CA3233718A1 - Injection container filled with an aqueous injectable composition - Google Patents
Injection container filled with an aqueous injectable composition Download PDFInfo
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- CA3233718A1 CA3233718A1 CA3233718A CA3233718A CA3233718A1 CA 3233718 A1 CA3233718 A1 CA 3233718A1 CA 3233718 A CA3233718 A CA 3233718A CA 3233718 A CA3233718 A CA 3233718A CA 3233718 A1 CA3233718 A1 CA 3233718A1
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- composition
- injection container
- hyaluronic acid
- container according
- composition comprises
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- 238000002347 injection Methods 0.000 title claims abstract description 51
- 239000007924 injection Substances 0.000 title claims abstract description 51
- 239000007972 injectable composition Substances 0.000 title claims abstract description 5
- 239000000203 mixture Substances 0.000 claims abstract description 105
- DFPAKSUCGFBDDF-UHFFFAOYSA-N nicotinic acid amide Natural products NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims abstract description 41
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims abstract description 35
- 229920002674 hyaluronan Polymers 0.000 claims abstract description 32
- 229960003160 hyaluronic acid Drugs 0.000 claims abstract description 32
- 235000005152 nicotinamide Nutrition 0.000 claims abstract description 26
- 239000011570 nicotinamide Substances 0.000 claims abstract description 26
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 229960003966 nicotinamide Drugs 0.000 claims abstract description 16
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229960003512 nicotinic acid Drugs 0.000 claims abstract description 12
- 239000011521 glass Substances 0.000 claims description 11
- 201000008482 osteoarthritis Diseases 0.000 claims description 9
- 229920002385 Sodium hyaluronate Polymers 0.000 claims description 8
- 229940010747 sodium hyaluronate Drugs 0.000 claims description 8
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 claims description 8
- 230000002917 arthritic effect Effects 0.000 claims description 7
- 210000001503 joint Anatomy 0.000 claims description 5
- 239000003708 ampul Substances 0.000 claims description 3
- 239000007853 buffer solution Substances 0.000 claims description 3
- 229920000642 polymer Polymers 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- -1 alkali metal salt Chemical class 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 230000015556 catabolic process Effects 0.000 description 10
- 238000006731 degradation reaction Methods 0.000 description 10
- 238000005259 measurement Methods 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 4
- 238000012417 linear regression Methods 0.000 description 4
- 210000000988 bone and bone Anatomy 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 239000000470 constituent Substances 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 235000001968 nicotinic acid Nutrition 0.000 description 2
- 239000011664 nicotinic acid Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 239000003932 viscosupplement Substances 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- 208000012659 Joint disease Diseases 0.000 description 1
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 1
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- AEMOLEFTQBMNLQ-WAXACMCWSA-N alpha-D-glucuronic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-WAXACMCWSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 230000003011 chondroprotective effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 125000000600 disaccharide group Chemical group 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000001050 lubricating effect Effects 0.000 description 1
- 229950006780 n-acetylglucosamine Drugs 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 210000001179 synovial fluid Anatomy 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
Classifications
-
- 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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/728—Hyaluronic acid
-
- 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
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- 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
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/20—Polysaccharides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/505—Stabilizers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/178—Syringes
- A61M5/31—Details
- A61M5/3129—Syringe barrels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/06—Materials or treatment for tissue regeneration for cartilage reconstruction, e.g. meniscus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/24—Materials or treatment for tissue regeneration for joint reconstruction
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Dermatology (AREA)
- Engineering & Computer Science (AREA)
- Transplantation (AREA)
- Oral & Maxillofacial Surgery (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Molecular Biology (AREA)
- Anesthesiology (AREA)
- Vascular Medicine (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to an injection container filled with an aqueous injectable composition, wherein the composition comprises hyaluronic acid and/or at least one salt of hyaluronic acid and wherein the composition comprises nicotinic acid and/or nicotinamide.
Description
INJECTION CONTAINER FILLED WITH AN AQUEOUS INJECTABLE
COMPOSITION
[0001] The invention relates to an injection container filled with an aqueous 5 injectable composition, in particular for intra-articular administration, wherein the composition comprises at least one salt of hyaluronic acid.
COMPOSITION
[0001] The invention relates to an injection container filled with an aqueous 5 injectable composition, in particular for intra-articular administration, wherein the composition comprises at least one salt of hyaluronic acid.
[0002] Osteoarthritis is a degenerative joint disease and is currently the most common joint disease worldwide. Due to the increasing average age of the 10 population, larger and larger proportions of the population are affected. In joints affected by osteoarthritis, in particular the layer of cartilage located between the bones of the joint and serving as a cushion diminishes, and as a result the distance between the bones of the joint becomes smaller and smaller and the strain on the joint under load increases until finally the bones of the joint are in 15 direct contact with one another. As a result of osteoarthritis, the joint is increasingly worn under load, and this is associated with severe pain.
[0003] To alleviate the symptoms, compositions comprising hyaluronic acid and/or its salts are ¨ as known ¨ administered into the intermediate space of 20 a joint affected by osteoarthritis; this is also referred to as viscosupplementation. Hyaluronic acid is a polysaccharide formed by a plurality of disaccharide repeat units, which each comprise D-glucuronic acid and N-acetyl-D-glucosamine. Hyaluronic acid is contained ¨ as a constituent of the extracellular matrix of humans ¨ in particular also in the natural joint 25 lubricant, which is also referred to as synovial fluid. Therefore, the administration of hyaluronic acid and/or its salts has joint-lubricating, anti-inflammatory and chondroprotective effects which contribute to the alleviation of arthritic symptoms. The compositions used in this context are also referred to as viscoelastics.
[0004] The shelf life of compositions comprising hyaluronic acid and/or its salt is determined in particular by the stability of hyaluronic acid and/or its salts. In aqueous compositions which are administered to treat osteoarthritis, hyaluronic acid and/or its salts are degraded by hydrolysis of the glycosidic bonds. According to the scientific article "Degradation of hyaluronic acid-Kinetic study and thermodynamics" (Eur. Polym. J., vol. 32, no. 8, 1996, pp.
5 1011 to 1014), the quantity of hyaluronic acid chains still present can be inferred by determining the viscosity of the composition. A smaller number of hyaluronic acid chains corresponds to a reduced viscosity of the composition and results in an increasingly lower efficacy of the administered composition, in particular an increasingly smaller protective effect on the joint affected by 10 osteoarthritis. This greatly limits the shelf life of the known compositions, and thus also the shelf life of the injection container filled therewith.
[0005] A further disadvantage in the administration of the known compositions is that they first have to be laboriously introduced into the administration 15 container. This not only requires spending additional time but is also susceptible to errors, since the introduced composition must always be visually inspected after the administration container has been filled. Finally, there is also the risk that the composition becomes contaminated during filling.
20 [0006] It is therefore the object of the invention to develop an injection container filled with the composition, said injection container having, in particular, improved shelf life and usability, while avoiding the disadvantages known from the prior art.
25 [0007] The object of the invention is achieved by an injection container of the type mentioned at the outset, which injection container is filled with the composition, wherein the composition comprises nicotinic acid and/or nicotinamide, wherein the composition comprises nicotinic acid and/or nicotinamide in a mass concentration of 1 mg/ml to 30 mg/ml overall, wherein 30 the injection container is at least one member of the following group:
syringe, syringe barrel, vial, ampule, wherein the injection container is a glass syringe and wherein the composition and the interior of the glass syringe are sterilized.
[0008] The invention is based on the basic idea that the nicotinic acid and/or nicotinamide contained in the composition of the injection container according to the invention serves as a stabilizing component by means of which the 5 degradation of the physiologically effective hyaluronic acid is slowed, so that the shelf life of the composition of the injection container according to the invention is substantially extended in comparison with the known compositions. The shelf life of the injection container is thereby also extended.
In addition, the injection container according to the invention can be used 10 directly and immediately. Since no drawing up or transferring is required before the injection container is used, a visual inspection of the injection container, in particular its composition, is not required either. In addition to improved shelf life, the usability of the injection container according to the invention, filled with the composition, is also improved.
[0009] The composition of the injection container according to the invention can, for simple administration, be in the form of a gel and/or be sterilized.
In a further embodiment, the composition of the injection container according to the invention comprises, for medical usability, at least one alkali metal salt of 20 hyaluronic acid, in particular sodium hyaluronate. The composition preferably comprises hyaluronic acid and/or its salts in a mass concentration of 10 mg/ml to 30 mg/ml overall, in particular 15 mg/ml to 25 mg/ml, most preferably approximately 25 mg/ml; the concentration specifications can relate to the combination of hyaluronic acid and its salts.
[0010] The hyaluronic acid and/or its salts in the composition can have a molecular weight of between 100 kDa and 3 MDa overall, where 1 Da corresponds to one atomic mass unit u.
30 [0011] According to the invention, the composition comprises nicotinic acid and/or nicotinamide in a mass concentration of 1 mg/ml to 30 mg/ml overall in order to slow the degradation of hyaluronic acid and/or its salt. The composition preferably comprises nicotinic acid and/or nicotinamide in a mass concentration of 1 mg/ml to 25 mg/ml overall, most preferably 5 mg/ml to 25 mg/ml, in order to further slow the degradation of hyaluronic acid and/or its salt. In a further embodiment, the composition comprises nicotinic acid and/or 5 nicotinamide in a mass concentration of approximately 15 mg/ml. The concentration specifications can relate to the combination of nicotinic acid and nicotinamide.
[0012] In a development of the invention, the composition comprises a buffer 10 solution, in particular a phosphate-containing buffer solution, in order to stabilize the pH of the composition, preferably at a pH of approximately 7.
[0013] The composition preferably has an osmolarity of 270 mOsm/I to 450 mOsm/1. In a development of the invention, the composition is free of 15 crosslinked hyaluronic acid polymers and/or hyaluronic acid salt polymers.
[0014] According to the invention, the injection container is at least one member of the following group: syringe, syringe barrel, vial, ampule. The injection container is in the form of a syringe in order to improve the shelf life 20 of the composition of the injection container and also the usability of the injection container. According to the invention, the injection container is made of glass for reasons of hygiene, the injection container being, according to the invention, a glass syringe.
25 [0015] The composition and the interior of the glass syringe are sterilized in order to form a sterile double barrier, so that the shelf life and usability of the injection container are further improved. This also increases safety for the user and for the patient. Preferably, the inner wall of the glass syringe is sterilized.
30 [0016] In a development of the invention, a glass syringe can be filled with the composition, the syringe being, in particular, in the form of a disposable syringe, for hygiene purposes. Alternatively, the syringe can be in the form of a reusable syringe in order to enable the administration of a plurality of doses of the composition.
[0017] The injection container according to the invention, filled with the 5 composition, can be intended for use in a method for treating osteoarthritis, in particular for treating an arthritic joint, wherein the composition is, in particular, injected intra-articularly into the arthritic joint.
[0018] Further advantages and features of the invention can be found in the 10 claims and in the following description, in which an exemplary embodiment of the invention is described in detail with reference to the tables and to the figure.
In the drawings:
Tab. 1 shows components of a composition known from the prior art, Tab. 2 hows components of a composition according to the invention, and 15 Fig. 1 shows measured viscosity values for both compositions over time in a t-y graph.
[0019] Tab. 1 shows the components of a composition A which is known from the prior art and which is used as a viscosupplement composition in particular 20 for the treatment of arthritic complaints. The left column, with the title I, presents the chemical formulas of the ingredients of composition A. The middle column of Tab. 1, with the title M, contains the names of the ingredients and their numbers in the European Pharmacopoeia. The right column, with the title c, contains the concentration specifications of the ingredients of composition A
25 in g/I. Composition A consequently comprises, in particular, sodium hyaluronate, the sodium salt of hyaluronic acid, in a mass concentration of 25.0 WI. According to the last row of Tab. 1, the amount of water for injection purposes (abbreviated with "H20" in Fig. 1) that is required to reach the desired volume of composition A, here 1 I, is provided.
[0020] Similar to the presentation in Tab. 1, Tab. 2 shows the components of a composition B, with which an injection container (not shown) according to the invention is filled, as a viscosupplement composition. Composition B of the injection container according to the invention essentially comprises the ingredients and their concentrations of composition A, but composition B of the injection container according to the invention additionally comprises 5 nicotinamide (also referred to as niacinamide), the amide of nicotinic acid, in a mass concentration of 15 g/1. Similar to composition A, composition B
comprises the amount of water for injection purposes that is required to reach the desired volume.
10 [0021] In the use of the known compositions for the treatment of arthritic complaints, the hyaluronic acid or its salt is the physiological active substance.
The degradation of hyaluronic acid or its salt as constituents of the compositions occurs by hydrolysis of the glycosidic bonds as a result of the water contained in the composition; this reduces the storage time of 15 compositions containing hyaluronic acid. The degradation of hyaluronic acid or its salt manifests itself physically in an increasingly lower viscosity of the composition, and therefore the determination of the viscosity of a composition can give information about the amount of hyaluronic acid or its salt still present in the composition.
[0022] To determine the effect of the nicotinamide contained only in composition B of the injection container according to the invention, said nicotinamide being contained more precisely in a mass concentration of 15 g/I, the viscosity of composition B was measured over a period of 45 days and 25 compared with the measured values of the viscosity for composition A, which does not comprise any nicotinamide. For this purpose, 2 liters of each of compositions A and B were provided, the pH of each of the two compositions being approximately 7.
30 [0023] To determine the long-term effects of the nicotinamide on the sodium hyaluronate in composition B, both compositions A and B were stored at a temperature of 50 C for the duration of the measurements, whereas in the
[0005] A further disadvantage in the administration of the known compositions is that they first have to be laboriously introduced into the administration 15 container. This not only requires spending additional time but is also susceptible to errors, since the introduced composition must always be visually inspected after the administration container has been filled. Finally, there is also the risk that the composition becomes contaminated during filling.
20 [0006] It is therefore the object of the invention to develop an injection container filled with the composition, said injection container having, in particular, improved shelf life and usability, while avoiding the disadvantages known from the prior art.
25 [0007] The object of the invention is achieved by an injection container of the type mentioned at the outset, which injection container is filled with the composition, wherein the composition comprises nicotinic acid and/or nicotinamide, wherein the composition comprises nicotinic acid and/or nicotinamide in a mass concentration of 1 mg/ml to 30 mg/ml overall, wherein 30 the injection container is at least one member of the following group:
syringe, syringe barrel, vial, ampule, wherein the injection container is a glass syringe and wherein the composition and the interior of the glass syringe are sterilized.
[0008] The invention is based on the basic idea that the nicotinic acid and/or nicotinamide contained in the composition of the injection container according to the invention serves as a stabilizing component by means of which the 5 degradation of the physiologically effective hyaluronic acid is slowed, so that the shelf life of the composition of the injection container according to the invention is substantially extended in comparison with the known compositions. The shelf life of the injection container is thereby also extended.
In addition, the injection container according to the invention can be used 10 directly and immediately. Since no drawing up or transferring is required before the injection container is used, a visual inspection of the injection container, in particular its composition, is not required either. In addition to improved shelf life, the usability of the injection container according to the invention, filled with the composition, is also improved.
[0009] The composition of the injection container according to the invention can, for simple administration, be in the form of a gel and/or be sterilized.
In a further embodiment, the composition of the injection container according to the invention comprises, for medical usability, at least one alkali metal salt of 20 hyaluronic acid, in particular sodium hyaluronate. The composition preferably comprises hyaluronic acid and/or its salts in a mass concentration of 10 mg/ml to 30 mg/ml overall, in particular 15 mg/ml to 25 mg/ml, most preferably approximately 25 mg/ml; the concentration specifications can relate to the combination of hyaluronic acid and its salts.
[0010] The hyaluronic acid and/or its salts in the composition can have a molecular weight of between 100 kDa and 3 MDa overall, where 1 Da corresponds to one atomic mass unit u.
30 [0011] According to the invention, the composition comprises nicotinic acid and/or nicotinamide in a mass concentration of 1 mg/ml to 30 mg/ml overall in order to slow the degradation of hyaluronic acid and/or its salt. The composition preferably comprises nicotinic acid and/or nicotinamide in a mass concentration of 1 mg/ml to 25 mg/ml overall, most preferably 5 mg/ml to 25 mg/ml, in order to further slow the degradation of hyaluronic acid and/or its salt. In a further embodiment, the composition comprises nicotinic acid and/or 5 nicotinamide in a mass concentration of approximately 15 mg/ml. The concentration specifications can relate to the combination of nicotinic acid and nicotinamide.
[0012] In a development of the invention, the composition comprises a buffer 10 solution, in particular a phosphate-containing buffer solution, in order to stabilize the pH of the composition, preferably at a pH of approximately 7.
[0013] The composition preferably has an osmolarity of 270 mOsm/I to 450 mOsm/1. In a development of the invention, the composition is free of 15 crosslinked hyaluronic acid polymers and/or hyaluronic acid salt polymers.
[0014] According to the invention, the injection container is at least one member of the following group: syringe, syringe barrel, vial, ampule. The injection container is in the form of a syringe in order to improve the shelf life 20 of the composition of the injection container and also the usability of the injection container. According to the invention, the injection container is made of glass for reasons of hygiene, the injection container being, according to the invention, a glass syringe.
25 [0015] The composition and the interior of the glass syringe are sterilized in order to form a sterile double barrier, so that the shelf life and usability of the injection container are further improved. This also increases safety for the user and for the patient. Preferably, the inner wall of the glass syringe is sterilized.
30 [0016] In a development of the invention, a glass syringe can be filled with the composition, the syringe being, in particular, in the form of a disposable syringe, for hygiene purposes. Alternatively, the syringe can be in the form of a reusable syringe in order to enable the administration of a plurality of doses of the composition.
[0017] The injection container according to the invention, filled with the 5 composition, can be intended for use in a method for treating osteoarthritis, in particular for treating an arthritic joint, wherein the composition is, in particular, injected intra-articularly into the arthritic joint.
[0018] Further advantages and features of the invention can be found in the 10 claims and in the following description, in which an exemplary embodiment of the invention is described in detail with reference to the tables and to the figure.
In the drawings:
Tab. 1 shows components of a composition known from the prior art, Tab. 2 hows components of a composition according to the invention, and 15 Fig. 1 shows measured viscosity values for both compositions over time in a t-y graph.
[0019] Tab. 1 shows the components of a composition A which is known from the prior art and which is used as a viscosupplement composition in particular 20 for the treatment of arthritic complaints. The left column, with the title I, presents the chemical formulas of the ingredients of composition A. The middle column of Tab. 1, with the title M, contains the names of the ingredients and their numbers in the European Pharmacopoeia. The right column, with the title c, contains the concentration specifications of the ingredients of composition A
25 in g/I. Composition A consequently comprises, in particular, sodium hyaluronate, the sodium salt of hyaluronic acid, in a mass concentration of 25.0 WI. According to the last row of Tab. 1, the amount of water for injection purposes (abbreviated with "H20" in Fig. 1) that is required to reach the desired volume of composition A, here 1 I, is provided.
[0020] Similar to the presentation in Tab. 1, Tab. 2 shows the components of a composition B, with which an injection container (not shown) according to the invention is filled, as a viscosupplement composition. Composition B of the injection container according to the invention essentially comprises the ingredients and their concentrations of composition A, but composition B of the injection container according to the invention additionally comprises 5 nicotinamide (also referred to as niacinamide), the amide of nicotinic acid, in a mass concentration of 15 g/1. Similar to composition A, composition B
comprises the amount of water for injection purposes that is required to reach the desired volume.
10 [0021] In the use of the known compositions for the treatment of arthritic complaints, the hyaluronic acid or its salt is the physiological active substance.
The degradation of hyaluronic acid or its salt as constituents of the compositions occurs by hydrolysis of the glycosidic bonds as a result of the water contained in the composition; this reduces the storage time of 15 compositions containing hyaluronic acid. The degradation of hyaluronic acid or its salt manifests itself physically in an increasingly lower viscosity of the composition, and therefore the determination of the viscosity of a composition can give information about the amount of hyaluronic acid or its salt still present in the composition.
[0022] To determine the effect of the nicotinamide contained only in composition B of the injection container according to the invention, said nicotinamide being contained more precisely in a mass concentration of 15 g/I, the viscosity of composition B was measured over a period of 45 days and 25 compared with the measured values of the viscosity for composition A, which does not comprise any nicotinamide. For this purpose, 2 liters of each of compositions A and B were provided, the pH of each of the two compositions being approximately 7.
30 [0023] To determine the long-term effects of the nicotinamide on the sodium hyaluronate in composition B, both compositions A and B were stored at a temperature of 50 C for the duration of the measurements, whereas in the
6 case of normal storage of the compositions a temperature of approximately 25 C can be assumed. From research results regarding the temperature-dependent degradation of sodium hyaluronate, it is known that sodium hyaluronate is degraded 34 times more quickly at a pH of 7 and at a 5 temperature of 50 C than at 25 C. The known composition A and composition B of the injection container according to the invention were stored for the duration of the viscosity measurements at a temperature of 50 for 45 days, which corresponds to 1,575 days, i.e., approximately 76.5 months, of regular storage at a temperature of 25 C. The viscosity of compositions A and B was 10 measured repeatedly over the entire duration of 45 days.
[0024] Fig. 1 shows the results of the viscosity measurements for composition A known from the prior art and for composition B of the injection container according to the invention; the results are plotted in a t-y graph, according to 15 which the t-axis corresponds to the time and the y-axis corresponds to the values of the viscosity n. The latter are presented in the unit millipoise (mP), where 1 P = 1 Pa*s. The drawn straight lines correspond to the measured viscosity values for compositions A and B. For mathematical modeling of the time curve of the viscosity values, linear regressions associated with the 20 respective measurement results were determined, and the values of these linear regressions are shown, with interpolation, as points in Fig. 1. Next to the straight lines, the parameters of the linear regressions are presented in Fig.
1.
The quality parameter R2 determined by the linear regression is 0.998 for the known composition A and 0.996 for composition B; in both cases, this indicates 25 good linear adaptation.
[0025] Fig. 1 reveals that, at the starting time t0=0 of the measurement series, the two compositions A and B have essentially equally viscosity values, which corresponds to the initially identical sodium hyaluronate concentrations of the 30 two compositions A and B. With increasing time, the viscosity n of the known composition A decreases more quickly than the viscosity n of composition B.
At the end of the measurements, thus after storage for 45 days at a
[0024] Fig. 1 shows the results of the viscosity measurements for composition A known from the prior art and for composition B of the injection container according to the invention; the results are plotted in a t-y graph, according to 15 which the t-axis corresponds to the time and the y-axis corresponds to the values of the viscosity n. The latter are presented in the unit millipoise (mP), where 1 P = 1 Pa*s. The drawn straight lines correspond to the measured viscosity values for compositions A and B. For mathematical modeling of the time curve of the viscosity values, linear regressions associated with the 20 respective measurement results were determined, and the values of these linear regressions are shown, with interpolation, as points in Fig. 1. Next to the straight lines, the parameters of the linear regressions are presented in Fig.
1.
The quality parameter R2 determined by the linear regression is 0.998 for the known composition A and 0.996 for composition B; in both cases, this indicates 25 good linear adaptation.
[0025] Fig. 1 reveals that, at the starting time t0=0 of the measurement series, the two compositions A and B have essentially equally viscosity values, which corresponds to the initially identical sodium hyaluronate concentrations of the 30 two compositions A and B. With increasing time, the viscosity n of the known composition A decreases more quickly than the viscosity n of composition B.
At the end of the measurements, thus after storage for 45 days at a
7 temperature of 50 C, the known composition A has a viscosity of approximately 205 P and composition B has a viscosity q of approximately 300 P.
[0026] The test results demonstrate that, under the same basic conditions, the 5 viscosity ri of the known composition A according to Tab. 1 decreases more quickly than the viscosity n of composition B of the injection container according to the invention according to Tab. 2. Due to the aforementioned relationship between the viscosity n and the degradation of hyaluronic acid, the test results thus show that the degradation of sodium hyaluronate is slower 10 in composition B of the injection container according to the invention than in the known composition A. This shows, in turn, that the nicotinamide present in composition B significantly inhibits the degradation of hyaluronic acid and extends the shelf life of composition B of the injection container according to the invention, in particular in comparison with the known composition A. This 15 also applies to the shelf life of a composition B located in an injection container in the form of a glass syringe.
[0026] The test results demonstrate that, under the same basic conditions, the 5 viscosity ri of the known composition A according to Tab. 1 decreases more quickly than the viscosity n of composition B of the injection container according to the invention according to Tab. 2. Due to the aforementioned relationship between the viscosity n and the degradation of hyaluronic acid, the test results thus show that the degradation of sodium hyaluronate is slower 10 in composition B of the injection container according to the invention than in the known composition A. This shows, in turn, that the nicotinamide present in composition B significantly inhibits the degradation of hyaluronic acid and extends the shelf life of composition B of the injection container according to the invention, in particular in comparison with the known composition A. This 15 also applies to the shelf life of a composition B located in an injection container in the form of a glass syringe.
8
Claims (10)
1. An injection container filled with an aqueous injectable composition, in particular for intra-articular administration, wherein the composition comprises hyaluronic acid and/or at least one salt of hyaluronic acid and wherein the composition comprises nicotinic acid and/or nicotinamide, wherein the composition comprises nicotinic acid and/or nicotinamide in a mass concentration of 1 mg/ml to 30 mg/ml overall, wherein the injection container is at least one member of the following group:
syringe, syringe barrel, vial, ampule, wherein the injection container is a glass syringe and wherein the composition and the interior of the glass syringe are sterilized.
syringe, syringe barrel, vial, ampule, wherein the injection container is a glass syringe and wherein the composition and the interior of the glass syringe are sterilized.
2. The injection container according to claim 1, characterized in that the composition comprises at least one alkali metal salt of hyaluronic acid, in particular sodium hyaluronate.
3. The injection container according to claim 1 or 2, characterized in that the composition comprises hyaluronic acid and/or its salt in a mass concentration of 10 mg/ml to 30 mg/ml overall.
4. The injection container according to any one of claims 1 to 3, characterized in that the hyaluronic acid and/or its salt has a molecular weight of between 100 kDa and 3 MDa overall.
5. The injection container according to any one of claims 1 to 4, characterized in that the composition comprises nicotinic acid and/or nicotinamide in a mass concentration of 1 mg/ml to 25 mg/ml overall.
6. The injection container according to any one of claims 1 to 5, characterized in that the composition comprises a buffer solution, in particular a phosphate-containing buffer solution.
7. The injection container according to any one of claims 1 to 6, characterized by an osmolarity of the composition of 270 mOsm/l to 450 mOsm/l.
8. The injection container according to any one of claims 1 to 7, characterized in that the composition is free of crosslinked hyaluronic acid polymers.
9. The injection container according to any one of claims 1 to 8, characterized in that the injection container is made of glass or plastic.
10. The injection container according to any one of claims 1 to 9 for use in a method for treating osteoarthritis, in particular for treating an arthritic joint, wherein the composition is injected intra-articularly into the arthritic joint.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102021126946.6A DE102021126946A1 (en) | 2021-10-18 | 2021-10-18 | Aqueous injectable composition and syringe filled with the composition |
| DE102021126946.6 | 2021-10-18 | ||
| PCT/EP2022/078815 WO2023066856A1 (en) | 2021-10-18 | 2022-10-17 | Injection container filled with an aqueous injectable composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA3233718A1 true CA3233718A1 (en) | 2023-04-27 |
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ID=84360494
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA3233718A Pending CA3233718A1 (en) | 2021-10-18 | 2022-10-17 | Injection container filled with an aqueous injectable composition |
Country Status (3)
| Country | Link |
|---|---|
| CA (1) | CA3233718A1 (en) |
| DE (1) | DE102021126946A1 (en) |
| WO (1) | WO2023066856A1 (en) |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2003529590A (en) | 2000-03-21 | 2003-10-07 | アスション デヴェロップメント エーピーエス | Chemical complex comprising pyridine carboxy derivative and H2 histamine receptor antagonist |
| FR2954165B1 (en) | 2009-12-18 | 2012-01-13 | Jean-Noel Thorel | INJECTABLE COMPOSITIONS FOR INTRA-ARTICULAR USE ASSOCIATING A VISCOSUPPLEMENTATION AGENT AND A FIBROBLAST GROWTH MEDIUM |
| WO2014026161A1 (en) * | 2012-08-10 | 2014-02-13 | Aquavit Pharmaceuticals, Inc. | Vitamin supplement compositions for injection |
| WO2014172784A1 (en) | 2013-04-25 | 2014-10-30 | Aluron Biopharma Inc. | Crosslinked hyaluronic acid compositions |
| CN113368027A (en) * | 2018-09-30 | 2021-09-10 | 白晋 | Autologous collagen hydro-acupuncture and preparation method thereof |
| CN112294668B (en) * | 2020-06-30 | 2024-04-02 | 西安博和医疗科技有限公司 | Hyaluronic acid injection |
| IT202000025264A1 (en) | 2020-10-26 | 2022-04-26 | Innate S R L | INJECTABLE COMPOSITION INCLUDING HYALURONIC ACID AND USE OF SUCH COMPOSITION. |
-
2021
- 2021-10-18 DE DE102021126946.6A patent/DE102021126946A1/en active Pending
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2022
- 2022-10-17 CA CA3233718A patent/CA3233718A1/en active Pending
- 2022-10-17 WO PCT/EP2022/078815 patent/WO2023066856A1/en active Application Filing
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| WO2023066856A1 (en) | 2023-04-27 |
| DE102021126946A1 (en) | 2023-04-20 |
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