Enteric coated hard-shell capsule for ileum and colon delivery of dosage forms

Abstract

The present invention relates to a pH responsive polymer composition for the enteric coating of hard shell capsules, which composition is suitable for the delivery of pharmaceutical dosage forms, in particular microbiota, to the ileum and colon. The pH responsive polymer composition comprises at least one anionic poly (meth) acrylate copolymer, at least one glidant, at least one plasticizer, and 1 to < 6% of at least one nonionic emulsifier based on the total weight of the pH responsive polymer composition.

Description

Technical Field

[0001] This invention relates to a pH-responsive polymer composition for enteric coating of hard-shell capsules used for drug delivery in the ileum and colon. The pH-responsive polymer composition comprises at least one anionic poly(meth)acrylate copolymer, at least one flow aid, at least one plasticizer, and at least one nonionic emulsifier. Background Technology

[0002] The normal pH range of the human stomach is approximately 1–3, but is usually closer to 2. Drug formulations typically have coatings to prevent release in the stomach environment. However, when food is present in the stomach, the pH can rise to 4–5, affecting the integrity of the coating. Furthermore, many active pharmaceutical ingredients (such as antibodies and bacteria) are unstable under acidic pH conditions. Therefore, for ingredients unstable under acidic pH conditions, the ideal release condition is a pH of 7.2 or higher.

[0003] WO2019096833A1 discloses a hard-shell capsule coated with a pH-responsive methacrylate copolymer. However, the release of the active ingredient / contents from such capsules either initiates at pH 6.8 or exhibits delayed release at pH 6.8 or 7.4. Delayed release at pH 7.2 may result in the capsule passing through the ileum and colon without releasing the active ingredient / contents. Therefore, there is an urgent need to develop a hard-shell capsule capable of targeted delivery at pH 7.2 (i.e., the ileum and colon).

[0004] WO2019097030A1 discloses a hard-shell capsule, the body and cap of which are respectively coated with a pH-responsive methacrylate copolymer, suitable for oral delivery of bacteria derived from fecal microbiota. This patent document indicates that the pH-responsive polymer composition comprises poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1, poly(methacrylate-co-ethyl acrylate) 1:1, glyceryl monostearate, at least one plasticizer, and 4–9 wt% of at least one nonionic emulsifier. The 6–9 wt% nonionic emulsifier (such as polysorbate 80) is particularly crucial for achieving the initiation of release of the active ingredient at pH 7.2 and no significant release at pH 6.8.

[0005] Schwartzberg et al. Advances in Therapy35, 754-767 (2018) points out that polysorbate 80 is a biologically active compound that may also possess pharmacological activity, and therefore may alter the pharmacological properties of the drug being formulated, or may directly cause adverse events. Therefore, it is necessary to reduce the amount of nonionic surfactants such as polysorbate 80 in the enteric coating composition of hard-shell capsules.

[0006] Therefore, the technical solutions disclosed in the prior art have certain defects. For example, in order to provide pH-responsive enteric coating (achieving stability up to pH 6.8 and releasing at pH 7.2), a relatively high amount of nonionic surfactant needs to be used.

[0007] Therefore, the object of the present invention is to provide a hard-shell capsule coated with a pH-responsive polymer composition, which can be used for delivery of drug or nutrient dosage forms in the ileum and colon, with a lower amount of nonionic surfactant, while ensuring stability at pH 6.8 without significant release (<10%), and releasing the contents in the pH 7.2 environment of the ileum and colon. Another object of the present invention is to provide a dosage form comprising a drug / nutrient active ingredient loaded in a hard-shell capsule coated with a pH-responsive polymer composition, for achieving immediate or sustained release of the contents within 60 minutes at pH 7.2. Another object of the present invention is to provide a dosage form comprising a pharmaceutical / nutritional active ingredient loaded in a hard-shell capsule coated with a pH-responsive polymer composition and / or a top coat / subcoat; wherein, as needed, the release of the API after reaching pH 7.2 can be adjusted (from sustained release to medium-rate release to immediate release within 60 minutes) by adjusting the polymer ratio in the pH-responsive polymer composition and controlling the coating thickness within the gap range between the uncoated capsule body and the capsule cap. A further object of the present invention is to provide a hard-shell capsule coated with a pH-responsive polymer composition and / or a top coat / subcoat, which can be efficiently used in capsule filling machines. Summary of the Invention

[0008] Research has found that a pH-responsive polymer composition comprising at least one anionic poly(meth)acrylate copolymer, at least one flow aid, at least one plasticizer, and a nonionic emulsifier content of less than 6% by weight can be used to prepare an enteric-coated hard-shell capsule that remains stable in environments with pH values ​​up to 6.8 and releases its contents in environments with pH values ​​of approximately 7.2.

[0009] Therefore, in a first aspect, the present invention relates to a hard-shell capsule coated with a pH-responsive polymer, wherein the pH-responsive polymer composition comprises: a. 40 to 90% by weight of at least one anionic poly(meth)acrylate copolymer; b. 0 to 40% by weight of at least one (meth)acrylate copolymer selected from poly(ethyl methacrylate), poly(methyl methacrylate), or combinations thereof; c. 2 to 6% by weight of at least one gliding agent; d. 3 to 20% by weight of at least one non-component c plasticizer; and e. 1 to <6% by weight of at least one nonionic emulsifier; The content of each component a to e is based on the total weight of the pH-responsive polymer composition. When component b is present, components a and b are not the same.

[0010] In a second aspect, the present invention relates to a method for preparing a hard-shell capsule coated with a pH-responsive polymer, the method comprising the following steps: i. A hard-shell capsule in a pre-locked state, the capsule comprising a capsule body and a capsule cap; ii. A solution, suspension or dispersion containing a pH-responsive polymer composition according to items 1-12 is coated onto the hard-shell capsule of step i to obtain a hard-shell capsule coated with a pH-responsive polymer.

[0011] In a third aspect, the present invention relates to a dosage form comprising a pharmaceutical / nutritional active ingredient contained in a hard-shell capsule coated with a pH-responsive polymer composition. Detailed Implementation

[0012] This invention relates to a hard-shell capsule coated with a pH-responsive polymer, wherein the pH-responsive polymer composition comprises: a. 40 to 90% by weight of at least one anionic poly(meth)acrylate copolymer; b. 0 to 40% by weight of at least one (meth)acrylate copolymer selected from poly(ethyl methacrylate), poly(methyl methacrylate), or combinations thereof; c. 2 to 6% by weight of at least one gliding agent; d. 3 to 20% by weight of at least one non-component c plasticizer; and e. 1 to <6% by weight or 1 to 20% by weight of at least one nonionic emulsifier; The content of each component a to e is based on the total weight of the pH-responsive polymer composition. When component b is present, components a and b are not the same.

[0013] In another preferred embodiment, the hard-shell capsule is coated with a pH-responsive polymer in a pre-locked state.

[0014] Hard-shell capsules Those skilled in the art are familiar with hard-shell capsules used in pharmaceuticals or nutritional supplements. Hard-shell capsules typically consist of a two-piece encapsulation, comprising two capsule halves, referred to as the body and the cap. The body and cap are usually made of a hard, and in some cases brittle, material. The body and cap are typically cylindrical with one open end and a closed, hemispherical shape at the other end. The shape and size of the body and cap are designed such that the body can be sleeved into the open end of the cap.

[0015] The capsule body and capsule cap have a potential overlapping matching area (overlapping area) located on the outer side of the capsule body and the inner side of the capsule cap; when the capsule is in a pre-locked state, they partially overlap; when the capsule is in a fully locked state, they completely overlap. The capsule is in a pre-locked state when the capsule cap partially slides onto the overlapping matching area of ​​the capsule body. The capsule is in a fully locked state when the capsule cap completely slides onto the overlapping matching area of ​​the capsule body. The capsule body and capsule cap typically have a snap-fit ​​locking structure (e.g., matching annular grooves or recesses, preferably elongated recesses) to maintain the capsule's pre-locked or fully locked state. Typically, the length of the capsule body is greater than that of the capsule cap. The capsule cap can cover the outer overlapping area of ​​the capsule body, thereby achieving capsule closure or locking. In the closed state, the capsule cap covers the outer overlapping area of ​​the capsule body in a pre-locked or fully locked form: in a fully locked state, the capsule cap completely covers the outer overlapping area of ​​the capsule body; in a pre-locked state, the capsule cap only covers a portion of the outer overlapping area of ​​the capsule body. The capsule cap can slide along the capsule body and is usually fixed in two different positions, so that the capsule is in a pre-locked or fully locked closed state respectively.

[0016] Hard-shell capsules are available commercially in various sizes. They are typically supplied empty, with the capsule body and cap pre-locked at the factory; however, capsule halves, bodies, and caps can also be supplied separately upon request. Pre-locked hard-shell capsules can be directly fed into a capsule filling machine, where the machine performs the opening, filling, and closing operations to convert them into a fully locked state. Hard-shell capsules are usually filled with dry materials, such as powders or granules containing bioactive ingredients.

[0017] Both the capsule body and the capsule cap have a closure structure that facilitates pre-locking (temporary locking) and / or complete locking of the capsule. Therefore, the inner wall of the capsule cap can have raised points, while the outer wall of the capsule body has correspondingly larger recessed points; their arrangement ensures that when the capsule is closed, the raised points can be embedded in the recesses. Alternatively, the raised points can be located on the outer wall of the capsule body, and the recesses on the inner wall of the capsule cap. The raised points or recesses can be annular or spiral, surrounding the sidewalls of the capsule body or capsule cap. Besides point-like raised and recessed designs, an annular structure can also be used, allowing the raised points or recesses to encircle the entire circumference of the sidewalls of the capsule cap or capsule body; however, it is preferable to add grooves and openings to facilitate gas exchange between the capsule interior and the external environment.

[0018] One or more protrusions can be arranged in a ring around the inner wall of the capsule cap and the outer wall of the capsule body, so that when the capsule is in the fully locked position, the protrusions on the capsule cap are adjacent to the protrusions on the capsule body. Sometimes the protrusions are located on the outer side of the capsule body near the opening end, while the recess is located on the capsule cap near the opening end, so that when the capsule reaches the fully locked state, the protrusions on the capsule body can engage with the recesses on the capsule cap. The protrusions can be designed such that, when the capsule is in the pre-locked state, the capsule cap can be opened at any time without damaging the capsule; or alternatively, once the capsule is closed, it cannot be opened again without damaging the capsule structure.

[0019] Preferably, capsules with one or more of the aforementioned engaging structures (clamps) are used (e.g., capsules with two annular grooves). A more preferred option is a capsule with at least two sets of engaging structures, each with different degrees of locking on the two parts of the capsule. In this type of capsule structure, the first set of engaging structures (recesses or annular grooves) can be located near the open ends of the capsule cap and body, while the second set of engaging structures (annular grooves) can be appropriately offset towards the closed ends of the capsule body and cap. The first set of engaging structures provides a weaker locking force on the two parts of the capsule than the second set. The advantage of this variation is that after empty capsule production, the capsule cap and body can be pre-locked together using the first set of engaging mechanisms. For capsule filling, the two parts of the capsule are then separated. After filling, the two parts of the capsule are pushed together until the second set of engaging structures completely locks the two parts of the capsule into a fully locked state.

[0020] The capsule body and cap of the hard-shell capsule preferably have annular grooves and / or recesses respectively in the area where the cap can slide onto the capsule body. The annular grooves of the capsule body and the recesses of the cap match each other to form a snap-fit ​​positioning mechanism. The recesses can be circular or designed as elongated ovals along the length of the capsule.

[0021] The annular groove on the capsule body and the annular groove on the capsule cap (precision-matching rings) can also cooperate to form a snap-fit ​​positioning mechanism. This design allows the capsule to achieve pre-locked or fully locked closure via the snap-fit ​​positioning mechanism. When the capsule is in the pre-locked state, the annular groove on the capsule body preferably matches the elongated elliptical recess on the capsule cap to fix the capsule body and capsule cap together. When the capsule is in the fully locked state, the annular grooves on the capsule body and capsule cap preferably match to fix and lock the capsule body and capsule cap together.

[0022] The area where the capsule cap can slide onto the capsule body is called the overlapping area between the capsule body and the capsule cap, or simply the overlapping area. If the capsule cap only partially covers the capsule body, up to 20%–90% or 60%–85% of the overlapping area, the hard-shell capsule is in a semi-closed state (pre-locked state). When the capsule body and the capsule cap have locking mechanisms such as matching annular grooves and / or recesses, this semi-closed capsule can be called a pre-locked capsule. If the capsule is polymer-coated in the pre-locked state, the coating layer will cover the entire outer surface of the capsule, including the portion of the capsule body and the overlapping area of ​​the capsule cap not covered by the capsule cap in the pre-locked state. When the capsule is polymer-coated in the pre-locked state and further pushed to the fully locked state, the coating layer of the capsule body and the overlapping area of ​​the capsule cap that was not covered by the capsule cap in the pre-locked state will be completely covered by the capsule cap. The presence of this portion of the coating layer sandwiched between the capsule body and the capsule cap in the fully locked state is sufficient to achieve a tight seal in the hard-shell capsule. This technical effect cannot be predicted by conventional means.

[0023] If the capsule cap completely covers the overlapping area of ​​the capsule body, the hard-shell capsule is in a final closed state or a fully locked state. When there is a locking mechanism, such as matching annular grooves and / or pits in the capsule body and the capsule cap, this final closed capsule can be called a fully locked capsule.

[0024] Generally, a recess is preferred for securing the capsule body and cap in a pre-locked state. As a non-limiting rule, the mating contact area of ​​the recess is smaller than that of the annular groove. Therefore, the external force required to release the snap fastening of the recess is less than that required to release the snap fastening formed by the mating annular groove.

[0025] The recesses in both the capsule body and the capsule cap are located in the area where the capsule cap can slide onto the capsule body. They are matched by a snap-fit ​​positioning mechanism, placing the capsule in a pre-locked state. For example, two, four, or preferably six grooves or recesses can be distributed along the circumference of the capsule cap. Typically, the recesses in the capsule cap and the annular grooves in the capsule body are located in the area where the capsule cap can slide onto the capsule body, and their matching allows the capsule to be closed in a pre-locked state via the snap-fit ​​positioning mechanism. Because the external force required to open a hard-shell capsule in the pre-locked state is relatively small, it can be opened manually or mechanically without damage. Therefore, the "pre-locked state" is sometimes also referred to as the "loosely capped state."

[0026] Typically, the annular grooves or matching locking rings of the capsule body and cap are located in the area where the cap can slide onto the capsule body. These mating elements allow the capsule to be fully locked in place via a snap-locking mechanism. Since opening a fully locked hard-shell capsule requires relatively large external force, damage is almost inevitable when opened manually or mechanically. The recesses and annular grooves are usually directly formed within the capsule body or cap. When capsule components with these protrusions and recesses are fitted together, a precisely sized and uniform gap is formed between the contact surfaces of the capsule body and the cap, with a width ranging from 10 micrometers to 150 micrometers, more preferably from 20 micrometers to 100 micrometers. The capsule body of a hard-shell capsule preferably has a tapered edge. This tapered edge prevents damage from collisions between the edges of the capsule body and cap during manual or mechanical closure.

[0027] Average gap between different brands of hard-shell capsules For hard-shell capsules of different brands and specifications, using a cap wall thickness of 100 micrometers as a baseline parameter, the gap width between the capsule body and the cap in both pre-locked and fully locked states was calculated. The calculation steps are as follows: First, subtract the cap wall thickness from the cap's outer diameter to obtain the cap's inner diameter; second, subtract the cap's inner diameter from the capsule body's outer diameter to obtain the average gap width between the capsule body and the cap in both pre-locked and fully locked states.

[0028] Average gap between different brands of hard-shell capsules

[0029] A fully closed, locked hard-shell capsule has a total length ranging from approximately 5 to 40 mm; a cap diameter ranging from approximately 4 to 12 mm; a body diameter ranging from approximately 2 to 11 mm; a cap length ranging from approximately 4 to 20 mm; a body length ranging from approximately 8 to 30 mm; and a filling volume ranging from approximately 0.1 to 2 ml. The difference in capsule length between the pre-locked and fully locked states can be approximately 1 to 5 mm.

[0030] Hard-shell capsules are available in standardized sizes, such as 000 to 5. Taking a size 000 closed capsule as an example, its total length is approximately 28 mm, the outer diameter of the capsule cap is approximately 9.9 mm, the outer diameter of the capsule body is approximately 9.5 mm, the length of the capsule cap is approximately 14 mm, the length of the capsule body is approximately 22 mm, and the filling volume is approximately 1.4 ml.

[0031] Taking size 5 closed capsule as an example, its total length is about 10 mm, the outer diameter of the capsule cap is about 4.8 mm, the outer diameter of the capsule body is about 4.6 mm, the length of the capsule cap is about 5.6 mm, the length of the capsule body is about 9.4 mm, and the filling volume is about 0.13 ml.

[0032] Taking size 0 capsules as an example, their length in the pre-locked state is approximately 23–24 mm, and their length in the fully locked state is approximately 20.5–21.5 mm. Therefore, the difference between the pre-locked length and the fully locked length is approximately 2–3 mm.

[0033] The uniform average gap width between the uncoated capsule body and the capsule cap ranges from 10 to 100 micrometers, preferably 20 to 100 micrometers, and most preferably 10 to 80 micrometers.

[0034] Materials of the cyst body and cyst cap The materials for the capsule body and cap can be selected from hydroxypropyl methylcellulose (HPMC), starch, gelatin, pullulan, and copolymers of C1-C4 alkyl esters of (meth)acrylic acid and (meth)acrylic acid. Preferred hard-shell capsules have a capsule body and cap containing or made of HPMC or gelatin; HPMC is most preferred due to its excellent adhesion to polymer coatings.

[0035] pH-responsive polymer compositions "pH-responsive polymers" refer to polymers whose solubility properties depend on the pH value of the environment. According to the present invention, such pH-responsive polymers should remain stable in environments with pH values ​​up to 7 and rapidly release the active pharmaceutical / nutritional ingredients.

[0036] Component a: Anionic (meth)acrylate copolymer Based on the total weight of the composition, the composition comprises 40–90 wt% anionic (meth)acrylate copolymer. The anionic (meth)acrylate copolymer is prepared by polymerizing the following monomers: 25–95 wt% of at least one C1-C4 alkyl ester of acrylic acid and / or methacrylic acid, and 5–75 wt% of acrylic acid and / or methacrylic acid, all based on the total weight of the monomers. In another embodiment, the anionic (meth)acrylate copolymer is polymerized from the following monomers: 40–60 wt% of at least one C1-C4 alkyl ester of acrylic acid and / or methacrylic acid, and 60–40 wt% of acrylic acid or methacrylic acid, all based on the total weight of the monomers. In yet another embodiment, the anionic (meth)acrylate copolymer is polymerized from the following monomers: 40–60 wt% of ethyl acrylate and 60–40 wt% of methacrylic acid, all based on the total weight of the monomers.

[0037] In another embodiment, the C1-C4 alkyl ester of acrylic acid and / or methacrylic acid is selected from methyl acrylate, ethyl acrylate, propyl acrylate, isopropyl acrylate, n-butyl acrylate, isobutyl acrylate, methyl methacrylate, ethyl methacrylate, propyl methacrylate, isopropyl methacrylate, n-butyl methacrylate, isobutyl methacrylate, or a mixture of two or more thereof. In yet another embodiment, the at least one C1-C4 alkyl ester of acrylic acid or methacrylic acid is selected from methyl acrylate, ethyl acrylate, methyl methacrylate, or a mixture of two or more thereof.

[0038] In another embodiment, the anionic (meth)acrylate copolymer contains 5–60% by weight of methacrylic acid based on the total weight of the monomers. In yet another embodiment, the anionic (meth)acrylate copolymer contains 40–60% by weight of methacrylic acid based on the total weight of the monomers.

[0039] Suitable anionic (meth)acrylate copolymers are commercially available under the following trade name: EUDRAGIT ® L 30D-55, EUDRAGIT ® L 100-55, EUDRAGIT ® L 100, EUDRAGIT ® S 100 and EUDRAGIT ® FS 30 D.

[0040] EUDRAGIT ® L 30 D-55 and EUDRAGIT ® L 100-55 (poly(methacrylate-co-ethyl acrylate) 1:1) is a commonly used commercially available (meth)acrylate copolymer product in the pharmaceutical field. EUDRAGIT® L 30 D-55 can be obtained as a 30% aqueous dispersion, while EUDRAGIT ® L 100-55 is sold in powder form. All prices are based on total monomer weight. EUDRAGIT ® L 30D-55 and EUDRAGIT ® L 100-55 contains 46–50.6% by weight of methacrylic acid and 49.4–54% by weight of ethyl acrylate. EUDRAGIT ® The L30 D-55 copolymer dissolves at an initial pH of approximately 5.5 in intestinal fluid or simulated intestinal fluid.

[0041] EUDRAGIT ® L 100 (poly(methacrylate-co-methyl methacrylate) 1:1) is a known commercially available (meth)acrylate copolymer polymerized from approximately 50% by weight of methyl methacrylate and approximately 50% by weight of methacrylic acid. EUDRAGIT ® The L-type copolymer dissolves at an initial pH of approximately 6.0 in intestinal fluid or simulated intestinal fluid.

[0042] EUDRAGIT ® S 100 (poly(methacrylate-co-methyl methacrylate) 1:2) is a known commercially available (meth)acrylate copolymer polymerized from approximately 70% by weight of methyl methacrylate and approximately 30% by weight of methacrylic acid. EUDRAGIT ® The S100 copolymer dissolves at an initial pH of approximately 7.0 in intestinal fluid or simulated intestinal fluid.

[0043] EUDRAGIT ® FS 30 D (poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1) is a known commercially available (meth)acrylate copolymer polymerized from approximately 10% by weight of methacrylic acid, approximately 65% ​​by weight of methyl acrylate, and approximately 25% by weight of methyl methacrylate. EUDRAGIT ® The initial pH value for the dissolution of FS-type copolymers in intestinal fluid or simulated intestinal fluid is approximately 7.0.

[0044] In another preferred embodiment, the anionic poly(meth)acrylate copolymer is selected from poly(ethyl methacrylate-co-ethyl acrylate) (1:1), poly(methyl methacrylate-co-methyl methacrylate) (1:1), poly(methyl methacrylate-co-methyl methacrylate) (1:2), poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) (7:3:1), or combinations thereof. The preferred anionic poly(meth)acrylate copolymer is poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) (7:3:1) because of EUDRAGIT. ® FS-type copolymers (such as the EUDRAGIT® FS series) have an initial pH of approximately 7.0 when dissolved in intestinal fluid or simulated intestinal fluid, and these polymers exhibit superior elongation at break and mechanical properties.

[0045] In another embodiment, 0.1–10 mol% of the anionic (meth)acrylate copolymer is present in the form of a salt. This partially neutralized form is particularly advantageous because it provides greater stability in environments with pH values ​​up to 7.

[0046] The base suitable for partial neutralization of anionic copolymers is selected from alkali metal hydroxides, alkali metal carbonates, alkaline earth metal hydroxides, alkaline earth metal carbonates, alkali metal and alkaline earth metal oxides, or ammonia, with sodium hydroxide and ammonia water being the most preferred.

[0047] Component b In another preferred embodiment, the content of component b in the pH-responsive polymer composition is 5–30% by weight, based on the total weight of the pH-responsive polymer composition. Partial neutralization of component a is optional whenever component b is present in the composition. Preferred component b is poly(methyl methacrylate-co-methyl methacrylate).

[0048] Component c: Glide aid Gliding agents or release agents are typically lipophilic and are generally added to spray suspensions to prevent polymer aggregation during film formation. Suitable examples of gliding agents include silica, kaolin, calcium silicate, magnesium silicate, talc, stearates (such as calcium stearate, magnesium stearate, zinc stearate), sodium stearate fumarate, starch, stearic acid, monoglycerides of fatty acids, diglycerides of fatty acids, triglycerides of fatty acids, or mixtures thereof. Preferred gliding agents are selected from monoglycerides of fatty acids, diglycerides of fatty acids, triglycerides of fatty acids, or mixtures thereof.

[0049] Based on the total weight of the pH-responsive polymer composition, the content of the flow aid in the pH-responsive polymer composition is 2–6% by weight, preferably 3.5–5% by weight.

[0050] Component d: Plasticizer The pH-responsive polymer composition comprises one or more plasticizers. The plasticizers lower the glass transition temperature and promote film formation through physical interaction with the (meth)acrylate copolymer. Suitable substances typically have a molecular weight between 100 and 20,000 and contain one or more hydrophilic groups, such as hydroxyl, ester, or amino groups, in their molecular structure. Examples of suitable plasticizers are selected from alkyl citrates, alkyl phthalates, alkyl sebacates, sucrose esters, sorbitan esters, diethyl sebacate, dibutyl sebacate, propylene glycol, polyethylene glycol, or mixtures thereof. Alkyl citrates are preferred plasticizers.

[0051] Component e: Nonionic emulsifier Nonionic emulsifiers help to form a homogeneous mixture in pH-responsive polymer compositions, which promotes the formation of a uniform coating film on the surface of hard-shell capsules without creating numerous microscopic defects. In another preferred embodiment, the content of the nonionic emulsifier is 3.5–5.8% by weight, preferably 4.1–5.8% by weight, based on the total weight of the pH-responsive polymer composition. Suitable examples of nonionic emulsifiers are selected from polysorbate 20, polysorbate 28, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85, poloxamer 124, poloxamer 181, poloxamer 188, poloxamer 237, poloxamer 331, poloxamer 338 and poloxamer 407, polyethoxylated castor oil, and polyethoxylated castor oil. Glycol-40 hydrogenated castor oil, polyethylene glycol 15-hydroxystearate, polyoxyethylene 15-hydroxystearate, polyethylene glycol-8 glyceryl caprylate / capric acid, D-α-tocopherol polyethylene glycol 1000 succinate, lecithin, sorbitan monopalmitate, cetyl alcohol, oleyl alcohol, sodium glycolate, sodium deoxycholate, alkyl glycosides, alkyl polyglucosides, octyl glucoside, decyl maltodextrin, or combinations thereof. Preferred nonionic emulsifiers are polysorbates and poloxamers.

[0052] Coating layer The surface of the hard-shell capsule is coated with a coating layer comprising the pH-responsive polymer composition described above.

[0053] The content of the polymer disclosed herein in the coating layer may be 10% by weight or higher, 20% by weight or higher, 30% by weight or higher, 40% by weight or higher, 50% by weight or higher, 60% by weight or higher, 70% by weight or higher, 80% by weight or higher, or 90% by weight or higher. The coating layer may contain 40–90% by weight, 45–90% by weight, 60–90% by weight, 60–85% by weight, or 70–80% by weight of the polymer disclosed herein.

[0054] amount and thickness of coating layer The amount of coating applied (i.e., the total weight gain of the coating layer) should be sufficient to fill the gaps between the overlapping areas outside the capsule body covered by the capsule cap. If the amount of coating applied is too low, it may not provide adequate enteric protection. When the capsule is closed to the fully locked state, insufficient coating between the capsule body and the capsule cap will result in poor capsule sealing, leakage, and no enteric protection.

[0055] For hard-shell capsules, the coating layer should not be too heavy. If the coating layer is applied too heavily, pre-locked hard-shell capsules coated with polymer will experience operational difficulties during subsequent capsule filling. If the coating layer is less than 6 mg / cm² (e.g., 1–5.5 mg / cm², 2–5 mg / cm², or 3–5 mg / cm²), conventional capsule filling machines can usually complete the process smoothly without modification.

[0056] In a preferred embodiment, the average thickness of the coating layer on the hard-shell capsule is about 5–60 micrometers (1–6 mg / cm²), 10–55 micrometers (1–5.5 mg / cm²), 20–50 micrometers (2–5 mg / cm²), or 30–50 micrometers (3–5 mg / cm²).

[0057] The uniform average gap between the uncoated capsule body and the capsule cap is 10–120 micrometers, preferably 20–100 micrometers or 10–80 micrometers. The thickness of the coating layer formed by the pH-responsive polymer composition is less than the uniform average gap between the uncoated capsule body and the capsule cap.

[0058] Average gap and average thickness of coating for target function of hard-shell capsules from different brands

[0059] For example, for size 0 capsules, the average functional coating thickness ranges from 10–60 micrometers, 10–50 micrometers, 10–40 micrometers, 10–30 micrometers, 10–20 micrometers, 20–60 micrometers, 20–50 micrometers, 20–40 micrometers, 20–30 micrometers, 25–60 micrometers, 25–50 micrometers, 25–40 micrometers, 30–60 micrometers, to 30–50 micrometers.

[0060] For example, for size 1 and size 2 capsules, the average functional coating thickness ranges from 10–50 micrometers, 10–40 micrometers, 10–30 micrometers, 10–20 micrometers, 20–50 micrometers, 20–40 micrometers, 20–30 micrometers, 25–50 micrometers, 25–40 micrometers, to 30–50 micrometers.

[0061] Active ingredients in pharmaceuticals / nutritional supplements Oral formulations for delivery to the ileum and colon, specifically designed to treat and prevent bacterial (iatrogenic or non-iatrogenic) gut microbiota dysbiosis and related conditions, including treatment or prevention of IBD, immunosuppressants, antibiotics, antitumor drugs, phytochemicals, and probiotics. Related conditions can include infectious diseases (such as Clostridium difficile infection), ulcerative colitis, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, type 2 diabetes, food allergies, cancer (including leukemia), refractory graft-versus-host disease (GvHD), obesity (e.g., GLP-1 receptor agonists (dulaglutide, exenatide, liraglutide, lixisenatide, and smegglutide)), and severe obesity. Other conditions associated with gut microbiota dysbiosis include autism, sclerosis, traveler's diarrhea, chronic vaginal infections (cystitis, fungal infections), bone and joint infections, intensive care unit (ICU)-related gut microbiota dysbiosis, Parkinson's disease, Alzheimer's disease, schizophrenia, bipolar disorder, and gut microbiota dysbiosis induced by anti-tumor chemotherapy or immunotherapy.

[0062] The term "dysbiosis" refers to a damaged microbiome, in which the proportion of normally dominant bacteria is reduced, or bacteria that are normally suppressed proliferate. When dysbiosis is caused by medical interventions (such as antibiotic treatment or enteral nutritional support), it is called iatrogenic dysbiosis.

[0063] Fecal microbiota transplantation (FMT) is a current method for reconstructing a "healthy" gut microbiota. In FMT, fecal material from a healthy donor or a healthy donor population is implanted into the digestive tract of a patient recipient to "reset" or cure the host's gut microbiota imbalance. This transplantation can be divided into allogeneic transplantation (i.e., the transplant material comes from a healthy individual donor or donor population, and the recipient is a patient) and autologous transplantation (i.e., a fecal sample of the individual is collected before the individual receives hospitalization, antibiotic treatment, or other treatments that may disrupt their microbiota, or any event that may cause dysbiosis).

[0064] In another preferred embodiment, the active pharmaceutical ingredient (API) is selected from mesalazine, prednisolone, budesonide, fluticasone, azathioprine, cyclosporine, methotrexate, metronidazole, ciprofloxacin, fluorouracil, actinomycin D, bleomycin, etoposide, taxol, vincristine, doxorubicin, cisplatin, daunorubicin, VP-16, raltitrexed, oxaliplatin, curcumin, and paclitaxel. Camptothecin, resveratrol, quercetin, 6-gingerol, 6-shogaol, mangiferin, Escherichia coli DH5, Lactobacillus casei, Bifidobacterium breve, Lactobacillus plantarum PTCC1058, Lactobacillus reuteri DPC16, Lactobacillus rhamnosus GG, Lactobacillus paracasei L26, Lactobacillus acidophilus KI, Bifidobacterium animalis BB-12, Bifidobacterium pseudochain G7, Bifidobacterium bifidum, Akkermansia myxophilum, Enterococcus strains, and Bacteroides fragilis.

[0065] Method for preparing hard-shell capsules coated with a pH-responsive polymer composition The present invention also discloses a method for preparing a hard-shell capsule coated with the pH-responsive polymer composition described above. This coated hard-shell capsule can be used as a carrier for bioactive components of pharmaceuticals or nutritional supplements, and is particularly suitable for delivering microbiota to the ileum and colon.

[0066] The preparation method includes the following steps: i. A hard-shell capsule in a pre-locked state, the capsule comprising a capsule body and a capsule cap; ii. A solution, suspension, or dispersion containing the pH-responsive polymer composition as described above is coated onto the hard-shell capsule obtained in step i to obtain a hard-shell capsule coated with the pH-responsive polymer.

[0067] The preparation method may further include the following steps: iii. Provide the coated hard-shell capsule obtained in step ii; iv. Open the encapsulated hard-shell capsule and fill it with the bioactive ingredients of the medicine or nutritional supplement, especially the microbiome; v. Close the capsule to a fully locked state to obtain a filled capsule.

[0068] Preferably, a roller coating machine is used to apply a coating solution, suspension or dispersion containing the pH-responsive polymer composition described above to a pre-locked hard-shell capsule by spray coating to form a coating layer that covers the outer surface of the pre-locked hard-shell capsule.

[0069] Solution, suspension or dispersion The coating composition of the present invention can be in the form of a solution, suspension, or dispersion, and is particularly preferred to be in the form of an aqueous solution, an aqueous suspension, or an aqueous dispersion. The aqueous dispersion or suspension consists of a solid phase and a liquid phase, the total of which is 100% by weight.

[0070] The liquid phase of the aqueous dispersion or aqueous solution may consist substantially or entirely of the dispersant / solvent—water. Therefore, the water content in the liquid phase is at least 95% by weight, preferably at least 98%, and most preferably 100%. The presence of an organic solvent, such as ethanol, isopropanol, or acetone, may not exceed 5% by weight, preferably not more than 2% by weight. In some cases, this organic solvent may be used to reduce surface tension or inhibit microbial contamination. Preferably, the solution is free of organic solvents.

[0071] The term "solution, suspension, or dispersion" refers to a solution in which all substances exist in a dispersed state, a dissolved state, or an intermediate state where some substances exist in a dispersed state and some in a dissolved state. The pH of the aqueous dispersion or solution is preferably 6.0–10.0, and more preferably 6.5–9.0. Within this pH range, the anionic (meth)acrylate copolymers present therein are primarily in a dispersed state, or at least partially in a dissolved state. Plasticizers are typically in a dissolved state, while other additives or excipients (such as talc) may be in a dispersed state.

[0072] Solid content The solid content of the aqueous solution, suspension, or dispersion may be higher than 10% by weight, preferably 5–25% by weight. Solutions, suspensions, or dispersions used in spray processes typically have a solid content of 15–20% by weight.

[0073] Elongation at break The elasticity of the dried polymer film can be characterized essentially by its elongation at break. The dried film prepared using the solution, suspension, or dispersion described in this invention (e.g., by casting) has an elongation at break of at least 15%, preferably 15–500%. The elongation at break (in %) can be determined by testing film samples according to DIN 53 455.

[0074] Capsule filling machine Subsequent process steps are preferably completed in a capsule filling machine, which can open polymer-coated hard-shell capsules, fill them with materials containing bioactive ingredients of drugs or nutrients, and close the capsules to a fully locked state.

[0075] After the aforementioned subsequent processing steps, a fully locked polymer-coated hard-shell capsule is obtained, which can be used as a container for bioactive ingredients in pharmaceuticals or nutritional supplements. This fully locked polymer-coated hard-shell capsule, used as a container for bioactive ingredients in pharmaceuticals or nutritional supplements, constitutes a pharmaceutical or nutritional supplement dosage form.

[0076] The drug or nutritional dosage form comprises a polymer-coated hard-shell capsule in a fully locked state, the hard-shell capsule containing a filler containing a bioactive drug / nutritional ingredient; wherein the polymer-coated hard-shell capsule includes a coating layer containing a pH-responsive polymer, wherein the coating layer covers the outer surface area of ​​the capsule in the pre-locked state, but does not cover the overlapping area of ​​the capsule body covered by the capsule cap in the pre-locked state.

[0077] Preferred implementation scheme A hard-shell capsule in a pre-locked state and coated with a pH-responsive polymer, wherein the pH-responsive polymer composition comprises: a. 40 to 90% by weight of at least one anionic poly(meth)acrylate copolymer; b. 0 to 40% by weight of at least one (meth)acrylate copolymer selected from the following: poly(ethyl methacrylate), poly(methyl methacrylate), or combinations thereof; c. 2 to 6% by weight of at least one gliding agent; d. 3 to 20% by weight of at least one non-component c plasticizer; and e. 1 to <6% by weight or 1 to 20% by weight of at least one nonionic emulsifier; The content of each component a to e is based on the total weight of the pH-responsive polymer composition. When component b is present, components a and b are distinct; and In the anionic (meth)acrylate copolymer of component a, 0.1–10 mol% of anionic groups exist in the form of salts.

[0078] A hard-shell capsule in a pre-locked state and coated with a pH-responsive polymer, wherein the pH-responsive polymer composition comprises: a. 40 to 90% by weight of at least one anionic poly(meth)acrylate copolymer selected from the following: poly(methacrylate-co-methyl methacrylate) 1:1, poly(methacrylate-co-methyl methacrylate) 1:2, poly(methyl acrylate-co-methyl methacrylate-co-methacrylate) 7:3:1 or a combination thereof; b. 0 to 40% by weight of at least one (meth)acrylate copolymer selected from the following: poly(ethyl methacrylate), poly(methyl methacrylate), or combinations thereof; c. 2 to 6% by weight of at least one gliding agent; d. 3 to 20% by weight of at least one non-component c plasticizer; and e. 3.5 to 5.8% by weight or 1 to 20% by weight of at least one nonionic emulsifier; The content of each component a to e is based on the total weight of the pH-responsive polymer composition.

[0079] A hard-shell capsule coated with a pH-responsive polymer, wherein the pH-responsive polymer composition comprises: a. 40 to 90% by weight of at least one anionic poly(meth)acrylate copolymer selected from the following: poly(methacrylate-co-methyl methacrylate) 1:1, poly(methacrylate-co-methyl methacrylate) 1:2, poly(methyl acrylate-co-methyl methacrylate-co-methacrylate) 7:3:1 or a combination thereof; b. 5 to 40% by weight of poly(methyl methacrylate-co-methyl methacrylate); c. 2 to 6% by weight of at least one gliding agent; d. 3 to 20% by weight of at least one non-component c plasticizer; and e. 1 to <6% by weight or 1 to 20% by weight of at least one nonionic emulsifier; The content of each component a to e is based on the total weight of the pH-responsive polymer composition.

[0080] A hard-shell capsule coated with a pH-responsive polymer, wherein the pH-responsive polymer composition comprises: a. 40 to 90% by weight of poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1; b. 5 to 40% by weight of poly(methyl methacrylate-co-methyl methacrylate); c. 2 to 6% by weight of at least one gliding agent; d. 3 to 20% by weight of at least one non-component c plasticizer; and e. 3.5 to 5.8% by weight of at least one nonionic emulsifier; The content of each component a to e is based on the total weight of the pH-responsive polymer composition.

[0081] A hard-shell capsule coated with a pH-responsive polymer composition, wherein the pH-responsive polymer composition comprises: a. 40 to 90% by weight of at least one anionic poly(meth)acrylate copolymer; b. 5 to 40% by weight of at least one (meth)acrylate copolymer selected from the following: poly(ethyl methacrylate), poly(methyl methacrylate), or combinations thereof; c. 2 to 6% by weight of at least one gliding agent; d. 3 to 20% by weight of at least one non-component c plasticizer; and e. 1 to <6% by weight or 1 to 20% by weight of at least one nonionic emulsifier; The content of each component a to e is based on the total weight of the pH-responsive polymer composition. When component b is present, components a and b are distinct; and In the anionic (meth)acrylate copolymer of component a, 0.1–10 mol% of anionic groups exist in the form of salts.

[0082] A hard-shell capsule coated with a pH-responsive polymer for oral delivery of microbiota to the ileum and colon, wherein the pH-responsive polymer composition comprises: a. 40 to 90% by weight of at least one anionic poly(meth)acrylate copolymer; b. 0 to 40% by weight of at least one (meth)acrylate copolymer selected from the following: poly(ethyl methacrylate), poly(methyl methacrylate), or combinations thereof; c. 2 to 6% by weight of at least one gliding agent; d. 3 to 20% by weight of at least one non-component c plasticizer; and e. 1 to <6% by weight or 1 to 20% by weight of at least one nonionic emulsifier; The content of each component a to e is based on the total weight of the pH-responsive polymer composition. When component b is present, components a and b are distinct; and In the anionic (meth)acrylate copolymer of component a, 0.1–10 mol% of anionic groups exist in the form of salts.

[0083] A hard-shell capsule coated with a pH-responsive polymer for oral delivery of microbiota to the ileum and colon, wherein the pH-responsive polymer composition comprises: a. 40 to 90% by weight of at least one anionic poly(meth)acrylate copolymer selected from the following: poly(methacrylate-co-methyl methacrylate) 1:1, poly(methacrylate-co-methyl methacrylate) 1:2, poly(methyl acrylate-co-methyl methacrylate-co-methacrylate) 7:3:1 or a combination thereof; b. 0 to 40% by weight of at least one (meth)acrylate copolymer selected from the following: poly(ethyl methacrylate), poly(methyl methacrylate), or combinations thereof; c. 2 to 6% by weight of at least one gliding agent; d. 3 to 20% by weight of at least one non-component c plasticizer; and e. 3.5 to 5.8% by weight of at least one nonionic emulsifier; The content of each component a to e is based on the total weight of the pH-responsive polymer composition.

[0084] A hard-shell capsule coated with a pH-responsive polymer for oral delivery of microbiota to the ileum and colon, wherein the pH-responsive polymer composition comprises: a. 40 to 90% by weight of at least one anionic poly(meth)acrylate copolymer selected from the following: poly(methacrylate-co-methyl methacrylate) 1:1, poly(methacrylate-co-methyl methacrylate) 1:2, poly(methyl acrylate-co-methyl methacrylate-co-methacrylate) 7:3:1 or a combination thereof; b. 5 to 40% by weight of poly(methyl methacrylate-co-methyl methacrylate); c. 2 to 6% by weight of at least one gliding agent; d. 3 to 20% by weight of at least one non-component c plasticizer; and e. 1 to <6% by weight or 1 to 20% by weight of at least one nonionic emulsifier; The content of each component a to e is based on the total weight of the pH-responsive polymer composition.

[0085] A hard-shell capsule coated with a pH-responsive polymer for oral delivery of microbiota to the ileum and colon, wherein the pH-responsive polymer composition comprises: a. 40 to 90% by weight of poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1; b. 5 to 40% by weight of poly(methyl methacrylate-co-methyl methacrylate); c. 2 to 6% by weight of at least one gliding agent; d. 3 to 20% by weight of at least one non-component c plasticizer; and e. 3.5 to 5.8% by weight of at least one nonionic emulsifier; The content of each component a to e is based on the total weight of the pH-responsive polymer composition.

[0086] A hard-shell capsule coated with a pH-responsive polymer composition for oral delivery of microbiota to the ileum and colon, wherein the pH-responsive polymer composition comprises: a. 40 to 90% by weight of at least one anionic poly(meth)acrylate copolymer; b. 5 to 40% by weight of at least one (meth)acrylate copolymer selected from the following: poly(ethyl methacrylate), poly(methyl methacrylate), or combinations thereof; c. 2 to 6% by weight of at least one gliding agent; d. 3 to 20% by weight of at least one non-component c plasticizer; and e. 1 to <6% by weight or 1 to 20% by weight of at least one nonionic emulsifier; The content of each component a to e is based on the total weight of the pH-responsive polymer composition. When component b is present, components a and b are distinct; and In the anionic (meth)acrylate copolymer of component a, 0.1–10 mol% of anionic groups exist in the form of salts.

[0087] A dosage form comprising a pharmaceutical / nutritional active ingredient encapsulated in a hard-shell capsule coated with a pH-responsive polymer for delivery to the ileum and colon, wherein the pH-responsive polymer composition comprises: a. 40 to 90% by weight of at least one anionic poly(meth)acrylate copolymer; b. 0 to 40% by weight of at least one (meth)acrylate copolymer selected from the following: poly(ethyl methacrylate), poly(methyl methacrylate), or combinations thereof; c. 2 to 6% by weight of at least one gliding agent; d. 3 to 20% by weight of at least one non-component c plasticizer; and e. 1 to <6% by weight or 1 to 20% by weight of at least one nonionic emulsifier; The content of each component a to e is based on the total weight of the pH-responsive polymer composition. When component b is present, components a and b are distinct; and In the anionic (meth)acrylate copolymer of component a, 0.1–10 mol% of anionic groups exist in the form of salts.

[0088] A dosage form comprising a pharmaceutical / nutritional active ingredient encapsulated in a hard-shell capsule coated with a pH-responsive polymer for delivery to the ileum and colon, wherein the pH-responsive polymer composition comprises: a. 40 to 90% by weight of at least one anionic poly(meth)acrylate copolymer selected from the following: poly(methacrylate-co-methyl methacrylate) 1:1, poly(methacrylate-co-methyl methacrylate) 1:2, poly(methyl acrylate-co-methyl methacrylate-co-methacrylate) 7:3:1 or a combination thereof; b. 0 to 40% by weight of at least one (meth)acrylate copolymer selected from the following: poly(ethyl methacrylate), poly(methyl methacrylate), or combinations thereof; c. 2 to 6% by weight of at least one gliding agent; and d. 3 to 20% by weight of at least one non-component c plasticizer; and e. 3.5 to 5.8% by weight of at least one nonionic emulsifier; The content of each component a to e is based on the total weight of the pH-responsive polymer composition.

[0089] A dosage form comprising a pharmaceutical / nutritional active ingredient encapsulated in a hard-shell capsule coated with a pH-responsive polymer for delivery to the ileum and colon, wherein the pH-responsive polymer composition comprises: a. 40 to 90% by weight of at least one anionic poly(meth)acrylate copolymer selected from the following: poly(methacrylate-co-methyl methacrylate) 1:1, poly(methacrylate-co-methyl methacrylate) 1:2, poly(methyl acrylate-co-methyl methacrylate-co-methacrylate) 7:3:1 or a combination thereof; b. 5 to 40% by weight of poly(methyl methacrylate-co-methyl methacrylate); c. 2 to 6% by weight of at least one gliding agent; d. 3 to 20% by weight of at least one non-component c plasticizer; and e. 1 to <6% by weight or 1 to 20% by weight of at least one nonionic emulsifier; The content of each component a to e is based on the total weight of the pH-responsive polymer composition.

[0090] A dosage form comprising a pharmaceutical / nutritional active ingredient encapsulated in a hard-shell capsule coated with a pH-responsive polymer for delivery to the ileum and colon, wherein the pH-responsive polymer composition comprises: a. 40 to 90% by weight of poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1; b. 5 to 40% by weight of poly(methyl methacrylate-co-methyl methacrylate); c. 2 to 6% by weight of at least one gliding agent; d. 3 to 20% by weight of at least one non-component c plasticizer; and e. 3.5 to 5.8% by weight of at least one nonionic emulsifier; The content of each component a to e is based on the total weight of the pH-responsive polymer composition.

[0091] A dosage form comprising a pharmaceutical / nutritional active ingredient encapsulated in a hard-shell capsule coated with a pH-responsive polymer for delivery to the ileum and colon, wherein the pH-responsive polymer composition comprises: a. 40 to 90% by weight of at least one anionic poly(meth)acrylate copolymer; b. 5 to 40% by weight of at least one (meth)acrylate copolymer selected from the following: poly(ethyl methacrylate), poly(methyl methacrylate), or combinations thereof; c. 2 to 6% by weight of at least one gliding agent; d. 3 to 20% by weight of at least one non-component c plasticizer; and e. 1 to <6% by weight or 1 to 20% by weight of at least one nonionic emulsifier; The content of each component a to e is based on the total weight of the pH-responsive polymer composition. When component b is present, components a and b are distinct; and In the anionic (meth)acrylate copolymer of component a, 0.1–10 mol% of anionic groups exist in the form of salts.

[0092] In another preferred embodiment, the active ingredient of the drug / nutrient is selected from Escherichia coli DH5, Lactobacillus casei, Bifidobacterium breve, Lactobacillus plantarum PTCC1058, Lactobacillus reuteri DPC16, Lactobacillus rhamnosus GG, Lactobacillus paracasei L26, Lactobacillus acidophilus KI, Bifidobacterium animalis BB-12, Bifidobacterium pseudochain G7, Bifidobacterium bifidum, Akkermansia myxotroph, Enterococcus spp. strains, and Bacteroides fragilis, preferably Akkermansia myxotroph, Enterococcus spp. strains, and Bacteroides fragilis.

[0093] project 1. A hard-shell capsule coated with a pH-responsive polymer, wherein the pH-responsive polymer composition comprises or consists of the following components: a. 40 to 90% by weight of at least one anionic poly(meth)acrylate copolymer; b. 0 to 40% by weight of at least one (meth)acrylate copolymer selected from the following: poly(ethyl methacrylate), poly(methyl methacrylate), or combinations thereof; c. 2 to 6% by weight of at least one gliding agent; d. 3 to 20% by weight of at least one non-component c plasticizer; and e. 1 to <6% by weight or 1 to 20% by weight of at least one nonionic emulsifier; The content of each component a to e is based on the total weight of the pH-responsive polymer composition. When component b is present, components a and b are not the same.

[0094] 2. The hard-shell capsule according to Project 1, wherein the content of the at least one nonionic emulsifier is 3.5–5.8% by weight based on the total weight percentage of the pH-responsive polymer composition.

[0095] 3. The hard-shell capsule according to any one of items 1 to 2, wherein the content of component b is 5–30% by weight based on the total weight of the pH-responsive polymer composition.

[0096] 4. The hard-shell capsule according to any one of items 1 to 3, wherein the content of the gliding agent is 3–5% by weight based on the total weight of the pH-responsive polymer composition.

[0097] 5. The hard-shell capsule according to any one of items 1 to 4, wherein 0.1–10 mol% of the anionic groups in the anionic (meth)acrylate copolymer are present in the form of salts.

[0098] 6. The hard-shell capsule according to any one of items 1 to 5, wherein the at least one anionic poly(meth)acrylate copolymer is poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid).

[0099] 7. The hard-shell capsule according to Item 6, wherein the poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) has a monomer ratio of 7:2:1 or 7:3:2.

[0100] 8. The hard-shell capsule according to any one of items 1 to 7, wherein the poly(methacrylate-co-ethyl acrylate) has a monomer ratio of 1:1.

[0101] 9. The hard-shell capsule according to any one of items 1 to 8, wherein the poly(methacrylate-co-methyl methacrylate) has a monomer ratio of 1:1 or 1:2.

[0102] 10. The hard-shell capsule according to any one of items 1 to 9, wherein the plasticizer is selected from alkyl citrate, alkyl phthalate, alkyl sebacate, sucrose ester, sorbitan ester, diethyl sebacate, dibutyl sebacate, propylene glycol, polyethylene glycol, or mixtures thereof.

[0103] 11. The hard-shell capsule according to any one of items 1 to 10, wherein the nonionic emulsifier is selected from polysorbate 20, polysorbate 28, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85, poloxamer 124, poloxamer 181, poloxamer 188, poloxamer 237, poloxamer 331, poloxamer 338 and poloxamer 407. Polyethoxylated castor oil, PEG-40 hydrogenated castor oil, polyethylene glycol 15-hydroxystearate, polyoxyethylene 15-hydroxystearate, PEG-8 glyceryl caprylate, D-α-tocopherol PEG 1000 succinate, lecithin, sorbitan monopalmitate, cetyl alcohol, oleyl alcohol, sodium glycolate, sodium deoxycholate, alkyl glycosides, alkyl polyglucosides, octyl glucosides, decyl maltodextrin, or combinations thereof.

[0104] 12. The hard-shell capsule according to any one of items 1 to 11, wherein the gliding agent is selected from silica, kaolin, calcium silicate, magnesium silicate, talc, stearates (such as calcium stearate, magnesium stearate, zinc stearate), sodium stearate fumarate, starch, stearic acid, fatty acid monoglycerides, fatty acid diglycerides, fatty acid triglycerides, or mixtures thereof.

[0105] 13. The hard-shell capsule according to any one of items 1 to 12, wherein the thickness of the pH-responsive polymer coating layer is 10–55 micrometers, 10–50 micrometers, 10–40 micrometers, 10–30 micrometers, 10–20 micrometers, 20–55 micrometers, 20–50 micrometers, 20–40 micrometers, 20–30 micrometers, 25–55 micrometers, 25–50 micrometers, 25–40 micrometers, 30–60 micrometers, or 30–50 micrometers; and / or the thickness of the coating layer is less than the gap between the uncoated capsule body and the capsule cap.

[0106] 14. The hard-shell capsule according to any one of items 1 to 13, wherein the amount of the pH-responsive polymer coating layer applied is 1–5.5 mg / cm².

[0107] 15. The hard-shell capsule according to any one of items 1 to 14, further comprising a top coating and / or a bottom coating.

[0108] 16. The hard-shell capsule according to any one of items 1 to 15, wherein the coating thickness of the pH-responsive polymer and the top coating and / or bottom coating is 5–55 micrometers, 10–55 micrometers, 10–50 micrometers, 10–40 micrometers, 10–30 micrometers, 10–20 micrometers, 20–55 micrometers, 20–50 micrometers, 20–40 micrometers, 20–30 micrometers, 25–55 micrometers, 25–50 micrometers, 25–40 micrometers, 30–60 micrometers, or 30–50 micrometers; and / or wherein the total coating thickness of the pH-responsive polymer and the top coating and / or bottom coating is less than the gap between the uncoated capsule body and the capsule cap.

[0109] 17. The hard-shell capsule according to any one of items 1 to 16, wherein the hard-shell capsule is used to release at least 50%, preferably more than 80%, of the active pharmaceutical / nutritional ingredient within 30 minutes, preferably 15 minutes, at a pH of about 7.2.

[0110] 18. The hard-shell capsule according to item 17, wherein the active ingredient of the drug / nutritional product is a microbiome, preferably a fecal microbiome selected from Akkermansia myxophilus, Enterococcus strains and Bacteroides fragilis.

[0111] 19. A method for preparing a hard-shell capsule coated with a pH-responsive polymer, wherein the method comprises the following steps: i. A hard-shell capsule comprising a capsule body and a capsule cap in a pre-locked state; ii. Coating the hard-shell capsule obtained in step i with a solution, suspension or dispersion containing a pH-responsive polymer composition according to any one of items 1 to 12 to obtain a hard-shell capsule coated with a pH-responsive polymer.

[0112] 20. The preparation method according to item 19, wherein the method further comprises the following steps: iii. Provide the coated hard-shell capsule obtained in step ii; iv. Open the encapsulated hard-shell capsule and fill it with the bioactive ingredients of the medicine or nutritional supplement; v. Close the capsule to a fully locked state to obtain a filled capsule.

[0113] 21. According to the preparation method described in Project 19, the solid content of the coating solution, suspension or dispersion containing the pH-responsive polymer composition is 5–25% by weight.

[0114] 22. The preparation method according to any one of items 19 to 21, wherein the coating is a spray coating performed using a roller coating machine.

[0115] 23. A dosage form comprising a pharmaceutical / nutritional active ingredient contained in a hard-shell capsule coated with a pH-responsive polymer composition according to any one of items 1 to 15.

[0116] 24. The dosage form according to item 23, wherein at least 50%, preferably more than 80%, of the active pharmaceutical / nutritional ingredient is released within 30 minutes, preferably within 15 minutes, at a pH of about 7.2.

[0117] 25. The dosage form according to any one of items 23 to 24, wherein at a pH below 7, no more than 5% of the active pharmaceutical / nutritional ingredient is released.

[0118] 26. The dosage form according to any one of items 23 to 25, wherein the active pharmaceutical ingredient is selected from mesalazine, prednisolone, budesonide, fluticasone, azathioprine, cyclosporine, methotrexate, metronidazole, ciprofloxacin, fluorouracil, actinomycin D, bleomycin, etoposide, paclitaxel, vincristine, doxorubicin, cisplatin, daunorubicin, VP-16, raltitrexed, oxaliplatin, curcumin, paclitaxel, and camptothecin. Alkali, resveratrol, quercetin, 6-gingerol, 6-shogaol, mangiferin, Escherichia coli DH5, Lactobacillus casei, Bifidobacterium breve, Lactobacillus plantarum PTCC1058, Lactobacillus reuteri DPC16, Lactobacillus rhamnosus GG, Lactobacillus paracasei L26, Lactobacillus acidophilus KI, Bifidobacterium animalis BB-12, Bifidobacterium pseudochain G7, Bifidobacterium bifidum, Akkermansia myxophilum, Enterococcus strains and Bacteroides fragilis.

[0119] Example Materials and Methods EUDRAGIT ® FS is a copolymer composed of approximately 25% by weight methyl methacrylate, approximately 65% ​​by weight methyl acrylate, and approximately 10% by weight methacrylic acid, and is available from Evonik Corporation. EUDRAGIT ® FS30 D contains 30% EUDRAGIT by weight. ® FS aqueous dispersion.

[0120] EUDRAGIT ® L100 is a copolymer of approximately 50% by weight methyl methacrylate and approximately 50% by weight methacrylic acid, and is available from Evonik Corporation.

[0121] EUDRAGIT ®S100 is a copolymer of approximately 70% by weight methyl methacrylate and approximately 30% by weight methacrylic acid, and is available from Evonik Corporation.

[0122] EUDRAGIT ® L100-55 is a copolymer composed of approximately 50% by weight ethyl acrylate and approximately 50% by weight methacrylic acid, and is available from Evonik Corporation. EUDRAGIT ® L30 D-55 contains 30% EUDRAGIT by weight. ® L100-55 aqueous dispersion.

[0123] Plasacryl ® HTP20 is available from Evonik Corporation and is an aqueous solution containing a flow aid (glyceryl monostearate), a plasticizer (triethyl citrate), and a nonionic surfactant (polysorbate 80).

[0124] Plasacryl ® T20 is available from Evonik Corporation and is an aqueous solution containing a flow aid (glyceryl monostearate), a plasticizer (triethyl citrate), and a nonionic surfactant (polysorbate 80).

[0125] Example 1 A pH-responsive polymer was used to coat size 0 hydroxypropyl methylcellulose capsules. The polymer composition is detailed in Table 1.

[0126] Table 1

[0127] Preparation of Coated Suspensions 1 N NaOH: Dissolve the required amount of sodium hydroxide in deionized water or mix it with deionized water to prepare a 1N solution in deionized water.

[0128] 33% Tween 80 (polysorbate 80) solution: Polysorbate 80 was dissolved in the required amount of water using a propeller agitator to prepare a 33% solution.

[0129] Plasacryl HTP 20: The material tank is stirred with a propeller agitator for at least 10 minutes to obtain a homogeneous product.

[0130] EUDRAGIT ® L100 preparation: Measure 700g of water and add it to the polymer while stirring with a propeller agitator. After 5 minutes, add sodium hydroxide solution dropwise and continue stirring for another hour. Then add TEC and continue stirring for another hour.

[0131] EUDRAGIT ® FS preparation: Pour the polymer into a container and stir with a propeller stirrer. Then add the remaining water, followed by the slow addition of polysorbate 80 solution, and then the slow addition of Plasacryl HTP20. Continue stirring for another 15 minutes.

[0132] Final step: While stirring, add EUDRAGIT ® Slowly pour L100 dispersion into EUDRAGIT ® The FS dispersion was then stirred for 15 minutes. The coating dispersion was sieved before spraying and stirred during the coating process.

[0133] In a GLATT GMPC2 standard roller coating machine (equipped with a 56-liter roller), the coating suspension is sprayed onto capsules in a pre-locked state. A Watson Marlow 504U is used as the peristaltic pump, and a 3 mm inner diameter silicone tube is used. A SCHLICK 930 series spray gun with ABC design is used. Process parameters are described in Table 2.

[0134] Table 2

[0135] Example 2 The 0-hydroxypropyl methylcellulose capsules were coated with a pH-responsive polymer, and the polymer composition is detailed in Table 3.

[0136] Table 3

[0137] Preparation of Coated Suspensions 1 N NaOH: Dissolve the required amount of sodium hydroxide in deionized water or mix it with deionized water to prepare a 1N solution in deionized water.

[0138] 33% Tween 80 (polysorbate 80) solution: Polysorbate 80 was dissolved in the required amount of water using a propeller agitator to prepare a 33% solution.

[0139] Plasacryl HTP 20: The material tank is stirred with a propeller agitator for at least 10 minutes to obtain a homogeneous product.

[0140] EUDRAGIT ® L100 preparation: Measure 700g of water and add it to the polymer while stirring with a propeller agitator. After 5 minutes, add sodium hydroxide solution dropwise and continue stirring for another hour. Then add TEC and continue stirring for another hour.

[0141] EUDRAGIT ® FS preparation: Pour the polymer into a container and stir with a propeller stirrer. Then add the remaining water, followed by the slow addition of polysorbate 80 solution, and then the slow addition of Plasacryl HTP20. Continue stirring for another 15 minutes.

[0142] Final step: While stirring, add EUDRAGIT ® Slowly pour L100 dispersion into EUDRAGIT ® The FS dispersion was then stirred for 15 minutes. The coating dispersion was sieved before spraying and stirred during the coating process.

[0143] In a GLATT GMPC2 standard roller coating machine (equipped with a 56-liter roller), the coating suspension is sprayed onto capsules in a pre-locked state. A Watson Marlow 504U is used as the peristaltic pump, and a 3 mm inner diameter silicone tube is used. A SCHLICK 930 series spray gun with ABC design is used. Process parameters are described in Table 4.

[0144] Table 4

[0145] Example 3 The 0-type hydroxypropyl methylcellulose capsules were coated with a pH-responsive polymer. The formulation of the polymer composition is detailed in Table 5.

[0146] Table 5

[0147] Preparation of Coated Suspensions 1 N NaOH: Dissolve the required amount of sodium hydroxide in deionized water or mix it with deionized water to prepare a 1N solution in deionized water.

[0148] 33% Polysorbate 80 solution: Polysorbate 80 was dissolved in the required amount of water using a propeller agitator to prepare a 33% solution.

[0149] Plasacryl HTP 20: The material tank is stirred with a propeller agitator for at least 10 minutes to obtain a homogeneous product.

[0150] EUDRAGIT ® L100 preparation: Measure 700g of water and add it to the polymer while stirring with a propeller agitator. After 5 minutes, add sodium hydroxide solution dropwise and continue stirring for another hour. Then add TEC and continue stirring for another hour.

[0151] EUDRAGIT ® FS preparation: Pour the polymer into a container and stir with a propeller stirrer. Then add the remaining water, followed by the slow addition of polysorbate 80 solution, and then the slow addition of Plasacryl HTP20. Continue stirring for another 15 minutes.

[0152] Final step: While stirring, add EUDRAGIT ® Slowly pour L100 dispersion into EUDRAGIT ® The FS dispersion was then stirred for 15 minutes. The coating dispersion was sieved before spraying and stirred during the coating process.

[0153] In a GLATT GMPC2 standard roller coating machine (equipped with a 56-liter roller), the coating suspension is sprayed onto capsules in a pre-locked state. A Watson Marlow 504U is used as the peristaltic pump, and a 3 mm inner diameter silicone tube is used. A SCHLICK 930 series spray gun with ABC design is used. Process parameters are described in Table 6.

[0154] Table 6

[0155] Example 4: Dissolution test of caffeine-filled capsules from Examples 1-3 Dissolution profiles were determined for hydroxypropyl methylcellulose capsules coated according to Examples 1-3, the capsules being filled with 500 mg of a caffeine-lactose 2:3 mixture.

[0156] (a) USP 2 dissolution test Three capsules were placed in the following pH environments: pH 1.2 (2 hours), then pH 6.8 (1 hour), and finally pH 7.2 (2 hours). USP 2 dissolution testing was performed using an ERWEKA DT700 paddle dissolution apparatus, set at 37°C and paddle speed at 75 rpm. At each time point, the caffeine content in the dissolution medium was determined by high-performance liquid chromatography-ultraviolet (HPLC-UV) to assess the capsule dissolution status. The HPLC-UV injection volume was 10 μL, using an Agilent 1100er series apparatus, with the specific operating parameters as follows: - Column: Gemini 2-micron C18 column (100 mm × 4.6 mm) - Mobile phase: Methanol-Licrosol-purified water (3:7) mixture - Flow rate: 1 ml / min - Running time: 8 minutes - Detection wavelength: 273 nanometers.

[0157] The results are shown in Table 7.

[0158] Table 7

Claims

1. A hard-shell capsule coated with a pH-responsive polymer, wherein the pH-responsive polymer composition comprises: a. 40 to 90% by weight of at least one anionic poly(meth)acrylate copolymer; b. 0 to 40% by weight of at least one (meth)acrylate copolymer selected from the following: poly(ethyl methacrylate), poly(methyl methacrylate), or combinations thereof; c. 2 to 6% by weight of at least one gliding agent; d. 3 to 20% by weight of at least one non-component c plasticizer; and e. 1 to <6% by weight of at least one nonionic emulsifier; The content of each component a to e is based on the total weight of the pH-responsive polymer composition. When component b is present, components a and b are not the same.

2. The hard-shell capsule according to claim 1, wherein the content of the at least one nonionic emulsifier is 3.5–5.8% by weight, based on the total weight percentage of the pH-responsive polymer composition.

3. The hard-shell capsule according to any one of claims 1 to 2, wherein the content of component b is 5–30% by weight based on the total weight of the pH-responsive polymer composition.

4. The hard-shell capsule according to any one of claims 1 to 3, wherein the content of the flow aid is 3–5% by weight based on the total weight of the pH-responsive polymer composition.

5. The hard-shell capsule according to any one of claims 1 to 4, wherein 0.1–10 mol% of the anionic groups in the anionic (meth)acrylate copolymer are present in the form of salts.

6. The hard-shell capsule according to any one of claims 1 to 5, wherein the at least one anionic poly(meth)acrylate copolymer is poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid).

7. The hard-shell capsule according to claim 6, wherein the poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) has a monomer ratio of 7:2:1 or 7:3:

2.

8. The hard-shell capsule according to any one of claims 1 to 7, wherein the poly(methacrylate-co-methyl methacrylate) has a monomer ratio of 1:1 or 1:

2.

9. The hard-shell capsule according to any one of claims 1 to 8, wherein the plasticizer is selected from alkyl citrate, alkyl phthalate, alkyl sebacate, sucrose ester, sorbitan ester, diethyl sebacate, dibutyl sebacate, propylene glycol, polyethylene glycol, or mixtures thereof.

10. The hard-shell capsule according to any one of claims 1 to 9, wherein the nonionic emulsifier is selected from polysorbate 20, polysorbate 28, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85, poloxamer 124, poloxamer 181, poloxamer 188, poloxamer 237, poloxamer 331, poloxamer 338, and poloxamer 407. Polyethoxylated castor oil, polyethylene glycol-40 hydrogenated castor oil, polyethylene glycol 15-hydroxystearate, polyoxyethylene 15-hydroxystearate, octanoic acid-capric acid-polyethylene glycol-8 glyceryl ester, D-α-tocopherol polyethylene glycol 1000 succinate, lecithin, sorbitan monopalmitate, cetyl alcohol, oleyl alcohol, sodium glycolate, sodium deoxycholate, alkyl glycosides, alkyl polyglucosides, octyl glucosides, decyl maltodextrin, or combinations thereof.

11. The hard-shell capsule according to any one of claims 1 to 10, wherein the flow aid is selected from silica, kaolin, calcium silicate, magnesium silicate, talc, stearates (such as calcium stearate, magnesium stearate, zinc stearate), sodium stearate fumarate, starch, stearic acid, monoglycerides of fatty acids, diglycerides of fatty acids, triglycerides of fatty acids, or mixtures thereof.

12. The hard-shell capsule according to any one of claims 1 to 11, wherein the average thickness of the pH-responsive polymer coating layer is 10–55 micrometers.

13. The hard-shell capsule according to any one of claims 1 to 12, wherein the amount of the pH-responsive polymer coating layer applied is 1–5.5 mg / cm².

14. A method for preparing a hard-shell capsule coated with a pH-responsive polymer, wherein the method comprises the following steps: i. A hard-shell capsule comprising a capsule body and a capsule cap in a pre-locked state; ii. A solution, suspension or dispersion containing the pH-responsive polymer composition as described in any one of claims 1 to 11 is coated onto the hard-shell capsule of step i to obtain a hard-shell capsule coated with the pH-responsive polymer.

15. A dosage form comprising a pharmaceutical / nutritional active ingredient in a hard-shell capsule coated with a pH-responsive polymer composition as described in any one of claims 1 to 13, or in a hard-shell capsule prepared by the method of claim 14.

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