CN102225093A - Preparation of Magnolia flower volatile oil soft capsule for treating allergic rhinitis and associated diseases - Google Patents
Preparation of Magnolia flower volatile oil soft capsule for treating allergic rhinitis and associated diseases Download PDFInfo
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- CN102225093A CN102225093A CN2011101747653A CN201110174765A CN102225093A CN 102225093 A CN102225093 A CN 102225093A CN 2011101747653 A CN2011101747653 A CN 2011101747653A CN 201110174765 A CN201110174765 A CN 201110174765A CN 102225093 A CN102225093 A CN 102225093A
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Abstract
The invention relates to a preparation method and an application of a Magnolia flower volatile oil soft capsule for treating allergic rhinitis and associated diseases. The Magnolia flower volatile oil soft capsule contains the following ingredients in parts by volume: 1 to 90 parts of Magnolia flower volatile oil, 10 to 90 parts of oil phase, 0 to 50 parts of emulsifier and 0 to 30 of co-solvent. The Magnolia flower volatile oil soft capsule, provided by the invention, is also available in the form of an enteric-coated soft capsule, so as to reduce irritation to the stomach and enhance the patient compliance. The soft capsule provided by the invention is used for treating allergic rhinitis, acute rhinitis, simple rhinitis, hypertrophic rhinitis, atrophic rhinitis, acute nasosinusitis, chronic nasosinusitis or complications thereof, as well as respiratory diseases such as acute upper respiratory infection, acute/chronic obstructive lung disease and asthma, with remarkable curative effects.
Description
Technical field
The present invention relates to treat the Flos Magnoliae volatile oil preparation of soft capsule method of allergic rhinitis and relevant disease thereof.
Background technology
(Allergicrhinetis AR), is a kind ofly to suck the non-infectious inflammation based on type that extraneous allergen takes place by susceptible individual to allergic rhinitis, and Chang Fanfu shows effect and to cause the disease of nasal mucosa chronic inflammatory disease pathological changes.Be principal character with nasal obstruction, rhinocnesmus, stream clear water sample nasal mucus, sneeze clinically, its clinical definition be the nasal mucosa contact allergy former after, a series of sniffles that caused by the inflammatory reaction of IgE mediation are one of common diseases of hals,Nasen und Ohrenheilkunde.31 member state's roundups of international hals,Nasen und Ohrenheilkunde community of association (IFOR), AR crowd's prevalence about 20%.By 2009, from reporting prevalence, conservative estimation China AR actual patient should be more than 5,000 ten thousand according to the key city.In addition, AR other chronic respiratory tract diseases that often occur together, approximately occur together asthma or the bronchial hyperreactivity symptom is arranged of the AR patient of 60%-80%.If can not get correct treatment or malpractice, part patient even can develop into pulmonary heart disease etc. has a strong impact on patient's body Health and Living quality.Along with the change of industrial development and living environment, the sickness rate of allergic rhinitis has the trend of increasing in recent years, has become the global health problem that needs to be resolved hurrily.
Simultaneously, the patient uses medicine to cause great financial burden in order to control its symptom in a large number, shows that as the up-to-date investigation of the U.S. direct economy burden of allergic rhinitis patients is 5,000,000,000 dollars, and this does not comprise the cost of over-the-counter drug.In the selecting for use of prescription class medicine, most of patients was used nasal spray in the past 1 month, wherein used the nose corticosteroid hormone up to 83% patient.More up to 99%, Canada's investigation shows that also 62% doctor can select the nose corticosteroid hormone when prescribing in this numeral of Canada.Aspect drug side effect, cause among the patient, the severe discomfort mainly be: dry sensation (34%), medicine flow into bottleneck throat (33%), drowsiness (33%), headache (25%), bad taste (22%) and burn feeling (18%).
Other medicine that often uses also has Decongestant, mast cell stabilizers, anticholinergic agent, antihistaminic and LTRA etc.Wherein Decongestant comprises oxymetazoline hydrochloride, phenylephrine, ephedrine of oral pseudoephedrine, phenylephrine and nasal cavity topical application etc.The untoward reaction of oral Decongestant has excitement, nasal mucosa drying, glaucoma, pain, hypertension (non-selective vasoconstriction type), insomnia, dysphoria, trembles, urine retention, cardiopalmus, tachycardia and premature contraction etc.The representative medicine of mast cell stabilizers is a sodium chromoglicate, but mechanism of action is not quite clear.But sodium chromoglicate is effective with corticosteroids not as good as oral antihistaminic medicine and nose.Be generally prophylactic, its untoward reaction mainly shows as sneeze, intranasal burning sensation etc.The anticholinergic agent that is used for the treatment of allergic rhinitis has ipratropium bromide etc., is mainly used in the alleviation Rhinorrhea, but can not improve symptoms such as nasal congestion, sneeze, rhinocnesmus, and main adverse reaction is dry nasal cavity and epistaxis.Antihistaminic is the conventional medicament of treatment of allergic rhinitis, also is clinical practice medicine the most widely, can improve the symptom of inductive allergic rhinitis symptom of histamine such as rhinorrhea, rhinocnesmus, sneeze and relevant throat and eye effectively, but invalid to nasal congestion.
Allergic rhinitis claims allergic rhinitis again, belongs to Chinese medicine " allergic rhinitis " category.Be cardinal symptom with burst rhinocnesmus, sneeze, snivel clinically, severe patient hyposmia or disappearance have brought bigger misery to the patient.Primary disease has the sickness rate height, is difficult for the characteristics of radical cure.
Flos Magnoliae is a Chinese traditional treatment nasosinusitis headache key medicine, has functions such as dispersing wind and cold, clearing the nasal passage, is used for headche due to wind-cold, nasal obstruction, nasal sinusitis, turbid nasal discharge." herbal classic " carries, Flos Magnoliae " main the five internal organs health cold and heat, wind syndrome of head headache, face husband ".Compendium of Material Medica is said: " nasal sinusitis, nose spoke, stuffy nose, nasal abscess after nasal abscess and the pox "." the suffering temperature of Flos Magnoliae, flat and go into lung, can help in the stomach clear sun up, thus can warming middle-JIAO, control the disease of women's head-ornaments order nose ".Flos Magnoliae mainly contains volatile oil; compositions such as lignanoid; wherein volatile oil component has antiallergic; antiinflammatory; effects such as antihistaminic and protection mastocyte and nasal mucosa; by many target spots; the different mechanisms of action are collaborative has an effect to allergic rhinitis; therefore it is obvious to treat the allergic rhinitis effect clinically, simultaneously for acute rhinitis; the simple rhinitis; hypertrophic rhinitis; the atrophic rhinitis; acute sinusitis; chronic sinusitis or its complication; acute upper respiratory tract infection; the acute and chronic obstructive pulmonary disease; the treatment of respiratory tract diseases such as asthma all has tangible clinical efficacy.
Summary of the invention
The object of the present invention is to provide the extraction of the Flos Magnoliae volatile oil that is used for the treatment of allergic rhinitis and relevant disease thereof and the preparation method of preparation.
Flos Magnoliae of the present invention is selected from Magnoliacea plant Flos Magnoliae Magnolia biondii Pamp., YULAN M.denudate Desr., Flos Magnoliae M.sprengeri Pamp., Drymotaenium miyoshianum (Mak.) Mak. M.lilifloraDesr1 or belong to the dry flower of other kind of plant together.
Flos Magnoliae volatile oil extracting method of the present invention is selected from steam distillation or supercritical carbon dioxide extraction method, described steam distillation may further comprise the steps: 1) Flos Magnoliae medical material or its coarse powder, put in the volatile oil extraction equipment, 2) water of 5～15 times of amounts of adding medical material weight, soaked 0～24 hour, 3) heating is steamed and was slipped 4 1～24 hour) collect volatile oil fraction, promptly.
Wet concentration of the present invention is preferably purified water from any or its combination of purified water, deionized water, distilled water.
Further, 1) step Flos Magnoliae medical material or its coarse powder, preferred coarse powder.
Further, 2) consumption of described water of step be Flos Magnoliae medical material amount 5-15 doubly, be preferably 8-12 doubly, more excellent is 10～12 times, optimum is 12 times.
Further, 2) described soak time is 0～24 hour the step, and preferred 4～16 hours, more excellent was 6～12 hours, and optimum is 8 hours.
Further.3) going on foot described distillation time is 1～24 hour, and preferred 4～16 hours, more excellent was 6～12 hours, and optimum is 9 hours.
Further, can be 3) charge into protective gas in the step still-process, described protective gas is selected from any or its combination of nitrogen, helium, is preferably nitrogen.
Described supercritical carbon dioxide extraction method may further comprise the steps: 1) Flos Magnoliae medical material or its coarse powder, put in the supercritical carbon dioxide extraction device, 2) with the carbon dioxide be extractant, extracting pressure is 10～40MPa (MPa, MPa), extraction temperature is 20～60 ℃, and separating pressure is 2.0～10.0MPa, separation temperature is 20～80 ℃, and the extraction time is 0.5～8 hour.
3) collect extract.
Further, 1) step Flos Magnoliae medical material or its coarse powder, preferred coarse powder.
Further, 2) extracting pressure of described carbon dioxide of step is 10～40MPa (MPa, a MPa), and extraction temperature is 20～60 ℃; Preferred extracting pressure is 20～30MPa (MPa, a MPa), and extraction temperature is 30～50 ℃.
Further, 2) described separating pressure is 2.0～10.0MPa the step, and separation temperature is 20～80 ℃; Preferred 4.0～8.0MPa, separation temperature is 30～70 ℃; More excellent is 6.0～7.0MPa, and separation temperature is 50～60 ℃.
Further, 2) the described extraction time in step is 0.5～8 hour; Preferred 1.0～4.0 hours; More excellent is 2～3.0 hours.
Flos Magnoliae volatile oil of the present invention can be made into various dosage form well known in the art, and can adopt the preparation technique of this area routine to prepare.Be suitable for preparation of the present invention and be selected from soft capsule.
Flos Magnoliae volatile oil soft capsule preparation of the present invention is made up of content and softgel shell, and content is made up of Flos Magnoliae volatile oil and adjuvant, and described adjuvant includes but are not limited to oil phase, emulsifying agent, solubilizing agent, antioxidant, antibacterial, odorant etc.
Oil phase includes but not limited to a kind of or its mixture in oil, the Polyethylene Glycol.Its medium oil comprises vegetable oil (soybean oil; Oleum Brassicae campestris; Oleum sesami; Semen Maydis oil; almond oil; Petiolus Trachycarpi oil; olive oil; Oleum Camelliae; Radix Oenotherae erythrosepalae oil; safflower oil); oleic acid and oleate (methyl oleate thereof; ethyl oleate; olein); glyceryl linoleate; (Arlacel 20 for fatty acid sorbitol ester; Arlacel 60; Arlacel 80; Arlacel 86); (Miglol 810 for the Miglol neutral fat; 812; 818; 829,840); acrylic ethylene glycol laurate; Polyethylene Glycol-6-iso stearic acid of glycerine ester; Polyethylene Glycol-12-hydroxy stearic acid ester; the Polyethylene Glycol glyceryl laurate ester; Oleum Cocois C8/C10 propylene glycol monoester or dibasic acid esters; Oleum Cocois C8/C10 glyceride (Oleum Cocois C8/C10 monoglyceride; Oleum Cocois C8/C10 glycerol dibasic acid esters; Oleum Cocois C8/C10 triglyceride); the acetylizad monoglyceride of purification; purification Oleum helianthi monoglyceride; in the triglyceride of oleic acid (25%) and linoleic acid (54%).Polyethylene Glycol comprises Macrogol 200, PEG400, Macrogol 600.Select one or more mixture for use.
Emulsifying agent comprise but be not limited to lecithin, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, poloxamer, polysorbate, dehydration polysorbate, Oleum Cocois C8/C10 polyethyleneglycol glyceride, almond oil oleic acid polyethyleneglycol glyceride, almond oil oleic acid polyethyleneglycol glyceride, polyoxyethylene (25) triolein, polyoxyethylene (20) sorbitan oleate, Polyethylene Glycol-8 glycerol sad/certain herbaceous plants with big flowers acid esters etc., select one or more mixture for use.
Cosolvent includes but not limited to long-chain alcohol, ethylene glycol, propylene glycol, glycerol, polyglycereol derivant, ethanol, isopropyl alcohol, glycerol, Polyethylene Glycol, ethylene glycol monomethyl ether, propylene carbonate etc., selects one or more mixture for use.
The used capsule material of the present invention comprises sizing material, plasticizer, additives and water.Wherein sizing material is selected from gelatin, arabic gum, selects one or more mixture for use; Plasticizer is selected from glycerol, sorbitol, selects one or more mixture for use; Additives comprise antiseptic, pigment, spice, opacifier and solubilizing agent etc.Wherein antiseptic is selected from methyl parahydroxybenzoate, propyl p-hydroxybenzoate, selects one or more mixture for use; Pigment is selected from water colo(u)r.
Further, to select gelatin-glycerol-water for use be the capsule material to softgel shell; Gelatin in the softgel shell: the weight ratio of glycerol is 20～150: 20～80; Be preferably 60～120: 30～60, more excellent is 80～100: 40～50.
Further, after suppressing at soft capsule, finalizing the design, wash ball, drying, can outside softgel shell, wrap the macromolecule enteric coat.To reduce soft capsule disintegrate sense of discomfort that the part patient is caused under one's belt, improve patient's compliance.
Further, described macromolecule enteric coat is this area enteric coat commonly used, include but not limited to formaldehyde-gelatin, Lac (Shellac), Cellulose Acetate Phthalate (CAP), the copolymer of acrylic acid and methacrylic acid, methacrylic acid-methylmethacrylate copolymer, methacrylic acid-acrylate copolymer, ethyl acrylate-methacrylate copolymer, cellulose acetate, ethyl cellulose, polyacrylic resin, EUDRAGIT NE 30 D EUDRAGIT NE 30D, this dicarboxylic acid esters of polyvinyl acetate (PVAP), phthalic acid hypromellose ester (HPMCP), hydroxypropyl emthylcellulose peptide acid esters, succinic acid acetic acid hydroxypropyl methylcellulose (HPMCAS) or crosslinked alginate etc. are preferably phthalic acid hypromellose ester (HPMCP), hydroxypropyl emthylcellulose peptide acid esters, pH sensitivity methacrylic acid copolymer, methacrylate copolymer.
When adopting the HPMCP material,, improve the water proofing property of coatings, between softgel shell and macromolecule coatings, wrap up transition zone in order to increase the compatibility of HPMCP and gelatin as the enteric coating coating material.In order to improve the outward appearance of enteric soft capsules, at coatings outer wrapping polishing layer.Therefore macromolecule enteric coating of the present invention is made up of transition zone, enteric coating layer and polishing layer successively.
Further, transition zone of the present invention consists of: with volume ratio is 70～90% alcoholic solution, hydroxypropyl emthylcellulose (phthalic acid hypromellose ester with 5～20 weight portions, HPMC, 60RT50) (HPMCP HP55) makes the solution of 1000 parts by volume with the hydroxypropyl emthylcellulose peptide acid esters of 15～50 weight portions; The volume ratio of preferred alcohol solution is 75～85%, more preferably 80%; The weight portion of preferred hydroxypropyl emthylcellulose is 7～15, more preferably 9～12, most preferably be 10～11; The weight portion of preferred hydroxypropyl methyl peptide acid esters is 20～40, more preferably 30～35, most preferably be 31～32.
Further, enteric coating layer of the present invention consists of: with volume ratio is 70～90% alcoholic solution, hydroxypropyl emthylcellulose peptide acid esters (phthalic acid hypromellose ester with 30～100 weight portions, HPMCP HP55) makes the solution of 1000 parts by volume with the dibutyl phthalate of 5～30 weight portions; The volume ratio of preferred alcohol solution is 75～85%, more preferably 80%; The weight portion of preferred hydroxypropyl emthylcellulose peptide acid esters is 40～90, more preferably 50～80, most preferably be 62～65; The weight portion of preferred dibutyl phthalate is 10～25, more preferably 15～20, most preferably be 15～18.
Further, polishing layer of the present invention consists of: with volume ratio is 70～90% alcoholic solution, and (HPMC 60RT50) makes the solution of 1000 parts by volume with the hydroxypropyl emthylcellulose of 10～30 weight portions; The volume ratio of preferred alcohol solution is 75～85%, more preferably 80%; The weight portion of preferred hydroxypropyl emthylcellulose is 15～25, more preferably 20～22.
Further, the consumption of macromolecule enteric coating is 1～10%, is preferably 2～8%, more preferably 6～7%.
When using pH sensitivity methacrylic acid copolymer and methacrylate copolymer as the enteric coating coating material, adopt mixing enteric coating coating solution to carry out coating, between softgel shell and macromolecule coatings, do not need to wrap up transition zone, at coatings outer wrapping polishing layer or do not wrap up polishing layer.
Further, enteric coating layer coating solution of the present invention is formed and preparation method is, with weight ratio is glyceryl monostearate 0.1-2%, tween 80 0.1-1.0%, add water and be prepared into emulsion, getting weight ratio then is the aqueous dispersion 2-20% of methacrylate copolymer, adds behind the thin up in the above-mentioned emulsion, add pH sensitivity methacrylic acid copolymer aqueous dispersion 10-80% again, mix and form.Preferred glyceryl monostearate 0.5-1.5%, tween 80 0.2-0.5%, the aqueous dispersion 5-15% of methacrylate copolymer, pH sensitivity methacrylic acid copolymer aqueous dispersion 20-50%.Glyceryl monostearate 1.0-1.5% more preferably, tween 80 0.2-0.5%, the aqueous dispersion 8-11% of methacrylate copolymer, pH sensitivity methacrylic acid copolymer aqueous dispersion 35-45%.
Further, in order to increase the film property in the coating process, can add the Polyethylene Glycol of 10-40% in above-mentioned enteric coating coating solution, Polyethylene Glycol comprises Macrogol 4000, polyethylene glycol 6000, Polyethylene Glycol 8000.With weight ratio is the 10-30% of above-mentioned coating solution, is preferably 15-25%.
The preparation method of Flos Magnoliae volatile oil soft capsule preparation of the present invention, its step is as follows:
1. the content proportion of composing part is 1～90 part of Flos Magnoliae volatile oil, 10～90 parts of oil phases, 0～50 part of emulsifying agent, 0～30 part of cosolvent by volume; Optimizing proportioning is 30～60 parts of Flos Magnoliae volatile oils, 25～50 parts of disperse medium, 0～20 part of emulsifying agent, 0～20 part of solubilizing agent.More excellent proportioning is 40～50 parts of Flos Magnoliae volatile oils, 30～40 parts of disperse medium, 0～10 part of emulsifying agent, 0～10 part of solubilizing agent.
Further, oil phase is selected from a kind of or its mixture in oil, the Polyethylene Glycol.Oil comprises vegetable oil (soybean oil; Oleum Brassicae campestris; Oleum sesami; Semen Maydis oil; almond oil; Petiolus Trachycarpi oil; olive oil; Oleum Camelliae; Radix Oenotherae erythrosepalae oil; safflower oil); oleic acid and oleate (methyl oleate thereof; ethyl oleate; olein); glyceryl linoleate; (Arlacel 20 for fatty acid sorbitol ester; Arlacel 60; Arlacel 80; Arlacel 86); (Miglol 810 for the Miglol neutral fat; 812; 818; 829,840); acrylic ethylene glycol laurate; Polyethylene Glycol-6-iso stearic acid of glycerine ester; Polyethylene Glycol-12-hydroxy stearic acid ester; the Polyethylene Glycol glyceryl laurate ester; Oleum Cocois C8/C10 propylene glycol monoester or dibasic acid esters; Oleum Cocois C8/C10 glyceride (Oleum Cocois C8/C10 monoglyceride; Oleum Cocois C8/C10 glycerol dibasic acid esters; Oleum Cocois C8/C10 triglyceride); the acetylizad monoglyceride of purification; purification Oleum helianthi monoglyceride; in the triglyceride of oleic acid (25%) and linoleic acid (54%).Polyethylene Glycol comprises Macrogol 200, PEG400, Macrogol 600.Select one or more mixture for use.
Further, emulsifying agent be selected from lecithin, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, poloxamer, polysorbate, dehydration polysorbate, Oleum Cocois C8/C10 polyethyleneglycol glyceride, almond oil oleic acid polyethyleneglycol glyceride, almond oil oleic acid polyethyleneglycol glyceride, polyoxyethylene (25) triolein, polyoxyethylene (20) sorbitan oleate, Polyethylene Glycol-8-glycerol sad/certain herbaceous plants with big flowers acid esters etc., select one or more mixture for use.
Further, cosolvent is selected from long-chain alcohol, ethylene glycol, propylene glycol, glycerol, polyglycereol derivant, ethanol, isopropyl alcohol, glycerol, Polyethylene Glycol, ethylene glycol monomethyl ether, propylene carbonate etc., selects one or more mixture for use.
2. get the foregoing thing and form, mix in proportion, promptly.
3. get above-mentioned Flos Magnoliae volatile oil soft capsule content, put encapsulating machine, adjust the rotating speed of encapsulating machine, loading amount control, temperature control makes press temperature be controlled at 40～55 ℃, and setting temperature is 10～20 ℃, is pressed into ball.
Further, the used capsule material of the present invention comprises sizing material, plasticizer, additives and water.
Further, sizing material is selected from gelatin, arabic gum, selects one or more mixture for use.
Further, plasticizer is selected from glycerol, sorbitol, selects one or more mixture for use.
Further, additives comprise antiseptic, pigment, spice, opacifier and solubilizing agent etc.Wherein antiseptic is selected from methyl parahydroxybenzoate, propyl p-hydroxybenzoate, selects one or more mixture for use;
Further, pigment is selected from water colo(u)r.
Further, to select gelatin-glycerol-water for use be the capsule material to softgel shell; Gelatin in the softgel shell: the weight ratio of glycerol is 20～150: 20～80; Be preferably 60～120: 30～60, more excellent is 80～100: 40～50.
4. the Flos Magnoliae volatile oil soft capsule that makes of pressure is put the blowing of low temperature below 10 ℃ typing 4～10 hours, takes out in 20-48 hour in low temperature blowing more than 10 ℃ then.Behind the oil reservoir of ethanol flush away soft gelatin capsule surface, descended dry 24～48 hours at 40～50 ℃ again, promptly.
5. get stereotyped soft capsule, put in the coating pan bag macromolecule enteric coating, it is moistening to spray into ethanol earlier, sprays into transition zone then, sprays into enteric coating layer again, sprays into polishing layer at last, drying, promptly.
Further, described macromolecule enteric coat is this area enteric coat commonly used, include but not limited to formaldehyde-gelatin, Lac (Shellac), Cellulose Acetate Phthalate (CAP), the copolymer of acrylic acid and methacrylic acid, methacrylic acid-methylmethacrylate copolymer, methacrylic acid-acrylate copolymer, ethyl acrylate-methacrylate copolymer, cellulose acetate, ethyl cellulose, polyacrylic resin, EUDRAGIT NE 30 D EUDRAGIT NE 30D, this dicarboxylic acid esters of polyvinyl acetate (PVAP), phthalic acid hypromellose ester (HPMCP), hydroxypropyl emthylcellulose peptide acid esters (HPMC), succinic acid acetic acid hydroxypropyl methylcellulose (HPMCAS) or crosslinked alginate etc. are preferably phthalic acid hypromellose ester (HPMCP) or hydroxypropyl emthylcellulose peptide acid esters (HPMC).
Further, described transition zone consists of: with volume ratio is 70～90% alcoholic solution, hydroxypropyl emthylcellulose (phthalic acid hypromellose ester with 5～20 weight portions, HPMC, 60RT50) (HPMCP HP55) makes the solution of 1000 parts by volume with the hydroxypropyl emthylcellulose peptide acid esters of 15～50 weight portions; The volume ratio of preferred alcohol solution is 75～85%, more preferably 80%; The weight portion of preferred hydroxypropyl emthylcellulose is 7～15, more preferably 9～12, most preferably be 10～11; The weight portion of preferred hydroxypropyl methyl peptide acid esters is 20～40, more preferably 30～35, most preferably be 31～32.
Further, described enteric coating layer consists of: with volume ratio is 70～90% alcoholic solution, hydroxypropyl emthylcellulose peptide acid esters (phthalic acid hypromellose ester with 30～100 weight portions, HPMCP HP55) makes the solution of 1000 parts by volume with the dibutyl phthalate of 5～30 weight portions; The volume ratio of preferred alcohol solution is 75～85%, more preferably 80%; The weight portion of preferred hydroxypropyl emthylcellulose peptide acid esters is 40～90, more preferably 50～80, most preferably be 62～65; The weight portion of preferred dibutyl phthalate is 10～25, more preferably 15～20, most preferably be 15～18.
Further, described polishing layer consists of: with volume ratio is 70～90% alcoholic solution, and (HPMC 60RT50) makes the solution of 1000 parts by volume with the hydroxypropyl emthylcellulose of 10～30 weight portions; The volume ratio of preferred alcohol solution is 75～85%, more preferably 80%; The weight portion of preferred hydroxypropyl emthylcellulose is 15～25, more preferably 20～22.
When using pH sensitivity methacrylic acid copolymer and methacrylate copolymer, adopt mixing enteric coating coating solution to carry out coating as the enteric coating coating material.
Further, enteric coating layer coating solution of the present invention is formed and preparation method is, with weight ratio is glyceryl monostearate 0.1-2%, tween 80 0.1-1.0%, add water and be prepared into emulsion, getting weight ratio then is the aqueous dispersion 2-20% of methacrylate copolymer, adds behind the thin up in the above-mentioned emulsion, add pH sensitivity methacrylic acid copolymer aqueous dispersion 10-80% again, mix and form.Preferred glyceryl monostearate 0.5-1.5%, tween 80 0.2-0.5%, the aqueous dispersion 5-15% of methacrylate copolymer, pH sensitivity methacrylic acid copolymer aqueous dispersion 20-50%.Glyceryl monostearate 1.0-1.5% more preferably, tween 80 0.2-0.5%, the aqueous dispersion 8-11% of methacrylate copolymer, pH sensitivity methacrylic acid copolymer aqueous dispersion 35-45%.
Further, in order to increase the film property in the coating process, can add the Polyethylene Glycol of 10-40% in above-mentioned enteric coating coating solution, Polyethylene Glycol comprises Macrogol 4000, polyethylene glycol 6000, Polyethylene Glycol 8000.With weight ratio is the 10-30% of above-mentioned coating solution, is preferably 15-25%.
The Flos Magnoliae volatile oil soft capsule of the present invention preparation have bioavailability height, good airproof performance, quantitatively accurately, characteristics such as good stability, good looking appearance.Its enteric coating soft capsule can make medicine in upper part of small intestine dissolving and absorption, to reduce the sense of discomfort of part patient to medicine, increases the compliance that the patient takes.
Another object of the present invention is that the Flos Magnoliae volatile oil soft capsule is in the application that prevents and treats allergic rhinitis and relevant disease thereof; Described allergic rhinitis and relevant disease thereof are selected from respiratory tract diseases such as allergic rhinitis, acute rhinitis, simple rhinitis, hypertrophic rhinitis, atrophic rhinitis, acute sinusitis, chronic sinusitis or its complication, acute upper respiratory tract infection, acute and chronic obstructive pulmonary disease, asthma.This soft capsule all has for above-mentioned disease treats good therapeutical effect.
The specific embodiment
Specify the present invention below with reference to embodiment, embodiments of the invention only are used to technical scheme of the present invention is described, and non-limiting essence of the present invention.
Embodiment 1The preparation of Flos Magnoliae soft capsule
1, the preparation of Flos Magnoliae volatile oil
Get Flos Magnoliae medical material 10kg, be ground into coarse powder, put in the volatile oil extractor, add the 120kg demineralized water, soaked 8 hours, added thermal distillation 9 hours, collect volatile oil; The a small amount of anhydrous sodium sulfate dehydration of collecting of volatile oil gets transparent faint yellow volatile oil.
2, the preparation of Flos Magnoliae volatile oil soft capsule content
Get above-mentioned Flos Magnoliae volatile oil 300ml, add soybean oil 340ml, propylene glycol 30ml, mix homogeneously promptly gets the Flos Magnoliae volatile oil soft capsule content.
3. the molding of Flos Magnoliae volatile oil soft capsule
Get above-mentioned Flos Magnoliae volatile oil soft capsule content, put encapsulating machine, adjust the rotating speed of encapsulating machine, loading amount control, temperature control makes press temperature be controlled at 40～55 ℃, and setting temperature is 10～20 ℃, is pressed into 1000 balls.
4. the typing of Flos Magnoliae volatile oil soft capsule
The Flos Magnoliae volatile oil soft capsule that pressure makes is put the blowing of low temperature below 10 ℃ typing 4～10 hours, takes out in 20-48 hour in low temperature blowing more than 10 ℃ then.Behind the oil reservoir of ethanol flush away soft gelatin capsule surface, descended dry 24～48 hours at 40～50 ℃ again, promptly.
Embodiment 2The preparation of Flos Magnoliae soft capsule
1. the preparation of Flos Magnoliae volatile oil
Get Flos Magnoliae medical material 10kg, be ground into coarse powder, put in the volatile oil extractor, add the 120kg demineralized water, soaked 8 hours, added thermal distillation 9 hours, collect volatile oil; The a small amount of anhydrous sodium sulfate dehydration of collecting of volatile oil gets transparent faint yellow volatile oil.
2. the preparation of Flos Magnoliae volatile oil soft capsule content
Get above-mentioned Flos Magnoliae volatile oil 300ml, add soybean oil 250ml, propylene glycol 30ml, lecithin 90ml, mix homogeneously promptly gets the Flos Magnoliae volatile oil soft capsule content.
3. the molding of Flos Magnoliae volatile oil soft capsule
Get above-mentioned Flos Magnoliae volatile oil soft capsule content, put encapsulating machine, adjust the rotating speed of encapsulating machine, loading amount control, temperature control makes press temperature be controlled at 40～55 ℃, and setting temperature is 10～20 ℃, is pressed into 1000 balls.
4. the typing of Flos Magnoliae volatile oil soft capsule
The Flos Magnoliae volatile oil soft capsule that pressure makes is put the blowing of low temperature below 10 ℃ typing 4～10 hours, takes out in 20-48 hour in low temperature blowing more than 10 ℃ then.Behind the oil reservoir of ethanol flush away soft gelatin capsule surface, descended dry 24～48 hours at 40～50 ℃ again, promptly.
Embodiment 3-5The Flos Magnoliae volatile oil preparation of soft capsule
Flos Magnoliae volatile oil 300ml among the embodiment 2-4 adds soybean oil 250ml, propylene glycol 30ml, and lecithin 90ml prepares its extract and soft capsule according to the preparation method of embodiment 1, and investigates its yield rate, the results are shown in Table 1.
The composition of table 1 embodiment 2-4 drop pill and yield rate are investigated
The result shows: soft capsule of the present invention has stable processing technique, product percent of pass height, advantages such as steady quality.
Embodiment 6The Flos Magnoliae volatile oil preparation of soft capsule
1. the preparation of Flos Magnoliae volatile oil
Get Flos Magnoliae medical material 10kg, be ground into coarse powder, put in the volatile oil extractor, add the 120kg demineralized water, soaked 8 hours, added thermal distillation 9 hours, collect volatile oil; The a small amount of anhydrous sodium sulfate dehydration of collecting of volatile oil gets transparent faint yellow volatile oil.
2. the preparation of Flos Magnoliae volatile oil soft capsule content
Get above-mentioned Flos Magnoliae volatile oil 300ml, add decanoyl/octanoyl glycerides 100ml, polyoxyethylene castor oil 250ml mixes under 30 ℃ of temperature and makes it become homogeneous, transparent solution, promptly gets the Flos Magnoliae volatile oil soft capsule content.
3. the molding of Flos Magnoliae volatile oil soft capsule
Get above-mentioned Flos Magnoliae volatile oil soft capsule content, put encapsulating machine, adjust the rotating speed of encapsulating machine, loading amount control, temperature control makes press temperature be controlled at 40～55 ℃, and setting temperature is 10～20 ℃, is pressed into 1000 balls.
4. the typing of Flos Magnoliae volatile oil soft capsule
The Flos Magnoliae volatile oil soft capsule that pressure makes is put the blowing of low temperature below 10 ℃ typing 4～10 hours, takes out in 20-48 hour in low temperature blowing more than 10 ℃ then.Behind the oil reservoir of ethanol flush away soft gelatin capsule surface, descended dry 24～48 hours at 40～50 ℃ again, promptly.
Embodiment 7The preparation of Flos Magnoliae volatile oil enteric soft capsules
1. the preparation of Flos Magnoliae volatile oil
Get Flos Magnoliae medical material 10kg, be ground into coarse powder, put in the volatile oil extractor, add the 120kg demineralized water, soaked 8 hours, added thermal distillation 9 hours, collect volatile oil; The a small amount of anhydrous sodium sulfate dehydration of collecting of volatile oil gets transparent faint yellow volatile oil.
2. the preparation of Flos Magnoliae volatile oil soft capsule content
Get above-mentioned Flos Magnoliae volatile oil 300ml, add decanoyl/octanoyl glycerides 100ml, polyoxyethylene castor oil 250ml mixes under 30 ℃ of temperature and makes it become homogeneous, transparent solution, promptly gets the Flos Magnoliae volatile oil soft capsule content.
3. the molding of Flos Magnoliae volatile oil soft capsule
Get above-mentioned Flos Magnoliae volatile oil soft capsule content, put encapsulating machine, adjust the rotating speed of encapsulating machine, loading amount control, temperature control makes press temperature be controlled at 40～55 ℃, and setting temperature is 10～20 ℃, is pressed into 1000 balls.
4. the typing of Flos Magnoliae volatile oil soft capsule
The Flos Magnoliae volatile oil soft capsule that pressure makes is put the blowing of low temperature below 10 ℃ typing 4～10 hours, takes out in 20-48 hour in low temperature blowing more than 10 ℃ then.Behind the oil reservoir of ethanol flush away soft gelatin capsule surface, descended dry 24～48 hours at 40～50 ℃ again, promptly.
5. the Flos Magnoliae volatile oil soft capsule is enteric coated
Soft capsule is put in the coating pan, and it is moistening to spray into 80% ethanol earlier, sprays into transition zone then, and weightening finish 0.5～1.0% sprays into enteric coating layer weightening finish 5～7% again, sprays into polishing layer weightening finish 0.2～0.5 at last, drying, promptly.
1) transition zone consists of: with volume ratio is 80 alcoholic solution, hydroxypropyl emthylcellulose (phthalic acid hypromellose ester with 10 weight portions, HPMC, 60RT50) (HPMCP HP55) makes the solution of 1000 parts by volume with the hydroxypropyl emthylcellulose peptide acid esters of 31 weight portions.
2) enteric coating layer consists of: with volume ratio is 80% alcoholic solution, hydroxypropyl emthylcellulose peptide acid esters (phthalic acid hypromellose ester with 63 weight portions, HPMCP HP55) makes the solution of 1000 parts by volume with the dibutyl phthalate of 15 weight portions.
3) polishing layer consists of: with volume ratio is 80% alcoholic solution, and (HPMC 60RT50) makes the solution of 1000 parts by volume with the hydroxypropyl emthylcellulose of 20 weight portions.
Embodiment 8-10The preparation of Flos Magnoliae volatile oil enteric soft capsules
Get Flos Magnoliae volatile oil 300ml by the foregoing description 8, add decanoyl/octanoyl glycerides 100ml, polyoxyethylene castor oil 250ml mixes under 30 ℃ of temperature and makes it become homogeneous, transparent solution, promptly gets the Flos Magnoliae volatile oil soft capsule content.Put encapsulating machine, press temperature is controlled at 40～55 ℃, and setting temperature is 10～20 ℃, is pressed into 1000 balls.The typing back is enteric coated.The results are shown in Table 2.
The composition of table 2 embodiment 8-10 drop pill and yield rate are investigated
The result shows: soft capsule of the present invention has stable processing technique, product percent of pass height, advantages such as steady quality.Can reduce the sense of discomfort of part patient, increase the compliance that the patient takes medicine.
Test example 1The Flos Magnoliae volatile oil soft capsule is to the effect of experimental allergic rhinitis
1. experiment material
1.1 experiment medicine and main agents: the Flos Magnoliae volatile oil soft capsule, every contains Flos Magnoliae volatile oil 300 μ l/ grains; Loratadine tablet [the accurate word H20051927 of traditional Chinese medicines]; 2,4-toluene-2,4-diisocyanate (TDI) (Chinese Shanghai reagent one factory).
1.2 laboratory animal: Cavia porcellus, male and female half and half, body weight 350～400g, medical faunae center, Department Of Medicine, Peking University provides.
1.3 statistical analysis technique: adopt SPSS 20.0 statistical softwares to analyze.
2 Flos Magnoliae volatile oil soft capsules are to the effect of Cavia porcellus allergic rhinitis model
2.1 animal modeling grouping and administration: adopt the TDI olive oil solution 10 μ l collunarium modelings of Cavia porcellus 10%.Score value divides into groups, administration according to marking in modeling success back.Blank group and model control group are irritated stomach normal saline 1.25mL/kg, positive controls gives loratadine 100mg/kg medicinal liquid, Drug therapy component low dose group (50 μ l/kg), middle dosage group (100 μ l/kg) and high dose group (200 μ l/kg), successive administration 14 days.
2.2 sniffle is observed: from sensitization the 9th day (being administration the 2nd day), situation and weight that observed and recorded sniffle such as rhinocnesmus, sneeze, watery nasal discharge etc. occur, the next day observation 1 time, according to the table 3 standard record of marking.Be in the 30min behind the TDI observing time.
Table 3 Cavia porcellus experimental allergic rhinitis symptom standards of grading
Result: model control group: typical rhinocnesmus, sneeze and thin nasal discharge appear in the TDI administration after 5 days.The blank group does not have tangible rhinocnesmus, sneeze and thin nasal discharge.Positive controls promptly alleviates (P＜0.05) in the 2nd day symptom of administration, administration after the 6th day symptom obviously alleviate (P＜0.01).The symptom of medication therapy groups after administration the 2nd day with the model control group no significant difference, administration after 3 days symptom begin to alleviate (P＜0.05), administration after the 6th day symptom obviously alleviate, difference has significance meaning (P＜0.01).
2.3 nasal mucosa Determination of thickness: after the Cavia porcellus femoral artery sacrificed by exsanguination, peel off nose upper jaw osseous part skin, upper jaw bone is dissociated out from skull, cut open along the nose center line, expose nasal septum and bilateral nasal cavity, the preceding stage casing of nasal septum is cut, be fixed in 10% formalin 72h, put into the decalcifying Fluid decalcification again 3 days, dehydration of alcohol, transparent step by step, paraffin embedding, conventional section 4 μ m, HE dyeing is at microscopically quantitative observation nasal mucosa thickness.The result shows, compares with the normal control group, and model control group rat nasal septum mucosal epithelium has disengaging in various degree, uneven thickness, underlying structure is unclear, and venule, blood capillary are obviously expanded in the lamina propria, interstice enlarges, and mucosa thickness obviously increases (P＜0.01).Compare with model control group, the above-mentioned pathological change of positive controls and medication therapy groups alleviates, and mucosa thickness obviously reduces (P＜0.001).The results are shown in Table 4.
2.4 nasal mucosa eosinophil count: it is the same to draw materials, cut into slices, dye
Under light microscopic, observe, choose the mucosa of pseudostratified ciliated columnar epithelium lining, count the eosinophilic granulocyte's number in 3～5 the high power field lamina proprias in this position, with reflection eosinophilic granulocyte infiltration degree.The mucosa place of the false multiple layer cilium columnar epithelium of model control group lining, visible obviously cell infiltration in the lamina propria is based on eosinophilic granulocyte's infiltration, with the lymphocytic infiltration that more or less.Eosinophilic granulocyte's circle or oval, nuclear is 2～3 leaf lobulateds, is full of thick acidophilia's granule uniformly in the endochylema, compares with the normal control group, and eosinophil count significantly increases (P＜0.01).Positive controls and medication therapy groups and normal control group compare, and eosinophil count significantly reduces (all P＜0.01).The results are shown in Table 4.
Table 4 thing of the present invention is to the influence of the inductive Cavia porcellus experimental allergic of TDI rhinitis (X ± s)
Annotate: compare with model group,
*P＜0.01.
3 conclusions
This experiment adopts the TDI sensitizing agent respectively the laboratory animal of Cavia porcellus to be carried out modeling, observe the nasal mucosa epithelium under the nasal mucosa HE dyeing light microscopic after the laboratory animal modeling of Cavia porcellus as a result disengaging is in various degree arranged, uneven thickness, underlying structure is unclear, venule, blood capillary are obviously expanded in the lamina propria, and interstice enlarges; A large amount of eosinophilic granulocytes sees in the lamina propria (Cavia porcellus), meets the pathological manifestations of allergic rhinitis.The cumulated volume experimental studies results shows: Flos Magnoliae volatile oil soft capsule of the present invention has definite therapeutical effect to rat, Cavia porcellus experimental allergic rhinitis, and its effect mainly shows as the following aspects: 1. alleviate local symptom.Flos Magnoliae volatile oil soft capsule of the present invention can reduce animal pattern sniffle score value, can alleviate nose rhinocnesmus, sneeze, thin nasal discharge symptom.2. improve hyperemia, the edema of local mucosa.Flos Magnoliae volatile oil soft capsule of the present invention can alleviate the swelling situation of animal pattern nose mucosa.3. reduce the eosinophilic granulocyte in the partial infiltration of inflammation.4. reduce mastocyte in the partial infiltration of inflammation.The effect of name extract of the present invention with obvious treatment allergic rhinitis.
Claims (10)
1. be used for the treatment of the Flos Magnoliae volatile oil preparation of soft capsule method of allergic rhinitis and diseases concerned with respiratory thereof, it is characterized in that: the content of this a soft capsule by volume part meter is made up of for 0～30 part 1～90 part of Flos Magnoliae volatile oil, 10～90 parts of oil phases, 0～50 part of emulsifying agent, cosolvent;
2. Flos Magnoliae volatile oil soft capsule content composition according to claim 1 by volume part is counted 30～60 parts of Flos Magnoliae volatile oils, 25～50 parts of oil phases, 0～20 part of emulsifying agent, 0～20 part of cosolvent.
3. form by volume according to the described Flos Magnoliae volatile oil soft capsule content of claim 1-2 and part count 40～50 parts of Flos Magnoliae volatile oils, 30～40 parts of oil phases, 0～10 part of emulsifying agent, 0～10 part of cosolvent.
4. according to each described Flos Magnoliae volatile oil of claim 1-3, its preparation method is selected from steam distillation or supercritical carbon dioxide extraction method.Described steam distillation may further comprise the steps: 1) Flos Magnoliae medical material or its coarse powder, put in the volatile oil extractor 2) add the water of 5～15 times of amounts of medical material weight, soaked 3 0～24 hour) heating steams and slipped 4 1～24 hour) the collection volatile oil fraction, promptly.Described supercritical carbon dioxide extraction method may further comprise the steps: 1) Flos Magnoliae medical material or its coarse powder, put in the supercritical carbon dioxide extraction device, 2) with the carbon dioxide be extractant, extracting pressure is 10～40MPa (MPa, MPa), extraction temperature is 20～60 ℃, and separating pressure is 2.0～10.0MPa, separation temperature is 20～80 ℃, and the extraction time is 0.5～8 hour.3) collect extract.
5. according to the described oil phase of claim 1-3, it contains a kind of or its mixture in oil, the Polyethylene Glycol.Its medium oil comprises vegetable oil (soybean oil; Oleum Brassicae campestris; Oleum sesami; Semen Maydis oil; almond oil; Petiolus Trachycarpi oil; olive oil; Oleum Camelliae; Radix Oenotherae erythrosepalae oil; safflower oil); oleic acid and oleate (methyl oleate thereof; ethyl oleate; olein); glyceryl linoleate; (Arlacel 20 for fatty acid sorbitol ester; Arlacel 60; Arlacel 80; Arlacel 86); (Miglol 810 for the Miglol neutral fat; 812; 818; 829,840); acrylic ethylene glycol laurate; Polyethylene Glycol-6-iso stearic acid of glycerine ester; Polyethylene Glycol-12-hydroxy stearic acid ester; the Polyethylene Glycol glyceryl laurate ester; Oleum Cocois C8/C10 propylene glycol monoester or dibasic acid esters; Oleum Cocois C8/C10 glyceride (Oleum Cocois C8/C10 monoglyceride; Oleum Cocois C8/C10 glycerol dibasic acid esters; Oleum Cocois C8/C10 triglyceride); the acetylizad monoglyceride of purification; purification Oleum helianthi monoglyceride; the mixture of one or more in the triglyceride of oleic acid (25%) and linoleic acid (54%).Polyethylene Glycol comprises one or more the mixture in Macrogol 200, PEG400, the Macrogol 600.
6. according to the described emulsifying agent of claim 1-3, it contain lecithin, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, poloxamer, polysorbate, dehydration polysorbate, Oleum Cocois C8/C10 polyethyleneglycol glyceride, almond oil oleic acid polyethyleneglycol glyceride, polyoxyethylene (25) triolein, polyoxyethylene (20) sorbitan oleate, Polyethylene Glycol-8 glycerol sad/one or more mixture in the certain herbaceous plants with big flowers acid esters.
7. according to the described solubilizing agent of claim 1-3, it contains one or more the mixture in long-chain alcohol, ethylene glycol, propylene glycol, glycerol, polyglycereol derivant, ethanol, isopropyl alcohol, glycerol, Polyethylene Glycol, ethylene glycol monomethyl ether, the propylene carbonate.
8. according to the described Flos Magnoliae volatile oil preparation of soft capsule of claim 1～3 method, its preparation method is: the content of 1) getting prescribed volume part is formed, and mixes in proportion.2) put the soft capsule make-up machine, adjust its rotating speed, loading amount control, temperature control, make press temperature be controlled at 40～55 ℃, setting temperature is 10～20 ℃, is pressed into ball.4) soft capsule that makes of pressure is put the blowing of low temperature below 10 ℃ typing 4～10 hours, takes out in 20-48 hour in low temperature blowing more than 10 ℃ then.Behind the oil reservoir of ethanol flush away soft gelatin capsule surface, descended dry 24～48 hours at 40～50 ℃ again, get product.
9. preparation method according to claim 8 after suppressing at soft capsule, finalizing the design, wash ball, drying, is wrapped the macromolecule enteric coat outside softgel shell.Described macromolecule enteric coat contains formaldehyde-gelatin, Lac (Shellac), Cellulose Acetate Phthalate (CAP), the copolymer of acrylic acid and methacrylic acid, methacrylic acid-methylmethacrylate copolymer, methacrylic acid-acrylate copolymer, EUDRAGIT L100-55, cellulose acetate, ethyl cellulose, polyacrylic resin, EUDRAGIT NE 30 D EUDRAGIT NE 30D, polyethylene acetic acid phthalic acid ester (PVAP), phthalic acid hypromellose ester (HPMCP), hydroxypropyl emthylcellulose peptide acid esters (HPMC), in succinic acid acetic acid hydroxypropyl methylcellulose (HPMCAS) or the crosslinked alginate one or more.
10. each described Flos Magnoliae volatile oil soft capsule of claim 1-9 is in the application that prevents and treats allergic rhinitis and relevant disease thereof; Described allergic rhinitis and relevant disease thereof are selected from respiratory tract diseases such as allergic rhinitis, acute rhinitis, simple rhinitis, hypertrophic rhinitis, atrophic rhinitis, acute sinusitis, chronic sinusitis or its complication, acute upper respiratory tract infection, acute and chronic obstructive pulmonary disease, asthma.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108135954A (en) * | 2015-05-13 | 2018-06-08 | 韩国生命工学研究院 | For preventing and treating the pharmaceutical composition containing Flos Magnoliae extract, fraction or active fractions active constituent of chronic obstructive pulmonary disease |
| CN111991442A (en) * | 2020-09-08 | 2020-11-27 | 陕西中医药大学 | Ocimum sinensis volatile oil microemulsion preparation and preparation method and application thereof |
-
2011
- 2011-06-27 CN CN2011101747653A patent/CN102225093A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108135954A (en) * | 2015-05-13 | 2018-06-08 | 韩国生命工学研究院 | For preventing and treating the pharmaceutical composition containing Flos Magnoliae extract, fraction or active fractions active constituent of chronic obstructive pulmonary disease |
| JP2018515528A (en) * | 2015-05-13 | 2018-06-14 | コリア リサーチ インスティチュート オブ バイオサイエンス アンド バイオテクノロジー | Pharmaceutical composition for preventing and treating chronic obstructive pulmonary disease, comprising Magnolia floss extract, fraction or active fraction thereof as an active ingredient |
| EP3295947A4 (en) * | 2015-05-13 | 2019-05-15 | Korea Research Institute of Bioscience and Biotechnology | Pharmaceutical composition for preventing and treating chronic obstructive lung disease containing, as active ingredient, magnoliae flos extract, fraction, or active fraction thereof |
| CN111991442A (en) * | 2020-09-08 | 2020-11-27 | 陕西中医药大学 | Ocimum sinensis volatile oil microemulsion preparation and preparation method and application thereof |
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Application publication date: 20111026 |