CN110420179A - A kind of andrographolide dry suspensoid agent and preparation method thereof - Google Patents
A kind of andrographolide dry suspensoid agent and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a kind of andrographolide dry suspensoid agent and preparation method thereof, andrographolide dry suspensoid agent includes andrographolide enteric-coated micro-pill, suspending agent, corrigent, and andrographolide enteric-coated micro-pill is made of pharmaceutical activity layer, separation layer, enteric layer, and partial size is 60-80 mesh；Pharmaceutical activity layer includes andrographolide, microcrystalline cellulose, lactose, hydroxypropyl methylcellulose, crospovidone, superfine silica gel powder, polyvinyl acetate.Andrographolide dry suspensoid agent prepared by the present invention has good mouldability and high yield, and the electrostatic hazard in coating process can be effectively reduced, guarantee being normally carried out for coating process, and meet the technical requirements of enteric coated preparations and dry suspensoid agent.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of andrographolide dry suspensoid agent and preparation method thereof.
Background technique
Andrographolide system plant Andrographis Paniculata-andrographolide through esterification, dehydration, at being dehydrated punching made of salt refining
Lotus lactone succinic acid half-ester k-na salt.The chemical name of andrographolide is two dehydrogenation andrographolide -3,19- of 14- deshydroxy -11,12-
One water object of disuccinic acid half ester k-na salt.The early stage capillary permeability that andrographolide can inhibit increase with inflammatory exudation and oedema,
Specifically excited Pituitary Adrenalcortical function, promotion ACTH release it can increase the biosynthesis of ACTH in anterior pituitary；
Have the function of a variety of viruses such as inactivated adenovirus, influenza virus, Respirovirus in vitro.Andrographolide has listed dosage form as injection
Agent (injection and freeze-dried powder) is suitable for viral pneumonia and viral infection of upper respiratory tract.
It is a highly unstable compound since andrographolide is Dehydrated Andrographolide Succinate Potassium Sodium Salt,
Lactonic ring in aqueous solution is easy to hydrolysis or is also easy polymerization at a certain temperature, causes serious adverse reaction；Its
Secondary chance acid can play displacement reaction, displace K+、Na+Ion, andrographolide are reduced into half ester, and solubility reduces and generates precipitating；Again
It is very sensitive to temperature, to control sterilization time and temperature.The only 12 months ' Tanhuning ' injection validity period listed, and
It happens occasionally before the deadline because quality problems occurs in andrographolide degradation, seriously limits the clinical application of andrographolide.
Chinese invention patent CN103479583A discloses a kind of potassium sodium dehydroandroan drographolide succinate enteric dry suspension and preparation method thereof, the hair
The potassium sodium dehydroandroan drographolide succinate enteric dry suspension of bright preparation includes: andrographolide pellet or particle 5%- in terms of the percentage composition of raw material gross weight
50%, drug administration by injection approach is changed to Oral administration, improves and use by suspending agent 1%-10% and corrigent 50%-95%
Medicine safety；Simultaneously by preparing enteric coated preparations, is destroyed to avoid andrographolide by gastric acid, discharge rapidly drug in intestinal juice
And absorption.But there is also some shortcomingss for the patent: (1) easy to produce static electricity when 40% ethyl alcohol prepares pellet as adhesive；
(2) starch will increase the viscosity of softwood as filler, will lead to bar and is difficult to be formed, can not be successfully extrusion and pelletization.
Summary of the invention
For the deficiency of above-mentioned patent, the present invention provides a kind of andrographolide dry suspensoid agents and preparation method thereof, pass through spy
The use in conjunction for determining auxiliary material makes andrographolide dry suspensoid agent have preferable mouldability and higher yield, and can effectively reduce packet
The harm of electrostatic during clothing guarantees that coating is normally carried out.
The purpose of the present invention is achieved through the following technical solutions:
A kind of andrographolide dry suspensoid agent, including andrographolide enteric-coated micro-pill, suspending agent, corrigent, andrographolide enteric-coated micro-pill by
Pharmaceutical activity layer, separation layer, enteric layer composition, feature exist, and the partial size of andrographolide enteric-coated micro-pill is 60-80 mesh；Pharmaceutical activity
Layer includes andrographolide, microcrystalline cellulose, lactose, hydroxypropyl methylcellulose, crospovidone, superfine silica gel powder, polyvinyl acetate.
Preferably, microcrystalline cellulose, lactose mass percent be 2.5-1.5:1, the weight percent of polyvinyl acetate
Content is 3-5%.
When using starch as diluent, softwood viscosity is dramatically increased, easy stick to each other during pellet extrusion spheronization,
Form the big ball of 2-3mm and strip.The present invention uses microcrystalline cellulose and lactose mixed diluent (especially microcrystalline cellulose, cream
The mass percent of sugar is 2.5-1.5:1) and polyvinyl acetate, andrographolide enteric-coated micro-pill is with good mouldability, greatly
Yield is improved greatly.
Preferably, pharmaceutical activity layer also includes lauryl sodium sulfate, and the weight percentage of lauryl sodium sulfate is
0.5-1%.Due to pellet partial size be 60-80 mesh, small volume, electrostatic interaction is stronger in coating process, thus take to
Electrostatic is eliminated or reduced to the mode that lauryl sodium sulfate is added in coating solution, to guarantee being normally carried out for coating.
Preferably, spacer layer coating material is povidone, and the weight of separation layer is the 5-10% of pharmaceutical activity layer weight.
Preferably, the coating material of enteric layer is by Utech L100, Eudragit L100-55 and diethyl phthalate group
At the weight of enteric layer is the 10-15% of pharmaceutical activity layer weight.
Utech L100 and Eudragit L100-55 are methacrylic acid and ethyl acrylate (1:1) copolymer, but are managed
Change is had any different in nature, and Utech L100 is dissolved in pH > 6, and Eudragit L100-55 is then dissolved in pH > 5.5.Andrographolide can be with
It is relatively stabilized in weakly acidic condition, enteric coating Eudragit L100-55 starts to dissolve in the environment of pH > 5.5, can start slowly
Drug is discharged, in pH > 6, Utech L100 starts the release that dissolution accelerates drug, extends andrographolide in the release of enteron aisle
Between and soak time, the availability of drug can be improved.
Preferably, Utech L100, Eudragit L100-55 mass percent be 1:2-3.
Preferably, the weight percentage of diethyl phthalate is 1-2%.Diethyl phthalate can improve clothing
The toughness of film forms clothing film finer and close and complete, reduces the breakage rate of pellet.But the type of plasticizer needs and kind
It is adapted, and used in amounts will be in reasonable range.Dosage is excessively high, and then electrostatic phenomenon is obvious in coating process, and clothing film is easily sent out
Raw adhesion, the acid-resistant strength of the too low meeting enteric-coated micro-pill of dosage.
Preferably, suspending agent is carboxymethyl cellulose, and corrigent is one of sucrose, xylitol, mannitol or a variety of.
The present invention provides the preparation methods of the andrographolide dry suspensoid agent characterized by comprising
1) active drug nitride layer is prepared
By andrographolide and microcrystalline cellulose, lactose, hydroxypropyl methylcellulose, crospovidone, superfine silica gel powder, polyvinyl acetate
Ester is uniformly mixed, and prepares active drug nitride layer using extrusion spheronization technology；
2) packet separation layer
1) active medicine of preparation is placed in coating granulator or fluidized-bed coating machine, is carried out with povidone coating material
Coating；
3) packet enteric layer
2) active medicine for wrapping separation layer obtained is placed in coating granulator or fluidized-bed coating machine, enteric is used
Layer coating material is coated, and obtains andrographolide enteric-coated micro-pill；
4) dry suspensoid agent is prepared
Corrigent, suspending agent are mixed with the andrographolide enteric-coated micro-pill of 3) preparation to get andrographolide dry suspensoid agent.
Preferably, when step 1) preparation active drug nitride layer, it is additionally added lauryl sodium sulfate.
Compared with prior art, advantageous effects of the invention are as follows:
(1) the andrographolide dry suspensoid agent prepared by the present invention makees diluent using microcrystalline cellulose and lactose, good moldability,
It is avoided that stick to each other or in long strip during pellet extrusion spheronization.
(2) polyvinyl acetate that the andrographolide dry suspensoid agent prepared by the present invention is used when preparing pharmaceutical activity layer,
The mouldability that pellet can be effectively improved improves the yield of finished product.
(3) lauryl sodium sulfate that the andrographolide dry suspensoid agent prepared by the present invention uses, can be effectively reduced and be coated
Electrostatic hazard in journey is conducive to being normally carried out for coating process.
(4) the andrographolide dry suspensoid agent prepared by the present invention uses Utech L100, Eudragit L100-55, O-phthalic
Diethyl phthalate is as enteric coating liquid, it is ensured that the release in simulated gastric fluid and simulated intestinal fluid meets the requirements.
Specific embodiment
Combined with specific embodiments below, specific embodiments of the present invention will be described in further detail.
Raw materials used in the embodiment of the present invention and comparative example is commercial product.
If not particularly pointing out, technological means used in the embodiment of the present invention is well known to the skilled person normal
Rule means.
A kind of andrographolide dry suspensoid agent of embodiment 1
1, composition:
2, preparation method:
(1), by the microcrystalline cellulose of the andrographolide of recipe quantity and recipe quantity, lactose, crospovidone, superfine silica gel powder, poly-
Vinyl acetate is crossed 80 meshes and is uniformly mixed, and prepares softwood using 2% hydroxypropyl methylcellulose solution as adhesive, is subsequently placed in extrusion
In device, orifice plate is squeezed out using 0.8mm, under the conditions of squeezing out frequency 25.0Hz, round as a ball frequency 25.0Hz and round as a ball time 8min
Prepare pharmaceutical activity layer；60-80 mesh pharmaceutical activity layer is collected after fluidized bed drying；
(2), active medicine prepared by (1) is placed in fluidized-bed coating machine, is coating material with 3% povidone aqueous solution
It is coated.Coating parameter: air inlet frequency 26Hz, atomizing pressure 0.04MPa, 30 DEG C of inlet air temperature, constant current flow rate pump 2ml/
min.Coating weight gain about 6%.
(3), the active medicine for wrapping separation layer for obtaining (2) is placed in fluidized-bed coating machine, Utech L100, outstanding
Special surprise L100-55, diethyl phthalate are coated after being prepared into enteric layer coating material with 80% ethyl alcohol, coating material
50ml.Coating parameter: air inlet frequency 26Hz, atomizing pressure 0.04MPa, 30 DEG C of inlet air temperature, constant current flow rate pump 4ml/min.Packet
Clothing weight gain about 12%.
(4), xylitol, carboxymethyl cellulose are mixed with andrographolide enteric-coated micro-pill prepared by (3), be distributed into 100 bags to get
Andrographolide dry suspensoid agent.Every bag of about 200mg containing andrographolide.
A kind of andrographolide dry suspensoid agent of embodiment 2
1, composition:
2, preparation method:
(1), by the microcrystalline cellulose of the andrographolide of recipe quantity and recipe quantity, lactose, crospovidone, superfine silica gel powder, poly-
Vinyl acetate is crossed 80 meshes and is uniformly mixed, and prepares softwood using 2% hydroxypropyl methylcellulose solution as adhesive, is subsequently placed in extrusion
In device, orifice plate is squeezed out using 0.8mm, under the conditions of squeezing out frequency 25.0Hz, round as a ball frequency 25.0Hz and round as a ball time 8min
Prepare pharmaceutical activity layer；60-80 mesh pharmaceutical activity layer is collected after fluidized bed drying；
(2), active medicine prepared by (1) is placed in fluidized-bed coating machine, is coating material with 3% povidone aqueous solution
It is coated.Coating parameter: air inlet frequency 26Hz, atomizing pressure 0.04MPa, 30 DEG C of inlet air temperature, constant current flow rate pump 2ml/
min.Coating weight gain about 8%.
(3), the active medicine for wrapping separation layer for obtaining (2) is placed in fluidized-bed coating machine, Utech L100, outstanding
Special surprise L100-55, diethyl phthalate, lauryl sodium sulfate carry out after being prepared into enteric layer coating material with 80% ethyl alcohol
Coating, coating material 50ml.Coating parameter: air inlet frequency 26Hz, atomizing pressure 0.04MPa, 30 DEG C of inlet air temperature, constant current flow rate pump
4ml/min.Coating weight gain about 15%.
(4), xylitol, carboxymethyl cellulose are mixed with andrographolide enteric-coated micro-pill prepared by (3), be distributed into 100 bags to get
Andrographolide dry suspensoid agent.Every bag of about 80mg containing andrographolide.
A kind of andrographolide dry suspensoid agent of embodiment 3
1, composition:
2, preparation method:
(1), by the microcrystalline cellulose of the andrographolide of recipe quantity and recipe quantity, lactose, crospovidone, superfine silica gel powder, poly-
Vinyl acetate is crossed 80 meshes and is uniformly mixed, and prepares softwood using 2% hydroxypropyl methylcellulose solution as adhesive, is subsequently placed in extrusion
In device, orifice plate is squeezed out using 0.8mm, under the conditions of squeezing out frequency 25.0Hz, round as a ball frequency 25.0Hz and round as a ball time 8min
Prepare pharmaceutical activity layer；60-80 mesh pharmaceutical activity layer is collected after fluidized bed drying；
(2), active medicine prepared by (1) is placed in fluidized-bed coating machine, is coating material with 3% povidone aqueous solution
It is coated.Coating parameter: air inlet frequency 26Hz, atomizing pressure 0.04MPa, 30 DEG C of inlet air temperature, constant current flow rate pump 2ml/
min.Coating weight gain about 5%.
(3), the active medicine for wrapping separation layer for obtaining (2) is placed in fluidized-bed coating machine, Utech L100, outstanding
Special surprise L100-55, diethyl phthalate are coated after being prepared into enteric layer coating material with 80% ethyl alcohol, coating material
50ml.Coating parameter: air inlet frequency 26Hz, atomizing pressure 0.04MPa, 30 DEG C of inlet air temperature, constant current flow rate pump 4ml/min.Packet
Clothing weight gain about 10%.
(4), xylitol, carboxymethyl cellulose are mixed with andrographolide enteric-coated micro-pill prepared by (3), be distributed into 100 bags to get
Andrographolide dry suspensoid agent.Every bag of about 160mg containing andrographolide.
A kind of andrographolide dry suspensoid agent of embodiment 4
1, composition:
2, preparation method:
(1), by the microcrystalline cellulose of the andrographolide of recipe quantity and recipe quantity, lactose, crospovidone, superfine silica gel powder, poly-
Vinyl acetate is crossed 80 meshes and is uniformly mixed, and prepares softwood using 2% hydroxypropyl methylcellulose solution as adhesive, is subsequently placed in extrusion
In device, orifice plate is squeezed out using 0.8mm, under the conditions of squeezing out frequency 25.0Hz, round as a ball frequency 25.0Hz and round as a ball time 8min
Prepare pharmaceutical activity layer；60-80 mesh pharmaceutical activity layer is collected after fluidized bed drying；
(2), active medicine prepared by (1) is placed in fluidized-bed coating machine, is coating material with 3% povidone aqueous solution
It is coated.Coating parameter: air inlet frequency 26Hz, atomizing pressure 0.04MPa, 30 DEG C of inlet air temperature, constant current flow rate pump 2ml/
min.Coating weight gain about 10%.
(3), the active medicine for wrapping separation layer for obtaining (2) is placed in fluidized-bed coating machine, Utech L100, outstanding
Special surprise L100-55, diethyl phthalate, lauryl sodium sulfate carry out after being prepared into enteric layer coating material with 80% ethyl alcohol
Coating, coating material 50ml.Coating parameter: air inlet frequency 26Hz, atomizing pressure 0.04MPa, 30 DEG C of inlet air temperature, constant current flow rate pump
4ml/min.Coating weight gain about 15%.
(4), xylitol, carboxymethyl cellulose are mixed with andrographolide enteric-coated micro-pill prepared by (3), be distributed into 100 bags to get
Andrographolide dry suspensoid agent.Every bag of about 40mg containing andrographolide.
A kind of andrographolide dry suspensoid agent of embodiment 5
1, composition:
2, preparation method:
(1), by the microcrystalline cellulose of the andrographolide of recipe quantity and recipe quantity, lactose, crospovidone, superfine silica gel powder, poly-
Vinyl acetate is crossed 80 meshes and is uniformly mixed, and prepares softwood using 2% hydroxypropyl methylcellulose solution as adhesive, is subsequently placed in extrusion
In device, orifice plate is squeezed out using 0.8mm, under the conditions of squeezing out frequency 25.0Hz, round as a ball frequency 25.0Hz and round as a ball time 8min
Prepare pharmaceutical activity layer；60-80 mesh pharmaceutical activity layer is collected after fluidized bed drying；
(2), active medicine prepared by (1) is placed in fluidized-bed coating machine, is coating material with 3% povidone aqueous solution
It is coated.Coating parameter: air inlet frequency 26Hz, atomizing pressure 0.04MPa, 30 DEG C of inlet air temperature, constant current flow rate pump 2ml/
min.Coating weight gain about 8%.
(3), the active medicine for wrapping separation layer for obtaining (2) is placed in fluidized-bed coating machine, Utech L100, outstanding
Special surprise L100-55, diethyl phthalate are coated after being prepared into enteric layer coating material with 80% ethyl alcohol, coating material
50ml.Coating parameter: air inlet frequency 26Hz, atomizing pressure 0.04MPa, 30 DEG C of inlet air temperature, constant current flow rate pump 4ml/min.Packet
Clothing weight gain about 15%.
(4), xylitol, carboxymethyl cellulose are mixed with andrographolide enteric-coated micro-pill prepared by (3), be distributed into 100 bags to get
Andrographolide dry suspensoid agent.Every bag of about 80mg containing andrographolide.
A kind of andrographolide dry suspensoid agent of comparative example 1
1, composition:
2, preparation method: same as Example 2.A kind of andrographolide dry suspensoid agent of comparative example 2
1, composition:
2, preparation method: same as Example 2.A kind of andrographolide dry suspensoid agent of comparative example 3
1, composition:
2, preparation method: same as Example 2.A kind of andrographolide dry suspensoid agent of comparative example 4
1, composition:
2, preparation method: same as Example 2.
Experimental example
1 drug release determination of experimental example
Release survey is carried out according to 2015 editions Rotating shakers of Chinese Pharmacopoeia to andrographolide dry suspensoid agent prepared by embodiment 1-5
It is fixed.Release use UV-VIS spectrophotometry, Detection wavelength 251m, revolving speed 75rmin, temperature (37 ± 0.5) DEG C,
Accumulation dissolution in 60-120min is measured in simulated gastric fluid in 2h in Accumulation dissolution and simulated intestinal fluid respectively.Selected is molten
Medium is respectively the hydrochloric acid solution (simulated gastric fluid) of 0.1mol/L and the phosphate buffer (simulated intestinal fluid) of pH6.8 out, manually
Intestinal juice preparation method: it takes 0.1mol/L hydrochloric acid solution to be uniformly mixed in 3:1 ratio with 0.2mol/L sodium radio-phosphate,P-32 solution, uses when necessary
2mol/L hydrochloric acid solution or 2mol/L sodium hydroxide solution adjust pH value to 6.8 ± 0.05.
As a result as shown in the table, the results showed that prepared andrographolide dry suspensoid agent cumulative release in 2h in simulated gastric fluid
Degree is less than the 10% of labelled amount, and Accumulation dissolution is greater than the 70% of labelled amount in 60min in simulated intestinal fluid, meets in 2015 editions
The standard of state's pharmacopeia.
The measurement of 2 sedimentation volume ratio of experimental example
To andrographolide dry suspensoid agent prepared by embodiment 1-5 according to 2015 editions progress sedimentation volume ratio surveys of Chinese Pharmacopoeia
It is fixed.Take andrographolide dry suspensoid agent it is appropriate (be equivalent to containing andrographolide 200mg), tool plug graduated cylinder be transferred to after adding water 50ml to vibrate, it is quiet
Set 3h.As a result as shown in the table, the results showed that using the sedimentation body of andrographolide dry suspensoid agent prepared by formulation and technology of the invention
Accumulate the standard than meeting existing Chinese Pharmacopoeia.
| Detection project | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 |
| Sedimentation volume ratio | 0.97 | 0.98 | 0.97 | 0.95 | 0.96 |
3 mouldability of experimental example
By the experimental phenomena and appearance in observation preparation process, the mouldability of pellet is evaluated；60- is collected using sieve formula
The pellet of 80 mesh, and evaluated with pellet yield, yield=target pellet/total dosage.Embodiment 2 and comparative example 1, comparison
Example 2, the mouldability result of comparative example 4 are as shown in the table:
The above is only preferred embodiments of the invention, are not intended to limit the scope of the present invention.It is all in the present invention
On the basis of it is made it is any modification, replacement etc., be intended to be limited solely by within protection scope of the present invention.
Claims (10)
1. a kind of andrographolide dry suspensoid agent, including andrographolide enteric-coated micro-pill, suspending agent, corrigent, the andrographolide enteric-coated micro-pill
It is made of pharmaceutical activity layer, separation layer, enteric layer, which is characterized in that the partial size of the andrographolide enteric-coated micro-pill is 60-80 mesh；
The pharmaceutical activity layer includes andrographolide, microcrystalline cellulose, lactose, hydroxypropyl methylcellulose, crospovidone, micro mist silicon
Glue, polyvinyl acetate.
2. andrographolide dry suspensoid agent according to claim 1, which is characterized in that the quality of the microcrystalline cellulose, lactose
Percentage is 2.5-1.5:1, and the weight percentage of the polyvinyl acetate is 3-5%.
3. andrographolide dry suspensoid agent according to claim 1, which is characterized in that the pharmaceutical activity layer also includes dodecane
Base sodium sulphate, the weight percentage of the lauryl sodium sulfate are 0.5-1%.
4. andrographolide dry suspensoid agent according to claim 1, which is characterized in that the spacer layer coating material is povidone,
The weight of separation layer is the 5-10% of pharmaceutical activity layer weight.
5. andrographolide dry suspensoid agent according to claim 1, which is characterized in that the coating material of the enteric layer is by Utech
L100, Eudragit L100-55 and diethyl phthalate composition, the weight of enteric layer are the 10- of pharmaceutical activity layer weight
15%.
6. andrographolide dry suspensoid agent according to claim 5, which is characterized in that the Utech L100, Utech L100-
55 mass percent is 1:2-3.
7. andrographolide dry suspensoid agent according to claim 5, which is characterized in that the weight of the diethyl phthalate
Percentage composition is 1-2%.
8. andrographolide dry suspensoid agent according to claim 1, which is characterized in that the suspending agent is carboxymethyl cellulose, institute
Stating corrigent is one of sucrose, xylitol, mannitol or a variety of.
9. a kind of preparation method of andrographolide dry suspensoid agent as described in claim 1 characterized by comprising
1) active drug nitride layer is prepared
Andrographolide and microcrystalline cellulose, lactose, hydroxypropyl methylcellulose, crospovidone, superfine silica gel powder, polyvinyl acetate are mixed
It closes uniformly, active drug nitride layer is prepared using extrusion spheronization technology；
2) packet separation layer
1) active medicine of preparation is placed in coating granulator or fluidized-bed coating machine, is wrapped with povidone coating material
Clothing；
3) packet enteric layer
2) active medicine for wrapping separation layer obtained is placed in coating granulator or fluidized-bed coating machine, with enteric layer packet
Dress material is coated, and obtains andrographolide enteric-coated micro-pill；
4) dry suspensoid agent is prepared
Corrigent, suspending agent are mixed with the andrographolide enteric-coated micro-pill of 3) preparation to get andrographolide dry suspensoid agent.
10. preparation method according to claim 9, which is characterized in that when step 1) prepares active drug nitride layer, be additionally added ten
Sodium dialkyl sulfate.
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