WO2022111379A1 - Implant intraoculaire axitinib - Google Patents

Implant intraoculaire axitinib Download PDF

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WO2022111379A1
WO2022111379A1 PCT/CN2021/131602 CN2021131602W WO2022111379A1 WO 2022111379 A1 WO2022111379 A1 WO 2022111379A1 CN 2021131602 W CN2021131602 W CN 2021131602W WO 2022111379 A1 WO2022111379 A1 WO 2022111379A1
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axitinib
weight
plga
implant
intraocular implant
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PCT/CN2021/131602
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English (en)
Chinese (zh)
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柯潇
郑强
陈洋
王虎山
刘立云
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成都康弘药业集团股份有限公司
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Publication of WO2022111379A1 publication Critical patent/WO2022111379A1/fr

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    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A61K9/0051—Ocular inserts, ocular implants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention belongs to the field of pharmaceutical preparations, and relates to an intraocular implant of axitinib and a preparation method.
  • Eye diseases are mainly divided into two types, anterior eye diseases, including but not limited to glaucoma, cataracts, blepharospasm, conjunctivitis, conjunctivitis and corneal diseases, etc., and posterior eye diseases, including but not limited to retinal vein occlusion ( RVO), uveitis, diabetic macular edema (DME), and age-related macular degeneration (wAMD and nAMD), inflammatory or degenerative eye diseases that affect millions of people worldwide and, if not treated properly, can lead to May cause permanent visual impairment or blindness.
  • anterior eye diseases including but not limited to glaucoma, cataracts, blepharospasm, conjunctivitis, conjunctivitis and corneal diseases, etc.
  • posterior eye diseases including but not limited to retinal vein occlusion ( RVO), uveitis, diabetic macular edema (DME), and age-related macular degeneration (wAMD and nAMD), inflammatory or degenerative
  • Vitreous implants have been developed, such as the marketed fluocinolone vitreous implant For the treatment of chronic non-infectious uveitis infecting the posterior segment of the eye.
  • Axitinib is a tyrosine kinase inhibitor with the chemical name N-methyl-2-[3-((e)2-pyridin-2-yl-vinyl)-1H-indazole-6- thio]-benzamide, having the following chemical structural formula (Compound I):
  • axitinib has the desired activity to inhibit CNV formation (Giddabasappa Anand, Lalwani Kush, Norberg Rand, et al. Axitinib inhibits retinal and choroidal neovascularization in vitro and in vivo models. Experimental Eye Research, 2016.145).
  • Patent WO2014204791 discloses axitinib eye drops, but its drug load is small, and due to the drug barrier effect and tear dilution, etc., it prevents a sufficient amount of the drug from reaching the treatment site, requiring repeated administration, and compliance. poor.
  • WO2017120600 discloses an ophthalmic injection of axitinib, but it does not pay attention to the stability of axitinib formulations.
  • axitinib is highly sensitive to light, and its content varies greatly under light conditions, which is not conducive to the stability of its medicinal preparation. At the same time, its low solubility property also reduces the bioavailability of axitinib pharmaceutical preparations.
  • the purpose of the present invention is to provide a stable, safe and long-term release axitinib implant for the treatment of glaucoma, cataract, retinal vein occlusion (RVO) ), uveitis, diabetic macular edema (DME), and age-related macular degeneration (wAMD and nAMD).
  • the present invention includes an axitinib intraocular implant comprising axitinib and a biodegradable polymer.
  • the biodegradable polymer is poly(lactic-co-glycolic acid) (PLGA) copolymer, polylactide (PLA), polyglycolide (PGA), polyethylene glycol (PEG) one or more of.
  • the biodegradable polymer is PLGA, and in one embodiment, the biodegradable polymer is ester terminated PLGA.
  • the ester-terminated PLGA has a molecular weight of 15,000-100,000. In certain embodiments, the ester-terminated PLGA has a molecular weight of 15,000-70,000. In a preferred embodiment, the molecular weight of the ester-terminated PLGA is 70,000. In a preferred embodiment, the molecular weight of the ester-terminated PLGA is 15,000.
  • the ratio of glycolic acid to lactic acid monomers in the PLGA is from 0:100 to 100:0, and in certain embodiments, the ratio of glycolic acid to lactic acid monomers is from 15:85 to 85:15 , in certain embodiments, the ratio of glycolic acid and lactic acid monomers is 50:50.
  • the implant comprises 20%-90% by weight axitinib, in certain embodiments, the implant comprises 30%-80% by weight axitinib, in certain embodiments, the implant comprises 30%-70% by weight of axitinib, in certain embodiments, the implant comprises 40%-70% by weight of axitinib, in certain In some embodiments, the implant comprises 45%-70% by weight of axitinib, in certain embodiments, the implant comprises 40%-50% by weight of axitinib, in certain embodiments In regimens, the implant comprises 45%-50% by weight of axitinib, and in certain embodiments, the implant comprises 50%-70% by weight of axitinib.
  • the implant comprises 30%-80% axitinib and 20%-70% ester-terminated PLGA by weight. In certain embodiments, the intraocular implant comprises 50%-70% axitinib and 30%-50% ester terminated PLGA by weight. In certain embodiments, the intraocular implant comprises 40%-70% axitinib and 30%-50% ester-terminated PLGA by weight. In certain embodiments, the intraocular implant comprises 40%-50% axitinib and 40%-50% ester terminated PLGA by weight. In certain embodiments, the intraocular implant comprises 70% by weight of axitinib and 30% by weight of ester-terminated PLGA.
  • the intraocular implant comprises by weight 50% axitinib and 40% ester terminated PLGA. In certain embodiments, the intraocular implant comprises by weight 50% axitinib and 45% ester terminated PLGA. In certain embodiments, the intraocular implant comprises by weight 50% axitinib and 50% ester terminated PLGA. In certain embodiments, the intraocular implant comprises 50% by weight axitinib and 50% ester-terminated PLGA, wherein the ester-terminated PLGA has a molecular weight of 70,000. In certain embodiments, the intraocular implant comprises 50% axitinib by weight and 50% ester-terminated PLGA, wherein the ester-terminated PLGA has a molecular weight of 15,000.
  • axitinib is included in the implant in a weight of 200 micrograms to 1.5 mg, in certain embodiments, axitinib is included in the implant in a weight of 200 micrograms to 1 mg, In certain embodiments, axitinib is included in the implant in a weight of 1 mg to 1.5 mg. In certain embodiments, the intraocular implant weighs 200 micrograms, 400 micrograms, 500 micrograms, 600 micrograms, 700 micrograms, 1 mg, or 150 mg.
  • release modifiers are included in the implant including hydroxypropyl methylcellulose, hyaluronic acid and its sodium salts, poloxamers, polyethers, polyvinyl alcohol, one or more of polyvinylpyrrolidone, lactose, polyethylene glycol, mannitol, glucose, maltose, sodium chloride, potassium chloride, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, or sucrose, in certain implementations
  • the release modifier includes one or more of polyethylene glycol, mannitol, sodium chloride, and polyvinylpyrrolidone.
  • the release modifier includes one or more of mannitol, sodium chloride, polyvinylpyrrolidone.
  • the release modifier is present in an amount of 0% to 10% by weight, in certain embodiments, the release modifier is present in an amount of 2.5% to 10% by weight, in certain embodiments. In embodiments, the release modifier is present in an amount of 5% to 10% by weight, in certain embodiments, the release modifier is present in an amount of 0% by weight, and in certain embodiments, the release modifier The agent content is 10% by weight.
  • the intraocular implant comprises: by weight 50% axitinib, 40% ester-terminated PLGA, and 10% mannitol, the ester-terminated PLGA having a molecular weight of 15,000 or 70,000.
  • the intraocular implant comprises: 50% by weight axitinib, 40% ester-terminated PLGA, and 10% polyvinylpyrrolidone, the ester-terminated PLGA molecular weight 15,000 or 70,000.
  • the intraocular implant comprises: 50% by weight axitinib, 45% ester-terminated PLGA, and 5% sodium chloride, the ester-terminated PLGA molecular weight 15,000 or 70,000.
  • intraocular implants are used for vitreous administration.
  • the present invention further provides a preparation method for preparing the above-mentioned intraocular implant.
  • the preparation method adopts a hot melt extrusion method
  • the preparation method adopts a single extrusion or double extrusion method
  • a single extrusion method is adopted. Secondary extrusion method.
  • the preparation method may include the specific steps of: pulverizing axitinib, physically mixing with polymers and/or other optional excipients (eg, release modifiers, etc.)
  • the screw hot-melt extruder extrudes, gradually heats up, and the temperature setting range is between 90°C and 180°C.
  • the preparation method may include the following specific steps: separately pulverizing axitinib and the polymer, physically mixing with other optional excipients (such as release modifiers, etc.), etc., adding the above mixture to the twin-screw
  • the hot melt extruder extrudes, gradually heats up, and the temperature setting range is between 90°C and 180°C.
  • the preparation method includes the steps of: physically mixing axitinib with PLGA and/or release modifier, adding the above mixture into a twin-screw hot-melt extruder, gradually increasing the temperature, and the temperature is set in the range of 90 Between °C and 180 °C, extrude, crush the rod-shaped object formed by the first extrusion, add it to the twin-screw extruder again, and perform the second extrusion molding. After the extrusion is completed, the extruded material is cut to desired length.
  • the present invention provides the use of the above implant in the manufacture of a medicament for ocular diseases, examples of which include but are not limited to glaucoma, cataract, retinal vein occlusion, uveitis, diabetic macular edema and age-related macular degeneration.
  • the present invention provides a stable, safe and sustained-release axitinib implant for at least 6 months, which can effectively treat diseases including but not limited to glaucoma, cataract, retinal vein occlusion (RVO), uveitis, diabetes
  • diseases including but not limited to glaucoma, cataract, retinal vein occlusion (RVO), uveitis, diabetes
  • RVO retinal vein occlusion
  • uveitis uveitis
  • diabetes for various eye diseases such as macular edema (DME) and age-related macular degeneration (wAMD and nAMD)
  • DME macular edema
  • wAMD and nAMD age-related macular degeneration
  • It has a high degree of stability required in the application, and has a good application prospect to meet the unmet clinical needs.
  • Figure 1 shows the in vitro release profiles of formulations 1 to 3
  • Fig. 2 is the intraocular fluorescence angiography of the monkey eye of prescription 22 (A is before modeling, B is after modeling, C is four weeks after administration)
  • Drug means any substance used to treat eye conditions.
  • Intraocular means the entire ocular region including but not limited to the anterior chamber, posterior chamber, vitreous cavity, choroid, periocular, ocular surface, suprachoroidal space, conjunctiva, subconjunctival space, cornea, intracorneal space, cornea External space, sclera, etc.
  • Molecular weight refers to the general term for relative molecular mass, that is, the sum of the atomic weights of the atoms that make up the molecule.
  • Biodegradable polymer refers to a polymer that can be converted in vivo to non-toxic degradation products over time, wherein degradation of the polymer over time is required to obtain the drug release kinetics according to the present invention.
  • Ester-terminated means having an ester bond at the end of the polymer, and typical ester-terminated groups include, but are not limited to, alkyl esters and aromatic esters.
  • Eye disease refers to a disease, disorder or disorder affecting or involving the eye or an area or area of the eye, such as retinal disease.
  • the eye includes the eyeball and the tissues and fluids that make up the eyeball, periocular muscles (eg, the oblique and rectus muscles), and the portion of the optic nerve within or adjacent to the eyeball.
  • Implant refers to a sterile preparation made of drugs and excipients for implantation into the body, including subcutaneous implantation, vitreous implantation, and contraceptive ring implantation.
  • implant is used interchangeably with “implant”
  • the present invention provides axitinib implants and methods for treating ocular disorders.
  • the implant continues to release axitinib to the ocular area for a period of time including, but not limited to, twelve months, nine months, six months, three months, or less than three months.
  • Implants of the present invention comprise axitinib dispersed in a biodegradable polymer for direct placement in the eye.
  • axitinib constitutes 20-90% by weight of the implant, in certain embodiments, axitinib constitutes 30-80% by weight of the implant, in one embodiment, Axitinib accounts for 50-70% by weight of the implant, in one embodiment axitinib accounts for 50% by weight of the implant, in one embodiment axitinib accounts for 50% by weight of the implant 70%.
  • axitinib is included in the implant in a weight of 200 micrograms to 1.5 mg, in certain embodiments, axitinib is included in the implant in a weight of 200 micrograms to 1 mg, In certain embodiments, axitinib is included in the implant in a weight of 1 microgram to 1.5 milligrams. In certain embodiments, axitinib is included in the implant in a weight of 1.5 mg, and in certain embodiments, axitinib is included in the implant in a weight of 1 mg. In certain embodiments, axitinib is included in the implant in a weight of 200 micrograms. In certain embodiments, axitinib is included in the implant in a weight of 400 micrograms.
  • axitinib is included in the implant in a weight of 500 micrograms. In certain embodiments, axitinib is included in the implant in a weight of 600 micrograms. In certain embodiments, axitinib is included in the implant in a weight of 700 micrograms, and in certain embodiments, axitinib is included in the implant in a weight of 750 micrograms.
  • axitinib can be uniformly dispersed in the biodegradable matrix of the pharmaceutical composition.
  • the choice of the biodegradable polymer matrix used can vary depending on the desired release kinetics, patient tolerance, the nature of the disease to be treated, and the like. Considered polymer properties include, but are not limited to, biocompatibility and biodegradability at the site of administration, compatibility with axitinib, and processing temperature.
  • the biodegradable polymer matrix is 20%-70% by weight of the implant, in one embodiment, the biodegradable polymer matrix is generally 30%-50% by weight of the implant, In one embodiment the biodegradable polymer matrix is typically 50% by weight of the implant, in one embodiment the biodegradable polymer matrix is typically 30% by weight of the implant, in one embodiment, The biodegradable polymer matrix is typically 40% by weight of the implant, and in one embodiment the biodegradable polymer matrix is typically 45% by weight of the implant. .
  • Useful biodegradable polymer matrices include, but are not limited to, polymers made from monomers such as organic esters or organic ethers, which upon degradation produce physiologically acceptable degradation products. Anhydrides, amides or orthoesters can also be used to polymerize themselves or to polymerize with other monomers.
  • the polymers are usually condensation polymers.
  • the polymers can be crosslinked or non-crosslinked.
  • oxygen and nitrogen are included, especially oxygen, which may be present in the form of oxygen-containing groups such as hydroxyl, carboxyl, ether, carbonyl, ester, and the like. Nitrogen can exist in the form of amide, amino and the like.
  • the biodegradable polymer comprises at least one of the following: poly(lactic-co-glycolic acid) (PLGA), polylactide (PLA), polyglycolide (PGA), polyethylene glycol Alcohol (PEG), D-lactide, D,L-lactide, L-lactide, D,L-lactide-co- ⁇ -caprolactone, L-lactide-co- ⁇ -caprolactone, D,L-lactide-co-glycolide-co- ⁇ -caprolactone, poly(D,L-lactide-co-caprolactone), poly(L-lactide-co-caprolactone) , poly(D-lactide-co-caprolactone), poly(D,L-lactide), poly(D-lactide), poly(L-lactide), poly(esteramide), or a combination thereof.
  • the biodegradable polymer comprises poly(lactide-co-glycolide) (PLGA).
  • Copolymers of glycolic acid and lactic acid are of particular interest, and the percentages of glycolic acid and lactic acid monomers in the PLGA may be 0-100%, 15-85%, 25-75%, or 35-65%. In a preferred embodiment, PLGA is used in a 50:50 ratio of glycolic acid to lactic acid monomers.
  • ester-terminated PLGA as a biodegradable polymer matrix can enhance the stability of axitinib pharmaceutical compositions, including but not limited to stability under high temperature and high humidity, light stability, long-term stability, etc.
  • Ester-terminated PLGAs have ester linkages at the polymer ends, and typical ester-terminated groups include, but are not limited to, alkyl esters and aromatic esters.
  • the molecular weight of the ester-terminated PLGA is between 15,000 and 100,000. In a variation, the molecular weight of the ester-terminated PLGA is between 15,000 and 70,000. In one embodiment, the molecular weight of the ester-terminated PLGA is 70,000.
  • axitinib may be pulverized into granules or micropowders, at least 90% of the axitinib granules or micropowders having a diameter of less than or equal to 20 microns, and in a variation, the at least 90% % Axitinib particles or micropowders are less than or equal to 15 microns in diameter.
  • the biodegradable polymers of the present invention may optionally be comminuted into granules or micropowders, with respect to the size of the polymer granules or micropowders, in a variation, at least 90% of the polymer micropowders or particles are 10-100 ⁇ m in diameter, in a In variations, at least 90% of the polymer micropowders or particles are 10-50 ⁇ m in diameter, and in a variation, at least 90% of the polymer micropowders or particles are 20-40 ⁇ m in diameter.
  • the implants of the present invention may also optionally and/or preferably contain other excipients, eg, release modifiers may be used.
  • the release modifier can be used to accelerate the release of axitinib while maintaining a smooth release profile of axitinib.
  • the release modifier is one or more polysaccharides, such as cellulose-based materials, including: Hydroxypropyl methylcellulose, hyaluronic acid, poloxamers, polyethers such as polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, and mixtures thereof.
  • the release modifier is a pore former and/or a stability enhancer, optionally lactose, mannitol, glucose, maltose, sodium chloride, potassium chloride, magnesium carbonate, sodium bicarbonate, Potassium bicarbonate or sucrose etc.
  • the release modifier is a mixture of two or more of the aforementioned modifiers.
  • the pharmaceutical composition does not contain any release modifier.
  • the release modifier is sodium chloride, in one embodiment of the present invention, the release modifier is polyvinylpyrrolidone, in one embodiment of the present invention, the release modifier is Mannitol.
  • the release modifier is present in an amount of 0% to 10% by weight, in certain embodiments of the present invention, the release modifier is present in an amount of 2.5% to 10% by weight, In certain embodiments of the present invention, the release modifier is present in an amount of 5% to 10% by weight, in certain embodiments, the release modifier is present in an amount of 0% by weight, in certain embodiments , the release modifier is present in an amount of 10% by weight, in certain embodiments, the release modifier is present in an amount of 5% by weight, and in certain embodiments, the release modifier is present in an amount of 2.5% by weight.
  • the intraocular implants herein are generally solid and can be prepared in the shape of particles, sheets, blocks, films, fibers, rods, discs, etc., or can be of any size or shape compatible with the chosen implantation site, so long as The implant has the desired release kinetics and is capable of delivering an amount of a drug that can treat ocular diseases.
  • the implant of the present invention preferably has a long cylindrical or thin rod-like appearance, with a length of 0.3 mm to 10 mm. mm, diameter 0.05mm-1mm, total weight 100-5000 micrograms, usually 500-1500 micrograms.
  • the implant is 5 millimeters in length, 0.5 millimeters in diameter, and has a total weight of 1000 micrograms. In certain embodiments, the implant is 0.5 millimeters in diameter, 5-7 millimeters in length, and weighs about 1.0-1.5 milligrams.
  • the present invention provides a preparation method for preparing an implant comprising the above-mentioned axitinib pharmaceutical composition, and the preparation method can be carried out by a hot melt extrusion method, for example, using a piston extruder, a single screw hot melt extrusion extruder or twin-screw hot-melt extruder to uniformly disperse and distribute axitinib in the biodegradable polymer.
  • the implant is prepared by a single extrusion or double extrusion, and in preferred embodiments, a single extrusion is used.
  • the hot melt extrusion process is used at a temperature of about 25°C to 180°C, in some embodiments, 90°C to 180°C, in some embodiments, 130°C to 180°C, and In certain embodiments, the temperature is 150 to 180°C.
  • the single extrusion method may include the steps of: pulverizing axitinib, physically mixing it with a polymer and/or other optional agents (such as release modifiers, etc.), Add the above mixture into the twin-screw hot melt extruder, gradually heat up, set the temperature between 90°C and 180°C, and control the speed between 5RPM and 30RPM, subject to the mixture being melted and fully mixed, extruding, extruding After completion the extrudate is cut to the desired length, in some embodiments 5 mm in length.
  • the preparation method may include the steps of: pulverizing axitinib and the polymer into granules or micropowders, respectively, and mixing the above granules or micropowders and/or other optional agents (such as release modifiers, etc.), etc. Physical mixing, add the above mixture into the twin-screw hot-melt extruder, gradually heat up, set the temperature between 90°C and 180°C, and control the speed between 5RPM and 30RPM, subject to the mixture being melted and fully mixed, extruding After pressing, the extrudate is cut to the desired length, in some embodiments 5 mm in length.
  • the preparation method may include the steps of: physically mixing axitinib with PLGA and/or release modifier, adding the above mixture into a twin-screw hot-melt extruder, gradually increasing the temperature, and setting the temperature within the range Between 90°C-180°C, control the speed between 5RPM and 30RPM, subject to the mixture being melted and fully mixed, extrude, pulverize the rod-shaped object extruded for the first time, and then add the twin-screw hot melt extrusion Out of the machine, a second extrusion molding is performed, and after the extrusion is completed, the extrudate is cut to the desired length, in some embodiments, the length is 5 mm.
  • Biodegradable implants can be placed in the eye by a variety of methods, including placement through forceps, syringes, trocars, or other types of drug delivery devices after making an incision in the iris. In some cases, forceps, syringes, trocars, or other types of drug delivery devices can be used without an incision. In a preferred variation, one or more implants can be placed into the eye using a hand-held drug delivery device.
  • the implantation method typically involves first entering a needle into a target area in the ocular region, and after entering the target area, eg, the vitreous cavity, pushing a handle on the hand-held drug delivery device to cause the pusher to advance the plunger. As the plunger advances, it pushes the implant into the target area.
  • a target area eg, the vitreous cavity
  • the implants of the present invention are useful in the treatment of ocular diseases, examples of which include, but are not limited to, glaucoma, cataracts, retinal vein occlusion, uveitis, diabetic macular edema, and age-related macular degeneration.
  • the medicines, reagents and instruments used are as follows:
  • release medium 0.9% NaCl+0.3% SDS
  • a cut implant preparation with a diameter of 0.5mm and a length of about 5-7mm is added, and shaken to make it sink to the liquid level
  • the thermostatic oscillator run the sample in insulation, measure the concentration of API in the medicinal liquid by high-performance liquid chromatography (chromatographic conditions are as follows) sampling at a predetermined time, wherein the sampling method is to pipet 3ml of 4ml of release liquid in the sample bottle , and replaced with 3ml of freshly prepared 0.9%NaCl+0.3%SDS solution, put it back into the equipment for investigation; and calculated the single release amount and cumulative release amount of the sample, and formed the release behavior measurement result.
  • Stability test The samples were exposed for 5 days, 10 days or 30 days under the conditions of high temperature (60°C), high humidity (92.5%RH), and light (4500lx ⁇ 500lx), and try to avoid other conditions. of cross effects.
  • axitinib to the jet mill to pulverize to the target particle size D90 ⁇ 15 microns, then physically mix the axitinib powder with the excipients, add it to the twin-screw hot melt extruder at a certain rate, and use a 0.5mm diameter die. Mouth, heating, gradually heating up, the temperature setting range is between 90 °C-180 °C, heating to prepare extrudate, it is advisable to extrude smoothly. The extruded samples were stretched using a crawler-type adaptor, and the speed was controlled between 5 RPM and 30 RPM to match the speed at which the extruded rods were collected smoothly.
  • Each of the above prescriptions is prepared in a way that the total amount of the prescription is 7g, and is prepared according to the proportion of the above prescription list, and the extruded preparation sample is controlled to be an implant preparation with a diameter of 0.5mm, a length of 5mm, and a weight of about 1.0mg.
  • the extrudate is prepared by heating, and it is advisable to extrude smoothly.
  • the extruded samples were stretched using a crawler-type adaptor, and the speed was controlled between 5 RPM and 30 RPM to match the speed at which the extruded rods were collected smoothly.
  • the prescription is prepared in a way that the total amount of the prescription is 6g, and is prepared according to the proportion of the above prescription list.
  • the extruded preparation sample is controlled to have a diameter of 0.5mm, a length of 5-6mm, and a weight of about 1.0-1.5mg.
  • the unit implant preparation is controlled to have a diameter of 0.5mm, a length of 5-6mm, and a weight of about 1.0-1.5mg.
  • the extrudate is prepared by heating, and it is advisable to extrude smoothly.
  • the extruded samples were stretched using a crawler-type adaptor, and the speed was controlled between 5 RPM and 30 RPM to match the speed at which the extruded rods were collected smoothly.
  • the prescription is prepared in a way that the total amount of the prescription is 6g, and is prepared according to the proportion of the above prescription list.
  • the extruded preparation sample is controlled to have a diameter of 0.5mm, a length of 5-6mm, and a weight of about 1.0-1.5mg.
  • the unit implant preparation is controlled to have a diameter of 0.5mm, a length of 5-6mm, and a weight of about 1.0-1.5mg.
  • the extrudate is prepared by heating, and it is advisable to extrude smoothly.
  • the extruded samples were stretched using a crawler-type adaptor, and the speed was controlled between 5 RPM and 30 RPM to match the speed at which the extruded rods were collected smoothly.
  • the prescription is prepared in a way that the total amount of the prescription is 6g, and is prepared according to the proportion of the above prescription list.
  • the extruded preparation sample is controlled to have a diameter of 0.5mm, a length of 5-6mm, and a weight of about 1.0-1.5mg.
  • the unit implant preparation is controlled to have a diameter of 0.5mm, a length of 5-6mm, and a weight of about 1.0-1.5mg.
  • axitinib to the jet mill to pulverize to the target particle size D90 ⁇ 15 microns, then physically mix the axitinib powder with the excipients, add it to the twin-screw hot melt extruder at a certain rate, and use a 0.5mm diameter die. Mouth, heating, gradually heating up, the temperature setting range is between 90 °C-180 °C, heating to prepare extrudate, it is advisable to extrude smoothly.
  • the extruded samples were stretched using a crawler-type adaptor, and the speed was controlled between 5 RPM and 30 RPM to match the speed at which the extruded rods were collected smoothly. The extrudate was collected as a pale yellow rod.
  • the above prescription is prepared in a way that the total amount of the prescription is 7g, according to the proportion of the above prescription list, and the extruded preparation sample is controlled to be an implant preparation with a diameter of 0.5mm, a length of 5mm, and a weight of about 1.0mg.
  • axitinib to the jet mill to pulverize to the target particle size D90 ⁇ 15 microns, then physically mix the axitinib powder with the excipients, add it to the twin-screw hot melt extruder at a certain rate, and use a 0.5mm diameter die. Mouth, heating, gradually heating up, the temperature setting range is between 90 °C-180 °C, heating to prepare extrudate, it is advisable to extrude smoothly.
  • the extruded samples were stretched using a crawler-type adaptor, and the speed was controlled between 5 RPM and 30 RPM to match the speed at which the extruded rods were collected smoothly. The extrudate was collected as a pale yellow rod.
  • the above recipe is prepared in a way that the total amount of the recipe is 7g, and is prepared according to the proportion of the above prescription list, and the extruded preparation sample is controlled to be an implant preparation with a diameter of 0.5mm, a length of 5mm, and a weight of 1.0mg.
  • axitinib powder particle size D90 ⁇ 76.6 ⁇ m
  • excipients add it to a twin-screw hot-melt extruder at a certain rate, use a 0.5mm diameter die, heat, and gradually increase the temperature.
  • the temperature setting range is Between 90°C and 180°C, the extrudate is prepared by heating, which is suitable for smooth extrusion.
  • the extruded samples were stretched using a crawler-type adaptor, and the speed was controlled between 5 RPM and 30 RPM to match the speed at which the extruded rods were collected smoothly. The extrudate was collected as a pale yellow rod.
  • the above recipe is prepared in a way that the total amount of the recipe is 7g, and is prepared according to the proportion of the above prescription list.
  • the extruded preparation sample is controlled to be an implant preparation with a diameter of 0.5mm, a length of 5mm, and a weight of 1.0mg.
  • axitinib to the jet mill and pulverize it to the target particle size D90 ⁇ 15 microns, physically mix the axitinib powder with the auxiliary powder, and add it to the twin-screw hot melt extruder at a certain rate, using a 0.5mm diameter die. Mouth, heating, gradually heating up, the temperature setting range is between 90 °C-180 °C, heating to prepare extrudate, it is advisable to extrude smoothly. The extruded samples were stretched using a crawler-type adaptor, and the speed was controlled between 5 RPM and 30 RPM to match the speed at which the extruded rods were collected smoothly.
  • the rod-shaped object extruded for the first time is ground and pulverized, and then added to the twin-screw hot-melt extruder again for the second extrusion molding, and the extrudate is collected.
  • the extrudate was obtained as a pale yellow rod.
  • Each of the above recipes is prepared in a way that the total amount of the recipe is 7g, and is prepared according to the proportions listed in the above recipes.
  • the extruded preparation sample is controlled to be an implant preparation with a diameter of 0.5mm, a length of 5mm, and a weight of 1.0mg.
  • Preparation process add axitinib to the jet mill to pulverize to the target particle size D90 ⁇ 15 microns, then physically mix the axitinib powder with the auxiliary materials, and add it to the twin-screw hot melt extruder at a certain rate, using 0.5 mm diameter die, heating, gradually heating up, the temperature setting range is between 90 °C-180 °C, heating to prepare extrudate, it is advisable to extrude smoothly.
  • the extruded samples were stretched using a crawler-type adaptor, and the speed was controlled between 5 RPM and 30 RPM to match the speed at which the extruded rods were collected smoothly. Cut the extrudate to the desired length.
  • Animals 2 cynomolgus monkeys aged 2.5 to 6, purchased from Chengdu Huaxi Haiqi Pharmaceutical Technology Co., Ltd. The average body weight at the time of purchase and modeling was 2.5-6.0 kg, and the individual body weight was within the range of mean ⁇ 20%.
  • Animal groups 1 monkey was given prescription 19 as prescription 19 group, and another monkey was given prescription 20 as prescription 20 group.
  • mice 2 samples of prescription 19 (the size of each preparation is 0.5mm*7mm, the total weight is about 1.42mg); 2 samples of prescription 20 (the size of each preparation is 0.5mm*7mm, the total weight is about 1.45mg)
  • vitreous body was implanted into the monkey's left eye by filling one implant of prescription 19 with a 22G needle, and the implant was pushed into the vitreous body of the monkey, and the implant was implanted;
  • Determination method of drug in lens Determination by high performance liquid chromatography (General Rule 0512 of Chinese Pharmacopoeia 2020), animal plasma standard with axitinib concentration of 0.2, 1, 4, 10, 14, 20ug/mL 6 concentration gradients were prepared. Axitinib content in the lens was calculated according to the following formula.
  • Determination method of drugs in vitreous humor using high performance liquid chromatography (Chinese Pharmacopoeia 2020 edition general rule 0512), prepare animal plasma with axitinib concentration of 0.2, 1, 4, 10, 14, 20ug/mL 6 concentration gradients respectively Standard solution, draw a standard curve by plotting the concentration against the peak area, and calculate the axitinib content in the vitreous humor according to the following formula.
  • Sample A Axitinib peak area in the sample to be tested
  • V dilution volume the dilution ratio of the vitreous humor to be tested.
  • Sample A Axitinib peak area in the sample to be tested
  • control control solution concentration
  • V dilution volume the dilution volume of the sample to be tested
  • m weight of drug segment the weight of the drug formulation.
  • a single injection of prescription 20 implant through the eye vitreous was used to study the efficacy of laser-induced choroidal neovascularization leakage and growth in cynomolgus monkeys. , to establish an animal model similar to that of human choroidal neovascularization. Fluorescein angiography was performed before photocoagulation and at 21 and 28 days after photocoagulation to determine the condition of modeling.
  • the 20 groups of monkeys who were prescribed were in good mental condition, normal autonomous activities, and normal appearance.
  • the area of fluorescent spots in the left eye was reduced, and the area of fluorescein leakage was reduced by 10.821 mm 2 ; the area of fluorescent spots in the right eye was reduced 28 days after administration, and the area of leakage of fluorescein decreased.
  • the amount is 7.193mm 2 .
  • the number of grade 4 fluorescent spots were 5 and 3, respectively, which were reduced compared with 12 before administration.
  • the optic disc was vaguely visible in the fundus; anterior chamber cells.
  • the cynomolgus monkeys with laser CNV model were given Prescription 20 implant by single injection into the vitreous body of both eyes.
  • Monkey CNV has inhibitory effect.
  • the axitinib implant of the present application can achieve a sustained-release therapeutic effect of not less than 6 months, has stability, and is expected to reduce the number of administrations, prolong the administration interval, reduce the cost of medication, and improve patient compliance.

Abstract

L'invention concerne un implant axitinib, comprenant de l'axitinib et un polymère biodégradable. L'implant est stable et peut présenter une libération prolongée pendant au moins six mois, ce qui permet d'éviter de multiples administrations répétées, et de réduire les effets secondaires. La préparation peut efficacement traiter des maladies oculaires telles que le glaucome, la cataracte, l'occlusion de la veine rétinienne, l'uvéite, l'oedème maculaire diabétique et la dégénérescence maculaire liée à l'âge.
PCT/CN2021/131602 2020-11-26 2021-11-19 Implant intraoculaire axitinib WO2022111379A1 (fr)

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CN102319432A (zh) * 2004-08-13 2012-01-18 阿勒根公司 由双挤压法制备的眼植入物
CN104379133A (zh) * 2012-06-25 2015-02-25 拜尔健康护理有限责任公司 含有阿昔替尼的局部眼科药物组合物
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WO2020219890A1 (fr) * 2019-04-25 2020-10-29 Ocular Therapeutix, Inc. Implants d'hydrogel oculaire à inhibiteur de tyrosine kinase
US20200375889A1 (en) * 2019-05-31 2020-12-03 Dose Medical Corporation Bioerodible polyester polymer implants and related methods of use

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CN102319432A (zh) * 2004-08-13 2012-01-18 阿勒根公司 由双挤压法制备的眼植入物
CN101204367A (zh) * 2007-11-29 2008-06-25 济南帅华医药科技有限公司 一种治疗实体肿瘤的阿西替尼缓释植入剂
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4236943A4 (fr) * 2020-10-27 2024-04-24 Ocular Therapeutix Inc Implant oculaire contenant un principe actif

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