CN107149599A - Drug delivery system - Google Patents
Drug delivery system Download PDFInfo
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- CN107149599A CN107149599A CN201610122492.0A CN201610122492A CN107149599A CN 107149599 A CN107149599 A CN 107149599A CN 201610122492 A CN201610122492 A CN 201610122492A CN 107149599 A CN107149599 A CN 107149599A
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- Prior art keywords
- grams
- delivery system
- drug delivery
- layer
- pellicle
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Abstract
According to an embodiment of this exposure there is provided a kind of drug delivery system, including：One pellicle, its surface includes an at least hole, and the pellicle is enclosed including one first area and one second area, and wherein firstth area is adjacent to the hole, and secondth area is away from the hole；One medicine layer, firstth area enclosed positioned at the pellicle, medicine layer includes 9-hydroxy-risperidone and its pharmaceutically acceptable salt class or esters；And one push layer, secondth area enclosed positioned at the pellicle, the pushing layer include low-substituted hydroxypropyl cellulose, wherein the substitution value of the low-substituted hydroxypropyl cellulose is between 8%~15%.
Description
Technical field
This exposure relates to a kind of drug delivery system, possesses the novel medicine for pushing layer material in particular to a kind of
Thing discharges system.
Background technology
The conventional antipsychotic drug of clinic, by pharmacological action, can be generally divided into typical case and the major class of atypia two：
(1) typical antipsychotic drug (traditional antipsychotic drug), representing medicine includes：Chlorpromazine, haloperole
Deng；(2) atypia antipsychotic drug (non-traditional antipsychotic drug), representing medicine includes 9-hydroxy-risperidone, chlorine
Nitrogen is flat, Risperidone etc..Compared with traditional antipsychotic drug, atypia antipsychotic drug and dopamine D 2 by
The affinity of body is relatively low, and higher with the affinity of serotonin and noradrenaline acceptor, meanwhile, it treats frequency spectrum extensively,
Conventional medicament is substantially better than to negative symptoms effect, safe, side effect is slight, and taking dose is small, greatly improves patient
Compliance.
9-hydroxy-risperidone (paliperidone) is antipsychotic agent, belongs to the derivative of benzo isoxazole class, its
Definite mechanism of action is unclear.It is now recognized that it is by blocking dopamine (D), serotonin 2A (5HT2) and adrenaline
Acceptor and the signal transduction for disturbing patient's intracerebral transmitter substance.
At present, commercially available 9-hydroxy-risperidone sustained release tablets (trade name：Invega it is) by the Janssen under U.S.'s Jonson's house flag
The benzo isoxazole class antipsychotic drug that LP companies develop, FDA (FDA) is in November, 2005
Approval listing on the 29th, is mainly used in treatment schizophrenia and two-phase manic disorder.
Chinese patent CN 1,684,670A disclose a kind of formulation and side for being used to provide the release of 9-hydroxy-risperidone ascending rate
Method.When being administered once a day, the slow release formulation can be provided to therapeutically effective blood plasma 9-hydroxy-risperidone concentration.The patent passes through warp
Mouth gives the scrotiform controlled release tablet containing 9-hydroxy-risperidone, obtains discharging 9-hydroxy-risperidone within the extension time with incremental rate of release.
The patent describes the preparation method of 9-hydroxy-risperidone scrotiform osmotic pump controlled release tablet in detail, and its label major auxiliary burden is macromolecule material
Material-polyoxyethylene (PEO).But, regrettably find based on the reason for following several respects, this three layers of scrotiform osmotic pump controlled-releasings
Also there are some defects in system, for example：
(1) preparation technology is special, and production cost is higher.The preparation technology of three layers of osmotic pump controlled release tablet is complex, prepares
During need to prepare the medicated layer particle of two kinds of different pharmaceutical contents, and determine its granule content respectively, then pressed again
Piece, its long preparation period, workload is big.The common dose of 9-hydroxy-risperidone includes 3mg, 6mg, 9mg, belongs to small dose drug, its
Higher is required to label uniformity of dosage units, for three-layer tablet, to reach that satisfied uniformity of dosage units difficulty is big.Therefore, make
Sheeting equipment (three laminate machines) needed for standby three layers of scrotiform osmotic pump controlled release tablet is more special, its processing for sheeting equipment
Precision has higher requirement.
(2) label major auxiliary burden heat endurance is poor.Polyoxyethylene (PEO) is that a kind of heat endurance is poor, Glass Transition temperature
The high molecular polymer of relatively low (62~67 DEG C) is spent, due to These characteristics, it is deposited in industrial preparation and storage process
In following problem：(a) drying of solvent is more difficult in pelletization.Polyoxyethylated drying temperature is generally no more than 40
DEG C, therefore, easily cause and dry insufficient, the problem of Determination of Residual Organic Solvents is higher；It is more complete to drying, it is necessary to relative
Longer drying time, add the production cost of enterprise；(b) storage temperature of tablet is unsuitable too high, must be at shady and cool lucifuge
Storage, adds the storage cost of auxiliary material.Meanwhile, it is some that too high placement temperature is easily caused polyoxyethylated physicochemical property generation
Change, for example, oxidative degradation occurs for polyoxyethylene, label viscosity declines, so that the release for ultimately resulting in controlled release tablet accelerates, this is just
Treatment to mental patient adds potential hazards；(c) in high speed tableting processes, friction generates heat repeatedly for punch die,
When temperature reaches 50 DEG C or so, easily there are the phenomenons such as glutinous punching, coarse, the label subregion crimping of label outward appearance, therefore, lead to
Special cooling installation is often needed to control the temperature of punch die.For osmotic pump controlled release tablet, label subregion crimping shows
As easily causing the tender spots that this region has coating membrane, this may result in clothing film and is ruptured during release, its result
The rate of release of medicine can be not only influenceed, and is more seriously, the prominent of medicine produced by this clothing film rupture is released, can be straight
Connecing causes the fluctuation of blood concentration, so as to add the potential dangerous and adverse reaction of mental patient's medication, this oozes with preparation
The original intention of saturating pump controlled-releasing tablet is disagreed.
(3) three layers of scrotiform osmosis pump control-release system discharge 9-hydroxy-risperidone, the ripple of blood concentration with incremental rate of release
It is dynamic relatively large, thus, reduce security, validity and the compliance of patient's medication.
Accordingly, it would be desirable to develop a kind of 9-hydroxy-risperidone osmotic pump controlled release tablet, its process for producing is simple, label cost of supplementary product
Low and heat endurance is good, and can effectively control rate of releasing drug, makes plasma concentration curve steady, reduces the fluctuation of blood concentration,
Thus increase patient takes medicine security, validity and compliance.
The content of the invention
According to an embodiment of this exposure there is provided a kind of drug delivery system, including：One pellicle, its surface is included extremely
A few hole, the pellicle is enclosed including one first area and one second area, and wherein firstth area is adjacent to the hole, and secondth area is remote
From the hole；One medicine layer, firstth area enclosed positioned at the pellicle, medicine layer includes 9-hydroxy-risperidone
And its pharmaceutically acceptable salt class or esters (paliperidone)；And one push layer, positioned at the pellicle enclosed should
Secondth area, pushing layer includes low-substituted hydroxypropyl cellulose.The wherein substitution value of the low-substituted hydroxypropyl cellulose can be between
8%~15%.
For above-mentioned purpose, feature and the advantage of this exposure can be become apparent, a preferred embodiment cited below particularly, and match somebody with somebody
Appended schema is closed, is described in detail below.
Brief description of the drawings
Fig. 1 systems are according to an embodiment of this exposure, a kind of structural representation of drug delivery system；
Drug delivery system and the dissolving-separating test ratio of the comparison medicine of comparing embodiment 6 prepared by Fig. 2 systems this exposure embodiment 1
Compared with；
Drug delivery system prepared by Fig. 3 systems this exposure embodiment 2~5 is molten from examination with the comparison medicine of comparing embodiment 6
Test and compare；
Drug delivery system prepared by Fig. 4 systems this exposure embodiment 5~8 is molten from examination with the comparison medicine of comparing embodiment 6
Test and compare；
Drug delivery system prepared by Fig. 5 systems this exposure embodiment 9~13 is molten from examination with the comparison medicine of comparing embodiment 6
Test and compare；
Drug delivery system and the dissolving-separating test ratio of the comparison medicine of comparing embodiment 6 prepared by Fig. 6 systems comparing embodiment 1
Compared with；
Drug delivery system and the dissolving-separating test ratio of the comparison medicine of comparing embodiment 6 prepared by Fig. 7 systems comparing embodiment 2
Compared with；
Drug delivery system and the dissolving-separating test ratio of the comparison medicine of comparing embodiment 6 prepared by Fig. 8 systems comparing embodiment 3
Compared with；
Drug delivery system and the dissolving-separating test ratio of the comparison medicine of comparing embodiment 6 prepared by Fig. 9 systems comparing embodiment 4
Compared with；
Drug delivery system and the dissolving-separating test ratio of the comparison medicine of comparing embodiment 6 prepared by Figure 10 systems comparing embodiment 5
Compared with.
Wherein, description of reference numerals is as follows：
10~drug delivery system；
12~pellicle；
14~hole；
The firstth area that 16~pellicle is enclosed；
The secondth area that 18~pellicle is enclosed；
20~medicine layer；
22~9-hydroxy-risperidone and its pharmaceutically acceptable salt class or esters；
24~push layer；
26~moisture film clothing.
Embodiment
Referring to Fig. 1, according to an embodiment of this exposure, there is provided a kind of drug delivery system 10.Drug delivery system 10 is wrapped
Include：One pellicle 12, its surface includes an at least hole 14, and pellicle 12 is enclosed including one first area 16 and one second area 18, wherein
First area 16 is adjacent to hole 14, and the second area 18 is away from hole 14；One medicine layer 20, the first area 16 enclosed positioned at pellicle 12,
Medicine layer 20 includes 9-hydroxy-risperidone, and (paliperidone, chemical formula is expressed as
) and its pharmaceutically acceptable salt class or esters 22；And one push layer 24, the second area 18 enclosed positioned at pellicle 12 is pushed away
Squeezing layer 24 includes low-substituted hydroxypropyl cellulose (low-substituted hydroxypropyl cellulose, L-HPC),
The wherein substitution value (degree of substitution) of low-substituted hydroxypropyl cellulose, i.e. hydroxypropyl in hydroxypropyl cellulose
Content, substantially between 8%~15%.
In some embodiments, above-mentioned pellicle 12 may include cellulose acetate, ethyl cellulose or its mixture.
In some embodiments, above-mentioned pellicle 12 can further include a pore-foaming agent, for example polyethylene glycol, PVP, water-soluble
Property inorganic salts (such as sodium chloride, potassium chloride) or its mixture.
In some embodiments, weight percent of the above-mentioned pore-foaming agent in pellicle 12 be substantially between 0.1~20%, or
Between 1~10%.
In some embodiments, above-mentioned pellicle 12 is relative to medicine layer and pushes the weight percent of layer substantially between 4
~30%, or between 5~20%.
In some embodiments, said medicine layer 20 can further include a bleeding agent, a binder, a lubricant or primary antibody
Oxidant.
In some embodiments, above-mentioned bleeding agent may include salt (such as sodium chloride, potassium chloride), carbohydrate (such as fruit
Sugar, sucrose, glucose etc.) or its mixture.
In some embodiments, above-mentioned binder may include PVP (PVP), hydroxypropyl methyl cellulose (HPMC), hydroxyl
Propyl cellulose (HPC) or its mixture.
In some embodiments, above-mentioned lubricant may include magnesium stearate (magnesium stearate), calcium stearate,
Stearic acid, fumaric acid odium stearate, fatty glyceride.
In some embodiments, above-mentioned antioxidant may include dibutyl hydroxy toluene (BHT), butylated hydroxy anisole
(BHA)。
In some embodiments, weight percent of the above-mentioned low-substituted hydroxypropyl cellulose (L-HPC) in pushing layer 24
Substantially between 20~90%, or between 25~90%.
In some embodiments, above-mentioned pushing layer 24 can further include a bleeding agent, a binder, a lubricant, an antioxygen
Agent, a colouring agent or a glidant.
In some embodiments, above-mentioned bleeding agent may include salt (such as sodium chloride, potassium chloride), carbohydrate (such as fruit
Sugar, sucrose, glucose etc.) or its mixture.
In some embodiments, above-mentioned binder may include PVP (PVP), hydroxypropyl methyl cellulose (HPMC), hydroxyl
Propyl cellulose (HPC) or its mixture.
In some embodiments, above-mentioned lubricant may include magnesium stearate (magnesium stearate), calcium stearate,
Stearic acid, fumaric acid odium stearate, fatty glyceride.
In some embodiments, above-mentioned antioxidant may include dibutyl hydroxy toluene (BHT), butylated hydroxy anisole
(BHA)。
In some embodiments, above-mentioned colouring agent may include pigment or iron oxide.
In some embodiments, above-mentioned glidant may include silica (silicon dioxide).
In some embodiments, said medicine layer 20 with push layer 24 weight ratio substantially between 1/10~9/2, or between
1/5~4/1.
In some embodiments, this exposure drug delivery system 10 further includes a moisture film clothing 26, coats above-mentioned pellicle 12.
In some embodiments, above-mentioned moisture film clothing 26 may include water soluble polymer, such as polyvinyl alcohol (PVA), hydroxypropyl
Ylmethyl cellulose (HPMC) or hydroxypropyl cellulose (HPC).
Embodiment/comparative example
Embodiment 1
The preparation (1) of this exposure drug delivery system
The preparation of medicine layer：
676.2 grams of hydroxypropyl celluloses (HPC) and 60.0 grams of 9-hydroxy-risperidone (paliperidone) are square to dissipate again
Method is uniformly mixed, then sequentially add 58.2 grams hydroxypropyl methyl cellulose (HPMC), 200.0 grams of sodium chloride, 0.50 gram
Dibutyl hydroxy toluene (BHT) is well mixed, finally, and the magnesium stearate for adding 5.10 grams is mixed, standby.
Push the preparation of layer：
First, bonding solution is prepared, 115.6 grams of PVP K30 is dissolved in pure water, 13% PVP is configured to
(PVP) solution, then 389.6 grams of sodium chloride is together dissolved, then, by the low of 58.8 grams of iron oxide red and 1433.4 grams
Substitution hydroxypropyl cellulose (L-HPC, hydroxypropyl content 14%) is inserted in granulation pot, and spray solution will be binded extremely with spray pattern
Granulate in pot, it is uniformly binded.Particle is with oven drying to acceptable humidity after granulating, with 16 eye mesh screen whole grains, then
2.00 grams of dibutyl hydroxy toluene (BHT), 0.60 gram of magnesium stearate is sequentially added to be well mixed, it is standby.
The preparation of bi-layer troche core：
Double-deck ingot is made with double-deck Ingot pressing machine according to recipe quantity with pushing layer in said medicine layer, first, by 200 milligrams push away
Squeeze to be placed in mold cavity and carry out precompressed, then 200 milligrams of medicine is placed on to the bilayer that appropriate hardness is pressed into mold cavity
Dragee cores.
The preparation of pellicle：
Preparing acetyl cellulose/polyethylene glycol film is matched somebody with somebody with 237.6 grams of cellulose acetate and 2.40 grams of Macrogol 6000
Clothing liquid, solvent is configured to 5% film clothing liquid, film clothing liquid uniformly is coated on into double-deck ingot with film clothing machine with the cosolvent of acetone/water
In agent core, the lozenge for completing film clothing is dried 48 hours under 45 DEG C of environment, to remove residual solvent.
The punching of pellicle：
One 0.3 millimeter of hole is drilled through with pellicle of the laser boring mode above medicine layer.
The preparation of moisture film clothing：
With 324.0 gramsII is preparedII film clothing liquid, works as solvent with pure water, then equal with film clothing machine
It is even that above-mentioned film clothing liquid is coated in bi-layer troche.
The drug delivery system of above-mentioned preparation is subjected to dissolving-separating test, as a result as shown in Figure 2.
Embodiment 2
The preparation (2) of this exposure drug delivery system
The preparation of medicine layer：
317.2 grams of hydroxypropyl celluloses (HPC) and 60.0 grams of 9-hydroxy-risperidone (paliperidone) are square to dissipate again
Method is uniformly mixed, then the sequentially hydroxypropyl methyl cellulose (HPMC) of 27.1 grams of addition, 93.0 grams of sodium chloride, the two of 0.30 gram
Butylated hydroxytoluene (BHT) is well mixed, finally, and the magnesium stearate for adding 2.40 grams is mixed, standby.
Push the preparation of layer：
First, bonding solution is prepared, 144.5 grams of PVP K30 is dissolved in pure water, 13% PVP is configured to
(PVP) solution, then 487.0 grams of sodium chloride is together dissolved, then, by the low of 73.5 grams of iron oxide red and 1791.7 grams
Substitution hydroxypropyl cellulose (L-HPC, hydroxypropyl content 14%) is inserted in granulation pot, and spray solution will be binded extremely with spray pattern
Granulate in pot, it is uniformly binded.Particle is with oven drying to acceptable humidity after granulating, with 16 eye mesh screen whole grains, then
2.50 grams of dibutyl hydroxy toluene (BHT), 0.80 gram of magnesium stearate is sequentially added to be well mixed, it is standby.
The preparation of bi-layer troche core：
Double-deck ingot is made with double-deck Ingot pressing machine according to recipe quantity with pushing layer in said medicine layer, first, by 250 milligrams push away
Squeeze to be placed in mold cavity and carry out precompressed, then 50 milligrams of medicine is placed on to the double-deck ingot that appropriate hardness is pressed into mold cavity
Agent core.
The preparation of pellicle：
Preparing acetyl cellulose/polyethylene glycol film is matched somebody with somebody with 237.6 grams of cellulose acetate and 2.40 grams of Macrogol 6000
Clothing liquid, solvent is configured to 5% film clothing liquid, film clothing liquid uniformly is coated on into double-deck ingot with film clothing machine with the cosolvent of acetone/water
In agent core, the lozenge for completing film clothing is dried 48 hours under 45 DEG C of environment, to remove residual solvent.
The punching of pellicle：
One 0.3 millimeter of hole is drilled through with pellicle of the laser boring mode above medicine layer.
The preparation of moisture film clothing：
With 324.0 gramsII is preparedII film clothing liquid, works as solvent with pure water, then equal with film clothing machine
It is even that above-mentioned film clothing liquid is coated in bi-layer troche.
The drug delivery system of above-mentioned preparation is subjected to dissolving-separating test, as a result as shown in Figure 3.
Embodiment 3
The preparation (3) of this exposure drug delivery system
The preparation of medicine layer：
496.4 grams of hydroxypropyl celluloses (HPC) and 60.0 grams of 9-hydroxy-risperidone (paliperidone) are square to dissipate again
Method is uniformly mixed, then sequentially add 42.7 grams hydroxypropyl methyl cellulose (HPMC), 146.7 grams of sodium chloride, 0.40 gram
Dibutyl hydroxy toluene (BHT) is well mixed, finally, and the magnesium stearate for adding 3.80 grams is mixed, standby.
Push the preparation of layer：
First, bonding solution is prepared, 144.5 grams of PVP K30 is dissolved in pure water, 13% PVP is configured to
(PVP) solution, then 487.0 grams of sodium chloride is together dissolved, then, by the low of 73.5 grams of iron oxide red and 1791.7 grams
Substitution hydroxypropyl cellulose (L-HPC, hydroxypropyl content 14%) is inserted in granulation pot, and spray solution will be binded extremely with spray pattern
Granulate in pot, it is uniformly binded.Particle is with oven drying to acceptable humidity after granulating, with 16 eye mesh screen whole grains, then
2.50 grams of dibutyl hydroxy toluene (BHT), 0.80 gram of magnesium stearate is sequentially added to be well mixed, it is standby.
The preparation of bi-layer troche core：
Double-deck ingot is made with double-deck Ingot pressing machine according to recipe quantity with pushing layer in said medicine layer, first, by 250 milligrams push away
Squeeze to be placed in mold cavity and carry out precompressed, then 75 milligrams of medicine is placed on to the double-deck ingot that appropriate hardness is pressed into mold cavity
Agent core.
The preparation of pellicle：
Preparing acetyl cellulose/polyethylene glycol film is matched somebody with somebody with 257.4 grams of cellulose acetate and 2.60 grams of Macrogol 6000
Clothing liquid, solvent is configured to 5% film clothing liquid, film clothing liquid uniformly is coated on into double-deck ingot with film clothing machine with the cosolvent of acetone/water
In agent core, the lozenge for completing film clothing is dried 48 hours under 45 DEG C of environment, to remove residual solvent.
The punching of pellicle：
One 0.3 millimeter of hole is drilled through with pellicle of the laser boring mode above medicine layer.
The preparation of moisture film clothing：
With 351.0 gramsII is preparedII film clothing liquid, works as solvent with pure water, then equal with film clothing machine
It is even that above-mentioned film clothing liquid is coated in bi-layer troche.
The drug delivery system of above-mentioned preparation is subjected to dissolving-separating test, as a result as shown in Figure 3.
Embodiment 4
The preparation (4) of this exposure drug delivery system
The preparation of medicine layer：
676.2 grams of hydroxypropyl celluloses (HPC) and 60.0 grams of 9-hydroxy-risperidone (paliperidone) are square to dissipate again
Method is uniformly mixed, then sequentially add 58.2 grams hydroxypropyl methyl cellulose (HPMC), 200.0 grams of sodium chloride, 0.50 gram
Dibutyl hydroxy toluene (BHT) is well mixed, finally, and the magnesium stearate for adding 5.10 grams is mixed, standby.
Push the preparation of layer：
First, bonding solution is prepared, 144.5 grams of PVP K30 is dissolved in pure water, 13% PVP is configured to
(PVP) solution, then 487.0 grams of sodium chloride is together dissolved, then, by the low of 73.5 grams of iron oxide red and 1791.7 grams
Substitution hydroxypropyl cellulose (L-HPC, hydroxypropyl content 14%) is inserted in granulation pot, and spray solution will be binded extremely with spray pattern
Granulate in pot, it is uniformly binded.Particle is with oven drying to acceptable humidity after granulating, with 16 eye mesh screen whole grains, then
2.50 grams of dibutyl hydroxy toluene (BHT), 0.80 gram of magnesium stearate is sequentially added to be well mixed, it is standby.
The preparation of bi-layer troche core：
Double-deck ingot is made with double-deck Ingot pressing machine according to recipe quantity with pushing layer in said medicine layer, first, by 250 milligrams push away
Squeeze to be placed in mold cavity and carry out precompressed, then 100 milligrams of medicine is placed on to the bilayer that appropriate hardness is pressed into mold cavity
Dragee cores.
The preparation of pellicle：
Preparing acetyl cellulose/polyethylene glycol film is matched somebody with somebody with 277.2 grams of cellulose acetate and 2.80 grams of Macrogol 6000
Clothing liquid, solvent is configured to 5% film clothing liquid, film clothing liquid uniformly is coated on into double-deck ingot with film clothing machine with the cosolvent of acetone/water
In agent core, the lozenge for completing film clothing is dried 48 hours under 45 DEG C of environment, to remove residual solvent.
The punching of pellicle：
One 0.3 millimeter of hole is drilled through with pellicle of the laser boring mode above medicine layer.
The preparation of moisture film clothing：
With 378.0 gramsII is preparedII film clothing liquid, works as solvent with pure water, then equal with film clothing machine
It is even that above-mentioned film clothing liquid is coated in bi-layer troche.
The drug delivery system of above-mentioned preparation is subjected to dissolving-separating test, as a result as shown in Figure 3.
Embodiment 5
The preparation (5) of this exposure drug delivery system
The preparation of medicine layer：
676.2 grams of hydroxypropyl celluloses (HPC) and 60.0 grams of 9-hydroxy-risperidone (paliperidone) are square to dissipate again
Method is uniformly mixed, then sequentially add 58.2 grams hydroxypropyl methyl cellulose (HPMC), 200.0 grams of sodium chloride, 0.50 gram
Dibutyl hydroxy toluene (BHT) is well mixed, finally, and the magnesium stearate for adding 5.10 grams is mixed, standby.
Push the preparation of layer：
First, bonding solution is prepared, 115.6 grams of PVP K30 is dissolved in pure water, 13% PVP is configured to
(PVP) solution, then 200.0 grams of sodium chloride is together dissolved, then, by the low of 58.8 grams of iron oxide red and 1623.0 grams
Substitution hydroxypropyl cellulose (L-HPC, hydroxypropyl content 14%) is inserted in granulation pot, and spray solution will be binded extremely with spray pattern
Granulate in pot, it is uniformly binded.Particle is with oven drying to acceptable humidity after granulating, with 16 eye mesh screen whole grains, then
2.00 grams of dibutyl hydroxy toluene (BHT), 0.60 gram of magnesium stearate is sequentially added to be well mixed, it is standby.
The preparation of bi-layer troche core：
Double-deck ingot is made with double-deck Ingot pressing machine according to recipe quantity with pushing layer in said medicine layer, first, by 200 milligrams push away
Squeeze to be placed in mold cavity and carry out precompressed, then 100 milligrams of medicine is placed on to the bilayer that appropriate hardness is pressed into mold cavity
Dragee cores.
The preparation of pellicle：
Preparing acetyl cellulose/polyethylene glycol film is matched somebody with somebody with 237.6 grams of cellulose acetate and 2.40 grams of Macrogol 6000
Clothing liquid, solvent is configured to 5% film clothing liquid, film clothing liquid uniformly is coated on into double-deck ingot with film clothing machine with the cosolvent of acetone/water
In agent core, the lozenge for completing film clothing is dried 48 hours under 45 DEG C of environment, to remove residual solvent.
The punching of pellicle：
One 0.3 millimeter of hole is drilled through with pellicle of the laser boring mode above medicine layer.
The preparation of moisture film clothing：
With 324.0 gramsII is preparedII film clothing liquid, works as solvent with pure water, then equal with film clothing machine
It is even that above-mentioned film clothing liquid is coated in bi-layer troche.
The drug delivery system of above-mentioned preparation is subjected to dissolving-separating test, as a result as shown in Figure 3.
Above-described embodiment 1~5 is the ratio (D/P ratio) for adjusting drug delivery system drug layer with pushing layer, its
It is molten from releasing result as shown in the 2nd, 3 figures, can be seen that in figure, this exposure 9-hydroxy-risperidone bi-layer troche is in D/P ratio=1/5
Control release effect can be reached between~1/2 within a certain period of time, and release rate has the trend gradually risen, insoluble drug release can
Up to more than 14 hours.
Embodiment 6
The preparation (6) of this exposure drug delivery system
The preparation of medicine layer：
676.2 grams of hydroxypropyl celluloses (HPC) and 60.0 grams of 9-hydroxy-risperidone (paliperidone) are square to dissipate again
Method is uniformly mixed, then sequentially add 58.2 grams hydroxypropyl methyl cellulose (HPMC), 200.0 grams of sodium chloride, 0.50 gram
Dibutyl hydroxy toluene (BHT) is well mixed, finally, and the magnesium stearate for adding 5.10 grams is mixed, standby.
Push the preparation of layer：
First, bonding solution is prepared, 115.6 grams of PVP K30 is dissolved in pure water, 13% PVP is configured to
(PVP) solution, then 200.0 grams of sodium chloride is together dissolved, then, by the low of 58.8 grams of iron oxide red and 1623.0 grams
Substitution hydroxypropyl cellulose (L-HPC, hydroxypropyl content 14%) is inserted in granulation pot, and spray solution will be binded extremely with spray pattern
Granulate in pot, it is uniformly binded.Particle is with oven drying to acceptable humidity after granulating, with 16 eye mesh screen whole grains, then
2.00 grams of dibutyl hydroxy toluene (BHT), 0.60 gram of magnesium stearate is sequentially added to be well mixed, it is standby.
The preparation of bi-layer troche core：
Double-deck ingot is made with double-deck Ingot pressing machine according to recipe quantity with pushing layer in said medicine layer, first, by 200 milligrams push away
Squeeze to be placed in mold cavity and carry out precompressed, then 100 milligrams of medicine is placed on to the bilayer that appropriate hardness is pressed into mold cavity
Dragee cores.
The preparation of pellicle：
Preparing acetyl cellulose/polyethylene glycol film is matched somebody with somebody with 228.0 grams of cellulose acetate and 12.0 grams of Macrogol 6000
Clothing liquid, solvent is configured to 5% film clothing liquid, film clothing liquid uniformly is coated on into double-deck ingot with film clothing machine with the cosolvent of acetone/water
In agent core, the lozenge for completing film clothing is dried 48 hours under 45 DEG C of environment, to remove residual solvent.
The punching of pellicle：
One 0.3 millimeter of hole is drilled through with pellicle of the laser boring mode above medicine layer.
The preparation of moisture film clothing：
With 324.0 gramsII is preparedII film clothing liquid, works as solvent with pure water, then equal with film clothing machine
It is even that above-mentioned film clothing liquid is coated in bi-layer troche.
The drug delivery system of above-mentioned preparation is subjected to dissolving-separating test, as a result as shown in Figure 4.
Embodiment 7
The preparation (7) of this exposure drug delivery system
The preparation of medicine layer：
676.2 grams of hydroxypropyl celluloses (HPC) and 60.0 grams of 9-hydroxy-risperidone (paliperidone) are square to dissipate again
Method is uniformly mixed, then sequentially add 58.2 grams hydroxypropyl methyl cellulose (HPMC), 200.0 grams of sodium chloride, 0.50 gram
Dibutyl hydroxy toluene (BHT) is well mixed, finally, and the magnesium stearate for adding 5.10 grams is mixed, standby.
Push the preparation of layer：
First, bonding solution is prepared, 115.6 grams of PVP K30 is dissolved in pure water, 13% PVP is configured to
(PVP) solution, then 200.0 grams of sodium chloride is together dissolved, then, by the low of 58.8 grams of iron oxide red and 1623.0 grams
Substitution hydroxypropyl cellulose (L-HPC, hydroxypropyl content 14%) is inserted in granulation pot, and spray solution will be binded extremely with spray pattern
Granulate in pot, it is uniformly binded.Particle is with oven drying to acceptable humidity after granulating, with 16 eye mesh screen whole grains, then
2.00 grams of dibutyl hydroxy toluene (BHT), 0.60 gram of magnesium stearate is sequentially added to be well mixed, it is standby.
The preparation of bi-layer troche core：
Double-deck ingot is made with double-deck Ingot pressing machine according to recipe quantity with pushing layer in said medicine layer, first, by 200 milligrams push away
Squeeze to be placed in mold cavity and carry out precompressed, then 100 milligrams of medicine is placed on to the bilayer that appropriate hardness is pressed into mold cavity
Dragee cores.
The preparation of pellicle：
Preparing acetyl cellulose/polyethylene glycol film is matched somebody with somebody with 237.6 grams of cellulose acetate and 2.40 grams of PEG3350
Clothing liquid, solvent is configured to 5% film clothing liquid, film clothing liquid uniformly is coated on into double-deck ingot with film clothing machine with the cosolvent of acetone/water
In agent core, the lozenge for completing film clothing is dried 48 hours under 45 DEG C of environment, to remove residual solvent.
The punching of pellicle：
One 0.3 millimeter of hole is drilled through with pellicle of the laser boring mode above medicine layer.
The preparation of moisture film clothing：
With 324.0 gramsII is preparedII film clothing liquid, works as solvent with pure water, then equal with film clothing machine
It is even that above-mentioned film clothing liquid is coated in bi-layer troche.
The drug delivery system of above-mentioned preparation is subjected to dissolving-separating test, as a result as shown in Figure 4.
Embodiment 8
The preparation (8) of this exposure drug delivery system
The preparation of medicine layer：
676.2 grams of hydroxypropyl celluloses (HPC) and 60.0 grams of 9-hydroxy-risperidone (paliperidone) are square to dissipate again
Method is uniformly mixed, then sequentially add 58.2 grams hydroxypropyl methyl cellulose (HPMC), 200.0 grams of sodium chloride, 0.50 gram
Dibutyl hydroxy toluene (BHT) is well mixed, finally, and the magnesium stearate for adding 5.10 grams is mixed, standby.
Push the preparation of layer：
First, bonding solution is prepared, 115.6 grams of PVP K30 is dissolved in pure water, 13% PVP is configured to
(PVP) solution, then 200.0 grams of sodium chloride is together dissolved, then, by the low of 58.8 grams of iron oxide red and 1623.0 grams
Substitution hydroxypropyl cellulose (L-HPC, hydroxypropyl content 14%) is inserted in granulation pot, and spray solution will be binded extremely with spray pattern
Granulate in pot, it is uniformly binded.Particle is with oven drying to acceptable humidity after granulating, with 16 eye mesh screen whole grains, then
2.00 grams of dibutyl hydroxy toluene (BHT), 0.60 gram of magnesium stearate is sequentially added to be well mixed, it is standby.
The preparation of bi-layer troche core：
Double-deck ingot is made with double-deck Ingot pressing machine according to recipe quantity with pushing layer in said medicine layer, first, by 200 milligrams push away
Squeeze to be placed in mold cavity and carry out precompressed, then 100 milligrams of medicine is placed on to the bilayer that appropriate hardness is pressed into mold cavity
Dragee cores.
The preparation of pellicle：
Preparing acetyl cellulose/polyethylene glycol film is matched somebody with somebody with 228.0 grams of cellulose acetate and 12.0 grams of PEG3350
Clothing liquid, solvent is configured to 5% film clothing liquid, film clothing liquid uniformly is coated on into double-deck ingot with film clothing machine with the cosolvent of acetone/water
In agent core, the lozenge for completing film clothing is dried 48 hours under 45 DEG C of environment, to remove residual solvent.
The punching of pellicle：
One 0.3 millimeter of hole is drilled through with pellicle of the laser boring mode above medicine layer.
The preparation of moisture film clothing：
With 324.0 gramsII is preparedII film clothing liquid, works as solvent with pure water, then equal with film clothing machine
It is even that above-mentioned film clothing liquid is coated in bi-layer troche.
The drug delivery system of above-mentioned preparation is subjected to dissolving-separating test, as a result as shown in Figure 4.
Above-described embodiment 5~8 is the molecular weight for adjusting pellicle polyethylene glycol (PEG) in drug delivery system, and vinegar
The ratio of acid cellulose and polyethylene glycol, its it is molten from releasing result as shown in figure 4, can be seen that in figure, this exposure 9-hydroxy-risperidone
Bi-layer troche is from the polyethylene glycol of different molecular weight (6,000 and 3,350) and the ratio of different cellulose acetates, same tool
The effect for having control release and slowly discharging.
Embodiment 9
The preparation (9) of this exposure drug delivery system
The preparation of medicine layer：
676.2 grams of hydroxypropyl celluloses (HPC) and 60.0 grams of 9-hydroxy-risperidone (paliperidone) are square to dissipate again
Method is uniformly mixed, then sequentially add 58.2 grams hydroxypropyl methyl cellulose (HPMC), 200.0 grams of sodium chloride, 0.50 gram
Dibutyl hydroxy toluene (BHT) is well mixed, finally, and the magnesium stearate for adding 5.10 grams is mixed, standby.
Push the preparation of layer：
First, bonding solution is prepared, 116.0 grams of PVP K30 is dissolved in pure water, 13% PVP is configured to
(PVP) solution, then 200.0 grams of sodium chloride is together dissolved, then, by the low of 58.0 grams of iron oxide red and 1603.0 grams
Substitution hydroxypropyl cellulose (L-HPC, hydroxypropyl content 8%) is inserted in granulation pot, and spray solution will be binded extremely with spray pattern
Granulate in pot, it is uniformly binded.Particle is with oven drying to acceptable humidity after granulating, with 16 eye mesh screen whole grains, then
The dibutyl hydroxy toluene (BHT), 20.0 grams of silica, the mixing of 1.00 grams of magnesium stearate for sequentially adding 2.00 grams are equal
It is even, it is standby.
The preparation of bi-layer troche core：
Double-deck ingot is made with double-deck Ingot pressing machine according to recipe quantity with pushing layer in said medicine layer, first, by 200 milligrams push away
Squeeze to be placed in mold cavity and carry out precompressed, then 100 milligrams of medicine is placed on to the bilayer that appropriate hardness is pressed into mold cavity
Dragee cores.
The preparation of pellicle：
Preparing acetyl cellulose/polyethylene glycol film is matched somebody with somebody with 171.0 grams of cellulose acetate and 9.00 grams of PEG3350
Clothing liquid, solvent is configured to 5% film clothing liquid, film clothing liquid uniformly is coated on into double-deck ingot with film clothing machine with the cosolvent of acetone/water
In agent core, the lozenge for completing film clothing is dried 48 hours under 45 DEG C of environment, to remove residual solvent.
The punching of pellicle：
One 0.3 millimeter of hole is drilled through with pellicle of the laser boring mode above medicine layer.
The preparation of moisture film clothing：
With 318.0 gramsII is preparedII film clothing liquid, works as solvent with pure water, then equal with film clothing machine
It is even that above-mentioned film clothing liquid is coated in bi-layer troche.
The drug delivery system of above-mentioned preparation is subjected to dissolving-separating test, as a result as shown in Figure 5.
Embodiment 10
The preparation (10) of this exposure drug delivery system
The preparation of medicine layer：
676.2 grams of hydroxypropyl celluloses (HPC) and 60.0 grams of 9-hydroxy-risperidone (paliperidone) are square to dissipate again
Method is uniformly mixed, then sequentially add 58.2 grams hydroxypropyl methyl cellulose (HPMC), 200.0 grams of sodium chloride, 0.50 gram
Dibutyl hydroxy toluene (BHT) is well mixed, finally, and the magnesium stearate for adding 5.10 grams is mixed, standby.
Push the preparation of layer：
First, bonding solution is prepared, 116.0 grams of PVP K30 is dissolved in pure water, 13% PVP is configured to
(PVP) solution, then 200.0 grams of sodium chloride is together dissolved, then, by the low of 58.0 grams of iron oxide red and 1603.0 grams
Substitution hydroxypropyl cellulose (L-HPC, hydroxypropyl content 8%) is inserted in granulation pot, and spray solution will be binded extremely with spray pattern
Granulate in pot, it is uniformly binded.Particle is with oven drying to acceptable humidity after granulating, with 16 eye mesh screen whole grains, then
The dibutyl hydroxy toluene (BHT), 20.0 grams of silica, the mixing of 1.00 grams of magnesium stearate for sequentially adding 2.00 grams are equal
It is even, it is standby.
The preparation of bi-layer troche core：
Double-deck ingot is made with double-deck Ingot pressing machine according to recipe quantity with pushing layer in said medicine layer, first, by 200 milligrams push away
Squeeze to be placed in mold cavity and carry out precompressed, then 100 milligrams of medicine is placed on to the bilayer that appropriate hardness is pressed into mold cavity
Dragee cores.
The preparation of pellicle：
Preparing acetyl cellulose/polyethylene glycol film is matched somebody with somebody with 228.0 grams of cellulose acetate and 12.0 grams of PEG3350
Clothing liquid, solvent is configured to 5% film clothing liquid, film clothing liquid uniformly is coated on into double-deck ingot with film clothing machine with the cosolvent of acetone/water
In agent core, the lozenge for completing film clothing is dried 48 hours under 45 DEG C of environment, to remove residual solvent.
The punching of pellicle：
One 0.3 millimeter of hole is drilled through with pellicle of the laser boring mode above medicine layer.
The preparation of moisture film clothing：
With 324.0 gramsII is preparedII film clothing liquid, works as solvent with pure water, then equal with film clothing machine
It is even that above-mentioned film clothing liquid is coated in bi-layer troche.
The drug delivery system of above-mentioned preparation is subjected to dissolving-separating test, as a result as shown in Figure 5.
Embodiment 11
The preparation (11) of this exposure drug delivery system
The preparation of medicine layer：
676.2 grams of hydroxypropyl celluloses (HPC) and 60.0 grams of 9-hydroxy-risperidone (paliperidone) are square to dissipate again
Method is uniformly mixed, then sequentially add 58.2 grams hydroxypropyl methyl cellulose (HPMC), 200.0 grams of sodium chloride, 0.50 gram
Dibutyl hydroxy toluene (BHT) is well mixed, finally, and the magnesium stearate for adding 5.10 grams is mixed, standby.
Push the preparation of layer：
First, bonding solution is prepared, 116.0 grams of PVP K30 is dissolved in pure water, 13% PVP is configured to
(PVP) solution, then 200.0 grams of sodium chloride is together dissolved, then, by the low of 58.0 grams of iron oxide red and 1603.0 grams
Substitution hydroxypropyl cellulose (L-HPC, hydroxypropyl content 8%) is inserted in granulation pot, and spray solution will be binded extremely with spray pattern
Granulate in pot, it is uniformly binded.Particle is with oven drying to acceptable humidity after granulating, with 16 eye mesh screen whole grains, then
The dibutyl hydroxy toluene (BHT), 20.0 grams of silica, the mixing of 1.00 grams of magnesium stearate for sequentially adding 2.00 grams are equal
It is even, it is standby.
The preparation of bi-layer troche core：
Double-deck ingot is made with double-deck Ingot pressing machine according to recipe quantity with pushing layer in said medicine layer, first, by 200 milligrams push away
Squeeze to be placed in mold cavity and carry out precompressed, then 100 milligrams of medicine is placed on to the bilayer that appropriate hardness is pressed into mold cavity
Dragee cores.
The preparation of pellicle：
Preparing acetyl cellulose/polyethylene glycol film is matched somebody with somebody with 216.0 grams of cellulose acetate and 24.0 grams of PEG3350
Clothing liquid, solvent is configured to 5% film clothing liquid, film clothing liquid uniformly is coated on into double-deck ingot with film clothing machine with the cosolvent of acetone/water
In agent core, the lozenge for completing film clothing is dried 48 hours under 45 DEG C of environment, to remove residual solvent.
The punching of pellicle：
One 0.3 millimeter of hole is drilled through with pellicle of the laser boring mode above medicine layer.
The preparation of moisture film clothing：
With 324.0 gramsII is preparedII film clothing liquid, works as solvent with pure water, then equal with film clothing machine
It is even that above-mentioned film clothing liquid is coated in bi-layer troche.
The drug delivery system of above-mentioned preparation is subjected to dissolving-separating test, as a result as shown in Figure 5.
Embodiment 12
The preparation (12) of this exposure drug delivery system
The preparation of medicine layer：
676.2 grams of hydroxypropyl celluloses (HPC) and 60.0 grams of 9-hydroxy-risperidone (paliperidone) are square to dissipate again
Method is uniformly mixed, then sequentially add 58.2 grams hydroxypropyl methyl cellulose (HPMC), 200.0 grams of sodium chloride, 0.50 gram
Dibutyl hydroxy toluene (BHT) is well mixed, finally, and the magnesium stearate for adding 5.10 grams is mixed, standby.
Push the preparation of layer：
First, bonding solution is prepared, 116.0 grams of PVP K30 is dissolved in pure water, 13% PVP is configured to
(PVP) solution, then 200.0 grams of sodium chloride is together dissolved, then, by the low of 58.0 grams of iron oxide red and 1603.0 grams
Substitution hydroxypropyl cellulose (L-HPC, hydroxypropyl content 8%) is inserted in granulation pot, and spray solution will be binded extremely with spray pattern
Granulate in pot, it is uniformly binded.Particle is with oven drying to acceptable humidity after granulating, with 16 eye mesh screen whole grains, then
The dibutyl hydroxy toluene (BHT), 20.0 grams of silica, the mixing of 1.00 grams of magnesium stearate for sequentially adding 2.00 grams are equal
It is even, it is standby.
The preparation of bi-layer troche core：
Double-deck ingot is made with double-deck Ingot pressing machine according to recipe quantity with pushing layer in said medicine layer, first, by 200 milligrams push away
Squeeze to be placed in mold cavity and carry out precompressed, then 100 milligrams of medicine is placed on to the bilayer that appropriate hardness is pressed into mold cavity
Dragee cores.
The preparation of pellicle：
Preparing acetyl cellulose/polyethylene glycol film is matched somebody with somebody with 324.0 grams of cellulose acetate and 36.0 grams of PEG3350
Clothing liquid, solvent is configured to 5% film clothing liquid, film clothing liquid uniformly is coated on into double-deck ingot with film clothing machine with the cosolvent of acetone/water
In agent core, the lozenge for completing film clothing is dried 48 hours under 45 DEG C of environment, to remove residual solvent.
The punching of pellicle：
One 0.3 millimeter of hole is drilled through with pellicle of the laser boring mode above medicine layer.
The preparation of moisture film clothing：
With 336.0 gramsII is preparedII film clothing liquid, works as solvent with pure water, then equal with film clothing machine
It is even that above-mentioned film clothing liquid is coated in bi-layer troche.
The drug delivery system of above-mentioned preparation is subjected to dissolving-separating test, as a result as shown in Figure 5.
Embodiment 13
The preparation (13) of this exposure drug delivery system
The preparation of medicine layer：
676.2 grams of hydroxypropyl celluloses (HPC) and 60.0 grams of 9-hydroxy-risperidone (paliperidone) are square to dissipate again
Method is uniformly mixed, then sequentially add 58.2 grams hydroxypropyl methyl cellulose (HPMC), 200.0 grams of sodium chloride, 0.50 gram
Dibutyl hydroxy toluene (BHT) is well mixed, finally, and the magnesium stearate for adding 5.10 grams is mixed, standby.
Push the preparation of layer：
First, bonding solution is prepared, 116.0 grams of PVP K30 is dissolved in pure water, 13% PVP is configured to
(PVP) solution, then 200.0 grams of sodium chloride is together dissolved, then, by the low of 58.0 grams of iron oxide red and 1603.0 grams
Substitution hydroxypropyl cellulose (L-HPC, hydroxypropyl content 8%) is inserted in granulation pot, and spray solution will be binded extremely with spray pattern
Granulate in pot, it is uniformly binded.Particle is with oven drying to acceptable humidity after granulating, with 16 eye mesh screen whole grains, then
The dibutyl hydroxy toluene (BHT), 20.0 grams of silica, the mixing of 1.00 grams of magnesium stearate for sequentially adding 2.00 grams are equal
It is even, it is standby.
The preparation of bi-layer troche core：
Double-deck ingot is made with double-deck Ingot pressing machine according to recipe quantity with pushing layer in said medicine layer, first, by 200 milligrams push away
Squeeze to be placed in mold cavity and carry out precompressed, then 100 milligrams of medicine is placed on to the bilayer that appropriate hardness is pressed into mold cavity
Dragee cores.
The preparation of pellicle：
Preparing acetyl cellulose/polyethylene glycol film is matched somebody with somebody with 432.0 grams of cellulose acetate and 48.0 grams of PEG3350
Clothing liquid, solvent is configured to 5% film clothing liquid, film clothing liquid uniformly is coated on into double-deck ingot with film clothing machine with the cosolvent of acetone/water
In agent core, the lozenge for completing film clothing is dried 48 hours under 45 DEG C of environment, to remove residual solvent.
The punching of pellicle：
One 0.3 millimeter of hole is drilled through with pellicle of the laser boring mode above medicine layer.
The preparation of moisture film clothing：
With 348.0 gramsII is preparedII film clothing liquid, works as solvent with pure water, then equal with film clothing machine
It is even that above-mentioned film clothing liquid is coated in bi-layer troche.
The drug delivery system of above-mentioned preparation is subjected to dissolving-separating test, as a result as shown in Figure 5.
Above-described embodiment 9~13 is the thickness for adjusting pellicle in drug delivery system, and its is molten from releasing result such as Fig. 5 institutes
Show, can be seen that in figure, this exposure 9-hydroxy-risperidone bi-layer troche can reach for a long time from the pellicle of different weight percentage
The effect of release.
Comparing embodiment 1
The preparation (1) of drug delivery system
The preparation of medicine layer：
By the 9-hydroxy-risperidone (paliperidone) of 1407.8 grams of N80 and 60.0 gram of poly- (oxirane) to dissipate method again
Uniform mixing, then the sequentially hydroxypropyl methyl cellulose (HPMC) of 120.6 grams of addition, 400.0 grams of sodium chloride, the two of 1.00 grams
Butylated hydroxytoluene (BHT) is well mixed, finally, and the magnesium stearate for adding 10.6 grams is mixed, standby.
Push the preparation of layer：
811.5 grams of poly- (oxirane) Coagulant is uniformly mixed with 29.4 grams of iron oxide red with dissipating method again,
Again sequentially add 57.8 grams PVP K30,100.0 grams of sodium chloride, 1.00 grams of dibutyl hydroxy toluene (BHT), 0.30
Gram magnesium stearate be well mixed, it is standby.
The preparation of bi-layer troche core：
Double-deck ingot is made with double-deck Ingot pressing machine according to recipe quantity with pushing layer in said medicine layer, first, by 200 milligrams of medicine
Nitride layer, which is placed in mold cavity, carries out precompressed, then 100 milligrams of pushing is placed on to the bilayer that appropriate hardness is pressed into mold cavity
Dragee cores.
The preparation of pellicle：
Preparing acetyl cellulose/polyethylene glycol film is matched somebody with somebody with 228.0 grams of cellulose acetate and 12.0 grams of PEG3350
Clothing liquid, solvent is configured to 5% film clothing liquid, film clothing liquid uniformly is coated on into double-deck ingot with film clothing machine with the cosolvent of acetone/water
In agent core, the lozenge for completing film clothing is dried 48 hours under 45 DEG C of environment, to remove residual solvent.
The punching of pellicle：
One 0.3 millimeter of hole is drilled through with pellicle of the laser boring mode above medicine layer.
The preparation of moisture film clothing：
With 324.0 gramsII is preparedII film clothing liquid, works as solvent with pure water, then equal with film clothing machine
It is even that above-mentioned film clothing liquid is coated in bi-layer troche.
The drug delivery system of above-mentioned preparation is subjected to dissolving-separating test, as a result as shown in Figure 6.
Above-mentioned comparing embodiment 1, which is medicine layer respectively in drug delivery system and pushes layer, uses poly- (oxirane)
(PEO), its it is molten from releasing result as shown in fig. 6, can be seen that in figure, the medicine layer of the 9-hydroxy-risperidone bi-layer troche and push layer
Control release effect can be reached within a certain period of time from poly- (oxirane), and insoluble drug release was up to more than 18 hours.
Comparing embodiment 2
The preparation (2) of drug delivery system
The preparation of medicine layer：
1597.1 grams of hydroxypropyl celluloses (HPC) and 60.0 grams of 9-hydroxy-risperidone (paliperidone) are square to dissipate again
Method is uniformly mixed, then sequentially add 130.5 grams hydroxypropyl methyl cellulose (HPMC), 450.0 grams of sodium chloride, 1.10 grams
Dibutyl hydroxy toluene (BHT) is well mixed, finally, and the magnesium stearate for adding 11.3 grams is mixed, standby.
Push the preparation of layer：
First, bonding solution is prepared, 29.0 grams of PVP K30 is dissolved in pure water, 13% PVP is configured to
(PVP) solution, then 50.0 grams of sodium chloride is together dissolved, then, low by 14.5 grams of iron oxide red and 400.8 grams takes
Inserted for hydroxypropyl cellulose (L-HPC, hydroxypropyl content 14%) in granulation pot, spray solution will be binded to making with spray pattern
In grain pot, it is set uniformly to bind.Particle is with oven drying to acceptable humidity after granulating, with 16 eye mesh screen whole grains, then according to
The dibutyl hydroxy toluene (BHT), 5.00 grams of silica, 0.30 gram of magnesium stearate that sequence adds 0.50 gram are well mixed,
It is standby.
The preparation of bi-layer troche core：
Double-deck ingot is made with double-deck Ingot pressing machine according to recipe quantity with pushing layer in said medicine layer, first, by 225 milligrams of medicine
Nitride layer, which is placed in mold cavity, carries out precompressed, then 50 milligrams of pushing is placed on to the double-deck ingot that appropriate hardness is pressed into mold cavity
Agent core.
The preparation of pellicle：
Preparing acetyl cellulose/polyethylene glycol film is matched somebody with somebody with 209.0 grams of cellulose acetate and 11.0 grams of PEG3350
Clothing liquid, solvent is configured to 5% film clothing liquid, film clothing liquid uniformly is coated on into double-deck ingot with film clothing machine with the cosolvent of acetone/water
In agent core, the lozenge for completing film clothing is dried 48 hours under 45 DEG C of environment, to remove residual solvent.
The punching of pellicle：
One 0.3 millimeter of hole is drilled through with pellicle of the laser boring mode above medicine layer.
The preparation of moisture film clothing：
With 297.0 gramsII is preparedII film clothing liquid, works as solvent with pure water, then equal with film clothing machine
It is even that above-mentioned film clothing liquid is coated in bi-layer troche.
The drug delivery system of above-mentioned preparation is subjected to dissolving-separating test, as a result as shown in Figure 7.
Above-mentioned comparing embodiment 2 is to release medicine system drug layer to adjust with pushing the ratio (D/P ratio) of layer
Into 4.5/1, its it is molten from releasing result as shown in fig. 7, substantially can be seen that in figure, the pushing layer nothing of the 9-hydroxy-risperidone bi-layer troche
Method promotes medicine layer to promote insoluble drug release, only discharges medicine, final 24 hours drug release rates only 34% with diffusion way.
Comparing embodiment 3
The preparation (3) of drug delivery system
The preparation of medicine layer：
676.2 grams of hydroxypropyl celluloses (HPC) and 60.0 grams of 9-hydroxy-risperidone (paliperidone) are square to dissipate again
Method is uniformly mixed, then sequentially add 58.2 grams hydroxypropyl methyl cellulose (HPMC), 200.0 grams of sodium chloride, 0.50 gram
Dibutyl hydroxy toluene (BHT) is well mixed, finally, and the magnesium stearate for adding 5.10 grams is mixed, standby.
Push the preparation of layer：
First, bonding solution is prepared, 116.0 grams of PVP K30 is dissolved in pure water, 13% PVP is configured to
(PVP) solution, then 200.0 grams of sodium chloride is together dissolved, then, by the low of 58.0 grams of iron oxide red and 1603.0 grams
Substitution hydroxypropyl cellulose (L-HPC, hydroxypropyl content 8%) is inserted in granulation pot, and spray solution will be binded extremely with spray pattern
Granulate in pot, it is uniformly binded.Particle is with oven drying to acceptable humidity after granulating, with 16 eye mesh screen whole grains, then
The dibutyl hydroxy toluene (BHT), 20.0 grams of silica, the mixing of 1.00 grams of magnesium stearate for sequentially adding 2.00 grams are equal
It is even, it is standby.
The preparation of bi-layer troche core：
Double-deck ingot is made with double-deck Ingot pressing machine according to recipe quantity with pushing layer in said medicine layer, first, by 200 milligrams push away
Squeeze to be placed in mold cavity and carry out precompressed, then 100 milligrams of medicine is placed on to the bilayer that appropriate hardness is pressed into mold cavity
Dragee cores.
The preparation of pellicle：
Preparing acetyl cellulose/polyethylene glycol film clothing is matched somebody with somebody with 85.5 grams of cellulose acetate and 4.5 grams of PEG3350
Liquid, solvent is configured to 5% film clothing liquid, film clothing liquid uniformly is coated on into bi-layer troche with film clothing machine with the cosolvent of acetone/water
In core, the lozenge for completing film clothing is dried 48 hours under 45 DEG C of environment, to remove residual solvent.
The punching of pellicle：
One 0.3 millimeter of hole is drilled through with pellicle of the laser boring mode above medicine layer.
The preparation of moisture film clothing：
With 309.0 gramsII is preparedII film clothing liquid, works as solvent with pure water, then equal with film clothing machine
It is even that above-mentioned film clothing liquid is coated in bi-layer troche.
The drug delivery system of above-mentioned preparation is subjected to dissolving-separating test, as a result as shown in Figure 8.
Above-mentioned comparing embodiment 3 is to reduce the weight percent of pellicle in drug delivery system, and its is molten from releasing result
As shown in figure 8, can be seen that in figure, the 9-hydroxy-risperidone bi-layer troche is relatively thin because of pellicle, and moisture content rapidly enters dragee cores, causes
Medicine discharged 99% at 12 hours, though with control release effect, it was found that, having 50% during insoluble drug release
Probability pellicle can split, and increase burst drug release risk, influence patient safe.
Comparing embodiment 4
The preparation (4) of drug delivery system
The preparation of medicine layer：
676.2 grams of hydroxypropyl celluloses (HPC) and 60.0 grams of 9-hydroxy-risperidone (paliperidone) are square to dissipate again
Method is uniformly mixed, then sequentially add 58.2 grams hydroxypropyl methyl cellulose (HPMC), 200.0 grams of sodium chloride, 0.50 gram
Dibutyl hydroxy toluene (BHT) is well mixed, finally, and the magnesium stearate for adding 5.10 grams is mixed, standby.
Push the preparation of layer：
First, bonding solution is prepared, 1519.0 grams of PVP K30 is dissolved in pure water, 13% PVP is configured to
(PVP) solution, then 200.0 grams of sodium chloride is together dissolved, then, by the low of 58.0 grams of iron oxide red and 200.0 grams
Substitution hydroxypropyl cellulose (L-HPC, hydroxypropyl content 8%) is inserted in granulation pot, and spray solution will be binded extremely with spray pattern
Granulate in pot, it is uniformly binded.Particle is with oven drying to acceptable humidity after granulating, with 16 eye mesh screen whole grains, then
The dibutyl hydroxy toluene (BHT), 20.0 grams of silica, the mixing of 1.00 grams of magnesium stearate for sequentially adding 2.00 grams are equal
It is even, it is standby.
The preparation of bi-layer troche core：
Double-deck ingot is made with double-deck Ingot pressing machine according to recipe quantity with pushing layer in said medicine layer, first, by 200 milligrams push away
Squeeze to be placed in mold cavity and carry out precompressed, then 100 milligrams of medicine is placed on to the bilayer that appropriate hardness is pressed into mold cavity
Dragee cores.
The preparation of pellicle：
Preparing acetyl cellulose/polyethylene glycol film is matched somebody with somebody with 228.0 grams of cellulose acetate and 12.0 grams of PEG3350
Clothing liquid, solvent is configured to 5% film clothing liquid, film clothing liquid uniformly is coated on into double-deck ingot with film clothing machine with the cosolvent of acetone/water
In agent core, the lozenge for completing film clothing is dried 48 hours under 45 DEG C of environment, to remove residual solvent.
The punching of pellicle：
One 0.3 millimeter of hole is drilled through with pellicle of the laser boring mode above medicine layer.
The preparation of moisture film clothing：
With 324.0 gramsII is preparedII film clothing liquid, works as solvent with pure water, then equal with film clothing machine
It is even that above-mentioned film clothing liquid is coated in bi-layer troche.
The drug delivery system of above-mentioned preparation is subjected to dissolving-separating test, as a result as shown in Figure 9.
Above-mentioned comparing embodiment 4 is to release medicine low-substituted hydroxypropyl cellulose (L-HPC) institute that layer is pushed in system
Accounting example is down to 10%, its it is molten from releasing result as shown in figure 9, can be seen that in figure, when the 9-hydroxy-risperidone bi-layer troche is pushed
Low-substituted hydroxypropyl cellulose content in layer is too low, will be unable to smoothly push medicine and portals outside.
Comparing embodiment 5
The preparation (5) of drug delivery system
The preparation of medicine layer：
676.2 grams of hydroxypropyl celluloses (HPC) and 60.0 grams of 9-hydroxy-risperidone (paliperidone) are square to dissipate again
Method is uniformly mixed, then sequentially add 58.2 grams hydroxypropyl methyl cellulose (HPMC), 200.0 grams of sodium chloride, 0.50 gram
Dibutyl hydroxy toluene (BHT) is well mixed, finally, and the magnesium stearate for adding 5.10 grams is mixed, standby.
Push the preparation of layer：
1719.0 grams of hydroxypropyl celluloses (HPC) are uniformly mixed with 58.0 grams of iron oxide red with dissipating method again, then
Sequentially add 200.0 grams sodium chloride, 2.00 grams of dibutyl hydroxy toluene (BHT), 20.0 grams of silica, 1.00 grams
Magnesium stearate is well mixed, standby.
The preparation of bi-layer troche core：
Double-deck ingot is made with double-deck Ingot pressing machine according to recipe quantity with pushing layer in said medicine layer, first, by 200 milligrams push away
Squeeze to be placed in mold cavity and carry out precompressed, then 100 milligrams of medicine is placed on to the bilayer that appropriate hardness is pressed into mold cavity
Dragee cores.
The preparation of pellicle：
Preparing acetyl cellulose/polyethylene glycol film is matched somebody with somebody with 228.0 grams of cellulose acetate and 12.0 grams of PEG3350
Clothing liquid, solvent is configured to 5% film clothing liquid, film clothing liquid uniformly is coated on into double-deck ingot with film clothing machine with the cosolvent of acetone/water
In agent core, the lozenge for completing film clothing is dried 48 hours under 45 DEG C of environment, to remove residual solvent.
The punching of pellicle：
One 0.3 millimeter of hole is drilled through with pellicle of the laser boring mode above medicine layer.
The preparation of moisture film clothing：
With 324.0 gramsII is preparedII film clothing liquid, works as solvent with pure water, then equal with film clothing machine
It is even that above-mentioned film clothing liquid is coated in bi-layer troche.
The drug delivery system of above-mentioned preparation is subjected to dissolving-separating test, as a result as shown in Figure 10.
Above-mentioned comparing embodiment 5 is to release medicine the pushing layer material in system with hydroxypropyl cellulose (HPC) to replace,
Its is molten as shown in Figure 10 from releasing result, can be seen that in figure, and the pushing layer of the 9-hydroxy-risperidone bi-layer troche has no pushing release
Effect, and in ingot processing procedure is beaten, about 50% ingot sector-meeting sliver, it is impossible to smoothly break into ingot piece.
Comparing embodiment 6
Comparison medicine：Commercially available 9-hydroxy-risperidone is sustained ingot (trade name：6 milligrams).
Comparison medicine is tested according to the 9-hydroxy-risperidone bi-layer troche method for elution that U.S. FDA is announced：Stir paddle method,
Rotating speed 50rpm, eluat is configured to 500 milliliters for the 0.0825N hydrochloride buffer sodium chloride that adds 0.2%, as a result such as the 2nd~
Shown in 10 figures.
Although the present invention is disclosed above with several preferred embodiments, so it is not limited to the present invention, any ability
Domain those of ordinary skill, without departing from the spirit and scope of the present invention, arbitrarily changes and retouches when that can make, therefore the present invention
Protection domain when depending on after the attached claim person of defining be defined.
Claims (17)
1. a kind of drug delivery system, including：
One pellicle, its surface includes an at least hole, and the pellicle is enclosed including one first area and one second area, wherein this
One area is adjacent to the hole, and secondth area is away from the hole；
One medicine layer, firstth area enclosed positioned at the pellicle, medicine layer includes 9-hydroxy-risperidone and its pharmaceutically acceptable
Salt or esters；And
One pushes layer, and secondth area enclosed positioned at the pellicle, pushing layer includes low-substituted hydroxypropyl cellulose.
2. the substitution value of drug delivery system according to claim 1, the wherein low-substituted hydroxypropyl cellulose is between 8%
~15%.
3. drug delivery system according to claim 1, the wherein pellicle include cellulose acetate, ethyl cellulose or
Its mixture.
4. drug delivery system according to claim 3, the wherein pellicle also include a pore-foaming agent.
5. drug delivery system according to claim 4, the wherein pore-foaming agent include polyethylene glycol, PVP, sodium chloride,
Potassium chloride or its mixture.
6. the weight percent of drug delivery system according to claim 4, the wherein pore-foaming agent in the pellicle is situated between
In 0.1~20%.
7. drug delivery system according to claim 1, the wherein pellicle are relative to medicine layer and the weight for pushing layer
Percentage is between 4~30%.
8. drug delivery system according to claim 1, the wherein medicine layer also include a bleeding agent, a binder, one
Lubricant or an antioxidant.
9. drug delivery system according to claim 8, the wherein bleeding agent include salt, carbohydrate or its mixture.
10. drug delivery system according to claim 8, the wherein binder include PVP, hydroxypropyl methyl fiber
Element, hydroxypropyl cellulose or its mixture.
11. drug delivery system according to claim 1, the wherein low-substituted hydroxypropyl cellulose are in pushing layer
Weight percent is between 20~90%.
12. drug delivery system according to claim 1, the wherein pushing layer also include a bleeding agent, a binder, one
Lubricant, an antioxidant, a colouring agent or a glidant.
13. drug delivery system according to claim 12, the wherein bleeding agent include salt, carbohydrate or its mixture.
14. drug delivery system according to claim 12, the wherein binder include PVP, hydroxypropyl methyl fiber
Element, hydroxypropyl cellulose or its mixture.
15. the weight ratio of drug delivery system according to claim 1, the wherein medicine layer and pushing layer is between 1/10
~4/1.
16. drug delivery system according to claim 1, in addition to a moisture film clothing, coat the pellicle.
17. drug delivery system according to claim 16, wherein the moisture film clothing include water soluble polymer.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610122492.0A CN107149599A (en) | 2016-03-02 | 2016-03-02 | Drug delivery system |
| TW105108415A TWI668017B (en) | 2016-03-02 | 2016-03-18 | Drug delivery systems |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610122492.0A CN107149599A (en) | 2016-03-02 | 2016-03-02 | Drug delivery system |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107149599A true CN107149599A (en) | 2017-09-12 |
Family
ID=59791423
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610122492.0A Pending CN107149599A (en) | 2016-03-02 | 2016-03-02 | Drug delivery system |
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| Country | Link |
|---|---|
| CN (1) | CN107149599A (en) |
| TW (1) | TWI668017B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113616610A (en) * | 2021-07-30 | 2021-11-09 | 石药集团欧意药业有限公司 | Paliperidone sustained-release tablet and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101711752A (en) * | 2009-11-26 | 2010-05-26 | 中国科学院上海药物研究所 | Controlled release preparation of benzo-isoxazole derivant and preparation method thereof |
| CN102670558A (en) * | 2011-03-14 | 2012-09-19 | 北京天衡药物研究院南阳天衡制药厂 | Paliperidone osmotic pump controlled-release tablet |
-
2016
- 2016-03-02 CN CN201610122492.0A patent/CN107149599A/en active Pending
- 2016-03-18 TW TW105108415A patent/TWI668017B/en active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101711752A (en) * | 2009-11-26 | 2010-05-26 | 中国科学院上海药物研究所 | Controlled release preparation of benzo-isoxazole derivant and preparation method thereof |
| CN102670558A (en) * | 2011-03-14 | 2012-09-19 | 北京天衡药物研究院南阳天衡制药厂 | Paliperidone osmotic pump controlled-release tablet |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113616610A (en) * | 2021-07-30 | 2021-11-09 | 石药集团欧意药业有限公司 | Paliperidone sustained-release tablet and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| TW201731490A (en) | 2017-09-16 |
| TWI668017B (en) | 2019-08-11 |
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