CN103070852B - Calcium and zinc gluconate liposome oral solution - Google Patents
Calcium and zinc gluconate liposome oral solution Download PDFInfo
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- CN103070852B CN103070852B CN201210548914.2A CN201210548914A CN103070852B CN 103070852 B CN103070852 B CN 103070852B CN 201210548914 A CN201210548914 A CN 201210548914A CN 103070852 B CN103070852 B CN 103070852B
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- Prior art keywords
- calcium
- zinc gluconate
- liposome
- gluconate
- oral solution
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- 239000002502 liposome Substances 0.000 title claims abstract description 92
- 229960000306 zinc gluconate Drugs 0.000 title claims abstract description 69
- 239000011670 zinc gluconate Substances 0.000 title claims abstract description 69
- 229940100688 oral solution Drugs 0.000 title claims abstract description 49
- 229960004494 calcium gluconate Drugs 0.000 title claims abstract description 27
- 239000004227 calcium gluconate Substances 0.000 title claims abstract description 27
- 235000013927 calcium gluconate Nutrition 0.000 title claims abstract description 27
- WHMDKBIGKVEYHS-IYEMJOQQSA-L Zinc gluconate Chemical compound [Zn+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O WHMDKBIGKVEYHS-IYEMJOQQSA-L 0.000 title claims abstract description 20
- 235000011478 zinc gluconate Nutrition 0.000 title claims abstract description 20
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 title abstract description 6
- 229910052791 calcium Inorganic materials 0.000 title abstract description 6
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims abstract description 66
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 claims abstract description 39
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 claims abstract description 39
- 235000012000 cholesterol Nutrition 0.000 claims abstract description 33
- 238000002360 preparation method Methods 0.000 claims abstract description 29
- NEEHYRZPVYRGPP-UHFFFAOYSA-L calcium;2,3,4,5,6-pentahydroxyhexanoate Chemical compound [Ca+2].OCC(O)C(O)C(O)C(O)C([O-])=O.OCC(O)C(O)C(O)C(O)C([O-])=O NEEHYRZPVYRGPP-UHFFFAOYSA-L 0.000 claims abstract description 25
- BVHLGVCQOALMSV-JEDNCBNOSA-N L-lysine hydrochloride Chemical compound Cl.NCCCC[C@H](N)C(O)=O BVHLGVCQOALMSV-JEDNCBNOSA-N 0.000 claims abstract description 17
- 229960005337 lysine hydrochloride Drugs 0.000 claims abstract description 17
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims abstract description 12
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- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 36
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- 239000004472 Lysine Substances 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a calcium and zinc gluconate liposome oral solution and its preparation method. The liposome oral solution is prepared from specific weight proportions of calcium gluconate, zinc gluconate, lysine hydrochloride, egg yolk lecithin, soy sterol, phosphatidyl glycerol, cholesterol and mycose. The liposome oral solution has the advantages of good preparation stability, maintenance of the good entrapment rate of liposome after long-term storage, improvement of the preparation product quality, increase of the retention time of medicines in the systematic circulation, improvement of the biological availabilities of the medicines, obvious improvement of the curative effect, simple preparation method and suitableness for the industrialized production.
Description
Technical field
The present invention relates to a kind of liposome oral solution and method for making thereof, be specifically related to a kind of calcium-zinc gluconate liposome oral solution and method for making thereof, belong to technical field of medicine.
Background technology
The blood calcium of normal person maintains 2.18-2.63 mM/l (9-11 milligram/decilitre), if lower than this scope, then regard as calcium deficiency.During child's calcium deficiency: not easily fall asleep, not easily enter deep sleep, like after falling asleep to cry, easily wake up with a start, hyperhidrosis after falling asleep; Paroxysmal abdominal pain, diarrhoea, knot, breastbone pain, " X ' type lower limb, " O " type lower limb, pigeon chest, fingernail is greyish white or have white trace; Anorexia, monophagia; Daytime irritability, be on tenterhooks; Intelligent development late, speak late; Learn to walk late; Teething is late, and tooth arrangement is sparse, irregular, tight, and tooth is pointed or zigzag darkly; Hair is sparse; Out of condition, easy to catch cold etc.During teenager calcium deficiency: can feel significantly to grow pain, lower limb is soft, cramp, and physical education results is not good; Weak, irritated, energy is not concentrated, easily tired; Monophagia, anorexia; Decayed tooth, hypoplasia of tooth; Easy allergy, easy catching a cold etc.During between twenty and fifty calcium deficiency: have regular asthenia, weak, knot, ache all over, the easy symptom such as allergy, easy catching a cold.After growing up, human body just slowly enters the negative calcium balance phase, and namely calcareous absorption reduces, excretion strengthens.Old people causes calcium deficiency phenomenon because of the loss of calcium; Senile dermatosis is had to itch; Heel aches, lumbar vertebra, cervical vertebra ache; Odontoseisis, to come off; Obvious hunchback, height reduce; Loss of appetite, digestive tract ulcer, constipation; The symptoms such as dreaminess, insomnia, agitation, irritability.Zinc is the large enzyme of human body six, the composition of 200 kinds of metalloenzyme or coenzyme, plays wide application to general metabolism.Zinc is mainly contained in meat and corn.During zinc deficiency, with loss of appetite, growth retardation, pica and dermatitis for outstanding behaviours, the multiple children's being born in <6 year.The symptom lacking lysine comprises fatigue, weak, feels sick, and vomiting is dizzy, does not have appetite, hypoevolutism, anemia etc.
Calcium gluconate and zinc gluconate are replenishing the calcium of being easily absorbed by the body and zinc supplement form.
Calcium gluconate is white crystalline or graininess powder, fusing point 201 DEG C (decomposition), and odorless is tasteless, is soluble in boiling water (20g/100ml), is slightly dissolved in cold water (3g/100ml, 20 DEG C), is insoluble to the organic solvent such as ethanol or ether.Aqueous solution aobvious neutral (pH is about 6-7).
Zinc gluconate is white crystals or particulate powder; Odorless, taste is micro-puckery; Very easily dissolve in boiling water, dissolve in water, insoluble in dehydrated alcohol, chloroform or ether.
Lysine hydrochloride is white crystals or crystalline powder, odorless, easily molten in water, and soluble,very slightly is in ethanol almost insoluble in ether.
At present, had the report of development Zinc and calcium supplement preparation, but existing preparation is all conventional formulation prepared by common process, its long-time stability and bioavailability aspect, all also have greatly improved.
Such as, patent CN102038670A the invention discloses a kind of Zinc calcium gluconate oral solution and preparation method thereof, it is characterized in that: it is prepared into 1000ml oral administration solution with 54-66g calcium gluconate, 1.8-2.2g zinc gluconate, 9-11g lysine hydrochloride, 1.8-2.2g active carbon, 135-165g sucrose, 10.8-13.2g lactose, 0.9-1.1g sodium chloride and 0.45-0.55ml essence.
Patent CN1957908A the invention discloses a kind of Zinc calcium gluconate oral solution and preparation method thereof, comprise the steps: jelly powder 40-60 part to add in the purified water of 95% to prepare 10000ml, stirred at ambient temperature makes its swelling 1 hour, calcium gluconate 600 parts, zinc gluconate 30 parts, lysine hydrochloride 100 parts, Aspartane 7 parts are added in above-mentioned swelling solution, be heated to about 80 DEG C, stirring and dissolving, boiling sterilization, add potassium sorbate 10 parts, hay-scented essence 2 parts, stirring and dissolving, load in bag while hot, to obtain final product.
Preparation prescription disclosed in above-mentioned patent, preparation technology, final dosage form are all different, but essence is more or less the same; The poor stability of medicine and bioavailability is low does not all improve.
In pharmaceutical carrier induction system, the research of the submicrons such as microemulsion, microsphere, nanoparticle, liposome, pharmacosomes has become field very active in novel pharmaceutical formulation research.Wherein, the research of liposome is comparatively extensive, and liposome has good targeting and biocompatibility in vivo.
As a kind of new medicinal preparation, Liposomal formulation has the following advantages:
(1) there is slow releasing function: active component slow releasing, delay renal excretion and metabolism, thus extend action time, improve mass effect;
(2) increase the dissolubility of medicine, improve the quality of the pharmaceutical preparations;
(3) there is targeting: the contained medicine of liposome maintains high concentration in liver, spleen reticuloendothelial system internal organs local, thus plays the effect of medicine organ targeting;
(4) there is the protective effect to active pharmaceutical ingredient;
(5) drug toxicity is reduced.
Liposome (Liposome) at first by British scholar Bangham and Standlish phospholipid is dispersed in water carry out electron microscopic observation time discovery.Phospholipid is dispersed in water self-assembling formation multilamellar vesicle, and every layer is all the bilayer of lipid; Separated by aqueous phase between vesicle central authorities and each layer, bilayer thickness is about 4nm.Afterwards, this bimolecular folliculus with similar biofilm structure was called liposome.Liposome can be divided into multilamelar liposome and unilamelar liposome.Unilamelar liposome is divided into again small unilamellar vesicle and large unilamellar vesicle.Small unilamellar vesicle is spherical, and size is generally 20-50 nanometer; Large unilamellar vesicle is of a size of micron number magnitude.
The people such as Britain Lai Men in 1971 start liposome to be used for pharmaceutical carrier, Main Function mechanism be drug powder or solution are wrapped in liposome bilayer lipid film in the aqueous phase closed or embed in liposome bilayer lipid film, this microgranule has class cellularity, enter principal agent in human body and activated the autoimmune function of body by reticuloendothelial system phagocytic, and change the distribution in vivo of encapsulated medicine, make drug main will liver, spleen, put aside in the histoorgan such as lung and bone marrow, thus improve the therapeutic index of medicine, reduce the therapeutic dose of medicine and reduce the toxicity of medicine.
In recent years, along with the continuous progress of biotechnology, liposomal preparation technique gradual perfection, liposome mechanism of action is illustrated further, in addition liposome is applicable to vivo degradation, avirulence and non-immunogenicity, particularly great number tested data proves that liposome can improve drug therapeutic indices as pharmaceutical carrier, reduces drug toxicity and reduce drug side effect, and reduces the advantages such as drug dose.
Due to the deficiency of common glucose Calciofon zinc oral administration solution, at present demand is existed for calcium-zinc gluconate liposome oral solution.
Summary of the invention
In order to form colory calcium-zinc gluconate liposome oral solution, importantly finding can be well compatible thus it well encapsulated and non-leakage filmogen with active component calcium gluconate, zinc gluconate and lysine hydrochloride, and finds suitable preparation technology.
In order to solve the problem, present inventor has performed and study with keen determination, found that: by selecting the Ovum Gallus domesticus Flavus lecithin of specified weight proportioning, soyasterol, phosphatidyl glycerol, cholesterol and trehalose, active component calcium gluconate, zinc gluconate and lysine hydrochloride can be made the liposome oral solution of excellent quality, circulation time in vivo extends, bioavailability improves, thus completes the present invention.
The object of the present invention is to provide a kind of calcium-zinc gluconate liposome oral solution, it is made up of the composition comprising following weight proportion:
Wherein, Ovum Gallus domesticus Flavus lecithin and the weight ratio between phosphatidyl glycerol weight sum and soyasterol are 5: 1-7: 1,
Ovum Gallus domesticus Flavus lecithin is 6: 1-10: 1 with phosphatidyl glycerol weight sum and the ratio of cholesterol weight.
Another object of the present invention is to the preparation method providing above-mentioned calcium-zinc gluconate liposome oral solution, the method comprises the following steps:
(1) Ovum Gallus domesticus Flavus lecithin, soyasterol, phosphatidyl glycerol and cholesterol are stirred ultrasonic 20min in water for injection, then under 300bar-1000bar pressure, carry out gradient homogenizing 5 ~ 7 times, obtain lipid solution;
(2) by calcium gluconate, zinc gluconate and lysine hydrochloride, add in the lipid solution of above-mentioned preparation, be heated to 60 DEG C, the ultrasonic 50min of insulated and stirred;
(3) after trehalose being dissolved in water for injection, pour above-mentioned solution into, use water for injection standardize solution, stir, 0.45 μm of filtering with microporous membrane, fill, obtains calcium-zinc gluconate liposome oral solution.
According to calcium-zinc gluconate liposome oral solution provided by the invention by selecting suitable material composition and adopting suitable preparation method to obtain, wherein liposomal particle size is little, even particle size distribution, envelop rate is high, stability is high, and the time of staying is long in vivo, and bioavailability is high.And preparation method is simple, is suitable for industrialized great production.
Accompanying drawing explanation
Fig. 1 illustrates the blood concentration-time curve of calcium-zinc gluconate liposome oral solution.
Detailed description of the invention
Below describe the present invention, the features and advantages of the invention can describe along with these and become more clear.
According to an aspect of the present invention, provide a kind of calcium-zinc gluconate liposome oral solution, it is made up of the composition comprising following weight proportion:
Wherein, Ovum Gallus domesticus Flavus lecithin and the weight ratio between phosphatidyl glycerol weight sum and soyasterol are 5: 1-7: 1,
Ovum Gallus domesticus Flavus lecithin is 6: 1-10: 1 with phosphatidyl glycerol weight sum and the ratio of cholesterol weight.
Preferably, provide a kind of calcium-zinc gluconate liposome oral solution, it is made up of the composition comprising following weight proportion:
Wherein, Ovum Gallus domesticus Flavus lecithin and the weight ratio between phosphatidyl glycerol weight sum and soyasterol are 5: 1-7: 1,
Ovum Gallus domesticus Flavus lecithin is 6: 1-10: 1 with phosphatidyl glycerol weight sum and the ratio of cholesterol weight.
More preferably, Ovum Gallus domesticus Flavus lecithin and the weight ratio between phosphatidyl glycerol weight sum and soyasterol are 6: 1-7: 1; Ovum Gallus domesticus Flavus lecithin is 8: 1-10: 1 with phosphatidyl glycerol weight sum and the ratio of cholesterol weight.
In the present invention, for the feature of active component calcium gluconate, zinc gluconate and lysine hydrochloride, the present inventor is found by research, film material based on the combination of Ovum Gallus domesticus Flavus lecithin, soyasterol and phosphatidyl glycerol is particularly suitable for, by being combined with cholesterol, the liposome oral fluid that envelop rate is high, stability is high can be obtained.When using other phospholipid, be difficult to form colory liposome, the property-deterioration such as the envelop rate of liposome, stability and percolation ratio.
In calcium-zinc gluconate liposome oral solution of the present invention, for the calcium gluconate of 60 weight portions, the consumption of Ovum Gallus domesticus Flavus lecithin is 120-200 weight portion.If the consumption of Ovum Gallus domesticus Flavus lecithin is lower than 120 weight portions, then cannot form stable liposome; Otherwise if the consumption of Ovum Gallus domesticus Flavus lecithin is higher than 200 weight portions, then the envelop rate as the calcium-zinc gluconate of active constituents of medicine declines, the quality of oral administration solution and curative effect reduce.
In calcium-zinc gluconate liposome oral solution of the present invention, for the calcium gluconate of 60 weight portions, the consumption of phosphatidyl glycerol is 20-40 weight portion.If the consumption of phosphatidyl glycerol is lower than 20 weight portions, then cannot form stable liposome; Otherwise if the consumption of phosphatidyl glycerol is higher than 40 weight portions, then the envelop rate as the calcium-zinc gluconate of active constituents of medicine declines, the quality of oral administration solution and curative effect reduce.
In the present invention, soyasterol is except as except film material, adjusting the stability of film.
In calcium-zinc gluconate liposome oral solution of the present invention, for the calcium gluconate of 60 weight portions, the consumption of soyasterol is 20-50 weight portion.If the consumption of soyasterol is lower than 20 parts, the stability of gained liposome is not enough; If the consumption of soyasterol is higher than 50 parts, then the envelop rate as the calcium-zinc gluconate of active constituents of medicine declines, and the quality of oral administration solution and curative effect reduce.
Especially, in the present invention, Ovum Gallus domesticus Flavus lecithin and the weight ratio between phosphatidyl glycerol weight sum and soyasterol are 5: 1-7: 1.If Ovum Gallus domesticus Flavus lecithin and the weight ratio between phosphatidyl glycerol weight sum and soyasterol are lower than 5: 1, active component is easy to seepage; If Ovum Gallus domesticus Flavus lecithin and the weight ratio between phosphatidyl glycerol weight sum and soyasterol higher than: 1, membrane stability is not enough.
In the present invention, in cholesterol for regulating the membrane stability of liposome.Cholesterol (cholesterol, Ch) is a kind of amphiphilic, combines with soybean lecithin, PHOSPHATIDYL ETHANOLAMINE and phosphatidyl glycerol, stops it to be condensed into crystal structure.Cholesterol mixes in the double-decker of soybean lecithin, PHOSPHATIDYL ETHANOLAMINE and phosphatidyl glycerol, is similar to " buffer agent " and equally plays the effect regulating membrane structure " mobility ".When lower than phase transition temperature, cholesterol can make film reduce ordered arrangement, increases mobility; When higher than phase transition temperature, cholesterol can increase the ordered arrangement of film, thus reduces the mobility of film.Cholesterol can make liposome bilayers film solidify, thus reduces the generation of free radical, reduces oxidation level, liposome stability is significantly strengthened.
In calcium-zinc gluconate liposome oral solution of the present invention, for the calcium gluconate of 60 weight portions, the consumption of cholesterol is 10-40 weight portion.If the consumption of cholesterol is lower than 10 weight portions, the stability of gained liposome obviously reduces; If the consumption of cholesterol is higher than 40 weight portions, then the envelop rate of active constituents of medicine also can decline thereupon, and the quality of injection and curative effect reduce.
Especially, in the present invention, Ovum Gallus domesticus Flavus lecithin is 6: 1-10: 1 with phosphatidyl glycerol weight sum and the ratio of cholesterol weight.If the ratio of Ovum Gallus domesticus Flavus lecithin and phosphatidyl glycerol weight sum and cholesterol weight is lower than 6: 1, liposome membrane mobility is too high, be wrapped in the easy seepage of active component in liposome, if the ratio of Ovum Gallus domesticus Flavus lecithin and phosphatidyl glycerol weight sum and cholesterol weight is higher than 10: 1, membrane stability is not enough.
Especially, when Ovum Gallus domesticus Flavus lecithin and the weight ratio between phosphatidyl glycerol weight sum and soyasterol are 6: 1-7: 1; Ovum Gallus domesticus Flavus lecithin is 8: 1-10: 1 with phosphatidyl glycerol weight sum and the ratio of cholesterol weight, and the liposome toxicity formed is minimum.
In calcium-zinc gluconate liposome oral solution of the present invention, the form of trehalose energy available protecting liposome particles and stability, improve the stability of liposome oral solution further.
Calcium-zinc gluconate liposome oral solution of the present invention, its specification is: 10ml is containing calcium gluconate 0.6g, zinc gluconate 0.03g and lysine hydrochloride 0.1g.
According to a further aspect in the invention, provide the preparation method of above-mentioned calcium-zinc gluconate liposome oral solution, method comprises the following steps:
(1) Ovum Gallus domesticus Flavus lecithin, soyasterol, phosphatidyl glycerol and cholesterol are stirred ultrasonic 20min in water for injection, then under 300bar-1000bar pressure, carry out gradient homogenizing 5 ~ 7 times, obtain lipid solution;
(2) by calcium gluconate, zinc gluconate and lysine hydrochloride, add in the lipid solution of above-mentioned preparation, be heated to 60 DEG C, the ultrasonic 50min of insulated and stirred;
(3) after trehalose being dissolved in water for injection, pour above-mentioned solution into, use water for injection standardize solution, stir, 0.45 μm of filtering with microporous membrane, fill, obtains calcium-zinc gluconate liposome oral solution.
In the method according to the invention, described gradient homogenizing is homogenizing 1-2 time under first 300bar-500bar pressure, then homogenizing 2-3 time under 500bar-800bar pressure, last 900bar-1000bar homogenizing 2 times again.
The stability of liposome and bioavailability have close corresponding relation; Stability is higher, and bioavailability is higher.The particle diameter of liposome is less, and particle size distribution is even, and in body, the time of staying is longer, is also one of factor that bioavailability is high.
Select above-mentioned raw materials, the standby liposome solutions prepared by said method, wherein form the vesicle that the envelop rate of well-balanced, suitable size is high, and its stability is high, not easy to leak.
embodiment
The present invention is further described below by way of exemplary embodiment.But, these illustrative examples are only illustrative, are not construed as limiting scope of the present invention.
The preparation of embodiment 1 calcium-zinc gluconate liposome oral solution
Raw materials used as follows:
Preparation process is as follows:
(1) by Ovum Gallus domesticus Flavus lecithin 120g, phosphatidyl glycerol 20g, soyasterol 20g and cholesterol 20g, ultrasonic 20min is stirred, then homogenizing 2 times under 300bar pressure, homogenizing 2 times under 800bar pressure in 800ml water for injection, last 900bar homogenizing 2 times again, obtains lipid solution;
(2) by calcium gluconate 60g, zinc gluconate 3g and lysine hydrochloride 10g, add in the lipid solution of above-mentioned preparation, be heated to 60 DEG C, the ultrasonic 50min of insulated and stirred;
(3) after trehalose 55g being dissolved in appropriate water for injection, pour above-mentioned solution into, mend water for injection to 1000ml, stir, 0.45 μm of filtering with microporous membrane, fill 10ml/ bottle, obtains 100 bottles of calcium-zinc gluconate liposome oral solution.
The preparation of embodiment 2 calcium-zinc gluconate liposome oral solution
Raw materials used as follows:
Preparation process is as follows:
(1) by Ovum Gallus domesticus Flavus lecithin 150g, phosphatidyl glycerol 30g, soyasterol 30g and cholesterol 20g, ultrasonic 20min is stirred, then homogenizing 1 time under 500bar pressure, homogenizing 3 times under 500bar pressure in 800ml water for injection, last 1000bar homogenizing 2 times again, obtains lipid solution;
(2) by calcium gluconate 60g, zinc gluconate 3g and lysine hydrochloride 10g, add in the lipid solution of above-mentioned preparation, be heated to 60 DEG C, the ultrasonic 50min of insulated and stirred;
(3) after trehalose 70g being dissolved in appropriate water for injection, pour above-mentioned solution into, mend water for injection to 1000ml, stir, 0.45 μm of filtering with microporous membrane, fill 10ml/ bottle, obtains 100 bottles of calcium-zinc gluconate liposome oral solution.
The preparation of embodiment 3 calcium-zinc gluconate liposome oral solution
Raw materials used as follows:
Preparation process is as follows:
(1) by Ovum Gallus domesticus Flavus lecithin 200g, phosphatidyl glycerol 40g, soyasterol 45g and cholesterol 40g, ultrasonic 20min is stirred, then homogenizing 1 time under 400bar pressure, homogenizing 2 times under 700bar pressure in 800ml water for injection, last 1000bar homogenizing 2 times again, obtains lipid solution;
(2) by calcium gluconate 60g, zinc gluconate 3g and lysine hydrochloride 10g, add in the lipid solution of above-mentioned preparation, be heated to 60 DEG C, the ultrasonic 50min of insulated and stirred;
(3) after trehalose 80g being dissolved in appropriate water for injection, pour above-mentioned solution into, mend water for injection to 1000ml, stir, 0.45 μm of filtering with microporous membrane, fill 10ml/ bottle, obtains 100 bottles of calcium-zinc gluconate liposome oral solution.
Comparative example 1-3
Adopt with respectively with identical production technology in embodiment 1-3, the composition in comparative example 1-3 is as shown in Table 1 below made calcium-zinc gluconate liposome oral solution respectively:
Composition used in table 1 comparative example 1-3
| Composition | Comparative example 1 | Comparative example 2 | Comparative example 3 |
| Calcium gluconate | 60g | 60g | 60g |
| Zinc gluconate | 3g | 3g | 3g |
| Lysine hydrochloride | 10g | 10g | 10g |
| Ovum Gallus domesticus Flavus lecithin | 120g | / | 250g |
| Phosphatidyl glycerol | 20g | / | / |
| Soyasterol | 20g | 30g | 70g |
| Soybean lecithin | / | 150g | / |
| Cholesterol | / | 20g | / |
| Trehalose | / | 70g | 30g |
| Mannitol | 55g | / | / |
Wherein, "/" represents and does not use.
the mensuration of test example 1 liposomal particle size
Under room temperature condition, the calcium-zinc gluconate liposome oral solution in Example 1-3 and comparative example 1-3, is placed in the sample cell of Submicron Particle Sizer Model 370 droplet measurement instrument, measures particle size distribution and mean diameter; Particle shape is observed with projection electron microscope.Result is shown in following table 2.
Table 2 liposomal particle size testing result
| Numbering | Liposome | Mean diameter (nm) | Percolation ratio (%) |
| Embodiment 1 | Spherical or oval entity | 292 | 0.73 |
| Embodiment 2 | Spherical or oval entity | 308 | 0.76 |
| Embodiment 3 | Spherical or oval entity | 312 | 0.81 |
| Comparative example 1 | Out-of-shape | 980 | 25.9 |
| Comparative example 2 | Out-of-shape | 915 | 25.4 |
| Comparative example 3 | Out-of-shape | 943 | 27.7 |
As known from Table 2, the liposomal particle size that embodiment 1-3 obtains is even, and aobvious spherical, size is homogeneous; The liposomal particle size that comparative example 1-3 obtains is uneven, and shape is indefinite, not of uniform size.
Specifically, even if when adopting same production technology, in embodiment 1-3, the particle appearance of gained calcium-zinc gluconate liposome and mean diameter thereof are obviously better than the calcium-zinc gluconate liposome of gained in comparative example 1-3.Illustrate when using the composition beyond the present invention's composition used, or when Ingredient Amount is when the Ingredient Amount scope that the present invention limits is outer, the outward appearance of gained calcium-zinc gluconate liposome is inferior to the present invention, and mean diameter goes out greatly a lot.
the mensuration of test example 2 envelop rate
By the calcium-zinc gluconate liposome oral solution prepared in embodiment 1-3 and comparative example 1-3 with the rotating speed high speed centrifugation of 5000r/min, centrifugal 20 minutes, get supernatant, water for injection dissolves, HPLC method surveys calcium gluconate Zn content, and computational envelope rate, result is shown in following table 3.
Table 3 entrapment efficiency determination result
As shown in Table 3, the envelop rate of Liposomal formulation prepared of embodiment 1-3 is significantly higher than the envelop rate of the Liposomal formulation of comparative example 1-3.Illustrate when using the composition beyond the present invention's composition used, or when Ingredient Amount is when the Ingredient Amount scope that the present invention limits is outer, the liposome encapsulation of gained liposome is lower than the present invention.
test example 3 study on the stability
The sample that embodiment of the present invention 1-3, comparative example 1-3 are prepared and listing Zinc calcium gluconate oral solution (lot number: 20111101, Yangzijiang Pharmaceutical Group Co., Ltd, production address: No. 1, Yangtse river Road(South), Gaogang District, Taizhou City, Jiangsu Province) be placed in lower 6 months of the condition of high temperature 40 DEG C, relative humidity 75% respectively, carry out accelerated test investigation, result is shown in following table 4.
Table 4 accelerated test result
As shown in Table 4, when accelerating June, listing formulation content reduces, and related substance raises; And the change of sample property of the present invention, content and related substance is all not obvious, illustrate that product stability of the present invention is good.
test example 4 percolation ratio is tested
Get sample prepared by test example 1-3 and comparative example 1-3, at ambient temperature, respectively at 0 day, 30 days, 60 days, 90 days and 180 days, make regular check on, measure envelop rate, the dose encapsulated with 0 day compares, and calculate percolation ratio, result is shown in following table 5.
Table 5 percolation ratio result of the test
As shown in Table 5, during long term storage, the calcium-zinc gluconate liposome oral solution percolation ratio change prepared in embodiment of the present invention 1-3 is little, and the oral administration solution percolation ratio prepared in comparative example 1-3 increases gradually, liposome seepage is serious, and this illustrates that calcium-zinc gluconate liposome oral solution prepared by the present invention has higher stability.
the mensuration of test example 5 blood drug level
49 rats are divided into 7 groups at random, often organize the oral administration solution prepared in coloclysis administration embodiment 1-3 and comparative example 1-3 respectively, and commercially available (lot number: 20111101, Yangzijiang Pharmaceutical Group Co., Ltd, production address: No. 1, Yangtse river Road(South), Gaogang District, Taizhou City, Jiangsu Province) specification is the Zinc calcium gluconate oral solution of 10ml.Respectively at 0.5h, 1h, 1.5h, 2h, 4h, 6h, 8h, 12h and 24h after administration, blood sampling, blood sample after treatment, measures blood drug level with HPLC-M S method.Draw in embodiment 1-3 blood drug level and the relation curve of time of the calcium-zinc gluconate liposome oral solution prepared, the calcium-zinc gluconate liposome oral solution prepared in comparative example 1-3 and commercial glucose saccharic acid calcium zinc oral administration solution, be shown in accompanying drawing 1.
As shown in Figure 1, compare with commercial glucose saccharic acid calcium zinc oral administration solution with the calcium-zinc gluconate liposome oral solution prepared in comparative example 1-3, the calcium-zinc gluconate liposome oral solution prepared in embodiment of the present invention 1-3 has the following advantages: release rate is in vivo slow, in body circulation, distribution time extends, reach slow release effect, bioavailability improves.
industrial applicibility
Calcium-zinc gluconate liposome of the present invention has good outward appearance, and granule is little, uniform particle sizes, and envelop rate is high, and stability is high, and percolation ratio is low, and the time of staying is in vivo long, and bioavailability is high, has good industrial application value.
Below through the specific embodiment and the embodiment to invention has been detailed description; but should understand; these explanations do not form any restriction to scope of the present invention; in the case of without departing from the spirit and scope of protection of the present invention; multiple modification, improvement and replacement can be carried out, because these all fall within the scope of protection of the present invention to technical solutions and their implementation methods of the present invention.
Each list of references mentioned in the application or quote, which is hereby incorporated by reference.
Claims (6)
1. a calcium-zinc gluconate liposome oral solution, it is made up of the composition of following weight proportion and water:
Wherein, Ovum Gallus domesticus Flavus lecithin and the weight ratio between phosphatidyl glycerol weight sum and soyasterol are 5:1-7:1;
Ovum Gallus domesticus Flavus lecithin is 6:1-10:1 with phosphatidyl glycerol weight sum and the ratio of cholesterol weight;
Wherein, 60g calcium gluconate makes the calcium-zinc gluconate liposome oral solution 100 bottles of 10ml/ bottle.
2. calcium-zinc gluconate liposome oral solution according to claim 1, it is made up of the composition of following weight proportion and water:
Wherein, Ovum Gallus domesticus Flavus lecithin and the weight ratio between phosphatidyl glycerol weight sum and soyasterol are 5:1-7:1;
Ovum Gallus domesticus Flavus lecithin is 6:1-10:1 with phosphatidyl glycerol weight sum and the ratio of cholesterol weight;
Wherein, 60g calcium gluconate makes the calcium-zinc gluconate liposome oral solution 100 bottles of 10ml/ bottle.
3. calcium-zinc gluconate liposome oral solution according to claim 1 and 2, wherein, Ovum Gallus domesticus Flavus lecithin and the weight ratio between phosphatidyl glycerol weight sum and soyasterol are 6:1-7:1.
4. calcium-zinc gluconate liposome oral solution according to claim 1 and 2, wherein, Ovum Gallus domesticus Flavus lecithin is 8:1-10:1 with phosphatidyl glycerol weight sum and the ratio of cholesterol weight.
5. prepare a method for calcium-zinc gluconate liposome oral solution according to any one of claim 1 to 4, the method comprises the following steps:
(1) Ovum Gallus domesticus Flavus lecithin, soyasterol, phosphatidyl glycerol and cholesterol are stirred ultrasonic 20min in water for injection, then under 300bar-1000bar pressure, carry out gradient homogenizing 5 ~ 7 times, obtain lipid solution;
(2) by calcium gluconate, zinc gluconate and lysine hydrochloride, add in the lipid solution of above-mentioned preparation, be heated to 60 DEG C, the ultrasonic 50min of insulated and stirred;
(3) after trehalose being dissolved in water for injection, pour above-mentioned solution into, use water for injection standardize solution, stir, 0.45 μm of filtering with microporous membrane, fill, obtains calcium-zinc gluconate liposome oral solution.
6. method according to claim 5, wherein, the homogenizing 1-2 time under first 300bar-500bar pressure when step (1) gradient homogenizing, then homogenizing 2-3 time under 500bar-800bar pressure, last 900bar-1000bar homogenizing 2 times again.
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| CN101897668A (en) * | 2009-05-27 | 2010-12-01 | 上海医药工业研究院 | A kind of oxaliplatin liposome and its preparation method and application |
| CN102038670A (en) * | 2010-12-16 | 2011-05-04 | 杭州洁康药业有限公司 | Calcium and zinc gluconate oral solution and preparation method thereof |
| CN102335133A (en) * | 2011-07-14 | 2012-02-01 | 海南美大制药有限公司 | Cefaclor lipidosome solid preparation |
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| CN101897668A (en) * | 2009-05-27 | 2010-12-01 | 上海医药工业研究院 | A kind of oxaliplatin liposome and its preparation method and application |
| CN102038670A (en) * | 2010-12-16 | 2011-05-04 | 杭州洁康药业有限公司 | Calcium and zinc gluconate oral solution and preparation method thereof |
| CN102335133A (en) * | 2011-07-14 | 2012-02-01 | 海南美大制药有限公司 | Cefaclor lipidosome solid preparation |
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