Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
  • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
  • A61K35/36—Skin; Hair; Nails; Sebaceous glands; Cerumen; Epidermis; Epithelial cells; Keratinocytes; Langerhans cells; Ectodermal cells
• • 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
  • A61K31/7012—Compounds having a free or esterified carboxyl group attached, directly or through a carbon chain, to a carbon atom of the saccharide radical, e.g. glucuronic acid, neuraminic acid
• • 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
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

• the present invention relates to an extract from inflamed skins of rabbits inoculated with vaccinia virus wherein the quality is more stabilized by confirming by such a means of tests or inspections that it contains a predetermined amount of N-acetylneuraminic acid and also to a preparation, etc. in which the extract is an active ingredient.
• a material substance being used for the production of a drug and able to be an active ingredient of a drug is called a “drug substance”.
• a drug substance is also necessary that its quality is warranted. That is because the quality of a drug depends upon the quality of a drug substance.
• a drug substance is stipulated as a drug which is exclusively used for the manufacture of other drug and, in terms of the definition therefore, a drug substance is covered by a drug.
• a medicament and a drug substance may be sometimes separately referred to for the sake of convenience and, in such a case, the meaning of a drug shall exclude a drug substance.
• an extract from inflamed skins of rabbits inoculated with vaccinia virus (hereinafter, it will be sometimes referred to as “the present extract”) is an extract containing a non-proteinous active substance extracted and separated from the inflamed skin tissues of rabbits by the inoculation of vaccinia virus.
• the present extract is liquid in an extracted state, it is also possible to make into a solid by means of drying.
• a preparation containing the present extract as an active ingredient (hereinafter, it will be sometimes called “the present preparation”) is very useful as a drug. Since the present extract is an active ingredient of the present preparation in that case, the present extract is a drug substance of the present preparation.
• a preparation containing an extract from inflamed skins of rabbits inoculated with vaccinia virus (trade name: NEUROTROPIN [registered trade mark]; hereinafter, it will be referred to as “NTP preparation”).
• NTP preparation there are injection (hereinafter, it will be referred to as “NTP injection”) and tablet (hereinafter, it will be referred to as “NTP tablet”) and both belong to an ethical drug.
• NTP extract An extract from inflamed skins of rabbits inoculated with vaccinia virus (hereinafter, it will be referred to as “NTP extract”) which is an active ingredient of NTP preparation is a drug substance of NTP preparation.
• NTP extract is covered by the present extract while NTP preparation (NTP injection and NTP tablet) is covered by the present preparation.
• Indications of NTP injection are “low back pain, cervicobrachial syndrome, symptomatic neuralgia, itchiness accompanied by skin diseases (eczema, dermatitis, urticaria), allergic rhinitis and sequelae of subacute myelo-optico-neuropathy (SMON) such as coldness, paresthesia and pain”.
• Indications of NTP tablet are “postherpetic neuralgia, low back pain, cervicobrachial syndrome, periarthritis scapulohumeralis and osteoarthritis”. NTP preparation has been created and developed as a drug by the applicant.
• NTP preparation has been appreciated for its excellent advantage for efficacy and safety, sold for many years and established a firm position in the Japanese pharmaceutical market. At present, NTP preparation is being exported to China and sold under a trade name of “ /NEUROTROPIN”. Indications of NTP preparation in China are the same as those in Japan.
• the present preparation is very useful as a drug and the present extract is also very useful as a drug substance for the present preparation.
• the present extract is extracted and separated from the inflamed skin tissues of rabbit by the inoculation of vaccinia virus. Therefore, the present extract contains quite a lot of substances (components) and the present preparation manufactured using the present extract also contains quite a lot of substances (components). Accordingly, it is a very important matter how to control the quality of the present extract and the present preparation in a stable one.
• the present extract is an extract from inflamed skin tissues of rabbits by the inoculation of vaccinia virus and contains quite many kinds of substances. It goes without saying that the present preparation where the present extract is an active ingredient also contains quite many kinds of substances.
• Said method is a biological test method where an analgesic coefficient is determined using SART-stressed (repeated cold stressed) animals which are chronic stressed animals showing a lowered pain threshold than normal animals ( Folia Pharmacologica Japonica , vol. 72, no. 5, pages 573 to 584, 1976).
• the analgesic coefficient is determined by conducting an analgesic test according to a Randall-Selitto method using SART-stressed (repeated cold stressed) animals.
• an analgesic effect is measured using a pressure weight as an index where the pressure stimulation is applied to the tail of mouse and the mouse shows an escape reaction.
• An analgesic coefficient is a value where the pressure weight measured after administration of a drug is divided by the value before the administration.
• NTP extract and NTP preparation the case where an analgesic coefficient showed more than a predetermined value defined by the applicant is judged to be positive for an analgesic effect and the rate of the numbers of animals judged to be positive is determined and used as an analgesic efficacy rate (%). This value is used and ED 50 value is determined from the result upon measurement of standard preparation diluted to various concentrations.
• Neurotropin Unit which is a unit of biological activity (titer) using for NTP preparation by the applicant is defined that the activity of 1 mg of the present extract where the ED 50 value is the dose of 100 mg/kg is 1 Neurotropin unit. ED 50 value for each NTP preparation is measured and compared with that of the standard preparation whereupon an analgesic activity (active ingredient content) is quantitatively determined.
• unit is used as a measure of the active ingredient content (titer) of the present extract and the present preparation and it is substantially in the same meaning as “Neurotropin Unit” used for NTP extract and NTP preparation.
• the present extract and the present preparation or NTP extract and NTP preparation manufactured by the applicant are to be subjected to the following plural identity tests in addition to the above-mentioned quantification of the analgesic activity and should conform to them.
• the present extract and the present preparation manufactured by the applicant not only the above-mentioned biological activity (titer) is used for guaranteeing the appropriateness of the manufactured lots but also the following plural identity tests are carried out and adaptation thereto is used as a necessary condition for use and shipment of the present extract and the present preparation.
• amino acids, ultraviolet absorbing substances, phosphorus, nucleic acid bases, etc. which are objects of the tests are the crucial effective ingredients of the present extract and the present preparation.
• identity test for amino acids, ultraviolet absorbing substances, phosphorus and nucleic acid bases is a qualitative test which merely confirms the presence of amino acids, etc. which are objects of the tests and does not check how much amount is contained therein.
• the amount of N-acetylneuraminic acid contained in the present extract and the present preparation is measured and, when the amount is within a predetermined range, it is treated that the present extract and the present preparation as such are appropriately manufactured or, in other words, their use and shipment are permitted.
• the variations among manufacturing lots of the present extract and the present preparation are further reduced and the quality thereof becomes more stable. Further, as a result, efficacy and safety of the present extract and the present preparation are guaranteed more strictly.
• the applicant has not stipulated a standard for the amount of N-acetylneuraminic acid contained in an NTP extract and an NTP preparation manufactured up to now and has not conducted such an act that the amount is measured and that, after confirming the measured amount is within a predetermined range, the corresponding NTP extract and NTP preparation are used, shipped, etc.
• Patent Documents 1 to 3 are available. Those documents disclose the content of amino acids and nucleic acid bases in the present extract or the present preparation. Further, with regard to the present extract or the present preparation, there is a disclosure for the content of silicons in Patent Document 4. However, in those Patent Documents 1 to 4, there is no disclosure at all how much a specific substance which is N-acetylneuraminic acid is contained in the present extract or the present preparation. It further goes without saying that, in those documents, there is neither disclosure nor suggestion at all to adopt the content of N-acetylneuraminic acid in the present extract or the present preparation as an index for the quality control of the present extract or the present preparation in more a stable manner.
• Patent Document 1 Chinese Patent Laid-Open No. CN 1205233A
• Patent Document 2 International Publication No. WO 2004/060381
• Patent Document 3 Chinese Patent Laid-Open No. CN 1613305A
• Patent Document 4 Japanese Patent Laid-Open No. Patent 07/097336
• the present invention is to warrant the quality of the present extract and the present preparation using the amount of N-acetylneuraminic acid contained in the present extract and the present preparation as an index.
• the present invention is to provide the present extract, the present preparation, etc. which are surely manufactured in an appropriate manner by means of confirmation of containing a stipulated amount of N-acetylneuraminic acid.
• the present extract and the present preparation in accordance with the present invention are such ones which contain predetermined amounts of N-acetylneuraminic acid. As a result thereof, it is possible to treat that the present extract and the present preparation in accordance with the present invention are appropriately manufactured.
• the present invention contributes in such a matter that the quality of the present extract and the present preparation is warranted in a more stable manner and efficacy and safety of the present extract and the present preparation become more constant.
• N-Acetylneuraminic acid is a kind of sialic acid.
• Sialic acid is a generic name for acyl derivatives of neuraminic acid. Although there are many kinds of sialic acids in nature, N-acetylneuraminic acid is the most abundant one among them and the next abundant one is N-glycolylneuraminic acid. Sialic acid is widely distributed in living bodies as a constituting component of glycoprotein, glycolipid, glycopeptide, etc. and it is particularly present on the cell membrane surface of animals or bacteria and plays an important role of biological functions such as participation in specific recognition mechanism of cells.
• Sialic acid is also considered to be important in medical and pharmaceutical viewpoints as a substance participating in cancer, inflammation, immune, viral infection, cell differentiation, hormone receptors, etc.
• Various studies have been conducted for sialic acid-containing biological components and also for sialic acid and derivatives thereof.
• N-acetylneuraminic acid With regard to said sialic acid and particularly to N-acetylneuraminic acid, the applicant has quite surprisingly found that said substance has an analgesic action and particularly an effect for non-inflammatory pain diseases such as neuropathic pain disease and, on the basis of such a finding, the applicant obtained patents (Japanese Patent No. 4005115 and Chinese Patent Publication No. CN 101600438B). Since the characteristic of NTP preparation manufactured and distributed by the applicant is also a treating effect for neuropathic pain disease, etc., N-acetylneuraminic acid is a rational substance (component) as an index for a strict control of the quality of the present extract and the present preparation in a more stable manner.
• the present extract can be prepared by such a manner that inflamed skin tissues of rabbits by the inoculation of vaccinia virus are collected, crushed and processed by adding an extraction solvent thereto, tissue fragments are removed therefrom, a treatment for removal of protein (deproteinization) is carried out, the resulting one is adsorbed with an adsorbent under an acidic condition and then an active ingredient is eluted under a basic condition therefrom.
• Vaccinia virus used herein may be in any strain. Examples thereof include Lister strain, Dairen strain, Ikeda strain, EM-63 strain and New York City Board of Health strain.
• any rabbit may be used so far as it belongs to Lagomorpha.
• Examples thereof include Oryctolagus cuniculus , domestic rabbit (domesticated Oryctolagus cuniculus ), hare (Japanese hare), mouse hare and snowshoe hare.
• it is appropriate to use domestic rabbit.
• Korean family rabbit called “Kato” which has been bred since old time and frequently used as livestock or experimental animal and it is another name of domestic rabbit.
• There are many breeds in domestic rabbit and the breeds being called Japanese white and New Zealand white are advantageously used.
• the inflamed skin tissues of rabbits by the intradermal inoculation of vaccinia virus are collected.
• the collected skin tissues are washed and disinfected using a phenol solution, etc.
• This inflamed skin tissues are crushed and an extraction solvent in 1- to 5-fold thereof by volume is added thereto.
• the term “crush” means to finely break down into minces using a mincing machine or the like.
• the extraction solvent there may be used distilled water, physiological saline, weakly acidic to weakly basic buffer, etc. and bactericidal/antiseptic agent such as phenol, stabilizer such as glycerin, salts such as sodium chloride, potassium chloride or magnesium chloride, etc. may be appropriately added thereto.
• the cell tissue is destroyed by a treatment such as freezing/melting, ultrasonic wave, cell membrane dissolving enzyme or surfactant so as to make the extraction easier.
• the resulting suspension is allowed to stand for 5 to 12 days. During that period, the suspension may be heated at 30 to 45° C. with or without appropriate stirring.
• the resulting liquid is subjected to a treatment for separating into solid and liquid (filtered or centrifuged, etc.) to remove the tissue fragments whereupon a crude extract (filtrate or supernatant) is obtained.
• the crude extract obtained in (A) is subjected to a deproteinizing treatment.
• the deproteinization may be carried out by a known method which has been usually conducted and a method such as heating treatment, treatment with a protein denaturant (such as acid, base, urea, guanidine or an organic solvent including acetone), isoelectric precipitation or salting-out may be applied.
• a protein denaturant such as acid, base, urea, guanidine or an organic solvent including acetone
• isoelectric precipitation or salting-out may be applied.
• a common method for the removal of insoluble matters such as filtration using filter paper (such as cellulose or nitrocellulose), glass filter, Celite or Seitz filter, ultrafiltration or centrifugation is conducted to give a filtrate or a supernatant wherefrom the separated insoluble protein is removed.
• the filtrate or supernatant obtained in (B) is adjusted to acidic or, preferably, to pH 3.5 to 5.5 to conduct an operation of adsorbing with an adsorbent.
• the usable adsorbent include activated carbon and kaolin.
• An adsorbent is added to the extract followed by stirring or the extract is passed through a column filled with an adsorbent so that the active ingredient can be adsorbed with the adsorbent.
• the adsorbent with which the active ingredient is adsorbed can be obtained by means of filtration, centrifugation, etc. to remove the solution.
• an elution solvent is added to said adsorbent and adjusted to basic or, preferably, to pH 9 to 12, elution is conducted at room temperature or with suitable heating, or with stirring, and then the adsorbent is removed by a common method such as filtration or centrifugation.
• the extraction solvent used there may be used a basic solvent such as water, methanol, ethanol, isopropanol or the like adjusted to basic pH or an appropriate mixed solvent thereof and preferably, water adjusted to pH 9 to 12 may be used. Amount of the extracting solvent may be appropriately set.
• the pH is appropriately adjusted to nearly neutral or the like whereby an extract from inflamed skins of rabbits inoculated with vaccinia virus (the present extract) can be finally obtained.
• the present extract is liquid at the stage of being prepared, it is also possible that said extract is appropriately concentrated or diluted to make into a desired concentration.
• a preparation is manufactured from the present extract, it is preferred to apply a sterilizing treatment with heating.
• For making into an injection preparation it is possible to add sodium chloride or the like so as to prepare a solution being isotonic to physiological saline.
• the present extract in a liquid state is subjected to an appropriate operation such as concentration to dryness whereby a solid preparation for oral administration such as tablet is manufactured.
• Specific methods for the manufacture of solid preparation for oral administration from the present extract are disclosed in the specifications of Japanese Patent Nos. 3,818,657 and 4,883,798.
• the present preparation includes an injection preparation, a solid preparation for oral administration, etc. prepared as such.
• the content of N-acetylneuraminic acid in the present extract and the present preparation can be measured by the usual quantifying method.
• a measuring method using liquid chromatograph mass spectrometer (LC-MS) or capillary electrophoretic mass spectrometer (CE-MS) a fluorescence labeling method using DMB (1,2-diamino-4,5-methylenedioxybenzene) and an enzymatic method.
• LC-MS liquid chromatograph mass spectrometer
• CE-MS capillary electrophoretic mass spectrometer
• DMB 1,2-diamino-4,5-methylenedioxybenzene
• the content of N-acetylneuraminic acid contained in the present extract and the present preparation manufactured by the applicant was measured by the above methods. As a result, although there were some scatters, the present extract and the present preparation contained 4000 ng or more of N-acetylneuraminic acid per unit. To be more specific, the present extract and the present preparation contained 4000 to 18000 ng of N-acetylneuraminic acid per unit. Accordingly, when quality of the present extract and the present preparation is controlled using the content of N-acetylneuraminic acid in the present extract and the present preparation as an index, it was judged to be possible to adopt the content as such as a standard. In the meanwhile, when variations happened in the method for the manufacture of the present extract and the present preparation, the applicant confirmed that the content of N-acetylneuraminic acid per unit may be lower than 4000 ng.
• the term “per unit” used herein means per the content of the active ingredient in the present extract and the present preparation.
• the present extract (NTP extract) manufactured by the applicant contains 1.2 units/mL of the active ingredient.
• the present preparation for injection (NTP injection) manufactured using the same also contains 1.2 unit/mL of the active ingredient.
• NTP injection the injection where the volume is 3 mL and 1 mL are available. Accordingly, a preparation of 3 mL contains 3.6 units of the active ingredient and a preparation of 1 mL contains 1.2 units of the active ingredient.
• the present preparation for oral administration (NTP tablet) manufactured by the applicant contains 4 units of the active ingredient per tablet.
• the present extract may be concentrated or diluted. Further, the present preparation containing various units may be also manufactured. In such cases, the amount of the active ingredient contained in a unit amount (such as per mL, per mg, per ampoule, per tablet, etc.) of the present extract and the present preparation may also vary. Therefore, it is basically meaningful that the content of N-acetylneuraminic acid is stipulated in relation to the amount of the active ingredient of the present extract and the present preparation. That is because such a thing is connected to the relation to efficacy and safety of the present extract or the present preparation. Accordingly, the applicant stipulated the content of N-acetylneuraminic acid in the present extract and the present preparation in terms of “per the content of the active ingredient” (“per unit”). On the other hand, since the applicant actually manufactures and distributes NTP preparation, it is also certainly meaningful to stipulate per mL or per ampoule of the specific injection or to stipulate per tablet in relation to the dose whereby such stipulation was also adopted.
• NTP injection there are generic drugs or similar drugs (hereinafter, they will be referred to as “other company's injections”) manufactured by the companies other than the applicant's company (hereinafter, they will be referred to as “other companies”) in Japan and in China.
• other company's injections an extract from inflamed skins of rabbits inoculated with vaccinia virus (the present extract) which is an active ingredient is also quantitatively determined by using its analgesic effect as an index using SART stress mice.
• the content of the active ingredient in other company's injections is merely mentioned as “unit” in plural other company's injections in Japan which are “ROSEMORGEN Inj.” (registered trade mark), “NABUTOPIN Inj.” (registered trade mark) and “NOLPORT Inj.” (registered trade mark), or is mentioned as “Analgecine unit” or “AGC unit” in one other company's injection in China which is “ /ANALGECINE” (registered trade mark).
• the content of the active ingredient is 1.2 units or 1.2 Analgecine (1.2 AGC) units per mL or 3.6 units or 3.6 Analgecine (3.6 AGC) units per ample of 3 mL preparation.
• the “Neurotropin unit” used by NTP preparation and the “unit” or “Analgecine unit” used by other companies are the same measure for stipulating the content of the active ingredient, and they are different just in terms of the expression. Under such circumstances, “unit” is used in the present application in expressing the content of the present extract which is an active ingredient not only for NTP preparation but also for all other company's injections.
• the present preparation in the present application is a conception including NTP preparation (NTP injection and NTP tablet) and other company's injections.
• NTP preparation NTP injection and NTP tablet
• other company's tablets other company's tablets
• the above conception also covers other company's tablets as such.
• the resulting deproteinized solution was adjusted to pH 4.0 to 4.3 with hydrochloric acid, activated carbon in an amount of 2% to the mass of the deproteinized solution was added thereto and the mixture was stirred for 2 hours and subjected to the solid-liquid separation.
• Water was added to the collected activated carbon followed by adjusting to pH 9.5 to 10 with sodium hydroxide and the mixture was stirred at 60° C. for 90 to 100 minutes and centrifuged to give a supernatant.
• Water was added again to the activated carbon precipitated upon the centrifugation followed by adjusting to pH 10.5 to 11 with sodium hydroxide and the mixture was stirred at 60° C. for 90 to 100 minutes and centrifuged to give a supernatant. Both supernatants were combined and neutralized with hydrochloric acid to give the present extract.
• the content of N-acetylneuraminic acid in the present extract and the present preparation was measured as follows using a high-performance liquid chromatographic mass spectrometer (LC-MS).
• the present extract (1.2 units/mL) manufactured according to Example 1 was diluted with water to an extent of 10-fold and injected into the LC-MS.
• the present preparation (NTP injection) manufactured using the present extract which was manufactured according to Example 1 was also diluted with water to an extent of 10-fold and injected into the LC-MS.
• NTP tablet manufactured using the present extract which was manufactured according to Example 1, three tablets thereof were washed with 3 mL of methanol/chloroform (1:1) for three times to remove the film coat layer, dried, suspended in 12 mL of water (1 unit/mL). After centrifugation of the suspension, the supernatant was diluted with water to an extent of 10-fold and injected into the LC-MS.
• N-acetylneuraminic acid a standard solution in an aqueous solution was prepared and a calibration curve was produced.
• Injection amount 5 ⁇ L; temperature set for the sample chamber: 4° C.
• N-acetylneuraminic acid (Identification No.) (ng/unit) (ng/mL) (ng/ampoule) NTP injection (NI01) 7450 8940 26800 NTP injection (NI02) 8420 10100 30300 NTP injection (NI03) 6540 7850 23600 NTP injection (NI04) 9500 11400 34200 NTP injection (NI05) 9580 11500 34500 NTP injection (NI06) 10400 12500 37500 Mean 8650 10400 31200
• NTP tablet (NT01) 12600 50400 NTP tablet (NT02) 4780 19100 NTP tablet (NT03) 10500 42000 NTP tablet (NT04) 8700 34800 NTP tablet (NT05) 10200 40800 NTP tablet (NT06) 9840 39400 NTP tablet (NT07) 9650 38600 NTP tablet (NT08) 8950 35800 NTP tablet (NT09) 9490 38000 NTP tablet (NT10) 7740 31000 NTP tablet (NT11) 8090 32400 NTP tablet (NT12) 9380 37500 NTP tablet (NT13) 6990 28000 Mean 8990 36000
• N-acetylneuraminic acid was contained in an amount of not less than 4000 ng/unit (Tables 2 to 4). Further, in the present extract and the present preparation manufactured by the applicant, N-acetylneuraminic acid was contained within a range of 4000 to 22500 ng/unit. On the contrary, among the present preparation manufactured by other companies, none of them contained such a high amount of N-acetylneuraminic acid (Table 5). Although it is not clear what is the cause for the difference in the contents of N-acetylneuraminic acid in the present preparation manufactured by each of the companies, it is strongly presumed to be caused by the difference in the manufacturing method for the present preparation in each company.
• N-acetylneuraminic acid has an analgesic action or, particularly, an effect for non-inflammatory pain diseases such as neuropathic pain disease whereby the applicant understands that the fact itself that this substance (component) is contained in more amount in the present preparation (NTP injection) manufactured by the applicant as compared with the injections by other companies constitutes the characteristic and is a favorable characteristic.
• N-acetylneuraminic acid is contained in the present extract and the present preparation.
• N-acetylneuraminic acid is contained within a range of 4000 to 15000 ng/unit in the present extract and the present preparation.
• N-acetylneuraminic acid is contained within a range of 4000 to 22500 ng/unit when the content of N-acetylneuraminic acid in the present extract and the present preparation is measured by a measuring method using other dilution ratio such as 50-fold dilution or 250-fold dilution with water (hereinafter, it will be referred to as a “different dilution method”) instead of 10-fold dilution method where the dilution ratio with water is 10-fold.
• a different dilution method such as 50-fold dilution or 250-fold dilution with water
• the present injection As the injection containing 1.2 units per mL (hereinafter, it will be referred to as “the present injection”) among the present preparation, it constitutes the characteristic of the present injection that not less than 4800 ng/mL of N-acetylneuraminic acid is contained therein. Similarly, it constitutes the characteristic of the present injection that, when measurement is done by the 10-fold dilution method, N-acetylneuraminic acid is contained within a range of 4800 to 18000 ng/mL.
• N-acetylneuraminic acid is contained within a range of 4800 to 27000 ng/mL.
• the present injection is that filled with 3 mL volume in an ampoule (hereinafter, the present injection as such will be referred to as “the present injection of 3 mL ampoule”)
• the present injection of 3 mL ampoule it constitutes the characteristic of the present injection of 3 mL ampoule that N-acetylneuraminic acid is contained in an amount of not less than 14400 ng per ampoule.
• N-acetylneuraminic acid is contained within the range of 14400 to 54000 ng/ampoule. It constitutes the characteristic of the present injection of 3 mL ampoule that, when the content of N-acetylneuraminic acid in the present injection of 3 mL ampoule is measured by a different dilution method, N-acetylneuraminic acid is contained within the range of 14400 to 81000 ng/ampoule. The reason why the upper limit hereinabove is 1.5 times more as compared with the case of the 10-fold dilution method will be also mentioned later.
• the present tablet As “the present tablet”) among the present preparation, it constitutes the characteristic of the present tablet that not less than 16000 ng/tablet of N-acetylneuraminic acid is contained therein. Similarly, it constitutes the characteristic of the present tablet that, when measurement is done by the 10-fold dilution method, N-acetylneuraminic acid is contained within the range of 16000 to 60000 ng/tablet.
• N-acetylneuraminic acid is contained within the range of 16000 to 90000 ng/tablet.
• the content of N-acetylneuraminic acid contained in the present extract and the present preparation is measured so as to confirm whether the present extract and the present preparation are appropriately manufactured whereby the quality thereof is controlled.
• the content of N-acetylneuraminic acid contained in the present extract and the present preparation is measured and, if it is found to be 4000 ng/unit or more, that is evaluated as being appropriately manufactured.
• the present extract and the present preparation are appropriately manufactured by means of such a confirmation that, when the content of N-acetylneuraminic acid contained in the present extract and the present preparation is measured by the 10-fold dilution method or by different dilution methods and is found to be within the range of 4000 to 15000 ng/unit or 4000 to 22500 ng/unit, respectively.
• the present injection it can be judged that the present injection is appropriately manufactured when the content of N-acetylneuraminic acid contained in the present injection is measured and is found to be 4800 ng/mL or more. It is further possible to judge that the present injection is appropriately manufactured by measuring the content of N-acetylneuraminic acid contained in the present injection by a 10-fold dilution method or by a different dilution method and by confirming to be within the range of 4800 to 18000 ng/unit or 4800 to 27000 ng/unit, respectively.
• the 3 mL ampoule injection is appropriately manufactured when the content of N-acetylneuraminic acid contained therein is measured and is found to be 14400 ng/mL or more or when it is within the range of 14400 to 54000 ng/unit or within the range of 14400 to 81000 ng/mL in the case of measurement by a 10-fold dilution method or by a different dilution method, respectively.
• the present tablet it can be evaluated that, when the content of N-acetylneuraminic acid contained in the present tablet is measured and is found to be 16000 ng/tablet or more, the said tablet is judged to be appropriately manufactured. It is further possible that, when the content of N-acetylneuraminic acid contained in the present tablet is measured by a 10-fold dilution method or by a different dilution method and is confirmed to be within the range of 16000 to 60000 ng/unit or 16000 to 90000 ng/tablet, respectively, then the said present tablet is judged to be appropriately manufactured.
• the content of N-acetylneuraminic acid is measured by means of LC-MS, and N-acetylneuraminic acid is apt to be affected by impurity ions (ion suppression).
• the present inventors measure a sample of the present extract, etc. after diluting to an extent of 10-fold but, when diluted to an extent of 50-fold or 250-fold, higher values were sometimes noted than the measured values in the case of the 10-fold dilution. It is likely that such a phenomenon is due to the fact that, in case the dilution degree is high, the affection by the concentration of impurity ions lowers.
• N-acetylneuraminic acid ng/unit
• ng/unit ng/unit
• ng/unit 10-fold 50-fold 250-fold
• Identification No. dilution dilution dilution or Lot No. sample sample sample A01 9920 10400 9830 A01 9670 10700 9750 A02 5980 6210 6460 B09 12000 13300 12700 B10 11700 13200 13900 C24 7420 8030 8100 C25 8670 10200 9750 NTP injection (NI04) 9500 12200 11300 NTP injection (NI05) 9580 12500 11400 NTP injection (NI06) 10400 13500 13800 NTP tablet (NT03) 10500 14100 12000 NTP tablet (NT04) 8700 12300 11200 NTP tablet (NT05) 10200 13900 13000 NTP tablet (NT06) 9840 13200 12300 NTP tablet (NT07) 9650 12300 11600 NTP tablet (NT08) 8950 11400 10700 NTP tablet (NT09) 9490 12000 11900
• the following inventions can be induced as the present invention although those are mere exemplification and the present invention is not limited thereto.
• the passage reading “by measuring the amount of N-acetylneuraminic acid” is usually used in such a meaning that the amount of N-acetylneuraminic acid is measured for each manufacturing lot of the present extract or the present preparation.
• the extract from inflamed skins of rabbits inoculated with vaccinia virus which is judged to be appropriately manufactured by such means that the amount of N-acetylneuraminic acid contained in the extract is measured and the content is confirmed to be 4000 ng or more per unit of the extract.
• the extract from inflamed skins of rabbits inoculated with vaccinia virus which is judged to be appropriately manufactured by such means that the amount of N-acetylneuraminic acid contained in the extract is measured and the content is confirmed to be 4000 to 22500 ng per unit of the extract.
• the preparation containing an extract from inflamed skins of rabbits inoculated with vaccinia virus which is judged to be appropriately manufactured by such means that the amount of N-acetylneuraminic acid contained in the preparation is measured and the content is confirmed to be 4000 ng or more per unit of the extract from inflamed skins of rabbits inoculated with vaccinia virus in the preparation.
• the preparation containing an extract from inflamed skins of rabbits inoculated with vaccinia virus which is judged to be appropriately manufactured by such means that the amount of N-acetylneuraminic acid contained in the preparation is measured and the content is confirmed to be 4000 ng to 22500 ng per unit of the extract from inflamed skins of rabbits inoculated with vaccinia virus in the preparation.
• the preparation containing an extract from inflamed skins of rabbits inoculated with vaccinia virus which is shipped by being judged to be appropriately manufactured by such means that the amount of N-acetylneuraminic acid contained in the preparation is measured and the content is confirmed to be 4000 ng or more per unit of the extract from inflamed skins of rabbits inoculated with vaccinia virus in the preparation.
• a preparation containing an extract from inflamed skins of rabbits inoculated with vaccinia virus the preparation containing an extract from inflamed skins of rabbits inoculated with vaccinia virus which is shipped by being judged to be appropriately manufactured by such means that the amount of N-acetylneuraminic acid contained in the preparation is measured and the content is confirmed to be 4000 to 22500 ng per unit of the extract from inflamed skins of rabbits inoculated with vaccinia virus in the preparation.
• the injection preparation containing an extract from inflamed skins of rabbits inoculated with vaccinia virus which is judged to be appropriately manufactured by such means that the amount of N-acetylneuraminic acid contained in the injection preparation is measured and the content is confirmed to be 4800 ng or more per mL of the injection preparation.
• the injectable preparation containing an extract from inflamed skins of rabbits inoculated with vaccinia virus which is judged to be appropriately manufactured by such means that the amount of N-acetylneuraminic acid contained in the injection preparation is measured and the content is confirmed to be 4800 to 27000 ng per mL of the injectable preparation.
• the injectable preparation containing an extract from inflamed skins of rabbits inoculated with vaccinia virus which is shipped after being judged to be appropriately manufactured by such means that the amount of N-acetylneuraminic acid contained in the injectable preparation is measured and the content is confirmed to be 4800 ng or more per mL of the injectable preparation.
• the injectable preparation containing an extract from inflamed skins of rabbits inoculated with vaccinia virus which is shipped after being judged to be appropriately manufactured by such means that the amount of N-acetylneuraminic acid contained in the injectable preparation is measured and the content is confirmed to be 4800 to 27000 ng per mL of the injectable preparation.
• the injectable preparation containing an extract from inflamed skins of rabbits inoculated with vaccinia virus which is shipped after complying with the standard that the amount of N-acetylneuraminic acid contained in the injectable preparation is measured and the content is 4800 ng or more per mL of the injectable preparation.
• the injectable preparation containing an extract from inflamed skins of rabbits inoculated with vaccinia virus which is shipped after complying with the standard that the amount of N-acetylneuraminic acid contained in the injectable preparation is measured and the content is 4800 to 27000 ng per mL of the injectable preparation.
• the 3 mL injectable preparation containing an extract from inflamed skins of rabbits inoculated with vaccinia virus which is judged to be appropriately manufactured by such means that the amount of N-acetylneuraminic acid contained in the injectable preparation is measured and the content is confirmed to be 14400 ng or more per ampoule of the injectable preparation.
• the 3 mL injectable preparation containing an extract from inflamed skins of rabbits inoculated with vaccinia virus which is judged to be appropriately manufactured by such means that the amount of N-acetylneuraminic acid contained in the injectable preparation is measured and the content is confirmed to be 14400 to 81000 ng per ampoule of the injectable preparation.
• the 3 mL injectable preparation containing an extract from inflamed skins of rabbits inoculated with vaccinia virus which is shipped after being judged to be appropriately manufactured by such means that the amount of N-acetylneuraminic acid contained in the injectable preparation is measured and the content is confirmed to be 14400 to 81000 ng per ampoule of the injectable preparation.
• the tablet containing an extract from inflamed skins of rabbits inoculated with vaccinia virus which is judged to be appropriately manufactured by such means that the amount of N-acetylneuraminic acid contained in the tablet is measured and the content is confirmed to be 16000 ng or more per tablet.
• a tablet containing an extract from inflamed skins of rabbits inoculated with vaccinia virus the tablet containing an extract from inflamed skins of rabbits inoculated with vaccinia virus which is judged to be appropriately manufactured by such means that the amount of N-acetylneuraminic acid contained in the tablet is measured and the content is confirmed to be 16000 to 90000 ng per tablet.
• the tablet containing an extract from inflamed skins of rabbits inoculated with vaccinia virus which is shipped after being judged to be appropriately manufactured by such means that the amount of N-acetylneuraminic acid contained in the tablet is measured and the content is confirmed to be 16000 to 90000 ng per tablet.
• the preparation containing an extract from inflamed skins of rabbits inoculated with vaccinia virus where the amount of N-acetylneuraminic acid contained in the preparation is measured and the content is confirmed to be 4000 ng or more per unit of the extract from inflamed skins of rabbits inoculated with vaccine virus in the preparation.
• the preparation containing an extract from inflamed skins of rabbits inoculated with vaccinia virus where the amount of N-acetylneuraminic acid contained in the preparation is measured and the content is confirmed to be 4000 to 22500 ng per unit of the extract from inflamed skins of rabbits inoculated with vaccine virus in the preparation.
• the injectable preparation containing an extract from inflamed skins of rabbits inoculated with vaccinia virus where the amount of N-acetylneuraminic acid contained in the injectable preparation is measured and the content is confirmed to be 4800 ng or more per mL of the injectable preparation.
• the injectable preparation containing an extract from inflamed skins of rabbits inoculated with vaccinia virus where the amount of N-acetylneuraminic acid contained in the injectable preparation is measured and the content is confirmed to be 4800 to 27000 ng per mL of the injectable preparation.
• a tablet containing an extract from inflamed skins of rabbits inoculated with vaccinia virus the tablet containing an extract from inflamed skins of rabbits inoculated with vaccinia virus where the amount of N-acetylneuraminic acid contained in the tablet is measured and the content is confirmed to be 16000 to 90000 ng per tablet.
• the preparation containing an extract from inflamed skins of rabbits inoculated with vaccinia virus where the amount of N-acetylneuraminic acid contained in the preparation before shipping is measured and the content is confirmed to be 4000 ng or more per unit of the extract from inflamed skins of rabbits inoculated with vaccine virus in the preparation.
• the injectable preparation containing an extract from inflamed skins of rabbits inoculated with vaccinia virus containing an extract from inflamed skins of rabbits inoculated with vaccinia virus where the amount of N-acetylneuraminic acid contained in the injectable preparation before shipping is measured and the content is confirmed to be 4800 ng or more per mL of the injectable preparation.
• the injectable preparation containing an extract from inflamed skins of rabbits inoculated with vaccinia virus where the amount of N-acetylneuraminic acid contained in the injectable preparation before shipping is measured and the content is confirmed to be 4800 to 27000 ng per mL of the injectable preparation.
• a tablet containing an extract from inflamed skins of rabbits inoculated with vaccinia virus the tablet containing an extract from inflamed skins of rabbits inoculated with vaccinia virus where the amount of N-acetylneuraminic acid contained in the tablet before shipping is measured and the content is confirmed to be 16000 ng or more per tablet.
• a tablet containing an extract from inflamed skins of rabbits inoculated with vaccinia virus the tablet containing an extract from inflamed skins of rabbits inoculated with vaccinia virus where the amount of N-acetylneuraminic acid contained in the tablet before shipping is measured and the content is confirmed to be 16000 to 90000 ng per tablet.
• (61) A method for inspection where the amount of N-acetylneuraminic acid contained in a preparation which contains an extract from inflamed skins of rabbits inoculated with vaccinia virus is measured and, when the content is 4000 to 22500 ng per unit of the extract from inflamed skins of rabbits inoculated with vaccinia virus in the preparation, manufacture of the extract is judged to be appropriately conducted.
• a method for controlling the manufacture of a preparation containing an extract from inflamed skins of rabbits inoculated with vaccinia virus where, when the amount of N-acetylneuraminic acid contained in the preparation is 4000 to 22500 ng per unit of the extract in the preparation, manufacture of the preparation is judged to be appropriately conducted.
• a method for controlling the manufacture of an injectable preparation containing an extract from inflamed skins of rabbits inoculated with vaccinia virus where, when the amount of N-acetylneuraminic acid contained in the injectable preparation is 4800 to 27000 ng per mL of the injectable preparation, manufacture of the injectable preparation is judged to be appropriately conducted.
• a method for controlling the manufacture of a 3 mL injectable preparation containing an extract from inflamed skins of rabbits inoculated with vaccinia virus where, when the amount of N-acetylneuraminic acid contained in the 3 mL injectable preparation is 14400 ng or more per ampoule of the injectable preparation, manufacture of the injectable preparation is judged to be appropriately conducted.
• a method for shipping a preparation containing an extract from inflamed skins of rabbits inoculated with vaccinia virus where amount of N-acetylneuraminic acid contained in the preparation is measured and, when the content is confirmed to be 4000 ng or more per unit of the extract from inflamed skins of rabbits inoculated with vaccinia virus, the preparation is judged to be appropriately manufactured and is judged to be able to be shipped.
• a method for shipping a preparation containing an extract from inflamed skins of rabbits inoculated with vaccinia virus where amount of N-acetylneuraminic acid contained in the preparation is measured and, when the content is confirmed to be 4000 to 22500 ng per unit of the extract from inflamed skins of rabbits inoculated with vaccinia virus, the preparation is judged to be appropriately manufactured and is judged to be able to be shipped.
• a method for shipping an injectable preparation containing an extract from inflamed skins of rabbits inoculated with vaccinia virus where amount of N-acetylneuraminic acid contained in the injectable preparation is measured and, when the content is confirmed to be 4800 ng or more per mL of the injectable preparation, the injectable preparation is judged to be appropriately manufactured and is judged to be able to be shipped.
• the preparation where the variations in the effect of the preparation among the manufacturing lots are reduced by such a means that the amount of N-acetylneuraminic acid contained in the preparation is measured for each manufacturing lot and the content is confirmed to be 4000 ng or more per unit of the extract from inflamed skins of rabbits inoculated with vaccinia virus in the preparation.
• the preparation where the variations in the effect of the preparation among the manufacturing lots are reduced by such a means that the amount of N-acetylneuraminic acid contained in the preparation is measured for each manufacturing lot and the content is confirmed to be 4000 to 22500 ng per unit of the extract from inflamed skins of rabbits inoculated with vaccinia virus in the preparation.
• the injectable preparation where the variations in the effect of the injectable preparation among the manufacturing lots are reduced by such a means that the amount of N-acetylneuraminic acid contained in the injectable preparation is measured for each manufacturing lot and the content is confirmed to be 4800 ng or more per mL of the injectable preparation.
• the injectable preparation where the variations in the effect of the injectable preparation among the manufacturing lots are reduced by such a means that the amount of N-acetylneuraminic acid contained in the injectable preparation is measured for each manufacturing lot and the content is confirmed to be 4800 to 27000 ng per mL of the injectable preparation.
• (111) A method for manufacturing a 3 mL injectable preparation containing an extract from inflamed skins of rabbits inoculated with vaccinia virus in which the variations in the effect of the injectable preparation among manufacturing lots are reduced, wherein it is judged that manufacture of the 3 mL injectable preparation is appropriately conducted in such a case that the amount of N-acetylneuraminic acid contained in the injectable preparation is measured for each manufacturing lot and that the content is 14400 ng or more per ampoule of the injection.
• (140) A method for shipping an injectable preparation containing an extract from inflamed skins of rabbits inoculated with vaccinia virus in which variations of the effect of the injectable preparation among the manufacturing lots are reduced, wherein the amount of N-acetylneuraminic acid contained in the injectable preparation is measured for each manufacturing lot and, in case the content is confirmed to be 4800 to 27000 ng per mL of the injectable preparation, the injectable preparation is judged to be appropriately manufactured.
• (141) A method for shipping a 3 mL injectable preparation containing an extract from inflamed skins of rabbits inoculated with vaccinia virus in which variations of the effect of the 3 mL injectable preparation among the manufacturing lots are reduced, wherein the amount of N-acetylneuraminic acid contained in the injectable preparation is measured for each manufacturing lot and, in case the content is confirmed to be 14400 ng or more per ampoule of the injectable preparation, the injectable preparation is judged to be appropriately manufactured.
• the present invention provides an extract from inflamed skins of rabbits inoculated with vaccinia virus or a preparation containing the extract which is deemed to be appropriately manufactured by such a means that the content of N-acetylneuraminic acid is measured so that the fact of containing a predetermined amount therein is confirmed.
• the present invention also provides an inspection method by which the extract and the preparation is deemed to be appropriately manufactured by means of confirming that each manufacturing lot of the extract contains a predetermined amount of N-acetylneuraminic acid. Since the extract and the preparation as such are manufactured using biological tissues, it is now possible to warrant the quality thereof for each lot in more strictly whereby that is very useful.

Landscapes

• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Engineering & Computer Science (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Cell Biology (AREA)
• Biomedical Technology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Dermatology (AREA)
• Immunology (AREA)
• Molecular Biology (AREA)
• Biotechnology (AREA)
• Developmental Biology & Embryology (AREA)
• Zoology (AREA)
• Virology (AREA)
• Neurosurgery (AREA)
• Neurology (AREA)
• Pain & Pain Management (AREA)
• Rheumatology (AREA)
• Physical Education & Sports Medicine (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines Containing Material From Animals Or Micro-Organisms (AREA)
• Hematology (AREA)
• Urology & Nephrology (AREA)
• Medicinal Preparation (AREA)
• Microbiology (AREA)
• Physics & Mathematics (AREA)
• Analytical Chemistry (AREA)
• Biochemistry (AREA)

Applications Claiming Priority (5)

Related Parent Applications (1)

Related Child Applications (1)

Publications (1)

Family

ID=49359802

Family Applications (2)

Family Applications After (1)

Country Status (10)

Families Citing this family (5)

Family Cites Families (13)

• 2013
  • 2013-05-28 CN CN201310202596.9A patent/CN103357006B/zh active Active
  • 2013-10-09 US US14/434,653 patent/US20150265655A1/en not_active Abandoned
  • 2013-10-09 CN CN201610519048.2A patent/CN106074607A/zh active Pending
  • 2013-10-09 KR KR1020157007421A patent/KR102131025B1/ko active IP Right Grant
  • 2013-10-09 IN IN3169DEN2015 patent/IN2015DN03169A/en unknown
  • 2013-10-09 TW TW102136477A patent/TWI594757B/zh active
  • 2013-10-09 CA CA2887117A patent/CA2887117C/en active Active
  • 2013-10-09 EP EP13845181.0A patent/EP2910249B1/en active Active
  • 2013-10-09 CN CN201380052290.8A patent/CN104703613B/zh active Active
  • 2013-10-09 CN CN201610519050.XA patent/CN106109498B/zh active Active
  • 2013-10-09 WO PCT/JP2013/077534 patent/WO2014057995A1/ja active Application Filing
  • 2013-10-09 AU AU2013327849A patent/AU2013327849B2/en active Active
• 2015
  • 2015-12-18 HK HK15112491.2A patent/HK1211496A1/zh unknown
• 2018
  • 2018-12-06 US US16/211,831 patent/US11529374B2/en active Active

Also Published As

Similar Documents

Legal Events