CONTROLLED DRUG RELEASE FORMULATION

Abstract

Pharmaceutical formulation dosage form (1) with a core (2) encapsulated by at least one shell (3) and comprising at least one active pharmaceutical ingredient (4), wherein the at least one active pharmaceutical ingredient (4) is embedded in said core (2) of the pharmaceutical formulation dosage form (1), preferably in that said core (2) is formed by a matrix based on xyloglucan (5) containing said active pharmaceutical ingredient (4), and wherein said shell (3) is a pH-responsive coating.

Claims

1. A pharmaceutical formulation dosage form with a core encapsulated by at least one shell and comprising at least one active pharmaceutical ingredient, wherein the at least one active pharmaceutical ingredient is embedded in said core or forming said core of the pharmaceutical formulation dosage form, wherein said shell comprises a pH-responsive coating, and wherein at least one of said core and said shell is based on xyloglucan.

2. The pharmaceutical formulation dosage form according to claim 1, wherein the at least one active pharmaceutical ingredient is embedded in said core of the pharmaceutical formulation dosage form in that said core is formed by a matrix based on xyloglucan containing said active pharmaceutical ingredient.

3. The pharmaceutical formulation dosage form according to claim 1, wherein said shell comprises at least one outer layer in the form of a pH responsive coating, based on xyloglucan or free from xyloglucan, as well as at least one inner layer based on xyloglucan if the outer layer is free from xyloglucan.

4. The pharmaceutical formulation dosage form according to claim 1, wherein it is adapted for oral administration and for targeted release of the active pharmaceutical ingredient in the colon, and wherein said shell comprises at least one or consists of at least one pH-responsive coating dissolving only at a pH of more than 6.5.

5. The pharmaceutical formulation dosage form according to claim 1, wherein said shell is based on a synthetic polymer and/or a biopolymer or a mixture thereof.

6. The pharmaceutical formulation dosage form according to claim 1, wherein said shell consists of a mixture of an anionic acrylate copolymer with further additives in a proportion of less than 25%.

7. The pharmaceutical formulation dosage form according to claim 1, wherein the dry coating amount of the at least one pH responsive coating or of the whole shell (3) is in the range of 1-10 mg/cm2.

8. The pharmaceutical formulation dosage form according to claim 1, wherein there is provided only one single encapsulating pH responsive coating forming said shell.

9. The pharmaceutical formulation dosage form according to claim 1, wherein said matrix of the core essentially or completely consists of xyloglucan.

10. The pharmaceutical formulation dosage form according to claim 1, wherein the core consists of: (A) 25-90% by weight of xyloglucan; (B) 10-60% by weight of at least one active pharmaceutical ingredient; and (C) 0-20% by weight of one or more pharmaceutically acceptable excipients; or wherein the core consists of granules consisting of: (A) 25-90% by weight of xyloglucan; (B) 10-60% by weight of at least one active pharmaceutical ingredient; and (C) 0-20% by weight of one or more pharmaceutically acceptable excipients, which granules are compacted to form a core before applying the shell.

11. The pharmaceutical formulation dosage form according to claim 1, wherein the weight ratio of the matrix of the core to the at least one active pharmaceutical ingredient is at least 1:2.

12. The pharmaceutical formulation dosage form according to claim 1 for the purpose of establishing, re-establishing and/or modifying the balance of the microbiome population in the colon or the physiology of the lower gastrointestinal tract, or for immunomodulation or immunosuppression or for the treatment of at least one of the following conditions: inflammatory bowel disease, in particular ulcerative colitis and/or Crohn's disease, Clostridium difficile infection, colon cancer, post colon surgical treatment.

13. The pharmaceutical formulation dosage form according to claim 1, wherein the active pharmaceutical ingredient is one or more selected from the group consisting of: mesalazine, budesonide, capecitabine, fluorouracil, irinotecan, oxaliplatin, UFT, cetuximab, panitumumab, immunomodulatory ingredients, immunosuppressive ingredients, immunosuppressive glucocorticoids, immunosuppressive cytostatics, immunosuppressive (poly- or monoclonal) antibodies, immunosuppressive drugs acting on immunophilins, interleukins, cytokines, chemokines, immunomodulatory imide drug, tacrolimus cyclosporin, materials for the purpose of establishing, reestablishing and/or modifying the balance of the microbiome population in the colon, and compounds which have a beneficial effect on the physiology of the lower gastrointestinal tract.

14. A method of treatment, comprising: administering the pharmaceutical formulation dosage form according to claim 1 to a patient in need thereof orally at least once a day, or twice a day, over a time span of at least one week, or at least two weeks, or at least two months or at least 1 year or even life-long.

15. A method for making a pharmaceutical formulation dosage form according to claim 1, wherein in a first step xyloglucan, at least one active pharmaceutical ingredient, as well as if needed one or more pharmaceutically acceptable excipients are mixed and then compacted to form the core or mixed and treated to form granules, with an average diameter in the direction of the smallest diameter of at least 3 mm, which are subsequently, if needed by first mixing the granules with a further treatment agent, compacted to form the core, and wherein the core is subsequently coated in a second step with at least one coating forming a shell.

16. The pharmaceutical formulation dosage form according to claim 1, wherein the core is a single solid compressed core with a relative density of at least 0.7.

17. The pharmaceutical formulation dosage form according to claim 1, wherein the core or the whole pharmaceutical formulation dosage form has an average diameter in the direction of the smallest diameter of at least 3 mm.

18. The pharmaceutical formulation dosage form according to claim 1, wherein the core or the whole pharmaceutical formulation dosage form has a crushing force of at least 25N.

19. The pharmaceutical formulation dosage form according to claim 1, wherein the dosage form is adapted for oral administration and for targeted release of the active pharmaceutical ingredient in the colon, and wherein said shell comprises at least one or consists of a pH-responsive coating dissolving only at a pH of at least 6.7.

20. The pharmaceutical formulation dosage form according to claim 1, wherein the at least one pH responsive coating of the shell is based on a synthetic polymer and/or a biopolymer or a mixture thereof, based on an anionic acrylate copolymer.

21. The pharmaceutical formulation dosage form according to claim 20, wherein the anionic acrylate copolymer is based on methyl acrylate, methyl methacrylate and methacrylic acid, wherein the ratio of the free carboxyl groups to the ester groups is in the range of 1:5-1:10.

22. The pharmaceutical formulation dosage form according to claim 20, wherein the anionic acrylate copolymer has a weight average molar mass (Mw) in the range of 200,000-400,000 g/mole.

23. The pharmaceutical formulation dosage form according to claim 1, wherein the at least one pH responsive coating of the shell consists of a mixture of an anionic acrylate copolymer based on methyl acrylate, methyl methacrylate and methacrylic acid, wherein the ratio of the free carboxyl groups to the ester groups is in the range of 1:5-1:10, wherein the anionic acrylate copolymer has a weight average molar mass (Mw) in the range of 200,000-400,000 g/mole, with further additives in a proportion of less than 25%, said further additives being selected from the group consisting of polyoxyethylene and derivatives thereof, anionic surfactants, including sodium laurylsulfate, talc, dye, iron(III)oxide, stabilizers, and triethyl citrate.

24. The pharmaceutical formulation dosage form according to claim 1, wherein the dry coating amount of the at least one pH responsive coating or of the whole shell is in the range of 2.5-6 mg/cm2.

25. The pharmaceutical formulation dosage form according to claim 1, wherein said matrix of the core essentially or completely consists of xyloglucan, wherein said xyloglucan is obtained from Tamarindus indica seeds and/or is cold water soluble and/or is amorphous, or wherein the xyloglucan used as starting material has a particle size (d50%) of at least 70 μm, or wherein the xyloglucan has a weight average molar mass (Mw) in the range of 400,000-500,000 g/mol, or wherein the xyloglucan is non-degalactosylated and/or native.

26. The pharmaceutical formulation dosage form according to claim 1, wherein said matrix of the core essentially or completely consists of xyloglucan which is a native, highly purified xyloglucan, of a cold-water soluble type.

27. The pharmaceutical formulation dosage form according to claim 1, wherein the core consists of: (A) 40-90% by weight of xyloglucan; (B) 10-60% by weight of at least one active pharmaceutical ingredient; and (C) 5-10% by weight of one or more pharmaceutically acceptable excipients selected from the group consisting of a diluent, a binder, an anti-adherent, a lubricant, a glidant, and a combination thereof, including the situation where the pharmaceutically acceptable excipient essentially consists of a binder or a binder and an anti-adherent, wherein the binder can be selected as PVP and the anti-adherent as magnesium stearate, or wherein the core consists of granules consisting of: (A) 40-90% by weight of xyloglucan; (B) 10-60% by weight of at least one active pharmaceutical ingredient; and (C) 5-10% by weight of one or more pharmaceutically acceptable excipients selected from the group consisting of a diluent, a binder, a lubricant, a glidant and a combination thereof, including the situation where the pharmaceutically acceptable excipient essentially consists of a binder, wherein the binder can be selected as PVP, wherein the granules are compacted to form a core before applying the shell, and wherein before compacting the granules can be blended with an anti-adherent, including in the form of magnesium stearate.

28. The pharmaceutical formulation dosage form according to claim 1, wherein the weight ratio of the matrix of the core to the at least one active pharmaceutical ingredient is at least 1:1.

29. A method for making a pharmaceutical formulation dosage form according to claim 1, wherein in a first step xyloglucan, at least one active pharmaceutical ingredient, as well as one or more pharmaceutically acceptable excipients are mixed and then compacted to form the core or mixed and treated to form granules, compressed to a single core with a relative density of at least 0.7 and/or with an average diameter in the direction of the smallest diameter of at least 3 mm, which are subsequently, if needed by first mixing the granules with a further treatment agent, compacted to form the core, wherein the mixing in both cases can take place using a fluidised bed granulator or high shear mixer, wherein the core is subsequently coated in a second step with at least one coating forming a shell, and wherein the coating formulation can be provided as a dispersion and can be applied further in a drum coater.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0070] Preferred embodiments of the invention are described in the following with reference to the drawings, which are for the purpose of illustrating the present preferred embodiments of the invention and not for the purpose of limiting the same. In the drawings,

[0071] FIG. 1 shows a schematic representation of the action mechanism;

[0072] FIG. 2 shows the release profile of different concentrations of the API in the matrix over time and conditions with mesalazine as API (5-ASA);

[0073] FIG. 3 shows the release profile of API in the presence of different concentrations of the xyloglucanase in the solution in the last phase over time and conditions with mesalazine as API (5-ASA);

[0074] FIG. 4 shows the property of xyloglucan to slow down active ingredient or drug release depending on the porosity of un-coated tablets;

[0075] FIG. 5 shows the release profile of API in the presence of different types of tablets with different thickness (amount) of the coating in solutions simulating the conditions of passage through the gastrointestinal tract over time with mesalazine as API (5-ASA).

DESCRIPTION OF PREFERRED EMBODIMENTS

[0076] FIG. 1 schematically shows the working principle of the proposed pharmaceutical dosage form 1. The dosage form 1 comprises a core 2 which is encapsulated in a shell 3. The core comprises a matrix 5, in this particular case xyloglucan, in which the active pharmaceutical ingredient 4 (API) is embedded.

[0077] The materials of the core, in particular its matrix, as well as of the shell are adapted for selective release of the API in the colon. In this respect it is to be noted that in the stomach typically there is a pH of 1.2, and the average residence time in the stomach is about two hours. Then follows the proximal small intestine again with a typical residence time of two hours and an increased pH of 6.5. This is followed by the distal small intestine with again a typical average residence time of two hours and a pH of 6.8. Only then follows the colon, first with the ascending colon followed by the descending colon, the residence time here depends on various factors, the pH is still in the range of 6.8.

[0078] The shell 3 of the proposed formulation dosage form is adapted to only dissolve significantly once the pH increases above 6.5, typically reaches a value of at least 6.8. Correspondingly the core portion of the tablet only starts to dissolve in the small intestine. However that is not yet the place where the API is to be released. To this end that xyloglucan is forming the matrix of the core. Under the physiological conditions in the small intestine the core portion now essentially without coating swells and forms a highly viscous mass but does not release the active ingredient to a significant extent. Only once this swollen matrix still containing the API enters the colon with the different micro-organisms containing enzymes digesting xyloglucan the matrix is digested and disintegrates and then also the API is released in a targeted manner to the place where it shall develop its effects.

[0079] This is evidenced by the release profile illustrated in FIG. 2. In in vitro experiments (for the detail see further below) for the first two hours the corresponding tablet is subjected to a pH of 1.2 simulating stomach conditions. No release of the API can be detected. Subsequently for another two hours the conditions of the proximal small intestine are simulated with a pH of 6.5. Again no release of the API can be detected. Then for another two hours the conditions of the distal small intestine are simulated by increasing the pH value of 6.8 but still not changing the enzymatic surrounding. One can see that at this moment in time first small portion of the API is released, which is associated with the dissolution of the pH-dependent coating. After that time period, so after six hours counting from the start, also the enzymatic conditions are adapted to the ones as present in the colon, in particular xyloglucanase is introduced into the medium. As from this moment on, there is a sharp and targeted release of the API. As a matter of fact, the release is largely independent of the concentration of the API in the xyloglucan matrix.

Material and Methods

Tablet Production

[0080] A three step process was employed.

1. Granulation

[0081] Granulation was carried out either in a fluidized bed granulator or in a high shear mixer. The composition was as follows:

Glyloid 3S (93-X) %

5-ASA (API) X %

Polyvinylpyrrolidone (Kollidon 30) 7%

[0082] Three different compositions with the following values of X were used: 33.3%; 50%; 66.7%. For fluidized bed granulation with batch size of 600 g the first two ingredients were first blended in a Turbula mixer for 7 min. at 32 rpm and the third ingredient was dissolved in purified water in a concentration of 10% w/w. This solution was sprayed in the fluidized bed at a rate of 14 g/min at first that was reduced to 7.3 and then 9.7 g/min. The atomizing pressure was 1.3 to 1.5 bar. The air volume stream was at first 40 m3/h and was increased to 80 m3/h. The inlet temperature was 50° C. and the product temperature was approx. 25° C. throughout the liquid addition and increased to 29° C. during drying. The total process duration was approx. 65 min and the residual moisture was 6.8%. The granules were passed through a 1 mm mesh screen.

[0083] For high shear granulation with batch size of 300 g all three ingredients were first blended in a Turbula mixer for 7 min at 32 rpm. Purified water was sprayed in the mixer at a rate of 6.5 g/min and an atomizing pressure of 0.12 bar. The rotation rate of the main impeller was 220 rpm and of the chopper 2200 rpm. Between 110 and 170 g of water was added yielding an increase of the power consumption of the main impeller from 82 to 91-93 Watt. The granules were passed through a 1 mm mesh screen, dried in a tray drier at 50° C. to a residual moisture of <5% and passed again through a 0.85 mm mesh screen.

2. Tableting

[0084] Granulated compositions were blended with 0.5% Mg-stearate in a Turbula mixer for 2 min at 32 rpm. Tablets with a diameter of 12 mm, a radius of curvature of 9 mm and a diametric crushing force of 50 N were produced in a single punch eccentric tableting machine at a rate of 20 tablets per minute. The tablet weight was adjusted based on the API content of the compositions determined after granulation to between 600 and 630 mg to reach an API content of 200, 300 and 400 mg per tablet. The compression force of the upper punch was between 10 and 13 kN.

3. Coating

[0085] Tablets were coated with Eudragit FS-30-D in a drum coater with batch size of 600 g. The composition of the coating dispersion was as follows:

TABLE-US-00001 Eudragit FS-30-D   43% Triethyl-citrate 0.65% Talc 6.45% Dye (iron III oxide)  0.2% Purified water 49.7%

[0086] The drum rotation speed was 20 rpm, the inlet air temperature 50° C., the product temperature 30-35° C., and the air volume stream 25-30 m3/h. The coating dispersion was sprayed at a rate of 4 g/min and an atomizing pressure of 1.3 bar. The nominal dry coating amount was L=5 mg/cm2 and the actual value was between L=3.5 and 4 mg/cm2.

Material Characteristics

Xyloglucan:

[0087] Brand name: Glyloid 3S and Glyloid 2A (DSP GOKYO FOOD & CHEMICAL Co., Ltd. Osaka, Japan)
Common name: Tamarind seed polysaccharide or tamarind seed gum
Chemical substance: Xyloglucan
Gras status declaration by FDA: GRN No. 503; Substance: Tamarind seed polysaccharide; Intended Use: Use as a thickener, stabilizer, emulsifier, and gelling agent in certain food categories; Notifier: DSP GOKYO FOOD & CHEMICAL Co., Ltd.; HERBIS OSAKA 20th Floor 2-5-25 Umeda Kita-ku, Osaka, 530-0001 Japan; Date of filing: Mar. 5, 2014 GRAS Notice (releasable information): 503; Date of closure: Aug. 12, 2014.

TABLE-US-00002 Physical-chemical properties declared by the supplier Glyloid 2A Glyloid 3S Content 80 - 99.99% 90 - 99.99% Glucose (inpurity)  0.01 - 20%  0.01 - 10% Water solubility Soluble Soluble Organic solvent Not soluble Not soluble solubility Molecular weight * Approx. 470,000 Approx. 470,000 Physical form White to light White to light brown powder brown powder Loss on drying * (more than of 3S quality) 1.1% Viscosity * (less than of 3S quality) 730 mPas * Values in the FDA document deviate

TABLE-US-00003 Physical-chemical properties determined on laboratory Glyloid 2A Glyloid 3S Water solubility Not completely Soluble at room soluble at room temperature temperature for for 2% w/v 2% w/v Soluble at 90° C. XRPD Semi-amorphous Amorphous (crystalline part corresponds to D-glucose) Particle size d(10%) = 25 μm d(10%) = 57.7 μm d(50%) = 60 μm d(50%) = 91.4 μm d(90%) = 164 μm d(90%) = 136.7 μm Viscosity Pseudo-plastic 603.7 Pseudo-plastic 721 - 852 mPas (at 100 s.sup.−1 mPas (at 100 s.sup.−1 room 90° C.) temperature) Molecular weight M.sub.r = 419,148 for from intrinsic k = 0.0008 viscosity [η] = kM.sub.r.sup.α α = 0.66 [0088] 5-ASA: Mesalazine, also known as mesalamine or 5-aminosalicylic acid, and is an aminosalicylate anti-inflammatory drug used to treat inflammatory bowel disease, including ulcerative colitis, or inflamed anus or rectum, and to maintain remission in Crohn's disease. [0089] Kollidon 30: Polyvinylpyrrolidone, with an average molecular weight expressed in terms of the K-value as in the pharmacopoeias valid in Europe, the USA and Japan, calculated from the relative viscosity in water in the range of 27.0-32.4. [0090] Eudragit FS-30-D: is the aqueous dispersion of an anionic copolymer based on methyl acrylate, methyl methacrylate and methacrylic acid. The ratio of the free carboxyl groups to the ester groups is approx. 1:10. It is provided as an aqueous dispersion with 30% dry substance. The dispersion contains 0.3% Sodium Laurilsulfate Ph. Eur./NF and 1.2% Polysorbate 80 Ph. Eur./NF on solid substance, as emulsifiers. Based on SEC method the weight average molar mass (Mw) is approx. 280,000 g/mole. [0091] Talc particle size: 99.5%<75 micrometer, median 19.3 micrometer, Ph. Eur. Specific surface (BET) 3.5 m2/g, producer: Imerys Talc, Italy SpA/Luzenac Pharma.

Experimental Methods:

[0092] Drug release was measured in a USP2 apparatus at 37° C. with paddle rotation rate 100 rpm. One tablet per vessel was used. A four stage test was performed with the following medium composition:

[0093] In the first two hours the medium consisted of 900 mL 0.1 N HCl solution in purified water with pH 1.2.

[0094] In the following two hours the medium consisted of 900 mL 100 mM potassium phosphate monobasic adjusted to pH 6.5 with NaOH.

[0095] In the following two hours the pH of the medium was adjusted to 6.8 with NaOH.

[0096] In the last stage the medium was exchanged with 200 mL of the same phosphate buffer pH 6.8 that contained different concentrations of xyloglucanase. The latter was a microbial enzyme of Paenibacillus sp. that is specific for digestion of Xyloglucan. The unit titer is calibrated with tamarind xyloglucan.

[0097] The first test stage (pH 1.2) simulates the stomach environment while the second test stage (pH 6.5) simulates the passage through the upper small intestine. The pH 6.8 stage corresponds to the movement of the tablet to the lower small intestine and the last stage with the reduced fluid volume and the presence of microbial enzyme corresponds to the environment in the colon, where release shall take place.

Results and Discussion:

[0098] Typical results are shown in the graphic in FIG. 3. No drug is released in the conditions reflecting the stomach and the upper small intestine, this being due to the polymeric coating. The residence time of two hours in each of these environments is representative for the transit time of solid dosage forms in the gastrointestinal tract after a light meal as found by scintigraphy and other methods.

[0099] The coating film was designed to dissolve and be removed from the surface of the tablet at pH 6.8. This results in a modest release of API that did not exceed 10% in two hours. The rate of drug release was markedly accelerated in the presence of the microbial enzyme in a concentration dependent fashion providing the proof of principle of controlled and position-triggered drug release by the developed delivery system.

[0100] After dissolution of the polymeric coating, release is inhibited by the Xyloglucan that does not allow the tablet to disintegrate forming a highly viscous gel or gluey mass instead which acts as diffusion barrier. Although pH values as high as 7.2 have been reported for the distal small intestine the coating is deliberately designed to dissolve at lower pH, the reason being that pH values and residence times in the intestine may fluctuate and exhibit inter-individual variability, and that the pH in the ascending colon can be again <7. Hence, if a film coating does not dissolve in the small intestine in a timely fashion, the tablet may be defecated intact as observed already with other experimental systems.

[0101] For the present delivery system, an early, i.e. at low pH, removal of the coating does not result in excessive release of drug in the small intestine and thus an undesirable loss of API for local action in the colon as this is prevented by the Xyloglucan matrix. Upon entering the colon the action of localized microbiome-specific enzymes ensures a rapid drug release. Hence the synergistic overlap of two control mechanisms provides a highly targeted delivery to the colon. The employed enzyme concentrations correspond to those reported and reasonably expected to be found in the human large intestine.

[0102] The property of Xyloglucan to slow down drug release is demonstrated in FIG. 4. Depending on the porosity of un-coated tablets release of the API can be adapted to take much longer than 24 hours while the release process follows approximately zero-order kinetics. The accelerating effect of enzymatic degradation of Xyloglucan on drug release is shown on FIG. 3.

[0103] FIG. 5 shows the drug release from tables as a function of time and pH for various modifications, for no coating (6) and with coating (7-10) situations. All cores of the tablets had a crushing force of 50 N. The coating thickness defined as coating mass per square centimeter of tablet surface increased from 2 mg/cm.sup.2 to 3.4. mg/cm.sup.2 to 4.9 mg/cm.sup.2 to 6.8 mg/cm.sup.2 for curves 7 to 10, respectively. The results show the optimal coating thickness for effective enteric coating and timely dissolution of the coating. The results also show that no burst release and therefore better release control takes place after the coating is dissolved at pH 6.8 contrary to the absence of a coating at the same pH (pH 7), shown in FIG. 4, underlining the synergy effect between coating and xyloglucan.

Distinction from Prior Art:

[0104] As for the distinction from the above-mentioned Yoo publication the following is to be noted: The results of the Yoo publication prove that the manufactured product (beads) do not work like the tablets proposed here. In FIG. 5 of Yoo the release of the active substance is measured first in the simulated stomach medium pH 1.2 and then in the simulated intestinal medium pH 7.4. The coated beads of Yoo show a release of about 10% in the first 2 hours at pH 1.2 and about 50% in the next 2 hours at pH 7.4. The formulation as described here shows a release of 0% at pH 1.2 after 2 hours, a release of 0% at pH 6.5 after 2 hours and a release of about 5% at pH 6.8 after a further 2 hours. Since the goal is to have as little release as possible under intestinal conditions, the product in Yoo by far does not meet our requirements.

[0105] Furthermore the experiment from Yoo was replicated as follows using native xyloglucan as used here instead of the degalactosylated type of Yoo: [0106] a 2% xyloglucan solution (quality 3S as in the tests here) in water was prepared at 4° C. while stirring with propeller stirrer during 24 hours. [0107] plant oil was heated at 40° C. and at 80° C. under magnetic stirring. [0108] 1 mL of xyloglucan solution was dripped through a syringe with needle (ID 0.71 mm corresponding to 22G) to the oil.

[0109] The result has been documented photographically.

[0110] At both temperatures, drops with a size of about 2 to 2.5 mm are formed at the beginning.

[0111] At 40° C. the drops flow together to worms after a few minutes.

[0112] At 80° C. air bubbles have formed in the droplets, the droplets have risen to the surface and flowed together during filtering.

[0113] Based on this the following interpretation has to be drawn: Native xyloglucan (not de-galactosylated) does not gel. De-galactosylated xyloglucan forms gels. The temperature of gel formation depends on the degree of de galactolysis. This is confirmed by independent work (e.g. above mentioned Brun-Graeppi publication). The xyloglucan of Yoo has a 44% galactose removal and gels at 40° C. Native xyloglucan shows nothing up to 60° C. (FIG. 3 of Brun-Graeppi). We have gone up to 80° C. but also no gelation seen, gelation means a solidification of the drops. This prevents the droplets from flowing together. In Yoo the droplets are cured for 30 minutes at 40° C., filtered, washed with acetone and dehydrated with successive water/ethanol mixtures. This was not possible with the drops using the native xyloglucan because they flowed together and coalesced. The difference lies clearly in the de-galactosylation and the associated gelation, making the Yoo method impossible using native xyloglucan.

[0114] The small beads of Yoo are fundamentally different from the compressed tables given here at least for the following reasons: The beads from Yoo, not coated, with a drug load of 27.77% (Charge XGID 100, Table 1) show a drug release of above 70% in 2 hours at pH 7.4 (FIG. 2a). Our tablets with a drug load of 30% (comparable to the beads) show a drug release between 10 and 35% at pH 7 within 2 hours (also comparable to the beads, FIG. 4 given here) depending on the strength of the compression. Strongly compressed tablets with a high strength (134 N crushing force) have a porosity of 14.8% i.e. a relative density of 0.852 (space filling of 85.2%) and show a release in 2 hours of almost 10%. Slightly compressed tablets (crushing force=30 N, relative density=0.713) show a release in 2 hours of about 35%. The results clearly demonstrate the great influence of the volume and/or density of the tablets and the compression process on the release (without coating). The density of the beads must be significantly below 70% due to the manufacturing method (syringe method as given above). One starts with a 2% xyloglucan solution to which one adds a maximum of 2% active ingredient. With this, one cannot reach a solid content of 70 V-% in the beads at the end. This is visible from the very different amount of release between beads and tablets in general.

[0115] The release with coating also works differently with the beads of Yoo than with our tablets. FIG. 5 of Yoo shows release after 2 hours pH 1.2 (stomach conditions) with coating almost 10% and after further 2 hours at pH 7.4 (small intestine conditions) release of total 50%. In the same duration under the same conditions without coating the release from the beads is about 65%. This means firstly that the coating makes a relatively small difference (50 vs. 65%) and secondly that the goal of releasing as little active substance as possible in the small intestine is not achieved. In our tablets (FIG. 3 given here) we have a release of 0% at pH 1.2 after 2 hours, a release of 0% after 2 hours at pH 6.5 (upper conditions of the small intestine) and a release of about 5% after a further 2 hours at pH 6.8 (conditions of the small intestine). Without coating under the same conditions we have a release of about 32% (FIG. 5 given here). This means, firstly, that the coating makes up a great deal (5 vs. 32%) and, secondly, that we achieve the goal of the lowest possible release in the small intestine (during a total of 6 hours).

[0116] In addition, the presence of the coating influences the release after the coating is dissolved and removed, i.e. at pH 6.8. If one compares the release in FIG. 4 at pH 7 with the release at pH 6.8 in further FIG. 5, one can see that in the case of a coating the burst effect (sudden increase) is omitted at the beginning while afterwards the release rate in the case of the coating is somewhat higher (than without coating). The latter can also be seen in the presence of the microbial enzyme. This has to do with the fact that the inside of the tablet is still intact in the first 4 to 6 hours during the coating, absorbs water and the xyloglucan starts to swell which influences the subsequent release. So there is a synergistic effect between xyloglucan core and coating which influences the release.

[0117] In contrast, using the formulation given here, tablets (several mm diameter) of core and API are prepared and the core is later coated with an enteric film. The release of the API is as follows: No or only minor release is expected and observed at low pH (gastric passage).

[0118] Upon neutralization (entry in the small intestine) the enteric coating dissolves. Water will now wet the tablet and water will diffuse into the tablet. In the outer surface of the tablet core xyloglucan (solid, no air) will form a highly viscous mass impeding release of API and slowing down water intrusion. Consequently, there will be only a minor release of the API for several hours (“delayed release”).

[0119] The polysaccharide xyloglucan is not degraded by human digestive enzymes. Instead, xyloglucan and other plant cell wall derived polysaccharides are degraded and metabolized by the colonic microbiome. We could indeed show that in the presence of xyloglucanase (the enzyme which initiates degradation of xyloglucan) the API release is accelerated which is probably caused by the accelerated erosion of the xyloglucan matrix by the enzymatic degradation. The specific degradation of xyloglucan by the colonic microbiome constitutes the second control mechanism of our technology.

TABLE-US-00004 LIST OF REFERENCE SIGNS  1 pharmaceutical formulation dosage form, tablet  2 core  3 shell  4 active pharmaceutical ingredient  5 matrix, xyloglucan  6 S-20-50N total mass 631 mg no coating  7 S-20-50N Eudragit F530, L = 2 Total mass 639 mg with coating  8 5-20-50N Eudragit F530, L = 3.5 Total mass 651 mg with coating  9 S-19-50N Eudragit F530, L = 4.9 Total mass 671 mg with coating 10 S-20-50N Eudragit F530, L = 6.8 Total mass 661 mg with coating