CN110384670A - A kind of composition and preparation method thereof containing acotiamide hydrochloride hydrate - Google Patents
A kind of composition and preparation method thereof containing acotiamide hydrochloride hydrate Download PDFInfo
- Publication number
- CN110384670A CN110384670A CN201810344310.3A CN201810344310A CN110384670A CN 110384670 A CN110384670 A CN 110384670A CN 201810344310 A CN201810344310 A CN 201810344310A CN 110384670 A CN110384670 A CN 110384670A
- Authority
- CN
- China
- Prior art keywords
- acotiamide hydrochloride
- hydrochloride hydrate
- active constituent
- disintegrating agent
- acotiamide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
-
- 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
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to pharmaceutical preparation field, in particular to a kind of composition and preparation method thereof containing acotiamide hydrochloride hydrate.A kind of composition containing acotiamide hydrochloride hydrate is mainly obtained by active constituent and auxiliary material using dry granulation；The active constituent is acotiamide hydrochloride hydrate and/or its hydrate.Acotiamide hydrochloride hydrate piece provided by the invention, is prepared using dry granulation process, avoids the risk that transformation of crystal easily occurs in the drying process for active constituent in wet granulation；Acotiamide hydrochloride hydrate tablet stability obtained is good, and dissolution rate is good.
Description
Technical field
The present invention relates to pharmaceutical preparation field, in particular to a kind of composition containing acotiamide hydrochloride hydrate and its
Preparation method.
Background technique
Acotiamide hydrochloride hydrate pieceJoined by Japanese Ze Li new drug Co., Ltd. and Astellas pharmacy group
Run hair jointly, for treating the functional dyspepsia FDs such as upper abdomen flatulence and too early full sense (FD) symptom, the medicine is by inhibiting periphery second
The activity of phatidylcholine enzyme and the degradation for inhibiting acetylcholine, so as to improve many FD symptoms.
The English name or Latin literary fame Acotiamide hydrochloride hydrate of acotiamide hydrochloride hydrate piece
Tablets, Chinese chemical name N- [2- (isopropylamino) ethyl] -2- (2- hydroxyl -4,5- dimethoxybenzoyl amino) thiazole -
4- carboxamide hydrochloride trihydrate, chemical structural formula:
Molecular formula is C21H30N4O5S·HCl·3H2O, molecular weight 541.06.
Acotiamide hydrochloride hydrate slightly soluble in water does not almost dissolve in 1.0 hydrochloric acid medium of pH, this has resulted in hydrochloric acid Ah examining
The problem that solubility for amine is small and dissolution rate is slow.Acotiamide hydrochloride hydrate is under the conditions of lower humidity (< 20%RH) simultaneously
It is easy dehydration, monohydrate is converted by trihydrate, and then influence the stability of tablet.Meanwhile acotiamide hydrochloride hydrate itself
Mobility is poor, and ratio is higher in the formulation, is unable to satisfy the requirement of vertical compression technique.
Since wet granulation technology need to be through high temperature drying, and bulk pharmaceutical chemicals are easy to lose in the drying process in conjunction with water, cause
Final products stability risk is very high.Meanwhile acotiamide hydrochloride hydrate mobility itself is poor, and ratio is higher in the formulation, nothing
Method meets the requirement of vertical compression technique.
In view of this, the present invention is specifically proposed.
Summary of the invention
The first object of the present invention is to provide a kind of composition containing acotiamide hydrochloride hydrate, good stability, dissolution rate
It is good.
The second object of the present invention is to provide the preparation method of the acotiamide hydrochloride amine composition, this method use
Dry granulation process avoids active constituent in wet granulation and the risk of transformation of crystal easily occurs in the drying process, and makes
Standby tablet hardness is moderate, and surface is smooth, and disintegration rate is fast.
In order to realize above-mentioned purpose of the invention, the following technical scheme is adopted:
A kind of composition containing acotiamide hydrochloride hydrate is mainly obtained by active constituent and auxiliary material using dry granulation；
The active constituent is acotiamide hydrochloride hydrate and/or its hydrate.
Composition provided by the invention containing acotiamide hydrochloride hydrate, is prepared using dry granulation process, is avoided
The risk of transformation of crystal easily occurs in the drying process for active constituent in wet granulation；Acotiamide hydrochloride hydrate tablet stability obtained
Good, dissolution rate is good.
Further, the active constituent is acotiamide hydrochloride hydrate and/or its hydrate, preferably acotiamide hydrochloride hydrate one
One or more of hydrate, acotiamide hydrochloride amine dihydrate and acotiamide hydrochloride trihydrate, more preferably hydrochloric acid
Acotiamide trihydrate.
The present invention (is confirmed) by taking acotiamide hydrochloride trihydrate as an example by thermogravimetic analysis (TGA) and determination of moisture, studies shadow
Ring the factor of active constituent stability of crystal form.It was found that under relatively high temperature and humidity conditions, acotiamide hydrochloride hydrate raw material liquid medicine
Point content does not change with the extension of higher temperature and humidity and standing time.Illustrate acotiamide hydrochloride hydrate in relatively high temperature
Trihydrate is its stable crystal form under damp condition.
Further, the storage temperature of the active constituent is 40-60 DEG C, stores humidity > 25%；
Preferably, storage humidity is 30%-35%.
Further, the partial size of the active constituent is D (v, 0.5)≤15 μm, D (v, 0.9)≤50 μm.
As in various embodiments, the partial size of active constituent is D (v, 0.5)≤12 μm, D (v, 0.9)≤48 μm；It can also
Think D (v, 0.5)≤10 μm, D (v, 0.9)≤45 μm；Or D (v, 0.5)≤10 μm, D (v, 0.9)≤40 μm；Etc..
It is investigated by raw material particle size, shows raw material particle size in D (v, 0.5)≤15 μm, when D (v, 0.9)≤50 μm, preparation is molten
It is good out, it is slack-off more than range dissolution to be lower.
Further, the auxiliary material includes filler, adhesive, disintegrating agent, glidant, lubricant and coating powder.
Preferably, the weight percent of each raw material in addition to the coating powder are as follows: active constituent 30%-50%, filler
30%-65%, adhesive 0.5%-15%, disintegrating agent 1%-15%, glidant 0.8%-10.5%, lubricant 0.12%-
1.5%；
The coating powder is the 1%-5% of above-mentioned raw materials weight.
Coordinated between each ingredient, acotiamide hydrochloride hydrate piece high comprehensive performance obtained.
Preferably, active constituent 38%-45%, filler 40%-54%, adhesive 2%-8%, disintegrating agent 3%-
10%, glidant 2%-5%, lubricant 0.5%-1%；
The coating powder is the 2%-4% of above-mentioned raw materials weight.
As in various embodiments, raw material includes: percentage, active constituent 30%, and filler 65% glues
Mixture 3.08%, disintegrating agent 1%, glidant 0.8%, lubricant 0.12%；
Or raw material includes: percentage, active constituent 50%, filler 30%, adhesive 15% collapses
Solve agent 2%, glidant 1.5%, lubricant 1.5%；
Or raw material includes: percentage, active constituent 33%, filler 40%, adhesive 0.5%,
Disintegrating agent 15%, glidant 10.5%, lubricant 1%；
Or raw material includes: percentage, active constituent 38%, filler 54%, adhesive 2% collapses
Solve agent 3%, glidant 2%, lubricant 1%；
Or raw material includes: percentage, active constituent 40%, filler 45%, adhesive 8% collapses
Solve agent 3%, glidant 3.5%, lubricant 0.5%；
Or raw material includes: percentage, active constituent 45%, filler 40%, adhesive 4.8%,
Disintegrating agent 5%, glidant 5%, lubricant 0.2%；
Or raw material includes: percentage, active constituent 40%, filler 41.2%, adhesive 5%,
Disintegrating agent 10%, glidant 3%, lubricant 0.8%；Etc..
Similarly, in different embodiments, coating powder can for above-mentioned each raw material gross weight 1%, 2%, 3%, 4%,
5% etc..
Further, the filler includes the instant ingredient of hydrophily and insoluble composition；
The instant ingredient of hydrophily includes one of lactose, sucrose, glucose, mannitol or a variety of；
The insoluble composition includes one of microcrystalline cellulose, starch, pregelatinized starch, dextrin or a variety of.
Further, described adhesive is hydroxypropylcellulose, povidone, hydroxypropyl methylcellulose, starch and carboxymethyl cellulose
One of plain sodium is a variety of, preferably hydroxypropylcellulose.
Further, the disintegrating agent includes low-substituted hydroxypropyl cellulose, croscarmellose sodium, the poly- dimension of crosslinking
One of ketone, pregelatinized starch, starch and carboxymethyl starch calcium are a variety of, preferably low-substituted hydroxypropyl cellulose.
Further, the glidant is one or both of silica, talcum powder.
Further, the lubricant is magnesium stearate, talcum powder, superfine silica gel powder, sodium stearyl fumarate, behenyl acid glycerol
One of ester and polyethylene glycol are a variety of, preferably magnesium stearate.
Further, the coating powder is film coating pre-mix dose.
The present invention also provides the preparation methods of the composition containing acotiamide hydrochloride hydrate, comprising the following steps:
Active constituent, filler, glidant, disintegrating agent and adhesive are weighed, is mixed；
Said mixture is placed in dry granulating machine and is pelletized, granule is obtained；
Lubricant is added into the granule, is uniformly mixed, tabletting, coating obtains the acotiamide hydrochloride hydrate piece.
Research shows that acotiamide hydrochloride hydrate bulk pharmaceutical chemicals crystallization water under the conditions of compared with low humidity (< 20%RH) easily loses, thus
Crystal form is caused to change.The present invention uses dry granulation process, avoids in wet granulation Yi Fasheng in active constituent drying process
The risk of transformation of crystal.Simultaneously vertical compression technique because this product specification it is larger, active constituent accounts for relatively high, and mobility is poor, especially
It is that partial size reduction, mobility are further deteriorated, are unable to satisfy the demand of vertical compression technique, select the work of dry granulation after being pulverized
Skill overcomes the problem.
Disintegrating agent is tested using the interior three kinds of modes for adding, adding inside and outside outer adduction, it is found that interior additional effect is more preferable.
Further, the disintegrating agent is added in two portions, and is once added before dry granulation, is once added together with the lubricant.
Further, the ratio for the weight that the disintegrating agent adds twice is 1:0.8-1.5.
As in various embodiments, the ratio for the weight that disintegrating agent adds twice can be 1:0.8,1:1,1:1.2,1:
1.5 etc..
Further, the pressure of the granulation is 0.2~2Mpa, preferably 0.2~1Mpa.
When pressure of pelletizing is larger, obtained particle is harder, unilateral to have pitted skin phenomenon, and tablet disintegration time limit extends, dissolves out simultaneously
Curve slows down；And reduce dry granulation pressure, it controls in 0.2-1Mpa, disintegration of tablet and dissolution are accelerated.
Compared with prior art, the invention has the benefit that
(1) present invention uses dry granulation process, avoids in wet granulation and transformation of crystal easily occurs in API drying process
Risk；The problem of wet granulation is unable to satisfy vertical compression technique is overcome simultaneously.
(2) bulk pharmaceutical chemicals partial size is controlled, the dissolution rate of drug is improved.
(3) pressure for controlling dry granulation process, keeps the tablet hardness of preparation moderate, surface is smooth, and disintegration rate is fast.
(4) the specific adding manner of disintegrating agent, has effectively facilitated the disintegration rate of drug.
(5) storage temperature and humidity of acotiamide hydrochloride hydrate bulk pharmaceutical chemicals are provided, so that acotiamide hydrochloride hydrate is stable
Trihydrate.
Detailed description of the invention
In order to more clearly explain the embodiment of the invention or the technical proposal in the existing technology, to embodiment or will show below
There is attached drawing needed in technical description to be briefly described.
Fig. 1 is in the embodiment of the present invention 1 under the conditions of 20 DEG C/18%RH, and the variation of the moisture content of different standing times dissipates
Point diagram；
Fig. 2 is in the embodiment of the present invention 1 under the conditions of 40 DEG C/35%RH, and the variation of the moisture content of different standing times dissipates
Point diagram；
Fig. 3 is in the embodiment of the present invention 1 under the conditions of 60 DEG C/35%RH, and the variation of the moisture content of different standing times dissipates
Point diagram；
Fig. 4 is that the dissolution of tablet made from the acotiamide hydrochloride trihydrate of different-grain diameter in the embodiment of the present invention 2 is bent
Line chart；
Fig. 5 is the dissolution curve of tablet made from the different addition manner of disintegrating agent in the embodiment of the present invention 3；
Fig. 6 is the dissolution curve of tablet made from granulation pressure different in the embodiment of the present invention 4；
Fig. 7 is the dissolution curve of tablet made from the embodiment of the present invention 5 and embodiment 6 and other embodiments.
Specific embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and is not construed as limiting the scope of the invention.It is not specified in embodiment specific
Condition person carries out according to conventional conditions or manufacturer's recommended conditions.Reagents or instruments used without specified manufacturer is
The conventional products that can be obtained by commercially available purchase.
Embodiment 1
Study the influence to acotiamide hydrochloride hydrate stability of crystal form of temperature and humidity, by bulk pharmaceutical chemicals, that is, active constituent respectively at
Under 18%RH and 35%RH damp condition, the situation of change of its moisture content is investigated.
(1) 20 DEG C/18%RH moisture is investigated
Under the conditions of 20 DEG C/18%RH, it is tested in the moisture content of different standing times, the results are shown in Table 1, accordingly
Scatter plot it is as shown in Figure 1.
Table 1 20 DEG C/18%RH moisture investigates data
| Standing time (h) | Moisture (%) |
| 0 | 9.98 |
| 2 | 9.65 |
| 4 | 9.18 |
| 6 | 8.98 |
| 8 | 8.51 |
| 10 | 7.24 |
| 12 | 6.35 |
| 24 | 5.47 |
| 32 | 4.72 |
| 40 | 4.39 |
| 48 | 4.35 |
| 60 | 4.38 |
Data show that acotiamide hydrochloride trihydrate is unstable crystal form under lower damp condition；With placement
The extension of time, by original trihydrate (moisture: 9.98%) lose two molecular waters eventually become monohydrate (moisture:
4.38%).
(2) 40 DEG C/35%RH moisture is investigated
Under the conditions of 40 DEG C/35%RH, it is tested in the moisture content of different standing times, the results are shown in Table 2, accordingly
Scatter plot it is as shown in Figure 2.
Table 2 40 DEG C/35%RH moisture investigates data
Data are shown: under the conditions of 40 DEG C/35%RH, before acotiamide hydrochloride trihydrate moisture content is by placing
9.98% finally maintains 9.97% or so, i.e. moisture does not change with the extension of standing time.Illustrate acotiamide hydrochloride hydrate
Trihydrate is stable crystal form under higher damp condition.
(3) 60 DEG C/35%RH moisture is investigated
Under the conditions of 60 DEG C/35%RH, it is tested in the moisture content of different standing times, the results are shown in Table 3, accordingly
Scatter plot it is as shown in Figure 3.
Table 3 60 DEG C/35%RH moisture investigates data
| Standing time (h) | Moisture (%) |
| 0 | 9.98 |
| 2 | 9.94 |
| 4 | 9.98 |
| 6 | 9.97 |
| 8 | 9.98 |
| 10 | 9.94 |
| 12 | 9.92 |
| 24 | 9.98 |
| 36 | 10.01 |
| 48 | 9.96 |
| 60 | 10.02 |
Data are shown: under relatively high temperature and humidity conditions, before acotiamide hydrochloride hydrate bulk pharmaceutical chemicals moisture content is by placing
9.96% finally maintain 10.02% or so, moisture does not change with the extension of higher temperature and humidity and standing time.It says
Bright acotiamide hydrochloride hydrate trihydrate under relatively high temperature and humidity conditions is its stable crystal form.
Acotiamide hydrochloride hydrate bulk pharmaceutical chemicals stability of crystal form the results show that humidity be influence active constituent crystal form it is main because
Element.Further experiment is found, under higher damp condition (> 25%RH), acotiamide hydrochloride hydrate is stable trihydrate；It is lower
Humidity (< 20%RH) under the conditions of, acotiamide hydrochloride trihydrate is eventually converted into monohydrate by dehydration.
Therefore, the storage temperature of the active constituent is 40-60 DEG C, stores humidity > 25%；Preferably, storage humidity is
30%-35%.
Embodiment 2
Raw material particle size: acotiamide hydrochloride hydrate slightly soluble in water does not almost dissolve, this is resulted in 1.0 hydrochloric acid medium of pH
The problem that the solubility of acotiamide hydrochloride hydrate piece is small and dissolution rate is slow.
4 raw material of table
| Drug/auxiliary material | Dosage (g) |
| Acotiamide hydrochloride trihydrate * | 100* |
| Lactose | 78 |
| Microcrystalline cellulose PH101 | 32 |
| Hydroxypropyl cellulose | 10 |
| Low-substituted hydroxypropyl cellulose | In 10 plus+10 is additional |
| Silica | 7.5 |
| Magnesium stearate | 2.5 |
| Film coating pre-mix dose | 7.5 |
| It is made | 257g/1000 piece |
Note: * is that inventory is calculated with anhydride
Weigh acotiamide hydrochloride trihydrate, the filler, glidant, disintegrating agent (interior plus part), bonding of recipe quantity
Agent, which is placed in three-dimensional mixer, mixes 20min.Said mixture is placed in dry granulating machine and is pelletized, pressure 0.2-1Mpa, sieve
Several 20 mesh of mesh.Lubricant and Extra Section disintegrating agent are added into particle, is uniformly mixed, tabletting, coating to label is increased weight
3%.
Influence of the acotiamide hydrochloride trihydrate of different-grain diameter to tablet is investigated, it is specific as shown in table 5.
The result of 5 different-grain diameter of table
Mechanical crushing in group 3 are as follows: Universalpulverizer top grade crushes.
In addition, also testing commercially available product, as a result as shown in Figure 4.
The present invention is investigated by acotiamide hydrochloride trihydrate partial size, shows raw material particle size in D (v, 0.5)≤15 μm, D
When (v, 0.9)≤50 μm, preparation dissolution is good, slack-off more than range dissolution to be lower.
Embodiment 3
Disintegrating agent adding manner: investigate disintegrating agent all in plus, all additional and interior additional (interior additional ratio 1:1)
Mode.
It is raw materials used as shown in table 6.
6 raw material of table
| Drug/auxiliary material | Dosage (g) |
| Acotiamide hydrochloride trihydrate * | 100* |
| Lactose | 78 |
| Microcrystalline cellulose PH101 | 32 |
| Starch | 10 |
| Low-substituted hydroxypropyl cellulose | 20 |
| Talcum powder | 7.5 |
| Magnesium stearate | 2.5 |
| Film coating pre-mix dose | 7.5 |
| It is made | 257g/1000 piece |
Note: * is that inventory is calculated with anhydride
Group 1:
Add in disintegrating agent: acotiamide hydrochloride trihydrate being mechanically pulverized, with embodiment group 3, weighs the work of recipe quantity
Property ingredient, filler, glidant, disintegrating agent, adhesive are placed in three-dimensional mixer and mix 20min.Said mixture is placed in
It pelletizes in dry granulating machine, pressure 0.2-1Mpa, 20 mesh of sieve mesh number.Lubricant is added into particle, is uniformly mixed, tabletting,
It is coated to label weight gain 3%.
Group 2:
Disintegrating agent is additional: acotiamide hydrochloride trihydrate being mechanically pulverized, with embodiment group 3, weighs the work of recipe quantity
Property ingredient, filler, glidant, adhesive are placed in three-dimensional mixer and mix 20min.Said mixture is placed in dry granulation
It pelletizes in machine, pressure 0.2-1Mpa, 20 mesh of sieve mesh number.Lubricant and disintegrating agent are added into particle, is uniformly mixed, tabletting,
It is coated to label weight gain 3%.
Group 3:
It is additional in disintegrating agent: acotiamide hydrochloride trihydrate being mechanically pulverized, with embodiment group 3, weighs recipe quantity
Active constituent, filler, glidant, disintegrating agent (interior plus part), adhesive are placed in three-dimensional mixer and mix 20min.It will be upper
It states mixture and is placed in dry granulating machine and pelletize, pressure 0.2-1Mpa, 20 mesh of sieve mesh number.Lubricant and outer is added into particle
Add partial disintegration agent, is uniformly mixed, tabletting, coating to label weight gain 3%.
Tablet made from each group carries out dissolution detection, and the results are shown in Table 7.
Influence of the different adding manner of 7 disintegrating agent of table to tablet
The corresponding curve graph of different groups is as shown in Figure 5.
Prove the added-time inside and outside disintegrating agent, this product disintegration rate is most fast, and dissolution rate is higher.
By upper result it is found that the addition of disintegrating agent may be selected in all plus, it is all additional or interior additional, wherein preferably interior
It is additional.
Embodiment 4
The control of dry granulation pressure: influence of the dry granulation pressure to final tablet appearance, hardness and dissolution rate is investigated.
8 raw material of table
| Drug/auxiliary material | Dosage (g) |
| Acotiamide hydrochloride trihydrate * | 100* |
| Lactose | 78 |
| Microcrystalline cellulose PH101 | 32 |
| Hydroxypropyl cellulose | 10 |
| Low-substituted hydroxypropyl cellulose | In 10 plus+10 is additional |
| Silica | 7.5 |
| Magnesium stearate | 2.5 |
| Film coating pre-mix dose | 7.5 |
| It is made | 257g/1000 piece |
Note: * is that inventory is calculated with anhydride
Group 1:
Preparation method: acotiamide hydrochloride trihydrate is mechanically pulverized, and with 2 group 3 of embodiment, weighs the activity of recipe quantity
Ingredient, filler, glidant, disintegrating agent (interior plus part), adhesive are placed in three-dimensional mixer and mix 20min.It will be above-mentioned mixed
Conjunction object, which is placed in dry granulating machine, pelletizes, pressure 1-2Mpa, 20 mesh of sieve mesh number.Lubricant and Extra Section are added into particle
Disintegrating agent is uniformly mixed, tabletting, coating to label weight gain 3%.
Group 2:
Preparation method: acotiamide hydrochloride trihydrate is mechanically pulverized, and with 2 group 3 of embodiment, weighs the activity of recipe quantity
Ingredient, filler, glidant, disintegrating agent (interior plus part), adhesive are placed in three-dimensional mixer and mix 20min.It will be above-mentioned mixed
Conjunction object, which is placed in dry granulating machine, pelletizes, pressure 0.2-1Mpa, 20 mesh of sieve mesh number.Lubricant and additional portion are added into particle
Divide disintegrating agent, is uniformly mixed, tabletting, coating to label weight gain 3%.
9 test result of table
The corresponding curve graph of table 9 is as shown in Figure 6.
The result shows that dry granulation pressure more bolus hardness is lower, while tablet dissolution is slack-off.Granulation pressure 0.2~
2Mpa can be further selected from 0.2~1Mpa.
In addition, obtained particle is harder when granulation pressure is larger, unilateral to have pitted skin phenomenon, tablet disintegration time limit extends, simultaneously
Dissolution curve slows down；Group 2 reduces dry granulation pressure, controls in 0.2-1Mpa, and disintegration of tablet and dissolution are accelerated.
Embodiment 5
Replace influence of the hydrophobicity filler to tablet.
10 raw material of table
Note: * is that inventory is calculated with anhydride
Preparation method: acotiamide hydrochloride trihydrate is mechanically pulverized, and with 2 group 3 of embodiment, weighs the activity of recipe quantity
Ingredient, filler, glidant, disintegrating agent (interior plus part), adhesive are placed in three-dimensional mixer and mix 20min.It will be above-mentioned mixed
Conjunction object, which is placed in dry granulating machine, pelletizes, pressure 0.2-1Mpa, 20 mesh of sieve mesh number.Lubricant and additional portion are added into particle
Divide disintegrating agent, is uniformly mixed, tabletting, coating to label weight gain 3%.
Embodiment 6
Adjust influence of the hydrophilic/hydrophobic filler ratio to tablet.
11 raw material of table
| Drug/auxiliary material | Dosage (g) |
| Acotiamide hydrochloride trihydrate * | 100* |
| Lactose | 55 |
| Pregelatinized starch | 55 |
| Hydroxypropyl cellulose | 10 |
| Low-substituted hydroxypropyl cellulose | 10+10 |
| Silica | 7.5 |
| Magnesium stearate | 2.5 |
| Film coating pre-mix dose | 7.5 |
| It is made | 257g/1000 piece |
Note: * is that inventory is calculated with anhydride
Preparation method: acotiamide hydrochloride trihydrate is mechanically pulverized, and with 2 group 3 of embodiment, weighs the activity of recipe quantity
Ingredient, filler, glidant, disintegrating agent (interior plus part), adhesive are placed in three-dimensional mixer and mix 20min.It will be above-mentioned mixed
Conjunction object, which is placed in dry granulating machine, pelletizes, pressure 0.2-1Mpa, 20 mesh of sieve mesh number.Lubricant and additional portion are added into particle
Divide disintegrating agent, is uniformly mixed, tabletting, coating to label weight gain 3%.
The dissolution curve of tablet made from different embodiments and commercially available product is as shown in Figure 7.
Dissolving-out method is measured using following steps:
1) method: dissolution method (Chinese Pharmacopoeia version in 2015 the 4th general rule " 0931 dissolution rate and drug release determination
The second method of method " (paddle method)).
2) dissolution medium: 0.1mol/L HCl, 900ml
3) revolving speed: 50 revs/min
4) sample time: 5min, 10min, 15min, 20min, 30min, 45min, 60min, 120min
5) detection method: UV-VIS spectrophotometry, Detection wavelength: 330nm
6) test solution is prepared: being taken solution 10ml in each time point, is filtered, precision measures subsequent filtrate 2ml, sets 10ml amount
In bottle, it is diluted to scale with 0.1mol/L HCl, is shaken up.
7) reference substance solution is prepared: being taken acotiamide hydrochloride hydrate reference substance about 20mg, is set in 50ml measuring bottle, adds methanol dissolution simultaneously
It is diluted to scale, is shaken up, precision measures 5ml, sets in 100ml measuring bottle, is diluted to scale with 0.1mol/LHCl, shakes up.
8) calculation formula:
Wr: sample weighting amount (mg) Vr: the extension rate of reference substance of reference substance
As: the absorbance A r: the absorbance of reference substance solution of test solution
Specification: 100mg
Note: 1.1110=MAcotiamide hydrochloride trihydrate/MAcotiamide hydrochloride hydrate anhydride, because reference substance content is therefore the dissolution rate in terms of anhydride
It need to carry out coefficient conversion.
Instrument model:
Intelligent dissolving-out tester (model: ZRS-8G, producer: Tianda Tianfa Technology Co., Ltd.)
The information of commercially available product is as follows:
Trade name:Tablets
Chinese name: acotiamide hydrochloride hydrate piece
English name: Acotiamide Hydrochloride Hydrate Tablets
Producer: Japanese Ze Li new drug Co., Ltd. and Astellas pharmacy group
Study batch: E317
As it can be seen that preparation prepared by the present invention is compared with commercially available product, dissolution rate is substantially better than commercially available product, has higher
Bioavilability.
Experimental example
Preparation stability test
1, stability study scheme pilot project
12 stability conditions of table
2, stability data
The test of 2.1 influence factors
Acotiamide hydrochloride hydrate piece influence factor test result table made from 3 group 3 of 13 embodiment of table
Note: // indicate undetermined
Other embodiments such as embodiment 5 and embodiment 6 are also tested using same method, as a result consistent with the above results,
It will not enumerate.
2.2 accelerated test
The accelerated test of tablet made from 4 group 2 of embodiment, embodiment 5 and embodiment 6.
Acceleration environment: 40 DEG C ± 2 DEG C, RH75% ± 5%.Packaging: aluminum-plastic blister.
14 acotiamide hydrochloride hydrate piece accelerated test of table investigates result
Note: // indicate undetermined
2.3 long term test
The long term test of tablet made from 4 group 2 of embodiment, embodiment 5 and embodiment 6.
Long-term conditions: 25 DEG C ± 2 DEG C, RH60% ± 5%.Packaging: aluminum-plastic blister.
The long-term experiment investigation result of 15 acotiamide hydrochloride hydrate piece of table
Note: // indicate undetermined
In addition, such as 3 group 3 of embodiment of other groups of stability test result is ibid consistent, will not enumerate.
Stability conclusion: influence factor test result shows:
1. under the conditions of high humidity 75% and high humidity 92.5%, sample weight gain is below 5%, and (weight gain is 2.96%~-4.62%
Between)；Under the conditions of 40 DEG C and 60 DEG C of high temperature of high temperature, sample weight loss is smaller (weightlessness is between 1.13%~-2.66%).
2. under the conditions of each, significant change does not occur for character, related substance, dissolution rate, content；
Accelerate and long-term stable experiment the result shows that:
1. placing 6 months under acceleration environment, the character of three batches of each sample of pilot scale, related substance, dissolution rate, content do not have
Apparent variation tendency.
2. placing 6 months under long-term conditions, the character of three batches of each sample of pilot scale, related substance, dissolution rate, content do not have
Apparent variation tendency.
Illustrate that acotiamide hydrochloride hydrate tablet stability provided by the invention can be excellent.
In addition, also carrying out following tests:
Active constituent select or mixtures thereof acotiamide hydrochloride hydrate monohydrate or acotiamide hydrochloride amine dihydrate or its
With the mixture of acotiamide hydrochloride trihydrate, remaining ingredient is prepared using the identical method of embodiment 5, is obtained with embodiment 5
The preparation location parameter arrived is almost the same with 5 effect of embodiment.
The instant ingredient of hydrophily selects sucrose, glucose, mannitol any one or more of and its mixing with lactose,
Remaining ingredient is prepared, obtained preparation location parameter is the same as 5 effect base of embodiment with embodiment 5 using the identical method of embodiment 5
This is consistent.
Insoluble composition selects dextrin or its combination any one or more with microcrystalline cellulose, starch, pregelatinized starch,
Remaining ingredient is prepared, obtained preparation location parameter is the same as 5 effect base of embodiment with embodiment 5 using the identical method of embodiment 5
This is consistent.
Adhesive selects one of hydroxypropylcellulose, povidone, hydroxypropyl methylcellulose and sodium carboxymethylcellulose or more
Kind and its mixing with starch, remaining ingredient are prepared with embodiment 5 using the identical method of embodiment 5, obtained preparation measurement
Parameter is almost the same with 5 effect of embodiment.
Disintegrating agent selects croscarmellose sodium, crospovidone, pregelatinized starch, starch and carboxymethyl starch calcium
One of or mixing a variety of and its with low-substituted hydroxypropyl cellulose, remaining ingredient it is identical using embodiment 5 with embodiment 5
Method preparation, obtained preparation location parameter is almost the same with 5 effect of embodiment.
Lubricant selects one of talcum powder, superfine silica gel powder, sodium stearyl fumarate, Compritol 888 ATO and polyethylene glycol
Or mixing a variety of and its with magnesium stearate, remaining ingredient are prepared using the identical method of embodiment 5, are obtained with embodiment 5
Preparation location parameter is almost the same with 5 effect of embodiment.
The proportion relation of feed change, with illustrating in summary of the invention, the similar embodiment 5-6 of ingredient kind, using 5 phase of embodiment
Same method preparation, obtained preparation location parameter are almost the same with embodiment 5 and 6 effect of embodiment.
Although illustrate and describing the present invention with specific embodiment, it will be appreciated that without departing substantially from of the invention
Many other change and modification can be made in the case where spirit and scope.It is, therefore, intended that in the following claims
Including belonging to all such changes and modifications in the scope of the invention.
Claims (10)
1. a kind of composition containing acotiamide hydrochloride hydrate, which is characterized in that mainly use dry method by active constituent and auxiliary material
Granulation obtains；
The active constituent is acotiamide hydrochloride hydrate and/or its hydrate；
Preferably, the active constituent is acotiamide hydrochloride hydrate monohydrate, acotiamide hydrochloride amine dihydrate and hydrochloric acid Ah examining
For one or more of amine trihydrate, more preferably acotiamide hydrochloride trihydrate；
Preferably, the storage temperature of the active constituent is 40-60 DEG C, stores humidity > 25%；
Preferably, storage humidity is 30%-35%.
2. the composition according to claim 1 containing acotiamide hydrochloride hydrate, which is characterized in that the grain of the active constituent
Diameter is D (v, 0.5)≤15 μm, D (v, 0.9)≤50 μm.
3. the composition according to claim 2 containing acotiamide hydrochloride hydrate, which is characterized in that the auxiliary material includes filling
Agent, adhesive, disintegrating agent, glidant, lubricant and coating powder；
Preferably, the weight percent of each raw material in addition to the coating powder are as follows: active constituent 30%-50%, filler 30%-
65%, adhesive 0.5%-15%, disintegrating agent 1%-15%, glidant 0.8%-10.5%, lubricant 0.12%-1.5%；
The coating powder is the 1%-5% of above-mentioned raw materials weight.
4. the composition according to claim 3 containing acotiamide hydrochloride hydrate, which is characterized in that active constituent 38%-
45%, filler 40%-54%, adhesive 2%-8%, disintegrating agent 3%-10%, glidant 2%-5%, lubricant 0.5%-
1%；
The coating powder is the 2%-4% of above-mentioned raw materials weight.
5. the composition according to claim 3 or 4 containing acotiamide hydrochloride hydrate, which is characterized in that the filler packet
Include the instant ingredient of hydrophily and insoluble composition；
The instant ingredient of hydrophily includes one of lactose, sucrose, glucose, mannitol or a variety of；
The insoluble composition includes one of microcrystalline cellulose, starch, pregelatinized starch, dextrin or a variety of；
Further, described adhesive is hydroxypropylcellulose, povidone, hydroxypropyl methylcellulose, starch and sodium carboxymethylcellulose
One of or a variety of, preferably hydroxypropylcellulose.
6. the composition according to claim 3 or 4 containing acotiamide hydrochloride hydrate, which is characterized in that the disintegrating agent packet
Include low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, pregelatinized starch, starch and carboxymethyl starch
One of calcium is a variety of, preferably low-substituted hydroxypropyl cellulose；
Further, the glidant is one or both of silica, talcum powder；
Further, the lubricant be magnesium stearate, talcum powder, superfine silica gel powder, sodium stearyl fumarate, Compritol 888 ATO and
One of polyethylene glycol is a variety of, preferably magnesium stearate；
Further, the coating powder is film coating pre-mix dose.
7. the preparation method of the described in any item compositions containing acotiamide hydrochloride hydrate of claim 3-6, which is characterized in that packet
Include following steps:
Active constituent, filler, glidant, disintegrating agent and adhesive are weighed, is mixed；
Said mixture is placed in dry granulating machine and is pelletized, granule is obtained；
Lubricant is added into the granule, is uniformly mixed, tabletting, coating obtains the acotiamide hydrochloride hydrate piece.
8. the preparation method of the composition according to claim 7 containing acotiamide hydrochloride hydrate, which is characterized in that described to collapse
Solution agent is added in two portions, and is once added before dry granulation, is once added together with the lubricant.
9. the preparation method of the composition according to claim 8 containing acotiamide hydrochloride hydrate, which is characterized in that
The ratio for the weight that the disintegrating agent adds twice is 1:0.8-1.5.
10. the preparation method of the composition according to claim 7 containing acotiamide hydrochloride hydrate, which is characterized in that described
The pressure of granulation is 0.2~2Mpa, preferably 0.2~1Mpa.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810344310.3A CN110384670A (en) | 2018-04-17 | 2018-04-17 | A kind of composition and preparation method thereof containing acotiamide hydrochloride hydrate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810344310.3A CN110384670A (en) | 2018-04-17 | 2018-04-17 | A kind of composition and preparation method thereof containing acotiamide hydrochloride hydrate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110384670A true CN110384670A (en) | 2019-10-29 |
Family
ID=68283963
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810344310.3A Pending CN110384670A (en) | 2018-04-17 | 2018-04-17 | A kind of composition and preparation method thereof containing acotiamide hydrochloride hydrate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110384670A (en) |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103622929A (en) * | 2013-12-05 | 2014-03-12 | 安徽省先锋制药有限公司 | Acotiamide hydrochloride sustained release tablet and preparation method thereof |
| CN104510719A (en) * | 2013-09-27 | 2015-04-15 | 江苏豪森药业股份有限公司 | Acotiamide tablet and preparation method thereof |
| CN105412026A (en) * | 2014-09-18 | 2016-03-23 | 中美华世通生物医药科技（武汉）有限公司 | Hydrochloric acid acotiamide tablets and preparation method thereof |
| CN105769784A (en) * | 2014-12-24 | 2016-07-20 | 广州朗圣药业有限公司 | Oral tablet of acotiamide hydrochloride trihydrate and preparation method thereof |
| CN105919967A (en) * | 2016-06-12 | 2016-09-07 | 佛山市腾瑞医药科技有限公司 | Acotiamide hydrochloride preparation and application thereof |
| JP2017002045A (en) * | 2015-06-12 | 2017-01-05 | ゼリア新薬工業株式会社 | Orally disintegrating tablet |
| CN106667945A (en) * | 2015-11-10 | 2017-05-17 | 天津汉瑞药业有限公司 | Acotiamide tablets and preparation method thereof |
| CN107496373A (en) * | 2017-09-12 | 2017-12-22 | 甘宜玲 | A kind of acotiamide hydrochloride hydrate composition capsule |
-
2018
- 2018-04-17 CN CN201810344310.3A patent/CN110384670A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104510719A (en) * | 2013-09-27 | 2015-04-15 | 江苏豪森药业股份有限公司 | Acotiamide tablet and preparation method thereof |
| CN103622929A (en) * | 2013-12-05 | 2014-03-12 | 安徽省先锋制药有限公司 | Acotiamide hydrochloride sustained release tablet and preparation method thereof |
| CN105412026A (en) * | 2014-09-18 | 2016-03-23 | 中美华世通生物医药科技（武汉）有限公司 | Hydrochloric acid acotiamide tablets and preparation method thereof |
| CN105769784A (en) * | 2014-12-24 | 2016-07-20 | 广州朗圣药业有限公司 | Oral tablet of acotiamide hydrochloride trihydrate and preparation method thereof |
| JP2017002045A (en) * | 2015-06-12 | 2017-01-05 | ゼリア新薬工業株式会社 | Orally disintegrating tablet |
| CN106667945A (en) * | 2015-11-10 | 2017-05-17 | 天津汉瑞药业有限公司 | Acotiamide tablets and preparation method thereof |
| CN105919967A (en) * | 2016-06-12 | 2016-09-07 | 佛山市腾瑞医药科技有限公司 | Acotiamide hydrochloride preparation and application thereof |
| CN107496373A (en) * | 2017-09-12 | 2017-12-22 | 甘宜玲 | A kind of acotiamide hydrochloride hydrate composition capsule |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103127109B (en) | Pharmaceutical composition containing dabigatran etexilate or salt and hydrate thereof | |
| CA2785857A1 (en) | Production method of solid preparations and the solid preparations produced by the method | |
| CN112220770B (en) | Pharmaceutical composition of selepag and preparation method thereof | |
| PH26518A (en) | A novel pharmaceutical composition comprising exifone and water-soluble polymer | |
| CN109528675A (en) | A kind of Tadalafei enteric coated tablet and preparation method thereof | |
| CN110420192A (en) | A kind of isosorbide mononitrate sustained release tablets and preparation method | |
| CN104523686B (en) | Acotiamide hydrochloride medicinal preparation and preparation method thereof | |
| CN103610677A (en) | Repaglinide troche and preparation method thereof | |
| CN103717209B (en) | The combination of oral medication of the stabilization containing prasugrel of quick-release | |
| CN105343028B (en) | A kind of pharmaceutical composition of Norfloxacin and preparation method thereof | |
| CN103816124B (en) | A kind of esomeprazole pastille pellet composition and preparation method thereof | |
| CN102805740A (en) | Rivastigmine capsules and preparation method thereof | |
| CN110384670A (en) | A kind of composition and preparation method thereof containing acotiamide hydrochloride hydrate | |
| Odunayo et al. | Evaluation of the binding property of some binders in metronidazole tablet formulation | |
| UA125706C2 (en) | Pharmaceutical composition containing quinoline derivative | |
| CN112741819B (en) | Fluoxetine hydrochloride capsule and preparation method thereof | |
| CN108014086A (en) | A kind of preparation method of algal polysaccharide sulfate capsule | |
| CN107405342A (en) | A kind of solid composite medicament containing diamine derivative or its salt | |
| CN107468665B (en) | A kind of olaparib composition capsule | |
| CN112023056A (en) | Fluconazole pharmaceutical composition and preparation method thereof | |
| CN100453116C (en) | Process for preparing compound aminophylline tablet | |
| KR20070040558A (en) | A solid pharmaceutical composition for internal use containing fexofenadine.hcl and its process | |
| CN105012961A (en) | Stable pharmaceutical composition and preparation method thereof | |
| CN114099506B (en) | Pharmaceutical composition containing sorafenib | |
| CN107496373A (en) | A kind of acotiamide hydrochloride hydrate composition capsule |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |