WO2016048189A1 - Nouvelle composition comprenant un conjugué de peg et d'interphéron alpha -2bêta moins douloureuse à l'injection - Google Patents

Nouvelle composition comprenant un conjugué de peg et d'interphéron alpha -2bêta moins douloureuse à l'injection Download PDF

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Publication number
WO2016048189A1
WO2016048189A1 PCT/RU2015/000164 RU2015000164W WO2016048189A1 WO 2016048189 A1 WO2016048189 A1 WO 2016048189A1 RU 2015000164 W RU2015000164 W RU 2015000164W WO 2016048189 A1 WO2016048189 A1 WO 2016048189A1
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composition
peg
hepatitis
compositions
interferon
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Russian (ru)
Inventor
Анна Валерьевна ГРЯЗНОВА
Александр Олегович ЯКОВЛЕВ
Алексей Юрьевич СКРИПКИН
Роман Алексеевич ИВАНОВ
Дмитрий Валентинович МОРОЗОВ
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Biocad JSC
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates

Definitions

  • Interferons are a group of biologically active proteins or glycoproteins produced by various cells in response to a viral infection or when certain chemical and biological substances are exposed to cells (Isaacs & Lindeman, 1957; Pestka et al., 2007).
  • the binding of IFN to cellular receptors leads to the induction of the synthesis of a number of intracellular proteins that mediate the antiviral, immunomodulatory and antiproliferative effects of IFN (Pestka et al., 2004; Bekisz, 2004).
  • IFN-based drugs are used in clinical practice to treat a range of viral, oncological and immune diseases (Pestka et al., 2004). Ifn drugs were most widely used for the treatment of viral hepatitis (Chevaliez & Pawlotsky, 2009), which represent one of the most serious social problems.
  • hepatitis B patients there are about 350 million chronic hepatitis B patients and 170 million hepatitis C patients in the world. (Marcellin, 2009).
  • hepatitis C disease acquires a chronic course with the formation of severe outcomes - liver cirrhosis and hepatocellular carcinoma (Modi & Liang, 2008).
  • the efficacy of native IFN preparations is limited by rapid absorption from subcutaneous tissues, large distribution volume, relatively low stability, short half-life, high immunogenicity and toxicity (Wills, 1 90).
  • a rapid decrease in the concentration of IFN in the blood plasma is observed, while interferon is not detected in the plasma 24 hours after the injection (Chatelut et al., 1999).
  • a decrease in the concentration of interferon creates the conditions for the resumption of virus replication and an increase in the concentration of viral particles (Lam et al., 1997). Therefore, there is a need for frequent injections of the drug to achieve effective therapeutic plasma concentrations, which leads to dose-related side effects.
  • the therapeutic efficacy of IFN can be enhanced by the use of sustained release drugs, in particular “PEGylated” IFN (Manns et al., 2001; Hadziyannis et al., 2004; Zeuzem et al., 2001).
  • PEGylated IFN consists in the chemical binding of an interferon molecule to a polymer of monomethoxypolyethylene glycol (mPEG), consisting of repeating subunits of ethylene oxide with a methoxy group at one end and a hydroxyl group at the other.
  • mPEG monomethoxypolyethylene glycol
  • the mPEG molecule may have a different molecular weight and stereochemical structure (linear or branched).
  • the hydroxyl group at the end of the MPEG is activated by various reactive functional groups.
  • An activated MPEG can covalently bind to a protein in one or more places, depending on the nature of the activated group and the reaction conditions (Zalipsky & Hums, 1997; Roberts et al., 2002).
  • PEGylation of IFN leads to an improvement in pharmacokinetics, an increase in the half-life of blood, a decrease in blood concentration fluctuations, a decrease in immunogenicity and toxicity, an increase in in vivo activity (with a decrease in in vitro activity); increased stability (Glue et al., 2000; Reddy et al., 2001).
  • conjugate PEG-IFN-2a obtained by conjugation of IFN-2a with branched PEG with a molecular weight of 40 kDa (patent RU 2180595, 1997).
  • the conjugate of PEGylated interferon-a-2b is also known, which is one positional isomer with monomethoxypolyethylene glycol attached to the ⁇ -terminal end cysteine, with a molecular weight of PEG from 20 to 40 kDa (patent RU 2447083).
  • composition of the drug "Pegasis” (manufacturer Hoffmann-La Roche, France) according to the instructions for medical use includes 0.5 ml:
  • Peginterferon alfa-2a (40 kDa) - 135 mcg or 180 mcg
  • Glacial acetic acid 0.0231 mg
  • PEG-IFN Another drug based on PEG-IFN contains, "PegIntron” (Schering-Plow, Belgium) contains:
  • the closest analogue of this invention can be considered a medicinal product "Algeron", having the following composition:
  • Active ingredient pegylated interferon alpha-2b (chainginterferon alpha-2b) as the active substance - 200 mg / ml.
  • the instructions for medical use report side effects expressed by the following most common symptoms: dry cough, joint pain, muscle pain, dry and peeling skin, skin itching and rash, inflammation at the injection site, and others.
  • Preparations of interferon and its analogues or derivatives, including and pegylated, are introduced only by injection through a syringe or a special device - an injector (syringe pen).
  • any injection injected subcutaneously can cause reactions at the injection site in the form of soreness, redness, swelling, infiltrates, and even necrosis.
  • the experience with the use of drugs that alter the course of multiple sclerosis indicates a high effect of tolerance at the injection site, the convenience and simplicity of injecting on long-term adherence to therapy or compliance (degree of correspondence between patient behavior and recommendations received from a doctor).
  • the effectiveness of interferons is dose-dependent in nature, and to a large extent can be reduced with skipped injections by the patient. Most patients report that they missed injections for various reasons: reactions at the injection site, forgetfulness, fear of needles, fear of other adverse reactions, travel. More than half of patients who refused treatment on their own, do this during the first 3.5 months from the start of therapy.
  • the effectiveness of interferon drugs in the treatment of multiple sclerosis is limited to 30%, a key strategy to increase the effectiveness of therapy is to increase compliance.
  • the best safety profile affects the informed choice of the drug by the patient and / or doctor (increase in the number of patients taking the drug);
  • the present invention provides a pharmaceutical composition for subcutaneous administration containing PEG-IFN-alpha-2beta and excipients, which has a reduced soreness of 20 when administered.
  • FIG. 1 - A visual analogue pain scale (YOUR) is shown with a graduation in points.
  • FIG. 2 - YOUR scores are shown with the introduction of compositions B 1-B5 25 (averaged).
  • FIG. 3 Shows YOUR points with the introduction of compositions D2 and D3.
  • FIG. 4 YOUR scores are shown with the introduction of compositions A1-A5, C1-C5, D1 (averaged).
  • FIG. 5 - VAS scores are shown with the introduction of compositions that are similar in composition to the Algeron preparation and composition K. Description of the invention
  • PEG is equal to 20 kDa, 10-3 LLC mkg
  • the osmotic agent contained in this composition is selected from the group consisting of sodium chloride, trehalose dihydrate, sucrose, sorbitol, mannitol, derivatives of mono and disaccharides.
  • the composition has antiviral, antiproliferative and immunomodulatory activity.
  • the composition according to the invention can be used as a medicine for the treatment of viral and oncological diseases and diseases accompanied by primary or secondary immunodeficiency states.
  • the viral disease may be hepatitis C or hepatitis B
  • the cancer may be myeloid leukemia, in particular melanoma.
  • a method for producing a composition for subcutaneous administration including:
  • the filtration step may be a sterilizing filtration.
  • a method for preparing a composition for subcutaneous administration involves packaging the resulting solution in dosage units, which may be pre-filled syringes, vials, or auto-injectors.
  • the invention provides a kit comprising a dosage unit and instructions for use for the prevention or treatment of diseases accompanied by primary or secondary immunodeficiency states, cancer, viral diseases.
  • the indicated viral disease may be hepatitis C or hepatitis B
  • the cancer may be myeloid leukemia, in particular melanoma.
  • An object of the present invention is to provide a new subcutaneous injection composition containing a PEG-IFN-alpha-2 beta conjugate having antiviral, antiproliferative and immunomodulating activity (IFN-alpha activity), while this composition has reduced soreness and better tolerance when administered.
  • the authors of the present invention unexpectedly found that with the introduction of a composition with a certain ratio of excipients, there is a decrease in side effects and a decrease in pain during administration.
  • the sodium acetate trihydrate content in the peginterferon-alpha composition was more than 5 mg / ml, a sharp increase in pain was observed upon administration.
  • the sodium acetate trihydrate content is less than 5 mg / ml in the peginterferon-alpha composition, improved tolerability by patients is observed upon administration and a decrease in pain and inflammation at the injection site.
  • the present invention provides a composition containing as an active substance the conjugate PEG-IFN-alpha-2-beta and as auxiliary substances sodium acetate trihydrate in a concentration of not more than 5 mg / ml, glacial acetic acid, osmotic agent, disodium edetate dihydrate and water for injection in the following ratios: Active substance:
  • a n takes such a value that the molecular weight of PEG is 20 kDa
  • excipients can be selected from buffering agents, osmotic agents, stabilizers, antioxidants, diluents, solvents and preservatives.
  • Various agents can be used as buffering agents, such as at least one substance selected from the group consisting of sodium acetate trihydrate, sodium / potassium hydro and / or dihydrogen phosphate, sodium or ammonium acetate, citrate, hydrogen carbonate, phosphate buffers.
  • mannitol sodium chloride, trehalose dihydrate, sucrose, arabitol, sorbitol, glycerin, derivatives of mono and disaccharides, lactose, dextran
  • stabilizers polysorbates, EDTA, polyvinylpyrrolidones, dextrans, HSA, para-hydroxybenzoic acid esters, alcohols (e.g. benzyl alcohol), phenols can be used.
  • compositions can be used in the treatment of viral and oncological diseases and diseases accompanied by primary or secondary immunodeficiency conditions.
  • Viral diseases can be hepatitis C or hepatitis B.
  • Oncological diseases can be myeloid leukemia, melanoma.
  • a method of obtaining this composition includes the steps of preparing a concentrate containing sodium acetate trihydrate, glacial acetic acid, an osmotic agent, disodium edetate dihydrate, and water for
  • compositions for subcutaneous administration 15 injections, and further adding to it the active substance, the PEG-interferon alpha-2b conjugate, filtering the resulting solution, and packaging the resulting solution in dosage units.
  • the active substance the PEG-interferon alpha-2b conjugate
  • filtering the resulting solution the PEG-interferon alpha-2b conjugate
  • packaging the resulting solution in dosage units.
  • other methods of preparing compositions for subcutaneous administration are known from the technology.
  • the components can be mixed in various proportions, fractionally
  • Filtration of the solution may be a sterilizing filtration, for example, through depth or membrane filters.
  • the pore size of the filters may be different, suitable for the sterilization process. Preferably, the pore size is selected no more than
  • Dosage units can be syringes, vials or auto-injectors pre-filled with a solution of the composition according to the invention.
  • Syringes Vials or auto-injectors can have any volume, and can be made of any material suitable for this (glass, polymer material), which involves the hermetic storage of this composition for a long time.
  • a kit for use by a patient on an outpatient basis or in a medical facility may include a dosage unit containing a composition of the present invention and instructions for using the composition.
  • This kit can be used in the treatment of viral and oncological diseases and diseases accompanied by primary or secondary immunodeficiency conditions.
  • Viral diseases can be hepatitis C or hepatitis B.
  • Oncological diseases can be myeloid leukemia, melanoma.
  • the present invention is illustrated by the examples below, which are not intended to limit the invention.
  • compositions according to the invention for subcutaneous administration A concentrate was prepared to obtain the final composition, including sodium acetate trihydrate, osmotic agent, disodium edetate dihydrate, and water for injection, adjusted with glacial acetic acid to pH 4.0-6.0. Next, a PEG-IFN formula conjugate of the formula was added to the concentrate
  • compositions were obtained having the following compositions: (shown in Table 1). Table 1.
  • Table 1 The composition of the compositions according to the invention
  • a medicine comprising an effective amount of the inventive composition obtained according to example 2 was poured in sterile conditions at 0.5, 0.8, 1.0 and 1.2 ml (for a dosage of 10-100 ⁇ g / ml), at 0.5 , 0.6, 0.75 and 0.9 ml (for a dosage of 200-500 ⁇ g / ml), 0.5, 0.6, 0.8, 1.0 and 1.2 ml (for a dosage of 500- 1000 ⁇ g / ml) in neutral glass syringes of hydrolytic class I, with soldered needles, covered with protective elastic or rigid caps, sealed with tips on pistons made of butyl rubber laminated with fluoropolymer.
  • Compositions with peginterferon alpha-2 beta concentration in excess of 1000 ⁇ g / ml were poured into bottles, sealed with rubber stoppers, crimped with aluminum caps.
  • kits comprising a packaged drug containing the claimed composition
  • the kit contains 1 or 4 syringes complete with a piston (1 or 4, respectively) / bottle in a blister strip of polymer film, together with instructions for use, which are placed in a pack of cardboard.
  • compositions used to evaluate pain when administered All compositions were obtained according to example 2.
  • compositions with the following composition were selected:
  • VAS visual analogue pain scale
  • compositions containing peginterferon alpha-2beta having the compositions as indicated in tables 2-5.
  • compositions B4-B5 and D5 were completed ahead of schedule on a small number of volunteers due to the excessive soreness of these compositions.
  • the average value of pain at the time of administration for the VZ composition was 6 points (9-3).
  • This indicator for composition D4, B 1-B2 was 5 points (7-2). Soreness 5 minutes after the introduction of these compositions had a value of 1 point (0-3). Hyperemia, edema, or other reactions at the injection site were not observed.
  • compositions A1-A5, C1-C5, D1-D3 have the least pain at the injection site in comparison with other studied compositions.
  • compositions A5 and C1-C5 were comparable and had an average of 0.44 (0-2) and 0.5 (0-2), respectively. After 5 minutes, the average pain for compositions A5 was 0.1 (0-1), C 1 -C5 - 0 (0).
  • compositions D2 and D3 When assessing the local irritant effect when applying compositions D2 and D3, mild reactions at the injection site were revealed in 4 of 9 subjects. In contrast, when administering C1-C5 compositions, one of 8 subjects showed mild itching, hyperemia of 15 minutes duration. Thus, with comparable pain indicators according to YOUR compositions C1-C5 have less local irritating effect. Table 7. Soreness with the introduction of compositions A1-A5, C1-D5, D3 and B1-B2.
  • Saline solution (composition A) showed moderate soreness at the injection site, the median of pain according to YOUR at the time of administration was 2.0.
  • composition A5 The formulations elicited mild transient reactions at the injection site. No clear differences were found for this indicator. In one subject, after administration of composition A5, discomfort at the injection site persisted for a long time.
  • the drug for prolonged use should not have soreness that affects daily activity and interfere with daily activities.
  • drugs with a high injection frequency and duration of therapy it is not advisable to use a buffer composition with pain more than 3 points according to YOURS.
  • the median pain at the time of administration for composition D2 was 4.0 [3.0; 5.0] and 0 [0; 3.0] for composition D3.
  • the values had statistically significant differences (MW-U test, p 0.015).
  • the median soreness 5 minutes after administration had a value of 0 [0; 0] for each group. Indicators of pain after 5 minutes did not differ.
  • the data are presented in FIG. 3.
  • compositions elicited mild transient reactions at the injection site see Table 9. No clear differences were found for this indicator.
  • composition D2 has a significantly better tolerance in terms of pain intensity according to YOUR at the time of administration. According to the indicators of pain 5 minutes after administration and reactions at the injection site, the compositions have good tolerance and do not have significant differences between themselves.
  • compositions caused mild transient reactions at the injection site, see table 10. Compositions C4 and C5 were worse tolerated.
  • composition A1 has a significantly better tolerance in terms of pain intensity according to YOUR at the time of administration. According to the pain indicators 5 minutes after administration and reactions at the injection site, the compositions have good tolerance and do not have significant differences among themselves. However, all compositions A1-A5, C1-C5 and D1-D3 can be used with long-term treatment, because with their introduction, YOUR points do not exceed 3.
  • compositions having a composition similar to the drug "Algeron” and containing polysorbate-80 The composition is shown in Tables 1 1 (alternative composition containing polysorbate-80) and Table 12 (the composition is similar to Algeron, selected as a prototype).
  • Lam NP Pitrak D., Speralakis R., Lau AH, Wiley T.E., Layden TJ (1997), "Effect of obesity on pharmacokinetics and biologic effect of interferon-alpha in hepatitis C", Dig. Dis. Sci .; 42 (l): 178-85. Manns MP, McHutchison JG, Gordon SC, et al. (2001) "Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial.” Lancet, 358: 958-65.

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Abstract

L'invention concerne une nouvelle composition comprenant un PEG-interphéron alpha et des substances complémentaires, notamment le dihydrate de disodium édétique dans des concentrations inférieures ou égales à 0,9 mg/ml et moins douloureuse à l'injection.
PCT/RU2015/000164 2014-09-22 2015-03-23 Nouvelle composition comprenant un conjugué de peg et d'interphéron alpha -2bêta moins douloureuse à l'injection Ceased WO2016048189A1 (fr)

Applications Claiming Priority (2)

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RU2014138150/15A RU2572800C1 (ru) 2014-09-22 2014-09-22 Новый состав, содержащий конъюгат пэг и интерферон-альфа-2бета, обладающий сниженной болезненностью при введении
RU2014138150 2014-09-22

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CN116510006A (zh) * 2022-01-31 2023-08-01 拜奥卡德联合股份公司 抗trbv9抗体的药物组合物及其用途
MA70850A1 (fr) * 2022-07-26 2025-10-31 Joint Stock Company "Biocad" Composition pharmaceutique d'anticorps anti-cd20 et son utilisation

Citations (2)

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Publication number Priority date Publication date Assignee Title
WO2008062481A2 (fr) * 2006-11-24 2008-05-29 Cadila Healthcare Limited Formulations de conjugués de peg-interféron alpha
RU2447083C1 (ru) * 2010-07-20 2012-04-10 Закрытое Акционерное Общество "Биокад" НОВЫЙ ФУНКЦИОНАЛЬНО АКТИВНЫЙ ВЫСОКООЧИЩЕННЫЙ СТАБИЛЬНЫЙ КОНЪЮГАТ ИНТЕРФЕРОНА α С ПОЛИЭТИЛЕНГЛИКОЛЕМ, ПРЕДСТАВЛЕННЫЙ ОДНИМ ПОЗИЦИОННЫМ ИЗОМЕРОМ ПЭГ-NαH-ИФН, С УМЕНЬШЕННОЙ ИММУНОГЕННОСТЬЮ, С ПРОЛОНГИРОВАННЫМ БИОЛОГИЧЕСКИМ ДЕЙСТВИЕМ, ПРИГОДНЫЙ ДЛЯ МЕДИЦИНСКОГО ПРИМЕНЕНИЯ, И ИММУНОБИОЛОГИЧЕСКОЕ СРЕДСТВО НА ЕГО ОСНОВЕ

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WO2008062481A2 (fr) * 2006-11-24 2008-05-29 Cadila Healthcare Limited Formulations de conjugués de peg-interféron alpha
RU2447083C1 (ru) * 2010-07-20 2012-04-10 Закрытое Акционерное Общество "Биокад" НОВЫЙ ФУНКЦИОНАЛЬНО АКТИВНЫЙ ВЫСОКООЧИЩЕННЫЙ СТАБИЛЬНЫЙ КОНЪЮГАТ ИНТЕРФЕРОНА α С ПОЛИЭТИЛЕНГЛИКОЛЕМ, ПРЕДСТАВЛЕННЫЙ ОДНИМ ПОЗИЦИОННЫМ ИЗОМЕРОМ ПЭГ-NαH-ИФН, С УМЕНЬШЕННОЙ ИММУНОГЕННОСТЬЮ, С ПРОЛОНГИРОВАННЫМ БИОЛОГИЧЕСКИМ ДЕЙСТВИЕМ, ПРИГОДНЫЙ ДЛЯ МЕДИЦИНСКОГО ПРИМЕНЕНИЯ, И ИММУНОБИОЛОГИЧЕСКОЕ СРЕДСТВО НА ЕГО ОСНОВЕ

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