Soft gelatin capsule and process for production

Abstract

The present invention relates to a soft gelatin capsule comprising a capsule shell and a filling encased by the capsule shell. The capsule shell comprises a low-viscosity gelatin having a viscosity of about 1.5 to about 2.4 mPa.s and a gel strength of about 150 to about 280 g Bloom, preferably of about 180 to about 250 g Bloom, in each case measured in a 6.67% gelatin solution at 60°C according to the GME monograph "Standardised Methods for the Testing of Edible Gelatine".

Description

[0001] Soft gelatin capsule and process for its manufacture

[0002] The present invention relates to a soft gelatin capsule comprising a capsule shell and a filling enclosed by the capsule shell.

[0003] The invention further relates to a process for producing soft gelatin capsules, as well as the use of a low-viscosity gelatin for producing soft gelatin capsules.

[0004] Soft gelatin capsules have long been a well-known dosage form for pharmaceutical products and dietary supplements. They are particularly suitable for encapsulating liquid or pasty fillings, enabling rapid absorption of the active ingredients after the capsule shell dissolves in the digestive tract. In addition to solutions or emulsions of active ingredients, hydrophobic liquids such as oils can also be administered using soft gelatin capsules.

[0005] Soft gelatin capsules are typically manufactured using the rotary die process. The surfaces of two gel strips, comprising gelatin, plasticizer, and water, are first melted superficially as they pass a filling wedge, pressed against each other, and thus bonded together. Due to thermal equilibrium with the environment, the melting zones solidify quickly, leading to the formation of a stable seam. Immediately after the melting of this first capsule side and the resulting first seam (leading seam), the filling process with the capsule filling begins. Immediately afterward, the second seam (following seam) is closed.

[0006] In particular, the fusion process of the subsequent seam can easily be disrupted under suboptimal process conditions, e.g., due to excessive restoring forces of the gel bands stretched by the capsule filling, or due to filling components getting between the gel bands. Such impairments of the seam formation, which can then at least occasionally lead to leaky seams (so-called leakers) between the capsule halves, are favored by factors such as high machine speed or a thinner gel band, which can, however, be desirable from an economic perspective.

[0007] The type of capsule filling can also influence the quality of the suture formation, with surface-active, pasty or particulate components of the filling, especially the adjuvants contained therein, being able to get between the gel bands and be enclosed in the suture.

[0008] Defective seams can lead to leaks in gelatin capsules immediately after production or during further packaging and / or storage. Even if only a few capsules are affected, this can lead to a deterioration in the quality of the entire batch.

[0009] The invention is therefore based on the object of proposing a soft gelatin capsule which can be produced with an improved seam formation so that the risk of leakage is reduced.

[0010] This object is achieved according to the invention in the gelatin soft capsule of the type mentioned at the outset in that the capsule shell comprises a low-viscosity gelatin which has a viscosity of approximately 1.5 to approximately 2.4 mPa-s and a gel strength of approximately 150 to approximately 280 g bloom, preferably approximately 180 to approximately 250 g bloom, in each case measured in a 6.67% gelatin solution at 60 °C according to the GME monograph "Standardised Methods for the Testing of Edible Gelatin".

[0011] In the context of the present invention, the term "low-viscosity gelatin" refers to the above-mentioned viscosity range of gelatin of approximately 1.5 to approximately 2.4 mPa-s, which is below the viscosity of typical gelatins for soft capsules according to the prior art (with viscosities of over approximately 2.5 to approximately 4 mPa-s). At the same time, the low-viscosity gelatin according to the invention exhibits typical gel strengths predominantly in the medium to high bloom range.

[0012] Viscosity and gel strength characterize essential physical and rheological properties of gelatin and influence both the processability of the gelatin gel in the production process for soft capsules and the properties of the resulting capsule shell. These two aspects can result in conflicting requirements for the optimal properties of the gelatin to be used. Within the scope of the invention, it was surprisingly discovered that a low-viscosity gelatin with the above-mentioned viscosity and bloom values ​​can be advantageously used in the production process for soft gelatin capsules and, at the same time, leads to soft gelatin capsules with improved seam formation. This advantage compared to standard gelatin can be demonstrated by the greater seam thickness and greater bursting force of the produced soft gelatin capsules.

[0013] While the reduced viscosity compared to typical gelatins improves the seam formation of the capsule shell, the viscosity in the range of approximately 1.5 to approximately 2.4 mPa-s (and with appropriate gel strength) is still sufficiently high to allow the gelatin gel to be processed in the production of the capsule shell using the rotary die process without problems (such as the risk of band tears).

[0014] On the other hand, such low-viscosity gelatins or gelatin mixtures, which also have a low gel strength (typically well below 150 g bloom), and which can be produced by suitable selection of parameters in the gelatin extraction process, are not suitable for the present invention, since they lead neither to a stable process during encapsulation using the rotary die process nor to soft gelatin capsules with sufficient physical stability. Surprisingly, it was also found that the soft capsules according to the invention require a significantly shorter drying time after encapsulation using the rotary die process than comparable soft capsules based on standard gelatin. The drying time required for the soft capsules according to the invention is sometimes shorter by a factor of about two, so that the production time can be significantly reduced by the invention.

[0015] The low-viscosity gelatin for the soft capsule according to the invention can be produced from known raw materials (typically cattle or pig skin or bones) using the acidic digestion process (type A gelatin) or the alkaline digestion process (type B gelatin). Depending on the raw material and digestion process, the following viscosity and bloom ranges are particularly preferred within the scope of the invention:

[0016] - a type A gelatin obtained from pig skin, which has a viscosity of approximately 1.5 to approximately 2.3 mPa-s and a gel strength of approximately 150 to approximately 240 g Bloom, preferably approximately 180 to approximately 220 g Bloom; or

[0017] - a type A gelatin obtained from bovine bones, which has a viscosity of approximately 1.6 to approximately 2.4 mPa-s and a gel strength of approximately 160 to approximately 260 g Bloom, preferably approximately 180 to approximately 230 g Bloom; or

[0018] - a type B gelatin obtained from bovine bones, which has a viscosity of approximately 1.6 to approximately 2.4 mPa-s and a gel strength of approximately 160 to approximately 260 g bloom, preferably approximately 190 to approximately 240 g bloom, more preferably approximately 205 to approximately 240 g bloom; or

[0019] - a type B gelatin obtained from bovine hide, having a viscosity of approximately 1.5 to approximately 2.3 mPa.s and a gel strength of approximately 160 to approximately 230 g bloom, preferably approximately 180 to approximately 220 g bloom, more preferably approximately 205 to approximately 220 g bloom; or - a mixture of two or more of the aforementioned gelatins.

[0020] The low-viscosity gelatin is preferably produced by partial enzymatic hydrolysis of one or more starting gelatins that exhibit a higher viscosity and higher gel strength than the low-viscosity gelatin. Enzymatic treatment of gelatin with suitable proteases or peptidases shifts the molecular weight distribution of the protein chains contained in the starting gelatin, which typically results in a reduction in viscosity and gel strength. By selecting the type and amount of enzyme and the hydrolysis conditions (e.g., reaction time, temperature, and pH), it is possible to specifically reduce the viscosity and gel strength of one or more starting gelatins to the above-mentioned target range for the low-viscosity gelatin.When using several starting gelatins for the enzymatic hydrolysis, these can in particular be different gelatin prints from the acidic or alkaline digestion of the collagen-containing raw material (such as skin or bone).

[0021] The partial enzymatic hydrolysis preferably comprises a treatment with one or more endopeptidases. The enzymatic treatment of gelatin with endopeptidases has been known in the art for some time. The endopeptidase is advantageously selected from collagenases, metalloproteases, serine proteases, cysteine ​​proteases, pepsin, trypsin, chymotrypsin, and elastase.

[0022] According to an alternative embodiment of the invention, the low-viscosity gelatin is produced by separating by microfiltration higher molecular weight fractions of one or more starting gelatins which have a higher viscosity and a higher gel strength than the low-viscosity gelatin.

[0023] The viscosity and in particular the gel strength of gelatin correlates to a certain extent with the average molecular weight. The low-viscosity gelatin according to the invention preferably has a weight-average molecular weight of approximately 45,000 to approximately 80,000 Da, with the molecular weight being determined in particular by gel permeation chromatography.

[0024] The low-viscosity gelatin preferably has a polydispersity of approximately 2.3 or less, more preferably from approximately 1.5 to approximately 2.3. As the quotient of the weight-average and number-average molecular weight (MW / MN), a low polydispersity correlates with a narrow molecular weight distribution of the protein chains in the gelatin. The polydispersity achievable with the low-viscosity gelatin depends in particular on the raw material and the gelatin digestion process. The low-viscosity gelatin preferably comprises

[0025] - a type A gelatin obtained from pig skin, which has a polydispersity of approximately 1.5 to approximately 1.9; or

[0026] - a type A gelatin obtained from bovine bones, which has a polydispersity of approximately 1.8 to approximately 2.3; or

[0027] - a type B gelatin obtained from bovine bones, which has a polydispersity of approximately 1.8 to approximately 2.3.

[0028] The corresponding starting gelatins from pig skin or cattle bones from which these low-viscosity gelatins are produced, in particular by means of partial enzymatic hydrolysis or microfiltration, regularly have a higher polydispersity, typically a polydispersity of approximately 3 or more.

[0029] In the case of type B gelatin obtained from bovine hide, the low-viscosity gelatin preferably has a polydispersity of approximately 4 to approximately 6. Starting gelatins from type B bovine hide typically have a significantly higher polydispersity of approximately 8 or more. With regard to the rheological properties of the low-viscosity gelatin, it is also advantageous if the proportion of gelatin with a molecular weight above 400,000 Da is as low as possible, and in particular less than approximately 1.5 wt.%. Gelatin fractions in this high molecular weight range are also referred to as microgels, which typically comprise cross-linked protein chains of alpha-collagen.According to the processes described above, this microgel can in particular be degraded enzymatically or separated by microfiltration in order to produce the low-viscosity gelatin for the soft capsule according to the invention from one or more starting gelatins which have a higher viscosity and a higher gel strength.

[0030] In the gelatin soft capsule according to the invention, the capsule shell preferably comprises a proportion of approximately 50 to approximately 75% by weight of gelatin, more preferably approximately 55 to approximately 70% by weight, in particular approximately 58 to approximately 67% by weight.

[0031] These figures are based on the dry substance of the gelatine, i.e. without the usual water content of gelatine of approximately 10 to 12% by weight.

[0032] In a further advantageous embodiment of the invention, the capsule shell further comprises a collagen hydrolysate with a weight-average molecular weight of approximately 1,500 Da or less, determined by gel permeation chromatography. Collagen hydrolysate itself does not exhibit gel formation due to its low molecular weight, but such an addition can further improve the processability and seam formation of the gelatin soft capsule according to the invention. The capsule shell preferably comprises the collagen hydrolysate in a proportion of approximately 1 to approximately 8 wt.%.

[0033] A further advantage resulting from the addition of collagen hydrolysate is reduced cross-linking of the gelatin during storage of the soft gelatin capsule. Such cross-linking is undesirable because it negatively affects the dissolution behavior of the capsule shell. Alternatively or in addition to collagen hydrolysate, the capsule shell can advantageously also contain one or more free amino acids, preferably in a proportion of up to approximately 8 wt.%. The addition of amino acids, such as glycine, also counteracts the undesirable cross-linking of the gelatin.

[0034] Typically, the capsule shell further comprises one or more plasticizers, preferably in a proportion of about 20 to about 40% by weight, more preferably about 23 to about 34% by weight, based on the dry substance of the plasticizer(s).

[0035] The plasticizer(s) are preferably selected from sugar alcohols and non-reducing sugars, in particular from glycerol, sorbitol, sorbitan, mannitol, maltitol, isomalt, isomaltulose, trehalose and sucrose.

[0036] The capsule shell of the soft capsule according to the invention preferably has a water content of approximately 6 to approximately 14% by weight.

[0037] The capsule shell may further comprise one or more dyes, preferably in a proportion of up to 6% by weight.

[0038] The capsule shell may further comprise one or more flavorings, preferably in a proportion of up to 6% by weight.

[0039] The capsule shell may further comprise one or more sweeteners, preferably in a proportion of up to 10% by weight.

[0040] The capsule shell of the gelatin soft capsule according to the invention is preferably made from a gel-like shell formulation comprising

[0041] - approximately 35 to approximately 50% by weight of the low-viscosity gelatin, based on its dry matter; - approximately 15 to approximately 25% by weight of one or more plasticizers, based on their dry matter;

[0042] - approx. 25 to approx. 50 wt.% water;

[0043] - optionally up to approximately 3% by weight of one or more dyes;

[0044] - optionally up to approximately 3% by weight of one or more flavoring substances; and

[0045] - optionally up to approximately 10% by weight of one or more sweeteners.

[0046] In particular, the soft gelatin capsule is manufactured using the rotary die process from two strips of gel-like shell formulation. It has been shown that such a shell formulation based on low-viscosity gelatin exhibits excellent properties for this manufacturing process and simultaneously results in a soft gelatin capsule with improved seam formation.

[0047] The capsule shell of the soft gelatin capsule according to the invention preferably has a wall thickness of approximately 100 to approximately 600 μm, more preferably approximately 150 to approximately 550 μm, in particular approximately 200 to approximately 500 μm. The wall thickness of the capsule shell can be influenced by the composition of the gel-like shell formulation and / or by the process parameters.

[0048] The filling enclosed by the capsule shell of the soft gelatin capsule according to the invention can be in the form of a solution, a suspension, an emulsion, or a pasty filling. The filling can be either hydrophilic, e.g., comprising a polyethylene glycol-based solution or suspension, or lipophilic or hydrophobic, e.g., comprising an oil or an oily emulsion.

[0049] The filling of the soft gelatin capsule according to the invention can comprise one or more pharmaceutically active ingredients for administration as a medicament, or one or more nutraceutical ingredients for administration as a dietary supplement. In addition to the active ingredients, the filling typically comprises one or more adjuvants. The invention is further based on the object of proposing a process for producing soft gelatin capsules with improved seam formation.

[0050] This object is achieved according to the invention by a method comprising the steps: a) providing a gel-like shell formulation comprising

[0051] - approximately 35 to approximately 50% by weight of a low-viscosity gelatin, based on its dry substance, which has a viscosity of approximately 1.5 to approximately 2.4 mPa-s and a gel strength of approximately 150 to approximately 280 g bloom, preferably approximately 180 to approximately 250 g bloom, in each case measured in a 6.67% gelatin solution at 60 °C according to the GME monograph "Standardised Methods for the Testing of Edible Gelatin";

[0052] - approx. 15 to approx. 25 wt.% of one or more plasticizers, based on their dry substance;

[0053] - approx. 25 to approx. 50 wt.% water;

[0054] - optionally up to approximately 3% by weight of one or more dyes;

[0055] - optionally up to approximately 3% by weight of one or more flavoring substances; and

[0056] - optionally up to approximately 10% by weight of one or more sweeteners, b) providing a capsule filling, and c) producing the gelatin soft capsules by enclosing the capsule filling with a capsule shell formed from the shell formulation.

[0057] The production of the gelatin soft capsules in step c) is preferably carried out by means of the rotary die process from two material strips of the gel-like shell formulation.

[0058] Particular advantages and further preferred embodiments of the process according to the invention have already been explained in connection with the soft gelatin capsule according to the invention.

[0059] A further aspect of the invention relates to the use of a low-viscosity gelatin for producing soft gelatin capsules, wherein the gelatin has a viscosity of approximately 1.5 to approximately 2.4 mPa-s and a gel strength of approximately 150 to approximately 280 g bloom, preferably approximately 180 to approximately 250 g bloom, each measured in a 6.67% gelatin solution at 60 °C according to the GME monograph "Standardized Methods for the Testing of Edible Gelatin"

[0060] These and other advantages of the invention are explained in more detail with reference to the following exemplary embodiments, which in no way limit the scope of protection.

[0061] The figures show:

[0062] Fig. 1 : Photographic representation of the wall cross-section of a soft gelatin capsule according to the invention; and

[0063] Fig. 2: Photographic representation of the wall cross-section of a gelatin soft capsule according to the prior art.

[0064] Examples

[0065] 1. Production of low-viscosity gelatins

[0066] The production of a low-viscosity gelatin for the capsule shell of a soft gelatin capsule according to the invention by means of partial enzymatic hydrolysis can be carried out, for example, according to the following protocols:

[0067] 1.1 Gelatin Type B from bovine bones

[0068] The starting gelatin used is a commercially available gelatin (type B from bovine bone) with a standard viscosity of 5.5 mPa-s and a gel strength of 288 g Bloom. 50 liters of a 20 wt.% aqueous solution of this gelatin (10 kg initial weight, 18% dry matter) are heated to 55 °C with moderate stirring (quickly, but without introducing air) and the pH is adjusted to 5.7. The kinematic starting viscosity of this gelatin solution at 55 °C is 140 mPa-s. A total of

[0069] 4.8 ml of a 40% solution of the enzyme bacillus lolysin (840 UHb / g), a bacterial metalloprotease (endopeptidase), was added in three steps of 1.6 ml each during the first 20 minutes. After one hour, the kinematic viscosity of the solution was 21.7 mPa-s, which corresponds to the desired standard viscosity of the partially hydrolyzed gelatin.

[0070] The protease is deactivated by briefly heating to 80 °C, the solution is gelled by cooling, and the gelatin is then dried. The standard viscosity of the resulting gelatin (in a 6.67% solution at 60 °C) is 2.1 mPa-s and the gel strength is 236 g Bloom.

[0071] 1.2 Gelatin Type A from pig skin

[0072] The starting gelatin used is a commercially available gelatin (Type A from pig skin) with a standard viscosity of 3.2 mPa-s and a gel strength of 300 g Bloom. 25 liters of a 30 wt.% aqueous solution of this gelatin (initial weight 7.5 kg, dry matter 27.5%) are heated to 55 °C with moderate stirring (quickly, but without introducing air), and the pH is adjusted to 5.7. The kinematic starting viscosity of this gelatin solution at 55 °C is 530 mPa-s.

[0073] After adding 410 μl of an enzyme solution (Endopeptidase COROLASE® 7089) and a reaction time of 115 min, the kinematic viscosity of the solution is approximately 82 mPa s, corresponding to a standard viscosity of the gelatin contained (in a 6.67% solution at 60°C) of 1.8 mPa s. The gel strength of the produced gelatin is 191 g Bloom.

[0074] 1.3 to 1.9 Other low-viscosity gelatins

[0075] In general, this process of partial enzymatic hydrolysis enables the production of low-viscosity gelatins from various types of starting gelatins with moderate bloom loss. To determine the required reaction time for a given amount of a specific enzyme, the kinematic viscosity of the gelatin solution can be measured during enzymatic hydrolysis, as described in the example above, until it corresponds to the desired standard viscosity of the gelatin, i.e., a viscosity of approximately 1.5 to approximately 2.4 mPa-s. Based on these results, the amount of enzyme can also be varied and, if necessary, adjusted to an optimal value in order to achieve the target gelatin viscosity within a given reaction time of, for example, 30 minutes.

[0076] In parallel to the viscosity reduction by partial enzymatic hydrolysis, the gel strength is also reduced, and it has been shown that the desired gel strength of the low-viscosity gelatin in the range of approximately 150 to approximately 280 g bloom can be easily achieved using the procedure described.

[0077] Table 1 below shows the starting and final values ​​of the standard viscosity and gel strength for Examples 1.1 and 1.2 above, as well as for a number of other low-viscosity gelatins that can be obtained by partial enzymatic hydrolysis. The gelatin type, weight-average molecular weight (MW), and polydispersity (MW / MN) are also given. The Type B gelatins are each obtained from bovine bone, while the Type A gelatins are obtained from pig skin (Ex. 1.2) and bovine bone (Ex. 1.3).

[0078] Table 1

[0079] The weight-average molecular weight of the gelatins is determined by gel permeation chromatography using a TSK 4000 SWXL column (Tosoh Bioscience GmbH) and a phosphate buffer containing 1% SDS at pH 5.3. A reference gelatin is used for calibration. The protein content in the eluent is measured using a UV detector at a wavelength of 210 nm.

[0080] In contrast to the enzymatically treated gelatins of Table 1, other low-viscosity gelatins, which also have a low gel strength (typically well below 150 g Bloom), and which can be produced by suitable selection of parameters in the gelatin extraction process, are not suitable for the production of gelatin soft capsules according to the invention.

[0081] 2. Composition of the capsule shell

[0082] The production of the gelatin soft capsule according to the invention takes place from a gel-like shell formulation which, in addition to the low-viscosity gelatin, essentially comprises water and preferably one or more plasticizers.

[0083] Example capsule shell compositions resulting from shell formulations with different plasticizers are shown in Table 2 below. This represents the quantitative composition after the drying process, during which the water content of the shell formulation is reduced from approximately 25 to approximately 50 wt.% to approximately 6 to approximately 10 wt.% of the capsule shell. All data are in percent by weight and refer to the dry mass of the gelatin and plasticizer. Table 2

[0084] 3. Production of gelatin soft capsules on a laboratory scale

[0085] The production of the soft gelatin capsules according to the invention is typically carried out using the known rotary die process. To investigate the seam formation properties, various soft capsules were produced on a laboratory scale from shell formulations based on the low-viscosity gelatins according to Examples 1.1, 1.2, or 1.3 above, and on standard soft capsule gelatins (a bovine bone gelatin type B with a viscosity of 3.3 mPa-s and 159 g Bloom, or a pigskin gelatin type A with a viscosity of 2.7 mPa-s and 198 g Bloom). Equal parts of glycerol and a mixture of sorbitol and sorbitan (ratio 60:40) were used as plasticizers. The composition of the capsule shell after drying corresponded to Example 2.7 above.

[0086] During the production of capsules from these shell formulations according to the standardized process, the machine rotation speeds were also varied (2.0 rpm and 3.5 rpm) and the temperature of the filling wedge was varied between 38.5 °C and 43.5 °C. After changing the rotation speed, the thickness of the gel ribbon was readjusted to 700 pm by opening the spreader box gap.

[0087] After complete drying in the tumble and / or tray dryer, the capsules were examined for their seam thickness and bursting force.

[0088] 4. Measurement of seam thickness and bursting force

[0089] When manufacturing gelatin soft capsules from two gel bands, as described above, a leading seam is first formed, followed by a follow-up seam after the capsule filling has been inserted. Due to the inherent design principle, the follow-up seam is always the weaker of these two seams, so the thickness of the follow-up seam was measured and compared as a key parameter for the gelatin's seam formation properties.

[0090] To measure the seam thickness, the dried capsules are divided into two approximately equal halves at their most bulging radius, perpendicular to the seams, emptied and cleaned, and then measured under a magnifying lens. In addition to the absolute seam thickness, the relative seam thickness is also measured, i.e., the ratio of the wall thickness directly at the seam to the maximum wall thickness next to the seam, where material accumulates during seam formation. The relative seam thickness is even more informative about the seam formation properties than the absolute seam thickness, as it is less dependent on the process conditions. The bursting force of the soft capsules is measured as a further parameter for the seam formation properties.The bursting force is the force required to burst a soft capsule placed between two compression tools with its seam parallel to the surface of the force-exerting tool jaws. The bursting force can be measured, for example, using the "Texture Analyzer TA-XTplus" or the "Zwick / Roell Z2.5 / TN1S" testing device.

[0091] The absolute and relative seam thicknesses and bursting forces for the gelatin soft capsules prepared from the shell formulations described above are given in Table 3 for a machine rotation speed of 2.0 rpm and in Table 4 for a machine rotation speed of 3.5 rpm.

[0092] Other low-viscosity gelatins, which also have a low gel strength (typically well below 150 g bloom), and which can be produced by suitable selection of parameters in the gelatin extraction process, do not lead to a stable process when encapsulated using the rotary die method, nor to soft gelatin capsules with sufficient physical stability.

[0093] Table 3: Results at 2.0 rpm

[0094]

[0095] The results show that, for both machine speeds, the absolute seam thickness of the subsequent seam and the bursting force are significantly higher for all soft capsules according to the invention than for soft capsules made from standard gelatins. At the higher speed of 3.5 rpm, this also applies to the relative seam thickness.

[0096] Increasing the machine rotation speed generally leads to a decrease in the absolute seam thickness, as can also be seen in the comparison.

[0097] The correlation between the seam thickness and the bursting force also shows that the follow-up seam is relevant as a potential weak point for the mechanical properties of the capsule shell and thus represents the main cause of leaking capsules (so-called leakers).

[0098] By using a low-viscosity gelatin according to the present invention, the seam formation properties of soft gelatin capsules can be significantly improved, thus reducing the risk of leakage. Figure 1 shows a photographic representation of the wall cross-section of a soft gelatin capsule according to the invention, which can be used to measure the absolute and relative seam thicknesses as described above. In this example, the follow-up seam is located at the bottom right of the image and has an absolute thickness of 408.93 μm. The maximum wall thickness next to the seam, where material enrichment occurs during seam formation, is 572.39 μm, so the relative thickness of the follow-up seam is 71%.

[0099] Figure 2 shows a corresponding photographic representation of the wall cross-section of a prior art soft gelatin capsule, i.e., based on a standard capsule gelatin. The follow-up seam is located on the left side and has an absolute thickness of 117.69 μm, corresponding to a relative thickness of 28% of the adjacent maximum wall thickness of 419.26 μm.

[0100] A comparison of Figures 1 and 2 also shows that in the soft capsule according to the invention, the material enrichment in the seam area is significantly more pronounced overall than in the capsule according to the prior art, i.e., the absolute seam thickness relative to the average wall thickness of the capsule (or to the wall thickness between the two seams) is significantly increased. In other words, and as can be clearly seen in the figures, the seam in Figure 2 (prior art) is significantly thinner than the average wall thickness, whereas in Figure 1 (capsule according to the invention) it is equal to or even greater than the average wall thickness.

[0101] 5. Production of gelatin soft capsules on an industrial scale

[0102] To investigate the seam formation properties, soft capsules with different fillings were also produced on an industrial-scale rotary die machine (production volume > 100,000 capsules). The shell formulations in these examples comprise the low-viscosity gelatin according to Example 1.1 above and, for comparison, a standard soft capsule gelatin, namely bovine bone gelatin Type B with a viscosity of 3.3 mPa-s and 159 g bloom.

[0103] Glycerol was used as a plasticizer, and the composition of the capsule shell after drying corresponds to Example 2.6 above.

[0104] Table 5 shows the absolute seam thicknesses, burst forces, and other process parameters for the gelatin soft capsules produced from the shell formulations described above with various fillings (krill oil, sunflower oil, and polysorbate). The seam thicknesses and burst forces were measured as described in Example 4.

[0105] Table 5: Results with different fillings

[0106] These tests also show a significant increase in absolute seam thickness when using low-viscosity gelatin compared to standard soft capsule gelatin, by approximately 108%, approximately 42%, or approximately 51%, depending on the filling. At the same time, the bursting force increases by approximately 100%, approximately 12%, or approximately 76%.

[0107] In a further series of experiments, the influence of rotation speed on the thickness of the subsequent seam was investigated. The low-viscosity gelatin according to Example 1.1 was used compared to a standard soft capsule gelatin (bovine bone gelatin type B with a viscosity of 3.3 mPa-s and 159 g bloom).

[0108] Glycerin was used as a plasticizer, and the composition of the capsule shell after drying corresponds to Example 2.6 above. A suspension of blueberry extract in sunflower oil (dry matter 25%) was used as the filling.

[0109] The absolute seam thicknesses of the produced soft capsules and other process parameters are given in Table 6.

[0110] Table 6: Results with different rotation speeds

[0111] When using the low-viscosity gelatin, at rotational speeds of 2.7 to 3.3 rpm, seam thicknesses can be achieved that are between approximately 34% and approximately 65% ​​higher than the seam thickness achieved with the standard gelatin at 2.7 rpm. Only when the speed is further increased to 3.6 rpm does the seam thickness return to approximately the level of the standard gelatin at 2.7 rpm. For the soft capsules containing standard gelatin, all capsules in a batch exhibited leakers after drying in the tumble dryer. In contrast, for the soft capsules containing the low-viscosity gelatin, between 70% and 89% of the capsules in a batch were free of leakers. This also demonstrates the significantly improved seam formation of the soft capsules according to the invention.

[0112] The drying time required for the soft capsules was 38 hours when using standard gelatin (final capsule hardness 10.0 N), whereas when using low-viscosity gelatin it was only 18 hours (final capsule hardness 10.6 N). The soft capsules according to the invention thus require a significantly shorter drying time than soft capsules made from standard gelatin, in this example less than half the time.

Claims

Patent claims 1. A soft gelatin capsule comprising a capsule shell and a filling enclosed by the capsule shell, characterized in that the capsule shell comprises a low-viscosity gelatin having a viscosity of approximately 1.5 to approximately 2.4 mPa-s and a gel strength of approximately 150 to approximately 280 g bloom, preferably approximately 180 to approximately 250 g bloom, each measured in a 6.67% gelatin solution at 60°C according to the GME monograph "Standardized Methods for the Testing of Edible Gelatin".

2. Gelatin soft capsule according to claim 1, wherein the low-viscosity gelatin - a type A gelatin obtained from pig skin, which has a viscosity of approximately 1.5 to approximately 2.3 mPa-s and a gel strength of approximately 150 to approximately 240 g Bloom, preferably approximately 180 to approximately 220 g Bloom; or - a type A gelatin obtained from bovine bones, which has a viscosity of approximately 1.6 to approximately 2.4 mPa-s and a gel strength of approximately 160 to approximately 260 g Bloom, preferably approximately 180 to approximately 230 g Bloom; or - a type B gelatin obtained from bovine bones, which has a viscosity of approximately 1.6 to approximately 2.4 mPa-s and a gel strength of approximately 160 to approximately 260 g Bloom, preferably approximately 190 to approximately 240 g Bloom, more preferably approximately 205 to approximately 240 g Bloom; or - a type B gelatin obtained from bovine hide, which has a viscosity of approximately 1.5 to approximately 2.3 mPa-s and a gel strength of approximately 160 to approximately 230 g bloom, preferably approximately 180 to approximately 220 g bloom, more preferably approximately 205 to approximately 220 g bloom; or - a mixture of two or more of the aforementioned gelatins.

3. A soft gelatin capsule according to claim 1 or 2, wherein the low-viscosity gelatin is produced by partial enzymatic hydrolysis of one or more starting gelatins which have a higher viscosity and a higher gel strength than the low-viscosity gelatin.

4. A soft gelatin capsule according to claim 3, wherein the partial enzymatic hydrolysis comprises a treatment with one or more endopeptidases, which are preferably selected from collagenases, metalloproteases, serine proteases, cysteine ​​proteases, pepsin, trypsin, chymotrypsin and elastase.

5. A soft gelatin capsule according to claim 1 or 2, wherein the low-viscosity gelatin is produced by separating by microfiltration higher molecular weight fractions of one or more starting gelatins which have a higher viscosity and a higher gel strength than the low-viscosity gelatin.

6. A soft gelatin capsule according to any one of the preceding claims, wherein the low-viscosity gelatin has a weight-average molecular weight of approximately 45,000 to approximately 80,000 Da, determined by gel permeation chromatography.

7. Gelatin soft capsule according to one of the preceding claims, wherein the low-viscosity gelatin has a polydispersity of about 2.3 or less, preferably from about 1.5 to about 2.3, more preferably wherein the low-viscosity gelatin - a type A gelatin obtained from pig skin, which has a polydispersity of approximately 1.5 to approximately 1.9; or - a type A gelatin derived from bovine bones, which has a polydispersity of approximately 1.8 to approximately 2.3; or - a type B gelatin obtained from bovine bones, which has a polydispersity of approximately 1.8 to approximately 2.

3.

8. Soft gelatin capsules according to any one of claims 1 to 6, wherein the low-viscosity gelatin comprises a type B gelatin derived from bovine hide having a polydispersity of about 4 to about 6.

9. A soft gelatin capsule according to any one of the preceding claims, wherein the low molecular weight gelatin has a proportion of gelatin with a molecular weight of more than 400,000 Da which is less than approximately 1.5% by weight.

10. A soft gelatin capsule according to any one of the preceding claims, wherein the capsule shell comprises a proportion of approximately 50 to approximately 75% by weight of gelatin, preferably approximately 55 to approximately 70% by weight, more preferably approximately 58 to approximately 67% by weight, based on the dry substance of the gelatin.

11. A soft gelatin capsule according to any one of the preceding claims, wherein the capsule shell further comprises a collagen hydrolysate having a weight-average molecular weight of approximately 1,500 Da or less, determined by gel permeation chromatography, preferably in a proportion of approximately 1 to approximately 8% by weight.

12. A soft gelatin capsule according to any one of the preceding claims, wherein the capsule shell further comprises one or more free amino acids, preferably in a proportion of up to about 8% by weight.

13. A soft gelatin capsule according to any one of the preceding claims, wherein the capsule shell further comprises one or more plasticizers, preferably in a proportion of about 20 to about 40% by weight, more preferably about 23 to about 34% by weight, based on the dry substance of the plasticizer(s).

14. A soft gelatin capsule according to claim 13, wherein the plasticizer(s) are selected from sugar alcohols and non-reducing sugars, in particular from glycerol, sorbitol, sorbitan, mannitol, maltitol, isomalt, isomaltulose, trehalose and sucrose.

15. A soft gelatin capsule according to any one of the preceding claims, wherein the capsule shell has a water content of approximately 6 to approximately 14% by weight.

16. A soft gelatin capsule according to any one of the preceding claims, wherein the capsule shell further comprises one or more colorants, preferably in a proportion of up to about 6% by weight.

17. A soft gelatin capsule according to any one of the preceding claims, wherein the capsule shell further comprises one or more flavoring agents, preferably in a proportion of up to about 6% by weight.

18. A soft gelatin capsule according to any one of the preceding claims, wherein the capsule shell further comprises one or more sweeteners, preferably in a proportion of up to about 10% by weight.

19. A soft gelatin capsule according to any one of the preceding claims, wherein the capsule shell is made from a gel-like shell formulation comprising - approx. 35 to approx. 50% by weight of the low-viscosity gelatin, based on its dry substance; - approx. 15 to approx. 25 wt.% of one or more plasticizers, based on their dry substance; - approx. 25 to approx. 50 wt.% water; - optionally up to approximately 3% by weight of one or more dyes; - optionally up to approximately 3% by weight of one or more flavoring substances; and - optionally up to approximately 10% by weight of one or more sweeteners.

20. A soft gelatin capsule according to claim 19, wherein the soft gelatin capsule is produced from two material strips of the gel-like shell formulation by means of the rotary die process.

21. A soft gelatin capsule according to any one of the preceding claims, wherein the capsule shell has a wall thickness of approximately 100 to approximately 600 pm, preferably approximately 150 to approximately 550 pm, more preferably approximately 200 to approximately 500 pm.

22. A soft gelatin capsule according to any one of the preceding claims, wherein the filling enclosed by the capsule shell is in the form of a solution, a suspension, an emulsion or a pasty filling.

23. A soft gelatin capsule according to any one of the preceding claims, wherein the filling is hydrophilic or lipophilic.

24. A soft gelatin capsule according to any one of the preceding claims, wherein the filling comprises one or more pharmaceutical or nutraceutical ingredients and one or more adjuvants.

25. A process for the preparation of soft gelatin capsules, comprising the steps of: a) providing a gel-like shell formulation comprising - approx. 35 to approx. 50 wt.% of a low-viscosity gelatine, based on its dry substance, which has a viscosity of approx. 1.5 to approx. 2.4 mPa-s and a gel strength of approximately 150 to approximately 280 g bloom, preferably approximately 180 to approximately 250 g bloom, each measured in a 6.67% gelatin solution at 60 °C according to the GME monograph "Standardised Methods for the Testing of Edible Gelatin"; - approx. 15 to approx. 25 wt.% of one or more plasticizers, based on their dry substance; - approx. 25 to approx. 50 wt.% water; - optionally up to approximately 3% by weight of one or more dyes; - optionally up to approximately 3% by weight of one or more flavoring substances; and - optionally up to approximately 10% by weight of one or more sweeteners, b) providing a capsule filling, and c) producing the gelatin soft capsules by enclosing the capsule filling with a capsule shell formed from the shell formulation.

26. Use of a low-viscosity gelatin for producing soft gelatin capsules, wherein the gelatin has a viscosity of approximately 1.5 to approximately 2.4 mPa-s and a gel strength of approximately 150 to approximately 280 g bloom, preferably approximately 180 to approximately 250 g bloom, each measured in a 6.67% gelatin solution at 60°C according to the GME monograph "Standardised Methods for the Testing of Edible Gelatin". * * *

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