CN109091451A - Oil phase liquid crystalline substance gel precursors preparation of hydrophilic medicament and preparation method thereof - Google Patents
Oil phase liquid crystalline substance gel precursors preparation of hydrophilic medicament and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to prodrug formulation arts, disclose a kind of preparation method of the oil phase liquid crystalline substance gel precursors preparation of hydrophilic medicament, the following steps are included: first preparing phospholipid dispersions and hydrophilic medicament solution, it is mixed and prepares aqueous phase solution, then oil-phase solution is prepared, then is lyophilized after oil liquid mutually compatible with water is mixed and freeze-drying sample is made, then prepares the miscella phase of phosphatide and glyceride again, miscella is added in freeze-drying sample and is mixed, hydrophilic medicament precursor formulation is made.Resulting hydrophilic medicament precursor formulation is with good stability, and gel can be formed by meeting water, has good had good sustained release effect.The system has many advantages, such as that preparation process is simple, differences between batches are small, influence factor is few, is the new technology and novel form of a kind of great commercial conversion value.
Description
Technical field
The invention belongs to prodrug formulation arts, and in particular to the oil phase liquid crystalline substance gel precursors preparation of hydrophilic medicament and
Preparation method.
Background technique
Drug can be divided into oral preparation, ejection preparation by different prescription formulas, through nasal preparation, preparation capable of permeating skin etc..No
Same administration mode needs to consider different factors.Such as, the polypeptide protein of half-life short, fat-soluble difference big for molecular weight
Class drug, oral preparation are easy to produce degradation inactivation by gastric acid and pepsin；Injection needs to consider the biofacies of carrier
Capacitive etc.；Preparation capable of permeating skin will investigate the difference absorption of drugs influence etc. of individual and site of action.In addition how medicine is improved
The storage stability of object, reduces drug side-effect at the bioavilability for reducing administration frequency, improving drug, in the exploitation of drug
With it is also of crucial importance in research.
Concentration is maintained within a certain range and can just generate beneficial effect the activating agent of many drugs in vivo, excessively high or mistake
Low that desired effect is all not achieved, drug concentration is excessively high to also result in toxic side effect.In addition the medicine shorter for some half-life period
The long-term high frequency administration of object can make the compliance of patient poor.
In view of the above-mentioned problems, drug release can be efficiently controlled it is necessary to develop the sustained release agent with better stability
Speed reduces side reaction, reduces medicining times, improves patient compliance.
Lysotropic liquid crystal gel is mainly the orderly system formed by one or more Amphi-pathic compounds and solvent.Due to it
Inside is made of lattice one by one, and the strong interaction force between ordered arrangement and amphiphile, amphiphilic molecule between lattice makes its appearance
On be gel.Lysotropic liquid crystal is gradually available for a variety of since the characteristics of its own structure has attracted the concern of numerous scientists
The carrier of drug can be made drug maintain effective concentration for a long time in vivo, be reached with the various polar medicines of long-acting slow-release in vivo
The purpose for improving its bioactivity, reducing administration number of times.
Have in existing gel preparation technology using phosphatide and glyceride as pharmaceutical carrier, due to the pole of different pharmaceutical
Property it is different, generally can be using a large amount of solvents and surface work be added in order to solve the problems, such as that some drugs dissolubility in system is poor
The method of property agent, after drug is dissolved in phosphatide or glyceride or solvent, is made injection after each component being mixed,
Also it adds water and liquid crystal nanoparticle is made.Injection react into after human body with water generation in human body, forms gel, is played drug and is delayed
The effect released.Liquid crystal nanoparticle can be used as oral preparation or nasal-cavity administration etc., and storage stability is good, and have good sustained release
Effect.As patent CN108272747A discloses oil phase liquid crystalline substance gel precursors preparation and its preparation side of a kind of hydrophilic medicament
Method, Chinese patent CN108309931A disclose a kind of preparation and preparation method thereof for treating synovitis.Chinese patent
CN108283621A discloses a kind of nasal cavity nanometer formulation momestasone furoate gel with liquid crystal structure nanoparticle and preparation method thereof.
However for hydrophilic drug, especially large hydrophilic molecular drug, such as protein IgG, PD-1, PD-L1, pancreas
Island element, it is poor to be made aqueous preparations stability, is easy hydrolysis；And hydrophilic medicament oil phase formulation currently on the market cannot be formed
Gel, the bad problem of generally existing slow release effect；And shelf stability is poor.Hydrophilic medicament is difficult to dissolve in oily phase,
Needing to be added water phase could dissolve, thus be difficult to that the gel with liquid crystal structure precursor formulation of homogeneous oil phase is made.Therefore it is badly in need of developing one
The oil phase formulation preparation method of the new hydrophilic medicament of kind, allows hydrophilic medicament that uniform oil phase formulation is made, both had
There is slow releasing function can be with good stability.
Summary of the invention
The present invention is directed at least solve one of prior art problem, the present invention provides a kind of parent with long-acting slow-release effect
Oil phase liquid crystalline substance gel precursors preparation of aqueous pharmaceutical and preparation method thereof.
The technical solution of the present invention is as follows: the preparation method of the oil phase liquid crystalline substance gel precursors preparation of hydrophilic medicament, including with
Lower step:
(S1) preparation of phospholipid dispersions: being weighed phosphatide and distilled water and be added in bottle with the mass ratio of 1:3~5, and sealing is put
Coarse dispersion is dispersed on shaking table；By ultrasonic disperse of popping one's head under coarse dispersion condition of ice bath, milky phospholipid dispersions are formed；
(S2) preparation of hydrophilic medicament solution: weighing hydrophilic drugs and water added to be completely dissolved, and the medicine of 1~20mg/ml is made
Object solution for standby；
(S3)) preparation of water phase: take phospholipid dispersions obtained and drug obtained in step (S2) in step (S1) molten
Liquid is uniformly mixed so as to obtain water phase with the volume ratio of 1:3~2:3；
(S4) preparation of oily phase: the surfactant of 0.01%~0.05wt% is added in glyceride, is uniformly mixed so as to obtain oil
Phase；
(S5) oil water phase mixes: weighing oil made from appropriate step (S4) and is added in water phase made from step (S3)
Make mass ratio 32:68~70:30 of phosphatide and glyceride in mixture, is vortexed after mixing, liquid nitrogen is lyophilized immediately, obtains pre-freeze
Good sample；
(S6) preparation freeze-drying sample: the good sample freeze-drying of pre-freeze is removed into aqueous media, freeze-drying sample is made；
(S7) prepare miscella phase: 32:68~70:30 in mass ratio has weighed phosphatide respectively and glyceride mixes, then plus
The cosolvent for entering 5~20wt% is placed on 35~40 DEG C of shaking table and shakes to being completely dissolved, obtains miscella phase；
(S8) prepare prodrug preparation: taking miscella made from appropriate step (S7) to be added to, step (S6) is obtained to freeze
In dry-eye disease, it is placed on and shakes the gel with liquid crystal structure precursor formulation for obtaining clear to being completely dissolved on 35~40 DEG C of shaking table, it is close
It seals, is spare.
The solution of the present invention can be used for hydrophilic small molecule drugs such as vitamin, can be used for large hydrophilic molecular such as
Antibody protein and insulin etc., it can also be used to small molecule and macromolecular hydrophilic medicament it is molten altogether.This programme is dispersed using phosphatide
It is mixed again with oil after body and pharmaceutical aqueous solution mixing, then after water removal is lyophilized, the miscella phase of phosphatide and glyceride is added
To solve the problems, such as that hydrophilic molecule insoluble in glyceride, improves the solubility of hydrophilic medicament, and prodrug obtained
Preparation has the multilayer protection of oily phosphatide and glyceride, and shelf stability is good.Prodrug preparation can be used as injection, enter
Human body meets water and forms gel, can achieve the effect of good sustained release, extends the action time of drug, reduces drug medication
Number, and improve its bioavilability.
When the hydrophilic medicament is the macromolecular drug insoluble in glyceride, preferably protein IgG, PD-1, PD-L1
Or one of insulin or a variety of, hydrophilic drugs concentration is 1~20mg/ml in prodrug preparation obtained.The present invention is outstanding
It is suitble to the large hydrophilic molecular drug in this programme, can significantly improve it in shelf stability, improve drug storage activity
And activity in vivo, and administration time is extended by sustained release, improve the adaptability of patient.
Preferably, the cosolvent be ethyl alcohol, medium chain fatty acid, long chain fatty acids, peanut oil, soybean oil, corn oil,
At least one of castor oil, sesame oil.It is further preferred that the cosolvent is ethyl alcohol.Preferred cosolvent biocompatibility
It is good, the solubility of drug can be improved, and viscosity is low, is suitable for injection, the inflammatory reaction of body will not be caused.
Preferably, surfactant is nonionic surface active agent, more preferably Tween 80.
Preferably, the glyceride is that glyceryl dioleate, olein, tristerin, palmitinic acid are sweet
At least one of grease.It is further preferred that the glyceride is glyceryl dioleate.Preferred glyceride cost is lower,
Good biocompatibility, and phosphatide is cooperated faster can to react to form the better gel with liquid crystal structure of stability with water.
Preferably, the phosphatide be soybean lecithin, phosphatidyl-ethanolamine, phosphatidylserine, in phosphatidyl glycerol extremely
Few one kind.The scheme preferred at low cost, good biocompatibility, amphiphilic good phosphatide, react system can quickly with water
Gel with liquid crystal structure is formed, and the bioavilability of drug is higher.
Preferably, in the phosphatide by the soybean lecithin of 80~90wt%, the phosphatidyl-ethanolamine of 5~10wt%, 5~
The phosphatidylserine of 10wt% forms.
Above-mentioned mixed phosphatide improves the stability of miscella phase, keeps the stability of hydrophilic drugs more preferable.
In conclusion storage is steady the invention has the benefit that hydrophilic medicament, which is dissolved in miscella, mutually forms oil phase formulation
It is qualitative good；It can be used for injecting, and be injected into and meet water formation gel in vivo, the slow releasing function of gel preparation can make drug longer
Time dimension holds effective concentration, reduces times for spraying；Raw material good biocompatibility will not cause body inflammatory to react.
Detailed description of the invention
Fig. 1 is the tired of hydrophilic medicament in the oil phase liquid crystalline substance gel precursors preparation of hydrophilic medicament made from embodiment 1-3
Product release rate figure；
The rheological property of the SPC/GDO sample of Fig. 2 different proportion；
Degradation situation of the gel of Fig. 3 different proportion SPC/GDO under the effect of different lipase contents.
Specific embodiment
In order to make the objectives, technical solutions, and advantages of the present invention clearer, with reference to embodiments, to the present invention
It is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, it is not used to
Limit the present invention.Based on the embodiments of the present invention, those of ordinary skill in the art are without making creative work
Every other embodiment obtained, shall fall within the protection scope of the present invention.Reagent that unless stated otherwise, the present invention uses,
Method and apparatus is the art conventional reagent, method and apparatus.
Embodiment 1
The oil phase liquid crystalline substance gel precursors preparation of the present embodiment hydrophilic medicament, is made by the preparation method of following steps:
(S1) preparation of phospholipid dispersions: weighing phosphatidyl glycerol 1g and distilled water 4g and be added in bottle, and sealing is placed on shaking table
On be dispersed into coarse dispersion；By the ultrasonic disperse 20min, 50% (650W), 1s/3s of popping one's head under coarse dispersion condition of ice bath, formed
Milky phospholipid dispersions；
(S2) it the preparation of hydrophilic medicament solution: weighs protein PD-15mg and 1.5ml water is added to be completely dissolved, be made
The drug solution of 3.33mg/ml is spare；
(S3)) preparation of water phase: medicine obtained in phospholipid dispersions 140uL obtained and step (S2) is taken in step (S1)
Object solution 300uL is uniformly mixed so as to obtain water phase；
(S4) preparation of oily phase: the Tween 80 of 0.3mg is added in 2.7g glyceryl dioleate, is uniformly mixed so as to obtain oily phase；
(S5) oil water phase mixes: it weighs oil made from 65mg step (S4) and is added in water phase made from step (S3),
It is vortexed after mixing, liquid nitrogen is lyophilized immediately, obtains the good sample of pre-freeze；
(S6) preparation freeze-drying sample: the good sample freeze-drying of pre-freeze is removed into aqueous media, freeze-drying sample is made；
(S7) it prepares miscella phase: claiming 175mg phosphatidyl glycerol and the mixing of 325mg glyceryl dioleate respectively, add
The medium chain fatty acid of 25mg is placed on 37 DEG C of shaking table and shakes to being completely dissolved, obtains miscella phase；
(S8) it prepares prodrug preparation: taking miscella made from 400uL step (S7) to be added to step (S6) obtained
It is lyophilized in sample, is placed on and shakes the prodrug preparation for obtaining clear to being completely dissolved on 37 DEG C of shaking table, seal, is standby
With.The protein PD-1 concentration of gained precursor formulation is 2mg/mL.
Made from the present embodiment 4 DEG C of hydrophilic medicament precursor formulation place 6 months, 9 months, 12 months after, centrifugal treating,
Without phenomenon, illustrate that preparation shelf stability is good.
Hydrophilic medicament precursor formulation prepared by the present invention carries out hydrophilic medicament release and investigates experimental method: weighing appropriate
Hydrophilic medicament oil phase liquid crystalline substance gel precursors preparation in clean dried EP manage, then be added certain volume 7.4 phosphorus of pH
After phthalate buffer, sealing is put into constant-temperature table and carries out oscillation release, constant-temperature table parameter setting: 37 DEG C of temperature, revolving speed
100rpm.It is sampled respectively at different time points, the dissolution medium of same volume is then added into delivery systme.The release of taking-up
Medium places -20 DEG C of spare, contents through hydrophilic medicament in HPLC detection dissolution medium.
16 days preparations of protein PD-1 in the oil phase liquid crystalline substance gel precursors preparation of the present embodiment hydrophilic medicament
About 10%, there is good slow release effect, medication cycle can be greatly prolonged, reduce times for spraying.Experimental result such as Fig. 1 institute
Show.The ratio of phosphatide and grease is different in oily phase, and slow release effect is also different.
Embodiment 2
The oil phase liquid crystalline substance gel precursors preparation of the present embodiment hydrophilic medicament, is made by the preparation method of following steps:
(S1) preparation of phospholipid dispersions: weighing soybean lecithin 1g and distilled water 4g and be added in bottle, and sealing is placed on shaking table
It is dispersed into coarse dispersion；By the ultrasonic disperse 20min, 50% (650W), 1s/3s of popping one's head under coarse dispersion condition of ice bath, cream is formed
White phospholipid dispersions；
(S2) it the preparation of hydrophilic medicament solution: weighs protein IgG 5mg and 1.5ml water is added to be completely dissolved, be made
The drug solution of 3.33mg/ml is spare；
(S3)) preparation of water phase: medicine obtained in phospholipid dispersions 200uL obtained and step (S2) is taken in step (S1)
Object solution 300uL is uniformly mixed so as to obtain water phase；
(S4) preparation of oily phase: the Tween 80 of 0.3mg is added in 2.7g glyceryl dioleate, is uniformly mixed so as to obtain oily phase；
(S5) oil water phase mixes: it weighs oil made from 50mg step (S4) and is added in water phase made from step (S3),
It is vortexed after mixing, liquid nitrogen is lyophilized immediately, obtains the good sample of pre-freeze；
(S6) preparation freeze-drying sample: the good sample freeze-drying of pre-freeze is removed into aqueous media, freeze-drying sample is made；
(S7) it prepares miscella phase: claiming 250mg soybean lecithin and the mixing of 250mg glyceryl dioleate respectively, add
The ethyl alcohol of 50mg is placed on 37 DEG C of shaking table and shakes to being completely dissolved, miscella phase；
(S8) it prepares prodrug preparation: taking miscella made from 400uL step (S7) to be added to step (S6) obtained
It is lyophilized in sample, is placed on and shakes the prodrug preparation for obtaining clear to being completely dissolved on 37 DEG C of shaking table, seal, is standby
With.The protein IgG concentration of gained preparation is 2mg/mL.
Made from the present embodiment 4 DEG C of hydrophilic medicament precursor formulation place 6 months, 9 months, 12 months after, centrifugal treating,
Without lamination, illustrate that preparation shelf stability is good.
16 days preparations of protein IgG are about 3.8% in the present embodiment, have good slow release effect, can be with
Medication cycle is greatly prolonged, times for spraying is reduced.
Embodiment 3
The oil phase liquid crystalline substance gel precursors preparation of the present embodiment hydrophilic medicament, is made by the preparation method of following steps:
(S1) preparation of phospholipid dispersions: weighing soybean lecithin 1g and phosphatidyl-ethanolamine 0.3g and bottle is added in distilled water 4g
In, sealing is placed on shaking table and is dispersed into coarse dispersion；By under coarse dispersion condition of ice bath pop one's head in ultrasonic disperse 20min, 50%
(650W), 1s/3s form milky phospholipid dispersions；
(S2) it the preparation of hydrophilic medicament solution: weighs insulin 20mg and 1ml water is added to be completely dissolved, be made 20mg/ml's
Drug solution is spare；
(S3)) preparation of water phase: medicine obtained in phospholipid dispersions 210uL obtained and step (S2) is taken in step (S1)
Object solution 300uL is uniformly mixed so as to obtain water phase；
(S4) preparation of oily phase: the Tween 80 of 1mg is added in 2.7g tripalmitin, is uniformly mixed so as to obtain oily phase；
(S5) oil water phase mixes: it weighs oil made from 30mg step (S4) and is added in water phase made from step (S3),
It is vortexed after mixing, liquid nitrogen is lyophilized immediately, obtains the good sample of pre-freeze；
(S6) preparation freeze-drying sample: the good sample freeze-drying of pre-freeze is removed into aqueous media, freeze-drying sample is made；
(S7) it prepares miscella phase: claiming 250mg soybean lecithin and the mixing of 250mg tripalmitin respectively, add
The ethyl alcohol of 50mg is placed on 37 DEG C of shaking table and shakes to being completely dissolved, miscella phase；
(S8) it prepares prodrug preparation: taking miscella made from 400uL step (S7) to be added to step (S6) obtained
It is lyophilized in sample, is placed on and shakes the prodrug preparation for obtaining clear to being completely dissolved on 37 DEG C of shaking table, seal, is standby
With.The insulin concentration of gained preparation is 10mg/mL.
Made from the present embodiment 4 DEG C of hydrophilic medicament precursor formulation place 6 months, 9 months, 12 months after, centrifugal treating,
Without lamination, illustrate that preparation shelf stability is good.
16 days preparations of insulin are about 11.5% in the present embodiment, have good slow release effect, Ke Yi great
It is big to extend medication cycle, reduce times for spraying.
Embodiment 4
Compared to embodiment 2, in the present embodiment phosphatide by the soybean lecithin of 80wt%, 10wt% phosphatidyl-ethanolamine,
The phosphatidylserine of 10wt% forms；Other preparation methods and use raw material are same as Example 2.
Comparative example 1
Compared to embodiment 2, in the preparation method of the oil phase liquid crystalline substance gel precursors preparation of this comparative example hydrophilic medicament:
Step (S1) is same as Example 2 to (S6), and step (S7) is changed to take 400uL glyceryl dioleate that step is added
(S6) it in freeze-drying sample obtained, is placed on 37 DEG C of shaking table and shakes to being completely dissolved, obtain prodrug preparation, clarified
Prodrug preparation, sealing, it is spare.The protein IgG concentration of gained preparation is 2mg/mL.
Made from this comparative example 4 DEG C of hydrophilic medicament precursor formulation place 6 months, 9 months after without layering, after 12 months go out
It is now layered, centrifugal treating also lamination, illustrates that preparation shelf stability is poor compared with embodiment after 9 months.
Comparative example 2
This comparative example provide hydrophilic medicament oil phase liquid crystalline substance gel precursors preparation the preparation method is as follows:
(S1) preparation of phospholipid dispersions: weighing soybean lecithin 1g and distilled water 4g and be added in bottle, and sealing is placed on shaking table
It is dispersed into coarse dispersion；By the ultrasonic disperse 20min, 50% (650W), 1s/3s of popping one's head under coarse dispersion condition of ice bath, cream is formed
White phospholipid dispersions；
(S2) it the preparation of hydrophilic medicament solution: weighs protein IgG 5mg and 1.5ml water is added to be completely dissolved, be made
The drug solution of 3.33mg/ml is spare；
(S3)) preparation of water phase: medicine obtained in phospholipid dispersions 200uL obtained and step (S2) is taken in step (S1)
Object solution 300uL is uniformly mixed so as to obtain water phase；Liquid nitrogen is lyophilized immediately, obtains the good sample of pre-freeze；
(S4) preparation freeze-drying sample: the good sample freeze-drying of pre-freeze is removed into aqueous media, freeze-drying sample is made；
(S5) it prepares miscella phase: claiming 250mg soybean lecithin and the mixing of 250mg glyceryl dioleate respectively, add
The ethyl alcohol of 50mg is placed on 45 DEG C of baking oven and is completely dissolved mixing, miscella phase；
(S6) it prepares prodrug preparation: taking miscella made from 400uL step (S5) to be added to step (S4) obtained
It is lyophilized in sample, is placed on 37 DEG C of shaking table and shakes to being completely dissolved, obtain prodrug preparation, seal, is spare.Gained preparation
Protein IgG concentration be 2mg/mL.
Made from this comparative example 4 DEG C of hydrophilic medicament precursor formulation place 6 months, 9 months, 12 months after occur without point
Layer, there is lamination in centrifugal treating after 12 months, illustrates that preparation shelf stability is poor compared with embodiment.
Comparative example 3
This comparative example provide hydrophilic medicament oil phase liquid crystalline substance gel precursors preparation the preparation method is as follows:
(S1) preparation of phospholipid dispersions: weighing soybean lecithin 1g and distilled water 4g and be added in bottle, and sealing is placed on shaking table
It is dispersed into coarse dispersion；By the ultrasonic disperse 20min, 50% (650W), 1s/3s of popping one's head under coarse dispersion condition of ice bath, cream is formed
White phospholipid dispersions；
(S2) it the preparation of hydrophilic medicament solution: weighs protein IgG 5mg and 1.5ml water is added to be completely dissolved, be made
The drug solution of 3.33mg/ml is spare；
(S3)) preparation of water phase: medicine obtained in phospholipid dispersions 200uL obtained and step (S2) is taken in step (S1)
Object solution 300uL is uniformly mixed so as to obtain water phase；Liquid nitrogen is lyophilized immediately, obtains the good sample of pre-freeze；
(S4) preparation freeze-drying sample: the good sample freeze-drying of pre-freeze is removed into aqueous media, freeze-drying sample is made；
(S5) preparation of oily phase: the Tween 80 of 0.3mg is added in 2.7g glyceryl dioleate, is uniformly mixed so as to obtain oily phase；
(S6) it prepares prodrug preparation: oil made from 400uL step (S5) being taken to be added to step (S4) freeze-drying obtained
It in sample, mixes, obtains prodrug preparation, seal, is spare.The protein IgG concentration of gained preparation is 2mg/mL.
Made from this comparative example 4 DEG C of hydrophilic medicament precursor formulation place 6 months, 9 months after without layering, after 12 months go out
It is now layered, centrifugal treating also lamination, illustrates that preparation shelf stability is poor compared with embodiment after 9 months.
Comparative example 4
A kind of preparation method of hydrophilic medicament, comprising the following steps: by 20mg insulin, 450mg phosphatide, 450mg bis-
Olein and 90mg ethyl alcohol and 30ug Tween 80 mixed dissolution are to get insulin liquid crystal gel precursors preparation.
There is lamination, explanation after placing 6 months at 4 DEG C in insulin liquid crystal gel precursors preparation made from this comparative example
The stability of this comparative example preparation storage wants poor compared to each group embodiment preparation.
Comparative example 5
The prodrug preparation of this comparative example is that the solution that concentration is 2mg/mL is made in the protein IgG that is directly dissolved in water.
Comparative example 6
The prodrug preparation of this comparative example is the insulin that is directly dissolved in water, and the solution that concentration is 10mg/mL is made.
By the IgG egg of IgG gel with liquid crystal structure precursor formulation release experiment release in comparative example and embodiment 2 and embodiment 4
It is white to use ethanol precipitation, take equivalent IgG as sample from comparative example, embodiment 2 and 4, it is limited to lead to luxuriant biotechnology using Shanghai
Immunoglobulin G (IgG) ELISA kit of company carries out enzyme-linked immunosorbent assay, and specific steps are said with kit operation
Bright book, experimental result are shown in Table 1.
The different group IgG enzyme-linked immunosorbent assay results of table 1
As it can be seen from table 1 the release of the preparation of the embodiment of the present invention 2 and 4 has for IgG gel with liquid crystal structure precursor formulation
The IgG protein content of bioactivity illustrates that the IgG protein structure of invention formulation release is complete, activity is steady compared with comparative example height
It is fixed, it is likely to since phosphatide in the method for the present invention and glyceride make IgG albumen to the formation multilayer protective effect of IgG albumen
Stability is good, reduce during freeze-drying and redissolution IgG albumen degradation or denaturation and caused by loss.
By the insulin ethyl alcohol of insulin liquid crystal gel precursors preparation release experiment release in embodiment 3 and comparative example
Precipitating, takes the insulin of 3 mean quality of comparative example and embodiment as sample, according to the Pharmacopoeia of the People's Republic of China (2015
Year version four) general rule 1211 biological insulin measuring method be measured, experimental result is shown in Table 2.
The different group biological insulin measurement results of table 2
| Group | Embodiment 3 | Comparative example 4 | Comparative example 6 |
| Blood glucose value (mmol/L) | 6.3±1.0 | 7.1±1.2 | 7.6±1.1 |
From table 2 it can be seen that for insulin liquid crystal gel precursors preparation, the effect of reducing blood sugar of 3 preparation of the embodiment of the present invention
Fruit is more excellent compared with comparative example 4 and 6, illustrates that the insulin bioactivity of invention formulation is higher, it is likely to due to the method for the present invention
Middle phosphatide and glyceride, which have, makes insulin stability good the protective effect of insulin, reduces during freeze-drying and redissolution
Loss of activity caused by the degradation or denaturation of insulin.
In addition soybean lecithin (SPC) and glyceryl dioleate (GDO) are also tested for respectively with 32:68,50:50 and 70:
The rheological property of sample, the elasticity modulus (G ') and viscous modulus (G ") of gel are investigated using rheometer after 30 ratio mixing,
Experimental result is shown in Fig. 2, it can be seen that as SPC/GDO ratio increases, the gel elastomer modulus first increases and then decreases being formed by.
In addition the sample of the soybean lecithin (SPC) and glyceryl dioleate (GDO) of also having investigated different proportion forms gel
Degradation situation under the effect of different lipase contents afterwards.Soybean lecithin (SPC) and glyceryl dioleate (GDO) are respectively with 35:
65, the ratio of 50:50 and 70:30, and the lipase of addition 0%, 2% and 5% respectively, test its weight change.As a result
As shown in Figure 3.It can be seen that water absorption and swelling first occurs for gel under the action of lipase, quality increases, and then degrades, quality
It reduces；And increase with the content of lipase, degradation speed is accelerated.
Comprehensive the above results can be seen that carrier in the oil phase liquid crystalline substance gel precursors preparation of hydrophilic medicament prepared by the present invention
It can degrade in vivo, chance water can form gel after preparation enters human body, external 16 days preparations of drug in gel
It is no more than 15%, hydrophilic medicament has permanent sustained release, and oil phase formulation and water phase made from method in relative contrast's example
Preparation can significantly improve the stability of hydrophilic medicament.
It although an embodiment of the present invention has been shown and described, for the ordinary skill in the art, can be with
A variety of variations, modification, replacement can be carried out to these embodiments without departing from the principles and spirit of the present invention by understanding
And modification, the scope of the present invention is defined by the appended.
Claims (9)
1. the preparation method of the oil phase liquid crystalline substance gel precursors preparation of hydrophilic medicament, which comprises the following steps:
(S1) preparation of phospholipid dispersions: being weighed phosphatide and distilled water and be added in bottle with the mass ratio of 1:3~5, and sealing is placed on and shakes
Coarse dispersion is dispersed on bed；By ultrasonic disperse of popping one's head under coarse dispersion condition of ice bath, milky phospholipid dispersions are formed；
(S2) preparation of hydrophilic medicament solution: weighing hydrophilic drugs and water added to be completely dissolved, and the drug that 1~20mg/ml is made is molten
Liquid is spare；
(S3)) preparation of water phase: take in step (S1) in phospholipid dispersions obtained and step (S2) drug solution obtained with
The volume ratio of 1:3~2:3 is uniformly mixed so as to obtain water phase；
(S4) preparation of oily phase: the surfactant of 0.01%~0.05wt% is added in glyceride, is uniformly mixed so as to obtain oily phase；
(S5) oil water phase mixes: weighing oil made from appropriate step (S4) and being added in water phase made from step (S3) makes to mix
Closing the mass ratio of phosphatide and glyceride in object is 32:68~70:30, is vortexed after mixing, liquid nitrogen is lyophilized immediately, and it is good to obtain pre-freeze
Sample；
(S6) preparation freeze-drying sample: the good sample freeze-drying of pre-freeze is removed into aqueous media, freeze-drying sample is made；
(S7) prepare miscella phase: 32:68~70:30 in mass ratio has weighed phosphatide and glyceride mixing respectively, add 5~
The cosolvent of 20wt% is placed on 35~40 DEG C of shaking table and shakes to being completely dissolved, obtains miscella phase；
(S8) prepare prodrug preparation: taking miscella made from appropriate step (S7) to be added to, step (S6) is obtained to be lyophilized sample
In product, it is placed on and shakes the gel with liquid crystal structure precursor formulation for obtaining clear to being completely dissolved on 35~40 DEG C of shaking table, sealing,
It is spare.
2. the preparation method of the oil phase liquid crystalline substance gel precursors preparation of hydrophilic medicament according to claim 1, feature exist
In one of macro-molecular protein IgG, PD-1, PD-L1 or insulin that, the hydrophilic medicament is insoluble in glyceride or
A variety of, hydrophilic drugs concentration is 1~20mg/ml in prodrug preparation obtained.
3. the preparation method of the oil phase liquid crystalline substance gel precursors preparation of hydrophilic medicament according to claim 1, feature exist
In the cosolvent is ethyl alcohol, medium chain fatty acid, long chain fatty acids, peanut oil, soybean oil, corn oil, castor oil, sesame
At least one of oil.
4. the preparation method of the oil phase liquid crystalline substance gel precursors preparation of hydrophilic medicament according to claim 3, feature exist
In the cosolvent is ethyl alcohol.
5. the preparation method of the oil phase liquid crystalline substance gel precursors preparation of hydrophilic medicament according to claim 1, feature exist
In the glyceride is glyceryl dioleate, at least one in olein, tristerin, tripalmitin
Kind.
6. the preparation method of the oil phase liquid crystalline substance gel precursors preparation of hydrophilic medicament according to claim 5, feature exist
In the glyceride is glyceryl dioleate.
7. the preparation method of the oil phase liquid crystalline substance gel precursors preparation of hydrophilic medicament according to claim 2, feature exist
In the phosphatide is at least one of soybean lecithin, phosphatidyl-ethanolamine, phosphatidylserine, phosphatidyl glycerol.
8. the preparation method of the oil phase liquid crystalline substance gel precursors preparation of hydrophilic medicament according to claim 7, feature exist
In, the phosphatide by the soybean lecithin of 80~90wt%, the phosphatidyl-ethanolamine of 5~10wt%, 5~10wt% phosphatidyl silk
Propylhomoserin composition.
9. according to claim 1 to prodrug preparation made from any one of 8 preparation methods.
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| CN113081954A (en) * | 2021-05-25 | 2021-07-09 | 南昌大学第二附属医院 | Gel drug-loaded patch drug delivery system |
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