Claims:WE CLAIM:

1. An acid resistant capsule formulation comprising of:
a) at least one film forming polymer;
b) a gum consisting essentially of a high acyl gellan gum and a low acyl gellan gum; and
c) a pectin.

2. The acid resistant capsule formulation according to claim 1, wherein the film forming polymer is selected from the group consisting of cellulose ether or mixture of cellulose ethers including but not limited to methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose (HPMC) or mixtures thereof.

3. The acid resistant capsule formulation according to claim 2 wherein the cellulose ether is preferably hydroxypropyl methylcellulose (HPMC).

4. The acid resistant capsule formulation according to claim 3, wherein the HPMC is of the chemistry grade HPMC 2208, HPMC 2906 and/or HPMC 2910 and combinations thereof.

5. The acid resistant capsule formulation according to claim 3, wherein the HPMC has intrinsic viscosity ranging from 3 cps to 15 cps.

6. The acid resistant capsule formulation according to claims 1 to 3 wherein:
a) the HPMC is present in an amount ranging from about 5% to about 25% w/w of the formulation.
b) the high acyl gellan gum is present in an amount ranging from about 0.05% to about 3% and the low acyl gellan gum is present in an amount ranging from about 0.1% to about 6% by weight of the film forming polymer.
c) the pectin is present in an amount ranging from about 3% to about 20% by weight of the film forming polymer.

7. The acid resistant capsuleformulation according to claim 6 wherein:
a) the HPMC is present preferably in an amount of about 14 to 18% w/w of the formulation
b) the high acyl gellan gum is present preferably in an amount ranging from about 0.1% to about 1%, more preferably in an amount of about 0.2% to 0.7% and the low acyl gellan gum is present in an amount ranging from about 0.2% to about 1%, more preferably in amount of about 0.5% to 1.5 %by weight of the film forming polymer.
c) the pectin is present in an amount more preferably ranging from about 5% to about 15% by weight of the film forming polymer.

8. The acid resistant capsule formulation according to claim 1, wherein the capsule retards for dissolution of the contents after at least about one hour in acidic pH.

9. The acid resistant capsule formulation according to claim 1, wherein the ratio of high acyl gellan gum to low acyl gellan gum ranges from about 1:0.5 to about 1:3, more preferably the ratio is 1:2.

10. The acid resistant capsule formulation according to claim 1, wherein the ratio of pectin to HPMC ranges from about 1:20 to about 1:5.

11. The acid resistant capsule formulation according to claim 1, wherein the capsule formulation further comprises plasticizer which is present in an amount of from 0.01 to about 5% w/w of the film forming polymer.

12. The acid resistant capsule formulation according to claim 1, wherein the formulation allows the release of the active ingredient in a pH-dependent way.

13. A process for making the acid resistance capsule of claim 1, wherein the process comprises of the steps:
i. making an aqueous composition of a film forming polymer such as hydroxypropyl methylcellulose by first dispersing in hot water and then cooling below its gelation temperature.

ii. making aqueous composition of high acyl gellan gum in hot water;

iii. making aqueous composition of low acyl gellan gum by dispersing low acyl gellan gum in hot water;

iv. mixing the said aqueous solution of film forming polymer of step (i), high acyl gellan gum of step (ii) and low acyl gellan gum of step (iii) under constant stirring

v. Pectin is added under constant stirring to the aqueous solution of step (iv)
vi.
vii. adding processing aid such as colouring agents, plasticizers, surfactants to the said solution of step (v) to maximum of 10% on dry weight basis of the composition;

viii. De-bubbling the solution of step (vi)

ix. pouring the said solution of step (vii) in dipping dish;
x. preheating the stainless steel pins to temperatures between 80 to 120 ?C prior to dipping;

xi. dipping the said pins in the said solution of step (vii) maintained at temperature between 25 to 35 ?C;

xii. withdrawing the said pins at a predefined sequence of velocity and time;

xiii. distributing and transferring the picked wet mass by the said pin to oven type of tunnel having temperature between 120 to 60?C to bring down water content of wet shell formation;

xiv. subjecting the said pins at lower temperature once the said wet shell water content reaches below 50% and air blasting between 30 to 40 ?C till the shell moisture reaches below 8 %;

xv. Removing the said shells of step (xii) from pins, cutting to required length and then joining together to form capsule.
, Description:Detailed Description of the Invention
As used herein the following definitions apply unless clearly indicated otherwise. It should also be noted that the singular forms “a” “an” and “the” include plural reference unless the context clearly dictates otherwise.

In the present specification, the above mentioned “Capsule” means a conventional hard pharmaceutical capsule intended for oral administration to a human being or animal, said capsule consisting of two co-axial, telescopically-joined parts, referred to as body and cap. Pharmaceutically, capsules are either hard (two-piece) or soft (one-piece) and are used to encapsulate pharmaceutical formulations.

Unless otherwise indicated, “acid resistance” or “acid resistant” means that when subjected to the United States pharmacopeia (USP)dissolution test, the capsules of the invention do not present leaks for at least 1 hour in acidic pH.

In the present invention, the term "enteric" means the substantially insoluble capsule in gastric acid or by the stomach is meant to dissolve in the intestine (small intestine, large intestine), herein, it is used interchangeably with the term "acid-resistant".

According to one embodiment of the present invention, the capsules of the present invention displays satisfactory dissolution properties in simulated gastric fluid at pH 1.2, 37±2° C. Dissolution profile of an exemplary capsule of the invention in simulated gastric and intestinal fluids is disclosed in the examples.

Examples of film forming polymer suitable for use in the present invention include, but are not limited methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose (HPMC) or mixtures thereof. The preferred film forming polymer is HPMC. The HPMC can be of different chemistry grades such as HPMC 2208, HPMC 2906 and/or HPMC 2910 or mixtures thereof. The HPMC present can have intrinsic viscosity ranging from 3 cps to 15 cps.

Gellan gum, as used herein, refers to the extracellular polysaccharide obtained by the aerobic fermentation of the microorganism Sphingomonas elodea (formerly Pseudomonas elodea) in a suitable nutrient medium. Gellan gum is a gel-forming polysaccharide. The blend of the present invention comprises at least two gellan gums with different acyl contents, one having a high acyl content and one having a low acyl content. Combining and varying the ratios of the two forms of gellan gum produces a wide variety of textures. Gellan gum is an effective and useful gelling agent for nutracetuicals, food products and drugs as it is effective at low concentrations, gels on cooling and give a wide variety of textures from brittle to elastic. The structure of gellan gum is as given below:

The native form of gellangum,has two acyl substituents – acetate and glycerate. Both substituents are located on the same glucose residue, and on average, there is one glycerate per repeat and one acetate per every two repeats. The high acyl gellan is used to increase the elasticity and is suitably present in an amount ranging from about 0.05% to about 3%.In low acyl gum, the acyl groups are removed completely. The gel characteristics are influenced by the presence acyl groups. The high acyl form produces soft, elastic, non-brittle gels, whereas the low acyl form produces firm, non-elastic brittle gels. The low acyl gellan gum is present in an amount ranging from about 0.1% to about 6% by weight of the formulation.Gellan gum is manufactured by fermentation of carbohydrates. The deacylation is carried out by treatment with alkali. Gellan gum is a free flowing white powder.

The formulation further comprises of pectin. Pectins are anionic polysaccharides present in the cell walls of most plants, which are used as gelling and thickening agents, and as stabilizers for application in the food, pharmaceutical, and cosmetics industries.Pectin has excellent enteric properties. A relatively low content of pectin from about 5 to about 10%, by weight in the composition, is appropriate to obtain capsule films with enteric properties. The capsule of the present invention can resist dissolution at least for an hourin invitro disintegration tests at pH 1.2, and is easily soluble at pH 6.8 (under USP dissolution conditions).

According to another embodiment, the formulation of the present invention may further include at least one plasticizer. The plasticizer may be used in any amount necessary to achieve the desired plasticizing effect. The plasticizer used will depend in part upon the end use application and is intended to include polyhydric alcohols such as glycerin, sorbitol, maltitol, triethyl citrate, propylene glycol, and polyethylene glycol, saccharides and polysaccharide.The plasticizers are preferably used in an amount of from 0.01 to about 5% w/w of the composition.

According to yet another embodiment, the other additives may optionally be included in the film formulation as is common in the industry as long as they do not adversely affect the film, including without limitation colours, flavours, preservatives, opacifying agents, embrittlement inhibiting agents, disintegrants and buffers.

The invention is illustrated in detail in the examples below.

Experimental Procedures
Dissolution Testand In vitro drug release studies
The two-stage dissolution method developed ( based on USP method)for the capsule formulation of the present invention consists of aone-hour acid stage dissolution in 0.1N HCl with threesampling time points, and a one-hour buffer stage dissolution in pH 6.8 phosphate buffer solution (PBS) with three sampling time points. The medium is changed by the analyst from the acid to the buffer after the first stage has been completed. Dissolution data was generated by sampling the dissolution medium at time points appropriate to characterize the dissolution profile.
OR

All formulations were based on HPMC (Pharmacoat 606; Shin Etsu, Japan), gellan gum and Pectin. Details of the formulations tested are given in Table 1.

Experiments
Example – 1
S-1) Preparationof 1kgAqueous composition of Low acyl gellan gum.
Take 50gm of low acyl gellan gum. Disperse it in 950gmhot water of 85?C under constant stirring. The reaction starts and aqueous solution of low acyl gellan gum get ready. Cool the solution to 50 ?C and hold it for some time to eliminate foam and bubbles.
S-2) Preparationof 1kgaqueous composition of High acyl gellan gum.
Take 15gm of high acyl gellan gum. Disperse it in 985gmhot water of 85?C under constant stirring. The reaction starts and aqueous solution of high acyl gellan gum get ready. Cool the solution to 50 ?C and hold it for some time to eliminate foam and bubbles.
S-3) Preparationof 1kgaqueous composition of Pectin
Take 75gm of Pectin. Disperse it in 925gmhot water of 85?C under constant stirring. The reaction starts and aqueous solution of high acyl gellan gum get ready. Cool the solution to 50 deg C and hold it for some time to eliminate foam and bubbles.
S-4) Preparationof 1kgaqueous composition of HPMC
Take 200 gm of HPMC of 2910 chemistry. Disperse it in 800 gm hot water of 80 ?C under constant stirring. Cool the solution to 10 ?C. Aqueous solution of HPMC will get ready. Hold it for some time to eliminate foam and bubbles.
Example – 2
Manufacturing capsules.
500 kg Solution of S-4 and 100 kg solution of S-1, S-2 and S-3 were prepared as per above method. 30 kg Solution was made for each of the following trial combination given in table 1 below. The solution was maintained at temperature below 35 ?C.

Table-1
- The solution was poured in dipping dish and maintained at 32?C.
- Pins were pre heated to 90 to 125 ?C and then dipped in dipping solution.
- The picked wet mass is then distributed around pin and subjected to high temperature in oven type tunnel. The air temperature is varied between 120 to 65 ?C till the shell water content reduces to below 50 %.
- The pins with wet film are then exposed to cold air blast of temperature between 25 to 40 ?C.
- The dried shells were then removed from pin, cut to specified length and joined to form capsules.
- The capsules were then evaluated for appearance, defects, taste, brittleness strength etc.
Table 1 Compositions of trial combination

Formulation HPMC (%w/w) Low Acyl Gellan gum (% w/w) High Acyl Gellan gum (% w/w) Pectin %
(USP-L)
1 15 - - 5
2 15 - - 10
3 15 - - 15
4 15 - 0.6 -
5 15 - 0.6 10
6 15 - 1 10
7 15 0.6 - -
8 15 0.6 - 5
9 15 0.6 - 7
10 15 0.6 - 10
11 15 0.3 0.3 10
12 15 0.6 0.3 5
13 15 0.6 0.3 7
14 15 0.6 0.3 10

Formulations 1-3 are a formulation of HPMC + Pectin. Formulations 4-6 are HPMC + High acyl gellan gum with varying percentage of Pectin. Formulations 7-10 are HPMC+ Low acyl gellan gum and with varying percentage of Pectin. Formulations 11-14 are HPMC+ Low acyl gellan gum + High acyl gellan gum+ Pectin.

Examples
Example 1: DR capsules Dissolution analyses
2. Analyses – Dissolution study drug release analyses
The capsules were filled with 650 mg Acetaminophen formulation. The capsules were first subjected to 0.1 N HCL (USP) solution. The capsules were then removed after 1hr and put in 6.8 mixed phosphate buffer (USP). The drug released was checked on UV method at specified time interval. The aim is to have acid resistance property at least for 1 hr. As per pharmacopeia guidelines 10 % drug release is allowed.

2.1 Analyses of formulation that contains only HPMC and pectin

It can be seen from dissolution results of trial 1,2 and 3 shows that pectin releases almost all drug within 60 mins in acidic pH.

2.2 Analyses of formulation that contains only HPMC and gellan gum

It can be seen from dissolution results of trial 4 and 7 that there is some acid resistance behaviour, however drug release is more then 10 % in acidic pH after 1 hr.

2.3 Analyses for formulation that contains only HPMC and either low or high acyl gellan gum along with Pectin.

It can be seen from trials 5,6,10,11 and 12 that only one type of gellan gum along with pectin in varying combinations is not getting desired acid resistance property.

2.4 Analyses of the formulation that contains combination of HPMC, gellan gum and pectin

As can be seen that the combination of low and high acyl gelan gum along with pectin gives desired acid resistance.

In vitro drug release capsule comparison- In vitro release of the drug from the capsule formulations of the present invention were compared with drug release from known capsule formulations of the prior art. The receptor solution of the diffusion cell was changed after 1hour from simulated gastric fluid at pH 1.2 to a simulated intestinal fluid at pH 6.8 to mimic gastrointestinal transit.The release profiles of the formulations of the present invention indicated a much slower release(% released) under acidic conditions compared with that from the known formulations of the prior art.