Oral dosage form having a gastroresistant capsule shell - Patents.com

Abstract

The present invention relates to a gastro-resistant capsule containing one or more proteases, the capsule shell of which comprises a water-soluble film-forming polymer and a water-soluble enteric polymer. The present invention also relates to a method for producing the gastro-resistant capsule and to the use thereof.

Description

[Technical field]

[0001] The present invention relates to a gastro-resistant capsule comprising one or more proteases. The present invention also relates to a method for producing the gastro-resistant capsule and to the use thereof. [Background technology]

[0002] Oral administration of protease has been shown to be associated with beneficial immunomodulatory effects. For example, in a randomized study of subjects with moderate to severe knee osteoarthritis, oral administration of protease was found to have efficacy comparable to diclofenac in reducing pain and improving function (Ueberall, MA, et al., 2016. Journal of pain research, 9, pp. 941-961).

[0003] Proteolytic enzymes have also been shown to be highly efficient potentiators for the antibacterial treatment of urogenital chlamydiosis (Sukhikh, GT, et al., 1997. International journal of immunotherapy, 13(3-4), pp. 131-133), to provide additional beneficial effects in patients suffering from cervical syndrome (Tilscher, H., et al., 1996. Wiener medizinische Wochenschrift, 146(5), pp. 91-95), and to reduce the incidence of obstructive bronchitis in children with recurrent obstructive bronchitis (Lanchava, N., et al., 2005. Georgian medical news, 127, pp. 50-53).

[0004] Currently, protease is usually orally administered in the form of enteric-coated tablets.However, in this case, to obtain an effective dose, subjects may be required to take 6 or more tablets per day (e.g., 2 tablets 3 times a day) (Ueberall, MA, et al., 2016. Journal of pain research, 9, pp.941-961).It may be difficult for subjects to comply with such a dosing schedule, and it is desirable to provide an oral dosage form that can provide an effective dose with fewer doses. Summary of the Invention

[0005] The present inventors have developed an oral dosage form that requires fewer administrations to deliver an effective amount of proteolytic enzymes.

[0006] The inventors have surprisingly found that a gastro-resistant capsule shell comprising a water-soluble film-forming polymer (e.g., HPMC) and a water-soluble enteric polymer (e.g., pectin) releases protease enzymes in the upper part of the small intestine, mimicking the kinetic profile of an enteric-coated tablet. In contrast, a gastro-resistant capsule shell comprising a water-soluble film-forming polymer (e.g., HPMC) and gellan gum does not release protease enzymes at the right point in the gastrointestinal tract.

[0007] In one aspect, the present invention provides a capsule comprising one or more proteases, wherein the capsule shell comprises a water-soluble film-forming polymer and a water-soluble enteric polymer. Preferably, the capsule is acid-resistant. More preferably, the capsule is gastro-resistant. In another aspect, the present invention provides a method for producing a capsule comprising one or more proteases, the method comprising: (a) providing a capsule shell comprising a water soluble film-forming polymer and a water soluble enteric polymer, preferably the capsule shell is acid resistant, more preferably the capsule shell is gastroresistant; (b) filling the capsule shell with a capsule composition comprising one or more proteases.

[0008] In another aspect, the present invention provides a capsule obtained or obtainable by the process of the present invention.

[0009] The capsule shell may be insoluble under gastric conditions and soluble under small intestinal conditions, preferably gastric conditions being about pH 2.0 at about 37° C. and / or small intestinal conditions being about pH 5.5 to about pH 7.0 at about 37° C.

[0010] The capsule shell may comprise a water soluble film-forming polymer in an amount of about 65% to about 97% by weight, a water soluble enteric polymer in an amount of about 3% to about 30% by weight, and / or have a moisture content of about 4% to about 7% by weight.

[0011] Any suitable water-soluble enteric polymer may be used. The water-soluble enteric polymer may be selected from one or more of pectin, propylene glycol alginate (PGA), or xanthan gum. In some embodiments, the water-soluble enteric polymer is pectin. Preferably, the pectin has a degree of esterification of about 15% to about 40%, or about 20% to about 35%, or about 20% to about 30%. Preferably, the pectin has a degree of amidation of about 0% to about 25%, or about 10% to about 25%, or about 15% to about 25%. Preferably, the water-soluble enteric polymer has a molecular weight of about 20 kDa to about 1000 kDa, about 40 kDa to about 400 kDa, or about 50 kDa to about 200 kDa.

[0012] Any suitable water-soluble film-forming polymer may be used. The water-soluble film-forming polymer may be selected from one or more of hydroxypropylmethylcellulose (HPMC), starch, gelatin, pullulan, polyvinyl alcohol, hydroxypropylated starch, hydroxyethyl starch, hydroxypropylcellulose, methylcellulose, hydroxyethylcellulose, and hydroxyethylmethylcellulose. In some embodiments, the water-soluble film-forming polymer is hydroxypropylmethylcellulose (HPMC). Preferably, the water-soluble film-forming polymer has a molecular weight of about 50 kDa to about 815 kDa, or about 50 kDa to about 400 kDa.

[0013] In some embodiments, the capsule shell optionally further comprises a solidifying agent, such as gellan gum, carrageen, agar, konjac gum, or locust bean gum, in an amount of about 0.5% to about 3% by weight.

[0014] In some embodiments, the capsule shell does not include a solidifying agent, hi some embodiments, the capsule shell does not include gellan gum and / or carrageenan.

[0015] Any suitable protease may be used. The one or more proteases may be selected from the group consisting of bromelain, trypsin, papain, pancreatin, chymotrypsin, serratiopeptidase, ficain, nattokinase, or any combination thereof. In some embodiments, the one or more proteases include or consist of bromelain and / or trypsin. In some embodiments, the one or more proteases include or consist of bromelain and trypsin.

[0016] The one or more proteases may be present in any suitable amount. Preferably, the capsule contains one or more proteases in a total amount of about 50 mg to about 1000 mg, about 75 mg to about 800 mg, about 100 mg to about 600 mg, about 125 mg to about 500 mg, about 150 mg to about 400 mg, or about 200 mg to about 300 mg. Preferably, the capsule contains one or more proteases in a total amount of about 1000 FIP units to about 12000 FIP units, about 1500 FIP units to about 10000 FIP units, about 2000 FIP units to about 8000 FIP units, about 2500 FIP units to about 6000 FIP units, or about 3000 FIP units to about 4000 FIP units. Preferably, the capsule contains bromelain in an amount of about 50 mg to about 500 mg, about 75 mg to about 400 mg, about 100 mg to about 300 mg, or about 125 mg to about 200 mg. Preferably, the capsule contains bromelain in an amount of about 400 FIP units to about 3000 FIP units, about 500 FIP units to about 2500 FIP units, about 600 FIP units to about 2000 FIP units, about 700 FIP units to about 1500 FIP units, or about 800 FIP units to about 1000 FIP units. Preferably, the capsule contains trypsin in an amount of about 20 mg to about 250 mg, about 30 mg to about 200 mg, about 40 mg to about 150 mg, about 50 mg to about 100 mg, or about 60 mg to about 80 mg. Suitably, the capsule contains trypsin in an amount of about 1000 FIP Units to about 10000 FIP Units, about 1500 FIP Units to about 8000 FIP Units, about 1750 FIP Units to about 6000 FIP Units, about 2000 FIP Units to about 5000 FIP Units, or about 2500 FIP Units to about 4000 FIP Units.

[0017] In some aspects, the capsule comprises bromelain in an amount of about 150 mg and / or trypsin in an amount of about 72 mg, hi some embodiments, the capsule comprises bromelain in an amount of about 900 FIP units and / or trypsin in an amount of about 2880 FIP units.

[0018] The capsule may contain one or more flavonoids. Any suitable flavonoid may be used in any suitable amount. Preferably, the one or more flavonoids are selected from rutin, quercetin, kaempferol, myricetin, fisetin, catechin, epicatechin, hydroxytyrosol, oleuropein, hesperidin, or any combination thereof. In some embodiments, the one or more flavonoids include or consist of rutin. Preferably, the capsule contains one or more flavonoids in a total amount of about 50 mg to about 1000 mg, about 100 mg to about 600 mg, about 125 mg to about 400 mg, or about 150 mg to about 300 mg. In some embodiments, the capsule contains one or more flavonoids in a total amount of about 200 mg.

[0019] The capsule may include one or more fillers. Any suitable filler may be used in any suitable amount. Preferably, the one or more fillers include or consist of one or more cellulose derivatives, such as powdered and microcrystalline cellulose (MCC), ethyl cellulose, hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose (HPMC), HPMC phthalate, HPMC acetate succinate, cellulose acetate (CA), CA phthalate, sodium (Na) and calcium (Ca) carboxymethylcellulose (CMC), croscarmellose sodium (XCMCNa), methylcellulose, and low-substituted HPC, or any combination thereof. In some embodiments, the one or more fillers include or consist of microcrystalline cellulose (MCC) and / or hydroxypropyl cellulose (HPC).

[0020] The capsule may further comprise one or more further ingredients. Preferably, the capsule further comprises one or more antioxidants, such as L-ascorbyl palmitate. Preferably, the capsule further comprises a medium chain triglyceride.

[0021] The capsule may remain substantially intact during the gastric phase and / or the capsule may substantially dissolve during the small intestinal phase. Preferably, the capsule remains completely intact during the gastric phase and / or the capsule dissolves completely during the small intestinal phase. Preferably, the protease activity is not substantially released during the gastric phase and / or the protease activity is not substantially released during the small intestinal phase. Preferably, the protease activity is not released during the gastric phase and / or the protease activity is completely released during the small intestinal phase. Preferably, the protease activity is not released during the gastric phase and / or the protease activity is completely released during the small intestinal phase.

[0022] In another aspect, the invention provides a pack comprising a plurality of capsules of the invention. Suitably, the pack comprises about 45 or more capsules, about 90 or more capsules, about 135 or more capsules, about 180 or more capsules, or about 270 or more capsules. Suitably, the pack comprises about 15 or more daily doses, about 30 or more daily doses, about 45 or more daily doses, about 60 or more daily doses, or about 90 or more daily doses.

[0023] In another aspect, the present invention provides the use of the capsules of the present invention as a dietary supplement.

[0024] In one aspect, the present invention provides a capsule of the present invention for use as a medicament.

[0025] In another aspect, the present invention provides a capsule of the present invention for use in the treatment and / or prevention of inflammatory diseases, joint pain, arthropathy, injuries, back pain, or sciatica, or for use in accelerating healing.

[0026] In another aspect, the present invention provides the present invention for use in the treatment and / or prophylaxis of an inflammatory disease, such as phlebitis, prostatitis, or cystitis.

[0027] In another aspect, the present invention provides a capsule of the present invention for use in the treatment and / or prevention of joint pain, such as shoulder joint pain, elbow joint pain, finger joint pain, knee joint pain, menopausal joint pain, or rheumatic pain.

[0028] In another aspect, the present invention provides a capsule of the present invention for use in the treatment and / or prevention of arthrosis, arthritis, or osteoarthritis, such as osteoarthritis of the hip joint, osteoarthritis of the knee joint, osteoarthritis of the metatarsophalangeal joint of the big toe, osteoarthritis of the fingers, osteoarthritis of the foot, osteoarthritis of the ankle, or Heberden's nodes and Bouchard's nodes.

[0029] In another aspect, the present invention provides a capsule of the present invention for use in the treatment and / or prevention of injuries such as sports injuries, muscle pain, pulled / strain, overload injuries, sprains, or bruises.

[0030] In another aspect, the present invention provides a capsule of the invention for use in the treatment and / or prevention of back pain, such as upper back pain, disc herniation, or lower back pain, or sciatica.

[0031] In another aspect, the present invention provides a capsule of the present invention for use in promoting healing, such as wound healing or post-operative healing.

[0032] The one or more proteases may be administered in any suitable dose. Preferably, the one or more proteases are administered in a total daily dose of about 100 mg to about 2000 mg, about 200 mg to about 1500 mg, about 300 mg to about 1200 mg, about 400 mg to about 1000 mg, about 500 mg to about 900 mg, or about 600 mg to about 800 mg. Preferably, the one or more proteases are administered in a total daily dose of about 2000 FIP units to about 30000 FIP units, about 4000 FIP units to about 25000 FIP units, about 6000 FIP units to about 20000 FIP units, about 8000 FIP units to about 15000 FIP units, or about 10000 FIP units to about 12000 FIP units. Preferably, bromelain is administered in a daily dose of about 100 mg to about 1000 mg, about 200 mg to about 900 mg, about 300 mg to about 800 mg, about 350 mg to about 700 mg, about 400 mg to about 600 mg, or about 450 mg to about 500 mg. Preferably, bromelain is administered in a daily dose of about 500 FIP units to about 10,000 FIP units, about 1,000 FIP units to about 8,000 FIP units, about 1,500 FIP units to about 6,000 FIP units, about 2,000 FIP units to about 4,000 FIP units, or about 2,500 FIP units to about 3,000 FIP units. Preferably, trypsin is administered in a daily dose of about 50 mg to about 500 mg, about 100 mg to about 400 mg, about 150 mg to about 350 mg, about 175 mg to about 300 mg, or about 200 mg to about 250 mg. Preferably, trypsin is administered in a daily dose of about 2000 FIP units to about 20000 FIP units, about 3000 FIP units to about 15000 FIP units, about 4000 FIP units to about 12000 FIP units, about 5000 FIP units to about 11000 FIP units, about 6000 FIP units to about 10000 FIP units, or about 7000 FIP units to about 9000 FIP units.

[0033] In some embodiments, the one or more proteases are administered in a total daily dose of about 666 mg and / or about 11340 FIP units. In some embodiments, bromelain is administered in a daily dose of about 450 mg and / or trypsin is administered in a daily dose of about 216 mg. In some embodiments, bromelain is administered in a daily dose of about 2700 FIP units and / or trypsin is administered in a daily dose of about 8640 FIP units.

[0034] Suitably, rutin is administered at a total daily dose of about 100 mg to about 1200 mg, about 200 mg to about 1000 mg, about 300 mg to about 900 mg, about 400 mg to about 800 mg, or about 500 mg to about 700 mg. In some embodiments, rutin is administered at a total daily dose of about 600 mg.

[0035] Suitably, the capsule is formulated to contain about 1 / 2 the daily dose, about 1 / 3 the daily dose, about 1 / 4 the daily dose, or about 1 / 5 the daily dose. In some embodiments, the capsule is formulated to contain about 1 / 2 the daily dose, or about 1 / 3 the daily dose. In some embodiments, the capsule is formulated to contain about 1 / 3 the daily dose.

[0036] Suitably, no more than 5, no more than 4, or no more than 3 capsules are administered daily. In some embodiments, 2 or 3 capsules are administered daily. In some embodiments, 3 capsules are administered daily. The capsules may be administered simultaneously or separately, or in any combination thereof.

[0037] Preferably, the capsule is administered in a fasted state, optionally at least about 45 minutes before a meal. Preferably, the capsule is administered for at least 15 days.

[0038] In another aspect, the present invention provides the use of a capsule shell comprising a water-soluble film-forming polymer and a water-soluble enteric polymer to deliver one or more proteases. The one or more proteases may be delivered to the small intestine. The capsule shell and the one or more proteases may be any of those described herein.

[0039] In another aspect, the present invention provides the use of a capsule for delivering one or more proteases, wherein the capsule shell comprises a water-soluble film-forming polymer and a water-soluble enteric polymer. The one or more proteases may be delivered to the small intestine. The capsule shell and the one or more proteases may be any of those described herein. [Brief description of the drawings]

[0040] [Figure 1A] Activity of Wobenzym PS tablets during the entire upper GIT Trypsin activity (Figures 1A and 1B; USP units / reactor) and bromelain activity (Figures 1C and 1D; units / reactor) of Wobenzym PS tablets during the entire upper gastrointestinal tract (GIT). Average values ​​of measurements (Figures 1A and 1C, expressed as mean ± standard deviation, n=3) and replicate single measurements (Figures 1B and 1D) are shown. Data are examples of the product itself and of samples taken during the gastric phase (ST 15 min, ST 30 min, ST 45 min) and during the small intestinal phase (SI 30 min, SI 60 min, SI 90 min, SI 120 min, SI 150 min, and SI 180 min). Additionally, capsule integrity scores at each sampling time point are shown above the bars in the figures (1=intact to 4=completely dissolved). [Figure 1B]Activity of Wobenzym PS tablets during the entire upper GIT Trypsin activity (Figures 1A and 1B; USP units / reactor) and bromelain activity (Figures 1C and 1D; units / reactor) of Wobenzym PS tablets during the entire upper gastrointestinal tract (GIT). Average values ​​of measurements (Figures 1A and 1C, expressed as mean ± standard deviation, n=3) and replicate single measurements (Figures 1B and 1D) are shown. Data are examples of the product itself and of samples taken during the gastric phase (ST 15 min, ST 30 min, ST 45 min) and during the small intestinal phase (SI 30 min, SI 60 min, SI 90 min, SI 120 min, SI 150 min, and SI 180 min). Additionally, capsule integrity scores at each sampling time point are shown above the bars in the figures (1=intact to 4=completely dissolved). [Figure 1C] Activity of Wobenzym PS tablets during the entire upper GIT Trypsin activity (Figures 1A and 1B; USP units / reactor) and bromelain activity (Figures 1C and 1D; units / reactor) of Wobenzym PS tablets during the entire upper gastrointestinal tract (GIT). Average values ​​of measurements (Figures 1A and 1C, expressed as mean ± standard deviation, n=3) and replicate single measurements (Figures 1B and 1D) are shown. Data are examples of the product itself and of samples taken during the gastric phase (ST 15 min, ST 30 min, ST 45 min) and during the small intestinal phase (SI 30 min, SI 60 min, SI 90 min, SI 120 min, SI 150 min, and SI 180 min). Additionally, capsule integrity scores at each sampling time point are shown above the bars in the figures (1=intact to 4=completely dissolved). [Figure 1D]Activity of Wobenzym PS tablets during the entire upper GIT Trypsin activity (Figures 1A and 1B; USP units / reactor) and bromelain activity (Figures 1C and 1D; units / reactor) of Wobenzym PS tablets during the entire upper gastrointestinal tract (GIT). Average values ​​of measurements (Figures 1A and 1C, expressed as mean ± standard deviation, n=3) and replicate single measurements (Figures 1B and 1D) are shown. Data are examples of the product itself and of samples taken during the gastric phase (ST 15 min, ST 30 min, ST 45 min) and during the small intestinal phase (SI 30 min, SI 60 min, SI 90 min, SI 120 min, SI 150 min, and SI 180 min). Additionally, capsule integrity scores at each sampling time point are shown above the bars in the figures (1=intact to 4=completely dissolved). [Figure 2A] Activity of Wobenzym Control HPMC Capsules During Upper GIT Transplant Trypsin activity (Figures 2A and 2B; USP units / reactor) and bromelain activity (Figures 2C and 2D, units / reactor) of Wobenzym Control HPMC Capsules during Upper GIT Transplant. Average values ​​of measurements (Figures 2A and 2C, expressed as mean ± standard deviation, n=3) and replicate single measurements (Figures 2B and 2D) are shown. Data are examples of the product itself and of samples taken during the gastric phase (ST 15 min, ST 30 min, ST 45 min) and during the small intestinal phase (SI 30 min, SI 60 min, SI 90 min, SI 120 min, SI 150 min, and SI 180 min). Additionally, capsule integrity scores at each sampling time point are shown above the bars in the figures (1=intact to 4=completely dissolved). [Figure 2B]Activity of Wobenzym Control HPMC Capsules During Upper GIT Transplant Trypsin activity (Figures 2A and 2B; USP units / reactor) and bromelain activity (Figures 2C and 2D, units / reactor) of Wobenzym Control HPMC Capsules during Upper GIT Transplant. Average values ​​of measurements (Figures 2A and 2C, expressed as mean ± standard deviation, n=3) and replicate single measurements (Figures 2B and 2D) are shown. Data are examples of the product itself and of samples taken during the gastric phase (ST 15 min, ST 30 min, ST 45 min) and during the small intestinal phase (SI 30 min, SI 60 min, SI 90 min, SI 120 min, SI 150 min, and SI 180 min). Additionally, capsule integrity scores at each sampling time point are shown above the bars in the figures (1=intact to 4=completely dissolved). [Figure 2C] Activity of Wobenzym Control HPMC Capsules During Upper GIT Transplant Trypsin activity (Figures 2A and 2B; USP units / reactor) and bromelain activity (Figures 2C and 2D, units / reactor) of Wobenzym Control HPMC Capsules during Upper GIT Transplant. Average values ​​of measurements (Figures 2A and 2C, expressed as mean ± standard deviation, n=3) and replicate single measurements (Figures 2B and 2D) are shown. Data are examples of the product itself and of samples taken during the gastric phase (ST 15 min, ST 30 min, ST 45 min) and during the small intestinal phase (SI 30 min, SI 60 min, SI 90 min, SI 120 min, SI 150 min, and SI 180 min). Additionally, capsule integrity scores at each sampling time point are shown above the bars in the figures (1=intact to 4=completely dissolved). [Figure 2D]Activity of Wobenzym Control HPMC Capsules During Upper GIT Transplant Trypsin activity (Figures 2A and 2B; USP units / reactor) and bromelain activity (Figures 2C and 2D, units / reactor) of Wobenzym Control HPMC Capsules during Upper GIT Transplant. Average values ​​of measurements (Figures 2A and 2C, expressed as mean ± standard deviation, n=3) and replicate single measurements (Figures 2B and 2D) are shown. Data are examples of the product itself and of samples taken during the gastric phase (ST 15 min, ST 30 min, ST 45 min) and during the small intestinal phase (SI 30 min, SI 60 min, SI 90 min, SI 120 min, SI 150 min, and SI 180 min). Additionally, capsule integrity scores at each sampling time point are shown above the bars in the figures (1=intact to 4=completely dissolved). [Figure 3A] Activity of Wobenzym HPMC / Gellan Gum Capsules During Upper GIT Transplant Trypsin activity (Figures 3A and 3B; USP units / reactor) and bromelain activity (Figures 3C and 3D; units / reactor) of Wobenzym HPMC / Gellan Gum Capsules during Upper GIT Transplant. Average values ​​of measurements (Figures 3A and 3C, expressed as mean ± standard deviation, n=3) and replicate single measurements (Figures 3B and 3D) are shown. Data are examples of the product itself and of samples taken during the gastric phase (ST 15 min, ST 30 min, ST 45 min) and the small intestinal phase (SI 30 min, SI 60 min, SI 90 min, SI 120 min, SI 150 min, and SI 180 min). Additionally, capsule integrity scores at each sampling time point are shown above the bars in the figures (1=intact to 4=completely dissolved). [Figure 3B]Activity of Wobenzym HPMC / Gellan Gum Capsules During Upper GIT Transplant Trypsin activity (Figures 3A and 3B; USP units / reactor) and bromelain activity (Figures 3C and 3D; units / reactor) of Wobenzym HPMC / Gellan Gum Capsules during Upper GIT Transplant. Average values ​​of measurements (Figures 3A and 3C, expressed as mean ± standard deviation, n=3) and replicate single measurements (Figures 3B and 3D) are shown. Data are examples of the product itself and of samples taken during the gastric phase (ST 15 min, ST 30 min, ST 45 min) and the small intestinal phase (SI 30 min, SI 60 min, SI 90 min, SI 120 min, SI 150 min, and SI 180 min). Additionally, capsule integrity scores at each sampling time point are shown above the bars in the figures (1=intact to 4=completely dissolved). [Figure 3C] Activity of Wobenzym HPMC / Gellan Gum Capsules During Upper GIT Transplant Trypsin activity (Figures 3A and 3B; USP units / reactor) and bromelain activity (Figures 3C and 3D; units / reactor) of Wobenzym HPMC / Gellan Gum Capsules during Upper GIT Transplant. Average values ​​of measurements (Figures 3A and 3C, expressed as mean ± standard deviation, n=3) and replicate single measurements (Figures 3B and 3D) are shown. Data are examples of the product itself and of samples taken during the gastric phase (ST 15 min, ST 30 min, ST 45 min) and the small intestinal phase (SI 30 min, SI 60 min, SI 90 min, SI 120 min, SI 150 min, and SI 180 min). Additionally, capsule integrity scores at each sampling time point are shown above the bars in the figures (1=intact to 4=completely dissolved). [Figure 3D]Activity of Wobenzym HPMC / Gellan Gum Capsules During Upper GIT Transplant Trypsin activity (Figures 3A and 3B; USP units / reactor) and bromelain activity (Figures 3C and 3D; units / reactor) of Wobenzym HPMC / Gellan Gum Capsules during Upper GIT Transplant. Average values ​​of measurements (Figures 3A and 3C, expressed as mean ± standard deviation, n=3) and replicate single measurements (Figures 3B and 3D) are shown. Data are examples of the product itself and of samples taken during the gastric phase (ST 15 min, ST 30 min, ST 45 min) and the small intestinal phase (SI 30 min, SI 60 min, SI 90 min, SI 120 min, SI 150 min, and SI 180 min). Additionally, capsule integrity scores at each sampling time point are shown above the bars in the figures (1=intact to 4=completely dissolved). [Figure 4A] Activity of Wobenzym HPMC / pectin capsules during upper GIT digestion Trypsin activity (Figures 4A and 4B; USP units / reactant) and bromelain activity (Figures 4C and 4D; units / reactant) of Wobenzym HPMC / pectin capsules during upper GIT digestion. Average values ​​of measurements (Figures 4A and 4C, expressed as mean ± standard deviation, n=3) and replicate single measurements (Figures 4B and 4D) are shown. Data are examples of the product itself and of samples taken during the gastric phase (ST 15 min, ST 30 min, ST 45 min) and during the small intestinal phase (SI 30 min, SI 60 min, SI 90 min, SI 120 min, SI 150 min, and SI 180 min). Additionally, capsule integrity scores at each sampling time point are shown above the bars in the figures (1=intact to 4=completely dissolved). [Figure 4B]Activity of Wobenzym HPMC / pectin capsules during upper GIT digestion Trypsin activity (Figures 4A and 4B; USP units / reactant) and bromelain activity (Figures 4C and 4D; units / reactant) of Wobenzym HPMC / pectin capsules during upper GIT digestion. Average values ​​of measurements (Figures 4A and 4C, expressed as mean ± standard deviation, n=3) and replicate single measurements (Figures 4B and 4D) are shown. Data are examples of the product itself and of samples taken during the gastric phase (ST 15 min, ST 30 min, ST 45 min) and during the small intestinal phase (SI 30 min, SI 60 min, SI 90 min, SI 120 min, SI 150 min, and SI 180 min). Additionally, capsule integrity scores at each sampling time point are shown above the bars in the figures (1=intact to 4=completely dissolved). [Figure 4C] Activity of Wobenzym HPMC / pectin capsules during upper GIT digestion Trypsin activity (Figures 4A and 4B; USP units / reactant) and bromelain activity (Figures 4C and 4D; units / reactant) of Wobenzym HPMC / pectin capsules during upper GIT digestion. Average values ​​of measurements (Figures 4A and 4C, expressed as mean ± standard deviation, n=3) and replicate single measurements (Figures 4B and 4D) are shown. Data are examples of the product itself and of samples taken during the gastric phase (ST 15 min, ST 30 min, ST 45 min) and during the small intestinal phase (SI 30 min, SI 60 min, SI 90 min, SI 120 min, SI 150 min, and SI 180 min). Additionally, capsule integrity scores at each sampling time point are shown above the bars in the figures (1=intact to 4=completely dissolved). [Figure 4D]Activity of Wobenzym HPMC / pectin capsules during upper GIT digestion Trypsin activity (Figures 4A and 4B; USP units / reactant) and bromelain activity (Figures 4C and 4D; units / reactant) of Wobenzym HPMC / pectin capsules during upper GIT digestion. Average values ​​of measurements (Figures 4A and 4C, expressed as mean ± standard deviation, n=3) and replicate single measurements (Figures 4B and 4D) are shown. Data are examples of the product itself and of samples taken during the gastric phase (ST 15 min, ST 30 min, ST 45 min) and during the small intestinal phase (SI 30 min, SI 60 min, SI 90 min, SI 120 min, SI 150 min, and SI 180 min). Additionally, capsule integrity scores at each sampling time point are shown above the bars in the figures (1=intact to 4=completely dissolved). [Diagram 5] Dissolution Behavior of Wobenzym HPMC / Pectin Capsules. Photographs are included for several distinct time points (i.e., products such as ST45, SI60, SI120, and SI180). The corresponding capsule score is included in the top left corner of each photograph. [Figure 6A] Daily trypsin activity for each product formulation. Average daily trypsin activity (USP units / day, expressed as mean ± standard deviation, n=3) for the different product formulations throughout the upper GIT. Results are shown for (A) Wobenzym PS tablets, (B) Wobenzym control HPMC capsules, (C) Wobenzym HPMC / gellan gum capsules, and (D) Wobenzym HPMC / pectin capsules. Data are representative of the product itself, as well as samples taken during the gastric phase (ST 15 min, ST 30 min, ST 45 min) and small intestinal phase (SI 30 min, SI 60 min, SI 90 min, SI 120 min, SI 150 min, and SI 180 min). Additionally, capsule integrity scores at each sampling time point are shown above the bars in the figure (1=still intact to 4=completely dissolved). [Figure 6B]Daily trypsin activity for each test formulation Average daily trypsin activity (USP units / day, expressed as mean ± standard deviation, n=3) for the different test formulations throughout the upper GIT. Results are shown for (A) Wobenzym PS tablets, (B) Wobenzym control HPMC capsules, (C) Wobenzym HPMC / gellan gum capsules, and (D) Wobenzym HPMC / pectin capsules. Data are examples of the products themselves and samples taken during the gastric phase (ST 15 min, ST 30 min, ST 45 min) and small intestinal phase (SI 30 min, SI 60 min, SI 90 min, SI 120 min, SI 150 min, and SI 180 min). Additionally, capsule integrity scores at each sampling time point are shown above the bars in the figure (1=still intact to 4=completely dissolved). [Figure 6C] Daily trypsin activity for each test formulation Average daily trypsin activity (USP units / day, expressed as mean ± standard deviation, n=3) for the different test formulations throughout the upper GIT. Results are shown for (A) Wobenzym PS tablets, (B) Wobenzym control HPMC capsules, (C) Wobenzym HPMC / gellan gum capsules, and (D) Wobenzym HPMC / pectin capsules. Data are examples of the products themselves and samples taken during the gastric phase (ST 15 min, ST 30 min, ST 45 min) and small intestinal phase (SI 30 min, SI 60 min, SI 90 min, SI 120 min, SI 150 min, and SI 180 min). Additionally, capsule integrity scores at each sampling time point are shown above the bars in the figure (1=still intact to 4=completely dissolved). [Figure 6D]Daily trypsin activity for each test formulation Average daily trypsin activity (USP units / day, expressed as mean ± standard deviation, n=3) for the different test formulations throughout the upper GIT. Results are shown for (A) Wobenzym PS tablets, (B) Wobenzym control HPMC capsules, (C) Wobenzym HPMC / gellan gum capsules, and (D) Wobenzym HPMC / pectin capsules. Data are examples of the products themselves and samples taken during the gastric phase (ST 15 min, ST 30 min, ST 45 min) and small intestinal phase (SI 30 min, SI 60 min, SI 90 min, SI 120 min, SI 150 min, and SI 180 min). Additionally, capsule integrity scores at each sampling time point are shown above the bars in the figure (1=still intact to 4=completely dissolved). [Figure 7A] Daily Bromelain Activity of Each Test Formulation Average daily Bromelain activity (units / day, expressed as mean ± standard deviation, n=3) of the different test formulations throughout the upper GIT. Results are shown for (A) Wobenzym PS tablets, (B) Wobenzym control HPMC capsules, (C) Wobenzym HPMC / gellan gum capsules, and (D) Wobenzym HPMC / pectin capsules. Data are examples of the products themselves and samples taken during the gastric phase (ST 15 min, ST 30 min, ST 45 min) and the small intestinal phase (SI 30 min, SI 60 min, SI 90 min, SI 120 min, SI 150 min, and SI 180 min). Additionally, capsule integrity scores at each sampling time point are shown above the bars in the figure (1=still intact to 4=completely dissolved). [Figure 7B]Daily Bromelain Activity of Each Test Formulation Average daily Bromelain activity (units / day, expressed as mean ± standard deviation, n=3) of the different test formulations throughout the upper GIT. Results are shown for (A) Wobenzym PS tablets, (B) Wobenzym control HPMC capsules, (C) Wobenzym HPMC / gellan gum capsules, and (D) Wobenzym HPMC / pectin capsules. Data are examples of the products themselves and samples taken during the gastric phase (ST 15 min, ST 30 min, ST 45 min) and the small intestinal phase (SI 30 min, SI 60 min, SI 90 min, SI 120 min, SI 150 min, and SI 180 min). Additionally, capsule integrity scores at each sampling time point are shown above the bars in the figure (1=still intact to 4=completely dissolved). [Figure 7C] Daily Bromelain Activity of Each Test Formulation Average daily Bromelain activity (units / day, expressed as mean ± standard deviation, n=3) of the different test formulations throughout the upper GIT. Results are shown for (A) Wobenzym PS tablets, (B) Wobenzym control HPMC capsules, (C) Wobenzym HPMC / gellan gum capsules, and (D) Wobenzym HPMC / pectin capsules. Data are examples of the products themselves and samples taken during the gastric phase (ST 15 min, ST 30 min, ST 45 min) and the small intestinal phase (SI 30 min, SI 60 min, SI 90 min, SI 120 min, SI 150 min, and SI 180 min). Additionally, capsule integrity scores at each sampling time point are shown above the bars in the figure (1=still intact to 4=completely dissolved). [Figure 7D]Daily Bromelain Activity of Each Test Formulation Average daily Bromelain activity (units / day, expressed as mean ± standard deviation, n=3) of the different test formulations throughout the upper GIT. Results are shown for (A) Wobenzym PS tablets, (B) Wobenzym control HPMC capsules, (C) Wobenzym HPMC / gellan gum capsules, and (D) Wobenzym HPMC / pectin capsules. Data are examples of the products themselves and samples taken during the gastric phase (ST 15 min, ST 30 min, ST 45 min) and the small intestinal phase (SI 30 min, SI 60 min, SI 90 min, SI 120 min, SI 150 min, and SI 180 min). Additionally, capsule integrity scores at each sampling time point are shown above the bars in the figure (1=still intact to 4=completely dissolved). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0041] Various preferred features and embodiments of the present invention will now be described by way of non-limiting examples.

[0042] It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0043] As used herein, the terms "comprising," "comprises," and "comprised of" are synonymous with "including," "includes," "containing," or "contains" and are all-inclusive, i.e., open-ended, and do not exclude additional, unrecited components, elements, or steps. The terms "comprising," "comprises," and "comprised of" also include the term "consisting of."

[0044] Numerical ranges include the numbers that define the range. As used herein, the term "about" means approximately, in the region of, roughly, or in the vicinity of. When the term "about" is used in conjunction with a numerical value or range, the value or range modifies the value or range by expanding the upper and lower boundaries of the stated numerical value(s). In general, the terms "about" and "approximately" are used herein to adjust numerical value(s) above and below the stated value(s) by 10%.

[0045] As used herein, "FIP Unit" refers to Protease Activity Units as defined by the Federation Internationale Pharmaceutique (International Union of Biochemistry. Nomenclature Committee: Enzyme Nomenclature. London: Academic Press; 1984).

[0046] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Any publications cited herein should not be construed as an admission that they constitute prior art to the claims appended hereto.

[0047] The present disclosure is not limited by the exemplary methods and materials disclosed herein, and any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present disclosure. It will be understood that one skilled in the art can combine all features of the invention disclosed herein without departing from the scope of the invention disclosed herein.

[0048] All publications mentioned herein are hereby incorporated by reference.

[0049] capsule In one aspect, the present invention provides a capsule comprising one or more proteases.

[0050] As used herein, "capsule" may refer to a dosage form in which the capsule contents (including one or more active ingredients) are enclosed within a capsule shell. The "capsule shell" may be formed of a body portion and a cap portion. The capsule of the present invention may be a hard shell capsule. The hard capsule shell is formed without the capsule contents and then filled with the capsule contents (including one or more active ingredients). After administration, the hard capsule shell dissolves and releases the capsule contents (including one or more active ingredients) enclosed therein.

[0051] The capsule may be acid-resistant. As used herein, "acid-resistant capsule" may refer to a capsule that does not release capsule contents (e.g., one or more active ingredients) in an acidic environment. The shell of the acid-resistant capsule may be insoluble in an acidic environment.

[0052] The capsule may be gastroresistant. As used herein, "gastroresistant capsule" may refer to a capsule in which the capsule contents (e.g., one or more active ingredients) are not released in the stomach, but are released further downstream in the gastrointestinal tract. The shell of the gastroresistant capsule may be insoluble in gastric acid. Gastric acid (also known as gastric juice or stomach acid) is a digestive fluid formed by the stomach wall, typically having a pH of about 1 to about 3.

[0053] Preferably, the capsule shell used in the present invention is insoluble under gastric conditions. As used herein, "gastric conditions" may refer to the highly acidic environment in the gastric lumen (Evans, DF, et al., 1988. Gut, 29(8), pp.1035-1041). Preferably, gastric conditions may be about pH 1 to about pH 3 (e.g., about pH 2.0) at about 37°C.

[0054] Preferably, the capsule shell used in the present invention is soluble under small intestinal conditions. As used herein, "small intestinal conditions" may refer to the environment in the small intestine (including the duodenum, jejunum, and ileum). The pH gradually increases from about pH 6 in the small intestine to about pH 7.4 at the terminal ileum (Fallingborg, J., 1999. Danish Medical Bulletin, 46(3), pp.183-196). Preferably, the small intestinal conditions may be about pH 5 to about pH 8 (e.g., about pH 5.5 to about pH 7.0) at about 37°C.

[0055] In some embodiments, the capsule used in the present invention is an HPMC capsule.As used herein, "HPMC capsule" can refer to a capsule whose capsule shell comprises hydroxypropylmethylcellulose (HPMC).See, for example, Majee, SB, et al., 2017.Int J Pharm Pharm Sci, 9(10), pp.1-6.

[0056] Suitably, the capsule used in the present invention is not an enteric coated capsule. As used herein, "enteric coated capsule" may refer to a capsule having an enteric coating (see, for example, Cole, ET, et al., 2002. International journal of pharmaceutics, 231(1), pp.83-95). "Enteric coating" may refer to a polymer barrier applied to an oral drug to prevent dissolution or disintegration in the gastric environment. Materials used for enteric coating include fatty acids, waxes, shellac, plastics, and vegetable fibers. Polymers commonly used as enteric coatings include anionic polymethacrylates, cellulose-based polymers (e.g., cellulose acetate phthalate), and polyvinyl derivatives (e.g., polyvinyl acetate phthalate).

[0057] Capsule Shell Water-soluble film-forming polymers The capsule shell used in the present invention comprises a water-soluble film-forming polymer.

[0058] As used herein, "water-soluble film-forming polymer" may refer to a water-soluble polymer that can be used to form a film. Examples of water-soluble film-forming polymers include hydroxypropyl methylcellulose, starch, gelatin, pullulan, polyvinyl alcohol, hydroxypropylated starch, hydroxyethyl starch, hydroxypropyl cellulose, methylcellulose, hydroxyethyl cellulose, and hydroxyethyl methylcellulose.

[0059] Preferably, the water-soluble film-forming polymer has a molecular weight of at least about 50 kDa. Preferably, the water-soluble film-forming polymer has a molecular weight of from about 50 kDa to about 815 kDa, or from about 50 kDa to about 400 kDa.

[0060] In some embodiments, the capsule shell used in the present invention comprises hydroxypropyl methylcellulose (HPMC).

[0061] Hydroxypropyl methylcellulose (also known as hypromellose) is a mixed methyl and hydroxypropyl ether of cellulose that is widely used as a capsule shell material (see, e.g., Majee, SB, et al., 2017. Int J Pharm Pharm Sci, 9(10), pp. 1-6).

[0062] Suitably, HPMC (or other water soluble film forming polymer) is present in the capsule shell in an amount of at least about 65% by weight, at least about 70% by weight, at least about 75% by weight, or at least about 80% by weight.

[0063] Suitably, HPMC (or other water soluble film forming polymer) is present in the capsule shell in an amount of about 97% by weight or less, about 95% by weight or less, about 90% by weight or less, or about 85% by weight or less.

[0064] Preferably, HPMC (or other water soluble film forming polymer) is present in the capsule shell in an amount of about 65% to about 97%, about 70% to about 95%, about 75% to about 90%, or about 80% to about 85% by weight.

[0065] Water-soluble enteric polymers The capsule shell used in the present invention comprises a water soluble enteric polymer.

[0066] As used herein, "water-soluble enteric polymer" may refer to a water-soluble polymer that is resistant to gastric acid. Preferably, the water-soluble enteric polymer is insoluble in gastric acid. The water-soluble enteric polymer may provide a capsule shell that is gastroresistant. Examples of water-soluble enteric polymers include pectin, propylene glycol alginate (PGA), and xanthan gum. Preferably, the water-soluble enteric polymer is pectin or PGA.

[0067] Preferably, the water-soluble enteric polymer has a molecular weight of at least about 20 kDa, at least about 30 kDa, at least about 40 kDa, or at least about 50 kDa. Preferably, the water-soluble enteric polymer has a molecular weight of about 1000 kDa or less, about 800 kDa or less, about 600 kDa or less, about 400 kDa or less, or about 200 kDa or less. Preferably, the water-soluble enteric polymer has a molecular weight of about 20 kDa to about 1000 kDa, about 40 kDa to about 400 kDa, or about 50 kDa to about 200 kDa.

[0068] Preferably, the ratio of hydrophobic functional groups to hydrophilic functional groups in the water-soluble enteric polymer is about 30:70 to about 70:30, about 40:60 to about 60:40, or about 45:55 to about 55:45. The ratio of hydrophobic functional groups to hydrophilic functional groups can be determined by any suitable method.

[0069] In some embodiments, the capsule shell used in the present invention comprises pectin.

[0070] Pectin, also known as pectic polysaccharide, is rich in galacturonic acid. Pectin may contain homogalacturonan, rhamnogalacturonan-I, and rhamnogalacturonan-II as components. Homogalacturonan is the most abundant pectin and is a homopolymer consisting of up to 200 units of α(1-4) linked D-galacturonic acid. Rhamnogalacturonan-I pectin contains the repeating disaccharide: 4)-α-D-galacturonic acid-(1,2)-α-L-rhamnose-(1) as the backbone. Rhamnogalacturonan-II is a less frequent, complex, highly branched polysaccharide.

[0071] Preferably, the pectin has a degree of esterification of at least about 15%, or at least about 20%. Preferably, the pectin has a degree of esterification of about 40% or less, about 35% or less, or about 30% or less. Preferably, the pectin has a degree of esterification of about 15% to about 40%, or about 20% to about 35%, or about 20% to about 30%.

[0072] Preferably, the pectin has a degree of amidation of at least about 0%, at least about 5%, at least about 10%, or at least about 15%. Preferably, the pectin has a degree of amidation of about 0% to about 25%, about 5% to about 25%, about 10% to about 25%, or about 15% to about 25%.

[0073] Preferably, the pectin has a degree of esterification of about 15% to about 40%, and a degree of amidation of about 0% to about 25%. Preferably, the pectin has a degree of esterification of about 20% to about 35%, and a degree of amidation of about 10% to about 25%. Preferably, the pectin has a degree of esterification of about 20% to about 30%, and a degree of amidation of about 15% to about 25%.

[0074] "Degree of esterification" (DE) may refer to the percentage of galacturonic acid that is esterified. The degree of esterification can be determined by any method known to those skilled in the art (see, for example, Guillotin, SE, et al., 2007. Food hydrocolloids, 21(3), pp. 444-451). For example, the degree of methyl esterification can be determined using the following formula: Degree of esterification = (mmol of methanol / mmol of uronic acid) x 100 where the uronic acid content is measured using a colorimetric method and the methanol content is measured by HPLC after alkaline treatment of the pectin sample, as described, for example, in Melton, LD and Smith, BG, 2001 Current Protocols in Food Analytical Chemistry, (1), E3-3.

[0075] "Degree of amidation" (DA) may refer to the percentage of galacturonic acid that is amidated. The degree of amidation can be determined by any method known to those skilled in the art, for example, as described in Reitsma, JCE, et al., 1986. Food hydrocolloids, 1(2), pp. 121-127.

[0076] Suitably, pectin (or other water soluble enteric polymer) is present in the capsule shell in an amount of at least about 3% by weight, at least about 5% by weight, at least about 10% by weight.

[0077] Suitably, pectin (or other water soluble enteric polymer) is present in the capsule shell in an amount of about 30% by weight or less, about 25% by weight or less, or about 20% by weight or less.

[0078] Suitably, pectin (or other water soluble enteric polymer) is present in the capsule shell in an amount of about 3% to about 30%, about 5% to about 25%, or about 10% to about 20% by weight.

[0079] Other Ingredients The capsule shells used in the present invention may contain one or more additional ingredients, such as a solidifying agent, moisture, colorants / opacifiers, plasticizers, or flavoring agents.

[0080] Preferably, the capsule shell used in the present invention comprises one or more solidifying agents. As used herein, "solidifying agent" may refer to an ingredient that aids in the formation of a film from a water-soluble film-forming polymer. Examples of solidifying agents include gellan gum, carrageenan, alginate, agar, konjac gum, and locust bean gum. Preferably, the solidifying agent has a molecular weight of about 450 kDa to about 550 kDa.

[0081] Suitably, the capsule shell used in the present invention further comprises gellan gum and / or carrageenan.

[0082] Suitably, the capsule shells used in the present invention contain gellan gum and / or carrageenan (or other solidifying agent) in an amount of about 0.5% to about 3% by weight.

[0083] Preferably, the capsule shell used in the present invention does not contain a coagulant. Preferably, the capsule shell used in the present invention does not contain gellan gum and / or carrageenan. Preferably, the capsule shell used in the present invention does not contain gellan gum.

[0084] Preferably, the capsule shell used in the present invention has a water content of at least about 2% by weight, at least about 3% by weight, or at least about 4% by weight. Preferably, the capsule shell used in the present invention has a water content of at least about 8% by weight or less, about 7% by weight or less, or about 6% by weight or less. Preferably, the capsule shell used in the present invention has a water content of about 2% by weight to about 8% by weight, about 3% by weight to about 7% by weight, about 4% by weight to about 7% by weight, or about 4% by weight to about 6% by weight.

[0085] Suitably, the capsule shells used in the present invention contain one or more colouring agents and / or opacifiers. Suitable colouring agents and opacifiers are known to those skilled in the art and include, for example, iron pigments, titanium dioxide, caramel, riboflavin, carmine, sodium cuprate and chlorophyllin.

[0086] Suitably, the capsule shell used in the present invention comprises one or more plasticizers. Suitable plasticizers are known to those skilled in the art and may include glycerol, PEG400, PEG1000 and triacetin (see, for example, Saringat, HB, et al., 2005. Pak J Pharm Sci, 18(3), pp.25-38). Suitably, the capsule shell may comprise one or more plasticizers in an amount of about 0% to about 10% by weight, about 0% to about 5% by weight, or about 5% by weight.

[0087] Preferably, the capsule shell used in the present invention comprises glycerol. Preferably, the capsule shell may comprise glycerol in an amount of about 0% to about 10% by weight, about 0% to about 5% by weight, or about 5% by weight.

[0088] Suitably, the capsule shells used in the present invention contain one or more flavouring agents. Suitable flavouring agents will be known to those skilled in the art. Preferably, the capsule shell used in the present invention comprises: (i) HPMC in an amount of about 65% to about 97% by weight; (ii) pectin in an amount of about 3% to about 30% by weight; (iii) a moisture content of about 4% to about 7% by weight, and

[0089] In this context, "consisting essentially of" may mean that additional water-soluble film-forming polymers, additional water-soluble enteric polymers, and solidifying agents are absent from the capsule shell, but other ingredients such as colorants / opacifiers, plasticizers, or flavoring agents are not excluded.

[0090] Method for producing capsule shells Suitable methods for producing capsule shells for use in the present invention are known to those skilled in the art (see, for example, Majee, SB, et al., 2017. Int J Pharm Pharm Sci, 9(10), pp. 1-6). Any commercially available capsule making machine may be used for the production method.

[0091] Typically, the process for producing the capsule shell comprises: (a) providing a capsule shell composition comprising a water soluble film-forming polymer (e.g., HPMC), a water soluble enteric polymer (e.g., pectin), a gelling aid (e.g., a divalent cation), and optionally other ingredients; (b) mixing the capsule shell composition with a solvent (e.g., water), thereby forming a capsule shell solution; (c) dipping a molding pin into the capsule shell solution; (d) withdrawing the mold pin, drying and stripping, thereby forming the body portion and / or the cap portion of the capsule shell.

[0092] Suitably, the capsule shell composition comprises HPMC (or other water soluble film forming polymer) in an amount of about 65% to about 97%, about 70% to about 95%, about 75% to about 90%, or about 80% to about 85% by weight.

[0093] Suitably, the capsule shell composition comprises pectin (or other water soluble enteric polymer) in an amount of from about 3% to about 30% by weight, or from about 5% to about 25% by weight, or from about 10% to about 20% by weight.

[0094] Suitably, the capsule shell composition comprises the gelling aid in an amount of about 0.05% to about 5% by weight, for example about 0.3% by weight.

[0095] As used herein, "gelling aid" may refer to an ingredient that aids in gelling during capsule shell formation, such as a monovalent or divalent cation or a salt thereof. Examples of gelling aids include potassium ions, sodium ions, calcium ions, magnesium ions, zinc ions, potassium chloride, sodium chloride, calcium chloride, magnesium chloride, etc. Divalent cations may act as gelling aids by forming ionic crosslinks between the ionized carboxyl groups of galacturonic acid in pectin.

[0096] Preferably, the gelling aid is a divalent cation or a salt thereof. Preferably, the gelling aid is a calcium ion, a magnesium ion, a zinc ion, or a salt thereof. Preferably, the gelling aid is a calcium ion or a magnesium ion, or a salt thereof. Preferably, the gelling agent is calcium chloride.

[0097] Suitably, the capsule shell composition used in the present invention comprises: (i) HPMC in an amount of about 65% to about 97% by weight; (ii) pectin in an amount of about 3% to about 30% by weight; and, comprising, consisting essentially of, or consisting of divalent cations in an amount of about 0.05% to about 5% by weight.

[0098] Any suitable conditions may be used for the manufacturing method. Preferably, mixing is performed at a temperature of about 40°C to about 100°C (e.g., about 80°C) so that the capsule shell composition is completely dissolved in the solvent. Preferably, immersion is performed at a temperature of about 40°C to about 100°C (e.g., about 55°C) for film formation. Preferably, drying is performed at a temperature of about 10°C to about 80°C (e.g., about 25°C) for forming the body portion and / or the cap portion.

[0099] Proteases The capsules of the present invention contain one or more proteases.

[0100] Proteases (also known as peptidases or proteinases) are enzymes that catalyze proteolysis, breaking down proteins into smaller polypeptides or amino acids. Proteases catalyze this reaction by cleaving peptide bonds in proteins through hydrolysis. Proteases can be classified into various groups including serine proteases, cysteine ​​proteases, threonine proteases, aspartic acid proteases, glutamic acid proteases, metalloproteases, and asparagine peptide lyases. Sources of proteases include plants, animals, and microorganisms. Any protease suitable for oral administration can be used in the present invention.

[0101] Preferably, the one or more proteases are of plant and / or animal origin. Preferably, the one or more proteases are selected from the group consisting of bromelain, trypsin, papain, chymotrypsin, pancreatin, serratiopeptidase, ficain, nattokinase, or any combination thereof. Preferably, the one or more proteases are selected from the group consisting of bromelain, trypsin, papain, and chymotrypsin, or any combination thereof.

[0102] In some embodiments, the one or more proteases comprise or consist of bromelain and / or trypsin, In some embodiments, the one or more proteases comprise or consist of bromelain and trypsin.

[0103] The capsules of the present invention may contain one or more proteases in any suitable amount.

[0104] Suitably, the capsule comprises one or more proteases in a total amount of at least about 50 mg, at least about 75 mg, at least about 100 mg, at least about 125 mg, at least about 150 mg, or at least about 200 mg.

[0105] Suitably, the capsule contains one or more proteases in a total amount of about 1000 mg or less, about 800 mg or less, about 600 mg or less, about 500 mg or less, about 400 mg or less, or about 300 mg or less.

[0106] Suitably, the capsule contains one or more proteases in a total amount of about 50 mg to about 1000 mg, about 75 mg to about 800 mg, about 100 mg to about 600 mg, about 125 mg to about 500 mg, about 150 mg to about 400 mg, or about 200 mg to about 300 mg.

[0107] Suitably, the capsule comprises one or more proteases in a total amount of at least about 1000 FIP units, at least about 1500 FIP units, at least about 2000 FIP units, all at least about 2500 FIP units, or at least about 3000 FIP units.

[0108] Suitably, the capsule comprises one or more proteases in a total amount of about 12000 FIP units or less, about 10000 FIP units or less, about 8000 FIP units or less, about 6000 FIP units or less, or about 4000 FIP units or less.

[0109] Preferably, the capsule contains one or more proteases in a total amount of about 1000 FIP Units to about 12000 FIP Units, about 1500 FIP Units to about 10000 FIP Units, about 2000 FIP Units to about 8000 FIP Units, about 2500 FIP Units to about 6000 FIP Units, or about 3000 FIP Units to about 4000 FIP Units.

[0110] Bromelain In some embodiments, the capsules of the present invention comprise bromelain.

[0111] Bromelain is an enzyme extract usually derived from the stem of pineapple, but is present in all parts of fresh pineapple. As used herein, the term "bromelain" may refer to either of two protease enzymes extracted from plants of the Bromeliaceae family, or to a combination of these enzymes with other compounds produced in the extract. Bromelain enzymes are called fruit bromelain (EC 3.4.22.33) and stem bromelain (EC 3.4.22.32). Sources of bromelain are known in the art (see, for example, Arshad, ZIM, et al., 2014. Applied microbiology and biotechnology, 98(17), pp.7283-7297). Preferably, the bromelain is stem bromelain.

[0112] Suitably, the capsule comprises bromelain in an amount of at least about 50 mg, at least about 75 mg, at least about 100 mg, or at least about 125 mg.

[0113] Suitably, the capsules contain bromelain in an amount of about 500 mg or less, about 400 mg or less, about 300 mg or less, or about 200 mg or less.

[0114] Suitably, the capsule contains bromelain in an amount of about 50 mg to about 500 mg, about 75 mg to about 400 mg, about 100 mg to about 300 mg, about 100 mg to about 200 mg, or about 125 mg to about 200 mg.

[0115] Suitably, the capsules contain bromelain in an amount of about 150 mg, about 180 mg, about 225 mg, or about 270 mg.

[0116] Preferably, the capsule contains bromelain in an amount of about 150 mg.

[0117] Suitably, the capsule comprises bromelain in an amount of at least about 400 FIP units, at least about 500 FIP units, at least about 600 FIP units, at least about 700 FIP units, or at least about 800 FIP units.

[0118] Suitably, the capsule comprises bromelain in an amount of about 3000 FIP units or less, about 2500 FIP units or less, about 2000 FIP units or less, about 1500 FIP units or less, or about 1000 FIP units or less.

[0119] Suitably, the capsule contains bromelain in an amount of about 400 FIP Units to about 3000 FIP Units, about 500 FIP Units to about 2500 FIP Units, about 600 FIP Units to about 2000 FIP Units, about 700 FIP Units to about 1500 FIP Units, or about 800 FIP Units to about 1000 FIP Units.

[0120] Suitably, the capsule contains bromelain in an amount of about 900 FIP units or about 1350 FIP units.

[0121] Preferably, the capsule contains bromelain in an amount of about 900 FIP units.

[0122] Trypsin In some embodiments, the capsules of the present invention comprise trypsin.

[0123] Trypsin (EC 3.4.21.4) is a serine protease present in the digestive system of many vertebrates. It is found in large amounts in the pancreas (e.g., porcine, bovine, or ovine pancreas) and can be easily purified.

[0124] Suitably, the capsule comprises trypsin in an amount of at least about 20 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, or at least about 60 mg.

[0125] Suitably, the capsule contains trypsin in an amount of about 250 mg or less, about 200 mg or less, about 150 mg or less, about 100 mg or less, or about 80 mg or less.

[0126] Suitably, the capsule contains trypsin in an amount of about 20 mg to about 250 mg, about 30 mg to about 200 mg, about 40 mg to about 150 mg, about 50 mg to about 100 mg, or about 60 mg to about 80 mg.

[0127] Suitably, the capsule contains trypsin in an amount of about 72 mg, about 96 mg, about 108 mg, or about 144 mg.

[0128] Preferably, the capsule contains trypsin in an amount of about 72 mg.

[0129] Suitably, the capsule comprises trypsin in an amount of at least about 1000 FIP units, at least about 1500 FIP units, at least about 1750 FIP units, at least about 2000 FIP units, at least about 2250 FIP units, or at least about 2500 FIP units.

[0130] Suitably, the capsule comprises trypsin in an amount of about 10,000 FIP units or less, about 8,000 FIP units or less, about 6,000 FIP units or less, about 5,000 FIP units or less, about 4,500 FIP units or less, or about 4,000 FIP units or less.

[0131] Preferably, the capsule contains trypsin in an amount of about 1000 FIP Units to about 10000 FIP Units, about 1500 FIP Units to about 8000 FIP Units, about 1750 FIP Units to about 6000 FIP Units, about 2000 FIP Units to about 5000 FIP Units, about 2250 FIP Units to about 4500 FIP Units, or about 2500 FIP Units to about 4000 FIP Units.

[0132] Preferably, the capsule contains trypsin in an amount of about 2880 FIP units or about 4320 FIP units.

[0133] Preferably, the capsule contains trypsin in an amount of about 2880 FIP units.

[0134] Suitably, the capsule comprises bromelain in an amount of about 50 mg to about 500 mg (eg, about 150 mg) and trypsin in an amount of about 20 mg to about 250 mg (eg, about 72 mg).

[0135] Suitably, the capsule comprises bromelain in an amount of about 400 FIP units to about 3000 FIP units (eg, about 900 FIP units) and trypsin in an amount of about 1000 FIP units to about 10000 FIP units (eg, about 2880 FIP units).

[0136] Flavonoids The capsules of the present invention may further comprise one or more flavonoids.

[0137] Flavonoids (also known as bioflavonoids) are a class of polyphenolic secondary metabolites present in plants and may include flavonoids, isoflavonoids, and neoflavonoids. Flavonoids, isoflavonoids, and neoflavonoids are natural products derived from 2-phenylchromen-4-ones (flavones), 3-phenylchromen-4-ones, and 4-phenylcoumarins, respectively (IUPAC. Compendium of Chemical Terminology, 2nd ed. (the "Gold Book"). Compiled by A.D. McNaught and A. Wilkinson. Blackwell Scientific Publications, Oxford (1997)). Flavonoids can be classified into various groups, including anthocyanidins, chalcones, flavonols, flavanones, flavan-3-ols, flavanonols, flavones, and isoflavonoids. Any flavonoid suitable for oral administration can be used in the present invention (see, for example, Ververidis, F., et al., 2007. Biotechnology Journal: Healthcare Nutrition Technology, 2(10), pp. 1214-1234).

[0138] Flavonoids can be found in plants in the form of glycosidic bonds and free aglycones. Preferably, the one or more flavonoids are in either form. In some embodiments, the one or more flavonoids are one or more flavonoid glycosides.

[0139] Preferably, the one or more flavonoids are derived from a plant. Preferably, the one or more flavonoids are selected from the group consisting of rutin, quercetin, kaempferol, myricetin, fisetin, catechin, epicatechin, hydroxytyrosol, oleuropein, hesperidin, or any combination thereof.

[0140] Suitably, the one or more flavonoids comprise or consist of one or more flavonols in glycosidically bound or free aglycone form, and optionally flavonol glycosides.

[0141] Suitably, the one or more flavonoids comprise or consist of quercetin in glycosidically bound or free aglycone form, and optionally quercetin glycosides.

[0142] In some embodiments, the one or more flavonoids include or consist of rutin.

[0143] Suitably, the capsule comprises one or more flavonoids in a total amount of at least about 50 mg, at least about 100 mg, at least about 125 mg, or at least about 150 mg.

[0144] Suitably, the capsule contains one or more flavonoids in a total amount of about 1000 mg or less, about 600 mg or less, about 400 mg or less, or about 300 mg or less.

[0145] Suitably, the capsule contains one or more flavonoids in a total amount of about 50 mg to about 1000 mg, about 100 mg to about 600 mg, about 125 mg to about 400 mg, or about 150 mg to about 300 mg.

[0146] Suitably, the capsule contains one or more flavonoids in a total amount of about 200 mg, about 250 mg, or about 300 mg.

[0147] Preferably, the capsule contains one or more flavonoids in a total amount of about 200 mg.

[0148] Preferably, the capsule contains one or more proteases in a total amount of about 50 mg to about 1000 mg, and one or more flavonoids in a total amount of about 50 mg to about 1000 mg.

[0149] Rutin In some embodiments, the capsules of the present invention comprise rutin.

[0150] Rutin (also called rutoside, quercetin-3-rutinoside, sophorin, 3,3',4',5,7-pentahydroxyflavone-3-rhamnoglucoside) is a flavonol found abundantly in plants such as passionflower, buckwheat, tea, and apple. Chemically, rutin is a glycoside containing the flavonol quercetin aglycone together with the disaccharide rutinose (see, e.g., Ganeshpurkar, A. and Saluja, AK, 2017. Saudi Pharmaceutical Journal, 25(2), pp. 149-164).

[0151] Suitably, the capsule comprises rutin in an amount of at least about 50 mg, at least about 100 mg, at least about 125 mg, or at least about 150 mg.

[0152] Suitably, the capsule contains rutin in an amount of about 1000 mg or less, about 600 mg or less, about 400 mg or less, or about 300 mg or less.

[0153] Suitably, the capsule contains rutin in an amount of about 50 mg to about 1000 mg, about 100 mg to about 600 mg, about 125 mg to about 400 mg, or about 150 mg to about 300 mg.

[0154] Suitably, the capsule contains rutin in an amount of about 200 mg, about 250 mg, or about 300 mg.

[0155] Preferably, the capsule contains rutin in an amount of about 200 mg.

[0156] Preferably, the capsule contains bromelain in an amount of about 50 mg to about 500 mg (e.g., about 150 mg), trypsin in an amount of about 20 mg to about 250 mg (e.g., about 72 mg), and rutin in an amount of about 50 mg to about 1000 mg (e.g., about 200 mg).

[0157] Suitably, the capsule contains bromelain in an amount of about 400 FIP units to about 3000 FIP units (e.g., about 900 FIP units), trypsin in an amount of about 1000 FIP units to about 10000 FIP units (e.g., about 2880 FIP units), and rutin in an amount of about 50 mg to about 1000 mg (e.g., about 200 mg).

[0158] Other Ingredients The capsules of the present invention may contain one or more additional components such as bulking agents, preservatives, stabilizers, binders, emulsifiers, solubilizers (e.g., oils, fats, waxes, lecithin, etc.), adsorbents, carriers, fillers, dispersants, wetting agents, processing aids, flow agents, weighting agents, taste masking agents, flavoring agents, and sweeteners. The capsules of the present invention may also contain one or more conventional pharmaceutical additives, adjuvants, excipients, or diluents.

[0159] Suitably, the capsule of the present invention may include one or more bulking agents. Any suitable bulking agent may be used, such as cellulose derivatives, insoluble fiber, rice flour, or lactose. Any suitable amount of bulking agent may be used, for example, depending on the concentration of the active ingredient. Suitably, the capsule contents include a bulking agent in an amount of about 25% by weight or less. Suitably, the capsule contents include a bulking agent in an amount of about 1% by weight or more, about 5% by weight or more, or about 10% by weight or more. Suitably, the capsule contents may include a bulking agent in an amount of about 1% by weight to about 25% by weight, about 5% by weight to about 25% by weight, or about 10% by weight to about 25% by weight.

[0160] Preferably, the bulking agent comprises or consists of one or more cellulose derivatives (see, for example, Mastropietro, DJ and Omidian, H., 2013. Drug development and industrial pharmacy, 39(2), pp. 382-392). Preferably, the cellulose derivative is selected from the group consisting of powdered microcrystalline cellulose (MCC), ethyl cellulose, hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose (HPMC), HPMC phthalate, HPMC acetate succinate, cellulose acetate (CA), CA phthalate, sodium (Na) and calcium (Ca) carboxymethylcellulose (CMC), croscarmellose sodium (XCMCNa), methylcellulose, and low-substituted HPC, or any combination thereof.

[0161] Suitably, the one or more fillers comprise or consist of microcrystalline cellulose (MCC) and / or hydroxypropyl cellulose (HPC).

[0162] Preferably, the capsule of the present invention may contain one or more preservatives. Any suitable preservative (e.g., antioxidant) may be used. Preferably, the capsule of the present invention contains L-ascorbyl palmitate. Preferably, the capsule contents contain one or more preservatives (e.g., antioxidants) in an amount of less than about 1% by weight.

[0163] Suitably, the capsules of the present invention include one or more anti-dusting agents. As used herein, "anti-dusting agent" may refer to anti-dusting materials that can be used to de-dust the granular enzyme preparation. Any suitable anti-dusting agent may be used. Suitably, the capsules of the present invention include medium chain triglycerides. Suitably, the capsule contents include one or more anti-dusting agents (e.g., medium chain triglycerides) in an amount of less than about 1% by weight. Preferably, the capsule contents are (i) bromelain in an amount of about 50 mg to about 500 mg (e.g., about 150 mg) or about 400 FIP units to about 3000 FIP units (e.g., about 900 FIP units); (i) trypsin in an amount of about 20 mg to about 250 mg (e.g., about 72 mg) or about 1000 FIP units to about 10000 FIP units (e.g., about 2880 FIP units); (iii) rutin in an amount of 50 mg to about 1000 mg (e.g., about 200 mg).

[0164] In this context, "consisting essentially of" may mean that the capsule shell does not encapsulate additional active ingredients, but does not exclude other ingredients such as fillers and preservatives.

[0165] Release Profile The capsules of the present invention can prevent the release of one or more proteases in the gastric phase and release one or more proteases in the small intestinal phase, thereby mimicking the kinetic profile of an enteric coated tablet.

[0166] "Gastric phase" may refer to the period during which the capsule is in the stomach after oral administration. "Small intestinal phase" may refer to the period during which the capsule is in the small intestine after oral administration.

[0167] In vitro assays for simulating the gastric and small intestinal phases are known in the art (see, for example, Van de Wiele, T., et al., 2015. The impact of food bioactives on health, pp. 305-317) and can be used to determine the kinetic profile of the capsules of the present invention. In the context of the in vitro assay, the "gastric phase" can refer to gastric conditions for about 45 minutes. Preferably, the gastric phase can include a pH of about 2.0 at 37°C for 45 minutes. In the context of the in vitro assay, the "small intestinal phase" can refer to small intestinal conditions for about 3 hours. Preferably, the small intestinal phase can include (i) a pH increase from about 5.5 to about 6.5 during the first hour at 37°C, (ii) a pH increase from about 6.5 to about 7.0 during the second hour at 37°C, and (iii) a constant pH of about 7.0 during the third hour at 37°C. Suitably, a liquid mixture of standardized enzymes and bile may be added to the small intestinal phase. Suitably, the gastric phase and / or the small intestinal phase may be simulated as described in the examples.

[0168] The capsule may remain intact during the gastric phase. Preferably, the capsule remains substantially intact during the gastric phase. In this context, "substantially intact" may mean that the capsule has minor damage as determined by visual inspection, but all the product is still within the capsule. Preferably, the capsule remains completely intact during the gastric phase. In this context, "completely intact" may mean that the capsule is undamaged as determined by visual inspection.

[0169] The capsule may be degraded in the small intestine phase. Preferably, the capsule is substantially degraded in the small intestine phase. In this context, "substantially degraded" (or "substantially dissolved") may mean that the capsule has broken down and all or substantially all of the product has been released, as determined by visual inspection. Preferably, the capsule is completely degraded in the small intestine phase. In this context, "completely degraded" (or "completely dissolved") may mean that the capsule has completely broken up, as determined by visual inspection.

[0170] The capsule contents may not be released in the gastric phase. Preferably, the protease activity is not substantially released in the gastric phase. In this context, "not substantially released" may mean that about 10% or less, about 5% or less, or about 1% or less of the protease activity present in the capsule is released. Preferably, the protease activity is not released during the gastric phase. In this context, "not released" may mean that the protease activity is not detectable in the gastric phase (e.g., the protease activity is not detectable or the protease activity is not significantly greater than the background protease activity).

[0171] The capsule contents may be released in the small intestinal phase. Preferably, the protease activity is substantially released in the small intestinal phase. In this context, "substantially released" may mean that at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% of the protease activity present in the capsule is released. Preferably, the protease activity is completely released in the small intestinal phase. In this context, "completely released" may mean that about 90% or more of the protease activity present in the capsule is released.

[0172] Protease activity can be determined by any suitable assay, for example, assays described in the Examples.Preferably, trypsin activity is determined using the TAME method.Preferably, bromelain activity is determined using the Z-RR-pNA method.

[0173] Dosage and Size Suitably, the capsules are formulated to provide an effective amount of one or more active ingredients.

[0174] Capsules may be formulated to provide a full or partial daily dose. Suitable daily doses are described herein.

[0175] Preferably, the capsule is formulated to contain about 1 / 2 the daily dose, about 1 / 3 the daily dose, about 1 / 4 the daily dose, about 1 / 5 the daily dose, or about 1 / 6 the daily dose. Preferably, the capsule is formulated to contain about 1 / 2 the daily dose, about 1 / 3 the daily dose, about 1 / 4 the daily dose, or about 1 / 5 the daily dose.

[0176] In some embodiments, the capsule is formulated to contain about 1 / 2 of the daily dose, or about 1 / 3 of the daily dose, hi some embodiments, the capsule is formulated to contain about 1 / 3 of the daily dose.

[0177] The capsule may be formulated to be any size suitable for oral administration. Preferably, the capsule size is 00, 0E, or 0. In a preferred embodiment, the capsule size is 00. Preferably, the mass of the capsule (excluding the capsule shell) is about 500 mg to about 800 mg. In some embodiments, the mass of the capsule (excluding the capsule shell) is about 700 mg to about 750 mg. In other embodiments, the mass of the capsule (excluding the capsule shell) is about 500 mg to about 600 mg. In some embodiments, the capsule size is 00 and the mass of the capsule (excluding the capsule shell) is about 700 mg to about 750 mg. In other embodiments, the capsule size is 0 and the mass of the capsule (excluding the capsule shell) is about 500 mg to about 600 mg.

[0178] Manufacturing method In one aspect, the present invention provides a method for producing a capsule comprising one or more proteases, the method comprising: (a) providing a capsule shell comprising a water soluble film-forming polymer and a water soluble enteric polymer; (b) filling the capsule shell with a capsule composition comprising one or more proteases.

[0179] The capsule shell can be any capsule shell described herein. For example, the capsule shell can comprise, consist essentially of, or consist of (i) HPMC in an amount of about 65% to about 97% by weight, (ii) pectin in an amount of about 3% to about 30% by weight, and (iii) a moisture content of about 4% to about 7% by weight. The method can further include producing the capsule shell, for example, by any method described herein. Preferably, the capsule shell is acid resistant. More preferably, the capsule shell is gastroresistant.

[0180] The capsule composition may include any suitable ingredient described herein. For example, the capsule composition may include (i) bromelain in an amount of about 50 mg to about 500 mg (e.g., about 150 mg) or about 400 FIP units to about 3000 FIP units (e.g., about 900 FIP units), (ii) trypsin in an amount of about 20 mg to about 250 mg (e.g., about 72 mg) or about 1000 FIP units to about 10000 FIP units (e.g., about 2880 FIP units), and (iii) rutin in an amount of 50 mg to about 1000 mg (e.g., about 200 mg).

[0181] Any suitable process for filling capsule shells may be used (see, e.g., Murachanian, D., 2010. Journal of GXP Compliance, 14(3), pp. 31-42). Suitable capsule filling machines are commercially available (see, e.g., Small, LE and Augsburger, LL, 1977. Journal of pharmaceutical sciences, 66(4), pp. 504-509). Typically, the process for filling hard capsules will include: (a) separating the body portion and the cap portion; (b) filling the body portion with a capsule composition; (c) locking the body portion and the cap portion together; and (d) ejecting the formed capsule.

[0182] In one aspect, the present invention provides a capsule obtained or obtainable by the aforementioned manufacturing method.

[0183] Pack of capsules In one aspect, the present invention provides a pack comprising a plurality of capsules according to the present invention.

[0184] Any suitable packaging may be used, such as a blister pack or a bottling pack. Preferably, the capsules are packaged in a bottle or container. The capsules may be packaged under sterile conditions. The pack may include suitable labels and / or instructions for oral administration.

[0185] Preferably, the pack comprises at least about a 15 day supply, at least about a 30 day supply, at least about a 45 day supply, at least about a 60 day supply, or at least about a 90 day supply. Preferably, the pack comprises about a 15 day supply, about a 30 day supply, about a 45 day supply, about a 60 day supply, or about a 90 day supply. Preferably, the pack comprises about a 30 day supply.

[0186] Preferably, the pack contains at least about 45 capsules, at least about 90 capsules, at least about 135 capsules, at least about 180 capsules, or at least about 270 capsules. Preferably, the pack contains about capsules, about 90 capsules, about 135 capsules, about 180 capsules, or about 270 capsules. Preferably, the pack contains about 90 capsules.

[0187] Supplements and medicines Oral administration of the capsules of the present invention may be associated with beneficial effects.

[0188] Oral administration of proteases may be associated with beneficial immunomodulatory effects. One possible mechanism is through modulation of the T cell activation threshold. At sites of inflammation where vascular permeability is locally increased, serum protein exudates can enter the interstitial compartment. Thus, trypsin and other proteases, together with complement components and IgM, are delivered to and concentrated at the site of inflammation. Proteases such as trypsin can cleave antigens that promote T cell activation, thereby modulating the immune response (see, for example, Lehmann, PV, 1996. Nephrology Dialysis Transplantation, 11(6), pp. 953-955).

[0189] Furthermore, oral administration of rutin has been previously investigated for a number of pharmacological effects, including immunomodulatory effects (see, for example, Ganeshpurkar, A. and Saluja, AK, 2017. Saudi Pharmaceutical Journal, 25(2), pp. 149-164).

[0190] In one aspect, the present invention provides the use of a capsule according to the present invention as a supplement. Suitably, the supplement is a dietary supplement.

[0191] In one aspect, the present invention provides a capsule of the present invention for use as a medicament.

[0192] In one aspect, the present invention provides a method of treatment comprising administering to a subject in need thereof a capsule according to the present invention.

[0193] In one aspect, the invention provides the use of one or more proteases in the manufacture of a medicament, wherein the medicament is in the form of a capsule according to the invention.

[0194] In one aspect, the invention provides a capsule of the invention for use in the treatment and / or prevention of inflammatory diseases, joint pain, arthropathy, injuries, back pain, or sciatica, or for use in accelerating healing.

[0195] In one aspect, the present invention provides a method of treating and / or preventing or promoting healing of inflammatory diseases, joint pain, arthropathy, injuries, back pain, or sciatica, comprising administering to a subject in need thereof a capsule according to the present invention.

[0196] In one aspect, the invention provides the use of one or more proteases in the manufacture of a medicament for treating and / or preventing or promoting healing of inflammatory diseases, joint pain, arthropathy, injuries, back pain, or sciatica, wherein the medicament is in the form of a capsule according to the invention.

[0197] inflammatory diseases Oral administration of proteases may be associated with beneficial effects in the treatment and / or prevention of inflammatory diseases. For example, oral administration of proteases has been shown to be a safe and effective option for treating acute thrombophlebitis in the absence of compression treatment (Baumueller, M. and Rau, S., 2018 Journal of Phlebology and Lymphology, 11(1), pp.7-12). Enzyme combinations of proteases have been shown to reduce and normalize biomarkers of inflammation in vestibulodynia and bladder pain syndrome (Murina, F., et al., V., 2013. Open Journal of Obstetrics and Gynecology, 3(4A), 33232).

[0198] In one aspect, the present invention provides a capsule according to the present invention for use in the treatment and / or prevention of an inflammatory disease.

[0199] In one aspect, the present invention provides a method for treating and / or preventing an inflammatory disease, comprising administering a capsule according to the present invention to a subject in need thereof.

[0200] In one aspect, the present invention provides the use of one or more proteases in the manufacture of a medicament for treating and / or preventing an inflammatory disease, wherein the medicament is in the form of a capsule according to the present invention.

[0201] As used herein, "inflammatory disease" may refer to a disease in which the immune system attacks the body's own tissues, resulting in inflammation. Examples of inflammatory diseases include encephalitis, myelitis, arachnoiditis, neuritis, dacryoadenitis / dacryocystitis, scleritis, episcleritis, keratitis, retinitis, chorioretinitis, blepharitis, conjunctivitis, uveitis, otitis externa, otitis media, labyrinthitis, mastoiditis, carditis, endocarditis, myocarditis, pericarditis, vasculitis, arteritis, phlebitis, capillaritis, sinusitis, rhinitis, pharyngitis, laryngitis, tracheitis, bronchitis, bronchiolitis, pneumonia, pleuritis, mediastinitis, stomatitis, gingivitis, gingivostomatitis, glossitis, tonsillitis, salivary gland inflammation / parotitis, cheilitis, pulpitis, jaw inflammation, esophagitis, gastritis, gastroenteritis, enteritis, colitis, enteritis, duodenitis, ileitis, appendicitis, proctitis, hepatitis, ascending Examples of such conditions include cholangitis, cholecystitis, pancreatitis, peritonitis, dermatitis, folliculitis, cellulitis, hidradenitis, arthritis, dermatomyositis, myositis, synovitis / tendinitis, bursitis, enthesitis, fasciitis, capsulitis, epicondylitis, tendonitis, panniculitis, osteochondritis, spondylitis, periostitis, chondritis, nephritis, ureteritis, cystitis, urethritis, oophoritis, salpingitis, endometritis, parametritis, cervicitis, vaginitis, vulvitis, mastitis, orchitis, epididymitis, prostatitis, seminal vesiculitis, balanitis, presitis, balanoposthitis, chorioamnionitis, omphalitis, omphalitis, insulitis, hypophysitis, thyroiditis, parathyroiditis, adrenitis, lymphangitis, and lymphadenitis.

[0202] In some embodiments, the inflammatory disease is selected from phlebitis, prostatitis, or cystitis.

[0203] Joint pain Oral administration of proteases may be associated with beneficial effects in the treatment and / or prevention of joint pain (see, e.g., Wald, M. and Rovensky, J., 2017. Systemic Enzyme Therapy in Comprehensive Treatment of Degenerative Rheumatic Diseases in the Elderly. In Gerontorheumatology (pp. 363-366). Springer, Cham).

[0204] In one aspect, the present invention provides a capsule according to the present invention for use in the treatment and / or prevention of joint pain.

[0205] In one aspect, the present invention provides a method for treating and / or preventing joint pain, comprising administering a capsule according to the present invention to a subject in need thereof.

[0206] In one aspect, the present invention provides the use of one or more proteases in the manufacture of a medicament for treating and / or preventing joint pain, wherein the medicament is in the form of a capsule according to the present invention.

[0207] As used herein, "joint pain" or "arthralgia" may refer to aching or pain in a joint (e.g., without inflammation). The causes of joint pain are diverse and range from those in terms of the joint, degenerative and destructive processes such as osteoarthritis and sports injuries, to inflammation of the tissues surrounding the joint, such as bursitis. Affected joints may include the knee, elbow, shoulder, hip, wrist, hand, and joints of the foot below the ankle.

[0208] In some embodiments, the joint pain is elbow joint pain, finger joint pain, knee joint pain, menopausal joint pain, or rheumatic pain.

[0209] Arthropathy Oral administration of proteases may be associated with beneficial effects in the treatment and / or prevention of arthropathy of joints. For example, in a randomized study of subjects with moderate to severe knee osteoarthritis, oral administration of proteolytic enzymes was found to have efficacy comparable to that of diclofenac in reducing pain and improving function (Ueberall, MA, et al., 2016. Journal of pain research, 9, pp. 941-961).

[0210] In one aspect, the present invention provides a capsule according to the present invention for use in the treatment and / or prevention of arthropathy.

[0211] In one aspect, the present invention provides a method for treating and / or preventing arthropathy comprising administering a capsule according to the present invention to a subject in need thereof.

[0212] In one aspect, the present invention provides the use of one or more proteases in the manufacture of a medicament for treating and / or preventing arthropathy, wherein the medicament is in the form of a capsule according to the present invention.

[0213] As used herein, "arthropathy" may include arthritis and other similar disorders. The term arthritis may include osteoarthritis, rheumatoid arthritis, gout and pseudogout, septic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, Still's disease, and psoriatic arthritis.

[0214] In one aspect, the present invention provides a capsule according to the present invention for use in the treatment and / or prevention of osteoarthritis.

[0215] In one aspect, the present invention provides a method for treating and / or preventing osteoarthritis, comprising administering a capsule according to the present invention to a subject in need thereof.

[0216] In one aspect, the present invention provides the use of one or more proteases in the manufacture of a medicament for treating and / or preventing osteoarthritis, wherein the medicament is in the form of a capsule according to the present invention.

[0217] Osteoarthritis is a type of degenerative disease of the joints caused by the destruction of articular cartilage and underlying bone. It can affect weight-bearing joints such as the hands, hips, and neck, as well as the knees, hips, and foot.

[0218] In some embodiments, the osteoarthritis is osteoarthritis of the hip, osteoarthritis of the knee, osteoarthritis of the metatarsophalangeal joint of the big toe, osteoarthritis of the fingers, osteoarthritis of the foot, osteoarthritis of the ankle, Heberden's nodes, and Bouchard's nodes.

[0219] In some embodiments, the osteoarthritis is osteoarthritis of the knee.

[0220] damage Oral administration of proteases may be associated with beneficial effects in the treatment and / or prevention of injuries, for example, it has been reported to be effective in the treatment of sports injuries such as contusions, sprains, and compression injuries (Pottgen, K., Nutrition as a form of treatment. Sports Medicine Newspaper 2017).

[0221] In one aspect, the present invention provides a capsule according to the present invention for use in the treatment and / or prevention of injury.

[0222] In one aspect, the present invention provides a method for treating and / or preventing damage comprising administering a capsule according to the present invention to a subject in need thereof.

[0223] In one aspect, the present invention provides the use of one or more proteases in the manufacture of a medicament for treating and / or preventing injury, wherein the medicament is in the form of a capsule according to the present invention.

[0224] In some embodiments, the injury is selected from a sports injury, muscle pain, pulled muscle / strain, overload injury, sprain, or contusion.

[0225] Back pain and sciatica Oral administration of proteases may be associated with beneficial effects in the treatment and / or prevention of back pain and sciatica.

[0226] In one aspect the present invention provides a capsule according to the present invention for use in the treatment and / or prevention of back pain or sciatica.

[0227] In one aspect, the present invention provides a method for treating and / or preventing back pain or sciatica comprising administering a capsule according to the present invention to a subject in need thereof.

[0228] In one aspect, the present invention provides the use of one or more proteases in the manufacture of a medicament for treating and / or preventing back pain or bone neuralgia, wherein the medicament is in the form of a capsule according to the present invention.

[0229] In some embodiments, the back pain is selected from upper back pain, prolapsed disc, or lower back pain.

[0230] healing Oral administration of proteases may be associated with beneficial effects in accelerating healing. For example, the proportion of patients with severe Caesarean section scars was lower in the group treated with proteolytic enzymes (Dosedla, E., et al., 2016. Ceska gynekologie, 81(3), pp. 202-207).

[0231] In one aspect, the invention provides a capsule according to the invention for use in promoting healing.

[0232] In one aspect, the present invention provides a method of promoting healing comprising administering a capsule according to the present invention to a subject in need thereof.

[0233] In one aspect, the invention provides the use of one or more proteases in the manufacture of a medicament for promoting healing, the medicament being in the form of a capsule according to the invention.

[0234] In some embodiments, the gastro-resistant capsule promotes wound healing or post-surgical healing.

[0235] Administration The gastro-resistant capsules of the present invention may be orally administered in any suitable regimen to deliver an effective amount of one or more active ingredients.

[0236] Preferably, 1, 2, 3, 4, 5 or 6 gastro-resistant capsules are administered daily. Preferably, 5 or less, 4 or less, or 3 or less gastro-resistant capsules are administered daily. In some embodiments, 2 or 3 gastro-resistant capsules are administered daily. In some embodiments, 3 gastro-resistant capsules are administered daily. The resistant capsules may be administered simultaneously or separately, or in any combination thereof.

[0237] Preferably, the gastro-resistant capsule is administered with at least about 200 mL of water.

[0238] Preferably, the gastroresistant capsule is administered in the fasted state. Preferably, the gastroresistant capsule is administered at least about 45 minutes before a meal.

[0239] Suitably, the gastroresistant capsule is administered for at least 15 days, at least 30 days, at least 45 days, or at least 60 days.

[0240] Total proteases Suitably, the one or more proteases are administered in a total daily dose of at least about 100 mg, at least about 200 mg, at least about 300 mg, at least about 400 mg, at least about 500 mg, or at least about 600 mg.

[0241] Suitably, the one or more proteases are administered in a total daily dose of about 2000 mg or less, about 1500 mg or less, about 1200 mg or less, about 1000 mg or less, about 900 mg or less, or about 800 mg or less.

[0242] Suitably, the one or more proteases are administered in a total daily dose of about 100 mg to about 2000 mg, about 200 mg to about 1500 mg, about 300 mg to about 1200 mg, about 400 mg to about 1000 mg, about 500 mg to about 900 mg, or about 600 mg to about 800 mg.

[0243] Suitably, the one or more proteases are administered in a total daily dose of about 666 mg or about 929 mg.

[0244] Preferably, the one or more proteases are administered in a total daily dose of about 666 mg.

[0245] Suitably, the one or more proteases are administered in a total daily dose of at least about 2000 FIP Units, at least about 4000 FIP Units, at least about 6000 FIP Units, at least about 8000 FIP Units, or at least about 10000 FIP Units.

[0246] Suitably, the one or more proteases are administered in a total daily dosage of about 30,000 FIP units or less, about 25,000 FIP units or less, about 20,000 FIP units or less, about 15,000 FIP units or less, or about 12,000 FIP units or less.

[0247] Suitably, the one or more proteases are administered in a total daily dose of about 2,000 FIP Units to about 30,000 FIP Units, about 4,000 FIP Units to about 25,000 FIP Units, about 6,000 FIP Units to about 20,000 FIP Units, about 8,000 FIP Units to about 15,000 FIP Units, or about 10,000 FIP Units to about 12,000 FIP Units.

[0248] Preferably, the one or more proteases are administered in a total daily dose of about 11340 FIP units.

[0249] Bromelain Suitably, bromelain is administered in a daily dose of at least about 100 mg, at least about 200 mg, at least about 300 mg, at least about 350 mg, at least about 400 mg, or at least about 450 mg.

[0250] Suitably, bromelain is administered in a daily dosage of about 1000 mg or less, about 900 mg or less, about 800 mg or less, about 700 mg or less, about 600 mg or less, or about 500 mg or less.

[0251] Preferably, bromelain is administered in a daily dose of about 100 mg to about 1000 mg, about 200 mg to about 900 mg, about 300 mg to about 800 mg, about 350 mg to about 700 mg, about 400 mg to about 600 mg, or about 450 mg to about 500 mg.

[0252] Preferably, bromelain is administered in a daily dosage of about 450 mg or about 540 mg.

[0253] Preferably, bromelain is administered in a daily dose of about 450 mg.

[0254] Suitably, bromelain is administered in a daily dose of at least about 500 FIP units, at least about 1000 FIP units, at least about 1500 FIP units, at least about 2000 FIP units, or at least about 2500 FIP units.

[0255] Suitably, bromelain is administered in a daily dose of about 10,000 FIP units or less, about 8,000 FIP units or less, about 6,000 FIP units or less, about 4,000 FIP units or less, or about 3,000 FIP units or less.

[0256] Preferably, bromelain is administered in a daily dose of about 500 FIP Units to about 10,000 FIP Units, about 1,000 FIP Units to about 8,000 FIP Units, about 1,500 FIP Units to about 6,000 FIP Units, about 2,000 FIP Units to about 4,000 FIP Units, or about 2,500 FIP Units to about 3,000 FIP Units.

[0257] Preferably, bromelain is administered in a daily dose of about 2700 FIP units.

[0258] Trypsin Suitably, trypsin is administered in a daily dose of at least about 50 mg, at least about 100 mg, at least about 150 mg, at least about 175 mg, or at least about 200 mg.

[0259] Suitably, trypsin is administered in a daily dosage of about 500 mg or less, about 400 mg or less, about 350 mg or less, about 300 mg or less, or about 250 mg or less.

[0260] Suitably, trypsin is administered in a daily dose of about 50 mg to about 500 mg, about 100 mg to about 400 mg, about 150 mg to about 350 mg, about 175 mg to about 300 mg, or about 200 mg to about 250 mg.

[0261] Suitably, trypsin is administered in a daily dose of about 216 mg or about 288 mg.

[0262] Suitably, trypsin is administered in a daily dose of about 216 mg.

[0263] Suitably, trypsin is administered in a daily dose of at least about 2000 FIP units, at least about 3000 FIP units, at least about 4000 FIP units, at least about 5000 FIP units, at least about 6000 FIP units or at least about 7000 FIP units.

[0264] Suitably, trypsin is administered in a daily dose of about 20,000 FIP units or less, about 15,000 FIP units or less, about 12,000 FIP units or less, about 11,000 FIP units or less, about 10,000 FIP units or less, or about 9,000 FIP units or less.

[0265] Suitably, trypsin is administered at a daily dose of about 2000 FIP Units to about 20000 FIP Units, about 3000 FIP Units to about 15000 FIP Units, about 4000 FIP Units to about 12000 FIP Units, about 5000 FIP Units to about 11000 FIP Units, about 6000 FIP Units to about 10000 FIP Units, or about 7000 FIP Units to about 9000 FIP Units.

[0266] Suitably, trypsin is administered in a daily dose of about 8640 FIP units.

[0267] Total Flavonoids Suitably, the one or more flavonoids are administered in a total daily dose of at least about 100 mg, at least about 200 mg, at least about 300 mg, at least about 400 mg, or at least about 500 mg.

[0268] Suitably, the one or more flavonoids are administered in a total daily dosage of about 1200 mg or less, about 1000 mg or less, about 900 mg or less, about 800 mg or less, or about 700 mg or less.

[0269] Suitably, the one or more flavonoids are administered in a total daily dose of from about 100 mg to about 1200 mg, from about 200 mg to about 1000 mg, from about 300 mg to about 900 mg, from about 400 mg to about 800 mg, or from about 500 mg to about 700 mg.

[0270] Preferably, the one or more flavonoids are administered in a total daily dose of about 600 mg.

[0271] Rutin Suitably, rutin is administered in a total daily dose of at least about 100 mg, at least about 200 mg, at least about 300 mg, at least about 400 mg, or at least about 500 mg.

[0272] Suitably, rutin is administered in a total daily dosage of less than about 1200 mg, less than about 1000 mg, less than about 900 mg, less than about 800 mg, or less than about 700 mg.

[0273] Suitably, rutin is administered in a total daily dose of about 100 mg to about 1200 mg, about 200 mg to about 1000 mg, about 300 mg to about 900 mg, about 400 mg to about 800 mg, or about 500 mg to about 700 mg.

[0274] Preferably, rutin is administered in a total daily dose of about 600 mg.

[0275] subject The subject to which the gastro-resistant capsule is administered may be any subject in need. For example, the subject may have or be at risk for any of the diseases or disorders described herein. The subject may be a human. The subject may be an adult.

[0276] Use of gastro-resistant capsules In one aspect, the present invention provides the use of a capsule shell to deliver one or more proteases. The gastro-resistant capsule shell and the one or more proteases may be any of those described herein.

[0277] In one aspect, the present invention provides the use of a gastro-resistant capsule to deliver one or more proteases. The gastro-resistant capsule and the one or more proteases may be any of those described herein.

[0278] The one or more proteases may be delivered to the small intestine (e.g., the duodenum, jejunum, and / or ileum). Preferably, the one or more proteases may be delivered to the duodenum. EXAMPLES

[0279] The present invention will now be further described by way of examples, which are meant to be provided to aid those skilled in the art in practicing the invention, and are not intended to limit the scope of the invention in any way.

[0280] Example 1. Release of trypsin and bromelain from various formulations by dynamic simulation of the upper gastrointestinal tract

[0281] Materials and Methods Product formulation Four different test formulations containing a mixture of trypsin and bromelain were tested. Tablet formulation, Wobenzym PS tablets. Negative control HPMC capsule formulation, Wobenzym control HPMC capsule. A gastro-resistant HPMC capsule formulation, the capsule shell of which comprises gellan gum, Wobenzym HPMC / gellan gum capsule. A gastro-resistant HPMC capsule formulation, wherein the capsule shell comprises pectin, Wobenzym HPMC / pectin capsule.

[0282] Trypsin activity assay To measure trypsin activity, the standard TAME method was used. p-Toluene-sulfonyl-L-arginine methyl ester (TAME) is a specific substrate for trypsin. One unit of trypsin hydrolyzes 1 μmol of TAME per minute at pH 8.1 and 25° C. Samples were analyzed by measuring the absorbance at 247 nm every 50 seconds for 10 minutes to assess trypsin activity. The trypsin activity of the samples was then calculated using the following formula:

[0283]

number

[0284] Taking into account the reactor volume in each small intestinal phase, the enzyme activity was expressed in USP units / reactor. Trypsin activity in TAME units / mL can be expressed as USP units / mL by incorporating a conversion factor of 19.2.

[0285] Bromelain activity assay Bromelain activity was measured using the method described in Hale, LP, et al., (2005). International Immunopharmacology 5(4), 783-793, except that soybean trypsin inhibitor (STI) was added to inhibit trypsin activity in the samples prior to the addition of substrate and the actual measurement. This inhibition period lasted 5 minutes and was carried out at 25°C.

[0286] One unit of bromelain hydrolyzes 1 μmol of Z-Arg-Arg-pNA per minute at pH 7.3 and 25° C. To assess bromelain activity, samples were analyzed by measuring absorbance at 410 nm every 55 seconds for 15 minutes. Trypsin activity of the samples was then calculated using the following formula:

[0287]

number

[0288] Simulation of the upper GIT The test formulations were tested using an adapted SHIME® system that represents physiological conditions of the stomach and small intestine in the same reactor over time. A specific gastric suspension is added to the reactor to mimic fed or fasted conditions. A standardized enzymatic bile liquid is then added to simulate small intestinal conditions. The incubation conditions (i.e., pH profile and incubation time) are optimized to resemble in vivo conditions in different regions of the gastrointestinal tract under fasted or fed conditions.

[0289] The InfoGest consensus method (see Mackie, A., and Rigby, N. (2015). InfoGest Consensus Method. In 'The Impact of Food Bioactives on Health', Springer International Publishing, pp. 13-22) was used, but with a dynamic pH profile that more closely mimics in vivo conditions. The conditions applied are summarized below.

[0290] Gastric Phase (Fasted State): Incubate for 45 minutes at 37°C, pH=2.0 with mixing by agitation. Pepsin is supplied standardized for activity by measuring the increase in absorbance at 280 nm of the TCA-soluble products upon digestion of hemoglobin (reference protein). Addition of phosphatidylcholine. The background medium provides only salts and mucin. Sampling at t=15 min, 30 min, and 45 min.

[0291] Small intestine phase: During mixing by stirring, the pH is automatically increased from 2.0 to 5.5 within 5 minutes, then the pH of the medium increases from 5.5 to 6.5 during the first hour, from 6.5 to 7.0 during the second hour, and finally remains constant at pH 7.0 during the third hour. During the small intestine phase, the temperature is set at 37° C. and is automatically controlled by the software. With regard to pancreatic enzymes, both raw animal pancreatic extracts (pancreatin) containing all the relevant enzymes in specific ratios are used, as well as defined ratios of different enzymes. For bile salts, 3.33 mM bovine bile extract is typically added (bovine bile is closer to human than porcine with respect to taurocholate and glycocholate). Sampling and visual scoring at t=30, 60, 90, 120, 150, and 180 min.

[0292] Top GIT Simulation Endpoints At each sampling time point, the capsules / tablets were visually inspected and their dissolution behavior during passage through different regions of the upper GIT was examined. A rating was given based on the following criteria: 1 = capsule in pristine condition 2 = Capsule is damaged, but almost all of the product is still inside the capsule. 3 = Capsule is damaged and all product has been released 4=Capsule broken The capsule / tablet scores at each sampling time point are shown above the bars in the figure.

[0293] Statistical analysis: Statistical analysis was performed separately for trypsin and bromelain to determine the statistically significant differences between enzyme activities between each sampling point and the previous sampling point during the experiment under fasting conditions to demonstrate changes in function of time. With regard to statistics, differences for all data discussed and indicated by "p<0.05" or "*" were significant at the 95% confidence interval as demonstrated using a paired Student's t-test.

[0294] result Wobenzym PS Tablets The activity of trypsin and bromelain released from Wobenzym PS tablet formulations during the upper GIT is shown in Figure 1 (Figures 1A and 1B: trypsin, Figures 1C and 1D: bromelain). Both mean values ​​(Figures 1A and 1C) and replicate values ​​(Figures 1B and 1D) are reported.

[0295] First, the intrinsic trypsin activity of the test product, i.e., the trypsin activity when the capsule contents are completely dissolved and unaffected by the harsh environmental conditions of the stomach and small intestine, was observed to be equivalent to 26,213 USP units / reactor and the intrinsic bromelain activity was observed to be equivalent to 58 units / reactor.

[0296] During the gastric phase, disintegration of the tablets was negligible (capsule / tablet score of 1), ie the tablets were associated with very limited trypsin, and furthermore there was no bromelain activity during gastric passage.

[0297] No significant tablet disintegration was observed at the beginning of the small intestinal phase (capsule / tablet score of 1 at SI30), but trypsin and bromelain activities increased significantly, indicating the onset of release. Further incubation led to complete disintegration of the tablets, and maximum trypsin and bromelain activities were observed after 90 min of small intestinal incubation. Thereafter, there was no effect on either enzyme activity, reaching average activities of approximately 34,802 USP units / reactant for trypsin and 60 units / reactant for bromelain at the end of the small intestinal phase incubation.

[0298] These activities corresponded to the inherent trypsin and bromelain activities of the test product, indicating that the tablet formulation was able to protect trypsin and bromelain from the harsh environment encountered during upper gastrointestinal transit, likely achieved by the reduced exposure of trypsin and bromelain to the harsh pH conditions (pH 2.0) encountered in the gastric phase, which protected these enzymes from denaturation and / or loss of activity.

[0299] Wobenzym Control HPMC Capsules The activity of trypsin and bromelain released from the Wobenzym control HPMC tablet formulation during the upper GIT is shown in Figure 2 (Figures 2A and 2B: trypsin, Figures 2C and 2D: bromelain). Both mean values ​​(Figures 2A and 2C) and replicate values ​​(Figures 2B and 2D) are reported.

[0300] First, the intrinsic trypsin activity of the test product, i.e., the trypsin activity when the capsule contents are completely dissolved and unaffected by the harsh environmental conditions of the stomach and small intestine, was observed to be equivalent to 79,111 USP units / reactor and the intrinsic bromelain activity was observed to be equivalent to 613 units / reactor.

[0301] During the gastric phase, the control capsules were damaged immediately and released (almost) all of their contents at the end of the gastric phase incubation. Although the capsules were completely disintegrated, the trypsin and bromelain activities remained low. This is most likely explained on the basis of enzyme denaturation at the low pH values ​​encountered during the gastric phase. Enzyme denaturation and precipitation were also visually observed during the experiment, as the released products were not completely dissolved.

[0302] During the small intestinal phase, the enzyme activities remained low and unaffected, indicating that exposure of trypsin and bromelain to the harsh conditions encountered in the gastric phase strongly affected their biological activities.

[0303] Wobenzym HPMC / Gellan Gum Capsules The activity of trypsin and bromelain released from Wobenzym HPMC / gellan gum capsule formulations during the upper GIT is shown in Figure 3 (Figures 3A and 3B: trypsin, Figures 3C and 3D: bromelain). Both mean values ​​(Figures 3A and 3C) and replicate values ​​(Figures 3B and 3D) are included.

[0304] First, the intrinsic trypsin activity of the test product, i.e., the trypsin activity when the capsule contents are completely dissolved and unaffected by the harsh environmental conditions of the stomach and small intestine, was observed to be equivalent to 42,100 USP units / reactor and the intrinsic bromelain activity was observed to be equivalent to 173 units / reactor.

[0305] Trypsin and bromelain activity was detected very little in the gastric phase, most likely as a result of the capsules remaining largely intact (capsule score 1-2), which means that release of the capsule contents was fairly limited.

[0306] However, during the small intestinal phase the capsule score remained at 2 and therefore the trypsin and bromelain activities also remained quite low. Thus, only limited amounts of capsule contents were released into the environment and the average trypsin and bromelain activities obtained at the end of the small intestinal phase were 4408 USP Units / reactor and 5 Units / reactor, respectively.

[0307] Since this is much lower than the trypsin and bromelain activity of the product itself, it can be concluded that this capsule formulation does not favor the release of large amounts of (active) trypsin and bromelain molecules between the upper GIT.

[0308] Wobenzym HPMC / Pectin Capsules The activity of trypsin and bromelain released from Wobenzym HPMC / pectin capsules during the upper GIT is shown in Figure 4 (Figures 4A and 4B: trypsin, Figures 4C and 4D: bromelain). Both mean values ​​(Figures 4A and 4C) and values ​​per replicate (Figures 4B and 4D) are included. Photographs of the capsules are included in Figure 5.

[0309] The average specific trypsin activity of the test products was 69,997 USP units / reactor, equivalent to an average specific bromelain activity of 386 units / reactor.

[0310] During the gastric phase, only very little trypsin activity was detected and no bromelain activity was observed, which corresponds to the capsules remaining (almost) completely intact (i.e., capsule score remained equal to 1 until ST45) and therefore the release of capsule contents to the environment was very limited, thus resulting in very limited exposure of the enzyme to the harsh environmental conditions encountered during the gastric phase.

[0311] Further degradation of the capsules occurred during the small intestinal phase. Complete dissolution of the capsules was obtained during the last 30 min of the small intestinal phase, i.e., between SI150 and SI180. As a result, the capsule contents were gradually released into the environment, leading to a gradual increase in trypsin activity. By the end of the small intestinal phase, an average trypsin activity of 62,644 USP units / reactor was obtained, which is about 90% of the corresponding intrinsic activity. By the end of the small intestinal phase, the average bromelain activity reached a maximum level, equal to 274 units / reactor, which was about 71% of the corresponding intrinsic activity.

[0312] The inherent dissolution behavior of this capsule formulation resulted in very high trypsin and bromelain activity by the end of the small intestinal phase, making this capsule formulation an ideal candidate for delivering high concentrations of the test enzymes to their active sites.

[0313] Comparison of daily doses To facilitate comparison between the different test formulations, the required daily dose was taken into account. The activity results were multiplied by the number of capsules / tablets administered per day. These multiplication factors are as follows: Wobenzym PS tablets = 6 units / day Wobenzym Control HPMC Capsules = 3 units / day Wobenzym HPMC / Gellan Gum Capsules = 3 units / day Wobenzym HPMC / Pectin Capsules = 3 units / day

[0314] The results for trypsin activity and bromelain activity are shown in Figures 6 and 7, respectively. On a per day basis, Wobenzym HPMC / pectin capsules were demonstrated to provide equivalent enzyme activity during small intestinal transit compared to Wobenzym PS tablets.

[0315] Embodiment Various preferred features and embodiments of the present invention are described with reference to the following numbered paragraphs.

[0316] 1. A gastro-resistant capsule containing one or more proteases, the capsule shell comprising: (i) a water soluble film-forming polymer in an amount of about 65% to about 97% by weight; (ii) a water soluble enteric polymer in an amount of about 3% to about 30% by weight.

[0317] 2. A gastro-resistant capsule according to paragraph 1, wherein the capsule shell is insoluble under gastric conditions and soluble under small intestinal conditions.

[0318] 3. A gastro-resistant capsule according to paragraph 2, wherein said gastric conditions are about pH 2.0 at about 37°C and / or said small intestinal conditions are about pH 5.5 to about pH 7.0 at about 37°C.

[0319] 4. A gastro-resistant capsule according to any of paragraphs 1 to 3, wherein the water-soluble enteric polymer is selected from one or more of pectin, propylene glycol alginate (PGA), or xanthan gum, preferably the water-soluble enteric polymer is pectin.

[0320] 5. The gastro-resistant capsule according to paragraph 4, wherein the pectin has a degree of esterification of from about 15% to about 40%, from about 20% to about 35%, or from about 20% to about 30%.

[0321] 6. A gastro-resistant capsule according to paragraph 4 or 5, wherein the pectin has a degree of amidation of from about 0% to about 25%, from about 10% to about 25%, or from about 15% to about 25%.

[0322] 7. A gastro-resistant capsule according to any of paragraphs 1 to 6, wherein the water-soluble enteric polymer has a molecular weight of from about 20 kDa to about 1000 kDa, from about 40 kDa to about 400 kDa, or from about 50 kDa to about 200 kDa.

[0323] 8. A gastro-resistant capsule according to any of paragraphs 1 to 7, wherein the water-soluble film-forming polymer is selected from one or more of hydroxypropyl methylcellulose (HPMC), starch, gelatin, pullulan, polyvinyl alcohol, hydroxypropylated starch, hydroxyethyl starch, hydroxypropyl cellulose, methylcellulose, hydroxyethyl cellulose, and hydroxyethyl methylcellulose, preferably the water-soluble film-forming polymer is hydroxypropyl methylcellulose (HPMC).

[0324] 9. A gastro-resistant capsule according to any of paragraphs 1 to 8, wherein the water-soluble film-forming polymer has a molecular weight of from about 50 kDa to about 815 kDa, or from about 50 kDa to about 400 kDa.

[0325] 10. A gastro-resistant capsule according to any of paragraphs 1 to 9, wherein the capsule shell further comprises a solidifying agent such as gellan gum, carrageen, agar, konjac gum, or locust bean gum in an amount of about 0.5% to about 3% by weight.

[0326] 11. A gastro-resistant capsule according to any of paragraphs 1 to 9, wherein the capsule shell does not contain a coagulant, preferably the capsule shell does not contain gellan gum and / or carrageenan.

[0327] 12. A gastro-resistant capsule according to any of paragraphs 1 to 11, wherein the capsule shell has a moisture content of about 4% to about 7% by weight.

[0328] 13. A gastro-resistant capsule according to any of paragraphs 1 to 12, wherein the one or more proteases are selected from the group consisting of bromelain, trypsin, papain, pancreatin, chymotrypsin, serratiopeptidase, ficain, nattokinase, or any combination thereof.

[0329] 14. A gastro-resistant capsule according to any of paragraphs 1 to 13, wherein the one or more proteases comprise or consist of bromelain and / or trypsin.

[0330] 15. A gastro-resistant capsule according to any of paragraphs 1 to 14, wherein the one or more proteases comprise or consist of bromelain and / or trypsin.

[0331] 16. The gastroresistant capsule according to any of paragraphs 1 to 15, wherein the gastroresistant capsule contains the one or more proteases in a total amount of about 50 mg to about 1000 mg, about 75 mg to about 800 mg, about 100 mg to about 600 mg, about 125 mg to about 500 mg, about 150 mg to about 400 mg, or about 200 mg to about 300 mg.

[0332] 17. The gastroresistant capsule of any of paragraphs 1 to 16, wherein the gastroresistant capsule comprises the one or more proteases in a total amount of about 1000 FIP Units to about 12000 FIP Units, about 1500 FIP Units to about 10000 FIP Units, about 2000 FIP Units to about 8000 FIP Units, about 2500 FIP Units to about 6000 FIP Units, or about 3000 FIP Units to about 4000 FIP Units.

[0333] 18. The gastroresistant capsule according to any of paragraphs 1 to 17, wherein the gastroresistant capsule comprises bromelain in an amount of about 50 mg to about 500 mg, about 75 mg to about 400 mg, about 100 mg to about 300 mg, or about 125 mg to about 200 mg.

[0334] 19. A gastroresistant capsule according to any of paragraphs 1 to 18, wherein the gastroresistant capsule comprises bromelain in an amount of about 150 mg.

[0335] 20. The gastroresistant capsule of any of paragraphs 1 to 19, wherein the gastroresistant capsule comprises bromelain in an amount of about 400 FIP Units to about 3000 FIP Units, about 500 FIP Units to about 2500 FIP Units, about 600 FIP Units to about 2000 FIP Units, about 700 FIP Units to about 1500 FIP Units, or about 800 FIP Units to about 1000 FIP Units.

[0336] 21. The gastroresistant capsule according to any of paragraphs 1 to 20, wherein the gastroresistant capsule comprises bromelain in an amount of about 900 FIP units.

[0337] 22. The gastroresistant capsule according to any of paragraphs 1 to 21, wherein the gastroresistant capsule comprises trypsin in an amount of about 20 mg to about 250 mg, about 30 mg to about 200 mg, about 40 mg to about 150 mg, about 50 mg to about 100 mg, or about 60 mg to about 80 mg.

[0338] 23. A gastroresistant capsule according to any of paragraphs 1 to 22, wherein the gastroresistant capsule comprises trypsin in an amount of about 72 mg.

[0339] 24. The gastroresistant capsule of any of paragraphs 1 to 23, wherein the gastroresistant capsule contains trypsin in an amount of about 1000 FIP Units to about 10000 FIP Units, about 1500 FIP Units to about 8000 FIP Units, about 1750 FIP Units to about 6000 FIP Units, about 2000 FIP Units to about 5000 FIP Units, or about 2500 FIP Units to about 4000 FIP Units.

[0340] 25. A gastroresistant capsule according to any of paragraphs 1 to 24, wherein the gastroresistant capsule comprises trypsin in an amount of about 2880 FIP units.

[0341] 26. The gastro-resistant capsule of any of paragraphs 1 to 25, wherein the gastro-resistant capsule comprises one or more flavonoids, such as rutin, quercetin, kaempferol, myricetin, fisetin, catechin, epicatechin, hydroxytyrosol, oleuropein, hesperidin, or any combination thereof.

[0342] 27. A gastro-resistant capsule according to paragraph 26, wherein the one or more flavonoids comprise or consist of rutin.

[0343] 28. The gastroresistant capsule according to paragraph 26 or 27, wherein the gastroresistant capsule comprises the one or more flavonoids in a total amount of about 50 mg to about 1000 mg, about 100 mg to about 600 mg, about 125 mg to about 400 mg, or about 150 mg to about 300 mg.

[0344] 29. A gastroresistant capsule according to any of paragraphs 26 to 28, wherein the gastroresistant capsule comprises the one or more flavonoids in a total amount of about 200 mg.

[0345] 30. The gastroresistant capsule according to any of paragraphs 1 to 29, wherein the gastroresistant capsule further comprises one or more fillers.

[0346] 31. A gastroresistant capsule according to paragraph 30, wherein the one or more fillers comprise or consist of one or more cellulose derivatives, such as powdered microcrystalline cellulose (MCC), ethyl cellulose, hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose (HPMC), HPMC phthalate, HPMC acetate succinate, cellulose acetate (CA), CA phthalate, sodium (Na) and calcium (Ca) carboxymethylcellulose (CMC), croscarmellose sodium (XCMCNa), methylcellulose, and low substituted HPC, or any combination thereof.

[0347] 32. A gastro-resistant capsule according to paragraphs 30 or 31, wherein the one or more fillers comprise or consist of microcrystalline cellulose (MCC) and / or hydroxypropyl cellulose (HPC).

[0348] 33. A gastro-resistant capsule according to any of paragraphs 1 to 32, wherein the gastro-resistant capsule further comprises one or more antioxidants, such as L-ascorbyl palmitate.

[0349] 34. A gastro-resistant capsule according to any of paragraphs 1 to 34, wherein the gastro-resistant capsule remains substantially intact during the gastric phase and / or the gastro-resistant capsule is substantially dissolved during the small intestinal phase.

[0350] 35. A gastro-resistant capsule according to any of paragraphs 1 to 35, wherein the gastro-resistant capsule remains completely intact during the gastric phase and / or the gastro-resistant capsule is completely dissolved during the small intestinal phase.

[0351] 36. A gastro-resistant capsule according to any of paragraphs 1 to 35, wherein the protease activity is not substantially released in the gastric phase and / or the protease activity is substantially released in the small intestine phase.

[0352] 37. A gastro-resistant capsule according to any of paragraphs 1 to 36, wherein the protease activity is not released in the gastric phase and / or the protease activity is completely released in the small intestine phase. 38. A method for producing a gastroresistant capsule containing one or more proteases, comprising: (a) (i) a water soluble film-forming polymer in an amount of about 65% to about 97% by weight; (ii) providing a gastro-resistant capsule shell comprising a water soluble enteric polymer in an amount of about 3% to about 30% by weight; (b) filling the gastro-resistant capsule shell with a capsule composition comprising one or more proteases.

[0353] 39. A gastro-resistant capsule obtained or obtainable by the method according to paragraph 38.

[0354] 40. A pack comprising a plurality of gastro-resistant capsules according to any of paragraphs 1 to 37 or paragraph 39.

[0355] 41. The pack of paragraph 40, wherein the pack comprises about 45 or more capsules, about 90 or more capsules, about 135 or more capsules, about 180 or more capsules, or about 270 or more capsules.

[0356] 42. A pack according to paragraph 40 or 41, wherein the pack comprises about 15 day doses or more, about 30 day doses or more, about 45 day doses or more, about 60 day doses or more, or about 90 day doses or more.

[0357] 43. Use of a gastro-resistant capsule according to any of paragraphs 1 to 37 or 39 as a dietary supplement.

[0358] 44. A gastroresistant capsule according to any of paragraphs 1 to 37 or 39 for use as a medicament.

[0359] 45. A gastroresistant capsule according to any of paragraphs 1 to 37 or 39 for use in the treatment and / or prevention of inflammatory diseases, joint pain, arthropathy, injuries, back pain or sciatica, or for use in promoting healing.

[0360] 46. ​​A gastroresistant capsule according to any of paragraphs 1 to 37 or 39 for use in the treatment and / or prevention of inflammatory diseases, such as, for example, phlebitis, prostatitis or cystitis.

[0361] 47. A gastroresistant capsule according to any of paragraphs 1 to 37 or 39 for use in the treatment and / or prevention of joint pain, such as shoulder joint pain, elbow joint pain, finger joint pain, knee joint pain, menopausal joint pain, or rheumatic pain.

[0362] 48. A gastro-resistant capsule according to any of paragraphs 1 to 37 or 39 for use in the treatment and / or prevention of arthrosis, preferably arthrosis, more preferably osteoarthritis, such as osteoarthritis of the hip joint, osteoarthritis of the knee joint, osteoarthritis of the metatarsophalangeal joint of the big toe, osteoarthritis of the fingers, osteoarthritis of the foot, osteoarthritis of the ankle, or Heberden's nodes and Bouchard's nodes.

[0363] 49. A gastro-resistant capsule according to any of paragraphs 1 to 37 or 39 for use in the treatment and / or prevention of injuries such as sports injuries, muscle pain, pulled / strain, overload injuries, sprains or bruises.

[0364] 50. A gastroresistant capsule according to any of paragraphs 1 to 37 or 39 for use in treating and / or preventing back pain, such as upper back pain, disc herniation or lower back pain, or sciatica.

[0365] 51. A gastroresistant capsule according to any of paragraphs 1 to 37 or 39 for use in promoting healing, such as wound healing or post-operative healing.

[0366] 52. A gastro-resistant capsule for the use according to paragraph 43 or for the use according to any of paragraphs 44 to 51, wherein the one or more proteases are administered in a total daily dose of from about 100 mg to about 2000 mg, from about 200 mg to about 1500 mg, from about 300 mg to about 1200 mg, from about 400 mg to about 1000 mg, from about 500 mg to about 900 mg, or from about 600 mg to about 800 mg.

[0367] 53. A gastro-resistant capsule for use according to paragraph 43 or 52, or for use according to any of paragraphs 44 to 52, wherein the one or more proteases are administered in a total daily dose of about 666 mg.

[0368] 54. The use according to any of paragraphs 43 or 52 to 53, or a gastro-resistant capsule for the use according to any of paragraphs 44 to 53, wherein the one or more proteases are administered in a total daily dose of about 2000 FIP Units to about 30000 FIP Units, about 4000 FIP Units to about 25000 FIP Units, about 6000 FIP Units to about 20000 FIP Units, about 8000 FIP Units to about 15000 FIP Units, or about 10000 FIP Units to about 12000 FIP Units.

[0369] 55. The use according to any of paragraphs 43 or 52-54, or a gastro-resistant capsule for the use according to any of paragraphs 44-54, wherein the one or more proteases are administered in a total daily dose of about 11340 FIP units.

[0370] 56. A gastro-resistant capsule for the use according to any of paragraphs 43 or 52 to 55, or for the use according to any of paragraphs 44 to 55, wherein bromelain is administered in a daily dose of about 100 mg to about 1000 mg, about 200 mg to about 900 mg, about 300 mg to about 800 mg, about 350 mg to about 700 mg, about 400 mg to about 600 mg, or about 450 mg to about 500 mg.

[0371] 57. A gastro-resistant capsule for the use according to any of paragraphs 43 or 52 to 56, or for the use according to any of paragraphs 44 to 56, wherein bromelain is administered in a daily dose of about 450 mg.

[0372] 58. A gastro-resistant capsule for the use according to any of paragraphs 43 or 52 to 57, or for the use according to any of paragraphs 44 to 57, wherein bromelain is administered in a daily dose of about 500 FIP Units to about 10,000 FIP Units, about 1,000 FIP Units to about 8,000 FIP Units, about 1,500 FIP Units to about 6,000 FIP Units, about 2,000 FIP Units to about 4,000 FIP Units, or about 2,500 FIP Units to about 3,000 FIP Units.

[0373] 59. A gastro-resistant capsule for the use according to any of paragraphs 43 or 52 to 58, or for the use according to any of paragraphs 44 to 58, wherein bromelain is administered in a daily dose of about 2700 FIP units.

[0374] 60. A gastro-resistant capsule for the use according to any one of paragraphs 43 or 52 to 59, or for the use according to any one of paragraphs 44 to 59, wherein trypsin is administered in a daily dose of about 50 mg to about 500 mg, about 100 mg to about 400 mg, about 150 mg to about 350 mg, about 175 mg to about 300 mg, or about 200 mg to about 250 mg.

[0375] 61. A gastro-resistant capsule for the use according to any of paragraphs 43 or 52 to 60, or for the use according to any of paragraphs 44 to 60, wherein trypsin is administered in a daily dose of about 216 mg.

[0376] 62. The use according to any one of paragraphs 43 or 52 to 61, or a gastro-resistant capsule for the use according to any one of paragraphs 44 to 61, wherein trypsin is administered in a daily dose of about 2000 FIP Units to about 20000 FIP Units, about 3000 FIP Units to about 15000 FIP Units, about 4000 FIP Units to about 12000 FIP Units, about 5000 FIP Units to about 11000 FIP Units, about 6000 FIP Units to about 10000 FIP Units, or about 7000 FIP Units to about 9000 FIP Units.

[0377] 63. The use according to any of paragraphs 43 or 52 to 62, or a gastro-resistant capsule for the use according to any of paragraphs 44 to 62, wherein trypsin is administered in a daily dose of about 8640 FIP units.

[0378] 64. The use according to any one of paragraphs 43 or 52 to 63, or a gastro-resistant capsule for the use according to any one of paragraphs 44 to 63, wherein rutin is administered in a total daily dose of from about 100 mg to about 1200 mg, from about 200 mg to about 1000 mg, from about 300 mg to about 900 mg, from about 400 mg to about 800 mg, or from about 500 mg to about 700 mg.

[0379] 65. The use according to any of paragraphs 43 or 52 to 64, or a gastro-resistant capsule for the use according to any of paragraphs 44 to 64, wherein rutin is administered in a total daily dose of about 600 mg.

[0380] 66. A gastro-resistant capsule for use according to any of paragraphs 43 or 52 to 65, or for use according to any of paragraphs 44 to 65, wherein the gastro-resistant capsule is formulated to contain about ½ of the daily dose, about ⅓ of the daily dose, about ¼ of the daily dose, or about ⅕ of the daily dose, preferably wherein the gastro-resistant capsule is formulated to contain about ½ of the daily dose or about ⅓ of the daily dose.

[0381] 67. A gastroresistant capsule for use according to any of paragraphs 43 or 52 to 66, or for use according to any of paragraphs 44 to 66, wherein the gastroresistant capsule is formulated to contain approximately 1 / 3 of the daily dose.

[0382] 68. The use according to any of paragraphs 43 or 52 to 67, or the gastro-resistant capsule for use according to any of paragraphs 44 to 67, wherein not more than 5, not more than 4, or not more than 3 said gastro-resistant capsules are administered daily.

[0383] 69. The use according to any of paragraphs 43 or 52 to 68, or a gastroresistant capsule for use according to any of paragraphs 44 to 68, wherein 2 or 3 of the gastroresistant capsules are administered daily, preferably 3 of the gastroresistant capsules are administered daily.

[0384] 70. A gastro-resistant capsule for use according to any of paragraphs 43 or 52 to 69, or for use according to any of paragraphs 44 to 69, wherein the resistant capsules are administered simultaneously or separately, or in any combination thereof.

[0385] 71. A gastroresistant capsule for use according to any of paragraphs 43 or 52 to 70, or for use according to any of paragraphs 44 to 70, wherein the gastroresistant capsule is administered in the fasted state, preferably at least about 45 minutes before a meal.

[0386] 72. A gastroresistant capsule for use according to any of paragraphs 43 or 52 to 71, or for use according to any of paragraphs 44 to 71, wherein the gastroresistant capsule is administered for at least 15 days. 73. Use of a gastro-resistant capsule shell for delivering one or more proteases, comprising: (i) a water soluble film-forming polymer in an amount of about 65% to about 97% by weight; (ii) a water soluble enteric polymer in an amount of about 3% to about 30% by weight. 74. Use of a gastro-resistant capsule for delivering one or more proteases, the capsule shell comprising: (i) a water soluble film-forming polymer in an amount of about 65% to about 97% by weight; (ii) a water soluble enteric polymer in an amount of about 3% by weight to about 30% by weight.

[0387] 75. The use according to paragraph 73 or 74, wherein the one or more proteases are delivered to the small intestine.

[0388] 76. The method of any of paragraphs 73 to 75, wherein the capsule shell is a capsule shell according to any of paragraphs 2 to 12.

[0389] 77. The use according to any of paragraphs 73 to 76, wherein the one or more proteases is a protease according to any of paragraphs 13 to 15.

Claims

1. A gastro-resistant capsule containing one or more proteases, wherein the capsule shell constituting the gastro-resistant capsule comprises: (i) hydroxypropyl methylcellulose (HPMC) in an amount of 65% to 97% by weight; (ii) pectin in an amount of 3% to 30% by weight.

2. The pectin (i) having a degree of esterification of 15% to 40%, or 20% to 35%, or 20% to 30%; (ii) has a degree of amidation of 0% to 25%, or 10% to 25%, or 15% to 25%, and / or (iii) The gastro-resistant capsule of claim 1, having a molecular weight of 20 kDa to 1000 kDa, 40 kDa to 400 kDa, or 50 kDa to 200 kDa.

3. 3. The gastro-resistant capsule of claim 1, wherein the one or more proteases are selected from the group consisting of bromelain, trypsin, papain, pancreatin, chymotrypsin, serratiopeptidase, ficain, nattokinase, and any combination thereof.

4. 3. A gastro-resistant capsule according to claim 1 or 2, wherein the one or more proteases comprise or consist of bromelain and / or trypsin.

5. 3. The gastroresistant capsule of claim 1 or 2, wherein the gastroresistant capsule comprises the one or more proteases in a total amount of (i) 50 mg to 1000 mg, 75 mg to 800 mg, 100 mg to 600 mg, 125 mg to 500 mg, 150 mg to 400 mg, or 200 mg to 300 mg, and / or (ii) 1000 FIP Units to 12000 FIP Units, 1500 FIP Units to 10000 FIP Units, 2000 FIP Units to 8000 FIP Units, 2500 FIP Units to 6000 FIP Units, or 3000 FIP Units to 4000 FIP Units.

6. 3. The gastro-resistant capsule according to claim 1 or 2, wherein the gastro-resistant capsule comprises one or more flavonoids.

7. The gastro-resistant capsule of claim 6, wherein the flavonoid is one or more flavonoids selected from the group consisting of rutin, quercetin, kaempferol, myricetin, fisetin, catechin, epicatechin, hydroxytyrosol, oleuropein, hesperidin, and any combination thereof.

8. 7. The gastro-resistant capsule of claim 6, wherein the flavonoid comprises or consists of rutin.

9. 7. The gastroresistant capsule of claim 6, wherein the gastroresistant capsule comprises the one or more flavonoids in a total amount of 50 mg to 1000 mg, 100 mg to 600 mg, 125 mg to 400 mg, or 150 mg to 300 mg.

10. 3. The gastroresistant capsule of claim 1, further comprising one or more fillers, optionally comprising or consisting of a cellulose derivative.

11. The gastroresistant capsule of claim 10, wherein the one or more fillers comprise or consist of one or more cellulose derivatives selected from the group consisting of powdered microcrystalline cellulose (MCC), ethyl cellulose, hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose (HPMC), HPMC phthalate, HPMC acetate succinate, cellulose acetate (CA), CA phthalate, sodium (Na) and calcium (Ca) carboxymethylcellulose (CMC), croscarmellose sodium (XCMCNa), methylcellulose, low-substituted HPC, and any combination thereof.

12. (i) the gastro-resistant capsule remains substantially intact during the gastric phase and / or the gastro-resistant capsule is substantially dissolved during the small intestinal phase; and / or 3. The gastro-resistant capsule of claim 1, wherein the one or more proteases are not substantially released in the gastric phase and / or the one or more proteases are substantially released in the small intestine phase.

13. 1. A method for producing a gastro-resistant capsule containing one or more proteases, comprising: (a) (i) HPMC in an amount of 65% to 97% by weight; (ii) pectin in an amount of 3% to 30% by weight; and (b) filling the gastro-resistant capsule shell with a capsule composition comprising one or more proteases.

14. A pack containing a plurality of gastro-resistant capsules according to claim 1 or 2.

15. 10. Use of a gastro-resistant capsule according to claim 1 or 2 as a dietary supplement.

16. 10. A gastro-resistant capsule according to claim 1 for use as a medicine.

17. 10. A gastroresistant capsule according to claim 1 for use in the treatment and / or prevention of inflammatory diseases, joint pain, arthropathy, injuries, back pain or sciatica, or for use in promoting healing.

18. 16. The use according to claim 15, wherein two or three gastro-resistant capsules are administered daily.

19. 18. A gastroresistant capsule according to claim 16 or 17, wherein two or three gastroresistant capsules are administered daily.

20. 1. Use of a gastro-resistant capsule shell for delivering one or more proteases, said gastro-resistant capsule shell comprising: (i) HPMC in an amount of 65% to 97% by weight; (ii) pectin in an amount of 3% to 30% by weight.

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