CN102078299B - Citicoline sodium liposome solid preparation - Google Patents
Citicoline sodium liposome solid preparation Download PDFInfo
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- CN102078299B CN102078299B CN201110000084A CN201110000084A CN102078299B CN 102078299 B CN102078299 B CN 102078299B CN 201110000084 A CN201110000084 A CN 201110000084A CN 201110000084 A CN201110000084 A CN 201110000084A CN 102078299 B CN102078299 B CN 102078299B
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Abstract
The invention relates to a citicoline sodium liposome solid preparation which is mainly prepared from citicoline sodium, phospholipid, an additive and other pharmaceutic adjuvants, wherein the citicoline sodium accounts for 1 part by weight, the phospholipids accounts for 2-12 parts by weight, and the additive accounts for 0.5-8 parts by weight. The liposome solid preparation prepared by the invention has the advantages that the stability of the active ingredient citicoline sodium is greatly improved, the valid period of product is prolonged, and phospholipid absorption is cooperated with the curative activity of the citicoline sodium, thus the bioavailability is improved, the product quality of the preparation is improved, and toxic and side effects are reduced.
Description
Technical field
The present invention relates to a kind of C14H25N4NaO11P2 lipidosome solid preparation and method for making thereof, belong to medical technical field.
Background technology
C14H25N4NaO11P2 is the abbreviation of CDP-Cholion, is the precursor substance of phospholipid phosphatidylcholine, is the synthetic necessary coenzyme of lecithin, and its molecular formula is C
14H
25N
4NaO
11P
2, structural formula is:
Citicoline is unbodied hygroscopic powder, has therapeutic use, for example as cerebral protective agent or neuroprotective.C14H25N4NaO11P2 be mainly used in clinically injury of head and brain postoperative with disturbance of consciousness, the acute disturbance of consciousness of cerebral infarction, promote stroke hemiplegia patient upper extremity function to recover and diseases such as acute pancreatitis.Particularly, citicoline is of value to the patient of cerebral infarction, brain trauma and possible neurodegenerative disease.In addition, citicoline is used to treat the disease of brain that caused by cranium wound, hemorrhage, cerebral thrombosis and atherosclerosis and unconscious (the Secades JJ CDP-choline: pharmacology and clinical summary (CDP-choline:pharmacologicai and clinical review) that produces.Methods?Find?Exp?Clin?Pharmacol?19995?Oct；17?Suppl?B：2-54)。
At present, it is main using clinically with the citicoline sodium injection, and oral formulations has C14H25N4NaO11P2 oral liquid and citicoline natrium capsule.The citicoline preparation is mostly at present to be injection, clinical use inconvenience.Ordinary preparation is short because of its biological half-life, thus eliminate in vivo after oral fast, the effective blood drug concentration weak point of holding time, it is more day to take number of times, therefore brings many inconvenience to the patient, and take often cause often the interior blood drug level of body than great fluctuation process.After processing slow release, controlled release preparation, can reduce administration number of times, improve patient's compliance, make better efficacy, side effect is littler.
For medicinal application, citicoline has been mixed with solution, is applicable to parenteral administration, normally intravenously administrable.But the citicoline of at present commercially available solid form also has many defectives.The water content of the citicoline of commercial form (or its salt, be generally C14H25N4NaO11P2) is no more than 5 weight % (with respect to citicoline), and it is the losing or measure through Karl Fischer psychrometrc analysis method of moisture during through drying.Under the normal condition, the water content in the C14H25N4NaO11P2 of commercial form is between 2-4 weight %.The citicoline of these conventional solid dosage formss is unsettled when being exposed to air humidity.Because the hygroscopicity of molecule, this unstability also is present in the solid dosage forms that comprises conventional citicoline, like tablet, capsule etc.
Because it is to moisture-sensitive, and said product specification all relates to water content, so citicoline must be handled, comprises low-humidity environment under specific conditions, to provide and to keep relatively low water content.The manufacturer of drug products must be able to show that their final dosage form is stable, and still in the specification limit of some statement, comprises water content, hardness and physical integrity.Avoid the infringement of dampness for this chemical compound of protection under the normal storage condition, must use special packaging material, comprise aluminium foil capsule and the double-layer polyethylene bag that desiccant is housed.Cause the increase of industrial cost, be unfavorable for the long preservation of medicine and patient's utilization on the other hand.
Liposome (liposomes) is a kind of targeted drug carrier, belongs to a kind of novel form of targeting drug delivery system (targeting drug delivery systems).Its type of having cellularity; Get into the interior principal agent of body is activated body by reticuloendothelial system phagocytic autoimmune function; And change and to be distributed in the body of entrapped drug, the drug main medicine is accumulated in histoorgans such as liver, spleen, lung and bone marrow, thereby improve medicine therapeutic index, reduce the therapeutic dose of medicine and reduce the toxicity of medicine.
The liposome that people's such as Frank Schuettauf article " Citicoline and lithium rescue retinal ganglion cells following partial optic nerve crush in the rat " has disclosed citicoline in the treatment cerebral ischemia better effectively.
People such as Massimo Fresta article " Biological effects of CDP-choline loaded long circulating liposomes on rat cerebral post-ischemic reperfusion " disclosed CDP-choline (CDPc) and be encapsulated in the monolayer long circulating liposomes to improve bioavailability, it has used cholesterol and DPPC.CDP-choline (CDPc) is dissolved in the phosphate buffer of 50ml, regulates ph to 7.4.The phospholipid of desired amount is dissolved in chloroform, avoids the use of the chloroform-methanol mixture, causes classification mutually during evaporation, and organic solvent rotary evaporation under 30 degree is removed, and multilamellar vesicle is processed, and lyophilizing obtains.
People's such as Rao Muralikrishna Adibhatla article " CDP-choline liposomes provide significant reduction in infarction over free CDP-choline in stroke " has wherein disclosed, and DPPC, DPPS, cholesterol and gm1 gangliosidosis (7/4/7/1.57 mol ratio or 35.8/20.4/35.8/8.0mol%) have constituted liposomal systems.
People's such as Puglisi G article " Liposomes as a potential drug carrier for citicoline (CDP-choline) and the effect of formulation conditions on encapsulation efficiency " has disclosed employing DPPA and DPPS prepares liposome.
Though prior art has instructed the citicoline can be through processing the form of liposome; Promote to pass through blood brain barrier; But its bioavailability still satisfies clinical actual needs, how to remain present pressing for through the bioavailability of selecting for use suitable excipient to improve the citicoline liposome.
Summary of the invention
The technical problem that the present invention will solve is to study a kind of clinical suitable citicoline sodium lipidosome and solid preparation thereof, not only significantly improves the fat-soluble of medicine, but also improves bioavailability of medicament significantly; Liposomal formulation has long lasting effect in addition, and prolong drug reduces patient's medicining times at the circulation time of blood.
But the present invention also will solve the method for preparing of the suitability for industrialized production of described citicoline sodium lipidosome and solid preparation thereof.
For addressing the above problem, the present invention provides following technical scheme:
The purpose of this invention is to provide a kind of C14H25N4NaO11P2 Liposomal formulation, mainly processed by C14H25N4NaO11P2, phospholipid, additives, is 1 part of C14H25N4NaO11P2, phosphatidase 12-12 part, additives 0.5-8 part based on the ratio of weight portion.Preferred ratio is: 1 part of C14H25N4NaO11P2, phosphatidase 14-10 part, additives 0.6-3 part.
Preparation Liposomal formulation membrane material commonly used is phospholipid and additives; Wherein phospholipid can be selected natural phospholipid and synthetic phospholipid for use usually, and said natural phospholipid is one or more in Ovum Gallus domesticus Flavus lecithin, hydrogenation egg yolk lecithin, EPG, egg yolk lecithin acyl serine, egg yolk lecithin acyl inositol, soybean lecithin, hydrogenated soya phosphatide, soybean phospholipid acyl glycerol, soy phosphatidylserine, the soybean phospholipid acyl inositol; Said synthetic phospholipid is one or more in dioleoyl phospholipid phatidylcholine, distearyl acid phosphatidylcholine, dipalmitoyl phosphatidyl choline, dimyristoyl phosphatidyl choline, two Laurel phosphatidyl cholines, DOPG, distearyl acid phosphatidyl glycerol, two palmityl phosphatidyl glycerols, GLYCEROL,DIMYRISTOYL PHOSPHATIDYL, the two lauroyl phosphatidyl glycerols.The membrane material of additives commonly used has cholesterol, 18-amine., phosphatidic acid, sodium deoxycholate and poloxamer 188.The membrane material that is used to prepare Liposomal formulation also has PHOSPHATIDYL ETHANOLAMINE, cholesterol second fat, paddy to carry alcohol, natrii tauroglycocholas, phosphatidyl silk amino acid, stearmide, single stearoyl phosphatidic acid, single stearoyl PHOSPHATIDYL ETHANOLAMINE, two cetyl phosphate (DCP), two palmityl PHOSPHATIDYL ETHANOLAMINEs, single palmityl PHOSPHATIDYL ETHANOLAMINE, two myristoyl PHOSPHATIDYL ETHANOLAMINEs.Additives generally are used for regulating membrane structure, change charged character, like cholesterol liposome bimolecular tunic are solidified, thereby reduce the generation of free radical, have reduced oxidation level, and liposome stability is significantly strengthened.
The preferred phospholipid of the present invention is the combination of Ovum Gallus domesticus Flavus lecithin and DOPG, further preferably 1: 3 combination of weight portion.
The preferred additives of the present invention are the combination of sodium deoxycholate and 18-amine., further preferably 2: 1 combination of weight portion.
One of the object of the invention provides a kind of method for preparing above-mentioned C14H25N4NaO11P2 Liposomal formulation, it is characterized in that may further comprise the steps:
(1) phospholipid, additives are dissolved in the organic solvent, mix homogeneously makes immobilized artificial membrane except that after desolvating;
(2) add the buffer solution that is dissolved with C14H25N4NaO11P2 and make the complete aquation of immobilized artificial membrane, form liposome turbid liquor;
Further, adopt the conventional spray-dired technology of this area to be prepared into the liposome powder, lyophilization destroys its crystal form.
In the above-mentioned described method for preparing, organic solvent is selected from one or more in ethanol, isopropyl alcohol, methanol, butanone, acetone, ethyl acetate, chloroform, the dichloromethane, and being preferably volume ratio is 1: 1 the acetone and the mixed solvent of dichloromethane.
In the above-mentioned described method for preparing, what buffer salt solution can be in phosphate buffer, citrate buffer, acetate buffer, carbonate buffer solution, the borate buffer solution is a kind of, is preferably pH value and is acetic acid-sodium-acetate buffer of 5.3.
The present invention also further provides a kind of method for preparing the C14H25N4NaO11P2 Liposomal formulation, comprises following preparation process:
(1) Ovum Gallus domesticus Flavus lecithin and DOPG and sodium deoxycholate and 18-amine. are dissolved in the organic solvent, place that decompression eliminates organic solvent on the rotating thin film evaporimeter, obtain immobilized artificial membrane;
(2) add the buffer solution be dissolved with C14H25N4NaO11P2 and make the complete aquation of immobilized artificial membrane, the solution mix homogeneously is incubated under the 50-70 ℃ of state supersound process 40-60 minute;
(3) above-mentioned steps (2) gained solution is carried out spray drying, promptly get citicoline sodium lipidosome powder.
Another object of the present invention provides a kind of C14H25N4NaO11P2 lipidosome solid preparation; By the spray-dried back of above-mentioned described C14H25N4NaO11P2 Liposomal formulation and pharmaceutically acceptable other mixed with excipients; Be prepared into solid preparations such as granule, tablet, capsule, and the amount of each excipient in pharmaceutical composition can change in the normal ranges of this area.
The not special restriction of above-mentioned described C14H25N4NaO11P2 lipidosome solid preparation, wherein said adjuvant can be the pharmaceutical necessities of solid preparation commonly used in the pharmaceutics; Specifically process: 1 part of citicoline sodium lipidosome by following component by weight; 0～2.4 part of filler, 0～0.2 part of disintegrating agent, 0.016～0.1 part of binding agent; 0～11.5 part of correctives, 0～0.08 part of 0～0.15 part of aromatic and lubricant.
Said filler can be selected from starch, pregelatinized Starch, microcrystalline Cellulose, optimization microcrystalline Cellulose, Powderd cellulose, saccharide, sugar derivatives, calsium supplement and their combination; Calsium supplement is selected from calcium carbonate, calcium phosphate, calcium hydrogen phosphate, Malic acid citric acid calcium, Citric acid calcium, calcium malate, calcium lactate or calcium acetate.
Said disintegrating agent can be selected from carboxymethylstach sodium, polyvinylpolypyrrolidone, primojel, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose and their combination.
Said binding agent can be selected from polyvidone, hypromellose, hydroxypropyl cellulose, starch and their combination; Polyvidone is preferably 30 POVIDONE K 30 BP/USP 30.
Said lubricant can be selected from silicon dioxide, magnesium stearate, calcium stearate, zinc stearate, calcium silicates, Pulvis Talci and their combination.
Described correctives is selected from sucrose, mannitol, Aspartane, saccharin sodium, sucralose, stevioside, the steviosin and their combination.
Described aromatic is selected from flavoring orange essence, oleum Citri sinensis, strawberry essence, Mentholum, cream flavour and their combination.
Another object of the present invention provides a kind of method for preparing above-mentioned C14H25N4NaO11P2 lipidosome solid preparation, mainly comprises the steps:
(1) the citicoline sodium lipidosome is pulverized, crossed 80 mesh sieves, subsequent use;
(2) with pulverizing such as filler, disintegrating agent, correctivess, cross 80 mesh sieves, mix, subsequent use;
(3) with above-mentioned supplementary material mix homogeneously, add binding agent, aromatic system soft material, the granulation of sieving, oven dry, the adding mix lubricant is even, granulate;
(4) dried granules is carried out packing, tabletting or be filled in the capsule promptly gets the C14H25N4NaO11P2 lipidosome solid preparation.
C14H25N4NaO11P2 lipidosome solid preparation provided by the invention, advantage comprises the following aspects:
(1) improves the stability of active component C14H25N4NaO11P2 greatly, prolonged the effect duration of product.
(2) the C14H25N4NaO11P2 lipidosome solid preparation that makes of the present invention meets the requirement of industrialized great production, and preparation technology is simple, and cost is low, and liposome encapsulation is high.
(3) improve the product quality of preparation, reduced toxic and side effects.
Description of drawings
Average blood drug level-the time graph of Fig. 1 patient's oral test preparation and reference preparation.
Fig. 2 is based on the average blood drug level-time graph that receives test preparation and Comparative Examples 1-3 of animal model.
The specific embodiment
The preparation of embodiment 1 citicoline sodium lipidosome
Prescription:
C14H25N4NaO11P2 100g
Ovum Gallus domesticus Flavus lecithin 100g
DOPG 300g
Sodium deoxycholate 40g
18-amine. 20g
Preparation technology:
(1) 100g Ovum Gallus domesticus Flavus lecithin and 300g DOPG and 40g sodium deoxycholate and 20g 18-amine. being dissolved in the 2000ml volume ratio is in 1: 1 the mixed solvent of acetone and dichloromethane; Placing reduces pressure on the rotating thin film evaporimeter eliminates organic solvent, obtains immobilized artificial membrane;
(2) adding the pH value be dissolved with the 100g C14H25N4NaO11P2 is that acetic acid-sodium acetate buffer solution 1000ml of 5.3 makes the complete aquation of immobilized artificial membrane, and the solution mix homogeneously was incubated under 70 ℃ of states supersound process 60 minutes;
(3) above-mentioned steps (2) gained solution is carried out spray drying, promptly get citicoline sodium lipidosome powder.
The preparation of Comparative Examples 1 citicoline sodium lipidosome (usage ratio of each component is different)
C14H25N4NaO11P2 100g
Ovum Gallus domesticus Flavus lecithin 48g
DOPG 146g
Sodium deoxycholate 32g
18-amine. 16g
Preparation technology makes the citicoline sodium lipidosome with embodiment 1.
The preparation of Comparative Examples 2 citicoline sodium lipidosomes (adopting the lyophilizing mode to process)
Prescription:
C14H25N4NaO11P2 100g
Ovum Gallus domesticus Flavus lecithin 100g
DOPG 300g
Sodium deoxycholate 40g
18-amine. 20g
Preparation technology:
(1) 100g Ovum Gallus domesticus Flavus lecithin and 300g DOPG and 40g sodium deoxycholate and 20g 18-amine. being dissolved in the 2000ml volume ratio is in 1: 1 the mixed solvent of acetone and dichloromethane; Placing reduces pressure on the rotating thin film evaporimeter eliminates organic solvent, obtains immobilized artificial membrane;
(2) adding the pH value be dissolved with the 100g C14H25N4NaO11P2 is that acetic acid-sodium acetate buffer solution 1000ml of 5.3 makes the complete aquation of immobilized artificial membrane, and the solution mix homogeneously was incubated under 70 ℃ of states supersound process 60 minutes;
(3) above-mentioned steps (2) gained solution is sub-packed in the stainless steel disc, places and carry out lyophilizing in the freezer dryer:
A, pre-freeze: the medicinal liquid that branch is installed is cooled to-45 ℃ by 3 ℃ of/minute speed, is incubated freezing 4 hours;
B, distillation: the medicinal liquid evacuation that pre-freeze is good, in 8 hours, at the uniform velocity slowly be warming up to-15 ℃ then, be incubated 2 hours, in 4 hours, at the uniform velocity be warming up to 12 ℃ again;
C, drying: the distillation medicinal liquid of stage after finishing that finish at the uniform velocity was warming up to 30 ℃ in 3 hours, heat preservation and dryness 3 hours makes the citicoline sodium lipidosome.
The preparation of embodiment 2 citicoline sodium lipidosomes
Prescription:
C14H25N4NaO11P2 100g
Ovum Gallus domesticus Flavus lecithin 250g
DOPG 750g
Sodium deoxycholate 200g
18-amine. 100g
Preparation technology:
(1) 250g Ovum Gallus domesticus Flavus lecithin and 750g DOPG and 200g sodium deoxycholate and 100g 18-amine. being dissolved in the 4000ml volume ratio is in 1: 1 the mixed solvent of acetone and dichloromethane; Placing reduces pressure on the rotating thin film evaporimeter eliminates organic solvent, obtains immobilized artificial membrane;
(2) adding the pH value be dissolved with the 100g C14H25N4NaO11P2 is that acetic acid-sodium acetate buffer solution 2000ml of 5.3 makes the complete aquation of immobilized artificial membrane, and the solution mix homogeneously was incubated under 50 ℃ of states supersound process 60 minutes;
(3) above-mentioned steps (2) gained solution is carried out spray drying, promptly get citicoline sodium lipidosome powder.
The preparation of Comparative Examples 3 citicoline sodium lipidosomes (component is different)
Prescription:
C14H25N4NaO11P2 100g
Soybean lecithin 1000g
Cholesterol 200g
18-amine. 100g
Preparation technology makes the citicoline sodium lipidosome with embodiment 2.
The preparation of embodiment 3 C14H25N4NaO11P2 liposome particles agent
Prescription (1000 bags)
Citicoline sodium lipidosome (in C14H25N4NaO11P2) 100g
Sucrose 650g
Mannitol 500g
Flavoring orange essence 15g
30 POVIDONE K 30 BP/USP 30 10g
Preparation technology:
The liposome that (1) will contain the 100g C14H25N4NaO11P2 is pulverized, and crosses 80 mesh sieves, and is subsequent use;
(2) sucrose is pulverized, crossed 80 mesh sieves, mix, subsequent use;
(3) with 650g sucrose, 500g mannitol and 100g citicoline sodium lipidosome mix homogeneously, add the 50% alcoholic solution 200ml system soft material of 5% 30 POVIDONE K 30 BP/USP 30 that contains the 15g flavoring orange essence, cross 20 mesh sieves and granulate 60 ℃ of oven dry, 18 mesh sieve granulate;
(4) dried granules is carried out packing, promptly get the agent of C14H25N4NaO11P2 liposome particles.
The preparation of embodiment 4 C14H25N4NaO11P2 liposome tablets
Prescription (1000)
Citicoline sodium lipidosome (in C14H25N4NaO11P2) 100g
Starch 110g
Microcrystalline Cellulose 130g
Cross-linking sodium carboxymethyl cellulose 20g
Hypromellose 3g
Magnesium stearate 4g
Silicon dioxide 4g
Preparation technology:
The liposome that (1) will contain the 100g C14H25N4NaO11P2 is pulverized, and crosses 80 mesh sieves, and is subsequent use;
(2) with 100g starch, 130g microcrystalline Cellulose, 20g cross-linking sodium carboxymethyl cellulose and 100g citicoline sodium lipidosome mix homogeneously; The 20% alcoholic solution 150ml system soft material that adds 2% hypromellose; Crossing 20 mesh sieves granulates; 60 ℃ of oven dry, 18 mesh sieve granulate add 4g magnesium stearate and 4g silicon dioxide mix homogeneously;
(3) tabletting promptly gets the C14H25N4NaO11P2 liposome tablet.
The preparation of embodiment 5 C14H25N4NaO11P2 lipidosome capsules
Prescription (1000)
Citicoline sodium lipidosome (in C14H25N4NaO11P2) 100g
Microcrystalline Cellulose 60g
Low-substituted hydroxypropyl cellulose 8g
Hypromellose 1.6g
Pulvis Talci 5g
Preparation technology:
The liposome that (1) will contain the 100g C14H25N4NaO11P2 is pulverized, and crosses 80 mesh sieves, and is subsequent use;
(2) with 60g microcrystalline Cellulose, 8g low-substituted hydroxypropyl cellulose and 100g citicoline sodium lipidosome mix homogeneously; Add the 20% alcoholic solution 80ml system soft material of 2% hypromellose, cross 30 mesh sieves and granulate 60 ℃ of oven dry; 20 mesh sieve granulate add 5g Pulvis Talci mix homogeneously;
(3) filled capsules promptly gets the C14H25N4NaO11P2 lipidosome capsule.
The mensuration of Test Example 1 envelop rate
Get the liposome of embodiment 1-2 and Comparative Examples 1-3 preparation, the total content of high effective liquid chromatography for measuring C14H25N4NaO11P2 is M, selects for use column chromatography to separate liposome.
Get 1.5g sephadex G-50, more than the phosphate buffer immersion swelling 12h with pH6.8, the chromatographic column interior (200 * 10mm) of packing into; With above-mentioned phosphate buffer flushing balance, get the citicoline sodium lipidosome that embodiment 1-2 and Comparative Examples 1-3 obtain and be dissolved in water, process the solution that every 1ml contains the about 1.8mg of C14H25N4NaO11P2; Get solution 1.8ml respectively and add the chromatographic column top; With phosphate buffer 50ml eluting, flow velocity 1.1ml/min, the eluent of collection add rupture of membranes agent (ethanol: 50ml benzyl alcohol=6: 1); Mixing, HPLC detects the content M of C14H25N4NaO11P2
1
Envelop rate %=M
1/ M * 100%
Table 1 entrapment efficiency determination result
Can know that by above result the liposome encapsulation that the present invention makes is very high, meet the actual production requirement basically; And the liposome encapsulation that the outer Comparative Examples prescription proportioning of the scope of the invention makes is very low, has compared tangible gap with embodiment, is not suitable for production requirement.
The detection of Test Example 2 particle diameters
Get the liposome of embodiment 1-2 and Comparative Examples 1-3 preparation, adopt micro-image analyzer to measure the particle size distribution of liposome, the result sees table 2:
Table 2 particle diameter testing result
Can be known that by above result implement the apparent spherical or ellipticity of liposome that row 1-2 makes, particle diameter is average, scope is 150-300nm, and the liposome outward appearance that Comparative Examples 1-3 makes is disorderly and unsystematic, the big and heterogeneity of particle diameter.
The research of the bioavailability of Test Example 3 products of the present invention and existing medicine
Adopt open, at random, single center EXPERIMENTAL DESIGN of dual crossing, two cycles, single oral dose.20 health volunteers are divided into 2 groups of A, B at random; Every group of each test of experimenter taken respectively and received test preparation (the citicoline sodium lipidosome sheet of embodiment 4) or reference preparation (commercially available C14H25N4NaO11P2 sheet: Sichuan Healthpalace Pharmaceutical Co.,Ltd., lot number: 20100301).After the 1d dinner, water 12h is can't help in fasting to the experimenter before test, morning next day empty stomach respectively word oral contain C14H25N4NaO11P2 200mg receive test preparation or reference preparation, with the 200mL warm water delivery service, and note down.The breakfast of seeking unity of standard behind the 2h of taking medicine can freely be drunk water.Duration of test is guarded by medical personnel, avoids strenuous exercise during being tried.The experimenter takes medicine preceding and take medicine back 0.5,1.0,2.0,3.0,4.0,5.0,6.0,8.0,10,12,16 and 24h respectively get veins of upper extremity blood 4ml, and anticoagulant heparin is placed the centrifugal blood plasma of obtaining behind the 30min ,-20 ℃ of preservations, and room temperature is thawed during mensuration.Adopt high-efficient liquid phase technique that the C14H25N4NaO11P2 in the blood plasma is measured, draw blood drug level-time graph (seeing accompanying drawing 1).
The relevant pharmacokinetic parameters of table 3
| Parameter | Receive test preparation | Reference preparation |
| C max(μg·mL -1) | 3.38±0.37 | 3.29±0.87 |
| T max(h) | 4.7±0.60 | 4.6±0.90 |
| t 1/2 | 4.98±0.58 | 5.28±0.77 |
| ?AUC 0-∞(h·μg·mL -1) | 32.58±7.77 | 32.68±8.26 |
| ?F(％) | 102.8±19.70 | / |
The research of Test Example 4 animal model bioavailability
Adopt open, at random, single center EXPERIMENTAL DESIGN of dual crossing, two cycles, single oral dose.20 mices are divided into two groups of A, B at random, and every group of each test irritated stomach respectively and taken the tablet that processed according to the technology of embodiment 4 by destination agent (from the tablet of the embodiment of the invention 4) and Comparative Examples 1-3.Adopt high-efficient liquid phase technique that the C14H25N4NaO11P2 in the blood plasma is measured, draw blood drug level-time graph.(seeing accompanying drawing 2)
The relevant pharmacokinetic parameters of table 4
Can find out by above experimental data; The C14H25N4NaO11P2 lipidosome solid preparation of embodiment of the invention preparation and the reference preparation and the contrast agents of listing are compared; Bioavailability improves greatly; Prove absolutely the present invention because the synergism of specific phospholipid combination improves bioavailability widely, obtained unexpected technical effect.
Claims (6)
1. a C14H25N4NaO11P2 Liposomal formulation is characterized in that being processed by C14H25N4NaO11P2, phospholipid, additives, is 1 part of C14H25N4NaO11P2, phosphatidase 12-12 part, additives 0.5-8 part based on the ratio of weight portion; Wherein phospholipid is 1: 3 the combination of weight portion of Ovum Gallus domesticus Flavus lecithin and DOPG; Additives are 2: 1 the combination of weight portion of sodium deoxycholate and 18-amine.;
Its preparation method may further comprise the steps:
(1) Ovum Gallus domesticus Flavus lecithin and DOPG and sodium deoxycholate and 18-amine. are dissolved in the organic solvent, place that decompression eliminates organic solvent on the rotating thin film evaporimeter, obtain immobilized artificial membrane;
(2) add the buffer solution be dissolved with C14H25N4NaO11P2 and make the complete aquation of immobilized artificial membrane, the solution mix homogeneously is incubated under the 50-70 ℃ of state supersound process 40-60 minute;
(3) above-mentioned steps (2) gained solution is carried out spray drying, promptly get citicoline sodium lipidosome powder;
Wherein, to be selected from volume ratio be 1: 1 the acetone and the mixed solvent of dichloromethane to organic solvent;
Buffer salt solution is that pH value is acetic acid-sodium-acetate buffer of 5.3.
2. C14H25N4NaO11P2 Liposomal formulation according to claim 1 is characterized in that ratio based on weight portion is 1 part of C14H25N4NaO11P2, phosphatidase 14-10 part, additives 0.6-3 part.
3. C14H25N4NaO11P2 lipidosome solid preparation; It is characterized in that processing: 1 part of claim 1 or 2 described citicoline sodium lipidosome by following component by weight; 0～2.4 part of filler, 0～0.2 part of disintegrating agent, 0.016～0.1 part of binding agent; 0～11.5 part of correctives, 0～0.08 part of 0～0.15 part of aromatic and lubricant.
4. a method for preparing the described C14H25N4NaO11P2 lipidosome solid preparation of claim 3 is characterized in that mainly comprising the steps:
(1) the citicoline sodium lipidosome is pulverized, crossed 80 mesh sieves, subsequent use;
(2) with pulverizing such as filler, disintegrating agent, correctivess, cross 80 mesh sieves, mix, subsequent use;
(3) with above-mentioned supplementary material mix homogeneously, add binding agent, aromatic system soft material, the granulation of sieving, oven dry, the adding mix lubricant is even, granulate;
(4) dried granules is carried out packing, tabletting or be filled in the capsule promptly gets the C14H25N4NaO11P2 lipidosome solid preparation.
5. claim 1 or the 2 described C14H25N4NaO11P2 Liposomal formulations application in the medicine of preparation cerebral protective agent or neuroprotective.
6. the application of the described C14H25N4NaO11P2 lipidosome solid preparation of claim 3 in the medicine of preparation cerebral protective agent or neuroprotective.
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| CN201110000084A CN102078299B (en) | 2011-01-04 | 2011-01-04 | Citicoline sodium liposome solid preparation |
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| CN201110000084A CN102078299B (en) | 2011-01-04 | 2011-01-04 | Citicoline sodium liposome solid preparation |
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| CN102078299B true CN102078299B (en) | 2012-09-26 |
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| CN201110000084A Expired - Fee Related CN102078299B (en) | 2011-01-04 | 2011-01-04 | Citicoline sodium liposome solid preparation |
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| IT201600103956A1 (en) * | 2016-10-17 | 2018-04-17 | Omikron Italia S R L | OPHTHALMIC FORMULATION INCLUDING CYTICOLINE VEHICULATED BY LIPOSOMAS FOR THE TREATMENT OF GLAUCOMA |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1833633A (en) * | 2005-12-29 | 2006-09-20 | 武汉海特生物制药股份有限公司 | Liposome able to transmit blood and brain screen, medicinal compsns. using hiposome as carrier and its prepn. method |
| CN101091714A (en) * | 2007-07-02 | 2007-12-26 | 中国药科大学 | Liposome of precursor containing ginsenoside Rh2, and preparation method |
| WO2010092597A2 (en) * | 2009-02-11 | 2010-08-19 | Lyka Labs Limited | Liposomal citicoline injection |
| CN101816640A (en) * | 2010-04-16 | 2010-09-01 | 海南美大制药有限公司 | Prasugrel liposome solid preparation |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1833633A (en) * | 2005-12-29 | 2006-09-20 | 武汉海特生物制药股份有限公司 | Liposome able to transmit blood and brain screen, medicinal compsns. using hiposome as carrier and its prepn. method |
| CN101091714A (en) * | 2007-07-02 | 2007-12-26 | 中国药科大学 | Liposome of precursor containing ginsenoside Rh2, and preparation method |
| WO2010092597A2 (en) * | 2009-02-11 | 2010-08-19 | Lyka Labs Limited | Liposomal citicoline injection |
| CN101816640A (en) * | 2010-04-16 | 2010-09-01 | 海南美大制药有限公司 | Prasugrel liposome solid preparation |
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| CN102078299A (en) | 2011-06-01 |
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