WO2021065768A1 - Agent de formation d'espace, préparation pour injection sous-cutanée, et procédé de formation d'espace - Google Patents

Agent de formation d'espace, préparation pour injection sous-cutanée, et procédé de formation d'espace Download PDF

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WO2021065768A1
WO2021065768A1 PCT/JP2020/036537 JP2020036537W WO2021065768A1 WO 2021065768 A1 WO2021065768 A1 WO 2021065768A1 JP 2020036537 W JP2020036537 W JP 2020036537W WO 2021065768 A1 WO2021065768 A1 WO 2021065768A1
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space
preparation
chondroitinase
administered
protein preparation
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PCT/JP2020/036537
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English (en)
Japanese (ja)
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まゆ 秦
恵子 大津
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テルモ株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • 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
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

  • the present invention relates to a space-forming agent, a subcutaneously administered preparation, and a space-forming method.
  • Such subcutaneous administration reduces the bioavailability of the drug (the rate at which it reaches the systemic circulation) compared to intravenous injection.
  • extracellular matrix such as hyaluronic acid and chondroitin sulfate is present in the subcutaneous tissue, the drug is more difficult to transfer into the blood, especially when a high molecular weight drug such as an antibody drug is subcutaneously administered.
  • Patent Document 1 shows that subcutaneous administration of soluble hyaluronidase glycoprotein facilitates administration of a high-concentration drug to the subcutaneous tissue.
  • Patent Document 1 states that the hyaluronidase rapidly depolymerizes hyaluronan HA in the extracellular space, thereby increasing the volume of the drug administered into the subcutaneous tissue.
  • Patent Document 1 uses an enzyme having a high concentration of soluble hyaluronidase glycoprotein of 2000 U / mL. This suggests that it is necessary to use soluble hyaluronidase glycoprotein at a certain high concentration in order to exert the effect of increasing the space volume in the subcutaneous tissue. When such a high concentration of enzyme is used, there is a concern that the enzyme itself may cause inflammatory or immunogenicity.
  • an object of the present invention is to provide a preparation that is co-administered with a protein preparation and that can increase the administration volume of the protein preparation even at a low concentration.
  • Another object of the present invention is to provide a preparation that is co-administered with a protein preparation and that can enhance the blood transferability of the protein preparation even at a low concentration. ..
  • the present inventors have clarified that by using chondroitinase, an effective space can be formed under the skin even at a low concentration of administration. It was also clarified that the use of chondroitinase can improve the bioavailability of protein preparations even at low concentrations. Based on these findings, the present inventors have completed the present invention.
  • the preferred embodiment of the present invention is as follows.
  • a space-forming agent containing chondroitinase that forms a space subcutaneously for subcutaneous administration of a protein preparation is provided.
  • a space forming method for subcutaneously administering a protein preparation which comprises subcutaneously administering chondroitinase.
  • X to Y indicating a range means "X or more and Y or less", and unless otherwise specified, operation and measurement of physical properties are performed at room temperature (20 to 25 ° C.) / relative humidity of 40 to 50% RH. Perform under the conditions of.
  • the first embodiment of the present invention is a space-forming agent containing chondroitinase, which forms a space subcutaneously for subcutaneous administration of a protein preparation.
  • the subcutaneous administration restriction amount of the protein preparation can be widened even when the protein preparation is administered at a low concentration. Further, according to the space-forming agent of the present embodiment, it is possible to enhance the subcutaneous transferability of the protein preparation even at a low concentration.
  • the space-forming agent is used in combination with a protein preparation that is subcutaneously administered. For this reason, the space-forming agent is also usually administered subcutaneously. Preferably the space-forming agent is injected subcutaneously.
  • subcutaneous administration means delivery by any suitable means (eg, injection) such that the therapeutic agent is delivered directly through the skin to the subcutaneous cavity.
  • subcutaneous cavity means connective tissue under the skin. This excludes blood vessels, blood flow and internal organs.
  • the pH of the space-forming agent when the space-forming agent is injected subcutaneously is not particularly limited, but can be neutral or acidic (pH is 8.0 or less), for example, 4 to 8. ..
  • the pH can be adjusted by a method known per se, for example, using a buffer or a pH adjuster.
  • Subcutaneous administration of the space-forming agent can be administered to the patient via any suitable route.
  • it is administered to a patient as a bolus or by a subcutaneous route by continuous infusion over a period of time.
  • the space-forming agent may be administered as a single dose or as a frequent dose.
  • the space-forming agent refers to a preparation in which the insertion pressure after administration (preferably 2 minutes after administration) is lower than that of the control (protein preparation only).
  • the insertion pressure after administration of the space-forming agent is 95% or less of the control, more preferably 90% or less, still more preferably 85% or less.
  • the insertion pressure after administration of the space-forming agent is not particularly limited, but may be, for example, 10% or more, and may be 20% or more.
  • the insertion pressure can be measured according to the method described in the following Examples. Further, in the following examples, the insertion pressure after administration of the space forming agent is about 50% (or less) of the control on average.
  • the space-forming agent is used in combination with a protein preparation that is subcutaneously administered.
  • any form may be used, such as a composition containing a space-forming agent and a protein preparation (single preparation), or a combination of separately formulating the space-forming agent and the protein preparation (drug kit).
  • the order of administration of the space-forming agent and the protein preparation is not particularly limited, and the space-forming agent and the protein preparation may be administered at the same time or may be administered at different times.
  • the space-forming agent is administered at different times, it is preferable to administer the protein preparation after the space-forming agent is administered. Since the formed space can be effectively used for administration of the protein preparation and the effect of improving the transferability of the protein preparation into blood can be easily obtained, it is preferable to administer the space-forming agent and the protein preparation at the same time. That is, a preferred form is a space-forming agent that is administered at the same time as the protein preparation.
  • the space-forming agent administered at the same time as the protein preparation is a combination of the space-forming agent and the protein preparation in the form of a composition (single preparation); the space-forming agent and the protein preparation are separately formulated. , A form in which a space-forming agent and a protein preparation are co-administered;
  • the mass (mg / kg / Day) ratio of the doses of the space-forming agent and the protein preparation is appropriately determined according to each individual case in consideration of the patient's symptoms, age, sex, and the like.
  • the chondroitinase is not particularly limited, and may be any of chondroitinase ABC, chondroitinase AC I, chondroitinase AC II, chondroitinase B, and chondroitinase C.
  • chondroitinases are chondroitin sulfate ABC, chondroitinase AC I, chondroitinase AC II, and chondroitinase C, because the effects of the present invention are likely to be exhibited.
  • the substrates are hyaluronic acid and chondroitin sulfate, chondroitinase ABC, chondroitinase AC I, and chondroitinase AC II, and chondroitinase ABC is particularly preferable.
  • the chondroitinase may be a recombinant type having at least 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, 99% or more homology with the wild type chondroitinase. Good.
  • chondroitinase ABC one derived from Proteus vulgaris can be used, or a commercially available product can be used.
  • the concentration of chondroitinase is not particularly limited as long as the chondroitinase is dissolved, but it is usually 0.1 to 100 U / mL in consideration of the dose and the like.
  • the space-forming agent is preferably liquid.
  • the term "liquid” refers to a liquid having fluidity at 25 ° C. More specifically, when the object is tilted by 45 °, the shape cannot be held for 10 minutes or more, and the shape changes.
  • a "protein preparation” contains an active ingredient consisting of a protein.
  • the active ingredient include antibodies, blood coagulation / fibrinolytic factors, hormones, enzymes, cytokines, interferons, serum proteins, vaccines, erythropoetins, fusion proteins and the like.
  • the molecular weight of the protein which is the active ingredient of the protein preparation, is preferably 10,000 Da or more, and in the preferred order, 20,000 Da or more and 50,000 Da or more.
  • it is necessary to increase the concentration of the protein preparation due to the restricted dose but it is difficult to increase the concentration of a protein having a high molecular weight due to aggregation.
  • due to its high molecular weight due to its high molecular weight, its absorbability in blood is also low.
  • the subcutaneous administration volume of the protein preparation can be increased by co-administering with the space-forming agent of the first embodiment, and it is not necessary to increase the concentration of the protein preparation.
  • the upper limit of the molecular weight of the protein is not limited, but is preferably 1,000,000 Da or less. When the molecular weight of the protein is in the above range, the aggregation of the protein is effectively suppressed.
  • the active ingredient of the protein preparation is an antibody. Since the antibody has a large molecular weight, it is difficult to increase the concentration by aggregation. Moreover, due to its high molecular weight, its absorbability in blood is also low.
  • the space-forming agent of the first embodiment By co-administering with the space-forming agent of the first embodiment, the limitation of the subcutaneous dose of the antibody can be widened, and the transferability of the antibody from the subcutaneous blood can be enhanced.
  • the antibody examples include antibody drugs.
  • the antibody drug includes not only a drug containing an artificially prepared antibody that specifically binds to a disease-related molecule, but also an immunoglobulin preparation purified from human plasma.
  • Target molecules in antibody drugs are various and are not particularly limited, such as cell surface molecules such as PD-1, PD-L1, PD-L2, TNF- ⁇ , VEGF, and CD20.
  • the type of antibody may be any of mouse antibody, chimeric antibody, humanized antibody and human antibody, but humanized antibody or human antibody is preferable.
  • antibody drugs include immune checkpoint inhibitors, antibody drugs that specifically react with cancer antigens and have ADCC and ADCP activities, and specifically, anti-PD-1 antibody, anti-PD-L1 antibody, and the like.
  • Immunocheckpoint inhibitors such as anti-CTLA4 antibody; antibody drugs having ADCC and ADCP activity by specifically reacting with cancer antigens such as anti-CD20 antibody, anti-HER2 antibody, and anti-EGFR antibody.
  • antibody drugs include adalimumab, muromonab-CD3, trastuzumab, rituximab, paribismab, infliximab, basiliximab, tosirizumab, gemtuzumab ozogamicin, bevacizumab, iburizumab butyximab, cetuximab, cetuximab.
  • Ecrizumab Panitumumab, Ustekinumab, Golimumab, Kanakinumab, Denosumab, Adalimumab, Cetuximab, Mogamurizumab, Celtrizumab Pegor, Ofatumumab, Pertuzumab, Trastuzumab Katsumakisomab, Adalimumab, Edrecolomab, Absiximab, Siltuximab, Dakrizumab, Efarizumab, Obinutuzumab, Bedrizumab, Pembrolizumab, Ixekizumab, Jiridabumab, Ipilimumab, Bevacizumab, Ipilimumab, Bevacizumab, Bevacizumab
  • the content of the protein preparation and physical characteristics such as pH are not particularly limited, and can be appropriately adjusted according to the type of protein preparation used.
  • protein preparations include stabilizers, solvents (eg physiological saline, buffers, water for injection, etc.), lysis aids, isotonic agents (eg, sodium chloride, glucose, glycerin, etc.) as required. ), Additives such as pH adjusters, soothing agents, reducing agents, antioxidants and the like.
  • solvents eg physiological saline, buffers, water for injection, etc.
  • isotonic agents eg, sodium chloride, glucose, glycerin, etc.
  • Additives such as pH adjusters, soothing agents, reducing agents, antioxidants and the like.
  • sorbitan fatty acid ester As additives, sorbitan fatty acid ester, glycerin fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbit fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyethylene glycol fatty acid ester, polyoxyethylene alkyl ether, Polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene alkylphenyl ether, polyoxyethylene hydrogenated castor oil, polyoxyethylene beeswax derivative, polyoxyethylene lanolin derivative, polyoxyethylene fatty acid amide, lecithin, glycerophospholipid, sphingolinlipid, Nonionic surfactants such as sucrose fatty acid esters, surfactants such as alkyl sulfates, polyoxyethylene alkyl ether sulfates, anionic surfactants such as alkyl sulfosuccinates; leucine,
  • Protein preparations are usually liquid in consideration of convenience when administered subcutaneously.
  • concentration of the protein preparation is appropriately set in consideration of the dose and solubility of the drug.
  • the dose of the protein preparation can be appropriately adjusted in consideration of the type, use, usage pattern of the protein preparation; patient's symptom, age, sex, etc.
  • space-forming agents include solvents (eg saline, water for injection, buffers, etc.), membrane stabilizers (eg cholesterol, etc.), isotonic agents (eg, sodium chloride, glucose, glycerin, etc.), It may contain antioxidants (eg tocopherols, ascorbic acid, glutathione, etc.), preservatives (eg chlorbutanol, parabens, etc.) and the like.
  • solvents eg saline, water for injection, buffers, etc.
  • membrane stabilizers eg cholesterol, etc.
  • isotonic agents eg, sodium chloride, glucose, glycerin, etc.
  • antioxidants eg tocopherols, ascorbic acid, glutathione, etc.
  • preservatives eg chlorbutanol, parabens, etc.
  • a second embodiment of the present invention is a subcutaneously administered formulation comprising 0.1-100 U / mL chondroitinase and protein formulation.
  • the chondroitinase and the protein preparation are as described in the first embodiment. According to this embodiment, even if a low concentration of chondroitinase is administered, the subcutaneous administration restriction amount of the protein preparation can be widened. Further, according to the present embodiment, even if a low concentration of chondroitinase is administered, the transdermal transferability of the protein preparation into the blood can be enhanced.
  • Examples of the subcutaneously administered preparation include a composition containing a chondroitinase and a protein preparation (single preparation), a combination of separately formulating the chondroitinase and the protein preparation (drug kit), and the like.
  • a preferred form is a composition (single formulation) containing chondroitinase and a protein formulation.
  • the administration order of chondroitinase and protein preparation is not particularly limited, and chondroitinase and protein preparation may be administered at the same time. However, they may be administered at different times.
  • the subcutaneously administered preparation is preferably a subcutaneous injection preparation because it can be efficiently administered subcutaneously.
  • the subcutaneously administered preparation is preferably a subcutaneous injection liquid preparation.
  • the pH when the subcutaneously administered preparation is a subcutaneous injection liquid preparation is not particularly limited, but can be neutral or acidic (pH is 8.0 or less), for example, 4 to 8.
  • the pH of the liquid preparation can be adjusted by a method known per se, for example, using a buffer or a pH adjuster.
  • Subcutaneous preparation means a drug that is subcutaneously administered and used for the prevention / treatment / diagnosis of any disease in mammals (humans, monkeys, rats, etc., preferably humans).
  • Subcutaneous administration of the preparation can be administered to the patient via any suitable route. For example, it is administered to a patient as a bolus or by a subcutaneous route by continuous infusion over a period of time.
  • the subcutaneous administration preparation may be administered once or frequently. In home care, it is often given frequently at home. Since the subcutaneous administration preparation of the present embodiment can increase the administration volume per administration, the number of administrations can be reduced and the burden on the patient is small.
  • the content of chondroitinase in the subcutaneously administered preparation is 0.1 to 100 U / mL. Chondroitinase can effectively form a space under the skin even by subcutaneous administration at a low concentration of 100 U / mL or less. Therefore, the dose (volume) of the protein preparation can be increased by co-administering with the protein preparation. In addition, chondroitinase can enhance the subcutaneous transferability of protein preparations even when administered at a low concentration of 100 U / mL or less.
  • chondroitinase when the dose of chondroitinase is 100 U / mL or less, there is little possibility that the dispersibility of the protein is lowered due to the excessive chondroitinase that does not contribute to the space forming ability or the degradation product of chondroitinase.
  • the content of chondroitinase in the subcutaneously administered preparation is the concentration in the subcutaneously administered preparation.
  • it is the content of chondroitinase with respect to the total amount of both.
  • the content of chondroitinase is 5 U / mL.
  • the content of chondroitinase in the subcutaneously administered preparation is preferably 0.1 to 80 U / mL, more preferably 0.5 to 50 U / mL.
  • the enzyme itself is a foreign substance to the living body, there is a concern that the enzyme itself may cause inflammatory or immunogenicity, and the concentration is required to be as low as possible.
  • the present invention is based on the finding that chondroitinase can form a space under the skin at a very low concentration, and chondroitinase has a low concentration of about 1/100 as compared with, for example, hyaluronidase. Shows the same space-forming ability in (see Examples below).
  • the dose of the protein preparation in the subcutaneous preparation is appropriately determined according to each individual case in consideration of the patient's symptoms, age, sex, etc.
  • the subcutaneous dose restriction amount of the protein preparation can be increased at one time. Therefore, it can be set to a higher dose (higher volume) than when it is usually administered subcutaneously alone.
  • the volume can be increased up to about 10 times the maximum dose (volume) when the liquid protein preparation is administered alone.
  • the administration volume of the protein preparation can be 2 mL or more per administration, and can be 2 to 20 mL.
  • the subcutaneous dose limit of the protein preparation can be increased, so the administration volume of the subcutaneous preparation should be 2 mL or more per administration. It can be 2 to 20 mL.
  • the mass (mg / kg / Day) ratio of the doses of the protein preparation and chondroitinase is also appropriately determined according to each individual case in consideration of the patient's symptoms, age, sex, and the like.
  • the subcutaneously administered preparation is preferably administered in a fixed cycle.
  • the administration cycle it is preferable to appropriately adjust the administration cycle so as to be suitable for concomitant use.
  • the specific administration frequency, dose, infusion administration time, administration cycle, etc. are appropriately determined according to individual cases in consideration of the patient's symptoms, age, gender, and the like.
  • the administration volume of a single protein preparation can be increased by co-administering chondroitinase, so that the administration interval of the subcutaneous administration preparation can be extended, which imposes a burden on the patient. It will be dramatically reduced.
  • the administration interval can be extended from 100 mg (1 mL) per week to 400 mg (4 mL) per month in the case of a subcutaneous administration preparation.
  • Another aspect of the present invention is a method for treating or preventing a disease, which comprises administering an effective amount of chondroitinase and an effective amount of a protein preparation to a subject in need of treatment or prevention.
  • the disease is cancer.
  • the above-mentioned subjects are preferably mammals, and particularly preferably humans.
  • a third embodiment of the present invention is a space forming method for subcutaneously forming a space for subcutaneously administering a protein preparation, which comprises subcutaneously administering chondroitinase. According to this embodiment, even if a low concentration of chondroitinase is administered, the subcutaneous administration restriction amount of the protein preparation can be widened. Further, according to the present embodiment, even if a low concentration of chondroitinase is administered, the transdermal transferability of the protein preparation into the blood can be enhanced.
  • the formation of the space is performed so that the insertion pressure after administration (preferably 2 minutes after administration) is lower than that of the control (protein preparation only), and the insertion pressure is preferably 95% or less of the control.
  • the chondroitinase is administered so as to be preferably 90% or less, more preferably 85% or less.
  • the dose of chondroitinase that achieves the formation of such a space is appropriately determined according to each individual case in consideration of the patient's symptoms, age, sex, and the like.
  • Example 1 The subcutaneous space-forming ability (space-forming ability) of a candidate substance (degrading substance) having an action of decomposing subcutaneous tissue was evaluated.
  • Insertion pressure when subcutaneously administering a drug to the abdomen of female domestic pigs (17.8-59.0 kg) using pigs, which are said to have similar subcutaneous structure, properties, and thickness to humans, as model animals. was measured and evaluated.
  • ⁇ Insert pressure measurement> The drug to be administered was collected in a syringe.
  • the syringe was connected to the female connector of the extension tube, and the holder of the three-way stopcock was connected to the male connector.
  • the female connector of the winged intravenous needle was connected to the lock adapter of the three-way stopcock, and the transducer was connected to the mixed injection part.
  • a winged intravenous needle was subcutaneously punctured in the abdomen of the pig. Tissue adhesive was applied around the needle to prevent liquid leakage from the needle hole.
  • the drug is subcutaneously administered at a rate of 2 mL / min using a syringe pump, and the insertion pressure is measured using the small animal blood pressure measurement system PowerLab from before administration to 5 minutes after the end of administration. did.
  • the insertion pressure measurement is completed, euthanasia is performed by bleeding from the carotid artery, etc., the tissue at the administration site is collected, fixed with 10% neutral buffered formalin (Wako Pure Chemical Industries, Ltd.), and then histopathological examination.
  • Alcian blue (pH 1.0) (Alcian blue) staining and biotinylated hyaluronic acid-binding protein (Biotin-HABP) staining were performed.
  • FIG. 2A is a micrograph of porcine skin on day 0 after administration of IgG only. As shown in the results, it was confirmed that the light blue-stained chondroitin sulfate disappeared and that chondroitinase ABC could decompose chondroitin sulfate in real time.
  • ⁇ Administration method When evaluating the subcutaneous space-forming ability of chondroitinase ABC (Ch ABC), 1 mL of the test drug was administered, followed by 9 mL of the IgG solution, as shown in FIG. When the hyaluronidase mixed IgG solution (HYAL) was administered as a positive control and the IgG solution (IgG) was administered as a solvent control, 10 mL was administered as shown in FIG. 1 below.
  • chondroitinase ABC exhibits a space-forming ability equal to or higher than that of hyaluronidase even at a low concentration.
  • Example 2 The ability to form subcutaneous space by dose of the candidate substance was evaluated.
  • the insertion pressure at the time of subcutaneous administration of the drug to the abdomen of female domestic pigs (13.2 to 14.5 kg) in the following group composition was measured and evaluated.
  • hyaluronidase 1514 U / mg, derived from Proteus vulgaris, Sigma-Aldrich
  • hyaluronidase solution 1.5 mL of the solution was added to 17.442 mg of hyaluronidase (1514 U / mg, derived from Proteus vulgaris, Sigma-Aldrich) and dissolved with gentle stirring at low temperature to prepare a hyaluronidase solution.
  • ⁇ Administration method 1 mL of hyaluronidase solution was added to 9 mL of IgG solution, mixed gently, and 10 mL was administered. The chondroitinase solution of each concentration was also administered in the same manner. As the solvent-controlled IgG, 1 mL of physiological saline was added to 9 mL of the IgG solution, mixed, and 10 mL was administered.
  • chondroitinase ABC exhibits a space-forming ability equal to or higher than that of hyaluronidase even at a low concentration.
  • the concentration of chondroitinase ABC the lower the insertion pressure. From this result, it is expected that chondroitinase ABC has a high space-forming ability and reaches the threshold of the space-forming ability with a small amount. It should be noted that this consideration is merely an estimate and does not limit the technical scope of the present invention.
  • Ch low + IgG is chondroitinase ABC solution (low concentration) + IgG solution
  • Ch medium + IgG is chondroitinase ABC solution (medium concentration) + IgG solution
  • Ch high + IgG is chondroitinase ABC solution.
  • HYL ++ IgG refers to hyaluronidase solution + IgG solution.
  • Example 3 Evaluation of pharmacokinetics The blood transferability of subcutaneously administered IgG was evaluated.
  • the drug was subcutaneously administered to the abdomen of female domestic pigs (10 to 15 kg) in the following group composition, and the plasma IgG concentration was measured.
  • hyaluronidase 1500 U / mg, Sigma-Aldrich
  • hyaluronidase solution 1.5 mL of the solution was added to 17.442 mg of hyaluronidase (1500 U / mg, Sigma-Aldrich) and dissolved with gentle stirring at a low temperature to prepare a hyaluronidase solution.
  • the chondroitinase solution was also administered in the same manner.
  • Venous blood was collected before administration, 5, 10, 30 minutes after the start of administration, 1, 3, 6, 12, 24, 48, 72 hours, and 1 week later using a disposable syringe and a needle.
  • the collected blood was placed in an EDTA / 2K addition container, centrifuged at 3000 rpm at 4 ° C. for 15 minutes, and the obtained plasma was dispensed into a sample tube to prepare a PK measurement sample.
  • the plasma IgG concentration of the PK measurement sample was measured by the ELISA method.
  • PK analysis (calculation of AUC, C max , T max , t 1/2 ) was performed from the IgG concentration.
  • HYL (1760 U / mL) + IgG refers to a hyaluronidase solution + IgG solution
  • Ch (5 U / mL) + IgG refers to a chondroitinase ABC solution + IgG solution.
  • chondroitinase ABC is small, increasing the C max of IgG than hyaluronidase was shortened T max. This suggests that chondroitinase ABC enhances blood transferability and improves bioavailability compared to hyaluronidase.

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Abstract

La présente invention concerne une préparation qui est co-administrée avec une préparation de protéine et peut accroître le volume d'administration de la préparation de protéine même lorsqu'elle est administrée sous une faible concentration. Cet agent de formation d'espace forme, sous la peau, un espace pour l'administration sous-cutanée d'une préparation de protéine comprenant de la chondroïtinase.
PCT/JP2020/036537 2019-09-30 2020-09-28 Agent de formation d'espace, préparation pour injection sous-cutanée, et procédé de formation d'espace WO2021065768A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011523940A (ja) * 2008-04-28 2011-08-25 ハロザイム インコーポレイテッド 超速効型インスリン組成物
WO2017190147A1 (fr) * 2016-04-29 2017-11-02 Inovio Pharmaceuticals, Inc. Utilisation in vivo de chondroïtinase et/ou d'hyaluronidase pour améliorer l'administration d'un agent
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