CN106063780A - A kind of tetradoxin fast release micropill preparation, preparation method and applications - Google Patents
A kind of tetradoxin fast release micropill preparation, preparation method and applications Download PDFInfo
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- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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Abstract
A kind of tetradoxin fast release micropill preparation, preparation method and applications, relate to drug preparation technique and application, described fast release micropill preparation administering mode is oral administration, with celphere as carrier, tetradoxin aqueous solution containing cosolvent and binding agent is upper drug solns, described tetradoxin consumption, according to weight ratio, tetradoxin consumption is the 0.0025%～0.3% of described capsule core；The oral dose of tetradoxin is not higher than 300 micrograms.Described tetradoxin fast release micropill preparation has that medicine-feeding rate is high, content uniformity is good, the features such as release is rapid, analgesic activity is rapid-action.Meanwhile, this fast release micropill preparation has that Clinical practice compliance is good, safety high.Additionally, this celphere fluid bed medicine-feeding method is suitable to the preparation of extremely low specification tetradoxin drug oral preparation.
Description
Technical field
The present invention relates to drug preparation technique and application, be specifically related to a kind of tetradoxin fast release micropill preparation, system
Preparation Method and application thereof.
Background technology
Tetradoxin (Fugu ocellatus toxin) is a kind of mainly to extract the marine biotoxins obtained from globe fish internal organs, for height
Spend selective Na-ion channel blocker, there is analgesia and control the effects such as Opioid Dependence withdrawal symptom.Tetradoxin is
A kind of amino perhydrogenating quinazoline compound, its structure is a kind of cage type ortho acid esters, generally deposits with the form of " amphion "
, the guanidine radicals in structure is function base necessary to its activity.Tetradoxin is unstable in acidity or alkaline environment, is easily dehydrated
Resolve into non-toxic products, be administered orally and be typically considered to not be suitable administering mode.Therefore, common in clinical research administering mode
For intramuscular administration.But tetradoxin activity is high, toxicity big, intramuscular administration treatment window is narrow, it is considered to the safety of Formulations for systemic administration, its preparation
The control of effective content is most important.Meanwhile, after tetradoxin intramuscular administration, the medicine half-life in vivo is shorter, effective blood
Concentration is only capable of maintaining about 2 hours.For maintaining drug effect, need frequent intramuscular administration, it is difficult to adapt to the need of Most patients treatment
, clinical compliance is poor.Therefore, if exploitation one can expand tetradoxin clinical practice treatment window, again Orally-administrable,
The preparation that clinical compliance is good, then can be greatly promoted the application and development of tetradoxin medicine.
The oral dose of tetradoxin is normally no higher than 300 micrograms, the humbleest content, uses routine techniques such as mixing
Oral tablet prepared by granulation or capsule is difficult to solve tetradoxin pharmaceutical preparation content uniformity and is difficult to meet medicinal oral system
The crucial problem of agent product development.
Micropill is a kind of diameter spherical preparation of spherical or class in the range of 0.5～2.5mm, have release stable, reliable,
Uniformly, the advantage such as good fluidity, capsule can be loaded or be pressed into tablet or other packaging for Clinical practice.Pellet is that one is the most single
Unit's dosage dispersion shape dosage form, a usual dosage is made up of tens to hundreds of piller, and compared with other one-pack type, pellet takes
Can be widely distributed in gastrointestinal tract after with, medicine increases at gastrointestinal tract surface distributed area, it is to avoid medicine local concentration is excessive,
Not only increase drug bioavailability but also decrease gastrointestinal stimulation.The preparation method of micropill is more, wherein fluid bed system
Ball method and extrusion spheronization pill method are the two kinds of microsphere and its preparations being most widely used at present.Extrusion-spheronization is used for
Prepare medicine carrying capsule core or celphere.Fluid bed pill method completes whole operation in closed system, and supplementary material is not suffered a loss,
There is medicine-feeding rate high, the features such as medicament contg is uniform, it is particularly suitable for the medicine-feeding of low content medicine.
The technical problem to be solved in the present invention is that drug half-life is short present in tetradoxin drug development, clinical practice
The problems such as injection poor compliance (cannot be administered orally).Treat by providing one can expand tetradoxin clinical practice
Window, again Orally-administrable, the preparation that clinical compliance is good solves above-mentioned technical problem.
Summary of the invention
The purpose of the present invention one is to provide the tetradoxin fast release micropill preparation of a kind of Orally-administrable.The mesh of the present invention
Two be to provide the preparation method of a kind of tetradoxin fast release micropill preparation.The purpose of the present invention three is to verify the present invention's
The tetradoxin fast release micropill preparation of Orally-administrable has that analgesic activity is rapid-action, clinical practice treatment window width, safety are good,
Clinical practice compliance is good.
For achieving the above object one, the solution of the present invention is: provide a kind of tetradoxin fast release micropill preparation, described
Fast release micropill preparation administering mode be oral administration, with celphere as carrier, containing cosolvent and the tetradoxin of binding agent
Aqueous solution is upper drug solns, described tetradoxin consumption, and according to weight ratio, tetradoxin consumption is described capsule core
0.0025%～0.3%；The oral dose of tetradoxin is not higher than 300 micrograms.
Further, described celphere is sucrose capsule core or microcrystalline Cellulose capsule core.
Further, one or more in citric acid, acetic acid, hydrochloric acid, ascorbic acid of described cosolvent.
Further, according to weight ratio, cosolvent consumption is the 20%～300% of tetradoxin.
Further, described binding agent selected from hypromellose (HPMC), polyvidone (PVP), syrup, starch slurry,
One or more in carmethose, gelatin, arabic gum, methylcellulose.
Further, according to weight ratio, binder dosage is the 0.1875%～1.6875% of celphere.
Further, any one tetradoxin fast release micropill preparation described also includes protecting tunic material；Described protection
One or more in acrylic resin, hypromellose of tunic material.
Further, described tetradoxin fast release micropill preparation, according to weight ratio, the consumption of protection tunic material is empty
The 1.0%～5.0% of white capsule core.
Further, described fast release micropill can fill in capsule or add be pressed into tablet after proper auxiliary materials after be administered orally to
Medicine.
For achieving the above object two, the solution of the present invention is: provide the system of a kind of tetradoxin fast release micropill preparation
Preparation Method, with celphere as carrier, is upper drug solns with the tetradoxin aqueous solution containing cosolvent and binding agent, uses fluidisation
The bed end, sprays prescription method and prepares medicine carrying micropill, adds protection tunic material solution and obtains tetradoxin fast release micropill through fluidized bed coating
Preparation.
A kind of preparation method of tetradoxin fast release micropill preparation, including:
Step one: the preparation of upper drug solns；
Step 2: spray medicine at the bottom of fluid bed；
Step 3: fluidized bed coating-protecting film layer；
Step 4: be dried afterwards.
Further, described step one is specially and weighs tetradoxin by formula, and the citric acid solution adding formula ratio is molten
Solve, be then dissolved in including in the pure water solution of binding agent and be configured to quantitatively to go up drug solns.
Further, described step 2 is specially and is placed in fluid bed by the celphere of formula ratio, starts fluid bed, to
The upper drug solns prepared in quantitative input step one in fluid bed.
Further, described input arranges fluid bed medicine-feeding parameter by the process conditions optimized during drug solns, including
Fan delivery 150～180m3·h-1, solution feed pump rotating speed 2～7r min-1, temperature of charge 25～40 DEG C, atomizing pressure
0.16MPa。
Further, described step 3 is specially presses formula ratio preparation 5% protection tunic material solution, and fluidized bed coating parameter sets
It is set to fan delivery 150～180m3·h-1, solution feed pump rotating speed 5～15r min-1, temperature of charge controls at 25～30 DEG C, atomization
Pressure 0.3MPa.Further, described step 4 after specially coating completes, adjusts fluid bed parameter, coated micropill in 30～
40 DEG C of fluidized dryings 15～45min.
For achieving the above object three, the solution of the present invention is: provide a kind of tetradoxin fast release micropill preparation, and it should
Develop for analgesic.
A kind of tetradoxin fast release micropill preparation, it is applied to drug addiction treatment process.
The invention has the beneficial effects as follows: remarkable advantage based on pellet preparations, fine with blank sucrose capsule core or blank crystallite
Dimension element capsule core is pharmaceutical carrier, is upper drug solns with the tetradoxin aqueous solution containing cosolvent and binding agent, uses on fluid bed
Medicine method prepares tetradoxin fast release micropill preparation, and tetradoxin fast release micropill preparation of the present invention has medicine-feeding rate height, content
The features such as uniformity is good, and release is rapid, analgesic activity is rapid-action.Meanwhile, this fast release micropill preparation has Clinical practice compliance
Good, safety high.Additionally, this celphere fluid bed medicine-feeding method is suitable to extremely low specification tetradoxin drug oral preparation
Preparation.Tetradoxin fast release micropill preparation prepared by this preparation method has that medicine-feeding rate is high, content uniformity is good, analgesic activity
Rapid-action, Clinical practice compliance is good, safety high.Additionally, this celphere fluid bed medicine-feeding method is suitable to extremely low rule
The preparation of lattice tetradoxin drug oral preparation.
Detailed description of the invention
Below in conjunction with specific embodiment, the foregoing of the present invention is described in detail, but this should be interpreted as this
Bright technical scheme is only limitted to following example.
Embodiment 1 formula 1
Preparation method:
(1) preparation of upper drug solns: weigh tetradoxin 600mg by formula, adds 0.3% acetum 200mL and dissolves,
It is then dissolved in including in the aqueous solution of hypromellose (HPMC) 67.5g and is configured to drug solns on 1500g.
(2) spray medicine at the bottom of fluid bed: be placed in fluid bed by microcrystalline Cellulose celphere 4000g, start fluid bed, if
Put fluid bed medicine-feeding parameter: fan delivery 150m3·h-1, solution feed pump rotating speed 5r min-1, temperature of charge control 30～40 DEG C,
Atomizing pressure 0.16MPa, adds medicine under fluidized state, after having added medicine to, and fluidized drying 15min.
(3) fluidized bed coating-protecting film layer: weigh pure water 3800g by formula, stirring adds into hydroxypropyl under stirring lower addition
Methylcellulose (HPMC) 200g, stirs that molten prepared concentration is the protection tunic material solution of 5% clearly, adds Pulvis Talci 50g, at a high speed
Emulsifying homogeneous 10 minutes, crosses 60 mesh sieves and obtains protecting film layer coating solution.Fluidized bed coating parameter is set: fan delivery 180m3·h-1,
Solution feed pump rotating speed 15r min-1, temperature of charge controls at 25～35 DEG C, and atomizing pressure 0.3MPa protects under fluidized state
Film layer coating.
(4) being dried afterwards: after coating completes, coated micropill is in 30～40 DEG C of fluidized drying 30min.
Embodiment 2 formula 2
Preparation method:
(1) preparation of upper drug solns: weigh tetradoxin 100mg by formula, add 0.1% citric acid solution 300mL molten
Solve, be then dissolved in including in the aqueous solution of polyvidone (PVP) 7.5g and be configured to drug solns on 1500g.
(2) spray medicine at the bottom of fluid bed: be placed in fluid bed by sucrose celphere 4000g, start fluid bed, fluidisation is set
Bed medicine-feeding parameter: fan delivery 150m3·h-1, solution feed pump rotating speed 5r min-1, temperature of charge control 30～40 DEG C, atomization pressure
Power 0.16MPa, adds medicine under fluidized state, after having added medicine to, and fluidized drying 15min.
(3) fluidized bed coating-protecting film layer: weigh by formula and add into acrylic resin under pure water 3800g, stirring
200g, stirs that molten prepared concentration is the protection tunic material solution of 5% clearly, and stirring is lower adds Pulvis Talci 50g, high-speed emulsifying homogeneous
10 minutes, cross 60 mesh sieves and obtain protecting film layer coating solution.Fluidized bed coating parameter is set: fan delivery 180m3·h-1, solution feed pump turns
Speed 15r min-1, temperature of charge controls at 25～35 DEG C, and atomizing pressure 0.3MPa carries out protecting film layer coating under fluidized state.
(4) being dried afterwards: after coating completes, coated micropill is in 30～40 DEG C of fluidized drying 30min.
Embodiment 3 formula 3
Preparation method:
(1) preparation of upper drug solns: weigh tetradoxin 1200mg by formula, add 0.6% hydrochloric acid solution 720mL molten
Solve, be then dissolved in including in the aqueous solution of syrup 65g and be configured to drug solns on 1500g.
(2) spray medicine at the bottom of fluid bed: be placed in fluid bed by sucrose celphere 4000g, start fluid bed, fluidisation is set
Bed medicine-feeding parameter: fan delivery 150m3·h-1, solution feed pump rotating speed 5r min-1, temperature of charge control 30～40 DEG C, atomization pressure
Power 0.16MPa, adds medicine under fluidized state, after having added medicine to, and fluidized drying 15min.
(3) fluidized bed coating-protecting film layer: weigh by formula and add into acrylic resin under pure water 3800g, stirring
200g, stirs that molten prepared concentration is the protection tunic material solution of 5% clearly, adds Pulvis Talci 60g, high-speed emulsifying homogeneous 10 minutes,
Cross 60 mesh sieves and obtain protecting film layer coating solution.Fluidized bed coating parameter is set: fan delivery 180m3·h-1, solution feed pump rotating speed 15r
min-1, temperature of charge controls at 25～35 DEG C, and atomizing pressure 0.3MPa carries out protecting film layer coating under fluidized state.
(4) being dried afterwards: after coating completes, coated micropill is in 30～40 DEG C of fluidized drying 30min.
Embodiment 4 formula 4
Preparation method:
(1) preparation of upper drug solns: weigh tetradoxin 1200mg by formula, add 6% ascorbic acid solution 120mL molten
Solve, be then dissolved in including in the aqueous solution of starch slurry 0.75g and be configured to drug solns on 150g.
(2) spray medicine at the bottom of fluid bed: be placed in fluid bed by sucrose celphere 400g, start fluid bed, fluidisation is set
Bed medicine-feeding parameter: fan delivery 150m3·h-1, solution feed pump rotating speed 2r min-1, temperature of charge control 30～40 DEG C, atomization pressure
Power 0.16MPa, adds medicine under fluidized state, after having added medicine to, and fluidized drying 15min.
(3) fluidized bed coating-protecting film layer: weigh pure water 380g by formula, stirring is lower adds HPMC 20g, stirs molten
Clearly, prepared concentration is the protection tunic material solution of 5%, adds Pulvis Talci 6g, high-speed emulsifying homogeneous 10 minutes, crosses 60 mesh sieves and must prevent
Cuticular layer coating solution.Fluidized bed coating parameter is set: fan delivery 180m3·h-1, solution feed pump rotating speed 5r min-1, temperature of charge
Control at 25～35 DEG C, atomizing pressure 0.3MPa, under fluidized state, carry out protecting film layer coating.
(4) being dried afterwards: after coating completes, coated micropill is in 30～40 DEG C of fluidized drying 30min.
Embodiment 5 formula 5
Preparation method:
(1) preparation of upper drug solns: weigh tetradoxin 200mg by formula, add 0.1% citric acid soln 200mL molten
Solve, be then dissolved in including in the aqueous solution of carmethose 67.5g and be configured to drug solns on 1500g.
(2) spray medicine at the bottom of fluid bed: be placed in fluid bed by sucrose celphere 4000g, start fluid bed, fluidisation is set
Bed medicine-feeding parameter: fan delivery 150m3·h-1, solution feed pump rotating speed 5r min-1, temperature of charge control 30～40 DEG C, atomization pressure
Power 0.16MPa, adds medicine under fluidized state, after having added medicine to, and fluidized drying 15min.
(3) fluidized bed coating-protecting film layer: weigh pure water 3800g by formula, stirring is lower adds HPMC 200g, stirs molten
Clearly, prepared concentration is the protection tunic material solution of 5%, adds Pulvis Talci 20g, high-speed emulsifying homogeneous 10 minutes, crosses 60 mesh sieves and obtains
Protecting film layer coating solution.Fluidized bed coating parameter is set: fan delivery 180m3·h-1, solution feed pump rotating speed 12r min-1, material
Temperature controls at 25～35 DEG C, and atomizing pressure 0.3MPa carries out protecting film layer coating under fluidized state.
(4) being dried afterwards: after coating completes, coated micropill is in 30～40 DEG C of fluidized drying 30min.
Embodiment 6 formula 6
Preparation method:
(1) preparation of upper drug solns: weigh tetradoxin 200mg by formula, add 0.1% citric acid soln 200mL molten
Solve, be then dissolved in including in the aqueous solution of gelatin 10g and be configured to drug solns on 1500g.
(2) spray medicine at the bottom of fluid bed: be placed in fluid bed by sucrose celphere 4000g, start fluid bed, fluidisation is set
Bed medicine-feeding parameter: fan delivery 150m3·h-1, solution feed pump rotating speed 7r min-1, temperature of charge control 30～40 DEG C, atomization pressure
Power 0.16MPa, adds medicine under fluidized state, after having added medicine to, and fluidized drying 15min.
(3) fluidized bed coating-protecting film layer: weigh pure water 3800g by formula, stirring is lower adds HPMC 200g, stirs molten
Clearly, prepared concentration is the protection tunic material solution of 5%, adds Pulvis Talci 20g, high-speed emulsifying homogeneous 10 minutes, crosses 60 mesh sieves and obtains
Protecting film layer coating solution.Fluidized bed coating parameter is set: fan delivery 180m3·h-1, solution feed pump rotating speed 15r min-1, material
Temperature controls at 25～35 DEG C, and atomizing pressure 0.3MPa carries out protecting film layer coating under fluidized state.
(4) being dried afterwards: after coating completes, coated micropill is in 30～40 DEG C of fluidized drying 30min.
Embodiment 7 formula 7
Preparation method:
(1) preparation of upper drug solns: weigh tetradoxin 200mg by formula, add 0.1% citric acid soln 200mL molten
Solve, be then dissolved in including in the aqueous solution of arabic gum 27.5g and be configured to drug solns on 1500g.
(2) spray medicine at the bottom of fluid bed: be placed in fluid bed by sucrose celphere 4000g, start fluid bed, fluidisation is set
Bed medicine-feeding parameter: fan delivery 150m3·h-1, solution feed pump rotating speed 5r min-1, temperature of charge control 30～40 DEG C, atomization pressure
Power 0.16MPa, adds medicine under fluidized state, after having added medicine to, and fluidized drying 15min.
(3) fluidized bed coating-protecting film layer: weigh pure water 3800g by formula, stirring is lower adds HPMC 200g, stirs molten
Clearly, prepared concentration is the protection tunic material solution of 5%, adds Pulvis Talci 20g, high-speed emulsifying homogeneous 10 minutes, crosses 60 mesh sieves and obtains
Protecting film layer coating solution.Fluidized bed coating parameter is set: fan delivery 180m3·h-1, solution feed pump rotating speed 15r min-1, material
Temperature controls at 25～35 DEG C, and atomizing pressure 0.3MPa carries out protecting film layer coating under fluidized state.
(4) being dried afterwards: after coating completes, coated micropill is in 30～40 DEG C of fluidized drying 30min.
Embodiment 8 formula 8
Preparation method:
(1) preparation of upper drug solns: weigh tetradoxin 200mg by formula, add 0.1% citric acid soln 200mL molten
Solve, be then dissolved in including in the aqueous solution of methylcellulose 57.5g and be configured to drug solns on 1500g.
(2) spray medicine at the bottom of fluid bed: be placed in fluid bed by sucrose celphere 4000g, start fluid bed, fluidisation is set
Bed medicine-feeding parameter: fan delivery 150m3·h-1, solution feed pump rotating speed 7r min-1, temperature of charge control 30～40 DEG C, atomization pressure
Power 0.16MPa, adds medicine under fluidized state, after having added medicine to, and fluidized drying 15min.
(3) fluidized bed coating-protecting film layer: weigh pure water 3800g by formula, stirring is lower adds HPMC 200g, stirs molten
Clearly, prepared concentration is the protection tunic material solution of 5%, adds Pulvis Talci 20g, high-speed emulsifying homogeneous 10 minutes, crosses 60 mesh sieves and obtains
Protecting film layer coating solution.Fluidized bed coating parameter is set: fan delivery 180m3·h-1, solution feed pump rotating speed 15r min-1, material
Temperature controls at 25～35 DEG C, and atomizing pressure 0.3MPa carries out protecting film layer coating under fluidized state.
(4) being dried afterwards: after coating completes, coated micropill is in 30～40 DEG C of fluidized drying 30min.
Embodiment 9 formula 9
Preparation method:
(1) preparation of upper drug solns: weigh tetradoxin 10mg by formula, adds 0.1% citric acid solution 20mL and dissolves,
It is then dissolved in including in the aqueous solution of HPMC 0.75g and is configured to drug solns on 150g.
(2) spray medicine at the bottom of fluid bed: be placed in fluid bed by sucrose celphere 400g, start fluid bed, fluidisation is set
Bed medicine-feeding parameter: fan delivery 150m3·h-1, solution feed pump rotating speed 2r min-1, temperature of charge control 30～40 DEG C, atomization pressure
Power 0.16MPa, adds medicine under fluidized state, after having added medicine to, and fluidized drying 15min.
(3) fluidized bed coating-protecting film layer: weigh pure water 380g by formula, stirring is lower adds HPMC 20g, stirs molten
Clearly, prepared concentration is the protection tunic material solution of 5%, adds Pulvis Talci 5g, high-speed emulsifying homogeneous 10 minutes, crosses 60 mesh sieves and must prevent
Cuticular layer coating solution.Fluidized bed coating parameter is set: fan delivery 180m3·h-1, solution feed pump rotating speed 5r min-1, temperature of charge
Control at 25～35 DEG C, atomizing pressure 0.3MPa, under fluidized state, carry out protecting film layer coating.
(4) being dried afterwards: after coating completes, coated micropill is in 30～40 DEG C of fluidized drying 30min.
Embodiment 10 formula 10
Preparation method:
(1) preparation of upper drug solns: weigh tetradoxin 60mg by formula, adds 0.3% citric acid solution 20mL and dissolves,
It is then dissolved in including in the aqueous solution of HPMC 1.5g and is configured to drug solns on 150g.
(2) spray medicine at the bottom of fluid bed: be placed in fluid bed by sucrose celphere 400g, start fluid bed, fluidisation is set
Bed medicine-feeding parameter: fan delivery 170m3·h-1, solution feed pump rotating speed 2r min-1, temperature of charge control 30～40 DEG C, atomization pressure
Power 0.16MPa, adds medicine under fluidized state, after having added medicine to, and fluidized drying 15min.
(3) fluidized bed coating-protecting film layer: weigh pure water 190g by formula, stirring is lower adds HPMC 10g, stirs molten
Clearly, prepared concentration is the protection tunic material solution of 5%, adds Pulvis Talci 5g, high-speed emulsifying homogeneous 10 minutes, crosses 60 mesh sieves and must prevent
Cuticular layer coating solution.Fluidized bed coating parameter is set: fan delivery 180m3·h-1, solution feed pump rotating speed 5r min-1, temperature of charge control
Make at 25～35 DEG C, atomizing pressure 0.3MPa, under fluidized state, carry out protecting film layer coating.
(4) being dried afterwards: after coating completes, coated micropill is in 30～40 DEG C of fluidized drying 30min.
Embodiment 11 formula 11
Preparation method:
(1) preparation of upper drug solns: weigh tetradoxin 120mg by formula, add 0.6% citric acid solution 20mL molten
Solve, be then dissolved in including in the aqueous solution of HPMC 4.5g and be configured to drug solns on 150g.
(2) spray medicine at the bottom of fluid bed: be placed in fluid bed by sucrose celphere 400g, start fluid bed, fluidisation is set
Bed medicine-feeding parameter: fan delivery 180m3·h-1, solution feed pump rotating speed 2r min-1, temperature of charge control 25～40 DEG C, atomization pressure
Power 0.16MPa, adds medicine under fluidized state, after having added medicine to, and fluidized drying 15min.
(3) fluidized bed coating-protecting film layer: weigh pure water 188g by formula, stirring is lower adds HPMC 12g, stirs molten
Clearly, prepared concentration is the protection tunic material solution of 5%, adds Pulvis Talci 6g, high-speed emulsifying homogeneous 10 minutes, crosses 60 mesh sieves and must prevent
Cuticular layer coating solution.Fluidized bed coating parameter is set: fan delivery 180m3·h-1, solution feed pump rotating speed 5r min-1, temperature of charge control
Make at 25～35 DEG C, atomizing pressure 0.3MPa, under fluidized state, carry out protecting film layer coating.
(4) being dried afterwards: after coating completes, coated micropill is in 30～40 DEG C of fluidized drying 45min.
Embodiment 12 prescription 12
Preparation method:
(1) preparation of upper drug solns: weigh tetradoxin 1200mg by formula, adds 6% citric acid solution 20mL and dissolves,
It is then dissolved in including in the aqueous solution of HPMC 0.75g and is configured to drug solns on 150g.
(2) spray medicine at the bottom of fluid bed: be placed in fluid bed by sucrose celphere 400g, start fluid bed, fluidisation is set
Bed medicine-feeding parameter: fan delivery 150m3·h-1, solution feed pump rotating speed 2r min-1, temperature of charge control 25～40 DEG C, atomization pressure
Power 0.16MPa, adds medicine under fluidized state, after having added medicine to, and fluidized drying 15min.
(3) fluidized bed coating-protecting film layer: weigh pure water 190g by formula, stirring is lower adds HPMC 10g, stirs molten
Clearly, prepared concentration is the protection tunic material solution of 5%, adds Pulvis Talci 5g, high-speed emulsifying homogeneous 10 minutes, crosses 60 mesh sieves and must prevent
Cuticular layer coating solution.Fluidized bed coating parameter is set: fan delivery 170m3·h-1, solution feed pump rotating speed 5r min-1, temperature of charge control
Make at 25～35 DEG C, atomizing pressure 0.3MPa, under fluidized state, carry out protecting film layer coating.
(4) being dried afterwards: after coating completes, coated micropill is in 30～40 DEG C of fluidized drying 30min.
Embodiment 13 prescription 13
Preparation method:
(1) preparation of upper drug solns: weigh tetradoxin 20mg by formula, adds citric acid solution 20mL and dissolves, then
It is dissolved in including in the aqueous solution of PVP 0.75g and is configured to drug solns on 150g.
(2) spray medicine at the bottom of fluid bed: be placed in fluid bed by sucrose celphere 400g, start fluid bed, fluidisation is set
Bed medicine-feeding parameter: fan delivery 180m3·h-1, solution feed pump rotating speed 2r min-1, temperature of charge control 30～40 DEG C, atomization pressure
Power 0.16MPa, adds medicine under fluidized state, after having added medicine to, and fluidized drying 15min.
(3) fluidized bed coating-protecting film layer: weigh pure water 76g by formula, stirring is lower adds acrylic resin 4g, stirring
Molten prepared concentration is the protection tunic material solution of 5% clearly, adds Pulvis Talci 2g, high-speed emulsifying homogeneous 10 minutes, crosses 60 mesh sieves and obtains
Protecting film layer coating solution.Fluidized bed coating parameter is set: fan delivery 180m3·h-1, solution feed pump rotating speed 5r min-1, temperature of charge
Control at 25～35 DEG C, atomizing pressure 0.3MPa, under fluidized state, carry out protecting film layer coating.
(4) being dried afterwards: after coating completes, coated micropill is in 30～40 DEG C of fluidized drying 30min.
Embodiment 14 prescription 14
Preparation method:
(1) preparation of upper drug solns: weigh tetradoxin 20mg by formula, adds citric acid solution 20mL and dissolves, then
It is dissolved in including in the aqueous solution of PVP 1.125g and is configured to drug solns on 150g.
(2) spray medicine at the bottom of fluid bed: be placed in fluid bed by microcrystalline Cellulose celphere 400g, start fluid bed, if
Put fluid bed medicine-feeding parameter: fan delivery 150m3·h-1, solution feed pump rotating speed 2r min-1, temperature of charge control 30～40 DEG C,
Atomizing pressure 0.16MPa, adds medicine under fluidized state, after having added medicine to, and fluidized drying 15min.
(3) fluidized bed coating-protecting film layer: weigh pure water 76g by formula, stirring is lower adds acrylic resin 4g, stirring
Molten prepared concentration is the protection tunic material solution of 5% clearly, adds Pulvis Talci 2g, high-speed emulsifying homogeneous 10 minutes, crosses 60 mesh sieves and obtains
Protecting film layer coating solution.Fluidized bed coating parameter is set: fan delivery 180m3·h-1, solution feed pump rotating speed 5r min-1, temperature of charge
Control at 25～35 DEG C, atomizing pressure 0.3MPa, under fluidized state, carry out protecting film layer coating.
(4) being dried afterwards: after coating completes, coated micropill is in 30～40 DEG C of fluidized drying 30min.
Embodiment 15 prescription 15
Preparation method:
(1) preparation of upper drug solns: weigh tetradoxin 20mg by formula, adds citric acid solution 20mL and dissolves, then
It is dissolved in including in the aqueous solution of HPMC 0.75g and is configured to drug solns on 150mg.
(2) spray medicine at the bottom of fluid bed: be placed in fluid bed by microcrystalline Cellulose celphere 400g, start fluid bed, if
Put fluid bed medicine-feeding parameter: fan delivery 150m3·h-1, solution feed pump rotating speed 2r min-1, temperature of charge control 30～40 DEG C,
Atomizing pressure 0.16MPa, adds medicine under fluidized state, after having added medicine to, and fluidized drying 15min.
(3) fluidized bed coating-protecting film layer: weigh pure water 190g by formula, stirring is lower adds HPMC 10g, stirs molten
Clearly, prepared concentration is the protection tunic material solution of 5%, adds Pulvis Talci 5g, high-speed emulsifying homogeneous 10 minutes, crosses 60 mesh sieves and must prevent
Cuticular layer coating solution.Fluidized bed coating parameter is set: fan delivery 180m3·h-1, solution feed pump rotating speed 5r min-1, temperature of charge control
Make at 25～35 DEG C, atomizing pressure 0.3MPa, under fluidized state, carry out protecting film layer coating.
(4) being dried afterwards: after coating completes, coated micropill is in 30～40 DEG C of fluidized drying 30min.
In order to illustrate that described tetradoxin fast release micropill preparation has Clinical practice safety high, we use
Acute toxicity test is illustrated:
Experimental technique
SPF level SD rat, adapts to 3 days under SPF barrier system feeding environment, and fasting 16h before being administered can't help water, animal
Weigh, labelling, packet, often group 10, male and female half and half, tetradoxin fast release micropill divides 5 dosage groups as follows: 814 μ g/kg, 692
μ g/kg, 588 μ g/kg, 500 μ g/kg, 425 μ g/kg, 1ml/100g water gavage takes, and to observation post administration 7 days, records nosotoxicosis
Shape and dead animal, use Bliss method to carry out computing, calculate LD50, the results are shown in Table 1.
Table 1 tetradoxin fast release micropill acute toxicity testing result
Bliss method is used to carry out computing:
LD50=517.43 μ g/kg
LD5095% credible be limited to 459.41～582.79 μ g/kg
Animal poisoning symptom is observed:
After high dose group (692 μ g/kg and 814 μ g/kg) is administered, i.e. state is poor, few dynamic, dispirited, the fastest 2 respectively at
Death after being administered 8 minutes and 10 minutes, rapid breathing, without other manifest symptoms.Death mostly occurs 2～6h, lasts till 10h,
Afterwards without dead, it is in good condition that next day observes animal, does not observes any abnormal response.
In order to illustrate that described tetradoxin fast release micropill preparation has significant analgesic activity and analgesic activity is rapid-action
Etc. effect, following pharmacological evaluation is used to be illustrated:
(1) hot plate method evaluates the tetradoxin fast release micropill analgesic activity to thermostimulation
Experimental technique
Female rats 180～220g, before being administered, screening animal, hot plate temperature 53 ° ± 0.5 °, occur licking metapedes with animal
Time, pain threshold was qualified 5～30s as pain threshold, rejected pain abnormal reaction animal and pain threshold not interval animal at this.
Qualified animal is surveyed every 15min again and once takes average, based on pain threshold.Weighing, packet, labelling, gavage gives tetradoxin
Fast release micropill test medicine, water delivery service 1ml/100g, matched group uses cloth Lip river to blank formulation water delivery service 1ml/100g, positive drug
Fragrant corresponding preparation.Timing after administration, after being administered, different time points measures pain threshold.If painless reaction in 60s, it is to avoid scald
Wound is taken out immediately, calculates by 60s.T-inspection, the difference between more each group is compareed between organizing.Calculate analgesia percentage rate.
Before threshold of pain increase rate (%)=(pain response time average before pain response time-medicine after medicine)/medicine, the pain response time is equal
Value × 100%
Data process and evaluation of effect
Calculate each group of threshold of pain and improve percentage rate, between organizing, compare t-inspection, the difference between more each group.Result Mean
± SEM represents, compares t-test and compare two-by-two between employing group, and p < 0.05 is for there being significant difference.
Evaluating drug effect principle: add up statistically significant between group, when meeting analgesia percentage rate more than 50%, just can recognize simultaneously
For there being preferable analgesic potency.
Experimental result
Experimental result is shown in Table 2.Blank Pellets improves percentage rate without significant change in each time point threshold of pain and the threshold of pain, relatively low
Fluctuate under level.Test medicine tetradoxin 10 μ g/kg, after 20 μ g/kg gastric infusions, 90min starts to play significantly analgesia
Acting on, the threshold of pain time is obviously prolonged, and 180min analgesia is notable, and 360min still continues in higher level, it is shown that low dose group has
There is persistently strong analgesic activity.After 40 μ g/kg, 60 μ g/kg and 80 μ g/kg gastric infusions, 15min shows slightly effect, and 30min i.e. plays bright
Aobvious analgesic activity, the threshold of pain time is obviously prolonged, and 30-60min each dosage group all shows preferably effect, and 90min still continues relatively
High level, 180min drug effect continues but degree reduces, 360min event resolves.Test medicine presents preferable time and dosage
The action character relied on.
Table 2 hot plate method evaluates the tetradoxin fast release micropill analgesic activity to thermostimulation
Oral LD in conjunction with tetradoxin quick releasing formulation50Being 517.43 μ g/kg, this experimental result is pointed out, tetradoxin speed
Release formulation is at LD501/50～1/10LD50I.e. there is preferable analgesic activity, belong to safer dosage, tetradoxin is described
Fast release micropill preparation Clinical practice safety is high.
(2) writhing method evaluates the tetradoxin fast release micropill analgesic activity to Encelialgia
Experimental technique
SD rat 180～220g, weighs, packet, labelling, and gavage gives tetradoxin fast release micropill test medicine, and water send
Taking 1ml/100g, matched group uses ibuprofen correspondence preparation to blank formulation water delivery service 1ml/100g, positive drug.Count after administration
Time, 15min, 30min, 45min, 60min, 90min, 120min, 150min, 180min and 360min time after being administered
Point gives 2% acetum, the writhing number of times that in record 30min, rat occurs.T-inspection is compareed, between more each group between organizing
Difference.And calculate analgesic activity inhibition percentage.
Analgesic activity inhibition percentage (%)=(matched group writhing number of times-administration group writhing number of times)/matched group writhing time
Number × 100%
Data process and evaluation of effect
Calculate each group of incubation period, each time point writhing number of times, between organizing, compare t-inspection, the difference between more each group.
Result X ± SD represents, compares t-test and compare two-by-two between employing group, and p < 0.05 is for there being significant difference.
Evaluating drug effect principle: add up statistically significant between group, when meeting analgesia inhibition percentage more than 50%, just simultaneously
Can think there is preferable analgesic potency.
As listed in table 3,20 μ g/kg medicines have a preferable analgesic activity to experimental result, 30min onset, and 60min effect is
By force, effect maintains 3h, and inhibitory action is centered around about 50%；30 μ g/kg effects are higher, 15min onset, and effect maintains 3h,
High inhibition percentage rate is about 66%；40 μ g/kg medicines nearly reach ceiling effect at 60min, and suppression ratio reaches about 97%, in 3h
Analgesia inhibition percentage is all more than 50%.
Table 3 writhing method evaluates the tetradoxin fast release micropill analgesic activity to Encelialgia
Oral LD in conjunction with tetradoxin quick releasing formulation50Being 517.43 μ g/kg, this experimental result is pointed out, tetradoxin speed
Release pellet preparations at LD501/20～1/10 i.e. there is preferable analgesic activity, belong to safer dosage, tetradoxin be described
Fast release micropill preparation Clinical practice safety is high.
In order to illustrate that the preparation method of described tetradoxin fast release micropill preparation has medicine-feeding rate height, content uniformity
The features such as good, release is rapid, our selected part formula has carried out the mensuration of medicine-feeding rate, uniformity of dosage units and vitro release,
Result is as shown in table 4, table 5, table 6.As can be seen from Table 4, formula 9～13, with sucrose celphere for medicine carrying capsule core, with
HPMC Yu PVP is binding agent, and tetradoxin loading rate is high；Formula 14～15, with microcrystalline Cellulose celphere for medicine carrying capsule core,
With HPMC Yu PVP as binding agent, medicine-feeding rate is relatively low.As can be seen from Table 5, containing of 10 parts of formula 10 samples is measured at random
Amount, its average content is 99.23%, and relative standard deviation RSD is 1.70%, illustrates that the tetradoxin micropill content of preparation is uniform
Spend.As can be seen from Table 6, each formula group release in vitro 0.5h, tetradoxin release rate is all higher than 90%, and principal agent release is basic
Completely；Release in vitro 2h, tetradoxin release rate is all higher than 97%, and principal agent release completely, illustrates the tetradoxin rapid release of preparation
Micropill, has the rapid feature of release.
Table 4 tetradoxin loading rate measurement result
| Formula number | 9 | 10 | 11 | 12 | 13 | 14 | 15 |
| Loading rate (%) | 89.59 | 91.39 | 90.00 | 96.78 | 89.23 | 36.82 | 36.00 |
Table 5 tetradoxin Determination of Content Uniformity result (formula 10)
Table 6 vitro release result of the test
Above content is to combine specific embodiment further description made for the present invention, it is impossible to assert this
Bright being embodied as is confined to these explanations.For general technical staff of the technical field of the invention, do not taking off
On the premise of present inventive concept, it is also possible to make some simple deduction or replace, all should be considered as belonging to the protection of the present invention
Scope.
Claims (12)
1. a tetradoxin fast release micropill preparation, it is characterised in that described fast release micropill preparation administering mode for be administered orally to
Medicine, with celphere as carrier, the tetradoxin aqueous solution containing cosolvent and binding agent is upper drug solns, described tetradoxin
Consumption, according to weight ratio, tetradoxin consumption is the 0.0025～0.3% of described capsule core；The oral dose of tetradoxin is the highest
In 300 micrograms.
2. tetradoxin fast release micropill preparation as claimed in claim 1, it is characterised in that described celphere is sucrose ball
Core or microcrystalline Cellulose capsule core；Described cosolvent is selected from one or more in citric acid, acetic acid, hydrochloric acid, ascorbic acid or presses
According to weight ratio, cosolvent consumption is the 20～300% of tetradoxin.
3. tetradoxin fast release micropill preparation as claimed in claim 1, it is characterised in that described binding agent is selected from hydroxypropyl first
One or many in cellulose, polyvidone, syrup, starch slurry, carmethose, gelatin, arabic gum, methylcellulose
Kind, according to weight ratio, binder dosage is the 0.1875～1.6875% of celphere.
4. any one tetradoxin fast release micropill preparation as described in claims 1 to 3, it is characterised in that also include overcoat
Film material；One or more in acrylic resin, hypromellose of described protection tunic material；According to weight ratio, anti-
Consumption is celphere the 1.0～5.0% of sheath film material.
5. any one tetradoxin fast release micropill preparation as described in Claims 1 to 4, it is characterised in that described rapid release is micro-
Ball is pressed into oral administration after tablet after filling in capsule or adding proper auxiliary materials.
6. the preparation method of a tetradoxin fast release micropill preparation, it is characterised in that with celphere as carrier, with containing hydrotropy
The tetradoxin aqueous solution of agent and binding agent is upper drug solns, sprays prescription method and prepares medicine carrying micropill, add at the bottom of employing fluid bed
Protection tunic material solution obtains tetradoxin fast release micropill preparation through fluidized bed coating.
7. a preparation method for tetradoxin fast release micropill preparation, including:
Step one: the preparation of upper drug solns；
Step 2: spray medicine at the bottom of fluid bed；
Step 3: fluidized bed coating-protecting film layer；
Step 4: be dried afterwards.
8. preparation method as claimed in claim 7, it is characterised in that described step one is specially and weighs for bent by formula
Pungent, the citric acid solution adding formula ratio dissolves, be then dissolved in including in the aqueous solution of binding agent be configured to quantitatively to add medicine to molten
Liquid.
9. preparation method as claimed in claim 7, it is characterised in that described step 2 is specially the celphere of formula ratio
Being placed in fluid bed, start fluid bed, the upper drug solns prepared in quantitative input step one in fluid bed, described input is added medicine to
During solution, fluid bed medicine-feeding parameter is set by the process conditions optimized, including fan delivery 150～180m3·h-1, solution feed pump turns
Speed 2～7r min-1, temperature of charge 25～40 DEG C, atomizing pressure 0.16MPa.
10. preparation method as claimed in claim 7, it is characterised in that described step 3 is specially pressed formula ratio preparation 5% and prevented
Sheath film material solution, fluidized bed coating parameter is set to fan delivery 150～180m3·h-1, solution feed pump rotating speed 5～15r min-1,
Temperature of charge controls at 25～30 DEG C, atomizing pressure 0.3MPa；Described step 4 after specially coating completes, adjusts fluid bed ginseng
Number, coated micropill is in 30～40 DEG C of fluidized dryings 15～45min.
11. 1 kinds of tetradoxin fast release micropill preparations, it is applied to analgesic exploitation.
12. 1 kinds of tetradoxin fast release micropill preparations, it is applied to drug addiction treatment process.
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| CN107737129A (en) * | 2017-10-20 | 2018-02-27 | 国家海洋局第三海洋研究所 | Tetradoxin new application |
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| CN107737129A (en) * | 2017-10-20 | 2018-02-27 | 国家海洋局第三海洋研究所 | Tetradoxin new application |
| CN107982243A (en) * | 2017-12-06 | 2018-05-04 | 佛山市腾瑞医药科技有限公司 | A kind of nebivolol hydrochloric acid fast release micropill preparation, preparation method |
| CN108014098A (en) * | 2017-12-06 | 2018-05-11 | 佛山市腾瑞医药科技有限公司 | A kind of tolvaptan fast release micropill preparation, preparation method |
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