Description:FIELD OF THE INVENTION
The present invention relates gastro-resistant capsules with external enteric protective shell prepared using conventional dipping technology. The capsule of the invention comprises two shells viz an inner base shell of water-soluble film forming base material, followed by an outer protective shell of enteric polymer which are resistant to the acid environment; specifically, an outer protective shell is prepared using an alkali neutralized hydroxypropyl methyl cellulose phthalate.
The present invention further relates to the process of preparing gastro-resistant capsules with external enteric protective shell using conventional dipping technology wherein after the preparation of first base shell of water-soluble film forming base material over the pins, the bars are transferred to another adjoining machine without removing shells from pins and then re-dipped to form an outer protective shell of an enteric polymer and thereby produces the enteric property by delaying the release of the drug

BACKGROUND OF THE INVENTION
Due to the various reasons, oral delivery is the universally preferred and most convenient route of drug administration. It is known for its physiological, nonintrusive, smooth, cheap, quick, effortless and pain-free way of entry for solid and liquid materials to the body.
Amongst the various oral dosage forms available, capsules are a common oral dosage form for pharma, health & nutrition. Capsules are generally required to dissolve in the stomach at acidic pH, releasing their content, however for certain purposes capsules are designed to exhibit first-pass metabolism wherein the capsules are passed through the stomach and into the intestine before dissolving at alkaline pH. Such capsules are commonly described by a variety of terms, not limited to gastro-resistant capsules, entero-soluble capsules, delayed-release capsules and/or double dipped enteric coated capsules.
Encapsulation of drugs in capsules further provides the potential to improve the bioavailability. This is mainly due to much lower pressure used in compacting dosage as compared to manufacturing process involved in manufacturing tablets. Unlike the tablet dosage form, the complete disintegration hence is not necessary for the active ingredients encapsulated in the capsule shell to become available for absorption.
Capsules are commonly a soft or a hard shell filled with one or more pharmaceuticals, nutraceuticals actives therein. Hard capsule shells are manufactured using dip moulding processes known for decades. In one of the process, stainless-steel mould pins are dipped into a solution of polymer, optionally comprising gelling agents and co-gelling agents; followed by the steps of removing the coated mould-pins from dipping solution, drying to form a film on the surface, removing the shells from moulds, cutting the caps and bodies to the desired length and later assembling them. In another process, the gelling agents or co-gelling agents are not used and thus the shells are formed by dipping the pre-heated moulding pins into the polymer solution. The technology available and used so far is allowing only one polymer solution to form the capsules. Such solutions may be made up with a single polymer or with a blend of polymers, optionally with other processing aids as required. In case of use of polymer blends, it is necessary to have compatibility of all the ingredients used supporting or enhancing properties of each ingredient. In case of non-compatibility, it is necessary to have polymer over polymer concept. This requires not only process development but also machine to manufacture capsule in this fashion.
Enteric capsules are generally prescribed for the drugs which are inactivated or deteriorated by gastric juices, and which inhibit the process of digestion in the stomach. In such type of capsules, the shells exhibit enteric property through their acid resistant nature. Several people have attempted to develop such a dosage form and become successful also, but with some side effects such as machinability issues, scale of operations, fineness and finish of empty capsules etc. The present invention uses a unique combination of polymers which will allow to overcome the challenges faced by several empty capsule manufacturers.
The enteric coated capsules are pH-dependent which are soluble only upto less than 10% under gastric conditions at pH of 1.2 and readily soluble under intestinal conditions at a pH of 6.8.
Owing to high consumer acceptance, various methods and techniques are developed over the years to prepare enteric coated capsule shells. Though there are plenty of processes are known to prepare the enteric coating of the capsule shell, these processes are only limited to the lab scale, and they face many challenges while transplanting them to the plant scale. Challenges include instability under different relative humidity conditions, use of solvent-based system is also not recommended for dipping solution as they are critical to handle in lieu of safety, regulatory and health reasons.
Thus, there is a need to develop gastro-resistant enteric coated capsules which strengthen the mechanical properties of the capsules and at the same time also impart the required enteric property to the active present within the shell of the capsule.
United States Patent Publication No. 2,526,683 B discloses medicinal capsules with etherified cellulosic material prepared using dipping method. The said reference does not disclose the double dipping method.
United States Patent Publication No. 10,004,692 B discloses hydroxypropyl methyl cellulose hard capsule shell wherein aqueous composition for the manufacture of hard capsules comprises hydroxypropyl methyl cellulose in water at 20° C. This is a solvent based system used for the formation of an enteric coat. However, solvent based system is critical to handle.
United Kingdom Publication No. GB 2 361 643 A discloses an enteric coated one-piece soft capsule having an inner layer and an outer layer with different solubility properties. The said reference particularly discloses the capsules wherein part of the inner layer constitutes the part of the outer surface, so that, when in the appropriate solvent, both the inner layer and the outer layer of the enclosing wall of the capsule get exposed to the solvent and they both behave differently under the same conditions. Such kind of capsule shell is not possible with mould dipping process.
United States Patent Publication No. 4,816,259 B discloses gelatine capsule formulation and sub-coating for imparting an enteric property. The said reference discloses the capsule shell formulation with gelatine (65-70%), glycerine (22-25%) and water (8-10%); followed by the sub coating with suspension of hydroxypropyl methylcellulose. This reference is failed to disclose the two piece hard capsule and its preparation process to have an enteric characteristic.
United States Patent Publication No. 8,852,631 B discloses acid resistant hard pharmaceutical capsule shells consisting of an aqueous composition of gelling agent and hydroxypropyl methyl cellulose.
United Kingdom Patent Publication No. 1 455 884 A discloses orally administering capsule with two layers wherein first inner layer is prepared from gelatine, calcium alginate, methyl cellulose and hydroxy cellulose-alkyl cellulose ethers while the outer layer is prepared from salol, benzoin, n-butyl stearate, carnauba wax, shellac, methacrylic acid polymers, carboxy-vinyl polymers, maleic anhydride-vinyl alkyl ether or alkene copolymers and cellulose derivatives.
United States Publication No. US 2013/0295188 A1 discloses capsule shell composition with hydroxypropyl methyl cellulose acetate succinate (HPMCAS) polymer, partially neutralized with an alkaline material. The said reference is failed to disclose the two layered capsule shells for achieving the enteric property.
United States Application Publication No. US 2019/0000768 discloses seamless enteric capsule consisting of a capsule fill, a shell layer; and an enteric coating. The enteric coating layer comprises polymers selected from methacrylic acid-based polymer, polyvinyl acetate phthalate, organic acid ester of hydroxypropyl methylcellulose, carboxy methyl ethyl cellulose, and cellulose acetate phthalate.
Japanese Patent Publication No. 58138458 discloses process for preparing enteric capsules from an aqueous solution of hydroxypropyl methyl cellulose acetate succinate. This reference describes two-step process involving the dipping of mould pins into an aqueous solution of hydroxypropyl methyl cellulose acetate succinate alkali metal salt and gelatine and thereafter dipping in aqueous solution. However, since the gelatine content was too low in this composition, the setting ability was too low.
United States Publication No. US 2023/0414524 A1 discloses two piece hard capsule shell for delayed release using double dipping technique. This reference claims the two layers of wall forming polymers wherein one inner layer is made up with a water-soluble film forming polymer of HPMC and one outer layer is made up with delayed-release polymer of HPMCAS. This prior art also uses the ammonium hydroxide with the delayed-release enteric polymer, and it acts as a neutralizing agent. However, use of ammonia to solubilize the enteric polymer attracts some of the major drawbacks wherein the capsules are found bitter and turning white over stability. Therefore, this art further suggests a post-treatment for optimal delayed-release performance and for avoiding any ammonia smell wherein the capsules were kept at 60° C. overnight, followed by a second equilibration at 50% RH at 22° C. for 1 day before the evaluation.
International Publication No. WO 2024/019133 A1 discloses multilayered enteric rigid capsule with first layer without any enteric properties, and a second layer with an enteric property. In this said reference, the second layer dipping solution is prepared by dissolving or dispersing an enteric polymer to a mixed solvent of water at room temperature and a hydrophilic organic solvent. Thus, this reference specifically discloses the solvent-based system for the preparation of an enteric coat.
Thus, as seen from above, the currently available enteric coated capsule is either prepared by encapsulation process or uses solvent-based system or uses synthetic materials for imparting the enteric properties and thereby increase the efforts while applying an enteric coat. The already existing state of arts are also not suitable on plant scale or large volume supplies.
In light of these drawbacks of already available processes, not limiting to the above stated prior arts, there exists a need to develop new gastro-resistant enteric capsule meeting all the criteria of USP standards, not restricting the process only at lab level and providing the adequate enteric effect to the patient.
The present invention provides gastro-resistant capsules with external enteric protective shell prepared using conventional dipping technology having inner base shell of hydroxypropyl methyl cellulose and outer protective shell of hydroxypropyl methyl cellulose phthalate wherein the capsules of the present invention are USP compliant with their dissolution parameters, dimensions etc. The invented method of the present invention is very much adaptable in hot pin process of capsule manufacturing and is also suitable at plant level.
SUMMARY OF THE INVENTION
The invention discloses the enteric capsules prepared from native starch and a modified starch in combination with pectin and polyvinyl alcohol. The enteric capsule prepared in this manner are designed to protect the formulation ingredients from being damaged or degraded by stomach acid and thereby prolonging the release of the drug.
The invention further discloses the preparation of acid-resistant or gastric-resistant capsules used to prevent the drug from inactivation which are degraded by gastric enzyme and are prepared by single-dip technology.

BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 - The capsule shells on hot pin process with varying concentration of hydroxypropyl methyl cellulose as base shell and hydroxypropyl methyl cellulose phthalate as protective shell.

DETAILED DESCRIPTION OF THE INVENTION
Capsules are solid oral dosage form which are constructed to facilitate the discharge of the contents filled therein, when the capsules are placed in the medium in which they are to be used. More particularly, the capsules are busted when they are placed in a an aqueous medium to release the contents.
The term “protective shell” as used throughout the specification refers to a polymer barrier applied to oral medication that prevents its dissolution or disintegration in the gastric environment. Such protective shell helps by either protecting drugs from the acidity of the stomach, the stomach from the detrimental effects of the drug, or to release the drug after the stomach, preferably into small intestine.
The term “base shell” as used through the specification refers to a polymer shell which is providing a foundation to provide strength to a capsule and support to the protective shell.
In one aspect, the invention provides the gastro-resistant capsule prepared from conventional dipping technology.
In another aspect, the invention provides the gastro-resistant capsule prepared from solvent-free mucilage of polymers used.
In another aspect, the invention provides the gastro-resistant capsules with uniform outer protective shell of acid resistant material and inner base shell of water-soluble film forming material.
In one embodiment, the conventional dipping technology disclosed in the present invention is applicable for two-piece capsule having the cap and the body.
In another embodiment, the gastro-resistant capsules with external protective shell of the present invention are capsule shells prepared using conventional dipping technology.
In another embodiment, the gastro-resistant capsules of the present invention are acid-resistant capsules or gastro-resistant capsules which prevent the drug from inactivation which are degraded by gastric enzyme.
In one aspect, the gastro-resistant capsule shells prepared in the present invention are designed to protect the formulation ingredient from being damaged or degraded by stomach acid and thereby allowing them to be released and absorbed in the small intestine instead of stomach.
In one aspect, the gastro-resistant capsules shell of the present invention comprises inner base shell of hydroxypropyl methyl cellulose (hereinafter may be referred as “HPMC” throughout the specification) and outer protective shell of hydroxypropyl methyl cellulose phthalate (hereinafter may be referred as “HPMC-P” throughout the specification).
In one embodiment, the inner base shell of hydroxypropyl methyl cellulose of gastro-resistant capsule provides strength to the capsule shell to support filling machine performance.
In another embodiment, the type of hydroxypropyl methyl cellulose used for the present invention is selected from the group consisting of 2910 or 2906 or combination thereof.
In another embodiment, the concentration of hydroxypropyl methyl cellulose used for the present invention is in the range of about 15% to about 25% in mucilage.
In another aspect, the outer protective shell of hydroxypropyl methyl cellulose phthalate of a gastro-resistant capsule protects the drug contained in the capsule shell from acidic pH and enzymatic degradation in the stomach.
In another embodiment, the concentration of hydroxypropyl methyl cellulose phthalate used for the present invention is in the range of about 15% to about 25% in mucilage.
In one aspect, the present invention provides solvent-free mucilage for the preparation of outer protective shell and inner base shell of the gastro-resistant capsules.
In another embodiment, dipping mucilage used for the outer and inner shells of a gastro-resistant capsule are organic solvent free wherein an organic solvent can be acetone, ethyl acetate, hexane, heptane, dichloromethane, methanol, ethanol, tetrahydrofuran, acetonitrile, dimethylformamide, toluene and/or dimethyl sulfoxide.
In one embodiment, the gastro-resistant capsule shell manufacturing starts with the preparation of mucilage. In the next step of dipping, plurality of moulding pins made of special grade of stainless steel are dipped into the mucilage for a certain amount of time and certain depth, separately for capsule cap and body part. This process of dipping lasts just a short period of time before the pins get removed from the mucilage at a predefined velocity and are further transferred to the oven for drying. The pins along with dried shells are then transferred on another capsule making machine with specially designed mechanism where another mucilage is maintained at certain temperature. The further process of dipping and drying is then continued as conventionally done. On this machine the shells with two polymers shells are then stripped, cut to the required size and thereafter, capsule body and capsule cap are joined to form capsule.
In one aspect of the invention, the present invention provides preparation outer protective shell mucilage with hydroxypropyl methyl cellulose phthalate wherein hydroxypropyl methyl cellulose phthalate is neutralized with an alkali.
In another aspect, the alkali used for the neutralizing the hydroxypropyl methyl cellulose phthalate is selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, liquid ammonia, and their mixtures thereof. More preferably, the alkali used for the neutralizing the hydroxypropyl methyl cellulose phthalate is sodium hydroxide or potassium hydroxide or combination thereof.
In another embodiment, the present invention provides neutralized hydroxypropyl methyl cellulose phthalate mucilage wherein the solid content ranges from about 15% to about 25% with viscosity of 1000-3000 cps at about 20 ºC to about 40ºC;
In one aspect of invention, the present invention optionally provides addition of gelling system/agent in neutralized hydroxypropyl methyl cellulose phthalate mucilage to have uniformity of polymer on already dipped and dried base shell.
In one aspect of invention, the gelling system/agent used is Agar and is used in the range of 0 to 12% of hydroxypropyl methyl cellulose phthalate on dry basis.
In one embodiment, the present invention provides an enteric gastro-resistant capsule prepared using conventional dipping technology comprising an inner base shell of hydroxypropyl methyl cellulose and an outer protective shell of hydroxypropyl methyl cellulose phthalate wherein the ratio of hydroxypropyl methyl cellulose to hydroxypropyl methyl cellulose phthalate ranges from about 90:10 to about 50:50 in the dried shell.
In one aspect of the invention, the present invention provides preparation inner base shell mucilage of hydroxypropyl methyl cellulose.
In another embodiment, the present invention provides hydroxypropyl methyl cellulose mucilage with 1200-2500 cps viscosity.
In one aspect of the invention, the dipping is done with conventional method on two separate machines.
In another aspect of the invention, the dipped and dried pin bars with base film forming polymer are transferred to another machine without removing shells from pins for subsequent dipping process with mucilage exhibiting enteric behaviour.
In one aspect of the invention, special pin bar transfer mechanism is developed in house to avoid any human intervention, handling contaminations.
In one aspect of the invention, the dipping process starts with the preparation of mucilage used for an inner base shell and for an outer protective shell, separately for capsule cap and capsule body part.
In another aspect of the invention, gastro-resistant capsules with external protective shell prepared using conventional dipping technology comprises capsule shell with -
A. An inner base shell of hydroxypropyl methyl cellulose; and
B. An outer protective shell of hydroxypropyl methyl cellulose phthalate.
In one embodiment, the present invention provides gastro-resistant capsules with external protective shell prepared using conventional dipping technology comprising –
A. Preparation of an inner base shell of a gastro-resistant capsule with hydroxypropyl methyl cellulose; followed by
B. Preparation of an outer protective shell of a gastro-resistant capsule with hydroxypropyl methyl cellulose phthalate.
In another embodiment, an inner base shell of a gastro-resistant capsule with hydroxypropyl methyl cellulose is prepared by the process comprising –
a) Preparation of hydroxypropyl methyl cellulose mucilage having 1200-2500 cps viscosity;
b) Keeping the mucilage of step (a) in dip bath at a temperature ranging from about 20ºC to about 27ºC;
c) Heating of pin bars by an induction heating technique for 10-20 seconds and at induction frequency of 30 to 50 Hz to achieve the pin temperature of about 100ºC;
d) Dipping the pin bars of step (c) in dip bath of step (b) for 2-3 seconds and thereafter pulling them out at predefined velocity;
e) Drying of the hydroxypropyl methyl cellulose coated pin bars under oven at a temperature ranging from about 70ºC to about 110ºC for about 45 minutes
In one aspect, the moisture of the inner base shell of gastro-resistant capsule is maintained between 7 to 15%.
In another embodiment, an outer protective shell of a gastro-resistant capsule with hydroxypropyl methyl cellulose phthalate is prepared by the process comprising –
f) Neutralizing the of hydroxypropyl methyl cellulose phthalate mucilage with an alkali wherein the solid content ranges from about 15% to about 25% with viscosity of 1000-3000 cps at about 20 ºC to about 40ºC;
g) Optionally, adding the desired quantity of Agar in the mucilage of step (f);
h) Transferring the dipped and dried pin bars with hydroxypropyl methyl cellulose coat of step (e) to another adjoining machine with suitable mechanism developed;
i) Re-dipping of pin bars with hydroxypropyl methyl cellulose of step (h) into a neutralized mucilage of step (g) at a temperature ranging from about 20ºC to 40ºC for 1-2 seconds and thereafter pulling them out at a predefined velocity;
j) Drying of the protective coated pin bars in oven at a temperature ranging from about 70ºC to about 110ºC for 35 to 50 minutes.
k) Stripping and cutting the cap and body shells separately and rejoining them on auto head to form capsule.
In one embodiment, the present invention provides gastro-resistant capsules with external protective shell prepared using conventional dipping technology comprising –
A. Preparation of an inner base shell of hydroxypropyl methyl cellulose wherein the process comprises –
a) Preparation of hydroxypropyl methyl cellulose mucilage having 1200-2500 cps viscosity;
b) Keeping the mucilage of step (a) in dip bath at a temperature ranging from about 20ºC to about 27ºC;
c) Heating of pin bars by an induction heating technique for 10-20 seconds and at induction frequency of 30 to 50 Hz to achieve the pin temperature of about 100ºC;
d) Dipping the pin bars of step (c) in dip bath of step (b) for 2-3 seconds and thereafter pulling them out at predefined velocity;
e) Drying of the hydroxypropyl methyl cellulose coated pin bars under oven at a temperature ranging from about 70ºC to about 110ºC for about 45 minutes.
B. Preparation of an outer protective shell of hydroxypropyl methyl cellulose phthalate wherein the process comprises –
f) Neutralizing the of hydroxypropyl methyl cellulose phthalate mucilage with an alkali wherein the solid content ranges from about 15% to about 25% with viscosity of 1000-3000 cps at about 20 ºC to about 40ºC;
g) Optionally, adding the desired quantity of Agar in the mucilage of step (f);
h) Transferring the dipped and dried pin bars with hydroxypropyl methyl cellulose coat of step (e) to another adjoining machine with suitable mechanism developed;
i) Re-dipping of pin bars with hydroxypropyl methyl cellulose of step (h) into a neutralized mucilage of step (g) at a temperature ranging from about 20ºC to 40ºC for 1-2 seconds and thereafter pulling them out at a predefined velocity;
j) Drying of the protective coated pin bars in oven at a temperature ranging from about 70ºC to about 110ºC for 35 to 50 minutes.
k) Stripping and cutting the cap and body shells separately and rejoining them on auto head to form capsule.
In another aspect, the present invention provides the induction heating technique for heating the pin bars.
Table 1: Parameters of pin bars and dipping
Hot dipping method is adopted for both dipping
Step Induction process Oven parameters ( tole +/- 20 %)
First Dip
(Hot process) Induction time – 15-25 sec
Induction frequency – 30-50 Hz HPMC Body & Cap
110 (5 min) / 80 (5 min) / 60 (30 min)
Second Dip
(Hot process) Induction time – 15-25 sec
Induction frequency – 30-50 Hz HPMC + HPMC-P Body & Cap
110 (5 min)/ 80 (5 min)/ 60 (35 min)

In one embodiment, the present invention also provides special mechanism to transfer dipped and dried pin bars from one machine to adjoining machine.
In one embodiment, the present invention also provides the varying concentration of hydroxypropyl methyl cellulose and hydroxypropyl methyl cellulose phthalate during the preparation of gastric resistant capsule shell with respect to size of capsule.
In another embodiment the, in polymer ratio, the concentration of hydroxypropyl methyl cellulose varies from 90% to 50% in tandem with the concentration of hydroxypropyl methyl cellulose phthalate increases from 10% to 50%. Fig. 1 represents the capsule shells on hot pin process with varying concentration of inner base shell of hydroxypropyl methyl cellulose and outer protective shell of hydroxypropyl methyl cellulose phthalate.
Illustrative Examples
Example 1: Finalisation of suitable ingredients
Trials were planned on suitability of different grades of HPMC, HPMC phthalate, role of neutralising alkali on shell properties, impact of gel system on second dipping process and shell. The trial combinations for size 0 capsules are as given below in table 2.

Inner base shell as well as outer protective shell of a gastric-resistant capsule of the present invention were produced as below using the combination as described in Table 2 -
Preparation of an inner base shell with first dipping
1. Hydroxypropyl methyl cellulose mucilage with 1800-2000 cps viscosity was prepared and kept in a dip bath at a temperature of 25-27ºC.
2. Pin bars were heated by induction process at induction frequency of about 35 Hz for 10-20 seconds.
3. Heated pin bars were then dipped in a dip bath containing hydroxypropyl methyl cellulose mucilage for 2-3 seconds and were pulled out thereafter at a predefined velocity.
4. Pin bars with hydroxypropyl methyl cellulose coat were then dried under oven at a temperature of 90-100ºC for 30 minutes.
5. The above process of preparing inner protective shell of hydroxypropyl methyl cellulose was repeated separately for capsule body and capsule cap.
Preparation an outer protective shell with second dipping:
6. Hydroxypropyl methyl cellulose phthalate mucilage was neutralized with an alkali wherein the solid content was present in the range of about 15% to about 20% with viscosity of 1000-1800 cps at 27-32ºC;
7. Desired quantity of Agar was added in the mucilage of step (6).
8. Dipped and dried pin bars with hydroxypropyl methyl cellulose coat of step (4) were transferred to another adjoining machine with suitable mechanism developed,
9. Pin bars with hydroxypropyl methyl cellulose of step (4) were re-dipped into a neutralized mucilage of step (7) at a temperature ranging from about 20ºC to 35ºC for 1-2 seconds and thereafter pulled them out at a predefined velocity;
10. Pin bars with wet protective coat were then dried in oven at a temperature ranging from about 90ºC to about 110ºC for 20 to 30 minutes.
11. The cap and body shells were stripped and cut separately and rejoined them on auto head to form capsule.
The capsules so prepared according to the present invention were then evaluated for following characteristics -
o Mucilage viscosity in cps on Brookfield viscometer.
o Capsule weight in mg.
o Strength of shells by feel.
o Brittleness by manually pressing 100 capsules by suitable metal rod.
o Taste of shells.
o Fit of capsule by feel.
o Appearance of capsules after exposure to 40C and 75% RH for 3 months.
After the evaluating the capsules of the invention as per the above-mentioned characteristics, the observations are as summarised in table 3 below.

As inferred from above, the capsules with complying parameters can be produced using any HPMC grade wherein agar can be also used without any issue.
Sodium hydroxide and potassium hydroxide are found to be suitable for neutralising hydroxypropyl methyl cellulose phthalate as against ammonia.
Example 2: Evaluation for drug release performance.
Few good combinations were selected and again capsules were formed as per table 4 below. The process followed for manufacturing capsules was exactly same as was done in example 1 above.

The capsules so produced were evaluated for dissolution test as prescribed in USP, IP monographs.
The two-stage dissolution method comprises two-hour acid stage dissolution in 0.1N hydrochloric acid with four sampling points; followed by one-hour buffer stage dissolution in pH 6.8 phosphate buffer with four sampling points. Table 5 discloses the dissolution data of capsule prepared with hydroxypropyl methyl cellulose and hydroxypropyl methyl cellulose phthalate in different ratios in gastro-resistant capsules with external protective shell prepared using conventional dipping technology of the present invention.

As inferred from above, the suggests that good shells exhibiting gastro resistant property can be produced with a gastro-resistant capsule having inner base shell of hydroxypropyl methyl cellulose and outer protective shell of hydroxypropyl methyl cellulose phthalate wherein the gastro resistant capsule is prepared using conventional dipping technology.
, Claims:1) The gastro-resistant capsule prepared using conventional dipping technology comprises capsule shell with an inner base shell of hydroxypropyl methyl cellulose; and an outer protective shell of hydroxypropyl methyl cellulose phthalate.

2) The gastro-resistant capsule as claimed in claim 1, is prepared from solvent-free mucilage of polymers used.

3) The gastro-resistant capsule of claim 1, wherein inner base shell of hydroxypropyl methyl cellulose provides strength to the capsule shell to support filling machine performance.

4) The gastro-resistant capsule of claim 3, wherein type of hydroxypropyl methyl cellulose is selected from the group consisting of 2910 or 2906 or combination thereof.

5) The gastro-resistant capsule of claim 3, wherein the concentration of hydroxypropyl methyl cellulose is in the range of about 15% to about 25% in mucilage.

6) The gastro-resistant capsule of claim 1, wherein outer protective shell of hydroxypropyl methyl cellulose phthalate prevents the drug from inactivation which are degraded by gastric enzyme.

7) The gastro-resistant capsule of claim 6, wherein the concentration of hydroxypropyl methyl cellulose phthalate is in the range of about 15% to about 25% in mucilage.

8) The outer protective shell of hydroxypropyl methyl cellulose phthalate of a gastro-resistant capsule as claimed in claim 1, is neutralized with an alkali while preparing mucilage.

9) The alkali as claimed in claim 8, is selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide and their mixtures thereof.

10) The alkali used for the neutralization, as claimed in claims 8 is sodium hydroxide or potassium hydroxide or mixture thereof.

11) The gastro-resistant capsule of claim 1, wherein the outer protective shell of hydroxypropyl methyl cellulose phthalate optionally comprises agar for uniformity of outer layer.

12) The agar as claimed in claim 11 is in the range of 0 to 12% of hydroxypropyl methyl cellulose phthalate on dry basis.

13) The gastro-resistant capsule prepared using conventional dipping technology comprises an inner base shell of hydroxypropyl methyl cellulose and an outer protective shell of hydroxypropyl methyl cellulose phthalate wherein the ratio of hydroxypropyl methyl cellulose to hydroxypropyl methyl cellulose phthalate ranges from about 90:10 to about 50:50 in the dried shell.

14) The gastro-resistant capsule with external protective shell prepared using conventional dipping technology comprises –
A. Preparation of an inner base shell of a gastro-resistant capsule with hydroxypropyl methyl cellulose; followed by
B. Preparation of an outer protective shell of a gastro-resistant capsule with hydroxypropyl methyl cellulose phthalate.

15) The preparation of an inner base shell of a gastro-resistant capsule with hydroxypropyl methyl cellulose as claimed in claim 14 comprises –
a) Preparation of hydroxypropyl methyl cellulose mucilage having 1200-2500 cps viscosity;
b) Keeping the mucilage of step (a) in dip bath at a temperature ranging from about 20ºC to about 27ºC;
c) Heating of pin bars by an induction heating technique for 10-20 seconds and at induction frequency of 30 to 50 Hz to achieve the pin temperature of about 100ºC;
d) Dipping the pin bars of step (c) in dip bath of step (b) for 2-3 seconds and thereafter pulling them out at predefined velocity;
e) Drying of the hydroxypropyl methyl cellulose coated pin bars under oven at a temperature ranging from about 70ºC to about 110ºC for about 45 minutes.

16) The preparation of an outer protective shell of a gastro-resistant capsule with hydroxypropyl methyl cellulose phthalate as claimed in claim 14 comprises -
f) Neutralizing the of hydroxypropyl methyl cellulose phthalate mucilage with an alkali wherein the solid content ranges from about 15% to about 25% with viscosity of 1000-3000 cps at about 20 ºC to about 40ºC;
g) Optionally, adding the desired quantity of Agar in the mucilage of step (f)
h) Transferring the dipped and dried pin bars with hydroxypropyl methyl cellulose coat of step (e) to another adjoining machine with suitable mechanism developed,
i) Re-dipping of pin bars with hydroxypropyl methyl cellulose of step (h) into a neutralized mucilage of step (g) at a temperature ranging from about 20ºC to 40ºC for 1-2 seconds and thereafter pulling them out at a predefined velocity;
j) Drying of the protective coated pin bars in oven at a temperature ranging from about 70ºC to about 110ºC for 35 to 50 minutes.
k) Stripping and cutting the cap and body shells separately and rejoining them on auto head to form capsule.

17) The alkali used for the neutralization, as claimed in claim 16, is selected from the group consisting of sodium hydroxide or potassium hydroxide or mixture thereof.

18) The gastro-resistant capsule with external protective shell prepared using conventional dipping technology comprising –
A. Preparation of an inner base shell of hydroxypropyl methyl cellulose wherein the process comprises –
a) Preparation of hydroxypropyl methyl cellulose mucilage having 1200-2500 cps viscosity;
b) Keeping the mucilage of step (a) in dip bath at a temperature ranging from about 20ºC to about 27ºC;
c) Heating of pin bars by an induction heating technique for 10-20 seconds and at induction frequency of 30 to 50 Hz to achieve the pin temperature of about 100ºC;
d) Dipping the pin bars of step (c) in dip bath of step (b) for 2-3 seconds and thereafter pulling them out at predefined velocity;
e) Drying of the hydroxypropyl methyl cellulose coated pin bars under oven at a temperature ranging from about 70ºC to about 110ºC for about 45 minutes.
B. Preparation of an outer protective shell of hydroxypropyl methyl cellulose phthalate wherein the process comprises -
f) Neutralizing the of hydroxypropyl methyl cellulose phthalate mucilage with an alkali wherein the solid content ranges from about 15% to about 25% with viscosity of 1000-3000 cps at about 20 ºC to about 40ºC;
g) Optionally, adding the desired quantity of Agar in the mucilage of step (f);
h) Transferring the dipped and dried pin bars with hydroxypropyl methyl cellulose coat of step (e) to another adjoining machine with suitable mechanism developed;
i) Re-dipping of pin bars with hydroxypropyl methyl cellulose of step (h) into a neutralized mucilage of step (g) at a temperature ranging from about 20ºC to 40ºC for 1-2 seconds and thereafter pulling them out at a predefined velocity;
j) Drying of the protective coated pin bars in oven at a temperature ranging from about 70ºC to about 110ºC for 35 to 50 minutes.
k) Stripping and cutting the cap and body shells separately and rejoining them on auto head to form capsule.

19) The gastro-resistant capsule comprising inner base shell of water-soluble film forming base material of hydroxypropyl methyl cellulose and outer protective shell of enteric polymer of hydroxypropyl methyl cellulose phthalate is prepared for delaying the drug release and to resist the acid in stomach.

20) The gastro-resistant capsule comprising inner base shell of hydroxypropyl methyl cellulose and outer protective shell of hydroxypropyl methyl cellulose phthalate is prepared to provide barrier to the drug release in acidic pH.