FORM 2
THE PATENT ACT, 1970
(39 OF 1970)
&
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(SEE SECTION 10; RULE 13)
"AN IMPROVED CAPSULE HAVING ENTERIC PROPERTIES"
SCITECH CENTRE AN INDIAN COMPANY REGISTERED UNDER THE PROVISION OF COMPANIES ACT, 1956. HAVING ADDRESS AT 7, PRABHAT NAGAR JOGESHWARI (WEST) MUMBAI-400 102
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

FIELD OF THE INVENTION:-
The present invention relates to an improved capsule having enteric properties, more particularly to manufacture capsules which does not dissolve in acidic pH and will dissolve only in pH above 5.0
BACK GROUND OF THE INVENTION:-
This invention relates to pharmaceutical capsules having enteric properties. Normally the pH of gastric fluid present in stomach has highly acidic pH (below 1.2) due to acid secretion. The normal capsule swallowed is first exposed to this and gets ruptured in stomach itself. Many pharmaceutical products, neutraceutical products and food supplements are very sensitive to this acidic pH and may gets destroyed / denatured if exposed to this. The medicinal substances which get greater therapeutic value if gets absorbed in upper portion of small intestine needs to be delivered safely through stomach till it reached small intestine.
Some medicines develop severe gastric disturbances and may also give unpleasant regurgitation of the drug.
Another use is to prevent the break down or dilution of drugs which are used for their effect in the intestinal tract, such as intestinal antiseptics or anthelmintics.
Many such applications demand a need of a container which will protect the product from acidic environment being reacted with acid secretion in stomach. Many polymers are available which possesses this property such as acrylic resins, methacrylate co polymers, (e.g. Eudragit), cellulose esters (e.g. ethyl cellulose, HPMC phthalate, cellulose acetate phthalate, HPMC acetate succinate) natural materials like shellac, grape seed extract etc.
Many attempts are made to overcome the acidic pH challenge. Tablets are pressed or capsules are filled with desired formulation and then coated with the above mentioned polymer or granules and pellets are coated and filled in the capsules. However, this is an additional process for manufacturing the product. Some also pre-

coated the gelatin or HPMC capsules and supplied to pharma companies to eliminate the additional process. However, the external coating is very thin and any small scratch or physical damage on outer surface leading to failure of enteric property. Also the other problems are poor solubility in intestinal juice, high organic solvent content, and inadequate stability and diffusion problems.
European patent EP 0056825 attempted to make capsules using HPMC phthalate. However, it required very ultrafine particle size and a viscosity thickener such as Methocel J20 MS. The problem with this method is poor thickness control and poor machinability due to lower strength. This patent used the aquas dispersion to get the enteric property film.
Japanese patent JP 2006016372 Also attempted to make the capsules by following similar process followed for making Gelatin capsules. However both the patents used Ammonium hydroxide to make solution of HPMC phthalate. The ammonia group remains present in the solution and also in the shells. This makes the capsule shells unstable, lose its shape and getting discolored. Also the capsules such produced leads to very bitter and unpleasant taste. Also the capsules are very brittle in nature.
OBJECT OF THE PRESENT INVENTION:-
It is object of the present invention is to make enteric capsules by dip molding process used for gelatin capsule manufacturing.
It is yet another object of the present invention is to make capsules having enteric property and which does not lose its shape and colour over period of time.
It is yet another object of present invention is to make capsules having enteric property and which does not have unpleasant taste.
It is yet another object of the present invention is to make capsules having enteric capsules and which are non brittle.

SUMMARY OF THE INVENTION:-
According to the first aspect, the present invention provides process for manufacturing capsules which possess enteric property. The capsules do not dissolve in stomach pH however dissolves at pH observed in upper portion of small intestine.
According to another aspect, the present invention provides process for manufacturing capsules which possess enteric property and used the manufacturing equipment same as is used to manufacture gelatin capsules.
According to yet another aspect, the present invention provides process for manufacturing capsules which possess enteric property by using complete solution of enteric polymer in water.
According to yet another aspect, the present invention provides process for manufacturing capsules which possess enteric property and which does not have bitter or unpleasant taste.
According to yet another aspect, the present invention provides process for manufacturing capsules which possess enteric property and which are not brittle.
According to yet another aspect, the present invention provides process for manufacturing capsules which possess enteric property and which does not lose shape and gets discoloured over long period.
The process according to the present invention furthermore provides an improved capsule product comprising several parts, which are combined with each other. The capsules produced by the present invention are very clear, smooth, non brittle, not having bad taste and stable having enteric property. More specifically , a process for manufacturing enteric capsules comprises the following steps.
a. Making complete solution of enteric polymer
b. Adding suitable plasticizer
c. Adding suitable gelling agent

d. Adding required colourants, opacifiers, surface active agents and another
processing aids.
e. Dipping the metal pins at low temperature
f. Drying the shells at drying chambers.
g. Stripping, cutting and joining the shells.
Moreover, shells comprising an improved capsules having enteric capsules obtainable by such process is described.
DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION;-
It has been unexpectedly found that the neutralizing agent used determines the flexibility of the capsule shell. Also the same is the reason for stability and discoloration of the capsule shell especially HPMC phthalate is used as base enteric polymer.
According to present invention, the preferred pH dependant enteric polymer is HPMC phthalate. Either HP-50 or HP-55 or HP-55S manufactured by Shinetsu or Samsung or any other manufacturer.
The composition of capsule shell comprises of HPMC phthalate of grades selected from available grades such as HP-50, HP-55, HP55S. Any other grade of chemical structure of HPMC phthalate with different solublising pH also can be used. The neutralizing agent added in water is necessarily NaOH.
The quantity of neutralizing agent used is based on the quantity of HPMC phthalate used . It is varying from 1% to 20% of the HPMC phthalate.
As mentioned earlier, the flexibility, taste, colour and stability is unexpectedly found to be improved when specific neutralisng agent is used in specific ratio with respect to HPMC phthalate. The preffered ratio is maintained based on the final solution pH. The final solution pH should range between 5.0 and 8.0
The preferred solution pH should be between 5.5 and 6.9.

The composition of present invention may further comprise gelling agents, gelling promoters, and coloring agents and so on.
The gelling agent is selected from different naturally occurring gums like different grades of AGAR,
According to present invention the gelling agent is present in the range of 0.2 to 8.0 % w/w on dry HPMC phthalate. These gelling agents are completely solubilized in water prior to addition in the enteric polymer solution.
The coloring agents and opacifiers are selected from permitted colorant and dyes as listed in Rule 27 of Drugs and Cosmetics Act and Rule (India) and permissible under the regulatory requirements of the country of use. They comply with the Bureau of Indian Standards ( BIS) and / or Code of Federal Regulations (CFR) and / or EEC directives.
In an embodiment, the coloring agent may be a color selected from the group comprising annatto, carotene, chlorophyll, cochineal, curcumin, caramel, riboflavin, red iron oxide, yellow iron oxide, titanium di-oxide, black iron oxide and mixtures thereof.
In yet another embodiment, the coloring agent may be selected from quinazarine green, alizarin cyanine green, fast green, tartrazine, sunset yellow, quinoline yellow, erythrosine, eosin YS, toney red, ponceau 4R, carmoisine, indigo carmine, brilliant blue, orange G, resorcin brown, naphthol blue black, allura red, and combinations thereof.
In another embodiment, the coloring agent may be lake salts (example aluminum) any of the above listed water soluble coloring agents and combinations thereof.
The coloring agent is preferably used in an amount of from 0.01 to about 20% w/w of dry HPMC phthalate.

The capsule shell material may furthermore contain from about 0 to about 30% pharmaceutically acceptable plasticizers based upon the weight of the hydrophilic polymer. The plasticizer which may be employed can be selected from polyethylene glycol, propylene glycol, glycerol, sorbitol, dioctyl-sodium sulfosuccinate, triethyl citrate, tributyl citrate, Di ethyl phthalate, di butyl phalate, 1,2- propyleneglycol, mono-, di, or tri-acetates of glycerol or mixtures thereof. Additionally polyvinyl pyrrolidone, polyvinyl alcohol, co polyvidone (plasdone S-630) can also be used to give better flexibility to the film.
Additionally, the capsule shell material may contain pharmaceutically acceptable lubricants in the range of from about 0 to about 10% based upon the weight of the hydrophilic polymer. The lubricant may be selected from aluminium stearate, calcium stearate, magnesium stearate, stearic acid, tinstearate, talc, sodium lauryl sulfate, lecithins, mineral oils, stearic acid or silicones or mixtures thereof.
Furthermore, the capsule shell material may contain pharmaceutically acceptable
extenders in the range of from about 0 to about 50% based upon the weight of the
hydrophilic polymer. The extender may be selected from sunflower proteins,
soybean proteins, cotton seed proteins, peanut proteins, rape seed proteins, lactose,
gum arabic, acrylates or methacrylates, cellulose acetyl phthalates, hydroxypropyl
methylcellulose, .hydroxypropyl methycelluose, hydroxypropyl
methylcellulosephthalate, hydroxymethylcellulose, polyvinylpyrrolidone, shellac, bentonite, polyvinyl acetatephtalate, phthalated gelatin, succinated gelatin, agar agar, hydroxyalkylstarches or mixtures thereof.
The formulation filled in the shell produced according to the present invention may, comprise a pharmaceutical, bio technologically or agrochemically active composition. Furthermore comprised in the solid dosage form can, for example, be foodstuff or a dyestuff composition. In case the solid dosage form of the present invention contains a pharmaceutical composition, the active substance of same can be the one which gets destroyed / denatured in acidic pH in stomach and / or the medicinal substances which gets greater therapeutic value if gets absorbed in upper

portion of small intestine and needs to be delivered safely through stomach till it reached small intestine.
The formulation filled in capsule can be in the form of powder, tablet, caplet, minitablets, micro tablets, pellets or liquid form of any active pharmaceutical ingredients. Especially wherein the pharmaceutical active ingredient is a pharmaceutically effective amount of compound selected from the group consisting of Acamprosate Calcium, Aminophyllin, Amino Salicylic, Aspirin, Bisacodyl, Budesonide, Divalproex Sodium, Dirithromycin, Didanosine Hydrochloride, Duloxetine Hydrochloride, Diclofenac sodium, Misoprostol , Doxycycline Hyclate, Erythromycin, Esomeprazole Magnesium, Fluoxetine, Ferrous sulphate, Fish oil, Garlic oil, Lansoprazole, Methenamine mandelate, Mesalazine, Naproxen, Omeprazole, Omeprazole Magnesium, Oxtriphyllin, Pancrealipase, Pantoprazole, Rabeprazole Sodium, SAMe, Solifenacin , Sulfasalazine and Valporic acid or a combination there of.
The detailed manufacturing process for preparation of improved capsule shell
comprises the following steps:
i) Disperse HPMC phthalate in hot water by constantly adding neutralizing agent mainly NaOH solution. Holding the same to get clear transparent solution. The ratio of NaOH to HPMC phthalate varies from 0 to 20 %. The ratio is finalized based on the pH of the final solution to get between 5.0 to 8.0 The solution is allowed to settle and get de-bubbled.
ii) The solution of gelling agent is separately prepared in hot water and said solutions are added at the predetermined temperature in the said solution of HPMC phthalate to give a capsule preparing solution;
iii) The capsule preparing solution of step (ii) is then added with suitable
pharmaceutically approved colouring agents, opicifers, lubricants, extenders, surface active agents, plastisizers and then the said solution is diluted by water.
iv) A dipping mould is inserted into the capsule preparing solution of step (iii) at a predetermined temperature and then the dipping mould is drawn out and inducing setting of the capsule preparing solution adhering to the pin.

According to present invention the preferred viscosity of the solution is 1000 to 1800 cps.
In a preferred embodiment, the hot water dispersion of said grades of HPMC phthalate is added neutralizing agent which is NaOH.
This manufacturing procedure is only shown as one typical method. Our invention is related with the composition of HPMC phthalate but does not limit the manufacturing methods.
The present invention shall now be specifically described by way of illustrative and non-limiting examples. It shall be understood that many variations and modifications thereto will be apparent to those skilled in the art without departing from the broadest scope and ambit of the invention as set forth herein above.
Experiments: Evaluation methods:
1) Solubility of shells/films and capsules
Six empty capsule filled with formulation (80 % Acetaminophen/Paracetamol powder blended with modified starch 20 % (pre-gelatinised starch), both are sank into the medium by using the sinker, is tested by the dissolution apparatus (paddle method). The shells are first exposed to acidic buffer solution for 2 hrs and then at mixed phosphate buffer. Drug release profile for entire 3 hrs is mapped at interval of every 30 mins. Test conditions; 900 ml, 50 rpm, 37 deg C. Test medium; 0.1 N HCI (1.2pH) and 50 mM phosphate buffer (pH 6.8)
2) Brittleness of shell
100 capsules are pressed by dropping 100 gm weight at 50 mm height. Number of broken capsules are measured.
3) Colour stability of empty shell
Keep 500 capsules in a poly bag. Store them at 25 deg C and 65 % RH. Observe its colour change after 3 months.

4) Taste of shells
Chew 2 shell of every experimental capsule and define its taste.
Sample preparation
Example 1
Enteric capsules with NaOH as neutralizing agent
I - Part A solution is prepared by adding HPMC Phthalate powder in hot water under constant stirring. The clear solution is obtained by holding the solution for period of 4 hrs to 24 hrs under constant temperature. The different compositions tried are as follows

Ex-1 Ex-2 Ex-3 Ex-4 Ex-5 Ex-6 Ex-7 Ex-8 Ex-9 Ex-
10
1 HP-50 of Shinetsu 2400 2400
2 HP-55 of Shinetsu 2400 2400 2400
3 HP-55S
of
Shinetsu 2400
4 HP-50 of Samsung 2400
5 HP-50 of Samsung 2400 2400 2400
6 Water 6700 6700 6700 6700 6700 6700 6700 6700 6700 6700
7 NaOH 180 200 150 300 325 270 300 200
8 Ammonia Solution 1200 1000
9 TEC 5 7.5 5 5 7.5 - - - - -
10 Glyserine - - - - - - - - 250 200
11 Plasdone s-630 350 300 300 350 300 100 200 250

12 SLS 5 7 7 5 7 - - - - -
13 Twin 80 2 - - - - - - 7 10 10
14 PEG - - - - - 200 100 - - -
2- AGAR solution is prepared by dispersing AGAR in cold water and then completely solublising the same by increasing the temperature. The quantity of AGAR used is as follows

Ex-1 Ex-2 Ex-3 Ex-4 Ex-5 Ex-6 Ex-7 Ex-8 Ex-9 Ex-
10
1 INA
AGAR
UP-37K 120 120 150 120 192
2 INA
AGAR
UX-100 100 150 130 168
3 Regular
AGAR
S-6 170
4 Water 2000 2000 2000 2400 2000 2500 2300 2500 3000 3000
3) Pins of size 0 cap and body manufactured by M/S Ajas are lubricated with suitable food grade mold releasing agent. They are dipped in the solution so prepared in the points discussed 1 and 2 above. Capsules are dried for time of 30 mins to 120 mins based on the air quality and quantity adjusted. Capsules are then strip , cut to 10 mm for cap and 18.5 mm for body shells. The cut shells are then joined on the automatics designed and developed by M/S ACG - Associated Capsules Pvt Ltd.
4) The capsules are then evaluated for parameters as discussed above. EVALUATION OF SAMPLS PREPARED

1) Evaluation for Solubility
The results of average % drug released is as follows

Ex-1 Ex-2 Ex-3 Ex-4 Ex-5 Ex-6 Ex-7 Ex-8 Ex-9 Ex-
10
1 After 30 mins at 0.1 NHCL Nil Nil Nil Nil Nil Nil Nil Nil Nil Nil
2 After 60 mins at 0.1 NHCL Nil Nil Nil Nil Nil Nil Nil Nil Nil Nil
3 After 90 mins at 0.1 NHCL Nil Nil Nil Nil Nil Nil Nil Nil Nil Nil
4 After 120 mins at 0.1 NHCL 3 5 5 3 10 10 8 7 12 14
5 After 30 mins at 6.8 Phosphate buffer 61 53 51 63 49 38 43 36 22 18
6 After 60 mins at 6.8 Phosphate buffer 85 70 75 81 77 70 73 75 53 58

It can be seen that the capsules where NaOH is used as neutralizing agent gives better results.
2) EVALUATION FOR BRITTLENESS, COLOUR AND TASTE

Experiment no Brittleness colour Taste
1 EX-1 2% No change SI. Salty
2 EX-2 3% No change SI. Salty
3 EX-3 2.5 % No change SI. Salty
4 EX-4 2% No change SI. Salty
5 EX-5 1.5% No change SI. Salty
6 EX-6 2% No change SI. Salty
7 EX-7 1.5% No change SI. Salty
8 EX-8 1 % No change SI. Salty
9 EX-9 32% White and deshaped Very Bitter and bad taste
10 EX-10 45% White and deshaped Very Bitter and bad taste

WE CLAIM:-
1. An enteric capsule comprising of :
i) enteric polymer in the range of 30% to 95%;
ii) neutralising agent in the range of 1 % to 20% w/w of the enteric polymer;
iii) plastisizer in the range of 0% to 30% w/w of the enteric polymer;
iv) internal Lubricants in the range of 0% to 10% w/w of the enteric polymer;
v) gelling agent in the range of 1 % to 8% w/w of the enteric polymer;
vi) opacifers and /or colouring agent in the rage of 0.01 % to 20 % w/w of enteric
polymer vii) surface active compounds in the range of 0% to 50%; viii) extenders in the range of 0% to 50% w/w of the enteric polymer.
2. An enteric coated capsule as claimed in claim 1, wherein the enteric polymer is selected from any grade of HPMC phthalate.
3. An enteric coated capsule as claimed in claiml and 2, wherein the polymer is selected from HP-50, HP-55 or HP-55S or any other grade developed for having enteric property.
4. An enteric coated capsule as claimed in claims 1 to 3, wherein the enteric polymer can be in the range of 30% to 95% w/w in the capsule shell.
5. An enteric coated capsule as claimed in claims 1 to 4, wherein the neutralizing agent can be any form of alkali having pH at 1 N above 8.
6. An enteric coated capsule as claimed in claims 1 to 5, wherein the neutralizing agent is sodium hydroxide.
7. An enteric coated capsule as claimed in claim 1to 6 wherein the gelling agent is quick soluble AGAR grade.
8. An enteric coated capsule as claimed in claim 1, wherein the plastisizer can be selected from polyethylene glycol, propylene glycol, glycerol, sorbitol, dioctyl-

sodium sulfosuccinate, triethyl citrate, tributyl citrate, Di ethyl phthalate, di butyl phthalate 1,2- propyleneglycol, mono-, di, or tri-acetates of glycerol or mixtures thereof. Additionally polyvinyl pyrrolidone, polyvinyl alcohol, co polyvidone (plasdone S-630)
9. An enteric coated capsule as claimed in claim 1, wherein the coloring agents and opacifiers are selected from permitted colorant and dyes as listed in Rule 27 of Drugs and Cosmetics Act and Rule ( India) and permissible under the regulatory requirements of the country of use. They comply with the Bureau of Indian Standards ( BIS) and / or Code of Federal Regulations (CFR) and / or EEC directives. The coloring agent may be a color selected from the group comprising annatto, carotene, chlorophyll, cochineal, curcumin, caramel, riboflavin, red iron oxide, yellow iron oxide, titanium di-oxide, black iron oxide and mixtures thereof. The coloring agent may also be selected from quinazarine green, alizarin cyanine green, fast green, tartrazine, sunset yellow, quinoline yellow, erythrosine, eosin YS, toney red, ponceau 4R, carmoisine, indigo carmine, brilliant blue, orange G, resorcin brown, naphthol blue black, allura red, and combinations thereof. The coloring agent may be lake salts (example aluminum) any of the above listed water soluble coloring agents and combinations thereof.
10. An enteric coated capsule as claimed in claim 1, wherein the lubricant may be selected from aluminium stearate, calcium stearate, magnesium stearate , tin stearate, talc, sodium lauryl sulfate, lecithins, mineral oils, stearic acid or silicones or any mixtures thereof.
11. An enteric coated capsule as claimed in claim 1, wherein the extender may be selected from sunflower proteins, soybean proteins, cotton seed proteins, peanut proteins, rape seed proteins, lactose, gum arabic, acrylates or methacrylates, cellulose acetyl phthalates, hydroxypropyl methylcellulose, ,hydroxypropyl methycelluose, hydroxypropyl methylcellulosephthalate, hydroxymethylcellulose, polyvinylpyrrolidone, shellac, bentonite, polyvinyl acetatephtalate, phthalated gelatin, succinated gelatin, agar, hydroxyalkylstarches or mixtures thereof.

12. A process for manufacturing enteric capsules comprises the steps of i) Making complete solution of enteric polymer; ii) Adding of suitable plasticizer; iii) Adding of suitable gelling agent; iv) Adding of required colorants, opacifiers, surface active agents and
another processing aids, v) Dipping the metal pins at low temperature vi) Drying the shells at drying chambers, vii) Stripping, cutting and joining the shells.