CN116270879B - Danzhiqing tablet dry paste powder and preparation process and composition thereof - Google Patents
Danzhiqing tablet dry paste powder and preparation process and composition thereof Download PDFInfo
- Publication number
- CN116270879B CN116270879B CN202310247262.7A CN202310247262A CN116270879B CN 116270879 B CN116270879 B CN 116270879B CN 202310247262 A CN202310247262 A CN 202310247262A CN 116270879 B CN116270879 B CN 116270879B
- Authority
- CN
- China
- Prior art keywords
- fluid extract
- extract
- decoction pieces
- glidant
- decoction
- 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.)
- Active
Links
- 239000000843 powder Substances 0.000 title claims abstract description 68
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 239000000203 mixture Substances 0.000 title claims abstract description 22
- 239000012530 fluid Substances 0.000 claims abstract description 59
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 34
- 239000001116 FEMA 4028 Substances 0.000 claims abstract description 34
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 34
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims abstract description 34
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims abstract description 34
- 229960004853 betadex Drugs 0.000 claims abstract description 34
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 34
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 34
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 34
- 238000001694 spray drying Methods 0.000 claims abstract description 24
- 240000007164 Salvia officinalis Species 0.000 claims abstract description 20
- 235000005412 red sage Nutrition 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 16
- 239000003814 drug Substances 0.000 claims abstract description 13
- 239000002994 raw material Substances 0.000 claims abstract description 13
- 241000208688 Eucommia Species 0.000 claims abstract description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 62
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- 239000000243 solution Substances 0.000 claims description 17
- 239000007788 liquid Substances 0.000 claims description 15
- 238000002156 mixing Methods 0.000 claims description 14
- 239000006228 supernatant Substances 0.000 claims description 14
- 238000003809 water extraction Methods 0.000 claims description 14
- 239000011259 mixed solution Substances 0.000 claims description 9
- 238000001556 precipitation Methods 0.000 claims description 8
- 239000012141 concentrate Substances 0.000 claims description 7
- 239000000463 material Substances 0.000 claims description 7
- 230000001376 precipitating effect Effects 0.000 claims description 5
- 238000012869 ethanol precipitation Methods 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 241000208689 Eucommia ulmoides Species 0.000 claims 2
- 230000000052 comparative effect Effects 0.000 description 26
- 238000003756 stirring Methods 0.000 description 11
- 244000132619 red sage Species 0.000 description 10
- 238000001035 drying Methods 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 8
- WTPPRJKFRFIQKT-UHFFFAOYSA-N 1,6-dimethyl-8,9-dihydronaphtho[1,2-g][1]benzofuran-10,11-dione;1-methyl-6-methylidene-8,9-dihydro-7h-naphtho[1,2-g][1]benzofuran-10,11-dione Chemical compound O=C1C(=O)C2=C3CCCC(=C)C3=CC=C2C2=C1C(C)=CO2.O=C1C(=O)C2=C3CCC=C(C)C3=CC=C2C2=C1C(C)=CO2 WTPPRJKFRFIQKT-UHFFFAOYSA-N 0.000 description 6
- 229920002774 Maltodextrin Polymers 0.000 description 5
- 239000005913 Maltodextrin Substances 0.000 description 5
- 244000237330 gutta percha tree Species 0.000 description 5
- 229940035034 maltodextrin Drugs 0.000 description 5
- 235000011135 Salvia miltiorrhiza Nutrition 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229920002261 Corn starch Polymers 0.000 description 3
- 238000000889 atomisation Methods 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 241000605447 Anemarrhena Species 0.000 description 2
- 208000001431 Psychomotor Agitation Diseases 0.000 description 2
- 206010038743 Restlessness Diseases 0.000 description 2
- 229930191283 anemarrhena Natural products 0.000 description 2
- 239000007888 film coating Substances 0.000 description 2
- 238000009501 film coating Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000002791 soaking Methods 0.000 description 2
- 206010063659 Aversion Diseases 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 206010013954 Dysphoria Diseases 0.000 description 1
- 206010014080 Ecchymosis Diseases 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 208000008454 Hyperhidrosis Diseases 0.000 description 1
- 208000006083 Hypokinesia Diseases 0.000 description 1
- 206010027304 Menopausal symptoms Diseases 0.000 description 1
- 206010033557 Palpitations Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 210000003414 extremity Anatomy 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 230000037315 hyperhidrosis Effects 0.000 description 1
- 210000003127 knee Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
- A61K36/487—Psoralea
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/46—Eucommiaceae (Eucommia family), e.g. hardy rubber tree
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
- A61K36/537—Salvia (sage)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/88—Liliopsida (monocotyledons)
- A61K36/896—Liliaceae (Lily family), e.g. daylily, plantain lily, Hyacinth or narcissus
- A61K36/8964—Anemarrhena
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Botany (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Medical Informatics (AREA)
- Biotechnology (AREA)
- Alternative & Traditional Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Gastroenterology & Hepatology (AREA)
- Urology & Nephrology (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a Danzhi qing tablet dry paste powder, a preparation process and a composition thereof, wherein the Danzhi qing tablet dry paste powder comprises the following raw materials: fluid extract of traditional Chinese medicine raw materials and a glidant accounting for 9-17% of the mass of the fluid extract; the glidant is prepared from the following components in percentage by mass: the beta-cyclodextrin and microcrystalline cellulose of (1-6), wherein the traditional Chinese medicine raw materials of the fluid extract are salted eucommia decoction pieces, rhizoma anemarrhenae decoction pieces and diacolated red sage root dregs, and the relative density of the fluid extract is 1.04-1.20 g/ml. The method can effectively improve the fluidity of the fluid extract in the spray drying process, obviously increase the yield of the self-flowing powder in the dry extract powder, and improve the yield of the self-flowing powder from 15% to 100% when no glidant is added.
Description
Technical Field
The invention relates to the field of traditional Chinese medicine preparation, in particular to Danzhiqing tablet dry paste powder, a preparation process and a composition thereof.
Background
The Danzhi qing's tablet is a pure traditional Chinese medicine preparation which is prepared by starting from the ' tonifying yang method ' and retaining salt eucommia ulmoides of tonifying kidney and supporting yang in the ' Qing ' prescription ' on the basis of ' Qing ' pill ' in the ' Tai Ping Hui Min He Ji prescription ', adding red sage root for activating blood and dissolving stasis and rhizoma anemarrhenae for clearing heat and relieving restlessness, namely, extracting and refining traditional Chinese medicine decoction pieces of salt eucommia ulmoides, red sage root, rhizoma anemarrhenae and the like by a scientific method according to clinical practice experience, wherein the weight parts of each component are as follows: 1 part of salted fructus psoraleae, 2 parts of red sage root, 2 parts of salted eucommia bark and 1 part of rhizoma anemarrhenae.
Danzhi Qing' e tablet has the functions of tonifying liver and kidney, clearing heat and relieving restlessness, and is used for perimenopausal and menopausal syndrome with symptoms of hectic fever, hyperhidrosis, dysphoria, palpitation, hypodynamia and soreness of waist and knees; or aversion to cold, cold limbs, pale red or reddish tongue with ecchymosis, thin and white coating, deep and thready pulse.
The dry paste powder of the Danzhi qing tablet is a raw material for preparing the Danzhi qing tablet or related preparations thereof, the dry paste powder of the Danzhi qing tablet disclosed in the prior art is obtained by combining salt eucommia decoction pieces, rhizoma anemarrhenae decoction pieces and diacolated red sage root dregs with prescription amounts, extracting with water, precipitating with ethanol, taking supernatant after precipitating with ethanol, concentrating and drying, and the second extract disclosed in Chinese patent application CN 103550484A is obtained.
In general, the drying mode of the general traditional Chinese medicine extract mainly adopts reduced pressure vacuum drying, spray drying and boiling drying; the spray drying is usually direct spray drying or spray drying with proper amount of auxiliary materials, but the auxiliary materials adopted in the conventional mode are usually beta-cyclodextrin, maltodextrin, dextrin, corn starch or potato starch and the like. A part of the dried dry paste powder is adhered to a drying tower and needs to be collected by a shovel tower, and the part of the dry paste powder is called shovel tower powder; the other part automatically flows out of the drying tower after drying, and the part of dry paste powder is called self-flowing powder; wherein, the self-flowing powder yield is the weight percentage of the self-flowing powder to the total dry paste powder. The existing conventional spray drying method is used for preparing the dry paste powder of the Danzhiqing E tablet, and the self-flowing powder yield is not higher than 60%.
Disclosure of Invention
Therefore, the technical problem to be solved by the invention is to overcome the defect of low self-flowing powder yield of the dry paste powder of the Danzhiqing tablet disclosed in the prior art, thereby providing the dry paste powder of the Danzhiqing tablet, the preparation process and the composition thereof, wherein the self-flowing powder yield is obviously improved.
A dry extract powder of Danzhiqing' e tablet comprises the following raw materials: fluid extract of traditional Chinese medicine raw materials and a glidant accounting for 9-17% of the mass of the fluid extract; the glidant is prepared from the following components in percentage by mass: the beta-cyclodextrin and microcrystalline cellulose of (1-6), wherein the traditional Chinese medicine raw materials of the fluid extract are salted eucommia decoction pieces, rhizoma anemarrhenae decoction pieces and diacolated red sage root dregs, and the relative density of the fluid extract is 1.04-1.20 g/ml.
The red sage herb residue after diacolation is obtained by diacolation of red sage herb decoction pieces, wherein the red sage herb decoction pieces are 2 parts by weight, the salted eucommia bark decoction pieces are 2 parts by weight, and the rhizoma anemarrhenae decoction pieces are 1 part by weight.
When the glidant is 9-12% of the mass of the fluid extract, the glidant is 1: beta-cyclodextrin and microcrystalline cellulose of (3-5).
A preparation process of Danzhi Qing' e tablet dry paste powder comprises the following steps:
Obtaining fluid extract: extracting salted eucommia ulmoides decoction pieces, rhizoma anemarrhenae decoction pieces and percolating radix salviae miltiorrhizae decoction dregs with water, precipitating with ethanol, collecting supernatant, and concentrating to obtain fluid extract;
And (3) obtaining dry paste powder: adding a glidant accounting for 9-17% of the mass of the fluid extract, wherein the glidant comprises the following components in percentage by mass: beta-cyclodextrin and microcrystalline cellulose of (1-6); and (5) uniformly mixing, and then carrying out spray drying to obtain the dry paste powder of the Danzhiqing tablet.
The decoction extract obtained after the water extraction is concentrated to have the relative density of 1.06-1.20 g/ml, and then is subjected to alcohol precipitation, wherein the alcohol content in the mixed solution is 65-75% during the alcohol precipitation.
The water extraction and alcohol precipitation process comprises the following steps:
Mixing the Chinese medicinal materials of the fluid extract with water, decocting to obtain decoction extract, and concentrating the decoction extract to obtain water extract concentrate; mixing the water concentrate with ethanol to obtain a mixed solution, and standing to obtain a supernatant;
concentrating the supernatant to obtain fluid extract.
In the decoction step, the weight of water is 8-10 times of that of the traditional Chinese medicine raw materials;
And/or the temperature of the decoction is 95-100 ℃ and the extraction time is 1.5-3 h;
and/or the times of decoction are 2-3 times;
and/or the relative density of the water extraction concentrated solution is 1.06-1.20 g/ml;
And/or the ethanol standing time is 8-36 h;
And/or the concentration of the ethanol is 95%, and the dosage of the ethanol is 3 times of the weight of the water extraction concentrated solution.
In the spray drying, the motor frequency of the liquid supply pump is 5-25 Hz, preferably 6-8 Hz.
The mass ratio of the beta-cyclodextrin to the microcrystalline cellulose is 1: (2-4);
and/or the addition amount of the glidant is 9-13% of the mass of the fluid extract.
A DANZHIQING 'E composition comprises a DANZHIQING' E tablet dry extract powder or a DANZHIQING tablet dry extract powder prepared by the above preparation process.
The technical scheme of the invention has the following advantages:
The invention provides a dry extract powder of Danzhi' e tablet, which is prepared by adding 9-17% of the mass of fluid extract into the fluid extract according to the mass ratio of 1: the beta-cyclodextrin and the microcrystalline cellulose in the steps (1-6) are used as glidants, so that the fluidity of the fluid extract in the spray drying process can be effectively improved, the yield of the self-flowing powder in the dry extract powder is obviously increased, and even the yield of the self-flowing powder can be increased to 100% from 15% when no glidant is added.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are needed in the description of the embodiments or the prior art will be briefly described, and it is obvious that the drawings in the description below are some embodiments of the present invention, and other drawings can be obtained according to the drawings without inventive effort for a person skilled in the art.
FIG. 1 is a flow chart of the preparation of the dry extract powder of the present invention.
Detailed Description
Example 1
A preparation process of Danzhi Qing' e tablet dry paste powder comprises the following traditional Chinese medicine raw materials: 133.4kg of salvia miltiorrhiza decoction pieces, 133.4kg of salted eucommia ulmoides decoction pieces and 66.7kg of rhizoma anemarrhenae decoction pieces, wherein the specific technical process is shown in figure 1 and comprises the following steps:
Percolating Saviae Miltiorrhizae radix decoction pieces to obtain percolate and Saviae Miltiorrhizae radix residue, respectively, mixing Saviae Miltiorrhizae radix residue, salted Eucommiae cortex and rhizoma anemarrhenae, adding water 8 times of total weight of decoction pieces, decocting at 95-100deg.C for 3 hr each time to obtain extractive solution, concentrating the extractive solution to relative density of 1.10-1.15 g/ml, and making into water concentrate;
Adding 95% ethanol with the concentration of 3 times of the weight of the water extraction concentrated solution into the water extraction concentrated solution, uniformly stirring to obtain mixed solution, standing the mixed solution for 20 hours, taking ethanol precipitation supernatant, and concentrating the supernatant under reduced pressure to obtain fluid extract with the relative density of 1.05-1.10 g/ml for later use;
Taking the fluid extract with the amount shown in the table 1, adding about 9% of a glidant in the fluid extract, wherein the glidant is prepared by the following components in percentage by mass: 3 and microcrystalline cellulose, and then spray drying the mixture after stirring uniformly. The spray drying process comprises the following steps: starting spray drying equipment, setting the air inlet temperature to be 140-150 ℃ to enable the air outlet temperature to be lower than 90 ℃, adjusting the frequency of a liquid supply pump motor to be 7Hz through purified water to enable the pressure of a tower body to be kept within a range of-110 Pa to-70 Pa, starting a dehumidifier and a blower, and adjusting the atomization oil temperature to be 45-60 ℃; and (3) supplying liquid to a spray tower which is regulated normally under the stirring condition, performing spray drying, collecting self-retaining powder, weighing, and collecting tower shoveling powder.
Example 2
This example differs from example 1 in that the weight of the mixture of beta-cyclodextrin and microcrystalline cellulose added to the fluid extract is 11% of the weight of the fluid extract.
Example 3
This example differs from example 1 in that the weight of the mixture of beta-cyclodextrin and microcrystalline cellulose added to the fluid extract is 13% of the weight of the fluid extract.
Example 4
This example differs from example 1 in that the weight of the mixture of beta-cyclodextrin and microcrystalline cellulose added to the fluid extract is 15% of the weight of the fluid extract.
Example 5
This example differs from example 1 in that the weight of the mixture of beta-cyclodextrin and microcrystalline cellulose added to the fluid extract is 17% of the weight of the fluid extract.
Example 6
This example differs from example 1 in that the mass ratio of beta-cyclodextrin to microcrystalline cellulose in the mixture is 1:4.
Example 7
This example differs from example 1 in that the mass ratio of beta-cyclodextrin to microcrystalline cellulose in the mixture is 1:5.
Example 8
This example differs from example 1 in that the mass ratio of beta-cyclodextrin to microcrystalline cellulose in the mixture is 1:6.
Example 9
This example differs from example 1 in that the mass ratio of beta-cyclodextrin to microcrystalline cellulose in the mixture is 1:2.
Example 10
This example differs from example 1 in that the mass ratio of beta-cyclodextrin to microcrystalline cellulose in the mixture is 1:1.
Example 11
The difference between this example and example 1 is that the preparation process parameters are different, specifically as follows:
In the preparation process of the Danzhi qing E tablet dry paste powder, the danshen decoction pieces with the same composition amount in the embodiment 1 are taken for diacolation to respectively obtain diacolation liquid and danshen decoction dregs, the danshen decoction dregs, salted eucommia bark and anemarrhena rhizome are mixed, water with the weight 10 times of the total weight of the decoction pieces is added, the decoction pieces are decocted for two times at the temperature of 95-100 ℃ for 1.5 hours each time to obtain extract, and the extract is concentrated to the relative density of 1.06-1.11 g/ml to prepare water concentrate;
Adding 95% ethanol with the concentration of about 2.2 times of the mass of the water extraction concentrated solution into the water extraction concentrated solution, so that the ethanol content in the mixed liquid reaches about 65%, uniformly stirring to obtain mixed liquid, standing the mixed liquid for 8 hours, taking an alcohol precipitation supernatant, and concentrating the supernatant under reduced pressure to obtain a fluid extract with the relative density of 1.10-1.15 g/ml for later use;
Taking the fluid extract with the amount shown in the table 1, adding about 9% of a glidant in the fluid extract, wherein the glidant is prepared by the following components in percentage by mass: 3 and microcrystalline cellulose, and then spray drying the mixture after stirring uniformly. The spray drying process comprises the following steps: starting spray drying equipment, setting the air inlet temperature to be 140-150 ℃ to enable the air outlet temperature to be lower than 90 ℃, adjusting the frequency of a liquid supply pump motor to be 5Hz through purified water to enable the pressure of a tower body to be kept within a range of-110 Pa to-70 Pa, starting a dehumidifier and a blower, and adjusting the atomization oil temperature to be 45-60 ℃; and (3) supplying liquid to a spray tower which is regulated normally under the stirring condition, performing spray drying, collecting self-retaining powder, weighing, and collecting tower shoveling powder.
Example 12
The difference between this example and example 1 is that the preparation process parameters are different, specifically as follows:
In the preparation process of the Danzhi qing E tablet dry paste powder, the danshen decoction pieces with the same composition amount in the embodiment 1 are taken for diacolation to respectively obtain diacolation liquid and danshen decoction dregs, the danshen decoction dregs, salted eucommia bark and anemarrhena rhizome are mixed, water with the weight of 9 times of the total weight of the decoction pieces is added, the decoction pieces are decocted for two times at the temperature of 95-100 ℃ for 1.5 hours each time to obtain extract, and the extract is concentrated to have the relative density of 1.15-1.20 g/ml to prepare water concentrate;
Adding 95% ethanol with the concentration of about 3.7 times of the mass of the water extraction concentrated solution into the water extraction concentrated solution, enabling the ethanol content in the mixed solution to reach about 75%, uniformly stirring to obtain mixed solution, standing the mixed solution for 36 hours, taking an alcohol precipitation supernatant, and concentrating the supernatant under reduced pressure to obtain a fluid extract with the relative density of 1.15-1.20 g/ml for later use;
Taking the fluid extract with the amount shown in the table 1, adding about 9% of a glidant in the fluid extract, wherein the glidant is prepared by the following components in percentage by mass: 3 and microcrystalline cellulose, and then spray drying the mixture after stirring uniformly. The spray drying process comprises the following steps: starting spray drying equipment, setting the air inlet temperature to be 140-150 ℃ to enable the air outlet temperature to be lower than 90 ℃, adjusting the frequency of a liquid supply pump motor to be 10Hz through purified water to enable the pressure of a tower body to be kept within a range of-110 Pa to-70 Pa, starting a dehumidifier and a blower, and adjusting the atomization oil temperature to be 45-60 ℃; and (3) supplying liquid to a spray tower which is regulated normally under the stirring condition, performing spray drying, collecting self-retaining powder, weighing, and collecting tower shoveling powder.
Example 13
The embodiment also provides a preparation method of the composition of the dry extract powder of the danzhi qing e tablet, in particular to a preparation method of the danzhi qing e tablet, which comprises the following specific processes:
Adding 70% ethanol with the amount of 2 times of the prescription amount into the salt fructus psoraleae, soaking for 12 hours, percolating the 70% ethanol at the flow rate of about 8 mL/kg.min, collecting percolate with the feeding amount of the salt fructus psoraleae being 15 times of the volume, recovering the ethanol from the percolate under reduced pressure, concentrating the ethanol to about 1:1.5 (the weight of the medicinal materials is the weight of the concentrated solution), standing for layering, pouring out the upper layer liquid, and taking the lower layer to obtain the salt fructus psoraleae thick extract for later use.
Adding 2 times of 95% ethanol into the prescription quantity of the salvia miltiorrhiza decoction pieces for soaking for 24 hours, percolating the 95% ethanol at the flow rate of about 16 mL/kg.min, collecting the volume percolate with the feeding quantity of the salvia miltiorrhiza, recovering the ethanol from the percolate under reduced pressure, concentrating to about 1:0.6 (the weight of the medicinal materials is the weight of the concentrated solution), adding the salt and fructus psoraleae thick extract, mixing and dissolving, and continuously concentrating to about 1 (0.1-0.3), wherein the concentration is 1:0.2 (the weight of the salvia miltiorrhiza medicinal materials is the weight of the concentrated solution) in the embodiment, thus obtaining the percolated concentrated solution extract. Mixing the percolate concentrated extract with appropriate amount of beta-cyclodextrin and microcrystalline cellulose, granulating, and drying to obtain granule I.
Mixing the salt eucommia ulmoides decoction pieces, the rhizoma anemarrhenae decoction pieces and the percolating red sage root decoction dregs, and preparing dry paste powder for later use according to the preparation method of the examples 1-12.
Mixing granule I, dry extract powder and microcrystalline cellulose, adding appropriate amount of 90% ethanol, mixing, granulating, drying, grading, mixing with hydroxypropyl cellulose, polyethylene glycol 6000 and magnesium stearate, tabletting, and making into Danzhiqing E tablet. The preparation process of the tablet of the Danzhi qing's element is a conventional process and is not repeated here.
Taking film coating powder, adding a proper amount of water under stirring, and continuously stirring for about 1 hour; gradually spraying film coating liquid at 40-50 ℃ to increase the weight of the coating to 4.5-6.0%, and stopping coating; the tablet can be prepared into Danzhiqing E tablet after being dried for more than 12 hours.
Comparative example 1
The difference between this comparative example and example 1 is that the amount of glidant added to the fluid extract was 0%, i.e., no glidant was added, as shown in Table 1.
Comparative example 2
The difference between this comparative example and example 1 is that the glidant added to the fluid extract is beta-cyclodextrin, and the added amount of beta-cyclodextrin is about 2.3%, as shown in Table 1.
Comparative example 3
The difference between this comparative example and example 1 is that the glidant added to the fluid extract is beta-cyclodextrin, and the added amount of beta-cyclodextrin is about 16.9%.
Comparative example 4
The difference between this comparative example and example 1 is that the glidant added to the fluid extract is microcrystalline cellulose, and the amount of microcrystalline cellulose added is about 6.9%.
Comparative example 5
The difference between this comparative example and example 1 is that the glidant added to the fluid extract is microcrystalline cellulose, which is added in an amount of about 16.9%.
Comparative example 6
The difference between this comparative example and example 1 is that the glidant added to the fluid extract is maltodextrin, and the added amount of maltodextrin is about 9%.
Comparative example 7
The difference between this comparative example and example 1 is that the glidant added to the fluid extract is corn starch, and the amount of corn starch added is about 9%.
Comparative example 8
The glidant added into the fluid extract is maltodextrin and beta-cyclodextrin with the total addition amount of about 9%, and the mass ratio of the maltodextrin to the beta-cyclodextrin is 3:1.
Experimental example:
the dry extract powders prepared in examples 1 to 12 and comparative examples 1 to 8 were tested and the test results are shown in tables 1 and 2 below:
TABLE 1
TABLE 2
| Shovel tower powder weight (kg) | Gravity flow powder weight (kg) | Total paste yield (kg) | Yield of free flowing powder (%) | |
| Example 1 | 0.0 | 78.0 | 78.0 | 100％ |
| Example 2 | 0.0 | 36.9 | 36.9 | 100％ |
| Example 3 | 2.1 | 39.2 | 41.3 | 94.9％ |
| Example 4 | 2.8 | 36.8 | 39.6 | 92.9％ |
| Example 5 | 8.9 | 80.2 | 89.1 | 90.0％ |
| Example 6 | 0.0 | 39.9 | 39.9 | 100％ |
| Example 7 | 0 | 15.9 | 15.9 | 100％ |
| Example 8 | 15.0 | 53.0 | 68.0 | 77.9％ |
| Example 9 | 1.0 | 34.6 | 35.6 | 97.2％ |
| Example 10 | 2.1 | 31.0 | 33.1 | 93.7％ |
| Example 11 | 0.0 | 35.7 | 35.7 | 100％ |
| Example 12 | 0.0 | 37.1 | 37.1 | 100％ |
| Comparative example 1 | 35.0 | 6.0 | 41.0 | 14.6％ |
| Comparative example 2 | 28.0 | 10.0 | 38.0 | 26.3％ |
| Comparative example 3 | 19.5 | 28.0 | 47.5 | 58.9％ |
| Comparative example 4 | 18.7 | 11.5 | 30.2 | 38.1％ |
| Comparative example 5 | 38.0 | 55.0 | 93.0 | 59.1％ |
| Comparative example 6 | 17.9 | 16.8 | 34.7 | 48.4％ |
| Comparative example 7 | 17.0 | 13.6 | 30.6 | 44.4％ |
| Comparative example 8 | 14.7 | 23.4 | 38.1 | 61.4％ |
TABLE 3 Table 3
TABLE 4 Table 4
TABLE 5
As can be seen from table 3, the self-powder yield was improved by about 12% with 2% beta cyclodextrin compared to comparative example 1 without glidant, and by about 24% with 7% microcrystalline cellulose compared to comparative example 1 without glidant; however, in the embodiment 1, the beta cyclodextrin and the microcrystalline cellulose are added simultaneously, so that the self-flowing powder yield is improved by about 85%, and the effect is quite remarkable; it is enough to prove that the beta cyclodextrin and the microcrystalline cellulose are mutually matched to serve as the glidant to have a synergistic effect.
From the results of table 4, it was found that when one glidant was added alone, the free-flowing powder yield increased gradually with increasing contents of beta cyclodextrin and microcrystalline cellulose of the glidant, and when the addition amount of the glidant reached 17%, the free-flowing powder yield was the highest, but the highest free-flowing powder yield was only 59.1%. The beta cyclodextrin and the microcrystalline cellulose are matched in a specific proportion, so that when the total content reaches 17%, the self-flowing powder yield can be improved to 90%, and the effect is quite remarkable. In combination with the data of table 3, it is further demonstrated that beta cyclodextrin and microcrystalline cellulose in specific proportions and amounts added act synergistically with each other as glidants.
As can be seen from the data in table 5, the glidants were used in a ratio of 1: compared with other types or other types of compounded glidants disclosed in the prior art, the beta cyclodextrin and microcrystalline cellulose in the range of (1-6) can achieve a remarkably better effect, and the self-flowing powder yield can be improved to 100% by the combination of the specific types and proportions of the glidants and the addition of the content, so that the effect is quite remarkable.
And through data conversion in table 1, the method of the invention can not only achieve that the paste yield can be obviously improved to more than 80%, but also can achieve more than 90%, wherein the paste yield= (total paste yield-glidant addition)/theoretical paste yield.
It is apparent that the above examples are given by way of illustration only and are not limiting of the embodiments. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary here nor is it exhaustive of all embodiments. While still being apparent from variations or modifications that may be made by those skilled in the art are within the scope of the invention.
Claims (9)
1. The Danzhi Qing' e tablet dry paste powder is characterized by comprising the following raw materials: fluid extract of traditional Chinese medicine raw materials and a glidant accounting for 9-17% of the mass of the fluid extract; the glidant is prepared from the following components in percentage by mass: the beta-cyclodextrin and microcrystalline cellulose of (1-6), wherein the traditional Chinese medicine raw materials of the fluid extract are salted eucommia decoction pieces, rhizoma anemarrhenae decoction pieces and diacolated red sage root dregs, and the relative density of the fluid extract is 1.04-1.20 g/ml;
Obtaining fluid extract: extracting salted eucommia ulmoides decoction pieces, rhizoma anemarrhenae decoction pieces and percolating radix salviae miltiorrhizae decoction dregs with water, precipitating with ethanol, collecting supernatant, and concentrating to obtain fluid extract; the red sage herb residue after diacolation is red sage herb residue obtained by diacolation of red sage herb decoction pieces, wherein the red sage herb decoction pieces are 2 parts by weight, the salted eucommia bark decoction pieces are 2 parts by weight, and the rhizoma anemarrhenae decoction pieces are 1 part by weight;
and (3) obtaining dry paste powder: adding glidant into the fluid extract, mixing uniformly, and spray drying to obtain the dry extract powder of Danzhiqing E tablet.
2. The dry extract powder of danzhiqing tablet as claimed in claim 1, wherein when the glidant is 9-12% of the mass of the fluid extract, the glidant is 1: and (3-5) beta-cyclodextrin and microcrystalline cellulose.
3. The preparation process of the Danzhi Qing' e tablet dry paste powder is characterized by comprising the following steps:
obtaining fluid extract: extracting salted eucommia ulmoides decoction pieces, rhizoma anemarrhenae decoction pieces and diacolated red sage root decoction dregs with water, precipitating with ethanol, collecting an ethanol precipitation supernatant, and concentrating to obtain a fluid extract, wherein the relative density of the fluid extract is 1.04-1.20 g/ml; the red sage herb residue after diacolation is red sage herb residue obtained by diacolation of red sage herb decoction pieces, wherein the red sage herb decoction pieces are 2 parts by weight, the salted eucommia bark decoction pieces are 2 parts by weight, and the rhizoma anemarrhenae decoction pieces are 1 part by weight;
and (3) obtaining dry paste powder: adding a glidant accounting for 9-17% of the mass of the fluid extract, wherein the glidant comprises the following components in percentage by mass: beta-cyclodextrin and microcrystalline cellulose of (1-6); and (5) uniformly mixing, and then carrying out spray drying to obtain the dry paste powder of the Danzhiqing tablet.
4. The preparation process according to claim 3, wherein the decoction extract obtained after the water extraction is concentrated to a relative density of 1.06-1.20 g/ml, and then subjected to alcohol precipitation, wherein the alcohol content in the mixed solution is 65% -75% during the alcohol precipitation.
5. The preparation process according to claim 3 or 4, wherein the water extraction and alcohol precipitation process comprises the following steps:
Mixing the Chinese medicinal materials of the fluid extract with water, decocting to obtain decoction extract, and concentrating the decoction extract to obtain water extract concentrate; mixing the water concentrate with ethanol to obtain a mixed solution, and standing to obtain a supernatant;
concentrating the supernatant to obtain fluid extract.
6. The preparation process according to claim 5, wherein in the decocting step, water is 8-10 times of the weight of the raw materials of the traditional Chinese medicine;
And/or the temperature of the decoction is 95-100 ℃ and the extraction time is 1.5-3 h;
And/or the times of decoction are 2-3 times;
And/or the relative density of the water extraction concentrated solution is 1.06-1.20 g/ml;
and/or the ethanol standing time is 8-36 h;
And/or the concentration of the ethanol is 95%, and the dosage of the ethanol is 3 times of the weight of the water extraction concentrated solution.
7. The process according to claim 3 or 4, wherein the frequency of the liquid supply pump motor in the spray drying is 5-25 hz.
8. The preparation process according to claim 3 or 4, wherein the mass ratio of the beta-cyclodextrin to the microcrystalline cellulose is 1: (2-4);
and/or the addition amount of the glidant is 9-13% of the mass of the fluid extract.
9. A danzhi qing ' e composition, characterized by comprising a danzhi qing ' e tablet dry paste powder as claimed in any one of claims 1-2 or a danzhi qing ' e tablet dry paste powder prepared by the preparation process as claimed in any one of claims 3-8.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310247262.7A CN116270879B (en) | 2023-03-08 | 2023-03-08 | Danzhiqing tablet dry paste powder and preparation process and composition thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310247262.7A CN116270879B (en) | 2023-03-08 | 2023-03-08 | Danzhiqing tablet dry paste powder and preparation process and composition thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN116270879A CN116270879A (en) | 2023-06-23 |
| CN116270879B true CN116270879B (en) | 2024-06-07 |
Family
ID=86830113
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310247262.7A Active CN116270879B (en) | 2023-03-08 | 2023-03-08 | Danzhiqing tablet dry paste powder and preparation process and composition thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116270879B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103550484A (en) * | 2013-10-30 | 2014-02-05 | 天津中医药大学 | Pharmaceutical composition for adjusting estrogen level as well as preparation method and application thereof |
-
2023
- 2023-03-08 CN CN202310247262.7A patent/CN116270879B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103550484A (en) * | 2013-10-30 | 2014-02-05 | 天津中医药大学 | Pharmaceutical composition for adjusting estrogen level as well as preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN116270879A (en) | 2023-06-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101810793B (en) | Application of corn stigma flavone in preparing medicament for curing hyperlipidemia | |
| CN1785284B (en) | Medicinal composition containing flowery knotwood root | |
| RU2009144878A (en) | MEDICINAL PRODUCT FOR TREATMENT OF DIABETES AND METHOD OF ITS PRODUCTION | |
| CN109645481A (en) | Fibrous root of Radix Ophiopogonis extract and its preparation method and application | |
| CN106511484A (en) | Extracting preparation technology for compound honeysuckle granules | |
| CN104224911B (en) | A kind of new Salvia root P.E and its preparation | |
| CN116270879B (en) | Danzhiqing tablet dry paste powder and preparation process and composition thereof | |
| CN107281264A (en) | A kind of preparation method and Cortex cinnamomi japonici (Ramulus Cinnamomi) extract that Cortex cinnamomi japonici (Ramulus Cinnamomi) extract is produced from cinnamomi cortex pulveratus residue | |
| CN115919991A (en) | Cough-relieving radix asteris particle composition and preparation method thereof | |
| CN103494916B (en) | Traditional Chinese medicine composition with effect of reducing blood sugar, as well as preparation method and application thereof | |
| CN103655898B (en) | The FUFANG EJIAO JIANG of dysmenorrhea can be treated | |
| CN103599244B (en) | The FUFANG EJIAO JIANG of nourishing the stomach of can enriching blood and preparation technology thereof | |
| CN103494894B (en) | A kind of have Chinese medicine composition reducing blood glucose effect and its preparation method and application | |
| CN112656866A (en) | Peach red four-ingredient particle and preparation method thereof | |
| CN112274567A (en) | Licorice root and platycodon root granules and preparation method thereof | |
| CN109288957A (en) | Alkali extraction and acid precipitation extracts the method and products thereof of effective component in the easypro composition of invigorating heart | |
| CN110179027A (en) | A kind of rhizoma polygonati composite beverage and preparation | |
| CN114028526B (en) | A pharmaceutical composition for treating gastric precancerous lesion and gastric cancer, and its preparation method | |
| CN107875368A (en) | A kind of preparation method for being used for pregnant woman and helping the health care Chinese medicine of Recovery | |
| CN1194715C (en) | Processing method of medicinal powder for diabetes | |
| CN108685845A (en) | A kind of preparation method of youngster's Bao oral liquid | |
| CN116327869B (en) | Preparation method of Chinese patent medicine Qianqu | |
| CN111000881B (en) | Propolis soft capsule rich in flavone and belonging to genus Brazilian breynia and preparation method thereof | |
| CN108042682A (en) | A kind of Long Lu Zishuiqinggan ball and preparation method thereof | |
| CN109771491A (en) | A kind of preparation method from hawthorn powder residue production haw thorn extract |
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 | ||
| GR01 | Patent grant |