FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
THE PATENT RULES, 2003


PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
COATED CAPSULE

SUN PHARMA ADVANCED RESEARCH COMPANY LTD.
A company incorporated under the laws of India having their office at 17/B, MAHAL INDUSTRIAL ESTATE, MAHAKALI CAVES ROAD, ANDHERI (E), MUMBAI - 400093, STATE OF MAHARASHTRA, INDIA.
The following specification describes the invention


The present invention relates to coated capsules for delivering an active ingredient over a period of time.
BACKGROUND OF THE INVENTION
Capsule technology has been developing for over one hundred years. The benefits of such a dosage form reside in the fact that the capsules are often easy for a patient or other consumer to swallow or use and can contain a large amount of the particular medicament for delivery to the individual in different forms such as powder, granules, liquid, pellets, mini tablets.
Hard gelatin capsules have been known to be coated to provide a gastric resistance. See for example, US 3656997 (patent '997). The '997 patent discloses a process for the production of transportable and storable gelatin capsules which are unaffected by gastric juices and soluble in the small intestines, comprising coating conventional gelatin capsules filled with an active ingredient or ingredients by spraying with a primary lacquer selected from the group consisting of polyvinyl pyrrolidones with a molecular weight of from 104 to 106, hydroxymethyl propyl cellulose, carboxyvinyl polymers with a molecular weight of about 2 * 106, and mixtures thereof, and thereafter coating said primary lacquer with a lacquer unaffected by gastric juices and soluble in intestinal juices. However, the patent does not disclose about opening of the coated capsules to release the contents in a programmed manner for example, controlled release, delayed release and combination thereof.
European patent number EP882449B1 claims a sustained release capsule in which an outer surface of a hard capsule mainly composed of gelatin is uniformly covered with a film material comprising a natural polysaccharide/polyhydric alcohol composition which is prepared by uniformly kneading at least one natural polysaccharide selected from the group consisting of carrageenan, alginic acid, salts of alginic acid, derivatives of alginic acid, agar, locust bean gum, guar gum, pectin, amylopectin, xanthane gum, glucomannan, chitin and pullulan in at least one system selected from the group consisting of polyhydric alcohols, sugar alcohols, monosaccharides, disaccharides, trisaccharides and oligosaccharides.
WO199535100 discloses a colonic drug delivery composition is provided and comprises a starch capsule containing a drug, the starch capsule being provided with a coating such that the drug will only be released from the capsule in the colon. The coating may be a pH-sensitive material, a redox-sensitive material or a material broken down by specific enzymes or bacteria present in the colon. The drug to be delivered may be one for local action in the colon, or a systemically active drug to be absorbed from the colon.
There are several prior arts that disclose the partial coating of the capsule i.e coating of the body of hard gelatin capsule to provide the pulsatile drug delivery system known under the tradename of Pulsincap® drug delivery

system where an empty gelatin capsule was coated with ethyl cellulose keeping the cap portion as such. One such technique is disclosed in United States patent US 5,631,022 (US Patent '022) describes a pulse capsule, such as Pulsincap® which is further described in U.K. Patent Application Nos. 2,230,441A and 5 2,230,442A of National Research Development Corporation and PCT Patent Application No. WO 91/12795 of National Research Corporation. The pulse capsules of this technology comprise a water-insoluble male capsule shell, a water-dispersible or swellable hydrophilic plug, and a water-soluble female capsule shell. The male and female shells preferably have the size, shape, and fit of conventional hard gelatin capsule male and female mating shells. The pulse capsule may contain a hydrophilic plug such that the hydrophilic plug blocks the entire opening of the male shell. The female shell covers the exposed portion of the plug and extends along the outer cylindrical surface of the male shell. In contact with the fluids of the stomach and the intestines beyond, the female shell of a pulse capsule dissolves and the hydrophilic plug hydrates. The composition and size of the hydrophilic plug is selected such that the hydrophilic plug disengages from the male capsule shell after a predetermined amount of time, releasing the active ingredient. However, such technique requires extra cost and the conventional hard capsules having the cap and the body made up of same material may not be suitable.
United states patent Number US 6.669,954 (hereinafter referred to as patent '954) discloses a drug delivery system comprising:
(a) a therapeutic amount of a pharmaceutical agent;
(b) a container having (i) at least one aperture and (ii) a wall having an inside and an outside;
(c) an excipient formulation disposed in said container regulating a difusional boundary layer is confined withi said container for a period of time to allow drug delivery to a desired location and continuosly releasing said pharmaceutical agent upon solvation at a rate of less than one-fifth of the initial release of said pharmaceutical agent in an uncoated form, the excipient formulation comprising a release control agent and an ingredient selected from a group consisting of: a lubricating agent, a filing agent and mixture thereof, the ratio of the release control agent to the ingredient ranging from 0.2 to 170; and
(d) a cover layer adhered to the wall, wherein at least one of the container or the cover layer is semi¬permeable to said pharmaceutical agent.
The '954 patent however, does not disclose use of a microporous coating on the wall. In case of semipermeable coating as taught in '954 patent, the contents of the caspule need to be selected such that the contents upon contact with an aqeuous environment are capable of exerting osmotic pressure which becomes essential for the opening of the caspule and thereafter release of the active ingredient. In contrast, according to the present invention, the use of a microporuous coating does not necessitate the use of an osmotically active capsule content. The present invention provides flexibility of choosing any type of material to be filled inside the capsule so that either a programmed release i.e a delayed or sustained or delayed with pulse release can be designed.

Although the prior arts cited above disclose the coating directly applied to the hard gelatin capsule, none of these prior arts disclose the coating composition comprising a mixture of a hydrophobic polymer and a hydrophilic substance.
The art teaches that there were attempts made to modify the coated hard gelatin capsules by incorporation of an intermediate, swellable layer between the hard gelatin capsule wall and the polymeric coating composition. One such attempt, as disclosed in the PCT WO200069419 describes a controlled active substance release capsule comprising a filling material containing an active substance, a capsule shell, a swelling layer and a water-insoluble layer, wherein the active substance is released after a delay phase. The corresponding journal publication, Journal of Controlled release 93 (2002-3); 331-339 describes this technology in detail. However, there is no disclosure of a coated capsule comprising
♦ capsule comprising therapeutically active ingredient and pharmaceutically acceptable carrier
and
♦ the coating composition comprising a hydrophobic polymer and a hydrophilic substance;
wherein the said coating composition is applied directly to the capsule and wherein the coated capsules upon
contact with the aqueous environment break open into the cap and the body and thereby providing a
programmed release of the therapeutically active ingredient.
Dashevsky A et al in Drug Dev Ind Pharm. 2004 Feb; 30(2):\71-9 discloses a process and formulation variables affecting the performance of a rupturable capsule-based drug delivery system with pulsatile drug release; Mohamad et al in the Eur J Pharm Biopharm, 2006 Oct; 64 (2): 173-9 describes a pH-independent pulsatile drug delivery system based on hard gelatin capsules and coated with aqueous dispersion Aquacoat ECD. Bussemer et al in the International Journal of Pharmaceutics_ 2003 Nov 28; 267(1-2): 59-68 describes a study to develop and evaluate a rupturable pulsatile drug delivery system based on soft gelatin capsules with or without a swelling layer and an external water-insoluble but -permeable polymer coating, which released the drug after a lag time. However, there is no disclosure of hard gelatin capsules coated with a coating composition wherein the coating composition comprising a hydrophobic polymer and a hydrophilic substance is directly applied to the hard gelatin capsules, wherein the coated capsules provide a release of the drug at a predetermined period of time.

SUMMARY OF THE INVENTION
The present invention may be summarized as follows: A coated capsule comprising
♦ capsule comprising therapeutically active ingredient and pharmaceutically acceptable carrier
and
♦ the coating composition comprising a hydrophobic polymer and a hydrophilic substance;
wherein the said coating composition is applied directly to the capsule and wherein the coated capsules upon
contact with the aqueous environment break open into the cap and the body and thereby providing a
programmed release of the therapeutically active ingredient.
DESCRIPTION OF THE DRAWINGS AND FIGURES
Figure 1 represents stage 1 of the coated capsule which is in contact with the aqueous environment. The numbering is described below:
1: aqueous environment
2: cap of the hard gelatin capsule
3: Body of the hard gelatin capsule
4: Coating composition comprising a mixture of hydrophobic polymer and a hydrophilic
substance
5: Junction of the cap and the body being covered with the coating composition 4
Figure 2 represents stage 2 of the coated capsule wherein upon contact with the aqueous environment, after a predetermined period of time, the coating at point 5 breaks and allows ingress of aqueous environment 1 causing the opening of the capsule into two, i.e cap 2 and body 3, exposing a defined surface area of the body 3 of the capsule containing the active ingredient along with the pharmaceutically acceptable carrier.
Figure 3 represent Stage 3 where after the detachment of the cap and the body, the contents 6 of the body 3 are exposed and emptied from the body leaving another fraction 7 of the contents of the capsule to get exposed to the aqueous environment
Figure 4 represents Stage 4 where the fraction 7 of the contents of the capsule is exposed to the aqueous environment releasing the active ingredient present in the fraction 7.

DETAILED DESCRITION OF THE INVENTION
The present invention may be summarized as follows:
A. A coated capsule comprising
♦ capsule comprising therapeutically active ingredient and pharmaceutically acceptable carrier
and
♦ the coating composition comprising a hydrophobic polymer and a hydrophilic substance;
wherein the said coating composition is applied directly to the capsule and wherein the coated capsules upon
contact with the aqueous environment break open into the cap and the body and thereby providing a
programmed release of the therapeutically active ingredient.
B. A coated capsule as defined in A wherein the capsule is a hard capsule made up of a material selected from
the group consisting of gelatin, hydroxypropyl methyl cellulose, starch, agar, methyl cellulose and the like.
C. A coated capsule as defined in A wherein the coating composition comprises a hydrophobic polymer
selected from the group consisting of ethyl cellulose, hydroxypropylmethyl cellulose phthalate, cellulose
acetate, cellulose acetate butyrate, polyurethane, ethyl methacrylate, hydroxyethylrnethacrylate and
combinations thereof.
D. A coated capsule as defined in A wherein the coating composition comprises a hydrophilic substance
selected from the group consisting of low molecular weight compounds such as sugar alcohols such as
mannitol, sugars such as sucrose, lactose, fructose, inorganic salts such as sodium chloride, or are selected
from the group consisting of water soluble polymers such as polymethacrylate polymers, water soluble
polymers such as hydroxypropyl methyl cellulose, methyl cellulose, hydroxyethyl cellulose and the like and
mixtures thereof.
E. A coated capsule as defined in D wherein the coating composition is applied directly in the amount of about
2 % to about 20 % by weight of the capsule with a coating composition comprising the hydrophobic polymer
to hydrophilic material in the ratio of about 30:70 to about 90:10.
F. A coated capsule as defined in E wherein the coating composition when applied in a ratio of 90: 10 and to a
weight gain of about 5 % by weight of the capsule, the capsule opens at a predetermined period of about 20
minutes.
G. A coated capsule as defined in E wherein the coating composition when applied in a ratio of 30: 70 and to a
weight gain of about 9 % by weight of the capsule, the capsule opens at a predetermined period of about 5
minutes without any substantial delay.
H. A coated capsule as defined in E wherein the coating composition when applied in a ratio of 90: 10 and to a
weight gain of about 10 % by weight of the capsule, the capsule opens at a predetermined period of about 1
hour.
I. A coated capsule as defined in A wherein the capsule is filled with a combination of controlled release
composition and a delayed immediate release composition containing fraction of the total dose of an active
ingredient.

J. A coated capsule as defined in A wherein the capsule contains a combination of an immediate release
composition of a fraction of dose of the active ingredient, controlled release fraction of the dose of the active
ingredient and delayed release fraction of the total dose of the active ingredient.
K. A coated capsule as defined in A wherein the coated capsule is further coated with a coating composition
comprising an immediate release fraction of the active ingredient.
L. A coated capsule as defined in A wherein the coated capsule comprises a controlled release fraction of the
active ingredient comprising granules of the active ingredient in the form of melt dispersion with a solubilizers
for example, polyethylene glycol and poloxamer.
M. A coated capsule as defined in A wherein the coated capsule comprises a delayed release fraction wherein
the delay is dependent upon the type of coating applied to such coating.
N. A coated capsule as defined in K wherein the coating applied on the delayed release composition is selected
from the group consisting of polymethacrylates, ethyl cellulose, hydroxypropylmethyl cellulose phthalate and
the like and mixtures thereof.
It will be appreciated by those versed in the art in the light of this invention, that the coated capsules of the present invention are designed to break open into the two halves unlike some of the osmotic capsules disclosed in the art where the coated capsules are coated with semi-permeable polymer and the capsule contents are required to be osmotically active in order to provide a controlled release of the drug for a long period of time. In contrast, the opening of the coated capsules of the present invention is not dependent on the contents of the capsule. It was in fact found that when the coated capsules were either filled with water soluble like lactose or water insoluble material like dicalcium phosphate, the opening time of the coated capsules was surprisingly not influenced by the nature of the contents of the capsule. The critical factor that determined the opening time of the coated capsules was the ratio of the hydrophobic polymer to hydrophilic substance of the coating composition.
In one embodiment of the present invention, the coated capsules can be designed to provide a programmed release of the active ingredient while the coated capsule is retained in the stomach for the longer period of times. The capsule is partially filled, i,e only the body of the capsule is filled whereas the cap of the capsule is only partially filled, leaving empty space or air. This causes the coated capsule to float because of low density. Depending upon the % weight gain and the ratio of the hydrophobic polymer and the hydrophilic substance and the nature of the two, the coated capsule may break open after a predetermined delay for example, ranging from 2 hours to 6 hours. After the predetermined delay in opening of the capsule, the contents of the capsule may then get released in the gastrointestinal environment where the programmed release of the active ingredient takes place.

According to the present invention, the pharmaceutically acceptable carrier of the coated capsule may take the form of the active material as such, e.g. as a particulate solid or may take the form of any other convenient dosage form. For example, the active agent may be combined with a conventional excipient and be introduced into the coated capsule as a powder or take the form of compressed tablets of excipient and carrier. Either a single tablet or a plurality of such tablets may be introduced. A further alternative is to introduce the active material in a modified dosage form. This enables the release profile of the device to be modified, e.g. where a particulate active material is employed it will be released as a pulse of active material, whereas where a modified dosage form is employed that form may be released into the environment after the pre-determined delay and the subsequent release profile wil] be that of the modified dosage form. A combination of these alternatives may be employed.
It will be understood by those of skill in the art that numerous modifications can be made without departing from the spirit of the present invention. Therefore, it should be clearly understood that the following examples are illustrative only and should not to be construed to limit the scope of the present invention.
EXAMPLE 1
The coated capsules of the present invention according to one embodiment of the present invention comprises The total dose of the active agents namely, Carbidopa (CD ) - 50 mg and Levodopa (LD) - 200 mg is divided into three fractions namely, immediate release fraction (CD/LD: 7.5 mg/70 mg), controlled release fraction (CD/LD; 20 mg/80 mg) and delayed immediate release fraction (CD/LD: 12.5 mg/ 50 mg).
The fraction 3 which is a delayed release fraction was prepared in the form of entericatly coated mini-tablets. The composition of the minitablets is as follows:
Table 1(a): Composition of the delayed release fraction

Sr. No. Ingredients mg/ caspule
1 Carbidopa anhydrous .USP 12.5
2 Levodopa USP. 50.00
3 Tartaric acid (ASTM 60# passed) 10.00
4 Prosolv SMCC 90 43.5
5 PVPK30 3.0
6 Crospovidone 5.0
7 Colloidal silicon dioxide 1.00
8 Talc 1.50
9 Magnesium Stearate 1.50
Eudragit L 100 polymer in the form of aqueous dispersion 1.6
Purified water- for 20 % dispersion q-s
Carbidopa , Levodopa , Tartaric acid (ASTM 60# passed), Prosolv SMCC 90, rospovidone, PVP K30 and colloidal silicon dioxide are mixed geometrically in a polybag and sifted through ASTM 40# sieve and blended in a double cone blender for 10 min. Magnesium stearate and talc are sifted through ASTM 60# sieve,

lubrication is carried out by addition of magnesium stearate and talc into the blend in step T and blending in a double cone blender for 10 min. Compression is carried out using 3.50 mm punches, the tablet weight adjusted to 32.0 mg. Acryl EZE MP White 93018508 is added to water & stirred for 45 mins. Tablets are coated in a Fluid Bed Coater to weight gain of 5%.
Table 2(a): Composition of the controlled release fraction

Sr. No. Intragranular ingredients mg/ Capsule
1. Carbidopa anhydrous USP 20.0
2. Levodopa USP 80.0
3. PEG 4000 158.0
4. Poioxamer 188 (Lutrol F68) 10.0
Table 2 (b): lubrication of the granules of Table 2 (a)
Sr.no
Extragranular ingredients mg/ Capsule
1 Granules of composition of Table 2 (a) 268.0
2 Polyethylene glycol 20.0
3 Mannitol SD200 100.0
4 Colloidal Silicon Dioxide 1.5
5 Stearic Acid 2.5
PEG 4000 and Poioxamer 188 are mixed in a polybag, sifted through ASTM 40# and heated to melt in water bath & maintained at 60 °C. Carbidopa and Levodopa mbced in a polybag sifted through ASTM 40# transferred to above container containing molten PEG 4000 and Poioxamer 188 and mixed .
The composition prepared according to table 1 (4 minitablets) and table 2 (b) were filled into hard gelatin capsule of size '0'. Capsule filling is carried out using size '0' elongated capsules by placing four enteric coated tablet into the body of each capsule and then filling CR blend.
The filled capsules were coated with a coating composition as described in Table 3 below. The coating composition contains a combination of hydrophobic polymer namely, ethyl cellulose, a combination of polymethacrylate and mannitol in a ratio of 30:30:40.

Table 3: coating composition directly applied on the hard gelatin capsules filled with the
compositions of Table 1 and table 2 (b)
Sr. No. Ingredients mg/ Capsule
1. Aquacoat ECD 30 28.869
2. Mannitol 25 10.393
3. Dibutyl sebacate 2.165
4. Triethyl citrate 1.131
5. Acryl Eze MP 93018508 12.991
6. Talc 2.844
Target wt gain% 6%
Functional Coated capsule weight 666.104
To the vortex of Aquacoat ECD 30, kept under stirring in a beaker, Dibutyl Sebacate is added, rinsed with small amount of purified water and stirred for 30 minutes, followed by Triethyl Citrate, rinsed with small amount of purified water and stirred for 30 minutes. To the vortex of Purified water , kept under stirring in another beaker Mannitol 25 is added followed by Talc and stirred for 15 minutes. The solution from step 2 is added into the vortex of solution from step 1 and stirred, later Acryl EZE MP white 93018508 was added and continued stirring for 45 minutes. The above dispersion was filtered through ASTM 60# sieve and kept under slow medium but continuous stirring through out the process. Core capsules are coated in a perforated coating pan using above dispersion at a bed temperature of 38-42°C to the weight gain of 6%.
The coated capsules were coated with an immediate release fraction of carbidopa and levodopa in the form of a coating composition of Table 4.
Table 4: coating composition of CDLD inmmediate release fraction

Sr. No. Ingredients mg/ Capsule % w/w
wrt solid
content
1. Carbidopa anhydrous USP. 17.50 32.58
2. Levodopa USP. 70.00 32.58
3. Polysorbate 80 1.40 0.78
4. Talc 10.40 7.16
5. Povidone K-30 5.45 3.26
6. Tartaric acid (milled and ASTM 100# passed) 17.50 6.51
7. Triethyl Citrate 1.40 0.97
8. Opadry 06A59037 Clear 23.35 16.16
Target wt gain % 22.069 % -
Weight after drug loading 813.106
Polysorbate 80, triethyl citrate and milled tartaric acid are dissolved in water. To the above solution is added a

previously mixed mixture of carbidopa, levodopa and povidone K-30 and stirred for further 10 min. To this dispersion is added Opadry 06A59037 Clear and stirred for 45 min. Talc is added to the above solution and stirred for 15 min. The dispersion from step '2' is passed through the colloidal mill for 15 min. and discharged at clearance '2', this was then filtered through ASTM 40#. Functional coated capsules are coated in a perforated coating pan using above dispersion at a bed temperature of 36-37°C till the desired weight gain.
The coated capsules with an immediate release fraction of CDLD coated on top of it were further coated with a coating of Opadry as per the Table 5. Opadry II white 85F18422 is added to the vortex of water and stirred for 45 min. Drug loaded capsules are coated in a perforated coating pan using above dispersion at a bed temperature of 36-37° C till the desired weight gain.
Table 5: Top coating with Opadry
Sr. No. Ingredients mg/ Tablet % w/w
Opadry II white 85F18422 24.393 100
Purified water 178.8 -
Target wt gain % 3% -
Weight after coating 837.499
EXAMPLE 2
The coated capsules prepared according to Example 1 were subjected to in vitro dissolution testing. It was found that the coated capsule splits into two at the junction of cap and body) after lhr 30 min to lhr 45 min. The coated capsules were initially subjected to the dissolution studies in acidic pH for example, 0.01 N HC1 and 4.5 pH acetate buffer 900 ml dissolution medium in Type II (Without Sinker) Change Over (after 5 hrs) to 6.8 buffer, 75 Rpm, 900ml Vol, Type II, for lhr. The figures 4 and figure 5 indicate the release of carbidopa and levodopa respectively.
The present invention may be summarized as follows: A. A coated capsule comprising
♦ capsule comprising therapeutically active ingredient and pharmaceutically acceptable carrier
and
♦ the coating composition comprising a hydrophobic polymer and a hydrophilic substance;
wherein the said coating composition is applied directly to the capsule and wherein the coated capsules upon
contact with the aqueous environment break open into the cap and the body and thereby providing a
programmed release of the therapeutically active ingredient.

B. A coated capsule as defined in A wherein the capsule is a hard capsule made up of a material selected from
the group consisting of gelatin, hydroxypropyl methyl cellulose, starch, agar, methyl cellulose and the like.
C. A coated capsule as defined in A wherein the coating composition comprises a hydrophobic polymer
selected from the group consisting of ethyl cellulose, hydroxypropylmethyl cellulose phthalate, cellulose
acetate, cellulose acetate butyrate, polyurethane, ethyl methacrylate, hydroxyethylmethacrylate and
combinations thereof.
D. A coated capsule as defined in A wherein the coating composition comprises a hydrophilic substance
selected from the group consisting low molecular weight compounds such as sugar alcohols such as mannitol,
sugars such as sucrose, lactose, fructose, inorganic salts such as sodium chloride, or are selected from the
group consisting of water soluble polymers such as polymethacrylate polymers, water soluble polymers such
as hydroxypropyl methyl cellulose, methyl cellulose, hydroxyethyl cellulose and the like and mixtures thereof.
E. A coated capsule as defined in D wherein the coating composition is applied directly in the amount of about
2 % to about 20 % by weight of the capsule with a coating composition comprising the hydrophobic polymer
to hydrophilic material in the ratio of about 30:70 to about 90: 10.
F. A coated capsule as defined in E wherein the coating composition when applied in a ratio of 90: 10 and to a
weight gain of about 5 % by weight of the capsule, the capsule opens at a predetermined period of about 20
minutes.
G. A coated capsule as defined in E wherein the coating composition when applied in a ratio of 30: 70 and to a
weight gain of about 9 % by weight of the capsule, the capsule opens at a predetermined period of about 5
minutes without any substantial delay.
H. A coated capsule as defined in E wherein the coating composition when applied in a ratio of 90: 10 and to a
weight gain of about 10 % by weight of the capsule, the capsule opens at a predetermined period of about 1
hour.
I. A coated capsule as defined in A wherein the capsule is filled with a combination of controlled release
composition and a delayed immediate release composition containing fraction of the total dose of an active
ingredient.
J. A coated capsule as defined in A wherein the capsule contains a combination of an immediate release
composition of a fraction of dose of the active ingredient, controlled release fraction of the dose of the active
ingredient and delayed release fraction of the total dose of the active ingredient.
K. A coated capsule as defined in A wherein the coated capsule is further coated with a coating composition
comprising an immediate release fraction of the active ingredient.
L. A coated capsule as defined in A wherein the coated capsule comprises a controlled release fraction of the
active ingredient comprising granules of the active ingredient in the form of melt dispersion with a solubilizers
for example, polyethylene glycol and poloxamer.
M. A coated capsule as defined in A wherein the coated capsule comprises a delayed release fraction wherein
the delay is dependent upon the type of coating applied to such coating.

N. A coated capsule as defined in K wherein the coating applied on the delayed release composition is selected from the group consisting of polymethycrylates, ethyl cellulose, hydroxylpropylmethyl cellulose phthalate and the like and mixtures thereof.