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WO2025048777A1 - Formulations orales traçables et leurs utilisations - Google Patents

Formulations orales traçables et leurs utilisations Download PDF

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Publication number
WO2025048777A1
WO2025048777A1 PCT/US2023/031244 US2023031244W WO2025048777A1 WO 2025048777 A1 WO2025048777 A1 WO 2025048777A1 US 2023031244 W US2023031244 W US 2023031244W WO 2025048777 A1 WO2025048777 A1 WO 2025048777A1
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WO
WIPO (PCT)
Prior art keywords
api
tissue
organ
composition
pharmaceutical composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2023/031244
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English (en)
Inventor
Michael SHTEIN
Guy YACHIN
Galia TEMTSIN-KRAYZ
Dannit Licht
Aaron FRENKEL
Pavel Kazhdan
Ofer Doron
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Xerient Pharma Ltd
IP Law Offices of Guy Levi LLC
Original Assignee
Xerient Pharma Ltd
IP Law Offices of Guy Levi LLC
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Filing date
Publication date
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Priority to PCT/US2023/031244 priority Critical patent/WO2025048777A1/fr
Publication of WO2025048777A1 publication Critical patent/WO2025048777A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4415—Pyridoxine, i.e. Vitamin B6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations
    • A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
    • A61K49/0438—Organic X-ray contrast-enhancing agent comprising an iodinated group or an iodine atom, e.g. iopamidol
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L1/00—Compositions of cellulose, modified cellulose or cellulose derivatives
    • C08L1/08—Cellulose derivatives
    • C08L1/10—Esters of organic acids, i.e. acylates
    • C08L1/14—Mixed esters, e.g. cellulose acetate-butyrate
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L1/00—Compositions of cellulose, modified cellulose or cellulose derivatives
    • C08L1/08—Cellulose derivatives
    • C08L1/26—Cellulose ethers
    • C08L1/28—Alkyl ethers
    • C08L1/284—Alkyl ethers with hydroxylated hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L3/00—Compositions of starch, amylose or amylopectin or of their derivatives or degradation products
    • C08L3/02—Starch; Degradation products thereof, e.g. dextrin
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00

Definitions

  • the disclosure is directed to solid oral formulations and their use. More specifically, the disclosure is related to compositions, methods and uses of solid oral formulations comprising a core-shell structure, with an active pharmaceutical ingredient, a radio-opaque tracer and a composition, which, following contact with a bodily fluid, becomes mucoadhesive.
  • a pharmaceutical composition of a solid oral drug delivery system comprising: a core or a plurality of mini cores (interchangeable with core sub-units), or core sub-units (in other words, beads, pellets, mini-tabs, powder and the like, each) comprising: an active pharmaceutical ingredient (API), or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt thereof; a radio-opaque contrast tracer; and a bio-adhesive composition; with or without a subcoating comprising polymer; and an outer lag-time coating comprising A pH depended coating polymer such as an acid resistant pharmaceutically acceptable coating polymer.
  • API active pharmaceutical ingredient
  • a method of determining the onset for irradiating a predetermined location on at least one of: a first tissue, and a first organ, the at least one of the first tissue, and the first organ are each being adjacent to at least one of : an adjacent second organ, and an adjacent second tissue, wherein each of the adjacent second organ, and the adjacent second tissue is sensitive to radiation comprising: administering to the patient an oral composition comprising: a core or a plurality of mini cores (interchangeable with core sub-units) (in other words, beads, pellets, mini-tabs, powder and the like, each) comprising: an active pharmaceutical ingredient (API), or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt thereof a radio-opaque tracer, and a bio-adhesive composition; sub-coating comprising a polymer; and an outer lag-time coating comprising coating the sub coated core with A pH
  • an oral composition comprising: a core or a plurality of mini cores (interchangeable with core sub-units) (in other words, beads, pellets, mini-tabs, powder and the like, each) comprising: an active pharmaceutical ingredient (API), or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt thereof a radioopaque contrast tracer; and a bio-adhesive composition; optionally a sub-coating comprising polymer; and an outer lag-time coating comprising a pH depended coating polymer such as an acid resistant pharmaceutically acceptable coating polymer for the process of determining the onset for irradiating a predetermined location of at least one of: a first tissue, and a first organ, the first tissue, and the first organ each being adjacent to at least one of : an adjacent second organ, and an adjacent second tissue, wherein each of the adjacent second organ, and the adjacent second tissue is sensitive to
  • FIG. 1 shows the release profile of a certain exemplary implementation of the solid oral pharmaceutical composition disclosed.
  • FIG. 2A is a schematic representation of the solid oral pharmaceutical composition, with FIG. 2B illustrating a core comprised of multiple components;
  • FIG. 3 A shows the release profile of the API from an exemplary implementation of the composition, with FIG. 3B, showing the release profile of the radio-opaque contrast tracer.
  • FIG. 4 depicts time series for dissolution
  • FIG. 5 depicts the accretion of the API along the duodenum
  • FIG. 6, is a schematic of the gut sections
  • FIG. 7A illustrates the fractional API concentration in each of the zones described in FIG. 5, and FIG. 7B illustrates the fractional concentration of adsorbed API, relative to the total amount of adsorbed API in the gut;
  • FIG. 8 shows the release profile of oral API from another exemplary implementation of the composition of Example III.
  • FIG. 9A shows a comparative dissolution profile in acid and buffer media
  • FIG. 9B illustrating the dissolution profile of the compositions in FIG. 9A, in pH 5.8 media.
  • the disclosure relates in one exemplary implementation to compositions, methods and uses of solid oral formulations comprising a core-shell structure, or a plurality of mini cores (interchangeable with core sub-units) (in other words, beads, pellets, mini-tabs, powder and the like, each) with an active pharmaceutical ingredient (API), or a prodrug or a pharmaceutically acceptable salt thereof; a radio-opaque tracer and a composition, which, following contact with a bodily fluid, becomes mucoadhesive.
  • API active pharmaceutical ingredient
  • Pancreatic cancer requires a biologically equivalent dose of more than 77 Gy to have a clinical (tumoricidal) benefit.
  • this is not practicable for most pancreatic tumors unless they are in a location that is at least 1cm away from the bowel wall.
  • a similar strength Gy may be required for other abdominal or pelvic cancers that cannot be treated definitively with radiation due to GI toxicity, such as hepatobiliary tumors, retroperitoneal sarcomas, or metastatic disease within the abdomen.
  • a pharmaceutical composition of a solid oral drug delivery comprising: a core or a plurality of mini units comprising: an effective amount of an active pharmaceutical ingredient, or prodrug or a pharmaceutically acceptable salt thereof; a radio-opaque contrast tracer; and a bio-adhesive composition; with or without a sub-coating comprising polymer; and an outer lag-time coating comprising a pH depended coating polymer such as an acid resistant pharmaceutically acceptable coating polymer.
  • the API is the prodrug S-2-(3- aminopropylamino)ethyl dihydrogen phosphorothioate (hereinafter WR-2721) having the formula: given orally at a predetermined time before radiation.
  • the pro-drug is rapidly activated by the endogenous digestive enzymes in the duodenum and jejunum to its active 2-[(3- Aminopropyl) amino] ethanethiol dihydrochloride (hereinafter WR-1065).
  • the prodrug API includes also its free mono-base or di-base conjugate, devoid of the respective HC1 and any other pharmaceutically acceptable salt formation once passage into or through the duodenum, as well as metabolite having the formula:
  • WR-2721 Due to the increased expression of non-tissue specific alkaline phosphatase in the intestine, enterally activated form of WR-2721 would accumulate in high concentrations in the intestines and provide selective localized radioprotection with fewer systemic side effects. This can be useful during radiation for pancreatic cancer, since the duodenum and jejunum arc doselimiting organs preventing ablative treatments.
  • the disclosure shows that oral WR-2721 is an effective radioprotector against otherwise lethal doses of radiation directed to the upper abdomen. Furthermore, demonstrated herein is the fact that the drug is well tolerated and accretes its active metabolite, WR-1065, in significantly higher levels in the GI tract compared to the serum, liver or spontaneous pancreatic tumors.
  • an “effective amount” of a subject compound refers to an amount of the cytoprotective pro-drug in a preparation which, when applied as part of a desired dosage regimen (dose, formulation, frequency), prevents from bringing about, e.g., a negative change in rate of survival of a cell according to clinically acceptable standards.
  • a desired dosage regimen dose, formulation, frequency
  • the term “accrete” and its grammatical derivatives e.g., “accretive” or “accretivly” refer in an exemplary implementation to the gradual increase in concentration of the active metabolite in the target tissue and/or organ that is to be radiation-protected.
  • the API pro-drug is WR-2721.
  • pro-drug refers to a pharmacologically inactive form of a compound that undergoes biotransformation prior to exhibiting its pharmacological effect(s).
  • a pro-drug is one that is converted in vivo by a subject after administration into a pharmacologically active form of the compound in order to produce the desired pharmacological effect. After administration to the subject, the pharmacologically inactive form of the compound is converted in vivo under the influence of biological fluids and/or enzymes into a pharmacologically active form of the compound.
  • Pro-drug forms of compounds can be utilized, for example, to improve bioavailability, mask unpleasant characteristics such as bitter taste, alter solubility for intravenous use, or to provide site-specific delivery of the compound.
  • Reference to a compound herein includes pro-drug forms of a compound and the drug conjugate (active form).
  • the oral dosage forms of WR-2721 can be also be a part of a composition comprising salt of a chelating agent selected from the group consisting of EDTA, EGTA, citrate and therapeutically acceptable salts thereof.
  • a preferred formulation can be made with the pharmacologically required dose of WR-2721 being between about 50 mg/unit of dosage form and about 2000 mg/unit dosage form or NMT 2000mg/ dosage form unit for example, between about 125 mg/ and about 750 mg or about 250 mg.
  • tissue/organ imaging technologies e.g., X-ray and computed tomography (CT), positron emission tomography (PET) and single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), ultrasound imaging, optical imaging
  • CT computed tomography
  • PET positron emission tomography
  • SPECT single photon emission computed tomography
  • MRI magnetic resonance imaging
  • ultrasound imaging optical imaging
  • the contrast in the generated image may be enhanced by introducing into the zone being imaged an agent (a “contrast agent”), which affects the organ or the methodology being used to increase the contrast between the imaged organ/tissue and its surrounding.
  • the contrast agent is operable to affect the spin re-equilibration (e.g., time) characteristics of nuclei (the “imaging nuclei” which generally are protons and more especially water protons) which are responsible for the resonance signals from which the images are generated.
  • the enhanced contrast thus obtained enables particular organs or tissues (e.g. blood, blood vessel walls, the small intestine walls, the large intestine walls and the like lumen walls) to be visualized more clearly by increasing or by decreasing the brightness of the image of the particular organ or tissue relative to that of its surroundings.
  • MRI employs a magnetic field, radio frequency energy and magnetic field gradients to make images of the body.
  • the contrast or signal intensity differences between tissues mainly reflect the Tl (longitudinal) and T2 (transverse) relaxation values and the proton density (effectively, the free water content) of the tissues.
  • a contrast medium can be used to change either the Tl, the T2 or the proton density of the tissue containing the contrast agent.
  • the term “contrast” refers to the relative difference of signal intensities in two adjacent regions of an image. Image contrast is heavily dependent on the chosen imaging technique (i.e., TE, TR, TI), and is associated with such parameters as proton density and Tl or T2 relaxation times.
  • the pharmaceutical; composition, using the radio-opaque contrast tracer can be imaged after administration using MRI, whereby post disintegration and release of the core, the radio-opaque contrast tracer will be discharged for example, in the duodenum providing the necessary contrast for imaging using MRI.
  • the radio-opaque contrast tracer used in the pharmaceutical compositions, methods and uses disclosed herein can be, for example, zirconium oxide, aluminum oxide, barium sulphate, sodium amidotrizoate, meglumine amidotrizoate, sodium diatrizoate, sodium calcium edetate, lodixanol, or triphenyl bismuth, diatrizoate (see e.g., FIG.3), metrizoate, iothalamate, ioxaglate, iopamidol, iohexol, ioxilan, iopromide, iodixanol, iobitridol, ioversol, or a composition comprising one or more of the foregoing.
  • the radio-opaque contrast tracer comprises about NET 3% (w/w tablet).
  • the term “radio-opaque agent” refers to any substance or agent which blocks, absorbs, scatters, or reflects any radiation outside the visible light spectrum, including, but not limited to. X-rays (in the wavelength range of 0.01 to 10 nm), beta rays (e.g., having velocities of about 35,000 to 180,000 miles per second), gamma rays (having an energy in the range of 10 4 to 10 7 eV), radiation used in radiation therapy (e.g., therapy to treat cancer), and other harmful radiation (such as that resulting from nuclear disasters and nuclear weapons).
  • X-rays in the wavelength range of 0.01 to 10 nm
  • beta rays e.g., having velocities of about 35,000 to 180,000 miles per second
  • gamma rays having an energy in the range of 10 4 to 10 7 eV
  • radiation used in radiation therapy e.g., therapy to treat cancer
  • other harmful radiation such as that resulting from nuclear disasters and nuclear weapons
  • Suitable radio-opaque agents include, but are not limited to, those comprising platinum, gold, silver, bismuth, mercury, lead, barium, calcium, zinc, aluminum, iron, gallium, iodine, tungsten, and any combination of any of the foregoing.
  • Other suitable radio-opaque agents include, but are not limited to, those commercially available as radio-opaque agents for medical uses, such as ionic and nonionic intravenous radiocontrast agents, diagnostic barium and gastrographin preparations, and gallium preparations.
  • the radio-opaque tracer can be selected based on its (i.e., the tracer’s) affinity to the tissue sought to be protected.
  • the radio-opaque tracer’s function is to provide indication of the tablet (or core sub-units, e.g., pellets, mini-tablets etc.) disintegration and the targeted release of the API
  • the radio-opaque tracer can function as an indicator of the API coverage of the area sought to be irradiated.
  • binding affinity refers to the strength of the binding of a single radio-opaque tracer to a tissue/organ site. Binding affinity depends on the closeness of stereochemical fit between single radio-opaque tracer to a tissue/organ site, on the size of the area of contact between them, on the distribution of charged and hydrophobic groups, etc.
  • the core further comprises the bio-adhesive composition (interchangeable with ‘mucoadhesive composition), which is adapted to form the bio-adhesive upon mixing with a body fluid, the bio-adhesive configured to adhere the API to a wall of a body lumen, such as the duodenum and jejunum.
  • the bio-adhesive composition interchangeable with ‘mucoadhesive composition
  • the bio-adhesive composition configured to adhere the API to a wall of a body lumen, such as the duodenum and jejunum.
  • drugs taken by oral administration always go quickly through the duodenum.
  • the bio-adhesive is, in an exemplary implementation, a mucoadhesive polymer composition, configured to prolong the residence time of the dosage form at the site of absorption (e.g., the duodenum, or jejunum), following the calculated lag in release, and to facilitate intimate contact of the dosage form with the underlying duodenum 1 inside surface to improve and enhance the efficacy of the therapeutically effective amount of the API.
  • the term “bio-adhesive”, or “mucoadhesive” denotes a compound exhibiting an affinity for a mucosal surface.
  • Mucoadhesive polymers are typically polymers having hydrogen bonding groups. See e.g.
  • “Mucoadhesion is the ability of materials to adhere to mucosal membranes in the human body and provide a temporary retention”. “Excellent mucoadhesive properties are typical for hydrophilic polymers possessing charged groups and/or non-ionic functional groups capable of forming hydrogen bonds with mucosal surfaces.” [Macromol Biosci. 2011 Jim 14; 1J(6): 748-64. doi: 10.1002/mabi.201000388.Epub 2010 Dec. 27].
  • the bioadhesive composition is a mucoadhesive composition that is comprised of hydroxylpropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), Hypromellose, starch, polyvinylpyrollidone (PVP), xanthan gum, thiolated chitosan, or a composition comprising one or more of the foregoing.
  • the bio-adhesive compositions comprises between about NET 2% (w/w tablet).
  • the core in the compositions disclosed used in the methods described is coated with a sub-coating of a polymer, and with enteric coating referring to a polymer which is preferentially soluble in the less acid environment of the intestine relative to the more acid environment of the stomach.
  • the sub-coat consequently lying beneath the outer lag-time coating comprising the acid-resistant, pharmaceutically acceptable coating polymer.
  • Suitable sub-coat materials include Hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC) or polyvinyl alcohol (PVA)
  • the Functional coating may be an essentially conventional coating material, for example, polymers that can be dissolved at pH value of no less than 5.0.
  • the polymer can be, for example poly(methacrylic acid-co-ethylacrylate, poly(methacylilc acid-co-methyl methacrylate), poly(methyl acrylate-co-methylmethacrylate-co-methacrylic acid) 7:3 , cellulose acetate phthalate, cellulose acetate succinate, methyl cellulose phthalate, methylhydroxy propylcellulose phthalate, ethyl hydroxycellulose phthalate, poly(vinylacetate phthalate, polyvinylbutyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic mono-ester copolymer, methyl aerylate-methacrylic acid copolymer, and methacrylate- methacrylic acid-octyl acrylate copolymer, and/or enter
  • the Functional coating may also include insoluble substances which are neither decomposed nor solubilized in living bodies, such as alkyl cellulose derivatives such as ethyl cellulose, crosslinked polymers such as styrene-divinylbenzene copolymer, polysaccharides having hydroxyl groups such as dextran, cellulose derivatives which are treated with bifunctional crosslinking agents such as epichlorohydrin, dichlorohydrin, 1, 2-, 3, 4-diepoxybutane, etc.
  • the enteric Functional coating may also include starch and/or dextrin.
  • the enteric-coating materials are the pharmaceutically acceptable methacrylic acid copolymer which are copolymers, anionic in character, based on methacrylic acid and methyl methacrylate, for example having a ratio of free carboxyl groups: methyl-esterified carboxyl groups of 1:>3, e.g. around 1:1 or 1:2, and with a mean molecular weight of 135,000.
  • Such Functional polymers are sold under the trade name EudragitTM, such as the Eudragit L series e.g. Eudragit L 12.5TM, Eudragit L 12.5PTM, Eudragit L100TM, Eudragit L 1 GO- 55TM, Eudragit L-30TM, Eudragit L-30 D-55TM, the Eudragit STM series e.g. Eudragit S 12.5, Eudragit S 12.5PTM, Eudragit SI 00TM, the Eudragit NETM series e.g. Eudragit NE 30DTM, the Eudragit RLTM series, e.g.
  • enteric polymers for example having a solubility in aqueous media at pH 5.5 and above, such as the commercially available “EUDRAGIT” (Trade Mark) enteric polymers, such as “Eudragit L100-55” (Trade Mark) or OPADRY® Enteric (94 Series) i.e.
  • a cationic polymer synthesised from dimethylaminoethyl methacrylate is known and sold as enteric polymers, for example having a solubility in aqueous media at pH 5.0 and above, such as the commercially available Functional polymers are sold under the trade name OPADRY Enteric-91 series.
  • enteric Functional coating may also include Polyvinyl Acetate Phthalate (Phthalavin enteric coating polymer, PVAP).
  • Aqueous plasticizers include propylene glycol or “Citroflex” or Citroflex A2” (Trade Marks) (mainly triethyl citrate or acetyl triethyl citrate).
  • Non-aqueous plasticizers include these, and also diethyl and dibutyl phthalate and dibutyl sebacate. The quantity of plasticizers included will be apparent to those skilled in the art.
  • the enteric coating may also include an anti-tack agent such as talc, silica or glyceryl monostearate.
  • an anti-tack agent such as talc, silica or glyceryl monostearate.
  • the quantity of plasticizers and anti-tack agent may be generally conventional to the art.
  • the coating may include around 10-40 wt. % plasticizer and up to around 50 wt. % of anti-tack agent, e.g. 2- 20 wt. % of anti-tack agent.
  • Enteric coating may be applied to the core by dissolving or suspending the enteric coating materials in a suitable medium, such as water, ethanol, isopropanol, acetone, methyl ethyl ketone, ethyl acetate, etc. or mixtures thereof, and the resultant solution or suspension may be sprayed on the core to coat them, followed by drying sufficiently with an airflow and screening.
  • a suitable medium such as water, ethanol, isopropanol, acetone, methyl ethyl ketone, ethyl acetate, etc. or mixtures thereof
  • an over-coat is also applied.
  • Suitable over-coat materials include copolymers of methacrylic acid and methyl methacrylate, and hydroxypropyl methyl cellulose.
  • the over-coat may be of the same material as the entericcoat.
  • such coatings may be applied by known techniques of aqueous film coating, using known unit operations.
  • the pharmaceutical composition exhibits a dissolution of not less than 85% of the API within 30 minutes as measured with a paddle apparatus with or without sinker at 75 - 100 revolutions per minute over 30 minutes in 150-900 ml, 500 mL of aqueous buffered solution at a pH of 5.5- pH 6.0.
  • the pharmaceutical composition exhibits a dissolution of not more than 10% of the API after 2 hours in 0.1N HC1. Moreover, the pharmaceutical composition exhibits a dissolution of not more than 10% of the API in 150-900 ml, or 500 mL of aqueous 0.1 N HC1 at 37°C, as measured with or without sinker with a paddle apparatus at 75rpm during 120 minutes, followed not less than 85% of the API over additional 30 minutes at 75 rpm in 500 mL of aqueous buffered solution at a pH of 5.5 at 37°C. The pharmaceutical composition exhibits a dissolution of not more than 10% of the API after 2 hours in 0.1N HC1.
  • the pharmaceutical composition exhibits a dissolution of not more than 10% of the API in 150-900 ml, or 500 mL of aqueous 0.1 N HC1 at 37°C, as measured with or without sinker with a paddle apparatus at lOOrpm during 120 minutes, followed not less than 85% of the API over additional 30 minutes at 100 rpm in 500 mL of aqueous buffered solution at a pH of 5.8 at 37°C.
  • compositions may also contain excipients such as fillers disintegrant, flowing agent, gliadents, binders, wetting agents, lubricants, and/or antioxidants addition, the oral compositions provided herein may also comprise an acceptable buffering agent mixture (e.g., tris buffer, phosphate buffer, and the like); a sweetening agent; and/or at least one flavor agent.
  • an acceptable buffering agent mixture e.g., tris buffer, phosphate buffer, and the like
  • sweetening agent e.g., a sweetening agent
  • at least one flavor agent e.g., a sweetening agent
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions provided herein can be varied so as to obtain an amount of the active ingredient or the prodrug (e.g., WR-2721) that is effective in achieving the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound provided herein, can employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs compounds (e.g., oxaliplatin, irinotecan, fluorouracil, leucovorin, gemcitabine in the case of metastatic pancreatic cancer), and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors and their combination.
  • drugs compounds e.g., oxaliplatin, irinotecan, fluorouracil, leucovorin, gemcitabine in the case of metastatic pancreatic cancer
  • materials used in combination with the particular compound employed the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors
  • compositions disclosed arc used in the methods described. Accordingly, provided herein is a method of determining the onset for irradiating a predetermined location on at least one of: a first tissue, and a first organ, the at least one of the first tissue, and the first organ are each being adjacent to at least one of : an adjacent second organ, and an adjacent second tissue, wherein each of the adjacent second organ, and the adjacent second tissue is sensitive to radiation, the method comprising: administering to the patient an oral composition comprising: a core or a plurality of mini cores (interchangeable with core sub-units) (in other words, beads, pellets, mini-tabs, powder and the like, each) comprising: an active pharmaceutical ingredient (API), or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt thereof, a radioopaque tracer, and a bio-adhesive composition; an optional sub-coating comprising a polymer; and
  • API active pharmaceutical ingredient
  • the core can be customized for the intended protection, by incorporating into the core a plurality of beads, mini tablets and/or pellets and/or powder comprising the API compositions disclosed or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt thereof a radio-opaque contrast tracer; and a bio-adhesive and the pH depended polymer such as enteric coating.
  • the mini tablets beads, and/or pellets, and/or mini-tablets used can have an enteric coating that can be configured to release the API with the mucoadhesive such that the API will be released over a larger area of the organ/tissue sought to be protected.
  • the multi-particles’ core can be customized ad-hoc by the physician to obtain optimal coverage of the area to be protected.
  • the core can have API 100, with contrast agent 200 and enteric coating 300.
  • An additional or alternative configuration is illustrated in FIG. 2B, where the core comprises multiple particles, where Functional or enteric coating 301 , 302, 303 all have different composition and/or thickness, configured when release, to cause API 100 to be released over a predetermined area length at a predetermined location e.g., along the duodenum.
  • pharmaceutically acceptable salt refers to salts prepared from pharmaceutically acceptable nontoxic acids and bases, including inorganic and organic acids and bases.
  • pharmaceutically acceptable salt also refers to a salt prepared from an API having an acidic functional group, such as a carboxylic acid functional group, and a pharmaceutically acceptable inorganic or organic base.
  • Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxysubstituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N- methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl)-amine, 2-hydroxy-tert-butylamine, or tris- (hydroxymethyl)methylamine, N,N,-di-lower alky 1-N- (hydroxy lower alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxye
  • the term “pharmaceutically acceptable salt” also refers to a salt prepared from the API, e.g., amifostine, 2- [(3- Aminopropyl) amino] ethanethiol dihydrochloride (hereinafter WR-1065), having a basic functional group, such as an amino functional group, and a pharmaceutically acceptable inorganic or organic acid.
  • API e.g., amifostine, 2- [(3- Aminopropyl) amino] ethanethiol dihydrochloride
  • Suitable acids can be, but are not limited to, hydrogen sulfate, citric acid, acetic acid, oxalic acid, hydrochloric acid, hydrogen bromide, hydrogen iodide, nitric acid, phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, succinic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucaronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
  • the language “at least one of: a first tissue, and a first organ” is intended to describe the tissue and/or organ where the tumor sought to be irradiated is located.
  • first tissue and/or organ is intended to describe the tissue and/or organ where the tumor sought to be irradiated is located.
  • the language “at least one of : an adjacent second organ, and an adjacent second tissue” is intended to describe the tissue and/or organ that are prohibitively sensitive to irradiation and are adjacent to the tumor location.
  • the first organ would be the pancreas head, and the second tissue would be the duodenum wall.
  • the first organ can be the prostate in the second organ can be the GI tract.
  • the tissues sensitive to radiation is the duodenum and/or jejunum.
  • typical limits for maximum radiation dose to the duodenum are thought to be about 50 Gray ( Gy) to one-third of the organ or 40 Gy to the entire organ, with recent guidelines recommending that only 195 cm 3 of small bowel receive >45 Gy.
  • biologically effective doses in (large) excess of 55 Gy may be necessary to achieve a high probability of tumor control.
  • the location and disintegration of the pharmaceutical composition can be monitored and upon release of the radio-opaque tracer, it is assumed the mucoadhesive composition has been activated and will “smear” on the wall of the adjacent organ and/or tissue in close proximity to the target tumor, where accretion can take place and cytoprotection maximized. At that point irradiation can then commence.
  • the step of commencing irradiation comprises: using fractionated stereotactic body radiation therapy, exposing the predetermined location on the at least one of the first tissue, and the first organ, to between 1 and about 5 irradiation fractions.
  • the step of exposing the at least one tissue and one organ to a therapeutically effective radiation dose comprises using stereotactic body radiation therapy (SBRT), administrating to the patient a total radiation dose of between about 5 Gy, and about 16 Gy per fraction for a total of between one and five fractions (25-80 Gy), which would be a total BED10 of 37.5 Gy- 208 Gy in three to five fractions or an D2EQ of 31.25 Gy to 173.3 Gy on three to five fractions.
  • SBRT stereotactic body radiation therapy
  • SBRT stereotactic body radiation therapy
  • a single or limited number of focused, high dose radiation fractions are configured to be delivered to the tumor, which enables the delivery of ablative doses to the tumor and immediately adjacent tissues.
  • SBRT can be an alternative to resection when a critical structure, which precludes its surgical resection, is presented.
  • the methods disclosed further comprise treatment planning using, for example, respiratory- correlated cone-beam computed tomography (4D-CT), with abdominal compression to limit the respiratory-associated movement of tumor during the step of delivering the fractionated radiation.
  • 4D-CT respiratory- correlated cone-beam computed tomography
  • fiducial markers are used during the course of treatment to actively track tumor movement.
  • a composition comprising: a core, or a plurality of mini cores (interchangeable with core sub-units) (in other words, beads, pellets, mini-tabs, powder and the like, each) with comprising: an active pharmaceutical ingredient (API), or prodrug or a pharmaceutically acceptable salt thereof; a radio-opaque contrast tracer; and a bio-adhesive composition; an optional sub-coating comprising polymer; and an outer lag-time coating comprising a pH depended polymer such as an acid resistant pharmaceutically acceptable coating polymer for the process of determining the onset for irradiating a predetermined location of at least one of: a first tissue, and a first organ, the first tissue, and the first organ each being adjacent to at least one of : an adjacent second organ, and an adjacent second tissue, wherein each of the adjacent second organ, and the adjacent second tissue is sensitive to radiation.
  • the release profile of the API in this case, amifostine, and the radio-opaque contrast tracer were measured.
  • the release profiles of API and tracer are similar when stored at 5°C, indicating that their release is controlled solely by the coating system’s structure. Therefore, the addition of the contract agent to the tablets is operable for tracing the tablet progression in Duodenum and API release and accretion along the duodenum.
  • Feed Fasted for x hours prior to activity
  • the tablet was administered to the fasted pig orally with 250ml water (eq. to glass of water).
  • the animal was placed on the bed in a slightly vertical position if possible, simulating (as much as possible), natural patient posture. Following dissection, the pig stomach and duodenum have undergone X-Ray to determine the location of the tablet.
  • a different wetted* coated tablet was placed directly into the duodenum.
  • the tablet that have soaked for 2 hours, at a temperature of 37°C of a 0.1N HC1 /gastric fluid (PH 1.2) and than directly placed in the duodenum and
  • the placement of the softened tablet will be undertaken by a selected product which will gently place the tablet in the correct position.
  • Sacrifice was done as per the EC and animal handling requirements. The animal was sacrificed 30 -45min after the coated tablet disintegrate and dissolved .
  • the duodenum was resected and removed, tied off and marked to show the ends of the duodenum and the position within the animal. It was labelled with the proximal and distal segments and the segment closest to the pancreas was noted.
  • the fluid was taken out from each organ and was labelled (X ml, Organ name).
  • the removed products was labelled, to identify
  • duodenum and other removed elements was placed in storage at -20°C/ -80°C within x timeframe of removal.
  • Bioanalytical samples are to be maintained at -20 or -80 °C during transport. Bioanalytical sectioning for analysis
  • the duodenum was sliced vertically to separate the proximal and distal sections. These were then be cut into predetermined portions over the relevant duodenal sections.
  • the activity had 2 phases i.
  • One coated tablet (no pre-treatment with HC1) was administered to the pig orally. The pig was subsequently anaesthetised, and visualisation of the tablet dissolution was undertaken via X-ray and Endoscopy. Due to the tablet being stuck behind food remnants in the stomach (undigested straw), after 2 hours in the stomach the pill was placed in the duodenum manually via an endoscope attachment.
  • One coated tablet (pre-treated with HC1) was placed in the duodenum using the endoscope attachment. The disintegration of the tablets was visualised using X-ray.
  • Results were as follows: i. 3.4% coating tablet does not disintegrate at 37°C in 0. IN HC1, but does in the duodenum within 30min, similarly to in-vitro results. ii. Diatrizoate is effective as a radio-opaque tracer. iii. The green coating seen in duodenum (see e.g., FIG. 5, bracketed area) are the result of methylene blue which was released from the tablet core and mixed with yellow gastric fluids. iv. WR-1065 Concentration is higher near duodenum (la>lb, 2a>2b, etc), see e.g., FIG.s 6, and 7B. v. Under the tested conditions, 20% of WR-1065 is absorbed on duodenum walls, 80% remains in the duodenal fluid.
  • compositions were reformulated to affect the release most of the API (>50%) in areas la (the duodenal cap) -2a (the superior duodenal flexure 602) of the duodenum 600 past the pylorus 601 (see e.g., FIG. 6), to improve the protection of the pancreas head 610.
  • composition #034-149-200 The sub-coating composition for composition #034-149-200 is provided in Table 5.
  • Table 5 Sub coating composition of #034-149-200 core
  • composition #034-44-200 is provided in Table 6.
  • composition #034-149-200 The enteric coating composition for composition #034-149-200 is provided in Table
  • Table 7 Enteric coating composition of #034-149-200 formulation Coating system
  • Opadry Enteric* is a proprietary mixture of: poly(vinyl acetate phthalate), TiOz, purified stearic acid, and triethyl citrate sold under the COLORCORNTM brand name.
  • Dissolution Medium #2 Citrate buffer pH 5.8
  • Standard solution for analysis 2.0 ml of Amifostine Working standard solution were transferred into 20 mL volumetric flask, where about 10 ml of water were admixed. 4 mL of IM Sulfuric acid was added, as well as 0.4 mL of 2.5% Ammonium molybdate, and 0.4 mL of 1% Ascorbic acid. The mixture was completed to 100% of the volume with water, where the open flask was heated in a boiling water bath for 15 min then cooled.
  • Dissolution Test Six dissolution vessels were filled with 500 mL of dissolution media, and the temperature of dissolution media was verified at 37 °C before starting the dissolution test. Previously weighed tablets were placed in each vessel. Stirring was initiated at a rate of 100 rpm for tablets with 100-200 mg Amifostine or at 150 rpm for tablets with 300 mg Amifostine. Then 5 ml was withdrawn from the dissolution media of each vessel through 20 pm filter at the specified time point for UV-VIS analysis in the spectrophotometer.
  • Wst is weight of Amifostine standard, mg
  • V medium is volume of dissolution medium, 500 mL
  • formulation #034-149-200 comprising 3.47% Opadry enteric coating with micronized talc, clearly shows over 80% dissolution of the API within 3 minutes following exposure to media 2, configured to emulate the conditions past the pylorus within the duodenum, namely 5.8 pH.
  • a pharmaceutical composition of a solid oral drug delivery comprising: a single unit core, or plurality of core units, each comprising: an active pharmaceutical ingredient (API), a prodrug or a pharmaceutically acceptable salt thereof; a radio-opaque contrast tracer; and a bio-adhesive composition; an outer coating comprising a pH depended polymer, pharmaceutically acceptable coating polymer, configured for a predetermined dissolution lag-time; and optionally, a subcoating comprising polymer, wherein (i) the API or pro-drug, or its pharmaceutically acceptable salt is a cytoprotectant pro-drug or a drug composition, (ii) the cytoprotectant pro-drug or a drug composition comprises at least one of: ergotamine, amifostine, pyridoxine, Amifostine thiol (WR- 1065) (iii) comprising S-2-(3-amino propylamino)
  • API active pharmaceutical ingredient
  • the radio-opaque contrast tracer is: Diatrizoate Sodium, zirconium oxide, aluminum oxide, barium sulphate, sodium amidotrizoate, meglumine amidotrizoate, sodium diatrizoate, sodium calcium edetate, lodixanol, or triphenyl bismuth, or a composition comprising one or more of the foregoing, (vi) the radioopaque contrast tracer (ROCT) has a lower affinity to a tissue affected by the API, than the API itself (ROCT ⁇ AP1), or, as meeded (vii) the radio-opaque contrast tracer has a higher affinity to a tissue affected by the API, than the API (ROCT>API), wherein (vii)
  • thermodynamically compatible plasticizer is: triethyl citrate (TEC), diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, acetylated citrate esters, dibutyl sebecate, castor oil, or a plasticizer composition comprising one or more of the foregoing, wherein (xvi) the pharmaceutical composition exhibits a
  • a method of determining the onset for irradiating a predetermined location on at least one of: a first tissue, and a first organ, the at least one of the first tissue, and the first organ are each being adjacent to at least one of : an adjacent second organ, and an adjacent second tissue, wherein each of the adjacent second organ, and the adjacent second tissue is sensitive to radiation comprising: administering to the patient an oral composition comprising: single unit core or plurality of core units, each (core, or core sub unit) comprising: an active pharmaceutical ingredient , prodrug (API), or a pharmaceutically acceptable salt thereof, a radio-opaque tracer, and a bio-adhesive composition; optionally, sub-coating comprising a polymer; and non-optionally, an outer lag-time coating comprising coating the sub coated core with an acid resistant pharmaceutically acceptable coating polymer configured for a predetermined dissolution lag-time; using an imaging device, imaging the at least one
  • an oral composition comprising: single unit core or plurality of core sub-units, each (core unit or subunits) comprising: an active or prodrug pharmaceutical ingredient (API), or a pharmaceutically acceptable salt thereof; a radio-opaque contrast tracer; and a bio-adhesive composition; optionally a sub-coating comprising polymer; and an acid resistant pharmaceutically acceptable coating polymer configured for a predetermined dissolution lag-time for use in the process of determining the onset for irradiating a predetermined location of at least one of: a first tissue, and a first organ, the first tissue, and the first organ each being adjacent to at least one of : an adjacent second organ, and an adjacent second tissue, wherein each of the adjacent second organ, and the adjacent second tissue is sensitive to radiation, wherein (xli) the radio-opaque contrast tracer has a lower affinity, or (xlii) higher affinity, to the at least one

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Abstract

La divulgation concerne des formulations orales solides et leur utilisation. Plus spécifiquement, la divulgation concerne des compositions, des méthodes et des utilisations de formulations orales solides comprenant une structure cœur-écorce, avec un ingrédient pharmaceutique actif, un traceur radio-opaque et une composition, qui, après contact avec un fluide corporel, devient mucoadhésive.
PCT/US2023/031244 2023-08-28 2023-08-28 Formulations orales traçables et leurs utilisations Pending WO2025048777A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5284874A (en) * 1987-06-04 1994-02-08 Massachusetts Institute Of Technology Chemical prevention or reversal of cataract by phase separation inhibitors
US20040018228A1 (en) * 2000-11-06 2004-01-29 Afmedica, Inc. Compositions and methods for reducing scar tissue formation
US20050064027A1 (en) * 2001-12-15 2005-03-24 Spherics, Inc. Bioadhesive drug delivery system with enhanced gastric retention
US20060045865A1 (en) * 2004-08-27 2006-03-02 Spherics, Inc. Controlled regional oral delivery
US20080311191A1 (en) * 2004-08-27 2008-12-18 Avinash Nangia Multi-Layer Tablets and Bioadhesive Dosage Forms
US20180000740A1 (en) * 2016-03-11 2018-01-04 Gateway Pharmaceutical LLC Pharmaceutical compositions for colon-specific delivery
US20190143076A1 (en) * 2017-11-10 2019-05-16 Merit Medical Systems, Inc. Systems and method for medical device strain relief

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5284874A (en) * 1987-06-04 1994-02-08 Massachusetts Institute Of Technology Chemical prevention or reversal of cataract by phase separation inhibitors
US20040018228A1 (en) * 2000-11-06 2004-01-29 Afmedica, Inc. Compositions and methods for reducing scar tissue formation
US20050064027A1 (en) * 2001-12-15 2005-03-24 Spherics, Inc. Bioadhesive drug delivery system with enhanced gastric retention
US20060045865A1 (en) * 2004-08-27 2006-03-02 Spherics, Inc. Controlled regional oral delivery
US20080311191A1 (en) * 2004-08-27 2008-12-18 Avinash Nangia Multi-Layer Tablets and Bioadhesive Dosage Forms
US20180000740A1 (en) * 2016-03-11 2018-01-04 Gateway Pharmaceutical LLC Pharmaceutical compositions for colon-specific delivery
US20190143076A1 (en) * 2017-11-10 2019-05-16 Merit Medical Systems, Inc. Systems and method for medical device strain relief

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