CN115040480A - A method for preparing medicine-LUXUEZHILIAO Capsule - Google Patents
A method for preparing medicine-LUXUEZHILIAO Capsule Download PDFInfo
- Publication number
- CN115040480A CN115040480A CN202210692635.7A CN202210692635A CN115040480A CN 115040480 A CN115040480 A CN 115040480A CN 202210692635 A CN202210692635 A CN 202210692635A CN 115040480 A CN115040480 A CN 115040480A
- Authority
- CN
- China
- Prior art keywords
- deer blood
- blood phospholipid
- medicine
- porphyrin
- vesicle
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
-
- 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
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
- A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
-
- 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
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1277—Processes for preparing; Proliposomes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
A preparation method of a medicine-deer blood phospholipid vesicle belongs to the technical field of biological medicine, and the specific scheme is as follows: a method for preparing medicine-deer blood phospholipid vesicle adopts deer blood phospholipid as membrane material, utilizes the antioxidation performance of deer blood phospholipid to regulate and control the biological function of medicine-deer blood phospholipid vesicle, and comprises the following steps: dissolving the medicine and deer blood phospholipid in organic phase, shaking, adding secondary distilled water, and performing ultrasonic treatment to obtain medicine-deer blood phospholipid vesicle. Compared with the covalent bonding preparation technology, the method has high practicability and controllability, can obtain ideal drug encapsulation rate by controlling the proportion of the drug-deer blood phospholipid membrane material, and can obtain composite vesicles with different particle sizes by controlling the time of mechanical dispersion and ultrasonic treatment so as to meet different pharmacy requirements.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a preparation method of a medicine-deer blood phospholipid vesicle.
Background
The deer blood phospholipid is animal phospholipid, has excellent oxidation resistance, and can form bilayer structures with different shapes by self-assembly in water. Because the deer blood phospholipid is a natural animal phospholipid, the biocompatibility is higher, and the deer blood phospholipid has good anti-aging effect; the deer blood phospholipid is used as an important component of natural phospholipid, has some characteristics of phospholipid molecules, including targeting property, long-acting property, drug toxicity reduction and other outstanding properties when being used as a drug carrier material. Therefore, the deer blood phospholipid may be used as a substitute of general liposome and as a drug carrier material to replace the current clinical liposome, such as: paclitaxel liposome for injection, doxorubicin hydrochloride liposome for injection, amphotericin B liposome for injection, etc. However, the preparation technology of the deer blood phospholipid as the drug carrier material is deficient at present, so the invention provides an experimental technology of the deer blood phospholipid embedded drug.
Disclosure of Invention
The invention provides a method for preparing a medicine-deer blood phospholipid vesicle by utilizing natural deer blood phospholipid, which is characterized in that the deer blood phospholipid is used as a membrane material, a mechanical dispersion method and an ultrasonic technology are combined to prepare the medicine-deer blood phospholipid vesicle, the medicine and the deer blood phospholipid are dissolved in a low-toxicity volatile organic phase, then secondary distilled water is added, quick oscillation is carried out, then ultrasonic treatment is carried out, and vesicles encapsulated by different medicines can be obtained, wherein the particle size distribution of the vesicles can be from nano-scale to micron-scale.
The technical scheme adopted by the invention is as follows:
a method for preparing medicine-deer blood phospholipid vesicle adopts deer blood phospholipid as membrane material, utilizes the antioxidation performance of deer blood phospholipid to regulate and control the biological function of medicine-deer blood phospholipid vesicle, and comprises the following steps: dissolving the medicine and deer blood phospholipid in organic phase, shaking, adding secondary distilled water, and performing ultrasonic treatment to obtain medicine-deer blood phospholipid vesicle.
Further, the mass ratio of the deer blood phospholipid to the medicine is 2:1-20: 1.
Preferably, the drug is one or more of adriamycin, paclitaxel, docetaxel, hydroxycamptothecin, cisplatin and porphyrin compound.
Preferably, the porphyrin compound comprises one or more of tetrahydroxyphenyl porphyrin, tetraaminophenyl porphyrin, hematoporphyrin and hemoglobin.
Further, the power of ultrasonic treatment is 300W, and the ultrasonic time is 2-5 minutes.
Further, the organic phase is dichloromethane, acetone, ethanol or ethyl acetate.
Further, the volume of the organic phase is defined as: on the premise of completely dissolving the medicine, the volume of the organic phase is reduced as much as possible.
Further, the volume ratio of the organic phase to the secondary distilled water is 1:2-1: 10.
Preferably, the drug is a porphyrin.
Preferably, the optimal mass ratio of the deer blood phospholipid to the porphyrin is 10: 1.
Compared with other phospholipids, the antioxidation of the deer blood phospholipid can regulate and control the phototoxicity of the porphyrin photosensitizer.
Compared with the prior art, the invention has the beneficial effects that:
compared with the covalent bonding preparation technology, the method has high practicability and controllability, can obtain ideal drug encapsulation rate by controlling the proportion of the drug-deer blood phospholipid membrane material, and can obtain composite vesicles with different particle sizes by controlling the time of mechanical dispersion and ultrasonic treatment so as to meet different pharmacy requirements.
Drawings
FIG. 1: (a) schematic diagrams of blank deer blood phospholipid vesicles and (b) porphyrin-deer blood phospholipid vesicles;
FIG. 2: standard curve of photosensitive drug porphyrin compound;
FIG. 3: ultraviolet-visible absorption spectrum of dichloromethane solution of tetraphenylporphyrin with each concentration;
FIG. 4: the effect of lipid drug ratio on porphyrin-liposome encapsulation efficiency;
FIG. 5: standard curve for the anticancer drug doxorubicin in PBS;
FIG. 6: scanning electron microscope picture of nanometer deer blood phospholipid vesicle;
FIG. 7: FIG. (a) microscopic image of blank deer blood phospholipid; (b) microscopic image of porphyrin-deer blood phospholipid vesicles;
FIG. 8: fluorescence microscopy images of porphyrin-deer serum phospholipid vesicles.
Detailed Description
The invention is described in further detail below with reference to the figures and specific embodiments. However, the present invention is not limited thereto, and any modification or equivalent replacement of the technical solution of the present invention without departing from the spirit and scope of the technical solution of the present invention should be covered thereby.
Example 1
The specific steps of the technology are described below by taking deer blood phospholipid and photosensitive porphyrin as examples, and the technology can be applied to coating anticancer drugs (adriamycin, taxol, docetaxel, hydroxycamptothecin, cisplatin and other similar anticancer drugs and porphyrin derivatives and other photosensitive drugs). As a wrapping material of the photosensitive drug, the deer blood phospholipid can effectively regulate and control the phototoxicity of the photosensitive drug and increase the compliance of patients in the photodynamic therapy process.
Process for preparing porphyrin liposome
Preparing porphyrin-liposome by combining a mechanical dispersion method and an ultrasonic technology: adopts deer blood phospholipid as membrane material, utilizes the antioxidation performance of the deer blood phospholipid to regulate and control the biological function of the medicine-deer blood phospholipid vesicle, and comprises the following steps: dissolving tetraphenylporphyrin and deer blood phospholipid in a mass ratio of 1:10 in organic phase dichloromethane, shaking uniformly, adding secondary distilled water, performing ultrasonic treatment for 5min, and shaking uniformly to obtain the liquid with micro-powder opalescence at the upper layer, namely the prepared porphyrin-liposome, and storing at low temperature and in the dark as shown in figure 1. Wherein the volume of the organic phase is defined as: on the premise of completely dissolving the medicine, the volume of the organic phase is reduced as much as possible, and the volume ratio of the organic phase to the secondary distilled water is 1: 5.
Drawing standard curve of tetraphenylporphyrin
A dichloromethane solution of tetraphenylporphyrin was determined to have an ultraviolet absorption maximum at a wavelength of 419 nm. Taking a proper amount of tetraphenylporphyrin standard solution, and respectively diluting the solution to a mass concentration of 2 multiplied by 10 -4 mg/mL、4×10 -4 mg/mL、6×10 -4 mg/mL、8×10 -4 mg/mL、1×10 -3 The ultraviolet absorbance value of the solution with each concentration is measured at the position of 419nm of the maximum ultraviolet absorption wavelength of the tetraphenylporphyrin solution of mg/mL by adopting an ultraviolet-spectrophotometry, a standard curve is drawn by taking the absorbance value A as a vertical coordinate and the mass concentration C of the tetraphenylporphyrin solution as a horizontal coordinate, and a regression equation is obtained by fitting the standard curve, wherein the regression equation is shown in figure 2.
The absorbance at 419nm of the tetraphenylporphyrin solutions for each concentration gradient is shown in Table 1. The ultraviolet absorption spectrum of the tetraphenylporphyrin solution at the corresponding concentration is shown in FIG. 3. As can be seen from fig. 3, the absorbance at λ max 419nm increases significantly with increasing solution concentration, with good positive correlation.
TABLE 1 maximum absorbance values of dichloromethane solutions of tetraphenylporphyrin at various concentrations
Encapsulation efficiency determination method
Taking the prepared porphyrin-liposome, absorbing the lower dichloromethane solution by using a pipette gun, transferring the solution into a 5mL centrifugal tube with scales, washing the solution twice by using a small amount of dichloromethane to ensure that the free tetraphenylporphyrin is completely dissolved in the dichloromethane, fixing the volume to 3mL, absorbing 1mL by using the pipette gun, placing the solution into a quartz cell, scanning by using an ultraviolet-spectrophotometer, measuring the light absorption value of the solution at the maximum absorption wavelength, substituting the light absorption value into a standard curve regression equation for calculation to obtain the mass of the free tetraphenylporphyrin,
and calculating the encapsulation efficiency according to a formula.
The encapsulation efficiency was (1-W1/W0). times.100%
In the formula: w1 is the mass of free drug and W0 is the total mass of added drug.
Lipid-drug ratio optimization of porphyrin-liposome
The preparation of porphyrin-liposome complexes is influenced by many relevant factors, with the amount of tetraphenylporphyrin dosed being directly related to the encapsulation efficiency of the liposome formulation. The experiment preliminarily sets the mass ratio of the deer blood phospholipid to the tetraphenylporphyrin as follows: the encapsulation efficiency of the prepared porphyrin-liposome was measured by 6 gradients of 2:1, 6:1, 10:1, 14:1, 16:1 and 20:1, and the influence of the amount of porphyrin added on the encapsulation efficiency was examined. The absorbance values and calculated entrapment efficiencies of porphyrin-liposomes prepared at different lipid-drug ratios are shown in table 2. According to table 2, a statistical bar graph is plotted with the lipid-drug ratio as abscissa and the encapsulation efficiency as ordinate, and the results are shown in fig. 4.
TABLE 2 entrapment efficiency of porphyrin-liposomes prepared with different drug-to-lipid ratios
It can be seen from fig. 4 that the entrapment efficiency of the porphyrin-liposome increases with the increase of the amount of the tetraphenylporphyrin, and reaches a maximum of 79.23% when the ratio of the deer blood phospholipid to the porphyrin is 10:1, and then the entrapment efficiency decreases with the increase of the porphyrin amount. This indicates that the degree of encapsulation into liposomes is higher with smaller quantities of porphyrin; when a certain critical value is reached, the deer blood phospholipid at a certain dosage can not load all the porphyrin, and the increase of the concentration of the porphyrin can have a certain influence on the formation of phospholipid vesicles, so that the encapsulation efficiency begins to decrease with the increase of the dosage of the porphyrin. The prepared deer blood phospholipid extract is prepared into deer blood phospholipid vesicles by combining a mechanical dispersion method and an ultrasonic technology, a proper amount of the deer blood phospholipid vesicles is placed in a sample table, and the microscopic morphology of the deer blood phospholipid vesicles is analyzed by a Scanning Electron Microscope (SEM), and is shown in figure 6. As can be seen from FIG. 6, the deer blood phospholipid vesicles have uniform particle size distribution, the particle size is about tens of nanometers to tens of micrometers, and the deer blood phospholipid vesicles are in tetrahedral and circular isotactic morphology. FIG. 7 shows the standard curve of doxorubicin hydrochloride as an anticancer drug, and the method is also applicable to the preparation of a vesicle similar to the doxorubicin anticancer drug-deer blood phospholipid according to the characteristics of the deer blood phospholipid and the characteristics of the drug, and the specific preparation process is the same as that of porphyrin.
Fig. 8 is a fluorescence microscopic image of porphyrin-liposome, the porphyrin itself has red fluorescence property and has good localization characteristics. As can be seen from the figure, the porphyrin is uniformly distributed in the membrane layer of deer blood phospholipid, which shows that the porphyrin and the deer blood phospholipid have good intermolecular affinity.
The same experimental procedure is also suitable for embedding some water-insoluble anticancer drugs, and the specific operation is shown in the preparation process of a photosensitive drug porphyrin-deer blood phospholipid.
Claims (9)
1. A preparation method of a medicine-deer blood phospholipid vesicle is characterized in that: adopts deer blood phospholipid as membrane material, utilizes the antioxidation performance of the deer blood phospholipid to regulate and control the biological function of the medicine-deer blood phospholipid vesicle, and comprises the following steps: dissolving the medicine and deer blood phospholipid in organic phase, shaking, adding secondary distilled water, and performing ultrasonic treatment to obtain medicine-deer blood phospholipid vesicle.
2. The method for preparing the deer blood phospholipid vesicle as defined in claim 1, wherein: the mass ratio of the deer blood phospholipid to the medicine is 2:1-20: 1.
3. The method for preparing the deer blood phospholipid vesicle as defined in claim 1, wherein: the medicine is one or more of adriamycin, paclitaxel, docetaxel, hydroxycamptothecin, cisplatin and porphyrin compound.
4. The method for preparing the deer blood phospholipid vesicle as defined in claim 3, wherein: the porphyrin compound comprises one or more of tetrahydroxyphenyl porphyrin, tetraaminophenyl porphyrin, hematoporphyrin and hemoglobin.
5. The method for preparing the deer blood phospholipid vesicle as defined in claim 1, wherein: the power of ultrasonic treatment is 300W, and the time of ultrasonic treatment is 2-5 minutes.
6. The method for preparing the deer blood phospholipid vesicle as defined in claim 1, wherein: the organic phase is dichloromethane, acetone, ethanol or ethyl acetate.
7. The method for preparing the deer blood phospholipid vesicle as defined in claim 1, wherein: the volume ratio of the organic phase to the secondary distilled water is 1:2-1: 10.
8. The method for preparing the drug-deer blood phospholipid vesicle according to claim 1 or 2, wherein: the drug is porphyrin.
9. The method for preparing the deer blood phospholipid vesicle as defined in claim 7, wherein: the optimal mass ratio of the deer blood phospholipid to the porphyrin is 10: 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210692635.7A CN115040480A (en) | 2022-06-17 | 2022-06-17 | A method for preparing medicine-LUXUEZHILIAO Capsule |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210692635.7A CN115040480A (en) | 2022-06-17 | 2022-06-17 | A method for preparing medicine-LUXUEZHILIAO Capsule |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115040480A true CN115040480A (en) | 2022-09-13 |
Family
ID=83163076
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210692635.7A Pending CN115040480A (en) | 2022-06-17 | 2022-06-17 | A method for preparing medicine-LUXUEZHILIAO Capsule |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115040480A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6890555B1 (en) * | 1992-02-05 | 2005-05-10 | Qlt, Inc. | Liposome compositions of porphyrin photosensitizers |
| US20080274169A1 (en) * | 2007-05-04 | 2008-11-06 | Ceramoptec Industries Inc. | Photosensitizer formulations for topical applications |
| CN102573914A (en) * | 2009-10-16 | 2012-07-11 | 大学健康网络 | Porphyrin nanovesicles |
| CN110882218A (en) * | 2018-08-16 | 2020-03-17 | 北京大学 | Liposome composition and preparation and application thereof |
-
2022
- 2022-06-17 CN CN202210692635.7A patent/CN115040480A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6890555B1 (en) * | 1992-02-05 | 2005-05-10 | Qlt, Inc. | Liposome compositions of porphyrin photosensitizers |
| US20080274169A1 (en) * | 2007-05-04 | 2008-11-06 | Ceramoptec Industries Inc. | Photosensitizer formulations for topical applications |
| CN102573914A (en) * | 2009-10-16 | 2012-07-11 | 大学健康网络 | Porphyrin nanovesicles |
| CN110882218A (en) * | 2018-08-16 | 2020-03-17 | 北京大学 | Liposome composition and preparation and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| 冯倩: "卟啉-脂质体靶向药物的制备、细胞毒性及131I标记研究", 《中国优秀硕士学位论文全文数据库》 * |
| 袁相恋等: "鹿血化学成分和药理作用及其应用研究进展", 《经济动物学报》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Budijono et al. | Synthesis of stable block-copolymer-protected NaYF4: Yb3+, Er3+ up-converting phosphor nanoparticles | |
| Pan et al. | PEGylated liposome coated QDs/mesoporous silica core-shell nanoparticles for molecular imaging | |
| Ren et al. | Near-infrared fluorescent carbon dots encapsulated liposomes as multifunctional nano-carrier and tracer of the anticancer agent cinobufagin in vivo and in vitro | |
| Zhang et al. | Dual stimuli-responsive smart fibrous membranes for efficient photothermal/photodynamic/chemo-therapy of drug-resistant bacterial infection | |
| Ji et al. | Curcumin-loaded mixed micelles: Preparation, characterization, and in vitro antitumor activity | |
| Cai et al. | A ph-activable chemo–photodynamic therapy based on cube-wrapped-cube α-naybf4: Tm@ caf2/nd@ zno nanoparticles mediated by 808 nm light | |
| Nesamony et al. | Development and characterization of nanostructured mists with potential for actively targeting poorly water-soluble compounds into the lungs | |
| de Morais et al. | Hypericin photodynamic activity in DPPC liposome. PART I: biomimetism of loading, location, interactions and thermodynamic properties | |
| CN106074451B (en) | Reduction stimulus response drug carrier containing carbon nanocages and preparation method and application thereof | |
| Lin et al. | A phthalocyanine-based liposomal nanophotosensitizer with highly efficient tumor-targeting and photodynamic activity | |
| CN110559454B (en) | Nano composite medicine for diagnosing and treating Alzheimer's disease | |
| CN110302161B (en) | Composite nano liposome and application thereof | |
| Zhu et al. | Bi-doped carbon quantum dots functionalized liposomes with fluorescence visualization imaging for tumor diagnosis and treatment | |
| CN112587502B (en) | Erythrocyte membrane coated MOFs nano-drug carrier and preparation method and application thereof | |
| CN106692059A (en) | Hypoxia response lipidosome drug carrier as well as preparation method and application thereof | |
| Asghari et al. | PEGylated cationic nano-niosomes formulation containing herbal medicine curcumin for drug delivery to MCF-7 breast cancer cells | |
| CN115040480A (en) | A method for preparing medicine-LUXUEZHILIAO Capsule | |
| CN107970224A (en) | A kind of preparation method and application of lipid-modified magnetic oxygenated graphene composite material | |
| Jin et al. | Synthesis and cell imaging of a near-infrared fluorescent magnetic “CdHgTe–dextran-magnetic layered double hydroxide–fluorouracil” composite | |
| Chatterjee et al. | Dual Stimuli-Responsive BSA-Protected Silver Nanocluster-Driven “FRET On–Off” within the Niosomal Membrane: An Amalgamation of Restoration of Aggregation-Induced Quenched Fluorescence and Energy Transfer | |
| Schmidt et al. | Antibody-conjugated soybean oil-filled calcium phosphate nanoshells for targetted delivery of hydrophobic molecules | |
| Zhou et al. | Emissive Nanoparticles from Co-assembly of Metallatetragon and Amphiphilic Tetraphenylethylene for Cancer Theranostics | |
| CN114222591B (en) | Nanoemulsion with porphyrin shell | |
| CN113134097A (en) | Biological peptide modified bionic multifunctional lipoprotein nanoparticle and preparation method and application thereof | |
| CN101011358A (en) | Nanostructured liposome vector with highly effective antineoplastic activity |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20220913 |