Oral dosage form and its use in the treatment of hyperoxaluria

Abstract

The present invention relates to an orally administrable pharmaceutical dosage form configured to target delivery to the distal portion of the gastrointestinal tract of a human subject, the pharmaceutical dosage form comprising lanthanum or a pharmaceutically acceptable salt or oxide thereof. The present invention further relates to a pharmaceutical dosage form used in the treatment of hyperoxaluria in a human subject, optionally wherein the hyperoxaluria is primary hyperoxaluria or secondary hyperoxaluria; and / or a pharmaceutical dosage form used in the treatment of one or more of nephrolithiasis, nephrocalcinosis or oxalosis in a human subject.

Description

Technical Field

[0001] The present invention relates, in a broad sense, to the field of medicine, and more precisely to the fields of nephrology and urology. In particular, the present invention relates to an orally administrable pharmaceutical dosage form, and its use for treating primary and secondary hyperoxaluria in a subject and / or its use for treating one or more of nephrolithiasis, nephrocalcinosis or oxalosis in a subject.

Background Art

[0002] Hyperoxaluria is a metabolic disorder in which the urinary oxalate concentration is significantly increased, caused by overproduction of oxalate in the liver due to a genetic defect, called primary hyperoxaluria, or due to excessive absorption of oxalate into the gastrointestinal tract (GI) followed by excretion into the urine, called secondary hyperoxaluria. Secondary hyperoxaluria is dietary, due to excessive intake of oxalate or oxalate precursors; enteric, due to chronic gastrointestinal disorders associated with malabsorption that make patients more prone to excessive absorption of oxalate, such as Crohn's disease (terminal ileitis) or short bowel syndrome as a result of bariatric surgery; or idiopathic, of unknown underlying cause. Kidney stones, the first sign of hyperoxaluria, are often painful and may require intervention. Severe hyperoxaluria in the case of enteric hyperoxaluria and primary hyperoxaluria can cause kidney damage (nephrocalcinosis), chronic kidney disease and end-stage renal disease, and can even be fatal.

[0003] Nephrolithiasis, also known as renal lithiasis or urolithiasis, is one of the most common renal urological diseases. According to recent estimates, the prevalence in the US population is 10.6% in men and 7.1% in women (Ziemba et al., 2017, Inv. Clin. Urol., 58, 299). Similar prevalences have been observed in Europe and Japan. 80% of all kidney stones are calcium oxalate (CaOx) stones. There has been no major progress in new potential medicines for the treatment of nephrolithiasis or nephrocalcinosis in the last 10 years.

[0004] Lanthanum carbonate is an intestinal phosphate adsorbent (e.g., Fosrenol, Shire Pharmaceuticals, Dublin, Ireland) and has been shown to reduce oxalate and CaOx crystaluria in a rat oxalate load (high dose) model. However, this finding was accompanied by a marked increase in phosphate excretion and a slight increase in calcium excretion (Robijn et al., 2013, J. Urol., 189(5):1960 - 1966). Therefore, use of lanthanum carbonate itself in patients with normal or slightly reduced renal function leads to phosphate depletion over time. Phosphate depletion has been shown to result in increased bone resorption, leading to serious side effects such as osteomalacia, fractures, and several severe extra - skeletal complications (Yvey et al., 1978, Adv Exp Med Biol, 193,373 - 380).

[0005] Recently, Allena Pharmaceuticals reported positive results in a clinical trial using the oral enzyme therapy reloxaliase in patients with enteric hyperoxaluria (EH), a more severe subset of secondary hyperoxaluria. In this study, the primary endpoint was achieved, with a mean 22.6% decrease in 24 - hour urinary oxalate excretion measured at weeks 1 to 4 in patients treated with reloxaliase, compared with a 9.7% decrease in the placebo group (least - squares mean treatment difference was - 14.3%, p = 0.004).

[0006] Furthermore, Alnylam Pharmaceuticals announced positive results in the Phase 3 trial of lumasiran (trade name Oxlumo). This RNAi drug is a double-stranded siRNA conjugated to N-acetyl-galactosamine that targets glycolic acid to promote its uptake into the liver and targets glycolate oxidase, which is involved in the production of large amounts of oxalate in the treatment of primary hyperoxaluria type 1. However, the use of lumasiran is limited to the treatment of primary hyperoxaluria type 1, the response is not optimal, and the cost of this treatment is considered to be particularly high.

[0007] Therefore, there is still a need in the art for additional and / or improved treatment options for the treatment of patients including the prevention of primary and secondary hyperoxaluria in patients and for the treatment of patients including the prevention of one or more of nephrolithiasis, nephrocalcinosis or oxalosis.

Summary of the Invention

Problems to be Solved by the Invention

[0008] As shown in Figure 1, the inventors have found the optimal site in the intestine where lanthanum release occurs and oxalate chelation is initiated, i.e., the distal part of the gastrointestinal tract including the ileum and colon, and have addressed one or more of the above-mentioned problems in the art by obtaining a combined effect of reducing hyperoxaluria without phosphate deficiency.

Means for Solving the Problems

[0009] Accordingly, a first aspect of the present invention relates to an orally administrable pharmaceutical dosage form configured to be targeted to the distal part of the gastrointestinal tract of a subject and containing lanthanum or a pharmaceutically acceptable salt or oxide thereof.

[0010] Preferably, a first aspect of the present invention is an orally administrable pharmaceutical dosage form comprising lanthanum or a pharmaceutically acceptable salt or oxide thereof, wherein the lanthanum or a pharmaceutically acceptable salt or oxide thereof is configured to be targeted to one or more of the ileum, cecum or colon of a human subject.

[0011] As shown in the Examples section, the pharmaceutical dosage form of the present invention enables the release of lanthanum and the chelation of oxalate only in the distal portion of the gastrointestinal tract, such as one or more of the ileum, cecum or colon, thereby reducing the absorption of oxalate in the distal gastrointestinal tract and lowering the urinary oxalate concentration. Furthermore, the pharmaceutical dosage form of the present invention enables the transfer of oxalate from the serum to the intestinal lumen by secretion. These effects are combined with the calcium channel blocking effect of lanthanum in the distal portion of the gastrointestinal tract, resulting in a significant reduction in urinary oxalate and a normal or slight decrease in urinary calcium concentration, thereby inhibiting the formation of calcium oxalate crystals and reducing kidney stones. Furthermore, the pharmaceutical dosage form of the present invention inhibits the interaction between lanthanum and phosphate in the proximal gastrointestinal tract, i.e., the duodenum and jejunum, thereby enabling the reabsorption of phosphate and preventing phosphate deficiency.

[0012] Accordingly, a further aspect relates to a pharmaceutical dosage form as taught herein for use in the treatment (including prevention) of hyperoxaluria in a subject, optionally wherein the hyperoxaluria is primary hyperoxaluria or secondary hyperoxaluria. Preferably, the subject is a human subject.

[0013] Yet another aspect relates to a pharmaceutical dosage form as taught herein for use in the treatment (including prevention) of one or more of nephrolithiasis, nephrocalcinosis or oxalosis in a subject, for example, one or more of nephrolithiasis, nephrocalcinosis or oxalosis caused by or associated with the formation of calcium oxalate in the subject. Preferably, the subject is a human subject.

[0014] According to related aspects, there is provided a method for treating one or more of hyperoxaluria, nephrolithiasis, nephrocalcinosis or oxalosis in a human subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical dosage form as defined herein. Preferably, the hyperoxaluria is primary hyperoxaluria or secondary hyperoxaluria.

[0015] Based on proof-of-concept studies, excellent results were obtained in 3 patients with primary oxaluria and 1 patient with secondary hyperoxaluria. After treating subjects, particularly human subjects, with the pharmaceutical dosage form of the present invention, the inventors found that: - Lanthanum is specifically released in the ileum and early colon; - Optimal gastrointestinal chelation of oxalate in the ileum and colon results in a significant decrease in urinary oxalate concentration, and further a normal or slightly decreased release of calcium into the urine, such that the urinary oxalate concentration is considered to be less than 0.50 mmol / L (44 mg / L), a concentration at which crystal formation does not occur when the calcium concentration is less than 4 mmol / L (160 mg / L), which is the case for 3 out of 4 patients with primary hyperoxaluria and the patient with secondary hyperoxaluria; - The urinary phosphate concentration is normal and stable, and the balance of phosphate is normal throughout the treatment period because the reabsorption of phosphate in the renal tubules is normal; - The urinary calcium concentration remains the same or slightly decreases throughout the treatment period; - There is no increase in calciuria, presumably due to calcium channel blockade by lanthanum in the gastrointestinal tract. were discovered.

[0016] The inventors have discovered that the pharmaceutical dosage form of the present invention prevents the formation of calcium oxalate crystals in the renal tubular fluid and urine of the kidney without causing a phosphate deficiency. Calcium oxalate crystals are the first important step in the formation of kidney stones and ultimately cause nephrolithiasis. Therefore, the pharmaceutical dosage form of the present invention is particularly advantageous for reducing hyperoxaluria associated with the deposition or stones of calcium oxalate, and further avoiding nephrolithiasis, nephrocalcinosis and oxalosis.

[0017] The above and other aspects and preferred embodiments of the present invention are described in the following sections and the appended claims. The subject matter of the appended claims is specifically incorporated herein.

Brief Description of the Drawings

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DETAILED DESCRIPTION OF THE INVENTION

[0019] As used herein, the singular forms "a", "an", and "the" include both singular and plural referents unless the context clearly dictates otherwise.

[0020] As used herein, the terms "comprising", "comprises", and "comprised of" are synonymous with "including", "includes", or "containing", "contains", are inclusive or open-ended and do not exclude additional members, elements or method steps not recited. These terms also include "consisting of" and "consisting essentially of".

[0021] The description of numerical ranges using endpoints includes not only the recited endpoints, but also all numbers and fractions included within each range.

[0022] As used herein, the term "about" when referring to a measurable value such as a parameter, quantity, duration, etc. means a variation from the specified value, particularly a variation of + / - 10% or less, preferably + / - 5% or less, more preferably + / - 1% or less, and even more preferably + / - 0.1% or less from the specified value, as long as such variation is appropriate in the disclosed invention. It should be understood that the value itself to which the modifier "about" refers is also specifically and preferably disclosed.

[0023] The term "one or more" such as one or more members of a group of members, while clear in itself, for further illustration, includes, inter alia, any one of the aforementioned members, or, for example, any two or more of the aforementioned members such as three or more, four or more, five or more, six or more, or seven or more of the aforementioned members, and references to all of the aforementioned members.

[0024] All documents cited herein are hereby incorporated by reference in their entirety.

[0025] Unless otherwise specified, all terms, including technical and scientific terms used in disclosing the present invention, have the meanings commonly understood by those skilled in the art to which the present invention pertains. Definitions of terms may be included as further guidance to better understand the teachings of the present invention.

[0026] Through extensive experimental tests, the inventors have found a pharmaceutical dosage form for treating one or more of hyperoxaluria, nephrolithiasis, nephrocalcinosis or oxalosis. This pharmaceutical dosage form enables the release of lanthanum in the distal part of the gastrointestinal tract, thereby avoiding the interaction between lanthanum and phosphate in the duodenum and jejunum, while oxalate is locally chelated in the form of lanthanum oxalate and calcium oxalate in the more distal part of the gastrointestinal tract. These chelation products are excreted via feces. As an overall result, oxalate absorption is significantly reduced and the renal burden is decreased, so that oxalateuria is decreased, calcium salturia is decreased or unchanged, thereby preventing the formation of calcium oxalate crystals. The phosphate balance remains unchanged since phosphate absorption in the proximal intestine is not impaired.

[0027] Accordingly, a first aspect of the present invention relates to an orally administrable pharmaceutical dosage form configured to be targeted to the distal part of the gastrointestinal tract of a subject and containing lanthanum or a pharmaceutically acceptable salt or oxide thereof.

[0028] Preferably, a first aspect of the present invention relates to an orally administrable pharmaceutical dosage form containing lanthanum or a pharmaceutically acceptable salt or oxide thereof, wherein the lanthanum or a pharmaceutically acceptable salt or oxide thereof is configured to be targeted (or specifically delivered) to one or more of the ileum, cecum and colon of a human subject.

[0029] The pharmaceutical dosage form taught herein is an orally administrable pharmaceutical dosage form, also referred to as an oral dosage form. Oral dosage forms have the advantages of high convenience, improved patient compliance with medication, relatively safe administration, and do not require a sterile preparation.

[0030] The expression "oral" or "orally administrable" refers to an administration route in which a substance or composition is configured to be ingested through the mouth.

[0031] An "orally administrable pharmaceutical dosage form" refers to a pharmaceutical dosage form configured to be ingested through the mouth.

[0032] The terms "pharmaceutical dosage form", "pharmaceutical unit dosage", or "dosage form" refer to a pharmaceutical product in a form that contains a specific mixture of one or more active ingredients and one or more inert components (e.g., excipients) in a specific configuration, is apportioned in a specific dosage, and is sold for use.

[0033] As used herein, the terms "pharmaceutical" or "pharmaceutically acceptable" are in accordance with the art and mean being compatible with the active ingredient and not being harmful to its recipient.

[0034] The terms "active ingredient" or "active component" can be used interchangeably and broadly refer to a compound or substance that produces a desired result when provided in an effective amount. The desired result can be therapeutic and / or prophylactic. Usually, the active ingredient achieves such a result through interaction with and / or modulation of living cells or organisms.

[0035] The term "effective" in the description of "active ingredient" or "active component" refers to being "pharmaceutically effective" and / or "physically effective".

[0036] In some embodiments, the pharmaceutical dosage form is configured for targeted delivery to the distal portion of the gastrointestinal tract of a subject.

[0037] As used herein, the terms "gastrointestinal tract", "GI tract", or "digestive tract" are used interchangeably and refer to the tube or passage of the digestive system that extends from the mouth to the anus. In humans and other animals, the GI tract includes all of the major organs of the digestive system, including the esophagus, stomach, small intestine, and large intestine.

[0038] The term "small intestine" or "small bowel" refers to the portion of the gastrointestinal tract that is located between the stomach and the large intestine and does not include the stomach and large intestine. The small intestine has three different regions: the duodenum, jejunum, and ileum.

[0039] The term "duodenum" refers to the first part of the small intestine. The length of the duodenum is usually about 20 - 25 cm. The duodenum receives chyme from the stomach along with pancreatic juice containing digestive enzymes and bile from the gallbladder.

[0040] The term "jejunum" refers to the middle part of the small intestine connecting the duodenum and the ileum. The length of the jejunum is usually about 2.5 meters. The jejunum contains circular folds, also called plicae circulares, and villi that increase the surface area.

[0041] The term "proximal small intestine" or "early small intestine" refers to the first and middle parts of the small intestine including the duodenum and the jejunum.

[0042] The term "ileum" refers to the last part of the small intestine. The length of the ileum is about 3 meters. The ileum contains villi similar to those in the jejunum.

[0043] The term "distal small intestine" or "late small intestine" refers to the last part of the small intestine including the ileum. The terms "ileum", "distal small intestine" or "late small intestine" are used interchangeably in this specification.

[0044] The terms "large intestine" or "large bowel" are used interchangeably and refer to the last part of the gastrointestinal tract. The large intestine is subdivided into the cecum, colon, rectum and anal canal.

[0045] The "cecum" refers to an intraperitoneal pouch connecting the ileum and the colon, especially the ascending colon. The cecum is separated from the ileum by the ileocecal valve (ICV) or Bauhin's valve. The cecum is separated from the colon by the cecocolic junction.

[0046] The term "colon" refers to the longest part of the large intestine. The colon includes four parts, namely the ascending colon, transverse colon, descending colon and sigmoid colon, and each part bends at the colonic flexures.

[0047] As used herein, the terms "early colon" or "proximal colon" refer to the ascending colon.

[0048] In embodiments of the things (e.g., pharmaceutical dosage forms), uses or methods taught herein, the distal portion of the gastrointestinal tract can be the ileum, cecum, colon or combinations thereof. In some embodiments, the distal portion of the gastrointestinal tract can be the ileum, colon or combinations thereof. In some embodiments, the distal portion of the gastrointestinal tract can be the ileum and colon. In some embodiments, the distal portion of the gastrointestinal tract can be the ileum, cecum, early colon or combinations thereof. In some embodiments, the distal portion of the gastrointestinal tract can be the ileum, early colon or combinations thereof. In some embodiments, the distal portion of the gastrointestinal tract can be the ileum, early colon or combinations thereof. In some embodiments, the distal portion of the gastrointestinal tract can be the ileum and early colon.

[0049] In some embodiments, the pharmaceutical dosage form may be configured for targeted delivery to the ileum, cecum and colon of a subject, particularly a human subject. In embodiments of the things, uses or methods taught herein, the pharmaceutical dosage form may be configured such that lanthanum or a pharmaceutically acceptable salt or oxide thereof is targeted to one or more of the ileum, cecum and colon of a subject, preferably a human subject. In embodiments of the things, uses or methods taught herein, the pharmaceutical dosage form may be configured such that lanthanum or a pharmaceutically acceptable salt or oxide thereof is targeted to one or more of the ileum, cecum and ascending colon of a subject, preferably a human subject. Specific delivery of lanthanum or a pharmaceutically acceptable salt or oxide thereof to one or more of the ileum, cecum and colon of a subject has the advantage that it can treat primary or secondary hyperoxaluria while avoiding the interaction of lanthanum with the phosphates of the duodenum and jejunum and avoiding undesirable phosphate deficiencies.

[0050] In some embodiments, the pharmaceutical dosage form may be configured for targeted delivery to the ileum and proximal colon of a subject.

[0051] In some embodiments, targeted delivery of lanthanum or a pharmaceutically acceptable salt or oxide thereof to one or more of the ileum, cecum or colon can be determined by imaging such as computerized tomography (CT) including X-ray imaging or ultra-low dose CT (ULDCT). As shown in the Examples section (Example 2), the targeted delivery of lanthanum can be readily verified by imaging (e.g., non-invasive X-ray imaging). For example, after oral ingestion of one or more pharmaceutical dosage forms according to embodiments of the present invention (e.g., capsules each containing 250 mg of elemental lanthanum), sequential images of the abdomen of a subject (e.g., a healthy volunteer or an affected subject) may be taken in the anteroposterior direction in an upright position. The images can be taken at 5, 10, 15, 20, 25, 30 minutes or 1 hour intervals over at least 360 minutes (6 hours). The pharmaceutical dosage forms taught herein can be seen as radiopaque structures on X-ray or CT images. As shown in the Examples section, the release of lanthanum carbonate from the pharmaceutical dosage forms taught herein is localized in the ileum, cecum and colon.

[0052] The term "targeted delivery" or "specific delivery" of lanthanum or a pharmaceutically acceptable salt or oxide thereof to one or more of the ileum, cecum or colon refers to the (substantially) exclusive delivery (or release) of lanthanum or a pharmaceutically acceptable salt or oxide thereof to one or more of the ileum, cecum or colon. Thus, the targeted delivery or specific delivery taught herein means that there is no (substantial) delivery (or release) of lanthanum or a pharmaceutically acceptable salt or oxide thereof to the outside of the ileum, cecum and colon. The targeted delivery or specific delivery taught herein means that there is no (substantial) delivery (or release) of lanthanum or a pharmaceutically acceptable salt or oxide thereof to the proximal part of the gastrointestinal tract, in other words, there is no (substantial) delivery (or release) of lanthanum or a pharmaceutically acceptable salt or oxide thereof to the stomach, duodenum or jejunum.

[0053] Delivery systems configured for targeted delivery to the distal part of the GI tract are known in the art and use differences in pH along the GI tract, the presence of the colonic microbiota, enzymes or one or more combinations thereof to achieve targeted delivery to the distal part of the GI tract.

[0054] Examples of delivery systems configured to target the pharmaceutical dosage forms taught herein to the distal part of the GI tract include coatings, colon-specific biodegradable delivery systems, matrix-based systems, sustained release systems, multiparticulate systems, polysaccharide-based delivery systems, pressure-controlled delivery systems, osmotic pressure-controlled delivery systems, Pulsincap systems and combinations thereof. These systems are known in the art, for example, as described in Amidon et al. (2015, AAPS PharmSciTech, 16, 4) and Philip et al. (2010, OMJ. 25, 70-78).

[0055] Briefly, colonic targeting by coating generally involves incorporating a medicament, such as a pharmaceutical dosage form containing the lanthanum described herein or a pharmaceutically acceptable salt or oxide thereof, into a pH-sensitive polymer to enable delayed release by protecting the medicament from the acidic pH in the stomach and proximal small intestine. Subsequently, the polymer degrades at the more basic pH of the ileum, thereby achieving targeted delivery of the medicament to the ileum and colon. Examples of pH-sensitive polymers commonly used in the design of pharmaceutical delivery systems targeting the ileum and colon include methacrylic acid-based polymers (also known as Eudragit® polymers) (Evonik Industries, Belgium).

[0056] Colon-specific biodegradable delivery systems are based on coating a medicament, such as a pharmaceutical dosage form containing the lanthanum described herein or a pharmaceutically acceptable salt or oxide thereof, with a polymer to protect the medicament from enzymatic degradation in the stomach and proximal small intestine while enabling enzymatic degradation and release of the medicament in the distal part of the GI tract.

[0057] Matrix-based systems are based on embedding a medicament, such as a pharmaceutical dosage form containing the lanthanum described herein or a pharmaceutically acceptable salt or oxide thereof, in a polymer matrix to trap and release it in the distal part of the GI tract. The matrix can be a pH-sensitive matrix or a biodegradable matrix.

[0058] Sustained-release systems are based on releasing a medicament, such as a pharmaceutical dosage form containing the lanthanum described herein or a pharmaceutically acceptable salt or oxide thereof, in the distal part of the GI tract after a specified time. This approach is dependent on the transit time through the small intestine, which is known to vary.

[0059] Multi-particle systems such as microspheres can be filled with an active ingredient such as lanthanum or a pharmaceutically acceptable salt or oxide thereof. For example, the microspheres can be coated with a pH-sensitive polymer such as Eudragit® polymer. The multi-particle system has a smaller particle size compared to a single-unit system and can more easily pass through the GI tract, so it can quickly reach the distal part of the GI tract.

[0060] Polysaccharide-based delivery systems are based on using one or more polysaccharides such as pectin, chitosan, chondroitin sulfate, galactomannan, or amylose as a thin film coating, compression coating, or matrix to deliver the active ingredient to the distal part of the GI tract.

[0061] The pressure-controlled delivery system is based on the luminal pressure of the colon. Since the reabsorption of water makes the contents of the large intestine more viscous, the luminal pressure of the large intestine becomes higher than that of the small intestine due to peristaltic movement.

[0062] Osmotic pressure-controlled delivery systems such as OROS-CT are systems controlled by osmotic pressure.

[0063] The Pulsincap system is based on the integration of sustained release and pH sensitivity.

[0064] In embodiments of the substances, uses, or methods taught herein, the pharmaceutical dosage form can include a coating configured for targeted delivery to the distal part of the gastrointestinal tract of a subject. In embodiments of the substances, uses, or methods taught herein, the pharmaceutical dosage form can include a coating configured such that lanthanum or a pharmaceutically acceptable salt or oxide thereof is targeted to be delivered to one or more of the ileum, cecum, or colon of a subject, particularly a human subject.

[0065] The term "coating" refers to a covering applied to the surface of an object. In particular, herein, the coating may be applied to the surface of a pharmaceutical dosage form.

[0066] In some embodiments, the coating can be a thin film coating or a compression coating.

[0067] The term "thin film coating" typically refers to a thin polymer-based coating that is sprayed onto solid pharmaceutical dosage forms such as tablets, capsules, pellets, or granules. The film coating can affect the appearance of the pharmaceutical dosage form (e.g., color, gloss, and branding), i.e., a non-functional film coating, and / or pharmacokinetics (i.e., a functional film coating). The thin film coating can be obtained by a dip coating process such as the process taught herein.

[0068] The terms "compression coating", "dry coating", "press coating", or "solventless coating" or "tablet-in-tablet" refer to a coating technique in which a core tablet (e.g., containing lanthanum or a pharmaceutically acceptable salt or oxide thereof) is coated with a coating material (e.g., powder) using a compression machine. This technique is advantageous because it avoids the use of solvents, requires a relatively short manufacturing process, and can significantly increase the weight of the core tablet. Compression coating can affect the pharmacokinetics of the pharmaceutical dosage form (i.e., a functional coating).

[0069] In some embodiments, the coating is a functional coating, whereby the pharmaceutical dosage form can be targeted to be delivered to the distal portion of the gastrointestinal tract. In some embodiments, the coating is a functional coating, whereby lanthanum or a pharmaceutically acceptable salt or oxide thereof can be targeted to one or more of the ileum, cecum, or colon.

[0070] In some embodiments, the coating can comprise (consist essentially of, or consist of) one or more materials configured for targeted delivery to the distal portion of the gastrointestinal tract. In some embodiments, the coating can comprise (consist essentially of, or consist of) one or more materials configured for targeted delivery of lanthanum or a pharmaceutically acceptable salt or oxide thereof to one or more of the ileum, cecum, or colon.

[0071] In embodiments of the compositions, uses, or methods taught herein, instead of comprising a coating configured for targeted delivery to the distal portion of the gastrointestinal tract of a subject, the pharmaceutical dosage form can comprise one or more materials configured for targeted delivery to the distal portion of the GI tract. In embodiments of the compositions, uses, or methods taught herein, instead of comprising a coating configured for targeted delivery to one or more of the ileum, cecum, or colon of a subject, the pharmaceutical dosage form can comprise one or more materials configured for targeted delivery to one or more of the ileum, cecum, or colon of the subject.

[0072] In some embodiments, the coating or dosage form can comprise a pH-sensitive polymer, a biodegradable polymer, a polysaccharide, or combinations thereof. In preferred embodiments, the coating or dosage form can comprise a pH-sensitive polymer. In some embodiments, the coating or dosage form can comprise a polymer that begins to degrade (i.e., disintegrates) under the pH conditions of the distal portion of the gastrointestinal tract, such as the ileum and colon, at least pH 7.0. In some embodiments, the coating or dosage form can comprise a polymer that does not degrade under the pH conditions of the stomach and the proximal small intestine (i.e., the jejunum and duodenum), such as less than pH 7.0, less than pH 6.8, or less than pH 6.5.

[0073] In some embodiments, the coating or dosage form is substantially insoluble below a pH range of about 7.0 to about 8.0. In some embodiments, the coating or dosage form is substantially soluble in a pH range of about 7.0 to about 8.0. In some embodiments, the coating or dosage form is substantially soluble in a pH range of about 6.5 to about 8.0. In some embodiments, the coating or dosage form is substantially soluble in a pH range of about 6.0 to about 8.0.

[0074] In some embodiments, the coating or dosage form can comprise (consist essentially of, or consist of) a polymer configured for targeted delivery to the distal portion of the GI tract. In some embodiments, the coating or dosage form can comprise (consist essentially of, or consist of) a polymer configured such that a lanthanum or a pharmaceutically acceptable salt or oxide thereof is targeted to be delivered to one or more of the ileum, cecum, or colon.

[0075] In some embodiments, examples of polymers configured for targeted delivery to the distal portion of the subject's GI tract, such as the ileum, cecum, and / or colon, include one or more polymers selected from the group consisting of a copolymer of methacrylic acid and methyl methacrylate, a copolymer of methacrylic acid, methyl acrylate, and methyl methacrylate, a copolymer of methacrylic acid and ethyl acrylate, and a copolymer of methacrylic acid and ethyl acrylate with the monomer of methyl acrylate added during polymerization. In some embodiments, examples of polymers configured for targeted delivery to the distal portion of the subject's GI tract, such as the ileum, cecum, and / or colon, include one or more polymers selected from the group consisting of a copolymer of methacrylic acid and methyl methacrylate, and a copolymer of methacrylic acid, methyl acrylate, and methyl methacrylate.

[0076] Suitable examples of polymers configured for targeted delivery to the distal portion of the gastrointestinal tract, such as the ileum, cecum and / or colon, include aqueous methacrylic acid copolymers such as Eudragit® polymers (Evonik Industries, Belgium). For example, suitable polymers for targeted delivery to the distal portion of the gastrointestinal tract such as the ileum and colon include Eudragit® S100, Eudragit® S12,5, Eudragit® FS 30D, Eudragit® FS 100, Eudragit® L100, Eudragit® L12,5 alone or in combination. These polymers dissolve preferably at pH above 7.0 (for example, Eudragit® S100, S12,5, FS 30D, FS 100), or at pH above 6.0 (for example, Eudragit® L100, Eudragit® L12,5).

[0077] In embodiments of the things, uses or methods taught herein, the coating or dosage form can comprise (consist essentially of, or consist of) a copolymer of methacrylic acid and a C 1-4 alkyl ester of methacrylic acid. In some embodiments, the coating or dosage form can comprise a copolymer of methacrylic acid and a methyl ester of methacrylic acid (i.e., methyl methacrylate). In some embodiments, the coating or dosage form can comprise a copolymer of methacrylic acid and an ethyl ester of methacrylic acid (i.e., ethyl methacrylate). In some embodiments, the coating or dosage form can comprise a copolymer of methacrylic acid and a propyl ester of methacrylic acid (e.g., n-propyl methacrylate). In some embodiments, the coating or dosage form can comprise a copolymer of methacrylic acid and a butyl ester of methacrylic acid (e.g., n-butyl methacrylate).

[0078] In embodiments of the articles, uses, or methods taught herein, the coating or dosage form can include a copolymer of methacrylic acid and methyl methacrylate in a ratio of 2:1 to 1:2, such as a ratio of 1:1. In a preferred embodiment, the coating or dosage form can include, consist essentially of, or consist of a copolymer of methacrylic acid and methyl methacrylate in a ratio of 1:2. Such a copolymer is, for example, Eudragit® S100.

[0079] In some embodiments, the coating can further include one or more additives or adjuvants such as a solvent, a plasticizer, a carrier, a surfactant, a thickening agent, a buffering agent, an antioxidant, a preservative, a flavoring agent, or a coloring agent. Suitable adjuvants are known in the art.

[0080] In embodiments of the articles, uses, or methods taught herein, the pharmaceutical dosage form can include at least three layers of coating. In some embodiments, the pharmaceutical dosage form can include at least four layers, at least five layers, or at least six layers of coating. Preferably, the pharmaceutical dosage form can include at least four layers of coating, such as four layers. The at least four layers of coating, such as four layers, are advantageous because they enable protection of the pharmaceutical dosage form in the proximal portion of the GI tract and delivery of the pharmaceutical dosage form to the distal portion of the GI tract, such as the ileum, cecum, and / or colon, and release of the lanthanum or a pharmaceutically acceptable salt or oxide thereof.

[0081] In embodiments of the articles, uses or methods taught herein, the thickness of the (overall) coating can be at least 20.0 μm, such as at least 21.0 μm, at least 22.0 μm, at least 23.0 μm, at least 24.0 μm, at least 25.0 μm, at least 26.0 μm, at least 27.0 μm, at least 28.0 μm, at least 29.0 μm, at least 30.0 μm, at least 31.0 μm, at least 32.0 μm, at least 33.0 μm, at least 34.0 μm or at least 35.0 μm. In some embodiments, the thickness of the coating can be from about 20.0 μm to about 100.0 μm. For example, the thickness of the coating can be from about 25.0 μm to about 60.0 μm, from about 30.0 μm to about 50.0 μm or from about 35.0 μm to about 40.0 μm. As shown in the Examples section, such thicknesses are advantageous because they enable delivery of the pharmaceutical dosage form and release of lanthanum carbonate to the distal portions of the gastrointestinal tract, such as the ileum, cecum and / or colon. The thickness of the (overall) coating can be measured using a microscope or a micrometer (also referred to as a micrometer screw gauge or a manual screw micrometer). The thickness of the (overall) coating can be calculated by determining the thickness of the coated dosage form and the thickness of the uncoated dosage form and subtracting the thickness of the uncoated capsule from the thickness of the coated capsule.

[0082] In embodiments of the articles, uses or methods taught herein, the thickness of each layer of the coating can be at least 4.0 μm, such as at least 5.0 μm, at least 6.0 μm or at least 7.0 μm. In some embodiments, the thickness of each layer of the coating can be from about 4.0 μm to about 25.0 μm. For example, the thickness of each layer of the coating can be from about 4.0 μm to about 20.0 μm, from about 5.0 μm to about 15.0 μm or from about 6.0 μm to about 10.0 μm.

[0083] In embodiments of the substances, uses or methods taught herein, the pharmaceutical dosage form can include at least three coatings, such as four layers, and the thickness of each layer can be at least 4.0 μm, for example at least 5.0 μm, at least 6.0 μm or at least 7.0 μm. In some embodiments, the pharmaceutical dosage form can include at least three coatings, such as four layers, and the thickness of each layer can be from about 4.0 μm to about 25.0 μm. For example, the pharmaceutical dosage form can include at least three coatings, such as four layers, and the thickness of each coating layer can be from about 4.0 μm to about 20.0 μm, from about 5.0 μm to about 15.0 μm or from about 6.0 μm to about 10.0 μm. Such coatings are advantageous because they can protect the pharmaceutical dosage form in the proximal part of the GI tract and deliver the pharmaceutical dosage form to the distal part of the GI tract, such as the ileum, cecum and / or colon, and release lanthanum or a pharmaceutically acceptable salt or oxide thereof.

[0084] In embodiments of the substances, uses or methods taught herein, the pharmaceutical dosage form can be a solid, semi-solid or liquid dosage form. For example, in the case of oral administration, the pharmaceutical dosage form includes pills, tablets, granules, capsules, aqueous solutions, alcoholic solutions or oily solutions, syrups, emulsions or suspensions. For example, the pharmaceutical dosage form can also be a colloidal dispersion system. The colloidal dispersion system includes, but is not limited to, polymer complexes, nanocapsules, microspheres, beads, and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, liposomes and lipid: compound complexes of unknown structure. Preferred colloidal dispersion systems are multiple liposomes. Liposomes are microscopic spheres having an aqueous core surrounded by one or more outer layers of lipids arranged in a bilayer configuration (see Chonn et al., 1995, Current Op. Biotech. 6, 698-708). Similarly, particulate or nanoparticulate polymeric bead dosage forms can also be used in the pharmaceutical dosage forms provided herein.

[0085] In embodiments of the substances, uses or methods taught herein, the pharmaceutical dosage form can be a liquid dosage form such as an aqueous solution, an alcoholic solution or an oily solution, a syrup, an emulsion or a suspension. For example, the pharmaceutical dosage form can be microspheres suspended in a solution.

[0086] In embodiments of the substances, uses or methods taught herein, the pharmaceutical dosage form can be a solid or semi-solid dosage form. In some embodiments, the pharmaceutical dosage form can be a pill, a pellet, a tablet, granules, or a capsule such as a hard capsule or a soft capsule.

[0087] In embodiments of the substances, uses or methods taught herein, the pharmaceutical dosage form can be a capsule or a tablet. Preferably, the pharmaceutical dosage form can be a capsule such as a capsule filled with a composition containing lanthanum or a pharmaceutically acceptable salt or oxide thereof; preferably, the lanthanum or a pharmaceutically acceptable salt or oxide thereof is in powder form.

[0088] In embodiments of the substances, uses or methods taught herein, the capsule can be made from one or more materials selected from the group consisting of cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose (HPMC), gelatin, pullulan, starch, water-soluble polyvinyl derivatives, polyethylene glycol and copolymers of C 1-4 alkyl esters of (meth)acrylic acid and (meth)acrylic acid.

[0089] In some embodiments, the capsule can be size 000, size 00E, size 00, size 0E, size 0, size 1, size 2, size 3, size 4 or size 5. In some embodiments, the capsule can be size 00, size 0E, size 0, size 1, size 2, size 3, size 4 or size 5.

[0090] In some embodiments, the capsule can be size 00 and can contain 500 mg to 600 mg of lanthanum element. For example, the capsule can be size 00 and can contain 560 mg of lanthanum element. In some embodiments, the capsule can be size 0 and can contain 400 mg to 500 mg of lanthanum element. For example, the capsule can be size 0 and can contain 420 mg of lanthanum element. In some embodiments, the capsule can be size 1 and can contain 250 mg to 400 mg of lanthanum element. For example, the capsule can be size 1 and can contain 295 mg of lanthanum element. In some embodiments, the capsule can be size 2 and can contain 200 mg to 300 mg of lanthanum element. For example, the capsule can be size 2 and can contain 230 mg of lanthanum element.

[0091] In embodiments of the articles, uses or methods taught herein, the capsule can include a coating configured for targeted delivery to the distal portion of the gastrointestinal tract of a subject; preferably, the coating includes a pH-sensitive polymer, a biodegradable polymer, a polysaccharide, or a combination thereof. In embodiments of the articles, uses or methods taught herein, the capsule can include a coating configured for targeted delivery of lanthanum or a pharmaceutically acceptable salt or oxide thereof to one or more of the ileum, cecum or colon of a subject; preferably, the coating includes a pH-sensitive polymer, a biodegradable polymer, a polysaccharide, or a combination thereof. As shown in the experimental section, the coated capsules taught herein are able to pass through the proximal gastrointestinal tract and reach the target sites, i.e., the ileum and colon, for releasing lanthanum or a pharmaceutically acceptable salt or oxide thereof. The physiological functions of the GI tract are complex, with wide ranges of pH values, body fluid volumes and transit times, and the presence of food and metabolic enzymes also increases the complexity of the physiological functions. Despite these factors, the coated capsules taught herein are able to reliably and efficiently deliver lanthanum or a pharmaceutically acceptable salt or oxide thereof to the distal portion of the GI tract, including the ileum and colon.

[0092] In some embodiments, the capsule can include one or more materials configured for targeted delivery to the distal portion of the gastrointestinal tract of a subject; preferably, the capsule includes a pH-sensitive polymer, a biodegradable polymer, a polysaccharide, or a combination thereof. In some embodiments, the capsule can include one or more materials configured for targeted delivery of lanthanum or a pharmaceutically acceptable salt or oxide thereof to one or more of the ileum, cecum or colon of a subject; preferably, the capsule includes a pH-sensitive polymer, a biodegradable polymer, a polysaccharide, or a combination thereof.

[0093] In embodiments of the compositions, uses, or methods taught herein, the capsule can comprise at least three layers of coating. In some embodiments, the capsule can comprise at least four, at least five, or at least six layers of coating. Preferably, the capsule can comprise at least four layers of coating, such as four layers. At least four layers of coating, such as four layers of coating, can advantageously protect the capsule from degradation in the proximal portion of the GI tract and allow the capsule to be delivered to the distal portion of the GI tract, such as the ileum, cecum, and / or colon, to release the lanthanum or a pharmaceutically acceptable salt or oxide thereof.

[0094] The pharmaceutical dosage forms taught herein comprise lanthanum or a pharmaceutically acceptable salt or oxide thereof. In embodiments of the compositions, uses, or methods taught herein, the pharmaceutically acceptable salt or oxide of lanthanum can be lanthanum carbonate or lanthanum oxide; preferably, the pharmaceutical dosage form comprises lanthanum carbonate.

[0095] The term "lanthanum" refers to the chemical element with atomic number 57 and the elemental symbol La. The molar mass of lanthanum is 138.91 g / mol.

[0096] The phrase "a pharmaceutically acceptable salt thereof" refers to a salt of lanthanum derived from a combination of lanthanum with an organic or inorganic acid (acid addition salt), or a combination of lanthanum with an organic or inorganic base (base addition salt).

[0097] In embodiments of the compositions, uses, or methods taught herein, the pharmaceutically acceptable salt of lanthanum can be lanthanum carbonate.

[0098] The term "lanthanum carbonate" refers to the compound with the chemical formula La2(CO3)3. This compound is a salt formed by lanthanum(III) cations and carbonate anions. The CAS number of lanthanum carbonate is 587-26-8. The molar mass of lanthanum carbonate is 457.838 g / mol. It can be calculated that 1000 mg (1 g) of lanthanum carbonate corresponds to approximately 606.8 mg of lanthanum element, or 1000 mg (1 g) of lanthanum element corresponds to 1648 mg of lanthanum carbonate.

[0099] Lanthanum carbonate is commercially available as a phosphate binder and is sold under the trade name Fosrenol (Shire Pharmaceuticals, Dublin, Ireland).

[0100] In embodiments of the substances, uses or methods taught herein, the pharmaceutically acceptable oxide of lanthanum can be lanthanum oxide.

[0101] The term "lanthanum oxide" or "lanthanum" refers to the compound with the chemical formula La2O3. This compound is an inorganic compound containing lanthanum(III) and oxygen. The CAS number of lanthanum oxide is 1312-81-8.

[0102] In some embodiments, lanthanum or a pharmaceutically acceptable salt or oxide thereof can be lanthanum, lanthanum carbonate or lanthanum oxide.

[0103] When referring to lanthanum, it shall refer to elemental lanthanum. However, when a pharmaceutical dosage form is said to contain a specific amount of elemental lanthanum, it means that the pharmaceutical dosage form contains the specific amount of elemental lanthanum as elemental lanthanum or as its pharmaceutically acceptable salt or oxide. For example, when a pharmaceutical dosage form is said to contain 250 mg of elemental lanthanum, it means that the pharmaceutical dosage form contains 250 mg of elemental lanthanum as elemental lanthanum or as its pharmaceutically acceptable salt or oxide. For example, a pharmaceutical dosage form said to contain 250 mg of elemental lanthanum may contain 250 mg of elemental lanthanum or about 412 mg of lanthanum carbonate.

[0104] In embodiments of the substances, uses or methods taught herein, the pharmaceutical dosage form can contain from 100 mg to 4000 mg (4 g) of elemental lanthanum. In some embodiments, the pharmaceutical dosage form can contain from 100 mg to 3500 mg (3.5 g), from 100 mg to 3000 mg (3 g), from 100 mg to 2500 mg (2.5 g), from 100 mg to 2000 mg (2 g), from 100 mg to 1500 mg (1.5 g) or from 100 mg to 1000 mg (1 g) of elemental lanthanum. In embodiments of the substances, uses or methods taught herein, the pharmaceutical dosage form can contain from 100 mg to 750 mg, from 100 mg to 500 mg or from 100 mg to 250 mg of elemental lanthanum. In embodiments of the substances, uses or methods taught herein, a pharmaceutical dosage form such as a capsule can contain from 200 mg to 750 mg of elemental lanthanum, such as from 250 mg to 600 mg of elemental lanthanum. In some embodiments, a pharmaceutical dosage form such as a capsule can contain from 500 mg to 600 mg of elemental lanthanum. In some embodiments, a pharmaceutical dosage form such as a capsule can contain from 400 mg to 500 mg of elemental lanthanum. In some embodiments, a pharmaceutical dosage form such as a capsule can contain from 250 mg to 400 mg of elemental lanthanum. In some embodiments, a pharmaceutical dosage form such as a capsule can contain from 200 mg to 300 mg of lanthanum element.In some embodiments, the pharmaceutical dosage form can contain at least 210 mg, at least 220 mg, at least 230 mg, at least 240 mg, at least 250 mg, at least 260 mg, at least 270 mg, at least 280 mg, at least 290 mg, at least 300 mg, at least 310 mg, at least 320 mg, at least 330 mg, at least 340 mg, at least 350 mg, at least 360 mg, at least 370 mg, at least 380 mg, at least 390 mg, at least 400 mg, at least 410 mg, at least 420 mg, at least 430 mg, at least 440 mg, at least 450 mg, at least 460 mg, at least 470 mg, at least 480 mg, at least 490 mg, at least 500 mg, at least 510 mg, at least 520 mg, at least 530 mg, at least 540 mg, at least 550 mg, at least 560 mg, at least 570 mg, at least 580 mg, at least 590 mg, at least 600 mg, at least 610 mg, at least 620 mg, at least 630 mg, at least 640 mg, at least 650 mg, at least 660 mg, at least 670 mg, at least 680 mg, at least 690 mg, at least 700 mg, at least 710 mg, at least 720 mg, at least 730 mg, at least 740 mg or at least 750 mg of elemental lanthanum.

[0105] In some embodiments, the pharmaceutical dosage forms taught herein can contain lanthanum carbonate, preferably lanthanum carbonate in powder form, and can be, for example, filled. In some embodiments, the capsules taught herein can contain lanthanum carbonate, preferably lanthanum carbonate in powder form, and can be, for example, filled. In some embodiments, the pharmaceutical dosage forms taught herein can contain from about 200 mg to about 2 g of lanthanum carbonate, preferably lanthanum carbonate in powder form, and can be, for example, filled. In some embodiments, the capsules taught herein can contain from about 200 mg to about 2 g of lanthanum carbonate, preferably lanthanum carbonate in powder form, and can be, for example, filled.

[0106] In some embodiments, the pharmaceutical dosage forms taught herein can include lanthanum or a pharmaceutically acceptable salt or oxide thereof for release in the distal portion of the GI tract and can be, for example, filled. In some embodiments, the pharmaceutical dosage forms taught herein can include lanthanum or a pharmaceutically acceptable salt or oxide thereof for release in one or more of the ileum, cecum, or colon and can be, for example, filled. Advantageously, the lanthanum or a pharmaceutically acceptable salt or oxide thereof in the dosage form is delivered to the distal portion of the GI tract without leakage of the lanthanum or a pharmaceutically acceptable salt or oxide thereof in the proximal portion of the gastrointestinal tract located prior to the ileum. In some embodiments, the pharmaceutical dosage forms taught herein can effect at least 80% delivery of the lanthanum or a pharmaceutically acceptable salt or oxide thereof to the distal portion of the GI tract, preferably at least 85%, at least 90%, at least 95% or at least 97%, or more, for example, at least 98%, at least 99% or 100% delivery of the lanthanum or a pharmaceutically acceptable salt or oxide thereof to the distal portion of the GI tract, such as the ileum, cecum and / or colon.

[0107] In some embodiments, the pharmaceutical dosage form can be a capsule filled with a composition comprising lanthanum or a pharmaceutically acceptable salt or oxide thereof.

[0108] In some embodiments, the composition comprising lanthanum or a pharmaceutically acceptable salt or oxide thereof can include one or more excipients.

[0109] As used herein, "carrier" or "excipient" includes any and all solvents, diluents, buffers (e.g., neutral buffered saline or phosphate buffered saline, etc.), solubilizing agents, colloids, dispersion media, vehicles, fillers, chelating agents (e.g., EDTA or glutathione, etc.), amino acids (e.g., glycine, etc.), proteins, disintegrants, binders, lubricants, wetting agents, emulsifying agents, sweeteners, coloring agents, flavoring agents, fragrances, thickening agents, agents for achieving depot effects, coating agents, antifungal agents, preservatives, antioxidants, tonicity modifiers, absorption delaying agents, etc. The use of such media and agents for pharmaceutical active ingredients is well known in the art. The use thereof in pharmaceutical dosage forms can be considered, except when any conventional media or agents are incompatible with the active ingredient.

[0110] In some embodiments, a composition comprising a salt of lanthanum or a pharmaceutically acceptable oxide thereof can comprise one or more excipients including dextran (hydrate), colloidal anhydrous silica, and magnesium stearate.

[0111] In some embodiments, the pharmaceutical dosage form can be a capsule filled with a composition comprising lanthanum or a pharmaceutically acceptable salt or oxide thereof, and the lanthanum or a pharmaceutically acceptable salt or oxide thereof, or the composition is in powder form.

[0112] The term "powder" refers to a dry, lumpy solid composed of a large number of very fine particles that flow freely when shaken or tilted.

[0113] In embodiments of the articles, uses or methods taught herein, the pharmaceutical dosage form can be a capsule filled with a composition comprising lanthanum or a pharmaceutically acceptable salt or oxide thereof and coated with a copolymer of methacrylic acid and a C 1-4 alkyl ester of methacrylic acid, and preferably, the composition comprising lanthanum or a pharmaceutically acceptable salt or oxide thereof is in powder form. Preferably, the capsule can contain 100 mg to 1 g of lanthanum, for example, 250 mg to 500 mg.

[0114] In some embodiments, the pharmaceutical dosage form is a capsule filled with a composition comprising lanthanum or a pharmaceutically acceptable salt or oxide thereof, such as lanthanum carbonate, and coated with at least four layers of a copolymer of methacrylic acid and a C 1-4 alkyl ester of methacrylic acid, preferably, the composition comprising lanthanum or a pharmaceutically acceptable salt or oxide thereof is in powder form. In some embodiments, the pharmaceutical dosage form can be a capsule filled with a composition comprising lanthanum or a pharmaceutically acceptable salt or oxide thereof, such as lanthanum carbonate, and coated with at least four layers of a copolymer of methacrylic acid and methyl methacrylate, preferably, the composition comprising lanthanum or a pharmaceutically acceptable salt or oxide thereof is in powder form. In some embodiments, the pharmaceutical dosage form can be a capsule filled with a composition comprising lanthanum or a pharmaceutically acceptable salt or oxide thereof, such as lanthanum carbonate, and coated with at least four layers of a copolymer of methacrylic acid and methyl methacrylate in a ratio of 1:2, preferably, the composition comprising lanthanum or a pharmaceutically acceptable salt or oxide thereof is in powder form. Preferably, the capsule can contain 100 mg to 1 g, such as 250 mg to 500 mg of lanthanum. As shown in the Examples section, when used as a medicine, such a pharmaceutical dosage form advantageously reduces the urinary oxalate level without changing the urinary phosphate level and maintains or reduces the urinary calcium level. Therefore, the pharmaceutical dosage form of the present invention can prevent the formation of calcium oxalate crystals in the renal tubular fluid and urine of the kidney without causing a lack of phosphate. Calcium oxalate crystals are the first important step in the formation of kidney stones and ultimately cause nephrolithiasis. Therefore, the pharmaceutical dosage form of the present invention is advantageous for reducing hyperoxaluria and even avoiding nephrolithiasis, nephrocalcinosis and oxalosis, especially nephrolithiasis, nephrocalcinosis and oxalosis caused by calcium oxalate.

[0115] According to a second aspect, there is provided a pharmaceutical dosage form as defined herein for use as a medicament in a subject, particularly a human subject. Thus, according to one aspect, there is provided an orally administrable pharmaceutical dosage form configured to target delivery to the distal portion of the gastrointestinal tract of a subject, the pharmaceutical dosage form comprising lanthanum or a pharmaceutically acceptable salt or oxide thereof for use as a medicament in the subject. Preferably, according to one aspect, there is provided an orally administrable pharmaceutical dosage form comprising lanthanum or a pharmaceutically acceptable salt or oxide thereof, the pharmaceutical dosage form being configured such that lanthanum or a pharmaceutically acceptable salt or oxide thereof is targeted to be delivered to one or more of the ileum, cecum, or colon of the subject and being for use as a medicament in the subject. Preferably, the subject is a human subject.

[0116] According to a further aspect, there is provided a pharmaceutical dosage form as defined herein for use in the treatment of hyperoxaluria in a subject. Thus, according to a further aspect, there is provided an orally administrable pharmaceutical dosage form configured to target delivery to the distal portion of the gastrointestinal tract of a subject, the pharmaceutical dosage form comprising lanthanum or a pharmaceutically acceptable salt or oxide thereof for use in the treatment of hyperoxaluria in the subject. Preferably, according to a further aspect, there is provided an orally administrable pharmaceutical dosage form configured such that lanthanum or a pharmaceutically acceptable salt or oxide thereof is targeted to be delivered to one or more of the ileum, cecum, or colon of the subject and being for use in the treatment of hyperoxaluria in the subject. In some embodiments, the hyperoxaluria can be primary hyperoxaluria or secondary hyperoxaluria. Preferably, the subject is a human subject.

[0117] According to a related aspect, - A method of treating hyperoxaluria, such as primary hyperoxaluria or secondary hyperoxaluria, in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical dosage form as taught herein, preferably by oral administration. - A method for treating hyperoxaluria such as primary hyperoxaluria or secondary hyperoxaluria in a human subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical dosage form taught herein, preferably by oral administration. - Use of a pharmaceutical dosage form taught herein for the manufacture of a medicament for the treatment of hyperoxaluria such as primary hyperoxaluria or secondary hyperoxaluria in a subject. - Use of a pharmaceutical dosage form taught herein for the manufacture of a medicament for the treatment of hyperoxaluria such as primary hyperoxaluria or secondary hyperoxaluria in a human subject. is provided.

[0118] The term "hyperoxaluria" or "Bird's disease" refers to a disease or condition characterized by excessive excretion of oxalate salts in the urine.

[0119] The term "oxalate" refers to the anion of the chemical formula C2O4 2- and its IUPAC name is ethanedioate.

[0120] The term "primary hyperoxaluria (PH)" refers to a rare genetic liver disease in which the liver does not produce sufficient enzymes to prevent the overproduction of oxalate salts or the enzymes do not function properly. There are three subtypes of primary hyperoxaluria, each involving a genetic defect in a different enzyme in the liver, all of which are involved in the overproduction of oxalate salts.

[0121] Type 1 primary hyperoxaluria (PH1) is the most common and severe form of PH. PH1 accounts for approximately 80% of cases of PH. PH1 is caused by a defect in alanine glyoxylate aminotransferase (AGT), a vitamin B6-dependent liver peroxisomal enzyme that catalyzes the transfer of an amino group from L-alanine and glyoxylate to pyruvate and lysine. This enzyme defect is thought to be due to a mutation in the AGXT gene on chromosome 2.

[0122] Type 2 primary hyperoxaluria (PH2) accounts for approximately 10% of PH patients. PH2 is caused by the dysfunction of glyoxylate / hydroxypyruvate reductase (GRHPR) that is secondarily generated by mutations in the GRHPR gene located on chromosome 10.

[0123] Type 3 primary hyperoxaluria (PH3) occurs in 10% of PH cases. PH3 is caused by a genetic defect in the HOGA1 gene located on chromosome 9 that encodes mitochondrial 4-hydroxy-2-oxoglutarate aldolase. This enzyme decomposes 4-hydroxy-2-oxoglutarate into pyruvate and glyoxylate, and further glyoxylate is converted into oxalate.

[0124] In some embodiments, primary hyperoxaluria can be type 1, type 2, or type 3 primary hyperoxaluria.

[0125] The term "secondary hyperoxaluria" refers to a disease or condition in which excessive oxalate is absorbed by the gastrointestinal (GI) tract and then excreted in the urine.

[0126] Reasons for increased absorption include: (1) intake of foods rich in oxalate or excessive intake of oxalate precursors (i.e., dietary hyperoxaluria), (2) changes in the intestinal flora, or susceptibility to conditions in which the GI tract absorbs more oxalate, such as Crohn's disease, inflammatory bowel disease, gastric bypass surgery, and other diseases where nutrients are not properly absorbed (i.e., enteric hyperoxaluria), or (3) unknown cause (i.e., idiopathic hyperoxaluria). Without intending to be bound by theory, malabsorption in the context of points (2) and (3) may cause an increase in the concentration of free fatty acids (FFA) in the intestine, which binds to calcium and may result in a decrease in free calcium that binds to oxalate. Second, an increase in bile acid concentration causes an increase in the permeability of the intestinal mucosa. Both mechanisms increase the concentration of free oxalate and thus increase the gastrointestinal absorption of oxalate.

[0127] In some embodiments, hyperoxaluria can be determined by one or more of: a urine test that measures the levels of oxalate and optionally other specific enzymes; a blood test that measures the amount of oxalate in the blood; and a scan of the kidneys and urinary tract (such as X-ray, ultrasound, and / or CT) to examine for kidney stones or calcium oxalate crystals. It is also possible to examine for crystals in the urine.

[0128] Hyperoxaluria is measured by measuring the urinary oxalate excretion in a 24-hour urine collection and adjusting for the oxalate excretion per 1.73 m 2 of body surface area (expressed, for example, as mmol / 1.73 m 2 / 24 hours). Urinary oxalate excretion can also be measured per volume of urine (expressed, for example, as mg / L). The urinary oxalate / urinary creatinine ratio (for example, mg oxalate / g creatinine) can be measured to determine the quality of the 24-hour urine collection. Since urinary creatinine is fairly stable over time (24 hours), if the creatinine value is too low, for example, the urine volume may be falsely detected as being low. The value can be corrected and the result rejected (Kaminska et al., 2020, Crit Rev Clin Lab Sci, 57, 5, 345-364). The urinary phosphate / urinary creatinine ratio (for example, mg phosphate / g creatinine), urinary phosphate (for example, phosphate mg / L), urinary calcium / urinary creatinine ratio (for example, mg calcium / g creatinine), and / or urinary calcium (for example, calcium mg / L) can be measured in the same way.

[0129] In a urine test, the amount of urinary oxalate, urinary calcium, or urinary phosphate in urine collected from the patient over a period of 24 hours (h) (for example, during a control period, during treatment, and / or after treatment) can be measured. The excretion of urinary oxalate, urinary calcium, or urinary phosphate is mmol / 24h / 1.73m 2Or it can be expressed in mg / 24h. Preferably, the excretion amount of urinary oxalate, urinary calcium or urinary phosphate is mmol / 24h / 1.73m per liter (L) of urine (hereinafter referred to as "mmol / L") or mg / 24h / 1.73m per liter of urine 2 (hereinafter referred to as "mg / L"). Since patients with hyperoxaluria consume a large amount of water and have a large amount of urine excretion, it is important to consider the amount of the patient's 24-hour urine. For example, without considering the amount of urine expressed in mmol / 24h / 1.73m 2 mentioning the excretion amount of urinary oxalate, urinary calcium or urinary phosphate may lead to an incorrect diagnosis. For example, a subject excreting 80 mg of oxalate in 2 L of urine per 24 hours may not be diagnosed as having hyperoxaluria (that is, 40 mg / L is below the normal upper limit (ULN) of 44 mg / L), while a subject excreting 80 mg of oxalate in 1 L of urine per 24 hours is diagnosed as having hyperoxaluria (that is, 80 mg / L is above the ULN of 44 mg / L). 2 Table 1 shows the expected urinary oxalate excretion amounts in healthy human patients and diseased human patients.

[0130] The normal urinary oxalate excretion amount used in this specification is defined as less than 0.50 mmol / L or less than 44 mg / L.

[0131]

Table 1

[0132] Hyperoxaluria can be characterized by a urinary oxalate excretion amount of 0.50 mmol / L or more or 44 mg / L or more.

[0133]

[0134] ​Primary hyperoxaluria is characterized by urinary oxalate excretion exceeding 1.0 mmol / L or 87 mg / L, for example, urinary oxalate excretion being 88 mg / L to 250 mg / L.

[0135] Secondary hyperoxaluria can be characterized by urinary oxalate excretion of 0.50 mmol / L or more or 44 mg / L or more. Dietary and idiopathic hyperoxaluria can be characterized by urinary oxalate excretion of 0.50 to 0.70 mmol / L or 44 to 61 mg / L. Enteric hyperoxaluria can be characterized by urinary oxalate excretion of 0.60 to 1.0 mmol / L or 53 to 87 mg / L.

[0136] Diagnosis of PH and type can be performed by examination of the AGXT gene, GRHPR gene, and HOGA1 gene. 150 mutations are known in AGXT, 16 mutations in GRHP, and 15 mutations in HOGA1. Williams et al. (2007, Clin Chem, 53: 1216 - 1221) showed that 34.5% of PH1 patients were diagnosed by analysis targeting the three most common mutations in AGXT (c.33_34insC, c.508G>A, and c.731T>C), and the diagnostic rate was improved by exon sequencing of exons 1, 4, and 7, with 50% of PH1 patients being diagnosed.

[0137] The term "oxalaturia" refers to the excretion of oxalate in urine or urinary oxalate.

[0138] The term "calciuria" refers to the excretion of calcium in urine or urinary calcium.

[0139] If the amount of calcium in urine is abnormally high, it is called hypercalciuria, and if it is abnormally low, it is called hypocalciuria.

[0140] The term "phosphaturia" refers to the excretion of phosphate in urine or urinary phosphate.

[0141] When the amount of phosphoric acid in urine is abnormally high, it is called hyperphosphaturia, and when it is abnormally low, it is called hypophosphaturia.

[0142] A further aspect relates to a pharmaceutical dosage form as defined herein for use in the treatment of one or more of nephrolithiasis, nephrocalcinosis or oxalosis in a subject, particularly a human subject. Thus, according to a further aspect, there is provided an orally administrable pharmaceutical dosage form configured to target delivery to the distal portion of the gastrointestinal tract of a subject, comprising lanthanum or a pharmaceutically acceptable salt or oxide thereof, for use in the treatment of one or more of nephrolithiasis, nephrocalcinosis or oxalosis in a subject, particularly a human subject. Preferably, according to a further aspect, there is provided an orally administrable pharmaceutical dosage form comprising lanthanum or a pharmaceutically acceptable salt or oxide thereof, configured such that lanthanum or a pharmaceutically acceptable salt or oxide thereof is targeted to be delivered to one or more of the ileum, cecum or colon in a subject, particularly a human subject, for use in the treatment of one or more of nephrolithiasis, nephrocalcinosis or oxalosis in the subject, particularly a human subject.

[0143] The terms "nephrolithiasis", "renal lithiasis" or "urolithiasis" refer to a crystalline disease in which solid substances (e.g., kidney stones) are formed in the urinary tract. The diagnosis of kidney stones is based on information obtained from the medical history, physical examination, urine test and radiological examination. Clinical diagnosis is usually based on the location and severity of pain, which is typically colicky (appearing and disappearing in spasmodic waves). Back pain occurs when a stone causes an obstruction in the kidney.

[0144] In some embodiments, nephrolithiasis may be caused by or associated with calcium oxalate, such as calcium oxalate stones or crystals.

[0145] The term "nephrocalcinosis" or "Albright's calcinosis" refers to renal parenchymal calcification diagnosed by radiology. The calcification may be diffuse fine calcification. The term "nephrocalcinosis" is used to explain the deposition of both calcium oxalate and calcium phosphate. Nephrocalcinosis can cause acute kidney injury. Nephrocalcinosis may be diagnosed by imaging techniques including ultrasound (US), plain abdominal radiographs, and computed tomography (CT) images.

[0146] In some embodiments, nephrocalcinosis may be caused by or associated with calcium oxalate, such as calcium oxalate deposition.

[0147] The term "oxalosis" refers to a disease or condition in which oxalate accumulates excessively in extra-renal organs after renal failure in patients suffering from hyperoxaluria. As a result, oxalate may deposit in blood vessels, bones, and body organs.

[0148] In some embodiments, oxalosis may be caused by or associated with calcium oxalate, such as calcium oxalate deposition, stones, or crystals.

[0149] In some embodiments, nephrolithiasis, nephrocalcinosis, or oxalosis in a subject may be caused by or associated with calcium oxalate, such as calcium oxalate deposition, stones, or crystals in the subject.

[0150] According to related aspects: - A method of treating one or more of nephrolithiasis, nephrocalcinosis, or oxalosis in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical formulation taught herein, preferably orally. - A method for treating one or more of nephrolithiasis, nephrocalcinosis or oxalosis in a human subject in need of treatment, comprising administering to the subject a therapeutically effective amount of a pharmaceutical dosage form taught herein, preferably orally. - Use of a pharmaceutical dosage form taught herein in the manufacture of a medicament for treating one or more of nephrolithiasis, nephrocalcinosis or oxalosis in a subject. - Use of a pharmaceutical dosage form taught herein in the manufacture of a medicament for treating one or more of nephrolithiasis, nephrocalcinosis or oxalosis in a human subject. is provided.

[0151] The terms "subject", "individual" or "patient" can be used interchangeably herein and typically preferably refer to a human, but may also include references to non-human animals, preferably warm-blooded animals, more preferably mammals, such as non-human primates, rodents, canines, felines, equines, ovines, porcines, etc. The term "non-human animal" includes all vertebrates, such as mammals including non-human primates (especially higher primates), sheep, dogs, rodents (e.g., mice or rats), guinea pigs, goats, pigs, cats, rabbits, cows, etc., and non-mammals such as chickens, amphibians, reptiles, etc. In some embodiments, the subject is a non-human mammal. In some embodiments, the subject is a human subject. The term does not refer to a particular age or gender. Thus, subjects, whether male or female, adult and neonatal as well as fetuses are subjects. Examples of subjects include humans, dogs, cats, cows, goats and mice. Further, the term subject shall also include transgenic species.

[0152] Suitable subjects include, but are not limited to, subjects who receive a physician's examination for screening for one or more of hyperoxaluria, nephrolithiasis, nephrocalcinosis, or oxalosis; subjects who present with one or more signs or symptoms of hyperoxaluria, nephrolithiasis, nephrocalcinosis, or oxalosis and receive a physician's examination; subjects who have received a diagnosis of one or more of hyperoxaluria, nephrolithiasis, nephrocalcinosis, or oxalosis; and subjects who have received one or more alternative (unsuccessful) treatments for hyperoxaluria, nephrolithiasis, nephrocalcinosis, or oxalosis.

[0153] In embodiments of the uses or methods taught herein, the subject is a human. As shown in the examples, the inventors have found the optimal site in the intestine of a human subject where lanthanum release occurs and oxalate chelation is initiated, i.e., the distal part of the gastrointestinal tract of the human subject, particularly one or more of the ileum, cecum, or colon of the human subject, and have found that a combined effect of reducing hyperoxaluria without phosphate deficiency can be obtained.

[0154] In embodiments of the uses or methods taught herein, the subject can be a human subject suffering from primary hyperoxaluria and treated with lumasiran, for example, for at least 6 months, for example, at least 8 months, at least 10 months, or at least 1 year, and / or according to the EMA lumasiran treatment schedule, i.e., starting with 4 administrations at monthly intervals in adults, followed by 1 administration every 3 months. In some embodiments, the subject can be a human subject suffering from primary hyperoxaluria and treated with lumasiran, but showing results that are not sufficient with lumasiran alone. Results that are not sufficient with lumasiran alone are obtained when the primary endpoint of treatment with lumasiran, i.e., the 24-hour urinary oxalate excretion does not reach about 1.5 times the upper limit of normal (ULN), i.e., less than 68 mg / 24 hours. Treatment with the pharmaceutical dosage form taught herein in combination with lumasiran may advantageously reduce urinary oxalate to less than 44 mg / L of ULN.

[0155] The term "lumasiran" refers to a double-stranded siRNA for the treatment of primary hyperoxaluria that has the trademark name Oxlumo (Alnylam Pharmaceuticals Inc.) and targets hepatic messenger ribonucleic acid (mRNA) of HAO1 to reduce the level of glycolic acid oxidase (GO) enzyme via RNA interference. Reduction of the GO enzyme level decreases the amount of available glyoxylic acid, which is a substrate for oxalate production.

[0156] In embodiments of the uses or methods taught herein, the subject can be a human subject suffering from primary hyperoxaluria, diagnosed with renal dysfunction, and optionally in need of a kidney transplant. Treatment combining the pharmaceutical dosage forms taught herein with lumasiran and frequent dialysis, e.g., dialysis over at least 2 to 4 months, can advantageously reduce the oxalate load in the body of such a subject.

[0157] In embodiments of the uses or methods taught herein, the subject is a human subject suffering from primary or secondary hyperoxaluria and renal dysfunction. In embodiments of the uses or methods taught herein, the subject is a human subject suffering from primary or secondary hyperoxaluria and renal failure. For example, the subject can be a human subject suffering from primary hyperoxaluria and chronic kidney disease 3 - 5 (CKD3 - 5). Treatment with the pharmaceutical dosage forms taught herein can advantageously enable solubilization and removal of most of the calcium oxalate from the kidneys via secretion from the serum to the ileum and colon.

[0158] In embodiments of the uses or methods taught herein, the subject is a human subject suffering from primary hyperoxaluria and end-stage CKD or renal dysfunction (eGFR < 40 ml / min). These subjects are undergoing dialysis and may require kidney and liver transplantation. Since lumasiliran can significantly suppress oxalate production in the liver, liver transplantation can be avoided. By combining the pharmaceutical dosage form taught herein, which has a high ability to chelate secreted oxalate and excrete it from the intestinal tract, with lumasiliran, the oxalate load in the body of such subjects can be advantageously reduced. To avoid doubt, the transplanted kidney must be placed in an environment where the urinary oxalate concentration is less than 44 mg / L or less than 0.51 mmol / L so that crystal formation is not shown when urine formation resumes after kidney transplantation.

[0159] In embodiments of the uses or methods taught herein, the subject is a human subject suffering from secondary hyperoxaluria and moderate renal insufficiency.

[0160] In embodiments of the uses or methods taught herein, the pharmaceutical dosage form is: - once or twice a day; - an amount of lanthanum from 100 mg to 2000 mg per administration; - an amount of lanthanum from 100 mg to 4000 mg per day; and / or - for at least one month; for example, for at least two months and can be administered.

[0161] Preferably, the pharmaceutical dosage form is administered orally.

[0162] In embodiments of the uses or methods taught herein, the pharmaceutical dosage form can be administered at least once a day, such as at least twice a day, at least three times a day, or at least four times a day. Preferably, the pharmaceutical dosage form is administered once or twice a day, thereby improving patient compliance. In some embodiments, the pharmaceutical dosage form can be administered once a day, such as in the morning or evening. In some embodiments, the pharmaceutical dosage form can be administered twice a day, such as in the morning and evening. Preferably, the pharmaceutical dosage form is administered immediately before a meal (i.e., up to 60 minutes before, up to 30 minutes before, up to 15 minutes before, or up to 5 minutes after), during the meal, or immediately after the meal (i.e., up to 60 minutes after, up to 30 minutes after, up to 15 minutes after, or up to 5 minutes after), for example, immediately before, during, or after the largest meal of the day.

[0163] In embodiments of the uses or methods taught herein, the pharmaceutical dosage form can be administered in an amount of 100 mg to 2000 mg of lanthanum per administration. In some embodiments, the pharmaceutical dosage form can be administered in an amount of 250 mg to 1500 mg, 500 mg to 1000 mg, or 750 mg to 1000 mg of lanthanum per administration. Per administration, it can be administered in at least one dosage form (e.g., a capsule), such as at least two dosage forms, at least three dosage forms, at least four dosage forms, at least five dosage forms, or at least six dosage forms.

[0164] In embodiments of the uses or methods taught herein, the pharmaceutical dosage form can be administered in an amount of 100 mg to 4000 mg of lanthanum per day. In some embodiments, the pharmaceutical dosage form can be administered in an amount of 200 mg to 4000 mg, 500 mg to 3000 mg, 1000 mg to 2000 mg, or 1500 mg to 2000 mg of lanthanum per day.

[0165] In embodiments of the uses or methods taught herein, the pharmaceutical dosage form can be administered for a period of at least 1 month. In some embodiments, the pharmaceutical dosage form can be administered for a period of at least 2 months, at least two and a half months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months. In some embodiments, the pharmaceutical dosage form can be administered for a period of at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or longer, for example, at least 1 year, at least 2 years, at least 3 years, at least 4 years, at least 5 years, or longer. The pharmaceutical dosage forms taught herein do not cause a deficiency of phosphoric acid and thus advantageously enable long-term treatment of patients with primary and secondary hyperoxaluria.

[0166] The pharmaceutical dosage forms taught herein enable the treatment of one or more of hyperoxaluria, nephrolithiasis, nephrocalcinosis, or oxalosis.

[0167] As used herein, phrases such as "subject in need of treatment" include subjects who would benefit from treatment of a particular condition, particularly one or more of hyperoxaluria, nephrolithiasis, nephrocalcinosis, or oxalosis. Such subjects include, but are not limited to, subjects diagnosed with the condition, subjects prone to developing the condition, and / or subjects in need of preventing the condition.

[0168] The terms "treating" or "treatment" include both therapeutic measures for a disease or condition already developed, such as the treatment of already developed hyperoxaluria, nephrolithiasis, nephrocalcinosis or oxalosis, and prophylactic or preventive measures aimed at preventing or reducing the possibility of the occurrence of an undesirable disease, such as the prevention of the occurrence, onset and progression of hyperoxaluria, nephrolithiasis, nephrocalcinosis or oxalosis. Beneficial or desirable clinical outcomes include, but are not limited to, the alleviation of one or more symptoms or one or more biological markers, the reduction of the degree of the disease, the stabilization of the disease state (i.e., not worsening), the delay or deceleration of the progression of the disease, the improvement of the disease state, and the like. This term may include ex vivo or in vivo treatment.

[0169] The term "prophylactically effective amount" refers to the amount of a pharmaceutical formulation or an active compound such as lanthanum or a pharmaceutically acceptable salt or oxide thereof that a researcher, veterinarian, physician or other clinician desires to inhibit or delay the onset of a disease in a subject.

[0170] By the methods taught herein, a therapeutically effective amount of a pharmaceutical formulation or an active compound such as lanthanum or a pharmaceutically acceptable salt or oxide thereof can be administered to a subject suffering from one or more of hyperoxaluria, nephrolithiasis, nephrocalcinosis or oxalosis. The term "therapeutically effective amount" as used herein refers to the amount of an active compound or pharmaceutical formulation that elicits a biological or medical response in a subject, including, but not limited to, the alleviation of the symptoms of the disease or condition being treated, as desired by a surgeon, researcher, veterinarian, physician or other clinician. Methods for determining the therapeutically effective amount of lanthanum or a pharmaceutically acceptable salt thereof are known in the art.

[0171] The appropriate therapeutically effective amount of the active compound taught herein can be determined by a qualified physician, taking fully into account the nature of the active compound, the medical condition and its severity, as well as the age, build and condition of the patient.

[0172] According to a further aspect, there is provided a method of preparing a pharmaceutical dosage form as defined herein, in particular a capsule, comprising: - filling the capsule with lanthanum or a pharmaceutically acceptable salt or oxide thereof; - sealing the capsule; and - immersing the capsule in a coating solution configured for targeted delivery to the distal portion of the gastrointestinal tract of a subject, in particular the ileum, cecum and / or colon of the subject is provided.

[0173] In some embodiments, the method can include a prior step of opening the capsule.

[0174] In embodiments of the methods taught herein: - the capsule may be immersed in the coating solution at least three times; - the immersion time in the coating solution may be at least 10 seconds; - the coating may be dried before the next immersion step; for example, the coating may be dried for at least 3 minutes before the next immersion step.

[0175] In some embodiments, the coating solution can include one or more materials configured for targeted delivery to the distal portion of the gastrointestinal tract of a subject, in particular the ileum, cecum and / or colon of the subject. In some embodiments, the coating solution can include a pH-sensitive polymer, a biodegradable polymer, a polysaccharide, or a combination thereof. In some embodiments, the coating solution can include a polymer configured for targeted delivery to the distal portion of the gastrointestinal tract of a subject, in particular the ileum, cecum and / or colon of the subject, as taught herein.

[0176] In some embodiments, the coating solution can further include one or more additives or adjuvants such as a solvent, a plasticizer, a carrier, a surfactant, a thickening agent, a buffering agent, an antioxidant, a preservative, a flavoring agent, or a coloring agent. Suitable adjuvants are known in the art.

[0177] The solvent can be an organic solvent such as acetone. The solvent can be an aqueous solvent (i.e., an aqueous carrier or an aqueous solution). In some embodiments, the coating solution may not contain an organic solvent. In some embodiments, the coating may not contain an organic solvent.

[0178] The plasticizer can be any suitable plasticizer known in the art, such as triethyl citrate.

[0179] The term "plasticizer" refers to a substance or composition that brings about or promotes the plasticity or viscosity of a material.

[0180] In some embodiments, the coating solution can include a copolymer of methacrylic acid and methyl methacrylate, a solvent, and a plasticizer. For example, the coating solution can include a copolymer of methacrylic acid and methyl methacrylate in a ratio of 1:2, acetone, and triethyl citrate.

[0181] In some embodiments, the coating solution can include 2% - 20% by weight of a copolymer of methacrylic acid and methyl methacrylate, 75% - 97.5% by weight of a solvent, and 0.5% - 5% by weight of a plasticizer. For example, the coating solution can include 10% by weight of a copolymer of methacrylic acid and methyl methacrylate in a ratio of 1:2, 89% by weight of acetone, and 1% by weight of triethyl citrate.

[0182] The terms "weight percent", "%(w / w)", "mass percent", "weight percent", or "wt%" are used interchangeably herein and refer to 100 times the mass fraction w i The mass fraction w i is, as defined in (1), the ratio of the mass m tot of one compound to the mass m i of the total mixture (e.g., the coating solution taught herein).

Number

[0183] In some embodiments, the coating solution is: - dissolving a plasticizer (e.g., triethyl citrate) in a solvent (e.g., acetone); and - adding a copolymer of methacrylic acid and methyl methacrylate (e.g., Eudragit S 100) while stirring until completely dissolved to obtain a coating solution and can be adjusted thereby.

[0184] Stirring can be performed using a magnetic stirrer. Stirring can be performed for at least 30 minutes, e.g., at least 1 hour or at least 2 hours.

[0185] In embodiments of the methods taught herein, the capsules can be immersed in the coating solution at least 3 times, e.g., at least 4 times, at least 5 times, or at least 6 times. Preferably, the capsules are immersed 4 times in the coating solution.

[0186] In embodiments of the methods taught herein, the capsules are immersed in the coating solution for at least 10 seconds (sec) (i.e., the time to immerse and lift), e.g., at least 15 seconds, at least 20 seconds, at least 25 seconds, at least 30 seconds, or more. Preferably, the capsules are immersed in the coating solution for 15 seconds (i.e., the time to immerse and lift).

[0187] In embodiments of the methods taught herein, the coating may be dried for at least 3 minutes prior to the next dipping step. In embodiments of the methods taught herein, the coating may be dried for at least 4 minutes, at least 5 minutes, at least 6 minutes, at least 7 minutes, at least 8 minutes, at least 9 minutes, at least 10 minutes or at least 15 minutes prior to the next dipping step. Preferably, the coating is dried for 5 minutes prior to the next dipping step.

[0188] In some embodiments, the coating may be dried for at least 5 minutes, at least 8 minutes, at least 10 minutes, at least 15 minutes, at least 20 minutes, at least 25 minutes, at least 30 minutes or at least 45 minutes after the last dipping step. Preferably, the coating is dried for 15 minutes after the last dipping step.

[0189] In some embodiments, pharmaceutical dosage forms such as capsules taught herein can be stored at room temperature (e.g., 20 - 24 °C) until use.

[0190] According to the present application, aspects and embodiments described in the following statements are also provided.

[0191] Statement 1. An orally administrable pharmaceutical dosage form configured for targeted delivery to the distal portion of the gastrointestinal tract of a subject, the pharmaceutical dosage form comprising lanthanum or a pharmaceutically acceptable salt or oxide thereof. Statement 2. The pharmaceutical dosage form according to Statement 1, wherein the distal portion of the gastrointestinal tract is the ileum, cecum, colon or a combination thereof. Statement 3. The pharmaceutical dosage form according to Statement 1 or 2, which is a solid dosage form or a semi - solid dosage form. Statement 4. A capsule or tablet such as a capsule filled with a composition comprising lanthanum or a pharmaceutically acceptable salt or oxide thereof, preferably wherein the lanthanum or a pharmaceutically acceptable salt or oxide thereof is in powder form, the pharmaceutical dosage form according to any one of Statements 1 - 3. Statement 5. The pharmaceutical dosage form or capsule comprises a coating configured to be targeted for delivery to the distal portion of the gastrointestinal tract of a subject; preferably, the coating comprises a pH-sensitive polymer, a biodegradable polymer, a polysaccharide, or a combination thereof, and the pharmaceutical dosage form according to any one of Statements 1 to 4. Statement 6. The pharmaceutical dosage form or coating is a copolymer of methacrylic acid and a C 1-4 alkyl ester of methacrylic acid; preferably, a copolymer of methacrylic acid and methyl methacrylate; more preferably, a copolymer of methacrylic acid and methyl methacrylate in a ratio of 1:2, and the pharmaceutical dosage form according to any one of Statements 1 to 5. Statement 7. The capsule is made of one or more materials selected from the group consisting of cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose (HPMC), gelatin, pullulan, starch, water-soluble polyvinyl derivatives, polyethylene glycol, and a copolymer of a C 1-4 alkyl ester of (meth)acrylic acid and (meth)acrylic acid, and the pharmaceutical dosage form according to any one of Statements 4 to 6. Statement 8. The pharmaceutical dosage form or capsule comprises at least three layers of coating; preferably, the capsule comprises at least four layers of coating; and / or the thickness of the coating is at least 20.0 μm, such as at least 25.0 μm, at least 30.0 μm, or at least 35.0 μm, and the pharmaceutical dosage form according to any one of Statements 1 to 7. Statement 9. The pharmaceutically acceptable salt or oxide of lanthanum is lanthanum carbonate or lanthanum oxide; preferably, the pharmaceutical dosage form comprises lanthanum carbonate, and the pharmaceutical dosage form according to any one of Statements 1 to 8. Statement 10. The pharmaceutical dosage form comprises 100 mg to 4000 mg of elemental lanthanum, and the pharmaceutical dosage form according to any one of Statements 1 to 9. Statement 11. The composition containing lanthanum or a pharmaceutically acceptable salt or oxide thereof is filled, and C of methacrylic acid and methacrylic acid1-4 Capsules coated with a copolymer with an alkyl ester. A pharmaceutical dosage form according to any one of Statements 1 to 10. Statement 12. A pharmaceutical dosage form according to any one of Statements 1 to 11, which is used in the treatment of hyperoxaluria in a subject, optionally wherein the hyperoxaluria is primary hyperoxaluria or secondary hyperoxaluria. Statement 13. A pharmaceutical dosage form according to any one of Statements 1 to 11, which is used in the treatment of one or more of nephrolithiasis, nephrocalcinosis or oxalosis in a subject. Statement 14. A pharmaceutical dosage form for use according to either Statement 12 or 13, wherein the subject is human. Statement 15. The pharmaceutical dosage form is: - once or twice a day; - an amount of lanthanum of 100 mg to 2000 mg per administration; - an amount of lanthanum of 100 mg to 4000 mg per day; and / or - for at least one month; for example, for at least two months A pharmaceutical dosage form for use according to any one of Statements 12 to 14, which is administered.

[0192] The above-described aspects and embodiments are further supported by the following non-limiting examples.

Example

[0193] Example 1: Preparation of an orally administrable pharmaceutical dosage form according to an embodiment of the present invention configured to be targeted for delivery to the distal portion of the gastrointestinal tract of interest According to this example, according to an embodiment of the present invention, there is provided a method for preparing an orally administrable pharmaceutical dosage form configured for targeted delivery to the distal portion of the gastrointestinal tract of a subject, in particular a capsule comprising a coating configured for targeted delivery to the distal portion of the gastrointestinal tract of the subject.

[0194] The capsules were cellulose acetate phthalate (CAP) capsules. The active ingredient was prepared from Fosrenol sub-packets (Shire Pharmaceutics, Dublin, Ireland) containing 750 mg of lanthanum element in the form of lanthanum carbonate (La2(CO3)3). The other ingredients of Fosrenol were dextran (hydrate), colloidal anhydrous silica and magnesium stearate.

[0195] The capsules were filled with a powder mixture of "Fosrenol sub-packet 750". One-third of the sub-packet was filled into the capsules, which means that 250 mg of lanthanum element was used, corresponding to ±500 mg of lanthanum carbonate per capsule.

[0196] The capsules were coated. The composition of the coating solution was: - Eudragit S 100: 10% (w / w) (Evonik Industries, Belgium) - Triethyl citrate: 1% (w / w) (Sigma Aldrich, Germany) - Acetone: 89% (w / w) (Acetone Extra Pure, Fagron, Netherlands) as follows.

[0197] The coating solution was prepared by dissolving triethyl citrate (plasticizer) in acetone. Eudragit S 100 was gradually added while stirring with a magnetic stirrer and completely dissolved over 1 - 2 hours.

[0198] Using a manual coater (Feton International), the filled size 00 capsules were manually coated with Eudragit according to the following procedure: First, the capsule body was immersed with an immersion and withdrawal time of 15 seconds; the immersion of the capsule body was repeated up to 3 times. Then, at the end of the test (see below), a fourth coating step was performed on the body with a coating configured to be targeted delivered to the distal part of the gastrointestinal tract of interest, thereby preparing a pharmaceutical dosage form as an example of the present invention.

[0199] The drying time between each layer was set at 5 minutes, and the fourth layer was dried for 15 minutes.

[0200] The prepared capsules were stored at room temperature of 20 - 24°C.

[0201] When a manual screw micrometer was used, the average thickness of the uncoated capsules was 0.145 mm ± 0.0054 mm (n = 5). The average thickness of the coated capsules (4 layers) was 0.174 mm ± 0.0037 mm (n = 5).

[0202] The coating efficiency tests were conducted under two different environments, an acidic environment and a more basic environment.

[0203] In the first test, as described in the protocol, the capsules were coated with 3 layers. One coated capsule was placed in a weighing cup containing acetic acid buffer at pH 4.6 (the acidity of gastric juice during digestion). The temperature was maintained at 35°C and it was left standing on a magnetic stirrer. After 2 hours, the capsule did not retain its complete form.

[0204] In the second test, as per the protocol, the capsules were coated with 3 layers. The coated capsules were placed in a carbonate buffer at pH 8. After 15 minutes, a color change appeared at the seam in about half of the capsules, and the coating began to penetrate and dissolve. After 20 minutes, the contents were released into the surrounding liquid.

[0205] Pilot experiments were conducted on healthy volunteers using capsules with different coating procedures (no layer, 1 layer, 2 layers, 4 layers, and 5 layers). During the experimental period: during the control period (i.e., before treatment), during treatment, and during the washout period (i.e., after treatment), 24-hour urine collections were performed daily. In all of these 24-hour urine collections, oxalate, phosphate, calcium, and creatinine were measured. By measuring creatinine, the accuracy of the 24-hour collection was confirmed. When capsules without a coating or capsules with a 1- or 2-layer coating were used, there was no effect or only a very slight effect on oxalate urine, phosphate urine, and calcium salt urine (results not shown).

[0206] However, when capsules with a 4-fold coating were used, there was a clear effect on oxalate urine, with urinary oxalate decreasing by up to 40% or more compared to the control value (see Example 2, Figure 3). During this short clinical trial, no clear effect was seen on phosphate urine and calcium salt urine (see Example 2, Figure 3). Two days after discontinuation of ingestion, oxalate urine was equivalent to the control value before the start of the experiment (see Example 2, Figure 3). When capsules with a 5-layer coating were used, the effect on the chelation of oxalate in patients did not seem to increase compared to when capsules with a 4-layer coating were used.

[0207] After monitoring the behavior of uncoated capsules in the intestinal tract of the test subjects with radiation, rapid release of the capsules was observed in the proximal part of the gastrointestinal tract (results not shown). Therefore, the capsules were coated with a fourth coating layer and, if necessary, a fifth coating layer, and an acceptable result of targeted release was obtained (for capsules with a 4-layer coating, see Example 2, Figure 2).

[0208] An exemplary pharmaceutical dosage form of the present invention, particularly an exemplary capsule of the present invention, contains 250 mg of elemental lanthanum and is coated with a four-layer coating configured for targeted delivery to the distal portion of the gastrointestinal tract of a subject, particularly to one or more of the ileum, cecum, or colon of the subject.

[0209] In a further preparation method of the exemplary pharmaceutical dosage form of the present invention, capsules of size 00, size 0, size 1, and size 2 were used. These capsules were filled with lanthanum such that they contained 560 mg, 420 mg, 295 mg, and 230 mg of elemental lanthanum, respectively.

[0210] Example 2: Release of lanthanum carbonate in the distal portion of the gastrointestinal tract from a pharmaceutical dosage form according to an embodiment of the present invention Using a Shimadzu Sonialvision G4 radiography device, the intestinal transit of an exemplary capsule of the present invention (i.e., one coated four times according to Example 1) was tested by X-ray. After ingestion of two capsules (each containing 250 mg of elemental lanthanum) orally, sequential images of the abdomen of a healthy volunteer were taken in the anteroposterior direction in an upright position. The images were taken every 30 minutes over a period of 360 minutes (6 hours). Immediately after swallowing both capsules, the capsules were visible in the stomach in the first image at "0 minutes" (Figure 6). After 30 minutes, the capsules were broken down into four large fragments and moved into the duodenum and jejunum (Figure 2A). After 60 minutes and 90 minutes, the large fragments moved further distally (Figure 2B, Figure 6). 120 minutes after oral ingestion, the large capsule-like fragment was approximately at the position of the distal ileum, and punctate lanthanum particles were clearly visible (Figure 6). After 150 minutes, the large capsule and punctate particles reached the position of the cecum via the Bauhin valve (results not shown). Over the next 30 minutes, the number of large capsule-like lanthanum fragments gradually decreased, and the punctate particles gradually increased, indicating further release of the capsule (Figure 6). After 240 minutes, lanthanum was released into the colon (Figure 2C, Figure 6). In the last exposure at 360 minutes, all fragments were in the colon, and the most distal capsule residue was at the hepatic corner of the colon.

[0211] This test was also conducted in two other patients with primary hyperoxaluria, and the same results were shown.

[0212] Furthermore, the effects of orally ingesting two capsules (each containing 250 mg of lanthanum; four-coated capsules) as an example of the present invention in the morning and another two (each 250 mg of lanthanum) in the evening (i.e., a total daily dose of 1000 mg of elemental lanthanum) were tested in healthy human individuals for 7 days (days 3 to 9 in Figure 3). The levels of urinary oxalate (mg / L), phosphate (P) (in mmol / L units), and calcium (Ca) (in mmol / L units) in 24-hour urine collections were measured (Figure 3). Figure 3 shows the effect of 1000 mg / day of elemental lanthanum by four administrations of 250 mg (two capsules of 250 mg in the morning and two capsules of 250 mg in the evening) on the excretion of urinary oxalate (mg / L) in healthy volunteers.

[0213] There was an obvious effect on oxalaturia, and during the 7-day treatment period, urinary oxalate decreased by up to 46% compared to the control value (Figure 3, black bars). During this short clinical trial after 7 days of treatment in healthy individuals, no measurable effects were seen on phosphaturia (dark gray) and calciuria (light gray) (Figure 3). Two days after discontinuation of ingestion, oxalaturia was equivalent to the control value before the start of the experiment (Figure 3, day 11).

[0214] From these results and the results of X-ray examinations, it was confirmed that lanthanum was mainly released in the ileum and proximal colon.

[0215] Example 3: Treatment of patients with primary and secondary hyperoxaluria using a pharmaceutical dosage form according to an embodiment of the present invention A proof-of-concept trial was initiated in four patients with primary hyperoxaluria and one patient with secondary hyperoxaluria. The patients were selected from the University Hospital of Ghent (Belgium) (n = 2) and the University Hospital of Antwerp (Belgium) (n = 2) and met the inclusion criteria / exclusion criteria: age: over 9 years, genetically confirmed primary hyperoxaluria, estimated glomerular filtration rate (eGFR) > 50 ml / min / 1.73 m 2and have not received treatment with lumasiran (Oxlumo), with urinary oxalate excretion of at least 0.60 mmol (52.2 mg) per 1.73 m 2 ² per 24 hours and no clinical evidence of extra-renal systemic oxalosis. Patients were asked to continue the standard treatment regimen for primary hyperoxaluria in place at the time of enrollment in this trial.

[0216] The primary endpoints were defined as follows: - Oxalate urine concentration of less than 0.50 mmol / L (44 mg / L) with calcium urine of less than 4 mmol / L (160 mg / L). These two conditions are considered essential in situations where calcium oxalate crystals do not form in the urine. - Stable and normal urinary phosphate concentration (> 350 mg / L to 1200 mg / L) and serum phosphate concentration (30 - 45 mg / L) indicate no progression of phosphate depletion over time. - Stable or slightly decreased calcium urine indicates a calcium channel blocking effect of the treatment.

[0217] Laboratory tests Various parameters of patients with primary hyperoxaluria are summarized in Table 2. All clinical tests (hematology, liver tests, and renal function tests) were performed at Algemeen Medisch Laboratorium (A.M.L., Antwerp, Belgium) according to international standards. Oxalate in urine and serum was measured by liquid chromatography - tandem - mass spectrometry (LC - tandem - MS). Oxalic acid - C13 was used as an internal standard. Samples were hydrolyzed and derivatized with a hydrochloric acid - butanol mixture. After incubation and centrifugation, 1 μl of the upper layer was injected into the instrument. Good to excellent results were obtained in the quality control of "Referenzinstitut fur Bioanalytik" Bonn, Prof D.C. Knabbe, 2021.

[0218]

Table 2

[0219] Dosage of the exemplary pharmaceutical dosage form of the present invention The patient was administered a capsule containing the pharmaceutical formulation prepared in Example 1, which is an example of the present invention, namely 250 mg of elemental lanthanum and a four-layer coating configured to be targeted for delivery to the distal portion of the gastrointestinal tract of the subject. At the start of treatment, two capsules were administered at the most frequent meal of the day, i.e., two capsules in the morning and two capsules in the evening (i.e., 4 × 250 mg = 1000 mg of elemental lanthanum per day). Depending on the results of urinary oxalate excretion (concentration > 44 mg / L, i.e., the upper normal limit), this starting dose was increased to three capsules in the morning and three capsules in the evening (i.e., 6 × 250 mg = 1500 mg of elemental lanthanum per day) at the same timing as the starting dose, and further to four capsules in the morning and four capsules in the evening (i.e., 8 × 250 mg = 2000 mg of elemental lanthanum per day).

[0220] Patients From the start of this proof-of-concept study, the patient was asked to collect 24-hour urine samples during the control period (before treatment), during the treatment period, and after treatment withdrawal. In all of these 24-hour collections, oxalate, phosphate, calcium, and creatinine were measured. The accuracy of the 24-hour collection was confirmed by measuring creatinine.

[0221] Among 4 patients with primary hyperoxaluria, 3 (see Table 2) showed an obvious positive response 2.5 to 3 months after the start of treatment. Figure 4 shows, for a patient with severe type 1 primary hyperoxaluria (Patient 1), (A) oxalate urine (mg / L), (B) oxalate urine (mg / gr creatinine), (C) calcium urine (mg / gr creatinine), (D) phosphate urine (mg / gr creatinine), and (E) serum oxalate (mg / L) before, during, and 2.5 months after treatment with the pharmaceutical dosage form that is an example of the present invention. As shown in Figure 4, the patient ate nuts during the low-phosphate treatment period. From various methods of measuring oxalate excretion, it was judged that the patient showed a good response to the treatment. The normal phosphate urine at the start of treatment did not change during the treatment period. The same was true for calcium urine (Figure 4).

[0222] The fourth patient with primary hyperoxaluria did not show a very good response initially. The oxalate concentration (mg / L) decreased by 36%. The 24-hour oxalate urine in urine decreased by 55%, but still did not reach the evaluation item. One year and 7 months later (there were several periods with insufficient medication compliance), the urinary oxalate value (n = 3) of the patient was 28 mg / L, which was clearly below the ULN of oxalate urine.

[0223] All patients reached the following three evaluation items. - Oxalate urine less than 0.50 mmol / L (44 mg / L) accompanied by calcium urine less than 4.0 mmol / L (160 mg / L) (Table 2, and Figures 4A, 4B, 4E) - Stably normal serum phosphate concentration (0.9 - 1.5 mmol / L; 30 - 45 mg / L) and urinary phosphate concentration (> 350 mg / L) (Table 2, and 4D) - Stable maintenance without an increase in the concentration of calcium urine during the treatment period (Table 2, and Figure 4C).

[0224] The results of patients with secondary hyperoxaluria are shown in Fig. 5. Fig. 5 shows, for a patient with secondary hyperoxaluria (patient 5, idiopathic calcium oxalate urolithiasis type), (A) oxalate urine (mg / L), (B) oxalate urine (mg / gr creatinine), (C) oxalate in serum (mg / L), (D) calcium urine (mg / gr creatinine), and (E) phosphate urine (mg / gr creatinine) before, during, and after treatment with a pharmaceutical dosage form according to an embodiment of the present invention.

[0225] Patients with secondary hyperoxaluria showed a reaction that the oxalate urine already decreased from 49 mg / L to 21 mg / L (i.e., a 58% decrease) one week after the start of treatment with a pharmaceutical dosage form according to an example of the present invention in which 1000 mg of lanthanum element is administered in two divided doses (i.e., 8 × 250 mg = 2000 mg / day of lanthanum element) (Fig. 5). 250 mg of lanthanum element was administered 4 times in the morning and 250 mg of lanthanum element was administered 4 times in the evening. After the end of treatment, the oxalate level increased to the pre-treatment level 2 days later. The reason that various oxalate urine parameters of patients with secondary hyperoxaluria normalized quite rapidly is considered to be that the oxalate pool of these patients is lower than that of patients with primary hyperoxaluria.

[0226] The patients reported no side effects during the treatment period.

[0227] Discussion A pharmaceutical dosage form containing a clearly defined amount of lanthanum carbonate exemplifying the present invention enables the targeted release of lanthanum at an exact location, namely the distal part of the gastrointestinal tract, such as the ileum, cecum, and anterior colon, whereby all physiological parameters are maximally satisfied. After testing several formulations, treatment with a pharmaceutical dosage form according to an embodiment of the present invention, in particular a capsule containing a four-layer coating configured for targeted delivery to the distal part of the gastrointestinal tract of the subject, showed that: - Lanthanum carbonate is released in the posterior small intestine (ileum) and anterior colon as tested using CT scan technology over 6 hours after ingestion of the pharmaceutical dosage form according to an embodiment of the present invention; - By optimal gastrointestinal chelation of oxalate (discovered by the inventors to be mainly absorbed in the ileum and colon), the urinary concentration is significantly reduced to less than 0.50 mmol / L (44 mg / L). Thus, administration of a pharmaceutical dosage form according to an embodiment of the present invention treats primary hyperoxaluria or secondary hyperoxaluria; - In patients suffering from primary hyperoxaluria and secondary hyperoxaluria, the urinary phosphorus concentration does not change and remains stably normal, maintaining a normal phosphate balance throughout the treatment period. These observations indicate that phosphate is reabsorbed in the more proximal gastrointestinal tract; - In contrast to the increase in calcium urine observed with all other currently known potent phosphate binders (aluminum, Sevelamer, calcium carbonate, etc.), which may promote the formation of calcium oxalate crystals, no increase in calcium urine is seen in patients treated with a pharmaceutical dosage form according to an embodiment of the present invention; - The pharmaceutical dosage form according to an embodiment of the present invention maintains or slightly decreases urinary calcium throughout the treatment period. This stably normal or, in some cases, slightly decreased calcium urine is due to the calcium channel blocking effect of lanthanum in the distal part of the GI tract and may contribute to preventing the formation of calcium oxalate crystals; - The rapid normalization of various oxalate urine parameters in patients with secondary hyperoxaluria can be explained by the fact that the oxalate pool accumulated in these patients is lower than that in patients with primary hyperoxaluria resulted in.

[0228] The final result of treatment with a pharmaceutical dosage form according to an embodiment of the present invention is unique. This is the first time as a treatment method to stop / prevent calcium oxalate crystal formation (oxalate urine of less than 44 mg / L or 0.50 mmol / L accompanied by calcium salt urine of less than 160 mg / L or 4.0 mmol / L) in the renal / urinary tubular fluid.

[0229] Advantageously, the pharmaceutical dosage form according to the embodiments of the present invention is not limited to the treatment of one type of primary hyperoxaluria or secondary hyperoxaluria (in contrast to, for example, lumasiran (Oxlumo, manufactured by Alnylam), where the inhibitory activity of oxalic acid synthesis in the liver is limited to type 1 primary hyperoxaluria), and its pharmacological activity lies in the optimal chelation of oxalate that is ingested and secreted in the distal part of the gastrointestinal tract (as shown in Table 2), and thus is effective for all forms of primary hyperoxaluria.

[0230] Furthermore, the treatment with the pharmaceutical dosage form according to the embodiments of the present invention (also referred to herein as "specially designed lanthanum carbonate capsule" or "sdc lanthanum carbonate" or "sdcLC") involves more than just the chelation of oxalate in daily diet. Without being bound by theory, it is hypothesized that the treatment with the pharmaceutical dosage form according to the embodiments of the present invention may mediate the secretion of oxalate from the serum to the colon by the SLG26A transporter. As can be seen in Figure 4A, as a result of the 2.5-month treatment of Patient 1 with the pharmaceutical dosage form according to the embodiments of the present invention, the urinary oxalate concentration was below the normal upper limit (ULN: 44 mg / L). Patient 1, who suffered from type 1 PH and had normal renal function, had an average oxalaturia of 94 mg / L ± 4.8 mg / L (control value n = 12, 24-hour urine collection) during the control period (Figure 4A, Table 2), and the average daily diuresis was 2.5 L / day ± 0.3 L / day. Considering that the average oxalate concentration in food was 150 - 200 mg / day (i.e., approximately 2 mmol / day) and 15 - 20% was absorbed in the intestinal tract (Holmes et al., 2000, Kidn Intern, 57, 1662 - 1667), the daily dietary oxalate load was approximately 30 mg / day (i.e., 200 mg / day × 15%) (Figure 7).

[0231] Six to eight weeks after the start of treatment, urinary oxalate excretion decreased from 94 mg / L to 18 mg / L (Figure 4A, Table 2). During treatment with the pharmaceutical formulation according to an embodiment of the present invention, lanthanum was administered at 1500 mg (11 mmol) per day, and the lanthanum / oxalate molar ratio was 5.5 (i.e., 11 mmol / 2 mmol), so it can be considered that almost all of the oxalate in food was chelated by lanthanum in the distal GI tract. Therefore, oxalate in food became unavailable for the body's oxalate load.

[0232] Chelating only 30 mg / day of dietary oxalate was insufficient to explain the marked decrease in urinary oxalate excretion from 235 mg (i.e., 94 mg / L × 2.5 L) to 45 mg (i.e., 18 mg / L × 2.5 L) over time. Oxalate production in the liver remained intact and there was no systemic effect of lanthanum. Furthermore, gastrointestinal absorption of lanthanum is negligible (0.01%) (Persy et al., 2006, Sem Dialysis, 19, 198 - 199).

[0233] Therefore, the above facts suggest that when treating patients with primary hyperoxaluria with the pharmaceutical formulation according to an embodiment of the present invention, another mechanism in addition to chelation of oxalate from food was functioning in the oxalate balance. One of them is perhaps the redirection of oxalate from serum to the distal intestinal lumen by secretion of oxalate (mediated by the SLC26A6 transporter), which further reduces the body's oxalate. This secreted oxalate was immediately chelated in the distal part of the GI tract, i.e., the ileum, cecum, and / or colon, containing free lanthanum released from the pharmaceutical formulation (Figure 7). The chelation product was preferably excreted via feces.

[0234] Conclusion The overall effect of the pharmaceutical dosage form according to the embodiments of the present invention lies in the optimal chelation of oxalate ingested daily in the distal part of the GI tract, whereby the secretion of oxalate (mediated, for example, by the SLC26A6 transporter) stimulates the re-direction of oxalate from the serum into the intestinal lumen.

[0235] The combination of the optimal chelation of oxalate, which results in a significant decrease in urinary oxalate, and the calcium channel blocking effect in the intestine of the pharmaceutical dosage form according to the embodiments of the present invention, which maintains or slightly decreases the urinary calcium concentration, prevents the formation of calcium oxalate crystals. Furthermore, the pharmaceutical dosage form according to the embodiments of the present invention provides the treatment of hyperoxaluria and normal and stable phosphate concentrations in the urine, indicating the absence of progressive phosphate deficiency in all types of primary and secondary hyperoxaluria.

[0236] Example 4: Investigation of the localization and release of an exemplary pharmaceutical dosage form of the present invention during gastrointestinal transit using a continuous X-ray imaging device and an ultra-low-dose computed tomography device The objective of this investigation is a proof of concept that the pharmaceutical dosage form exemplifying the present invention can release lanthanum in the ileum and colon. The pharmaceutical dosage form exemplifying the present invention (hereinafter also referred to as "specially designed capsule lanthanum carbonate" or "sdc lanthanum carbonate" or "sdcLC") was prepared as described in Example 1, i.e., as a capsule containing 250 mg of lanthanum element, or similarly as a capsule containing up to 500 mg of lanthanum element. As shown in Figure 8, the capsule appeared as a radiopaque structure on the X-ray image.

[0237] Design and execution of a task verification test Preliminary results Since lanthanum is a metallic chemical element with an atomic weight of 138.91 g / mol, it is radiopaque and can be easily confirmed in X-ray images. In order to achieve appropriate pharmacological activity, the inventors have found that lanthanum needs to reach the ileum, cecum and / or colon intact, and at the same time it is necessary not to interfere with the reabsorption of phosphate in the proximal part of the gastrointestinal tract. The test was conducted using a Shimadzu Sonialvision G4 radiography device for the small intestine transit test (see Example 2).

[0238] Test design From this preliminary test, a forward study is conducted using continuous ultra-low dose computed tomography (ULDCT) as an alternative mode of continuous RX imaging, so that the topography can be optimized and the location where lanthanum dissolves can be displayed in detail. The radiation dose may be optimized to be lower than the dose administered in conventional small intestine transit tests. The ULDCT scan protocol is derived by reducing the exposure parameters and adjusting the standard CT abdomen protocol using Adaptive Statistical Iterative Reconstructions (ASIR (registered trademark)), which is an iterative reconstruction available in the system. The tube voltage is reduced to 120 kV to 100 kV, the noise index is increased to 28 to 70, and the tube current window is between 30 mA and 400 mA to maintain a constant image quality. The data is reconstructed with 100% ASIR. The effective dose of one ULDCT scan of the abdomen (CTDIvol = 1.7 mGy, DLP = 58 mGycm) is 0.3 to 0.4 mSv, while the effective dose of a standard diagnostic CT scan (CTDIvol = 12.7 mGy, DLP = 673 mGycm) is 10.4 mSv. In the case of a standard plain abdominal radiograph, the effective dose is approximately 0.8 mSv (two projections).

[0239] It is expected that the pace of intestinal activity varies somewhat from patient to patient, and thus the distal movement of the lanthanum particles also varies. To identify the position of lanthanum release from the capsule, continuous scans are performed at the following time intervals: immediately after ingestion of 3 capsules (the dosage varies for children aged 6 - 11 years and adults, and for children it is determined based on body surface area), and scans are performed every 30 minutes until all of the lanthanum particles, which appear as punctate radiopaque points in the intestine, are located within the colon. This is expected to be completed within 360 minutes (6 hours).

[0240] Several healthy volunteers (n = 5) and several patients suffering from PH (n = 5, 3 adults and 2 children aged 6 - 11 years) participated in this study. These subjects were administered pharmaceutical dosage forms according to embodiments of the present invention (for example, 3 capsules of 500 mg of elemental lanthanum for adults and 3 small capsules of 250 mg of elemental lanthanum for children), and ULDCT was performed before the actual treatment began.

[0241] The GI tract is divided into six compartments: the stomach, duodenum, jejunum, ileum, ascending colon, and descending colon. When analyzing the photographs of healthy subjects and PH patients, the presence of intact lanthanum and released lanthanum is scored in a blinded manner. The scoring is as follows: 0 points if no lanthanum particles are present in the compartment, 1 point if an intact capsule is present, 2 points if large fragments of the capsule are present, 3 points if larger punctate fragments are visible, and 4 points if only punctate fragments are present in the compartment.

[0242] Delivery Clinical verification of the localization of lanthanum carbonate release from the capsule and the final concentration of lanthanum in the ileum and colon.

[0243] Landmark This study is planned over a period of 1.5 years to ensure time for recruiting healthy volunteers and patients before starting treatment with sdcLC.

[0244] Risk Scientific risk: The verification test does not meet the success criteria: Considering the results obtained from the proof-of-concept conducted three times in healthy individuals, the score is low.

[0245] The recruitment of healthy subjects and patients in this trial is slow, and the number of participating adults and children cannot be found: The score is low. So far, we have not faced refusal from patients suffering from PH. The extra effort of 24-hour urine collection has not been refused. Participating in the flow cytometry analysis of all urine samples for half a day and staying in the laboratory are acceptable. Accurate and open information about the patients and the relevance of the investigation is helpful.

[0246] The proposed technology enables the realization of radiation for ultra-low-dose CT (ULDCT).

[0247] Example 5: Clinical validation study of the pharmacological efficacy of a pharmaceutical dosage form according to an embodiment of the present invention in patients with primary hyperoxaluria A controlled, randomized, multi-center, international (Belgium, Algeria, Tunisia, Morocco), double-blind, crossover clinical trial will be planned for 30 patients with primary hyperoxaluria (PH). After a 1-month control period, a 6-month × 2 treatment period with a 2-month washout period will be applied. Randomization is planned centrally, and blinding will be applied to both patients and treating physicians at the treatment sites. Treatment starts, for example, with the pharmaceutical form according to an embodiment of the invention, i.e., sdc lanthanum carbonate capsules prepared as described in Example 1, with elemental lanthanum at about 1000 mg / day. The treatment can be gradually increased, for example, up to about 2000 mg / day of elemental lanthanum. For children aged 5 - 15 years, in consultation with the attending pediatrician, a dose according to body surface area will be prescribed. Patients in the placebo group will be randomly selected, and the investigational medicinal product (IMP) will be gradually increased accordingly. The results of the treatment will be investigated by collecting 24-hour urine samples regularly (twice a month) for central measurement of oxalate. The hypotheses to be tested are: (1) whether treatment with sdcLC for 6 months reduces oxalate urine to a level at which calcium oxalate crystals do not form in the urine (ULN: 44 mg / L), and thus whether oxalate urine is reduced to a maximum of 44 mg / L, and (2) whether treatment with sdcLC for 6 months reduces oxalate urine by 60% in at least 75% of the patients.

[0248] Example 6: Enriched uses for the treatment of patients using a pharmaceutical dosage form according to an embodiment of the present invention Clinical validation of the additional effect of sdcLC administered to patients treated with lumaciran and showing results that are not sufficient with lumaciran alone According to the results of the lumasiran study (Garrelfs et al., 2021, N Engl J Med, 384(13): 1216-1226), among patients with PH, the proportion of patients with a 24-hour urinary oxalate excretion level below the upper limit of normal (ULN) (ULN = 0.51 mmol / L or 44 mg / L) at 6 months was 52%. Therefore, among the patients treated with this medicine, there were also those with very low urinary oxalate levels or those who did not reach the level where crystal formation does not occur. Patients were considered eligible for enrollment after being treated with lumasiran for 6 months according to the correct EMA lumasiran treatment schedule (i.e., for adults, administered 4 times at monthly intervals and then once every 3 months). If the main endpoint of lumasiran treatment was not reached after 6 months, patients were asked to participate in this observational study. The main endpoint of lumasiran treatment is for the 24-hour urinary oxalate excretion level to reach less than about 1.5 times the upper limit of normal (ULN), i.e., less than 68 mg / 24 hours. Patients (n = 5) were additionally treated with sdcLC, which is elemental lanthanum at, for example, about 1000 mg / day. The treatment can be gradually increased to elemental lanthanum up to about 2000 mg / day. Sampling is the same as the requirements described in the clinical validation test of Example 5.

[0249] A second group of PH patients is also a candidate for combination treatment with lumasiran and sdcLC, i.e., PH patients with end-stage renal failure during dialysis who require kidney transplantation. To significantly reduce the oxalate load present in the body of this type of patient, a strong and intensive removal treatment is necessary. This treatment may consist of a combination of lumasiran treatment and sdcLC combined with frequent dialysis for at least 2 to 4 months. Since the patients do not have significant renal function, it is essential to monitor the plasma oxalate level. SdcLC treatment and sampling are the same as the requirements described in the clinical validation test of Example 5.

[0250] Clinical validation of the effect of sdcLC administered to patients suffering from primary or secondary hyperoxaluria and renal dysfunction Patients suffering from primary hyperoxaluria and chronic kidney disease (CKD3 - 5) have significant accumulation of calcium oxalate in tissues and need treatment to solubilize and remove most of the calcium oxalate through secretion from serum to the ileum and colon, so they are candidates for treatment with sdcLC capsules.

[0251] Furthermore, patients suffering from PH and end - stage CKD or renal dysfunction (eGFR < 40 ml / min) who are on dialysis and in need of kidney and liver transplantation are also candidates for treatment with sdcLC capsules. Since lumasiran can significantly suppress oxalate production in the liver, physicians have been trying to limit transplantation to kidney transplantation for several years. Since lumasiran does not always produce satisfactory effects and serum levels may remain too high to safely perform kidney transplantation, sdcLC treatment with a high ability to chelate secreted oxalate and excrete it from the intestine is very interesting. To avoid doubt, the transplanted kidney needs to be placed in an environment with a urinary oxalate concentration of less than 44 mg / L to prevent crystal formation when urine formation resumes after kidney transplantation.

[0252] A further group of patients in need of treatment with sdcLC are those with secondary hyperoxaluria associated with moderate renal insufficiency.

[0253] Comparative example: Administration of uncoated lanthanum carbonate to humans To compare the effects of uncoated lanthanum carbonate capsules and the coated lanthanum carbonate capsules (see Example 1 and Figure 3) which are examples of the present invention on oxalateuria, calciuria and phosphaturia, healthy human volunteers were orally administered Fosrenol (Shire Pharmaceuticals), that is, lanthanum carbonate itself, at a dose of 500 mg / day of elemental lanthanum (2 × 250 mg elemental lanthanum). Healthy human volunteers (male, 74 years old, eGFR 73 ml / min / 1.73 m 2) had normal kidney function, no diabetes, normal blood pressure, and no other medical conditions. Figure 9 is a graph showing (A) the urinary oxalate concentration (mg / g creatinine, dark gray bars) and urinary calcium (Ca) concentration (mmol / g creatinine, light gray bars), or (B) the urinary phosphate (P) concentration (mmol / L, gray bars) and serum phosphate (P) concentration (mmol / L, black bars) in healthy volunteers who orally ingested Fosrenol. From this figure, it can be seen that during this short clinical trial, administration of uncoated lanthanum carbonate decreased the urinary phosphate concentration (Figure 9B), but had no effect on the serum phosphate concentration (Figure 9B) or urinary oxalate concentration (Figure 9A). These results are in contrast to the results obtained after administration of the pharmaceutical dosage form (Example 1, Figure 3) of the present invention, in which urinary oxalate decreased by more than 40% compared to the control value (see Figure 3). No obvious effect on phosphateuria and calciuria was observed (see Figure 3). Administration of uncoated lanthanum carbonate decreased urinary phosphate but had little effect on oxaluria, suggesting that phosphate is preferentially chelated over oxalate (phosphate / oxalate ratio in food 10 / 1), and thereby, in subjects whose renal function is not impaired or relatively preserved (eGFR > 40 ml / min / 1.73m 2 ) It was confirmed that when lanthanum carbonate was administered to, phosphate deficiency occurred over time and severe complications such as osteomalacia occurred.

Claims

1. An orally administered pharmaceutical dosage form comprising lanthanum or a pharmaceutically acceptable salt or oxide thereof, wherein the lanthanum or a pharmaceutically acceptable salt or oxide thereof is configured to be targeted and delivered to one or more parts of the ileum, cecum, or colon of a human subject, and the pharmaceutical dosage form comprises a polymer that does not decompose at a pH of less than 6.

8.

2. The pharmaceutical dosage form according to claim 1, wherein the lanthanum or a pharmaceutically acceptable salt or oxide thereof is configured to be targeted and delivered to one or more parts of the ileum, cecum, or ascending colon of a human subject.

3. The pharmaceutical dosage form according to claim 1, which is a solid dosage form or a semi-solid dosage form.

4. The pharmaceutical dosage form according to claim 1, which is a capsule or tablet, such as a capsule, filled with a composition containing the lanthanum or a pharmaceutically acceptable salt or oxide thereof, preferably in the form of a powder, wherein the lanthanum or a pharmaceutically acceptable salt or oxide thereof is in powder form.

5. The pharmaceutical dosage form or capsule according to claim 1, wherein the pharmaceutical dosage form or capsule comprises a coating configured such that the lanthanum or a pharmaceutically acceptable salt or oxide thereof is targeted delivery to one or more parts of the ileum, cecum, or colon of a human subject, and the coating comprises a polymer that does not decompose at a pH of less than 6.

8.

6. The pharmaceutical dosage form or coating according to claim 1, wherein the pharmaceutical dosage form or coating comprises a copolymer of methacrylic acid and a C1-4 alkyl ester of methacrylic acid; preferably a copolymer of methacrylic acid and methyl methacrylate; more preferably a copolymer of methacrylic acid and methyl methacrylate in a 1:2 ratio.

7. The pharmaceutical dosage form according to claim 4, wherein the capsule is made from one or more materials selected from the group consisting of cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose (HPMC), gelatin, pullulan, starch, water-soluble polyvinyl derivatives, polyethylene glycol, and copolymers of C1-4 alkyl esters of (meth)acrylic acid and (meth)acrylic acid.

8. The pharmaceutical dosage form or capsule according to claim 1, wherein the pharmaceutical dosage form or capsule comprises at least three layers of coating, preferably the capsule comprises at least four layers of coating; and / or the thickness of the coating is at least 20.0 μm, for example, at least 25.0 μm, at least 30.0 μm, or at least 35.0 μm.

9. The pharmaceutical dosage form according to claim 1, wherein the pharmaceutically acceptable salt or oxide of lanthanum is lanthanum carbonate or lanthanum oxide; preferably, the pharmaceutical dosage form comprises lanthanum carbonate.

10. The pharmaceutical dosage form according to claim 1, wherein the pharmaceutical dosage form contains 100 mg to 4000 mg of elemental lanthanum.

11. The pharmaceutical dosage form according to claim 1, wherein the capsule is filled with a composition containing lanthanum or a pharmaceutically acceptable salt or oxide thereof, and is coated with a copolymer of methacrylic acid and a C1-4 alkyl ester of methacrylic acid.

12. A pharmaceutical dosage form according to claim 1, comprising a composition containing lanthanum or a pharmaceutically acceptable salt or oxide thereof, and having a coating of a copolymer of methacrylic acid and a C1-4 alkyl ester of methacrylic acid, wherein the coating is in four layers.

13. A pharmaceutical dosage form according to claim 1, comprising a composition containing lanthanum or a pharmaceutically acceptable salt or oxide thereof, and having a coating of a copolymer of methacrylic acid and a C1-4 alkyl ester of methacrylic acid, wherein the thickness of the coating is at least 20.0 μm.

14. The pharmaceutical dosage form according to claim 1, used in the treatment of hyperoxaluria in human subjects, wherein the hyperoxaluria is optionally primary hyperoxaluria or secondary hyperoxaluria.

15. The pharmaceutical dosage form according to claim 1, used for the treatment of one or more of nephrolithiasis, nephrocalcinosis, or oxalic acidosis in human subjects.

16. The aforementioned pharmaceutical dosage form is - Once or twice a day; - Lanthanum in doses of 100 mg to 2000 mg per administration; - Lanthanum in amounts of 100 mg to 4000 mg per day; and / or - A pharmaceutical dosage form for use according to claim 14 or 15, administered for at least one month; for example, for at least two months.

17. A method for treating one or more of the following conditions in a human subject requiring treatment: hyperoxaluria, nephrolithiasis, nephrocalcinosis, or oxalic acidosis, comprising administering a therapeutically effective amount of the pharmaceutical dosage form described in claim 1 to the subject.

18. The method according to claim 17, wherein the hyperoxaluria is primary hyperoxaluria or secondary hyperoxaluria.

19. The aforementioned pharmaceutical dosage form is - Once or twice a day; - Lanthanum in doses of 100 mg to 2000 mg per administration; - Lanthanum in amounts of 100 mg to 4000 mg per day; and / or - The method according to claim 17 or 18, administered for at least one month; for example, for at least two months.

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