EA044207B1 - OBTAINING SOLID DOSAGE FORMS CONTAINING ANTIBODIES BY LAYERING A SUSPENSION SOLUTION - Google Patents

Description

Field of technology

The present invention relates to a method for preparing immediate and sustained release solid dosage forms containing antibodies and functional fragments thereof by layering a solution/suspension, optionally with a delayed release coating; solid dosage forms obtained using the specified method; and the use of said solid dosage forms for local treatment in the gastrointestinal tract of the patient.

State of the art

Various pharmaceutical compositions prepared by various methods have been proposed, and in some cases, the embodiments contained biologically active polypeptides such as enzymes or hormones. Such biologically active polypeptides, in particular large polypeptides with antigen-binding activity, such as antibodies and their functional fragments, due to their natural properties, are sensitive to any changes in the environment, which accounts for their inherent instability. Accordingly, ensuring their stability and activity, as well as therapeutically effective release when included in a pharmaceutical composition, is very difficult and is of paramount importance due to the extremely high cost of such antibodies in quantities allowing their therapeutic use in the patient. Typically, this inherent instability of antibodies is independent of whether they are used to prepare a pharmaceutical composition in a liquid, gel, semi-solid, solid or any other form. However, particularly in the case of solid dosage forms, many processing steps during preparation may have a negative impact on the stability and activity of the antibody or functional fragment thereof.

The use of solid dosage forms for pharmaceutical compositions intended for enteral administration is very common. Enteral administration and, in particular, oral administration of solid dosage forms containing biologically active polypeptides have become increasingly important in recent years, since they allow, in addition to systemic treatment, local treatment of symptoms of diseases of the gastrointestinal tract, such as, for example, inflammatory diseases intestinal tract (IBD), colorectal cancer, diarrhea or microbial infections.

Many factors can influence the chemical and physical stability and thus the activity of large biologically active polypeptides, such as antibodies and functional fragments thereof, when incorporated into a solid dosage form. The chemical instability of large polypeptides, for example in the form of fragmentation, oxidation, deamination, isomerization, disulfide bond formation or acid/base formation, is directly affected by the excipients used in the solid dosage form, as well as the pH, physical stress and temperature during preparation and subsequent storage of said solid dosage form. Physical instability, for example in the form of denaturation, aggregation or adsorption, may result from shear stress, temperature changes or high pressure during receipt and subsequent storage. For example, even moderately elevated temperatures above 55°C have been shown to cause some denaturation of immunoglobulin G (IgG), thereby affecting the integrity of the polypeptide, and the most sensitive to elevated temperature is the antigen-binding fragment (Fab), which is part of the specified polypeptide ( Vermeer et al., Biophys J., 2000 Jan, 78(1): 394-404). Biological instability, for example in the form of proteolytic cleavage or post-translational modification, can result from the action of proteases and other enzymes, as well as other biological factors that can affect the integrity of large polypeptides. The processing of large biologically active polypeptides, such as antibodies and functional fragments thereof, for incorporation into solid dosage forms accordingly poses considerable difficulties, in particular with regard to the selection of individual excipients as well as with regard to processing parameters. In addition to directly affecting the stability and activity of the large biologically active polypeptide, the choice of method for preparing the solid dosage form also affects the properties of the resulting solid dosage form, that is, its stability, integrity, quality and dissolution behavior.

Solid dosage forms can be prepared by layering the drug substance. For example, drug layering by powder layering can be used to apply a coating containing the active agent to the core. Layering of a drug substance by powder layering involves layering a powder, eg containing an active agent, onto a core, eg in a pan, using a binding liquid. Methods for drug layering with powder layering are known in the art and are disclosed, for example, in US9107804, US6354728 or WO 2005/115340. However, the process of layering the powder is time-consuming due to the need for multiple repetitions. Powder layering has other disadvantages, including the occurrence of core agglomeration, uneven surface of the resulting layered cores, and low active agent content. In addition, for layering

- 1 044207 powder requires that the protein (antibody) be previously spray-dried or lyophilized, which leads to additional production steps.

Drug layering using solution/suspension layering (or solution/suspension coating), on the other hand, involves depositing a substance dissolved or dispersed in a solvent onto the surface of a substrate. One method of depositing a substance onto a substrate is by spray coating, such as air suspension or fluid bed spraying. In fluidized bed spray coating, one or more substances are dissolved or dispersed in a liquid carrier in the form of a solvent. Said solution or dispersion is then sprayed onto a substrate, for example an inert core (spheres of sucrose or microcrystalline cellulose, etc.), suspended in the fluidized bed of the spray apparatus. The use of fluidized bed spraying to apply a functional coating to a core, which optionally contains an active agent, is known in the art. A functional coating in this context may refer to an insulating coating, for example to protect the core from mechanical and chemical stress, or a modified release coating, for example to modify the timing or rate of release of the active agent contained in the core (for example, a coating for extended release or delayed release coating). Such methods for applying a functional coating by fluidized bed spraying are disclosed, for example, in WO 2004/062577, EP1684729, WO 2005/046561 or WO2005/115340.

Layering of the drug substance using solution/suspension layering produces solid dosage forms characterized by a uniform size distribution and morphology with a smooth surface. Compared to other methods for preparing solid dosage forms, such as powder layering, drug layering by spraying thus has the potential to provide stable and reproducible drug dissolution, desirable in particular for sustained-release solid dosage forms. Methods for layering a drug substance by layering a solution/suspension of the active agent in the form of smaller molecules with low sensitivity to physical and chemical stress are known in the art and include, for example, those disclosed in EP 1643 977, WO2004/062577, EP1037968 or EP1643977, and used in commercial products such as Sporanox® or Entocort®.

These methods of layering a drug substance known in the art by layering a solution/suspension are in most cases not suitable for use with antibodies and functional fragments thereof. In particular, processing parameters including inlet air temperature, agitation, feed rate, atomization pressure, and drying temperature can affect the stability and activity of the antibody or functional fragment thereof used. In addition, the antibody or functional fragment thereof may be incompatible with certain excipients used. Finally, the weight ratio of active agent to excipients used in coating solutions according to these methods may be very low and, accordingly, may not provide sufficient amounts of large biologically active polypeptide, such as an antibody and a functional fragment thereof, to be deposited on the substrate. for oral or rectal administration of a therapeutically effective dose of said antibody and a functional fragment thereof to a human patient using a solid dosage form. It is important to note that, particularly in the case of antibodies and functional fragments thereof, high concentration in solution or suspension often has a detrimental effect on the stability and activity of said antibody and functional fragment thereof.

In IBDs such as ulcerative colitis or Crohn's disease, the antibody must remain sufficiently stable and active prior to uptake into the target mucosa to ensure that the inflamed colonic mucosa is exposed to a concentration of antibody that is effective for topical treatment. To minimize antibody degradation in colonic luminal fluids (Yadav et al., International Journal of Pharmaceutics, 2016. 502(1-2): p. 181-187), it is desirable to ensure a slow and controlled release of antibodies or their functional fragments from solid dosage form. This ensures that said antibody or functional fragment thereof is released from the solid dosage form at a rate that allows efficient mucosal uptake and continuous delivery of the antibody or functional fragment thereof over a period of several hours to days. In addition, it allows treatment to be carried out over a larger target area of the inflamed mucosa, since it allows the solid dosage form to release antibodies or functional fragments thereof as it moves through the gastrointestinal tract. However, recovery of antibodies or functional fragments from solid dosage forms can be further reduced by using polymers suitable for sustained release of said antibody or functional fragment thereof (ie, sustained release polymeric binders).

There is significant inter-individual and intra-individual variability over time.

- 2 044207 transit of solid dosage forms through the gastrointestinal tract, in particular, transit through the large intestine (Varum et al., Int. J. Pharm., 2010. 395(1-2): p. 26-36). In addition, IBD such as ulcerative colitis or Crohn's disease may also affect transit time. In some cases, colonic transit time has been shown to be prolonged in ulcerative colitis in areas proximal to the inflamed mucosa. Accordingly, the dosage form lingers longer in these areas before reaching the inflamed mucosa. In cases where the antibody is not present in a sufficiently stable form, this may indicate premature degradation of the antibody, resulting in reduced levels of antibody reaching distal areas of the colon mucosa. On the other hand, in some cases, transit through the inflamed area may be accelerated, further complicating the design of the dosage form for efficient delivery of antibodies to the ileum and colon.

Due to the biopharmaceutical advantages of multiparticulates over single units, such as longer colonic transit times than single units and wider dose distribution when using multiple small units (Varum et al., Int. J. Pharm., 2010. 395(1-2): pp. 26-36), the choice of a multiparticle drug delivery system is preferred. To achieve sustained release of antibodies, unit formulations for such a multiparticulate drug delivery system can be developed.

Accordingly, there is a need for a method of preparing a solid dosage form by layering a drug substance containing antibodies or functional fragments thereof, minimizing the loss of biological activity of said antibody or functional fragment thereof used to prepare said solid dosage form. In particular, said method should minimize the processing time of said solid dosage form, maintain stability and activity of said antibody or functional fragment thereof during individual production steps, allow release over a short or extended period of time, and reduce interactions of said antibody or its functional fragment. functional fragment with other ingredients of the specified solid dosage form, limiting the recovery of the antibody.

Brief description of the invention

After testing various processing conditions and excipients, the inventors of the present invention have discovered a favorable method for preparing a solid dosage form containing at least one antibody or a functional fragment thereof by layering the drug substance. This method provides a quick and simple preparation of the specified solid dosage form, maintains the stability and activity of the antibodies or their functional fragments used for production, and allows for the extraction of the optimal amount of the specified antibody or its functional fragment from the solid dosage form under controlled dissolution. In addition, this method allows you to obtain a solid dosage form for extended release, which provides a prolonged and controlled release from the specified solid dosage form over a specified period of time, for example, throughout the day; and a delayed-release oral dosage form that prevents release before reaching the target site in the patient's gastrointestinal tract.

Accordingly, according to the present invention, a new method is provided for the preparation of a solid dosage form containing as an active agent at least one antibody or a functional fragment thereof using drug layering. The present invention relates to the subject matter defined by claims 1 to 161 below.

[1] A method of producing a solid dosage form containing i) an inert core and ii) a drug coating containing at least one antibody or a functional fragment thereof as an active agent, a buffer and at least one polymeric binder deposited on the inert core by layering medicinal substance; this method includes the following steps:

a) obtaining a liquid for coating with an active agent containing at least one antibody or a functional fragment thereof, a buffer and at least one polymer binder in the form of an aqueous solution or suspension;

b) layering a liquid onto the inert core to coat the active agent by spraying, preferably by fluidized bed spraying; And

c) drying the wet drug-coated inert core, while performing step b) or upon completion of step b), to obtain a dried solid dosage form.

[2] The method according to claim 1, characterized in that in step a) said at least one antibody or a functional fragment thereof in powder form is added to the aqueous solution or suspension before or after the addition of said at least one polymer binder.

[3] The method according to claim 1 or 2, characterized in that said at least one antibody or its

- 3 044207 the functional fragment is dissolved in the coating liquid with the active agent from step a).

[4] The method according to any one of claims 1 to 3, characterized in that the liquid for coating with the active agent is an aqueous suspension, and 100% of the solvent used is water.

[5] The method according to any of the preceding claims, characterized in that in step b) fluidized bed spray coating or pan coating is used, preferably fluidized bed spray coating.

[6] A method as claimed in any one of the preceding claims, characterized in that the active agent coating liquid is sprayed onto the inert core using a top-spray or bottom-spray fluidized bed sprayer.

[7] The method according to any one of the preceding claims, characterized in that the liquid for coating the active agent contains 0.01-100 mg/ml, preferably 0.1-50 mg/ml, more preferably 0.5-50 mg/ml, even more preferably 1-50 mg/ml, even more preferably 1-30 mg/ml, even more preferably 1-25 mg/ml, even more preferably 5-25 mg/ml, most preferably about 25 mg/ml, optionally , most preferably about 15 mg/ml of said at least one antibody or functional fragment thereof.

[8] The method according to any of the preceding paragraphs, characterized in that the coating liquid with the active agent contains 5-300 wt.%, preferably 20-200 wt.%, more preferably 50-150 wt.%, even more preferably 50-115 wt. %, even more preferably 85-115 wt.%, most preferably about 90-105 wt.%, alternatively, most preferably about 45-60 wt.% of said at least one antibody or functional fragment thereof, based on the total weight of solid polymer binders in the coating liquid with the active agent.

[9] Method according to any one of the preceding claims, characterized in that the active agent coating liquid contains:

i) 0.001-10 wt.%, preferably 0.01-7 wt.%, more preferably 0.05-5 wt.%, even more preferably 0.1-3.5 wt.%, even more preferably 0.5 -2.5 wt.%, most preferably about 1.4 wt.%, optionally, most preferably about 4.7 wt.% of the specified at least one antibody or functional fragment thereof;

ii) 0.1-20% by weight, preferably 0.5-10% by weight, more preferably 1-5% by weight, even more preferably 1-3% by weight, even more preferably 2-3% by weight, most preferably about 2.5 wt.% polymer binder, alternatively, most preferably about 77.5 wt.% polymer binder; and iii) 0-5 wt.%, preferably 0.01-3 wt.%, more preferably 0.1-2 wt.%, even more preferably 0.1-1 wt.%, even more preferably 0.2- 0.6 wt.%, most preferably about 0.25 wt.% anti-caking agent.

[10] The method according to claim 9, characterized in that the liquid for coating with the active agent contains:

i) 0.5-5 wt.% antibody or functional fragment thereof;

ii) 1-5 wt.% polymer binder; and iii) 0-1.25 wt.% anti-caking agent.

[11] The method according to claim 9, characterized in that the liquid for coating with the active agent contains:

i) 0.5-2.5 wt.% antibody or functional fragment thereof;

ii) 1-3 wt.% polymer binder; and iii) 0.2-0.6 wt.% anti-caking agent.

[12] The method according to claim 9, characterized in that the liquid for coating with the active agent contains:

i) approximately 2.5% by weight of an antibody or functional fragment thereof;

ii) approximately 2.5 wt.% polymer binder; and iii) approximately 0.25 wt.% anti-caking agent.

[13] The method according to claim 9, characterized in that the liquid for coating with the active agent contains:

i) approximately 1.5% by weight of an antibody or functional fragment thereof;

ii) approximately 2.5 wt.% polymer binder; and iii) approximately 0.25 wt.% anti-caking agent.

[14] The method according to claim 9, characterized in that the liquid for coating with the active agent contains:

i) 0.01-5 wt.% antibody or functional fragment thereof;

ii) 0.5-10 wt.% polymer binder; and iii) 0.01-5 wt.% anti-caking agent.

[15] The method according to claim 9, characterized in that the liquid for coating with the active agent contains:

i) 0.5% by weight of an antibody or functional fragment thereof;

ii) 1-3 wt.% polymer binder; and iii) 0.2-0.6 wt.% anti-caking agent.

[16] The method according to any one of the preceding claims, characterized in that the liquid for coating the active agent contains 0.01-20 wt.%, preferably 0.1-10 wt.%, more preferably 0.5-5 wt.%, even more preferably 1-5 wt%, most preferably about 4.5 wt%, optionally most preferably about 15 wt% buffer.

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[17] The method according to any of the preceding claims, characterized in that during spray coating, the air atomization pressure at the spray nozzle is less than 200 kPa, preferably 100 kPa, more preferably 10 to 100 kPa, even more preferably 10 to 50 kPa, even more preferably is from 25 to 50 kPa, even more preferably is about 25 kPa.

[18] A method according to any one of the preceding claims, characterized in that said spray apparatus has an inlet air temperature below 65° C., preferably between 25 and 60° C., more preferably between 35° C. to 55°C, even more preferably from 40 to 50°C, even more preferably from 42 to 50°C.

[19] The method according to any one of the preceding claims, characterized in that the liquid for coating the active agent contains 0.1-20 wt.%, preferably 0.5-10 wt.%, more preferably 0.5-5 wt.%, even more preferably 1-5 wt%, even more preferably 1-3 wt%, even more preferably about 2.5 wt%, optionally, most preferably about 77.5 wt% polymer binder.

[20] A method according to any one of the preceding claims, wherein said inert core is an inert pellet, mini-pellet, tablet, granule, core, microcarrier, mini-sphere or sphere.

[21] The method according to any of the preceding claims, wherein said inert core contains a monosaccharide, disaccharide, oligosaccharide, polysaccharide, silica, tartaric acid, calcium carbonate or a combination thereof as a main component.

[22] The method according to any of the preceding claims, characterized in that said inert core is a pellet with a degree of sphericity equal to at least 0.6, preferably at least 0.7, more preferably at least 0.8, more more preferably at least 0.9, even more preferably at least 0.95.

[23] The method according to any of the preceding claims, characterized in that said inert core is a pellet with a median particle size of 50-10000 μm, preferably 1003000 μm, more preferably 350-2000 μm, even more preferably 500-1500 μm, most preferably 700-1200 microns.

[24] The method according to any of the preceding claims, characterized in that said inert core is a pellet with a particle size distribution such that at least 85% of the pellets have a particle size of 50-3000 μm, preferably 100-1500 μm, more preferably 350-1400 µm, even more preferably 500-1200 µm, most preferably 700-1200 µm.

[25] The method according to any of the preceding claims, wherein said inert core is a pellet containing a sphere consisting of microcrystalline cellulose, sucrose, starch, mannitol, calcium carbonate, silica, tartaric acid, lactose or a combination thereof.

[26] The method according to any of the preceding claims, characterized in that said inert core is a pellet containing a sphere consisting of microcrystalline cellulose.

[27] The method according to any of the preceding claims, characterized in that said inert core is pharmacologically inactive and contains a monosaccharide, disaccharide, oligosaccharide, polysaccharide, silica, tartaric acid or a combination thereof as a main component.

[28] The method according to any one of claims 1 to 27, characterized in that said inert core is a pellet in the form of a sphere consisting of microcrystalline cellulose, sucrose, starch, mannitol, calcium carbonate, silica, tartaric acid, lactose or a combination of the above , preferably microcrystalline cellulose.

[29] The method according to any of the preceding claims, characterized in that said inert core is pharmaceutically inactive.

[30] Method according to any one of claims 1 to 26, characterized in that said inert core contains at least one active agent.

[31] The method according to claim 30, characterized in that said at least one active agent is in the form of at least one antibody or a functional fragment thereof.

[32] The method of claim 31, wherein said at least one antibody or functional fragment thereof is the same antibody as the at least one antibody in the drug coating or a different antibody.

[33] The method according to any one of claims 30 to 32, characterized in that said at least one active agent of the inert core is released simultaneously with said at least one antibody in the drug coating when said solid dosage form is immersed in an aqueous medium.

[34] Method according to any one of claims 30-32, characterized in that the release of at least one active agent of the inert core starts later and/or is characterized by a higher/lower speed

- 5 044207 release than that of at least one antibody or functional fragment thereof in a drug coating when said solid dosage form is immersed in an aqueous medium.

[35] The method according to any one of claims 20-35, characterized in that said pellet contains a coating deposited on the sphere (for example, an insulating coating).

[36] The method according to any of the preceding claims, characterized in that said polymeric binder in the drug coating is selected from hydroxypropyl methylcellulose (HPMC); methylcellulose (MC); polyvinylpyrrolidone (PVP); hydroxypropylcellulose (HPC); macrogol-poly(vinyl alcohol) graft copolymer (eg Kollidon® IR); and their combinations; preferably HPMC or MC; more preferably HPMC.

[37] The method according to any one of the preceding claims, characterized in that said polymeric binder in the drug coating is suitable for immediate release drug coating.

[38] The method according to any of the preceding claims, characterized in that the wet drug-coated inert core is dried while carrying out step b), preferably with an air flow at the inlet of the fluidized bed.

[39] The method according to claim 38, characterized in that said inlet air has a temperature of up to 65°C, preferably up to 60°C, more preferably up to 55°C, more preferably from 40 to 50°C, even more preferably approximately 45°C.

[40] The method according to any one of claims 1 to 35, characterized in that said polymeric binder in the drug coating contains at least one polymeric binder for sustained release.

[41] The method according to claim 40, wherein said polymeric binder in the drug coating is suitable for a sustained release drug coating.

[42] The method according to claim 40 or 41, characterized in that said at least one sustained release polymeric binder is added to the active agent coating liquid in the form of an aqueous suspension (aqueous dispersion).

[43] Method according to any one of claims 40 or 42, characterized in that the wet drug-coated inert core is dried after completion of step b).

[44] The method according to claim 43, characterized in that the drying temperature does not exceed 65°C, preferably does not exceed 60°C, more preferably does not exceed 55°C, and the drying is preferably carried out in an oven or fluidized bed equipment, more preferably on large scale fluidized bed equipment.

[45] The method according to claim 43 or 44, characterized in that the wet drug-coated inert core is dried for 30 minutes - 30 hours, preferably for about 30 minutes - 24 hours.

[46] The method according to any one of claims 40 to 45, characterized in that said at least one sustained release polymeric binder is selected from the group consisting of poly(ethyl acrylate, methyl methacrylate) 2:1 (for example, Eudragit® NM 30D, Eudragit® NE 30D); poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1 (e.g. Eudragit® RS 30D); poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2 (for example, Eudragit® RL 30D); ethylcellulose (eg Surelease® or Aquacoat® ECD), polyvinyl acetate (eg Kollicoat® SR 30D); and combinations of the above.

[47] The method according to any one of claims 40-46, characterized in that the ratio of said at least one polymeric binder for sustained release to said at least one antibody or functional fragment thereof (by weight) modifies the release rate of said at least one antibody or a functional fragment thereof, with a higher ratio resulting in a lower release rate.

[48] The method according to any one of claims 40 to 47, characterized in that said at least one sustained release polymeric binder (S) and said at least one antibody or functional fragment thereof (A) are present in the active coating liquid agent in an S/A ratio (by weight) of 0.5 to 100, preferably 10 to 30, more preferably -15 to 25.

[49] The method as claimed in any one of the preceding claims, wherein the active agent coating liquid further comprises an anti-caking agent.

[50] The method of claim 49, wherein said anti-caking agent is selected from colloidal silica, mesoporous silica, glycerol monostearate (MSG), stearic acid, magnesium stearate and talc, preferably mesoporous silica or MSH, more preferably mesoporous silica.

[51] The method according to claim 49 or 50, characterized in that the liquid for coating the active agent contains 0.1-50 wt.%, preferably 1-30 wt.%, more preferably 10-20 wt.% or 5-50 wt.% anti-caking agent based on the total mass of solid polymer binders.

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[52] The method according to any of the preceding claims, characterized in that the liquid for coating with the active agent further contains a plasticizer.

[53] The method according to claim 52, characterized in that said plasticizer is selected from the group consisting of triethyl citrate (TEC), polyethylene glycol, acetyl triethyl citrate, butyl citrate, polysorbates,

1,2-polypropylene glycol and dibutyl sebacate (DBS).

[54] The method according to claim 52 or 53, characterized in that the liquid for coating with the active agent contains 5-35 wt.%, preferably 10-30 wt.%, more preferably about 20-25 wt.% plasticizer based on the total weight of solids polymer binders in the liquid for coating with the active agent.

[55] The method according to any one of the preceding claims, characterized in that the liquid for coating with the active agent contains a coalescence enhancer.

[56] The method of claim 55, wherein said coalescence enhancer is selected from the group consisting of 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, glyceryl monostearate, polyethoxylated castor oil, PEG-40 hydrogenated castor oil, macrogol 15 hydroxystearate, polyoxyl-15-hydroxystearate, caprylocaproyl macrogol-8 gly ceride, D-a-tocopherol polyethylene glycol -1000 succinate, glyceryl monostearate, lecithin, sorbitan monopalmitate, fatty alcohols such as cetyl alcohol or oleyl alcohol, sodium glycolate, sodium de(s)oxycholate, polyethylene glycol, polypropylene glycol, alkyl poly(ethylene oxide), alkyl glycoside, alkyl polyglucoside, octyl glucoside, decyl altoside, monolaurate propylene glycol (for example, lauroglycol (Lauroglycol 90)); and combinations of the above, preferably polysorbate, such as polysorbate 20, 28, 40, 60, 65, 80, 81 and 85; a poloxamer such as poloxamer 124, 181, 188, 237, 331, 338 and 407; alkyl polyglucoside (eg octyl glucoside and decyl maltoside); or propylene glycol monolaurate (eg lauroglycol 90); more preferably propylene glycol monolaurate (eg Lauroglycol 90).

[57] The method according to claim 55 or 56, characterized in that the coating liquid with the active agent contains 1-20 wt.%, preferably 2-15 wt.%, more preferably 5-10 wt.% coalescence enhancer based on the total weight of solids polymeric binders for sustained release in liquid for coating with the active agent.

[58] The method according to any one of the preceding claims, characterized in that said buffer (buffer salt) is selected from the group consisting of acetate buffer, citrate buffer, histidine buffer, succinate buffer, phosphate buffer, hydroxymethylaminomethane (TRIS) buffer; and combinations thereof, preferably a buffer with a pH compatible with at least one antibody or functional fragment thereof, alternatively preferably a buffer with a physiological pH.

[59] The method according to any of the preceding claims, characterized in that said solid dosage form is a pellet, microcarrier, sphere, mini-sphere, granule, tablet or mini-tablet, preferably a pellet.

[60] Method according to any of the preceding claims, characterized in that said drug coating after step c) has an average thickness of 0.5-300 µm, preferably 0.5-100 µm, more preferably 1-50 µm, even more preferably 1 -30 microns.

[61] The method according to any of the preceding claims, characterized in that the drug-coated and dried solid dosage form after step c) contains 0.01-25 wt.%, preferably 0.05-15 wt.%, more preferably 0. 1-10 wt.%, even more preferably 0.5-5 wt.%, even more preferably 0.7-3 wt.%, even more preferably 0.9-2.5 wt.% of said at least one antibody or a functional fragment thereof.

[62] The method according to any of the preceding paragraphs, characterized in that said drug coating contains 0.5-60 wt.% of the antibody or functional fragment thereof, 1-90 wt.% binder, 0.001-70 wt.% buffer and 0- 20 wt.% anti-caking agent; preferably 550 wt.% antibody or functional fragment thereof, 10-90 wt.% binder, 0.1-60 wt.% buffer and 0-15 wt.% anti-blocking agent; more preferably 10-50 wt.% antibody or functional fragment thereof, 20-85 wt.% binder, 0.1-60 wt.% buffer and 0.5-10 wt.% anti-blocking agent; most preferably 20-50 wt.% antibody or functional fragment thereof, 30-80 wt.% binder, 1-60 wt.% buffer and 0-8 wt.% anti-blocking agent based on the total weight of the dried drug coating.

[63] The method according to any of the preceding claims, further comprising, after step c), step d) applying at least one additional coating in the form of a sustained release coating, by layering the solid dosage form of step c) with a liquid sustained release coating c using spraying, preferably fluidized bed spraying, followed by drying said layered wet solid dosage form, preferably using a fluidized bed device.

- 7 044207 eat or stove.

[64] The method of claim 63, wherein the sustained release coating liquid comprises at least one sustained release polymer selected from the group consisting of 2:1 poly(ethyl acrylate, methyl methacrylate) (e.g., Eudragit® NM 30D, Eudragit® NE 30D); poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1 (e.g. Eudragit® RS 30D); poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2 (for example, Eudragit® RL 30D); ethylcellulose (eg Surelease® or Aquacoat® ECD), polyvinyl acetate (eg Kollicoat® SR 30D); and combinations of the above.

[65] The method according to claim 63 or 64, characterized in that in the solid dosage form after step d) the weight of the polymer increases by 1-35 wt.%, preferably by 2.5-25 wt.%, for example by 4.5 -25 wt.%, 5-20 wt.% or 10-20 wt.% relative to the solid dosage form up to step d).

[66] The method according to any one of claims 63-65, characterized in that the sustained release coating liquid contains 0.1-20% by weight, preferably 1-15% by weight, more preferably 2-10% by weight , even more preferably 5-10 wt.%, even more preferably 6-9 wt.%, for example about 7-9 wt.%, about 6-8.5 wt.%, 6.5-8 wt.%, about 7-7.5 wt.% or about 8 wt.% sustained release polymer based on the total weight of the sustained release coating liquid.

[67] Method according to any one of claims 63 to 66, characterized in that in step d) when drying, the fluidized bed or oven has a temperature of from 40 to 65°C, preferably from about 40 to 60°C.

[68] The method according to any one of claims 63 to 67, wherein said sustained release coating liquid further comprises an anti-caking agent.

[69] The method according to any one of claims 63 to 68, characterized in that said sustained release coating liquid further comprises a plasticizer.

[70] The method according to any one of claims 63 to 69, characterized in that said plasticizer is selected from the group consisting of triethyl citrate (TEC), polyethylene glycol, acetyl triethyl citrate, butyl citrate, polysorbates, 1,2-polypropylene glycol and dibutyl sebacate (DBS).

[71] The method according to any one of claims 63-70, characterized in that said sustained release coating liquid contains 5-35 wt.%, preferably 10-30 wt.%, more preferably about 20-25 wt.% plasticizer based on the total weight of sustained release polymer solids in the sustained release coating liquid.

[72] The method according to any one of claims 63 to 71, characterized in that said sustained release coating liquid contains a coalescence enhancer.

[73] The method according to any one of claims 63-72, characterized in that said coalescence enhancer is selected from the group consisting of 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, glyceryl monostearate, 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, glyceryl monostearate, lecithin, sorbitan monopalmitate, fatty alcohols such as cetyl alcohol or oleyl alcohol, sodium glycolate, sodium de(h)oxycholate, polyethylene glycol, polypropylene glycol, alkyl poly(ethylene oxide), alkyl glycoside, alkyl polyglucose yes, octyl glucoside , decyl maltoside, propylene glycol monolaurate (for example, Lauroglycol 90); and combinations of the above, preferably polysorbate, such as polysorbate 20, 28, 40, 60, 65, 80, 81 and 85; a poloxamer such as poloxamer 124, 181, 188, 237, 331, 338 and 407; alkyl polyglucoside (eg octyl glucoside and decyl maltoside); or propylene glycol monolaurate (eg Lauroglycol 90); more preferably propylene glycol monolaurate (eg Lauroglycol™ 90).

[74] The method according to any one of claims 63 to 73, characterized in that said sustained release coating liquid contains 1-20% by weight, preferably 2-15% by weight, more preferably 5-10% by weight of an enhancer coalescence from the total mass of sustained release polymer solids into the sustained release coating liquid.

[75] The method according to any one of claims 63-74, characterized in that at stage d) in said spraying apparatus the inlet air temperature does not exceed 65°C, preferably 35-60°C, and the atomization pressure at the nozzle is 25 -100 kPa.

[76] The method according to any one of claims 63 to 75, characterized in that said at least one sustained release polymer is poly(ethyl acrylate, methyl methacrylate,

- 8 044207 trimethylammonioethyl methacrylate chloride) 1:2:0.1 (for example Eudragit® RS 30D), or poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2 (for example Eudragit® RL 30D), or their mixture, and in that the layered wet solid dosage form is dried in a fluidized bed or oven, at 35-45°C, preferably about 40°C, for 30 minutes

- 30 hours, preferably 30 minutes - 24 hours.

[77] The method of claim 76, wherein said sustained release coating liquid contains about 6-8.5 wt%, preferably 6.5-8 wt%, more preferably about 7-7.5 % by weight of polymer relative to the total weight of the sustained release coating liquid.

[78] The method according to any one of claims 76-77, characterized in that during spray coating the inlet air temperature is approximately 40°C.

[79] The method according to any one of claims 76-78, characterized in that during spray coating the air atomization pressure at the spray nozzle is approximately 25-100 kPa, preferably 25-50 kPa.

[80] The method according to any one of claims 76-79, characterized in that in the solid dosage form after step d) the weight of the polymer increases by 16.5-20 wt.%, preferably by approximately 19 wt.% relative to the solid dosage form to stage d) and does not contain a coalescence enhancer.

[81] The method of claims 76-79, wherein the sustained release coating liquid contains 5-10% by weight of a coalescence enhancer based on the total weight of the sustained release polymer solids in the sustained release coating liquid.

[82] The method of claim 81, wherein said coalescence enhancer is selected from the group consisting of 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, glyceryl monostearate, polyethoxylated castor oil, PEG-40 hydrogenated castor oil, macrogol 15 hydroxystearate, polyoxyl-15-hydroxystearate, caprylocaproyl macrogol-8 gly ceride, D-a-tocopherol polyethylene glycol -1000 succinate, glyceryl monostearate, lecithin, sorbitan monopalmitate, fatty alcohols such as cetyl alcohol or oleyl alcohol, sodium glycolate, sodium de(h)oxycholate, polyethylene glycol, polypropylene glycol, alkyl poly(ethylene oxide), alkyl glycoside, alkyl polyglucoside, octyl glucoside, decyl altoside, monolaurate propylene glycol (eg Lauroglycol™ 90); and combinations of the above, preferably polysorbate, such as polysorbate 20, 28, 40, 60, 65, 80, 81 and 85; a poloxamer such as poloxamer 124, 181, 188, 237, 331, 338 and 407; alkyl polyglucoside (eg octyl glucoside and decyl maltoside); or propylene glycol monolaurate (eg Lauroglycol™ 90); more preferably propylene glycol monolaurate (eg Lauroglycol™ 90).

[83] The method according to claim 81 or 82, characterized in that in the solid dosage form after step d) the weight of the polymer in the sustained release coating increases by 3-10 wt.%, preferably by about 5-20 wt.% relative to the solid dosage form up to stage d).

[84] The method according to any one of claims 81-83, characterized in that the wet solid dosage form is dried at approximately 40°C.

[85] The method according to any one of claims 81 to 84, characterized in that said sustained release coating further comprises an anti-blocking agent.

[86] The method of claim 85, wherein said anti-caking agent is mesoporous silica.

[87] The method of claim 85 or 86, wherein said sustained release coating comprises 5-25 wt%, preferably about 10 wt%, of the antiblocking agent based on the total weight of the sustained release polymeric solids in the application liquid sustained release coatings.

[88] The method according to any one of claims 76-87, characterized in that said sustained release coating further comprises a plasticizer, and in that said plasticizer is preferably DBS or TEC, more preferably TEC.

[89] The method of claim 88, wherein said sustained release coating contains 5-35 wt%, preferably 15-25 wt%, more preferably about 20 wt% plasticizer based on the total weight of the sustained release polymer solids. release in coating liquid for sustained release.

[90] The method according to any one of claims 63-75, characterized in that said at least one sustained-release polymer is an aqueous dispersion of ethylcellulose, and in that the wet layered solid dosage form is dried at 55-65°C , preferably about 60°C, for a period of up to 30 hours, preferably from 30 minutes to 24 hours, more preferably from about 30 minutes to 24 hours.

- 9 044207

[91] The method of claim 90, wherein said sustained release coating liquid contains (by weight) 6-9 wt.%, preferably about 8 wt.% polymer, based on the total weight of the sustained release coating liquid .

[92] The method of claim 90 or 91, wherein the spray coating uses a fluidized bed coater wherein the inlet air temperature is preferably approximately 55-60°C.

[93] The method according to any one of claims 90-92, characterized in that during spray coating the air atomization pressure at the spray nozzle is 25-100 kPa, preferably approximately 25-50 kPa.

[94] The method according to any one of claims 90-93, characterized in that in the solid dosage form after step d) the weight of the polymer increases by 3-30 wt.%, preferably approximately 15-25 wt.% of the sustained release coating relative to the solid dosage form to step d), and it does not contain a coalescence enhancer.

[95] The method according to any one of claims 90-94, characterized in that said sustained release coating liquid contains 5-15% by weight, preferably about 10% by weight, of a coalescence enhancer based on the total weight of the sustained release polymeric solids in the coating liquid for extended release.

[96] The method of claim 95, wherein said coalescence enhancer is selected from the group consisting of 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, glyceryl monostearate, polyethoxylated castor oil, PEG-40 hydrogenated castor oil, macrogol 15 hydroxystearate, polyoxyl-15-hydroxystearate, caprylocaproyl macrogol-8 gly ceride, D-a-tocopherol polyethylene glycol -1000 succinate, glyceryl monostearate, lecithin, sorbitan monopalmitate, fatty alcohols such as cetyl alcohol or oleyl alcohol, sodium glycolate, sodium de(h)oxycholate, polyethylene glycol, polypropylene glycol, alkyl poly(ethylene oxide), alkyl glycoside, alkyl polyglucoside, octyl glucoside, decyl altoside, monolaurate propylene glycol (eg Lauroglycol™ 90); and combinations of the above, preferably polysorbate, such as polysorbate 20, 28, 40, 60, 65, 80, 81 and 85; a poloxamer such as poloxamer 124, 181, 188, 237, 331, 338 and 407; alkyl polyglucoside (eg octyl glucoside and decyl maltoside); or propylene glycol monolaurate (eg Lauroglycol™ 90); more preferably propylene glycol monolaurate (eg Lauroglycol™ 90).

[97] The method according to any one of claims 95 or 96, characterized in that in the solid dosage form after step d) the weight of the polymer increases by 3-20 wt.% relative to the solid dosage form before step d).

[98] The method according to any one of claims 95-97, characterized in that the wet solid dosage form is dried at approximately 60°C for 30 minutes - 24 hours, preferably for 30 minutes 10 hours.

[99] The method according to any one of claims 90-98, characterized in that said sustained release coating further comprises a plasticizer.

[100] The method according to claim 99, characterized in that said plasticizer is TES or DBS, preferably DBS.

[101] The method according to any one of claims 90-100, characterized in that said sustained release coating contains 5-35 wt.%, preferably 10-25 wt.%, more preferably about 25 wt.% plasticizer based on the total weight of solids polymeric substances for sustained release in liquid for coating for sustained release.

[102] The method according to any one of claims 40 to 101, wherein said sustained release coating or said sustained release polymeric binder in the drug coating provides a release profile of at least one antibody or fragment thereof that provides sustained release according to at least one antibody or fragment thereof in a solid dosage form with a substantially constant release rate of at least 80%, preferably at least 90%, over 430 hours, preferably 8-24 hours, more preferably 16-24 hours, even more preferably 24 hours, with said solid dosage form continuously immersed in the aqueous solution and continuously shaken.

[103] The method according to any one of claims 40 to 102, characterized in that the amount of sustained release coating relative to the total weight of the solid dosage form after step d) or the amount of sustained release polymer binder in the drug coating in the total weight of the drug coating directly correlates with the rate of release of said at least one antibody or functional fragment thereof from said solid drug

- 10 044207 form, wherein a greater amount of sustained release coating or a greater amount of sustained release polymer binder in the drug coating results in a slower release rate.

[104] The method according to any of the preceding claims, characterized in that the active agent coating liquid in step a) and/or the sustained release coating liquid in step d) contains at least one surfactant.

[105] The method according to claim 104, characterized in that the active agent coating liquid and/or the sustained release coating liquid contains 0.005-2.0 wt.%, 0.01-1 wt.%, more preferably 0 .05-0.8 wt.%, even more preferably about 0.1-0.5 wt.% surfactant.

[106] The method according to claim 104 or 105, characterized in that said surfactant is selected from the group consisting of 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, glyceryl monostearate, 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, glyceryl monostearate, lecithin, sorbitan monopalmitate, cetyl alcohol, oleyl alcohol, sodium glycolate, sodium de(h)oxycholate, polyethylene glycol, polypropylene glycol, alkyl poly(ethylene oxide), alkyl glycoside, alkyl polyglucoside, octyl glucoside, decyl maltoside; and combinations of the above.

[107] Method according to any of the preceding claims, characterized in that the active agent coating liquid in step a) and/or the sustained release coating liquid in step d) contains at least one additional excipient selected from antioxidants, humectants, protective colloids, dyes, fillers, protease inhibitors, permeability enhancers; and combinations of the above.

[108] The method according to any of the preceding claims, characterized in that said solid dosage form contains an amount of said at least one antibody or functional fragment thereof allowing the administration of a therapeutically effective dose of said at least one antibody or functional fragment thereof in a single dose. doses.

[109] The method according to any one of the preceding claims, characterized in that said functional fragment of the antibody is a Fab fragment, F(ab')2 fragment, Fab' fragment, scFv, dsFv, VHH, diabody, tribody, tetrabody, Fc fusion protein or minibody.

[110] The method according to any of the preceding claims, characterized in that said at least one antibody or functional fragment thereof is selected from antibodies specific for tumor necrosis factor alpha (TNF-α) and functional fragments thereof, antibodies specific for integrin α4β7, and functional fragments thereof, antibodies specific for CD3, CD4 or CD20, and functional fragments thereof, antibodies specific for interleukin 6 (IL-6), interleukin 12 (IL-12), interleukin 13 (IL-13), interleukin 23 (IL-23) or receptors thereof and functional fragments thereof, antibodies specific to CXCL10/IP-10 and functional fragments thereof, and antibodies specific to the p40 protein subunit and functional fragments thereof.

[111] A method according to any one of the preceding claims, wherein said antibody or functional fragment thereof is suitable for use in the treatment of inflammatory bowel disease (IBD), such as Crohn's disease or ulcerative colitis.

[112] The method according to any of the preceding claims, characterized in that said at least one antibody or a functional fragment thereof is selected from infliximab, adalimumab, etanercept, certolizumab pegol, golimumab, visilizumab, eldemumab, abrilumab, canakinumab, tocilizumab, ustekinumab, natalizumab , etrolizumab, priliximab, vedolizumab and their functional fragments; of anti-TNF-α antibodies or functional fragments thereof with light chain variable domains and/or heavy chain variable domains containing complementarity determining regions (CDRs) with the amino acid sequences disclosed in claim 2 of PCT/EP2017/056218, in claim 2 of the PCT /EP2017/056246, in claim 2 PCT/EP2017/056237 and/or in claim 2 PCT/EP2017/056227, as originally filed; from antibodies against TNF-α or functional fragments thereof containing the amino acid sequence of the heavy chain variable domain and/or the amino acid sequence of the light chain variable domain according to claim 4 of PCT/EP2017/056218, claims 5 and 6 of PCT/EP2017/056246, claims 5 and 6 of PCT/EP2017/056237, and/or claim 4 of PCT/EP2017/056227, as originally filed; and combinations of the above.

[113] The method according to any of the preceding claims, characterized in that said antibody or functional fragment thereof is selected from TNF-α-specific antibodies and functional fragments thereof.

[114] The method according to claim 113, characterized in that said antibody specific for

- 11 044207

TNF-α, or a functional fragment thereof, is selected from infliximab, adalimumab, etanercept, certolizumab pegol, golimumab and functional fragments thereof; of anti-TNF-α antibodies or functional fragments thereof with light chain variable domains and/or heavy chain variable domains containing complementarity determining regions (CDRs) with the amino acid sequences disclosed in claim 2 of PCT/EP2017/056218, claim 2 of PCT/ EP2017/056246, claim 2 PCT/EP2017/056237 and/or claim 2

PCT/EP2017/056227, as originally filed; from antibodies against TNF-α or functional fragments thereof containing the amino acid sequence of the variable domain of the heavy chain and/or the amino acid sequence of the variable domain of the light chain according to claim 4 of PCT/EP2017/056218, claims 5 and 6 of PCT/EP2017/056246, claims 5 and 6 of PCT/EP2017/056237 and/or claim 4 of PCT/EP2017/056227, as originally filed; and combinations of the above.

[115] The method according to any of the preceding claims, characterized in that at any time during steps a) and c) the temperature of the at least one antibody or functional fragment thereof is below the melting temperature (Tm) of the at least one antibody or functional fragment thereof fragment.

[116] The method according to any of the preceding claims, characterized in that at any time during steps a) and c) the temperature of said antibody or functional fragment thereof is below 65°C, preferably not above 60°C, more preferably not above 55°C , more preferably about 45-50°C.

[117] The method according to any one of claims 63 to 116, characterized in that step d) is carried out at a temperature not higher than 65°C, preferably not higher than 60°C.

[118] The method according to any one of claims 63 to 117, characterized in that step d) is carried out at a temperature below the melting temperature (Tm) of said at least one antibody or functional fragment thereof in said solid dosage form.

[119] The method according to any one of claims 63 to 116, characterized in that at any time during steps a) and d) the temperature of said at least one antibody or functional fragment thereof is below the melting temperature (Tm) of said at least one antibody or a functional fragment thereof.

[120] The method according to any one of claims 63 to 119, characterized in that in step d) an aqueous dispersion of ethylcellulose is used, and in that step d) is carried out at a temperature below 65°C, preferably not above 60°C.

[121] The method according to any one of claims 63 to 119, characterized in that in step d) an aqueous dispersion of poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1 (for example, Eudragit® RS 30D) or poly (ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2 (for example, Eudragit® RL 30D) or mixtures thereof, and that step d) is carried out at a temperature below 55°C, preferably not higher than 50°C, more preferably not higher than 45°C.

[122] The method according to any of the preceding claims, characterized in that said solid dosage form is a sustained release dosage form allowing sustained release of said at least one antibody or functional fragment thereof over a period of time of at least 5 hours, preferably at least 10 hours, more preferably at least 12 hours, even more preferably at least 15 hours, even more preferably at least 20 hours, most preferably at least 24 hours, while continuously immersing said solid dosage form in an aqueous solution and with continuous shaking.

[123] The method according to any of the preceding claims, characterized in that after drying in step c) or after step d), in the case of applying at least one additional coating in the form of a sustained release coating as step d), the moisture content in said solid dosage form is less than 10 wt.%, preferably less than 8 wt.%, more preferably less than 5 wt.%, even more preferably less than 3 wt.%, even more preferably 1.5 wt.% most preferably less than 1 wt.% based on the total weight of said solid dosage form after step c) or after step d), respectively.

[124] The method according to any one of the preceding claims, characterized in that said solid dosage form is intended for oral administration.

[125] The method according to any of the preceding claims, further comprising, after step c) or after step d), in the case of applying at least one additional coating in the form of a sustained release coating as step d), the step of applying at least one additional coating in the form of a delayed release coating, said solid dosage form being intended for oral administration.

[126] The method of claim 125, wherein said delayed release coating is applied by spraying, preferably by fluidized bed spraying.

- 12 044207

[127] The method of claim 125 or 126, wherein said delayed release coating comprises at least one component selected from coating materials that degrade in a pH-dependent manner; coating materials that degrade in a time-dependent manner; coating materials that break down due to enzymatic triggers in the intestinal environment; and combinations of the above.

[128] The method according to claim 127, characterized in that the coating materials that degrade in a pH-dependent manner are selected from polyvinyl acetate phthalate; cellulose acetate trimellitate; hydroxypropyl methylcellulose phthalate HP-50, HP-55 or HP-55S; cellulose acetate phthalate; hydroxypropyl methylcellulose acetate succinate (HPMC-AS); poly(methacrylic acid, ethyl acrylate) 1:1 (Eudragit® L100-55, Eudragit® L30D-55); poly(methacrylic acid, methyl methacrylate) 1:1 (Eudragit® L-100, Eudragit® L12.5); poly(methacrylic acid, methyl methacrylate) 1:2 (Eudragit® S-100, Eudragit® S12.5, Eudragit® FS30D); and combinations of the above;

coating materials that degrade in a pH-dependent manner are selected from poly(ethyl acrylate, methyl methacrylate) 2:1 (eg Eudragit® NM 30D); poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1 (e.g. Eudragit® RS 30D); ethylcellulose (eg Surelease® or Aquacoat® ECD); poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2 (for example, Eudragit® RL 30D); polyvinyl acetate (eg Kollicoat® SR 30D); and their combinations; and coating materials that break down due to enzymatic triggers in the intestinal environment are selected from chondroitin sulfate; cyclodextrin; pectin; guar gum; chitosan; inulin; lactulose; raffinose; stachyoses; alginate; dextran; xanthan gum; locust bean gum; arabinogalactan; amylose; pullulana; carrageenan; scleroglucan; chitin; Kurdulana; levana; amylopectin; starch; resistant starch; azo compounds decomposed by bacteria that break down azo bonds; and combinations of the above.

[129] The method of any one of claims 125 to 128, wherein said delayed release coating comprises a combination of at least one pH dependent coating material and at least one pH dependent coating material. enzymatic triggers in the intestinal environment.

[130] The method according to any one of claims 125-129, characterized in that said delayed release coating contains a combination of at least one enteric polymer, preferably poly(methacrylic acid, methyl methacrylate) 1:2 (for example, Eudragit® S), and at least one polysaccharide selected from chondroitin sulfate, cyclodextrin, chitosan, dextran, arabinogalactan, amylose, pullulan, carrageenan, scleroglucan, chitin, curdulan, levan, amylopectin, starch, resistant starch; and combinations of the above, preferably resistant starch.

[131] The method according to any one of claims 125-130, characterized in that said delayed release coating comprises i) an inner coating containing a partially neutralized enteric polymer with a pH adjusted to 8, for example, partially neutralized poly(methacrylic acid, methyl methacrylate 1:2 (Eudragit® S) with a pH adjusted to 8 and containing a buffer salt; and ii) an outer coating containing a combination of at least one enteric polymer, preferably poly(methacrylic acid, methyl methacrylate) 1:2 (Eudragit ® S), and at least one polysaccharide selected from chondroitin sulfate, cyclodextrin, chitosan, dextran, arabinogalactan, amylose, pullulan, carrageenan, scleroglucan, chitin, curdulan, levan, amylopectin, starch, resistant starch; and combinations of the above, preferably resistant starch.

[132] The method according to claim 130 or 131, characterized in that said at least one component, for example a combination of at least one enteric polymer, preferably poly(methacrylic acid, methyl methacrylate) 1:2 (for example, Eudragit® S) , and at least one polysaccharide selected from chondroitin sulfate, cyclodextrin, chitosan, dextran, arabinogalactan, amylose, pullulan, carrageenan, scleroglucan, chitin, curdulan, levan, amylopectin, starch, resistant starch; and combinations of the above, preferably resistant starch, dispersed in an organic solvent, a mixture of organic solvents or a mixture of at least one organic solvent and water, which is applied to a solid dosage form, for example, by spray coating, preferably fluid bed spray coating.

[133] The method of claim 132, wherein said combination is dispersed in a mixture of at least one organic solvent and water obtained by mixing an enteric polymer dissolved in an organic solvent with an aqueous redispersion of at least one polysaccharide.

[134] The method according to any one of claims 125-133, characterized in that said coating for delayed

- 13 044207 This release is applied by spraying, preferably by fluidized bed spraying.

[135] The method according to any one of claims 125-134, comprising initiating targeted release of said at least one antibody or functional fragment thereof from the delayed release coating in the terminal ileum, small colon, ascending colon, transverse colon or descending colon. colon.

[136] The method according to any of the preceding paragraphs, characterized in that the proportion of the total content of the antibody or its functional fragment present in the solid dosage form in the form of dimers and other aggregates does not exceed more than 15%, preferably 12%, more preferably by 10%, even more preferably by 8%, even more preferably by 7%, even more preferably by 5%, even more preferably by 3%, 2% or 1.5% of the total content of the antibody or functional fragment found in form of dimers and other aggregates at the time of adding the specified antibody or its functional fragment to the liquid for coating with the active agent.

[137] The method according to any of the preceding claims, characterized in that the proportion of the total content of the antibody or functional fragment thereof present in the solid dosage form in the form of fragments of the full-length antibody or functional fragment thereof does not substantially increase from the time of addition of said antibody or functional fragment thereof. fragment into liquid for coating with the active agent.

[138] The method according to any of the preceding claims, characterized in that the proportion of the total content of the antibody or functional fragment thereof present in the solid dosage form in the form of fragments of the full-length antibody or functional fragment thereof does not exceed more than 15%, preferably 12% , more preferably 10%, even more preferably 8%, even more preferably 7%, even more preferably 5%, even more preferably 3%, 2% or 1.5% of the total content of the antibody or functional fragment thereof , present in the form of fragments of a full-length antibody or a functional fragment thereof at the time of addition of said antibody or functional fragment thereof to the liquid for coating with the active agent.

[139] The method according to any of the preceding claims, characterized in that said solid dosage form contains an immediate release drug coating providing a recovery of at least 70%, preferably at least 80%, more preferably at least 90%, even more preferably at least 95%, even more preferably at least 97%, even more preferably at least 99% of said at least one antibody or functional fragment thereof from said drug coating within 1 hour of continuous immersion of the drug-coated solid dosage form as an outer coating into an aqueous solution with continuous shaking.

[140] The method of any one of the preceding claims, wherein said polymeric binder in the drug coating contains at least one sustained release polymeric binder providing a recovery of at least 40%, preferably at least 50%, more preferably at least at least 60%, even more preferably at least 70%, even more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, even more preferably at least 93%, most preferably at least 95% of said at least one antibody or functional fragment thereof from said drug coating within 4 hours, or 6 hours, or 8 hours, or 10 hours, or 12 hours, or 14 hours, or 16 hours, or 18 hours, or 20 hours, or 22 hours, or 24 hours, or 26 hours, or 28 hours, or 30 hours, etc., of continuous immersion of the specified solid dosage form in an aqueous solution with continuous shaking.

[141] The method of any one of the preceding claims, including the further step of providing a multiparticulate drug delivery system, for example, a sachet/stick pack, a drinking straw device (XStraw®), a tablet/mini-tablet or capsule, preferably containing a common an amount of said at least one antibody or functional fragment thereof suitable for oral administration to a human patient.

[142] Solid dosage form obtained by the method according to any one of claims 1 to 141.

[143] A solid dosage form according to claim 142 for use in the topical treatment of a gastrointestinal disease, preferably IBD, colorectal cancer, small intestinal cancer, celiac disease, gastrointestinal tract infections (for example, Clostridium difficile infections), more preferably IBD .

[144] A solid dosage form for use according to claim 143, wherein said IBD is Crohn's disease or ulcerative colitis.

[145] A solid dosage form according to any one of claims 142 to 144 for use in local treatment of the terminal ileum, small colonic region, ascending colon, transverse colon or descending colon of a patient.

- 14 044207

[146] A multiparticulate drug delivery system comprising multiple solid dosage forms, each of which can be prepared by the method of any one of claims 1 to 141, wherein the multiparticulate drug delivery system is preferably a sachet/stick pouch , drinking straw device (XStraw®), capsule or tablet/mini tablet.

[147] A multiparticulate drug delivery system comprising a plurality of solid dosage form units, each of which contains i) an inert core and ii) a drug coating containing at least one antibody or functional fragment thereof, a buffer and at least one polymer binder; and, optionally, an anti-caking agent and/or surfactant, wherein each solid dosage unit preferably comprises a predetermined axis and the same predetermined cross-sectional profile, with at least 80% of said solid dosage units preferably 90%, more preferably 95%, have a median aspect ratio of 0.7 to 1.7, where the aspect ratio is defined as the result of dividing the unit length of the solid dosage form along a predetermined axis by the smallest transverse dimension.

[148] The multiparticulate drug delivery system of claim 147, wherein the median aspect ratio is greater than 0.8, preferably greater than 0.9, and less than 1.6, preferably less than 1.5, more preferably less than 1, 4, even more preferably below 1.3, even more preferably below 1.2, most preferably around 1.

[149] The multiparticulate drug delivery system of claim 147 or 148, wherein the aspect ratio range of said solid dosage form units is less than 0.9, preferably less than 0.8, more preferably less than 0.7, even more preferably less than 0.6, most preferably less than 0.5.

[150] The multiparticulate drug delivery system of any one of claims 147149, providing a recovery of at least 80%, preferably at least 85%, more preferably at least 93%, even more preferably at least 95%, more more preferably at least 97%, even more preferably at least 98% of the at least one antibody or functional fragment thereof from the solid dosage form units.

[151] The multiparticulate drug delivery system of any one of claims 147150, providing a recovery of at least 80%, preferably at least 85%, more preferably at least 93%, even more preferably at least 95%, more more preferably at least 97%, even more preferably at least 98% of said at least one antibody or functional fragment thereof from solid dosage form units within 30 minutes, or 1 hour, or 2 hours of continuous immersion of said solid dosage form in aqueous solution with continuous shaking (immediate release).

[152] The multiparticulate drug delivery system of any one of claims 147150, wherein the solid dosage units of the multiparticulate drug delivery system are sustained release solid dosage units.

[153] The multiparticulate drug delivery system of any one of claims 150 or 152, providing a recovery of at least 80%, preferably at least 85%, more preferably at least 93%, even more preferably at least 95% , even more preferably at least 97%, even more preferably at least 98% of said at least one antibody or functional fragment thereof from solid dosage form units within 4 hours, or 6 hours, or 8 hours, or 10 hours, or 12 hours, or 14 hours, or 16 hours, or 18 hours, or 20 hours, or 22 hours, or 24 hours, or 26 hours, or 28 hours, or 30 hours, or 32 hours, or 34 hours, or 36 h, etc. continuous immersion of the specified solid dosage form in an aqueous solution with continuous shaking (extended release).

[154] The multiparticulate drug delivery system of any one of claims 147153, wherein said solid dosage unit comprises an antibody or functional fragment thereof, a buffer and at least one polymeric binder in a drug coating which is applied to an inert core by spraying.

[155] The multiparticulate drug delivery system of any one of claims 147 or 154, characterized in that the solid dosage units comprise at least one additional coating in the form of a sustained release coating, and in that said sustained release coating preferably has properties as defined in any one of claims 64-75.

[156] The multiparticulate drug delivery system of any one of claims 147 or 155, wherein said solid dosage units are solid dosage forms obtained by layering the drug substance in accordance with the method of any one of claims 1 to 141 .

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[157] The multiparticle drug delivery system according to any one of claims 147156, characterized in that said multiparticle drug delivery system is prepared from several units of a solid dosage form by compression encapsulation.

[158] The multiparticle drug delivery system according to any one of claims 147157, characterized in that said at least one antibody or functional fragment thereof meets the definition of any one of claims 109-114; and/or that the buffer meets the definition of claim 58; and/or in that the at least one polymeric binder meets the definition of any one of claims 36-37 and 46-48, and/or in that the optional anti-blocking agent and/or surfactant and/or additional additives comply with the definitions according to any of paragraphs 49-50, 52-53, 55-56 and 106.

[159] The multiparticulate drug delivery system of any one of claims 147158, wherein said dosage form units have properties as defined in any one of claims 61, 62 and 108.

[160] The multiparticulate drug delivery system of any one of claims 147159, wherein said multiparticulate drug delivery system or individual solid dosage units further comprise a delayed release coating which is applied as an additional coating, and in that said delayed release coating preferably corresponds to the definition of any one of claims 126-135.

[161] A solid dosage form comprising a dosage unit dosage form as part of a multiparticulate drug delivery system according to any one of claims 147160.

Brief description of drawings

Fig. 1: General description of the composition of the coating suspensions and the effects of the process on adalimumab. The effect of several process variables on adalimumab in a HPMCsyloid suspension (HPMCSyloid® 244 FP) containing 5 mg/ml adalimumab was assessed in terms of total protein content, aggregation and fragmentation (Fig. 1A-C). There was no significant increase in dimer content (Figure 1B) compared to the positive control (1.0 mg/mL standard) for samples collected during the process. Likewise, no significant increase in fragment levels was observed compared to the positive control (Fig. 1C).

In fig. Figure 2 shows the release of adalimumab from layered microcrystalline HPMC (Example 1) and sucrose (Example 2) pellets in citrate TRIS buffer pH 7. Extracted protein in citrate TRIS dissolution buffer pH 7 was quantified by total protein determination. Complete release of adalimumab was achieved very quickly in both cases. The mean and standard deviation for 3 measurements are shown.

In fig. 3: (A) shows the relative abundance of dimers and monomers of adalimumab released from HPMC layered pellets in citrate TRIS buffer pH 7 over time as determined by HPLC-EC. There was no significant increase in dimer content compared to the positive control upon dissolution, regardless of adalimumab loading ([Ada]) and initial concentration (Example 3, 4 and 5). The concentration of adalimumab in the coating suspensions and the target loading were varied. (B) shows the relative fragmentation profile of adalimumab released in citrate TRIS buffer pH 7 over time. No significant fragmentation was observed compared to the positive control in Examples 3, 4 and 5.

In fig. 4: (A) shows the composition of the coating suspension prepared using adalimumab at an increased concentration. (B) shows the release of adalimumab from coated pellets in citrate TRIS buffer pH 7 when different coating suspensions were used to layer the pellets (Examples 14, 15, 16 and 17). (C) shows the relative aggregation and fragmentation profile of adalimumab from dissolved pellet samples from Example 14 compared to adalimumab standard.

Fig. 5: Eudragit® RS 30D coating of adalimumab coated pellets. (A) General description of the lot. (B) shows the release of adalimumab from Eudragit® RS 30D coated pellets (Example 6, 7 and 8) in citrate TRIS buffer pH 7 compared to immediate release pellets with adalimumab layering (Comparative Example 1). Results are presented as the average of 3 replicates with corresponding standard deviations. (C) shows the relative aggregation and fragmentation profile of adalimumab from dissolved pellet samples from Example 8 compared to adalimumab standard.

Fig. 6: (A) General description of the batch of ethylcellulose-coated adalimumab pellets. (B) shows DBS (hydrophobic plasticizer) coated pellets and TEC (25 wt.% based on polymer solids) coated pellets; in both cases, the coating was applied until approximately 17% increase in polymer weight was achieved. Replacing CHP (example 9) as a plasticizer with

- 16 044207

DBS (example 10) leads to a significantly slower release of adalimumab in citrate TRIS buffer with pH 7 with the same amount of polymer applied to the pellets. (C) shows the relative aggregation and fragmentation profile of adalimumab from the dissolved coated pellet samples of Example 9 and Example 10. Regardless of which plasticizer was used, there was no significant increase in the level of adalimumab aggregates and fragments from the dissolved samples compared to the adalimumab standard.

Fig. 7: (A) General description of a batch of Eudragit® RS 30D coated pellets with and without coalescence enhancer. (B) As shown, the addition of the coalescence enhancer Laurogylcol™ 90 (Example 12) significantly improved the sustained release profile of adalimumab compared to the coating without the coalescence enhancer, even with a smaller increase in polymer weight (Example 6, Figure 7B).

Fig. 8: (A) Release of adalimumab from ethylcellulose-coated pellets containing Lauroglycol™ 90 dried/cured at 60°C for 1, 2.5 and 24 hours in citrate TRIS buffer pH 7. (B) Relative aggregation profile and fragmentation of adalimumab from dissolved coated pellet samples from Example 11 compared to adalimumab standard. Addition of Lauroglycol™ to the ethylcellulose formulation or processing conditions, including the curing (drying) step for up to 24 hours, did not significantly increase the level of aggregates or fragments formed in samples collected after dissolution (Figure 8B).

Fig. 9: (A) ELISA assay of adalimumab released upon dissolution in Example 8 (Eudragit® RS 30D coated pellets) in citrate TRIS buffer pH 7. (B) ELISA assay of adalimumab released upon dissolution in Example 13 (increase in pellet weight, coated with Aquacoat® ECD polymer, 21.67%) in citrate TRIS buffer with pH 7. FIG. 9A-B shows that the integrity of adalimumab is maintained and it is able to bind to TNF-α. For comparison, in Fig. 9A-B show the results of total protein quantitation (B) and ELISA (E).

Detailed Description of the Invention

The present invention relates to a method for preparing a solid dosage form containing i) an inert core; and ii) a drug coating comprising at least one antibody or functional fragment thereof as an active agent, a buffer and at least one polymeric binder, the deposition of which onto an inert core occurs by layering the drug substance; wherein said method includes the following steps: a) obtaining a liquid for coating with an active agent containing at least one antibody or a functional fragment thereof, a buffer and at least one polymer binder, in the form of an aqueous solution or suspension; b) layering a liquid onto the inert core to coat the active agent by spraying, preferably by fluidized bed spraying; and c) drying the wet drug-coated inert core, while performing step b) or upon completion of step b), to obtain a dried solid dosage form.

The term solid dosage form as used herein may be understood as the equivalent of a solid pharmaceutical dosage form or a pharmaceutical composition within a solid dosage form and includes, for example, pellets, capsules, granules, tablets, mini-tablets, and the like. According to one embodiment of the present invention, the solid dosage form is a pellet, sphere, mini-sphere, microcarrier, granule, tablet or mini-tablet. According to a preferred embodiment of the present invention, the solid dosage form is a pellet. Multiple solid dosage forms of the present invention may be combined in a single formulation, for example, in the form of a tablet, hard gelatin capsule, sachet, caplet or pill.

The term inert core is not limited in any particular way herein. The term inert core as used herein may mean an inert pellet, mini-tablet, tablet, granule, core, microcarrier, mini-sphere or sphere that is composed of one or more soluble or insoluble inert materials and the like, all of which are pharmacologically inactive. Alternatively, the term inert core may mean an inert pellet, mini-tablet, tablet, granule, core, microcarrier, mini-sphere or sphere already containing at least one active agent. Where the inert core contains at least one active agent, said at least one active agent is preferably in the form of at least one antibody or functional fragment thereof. The at least one antibody or functional fragment thereof in the inert core may be the same as or different from the antibody or functional fragment thereof in the drug coating. Said inert core may optionally be coated with an insulating coating to increase the core's ability to resist mechanical pressure during processing.

The inert core is inert towards the at least one antibody or functional fragment thereof in the drug coating. Thus, it does not reduce the stability and activity of the at least one antibody or functional fragment thereof in

- 17 044207 drug coating under the conditions used in obtaining said solid dosage form according to the method proposed according to the present invention, during its storage and subsequent administration and dissolution.

The term approximately as used herein indicates that the value or range of a specified quantity may include values within ±10% of the specified value or range, or optionally within ±5% of the specified value or range, or, in some embodiments , within ±1% of the specified value or range. In an embodiment wherein the inert core contains at least one active agent, the solid dosage form prepared using the method of the present invention may be designed to release said active agent in the inert core simultaneously with at least one antibody or its functional moiety in the drug coating, or may be designed to release at a different rate and/or at different times. In accordance with one embodiment of the present invention, the active agent in the inert core is released simultaneously with at least one antibody or functional fragment thereof in the drug coating. In accordance with another embodiment of the present invention, the active agent in the inert core is not released simultaneously with the at least one antibody or functional fragment thereof in the drug coating. For example, if the active agent in the inert core is not released simultaneously with at least one antibody or functional fragment thereof in the drug coating, its release may begin later and/or occur at a faster/slower rate than the release of at least one antibody or a functional fragment thereof in a drug coating.

The inert core may be a pellet, mini-pellet, sphere, mini-sphere, granule, microcarrier, mini-pellet or tablet, for example prepared from a mixture of excipients and optionally active agents by compression, extrusion with spheronization or encapsulation. According to one embodiment of the present invention, the inert core contains a monosaccharide, disaccharide, oligosaccharide, polysaccharide, silica, tartaric acid, calcium carbonate, or a combination thereof as the main component. In a specific embodiment, the inert core contains microcrystalline cellulose, sucrose, starch, mannitol, calcium carbonate, silica, tartaric acid, lactose, or a combination thereof as a major component. According to another embodiment of the present invention, the inert core is pharmacologically inactive and contains a monosaccharide, disaccharide, oligosaccharide, polysaccharide, silica, tartaric acid, calcium carbonate or a combination thereof, preferably microcrystalline cellulose, sucrose, starch, mannitol, calcium carbonate, silica, tartaric acid, lactose or a combination of these as the main ingredient. The main component in this context refers to an inert core containing at least 50 wt.%, preferably at least 70 wt.%, more preferably at least 90 wt.%, even more preferably at least 95 wt.% of said component . In the context of the above-described inert core, wt.% refers to the mass percentage of the substance relative to the mass of the inert core.

Generally, unless otherwise specified, wt.% herein refers to the weight percent of the substance relative to the total weight of the entire solid dosage form. In some cases, where indicated, wt.% may refer to the weight percent of the substance relative to the weight of the specified solid dosage form after a particular specified stage of its preparation.

According to one embodiment, said inert core is a pellet. The pellet may have a median particle size of 50-10000 µm, preferably 100-3000 µm, more preferably 350-2000 µm, even more preferably 500-1500 µm, most preferably 700-1200 µm. According to another embodiment, said inert core is a pellet with a particle size distribution such that at least 85% of the pellets have a particle size of 503,000 microns, preferably 100-1500 microns, more preferably 350-1400 microns, even more preferably 500-1200 µm, most preferably 700-1200 µm.

The shape of the pellets is not limited in any particular way. According to one embodiment, said inert core is a pellet with a degree of sphericity of at least 0.6, preferably at least 0.7, more preferably at least 0.8, even more preferably at least 0.9, more more preferably at least 0.95. According to a preferred embodiment, said inert core is a pellet containing a sphere. The term sphere as used herein refers to a particle with a degree of sphericity of at least 0.8. Said sphere may be coated with a coating deposited on the sphere, such as an insulating coating. The sphere may consist of microcrystalline cellulose, sucrose, starch, mannitol, calcium carbonate, silica, tartaric acid, lactose, or a combination thereof. In another embodiment, said inert core is a pellet consisting of a sphere consisting of microcrystalline cellulose, sucrose, starch, mannitol, calcium carbonate, silica, tartaric acid, lactose or a combination thereof, preferably microcrystalline cellulose. Examples of commercially available inert cores include CELLETS® (Pharmatrans-Sanaq AG) and SUGLETS® sugar spheres (Colorcon® Ltd).

The term drug coating as used herein refers to a coating or shell containing at least one active agent, in the form of at least one antibody or functional fragments thereof, deposited on an inert core. The term coating or shell as used herein refers to a film containing one or more layers. The specific coating can be separated from the inert core or additional coatings that can be applied separately due to different physicochemical properties. Accordingly, the drug coating can be separated from the inert core and additional coatings that can be applied separately after the drug coating due to different physicochemical properties.

The term antibody in the context of the present invention refers to an immunoglobulin (Ig), defined as a protein belonging to the class IgG, IgM, IgE, IgA or IgD (or any subclass thereof), and includes all standard known antibodies and functional fragments thereof. At least one antibody or functional fragment thereof used in accordance with the present invention is an active agent, i.e. said at least one antibody or functional fragment thereof is included in the solid dosage form due to the pharmacological activity of said antibody or functional fragment thereof in a patient.

In the context of the present invention, a functional antibody/immunoglobulin fragment is defined as an antigen binding fragment or other derivative of the parent antibody substantially retaining the properties of such parent antibody. An antigen-binding fragment of an antibody/immunoglobulin is defined as a fragment (eg, an IgG variable region) retaining the antigen-binding region. The antigen binding region of an antibody is typically located in one or more hypervariable regions of the antibody, i.e. regions CDR-1, CDR-2 and/or CDR-3. The antigen binding fragments of the present invention include the F(ab')2 domain and the Fab domain. Functional fragments of the present invention include Fab fragment, F(ab')2 fragment, Fab' fragment, scFv, dsFv, VHH, diabody, tribody, tetrabody, Fc fusion protein and minibody. The F(ab')2 or Fab domain can be designed to minimize or completely eliminate the occurrence of intermolecular disulfide interactions between the CH1 and CL domains. Antibodies or functional fragments thereof used in the present invention may be part of bifunctional or multifunctional constructs.

Fab fragments can be obtained as purified products of antibody digestion with a cysteine proteinase such as papain (EC 3.4.22.2). F(ab')2 fragments can be obtained as purified products of antibody cleavage with pepsin (EC 3.4.23.1) or IdeS (immunoglobulin degrading enzyme of Streptococcus pyogenes; EC 3.4.22). Fab' fragments can be obtained from F(ab')2 fragments under mild reducing conditions, with each F(ab')2 molecule giving rise to two Fab' fragments. scFv is a single-chain Fv fragment, where the light chain variable domain ( _VL ) and the heavy chain variable domain (VH) are connected by a peptide bridge.

A diabody is a dimer consisting of two moieties, each of which contains variable regions connected to each other by a linker or the like. (hereinafter referred to as diabody-forming moieties); and, as a rule, containing two V _L and two VH. Diabody-forming fragments include fragments consisting of VL and VH, VL and _VL , _VH and VH, etc.; preferably _VH and _VL . In diabody-forming fragments, the linker connecting the variable regions is not limited in any particular way, but is preferably short enough to avoid the formation of non-covalent bonds between variable regions in the same fragment. Those skilled in the art can determine the appropriate length of such a linker, however, typically 2-14 amino acids are used, preferably 3-9 amino acids, in particular 4-6 amino acids. In this case, VL and VH, encoded in the same fragment, are connected by a linker short enough to avoid the formation of non-covalent bonds between V _L and V _H on the same chain and the formation of single-chain variable region fragments, which can lead to the formation of dimers with another fragment. The formation of dimers can occur due to covalent or non-covalent bonds between diabody-forming fragments, or both.

In addition, the diabody-forming moieties can be connected through a linker or the like to form single-chain diabodies (sc(Fv)2). By joining the diabody-forming moieties using a long linker of approximately 15-20 amino acids in size, non-covalent bonds can be formed between the diabody-forming moieties on the same chain to form dimers. Using the same principle as for the preparation of diabodies, polymerized antibodies, such as trimers or tetramers, can also be prepared by combining three or more diabody-forming moieties.

According to one embodiment, the functional fragment in said solid dosage form obtained using the method of the present invention is a Fab fragment, F(ab')2 fragment, Fab' fragment, scFv, dsFv, VHH , diabody, tribody, tetrabody, Fc fusion protein or minibody. Preferred functional fragments used in the present invention are Fab fragments, F(ab')2 fragments, Fab fragments, scFvs and diabodies.

The antibody or a functional fragment thereof used according to the method of obtaining said solid dosage form according to the present invention is not limited in any particular way. In one embodiment, said antibody or functional fragment thereof is an antibody. According to another embodiment of the present invention, said antibody or functional fragment thereof is a functional fragment as defined above. The antibody or functional fragment thereof may further contain one or more modifications, for example in the form of added or replaced residues, to improve stability, specificity or targeting. These modifications may include any such modifications known in the art.

The antigen against which said antibody or a functional fragment thereof is directed, i.e. the immunogen, peptide, protein or other molecular structure to which the antibody or functional fragment thereof can specifically bind is not limited. In the most general case (and in the absence of a specific reference description), specificity or specific binding refers to the ability of the specified antibody or functional fragment thereof to distinguish between a target of interest and an unrelated biomolecule (for example, in the case of antibodies specific for human TNF-α, to distinguish between TNF-α α human and an unrelated biomolecule), determined, for example, in accordance with specificity assay methods known in the art. Such methods include, but are not limited to, Western blot and enzyme-linked immunosorbent assay (ELISA) tests. For example, a standard ELISA assay may be performed. Typically, determination of binding specificity is carried out using not a single reference biomolecule, but a set of approximately three to five unrelated biomolecules, such as milk powder, BSA, transferrin, or the like. In one embodiment of the present invention, said antibody or functional fragment thereof is suitable for use in the treatment of inflammatory bowel disease (IBD, e.g., Crohn's disease or ulcerative colitis. In another embodiment of the present invention, said antibody or functional fragment thereof is suitable for use in the topical treatment of the gastrointestinal tract in the patient's ileum or colon.

According to a further embodiment of the present invention, said antibody or functional fragment thereof is selected from tumor necrosis factor alpha (TNF-α)-specific antibodies and functional fragments thereof, α4β7 integrin-specific antibodies and functional fragments thereof, antibodies, specific for CD3, CD4 or CD20, and their functional fragments, antibodies specific for interleukin 6 (IL-6), interleukin 12 (IL-12), interleukin 13 (IL-13), interleukin 23 (IL-23) or their receptors and their functional fragments, antibodies specific to CXCL10/IP-10 and their functional fragments, and antibodies specific to the p40 protein subunit and their functional fragments. According to yet another embodiment of the present invention, said antibody or functional fragment thereof is selected from infliximab, adalimumab, etanercept, certolizumab pegol, golimumab, visilizumab, eldemumab, abrilumab, canakinumab, tocilizumab, ustekinumab, natalizumab, etrolizumab, priliximab, vedolizumab, and their functional fragments.

According to one embodiment of the present invention, said antibody or functional fragment thereof in said solid dosage form obtained using the method of the present invention specifically binds to TNF-α. The terms anti-TNF antibody, anti-TNF-α antibody, and TNF-α-specific antibody are used interchangeably herein. In one embodiment, specific binding refers to the ability of an antibody or antibody fragment to distinguish between human TNF-α and human TNF-β. According to a preferred embodiment of the present invention, the anti-TNF-α antibody or a functional fragment thereof is an anti-TNF-α antibody. According to an alternative preferred embodiment of the present invention, the anti-TNF-α antibody or a functional fragment thereof is a functional fragment of an anti-TNF-α antibody.

Several anti-TNF-α monoclonal antibodies have been described in the prior art. Meager et al (Hybridoma, 6, 305-311, 1987) describe mouse monoclonal antibodies against recombinant TNF-α. Fendly et al (Hybridoma, 6, 359-370, 1987) describe the use of mouse monoclonal antibodies against recombinant TNF-α to identify neutralizing epitopes on TNF. In addition, international patent application WO 92/11383 discloses recombinant antibodies, including CDR-grafted antibodies, specific for TNF-α. US Patent No. 5,919,452 discloses chimeric antibodies against TNF-α and their use in the treatment of pathologies associated with the presence of TNF-α. Additional anti-TNF-α antibodies are disclosed in:

Stephens et al. (Immunology, 85, 668-674, 1995), GB-A-2246570, GB-A-2297145, US 8673310, US

2014/0193400, EP 2390267B1, US 8293235, US 8697074, WO 2009/155723 A2 and WO 2006/131013 A2.

Currently approved anti-TNF-α antibodies include (i) infliximab, a chimeric monoclonal IgG antibody against human TNF-α (Remicade®); (ii) etanercept, a dimeric IgG1 Fc-fusion protein of the TNF receptor TNFR2 (Enbrel®); (iii) adalimumab, a fully human monoclonal antibody (mAb) (Humira®), (iv) certolizumab, a pegylated Fab fragment (Cimzia®), and (v) golimumab, a human monoclonal IgG1K antibody (Simponi®). In addition, various biosimilars are being developed. Accordingly, according to one embodiment of the present invention, said antibody or functional fragment thereof is selected from infliximab, adalimumab, etanercept, certolizumab pegol and golimumab, or functional fragments thereof. According to another embodiment of the present invention, said antibody or functional fragment thereof is an anti-TNF antibody or functional fragment thereof as disclosed in PCT applications PCT/EP2017/056218, PCT/EP2017/056246, PCT/EP2017/056237 and PCT/EP2017/ 056227, as originally filed. According to yet another embodiment of the present invention, the at least one antibody or functional fragment thereof is an anti-TNF antibody or functional fragment thereof with a light chain variable domain and/or a heavy chain variable domain containing complementarity determining regions (CDRs) with amino acid sequences according to disclosed in PCT applications PCT/EP2017/056218, PCT/EP2017/056246, PCT/EP2017/056237 and PCT/EP2017/056227, as originally filed.

According to a preferred embodiment of the present invention, said at least one antibody or functional fragment thereof is an anti-TNF antibody or functional fragment thereof with a light chain variable domain and/or a heavy chain variable domain containing one or more CDR regions with amino acid sequences as disclosed in SEQ ID NO: 7, 9, 12, 14, 24 and 25 from PCT/EP2017/056218, SEQ ID NO: 7-11 and 6 from PCT/EP2017/056246, SEQ ID NO: 7-12 from PCT/EP2017/ 056237, SEQ ID NO: 1-4, 7 and 6 from PCT/EP2017/056227; and their combinations. According to another preferred embodiment of the present invention, the at least one antibody or functional fragment thereof is an anti-TNF antibody or functional fragment thereof with a light chain variable domain and a heavy chain variable domain containing CDR regions with the amino acid sequences disclosed in claim 2 of the PCT /EP2017/056218, in claim 2 PCT/EP2017/056246, in claim 2 PCT/EP2017/056237 and/or in claim 2 PCT/EP2017/056227, as originally filed. According to yet another preferred embodiment of the present invention, said at least one anti-TNF antibody or functional fragment thereof is selected from the group consisting of anti-TNF-α antibodies or functional fragments thereof comprising a heavy chain variable domain amino acid sequence and/or sequence amino acids of the light chain variable domain according to clause 4 of PCT/EP2017/056218, clauses 5 and 6 of PCT/EP2017/056246, clauses 5 and 6 of PCT/EP2017/056237, clause 4 of PCT/EP2017/056227; and combinations of the above.

Said drug coating contains a buffer. The nature of the buffer is not limited in any particular way and includes all buffers that ensure the stability and activity of antibodies and functional fragments thereof in solution. According to one embodiment of the present invention, said buffer is selected from the group consisting of an acetate buffer; citrate buffer; histidine buffer; succinate buffer; phosphate buffer; hydroxymethylaminomethane (TRIS) buffer; and combinations of the above.

The polymer binder used according to the method of obtaining the specified solid dosage form according to the present invention is not limited in any particular way. Examples of a polymeric binder suitable for use in the present invention include hydroxypropyl methylcellulose (HPMC); hydroxypropylcellulose (HPC), methylcellulose (MC); polyvinylpyrrolidone (PVP); macrogol-poly(vinyl alcohol) graft copolymer (eg Kollidon® IR); poly(ethyl acrylate, methyl methacrylate) 2:1 (e.g. Eudragit® NM 30D or Eudragit® NE 30D); poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1 (e.g. Eudragit® RS 30D); poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2 (for example, Eudragit® RL 30D); ethylcellulose (eg Surelease® or Aquacoat® ECD); polyvinyl acetate (eg Kollicoat® SR 30D); and combinations of the above. Said polymeric binder may be in any form that allows said polymeric binder to be dissolved or dispersed in an aqueous solution or suspension.

According to a preferred embodiment of the present invention, said polymer binder is represented by an aqueous solution or dispersion (suspension).

According to one embodiment of the present invention, said polymeric binder in the drug coating is suitable for immediate release drug coating. Accordingly, drug coating of said solid dosage form prepared by the method of the present invention using polymeric binders suitable for immediate release coating results in immediate release of said at least one antibody or functional fragment thereof from said dosage form. As used herein, the term immediate release describes a drug coating from which more than 60%, preferably more than 70%, more preferably more than 80%, even more preferably more than 90%, most preferably 95% of the specified antibody or functional fragment thereof is released through 2 hours, preferably after 1 hour, even more preferably after 0.5 hours of exposure to the aqueous environment. The term aqueous medium in the context of the present invention may refer to a solution or suspension, a significant portion of which is water. This environment includes intestinal fluid.

To measure the amount of antibody or functional moiety released into an aqueous solution from a drug coating serving as the outer coating of a solid dosage form, the drug layer deposited on an inert core can be immersed in a specified volume of an aqueous solution (preferably buffered) for a specified period of time at continuous shaking of the aqueous solution; the final concentration of the at least one antibody or functional fragment thereof in the aqueous solution may be determined and compared with the initial amount applied during the layering process, taking into account process efficiency and weight gain. The term aqueous solution as used herein may refer to a solution or suspension of which a significant portion is water (e.g., more than 30% by weight water, preferably more than 40% by weight, preferably more than 50% by weight, preferably more than 60% by weight, most preferably more than 70 wt.%). The aqueous solution for dissolution testing may preferably contain a buffer. Likewise, release from a solid dosage form with additional coatings deposited on said drug coating, such as a sustained release coating or a delayed release coating, can be determined. Methods for determining the concentration of antibodies in an aqueous solution are known in the art and include, for example, measuring absorbance at 280 nm, or using a colorimetric protein reagent assay, such as the Bradford assay, or ELISA.

It should be understood that in the text of this description, any reference to the dissolution or recovery of antibodies or functional fragments thereof from a solid dosage form/drug delivery system with multiple particles (as in the immediately preceding section and below), for example, by continuous immersion of the solid dosage form/ drug delivery systems with multiple particles in an aqueous (buffer) solution with constant (continuous) shaking, for example, the following standard test settings, or similar standard test settings known to one of ordinary skill in the art, can be used: assessing the release of said at least one antibody or a functional fragment thereof can be carried out using a standard dissolution apparatus I (basket), II (paddle stirrer), III (oscillating cylinder) or apparatus IV (flow cell) where the buffer (i.e., aqueous buffer solution) is equilibrated at 37°C. The volume of buffer used for dissolution testing can be tailored, for example, by using mini-vessels in apparatus I or II, to provide reduced volume requirements and greater bioadequacy. The release of antibodies or their functional fragments upon dissolution can be quantified offline by ELISA.

According to one embodiment of the present invention, said drug coating is an immediate release drug coating providing a recovery of at least 70%, preferably at least 80%, more preferably at least 90%, even more preferably at least 95%, more more preferably at least 97%, even more preferably at least 99% of said at least one antibody or functional fragment thereof from said drug coating within 1 hour of continuous immersion of the drug-coated solid dosage form as an outer coating in an aqueous solution ( for example, at a temperature of 25°C or higher (for example, 2540°C, preferably about 37°C)), with continuous shaking of the aqueous solution.

Polymeric binders suitable for immediate release coating include hydroxypropyl methylcellulose (HPMC); hydroxypropylcellulose (HPC), methylcellulose (MC); polyvinylpyrrolidone (PVP); macrogol-poly(vinyl alcohol) graft copolymer (eg Kollidon® IR) Preferably, the polymer binder suitable for the immediate release coating is selected from HPMC, MC and combinations thereof, preferably -HPMC.

According to another embodiment of the present invention, said polymeric binder in the drug coating contains at least one sustained release polymeric binder. The at least one sustained release polymeric binder is not limited in any particular way, provided that it ensures sustained release from the drug coating, and provided that it does not affect the stability of the drug coating.

- 22 044207 potency, activity and solubility of said at least one antibody or functional fragment thereof. The term extended release is known in the art. As used herein, the term sustained release may be used to describe the release of an active agent from a drug coating or solid dosage form such that a significant proportion of the antibody or functional fragment thereof is released from said drug coating or solid dosage form upon exposure to an aqueous environment over an extended period of time, for example, for at least 6 hours, preferably at least 10 hours, more preferably at least 14 hours, even more preferably at least 18 hours, most preferably at least 24 hours.

According to one embodiment of the present invention, said polymeric binder in the drug coating comprises at least one sustained release polymeric binder providing a recovery of at least 40%, preferably at least 50%, more preferably at least 60%, even more preferably at at least 70%, even more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, even more preferably at least 93%, most preferably at least 95% of the specified at least one antibody or functional fragment thereof from said drug coating within a specified period of time (e.g., 4 hours, or 6 hours, or 8 hours, or 10 hours, or 12 hours, or 14 hours, or 16 hours, or 18 hours , or 20 hours, or 22 hours, or 24 hours, or 26 hours, or 28 hours, or 30 hours, or 32 hours; etc.) of continuous immersion of the specified solid dosage form in an aqueous solution (for example, at a temperature of 25 °C or higher (eg 25-40°C, preferably about 37°C)) with continuous shaking. According to a preferred embodiment of the present invention, said polymeric binder in the drug coating comprises at least one sustained release polymeric binder providing sustained release of said at least one antibody or functional fragment thereof over a period of time of at least 5 hours, preferably over at least 10 hours, more preferably at least 15 hours, even more preferably at least 20 hours, most preferably at least 24 hours, etc., while continuously immersing said solid dosage form in an aqueous solution and continuously shaking said aqueous solution. According to an alternative preferred embodiment of the present invention, said polymeric binder in the drug coating comprises at least one sustained release polymeric binder providing sustained release of said at least one antibody or functional fragment thereof over a period of time of at least 8 hours, according to at least 10 hours, at least 12 hours, at least 14 hours, or at least 16 hours while continuously immersing said solid dosage form in the aqueous solution and continuously shaking.

In particular, for conditions that affect a section of the gastrointestinal tract, including the ileum and colon, such as Crohn's disease and ulcerative colitis, the use of a sustained release solid dosage form with an active biological agent in the form of an antibody may be desirable. or a functional fragment thereof, exhibiting limited systemic absorption.

The sustained release coating may use at least one sustained release polymer binder as the polymer binder. In this case, more than one, for example two, three or four polymeric binders for sustained release, can be used in the form of a liquid polymer binder for coating with the active agent.

Sustained release polymer binders suitable for use in the present invention include poly(ethyl acrylate, methyl methacrylate) 2:1 (eg, Eudragit® NM 30D or Eudragit® NM 30D); poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1 (e.g. Eudragit® RS 30D); poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2 (for example, Eudragit® RL 30D); ethylcellulose (eg Surelease® or Aquacoat® ECD), polyvinyl acetate (eg Kollicoat® SR 30D); and combinations of the above. According to one embodiment of the present invention, the at least one sustained release polymeric binder is selected from the group consisting of 2:1 poly(ethyl acrylate, methyl methacrylate) (eg, Eudragit® NM 30D or Eudragit® NE 30D); poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1 (e.g. Eudragit® RS 30D); poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2 (for example, Eudragit® RL 30D); ethylcellulose (eg Surelease® or Aquacoat® ECD), polyvinyl acetate (eg Kollicoat® SR 30D); and combinations of the above.

The method proposed according to the present invention, in the most general case, includes as a first stage step a): obtaining a liquid for coating with an active agent containing

- 23 044207 at least one antibody or a functional fragment thereof, a buffer and at least one polymer binder, in the form of an aqueous solution or suspension. Individual components of coating liquid with active agent, i.e. at least one antibody or functional fragment thereof, a buffer and at least one polymeric binder as defined above may be presented in any form that allows them to be introduced into an aqueous solution or suspension. For example, said individual component may be in the form of powders, granules, or suspended or dissolved in a solvent, and then dissolved or dispersed in an aqueous solution or suspension.

The term aqueous solution or suspension as used herein refers to a solution or suspension characterized in that at least 60%, preferably at least 70%, more preferably at least 80%, even more preferably at least 90%, even more preferably at least 95, 97, 98, 99 or 99.5%, even more preferably at least 99.9%, most preferably 100% of the solvent used is water. According to one embodiment of the present invention, the active agent coating liquid is an aqueous solution or suspension, with 100% of the solvent used being water.

The method in which the at least one antibody or functional fragment thereof is introduced into the liquid for coating with the active agent is not limited in any particular way. For example, said antibody or functional fragment thereof may be added in the form of a powder containing particles containing the antibodies or functional fragments thereof, for example, as a lyophilized, spray-dried, air-dried or vacuum-dried powder, thereby directly dissolving said antibody or functional fragment thereof. functional moiety in the liquid for coating with the active agent. The term powder in this context means, in its broadest sense, including fine particles as well as larger particles and granules. Alternatively, said antibody or functional fragment thereof may already be added to the solution, for example as part of a buffered aqueous solution.

According to one embodiment of the present invention, the at least one antibody or functional fragment thereof is provided in the form of a powder that is added to a liquid for coating with the active agent. It has been found that by adding at least one antibody or functional fragment thereof in powder form to the active agent coating liquid, a higher concentration of said at least one antibody or functional fragment thereof can be achieved in the active agent coating liquid, thereby ensuring high the concentration of said at least one antibody or functional fragment thereof in the dosage coating, thereby minimizing the processing time and exposure of the solid dosage form to external factors. According to a preferred embodiment, said at least one antibody or functional fragment thereof is dissolved in the coating liquid with the active agent of step a).

The concentration of said antibody or functional fragment thereof in the active agent coating liquid is not limited in any particular way, provided that the target loading of the solid dosage form can be achieved by said at least one antibody or functional fragment thereof, and provided that the stability, activity and minimal irreversible interactions with other components of the liquid for coating the active agent of the specified at least one antibody or functional fragment thereof. According to one embodiment of the present invention, the active agent coating liquid contains 0.01-100 mg/ml, preferably 0.1-50 mg/ml, more preferably 0.5-50 mg/ml, even more preferably 1-50 mg/ml ml, even more preferably 1-30 mg/ml, even more preferably 1-25 mg/ml, even more preferably 5-25 mg/ml, most preferably about 25 mg/ml, optionally most preferably about 15 mg/ml said at least one antibody or functional fragment thereof. According to another embodiment of the present invention, said active agent coating liquid contains 0.001-15% by weight, preferably 0.001-10% by weight, more preferably 0.01-7% by weight, even more preferably 0.05-5% by weight. , even more preferably 0.1-3.5 wt.%, even more preferably about 0.5-2.5 wt.%, most preferably about 1.4 wt.%, alternatively, most preferably about 4.7 wt. .% of said at least one antibody or functional fragment thereof. According to an alternative embodiment of the present invention, the active agent coating liquid contains 5-300 wt%, preferably 20-200 wt%, more preferably 50-150 wt%, even more preferably 50-115 wt%, even more preferably 85 -115 wt.%, most preferably about 90-105 wt.%, alternatively, most preferably about 45-60 wt.% of the at least one antibody or functional fragment thereof, based on the total weight of solid polymer binders in the active agent coating liquid .

According to an alternative embodiment of the present invention, the concentration of the antibody in the active agent coating liquid provides the amount of antibody or function thereof.

- 24 044207 nal fragment in the specified solid dosage form obtained using the method according to the present invention, so that a therapeutically effective dose of the specified at least one antibody or functional fragment thereof can be administered in a single single dose, for example, in the form of a tablet or capsule, containing solid dosage forms with multiple units (for example, in the form of multiple pellets, microcarriers or granules). The term administration refers to the manner and form of first contact of the composition with the patient's body. The solid dosage form obtained using the method proposed according to the present invention can be administered orally or by any other method that ensures the accumulation of the specified solid dosage form at the intended site of local application and/or absorption into the body tissue. Preferably, the solid dosage form of the present invention is for oral administration. A therapeutically effective dose is the amount of the at least one antibody or functional fragment thereof required to provide the desired therapeutic effect. The exact amount for different antibodies or functional fragments thereof, and/or for individual patients may vary, but can be determined by one skilled in the art.

The active agent coating liquid contains a buffer. The nature of the buffer is not limited in any particular way and includes all buffers that ensure the stability and activity of antibodies and functional fragments thereof in solution. According to one embodiment of the present invention, the buffer is selected from the group consisting of an acetate buffer; citrate buffer; histidine buffer; succinate buffer; phosphate buffer; hydroxymethylaminomethane (TRIS) buffer; and their combinations; preferably a buffer with a specific pH at which the given antibody is stable. This buffer may be present in the coating suspension with the active agent in any amount to ensure the stability and activity of the antibodies and their functional fragments in solution. According to one embodiment of the present invention, the active agent coating suspension contains 0.01-20 wt%, preferably 0.1-10 wt%, more preferably 0.5-5 wt%, even more preferably 1-5 wt.%, most preferably about 4.5 wt.%, alternatively, most preferably about 15 wt.% buffer.

The polymeric binder as defined above can be used in any form that allows for dissolution or dispersion in the liquid to be coated with the active agent. According to one embodiment of the present invention, said polymeric binder is added to the aqueous solution or suspension in the form of a solid, for example, in the form of a powder or granules. According to another embodiment, said polymeric binder is already in solution or suspension, preferably as part of an aqueous solution or suspension, and as such is added to the coating liquid with the active agent. If the polymer binder is suitable for immediate release, the polymer binder is characterized by high solubility in an aqueous environment. Accordingly, the polymeric binder in a form suitable for dissolution or dispersion can be readily dissolved or dispersed in the coating liquid with the active agent. In case the polymeric binder contains at least one sustained release polymeric binder, the at least one sustained release polymeric binder may be used in any form that allows for dissolution or dispersion in the coating liquid with the active agent. According to a preferred embodiment, said at least one sustained release polymeric binder is added to the active agent coating liquid in the form of an aqueous suspension (aqueous dispersion).

The amount of polymeric binder in the active agent coating liquid is not limited in any particular way, provided that the active agent coating liquid can be used for spray treatment while providing stability, activity and minimal irreversible interaction with other components liquid for coating with an active agent at least one antibody or functional fragment thereof. According to one embodiment of the present invention, the active agent coating fluid contains a polymer binder at a concentration that maximizes processing speed (ie, spray rate) while minimizing clogging of the tubes and spray nozzle. According to another embodiment of the present invention, the active agent coating liquid contains 0.1-20 wt.%, preferably 0.5-10 wt.%, more preferably 0.5-5 wt.%, even more preferably 1-5 wt. %, even more preferably 1-3 wt.%, most preferably about 2.5 wt.% (preferred embodiment where the drug coating is an immediate release drug coating), alternatively, most preferably about 7-7.5 wt. .% (preferred embodiment wherein the drug coating is a sustained release drug coating) of the polymeric binder.

According to one embodiment of the present invention, the liquid for coating with the active agent in step a) contains at least one anti-caking agent. Pre

- 25 044207 anti-caking agent can facilitate manipulation of the active agent coating solution. The anti-blocking agent may be particularly beneficial when using polymeric binders such as hydroxypropyl methylcellulose (HPMC); hydroxypropylcellulose (HPC), methylcellulose (MC); polyvinylpyrrolidone (PVP); macrogolapoly(vinyl alcohol) graft copolymer (e.g. Kollidon® IR), poly(ethyl acrylate, methyl methacrylate) 2:1 (e.g. Eudragit® NM 30D or Eudragit® NE 30D); poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1 (e.g. Eudragit® RS 30D); poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2 (for example, Eudragit® RL 30D); ethylcellulose (e.g. Surelease® or Aquacoat® ECD), polyvinyl acetate (e.g. Kollicoat® SR 30D). The anti-caking agent for use in the active agent coating liquid is not particularly limited. According to one embodiment of the present invention, the anti-caking agent is selected from colloidal silica, mesoporous silica, glycerol monostearate (MGS), stearic acid, magnesium stearate and talc, preferably mesoporous silica or MSG, more preferably mesoporous silica. The amount of anti-blocking agent to be used in the active agent coating liquid is not limited in any particular way. According to one embodiment of the present invention, the active agent coating liquid contains 0.1-50 wt%, preferably 1-30 wt%, more preferably 10-20 wt% or 5-50 wt% anti-caking agent based on the total weight solid polymer binders in liquid for coating with the active agent.

According to another embodiment of the present invention, the active agent coating liquid contains i) 0.001-10% by weight, preferably 0.01-7% by weight, more preferably 0.05-5% by weight, even more preferably 0.1-3 .5 wt.%, even more preferably 0.5-2.5 wt.%, most preferably about 1.4 wt.%, alternatively, most preferably about 4.7 wt.% of said at least one antibody or functional fragment; ii) 0.1-20% by weight, preferably 0.5-10% by weight, more preferably 1-5% by weight, even more preferably 1-3% by weight, even more preferably 2-3% by weight, most preferably about 2.5 wt.% (preferred embodiment wherein the drug coating is an immediate release drug coating), alternatively most preferably about 7-7.5 wt.% (preferred embodiment wherein the drug coating is drug coating for sustained release), polymer binder; and iii) 0-5 wt.%, preferably 0.01-3 wt.%, more preferably 0.1-2 wt.%, even more preferably 0.1-1 wt.%, even more preferably 0.2- 0.6 wt.%, most preferably about 0.25 wt.% anti-caking agent. According to a further embodiment, said active agent coating liquid contains i) 0.5-5% by weight of an antibody or functional fragment thereof; ii) 15 wt.% polymer binder; and iii) 0-1.25 wt.% anti-caking agent.

In a preferred embodiment, the active agent coating liquid contains i) 0.5-2.5% by weight of an antibody or functional fragment thereof; ii) 1-3 wt.% polymer binder; and iii) 0.2-0.6 wt.% anti-caking agent. In an alternative preferred embodiment, the active agent coating liquid contains i) approximately 2.5 wt.% antibody or functional fragment thereof; ii) approximately 2.5 wt.% polymer binder; and iii) approximately 0.25 wt.% anti-caking agent. In another alternative preferred embodiment, the active agent coating liquid contains i) approximately 1.5 wt.% antibody or functional fragment thereof; ii) approximately 2.5 wt.% polymer binder; and iii) approximately 0.25 wt.% anti-caking agent. The embodiments presented in this paragraph are particularly preferred if said at least one polymeric binder is suitable for immediate release.

In an alternative embodiment, the active agent coating liquid contains i) 0.01-5% by weight of an antibody or functional fragment thereof; ii) 0.5-20 wt.% polymer binder; and iii) 0-5 wt.% anti-caking agent. In another alternative embodiment, the active agent coating liquid contains i) 0.1-2% by weight of an antibody or functional fragment thereof; ii) 2-15 wt.% polymer binder; and iii) 0-1 wt.% anti-caking agent. The embodiments presented in this paragraph are particularly preferred if the at least one polymeric binder includes at least one sustained release polymeric binder.

The present inventors have discovered that by using a polymeric binder containing at least one sustained release polymeric binder in a drug coating, the release of said at least one antibody or functional fragment thereof from said drug coating in an aqueous medium can be modified to determine the profile extended release. By adjusting the ratio of said at least one sustained release polymeric binder and said at least one antibody or functional fragment thereof (by weight) in the liquid

- 26 044207 For coating with an active agent, the release rate of said at least one antibody or functional fragment thereof may be modified, with a higher ratio resulting in a lower release rate. Thus, the rate of release of said at least one antibody or functional fragment thereof from said drug coating can be tailored to suit the individual requirements of the antibody or functional fragment thereof used, the release site and the condition to be treated by said solid dosage form. Accordingly, according to one embodiment of the present invention, said at least one sustained release polymeric binder (S) and said at least one antibody or functional fragment thereof (A) are present in the active agent coating liquid at a ratio S/A (by weight ), amounting to 0.5 to 100, preferably 0.5 to 50, more preferably 1 to 30, even more preferably 5 to 30, even more preferably 10 to 30, even more preferably 15 to 25, as an option - 0.5 to 200.

According to other embodiments of the present invention, the liquid for coating with the active agent in step a) contains at least one plasticizer. The present inventors have discovered that a plasticizer, particularly when the polymer binder includes at least one sustained release polymer binder, can significantly improve the properties of the final drug coating, including the integrity of the final drug coating and the sustained release profile. Said plasticizer for use in the active agent coating liquid is not limited in any particular way. According to one embodiment of the present invention, the plasticizer is selected from the group consisting of triethyl citrate, polyethylene glycol, acetyl triethyl citrate, butyl citrate, polysorbates, 1,2-polypropylene glycol (TEG) and dibutyl sebacate (DBS). According to a preferred embodiment of the present invention, the plasticizer is selected from the group consisting of triethyl citrate (TEC) and dibutyl sebacate (DBS). The amount of plasticizer to be used in the active agent coating liquid is not limited in any particular way. According to one embodiment of the present invention, the active agent coating liquid contains 5-35 wt.%, preferably 10-30 wt.%, more preferably about 20-25 wt.% plasticizer based on the total weight of solid polymer binders in the active agent coating liquid.

In addition, the present inventors have discovered that in the case of solid dosage forms, if a slow and continuous sustained release is desired, for example over 20 hours, or 24 hours, or over a longer period of time, a hydrophobic plasticizer such as DBS (compared to a more hydrophilic plasticizer), gives very favorable results by causing a slower and more constant release of the at least one antibody or functional fragment thereof in the drug layer. Thus, in accordance with one embodiment of the present invention, if the polymer binder contains at least one sustained release polymer binder, the plasticizer in the active agent coating liquid is DBS.

According to another embodiment of the present invention, said active agent coating liquid in step a) contains at least one coalescence enhancer. The coalescence enhancer, particularly if the polymer binder contains at least one sustained release polymer binder, can significantly improve the properties of the final drug coating, including the integrity of the final drug coating and the sustained release profile. Said coalescence enhancer for use in the active agent coating liquid is not limited in any particular way. In accordance with one embodiment of the present invention, the coalescence enhancer for use in the sustained release coating fluid is selected from the group consisting of 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, glyceryl monostearate, 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, glyceryl monostearate, lecithin, sorbitan monopalmitate, fatty alcohols such as cetyl alcohol or oleyl alcohol, sodium glycolate, sodium de(h)oxycholate, polyethylene glycol, polypropylene glycol, alkyl poly(ethylene oxide), alkyl glycoside, alkyl polyglucose yes, octyl glucoside , decyl maltoside, propylene glycol monolaurate (eg Lauroglycol™ 90); and combinations of the above. According to a preferred embodiment of the present invention, the coalescence enhancer is propylene glycol monolaurate (eg, Lauroglycol™ 90). The amount of coalescence enhancer for use in the active agent coating liquid is not limited in any particular way. According to one embodiment of the present invention, the active agent coating liquid contains 1-20 wt.%, preferably 2-15 wt.%, more preferably 5-10 wt.% coalescence enhancer based on the total weight of the solid polymer binders

- 27 044207 agents for prolonged release in liquid for coating with the active agent.

According to one embodiment, the active agent coating liquid in step a) and/or the sustained release coating liquid in step d) contains at least one surfactant. Said surfactant may be present in the active agent coating liquid and/or sustained release coating liquid at a concentration of 0.005-2.0% by weight, 0.01-1% by weight, more preferably 0.05-0. .8 wt.%, even more preferably about 0.1-0.5 wt.% surfactant. Suitable surfactants for the active agent coating liquid in step a) and/or the sustained release coating liquid in step d) are selected from the group consisting of 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, glyceryl monostearate, 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, glyceryl monostearate, lecithin, sorbitan monopalmitate, cetyl alcohol, oleyl alcohol, sodium glycolate, sodium de(h)oxycholate, polyethylene glycol, polypropylene glycol, alkyl poly(ethylene) oxide), alkyl glycoside , alkyl polyglucoside, octyl glucoside, decyl maltoside; and combinations of the above.

The active agent coating liquid in step a) and/or the sustained release coating liquid in step d) of the method according to the present invention may optionally contain at least one additional auxiliary substance. The term excipient as used herein refers to a non-therapeutic agent added to a formulation to provide the desired consistency, viscosity or stabilizing effect. In accordance with one embodiment of the present invention, said at least one additional excipient is selected from pharmaceutically acceptable excipients such as antioxidants, humectants, protective colloids, dyes, fillers, protease inhibitors, penetration enhancers; and combinations of the above. According to a specific embodiment of the present invention, the active agent coating liquid in step a) contains at least one excipient, preferably selected from the group consisting of dextrose, mannitol, sorbitol, xylitol, trehalose, sucrose, amino acids such as arginine, histidine , glycine, alanine, lysine, proline, leucine, glutamic acid, serine, aspartic acid and asparagine, and the corresponding amino acid salts. Said active agent coating liquid may contain, for example, 0.01-30 wt.%, 0.1-20 wt.% or 0.5-10 wt.% of said at least one filler based on the total solids content of the liquid for coating with active agent.

The individual components of step a) can be mixed to form an active agent coating liquid using any standard mixing device. Such mixing devices are known in the art and include, for example, a paddle stirrer, a magnetic stirrer. Said mixing device may be an integral part of the spraying apparatus used in step b).

In step b) of the method of the present invention, layers of liquid are sprayed onto the inert core to coat the active agent. In this step, for example, a fluidized bed sprayer or a pan can be used. In accordance with a preferred embodiment of the present invention, a fluid bed spraying apparatus is used. The use of a fluid bed sprayer to spray coat an inert core is known in the art. The present inventors have discovered that in spray coating, control of the temperature and pressure applied to the active agent coating liquid, as well as the duration of treatment, is critical to maintaining the activity and stability of the at least one antibody or functional fragment thereof. Thus, careful control of the parameters and conditions used during spray coating is beneficial for at least one antibody or functional fragment thereof in a solid dosage form obtained using the method of the present invention.

Thus, according to one embodiment of the present invention, when spray coating in step b), the air atomization pressure at the spray nozzle is less than 200 kPa, preferably less than 100 kPa, more preferably 10-100 kPa, even more preferably 10-50 kPa , even more preferably is 25-50 kPa. According to another embodiment of the present invention, the spray apparatus is set at a temperature below the melting temperature (Tm) of the at least one antibody or functional fragment thereof. The foregoing means that in cases where more than one antibody or functional fragment is included in the active agent coating liquid, the temperature must be below the melting temperature (Tm) of said antibody or functional fragment thereof with the active agent.

- 28 044207 minimum Tm. According to another embodiment of the present invention, the temperature of the spray apparatus is set to below 65°C, preferably from 25 to 60°C, more preferably from 35 to 55°C, even more preferably from 40 to 50°C, even more preferably from 42 to 50°C. According to yet another embodiment of the present invention, a fluid bed spray apparatus is used, and said fluid bed spray apparatus is set to an inlet air temperature of less than 65° C., preferably 25 to 60° C., more preferably 35 to 55° C. , even more preferably from 40C to 50°C, even more preferably from 42 to 50°C. The inlet air temperature or inlet temperature is the temperature of the air that is used to fluidize the bed. Therefore, the inlet air temperature, along with the spray rate, determines the temperature in the spray chamber, and accordingly, the temperature applied to the antibody or functional moiety in the coating fluid during spray coating.

The fluid bed spray apparatus for use according to the present invention is not limited in any particular way. Fluidized bed spraying apparatuses are known in the art and include, for example, fluidized bed equipment developed and marketed by GEA Group, Glatt GmbH, Freund-Vector Corporation and Inora Pharmaceutical Machinery Co. According to one embodiment of the present invention, the active agent coating liquid is sprayed onto the inert core using a bottom-spray fluidized bed sprayer. According to another embodiment of the present invention, the active agent coating liquid is sprayed onto the inert core using a top-spray fluidized bed sprayer. Additional parameters in the context of a top-spray fluid bed spray apparatus that can be adjusted in a manner favorable to use in the method of the present invention include the frequency of shaking the container; nozzle position; pump feed speed; spray speed; and inlet air flow.

In accordance with step c) of the method according to the present invention, the wet drug-coated inert core is dried, either simultaneously with step b), or upon completion of step b), to obtain a dried solid dosage form. The term wet drug-coated inert core refers to an inert core to which layers of active agent coating liquid have been applied by spraying, but retaining sufficient solvent from said active agent coating liquid to keep the applied drug coating wet. When drying, the solvent on the wet drug-coated inert core is removed. Methods for drying a wet drug-coated inert core are known in the art and include, for example, a fluidized bed, an oven, or an oven.

The term dried or dried in relation to a solid dosage form (eg, a dried solid dosage form) means a solid dosage form containing preferably less than 10%, more preferably less than 7%, even more preferably less than 5%, even more preferably less than 3%, more more preferably less than 2% and most preferably less than 1.5% residual solvent. The residual solvent content can be determined by measuring the moisture content of said solid dosage form. Accordingly, the moisture content in the solid dosage form according to the present invention after step c) or after step d) in the case where an additional coating in the form of a sustained release coating is applied after step c) is preferably less than 10%, preferably less than 7%, more preferably less than 5%, even more preferably less than 3% and most preferably less than 1.5%. One of the methods for determining the moisture content in a particular solid dosage form is represented by the method of determining weight loss upon drying (Loss on Drying, LOD). For example, the moisture content of a solid dosage form can be measured gravimetrically using LOD at 105°C for 1 hour.

The activity and stability of the antibodies and their functional fragments used according to the present invention are very sensitive to external stress, such as temperature fluctuations and, in particular, elevated temperatures. Thus, according to the method of the present invention, drying uses a temperature at which the activity and stability of these antibodies and functional fragments thereof are maintained, and at the same time, effective drying of the wet drug-coated inert core can be ensured.

In accordance with one embodiment of the present invention, the wet drug-coated inert core is dried while performing step b). Said wet drug-coated inert core can be dried while carrying out step b) with air flow at the inlet of the fluidized bed. According to the present invention, simultaneous drying of the wet drug-coated inert core is particularly suitable for immediate release drug coatings, i.e. medicinal coatings, characterized in that at least one polymer binder is suitable for

- 29 044207 immediate release as defined above. Simultaneous drying of wet drug-coated inert cores has the advantage of reducing processing time by combining spray coating and drying of the inert core in a single step. According to one embodiment of the present invention, if a fluid bed spray apparatus is preferably used and the wet drug-coated inert cores are dried simultaneously with step b), the inlet air has a temperature of up to 65° C., preferably up to 60°C, more preferably up to 55°C, more preferably 40 to 50°C.

According to another embodiment of the present invention, the wet drug-coated inert core is dried upon completion of step b). The present inventors have discovered that in the case of drug coatings containing at least one sustained release polymeric binder intended for sustained release in an aqueous medium, drying the wet drug coated inert core at the end of step b) improves the sustained release profile of the resulting drug coating due to curing of the polymer coating. Thus, according to a preferred embodiment of the present invention, the wet drug-coated inert core, which is dried at the end of step b), contains at least one sustained release polymer binder.

In addition, the inventors of the present invention have surprisingly discovered that in case the drug-coated polymer binder contains at least one sustained-release polymer binder, drying the wet drug-coated inert core after step b) in a fluidized bed equipment or oven with a certain set temperature significantly improves the dissolution of the final drug coating, causing an improved sustained release profile of the at least one antibody or functional fragment thereof from the drug coating in an aqueous environment. The term oven as used herein should be understood in its broadest sense, i.e. This is a chamber used for heating and drying; it also includes, for example, the term drying cabinet. Suitable ovens or ovens for use in the method according to the present invention are known in the art. Suitable fluidized bed equipment for use in the process of the present invention is known in the art and includes, for example, large scale fluidized bed equipment. The temperature at which the wet drug-coated inert core is dried, if drying is carried out after completion of step b), is not limited in any particular way, provided that it maintains the stability and activity of the at least one antibody or its functional fragment in the composition of the drug coating. It has been found that a temperature not exceeding 65° C., when drying at the end of step b), allows the wet drug-coated inert core containing at least one sustained release polymer binder to dry sufficiently to obtain an optimal sustained release profile, at maintaining at the same time the stability and activity of said at least one antibody or functional fragment thereof in the drug coating. Thus, in accordance with one embodiment of the present invention, said temperature during drying of the wet drug-coated inert core containing at least one sustained release polymer binder does not exceed 65° C., preferably does not exceed 60° C., more preferably not exceeds 55°C. According to another embodiment of the present invention, during drying of the wet drug-coated inert core containing at least one polymeric binder for sustained release, a temperature below the melting temperature (Tm) of the at least one antibody or functional fragment thereof is used. The foregoing means that in cases where more than one antibody or functional fragment is included in the wet drug-coated inert core, the temperature must be below the melting temperature (Tm) of said antibody or functional fragment thereof with a minimum Tm. Drying of the wet drug-coated inert core can be continued until a dry solid dosage form is obtained. A solid dosage form is dry if a significant proportion of the solvent used in the liquid to coat the active agent has been removed by evaporation. According to one embodiment of the present invention, a solid dosage form is considered dry if the residual solvent content of the solid dosage form is preferably less than 15%, more preferably less than 10%, even more preferably less than 7%, even more preferably less than 5%, most preferably less than 3 %, 2%, 1% or 0.5% of the total weight of the specified solid dosage form. In accordance with a preferred embodiment of the present invention, the wet drug-coated inert core containing at least one sustained release polymeric binder is dried for a period of up to 30 hours, more preferably for a period of about 30 minutes to 24 hours. When drying, a vacuum can additionally be used.

In accordance with one embodiment, the method of the present invention further includes, after step c), step d) applying at least one additional coating in the form of a sustained release coating by layering a liquid sustained release coating on the solid dosage form of step c ) using spraying, preferably fluidized bed spraying, and then drying said layered wet solid dosage form in an oven or fluidized bed equipment.

The at least one sustained release polymer for use in step d) is not limited in any particular way so long as it ensures sustained release of the at least one antibody or functional fragment thereof from the solid dosage form. In the sustained release coating, at least one sustained release polymer may be used as the polymer. However, more than one, for example two, three or four sustained release polymers may be used as polymers in the sustained release coating liquid.

Sustained release polymers suitable for the sustained release coating of step d) according to the present invention include poly(ethyl acrylate, methyl methacrylate) 2:1 (eg Eudragit® NM 30D, Eudragit® NE 30D); poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1 (e.g. Eudragit® RS 30D); poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2 (for example, Eudragit® RL 30D); ethylcellulose (e.g. Surelease® or Aquacoat® ECD), polyvinyl acetate (e.g. Kollicoat® SR 30D). According to one embodiment of the present invention, said at least one sustained release polymer is selected from the group consisting of 2:1 poly(ethyl acrylate, methyl methacrylate) (eg, Eudragit® NM 30D, Eudragit® NE 30D); poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1 (e.g. Eudragit® RS 30D); poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2 (for example, Eudragit® RL 30D); ethylcellulose (eg Surelease® or Aquacoat® ECD), polyvinyl acetate (eg Kollicoat® SR 30D); and combinations of the above. According to a preferred embodiment of the present invention, said sustained release polymers are in the form of an aqueous dispersion.

The concentration of the sustained release polymer in the sustained release coating liquid of step d) is not particularly limited as long as it allows the sustained release coating liquid to be applied to the drug layered inert core by spraying; and provided that the resulting sustained release coating provides a sustained release profile of at least one antibody or functional moiety thereof in the drug coating upon exposure of a solid dosage form containing said sustained release coating deposited on top of the drug coating to an aqueous environment. According to one embodiment of the present invention, said sustained release coating fluid contains polymer at a concentration that maximizes processing speed (ie, spray rate) while minimizing clogging of the tubes and spray nozzle. According to a preferred embodiment of the present invention, said sustained release coating liquid contains 0.1-20% by weight, preferably 1-15% by weight, more preferably 2-10% by weight, even more preferably 5-10% by weight. , even more preferably 6-9 wt.%, for example about 7-9 wt.%, about 6-8.5 wt.%, 6.5-8 wt.%, about 7-7.5 wt.% or about 8 % by weight of the sustained release polymer based on the total weight of the sustained release coating liquid.

It has been found that the amount of sustained release coating deposited on the drug-coated inert core influences the sustained release profile, with more sustained release coating slowing the release of said at least one antibody or functional fragment thereof from the solid dosage form in the aqueous environment. In accordance with one embodiment of the present invention, the weight of the polymer in solid dosage form after step d) is increased by 1-35 wt.%, preferably by 2.5-25 wt.%, for example, 4.5-25 wt.%, 5 -20 wt.% or 10-20 wt.% relative to the solid dosage form up to stage d).

The sustained release coating liquid is applied to the dried solid dosage form of step c) (ie, the drug-coated inert core) by spraying, preferably fluidized bed spraying. As regards the general parameters for spray coating in general and fluidized bed spray coating in particular, they relate to the parameters and settings described above for step b) of the method according to the present invention. According to one embodiment of the present invention, in step d), when using a fluidized bed coater, said fluidized bed coater has an inlet air temperature of not more than 65°C, preferably 35-60°C, more preferably 45-55°C; and/or the atomization pressure at the nozzle is 10-100 kPa, preferably 10-100 kPa, more preferably 25-100 kPa.

The temperature at which the coated wet solid dosage form is dried in an oven or fluidized bed device is not particularly limited as long as the stability and activity of the at least one antibody or functional fragment thereof in the drug coating is maintained , and provided that the temperature is sufficient to ensure that the final dosage form is dry. It has been found that a temperature not exceeding 65° C., preferably about 40-60° C., allows a wet layered solid dosage form containing at least one sustained release polymer to dry sufficiently to obtain an optimal sustained release profile. , while maintaining the stability and activity of the at least one antibody or functional fragment thereof in the drug coating. Thus, in accordance with one embodiment of the present invention, the temperature of the oven or fluidized bed device during drying of the layered wet solid dosage form of step d) containing at least one sustained release polymer does not exceed 65° C., preferably , is approximately 40-60°C.

Drying of the layered wet solid dosage form may continue until a dry solid dosage form is obtained containing the drug coating and the sustained release coating on top of the drug layer. The sustained release coating of said solid dosage form is dry if a significant portion of the solvent used in the sustained release coating liquid applied to the dried solid dosage form in step c) has been removed by evaporation. According to one embodiment of the present invention, said sustained release coating from step d) is considered to be dry if the residual solvent content of said solid dosage form is preferably less than 15%, more preferably less than 10%, even more preferably less than 7%, even more preferably less than 5%, most preferably less than 3, 2, 1 or 0.5% of the total weight of said solid dosage form.

In accordance with one embodiment of the present invention, the sustained release coating liquid further comprises an anti-blocking agent. Said anti-caking agent is preferably selected from the group of anti-caking agents listed above for the active agent coating liquid, and is preferably present in the sustained release coating liquid in an amount of 0.5-50 wt%, preferably 1-30 wt%, more preferably 5-20 wt.%, even more preferably about 10 wt.% of the total polymer solids. In particular, in case the sustained release polymer is poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1 (e.g. Eudragit® RS 30D), poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2 :0.2 (e.g. Eudragit® RL 30D), a combination thereof, etc., an anti-caking agent, for example at 10 wt.% of the total polymer solids in the coating fluid, can minimize agglomeration .

According to another embodiment of the present invention, the sustained release coating liquid in step d) contains at least one plasticizer. The use of a plasticizer can significantly improve the properties of the final sustained release coating, including the integrity of the final sustained release coating and the sustained release profile. The type of plasticizer included in the sustained release coating fluid can influence the sustained release profile in an aqueous environment.

The plasticizer for use in the sustained release coating liquid is not limited in any particular way. According to a preferred embodiment of the present invention, said plasticizer is selected from the group consisting of triethyl citrate (TEC), polyethylene glycol, acetyl triethyl citrate, butyl citrate, polysorbates, 1,2 polypropylene glycol and dibutyl sebacate (DBS), preferably DBS. The amount of plasticizer to be used in the sustained release coating liquid is not limited in any particular way. According to one embodiment of the present invention, the sustained release coating liquid contains 5-35 wt.%, preferably 10-30 wt.%, more preferably about 20-25 wt.% plasticizer based on the total weight of the polymer solids for sustained release in the coating liquid for sustained release.

The present inventors have found that in the case of solid dosage forms, where a slow and continuous sustained release is desired, for example over 20 hours or 24 hours, a hydrophobic plasticizer such as DBS (compared to a more hydrophilic plasticizer) provides very favorable results by providing a slower and more constant sustained release of said at least one antibody or functional fragment thereof from the drug layer. Thus, in accordance with one embodiment of the present invention, the plasticizer in the sustained release coating fluid is DBS.

In accordance with yet another embodiment of the present invention, the sustained release coating liquid in step d) contains at least one coalescence enhancer. The present inventors have discovered that the presence of a coalescence enhancer, such as propylene glycol monolaurate, in the sustained release coating liquid can significantly improve the properties of the final sustained release coating, including the integrity of the final sustained release coating and the sustained release profile. In addition, the presence of a coalescence enhancer, such as propylene glycol monolaurate, in the sustained release coating liquid can significantly reduce the drying time required to prepare a solid dosage form, thereby reducing processing time and cost. If a coalescence enhancer is included in the sustained release coating liquid, the resulting sustained release coating may provide a significantly more consistent rate of release of the at least one antibody or functional fragment thereof in the drug layer, for example, over 24 hours per aquatic environment. Finally, the presence of a coalescence enhancer in the sustained release coating liquid may significantly reduce the amount of sustained release coating required to provide a relatively slow release and a release profile of said at least one antibody or functional fragment thereof comparable to that in the absence of the coalescence enhancer. due to its positive effect on film drying when using polymer aqueous dispersions.

The coalescence enhancer for use in the sustained release coating fluid is not limited in any particular way. In accordance with one embodiment of the present invention, the coalescence enhancer for use in the sustained release coating fluid is selected from the group consisting of 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, glyceryl monostearate, polyethoxylated castor oil, PEG-40 hydrogenated castor oil, macrogol 15 hydroxystearate, polyoxyl-15hydroxystearate, cap rilocaproyl macrogol-8 glyceride, D-a- tocopherol polyethylene glycol-1000 succinate, glyceryl monostearate, lecithin, sorbitan monopalmitate, fatty alcohols such as cetyl alcohol or oleyl alcohol, sodium glycolate, sodium de(h)oxycholate, polyethylene glycol, polypropylene glycol, alkyl poly(ethylene oxide), alkyl glycoside, alkyl polyglucoside, ca. tilglucoside, decylmaltoside , propylene glycol monolaurate (e.g. Lauroglycol™ 90); and combinations of the above. In a preferred embodiment of the present invention, the coalescence enhancer for use in the sustained release coating fluid is propylene glycol monolaurate (eg, Lauroglycol™ 90). The amount of coalescence enhancer to be used in the sustained release coating liquid is not limited in any particular way. According to one embodiment of the present invention, the sustained release coating liquid contains 1-20 wt%, preferably 2-15 wt%, more preferably 5-10 wt% coalescence enhancer based on the total weight of the sustained release polymer solids in the liquid for extended release coating.

According to one embodiment of the present invention, the sustained release coating of step d) provides a recovery of at least 60%, preferably at least 70%, more preferably at least 80%, even more preferably at least 90%, even more preferably at at least 95%, even more preferably at least 97%, even more preferably at least 98%, even more preferably at least 99%, most preferably at least 99.5% of said at least one antibody or functional thereof fragment from a solid dosage form with prolonged release within a specified period of time (for example, 4 hours, or 6 hours, or 8 hours, or 10 hours, or 12 hours, or 14 hours, or 16 hours, or 18 hours , or 20 hours, or 22 hours, or 24 hours, or 26 hours, or 28 hours, or 30 hours, or 32 hours; etc.) continuous immersion of the specified solid dosage form in an aqueous solution, with continuous shaking of the specified aqueous solution. According to another embodiment of the present invention, the sustained release coating of step d) provides a recovery of at least 60%, preferably at least 70%, more preferably at least 80%, even more preferably at least 90%, even more preferably at least 95%, even more preferably at least 97%, even more preferably at least 98%, even more preferably at least 99%, most preferably at least 99.5% of said at least one antibody or functional fragment from a solid dosage form within a specified period of time (for example, 4 hours, or 6 hours, or 8 hours, or 10 hours, or 12 hours, or 14 hours, or 16 hours, or 18 hours, or 20 hours, or 22 hours, or 24 hours, or 26 hours, or 28 hours, or 30 hours, or 32 hours; etc.) continuous immersion of the specified solid dosage form in an aqueous solution with continuous shaking of the specified aqueous solution, with a prolonged release essentially at a constant rate for at least 8 hours, preferably at least 12 hours, more preferably at least 16 hours, even more preferably at least 20 hours, most preferably at least 24 hours.

According to yet another embodiment of the present invention, the sustained release coating of step d) ensures sustained release of said at least one antibody or functional fragment thereof over a period of time of at least 5 hours, preferably at least 8 hours, more preferably over at least 10 hours, even more preferably at least 14 hours, even more preferably at least 18 hours, even more preferably at least 20 hours, most preferably at least 24 hours, while continuously immersing said solid dosage form in an aqueous solution and continuously shaking the said aqueous solution. According to yet another embodiment of the present invention, the sustained release coating of step d) ensures sustained release of said at least one antibody or functional fragment thereof at a substantially constant release rate for at least 5 hours, preferably at least 8 hours, more preferably at least 10 hours, even more preferably at least 14 hours, even more preferably at least 18 hours, even more preferably at least 20 hours, most preferably for at least 24 hours, with continuous immersion of said solid drug form into an aqueous solution and continuously shaking said aqueous solution.

In accordance with the present invention, in order to maintain the activity and stability of the antibody and its functional fragment used according to the present invention, when preparing the specified solid dosage form, conditions are used that promote the activity and stability of the specified antibodies and their functional fragments (for example, by avoiding elevated temperatures, pressure , shear forces, enzymatic contamination, etc.). Accordingly, according to one embodiment of the present invention, at any time during steps a) and c), the temperature of the at least one antibody or functional fragment thereof is below the melting temperature (Tm) of the at least one antibody or functional fragment thereof. The above means that in cases where more than one antibody or functional fragment is included in the drug coating, the temperature must be below the melting temperature (Tm) of said antibody or functional fragment thereof with a minimum Tm. According to an alternative embodiment of the present invention, at any time during steps a) and c), the temperature of said antibody or functional fragment thereof is below 65°C, preferably not above 60°C, more preferably not above 55°C. According to another embodiment of the present invention, characterized in that after step c) at least one additional coating is applied as step d) in the form of a sustained release coating, the temperature of said solid dosage form containing at least one antibody or its functional fragment, at any time in step d) below the melting temperature (Tm) of the at least one antibody or functional fragment thereof. According to another embodiment of the present invention, characterized in that after step c) at least one additional coating is applied as step d) in the form of a sustained release coating, the temperature of said solid dosage form containing said antibody or functional fragment thereof is at at any time in step d) does not exceed 65°C, preferably does not exceed 60°C.

The amount of said antibody or functional fragment thereof in solid dosage form obtained using the method of the present invention varies depending on the pharmacological activity of said antibody or functional fragment thereof, indications for treatment, target dosage regimen, intended route of administration, integrity, stability, behavior during dissolution of the final composition and other similar circumstances. The amount of said at least one antibody or functional antibody thereof

- 34 044207 fragment is preferably at least 0.01 wt.%, more preferably at least 0.05 wt.%, even more preferably at least 0.1 wt.%, even more preferably at least 0.5 wt%, 0.7 wt% or 0.9 wt%, most preferably at least 2 wt% of the total weight of the drug-coated and dried solid dosage form after step c). The amount of said antibody or functional fragment thereof is preferably typically up to 30% by weight, more preferably up to 25% by weight, even more preferably at least 15% by weight, even more preferably up to 10% by weight, based on the total mass coated with the drug and dried solid dosage form after step c).

According to another embodiment of the present invention, the drug-coated and dried solid dosage form after step c) contains 0.01-25 wt.%, preferably 0.05-15 wt.%, more preferably 0.1-10 wt.%, even more preferably 0.5-5 wt.%, even more preferably 0.7-3 wt.%, even more preferably 0.9-2.5 wt.% of said at least one antibody or functional fragment thereof. According to another embodiment of the present invention, said drug coating contains 0.5-60 wt.% antibody or functional fragment thereof, 1-90 wt.% binder, 0.001-70 wt.% buffer and 0-20 wt.% anti-caking agent ; preferably 5-50 wt.% antibody or functional fragment thereof, 10-90 wt.% binder, 0.1-60 wt.% buffer and 0-15 wt.% anti-blocking agent; more preferably 10-50 wt.% antibody or functional fragment thereof, 20-85 wt.% binder, 0.1-60 wt.% buffer and 0.5-10 wt.% anti-blocking agent; most preferably 2050 wt.% antibody or functional fragment thereof, 30-80 wt.% binder, 1-60 wt.% buffer and 08 wt.% anti-blocking agent based on the total weight of the dried drug coating.

According to one embodiment, the thickness of the drug coating after step c) of the method of the present invention is not limited in any particular way. The thickness of the drug coating of the solid dosage form after step c) determines the amount of the specified antibody or functional fragment thereof in the solid dosage form obtained using the method proposed according to the present invention at a given concentration of the antibody or functional fragment thereof and a given composition in the liquid for coating with the active agent.

The method proposed according to the present invention guarantees the preservation of the activity and stability of the specified at least one antibody or a functional fragment thereof in the specified solid dosage form obtained in accordance with the method proposed according to the present invention. An assessment of the stability and activity of an antibody or fragment thereof can be carried out, for example, by determining the proportion of the antibody or functional fragment thereof that is in the form of dimers and other aggregates. In accordance with one embodiment of the present invention, the proportion of the total content of the antibody or functional fragment thereof present in said solid dosage form in the form of dimers and other aggregates does not exceed more than 15%, preferably does not exceed more than 12%, more preferably not exceeds more than 10%, even more preferably does not exceed more than 8%, even more preferably does not exceed more than 7%, even more preferably does not exceed more than 5%, even more preferably does not exceed more than 3% , 2% or 1.5% share in the total content of the antibody or functional fragment thereof present in the form of dimers and other aggregates at the time of addition of said antibody or functional fragment thereof to the liquid for coating with the active agent. Methods for determining the proportion of polypeptide that is in the form of dimers and other aggregates are known in the art and include, for example, size exclusion chromatography (SEC).

Evaluation of the stability and activity of an antibody or functional fragment thereof can also be carried out, for example, by determining the proportion of the antibody or functional fragment thereof found as fragments of the full-length antibody or functional fragment thereof. Accordingly, according to another embodiment of the present invention, the proportion of the total antibody or functional fragment thereof present in said solid dosage form as full-length antibody fragments or functional fragment thereof does not substantially increase from the time said antibody or functional fragment thereof is added to the coupling liquid. The term substantially as used herein refers to a deviation from the specified condition by no more than 50%, preferably no more than 20%, more preferably no more than 15%, even more preferably no more than 10%, even more preferably not more than 7%, even more preferably no more than 5, 3, 2, 1.5 or 1%.

According to an additional embodiment of the present invention, the proportion of the total content of the antibody or functional fragment thereof contained in said solid dosage form in the form of fragments of a full-length antibody or fragment thereof is no more than 15%, preferably no more than 12%, more preferably no more than by 10%, even more preferably by no more than 8%, even more preferably by no more than 7%, even more preferably by no more than 5%, even more preferably by no more than 3%, 2% or 1.5 % exceeds the proportion of the total content of the antibody or its functional fragment that is in the form of fragments of the full-length antibody or its functional fragment at the time of adding the specified antibody or its functional fragment to the liquid for coating with the active agent. Methods for determining the proportion of an antibody or functional fragment thereof present as fragments of a full-length antibody or functional fragment thereof are known in the art and include, for example, microarray electrophoretic analysis.

According to one embodiment of the present invention, said antibody or functional fragment thereof is suitable for use in topical treatment in the gastrointestinal tract of a patient. The term topical treatment in the context of the present invention is used to describe the local application of the specified solid dosage form, as opposed to the systemic application of a dosage form containing antibodies or functional fragments thereof, for example, by infusion, injection or implantation. The term gastrointestinal tract as used herein describes the organ system in the human body that includes all the structures from the mouth to the anus that form a continuous pathway and are responsible for the digestion of ingested material, the absorption of nutrients, and the excretion of excrement. The term patient as used herein refers to a living organism suffering from or susceptible to a condition that can be treated or prevented by administering said at least one antibody or functional fragment thereof. In a preferred embodiment, said patient is a human.

The pharmaceutical composition in the form of one or more solid dosage forms allows for daily single delivery of the above-described classes of antibodies and their functional fragments. Local treatment in the gastrointestinal tract, such as the ileum or colon, ensures specific targeting of the gastrointestinal wall for more effective treatment of diseases of the ileum and colon, providing a high local concentration of the antibody or its functional fragment while minimizing side effects effects resulting from drug release in the upper gastrointestinal tract or inappropriate systemic absorption.

Accordingly, according to another embodiment of the present invention, the solid dosage form obtained using the method of the present invention is intended for use in the treatment of a disease in the gastrointestinal tract, preferably in the ileum and colon. Such diseases include, for example, IBD, cancer (such as colorectal cancer or small intestine cancer), celiac disease, infections (such as Clostridium difficile infection) of the small intestine and colon, and diarrhea. According to a preferred embodiment of the present invention, the solid dosage form obtained using the method of the present invention is intended for use in the treatment of IBD, for example, Crohn's disease or ulcerative colitis.

According to one embodiment of the present invention, the solid dosage form obtained using the method according to the present invention is intended for oral administration. Oral administration in the context of the present invention means the administration of said solid dosage form to the gastrointestinal tract through the mouth.

In accordance with one embodiment of the present invention, at least one additional coating in the form of a delayed release coating is applied to the solid dosage form after drying in step c) or after step d) in the case of application of at least one additional coating in the form of a sustained release coating. release as step d). A delayed release coating according to the present invention means a coating that prevents the release of the specified antibody or functional fragment thereof from a solid dosage form until a specific event occurs, for example, in the form of a chemical or enzymatic trigger, or until a certain period of time has elapsed after immersion in solution.

In a preferred embodiment, the solid dosage form prepared using the method of the present invention is for oral administration in the form of a pellet, microcarrier, sphere, mini-spheres, tablet, mini-tablet or granule coated with a delayed release coating that prevents release of the composition before entering the ileum, preferably before entering the terminal ileum, more preferably before entering the small intestinal region, optionally before entering the ascending colon, before entering the transverse colon, or before entering the descending colon of the gastrointestinal tract. The small intestinal region is the region of the gastrointestinal tract where the small intestine connects to the large intestine. The large intestine is the pre-terminal portion of the gastrointestinal tract and can be further subdivided into the cecum, colon, and rectum. The colon is further divided into ascending colon, transverse colon, and descending colon. The terminal ileum is the pre-terminal portion of the small intestine immediately adjacent to the cecum.

- 36 044207

The method of coating for delayed release is not limited in any particular way, provided that it does not affect the stability and activity of the at least one antibody or functional fragment thereof in the drug coating. Delayed release coating methods are known in the art. According to one embodiment of the present invention, said delayed release coating is applied by spraying, preferably by fluidized bed spraying.

Coating materials for delayed release of a solid dosage form, particularly for targeted release in the ileum or colon upon oral administration, are known in the art. They can be divided into coating materials that degrade at pH values above a specific pH value, coating materials that degrade after a specific retention time in the gastrointestinal tract, and coating materials that degrade due to enzymatic triggers specific to the microflora of a specific intestinal region. . Coating materials from these three different categories for targeting the colon have been described, for example, in Bansal et al. (Polim. Med. 2014, 44, 2, 109-118). Applications of such coating materials have also been described, for example, in WO2007/122374A2, WO0176562A1, WO03068196A1 and GB2367002A. According to one embodiment of the present invention, the delayed release coating contains at least one component selected from coating materials that degrade in a pH-dependent manner, coating materials that degrade in a time-dependent manner, coating materials that degrade due to enzymatic triggers in the environment intestines (preferably in the ileum and colon); and combinations of the above.

Preferred coating materials among coating materials that degrade in a pH-dependent manner are selected from polyvinyl acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate HP-50, HP-55 or HP-55S, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate (HPMC-AC), poly (methacrylic acid, ethyl acrylate) 1:1 (Eudragit® L100-55, Eudragit® L30D-55), poly(methacrylic acid, methyl methacrylate) 1:1 (Eudragit® L-100, Eudragit® L12.5), poly(methacrylic acid acid, methyl methacrylate) 1:2 (Eudragit® S-100, Eudragit® S12.5, Eudragit® FS30D); and combinations of the above. Preferred coating materials among coating materials that degrade in a time-dependent manner are selected from Eudragit® RL, Eudragit® RS, ethylcellulose, and combinations thereof.

Preferred Coating Materials Preferred coating materials for coatings that break down due to enzymatic triggers in the colonic environment are selected from chondroitin sulfate, pectin, guar gum, chitosan, inulin, lactulose, raffinose, stachyose, alginate, dextran, xanthan gum, locust bean gum wood, arabinogalactan, cyclodextrin, pullulan, carrageenan, scleroglucan, chitin, curdulan, levan, amylopectin, starch, amylose, resistant starch, azo compounds degraded by azo-degrading bacteria, and combinations of the above. Said delayed release coating optionally contains at least one additional excipient, such as those listed in the description of one of the embodiments above.

According to one embodiment of the present invention, the delayed release coating material contains one, two, three components, etc., selected from pH-dependent coating materials, time-dependent coating materials, and coating materials broken down by enzymatic triggers in the intestinal environment listed above; and combinations of the above. According to another embodiment of the present invention, a delayed release coating comprises a combination of at least one coating material that degrades in a pH-dependent manner and at least one coating material that degrades due to enzymatic triggers in the colon environment.

For example, a delayed release coating may be designed such that delivery of the antibody or functional fragment thereof is entirely concentrated in the large intestine, starting with the cecum, continuing in the ascending, transverse and descending colon, and ending in the sigmoid colon. Alternatively, for example, a delayed release coating may be designed such that delivery of said antibody or functional fragment thereof begins in the jejunum and ends in the transverse colon. There are numerous possibilities and combinations.

According to one embodiment of the present invention, the delayed release coating comprises a combination of at least one pH-sensitive (enteric) polymer, for example, 1:2 poly(methacrylic acid, methyl methacrylate), and at least one polysaccharide selected from chondroitin sulfate, cyclodextrin, chitosan, dextran, arabinogalactan, amylose, pullulan, carrageenan, scleroglucan, chitin, curdulan, levan, amylopectin, starch, resistant starch; and combinations of the above, for example, resistant starch. Co

- 37 044207 According to a preferred embodiment of the present invention, the delayed release coating is a combination of poly(methacrylic acid, methyl methacrylate) 1:2 (Eudragit® S) and resistant starch (eg Phloral® technology). Said delayed release coating comprising at least one component, for example a combination of at least one enteric polymer, for example poly(methacrylic acid, methyl methacrylate) 1:2, and at least one polysaccharide, for example resistant starch, may be dispersed in an organic solvent, a mixture of organic solvents, or a mixture of at least one organic solvent and water, and then applied to a solid dosage form, for example, by fluidized bed spraying.

In another embodiment, said delayed release coating comprises i) an inner coating comprising a partially neutralized pH-sensitive (enteric) polymer with a pH adjusted to 8 (e.g., neutralized 1:2 poly(methacrylic acid, methyl methacrylate) with a pH brought to 8) and buffer salt; and ii) an outer coating comprising a combination of at least one enteric polymer (preferably poly(methacrylic acid, methyl methacrylate) 1:2) and at least one polysaccharide selected from chondroitin sulfate, cyclodextrin, chitosan, dextran, arabinogalactan, amylose, pullulan , carrageenan, scleroglucan, chitin, curdulan, levan, amylopectin, starch, resistant starch; and combinations thereof, preferably resistant starch (eg, OPTICORE™). A description of another preferred embodiment of a delayed release coating can be found in the embodiments disclosed in WO2007122374A2. In accordance with a further aspect of the present invention, in an additional step, a sachet/stick pouch, spheroid/sphere, tablet, drinking straw device (i.e., X-Straw®) or capsule (e.g., hard or soft gelatin capsule) is prepared. a multiparticulate drug delivery system) containing multiple solid dosage units obtained using the method of the present invention, in accordance with one of the embodiments described above. Methods for preparing sachet/stick packets, tablets or capsules containing multiple units of solid dosage form are known in the art. The sachet/stick, drinking straw device (Xstraw®), spheroid/sphere, tablet or capsule may contain a total amount of the at least one antibody or functional fragment thereof suitable for oral administration to a human patient. In another embodiment, the sachet/stick pouch, drinking straw device (Xstraw®), tablet, or capsule contains a therapeutically effective dose of said at least one antibody or functional fragment thereof suitable for oral administration to a human patient.

According to an alternative embodiment of the present invention, several units of a solid dosage form obtained by performing steps a) - c), or, alternatively, by performing steps a) - d) of the method proposed according to the present invention in accordance with the description of one of the proposed according to the present invention embodiments above may be combined in a multiparticulate drug delivery system, such as a tablet, spheroid/sphere, or capsule. Methods for preparing such multi-unit tablets or capsules are known in the art. The thus obtained multiparticulate drug delivery system (e.g., tablet, spheroid/sphere or capsule) can then be coated for delayed release as described above.

In addition to the method for preparing a solid dosage form from the description of the embodiments above, the present invention also relates to solid dosage forms that can be obtained using the method according to the present invention according to any of the embodiments described above. The solid dosage forms provided by the present invention may be in the form of pellets, microcarriers, spheres, mini-spheres, granules, tablets or mini-tablets. The present invention also relates to a multiparticulate drug delivery system in the form of a sachet/stick, drinking straw (XStraw®), capsule, spheroid/sphere or tablet/mini-tablet containing multiple solid dosage forms derived from using the method proposed according to the present invention, described above. In addition, the present invention relates to these solid dosage forms and multiparticulate drug delivery systems for use in the treatment of gastrointestinal disease, for example, IBD, colorectal cancer, small intestinal cancer, celiac disease or gastrointestinal tract infections (eg, Clostridium difficile infection), preferably IBD, such as Crohn's disease or ulcerative colitis. The present invention also relates to solid dosage forms and multiparticulate drug delivery systems prepared using the inventive method described above for use in topical treatment in the gastrointestinal tract of a patient. Finally, the present invention relates to said solid dosage forms and multiparticulate drug delivery systems according to the present invention for use in the treatment of a patient suffering from a gastrointestinal disease, preferably IBD, colorectal cancer, small intestinal cancer or infections of the gastrointestinal tract, more preferably IBD.

According to a further aspect, the present invention relates to a multiparticulate drug delivery system comprising a plurality of solid dosage units (i.e., solid dosage units, e.g., spheroids/spheres), each of which contains i) an inert core, and ii) a drug coating comprising at least one antibody or functional fragment thereof, a buffer and at least one polymeric binder, and optionally an anti-caking agent and/or surfactant; and preferably, each solid dosage unit has a predetermined axis and the same predetermined cross-sectional profile, wherein at least 80% of said solid dosage units, preferably 90%, more preferably 95%, have a median aspect ratio from 0.7 to 1.7, where the aspect ratio is defined as the result of dividing the length of a unit of solid dosage form along a predetermined axis by the smallest transverse dimension.

In accordance with one embodiment of the multiparticulate drug delivery system of the present invention, the median aspect ratio is greater than 0.8, preferably greater than 0.9, and less than 1.6, preferably less than 1.5, more preferably 1.4, even more preferably less than 1.3, even more preferably less than 1.2, most preferably about 1. According to another embodiment of the multiparticulate drug delivery system of the present invention, the solid dosage unit aspect ratio range is less than 0. 9, preferably less than 0.8, more preferably less than 0.7, even more preferably less than 0.6, most preferably less than 0.5. Additional more detailed information regarding the relationship of geometric dimensions, predetermined axis, predetermined profile and cross-sectional span (including definitions and implementation options) is disclosed in EP2512453. It should be understood that the above definitions and embodiments with respect to the ratio and range of geometric dimensions of the specified units of solid dosage form are equally applicable to the solid dosage forms proposed according to the present invention in accordance with any of the embodiments described above, as well as to solid dosage forms obtained using any of the embodiments of the proposed method according to the present invention described above.

In accordance with a further embodiment of the present invention, the multiparticulate drug delivery system of the present invention provides a recovery of at least 80%, preferably at least 85%, more preferably at least 93%, even more preferably at least 95%, even more preferably at least 97%, even more preferably at least 98% of the at least one antibody or functional fragment thereof from the solid dosage form units.

In accordance with yet another embodiment of the present invention, the multiparticulate drug delivery system of the present invention provides a recovery of at least 80%, preferably at least 85%, more preferably at least 93%, even more preferably at least 95% , even more preferably at least 97%, even more preferably at least 98% of said at least one antibody or functional fragment thereof from solid dosage form units, with immediate release, within 30 minutes, or 1 hour, or 2 hours , or 4 hours of continuous immersion of the specified solid dosage form in an aqueous solution with continuous shaking.

In accordance with yet another embodiment of the present invention, the solid dosage units of a multiparticulate drug delivery system are sustained release solid dosage units. In accordance with yet another embodiment of the present invention, the multiparticulate drug delivery system of the present invention provides a recovery of at least 80%, preferably at least 85%, more preferably at least 93%, even more preferably at least 95% , even more preferably at least 97%, even more preferably at least 98% of said at least one antibody or functional fragment thereof from solid dosage form units, in a sustained release within 4 hours, or 6 hours, or 8 hours , or 10 hours, or 12 hours, or 14 hours, or 16 hours, or 18 hours, or 20 hours, or 22 hours, or 24 hours, or 26 hours, or 28 hours, or 30 hours, or 32 hours, or 34 hours, or 36 hours, etc. continuous immersion of the specified solid dosage form in an aqueous solution with continuous shaking.

In one embodiment of a multiparticulate drug delivery system, the solid dosage form units comprise an antibody or functional fragment thereof, a buffer, and at least one drug-coated polymer binder that

- 39 044207 is applied to the inert core by spraying. In accordance with a specific embodiment of the present invention, the solid dosage units of a multiparticulate drug delivery system are solid dosage forms prepared by layering a drug substance in accordance with a method as described in any of the embodiments above.

According to a further embodiment of the present invention, the multiparticulate drug delivery system or individual solid dosage units comprise a delayed release coating which is applied as an additional coating. Additional embodiments of multiparticulate drug delivery systems are described in EP2512453 and are applicable to the present invention regardless of whether such embodiments are disclosed in EP2512453 in relation to spheronized/non-spheronized solid dosage units. In another aspect, the present invention provides a solid dosage form that consists of a dosage unit corresponding to one of the dosage units in a multiparticulate drug delivery system as defined in the description of any of the embodiments above.

Examples

Materials and methods used in the examples.

Table 1 Variation of instrumental parameters for process optimization when using Caleva Minicoater

Instrument parameters Range Diameter of silicone tubes (mm) 0.8 and 1.6 Feed speed (rpm) 2-4 Inlet temperature (°C) 40-55 Fan speed(m/s) 12-15 Container vibration frequency(Hz) 10-14 Atomization pressure (kPa) 20-25 Nozzle position (depth), cm 10-15

Preparation of citrate TRIS buffer with pH 7.

A citrate TRIS buffer with pH 2.0 was prepared by adjusting the pH of 200 ml of 0.1 M citric acid solution to 3.5 by adding the required amount of 0.1 M sodium citrate solution. The pH of the final citrate buffer was then adjusted to 7.0 by adding the required amount of 1 M TRIS solution.

Layering.

Layering onto pellets (Cellets®/Suglets®) was performed using a fluid bed coater (Minicoater). 10-20 g of microcrystalline cellulose pellets (Cellets®) or sucrose pellets (Suglets®) were placed in a container and preheated by shaking at 10 Hz at 45°C and a fan speed of 12 m/s for 10 min. The nozzle was placed at a certain height above the pellet layer. Then the fan, shaker and heater were turned on and atomization was started, including the pump and air supply for atomization. In table Table 1 shows varying instrumental parameters to optimize layering.

Microarray electrophoretic analysis.

Microarray (Labchip) electrophoretic analysis was performed using standard conditions and settings. Briefly, supernatant (2 μl) from adalimumab-containing samples was tested for the presence of fragments by microarray gel electrophoresis under non-reducing conditions. All experiments used a positive control for adalimumab at a concentration of 1 mg/ml in citrate TRIS buffer pH 7. Samples were diluted to obtain an adalimumab concentration of 1 mg/ml.

Size exclusion chromatography (SEC).

High performance liquid chromatography (HPLC)-EC was performed using standard conditions and settings. Briefly, supernatant from samples containing adalimumab was tested for the presence of aggregates (dimers, oligomers) using SEC. A positive control for adalimumab at a concentration of 1 mg/ml in TRIS citrate buffer pH 7 was used in all experiments.

-40044207

Effect of process parameters on adalimumab stability.

The effect of process parameters on adalimumab was assessed by treating a 2.5 wt% HPMC solution containing 0.25 wt% Syloid® 244FP and 5 mg/ml adalimumab. 500 μl samples of the coating suspension were taken at various intermediate stages of processing. The formation of dimers and other aggregates, fragments, and total protein content was measured using SEC, microarray gel electrophoresis, and the Bradford method, respectively. A solution of adalimumab at a concentration of 1 mg/ml in citrate TRIS buffer with pH 7 was used as a positive control (standard).

Determination of relative humidity.

The amount of moisture (water) contained in the inert cores and microcrystalline cellulose/sucrose multilayer pellets and coated pellets was measured gravimetrically based on loss on drying (LOD) at 105°C for 1 h.

Calculation of adalimumab load.

The theoretical loading of adalimumab was calculated based on the amount of solid material of the layers and the known concentration of adalimumab in the nebulization suspension. Accordingly, the pellets were weighed before and after layering and drying. The exact amount of moisture in the original inert cores, adalimumab layered pellets, and coated sustained release pellets must be taken into account.

Pellet coating with adalimumab layering Eudragit® RS 30D.

The adalimumab layered pellet (HPMC based formulation) was further coated with an aqueous redispersion of Eudragit® RS 30D. When preparing Eudragit® RS 30D, standard recommendations from Evonik were followed. Eudragit® RS 30D 10% solids coating suspensions were prepared from a commercial 30% solids dispersion.

Triethyl citrate (TEC) was used as the plasticizer and Syloid® 244 FP as the anti-blocking agent unless otherwise noted. The coating suspension was prepared in excess to account for spray losses due to the small batch size. Adalimumab layered pellets were coated until the target increase in polymer weight was achieved (5-25%). Then the coated pellets were cured for up to 24 hours at 40°C in a drying cabinet (oven) with air circulation. Selected formulations used propylene glycol monolaurate (Lauroglycol™ 90) as a coalescence enhancer.

Pellet coating with adalimumab layering Aquacoat® ECD.

The adalimumab layered pellets (HPMC based formulation) were further coated with an aqueous redispersion of ethylcellulose (Aquacoat® ECD). Aquacoat® ECD formulations do not require the presence of an anti-caking agent. Triethyl citrate (TEC) and dibutyl sebacate (DBS) were used as plasticizer (20-25% based on polymer solids content). In addition, the selected formulations also contained a coalescence enhancer (Lauroglycol™ 90). Adalimumab layered pellets were coated until the target increase in polymer weight was achieved (5-20%). The coating suspension was prepared in excess to account for spray losses due to the small batch size. Then the coated pellets were cured for up to 24 hours at 60°C in a drying cabinet (oven) with air circulation, taking intermediate samples.

Release of adalimumab.

Dissolution of coated pellets (Cellets®/Suglets®) was performed by shaking the coated pellets in citrate TRIS buffer pH 7. The number of coated pellets by weight per tube was calculated to give a theoretical adalimumab concentration of 1 or 1 .5 mg/ml in buffer taking into account the theoretical load of adalimumab. At specified time points, 200 μl of the supernatant was added by pipetting into an Eppendorf tube and diluted, if necessary, with citrate TRIS buffer pH 7. The samples were then centrifuged for 5 min at RCC 3000 and the supernatant was used for further analysis.

Determination of total protein.

Total protein quantification was performed by colorimetry after applying the Bradford method in a Coomassie assay (Coomassie Plus, Thermo Scientific). Briefly, 6.6 μL of sample was pipetted to the bottom of a disposable cuvette, 200 μL of Coomassie Plus reagent was added, and mixed by shaking for 30 seconds at 500 rpm. The samples were then incubated at room temperature for 10 minutes, after which the absorbance was recorded at 595 nm using a spectrophotometer and the blanks were subtracted. Quantification was performed using a freshly prepared standard curve.

ELISA assay.

The binding of adalimumab to TNF-α was assessed by ELISA. Briefly, plate wells were coated with human TNF-α (0.5 mg/ml) in PBS using 100 μl/well for 1 h at room temperature. Adalimumab binding was assessed using the donkey anti-human IgG (H+L)HRP AffiniPure antibody at a concentration of 0.05 μg/ml using tetramethylbenzidine (TMB) as a substrate. Samples were centrifuged and diluted with 1% BSA in PBS to the target ada concentration

- 41 044207 limumab 10 ng/ml.

Results.

table 2

General description of the composition of coated pellets

Compound Inert nuclei Release profile Example 1 Microcrystalline cellulose pellets Immediate release Example 2 Sucrose pellets Immediate release Example 3 Microcrystalline cellulose pellets Immediate release Example 4 Microcrystalline cellulose pellets Immediate release Example 5 Microcrystalline cellulose pellets Immediate release Comparative example 1 Sucrose pellets Immediate release Example 6 Sucrose pellets Extended release Example 7 Sucrose pellets Extended release Example 8 Sucrose pellets Extended release Example 9 Sucrose pellets Extended release Example 10 Sucrose pellets Extended release Example 11 Sucrose pellets Extended release Example 12 Sucrose pellets Extended release Example 13 Sucrose pellets Extended release Example 14 Sucrose pellets Immediate release Example 15 Sucrose pellets Immediate release Example 16 Sucrose pellets Immediate release Example 17 Sucrose pellets Immediate release

Experiment 1: Immediate Release Coating of Pellets Effect of Process Parameters on Adalimumab Stability.

The effect of several process variables on adalimumab in a HPMC-Syloid® 244 FP suspension containing 5 mg/ml adalimumab was assessed in terms of total protein content, aggregation and fragmentation (Fig. 1A-C). Complete recovery of adalimumab from the nebulization liquid after each treatment step indicates that it is not adsorbed to the surfaces through which the suspension is passed. Due to the rapid evaporation of droplets after atomization (volume reduction), an apparent higher recovery rate of adalimumab was observed, exceeding 100%. There was no significant increase in dimer content (Figure 1B) compared to the positive control (1.0 mg/mL standard) for samples collected during the process. Likewise, there was no significant increase in adalimumab fragment levels compared to the positive control (Fig. 1C).

Layering of adalimumab onto inert cores (pellets).

Pellet layering was performed using optimized process parameters determined from preliminary placebo trials.

Release of adalimumab from layered microcrystalline HPMC (Cellets®) and sucrose (Suglets®) pellets.

In fig. Figure 2 shows the release of adalimumab from HPMC layered pellets in pH 7 citrate TRIS buffer. Adalimumab released into pH 7 citrate TRIS buffer upon dissolution over time was quantified by total protein determination. Complete release of adalimumab was achieved very quickly in both cases. As expected, for the release of the layered antibody, it does not matter which inert core is used for the layering process. Likewise, this inert core had no effect on the dimer/monomer content and fragmentation profile of adalimumab after preparation and recovery from dissolved samples (data not shown).

In fig. 3A shows the relative content of dimers and monomers of adalimumab released

- 42 044207 from pellets with layering of HPMC in citrate TRIS buffer with pH 7 over time. There was no significant increase in dimer content compared to the adalimumab standard (positive control) upon dissolution, regardless of adalimumab loading and initial concentration, as seen in Examples 3, 4 and 5, where the initial concentration of adalimumab in the layering suspension was varied from 5 to 14. 2 mg/ml, and adalimumab pellet loading varied from 0.9 to 2.7 wt%. In fig. 3B shows the relative fragmentation profile of adalimumab released in citrate TRIS buffer pH 7 over time. No significant fragmentation was observed compared to the positive control. The performance of adalimumab in terms of acid and base formation (no significant differences in protein surface charge) was also maintained (data not shown). Similar results for aggregation, fragmentation, acidic and basic species formation upon release from the layered pellets were observed for the methylcellulose layered pellets (data not shown).

Experiment 2: Immediate release coating using high concentration of adalimumab in coating suspension.

The concentration of adalimumab in the initial coating suspension was increased from 14.2 mg/ml to 25 mg/ml or 50 mg/ml, which could potentially shorten the process time and reduce production costs (see Fig. 4A). All of the resulting coated pellets (Examples 14, 15, 16, and 17) exhibited a rapid release profile in pH 7 citrate TRIS buffer, with complete release within 30 min (Figure 4B). Accordingly, there is no effect of the concentration of adalimumab in the coating suspension on the release profile. Increasing the antibody concentration to 50 mg/ml (example 14) in the original suspension did not lead to an increase in the level of aggregates by more than 1.5% and an increase in the level of fragments by more than 3% compared to the standard adalimumab 1.0 mg/ml (Fig. .4C).

Experiment 3. Polymer binder for sustained release in drug coating.

A sustained release polymer binder was tested for inclusion in a drug coating. Polymer binders tested included Eudragit® NM 30D, Surelease® (aqueous dispersion of ethylcellulose) and Eudragit® RS 30D. Compatibility studies consistent with those performed for HPMC and MC in Example 1 did not detect a significant increase in adalimumab aggregation and fragmentation (data not shown). The pellets were layered with a coating suspension containing at least one sustained release polymer binder using optimized layering parameters. The ratio of sustained release polymer vehicle concentration to adalimumab concentration varied. It has been found that by changing the ratio of polymer binder to antibody, the release of the antibody from the drug coating can be modified.

Experiment 4: Sustained release coating of adalimumab from immediate release coated pellets.

Starting material for sustained release coating.

In the first step, adalimumab was layered onto pellets (Suglets®) using a HPMC-based formulation containing 10% Syloid® 244 FP (based on solid polymer binders) as described above. The adalimumab layered pellets were then used to test Eudragit® RS 30D or Aquacoat® ECD as sustained release polymers.

Eudragit® RS SOD coated pellets.

In fig. 5A provides a general description of batches produced with Eudragit® RS 30D as a sustained release polymer. Increasing the amount of Eudragit® RS 30D coating applied (from 6.89 wt.% to 23.14 wt.%) significantly reduced the release rate of adalimumab from coated pellets (Fig. 5B) in citrate TRIS buffer pH 7. Minimum amount coating (Example 6) was sufficient to continue release of adalimumab for 8 hours. Increasing the coating amount to 23.14 wt.% (Example 8) resulted in sustained release over 24 hours (Fig. 5B). The composition itself, as well as the processing conditions and duration, including the drying step for 24 hours at 40°C, did not affect the stability of adalimumab after release from the coated pellets as described for examples 8a-c (in triplicate). There were no significant differences observed in the aggregation profile and fragmentation profile of adalimumab compared to the adalimumab standard solution (Figure 5C).

Dibutyl sebacate (DBS) and triethyl citrate (TEC) as plasticizers in ethylcellulose coated (Aquacoat ECD) pellets.

DBS (hydrophobic plasticizer) was used at the same concentration as TEC (25 wt.%, based on polymer solids content), in both cases the coating was applied until approximately 17% increase in polymer weight was achieved (Fig. 6A). Replacing TEC (Example 9) as a plasticizer with DBS (Example 10) had a significant effect on the release of adalimumab from the coated pellets, resulting in a significantly slower release of adalimumab

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Claims (15)

when applying approximately the same amount of polymer to the pellets (Fig. 6B). This means that the target drug release profile (i.e. drug release within 24 hours) can be achieved using less sustained release polymer, making the process shorter and cheaper. In the case of both CHP and DBS, curing time plays a role in film formation, as pellets cured (dried) for 24 h exhibited slightly slower drug release compared to pellets cured (dried) for 2 h. Regardless plasticizer used, there was no significant increase in levels in adalimumab aggregate and fragment profiles from dissolved samples compared to adalimumab standard (Figure 6C). This indicates that neither the composition nor the process (including the curing step at 60°C for 24 hours) has a negative impact on the stability of the antibody according to these embodiments. Experiment 5: Sustained release coating of immediate release adalimumab pellets with coalescence enhancer. Eudragit® RS 30D coating of the pellets was repeated with adalimumab layered and Laurogylcol 90 coalescence enhancer was added (see Figures 7A-B). As shown in FIG. 7B, the addition of Laurogylcol 90 coalescence enhancer (Example 12) (pellets cured for 1, 2 or 24 hours) measurably improved the sustained release profile compared to the coating without coalescence enhancer (Example 6, Fig. 7B) for pellets cured for 24 hours. The addition of Laurogylcol 90 to the Eudragit® RS 30D coating formulation consequently improved film formation and significantly reduced the amount of coating required to achieve the target release profile. A similar effect was observed when using an aqueous ethylcellulose dispersion (Aquacoat ECD) as a sustained release polymer in combination with Laurogylcol 90 (Figure 8A) compared to the Aquacoat® ECD sustained release coating without Laurogylcol 90 (Figure 6B). The addition of Laurogylcol 90 to the formulation (10 wt.%, based on polymer solids) clearly improved film formation, as demonstrated by the lack of significant differences in the drug release profiles obtained for pellets cured for different periods of time (from 1 to 24 hours ). Neither the addition of Lauroglycol™ 90 to ethylcellulose nor the processing conditions, including the curing step (drying) for up to 24 hours at 60°C in an oven, resulted in a significant increase in the level of aggregates or fragments formed in samples collected after dissolution in citrate TRIS -buffer with pH 7 (Fig. 8B). ELISA assay for binding of adalimumab to TNF-α after release from pellets. An ELISA assay was used to assess the binding of adalimumab released from the coated pellets to TNF-α in citrate TRIS buffer pH 7 (Fig. 9A-B). ELISA analysis of adalimumab dissolution release in Example 8 (Eudragit® RS 30D coated pellets) in FIG. 9A and in example 13 (increase in the mass of pellets coated with Aquacoat® ECD polymer 21.67%) in FIG. 9B showed that the integrity of adalimumab is preserved and adalimumab is able to bind to TNF-α. For comparison, in Fig. 9A-B show the results of total protein quantitation (B) and ELISA (E). CLAIM 1. A method for producing a solid dosage form containing i) an inert core and ii) a drug coating containing at least one antibody or a functional fragment thereof as an active agent, a buffer and at least one polymer binder deposited on the inert core by layering the drug facilities; this method includes the following stages: a) providing an active agent coating liquid containing at least one antibody or functional fragment thereof, a buffer and at least one polymeric binder, in the form of an aqueous solution or suspension; b) coating the inert core with liquid to coat the active agent by spraying; c) drying the wet inert drug-coated core while performing step b) or upon completion of step b) to obtain a dried solid dosage form; and after stage c) d) applying at least one additional coating in the form of a sustained release coating by spray coating the solid dosage form of step c with a liquid sustained release coating, and then drying said wet layered solid dosage form using a fluidized bed. or ovens; and after stage d) e) applying at least one additional coating in the form of a delayed release coating, wherein said solid dosage form is intended for oral administration. 2. The method according to claim 1, characterized in that said liquid for coating with an active agent co- - 44 044207 contains 0.01-50 mg/ml of said at least one antibody or functional fragment thereof. 3. Method according to any of the preceding claims, characterized in that the liquid for coating with the active agent contains: i) 0.5-5 wt.% antibody or functional fragment thereof; ii) 1-20 wt.% polymer binder; and iii) 0-2 wt.% anti-caking agent. 4. Method according to any of the preceding claims, characterized in that in fluidized bed spray coating, the air pressure for atomization in the spray nozzle is below 200 kPa, preferably between 10 and 100 kPa. 5. The method according to any of the preceding claims, characterized in that at any time during steps a) and c) the temperature of the at least one antibody or functional fragment thereof is below the melting temperature (Tm) of the at least one antibody or functional fragment thereof . 6. The method according to any of the preceding claims, characterized in that said polymeric binder in the drug coating is selected from hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), hydroxypropylcellulose (HPC), macrogol-poly(vinyl alcohol) graft copolymer, polyvinylpyrrolidone (PVP) and combinations of the above. 7. Method according to any of the preceding claims, characterized in that said drug coating is suitable for immediate release of the active agent, and in that the wet inert core coated with the drug is dried while simultaneously carrying out step b) the air flow at the entrance to the fluidized bed , while the inlet air has a temperature of up to 60°C. 8. Method according to any one of claims 1 to 5, characterized in that said drug-coated polymer binder contains at least one sustained release polymer binder, and in that said drug-coated wet inert core is dried upon completion of the step b) at a temperature not exceeding 65°C, preferably up to 60°C. 9. The method according to claim 8, characterized in that said at least one sustained release polymeric binder (S) and said at least one antibody or functional fragment thereof (A) are present in the active agent coating liquid in the ratio S/ A (by mass), amounting to 0.5 to 100. 10. The method according to any of the preceding claims, characterized in that said sustained release coating liquid contains 5-20% by weight of a sustained release polymer based on the total weight of the sustained release coating liquid, and in that the weight of the polymer in the specified solid dosage form after stage d) increases by 2.5-25 wt.% compared to the solid dosage form before stage d). 11. The method according to any of the preceding claims, characterized in that said at least one sustained release polymer binder and/or said sustained release polymer is selected from the group consisting of poly(ethyl acrylate, methyl methacrylate) 2:1; poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1; poly(ethyl acrylate, methyl methacrylate) 2:1; poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2; ethylcellulose; polyvinyl acetate; and combinations of the above. 12. The method according to any of the preceding claims, characterized in that the active agent coating liquid and/or the sustained release coating liquid further comprises an anti-blocking agent, a surfactant, a filler, a plasticizer and/or a coalescent agent . 13. The method according to claim 12, characterized in that said active agent coating liquid and/or sustained release coating liquid contains 5-50 wt.% anti-blocking agent, 10-30 wt.% plasticizer and /or 2-15 wt.% coalescence enhancer based on the total weight of solid polymeric binders in the active agent coating liquid and/or solid polymeric substances in the sustained release coating liquid, and/or 0.01-2 wt.% surface- active agent based on the total weight of the active agent coating liquid and/or sustained release coating liquid. 14. The method according to any of the preceding claims, characterized in that said at least one antibody or functional fragment thereof is selected from antibodies specific to tumor necrosis factor alpha (TNF-α) and functional fragments thereof, antibodies specific to integrin α4β7, and their functional fragments, antibodies specific to CD3, CD4 or CD20, and their functional fragments, antibodies specific to interleukin 6 (IL-6), interleukin 12 (IL-12), interleukin 13 (IL-13 ), interleukin 23 (IL-23) or their receptors, and functional fragments thereof, antibodies specific to CXCL10/IP-10 and functional fragments thereof, and antibodies specific to the p40 protein subunit and functional fragments thereof. 15. The method according to any of the preceding paragraphs, characterized in that said coating -