WO2010122574A2

WO2010122574A2 - Coated capsule

Info

Publication number: WO2010122574A2
Application number: PCT/IN2010/000242
Authority: WO
Inventors: Yashoraj Rupsinh Zala; Nitin Bhalachandra Dharmadhikari
Original assignee: Sun Pharma Advanced Research Company Ltd.
Priority date: 2009-04-20
Filing date: 2010-04-15
Publication date: 2010-10-28
Also published as: WO2010122574A3

Abstract

The present invention relates to coated capsules comprising capsule comprising (i) therapeutically active ingredient and pharmaceutically acceptable carrier and (ii) 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

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 3, 656, 997 (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 x l(f, 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.

WO 199535100 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. 2,230,44 IA 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 semipermeable 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;30β):n\-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. Bussemei et a/ 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 composition4

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

❖ 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 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.

In one embodiment of the present invention, the coated capsules are designed to release the active ingredient at a zero order. This zero order or constant release order is achieved because of exposure of a defined surface area of the body of the capsule once the capsule opens into two, i.e the cap and the body. The capsule fill in the body comprising the active ingredient designed to be released in a zero order, is formulated such that it is slug fit into the body of the capsule. This can be achieved by using particular excipients which will have adhering properties to the inside wall of the body of the capsule or the material may be placed inside the body of capsule by application of pressure. When a material which has adhering property is used, preferably such a material is selected from the group consisting of excipients that are sticky in nature, or having a melting point below 100⁰C. Such material may be a lipophilic or hydrophilic waxy material Ike polyethylene glycols, fatty alcohols, fatty acids, cetyl esters of fatty acids, triglycerides, glyceryl monostearate, high molecular weight Gelucire, hydrogenated castor oil, poloxomers and the like and mixtures thereof. Apart from these types of materials, other rate controlling excipients may be included to further control the release of the active ingredient. Any rate controlling excipients may be used which is commonly known to a person skill in the controlled release technology. Because of the adhering nature of such materials, the contents of the capsule are not emptied once the capsule opens into the cap and the body and thus, a defined constant surface area corresponding to the diameter of the body of the capsule is available for providing a zero order release of the active ingredient. 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 will be that of the modified dosage form. A combination of these alternatives may be employed.

In one embodiment of the present invention, carbidopa and levodopa is used as a model drug. This embodiment demonstrates the programming of the release with the help of the novel and inventive coated capsules of the present invention. The programmed release includes a combination of immediate release, controlled release and a delayed release. Also, because of the novel and inventive coating, it is possible to suitably alter the ratio of hydrophobic polymer to hydrophilic substance in the coating composition to get varying permeability in fasted state and fed condition. Alternately, it is possible to get varying permeability when the coated capsule is in stomach and when it is intestine, irrespective of gastric motility and gastric emptying time. In a preferred embodiment, the ratio of hydrophobic polymer to hydrophilic substance in the coating composition changes from 60:40 (in stomach) to 30:70 in intestine.

It is also a feature of the invention to use methods known in the art to arrive at different optimum ratios of hydrophilic substance and hydrophobic polymer to get varying permeabilities and get desired release profile in fasted or fed condition or targeted release in any region of the gastrointestinal tract. In another embodiment of the present invention, the coated capsule upon contact with the aqueous environment breaks open at a predetermined time into the cap and body, thereby exposing a defined surface area that provides a zero-order or near constant release of the medicament at a controlled rate (Fig 4 & 5).

It will be understocd 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 of the total dose of the active agents namely, Carbidopa (CD) - 50 mg and Levodopa (LD) - 200 mg which is divided into three fractions namely, immediate release fraction (CD/LD: 17.5 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 enterically coated minitablets. The composition of the minitablets is as follows:

Table l(a): Composition of the delayed release fraction

Carbidopa , Levodopa , Tartaric acid , MCC (Silicified), crospovidone, Polyvinyl pyrrolidone and colloidal silicon dioxide are mixed geometrically and blended in a double cone blender for 10 tnin. Lubrication is carried out by addition of magnesium stearate and talc into the blend and further blended for 10 min. The blend is compressed into tablets and further coated with Eudragit L 100 (aqueous dispersion) in a Fluid Bed Coater.

Table 2(a): Composition of the controlled release fraction

PEG 4000 and Poloxamer are mixed and heated to melt in water bath. The molten mass is cooled to 60⁰C. A pre-mixed blend of Carbidopa, Levodopa and mannitol is then mixed with the molten mass to form controlled release blend.

The composition prepared according to table 1 (4 minitablets) and table 2 (b) were filled into hard gelatin capsule of size O'. Capsule filling is carried out 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.

To the vortex of Aquacoat , dibutyl sebacate, triethyl citrate and mannitol are added followed by talc and stirred for 15 minutes. Eudragit L 100 polymer in the form of aqueous dispersion was then added to the above dispersion. Core capsules are coated in a perforated coating pan using above dispersion 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 immediate release fraction

Polysorbate, 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 with stirring. To this dispersion is added Opadry and talc and stirred for 15 min. Functional coated capsules are coated in a perforated coating pan using above dispersion till the desired weight gain.

The eoated capsules with an immediate release fraction of Carbidopa levodopa were further coated with a coating of Opadry II as per the Table 5. Drug loaded capsules are coated in a perforated coating pan using above dispersion till the desired weight gain.

Table 5: To coatin with O adr

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 HCl 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 VoI, Type II, for lhr. The figures 4 and figure 5 indicate the release of carbidopa and levodopa, respectively.

Claims

Claims:

1. A coated capsule comprising

• capsule comprising therapeutically active ingredient and pharmaceutically accepfcble 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.

2. A coated capsule as claimed in claim 1 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.

3. A coated capsule as claimed in claim 1 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.

4. A coated capsule as claimed in claim 1 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.

5. A coated capsule as claimed in claim 1 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.

6. A coated capsule as claimed in claim 5 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.

7. A coated capsule as claimed in claim 5 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.

8. A coated capsule as claimed in claim 5 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.

9. A coated capsule as claimed in claim 1 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.

10. A coated capsule as claimed in claim 1 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.