Methods and pharmaceutical compositions for treating Candida auris in the blood.

Abstract

This provides a method for treating Candida auris in the blood. [Solution] A method comprising the step of administering tauroridine and / or one or more tauroridine derivatives into the blood at a concentration effective for treating C. auris in the blood.

Description

Technical Field

[0001] Reference to Related Prior Patent Application This patent application claims the benefit of U.S. Patent Application No. 62 / 608,843 (Attorney Docket No. CORMEDIX-24 PROV), a related pending U.S. patent application filed on December 21, 2017 by CorMedix, Inc. and Robert DiLuccio et al., for METHODS AND PHARMACEUTICAL COMPOSITIONS FOR TREATING CANDIDA AURIS IN BLOOD, which is incorporated herein by reference in its entirety.

[0002] The present invention generally relates to methods and pharmaceutical compositions for treating a patient, and more particularly to methods and pharmaceutical compositions for treating Candida auris in blood.

Background Art

[0003] 1. Overview of Candida auris Candida auris is a type of fungus that grows as a yeast and was first described in 2009. It is one of the few species within the Candida genus that causes candidiasis (a fungal infection caused by Candida) in humans. In many cases, candidiasis occurs as a nosocomial infection in patients with a weakened immune system. Candida auris (sometimes called C. auris) can cause invasive candidiasis, infecting the bloodstream (fungemia), central nervous system, internal organs, etc. Candida auris has recently attracted increasing attention due to its multidrug resistance. Candida auris is difficult to treat because it is easily misidentified as other Candida species.

[0004] 2. Clinical Significance As mentioned above, Candida auris (C. auris) is one of the few Candida species that can cause candidiasis in humans, often as a hospital-acquired infection in patients with weakened immune systems. It can cause invasive candidiasis, in which the bloodstream (fungemia), central nervous system, internal organs (e.g., kidneys, liver, spleen), bones, muscles, joints, and eyes are affected. C. auris is attracting increasing clinical attention due to its multidrug resistance.

[0005] As mentioned above, C. auris is easily mistaken for other Candida species, making its treatment complicated. A summary of the clinical relevance of C. auris as of 2016, in a format understandable to the general public, was published by the Center for Infectious Disease Research and Policy at the University of Minnesota.

[0006] 3. History C. auris was first described after being isolated from the external auditory canal of a 70-year-old Japanese woman at the Tokyo Metropolitan Institute of Gerontology in Japan. It was isolated based on its ability to grow in the presence of the echinocandin-type fungicide micafungin. Phenotypic, chemotactic, and phylogenetic analyses of the strain established C. auris as a new strain of the genus Candida.

[0007] The first three cases of pathogenic C. auris were reported from South Korea in 2011. Two isolates were obtained during a 2009 study, and the third was discovered from stored samples dating back to 1996. All three cases had persistent fungal infections, i.e., bloodstream infections, and two of the patients subsequently died due to complications from the bloodstream infections. Notably, the isolates were identified using standard methods as Candida haemuloni and Rhodotorula. Initially misidentified as glutinis, it was later correctly identified as C. auris through DNA sequencing analysis. These initial cases highlight the importance of accurate species identification and timely application of the correct antifungal agent for effective treatment of candidiasis caused by C. auris.

[0008] Between 2009 and 2011, twelve C. auris isolates were obtained from patients in two hospitals in Delhi, India. The same genotype was found in distinct settings, namely intensive care, surgery, internal medicine, oncology, neonatology, and pediatric wards, and they were mutually exclusive with respect to healthcare workers. Most of these patients had persistent candidiasis, and a high mortality rate was observed. All isolates belonged to the same clonal strain and were definitively identified only by DNA sequencing analysis (as before, the strains had been misidentified using established diagnostic clinical tests). In 2013, Indian researchers wrote that "C. auris is likely far more prevalent than reported, as most diagnostic laboratories do not use DNA sequencing-based methods to identify strains, and therefore the C. auris epidemic is almost certainly underestimated."

[0009] C. auris has spread to other continents, and in early 2016, multidrug-resistant strains were finally discovered in Southeast Asian countries. The first reported case of C. auris in Europe was an outbreak at Brompton Royal Hospital, a cardiothoracic hospital in London, in October 2016.

[0010] In April 2017, CDC Director Anne Schuchat described C. auris as a “catastrophic threat.” As of May 2017, the CDC had reported 77 cases of C. auris in the United States on its website. Of these, 69 cases were from samples taken in New York and New Jersey.

[0011] Therefore, there is a need for effective methods to treat C. auris infections, particularly bloodborne infections caused by C. auris. [Overview of the project]

[0012] The present invention relates to a method and pharmaceutical composition for treating bloodborne infections caused by C. auris. More specifically, the present invention relates to the use of 4,4'-methylene-bis(tetrahydro-1,2,4-thiadiazine)-1,1,1',1',-tetraoxide, commonly known as tauroridine, and / or tauroridine derivatives (see below), for neutralizing the bloodborne pathogen C. auris.

[0013] According to the present invention, tauroridine and / or tauroridine derivatives (see below) can be incorporated into a pharmaceutical composition with a suitable carrier acceptable for parenteral delivery of the compound to treat C. auris in the blood.

[0014] A key aspect of the present invention is to provide tauroridine and / or tauroridine derivatives (see below) that hydrolyze over a long period of time in the vicinity of the C. auris pathogen, so that the active portion of tauroridine and / or tauroridine derivatives (see below) released by the hydrolysis process can be highly effective against the C. auris pathogen. For this purpose, tauroridine and / or tauroridine derivatives (see below) are preferably provided in the following form: (i) Degradable nanoparticles incorporating tauroridine and / or tauroridine derivatives (see below), such as a tauroridine solid core coated with a solid excipient coating, or a tauroridine liquid core coated with a solid excipient coating, or a tauroridine liquid core supported on a porous material and subsequently sealed with a solid excipient coating (Note: For the purposes of this invention, the term nanoparticle is intended to include any particles having dimensions of nanoscale size or larger, including microscale dimensions); (ii) Polymer-based systems in which tauroridine and / or tauroridine derivatives (see below) are bonded to a polymer for delivery to the treatment site, for example, PEGylated systems in which tauroridine and / or tauroridine derivatives are bonded to polyethylene glycol (PEG) for delivery to the treatment site; (iii) Suspensions of solid tauroridine-containing and / or tauroridine derivative-containing particles (see below); (iv) a prodrug resulting from tauroridine and / or tauroridine derivatives (see below); or (v) A tauroridine-containing and / or tauroridine derivative-containing solution (see below) that can extend the effects of tauroridine and / or tauroridine derivatives (see below).

[0015] A preferred embodiment of the present invention provides a method for treating Candida auris in the blood, comprising the step of administering tauroridine and / or one or more tauroridine derivatives into the blood at a concentration effective for treating C. auris in the blood.

[0016] In another preferred embodiment of the present invention, A core comprising tauroridine and / or one or more tauroridine derivatives; and Hydrolyzable coating that temporarily shields the core nanoparticles containing A pharmaceutical composition containing the following is provided.

[0017] In another preferred embodiment of the present invention, a pharmaceutical composition is provided comprising tauroridine and / or one or more tauroridine derivatives bonded to a polymer. In another preferred embodiment of the present invention, a pharmaceutical composition is provided comprising tauroridine and / or one or more tauroridine derivatives dispersed in one or more polymer-carbohydrate-lipid conjugates.

[0018] These and other objects and features of the present invention will be more fully disclosed or made apparent by the following detailed description of preferred embodiments of the present invention. These should be considered in conjunction with the accompanying drawings, where similar numbers in the drawings refer to similar components. [Brief explanation of the drawing]

[0019] [Figure 1] It is a schematic diagram showing the mechanism of action of taurolidine. [Figure 2] It is a table showing the effectiveness of using taurolidine and / or taurolidine derivatives to treat bloodstream infections of C. auris.

Mode for Carrying Out the Invention

[0020] 1. Taurolidine Overview Taurolidine (4,4’-methylene-bis(tetrahydro-1,2,4-thiadiazine)-1,1,1’,1’,-tetraoxide) and / or taurolidine derivatives (see below reference) are known to have antibacterial and anti-lipopolysaccharide properties. Taurolidine and / or taurolidine derivatives (see below reference) are also known to have anti-inflammatory properties. The immunomodulatory effects of taurolidine and / or taurolidine derivatives (see below reference) are reported to be mediated by the priming and activation of macrophages and polymorphonuclear leukocytes.

[0021] Taurolidine is derived from the amino acid taurine. In an aqueous solution, the parent molecule taurolidine forms an equilibrium with N-hydroxymethyltaurultam and taurultam, and taurine amide, methylene glycol, and formaldehyde are downstream derivatives. For the purposes of the present invention, N-hydroxymethyltaurultam, taurultam, taurine amide, methylene glycol, and formaldehyde can all be considered taurolidine derivatives. See FIG. 1 showing the mechanism of action of taurolidine.

[0022] The active part of taurolidine and / or taurolidine derivatives is considered to be the methylol group of the derivative, which reacts with the primary amino groups of the bacterial cell wall, cell membrane, and cell membrane proteins, as well as endotoxins and exotoxins. The microorganisms are killed and the resulting toxins are inactivated. The destruction time in vitro is approximately 30 minutes.

[0023] Taurolidine has the molecular formula C7H 16 It exists as a white to off-white powder with the composition N4O4S2 and a melting point of 154°C. General properties of tauroridine include acceptable stability in the solid state when stored under ambient conditions, melting with decomposition at approximately 170°C, and the following solubility in aqueous solutions and organic solvents: Water: 1% at 20℃ Dilute HCl: soluble Dilute NaOH: soluble CHCl3: Insoluble EtOH: poorly soluble DMF: 1g per 2mL at approximately 60°C Acetone: 1g per 120mL Boiling ethanol: 1g per 130mL Boiling methanol: 1g per 170mL Boiling ethyl acetate: 1g per 200mL A saturated solution of tauroridine in deionized water has a pH of 7.4, which is approximately the pH of blood. The apparent partition coefficient of tauroridine between octanol and water (buffered at pH 7.2) is approximately 0.13, and therefore it should be predicted that it will not accumulate in adipose tissue to any significant degree.

[0024] The synthesis of taurolidine is covered in several patents (including U.S. Patent No. 3,423,408; Swiss Patent No. 482,713; and British Patent No. 1,124,285) and is carried out in five steps: (1) Potassium phthalimide ethanesulfonate is prepared from taurine, phthalic anhydride, glacial acetic acid, and potassium acetate; (2) Next, potassium phthalimide ethanesulfonate is converted to phthalimide ethanesulfonyl chloride by chlorination with phosphorus oxychloride; (3) React phthalimide ethanesulfonyl chloride with ammonia to form phthalimide ethanesulfonamide; (4) Reacting phthalimidoethanesulfonamide with hydrazine hydrate to form taurinamide hydrochloride; and (5) Taurolidine is prepared from taurinamide hydrochloride and formaldehyde. To manufacture.

[0025] The antibacterial activity of tauroridine is documented in U.S. Patent Application No. 09 / 151,885, filed September 11, 1998; U.S. Patent No. 3,423,408; and other documents. In addition, the following U.S. patents describe various uses of tauroridine and various compositions containing tauroridine: U.S. Patent No. 4,107,305, treatment of endotoxemia; U.S. Patent No. 4,337,251, elimination of adhesion formation as a result of surgery; U.S. Patent No. 4,587,268, absorbable aqueous gel; U.S. Patent No. 4,604,391, prevention of the development of osteitis or osteomyelitis; U.S. Patent No. 4,626,536, countermeasures against toxic proteins or peptides in the blood; U.S. Patent No. 4,772,468, treatment of bone cavities; and U.S. Patent No. 4,882,149, which covers a method for filling congenital, surgical, or traumatic defects with a composition containing natural bone mineral in which tauroridine is absorbed.

[0026] Taurolidine has been shown to be safe and well-tolerated at systemic doses exceeding 40 g / day, as well as at cumulative doses up to and exceeding 300 g.

[0027] 2. Novel pharmaceutical composition of the present invention This study discovered that tauroridine and / or tauroridine derivatives can be applied to C. auris bloodborne infections to neutralize the C. auris bloodborne pathogen. For example, see Figure 2, which illustrates the effectiveness of treating the C. auris bloodborne pathogen with tauroridine and / or tauroridine derivatives.

[0028] According to the present invention, tauroridine and / or tauroridine derivatives can be incorporated into a pharmaceutical composition and formulated with a suitable carrier acceptable for parenteral delivery of the compound to treat C. auris in the blood.

[0029] A key aspect of the present invention is to provide tauroridine and / or tauroridine derivatives (see below) that hydrolyze over a long period of time in the vicinity of the C. auris pathogen, so that the active portion of the tauroridine and / or tauroridine derivative released by the hydrolysis process can be highly effective against the C. auris pathogen. For this purpose, the tauroridine and / or tauroridine derivatives are preferably provided in the following form: (i) Degradable nanoparticles incorporating tauroridine and / or tauroridine derivatives, such as a tauroridine solid core coated with a solid excipient coating, or a tauroridine liquid core coated with a solid excipient coating, or a tauroridine liquid core supported on a porous material and subsequently sealed with a solid excipient coating (Note: For the purposes of this invention, the term nanoparticle is intended to include any particles having dimensions of nanoscale size or larger, including microscale dimensions); (ii) Polymer-based systems in which tauroridine and / or tauroridine derivatives are bonded to a polymer for delivery to the treatment site, for example, PEGylated systems in which tauroridine and / or tauroridine derivatives are bonded to polyethylene glycol (PEG) for delivery to the treatment site; (iii) Suspensions of solid tauroridine-containing and / or tauroridine derivative-containing particles; (iv) a prodrug resulting from tauroridine and / or a tauroridine derivative; or (v) A tauroridine-containing and / or tauroridine derivative-containing solution that can extend the effects of tauroridine and / or tauroridine derivatives.

[0030] Taurolidine itself should be buffered to the pH of blood, i.e., between 7.5 and 7.4 (and taurolidine derivatives may be buffered if desired), and the pharmaceutical composition is advantageous. Furthermore, the novel taurolidine-containing pharmaceutical composition may contain a substance that increases cell permeability.

[0031] Novel taurolidine-containing and / or taurolidine derivative-containing pharmaceutical compositions suitable for introduction into the bloodstream may be in the form of a powder, solution (e.g., aqueous solution), or suspension buffered to pH 7.5-7.4, and can be formulated together with anticoagulants and preservatives that are typically incorporated into parenteral dosage forms.

[0032] The present invention provides novel pharmaceutical compositions comprising tauroridine and / or tauroridine derivatives together with one or more carriers (these are excipients). The carriers may, for example, be conventional in such form and may include gelatin, sterile water, and / or suspending agents, emulsifiers, dispersants, thickeners, or gelling agents.

[0033] The pharmaceutical compositions of the present invention, in the form of powder, solution, or suspension, may contain tauroridine at a concentration between about 0.10% by weight and about 20.0% by weight, preferably between about 0.5% by weight and about 2.0% by weight, in the case of a solution (e.g., aqueous solution) or suspension, or may contain tauroridine at a concentration up to about 10% by weight, in the case of a powder. The formulations of tauroridine in the present invention are preferably about 0.5%, 1.0%, 2.0%, or 4.0% w / vol.

[0034] The amount of tauroridine and / or tauroridine derivatives introduced into the bloodstream varies depending on the concentration of C. auris pathogens in the blood, and is adjusted so that the amount of tauroridine and / or tauroridine derivatives is sufficient to treat the C. auris present in the blood.

[0035] 3. Nanoparticles 3.1 Nanoparticle Delivery System In one embodiment of the present invention, the hydrolyzable tauroridine and / or tauroridine derivatives are encapsulated within the hydrolyzable coating (which is an excipient) to form nanoparticles, so as to protect the hydrolyzable tauroridine and / or tauroridine derivatives from excessive hydrolysis in the blood when the mixture is introduced into the bloodstream (the nanoparticles consist of a core of the tauroridine and / or tauroridine derivative and a coating of the hydrolyzable excipient). Subsequently, when the hydrolyzable coating is hydrolyzed and the hydrolyzable tauroridine and / or tauroridine derivatives are exposed to the blood, the hydrolyzable tauroridine and / or tauroridine derivatives are hydrolyzed to their active site (i.e., the methylol group), thereby providing a topical antimicrobial effect that treats the C. auris pathogen. Thus, encapsulation of hydrolyzable tauroridine and / or tauroridine derivatives delays the hydrolysis of tauroridine and / or tauroridine derivatives, resulting in a sustained antimicrobial effect against the C. auris pathogen.

[0036] In other words, in one embodiment of the present invention, hydrolyzable tauroridine and / or tauroridine derivatives are coated with a hydrolyzable coating (which is an excipient) in a state in which they are encapsulated by a hydrolyzable coating, i.e., in a state in which they form nanoparticles. When the nanoparticles are introduced into the bloodstream, the hydrolyzable excipient coating first protects the hydrolyzable tauroridine and / or tauroridine derivatives from premature hydrolysis. When the hydrolyzable coating is hydrolyzed, and the hydrolyzable tauroridine and / or tauroridine derivatives are exposed to the blood, the tauroridine and / or tauroridine derivatives hydrolyze to treat (or prevent recurrence of) C. auris infection. This becomes the active portion (i.e., the methylol portion). Thus, encapsulation of hydrolyzable tauroridine and / or tauroridine derivatives delays the hydrolysis of tauroridine and / or tauroridine derivatives to provide a sustained antibacterial effect against the C. auris pathogen.

[0037] Note: For the purposes of this invention, the term nanoparticle is intended to include any particles having dimensions of nanoscale size or larger, including microscale dimensions. In a preferred embodiment of the present invention, the nanoparticles comprise a tauroridine solid core covered with a solid excipient coating.

[0038] In another preferred embodiment of the present invention, the nanoparticles comprise a tauroridine liquid core covered with a solid excipient coating. In yet another preferred embodiment of the present invention, the nanoparticles comprise a tauroridine liquid core supported by a porous body and subsequently sealed with a solid excipient coating.

[0039] In one embodiment of the present invention, the hydrolyzable excipient coating includes, for example, a slowly absorbed solid polymer. For example, but not limited to, the polymer coating may include a polylactide or polylactate.

[0040] In one embodiment of the present invention, the solid excipient coating may include a polysaccharide, most preferably an indigestible polysaccharide, that specifically binds to fungal mannoproteins. For example, but not limited to, in a preferred embodiment of the present invention, the polysaccharide coating may include chitosan, starch, or alginate.

[0041] In a preferred embodiment of the present invention, nanoparticles are delivered to the blood via a suitable pharmaceutical carrier, for example, a fluid. In a preferred embodiment of the present invention, the suitable pharmaceutical carrier may include a hyaluronic acid hydrogel.

[0042] 3.2 Taurolidine Nanoparticles Tauroridine nanoparticles contain a tauroridine and / or tauroridine derivative core sealed by an excipient coating.

[0043] In a preferred embodiment of the present invention, the nanoparticles comprise a tauroridine solid core coated with a solid excipient coating. For example, but not limited to, the tauroridine solid core may be formed from tauroridine powder, and the solid excipient coating may be formed from a slow-absorbing solid polymer, such as one containing polylactide or polylactate. In a preferred embodiment of the present invention, the solid excipient coating may also comprise a polysaccharide, most preferably an indigestible polysaccharide, that specifically binds to fungal mannoproteins. For example, but not limited to, in a preferred embodiment of the present invention, the polysaccharide coating may comprise chitosan, starch, or alginate.

[0044] In another preferred embodiment of the present invention, the nanoparticles comprise a tauroridine liquid core coated with a solid excipient coating. For example, but not limited to, the tauroridine liquid core may be formed from a tauroridine solution or suspension in oil, preferably nutrients, most preferably medium-chain triglycerides, at a concentration of 1,000 μg (mcg) / mL to 5,000 μg (mcg) / mL, most preferably 3,000 μg (mcg) / mL, and the solid excipient coating may be formed from a slowly absorbed solid polymer, such as one containing polylactide or polylactate. In a preferred embodiment of the present invention, the solid excipient coating may also comprise a polysaccharide, most preferably an indigestible polysaccharide, that specifically binds to fungal mannoproteins. In this context, the polysaccharide coating may also contain chitosan, starch, or alginate.

[0045] In another preferred embodiment of the present invention, the nanoparticles comprise a tauroridine liquid core supported by a porous body and subsequently sealed with a solid excipient coating. For example, but not limited to, the tauroridine core comprises a tauroridine solution or suspension in oil, preferably nutrients, most preferably medium-chain triglycerides, at concentrations of 1,000 μg (mcg) / mL to 5,000 μg (mcg) / mL, most preferably 3,000 μg (mcg) / mL. The tauroridine liquid core is contained within a porous body and then sealed with a solid excipient coating to form tauroridine nanoparticles. For example, but not limited to, the tauroridine core may be contained within porous silicate spheres or carbon nanotubes. When tauroridine is contained within porous silicate spheres or carbon nanotubes, the openings ("pores") of the porous silicate spheres or nanotubes may be blocked with a coating of a slowly absorbing solid polymer, such as polylactide or polylactate. In a preferred embodiment of the present invention, when tauroridine is contained within porous silicate spheres or carbon nanotubes, the openings ("pores") of the spheres or nanotubes may also be blocked with a coating of a polysaccharide, most preferably an indigestible polysaccharide, that specifically binds to fungal mannoproteins. As an example, but not limited to, in a preferred embodiment of the present invention, the polysaccharide coating may include chitosan, starch, or alginate.

[0046] 3.3 Production of tauroridine nanoparticles in which tauroridine is contained within porous silicate spheres or carbon nanotubes When tauroridine is contained within porous silicate spheres or carbon nanotubes, the porous silicate spheres or carbon nanotubes preferably have a size of 10 nm to 1000 nm. The porous silicate spheres or nanotubes are thoroughly cleaned and sterilized before filling and coating. A tauroridine solution or suspension is prepared, and the lipophilicity of the porous silicate spheres or nanotubes facilitates filling the porous silicate spheres or nanotubes with the tauroridine solution or suspension.

[0047] The filled spheres or nanotubes are then coated with a type of coating in a slowly absorbable solid polymer, such as polylactide or polylactate. In a preferred embodiment of the present invention, the filled spheres or nanotubes are coated with a polysaccharide that specifically binds to fungal mannoproteins. For example, but not limited to, in a preferred embodiment of the present invention, the polysaccharide coating may include chitosan, starch, or alginate. The sealing coating (e.g., polylactide, polylactate, or polysaccharide) may be applied to the filled spheres or nanotubes through a spray-drying process.

[0048] The nanoparticles are then mixed in a pharmaceutical carrier suitable for delivery into the bloodstream, such as a fluid. In a preferred embodiment of the present invention, the suitable pharmaceutical carrier may include a hyaluronic acid hydrogel.

[0049] 3.4 Mechanism of antifungal activity of tauroridine nanoparticles In use, the pharmaceutical composition (e.g., a carrier and tauroridine-containing nanoparticles) is introduced into the patient's bloodstream. As the pharmaceutical composition moves from the entry point to the site of C. auris infection, the hydrolyzable polymer coating covering the tauroridine core acts as a kind of sacrificial layer, slowly degrading over time as the nanoparticles travel through the bloodstream. Eventually, the hydrolyzable polymer coating degrades until the tauroridine core is exposed to the blood. The tauroridine core then hydrolyzes to target the C. auris infection. This forms the active portion (methylol derivative).

[0050] When nanoparticles contain an outer coating with a polysaccharide that specifically binds to fungal mannoproteins, when tauroridine nanoparticles collide with the fungal cell wall, the outer polysaccharide coating of the nanoparticles binds to the fungal mannoprotein, and Brownian motion provides energy to the fungal cell wall to remove the packing material from the pores in the nanoparticles. Once the packing material is removed from the pores, the tauroridine oil or suspension is released, and the tauroridine dissolves in the blood or tissue fluid. When tauroridine is exposed to water, it hydrolyzes to form an active site (methylol derivative) that is created very close to the fungal cell wall. This ultralocal delivery of the active site of tauroridine enhances the selectivity of tauroridine against the target microorganism.

[0051] 4. Parenteral delivery system having a polymer carrier (e.g., PEG) In another embodiment of the present invention, the parenteral delivery system may include tauroridine and / or tauroridine derivatives bound to a polymer for delivery to the treatment site (for example, tauroridine and / or tauroridine derivatives bound to polyethylene glycol (PEG) for delivery to the treatment site).

[0052] In a preferred embodiment of the present invention, tauroridine and / or tauroridine derivatives are formulated into a drug composition by being dispersed in a polymer-carbohydrate-lipid conjugate (or combination of polymer-carbohydrate-lipid conjugates), such as a PEG-carbohydrate-lipid conjugate (or combination of PEG-carbohydrate-lipid conjugates), to increase the solubility of tauroridine and / or tauroridine derivatives, or to increase their dispersibility, as well as to enhance their stability and to delay their hydrolysis, in order to provide a sustained antimicrobial effect.

[0053] In one embodiment of the present invention, a novel pharmaceutical composition for parenteral administration of tauroridine and / or tauroridine derivatives is provided, wherein the novel pharmaceutical composition is as follows: a) Aqueous solutions or mixtures of polymer-carbohydrate-lipid conjugates or combinations of polymer-carbohydrate-lipid conjugates (e.g., including PEG-carbohydrate-lipid conjugates or combinations of PEG-carbohydrate-lipid conjugates); b) Tauroridine and / or tauroridine derivatives; and c) Soluble accelerators comprising polymer-carbohydrate-lipid conjugates or combinations of polymer-carbohydrate-lipid conjugates (e.g., PEG-carbohydrate-lipid conjugates or combinations of PEG-carbohydrate-lipid conjugates) Includes.

[0054] In one embodiment of the present invention, a method for preparing a novel pharmaceutical composition for parenteral administration of tauroridine is as follows: The step of adding an aqueous solution of a polymer-carbohydrate-lipid conjugate or a combination of polymer-carbohydrate-lipid conjugates (e.g., PEG-carbohydrate-lipid conjugate or a combination of PEG-carbohydrate-lipid conjugates) to a container; - Adding tauroridine and / or tauroridine derivatives in liquid or slurry form to a container; - A step of mixing tauroridine and / or tauroridine derivatives in an aqueous solution of polymer-carbohydrate-lipid conjugate or a combination of polymer-carbohydrate-lipid conjugates (e.g., PEG-carbohydrate-lipid conjugate or a combination of PEG-carbohydrate-lipid conjugates) until visibly dispersed; The steps include adding a pre-dissolved excipient (e.g., polymer-carbohydrate-lipid conjugate, e.g., PEG-carbohydrate-lipid conjugate) to the container; and • Mix until a homogeneous solution is obtained. Includes.

[0055] The present invention includes various aqueous and polymer-carbohydrate-lipid based (e.g., PEG-carbohydrate-lipid based) formulations of poorly water-soluble tauroridine and / or tauroridine derivatives, including compositions for parenteral formulations such as intravenous injection. One aspect of the present invention includes a solution of tauroridine and / or tauroridine derivatives with a PEG-carbohydrate-lipid conjugate for enhancing the solubility of tauroridine and / or tauroridine derivatives in aqueous solutions or increasing their dispersion.

[0056] Preferred embodiments of the present invention may include an aqueous pharmaceutical composition for injection comprising, but not limited to, tauroridine and / or a tauroridine derivative and oleoyl triethylenetetramine-polyethylene glycol lactobionate (OTL-PEG) or oleoyl diethylenetetramine-dodecaethylene glycol lactobionate (ODL-PEG). In at least one aspect of the present invention, the solution contains tauroridine at a concentration in the range of 0.05 mg / mL to 50 mg / mL, and the ratio of PEG-carbohydrate-lipid to tauroridine is in the range of 0.2 to 25 (w / v). In one embodiment of the present invention, the concentration of tauroridine is in the range of 0.5 mg / mL to 50 mg / mL. In one embodiment of the present invention, the concentration of tauroridine is in the range of 0.5 mg / mL to 10 mg / mL, and the proportion (%) of PEG-carbohydrate-lipid conjugate is in the range of 0.5 to 10 (w / v) of the whole solution.

[0057] A further aspect of the present invention may provide an aqueous tauroridine solution for injection, wherein the diluent consists of 0.5 to 25 percent (w / v) PEG-carbohydrate-lipid conjugate and 75 to 99.5 percent (v / v) water, buffer, saline, or dextrose solution. An aqueous tauroridine solution for injection is also preferred, wherein 85 to 99 percent (v / v) of the total solution is water, buffer, saline, or dextrose solution.

[0058] In one embodiment of the present invention, the tauroridine aqueous solution for injection comprises tauroridine in a lipid cubic phase (LCP) containing an aqueous medium in addition to OTL-PEG or ODL-PEG, with a concentration of tauroridine ranging from 0.5 mg / mL to 50 mg / mL, PEG-carbohydrate-lipid conjugate at 0.5 to 25 percent (w / v), and water at 75 to 99.5 percent (v / v), where the concentration of tauroridine in the combined solution is in the range of 0.5% to 5%.

[0059] The taurolidine aqueous solution for injection according to the present invention may be administered by bolus injection or by drip infusion. Drip infusion may be preferred for solutions with a taurolidine concentration greater than 0.01 mg / mL. In the case of drip infusion, the duration of the infusion may be preferably 30 minutes to 6 hours, and preferably within 24 hours.

[0060] Aspects of the present invention may include solubilizing tauroridine by using one or more amphiphilic PEG conjugates. (i) a combination of tauroridine (and / or a tauroridine derivative) in LCP with PEG-carbohydrate-lipid and (ii) a polysorbate may be a preferred solubilizer in which the acyl chain contains the lipophilic portion of the amphiphilic PEG conjugate.

[0061] Branched PEG-carbohydrate-lipid conjugates, in which the PEG polymer contains multiple PEG chains in the conjugate, can also serve as excellent solubilizers. Similarly, branched PEG-carbohydrate-lipid conjugates may also be used as solubilizers. Like LCP solubilizers, these compounds are typically waxy solids or semi-solids at the solubilization temperature, and these PEG-carbohydrate conjugates can also serve as excellent solubilizers. Carbohydrate-lipid conjugates typically have melting points above approximately 25°C. Such solubilizers may be used to prepare intravenous formulations and oral or topical liquids. The first step of solubilization may involve combining tauroridine with a hydrophilic PEG conjugate(s) that may be semi-solid or solid at the solubilization temperature. When formulating a tauroridine solution at room temperature (which may be preferred), a concentrated solution of the PEG-carbohydrate-lipid conjugate may be desirable. Such solubilization may be carried out by first adding tauroridine in liquid form to a concentrated solution of the PEG-carbohydrate-lipid conjugate. This aqueous solution may be further diluted with water or buffer. Alternatively, tauroridine may be pre-dissolved in a small amount of acid, base, or alcohol and then mixed with the PEG-carbohydrate-lipid conjugate in aqueous solution.

[0062] By performing solubilization by raising the temperature, PEG-carbohydrate-lipid conjugates with higher melting points can be used as solubilizers. When forming an aqueous solution, it is sometimes preferable to add the aqueous solution by raising the temperature as well.

[0063] If terminal groups are attached to a PEG chain, it can contain a wide variety of chemical moieties. Such moieties can have a molecular weight of less than 650. Examples of such moieties include -NH2, -COOH, -OCH2CH3, -OCH2CH2OH, -COCH=CH2, -OCH2CH2NH2, -OSO2CH3, -OCH2C6H6, -OCH2COCH2CH2COONC4H4O2, -CH2CH2=CH2, and -C 10Examples include Hi6N2O3S and -OC6H6. The terminal groups may be functional groups that facilitate the linking of tauroridine to the surface of lipid vesicle aggregates. Amino acids, aminoalkyl esters, biotin, maleimide, diglycidyl ether, maleimide propionate, methyl carbamate, tosylhydrazone salts, azides, propargylamines, propargyl alcohols, NHS esters (e.g., propargyl NHS ester, NHS-biotin, sulfo-NHS-LC-biotin, or NHS carbonate), hydrazides, succinimidyl esters, succinimidyl tartrate, succinimidyl succinate, and toluenesulfonates.

[0064] The ligated therapeutic and targeting agents may include Fab fragments (antigen-binding fragments), cell surface binding agents, and the like. In addition, the terminal groups may include molecules such as functional cell-targeting ligands, e.g., folic acid, transferrin, and monoclonal antibodies, cell receptor ligands, or specific peptide sequences that can bind to the surface of liposomes to provide specific binding sites. The terminal group may be neutral, or it may include a negatively or positively charged head group, such as decanolamine, octadecylolamine, octanolamine, butanolamine, dodecanolamine, hexanolamine, tetradecanolamine, hexadecanolamine, oleylamine, decanoltrimethylaminium, octadecyloltrimethylaminium, octanoltrimethylaminium, butanoltrimethylaminium, dodecanoltrimethylaminium, hexanoltrimethylaminium, tetradecanoltrimethylaminium, hexadecanoltrimethylaminium, and / or oleyltrimethylaminium. Other useful R groups include alkyl groups such as alkoxy moieties, amino acids, and sugars including monosaccharides, disaccharides, trisaccharides, and oligosaccharides containing 1, 2, 3, and 4 or more monosaccharide units, respectively. In addition, targeting moieties such as antibody fragments and vitamins may also be used as R groups. In general, R groups can be highly soluble in water. The molecular weight of an R group may be less than approximately 650 daltons (Da), and for most applications, R groups can be readily polarized to increase binding and interaction with proteins at the target site.

[0065] The PEG-carbohydrate-lipid conjugate combination used in the present invention may also be a mixture of PEG-carbohydrate-lipid conjugates, and the properties of the lipid mixture (e.g., melting point or average size of PEG chains) can be calculated by known methods or determined empirically.

[0066] The preparation of the parenteral solution may first involve adding tauroridine to a concentrated PEG-carbohydrate-lipid conjugate solution and mixing until homogeneous, which may be carried out at room temperature. Next, a pre-mixed aqueous preparation may be added to the lipid-tauroridine mixture and mixed until a homogeneous solution is obtained. This solution may then be filtered for sterilization, which is done while maintaining an overlay of sterile filtered nitrogen throughout the process. The appropriate volume of the solution may be filled into ampoules using aseptic techniques and sealed. Sterilization conditions may be maintained throughout the filtration, filling, and sealing operations, in accordance with the standard manufacturing procedures for infusion pharmaceuticals. The formulated product may be stable at room temperature, but may preferably be refrigerated to extend its shelf life.

[0067] When a sterile filtration process is not possible due to high concentrations of PEG-carbohydrate-lipid conjugate, preservatives may be desirable, and possible preservatives may be selected from the group of antimicrobial agents consisting of benzyl alcohol, chlorobutanol, methylparaben, propylparaben, phenol, ethylenediaminetetraacetic acid, and m-cresol.

[0068] In one aspect of the present invention, a novel pharmaceutical composition for administration by intravenous injection is provided. The novel pharmaceutical composition comprises an aqueous solution; a PEG-carbohydrate-lipid conjugate or a combination of PEG-carbohydrate-lipid conjugates; and tauroridine at a concentration between about 0.05 mg / mL and about 50 mg / mL. The ratio of PEG-carbohydrate-lipid conjugate to tauroridine may be between about 0.2 and 25 (w / v). The average molecular weight of the PEG chain in the PEG-carbohydrate-lipid conjugate (or mixture of PEG-carbohydrate-lipid conjugates) may be less than about 1500 daltons (Da). The concentration of tauroridine may preferably be between about 0.2 mg / mL and 50 mg / mL. The concentration of PEG-carbohydrate-lipid conjugate may preferably be between about 0.5 and 25 percent (w / v) of the total solution.

[0069] In another aspect of the present invention, the present invention provides a method for preparing a pharmaceutical composition suitable for administration by intravenous injection. The method comprises mixing a PEG-carbohydrate-lipid conjugate or a combination of PEG-carbohydrate-lipid conjugates with tauroridine, and adding an aqueous solution while mixing to prepare a suspension. The final concentration of tauroridine may preferably be between about 0.05 mg / ml and about 50 mg / ml. The ratio of the total PEG-carbohydrate-lipid conjugate to tauroridine may preferably be between about 0.2 and 25 (w / v). The average molecular weight (MW) of the PEG chain in the PEG-carbohydrate-lipid conjugate or combination of PEG-carbohydrate-lipid conjugates may preferably be less than about 1500 daltons (Da). The method may further include sealing the aqueous suspension in a sterile container or adding an antimicrobial preservative.

[0070] In another aspect of the present invention, a novel method for treating a disease in mammals is provided. The novel method comprises preparing a novel pharmaceutical composition comprising an aqueous solution, a PEG-carbohydrate-lipid conjugate or a combination of PEG-carbohydrate-lipid conjugates, and tauroridine at a concentration between about 0.05 mg / mL and about 50 mg / mL. The ratio of PEG-carbohydrate-lipid conjugate to tauroridine may be between about 0.2 and 25 (w / v). The novel pharmaceutical composition may be administered intravenously to mammals. The average molecular weight (MW) of a single PEG chain in the PEG-carbohydrate-lipid conjugate or combination of PEG-carbohydrate-lipid conjugates is preferably about 1500 daltons (Da). The concentration of tauroridine may be between approximately 0.2 mg / mL and 25 mg / mL. The concentration of PEG-carbohydrate-lipid conjugate may be between approximately 0.5 and 25 percent (w / v) of the total solution. The novel pharmaceutical composition may further contain a preservative, the concentration of which may be between approximately 0.1 and 2% (w / v).

[0071] 4.1 PEGylation of tauroridine PEGylation is the process of attaching PEG polymer chains to tauroridine. This results in alterations of physiological and chemical properties, including changes in conformation, electrostatic coupling, and hydrophobicity. These physical and chemical changes increase the systemic retention rate of tauroridine. Furthermore, it can influence the binding affinity of the therapeutic portion of tauroridine to cell receptors and alter its absorption and distribution patterns.

[0072] PEGylation, by increasing the molecular weight of tauroridine, can confer several significant pharmacological advantages over the unmodified form, such as the following: • Improved solubility of tauroridine; • Reducing the frequency of medication (potentially reducing toxicity without reducing effectiveness); • Extension of the cycle life; • Increased stability of tauroridine; and • Enhanced protection against protein degradation.

[0073] PEG is a particularly attractive polymer for conjugation with tauroridine. The specific properties of the PEG moiety for application with tauroridine are as follows: ·Water soluble; • High mobility in solution; • Lack of toxicity and low immunogenicity; • Immediate clearance from the body; and • Modification of distribution within the body.

[0074] 4.2 PEGylation process of tauroridine The first step in PEGylation of tauroridine is the appropriate functionalization of one or both ends of the PEG polymer. PEG activated at the same reactive moiety at each end is known as "homobifunctional," while PEG derivatives with different functional groups are called "heterobifunctional" or "heterofunctional." Chemically active or activated derivatives of the PEG polymer are prepared to bond PEG to tauroridine.

[0075] Generally, PEGylation processes can be broadly classified into two types: solution-phase batch processes and on-column fed-add processes. A commonly employed simple batch process involves mixing reagents together in a suitable buffer, preferably at a temperature between 4°C and 6°C, and then separating and purifying the desired product using appropriate techniques based on its physicochemical properties, including size exclusion chromatography (SEC), ion exchange chromatography (IEX), hydrophobic interaction chromatography (HIC), and membrane or aqueous two-phase systems.

[0076] The selection of suitable functional groups for PEG derivatives is based on the type of reactive group available on the molecule that you intend to couple with PEG. The technique used to form first-generation PEG derivatives generally involves reacting the PEG polymer with a group reactive to the hydroxyl group, typically anhydrides, acid chlorides, chloroformates, and carbonates. Second-generation PEGylation chemical reactions utilize more efficient functional groups, such as aldehydes, esters, and amides, for conjugation. It will become available.

[0077] As the application of PEGylation becomes increasingly sophisticated, the need for conjugating heterobifunctional PEGs is growing. These heterobifunctional PEGs are extremely useful when a hydrophilic, flexible, and biocompatible spacer is required to link two entities. Preferred terminal groups for heterobifunctional PEGs are maleimide, vinyl sulfone, pyridyl disulfide, amine, carboxylic acid, and NHS ester.

[0078] Third-generation PEGylating agents with branched, Y-shaped, or comb-shaped polymer structures are available, exhibiting reduced viscosity and no accumulation in organs. Taurolidine may be PEGylated according to any of the techniques described above.

[0079] 5. Suspension of solid tauroridine-containing and / or tauroridine derivative-containing particles In another embodiment of the present invention, a suspension of tauroridine-containing particles and / or tauroridine derivative-containing particles can be administered intravenously to a patient to treat candidiasis in the bloodstream. In this embodiment of the present invention, the suspension may be formed by mixing the tauroridine-containing particles and / or tauroridine derivative-containing particles in a hyaluronic acid hydrogel.

[0080] 6. Prodrugs that deliver tauroridine and / or tauroridine derivatives In another embodiment of the present invention, a prodrug containing tauroridine and / or a tauroridine derivative can be administered intravenously to a patient to treat candidiasis in the bloodstream. In this embodiment of the present invention, the prodrug may contain a molecule to which tauroridine and / or a tauroridine derivative is chemically bound, and which releases tauroridine or a tauroridine derivative when "cleaved".

[0081] 7. Taurolidine-containing and / or taurolidine derivative-containing solutions that can extend the effects of taurolidine. In another embodiment of the present invention, a tauroridine-containing and / or tauroridine derivative-containing solution that can extend the effects of tauroridine can be intravenously administered to a patient to treat candidiasis in the bloodstream. In this embodiment of the present invention, the solution may comprise tauroridine and / or a tauroridine derivative and hyaluronic acid hydrogel.

[0082] Modification of Preferred Embodiments It should be understood that those skilled in the art can make many additional modifications to the details, materials, steps, and arrangements of components described and illustrated herein in order to illustrate the essence of the present invention, without deviating from the principles and scope of the present invention.

Claims

1. A method for treating Candida auris in the blood, comprising the step of administering tauroridine and / or one or more tauroridine derivatives into the blood at a concentration effective for treating C. auris in the blood.

2. The method according to claim 1, wherein tauroridine and / or one or more tauroridine derivatives are present in the nanoparticle delivery system.

3. The method according to claim 2, wherein the nanoparticle delivery system comprises nanoparticles having a solid core of tauroridine and / or one or more tauroridine derivatives covered with a solid excipient coating.

4. The method according to claim 3, wherein the solid excipient coating comprises a powder of tauroridine and / or one or more tauroridine derivatives, and the solid excipient coating comprises a solid polymer.

5. The method according to claim 4, wherein the solid polymer comprises one from the group consisting of polylactides and polylactates.

6. The method according to claim 4, wherein the solid polymer contains a polysaccharide that specifically binds to fungal mannoproteins.

7. The method according to claim 6, wherein the polysaccharide comprises chitosan, starch, or alginate.

8. The method according to claim 3, wherein the nanoparticle delivery system further comprises a carrier.

9. The method according to claim 8, wherein the carrier comprises hyaluronic acid hydrogel.

10. The method according to claim 2, wherein the nanoparticle delivery system comprises nanoparticles containing a liquid core of tauroridine and / or one or more tauroridine derivatives covered with a solid excipient coating.

11. The method according to claim 10, wherein the liquid core comprises a solution or suspension, and the solid excipient coating further comprises a solid polymer.

12. The method according to claim 11, wherein the solid polymer comprises one from the group consisting of polylactides and polylactates.

13. The method according to claim 11, wherein the solid polymer contains a polysaccharide that specifically binds to fungal mannoproteins.

14. The method according to claim 13, wherein the polysaccharide comprises chitosan, starch, or alginate.

15. The method according to claim 10, wherein the nanoparticle delivery system further comprises a carrier.

16. The method according to claim 15, wherein the carrier comprises hyaluronic acid hydrogel.

17. The nanoparticle delivery system is supported by a porous material and subsequently sealed with a solid excipient coating. The method according to claim 2, comprising nanoparticles containing a liquid core of tauroridine and / or one or more tauroridine derivatives.

18. The method according to claim 17, wherein the liquid core comprises a solution or suspension, the porous body comprises porous spheres or nanotubes, and the solid excipient coating comprises a solid polymer.

19. The method according to claim 18, wherein the solid polymer comprises one from the group consisting of polylactides and polylactates.

20. The method according to claim 18, wherein the solid polymer contains a polysaccharide that specifically binds to fungal mannoproteins.

21. The method according to claim 20, wherein the polysaccharide comprises chitosan, starch, or alginate.

22. The method according to claim 17, wherein the nanoparticle delivery system further comprises a carrier.

23. The method according to claim 22, wherein the carrier comprises hyaluronic acid hydrogel.

24. The method according to claim 1, wherein tauroridine and / or one or more tauroridine derivatives are bound to a polymer for delivery to the treatment site.

25. The method according to claim 24, wherein the polymer comprises polyethylene glycol (PEG).

26. The method according to claim 1, wherein tauroridine and / or one or more tauroridine derivatives are dispersed in one or more polymer-carbohydrate-lipid conjugates.

27. The method according to claim 26, wherein one or more polymer-carbohydrate-lipid conjugates include a PEG-carbohydrate-lipid conjugate.

28. The method according to claim 27, wherein the PEG-carbohydrate-lipid conjugate comprises oleoyltriethylenetetramine-polyethylene glycol lactobionate.

29. The method according to claim 27, wherein the PEG-carbohydrate-lipid conjugate comprises oleoyldiethylenetetramine-dodecaethylene glycol lactobionate.

30. A core comprising tauroridine and / or one or more tauroridine derivatives; and A hydrolyzable coating that temporarily shields the core. nanoparticles containing A pharmaceutical composition containing the following:

31. The pharmaceutical composition according to claim 30, comprising a tauroridine solid core covered with a solid hydrolyzable coating, wherein the nanoparticles are covered with a solid hydrolyzable coating.

32. The pharmaceutical composition according to claim 31, wherein the solid hydrolyzable coating comprises one from the group consisting of polylactides and polylactates.

33. The solid hydrolyzable coating contains a polysaccharide that specifically binds to fungal mannoproteins. The pharmaceutical composition described in item 31.

34. The pharmaceutical composition according to claim 33, wherein the polysaccharide comprises chitosan, starch, or alginate.

35. The pharmaceutical composition according to claim 31, further comprising a carrier.

36. The pharmaceutical composition according to claim 35, wherein the carrier comprises hyaluronic acid hydrogel.

37. The pharmaceutical composition according to claim 30, comprising a tauroridine liquid core in which nanoparticles are covered with a solid hydrolyzable coating.

38. The pharmaceutical composition according to claim 37, wherein the solid hydrolyzable coating comprises one from the group consisting of polylactides and polylactates.

39. The pharmaceutical composition according to claim 37, wherein the solid hydrolyzable coating contains a polysaccharide that specifically binds to fungal mannoproteins.

40. The pharmaceutical composition according to claim 39, wherein the polysaccharide comprises chitosan, starch, or alginate.

41. The pharmaceutical composition according to claim 37, further comprising a carrier.

42. The pharmaceutical composition according to claim 41, wherein the carrier comprises hyaluronic acid hydrogel.

43. The pharmaceutical composition according to claim 30, comprising a tauroridine liquid core in which nanoparticles are supported by a porous material and subsequently sealed with a solid hydrolyzable coating.

44. The pharmaceutical composition according to claim 43, wherein the solid hydrolyzable coating comprises one from the group consisting of polylactides and polylactates.

45. The pharmaceutical composition according to claim 43, wherein the solid hydrolyzable coating contains a polysaccharide that specifically binds to fungal mannoproteins.

46. The pharmaceutical composition according to claim 45, wherein the polysaccharide comprises chitosan, starch, or alginate.

47. The pharmaceutical composition according to claim 43, further comprising a carrier.

48. The pharmaceutical composition according to claim 47, wherein the carrier comprises hyaluronic acid hydrogel.

49. A pharmaceutical composition comprising tauroridine and / or one or more tauroridine derivatives bonded to a polymer.

50. The pharmaceutical composition according to claim 49, wherein the polymer comprises polyethylene glycol (PEG).

51. A pharmaceutical composition comprising tauroridine and / or one or more tauroridine derivatives dispersed in one or more polymer-carbohydrate-lipid conjugates.

52. The pharmaceutical composition according to claim 51, wherein one or more polymer-carbohydrate-lipid conjugates include a PEG-carbohydrate-lipid conjugate.

53. The pharmaceutical composition according to claim 52, wherein the PEG-carbohydrate-lipid conjugate comprises oleoyltriethylenetetramine-polyethylene glycol lactobionate.

54. The pharmaceutical composition according to claim 52, wherein the PEG-carbohydrate-lipid conjugate comprises oleoyldiethylenetetramine-dodecaethylene glycol lactobionate.

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