CN1706371A

CN1706371A - A kind of efficient irinatin preparation and preparation method thereof

Info

Publication number: CN1706371A
Application number: CN 200510046524
Authority: CN
Inventors: 邓意辉; 吴红兵; 徐速; 吴琼
Original assignee: Shenyang Pharmaceutical University
Current assignee: Shenyang Pharmaceutical University
Priority date: 2005-05-27
Filing date: 2005-05-27
Publication date: 2005-12-14
Anticipated expiration: 2025-05-27
Also published as: CN1706371B

Abstract

The present invention is efficient sword-like iris seed preparation and its preparation process. The sword-like iris seed preparation may be liposome, emulsifier, nanometer particle or spray dried or freeze dried powder for orally taking or injection, and may have pharmaceutically acceptable preservative, sweetener and essence. The liposome consists of medicine, phospholipid and cholesterol in the weight ratio of 1 to 5-100 to 0-50, and has pH value of 4-8 and granularity of 5-5000 nm. The preparation process includes: 1. preparing oil phase in compounding tank, 2. preparing water phase in compounding tank, 3. adding water phase into oil phase to form initial emulsion, 4. suction filtering the initial emulsion in G3 funnel, regulating pH value to 3-9, and 5. processing in homogenizer, freeze drying and packing as emulsion. The preparation process of the present invention has fast and effective absorption and high blood medicine concentration.

Description

A kind of sword-like iris seed preparation and preparation method thereof efficiently

Technical field:

The present invention relates to medical technical field, exactly it is a kind of sword-like iris seed preparation and preparation method thereof efficiently.

Background technology:

The chemical name of Irisquinonum is: irisquinone, 6-methoxyl group-2-Δ ^{10 '}-along 17 alkene-1,4-benzoquinone.But also contain the part dihydroirisquinone, pallason B.

Its structural formula is:

Irisquinone

Molecular formula: C ₂₄H ₃₈O ₃

Molecular weight: 374.56

Dihydroirisquinone, pallason B

Molecular formula: C ₂₄H ₄₀O ₃

Molecular weight: 376.58

The pharmacological action of Irisquinonum: be radiosensitizer, the growth of cell strain, tumor animal tumor and anoxic cells such as human cervical carcinoma, mice ehrlich ascites tumor, mouse lymphocyte leukemia is had radiosensitizing effect.Its mechanism of action is: suppress malignant cell and breathe, reduce oxygen consumption; Selectivity reduces malignant cell glutathion inside content; Suppress the synthetic and post-rift reparation of malignant cell DNA; Retardance malignant cell growth cycle is in to the ray sensitive G ₁Phase.Acute toxicity: Irisquinonum is once irritated stomach LD ₅₀Be 2590.6mg/kg; Mice once abdominal cavity injection LD ₅₀Be 35.06 ± 0.99mg/kg.The animal poisoning symptom is hair pine, anorexia, loose stool, the visible flatulence of postmortem.Long term toxicity: 1. irritate stomach every day and give rat Irisquinonum 62.5,125,250mg/kg three months, the result shows liver function outer (SGPT slightly Irisquinonum raises), and hemogram and other main biochemical indicator do not have obvious change.2. irritate stomach every day and give Canis familiaris L. Irisquinonum 30mg/kg, 60mg/kg two months, the result shows that main organs do not see the substance damage that causes because of medicine.Main toxicity is gastrointestinal reaction, and this reaction prolongs or reduce dosage in time and recovery voluntarily.Tertogenicity test: the result shows continuous 10 days of the oral Irisquinonum 300mg/kg of pregnant Mus, can cause 25% animal dead, and can cause serious fetal toxicity reaction, makes most of pregnant Mus miscarry, absorb tire in early days, but tire Os Mus bone internal organs are not caused deformity; 60mg/kg treated animal filling stomach did not have obvious poisoning symptom in 10 days except that part animal perineum place secretions increase, symptom disappears automatically after the drug withdrawal, and skeleton of tire Mus and internal organs all do not cause deformity, show that Irisquinonum is non-teratogen.Mutagenicity test: microorganism reverse mutation test, sister chromatid exchange test, micronucleus test show that Irisquinonum is non-mutagen.Its plasma concentration is two chambers model, t after the oral this product of mice with tumor _{1/2 α}Be 0.096 hour, t _{1/2 β}Be 73.72 hours, Vd is 0.150L, shows that this product infiltration rate is fast, and the elimination time is long; The tissue distribution situation shows that medicine holdup time in digestive tract is long, and the tumor body radioactivity was the highest in 12 hours, and blood drug level still maintained this level in 24 hours, also has in lung and the thymus than high radioactivity, and brain and muscle are minimum.Behind this product single administration, existing than high radioactivity in the urine after half an hour, the discharge rate after 24 hours in excrement and the urine is respectively 14.8% and 30.3%.This product is a radiosensitizer, is used for the radiotherapy of radiocurable pulmonary carcinoma, esophageal carcinoma and incidence cancer etc.Oral meal, 2 times on the one, one time 2, take respectively at radiotherapy is forward and backward.Children's is cut down according to the circumstance.This product should begin to take before accepting radiotherapy 2-3 day, takes continuously until radiotherapy and finishes.Untoward reaction: part patient has slight gastrointestinal reaction, and as nausea,vomiting,diarrhea etc., its incidence rate height during than radiotherapy alone does not generally influence the continuation medication, reacts the patient individually, but decrement or symptomatic treatment, and one after each meal can reduce the reaction of stomach.Existing dosage form is capsule 55mg (in irisquinone and a dihydroirisquinone, pallason B total amount)

Irisquinonum is indissoluble in water, the while less stable, in order to improve dissolubility and stability in the water, there is the author to be made into cyclodextrin inclusion complex (the beta-schardinger dextrin-inclusion complex research Acta Pharmaceutica Sinica of cancer therapy drug Irisquinonum: 2002,37 (12): 963～966).In addition, because Irisquinonum indissoluble in water, its oral absorption is few (can be from irritating stomach LD ₅₀2590.6mg/kg; Mice once abdominal cavity injection LD ₅₀Be 35.06 ± 0.99mg/kg, differ 70 surplus times) and individual variation big.For the injection feasibility is described, there is research worker to measure apparent pharmacokinetic parameters with chmice acute cumulative mortality method, the result shows that the apparent pharmacokinetic parameters of ip route of administration is similar to the gastric infusion approach, therefore taking drug administration by injection is feasible (the research Tianjin pharmacy 2002,14 (3) of the chmice acute cumulative mortality method mensuration apparent pharmacokinetic parameters of Irisquinonum: 36～37).

Irisquinonum is widely used (the Chinese clinical tumor of the perspective study of Irisquinonum radiation sensitization (attached 120 routine clinical analysis): 2003,30 (5): 328～330 in clinical; Irisquinonum is to anti-cisplatin Lu-csf-1 ADDP549 drug resistance inversion and possible machine-processed Chinese Medical Journal 2001,81 (22): 1392～1393; The clinical research Nanjing Medical University journal (natural science edition) 2001,21 (4): 328～330 of Irisquinonum sensitization in nasopharyngeal carcinoma radiotherapy; Treatment middle and advanced stage nasopharyngeal carcinoma efficacy analysis China clinical tumor 2001,28 (6): 439～440 is share in Irisquinonum and radiotherapy; Irisquinonum radiation sensitization treatment curative effect of esophageal carcinoma is observed Journal of Clinical Oncology: 2000,5 (4): 272～274; Irisquinonum influences Zhongshan Medical Univ.'s journal to 153SmEDTMP treatment nasopharyngeal carcinoma metastatic tumor of bone: 1998,19 (2): 142～143,149), and clinical effectiveness is remarkable, and effective percentage brings up to 62.5% by 10% during as therapeutic alliance; During the radiotherapy full dose, the tumor rate that disappears entirely brings up to 80% by 40%, and (the Irisquinonum capsule merges the Chinese clinical tumor of radiotherapy 62 routine esophageal carcinoma clinical observations: 1999,26 (8): 639～640), primary tumor and metastasis effective percentage, by 78.6%, 70.0% brings up to 94.3%, 87.5%, and (peace stuck glue capsule merges the Chinese clinical tumor 1999,26 (7) of radiotherapy malignant tumor 140 routine phase clinical observations: 547～548).

Blood albumin has important physiological function in blood, the normal osmotic pressure of blood is relevant with keeping, and is the main adjusting material of blood total osmotic pressure, lacks this albumin and may cause the body edema.Another effect of human albumin is to transport fatty acid as the carrier participation of fatty acid.Can utilize the human albumin as pharmaceutical carrier, the preparation nanometer formulation.

Summary of the invention:

But the objective of the invention is to prepare the preparation method of a kind of sword-like iris seed preparation efficiently and industrial applications thereof.Said efficient sword-like iris seed preparation comprises " liposome ", " Emulsion ", " nanoparticle ", and spray drying or lyophilized powder, prepared preparation can oral (antiseptic, sweeting agent, the essence that can add as required, the medicament allowed band) or drug administration by injection.Said antiseptic (antibacterial) is benzyl alcohol, benzoic acid (and salt), sorbic acid (and salt), parabens.Sweeting agent is sucrose, glucide, aspartame, protein sugar etc.; Essence is cream flavour, Fructus Citri tangerinae essence, cocoanut flavour, flavoring pineapple essence etc.Said lipid system is made up of medicine and phospholipid, cholesterol, and the ratio that medicine and phospholipid, cholesterol are formed is: 1: 5-100: 0-50 (W/W/W), its pH scope is: 4-8 (the medicine indissoluble is separated in this scope), particle size range is 10nm-5000nm.Said phospholipid is that PC (phosphatidylcholine) content is greater than 40% natural phospholipid, semi-synthetic phospholipid or synthetic phospholipid.Natural phospholipid comprises soybean lecithin, Ovum Gallus domesticus Flavus lecithin; Semi-synthetic phospholipid comprises hydrogenated soy phosphatidyl choline (HSPC), hydrogenated yolk lecithin; Synthetic phospholipid comprises DSPC (distearoyl phosphatidylcholine), DPPC (dipalmitoyl phosphatidyl choline), DMPC (dimyristoyl phosphatidyl choline), DLPC (two Laurel phosphatidyl cholines), DSPG (distearyl phosphatidyl glycerol), DPPG (two palmityl phosphatidyl glycerols), DMPG (GLYCEROL,DIMYRISTOYL PHOSPHATIDYL), DLPG (two lauroyl phosphatidyl glycerols), PA (phosphatidic acid), PI (phosphatidylinositols), PS (Phosphatidylserine).Said Emulsion is made up of medicine and oil phase, emulsifying agent, co-emulsifier, the proportion of composing of medicine and oil phase, emulsifying agent, co-emulsifier is: 1: 0.5-500: 1-50: 0-50 (W/W/W), its pH scope is: 4-8 (the medicine indissoluble is separated in this scope), particle size range is 10nm-5000nm.Said oil phase is C ₀-C ₁₈Vegetable oil or animal oil (comprising), triglyceride through the vegetable oil after structure of modification and the hydrolysis, as Oleum Cocois, olive oil, soybean oil, safflower oil, seal oil, hot certain herbaceous plants with big flowers acid glyceride (Delios ) (being called medium chain triglycerides MCT); The derivant that also comprises fatty acid is as ethyl oleate.Emulsifying agent comprises one or more mixture in phospholipid, HS15 (Polyethylene Glycol 12-hydroxy stearic acid ester, polyethylene glycol 660 hydroxystearate), vitamin E polyethylene glycol succinic acid ester (TPGS), the Tweens; Co-emulsifier comprises ethanol, glycerol, C ₈-C ₃₀Saturated or unsaturated fatty acid, as caproic acid, sad, certain herbaceous plants with big flowers is sour, one or more mixture in lauric acid, Palmic acid, (Asia) oleic acid, linoleic acid, stearic acid, docosahexenoic acid (DHA), cholic acid (pig, goose, ursodesoxycholic acid), dehydrocholic acid and the salt thereof; Said nanoparticle comprises " lipid nanoparticle " and " human albumin's (comprising human serum albumin (HSA), albumin human) nanoparticle ".Wherein " lipid nanoparticle " is made up of medicine and phospholipid substance, proportion of composing is: 1: whether 10-1000 (can change 1 into: 1-1000 embodiment 11) (W/W), also can add other appropriate ingredients as required, as vitamin E, HS15 (Polyethylene Glycol 12-hydroxy stearic acid ester, polyethylene glycol 660 hydroxystearate), vitamin E polyethylene glycol succinic acid ester (TPGS), DSPE-PEG, Poloxamer 407; Its pH scope is: 3-9, particle size range is 5nm-1000nm." human albumin's (comprising human serum albumin (HSA), albumin human) nanoparticle " is made up of medicine and human albumin, and wherein the ratio of Irisquinonum and human albumin, oil is 1: 1-100: 0-10, said oil are C ₆-C ₁₈Vegetable oil (comprising), triglyceride through the vegetable oil after structure of modification and the hydrolysis, as Oleum Cocois, olive oil, soybean oil, safflower oil, seal oil, hot certain herbaceous plants with big flowers acid glyceride (Delios ) (being called medium chain triglycerides MCT), its pH scope is: 3-9, particle size range is 5nm-1000nm.Said phospholipid substance comprises that PC (phosphatidylcholine) content forms greater than 40% albumin, and wherein the ratio of Irisquinonum and human albumin, oil is 1: 1～100: 0～10, and said oil is C ₆～C ₁₈Vegetable oil (comprising), triglyceride through the vegetable oil after structure of modification and the hydrolysis, as Oleum Cocois, olive oil, soybean oil, safflower oil, seal oil, hot certain herbaceous plants with big flowers acid glyceride (Delios ) (being called medium chain triglycerides MCT), its pH scope is: 3～9, and particle size range is 5nm～1000nm.Said phospholipid substance comprises that PC (phosphatidylcholine) content is greater than 40% natural phospholipid, semi-synthetic phospholipid or synthetic phospholipid.Natural phospholipid comprises soybean lecithin, Ovum Gallus domesticus Flavus lecithin; Semi-synthetic phospholipid comprises hydrogenated soy phosphatidyl choline, hydrogenated yolk lecithin; Synthetic phospholipid comprises DSPC (distearoyl phosphatidylcholine), DPPC (dipalmitoyl phosphatidyl choline), DMPC (dimyristoyl phosphatidyl choline), DLPC (two Laurel phosphatidyl cholines), DSPG (distearyl phosphatidyl glycerol), DPPG (two palmityl phosphatidyl glycerols), DMPG (GLYCEROL,DIMYRISTOYL PHOSPHATIDYL), DLPG (two lauroyl phosphatidyl glycerols), PA (phosphatidic acid), PI (phosphatidylinositols), PS (Phosphatidylserine).Can add antioxidant in the sword-like iris seed preparation of said injectable administration, comprise one or more mixture among Butylated hydroxyanisole (BHA), dibenzylatiooluene (BHT), alpha-tocopherol, α-tocopheryl acetate, alpha-lipoic acid, vitamin C, sodium L-ascorbate-2-phosphate, sulfurous acid (hydrogen) sodium, noble gas (nitrogen, argon), the EDTA (2Na or sodium calcium salt).The freeze drying protectant that said lyophilization injectable powder relates to is: one or more mixture in glucose, lactose, mannitol, sorbitol, xylitol, sucrose, trehalose, dextran, polyvinylpyrrolidone (PVP), glycine, succinylated gelatin, human albumin, the sodium chloride etc.; the content of freeze drying protectant is 2%～20% (W/V, protectant concentration in the preceding solution of lyophilizing).Described injection preparation method, with Emulsion is that example is described as follows: 1) prepare oil phase (medicine phase) in preparing tank: in preparing tank, oil for injection is heated to 20-90 ℃ when medicine (simple non-refuelling), adds emulsifying agent, strong agitation is to dissolving in the time of 20～80 ℃; Be cooled to 20～40 ℃ again, in stirring, add medicine.2) in preparing tank, prepare water: water and glycerol are stirred 5min down at 20～90 ℃, make it complete miscibility.3) in the time of 20～50 ℃, water is added in the oil phase, strong agitation 10～30min forms colostrum.4) colostrum is crossed G ₃The funnel sucking filtration is regulated pH value to 4～8.5) cross the homogenizing instrument, the first step is regulated homogenize pressure to 520～600kg/cm ², second step re-adjustment to 100～140kg/cm ²(or the microjet instrument, the first step is regulated homogenize pressure to 4000-8000psi, and the second step re-adjustment is to 10000-16000psi), form Emulsion.Cross the following microporous filter membrane of 0.8um or 0.8um, packing (add protective agent, carry out lyophilization, or carry out spray drying) promptly gets Emulsion.

Advantage of the present invention is: the mice in vivo test is the result show, prepared preparation infiltration rate of the present invention and degree are better than the commercial preparation far away, blood drug level is higher than the commercial preparation (nanoparticle of the Emulsion of the liposome of embodiment 2, embodiment 7, embodiment 14, its with respect to the bioavailability of commercial preparation all greater than 200%), the time of keeping also is longer than the commercial preparation.The curative effect of anti-mice ehrlich ascites tumor also is better than the commercial preparation.

The specific embodiment:

Detailed component of the present invention is provided by the following example, but protection scope of the present invention not only is confined to this.

Particle size analyzer: use PSS.NICOMP in this experiment ^TM380 as the instrument of measuring particle diameter.

Microjet instrument (Microfluidic company, the U.S.), homogenizer etc.

HPLC analyzes: chromatographic column: ODS post; Mobile phase: methanol-water-acetonitrile-ether (65: 25: 20: 20); Detect wavelength: 270nm; Flow velocity: 1mL/ minute.50μl。

Embodiment 1 Irisquinonum liposome

Composition weight (gram)

Irisquinonum 1

Soybean lecithin 5

Ethanol is an amount of

Citrate buffer solution adds to 100

Preparation technology:

Take by weighing Irisquinonum, the soybean lecithin of recipe quantity, behind an amount of dissolve with ethanol, (0.01mol/L, pH4.0), 40 ℃ are stirred aquation down, cross homogenizer (or microjet) (first step adjusting homogenize pressure 520～600kg/cm to add citrate buffer solution ², second step re-adjustment 100～140kg/cm ²Microjet instrument, the first step are regulated homogenize pressure to 4000-8000psi, and the second step re-adjustment is to 10000-16000psi) get the Irisquinonum liposome, its granularity is 15nm～550nm.The trehalose that gained liposome liquid can add 12% (W/V) carries out lyophilization, gets freeze-dried lipidosome.After the redissolution, its granularity is 10nm～710nm.The gained preparation can oral or injection.

Embodiment 2 Irisquinonum liposomees

Composition weight (gram)

Irisquinonum 1

Soybean lecithin 50

Ethanol is an amount of

Alpha-tocopherol 0.1

Phosphate buffer adds to 1000

Preparation technology:

Take by weighing Irisquinonum, soybean lecithin, the alpha-tocopherol of recipe quantity, behind an amount of dissolve with ethanol, (0.01mol/L, pH5.0), 40 ℃ are stirred aquation down, cross homogenizer (or microjet), first step adjusting homogenize pressure 520kg/cm to add phosphate buffer ², the second step re-adjustment 100kg/cm ²(or the microjet instrument, the first step is regulated homogenize pressure to 4000psi, and the second step re-adjustment is to 10000psi), get the Irisquinonum liposome, cross the 0.22um microporous filter membrane, its granularity is 25nm～430nm, envelop rate is greater than 90%.The glucose that gained liposome liquid can add the mannitol and 1% (W/V) of 6% (W/V) carries out lyophilization, gets freeze-dried lipidosome, every 5mg Irisquinonum (or vacuum gland).After the redissolution, its granularity is 20nm～710nm.The gained preparation can be oral (can add 0.1% sodium benzoate) or injection.

Embodiment 3 Irisquinonum liposomees

Composition weight (gram)

Irisquinonum 1

Ovum Gallus domesticus Flavus lecithin 20

Cholesterol 1

Alpha-lipoic acid 0.5

Ethanol is an amount of

Acetate buffer adds to 1000

Preparation technology:

Take by weighing Irisquinonum, Ovum Gallus domesticus Flavus lecithin, cholesterol, the alpha-lipoic acid of recipe quantity, behind an amount of dissolve with ethanol, adopt alcohol injection to add phosphate buffer (0.03mol/L, pH6.0) in, 50 ℃ are stirred aquation down, cross homogenizer (or microjet), the first step is regulated homogenize pressure to 600kg/cm ², the second step re-adjustment is to 100kg/cm ²(or the microjet instrument, the first step is regulated homogenize pressure to 5000psi, and the second step re-adjustment is to 10000psi), getting the Irisquinonum liposome, its granularity is 10nm～820nm, crosses the 0.22um microporous filter membrane, envelop rate is greater than 90%.The lactose that gained liposome liquid can add the sucrose, 5% (W/V) of 10% (W/V) carries out lyophilization, promptly gets freeze-dried lipidosome; Or carry out spray drying, get pro-liposome.The packing inflated with nitrogen gets Liposomal formulation, every 5mg Irisquinonum (or vacuum gland).After the redissolution, its granularity is 20nm～780nm.The gained preparation can be oral (can add 0.1% sodium benzoate, 0.05% ethyl hydroxybenzoate) or injection.

Embodiment 4 Irisquinonum liposomees

Composition weight (gram)

Irisquinonum 1

DSPG 100

Cholesterol 50

Sodium L-ascorbate-2-phosphate 0.2

Ethanol is an amount of

Phosphate buffer adds to 5000

Preparation technology:

Take by weighing Irisquinonum, DSPG, the cholesterol sodium L-ascorbate-2-phosphate of recipe quantity, behind an amount of dissolve with ethanol, adopt alcohol injection to add phosphate buffer (0.03mol/L, pH7.0) in, 50 ℃ are stirred aquation down, cross homogenizer (or microjet), the first step is regulated homogenize pressure to 600kg/cm ², the second step re-adjustment 140kg/cm ²(or the microjet instrument, the first step is regulated homogenize pressure to 8000psi, and the second step re-adjustment is to 16000psi), get the Irisquinonum liposome, cross the 0.3um microporous filter membrane, its granularity is 20nm～900nm, envelop rate is greater than 80%.The sucrose that gained liposome liquid can add 20% (W/V) carries out lyophilization, promptly gets freeze-dried lipidosome; Or carry out spray drying, get pro-liposome.The packing inflated with nitrogen gets Liposomal formulation, every 10mg Irisquinonum (or vacuum gland).After the redissolution, its granularity is 20nm～800nm.The gained preparation can oral or injection.

Embodiment 5 Irisquinonum liposomees

Composition weight (gram)

Irisquinonum 1

HSPC 10

DMPC 20

Ethanol is an amount of

Water for injection adds to 1000ml

Preparation technology:

Take by weighing Irisquinonum, HSPC, the DMPC of recipe quantity, behind an amount of dissolve with ethanol, add injection 600ml, in the gnotobasis, 50 ℃ are stirred aquation down, get the Irisquinonum liposome, and its granularity is 362nm～5000nm, and envelop rate is greater than 90%.The packing inflated with nitrogen gets Liposomal formulation, and every 5mg contains Irisquinonum (or vacuum gland).

Embodiment 6 Irisquinonum Emulsions

Composition weight (gram)

Irisquinonum 1

Soybean oil 0.5

Phosphatidase 11 0

Oleic acid 0.05

Glycerol 2.4

Water for injection adds to 200ml

Preparation technology:

1) prepare oil phase (medicine phase) in preparing tank: in preparing tank, add (injection) soybean oil, oleic acid (20 ℃), add emulsifying agent phospholipid, strong agitation is to dissolving in the time of 50 ℃; Be cooled to 40 ℃ again, in stirring, add medicine.2) in preparing tank, prepare water: water and glycerol are stirred 5min down at 90 ℃, make it complete miscibility.3) in the time of 50 ℃, water is added in the oil phase, strong agitation 30min forms colostrum.4) colostrum is crossed G ₃The funnel sucking filtration.5) cross the homogenizing instrument, the first step is regulated homogenize pressure to 520kg/cm ², the second step re-adjustment 140kg/cm ²(or the microjet instrument, the first step is regulated homogenize pressure 4000psi, and the second step re-adjustment is to 10000psi), form Emulsion, regulate pH value to 4.Cross the 0.3um microporous filter membrane, packing, inflated with nitrogen, every 1ml (containing medicine 5mg), every 2ml (containing medicine 10mg) or every 10ml (containing medicine 50mg), sterilization promptly gets (injection) Emulsion.Granularity is 10nm～1000nm, particle mean size 152nm.Add 20% (W/V) lactose, carry out lyophilization after the dissolving, promptly get freeze-dried emulsion; Or carry out spray drying, get precursor Emulsion.The packing inflated with nitrogen, every 5mg Irisquinonum.The gained preparation can oral or injection.

Embodiment 7 Irisquinonum Emulsions

Composition weight (kilogram)

Irisquinonum 1

Hot certain herbaceous plants with big flowers acid glyceride 20

HS15 2

Phosphatidase 11 0

Glycerol 12

Water for injection adds to 1000

Preparation technology:

1) prepare oil phase (medicine phase) in preparing tank: in preparing tank, add (injection or oral level) hot certain herbaceous plants with big flowers acid glyceride (50 ℃), add emulsifying agent phospholipid, HS15, strong agitation is to dissolving in the time of 80 ℃; Lower the temperature 30 ℃ again, in stirring, add medicine.2) in preparing tank, prepare water: water and glycerol are stirred 5min down at 90 ℃, make it complete miscibility.3) in the time of 40 ℃, water is added in the oil phase, strong agitation 30min forms colostrum.4) colostrum is crossed G ₃The funnel sucking filtration is regulated pH value to 6.5) cross the homogenizing instrument, the first step is regulated homogenize pressure to 450kg/cm ², the second step re-adjustment is to 120kg/cm ²(or the microjet instrument, the first step is regulated homogenize pressure to 6000psi, the second step re-adjustment 12000psi), form Emulsion.Cross the 0.3um microporous filter membrane, packing, inflated with nitrogen, every 3ml (containing medicine 3mg) or every 6ml (containing medicine 6mg), sterilization promptly gets injectable emulsion.Granularity is 50nm～700nm, particle mean size 178nm.The sucrose that can add 20% (W/V) in the gained Emulsion carries out lyophilization, promptly gets freeze-dried emulsion; Or carry out spray drying, get precursor Emulsion.The packing inflated with nitrogen, every 5mg Irisquinonum.After the redissolution, its granularity is 65nm～960nm.The gained preparation can be oral (can add 0.1% sodium benzoate, 0.05% ethyl hydroxybenzoate, cream flavour) or injection.

Embodiment 8 Irisquinonum Emulsions

Composition weight (gram)

Irisquinonum 1

Oleum Cocois 10

TPGS 10

Glycerol 12

Alpha-tocopherol 1

Water for injection adds to 1000

Preparation technology:

Operation is with embodiment 7, and granularity is 20nm～750nm, particle mean size 89nm.Every 5ml (containing medicine 5mg) or every 10ml (containing medicine 10mg) (applying argon gas).Mannitol, 2% xylitol that can add 8% (W/V) in the gained Emulsion carry out lyophilization, promptly get freeze-dried emulsion; Or carry out spray drying, get precursor Emulsion.The packing inflated with nitrogen, every 5mg Irisquinonum.After the redissolution, its granularity is 15nm～680nm.The gained preparation can oral (0.1% ethyl hydroxybenzoate, 0.05% propylparaben, protein sugar, cocoanut flavour) or injection.

Embodiment 9 Irisquinonum Emulsions

Composition weight (gram)

Irisquinonum 0.1

Hot certain herbaceous plants with big flowers acid glyceride 50

Soybean oil 0.5

TPGS 10

Poloxamer?407 5

Glycerol 2.4

Alpha-lipoic acid 1

Water for injection adds to 200

Preparation technology:

Operation is with embodiment 7, and granularity is 50nm～1060nm.Every 10ml (containing medicine 5mg) (argon).The gained preparation can oral or injection.

Embodiment 10 Irisquinonum Emulsions

Composition weight (kilogram)

Irisquinonum 1

Ethyl oleate 10

Phosphatidase 12

HS15 2

DHA 10

Glycerol 1.2

Alpha-lipoic acid 0.2

Water for injection adds to 200

Preparation technology:

Operation is with embodiment 7, pH8, and the sterile working, granularity is 100nm～5000nm.Every 1ml (containing medicine 5mg) or every 2ml (containing medicine 10mg), (applying argon gas).Add 6% mannitol, 6% xylitol, lyophilizing or spray drying get pressed powder.The gained preparation can oral or injection.

Embodiment 11 Irisquinonum nanoparticles

Composition weight (gram)

Irisquinonum 1

Soybean lecithin 10

HS15 5

Ethanol is an amount of

Alpha-lipoic acid 1

Glycerol 2

Water adds to 1000

Preparation technology:

Take by weighing Irisquinonum, phospholipid, HS15, the alpha-lipoic acid of recipe quantity, place material-compound tank, add ethanol, after 50 ℃ of heating for dissolving, add entry (containing glycerol) and stir, disperse, transfer pH to 4, cross homogenizer (or microjet), the first step is regulated homogenize pressure to 600kg/cm ², the second step re-adjustment is to 140kg/cm ²(or the microjet instrument, the first step is regulated homogenize pressure to 8000psi, and the second step re-adjustment is to 16000psi), get the Irisquinonum liquid nano, cross 0.22 μ m microporous filter membrane degerming, packing, every 10ml (containing medicine 10mg) (applying argon gas).The mensuration granularity is 5nm～500nm.Add 10% sucrose in the gained liquid, carry out spray drying or lyophilization, get sterilized powder.Granularity after spray drying or the lyophilization gained solid rehydration is: 10nm～1000nm.The gained preparation can oral or injection.

Embodiment 12 Irisquinonum nanoparticles

Composition weight (gram)

Irisquinonum 0.1

Ovum Gallus domesticus Flavus lecithin 100

Hydrogenated soy phosphatidyl choline 1

Ethanol is an amount of

Vitamin E 1

Glycerol 30

Mannitol 50

Water adds to 1000

Preparation technology:

Take by weighing Irisquinonum, phospholipid, vitamin E, the hydrogenated soy phosphatidyl choline of recipe quantity, place material-compound tank, add ethanol, after 60 ℃ of heating for dissolving, standby.Take by weighing mannitol, the glycerol of recipe quantity in addition, behind the adding water dissolution, mix with above-mentioned Irisquinonum phospholipid solution, stir aquation, transfer pH to 6, cross homogenizer (or microjet), the first step is regulated homogenize pressure to 500kg/cm ², the second step re-adjustment is to 120kg/cm ²(or the microjet instrument, the first step is regulated homogenize pressure to 6000psi, and the second step re-adjustment is to 13000psi), get the Irisquinonum liquid nano.Its granularity is 5nm～300nm.Cross 0.22 μ m microporous filter membrane degerming, packing, inflated with nitrogen.Gained liquid carries out spray drying or lyophilization, gets sterilized powder.Granularity after the rehydration is: 10nm～400nm.The gained preparation can oral or injection.

Embodiment 13 Irisquinonum nanoparticles

Composition weight (gram)

Irisquinonum 0.1

The human albumin 3

Dichloromethane is an amount of

Preparation technology:

Take by weighing the Irisquinonum of recipe quantity,, make the solution of 100mg/ml with the dichloromethane dissolving, standby.Get commercially available human albumin (25%) and be diluted to 5% solution, and be 5.5 with hydrochloric acid adjusting pH value with water for injection, standby.Under 0 ℃ the Irisquinonum dichloromethane solution is mixed with human albumin's solution, cross homogenizer (or microjet), the first step is regulated homogenize pressure to 600kg/cm ², the second step re-adjustment is to 140kg/cm ²(or the microjet instrument, the first step is regulated homogenize pressure to 6000psi, and the second step re-adjustment is to 36000psi), get the Irisquinonum liquid nano.Its granularity is 5nm～550nm.Cross 0.22 μ m microporous filter membrane degerming, packing, lyophilization gets sterilized powder.Particle mean size after the rehydration (normal saline or sterilized water for injection) is: 170nm.Can be with different ratios, different acid replaces hydrochloric acid as citric acid, phosphoric acid, tartaric acid, acetic acid, and pH value is 3～8, can obtain similar results.The gained preparation can oral or injection.

Embodiment 14 Irisquinonum nanoparticles

Composition weight (gram)

Irisquinonum 1

Ovum Gallus domesticus Flavus lecithin 30

Ethanol is an amount of

Vitamin E 1

Deoxycholic acid 10

Mannitol 50

Glucose 10

Water adds to 1000

Preparation technology:

Take by weighing Irisquinonum, phospholipid, vitamin E, the deoxycholic acid of recipe quantity, place material-compound tank, add ethanol, after 50 ℃ of heating for dissolving, standby.Take by weighing mannitol, the glucose of recipe quantity in addition, behind the adding water dissolution, mix with above-mentioned Irisquinonum phospholipid solution, stir aquation, transfer pH to 8, cross homogenizer (or microjet), the first step is regulated homogenize pressure to 600kg/cm ², the second step re-adjustment is to 140kg/cm ²(or the microjet instrument, the first step is regulated homogenize pressure to 7000psi, and the second step re-adjustment is to 26000psi), get the Irisquinonum liquid nano.Its granularity is 5nm～500nm.Cross 0.22 μ m microporous filter membrane degerming, packing, every 5ml (contains medicine (inflated with nitrogen).Gained liquid carries out spray drying or lyophilization, gets sterilized powder.Granularity after the rehydration is: 10nm～500nm.The gained preparation can oral or injection.

Claims

1, a kind of efficient irinatin preparation, it is characterized in that: irinatin preparation is made into " liposome ", " emulsion ", " nanoparticle ", and spray-dried or freeze-dried powder thereof, can add medicament to allow A wide range of preservatives, sweeteners, flavors, prepared preparations can be administered orally or by injection.

2. A kind of high-efficiency irinatin preparation according to claim 1, characterized in that: preservatives or antibacterial agents are benzyl alcohol, benzoic acid or its salts, sorbic acid or its salts, paraben esters ; Sweeteners are sucrose, saccharin, aspartame, protein sugar, etc.; flavors are cream flavor, orange flavor, coconut flavor, pineapple flavor.

3. A kind of high-efficiency echinacea preparation according to claim 1, characterized in that: said lipid system is composed of medicine, phospholipid and cholesterol, and the ratio of medicine, phospholipid and cholesterol is: 1:5～ 100: 0-50 (W/W/W), the pH range is 4-8, the particle size range is 5nm-5000nm, the liposome preparation method is ethanol injection method, or ethanol dissolution and dispersion method.

4. A kind of high-efficiency irinatin preparation according to claim 3, characterized in that: said phospholipid is PC or natural phospholipid, semi-synthetic phospholipid or synthetic phospholipid with phosphatidylcholine content greater than 40%, natural Phospholipids include soybean lecithin, egg yolk lecithin; semi-synthetic phospholipids include hydrogenated soybean lecithin HSPC, hydrogenated egg yolk lecithin; synthetic phospholipids include DSPC distearoylphosphatidylcholine, DPPC dipalmitoylphosphatidylcholine, DMPC dimeat Myristoylphosphatidylcholine, DLPC dilauroylphosphatidylcholine, DSPG distearoylphosphatidylglycerol, DPPG dipalmitoylphosphatidylglycerol, DMPG dimyristoylphosphatidylglycerol, DLPG dilauroylphosphatidylglycerol, PA phosphatidic acid, PI phosphatidylinositol, PS phosphatidylserine.

5, according to said a kind of high-efficiency irinacid preparation in claim 1, it is characterized in that: said emulsion is made up of medicine and oil phase, emulsifier, co-emulsifier, medicine and oil phase, emulsifier, co-emulsifier The composition ratio of the agent is: 1:0.5-500:1-50:0-50 (W/W/W), the pH range is 4-8, and the particle size range is 10nm-5000nm.

6. A kind of high-efficiency irinatin preparation according to claim 1, characterized in that: said oily phase is vegetable oil or animal oil of _C6 ～ _C18 , triglyceride, coconut oil, olive oil, Soybean oil, safflower oil, seal oil, glyceryl caprylate or known as medium-chain triglycerides MCT; also includes derivatives of fatty acids such as ethyl oleate. Emulsifiers include one or more mixtures of phospholipids, HS15TPGS, DSPE-PEG, Poloxamer 407, and Tweens; co-emulsifiers include ethanol, glycerin, C ₆ ~ C ₃₀ saturated or unsaturated fatty acids, such as caproic acid, Caprylic acid, capric acid, lauric acid, palmitic acid, oleic acid or linoleic acid, linoleic acid, stearic acid, docosahexaenoic acid DHA, cholic acid, deoxycholic acid, dehydrocholic acid and their salts One or a mixture of several of them;

7. According to claim 1, said a kind of high-efficiency echinacin preparation is characterized in that: said nanoparticles include "lipid nanoparticles" and "human albumin nanoparticles"; wherein "lipid nanoparticles "It is composed of drugs and phospholipids, and the composition ratio is: 1:1~1000 (W/W). Vitamin E, HS15 (polyethylene glycol 12-hydroxystearate, vitamin E polyethylene glycol) can also be added as needed. Diol succinate is TPGS, DSPE-PEG, Poloxamer 407; its pH range is: 3-9, and the particle size range is 5nm-1000nm; "Human albumin nanoparticles" are composed of drugs and human albumin, of which horse The ratio of Linzisu to human serum albumin and oil is 1:1~100:0~10, and the said oil is C ₆ ~C ₁₈ vegetable oil and triglyceride, such as coconut oil, olive oil, soybean oil, red Flower oil, seal oil, caprylic acid glyceride or medium-chain triglyceride MCT, its pH range is 3-9, and the particle size range is 5nm-1000nm.

8. According to a kind of high-efficiency irinatin preparation according to claim 7, it is characterized in that: said phospholipids include phosphatidylcholine, natural phospholipids, semi-synthetic phospholipids or synthetic phospholipids with a content greater than 40%; natural Phospholipids include soybean lecithin, egg yolk lecithin; semi-synthetic phospholipids include hydrogenated soybean lecithin, hydrogenated egg yolk lecithin; synthetic phospholipids include DSPC distearoylphosphatidylcholine, DPPC dipalmitoylphosphatidylcholine, DMPC dimyrist Acylphosphatidylcholine, DLPC dilauroylphosphatidylcholine, DSPG distearoylphosphatidylglycerol, DPPG dipalmitoylphosphatidylglycerol, DMPG dimyristoylphosphatidylglycerol, DLPG dilauroylphosphatidylglycerol, PA Phosphatidic acid, PI phosphatidylinositol, PS phosphatidylserine.

9. A high-efficiency irinazoline preparation according to claim 1, characterized in that: antioxidants can be added to said irinazoline preparation, including butyl hydroxyanisole BHA, dibutyl hydroxytoluene BHT, α - One or more mixtures of tocopherol, α-tocopheryl acetate, α-lipoic acid, vitamin C, vitamin C palmitate, sodium sulfite or sodium bisulfite, inert gas, EDTA 2Na, or sodium calcium salt; The lyoprotectant involved in said spray-drying or freeze-drying powder injection is: glucose, lactose, mannitol, sorbitol, xylitol, sucrose, trehalose, dextran, polyvinylpyrrolidone (PVP), glycine, One or more mixtures of succinic gelatin, human serum albumin and sodium chloride, the content of the freeze-drying protectant is 2% to 20% (W/V), and the concentration of the protectant in the solution before freeze-drying.

10, a kind of preparation method of a kind of efficient echinacea preparation as said in claim 1, it is characterized in that: emulsion preparation method is as follows: 1) prepare oily phase and medicine phase in preparation tank, in preparation tank, Heat the oil to 20-90°C and add the emulsifier without oil when the medicine is pure, and stir vigorously until it dissolves at 20-80°C; then cool down to 20-40°C, add the medicine while stirring, 2) prepare water in the preparation tank Phase: Stir water and glycerin at 20-90°C for 5 minutes to make them completely miscible. 3) Add the water phase to the oil phase at 20-50°C and stir vigorously for 10-30 minutes to form colostrum; 4) Filter the colostrum through a G3 funnel, adjust the pH value to 3~9, 5) pass through a homogenizer, adjust the homogenization pressure to 520~600kg/cm ² in the first step, and then adjust it to 100~140kg/cm2 in the second step ² or pass through a microfluidizer, adjust the homogenization pressure to 4000-8000psi in the first step, and then adjust to 10000-16000psi in the second step to form an emulsion; pass through a microporous membrane of 0.8um or less, add a protective agent, and carry out Freeze-drying or spray-drying, sub-packaging to obtain the emulsion.