 20 of an immediate release part comprising prokinetic agent and one or more pharmaceutically acceptable excipients and sustained release part comprising prokinetic agent and one or more pharmaceutically acceptable excipients.
In another embodiment, the tablet-in-tablet composition of the present invention, the inner tablet comprises 30-80 wt.% PPIs based on total weight of uncoated inner 25
9
core tablet wherein PPIs are selected from group consisting of Omeprazole, Esomeprazole, Lansoprazole, Dexlansoprazole, Pantoprazole and Rabeprazole. As PPIs are acid-liable, the inner tablet of the present invention are protected by Gastro-resistant polymers.
In an embodiment Gastro-resistant polymers provide pH dependent release which is 5 insoluble in acidic pH and soluble in basic pH which provide delayed release of PPIs.
In an embodiment the Gastro-resistant polymers are selected from but not 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, 10 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 cellulose acetate trimellitate.
In an embodiment Gastro-resistant polymer is present in an amount ranging from 5 15 to 20 % based on total weight of coated inner core tablet.
In a preferred embodiment Gastro-resistant polymer is cellulose acetate phthalate.
In an another embodiment the inner core tablets were further coated with one or more seal coating.
In an another embodiment an inner core tablet further comprise one or more 20 pharmaceutical acceptable excipient selected from group consisting of diluent, stabilizer, disintegrant, binder, lubricant or anti-capping agent and combinations thereof.
10
In an another embodiment the present invention provides outer shell surrounding the inner core wherein outer shell is compressed over inner tablet to obtain tablet-in-tablet dosage form.
The outer shell or tablet of the present invention comprises prokinetic agents selected from group consisting of Cisapride, Metoclopramide, Domperidone, Itopride, 5 Mosapride, Renzapride, Levosulpiride or combinations thereof. In a preferred embodiment prokinetic agent is Domperidone or pharmaceutically acceptable salts wherein maleate salt is being preferred.
In an embodiment Domperidone is present in an amount ranging from 1 to 50 % weight of total outer shell more preferably 2 to 30%. 10
In an embodiment the outer shell or tablet provides dual release of Domperidone maleate 30 which exhibit immediate 10 as well sustained release 20 and present as separate individual layers wherein inner tablet 4 is placed or stacked in between and completely surrounded by the immediate and delayed release layers as represented in figure 1. 15
In a further embodiment of the present invention, the outer shell or tablet comprises Domperidone maleate, wherein the outer shell or tablet has bi-layer tablet structure, wherein the bilayer outer tablet is completely and uniformly surrounding the inner tablet, and wherein bi-layer exhibits dual release characteristics present as:
„h An immediate release layer comprising 2-5 wt.% of Domperidone 20 maleate eq. to Domperidone based on individual layer and further comprises pharmaceutical acceptable excipients.
„h A sustained release layer comprising 10-15 wt.% of Domperidone maleate eq. to Domperidone based on individual layer and further comprises pharmaceutical acceptable excipients. 25
11
Wherein inner tablet is present in-between immediate release layer and sustained release layer.
In an embodiment the present invention provide immediate release layer further comprises pharmaceutical acceptable excipients selected from diluents, disintegrant, binder, wetting agent, glidant, lubricants and anti-capping agents. 5
In an embodiment the present invention provides sustained release layer further comprising pharmaceutical acceptable excipients selected from release controller, diluent, colorant, binder, lubricant, glidant and anti-capping agent.
In an another embodiment the sustained release layer comprises release controller selected from group consisting of hydroxypropylmethylcellulose, polyethylene oxide, 10 hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, polyvinylpyrrolidone, xanthan gum, and guar gum. In a preferred embodiment release controller is hydroxypropylmethylcellulose which include METHOCEL. line of hydroxypropylmethylcellulose polymers such as METHOCEL. Premium K100M CR, METHOCEL. K-4M, and METHOCEL. Premium K100 LV (Dow Chemical Co., Midland, 15 Ml) more particularly METHOCEL. K-4M present in amount ranging 15-25 wt.%
In an embodiment the present invention provides tablet-in-tablet composition comprising:
i. Inner tablet comprising 30-80 wt.% PPIs based on total weight of uncoated inner core tablet and; 20
ii. Outer tablet having bilayer structure comprising:
a) An immediate release layer comprising 2-5 wt.% of Domperidone maleate eq. to Domperidone based on individual layer and;
b) A sustained release layer comprising 10-15 wt.% of Domperidone maleate eq. to Domperidone based on individual layer 25
12
A tablet-in-tablet composition comprising:
i. An inner tablet comprising 30.93% rabeprazole sodium based on total weight of uncoated inner tablet and;
ii. An outer tablet comprising:
a) An immediate release layer comprising 3.19% Domperidone Maleate Eq. 5 to Domperidone based on individual layer and;
b) A sustained release layer comprising 13.970% Domperidone Maleate Eq. to Domperidone based on individual layer
In an another embodiment the present invention provides tablet-in-tablet comprising: 10
i. An inner tablet comprising 71.78% Esomeprazole Magnesium Trihydrate based on total weight of uncoated inner tablet and;
ii. An outer tablet comprising:
a) An immediate release layer comprising 3.19% Domperidone Maleate Eq. to Domperidone based on individual layer and; 15
b) A sustained release layer comprising 13.970% Domperidone Maleate Eq. to Domperidone based on individual layer.
In an another embodiment the present invention provides tablet-in-tablet composition comprising:
i. An inner tablet comprising 70.99% Pantoprazole Sodium based on total 20 weight of uncoated inner tablet and;
ii. An outer tablet comprising:
a. An immediate release layer comprising 3.19 % Domperidone Maleate Eq. to Domperidone based on individual layer and;
13
b. A sustained release layer comprising 13.972 % Domperidone Maleate Eq. to Domperidone based on individual layer.
The present invention also provides method of preparing tablet-in-tablet composition. In an embodiment, the process further comprises following steps:
Step 1: Preparation of Proton pump inhibitors (PPIs) as an inner core tablet 5
Step 2: Preparation of Prokinetic agent (Domperidone maleate) as an immediate release part of an outer shell
Step 3: Preparation of Prokinetic agent (Domperidone maleate) as a sustained release part of outer shell
Step 4: compressing immediate and sustained release part of outer shell with inner 10 core tablet to obtain bi-layer tablet-in-tablet
The present invention will hereinafter be described in further details by examples. It is to be understood that these examples are presented for illustrative purpose only and not intended to limit the scope of the present invention.
Example-1: Preparation of tablet-in-tablet 15
Formula-1 Rabeprazole sodium (PPIs) Gastro-resistant tablet 20 mg (inner core tablet)
S. No.
Ingredients
Function
%age DRY MIX
1.
Rabeprazole Sodium
Active
30.93
2.
Mannitol
Diluent
22.06
3.
Light Magnesium Oxide
Stabilizer
30.15
4.
Crospovidone INF10
Disintegrant
5.882 BINDER
14
5.
Hydroxy Propyl Cellulose (Klucel Exf)
Binder
0.735
6.
Isopropyl Alcohol
Solvent
q.s. LUBRICATION
7.
Magnesium Stearate
Lubricant
0.735
8.
Sodium Stearyl Fumarate
Lubricant
1.470
9.
Hydroxy Propyl Cellulose (HPC -LH11)
Disintegrant/Anti capping Agent
8.088
10.
Instacoat sol IC-S-1643
Film Former
--
11.
Iso Propyl Alcohol
Solvent
--
12.
Methylene Chloride
Chloride
Solvent
--
13.
Opadry Clear 1R 7006
Film Former
--
14.
Iso Propyl Alcohol
Solvent
--
15.
Methylene Chloride
Solvent
--
16.
Cellulose Acetate Phthalate (Instacoat EN)
Delayed Release material
--
17.
Isopropyl Alcohol
Solvent
--
18.
Methylene Chloride
Solvent
--
Formula-2 Domperidone Immediate Release Part: S. No.
Ingredients
Function
%age Dry Mixing:
1.
Domperidone Maleate Eq. to Domperidone
API
3.190
2.
Microcrystalline Cellulose
Diluent
29.08
3.
Lactose
Diluent
24.69
15
4.
Starch (Maize)
Diluent
24.69
5.
Sodium Starch Glycolate
Disintegrant
1.975 Binder Preparation
6.
Polyvinyl pyrrolidone
(PVPK-30)
Binder
3.703
7.
Purified water
Solvent
----- Lubrication
8.
Sodium Lauryl Sulphate
Wetting Agent
0.740
9.
Sodium Starch Glycolate (Primojel)
Disintegrant
3.20
10.
Microcrystalline Cellulose
PH-102
Diluent
6.172
11.
Talcum
Disintegrant
1.111
12.
Colloidal silicon dioxide
Glidant
1.234
13.
Magnesium Stearate
Lubricant
1.185
14.
Hydroxy propyl cellulose LH-11
Anti-Capping Agent
1.481
Formula-3: Domperidone Sustained Release part S.NO.
Ingredients
Function
%age Dry Mixing:
1.
Domperidone Maleate Eq. to Domperidone
Active
13.970
2.
Microcrystalline Cellulose PH-102
Diluent
37.49
3.
Methocel K-4 M (Dow Chem.)
Release Controller
20.000
4.
Iron Oxide (Ferric Oxide) Red
Colour
0.081 Binder Preparation:
5.
Polyvinyl pyrrolidone (PVPK-30)
Binder
3.243
16
6.
Isopropyl alcohol
Solvent
7.
Purified Water
Solvent
------ Lubrication
8.
Microcrystalline Cellulose PH-102
Diluent
14.590
9.
Talcum
Lubricant
0.757
10.
Colloidal silicon dioxide
Glidant
0.811
11.
Magnesium Stearate
Lubricant
0.865
12.
Iron Oxide (Ferric Oxide USPNF) Red
Colour
0.081
13.
Hydrogenated Castor Oil
Lubricant
5.405
14.
Hydroxy Propyl Cellulose-LH-11
Anti-capping Agent
2.703
Example-2: Process of preparation of tablet-in-tablet:
1. Preparation of Inner tablet comprising PPIs:
a. Dry mixing the sifted PPI, diluent, stabilizer and disintegrant to obtain a dry blend and; 5
b. Adding isopropyl alcohol to binder to prepare a binder solution
c. The dry blend was granulated by adding binder solution to rapid mixer granulator to obtain wet granulation
d. The wet granulation was dried in fluid bed dryer for 25-35 minutes at inlet temperature 50.C-60.C. 10
e. The dry granules were lubricated in a Vibro Sifter with lubricant and disintegrant
f. The lubricated granules were compressed into inner tablet using compression machine.
g. The obtained uncoated tablets were coated with seal coating 15
17
h. The seal coated tablets were further coated with enteric coating to obtain enteric coated inner tablet.
2. Preparation of Domperidone immediate release outer layer
a. Dry mixing Domperidone maleate, diluents and disintegrant in rapid mixing granulator for 10 minutes to obtain a dry blend and; 5
b. Adding water to binder to obtain binder solution
c. The dry blend was granulated by adding binder solution to obtain wet granulation in a RMG mixer for 2-4 minutes.
d. The wet granules were air dried in fluid bed dryer for 10 minutes at inlet temperature 60.C-70.C. 10
e. The dry granules were sifted with wetting agent, disintegrants, diluent, glidant, lubricant and anti-capping agents in a Vibro sifter sift.
f. The sifted granules were lubricated with lubricant in octagonal/rotocube mixer for 15 minutes.
3. Preparation of Domperidone Sustained release outer layer 15
a. Dry mixing the sifted Domperidone maleate, diluent, a release controller and colorant in a rapid mixing granulator for 10 minutes.
b. Adding purified water, IPA and PVPK-30 to binder to obtain binder solution.
c. The dry blend was wet granulated with binder solution to obtain wet coarse granules; 20
d. The wet granules were air dried in fluidized bed dryer for 10 minutes at inlet temperature 55.C-65.C.
e. The dried granules were sifted in a mechanical sifter and diluent, lubricants, glidant, colorant and anti-capping agent were sifted separately
f. The sifted granules and excipients were lubricated with lubricant in a blender 25 for 5 minutes.
4. Preparation of dual layer tablet in tablet
18
The Domperidone maleate immediate release layer and Domperidone maleate sustained release were compressed with PPIs sodium enteric coated tablet to obtain bi-layered tablet-in-tablet formulation containing Domperidone maleates sustained release as upper layer and PPIs enteric coated middle layer and Domperidone maleate immediate release as lower layer. 5
Example-3: Tablet-in-tablet Preparation
FORMULA-4 Esomeprazole as Gastro-resistant Tablet (inner core tablet)
S. No.
Ingredients
Function
%age DRY MIX
1.
Esomeprazole Magnesium Trihydrate
Active
71.78
2.
Starch (Maize)
Diluent
3.030
3.
Sodium Carbonate
Stabilizer
3.584
4.
Sodium starch glycollate
Disintegrant
3.788
5.
Sodium Lauryl Sulfate
Wetting Agent
0.606
6.
Colloidal silicon di oxide
Adsorbent
0.303 BINDER
7.
HPMC-E5
Binder
0.758
8.
Polysorbate 80 (Tween 80)
Wetting Agent
1.515
9.
Purified Water
Solvent
q.s. LUBRICATION
10.
Sodium Lauryl Sulfate
Wetting Agent
2.273
11.
Colloidal silicon di oxide
Glidant
0.758
12.
Magnesium stearate
Lubricants
1.121
13.
Talcum
Lubricants
1.515
14.
Crosspovidone
Disintegrant
8.970
19
COATING SEAL COATING 1
15.
Instacoat sol IC-S-1643
Film Former
QS
16.
Iso Propyl Alcohol
Solvent
QS
17.
Methylene Chloride
Solvent
QS SEAL COATING 2
18.
Opadry Clear 1R 7006
Film Former
QS
19.
Iso Propyl Alcohol
Solvent
QS
20.
Methylene Chloride
Solvent
QS
DELAYED RELEASE COATING
21.
Cellulose Acetate Phthalate (Instacoat EN)
Delayed Release material
QS
22.
Quinoline Yellow Lake
Colouring Material
QS
23.
Isopropyl Alcohol
Solvent
QS
24.
Methylene Chloride
Solvent
QS
Formula-5: Domperidone immediate release part: S. No.
Ingredients
Function
%age Dry Mixing:
1.
Domperidone Maleate Eq. to Domperidone
API
3.191
2.
Microcrystalline Cellulose
Diluent
29.08
3.
Lactose
Diluent
24.69
4.
Starch (Maize)
Diluent
24.69
5.
Sodium Starch Glycolate
Disintegrant
1.975
20
Binder Preparation
6.
Polyvinyl pyrrolidone (PVPK-30)
Binder
3.704
7.
Purified water
Solvent
----- Lubrication
8.
Sodium Lauryl Sulphate
Wetting Agent
0.741
9.
Sodium Starch Glycolate (Primojel)
Disintegrant
3.21
10.
Microcrystalline Cellulose PH-102
Diluent
6.173
11.
Talcum
Disintegrant
1.111
12.
Colloidal silicon dioxide
Glidant
1.235
13.
Magnesium Stearate
Lubricant
1.185
14.
Hydroxy propyl cellulose LH-11
Anti-Capping Agent
1.481
Formula 6- Domperidone Sustained Release Part S.NO.
Ingredients
Function
% age Dry Mixing:
1.
Domperidone Maleate Eq. to Domperidone
Active
13.970
2.
Microcrystalline Cellulose PH-102
Diluent
37.49
3.
Methocel K-4 M (Dow Chem.)
Release Controller
20.000
4.
Iron Oxide (Ferric Oxide) Red
Colour
0.081 Binder Preparation:
5.
Polyvinyl pyrrolidone (PVPK-30)
Binder
3.243
6.
Isopropyl alcohol
Solvent
QS
7.
Purified Water
Solvent
---
21
Lubrication
8.
Microcrystalline Cellulose PH-102
Diluent
14.590
9.
Talcum
Lubricant
0.757
10.
Colloidal silicon dioxide
Glidant
0.811
11.
Magnesium Stearate
Lubricant
0.865
12.
Iron Oxide (Ferric Oxide USPNF) Red
Colour
0.081
13.
Hydrogenated Castor Oil
Lubricant
5.405
14.
Hydroxy Propyl Cellulose-LH-11
Anti-capping Agent
2.703
Example 4- Tablet-in-tablet Preparation
Formula 7- Pantoprazole sodium as Gastro resistant tablet (intermediate)
S. No.
Ingredients
Function
%age DRY MIX
1.
Pantoprazole Sodium
Active
70.99
2.
Starch (Maize)
Diluent
1.667
3.
Sodium Carbonate
Stabilizer
5.303
4.
Sodium starch glycollate
Disintegrant
3.788
5.
Sodium lauryl sulfate
Wetting Agent
0.757
6.
Colloidal silicon di oxide
Adsorbent
0.378 BINDER
7.
HPMC-E5
Binder
0.833
8.
Polysorbate 80
Wetting Agent
1.515
9.
(Tween 80)
Solvent
q.s. LUBRICATION
10.
Sodium lauryl sulfate
Wetting Agent
2.272
22
11.
Colloidal silicon di oxide
Glidant
0.757
12.
Magnesium stearate
Lubricants
1.136
13.
Talcum
Lubricants
1.515
14.
Crosspovidone
Disintegrant
9.090 COATING SEAL COATING 1
15.
Instacoat sol IC-S-1643
Film Former
QS
16.
Iso Propyl Alcohol
Solvent
QS
17.
Methylene Chloride
Solvent
QS SEAL COATING 2
18.
Opadry Clear 1R 7006
Film Former
QS
19.
Iso Propyl Alcohol
Solvent
QS
20.
Methylene Chloride
Solvent
QS
DELAYED RELEASE COATING
21.
Cellulose Acetate Phthalate (Instacoat EN)
Delayed Release material
QS
22.
Ponceau 4 R Lake
Colouring Material
QS
23.
Isopropyl Alcohol
Solvent
QS
24.
Methylene Chloride
Solvent
QS
Formula-8: Domperidone immediate release part: S. No.
Ingredients
Function
%age Dry Mixing:
1.
Domperidone Maleate Eq. to Domperidone
API
3.190
2.
Microcrystalline Cellulose
Diluent
29.08
23
3.
Lactose
Diluent
24.69
4.
Starch (Maize)
Diluent
24.69
5.
Sodium Starch Glycolate
Disintegrant
1.975 Binder Preparation
6.
Polyvinyl pyrrolidone (PVPK-30)
Binder
3.703
7.
Purified water
Solvent
----- Lubrication
8.
Sodium Lauryl Sulphate
Wetting Agent
0.740
9.
Sodium Starch Glycolate (Primojel)
Disintegrant
3.20
10.
Microcrystalline Cellulose PH-102
Diluent
6.172
11.
Talcum
Disintegrant
1.111
12.
Colloidal silicon dioxide
Glidant
1.234
13.
Magnesium Stearate
Lubricant
1.185
14.
Hydroxy propyl cellulose LH-11
Anti-Capping Agent
1.481
Formula 9- Domperidone Sustained Release Part S.NO.
Ingredients
Function
%age Dry Mixing:
1.
Domperidone Maleate
Active
13.971
2.
Eq. to Domperidone
Diluent
37.49
3.
Microcrystalline Cellulose PH-102
Release Controller
20.000
4.
Methocel K-4 M (Dow Chem.)
Colour
0.081 Binder Preparation:
5.
Polyvinyl pyrrolidone (PVPK-30)
Binder
3.243
6.
Isopropyl alcohol
Solvent
QS
24
7.
Purified Water
Solvent
--- Lubrication
8.
Microcrystalline Cellulose PH-102
Diluent
14.590
9.
Talcum
Lubricant
0.757
10.
Colloidal silicon dioxide
Glidant
0.811
11.
Magnesium Stearate
Lubricant
0.865
12.
Col. Ponceau 4 R Lake
Colour
0.081
13.
Hydrogenated Castor Oil
Lubricant
5.405
14.
Hydroxy Propyl Cellulose-LH-11
Anti-capping Agent
2.703
25
Example-5 Stability Study:
The Rabeprazole sodium and Domperidone tablet in tablet (20 mg+30 mg) prepared from example-2 were subjected to stability study under different conditions:
i. Temp. 30¢XC ¡Ó 2¢XC & RH 75 % ¡Ó 5 % for 18 months
Test
Acceptance criteria
Initial testing
3 months
6 month
9 month
12 month
18 month
Description
Light brown & white colored, round, biconvex, both sides plain & uncoated bilayered tablet contains one brown coloured, round, biconvex, both side plain & enteric coated
Light brown & white colored, round, biconvex, both sides plain & uncoated bilayered tablet contains one brown coloured, round, biconvex, both side plain & eneteric coated tablet of
Light brown & white colored, round, biconvex, both sides plain & uncoated bilayered tablet contains one brown coloured, round, biconvex, both side plain & enteric
Light brown & white colored, round, biconvex, both sides plain & uncoated bilayered tablet contains one
Light brown & white colored, round, biconvex, both sides plain & uncoated bilayered tablet contains one
Light brown & white colored, round, biconvex, both sides plain & uncoated bilayered tablet contains one
Light brown & white colored, round, biconvex, both sides plain & uncoated bilayered tablet contains one
26
tablet of Rabeprazole as tablet in tablet
Rabeprazole as tablet in tablet
coated tablet of Rabeprazole as tablet in tablet
brown coloured, round, biconvex, both side plain & enteric coated tablet of Rabeprazole as tablet in tablet
brown coloured, round, biconvex, both side plain & enteric coated tablet of Rabeprazole as tablet in tablet
brown coloured, round, biconvex, both side plain & enteric coated tablet of Rabeprazole as tablet in tablet
brown coloured, round, biconvex, both side plain & enteric coated tablet of Rabeprazole as tablet in tablet
Identification (by HPLC)
Rabeprazole sodium
In the assay, the principal
complies
complies
complies
complies
complies
complies
27
peak in the chromatogram obtained with the test solution corresponds to the peak in the chromatogram obtained with the standard solution.
Domperidone
In the assay, the principal peak in the chromatogram obtained with the test solution
complies
complies
complies
complies
complies
complies
28
corresponds to the peak in the chromatogram obtained with the standard solution.
Average weight
669.00 mg¡Ó 5%
673.66 mg
670.85 mg
674.88 mg
674.85 mg
678.15
673.80
Water content (by K.F)
For record purpose only
5.61% w/w
4.83% w/w
6.86% w/w
6.53% w/w
5.69% w/w
3.98% w/w
Dissolution (by HPLC)
Rabeprazole sodium
In acidic medium (0.1 M Hydrochloric acid)
Not more than 10% released in 120 minute
Min.
0.00 %
0.005 %
0.00 %
0.00 %
0.00 %
0.00 %
Max.
0.00 %
1.47%
5.19%
0.00%
1.5%
0.00 %
Avg.
0.00 %
0.25%
1.73%
0.00%
0.41%
0.00%
In buffer medium (Tris
Level S1 (No. of tablets tested 6 units):
Min.
94.86%
93.84%
87.48%
82.59%
87.11%
88.31%
Max.
98.88 %
97.60 %
90.63%
84.15 %
92.16%
90.74 %
29
buffer pH 8.0)
each unit is not less than 70% + 5% in 45 minutes.
Level S2 (No. of tablets tested 6 units):
average of 12 units (S1+ S2) is equal to or greater than 70% & no unit is less than 55% (D-15%) IN 45 mintues.
Level S3 (No. of tablets tested 12 units):
Average of 24 units (S1+S2+S3) is equal to or greater than
Avg.
97.07%
95.66%
88.54%
83.61%
89.93%
89.68%
30
75% , not more than 2 units are less than 55% (D-15%) & no unit is less than 45% (D-25%) in 45 minutes
Domperidone
Level L1 (No. of tablets tested 6 units):
No individual value lies than 70% + 5% in 45 minutes
Level L2 (No. of tablets tested 6 units):
The average value of the 12 units (L1+L2) lies within each of the stated ranges and is not less than the stated amount at the final test time, none is more than 10% of labelled content outside each of the stated ranges and none is more than 10% of labelled amount below the stated amount at the final test time
Level L3 (No. of tablets tested 12 units):
The average of 24 units (L1+L2+L3) lies withib each of the stated ranges, and is not less than the stated amount at the final test time, not more tha 2 of the 24 units are more than 10% of labelled content outside each of the stated amount at the final test time, and none of the units is more than 20% of labelled content outside each of the stated ranges or more than 20% of labelled content below the stated amount at the final test time.
After 1 hour
min
45.30%
40.70%
42.67 %
52.01%
48.04%
40.70
31
Between 35% to 70%
Max
51.79%
47.70%
44.91
53.51
53.22
45.14
avg
49.45%
44.64%
43.89
53.19
50.31
43.44
After 4 hours
Between 55% to 90%
min
63.60%
57.30%
57.00
71.74
58.54
62.00
Max
81.10%
71.31%
60.10
72.95
71.39
67.12
avg
75.07%
65.27%
58.63
72.65
67.27
64.55
After 12 hours
Not less than 70%
min
88.20%
77.53%
75.49
99.89
84.79
86.30
Max
109.66%
98.88%
89.04
102.53
103.57
107.18
avg
103.58%
91.31%
83.05
101.48
94.85
94.75
Related Substance (by HPLC)
Rabeprazole sodium
Single maximum impurity
Not more than 2.0%
0.146
0.231
0.303
0.348
0.418
0.521
Total impurities
Not more than 6.0%
0.410
0.437
0.452
0.433
0.724
1.061
Domperidone
Single maximu
Not more than 0.5%
0.27
0.053
0.008
0.094
0.079
0.059
32
m impurity
Total impurities
Not more than 2.0%
0.34
0.075
0.021
0.129
0.298
0.113
Microbial contamination
Total viable count
Total aerobic bacterial count
Not more than 1000 cfu/gm
<10 cfu/gm
-
-
-
<10 cfu/gm
-
Total combined yeast & mould count
Not more than 100 cfu/gm
<10 cfu/gm
-
-
-
<10 cfu/gm
Test for specified microorganism
Escherichia coli
Should be absent/gm
absent/gm
-
-
-
absent/gm
Salmonella
Should be absent/10 gm
absent/10 gm
-
-
-
absent/10 gm
Pseudomonas aeruginos
Should be absent/gm
absent/gm
-
-
-
absent/ gm
33
Staphylococcus aureus
Should be absent/gm
absent/gm
-
-
-
absent/ gm
Shigella
Should be absent/10 gm
absent/10 gm
-
-
-
absent/ 10 gm
Bile-tolerant gram-negative (enterobacteria)
Should be absent/gm
absent/gm
-
-
-
absent/ gm
Assay : Each uncoated bilayered tablet contains:
Rabeprazole sodium (As delayed release form) 20 mg
NLT 18.00 mg to NMT 22.00 mg
(NLT 90.00% to NMT 110.0% of labelled claimed)
19.73 mg
(98.65%)
20.52 mg
(102.60 %)
19.87 mg
(99.35%)
20.09 mg
(100.45%)
19.80 mg
(99.00%)
19.58 mg
(97.90%)
Domperidone Maleate
NLT 27.00 mg to
29.92 mg
(99.73%)
28.74 mg
(95.80%)
30.32 mg
30.03 mg
31.01 mg
30.13 mg
34
IP Eq. to Domperidone (10 mg as immediate release and 20 mg as Sustained release) 30 mg
NMT 33.00 mg
(NLT 90.00% to NMT 110.0% of labelled claimed)
(101.07 %)
(100.10 %)
(100.03%)
(100.43%)
From above study it was found that Rabeprazole sodium and Domperidone tablet in tablet (20 mg+30 mg) prepared from example-2 was found to stable for 18 months when stored at temp. 30¢XC ¡Ó 2¢XC & RH 75 % ¡Ó 5 %.
5
ii.Temp. 40¢XC ¡Ó 2¢XC & RH 75% ¡Ó 5% for 6 months
Test
Acceptance criteria
Initial testing
3 months
6 months
Description
Light brown & white colored, round, biconvex, both sides plain & uncoated
Light brown & white colored, round, biconvex,
Light brown & white colored, round, biconvex,
Light brown & white colored, round, biconvex,
35
bilayered tablet contains one brown coloured, round, biconvex, both side plain & enteric coated tablet of Rabeprazole as tablet in tablet
both sides plain & uncoated bilayered tablet contains one brown coloured, round, biconvex, both side plain & eneteric coated tablet of Rabeprazole as tablet in tablet
both sides plain & uncoated bilayered tablet contains one brown coloured, round, biconvex, both side plain & enteric coated tablet of Rabeprazole as tablet in tablet
both sides plain & uncoated bilayered tablet contains one brown coloured, round, biconvex, both side plain & enteric coated tablet of Rabeprazole as tablet in tablet
Rabeprazole sodium
In the assay, the principal peak in the chromatogram obtained with the test solution corresponds to the peak in the
complies
complies
complies
36
chromatogram obtained with the standard solution.
Domperidone
In the assay, the principal peak in the chromatogram obtained with the test solution corresponds to the peak in the chromatogram obtained with the standard solution.
complies
complies
complies
Average weight
669.00 mg¡Ó 5%
673.66 mg
673.22 mg
671.48 mg
Water content (by K.F)
For record purpose only
5.61% w/w
4.86 % w/w
6.98 % w/w
Dissolution (by HPLC)
Rabeprazole sodium
In acidic medium (0.1 M Hydrochloric acid)
Not more than 10% released in 120 minute
Min.
0.00 %
0.00 %
1.57 %
Max.
0.00 %
0.00 %
3.92 %
Avg.
0.00 %
0.00 %
3.04 %
In buffer medium (Tris buffer pH 8.0)
Level S1 (No. of tablets
Min.
94.86%
89.25 %
83.77 %
Max.
98.88 %
93.99 %
88.89%
37
tested 6 units):
each unit is not less than 70% + 5% in 45 minutes.
Level S2 (No. of tablets tested 6 units):
average of 12 units (S1+ S2) is equal to or greater than 70% & no unit is less than 55% (D-15%) IN 45 mintues.
Level S3 (No. of tablets tested 12 units):
Average of 24 units (S1+S2+S3) is equal to or
Avg.
97.07%
92.23%
86.46%
38
greater than 75% , not more than 2 units are less than 55% (D-15%) & no unit is less than 45% (D-25%) in 45 minutes
Domperidone
After 1 hour
Between 35% to 70%
min
45.30%
53.21
43.59
Max
51.79%
57.23
47.07
avg
49.45%
55.41
45.86
After 4 hours
Between 55% to 90%
min
63.60%
68.41
59.52
Max
81.10%
84.38
66.09
avg
75.07%
79.79
63.16
After 12 hours
Not less than 70%
min
88.28%
93.46
77.39
Max
109.66%
104.21
98.09
avg
103.68%
100.07
85.61
Related Substance (by HPLC)
Rabeprazole sodium
Single maximum impurity
Not more than 2.0%
0.146
0.336
0.800
39
Total impurities
Not more than 6.0%
0.410
0.536
1.086
Domperidone
Single maximum impurity
Not more than 0.5%
0.27
0.030
0.077
Total impurities
Not more than 2.0%
0.34
0.091
0.284
Total aerobic bacterial count
Not more than 1000 cfu/gm
<10 cfu/gm
-
-
Total combined yeast & mould count
Not more than 100 cfu/gm
<10 cfu/gm
-
-
Escherichia coli
Should be absent/gm
absent/gm
-
-
Salmonella
Should be absent/10 gm
absent/10 gm
-
-
Pseudomonas aeruginos
Should be absent/gm
absent/gm
-
-
Staphylococcus aureus
Should be absent/gm
absent/gm
-
-
Shigella
Should be absent/10 gm
absent/10 gm
-
-
Bile-tolerant gram-negative (enterobacteria)
Should be absent/gm
absent/gm
-
-
40
Assay : Each uncoated bilayered tablet contains:
Rabeprazole sodium (As delayed release form) 20 mg
NLT 18.00 mg to NMT 22.00 mg
(NLT 90.00% to NMT 110.0% of labelled claimed)
19.73 mg
(98.65%)
19.83 mg
(99.15 %)
18.22 mg
(91.10 %)
Domperidone Maleate IP Eq. to Domperidone (10 mg as immediate release and 20 mg as Sustained release) 30 mg
NLT 27.00 mg to NMT 33.00 mg
(NLT 90.00% to NMT 110.0% of labelled claimed)
29.92 mg
(99.73%)
29.16 mg
(97.20 %)
29.44 mg
(98.13 %)
From above study it was found that Rabeprazole sodium and Domperidone tablet in tablet (20 mg+30 mg) prepared from example-2 was found to stable for 6 months when stored at temp. 40¢XC ¡Ó 2¢XC & RH 75% ¡Ó 5%
41
iii.Pantoprazole 40 mg & Domperidone 30 mg Tablet in tablet:
Pantaprazole and Domperidone Tablet in tablet prepared from example-4 was subjected to stability study temperature 40¢XC ¡Ó 2¢XC & RH 75% ¡Ó 5%
Test
Acceptance criteria
Initial testing
3 months
6 months
Description
Pink/white to off white coloured, round, biconvex, both side plain & uncoated bilayered tablets
Pink/white to off white coloured, round, biconvex, both side plain & uncoated bilayered tablets
Pink/white to off white coloured, round, biconvex, both side plain & uncoated bilayered tablets
Pink/white to off white coloured, round, biconvex, both side plain & uncoated bilayered tablets
Average weight
680.00 mg¡Ó 5%
679.56 mg
675.71 mg
678.59 mg
Water content (by K.F)
For record purpose only
3.03 % w/w
5.62 % w/w
7.41 % w/w
Dissolution (by HPLC)
Pantoprazole
Acid release
Not more than 10% released in 120 minute
Min.
0.00 %
0.79 %
0.00 %
Max.
1.92 %
5.01 %
0.00 %
Avg.
0.32 %
3.38 %
0.00 %
Buffer release
Not less than 75% in 60 minutes
Min.
96.86%
91.96 %
95.23 %
Max.
101.64
99.20
104.01
Avg.
99.38
97.04
99.19
Domperidone
After 1 hour
Between 35% to 70%
min
53.12
41.84
38.98
Max
65.68
52.46
41.62
avg
59.75
47.02
39.92
After 4 hours
Between 55% to 90%
min
75.29
65.68
62.95
Max
82.23
73.53
64.66
42
avg
80.11
69.26
63.86
After 12 hours
Not less than 70%
min
89.35
76.84
78.99
Max
93.88
84.15
81.74
avg
91.93
79.74
80.51
Related Substance (by HPLC)
Pantoprazole
Related compound A
Not more than 0.5%
0.029
0.130
0.053
Related compound B
Not more than 0.3%
0.005
0.067
0.034
Related compound D & F
Not more than 0.75%
0.017
0.316
0.322
Single maximum impurity
Not more than 0.5 %
0.108
0.176
0.122
Total impurities
Not more than 2.0%
0.223
0.721
0.531
Domperidone
Single maximum impurity
Not more than 0.5%
0.138
Not detected
Not detected
Total impurities
Not more than 2.0%
0.323
Not detected
Not detected
Microbial contamination
total viable count
Total aerobic bacterial count
Not more than 1000 cfu/gm
<10 cfu/gm
-
-
Total combined yeast & mould count
Not more than 100 cfu/gm
<10 cfu/gm
-
-
Escherichia coli
Should be absent/gm
absent/gm
-
-
Salmonella
Should be absent/10 gm
absent/10 gm
-
-
Staphylococcus aureus
Should be absent/gm
absent/gm
-
-
Pseudomonas aeruginosa
Should be absent/gm
absent/gm
-
-
Shigella
Should be absent/10 gm
absent/10 gm
-
-
Bile-tolerant gram-negative (enterobacteria)
Should be absent/gm
absent/gm
-
-
Assay : Each uncoated bilayered tablet contains:
43
Rabeprazole sodium (As delayed release form) 20 mg
NLT 18.00 mg to NMT 22.00 mg
(NLT 90.00% to NMT 110.0% of labelled claimed)
19.73 mg
(98.65%)
19.83 mg
(99.15 %)
18.22 mg
(91.10 %)
Domperidone Maleate IP Eq. to Domperidone (10 mg as immediate release and 20 mg as Sustained release) 30 mg
NLT 27.00 mg to NMT 33.00 mg
(NLT 90.00% to NMT 110.0% of labelled claimed)
29.92 mg
(99.73%)
29.16 mg
(97.20 %)
29.44 mg
(98.13 %)
From above study it was found that Pantaprazole and Domperidone Tablet in tablet prepared from example-4 was found to be stable at temperature 40¢XC ¡Ó 2¢XC & RH 75% ¡Ó 5% for 6 months.
,CLAIMS:Claim 1- A tablet-in-tablet composition comprising
a) an enteric coated inner tablet wherein the inner tablet comprises of one or more pharmaceutically active agent,
and wherein the inner tablet exhibits delayed drug release profile.
b) an outer tablet wherein the outer tablet is compressed over the inner tablet, completely surrounding the inner tablet,
wherein the outer tablet is a bilayer tablet composed of sustained release layer and an immediate release layer and wherein the sustained release layer and immediate release layer comprises same or different pharmaceutically active ingredients.
Claim 2-The tablet-in-tablet composition according claim 1, wherein the pharmaceutically active agent present in the inner tablet is a PPI, wherein PPI’s are selected from group consisting of Omeprazole, Esomeprazole, Lansoprazole, Dexlansoprazole, Pantoprazole and Rabeprazole.
Claim 3- The inner tablet according to claim 2, wherein the PPI is present in the amount of 30-80 wt.% PPIs based on total weight of uncoated inner core tablet.
Claim 4- The inner tablet according to claim 1-3, wherein the enteric coat is composed of gastro-resistant polymers selected fromhydroxypropyl methylcellulose phtalate (HMPCP), polyvinyl acetate 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 cellulose acetate trimellitate and wherein the gastro-resistant polymers are present in an amount ranging from 5 to 20 % based on total weight of coated inner core tablet.
Claim 5- The inner tablet according to claim 1-4, further comprises pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients are diluent, stabilizer, disintegrant, binder, lubricant or anti-capping agent and combinations thereof.
Claim 6-The pharmaceutical composition according to claim 1 wherein the pharmaceutically active agent present in the bilayer outer tablet is Domperidone, wherein the active agent Domperidone is present in the amount of 2 to 30 % based on total weight of outer shell.
Claim 7- The bilayer outer tablet according to claim 1 and 6, wherein the bilayer tablet is composed of:
a) An immediate release layer comprising 2-5 wt.% of Domperidone maleate eq. to Domperidone based on individual layer and further comprises pharmaceutical acceptable excipients and;
b) A sustained release layer comprising 10-15 wt.% of Domperidone maleate eq. to Domperidone based on individual layer and further comprises pharmaceutical acceptable excipients
Wherein the inner tablet is stacked between the immediate release layer and the sustained release layer.
Claim 8 – The bilayer outer tablet according to claim 7, wherein the pharmaceutically acceptable excipients present in the immediate release layer are diluents, disintegrant, binder, wetting agent, glidant, lubricants and anti-capping agents.
Claim 9- The bilayer outer tablet according to claim 7, wherein the pharmaceutically acceptable excipient present in the sustained release layer are release controller, diluent, colorant, binder, lubricant, glidant and anti-capping agent.
Claim 10- The bilayer outer tablet according to claim 9, wherein the sustained release polymers are selected from hydroxypropylmethylcellulose, polyethylene oxide, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, polyvinylpyrrolidone, xanthan gum, and guar gum
Claim 11 - A tablet-in-tablet composition as claimed in claim 1 comprising:
a) An enteric coated inner tablet comprising 30-80 wt.% PPIs based on total weight of uncoated inner core tablet and;
b) A bilayer outer tablet comprising:
i) An immediate release layer comprising 2-5 wt.% of Domperidone maleate eq. to Domperidone based on individual layer and;
ii) A sustained release layer comprising 10-15 wt.% of Domperidone maleate eq. to Domperidone based on individual layer
Claim 12- A method of preparing tablet-in-tablet composition comprising following steps:
a) Preparation of inner core tablet comprising Proton pump inhibitors comprising the steps of
i) Preparing granules comprising PPI through wet or dry granulation
ii) Compressing the granules obtained from step i) to form the inner tablet
iii) Coating of the inner tablet with gastro resistant polymer to obtain the enteric coated enteric coated inner tablet
b) Preparation of bilayer outer tablet comprising the steps of
i) Preparing immediate release granules comprising Domperidone through wet or dry granulation
ii) Preparing sustained release granules comprising Domperidone
iii) Compressing immediate release granules over 50% of the inner tablet surface area to obtain the immediate release layer of the outer tablet
iv) Compressing the sustained release granules over the remaining 50% of the inner tablet surface area to obtain the sustained release layer of the outer tablet.