WO2021226178A1 - Composition d'uricase stable - Google Patents

Composition d'uricase stable Download PDF

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Publication number
WO2021226178A1
WO2021226178A1 PCT/US2021/030793 US2021030793W WO2021226178A1 WO 2021226178 A1 WO2021226178 A1 WO 2021226178A1 US 2021030793 W US2021030793 W US 2021030793W WO 2021226178 A1 WO2021226178 A1 WO 2021226178A1
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WO
WIPO (PCT)
Prior art keywords
uricase
composition
encapsulated
crosslinked silica
silica
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PCT/US2021/030793
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English (en)
Inventor
Matthew Herbert NIEDER
Adam MENG
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Nieder Matthew Herbert
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Publication of WO2021226178A1 publication Critical patent/WO2021226178A1/fr

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02—Making microcapsules or microballoons
    • B01J13/06—Making microcapsules or microballoons by phase separation
    • B01J13/14—Polymerisation; cross-linking
    • B01J13/18—In situ polymerisation with all reactants being present in the same phase
    • B01J13/185—In situ polymerisation with all reactants being present in the same phase in an organic phase
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5115—Inorganic compounds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02—Making microcapsules or microballoons
    • B01J13/20—After-treatment of capsule walls, e.g. hardening
    • B01J13/206—Hardening; drying

Definitions

  • the present invention relates to a uricase composition
  • a uricase composition comprising crosslinked silica and uricase, wherein the uricase is encapsulated by the crosslinked silica.
  • the uricase composition provides an improved stability of the enzyme activity when orally administered to a subject and is effective to treat hyperuricemia and treat gout.
  • the present invention also provides a process for preparing the silica coated uricase composition.
  • Gout is a debilitating disease especially common among the elderly resulting from sodium urate crystal deposition in joints. Gout is characterized by sudden, severe attacks of pain, swelling, redness and tenderness in the joints, often the joint at the base of the big toe.
  • the disease is essentially limited to humans since the precursor condition, hyperuricemia (excess blood uric acid), occurs in only in humans and higher apes due to absence of the enzyme uricase (urate oxidase, EC 1.7.3.3).
  • Uricase oxidizes uric acid, a product of purine metabolism, to 5’-hydroxyisourate, which is a more water soluble, easily degraded and excreted product.
  • the uricase reaction is shown in the following scheme.
  • Uricase is a homotetrameric enzyme containing four identical active sites situated at the interfaces between its four subunits. Uricase from A. flavus is made up of 301 residues and has a molecular weight of 33,438 Daltons. Uricase is found in nearly all organisms, from bacteria to mammals, but is inactive in humans and several other great apes, having been lost in primate evolution. This leads to humans having much higher and more highly variable levels of urate in the blood than most other mammals.
  • uric acid can also be excreted into the intestine if intestinal uric acid concentration is low relative to that in the blood.
  • Gout is treated with diet, anti-inflammatories such as NSAIDs, glucocorticoids, inhibitors of xanthine oxidase such as febuxostat, or uricosuric agents such as probenecid. These remedies may be ineffective and/or result in severe side effects. Administering the enzyme uricase from a non-human source has also been shown to treat hyperuricemia and gout. Two uricase preparations are commercially available for gout therapy. Rasburica.se (Elitek® Fasturtec®), a genetically modified fungal uricase, is licensed for treatment of chemotherapy-induced gout (tumor lysis syndrome) and pegloticase (Krystexxa®,
  • Puricase® a polyethylene glycol conjugated genetically modified mammalian uricase, is for chronic gout when alternate therapeutics are contraindicated. Both products are sterile preparations for systemic delivery. Commercial acceptance and use of the two preparations are limited by rapid formation of neutralizing antibodies in patients and high cost.
  • FIG. 1 shows hydrolysis and condensation of tetraethoxysilane (TEQ8) at the reverse micelle surface.
  • the first step show's the hydrolysis reaction of TEOS with water at the reverse micelle surface.
  • the second and third steps show condensation and further hydrolysis of partially hydrolyzed ethoxy silane molecules to form poly silicates.
  • FIG. 2 shows the structure of siliconized particle with dark dots indicating hydroxyl groups of the silica polymer.
  • FIG. 3 shows the uricase activity (hack calculated to original 10 mg/niL solution based on dilution steps) measured at different times after incubation at room temperature in mode) intestinal fluid (MIF). Circles are unease-containing silica hollow particles (Example 1); squares are the untreated uricase enzyme control.
  • the present invention is directed to a uricase composition
  • a uricase composition comprising crosslinked silica and uricase, wherein uricase is encapsulated by the crosslinked silica, wherein the uricase composition has improved stability in terms of maintaining its activity over non- encapsulated uricase in model intestinal fluid.
  • the invention provides a stable uricase composition containing uricase enzyme enclosed or encapsulated in a porous crosslinked silica shell.
  • the oral dosage form of the uricase composition of the present invention prevents access and digestion by intestinal proteases such as trypsin, chymotrypsin, and carboxypeptidase, but permits diffusion of small molecules such as substrate urate salt, water, and oxygen, and also subsequent release of the catalyzed reaction products, 5 -hydroxyisourate and hydrogen peroxide.
  • silica silicon dioxide
  • silica is an inexpensive, pharmacologically safe material which can be formed into an inert porous shell around the enzyme in an appropriate aqueous buffer.
  • Silica is stable in human gut pH (pH 6, 5-7, 5) with no known gut enzymes or microbes capable of breaking it down. Orally ingested silica is considered non-toxic (generally regarded as safe) for food use as an anticaking agent and as stabilizer or adsorbent for dietary ' supplements (21CFR 172.480).
  • Silica occurs naturally in a wide variety of plant or animal -based foods, especially in oats, wheat flour, milk and meats.
  • the source uricase for the present invention can be selected for acceptable stability under conditions of use and preparation, optimal activity characteristics (for example, k cat , KM, pH/activity, temperature/activity, cofactor requirements), physicochemical characteristics (quaternary structure, size, pI), and ease of production in safe, pharmaceutically acceptable purity.
  • the source uricase can be selected from natural sources such as animal, plant, fungal or bacterial cells, transfected organisms, or genetically altered variants to generate or enhance such characteristics.
  • uricase from Arthrobacter globiformis and Aspergillus fiavus are suitable for the present invention.
  • the present invention also provides a process for preparing the uricase composition.
  • One way to form the porous shell is to apply a silicon dioxide polymer coat. Hollow silica particles containing uricase are generated under gentle conditions by suspending the uricase enzyme in an aqueous buffer in reverse micelles within a nonpolar organic solvent and then adding tetra-alkoxysilicate. After permitting time for the tetra-aikoxysilicate to react on the reverse micelle surface, resulting nascent silicated particles are extracted into an aqueous extraction solution to permit further crosslinking or “curing” to take place in the absence of the organic solvent.
  • the resulting silicon dioxide polymer coat is a porous shell.
  • the present process comprises the steps of: (a) mixing a first aqueous solution comprising uricase at pH 7-10 with a non-polar organic solvent containing an anionic surfactant or a cationic surfactant to form a reverse micelle formulation; (b) adding a silanizing agent such as tetraalkoxylsilane, trialkoxysilane, or trihalosilane to the mixture of (a) and allowing sufficient time to permit formation of a nascent crosslinked silica shell comprising encapsulated uricase; (c) mixing in a second aqueous solution or modifying the ionic strength of the aqueous phase to at least 100 mM at pH 8-10 to extract the uricase- encapsulated nascent crosslinked silica shell into an aqueous phase; (d) separating the aqueous phase containing uricase-encapsulated crosslinked silica shell from the organic phase from the organic phase, and (e) curing and forming a
  • uricase is enclosed in reverse micelles suspended in a nonpolar organic solvent.
  • the first aqueous solution that contains uricase may be water or a buffer having pH 7-10 , preferably 8-9.
  • the aqueous solution may contain a small amount (e.g. 0.5-5%, or 1-2%) of polar organic solvent such as isopropanol, ethanol, or methanol.
  • the non-polar organic solvent can be any suitable organic solvent, for example, hexane, ether, isooctane, or heptane.
  • a reverse micelle-forming surfactant is added to either the aqueous or organic phase.
  • the aqueous solution is mixed with the non-polar organic solvent to extract or dissolve the enzyme into the reverse micelles.
  • the first aqueous buffer should have a low ionic strength with a pH ranging from 7 to 1(3, preferably pH 8, for example, 10 mM pH 8 tris hydroxymethylaminomethane (Tris).
  • Uricases typically have a pI below pH 7, so the enzyme will have a net negative charge above pH 7.
  • a cationic surfactant or an anionic surfactant along with divalent cationic salts such as CaCl 2
  • divalent cationic salts such as CaCl 2
  • An example of an anionic reverse micelle system is dioctyl sulfosuccinate sodium (AOT) in hexane/water with 1-2% isopropanol (aqueous phase) as cosolvent.
  • An example of a cationic reverse micelle system is cetyltrimethylammonium bromide in hexane/water with 6-7% hexanoi.
  • the nonpolar organic solvent in general contains 50-280 mM AOT, preferably 100-200 mM AOT, and the molar ratio of water to AOT in the mixture is about 10-50.
  • the concentration of AOT in the non-polar organic solvent is at least 50 mM, preferably at least 200 mM, in order to capture the uricase inside of reverse micelles rather than forming an organic soluble ion pair coupling with the uricase structure. This permits uricase to he more mobile within the silica shell and for the shell diameter to range from about 5-200 nm, or about 7-100 nm, and preferably about 10-50 nm.
  • the particle diameter can be determined.
  • AOT reverse micelle spherical diameter increases with increased molar ratio of water to AOT.
  • the maximum volume of water that can be held in the reverse micelle formulation depends on the concentration and properties of the surfactant used. For example, when 100 mM AOT is used to form reverse micelles, the volume ratio of the first aqueous solution to the organic solvent i s about 0.03 : 1 to 1 : 1 preferably 0.06: 1 to 0.2 : 1. When the volume ratio of aqueous buffer to organic solvent is 1 : 1 and the surfactant is AOT, two phases are present. When the volume ratio of aqueous buffer to organic solvent is 0.06: 1 and the surfactant is 100 mM AOT, only one phase is present.
  • a silanizing agent such as tetramethoxysilane (TMOS) or tetraethoxysilane (TEOS) is added and allowed to react (hydrolyze) with the water at the micelle surface ( Figure 1, first step).
  • TMOS tetramethoxysilane
  • TEOS tetraethoxysilane
  • the volume ratio of tetra alkoxysilane to organic solvent can range from 1 :48 to 1 :6, for example, 1 : 12 for TEOS in hexane.
  • Hydrolysis may be carried out from -20°C to 60°C, preferable 2-8°C,
  • the resulting partially hydrolyzed alkoxysilane continues to combine with water to form hydroxysiiicates but also begins to condense with other partially hydrolyzed alkoxysilane molecules to form polysilicates ( Figure 1, second and third steps).
  • the condensation process can van, ' from 10 minutes to 24 hours or longer, preferably 15 hours or overnight.
  • Addition of more organic phase may optionally be used in step b to dilute the nascent silicated particles, thus limiting crosslinking between them and resultant formation of aggregates with reduced catalytic activity.
  • step (c) of the process nascent condensed silica shell with encapsulated uriease is extracted from the organic phase.
  • the aqueous phase may be removed and replaced with an extraction solution, or salts and buffers may be added to convert the aqueous phase into an extraction solution.
  • an aqueous extraction solution is added to form a two-phase system with a 1:1 to 0.1:1 aqueous to organic volume ratio.
  • the extraction solution is buffered to a basic pH (pH 8-10.5, preferably pH 10) and divalent cation such as calcium may be added to stabilize the negatively charged uriease enzyme within the negatively charged silica shell.
  • the second aqueous solution in step (c) is an extraction solution having an ionic strength of at least 100 mM at pH 8-10, which is added to the nascent crossiinked silica shell solution to extract the uricase-encapsulated nascent crossiinked silica shell into an aqueous phase. It is important that the extraction solution have a high ionic strength of at least 100 m M, preferably at least 200 niM, 400 mM, 500 mM, or IM; the high ionic strength provides a good yield for exacting the silica coated uricase particles from the organic phase. For example, the extraction solution has an ionic strength of 200 m M to 2M or 500 mM to 1.5 mM.
  • Ammonium salt, and alkyl ammonium (e.g., methyl ammonium, glycine) salt are preferred salts in an extraction solution.
  • ammonium chloride, ammonium fluoride, and ammonium bromide can be used as an extraction solution.
  • An example of an extraction solution is pH 10, IM ammonium (chloride) or 0.5 M glycine (sodium) with 2 mM calcium chloride.
  • Extraction is carried out by fully mixing the extracting solution with organic phase such as by shaking or vigorous stirring for approximately 10 minutes.
  • step (d) of the process the aqueous phase containing the silica coated uricase particle and the organic phase are fully separated either by allowing the denser liquid phase to settle or centrifugation at a rate and time necessary to form two clear fractions.
  • the aqueous fraction containing the silica particles is collected.
  • step (e) of the process the aqueous fraction (the extraction solution) containing the silica particles is held for a sufficient time such as 3 to 14 days with or without stirring at 0°C to 30°C, preferably 2°C to 8°C, to enable the shells to strengthen or “cure” due to further condensation/crosslinking of the silica polymer.
  • FIG. 2 The structure of the mature siliconized particles is shown in FIG. 2 where the aqueous sphere containing uricase is coated with a thin shell of amorphous silica, also called silica gel.
  • amorphous silica also called silica gel.
  • the cured uricase containing particles can be stabilized by, for example, exchanging buffer or salts using ultrafiltration, gel filtration, or dialysis, and then removing the water by spray drying or lyophilization.
  • the resulting dry material can then be stored with little or no loss of activity before being incorporated into an enteric coated solid or encapsulated liquid oral drug product for therapeutic use.
  • the present invention provides pharmaceutical compositions comprising one or more pharmaceutically acceptable carriers and the crosslinked silica encapsulating uricase composition of the present invention.
  • the uricase composition in the pharmaceutical compositions in general is in an amount of about 1-90% for a tablet formulation, about 1- 100% for a capsule formulation.
  • the pharmaceutical composition is in a dosage form such as tablets, capsules, granules, fine granules, powders, syrups, or the like.
  • the above pharmaceutical composition can be prepared by conventional methods.
  • a tablet formulation or a capsule formulation of the uricase composition may contain other excipients that have no bioactivity and no reaction with the active compound.
  • Excipients of a tablet or a capsule may include fillers, binders, lubricants and glidants, disintegrators, wetting agents, and release rate modifiers. Binders promote the adhesion of particles of the formulation and are important, for a tablet formulation.
  • binders include, but not limited to, carboxymethylcellulose, cellulose, ethylcellulose, hydroxypropylmethylcellulose, methylcellulose, karaya gum, starch, starch, and tragacanth gum, poly(acrylic acid), and polyvinylpyrrolidone.
  • the cured uricase composition is coated with an enteric coating.
  • An enteric coating is a polymer barrier applied on oral medication that prevents its dissolution or disintegration in the gastric environment.
  • Materials used for enteric coatings include fatty acids, waxes, shellac, plastics, and plant fibers, which are known to a person skilled in the art. Since uricase is inactivated in acid, it is preferable that the oral dosing medicament of the uricase composition is coated with an enteric coating and protected from acidic gastric pH conditions.
  • the solid oral uricase dosage form or uricase particles suspended in a liquid dosage form may be enteric coated such that the active uricase containing particles are protected in the acidic gastric environment and only released after passing through the stomach into the duodenum where the pH is near or at pH 7. Two or more doses per day may be necessary to ensure adequate residence time in the ileum where uricase activity is expected to have the most effect, on blood uric acid levels.
  • the present invention is further directed to a method for treating gout.
  • the method comprises the step of administering to a subject suffering from gout an effective amount of the uricase composition of the present invention.
  • “An effective amount,” as used herein, is the amount effective to treat gout by ameliorating the pathological condition or reducing the symptoms of gout.
  • the present method is effective to reduce pain, swelling, redness and/or tenderness in the joints.
  • the pharmaceutical composition of the present invention can be applied by systemic administration including oral, rectal, parenteral (such as intravenous, intramuscular, subcutaneous), and other systemic routes of administration. In systemic, rectal or parenteral administration, the silica coating may prevent immunogenic removal or inflammatory reactions.
  • the enzyme does not necessarily need to circulate as long as the particles are deposited in a location that is oxygenated and in equilibrium with blood urate.
  • Oral administration is a preferred route of administration.
  • the oral dosage of the enteric coated silica particles containing uricase of the present invention is adequately protected from the proteases present in the human gut to survive within the intestine, and uricase in the intestine can sufficiently reduce urate concentration in the intestine to resolve hyperuricemia and thus, treat gout.
  • Dosing of the composition can van,' based on the extent of the disease and each patient's individual response.
  • the present invention is useful in treating a mammal subject.
  • the present invention is particularly useful in treating humans or higher apes.
  • Example 1 Preparation of silica encapsulated uricase.
  • Enzyme particles were extracted from the hexane solution by mixing 220 RPM on a rotary shaker with 5 mL pH 9.7 carbonate (ammonium salt) aqueous buffer, 2 mM CaCl 2 . The aqueous phase was separated by centrifugation at 2-8°C, 8000xg and retained. The preparation was cured at 2-8°C for 13 days.
  • the uricase activity of the enzyme preparation of Example 1 was compared to that of uncoated Arthrobacier globiformis control enzyme prepared to the same dilution in model intestinal fluid (MIl ⁇ ).
  • MIF contains pH 7.0 purified water, 25 mM phosphate(sodium), 140 mM NaCl, 3 mM sodium deoxycholate, and 3 nig/mL pancreatin from porcine pancreas (BxUSP), Sigma P7545.
  • Uricase activities rvere measured based on spectrophotometric detection of decreased uric acid concentration (Mahler et al J. Biol. Chem, 216: 625-641 (1955)).
  • the initial rate of the reaction was monitored at 293 nm in pH 9.0, 50 mM borate buffer using a starting urate concentration of 115 mM.
  • the enzyme activities were shown in Activity Units (AU), which are defined as ⁇ moles of urate decrease per minute as determined with the 293 nm extinction coefficient for urate at the reaction pH.
  • AU Activity Units
  • Example 3 Stability' of silica coated uricase particles extracted and cured in different concentrations of ammonium chloride.
  • Nascent coated particles were extracted from the hexane solution by adding 0.5 mL pH 9.7 ammonium chloride aqueous buffer, 2 mM CaCl 2 and agitating 220 RPM on a rotary shaker. Ammonium chloride concentrations of extractant in each vial were as used for the first hydrolysis step (1M, 200 mM, 100 mM, 50 mM respectively). The aqueous phase was separated by centrifugation at 2- 8°C, 8000xg and retained.
  • model intestinal fluid MIF
  • uricase activity was measured.
  • Table 1 Little MIF stable enzyme w'as obtained from the material extracted/cured using 50 mM ammonium chloride while the highest activity was found using a 1M ammonium chloride concentration.
  • Table 1 Model intestinal fluid (MIF ⁇ ) stability of silica coated unease particles extracted and cured in different concentrations of ammonium chloride

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Abstract

La présente invention concerne une composition d'uricase comprenant de la silice réticulée et de l'uricase, l'uricase étant encapsulée par la silice réticulée, et l'uricase encapsulée présentant une stabilité améliorée par rapport à l'uricase non encapsulée dans un fluide intestinal modèle. La présente invention porte également sur un procédé pour préparer la composition d'uricase recouverte de silice. La composition d'uricase est appropriée pour la préparation d'un médicament oral pour réduire la quantité d'acide urique dans le sang et traiter la goutte.
PCT/US2021/030793 2020-05-08 2021-05-05 Composition d'uricase stable WO2021226178A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114903983A (zh) * 2022-05-23 2022-08-16 江苏恰瑞生物科技有限公司 一种固定化的尿酸酶颗粒及其制备方法和应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060280799A1 (en) * 2003-05-21 2006-12-14 The University Of Manchester Carrier particles
US20160243262A1 (en) * 2013-09-17 2016-08-25 The Regents Of The University Of California Enzyme-encapsulated nanoparticle platform
US20180050115A1 (en) * 2016-08-19 2018-02-22 National Taiwan University Hollow silica nanoparticles with encapsulated bioactive ingredients, preparation process and applications thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060280799A1 (en) * 2003-05-21 2006-12-14 The University Of Manchester Carrier particles
US20160243262A1 (en) * 2013-09-17 2016-08-25 The Regents Of The University Of California Enzyme-encapsulated nanoparticle platform
US20180050115A1 (en) * 2016-08-19 2018-02-22 National Taiwan University Hollow silica nanoparticles with encapsulated bioactive ingredients, preparation process and applications thereof

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114903983A (zh) * 2022-05-23 2022-08-16 江苏恰瑞生物科技有限公司 一种固定化的尿酸酶颗粒及其制备方法和应用
CN114903983B (zh) * 2022-05-23 2023-08-15 江苏恰瑞生物科技有限公司 一种固定化的尿酸酶颗粒及其制备方法和应用

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