Title:  Film forming compositions comprising modified starches and iota-carrageenan and methods for manufacturing soft capsules using same

United States Patent:  6,582,727

Issued:  June 24, 2003

Inventors:  Tanner; Keith Edward (Safety Harbor, FL); Getz; John J. (Delray Beach, FL); Burnett; Stephen W. (Clearwater, FL); Youngblood; Elizabeth (Valrico, FL); Draper; Peter Robert (LaSalle, CA)

Assignee:  R. P. Scherer Technologies, Inc. (Paradise Valley, NV)

Appl. No.:  008694

Filed:  November 8, 2001

Abstract

Disclosed herein are composition comprising a modified starch and a carrageenan, especially iota-carrageenan, where the compositions are suitable for use in manufacturing soft capsules.

SUMMARY OF THE INVENTION

The present invention provides compositions for manufacturing capsules, in particular, soft capsules, and especially soft capsules manufactured using the rotary die encapsulation apparatus. The invention provides compositions that do not employ mammalian gelatin and, therefore, overcome the disadvantages associated with collagen-derived material. Compositions of the invention do not contain any significant amounts of gelatin but, instead, require at least two (2) agents: 1) a modified starch having a hydration temperature below about 90^oC. and 2) iota-carrageenan.

As those skilled in the art of soft capsule manufacture will appreciate, the film formed on the drum of the encapsulation machine is called the "wet film". This film is used in the rotary encapsulation machine to form the filled capsules. The capsules are then dried using any number of techniques. During the drying process, water is removed from the fill material (when the fill material is hydrophilic) and the capsule shell. The result is a soft capsule with a "dry film". The dry film comprises the various components, i.e., carrageenan, plasticizer, modified starch and the like and "bound water". The bound water, from about 6 to 12% by weight of the dry film, is not easily removable using conventional drying techniques and is not considered when describing the components of the dried film as a percentage of the composition. The dried film numbers are calculated numbers based upon a assumed weight percent of the bound water.

Thus, for example, Table I sets out the components of the inventive film forming composition and representative weight percent ranges for the wet film and the dry film.

TABLE I

                        Prototypic Formula
        Component     Weight % of Wet Film Weight % of Dry Film
    Iota-carrageenan          6-12                12-24
     Modified starch         12-30                30-60
       Plasticizer            5-30                10-60
         Buffer             0.5-2                  1-4
      Preservative            0-0.2                0-0.4
 

As will be demonstrated in the Examples, one aspect of the present invention resides in the discovery that the weight ratio of the modified starch to the iota-carrageenan is crucial to forming a satisfactory film. The weight ratio of the modified starch to the iota-carrageenan is at least 1.5:1, with a preferred range being 1.5:1 to 4:1. Another feature useful in characterizing the inventive film is fusion pressure. The mixture of modified starch, iota-carrageenan and other components should result in a wet film that fuses at pressures above 207 kPa.

Thus, there is disclosed, a composition suitable for forming a film for encapsulating materials, the composition comprising a modified starch and iota-carrageenan in a ratio by weight of at least 1.5:1; said film capable of fusion under a pressure of at least about 207 kPa (30 psi). There is further disclosed a composition wherein the weight ratio of modified starch to iota-carrageenan ranges from 1.5:1 to 4:1, more preferably from 2:1 to 3:1. Further, the invention relates to a film forming composition that is capable of fusion, under pressure, in the range of 207 kPa to 2070 kPa (30 to 300 psi) and at temperatures in the range of from 25-80^oC. In a yet more preferred embodiment, the film according to the present invention has a melting temperature of from 2 to 25^oC., more preferably 3-15^oC. and most preferably 4-9^oC. above its fusion temperature.

More specifically, the compositions according to the invention (expressed as wet film) comprise from 5-50% by weight modified starch; more preferably 15-40% by weight and the preferred modified starch is hydroxypropylated acid modified corn starch. The invention is also most preferably a composition wherein iota-carrageenan comprises at least 6 and up to 12% by weight of the composition. The composition according to the present invention may also contain a plasticizer such as glycerin and the plasticizer may comprise up to 50% by weight of the composition, more preferably up to 30% by weight.

There is also disclosed a dried film composition for soft capsules, the composition consisting essentially of from 42-84% by weight gel formers comprising a mixture of iota-carrageenan and modified starch; a plasticizer; and a buffer.

There is further disclosed a composition suitable for forming a soft capsule, the composition comprising iota-carrageenan and at least one modified starch selected from the group consisting of hydroxypropylated tapioca starch, hydroxypropylated maize starch, acid thinned hydroxypropylated corn starch, potato starch, pregelatinized modified corn starches, and wherein said starch has a hydration temperature below about 90^oC. and wherein the weight ratio of modified starch to iota-carrageenan ranges from 1.5:1 to 4.0:1. The invention also relates to a soft capsule comprising a shell and a fill material wherein the shell is a film according to the present invention.

In general, the invention provides compositions that function effectively as replacements for the conventional mammalian gelatin based compositions. Thus, the compositions of the invention possess many of the desirable important characteristics of gelatin. The inventive compositions form films that are mechanically strong and exhibit elasticity sufficient to allow the film to stretch during filling (blow-molding). Thus, the invention films have dimensional stability, elasticity and strength adequate for use in a continuous process which requires their removal from a casting drum and subsequent transport to rotary dies. Unexpectedly, the fusion or sealing temperature is substantially less than the melting point of the inventive film. Thus, films formed from the compositions of the invention simultaneously fuse together during the filling and cutting portion of the rotary die process when subjected to sufficient pressure and elevated temperature.

An additional unexpected property of the films according to the invention is that sealing occurs at substantially lower pressures than those experienced with mammalian gelatin based compositions. For example, conventional mammalian gelatin based films seal at pressures of about 1,724 kPa (250 psi) whereas the new films according to the present invention seal at about 207 kpa, more preferably about 552 kPa (30-80 psi). This saves energy and reduces the wear experienced by the rotary die. Also, the inventive film, when dry, (the film contains about 6 to 12% by weight water) is durable and impermeable to hydrophobic liquids.

As used herein and in the claims, the term "fusion" is meant to mean the welding of two (2) films by the use of pressure so as to result in a bond that is not easily separated. The fusion of the two films during the rotary die process results in a seal that is adequate to hold the liquid fill of the soft capsule during its anticipated shelf life.

In a preferred embodiment, the invention provides compositions comprising at least one modified starch and iota-carrageenan in a ratio by weight in the range of 1.5:1 to 4:1; plasticizers; buffers and optionally preservatives. Such materials can be formed into films that have sufficient structure, elasticity and strength to be removed from a temperature-controlled casting surface. It has unexpectedly been found that a combination of carrageenan, especially iota-carrageenan, and at least one modified starch, forms films having characteristics that allow the film to be reversibly stretched during the capsule filling step. These compositions, as wet films, preferably comprise water, 6-12 weight % iota-carrageenan, 12-30 weight % modified starch, 5-30 weight % plasticizers, 0.5-2 weight % buffers and optionally 0-0.2 weight % preservatives.

In another embodiment, the invention provides films comprising water and a solids system. In the films of the present invention, the solids system comprises modified starch and iota-carrageenan. The films of the invention are capable of maintaining their form without being applied to a support; they do not lose their shape through splitting, lengthening, disintegration or otherwise by breakdown of the film when unsupported. However, the films may be stretched when pulled or compressed to a certain extent when an appropriate external force is applied.

As used herein and in the claims, the term "modified starch" includes such starches as hydroxypropylated starches, acid thinned starches and the like. The only native starch determined to be functional with iota-carrageenan in preparing the films according to the invention is potato starch, thereby the term "modified starch" is meant to include native, unmodified potato starch. In general, modified starches are products prepared by chemical treatment of starches, for example, acid treatment starches, enzyme treatment starches, oxidized starches, cross-bonding starches, and other starch derivatives. It is preferred that the modified starches be derivatized wherein side chains are modified with hydrophilic or hydrophobic groups to thereby form a more complicated structure with a strong interaction between side chains.

Through the diligent work of the inventors herein, they have determined that some starches are barely functional in their inventive compositions and include high amylose starches, native starches other than potato starch and cross-linked starches. Hydrogenated starch hydrolysates that have been used to promote the disintegration of the gelatin capsule would likewise not be useful in the present invention.

There are two characteristics that help characterize modified starches that are useful in the present invention and they are 1) hydration temperatures below about 90^oC. and 2) film forming capabilities. Through a careful study of numerous starches, it has been determined that the following starches are not useful in the present invention: tapioca dextrin, high amylose non-modified corn starch, modified waxy maize starch, non-granular starch, modified high amylose corn starch and pregelatinized rice flour.

There is further disclosed an edible, soft capsule which comprises:

a) a soft, dry shell which comprises:

(i) about 12-24 weight % iota-carrageenan;

(ii) about 30-60 weight % modified starch;

(iii) about 10-60 weight % plasticizer;

(iv) about 1-4 weight % sodium phosphate dibasic buffer system; and

wherein said shell encloses:

b) a soft capsule fill material.

In a further embodiment of the invention, there is disclosed a capsule wherein the plasticizer is comprised of glycerin or sorbitol or a mixture thereof and the modified starch is selected from modified corn starch, acid modified hydroxypropylated corn starch and hydroxypropylated acid modified tapioca starch.

Carrageenan has been known for decades as a useful food ingredient. While salt and sugar are rather simple food ingredients, technologically, carrageenans are rather complex and there are hundreds of different products available in the market called carrageenan with highly different price levels and functionalities. Carrageenan is obtained by aqueous extraction of natural strains of seaweeds of Gigartinaceae, Solieriaceae, Phyllophoraceae, and Hypneaceae, families of the class Rhodophyceae (red seaweeds). The three major forms of carrageenan are known as iota, kappa and lambda carrageenan. Lambda and kappa carrageenans do not typically occur together in the same plant, however, since the various species are harvested together, extraction yields a typical mixture of kappa and lambda with an average of around 70% kappa and 30% lambda. Euchema Spinosum is the seaweed source for production of iota-carrageenan either as an extract or as a processed Euchema seaweed. During the production of carrageenans, it is common that no sorting takes place before shipment of the seaweed to the carrageenan rendering facilities. Seaweeds are typically sold based on seaweed type and content of sand, salt, stones and humidity and not based on functional specifications. Thus, carrageenan manufacturers need to test each seaweed shipment to determine the quality of the extractable carrageenan in order to see if any processing adjustments are needed for obtaining the desired specifications. Carrageenans are available in the market place as standardized and non-standardized carrageenans. Standardization is done either by blending different pure carrageenan batches (cross-blending) or by blending one or more carrageenan batches with other ingredients such as salts (KCl, NaCl, and CaCl₂) and/or sugars (saccharose, dextrose, maltodextrins, lactose) in order to reach the desired specification. As used herein an in the claims, the recited weight percents for iota-carrageenan include the standardizing ingredient.

All carrageenans are water soluble gums having the common structural feature of being linear polysaccharides with a sugar backbone of alternating units consisting of galactose units linked by 1,3-.beta.-D-linkages, as well as 1,4-.alpha.-D-linkages. The fundamental properties of iota, kappa and lambda are a function of the number and position of the ester sulfate groups. Iota-carrageenan contains approximately 30% by weight 3,6 anhydro-D-galactose and 32% ester sulfate by weight. In contrast, kappa carrageenan contains more than 36% by weight 3,6 anhydro-D-galactose and 32% ester sulfate by weight. Molecular weight ranges from 100,000 to 500,000 Daltons. The gelling carrageenans (kappa and iota) contain an "internal" ring--the 3,6-anhydro ring. The presence of ester sulfate makes carrageenans negatively charged at all pH values and is responsible for carrageenans being highly reactive molecules. Commercially available carrageenans are typically not well defined chemical compounds. However, through careful quality control, relatively pure materials with specified properties are available commercially.

The gelling carrageenan types (kappa and iota) are biosynthesized by the living seaweed as a non-gelling precursor, which is then turned into the gelling form by the action of the enzyme, dekinkase, which catalyzes the formation of the 3,6-anhydroglacatose ring. As mentioned previously, iota-carrageenan is only produced from Euchema Spinosum and produces the strongest gels with calcium ions (Ca⁺⁺). The gels are very elastic and completely syneresis free at the normal concentrations for food application (i.e., 0.5 to 2% by weight). Although iota-carrageenan does not gel with Na+, diluted iota-carrageenan solutions will form thixotropic solutions also with Na+ as it acts as a stabilizing agent. In the best mode of the present invention, the Ca⁺⁺ content is kept to a minimum.

In iota-carrageenan, the 1,3- and 1,4- linked units are respectively D-galactose-4-sulfate and 3,6-anhydro-D-galactose-2-sulfate. However, some of the 3,6-anhydro-D-galactose-2-sulfate rings may be replaced by D-galactose-6-sulfate, which may reduce considerably the gelling power of the iota-carrageenan.

The iota-carrageenans useful in the composition according to the invention should conform to the specification laid down by the USA and European regulatory authorities. The iota-carrageenan should not be degraded and should conform to minimum viscosity standards, which correspond to a molecular weight of about 100K Daltons.

Syneresis is often measured on carrageenan gels to determine breaking force and characterize the iota from the kappa carrageenan. After breaking force has been measured, the gel is transferred to a petri dish and covered to avoid evaporation from the gels. After typically about four (4) hours, the amount of free water (the syneresis) is measured. A high value indicates a strong gelling kappa, whereas no syneresis indicates iota.

Table II sets out typical analytical patterns and values for iota-carrageenan.

TABLE II

    Typical Analytical Parameters and Values for Iota-carrageenan
      Parameter   Typical Values (Ca-iota) Typical Values (Na-iota)
    Gel strength  0-100 g/cm.sup.2 (1.5%           0
                       carrageenan)
         pH         7-10 (in 1.5% gel)            7-10
      Viscosity   10-30 cP (1.5% at 75.degree. C.)         10-30
      Chloride        0-1% (as KCl)                0-1%
       Calcium             2-6%                   0-0.5%
       Sodium            .about.1%                 3-5%
      Potassium            3-5%                    4-7%
 

Through extensive investigative efforts, the inventors have determined that iota-carrageenan alone does not produce an acceptable film and that the modified starches alone do not produce a useable film for encapsulation. Without being bound to any theory or mechanism, it is speculated that the iota-carrageenan and modified starches interact synergistically to provide films of sufficient strength and elasticity to be useful in the encapsulation process.

The films made from the compositions of the invention possess the desirable properties of the films made from gelatin and function as effective replacements for gelatin films in virtually all processes that employ aqueous-gelatin compositions for the production of soft capsules. Among those processes are rotary die encapsulation processes, reciprocating die encapsulation processes, concentric cylinder processes, and processes for film-enrobing tablets. The film-enrobing process is also a rotary die process, as described in U.S. Pat. No. 5,146,730, the disclosure of which is incorporated herein by reference in its entirety. Thus, the compositions of the present invention provide:

i) mechanically strong, elastic films that set on a temperature-controlled casting drum generally within from about 15 to about 60 seconds, preferably less than about 20 seconds;

ii) films that, when brought into contact with one another, fuse together at temperatures of from about 25-80^oC. and pressures of from about 207 to about 2070 kPa (30-300 psi);

iii) films that fuse (form seals in the rotary die process) at temperatures significantly below the melting point of the films; and

iv) strong, durable dried films.

Still other advantages of the inventive compositions include:

i) finished capsules are not prone to cross-linking or insolubilization due to interaction with materials such as aldehydes, phenols ketones, that may be present within the capsule fill or shell, or that are formed over time by oxidization; and

ii) finished capsules exhibit greater stability when exposed to elevated humidity and temperature than capsules made using gelatin.

The compositions of the present invention are capable of forming unsupported wet and/or dry films, i.e., the films do not require a support to maintain their shape and structure. Further, they do not disintegrate, tear or fracture unless some significant external force is applied. The compositions of the invention are formed into films by any of a variety of suitable methods. While casting or extruding onto a casting drum is preferred in connection with the rotary die process, other processes for forming films will be apparent to those skilled in the art.

Other components may also be incorporated into the compositions provided they do not alter the melting point/fusion point characteristics of the inventive film. Representative of these additional components include flavoring agents, opacifying agents, preservatives, embrittlement inhibiting agents, colorants and disintegrants. The inventive compositions are typically in the molten state when these components are added. Use of conventional pharmaceutical or food grade ingredients is acceptable.

As used herein and in the claims, the phrase "an amount of modified starch effective to form a structured film" means an amount of a modified starch sufficient to form a film or gel that does not flow, but has dimensional stability. More preferably, the phrase "effective to form a structured film" means an amount of a modified starch sufficient to form a dimensionally stable film having a thickness of at least about 0.01 inches.

The phrase "effective elasticizing amount" means an amount of iota-carrageenan sufficient to provide a starch based composition in the form of film with sufficient strength to be removed from a casting drug during rotary die processing and also sufficient elasticity to be deformed during the rotary die process when a fill material is presented between a pair of films of the composition (blow molded).

The phrase "fusion temperature" means the temperature at which two opposing films, in contact with each other, will blend at their contact interface to become one, indistinguishable and inseparable structure.

The weight ratio of modified starch to iota-carrageenan in this invention is at least 1.5:1, more preferably from about 1.5:1 to about 4:1, most preferably, from about 2:1 to about 3:1. Unexpectedly, the compositions of the invention possess the important characteristic of having a melting point temperature that is substantially higher than the fusion temperature. Preferably, the melting point temperature of a film according to the invention, is from about 3-15^oC., and more preferably from about 4 to 9^oC., above its fusion temperature.

While not being bound to any theory or mechanism, it is believed that the iota-carrageenan functions as an elasticizing agent. In other words, this elasticizing agent renders an otherwise in-elastic, modified starch film, elastic. Consequently, the films of the invention have a "memory" and are capable of returning substantially to their original size and shape after being subjected to a deforming force. For example, a film made from the starch/carrageenan compositions of the invention that is stretched along its length and/or width will substantially return to its original length over time.

As discussed previously, the modified starches useful in the present invention include those starches that have a hydration temperature below about 90^oC. Hydration temperatures for most starches are available in the literature, such as product data for commercially available starches. Where they are not available via the literature, such hydration temperatures may be readily determined employing techniques well know to those skilled in the art. Suitable starches also must be capable of forming an aqueous mixture with water at a concentration of at least from about 20 weight % to give a mixture having a viscosity below about 60,000 to 80,000 centipoise (cps) measured at a 10 sec-1 shear rate at the temperature at which starch hydration occurs.

Representative of the commercially available starches useful in the present invention include Pure Cote.TM. B760 and B790 (an acid-modified hydroxypropylated corn starch), Pure-Cote.TM. B793 (a pre-gelatinized modified corn starch), Pure-Cote.TM. B795 (a pre-gelatinized modified corn starch) and Pure-Set.TM. B965 (a flash-dried acid modified native corn dent starch), all available from the Grain Processing Corporation of Muscatine, Iowa. Other useful, commercially available, modified starches include C*AraTex.TM. 75701 (hydroxypropylated acid modified tapioca starch), available from Cerestar, Inc. of Hammond, Ind.; M250 and M180 (maltrins) and Pure-Dent.TM. B890 (modified corn starch) from Grain Processing Corporation; and Midsol Crisp (modified high amylose corn starch) from Midwest Grain, Inc. of Atkinson, Kans. The only native (unmodified) starch suitable for use herein is potato starch. Such a starch is available from Roquette as Potato Starch Supra Bacter.

The invention may include genetically (recombinantly) modified and hybridized starches. Genetically modified and hybridized starches include those that have been developed to alter the physical properties and/or the amylose/amylopectin ratios. The preferred starch is an acid hydrolyzed corn starch modified with 2-hydroxypropyl ether functional groups. This starch is identified by Chemical Abstracts Service Registry No.68584-86-1. This material is commercially available as PURE-COTE.TM. B760 and B790 from Grain Processing Corporation.

The iota-carrageenan is present in the inventive compositions in an amount that, in combination with starch, effectively causes the compositions to have the required gelatin-like functional properties. As discussed previously, as those skilled in the art will appreciate, the film has what is known as a wet shell composition and a dry shell composition. This results from the evaporation of water from the film during the manufacturing process of the soft capsule. Preferred amounts of iota-carrageenan range from about 6 to 12% by weight of the wet shell composition. More preferred amounts of iota-carrageenan range from about 7-12% by weight of the wet composition. Particularly preferred compositions contain from about 9-11 weight % of iota-carrageenan, based on the weight of the wet composition. Even more preferred compositions contain about 10 weight % of iota-carrageenan by weight of the wet composition.

As will be demonstrated in the Examples, not all members of the carrageenans family can be used herein. Standardized iota-carrageenans are preferred. A particular preferred standardized iota-carrageenan is commercial available from the FMC Corporation of Princeton, N.J., known as VISCARIN.RTM. SD389, standardized with 15% by weight dextrose. Other useful iota-carrageenans include a non-standardized iota-carrageenan from SKW BioSystems of Baupt, France known as XPU-HGI and a non-standardized iota-carrageenan from FMC.

In general, the film forming compositions may consist of the iota-carrageenan, at least one modified starch with the balance of the composition being water. However, preferred compositions of the invention include a plasticizer. Suitable plasticizers include the materials used for the same purpose in the manufacture of mammalian gelatin capsules. Representative plasticizers are any of a variety of polyhydric alcohols such as glycerin, sorbitol, propylene glycol, polyethylene glycol and the like. Other plasticizers include saccharides and polysaccharides. The saccharides and polysaccharides suitable for use herein may be produced by hydrolysis and/or hydrogenation of a simple or complex polysaccharides.

Where plasticizers are employed, they can be used in amounts of up to about 60% by weight of the dry shell composition or 30% of the wet shell composition. More preferred compositions contain from about 10 to 25% by weight, based on the weight of the wet shell composition and 30-50% by weight of the dry shell composition.

Also, the capsule forming composition, i.e., the shell mass composition, may optionally contain an embrittlement inhibiting composition. An example of embrittlement inhibiting compositions is a mixture of sorbitol and one or more sorbitans. See U.S. Pat. No. 4,780,316.

Optionally, the film forming composition may contain preservatives and stabilizers such as mixed parabens, ordinarily methyl or propyl parabens, in about a 4:1 ratio. The parabens may be incorporated in the compositions at levels of 0-0.2 weight % for the wet shell and 0-0.4 weight % for the dry shell. It should be noted that in the following Examples, preservatives were included in the experimental formulation to facilitate un-dried sample retention for later evaluations. Without preservatives, the retained wet ribbons would be spoiled by microbial growth in a day or two. On a commercial scale, preservatives would typically note be added to the film forming composition because the wet ribbon would be quickly processed through the encapsulation machines and then the dryers. The dried film does not support microbial growth.

It has been found by the inventors that the use of a buffer system in the inventive compositions is highly desirable. Any known buffer can be used with phosphate buffers being preferred. Controlling the pH of the melt and film is highly important as carrageenans are rapidly broken down in conditions of high temperature and acidity. As mentioned previously, the presence of Ca⁺⁺ ions should be kept to a minimum.

Soft capsules may be manufactured in accordance with conventional techniques as set forth in Ebert, W. R., "Soft elastic gelatin capsules: a unique dosage form", Pharmaceutical Tech., October 1977; Stanley, J. P., "Soft Gelatin Capsules", in The Theory and Practice of Industrial Pharmacy, 359-84 (Lea and Febiger ed. 1970); U.S. Pat. Nos. 1,970,396; 2,288,327; and 2,318,718.

The capsules made using the rotary die process, will typically have wet shell thicknesses varying from about 0.024 to 0.1778, preferably from about 0.0508 to 0.127 and more preferably from about 0.0508 to 0.0762 cm in thickness. The capsules of the invention may be manufactured in any desired shape using the above-mentioned rotary die process.

The fill materials for the soft capsules may be any of a wide variety of materials suitable for encapsulation using the rotary die apparatus. Among the types of materials that are suitable for encapsulation include oils, hydrophilic liquids and emulsions. The active components that may be contained within the oils and emulsions are hydrophobic and hydrophilic actives. Those skilled in the art are familiar with and will recognize suitable fill materials. These fill materials may contain cosmetics, foods including vitamins, liquids, semi-solids, suspensions, flavorings and pharmaceuticals. After filling, the capsules are typically dried according to conventional techniques, e.g., tray drying, using a drum dryer or other suitable drying methods.

Claim 1 of 22 Claims

We claim:

1. A dried film composition suitable for soft capsules the composition consisting essentially of from 42-84% by weight gel formers comprising a mixture of iota-carrageenan and modified starch; water; a plasticizer, aid a buffer, wherein said iota-carrageenan and said modified starch are at a weight ratio of at least 1.5:1.

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