WO2025212427A1 - Orally-administered polypeptide formulations and methods of use - Google Patents

Abstract

The present disclosure relates to solid pharmaceutical compositions comprising a polypeptide as active agent and comprising mannitol. In some embodiments, the polypeptide active agent has been co-spray-dried with mannitol. In some cases, additional mannitol can be added after spray-drying. In some embodiments, the compositions comprise a compressed core comprising the co-spray-dried polypeptide active agent and mannitol. A variety of polypeptide active agents can be included in the compositions, as well as a variety of further excipients. In some cases, the compositions further comprise a coating, such as a seal coating and/or an enteric coating, such as a pH dependent enteric coating. In some embodiments, they can be orally administered. For example, the compositions can be in the form of tablets, pellets, capsules, or pills or the like, intended for oral administration. The disclosure also relates to methods of making and using the compositions, and kits comprising the compositions.

Description

ORALLY-ADMINISTERED POLYPEPTIDE FORMULATIONS AND

METHODS OF USE

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Application No. 63/572,732, filed April 1, 2024, the entire contents of which are incorporated by reference herein for all purposes.

FIELD

The present disclosure relates to solid pharmaceutical compositions comprising a polypeptide as active agent and comprising mannitol. In some embodiments, the polypeptide active agent has been co-spray-dried with mannitol. In some cases, additional mannitol can be added after spray-drying. In some embodiments, the compositions comprise a compressed core comprising the co-spray-dried polypeptide active agent and mannitol. A variety of polypeptide active agents can be included in the compositions, as well as a variety of further excipients. In some cases, the compositions further comprise a coating, such as an enteric coating, such as a pH dependent enteric coating. In some embodiments, they can be orally administered. For example, the compositions can be in the form of powders, tablets, pellets, capsules, or pills or the like, intended for oral administration. The disclosure also relates to methods of making and using the compositions, and kits comprising the compositions.

BACKGROUND

Protein pharmaceuticals are typically formulated in liquid dosage forms for administration by intravenous or subcutaneous or intramuscular or similar administration routes. As such administration routes can be expensive, such as requiring a visit to a medical facility for intravenous administration, or difficult and cumbersome for patients, such as requiring frequent injections for subcutaneous or intramuscular administration routes with risks of injection site reactions, and as such dosage forms may require storage under refrigeration for sufficient shelf life, there is a need in the art for dosage forms that can simplify both storage and handling of protein pharmaceuticals as well as their administration burden on patients.

Dosage forms in which a protein pharmaceutical is in a dried powder format, such as via spray drying, would be useful, as would oral dosage forms or other types of solid dosage forms using such protein powders. However, very few spray-dried protein pharmaceutical formulations have been approved by the US Food and Drug Administration to date, generally for inhalation, topical administration, or intramuscular injection. See, e.g, J.T. Pinto et al., Drying Technology 39(11): 1415-46 (2021). Thus, there remains a need for improved dried protein powder formulations and associated compressed protein powder formulations such as tablets, granulated powders, pellets and capsules which can be administered orally.

SUMMARY

The present disclosure relates, for example, to a solid pharmaceutical composition comprising a polypeptide active agent and mannitol, wherein the polypeptide active agent and the mannitol have been co-spray dried. In some embodiments, the solid pharmaceutical composition is in compressed form, for example, comprising a compressed core, the compressed core comprising the polypeptide active agent and mannitol, wherein the polypeptide active agent and the mannitol have been co-spray-dried prior to compression of the core. In some cases, the compressed core further comprises a filler, disintegrant, lubricant, and/or glidant. In some cases, the polypeptide active agent has a molecular weight of 1-400 KDa, 3-400 KDa, 3-200 KDa, 5- 400 KDa, 5-200 KDa, 3-150 KDa, 5-150 KDa, 20-100 KDa, 20-75 KDa, 3-50 KDa, 3-20 KDa, 5-20 DKa, or 5-50 KDa. In some cases, the polypeptide active agent is present at a concentration of at least 50%, such as 50-75%, 50-70%, 50-65%, 50-60%, 50-55%, 60-75%, 60-70%, 62-68%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, or 70% w/w relative to the weight of the compressed core. In some cases, the mannitol is present at a concentration of up to 50%, such as 5-50%, 5-40%, 10-50%, 10-40%, 10-20%, 20-40%, 30-50%, 20-30%, 12-18%, 12-16%, 14-18%, 14-16%, 15-16%, 12%, 13%, 14%, 15%, 16%, 17%, or 18%, 20%, 25%, 30%, 35%, or 40% w/w compared to the weight of the compressed core. In some cases, the compressed core further comprises microcrystalline cellulose, optionally wherein the microcrystalline cellulose is present at a concentration of 20-40%, 25-35%, 25-32%, or 27- 30% w/w relative to the weight of the compressed core. In some cases, additional mannitol is mixed with the polypeptide active agent after spray-drying but prior to compression. In some cases, additional mannitol is mixed with the polypeptide active agent after compression. In some cases, additional mannitol is mixed with the polypeptide active agent both after spray-drying but prior compression as well as after compression. In some cases, the ratio of the concentration of mannitol to the concentration of polypeptide active agent is from 2: 1 to 10:1, such as from 2: 1 to 5: 1, from 3: 1 to 10: 1, from 3: 1 o 5: 1, or from 5: 1 to 10: 1, or 2: 1, 3: 1, 5: 1, or 10: 1, wherein the concentrations of the mannitol and the polypeptide are each w/w relative to the weight of the compressed core. In some cases, the compressed core of a solid pharmaceutical composition herein comprises a disintegrant, optionally wherein the disintegrant comprises sodium starch glycolate or croscarmellose sodium, optionally wherein the sodium starch glycolate or croscarmellose sodium is present at 2-6%, 3-5%, 3%, 4%, or 5% w/w relative to the weight of the compressed core. In some cases, the compressed core further comprises a glidant, optionally wherein the glidant comprises silica, such as hydrophobic fumed silica. In some cases, the compressed core further comprises a lubricant, optionally wherein the lubricant comprises stearic acid or its salts, such as magnesium stearate or calcium stearate, sodium stearyl fumarate, or a hydrogenated vegetable oil. In some cases, the composition further comprises a coating. In some cases, the coating comprises an enteric coating, such as a pH sensitive enteric coating, optionally wherein the pH sensitive enteric coating has a thickness of 50-250 pm, 70-200 pm, 50-150 pm, or 100- 200 pm, optionally wherein the enteric coating comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS) or copolymers derived from esters of acrylic and methacrylic acid, and optionally wherein the pH sensitive enteric coating is up to 30% by weight of the composition. In cases, where a pH sensitive enteric coating is included, the pH sensitive enteric coating dissolves at basic pH. In some cases, the coating comprises more than one coating layer. In some cases, the coating comprises a seal coating and/or an enteric coating such as a pH sensitive enteric coating.

In some embodiments, the composition is in the form of tablets, optionally wherein each tablet has a weight of 1-400 mg, 20-400 mg, 20-200 mg, 50-200 mg, 100-200 mg, 1-50 mg, 1-20 mg, 1 mg, 5 mg, 10 mg, 20 mg, 50 mg, 100 mg, 200 mg, 250 mg, 300 mg, or 400 mg.

In some embodiments, the polypeptide active agent is an antibody, optionally wherein the antibody is an IgG, a camelid antibody, or an antigen binding fragment. In some cases, the polypeptide active agent comprises at least one P-sheet. In some cases, the polypeptide active agent is soluble in water greater than 10 mg/mL or greater than 30 mg/mL.

In some cases, the compressed core is substantially free of sugars or sugar alcohols other than mannitol, or wherein sugars and/or sugar alcohols other than mannitol are not mixed with the polypeptide active agent and are not added to the composition. In some embodiments, the compressed core is prepared by dry granulation. In some embodiments, the compressed core is not prepared by wet granulation.

In some cases, the polypeptide active agent is at least 80%, at least 85%, at least 90%, or at least 95% dissolved after thirty minutes, or after one hour at 75 rpm agitation, in a 50 mM pH 6.8 phosphate buffer or in Fasted State Simulated Intenstinal Fluid (FaSSIF) buffer at 37 °C, wherein the percentage is calculated as the weight of the polypeptide active agent compared to the total weight of the composition. In some such cases, the polypeptide active agent dissolves more quickly in a 50 mM pH 6.8 phosphate buffer or in Fasted State Simulated Intenstinal Fluid (FaSSIF) buffer at 37 °C than the same polypeptide active agent comprised within the compressed core of a control solid pharmaceutical composition in which the mannitol has not been co-spray-dried with the polypeptide active agent but has been added after spray-drying of the polypeptide active agent, wherein the control pharmaceutical composition and the solid pharmaceutical composition are otherwise identical. In some such cases, the polypeptide active agent dissolves more quickly in a 50 mM pH 6.8 phosphate buffer or in Fasted State Simulated Intenstinal Fluid (FaSSIF) buffer at 37 °C than the same polypeptide active agent comprised within the compressed core of a control solid pharmaceutical composition in which the compressed core does not comprise mannitol, or that replaces the mannitol with trehalose, sucrose, and/or histidine, wherein the control solid pharmaceutical composition is otherwise identical to the solid pharmaceutical composition comprising the mannitol.

The disclosure herein also relates, inter alia, to a method of preparing a solid pharmaceutical composition as described herein, comprising co-spray-drying a solution comprising the polypeptide active agent and the mannitol to form a spray-dried powder. In some embodiments, the method further comprises compressing the spray-dried powder. In some cases, the method further comprises performing granulation and compression of the spray-dried powder, such as dry or wet granulation. In some cases, the granulation does not comprise wet granulation. In some cases, the granulation is dry granulation. In some cases, the method further comprises adding microcrystalline cellulose to the spray-dried powder prior to compressing the spray-dried powder. In some cases, the method further comprises adding additional mannitol to the spray-dried powder prior to compression, prior to granulation and compression, or after compression. In some cases, the method comprises adding one or more of a glidant, lubricant, or disintegrant to the spray-dried powder either prior to compression, prior to granulation and compresson, or after compression. In some cases, the method comprises adding a coating to the compressed spray-dried powder, such as an enteric coating, such as a pH sensitive enteric coating, for example, a pH enteric coating discussed herein.

The disclosure herein also includes a method of administering the solid pharmaceutical composition described herein to a subject, for example, comprising orally administering the composition to the subject. The disclosure herein also relates to use of the solid pharmaceutical composition herein in the preparation of a medicament for oral administration to a subject, and to a solid pharmaceutical composition herein for use in oral administration to a subject. In some such cases, the composition is such that the polypeptide active agent is released in the intestinal tract of the subject. All references cited herein are incorporated by reference herein. Furthter description of certain embodiments is provided in the figures and in the subsequent sections and claims.

BRIEF DESCRIPTION OF THE FIGURES

Fig. 1 shows results of a dissolution test of VHH polypeptide tablets made from VHH samples spray dried from PBS buffer (comprising 50 mg/mL protein in PBS at pH 7.4).

Fig. 2 shows dissolution test data of VHH polypeptide tablets, either coated or uncoated, made from VHH spray dried with (uncoated and coated tablets) or without (“neat VHH”) tableting excipients such as a disintegrant, glidant, and lubricant. Dissolution of these tablets remained slow.

Fig. 3 shows the impact of switching from PBS to histidine buffers. Dissolution remained slow.

Fig. 4 shows the effect of compression on dissolution of VHH spray dried in histidine buffer. Compression significantly slowed dissolution.

Fig. 5 shows data from dissolution tests of tablets with and without co-spray drying a VHH protein with mannitol. Addition of mannitol dramatically improved dissolution.

Fig. 6 shows a comparison of tablets made from spray-dried VHH at a 2: 1 protein to mannitol weight ratio to those made from VHH to which the equivalent amount of mannitol was blended with the spray-dried powder to achieve a 2: 1 protein to mannitol weight ratio. The results show that co-spray-drying the VHH with mannitol was superior to blending in mannitol after spray-drying.

Figs. 7A-7B show tests of the impact of mannitol on protein activity and formation of high molecular weight species (HMWS). Fig. 7a shows that addition of mannitol did not affect the activity of a VHH protein. Fig. 7b shows that the mannitol excipient acted to protect against the formation of HMWS after compression.

Figs. 8A-8B show the impact of changing the VHH-Mannitol ratio on both dissolution (Fig. 8a) and formation of HMWS (Fig. 8b).

Figs. 9A-9B show the effect of various excipients on dissolution of VHH from compressed tablets, mannitol vs. trehalose (Fig. 9a) and mannitol vs. histidine alone or histidine plus sucrose (Fig. 9b).

Figs. 10A-10B: Fig. 10A shows a comparisons of dissolution at different mannitol concentrations, in which mannitol was blended with spray-dried VHH powder.Fig. 10B shows a test of blending further mannitol at two different particle sizes with a spray-dried VHH, histidine, sucrose, mannitol composition, and the impact on dissolution rates. Fig. 11 A and 1 IB show effects of adding mannitol and other excipients to spray-dried VHH in a histidine/sucrose buffer solution. As shown in the figures, mannitol alone is superior to other excipients tested. Fig. 11 A shows that minitablets comprising the mannitol dissolved more quickly and completely than those with either lactose or MCC. Fig. 1 IB shows that faster dissolution was achieved with mannitol rather than a combination of mannitol and sucrose.

Fig. 12 shows results for a peptide drug spray-dried in specific buffers with no mannitol, to which mannitol was added after spray drying to achieve increasing weight ratios of polypeptide (“drug”) to mannitol. The figure shows that presence of mannitol enhanced dissolution of the peptide.

Fig. 13 shows results for a Fab molecule spray-dried in specific buffers with no mannitol, to which mannitol was added after spray drying to achieve increasing weight ratios of polypeptide (“drug”) to mannitol. The figure shows that presence of mannitol enhanced dissolution of the peptide.

Fig. 14 shows results for an IgG molecule spray-dried in specific buffers with no mannitol, to which mannitol was added after spray drying to achieve increasing weight ratios of polypeptide (“drug”) to mannitol. The figure shows that presence of mannitol enhanced dissolution of the peptide.

Fig. 15 shows the impact of wet granulation and dry granulation prior to tablet formation was tested in the VHH samples.

DETAILED DESCRIPTION

I. DEFINITIONS

As used herein, the term about refers to a numeric value, including, for example, whole numbers, fractions, and percentages, whether or not explicitly indicated. The term about generally refers to a range of numerical values (e.g., +/-5-10% of the recited range) that one of ordinary skill in the art would consider equivalent to the recited value (e.g., having the same function or result). When terms such as at least and about precede a list of numerical values or ranges, the terms modify all of the values or ranges provided in the list. In some instances, the term about may include numerical values that are rounded to the nearest significant figure.

Unless otherwise defined, scientific and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. In this application, the use of “or” means “and/or” unless stated otherwise. In the context of a multiple dependent claim, the use of “or” refers back to more than one preceding independent or dependent claim in the alternative only. Also, terms such as “element” or “component” encompass both elements and components comprising one unit and elements and components that comprise more than one subunit unless specifically stated otherwise.

As utilized in accordance with the present disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

An “active agent” or “active pharmaceutical agent” or “active ingredient” or “therapeutic agent” or “drug” or the like, as used herein, refers to a molecule or set of molecules that, when administered to a subject, such as a mammalian subject, is intended to alter some biological activity or function in the subject, or to act therapeutically in the subject in some fashion. The term is intended to be construed broadly to cover any such agent that can have therapeutic use, including pharmaceuticals and supplements and the like. A “polypeptide active agent” herein refers to an active agent that comprises at least one polypeptide. In some cases, a polypeptide active agent can comprise more than one polypeptide, such as a two or more different polypeptides or a complex of polypeptides. In some cases, the polypeptide active agent can also comprise more than one active agent, such as two or more different polypeptide active agents. A composition herein can also comprise a polypeptide active agent as well as one or more nonpolypeptide active agents.

A “subject” or “recipient” or “patient” mean an individual receiving a dose of a solid pharmaceutical composition herein. Subjects include individuals capable of being administered an oral pharmaceutical formulation, for example. A subject can be an animal, such as a mammal, such as a human, a laboratory animal such as a mouse, rat, hamster, guinea pig, or rabbit, or a domestic mammal, such as a dog, cat, or rodent, or a livestock mammal, such as a cow, pit, goat, sheep, horse, llama, camel, alpaca, or the like. Other subjects can in some cases be avian or reptilian subjects such as birds, lizards, iquanas, or the like. Additional subject can be zoo animals.

A “carrier” or “excipient” refers to a non-toxic solid, semisolid, or liquid filler, diluent, encapsulating material, formulation auxiliary, or carrier conventional in the art for use with an active agent that together comprise a “pharmaceutical composition” intended for administration to a subject. In general, a carrier or excipient used in a pharmaceutical composition is “pharmaceutically acceptable.” A “pharmaceutically acceptable” carrier is a carrier that is nontoxic to recipient subjects at the dosages and concentrations employed and is compatible with other ingredients of the formulation. The term “effective amount” herein refers to an amount of an active agent that is sufficient to result in a desired outcome, such as treatment, inhibition, or reduction as described above.

A “pharmaceutical composition” means a composition that is intended to be used pharmaceutically. Such a composition typically comprises at least one active agent and at least one carrier or excipient. A “solid pharmaceutical composition” means such a composition in solid or particulate form, i.e., a tablet, capsule, powder, pellet, pill, or the like.

In some cases, a “pharmaceutical composition” is “suitable for oral administration” or can be delivered orally or the like, meaning that it is expected to be safe to administer orally or is made from ingredients that are expected to be safe to administer orally.

The term “compression” as applied to a pharmaceutical composition herein refers to a process of compacting a powder or other particulate solid composition, such as a granulated or agglomerated composition together to form a compacted solid composition.

A “core” of a solid pharmaceutical composition refers herein to the composition present at the center or interior of the composition, such as the center of a tablet, capsule, pellets, or pill or the like. A “compressed core” of a “solid pharmaceutical composition” herein refers to the material comprising the core of such a composition that has been physically compressed in some fashion, for example so that individual grains or particles will agglomerate or stick together. In contrast, the material in a core that has not been compressed can act as a flowable powder if a solid pharmaceutical composition is cut in half and the core material is exposed.

A “coating” of a solid pharmaceutical composition means the composition making up the exterior layer or layers of the solid pharmaceutical composition. A coated solid pharmaceutical composition can have a coating comprising one or more layers, and which differ in chemical composition from the core of the solid pharmaceutical composition.

An “enteric coating” as used herein means a coating comprised of material that allows a solid pharmaceutical composition to pass through the stomach of a recipient subject intact.

Often this is achieved by a “pH dependent enteric coating.” A “pH dependent enteric coating” or similar terms such as a “pH sensitive enteric coating” herein refers to a coating that remains intact at the highly acidic pH’s of a subject’s stomach (e.g., pH 1-3), but that disintegrates at higher pH’s, such as those of a recipient’s intestinal tract (e.g., pH 5 or higher, pH 5.5 or higher, pH 6 or higher, or pH 6.5 or higher, etc.).

A “filler” refers to a substance that provides additional volume or material for the compressed core.

A “disintegrant” is a substance that helps a compressed core of a solid pharmaceutical composition break apart when placed in acqueous solution or in the digestive tract of a subject. For example, it can comprise a substance that expands upon contact with water so that this expansion causes the compressed core to rupture. Examples include sodium starch glycolate and croscarmellose sodium.

A “lubricant” is a substance that is added to aid in lubricating the material to be compressed in interacting with certain granulation or compression equipment. Examples include lipids such as calcium stearate, stearic acid, sodium stearyl fumarate, and hydrogenated vegetable oils.

A “glidanf ’ refers to a substance added to a solid pharmaceutical form to improve flowability of the particles comprising the active agent. An example is silica, such as hydrophobic fumed silica.

The term “spray-drying” refers to a process of removing water from a solution, slurry, or emulsion, by atomizing the solution, slurry or emusion into droplets by spraying, followed by rapid evaporation of the droplets, for example, using hot gas under controlled temperature and pressure conditions, such that a dried powder is formed from the starting solution, slurry, or emulsion. The term “co-spray-drying” of two or more components herein refers to a spraydrying process in which the solution, slurry, or emulsion that comprises the two ore more components. In other words, the two or more components to be co-spray-dried are mixed together before spray-drying.

The term “granulation” refers to a mechanical process used to facilitate the agglomeration of powder grains into larger particles. In “dry granulation,” a mechanical process is used to agglomerate the powder grains or particles. In “wet granulation,” a solvent or binder substance is added to the powder in order to facilitate the adhesion and agglomeration of the grans or particles.

The terms “polypeptide” and “protein” are used interchangeably to refer to a polymer of amino acid residues, and are not limited to a minimum length. Such polymers of amino acid residues can contain natural or non-natural amino acid residues, and include, but are not limited to, peptides, oligopeptides, dimers, trimers, and multimers of amino acid residues. Both full- length proteins and fragments thereof are encompassed by the definition. The terms also include post-expression modifications of the polypeptide, for example, glycosylation, sialylation, acetylation, phosphorylation, and the like. Furthermore, for purposes of the present disclosure, a "polypeptide" refers to a protein which includes modifications, such as deletions, additions, and substitutions (generally conservative in nature), to the native sequence, as long as the protein maintains the desired activity. These modifications can be deliberate, as through site-directed mutagenesis, or may be accidental, such as through mutations of hosts which produce the proteins or errors due to PCR amplification. In some cases, a polypeptide may also be attached to another molecule, such as a label, non-polypeptide linker, or non-polypeptide drug.

A “peptide” is a relatively short polypeptide, which may typically comprise, for example, 50 or fewer amino acids in length, such as from 3 to 50 amino acids. For example, in some embodiments, a peptide has a molecular weight of 300 Da to 6 KDa. In some cases a peptide can be manufactured synthetically, while in other cases it may be expressed from a host cell. Peptides can be linear or cyclic, and examples of peptides include hormones and macrocyclic peptides.

The term “antibody” herein refers to a type of polypeptide comprising at least complementarity-determining region (CDR) 1, CDR2, and CDR3 of a heavy chain and at least CDR1, CDR2, and CDR3 of a light chain or alternatively comprising at least CDR1, CDR2, and CDR3 of a camelid antibody heavy chain, wherein the molecule is capable of binding to antigen. The term “antibody” is used in the broadest sense and encompasses various antibody structures, including but not limited to full length antibodies of various classes such as IgA, IgM, and IgG, single-chain antibodies, camelid antibodies (e.g. VHH domains or nanobodies), antibody conjugates, antibody fusion polypeptides, monobodies, multi-specific antibodies such as bi- specific antibodies, and a varieity of antibody fragments, so long as they exhibit the desired antigen binding activity. The term “VHH” or “VHH domain” or “VHH region” refers to the heavy chain variable region of a camelid antibody, which may comprise the associated heavy chain (HC) CDR1-FR2-CDR2-FR3-CDR3 with or without all or a portion of FR1 and/or FR. An “antibody fragment” or “antigen binding fragment” refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds. Examples of antibody fragments include but are not limited to Fv, Fab, Fab', Fab’-SH, F(ab')2; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv and scFab); single domain antibodies (sdAbs, VHH, nanobodies); and multispecific antibodies formed from antibody fragments. Antibody fragments in some cases may also be fusion polypeptides with polypeptide segments from other proteins fused to all or part of a variable region antibody segment, e.g., monobodies. For a review of certain antibody fragments, see Holliger and Hudson, Nature Biotechnology 23 : 1126-1136 (2005).

II. EXEMPLARY SOLID PHARMACEUTICAL COMPOSITIONS

The disclosure herein relates, inter alia, to a solid pharmaceutical composition comprising a polypeptide active agent. In some embodiments, the solid pharmaceutical composition comprises a powder comprising the polypeptide active agent, such as a spray-dried powder. In some embodiments, the solid pharmaceutical composition is suitable for oral administration to a subject. In some embodiments, the solid pharmaceutical composition comprises a compressed core, the compressed core comprising the polypeptide active agent. For example, in some cases, the compressed core is made from a powder comprising the polypeptide active agent, such as a spray-dried powder, optionally with further excipients to assist in compression of the powder and/or to assist in disintegration of the compressed core once in a suitable aqueous environment.

In some embodiments, the compressed core comprises the polypeptide active agent and mannitol, optionally wherein the polypeptide active agent and the mannitol have been co-spray- dried prior to compression of the core. In some cases, the compressed core further comprises a filler, disintegrant, lubricant, and/or glidant. In some cases, the composition further comprises a coating, such as an enteric coating, such as a pH dependent enteric coating.

A wide variety of polypeptide active agents can be included in the solid pharmaceutical compositions herein, of various molecular weights. For instance, in some cases, the polypeptide active agent has a molecular weight of 1-400 KDa, 3-400 KDa, 3-200 KDa, 5-400 KDa, 5-200 KDa, 3-150 KDa, 5-150 KDa, 20-100 KDa, 20-75 KDa, 3-50 KDa, 3-10 KDa, 3-20 KDa, 5-20 KDa, or 5-50 KDa. Examples of polypeptide active agents include peptide drugs such as macrocycles and hormones, or small polypeptides such as insulin. For example, a peptide can have a length of from 3 to 50 amino acids in some embodiments, or a molecular weight of from 300 Da to 6 KDa, such as from 1-6 KDa, 1-5 KDa, 1-3 KDa, or 3-6 KDa. Further examples include antibodies, such as IgG, IgA, or IgM antibodies, single-chain antibodies, camelid antibodies (e.g. VHH domains or nanobodies), antibody conjugates, antibody fusion polypeptides, multi-specific antibodies such as bi-specific antibodies, monobodies, and a varieity of antibody fragments, including antibody fragments such as Fv, Fab, Fab', Fab’-SH, F(ab')2; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv and scFab); single domain antibodies (sdAbs, VHH, nanobodies); and multispecific antibodies formed from antibody fragments. In some embodiments, the antibody is a camelid antibody (also called a VHH or nanobody). In some embodiments, the antibody is an IgG antibody. Additional proteins that can be formulated as described herein include other therapeutic proteins such as fusion polypeptides comprising an Fc domain and/or albumin or another fusion domain. In some cases, a polypeptide active agent can comprise a mixture of two or more different polypeptides. In some cases, a polypeptide active agent can comprise a dimer or higher order complex of polypeptides. In some cases, such a complex can also comprise non-polypeptide molecules such as cofactors, labels, drugs, or the like.

Additional polypeptide active agents that can be included in the solid pharmaceutical compositions herein include, for example, enzymes. Further examples include fusion proteins, such as comprising a polypeptide active domain coupled to a fusion partner such as an Fc domain of an antibody or albumin, among other choices.

In some cases, the polypeptide active agent comprises at least one P-sheet. In some cases, the polypeptide active agent is soluble in water greater than 10 mg/mL or greater than 30 mg/mL.

In some embodiments, the polypeptide active agent is present at a concentration of at least 50%, such as 50-75%, 50-70%, 50-65%, 50-60%, 50-55%, 60-75%, 60-70%, 62-68%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, or 70% w/w relative to the weight of the compressed core. The chosen protein concentration may depend upon the type of protein to be formulated and the desired drug load (i.e., polypeptide active agent concentration) in the compressed core. In some embodiments, the ratio of polypeptide to mannitol can be adjusted over a range of, for example from 2:1 to 10: 1, such as 2: 1 to 5: 1, 5: 1 to 10:1, 3: 1 to 10: 1, 3: 1 to 5: 1, or 3: 1 to 7: 1, wherein the concentrations of the mannitol and the polypeptide are each w/w relative to the weight of the compressed core. In some embodiments, the mannitol is present at a concentration of up to 50%, such as 5-50%, 5- 40%, 10-50%, 10-40%, 10-20%, 20-40%, 30-50%, 20-30%, 12-18%, 12-16%, 14-18%, 14-16%, 15-16%, 12%, 13%, 14%, 15%, 16%, 17%, or 18%, 20%, 25%, 30%, 35%, or 40% w/w compared to the weight of the compressed core. The concentration of mannitol may vary with the intended drug load, with higher drug loads having lower concentrations of mannitol and lower drug loads having higher concentrations of mannitol.

In general, in solid pharmaceutical compositions herein the mannitol is co-spray dried with the polypeptide active agent, meaning that the polypeptide and mannitol are in solution together prior to the spray drying process. However, in some cases, in addition to the co-spray dried mannitol, additional mannitol is used as a filler to mix with the polypeptide active agent after spray-drying but prior to compression, and for example, where granulation is performed before compression, prior to granulation. In some cases, additional mannitol could be added after compression of the core. In some cases, additional mannitol is mixed with the polypeptide active agent both after spray-drying but prior compression as well as after compression. In other cases, the mannitol is not co-spray dried with the polypeptide active agent, but is instead mixed with the polypeptide entirely after spray drying, such as by blending with the polypeptide spray dried powder. In cases where mannitol is added after spray drying, the mannitol is blended with the polypeptide spray dried powder prior to compression of the powder. In addition, if granulation is also performed before the spray dried powder is compressed, the mannitol can be blended with the polypeptide spray dried powder before granulation. In some cases, mannitol blended into spray-dried polypeptide powder has a particle size of 100-200 nm, such as of 100 nm or 200 nm.

In some embodiments, the compressed core further comprises additional excipient ingredients. For example, the polypeptide solution comprising the mannitol can also comprise further buffer ingredients or excipients, such as phosphate, PBS (phosphate buffered saline), Tris (tromethamine, tri s(hydroxymethyl)aminom ethane), HEPES (4-(2 -hydroxy ethyl)- 1- piperazineethanesulfonic acid), citrate, histidine, or similar buffers, or other excipients such as a sugar, such as sucrose or lactose or trehalose or maltose, a sugar alcohol, an amino acid, a lipid, and a surfactant such as polysorbate 20 or polysorbate 80, pol oxamer 188, or the like. Exemplary sugars or sugar alcohols include, for example, sucrose, trehalose, melbiose, mannose, maltose, lactose, erythritol, myo-inositol, sorbitol, xylitol, and the like. Exemplary amino acids include, for example, glycine, proline, arginine, valine, alanine, isoleucine, leucine, and other naturally occurring amino acids. Additional optional excipients include polysaccharides such as cyclodextrins, dextran, and the like. In some embodiments, such excipients such as buffers and sugars, sugar alcohols, and surfactants are included in the polypeptide solution prior to spray drying and are thus co-spray dried with the polypeptide and the mannitol. For example, in some cases, the composition prior to spray drying comprises a buffer and mannitol, or comprises a buffer, a sugar such as sucrose, and mannitol. For instance, in some cases, the composition prior to spray drying comprises a buffer, sucrose, and mannitol. In some such cases, the composition prior to spray drying further includes a surfactant such as a polysorbate. In some such cases, the polypeptide active agent is an antibody such as a VHH or IgG antibody, or a peptide, such as a macrocycle or peptide hormone.

In some cases, as noted above, additional buffer or excipient ingredients can be added after spray drying, such as by blending them into the spray-dried polypeptide powder. In some cases, however, the compressed core is substantially free of sugars or sugar alcohols other than mannitol. In some cases, sugars and/or sugar alcohols other than mannitol are not mixed with the polypeptide active agent and are not added to the composition.

In some cases, after spray drying, the spray-dried powder is compressed, such as to form tablets. In some cases, the spray-dried powder is first subjected to granulation, such as dry or wet granulation.

Other excipients that assist in tablet formation or compression or granulation of the core can be included, for example. For instance, in some embodiments, the compressed core comprises microcrystalline cellulose (MCC). In some cases, the microcrystalline cellulose is present at a concentration of 20-40%, 25-35%, 25-32%, or 27-30% w/w relative to the weight of the compressed core. In some cases, the compressed core comprises a disintegrant, optionally wherein the disintegrant comprises sodium starch glycolate or croscarmellose sodium, optionally wherein the sodium starch glycolate or croscarmellose sodium is present at 2-6%, 3-5%, 3%, 4%, or 5% w/w relative to the weight of the compressed core. For example, a disintegrant can assist in allowing the compressed core to break apart once immersed in an aqueous environment, by comprising a material that expands in volume upon exposure to water. In some cases, the compressed core further comprises a glidant, optionally wherein the glidant comprises silica, such as hydrophobic fumed silica. In some cases, the compressed core further comprises a lubricant, optionally wherein the lubricant comprises stearic acid or its salts, such as magnesium stearate or calcium stearate, sodium stearyl fumarate, or a hydrogenated vegetable oil. For example, a lubricant can be added to facilitate compression or granulation by preventing the composition from interfering with the granulation or compression equipment. These further microcrystalline cellulose, disintegrant, glidant, and lubricant excipients, for example, can be added to the spray-dried powder prior to compression and, where granulation is performed, prior to or in conjunction with granulation.

In some cases, the composition is in the form of tablets. In some cases, each tablet has a weight of 1-400 mg, 20-400 mg, 20-200 mg, 50-200 mg, 100-200 mg, 1-50 mg, 1-20 mg, 1 mg, or 5 mg. In such cases, the compressed core can be formed into a tablet shape. In some such cases, the solid pharmaceutical composition consists of the compressed core formed into a tablet shape. In other cases, the solid pharmaceutical composition comprises the compressed core formed into a tablet shape, as well as one or more other excipients or ingredients, such as a ingredients that form a coating for the tablets. In other embodiments, the compressed core can be comprised within a capsule, or other form of orally available drug product. For example, a capsule may in some embodiments contain compressed materials such as a granulated powder, or grains or particles, or mini-tablets or mini-pellets or the like, which may or may not be coated.

In some cases, the compressed core is prepared after dry granulation. In other cases, the compressed core is prepared after granulation, wherein the granulation is not wet granulation.

In some embodiments, the composition further comprises a coating, surrounding the compressed core. A coating can comprise one or more layers of material. In some embodiments, the coating comprises an enteric coating, thus allowing for passage of the compressed core of the solid pharmaceutical composition through the stomach after oral administration and thus, allowing for disintegration and dissolution in the intestinal tract. In some cases, the coating is a pH sensitive enteric coating, such that it will disintegrate at certain pH’s but remain intact at others. For example, as the stomach has a very low pH, such as from 1.5 to 3.5, a pH sensitive enteric coating may remain intact in the stomach but disintegrate at the higher pH of the intestinal tract. For example, in some cses, a pH sensitive enteric coating disintegrates at basic pH. In some cases, it disintegrates at neutral pH. In some such cases it does not disintegrate at stomach pH ranges, for example, of 1.5 to 3.5, but disintegrates at higher pH’s such as a pH of 5.0 or higher, 5.5 or higher, or 6.0 or higher. In some such cases it does not disintegrate at stomach pH ranges, for example, of 1.5 to 3.0, but disintegrates at higher pH’s such as a pH of 5.0 or higher, 5.5 or higher, or 6.0 or higher. In some cases, the enteric coating has a thickness of 50-250 pm, 70-200 pm, 50-150 pm, or 100-200 pm, optionally wherein the enteric coating is up to 30% by weight of the composition, such as up to 10%, up to 20%, or up to 30%.

In some embodiments, a pH dependent enteric coating is made from one or more polymers, such as a cellulose acetate, hydroxypropylcellulose acetate, or polyvinyl acetate polymer, such as hydroxypropyl methylcellulose phthalate (HP55), cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropylmethyl cellulose acetate succinate, or polyvinyl acetate phthalate, or an acrylate or methacrylate polymer or polymer mixture, such as 1 : 1 polymer of methacrylic acid to methyl methacrylate, or a 1 : 1 polymer of methacrylic acid to ethyl acrylate, or a 1 :2 polymer of methacrylic acid to methyl methacrylate, and the like. Other examples of materials useful in enteric coatings include EUDRAGIT® L30D or EUDRAGIT® L100-55, ACRYL-EZE®, and AQUARIUS™ Control ENA, which are poly methacrylic acid - ethyl acrylate polymers, HP-F™, an HPMCP polymer, SURETERIC®, a PVAP polymer, AQUATERIC®, AQUACOAT® ECD, which are CAP polymers, and AQUASOLVE®. In some cases, the pH sensitive enteric coating comprises a hydroxypropyl methylcellulose acetate succinate (HPMCAS) polymer. Such polymers, for example, come in a variety of grades, depending on the pH at which the polymer begins to disintegrate. HPMCAS is available in several grades, L, M, and H, depending on the relative percentages of acetate and succinate, which are in turn broken down into F(fine) and G (granular) types. For example, in some cases, an enteric coating comprises HPMCAS-M, such as HPMCAS-MF, which disintegrates at pH’s at 6.0 or above. In other cases, the grade is HPMCAS-L or -LF, which disintegrates at pH’s at 5.5 or above. In other cases, the grade is HPMCAS-H or -HF, which disintegrates at pH’s at 6.8 or above.

In some embodiments, a coating may comprise more than one layer of coating material, such as two or more different coating layers. For instance, in some embodiments, a coating may comprise a seal coating, such as comprising a polymer film, which may assist in bridging the compressed core material with a further, outer coating such as an enteric coating. Thus, in some cases, the compressed core may comprise a coating comprising a seal coating and/or one or more further coating layers external to the seal coating, such as an enteric coating such as a pH dependent enteric coating. A nonlimiting, exemplary seal coating is Opadry® II (Colorcon), for example, which comprises a water-soluble, colored polymer film that allows for rapid disintegration.

In some cases, a dissolution test can be performed on the compressed core in order to assess the properties of the compressed core, and hence, of the solid pharmaceutical composition. In some embodiments, a dissolution test is performed in conditions intended to mimic the environment of the small intestines. In some embodiments, a dissolution test is performed according to US Pharmacopoeia 711, published December 1, 2011, which is incorporated herein by reference. In some embodiments, the dissolution test can be performed in an apparatus described in USP 711, such as USP 711 apparatus 1 (a basket apparatus), apparatus 2 (a paddle apparatus), or apparatus 3 (a reciprocating cylinder). In some embodiments, the test is performed in USP 711 apparatus 2, as described in USP 711. For example, when testing dissolution of the compressed core without coating, a test for immediate-realease dosage forms of USP 711 can be performed. For example, such a test can be performed at 37 °C (+/- 0.5 °C) in an apparatus as described in USP 711. In some embodiments, a dissolution test is performed at 37 °C (+/- 0.5 °C) in a USP 711 apparatus 2 (paddle apparatus) with 75 rpm agitation, in a 50 mM phosphate buffer at pH 6.8 or alternatively in a Fasted State Simulated Intenstinal Fluid (FaSSIF) buffer. For example, FaSSIF buffer comprises salts, lipids, and other components present in the fluid of the upper intestinal tract, in order to obtain an average pH of 6.5 to 6.8 and osmolarity of 270 mOsmol/L. FaSSIF buffer may accordingly comprise taurocholate (3 mM), phospholipids such as lecithin (0.75 mM), sodium (148 mM), chloride (106 mM), and phosphate (29 mM), with pH 6.5 to 6.8. FaSSIF buffers may be obtained, for instance, from Biorelevant, London, UK.

In some cases, testing a compressed core as described herein in a dissolution test at 37 °C (+/- 0.5 °C) in a paddle apparatus (e.g., USP 711 apparatus 2) with 75 rpm agitation, in a 50 mM phosphate buffer at pH 6.8 or in FaSSIF buffer, the polypeptide active agent in a compressed core as described above, in which the polypeptide active agent is co-spray dried with mannitol, the polypeptide active agent dissolves more quickly than the same polypeptide active agent comprised within the compressed core of a control solid pharmaceutical composition in which the mannitol has not been co-spray-dried with the polypeptide active agent but has been added after spray-drying of the polypeptide active agent, wherein the control pharmaceutical composition and the solid pharmaceutical composition are otherwise identical. In some such cases, the polypeptide active agent in a compressed core in which the polypeptide active agent is co-spray dried with mannitol dissolves more quickly than the same polypeptide active agent comprised within the compressed core of a control solid pharmaceutical composition in which the compressed core does not comprise mannitol, or that replaces at least part of the mannitol with trehalose, sucrose, lactose, microcrystalline cellulose (MCC) and/or histidine, wherein the control solid pharmaceutical composition is otherwise identical to the solid pharmaceutical composition comprising the mannitol. For example, in such cases, the additional excipient takes the place of a portion of the mannitol, such as at least one quarter, at least one third, or at least one half of the mannitol. For instance, one may compare a composition prepared from spray drying a solution of polypeptide with 20 mM mannitol with a composition prepared from spray drying a solution of 10 mM mannitol and 10 mM sucrose, in which one half of the mannitol is replaced by sucrose.

For example, in some cases, in a dissolution test as described above, at 37 °C (+/- 0.5 °C) in a paddle apparatus (e.g., USP 711 apparatus 2) with 75 rpm agitation, in a 50 mM phosphate buffer at pH 6.8 or in FaSSIF buffer, of an uncoated compressed core of the solid pharmaceutical composition, the polypeptide active agent is at least 80% (w/w) dissolved within the first 30 minutes of the test, the percentage being calculated from the weight of the polypeptide active agent compared to the total weight of the compressed core. In some cases, the polypeptide active agent is at least 85%, at least 90%, or at least 95% dissolved within the first 30 minutes of the test, all w/w percentages, the percentages being calculated from the weight of the polypeptide active agent compared to the total weight of the compressed core.

In some cases, a dissolution test is conducted to compare a solid pharmaceutical composition in which the polypeptide active agent is co-spray dried with mannitol to other solid pharmaceutical compositions. For instance, in some embodiments, the solid pharmaceutical composition herein in which the polypeptide active agent is co-spray dried with mannitol dissolves at a higher percentage (w/w) in a dissolution test as described above compared to a composition that that is otherwise identical but that does not comprise mannitol. In some embodiments, the solid pharmaceutical composition herein in which the polypeptide active agent is co-spray dried with mannitol dissolves at a higher percentage (w/w) in a dissolution test as described above compared to a composition that is otherwise identical but wherein the polypeptide active agent is co-spray dried with one or more excipients such as sucrose, trehalose, histidine, or lactose, or mixtures thereof, such as histidine and sucrose. In some embodiments, the solid pharmaceutical composition herein in which the polypeptide active agent is co-spray dried with mannitol dissolves at a higher percentage (w/w) in a dissolution test as described above compared to a composition that that is otherwise identical but in which the mannitol is added to the polypeptide active agent after the polypeptide active agent is spray dried. In some embodiments, the solid pharmaceutical composition herein in which the polypeptide active agent is co-spray dried with mannitol dissolves at a higher percentage (w/w) in a dissolution test as described above compared to a composition that that is otherwise identical but wherein the polypeptide active agent is co-spray dried with a combination of mannitol and sucrose, or mannitol and trehalose, or mannitol and lactose, wherein the overall concentration of the mannitol and additional excipient (sucrose, trehalose, or lactose) is the same as the concentration of mannitol in the mannitol only composition. For example, in such cases, the additional excipient takes the place of a portion of the mannitol, such as at least one quarter, at least one third, or at least one half of the mannitol. For instance, one may compare a composition prepared from spray drying a solution of polypeptide with 20 mM mannitol with a composition prepared from spray drying a solution of 10 mM mannitol and 10 mM sucrose, in which one half of the mannitol is replaced by sucrose.

In some cases, the composition is prepared by dry granulation. In some cases, a dissolution test as described above, comparing the composition prepared by dry granulation to that prepared by wet granulation is performed, and the composition prepared by dry granulation dissolves to at least 80% w/w, and/or dissolves more quickly and/or more completely than the same composition prepared by wet granulation. In any of the above comparison tests, in some embodiments, the dissolution test is performed at 37 °C (+/- 0.5 °C) in a paddle apparatus (e.g., USP 711 apparatus 2) with 75 rpm agitation, in a 50 mM phosphate buffer at pH 6.8 or in FasSSIF buffer on an uncoated compressed core.

In some embodiments, a solid pharmaceutical composition comprising a polypeptide active agent, wherein the polypeptide active agent is co-spray dried with mannitol is in an uncompressed dried powder form. In other embodiments, the composition is in a form that can be added to a capsule rather than a tablet, such as compressed into grains or larger coated or uncoated particles or into mini-tablets or mini-pellets, to be placed inside a capsule. For example, in some cases, the composition can comprise multiple coated particles each comprising a coated or uncoated compressed core, placed inside an oral administration vehicle such as a capsule, as opposed to a single coated or uncoated tablet oral administration vehicle.

III. EXEMPLARY METHODS OF MANUFACTURE, USES, AND KITS

The disclosure herein also includes methods of preparing and using solid pharmaceutical compositions as described above and elsewhere in this application. For example, methods herein of preparing a solid pharmaceutical composition can comprise co-spray-drying a solution comprising the polypeptide active agent and mannitol, in order to make a spray dried powder comprising the polypeptide active agent. In some cases, the dried powder can be formulated into dosage forms for various types of administration, including dosage forms for subcutaneous, intramuscular, inhalation, topical, and oral administration. In some cases, the spray-dried powder comprising the polypeptide active agent is compressed, such as into a compressed core form that can be used to prepare a granulated powder, tablet, pellet, pill, capsule, or other type of dosage form, for example, for oral administration. Methods herein, accordingly, can also comprise compressing a spray-dried powder made from spray-drying a solution of polypeptide active agent and mannitol. In some instances, the spray-dried powder is subjected to wet or dry granulation prior to compression, while in other instances, granulation is not performed.

In some embodiments, the compressed composition can be shaped into a tablet form for oral administration. In some cases, each tablet has a weight of 1-400 mg, 20-400 mg, 20-200 mg, 50-200 mg, 100-200 mg, 1-50 mg, 1-20 mg, 1 mg, or 5 mg. In other embodiments, the compressed composition can be shaped into pellets, for example. In other cases, after compression the composition can be contained within a capsule, such as compressed into grains or larger coated or uncoated particles, or into coated or uncoated mini-tablets or mini-pellets, for example, to be placed inside a capsule.

For example, tablets (including mini -tablets) can be made from a powder mixture in several ways. One option is direct compression, in which the powder is simply compressed by appropriate equipment or machinery into the appropriate tablet size and shape without any intermediate granulation process. Another option is by granulation followed by compression. Granulation is a process by which small particles of a substance are converted into large agglomerates. Granulation can be performed, for example, to increase the uniformity and improve the mechanical properties of the particles to be compressed or to increase their density so that a compressed solid drug form will contain more active ingredient per unit area, as well as to reduce exposure during the manufacturing such as by preventing dust formation. There are two main types of granulation methods - wet granulation and dry granulation. Wet granulation uses a binder or solvent to facilitate agglomeration of particles. Dry granulation instead uses mechanical methods such as mechanical compression or roller compaction, for example. Thus, a process that does not involve wet granulation is one in which a solvent is not used. A review of granulation and compression procedures may be found, for example, in S. Shanmugam, Biolmpacts 5(1): 55-63 (2015).

Compression into larger particles, pellets, or tablets, for example, can be performed directly after spray-drying, i.e., by direct compression. In other cases, it is performed after granulation, such as after dry granulation or after a granulation process that does not comprise wet granulation. In these cases, for example, compression can be performed by equipment such as a mechanical press or the like. In some cases, further excipients, such as a lubricant, are added prior to compression in order to improve the interaction between the spray-dried powder, either with or without granulation, and the compression equipment. In some cases, further excipients such as a filler, disintegrant and/or glidant can be added prior to compression, or prior to granulation.

In some embodiments, the polypeptide solution prior to spray drying comprises not only mannitol and the polypeptide active agent, but also comprises further buffer ingredients or excipients, such as phosphate, PBS, Tris, Hepes, histidine, citrate, or similar buffers, or other excipients such as a sugar and/or sugar alcohol, an amino acid, a lipid, and a surfactant such as polysorbate 20 or polysorbate 80 or the like. Exemplary sugars or sugar alcohols include, for example, sucrose, trehalose, melbiose, mannose, maltose, lactose, erythritol, myo-inositol, sorbitol, xylitol, and the like. Exemplary amino acids include, for example, glycine, proline, arginine, valine, alanine, isoleucine, leucine, and other naturally occurring amino acids. Additional optional excipients include polysaccharides such as cyclodextrins, dextran, and the like. In some embodiments, such excipients are included in the polypeptide solution prior to spray drying and are thus co-spray dried with the polypeptide and the mannitol. In some cases, additional buffer or excipient ingredients can be added after spray drying. In some cases, however, the composition after spray drying is substantially free of sugars or sugar alcohols other than mannitol, or wherein sugars and/or sugar alcohols other than mannitol are not mixed with the polypeptide active agent and are not added to the solution after spray drying.

Other excipients that assist in tablet formation or compression or granulation of the core can be included. For instance, in some embodiments, the compressed core comprises a filler. In some embodiments, the compressed core comprises microcrystalline cellulose (MCC) as a filler. In some cases, the microcrystalline cellulose is present at a concentration of 20-40%, 25-35%, 25-32%, or 27-30% w/w relative to the weight of the compressed core. In some cases, the compressed core comprises a disintegrant, optionally wherein the disintegrant comprises sodium starch glycolate or croscarmellose sodium, optionally wherein the sodium starch glycolate or croscarmellose sodium is present at 2-6%, 3-5%, 3%, 4%, or 5% w/w relative to the weight of the compressed core. For example, a disintegrant can assist in allowing the compressed core to break apart once immersed in an aqueous environment, by comprising a material that expands in volume upon exposure to water. In some cases, the compressed core further comprises a glidant, optionally wherein the glidant comprises silica, such as hydrophobic fumed silica. In some cases, the compressed core further comprises a lubricant, optionally wherein the lubricant comprises stearic acid or its salts, such as magnesium stearate or calcium stearate, sodium stearyl fumarate, or a hydrogenated vegetable oil. For example, a lubricant can be added to facilitate compression or granulation by preventing the composition from interfering with the granulation or compression equipment. Accordingly, in some cases, microcrystalline cellulose is added to the spray-dried powder prior to compressing the spray-dried powder. In some cases, additional mannitol is added to the spray-dried powder prior to compression and/or after compression. In some cases, one or more of a glidant, lubricant, or disintegrant to the spray dried powder either prior to compression or after compression.

In some embodiments, methods herein further comprise adding a coating to the compressed spray-dried powder. In some cases, the coating is an enteric coating. In some cases, it is a pH sensitive enteric coating. Such a coating can comprise one or more layers of material. In some embodiments, the coating is an enteric coating, thus allowing for passage of the compressed core of the solid pharmaceutical composition through the stomach after oral administration and thus, disintegration and dissolution in the intestinal tract. In some cases, the coating is a pH sensitive enteric coating, such that it will disintegrate at certain pH’s but remain intact at others. For example, as the stomach has a very low pH, such as from 1.5 to 3.5, a pH sensitive enteric coating can remain intact in the stomach but disintegrate at the higher pH of the intestinal tract. For example, in some cases, a pH sensitive enteric coating disintegrates at basic pH. In some cases, it disintegrates at neutral pH. In some such cases it does not disintegrate at stomach pH ranges, for example, of 1.5 to 3.5, but disintegrates at higher pH’s such as a pH of 5.0 or higher, 5.5 or higher, or 6.0 or higher. In some such cases it does not disintegrate at stomach pH ranges, for example, of 1.5 to 3.0, but disintegrates at higher pH’s such as a pH of 5.0 or higher, 5.5 or higher, or 6.0 or higher. In some cases, the enteric coating has a thickness of 50-250 pm, 70-200 pm, 50-150 pm, or 100-200 pm, optionally wherein the enteric coating is up to 30% by weight of the composition, such as up to 10%, up to 20%, or up to 30%.

In some embodiments, a pH dependent enteric coating is made from one or more polymers, such as a cellulose acetate, hydroxypropylcellulose acetate, or polyvinyl acetate polymer, such as hydroxypropyl methylcellulose phthalate (HP55), cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropylmethyl cellulose acetate succinate, or polyvinyl acetate phthalate, or an acrylate or methacrylate polymer or polymer mixture, such as 1 : 1 polymer of methacrylic acid to methyl methacrylate, or a 1 : 1 polymer of methacrylic acid to ethyl acrylate, or a 1 :2 polymer of methacrylic acid to methyl methacrylate, and the like. Other examples of materials useful in enteric coatings include Eudragit® L30D or Eudragit® L100-55, Acryl-Eze®, and Aquarius™ Control ENA, which are poly methacrylic acid - ethyl acrylate polymers, HP-F™, an HPMCP polymer, Sureteric®, a PVAP polymer, Aquateric®, Aquacoat® ECD, which are CAP polymers, and Aquasolve®. In some cases, the pH sensitive enteric coating comprises a hydroxypropyl methylcellulose acetate succinate (HPMCAS) polymer. Such polymers, for example, come in a variety of grades, depending on the pH at which the polymer begins to disintegrate. HPMCAS is available in several grades, L, M, and H, depending on the relative percentages of acetate and succinate, which are in turn broken down into F(fine) and G (granular) types. For example, in some cases, an enteric coating comprises HPMCAS-M, such as HPMCAS-MF, which disintegrates at pH’s at 6.0 or above. In other cases, the grade is HPMCAS-L or -LF, which disintegrates at pH’s at 5.5 or above. In other cases, the grade is HPMCAS-H or -HF, which disintegrates at pH’s at 6.8 or above.

The disclosure herein also relates to methods of using solid pharmaceutical compositions according to the disclosure. In some cases, wherein the spray-dried powder is not compressed, for example, the pharmaceutical composition can be administered, for example, subcutaneously, intramuscularly, topically, by inhalation, or orally, among other options. In some cases, it is administered orally. In some cases, it is administered orally in a compressed form, such as in a tablet or pellet or pill or capsule. In some cases, therefore, the disclosure relates to a method of orally administering a solid pharmaceutical composition as described herein to a subject. The disclosure also relates to use of a solid pharmaceutical composition herein in the preparation of a medicament for oral administration to a subject. The disclosure also relates to a solid pharmaceutical composition for use in oral administration to a subject. In some cases, the polypeptide active agent is released in the intestinal tract of the subject. In some such cases, the solid pharmaceutical composition comprises an enteric coating, such as a pH sensitive enteric coating, which remains intact in the highly acidic stomach environment but can disintegrate in the pH ranges found in the upper intestines. In some cases, the solid pharmaceutical composition comprises a seal coating. In some cases, it comprises both a seal coating and an enteric coating such as a pH sensitive enteric coating. In some such methods or uses, the composition is capable of treating a disease or disorder in the subject.

EXAMPLES

The following are examples of methods and compositions of the disclosure. It is understood that various other embodiments can be practiced, given the general description provided above.

Example 1: Preparation and Testing of a Solid Pharmaceutical Composition comprising a Polypeptide with Various Co-Spray-Dried Excipients

The goal of this study was to prepare tablets comprising a polypeptide active agent with various excipients and to test the dissolution properties of the tablets in order to identify tablet compositions suitable for oral administration. Spray-Drying Samples and Procedure

Solutions comprising the polypeptide, in this case a VHH antibody, were spray dried and then the resulting spray-dried powder was directly compressed into tablets, and the dissolution properties of the tablets were examined.

Spray drying parameters used were as follows:

• Buchi B-290 mini spray dryer, set to open blow mode

• Inlet temp: 120°C

• Nozzle flow: 40 L/h

• Nozzle cap: 1.5 mm

• Nozzle tip: 0.7 mm

• Needle: 0.5 mm

• Aspirator: 80% (~35 m³/h with high performance cyclone)

• Pump rate: ~3 mL/min (12.0)

• Outlet temp: 80°C (idle), 70°C (running)

Preparation of Tablets

The spray-dried powder was directly compressed into 100 mg tablets using laboratory scale equipment (Korsch XP-1 with Natoli, 3 mm round concave 8-tip D tooling). As noted below, prior to compression the spray-dried powder was optionally blended manually with a disintegrant, or with a combination of a diluent/filler, disintegrant, glidant, and lubricant, as shown in Table 1.

Dissolution Procedure

Dissolution experiments were conducted in Fasted State Simulated Intenstinal Fluid (FaSSIF) buffer at 37 °C using a USP Type 2 (Paddles) system with a total volume of 1 L. The dissolution was tested at 75 rpm for 60 minutes and infinity at 250 rpm. The percent polypeptide dissolved was calculated by determining peptide/protein concentration with reversed-phase liquid chromatography at 80 °C..

Results and Discussion

The dissolution data of the 100 mg VHH polypeptide tablets made from VHH samples spray dried from PBS buffer (comprising 50 mg/mL protein in PBS at pH 7.4) is shown in Fig. 1. Spray-dried protein in the PBS buffer as active ingredient was blended with the diluent/filler, disintegrant, glidant, and lubricant as shown in Table 1 prior to compression of the tablets, in order to understand if adding excipients such as disintegrants and fillers can improve the dissolution behavior of the tablets. These tablets were then coated with a HPMCAS-MF (Hypromellose acetate succinate -MF grade) polymer to provide enteric protection to the polypeptide. The HPMCAS in -MF grade is reported to be soluble at or above pH 6.0. This composition and process was selected to mimic what would be considered an actual VHH polypeptide formulation that could be produced for clinical use. Varying amounts of the enteric polymer from 0 to 30% were used. A “neat VHH tablet” was also prepared, which did not comprise the further diluent/filler, disintegrant, glidant, and lubricant shown in Table 1.

The dissolution data for all of these formulated VHH tablets is shown in Fig. 2. VHH dissolution was incomplete even after 80 minutes and dissolution rate was slow for an immediate release oral formulation.

Table 1 : Composition of 100 mg tablet made from a blend of VHH spray dried in PBS and standard tableting excipients.

Unexpectedly, the formulated tablets fared worse than the tablets made from the neat VHH powder spray dried powder. In addition, the tablets never reached complete disintegration even after infinity sequence. The disintegration mechanism appeared to be erosion. Swelling was observed, but tablets never disintegrated into smaller fragments. The uncoated neat VHH tablet appeared to slowly erode on the surface, appearing more translucent in nature as water diffused into the tablet core, yet the undissolved particles appeared to agglomerate/aggregate to form loose lumps that could easily be dispersed by poking with the tip of a spatula; the core remained solid. These aggregates, however, seemed to be quite stable and did not disperse at all at 75 RPM agitation. Unexpectedly, disintegrant did not seem to help the tablet to dissolve.

It was unclear if the dissolution slowdown was related to PBS or if it was related to the behavior of the compressed VHH molecule itself. For the next round of experiments, PBS was replaced with buffer compositions containing Histidine and mixtures of Histidine and sucrose along with small of amounts of Tween 80. The composition of these buffers is shown in Table 2. All samples comprised 50 mg/mL VHH protein, and the pH of the samples in histidine buffer was 5.8. Table 2: Composition of excipients tested in the spray drying process.

These buffers were spray dried and spray dried powder was directly compressed to 20 mm minitablets to mimic future clinical use. The dissolution data for 20-mm tablets made from spray-dried VHH samples H/T with 10 mM histidine and 0.02% Tween 80, or H/T/S10 with 10 mM histidine plus 10 mM sucrose and 0.02% Tween 80, or H/T/S50 with 10 mM histidine plus 50 mM sucrose and 0.02% Tween 80 are shown in Fig. 3.

The data in Fig. 3 clearly showed that even when the buffer is changed to Histidine or Histidine + Sucrose, the dissolution was incomplete and slow. In fact, replacing PBS with Histidine or Histidine + Sucrose further slowed the dissolution. To investigate whether compression was the issue, the dissolution profiles of the noncompressed spray-dried powder made from VHH in the H/T 10 mM Histidine and 0.02% Tween 80 buffer filled into a capsule (powder in capsule: PIC) was compared against 20-mm compressed tablets made from the corresponding spray dried powder. The data are shown in

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When the uncompressed powder was filled into the capsule, the dissolution reached close to 100%, while the dissolution of the compressed tablet was below 10%. The data clearly showed that compression of VHH was the root cause of dissolution slowdown. It was hypothesized the reason for dissolution slowdown upon compression may be related to the formation of surface aggregates. Mannitol was tested to see if it could provide dissolution improvement. Mannitol was added to the VHH drug substance in 10 mM Histidine plus 15 mM sucrose. (See Table 2, sample buffer H/S15/M21.) The VHH to Mannitol weight ratio was kept at 2:1 (50 mg/mL protein to 25 mg/mL mannitol). The solutions were spray dried and then compressed into 20 mm minitablets. The dissolution of VHH/Mannitol minitablets was tested and the data are shown in Fig. 5. Surprisingly, addition of mannitol dramatically improved the dissolution of compressed VHH.

Further experiments were conducted to understand the minimum amount of mannitol required and how this mannitol should be added - either before spray drying as a co-spray drying excipient or after spray drying, blended into the spray dried protein powder. Fig. 6 shows a comparison of tablets made from spray-dried VHH in buffer H/S15/M21 at a 2: 1 protein to mannitol weight ratio to those made from VHH in buffer H/S15 to which the equivalent amount of mannitol was blended with the spray-dried powder to achieve a 2: 1 protein to mannitol weight ratio. The figure shows that even if mannitol was physically blended into the spray dried VHH powder, it could have a beneficial impact on dissolution. However, the beneficial impact of mannitol on dissolution was larger when it was added to the protein solution before spray drying, and thus co-spray dried with the protein. (See Fig. 6 comparing VHH-mannitol SD (spray dried) and VHH-mannitol blend.)

The IC50 representing the activity of the VHH protein against its binding target and the % high molecular weight species (HMWS) were monitored in the compressed 20 mm minitablets made from the spray dried VHH/Mannitol (2: 1) solution (from the H/S15/M21 buffer) compared to those made without mannitol (from the H/S15 buffer). The data are shown in Fig. 7a and 7b. The results in Fig. 7a showed that addition of mannitol did not affect the activity of the protein. Fig. 7b shows that the mannitol excipient acted to protect against the formation of HMWS after compression.

Fig. 8 shows the impact of changing the VHH-Mannitol ratio on both dissolution (Fig. 8a) and formation of HMWS (Fig. 8b). The dissolution profiles for tablets made from VHH in buffers allowing for a 2: 1, 3: 1, and 5: 1 VHHMannitol weight ratio in 10 mM histidine plus 15 mM sucrose buffer were all similar. (See Table 2; buffers H/S15/M21, H/S15/M31, H/S15/M51, and H/S15/M101, having 2:1, 3: 1, 5: 1, and 10: 1 VHH:mannitol weight ratios.) When VHH:Mannitol ratio was reduced to 10: 1, a slight dissolution slowdown was observed. The % of HMWS was found to increase from 1 to 2% when the VHH:Mannitol ratio was changed from 3: 1 to 10: 1.

Fig.9 shows the impact of changing the co-spray dry excipient by comparing mannitol with trehalose (Fig. 9a) and no excipient and sucrose (Fig. 9b). Fig. 9a compared H/S15/M21 and H/S15/T and Fig. 9b compared H/S15/M21, H/S15 and H/T. In summary, mannitol outperforms sucrose and trehalose in the dissolution rate of the tablets.

In each of the above cases, further excipients such as fillers, diluents, disintegrants, glidants and lubricants were not included in the tested tablets.

In conclusion, tablets made by compacting VHH spray dried from PBS showed slow and incomplete dissolution. To alleviate the dissolution problem and make immediate release oral tablets, changing the buffer from PBS to Histidine and Histidine + sucrose mixtures were explored. However, the dissolution issue could not be resolved with the addition of Histidine or Histidine + sucrose. The addition of Mannitol was able to dramatically improve the dissolution profile leading to the release of 100% of the drug within 45 minutes in the dissolution medium.

Example 2: Comparison of Compositions Prepared using Mannitol and Other Excipients as Fillers

Next, experiments were performed to test the effect on dissolution of different concentrations and particle sizes of mannitol added as fillers post-spray-drying, and also to test the effects of adding further excipients to mannitol-comprising protein tablets. The spray drying procedure and dissolution test procedure are described below, followed by a description of the samples tested.

Spray Drying Procedure

Solutions comprising the polypeptide, in this case a VHH antibody formulated in 10 mM histidine and 15 mM sucrose at pH 5.8 at 50 mg/mL, were spray dried in open loop mode with the Buchi B-290 using these parameters: inlet temperature = 120°C, nozzle flow = 40 L/hr, aspirator = 35 m³/hr with high performance cyclone and nozzle cap = 1.5 mm (needle = 0.5 mm). A Gilson Multipuls 3 was used as an external peristaltic pump and was set to spray at 3 mL/min. During the spray process, the outlet temperature reached 80°C while idle and and lowered to 70°C while spraying. Dissolution Procedure

Dissolution experiments were conducted in Fasted State Simulated Intenstinal Fluid (FaSSIF) buffer at 37 °C using a USP Type 2 (Paddles) system with a total volume of 1 L. The dissolution was tested at 75 rpm for 60 minutes and infinity at 250 rpm. The percent polypeptide dissolved was calculated by determining peptide/protein concentration with reversed-phase liquid chromatography at 80 °C.

Granulation Procedure

The wet granulation was done through a Diosna Pl/6 high shear granulator with bottom driven impeller using these parameters: Bowl: 0.5L, Pump flow rate: 2 g/min @ 3 psi, and Impeller: 100 RPM, chopper: 100 RPM. HPMC was added as the wet binder at 6% w/v in water solution.

The dry granulation was performed using Korsch XP-1 system with a Natoli, 24 mm round flat face, D-tooling with automatic mode and 20/min stroke.

Tablet Preparation Protocol and Samples Tested

Fig. 10A shows a comparisons of dissolution at different mannitol concentrations, in which mannitol was blended with spray-dried VHH powder. Spray dried VHH in H/S15 buffer was blended with manitol at weight % of 31.5, 18.5 and 5.3 and with 3% HPMC disintegrant through wet granulation and then compacted into 3 mm round concave minitablets. As shown in the figure, higher concentrations of mannitol led to higher dissolution rates.

Fig. 10B shows a test of blending further mannitol at two different particle sizes with a spray-dried VHH, histidine, sucrose, mannitol composition, and the impact on dissolution rates. Spray dried VHH in H/S 15/MI 01 was blended with 5% manitol of 200 nm and 100 nm particle size and 3% HPMC through wet granulation and compacted into 3 mm round concave minitablets. As shown in the figure, the larger particle size led to faster dissolution.

Fig. 11 A and 1 IB show effects of adding mannitol and other excipients to spray-dried VHH in H/S 15 buffer. As shon in the figures, mannitol alone is superior to other excipients tested. In Fig. 11 A, spray dried H/S 15 was blended manually with 50% w/w MCC (microcrystalline cellulose), lactose and mannitol and directly compacted into 3 mm round concave minitablets. The minitablets comprising the mannitol dissolved more quickly and completely than those with either lactose or MCC. In Fig. 1 IB, VHH in histidine buffer was spray dried with and without 15 mM sucrose and then blended with 28.6% mannitol with dry granulation and then compacted into 3 mm round concave minitablets. As the figure shows, faster dissolution was achieved when sucrose was not included. Example 3: Preparation of Solid Pharmaceutical Compositions comprising Co-Spray- Dried Mannitol with Different Polypeptide Agents

Next experiments were performed varying the polypeptide species in the tablets to test whether the effects would be observed with other classes of polypeptides. The spray-drying procedure and dissolution procedure are described below. The spray-drying procedure was the same as in Examples 1 and 2, while the dissolution was performed as in Examples 1 and 2 but with a phosphate buffer substituting for the FaSSIF buffer.

Spray Drying Procedure

Solutions comprising the polypeptide were spray dried in open loop mode with the Buchi B-290 using these parameters: inlet temperature = 120°C, nozzle flow = 40 L/hr, aspirator = 35 m³/hr with high performance cyclone and nozzle cap = 1.5 mm (needle = 0.5 mm). A Gilson Multipuls 3 was used as an external peristaltic pump and was set to spray at 3 mL/min. During the spray process, the outlet temperature reached 80°C while idle and and lowered to 70°C while spraying.

Dissolution Procedure

Dissolution experiments were conducted in Fasted State Simulated Intenstinal Fluid (FaSSIF) buffer at 37 °C using a USP Type 2 (Paddles) system with a total volume of 1 L. The dissolution was tested at 75 rpm for 60 minutes and infinity at 250 rpm. The percent polypeptide dissolved was calculated by determining peptide/protein concentration with reversed-phase liquid chromatography at 80 °C.

Figures 12-14 show results for each of three different types of polypeptides spray-dried in specific buffers to which mannitol was added before spray drying at different weight ratios of polypeptide (“drug”) to mannitol. In these experiments, further excipients such as diluents, disintegrants, glidants and lubricants were not included in the tested tablets.

Fig. 12 shows results for a peptide drug molecule with a molecular weight around 3000 Da. The solid peptide was first dissolved in water at 50 mg/mL and solid mannitol was added based on the peptide:manntiol ratio, and then the solution was spray dried. Fig. 13 shows results for an Fab molecule with a molecular weight of around 50,000 Da spray-dried from a solution comprising protein at 50 mg/mL concentration with 10 mM Histidine chloride, 240 mM sucrose, 0.01%(w/v) polysorbate 20 at pH 5.5 with solid mannitol added based on the proteimmanntiol ratio, to produce protein powder. Fig. 14 shows results for an IgG molecule with a molecular weight of around 150,000 Da spray-dried from a buffer comprising 50 mg/mL protein concentration with 20 mM Histidine acetate, 240 mM sucrose, 10 mM L-methionine, 0.06% polysorbate 20 at pH 5.8 with solid mannitol added based on the proteimmanntiol ratio, to produce protein powder. In each case, after spray-drying, the material was directly compacted (without granulation) into 3 mm round concave minitablets and dissolution tested. As the figures show, in each case, mannitol enhanced dissolution of the protein or peptide.

Example 4: Comparison of Wet Granulation to Dry Granulation

Finally, the impact of wet granulation and dry granulation prior to tablet formation was tested in the VHH samples. The powder used for dry and wet granulation testing comprised VHH spray dried with 15 mM sucrose and 10% mannitol, which was then further blended with 7.2% mannitol and 3% HPMC. This powder was subjected to dry or wet granulation and then compacted into 3 mm round concave minitablets. The solution was spray dried in open loop mode with the Buchi B-290 using these parameters: inlet temperature = 120°C, nozzle flow = 40 L/hr, aspirator = 35 m³/hr with high performance cyclone and nozzle cap = 1.5 mm (needle = 0.5 mm). A Gilson Multipuls 3 was used as an external peristaltic pump and was set to spray at 3 mL/min. During the spray process, the outlet temperature reached 80°C while idle and and lowered to 70°C while spraying. The wet granulation was performed with a Diosna Pl/6 high shear granulator with bottom driven impeller using these parameters: Bowl: 0.5L, Pump flow rate: 2 g/min @ 3 psi, and Impeller: 100 RPM, chopper: 100 RPM. HPMC was added as the wet binder at 6% w/v in water solution. The dry granulation was performed using Korsch XP-1 system with a Natoli, 24 mm round flat face, D-tooling with automatic mode and 20/min stroke.

Results in Fig. 15 show that dry granulation led to superior dissolution than wet granulation.

Claims

WHAT IS CLAIMED IS:

1. A solid pharmaceutical composition comprising a compressed core, the compressed core comprising a polypeptide active agent and mannitol, wherein the polypeptide active agent and the mannitol have been co-spray-dried prior to compression of the core, and optionally wherein the compressed core further comprises a disintegrant, lubricant, and/or glidant.

2. The solid pharmaceutical composition of claim 1, wherein the polypeptide active agent has a molecular weight of 1-400 KDa, 3-400 KDa, 3-200 KDa, 5-400 KDa, 5-200 KDa, 3-150 KDa, 5-150 KDa, 20-100 KDa, 20-75 KDa, 3-50 KDa, 3-20 KDa, 5-20 DKa, or 5-50 KDa.

3. The solid pharmaceutical composition of claim 1, wherein the polypeptide active agent is present at a concentration of at least 50%, such as 50-75%, 50-70%, 50-65%, 50-60%, 50-55%, 60-75%, 60-70%, 62-68%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, or 70% w/w relative to the weight of the compressed core.

4. The solid pharmaceutical composition of any one of claims 1-3, wherein the mannitol is present at a concentration of up to 50%, such as 5-50%, 5-40%, 10-50%, 10-40%, 10-20%, 20- 40%, 30-50%, 20-30%, 12-18%, 12-16%, 14-18%, 14-16%, 15-16%, 12%, 13%, 14%, 15%, 16%, 17%, or 18%, 20%, 25%, 30%, 35%, or 40% w/w compared to the weight of the compressed core.

5. The solid pharmaceutical composition of any one of claims 1-4, wherein the compressed core further comprises microcrystalline cellulose, optionally wherein the microcrystalline cellulose is present at a concentration of 20-40%, 25-35%, 25-32%, or 27-30% w/w relative to the weight of the compressed core.

6. The solid pharmaceutical composition of any one of claims 1-5, wherein additional mannitol is mixed with the polypeptide active agent after spray-drying but prior to compression.

7. The solid pharmaceutical composition of any one of claims 1-5, wherein additional mannitol is mixed with the polypeptide active agent after compression.

8. The solid pharmaceutical composition of any one of claims 1-5, wherein additional mannitol is mixed with the polypeptide active agent both after spray-drying but prior compression as well as after compression.

9. The solid pharmaceutical composition of any one of claims 1-8, wherein the ratio of the concentration of mannitol to the concentration of polypeptide active agent is from 2: 1 to 10: 1, such as from 2: 1 to 5: 1, from 3: 1 to 10: 1, from 3: 1 o 5: 1, or from 5: 1 to 10: 1, or 2: 1, 3: 1, 5: 1, or 10: 1, wherein the concentrations of the mannitol and the polypeptide are each w/w relative to the weight of the compressed core.

10. The solid pharmaceutical composition of any one of claims 1-9, wherein the compressed core comprises a disintegrant, optionally wherein the disintegrant comprises sodium starch glycolate or croscarmellose sodium, optionally wherein the sodium starch glycolate or croscarmellose sodium is present at 2-6%, 3-5%, 3%, 4%, or 5% w/w relative to the weight of the compressed core.

11. The solid pharmaceutical composition of any one of claims 1-10, wherein the compressed core further comprises a glidant, optionally wherein the glidant comprises silica, such as hydrophobic fumed silica.

12. The solid pharmaceutical composition of any one of claims 1-11, wherein the compressed core further comprises a lubricant, optionally wherein the lubricant comprises stearic acid or its salts, such as magnesium stearate or calcium stearate, sodium stearyl fumarate, or a hydrogenated vegetable oil.

13. The solid pharmaceutical composition of any one of claims 1-12, wherein the composition further comprises a coating.

14. The solid pharmaceutical composition of claim 13, wherein the coating comprises an enteric coating, such as a pH sensitive enteric coating, optionally wherein the pH sensitive enteric coating has a thickness of 50-250 pm, 70-200 pm, 50-150 pm, or 100-200 pm, optionally wherein the enteric coating comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS) and optionally wherein the pH sensitive enteric coating is up to 30% by weight of the composition.

15. The solid pharmaceutical composition of claim 14, wherein the pH sensitive enteric coating dissolves at basic pH.

16. The solid pharmaceutical composition of any one of claims 1-15, wherein the composition is in the form of tablets, optionally wherein each tablet has a weight of 1-400 mg, 20-400 mg, 20-200 mg, 50-200 mg, 100-200 mg, 1-50 mg, 1-20 mg, 1 mg, 5 mg, 10 mg, 20 mg, 50 mg, 100 mg, 200 mg, 250 mg, 300 mg, or 400 mg.

17. The solid pharmaceutical composition of any one of claims 1-16, wherein the polypeptide active agent is an antibody, optionally wherein the antibody is an IgG, a camelid antibody, or an antigen binding fragment.

18. The solid pharmaceutical composition of any one of claims 1-17, wherein the polypeptide active agent comprises at least one P-sheet.

19. The solid pharmaceutical composition of any one of claims 1-18, wherein the polypeptide active agent is soluble in water greater than 10 mg/mL or greater than 30 mg/mL.

20. The solid pharmaceutical composition of any one of claims 1-19, wherein the compressed core is substantially free of sugars or sugar alcohols other than mannitol, or wherein sugars and/or sugar alcohols other than mannitol are not mixed with the polypeptide active agent and are not added to the composition.

21. The solid pharmaceutical composition of any one of claims 1-20, wherein the compressed core is prepared by dry granulation.

22. The solid pharmaceutical composition of any one of claims 1-20, wherein the compressed core is not prepared by wet granulation.

23. The solid pharmaceutical composition of any one of claims 1-22, wherein the polypeptide active agent is at least 80%, at least 85%, at least 90%, or at least 95% dissolved after thirty minutes, or after one hour at 75 rpm agitation, in a 50 mM pH 6.8 phosphate buffer or in Fasted State Simulated Intenstinal Fluid (FaSSIF) buffer at 37 °C, wherein the percentage is calculated as the weight of the polypeptide active agent compared to the total weight of the composition.

24. The solid pharmaceutical composition of claim 23, wherein the polypeptide active agent dissolves more quickly in a 50 mM pH 6.8 phosphate buffer or in Fasted State Simulated Intenstinal Fluid (FaSSIF) buffer at 37 °C than the same polypeptide active agent comprised within the compressed core of a control solid pharmaceutical composition in which the mannitol has not been co-spray-dried with the polypeptide active agent but has been added after spraydrying of the polypeptide active agent, wherein the control pharmaceutical composition and the solid pharmaceutical composition are otherwise identical.

25. The solid pharmaceutical composition of claim 23 or 24, wherein the polypeptide active agent dissolves more quickly in a 50 mM pH 6.8 phosphate buffer or in Fasted State Simulated Intenstinal Fluid (FaSSIF) buffer at 37 °C than the same polypeptide active agent comprised within the compressed core of a control solid pharmaceutical composition in which the compressed core does not comprise mannitol, or that replaces the mannitol with trehalose, sucrose, and/or histidine, wherein the control solid pharmaceutical composition is otherwise identical to the solid pharmaceutical composition comprising the mannitol.

26. A method of preparing a solid pharmaceutical composition of any one of claims 1-25, comprising co-spray-drying a solution comprising the polypeptide active agent and the mannitol, to form a spray-dried powder, and compressing the spray-dried powder.

27. The method of claim 26, further comprising adding microcrystalline cellulose to the spray-dried powder prior to compressing the spray-dried powder.

28. The method of claim 26 or 27, further comprising performing granulation prior to compressing the spray-dried powder.

29. The method of claim 28, wherein the granulation is dry granulation or wherein the granulation is not wet granulation.

30. The method of claim 28, wherein the granulation is wet granulation.

31. The method of any one of claims 26-30, further comprising adding additional mannitol to the spray-dried powder prior to compression, prior to granulation, or after compression.

32. The method of any one of claims 26-31, further comprising adding one or more of a glidant, lubricant, or disintegrant to the spray dried powder either prior to compression, prior to granulation, or after compression.

33. The method of any one of claims 26-32, further comprising adding a coating to the compressed spray-dried powder, such as an enteric coating, such as a pH sensitive enteric coating.

34. A method of administering the solid pharmaceutical composition of any one of claims 1- 25 to a subject, comprising orally administering the composition to the subject.

35. Use of the solid pharmaceutical composition of any one of claims 1-25 in the preparation of a medicament for oral administration to a subject.

36. The solid pharmaceutical composition of any one of claims 1-25 for use in oral administration to a subject.

37. The method or use or composition of claim 34, 35, or 36, wherein the polypeptide active agent is released in the intestinal tract of the subject.