Oral biopolymer delivery systems

Abstract

The present invention relates to pharmaceutical dosage forms suitable for gastrointestinal delivery and methods for treating conditions suitable for treatment by gastrointestinal delivery.

Description

[Technical Field]

[0001] The present invention relates to pharmaceutical dosage forms suitable for gastrointestinal delivery and methods for treating conditions suitable for treatment by gastrointestinal delivery. [Background technology]

[0002] When a biopolymer, such as a protein or peptide, is orally administered, the body processes it as a nutrient, typically digesting it into dipeptides, tripeptides, and amino acids, which are then absorbed as nutrients. When this occurs, if a therapeutic effect is intended, the biopolymer is no longer in its intact native conformation and will not exert its intended effect. Therefore, to retain its intended effect, the biopolymer must be sufficiently protected from digestion in the gastrointestinal tract (GIT) and sufficiently maintained in its active native conformation, whether locally in the GIT for a local effect on the GIT mucosa or for systemic absorption across the GI membrane into the bloodstream.

[0003] Ideally, the composition will exhibit a high surface area to volume (SA / Vol) ratio due to the larger contact surface area with the GIT luminal folds, rather than being concentrated within a single large, low surface area contact point as is the case with larger tablets of standard size.

[0004] A larger contact surface area within the GIT lumen may reduce adverse effects (GI membrane irritation, ulceration, etc.) and increase contact points with the GIT mucosa for more effective delivery. Achieving a higher SA / Vol ratio for the dosage form will facilitate a larger contact surface area.

[0005] However, a drawback of a high SA / Vol ratio is the increased exposure of the biopolymer active pharmaceutical ingredient (API) to the digestive mechanisms (pH, enzymes, microorganisms) in the GIT. Increasing the SA / Vol ratio typically means that GI fluids penetrate the composition more quickly, resulting in the digestion of a larger proportion of the biopolymer API dose within a given time frame. Increasing the SA / Vol ratio without increasing macromolecule digestion would be ideal, but counterintuitive. The present invention breaks this paradigm of opposing directions. Summary of the Invention [Problem to be solved by the invention]

[0006] It is an object of embodiments of the present invention to provide a pharmaceutical solid dosage form for the treatment of conditions by gastrointestinal delivery of one or more therapeutically active biopolymers. [Means for solving the problem]

[0007] The present invention relates in a broad aspect to a multi-site microenvironment concept in the form of a solid dosage form for the effective delivery of biomacromolecules through the gastrointestinal system.

[0008] Thus, in a first aspect, the present invention provides a pharmaceutical solid dosage form for the treatment of a condition by gastrointestinal delivery comprising a plurality of single units, each single unit comprising: a) one or more therapeutically active biopolymers; b) one or more water-soluble polymers in an amount of about 50% by weight or less; c) a small molecule weak acid (WA), weak acid surfactant (WAS) or salt thereof in an amount of about 75% by weight or less Each single unit contains 1.0 mm -1 Surface area to volume (SA / Vol) ratio of over 1.0 g / cm 3 The present invention relates to a pharmaceutical solid dosage form having a single unit density greater than 1000 mg / kg, wherein the solid dosage form comprises a therapeutically effective amount of a therapeutically active biopolymer obtained from a combined multiple of each single unit.

[0009] In a second aspect, the present invention relates to a method of treating a subject in need of a biopolymer as defined herein, the method comprising: (a) providing a solid oral dosage form according to the present invention; and (b) orally administering the solid oral dosage form to the patient. In some embodiments, the solid dosage form provides a pharmacokinetic profile of the active biopolymer having a T lag of greater than 1.0 hour and less than 16 hours after administration, and a T max of greater than (T lag + 0.5 hour) and less than 20 hours after administration.

[0010] In a third aspect, the present invention relates to a process for the preparation of a pharmaceutical solid dosage form as defined herein, comprising the steps of providing components a), b) and c) and formulating the dosage form into a tablet or capsule by tabletting, direct compression tabletting, dry granulation followed by tabletting, roller compaction followed by tabletting, dry powder layering, pelleting, slugging, or the like, and optionally including an encapsulation step. DETAILED DESCRIPTION OF THE INVENTION

[0011] The present invention is directed to compositions having a higher SA / Vol ratio due to a larger contact surface area with the GIT luminal folds, while also protecting the biopolymer API from digestion to a similar extent as a standard-sized tablet with a lower SA / Vol. That is, the compositions of the present invention have a higher SA / Vol ratio than standard-sized tablets due to a larger contact surface area, without sacrificing the protection of the biopolymer API from the digestive mechanism that would otherwise occur with a high SA / Vol. Thus, the intact biopolymer API has more time and contact surface area for either the required localized action or systemic absorption. Thus, the contradictory direction paradigm is broken when a high SA / Vol is achieved without the drawback of increasing the susceptibility of the biopolymer API to the digestive mechanism.

[0012] The composition will also exhibit sufficient single unit density to facilitate sinking of the composition into the GIT luminal folds.

[0013] Bulkier biopolymers are approximately 10-4 P of a small molecule app Coefficient of about 10 -9 P app It should be understood that small molecules diffuse more slowly by a factor of 1, i.e., about 5 times faster than P app By formulating a water-soluble polymer into a single unit containing the composition, a hydrogel is formed, allowing the small molecule weak acid (WA), weak acid surfactant (WAS) or salt thereof to diffuse more slowly than the biopolymer, keeping the small molecule weak acid (WA), weak acid surfactant (WAS) or salt thereof in close proximity to the biopolymer, and creating a microenvironment around each unit of the composition that adequately protects the biopolymer from GIT digestive mechanisms for up to at least one hour.

[0014] As a result, there are multiple units of the composition within a specific location in the GIT, each with its own microenvironment, which function to sufficiently protect the biopolymer from digestion for up to at least one hour to increase the availability of the intact biopolymer API within the GIT lumen for its intended effect.

[0015] Although the volume of fluid in the GIT at any given time is relatively small, there is significant turnover of fluid flowing through and being reabsorbed through the GIT. A solid dosage form according to the present invention facilitates retaining the majority of the faster diffusing small molecule weak acid (WA), weak acid surfactant (WAS) or salt thereof in close proximity to the slower diffusing biopolymers for enhanced protection from digestion, even in the presence of high GIT fluid turnover.

[0016] biopolymers As used herein, "therapeutically active biopolymer" refers to a molecule having a molecular weight of about 500 Da or greater that has a therapeutic effect in a subject in need thereof. Accordingly, the present invention does not contemplate a small organic molecule API used alone, but it should be understood that one or more small organic molecule APIs can be combined with one or more biopolymers. Suitable therapeutically active biopolymers within the present invention include oligonucleotides, DNA fragments, RNA fragments, messenger RNA, small interfering RNA, modified RNA, oligopeptides, peptides and polypeptides from smaller peptides to larger antibodies and multi-subunit proteins (synthetic polypeptides, hormones, insulin, growth factors, monoclonal antibodies, fusion proteins, enzymes, therapeutic enzymes, bispecific antibodies, multispecific antibodies, antibody fragments, interleukins, cytokines, antibody-drug conjugates, glycoproteins and viral proteins, e.g., leuprolide, insulin, Vasopressin, calcitonin, calcitonin gene-related peptide, desmopressin, gonadotropin-releasing hormone (GnRH), luteinizing hormone-releasing factor, adrenocorticotropic hormone, enkephalin, glucagon, glucagon-like peptide-1, glucagon-like peptide-2, somatostatin, gastrin, glucose insulinotropic polypeptide, peptide yy, amylin, islet amyloid polypeptide, linaclotide, octreotide, semaglutide, liraglutide, tirzepatide, dulaglutide, exenatide, lixisenatide, econoglutide, oxytocin and 2,A peptide or antibody selected from the group consisting of 6-dimethyltyrosine-D-arginine-phenylalanine-lysine amide, a vaccine, lactoferrin, parathyroid hormone, growth hormone, human growth hormone, cytokine, interferon, interleukin or an antagonist thereof, for example, any of IL1 to IL40, for example, IL1, IL2, IL10, IL12, IL19, IL21, IL23, IL26, IL27, IL28, IL29, IL36, IL37, IL38, IL39, IL40, lysozyme, β-casein, albumin, α-1 antitrypsin, antithrombin III, collagen, factor VII, factor VIII, factor IX, factor X, fibrinogen, insulin, protein C, erythropoietin (EP Examples of peptides include, but are not limited to, polypeptides or proteins selected from the group consisting of: α-, α-, α-CSF, granulocyte-macrophage colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), tissue-type plasminogen activator (tPA), somatotropin, integrins, alpha-4, beta-7 integrins, chymotrypsin, lipase, pancrelipase, amylase and protease, adalimumab, tofacitinib, forarumab, bevacizumab, rituximab, trastuzumab, denosumab, ranibizumab, tocilizumab, certolizumab, golimumab, secukinumab, griffithsin, alpha 1,2-fucosidase, xylanase, phytase, and tumor necrosis factor (TNF). As used herein, peptide refers to a collection of amino acids linked together via peptide (amide) bonds. Polypeptides generally refer to longer chains of amino acids having more than 50 amino acids, while oligopeptides refer to chains of fewer than 20 amino acids. The terms peptide, oligopeptide, and polypeptide are intended to include both branched and continuous unbranched chains of amino acids. Protein, as used herein, refers to chains of amino acids, such as peptides or polypeptides, of any primary, secondary, tertiary, and quaternary structure, potentially including any post-translational modifications such as phosphorylation, glycosylation, ubiquitination, nitrosylation, methylation, acetylation, lipidation, and proteolysis.

[0017] In some embodiments, the therapeutically active biopolymer comprises an enzyme. In some embodiments, the enzyme comprises a lipase, a protease, an amylase, enterokinase, or a carbohydrate enzyme. In some such embodiments, the enzyme comprises a lipase. In some embodiments, the enzyme comprises a lipase. In some embodiments, the enzyme comprises a colipase. In some embodiments, the enzyme comprises a phospholipase A1 or a phospholipase A2. In some embodiments, the enzyme comprises an esterase. In some embodiments, the enzyme comprises pancreatic lipase-related protein 2. In some embodiments, the enzyme comprises a gastric lipase. In some embodiments, the enzyme comprises a protease. In some embodiments, the protease comprises trypsin, chymotrypsin, carboxypolypeptidase, elastase, nuclease, pepsin, or subtilisin. In some embodiments, the enzyme comprises an amylase. In some such embodiments, the amylase comprises an alpha-amylase, beta-amylase, or glucoamylase. In some embodiments, the enzyme comprises enterokinase. In some embodiments, the enzyme comprises a carbohydrate enzyme. In some such embodiments, the enzyme comprises a cellohydrolase, beta-glucosidase, lactase, galactase, trehalase, mannanase, alpha-glucosidase, sucrase, isomaltase, or xylanase.

[0018] Water-soluble polymers As used herein, "water-soluble polymer" refers to any water-soluble polymer known to those skilled in the art, including those suitable for pharmaceutical use. Suitable known water-soluble polymers that can be used in accordance with the present invention include cellulose derivative polymers, such as those selected from the list consisting of hydroxypropylmethylcellulose (HPMC), methylcellulose (MC), carboxymethylcellulose (CMC), e.g., sodium carboxymethylcellulose, hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), and hydroxyethylmethylcellulose (HEMC). Suitable known water-soluble polymers also include alginates, e.g., sodium alginate, carrageenan, pectin, chitosan, trimethylchitosan, hyaluronic acid, polycarbophil, carbomer, polyethylene oxide, polyvinylpyrrolidone and their copolymers, and methacrylic acid derivative polymers, as well as derivatives and salts thereof. The water-soluble polymer can act as a hydrogel former.

[0019] cellulose or cellulose derivative polymers Any suitable cellulose or cellulose derivative polymer may be used in accordance with the present invention, and those skilled in the art will be aware of suitable polymers. Suitable cellulose or cellulose derivative polymers for use in accordance with the present invention include cellulose, microcrystalline cellulose (MCC), low-viscosity hydroxypropyl cellulose (HPC), ethyl cellulose (EC), methyl cellulose (MC), carboxymethyl cellulose (CMC), and hydroxypropyl methylcellulose (HPMC), such as hypromellose 2910 (7-12% HP, 28-30% methoxy), hypromellose 2906 (4-7.5% HP, 27-30% methoxy), hypromellose 2208 (4-12% HP, 19-24% methoxy), and hypromellose 1828 (23-32% HP, 16.5-20% methoxy). Commercially available microcrystalline cellulose (MCC) includes Avicel® from IFF and Emcocel from JRS Pharma. Commercially available carboxymethylcellulose (CMC) includes TEXTURECEL™ from IFF, CPKelco's Celetec™, Ashland's Aqualon™, USK Kimya AS's Rheoflo™, and Nouryon's (formerly AkzoNobel) Akucell™. Commercially available methylcellulose and hydroxypropyl methylcellulose include the METOLOSE and PHARMACOAT™ series of the Japanese Pharmacopoeia and the METOLOSE and PHARMACOAT series for food additives from Shin-Etsu Chemical Co., Ltd., the AnyCoat-C or AnyAddy™ series from Lotte (formerly Samsung) Fine Chemicals Co., Ltd., the METHOCEL™ series from International Flavors & Fragrances (IFF) (formerly DOW Chemical Company), and Ashland's Benecel™ series.

[0020] Methylcellulose is one type of cellulose derivative polymer suitable for the present invention. Methylcellulose has anhydroglucose units joined by one to four linkages. Each anhydroglucose unit contains hydroxyl groups at the 2, 3, and 6 positions. Partial or complete replacement of these hydroxyl groups with methoxyl groups results in methylcellulose. For example, treatment of cellulose fibers with a caustic solution followed by a methylating agent results in a cellulose ether substituted with one or more methoxyl groups. When not further substituted with other alkyls, this cellulose ether is known as methylcellulose. Methylcellulose is characterized by the weight percent of methoxyl groups. By convention, the weight percent is an average weight percentage based on the total weight of the cellulose repeating units, including all substituents. The methoxyl content is reported based on the mass of the methoxyl groups (i.e., -OCH3). Determination of the % methoxyl in methylcellulose (MC) polymers is performed according to the United States Pharmacopeia (USP 37, "Methylcellulose," pages 3776-3778). The % methoxyl can be converted to the degree of substitution (DS) for methyl substituents, i.e., DS(methyl). The DS(methyl) of methylcellulose, also known as DS(methoxyl), is the average number of OH groups replaced with methyl groups per anhydroglucose unit.

[0021] Hydroxyalkyl methylcellulose is another cellulose derivative polymer suitable for the present invention. Hydroxyalkyl methylcellulose is a cellulose ether having anhydroglucose units joined by 1 to 4 linkages and having both methyl and hydroxyalkyl groups. The hydroxyalkyl groups can be the same or different from each other. Preferably, the cellulose ether contains one or two hydroxyalkyl groups, more preferably one or more hydroxy-C1-3-alkyl groups, such as hydroxypropyl and / or hydroxyethyl. Useful optional alkyl groups are, for example, ethyl or propyl. Preferred ternary cellulose ethers are ethyl hydroxypropyl methylcellulose, ethyl hydroxyethyl methylcellulose, or hydroxyethyl hydroxypropyl methylcellulose. Preferred cellulose ethers are hydroxyalkyl methylcelluloses, particularly hydroxy-C1-3-alkyl methylcelluloses, such as hydroxypropyl methylcellulose or hydroxyethyl methylcellulose.

[0022] The cellulose ether has a DS(methyl) of 1.2 to 2.2, preferably 1.2 to 1.6. The degree of methyl substitution of a cellulose ether, DS(methyl), is the average number of OH groups replaced by methyl groups per anhydroglucose unit. For purposes of determining DS(methyl), the term "OH groups substituted by methyl groups" includes not only methylated OH groups directly attached to carbon atoms of the cellulose backbone, but also methylated OH groups formed after hydroxyalkylation.

[0023] The cellulose ether has an MS (hydroxyalkyl) of 0.05 to 1.00, preferably 0.08 to 0.80, more preferably 0.12 to 0.70, even more preferably 0.15 to 0.60, most preferably 0.20 to 0.40, and especially 0.25 to 0.35. The degree of hydroxyalkyl substitution is described by the MS (molar substitution). MS (hydroxyalkyl) is the average number of hydroxyalkyl groups attached by ether bonds per mole of anhydroglucose unit. During hydroxyalkylation, multiple substitutions can result in side chains.

[0024] In the case of hydroxypropyl methylcellulose, the determination of methoxyl% and hydroxypropoxyl% in hydroxypropyl methylcellulose is carried out according to the United States Pharmacopoeia (USP 43). The values ​​obtained are methoxyl% and hydroxypropoxy%. These are then converted to the degree of substitution (DS) for the methyl substituent and the molar substitution (MS) for the hydroxypropyl substituent. The residual amount of salts was taken into account in the conversion. The DS (methyl) and MS (hydroxyethyl) of hydroxyethyl methylcellulose are determined by Zeisel cleavage with hydrogen iodide followed by gas chromatography. (G. Bartelmus and R. Ketterer, Z. Anal. Chem. 286 (1977) 161-190)

[0025] The viscosity of the cellulose ethers of the present invention is determined as a 2 wt. % solution in water using a Brookfield rotational viscometer or an Ubbelohde tube according to the United States Pharmacopoeia (USP 43). Solutions for viscosity measurement of the cellulose ethers are prepared by adding an appropriate amount of cellulose ether powder to an appropriate amount of water to achieve a 2% concentration while stirring with an overhead laboratory stirrer at elevated temperature. The solution is then equilibrated to a lower temperature as specified in USP 43.

[0026] Solutions for viscosity measurements of sodium carboxymethylcellulose (CMC, e.g., TEXTURACEL™ 20000 PA 07) are prepared by adding an appropriate amount of CMC powder to an appropriate amount of water to achieve a concentration of 1 or 2% according to USP 43, while stirring with an overhead laboratory stirrer at ambient temperature for at least 1 hour. Viscosity is measured according to USP 43.

[0027] Alginates and their salts. Alginates, particularly those derived from brown algae, are linear, unbranched biopolymers composed of (1-4)-linked β-D-mannuronic acid (M) and α-L-guluronic acid (G) residues. Alginates are not random copolymers, but consist of blocks of similar and alternating sequences of residues, such as MMMM, GGGG, and GMGM. In their extracted form, alginates rapidly absorb water. The physical properties of alginate may depend on the relative proportions of M and G blocks. Gel formation at neutral pH requires a calcium source to provide calcium ions for interaction with the G blocks. The greater the proportion of these G blocks, the stronger the gel.

[0028] "Alginate" is a term usually used for salts of alginic acid, but can also refer to all derivatives of alginic acid and alginic acid itself. Alginate exists in the cell walls of brown algae as calcium, magnesium, and sodium salts of alginic acid. Dry, powdered sodium or potassium alginate can be obtained from this brown algae extraction process. The seaweed residue is then removed by filtration, and the remaining alginate can then be recovered from the aqueous solution.

[0029] Another method for recovering alginate from the initial extraction solution is to add calcium salts, which form calcium alginate with a fibrous structure that is insoluble in water and can be separated from the water. The separated calcium alginate is suspended in water and acid is added to convert it to alginic acid.

[0030] Alginates suitable for use in the practice of the present invention typically have a molecular weight such that they exhibit a viscosity in the range of 5 to 1,000 mPa·s. -1 When measured at 2 wt % at 20°C using a cup-and-bob rheometer configuration at a shear rate of 100 Hz. In some embodiments, when so measured, such alginates exhibit a viscosity of 6 to 600 mPa·s, e.g., 7 to 500 mPa·s or 8 to 500 mPa·s. In some other embodiments, when so measured, such alginates exhibit a viscosity of 8 to 400 mPa·s, e.g., 8 to 300 mPa·s, e.g., 9 to 200 mPa·s or 10 to 100 mPa·s. In some embodiments according to the present invention, a high G alginate is used. By high G alginate, it is meant that the alginate used in the practice of the present invention has an average of at least 50 percent adjacent G units. In some embodiments, the alginates will have an average of at least 52 percent adjacent G units, in other embodiments, such alginates will have an average of at least 55 percent or more adjacent G units, and in other embodiments, such alginates will have an average of at least 60, 65, or 70 percent or more adjacent G units, and therefore, a higher content of adjacent G units may result in improved texture of the product.

[0031] According to the present invention, the alginate, such as alginic acid or an alginate salt, is present in an amount of 30% (w / w) or less based on the total weight of the final composition. In the present invention, alginate refers to alginic acid or an alginate salt, such as sodium alginate, magnesium alginate, potassium alginate, triethanolamine alginate, or propylene glycol monoglycolate.

[0032] Another suitable water-soluble polymer that can be used in accordance with the present invention is carrageenan. As will be understood by those skilled in the art, ingredients obtained from seaweeds of the class Rhodophyta contain carrageenan. Carrageenan refers to a family of linear sulfated polysaccharides extracted from edible red algae. Carrageenan is a high-molecular-weight polysaccharide composed of repeating galactose units and 3,6 anhydrogalactose (3,6-AG) units, both sulfated and non-sulfated. The units are joined alternately by α-1,3 glycosidic linkages and β-1,4 glycosidic linkages.

[0033] Suitable carrageenan products for the pharmaceutically acceptable blends or pharmaceutical formulations herein include various commercially available carrageenans, such as Gelcarin® carrageenan and Viscarin® carrageenan grades, such as Gelcarin® GP-379NF, Viscarin® 101, Viscarin® GP-328NF, Viscarin® GP-209NF, Viscarin® GP109, Gelcarin® GP911, Gelcarin® GP-812NF (IFF Nutrition & Biosciences).

[0034] Another suitable water-soluble polymer that can be used in accordance with the present invention is pectin. The term "pectin" should be understood as the water-soluble form of pectin substance obtained by extracting pectin from plant material. Pectin has a structure comprising blocks of linear galacturonan chains (polymers of α-(1-4)-linked-D-galacturonic acid) interrupted by a rhamnogalacturonan backbone (polymers of the repeating disaccharide α-(1-4)-D-galacturonic acid-α-(1-2)-L-rhamnose), which often have side chains of polymeric arabinogalactan linked by glycosidic bonds to the O-3 or O-4 positions of L-rhamnose. The galacturonan sequences can have D-xylose and D-apiose linked by glycosidic bonds at their O-2 or O-3 positions, which can be substituted with acetyl groups linked by ester bonds. The long chains of α-(1-4)-linked D-galacturonic acid residues are commonly referred to as the "smooth regions" and the highly branched rhamnogalacturonan regions are commonly referred to as the "hairy regions".

[0035] Pectin is a common and important polysaccharide with applications in both food and pharmaceuticals, and there are many commercial sources. The sources of most commercial pectin products are citrus peel and apple pomace, where protopectin accounts for 10-40% by weight of the dry matter.

[0036] Pectin is present in almost all higher plants. Several food industry by-products, such as citrus peel (a by-product of citrus juice production), apple pomace (a by-product of apple juice production), beet (a by-product of the beet sugar industry), slightly expanded beet fiber, sunflower heads (a by-product of oil production), and onions, are used for pectin extraction (May 1990, Carbohydr. Polymers, 12:79-99). A typical method for extracting highly methylated (HM) pectin from pomace or peel is extraction in dilute mineral acid at high temperatures of 50-90°C at pH 1-3 for 3-12 hours (Rolin, 2002, in Pectins and Their Manipulation; Seymour GB, Knox JP, Blackwell Publishing Ltd, pp. 222-239). Dried citrus peels contain 20-30% pectin (based on dry matter), while pectin in dried apple pomace is present in smaller amounts (10-15%) (Christensen, 1986, Pectins. Food Hydrocolloids, 3, 205-230). Pectin is precipitated by the addition of alcohol (usually isopropanol, but also methanol or ethanol). Finally, the gelatinous material is pressed, washed, dried, and ground (Carbohydr. Polymers, 12:79-99, May 1990). Depending on the process conditions, pectin can be obtained as described in Rolin, 2002, in Pectins and Their Manipulation; Seymour GB, Knox JP, Blackwell Publishing Ltd, 222-239).

[0037] Low-methylated (LM) pectin can be obtained by deesterification of highly methylated (HM) pectin, primarily by controlling the acidity, temperature, and time during the extraction process. To produce other types of pectin, the esters can be hydrolyzed with acid or base before or during extraction, either as a concentrate or in an alcoholic slurry, followed by separation and drying. When a base is used, the reaction must be carried out at low temperature and in an aqueous solution to avoid β-elimination degradation of the polymer (Kravtchenko et al., 1992, Carbohydrate Polymers, 19, 115-124). LM pectin (e.g., potato pectin) can also be extracted with aqueous chelating agents such as hexametaphosphate (Voragen et al., 1995, in Food polysaccharides and their applications; Stephen AM, New York: Marcel Dekker Inc., 287-339). The use of pectin methylesterase (PME) to produce LM pectin can be used as an alternative to chemical extraction (Christensen, 1986, Pectins. Food Hydrocolloids, 3, 205-230).

[0038] Commercially available LM pectin is derived almost entirely from HM pectin, although natural sources of LM pectin exist, such as mature sunflower heads (Thakur et al., 1997, Critical Reviews in Food Science and Nutrition, 37(1):47-73). One method for producing pectin is described in International Patent Application WO 2013 / 109721, in which citrus peels are processed to obtain homogenized citrus peels, which are washed with an organic solvent, followed by a desolventization and drying step to recover a fiber-containing pectin product or pectin. In some embodiments, a micronization or grinding step is performed after the drying step.

[0039] Alternatively, a suitable pectin product can be obtained according to the method described in U.S. Patent No. 7,833,558, which describes a method for providing a fiber-containing pectin product from a plant material, the method comprising the steps of: (i) swelling the plant material in an aqueous solution comprising at least one salt to provide an in situ reaction system; (ii) subjecting the pectin present in the swollen plant material from step (i) to a de-esterification process; and (iii) isolating the de-esterified fiber-containing pectin product. In some embodiments, the plant material is a natural pectin-containing plant material, including peel or pulp from citrus fruits such as lemon, orange, mandarin, lime, and grapefruit.

[0040] Exemplary commercially available pectins include, but are not limited to, apple pectin (SIGMA-ALDRICH, Product No. 93854), citrus peel pectin (SIGMA-ALDRICH, Product No. P9135), citrus pectin with a 60% degree of esterification (SIGMA-ALDRICH, Product No. P9436), and citrus pectin with a 90% degree of esterification (SIGMA-ALDRICH, Product No. P9561), GRINDSTED Pectin RS 400, Andre Pectin AP 101, GENUPECTIN B Rapid Set, UNIPECTIN RS 150, Classic AF 101, GRINDSTED Pectin AMD 780, Andre Pectin AP 140, GENUPECTIN JMJ, UNIPECTIN AYD 20, Classic CM 201 / 203, GRINDSTED Pectin LC 810, Andre Pectin AP 310, GENUPECTIN 18 CG and UNIPECTIN OF 400, Classic AF 701.

[0041] Small molecule weak acids (WA), weak acid surfactants (WAS) The solid dosage form according to the present invention comprises a small molecule weak acid (WA) or weak acid surfactant (WAS). The term "weak acid" is used herein in its ordinary sense, known to those skilled in the art, to refer to an acid that partially dissociates into its ions in aqueous solution or water. Furthermore, a small molecule weak acid (WA) is an acid having a molecular weight of less than 500 Da. In some embodiments, the small molecule weak acid (WA), weak acid surfactant (WAS), or salt thereof has a molecular weight of less than 400 Da, e.g., less than 300 Da, e.g., less than 200 Da. The difference between a weak acid (WA) and a weak acid surfactant (WAS) is that a WAS has amphiphilic properties. As the chain length increases, a WA can become a WAS. For example, citric acid is considered a branched WA with a total of six carbons and three carboxyl groups, with one carboxyl group at each end of the five-carbon chain and one carboxyl group at the third carbon of the five-carbon chain. Sodium caprylate can be considered either a WA or a WAS, a linear eight-carbon chain with a carboxyl group at one end. Its amphiphilic properties result from the non-polar nature of the eight-carbon chain and the polar nature of the carboxyl group. WA or WAS can act as a buffer, surfactant, and / or absorption enhancer.

[0042] Suitable small molecule weak acids (WA), weak acid surfactants (WAS) or salts thereof for use in accordance with the present invention include carbonic acid, monovalent metal phosphates, citric acid, succinic acid, oleic acid, caprylic acid, capric acid, decanoic acid, lauric acid, phosphatidylcholine, salicylic acid, methylsalicylic acid, ethylenediaminetetraacetic acid, acetic acid, cholic acid, deoxycholic acid, glycolic acid, glycocholic acid, glycodeoxycholic acid, taurocholic acid, taurodihydrofusidic acid, sodium caprate, sodium decanoate, sodium caprylate, sodium octanoate, sodium laurate, sodium dodecyl sulfate, dioctanoic acid, benzo ... The surfactant may be any one selected from, but is not limited to, sodium methylsulfosuccinate, glyceryl behenate, glyceryl dibehenate, glyceryl monostearate, sodium N-[8-(2-hydroxybenzoyl)aminocaprylate], sodium salcaprozate, SNAC, N-(5-chlorosalicyloyl)-8-aminocaprylic acid, 5-CNAC, N-[10-(2-hydroxybenzoyl)aminocapric acid], N-[10-(2-hydroxybenzoyl)aminodecanoic acid], sodium lauryl sulfate, sodium stearyl fumarate, and sodium deoxycholate.

[0043] Surface area to volume (SA / Vol) ratio and single unit density The solid dosage form according to the present invention consists of multiple single units with a relatively high surface area to volume (SA / Vol) ratio due to a larger surface area of ​​contact with the luminal folds of the gastrointestinal tract. The surface area to volume (SA / Vol) ratio and single unit density can be measured as described in Example 1. The terms "minitablet" and "single unit" are used interchangeably.

[0044] Multi-unit bulk density Multi-unit bulk density refers to the density of the total amount of individual single units. In some embodiments, multi-unit bulk density is 0.70 g / cm 3 Greater than.

[0045] As detailed above, the present invention relates to a pharmaceutical solid dosage form for the treatment of a condition by gastrointestinal delivery comprising a plurality of single units, each single unit comprising: a) one or more therapeutically active biopolymers; b) one or more water-soluble polymers in an amount of about 50% by weight or less; c) a small molecule weak acid (WA), weak acid surfactant (WAS) or salt thereof in an amount of about 75% by weight or less Each single unit contains 1.0 mm -1 Surface area to volume (SA / Vol) ratio of over 1.0 g / cm 3 The solid dosage form has a single unit density greater than 1000 mg / kg, and contains a therapeutically effective amount of the therapeutically active biopolymer obtained from multiple combined doses of each single unit.

[0046] In some embodiments, the solid dosage form comprises at least two single units, such as at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, or 250 single units, as defined above.

[0047] In some embodiments, the solid dosage form comprises about 500 or fewer single units, e.g., about 400 or fewer single units, about 300 or fewer single units, about 200 or fewer single units, about 180 or fewer single units, about 160 or fewer single units, about 140 or fewer single units, about 120 or fewer single units, about 100 or fewer single units.

[0048] In some embodiments, the solid dosage form has a density of 0.70 g / cm 3 Ultra, e.g., 0.72 g / cm 3 Super, 0.74g / cm 3 Super, 0.76g / cm 3 Super, 0.78g / cm 3 Super, 0.80g / cm 3 Super, 0.82g / cm 3 Super, 0.84g / cm 3 Super, 0.86g / cm 3 Super, 0.88g / cm 3 Super, 0.90g / cm 3 Super, 0.92g / cm 3 Super, 0.94g / cm 3 Super, 0.96g / cm 3Super, 0.98g / cm 3 Super, 1.00g / cm 3 It has a high unit bulk density of over 10 ...

[0049] In some embodiments, the viscosity of the one or more water-soluble polymers is less than 3000 mPa-s (or cP), such as less than about 2800 mPa-s (or cP), for example less than about 2600 mPa-s (or cP), for example less than about 2400 mPa-s (or cP), for example less than about 2200 mPa-s (or cP), for example less than about 2000 mPa-s (or cP), for example less than about 1800 mPa-s (or cP), for example less than about 1600 mPa-s (or cP), for example less than about 1400 mPa-s (or cP).

[0050] In some embodiments, each single unit is 1.0 mm -1 Ultra, for example 1.5mm -1 Ultra, for example 2.0 mm -1 Ultra, for example 2.5mm -1 Ultra, for example 3.0 mm -1 It has a surface area to volume (SA / Vol) ratio of .

[0051] In some embodiments, each single unit has a density of 1.0 g / cm 3 Ultra, e.g. 1.1g / cm 3 Ultra, e.g. 1.2g / cm 3 Ultra, e.g. 1.3g / cm 3 It has a single unit density of greater than 1000kJ / cm.

[0052] In some embodiments, the one or more water-soluble polymers are present in an amount of about 50% or less, such as about 45% or less, for example about 40% or less, for example about 35% or less, such as about 30% or less, for example about 28% by weight or less, such as about 26% by weight or less, for example about 24% by weight or less, such as about 22% by weight or less, for example about 20% by weight or less, such as about 18% by weight or less, for example about 16% by weight or less, such as about 14% by weight or less, for example about 12% by weight or less, for example about 10% by weight or less.

[0053] In some embodiments, the small molecule weak acid (WA), weak acid surfactant (WAS) or salt thereof is present in an amount of about 70% by weight or less, such as about 65% by weight or less, for example about 60% by weight or less, such as about 55% by weight or less, for example about 50% by weight or less, such as about 45% by weight or less, for example about 40% by weight or less.

[0054] In some embodiments, the one or more biopolymers are independently selected from proteins, peptides, polypeptides, oligopeptides, synthetic polypeptides, hormones, insulin, growth factors, monoclonal antibodies, fusion proteins, enzymes, therapeutic enzymes, bispecific antibodies, multispecific antibodies, antibody fragments, interleukins, cytokines, antibody-drug conjugates, glycoproteins, viral proteins, oligonucleotides, DNA fragments, RNA fragments, messenger RNA, small interfering RNA, modified RNA, or any combination thereof.

[0055] In some embodiments, one or more biopolymers are combined with one or more small molecule APIs.

[0056] In some embodiments, the one or more biopolymers are peptides selected from the group consisting of leuprolide, insulin, vasopressin, calcitonin, calcitonin gene-related peptide, desmopressin, gonadotropin-releasing hormone (GnRH), luteinizing hormone-releasing factor, adrenocorticotropic hormone, enkephalin, glucagon, glucagon-like peptide-1, glucagon-like peptide-2, somatostatin, gastrin, glucose insulinotropic polypeptide, peptide yy, amylin, islet amyloid polypeptide, linaclotide, octreotide, semaglutide, liraglutide, tirzepatide, dulaglutide, exenatide, lixisenatide, econoglutide, oxytocin, and 2,6-dimethyltyrosine-D-arginine-phenylalanine-lysine amide.

[0057] In some embodiments, the one or more biopolymers are selected from the group consisting of antibodies, vaccines, lactoferrin, parathyroid hormone, growth hormone, human growth hormone, cytokines, interferons, interleukins or antagonists thereof, such as any of IL1-40, e.g., IL1, IL2, IL10, IL12, IL19, IL21, IL23, IL26, IL27, IL28, IL29, IL36, IL37, IL38, IL39, IL40, lysozyme, β-casein, albumin, alpha-1 antitrypsin, antithrombin III, collagen, factor VII, factor VIII, factor IX, factor X, fibrinogen, insulin, protein C, erythropoietin, and the like. The protein is selected from the group consisting of epidermal growth factor (EPO), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), tissue-type plasminogen activator (tPA), somatotropin, integrins, alpha-4, beta-7 integrins, chymotrypsin, lipase, pancrelipase, amylase and protease, adalimumab, tofacitinib, forarmumab, bevacizumab, rituximab, trastuzumab, denosumab, ranibizumab, tocilizumab, certolizumab, golimumab, secukinumab, griffithsin, alpha 1,2-fucosidase, xylanase, phytase and tumor necrosis factor (TNF).

[0058] In some embodiments, the one or more biopolymers have a molecular weight of more than about 500 Da, such as more than about 2000 Da, for example more than about 3000 Da, such as more than about 4000 Da, for example more than about 5000 Da, such as more than about 6000 Da, for example more than about 8000 Da, such as more than about 10 kDa, for example more than about 20 kDa, such as more than about 30 kDa, for example more than about 40 kDa, such as more than about 50 kDa, for example more than about 60 kDa, such as more than about 70 kDa, for example more than about 80 kDa, such as more than about 90 kDa, for example more than about 100 kDa, such as more than about 110 kDa, for example more than about 120 kDa, such as more than about 130 kDa, for example more than about 140 kDa, for example more than about 150 kDa.

[0059] In some embodiments, the solid dosage form further comprises one or more additional ingredients that provide processability, densification, or differentiation, such as, but not limited to, microcrystalline cellulose, mannitol, lactose, maltose, maltitol, dicalcium phosphate, talc, silicon dioxide, non-ionic surfactants, bromphenol blue, and bromocresol green.

[0060] In some embodiments, the one or more water soluble polymers are independently selected from the list consisting of hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), carboxymethylcellulose (CMC), such as sodium carboxymethylcellulose (CMC), alginates, such as sodium alginate, carrageenan, pectin, hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), hydroxyethyl methylcellulose (HEMC), chitosan, trimethylchitosan, hyaluronic acid, polycarbophil, carbomer, polyethylene oxide, and methacrylic acid derivatives, derivatives and salts thereof.

[0061] In some embodiments, the one or more water soluble polymers is HPMC, such as a highly hydrophilic, low molecular weight HPMC, for example an HPMC having a viscosity of less than 3000 mPa-s (or cP), such as less than 1000 mPa-s (or cP), for example less than 750 mPa-s (or cP), such as less than 500 mPa-s (or cP), for example less than 400, 350, 300, 250, 200, 150, 120, 100 or 80 mPa-s (or cP).

[0062] In some embodiments, the small molecule weak acid (WA), weak acid surfactant (WAS) or salt thereof is selected from the group consisting of carbonic acid, monovalent metal phosphate, citric acid, succinic acid, oleic acid, caprylic acid, capric acid, decanoic acid, lauric acid, phosphatidylcholine, salicylic acid, methylsalicylic acid, ethylenediaminetetraacetic acid, acetic acid, cholic acid, deoxycholic acid, glycolic acid, glycocholic acid, glycodeoxycholic acid, taurocholic acid, taurodihydrofusidic acid, sodium caprate, sodium decanoate, sodium caprylate, sodium octanoate, sodium laurate, dodecyl sulfate, and the like. The hydroxybenzoylaminocapric acid may be selected from sodium hydroxybenzoate, sodium dioctyl sulfosuccinate, glyceryl behenate, glyceryl dibehenate, glyceryl monostearate, sodium N-[8-(2-hydroxybenzoyl)aminocaprylate], sodium salcaprozate, SNAC, N-(5-chlorosalicyloyl)-8-aminocaprylic acid, 5-CNAC, N-[10-(2-hydroxybenzoyl)aminocapric acid], N-[10-(2-hydroxybenzoyl)aminodecanoic acid], sodium lauryl sulfate, sodium stearyl fumarate, and sodium deoxycholate.

[0063] In some embodiments, the pharmaceutical solid dosage form further comprises one or more additional components that protect biopolymers from enzymatic digestion, such as a sacrificial enzyme substrate. The sacrificial enzyme substrate may be selected from a protease inhibitor or a small peptide. The protease inhibitor may be selected from aprotinin, cysteine, threonine, asparagine, serpin, soybean trypsin inhibitor, or a derivative thereof. The small peptide may be selected from a dipeptide, tripeptide, tetrapeptide, pentapeptide, hexapeptide, heptapeptide, or octapeptide.

[0064] In some embodiments, the solid dosage form is substantially homogeneous without a coating or barrier.

[0065] In some embodiments, the pharmaceutical solid dosage form is coated with one or more polymers to target a particular region of the gastrointestinal tract, such as the stomach, duodenum, jejunum, ileum, cecum, or colon.

[0066] In some embodiments, the solid dosage form is coated with one or more pH-dependent polymers.

[0067] In some embodiments, the solid dosage form is coated with one or more pH-independent polymers.

[0068] In some embodiments, the biopolymer is protected from degradation following exposure of the pharmaceutical solid dosage form to a solution of HCl at pH 1.2 with or without pepsin to such an extent that the area under the curve (AUC) from 0 to 60 minutes is greater than 830%-min, e.g., greater than 1000%-min, e.g., greater than 1500%-min, for intact biopolymer content versus time.

[0069] Purpose The dosage forms disclosed herein can be used in a variety of applications. In some embodiments, the dosage form is used in human therapeutics. In some embodiments, the dosage form is used in veterinary therapeutics. In some embodiments, the dosage form is used in pet therapeutics. In some embodiments, the dosage form is used in veterinary therapeutics, such as swine, poultry, or bovine nutrition. In some embodiments, the dosage form is used in human nutrition. In some embodiments, the dosage form is used in human dietary supplements. In some embodiments, the dosage form is used in veterinary nutrition. In some embodiments, the dosage form is used in veterinary supplements. In some embodiments, the dosage form is used in pet nutrition. In some embodiments, the dosage form is used in livestock nutrition.

[0070] In some embodiments, the dosage forms disclosed herein are administered to a subject (human or animal) to treat a condition that can be treated by a therapeutically active biopolymer. In some embodiments, the dosage forms disclosed herein are administered to a subject (human or animal) to treat a condition that can be treated by one or more enzymes disclosed herein. In some embodiments, the condition comprises a gastrointestinal disorder. In some embodiments, the symptom comprises an oral condition. In some embodiments, the symptom comprises a digestive or intestinal condition. In some embodiments, the symptom comprises a metabolic disorder. In some embodiments, the symptom comprises an inherited metabolic disorder. In some embodiments, the symptom comprises phenylketonuria (PKU) or tyrosinuria. In some embodiments, the symptom comprises exocrine pancreatic insufficiency. In some embodiments, the symptom (e.g., exocrine pancreatic insufficiency) results from cystic fibrosis, pancreatitis, pancreatic cancer, diabetes, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), celiac disease, or a condition associated with indigestion and / or malabsorption. In some embodiments, the symptom comprises homocystinuria. In some embodiments, the symptom comprises maple syrup urine disease. In some embodiments, the symptom is related to gluten management, such as gluten intolerance, gluten allergy, or celiac disease. In some embodiments, the symptom comprises a lysosomal storage disorder.

[0071] In some embodiments, the dosage form is administered to a subject (i.e., a human or an animal) to treat a condition disclosed in the previous paragraph, and the therapeutically active biopolymer comprises an enzyme (e.g., an enzyme disclosed herein). [Example]

[0072] Example 1 The following powder ingredients were weighed: Bovine lactoferrin 15g (Parchem) Sodium emulsifier caprylate 150g (Merck Millipore Sigma) ·Avicel PH101 Microcrystalline Cellulose 100.5g (IFF) METHOCEL K100LV HPMC (22.9% methyl, 10.1% hydroxypropyl, 104 mPa-s viscosity, 71.4% sieved through a 230-mesh screen) 30g (IFF) Bromocresol Green 3g (Merck Millipore Sigma) Alubra Sodium Stearyl Fumarate 1.5g (IFF) 300g total powder blend for tableting

[0073] The formulation ingredients, except for Alubra's sodium stearyl fumarate, were blended together by placing the ingredients in a glass jar, capping, and blending for 10 minutes in a Turbula mixer. Alubra's sodium stearyl fumarate was added after the first 10 minutes of blending, followed by 1 minute of blending. Using Biconvex 2 mm round minitablet tooling, the powder blend was compressed using 14 of 16 stations in a Manesty Beta rotary press. To observe die filling during tableting, the turret speed was set at 13 rpm, and a compression force of 500 pounds (lb.) or 2.2 kN was targeted. The minitablet formulations were then sealed and stored in Ziploc bags at ambient room conditions for at least overnight before analysis.

[0074] Twenty minitablets were individually weighed to determine the single-unit weight, diameter, and thickness. The single-unit weight was determined by an analytical balance. Calipers were used to determine the single-unit diameter and thickness. Individual minitablet dimensional measurements and tool cup dimensional specifications provided by the minitablet tooling manufacturer, Natoli Engineering, were used to determine the single-unit surface area (SA), single-unit surface area to volume (SA / Vol), single-unit volume, and single-unit density. Further details are provided for single-unit SA, single-unit SA / Vol, single-unit volume, single-unit density, intact lactoferrin content vs. time, and area under the intact lactoferrin content vs. time curve (AUC 0~60分The single unit SA / Vol and single unit density of the composition of Example 1 were 3.49±0.098 mm, respectively. -1 and 1.32±0.053g / cm 3 AUC 0~60分 was 1840.00±513.400%-min.

[0075] Determining the physical characteristics of a single unit The mini-tablets were not flat but biconvex, so the surface area (SA (mm 2 )) was calculated according to the following formula: Single unit SA (mm 2 )=(2×tool cup area)+2πr(r+t)-2πr 2 where t is the band thickness of the minitablet and r is the radius of the minitablet. 2 The term is removed to account for the combined surface area of ​​the two recessed flat surfaces, since the minitablets are biconvex rather than flat.

[0076] The minitablet radius was calculated by dividing the minitablet diameter in half.

[0077] The tool cup area specified by the mini tablet tool manufacturer, Natoli Engineering, is 3.3800mm 2 is.

[0078] The thickness of the minitablet band was calculated according to the following formula: Single unit band thickness (mm) = total single unit thickness - 2 (cup depth)

[0079] The mini-tablet tooling cup depth specified by Natoli Engineering is 0.2800 mm.

[0080] Mini-tablet surface area to volume ratio (SA / Vol(mm -1)) was calculated according to the following formula:

number

[0081] The mini tablet tool cup volume specified by Natoli Engineering is 0.4100mm 3 is.

[0082] Mini tablet volume (cm 3 ) was calculated according to the following formula:

number

[0083] Mini-tablet density (g / cm 3 ) was calculated according to the following formula:

number

[0084] Determination of intact lactoferrin content A 200 mg minitablet (typically containing 5% lactoferrin) was added to 10 mL of pH 1.2 HCl + pepsin in a 50 mL centrifuge tube. A 200 mg minitablet is approximately 50 minitablets. The pH 1.2 HCl + pepsin was prepared according to the United States Pharmacopoeia recipe for simulated gastric fluid (SGF). The tube was capped and placed on an inclined roller (rotating at 6-7 rpm and equilibrated to 37°C) for the specified period (0, 10, 20, 30, 40, 50, or 60 minutes). The entire roller set was located within a temperature-controlled chamber, allowing the temperature to be controlled at 37°C. The roller was inclined at 7°, so that 10 mL of pH 1.2 HCl + pepsin was rolled up, immersed in the dose being tested, and pooled toward the bottom of the tube as it was gently agitated. At the designated time points, the centrifuge tubes were removed from the roller, and 20 mL of pH 9.0 neutralization buffer was added to the tubes to neutralize them to pH 7, followed by vortexing for 1 minute. pH 9.0 neutralization buffer was prepared by dissolving 14.2 g of anhydrous disodium phosphate in 1 L of deionized water. Two sets of roller time point samples were tested per day, with n = 3 replicates per roller time point sample set. Thus, a total of six samples could be tested each day. Each neutralized sample was then frozen. Each frozen neutralized sample was removed from the freezer and thawed overnight on a roller placed in a refrigerator (4.8 °C). The chromogen, working buffer stock, washing buffer stock, and stop solution (all supplied with the ELISA assay kit) were removed from the storage refrigerator (6 °C) the morning before analysis and equilibrated to ambient room temperature. The working buffer stock was diluted 5-fold before use to 16 mL of Milli-Q water + 4 mL of working buffer stock. The washing buffer stock was diluted 20-fold before use to 19 mL of Milli-Q water + 1 mL of washing buffer stock. Four 2 mL centrifuge tubes, Tubes A-D, were prepared for each sample. More or fewer tubes were used depending on the lactoferrin concentration used. 0.9 mL of diluted working buffer was pipetted into each tube.0.1 mL of the thawed neutralized roller sample was pipetted into Tube A, followed by five up-and-down strokes and vortexing for a few seconds. 0.1 mL from Tube A was pipetted into Tube B, followed by five up-and-down strokes and vortexing for a few seconds. 0.1 mL from Tube B was pipetted into Tube C, followed by five up-and-down strokes and vortexing for a few seconds. 0.1 mL from Tube C was pipetted into Tube D, followed by five up-and-down strokes and vortexing for a few seconds. 0.1 mL from Tube D was pipetted into the wells of an ELISA assay plate. (Bovine Lactoferrin ELISA Kit, ab274406, by Abcam. See https: / / www.abcam.com / bovine-lactoferrin-elisa-kit-ab274406.html for more information about the Bovine Lactoferrin ELISA assay plate.) The above steps were repeated for each of the remaining five thawed neutralized roller samples. The assay plate was covered with microplate sealing tape (Thermofisher Scientific, part number 9503130) and the plate was placed in a Tecan plate reader. The plate was shaken for 3 minutes and held at 23°C for 27 minutes. The assay plate was removed from the Tecan instrument and the wells were washed five times by filling them with diluted Washing Buffer and then tapping them onto a paper towel. For the final rinse, the diluted Washing Buffer was left in the wells for 2 minutes before being emptied by tapping onto a paper towel. The tubes containing the antibody (supplied with the ELISA kit) were removed from the storage refrigerator (6°C) and allowed to equilibrate at ambient room temperature (approximately 0.5 hours). 0.990 mL of diluted Working Buffer was added to a new mini-vial. 0.010 mL of equilibrated antibody solution was added to the vial. 0.100 mL of the prepared solution was added to each of the five rinsed wells of the assay plate. (Note: One tube of diluted antibody solution is required per well strip.)) The assay plate was again covered with microplate tape and placed in the Tecan, shaken for 3 minutes, and held at 23°C for 27 minutes. The assay plate was removed from the Tecan, and the wells were washed five times with diluted Washing Buffer. For the final rinse cycle, the diluted Washing Buffer was left in the wells for 2 minutes before being emptied. 0.100 mL of chromogen solution (equilibrated to ambient room temperature) was added to each of the five rinsed wells of the assay plate. The assay plate was covered with sealing tape and placed in the Tecan. The assay plate was shaken for 3 minutes and then held at 23°C for 7 minutes. The assay plate was removed from the Tecan, and 0.100 mL of Stop Solution (supplied with the ELISA assay kit) was added to the wells. The assay plate was immediately returned to the Tecan, this time without microplate tape. The plate reader was set to hold for 1 minute, and then the wells were analyzed by UV spectrophotometer at a wavelength of 450 nm. Upon completion of the analysis, intact lactoferrin content data was provided. The intact lactoferrin content vs. time curve from 0 to 60 minutes was plotted and the area under the intact lactoferrin content vs. time curve, AUC, was calculated. 0~60分 was calculated.

[0085] Preparation of calibration standards for the determination of intact lactoferrin Approximately 17 mg of lactoferrin was added to 100 mL of milliQ water in a vial, which was then capped and rolled for at least 2 hours under refrigeration (4.8°C). This served as the lactoferrin stock solution used to make the calibration standards. A 10x dilution was made by diluting 0.1 mL of lactoferrin stock with 0.9 mL of diluted working buffer. The 10x dilution was mixed together by pipetting five times, followed by vortexing for several seconds. A 100x dilution was made by further diluting 0.1 mL from the 10x dilution with 0.9 mL of diluted working buffer. The 100x dilution was mixed together by pipetting five times, followed by vortexing for several seconds. Eight 2-mL centrifuge tubes were prepared for the calibration standards (labeled 1–8). 1 mL of Diluted Working Buffer was pipetted into Tubes 1 and 8. 0.400 mL of Diluted Working Buffer was pipetted into Tubes 2–7. 0.050 mL of the 100x Dilution was pipetted into Tube 1 and mixed. 0.040 mL of the 100x Dilution was pipetted into Tube 8 and mixed. 0.400 mL from Tube 1 was pipetted into Tube 2, the pipette tip was rinsed by drawing up and expelling five times, and then vortexed for a few seconds. 0.400 mL from Tube 2 was pipetted into Tube 3, the pipette tip was rinsed by drawing up and expelling five times, and then vortexed for a few seconds. Serial dilutions were performed through Tube 6. Tube 7 contained only a blank solution of Diluted Working Buffer (no lactoferrin). 0.100 mL of each calibration standard was pipetted into each well of that particular row of the ELISA assay plate, and each of these wells was prepared and analyzed accordingly as described above. This row was used to generate a calibration curve.

[0086] Comparative example A The following powder ingredients were weighed: 15g bovine lactoferrin Emprove Sodium Caprylate 150g Avicel PH102 Microcrystalline Cellulose 132g (IFF) 1.5g Cabosil M5P silicon dioxide (Cabot) Alubra Sodium Stearyl Fumarate 1.5g (IFF) 300g total powder blend for tableting

[0087] As in Example 1, the formulation ingredients, except for Alubra's sodium stearyl fumarate, were blended together for 10 minutes, then Alubra's sodium stearyl fumarate was added and blended for 1 minute. Biconvex 7.94-mm round tablet tooling was used to compress the powder blend using 8 of 16 stations on a Manesty Beta rotary press. To observe die filling during tableting, the turret speed was set at 13 rpm, and a compression force of 5,000 pounds (lb.) or 22.2 kN was targeted. The tablet formulations were then sealed in Ziploc bags and stored at least overnight at ambient room temperature conditions before analysis, as was done for Example 1.

[0088] The weight and dimensions of 20 individual tablets were measured as in Example 1. However, for Comparative Example A, the individual tablet dimension measurements were based on the biconvex 7.94-mm circular tool cup dimension specifications provided by Natoli Engineering. The 7.94-mm tool cup area, cup volume, and cup depth were 51.8257 mm, respectively. 2 , 21.6309mm 3 and 0.8636 mm. The single unit surface area (SA), single unit surface area to volume (SA / Vol), single unit volume, and single unit density were determined using the formulas previously provided for Example 1. Intact lactoferrin was determined in HCl at pH 1.2 with pepsin by ELISA measurement of intact lactoferrin content using the methodology described for Example 1. The single unit SA / Vol and single unit density for the composition of Comparative Example A were 1.00±0.003 mm, respectively.-1 and 1.18±0.008g / cm 3 AUC 0~60分 was 1801.67±352.628%-min.

[0089] Comparative example B The multiparticulates comprised sucrose nonpareil beads coated in a Glatt GPCG-1 fluid-bed coater via bottom spray (starting at a spray rate of 3 g / min and gradually increasing to 5.7 g / min) using a Wurster column insert with a 10% aqueous solution containing METHOCEL™ E5 LV and lactoferrin in a 1:1 weight ratio. The liquid forming the solution was deionized (DI) water. After 2.5 hours of processing at an outlet temperature of 45°C, 400 g of nonpareil sucrose beads were coated to a final weight of 436 g.

[0090] Since the multiparticulates were spherical, SA was calculated using the following formula: SA(mm 2 )=4πr 2 Vol was measured according to the following formula:

number

[0091] SA / Vol was measured according to the following formula:

number

[0092] Because it was not feasible to load EMPROVE sodium caprylate into the multiparticulates at the required level, sodium caprylate powder was added to the coated multiparticulates in pH 1.2 HCl containing pepsin to determine intact lactoferrin versus time. The ELISA methodology described for Example 1 was used to quantitate intact lactoferrin. The single unit SA / Vol and single unit density of the composition of Comparative Example B were 6.47±0.258 mm, respectively. -1and 1.64±0.321g / cm 3 AUC 0~60分 was 263.33±241.109%-min.

[0093] Comparative example C The following powder ingredients were weighed: 15g bovine lactoferrin Emprove Sodium Caprylate 150g Avicel PH101 Microcrystalline Cellulose 130.5g Bromocresol Green 3g Alubra Sodium Stearyl Fumarate 1.5g 300g total powder blend for tableting

[0094] As in Example 1, the formulation ingredients, except for Alubra's sodium stearyl fumarate, were blended together for 10 minutes, then Alubra's sodium stearyl fumarate was added and blended for 1 minute. As in Example 1, the powder blend was compressed using biconvex 2-mm circular minitablet tooling in a Manesty Beta rotary press, using 14 of 16 stations. To observe die filling during tableting, the turret speed was set at 13 rpm, and the compression force was targeted at 500 pounds (lb.) or 2.2 kN, as was also done for Example 1. The minitablet formulations were then sealed in Ziploc bags and stored at least overnight at ambient room temperature conditions before analysis, as was done for Example 1.

[0095] The weight and dimensions of 20 individual minitablets were measured as in Example 1. The single unit surface area (SA), single unit surface area to volume (SA / Vol), single unit volume, and single unit density were determined using the formulas previously provided for Example 1. Intact lactoferrin was determined in HCl at pH 1.2 with pepsin by ELISA measurement of intact lactoferrin content using the methodology described for Example 1. The single unit SA / Vol and single unit density for the composition of Comparative Example C were 3.61±0.149 mm, respectively. -1and 1.50±0.097g / cm 3 AUC 0~60分 was 977.50±312.630%-min.

[0096] [Table 1]

[0097] Example 2 For Example 2(a), the following powder ingredients were weighed: Lipase Mix 2.5g (IFF) Emprove Sodium Caprylate 25g (Merck Millipore Sigma) ·Avicel PH101 Microcrystalline Cellulose 17g (IFF) METHOCEL K100LV HPMC (22.9% methyl, 10.1% hydroxypropyl, 104 mPa-s viscosity, 71.4% sieved through a 230-mesh screen) 5g (IFF) Cabosil M5P silicon dioxide 0.25g (Cabot) Alubra Sodium Stearyl Fumarate 0.25g (IFF) 50g total powder blend for tableting

[0098] For Example 2(b), the following powder ingredients were weighed out: Lipase Mix 2.5g (IFF) Emprove Sodium Caprylate 12.5g (Merck Millipore Sigma) ·Avicel PH101 Microcrystalline Cellulose 29.5g (IFF) METHOCEL K100LV HPMC (22.9% methyl, 10.1% hydroxypropyl, 104 mPa-s viscosity, 71.4% sieved through a 230-mesh screen) 5g (IFF) Cabosil M5P silicon dioxide 0.25g (Cabot) Alubra Sodium Stearyl Fumarate 0.25g (IFF) 50g total powder blend for tableting

[0099] The formulation ingredients (except Alubra's sodium stearyl fumarate) were placed on a #20 mesh screen and hand-sieved through the screen. The sieved ingredients were blended together by placing them in a glass jar, capping it, and blending via a Turbula mixer for 10 minutes. Alubra's sodium stearyl fumarate was added after the first 10 minutes of blending, followed by 1 minute of blending. The powder blend was compressed using the same biconvex 2-mm round minitablet tooling described in Example 1 in a Manesty Beta rotary press, utilizing two to three stations at a time. Due to cost and the small amount of raw material, the blended powder was manually fed into two to three sets of dies available in the turret with the tablet press turned off, and the press was then jogged with a force of approximately 2.2 kN and a turret speed set at 13 rpm to compress the powder into minitablets. The minitablets were then recovered from the turret using a spatula and sealed and stored in Ziploc bags at ambient laboratory conditions for at least overnight before analysis.

[0100] Twenty minitablets containing the lipase mixture were individually weighed to determine the weight, diameter and thickness of a single unit using the methodology described in Example 1. The SA / Vol and unit density were calculated using the formulas described in Example 1 and are shown in Table 2.

[0101] [Table 2]

[0102] Example 3 The following powder ingredients were weighed: Semaglutide 50mg (BOC Sciences) Emprove Sodium Caprylate 500mg (Merck Millipore Sigma) ·Avicel PH101 Microcrystalline Cellulose 345mg (IFF) METHOCEL K100LV HPMC (22.9% methyl, 10.1% hydroxypropyl, 104 mPa-s viscosity, 71.4% sieved through a 230-mesh screen) 100 mg (IFF) Alubra Sodium Stearyl Fumarate 5mg (IFF) 1000mg total powder blend for tableting

[0103] The formulation ingredients, except for Alubra's sodium stearyl fumarate, were placed in a glass jar, capped, and blended together for 10 minutes using a Turbula mixer. Alubra's sodium stearyl fumarate was added after the first 10 minutes of blending, followed by 1 minute of blending. The powder blend was compressed using the same biconvex 2-mm round minitablet tooling described in Example 1, utilizing two to three stations at a time, in a Manesty Beta rotary press. Due to cost and the small amount of raw material, the blended powder was manually fed into two to three sets of dies available in the turret with the tablet press turned off. The press was then jogged at a force of approximately 2.2 kN and a turret speed set at 13 rpm to compress the powder into minitablets. The minitablets were then retrieved from the turret using a spatula and sealed and stored in Ziploc bags in a -20°C freezer for at least overnight before analysis. To experimentally adjust the amount of sodium caprylate, a placebo version of the minitablets was produced by running the press in all operating modes using the parameters described in Example 1. This allows for the combination of active and placebo minitablets with varying doses of sodium caprylate while keeping the dose of semaglutide constant.

[0104] Twenty minitablets containing semaglutide were individually weighed to determine the weight, diameter and thickness of a single unit using the methodology described in Example 1.

[0105] Determination of intact semaglutide content A 60 mg minitablet (containing 5% semaglutide) was added to 10 mL of pH 1.2 HCl + pepsin in a 50 mL centrifuge tube. The pH 1.2 HCl + pepsin was prepared according to the US Pharmacopoeia recipe for simulated gastric fluid (SGF). Each 60 mg minitablet contained approximately 3 mg of semaglutide, equivalent to approximately 12 minitablets. To adjust the sodium caprylate level, a placebo version of the minitablet (containing all ingredients except semaglutide) was measured and added as needed. For example, to increase the sodium caprylate dose to 100 mg while keeping the semaglutide dose constant at 3 mg, a 140 mg placebo minitablet was added together with a 60 mg semaglutide minitablet. Example 3(a) includes 60 mg semaglutide minitablets + 140 mg placebo minitablets. Example 3(b) contains only 60 mg semaglutide minitablets.

[0106] 50 mL centrifuge tubes were capped and placed on an inclined roller (rotating at 6-7 rpm) for the specified time period (0, 10, 20, 30, 40, or 50 minutes). As in Example 1, the entire roller setup was located within a temperature-controlled chamber, allowing the temperature to be controlled at 37°C. The roller was inclined at 7°, allowing 10 mL of pH 1.2 HCl + pepsin to roll up and immerse the formulation being tested, pooling toward the bottom of the tube with gentle agitation. At the specified time point, the centrifuge tube was removed from the roller, and 20 mL of pH 9.0 Neutralizing Buffer was added to the centrifuge tube to neutralize it to pH 7, followed by vortexing for 1 minute. The neutralized sample was then placed on the roller in a refrigerator and rolled overnight for ELISA analysis, starting the next morning. The temperature in the refrigerator was set to 4°C. The intact semaglutide content versus time curve from 0 to 50 minutes was plotted and the area under the intact semaglutide content versus time curve, AUC 0~50分 was calculated.

[0107] ELISA assay to determine intact semaglutide The amount of intact semaglutide was determined using an ELISA kit from OriGene Technologies (catalog number: S-1530). The ELISA kit included an immunoplate containing twelve 8-well strips, antiserum powder, biotinylated tracer, ELISA buffer, streptavidin-HRP (horseradish peroxidase), TMB (3,3',5,5'-tetramethylbenzidine) substrate solution, TMB substrate buffer, and 2N HCl as a stop solution. The protocol included with the kit was followed during testing. For each test run, one strip of the immunoplate was used to apply the calibration standard, and another strip was used to apply the sample. In the standard strip, the first well contained 75 μL of ELISA buffer, and the remaining wells contained 50 μL of semaglutide standard at various concentrations and 25 μL of antiserum. In the sample strip, each well contained 50 μL of control or test sample and 25 μL of antiserum. The strips were then incubated for 1 hour at 23°C in a Tecan microplate reader (INFINITE 200 PRO). Then, 25 μL of biotinylated tracer solution was added to all wells. The plate was transferred to the microplate reader and incubated for 2 hours. After incubation, the solution in the wells was decanted, and the strips were washed five times with ELISA buffer. After washing, 100 μL of streptavidin-HRP solution was added to all wells, and the strips were again incubated for 1 hour in the microplate reader. The strips were then washed again five times using ELISA buffer. TMB color development solution was then added to all wells by pipetting 100 μL into each well. After 10 minutes of incubation in the microplate reader, 100 μL of stop solution was added to all wells. After a 5-minute incubation, the UV absorbance of all wells was read at 450 nm.

[0108] The absorbance of the standards after subtraction from the absorbance of the blank was plotted against their concentration on a semi-logarithmic scale, with the log of the UV absorbance on the y-axis and the concentration of the standard on the x-axis. The data were fitted by a four-parameter logistic regression, and the derived parameters were used to calculate the intact peptide concentration from the UV readings of the controls and samples after blank subtraction.

[0109] The effect of pH 1.2 HCl + pepsin on semaglutide was first studied by adding 100 μL of semaglutide solution (1 mg / mL in ELISA buffer) to 900 μL of pH 1.2 HCl + pepsin, and then placing the solution on a roller. The same semaglutide solution was also added to 900 μL of deionized water as a control. After mixing for a given time (1, 5, 15, 30, 60 minutes), both the pH 1.2 HCl + pepsin solution and the control solution were diluted 10,000-fold with ELISA buffer. Dilutions were performed in four 10-fold steps by adding 100 μL of peptide solution to 900 μL of ELISA buffer. The solutions were then added to strips of an immunoplate for measurement of intact peptide concentration. The percentage of intact peptide after treatment with pH 1.2 HCl + pepsin was determined as follows: % intact semaglutide = concentration in HCl + pepsin solution at pH 1.2 / concentration in control solution x 100

[0110] After pH 1.2 HCl + pepsin treatment and neutralization, aliquots of the tested formulations were filtered into minicentrifuge tubes using PVDF syringe filters. The filtered solutions were diluted in four steps with ELISA buffer. 100 μL of sample solution was added to 900 μL of ELISA buffer, resulting in a 10-fold dilution factor for each step. To determine the concentration of intact peptide, the sample solutions were applied to strips on an immunoplate. A semaglutide control (Fisher catalog number: 50-225-9952) was also applied to the same strips. The concentration of intact semaglutide in solution was determined as follows: Intact semaglutide concentration = measured concentration of sample / measured concentration of control × concentration of control from preparation % intact semaglutide = concentration of intact semaglutide from ELISA / concentration of semaglutide from preparation x 100

[0111] Preparation of calibration standards for the determination of intact semaglutide A 1 mg / mL stock standard solution was prepared by dissolving 5 mg of semaglutide (obtained from BOC Sciences) in 5 mL of ELISA buffer. The 5 mL solution was separated into 120 μL aliquots in multiple vials. All aliquots were stored in a -18°C freezer. One aliquot of the stock standard solution was transferred to a refrigerator to store the sample prior to the day of the ELISA assay. The aliquot was diluted 1000-fold with ELISA buffer in three successive steps, adding 100 μL of the standard solution to 900 μL of buffer. The 1 μg / mL standard solution was then diluted in six successive steps to prepare the standard for application to the immunoplate strips. The first step was to dilute the standard 10-fold by adding 100 μL of the standard solution to 900 μL of ELISA buffer to create the most concentrated standard (S1). The second step was to add 200 μL of S1 to 600 μL of ELISA buffer to create S2. The third, fourth, fifth, and sixth steps were to create decreasing concentrations of standards by adding 200 μL of S2 to 600 μL of ELISA buffer to create S3, 200 μL of S3 to 600 μL of ELISA buffer to create S4, 200 μL of S4 to 600 μL of ELISA buffer to create S5, and 200 μL of S5 to 600 μL of ELISA buffer to create S6. S7 was buffer without peptide, which served as a zero-concentration standard. In one strip of the immunoplate, the first well contained 75 μL of ELISA buffer as a blank. Wells 2 through 8 contained 50 μL of S1 through S7 standards and 25 μL of antiserum, respectively.

[0112] Preparation of intact semaglutide factoring standards Semaglutide (Cat. No. 50-225-9952) from Fisher Scientific was used as the factoring standard. The peptide was received in an amount of 5 mg and dissolved in 5 mL of ELISA buffer. The solution was distributed into multiple vials. Each vial contained a 120 μL aliquot of solution. All aliquots were stored in a -18°C freezer. Prior to the test day, one aliquot was transferred from the freezer to the refrigerator, which also contained the test samples. The aliquots were diluted 100,000-fold by adding 100 μL of the control solution to 900 μL of ELISA buffer in five successive steps. The diluted factoring standard control solution was applied to the same strip of the immunoplate as the sample solution.

[0113] Disintegration test Disintegration tests were performed using a Sotax DT50 Disintegration Tester (Sotax Corp., Westborough, MA, USA). Using a 1000 mL Sotax beaker (3061-1) with an induction plate (14728-01) placed at the bottom, 800 mL of degassed HCl (pH 1.2) was added and heated to 37°C. The basket type used was an SKx with a trigger value set at 0.5 mm. The basket was assembled with a 20-mesh screen and glass tubes. Each glass tube contained a 200 mg minitablet, and the sensor disk (red side facing downward) was placed on top of the minitablet. The basket was attached to the holder in the main unit, and the test was performed using "Direct Test" in the main menu. Default test parameters were used. The endpoint was automatically recorded when the sensor disk reached the 0.5-mm trigger value.

[0114] [Table 3]

[0115] In Table 3, AUC 0~50分is the area under the time profile for intact semaglutide versus 0–50 min. To preserve semaglutide, a disintegration time study was also performed with a placebo version in a multi-site microenvironment rather than a formulation containing the peptide API.

Claims

1. 1. A pharmaceutical solid dosage form for the treatment of a condition by gastrointestinal delivery comprising a plurality of single units, each single unit comprising: a) one or more therapeutically active biopolymers; b) one or more water-soluble polymers in an amount of about 50% by weight or less; c) a small molecule weak acid (WA), weak acid surfactant (WAS), or salt thereof, in an amount of about 75% by weight or less Each single unit comprises 1.0 mm －１ Surface area to volume (SA / Vol) ratio of greater than 1.0 g / cm ３ 1. A pharmaceutical solid dosage form having a single unit density of greater than 1000 mg / kg, said solid dosage form comprising a therapeutically effective amount of said therapeutically active biopolymer obtained from a combined multiple of each single unit.

2. 10. The pharmaceutical solid dosage form of claim 1, having at least 2 single units, such as at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, or 250 single units.

3. 3. The pharmaceutical solid dosage form of claim 1 or 2, having about 500 or less single units, such as about 400 or less single units, about 300 or less single units, about 200 or less single units, about 180 or less single units, about 160 or less single units, about 140 or less single units, about 120 or less single units, about 100 or less single units.

4. 0.70 g / cm ３ greater than, for example, 0.72 g / cm ３ Super, 0.74g / cm ３ Super, 0.76g / cm ３ Super, 0.78g / cm ３ Super, 0.80g / cm ３ Super, 0.82g / cm ３ Super, 0.84g / cm ３ Super, 0.86g / cm ３ Super, 0.88g / cm ３ Super, 0.90g / cm ３ Super, 0.92g / cm ３ Super, 0.94g / cm ３ Super, 0.96g / cm ３ Super, 0.98g / cm ３ Super, 1.00g / cm ３ 4. The pharmaceutical solid dosage form of any one of claims 1 to 3, optionally having a multiple unit bulk density of greater than 1000 sq ft.

5. 5. The pharmaceutical solid dosage form according to any one of claims 1 to 4, wherein the viscosity of the one or more water-soluble polymers is less than 3000 mPa-s (or cP), such as less than about 2800 mPa-s (or cP), for example less than about 2600 mPa-s (or cP), such as less than about 2400 mPa-s (or cP), for example less than about 2200 mPa-s (or cP), such as less than about 2000 mPa-s (or cP), for example less than about 1800 mPa-s (or cP), such as less than about 1600 mPa-s (or cP), for example less than about 1400 mPa-s (or cP).

6. Each single unit is 1.0 mm －１ Over, for example, 1.5 mm －１ Over, for example, 2.0 mm －１ Ultra, for example, 2.5 mm －１ Over, for example, 3.0 mm －１ 6. The pharmaceutical solid dosage form according to any one of claims 1 to 5, having a surface area to volume (SA / Vol) ratio of greater than 10 ...

7. Each single unit has a density of 1.0 g / cm ３ greater than, for example, 1.1 g / cm ３ greater than, for example, 1.2 g / cm ３ greater than, for example, 1.3 g / cm ３ 7. The pharmaceutical solid dosage form according to any one of claims 1 to 6, having a single unit density of greater than 10 ...

8. 8. The pharmaceutical solid dosage form according to any one of claims 1 to 7, wherein the one or more water soluble polymers are present in an amount of about 50% by weight or less, such as about 45% by weight or less, for example about 40% by weight or less, such as about 35% by weight or less, for example about 30% by weight or less, such as about 28% by weight or less, for example about 26% by weight or less, such as about 24% by weight or less, for example about 22% by weight or less, such as about 20% by weight or less, for example about 18% by weight or less, such as about 16% by weight or less, for example about 14% by weight or less, such as about 12% by weight or less, for example about 10% by weight or less.

9. 9. The pharmaceutical solid dosage form according to any one of claims 1 to 8, wherein the small molecule weak acid (WA), weak acid surfactant (WAS) or salt thereof is present in an amount of about 70% by weight or less, such as about 65% by weight or less, for example about 60% by weight or less, such as about 55% by weight or less, for example about 50% by weight or less, such as about 45% by weight or less, for example about 40% by weight or less.

10. 10. The pharmaceutical solid dosage form of any one of claims 1 to 9, wherein the one or more biopolymers are independently selected from proteins, peptides, polypeptides, oligopeptides, synthetic polypeptides, hormones, insulin, growth factors, monoclonal antibodies, fusion proteins, enzymes, therapeutic enzymes, bispecific antibodies, multispecific antibodies, antibody fragments, interleukins, cytokines, antibody-drug conjugates, glycoproteins, viral proteins, oligonucleotides, DNA fragments, RNA fragments, messenger RNA, small interfering RNA, modified RNA, or any combination thereof.

11. 11. The pharmaceutical solid dosage form of any one of claims 1 to 10, wherein the one or more biopolymers are peptides selected from the group consisting of leuprolide, insulin, vasopressin, calcitonin, calcitonin gene-related peptide, desmopressin, gonadotropin-releasing hormone (GnRH), luteinizing hormone-releasing factor, adrenocorticotropic hormone, enkephalin, glucagon, glucagon-like peptide-1, glucagon-like peptide-2, somatostatin, gastrin, glucose insulinotropic polypeptide, peptide yy, amylin, islet amyloid polypeptide, linaclotide, octreotide, semaglutide, liraglutide, tirzepatide, dulaglutide, exenatide, lixisenatide, econoglutide, oxytocin, and 2,6-dimethyltyrosine-D-arginine-phenylalanine-lysine amide.

12. The one or more biopolymers may be selected from the group consisting of antibodies, vaccines, lactoferrin, parathyroid hormone, growth hormone, human growth hormone, cytokines, interferons, interleukins or antagonists thereof, for example, any of IL1 to IL40, for example, IL1, IL2, IL10, IL12, IL19, IL21, IL23, IL26, IL27, IL28, IL29, IL36, IL37, IL38, IL39, IL40, lysozyme, β-casein, albumin, α-1 antitrypsin, antithrombin III, collagen, factor VII, factor VIII, factor IX, factor X, fibrinogen, protein C, erythropoietin (EPO), granulocyte colony-stimulating factor ( 11. The pharmaceutical solid dosage form of any one of claims 1 to 10, wherein the protein is selected from the group consisting of: granulocyte-macrophage colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), tissue-type plasminogen activator (tPA), somatotropin, integrins, alpha-4, beta-7 integrins, chymotrypsin, lipase, pancrelipase, amylase and protease, adalimumab, tofacitinib, forarmumab, bevacizumab, rituximab, trastuzumab, denosumab, ranibizumab, tocilizumab, certolizumab, golimumab, secukinumab, griffithsin, alpha 1,2-fucosidase, xylanase, phytase and tumor necrosis factor (TNF).

13. The one or more biopolymers may be more than about 500 Da, such as more than about 800 Da, for example more than about 1000 Da, for example more than about 1200 Da, such as more than about 1400 Da, for example more than about 1600 Da, such as more than about 1800 Da, for example more than about 2000 Da, such as more than about 3000 Da, for example more than about 4000 Da, such as more than about 5000 Da, for example more than about 6000 Da, such as more than about 8000 Da, for example more than about 10 kDa, such as about 20 kDa.

13. The pharmaceutical solid dosage form according to any one of claims 1 to 12, having a molecular weight of more than about 30 kDa, such as more than about 30 kDa, for example more than about 40 kDa, such as more than about 50 kDa, for example more than about 60 kDa, such as more than about 70 kDa, for example more than about 80 kDa, such as more than about 90 kDa, for example more than about 100 kDa, such as more than about 110 kDa, for example more than about 120 kDa, such as more than about 130 kDa, for example more than about 140 kDa, such as more than about 150 kDa.

14. 14. The pharmaceutical solid dosage form of any one of claims 1 to 13, further comprising one or more additional ingredients that provide processability, densification or differentiation, such as, but not limited to, microcrystalline cellulose, mannitol, lactose, maltose, maltitol, dicalcium phosphate, talc, silicon dioxide, non-ionic surfactants, bromphenol blue and bromocresol green.

15. 15. The pharmaceutical solid dosage form of any one of claims 1 to 14, wherein the one or more water soluble polymers are independently selected from the list consisting of hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), carboxymethylcellulose (CMC), such as sodium carboxymethylcellulose (CMC), alginates, such as sodium alginate, carrageenan, pectin, hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), hydroxyethyl methylcellulose (HEMC), chitosan, trimethylchitosan, hyaluronic acid, polycarbophil, carbomer, polyethylene oxide and methacrylic acid derivatives, derivatives and salts thereof.

16. 16. The pharmaceutical solid dosage form of claim 15, wherein the one or more water soluble polymers is HPMC, such as a highly hydrophilic, low molecular weight HPMC, for example an HPMC having a viscosity of less than 3000 mPa-s (or cP), such as less than 1000 mPa-s (or cP), for example less than 750 mPa-s (or cP), such as less than 500 mPa-s (or cP), for example less than 400, 350, 300, 250, 200, 150, 120, 100 or 80 mPa-s (or cP).

17. The small molecule weak acid (WA), weak acid surfactant (WAS) or salt thereof may be selected from the group consisting of carbonic acid, monovalent metal phosphate, citric acid, succinic acid, oleic acid, caprylic acid, capric acid, decanoic acid, lauric acid, phosphatidylcholine, salicylic acid, methylsalicylic acid, ethylenediaminetetraacetic acid, acetic acid, cholic acid, deoxycholic acid, glycolic acid, glycocholic acid, glycodeoxycholic acid, taurocholic acid, taurodihydrofusidic acid, sodium caprate, sodium decanoate, sodium caprylate, sodium octanoate, sodium laurate, sodium dodecyl sulfate, sodium dioctyl sulfosuccinate, glyceryl behenate, glyceryl dibehenate, monostearate, glyceryl hydroxybenzoate ...

17. The pharmaceutical solid dosage form according to any one of claims 1 to 16, wherein the surfactant is selected from glyceryl phosphate, sodium N-[8-(2-hydroxybenzoyl)aminocaprylate], sodium salcaprozate, SNAC, N-(5-chlorosalicyloyl)-8-aminocaprylic acid, 5-CNAC, N-[10-(2-hydroxybenzoyl)aminocapric acid], N-[10-(2-hydroxybenzoyl)aminodecanoic acid], sodium lauryl sulfate, sodium stearyl fumarate, sodium deoxycholate, a small molecule weak acid (WA), for example having a molecular weight of less than 400 Da, such as less than 300 Da, for example less than 200 Da, a weak acid surfactant (WAS) or a salt thereof.

18. 18. The pharmaceutical solid dosage form of any one of claims 1 to 17, further comprising one or more additional components that protect the biopolymer from enzymatic digestion, such as a sacrificial enzyme substrate.

19. 20. The pharmaceutical solid dosage form of claim 18, wherein the sacrificial enzyme substrate is selected from a protease inhibitor or a small peptide.

20. 20. The pharmaceutical solid dosage form of claim 19, wherein the protease inhibitor is aprotinin, cysteine, threonine, asparagine, serpin, soybean trypsin inhibitor or a derivative thereof.

21. 20. The pharmaceutical solid dosage form of claim 19, wherein the small peptide is a dipeptide, tripeptide, tetrapeptide, pentapeptide, hexapeptide, heptapeptide, or octapeptide.

22. 22. The pharmaceutical solid dosage form of any one of claims 1 to 21, which is substantially homogeneous without a coating or barrier.

23. 23. The pharmaceutical solid dosage form according to any one of claims 1 to 22, coated with one or more polymers to target specific regions of the gastrointestinal tract, such as the stomach, duodenum, jejunum, ileum, cecum or colon.

24. 24. The pharmaceutical solid dosage form according to any one of claims 1 to 23, which is coated with one or more pH-dependent polymers.

25. 24. The pharmaceutical solid dosage form according to any one of claims 1 to 23, which is coated with one or more pH-independent polymers.

26. 26. The pharmaceutical solid dosage form of any one of claims 1 to 25, wherein the biopolymer is protected from degradation after exposure of the pharmaceutical solid dosage form to a solution of HCl at pH 1.2 with or without pepsin to such an extent that the area under the curve (AUC) from 0 to 60 minutes is greater than 830%-min, such as greater than 1000%-min, for example greater than 1500%-min, of intact biopolymer content versus time.

27. 27. The pharmaceutical solid dosage form of any one of claims 1 to 26, wherein the one or more biopolymers are combined with one or more small molecule APIs.

28. 11. The pharmaceutical solid dosage form of claim 10, wherein the one or more biopolymers comprise an enzyme.

29. 30. The pharmaceutical solid dosage form of claim 28, wherein the enzyme comprises a lipase, a protease, an amylase, an enterokinase, or a carbohydrate enzyme.

30. 30. A method of treating a subject in need of the biopolymer of any one of claims 10-13, 28 or 29, comprising: (a) providing a solid oral dosage form of any one of claims 1-29; and (b) orally administering the solid oral dosage form to a patient.

31. 31. The method of claim 30, wherein the solid dosage form provides a pharmacokinetic profile of the active biopolymer having a T lag of greater than 1.0 hour and less than 16 hours after administration, and a T max of greater than (T lag + 0.5 hour) and less than 20 hours after administration.

32. 32. The method of claim 30 or 31, wherein the solid dosage form is administered to treat a condition in the subject selected from the group consisting of an oral condition, a gastrointestinal or intestinal condition, a metabolic disorder such as an inherited metabolic disorder, phenylketonuria, tyrosinemia, exocrine pancreatic insufficiency such as due to cystic fibrosis, pancreatitis, pancreatic cancer, diabetes, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), celiac disease or a condition related to maldigestion and / or malabsorption, homocystinuria, maple syrup urine disease, a condition related to gluten management, and a lysosomal storage disorder.

33. 30. A process for preparing the pharmaceutical solid dosage form of any one of claims 1 to 29, comprising the steps of providing components a), b) and c) and formulating the dosage form into a tablet or capsule by tabletting, direct compression tabletting, dry granulation followed by tabletting, roller compaction followed by tabletting, dry powder layering, pelleting, slugging, or the like, and optionally including an encapsulation step.

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