CN109431997A - A kind of rapamycin locally injecting preparation and preparation method thereof - Google Patents
A kind of rapamycin locally injecting preparation and preparation method thereof Download PDFInfo
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Abstract
The present invention discloses a kind of rapamycin locally injecting preparation and preparation method thereof, and lesion is serious, located subcutaneously deeper vascular malformation for treating, and has the effect of long-acting slow-release, and compatibility is good in vivo, is easy metabolism.The rapamycin locally injecting preparation includes the stabilizer of the rapamycin of 0.02-0.05g, the organic solvent of 1-3g, 6-10g phosphatide, the glyceride of 8-12g and 0.6-1.2g；In organic solvent by rapamycin dissolution, phosphatide, glyceride and stabilizer is then added, is uniformly mixed, rapamycin locally injecting preparation can be obtained.
Description
Technical field
The invention belongs to drug fields, and in particular to a kind of rapamycin locally injecting preparation and preparation method thereof.
Background technique
Vascular malformation (vascular tumor) is also known as cast tumor, claims hemangioma according to diseased region and hypotype or respectively,
Lymphangioma.Vascular malformation is not true neoplasm system from blood vessel or vasculolymphatic paraplasm.
Currently, having oral and external medication, operation excision, laser therapy, firmly to vascular malformation treatment common method
Agent injection etc., there are no a kind of methods can treat all types of vascular malformations；It should be according to the type of lesion, position, depth
Depending on the factors such as shallow and patient age.It is larger that operative treatment applies in general to diseased region, non-exposed position, for independent disease
The patient that stove works well.But since lesion locations rich blood vessel, blood volume are big, surgical procedure risk is larger, cuts off lesion group
After knitting, cause local deformity, even dysfunction sometimes.Laser therapy is obvious to shallow vascular malformation therapeutic effect,
Side effect is smaller, but can not treat deep-level blood vessel deformity.Injection of sclerosing agent can make vascular tissue's fibrosis, locking generate scar
Trace is shunk, and reduces knurl, but after injection of sclerosing agent, lesion locations vascular tissue fibrosis, may will affect even forfeiture machine
The function of body part, the vascular malformation of unsuitable treatment key position and large volume.
Drug therapy vascular malformation is a kind of important means.Propranolol, thiophene are commonly used in the treatment of infant hemangioma
Luo Er, bleomycin A5 etc., such as patent CN107281094A, CN102836418A, adult vascular malformation is often hard with locally injecting
Agent, oral rapamycin etc..Different dosage forms can be made in drug, and according to different lesion situations, it is more suitable to can choose
Dosage form.It, can be using external preparations such as cream preparation or patches such as the vascular malformation of skin surface；Internal lesser blood vessel is abnormal
Shape can use oral preparation；And serious for lesion, located subcutaneously deeper vascular malformation, external preparation are difficult to reach and control
The effect for the treatment of, it is oral because the concentration of topical remedy is not high to be also extremely difficult to therapeutic effect, office is usually required in order to control the state of an illness
Portion's injection.Locally injecting medication is a kind of clinically used treatment method, has local drug concentration height, good effect, uses prescription
Just the advantages that.But after common injection locally injecting lesions position drug can because blood circulation and being pulled away leads to lesion
Fraction medicine concentration reduces, simultaneously as drug constantly also cannot affect therapeutic effect in diseased region release.Therefore thunder
The durative action preparation of pa mycin locally injecting is expected to bring better therapeutic effect.The durative action preparation of locally injecting generallys use at present
The technologies such as microballoon, thermo-sensitive gel.Long-acting locally injecting preparation is: first is that the selection of pharmaceutical carrier, needs
There is good compatibility and degradability with human body, to avoid generating serious side effects, such as mistake after being injected into human body
Quick reaction etc.；Second is that locally injecting preparation needs to have good slow releasing function, otherwise drug is too fast enters systemic blood circulation,
Cause excessively high blood concentration, lead to the adverse reactions such as fever, low blood pressure, bradycardia, while being also unfavorable in diseased region
Enduringly play drug effect.
Lysotropic liquid crystal is a kind of liquid crystal that two or more compounds comprising including solvated compounds are formed, in aqueous solution
Middle concentration just will appear liquid crystalline phase when being in a certain range, lysotropic liquid crystal has obtained extensive concern in terms of pharmaceutical carrier,
Especially as long-acting injection agent carrier application aspect.Ingredient phosphatide, glyceride in lysotropic liquid crystal are that human compatibility is good
Material, metabolism is easy in human body, and can quickly form liquid crystal after being injected into human body, to play the role of sustained release.
If CN106924172A discloses a kind of huperzine lysotropic liquid crystal preparation, there is good middle long-acting slow-release performance.
At present in vascular malformation therapy field, need that a kind of lesion is serious, located subcutaneously deeper blood vessel is abnormal for treating
The local sustained release long acting injection of shape.
Summary of the invention
In response to the problems existing in the prior art, the purpose of the present invention is to provide a kind of rapamycin locally injecting preparations, use
In treatment lesion, serious, located subcutaneously deeper vascular malformation, has the effect of long-acting slow-release, and in vivo compatibility it is good,
It is easy metabolism.
To achieve the above object, the technical solution adopted by the present invention is that:
A kind of rapamycin locally injecting preparation, organic solvent, the 6- of rapamycin, 1-3g including 0.02-0.05g
The phosphatide of 10g, the glyceride of 8-12g and 0.6-1.2g stabilizer.
Preferably, rapamycin locally injecting preparation, the organic solvent of rapamycin, 1-2g including 0.02-0.05g,
The stabilizer of the phosphatide of 7-9g, the glycerolipid of 8-10g and 0.8-1g.
Further, the phosphatide includes one or both of soybean lecithin, egg yolk lecithin, preferably yolk lecithin
Rouge.
Further, the glyceride includes one in glyceryl dioleate, olein and tristerin
Kind is a variety of, preferably glyceryl dioleate.
Further, the organic solvent is ethyl alcohol.
Further, the stabilizer is poloxamer188 or low-molecular-weight polyethylene glycol.
The present invention also provides the preparation methods of the rapamycin locally injecting preparation: rapamycin being dissolved in organic
In solvent, phosphatide, glycerolipid and stabilizer is then added, is uniformly mixed and obtains working fluid, finally through filtration sterilization, obtain thunder
Pa mycin locally injecting preparation.
Compared with prior art, the beneficial effects of the present invention are:
(1) rapamycin locally injecting preparation is that the prior art does not have, and local sustained release injection system is made in rapamycin
Agent is conducive to the targeting for improving rapamycin treatment vascular malformation, especially suitable for treating to the deeper vascular malformation of lesion.
(2) select phosphatide and glyceride as lyotropic liquid crystal material, easy metabolism good with human compatibility.
(3) viscosity of rapamycin locally injecting preparation is small, convenient for injection；Chance water is transformed into liquid after being injected into lesion locations
Crystalline substance, plays good slow releasing function, and slow-release time can be more than 20 days.
(4) stabilizer is added in the formulation, is conducive to the stability for improving solute liquid crystal, extends slow-release time.
Detailed description of the invention
Fig. 1 is that rapamycin locally injecting agent in vitro is sustained accumulative release rate curve.
Specific embodiment
Below in conjunction with the attached drawing in the present invention, technical solution of the present invention is clearly and completely described, it is clear that
Described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments.Based on the implementation in the present invention
Example, those of ordinary skill in the art's all other embodiment obtained under the conditions of not making creative work belong to
The scope of protection of the invention.
Combined with specific embodiments below, technical solution of the present invention is described in further detail.
Embodiment 1
The preparation of rapamycin locally injecting preparation
(1) a kind of rapamycin locally injecting preparation, including 0.02g rapamycin, 2g ethyl alcohol, 7g soybean lecithin, 10g
Glyceryl dioleate, 0.6g poloxamer188.The preparation method is as follows: 0.02g rapamycin is dissolved in 2g ethyl alcohol, stir
After dissolution completely, 7g soybean lecithin, 10g glyceryl dioleate and 0.6g poloxamer188 is added, continues stirring 1h and is flowed
Hydrodynamic body, most passes through afterwards60The gamma Rays sterilizing of Co irradiation, obtains rapamycin locally injecting preparation A1.
(2) a kind of rapamycin locally injecting preparation, rapamycin, 2g ethyl alcohol, 8g egg yolk lecithin including 0.03g,
8g glyceryl dioleate, 1g polyethylene glycol 200.The preparation method is as follows: 0.03g rapamycin is dissolved in 2g ethyl alcohol, stir
After dissolution completely, 8g egg yolk lecithin, 8g glyceryl dioleate and 1g polyethylene glycol 200 is added, continues stirring 0.5h and is flowed
Hydrodynamic body, most passes through afterwards60The gamma Rays sterilizing of Co irradiation, obtains rapamycin locally injecting preparation A2.
(3) a kind of rapamycin locally injecting preparation, rapamycin, 3g ethyl alcohol, 7g egg yolk lecithin including 0.04g,
8g olein, 1.2g poloxamer188.The preparation method is as follows: 0.04g rapamycin is dissolved in 3g ethyl alcohol, stir
After mixing dissolution completely, 7g egg yolk lecithin, 8g olein and 1.2g poloxamer188 is added, continues stirring 2h and obtains
Working fluid most passes through afterwards60The gamma Rays sterilizing of Co irradiation, obtains rapamycin locally injecting preparation A3.
(4) a kind of rapamycin locally injecting preparation, rapamycin, 1g ethyl alcohol, 6g egg yolk lecithin including 0.05g,
12g tristerin, 0.8g polyethylene glycol 400.The preparation method is as follows: 0.05g rapamycin is dissolved in 5g ethyl alcohol, stir
After mixing dissolution completely, 30g egg yolk lecithin, 60g tristerin and 4g polyethylene glycol 400 is added, continues stirring 2h and obtains
Working fluid most passes through afterwards60The gamma Rays sterilizing of Co irradiation, obtains rapamycin locally injecting preparation A4.
(5) a kind of rapamycin locally injecting preparation, including 0.02g rapamycin, 2g ethyl alcohol, 7g soybean lecithin, 10g
Glyceryl dioleate.The preparation method is as follows: 0.02g rapamycin is dissolved in 2g ethyl alcohol, after stirring and dissolving is complete, 7g is added
Soybean lecithin and 10g glyceryl dioleate continue stirring 1h and obtain working fluid, most pass through afterwards60The gamma Rays of Co irradiation
Sterilizing, obtains rapamycin locally injecting preparation B1.
(6) a kind of rapamycin locally injecting preparation, including 0.02g rapamycin, 2g ethyl alcohol, 4g soybean lecithin, 13g
Glyceryl dioleate, 0.6g poloxamer188.The preparation method is as follows: 0.02g rapamycin is dissolved in 2g ethyl alcohol, stir
After dissolution completely, 4g egg yolk lecithin and 13g glyceryl dioleate is added, continues stirring 0.5h and obtains working fluid, most pass through afterwards60The gamma Rays sterilizing of Co irradiation, obtains rapamycin locally injecting preparation B2.
(7) a kind of rapamycin locally injecting preparation, rapamycin, 3g ethyl alcohol, 11g egg yolk lecithin including 0.03g,
4g olein, 1.2g poloxamer188.The preparation method is as follows: 0.03g rapamycin is dissolved in 3g ethyl alcohol, stir
After mixing dissolution completely, 11g egg yolk lecithin, 4g olein and 1.2g poloxamer188 is added, continues stirring 2h and obtains
Working fluid most passes through afterwards60The gamma Rays sterilizing of Co irradiation, obtains rapamycin locally injecting preparation B3.
Embodiment 2
Rapamycin locally injecting preparation anti-washout capacity and syringeability experiment
Rapamycin locally injecting preparation A1-A4, the B1-B3 prepared in 0.5ml embodiment 1 is taken respectively, is placed in 5ml centrifugation
4ml water is added in Guan Zhong, has seen whether that diffusion phenomena, no diffusion phenomena illustrate that preparation anti-washout capacity can be good.Diffusion is denoted as
"-" does not spread and is denoted as "+".Take rapamycin locally injecting preparation A1-A4, B1-B3 respectively again, using 1ml sterilizing syringe and
No. 5 syringe needles carry out syringeability experiment, and preparation, which can be injected smoothly, shows that its syringeability is good.It passes through and is recorded as "+", Bu Nengshun
Benefit is by being denoted as "-".Test result is as shown in table 1.
Table 1: anti-washout capacity and syringeability experiment
| Sample number | Anti-washout capacity | Syringeability |
| A1 | + | + |
| A2 | + | + |
| A3 | + | + |
| A4 | + | + |
| B1 | - | + |
| B2 | - | + |
| B3 | - | - |
Rapamycin locally injecting preparation of the invention has good anti-washout capacity and syringeability, when stabilizer is not added
Or phosphatide dosage it is relatively low when, will lead to that anti-washout capacity is poor, and the dosage of phosphatide is higher will lead to anti-washout capacity and syringeability
The demand of preparation is not achieved.
Embodiment 3
The sustained release experiment of rapamycin locally injecting agent in vitro
Rapamycin locally injecting preparation A1-A4, the B1-B3 prepared in Example 1 is carried out external using Bag filter method
Release characteristics experiment is investigated.Dissolution medium is the PBS buffer solution comprising 5% polysorbas20 of pH7.4.Specific experiment step are as follows: point
It does not take 5g rapamycin locally injecting preparation that the water of equivalent is added, stands 0.5h and form liquid crystal.Then it is added in bag filter, both ends
It is clamped with clip, bag filter is put into the PBS buffer solution comprising 5% polysorbas20 of the pH7.4 of 300ml, it is T that water-bath, which keeps temperature,
=37 DEG C, revolving speed 30r/min seals whole system, prevents from evaporating, respectively at the 0.5th, 1,2,3,4,5,6,8,10,12,
14,16,18,20,24 days sampling 1mL, fill into 1mL dissolution medium again every time.The sample of taking-up crosses 0.22 μm of miillpore filter, and HPLC is surveyed
Determine rapamycin concentrations.The accumulative release rate Q at each time point is calculated, as shown in Figure 1.
From figure 1 it appears that embodiment A1-A4 has excellent slow release method effect, knot can be sustained more than 20 talentes
Beam, thus prove the technical effect that locally injecting preparation made of rapamycin is had into long-acting slow-release.And comparative example B1-B3
Slow release effect is poor.Wherein B1 is not used stabilizer, but since phosphatide and glyceride are with relatively good, also there is certain sustained release effect
Fruit can be sustained and finish, but be inferior to embodiment due to lacking stabilizer slow release effect for general 10 days.B2 and B3 phosphatide and glyceride
Ratio fall in except the range of usage ratio of the present invention, although there is the addition of stabilizer, slow release effect is also poor, and is inferior to
Comparative example B1.Thus it proves, the ratio of phosphatide and glyceride plays a decisive role to slow release effect, and effect is greater than the work of stabilizer
With.The accumulative release rate that can be seen that all samples from final accumulative release rate illustrates close to 100% using invention formula
The rapamycin locally injecting preparation of preparation can finally discharge completely.
Embodiment 4
The experiment of rapamycin locally injecting preparation stability
Temperature influences: taking the rapamycin locally injecting preparation of same batch A1 appropriate, is loaded on the palm fibre of sealing clean respectively
In color cillin bottle, under the conditions of 4 DEG C, 25 DEG C, 37 DEG C and 60 DEG C temperature, sampled respectively at the 0th day, 5 days and the 10th day, and it is initial
Sample controls compare the variation of its face shaping and medicament contg, measure content using HPLC method, investigate temperature to rapamycin
Locally injecting preparation, experimental result are as shown in table 2.The result shows that temperature can be to rapamycin locally injecting preparation higher than 25 DEG C
Stability has an impact, thus rapamycin locally injecting preparation needs to save in the cool.
Table 2: the influence of warm septuagenarian pair of rapamycin locally injecting preparation
| Temperature (DEG C) | Time (day) | Appearance character | Content (%) |
| 4 | 0 | Pale yellow oily liquid | 100.13 |
| 4 | 5 | Pale yellow oily liquid | 100.13 |
| 4 | 10 | Pale yellow oily liquid | 100.12 |
| 25 | 0 | Pale yellow oily liquid | 100.13 |
| 25 | 5 | Pale yellow oily liquid | 99.87 |
| 25 | 10 | Pale yellow oily liquid | 99.86 |
| 37 | 0 | Pale yellow oily liquid | 100.13 |
| 37 | 5 | Pale yellow oily liquid | 99.59 |
| 37 | 10 | Yellow deepens liquid | 99.42 |
| 60 | 0 | Pale yellow oily liquid | 100.13 |
| 60 | 5 | Yellow is deepened, deposition | 87.42 |
| 60 | 10 | Buff, solidification | 76.21 |
Long-time stability: taking the rapamycin locally injecting preparation of A1-A4 appropriate, respectively the brown west loaded on sealing clean
In woods bottle, under the conditions of 4 DEG C of temperature, was sampled respectively at the 0th day, 5 days and the 10th day, compareed with initial sample, compare its appearance
The variation of shape and medicament contg measures content using HPLC method, investigates temperature to rapamycin locally injecting preparation, experiment knot
Fruit is as shown in table 3.The result shows that the performance of rapamycin locally injecting preparation is stablized under conditions of being sealed for 4 DEG C.
Table 3: long-time stability experimental result
| Temperature (DEG C) | Time (moon) | Appearance character | Content (%) |
| A1 | 0 | Pale yellow oily liquid | 100.13 |
| A1 | 1 | Pale yellow oily liquid | 100.10 |
| A1 | 2 | Pale yellow oily liquid | 100.02 |
| A2 | 0 | Pale yellow oily liquid | 100.25 |
| A2 | 1 | Pale yellow oily liquid | 100.24 |
| A2 | 2 | Pale yellow oily liquid | 100.24 |
| A3 | 0 | Pale yellow oily liquid | 99.36 |
| A3 | 1 | Pale yellow oily liquid | 99.35 |
| A3 | 2 | Pale yellow oily liquid | 99.30 |
| A4 | 0 | Pale yellow oily liquid | 100.14 |
| A4 | 1 | Pale yellow oily liquid | 100.11 |
| A4 | 2 | Pale yellow oily liquid | 100.09 |
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. a kind of rapamycin locally injecting preparation, which is characterized in that rapamycin, 1-3g including 0.02-0.05g it is organic
Solvent, the phosphatide of 6-10g, the glyceride of 8-12g and 0.6-1.2g stabilizer.
2. a kind of rapamycin locally injecting preparation according to claim 1, which is characterized in that including 0.02-0.05g's
Rapamycin, the organic solvent of 1-2g, the phosphatide of 7-9g, the glyceride of 8-10g and 0.8-1g stabilizer.
3. a kind of rapamycin locally injecting preparation according to claim 1, which is characterized in that the phosphatide includes soybean
One or both of lecithin and egg yolk lecithin.
4. a kind of rapamycin locally injecting preparation according to claim 1, which is characterized in that the phosphatide is yolk ovum
Phosphatide.
5. a kind of rapamycin locally injecting preparation according to claim 1, which is characterized in that the glyceride packet
Include one of glyceryl dioleate, olein and tristerin or a variety of.
6. a kind of rapamycin locally injecting preparation according to claim 1, which is characterized in that the glyceride is two oil
Acid glyceride.
7. a kind of rapamycin locally injecting preparation according to claim 1, which is characterized in that the organic solvent is second
Alcohol.
8. a kind of rapamycin locally injecting preparation according to claim 1, which is characterized in that the stabilizer is pool Lip river
Husky nurse 407 or low-molecular-weight polyethylene glycol.
9. the preparation method of any one of the claim 1-8 rapamycin locally injecting preparation, which is characterized in that thunder pa is mould
In organic solvent, phosphatide, glyceride and stabilizer is then added in element dissolution, is uniformly mixed, finally through filtration sterilization, obtains thunder
Pa mycin locally injecting preparation.
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