An enteric coated hard shell capsule for delivery of a dosage form in the ileum and colon

Abstract

The present invention relates to a pH responsive polymer composition for enteric coating of a hard shell capsule for delivering a pharmaceutical dosage form, especially microbiota, in 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 wt. % of at least one non-ionic emulsifier based on total wt. % of the pH responsive polymer composition.

Description

[0001] An enteric coated hard shell capsule for delivery of a dosage form in the ileum and colon

[0002] Field of the invention

[0003] The present invention relates to a pH responsive polymer composition for enteric coating of a hard shell capsule for delivering a pharmaceutical dosage form in 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 at least one non-ionic emulsifier.

[0004] Background of the invention

[0005] The normal human stomach has a pH which can range from approximately 1 -3, however, usually it is closer to 2. A pharmaceutical dosage form usually contains a coating that prevents the drug release in gastric environment. However, the integrity of this coating can come under question when there is food in the stomach as thereby the pH can raise to 4-5. Further, many active pharmaceutical ingredients such as antibodies, bacteria etc. are not stable at acidic pH. Therefore, it is desirable for ingredients which are not stable at acidic pH to be released only at a pH 7.2 and above.

[0006] WO 2019096833 A1 discloses a hard shell capsule coated with a pH responsive methacrylate copolymer. However, the release of the active ingredient / the fill from these capsules either initiates at pH 6.8 or displays a delayed release of the active ingredient / the fill at a pH of 6.8 or 7.4. The delayed release at a pH 7.2 can lead to passing of the capsule without release of the active ingredient / the fill at ileum and colon. Thus, there is a need for developing hard shell capsule for target delivery at pH 7.2, i.e., at ileum and colon.

[0007] WO 2019097030 A1 discloses a hard shell capsule, wherein the body and the cap, is coated separately with a pH responsive methacrylate copolymer for oral delivery of bacteria derived from fecal microbiota. It discloses that the pH responsive polymer composition comprises poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1 , poly(methacrylic acid-co-ethyl acrylate) 1 :1 , glycerol monostearate, at least one plasticizer, and 4 to 9% by weight of at least one non-ionic emulsifier. The amount of 6-9 wt. % of non-ionic emulsifier such as polysorbate 80 is particularly important to achieve the release initiation at pH 7.2 without significant release at pH 6.8.

[0008] Schwartzberg et. al., Advances in Therapy 35, 754-767 (2018) discloses that polysorbate 80 is a biologically and possibly pharmacologically active compound and consequently may alter the pharmacologic properties of the drug it is formulated with or may itself directly mediate adverse events. Thus, it is desirable to reduce the amount of non-ionic surfactant such as polysorbate 80 in the enteric coating composition of a hard shell capsule. Therefore, the technical solutions disclosed in the prior art suffer from drawbacks such as the use of undesirably high amount of non-ionic surfactant for providing a pH responsive enteric coating which enables stability up to pH 6.8 and release at a pH 12.

[0009] Thus, it is an object of the present invention to provide a hard shell capsule coated with a pH responsive polymer composition for delivering a pharmaceutical or nutraceutical dosage form in the ileum and colon with reduced amount of non-ionic surfactant, yet provide stability without significant release (< 10 %) at a pH 6.8 and a release of the content at a pH 7.2 in the ileum and colon. Yet another object of the present invention is to provide a dosage form comprising a pharmaceutical / nutraceutical active ingredient in a hard shell capsule coated with a pH responsive polymer composition for immediate release, or a slow release of the content at a pH of 7.2 within 60 minutes. Another object of the present invention is to provide a dosage form comprising a pharmaceutical / nutraceutical active ingredient in a hard shell capsule coated with a pH responsive polymer composition and / or a top coat / subcoat(s), wherein based on the need to modulate the release of the API (slow to moderate to immediate release within 60 minutes) after reaching a pH of 7.2 by adjusting the ratio of the polymer in the pH responsive polymer composition and maintaining the thickness of the coating within the gap of a uncoated body and cap. Still another object of the present invention is to provide a hard shell capsule coated with a pH responsive polymer composition and / or a top coatZsubcoat(s) and use in a capsule filling machine with high efficiency.

[0010] Summary of the invention

[0011] It was found that a pH responsive polymer composition comprising at least one anionic poly(meth)acrylate copolymer, at least one glidant, at least one plasticizer and less than 6 wt. % of non-ionic emulsifier allows the provision of an enteric coated hard shell capsule which enables a stability up to pH 6.8 and releases the content at a pH around 1 .

[0012] Thus, in a first aspect, the present invention is directed to a hard shell capsule coated with a pH responsive polymer, wherein the pH responsive polymer composition comprises: a. 40 to 90 wt. % of at least one anionic poly(meth)acrylate copolymer, b. 0 to 40 wt. % at least one (meth)acrylate copolymer selected from poly(methacrylic acid- co-ethyl acrylate), poly(methacrylic acid-co-methyl methacrylate), or a combination thereof, c. 2 to 6 wt. % of at least one glidant, d. 3 to 20 wt. % of at least one plasticizer other than component c., and e. 1 to < 6 wt. % of at least one non-ionic emulsifier, wherein the amount of each component a. to e. is based on total wt. % of the pH responsive polymer composition, when component b. is present, components a. and b. are different. In a second aspect, the present invention is directed to a process for preparing a hard shell capsule coated with a pH responsive polymer, wherein the process comprising the steps of: i. providing a hard shell capsule comprising a body and a cap in a pre-locked state, ii. coating a solution, suspension or dispersion comprising a pH responsive polymer composition according to item 1 to 12 to the hard shell capsule of step i. to obtain the hard shell capsule coated with a pH responsive polymer.

[0013] In a third aspect, the present invention is directed to a dosage form comprising a pharmaceutical / nutraceutical active ingredient in a hard shell capsule coated with a pH responsive polymer composition.

[0014] Detailed description of the invention

[0015] The present invention is directed to a hard shell capsule coated with a pH responsive polymer, wherein the pH responsive polymer composition comprises: a. 40 to 90 wt. % of at least one anionic poly(meth)acrylate copolymer, b. 0 to 40 wt. % at least one (meth)acrylate copolymer selected from poly(methacrylic acid-co-ethyl acrylate), poly(methacrylic acid-co-methyl methacrylate), or a combination thereof, c. 2 to 6 wt. % of at least one glidant, d. 3 to 20 wt. % of at least one plasticizer other than component c., and e. 1 to < 6 wt. %, or 1 to 20 wt. % of at least one non-ionic emulsifier, wherein the amount of each component a. to e. is based on total wt. % of the pH responsive polymer composition, when component b. is present, components a. and b. are different.

[0016] In another preferred embodiment the hard shell capsule is coated with a pH responsive polymer in a pre-locked state.

[0017] Hard shell capsule

[0018] Hard shell capsules for pharmaceutical or nutraceutical purposes are well known to a skilled person. A hard shell capsule usually consists of two pieces encapsulation capsule comprising of the two capsule halves, called the body and the cap. The capsule body and cap material is usually made from a hard and sometimes brittle material. The body and the cap are usually of a one open end cylindrical form with closed rounded hemispherical ends on the opposite end. The shape and size of the cap and body are such that the body can be pushed telescopically with its open end into the open end of the cap. The body and the cap comprise a potential overlapping matching area (overlap area) outside the body and inside the cap which partially overlap when the capsule is closed in the pre-locked stage and totally overlap in the final-locked stage. When the cap is partially slid over the overlapping matching area of the body the capsule is in the pre-locked stage. When the cap is totally slid over the overlapping matching area of the body the capsule is in the final-locked stage. The maintenance of the pre-locked stage or of the final-locked stage is usually supported by snap-in locking mechanisms of the body and the cap such as matching encircling notches or dimples, preferably elongated dimples. Usually, the body is longer than the cap. The outside overlapping area of the body can be covered by the cap in order to close or to lock the capsule. In the closed stage the cap covers the outside overlap area of the body either in a pre-locked state or in a final-locked state. In the final-locked state the cap covers the outside overlap area of the body in total, in the pre-locked state the cap overlaps the outside overlapping area of the body only partially. The cap can be slid over the body to be fixed in usually one of two different positions in which the capsule is closed either in a pre-locked state or in a final-locked state.

[0019] Hard shell capsules are commercially available in different sizes. Hard shell capsules are usually delivered as empty containers with the body and cap already positioned in the pre-locked state and on demand as separate capsules halves, bodies, and caps. The pre-locked hard shell capsules can be provided to a capsule-filling machine, which performs the opening, filling, and closing of the capsule into the final-locked state. Usually, hard shell capsules are filled with dry materials, for instance with powders or granules comprising a biologically active ingredient.

[0020] The cap and body are provided with closure means that are advantageous for the pre-locking (temporary) and / or final locking of the capsule. Therefore, elevated points may be provided on the inner wall of the cap and somewhat larger indented points are provided on the outer wall of the body, which are arranged so that when the capsule is closed the elevations fit into the indentations. Alternatively, the elevations may be formed on the outer wall of the body and the indentations on the inner wall of the cap. The elevations or indentations are arranged in a ring or spiral around the wall. Instead of the point-like configuration of the elevations and indentations, these may encircle the wall of the cap or body in an annular configuration, although advantageously recesses and openings are provided which enable an exchange of gases into and out of the capsule interior.

[0021] One or more elevations may be provided in an annular arrangement around the inner wall of the cap and the outer wall of the body such that, in the final-locked position of the capsule, an elevation on the cap is located adjacent to an elevation on the body. Sometimes elevations are formed on the outside of the body close to the open end and indentations are formed in the cap close to the open end such that the elevations on the body latch into the indentations in the cap in the final-locked position of the capsule. The elevations may be such that the cap can be opened in the pre-locked state at any time without damage to the capsule or, alternatively, so that once it has been closed the capsule cannot be opened again without destroying it. Capsules with one or more such latching mechanisms (latches) (for example two encircling grooves) are preferred. More preferred are capsules with at least two such latching means which secure the two capsule parts to different degrees. In a part of this kind, a first latching (dimples or circular notches) means may be formed close to the openings in the capsule cap and the capsule body and a second latching (circular notches) can be shifted somewhat further towards the closed end of the capsule parts. The first latching means secure the two capsule parts less strongly than the second does. This variant has the advantage that after the production of the empty capsules the capsule cap and capsule body can initially be pre-locked joined together using the first latching mechanism. In order to fill the capsule, the two capsule parts are then separated again. After filling, the two capsule parts are pushed together until the second set of latches firmly secures the capsule parts in a final- locked stage.

[0022] Preferably, the body and the cap of the hard shell capsule are comprising each encircling notches and / or dimples in the area, where the cap can be slid over the body. Encircling notches of the body and dimples of the cap match to each other to provide a snap-in or snap into-place mechanism. The dimples may be circular or elongated (oval) in the longitudinal direction.

[0023] Encircling notches of the body and encircling notches of the cap (closely matched rings) also match to each other to provide a snap-in or snap into-place mechanism. This allows the capsule to be closed by a snap-into-place mechanism either in a pre-locked state or in a final-locked state.

[0024] Preferably, matching encircling notches of the body and elongated dimples of the cap are used to fix the body and the cap to each other in the pre-locked state. Matching encircling notches of the body and the cap are preferably used to fix or lock the body and the cap to each other in the final-locked state.

[0025] The area, where the cap can be slid over the body may be called the overlapping area of the body and the cap or briefly the overlap area. If the cap overlaps the body only partially, maybe to 20 to 90 or 60 to 85 % of the overlap area, the hard shell capsule is only partially closed (pre-locked). Preferably, in the presence of a locking mechanism, like matching encircling notches and / or dimples in body and cap, the partially closed capsule may be called pre-locked. When the capsule is polymer- coated in the pre-locked stage the coating will cover the complete outer surface including that part of the overlap area of the body and cap that is not overlapped by the cap in this pre-locked stage. When the capsule is polymer-coated in the pre-locked stage and then closed to the final-locked stage the coating of that part of the overlap area of the body and cap that was not overlapped by the cap in the pre-locked stage will then become covered by the cap. The presence of that part of the coating which is then enclosed in the final-locked stage between the body and the cap is sufficient for the hard shell capsule to be tightly sealed. This was not to be foreseen by any means. If the cap overlaps the body the total overlapping area of the body, the hard shell capsule is finally closed or in the final-locked state. Preferably, in the presence of a locking mechanism, like matching encircling notches and / or dimples in body and cap, the finally closed capsule may be called final- locked.

[0026] Usually, dimples are preferred for fixing the body and the cap in the pre-locked state. As a nonbinding rule the matching area of dimples is smaller than the matching area of encircling notches. Thus, snapped-in dimples may be snapped-out again by applying less forces than those that would be necessary to snap-out a snapped-in fixation by matching encircling notches.

[0027] The dimples of the body and cap are located in the area, where the cap can be slid over the body match to each other in the pre-locked state by a snap in or snap into-place mechanism. There may be for example 2, 4, or preferably 6 notches or dimples located distributed circular around the cap. Usually, the dimples of the cap and the encircling notches of the body are in the area, where the cap can be slid over the body match to each other so that they that allow the capsule to be closed by a snap-into-place mechanism in the pre-locked state. In the pre-locked state, the hard shell capsule can be re-opened manually or by a machine without damaging, because the forces needed to open are comparatively low. So, the “pre-locked state” is sometimes designated also as “loosely capped”.

[0028] Usually, the encircling notches or matching locking rings of the body and the cap in the area, where the cap can be slid over the body match to each other so that they that allow the capsule to be closed by a snap-into-place mechanism in the final-locked state. In the final-locked state, the hard shell capsule cannot or can only hardly be re-opened manually or by a machine without damaging, because the forces needed to open are comparatively high. Usually dimples and the encircling notches are formed in the capsule body or capsule cap. When the capsule parts provided with these elevations and indentations are fitted into one another, ideally defined uniform gaps of from 10 microns to 150 microns, more particularly 20 microns to 100 microns, are formed along the contact surface between the capsule body and the capsule cap placed thereon. Preferably, the body of the hard shell capsule comprises a tapered rim. The tapered rim prevents the rims of the body and the cap to collide and becoming damaged when the capsule is closed manually or by a machine.

[0029] Average Gap of hard-shell capsules of different brands:

[0030] The gap between the capsule body and cap in a pre-locked or in a final-locked state for different brands was calculated on basis of a value of 100 pm capsule cap wall thickness for different capsule size. The capsule cap wall thickness was subtracted from the external capsule cap diameter getting to the internal capsule cap diameter. In the next step, the capsule cap internal diameter was subtracted from the capsule body external diameter and resulted in the average gap width between capsule body and cap in the pre-locked or final-locked state. Average gap of hard-shell capsules of different brands

[0031] Size of hard shell capsules

[0032] A closed, final-locked hard shell capsule may have a total length in the range from about 5 to 40 mm. The diameter of the cap may be in the range from about 4 to 12 mm. The diameter of the body may be in the range from about 2 to 11 mm. The length of the cap may be in the range from about 4 to 20 mm and that of the body in the range from 8 to 30 mm. The fill volume may be between about from 0.1 to 2 ml. The difference between the pre-locked length and the final-locked length may be about 1 to 5 mm.

[0033] Capsules can be divided into standardized sizes for example from sizes 000 to 5. A closed capsule of size 000 has, for example, a total length of about 28 mm with an outer diameter of the cap of about 9.9 mm and an outer diameter of the body of about 9.5 mm. The length of the cap is about 14 mm, that of the body about 22 mm. The fill volume is about 1 .4 ml.

[0034] A closed capsule of size 5 has, for example, a total length of about 10 mm and an outer diameter of the cap of about 4.8 mm and an outer diameter of the body of about 4.6 mm. The length of the cap is about 5.6 mm, that of the body about 9.4 mm. The fill volume is about 0.13 ml.

[0035] A size 0 capsule may show a length of about 23 to 24 mm in the pre-locked stage and of about 20.5 to 21 .5 mm in the final-locked stage. Thus, the difference between the pre-locked length and the final-locked length may be about 2 to 3 mm.

[0036] The uniform average gap between the uncoated capsule body and capsule cap is in the range of 10 to 100 pm, preferably 20 to 100 pm, most preferably 10 to 80 pm.

[0037] Material of the body and the cap The material of the body and the cap may be selected from hydroxypropyl methyl cellulose (HPMC), starch, gelatin, pullulan, and a copolymer of Ci- to C4-alkylester of (meth)acrylic acid and (meth)acrylic acid. Preferred are hard shell capsules where body and cap are comprising or consisting of HPMC or gelatin, most preferred is HPMC because of its good adhesion properties for the polymer coating. pH responsive polymer composition

[0038] A "pH responsive polymer" means that a polymer dissolution dependent on the at a given pH. According to present invention the pH responsive polymer should be stable up to a pH of 7 and immediately release the pharmaceutical / nutraceutical ingredient.

[0039] Component a.: anionic (meth)acrylic copolymer

[0040] The composition comprises 40 to 90 % by weight, based on the total weight of the composition, of an anionic (meth)acrylic copolymer. The anionic (meth)acrylic copolymer is obtained by polymerizing 25 to 95 % by weight, based on the total weight of the monomers, of at least one Ci — C4 -alkyl ester of acrylic acid, and / or of methacrylic acid, and 5 to 75 % by weight, based on the total weight of the monomers, of acrylic acid, and / or methacrylic acid. In another embodiment the anionic (meth)acrylic copolymer is polymerized from 40 to 60 % by weight, based on the total weight of the monomers, of at least one Ci — C4 -alkyl ester of acrylic acid, and / or of methacrylic acid, and 60 to 40 % by weight, based on the total weight of the monomers, of acrylic acid, or methacrylic acid. Yet in another embodiment the anionic (meth)acrylic copolymer is polymerized from 40 to 60 % by weight, based on the total weight of the monomers, of ethyl acrylate, and 60 to 40 % by weight, based on the total weight of the monomers, of methacrylic acid.

[0041] In another embodiment the Ci — C4 -alkyl ester of acrylic acid and / or of 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. Yet in another embodiment, the at least one Ci — C4 -alkyl ester of acrylic acid or of methacrylic acid is selected from methyl acrylate, ethyl acrylate, methyl methacrylate or a mixture of two or more thereof.

[0042] In another embodiment the anionic (meth)acrylic copolymer has 5 to 60 % by weight, based on the total weight of the monomers, of methacrylic acid. Yet in another embodiment the anionic (meth)acrylic copolymer has 40 to 60 % by weight, based on the total weight of the monomers, of methacrylic acid.

[0043] Suitable anionic (meth)acrylic copolymers are commercially available under the trade names EUDRAGIT® L 30 D-55, EUDRAGIT® L 100-55, EUDRAGIT® L 100, EUDRAGIT® S 100, and EUDRAGIT® FS 30 D. EUDRAGIT® L 30 D-55 and EUDRAGIT® L 100-55 (poly(methacrylic acid-co-ethyl acrylate) 1 :1) are well-known commercially available (meth)acrylate copolymer products for pharmaceutical applications. EUDRAGIT® L 30 D-55 is available as 30 % aqueous dispersion and EUDRAGIT® L 100-55 is sold in powder form. EUDRAGIT® L 30 D-55 and EUDRAGIT® L 100-55 comprise 46 to 50.6 % by weight of methacrylic acid and 49.4 to 54 % by weight of ethyl acrylate, each based on the total weight of monomers. The dissolution of EUDRAGIT® L 30 D-55 type copolymer in intestinal juice or simulated intestinal fluid can be stated to be at about pH 5.5.

[0044] EUDRAGIT® L 100 (poly(methacrylic acid-co-methyl methacrylate) 1 :1) is a well-known commercially available (meth)acrylate copolymer polymerized from around 50 % by weight of methyl methacrylate and around 50 % by weight of methacrylic acid. The dissolution of EUDRAGIT® L type copolymer in intestinal juice or simulated intestinal fluid can be stated to be at about pH 6.0.

[0045] EUDRAGIT® S 100 (poly(methacrylic acid-co-methyl methacrylate) 1 :2) is a well-known commercially available (meth)acrylate copolymer polymerized from around 70 % by weight of methyl methacrylate and around 30 % by weight of methacrylic acid. The dissolution of EUDRAGIT® S 100 type copolymer in intestinal juice or simulated intestinal fluid can be stated to be at about pH 7.0.

[0046] EUDRAGIT® FS 30 D (poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1) is a well-known commercially available (meth)acrylate copolymer polymerized from around 10 % by weight of methacrylic acid, around 65 % by weight of methyl acrylate, and around 25 % by weight of methyl methacrylate. The dissolution of EUDRAGIT® FS type copolymer in intestinal juice or simulated intestinal fluid can be stated to be at about pH 7.0.

[0047] In another preferred embodiment the anionic poly(meth)acrylate copolymer is selected from poly(methacrylic acid-co-ethyl acrylate) 1 :1 , poly(methacrylic acid-co-methyl methacrylate) 1 :1 , poly(methacrylic acid-co-methyl methacrylate) 1 :2, poly(methyl acrylate-co-methyl methacrylate-co- methacrylic acid) 7:3:1 , or a combination thereof. The preferred anionic poly(meth)acrylate copolymer is poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1 as the dissolution of EUDRAGIT® FS type in intestinal juice or simulated intestinal fluid can be stated to be at about pH 7.0. Also, this copolymer provides better elongation at break and mechanical properties.

[0048] In another embodiment 0.1 to 10 mole percent of the anionic groups of the anionic (meth)acrylic copolymer are present in salt form. The partial neutralization is particularly advantageous as it provides an improved stability at a pH up to 7.

[0049] The suitable base for partial neutralization of the anionic copolymer is selected from alkali metal hydroxides, alkali metal carbonates, alkaline earth metal hydroxides, alkaline earth metal carbonates, alkali and alkaline metal oxides, or ammonia. The most preferred are sodium hydroxides and aqueous ammonia.

[0050] Component b.

[0051] In another preferred embodiment the pH responsive polymer composition comprises component b present in an amount in the range of 5 to 30 wt. %, based on total wt. % of the pH responsive polymer composition. Whenever, component b. is present in the composition then the partial neutralization of component a. is optional. The preferred component b. is poly(methacrylic acid-co-methyl methacrylate).

[0052] Component c.: glidant

[0053] Glidants or release agents usually have lipophilic properties and are usually added to spray suspensions. They prevent agglomeration of the polymers during film formation. The suitable examples for glidants are selected from silica, kaolin calcium silicate, magnesium silicate, talc, stearate salts like calcium stearate, magnesium stearate, zinc stearate, sodium stearyl fumarate, starch, stearic acid, fatty acid monoglyceride, fatty acid diglyceride, fatty acid triglyceride, or mixtures thereof. The preferred glidants are selected from fatty acid monoglyceride, fatty acid diglyceride, fatty acid triglyceride, or mixtures thereof.

[0054] The amount of glidant is present in the pH responsive polymer composition is in the range of 2 to 6 wt. %, preferably 3.5 to 5 wt. %, each based on total wt. % of the pH responsive polymer composition.

[0055] Component d.: plasticizer

[0056] The pH responsive polymer composition comprises one or more plasticizers. The plasticizers through physical interaction with the (meth)acrylate copolymer reduce the glass transition temperature and promote film formation. Suitable substances usually have a molecular weight of between 100 and 20,000 and comprise one or more hydrophilic groups in the molecule, e.g., hydroxyl, ester, or amino groups. An example for suitable the plasticizer is selected from alkyl citrates, alkyl phthalates, alkyl sebacate, sucrose esters, sorbitan esters, diethyl sebacate, dibutyl sebacate, propylene glycol, polyethylene glycol, or a mixture thereof. The preferred plasticizer is alkyl citrates.

[0057] Component e.: non-ionic emulsifier

[0058] Non-ionic emulsifier helps in forming a homogenous mixture of pH responsive polymer composition which promote the formation of uniform film without much micro irregularity over the hard shell capsule. In another preferred embodiment the non-ionic emulsifier is present in an amount in the range of 3.5 to 5.8 wt. %, preferably 4.1 to 5.8 wt.%, each based on total wt. % of the pH responsive polymer composition. Examples for suitable non-ionic 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, macrogol 15 hydroxystearate, polyoxyl 15 hydroxystearate, caprylocaproyl macrogol-8 glyceride, D- a-tocopherol polyethylene glycol 1000 succinate, lecithin, sorbitan monopalmitate, cetyl alcohol, oleyl alcohol, sodium glycolate, sodium de(s)oxycholate, alkyl glycoside, alkyl polyglucoside, octyl glucoside, decyl maltoside, or a combination thereof. The preferred non-ionic emulsifier is polysorbate and poloxamer type.

[0059] Coating Layer

[0060] The hard shell capsule is coated with a coating layer comprising the pH responsive polymer composition as disclosed.

[0061] The coating layer may comprise 10 % or more, 20 % or more, 30 % or more, 40 % or more, 50 % or more, 60 % or more, 70 % or more, 80 % or more, 90 % or more by weight of the polymer as disclosed herein. The coating layer may comprise 40 - 90, 45 - 90, 60 - 90, 60 - 85 or 70 - 80 % by weight of the polymer as disclosed herein.

[0062] Amount and thickness of the coating layer

[0063] The amount of the coating layer (= total weight gain of the coating layer) applied should be sufficient to allow filling of the capillary between the outside overlapping area of the body covered by the cap. If the amount of coating layer applied is too low, this may not provide sufficient enteric protection. There may be not enough amount of coating layer between the body and the cap when the capsule is closed in the final-locked stage, which may result in insufficient tightness and leakage of the capsule without enteric protection.

[0064] For hard shell capsules, the amount of the coating layer should not be too high. If the amount of coating layer applied is too high this may result in difficulties to process the polymer-coated prelocked hard shell capsules subsequently in a capsule-filling machine. If the amount of coating layer is less than 6 mg / cm2, for instance 1 to 5.5 mg / cm2or 2 to 5 mg / cm2or 3 to 5 mg / cm2usually no problem with standard capsule-filling machines without modification will occur.

[0065] In a preferred embodiment the coating layer on the hard shell capsules may have an average thickness of about 5 to 60 pm (1 to 6 mg / cm2), 10 to 55 pm (1 to 5.5 mg / cm2), 20 to 50 pm (2 to 5 mg / cm2), or 30 to 50 pm (3 to 5 mg / cm2).

[0066] The uniform average gap between the uncoated capsule body and capsule cap is in the range of 10 to 120 pm, preferably 20 to 100 pm or 10 to 80 pm. The thickness of the coating layer formed with a pH responsive polymer composition is less than the uniform average gap between the uncoated capsule body and capsule cap.

[0067] Average gap of hard-shell capsules of different brands and desired average functional coating thickness

[0068] For example, for a size 0 capsule the average functional coating thickness is in the range of 10 to 60 pm, 10 to 50 pm, 10 to 40 pm, 10 to 30 pm, 10 to 20 pm, 20 to 60 pm, 20 to 50 pm, 20 to 40 pm, 20 to 30 pm, 25 to 60 pm, 25 to 50 pm, 25 to 40 pm, 30 to 60 pm, 30 to 50 pm.

[0069] For example, for size 1 and 2 capsules the average functional coating thickness is in the range of 10 to 50 pm, 10 to 40 pm, 10 to 30 pm, 10 to 20 pm, 20 to 50 pm, 20 to 40 pm, 20 to 30 pm, 25 to 50 pm, 25 to 40 pm, 30 to 50 pm.

[0070] Pharmaceutical / nutraceutical active ingredient

[0071] The pharmaceutical oral formulations to be administered to the colon and ileum is specifically for the treatment and prevention of bacterial (iatrogenic or non-iatrogenic) gut dysbiosis and associated pathologies, treatment, or prevention of IBD, Immunosuppressants, Antibiotics, Antineoplastic agents, Phytochemicals and Probiotic. The pathologies concerned may be infection, such as Clostridium difficile, ulcerative colitis, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, type II diabetes, food allergies, cancer, including leukemia, refractory Graft-versus-host disease (GvHD), obesity such as GLP-1 -receptor agonists (Dulaglutide, Exenatide, Liraglutide, Lixisenatide and Semaglutide) and morbid obesity. Other pathologies associated with dysbiosis are autism, sclerosis, traveller's diarrhea, chronic vaginal infection (cystitis, mycoses), bone and joint infections, intensive care unit (ICU) related dysbiosis, Parkinson's disease, Alzheimer's disease, schizophrenia, and bipolar disorders and gut dysbiosis associated with anti-cancer chemotherapy or immunotherapy.

[0072] The term "dysbiosis" means an impaired microbiota, wherein a normally dominating species becomes under-represented, or species that are normally outcompeted or contained, are increased in population. When the dysbiosis is caused by a medical intervention, such as treatment with antibiotics or enteral feeding, it is known as iatrogenic dysbiosis. Fecal microbiota transplant (FMT) is one method that is used today to restore a "healthy" intestinal microbiota. In FMT, fecal matter from a healthy donor or a group of healthy donors is introduced into the digestive tract of a patient receiver, to "reset" or cure the intestinal dysbiosis of the host. The transplantation may be allogenic (i.e. , from an individual healthy donor or group of donors towards a patient) or it may be autologous, wherein fecal samples are taken from an individual before undergoing hospitalization, or antibiotic treatment, or other treatment that is likely to perturb the individual's microbiota or any event possibly generating dysbiosis.

[0073] In another preferred embodiment the pharmaceutical / nutraceutical active ingredients are selected from mesalamine, prednisolone, budesonide, fluticasone, azathioprine, cyclosporin, methotrexate, metronidazole, ciprofloxacin, fluorouracil, methotrexate, dactinomycin, bleomycin, etoposide, taxol, vincristine, doxorubicin, cisplatin, daunorubicin, VP-16, raltitrexed, oxaliplatin, curcumin, paclitaxel, camptothecin, resveratrol, quercetin, 6-gingerol, 6-shogaol, mangiferin, E. coli DH 5, Lactobacillus casei, Bifidobacterium breve, Lactobacillus plantarum PTCC 1058, L. reuteri DPC16, Lactobacillus rhamnosus GG, Lactobacillus paracasei L26, Lactobacillus acidophilus KI and Bifidobacterium animalis BB-12, B. pseudocatenulatum G7, B. bifidum, Akkermansia muciniphila , Enterococcus spp., and Bacteroides fragilis.

[0074] Process for preparing a hard shell capsule coated with a pH responsive polymer composition

[0075] Described is a process for preparing a hard shell capsule coated with a pH responsive polymer composition as described above. The coated hard shell capsule is suitable as a container for pharmaceutical or nutraceutical biologically active ingredients, especially for delivery microbiome to the colon and ileum.

[0076] The process comprising the steps of: i. providing a hard shell capsule comprising a body and a cap in a pre-locked state, ii. coating a solution, suspension or dispersion comprising a pH responsive polymer composition as described above to the hard shell capsule of step i. to obtain the hard shell capsule coated with the pH responsive polymer.

[0077] The process further comprises the steps of:

[0078] Hi. providing the coated hard shell capsule obtained in step ii., iv. opening the coated hard shell capsule and filling with a pharmaceutical or nutraceutical biologically active ingredient, especially with a microbiome, and v. closing to the final-locked state to obtain a filled capsule.

[0079] The hard shell capsule in the pre-locked state is preferably spray-coated in a drum coater with a coating solution, suspension or dispersion comprising a pH responsive polymer composition as described above to create a coating layer which covers the outer surface of the hard shell capsule in the pre-locked state.

[0080] Solution, suspension or dispersion

[0081] The coating composition according to the invention may be in the form of a solution, suspension or dispersion. Specially in the form of an aqueous solution, suspension or dispersion. The aqueous dispersion or suspension consists of a solid phase and a liquid phase. The solids phase and the liquid phase total 100% by weight.

[0082] The liquid phase of the aqueous dispersion or solution may be based essentially or completely on the dispersant or solvent water. The liquid phase thus consists of at least 95% by weight, preferably at least 98% by weight, in particular 100% by weight, of water. Organic solvents, such as, for example, ethanol, isopropanol or acetone, may be present up to 5% by weight, preferably up to 2% by weight. This may be of use in individual cases for lowering the surface tension or for preventing microbiological contamination. Preferably, no organic solvents may be present.

[0083] The term “solution, suspension or dispersion” refers to the fact that the substances present may in their totality be present either in dispersed form, dissolved form or else partly dispersed or dissolved in an intermediate state. The aqueous dispersion or solution preferably may have a pH of from 6.0 to 10.0, in particular from 6.5 to 9.0. In this pH range, the anionic (meth)acrylate copolymers present may be predominantly in dispersed or at least partly dissolved form. Plasticizers are generally present in dissolved form. Other additives or auxiliaries, such as, for example, talc, may be present in dispersed form.

[0084] Solids Content

[0085] The solids content of the aqueous solution, suspension or dispersion may be more than 10% by weight, preferably in the range of 5-25% by weight. The solids contents of solution, suspension or dispersion which are used in spraying processes are generally in the range of 15-20 % by weight.

[0086] Elongation at Break

[0087] The elasticity of the dried polymer film may essentially be characterized by its elongation at break. A dried film produced from the solution, suspension or dispersion according to the invention, e.g. by pouring, has an elongation at break of at least 15, preferably in the range of 15 to 500%. The elongation at break in [%] can be determined on sample films in accordance with DIN 53 455.

[0088] Capsule-filling machine

[0089] This further process step is preferably performed in a capsule-filling machine, which performs the opening, filling with a fill comprising a pharmaceutical or a nutraceutical biologically active ingredient and closing of the polymer-coated hard shell capsule to the final-locked state. This further process step results in a final-locked polymer-coated hard shell capsule, which is a container for pharmaceutical or nutraceutical biologically active ingredient. The final-locked polymer- coated hard shell capsule, which as a container for pharmaceutical or nutraceutical biologically active ingredient is a pharmaceutical or nutraceutical dosage form.

[0090] The pharmaceutical or nutraceutical dosage form is comprising a polymer-coated hard shell capsule in the final-locked stage containing a fill comprising a pharmaceutical or nutraceutical biologically active ingredient, wherein the polymer-coated hard shell capsule comprises a coating layer comprising a pH responsive polymer composition, where the coating layer covers the outer surface area of the capsule in the pre-locked stage but not the overlapping area where the cap covers the body in the pre-locked stage.

[0091] Preferred Embodiments

[0092] A hard shell capsule coated with a pH responsive polymer in a pre-locked state, wherein the pH responsive polymer composition comprises: a. 40 to 90 wt. % of at least one anionic poly(meth)acrylate copolymer, b. 0 to 40 wt. % at least one (meth)acrylate copolymer selected from poly(methacrylic acid-co- ethyl acrylate), poly(methacrylic acid-co-methyl methacrylate), or a combination thereof, c. 2 to 6 wt. % of at least one glidant, d. 3 to 20 wt. % of at least one plasticizer other than component c., and e. 1 to < 6wt. %, or 1 to 20 wt. % of at least one non-ionic emulsifier, wherein the amount of each component a. to e. is based on total wt. % of the pH responsive polymer composition, when component b. is present, components a. and b. are different, and

[0093] 0.1 to 10 mole percent of the anionic groups of the anionic (meth)acrylic copolymer of component a. are present in salt form.

[0094] A hard shell capsule coated with a pH responsive polymer in a pre-locked state, wherein the pH responsive polymer composition comprises: a. 40 to 90 wt. % of at least one anionic poly(meth)acrylate copolymer selected from poly(methacrylic acid-co-methyl methacrylate) 1 :1 , poly(methacrylic acid-co-methyl methacrylate) 1 :2, poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1 , or a combination thereof, b. 0 to 40 wt. % at least one (meth)acrylate copolymer selected from poly(methacrylic acid-co- ethyl acrylate), poly(methacrylic acid-co-methyl methacrylate), or a combination thereof, c. 2 to 6 wt. % of at least one glidant, d. 3 to 20 wt. % of at least one plasticizer other than component c., and e. 3.5 to 5.8 wt. %, or 1 to 20 wt. % of at least one non-ionic emulsifier, wherein the amount of each component a. to e. is based on total wt. % of the pH responsive polymer composition.

[0095] A hard shell capsule coated with a pH responsive polymer, wherein the pH responsive polymer composition comprises: a. 40 to 90 wt. % of at least one anionic poly(meth)acrylate copolymer selected from poly(methacrylic acid-co-methyl methacrylate) 1 :1 , poly(methacrylic acid-co-methyl methacrylate) 1 :2, poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1 , or a combination thereof, b. 5 to 40 wt. % poly(methacrylic acid-co-methyl methacrylate, c. 2 to 6 wt. % of at least one glidant, d. 3 to 20 wt. % of at least one plasticizer other than component c., and e. 1 to < 6 wt. %, or 1 to 20 wt. % of at least one non-ionic emulsifier, wherein the amount of each component a. to e. is based on total wt. % of the pH responsive polymer composition.

[0096] A hard shell capsule coated with a pH responsive polymer, wherein the pH responsive polymer composition comprises: a. 40 to 90 wt. % of poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1 , b. 5 to 40 wt. % poly(methacrylic acid-co-methyl methacrylate, c. 2 to 6 wt. % of at least one glidant, d. 3 to 20 wt. % of at least one plasticizer other than component c., and e. 3.5 to 5.8 wt. % of at least one non-ionic emulsifier, wherein the amount of each component a. to e. is based on total wt. % of the pH responsive polymer composition.

[0097] A hard shell capsule coated with a pH responsive polymer composition, wherein the pH responsive polymer composition comprises: a. 40 to 90 wt. % of at least one anionic poly(meth)acrylate copolymer, b. 5 to 40 wt. % at least one (meth)acrylate copolymer selected from poly(methacrylic acid-co- ethyl acrylate), poly(methacrylic acid-co-methyl methacrylate), or a combination thereof, c. 2 to 6 wt. % of at least one glidant, d. 3 to 20 wt. % of at least one plasticizer other than component c., and e. 1 to < 6 wt. %, or 1 to 20 wt. % of at least one non-ionic emulsifier, wherein the amount of each component a. to e. is based on total wt. % of the pH responsive polymer composition, when component b. is present, components a. and b. are different, and

[0098] 0.1 to 10 mole percent of the anionic groups of the anionic (meth)acrylic copolymer of component a. are present in salt form. A hard shell capsule coated with a pH responsive polymer for oral delivery of microbiota to ileum and colon, wherein the pH responsive polymer composition comprises: a. 40 to 90 wt. % of at least one anionic poly(meth)acrylate copolymer, b. 0 to 40 wt. % at least one (meth)acrylate copolymer selected from poly(methacrylic acid-co- ethyl acrylate), poly(methacrylic acid-co-methyl methacrylate), or a combination thereof, c. 2 to 6 wt. % of at least one glidant, d. 3 to 20 wt. % of at least one plasticizer other than component c., and e. 1 to < 6 wt. %, or 1 to 20 wt. % of at least one non-ionic emulsifier, wherein the amount of each component a. to e. is based on total wt. % of the pH responsive polymer composition, when component b. is present, components a. and b. are different, and

[0099] 0.1 to 10 mole percent of the anionic groups of the anionic (meth)acrylic copolymer of component a. are present in salt form.

[0100] A hard shell capsule coated with a pH responsive polymer for oral delivery of microbiota to ileum and colon, wherein the pH responsive polymer composition comprises: a. 40 to 90 wt. % of at least one anionic poly(meth)acrylate copolymer selected from poly(methacrylic acid-co-methyl methacrylate) 1 :1 , poly(methacrylic acid-co-methyl methacrylate) 1 :2, poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1 , or a combination thereof, b. 0 to 40 wt. % at least one (meth)acrylate copolymer selected from poly(methacrylic acid-co- ethyl acrylate), poly(methacrylic acid-co-methyl methacrylate), or a combination thereof, c. 2 to 6 wt. % of at least one glidant, d. 3 to 20 wt. % of at least one plasticizer other than component c., and e. 3.5 to 5.8 wt. % of at least one non-ionic emulsifier, wherein the amount of each component a. to e. is based on total wt. % of the pH responsive polymer composition.

[0101] A hard shell capsule coated with a pH responsive polymer for oral delivery of microbiota to ileum and colon, wherein the pH responsive polymer composition comprises: a. 40 to 90 wt. % of at least one anionic poly(meth)acrylate copolymer selected from poly(methacrylic acid-co-methyl methacrylate) 1 :1 , poly(methacrylic acid-co-methyl methacrylate) 1 :2, poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1 , or a combination thereof, b. 5 to 40 wt. % poly (methacrylic acid-co-methyl methacrylate), c. 2 to 6 wt. % of at least one glidant, d. 3 to 20 wt. % of at least one plasticizer other than component c., and e. 1 to < 6 wt. %, or 1 to 20 wt. % of at least one non-ionic emulsifier, wherein the amount of each component a. to e. is based on total wt. % of the pH responsive polymer composition. A hard shell capsule coated with a pH responsive polymer for oral delivery of microbiota to ileum and colon, wherein the pH responsive polymer composition comprises: a. 40 to 90 wt. % of poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1 , b. 5 to 40 wt. % poly(methacrylic acid-co-methyl methacrylate, c. 2 to 6 wt. % of at least one glidant, d. 3 to 20 wt. % of at least one plasticizer other than component c., and e. 3.5 to 5.8 wt. % of at least one non-ionic emulsifier, wherein the amount of each component a. to e. is based on total wt. % of the pH responsive polymer composition.

[0102] A hard shell capsule coated with a pH responsive polymer composition for oral delivery of microbiota to ileum and colon, wherein the pH responsive polymer composition comprises: a. 40 to 90 wt. % of at least one anionic poly(meth)acrylate copolymer, b. 5 to 40 wt. % at least one (meth)acrylate copolymer selected from poly(methacrylic acid-co- ethyl acrylate), poly(methacrylic acid-co-methyl methacrylate), or a combination thereof, c. 2 to 6 wt. % of at least one glidant, d. 3 to 20 wt. % of at least one plasticizer other than component c., and e. 1 to < 6 wt. %, or 1 to 20 wt. % of at least one non-ionic emulsifier, wherein the amount of each component a. to e. is based on total wt. % of the pH responsive polymer composition, when component b. is present, components a. and b. are different, and

[0103] 0.1 to 10 mole percent of the anionic groups of the anionic (meth)acrylic copolymer of component a. are present in salt form.

[0104] A dosage form comprising a pharmaceutical / nutraceutical active ingredient in a hard shell capsule coated with a pH responsive polymer for delivery at ileum and colon, wherein the pH responsive polymer composition comprises: a. 40 to 90 wt. % of at least one anionic poly(meth)acrylate copolymer, b. 0 to 40 wt. % at least one (meth)acrylate copolymer selected from poly(methacrylic acid-co- ethyl acrylate), poly(methacrylic acid-co-methyl methacrylate), or a combination thereof, c. 2 to 6 wt. % of at least one glidant, d. 3 to 20 wt. % of at least one plasticizer other than component c., and e. 1 to < 6 wt. %, or 1 to 20 wt. % of at least one non-ionic emulsifier, wherein the amount of each component a. to e. is based on total wt. % of the pH responsive polymer composition, when component b. is present, components a. and b. are different, and

[0105] 0.1 to 10 mole percent of the anionic groups of the anionic (meth)acrylic copolymer of component a. are present in salt form. A dosage form comprising a pharmaceutical / nutraceutical active ingredient in a hard shell capsule coated with a pH responsive polymer for delivery at ileum and colon, wherein the pH responsive polymer composition comprises: a. 40 to 90 wt. % of at least one anionic poly(meth)acrylate copolymer selected from poly(methacrylic acid-co-methyl methacrylate) 1 :1 , poly(methacrylic acid-co-methyl methacrylate) 1 :2, poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1 , or a combination thereof, b. 0 to 40 wt. % at least one (meth)acrylate copolymer selected from poly(methacrylic acid-co- ethyl acrylate), poly(methacrylic acid-co-methyl methacrylate), or a combination thereof, c. 2 to 6 wt. % of at least one glidant, d. 3 to 20 wt. % of at least one plasticizer other than component c., and e. 3.5 to 5.8 wt. % of at least one non-ionic emulsifier, wherein the amount of each component a. to e. is based on total wt. % of the pH responsive polymer composition.

[0106] A dosage form comprising a pharmaceutical / nutraceutical active ingredient in a hard shell capsule coated with a pH responsive polymer for delivery at ileum and colon, wherein the pH responsive polymer composition comprises: a. 40 to 90 wt. % of at least one anionic poly(meth)acrylate copolymer selected from poly(methacrylic acid-co-methyl methacrylate) 1 :1 , poly(methacrylic acid-co-methyl methacrylate) 1 :2, poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1 , or a combination thereof, b. 5 to 40 wt. % poly(methacrylic acid-co-methyl methacrylate, c. 2 to 6 wt. % of at least one glidant, d. 3 to 20 wt. % of at least one plasticizer other than component c., and e. 1 to < 6 wt. %, or 1 to 20 wt. % of at least one non-ionic emulsifier, wherein the amount of each component a. to e. is based on total wt. % of the pH responsive polymer composition.

[0107] A dosage form comprising a pharmaceutical / nutraceutical active ingredient in a hard shell capsule coated with a pH responsive polymer for delivery at ileum and colon, wherein the pH responsive polymer composition comprises: a. 40 to 90 wt. % of poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1 , b. 5 to 40 wt. % poly(methacrylic acid-co-methyl methacrylate, c. 2 to 6 wt. % of at least one glidant, d. 3 to 20 wt. % of at least one plasticizer other than component c., and e. 3.5 to 5.8 wt. % of at least one non-ionic emulsifier, wherein the amount of each component a. to e. is based on total wt. % of the pH responsive polymer composition. A dosage form comprising a pharmaceutical / nutraceutical active ingredient in a hard shell capsule coated with a pH responsive polymer for delivery at ileum and colon, wherein the pH responsive polymer composition comprises: a. 40 to 90 wt. % of at least one anionic poly(meth)acrylate copolymer, b. 5 to 40 wt. % at least one (meth)acrylate copolymer selected from poly(methacrylic acid-co- ethyl acrylate), poly(methacrylic acid-co-methyl methacrylate), or a combination thereof, c. 2 to 6 wt. % of at least one glidant, d. 3 to 20 wt. % of at least one plasticizer other than component c., and e. 1 to < 6 wt. %, or 1 to 20 wt. % of at least one non-ionic emulsifier, wherein the amount of each component a. to e. is based on total wt. % of the pH responsive polymer composition, when component b. is present, components a. and b. are different, and

[0108] 0.1 to 10 mole percent of the anionic groups of the anionic (meth)acrylic copolymer of component a. are present in salt form.

[0109] In another preferred embodiment the pharmaceutical / nutraceutical active ingredient is selected from E. coli DH 5, Lactobacillus casei, Bifidobacterium breve, Lactobacillus plantarum PTCC 1058, L. reuteri DPC16, Lactobacillus rhamnosus GG, Lactobacillus paracasei L26, Lactobacillus acidophilus KI and Bifidobacterium animalis BB-12, B. pseudocatenulatum G7, B. bifidum, Akkermansia muciniphila , Enterococcus spp., and Bacteroides fragilis, preferably Akkermansia muciniphila , Enterococcus spp., and Bacteroides fragilis.

[0110] Items:

[0111] 1. A hard shell capsule coated with a pH responsive polymer, wherein the pH responsive polymer composition comprises or consisting of: a. 40 to 90 wt. % of at least one anionic poly(meth)acrylate copolymer, b. 0 to 40 wt. % at least one (meth)acrylate copolymer selected from poly(methacrylic acid-co-ethyl acrylate), poly(methacrylic acid-co-methyl methacrylate), or a combination thereof, c. 2 to 6 wt. % of at least one glidant, d. 3 to 20 wt. % of at least one plasticizer other than component c., and e. 1 to < 6 wt. %, 1 to 20 wt.% of at least one non-ionic emulsifier, wherein the amount of each component a. to e. is based on total wt. % of the pH responsive polymer composition, when component b. is present, components a. and b. are different. 2. The hard shell capsule according to item 1 , wherein the at least one non-ionic emulsifier is present in an amount in the range of 3.5 to 5.8 wt. %, based on total wt. % of the pH responsive polymer composition.

[0112] 3. The hard shell capsule according to any one of the items 1 to 2, wherein the component b is present in an amount in the range of 5 to 30 wt. %, based on total wt. % of the pH responsive polymer composition.

[0113] 4. The hard shell capsule according to any one of the items 1 to 3, wherein the glidant is present in an amount in the range of 3 to 5 wt. %, based on total wt. % of the pH responsive polymer composition.

[0114] 5. The hard shell capsule according to any one of the items 1 to 4, wherein 0.1 to 10 mole percent of the anionic groups of the anionic (meth)acrylic copolymer are present in salt form.

[0115] 6. The hard shell capsule according to any one of the items 1 to 5, wherein the at least one anionic poly(meth)acrylate polymer is poly(methyl acrylate-co-methyl methacrylate-co- methacrylic acid).

[0116] 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.

[0117] 8. The hard shell capsule according to any one of the items 1 to 7, wherein the poly(methacrylic acid-co-ethyl acrylate) has a monomer ratio of 1 :1 .

[0118] 9. The hard shell capsule according to any one of the items 1 to 8, wherein the poly(methacrylic acid-co-methyl methacrylate) has a monomer ratio of 1 :1 , or 1 :2.

[0119] 10. The hard shell capsule according to any one of the items 1 to 9, wherein the plasticizer is selected from alkyl citrates, alkyl phthalates, alkyl sebacate, sucrose esters, sorbitan esters, diethyl sebacate, dibutyl sebacate, propylene glycol, polyethylene glycol, or a mixture thereof.

[0120] 11. The hard shell capsule according to any one of the items 1 to 10, wherein the non-ionic 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, macrogol 15 hydroxystearate, polyoxyl 15 hydroxystearate, caprylocaproyl macrogol-8 glyceride, D-a-tocopherol polyethylene glycol 1000 succinate, lecithin, sorbitan monopalmitate, cetyl alcohol, oleyl alcohol, sodium glycolate, sodium de(s)oxycholate, alkyl glycoside, alkyl polyglucoside, octyl glucoside, decyl maltoside, or a combination thereof.

[0121] 12. The hard shell capsule according to any one of the items 1 to 1 1 , wherein the glidant is selected from silica, kaolin calcium silicate, magnesium silicate, talc, stearate salts like calcium stearate, magnesium stearate, zinc stearate, sodium stearyl fumarate, starch, stearic acid, fatty acid monoglyceride, fatty acid diglyceride, fatty acid triglyceride, or mixtures thereof.

[0122] 13. The hard shell capsule according to any one of the items 1 to 12, wherein the pH responsive polymer coating layer has a thickness in the range of 10 to 55 pm, 10 to 50 pm, 10 to 40 pm, 10 to 30 pm, 10 to 20 pm, 20 to 55 pm, 20 to 50 pm, 20 to 40 pm, 20 to 30 pm, 25 to 55 pm, 25 to 50 pm, 25 to 40 pm, 30 to 60 pm, 30 to 50 pm, and / or wherein the coating layer thickness is less than the gap between the uncoated body and the cap.

[0123] 14. The hard shell capsule according to any one of the items 1 to 13, wherein the pH responsive polymer coating layer applied in an amount 1 to 5.5 mg / cm2.

[0124] 15. The hard shell capsule according to any one of the items 1 to 14 further comprises a top coat and / or subcoat.

[0125] 16. The hard shell capsule according to any one of the items 1 to 15, wherein the coating layer thickness of pH responsive polymer, and a top coat and / or subcoat(s) is in the range of 5 to 55 pm, 10 to 55 pm, 10 to 50 pm, 10 to 40 pm, 10 to 30 pm, 10 to 20 pm, 20 to 55 pm, 20 to 50 pm, 20 to 40 pm, 20 to 30 pm, 25 to 55 pm, 25 to 50 pm, 25 to 40 pm, 30 to 60 pm, 30 to 50 pm, and / or wherein the coating layer thickness of pH responsive polymer, and a top coat and / or subcoat(s) together is less than the gap between the uncoated body and the cap.

[0126] 17. The hard shell capsule according to any one of the items 1 to 16 is used for releasing at least 50 %, preferably more than 80 % of the pharmaceutical / nutraceutical active ingredient at a pH around 7.2 within 30 minutes, preferably within 15 minutes.

[0127] 18. The hard shell capsule according to item 17 the pharmaceutical / nutraceutical active ingredient is microbiota, preferably fecal microbiota selected from Akkermansia muciniphila, Enterococcus spp., and Bacteroides fragilis. 9. A process for preparing a hard shell capsule coated with a pH responsive polymer, wherein the process comprising the steps of: i. providing a hard shell capsule comprising a body and a cap in a pre-locked state, ii. coating a solution, suspension or dispersion comprising a pH responsive polymer composition according to item 1 to 12 to the hard shell capsule of step i . to obtain the hard shell capsule coated with a pH responsive polymer.

[0128] 20. The process according to item 19 further comprising the steps of:

[0129] Hi. providing the coated hard shell capsule obtained in step ii., iv. opening the coated hard shell capsule and filling with a pharmaceutical or nutraceutical biologically active ingredient, and v. closing to the final-locked state to obtain a filled capsule.

[0130] 21. The process according to item 19, wherein the coating solution, suspension or dispersion comprising a pH responsive polymer composition has a solid content in the range of 5 to 25 wt. %.

[0131] 22. The process according to any one of the items 19 to 21 , wherein the coating is by spray coating using a drum coater.

[0132] 23. A dosage form comprising a pharmaceutical / nutraceutical active ingredient in a hard shell capsule coated with a pH responsive polymer composition according any one of the items 1 to 15.

[0133] 24. The dosage form according to item 23, wherein at least 50 %, preferably more than 80 % of the pharmaceutical / nutraceutical active ingredient is released at a pH around 7.2 within 30 minutes, preferably within 15 minutes.

[0134] 25. The dosage form according to any one of the items 23 to 24, wherein no more than 5 % of the pharmaceutical / nutraceutical active ingredient is released at a pH below 7.

[0135] 26. The dosage form according to any one of the items 23 to 25, wherein the pharmaceutical / nutraceutical active ingredient is selected from mesalamine, prednisolone, budesonide, fluticasone, azathioprine, cyclosporin, methotrexate, metronidazole, ciprofloxacin, fluorouracil, methotrexate, dactinomycin, bleomycin, etoposide, taxol, vincristine, doxorubicin, cisplatin, daunorubicin, VP-16, raltitrexed, oxaliplatin, curcumin, paclitaxel, camptothecin, resveratrol, quercetin, 6-gingerol, 6-shogaol, mangiferin, E. coli DH 5, Lactobacillus casei, Bifidobacterium breve, Lactobacillus plantarum PTCC 1058, L. reuteri DPC16, Lactobacillus rhamnosus GG, Lactobacillus paracasei L26, Lactobacillus acidophilus KI and Bifidobacterium animalis BB-12, B. pseudocatenulatum G7, B. bifidum, Akkermansia muciniphila , Enterococcus spp., and Bacteroides fragilis. Examples

[0136] Materials and methods

[0137] EUDRAGIT® FS is a copolymer polymerized from around 25% by weight methyl methacrylate, around 65% by weight methyl acrylate and around 10% by weight methacrylic acid and is commercially available from Evonik Corporation. EUDRAGIT® FS 30 D is an aqueous dispersion comprising 30% by weight EUDRAGIT® FS.

[0138] EUDRAGIT® L 100 is a copolymer polymerized from around 50% by weight methyl methacrylate and around 50% by weight methacrylic acid and is commercially available from Evonik Corporation.

[0139] EUDRAGIT® S 100 is a copolymer polymerized from around 70% by weight methyl methacrylate and around 30% by weight methacrylic acid and is commercially available from Evonik Corporation.

[0140] EUDRAGIT® L 100-55 is a copolymer polymerized from around 50% by weight ethyl acrylate and around 50% by weight methacrylic acid and is commercially available Evonik Corporation. EUDRAGIT® L 30 D-55 is an aqueous dispersion comprising 30% by weight EUDRAGIT® L 100-55.

[0141] Plasacryl® HTP 20 is commercially available from Evonik Corporation. It is an aqueous solution of glidant (glycerol monostearate), plasticizer (triethyl citrate) and non-ionic surfactant (polysorbate 80).

[0142] Plasacryl® T 20 is commercially available from Evonik Corporation. It is an aqueous solution of glidant (glycerol monostearate), plasticizer (triethyl citrate) and non-ionic surfactant (polysorbate 80).

[0143] Example 1

[0144] Size 0 hypromellose capsules were coated with a pH responsive polymer. The polymer composition is described in Table 1 .

[0145] Table 1

[0146] Preparation of the coating suspension:

[0147] 1 N NaOH:

[0148] The desired amount of NaOH was dissolved or mixed in demin. water for a 1 N solution in demin. water.

[0149] 33% Tween 80 (Polysorbate 80) Solution:

[0150] Polysorbate 80 was dissolved in the desired amount of water for a 33% solution using a propeller stirrer.

[0151] Plasacryl HTP 20:

[0152] The bucket was stirred with a propeller stirrer for at least 10 min to get a homogenous product.

[0153] EUDRAGIT® L 100 preparation:

[0154] 700 g of water were taken and added under stirring with propeller stirrer to the polymer. After 5 min the NaOH solution was added dropwise and stirring was continued for a further 1 h. Subsequently, the TEC was added and stirring was continued for a further 1 h.

[0155] EUDRAGIT® FS preparation:

[0156] The polymer was poured into a container and stirred with a propeller stirrer. Subsequently, the remaining water was added, followed by the slow addition of the Polysorbate 80 solution and the slow addition of the Plasacryl HTP 20, and stirring was continued for 15min. Final step:

[0157] The EUDRAGIT® L 100 dispersion was slowly poured into the stirred EUDRAGIT® FS dispersion and stirred for 15min. The coating dispersion was sieved before spraying. The coating dispersion was agitated during coating.

[0158] The coating suspension was sprayed onto the capsules in a pre-locked state in the GLATT GMPC 2 conventional drum coater with 56 L drum installed. As peristaltic pump Watson Marlow 504U and a silicon tube with 3 mm inner diameter was selected. As spray gun SCHLICK Series 930 with ABC design was chosen. Process parameters are described in Table 2.

[0159] Table 2

[0160] Example 2 Size 0 hypromellose capsules were coated with a pH responsive polymer. The polymer composition is described in Table 3.

[0161] Table 3

[0162] Preparation of the coating suspension:

[0163] 1 N NaOH:

[0164] The desired amount of NaOH was dissolved or mixed in demin. water for a 1 N solution in demin. water.

[0165] 33% Tween 80 (Polysorbate 80) Solution:

[0166] Polysorbate 80 was dissolved in the desired amount of water for a 33% solution using a propeller stirrer.

[0167] Plasacryl HTP 20:

[0168] The bucket was stirred with a propeller stirrer for at least 10 min to get a homogenous product.

[0169] EUDRAGIT® L100 preparation:

[0170] 700 g of water were taken and added under stirring with propeller stirrer to the polymer. After 5min the NaOH solution was added dropwise and stirring was continued for a further 1 h. Subsequently, the TEC was added and stirring was continued for a further 1 h.

[0171] EUDRAGIT® FS preparation:

[0172] The polymer was poured into a container and stirred with a propeller stirrer. Subsequently, the remaining water was added, followed by the slow addition of the Polysorbate 80 solution and the slow addition of the Plasacryl HTP 20, and stirring was continued for 15 min. Final step:

[0173] The EUDRAGIT® L100 dispersion was slowly poured into the stirring EUDRAGIT® FS dispersion and stirred for 15 min. The coating dispersion was sieved before spraying. The coating dispersion was agitated during coating.

[0174] The coating suspension was sprayed onto the capsules in a pre-locked state in the GLATT GMPC 2 conventional drum coater with 56 L drum installed. As peristaltic pump Watson Marlow 504U and a silicon tube with 3 mm inner diameter was selected. As spray gun SCHLICK Series 930 with ABC design was chosen. Process parameters describes in Table 2

[0175] Table 4

[0176] Example 3

[0177] Size 0 hypromellose capsules were coated with a pH responsive polymer. The polymer composition is described in Table 3.

[0178] Table 5

[0179] Preparation of the coating suspension: I N NaOH:

[0180] The desired amount of NaOH was dissolved or mixed in demin. water for a 1 N solution in demin. water.

[0181] 33% Polysorbate 80 Solution:

[0182] Polysorbate 80 was dissolved in the desired amount of water for a 33% solution using a propeller stirrer.

[0183] Plasacryl HTP 20:

[0184] The bucket was stirred with a propeller stirrer for at least 10 min to get a homogenous product.

[0185] EUDRAGIT® L100 preparation:

[0186] 700 g of water were taken and added under stirring with a propeller stirrer to the polymer. After 5min the NaOH solution was added dropwise and stirring was continued for a further 1 h.

[0187] Subsequently, the TEC was added and stirring was continued for a further 1 h.

[0188] EUDRAGIT® FS preparation: The polymer was poured into a container and stirred with a propeller stirrer. Subsequently, the remaining water was added, followed by the slow addition of the Polysorbate 80 solution and the slow addition of the Plasacryl HTP 20, and stirring was continued for 15 min.

[0189] Final step:

[0190] The EUDRAGIT® L100 dispersion was slowly poured into the stirring EUDRAGIT® FS dispersion and stirred for 15 min. The coating dispersion was sieved before spraying. The coating dispersion was agitated during coating.

[0191] The coating suspension was sprayed onto the capsules in a pre-locked state in the GLATT GMPC 2 conventional drum coater with 56 L drum installed. As peristaltic pump Watson Marlow 504U and a silicon tube with 3 mm inner diameter was selected. As spray gun SCHLICK Series 930 with ABC design was chosen. Process parameters are described in Table 2.

[0192] Table 6

[0193] Example 4: Dissolution testing of caffein filled capsules of Example 1 -3

[0194] The dissolution profiles of hypromellose capsules, that were coated according to Example 1 -3 and filled with a blend of 500 mg caffein / lactose 2:3, were determined.

[0195] (a) USP 2 dissolution tests

[0196] Three capsules were exposed to pH 1 .2 for 2 hours, then, pH 6.8 for 1 hour and finally, pH 7.2 for 2 hours. USP 2 dissolution tests were performed using ERWEKA DT 700 Paddle Apparatus, set at 37°C and 75 rpm. At each timepoint, capsule deterioration was determined using caffein detection in the media with HPLC-UV. HPLC-UV was performed on 10pL of the media, on an Agilent 1 10Oer series using the following run parameters. - Column: Gemini 2pm C18 100 mm x 4.6 mm

[0197] - Mobile phase: mix of methanol Licrosol and purified water (3:7)

[0198] - Flow rate 1 mL / min

[0199] - Runtime 8 minutes - Detector wavelength 273 nm

[0200] The results are shown in Table 7.

[0201] Table 7

Claims

Claims:

1. A hard shell capsule coated with a pH responsive polymer, wherein the pH responsive polymer composition comprises: a. 40 to 90 wt. % of at least one anionic poly(meth)acrylate copolymer, b. 0 to 40 wt. % at least one (meth)acrylate copolymer selected from poly(methacrylic acid-co-ethyl acrylate), poly(methacrylic acid-co-methyl methacrylate), or a combination thereof, c. 2 to 6 wt. % of at least one glidant, d. 3 to 20 wt. % of at least one plasticizer other than component c., and e. 1 to < 6 wt. % of at least one non-ionic emulsifier, wherein the amount of each component a. to e. is based on total wt. % of the pH responsive polymer composition, when component b. is present, components a. and b. are different.

2. The hard shell capsule according to claim 1 , wherein the at least one non-ionic emulsifier is present in an amount in the range of 3.5 to 5.8 wt. %, based on total wt. % of the pH responsive polymer composition.

3. The hard shell capsule according to any one of the claims 1 to 2, wherein the component b is present in an amount in the range of 5 to 30 wt. %, based on total wt. % of the pH responsive polymer composition.

4. The hard shell capsule according to any one of the claims 1 to 3, wherein the glidant is present in an amount in the range of 3 to 5 wt. %, based on total wt. % of the pH responsive polymer composition.

5. The hard shell capsule according to any one of the claims 1 to 4, wherein 0.1 to 10 mole percent of the anionic groups of the anionic (meth)acrylic copolymer are present in salt form.

6. The hard shell capsule according to any one of the claims 1 to 5, wherein the at least one anionic poly(meth)acrylate polymer 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 the claims 1 to 7, wherein the poly(methacrylic acid-co-methyl methacrylate) has a monomer ratio of 1 :1 , or 1 :2.

9. The hard shell capsule according to any one of the claims 1 to 8, wherein the plasticizer is selected from alkyl citrates, alkyl phthalates, alkyl sebacate, sucrose esters, sorbitan esters, diethyl sebacate, dibutyl sebacate, propylene glycol, polyethylene glycol, or a mixture thereof.

10. The hard shell capsule according to any one of the claims 1 to 9, wherein the non-ionic 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, macrogol 15 hydroxystearate, polyoxyl 15 hydroxystearate, caprylocaproyl macrogol-8 glyceride, D-a-tocopherol polyethylene glycol 1000 succinate, lecithin, sorbitan monopalmitate, cetyl alcohol, oleyl alcohol, sodium glycolate, sodium de(s)oxycholate, alkyl glycoside, alkyl polyglucoside, octyl glucoside, decyl maltoside, or a combination thereof.

11. The hard shell capsule according to any one of the claims 1 to 10, wherein the glidant is selected from silica, kaolin calcium silicate, magnesium silicate, talc, stearate salts like calcium stearate, magnesium stearate, zinc stearate, sodium stearyl fumarate, starch, stearic acid, fatty acid monoglyceride, fatty acid diglyceride, fatty acid triglyceride, or mixtures thereof.

12. The hard shell capsule according to any one of the claims 1 to 1 1 , wherein the pH responsive polymer coating layer has an average thickness in the range of 10 to 55 pm.

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

14. A process for preparing a hard shell capsule coated with a pH responsive polymer, wherein the process comprising the steps of: i. providing a hard shell capsule comprising a body and a cap in a pre-locked state, ii. coating a solution, suspension or dispersion comprising a pH responsive polymer composition according to claim 1 to 11 to the hard shell capsule of step i. to obtain the hard shell capsule coated with a pH responsive polymer.

15. A dosage form comprising a pharmaceutical / nutraceutical active ingredient in a hard shell capsule coated with a pH responsive polymer composition according to any one of the claims 1 to 13 or in a hard shell capsule obtained by a process according to claim 14.

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