WO2004012701A2

WO2004012701A2 - NOVEL pH DEPENDENT ROBUST ENTERIC POLYMERIC CONTAINER, AN IMPROVEMENT OVER EXISTING ENTERIC DOSAGE FORMS.

Info

Publication number: WO2004012701A2
Application number: PCT/IN2003/000263
Authority: WO
Inventors: Ajit Singh; Meena Parashuraman
Original assignee: Scitech Centre
Priority date: 2002-08-02
Filing date: 2003-08-01
Publication date: 2004-02-12
Also published as: WO2004012701A3; AU2003274683A1; AU2003274683A8

Abstract

The present invention relates to a novel pH dependent robust enteric polymeric containers such as hard capsules and a process of manufacturing the same wherein polymeric containers are characterized by having improved elasticity containing right proportion of plasticizers within the capsule shell composition rather than the coating composition.

Description

TITLE OF INVENTION

NOVEL pH DEPENDENT ROBUST ENTERIC POLYMERIC CONTAINER, AN IMPROVEMENT OVER EXISTING ENTERIC DOSAGE FORMS.

The present invention relates to enteric polymeric capsules and more

particularly to two-piece hard capsules for pharmaceutical, nutraceuticals,

herbal, and the like applications.

At present, capsules for pharmaceutical applications consists of capsule

shell and a coating there on. Such capsules contain two parts: a capsule

body and a cap.

Conventionally, made enteric hard gelatin capsules are somewhat brittle

in nature, thus creating a major problem on the capsule filling machines.

It is known in the art to use plasticizer particularly triethyl citrate as a

stabilizing agent with regard to gelatin capsules. Japanese Patent No.

JP62016432A2 titled ENTERIC COATING COMPOSITION also teaches

the use of triethyl citrate as a stabilizing agent. The enteric coating

composition as disclosed by JP62016432A2 consists essentially of a

water- dispersible copolymer obtained by emulsion polymerizing of ethyl

acrylate with methacrylic acid and triethyl citrate. Although the above-

mentioned water - dispersible copolymer is used in an enteric coating, the

addition of a plasticizer is indispensable to prevent the cracking and

embrittling of the coating layer. However the above mentioned Japanese

patent uses triethyl citrate in mixed form with the enteric coating

composition. Various plasticizers are known in the art for use in the capsules. In the

case of the polyethylene glycol as plasticizer, the delay in disintegration

time is sometimes recognized with time. If triacetin is used, there is a problem of acetic acid smell formation with time.

Soft Gelatin capsules known in the art are found to use Glycerol

combined with Triethyl citrate as plasticizer in the shell composition.

Moreover the soft gelatin capsule is prepared along with the inside

content. The present invented capsule can be supplied as empty

containers with enteric properties where any kind of material can be filled

inside the container.

German Patent No. DE 322 22476 describes a pharmaceutical

composition in which a soft gelatin capsule that is resistant to digestive

juice whose wall includes gelatin mass which contain polyvinyl acetate

phthalate, hydroxypropyl methylcellulose phthalate or a vinyl acetate or

crotonic acid copolymer and an alkali metal salt, ammonia salt, or amino

salt of the same in their wall, and which released its contents readily in

the intestines within the prescribed time. The capsules are further treated

on the surface with an aldehyde-coating agent. However, this

composition has a disadvantage that the free acidic groups of the

polymer in the shell reacts with the active ingredient and reduces the

efficacy of the product during its storage or shelf life period.

US Patent No. 4, 138, 013 describes a hard-shell pharmaceutical capsule

being characterized by relative freedom from brittleness and by

substantial absence of degradation on exposure to artificial gastric juice

for 120 minutes, and the body and cap portions being formed by the dip- molding technique from a homogeneous film-forming composition

comprising hydroxypropyl methylcellulose and an ammonium salt of cellulose acetate phthalate polymer or gelatin and an ammonium salt of a

copolymer of methacrylic acid and methacrylic acid ester, optionally with

the inclusion of plasticizer and/or coloring agents. The patent claims glycerin and propylene glycol as plasticizers. Further, the patent claims

that use of plasicizers is optional. The present invention shows that the

use of plasticizer is not just optional, but it is mandatory requirement in

view of avoiding brittleness. Moreover, the present invention describes

the use of triethyl citrate as plasticizer in a particular proportion to

overcome the brittleness of the capsule since the use of propylene glycol

and glycerin as plasticizers renders the capsule soft and pliable, and the

capsules become non-sturdy.

OBJECTS OF THE INVENTION

The primary object of the present invention is to overcome the above

problems and particularly the problem of brittleness and also to make the

capsule commercially feasible.

Still most important object of the present invention is to eliminate the step

of coating the capsules as practiced at present thus saving in cost of

manufacture and simultaneously reducing its undesirable brittleness to

the desired extent.

Another object of the present invention is to provide a process for

producing the capsule without conventional coating wherein desired plasticity of the capsule is maintained wherein use of glycerol or propylene glycol are done away with.

SUMMARY AND DETAILED DESCRIPTION OF THE INVENTION

The present invention essentially resides in a surprising discovery that triethyl citrate (TEC) in particular and other plasticizers in general when

used with polymeric composition, especially gelatin and other compositions like HPMC, modified starch, modified polyvinyl acetate

(PVA), carrageenan or any other suitable material to make the enteric hard capsules the step of providing enteric coating can be dispensed with

still retaining the desired enteric property of the capsules and also

undesired brittleness of the capsules can be eliminated. The other

substances which can substitute triethyl citrate are dibutyl pthalate, diethyl pthalate, benzyl phenyl formate, sorbitol and others.

In commerce, coating of tablets and capsules are the general methods

adapted for enteric or controlled dissolution properties. Uniform coating of

the polymer and uniform release of the drug are the most common

problems encountered. Some of the coated tablets when tested for the

release of the drug in gastric medium shows variation from 4% to 12.8% . The present invention gives an answer to the coating problems and gives

a ready to use enteric container which releases only up to 2% of the drug

in the gastric medium.

The present invention comprises the use of enteric polymers such as

methacrylic acid copolymer, cellulose acetate phthalate, hydroxy propyl methylcellulose and hydroxypropyl methylcellulose phthalate, Polyvinyl acetate phthalate and other gastro resistant polymers and combinations thereof.

The present invention provides a novel pH dependent robust enteric polymeric container consisting of a body and a cap such as hard capsules and the like and a process of manufacturing the same comprising the steps of:

(a) neutralizing enteric polymer slowly in alkaline solution under stirring,

(b) de-aeration of the solution on the water bath,

(c) adding plasticizer to the polymer solution under stirring and homogenized,

(d) adding gelatin solution to the polymer solution under stirring at

desired temperature,

(e) de-aeration of the final solution at desired temperature,

(f) dipping and molding the capsule, by conventional process known

in the art.

The alkaline solution used for neutralizing enteric polymer is prepared by

adding water to a base like ammonia, sodium carbonate, sodium

bicarbonate and like under stirring.

The enteric polymer is selected in the range 1 % to 60%.

The plasticizer is selected in the range of 0.5% to 7% preferably 1 to 5%. The aqueous gelatin solution is in the range of 3 to 35% preferably in the range 5 to 25%.

The gelatin solution was added at a temperature in the range 45°C to 55° C, preferably in the range 46°C to 52°C.

The enteric polymer is selected from a group consisting methacrylic acid

copolymer in the range .5% to 60% W/W, Cellulose acetate phthalate in

the range of 2 to 12% preferably 3 to 8%, hydroxypropyl methylcellulose

phthalate in the range of 1 to 20%.

Methacrylic acid copolymer comprises 5% W/W to 60% W/W preferably it

within the range 8% to 20%, more preferably within the range 12% to

18%.

Cellulose acetate phthalate (CAP) is to be used in the range of 2 to 12%,

more preferably within the range 3% to 8%.

Hydroxypropyl methylcellulose pthalate is to be used within the range of 1

to 20%..

Gelatin is used in the range of 3 to 35% in the composition, preferably

should be in range of 5 to 25%.

Colourants, surfactants, opacifiers, silicon dioxide, preservatives like

parabens, acetic acid, sweeteners, flavours can be incorporated in the

capsule body shell and cap shell like any other regular capsule.

The containers may or may not be sealed either by applying an enteric

polymeric band around the container or by sealing the cap and body by

any other suitable process. The above said containers can be printed both axially and radially in one

or more colours.

The present invention also teaches an improved process for reducing the

brittleness in enteric hard gelatin capsule by the following examples and

illustrations.

A series of experiments were designed with varying concentrations of

Triethyl citrate to optimize the correct desired concentration. Triethyl

citrate was used in 0.5, 1 .0, 1 .5, 2, 3, 4, 5, 6 and 7% addition level. The

brittleness was checked by standard brittleness checking equipment at 0

hr. 17 hrs., 24 hrs., 65 hrs. and 240 hrs. The capsules prepared with 1 to

2.5 % TEC did not become brittle and was having good mechanical

strength to run on the machines.

Triethyl citrate (TEC) finds use in this invention as mentioned herein:

Methacrylic acid polymer was added in ammoniated water and stirred for

complete dissolution. Triethyl citrate was added in the solution. The

entire mixture was homogenized, which was an important step, otherwise

the TEC floats on top and does not give uniform solution.

The containers of the present invention are made by the conventional dip

molding process. Other modified processes can also be used to make

the containers such as injection- moulding and the like.

In general the present invention suggests the use of 0.5% - 5% of triethyl

citrate for achievement of better stability in the hard gelatin capsules. Accelerated stability study shows that the capsules are stable at storage conditions of 40°C and 75%> relative humidity and room temperature for three months.

The following table explains the dissolution data of three months accelerated stability, performed with diclofenac sodium drug formulation filled in the enteric hard gelatin capsule.

The following examples enable a better understanding of the invention.

Example-1

Ingredients Composition

Methacrylic acid copolymer 7.86 g.

Water 53.70 g.

Ammonia solution ( 10 % v/v ) q.s

Propylene Glycol 1.96 g

Gelatin Solution ( 33.33% ) 40.00 g

To water add propylene glycol and ammonia solution under stirring. Add Eudragit slowly to above solution under stirring, de-aerate the solution on the water bath. Gelatin solution is added to the polymer solution under stirring at temp 52°C and deareate the final solution at temp 52°C. Hard gelatin capsules are molded in conventional dip molding process. Propylene glycol is a plasticizer and gives capsules that are not sturdy. The capsules were soft and pliable.

Example-2

Ingredients Composition

Methacrylic acid copolymer 13.79 g.

Water 60.00 g. Ammonia solution ( 25 % w/v ) q.s g.

Propylene Glycol 1 .00 g.

Gelatin Solution ( 33.33% ) 24.21 g.

To water add propylene glycol and ammonia solution under stirring. Add Methacrylic acid copolymer C slowly to above solution under stirring de- aerate the solution on the water bath. Gelatin solution is added to the polymer solution under stirring at temp 52°C and deareate the final solution at temp 52°C. Hard gelatin capsules are molded in conventional dip molding process. Propylene glycol is a plasticizer and gives capsules that are not sturdy. The capsules were soft and pliable.

Example-3

Ingredients Composition in g.

Methacrylic acid copolymer 13.79 Water 57.47

Ammonia solution ( 25 % w/v ) q.s

Propylene Glycol 3.45

Gelatin Solution ( 33.33% w/v ) 21 .83

To water add propylene glycol and ammonia solution under stirring. Add

Methacrylic acid copolymer C slowly to above solution under stirring deareate the solution on the water bath. Gelatin solution is added to the polymer solution under stirring at temp 52°C and deareate the final solution at temp 52°C. Hard gelatin capsules are molded in conventional dip molding process. Propylene glycol is a plasticizer and gives capsules that are not sturdy. The capsules were soft and pliable.

Example-4

Ingredients Composition in g.

Methacrylic acid copolymer 10.06

Water 56.54

Ammonia solution ( 25 % w/v ) q.s

Propylene Glycol 0.7 Triethyl citrate 5.10

Gelatin Solution ( 33.33% w/v ) 26.81

To water add ammonia solution under stirring. Add Methacrylic acid copolymer C slowly to above solution under stirring deareate the solution on the water bath. Add propylene glycol and triethyl citrate to the polymer solution under stirring. Gelatin solution is added to the polymer solution under stirring at temp 52°C and de-aerate the final solution at temp 52°C. Hard gelatin capsules are molded in conventional dip molding process. Propylene glycol is a plasticizer and gives capsules that are not sturdy. The capsules were soft and pliable.

Example-5

Ingredients Composition in g. Methacrylic acid copolymer 14.00

Water 45.00

Ammonia solution ( 25 % w/v ) q.s

Triethyl citrate 0.5

Gelatin Solution ( 33.33% w/v ) 40.00

To water add ammonia solution under stirring. Add Methacrylic acid copolymer C slowly to above solution under stirring de-aerate the solution on the water bath. Add triethyl citrate to the polymer solution under stirring. Gelatin solution is added to the polymer solution under stirring at temp 52°C and dearate the final solution at temp 52°C. Hard gelatin capsules are molded in- conventional dip molding process. Capsules were brittle.

Example-6

Ingredients Composition in g.

Methacrylic acid copolymer 14.00

Water ^' 45.00

Ammonia solution ( 25 % w/v ) q.s Triethyl citrate 0.75

Gelatin Solution ( 33.33%> w/v ) 40.00

To water add ammonia solution under stirring. Add Methacrylic acid copolymer C slowly to above solution under stirring deareate the solution on the water bath. Add triethyl citrate to the polymer solution under stirring. Gelatin solution is added to the polymer solution under stirring at temp 52°C and dearate the final solution at temp 52°C. Hard gelatin capsules are molded in conventional dip molding process. Capsules were brittle.

Example-7

Ingredients Composition in g.

Methacrylic acid copolymer 17.00 Water 46.00

Ammonia solution ( 25 % w/v ) q.s

Triethyl citrate 0.5

Gelatin Solution ( 33.33% w/v ) 36.5

To water add ammonia solution under stirring.Add Methacrylic acid copolymer C slowly to above solution under stirring de-aerate the solution on the water bath. Add triethyl citrate to the polymer solution under stirring. Gelatin solution is added to the polymer solution under stirring at temp 52°C and de-aerate the final solution at temp 52°C. Hard gelatin capsules are molded in conventional dip molding process. Capsules were brittle.

Example-8

Ingredients Composition in g.

Methacrylic acid copolymer 17.00

Water 46.00

Ammonia solution ( 25 % w/v ) q.s

Triethyl citrate 1 .0 Gelatin Solution ( 33.33% w/v ) 36.00

To water add ammonia solution under stirring. Add Methacrylic acid copolymer C slowly to above solution under stirring de-aerate the solution on the water bath. Add triethyl citrate to the polymer solution under stirring. Gelatin solution is added to the polymer solution under stirring at temp 52°C and dearate the final solution at temp 52°C. Hard gelatin capsules are molded in conventional dip molding process. Capsules were brittle after some time.

Example-9

Ingredients Composition in g.

Methacrylic acid copolymer 17.00

Water 46.00 Ammonia solution ( 25 % w/v ) q.s

Triethyl citrate 1 .5

Gelatin Solution ( 33.33% w/v ) 35.5

To water add ammonia solution under stirring. Add Methacrylic acid copolymer C slowly to above solution under stirring deareate the solution on the water bath. Add triethyl citrate to the polymer solution under stirring. Gelatin solution is added to the polymer solution under stirring at temp 52°C and de-aerate the final solution at temp 52°C. Hard gelatin capsules are molded in conventional dip molding process. Capsules were not brittle for 10 days. Example-10

Ingredients Composition in g.

Methacrylic acid copolymer 17.00

Water 46.00

Ammonia solution ( 25 % w/v ) q.s

Triethyl citrate 2.0

Gelatin Solution ( 33.33% w/v ) 35.0

To water add ammonia solution under stirring. Add Methacrylic acid copolymer C slowly to above solution under stirring de-aerate the solution on the water bath. Add triethyl citrate to the polymer solution under stirring. Gelatin solution is added to the polymer solution under stirring at temp 52°C and de-aerate the final solution at temp 52°C. Hard gelatin capsules are molded in conventional dip molding process. Capsules were not brittle for 10 days and retained the mechanical strength.

Example-11

Ingredients Composition in g.

Methacrylic acid copolymer 17.00

Water 45.00

Ammonia solution ( 25 % w/v ) q.s Triethyl citrate 3.0

Gelatin Solution ( 33.33% w/v ) 35.00

To water add ammonia solution under stirring. Add Methacrylic acid copolymer C slowly to above solution under stirring de-aerate the solution on the water bath at temp 52°C . Add triethyl citrate to the polymer solution under stirring. Gelatin solution is added to the polymer solution under stirring at temp 52°C and de-aerate the final solution at temp 52°C. Hard gelatin capsules are molded in conventional dip molding process. Capsules were not brittle , but they were very soft and were not sturdy to hold the medicaments.

Example-12

Ingredients Composition in g.

Methacrylic acid copolymer 17.00

Water 44.00

Ammonia solution ( 25 % w/v ) q.s

Triethyl citrate 4.0 Gelatin Solution ( 33.33% w/v ) 35.00

To water add ammonia solution under stirring.Add Methacrylic acid copolymer C slowly to above solution under stirring deareate the solution on the water bath. Add triethyl citrate to the polymer solution under stirring. Gelatin solution is added to the polymer solution under stirring at temp 52°C and de-aerate the final solution at temp 52°C. Hard gelatin capsules are molded in conventional dip molding process. Capsules were not brittle , but they were very soft and were not sturdy to hold the medicaments.

Example-13

Ingredients Composition in g.

Methacrylic acid copolymer 17.00 Water 43.00

Ammonia solution ( 25 % w/v ) q.s

Triethyl citrate 5.0

Gelatin Solution ( 33.33% w/v ) 35.00

Example-14

Ingredients Composition in g.

Methacrylic acid copolymer suspension 56.0

Ammonia solution ( 25 % w/v ) q.s

Triethyl citrate 2.0

Gelatin Solution ( 33.33% w/v ) 42.00

To Methacrylic acid copolymer C Suspension slowly add ammonia solution under stirring de-aerate the solution on the water bath. Add triethyl citrate to the polymer solution under stirring. Gelatin solution is added to the polymer solution under stirring at temp 52°C and de-aerate the final solution at temp 52°C. Hard gelatin capsules are molded in conventional dip molding process.

Example-15

Ingredients Composition in g.

Cellulose Acetate Phthalate 3.0

Water 36.0

Ammonia solution ( 25 % w/v ) q.s Triethyl citrate 1.0

Gelatin Solution ( 33.33% w/v ) 60.0

To water add ammonia solution under stirring. Add Cellulose Acetate Phthalate slowly to above solution under stirring de-aerate the solution on the water bath. Add triethyl citrate to the polymer solution under stirring.

Gelatin solution is added to the polymer solution under stirring at temp 52°C and de-aerate the final solution at temp 52°C. Hard gelatin capsules are molded in conventional dip molding process. Capsules were not brittle for 10 days and retained the mechanical strength. But cellulose acetate phthalate (CAP) did not give good result in stability studies. Example-16

Ingredients Composition in g.

Cellulose Acetate Phthalate 6.0

Water 40.0

Ammonia solution ( 25 % w/v ) q.s

Triethyl citrate 1 .0

Gelatin Solution ( 33.33% w/v ) 53.0

To water add ammonia solution under stirring.Add Cellulose Acetate Phthalate slowly to above solution under stirring de-aerate the solution on the water bath. Add triethyl citrate to the polymer solution under stirring. Gelatin solution is added to the polymer solution under stirring at temp 52°C and de-aerate the final solution at temp 52°C. Hard gelatin capsules are molded in conventional dip molding process. Capsules were not brittle for 10 days and retained the mechanical strength.

Example 17

Ingredients Composition in g.

Gelatin solution ( 33.33%w/v) 35 g.

Methacrylic acid copolymer 17 g.

Water 30.5 g. Glycerin 10 g.

Ammonia solution ( 25%) q.s.

Triethyl citrate 7.5 g.

To water added glycerin and stirred until it mixes with water. Added ammonia and stirred. Added methacrylic acid copolymer to the above and de-aerated the solution for overnight at temperature 40 deg. C. Added triethyl citrate to the above and stirred well. Added gelatin solution to the above solution. This solution was taken for hard capsule dip molding process. The viscosity was very high and the hard capsules were not formed. Very soft capsules were formed that are not sturdy. This combination was not found suitable for dip molding process of capsules.

Example 18

Ingredients Composition in g

Sodium carbonate 10 g.

Water 100 ml.

Methacrylic acid copolymer 15 g. Gelatin solution ( 33.33%, w/v) 100 ml

Added water to sodium carbonate and mixed well. Added methacrylic acid copolymer to the above and stirred. Gelatin solution was added to above solution and mixed well. De-aerated the solution at 40 deg. C on a water bath. Films were prepared before dip molding the capsules to check the disintegration properties. The films were not stable at gastric pH and disintegrated completely at 25 mins. This composition was not found suitable to retain enteric properties.

Example 19

Ingredients Composition in g

Sodium - Bicarbonate 19 g.

Water 190 ml.

Methacrylic acid copolymer 38 g.

Gelatin solution ( 33.33%) w/v) 53 ml

Added water to sodium bicarbonate and mixed, well. Added methacrylic acid copolymer to the above and stirred. Gelatin solution was added to above solution and mixed well. De-aerated the solution at 40 deg. C on a water bath. Films were prepared before dip molding the capsules to check the disintegration properties. The films did not disintegrate in gastric pH for 2 hrs. This passes the enteric test. The films were soft without any brittleness. Example 20

Ingredients Composition in g

Methacrylic acid copolymer 6 g.

Isopropyl alcohol 85 ml

Water 5 ml

Triethyl citrate 0.6 g.

Added methacrylic acid copolymer into isopropyl alcohol and dissolved . Added water and TEC and stirred well. Films were made with this solution

. Films were not brittle and were very elastic with no mechanical strength. Added gelatin solution to give mechanical strength , but there was an incompatibility and gelatin precipitated out in the solvent.

Example 21

Ingredients Composition in g.

Hydroxypropyl methyl cellulose phthalate 10 g.

Water 50 ml. Ammonia solution ( 25 % ) 3 ml

Gelatin solution ( 33.33 % w/v) 15 ml

Carrageenan ( gelling aid ) 0.12 g.

Potassium chloride 0.04 g.

HPMCP was dispersed in water and ammonia was added to solubilise it.

Carrageenan and potassium chloride was added and gelatin solution was added to the above. A film was prepared to check the disintegration properties. The film was very BRITTLE and did not dissolve in gastric pH for 2 hours. Example 22

Ingredients Composition in g.

Hydroxypropylmethyl cellulose phthalate 10 g.

Water 50 ml.

Ammonia solution ( 25 % ) 3 ml

Gelatin solution ( 33.33 % w/v) 15 ml

Carrageenan ( gelling aid ) 0.4 g.

Potassium chloride 0.04 g.

HPMCP was dispersed in water and ammonia was added to solubilise it. Carrageenan and potassium chloride was added and gelatin solution was added to the above. A film was prepared to check the disintegration properties. The film was very BRITTLE and did not dissolve in gastric pH for 2 hours.

Example 23

Ingredients Composition in g. Hydroxypropylmethyl cellulose phthalate 10 g.

Water 60 ml.

Ammonia solution ( 25 % ) 3 ml

Gelatin solution ( 33.33 % w/v) 15 ml

Carrageenan ( gelling aid ) 0.5 g. Potassium chloride 0.04 g.

HPMCP was dispersed in water and ammonia was added to solubilise it. Carrageenan and potassium chloride was added and gelatin solution was added to the above. A film was prepared to check the disintegration properties. The film was very BRITTLE and did not dissolve in gastric pH for 2 hours. Study of Brittleness of Enteric capsules with different concentrations of Triethyl citrate.

Brittleness is checked by Brittleness Rod

Brittleness: Take 100 capsule shells devoid of long short, broken or separated ones, place each shell on a smooth hard surface. Using a brass rod of 150mm length and 25 mm diameter and weighing approximately 0.5 kg, press the entire length of the shell until the sides meet. Repeat with another 99 shells. Not more than two shells crack, ship or break. If more than two but less than six shells fail to comply with the test, repeat the test with another 100 shells taken at random. The sample being examined if not more than six out of 200 shells fail to comply with the test.

Claims

1. A novel pH dependent robust enteric polymeric container without coating comprising a body and a cap such as hard capsules and the like and a process of manufacturing the same comprising the steps of:

(a). neutralizing enteric polymer slowly in alkaline solution under stirring,

(b) de-aerating the solution on the water bath,

(c) adding plasticizer to the polymer solution under stirring and

homogenized,

(d) adding gelatin solution to the polymer solution under stirring

at desired temperature,

(e) de-aerating the final solution at desired temperature,

(f) dipping and molding the capsule by conventional process

known in the art.

2. A novel pH dependent robust enteric polymeric container without

coating comprising a body and a cap such as hard capsules and the like

and a process of manufacturing the same as claimed in claim 1 wherein;

(a) the alkaline solution used for neutralizing enteric polymer is

prepared by adding water to a base like ammonia, sodium

carbonate, sodium bicarbonate, sodium hydroxide and the

like under stirring.

(b) the enteric copolymer is selected in the range of 1 % to 60%. (c ) the plasticizer is selected in the range of 0.5% to 7%, preferably 1 % to 5%. (d) aqueous gelatin solution in the range of 3% to 35%, preferably 5% to 25%.

(e) adding gelatin solution at a temperature in the range of 45 degree centigrade to 55 degree centigrade, preferably between 46 degree centigrade and 52 degree centigrade.

3. A novel pH dependent robust enteric polymeric container without coating comprising a body and a cap such as hard capsules and the like and a process of manufacturing the same as claimed in claim 1 wherein the enteric polymer is selected from a group consisting of methacrylic acid copolymer in the range of 5% w/w to 60% w/w, preferably 8% to 20%; a more preferably 12 to 18%. Cellulose acetate phthalate in the range of 2% to 12%, preferably 3% to 8%; hydroxypropyl methylcellulose phthalate in the range of 1 % to 20%, polyvinyl acetate phthalate and other gastro resistant polymers and the like and combinations thereof, in powdered form or in suspension form.

4. A novel pH dependent robust enteric polymeric container without coating comprising a body and a cap such as hard capsules and the like and a process of manufacturing the same as claimed in claim 1 wherein

the plasticizer is selected from a group comprising triethyl citrate

dibutyl phthalate, diethyl phthalate, benzyl phenylformate, sorbitol,

polyethylene glycol, and the like and combinations thereof.

5. A novel pH dependent robust enteric polymeric container without coating comprising a body and a cap such as hard capsules and the like and a process of manufacturing the same as claimed in claim 1 wherein the plasticizer is triethyl citrate.

6. A novel pH dependent robust enteric polymeric container without coating comprising a body and a cap such as hard capsules and the like and a process of manufacturing the same as claimed in claim 1 wherein the container is a capsule.

7. A novel pH dependent robust enteric polymeric container without coating comprising a body and a cap such as hard capsules and the like and a process of manufacturing the same as claimed in claim 1 wherein the container may optionally include colourants, surfactants, opacifiers, silicon dioxide, preservatives, sweeteners, flavours, and the like.

8. A novel pH dependent robust enteric polymeric container without coating comprising a body and a cap such as hard capsules and the like and a process of manufacturing the same as claimed in claim 1 wherein the container may or may not be sealed.

9. A process for manufacturing novel pH dependent robust enteric

polymeric container without coating such as hard capsule as claimed in

claim 1 wherein the container may optionally be printed axially and/or

radially in one or more colours.

10. A novel pH dependent robust enteric polymeric container without

coating comprising a body and a cap such as hard capsules and the like

and a process of manufacturing the same as claimed in claim 5 wherein

triethyl citrate is selected in the range 1 to 5%.

11. A novel pH dependent robust enteric polymeric container without coating comprising a body and a cap such as hard capsules and the like and a process of manufacturing the same as claimed in claim 5 & 10 wherein triethyl citrate is selected preferably in the range 1 to 2.5%.

12. A novel pH dependent robust enteric polymeric container without coating comprising a body and a cap such as hard capsules and the like and a process of manufacturing the same as claimed in claim 5 & 10 wherein triethyl citrate is selected more preferably in the range 2%.

13. A novel pH dependent robust enteric polymeric container without coating and a process as claimed in claim 3 wherein Methacrylic acid copolymer is either in suspension form or in the form of powder.

14. A novel pH dependent robust enteric polymeric container without coating and a process for preparing the same as claimed in claim 3 and 13 wherein Methacrylic acid copolymer can be substituted by Hydroxypropyl methylcellulose phthalate (HPMCP), Cellulose Acetate

Phthalate (CAP) and the like with or without gelling agent.

15. An enteric polymeric container made by the process as claimed in claim 1 to 14.