Oral dosage form

Abstract

The present invention relates generally to encapsulated pharmaceutical compositions that allow for improved oral delivery, and methods of using such compositions.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 299,128, filed January 13, 2022, the disclosure of which is incorporated herein by reference in its entirety for all purposes.

[0002] The present invention relates generally to encapsulated pharmaceutical compositions that allow for improved oral delivery, and methods of using such compositions. [Background technology]

[0003] Oral bioavailability of peptides and proteins can be limited due to poor absorption of intact active molecules from the gastrointestinal tract into the blood. Therefore, to achieve systemic exposure, peptide drugs are usually injected. Chiasma's proprietary technology, Transient Permeability Enhancer (TPE®), enables oral delivery of peptides.

[0004] The drug product is in the form of an oily suspension and is filled into enteric-coated hard gelatin capsules. The active agent (octreotide) comprises the solid phase of the suspension, together with a permeation enhancer (sodium caprylate = NaC8) and matrix-forming excipients. The drug product is called Mycapssa® and is an oral octreotide capsule for the treatment of acromegaly. Octreotide acetate is formulated in a transient permeability enhancer (TPE®) excipient mixture to form an oily suspension of solid hydrophilic particles in a lipophilic medium. The oily suspension is filled into hard gelatin capsules, which are then banded with gelatin and film-coated with an enteric coating system, allowing delivery of the capsule contents to the intestine. This is particularly described in coassigned U.S. Pat. No. 8,329,198. Oral ingestion of Mycapssa has proven sufficient to deliver the required dose to acromegalic patients and to elicit the regulation of GH and IGF-1 in acromegalic patients.

[0005] It would be desirable to produce new products with improved pharmacokinetic properties and / or administration regimens to allow for the administration of higher doses of octreotide, as needed for acromegaly or for other indications requiring higher dosages, which could allow for the administration of higher doses of other therapeutically active agents.

[0006] It would therefore be desirable to improve the level of bioavailability of encapsulated polypeptides. Summary of the Invention

[0007] The present inventors have discovered that the absorption of certain therapeutic agents, such as polypeptides, in a subject may be improved when administered in an oral dosage form using the coatings described herein.

[0008] One embodiment of the present invention is an oral dosage form comprising a capsule containing a therapeutic agent, e.g., a polypeptide, coated with a first coating comprising polyvinyl alcohol and a second coating over the first coating comprising a methacrylic acid-ethyl acrylate copolymer dispersion.

[0009] Another embodiment of the invention is an oral dosage form comprising a capsule containing a therapeutic agent, eg, a polypeptide, where the capsule is coated with a coating comprising a methacrylic acid-ethyl acrylate copolymer dispersion.

[0010] Further aspects, embodiments, and advantages of these exemplary aspects and embodiments are discussed in detail below. Moreover, it should be understood that both the preceding information and the following detailed description are merely illustrative examples of the various aspects and embodiments, and are intended to provide an overview or framework for understanding the nature and features of the claimed aspects and embodiments. The accompanying drawings are included to provide an illustration and a further understanding of the various aspects and embodiments, and are incorporated in and constitute a part of this specification. The drawings, together with the remainder of the specification, explain the principles and operation of the aspects and embodiments described in the description and claims.

[0011] Throughout this application, various publications, including U.S. patents, are referenced by author and year as well as patents and applications by number. The disclosures of these publications and patents and patent applications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains. [Brief description of the drawings]

[0012] Various aspects of at least one embodiment are discussed below with reference to the accompanying drawings, which are provided for purposes of illustration and description and are not intended as a definition of the limits of the invention.

[0013] [Figure 1]FIG. 1 shows a manufacturing flow chart for the preparation of the octreotide capsules referred to in Example 1 attached hereto.

[0014] [Diagram 2] FIG. 2 shows the dissolution of the prototype at pH 6.8, as referred to in attached Example 2.

[0015] [Diagram 3] FIG. 3 shows the canine PK results of NC02 and NC04 relative to the control (Mycapssa product) referenced in attached Example 2.

[0016] [Figure 4] FIG. 4 shows a manufacturing flow chart for capsules with the new coating (NC04) referred to in attached Example 3.

[0017] [Diagram 5] FIG. 5 shows the dissolution of batch OCT-CCP-035 at pH 6.8, as referred to in Example 3 attached hereto.

[0018] [Figure 6] FIG. 6 shows a flow chart for the manufacture of terlipressin capsules, which is referred to in Example 4 attached herewith.

[0019] [Figure 7] FIG. 7 shows the dissolution rates of prototypes of terlipressin at pH 6.8, as referred to in Example 4 attached hereto. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] The present invention relates generally to oral dosage forms comprising pharmaceutical compositions contained within oral dosage forms having a coating that allows for improved delivery, e.g., oral delivery, and methods of using such compositions. Particular embodiments of the present invention include oral dosage forms comprising pharmaceutical compositions, particularly oral dosage forms that are enteric coated with a coating that allows for improved delivery. Further embodiments of the present invention include capsules containing the compositions of the present invention, and in various embodiments, the capsules are hard gel or soft gel capsules, and the capsules are enteric coated as described herein. In other embodiments, the coating is applied to pellets (microparticles or minitablets) that are then filled into capsules or other dosage forms, such as hard gel capsules, or the pellets are compressed into tablets, or provided in the form of sachets.

[0021] One embodiment of the present invention is an oral dosage form comprising a capsule containing a therapeutic agent, e.g., a polypeptide, coated with a first coating comprising polyvinyl alcohol and a second coating over the first coating comprising a methacrylic acid-ethyl acrylate copolymer dispersion (commonly referred to as Eudragit® or Kolicoat®). A third coating (e.g., comprising talc) can be coated over the second coating.

[0022] Another embodiment of the invention is an oral dosage form comprising a capsule containing a polypeptide, wherein the capsule coating comprises a methacrylic acid-ethyl acrylate copolymer dispersion (commonly referred to as Eudragit or Kolicoat), and talc can be an additional coating.

[0023] In another embodiment of the invention, the ratio of methacrylic acid to ethyl acrylate in the dispersion is within the range of 1.3:1 to 1:1.3 methacrylic acid and ethyl acrylate copolymer, or 1.2:1 to 1:1.2 methacrylic acid and ethyl acrylate copolymer, or 1:1 methacrylic acid and ethyl acrylate copolymer.

[0024] In one embodiment of the present invention, the polyvinyl alcohol is partially hydrolyzed, the polyvinyl alcohol having a molecular weight of 20,000 to 35,000, preferably between 26,300 and 30,000.

[0025] In another embodiment of the invention, the methacrylic acid-ethyl acrylate copolymer has a molecular weight between 30,000 and 40,000, preferably about 34,000 (average number molecular weight (Mn) is about 15,000).

[0026] In one embodiment of the invention, the polyvinyl alcohol is partially hydrolyzed, the polyvinyl alcohol having an average molecular weight of 20,000 to 35,000 Da, preferably between 26,300 and 30,000 Da.

[0027] In another embodiment of the invention, the methacrylic acid-ethyl acrylate copolymer has an average molecular weight between 30,000 and 40,000 Da, preferably about 34000 (average number molecular weight (Mn) is about 15000 Da).

[0028] In another embodiment, there is a third coating over the second coating, which may include talc.

[0029] In another embodiment, the capsule is made of gelatin or HPMC, particularly a hard gelatin capsule.

[0030] In another embodiment of the invention, the second coating further comprises sodium lauryl sulfate and polysorbate 80 and does not comprise sodium bicarbonate or titanium dioxide.

[0031] In another embodiment of the invention, the first coating comprising polyvinyl alcohol (partially hydrolyzed) further comprises talc, glycerol monocaprylocaprate type 1 and sodium lauryl sulfate, commercially available as OPADRY® amb II (Colorcon).

[0032] In another embodiment of the invention, the second coating comprising the methacrylic acid-ethyl acrylate copolymer dispersion also comprises sodium lauryl sulfate and polysorbate 80, which is commercially available as Eudragit L30 D-55 (Evonik) or Kolicoat MAE 30DP (BASF). (Eudragit L30 D55 is a prepared suspension of Eudragit L100, which is the polymer alone.)

[0033] In another embodiment of the invention, the therapeutic agent is a polypeptide. In another embodiment of the invention, the polypeptide is terlipressin or an analog thereof, or octreotide or an analog thereof.

[0034] In another embodiment of the invention, the polypeptide is terlipressin or a salt thereof, or octreotide or a salt thereof, typically octreotide acetate. Octreotide and octreotide acetate are used interchangeably herein.

[0035] In another embodiment of the invention, the therapeutic agent, e.g., a polypeptide, e.g., octreotide or terlipressin, is present in the oral dosage form in an amount of 1-50 mg, e.g., about 10-20 mg. In another embodiment of the invention, the therapeutic agent, e.g., a polypeptide, is present in the oral dosage form in an amount of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 mg. In another embodiment of the invention, the octreotide or terlipressin is present in the oral dosage form in an amount of 5-50 mg, preferably 10 mg, 20 mg, or 30 mg.

[0036] In another embodiment of the invention, the therapeutic agent, e.g., a polypeptide, e.g., octreotide or terlipressin, is present at 1-50 mg, e.g., 10-20 mg, per capsule. In another embodiment of the invention, the therapeutic agent, e.g., a polypeptide, is present at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 mg, per capsule. In another embodiment of the invention, the octreotide or terlipressin is present at 5-50 mg, preferably 10 mg, 20 mg, or 30 mg, per capsule.

[0037] Another embodiment of the present invention is directed to a method of treating a subject suffering from hypotension, portal hypertension, variceal bleeding, or hepatorenal syndrome, or ascites, comprising administering to the subject a therapeutically effective amount of an oral dosage form of the present invention comprising terlipressin as an active pharmaceutical agent. Hypotension can be, for example, orthostatic hypotension or postprandial hypotension, portal hypertension can include bleeding esophageal varices associated with portal hypertension, ascites can be associated with cirrhosis, and can be cirrhotic ascites or severe cirrhotic ascites, and hepatorenal syndrome (HRS) can be HRS I or HRS II. The subject can suffer from two or more of these conditions.

[0038] Another embodiment of the present invention is directed to a method of treating a subject suffering from acromegaly or neuroendocrine tumors (NETs), GI motility disorders, carcinoid syndrome, episodes of flushing associated with NETs / carcinoid syndrome, portal hypertension, gastroparesis, diarrhea, particularly refractory diarrhea, diarrhea and / or flushing associated with NETs / carcinoid syndrome, pancreatic leak or pancreatic pseudocysts, polycystic disease, e.g., polycystic kidney disease or polycystic liver cysts or PCOS, or hypotension, particularly neurogenic orthostatic hypotension and postprandial hypotension, comprising administering to the subject a therapeutically effective amount of an oral dosage form of the present invention. In another embodiment of the present invention, the oral dosage forms of the present invention comprising octreotide as the active pharmaceutical agent are indicated for the long-term treatment of episodes of severe diarrhea and flushing associated with metastatic carcinoid tumors.

[0039] Another embodiment of the invention is a method of treating a subject comprising administering to the subject any of the oral dosage forms described herein, wherein the dosage is administered once, twice, or three times daily, and in another embodiment of the invention, the administration is at least 1 hour before a meal or at least 2 hours after a meal, and in another embodiment of the invention, the administration is on an empty stomach. In one embodiment of the invention, one, two, three, or four dosage forms may be administered simultaneously. In certain embodiments, one or two dosage forms may be administered simultaneously.

[0040] Another embodiment of the present invention is an oral dosage form wherein the first coating comprises 40-80% (wt%) polyvinyl alcohol, 20-55% (wt%) talc, 1-20% (wt%) glycerol monocaprylate, and 1-5% (wt%) sodium lauryl sulfate, and the second coating comprises 80-99.0% (wt%) methacrylic acid-ethyl acrylate copolymer, 0.1%-2% (wt%) sodium lauryl sulfate, and 0.5-4% (wt%) polysorbate, and further triethyl citrate.

[0041] Another embodiment of the present invention is an oral dosage form wherein the first coating comprises 50-60% (wt%) polyvinyl alcohol, 30-40% (wt%) talc, 4-10% (wt%) glycerol monocaprylate, and 2-4% (wt%) sodium lauryl sulfate, and the second coating comprises 90-99.0% (wt%) methacrylic acid-ethyl acrylate copolymer, 0.3%-1% (wt%) sodium lauryl sulfate, and 1-3% (wt%) polysorbate, and further triethyl citrate.

[0042] Another embodiment of the present invention is an oral dosage form, wherein the capsule coating comprises 57.0% (wt%) polyvinyl alcohol, 34.0% (wt%) talc, 6% (wt%) glycerol monocaprylate, and 3% (wt%) sodium lauryl sulfate as a first coating, and the second coating comprises 97.0% (wt%) methacrylic acid-ethyl acrylate copolymer, 0.7% (wt%) sodium lauryl sulfate, and 2.3% (wt%) polysorbate, and further triethyl citrate.

[0043] In another embodiment of the invention, triethyl citrate is present in an amount of 5-30% (wt%) of the second coating, or in an amount of 10-20% (wt%) of the second coating, preferably in an amount of 17% (wt%) of the second coating, most preferably in an amount of 16.9% (wt%) (8 mg per capsule).

[0044] In another embodiment of the invention, there is additionally a third coating over the second coating, hi another embodiment of the invention, this coating is talc.

[0045] In yet another embodiment of the present invention, talc is present in an amount of 0.1-3 mg per capsule, preferably 0.5-2 mg per capsule, and most preferably 1 mg per capsule.

[0046] Another embodiment of the present invention is a method of producing an enteric coated capsule containing a pharma- ceutically active polypeptide comprising applying a first coating to a capsule comprising polyvinyl alcohol, talc, glycerol monocaprylate, and sodium lauryl sulfate, and further applying a second coating over the first coating, wherein the second coating comprises a methacrylic acid-ethyl acrylate copolymer dispersion, sodium lauryl sulfate, polysorbate, and triethyl citrate; in yet another embodiment, the method comprises applying a third coating over the second coating, wherein the third coating is talc.

[0047] Another embodiment of the present invention is an oral dosage form having a single coating comprising 80-99.0% (wt%) methacrylic acid-ethyl acrylate copolymer, 0.1%-2% (wt%) sodium lauryl sulfate, and 0.5-4% (wt%) polysorbate, and further comprising triethyl citrate.

[0048] Another embodiment of the present invention is an oral dosage form having a single coating comprising 90-99.0% (wt%) methacrylic acid-ethyl acrylate copolymer, 0.3%-1% (wt%) sodium lauryl sulfate, and 1-3% (wt%) polysorbate, and further comprising triethyl citrate.

[0049] Another embodiment of the present invention is an oral dosage form, wherein the capsule coating comprises 97.0% (wt%) methacrylic acid-ethyl acrylate copolymer, 0.7% (wt%) sodium lauryl sulfate, and 2.3% (wt%) polysorbate, and further comprises triethyl citrate.

[0050] In another embodiment of the invention, triethyl citrate is present in an amount of 5-30% (wt %) of the coating, or in an amount of 10-20% of the coating, preferably 17% (wt %) of the second coating, most preferably 16.9% (wt %) (8 mg per capsule).

[0051] In another embodiment of the invention, there is an additional coating over the single coating, hi another embodiment of the invention, the coating is talc.

[0052] In yet another embodiment of the present invention, talc is present in an amount of 0.1-3 mg per capsule, preferably 0.5-2 mg per capsule, and most preferably 1 mg per capsule.

[0053] Another embodiment of the present invention is a method of making an enteric coated capsule containing a pharma- ceutical active polypeptide comprising applying a single coating to a capsule, the coating comprising a methacrylic acid-ethyl acrylate copolymer dispersion, sodium lauryl sulfate, polysorbate, and triethyl citrate, and in yet another embodiment, the method comprises applying an additional coating over the single coating, the additional coating being talc. [Table 1]

[0054] An additional embodiment is an oral dosage form comprising a capsule containing a formulation comprising a therapeutic agent, the capsule comprising a first coating comprising hydroxypropyl methylcellulose (HPMC) or hydroxypropyl cellulose (HPC) or hydroxyethyl cellulose or shellac or cellulose acetate phthalate or cellulose acetate butyrate or sodium alginate or carboxymethyl cellulose or polyvinylpyrrolidone, and further comprising a second coating over the first coating comprising a methacrylic acid-ethyl acrylate copolymer dispersion. There may be a third coating over the second coating, e.g., talc.

[0055] The therapeutic agent may be a polypeptide, such as octreotide or terlipressin.

[0056] The formulation may be as described herein and may include, for example, a medium chain fatty acid salt and polyvinylpyrrolidone (PVP).

[0057] Another embodiment is an oral dosage form comprising a capsule or tablet or sachet containing pellets containing a therapeutic agent, the pellets (also referred to as microparticles or minitablets) comprising a first coating comprising polyvinyl alcohol and further comprising a second coating over the first coating comprising a methacrylic acid-ethyl acrylate copolymer dispersion (commonly referred to as Eudragit L100). The therapeutic agent may be a polypeptide, e.g., octreotide or terlipressin.

[0058] The formulation may be as described herein and may include, for example, a medium chain fatty acid salt and polyvinylpyrrolidone (PVP).

[0059] Exemplary dosage forms include gelatin capsules, or vegetable capsules such as starch capsules or hydroxypropylmethylcellulose ("HPMC") capsules, which are enteric coated and contain bulk pharmaceuticals. Capsules that can be used to encapsulate the compositions of the present invention are known in the art and are described, for example, in Pharmaceutical Capsules (2004), edited by Podczech and Jones, Pharmaceutical Press, and Hard gelatin capsules today - and tomorrow, 2nd edition, Steggeman ed (2002), published by Capsugel Library.

[0060] Coating Examples

[0061] OPADRY AmbII

[0062] OPADRY® AmbII is a branded formulation (Colorcon) composed of PVA, plasticizers, and optional pigments. It is used primarily as a moisture barrier film coating and as a subcoating to improve adhesion of functional coatings onto the dosage form surface.

[0063] Eudragit L 30 D-55 Eudragit is a brand name of Evonik Industries (Germany). Kollicoat produces a similar product.

[0064] 97.0% Methacrylic acid copolymer type C (NF, PhEur, JPE)

[0065] 0.7% Sodium Lauryl Sulfate Ph.Eur. / NF

[0066] 2.3% Polysorbate 80 Ph.Eur. / NF

[0067] The product is a dispersion of a copolymer produced using methacrylic acid and ethyl acrylate in an aqueous solution of polysorbate 80 and sodium lauryl sulfate. Chemical name: Dispersion of poly[(methacrylic acid)-co-(ethyl acrylate)] Structural formula: [ka]

[0068] Coatings are applied as known in the art, see, e.g., Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (2017) Linda A. Felton ed., CRC press.

[0069] Oral dosage form

[0070] The oral dosage forms described herein comprise a pharmaceutical agent, specifically a polypeptide, and a medium chain fatty acid salt in intimate contact with or associated with a substantially hydrophobic vehicle, which are encapsulated and coated with at least two different coatings to provide release of the contents between pH 4.5 and 6.0.

[0071] The polypeptides of the invention are, for example, terlipressin and its analogs (agonists), or octreotide and its analogs (agonists).

[0072] Alternatively, the agent may be a non-polypeptide.

[0073] For example, the polypeptide and medium chain fatty acid or its derivative may be coated, suspended, sprayed, or immersed in a substantially hydrophobic medium to form a suspension. The composition of the present invention is not an emulsion. The composition is an oil suspension, and the amount of water in the composition is very small, usually less than 1% or less than 0.5%. This is known as Chiasma's TPE® technology.

[0074] The suspension may be a liquid suspension incorporating a solid material or a semi-solid suspension incorporating a solid material (ointment). Many of the compositions described herein include a suspension comprising an admixture of a hydrophobic medium and a solid form, the solid form comprising a therapeutically effective amount of a polypeptide and at least one salt of a medium chain fatty acid, the medium chain fatty acid salt being present in the composition in an amount of 10% by weight or more. The solid form may comprise particles (e.g., consist essentially of particles or consist of particles). The particles may be produced by methods known in the art, for example, by freeze-drying, by spray drying by granulation, or by roller compaction.

[0075] Medium chain fatty acid salts can generally promote or enhance the permeability and / or absorption of polypeptides. In some embodiments, medium chain fatty acid salts include derivatives of medium chain fatty acid salts. The polypeptide and medium chain fatty acid salts are in solid form, for example, solid particles such as lyophilized particles, granular particles, pellets, or microspheres. In preferred embodiments, the polypeptide and medium chain fatty acid salts are both in the same solid form, for example, both are the same particle. In other embodiments, the polypeptide and medium chain fatty acid salts may each be in a different solid form, for example, each may be a separate particle.

[0076] Unlike emulsion, when water is an essential component of formulation, the composition described herein provides solid form such as particle containing polypeptide, which is then associated with hydrophobic (oily) medium.The amount of water in composition is generally less than 3% by weight, usually less than about 2% by weight or less than 1% by weight, or about 0.5% by weight or less.

[0077] The compositions described herein are suspensions comprising an admixture of a hydrophobic medium and a solid form, the solid form comprising a therapeutically effective amount of a polypeptide and at least one salt of a medium chain fatty acid. The solid form may be particulate (e.g., consisting essentially of or consisting of particles). The particles may be produced by freeze-drying, or by spray-drying, or by granulation, or by roller compaction. The medium chain fatty acid salt is generally present in the compositions described herein in an amount of 10% by weight or more. In certain embodiments, the medium chain fatty acid salt is present in the composition in an amount of 10% to 50% by weight, preferably 11% to 18% by weight, or about 11% to 17% by weight, or 12% to 16% by weight, or 12% to 15% by weight, or 13% to 16% by weight, or 13% to 15% by weight, or 14% to 16% by weight, or 14% to 15% by weight, or 15% to 16% by weight, or most preferably 15% or 16% by weight, and the medium chain fatty acid has a chain length of from about 6 to about 14 carbon atoms, preferably 8, 9, or 10 carbon atoms.

[0078] In some embodiments of the above-mentioned compositions, the solid form containing the polypeptide also contains a stabilizer (e.g., a protein structure stabilizer). The protein structure stabilizer is a compound that can stabilize protein structure or reduce or prevent aggregation of the polypeptide under aqueous or non-aqueous conditions, for example, during a drying process such as lyophilization, or by roller compaction, or by spray drying or other processing steps. The structure stabilizer can be a polyanionic molecule, such as a polyvalent ion such as phytic acid, Ca, Zn, or Mg; a sugar, such as a disaccharide (e.g., trehalose, maltose), or an oligo- or polysaccharide, such as dextrin or dextran, or a sugar alcohol such as mannitol; or an amino acid such as glycine; or a surfactant, such as polyoxyethylene sorbitan monooleate (Tween 80) or pluronic acid. Non-charged polymers such as mannitol, methylcellulose, and polyvinyl alcohol are also suitable stabilizers.

[0079] Polyvinylpyrrolidone (PVP) is known in the art as a stabilizer, but in the compositions of the invention described herein, PVP polymers, such as PVP-12, can function, for example, synergistically, to increase the effect of the permeation enhancer. See coassigned U.S. Patent Nos. 8,329,198 and 9,566,246. Dextran and other matrix-forming polymers can have a similar effect as PVP.

[0080] In some embodiments, bulking agents such as mannitol or glycine may be added.

[0081] In a specific embodiment of the compositions described herein, the salt of a fatty acid is sodium octanoate and the hydrophobic medium is castor oil, in another specific embodiment, the composition further comprises glyceryl monooleate and sorbitan monopalmitate or glyceryl monocaprylate and glyceryl tricaprylate and polyoxyethylenesorbitan monooleate, and in another specific embodiment, the composition further comprises glyceryl tributyrate, lecithin, ethyl isovalerate, and at least one stabilizer.

[0082] Medium chain fatty acid salts:

[0083] The compositions described herein include the salt of a medium chain fatty acid or a derivative thereof in a solid form. For example, the salt of the medium chain fatty acid is in the form of a particle, such as a solid particle. In some embodiments, the particle may be characterized as a granular particle. In at least some embodiments, the solid form may generally result from a process of spray drying or evaporation. In a preferred embodiment, the salt of the medium chain fatty acid is in the same particle as the polypeptide. For example, the polypeptide and the salt of the medium chain fatty acid can be prepared together by first preparing a solution, such as an aqueous solution, containing both the polypeptide and the medium chain fatty acid salt, and co-freezing the solution to provide a solid form or particle containing both the polypeptide and the medium chain fatty acid salt (and other components). As described above, the resulting solid particle can be associated with a hydrophobic medium. For example, the solid particle can be suspended or immersed in the hydrophobic medium.

[0084] In different embodiments of the compositions described herein, the medium chain fatty acid salt may be in the same particle as the particle of the API or in a different particle. If the medium chain fatty acid salt and the polypeptide are co-solubilized in the hydrophilic fraction and then dried, they will be in the same particle in the final powder.

[0085] Medium chain fatty acid salts include those having a carbon chain length of about 6 to about 14 carbon atoms. Examples of fatty acid salts are sodium hexanoate, sodium heptanoate, sodium octanoate (also called sodium caprylate), sodium nonanoate, sodium decanoate, sodium undecanoate, sodium dodecanoate, sodium tridecanoate, and sodium tetradecanoate. In some embodiments, the medium chain fatty acid salt contains a cation selected from the group consisting of potassium, lithium, ammonium, and other monovalent cations, for example, the medium chain fatty acid salt is selected from lithium octanoate or potassium octanoate or arginine octanoate, or other monovalent salts of medium chain fatty acids.

[0086] Generally, the amount of medium chain fatty acid salt in the compositions described herein can be from 10% up to about 50% by weight of the bulk pharmaceutical composition. For example, the medium chain fatty acid salt may be present at about 10% to 50% by weight of the bulk pharmaceutical composition, preferably about 11% to 40% by weight, and most preferably about 11% to 28% by weight, such as about 12% to 13% by weight, 13% to 14% by weight, 14% to 15% by weight, 15% to 16% by weight, 16% to 17% by weight, 17% to 18% by weight, 18% to 19% by weight, 19% to 20% by weight, 20% to 21% by weight, 21% to 22% by weight, 22% to 23% by weight, 23% to 24% by weight, 24% to 25% by weight, 25% to 26% by weight, 26% to 27% by weight, or 27% to 28% by weight. In other embodiments, the medium chain fatty acid salt may be present in an amount of at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, or at least about 28% by weight of the bulk pharmaceutical composition. In certain embodiments, the medium chain fatty acid salt (sodium, potassium, lithium, or ammonium salt, or mixtures thereof) is present at about 12% to 21% by weight of the bulk pharmaceutical composition, preferably 11% to 18%, or about 11% to 17%, or 12% to 16%, or 12% to 15%, or 13% to 16%, or 13% to 15%, or 14% to 16%, or 14% to 15%, or 15% to 16%, or most preferably 15% or 16%.In certain embodiments, the medium chain fatty acid salts (having a carbon chain length of about 6 to about 14 carbon atoms, specifically 8, 9, or 10 carbon atoms) are present at about 12% to 21% by weight of the bulk pharmaceutical composition, preferably 11% to 18%, about 11% to 17%, or 12% to 16%, or 12% to 15%, or 13% to 16%, or 13% to 15%, or 14% to 16%, or 14% to 15%, or 15% to 16%, or most preferably 15% or 16%. In certain embodiments, the medium chain fatty acid salt (e.g., salt of octanoic acid, salt of suberic acid, salt of geranic acid) is present in about 12% to 21% by weight of the bulk pharmaceutical composition, preferably 11% to 18%, about 11% to 17%, or 12% to 16%, or 12% to 15%, or 13% to 16%, or 13% to 15%, or 14% to 16%, or 14% to 15%, or 15% to 16%, or most preferably 15% or 16% by weight. In certain embodiments, the medium chain fatty acid salt is present in the solid powder in an amount of 50% to 90%, preferably 70% to 80%.

[0087] One embodiment of the present invention includes a composition comprising a suspension consisting essentially of an admixture of a hydrophobic medium and a solid form, the solid form comprising a therapeutically effective amount of a polypeptide and at least one salt of a medium chain fatty acid, the medium chain fatty acid salt being not a sodium salt, the salt may be of another cation, such as lithium, potassium, or ammonium, with the ammonium salt being preferred.

[0088] Matrix forming polymer:

[0089] In certain embodiments, the compositions of the present invention include suspensions comprising an admixture of a hydrophobic medium and a solid form, the solid form comprising a therapeutically effective amount of a polypeptide, at least one salt of a medium chain fatty acid, and a matrix-forming polymer, the matrix-forming polymer being present in the composition in an amount of 3% by weight or more. In certain embodiments, the compositions include suspensions consisting essentially of an admixture of a hydrophobic medium and a solid form, the solid form comprising a therapeutically effective amount of a polypeptide, at least one salt of a medium chain fatty acid, and a matrix-forming polymer, the matrix-forming polymer being present in the composition in an amount of 3% by weight or more. In certain embodiments, the matrix-forming polymer is dextran or polyvinylpyrrolidone polymer (PVP), available in various molecular weights from BASF. In certain embodiments, the polyvinylpyrrolidone is present in the composition in an amount of about 2% by weight to about 20% by weight, preferably about 3% by weight to about 18% by weight, more preferably about 5% by weight to about 15% by weight, and most preferably about 10% by weight. In certain embodiments, the polyvinylpyrrolidone is PVP-12 and / or has a molecular weight of about 3000. Other matrix-forming polymers have similar effects in the compositions of the invention, including ionic (e.g., alginic acid and alginates) or neutral polysaccharides (e.g., dextran and HPMC), derivatives of polyacrylic and polymethacrylic acid, and high molecular weight organic alcohols (e.g., polyvinyl alcohol).

[0090] Hydrophilic fraction:

[0091] In an embodiment of the present invention, the above-mentioned compound, including polypeptide and medium-chain fatty acid salt, is solubilized in an aqueous medium, and then dried to produce a powder.The drying process can be achieved, for example, by freeze-drying or spray-drying or granulation, or by roller compaction.The resulting powder is called "hydrophilic fraction".In the hydrophilic fraction, water is usually present in an amount of less than 6%, or less than 3%, or about 2% or less.

[0092] Lyophilization may be carried out by methods known in the art, for example as described in Lyophilization: Introduction and Basic Principles, Thomas Jennings (1999, 2002), published by Interpharm / CRC Press. The lyophilisate may be optionally milled (e.g., to less than 150 microns) or ground in a mortar. During industrial production, it is preferable to mill the lyophilisate before mixing the hydrophilic fraction with the hydrophobic medium to create batch-to-batch reproducibility.

[0093] Spray drying may be carried out by methods known in the art, for example, as described in Walters et al (2014) Next Generation Drying Technologies for Pharmaceutical Applications, J. of Pharm Sci 103; 2673-2695.

[0094] Granulation is described, for example, in Granulation, Salman et al, eds, Elsevier (2006) and in Handbook of Pharmaceutical Granulation Technology, 2 nd Granulation may be performed as directed by methods known in the art, such as those described in the above two references, such as cellulose (including microcrystalline cellulose), lactose (e.g., lactose monohydrate), dextrose, starch, and mannitol, as well as other binders.

[0095] Hydrophobic medium (lipophilic fraction):

[0096] Oil: As mentioned above, in the compositions of the present invention described herein, the polypeptide and the medium chain fatty acid salt are in contact with or associated with a hydrophobic medium. For example, one or both may be coated, suspended, immersed or otherwise bound by the hydrophobic medium. Suitable hydrophobic mediums may include, for example, aliphatic, cyclic or aromatic molecules. Examples of suitable aliphatic hydrophobic mediums include, but are not limited to, mineral oil, fatty acid monoglycerides, diglycerides, triglycerides, ethers, esters and combinations thereof. Examples of suitable fatty acids are octanoic acid, decanoic acid and dodecanoic acid, as well as C7 and C9 fatty acids, and diacids such as sebacic acid and suberic acid, and derivatives thereof. Examples of triglycerides include, but are not limited to, long chain triglycerides, medium chain triglycerides and short chain triglycerides. For example, the long-chain triglyceride may be castor oil or coconut oil or olive oil, the short-chain triglyceride may be glyceryl tributyrate, and the medium-chain triglyceride may be glyceryl tricaprylate. Monoglycerides are considered surfactants and are described below. Exemplary esters include ethyl isovalerate and butyl acetate. Examples of suitable cyclic hydrophobic media include, but are not limited to, terpenoids, cholesterol, cholesterol derivatives (e.g., cholesterol sulfate), and cholesterol esters of fatty acids. Non-limiting examples of aromatic hydrophobic media include benzyl benzoate.

[0097] In some embodiments of the compositions described herein, it is desirable for the hydrophobic medium to comprise a plurality of hydrophobic molecules. In some embodiments of the compositions described herein, the hydrophobic medium also comprises one or more surfactants (see below).

[0098] In some embodiments of the compositions described herein, the hydrophobic medium also includes one or more adhesive polymers, such as methylcellulose, ethylcellulose, hydroxypropylmethylcellulose (HPMC), or the poly(acrylate) derivative Carbopol® 934P (C934P). Such adhesive polymers may aid in the hardening of the formulation and / or aid in its adhesion to the mucosal surface.

[0099] Surfactants (surfactants):

[0100] The compositions of the invention described herein may further comprise a surfactant. For example, the surfactant may be a component of the hydrophobic medium described above, and / or the surfactant may be a component of the solid form described above, such as a solid form or particle that comprises a polypeptide.

[0101] Suitable surfactants include ionic and non-ionic surfactants. Examples of ionic surfactants are lecithin (phosphatidylcholine), bile salts, and detergents. Examples of non-ionic surfactants include monoglycerides, cremophor, polyethylene glycol fatty alcohol ethers, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, Solutol HS15, or poloxamers, or combinations thereof. Examples of monoglycerides are glyceryl monocaprylate (also called glyceryl monooctanoate), glyceryl monodecanoate, glyceryl monolaurate, glyceryl monomyristate, glyceryl monostearate, glyceryl monopalmitate, and glyceryl monooleate. Examples of sorbitan fatty acid esters include sorbitan monolaurate, sorbitan monooleate, and sorbitan monopalmitate (Span 40), or combinations thereof. Examples of polyoxyethylene sorbitan fatty acid esters include polyoxyethylene sorbitan monooleate (Tween 80), polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate, or combinations thereof. The commercial preparations of monoglycerides used also contain varying amounts of diglycerides and triglycerides.

[0102] Compositions described herein that include a surfactant generally include less than about 12% by weight of total surfactant (e.g., less than about 10% by weight, less than about 8% by weight, less than about 6% by weight, less than about 4% by weight, less than about 2% by weight, or less than about 1% by weight). In a specific embodiment of the invention, the sum of all surfactants is about 6%.

[0103] Methods of Making Pharmaceutical Compositions and Compositions Produced

[0104] The present invention also includes methods of producing the compositions described herein. Accordingly, one embodiment of the present invention is a process for producing a pharmaceutical composition comprising preparing a water-soluble composition comprising a therapeutically effective amount of a polypeptide and a medium chain fatty acid salt (as described above), drying the water-soluble composition to obtain a solid powder, and suspending the solid powder in a hydrophobic medium to produce a suspension containing the solid form polypeptide and the medium chain fatty acid salt, thereby producing the pharmaceutical composition, the pharmaceutical composition containing 10% by weight or more of the medium chain fatty acid salt.

[0105] One embodiment is a process for producing a pharmaceutical composition comprising providing a therapeutically effective amount of a solid powder of a polypeptide and a solid powder comprising a medium chain fatty acid salt, and suspending the solid powders in a hydrophobic medium to produce a suspension containing the polypeptide and the medium chain fatty acid salt in solid form, thereby producing the pharmaceutical composition, the pharmaceutical composition containing 10% or more by weight of the medium chain fatty acid salt.

[0106] In one embodiment of the process and compositions described herein, the water-soluble composition is an aqueous solution. In certain embodiments, the drying of the water-soluble composition is accomplished by lyophilization, or by spray drying, or by granulation, or by roller compaction. In certain embodiments, the drying step removes sufficient water such that the water content in the bulk pharmaceutical composition is about 6% by weight, about 5% by weight, about 4% by weight, about 3% by weight, or about 2% by weight, or about 1% by weight, or about 0.5% by weight or less. In certain embodiments of the process and compositions described herein, the drying step removes an amount of water such that the water content in the solid powder is less than 6% by weight, or less than 5% by weight, or less than 4% by weight, or less than 3% by weight, or preferably less than 2% by weight. The water content is usually low, and water may be adsorbed to the solid phase during lyophilization, i.e., water may be retained by intermolecular bonds. In certain embodiments, the water-soluble composition further comprises a stabilizer, such as methylcellulose. In a preferred embodiment of the process and composition described herein, the hydrophobic medium is castor oil or glyceryl tricaprylate or glyceryl tributyrate or a combination thereof, and may further contain octanoic acid. In a particular embodiment, the hydrophobic medium comprises an aliphatic compound, an olefinic compound, a cyclic compound, or an aromatic compound, a mineral oil, a paraffin, a fatty acid such as octanoic acid, a monoglyceride, a diglyceride, a triglyceride, an ether or an ester, or a combination thereof. In a particular embodiment of the process and composition described herein, the triglyceride is a long-chain triglyceride, the medium-chain triglyceride is preferably glyceryl tricaprylate, or the short-chain triglyceride is preferably glyceryl tributyrate, and the long-chain triglyceride is castor oil or coconut oil, or a combination thereof. In certain embodiments of the processes and compositions described herein, the hydrophobic medium comprises castor oil or glyceryl tricaprylate or glyceryl tributyrate or combinations or mixtures thereof, and may further comprise octanoic acid. In certain embodiments of the processes and compositions described herein, the hydrophobic medium comprises glyceryl tricaprylate or a low molecular weight ester, such as ethyl isovalerate or butyl acetate.In certain embodiments of the processes and compositions described herein, the main component by weight of the hydrophobic medium is castor oil and may further include glyceryl tricaprylate.In certain embodiments of the processes and compositions described herein, the main component by weight of the hydrophobic medium is glyceryl tricaprylate and may further include castor oil.

[0107] In certain embodiments, the composition comprises a suspension consisting essentially of an admixture of a hydrophobic medium and a solid form, the solid form comprising a therapeutically effective amount of a polypeptide and at least one salt of a medium chain fatty acid, the medium chain fatty acid salt being present in the composition in an amount of 10% by weight or more. In certain embodiments, the hydrophobic medium consists essentially of castor oil, glyceryl monooleate, and glyceryl tributyrate, or the hydrophobic medium consists essentially of glyceryl tricaprylate and glyceryl monocaprylate, or the hydrophobic medium consists essentially of castor oil, glyceryl tricaprylate, and glyceryl monocaprylate. In certain embodiments, the hydrophobic medium comprises a triglyceride and a monoglyceride, and in certain embodiments, the monoglyceride has the same fatty acid radical as the triglyceride. In certain of these embodiments, the triglyceride is glyceryl tricaprylate and the monoglyceride is glyceryl monocaprylate. In certain embodiments, the medium chain fatty acid salt in the water soluble composition has the same fatty acid radical as the medium chain monoglyceride or medium chain triglyceride or a combination thereof, in certain of these embodiments, the medium chain fatty acid salt is sodium caprylate (sodium octanoate), the monoglyceride is glyceryl monocaprylate, and the triglyceride is glyceryl tricaprylate.

[0108] Many of the compositions described herein include suspensions that include an admixture of a hydrophobic medium and a solid form, the solid form comprising a therapeutically effective amount of a polypeptide and at least one salt of a medium chain fatty acid, the medium chain fatty acid salt preferably being present in the composition in an amount of 10% by weight or more. The solid form may be particulate (e.g., consisting essentially of or consisting of particles). The particles may be produced by lyophilization, or by granulation, or by spray drying, or by roller compaction. In one embodiment, the formulation consists essentially of or comprises a suspension comprising an admixture of a hydrophobic medium and a solid form, the solid form comprising a therapeutically effective amount of the polypeptide and about 10-20%, preferably 15%, of a medium chain fatty acid salt, preferably sodium octanoate, and a polyvinylpyrrolidone polymer, such as PVP-12, the hydrophobic medium comprising about 20-80%, preferably 30-70%, of a medium or short chain triglyceride, preferably glyceryl tricaprylate or glyceryl tributyrate, about 0-50%, preferably 0-30%, of castor oil, about 3-10% of a surfactant, preferably about 6%, preferably glyceryl monocaprylate and Tween 80, and in specific embodiments, the polypeptide is present in an amount of less than 33%, or less than 25%, or less than 10%, or less than 3% or less than 2%.

[0109] In the above formulations, the percentages are weight / weight.

[0110] In another embodiment, the formulation comprises a medium chain fatty acid salt and polyvinylpyrrolidone.

[0111] Under normal storage conditions, the polypeptide in the formulation of the present invention is stable for a long period of time.The chemical and physical state of the formulation is stable.When administered to the intestine, the polypeptide is protected from damage by the GI environment because the formulation is oil-based, creating an isolated local environment in the intestine.Here, terlipressin is contained in particles suspended in oil, which provides stability in vivo.

[0112] In certain embodiments, the process produces a composition consisting essentially of a polypeptide and a medium chain fatty acid salt and a hydrophobic medium. In an embodiment of the invention, the solid powder (solid form) consists essentially of a polypeptide and a medium chain fatty acid salt. Yet another embodiment of the invention is a pharmaceutical composition produced by the process described herein. The polypeptide and / or medium chain fatty acid salt, or any combination of the polypeptide and other components such as a protein stabilizer, can be prepared in solution (e.g., form an aqueous solution or mixture) of the mixture that can be lyophilized together and then suspended in a hydrophobic medium. Other components of the composition can also be optionally lyophilized or added during reconstitution of the solid material.

[0113] In some embodiments, the polypeptide is solubilized in a mixture containing one or more additional components, such as, for example, a medium chain fatty acid salt, a stabilizer, and / or a surfactant, and the solvent is removed to provide a resulting solid powder (solid form), which is suspended in a hydrophobic medium. In some embodiments, the polypeptide and / or medium chain fatty acid salt may then be formed into granular particles that are associated with the hydrophobic medium (e.g., suspended in or coated by the hydrophobic medium). If necessary, the pharmaceutical composition may also contain small amounts of non-toxic auxiliary substances, such as pH buffers, and other substances, such as, for example, sodium acetate and triethanolamine oleate.

[0114] In some embodiments, the solid form may be particulate (e.g., consisting essentially of or consisting of particles). In some embodiments, the particles may be produced by freeze-drying, by spray-drying, by granulation, or by roller compaction. In some embodiments of this process, the fatty acid salt is sodium octanoate, and in yet another embodiment of this process, the medium chain fatty acid salt is present in the composition in an amount of about 11% to about 40% by weight, or in an amount of about 11% to about 28% by weight, or in an amount of about 15% by weight. In some embodiments of this process, the composition further comprises a matrix-forming polymer, and in a specific embodiment of this process, the matrix-forming polymer is dextran or polyvinylpyrrolidone polymer (PVP), and in yet another embodiment of this process, the polyvinylpyrrolidone is present in the composition in an amount of about 2% to about 20% by weight, or in an amount of about 4% to about 15% by weight, or in an amount of about 10% by weight. In a specific embodiment of this process, the polyvinylpyrrolidone polymer is PVP-12 and / or has a molecular weight of about 3000 Da. The composition may further include a surfactant as described above. The solid form may also contain a binder. There may also be small amounts of other hydrophobic components as described above. Pharmaceutical products of these processes are yet another embodiment of the present invention.

[0115] kit

[0116] The oral dosage form may be provided in a pack or dispenser device, such as an FDA approved kit, which may contain one or more unit dosage forms containing the active ingredient and instructions, if desired. The pack may comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice associated with the container, in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects the form of the composition or the approval by the agency for human or veterinary administration. Such notice may be, for example, the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or an approved product insert.

[0117] definition

[0118] As used herein, the term "polypeptide" refers to a molecule composed of covalently linked amino acids, and includes peptides, polypeptides, proteins, and peptidomimetics. Peptidomimetics are compounds that contain non-peptidic structural elements that can mimic the biological action of natural parent peptides. Some of the characteristics of classical peptides, such as peptide bonds that are susceptible to enzymatic cleavage, are not usually present in peptidomimetics. A peptidomimetic of a polypeptide can be an analog of that polypeptide.

[0119] The term "amino acid" refers to a molecule that includes any one of the 20 naturally occurring amino acids, or amino acids that have been chemically modified, or synthetic amino acids.

[0120] As used herein, a polypeptide "analog" or "agonist" refers to a compound having a similar chemical structure and biological activity to the peptide.

[0121] As used herein, the term "pharmacologically or therapeutically effective amount" means an amount of a drug or pharmaceutical (therapeutic) agent (e.g., terlipressin, octreotide) that elicits a biological or medical response in a tissue, system, animal, or human that is being sought and / or treated by a researcher or clinician, stops or reduces the progression of the condition being sought and / or treated, or otherwise cures or palliates, in whole or in part, a condition described herein, or prevents the development of a condition described herein (e.g., acromegaly or hepatorenal syndrome, portal hypertension, varices, e.g., bleeding esophageal varices, ascites and / or cirrhosis and / or cirrhotic ascites or severe cirrhotic ascites).

[0122] As used herein, administering "in combination" means that two (or more) different therapeutic agents are delivered to a subject during the course of the subject's illness, e.g., two or more therapeutic agents are delivered after the subject is diagnosed with the disorder and before the disorder is cured or eliminated for other reasons, or before treatment is stopped. In some embodiments, delivery of one therapeutic agent is still occurring when delivery of the second begins, and thus there is overlap in terms of administration. This is sometimes referred to herein as "simultaneous" or "co-delivery." In other embodiments, delivery of one therapeutic agent ends before delivery of the other treatment begins. In either case, in some embodiments, the therapeutic agents are more effective because of the combined administration. For example, the second therapeutic agent is more effective, e.g., a comparable effect is seen with a smaller amount of the second therapeutic agent, or the second therapeutic agent reduces symptoms and side effects to a greater extent than would be seen if the second therapeutic agent was administered in the absence of the first therapeutic agent or in a similar situation with the first therapeutic agent. In some embodiments, the delivery is such that the reduction in symptoms, or other parameters associated with the disorder, is greater than that observed with one therapeutic agent delivered in the absence of the other. The effects of the two therapeutic agents may be partially additive, wholly additive, or greater than additive. Delivery may be such that the effect of the first therapeutic agent delivered is still detectable when the second therapeutic agent is delivered.

[0123] As used herein, the terms "treatment", "treat", or "treating", e.g., in "treatment method", refer to therapeutic treatment, the purpose of which is to reduce or reverse or prevent symptoms or side effects of a disease or disorder. In some embodiments, a compound or composition disclosed herein is administered prior to the onset of a disease or disorder. In some embodiments, a compound or composition disclosed herein is administered during or after the onset of a disease or disorder.

[0124] The functionality and advantages of these and other embodiments will be more fully understood from the following examples, which are intended to be exemplary in nature and should not be considered as limiting the scope of the systems and methods discussed herein. EXAMPLES

[0125] Example 1: Preparation of Mycapssa capsules

[0126] The preparation of Mycapssa octreotide capsules is described, inter alia, in coassigned U.S. Patent No. 8,329,198. The oil suspension (capsule fill mass) contains, in addition to the octreotide salt, 10% polyvinylpyrrolidone K12, 15% sodium caprylate (octanoate), 0.6% magnesium chloride, 2% polysorbate 80 (Tween 80), 4% glyceryl monocaprylate, and 65.1% glyceryl tricaprylate. See FIG. 1, which shows a manufacturing flow chart for the preparation of octreotide capsules (Mycapssa® product).

[0127] Example 2: Comparison of different coatings for a 20 mg octreotide formulation and results of a dog PK study

[0128] In this study, the effect of modifying the enteric coating and / or permeation enhancer on the bioavailability of octreotide was evaluated. Beagle dogs were used as an animal model since it is a suitable model for testing oral dosage forms. Various enteric coats and permeation enhancers, sodium caprate (NaC), were used instead of sodium caprate (NaC), as used in Mycapssa. 10 ) was used. 10 may be more efficient in enhancing macromolecule delivery across epithelial membranes.

[0129] Therefore, this study compared the oral bioavailability and pharmacokinetic (PK) parameters of Mycapssa and other formulation / coating prototypes following oral administration to dogs. The various prototypes were tested in vitro in dissolution assays and then in vivo in dogs. The coatings tested were as follows (described in further detail throughout the specification): [Table 2] The formulation changes were as follows: 1. Sodium caprate (NaC) was used as a permeation enhancer instead of sodium caprylate (NaC8). 10 )fart. 2. Two concentrations of NaC 10 (15% and 20%). 3. Two enteric coats (NC02, NC04) - may have different (higher) acid resistance than Acryl-EZE. Goal - resistant to pH 4.5 and dissolves above pH 5.5. The term resistant to pH 4.5 means that each individual capsule must exhibit less than 10% dissolution or 0% dissolution in citric acid solution at pH 4.5 (and similarly for other pH values) for up to 2 hours. The term dissolves above pH 5.5 means that the dosage form coating dissolves and the dosage form releases its contents above pH 5.5 (and similarly for other pH values). NC02 is Eudragit / Eudragit. (It is called Eudragit / Eudragit because, like Acryl-EZE, the material is sprayed at two different rates to improve adhesion to the capsule. A few mg is sprayed at a slow rate initially, then the spray rate is increased until full weight gain of the coating is achieved. The total amount of Eudragit on each capsule is the same for NC02 and NC04.

[0130] NC04 contains a white subcoat of OPADRY ambII (first coating) and a topcoat of Eudragit L 30 D-55 (second coating). 4. NC03: An enteric coat that dissolves above pH 7, including Eudragit FS30, which was found to dissolve above pH 6.5 and to be unsuitable for its intended purpose. 5.NC05: A combination of two enteric polymers resulted in a coating that dissolved at about pH 6.5. This coating contains a mixture of Eudragit FS30 and Eudragit L 30 D-55. This coating caused a long delay in the dissolution process and was found to be unsuitable for the intended purpose. The composition of the experimental capsules is shown in Table 1 below. [Table 3]

[0131] I. Dissolution test Analysis method Assay and impurities / degradation products of octreotide capsule formulations were determined by reversed-phase HPLC-UV / Fluo method via an Aeris Peptide (or equivalent) column and an acetonitrile:water:TFA mobile phase. Capsule contents were extracted with methanol, diluted, and injected into the HPLC. USP <711> The drug release (dissolution) profile was determined using a USP-II apparatus by a two-stage dissolution method according to and Ph.Eur.2.9.3. The tests were carried out in 900 mL of dissolution medium maintained at 37±0.5° C. at 50 rpm. The tests consisted of a two-hour acid-stage dissolution in citrate buffer at pH 4.5 (except for Mycapssa, which is tested in 0.1 N HCl, pH 1), followed by a buffer-stage dissolution in phosphate buffer at pH 6.8 for up to 60 minutes. For formulation F1C4P1, a buffer at pH 7.2 (instead of 6.8) was used. Dissolution aliquots were removed from the dissolution bath at the indicated time points and analyzed by HPLC.

[0132] Final product test results

[0133] The assay / impurity and content uniformity (CU) results of the tested formulations are shown below in Table 2. All results were within specification. [Table 4]

[0134] Dissolution test results

[0135] A two-stage (sequential) dissolution method was used, with the pass criterion for the acid stage being "no individual capsules more than 10% dissolved in 2 hours" and for the buffer stage a Q value of 75% was set at 45 minutes. The dissolution performance of the prototypes at the buffer stage (pH 6.8) is presented in FIG. Different dissolution profiles were observed between the prototypes. Mean data for % API release are presented.

[0136] Statistical analysis was performed to assess whether the difference was significant. The results of statistical analysis showed that no statistically significant difference was found between the slopes of batches with overlapping confidence intervals, such as batches OCT-CCP-010 and OCT-CCP-013. Batch OCT-CCP-016 has a significantly slower release rate compared to batches RB1 (Mycapssa), OCT-CCP-014, OCT-CCP-013, OCT-CCP-012, and OCT-CCP-010. In addition, OCT-CCP-011 exhibits a significantly slower release than OCT-CCP-016. It is noted that all batches except OCT-CCP-011 and OCT-CCP-016 cluster together to show a faster release.

[0137] A series of five different coating formulations were tested using capsules filled with the same TPE formulation as the Mycapssa product (Groups 1, 2, 3, and 4 in Phase 1, Group 4 in Phase 2). The various experimental coat compositions produced improved acid resistance compared to the Mycapssa coat (Acryl-EZE coating). The Mycapssa enteric coat was stable at pH 1, but delaminates the capsules above pH 3 (a floating film was observed in the dissolution vessel). All other experimental coats survived 2 hours at pH 4.5 without opening. This higher acid resistance resulted in less variability in Tlag and Tmax.

[0138] It should be noted that some of the coats, namely NC02 and NC04, when combined with NaC8 as a permeation enhancer and tested in dogs, produced higher bioavailability than the Mycapssa product. See below and Figure 3, which presents the dog PK results of NC02 and NC04 (the best two coats) versus the control (Mycapssa product).

[0139] Since the enteric film coatings (NC02, NC04, and Mycapssa) dissolved at low pH (<pH 5.5), except for NC03 and NC05, the dissolution rate of octreotide is not controlled by pH 6.8, and therefore the potential different absorption rates of the different film coatings cannot be predicted.

[0140] The experimental coats NC03 and NC05 were designed to dissolve at a higher pH than NC02 and NC04. Therefore, their dissolution profiles were clearly different from Mycapssa, NC02, and NC04 groups. NC05 dissolved very slowly at pH 6.8, whereas NC03 did not dissolve at all at pH 6.8, and its drug release profile at pH 7.2 was slower than all other coats. These differences in drug release profile resulted in longer Tlag and Tmax compared to NC02, NC03, and Mycapssa. Another effect was lower bioavailability compared to NC02 and NC04.

[0141] II. Animal testing Experimental design

[0142] Twenty-four male beagle dogs (8-12 kg) obtained from MPI Research's stock colony of non-naive beagles were used after a 10-day acclimation period. All animals were fasted for at least 12 hours prior to dose administration and for the first 4 hours of blood sampling. For treatments 1-4 in phase 1 and treatments 2-4 in phase 2, each animal received a single subcutaneous (SC) injection of pentagastrin (0.12 mg / mL) at a dose level of 0.006 mg / kg and a dose volume of 0.05 mL / kg approximately 30 minutes prior to dose administration to acidify the dog's stomach. Each dog was used for two treatments (Phase 1 and Phase 2) with a washout period of 58 days. Blood was collected at designated time points, processed to plasma, and frozen at -70°C. Octreotide concentrations were measured using an LC-MS / MS method. Octreotide exposure was calculated using the linear trapezoidal method. Octreotide SC data was used as the reference for calculation of the relative octreotide bioavailability (Frel) of the orally administered formulation. [Table 5]

[0143] The composition of the test capsules is set forth in Table 1 above.

[0144] Animal testing

[0145] Animal studies were performed at MPI Research (Kalamazoo, Michigan, USA). Non-naive beagle dogs obtained from the MPI Research stock colony (8–12 kg) were used as animal models.

[0146] Test article administration: Animals were fasted for at least 12 hours prior to dose administration and for the first 4 hours of blood sampling (food was returned within 30 minutes after the last blood sample was taken at each 4-hour sampling interval). There were 58 days separating the two dosing phases, Phases 1 and 2.

[0147] Capsule Administration: The pH of the dog stomach is a good surrogate for the fasted human stomach with pentagastrin pretreatment. To acidify the stomach, each animal received a single subcutaneous injection of pentagastrin (0.12 mg / mL) at a dose level of 0.006 mg / kg and a dose volume of 0.05 mL / kg approximately 30 minutes (± 5 minutes) prior to dose administration. Details of the preparation and use of pentagastrin are known in the art. Designated animals received a single capsule dose of the appropriate test article formulation, as outlined in Table 3. Subcutaneous Administration: Selected animals in Group 1 of Phase 2 received a single subcutaneous dose of 0.1 mg Sandostatin.

[0148] Blood collection: Blood samples (approximately 2 mL / sample) were collected from the jugular vein and placed into tubes containing K3EDTA. Collection times were pre-dose (0 hours) and approximately 0.083, 0.25, 0.5, 0.75, 1, 1.33, 1.67, 2, 2.5, 3, 4, and 5 hours (13 blood samples) for the SC group, and pre-dose (0 hours) and approximately 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5.5, 6.5, 7.5, and 9 hours (13 blood samples) for the orally delivered octreotide. All blood samples were placed on ice blocks (or wet ice) after collection. Samples were centrifuged and the resulting plasma was separated and divided into approximately two equal aliquots of 500 μl each. Each plasma sample was placed in a pre-chilled tube pre-loaded with 25 μL of aprotinin. Plasma samples were frozen at −60° C. to −90° C. in pre-labeled plastic vials within 1 hour after centrifugation.

[0149] Bioanalysis: Analysis of plasma samples was performed using an LC-MS / MS method to determine octreotide in dog serum.

[0150] Pharmacokinetic Analysis: The pharmacokinetic parameters of octreotide were calculated. The maximum plasma concentration (Cmax) and time to Cmax (Tmax) were directly derived from the data. The elimination rate constant, λz, and elimination half-life (t 1 / 2 ) was calculated using standard methods.

[0151] The area under the curve was calculated and the absorption lag time, Tlag, was taken directly from the data as the first time after the first sampling time at which the concentration was ≥ LOQ. If the concentration was ≥ LOQ at the first sampling time, no lag time was estimated.

[0152] The bioavailability F of each oral treatment compared to the SC treatment was calculated as AUC(inf).

[0153] Pharmacokinetics

[0154] The small number of animals per experimental group resulted in very high variability, which made it difficult to show statistically significant differences between treatments. Nevertheless, it is possible to point to differences in Tlag and Tmax between Mycapssa and all other experimental groups. Compared to the other experimental groups, which had median Tlags ranging from 1.76 to 2-2.74, and smaller Tlag ranges within each group, Mycapssa had a much shorter and more variable Tlag (median 0.51 hours and range 0.50-3.48 hours).

[0155] Compared to the control formulation (Mycapssa), which had a median Tmax of 1.76 hours, the medians were slightly longer for all groups, ranging from 2.02 to 3.50 hours. Formulation F1C4P1 (OCT-CCP-011) was approximately twice as long as Mycapssa, at 3.50 hours. As with the lag times, there was an overlap between ranges for oral procedures.

[0156] The mean values ​​of Cmax, AUC(0-t), and AUC(inf) of group 3 (F1C3P1=OCT-CCP-0012, also referred to as NC04) in Phase 1 were the highest compared to the control and all other oral formulations. The formulation of group 2 in Phase 1 (F1C2P1-OCT-CCP-010, also referred to as NC02) had results between the control and NC04 formulations.

[0157] The Phase 1 arm 4 (F1C4P1-OCT-CCP-011) had lower Cmax, AUC(0-t), and AUC(inf) values ​​than the control (Mycapssa).

[0158] Although variability precluded a clear ranking, the overall rank order of bioavailability from test and control formulations based on AUC(0-t) was F1C3P1 ((NC04)>F1C2P1>F1C1P1 (control)>F1C4P1, F1C5P1>F3C2P1>F2C2P1.

[0159] (Alternative Codes: OCT-CCP-0012 (NC04) > OCT-CCP-010 (NC02) > Mycapssa Control > OCT-CCP-011, OCT-CCP-016 > OCT-CCP-014 > OCT-CCP-013)

[0160] The best results were obtained with capsules coated with Mycapssa formulation F1C3P1 (OCT-CCP-0012) and the new coating NC04, which is a subcoat of OPADRY ambII white (first coating) and a topcoat of Eudragit L 30 D-55 (second coating). Also, good bioavailability was obtained from capsules coated with Mycapssa formulation along with NC02 (only Eudragit L 30 D-55 as coating). See Figure 3.

[0161] Effect of permeation enhancer type on bioavailability

[0162] The permeation enhancer used in the Mycapssa product is sodium caprylate (NaC8). In this study, sodium caprate (NaC 10 These experimental groups were coated with the enteric coat NC02 and therefore could be compared to Phase 1 Group 2, which had the same coating but with NaC8 as the permeation enhancer. 10 The use of NaC8 as an enhancer reduced bioavailability compared to formulations containing NaC8. It should be noted that two coats, NC02 and NC04, when combined with NaC8 as a permeation enhancer, produced higher bioavailability than Mycapssa when tested in dogs. See above and Figure 3. This higher bioavailability could not be predicted based on the dissolution profile in buffer conditions (pH 6.8). This is because the octreotide dissolution rate was not modulated by pH 6.8 and therefore there was not much difference between the profiles of Mycapssa, NC02, and NC04 (Phase 1 Groups 1, 2, and 3). The experimental coats NC03 and NC05 were designed to dissolve at a higher pH than NC02 and NC04. Therefore, their dissolution profiles were clearly different from Mycapssa, NC02, and NC04 groups. NC05 dissolved very slowly at pH 6.8, whereas NC03 did not dissolve at all at pH 6.8, and its drug release profile at pH 7.2 was slower than all other coats. These differences in drug release profile resulted in longer Tlag and Tmax compared to NC02, NC03, and Mycapssa. Another effect was lower bioavailability compared to NC02 and NC04. [Table 6]

[0163] conclusion This study evaluated the bioavailability of different enteric coatings that are more acid stable at higher pH (up to pH 4.5). Although the high variability in absorption in dogs does not allow a clear ranking, it can be said that the six test formulations had longer lag times and median Tmax compared to the control, although there was overlap between the ranges of all seven oral formulations.

[0164] Bioavailability was higher than that of NaC in formulations containing NaC8. 10 was found to be higher than

[0165] Based on AUC(0-t), the general rank order of bioavailability of the various enteric coats was NC04>NC02>Acryl-EZE(Mycapssa)>NC05>NC03. The bioavailability estimates for the Phase 1 Group 3 (NC04) were substantially greater than the control and other treatment groups (approximately a two-fold increase in bioavailability compared to Mycapssa), and NC02 also had a significant increase in bioavailability compared to Mycapssa. See Table 4. Therefore, it is envisioned that both the NC02 and NC04 coatings will be further evaluated to create oral dosage forms with improved bioavailability, referred to as second generation capsules.

[0166] Example 3: Preparation of 30 mg Octreotide Capsules with a New Coating Example 2 supra describes a second generation 20 mg octreotide capsule with a new improved coating (NC04) that is acid stable up to pH 4.5, which exhibited approximately two-fold improved bioavailability compared to Mycapssa capsules.

[0167] Based on the coating of these 20 mg capsules, it was decided to develop a 30 mg capsule with the same coating (NC04) as described in this example for indications requiring higher dosages of octreotide.

[0168] Five prototypes were prepared at a 30 mg dose as specified in Table 5 with the goal of establishing bioavailability similar to that of the 20 mg capsule containing the NC04 coating. [Table 7]

[0169] The manufacturing flow chart of the 30 mg octreotide prototype capsule is shown in FIG. 4, the composition of the HFC hydrophilic fraction is shown in Table 6, and the composition of the OS-oil suspension is shown in Table 7. [Table 8] [Table 9]

[0170] Filling of OS into size 0 hard gelatin capsules Size 0 hard gelatin capsules (HGC) were manually filled with OS at a target fill weight of 600.0 mg ± 2.5%. In-process weight checks were used to verify filling accuracy at predetermined intervals.

[0171] Gelatin capsule banding A banding solution containing gelatin powder (22%), polysorbate 80 (1.3%), and irrigation water (76.7%) was prepared at a temperature of 50-55°C. After preparation of the banding solution, it was equilibrated at low mixing speed to reduce the amount of air bubbles in the solution. The banding was then applied onto the capsules at 43°C ± 2°C. All banded capsules were subjected to a leakage test under vacuum. Only capsules that passed the leakage test proceeded to the coating stage.

[0172] New Coating The new coating formulation with the highest bioavailability (designated NC04) consists of a three-layer film coat.

[0173] Subcoat (first coating) - OPADRY ambII White

[0174] OPADRY ambII white is a polyvinyl alcohol (PVA)-based high performance moisture barrier film coating originally developed for coating oral solid dosage forms that require protection from environmental moisture.

[0175] In these capsules, OPADRY amb II white is used as a subcoat to optimize adhesion of the enteric film to the hard gelatin capsule (HGC).

[0176] The results presented herein show an increase in AUC with this subcoat. Without wishing to be bound by theory, it is suggested that the PVA subcoat acts as a moisture barrier and maintains the required moisture barrier level in the capsule shell. The purpose of the moisture barrier is to prevent the gelatin capsule shell from drying out, i.e., losing moisture, which should be about 13% so that the capsule does not become brittle. Normally, PVA is used to exclude moisture (especially for tablets), but in the present invention, without wishing to be bound by theory, PVA is used to retain moisture.

[0177] Enteric Coat (Second Coating) – Eudragit L 30 D-55 Eudragit L 30 D-55 is an aqueous dispersion of an anionic polymer with methacrylic acid as the functional group. It is an effective and stable enteric coating.

[0178] Top coat (third coating) – talc

[0179] Talc is employed as an anti-adherent agent to prevent sticking during storage in bulk of the capsules.

[0180] In vitro experiments were performed with different capsules. The best BA results in dogs were obtained with capsule OCT-CCP-035, so the in vitro results of this capsule are shown in FIG. 5.

[0181] Figure 5 shows the dissolution of batch OCT-CCP-035 at pH 6.8. It shows that the release at the buffer stage (phosphate buffer, pH 6.8) met specifications (>75% at 45 minutes). The average API release was 111% at 45 minutes. (As dissolution results of >100% were observed, this issue was investigated and found to be due to changes made in the sample preparation step of the method that resulted in higher than accurate peak areas.)

[0182] Dissolution performance of batch OCT-CCP-035 at acid step pH 4.5 shows acid resistance of 6 / 6 capsules after 120 minutes. The new coating remains on the capsules at pH=4.5. For Mycapssa, the coating comes off the capsules at pH=3.5 and the capsules dissolve.

[0183] Dissolution performance of Mycapssa capsules in acidic stage (citrate buffer, pH 1.2) showed leakage from 1 / 6 capsules after 120 min (maximum 3.2% API release). API release was in accordance with the standard (<10% at 120 min).

[0184] Dissolution test results for Mycapssa capsules in acidic stage (citrate buffer, pH 4.5) showed leakage from 6 / 6 capsules after 60 minutes. API release did not comply with criteria (<10% at 120 minutes).

[0185] Dissolution performance of Mycapssa capsules at pH 6.8 (phosphate buffer, pH 6.8) showed API release according to the standard (>75% at 45 min). Mean API release was 103% at 45 min. Two-stage dissolution = 2 hours in acid medium followed by 45 minutes in neutral buffer. For Mycapssa, 2 hours in acid medium at pH 1 followed by 45 minutes in buffer at pH 6.8. For 30 mg octreotide in new coating (NC04), 2 hours in acid medium at pH 4.5 followed by 45 minutes in buffer at pH 6.8. Dissolution of Mycapssa in buffer is the same as 30 mg octreotide in new coating (NC02) despite the different acid exposure.

[0186] The relative bioavailability of octreotide in capsules when administered with pentagastrin to male beagle dogs is compared in Table 8. Formulation CHIP4F4C3P1 had the highest relative bioavailability of 125% and 124% when administered as 30 mg (Phase 1) and 60 mg (Phase 2) doses, respectively. Formulation CHIP4F5C3P1, which contained a lower amount of GTC, had the next highest bioavailability of 94%, and formulations CHIP4F4C3P4 and CHIP4F4C3P2, which contained sieved HF and spray-dried HF, respectively, had the lowest bioavailability of 80% and 71%, respectively. [Table 10]

[0187] Example 4: Preparation and testing of terlipressin capsules

[0188] Terlipressin (also known as triglycyllysine vasopressin) is a synthetic analog of the neuropeptide hormone vasopressin and a prodrug of 8-lysine vasopressin (LVP). Terlipressin is administered by intravenous (iv) infusion or bolus in the hospital to treat acute bleeding of esophageal varices that develop in people with portal hypertension due to cirrhosis, and also in hepatorenal syndrome types 1 and 2, and ascites that may be cirrhotic or severe cirrhotic ascites.

[0189] An oral terlipressin (TP) capsule is presented based on the formulation developed for 30 mg octreotide NC04 (Example 3). The study evaluated the pharmacokinetic parameters in dogs of terlipressin administered by IV bolus injection (2 ascending doses) and oral capsule (2 ascending doses). This example describes the manufacture and characteristics of the terlipressin capsule prototype used in the dog PK study, as well as the results of that study.

[0190] Three prototypes were prepared that differed in their dosage strength (2 mg or 10 mg) and the amount and type of PVP used (PVP-12 or PVP K-30), and the amount of PVP in the formulation was adjusted to result in the same total formulation viscosity.) The amounts of other ingredients (sodium caprylate, magnesium chloride, polysorbate 80, glyceryl monocaprylate, and glyceryl tricaprylate) were essentially the same as in Mycapssa (Example 1).

[0191] manufacturing process

[0192] The manufacturing flow chart for terlipressin capsules is illustrated in FIG.

[0193] Preparation of Crude Hydrophilic Fraction and Hydrophilic Fraction (HF - also called Hydrophobic Medium)

[0194] Terlipressin acetate, PVP-12 or PVP-30, and MgCl2 were dissolved in water to form a HF-SA solution. Separately, sodium caprylate was dissolved in water to form a HF-SC solution. After achieving a clear solution, the HF-SA and HF-SC solutions were combined with mixing (HF-SA was added to HF-SC) until an off-white suspension was achieved. The suspension was then freeze-dried. After freeze-drying, the dried HFC was sieved through a 100 mesh (150 μm) screen to form the HF.

[0195] Preparation of lipophilic fraction (LF)

[0196] Glycerol monocaprylate (GMC) was melted in an oven at 55° C. LF was prepared by mixing GMC with polysorbate 80 and glycerol tricaprylate (GTC) in a glass beaker at room temperature.

[0197] Preparation of oil suspension (OS)

[0198] The HF was added to the LF with continuous stirring, followed by high shear mixing.

[0199] Filling of OS into size 0 hard gelatin capsules

[0200] Size 0 hard gelatin capsules were manually filled with OS using an Eppendorf pipette at a target fill weight of 600.0 mg ± 2.5%.

[0201] Gelatin capsule banding

[0202] A banding solution containing gelatin powder (22%), polysorbate 80 (1.3%), and irrigation water (76.7%) was prepared at a temperature of 50-55°C. After preparation of the banding solution, it was equilibrated at low mixing speed to reduce the amount of air bubbles in the solution. The banding was then applied onto the capsules at 43°C ± 2°C. All banded capsules were subjected to a leakage test. Only capsules that passed the leakage test proceeded to the coating stage.

[0203] Preparation of coating prototypes

[0204] Three coating layers were applied to each prototype. OPADRY ambII white was applied as the subcoat (first coating), followed by Eudragit L 30 D-55 as the topcoat (second coating) and talc as the third coat (third coating). The dry coating formulations for these three batches are shown in Table 9. The coating in Table 9 is the NC04 coating.

[0205] Alternatively, it should be noted that terlipressin capsules can be prepared as described above, but with a coating of Eudragit only (NC02). The capsules are manufactured as described above, and the coatings are applied as described above, but without the coating of OPADRY amb II white (first coating). [Table 11]

[0206] The results of final product testing of the prototype PK study are shown in Table 10, and the composition of the capsules produced is shown in Table 11. [Table 12] [Table 13]

[0207] Dissolution test results

[0208] A two-stage (sequential) dissolution method was used, with the pass criterion for the acid stage being "no individual capsules more than 10% dissolved in 2 hours" and for the buffer stage a Q value of 75% was set at 45 minutes.

[0209] The dissolution performance at pH 6.8 of the terlipressin prototype used in the PK study is shown in FIG.

[0210] Container 2 of the TP-CCP-002 batch showed outlier results (2440% release in 30 minutes) and was therefore excluded from the dissolution profile results. Capsules placed in container 5 did not exhibit acid resistance (40.8% release in 120 minutes) and were therefore excluded from the dissolution profile results.

[0211] Melting results:

[0212] Dissolution performance of batch TP-CCP-001 in acidic stage (pH 4.5) showed acid resistance in 6 / 6 capsules after 120 minutes.

[0213] Dissolution performance of batch TP-CCP-001 at pH 6.8 showed API release in the buffer stage (phosphate buffer, pH 6.8) according to the criteria (≧75% at 45 min). The average API release was 87% at 45 min.

[0214] Dissolution performance of batch TP-CCP-002 in acidic stage (pH 4.5) showed acid resistance of 5 / 6 capsules after 120 minutes.

[0215] Dissolution performance of batch TP-CCP-002 at pH 6.8 (phosphate buffer) showed API release according to the criteria (>75% at 45 min). The average API release was 96% at 45 min.

[0216] The dissolution performance of batch TP-CCP-003 in the acid stage (pH 4.5) showed an acid resistance of 6 / 6 capsules after 120 minutes.

[0217] Dissolution performance of batch TP-CCP-003 at pH 6.8 (phosphate buffer) showed lower release than expected for a modified release product following ICH guidelines (>75% at 45 min). The mean API release was 72% at 45 min.

[0218] PK study of terlipressin capsules in dogs

[0219] A dog PK study with terlipressin capsules was performed essentially as described in Example 2, with the main differences being:

[0220] Test article administration: Animals were fasted for at least 12 hours prior to dose administration and for the first 4 hours of blood sampling (food was returned within 30 minutes after the last blood sample was taken at each 4-hour sampling interval).

[0221] Dosing of the animals was carried out in phases 1 and 2. There were 7 days separating the two dosing phases.

[0222] Intravenous administration: Animals in Phase 1 (Groups 1 and 2) received a single intravenous dose of glypressin at 0.04 mg or 0.2 mg terlipressin base (0.24 mL / animal or 1.2 mL / animal, respectively). Dose administration was by slow injection over 1 minute via the cephalic vein using a catheter.

[0223] Capsule Administration: Each animal received a single subcutaneous injection of pentagastrin (0.12 mg / mL) at a dose level of 0.006 mg / kg and a dose volume of 0.05 mL / kg approximately 30 minutes (± 5 minutes) prior to dose administration to acidify the stomach. Designated animals were administered one or two capsules of the appropriate test article formulation as outlined above.

[0224] Blood Collection: Blood samples (approximately 3 mL / sample) were collected from the jugular vein at the following time points:

[0225] Intravenous: Pre-dose, 0.083 hours, 0.166 hours, 0.33 hours, 0.66 hours, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, and 9 hours after administration.

[0226] Oral capsules: Pre-dose, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5.5 hours, 6.5 hours, 7.5 hours, 9 hours, and 12 hours after dose.

[0227] Blood samples were placed into tubes containing K2EDTA. Samples were centrifuged under refrigerated (2-8°C) conditions within 30 minutes of sample collection, and the resulting plasma was separated and divided into approximately two equal aliquots. Each plasma sample was placed in a pre-chilled tube on dry ice until frozen at -60°C to -90°C. Bioanalysis was performed for plasma concentrations of both terlipressin and LVP.

[0228] Bioanalysis of plasma samples was performed using an LC-MS / MS method for the quantification of terlipressin and [Lys8]-vasopressin in dog plasma.

[0229] Pharmacokinetic analysis was performed essentially as described in Example 2.

[0230] result

[0231] Phase 1. [Table 14]

[0232] As shown in Table 12, there was a dose-dependent increase in the arithmetic mean plasma concentrations of terlipressin after intravenous administration of terlipressin at doses of 0.04 mg and 0.2 mg. The arithmetic mean values ​​of Cmax, AUC(0-t), and AUC(inf) increased approximately 5-fold, consistent with the 5-fold higher dose. Plasma concentrations could be followed for 0.67 hours at the lower dose and 1.5 hours at the higher dose. Thus, the data after administration of the 0.2 mg dose should be considered more representative of the PK of terlipressin in beagle dogs. Arithmetic mean t 1 / 2 was 0.074 hours for the 0.04 mg cohort and 0.232 hours for the 0.2 mg cohort (Table 10C). This difference is most likely due to concentrations ≧LOQ for the higher dose groups for a longer period of time.

[0233] The arithmetic mean plasma concentrations of LVP also increased in a dose-dependent manner, but the increase in Cmax (3.9-fold) and both AUCs (3.7-fold) was less than with a 5-fold dose increase. 1 / 2 were essentially the same for both doses, 0.65 h and 0.68 h, and 0.04 mg and 0.2 mg, respectively. Phase 2 [Table 15]

[0234] As shown in Table 13, after oral administration of a 2 mg capsule (Group 1), plasma terlipressin was undetectable in many dogs and the number of dogs with concentrations ≧LOQ was too small (≦3) to perform PK analysis.

[0235] Both Groups 2 and 3 received the two 10 mg terlipressin capsules. The only difference between the two capsule formulations was the use of PVP-12 in formulation TP-02 and PVP-K30 in formulation TP-03. The arithmetic mean plasma terlipressin concentrations in Group 2 (TP-02) were higher than those in Group 3 (TP-03). Group 2 animals had approximately 2-fold higher arithmetic mean Cmax, AUC(0-t), and AUC(inf) than Group 3 animals. Median and range of Tlag and Tmax were comparable for both 10 mg doses. Based on the AUC(inf) of these groups and the AUC(inf) of Group 2 (0.2 mg IV) in Phase 1, bioavailability was higher in Group 2 than in Group 3.

[0236] Plasma LVP concentrations were detectable for all three groups, but the arithmetic mean concentrations after the 2 mg dose (Group 1) were substantially lower than the two groups receiving the 20 mg dose (Group 2-TP-02, Group 3-TP-03). The increases in arithmetic mean Cmax, AUC(0-t), and AUC(inf) between the 2 mg dose and either 20 mg dose were significantly more than proportional to dose. Median and ranges of Tlag and Tmax were similar for both 20 mg doses. Although the dose was the same 20 mg, exposure to LVP from the TP-02 formulation was >5-fold higher than exposure from the TP-03 formulation.

[0237] The bioavailability was highest for TP-02, followed by TP-03 and then TP-01.

[0238] conclusion

[0239] The sensitivity of the bioanalytical methods for terlipressin and LVP appears adequate for the determination of plasma concentrations after intravenous and oral doses as low as 0.04 mg and 20 mg, respectively.

[0240] The PK of terlipressin and LVP appears to be linear following intravenous administration of 0.04 mg and 0.2 mg doses.

[0241] The plasma concentration of terlipressin after oral administration of 2 mg was <LOQ in most of the samples, and PK could not be determined. Therefore, linearity after oral administration could not be evaluated. Two oral 20 mg doses (2 × 10 mg capsules), namely TP-02 and TP-03, resulted in different degrees of exposure, and the bioavailability of terlipressin in TP-02 was higher than that in TP-03.

[0242] The PK of LVP could be determined for both the 2 mg formulation and the 20 mg formulation. The increase in the arithmetic mean Cmax, AUC(0-t), and AUC(inf) between the 2 mg formulation and either of the 20 mg formulations was much greater than proportional to the dose, suggesting non-linear absorption. The bioavailability of LVP was highest for TP-02, followed by TP-03.

[0243] A clear advantage was shown by the formulation containing PVP-12 compared to the formulation containing PVP-K30.

[0244] Example 5: Description of the prepared octreotide capsules and terlipressin capsules

[0245] The components of a single octreotide capsule and a single terlipressin capsule prepared with a combination of improved coatings are shown in Table 14.

Table 16

[0246] Note: Alternatively, the capsules can be prepared as described above, but without the first coating (i.e., without OPADRY amb II). This results in capsules coated only with Eudragit 30 D-55 (and TEC), and then talc is applied on top of that coating. Embodiment 1. An oral dosage form comprising a capsule containing a therapeutic agent, the capsule comprising a first coating comprising polyvinyl alcohol and further comprising a second coating over the first coating comprising a methacrylic acid-ethyl acrylate copolymer dispersion (commonly referred to as Eudragit L100). 2. The oral dosage form of embodiment 1, wherein the dispersion is in the range of 1.4:1 to 1:1.4 methacrylic acid-ethyl acrylate copolymer. 3. The oral dosage form of embodiment 2, wherein the dispersion is in the range of 1.2:1 to 1:1.2 methacrylic acid-ethyl acrylate copolymer. 4. The oral dosage form of embodiment 1, wherein the dispersion is a 1:1 methacrylic acid-ethyl acrylate copolymer. 5. The oral dosage form of embodiment 1, wherein the polyvinyl alcohol is partially hydrolyzed. 6. The oral dosage form of embodiment 1, wherein the polyvinyl alcohol has a molecular weight of 20,000 to 35,000, preferably 26,300 to 30,000. 7. The oral dosage form of embodiment 1, wherein the methacrylic acid-ethyl acrylate copolymer has a molecular weight between 30,000 and 40,000, preferably about 34,000. 8. The oral dosage form of embodiment 1, further comprising a third coating over the second coating comprising talc. 9. The oral dosage form of embodiment 1, wherein the capsule is made of gelatin, e.g. a hard gelatin capsule or HPMC. 10. The oral dosage form of embodiment 1, wherein the second coating further comprises sodium lauryl sulfate and polysorbate 80. 11. The oral dosage form of embodiment 1, wherein the second coating does not contain sodium bicarbonate. 12. The oral dosage form of embodiment 1, wherein the second coating does not include titanium dioxide. 13. The oral dosage form of embodiment 1, wherein the first coating further comprises talc, glycerol monocaprylocaprate type 1, and sodium lauryl sulfate. 14. The oral dosage form of embodiment 13, wherein the second coating comprises sodium lauryl sulfate and polysorbate 80. 15. The oral dosage form of embodiment 1, wherein the therapeutic agent is a polypeptide. 16. The oral dosage form of embodiment 14, wherein the therapeutic agent is a polypeptide. 17. The oral dosage form of embodiment 15, wherein the polypeptide is terlipressin or an analog thereof, or octreotide or an analog thereof. 18. The oral dosage form of embodiment 16, wherein the polypeptide is terlipressin or an analog thereof, or octreotide or an analog thereof. 19. The oral dosage form of embodiment 15, wherein the polypeptide is terlipressin or a salt thereof. 20. The oral dosage form of embodiment 15, wherein the polypeptide is octreotide or a salt thereof. 21. The oral dosage form of embodiment 15, wherein the oral dosage form is a gelatin capsule. 22. The oral dosage form of embodiment 21, wherein the oral dosage form is a hard gelatin capsule. 23. The oral dosage form of embodiment 19, wherein terlipressin is present in an amount of 5 to 50 mg, preferably 10 mg, or 20 mg, or 30 mg per capsule. 24. The oral dosage form according to embodiment 20, wherein octreotide is present in an amount of 5 to 50 mg, preferably 10 mg, or 20 mg, or 30 mg per capsule. 25. A method for treating a subject suffering from hypotension, or portal hypertension, or variceal bleeding, or hepatorenal syndrome, or ascites (particularly severe cirrhotic ascites), or a combination thereof, comprising administering to the subject a therapeutically effective amount of the oral dosage form of embodiment 19. 26. A method for treating a subject suffering from acromegaly or a neuroendocrine tumor, comprising administering to the subject a therapeutically effective amount of the oral dosage form of embodiment 20. 27. A method for treating a subject suffering from symptoms of a neuroendocrine tumor, such as diarrhea and / or flushing, comprising administering to the subject a therapeutically effective amount of the oral dosage form of embodiment 20. 28. The oral dosage form of any one of embodiments 1 to 5, wherein the first coating comprises 40-80% polyvinyl alcohol, 20-55% talc, 1-20% glycerol monocaprylate, and 1-5% sodium lauryl sulfate, and the second coating comprises 80-99.0% methacrylic acid-ethyl acrylate copolymer, 0.1%-2% sodium lauryl sulfate, and 0.5-4% polysorbate, and further comprises triethyl citrate. 29. The oral dosage form of any one of embodiments 1 to 5, wherein the first coating comprises 50-60% polyvinyl alcohol, 30-40% talc, 4-10% glycerol monocaprylate, and 2-4% sodium lauryl sulfate, and the second coating comprises 90-99.0% methacrylic acid-ethyl acrylate copolymer, 0.3%-1% sodium lauryl sulfate, and 1-3% polysorbate, and further comprises triethyl citrate. 30. The oral dosage form of any one of embodiments 1 to 5, wherein the capsule coating comprises 57.0% polyvinyl alcohol, 34.0% talc, 6% glycerol monocaprylate, and 3% sodium lauryl sulfate as a first coating, and the second coating comprises 97.0% methacrylic acid-ethyl acrylate copolymer, 0.7% sodium lauryl sulfate, and 2.3% polysorbate, and further comprises triethyl citrate. 31. The oral dosage form of embodiments 28-30, wherein triethyl citrate is present in an amount of 5-30% of the second coating. 32. The oral dosage form according to embodiments 28-30, wherein triethyl citrate is present in an amount of 10-20% of the second coating, preferably about 17% of the second coating, and most preferably 16.9% (8 mg per capsule). 33. The oral dosage form of embodiments 28-32, further comprising a third coating. 34. The oral dosage form of embodiment 33, wherein the third coating is talc. 35. The oral dosage form of embodiment 34, wherein the talc is present in an amount of 0.1 to 3 mg per capsule, preferably 0.5 to 2 mg per capsule, and most preferably 1 mg per capsule. 36. A method for producing an enteric coated capsule containing a therapeutic agent, comprising applying a first coating to the capsule comprising polyvinyl alcohol, talc, glycerol monocaprylate, and sodium lauryl sulfate, and further applying a second coating over the first coating, the second coating comprising a methacrylic acid-ethyl acrylate copolymer dispersion, sodium lauryl sulfate, polysorbate, and triethyl citrate. 37. The method of embodiment 36, further comprising applying a third coating over the second coating, the third coating being talc. 38. The method of embodiment 36, wherein the therapeutic agent is a polypeptide. 39. The method of embodiment 38, wherein the polypeptide is terlipressin or octreotide. 40. An oral dosage form comprising a capsule or tablet or sachet containing pellets containing a therapeutic agent, the pellets comprising a first coating comprising polyvinyl alcohol and further comprising a second coating over the first coating comprising a methacrylic acid-ethyl acrylate copolymer dispersion (commonly referred to as Eudragit L100). 41. The oral dosage form of embodiment 40, wherein the therapeutic agent is a polypeptide. 42. The oral dosage form of embodiment 41, wherein the polypeptide is octreotide or terlipressin. 43. The oral dosage form of embodiment 40, wherein the pellet comprises a medium chain fatty acid salt and polyvinylpyrrolidone (PVP). 44. An oral dosage form comprising a capsule containing a formulation comprising a therapeutic agent, the capsule being made of hydroxypropyl methylcellulose (HPMC) or hydroxypropyl cellulose (HPC). or a first coating comprising shellac, and further comprising a second coating over the first coating comprising the methacrylic acid-ethyl acrylate copolymer dispersion. 45. The oral dosage form of embodiment 44, wherein the therapeutic agent is a polypeptide. 46. ​​The oral dosage form of embodiment 45, wherein the polypeptide is octreotide or terlipressin. 47. The oral dosage form of embodiment 44, wherein the formulation comprises a medium chain fatty acid salt and polyvinylpyrrolidone (PVP). 48. The oral dosage form of embodiment 44, further comprising a third coating. 49. The oral dosage form of embodiment 48, wherein the third coating is talc. 50. A method of treating a subject comprising administering to the subject any one of the oral dosage forms of embodiments 1-26, 28-35, or 40-49, wherein the dosage is administered once, twice, or three times daily. 51. A method of treatment according to embodiment 50, wherein administration is performed at least 1 hour before a meal or at least 2 hours after a meal. 52. The method of treatment according to embodiment 50, wherein administration is performed on an empty stomach. 53. An oral dosage form comprising a capsule containing a suspension comprising an admixture of a hydrophobic oily medium and a solid form, wherein the solid form comprises a therapeutically effective amount of a polypeptide, at least one salt of a medium chain fatty acid in an amount of at least 10% by weight, and polyvinylpyrrolidone (PVP) in an amount of at least 3% by weight or more, and the capsule comprises a coating comprising a methacrylic acid-ethyl acrylate copolymer dispersion (commonly referred to as Eudragit L100). 54. The oral dosage form of embodiment 53, wherein the dispersion is in the range of 1.4:1 to 1:1.4 methacrylic acid-ethyl acrylate copolymer. 55. The oral dosage form of embodiment 53, wherein the dispersion is in the range of 1.2:1 to 1:1.2 methacrylic acid-ethyl acrylate copolymer. 56. The oral dosage form of embodiment 53, wherein the dispersion is a 1:1 methacrylic acid:ethyl acrylate copolymer. 57. The oral dosage form of embodiment 53, wherein the methacrylic acid-ethyl acrylate copolymer has a molecular weight between 30,000 and 40,000, preferably about 34,000. 58. The oral dosage form of embodiment 53, further comprising another coating over the coating comprising talc. 59. The oral dosage form according to embodiment 53, wherein the capsule consists of gelatin, e.g. a hard gelatin capsule or HPMC. 60. The oral dosage form of embodiment 53, wherein the coating further comprises sodium lauryl sulfate and polysorbate 80. 61. The oral dosage form of embodiment 1, wherein the coating does not contain sodium bicarbonate. 62. The oral dosage form of embodiment 53, wherein the coating does not contain titanium dioxide. 63. The oral dosage form of embodiment 53, wherein the therapeutic agent is a polypeptide. 64. The oral dosage form of embodiment 60, wherein the therapeutic agent is a polypeptide. 65. The oral dosage form of embodiment 63, wherein the polypeptide is terlipressin or an analog thereof, or octreotide or an analog thereof. 66. The oral dosage form of embodiment 64, wherein the polypeptide is terlipressin or an analog thereof, or octreotide or an analog thereof. 67. The oral dosage form of embodiment 66, wherein the polypeptide is terlipressin or a salt thereof. 68. The oral dosage form of embodiment 66, wherein the polypeptide is octreotide or a salt thereof. 69. The oral dosage form of embodiment 60, wherein the oral dosage form is a gelatin capsule. 70. The oral dosage form of embodiment 69, wherein the oral dosage form is a hard gelatin capsule. 71. The oral dosage form according to embodiment 66, wherein terlipressin is present in an amount of 5 to 50 mg per capsule, preferably 10 mg, or 20 mg, or 30 mg per capsule. 72. The oral dosage form according to embodiment 68, wherein octreotide is present in an amount of 5 to 50 mg per capsule, preferably 10 mg, or 20 mg, or 30 mg per capsule. 73. A method for treating a subject suffering from hypotension, or portal hypertension, or variceal bleeding, or hepatorenal syndrome, or ascites (particularly severe cirrhotic ascites), or a combination thereof, comprising administering to the subject a therapeutically effective amount of the oral dosage form of embodiment 67. 74. A method for treating a subject suffering from acromegaly or a neuroendocrine tumor, comprising administering to the subject a therapeutically effective amount of an oral dosage form of embodiment 68. 75. A method for treating a subject suffering from a symptom of a neuroendocrine tumor, such as diarrhea and / or flushing, comprising administering to the subject a therapeutically effective amount of an oral dosage form of embodiment 68. 76. The oral dosage form of any one of embodiments 53 to 72, wherein the coating comprises 80-99.0% methacrylic acid-ethyl acrylate copolymer, 0.1%-2% sodium lauryl sulfate, and 0.5-4% polysorbate, and further comprises triethyl citrate. 77. The oral dosage form of any one of embodiments 1 to 5, wherein the coating comprises 90-99.0% methacrylic acid-ethyl acrylate copolymer, 0.3%-1% sodium lauryl sulfate, and 1-3% polysorbate, and further comprises triethyl citrate. 78. The oral dosage form of any one of embodiments 1 to 5, wherein the capsule coating comprises 97.0% methacrylic acid-ethyl acrylate copolymer, 0.7% sodium lauryl sulfate, and 2.3% polysorbate, and further comprises triethyl citrate. 79. The oral dosage form of embodiments 28-30, wherein triethyl citrate is present in an amount of 5-30% of the coating. 80. The oral dosage form according to embodiments 28-30, wherein triethyl citrate is present in an amount of 10-20% of the coating, preferably about 17% of the second, and most preferably 16.9% (8 mg per capsule). 81. The oral dosage form of embodiments 28-32, comprising an additional coating. 82. The oral dosage form of embodiment 33, wherein the additional coating is talc. 83. The oral dosage form of embodiment 34, wherein the talc is present in an amount of 0.1 to 3 mg per capsule, preferably 0.5 to 2 mg per capsule, and most preferably 1 mg per capsule. 84. A method for producing an enteric coated capsule containing a therapeutic agent, comprising applying a first coating to the capsule comprising polyvinyl alcohol, talc, glycerol monocaprylate, and sodium lauryl sulfate, and further applying a second coating over the first coating, the second coating comprising a methacrylic acid-ethyl acrylate copolymer dispersion, sodium lauryl sulfate, polysorbate, and triethyl citrate. 85. The method of embodiment 36, further comprising applying an additional coating over the coating, the additional coating being talc. 86. The method of embodiment 36, wherein the therapeutic agent is a polypeptide. 87. The method of embodiment 86, wherein the polypeptide is octreotide or terlipressin. 88. A method of treating a patient suffering from episodes of severe diarrhea and / or flushing associated with metastatic carcinoid tumors by administering to the patient any of the oral dosage forms described above, wherein the oral dosage form contains a therapeutically effective amount of octreotide. 89. The method of treatment of embodiment 88, wherein administration is performed at least 1 hour before a meal or at least 2 hours after a meal. 90. The method of treatment according to embodiment 88, wherein administration is performed on an empty stomach. 91. The method of treatment according to embodiment 88, wherein the administration is 10 to 80 mg per day. 92. The method of treatment of embodiment 88, wherein the administration is 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, or 80 mg per day.

Claims

1. 1. An oral dosage form comprising a capsule containing a therapeutic agent, the capsule being coated with a first coating comprising polyvinyl alcohol and a second coating over the first coating comprising a methacrylic acid-ethyl acrylate copolymer dispersion.

2. 2. The oral dosage form of claim 1, wherein the ratio of methacrylic acid to ethyl acrylate in the dispersion is from 1.4:1 to 1:1.

4.

3. 10. The oral dosage form of claim 1, wherein the polyvinyl alcohol is partially hydrolyzed.

4. 10. The oral dosage form of claim 1, wherein the polyvinyl alcohol has an average molecular weight between 20,000 and 35,000 Da.

5. 2. The oral dosage form of claim 1, wherein the methacrylic acid / ethyl acrylate copolymer has an average molecular weight between 30,000 and 40,000 Da.

6. 10. The oral dosage form of claim 1, further comprising a third coating over the second coating, the third coating comprising talc.

7. 2. The oral dosage form of claim 1, wherein the capsule is comprised of i) gelatin or ii) HPMC.

8. 10. The oral dosage form of claim 1, wherein the second coating further comprises sodium lauryl sulfate and polysorbate 80.

9. 10. The oral dosage form of claim 1, wherein the second coating does not contain sodium bicarbonate or titanium dioxide.

10. 10. The oral dosage form of claim 1, wherein the first coating further comprises talc, glycerol monocaprylocaprate type 1, and sodium lauryl sulfate.

11. 10. The oral dosage form of claim 1, wherein the second coating comprises sodium lauryl sulfate and polysorbate 80.

12. The oral dosage form of claim 1 , wherein the therapeutic agent is a polypeptide.

13. 13. The oral dosage form of claim 12, wherein the polypeptide is octreotide or a salt thereof.

14. 14. The oral dosage form of claim 13, wherein the oral dosage form comprises 5 to 50 mg of octreotide.

15. 15. The oral dosage form of any one of claims 1 to 14, wherein the first coating comprises 40 to 80% (wt%) polyvinyl alcohol, 20 to 55% (wt%) talc, 1 to 20% (wt%) glycerol monocaprylate, and 1 to 5% (wt%) sodium lauryl sulfate, and the second coating comprises 80 to 99.0% (wt%) methacrylic acid-ethyl acrylate copolymer, 0.1 to 2% (wt%) sodium lauryl sulfate, and 0.5 to 4% (wt%) polysorbate, and further comprises triethyl citrate.

16. 16. The oral dosage form of claim 15, wherein the second coating comprises 5 to 30% (by weight) triethyl citrate.

17. The oral dosage form of any one of claims 12 to 14, wherein the polypeptide is formulated in a suspension comprising an admixture of a hydrophobic medium and a solid form, An oral dosage form wherein the solid form comprises a therapeutically effective amount of the polypeptide, at least one salt of a medium chain fatty acid, and a matrix-forming polymer, wherein the matrix-forming polymer is present in the composition in an amount of 3% by weight or greater.

18. The oral dosage form of any one of claims 12 to 14, wherein the polypeptide is formulated in a suspension comprising an admixture of a hydrophobic medium and a solid form, An oral dosage form wherein said solid form comprises a therapeutically effective amount of said polypeptide and at least one salt of a medium chain fatty acid, wherein the medium chain fatty acid salt is preferably present in the composition in an amount of 10% by weight or greater.

19. 1. A method for producing an enteric coated capsule containing a therapeutic agent, comprising: applying a first coating to the capsule comprising polyvinyl alcohol, talc, glycerol monocaprylate, and sodium lauryl sulfate; applying a second coating over the first coating, the second coating comprising a methacrylic acid-ethyl acrylate copolymer dispersion, sodium lauryl sulfate, polysorbate, and triethyl citrate.

20. An oral dosage form comprising a capsule containing a suspension comprising an admixture of a hydrophobic oily medium and a solid form, wherein the solid form comprises a therapeutically effective amount of a polypeptide, at least one salt of a medium-chain fatty acid in an amount of at least 10% by weight, and polyvinylpyrrolidone (PVP) in an amount of at least 3% by weight, and the capsule is coated with a coating comprising a methacrylic acid-ethyl acrylate copolymer dispersion.

21. 21. The oral dosage form of claim 20, wherein the ratio of methacrylic acid to ethyl acrylate in the dispersion is from 1.4:1 to 1:1.

4.

22. 21. The oral dosage form of claim 20, wherein the methacrylic acid / ethyl acrylate copolymer has an average molecular weight between 30,000 and 40,000 Da.

23. 21. The oral dosage form of claim 20, wherein the coating further comprises sodium lauryl sulfate and polysorbate 80.

24. 24. The oral dosage form of any one of claims 20 to 23, wherein the polypeptide is terlipressin or an analog thereof, or octreotide or an analog thereof.

25. 25. The oral dosage form of claim 24, wherein the oral dosage form comprises 5 to 50 mg of octreotide.

Images