WO2012028702A1

WO2012028702A1 - Hard capsules based on starch, and also dip-coating composition, dipping bath and process for preparing same

Info

Publication number: WO2012028702A1
Application number: PCT/EP2011/065163
Authority: WO
Inventors: Rolf Müller; Federico Innerebner
Original assignee: Innogel Ag
Priority date: 2010-09-02
Filing date: 2011-09-02
Publication date: 2012-03-08

Abstract

In a dipping process for producing hard starch capsules a dip-coating mixture is used which comprises an aqueous film-forming coating mixture for hard capsule manufacture that comprises > 70% by weight, more particularly > 80% by weight of starch, based on the dry mixture after removal of the plasticizer, with more than 50% by weight of the starch in the liquid phase being present in the form of granular starch particles. Additionally present are plasticizers at 15% - 60% by weight of the dry mixture, a thickener at 0% - 10% by weight of the dry mixture, after removal of the plasticizer, and water at 15% - 70% by weight of the overall mixture. For the production of the hard capsules, a dipping bath is provided which comprises said dip-coating mixture. At least one hard capsule pin is immersed into the dipping bath, and so a coating is formed on the hard capsule pin; the at least one hard capsule pin is removed from the dipping bath; the hard capsule pin is optionally rotated by at least 180°; the coating adhering to the hard capsule pin is solidified by an increase in the temperature of this coating during and/or after immersion, more particularly by more than 5°C, to give a hard capsule; the hard capsule, comprising destructured starch particles, is dried; and, finally, the hard capsule is removed from the hard capsule pin.

Description

Starch-based hard capsule and dip coating composition, dip and

Method for Producing the Same The present invention relates to hard-paste capsules and a dipping method for producing the same. Further, it relates to a dip coating composition and a dipping bath used in the dipping method.

State of the art

Hard capsules (also known as "capsules" or "two-piece capsules") are among the most widely used oral dosage forms, with some 370 billion hard capsules produced worldwide in 2007. For example, hard capsules are used to contain active pharmaceutical ingredients, dietary supplements and nutritional supplements consist of two parts, which are also referred to as body and cap, wherein the active ingredient is filled into the body and the capsule is capped in. Usually the shell of hard capsules consists mainly of gelatin, which is why the capsules also often referred to as hard gelatin capsules Although gelatine is used almost exclusively, it has many drawbacks: gelatine is a material of animal origin which has been the subject of concern and public criticism for the first time since the BSE crisis cher base searched. After the BSE crisis recurring misgivings arose in the environment of recurring meat scandals and there was a general increase in the trend towards vegetarian solutions. Furthermore, gelatin capsules are undesirable in vegetarians and unacceptable in vegans. In addition, since gelatin is largely derived from pig slaughter, gelatin capsules are unacceptable for consumers who require kosher or halal products.

The patent US Pat. No. 1,787,777 describes a method for producing gelatin hard capsules. In this case, so-called pins, dip plugs or docks are called, ie the Negative forms of the two pieces of hard capsules, immersed in a dip with a gelatine melt. After pulling out the pins, they are covered with a uniform layer of gelatin. Since the gelatin gels slightly below 40 ° C, this layer of gelatin melt solidifies due to cooling by the pins. In order for the gelatin melt to gel even with slight lowering of the temperature, the temperature of the melt will usually be slightly above the temperature of the sol-gel transition of gelatin. This is the tricky point in the production of hard capsules in the dipping process. The layer on the pin must be solidified as quickly as possible, so that the material does not flow down due to gravity and uneven wall thicknesses are obtained at different locations of the capsule. Such defective capsules are not useful because they break in the bottling machine. After removing the pins from the dipping bath and fixing the wall thickness by cooling, the moist hard capsules are dried on the pins at a temperature below the melting temperature of the gelatin gel, the dry capsule parts are cut and demoulded. During drying, if necessary, further solidification takes place.

Hard capsules based on vegetable materials can be produced, for example, from modified cellulose. EP 0 401 832 A2 describes the preparation of hard capsules based on modified cellulose instead of gelatin. The cellulose solution forms a reversible gel on the surface of hot pins. However, its strength is not sufficient, or the gel liquefies again on cooling. Thus, the requirements for the constancy of the wall thickness at different locations of the capsule can not be met. The solution of EP 0 401 832 A2 for solving this problem uses the pseudoplastic behavior of solutions of modified cellulose, ie the phenomenon that at low shear rate, the viscosity is greater than at high, so that the dimensional stability of the layer on the pin by a high viscosity , ie very slow flow, is supported. Basically, however, hard capsules made of modified cellulose have the disadvantage that cellulose derivatives as a raw material for hard capsule production generate a multiple of the cost of gelatin. Therefore, such hard capsules are only limitedly competitive. Another material for making hard capsules derived from vegetable sources is starch. Starch is a much cheaper raw material than gelatin. The patents US 4,738,724, US 4,539,060 and US 4,591,475 describe hard capsules consisting of amorphous thermoplastic starch, which can be produced by injection molding. However, such hard capsules are brittle and break under the high stresses in high speed automatic filling machines, so that this technology could not prevail.

Dipping processes for the preparation of starch hard capsules from aqueous starch solutions similar to the preparation of hard capsules from gelatin or HPMC (hydroxypropylmethylcellulose) are limited by the necessarily low starch and high water content of such solutions. Mixtures of completely destructurized or dissolved starch are already so viscous at typically 5% by weight of starch that carrying out dipping processes is no longer possible. The cause is the very high molecular weight of starch, which can amount to 100,000,000 g / mol. Also, starch solutions have no gelation process, which would solidify the starch solution adhering to the pins and easily control the wall thickness of the capsule.

By optionally hydrolyzing the starch used and thus reducing the molecular weight and dissolving the starch granules by boiling and / or shearing, solutions of starch at higher concentrations can also be obtained. However, the mechanical properties of the material are damaged and above all, no gelation in the starch layer can be obtained after pulling out the coated pins, but the solution is gradually solidified by cooling and slowly drying. Since this cooling process takes a period of minutes or even hours, flow processes take place as a result of gravitation, which leads to intolerable scattering of the wall thickness. Such a process for producing hard-paste capsules is described, for example, in US Pat. No. 7,374,780 B2. There, potato starch is dissolved by boiling at 140 ° C. Pins are immersed in this starch solution and the starch deposited on these pins is cooled in several steps starting at 65 ° C to a temperature of 15 ° C to solidify it to hard capsule shells. Complete destructuring of starch, such as occurs in US Pat. No. 7,374,780 B2, is obtained by heating starch in an aqueous medium, with increasing destructuring as the temperature increases. If the starch granules are mechanically stressed simultaneously by shear forces, a higher destructuring is obtained at the same temperature. If the crystallinity of the starch granules is substantially destroyed, even low shear forces, as occur, for example, in simple mixing and flow processes of starch mixtures in order to further increase the degree of destructuring and substantially destroy the swollen starch grains, and also significantly reduces the molecular weight of the starch macromolecules can be. The degree of destructuring can be divided into the following stages:

Stage 1: the crystallinity of the starch is partially destroyed; in the polarizing microscope, stage 1.1: at most 5% of the grains are no longer birefringent

Level 1.2: 5 - 10% of the grains no longer birefringent

Stage 1.3: 10 - 20% of the grains no longer birefringent

Level 1.4: 20 - 30% of the grains no longer birefringent

Level 1.5: 30 - 40% of the grains no longer birefringent

Stage 2: the crystallinity of the starch is substantially destroyed, in the polarizing microscope stage 2.1: 40-50% of the grains are no longer birefringent

Stage 2.2: 50 - 60% of the grains no longer birefringent

Level 2.3: 60 - 80% of grains no longer birefringent

Level 2.4: 80 - 100% of the grains no longer birefringent. Level 3: at most 5% of the grains are birefringent

Stage 3.1: and 1 - 10% of the grains have burst

Stage 3.2: and 10 - 20% of the grains have burst

Stage 3.3: and 20 - 30% of the grains have burst

Stage 3.4: and 30 - 50% of the grains have burst

Level 3.5: and 50 - 70% of the grains have burst

Level 3.6: and 70 - 100% of the grains have burst Thickened starch granules are characterized by the fact that the starch granules have cracks on the surface and / or the previously relatively smooth surface has been significantly deformed (for example "shriveled" surface) Starch grains as well as the fragments are still recognizable as entities.

Step 4: No birefringence is observed, the starch grains are substantially destroyed.

Stage 4.1: Fragments of starch grains are still present, the starch is mostly dissolved. Level 4.2: The strength is completely dissolved.

The term "destructurized starch" is not used uniformly in the art: "destructured starch" refers to a starch which has been destructured at most up to stage 4.1, ie the starch is at least partially present in the form of particles has been destructurized to the stage 4.2, according to the invention is called completely destructured starch Such a complete destructuring can be achieved, for example, by heating starch to at least 80 ° C.

All hard-paste capsules made from solutions of completely destructured starch have in common that the molecular weight of the starch has been significantly reduced and / or the starch particles have been substantially completely destroyed. Hard capsules according to the cited publication US Pat. No. 7,374,780 B2 therefore contain essentially only starch of the destructuring stage 4.2. The term hard capsule in the following both the hard capsule as a whole, d. H. the hard capsule shell plus content, as well as the hard capsule shell alone or their parts (cap and body) referred. This term is to be understood in the text mutatis mutandis.

Object of the present invention is to provide a simple and inexpensive to produce hard capsule with good mechanical properties. The starting materials of this hard capsule should be of vegetable origin and should not exceed the cost of gelatin. It should be possible to dispense with additives which are suspected to be harmful to health. Furthermore, the hard capsule with the standard immersion method should be produced. The preparation of the hard capsules should be done with rapid solidification of the film-forming starting mixture used, so that they have a uniform wall thickness. Furthermore, the film-forming mixture used to prepare the hard capsules should have a low water content, so that rapid drying of the hard capsules is possible.

Description of the invention

This object is achieved according to a first aspect of the present invention by a dipping method for producing a starch-based hard capsule. For this dipping process, an aqueous film-forming dip coating composition M (w) according to the invention is required which comprises the following constituents: a)> 70% by weight, in particular> 80% by weight, of the dry mixture M (t), after removal of the plasticizer, starch, wherein more than 50% by weight of the starch in the liquid phase is present as particles of granular starch,

b) 15-60% by weight of the dry blend M (t) plasticizer

c) 0 - 10 wt .-% of the dry mixture M (t), after subtracting the plasticizer, a Verdiktungsmittels, and

d) 15-70% by weight of the total mixture M (w) water.

The aqueous, film-forming dip coating composition or dip coating mixture M (w) according to the invention may also be referred to below as a mixture, starting mixture or starch mixture. These terms are to be understood in the text mutatis mutandis.

In a preferred embodiment, the particles of granular starch in the dip coating composition are destructured at most up to stage 2.2, with starch being characterized by destructuring of stage 2.2 in that 50-60% of the starch grains are no longer birefringent in the polarizing microscope.

The liquid phase of the dip coating composition includes water and plasticizer. Furthermore, an immersion bath is required for the dipping process, which contains the aqueous, film-forming dip coating mixture according to the invention. The dipping method according to the invention comprises the following steps:

Providing a dipping bath according to the invention,

Immerse at least one hard capsule pin in the dip so that a coating is formed on the hard capsule pin,

Removing the at least one hard capsule pin from the immersion bath,

if necessary turning the hard capsule pin by at least 180 °,

Solidifying the coating adhering to the hard capsule pin by means of gelatinization by raising the temperature of this coating during and / or after immersion, in particular by more than 5 ° C., to obtain a hard capsule,

Drying the hard capsule comprising particles of destructured starch, and

Remove the hard capsule from the hard capsule pin.

Before immersion, the at least one hard capsule pin is optionally greased. Due to the local temperature increase of the film-forming, aqueous starch mixture M (w) on the surface of the hot pin there is at least a partial destructuring, ie. H. triggered gelatinization of the granular starch, which immediately leads to solidification. As a result, subsequent flow processes in the solidified or at least partially gelatinized layer are rendered impossible, and thus hard capsules or hard capsule parts having a uniform layer thickness can be obtained. This is an advantage over the production of hard capsules from conventional starch blends, since solidification requires a period of minutes or even hours.

According to the invention, the molecular weight of the starch is not significantly impaired. As a result, particularly good mechanical properties of the fresh hard capsule and the dried hard capsule are possible. Furthermore, the heterogeneous structure of the material also contributes substantially to this, since the destructured particles of granular starch produced at the solidification temperature already have a certain strength and elasticity per se. which has an advantageous effect on the handling of the fresh hard capsules as well as on the dried hard capsules.

In the subclaims advantageous embodiments of the invention are included.

For good mechanical properties of the hard capsules, the molecular weight of the starch and its proportion in the starting mixture M (w), ie the aqueous, film-forming dip coating composition M (w), should be large enough. The initially contradictory combination of low viscosity required for the dipping process and high molecular weight of the starch is achieved according to the invention in that the mixture M (w) has starch in the form of particles of granular starch. Then, the viscosity of the mixture M (w) is determined primarily by the viscosity of water and plasticizer and is correspondingly deep. Thus, for example, a starch blend containing about 35% by weight of water and 65% by weight of total starch and 35% by weight of glycerin, based on the starch content, has a viscosity in the range required for the dipping process. A mixture of the same composition, but with the starch present in completely destructurized, dissolved or plasticized form prior to molding, would have a viscosity of at least 10,000 times greater than 10,000 Pas. If the starch mixture M (w) is heated, there is an increasing swelling and destructuring of the starch particles, whereby the particles absorb water, soften and swell and stick together. An agglomerate or conglomerate of particles is obtained, ie a heterogeneous structure consisting of a mixture of starch particles.

The solidification of the previously low-viscosity, pourable mixture M (w) to a viscoelastic, solid material, which can be characterized by a typical Fesfkörpereigenschaft, such as the modulus E, takes place almost simultaneously with the increase in temperature and arises from the fact that the liquid phase of Water and plasticizer disappears, ie diffused into the starch particles, within the starch particles by entanglements of macromolecules a network, ie a gel structure, is formed and the particles are glued together. The adhesion of the particles can optionally be further modified by the addition of a thickening agent. Solidification of the mixture M (w) is to be understood as primary solidification, with granular starch destructuring, ie phase transformation of the starch, and the properties of the mixture changing by orders of magnitude. This phase transformation manifests itself as gelation of the starch mixture M (w) into a solid film on the pins. For this purpose, no further gelling agents are needed except starch. After primary consolidation of the M (w) mixture, secondary solidification occurs upon drying, accompanied by a gradual change in material properties when the temperature of the primary solidified film of the hard capsule shell and / or its water content is reduced and / or by slow network formation the starch used, which is caused by retrogradation, ie crystallization of the starch macromolecules.

According to the invention, mixtures M (w) of starch with high starch contents can be processed into hard capsules by a simple dipping process. Compared with a mixture in which the same amount of starch is in dissolved form, lower viscosities of the mixture are obtained by orders of magnitude. The solidification of the mixture M (w) to an isotropic hard capsule material is achieved by an increase in temperature. It is advantageous that the molecular weight of the starch is not significantly impaired in the process according to the invention. Preferably, the quotient M _w 2 / M _w l> 0.3, more preferably> 0.4, more preferably> 0.5, even more preferably> 0.6, even more preferably> 0.7, more preferably> 0.8 where M _w l is the weight average molecular weight distribution of the starch used, ie the starch contained in the dip coating composition, and M _w 2 is the weight average molecular weight distribution of the starch in the hard capsule produced. It should be noted that the molecular weight of starch is very sensitive to mechanical stress. For example, the molecular weight of dissolved starch is already measurably reduced by merely shaking the solution.

The starch mixtures M (w) used according to the invention can be processed into hard capsules in almost the same way as is the case with gelatin dip processes. This is a particularly favorable condition to replace gelatin hard capsules, since the same equipment can be used. The procedural difference to gelatin hard capsules consists essentially in the fact that gelatin melts on cooling, while gelatin mixtures of the invention M (w) gel as a result of an increase in temperature. The fiction, contemporary hard capsules not only have the well-known quality of gelatin hard capsules, also the previous method is not expensive and the new technology requires no major investment. Rather, even the elaborate preparation of the gelatin melt away, or can be replaced by a simple mixing process.

Strength

In principle, any starches or mixtures thereof can be used with regard to the origin and the preparation. They can be used, for example, in the native state, as well as in the physically and / or chemically / enzymatically modified state.

With regard to the origin, root starches, such as, for example, potato starches or tapioca starches, are preferred because they have low gelatinization temperatures compared to starches of other origin and solidification or gelation of the starch mixture is therefore possible even at low temperatures. Particularly preferred is tapioca starch. Tapioca starch is colorless, tasteless, has a very good transparency and there are no known genetically modified variants of tapioca starch.

In a preferred embodiment, the strength is native, i. H. unmodified state used. This good properties can be obtained at low cost.

In a further preferred embodiment, substituted starches such as starch esters and starch ethers are used, such as, for example, hydroxypropylated or acetylated starches. These modifications lead to particularly high transparency and rapid disintegration of the hard capsules.

Alternatively, oxidized starches are used.

In a further preferred embodiment, crosslinked starches are used, in particular crosslinked starch esters and / or crosslinked starch ethers, for example starch phosphates and starch adipates. By increasing the molecular weight, which is accompanied by the crosslinking, improved mechanical properties are obtained and the starch granules are also mechanically stabilized as units, which is particularly advantageous for the process. because the contribution of the starch particles to the mechanical properties can be increased. In the case of highly crosslinked starches, the destructured starch grain practically forms a molecule of gigantic molecular weight and has a particularly high stability. In a further preferred embodiment, substituted tapioca starch is used, in particular crosslinked substituted tapioca starch, for example hydroxypropylated starch phosphate.

The preferred weight average molecular weight distribution M _w l of the starch used, ie the starch used, is at least 500,000 g / mol, more preferably at least 1,000,000 g / mol, even more preferably at least 2,500,000 g / mol, more preferably at least 3,000 .000 g / mol, more preferably at least 4,000,000 g / mol, even more preferably at least 5,000,000 g / mol, even more preferably at least 7,000,000 g / mol, most preferably at least 10,000,000 g / mol ,

The amylose content of the starches in% by weight is preferably <50, more preferably <40, even more preferably <35, more preferably <30, even more preferably <27, even more preferably <25, most preferably <20. At high amylose contents, the resulting Hard capsules in terms of gloss and transparency of inferior quality. In addition, their disintegration properties in aqueous medium worsen.

Furthermore, Waxy starches are preferred, in particular crosslinked and / or substituted Waxy starches. Waxy starches are beneficial in terms of transparency. The amylose content of the starches in wt .-% is preferably> 0, more preferably> 0.3, more preferably> 0.5, more preferably> 0.7, more preferably> 1, even more preferably> 2, most preferably> 3 Too low amylose levels may result in reduced flexibility of the hard capsules. Also preferred are starches having a gelatinization temperature <90 ° C, more preferably <80 ° C, even more preferably <75 ° C, even more preferably <70 ° C, even more preferably <67 ° C, most preferably <65 ° C. The gelatinization temperature is determined by DSC (differential thermal calorimetry) as the peak temperature during heating at 10 ° C / min of a starch / water mixture containing 65% by weight of water. As the gelatinization temperature decreases, the strengthening of the starch film on the pins becomes possible at lower temperatures, making the process both easier and faster. Further preferred are starches having a dextrose equivalent (DE) of <10, more preferably <1, even more preferably <0.7, even more preferably <0.5, even more preferably <0.2, even more preferably <0.1, very particularly preferably <0.05. The dextrose equivalent of a polysaccharide mixture refers to the percentage of reducing sugars in the dry matter. It corresponds to the amount of glucose (= dextrose), which would have the same reducing power per 100 g of dry matter. The DE value is a measure of how far the polymer degradation has occurred, so low DE products contain high levels of polysaccharides and low levels of low molecular weight sugars (oligosaccharides), while high DE value products are largely only consist of low molecular weight sugars. The dextrose equivalent is determined according to ISO standard 5377. As the DE value decreases, the strength and toughness of the hard capsule increases after solidification.

In a preferred embodiment of the invention, the starch content of the dry blend M (t), after deduction of the plasticizer (ie after mathematical subtraction of the plasticizer from the dry blend M (t), consisting of starch, plasticizer and any optional ingredients), is in wt. % at> 80, more preferably> 90, most preferably> 95.

Granular starch

The granular starch in the dip coating mixture M (w) is preferred with a destructuring to at most 2.2, more preferably to 2.1, even more preferably to 1.5, more preferably to 1.4, even more preferably to 1.3 more preferably used up to stage 1.2, more preferably up to stage 1.1, most preferably in the native, non-destructured state. With decreasing destructuring the viscosity of the mixture M (w) decreases, so that mixtures with a lower water content can be used advantageously. The granular starch is used according to the invention in the form of particles, these particles correspond in shape to the original starch granules or agglomerates thereof. Typical sizes of the starch granules in the non-swollen state are: 5-100 μηι for potato starch, 5-30 μιη for corn starch, 1-45 μηι for wheat starch, 4-35 μηι for tapioca starch, 1-30 μηι for rice starch. In a partial De structuring the original starch grains may have been changed in terms of geometry and size, in particular, the size of the destructuring significantly. As granular starch it is also possible to use mixtures of different granular starches. The proportion of the granular starch in the total starch portion of the mixture is preferably in% by weight, more preferably> 60, more preferably> 65, more preferably> 70, even more preferably> 75, even more preferably> 80, even more preferably> 85. very particularly preferably> 90. water

Water is important for the adjustment of the viscosity of the starch mixture M (w) and for the solidification of the hard capsules. The higher the water content, the lower the required temperature increase. On the other hand, a high water content reduces the strength of the fresh hard capsules and longer drying times are required because then more water must be removed from the hard capsule. With regard to the process costs, a low water content is advantageous.

The upper limit for the water content of the starch mixture M (w) in wt .-% is 70, preferably 65, more preferably 60, more preferably 50, more preferably 45, most preferably 40, while the lower limit of the water content of the starch mixture in wt %, Preferably 20, more preferably 25, even more preferably 28, most preferably 30. softener

In principle, all plasticizers listed in the state of the art for starch are suitable as plasticizers. A low plasticizer content leads to embrittlement of the hard capsules low humidities, while a high plasticizer content leads to poor high humidity properties.

Plasticizers can be used singly or in mixtures of different plasticizers. Preferably, polyols are used, such as glycerol, sorbitol, maltitol, erythritol, xylitol, mannitol, galactitol, tagatose, lactitol, maltulose, isomalt, maltol, etc., but also various sugars such as sucrose, maltose, trehalose, lactose, lactulose, galactose, Fructose, etc. as well as mono- and oligosaccharides. Glycerol is particularly preferred as a plasticizer. In addition to its plasticizer property, sucrose has the further advantage of improving the oxygen barrier properties of the hard capsule. Water is also a plasticizer for starch, but is not included in the plasticizers and taken into account separately.

The upper limit for the plasticizer content in% by weight of the dry mixture M (t) is 60, preferably 50, more preferably 45, even more preferably 43, even more preferably 41, most preferably 39, while the lower limit is in% by weight. preferably 15, more preferably 20, even more preferably 25, even more preferably 27, even more preferably 28 still more preferably 29, most preferably 30. In a preferred embodiment, plasticizers having a maximum melting temperature of the anhydrous plasticizer of 150 ° C, preferably 125 ° C, more preferably 1 10 ° C, more preferably 95 ° C, most preferably 70 ° C are used. The proportion of plasticizers in the total plasticizer content which fulfills this condition is in% by weight> 50, preferably> 70, particularly preferably> 80, with very particular preference> 90.

Optional components of the starch mixture Short-chain amylose The starch mixture may contain short-chain amylose. For example, this short-chain amylose can be obtained by the action of enzymes on the granular starch in the granular starch or applied to the granular starch by spraying the granular starch with dissolved short-chain amylose. This short-chain amylose may be supplied together with at least one of the starches used to make the film, or it may also be fed separately to the mixture, for example in the form of a short-chain starch or spray-dried short-chain starch solution, the short-chain spray-dried Starch may have other spray-dried starches than mixture. Preferably, the short chain amylose is present in and / or on the granular starch in non-crystalline form.

Short Chain Amylose (SCA) consists of substantially unbranched amyloses and is used in a preferred embodiment. The degree of branching (number of branches per monomer unit) of the short-chain amyloses is <0.01, preferably <0.005, more preferably <0.003, more preferably <0.001, even more preferably <0.0007, even more preferably <0.0004, even more preferably <0 , 0,001th Ideally, the short-chain amylose has a degree of branching of 0 or near zero, for example when obtained by complete debranching (for example by pullulanase). With decreasing degree of branching, the crystallizability of the short-chain amylose increases and thus also the network formation (under heterocrystallization with longer starch macromolecules), which causes the short-chain amylose. With increasing network formation improved properties of the hard capsules according to the invention are obtained, in particular higher moduli of elasticity at high humidities, whereby the hard capsules can be used in a wide range of climates with different humidities.

Short-chain amylose has a mean degree of polymerization (DPn: number average) of> 8 and <500. According to the invention, it is preferably <300, more preferably <100, even more preferably <70, even more preferably <50, most preferably <30. Furthermore, it is preferred according to the invention that the average degree of polymerization is> 10, particularly preferably> 12, more preferably> 14, very particularly preferably> 15. With decreasing average degree of polymerization DPn, the transparency of the hard capsules is improved since the heterocrystallites consisting of short-chain amylose and longer starch macromolecules with decreasing average degree of polymerization DPn of the short-chain amylose become smaller, whereby the light scattering is reduced. If the average degree of polymerization DPn is too low, crystallization is no longer possible. Short-chain amylose can be obtained, for example, by polymerization of glucose synthetically or by the action of enzymes (for example cc-amylase, β-amylase, isoamylase, pullulanase) from starch. Preferably, the proportion of short-chain amylose in the total starch content of the mixture in wt .-% <15, more preferably <10, more preferably <7.5, more preferably <5, more preferably <3, most preferably = 0.

thickener

A thickening agent may be added to the starch-containing mixture to adjust the viscosity of the mixture to a desired value, thus allowing optimization of the viscosity of the mixture for the dipping process. In addition, thickeners are advantageously used to weaken the bonds between the destructured starch particles in the solidified hard capsules in terms of accelerated decomposition behavior in an aqueous medium. The thickener may be in the form of particles, in swollen form or in dissolved form at the time of solidification of the mixture on the hard capsule pins. Suitable thickeners are in principle all hydrophilic substances and mixtures thereof which increase the viscosity, in particular hydrophilic polymers and preferably those from vegetable sources. Examples are hydrocolloids and gums such as galactomannans such as guar gum or locust bean gum; Cellulose derivatives; Pectins, especially rhamnogalacturonans and protopectins; dextrans; xanthan; zymosan; Seaweed hydrocolloids such as alginates, agar-agar, agarose, carrageenan and carrageenans; furcellaran; Lycopene hydrocolloids such as Lichenine and Isolichenine or hydrocolloids as exudates of wood such as tragacanth (Astragalus gum), karaya gum, gum arabic, kutira gum; inulin; Latex; chitin; chitosan; gellan; collagen; Gelatin; Casein. Dissolved starch can be used for the same functionality as the thickeners, but is not expected to be thickeners and treated separately.

Some of these thickeners, such as gelatin, carrageenan, gellan and pectin, are also known as gelling agents, but they gel on cooling rather than in the gel Heat. They do not contribute to the gelation during the solidification of the starch mixture according to the invention during the temperature increase and are also not used for this purpose.

In a preferred embodiment, the maximum amount of thickener in 5 wt .-%, based on the dry formulation M (t), after subtracting the plasticizer, 10, more preferably 5, more preferably 2.5, most preferably 1.

In a further preferred embodiment, the maximum proportion of carrageenans and carrageenans in% by weight, based on the dry formulation M (t), after removal of the plasticizer, is 7.5, more preferably 5, even more preferably 3, still more preferably 2, more preferably 1, even more preferably 0.5, even more preferably 0.1, even more preferably 0.01, most preferably 0. Owing to the high raw material costs and the suspected carcinogenicity, the proportion of carrageenan and carrageenans is kept as low as possible.

In a further preferred embodiment, the maximum content of gelatin in% by weight, based on the dry formulation M (t), after removal of the plasticizer, is 7.5, more preferably 5, even more preferably 3, even more preferably 2 more preferably 1, more preferably 0.5, most preferably 0. Because of the general gelatin problem, the proportion of gelatin is kept as low as possible.

Z0

In a further preferred embodiment, the maximum content of gellan in% by weight, based on the dry formulation M (t), after removal of the plasticizer, is 5, more preferably 2.5, more preferably 2, even more preferably 1.5, even more preferably 1, more preferably 0.5, even more preferably 0.2, most preferably 0. Owing to the high raw material costs, the Z5 content of gellan is kept as low as possible.

In a further preferred embodiment, the maximum fraction of pectin in% by weight, based on the dry formulation M (t), after removal of the plasticizer, is 5, more preferably 2.5, more preferably 2, even more preferably 1.5, even more preferably 1, more preferably 0.5, still 30 more preferably 0.2, most preferably 0. Owing to the high raw material costs and the problematic processability, the proportion of pectin is kept as low as possible. In a further preferred embodiment, the maximum fraction of cellulose derivatives in% by weight, based on the dry formulation M (t), after removal of the plasticizer, is 5, more preferably 2.5, even more preferably 1, even more preferably 0.5, most preferably 0. Owing to the high raw material costs and the segregation or precipitation of cellulose derivatives from the starch mixture at elevated temperatures, the proportion of cellulose derivatives is kept as low as possible.

In a particularly preferred embodiment, the dry formulation M (t) contains, after removal of the plasticizer, at most 5% by weight, more preferably at most 2.5, even more preferably at most 1% by weight, even more preferably at most 0.5% by weight. %, more preferably 0% by weight of thickeners selected from the group consisting of agar-agar, agarose, alginate, cellulose derivatives, carrageenan, carrageenans, pectin, gum arabic, xanthan and mixtures thereof. Most preferably, it contains substantially no carrageenan.

Dissolved starch

Dissolved starch can be used as well as the aforementioned thickening agents to increase the viscosity of the mixture M (w) and to modify the bond between the starch particles. Their use is optional since the adjustment of the viscosity suitable for the dipping process can also be obtained by a suitable increase in the temperature of the starch mixture, the granular starch increasing the viscosity due to swelling. However, since then the temperature of the starch mixture needs to be accurately adjusted and controlled, the process of using dissolved starch (or thickener) is simpler and therefore preferred.

Concerning the dissolved strength, the same statements apply to suitable strengths and preferred types as to the strength in general. However, the dissolved starch may also have a lower molecular weight than is generally preferred for the starch. In addition, it is preferred to use strong retrogradation-stabilized starches for the dissolved starch, for example highly substituted starches or highly branched dextrins, whereby the disintegration of the hard capsule in an aqueous medium can be accelerated. The dissolved starch differs from the granular starch in its state in the starch mixture, where it is present in dissolved form or in a predominantly destructured form, while the granular starch at this time is still predominantly non-destructured. Dissolved starch can be obtained, for example, by dissolving from amorphous, extruded starch, or it can be obtained from pregelatinized starch. According to the invention, the term "dissolved starch" is also understood to mean pregelatinized starch (such as roller-dried pregelatinized starch), even if it is present in undissolved form or only partially dissolved.Pegelatinized starch is preferably destructured at least up to stage 2.3, more preferably at least up to the stage 2.4, more preferably at least until stage 3.1, even more preferably at least until stage 3.3.

In a preferred embodiment, dissolved starch is destructured in the mixture at least to stage 2.3, more preferably at least to stage 2.4, even more preferably at least to stage 3.1, even more preferably at least to stage 3.3, even more preferably at least to stage 3.5 more preferably at least up to level 3.6, more preferably at least until stage 4.1, most preferably up to stage 4.2.

Furthermore, it is preferred according to the invention that the upper limit for the proportion of the dissolved starch, based on the anhydrous mixture M (t), after removal of the plasticizer, in wt.% Is 40, particularly preferably 30, more preferably 20, even more preferably 15 , more preferably 10, most preferably 5.

Other ingredients (additives and auxiliaries)

Further optional constituents of the starch mixture may be dyes and pigments and fillers, in particular mineral fillers, such as talc, or modifying substances, such as polyethylene glycols, or disintegrating agents, such as carbonates or bicarbonates, or additives, such as preservatives, antioxidants, or emulsifiers, such as For example, lecithins, mono-, di- and triglycerides of fatty acids, polyglycerol esters, polyethylene esters or sugar esters. In principle, all additives which are used in gelatin hard shell capsules, according to the invention are also used, in particular additives which are used to the hard capsule shell on the Ingredient to adapt (formulation adjuvants). Thickening agent and dissolved starch are not considered as additives or auxiliaries for the purposes of this invention.

Shaping and consolidation

The starch in the form of particles of granular starch is destructured during and / or after the dip of the pin in the starch mixture at the surface of the pin by a temperature increase, whereby a rapid solidification of the starch mixture is obtained on the pin.

Preferably, the upper limit for the dynamic viscosity of the mixture M (w) in the immersion process (ie the viscosity at the corresponding temperature) in Pas at 500, more preferably 300, more preferably 200, more preferably 150, even more preferably 120, more preferably 100, more preferably 70, most preferably 50. It is further preferred that the lower limit for the dynamic viscosity of the mixture before or during the forming in Pas at 0.01, more preferably 0.05, more preferably 0.1, still more preferably 0.5, very particularly preferably 1. The viscosities refer to a shear rate of 1.1 / s. High viscosities correlate with high wall thicknesses of the hard capsules drawn from the mixture and low viscosities with deep wall thicknesses.

Preferably, the upper limit for the temperature in ° C of the starch mixture M (w) in the immersion bath is 65, more preferably 60, more preferably 55, most preferably 50. High temperatures of the immersion bath are to be avoided so as not to a substantial destruction or destructuring of the starch granules comes. Furthermore, in a preferred embodiment, the lower limit for the temperature of the starch mixture M (w) in the dipping bath in ° C is -20, more preferably -10, more preferably 0, even more preferably 10, even more preferably 20, even more preferable at 30, more preferably at 35, most preferably at 40. Based on the temperature of the starch mix M (w) in the dip, the temperature of the starch mix M (w) on the surface of the hard capsule pins is increased to solidify them. Preferably, the lower limit for the temperature increase of the starch mixture in ° C to initiate the solidification at 10, more preferably 15, more preferably 20, still more preferably at 25, more preferably at 30, even more preferably at 35, most preferably at 40. Further, in a preferred embodiment, the upper limit of the temperature increase in ° C is 130, more preferably 110, even more preferably 90, more particularly preferably at 70. As the temperature increases, the solidification is accelerated and better mechanical properties are obtained since the starch particles are better bound together. The upper limit is given by the increasing or increasing bubble formation with increasing temperature.

The temperature increase of the starch mixture on the surface of the hard capsule pins is preferably achieved by immersing the pins with a temperature which is higher than the temperature of the starch mixture. The limits for the temperature increase, d. H. the lower limit and the upper limit for the temperature difference between the starch mixture and hard capsule, correspond to the limits of the temperature increase at the surface of the hard capsule pins.

Hereby, a uniform coating of the pin is achieved, which is at least so stable that it no longer flows after pulling out of the pins, so a uniform layer thickness is maintained. Then the capsules can be dried. Alternatively, however, a further destructuring of the strength of the mixture on the pin can be carried out after pulling out the pins. The temperature of the coating of the pin is increased to a temperature in ° C of <1 15, preferably <1 10, more preferably <105, while the lower limit for this temperature increase at a temperature> 50, preferably> 60, more preferably> 70, more preferably> 80, most preferably> 85 ° C. Advantageously, the water content in the starch layer in this further destructuring is in the same range as in the starch mixture in the dipping bath. This further destructuring leads to an improved homogeneity of the starch layer on the pins, since then the entire starch has the same degree of destructuring. In particular, the transparency and the mechanical properties (eg toughness) are improved.

Preferred embodiments for this further destructuring are z. As the application of hot steam, the application of hot air with a humidity of> 50% or immersing the coated pins in a bath, especially an oil bath. hard capsules

Starch-based hard capsules according to the invention comprise: a)> 70% by weight, in particular> 80% by weight, of the dry hard capsule, after removal of the plasticizer, starch,

b) 15-60% by weight of the dry hard capsule plasticizer,

c) 0-10% by weight of the dry hard capsule, after removal of the plasticizer, of a thickening agent,

d) 0, 1 - 50 wt .-% of the total hard capsule water, and

e) optionally conventional additives and auxiliaries, wherein the hard capsule has interconnected starch particles, in particular interconnected particles of destructured starch.

According to a preferred embodiment of the present invention, the starch-based hard capsules according to the invention are obtainable by the dipping method according to the invention using the likewise disclosed dipping bath with an aqueous, film-forming dip coating composition M (w) according to the invention. More preferably, they are obtained by the dipping method of the invention using the disclosed dipping bath with an aqueous film-forming dip coating composition M (w) according to the present invention. Preferably, the interconnected starch particles of the hard capsule form a matrix, wherein optionally further phases are included in this matrix. The proportion of the further phases in% by weight is preferably <30, more preferably <20, even more preferably <10, even more preferably <5, even more preferably <2.5, very particularly preferably <1.5. These starch particles in the hard capsules are destructured starch particles which have arisen from the granular starch during the gelation of the starch mixture M (w), whereupon there may still be destructured starch particles which, even before the gelation of the starch Starch mixture in this state and derived from the dissolved starch (with their degree of destructuring preferably at least equal to that of the granular starch).

The starch particles of the granular starch preferably still exist as individual starch particles, preferably with a mean diameter of at least 2 μm, more preferably of at least 4 μm, even more preferably of at least 6 μm. The starch particles formed from granular starch are preferably destructured at least up to stage 2.1, particularly preferably up to stage 2.2, more preferably up to stage 2.3, even more preferably up to stage 2.4, very particularly preferably up to stage 3.1. With increasing destructuring the handling of the fresh capsules as well as the mechanical and optical properties of the fresh and dried hard capsule are improved. On the other hand, the starch particles are preferably destructured at most up to stage 4.1, more preferably up to stage 3.6, even more preferred up to stage 3.5, even more preferred up to stage 3.4, even more preferred up to stage 3.3, most especially preferred up to stage 3.2. In order to achieve a very high destructuring, very high temperatures during solidification are necessary, which is technically complex to control, in particular the control of the water content and the formation of undesirable air bubbles. In addition, with very high destructuring, as the starch granules increasingly disintegrate, the positive contribution of the starch particles to the mechanical properties of the hard capsules decreases.

The granular starch is present in the starch mixture of the immersion bath in the form of solid, at most partially swollen particles, which are preferably destructured at most up to the stage 2.2. In the solidified starch mixture, ie in the hard capsule, this starch is present in the form of strongly swollen, destructured starch particles which are bound together, either directly by coupling surfaces of such particles or indirectly via an intermediate layer, this intermediate layer optionally a binder and / or or starch, in particular dissolved starch. The ratio of the average thickness of the intermediate layer divided by the mean diameter of the swollen particles is preferably <0.4, more preferably <0.2, more preferably <0.15, even more preferably <0.1, even more preferably <0.05. Ie. Preferably, the particles are densely packed, most preferably, the particles touch each other in a dense, in particular a densest pack (ie, a pack without gaps). The compound between the starch particles may optionally be improved by the dissolved starch between the particles or by another binder, but even without this measure a sufficient compound is obtained. The build up of the starch film or hard capsule as a dense agglomerate of particles is clearly expressed when the film or hard capsule is placed in water and agitated with a magnetic stirrer, e.g. At room temperature or at 70 ° C. The hard capsule decays, optionally (at room temperature) under the action of slight trituration, first in a fine uniform paste. If this mass is further diluted with water, it can be used to recover individual starch particles which, under the light microscope, can be identified as swollen particles of destructured starch due to their shape. From destructured starch granules, which can be recovered from the hard capsule, even the origin or type of starch used can be determined, since different strengths have different grain shapes and particle size distributions. To make the particles clear in the microscope, they are advantageously stained with an iodine solution (Lugol's solution). Another way to make the original starch particles visible again is to place a drop of the water-diluted mass on a slide instead of staining. After the water has evaporated, the starch particles can be identified by light microscopy. Due to the scrubbing of the swollen starch particles during drying, these particles have characteristic deformations and possibly cracks.

The preferred weight average molecular weight distribution M _w 2 of the starch (in the hard capsule produced) is, as well as the preferred weight average molecular weight distribution M _w l of the starch in the immersion bath, at least 500,000 g / mol, more preferably at least 1,000,000 g / mol, more preferably at least 2,500,000 g mol, even more preferably at least 3,000,000 g / mol, even more preferably at least 4,000,000 g / mol, even more preferably at least 5,000,000 g / mol, even more preferably at least 7,000 .000 g / mol, most preferably at least 10,000,000 g / mol.

With regard to the constituents of the hard capsule, the statements concerning the starch mixture used in the process apply, with the exception of the water content. The upper limit for the water content of the hard capsule according to the invention in wt .-% is preferably 40, more preferably 30, more preferably 25, more preferably 20, most preferably 17, while the lower limit of the water content of the hard capsule in wt % is preferably 1, more preferably 3, more preferably 5, most preferably 7. As the water content increases, the hard capsule loses its mechanical properties and in particular becomes too soft. As the water content gets lower, the hard capsule becomes too hard. Insoluble constituents of the starch mixture or of the hard capsule

The hard capsules produced are composed of particles of starch, which in a preferred embodiment are densely packed, resulting in advantageous properties for the processing and for the properties of the finished hard capsules. These particles of starch may, for. B. by dissolving the film at 70 ° C for 30 min of the soluble components (these are particularly plasticizer, soluble starch, optionally thickener) are separated and their quantitative proportion in the capsule material can thus be measured. Recovery Method No. 1

In a preferred embodiment, the minimum amount in weight percent of the starch in the hard capsule shell that can be recovered after dissolving the hard capsule at 70 ° C for 30 minutes is 30, preferably 40, more preferably 50, still more preferably 55 more preferably 60, more preferably 65, most preferably 70%.

Recovery Method No. 2

In a further preferred embodiment, the proportion of the mass which can be recovered after dissolving the hard capsule shell at 70 ° C. for 30 minutes and based on the mass of the dry film of the hard capsule is determined. The determination according to this definition is simpler than that according to recovery method no. 1, because it can be applied even if the composition of the hard capsule shell is not well known. The minimum percentage by weight of the mass that can be recovered is 25, preferably 35, more preferably 40, more preferably 45, most preferably 50. Advantages of the method according to the invention and the hard capsules according to the invention

Starch mixtures according to the invention which are suitable for the dip bath according to the invention are easy to prepare (invention: simple mixing process; gelatin: complex gel preparation). However, the dipping method per se is advantageously similar to the method for producing gelatin hard capsules, so that switching from the gelatin process to the process according to the invention is easily possible, but the solidification takes place by increasing the temperature and not by lowering the temperature as in the gelatin process. Fast solidification (as a result of gelatinization) results in high and competitive production rates. The solidified starch mixture is isotropic, as in the gelatin process. H. its properties are not directional.

The essential feature of the starch mixture used in the process according to the invention is that this mixture has starch in the form of particles, i. H. the mixture is a dispersion of the particles in an aqueous medium. This mixture is stable for a long time.

The raw material costs for the capsule preparation according to the invention are lower than in the production of gelatine hard capsules.

Hard capsules according to the invention also have good mechanical properties, in particular high elasticity and toughness. The hard capsules are composed of interconnected, densely packed, individual starch particles. These starch particles are in a swollen state and preferably in a dense packing.

Surprisingly, in view of the particulate structure of the starch, a hard capsule according to the invention has even better mechanical properties, for example a higher modulus of elasticity, than a hard capsule of the same composition prepared from dissolved starch (see the above-mentioned US Pat. No. 7,374,780 B2 ). One would have to first expect that the joints between the starch particles are weak points and therefore worse mechanical properties are to be expected. Since the particles of the hard capsule shell are densely packed, it has a high density. It is preferably in the range 1.07-1.3 g / cm.

When using starch mixtures which do not have the transparency-reducing additives, such as pigments, the starch mixture, which has starch particles and therefore is virtually completely non-transparent, becomes increasingly transparent as the solidification progresses. After completion of solidification, the hard capsule is then almost completely transparent. This means that a writing that can be read by a person at a distance can still be read by that person at the same distance when using a transparent film (about 0.5 mm thick) from the starch mixture is covered for the production of hard capsule, and the font size was increased by a maximum of 50%.

Hard capsules of the present invention are stable in a wide range of humidities and temperatures, while gelatin hard capsules become very soft at high humidities and melt at high temperatures. They have a lower oxygen permeability than gelatin hard capsules.

The good mechanical properties of the hard capsules according to the invention are a consequence of the structure of the capsule material as an agglomerate of densely packed, destructured starch granules, as well as a consequence of the high molecular weight of the starch which is made possible by the process according to the invention. The destructured starch granules have a certain strength and therefore contribute to the good mechanical properties of the hard capsule in a wide range of humidities.

Device for the production of hard capsules

The dipping method described for the preparation of hard-paste capsules is very similar to the process for producing gelatin hard capsules and HMPC hard capsules. When converting from gelatin to starch, while certain process parameters must be adjusted, there are no fundamental changes to the apparatus used, in particular, the efficiency of the dipping process is maintained, which can produce within 24 hours 50,000 and more hard capsules. For example, 5 bars with, for example, 30 pins simultaneously immersed in the viscous starch mixture and pulled out again and turned two and a half times about its longitudinal axis so that the viscous starch mixture evenly distributed on the immersion bodies. The rotation may optionally be reduced to one turn or even one-half turn (180 °) since the starch mix solidifies faster on the dip bodies than gelatin. The immersion bodies have a temperature which is above the temperature of the viscous starch mixture. For example, the immersion bodies may be actively heated, such as by resistance heating or induction, or they may be set to the desired temperature prior to immersion in a controlled temperature process zone. Subsequently, if necessary, a heat treatment. For this purpose, the device optionally has a process zone for carrying out a heat treatment, wherein after the first destructuring step a second destructuring step is carried out. Finally, the hard capsules are dried in a drying apparatus. Then the capsule blanks are removed from the pins, cut to the required length and two capsule halves put together, ie pre-sealed. In principle, therefore, the same systems which are used for the production of gelatin or HPMC hard capsules can also be used for the production of hard-paste capsules. The process for producing starch-based hard capsules is continuous in the same manner as the process for producing gelatin-based hard capsules, ie after a cycle commencing with the preparation of the immersion bodies (eg greasing) and with the Taking off the dried capsules ends, a new cycle begins.

It is advantageous in comparison to the process for the preparation of gelatine hard capsules that the step of producing the gelatin melt is omitted or can be replaced by the much simpler and quicker step of preparing the starch mixture. This starch mixture is obtained very simply by mixing the components with stirring, with usual simple stirrers being sufficient.

Brief description of the drawings

1 shows a photomicrograph of a hard capsule shell according to the invention based on granular, hydroxypropylated tapioca starch according to Example 1, which was worked up as follows to obtain the microscopic image: A section of the hard capsule shell was pressed flat between two slides and mixed with water to slightly separate the interconnected starch grains of the hard capsule film. In order to mix the water better in the sample material, the film was mechanically stressed by rubbing the slides together, whereby the starch grains were partially destroyed. The starch particles were stained with an iodine solution. The picture shows a section of the specimen with a width (long side of the picture) of 0.6 mm.

FIG. 2 shows a further light-microscopic image of a hard capsule shell according to the invention, analogously to FIG. 1. Here too, the sample material was worked up as described in FIG. 1 to obtain the microscopic image. However, the film was subjected to more mechanical stress, so that the starch granules separated even further and in some cases even more strongly destroyed. The picture shows a section of the specimen with a width (long side of the picture) of 0.6 mm. Examples

The present invention will now be described in more detail with reference to the following examples, but without limiting the objects of the present invention thereto. In all attempts to make hard capsules, completely transparent hard capsules of good quality were obtained, in particular they were dimensionally stable, easy to clean and to dry.

In all of the examples of the invention, microscopic analysis showed that the hard capsules were composed of densely packed, destructured starch granules (<5% birefringent starch granules) and the hard capsules could be redissolved in water in these components, i. H. After decay of the hard capsules, the destructured starch granules could be detected again in the water and their weight determined (recovery method no. 1).

The disintegration of the hard capsules was determined in a shaking bath at 37 ° C. in 0.5% strength hydrochloric acid on hard capsules which, after production, had been dried to about 10% water content and then stored for 20 days at 33% atmospheric humidity. example 1

13.6 g of an amorphous starch AI (obtained from a starch Gl (= granular hydroxypropylated tapioca starch (E No. 1442) with a water content of 12% by weight) by plasticizing and admixing 10% SCA (molecular dispersion in the plasticized starch Gl mixed in) with an average degree of polymerization DPn of 25, with a water content of 10.6% by weight and a particle size in the range 30-150 μmol) were stirred into 155.6 g of water and 76.5 g of glycerol at room temperature and stirred dissolved, resulting in a viscous solution. In this solution, 212.5 g of the starch was mixed by stirring. The viscosity of this intransparent mixture Ml was at 50 ° C at 7 Pas (1, 1 / s) and its water content at 39.8% by weight.

At a temperature of 50 ° C of the mixture Ml negatives of hard capsules (pins or Doken) were dipped with a temperature of 85 ° C and pulled out again after 2 seconds and rotated. In this case, a partially solidified, with respect to the gravity dimensionally stable layer of the mixture Ml was obtained on the negatives. Subsequently, the moldings were stored for 20 seconds at a temperature of 95 ° C and 100% humidity. The layer was completely transparent and the bars G1 were destructured to level 2.4 (light microscopic examination). Subsequently, the moldings were dried at room temperature and about 30% humidity, whereby dimensionally stable, pluggable hard capsule parts were obtained with a wall thickness of 0, 12 mm. When these hard capsules were placed in water, they disintegrated within minutes into a thin viscous mass consisting of starch granules destarched to level 2.4, as verified by microscopy.

Alternatively, after being withdrawn from the starch mix Ml, the shaped bodies were immersed in an oil bath having a temperature of 83 ° C for 5 seconds. This has achieved the same effect as heat treatment at 100% humidity and 95 ° C. Example 2

Example 1 was repeated but the temperature of the immersion bodies was 100 ° C and the immersion and extraction took 1 second. The same products were obtained as in Example 1.

Example 3 Example 1 was repeated, but 130 g of water were used, so that the water content of the mixture Ml was 36.3 wt .-%. The mixture Ml was heated to 58 ° C, with a viscosity of 15 Pas was measured. The same products were obtained as in Example 1. Example 4

Example 1 was repeated, but instead of the granular hydroxypropylated tapioca starch GI, a granular native tapioca starch G2 was stirred into the viscous premix. This mixture was heated to 65 ° C to give a viscosity of about 4 Pas. The immersion bodies were immersed at a temperature of about 100 ° C for about 2 seconds and pulled out again. The conditions of the steam heat treatment were the same as in Example 1, the temperature of the oil bath was 90 ° C. The same products were obtained as in Example 1. Example 5

Example 1 was repeated except that a suspension of an amorphous starch A2 (corresponding to Al, but having a particle size in the range 70-100 μm) containing 37% by weight of water and 30% by weight of glycerol, with a temperature of 5 ° C used. The immersion bodies had a temperature of 50 ° C. After coating the immersion bodies, the shaped bodies were no longer treated, stored for 5 minutes, then dried. The same hard capsules as in Example 1 were also obtained herewith. measurement methods

Dynamic viscosities were determined using a Brookfield Viscometer LVDV-I + at a shear rate of 1, 1 / s (5 rpm, Spindle 25) and the temperatures indicated.

Water contents were measured by drying over phosphorus pentoxide at 80 ° C for 48 hours.

The determination of the insoluble component in the film is carried out as follows: The dried hard capsules were previously stored at 57% atmospheric humidity for 2 months. A sample amount of 100-150 mg (dry mass MO) in the form of a piece of hard capsule shell film of 0.5 mm thickness is swollen and / or agitated at 70 ° C. with 7 g demineralized water in a test tube for 30 minutes with slow stirring with a magnetic stirrer solved. Thereafter, the test tube is centrifuged until the undissolved constituents have sedimented and the supernatant has become clear. The supernatant is then decanted. Then 7 g of demineralized water are added and stirred with the sediment, centrifuged again and then decanted. This process is repeated again to ensure that there are no more soluble constituents in the sediment. This sediment consists of a film consisting of starch and plasticizer, of undissolved starch. Finally, the sediment is dried for 48 h at 80 ° C over phosphorus pentoxide and determines the dry mass (Ml). The proportion of the mass, which can be recovered after the dissolution process, thus results in wt .-% to 100 ^χ M1 / M0. The amount of starch that can be recovered after the dissolution process results in a starch film consisting of starch and plasticizer, in wt .-% to 100 ^χ M1 / (M0 (1- (WM / 100)), where WM In general, the starch film in addition to the starch particles at most still minimal levels of insoluble constituents, such as pigments (typically <0.5%) or fillers such as titanium dioxide (typically <1.5%). Such components are optionally subtracted at the dry mass MO and the mass Ml.

Claims

claims

Aqueous, film-forming, dip-coating composition M (w) for hard capsule preparation, comprising the following constituents:

a)> 70 wt .-%, in particular> 80 wt .-%, of the dry mixture M (t), after removal of the plasticizer, starch, wherein more than 50 wt .-% of the starch in the liquid phase as particles of granular starch present

b) 15-60% by weight of the dry blend M (t) plasticizer

c) 0 - 10 wt .-% of the dry mixture M (t), after subtracting the plasticizer, a thickener, and

d) 15-70% by weight of the total M (w) water mixture.

A dip coating composition according to claim 1, wherein the granular starch is destructured at most up to the step 2.2, wherein a starch having a destructuring step 2.2 is characterized in that 50-60% of the starch granules are no longer birefringent in the polarizing microscope.

Dip coating mixture according to claim 1 or 2, wherein it contains not more than 5 wt .-%, in particular not more than 2.5 wt .-%, of the dry mixture M (t), after removal of the plasticizer, thickeners selected from the group consisting from agar-agar, agarose, alginate, cellulose derivatives, carrageenan, carrageenans, pectin, gum arabic, xanthan and mixtures thereof, and in particular contains substantially no carrageenan.

The dip coating composition of any one of claims 1 to 3, further comprising at least one adjuvant selected from the group consisting of dyes, pigments, fillers, modifiers, disintegrants, additives, antioxidants, emulsifiers, and formulation adjuvants.

Dipping bath containing a dip coating mixture according to one of claims 1 to A dipping method for producing a starch-based hard capsule, comprising the following steps:

Providing a dip bath according to claim 5,

Removing the at least one hard capsule pin from the immersion bath,

if necessary turning the hard capsule pin by at least 180 °,

Drying the hard capsule having particles of destructured starch, and

Remove the hard capsule from the hard capsule pin.

A method according to claim 6, wherein the immersion bath has a maximum temperature of 65 ° C.

A method according to claim 6 or 7, wherein the film-forming, aqueous mixture M (w) in the dipping bath has a dynamic viscosity of <500 Pas, measured at the temperature of the dipping bath and a shear rate of 1, 1 / s.

A process according to any one of claims 6 to 8, wherein the quotient M _w 2 / M _w l is> 0.3, wherein M _w l is the weight average molecular weight distribution of the starch used in the aqueous mixture M (w) and M _w 2 is the Weight average molecular weight distribution of the starch in the produced hard capsule is.

Starch-based hard capsule comprising

a)> 70% by weight, in particular> 80% by weight, of the dry hard capsule, after removal of the plasticizer, starch,

b) 15-60% by weight of the dry hard capsule plasticizer,

c) 0 - 10 wt .-% of the dry hard capsule, after subtracting the plasticizer, a thickener, and

d) 0.1-50% by weight of the total hard capsule of water,

wherein the hard capsule comprises interconnected particles of destructured starch. A starch-based hard capsule according to claim 10, wherein the interconnected particles of destructured starch are destructured at least up to stage 2.1 and at most to stage 4.1, wherein a starch having a destructuring stage 2.1 is characterized in that 40-50% of the starch grains in the polarizing microscope are no longer birefringent, and wherein a starch with a destructuring of the stage 4.1 is characterized in that there are still fragments of starch granules and the starch is largely dissolved.

Starch-based hard capsule according to claim 10 or 11, wherein the hard capsule comprises at least one additive or excipient selected from the group consisting of dyes, pigments, fillers, modifying substances, disintegrants, additives, antioxidants, emulsifiers and formulation auxiliaries.

A starch-based hard capsule according to any one of claims 10 to 12, wherein the hard capsule contains not more than 5% by weight, in particular not more than 2.5% by weight, of the dry hard capsule, after removal of the plasticizer, of thickeners selected from the group consisting of consisting of agar-agar, agarose, alginate, cellulose derivatives, carrageenan, carrageenans, pectin, gum arabic, xanthan and mixtures thereof, and in particular contains substantially no carrageenan.

A starch-based hard capsule according to any one of claims 10 to 13, wherein the hard capsule comprises a matrix of interconnected particles of destructured starch.

A starch-based hard capsule according to any one of claims 10 to 14, wherein the hard capsule shell has a starch content of at least 30%, which after dissolving the hard capsule at 70 ° C for 30 min in the form of particles and can be recovered by sedimentation.

A starch-based hard capsule according to any one of claims 10 to 15, wherein the dry hard capsule shell has a content of at least 25 wt .-% solids content, which can be recovered after dissolving the hard capsule at 70 ° C while by sedimentation.

17. A starch-based hard capsule according to any one of claims 10 to 16, wherein the weight-average molecular weight distribution M _w 2 of the starch in the hard capsule is at least 500,000 g / mol, in particular at least 1,000,000 g / mol.

18. A starch-based hard capsule according to any one of claims 10 to 17, obtainable by a process according to any one of claims 6 to 9.