Oral biomacromolecule delivery system

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 amenable to treatment by gastrointestinal delivery. Background Art

[0002] When a biomacromolecule (e.g., 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. If this occurs, the biomacromolecule (if intended for therapeutic effect) will no longer be in its intact native conformation to exert its intended effect. Therefore, the biomacromolecule must be fully protected from digestion in the gastrointestinal tract (GIT) and fully retained in its active native conformation in order to retain the ability to have its intended effect, whether that effect is locally in the GIT for a local effect on the GIT mucosa or for systemic absorption across the GI membrane into the bloodstream for the intended effect.

[0003] Ideally, the composition exhibits a high surface area to volume (SA / Vol) ratio to allow for greater surface area contact 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 luminal folds can reduce adverse effects (GI membrane irritation, ulceration, etc.) and increase contact points with the GIT mucosa for greater delivery efficacy. Achieving a higher SA / Vol ratio of the dosage form will contribute to a larger contact surface area.

[0005] However, a disadvantage of a larger SA / Vol ratio would be greater exposure of the biomacromolecule active pharmaceutical ingredient (API) to the digestive mechanisms (pH, enzymes, microorganisms) in the GIT. Increasing the SA / Vol ratio would generally mean that GI fluid would penetrate the composition more quickly, thus digesting a larger portion of the biomacromolecule API dose within a given timeframe. Increasing the SA / Vol ratio without increasing macromolecular digestion would be ideal, but counterintuitive. The present invention breaks this opposing directional paradigm. Summary of the Invention

[0006] An object of embodiments of the present invention is to provide a pharmaceutical solid dosage form for delivering one or more therapeutically active biomacromolecules through the gastrointestinal tract to treat a condition.

[0007] In a broad sense, the present invention relates to a multi-site microenvironment concept for the efficient delivery of biomacromolecules through the gastrointestinal system in the form of a solid dosage form.

[0008] Thus, in a first aspect, the present invention relates to a pharmaceutical solid dosage form for delivery via the gastrointestinal tract to treat a condition, the pharmaceutical solid dosage form comprising a plurality of single units, each single unit comprising:

[0009] a) one or more therapeutically active biomacromolecules;

[0010] b) one or more water-soluble polymers in an amount not exceeding about 50% by weight;

[0011] c) a small molecule weak acid (WA), a weak acid surfactant (WAS), or a salt thereof in an amount not exceeding about 75% by weight;

[0012] Each single unit has a diameter greater than 1.0 mm -1 Surface area to volume (SA / Vol) ratio

[0013] and greater than 1.0 g / cm 3 The solid dosage form comprises a therapeutically effective amount of a therapeutically active biomacromolecule derived from a combination of multiple amounts of each single unit.

[0014] In a second aspect, the present invention relates to a method for treating a subject in need of a biomacromolecule 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 a patient. In some embodiments, the solid dosage form provides a pharmacokinetic profile of the active biomacromolecule, wherein T lag is greater than 1.0 h and less than 16 h after administration, and T max is greater than (T lag + 0.5 h) and less than 20 h after administration.

[0015] In a third aspect, the present invention relates to a process for preparing 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, for example by tableting, direct compression tableting, dry granulation followed by tableting, roller compaction followed by tableting, dry powder layering, granulation, slugging; the process optionally comprising an encapsulation step. DETAILED DESCRIPTION

[0016] The present invention relates to a composition having a high SA / Vol ratio to provide greater surface area contact with the GIT luminal folds, while also protecting a biomacromolecular API from digestion to a degree similar to that of a lower SA / Vol, standard-sized tablet. That is, the composition of the present invention has a greater SA / Vol ratio than a standard-sized tablet to achieve greater surface area contact without sacrificing protection of the biomacromolecular API from the digestive mechanisms that would otherwise occur at a high SA / Vol. As a result, the intact biomacromolecular API has more time and surface area contact, allowing for local action or systemic absorption, as desired. Thus, the relative directional paradigm is broken, wherein a high SA / Vol is achieved without the disadvantage of increasing the biomacromolecular API's susceptibility to digestive mechanisms.

[0017] The composition should also exhibit a single unit density sufficient to facilitate sinking of the composition into the folds of the GIT lumen.

[0018] It is understood that larger biomacromolecules diffuse more slowly and their P app Coefficient relative to P of small molecules app Coefficient (about 10 -4 ) is about 10 -9 That is, small molecules have a P that is about 5 orders of magnitude faster. app Formulating a water-soluble polymer into a single unit comprising the composition can form a hydrogel, causing the diffusion of small molecule weak acids (WAs), weak acid surfactants (WASs), or salts thereof to be slower and more comparable to the diffusion rate of biomacromolecules, thereby keeping the small molecule weak acids (WAs), weak acid surfactants (WASs), or salts thereof in close proximity to the biomacromolecules and creating a microenvironment around each unit of the composition to fully protect the biomacromolecules from the effects of the GIT digestive mechanism for at least 1 hour.

[0019] The result is multiple units of the composition within a specific location in the GIT, each with its own microenvironment (whose function is to adequately protect the biomacromolecule from digestion for at least 1 h) to achieve greater availability of the intact biomacromolecule API within the GIT lumen, thereby achieving its intended effect.

[0020] At any given time, the volume of fluid in the GIT is relatively small, but the turnover rate of fluid flowing through the GIT and being reabsorbed is high. Even in the presence of high GIT fluid turnover, the solid dosage form according to the present invention helps to keep a larger portion of the faster diffusing small molecule weak acid (WA), weak acid surfactant (WAS) or salt thereof in close proximity to the slower diffusing biomacromolecules, thereby providing greater protection from digestion.

[0021] biological macromolecules

[0022] As used herein, "therapeutically active biomacromolecule" refers to a molecule having a molecular weight equal to or greater than about 500 Da and having a therapeutic effect in a subject in need thereof. Therefore, it should be understood that the present invention is not intended for small organic molecule APIs used alone, but rather is intended to allow one or more small organic molecule APIs to be combined with one or more biomacromolecules. Suitable therapeutically active biomacromolecules in the present invention include, but are not limited to, 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, including but not limited to 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, such as peptides selected from the group consisting of: leuprorelin, insulin, vasopressin, calcitonin, calcitonin gene-related peptide, desaminoglycans, leuprorelin, insulin, vasopress ... Vasopressin, 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, amylin, linaclotide, octreotide, semaglutide, liraglutide, telportide, dulaglutide, exenatide, lixisenatide, enoglutide, oxytocin and 2,6-dimethyltyrosine-D-arginine-phenylalanine-lysine amide; or a polypeptide or protein selected from the group consisting of an antibody, a vaccine, lactoferrin, thyroid parathyroid hormone, growth hormone, human growth hormone, cytokine, interferon, interleukin or its antagonist, for example any of IL1-40, for example IL1, IL2, IL10, IL12, IL19, IL21, IL23, IL26, IL27, IL28, IL29, IL36, IL37, IL38, IL39, IL40, lysozyme, beta-casein, albumin, alpha-1 antitrypsin, antithrombin III, collagen, factor VII, factor VIII, factor IX, factor X, fibrinogen, insulin, protein C, erythropoietin (EPO), granulocyte colony-stimulating factor, CSF, granulocyte macrophage colony-stimulating factor (GM-CSF), tissue plasminogen activator (tPA), growth hormone, integrins, alpha-4, beta-7 integrins, chymotrypsin, lipase, pancreatic lipase, amylase and protease, monoclonal antibodies such as adalimumab, tofacitinib, foraminib, bevacizumab, rituximab, trastuzumab, denosumab, ranibizumab, tocilizumab, certolizumab pegol, 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 by peptide (amide) bonds. Polypeptide refers to a relatively long amino acid chain generally having more than 50 amino acids, while oligopeptide refers to a chain having less 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 an amino acid chain, such as a peptide or polypeptide in any primary, secondary, tertiary, and quaternary structure, and may include any post-translational modification, such as phosphorylation, glycosylation, ubiquitination, nitrosylation, methylation, acetylation, lipidation, and proteolysis.

[0023] In some embodiments, the therapeutically active biomacromolecule comprises an enzyme. In some embodiments, the enzyme comprises a lipase, a protease, an amylase, an enterokinase, or a carbohydrase. 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 gastric lipase. In some embodiments, the enzyme comprises a protease. In some embodiments, the protease comprises trypsin, chymotrypsin, carboxypeptidase, elastase, nuclease, pepsin, or subtilisin. In some embodiments, the enzyme comprises an amylase. In some such embodiments, the amylase comprises α In some embodiments, the enzyme comprises a β-amylase, a β-amylase, or a gluco-amylase. In some embodiments, the enzyme comprises enterokinase. In some embodiments, the enzyme comprises a carbohydrase. In some such embodiments, the enzyme comprises a cellulase, a β-glucosidase, a lactase, a galactase, a trehalase, a mannanase, an α-glucosidase, a sucrase, an isomaltase, or a xylanase.

[0024] Water-soluble polymers

[0025] As used herein, "water-soluble polymer" refers to any water-soluble polymer known to those skilled in the art, such as water-soluble polymers suitable for pharmaceutical use. Suitable known water-soluble polymers that can be used according to the present invention include cellulose derivative polymers, such as polymers selected from the following list: hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), carboxymethylcellulose (CMC) such as sodium carboxymethylcellulose, hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), hydroxyethyl methylcellulose (HEMC). Suitable known water-soluble polymers also include alginates such as sodium alginate, carrageenan, pectin, chitosan, trimethyl chitosan, hyaluronic acid, polycarbophil, carbomer, polyethylene oxide, polyvinyl pyrrolidone and copolymers thereof, and methacrylic acid derivative polymers, and derivatives and salts thereof. Water-soluble polymers can play the role of hydrogel forming agents.

[0026] Cellulose or cellulose derivative polymers

[0027] Any suitable cellulose or cellulose derivative polymer may be used according to the present invention. Suitable polymers will be known to those skilled in the art.

[0028] 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 methyl cellulose (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 HPC from International Flavors & Fragrances (IFF). and Emcocel from JRS Pharma. Commercially available carboxymethyl cellulose (CMC) includes TEXTURECEL from International Flavors & Fragrances (IFF). TM , Celetec from CPKelco TM , Aqualon from Ashland TM , from USK Kimya AS and from Nouryon (formerly AkzoNobel) Commercially available methylcellulose and hydroxypropyl methylcellulose include the Japanese Pharmacopoeia METOLOSE and PHARMACOAT (trademark) series and METOLOSE and PHARMACOAT series for food additives from Shin-Etsu Chemical Co., Ltd., the AnyCoat-C or AnyAddy (trademark) series from Lotte (formerly Samsung) Fine Chemicals, the METHOCEL (trademark) series from International Flavors & Fragrances (IFF) (formerly DOW Chemical Company), and the Benecel (trademark) series from Ashland.

[0029] Methylcellulose is a cellulose derivative polymer suitable for the present invention. Methylcellulose has anhydroglucose units connected by 1-4 bonds. Each anhydroglucose unit contains hydroxyl groups at the 2-, 3-, and 6-positions. Partial or complete substitution of these hydroxyl groups with methoxy groups produces methylcellulose. For example, cellulose fiber is treated with a caustic solution and then treated with a methylating agent to produce a cellulose ether substituted with one or more methoxy groups. If not further substituted with other alkyl groups, such a cellulose ether is called methylcellulose. Methylcellulose is characterized by the weight percentage of methoxy groups. By convention, the weight percentage is the average weight percentage based on the total weight of the cellulose repeating units (including all substituents). The content of methoxy groups is reported based on the mass of methoxy groups (i.e., -OCH3). The determination of methoxy% in methylcellulose (MC) polymer is carried out according to the United States Pharmacopoeia (USP37, "Methylcellulose", pages 3776-3778). The methoxy% can be converted into the degree of substitution (DS) of the methyl substituent, DS(methyl). The DS(methyl) of methylcellulose, also known as DS(methoxy), is the average number of OH groups substituted with methyl groups per anhydroglucose unit.

[0030] Hydroxyalkyl methylcellulose is another cellulose derivative polymer suitable for the present invention. Hydroxyalkyl methylcellulose is a cellulose ether having anhydroglucose units connected by 1-4 bonds and having both methyl and hydroxyalkyl groups. The hydroxyalkyl groups can be the same or different from each other. Preferably, the cellulose ether comprises 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 methylcellulose, particularly hydroxy-C1-3-alkyl methylcellulose, such as hydroxypropyl methylcellulose or hydroxyethyl methylcellulose.

[0031] The cellulose ether has a DS(methyl) of 1.2 to 2.2, preferably 1.2 to 1.6. The degree of methyl substitution (DS(methyl)) of the cellulose ether is the average number of OH groups substituted with methyl groups per anhydroglucose unit. For the purpose of determining DS(methyl), the term "OH groups substituted with methyl groups" includes not only methylated OH groups directly bonded to carbon atoms of the cellulose backbone, but also methylated OH groups formed after hydroxyalkylation.

[0032] 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 in particular 0.25 to 0.35. The degree of hydroxyalkyl substitution is described by MS (molar substitution). MS(hydroxyalkyl) is the average number of hydroxyalkyl groups bound by ether bonds per mole of anhydroglucose units. During hydroxyalkylation, multiple substitutions can result in side chains.

[0033] For hydroxypropyl methylcellulose, the % methoxy and % hydroxypropoxy groups in hydroxypropyl methylcellulose are determined according to the United States Pharmacopoeia (USP 43). The values obtained are % methoxy and % hydroxypropoxy. These are then converted to the degree of substitution (DS) of the methyl substituent and the molar substitution (MS) of the hydroxypropyl substituent. The residual amount of salt is taken into account during the conversion. The DS (methyl) and MS (hydroxyethyl) values in hydroxyethyl methylcellulose are determined by Zeisel cleavage with hydrogen iodide followed by gas chromatography. (G. Bartelmus and R. Ketterer, Z. Anal. Chem. [Analytical Chemistry] 286 (1977) 161-190).

[0034] The viscosity of the cellulose ethers of the present invention is determined as a 2% by weight aqueous solution using a Brookfield rotational viscometer or an Ubbelohde viscometer according to the United States Pharmacopoeia (USP 43). The solution used for viscosity measurement of the cellulose ether is prepared by adding an appropriate amount of cellulose ether powder to an appropriate amount of water to achieve a 2% concentration while stirring at elevated temperature with an overhead laboratory stirrer. The solution is then equilibrated to the lower temperature specified in USP 43.

[0035] For sodium carboxymethylcellulose (CMC, such as TEXTURACEL TM Solutions for viscosity measurements of 20,000 Pa (07) were 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 was measured according to USP 43.

[0036] Alginate and its salts.

[0037] Alginate, especially derived from brown seaweed, is a linear, unbranched biopolymer consisting of β-D-mannuronic acid (M) and α-L-guluronic acid (G) residues connected by (1-4)-bonds. Alginate is not a random copolymer, but is composed of blocks of similar and alternating residue sequences, such as MMMM, GGGG and GMGM. Alginate in the form of extraction absorbs water rapidly. The physical properties of alginate may depend on the relative proportions of the M block and the G block. Gel formation at neutral pH requires a calcium source to provide calcium ions to interact with the G-block. The greater the ratio of these G-blocks, the greater the gel strength.

[0038] "Alginate" is a term typically used for salts of alginic acid, but it can also refer to all its derivatives and alginic acid itself; alginates are present in the cell walls of brown algae as calcium, magnesium, and sodium salts. Dry, powdered sodium or potassium alginate can be obtained from this brown algae extraction process. The algal residue is then removed by filtration, and the remaining alginate can be recovered from the aqueous solution.

[0039] Another method for recovering alginate from the initial extraction solution is to add calcium salts. This results in the calcium alginate developing a fibrous texture; it is insoluble in water and can be separated from it. The separated calcium alginate is suspended in water and acid is added to convert it into alginic acid.

[0040] Alginates suitable for use in the practice of the present invention will typically have a molecular weight such that when subjected to flow at 20°C using a rheometer apparatus equipped with cup and bob geometry for 10 s -1 When measured at a shear rate of 2 wt %, these alginates exhibit a viscosity in the range of 5-1,000 mPa s. In some embodiments, when measured in this manner, such alginates will exhibit a viscosity between 6 and 600 mPa s, for example, between 7 and 500 mPa s or between 8 and 500 mPa s. In some other embodiments, when measured in this manner, such alginates will exhibit a viscosity between 8 and 400 mPa s, for example, between 8 and 300 mPa s, for example, between 9 and 200 mPa s or between 10 and 100 mPa s. In some embodiments according to the present invention, high G-type alginates are used. High G-type alginates mean that the one or more alginates used in the practice of the present invention have an average of at least 50% adjacent G units. In some embodiments, the alginates will have an average of at least 52% adjacent G units; in other embodiments, such alginates will have an average of at least 55% or more adjacent G units, and in other embodiments, such alginates will have an average of at least 60%, 65%, or 70% or more adjacent G units, so that higher adjacent G unit content can result in improved product texture.

[0041] According to the present invention, an alginate, such as alginic acid or an alginate salt, is present in an amount not exceeding 30% (w / w) based on the total weight of the final composition. In the present invention, an alginate refers to any alginic acid or alginate salt, such as sodium alginate, magnesium alginate, potassium alginate, triethanolamine alginate or propylene glycol monoglycolate.

[0042] Another suitable water-soluble polymer that can be used according to this specification is carrageenan. As will be understood by those skilled in the art, ingredients obtained from seaweed of the class Rhodophyta will contain carrageenan. Carrageenan refers to a family of linear sulfated polysaccharides extracted from red edible seaweed. Carrageenan is a high molecular weight polysaccharide that is composed of repeated galactose units and 3,6 anhydrogalactose (3,6-AG), including both sulfated and non-sulfated ones. These units are connected by alternating α-1,3 and β-1,4 glycosidic bonds.

[0043] Suitable carrageenan products for use in pharmaceutically acceptable blends or pharmaceutical formulations according to the present specification include various commercial carrageenans, such as Carrageenan and Carrageenan grades, such as GP-379NF, 101. GP-328NF, GP-209NF, GP109, GP911, GP-812NF (International Flavors & Fragrances (IFF), DuPont Nutrition & Biosciences).

[0044] Another suitable water-soluble polymer that can be used according to the present invention is pectin. The term "pectin" should be understood as the water-soluble form of the pectin substance obtained by extracting pectin from plant materials. Pectin has a structure comprising a block of linear galacturonic acid chains (polymers of α-(1-4)-connected-D-galacturonic acid) interrupted by a rhamnose-galacturonic acid backbone (polymers of repeated disaccharides α-(1-4)-D-galacturonic acid-α-(1-2)-L-rhamnose), which typically has a side chain of a polymerized arabinogalactan glycosidically linked to the O-3 or O-4 position of L-rhamnose. The galacturonic acid sequence can have D-xylose and D-apiose glycosidically linked to their O-2 or O-3 position, which can also be substituted by the acetyl groups linked by esters. The long chains of α-(1-4)-linked D-galacturonic acid residues are often referred to as "smooth regions," whereas the highly branched rhamnogalacturonic acid regions are often referred to as "hairy regions."

[0045] Pectin is a common and important polysaccharide with applications in food and pharmaceuticals, and there are many commercial sources. Most commercial pectin products are derived from citrus peel and apple pomace, where raw pectin comprises 10% to 40% by weight of the dry matter.

[0046] Pectin is present in almost all higher plants. Several by-products of the food industry are used for pectin extraction, such as citrus peel (a by-product of citrus juice production), apple pomace (a by-product of apple juice production), beets (a by-product of the beet sugar industry), and to a lesser extent potato fiber, sunflower discs (a by-product of oil production), and onions (Carbohydr. Polymers, 12: 79-99, May 1990). A typical method for extracting highly methylated (HM) pectin from pomace or peel is extraction in hot, dilute mineral acid at pH 1-3 at 50°C-90°C for 3-12 hours (Rolin, 2002, in Pectins and their Manipulation; Seymour GB, Knox JP, Blackwell Publishing Ltd, 222-239). Dried citrus peel contains 20% to 30% pectin (based on dry matter), while pectin is present in lower amounts (10% to 15%) in dried apple pomace (Christensen, 1986, Pectins. Food Hydrocolloids, 3, 205-230). Pectin is precipitated by adding alcohol (usually isopropanol, but methanol or ethanol may also be used). 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, Pectins and their Manipulation; Seymour GB, Knox JP, Blackwell Publishing Ltd, 222-239.

[0047] Low methylation (LM) pectin can be obtained by deesterifying high methylation (HM) pectin, which is mainly carried out by controlling the acidity, temperature and time during the extraction process. In order to produce other types of pectin, the ester can be hydrolyzed as a concentrated liquid or hydrolyzed in an alcoholic slurry by acid or alkali before or during extraction, and then separated and dried. When using alkali, the reaction must be carried out at low temperatures and in an aqueous solution to avoid the β-elimination degradation of the polymer (Kravtchenko et al., 1992, Carbohydrate Polymers [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 [food polysaccharides and their applications]; Stephen AM, New York: Marcel Dekker Inc (Marcel Dekker Company), 287-339). The production of LM pectin using pectin methylesterase (PME) can be used as an alternative to chemical extraction (Christensen, 1986, Pectins. Food Hydrocolloids, 3, 205-230).

[0048] Although commercial LM pectin is almost entirely derived from HM pectin, LM pectin also has natural sources, such as ripe sunflower discs (Thakur et al., 1997, Critical Reviews in Food Science and Nutrition, 37(1): 47-73). International patent application WO 2013 / 109721 describes a method for producing pectin, wherein citrus peel is treated to obtain homogenized citrus peel, the homogenized citrus peel is washed with an organic solvent, and then a desolventizing and drying step is performed to recover a fiber-containing pectin product or pectin. In some embodiments, the drying step is followed by a crushing or grinding step.

[0049] Alternatively, a suitable pectin product is obtained according to the process 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) providing an in situ reaction system by swelling the plant material in an aqueous solution comprising at least one salt, (ii) subjecting the pectin present in the swollen plant material from step (i) to a deesterification treatment, and (iii) isolating the deesterified fiber-containing pectin product. In some embodiments, the plant material is a natural pectin-containing plant material, including the peel or pulp from citrus fruits such as lemons, oranges, tangerines, limes, and grapefruits.

[0050] Exemplary commercially available pectins include, but are not limited to, apple pectin (SIGMA-ALDRICH, product number 93854), citrus peel pectin (SIGMA-ALDRICH, product number P9135), citrus pectin with a degree of esterification of 60% (SIGMA-ALDRICH, product number P9436), and citrus pectin with a degree of esterification of 90% (SIGMA-ALDRICH, product number P9561), GRINDSTED Pectin RS 400, ANDRE Pectin AP 101, GENUPECTIN B (fast setting type), UNIPECTIN RS150, 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 LM 18CG and UNIPECTIN OF 400, Classic AF 701.

[0051] Small molecule weak acid (WA), weak acid surfactant (WAS)

[0052] The solid dosage form according to the present invention comprises a small molecule weak acid (WA) or a weak acid surfactant (WAS). The term "weak acid" is used herein with its normal meaning known to technicians, and refers to an acid that partially dissociates into its ions in an aqueous solution or water. In addition, a small molecule weak acid (WA) is an acid with a molecular weight of less than 500Da. In certain embodiments, a small molecule weak acid (WA), a weak acid surfactant (WAS), or a salt thereof has a molecular weight of less than 400Da, for example, less than 300Da, for example, less than 200Da. The difference between a weak acid (WA) and a weak acid surfactant (WAS) is that WAS will have amphiphilic properties. As the chain length increases, WA can become WAS. For example, citric acid is considered to be a branched chain WA with a total of 6 carbons and three carboxyl groups. There is a carboxyl group at each end of the five-carbon chain and a carboxyl group at the third carbon of the five-carbon chain. Sodium octanoate can be considered to be WA or WAS and is a straight chain 8-carbon chain with a carboxyl group at one end. The amphiphilic property comes from the non-polar nature of the eight-carbon chain and the polar nature of the carboxyl group. WA or WAS may function as a buffer, surfactant and / or absorption enhancer.

[0053] Suitable small molecule weak acids (WAs), weak acid surfactants (WASs), or salts thereof to be used according to the present invention may be, but are not limited to, any one selected from the group consisting of carbonic acid, monovalent metal phosphates, citric acid, succinic acid, oleic acid, caprylic acid, capric acid, n-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 decanoate, sodium n-decanoate, sodium caprylate, sodium caprylate, octanoate), sodium laurate, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, glyceryl behenate, glyceryl dibehenate, glyceryl monostearate, sodium N-[8-(2-hydroxybenzoyl)aminocaprylate], sodium sapolic acid, SNAC, N-(5-chlorosalicyloyl)-8-aminocaprylic acid, 5-CNAC, N-[10-(2-hydroxybenzoyl)aminodecanoate], N-[10-(2-hydroxybenzoyl)amino-n-decanoate], sodium lauryl sulfate, sodium stearoyl fumarate, or sodium deoxycholate.

[0054] Surface area to volume (SA / Vol) ratio and unit density

[0055] The solid dosage form according to the present invention is composed of a plurality of single units having a relatively high surface area to volume (SA / Vol) ratio to obtain a larger surface area in contact with the luminal folds of the gastrointestinal tract. The surface area to volume (SA / Vol) ratio and the density of the single unit can be measured as described in Example 1. The terms "minitablet" and "single-unit" are used interchangeably.

[0056] Multi-unit bulk density

[0057] The multi-unit bulk density refers to the density of the combined amount of individual units. In some embodiments, the multi-unit bulk density is greater than 0.70 g / cm 3 .

[0058] As detailed above, the present invention relates to a pharmaceutical solid dosage form for treating a condition via gastrointestinal delivery, the pharmaceutical solid dosage form comprising a plurality of single units, each single unit comprising:

[0059] a) one or more therapeutically active biomacromolecules;

[0060] b) one or more water-soluble polymers in an amount not exceeding about 50% by weight;

[0061] c) a small molecule weak acid (WA), a weak acid surfactant (WAS), or a salt thereof in an amount not exceeding about 75% by weight;

[0062] Each single unit has a diameter greater than 1.0 mm -1 Surface area to volume (SA / Vol) ratio

[0063] and greater than 1.0g / cm 3 The solid dosage form comprises a therapeutically effective amount of a therapeutically active biomacromolecule derived from a combination of multiple amounts of each single unit.

[0064] In some embodiments, this solid dosage form comprises at least 2 single units as defined above, e.g., 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.

[0065] In some embodiments, the solid dosage form comprises no more than about 500 single units, for example, no more than about 400 single units, no more than about 300 single units, no more than about 200 single units, no more than about 180 single units, no more than about 160 single units, no more than about 140 single units, no more than about 120 single units, no more than about 100 single units.

[0066] In some embodiments, this solid dosage form has a viscosity greater than 0.70 g / cm 3 , for example, greater than 0.72 g / cm 3 , greater than 0.74g / cm 3 , greater than 0.76g / cm 3 , greater than 0.78g / cm 3 , greater than 0.80g / cm 3 , greater than 0.82g / cm 3 , greater than 0.84g / cm 3 , greater than 0.86g / cm 3 , greater than 0.88g / cm 3 , greater than 0.90g / cm 3 , greater than 0.92g / cm 3 , greater than 0.94g / cm 3 , greater than 0.96g / cm 3 , greater than 0.98g / cm 3 , greater than 1.00g / cm 3 Multi-unit bulk density.

[0067] In some embodiments, the viscosity of the one or more water-soluble polymers is less than 3000 mPa-s (or cP), for example, 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).

[0068] In some embodiments, each single unit has a size greater than 1.0 mm -1 , for example, greater than 1.5 mm -1 , for example, greater than 2.0 mm -1 , for example, greater than 2.5 mm -1 , for example, greater than 3.0 mm -1 The surface area to volume (SA / Vol) ratio.

[0069] In some embodiments, each single unit has a mass greater than 1.0 g / cm 3 , for example, greater than 1.1 g / cm 3 , for example, greater than 1.2 g / cm 3 , for example, greater than 1.3 g / cm 3 single unit density.

[0070] In some embodiments, the one or more water-soluble polymers are present in an amount of no more than about 50%, such as no more than about 45%, such as no more than about 40%, such as no more than about 35%, such as no more than about 30%, such as no more than about 28 wt %, such as no more than about 26 wt %, such as no more than about 24 wt %, such as no more than about 22 wt %, such as no more than about 20 wt %, such as no more than about 18 wt %, such as no more than about 16 wt %, such as no more than about 14 wt %, such as no more than about 12 wt %, such as no more than about 10 wt %.

[0071] In some embodiments, the small molecule weak acid (WA), weak acid surfactant (WAS), or salt thereof is present in an amount of no more than about 70 wt %, for example, no more than about 65 wt %, for example, no more than about 60 wt %, for example, no more than about 55 wt %, for example, no more than about 50 wt %, for example, no more than about 45 wt %, for example, no more than about 40 wt %.

[0072] In some embodiments, the one or more biomacromolecules 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.

[0073] In some embodiments, the one or more biomacromolecules are combined with one or more small molecule APIs.

[0074] In some embodiments, the one or more biomacromolecules 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, amylin, linaclotide, octreotide, semaglutide, liraglutide, telportide, dulaglutide, exenatide, lixisenatide, enoglutide, oxytocin, and 2,6-dimethyltyrosine-D-arginine-phenylalanine-lysine amide.

[0075] In some embodiments, the one or more biomacromolecules are proteins 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, such as IL1, IL2, IL10, IL12, IL19, IL21, IL23, IL26, IL27, IL28, IL29, IL36, IL37, IL38, IL39, IL40, lysozyme, beta-casein, albumin, alpha-1 antitrypsin, antithrombin III, collagen, factor VII, factor VIII, factor IX, factor X , fibrinogen, insulin, protein C, erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), tissue plasminogen activator (tPA), growth hormone, integrins, alpha-4, beta-7 integrins, chymotrypsin, lipase, pancreatic lipase, amylase and protease, adalimumab, tofacitinib, foraminciclozumab, bevacizumab, rituximab, trastuzumab, denosumab, ranibizumab, tocilizumab, certolizumab pegol, golimumab, secukinumab, grefsen, alpha 1,2-fucosidase, xylanase, phytase, and tumor necrosis factor (TNF).

[0076] In some embodiments, the one or more biomacromolecules have a molecular weight greater than about 500 Da, such as greater than about 2000 Da, such as greater than about 3000 Da, such as greater than about 4000 Da, such as greater than about 5000 Da, such as greater than about 6000 Da, such as greater than about 8000 Da, such as greater than about 10 kDa, such as greater than about 20 kDa, such as greater than about 30 kDa, such as greater than about 40 kDa, such as greater than about 50 kDa, such as greater than about 60 kDa, such as greater than about 70 kDa, such as greater than about 80 kDa, such as greater than about 90 kDa, such as greater than about 100 kDa, such as greater than about 110 kDa, such as greater than about 120 kDa, such as greater than about 130 kDa, such as greater than about 140 kDa, such as greater than about 150 kDa.

[0077] In some embodiments, the solid dosage form further comprises one or more additional ingredients that provide processability, densification, or identification, such as, but not limited to, microcrystalline cellulose, mannitol, lactose, maltose, maltitol, dicalcium phosphate, talc, silicon dioxide, nonionic surfactants, bromophenol blue, and bromocresol green.

[0078] 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, trimethyl chitosan, hyaluronic acid, polycarbophil, carbomer, polyethylene oxide, and methacrylic acid derivatives; derivatives and salts thereof.

[0079] In some embodiments, the one or more water-soluble polymers is HPMC, e.g., a highly hydrophilic, lower molecular weight HPMC, e.g., an HPMC having a viscosity of less than 3000 mPa-s (or cP), e.g., a viscosity of less than 1000 mPa-s (or cP), e.g., less than 750 mPa-s (or cP), e.g., less than 500 mPa-s (or cP), e.g., less than 400, 350, 300, 250, 200, 150, 120, 100, or 80 mPa-s (or cP).

[0080] In some embodiments, the small molecule weak acid (WA), weak acid surfactant (WAS), or a salt thereof is selected from carbonic acid, monovalent metal phosphate, citric acid, succinic acid, oleic acid, caprylic acid, capric acid, n-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 decanoate, sodium n-decanoate, sodium octanoate (sodium caprylate), sodium octanoate, sodium laurate, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, glyceryl behenate, glyceryl dibehenate, glyceryl monostearate, sodium N-[8-(2-hydroxybenzoyl)aminocaprylate], sodium saprolisalate, SNAC, N-(5-chlorosalicyloyl)-8-aminocaprylic acid, 5-CNAC, N-[10-(2-hydroxybenzoyl)aminodecanoate], N-[10-(2-hydroxybenzoyl)amino-n-decanoate], sodium lauryl sulfate, sodium stearoyl fumarate, sodium deoxycholate.

[0081] In certain embodiments, the pharmaceutical solid dosage form further comprises one or more additional ingredients that protect the biomacromolecule from enzymatic digestion, such as a sacrificial enzyme substrate. The sacrificial enzyme substrate can be selected from a protease inhibitor or a small peptide. The protease inhibitor can be selected from aprotinin, cysteine, threonine, asparagine, serine protease inhibitor, soybean trypsin inhibitor or a derivative thereof. The small peptide can be selected from a dipeptide, a tripeptide, a tetrapeptide, a pentapeptide, a hexapeptide, a heptapeptide or an octapeptide.

[0082] In some embodiments, the solid dosage form is substantially homogeneous, without coatings or barriers.

[0083] In some embodiments, the solid dosage form is coated with one or more polymers to target a specific region of the gastrointestinal tract, such as the stomach, duodenum, jejunum, ileum, cecum, or colon.

[0084] In some embodiments, the solid dosage form is coated with one or more pH-dependent polymers.

[0085] In some embodiments, the solid dosage form is coated with one or more pH-independent polymers.

[0086] In some embodiments, upon exposure of the pharmaceutical solid dosage form to a solution of HCl pH 1.2 with or without pepsin, the biomacromolecule is protected from degradation to an extent such that the area under the intact biomacromolecule content-time curve (AUC) from 0-60 min is greater than 830%-min, e.g., greater than 1000%-min, e.g., greater than 1500%-min.

[0087] application

[0088] The dosage forms disclosed herein can be used in a variety of applications. In some embodiments, the dosage forms are used in human therapeutics. In some embodiments, the dosage forms are used in animal therapeutics. In some embodiments, the dosage forms are used in pet therapeutics. In some embodiments, the dosage forms are used in farm animal therapeutics, such as for swine, poultry, or cattle nutritional applications. In some embodiments, the dosage forms are used in human nutritional applications. In some embodiments, the dosage forms are used in human dietary supplements. In some embodiments, the dosage forms are used in animal nutritional applications. In some embodiments, the dosage forms are used in animal dietary supplements. In some embodiments, the dosage forms are used in pet nutritional applications. In some embodiments, the dosage forms are used in farm animal nutritional applications.

[0089] 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 biomacromolecule. 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 condition comprises an oral condition. In some embodiments, the condition comprises a digestive or intestinal condition. In some embodiments, the condition comprises a metabolic disorder. In some embodiments, the condition comprises an inherited metabolic disorder. In some embodiments, the condition comprises phenylketonuria (PKU) or tyrosinemia. In some embodiments, the condition comprises exocrine pancreatic insufficiency. In some embodiments, the condition (e.g., exocrine pancreatic insufficiency) is caused by 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 condition comprises homocystinuria. In some embodiments, the condition comprises maple syrup urine disease. In some embodiments, the condition is related to gluten management, such as gluten intolerance, gluten sensitivity, or celiac disease. In some embodiments, the condition comprises a lysosomal storage disorder.

[0090] In some embodiments, the dosage form is administered to a subject (ie, human or animal) to treat a condition disclosed in the preceding paragraph, and the therapeutically active biomacromolecule comprises an enzyme (eg, an enzyme disclosed herein).

[0091] Examples

[0092] Example 1

[0093] Weigh the following powder ingredients:

[0094] Bovine lactoferrin 15g (Parchem)

[0095] Emprove sodium caprylate 150g (Merck Millipore Sigma)

[0096] Avicel PH 101 microcrystalline cellulose 100.5g (IFF)

[0097] METHOCEL K100LV HPMC (22.9% methyl, 10.1% hydroxypropyl, 104 mPa-s viscosity, 71.4% passing through 230 mesh) 30 g (IFF)

[0098] Bromocresol green 3g (Merck Millipore Sigma)

[0099] · Alubra Sodium Stearoyl Fumarate 1.5g (IFF)

[0100] Total powder blend for tableting 300g

[0101] By placing the formulation ingredients (except Alubra sodium stearyl fumarate) in a glass jar, capping and blending them via a Turbula mixer for 10 minutes, these ingredients are blended together. After the first 10 minutes of blending, Alubra sodium stearyl fumarate is added, and then blended for 1 minute. On a Manesty Beta rotary tablet press, biconvex 2-mm round mini tablet tools are used to compact the powder blend using 14 of the 16 stations. The turret speed is set to 13 rpm to observe die filling during tableting, and the target of the compression force is 500 pounds (lb.) or 2.2 kN. The mini tablet formulation is then sealed and stored in a Ziploc bag under ambient room conditions for at least the duration of the night before analysis.

[0102] Twenty microtablets were individually measured to determine the unit weight, diameter, and thickness. The unit weight was determined by an analytical balance. The unit diameter and thickness were determined using a caliper. The unit surface area (SA), unit surface area-volume (SA / Vol), unit volume, and unit density were determined using the individual microtablet size measurements and the tool cup dimensions provided by Natoli Engineering, the manufacturer of the microtablet tool. The methods used to determine the unit SA, unit SA / Vol, unit volume, unit density, the relationship between intact lactoferrin content and time, and the area under the intact lactoferrin content-time curve (AUC) are described in the following sections. 0-60min The single unit SA / Vol and single unit density of the composition of Example 1 were 3.49±0.098 mm -1 and 1.32±0.053g / cm 3AUC 0-60min It is 1840.00±513.400%-min.

[0103] Determine the physical characteristics of a single unit

[0104] Since the microtablets are biconvex rather than planar, the microtablet surface area (SA, in mm) was calculated according to the following equation: 2 (units):

[0105] Single unit SA (mm 2 ) = (2 × tool cup area) + 2πr (r + t) - 2πr 2

[0106] Where t is the minitablet band thickness and r is the minitablet radius. The final 2πr in the equation 2 The combined surface area of the two embedded flat faces was taken into account and removed because the minitablets are biconvex rather than planar.

[0107] The microtablet radius was calculated by dividing the microtablet diameter by two.

[0108] The tool cup area specified by micro-tablet tool manufacturer Natoli Engineering is 3.3800mm 2 .

[0109] The microtablet tape thickness was calculated according to the following equation:

[0110] Single unit belt thickness (mm) = total single unit thickness - 2 (cup depth)

[0111] The micro-tablet tool cup depth specified by Natoli Engineering is 0.2800mm.

[0112] The surface area to volume ratio (SA / Vol, in mm) of the microtablets was calculated according to the following equation: -1 ):

[0113]

[0114] The micro-tablet tool cup volume specified by Natoli Engineering is 0.4100 mm 3 .

[0115] The volume of the microtablet (cm) was calculated according to the following equation: 3 ):

[0116]

[0117] The density of the microtablets (g / cm) was calculated according to the following equation: 3 ):

[0118]

[0119] Determination of intact lactoferrin content

[0120] 200mg mini tablets (usually containing 5% lactoferrin) are added to 10mL pH 1.2HCl+pepsin in a 50mL centrifuge tube. 200mg mini tablets are approximately 50 mini tablets. pH 1.2 HCl+pepsin was prepared according to the USP formula for simulated gastric fluid (SGF). The tube is capped and placed on an inclined roller (rolled and balanced to 37°C at 6-7rpm) for a specified duration (0, 10, 20, 30, 40, 50, or 60min). The entire roller is set in a thermostatic chamber so that the temperature can be controlled at 37°C. The roller is tilted 7° so that when it rolls, 10mL of pH 1.2HCl+pepsin converges towards the bottom of the tube, thereby immersing and gently stirring the tested dosage. At the specified time point, the centrifuge tube is taken out from the roller, and 20mL of pH 9.0 neutralizing buffer is added to the centrifuge tube to neutralize to pH 7, followed by vortexing for 1min. A pH 9.0 neutralization buffer was prepared by dissolving 14.2 g of anhydrous sodium hydrogen phosphate in 1 L of deionized water. Two sets of roller time point samples were tested each day, with n=3 replicates for each roller time point sample set. That is, a total of 6 samples could be tested each day. Each neutralized sample was then frozen. Each frozen neutralized sample was taken out of the freezer and rolled on a roller in a refrigerator (4.8° C.) overnight to thaw. The colorimetric sample, working buffer stock solution, wash buffer stock solution, and stop solution (all provided with the ELISA assay kit) were taken out of the storage refrigerator (6° C.) the morning before analysis and equilibrated to ambient room temperature. The working buffer stock solution was diluted 5X before use, with 16 mL milli-Q water + 4 mL working buffer stock solution. The wash buffer stock solution was diluted 20X before use, with 19 mL milli-Q water + 1 mL wash buffer stock solution. Four 2-mL centrifuge tubes, tubes A to D, were prepared for each sample. More or fewer tubes were used depending on the concentration of lactoferrin used. Pipette 0.9 mL of diluted working buffer into each tube. Pipette 0.1 mL of the thawed neutralization roller sample into tube A, followed by aspiration into the pipette and expelling from the pipette 5 times, and then vortexing for a few seconds. Pipette 0.1 mL from tube A into tube B, followed by aspiration into the pipette and expelling from the pipette 5 times, and then vortexing for a few seconds. Pipette 0.1 mL from tube B into tube C, followed by aspiration into the pipette and expelling from the pipette 5 times, and then vortexing for a few seconds. Pipette 0.1 mL from tube C into tube D, followed by aspiration into the pipette and expelling from the pipette 5 times, and then vortexing for a few seconds. Pipette 0.1 mL from tube D into the wells of an ELISA assay plate. (Bovine Lactoferrin ELISA Kit, ab274406, Abcam) For more information on Bovine Lactoferrin ELISA assay plates, please refer to https: / / www.abcam.com / bovine-lactoferrin-elisa-kit-ab274406.html. ) Repeat the above steps for each of the remaining five thawed neutralization roller samples. The assay plate is covered with microplate sealing tape (Thermofisher Scientific, part number 9503130) and the plate is placed in a Tecan plate reader. The plate is shaken for 3 minutes and kept at 23°C for 27 minutes. The assay plate is taken out from the Tecan instrument and the wells are cleaned 5 times by filling the wells with diluted wash buffer and then emptying them on a paper towel. For the last rinse, the diluted wash buffer is left in the wells for 2min, then emptied on a paper towel. The tube containing the antibody (provided with the ELISA kit) is taken out from the storage refrigerator (6°C) and equilibrated to ambient room temperature (approximately 0.5h). 0.990mL of the diluted working buffer is added to a new vial. 0.010mL of the balanced antibody solution is added to the vial. 0.100mL of the prepared solution is added to each of the 5X rinse wells of the assay plate. (Note: Each well strip requires one tube of diluted antibody solution.) The assay plate was covered with microplate tape again and placed in a Tecan to vibrate for 3 minutes and kept at 23°C for 27 minutes. The assay plate was taken out from the Tecan and the wells were cleaned 5 times with diluted wash buffer. For the last rinse cycle, the diluted wash buffer was left in the wells for 2 minutes before draining. 0.100mL of chromogen solution (equilibrated to ambient room temperature) was added to each of the 5X rinse wells of the assay plate. The assay plate was covered with sealing tape and placed in the Tecan. The assay plate was vibrated for 3 minutes and then kept at 23°C for 7 minutes. The assay plate was taken out from the Tecan and 0.100mL of stop solution (provided with the ELISA assay kit) was added to the wells. The assay plate was immediately put back into the Tecan, without using microplate tape this time. The plate reader was set to hold for 1 minute, and then the UV spectrophotometer analyzed the wells at a wavelength of 450nm. Complete lactoferrin content data was provided after the analysis was complete. The intact lactoferrin content-time curve from 0-60 min was drawn, and the area under the intact lactoferrin content-time curve AUC was calculated. 0-60min .

[0121] Preparation of calibration standards for the determination of intact lactoferrin

[0122] Approximately 17 mg of lactoferrin was added to 100 mL of milliQ water in a vial, which was then capped and rolled under refrigeration (4.8°C) for at least 2 hours. This was used as a lactoferrin stock solution for preparing calibration standards. 0.1 mL of lactoferrin stock solution was diluted with 0.9 mL of diluted working buffer to prepare a 10X dilution. The 10X dilution was mixed by aspirating into a pipette and expelling from the pipette 5 times, followed by vortexing for a few seconds. 0.1 mL from the 10X dilution was further diluted with 0.9 mL of diluted working buffer to prepare a 100X dilution. The 100X dilution was mixed by aspirating into a pipette and expelling from the pipette 5 times, followed by vortexing for a few seconds. Eight 2-mL centrifuge tubes were prepared for 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 to 7. 0.050mL 100X diluent is pipetted into pipe 1 and mixed. 0.040mL 100X diluent is pipetted into pipe 8 and mixed. 0.400mL from pipe 1 is pipetted into pipe 2, by suction and discharge, pipette tip is rinsed 5 times, then vortex for a few seconds. 0.400mL from pipe 2 is pipetted into pipe 3, by suction and discharge, pipette tip is rinsed 5 times, then vortex for a few seconds. Serial dilution is carried out by pipe 6. Pipe 7 contains only the working buffer blank solution (without lactoferrin) of dilution. Each calibration standard of 0.100mL is pipetted into each well in the specific row of ELISA assay plate, and each in these wells is prepared as previously described and analyzed accordingly. This row is used to produce a calibration curve.

[0123] Comparative Example A

[0124] Weigh the following powder ingredients:

[0125] ·Bovine lactoferrin 15g

[0126] Emprove Sodium Caprylate 150g

[0127] Avicel PH 102 microcrystalline cellulose 132g (IFF)

[0128] Cabosil M5P silicon dioxide 1.5g (Cabot)

[0129] · Alubra Sodium Stearoyl Fumarate 1.5g (IFF)

[0130] Total powder blend for tableting 300g

[0131] As in Example 1, the formulation ingredients except Alubra sodium stearyl fumarate are blended together for 10 minutes, and then Alubra sodium stearyl fumarate is added and blended for 1 minute. On a Manesty Beta rotary tablet press, biconvex 7.94-mm round tablet tools are used to utilize 8 of the 16 stations to compact the powder blend. The turret speed is set to 13 rpm to observe the die filling during tableting, and the target of the compression force is 5000 pounds (lb.) or 22.2 kN. As done for Example 1, the tablet formulation is then sealed in a Ziploc bag and stored at least overnight under ambient room conditions before analysis.

[0132] The weight and dimensions of 20 individual tablets were measured similarly to Example 1. However, for Comparative Example A, the dimensional measurements of the individual tablets were based on the biconvex 7.94-mm round tool cup dimensions 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 unit surface area (SA), unit surface area-volume (SA / Vol), unit volume, and unit density were determined using the equations provided for Example 1. Intact lactoferrin was determined by ELISA in pH 1.2 HCl containing pepsin using the method described for Example 1. The unit SA / Vol and unit density of the comparative example A composition were 1.00 ± 0.003 mm, respectively. -1 and 1.18±0.008g / cm 3 AUC 0-60min It is 1801.67±352.628%-min.

[0133] Comparative Example B

[0134] Multiparticulates were prepared by coating in a Glatt GPCG-1 fluid bed coater via bottom spray (starting at 3 g / min spray rate and gradually increasing to 5.7 g / min) using a Wurster column insert with a 1:1 weight ratio of METHOCEL TM The sucrose beads (nonpareil beads) were coated with E5 LV and a 10% aqueous solution of lactoferrin. The solution was formed with deionized (DI) water. After processing at an outlet temperature of 45°C for 2.5 hours, 400g of the sucrose beads were coated to a final weight of 436g.

[0135] Since multiparticulates are spherical, SA is measured according to the following equation:

[0136] SA(mm 2 )=4πr 2

[0137] And Vol is measured according to the following equation:

[0138]

[0139] SA / Vol is measured according to the following equation:

[0140]

[0141] It was not feasible to load the multiparticulates with EMPROVE sodium octanoate at the desired level, so sodium octanoate powder was added to the coated multiparticulates in pH 1.2 HCl with pepsin to determine the change in intact lactoferrin over time. Intact lactoferrin was quantified using the ELISA method described for Example 1. The single unit SA / Vol and single unit density of the Comparative Example B composition were 6.47 ± 0.258 mm, respectively. -1 and 1.64±0.321g / cm 3 AUC 0-60min It is 263.33±241.109%-min.

[0142] Comparative Example C

[0143] Weigh the following powder ingredients:

[0144] ·Bovine lactoferrin 15g

[0145] Emprove Sodium Caprylate 150g

[0146] Avicel PH 101 microcrystalline cellulose 130.5g

[0147] Bromocresol green 3g

[0148] Alubra Sodium Stearoyl Fumarate 1.5g

[0149] Total powder blend for tableting 300g

[0150] As in Example 1, the formulation ingredients except Alubra sodium stearyl fumarate are blended together for 10 min, and then Alubra sodium stearyl fumarate is added and blended for 1 min. As in Example 1, a biconvex 2-mm round mini tablet tool is used on a Manesty Beta rotary tablet press to compact the powder blend using 14 of the 16 stations. Similarly, as done for Example 1, the turret speed is set to 13 rpm to observe the die filling during tableting, and the target of the compression force is 500 pounds (lb.) or 2.2 kN. And as done for Example 1, the mini tablet formulation is then sealed in a Ziploc bag and stored at least overnight under ambient room conditions before analysis.

[0151] The weight and dimensions of 20 individual minitablets were measured similarly to Example 1. The unit surface area (SA), unit surface area-volume (SA / Vol), unit volume, and unit density were determined using the equations already provided for Example 1. Intact lactoferrin was determined by ELISA in pH 1.2 HCl containing pepsin using the method described for Example 1. The unit SA / Vol and unit density of the comparative example C composition were 3.61 ± 0.149 mm, respectively. -1 and 1.50±0.097g / cm 3 AUC 0-60min It is 977.50±312.630%-min.

[0152] Table 1

[0153]

[0154] AUC in Table 1 0-60min is the area under the intact lactoferrin-time curve from 0 to 60 min.

[0155] Example 2

[0156] For Example 2(a), the following powder ingredients were weighed:

[0157] Lipase mixture 2.5g (IFF)

[0158] Emprove sodium caprylate 25g (Merck Millipore Sigma)

[0159] Avicel PH 101 microcrystalline cellulose 17g (IFF)

[0160] METHOCEL K100LV HPMC (22.9% methyl, 10.1% hydroxypropyl, 104 mPa-s viscosity, 71.4% passing through 230 mesh) 5g (IFF)

[0161] Cabosil M5P silicon dioxide 0.25g (Cabot Corporation)

[0162] Alubra Sodium Stearoyl Fumarate 0.25g (IFF)

[0163] Total powder blend for tableting 50g

[0164] For Example 2(b), the following powder ingredients were weighed:

[0165] Lipase mixture 2.5g (IFF)

[0166] Emprove sodium caprylate 12.5g (Merck Millipore Sigma)

[0167] Avicel PH 101 microcrystalline cellulose 29.5g (IFF)

[0168] METHOCEL K100LV HPMC (22.9% methyl, 10.1% hydroxypropyl, 104 mPa-s viscosity, 71.4% passing through 230 mesh) 5g (IFF)

[0169] Cabosil M5P silicon dioxide 0.25g (Cabot Corporation)

[0170] Alubra Sodium Stearoyl Fumarate 0.25g (IFF)

[0171] Total powder blend for tableting 50g

[0172] The formulation ingredients except Alubra sodium stearyl fumarate were placed on a #20 mesh screen and manually sieved through a screen. The sieved ingredients were blended together by placing them in a glass jar, capping them, and blending them for 10 minutes using a Turbula mixer. Alubra sodium stearyl fumarate was added after the first 10 minutes of blending, and then blended for 1 minute. The powder blend was compacted using 2-3 stations of the same biconvex 2-mm circular mini tablet tool as described in Example 1 on a Manesty Beta rotary tablet press. Due to the cost and small supply of raw materials, the blended powder was manually fed into 2-3 groups of dies available on the turret while the tablet press was turned off, and then the tablet press was activated with a force of approximately 2.2 kN to compress the powder into mini tablets when the turret speed was set to 13 rpm. Mini tablets were then collected from the turret using a spatula and sealed and stored in a Ziploc bag at least overnight under ambient laboratory conditions before analysis.

[0173] Twenty minitablets containing the lipase mixture were individually measured to determine unit weight, diameter, and thickness using the methods described in Example 1. SA / Vol and unit density were calculated using the equations described in Example 1 and are shown in Table 2.

[0174] Table 2

[0175] Delivery system type Role <![CDATA[SA / Vol(mm -1 )]]> <![CDATA[Unit density (g / cm 3 )]]> Multi-site microenvironment Example 2(a) 2.88±0.069 1.28±0.050 Multi-site microenvironment Example 2(b) 2.87±0.066 1.32±0.071

[0176] Example 3

[0177] Weigh the following powder ingredients:

[0178] Semaglutide 50 mg (Boc Sciences)

[0179] Emprove sodium caprylate 500mg (Merck Millipore Sigma)

[0180] Avicel PH 101 microcrystalline cellulose 345 mg (IFF)

[0181] METHOCEL K100LV HPMC (22.9% methyl, 10.1% hydroxypropyl, 104 mPa-s viscosity, 71.4% passing through 230 mesh) 100 mg (IFF)

[0182] Alubra Sodium Stearoyl Fumarate 5mg (IFF)

[0183] Total powder blend for tableting 1000 mg

[0184] The formulation ingredients, except Alubra sodium stearyl fumarate, were blended together by placing them in a glass jar, capping them, and blending them for 10 minutes using a Turbula mixer. Alubra sodium stearyl fumarate was added after the first 10 minutes of blending, and then blended for 1 minute. The powder blend was compacted using the same biconvex 2-mm round mini-tablet tooling as described in Example 1, using 2-3 stations at a time on a Manesty Beta rotary tablet press. Due to the cost and limited availability of raw materials, the blended powder was manually fed into 2-3 sets of dies available on the turret while the tablet press was turned off, and then the tablet press was activated with a force of approximately 2.2 kN to compress the powder into mini-tablets while the turret speed was set to 13 rpm. The mini-tablets were then collected from the turret using a spatula and sealed and stored in Ziploc bags in a -20°C freezer for at least overnight prior to analysis. To experimentally adjust the amount of sodium octanoate, a placebo version of the mini-tablets was produced with the tablet press running in full operational mode using the parameters described in Example 1. This allowed the combination of active and placebo mini-tablets to vary the sodium octanoate dose while keeping the semaglutide dose constant.

[0185] Twenty minitablets containing semaglutide were individually measured using the methods described in Example 1 to determine single unit weight, diameter, and thickness.

[0186] Determination of intact semaglutide content

[0187] A 60 mg mini-tablet (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 USP formulation for simulated gastric fluid (SGF). The 60 mg mini-tablet contains approximately 3 mg of semaglutide and is approximately 12 mini-tablets. If the level of sodium octanoate needs to be adjusted, a placebo version of the mini-tablet (containing all ingredients except semaglutide) is measured and added. For example, a 140 mg placebo mini-tablet is added along with a 60 mg semaglutide mini-tablet to increase the sodium octanoate dose to 100 mg while keeping the semaglutide dose constant at 3 mg. Example 3(a) contains a 60 mg semaglutide mini-tablet plus a 140 mg placebo mini-tablet. Example 3(b) contains only a 60 mg semaglutide mini-tablet.

[0188] The 50mL centrifuge tube is capped and placed on an inclined roller (rolling at 6-7rpm) for a specified duration (0, 10, 20, 30, 40 or 50min). As in Example 1, the entire roller setting is located in a thermostatic chamber, so the temperature can be controlled at 37°C. The roller is tilted 7°, so when it rotates, 10mL of pH 1.2 HCL+ pepsin converges toward the bottom of the tube, thereby immersing and gently stirring the tested formulation. The centrifuge tube is taken out from the roller at a specified time point, and 20mL of pH 9.0 neutralization buffer is added to the centrifuge tube to neutralize to pH 7, followed by vortexing for 1min. The neutralized sample is then placed on a roller in a refrigerator and rolled overnight for ELISA analysis starting the next morning. The temperature in the refrigerator is set to 4°C. The complete semaglutide content-time curve from 0-50min is drawn, and the area under the complete semaglutide content-time curve AUC is calculated. 0-50min .

[0189] ELISA assay for intact semaglutide

[0190] The amount of intact semaglutide was determined using an ELISA kit from OriGene Technologies (Catalog Number: S-1530). The ELISA kit contained an immunoplate with 12 eight-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 in the kit was followed during the test. Each time the test was run, one strip of the immunoplate was used to apply a calibration standard, and another strip was used to apply a sample. In the strip for the standard, the first well had 75 μL ELISA buffer, and the remaining wells had 50 μL of semaglutide standards of different concentrations and 25 μL of antiserum. In the strip for the sample, the wells had 50 μL of control or test sample and 25 μL of antiserum, respectively. The strips were then incubated at 23°C in a Tecan microplate reader (INFINITE 200 PRO) for one hour. Afterwards, 25 μL of biotinylated tracer solution was added to all wells. The plate was transferred to a microplate reader for incubation for two 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 incubated again in the microplate reader for one hour. The strips were then washed five more times with ELISA buffer. TMB colorimetric solution was added to all wells by pipetting 100 μL into each well. After incubation in the microplate reader for 10 minutes, 100 μL of stop solution was added to all wells. After incubation for 5 minutes, the UV absorbance of all wells was read at 450 nm.

[0191] The absorbance of the standards minus the blank absorbance was plotted against their concentration on a semi-logarithmic scale, with the logarithm of UV absorbance on the y-axis and the standard concentration on the x-axis. The data were fitted by a four-parameter logistic regression, and the derived parameters were used to calculate intact peptide concentrations based on UV readings of the blank-subtracted controls and samples.

[0192] First, the effect of pH 1.2HCl+pepsin on semaglutide was studied by adding 100 μL semaglutide solution (1 mg / mL in ELISA buffer) to 900 μL pH 1.2 HCl+pepsin, and then the solution was placed 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 min), both pH 1.2 HCl+pepsin solution and control solution were diluted 10,000X with ELISA buffer. By adding 100 μL of peptide solution to 900 μL of ELISA buffer, dilution was performed in 4 consecutive steps at a 10X ratio. The solution was then added to the strip of the immunoplate for complete peptide concentration measurement. The percentage of complete peptide after treatment with pH 1.2HCl+pepsin was determined as:

[0193] % intact semaglutide =

[0194] Concentration in pH 1.2 HCl+pepsin solution / concentration in control solution × 100

[0195] After pH 1.2 HCl + pepsin treatment and neutralization, an aliquot of the test formulation was filtered through a PVDF syringe filter into a microcentrifuge tube. The filtered solution was diluted with ELISA buffer in 4 consecutive steps. The dilution ratio in each step was 10X by adding 100 μL of sample solution to 900 μL of ELISA buffer. The sample solution was applied to the strip of the immunoplate for determination of the concentration of the intact peptide. A semaglutide control (Fisher catalog number: 50-225-9952) was also applied to the same strip. The concentration of intact semaglutide in the solution was determined as:

[0196] Intact semaglutide concentration = measured concentration of sample / measured concentration of control × prepared control concentration

[0197] % intact semaglutide =

[0198] Intact semaglutide concentration according to ELISA / semaglutide concentration according to preparation × 100

[0199] Preparation of calibration standards for the determination of intact semaglutide

[0200] Semaglutide (5mg) received from BOC Sciences was dissolved in 5mL ELISA buffer to prepare a stock standard solution of 1mg / mL. The 5-mL solution was dispensed into multiple vials in 120-μL aliquots. All aliquots were stored in a -18°C freezer. An aliquot of the stock standard solution was transferred to a refrigerator where samples were stored until the day of the ELISA assay. The aliquots were diluted 1,000X with ELISA buffer in three consecutive steps in which 100μL of standard solution was added to 900μL of buffer. The 1μg / mL standard solution was then diluted in six consecutive steps to prepare the standard to be applied to the strip of the immunoplate. The first step was to dilute the standard 10X to prepare the highest concentration standard (S1) by adding 100μL of standard solution to 900μL of ELISA buffer. The second step was to add 200μL of S1 to 600μL of ELISA buffer to prepare S2. In steps 3, 4, 5, and 6, standards of decreasing concentrations were prepared as follows: 200 μL of S2 was added to 600 μL of ELISA buffer to prepare S3; 200 μL of S3 was added to 600 μL of ELISA buffer to prepare S4; 200 μL of S4 was added to 600 μL of ELISA buffer to prepare S5; and 200 μL of S5 was added to 600 μL of ELISA buffer to prepare S6. S7 is a buffer solution without peptide and serves as the zero-concentration standard. In one strip of the immunoplate, the first well contains 75 μL of ELISA buffer as a blank. Wells 2 through 8 each contain 50 μL of standards S1 through S7 and 25 μL of antiserum.

[0201] Preparation of intact semaglutide factor standards

[0202] Semaglutide (catalog number: 50-225-9952) from Fisher Scientific was used as a factor 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 had a 120 μL aliquot of solution. All aliquots were stored in a freezer at -18°C. Before the test day, one aliquot was transferred from the freezer to a refrigerator. The same refrigerator also had samples for testing. The aliquots were diluted 100,000X by adding 100 μL of control solution to 900 μL of ELISA buffer in five consecutive steps. The diluted factor standard control solution was applied to the same strip of the immunoplate to which the sample solution was applied.

[0203] Disintegration test

[0204] Disintegration testing was performed using a Sotax DT50 disintegration tester (Sotax Corp., Westborough, MA USA). A 1000 mL beaker (3061-1) from Sotax was used with a sensor plate (14728-01) placed at the bottom of the beaker, 800 mL of degassed pH 1.2 HCl was added and heated to 37°C. The basket type used was SKx, and the trigger value was set to 0.5 mm. The basket was equipped with a 20 mesh screen, a glass tube, each containing 200 mg of a mini tablet, and a sensor disc (red side down) placed on top of the mini tablet. Once the basket was attached to the bracket on the main unit, the test was run under "Direct Test" on the main menu. The default test parameters were used. Once the sensor disc reached the 0.5-mm trigger value, the endpoint was automatically recorded.

[0205] Table 3

[0206]

[0207] In Table 3, AUC 0-50min is the area under the intact semaglutide-time curve from 0 to 50 min. In addition, to preserve semaglutide, disintegration time testing was performed on placebo versions of the multisite microenvironment rather than on formulations containing the peptide API.

Claims

1. A pharmaceutical solid dosage form for delivery via the gastrointestinal tract to treat a condition, the pharmaceutical solid dosage form comprising a plurality of single units, each single unit comprising: a) one or more therapeutically active biomacromolecules; b) one or more water-soluble polymers in an amount not exceeding about 50% by weight; c) a small molecule weak acid (WA), a weak acid surfactant (WAS), or a salt thereof in an amount not exceeding about 75% by weight; Each single unit has a diameter greater than 1.0 mm -1 The surface area to volume (SA / Vol) ratio is greater than 1.0 g / cm 3 The solid dosage form comprises a therapeutically effective amount of the therapeutically active biomacromolecule derived from a combination of multiple amounts of each single unit.

2. The pharmaceutical solid dosage form according to claim 1 , having at least 2 single units, e.g., 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. The pharmaceutical solid dosage form according to claim 1 or 2, having no more than about 500 single units, for example, having no more than about 400 single units, no more than about 300 single units, no more than about 200 single units, no more than about 180 single units, no more than about 160 single units, no more than about 140 single units, no more than about 120 single units, no more than about 100 single units.

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

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), e.g., less than about 2800 mPa-s (or cP), e.g., less than about 2600 mPa-s (or cP), e.g., less than about 2400 mPa-s (or cP), e.g., less than about 2200 mPa-s (or cP), e.g., less than about 2000 mPa-s (or cP), e.g., less than about 1800 mPa-s (or cP), e.g., less than about 1600 mPa-s (or cP), e.g., less than about 1400 mPa-s (or cP).

6. The pharmaceutical solid dosage form according to any one of claims 1 to 5, wherein each single unit has a diameter greater than 1.0 mm. -1 , for example, greater than 1.5 mm -1 , for example, greater than 2.0 mm -1 , for example, greater than 2.5 mm -1 , for example, greater than 3.0 mm -1 The surface area to volume (SA / Vol) ratio.

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

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 no more than about 50 wt%, e.g., no more than about 45 wt%, e.g., no more than about 40 wt%, e.g., no more than about 35 wt%, e.g., no more than about 30 wt%, e.g., no more than about 28 wt%, e.g., no more than about 26 wt%, e.g., no more than about 24 wt%, e.g., no more than about 22 wt%, e.g., no more than about 20 wt%, e.g., no more than about 18 wt%, e.g., no more than about 16 wt%, e.g., no more than about 14 wt%, e.g., no more than about 12 wt%, e.g., no more than about 10 wt%.

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 a salt thereof is present in an amount of no more than about 70 wt %, e.g., no more than about 65 wt %, e.g., no more than about 60 wt %, e.g., no more than about 55 wt %, e.g., no more than about 50 wt %, e.g., no more than about 45 wt %, e.g., no more than about 40 wt %.

10. The pharmaceutical solid dosage form according to any one of claims 1 to 9, wherein the one or more biomacromolecules 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. The pharmaceutical solid dosage form according to any one of claims 1 to 10, wherein the one or more biomacromolecules 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, amylin, linaclotide, octreotide, semaglutide, liraglutide, telportide, dulaglutide, exenatide, lixisenatide, enoglutide, oxytocin, and 2,6-dimethyltyrosine-D-arginine-phenylalanine-lysine amide.

12. The pharmaceutical solid dosage form according to any one of claims 1 to 10, wherein the one or more biomacromolecules are proteins 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 one of IL1-40, such as IL1, IL2, IL10, IL12, IL19, IL21, IL23, IL26, IL27, IL28, IL29, IL36, IL37, IL38, IL39, IL40, lysozyme, beta-casein, albumin, alpha-1 antitrypsin, antithrombin III, collagen, factor VII, factor VIII, factor Factor IX, factor X, fibrinogen, protein C, erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), tissue plasminogen activator (tPA), growth hormone, integrins, alpha-4, beta-7 integrins, chymotrypsin, lipase, pancreatic lipase, amylase and protease, adalimumab, tofacitinib, foramincitumomab, bevacizumab, rituximab, trastuzumab, denosumab, ranibizumab, tocilizumab, certolizumab pegol, golimumab, secukinumab, griffithsin, alpha 1,2-fucosidase, xylanase, phytase, and tumor necrosis factor (TNF).

13. The pharmaceutical solid dosage form according to any one of claims 1 to 12, wherein the one or more biomacromolecules have a molecular weight greater than about 500 Da, such as greater than about 800 Da, such as greater than about 1000 Da, such as greater than about 1200 Da, such as greater than about 1400 Da, such as greater than about 1600 Da, such as greater than about 1800 Da, such as greater than about 2000 Da, such as greater than about 3000 Da, such as greater than about 4000 Da, such as greater than about 5000 Da, such as greater than about 6000 Da, such as greater than about 7000 Da, A molecular weight of higher than about 8000 Da, such as higher than about 10 kDa, such as higher than about 20 kDa, such as higher than about 30 kDa, such as higher than about 40 kDa, such as higher than about 50 kDa, such as higher than about 60 kDa, such as higher than about 70 kDa, such as higher than about 80 kDa, such as higher than about 90 kDa, such as higher than about 100 kDa, such as higher than about 110 kDa, such as higher than about 120 kDa, such as higher than about 130 kDa, such as higher than about 140 kDa, such as higher than about 150 kDa.

14. The pharmaceutical solid dosage form according to any one of claims 1 to 13, wherein the solid dosage form further comprises one or more additional ingredients that provide processability, densification, or identification, such as, but not limited to, microcrystalline cellulose, mannitol, lactose, maltose, maltitol, dicalcium phosphate, talc, silicon dioxide, nonionic surfactants, bromophenol blue, and bromocresol green.

15. The pharmaceutical solid dosage form according to 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, trimethyl chitosan, hyaluronic acid, polycarbophil, carbomer, polyethylene oxide, and methacrylic acid derivatives; derivatives and salts thereof.

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

17. The pharmaceutical solid dosage form according to any one of claims 1 to 16, wherein the small molecule weak acid (WA), weak acid surfactant (WAS), or a salt thereof is selected from the group consisting of carbonic acid, monovalent metal phosphate, citric acid, succinic acid, oleic acid, caprylic acid, capric acid, n-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 decanoate, sodium n-decanoate, sodium caprylate, sodium caprylate, sodium octanoate, cholic acid, glycocholic acid, glycodeoxycholic acid, taurocholic acid, taurodihydrofusidic acid, sodium decanoate, sodium n-decanoate, sodium caprylate, sodium octanoate, cholic acid, glycocholic acid, glycodeoxycholic acid, taurodihydrofusidic acid, cholic acid, glycocholic acid, glycocholic acid, glycodeoxycholic acid, taurodihydrofusidic acid, sodium decanoate, sodium decanoate, sodium caprylate, sodium octanoate, cholic acid, glycocholic acid, glycocholic acid, glycodeoxycholic acid, taurodihydrofusidic ... octanoate), sodium laurate, sodium lauryl sulfate, sodium dioctyl sulfosuccinate, glyceryl behenate, glyceryl dibehenate, glyceryl monostearate, sodium N-[8-(2-hydroxybenzoyl)aminocaprylate], sodium sapolic acid, SNAC, N-(5-chlorosalicyloyl)-8-aminocaprylic acid, 5-CNAC, N-[10-(2-hydroxybenzoyl)aminocaprate], N-[10-(2-hydroxybenzoyl)aminodecanoate], sodium lauryl sulfate, sodium stearyl fumarate, sodium deoxycholate, for example, a small molecule weak acid (WA) having a molecular weight of less than 400 Da, for example, less than 300 Da, for example, less than 200 Da, a weak acid surfactant (WAS) or a salt thereof.

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

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

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

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

22. The pharmaceutical solid dosage form of any one of claims 1-21, wherein the solid dosage form is substantially homogeneous and lacks a coating or barrier layer.

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

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

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

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

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

28. The pharmaceutical solid dosage form of claim 10, wherein the one or more biomacromolecules comprises an enzyme.

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

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

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

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 digestive or intestinal condition; a metabolic disorder, such as an inborn error of metabolism; phenylketonuria; tyrosinemia; exocrine pancreatic insufficiency, such as that caused by cystic fibrosis, pancreatitis, pancreatic cancer, diabetes, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), celiac disease, or a condition associated with maldigestion and / or malabsorption; homocystinuria; maple syrup urine disease; a condition related to gluten management; and a lysosomal storage disease.

33. A process for preparing a pharmaceutical solid dosage form according to any one of claims 1 to 29, comprising the steps of: Components a), b) and c) are provided, and the dosage form is formulated into tablets or capsules, for example, by compression, direct compression, dry granulation followed by compression, roller compaction followed by compression, dry powder layering, granulation, slugging; the process optionally includes an encapsulation step.

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