Porous starch

Abstract

The present invention relates to improving the flowability and compressibility (tensile strength) of starch by using an enzyme, enhancing the porosity of starch particles, and using porous starch particles for direct compression of tablets.

Description

[0001] Starch has a long history of use as an excipient in pharmaceutical dosage forms. Native starch, such as corn starch, is white or off-white, odorless and tasteless, and is one of the most widely used fillers / binders in tablet manufacturing.

[0002] This biomaterial possesses unique physicochemical and functional properties, as well as various advantages such as low cost, relatively easy isolation from plant sources in pure form, non-toxicity, biodegradability, good biocompatibility, non-hygroscopicity, inertness (no pharmacological activity), and no interaction with living cells.

[0003] Virgin starch is used as a filler / diluent, binder, and disintegrant in tablet formulations. It has only acceptable compressibility, very poor flowability, and exhibits elastic recovery, which leads to tablet capping and lamination. Therefore, starch is generally not used for direct compression, which is the preferred route for efficient and cost-effective tablet manufacturing. Especially for higher content active ingredients or when using active ingredients with poor compressibility, a wet granulation step is required for starch-based formulations. Various physically and chemically modified starches have been proposed as direct compression excipients for tablet formulations (Lawal, MV: Modified Starch as Direct Compression Excipients - Effect of Physical and Chemical Modifications on Tablet Properties: A Review. Starch - Stärke 2019, 71 DOI OI: 10.1002 / star.201800040). WO2021195216 discloses a product for inhibiting porous granular starch, which involves hydrolyzing the granular starch feed using one or more enzymes. Lacerda et al. described the synthesis of porous rice starch and the dependence of its physical properties on enzymatic hydrolysis conditions. (Liziane Lacerda, Daiani C. Leite, Nádya P. da Silveira, Journal of Cereal Science, Vol. 89, 2019, 102819). WO2013017388-A1 discloses the encapsulation of anionic or cationic insecticides with porous starch granules.

[0004] These products typically exhibit improved compressibility compared to virgin starch. One such modified starch is STARTAB. ®(Colorcon) is a grade used for direct pressing and has high flowability and compressibility. For high-dose formulations and difficult-to-formulate active ingredients, additional fillers / dry binders must often be added to achieve optimal formulation performance. Another modified starch is N-Zorbit, which is manufactured through partial hydrolysis and is designed as a coating agent with high absorption capacity for liquid active ingredients. N-Zorbit has a porous and granular structure, thus possessing the ability to carry high flavor concentrations.

[0005] Another approach to improving the tableting performance of virgin starch is to combine it with other excipients in so-called "co-processed" excipient formulations. These co-processed excipients combine the individual excipients in a physical form without significant chemical changes to achieve synergistic functional properties. An example of a starch-based excipient is StarLac. ® (Meggle, Germany) contains 85% α-lactose monohydrate and 15% native corn starch. This excipient combines lactose (a typical filler used in direct compression) with starch, which contributes to binding and disintegration properties. Such co-processed excipients exhibit properties in tableting that cannot be achieved with simple physical mixtures of the ingredients.

[0006] This invention relates to porous starch granules, characterized by physicochemical parameters, namely nitrogen adsorption, particle size, and Δ. p The measurement, Δ p This refers to the permeability of the accumulated starch material. Enzyme-treated starch should meet at least one parameter. Preferably, it is a combination of two parameters that enzyme-treated starch should meet, and even more preferably, a combination of all three parameters.

[0007] The present invention also relates to the use of enzymatically hydrolyzed porous starch granules having high interparticle porosity, large specific surface area, improved flowability, and thus improved tableting performance.

[0008] Powder flowability is improved through spray drying or spray agglomeration steps. Modification of individual particles via partial enzymatic hydrolysis results in significantly improved compressibility compared to starches known in the art. Even though tablets made from this porous starch exhibit surprisingly high tensile strength, disintegration time remains low, which is common for starches. Due to this property, rapidly disintegrating tablets can be formulated, enabling the active ingredient to take effect quickly without the addition of disintegrants.

[0009] Drug dosage forms include tablets, pills, small tablets, lozenges, and other comprimat formulations.

[0010] Typically, pharmaceutical dosage forms consist of the following excipients in addition to the active pharmaceutical ingredient (API): fillers, binders, disintegrants, and lubricants. The porous starch according to the invention exhibits the properties of a filler, binder, and disintegrant, enabling the production of simple starch-based tablet formulations via direct compression. The amount of excipients in the formulation can be reduced, and the direct compression route is cost-effective and suitable for integration into continuous manufacturing lines, resulting in very simple direct-compression pharmaceutical dosage forms. Direct-compression pharmaceutical dosage forms can be manufactured without a granulation step and contain little or no additional fillers, binders, lubricants, and disintegrants.

[0011] On the other hand, the present invention relates to the use of porous starch according to the invention in the production of tablets, pills, and small capsule fillers. Porous starch is also suitable as a carrier of active ingredients, which can be used as a liquid, as a solution, or impregnated during the melting stage. Starch is currently used in pharmaceuticals as a binder, disintegrant, and film-forming material. Direct tableting with starch is unsuitable due to its poor flowability and compressibility.

[0012] This invention relates to improving the compressibility of starch by using enzymes, preferably amylases, more preferably α-amylases, including flowability and compressibility (tensile strength of compressed tablets), increasing the porosity of starch granules, and improving flowability by spray drying and granule agglomeration.

[0013] Enzymatic hydrolysis of porous starch Enzymatically hydrolyzed porous starch is granular starch that has been hydrolyzed by one or more starch-degrading enzymes. Enzymatically hydrolyzed porous starch can be prepared by enzymatically hydrolyzing untreated or chemically treated native starch granules at temperatures below the starch gelatinization temperature using one or more starch-degrading enzymes, such as α-amylase and amyloglucosidase. The production of enzymatically hydrolyzed porous starch may include the following steps: a) Hydrolyzing starch using one or more starch-degrading enzymes, preferably amylases. b) After hydrolysis, the porous starch is hydrolyzed by a separating enzyme, preferably by filtration. c) Optionally, wash the separated enzymatically hydrolyzed porous starch with water, preferably deionized water. d) Hydrolyze porous starch with a drying enzyme, preferably by spray drying or freeze drying, more preferably by spray drying.

[0014] In one embodiment, the enzymatically hydrolyzed porous starch granules have a relatively excessive specific surface area ( S 过量 ), 2< S 过量 <10. In a more preferred embodiment, the enzymatically hydrolyzed porous starch granules have a relatively excess specific surface area ( S过量 ), 2.5 S 过量 <7, more preferably 2.9< S 过量 <6.1.

[0015] In another embodiment, the enzymatically hydrolyzed porous starch granules have a polar interaction component (δ) as determined by reversed-phase gas chromatography. P 2), δ P 2 < 8.8. In a more preferred embodiment, the enzymatically hydrolyzed porous starch granules have a polar interaction component (δ) determined by reversed-phase gas chromatography. P 2), δ P 2 < 8.70, more preferably δ P 2 < 8.66.

[0016] In another embodiment, the enzymatically hydrolyzed porous starch granules have a pressure difference (ΔΔ) across a GC column packed with starch sample and purged with helium at a flow rate of 15 mL / min. p ), 200 millibars < Δ p <800 mbar. In a more preferred embodiment, the enzymatically hydrolyzed porous starch granules have a pressure differential (Δ) across a GC column packed with starch sample and purged with helium at a flow rate of 15 mL / min. p ), 200 millibars < Δ p <700 mbar, more preferably 235 mbar <Δ p <667 millibars.

[0017] Native starch granules can be based on cassava, glutinous rice, corn, peas, potatoes, glutinous potatoes, wheat, glutinous wheat, glutinous corn, mung beans, rice, glutinous rice, sweet potatoes, glutinous sweet potatoes, millet, sago, sorghum, quinoa, arrowroot, amaranth, lotus root, and buckwheat.

[0018] Typically, starch used in pharmaceutical applications is derived from corn, rice, wheat, potatoes, millet, barley, peas, and cassava. Preferably, native starch is derived from corn.

[0019] amylase The "amylases" (α and / or β) according to the present invention include those of bacterial or fungal origin (EC 3.2.1.1 and 3.2.1.2, respectively). Preferably, the amylases are selected from the group including α-amylases (EC 3.2.1.1). This includes chemically modified or protein-engineered mutants.

[0020] The amylase according to the present invention has "starch-degrading activity" or "amylase activity," which involves the (internal) hydrolysis of glycosidic bonds in polysaccharides. α-Amylase activity can be determined by assays known to those skilled in the art for measuring α-amylase activity. Examples of assays for measuring α-amylase activity are: α-Amylase activity can be determined using Phadebas tablets as a substrate (Phadebas amylase assay, provided by Magle Life Science). Starch is hydrolyzed by α-amylase, producing a soluble blue fragment. The absorbance of the resulting blue solution, measured spectrophotometrically at 620 nm, is a function of α-amylase activity. The measured absorbance is proportional to the specific activity (activity / mg pure α-amylase protein) of the α-amylase considered under given conditions.

[0021] α-Amylase activity can also be determined using the method with ethylidene-4-nitrophenyl-α-D-maltoheptaglycoside (EPS). D-maltoheptaglycoside is a blocked oligosaccharide that can be cleaved by endoamylase. After cleavage, the α-glucosidase contained in the kit digests the substrate to release free PNP molecules, which are yellow and can therefore be measured by visible spectrophotometry at 405 nm. The kit containing EPS substrate and α-glucosidase is manufactured by Roche Costum Biotech (catalog number 10880078103). The slope of the time-dependent absorption curve is proportional to the specific activity (activity per mg of enzyme) of α-amylase considered under given conditions.

[0022] Starch-degrading activity can be provided in units per gram of enzyme. For example, 1 unit of α-amylase can release 1.0 mg of maltose from starch within 3 minutes at 20°C and pH 6.9.

[0023] Preferred amylases are Bacillus licheniformis having SEQ ID NO:2 as described in WO 95 / 10603. Bacillus licheniformis(and at least 95% of its variants. Suitable variants are described in WO 95 / 10603, which contain one or more substitutions at the following positions: 15, 23, 105, 106, 124, 128, 133, 154, 156, 178, 179, 181, 188, 190, 197, 201, 202, 207, 208, 209, 211, 243, 264, 304, 305, 391, 408, and 444, which have starch-degrading activity. Variants are described in SEQ ID NO:4 of WO 94 / 02597, WO 94 / 018314, WO 97 / 043424, and WO 99 / 019467. An exemplary sequence is added herein as SEQ ID NO:1.)

[0024] Other preferred amylases are derived from Aspergillus oryzae ( Aspergillus oryzae ), and described, for example, in: Brzozowski et al., Biochemistry 1997. Suitable variants are described, for example, in US20110159545. Suitable variants are added herein as SEQ ID NO:2.

[0025] Amylase can also be derived from Bacillus stearothermophilus ( Geobacillus stearothermophilus (This refers to a sequence containing SEQ ID NO:6 as disclosed in WO 02 / 10355, or optionally containing an amylase with a C-terminus truncated in the wild-type sequence. Suitable variants of SEQ ID NO:6 include those containing deletions at positions 179 and / or 181 and / or 182 and / or substitutions at position 193.)

[0026] TVB146 is a variant of the thermophilic stearothermophilus (originally named B. stearothermophilus) “similar amylase”[1] – an amylase represented by PDB entry 1hvx (Suvd et al., 2001). Compared with most residue deletions ([1] 181-182; discussed below) and the single-site variant N193F (1hvx number; corresponding to Phe191 in 4 uzu). The TVB146 enzyme shows 97% sequence identity compared with the sequence present in 1hvx, and differs at A73T, N193F, S217N, M278T, N281D, T304A and V416G except for two residue deletions[1] 181-182.

[0027] Amylase can also be derived from Bacillus species having SEQ ID NO:6 as disclosed in WO 99 / 19467. Bacillus sp.) 707and at least 95% of its variants. Preferred variants of SEQ NO: 6 are those with substitutions, deletions or insertions in one or more of the following positions: R181, G182, H183, G184, N195, I206, E212, E216 and K269.

[0028] Amylase can also be derived from salicylic acid-sensitive Bacillus species having SEQ ID NO:2 or SEQ ID NO:7 as described in WO 96 / 23872. Bacillus halmapalus This is also described herein as SP-722. Preferred variants are described, for example, in WO97 / 3296, WO 99 / 194671 and WO 2013 / 001078.

[0029] Amylase can also be derived from Bacillus genus DSM12649 and at least 95% of its variants, as disclosed in WO 00 / 22103, which is SEQ ID NO:4.

[0030] Amylases can also be derived from Bacillus genus A7-7 (DSM 12368), which has an amino acid sequence that is at least 95% identical to that of SEQ ID NO:2 disclosed in WO 02 / 10356, particularly in the region of amino acids 32 to 516 according to SEQ ID NO:2.

[0031] Amylase can also be derived from Bacillus strain TS-23 and its variants, as disclosed in WO 2009 / 061380, which has SEQ ID NO:2.

[0032] Amylase can also be derived from the genus *Fibrophagium*, as disclosed in WO 2013 / 184577 (SEQ ID NO:1). Cytophaga sp .) and at least 95% of its variants.

[0033] Amylase may be derived from Bacillus megaterium with SEQ ID NO:1 as disclosed in WO 2010 / 104675 ( Bacillus megaterium DSM 90 and at least 95% of its variants.

[0034] Amylase can also be derived from Bacillus species containing amino acids 1 to 485 as described in SEQ ID NO:2 as in WO 00 / 60060 and at least 95% of their variants.

[0035] Amylase can also come from Bacillus amyloliquefaciens (Bambusa amyloliquefaciens) Bacillus amyloliquefaciens The amylase or a variant thereof, preferably selected from the amylase according to SEQ ID NO:3 as described in WO 2016 / 092009.

[0036] Amylases may have SEQ ID NO:12 as described in WO 2006 / 002643, or amylase variants thereof comprising substitutions for Y295F and M202LITV within said SEQ ID NO:12.

[0037] Amylases may have SEQ ID NO:6 or amylase variants as described in WO 2011 / 098531, which contain substitutions at one or more positions selected from the group consisting of: 193 [G, A, S, T or M], 195 [F, W, Y, L, I or V], 197 [F, W, Y, L, I or V], 198 [Q or N], 200 [F, W, Y, L, I or V], 203 [F, W, Y, L, I or V], 206 [F, W, Y, N, L, I, V, H, Q, D or E], 210 [F, W, Y, L, I or V], 212 [F, W, Y, L, I or V], 213 [G, A, S, T or M], and 243 [F, W, Y, L, I or V].

[0038] Amylase may have SEQ ID NO:1 as described in WO 2013 / 001078, or contain altered amylase variants at two or more of the positions G304, W140, W189, D134, E260, F262, W284, W347, W439, W469, G476, and G477 within said SEQ ID NO:1.

[0039] The amylase may have SEQ ID NO:2 as described in WO 2013 / 001087 or a variant of the amylase containing the deletion of positions 181+182, 182+183, or 183+184 within SEQ ID NO:2, optionally including one or two or more modifications at any position corresponding to W140, W159, W167, Q169, W189, E194, N260, F262, W284, F289, G304, G305, R320, W347, W439, W469, G476, and G477 within SEQ ID NO:2.

[0040] The amylase can be a hybrid α-amylase derived from the above-mentioned amylases, such as that described in WO 2006 / 066594.

[0041] The heterozygous amylase can be based on WO 2014 / 183920, wherein the A and B domains are at least 90% identical to SEQ ID NO:2 of WO 2014 / 183920, and the C domain is at least 90% identical to SEQ ID NO:6 of WO 2014 / 183920, wherein the heterozygous amylase has starch-degrading activity; preferably, the heterozygous α-amylase is at least 95% identical to SEQ ID NO:23 of WO 2014 / 183920 and has starch-degrading activity.

[0042] The heterozygous amylase can be classified according to WO 2014 / 183921, wherein the A and B domains have at least 75% identity with SEQ ID NO: 2, SEQ ID NO: 15, SEQ ID NO: 20, SEQ ID NO: 23, SEQ ID NO: 29, SEQ ID NO: 26, SEQ ID NO: 32 and SEQ ID NO: 39 disclosed in WO 2014 / 183921, and the C domain has at least 90% identity with SEQ ID NO: 6 of WO 2014 / 183921, wherein the heterozygous amylase has starch-degrading activity; preferably, the heterozygous α-amylase is at least 95% identical with SEQ ID NO: 30 disclosed in WO 2014 / 183921 and has starch-degrading activity; Hybrid amylases can be classified according to WO 2021 / 032881, which contains A and B domains of α-amylase derived from Bacillus spp. A7-7 (DSM12368) and from Bacillus cereus (…). Bacillus cereus The C domain of the α-amylase; preferably, the A and B domains are at least 75% identical to the amino acid sequence of SEQ ID NO: 42, and the C domain is at least 75% identical to the amino acid sequence of SEQ ID NO: 44, both sequences being disclosed in WO 2021 / 032881; more preferably, the heterozygous amylase is at least 80% identical to SEQ ID NO: 54 disclosed in WO 2021 / 032881.

[0043] Suitable amylases also include those that are variants of the aforementioned amylases having starch-degrading activity. In one embodiment, the amylase variant includes a variant having at least 40% to 100% identity with the full-length polypeptide sequence of the parent enzyme as disclosed above. In one embodiment, the amylase variant having starch-degrading activity has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the full-length polypeptide sequence of the parent enzyme as disclosed above.

[0044] In another embodiment, the present invention relates to amylase variants comprising conserved mutations that do not belong to the functional domains of the corresponding amylase. The amylase variant of this embodiment having starch-degrading activity may be at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% similar to the full-length polypeptide sequence of the parent enzyme.

[0045] In one embodiment, the amylase variant has starch-degrading activity according to the invention when it exhibits increased starch-degrading activity compared to the parental amylase.

[0046] In one embodiment, the amylase variant has starch-degrading activity according to the invention when it exhibits at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% of the starch-degrading activity of the corresponding parental amylase.

[0047] In one embodiment, at least one amylase is selected from commercially available amylases, including but not limited to those marketed under the trade name Duramyl. ™ Terminyl ™ Fungaly ™ Stainzyme ™ Stainzyme Plus ™ Natalase ™ Liquozyme X and BAN ™ Amplify ™ Amplify Prime ™ (From Novozymes A / S) and Rapidase ™, Purastar ™ , Powerase ™ , Effectenz ™ (M100 from DuPont), Preferenz ™ (S1000, S110 and F1000; from DuPont), PrimaGreen ™ (all; DuPont), Optisize ™ Products sold by (DuPont).

[0048] >SEQ ID NO: 1 ANLNGTLMQYFEWYMPNDGQHWKRLQNDSAYLAEHGITAVWIPPAYKGTSQADVGYGAYDLYDLGEFHQKGTVRTKYGTKGELQSAIKSLHSRDINVYGDVVINHKGGADATEDVTAVEVDPADRNRVISGEHRIKAWTHFHFPGRGSTYSDFKWHWYHFDGTDWDESRKLNRIYKFQGKAWDWEVSNENGNYDYLMYADIDYDHPDVAAEIKRWGTWYANELQLDGFRLDAVKHIKFSFLRDWVNHVREKTGKEMFTVAEYWQNDLGALENYLNKTNFNHSVFDVPLHYQFHAASTQGGGYDMRKLLNSTVVSKHPLKAVTFVDNHDTQPGQSLESTVQTWFKPLAYAFILTRESGYPQVFYGDMYGTKGDSQREIPALKHKIEPILKARKQYAYGAQHDYFDHHDIVGWTREGDSSVANSGLAALITDGPGGAKRMYVGRQNAGETWHDITGNRSEPVVINSEGWGEFHVNGGSVSIYVQR >SEQ ID NO: 2 ATPADWRSQSIYFLLTDRFARTDGSTTATCNTADRKYCGGTWQGIIDKLDYIQGMGFTAIWITPVTAQLPQTTAYGDAYHGYWQQDIYSLNENYGTADDLKALSSALHERGMYLMVDVV ANHMGYDGAGSSVDYSVFKPFSSQDYFHPFCLIQNYEDQTQVEDCWLGDNTVSLPDLDTTKDVVKNEWYDWVGSLVSNYSIDGLRIDTVKHVQKDFWPGYNKAAGVYCIGEVLDGDPAYT CPYQNVMDGVLNYPIYYPLLNAFKSTSGSMDDLYNMINTVKSDCPDSTLLGTFVENHDNPRFASYTNDIALAKNVAAFIILNDGIPIIYAGQEQHYAGGNDPANREATWLSGYPTDSELY KLIASANAIRNYAISKDTGFVTYKNWPIYKDDTTIAMRKGTDGSQIVTILSNKGASGDSYTLSLSGAGYTAGQQLTEVIGCTTVTVGSDGNVPVPMAGGLPRVLYPTEKLAGSKICSSS.

[0049] Tensile strength The tensile strength of tablets is an important property because tablets need to be mechanically strong enough to withstand further processing, such as film coating, packaging, transportation and final use by patients, but weak enough to rupture in the body and thus release their contents.

[0050] Tensile strength refers to a material's ability to resist fracture or deformation under tension. In the case of tablets, tensile strength refers to the tablet's strength against forces applied to it during handling, packaging, and transportation. Tablets with high tensile strength are less likely to crack or break, ensuring their structural integrity and preventing loss of their active ingredient. This is particularly important for tablets that require further processing, such as those used for film coating or those that are typically handled and transported extensively, as is common in the pharmaceutical industry. Manufacturers use various techniques to enhance the tensile strength of tablets. These include using appropriate excipients, optimizing compressibility and compaction during tablet manufacturing, and incorporating binders or disintegrants to improve tablet stiffness and integrity. Tensile strength testing is typically performed using equipment such as a hardness tester or a tablet tensile strength tester. This helps manufacturers assess the tablet's ability to withstand applied forces and ensure its overall quality. In conclusion, tablets with high tensile strength are preferred because they are less likely to crack, thus ensuring the quality and efficacy of the drug they contain.

[0051] The minimum tensile strength of a tablet can vary depending on the specific tablet formulation and intended use. However, generally, tablets containing an active pharmaceutical ingredient (API) should have a tensile strength of at least 1–2 MPa to ensure they can withstand handling and transportation without breaking. To achieve this, API-free tablets made from excipients should have a tensile strength of at least 4 MPa.

[0052] Different devices can be used to manufacture tablets, such as hydraulic hand-operated presses or compactor simulators. These different devices have different holding times, which affect the tensile strength of the tablets produced by that device. Holding time during compression is the amount of time required for the punch to stop its vertical movement and achieve maximum penetration in the die below the main compression roller. Holding time occurs when the pressure roller makes flat contact with the punch. The punch flat dimension divided by the turntable tangential speed gives the tableting machine's holding time calculation. As a core parameter, holding time significantly affects the overall quality of many tablet products and the production speed of these products. Specifically, it affects tablet strength and facilitates product transfer between tableting machines. Subsequently, increasing or decreasing the holding time can significantly affect the outcome of the tablet manufacturing process.

[0053] In the example, a Specac AtlasManual 15T hydraulic hand press with a 10-second holding time from SPECAC INC. or a StylOne Evo compaction simulator with a <10ms holding time (Medelpharm, Germany) is used.

[0054] The enzymatic hydrolysis of porous starch according to the present invention produces a solid dosage form with a tensile strength >4 MPa, compressed under a pressure of 150 MPa and a holding time of 10 s. In a preferred embodiment, the tensile strength is >5 MPa.

[0055] The enzymatic hydrolysis of porous starch according to the present invention produces a solid dosage form with a tensile strength >3 MPa, compressed under a pressure of 150 MPa and a holding time of 10 ms. In a preferred embodiment, the tensile strength is >4 MPa.

[0056] Direct-suppression drug dosage form Novel porous starches are single excipients that provide multiple functions required for tablet formulation: this single component combines the functions of a filler, binder, and disintegrant, rendering the addition of these materials obsolete. Optionally, flow agents, such as silica (typically used at a concentration of 0.2-1% w / w), may be added, and lubricants (typically used at a concentration of 0.5-3% w / w) are required to reduce ejection forces during tablet manufacturing.

[0057] Therefore, direct-compressed drug dosage forms prepared with this novel porous starch can contain little or no additional excipients, such as fillers, lubricants, binders, and disintegrants, thus enabling very simple formulations and helping to minimize the amount of inactive ingredients in tablets.

[0058] In one embodiment, the directly compressed pharmaceutical dosage form according to the invention contains a lubricant and flow agent concentration of no more than 10%, preferably no more than 7.5%, and even more preferably no more than 5% based on the total weight of the dosage form.

[0059] In another embodiment of the invention, the directly compressed pharmaceutical dosage form comprises enzymatically hydrolyzed porous starch granules according to the invention. This dosage form can be a tablet, pill, small tablet, lozenge, or other solid tablet. Preferably, the dosage form according to the invention prepared at 150 MPa (without API or other additional excipients) exhibits a tensile strength >4 MPa.

[0060] In another embodiment of the invention, the directly compressed pharmaceutical dosage form comprises porous starch granules present at a concentration of 1% to 98% by weight, preferably 40% to 95% by weight, and more preferably 49% to 94% by weight, based on the total weight of the dosage form.

[0061] In another embodiment of the invention, the directly compressed pharmaceutical dosage form contains one or more active pharmaceutical ingredients present at a concentration of 1% to 80% by weight, preferably 10% to 80% by weight, and more preferably 25% to 50% by weight, based on the total weight of the dosage form.

[0062] The following experiments were conducted on each sample in Tables 1 and 2 (regarding relative excess surface area, pressure difference, and polarity interaction). (using portions) .

[0063] Relative excess surface area ( S 过量 ) 1) Specific surface area was determined by nitrogen adsorption experiment. The specific surface areas of porous and non-porous starches were determined by nitrogen adsorption, a technique that measures the amount of test gas (in this case, nitrogen) adsorbed on a specified amount of solid sample at equilibrium under specified conditions. This yields adsorption isotherms, which can be evaluated using the Brunauer, Emmett, and Teller (BET) model [1] or the Langmuir theory [2]. In both cases, the values ​​of the surface area available for adsorption per unit mass of solid material were obtained (respectively...). S BET and S 朗缪尔 ), while BET evaluation provides the interaction constant ( C BET The affinity of gas molecules for adsorption on a solid surface is used as an additional parameter.

[0064] For the measurement, approximately 2.5 g of solid sample was packed into a glass column (inner diameter: 9.5 mm) with a known tare weight. The packed column was then evacuated to a pressure of 0.1 mbar and conditioned at this pressure at 25 °C for 48 hours using the degassing unit of an ASAP 2420 surface area and porosity analyzer from Micromeritics (Unterschleißheim, Germany) to remove any volatile components (including water) from the solid sample. After conditioning, the weight of the remaining material in the column was determined to an accuracy of 0.1 mg. The column was then transferred to the sampling port of the ASAP 2420 instrument, and the free volume in the sample container was measured by metering the addition of non-adsorbed helium. After removing the inert He, the N2 adsorption isotherm was recorded at the nitrogen condensation temperature. Coverage ≤ 0.06 was achieved using the five-point method implemented in the supplier's software. p / p The typical partial pressure range of 0 ≤ 0.20 is determined from the obtained isotherms. S BET , C BET and S 朗缪尔 The proposed procedure strictly follows the procedures defined in DIN ISO 9277:2003-05.

[0065] References [1] S. Brunauer, PH Emmett, E. Teller, J. Am. Chem. Soc. 1938, 60 , 309-319.

[0066] [2] I. Langmuir, J. Am. Chem. Soc. 1918, 40 , 1361-1402.

[0067] 2) Particle size was determined by laser diffraction. The particle size distribution of porous starch samples was determined using a Mastersizer 2000 equipped with a Scirocco 2000 sample processing unit, manufactured by Malvern Panalytical Ltd. (Worcestershire, UK). This instrument measures the angular change in the intensity of scattered light as a laser beam passes through a dispersed particulate sample. Larger particles primarily scatter light at a small angle relative to the laser beam, while smaller particles contribute more to the light scattered at a large angle. The following detailed settings were used for the measurements: • Optical limit: 0.1-6.0 optical limit • Timeout period: 2 minutes • Result range: 0.02-2000μm • Result Calculation: General • Measurement time: 60 seconds • Measurement snapshot: 60,000 • Background time: 5 seconds • Background snapshot: 5.000 Porous starch granules in dry powder form were measured for approximately 30–60 seconds at a dispersion air pressure of 0.5 bar. From the collected angular scattering intensity data, the particle size distribution was calculated using software provided by the manufacturer (version 6.00), which applied a simplified Fraunhofer approximation method for evaluation [3]. The particle size was obtained as the diameter of a volume-equivalent sphere and as the lower 10% (d) encompassing the entire distribution. 10 ), 50% (d 50 ) and 90% (d 90 ) characteristic percentile value report.

[0068] References [3] J. Vargas-Ubera, JF Aguilar, DM Gale, Appl.Opt. 2007, 46 , 124-132.

[0069] 3) Calculation of relative excess specific surface area Based on light scattering d 50 The value, assuming a spherical geometry, is calculated using the following equation to determine the envelope volume of the detected substance (a single starch granule or its aggregate). V 包络 ) and surface area ( A 包络 ): Using these parameters, experimental measurements are possible. d 50 The theoretical specific surface area of ​​a compact (i.e., non-porous) solid. S 包络 It can be obtained from the following: Here ρ 淀粉 This refers to the density of unprocessed starch (for corn starch, it is 1.5301 g / cm³ at 25°C). 3(e.g., determined by a helium specific gravity flask). The calculated envelope specific surface area is compared with the corresponding value of the experimentally measured treated starch ( S BET This is correlated with the relative excess specific surface area ( ) to obtain the relative excess specific surface area ( ) S 过量 ): The dimensionless values ​​obtained in this way represent the increase in surface area (and therefore overall porosity) due to the pores within the particles caused by prior amylase treatment and the voids between individual particles in the aggregated structure. Both of these contributions alter the properties of the treated starch product and affect the final mechanical properties. Table 1 provides experimentally determined and calculated parameter values ​​for different types of treated and untreated starch samples, with tensile strength as... S 过量 The curve of the function is as follows Figure 1 As shown.

[0070] Reversed-phase gas chromatography (iGC), pressure difference (Δ) p ) To investigate the surface properties of starch materials treated and untreated by iGC, samples were packed into a stainless steel GC column with an inner diameter of 4 mm and a length of 10 cm. One end of the stainless steel GC column was sealed with a thin layer of silanized glass wool. Uniform and reproducible packing of the solid sample was achieved by vibrating the column under controlled conditions. In this manner, the column was filled with starch sample to a height of approximately 9.5 cm (for the desired sample mass). m (See Table 2), then the remaining open end was sealed with silanized glass wool. The packed column was connected to the syringe module of a GC 1310 gas chromatograph from Thermo Fisher Scientific GmbH (Dreieich, Germany) using Wagelok fittings and placed in the GC instrument's oven. After equilibration at 22.7°C, the sample in the column was purged with helium (Nippon Gases, 6.0 mass) at a set inlet flow rate of 15 mL / min (controlled by the instrument's injection module), which was independently measured at the inlet of the injection module using a calibrated mass flow meter (Brooks SLA 5800). Due to the varying overall porosity in the packed starch column (due to different particle sizes and aggregation degrees), the pressure required to maintain the target flow rate varied between samples and was measured at the column inlet. The difference between this pressure value and the atmospheric pressure at the column outlet ( Δp The parameters used to describe the permeability of the filling starch material are listed in Table 2, and are related to... Figure 2 The tensile strength obtained from mechanical testing is related to this.

[0071] Polar interaction component (δ) P 2) Determination In measuring Δ pAfter the values ​​were obtained, the packed column was conditioned at 27 °C in a dry helium flow of 10 mL / min for 12 hours to remove any residual volatile compounds and thus equilibrate the starch surface under so-called “infinite dilution” (ID) conditions for subsequent iGC measurements [4]. For this purpose, small amounts of different test molecules were injected into the helium carrier gas at predetermined times (using a PAL3 RSI injection system) and thus guided through the packed column, where they interacted with the starch sample. The retention time of each probe was measured by a flame ionization detector (Trace1300 / 1600 FID module from Thermo Fisher Scientific GmbH) located at the column outlet. t R The following probe molecules were selected: n-heptane, n-octane, n-nonane, n-decane, n-undecane, chloroform, acetone, 2-butanone, diethyl ether, tetrahydrofuran, benzene, and toluene. Stagnation time was determined by injecting methane as a non-interacting molecule. t 0, thus allowing passage t N = t R - t 0. Calculate the net retention time for each test probe. t N Based on this, the following equation [4] is used to obtain the volume relative to the retention volume. V g : Here T It is an absolute analytical temperature. D c Corrected flow rate (using the James-Martin coefficient) j and ambient temperature T 0 passed D c = j · F 输出 · T / T 0 correction for the flow rate measured at the column outlet F 输出 get), m Sample quality, and S BET Its specific surface area was determined by nitrogen adsorption based on BET theory (see Table 1). S ref It is the specific surface area of ​​the reference state, which is arbitrarily chosen as S ref =1m 2 / g. Then, using each probe molecule obtained in this wayV g The value is calculated using the following equation [5] for the corresponding Flory-Huggins interaction parameter at infinite dilution. χ 12 ∞ : Here M 1. p 1. v 1. ρ 1 and B 11 These are the known molecular weight, vapor pressure, molar volume, specific gravity, and second virial coefficient of the injected probe. The density and molar volume of the stationary phase (i.e., the starch sample) are assumed to be... ρ 2 = 1.5301 g / cm³ 3 and v 2 = 466cm 3 / mol.

[0072] According to [5,6], χ 12 ∞ The squared distance between the interacting pair in the Hansen solubility parameter (HSP) space D Related: in Here δ D i δ P i and δ H i The dispersion, polarity, and hydrogen bonding components represent the interaction between the probe molecules (1) injected within the framework of HSP theory and the surface (2) provided by the material in the pillar. Using δ D 1. δ P 1 and δ H The known value of 1 allows for the selection of each probe and δ. D 2. δ P 2 and δ H The Flory-Huggins parameters are calculated using a set of given assumptions. In the iterative method [7], the experimental measurements of all studied probe molecules are compared with the calculated values. χ 12 ∞ The correlation coefficient of the linear fit was maximized to extract the Hansen solubility parameter of the starch sample that best describes the experimental data. Table 2 lists the δ values ​​of the selected porous and non-porous starch materials. D 2. δ P2 and δ H 2. Although the above theory was initially developed for soft materials that allow 3D interactions (e.g., liquids on solid supports or polymers above their glass transition temperatures), the polar HSP components measured for porous starch materials show a clear correlation with the tensile strength obtained from mechanical testing, such as... Figure 3 As shown.

[0073] References [4] E. Brendle, E. Papirer, using reversed-phase gas chromatography (iGC) Surface property characterization of applications ( Surface Properties Characterization by Inverse Gas Chromatography (iGC) Applications Powders and Fibers: Interface Science and Applications () Powders and Fibers: Interfacial Science and Applications ); CRC Press, 2006, pp. 47-122.

[0074] [5] https: / / www.stevenabbott.co.uk / practical-chromatography / hsp.php [6] C. Hansen, Hansen Solubility parameters: User manual ( Hansen Solubility Parameters: A User's Handbook ); CRC Press, 2007.

[0075] [7] https: / / www.hansen-solubility.com / HSPiP / .

[0076] In the first embodiment, the enzymatically hydrolyzed porous starch granules have a polar interaction component (δ) as determined by reversed-phase gas chromatography. P 2), δ P 2<8.8.

[0077] In the second embodiment, the enzymatically hydrolyzed porous starch granules according to the first embodiment have a relatively excessive specific surface area ( S 过量 ), 2< S 过量 <10.

[0078] In the third embodiment, the enzymatically hydrolyzed porous starch granules according to embodiment 1 or 2 have a pressure difference (Δ) across a GC column packed with starch sample and purged with helium at a flow rate of 15 mL / min. p ), 200 millibars < Δ p <800 millibars.

[0079] In the fourth embodiment, the enzymatically hydrolyzed porous starch granules according to embodiments 1 to 3 are enzymatically hydrolyzed by an enzyme selected from the group consisting of amylases.

[0080] In the fifth embodiment, the enzymatically hydrolyzed porous starch granules according to embodiments 1 to 3 are enzymatically hydrolyzed by an enzyme selected from the group consisting of α-amylase.

[0081] In the sixth embodiment, the enzymatically hydrolyzed porous starch granules according to embodiments 1 to 5 are selected from the group including corn, rice, wheat, potato and cassava starch.

[0082] In the seventh embodiment, the enzymatically hydrolyzed porous starch granules according to embodiment 6 are selected from corn starch.

[0083] In the eighth embodiment, the tablets, pills, and small capsules contain enzymatically hydrolyzed porous starch granules according to embodiments 1 to 7.

[0084] In the ninth embodiment, tablets, pills, and small capsules prepared with a compression pressure of 150 MPa according to embodiment 8 exhibit a tensile strength of >4 MPa.

[0085] In the tenth embodiment, the pharmaceutical preparation, pharmaceutical excipient, supplement, nutritional supplement, health food or cosmetic contains enzymatically hydrolyzed porous starch granules according to embodiments 1 to 3.

[0086] In the eleventh embodiment, the enzymatically hydrolyzed porous starch granules according to embodiments 1 to 3 are used for direct compression of tablets. Attached image description: Figure 1 : A graph showing the tensile strength of tablets prepared under a compression pressure of 150 MPa as a function of the relative excess specific surface area obtained by a combination of particle size and nitrogen adsorption measurements. Hollow circles: Porous starch samples prepared according to the method described in the invention in the presence of amylase, wherein only 2 < S A tensile strength of >4 MPa was observed when the excess was <10. Solid circle: A non-porous sample prepared according to the method described in this invention in the absence of amylase. Solid square: Reference material as described in Table 1.

[0088] Figure 2 : A graph showing the tensile strength of tablets prepared with a compression pressure of 150 MPa as a function of the pressure difference across a GC column packed with starch sample and purged with helium at a flow rate of 15 mL / min. Hollow circles: Porous starch samples prepared according to the method described in the invention in the presence of amylase, wherein only at 200 mbar < Δ pTensile strength >4 MPa was observed at <700 mbar. Solid circle: Non-porous sample prepared according to the method described in this invention in the absence of amylase. Solid square: Reference material as described in Table 2.

[0089] Figure 3 Within the framework of HSP theory, a graph showing the tensile strength of tablets prepared with a compression pressure of 150 MPa as a function of the polar interaction components determined by reversed-phase gas chromatography at infinite dilution. Hollow circles: Porous starch samples prepared according to the method described in the invention in the presence of amylase, wherein only δ... P Tensile strength >4 MPa was observed when 2 < 8.8, where σ 150 is more or less linearly dependent on δ P 2 (dashed line). Solid circle: A non-porous sample prepared according to the method described in this invention in the absence of amylase. Solid square: Reference material as described in Table 2.

[0090] Figure 4 Scanning electron microscopy (SEM) images (row 1) and fluorescein microscopy images (row 2) of native corn starch, N-ZORBIT, and porous starch granules. The highest porosity can be observed in porous starch. Scanning electron micrographs of tablets ruptured from the corresponding granules under a compression pressure of 150 MPa (row 3).

[0091] Example Production method of porous starch granules (Examples 1 to 27) Example 1 Add 3185 g of deionized water to a 4 L glass reactor. Add 702 g of corn starch (dry weight, anhydrous) and stir the mixture. Add 1.23 g of calcium acetate monohydrate and heat the mixture to 58 °C for 1 hour. Add 14.1 g of Termamyl amylase and stir the mixture at 58 °C for 4.8 hours. Cool the mixture to ambient temperature and filter to separate the starch granules. Load the wet starch filter cake into a 4 L glass reactor containing 2000 g of deionized water and stir the mixture at ambient temperature (20 °C to 25 °C) for 1 hour. Filter the mixture and cool the wet filter cake to -40 °C. Freeze-dry the frozen filter cake for 120 hours to remove the frozen water.

[0092] Yield: 365g white powder.

[0093] Example 2 Add 3185 g of deionized water to a 4 L glass reactor. Add 717 g of corn starch (dry weight, anhydrous) and stir the mixture. Add 1.23 g of calcium acetate monohydrate and heat the mixture to 58 °C for 1 hour. Add 14.1 g of Termamyl amylase and stir the mixture at 58 °C for 3 hours. Cool the mixture to ambient temperature and filter to separate the starch granules. Load the wet starch filter cake into a 4 L glass reactor containing 2000 g of deionized water and stir the mixture at ambient temperature (20 °C to 25 °C) for 1 hour. Filter the mixture and cool the wet filter cake to -40 °C. Freeze-dry the frozen filter cake for 96 hours to remove the frozen water.

[0094] Yield: 398g white powder.

[0095] Example 3 Add 3185 g of deionized water to a 4 L glass reactor. Add 717 g of corn starch (dry weight, anhydrous) and stir the mixture. Add 1.23 g of calcium acetate monohydrate and heat the mixture to 58 °C for 1 hour. Add 14.1 g of Termamyl amylase and stir the mixture at 58 °C for 4.6 hours. Cool the mixture to ambient temperature and filter to separate the starch granules. Load the wet starch filter cake into a 4 L glass reactor containing 2000 g of deionized water and stir the mixture at ambient temperature (20 °C to 25 °C) for 1 hour. Filter the mixture and cool the wet filter cake to -40 °C. Freeze-dry the frozen filter cake for 96 hours to remove the frozen water.

[0096] Yield: 360g white powder.

[0097] Example 4 Add 3185 g of deionized water to a 4 L glass reactor. Add 732 g of corn starch (dry weight, anhydrous) and stir the mixture. Add 1.23 g of calcium acetate monohydrate and heat the mixture to 58 °C for 1 hour. Add 14.1 g of Termamyl amylase and stir the mixture at 58 °C for 2 hours. Cool the mixture to ambient temperature and filter to separate the starch granules. Load the wet starch filter cake into a 4 L glass reactor containing 2000 g of deionized water and stir the mixture at ambient temperature (20 °C to 25 °C) for 1 hour. Filter the mixture and cool the wet filter cake to -40 °C. Freeze-dry the frozen filter cake for 96 hours to remove the frozen water.

[0098] Yield: 429g white powder.

[0099] Example 5 Add 3185 g of deionized water to a 4 L glass reactor. Add 732 g of corn starch (dry weight, anhydrous) and stir the mixture. Add 1.23 g of calcium acetate monohydrate and heat the mixture to 58 °C for 1 hour. Add 14.1 g of Termamyl amylase and stir the mixture at 58 °C for 7 hours. Cool the mixture to ambient temperature and filter to separate the starch granules. Load the wet starch filter cake into a 4 L glass reactor containing 2000 g of deionized water and stir the mixture at ambient temperature (20 °C to 25 °C) for 1 hour. Filter the mixture and cool the wet filter cake to -40 °C. Freeze-dry the frozen filter cake for 96 hours to remove the frozen water.

[0100] Yield: 335g white powder.

[0101] Example 6 Add 3185 g of deionized water to a 4 L glass reactor. Add 732 g of corn starch (dry weight, anhydrous) and stir the mixture. Add 1.23 g of calcium acetate monohydrate and heat the mixture to 58 °C for 1 hour. Add 14.1 g of Termamyl amylase and stir the mixture at 58 °C for 3.8 hours. Cool the mixture to ambient temperature and filter to separate the starch granules. Load the wet starch filter cake into a 4 L glass reactor containing 2000 g of deionized water and stir the mixture at ambient temperature (20 °C to 25 °C) for 1 hour. Filter the mixture and cool the wet filter cake to -40 °C. Freeze-dry the frozen filter cake for 96 hours to remove the frozen water.

[0102] Yield: 380g white powder.

[0103] Example 7 Comparative example without amylase Add 3160 g of deionized water to a 4 L glass reactor. Add 720 g of corn starch (dry weight, anhydrous) and stir the mixture. Heat the mixture to 61 °C for 2.75 hours. Cool the mixture to ambient temperature and filter to separate the starch granules. Crush the wet filter cake by pushing it through a sieve with a 4000 μm aperture. Transfer the wet starch to a vacuum dryer and dry at 40 °C under reduced pressure of 40 mbar to 60 mbar for 24 hours. First, push the dried starch granules through a sieve with a 2000 μm aperture, then through a sieve with a 1000 μm aperture. Remove fine particles by passing them through a sieve with a 50 μm aperture and collect 592 g of starch granules with a particle size fraction of 50 μm to 1000 μm.

[0104] Example 8 Add 3160 g of deionized water to a 4 L glass reactor. Add 720 g of corn starch (dry weight, anhydrous) and stir the mixture. Add 1.23 g of calcium acetate monohydrate and heat the mixture to 61 °C for 1 hour. Add 14.1 g of Termamyl amylase and stir the mixture at 61 °C for 1.75 hours. Cool the mixture to ambient temperature and filter to separate the starch granules. Load the wet starch filter cake into a 4 L glass reactor containing 2000 g of deionized water and stir the mixture at ambient temperature (20 °C to 25 °C) for 1 hour. Filter the mixture, crushing it by pushing the wet filter cake through a sieve with a 4000 μm mesh size. Transfer the wet starch to a vacuum dryer and dry at 40 °C under reduced pressure of 40 mbar to 60 mbar for 24 hours. First, push the dried starch granules through a sieve with a 2000 μm mesh size, then through a sieve with a 1000 μm mesh size. Fine particles were removed by sieving through a sieve with a sieve aperture size of 50 μm, and 431 g of starch granules with a particle size range of 50 μm to 1000 μm were collected.

[0105] Example 9 Add 3185 g of deionized water to a 4 L glass reactor. Add 720 g of corn starch (dry weight, anhydrous) and stir the mixture. Add 1.23 g of calcium acetate monohydrate and heat the mixture to 61 °C for 1 hour. Add 14.1 g of Termamyl amylase and stir the mixture at 61 °C for 3 hours. Cool the mixture to ambient temperature and filter to separate the starch granules. Load the wet starch filter cake into a 4 L glass reactor containing 2000 g of deionized water and stir the mixture at ambient temperature (20 °C to 25 °C) for 1 hour. Filter the mixture and crush it by pushing the wet filter cake through a sieve with a 4000 μm mesh size. Transfer the wet starch to a vacuum dryer and dry at 40 °C under reduced pressure of 40 mbar to 60 mbar for 96 hours. First push the dried starch granules through a sieve with a 2000 μm mesh size, then through a sieve with a 1000 μm mesh size. Fine particles were removed by sieving through a sieve with a sieve aperture size of 50 μm, and 324 g of starch granules with a particle size range of 50 μm to 1000 μm were collected.

[0106] Example 10 Comparative example without amylase Add 1585g of deionized water to a 4L glass reactor. Add 360g of corn starch (dry weight, anhydrous) and stir the mixture. Heat the mixture to 61°C for 1 hour. Cool the mixture to ambient temperature and spray dry. Spray drying was performed on a Büchi Mini spray dryer B-290 (BüchiLabortechnik AG) equipped with a 2.2mm dual-fluid nozzle, inert circuit B-295, and desiccant B-296 under the following conditions: nitrogen flow rate: 30m³ / h. 3 / h; inlet temperature 145℃±5℃; outlet temperature 80℃±5℃ and liquid flow rate 8g / min to 13g / min. Use a cyclone separator to collect the product.

[0107] Example 11 Add 3170 g of deionized water to a 4 L glass reactor. Add 720 g of corn starch (dry weight, anhydrous) and stir the mixture. Add 1.23 g of calcium acetate monohydrate and heat the mixture to 61 °C for 1 hour. Add 14.1 g of Termamyl amylase and stir the mixture at 61 °C for 0.5 hours. Cool the mixture to ambient temperature and filter to separate the starch granules. Load the wet starch filter cake into a 4 L glass reactor containing 2000 g of deionized water and stir the mixture at ambient temperature (20 °C to 25 °C) for 1 hour. Filter the mixture and separate the wet filter cake. Wash with 2000 g of deionized water and filter, repeating twice. Finally, mix the wet filter cake with 500 g of deionized water and spray dry. Spray drying was performed on a GEA Niro MM-PSR Mobile Minor spray dryer (GEA ProcessEngineering Pte. Ltd.) equipped with a 1.0 mm dual-fluid nozzle as follows: inlet temperature 145℃±5℃; outlet temperature 80℃±5℃; atomization pressure 0.2 bar; and liquid flow rate 25 g / min to 35 g / min. A cyclone separator was used to collect the product.

[0108] Example 12 Add 3170 g of deionized water to a 4 L glass reactor. Add 720 g of corn starch (dry weight, anhydrous) and stir the mixture. Add 1.23 g of calcium acetate monohydrate and heat the mixture to 61 °C for 1 hour. Add 14.1 g of Termamyl amylase and stir the mixture at 61 °C for 1.5 hours. Cool the mixture to ambient temperature and filter to separate the starch granules. Load the wet starch filter cake into a 4 L glass reactor containing 2000 g of deionized water and stir the mixture at ambient temperature (20 °C to 25 °C) for 1 hour. Filter the mixture and separate the wet filter cake. Wash with 2000 g of deionized water and filter, repeating twice. Finally, mix the wet filter cake with 500 g of deionized water and spray dry. Spray drying was performed on a GEA Niro MM-PSR Mobile Minor spray dryer (GEA ProcessEngineering Pte. Ltd.) equipped with a 1.0 mm dual-fluid nozzle as follows: inlet temperature 145℃±5℃; outlet temperature 80℃±5℃; atomization pressure 0.2 bar; and liquid flow rate 25 g / min to 35 g / min. A cyclone separator was used to collect the product.

[0109] Example 13 Add 3170 g of deionized water to a 4 L glass reactor. Add 720 g of corn starch (dry weight, anhydrous) and stir the mixture. Add 1.23 g of calcium acetate monohydrate and heat the mixture to 61 °C for 1 hour. Add 14.1 g of Termamyl amylase and stir the mixture at 61 °C for 2.5 hours. Cool the mixture to ambient temperature and filter to separate the starch granules. Load the wet starch filter cake into a 4 L glass reactor containing 2000 g of deionized water and stir the mixture at ambient temperature (20 °C to 25 °C) for 1 hour. Filter the mixture and separate the wet filter cake. Wash with 2000 g of deionized water and filter, repeating twice. Finally, mix the wet filter cake with 500 g of deionized water and spray dry. Spray drying was performed on a GEA Niro MM-PSR Mobile Minor spray dryer (GEA ProcessEngineering Pte. Ltd.) equipped with a 1.0 mm dual-fluid nozzle as follows: inlet temperature 145℃±5℃; outlet temperature 80℃±5℃; atomization pressure 0.2 bar; and liquid flow rate 25 g / min to 35 g / min. A cyclone separator was used to collect the product.

[0110] Example 14 Add 3170 g of deionized water to a 4 L glass reactor. Add 720 g of corn starch (dry weight, anhydrous) and stir the mixture. Add 1.23 g of calcium acetate monohydrate and heat the mixture to 61 °C for 1 hour. Add 14.1 g of Termamyl amylase and stir the mixture at 61 °C for 5 hours. Cool the mixture to ambient temperature and filter to separate the starch granules. Load the wet starch filter cake into a 4 L glass reactor containing 2000 g of deionized water and stir the mixture at ambient temperature (20 °C to 25 °C) for 1 hour. Filter the mixture and separate the wet filter cake. Wash with 2000 g of deionized water and filter, repeating twice. Finally, mix the wet filter cake with 500 g of deionized water and spray dry. Spray drying was performed on a GEA Niro MM-PSR Mobile Minor spray dryer (GEA ProcessEngineering Pte. Ltd.) equipped with a 1.0 mm dual-fluid nozzle as follows: inlet temperature 145℃±5℃; outlet temperature 80℃±5℃; atomization pressure 0.2 bar; and liquid flow rate 25 g / min to 35 g / min. A cyclone separator was used to collect the product.

[0111] Example 15 Add 3170 g of deionized water to a 4 L glass reactor. Add 720 g of corn starch (dry weight, anhydrous) and stir the mixture. Add 1.23 g of calcium acetate monohydrate and heat the mixture to 61 °C for 1 hour. Add 14.1 g of Termamyl amylase and stir the mixture at 61 °C for 1.75 hours. Cool the mixture to ambient temperature and filter to separate the starch granules. Load the wet starch filter cake into a 4 L glass reactor containing 2000 g of deionized water and stir the mixture at ambient temperature (20 °C to 25 °C) for 1 hour. Filter the mixture and separate the wet filter cake. Finally, mix the wet filter cake with 500 g of deionized water and spray dry. Spray drying was carried out on a BüchiMini spray dryer B-290 (Büchi Labortechnik AG) equipped with a 2.2 mm dual-fluid nozzle, inert circuit B-295, and desiccant B-296 under the following conditions: nitrogen flow rate: 30 m / s². 3 / h; inlet temperature 145℃±5℃; outlet temperature 80℃±5℃ and liquid flow rate 8g / min to 13g / min. Use a cyclone separator to collect the product.

[0112] Example 16 Add 3160 g of deionized water to a 4 L glass reactor. Add 720 g of corn starch (dry weight, anhydrous) and stir the mixture. Heat the mixture to 61 °C for 2.75 hours. Cool the mixture to ambient temperature and filter to separate the starch granules. Load the wet starch filter cake into a 4 L glass reactor containing 2000 g of deionized water and stir the mixture at ambient temperature (20 °C to 25 °C) for 1 hour. Filter the mixture, crushing it by pushing the wet filter cake through a sieve with a 4000 μm sieve aperture. Transfer the wet starch to a vacuum dryer and dry at 40 °C under reduced pressure of 40 mbar to 60 mbar for 24 hours. First, push the dried starch granules through a sieve with a 2000 μm sieve aperture, then through a sieve with a 1000 μm sieve aperture. Remove fine particles by passing through a sieve with a 50 μm sieve aperture and collect 550 g of starch granules with a particle size fraction of 50 μm to 1000 μm.

[0113] Example 17 Add 3160 g of deionized water to a 4 L glass reactor. Add 720 g of corn starch (dry weight, anhydrous) and stir the mixture. Add 1.23 g of calcium acetate monohydrate and heat the mixture to 58 °C for 1 hour. Add 14.1 g of Termamyl amylase and stir the mixture at 58 °C for 0.5 hours. Cool the mixture to ambient temperature and filter to separate the starch granules. Load the wet starch filter cake into a 4 L glass reactor containing 2000 g of deionized water and stir the mixture at ambient temperature (20 °C to 25 °C) for 1 hour. Filter the mixture, crushing it by pushing the wet filter cake through a sieve with a 4000 μm mesh size. Transfer the wet starch to a vacuum dryer and dry at 40 °C under reduced pressure of 40 mbar to 60 mbar for 24 hours. First, push the dried starch granules through a sieve with a 2000 μm mesh size, then through a sieve with a 1000 μm mesh size. Fine particles were removed by sieving through a sieve with a sieve aperture size of 50 μm, and 431 g of starch granules with a particle size range of 50 μm to 1000 μm were collected.

[0114] Example 18 Add 3160 g of deionized water to a 4 L glass reactor. Add 720 g of corn starch (dry weight, anhydrous) and stir the mixture. Add 1.23 g of calcium acetate monohydrate. Add 14.1 g of Termamyl amylase and stir the mixture at 61 °C for 5 hours. Cool the mixture to ambient temperature and filter to separate the starch granules. Load the wet starch filter cake into a 4 L glass reactor containing 2000 g of deionized water and stir the mixture at ambient temperature (20 °C to 25 °C) for 1 hour. Filter the mixture, crushing it by pushing the wet filter cake through a sieve with a 4000 μm mesh size. Transfer the wet starch to a vacuum dryer and dry at 40 °C under reduced pressure of 40 mbar to 60 mbar for 24 hours. First, push the dried starch granules through a sieve with a 2000 μm mesh size, then through a sieve with a 1000 μm mesh size. Fine particles were removed by sieving through a sieve with a sieve aperture size of 50 μm, and 344 g of starch granules with a particle size range of 50 μm to 1000 μm were collected.

[0115] Example 19 Add 3160 g of deionized water to a 4 L glass reactor. Add 720 g of corn starch (dry weight, anhydrous) and stir the mixture. Add 1.23 g of calcium acetate monohydrate and heat the mixture to 61 °C for 1 hour. Add 14.1 g of Termamyl amylase and stir the mixture at 61 °C for 6 hours. Cool the mixture to ambient temperature and filter to separate the starch granules. Load the wet starch filter cake into a 4 L glass reactor containing 2000 g of deionized water and stir the mixture at ambient temperature (20 °C to 25 °C) for 1 hour. Filter the mixture, crushing it by pushing the wet filter cake through a sieve with a 4000 μm mesh size. Transfer the wet starch to a vacuum dryer and dry at 40 °C under reduced pressure of 40 mbar to 60 mbar for 24 hours. First, push the dried starch granules through a sieve with a 2000 μm mesh size, then through a sieve with a 1000 μm mesh size. Fine particles were removed by sieving with a sieve having a sieve aperture size of 50 μm, and 336 g of starch granules with a particle size range of 50 μm to 1000 μm were collected.

[0116] Example 20 Add 3160 g of deionized water to a 4 L glass reactor. Add 720 g of corn starch (dry weight, anhydrous) and stir the mixture. Add 1.23 g of calcium acetate monohydrate and heat the mixture to 61 °C for 1 hour. Add 14.1 g of Termamyl amylase and stir the mixture at 61 °C for 6 hours. Cool the mixture to ambient temperature and filter to separate the starch granules. Load the wet starch filter cake into a 4 L glass reactor containing 2000 g of deionized water and stir the mixture at ambient temperature (20 °C to 25 °C) for 1 hour. Filter the mixture, crushing it by pushing the wet filter cake through a sieve with a 4000 μm mesh size. Transfer the wet starch to a vacuum dryer and dry at 40 °C under reduced pressure of 40 mbar to 60 mbar for 24 hours. First, push the dried starch granules through a sieve with a 2000 μm mesh size, then through a sieve with a 1000 μm mesh size. Fine particles were removed by sieving through a sieve with a sieve aperture size of 50 μm, and 302 g of starch granules with a particle size range of 50 μm to 1000 μm were collected.

[0117] Example 21 Add 3160 g of deionized water to a 4 L glass reactor. Add 720 g of corn starch (dry weight, anhydrous) and stir the mixture. Add 1.23 g of calcium acetate monohydrate and heat the mixture to 58 °C for 1 hour. Add 14.1 g of Termamyl amylase and stir the mixture at 58 °C for 0.5 hours. Cool the mixture to ambient temperature and filter to separate the starch granules. Load the wet starch filter cake into a 4 L glass reactor containing 2000 g of deionized water and stir the mixture at ambient temperature (20 °C to 25 °C) for 1 hour. Filter the mixture, crushing it by pushing the wet filter cake through a sieve with a 4000 μm mesh size. Transfer the wet starch to a vacuum dryer and dry at 40 °C under reduced pressure of 40 mbar to 60 mbar for 24 hours. First, push the dried starch granules through a sieve with a 2000 μm mesh size, then through a sieve with a 1000 μm mesh size. Fine particles were removed by sieving through a sieve with a sieve aperture size of 50 μm, and 572 g of starch granules with a particle size range of 50 μm to 1000 μm were collected.

[0118] Example 22 Add 3160 g of deionized water to a 4 L glass reactor. Add 720 g of corn starch (dry weight, anhydrous) and stir the mixture. Add 1.23 g of calcium acetate monohydrate and heat the mixture to 61 °C for 1 hour. Add 14.1 g of Termamyl amylase and stir the mixture at 61 °C for 1.8 hours. Cool the mixture to ambient temperature and filter to separate the starch granules. Load the wet starch filter cake into a 4 L glass reactor containing 2000 g of deionized water and stir the mixture at ambient temperature (20 °C to 25 °C) for 1 hour. Filter the mixture, crushing it by pushing the wet filter cake through a sieve with a 4000 μm mesh size. Transfer the wet starch to a vacuum dryer and dry at 40 °C under reduced pressure of 40 mbar to 60 mbar for 24 hours. First, push the dried starch granules through a sieve with a 2000 μm mesh size, then through a sieve with a 1000 μm mesh size. Fine particles were removed by sieving through a sieve with a sieve aperture size of 50 μm, and 442 g of starch granules with a particle size range of 50 μm to 1000 μm were collected.

[0119] Example 23 Add 3160 g of deionized water to a 4 L glass reactor. Add 720 g of corn starch (dry weight, anhydrous) and stir the mixture. Heat the mixture to 61 °C for 2.75 hours. Cool the mixture to ambient temperature and filter to separate the starch granules. Crush the wet filter cake by pushing it through a sieve with a 4000 μm aperture. Transfer the wet starch to a vacuum dryer and dry at 40 °C under reduced pressure of 40 mbar to 60 mbar for 24 hours. First, push the dried starch granules through a sieve with a 2000 μm aperture, then through a sieve with a 1000 μm aperture. Remove fine particles by passing them through a sieve with a 50 μm aperture and collect 610 g of starch granules with a particle size fraction of 50 μm to 1000 μm.

[0120] Example 24 Add 3160 g of deionized water to a 4 L glass reactor. Add 720 g of corn starch (dry weight, anhydrous) and stir the mixture. Add 1.23 g of calcium acetate monohydrate and heat the mixture to 61 °C for 1 hour. Add 14.1 g of Termamyl amylase and stir the mixture at 61 °C for 1.8 hours. Cool the mixture to ambient temperature and filter to separate the starch granules. Load the wet starch filter cake into a 4 L glass reactor containing 2000 g of deionized water and stir the mixture at ambient temperature (20 °C to 25 °C) for 1 hour. Filter the mixture and store the wet filter cake at 40 °C for 24 hours.

[0121] The wet filter cake was loaded into a 4L glass reactor containing 2000g of deionized water, and the mixture was stirred at ambient temperature (20°C to 25°C) for 1 hour. The mixture was filtered to separate the starch granules. The wet filter cake was crushed by pushing it through a sieve with a 4000μm aperture. The wet starch was transferred to a vacuum dryer and dried at 40°C under reduced pressure of 40-60 mbar for 24 hours. The dried starch granules were first pushed through a sieve with a 2000μm aperture, then through a sieve with a 1000μm aperture. Fine particles were removed by passing the sieve through a sieve with a 50μm aperture, and 588g of starch granules with a particle size fraction of 50μm to 1000μm were collected.

[0122] Example 25 Add 3160 g of deionized water to a 4 L glass reactor. Add 720 g of corn starch (dry weight, anhydrous) and stir the mixture. Add 1.23 g of calcium acetate monohydrate and heat the mixture to 61 °C for 1 hour. Add 14.1 g of Termamyl amylase and stir the mixture at 61 °C for 1.8 hours. Cool the mixture to ambient temperature and filter to separate the starch granules. Load the wet starch filter cake into a 4 L glass reactor containing 2000 g of deionized water and stir the mixture at ambient temperature (20 °C to 25 °C) for 1 hour. Filter the mixture and store the wet filter cake at 40 °C for 24 hours.

[0123] The wet filter cake was loaded into a 4L glass reactor containing 2000g of deionized water, and the mixture was stirred at ambient temperature (20°C to 25°C) for 1 hour. The mixture was filtered to separate the starch granules. The mixture was washed with 2000g of deionized water and filtered, repeated twice. The wet filter cake was crushed by pushing it through a sieve with a 4000μm aperture. The wet starch was transferred to a vacuum dryer and dried at 40°C under reduced pressure of 40-60 mbar for 24 hours. The dried starch granules were first pushed through a sieve with a 2000μm aperture, then through a sieve with a 1000μm aperture. Fine particles were removed by passing the sieve through a sieve with a 50μm aperture, and 324g of starch granules with a particle size fraction of 50μm to 1000μm were collected.

[0124] Example 26 Virgin corn starch, purchased from Sigma-Aldrich, was dispersed in deionized water at a ratio of 4:6. Spray drying was carried out on a Büchi Mini spray dryer B-290 (Büchi Labortechnik AG) equipped with a 2.2mm dual-fluid nozzle, an inert circuit B-295, and a desiccant B-296, under the following conditions: nitrogen flow rate: 30 m / s². 3 / h; inlet temperature 140℃±5℃; outlet temperature 80℃±5℃ and liquid flow rate 8g / min to 13g / min. Use a cyclone separator to collect the product.

[0125] Example 27 Add 2570 g of deionized water to a 4 L glass reactor. Add 1227 g of corn starch (dry weight, anhydrous), stir the mixture, and heat to 61 °C for 1 hour. Add 1.85 g of calcium acetate monohydrate and dissolve for 5 minutes. Add 211 g of amylase (Temucam 120 L) or 5.3 g (Temucam 2X), and stir the mixture at 61 °C for 2 hours. Cool the mixture to ambient temperature, filter, and wash with 1000 g of deionized water. Spray dry in a GEA Niro MM-PSR with an inlet temperature of 150 °C and an outlet temperature of 75 °C. Finally, determine the sugar content of the dried product (<5%, w / w).

[0126] Yield: Approximately 550g of white powder.

[0127] Reference N-Zorbit : N-Zorbit was purchased from Ingredion. N-Zorbit has a sugar content of 20%, which results in a high disintegration time.

[0128] N-Zorbit is used as is or in the washing method described below.

[0129] 100 g of N-Zorbit was placed in a 1 L beaker containing 250 mL of deionized water, and the mixture was stirred at ambient temperature (20°C to 25°C) for 1 hour, followed by separation using a Nutsche suction filter. The resulting wet solid was washed three more times, each time with 250 mL of deionized water, and separated using a Nutsche filter. The wet filter cake was crushed by pressing through a sieve with a 4000 μm aperture and stored at 40°C or 20°C to 25°C for 24 hours. The wet product was transferred to a vacuum dryer and dried at 40°C under reduced pressure of 40 mbar to 60 mbar for 24 hours. The dried particles were first passed through a sieve with a 2000 μm aperture, then through a sieve with a 1000 μm aperture. Fine particles were removed by passing through a sieve with a 50 μm aperture, and the product with a particle size fraction of 50 μm to 1000 μm was collected.

[0130] Table 1+2 and Figure 1 Physicochemical characterization of porous starch granules from each sample As mentioned above, the relative excess surface area (S) is measured. 过量 ), δP2, Δp and other parameters.

[0131] Scanning electron microscopy examination The starch granules were then mounted onto short inserts using Leit-C (conductive carbon cement). After sputtering a 9 nm thick platinum layer onto the granule surface, the samples were transferred to a scanning electron microscope (Zeiss Gemini 500). Images of the starch granules were captured using secondary electron contrast (based on an Everhart Thornley detector) with an accelerating voltage of 5 kV.

[0132] Fluorescence microscopy examination Starch granules were dispersed in water, and 100 ppm of sodium fluorescein was added. After approximately 1 hour, images of the fluorescein fluorescence stacking of the stained starch structures were captured at an excitation wavelength of 488 nm. The emission was integrated between 500 nm and 600 nm using a confocal laser scanning microscope (Leica, SP8).

[0133] Tablet production a) Produce tablets using a hand press (holding time is 10 seconds). To prepare tablets, a Specac Atlas Manual 15T hydraulic hand press from SPECAC INC. was used. The hand press was equipped with a 10mm diameter double-plane punch. Prior to the compression step, all powders were adjusted to the same moisture content as native starch (8.2 ± 0.8%). The matrix was filled with 300 mg of the powder thus prepared. Compression forces of 400 kg, 800 kg, 1200 kg, 1600 kg, and 2000 kg were applied, corresponding to compression pressures of 50 MPa, 100 MPa, 150 MPa, 200 MPa, and 250 MPa, and a retention time of 10 seconds. For each compression pressure, 11 tablets were prepared in the same manner.

[0134] Characterization of tablets To characterize the tablets, a Sotax ST 50 from Sotax AG with pre-installed q-doc i software was used. The following five physical parameters were analyzed using the Sotax ST 50: tablet hardness, diameter, thickness, and mass. The measured tablet hardness was converted to tensile strength by applying the following equation: τσ = tensile strength ( MPa ) ；F= Tablet hardness ( N ) ；D= diameter( mm ) ；h= thickness( mm ) Five tests were performed on a single sample (corresponding to a powder produced under one compression pressure). The calculated average value was taken as the result.

[0135] Scanning electron microscopy examination of tablet cross sections The tablet was manually split in half. The cross-section was then mounted onto a short insert using Leit-C (conductive carbon cement). After sputtering a 12 nm thick platinum layer onto the cross-section surface, the sample was transferred to a scanning electron microscope (Zeiss Gemini 500). Images of the cross-section were captured using secondary electron contrast (based on an Everhart Thornley detector) with an accelerating voltage of 5 kV.

[0136] Overview of all measurements in each embodiment

[0137] Table 1: Results of particle size measurement (median diameter) d 50 ), nitrogen adsorption experiment (based on BET and Langmuir theory of specific surface area) product, S BET and S 朗缪尔 And the interaction constant from BET theory, C BET ) and mechanical testing (after compression at 150 MPa) Tensile strength, σ 150 The properties of treated and untreated starch products were determined. Assuming a spherical geometry, [the following is a list of parameters]. d 50 Values Calculate the envelope specific surface area ( S 包络 ), while the relative excess specific surface area ( S 过量 As S BET and S 包络 The ratio is given .

[0138] Table 2: Selected properties of treated and untreated starch products determined by reversed-phase gas chromatography: column Sample mass required to fill to a height of approximately 9.5 cm m The pressure difference Δ measured across the packed column in a helium flow of 15 mL / min. p ; The Hansen solubility parameter (HSP) represents the dispersion of surfaces provided by the material in the column under infinite dilution conditions. Quantity ( δD 2) Polar components ( δP 2) and hydrogen bond component (δ) H 2). For comparison, preparation using a compression pressure of 150 MPa is also shown. The corresponding value of the tensile strength of the tablet ( σ 150 ) .

[0139] The following experiments were conducted using the porous starch from Example 27. : Determination of sugar content in dried porous starch: Determine the solids content of the porous starch sample (e.g., a solids content of 95% means the sample consists of 9.5g of product and 0.5g of water). Provide 25g of water to a beaker and add 10g of the porous starch sample while stirring, taking into account the sample's solids content. Stir at room temperature for 1 hour and then vacuum through a blue ribbon filter. Determine the solids content of the filtrate at 120°C (vacuum) for 2 hours.

[0140] Tableting experiment without active ingredients (starch), (holding time <10ms) Tableting experiments were conducted using a fully instrumented compaction simulator, StylOne Evo (Medelpharm, Germany), equipped with a round, flat punch (10 mm in diameter). Each tablet contained 300 mg and was compressed at forces of 4 kN, 8 kN, 12 kN, 16 kN, and 20 kN. Tablet weight, dimensions, and hardness were measured using a Sotax tablet hardness tester (Sotax, Switzerland).

[0141] 1) Calculate the compression pressure using the following formula: 2) Calculate the tensile strength of the tablet using the following formula: 3) Particle size was determined by laser diffraction. The particle size distribution of the samples was determined using a Mastersizer 2000 equipped with a Scirocco 2000 sample processing unit, manufactured by Malvern Panalytical Ltd. (Worcestershire, UK). This instrument measures the angular change in the intensity of scattered light as a laser beam passes through a dispersed particulate sample. Larger particles primarily scatter light at a small angle relative to the laser beam, while smaller particles contribute more to the light scattered at a large angle. The following detailed settings were used for the measurements: • Optical limit: 0.1-6.0 optical limit • Timeout period: 2 minutes • Result range: 0.02-2000μm • Result Calculation: General • Measurement time: 60 seconds • Measurement snapshot: 60,000 • Background time: 5 seconds • Background snapshot: 5.000 Porous starch granules in dry powder form were measured for approximately 30–60 seconds at a dispersion air pressure of 0.5 bar or 1.0 bar. From the collected angular scattering intensity data, the particle size distribution was calculated using software provided by the manufacturer (version 6.00), which applied a simplified Fraunhofer approximation for evaluation [1]. The particle size was obtained as the diameter of a volume-equivalent sphere and reported as characteristic percentile values ​​of the lower 10% (d10), 50% (d50), and 90% (d90) of the entire distribution.

[0142] References [3] J. Vargas-Ubera, JF Aguilar, DM Gale, Appl. Opt. 2007, 46,124-132.

[0143] 4) Determination of drying loss To determine drying loss, an IR moisture analyzer MA150 from Sartorius (Sartorius, Germany) was used. 5–6 g of sample was evenly distributed on a sample tray and dried at 105 °C until constant mass was achieved.

[0144] Table 3: Results of tablet compression experiment (starch, without active ingredients)

[0145] It's impossible to compress the tablets.

[0146] Tableting experiment using active ingredients Propranolol hydrochloride, acetaminophen, and diclofenac sodium were used as model active ingredients to demonstrate the performance of novel porous starch as a multifunctional tableting excipient.

[0147] The composition of the formulation is shown in Table 4. :

[0148] The active ingredient and starch-based excipient were sieved (800 μm sieve) and mixed in a Turbula mixer for 8 minutes. Sodium stearoyl fumarate (pre-sieved through an 800 μm sieve) was added to the mixture, and the mixture was mixed for another 2 minutes.

[0149] Tableting experiments were conducted using a fully instrumented compaction simulator, StylOne Evo (Meldelpharm, Germany), equipped with a round, flat punch (10 mm) in diameter. Each tablet contained 300 mg of active ingredient (including, for example, (50% API formulation): 150 mg of active ingredient, 147 mg of starch-based excipients, and 3 mg of sodium stearoyl fumarate). Tablets were compressed under compression forces of 4 kN, 8 kN, 12 kN, 16 kN, and 20 kN (holding time <10 ms).

[0150] Calculate the compression pressure using the following formula: Calculate the tensile strength of the tablet using the following formula: Disintegration time (minutes) was measured using a Sotax ST50 disintegration tester according to United States Pharmacopeia Chapter 701 disintegration. Six tablets were tested in water at 37°C.

[0151] Table 5: Results for 50% (w / w) active ingredient

[0152] It's impossible to compress the tablets.

[0153] Table 6: Results for 25% (w / w) active ingredient

[0154] Table 7: Results of 5% (w / w) active ingredient

[0155] In addition, experiments were conducted using tablets (starch) without active ingredients at different holding times. N-Zorbit was purchased from Ingredion. N-Zorbit contains 20% sugar, which results in a high disintegration time. In the following examples, N-Zorbit was used as is (N-Zorbit-W0).

[0156] 1. Production of porous starch Example H202-24) Add 2570 g of deionized water to a 4 L glass reactor. Add 1227 g of corn starch (dry weight, anhydrous), stir the mixture, and heat to 61 °C for 1 hour. Add 1.85 g of calcium acetate monohydrate and dissolve for 5 minutes. Add 21.1 g of amylase (Temucam 120 L) or 5.3 g of (Temucam 2X), and stir the mixture at 61 °C for 2 hours. Set the product medium to pH 3 with 1 N sulfuric acid and stir for another 30 minutes, then set the pH to 6.5 with 1 N NaOH (H2O2-24-01-WO). Cool the mixture to ambient temperature, filter, and wash with 1000 g of deionized water for 30 minutes (using one or three washing steps). Spray dry in a B290 Advanced Büchi with an inlet temperature of 135 °C and an outlet temperature of 75 °C. Yield: Approximately 110 g of white powder.

[0157] H202-24-01-W1 (has one washing step) H202-24-03-W3 (has three washing steps).

[0158] 2. Produce tablets using a hand press (holding time is 10 seconds). To prepare tablets, a Specac Atlas Manual 15T hydraulic hand press from SPECAC INC. was used. The hand press was equipped with a 10mm diameter double-plane punch. Prior to the compression step, all powders were adjusted to the same moisture content as native starch (8.2 ± 0.8%). The matrix was filled with 300 mg of the powder thus prepared. Compression forces of 400 kg, 800 kg, 1200 kg, 1600 kg, and 2000 kg were applied, corresponding to compression pressures of 50 MPa, 100 MPa, 150 MPa, 200 MPa, and 250 MPa, and a holding time of 10 seconds. For each compression pressure, 11 tablets were prepared in the same manner.

[0159] Characterization of tablets To characterize the tablets, a Sotax ST 50 from Sotax AG with pre-installed q-doc i software was used. The following five physical parameters were analyzed using the Sotax ST 50: tablet hardness, diameter, thickness, and mass. The measured tablet hardness was converted to tensile strength by applying the following equation: τσ = tensile strength (MPa); F= Tablet hardness (N); D= diameter (mm); h= thickness (mm) Five tests were performed on a single sample (corresponding to a powder produced under one compression pressure). The calculated average value was taken as the result.

[0160] 3. Produce tablets using a compaction simulator (holding time <10ms) Tableting experiments were conducted using a fully instrumented compaction simulator, StylOne Evo (Medelpharm, Germany), equipped with a 10mm diameter dual-plane punch. Prior to the compression step, all powders were adjusted to the same moisture content (8.2% ± 0.8%). Each tablet contained 300 mg and was compressed at compressive forces of 4 kN, 8 kN, 12 kN, 16 kN, and 20 kN (corresponding to 50 MPa, 100 MPa, 150 MPa, 200 MPa, and 250 MPa) and holding times of <10 ms. For each compression pressure, 10 tablets were prepared in the same manner. Tablet weight, dimensions, and hardness were measured using a Sotax tablet hardness tester (Sotax, Switzerland).

[0161] 1) Calculate the compression pressure using the following formula: 2) Calculate the tensile strength of the tablet using the following formula:

[0162] Table 8: Results of particle size measurement (median diameter) d 50 ), nitrogen adsorption experiment (based on BET and Langmuir theory of specific surface area) product, S BET and S 朗缪尔 And the interaction constant from BET theory, C BET ) and mechanical testing (after compression at 150 MPa) Tensile strength, σ 150 The properties of treated and untreated starch products were determined. Assuming a spherical geometry, [the following is a list of parameters]. d 50 Values Calculate the envelope specific surface area ( S 包络 ), while the relative excess specific surface area ( S 过量 As S BET and S 包络 The ratio is given .

[0163] Table 9: Selected properties of treated and untreated starch products determined by reversed-phase gas chromatography: column Sample mass required to fill to a height of approximately 9.5 cm m The pressure difference Δ measured across the packed column in a helium flow of 15 mL / min. p ; The Hansen solubility parameter (HSP) represents the dispersion of surfaces provided by the material in the column under infinite dilution conditions. Quantity ( δD 2) Polar components ( δP 2) and hydrogen bond component (δ) H 2). For comparison, preparation using a compression pressure of 150 MPa is also shown. The corresponding value of the tensile strength of the tablet ( σ 150 ) .

Claims

1. Enzymatic hydrolysis of porous starch granules results in a relatively excess specific surface area (...). S 过量 ), 2< S 过量 <10.

2. Enzymatic hydrolysis of porous starch granules, which exhibit polar interaction components (δ0.05) as determined by reversed-phase gas chromatography. P 2), δ P 2 < 8.

8.

3. Enzymatic hydrolysis of porous starch granules, which has a pressure difference (Δ) across a GC column packed with starch sample and purged with helium at a flow rate of 15 mL / min. p ), 200 millibars < Δ p <800 millibars.

4. Enzymatic hydrolysis of porous starch granules results in a relatively excess specific surface area (...). S 过量 ), 2< S 过量 <10, and has a polar interaction component (δ) as determined by reversed-phase gas chromatography. P 2), δ P 2 < 8.

8.

5. Enzymatic hydrolysis of porous starch granules results in a relatively excessive specific surface area ( S 过量 ), 2< S 过量 <10, and has a pressure difference (Δ) across a GC column packed with starch sample and purged with helium at a flow rate of 15 mL / min. p ), 200 millibars < Δ p <800 millibars.

6. Enzymatic hydrolysis of porous starch granules results in a relatively excess specific surface area ( S 过量 ), 2< S 过量 <10, and has a polar interaction component (δ) as determined by reversed-phase gas chromatography. P 2), δ P 2 < 8.8, and has a pressure difference (Δ) across a GC column packed with starch sample and purged with helium at a flow rate of 15 mL / min. p ), 200 millibars < Δ p <800 millibars.

7. The enzymatically hydrolyzed porous starch granules according to claims 1 to 6, wherein the granules have a relatively excess specific surface area (… S 过量 ), 2< S 过量 <7.

8. The enzymatic hydrolysis of porous starch granules according to claims 1 to 7, wherein the enzyme is selected from the group consisting of amylases.

9. The enzymatic hydrolysis of porous starch granules according to claim 8, wherein the enzyme is selected from the group consisting of α-amylase.

10. The enzymatically hydrolyzed porous starch granules according to claims 1 to 9, wherein the porous starch is selected from the group consisting of corn starch, rice starch and potato starch.

11. The enzymatically hydrolyzed porous starch granules according to claim 10, wherein the selected starch is corn starch.

12. The enzymatically hydrolyzed porous starch granules according to claims 1 to 11, wherein the porous starch granules preferably have a sugar and oligosaccharide content of no more than 5% by weight, more preferably no more than 1.5% by weight, and even more preferably no more than 0.5% by weight.

13. The enzymatically hydrolyzed porous starch granules according to claims 1 to 12, when compressed under a pressure of 150 MPa, yield a solid dosage form with a tensile strength of >4 MPa.

14. The enzymatically hydrolyzed porous starch granules according to claims 1 to 13, when compressed at a pressure of 150 MPa and a holding time of 10 s, yield a solid dosage form with a tensile strength of >4 MPa.

15. A dosage form comprising enzymatically hydrolyzed porous starch granules according to any one of claims 1 to 14.

16. The direct-compressed pharmaceutical dosage form according to claim 15, wherein the dosage form is a tablet, pill, small tablet, lozenge, or other solid tablet.

17. The direct-pressed pharmaceutical dosage form according to claim 16, comprising porous starch granules present at a concentration of 1% to 98% by weight based on the total weight of the dosage form.

18. The direct-pressed pharmaceutical dosage form according to claims 15 to 17, comprising one or more active pharmaceutical ingredients present at a concentration of 1% to 80% by weight based on the total weight of the dosage form.

19. The direct-pressed pharmaceutical dosage form according to claim 17, wherein one or more active pharmaceutical ingredients are mixed with and / or loaded into the enzymatically hydrolyzed porous starch granules.

20. The direct-pressed pharmaceutical dosage form according to claims 16 to 19, wherein the concentration of lubricant and flow agent, based on the total weight of the dosage form, does not exceed 10%, preferably not more than 7.5%, and even more preferably not more than 5%.

21. A pharmaceutical preparation, food preparation, feed preparation, agrochemical preparation or cosmetic preparation, comprising enzymatically hydrolyzed porous starch granules according to any one of claims 1 to 15.

22. The directly compressed pharmaceutical dosage form according to claims 15 to 20, characterized in that: The directly compressed pharmaceutical dosage form according to claims 16 to 20, characterized in that: The active pharmaceutical ingredient (API) content is 10% to 80% by weight, the tensile strength of the tablet (compressed at 150 MPa) is >1.5 MPa, and the disintegration time is <5 minutes, but it does not contain disintegrants.

23. The direct-pressed pharmaceutical dosage form according to claim 22, wherein the API content is 25% to 50% by weight, preferably 25% by weight.

24. The directly compressed pharmaceutical dosage form according to claims 15 to 20, having the following characteristics: The directly compressed pharmaceutical dosage form according to claims 16 to 20, having the following characteristics: The API content is 10% to 80% by weight, preferably 25% to 50% by weight, more preferably 25% by weight, and the tablet has a tensile strength (when compressed at 150 MPa, holding time <10 ms) >1.5 MPa and a disintegration time <5 minutes, but does not contain disintegrants.

25. Use of the enzymatically hydrolyzed porous starch granules according to claims 1 to 14 for the direct compression of tablets, pills, small tablets, lozenges and other pharmaceutical tablets.

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