DESC:FIELD OF THE INVENTION
[001] The present disclosure pertains to the field of empty capsules and method for making the same. More particularly, present disclosure relates to a composition for acid resistant empty capsules and method for preparation thereof.

BACKGROUND OF THE INVENTION
[002] Capsules are a unique dosage form with a long history of use in pharmacy. The basic idea of a capsule is to enclose the drug or active pharmaceutical ingredient (API) in an odourless and tasteless shell. Typically, there are two main types of capsules the hard capsule and the soft capsule. Both are designed as per the requirement and the enclosed drug/API within. Generally, dry fills such as powder or pallets or granules or mini tablets or liquids, and semisolids are filled within the hard capsules and liquids and semisolids are exclusively filled in soft capsules.
[003] Delayed release products are widely marketed in the solid oral dosage field and are now a significant factor in the administration of a variety of active pharmaceutical ingredients, nutraceuticals, food supplements etc. Delayed release dosages are intended to protect the contents of the dosage, especially form from gastric conditions. The advantages of such long acting or sustained release products are well understood and a very substantial industry has developed around these products.
[004] Conventionally, delayed release dosage forms are produced by adding a pH dependent coating to the surface of a manufactured dosage forms. These coatings can be applied through techniques like spraying followed by drying usually at elevated temperatures. Currently, most commercially available coatings utilize a synthetic cellulosic polymer such as HPMC- phthalate, HPMC-AS, methacrylate copolymer etc. Other synthetic film-formers, which are commonly used, include ethyl cellulose, methylcellulose, polyvinylpyrrolidone, and polydextrose. This method of coating the dosage forms with a pH dependent coating may lead to disadvantages in terms of performance and appearance. A particular disadvantage of coatings based primarily on HPMC is that the coating may harden over time and therefore increase tablet disintegration times and/or non-uniform coating leading to early rupture in acidic medium. An increase in disintegration time delays the bioavailability of the active ingredient at least in proportion to the increase in disintegration time. Also, the capsule may appear rough, the coating may be applied unevenly, and/or the coating can be prone to cracking or flaking off the dosage form. Additionally, the process of applying a pH dependent coating is very inefficient.
[005] US5139783 discloses alginate capsules which may contain a cosmetic active agent such as a biological compound, and which may be contained in an external gel phase. The present compositions differ from those of US5139783 in that the biologically active material is introduced during the formation of the microcapsules, not afterwards. WO 2007/098612 A1 discloses gastric-resistant gelatin compositions for use in the preparation of dosage forms, comprising modified gelatin with additional functional groups such as carboxylate groups or acyl groups and further addition of sodium alginate and fatty acid derivatives. The modified gelatin is used in normal softgel and hard gelatin capsule production processes. However, the reaction rate and viscosity of the modified gelatin is not easy to control.
[006] US10231934B2 discloses an aqueous composition for the manufacture of acid resistant hard pharmaceutical capsules comprising an aqueous solvent, gellan gum and one or more water soluble, film forming polymers such that the weight ratio of gellan gum to the at least one water-soluble film forming polymer is between 4 to 15 parts by weight of gellan gum per 100 parts by weight of the at least one water-soluble film forming polymer. The water-soluble film forming polymer is HPMC.
[007] WO 2009/024376 discloses a microcapsule for immobilizing organic or inorganic solids, lipophilic compounds, lipids or microorganisms for use in food additives, or as dietary supplements based on a spherical matrix encapsulation using alginate as the substance. The capsule comprises additional adjuncts and stabilizers in the alginate matrix. The immobilized ingredients are released after ingestion of the capsule only after passing through the stomach into the duodenum, and are protected from the prior digestive effects of the stomach. The capsules of WO 2009/024376 are prepared by complex mixing and spray drying or formation of beadlets, with collection of the particles from a CaCl2 bath, followed by drying.
[008] WO 2010/029433 discloses capsules comprising at least one oily phase that comprises a fatty acid oil mixture and at least one surfactant in an alginate capsule formulation. It is mentioned that other polymers, e.g. gelatin, might be present in the capsule shell. The shell of the capsules of WO 2010/029433 is thinner compared to gelatin capsules, thereby allowing a larger amount of material to be encapsulated. Furthermore, it is stated that alginate capsules may offer several benefits over gelatin capsules with regard to temperature and humidity stability, decrease in gastrointestinal reflux symptoms, as well as no need for testing for bovine spongiform encephalopathy (BSE). However, the production of the capsules of WO 2010/029433 is disadvantageous as inter alia it requires large amounts of water to wash the capsules, in order to remove the excess CaCl2.
[009] Given the aforementioned drawbacks, the other technique used to delayed release capsules are by incorporating the use of delayed release agents/polymers during the process of preparation of the capsules. However, only using delayed release agents/polymers make the capsule water sensitive and/or brittle, thereby resulting in loss of the intended function. Thus, there is a need to develop a reliable, safe, and economic way to manufacture commercially sustainable capsule shells exhibiting delayed release properties.

SUMMARY OF THE INVENTION
[0010] In accordance with an embodiment of the present invention, disclosed is a composition for preparing delayed release capsules. The composition comprises at least one acid resistant polymer in an amount in the range of 1.0 to 50 %, at least one capsule film forming agent in an amount in the range of 1.0 to 80 wt%, at least one gelling agent in an amount in the range of 0.1 to 20 wt%, and at least one excipient in an amount in the range of 0.1 to 20 wt%. In accordance with another embodiment of the present invention, disclosed is a method for preparing delayed release capsules. The method comprises initially mixing pre-determined amounts of at least one acid resistant polymer and water to form an aqueous mixture. Further, at least one capsule film forming agent, at least one gelling agent and at least one excipient are added in pre-determined amounts to the aqueous mixture under stirring conditions to obtain the aqueous homogeneous film-forming composition. This aqueous homogeneous film-forming composition is then poured in a dipping dish and simultaneously suitable metal mold pins are maintained to attain a pre-determined temperature. These pins are then dipped in the aqueous homogeneous film-forming composition followed by withdrawing the dipped pins from the aqueous homogeneous film-forming composition at a predefined sequence of velocity and time such that a wet film has formed on the pins upon lifting from the composition. Then, the pins are subjected to stream of air of pre-determined temperature, relative humidity and velocity such that the wet film is gradually dried to obtain a capsule body and cap portions. The capsule body and cap portions are cut at required length and joined to obtain the delayed release capsule.

DETAILED DESCRIPTION OF THE INVENTION
[0011] The following is a detailed description of embodiments of the present disclosure. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.
[0012] Unless the context requires otherwise, throughout the specification which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense that is as “including, but not limited to.”
[0013] Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
[0014] As used in the description herein and throughout the claims that follow, the meaning of “a,” “an,” and “the” includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of “in” includes “in” and “on” unless the context clearly dictates otherwise.
[0015] In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable.
[0016] The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein.
[0017] All methods described herein can be performed in suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
[0018] The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
[0019] Various terms are used herein. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.
[0020] The present disclosure discloses delayed release capsules and a method for preparation thereof. In one aspect, the present disclosure discloses delayed release capsules. More particularly, the delayed release capsules have telescopically engaged body and cap portions. As used herein, the term "delayed release" means the time taken to disintegrate/ rupture capsule in 0.1M HCL solution to release the fill/ active ingredient at a time other than immediately after administration. The present disclosure provides delayed release capsules resistant to gastric fluid to a degree that is controllable and thereby capable of delivering the fill/ active ingredient in the stomach or in the intestine by regulating the dissolution of the shell according to a set pH, thereby protecting the active ingredient against low pH values for required period of time.
[0021] The term "capsules" means empty hard shell capsules (optionally containing medicament) each having telescopically engaged body and cap portions formed by a technique commonly known as the dip-molding technique.
[0022] The capsules of the present disclosure, have capsule body and cap portions formed by dip-molding using an aqueous homogeneous film-forming composition. The composition comprises at least one acid resistant polymer, at least one capsule film forming agent, at least one gelling agent and at least one excipient. The "aqueous composition" used herein indicates a composition in which the at least one acid resistant polymer, the capsule film forming agent, the gelling agent and one or more excipient are dissolved in water. The at least one acid resistant polymer is selected from the group consisting of, but not limited to sodium alginate, Potassium alginate, chitosan, Pectin etc. The acid resistant polymer is not easily dissolved in gastric juice having an acidic pH.
[0023] Alginates are naturally occurring high molecular weight polysaccharides derived from brown algae or extracts from the cell walls of phaeophyta. The chemical structure of alginates is a salt of alginic acid, which, in turn, consists of D-mannuronic and L-guluronic acids. Sodium alginate is formed by connecting by glycosidic link by beta-D-mannuronic acid (M district) and a-L-guluronic acid (G district). Alginic acid salts formed by monovalent cations (such as sodium, potassium, ammonium, etc.) are soluble in water.
[0024] Physical properties and the gel property of alginates depend on the relative composition of uronic acid residue and the distribution in three districts, because sodium alginate has good sol-gel characteristic, therefore be widely used in the various fields such as industry, agricultural, medicine, and demonstrate good application prospect. A characteristic feature of soluble alginates is their ability to form viscous solutions, which is why they are widely used in various industries as effective thickeners. Its mucoadhesive property can be utilized for the preparation of controlled drug-delivery systems in order to achieve an enhanced drug bioavailability.
[0025] Alginates are known for their acid resistant properties. In stomach it reacts with acids to form alginic acid which resists in the polymer hydrolysis or degradation. This is the reason alginates may be used as an encapsulant for drug which are desired to have slow release or enteric property.
[0026] Typically, the at least one capsule film forming agent is selected from the group consisting of, but not limited to, pullulan, gelatin, starch and a combination of pullulan and starch. Typically, the capsule film forming agent improves elasticity of the fragile film of the acid resistant capsule to improve capsule formability/ flexibility.
[0027] Pullulan (other name: 4,4,6-trigluco-polysaccharide) is a natural, viscous polysaccharide extracellularly produced by growing certain yeasts (fungus of Aureobasidium) on starch syrups. It has good film forming properties and a particularly low oxygen a moisture content at 50% RH of about 12%. Its existence was reported for the first time in 1938.
[0028] Chemically pullulans, is an a-glucan consisting mainly of maltotriose as repeating units linearly jointed through a-1,6-glycosidic linkages. The pullulan is usually obtained in the form of an amorphous white powder and is non-toxic, odorless, edible but is non-digestible.
[0029] Pullulan is a natural product of non-animal origin made without the need for chemical modification. The resulting films formed with pullulan have excellent homogeneity and transparency. In addition, such films have very low oxygen permeability. Such films and resulting capsules made from pullulan also have relatively low water content, and exhibit high stability over storage, such as with respect to mechanical and dissolution properties
[0030] Typically, the at least one gelling agent is selected from the group consisting of, but not limited to, gellan gum, carrageenan, agar, locust bean gum, xanthan gum, curdaline and any other polysaccharide having gelling ability along with its supportive co-gelling agent.
[0031] Typically, the amount of the at least one acid resistant polymer may be in the range of 1.0 to 50 % based on the total weight of the dry film composition.
[0032] The amount of the at least one capsule film forming agent may be in the range of 1.0 to 80 % based on the total weight of the dry film composition.
[0033] The amount of the at least one gelling agent along with co gelling agent may be in the range of 0.1 to 20 % based on the total weight of the dry film composition.
[0034] The amount of the at least one excipient may be in the range of 0.1 to 20 % based on the total weight of the dry film composition.
[0035] In an embodiment of the present disclosure, the at least excipient can be included in the composition as is common in the industry as long as they do not adversely affect the composition. The at least one excipient can be selected from the group of, but not limited to, emulsifier, plasticiser, opacifier, neutraliser, diluent, glidant, disintegrant, colouring agents, flavours, preservatives, opacifying agents, embrittlement inhibiting agents, disintegrants, buffers and the likes.
[0036] In an exemplary embodiment of the present disclosure, the composition comprises:
- Pullulan and/ or starch;
- Sodium alginate;
- Gellan Gum and/ or agar; and
- at least one or more excipient.
[0037] Sodium alginate helps in the acid resistance as they are highly dependent on the pH condition of the dissolution medium. In gastric fluids, at low pH, sodium alginate produces a gelled layer on the surface of the capsule which delays diffusion of the active ingredient. As pH conditions increase (e.g. in the intestine), sodium alginate rapidly dissolves.
[0038] In an exemplary embodiment of the present disclosure, the composition is prepared to form a capsule. Depending upon the requirements the composition may comprise further excipients necessary for the manufacture of the preferred dosage form and its breakdown following ingestion and may be chosen by those skilled in the art.
[0039] In another aspect of the present disclosure, disclosed is a method for preparing the delayed release capsules. The method comprises initially the following steps:
(i) mixing pre-determined amounts of at least one acid resistant polymer and water to form an aqueous mixture;
(ii) adding at least one capsule film forming agent or combination of film forming agents, at least one gelling agent and at least one excipient in pre-determined amounts to the aqueous mixture under stirring conditions to obtain the aqueous homogeneous film-forming composition;
(iii) pouring the aqueous homogeneous film-forming composition in a dipping dish and simultaneously maintaining suitable metal mold pins to attain a pre-determined temperature;
(iv) dipping the pre-conditioned pins in the aqueous homogeneous film-forming composition;
(v) withdrawing the dipped pins from the aqueous homogeneous film-forming composition at a predefined sequence of velocity and time such that a wet film has formed on the pins upon lifting from the composition.
(vi) subjecting the pins to a stream of air of pre defined temperature, relative humidity and velocity, such that the wet film is gradually dried to obtain a rigid capsule body and cap portions; and
(vii) cutting the capsule body and cap portions to required length to obtain the delayed release capsule.
[0040] Typically, the wall thickness of capsules produced by the dip-molding depends on the viscosity of the dipping solution. If a thin-walled capsule is desired more water is used, whereas if a thick-walled capsule is desired a more concentrated or viscous solution is used.
[0041] EXAMPLES:
A- Preparation of Acid resistant base:
500 gm of sodium alginate was dissolved in 2000 gm of hot water at 85 ? under constant stirring for 200 mins followed by settling. Further a vacuum was applied to obtain a bubble free solution which was stabilised at 65 ?.
B- Preparation of film forming base solution- Type-1
500 gm of a pharmaceutical grade Pullulan dry powder was dissolved in 2000 gm of hot water at 85 ? under constant stirring for 120 mins followed by settling. Further a vacuum was applied to obtain a bubble free solution which was stabilised at 65 ?.
C- Preparation of film forming base solution – Type-2
500 gm of food grade Tapioca starch dry powder was dissolved in 2000 gm of hot water at 85 ? under constant stirring for 175 mins followed by settling. Further a vacuum was applied to obtain a bubble free solution which was stabilised at 65 ?.
D- Dipping composition trials matrix
All the above solutions (A, B, C) were mixed at 65 ? under gentle stirring of 100 to 150 RPM with Marine propeller mixer as details given below. Quantities below are in percentage of dry basis for col 1,2,3 and on percentage of total of col 1 to 3 for col 4 to 8.
Trial no Acid resistant base Film forming base type-1 Film forming base type- 2 Gellan gum Na2CO3 EDTA Carrageenan KCL Solution conc
(1) (2) (3) (4) (5) (6) (7) (8)
1 20 80 - 2.5 0.4 0.8 - - 17.5
2 20 80 - 4.0 0.7 1.4 - - 15.5
3 20 70 10 3.5 0.6 1.2 - - 17.0
4 25 75 - 2.5 0.4 0.8 - - 16.0
5 25 75 - 3.0 0.5 1.0 - - 16.0
6 25 55 20 3.0 0.5 1.0 - - 16.5
7 25 75 - - - - 1.2 0.9 18.0
8 30 70 - 2.0 0.35 0.7 - - 16.5
9 30 70 - 3.0 0.5 1.0 - - 16.0
10 30 70 - 3.5 0.6 1.2 - - 16.0
11 30 60 10 3.0 0.5 1.0 - - 16.5
12 30 60 20 4.0 0.7 1.4 - - 17.0
13 30 70 - - - - 1.2 1.0 17.0
14 35 65 - 3.0 0.5 1.0 - - 16.0
15 35 65 - 3.5 0.6 1.2 - - 16.5
16 35 45 20 - - - 1.4 1.2 15.0
17 40 60 - 3.0 0.5 1.0 - - 16.0
18 40 60 - 4.0 0.7 1.4 - - 17.0

E- Capsule formation and evaluation
a. The solutions were made as per matrix allocated quantities.
b. Solution was measured for concentration by gravimetric method, viscosity on Brookfield viscometer, gelling ability by hand dipping cold pins, clarity and homogeneity of solution.
c. Capsules were manufactured on specially designed mini capsule making machine developed inhouse by ACG Associated Capsules Private Ltd. The capsules were evaluated for dimensions such as weight, length, top wall thickness, wall thickness and other surface defects. Only good capsules were considered for functional test such as disintegration test method at 0.1 M HCL solution and as defined in Brazilian pharmacopoeia. (compliance for 60 mins without rupture). The trial combinations where the capsule formation was not possible were discarded.
Solution Evaluation and test results
Trial no Solution concentration in % Viscosity in cps at 65 C Capsule forming ability Clarity and Homogeneity of solution.
1 17.47 1326 Not able to form Clear solution
2 15.88 1215 Yes- able to form Clear solution
3 17.05 1401 Yes- able to form Clear solution
4 16.12 806 Not able to form Clear solution
5 16.2 760 Yes- able to form Clear solution
6 16.32 800 Not able to form Clear solution
7 17.91 780 Yes- able to form Clear solution
8 16.26 532 Not able to form Clear solution
9 16.12 601 Yes- able to form Clear solution
10 16.25 650 Yes- able to form Clear solution
11 16.42 721 Not able to form Clear solution
12 17.12 690 Not able to form Clear solution
13 17.1 661 Yes- able to form Clear solution
14 16.11 597 Not able to form Clear solution
15 16.32 550 Yes- able to form Clear solution
16 15.04 490 Yes- able to form Clear solution
17 16.12 520 Not able to form Clear solution
18 17.31 635 Not able to form Clear solution

Capsule evaluation and test results (only for trials where good capsules can be formed)
Trial no Disintegration test results as per Brazil pharmacopeia.
4 Fail- one or more test capsules rupture before 60 mins
5 Pass- All test capsules did not rupture up to 60 mins
6 Fail- one or more test capsules rupture before 60 mins
8 Fail- one or more test capsules rupture before 60 mins
9 Pass- All test capsules did not rupture up to 60 mins
10 Pass- All test capsules did not rupture up to 60 mins
11 Fail- one or more test capsules rupture before 60 mins
12 Fail- one or more test capsules rupture before 60 mins
14 Fail- one or more test capsules rupture before 60 mins
15 Pass- All test capsules did not rupture up to 60 mins
17 Fail- one or more test capsules rupture before 60 mins
18 Fail- one or more test capsules rupture before 60 mins

The above results clearly demonstrates that few combinations confirms to pharmacopeial test criteria hence the composition can be confirmed as working.
[0042] While the foregoing description discloses various embodiments of the disclosure, other and further embodiments of the invention may be devised without departing from the basic scope of the disclosure.
,CLAIMS:1.) A composition for preparing delayed release capsules, comprising:
- at least one acid resistant polymer in an amount in the range of 1.0 to 50 % based on the total weight of the dry film composition;
- at least one capsule film forming agent in an amount in the range of 1.0 to 80 % based on the total weight of the dry film composition;
- at least one gelling agent in an amount in the range of 0.1 to 20 % based on the total weight of the dry film composition; and
- at least one excipient in an amount in the range of 0.1 to 20 wt% based on the total weight of the dry film composition.

2.) The composition as claimed in claim 1, wherein said at least one acid resistant polymer is selected from the group consisting of sodium alginate, Potassium alginate, chitosan and Pectin.
3.) The composition as claimed in claim 1, wherein said at least one capsule film forming agent is selected from the group consisting of pullulan, gelatin, starch and a combination of pullulan and starch.
4.) The composition as claimed in claim 1, wherein said at least one gelling agent is selected from the group consisting of gellan gum, carrageenan, agar, locust bean gum, xanthan gum and curdaline.
5.) The composition as claimed in claim 1, wherein said at least one excipient is selected from the group consisting of emulsifier, plasticiser, opacifier, neutraliser, diluent, glidant, disintegrant, colouring agent, flavour, preservative, opacifying agent, embrittlement inhibiting agent, disintegrant and buffer.
6.) The capsules as claimed in claim 1, wherein said capsules withstand disintegration test in 0.1M HCL solution maintained at 37 ? for at least 60 mins without disintegrating.
7.) A composition for preparing delayed release capsules comprising sodium alginate, combination of pullulan and tapioca starch, gellan gum, sodium bicarbonate, EDTA (Ethylene diamine tetra acetic acid) and at least one excipient.
8.) A method for preparing the delayed release capsules, said method comprises:
- mixing pre-determined amounts of at least one acid resistant polymer and water to form an aqueous mixture;
- adding at least one capsule forming agent, at least one gelling agent and at least one excipient in pre-determined amounts to the aqueous mixture under stirring conditions to obtain the aqueous homogeneous film-forming composition;
- pouring the aqueous homogeneous film-forming composition in a dipping dish and simultaneously maintaining the suitable metal mold pins to attain a pre-determined temperature;
- dipping the pre-conditioned pins in the aqueous homogeneous film-forming composition;
- withdrawing the dipped pins from the aqueous homogeneous film-forming composition at a predefined sequence of velocity and time such that a wet film has formed on the pins upon lifting from the composition;
- subjecting the pins to a stream of air of pre-defined temperature, relative humidity and velocity such that the wet film is gradually dried to obtain a capsule body and cap portions; and
- cutting the capsule body and cap portions to required length and telescopically joining to obtain the delayed release capsule.