CN105037361A - Doxofylline compound and medicine composition thereof - Google Patents
Doxofylline compound and medicine composition thereof Download PDFInfo
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- CN105037361A CN105037361A CN201510323278.7A CN201510323278A CN105037361A CN 105037361 A CN105037361 A CN 105037361A CN 201510323278 A CN201510323278 A CN 201510323278A CN 105037361 A CN105037361 A CN 105037361A
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- doxofylline
- compound
- injection
- degrees
- tablet
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
-
- 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
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention belongs to the technical field of medicines and in particular provides a doxofylline compound and a medicine composition thereof. Characteristic peaks of X-ray powder diffraction, measured by using a Gu-Kalpha ray, of the doxofylline compound are shown at 31.1 degrees, 32 degrees, 34.3 degrees, 37.5 degrees, 41.3 degrees, 43 degrees, 53.8 degrees, 56.5 degrees, 58 degrees and 62.5 degrees. The melting point of the doxofylline compound is 136-137 DEG C. The doxofylline compound has crystal purity higher than 99.9%. Doxofylline has good stability. Tablets and injections prepared by using the doxofylline medicine composition containing doxofylline have good stability and have total impurity rates lower than 0.5% after being placed for 36 months.
Description
Technical field
The invention belongs to medical art, be specifically related to doxofylline compound and the pharmaceutical composition containing doxofylline.
Background technology
Asthma is a kind of common disease in China, frequently-occurring disease, hazardness is very big, seriously threaten the health of numerous people, wherein part population can become lifelong chronic illness, pants in addition and is the cardinal symptom of respiratory system disease, and patient is difficult to stand at body & mind, need safe and effective anti-asthmatic very urgently, to alleviate and to eliminate symptom.Doxofylline has good market outlook as a kind of class medicine of relievining asthma of par.
Doxofylline is the derivative of methyl xanthine, and it is a kind of bronchodilator, can directly act on segmental bronchus, lax tracheal smooth muscle.Doxofylline by suppressing the phosphodiesterase in smooth muscle cell, relaxing smooth muscle, thus reaches the effect suppressing asthma.
Doxofylline.Its chemical name is 1,3-dimethyl-7-(1,3-dioxy cyclopentyl-2-base) methyl-3,7-dihydro-1H-purine-2,6-diketone.
Molecular formula: C
11h
14n
4o
4
Molecular weight: 266.26
Indication: the expiratory dyspnea that bronchial asthma, asthmatic chronic bronchitis and other bronchospasm cause.
More doxofylline formulation is used to have clinically: injection liquid, powder pin, Tablet and Capsula etc.Water-soluble and the less stable of doxofylline, injection liquid often has effective constituent to separate out phenomenon, and existing technology is difficult to solve this phenomenon, and in formula, the application of auxiliary material can alleviate this phenomenon, but means are complicated, limits the Clinical practice of doxofylline.
For the polymorphic of medicine, different polymorphics can have different characteristics, as fusing point, and chemical stability, apparent solubility and density etc.These character directly can affect pre-treatment and the production of bulk drug and preparation, and have impact to the stability of medicine, solubleness and bioavailability.For the preparation having the polymorphic of effective constituent to make, solubleness directly can have influence on bioavailability.Therefore, the polymorphic of medicine is significant to the quality of pharmaceutical preparation, security and validity.
Application number is that the invention of CN95111601.0 relates to the novel method preparing doxofylline.The method adopts theophylline to be raw material and Haloacetaldehydes condensed ethandiol, by N-hydroxylating, and directly obtained doxofylline.Application number CN201310108627.4 discloses the patent of a kind of doxofylline crystal and preparation method thereof and composite medicine.Application number CN201310520131.8 discloses a kind of synthetic method of Doxofylline hemihydrate.
Analyze discovery after deliberation, above-mentioned disclosed doxofylline raw material and preparation Shortcomings in quality stability, in long-term storage process, active constituent content reduces significantly, and dissolution rate significantly declines, and is unfavorable for ensureing clinical drug safety.
Therefore, still need to improve prior art, the quality stability of further raising doxofylline tablet and injection, by the impurity of its preparation, the Key Quality such as dissolution rate and content item controlled controls in safety range, obtain the doxofylline preparation of resistance to long storage periods, guarantee doxofylline clinical drug safety.
For solving the problem, the present invention obtains a kind of doxofylline of crystalline form on the basis of great many of experiments, even if moisture absorption weightening finish is also not obvious at high humidity.With doxofylline of the present invention for raw material, the injection liquid made and tablet have better stability.
Summary of the invention
The invention provides one and stablize doxofylline compound and pharmaceutical composition thereof.
In the present invention, the chemical structural formula of doxofylline is:
The X-ray powder art diffraction that described doxofylline compound uses Gu-K alpha-ray to measure is at 31.1 °, and 32 °, 34.3 °, 37.5 °, 41.3 °, 43 °, 53.8 °, 56.5 °, 58 °, 62.5 ° of places show characteristic peak.
The X-ray powder diffraction figure of described doxofylline compound is shown in Fig. 1.
The fusing point of described doxofylline is 136-137 DEG C.
The preparation method of doxofylline compound of the present invention comprises the steps:
1), under the stirring velocity of 50-60 DEG C, 100-150 rev/min, theophylline and bromo-1, the 3-dioxolane of 2-are added reactor according to weight ratio 1.0 ~ 1.2.Add sodium carbonate as catalyzer, dimethyl formamide heats up as starting after solvent, keeps temperature of reaction at 110-115 DEG C.
2), after reaction terminates, dimethyl formamide is reclaimed in underpressure distillation.Cooling reactant, to 20-25 DEG C, filters and uses pure water rinsing.
3) the doxofylline crude product filtered out, adds gac and the trace toluene of about 1.5% of doxofylline weight, 150 ~ 200 revs/min, stirs 30 minutes, filters carbon removal, by filtrate through 0.22 μm of membrane filtration.Then toluene was removed at dry 6 hours at 95-100 DEG C.
4) the dry doxofylline of the vacuum tray drier at 95-100 DEG C, to constant weight, obtains doxofylline dry powder.
5) use shredder grinding, obtain even-grained doxofylline.
Second object of the present invention is to provide a kind of containing the preparation of doxofylline compound and the preparation of pharmaceutical composition, and described composite preparation is injection liquid and tablet.Based on the feature of doxofylline prepared by the present invention, available following scheme obtains stable doxofylline preparation.
An injection liquid containing doxofylline, filling a prescription is: doxofylline 10 ~ 30g, water for injection 1 ~ 2L
The pharmaceutical composition of described doxofylline is prepared into injection, and its preparation method comprises the following steps:
By prescription doxofylline compound 10-30g, water for injection 1-2L, by the water for injection of doxofylline compound full dose 80% of the present invention 50 DEG C of dissolvings, regulates pH5.8-6.4 with hydrochloric acid, add to the full amount of water for injection, stir, with 0.22 μm of membrane filtration, ampoule is filling, inflated with nitrogen, sealing by fusing, 121 DEG C of moist heat sterilizations 30 minutes, obtain Doxofylline injection.
A kind of tablet containing doxofylline, comprise doxofylline and excipient substance carrier, excipient substance carrier comprise Microcrystalline Cellulose and Xylo-Mucine, Pregelatinized corn, starch, Spherolac 100, talcum powder, PVP K30 water-containing column one or more.
Doxofylline tablet, the proportion of each component is: doxofylline 6 parts of weights, Microcrystalline Cellulose and Xylo-Mucine 1-1.5 part are heavy, and pregelatinized corn starch 0.5-1 part is heavy, and Spherolac 100 0.5-1 part is heavy.
The pharmaceutical composition of described doxofylline is prepared into tablet, and its preparation method comprises the following steps:
(1) doxofylline, Microcrystalline Cellulose and Xylo-Mucine, pregelatinized corn starch, Spherolac 100 crosses 120 mesh sieves successively.
(2) do tackiness agent wet granulation by after the mixing of doxofylline excipient substance with 6% PVP K30 ethanolic soln, cross 16 mesh sieves, 60 DEG C of dryings 5 hours, mensuration content, upper tabletting machine, packs after the assay was approved and obtains doxofylline sheet.
The present invention is the doxofylline compound being obtained above-mentioned crystalline form by test of many times, and this compound has obviously good water-soluble and quality stability.The preparation that this doxofylline is made, can keep high stability, substantially increase the clinical safety of doxofylline.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction pattern of doxofylline prepared by the embodiment of the present invention 1.
Embodiment
The preparation of embodiment 1 doxofylline compound
Under the stirring velocity of 50-60 DEG C, 100-150 rev/min, theophylline and bromo-1, the 3-dioxolane of 2-are added reactor according to weight ratio 1: 1.2.Add sodium carbonate as catalyzer, dimethyl formamide heats up as starting after solvent, keeps temperature of reaction at 110-115 DEG C.After reaction terminates, dimethyl formamide is reclaimed in underpressure distillation.Cooling reactant, to 20-25 DEG C, filters and uses pure water rinsing.The doxofylline crude product filtered out, adds gac and the trace toluene of about 1.5% of doxofylline weight, 150 ~ 200 revs/min, stirs 30 minutes, filters carbon removal, by filtrate through 0.22 μm of membrane filtration.Then toluene was removed at dry 6 hours at 95-100 DEG C.The dry doxofylline of vacuum tray drier at 95-100 DEG C, to constant weight, obtains doxofylline dry powder.Use shredder grinds, and obtains even-grained doxofylline.The fusing point of this compound is 136-137 DEG C.HPLC checks that purity is 99.95%.X-ray powder diffraction is shown in accompanying drawing 1, and in its collection of illustrative plates, characteristic peak is at 31.1 °, 32 °, 34.3 °, 37.5 °, 41.3 °, 43 °, 53.8 °, 56.5 °, 58 °, 62.5 ° of displays.
The preparation of embodiment 2 doxofylline compound
Under the stirring velocity of 50-60 DEG C, 100-150 rev/min, theophylline and bromo-1, the 3-dioxolane of 2-are added reactor according to weight ratio 1: 1.Add sodium carbonate as catalyzer, dimethyl formamide heats up as starting after solvent, keeps temperature of reaction at 110-115 DEG C.After reaction terminates, dimethyl formamide is reclaimed in underpressure distillation.Cooling reactant, to 20-25 DEG C, filters and uses pure water rinsing.The doxofylline crude product filtered out, adds gac and the trace toluene of about 1.5% of doxofylline weight, 150 ~ 200 revs/min, stirs 30 minutes, filters carbon removal, by filtrate through 0.22 μm of membrane filtration.Then toluene was removed at dry 6 hours at 95-100 DEG C.The dry doxofylline of vacuum tray drier at 95-100 DEG C, to constant weight, obtains doxofylline dry powder.Use shredder grinds, and obtains even-grained doxofylline.The fusing point of this compound is 136-137 DEG C.HPLC checks that purity is 99.93%.X-ray powder diffraction is identical with accompanying drawing 1.
The preparation of embodiment 3 Doxofylline injection
Prescription:
Doxofylline compound 10g
Water for injection 1L
Make 100
By the doxofylline compound of recipe quantity with the water for injection of full dose 80% 50 DEG C of dissolvings, pH5.8-6.4 is regulated with hydrochloric acid, add to the full amount of water for injection, stir, with 0.22 μm of membrane filtration, ampoule is filling, inflated with nitrogen, sealing by fusing, 121 DEG C of moist heat sterilizations 30 minutes, obtain 10g: 10ml Doxofylline injection.
The Doxofylline injection prepare this EXPERIMENTAL EXAMPLE 3 and commercially available Doxofylline injection carry out permanent stability investigation (25 DEG C ± 2 DEG C; 60% ± 5%RH), the results are shown in Table 1.
Table 1 Doxofylline injection permanent stability investigation table
Conclusion: place Doxofylline injection 36 months every quality index under long-term room-temperature condition without considerable change, total assorted content is lower than 0.5%, and doxofylline stable content, is better than commercially available prod, shows that doxofylline compound prepared by present method has good stability.
The preparation of embodiment 4 doxofylline tablet
By doxofylline, Microcrystalline Cellulose and Xylo-Mucine, pregelatinized corn starch, Spherolac 100 crosses 120 mesh sieves successively.Do tackiness agent wet granulation by after the mixing of doxofylline excipient substance with 6% PVP K30 ethanolic soln, cross 16 mesh sieves, 60 DEG C of dryings 5 hours, mensuration content, upper tabletting machine, packs after the assay was approved and obtains doxofylline sheet.
The doxofylline sheet this EXPERIMENTAL EXAMPLE 4 prepared carries out permanent stability investigation (25 DEG C ± 2 DEG C; 60% ± 5%RH), the results are shown in Table 2.
The long-term study on the stability table of table 2 doxofylline sheet
Conclusion: place doxofylline sheet 36 months every quality index under long-term room-temperature condition without considerable change, total assorted content is lower than 0.5%, and doxofylline stable content, is better than commercially available prod, shows that doxofylline compound prepared by present method has good stability.
Doxofylline crystal purity of the present invention is high, and compound purity is high, good stability, injection liquid obtained thus and tablet stability good
Claims (8)
1. a doxofylline compound, its chemical formula is
It is characterized in that X-ray powder diffraction that described doxofylline compound uses Gu-K alpha-ray to measure is at 31.1 °, 32 °, 34.3 °, 37.5 °, 41.3 °, 43 °, 53.8 °, 56.5 °, 58 °, 62.5 ° of places are aobvious characteristic peak.
2. doxofylline compound according to claim 1, fusing point is 136-137 DEG C.
3. the doxofylline compound according to any one of claim 1-2, is characterized in that, the preparation method of described doxofylline compound is:
1) dimethyl formamide is added reactor, start to be heated to 50-60 DEG C, then add theophylline, limit edged stirs, then adds sodium carbonate, catalyzer and bromo-1, the 3-dioxolane of 2-; Start to heat and keep temperature of reaction at 110-115 DEG C; Dimethyl formamide is reclaimed in underpressure distillation; Cooling reactant, to 20-25 DEG C, filters and uses pure water rinsing;
2) the doxofylline crude product toluene filtered out and activated carbon purification, drying 6 hours at 95-100 DEG C;
3) vacuum tray drier dry doxofylline at 95-100 DEG C, to constant weight, obtains doxofylline end product;
4) use shredder grinding, obtain even-grained doxofylline.
4. the doxofylline compound according to any one of claim 1-2, is characterized in that compound is prepared into tablet or injection.
5. composite medicine according to claim 4, is characterized in that: when pharmaceutical composition is injection liquid, only comprises a kind of auxiliary material carrier.
6. Doxofylline injection according to claim 5, is characterized in that, described Doxofylline injection formula is: doxofylline 10 ~ 30g, water for injection 1 ~ 2L.
7. composite medicine according to claim 4, it is characterized in that: when pharmaceutical composition is tablet, comprise excipient substance carrier, excipient substance carrier comprise Microcrystalline Cellulose and Xylo-Mucine, Pregelatinized corn, starch, Spherolac 100, talcum powder, PVP K30 water-containing column one or more.
8. doxofylline tablet according to claim 7, its feature is being, the tablet of described doxofylline, the proportion of each component is: doxofylline 6 parts of weights, Microcrystalline Cellulose and Xylo-Mucine 1-1.5 part are heavy, pregelatinized corn starch 0.5-1 part is heavy, and Spherolac 100 0.5-1 part is heavy.
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| CN201510323278.7A CN105037361A (en) | 2015-06-10 | 2015-06-10 | Doxofylline compound and medicine composition thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105287373A (en) * | 2015-12-01 | 2016-02-03 | 李正梅 | Anti-bronchial asthma doxofylline injection |
| CN110898019A (en) * | 2019-12-19 | 2020-03-24 | 上海宣泰海门药业有限公司 | Doxofylline tablet and preparation method thereof |
| CN111233864A (en) * | 2020-03-07 | 2020-06-05 | 安徽恒星制药有限公司 | Novel method for simply, conveniently and industrially producing doxofylline in green |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1133842A (en) * | 1995-04-18 | 1996-10-23 | 绍兴市医药工业研究所 | Process for preparing doxofylline |
| CN102367254A (en) * | 2011-08-26 | 2012-03-07 | 贺金凤 | More stable doxofylline compound and pharmaceutical composite thereof |
| CN102936248A (en) * | 2012-10-30 | 2013-02-20 | 开封明仁药业有限公司 | Method for preparing doxofylline |
| CN103159769A (en) * | 2013-04-01 | 2013-06-19 | 湖北美林药业有限公司 | Doxofylline compound and medicine composition thereof |
-
2015
- 2015-06-10 CN CN201510323278.7A patent/CN105037361A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1133842A (en) * | 1995-04-18 | 1996-10-23 | 绍兴市医药工业研究所 | Process for preparing doxofylline |
| CN102367254A (en) * | 2011-08-26 | 2012-03-07 | 贺金凤 | More stable doxofylline compound and pharmaceutical composite thereof |
| CN102936248A (en) * | 2012-10-30 | 2013-02-20 | 开封明仁药业有限公司 | Method for preparing doxofylline |
| CN103159769A (en) * | 2013-04-01 | 2013-06-19 | 湖北美林药业有限公司 | Doxofylline compound and medicine composition thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105287373A (en) * | 2015-12-01 | 2016-02-03 | 李正梅 | Anti-bronchial asthma doxofylline injection |
| CN110898019A (en) * | 2019-12-19 | 2020-03-24 | 上海宣泰海门药业有限公司 | Doxofylline tablet and preparation method thereof |
| CN111233864A (en) * | 2020-03-07 | 2020-06-05 | 安徽恒星制药有限公司 | Novel method for simply, conveniently and industrially producing doxofylline in green |
| CN111233864B (en) * | 2020-03-07 | 2020-12-22 | 安徽恒星制药有限公司 | Method for industrially producing doxofylline |
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Application publication date: 20151111 |