CN109771380A - Desmethylvenlafaxine hydrochloride drug composition and preparation method thereof - Google Patents
Desmethylvenlafaxine hydrochloride drug composition and preparation method thereof Download PDFInfo
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Abstract
The present invention relates to a kind of desmethylvenlafaxine hydrochloride drug compositions and preparation method thereof.Desmethylvenlafaxine hydrochloride drug of the present invention contains desmethylvenlafaxine hydrochloride, gelatum skeleton material, filler, lubricant and antitackiness agent, which can be made by tabletting after wet granulation.The In-vitro release curves of desmethylvenlafaxine hydrochloride drug composition and reference preparation provided by the invention are almost the same, and have good stability.Production technology is easy to operate, production process is smoothly easy to industrialized production.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, and in particular to a kind of tablet and its system containing desmethylvenlafaxine hydrochloride
Preparation Method.
Background technique
Venlafaxine is a kind of phenyl ethylamine class novel antidepressant, is that first serotonin and norepinephrine are dual
Reuptake high inhibition medicine, the weak depressant of dopamine have many advantages, such as that rapid-action, adverse reaction is less, are compared with similar drugs
The first-line treatment drug of major depression.Desmethylvenlafaxine is the main metabolites of Venlafaxine, passes through selective exclusion
The reuptake of serotonin and norepinephrine reaches antidepressant effect.Desmethylvenlafaxine is developed by Hui Shi, with it
Succinate form listing；United States Patent (USP) No.2004044241 discloses desmethylvenlafaxine succinate.Have several companies
The imitation medicine application that the salt is submitted to FDA, such as Anchen, Apotex, Dr.Reddy ' sLaboratories,
Intellipharmaceutics、Lupin、Mylan、Roxane、Sandoz、Teva、Watson(Actavis)、
Wockhardt、Zydus。
But also there are demand behaviors to develop the other forms of the metabolin.For example, to have studied its optics different for Sepracor company
Structure body, as AU2005200129 discloses (+)-O-Goven Wenfasin free alkali and its preparation.For another example, ratify to list through FDA
Alembic, Osmotica company new drug, be its free alkali form.For another example, the Sun Microsystems of Teva company and India to
The new drug of FDA application is its fumarate, and Teva company has stopped production at present, and Sun Microsystems have gone through, and the salt is in United States Patent (USP)
No.4,535,186 is disclosed.Other the salt ground be oxalates, lactate, benzoate, Saccharinate salt, formates,
As United States Patent (USP) No.2003236309 discloses its formates.102249936 B of Chinese patent CN is related to desmethylvenlafaxine
Hydrate of hydrochloride and preparation method thereof.
Wyeth has in the succinic acid desmethylvenlafaxine that the patent of invention CN100567253C of China's application is mentioned
The particularly suitable property as drug, including improved solubility, permeability and bioavilability, solubility in water is general
Greater than 30mg/ml.Teva company specifically mentions fumaric acid desmethylvenlafaxine on the specification that FDA is announced and is slightly soluble in water, FDA
The solubility being published in pH1.0 aqueous solution is 61.8mg/ml, and about the 561 of desmethylvenlafaxine times, hydrochloric acid removes first Wen Lafa
2015 editions note on the use measurement dissolubilities of pungent basis " Chinese Pharmacopoeia " are easily to dissolve.By information above it is found that solubility is by big in water
First Wen Lafa is removed to the small hydrochloric acid desmethylvenlafaxine > succinic acid desmethylvenlafaxine > fumaric acid desmethylvenlafaxine > that is ordered as
It is pungent.
The succinic acid desmethylvenlafaxine sustained release tablets label group of Wyeth's listing becomes succinic acid desmethylvenlafaxine, hydroxyl
Third methylcellulose, magnesium stearate, microcrystalline cellulose, talcum powder, titanium dioxide and xanthan gum, wherein titanium dioxide and xanthan gum are
Coating material composition.The fumaric acid desmethylvenlafaxine sustained release tablets constituent that TEVA company develops is that fumaric acid goes first text to draw
Method is pungent, hydroxypropyl methylcellulose, microcrystalline cellulose, talcum powder and magnesium stearate；The fumaric acid desmethylvenlafaxine that SUN lists a company
Sustained release tablets constituent be fumaric acid desmethylvenlafaxine, hydroxypropyl methylcellulose, microcrystalline cellulose, talcum powder and magnesium stearate,
Coating material composition is iron oxide red and colloidal silicon dioxide.Since succinic acid desmethylvenlafaxine sustained release tablets, fumaric acid are gone
The dissolubility of active constituent in first venlafaxine sustained-release piece is opposite small with hydrochloric acid desmethylvenlafaxine, comparatively technique also compares
It is relatively simple, it can be completed using simple wet granulation technology.
Hydrochloric acid desmethylvenlafaxine is highly soluble in water, for tablet, is conducive to the biology for improving desmethylvenlafaxine
Availability；But the dissolubility due to hydrochloric acid desmethylvenlafaxine pole differed with the dissolubility of succinic acid desmethylvenlafaxine compared with
Greatly, it to obtain with the same dissolution rate in vitro of succinic acid desmethylvenlafaxine sustained release tablets (trade name Pristiq) and raw in vivo
Object availability need to be screened and be optimized to hydrochloric acid desmethylvenlafaxine prescription.
In addition, common wet granulation technology easily causes bonding since hydrochloric acid desmethylvenlafaxine is highly soluble in water
Agent is added unevenly, and granular size obtained is uneven, and hardness is too big, it is not easy to which tabletting, or the plain piece hardness of preparation are special
It is small, lead to not be coated, is difficult to realize industrialized production.
Summary of the invention
It is an object of the invention to solve above-mentioned technical problem, a kind of drug of new desmethylvenlafaxine hydrochloride is provided
Composition and preparation method thereof.
Desmethylvenlafaxine hydrochloride drug composition provided by the invention, by desmethylvenlafaxine hydrochloride hydrate,
Gelatum skeleton material and filler, lubricant, antitackiness agent are formed by following weight proportions, and wherein desmethylvenlafaxine hydrochloride accounts for
Composition weight ratio is 10%~45%, and it is 50%~80% that gelatum skeleton material, which accounts for composition weight ratio, and filler accounts for combination
Object weight ratio is 0.5%~10%, and it is 0.5%~3% that antitackiness agent, which accounts for composition weight ratio, and lubricant accounts for composition weight ratio and is
0.1%~2%；Can also be that desmethylvenlafaxine hydrochloride accounts for composition weight ratio is 10%~40%, gelatum skeleton material
Accounting for composition weight ratio is 50%~80%, and it is 2%~6% that filler, which accounts for composition weight ratio, and antitackiness agent accounts for composition weight
Than being 1%~3%, it is 0.5%~2% that lubricant, which accounts for composition weight ratio,.
Wherein, gelatum skeleton material is selected from hydroxypropyl methylcellulose, sodium carboxymethylcellulose, hydroxypropyl cellulose, polyethylene
Pyrrolidones, polyethylene glycol oxide, sodium alginate or xanthan gum, can be hydroxypropyl methylcellulose.
Filler is selected from microcrystalline cellulose, lactose or sucrose, can be microcrystalline cellulose.
Antitackiness agent is selected from talcum powder or colloidal silicon dioxide, can be talcum powder.
Lubricant is selected from magnesium stearate, hydrogenated vegetable oil, polyethylene glycols or sldium lauryl sulfate, can be stearic acid
Magnesium.
As a kind of currently preferred embodiment, hydroxypropyl methylcellulose hydrogel matrix tablet composition is relatively simple
It is single.Filler or pore-foaming agent (microcrystalline cellulose, lactose, sucrose etc.), lubrication is added as framework material in hydroxypropyl methylcellulose
Agent, antiplastering aid etc. form complete Core formulation.Hydroxypropyl methylcellulose when meeting water can aquation form gel layer, drug is from matrix tablet
The mechanism of middle release mainly has gel layer diffusion and two kinds of gel layer corrosion, and sustained release preparation, which is made, to be had up to slow releasing function for 24 hours.
Microcrystalline cellulose is formed insoluble as common filler when hydroxypropyl methylcellulose hydrogel matrix tablet is contacted with liquid
Gap, is conducive to the slow release of drug, and the water-soluble fillers such as lactose, sucrose, in hydroxypropyl methylcellulose hydrophilic gel bone
Dissolution when frame piece and liquid contact, hydroxypropyl methylcellulose realize that drug slowly discharges by " dilution ".Lubricant and antiplastering aid
It acts on and is to promote going on smoothly for preparation process, reduce sticking phenomenon when tabletting.
Prescription screening discovery, when the dosage of gelatum skeleton material especially hydroxypropyl methylcellulose is more than 30%, can show
Good slow release effect, and with the increase of dosage, slow releasing function enhancing, drug release rate slows down, in order to reach different release effects
The dosage of fruit, gelatum skeleton material can be arrived to 80% or more.But as the dosage of gelatum skeleton material increases, for preparation work
Skill causes to challenge.
The preparation method of desmethylvenlafaxine hydrochloride drug composition includes the following steps, a, by desmethylvenlafaxine salt
Hydrochlorate, partial gel framework material and filler are uniformly mixed；B, wetting agent granulation is added by spraying, wet granular obtained is done
Dry particl is obtained after dry, whole grain；C, tabletting after addition remainder gelatum skeleton material, lubricant and antitackiness agent total mix.
Wherein, wetting agent is selected from the ethanol water of ethyl alcohol or different volumes ratio；In ethanol water, the volume ratio of ethyl alcohol
More than or equal to 60%.Wetting agent is added in spraying mode, and addition speed is 5 Grams Per Seconds~40 Grams Per Seconds.
Hydrochloric acid desmethylvenlafaxine pharmaceutical composition provided by the invention, In-vitro release curves and reference preparation basic one
It causes, and there is good stability.
The present invention prepares the hydrochloric acid desmethylvenlafaxine medicine containing high proportion gelatum skeleton material using wet granulation technology
Compositions, overcome preparation process adhesive be added it is uneven, the uneven hardness of granular size obtained is too big, it is not easy to press
The problems such as piece, production technology is easy to operate, production process is smoothly easy to industrialized production.
Detailed description of the invention
Fig. 1 is that 16 sample of embodiment accelerates 6 months vitro release results；
Fig. 2 is the long-term 24 months vitro release results of 16 sample of embodiment.
Specific embodiment
Below with reference to embodiment, the present invention program is described in detail.Following example is merely to illustrate the present invention, and
It should not be taken as limiting the scope of the invention.
Preparation method and quality assessment method:
A, preparation method: by part hydroxypropyl methylcellulose K100M, hydrochloric acid desmethylvenlafaxine and microcrystalline cellulose in wet process
It is mixed in granulation pot, then with wetting agent granulation is added by spraying, it is 5g-40g/s that speed, which is added, in wetting agent, and dry and whole grain adds
Enter remainder hydroxypropyl methylcellulose K100M, talcum powder, magnesium stearate mixing, then tabletting.
B, quality assessment
(1) complexity, dry particl heap density when uniformity, the whole grain of particle is made.
(2) dissolution test
According to " Chinese Pharmacopoeia " four 0931 dissolution rates of general rule characteristic check method of version in 2015 and one method of drug release determination method
Basket method carries out dissolution test to the preparation of preparation.Measuring condition is as described below.
Testing liquid: 0.9%NaCl solution
Revolving speed: 100rpm
Experimental liquid volume: 900ml
Sampling time point: 2h, 4h, 8h, 12h, for 24 hours
(3) similitude of dissolution characteristic
Self-control preparation and reference preparation dissolved corrosion difference are evaluated using similar factors, calculation formula is as follows:
RtIt is averaged the amount of dissolution for t time reference sample；
TtSample average the amount of dissolution is made by oneself for the t time；
N is the number of sampling time point.
Judgment criteria: 1, using similar factors (f2) method is when comparing dissolution curve similitude, under normal circumstances, when two it is molten
Curve similar factors (f out2) numerical value be not less than 50 when, it is believed that dissolution curve is similar.2, when self-control sample and reference sample exist
When 15 minutes average the amount of dissolutions are not less than 85%, it is believed that dissolution curve is similar.
Embodiment 1-6
The concentration of 6 experiment investigation wetting agents is designed to granulation mass after obtained graininess, sieving complexity and drying
Density size determines the ratio of ethanol/water.
(a) prescription of plain piece
1 unit of table: mg
(b) above-mentioned prescription is prepared according to A, preparation method, investigates the complexity of granulation process in preparation process,
Each test is mainly evaluated using complexity, dry particl heap density when the uniformity of particle, whole grain as evaluation index.
Table 2: evaluation result
As shown in table 2, particle obtained is uniform when concentration of alcohol is 60%~95% or dehydrated alcohol, is easy sieving, and
Material heap medium density, conducive to the filling of material when tabletting.
Embodiment 7-10
Design influence of the dosage of 4 experiment investigation difference hydroxypropyl methylcelluloses to dissolution, dissolution characteristic f2The factor into
Row evaluation.
(a) prescription of plain piece
3 unit of table: mg
(b) above-mentioned prescription is prepared according to A, preparation method, f2The factor is that inspection target is evaluated.
Table 4: evaluation result (unit: %)
As shown in table 4, hydroxypropyl methylcellulose dosage is similar in 50%~80% release profiles.When hydroxypropyl methylcellulose dosage
Less than 50%, release profiles are dissimilar；When hydroxypropyl methylcellulose dosage be greater than 80%, be difficult to prepare piece according to A, preparation method
Agent.
Embodiment 11-14
Design influence of the dosage of 4 experiment investigation difference hydroxypropyl methylcelluloses to dissolution, dissolution characteristic f2The factor into
Row evaluation.
(a) prescription of plain piece
5 unit of table: mg
(b) above-mentioned prescription is prepared according to A, preparation method, f2The factor is that inspection target is evaluated.
Table 6: evaluation result (unit: %)
As shown in table 6, hydroxypropyl methylcellulose dosage is similar in 60%~80% release profiles.
Embodiment 15-16
Design influence of 2 experiment investigation difference grain made parameter techniques to dissolution, dissolution characteristic f2The factor is evaluated,
And investigate technique can amplification and industrialization production (200,000).
(a) composition
7 unit of table: mg
(b) 15 preparation process of embodiment
A. the preparation of wetting agent solution: the purified water of recipe quantity and ethyl alcohol being added in mixer, stirred evenly, and are made
70% ethanol water is to get wetting agent.
B. it mixes: recipe quantity microcrystalline cellulose PH200, hydrochloric acid desmethylvenlafaxine and hydroxypropyl methylcellulose K100M is (interior
Add) wet mixing pelletizer is added, 150rpm is stirred 10 minutes.
C. it pelletizes: wetting agent solution is added in LHS50 wet mixing pelletizer, start I speed stirring granulation 4 minutes,
II speed stirring granulation 3 minutes, discharges after granulation.
Agitating paddle: I speed 150rpm, II speed 180rpm
Shredder bar: I speed 1500rpm, II speed 2000rpm
D. it dries: wet granular being fitted into GPCG15 boiling coating of pellets machine, sets 50 DEG C of inlet air temperature, starting boiling is micro-
Ball seed-coating machine starts drying, and control temperature of charge is 40 ± 10 DEG C, and pellet moisture is controlled 3.00%~6.00%.
E. whole grain: confirm that multi-functional pelletizing machine has installed the intact sieve of 1.5mm, set multi-functional pelletizing machine flying knife speed
It is 300~500rpm, whole grain for revolving speed.
F. total mix: the dry particl of whole grain, hydroxypropyl methylcellulose K100M (additional), talcum powder and magnesium stearate are added
Into stationary hopper mixing machine, setting speed 10rpm mixes 20min, sample detection granule content and moisture.
G. 50mg specification tablet is suppressed using P2020 rotary pelleting machine, tabletting weight, setting pressure is answered according to granule content calculating
Piece relevant parameter: tabletting speed: 30~120,000 tablets hs, sizer revolving speed: 20~100rpm, filler depth 9.50~
13.50mm, tablet main pressure 0.50~3.00mm of thickness, tablet precompressed 1.30~3.00mm of thickness, principal pressure average value: 8.0~
20.0KN, formed punch is having a size of Φ 10.5mm dimple form.Control weight differential should be ± 5%, and hardness is 5.00~18.00kg/
cm2, friability≤1%, and the piece of fracture, cracking and crushing must not be detected.
H. it is coated:
1. preparing coating solution: recipe quantity ethyl alcohol and purified water being added in pneumatic stirring bucket, stirring is opened, is added with stirring
Recipe quantity film coating pre-mix dose (stomach dissolution type, 85G68918), starts timing, mixing time is not less than after the entry to be completely
60min is sieved with 100 mesh sieve until being uniformly dispersed, spare.
2. coating parameter: taking label to be placed in high-efficiency coating pot, setting coating relevant parameter: setting inlet air temperature 55~65
DEG C, coating pan 6~12rpm of revolving speed, 6~20rpm of wriggling revolution speed, control sheet bed tempertaure is 35~45 DEG C in coating process, until
When coating weight gain 2.0%~3.0%, stop coating.
(c) 16 preparation process of embodiment
A. the preparation of wetting agent solution: the purified water of recipe quantity and ethyl alcohol being added in mixer, stirred evenly, and are made
70% ethanol water is to get wetting agent.
B. it mixes: recipe quantity microcrystalline cellulose PH200, hydrochloric acid desmethylvenlafaxine and hydroxypropyl methylcellulose K100M is (interior
Add) wet mixing pelletizer is added, 150rpm is stirred 10 minutes.
C. it pelletizes: starting agitating paddle and shredder bar granulation, pelletized using I speed, while wetting agent solution being added to
In LHS50 wet mixing pelletizer, the addition speed for controlling wetting agent is 5 Grams Per Seconds~40 Grams Per Seconds, and adjustable spraying pressure is
0.1MPa continues I fast stirring granulation 4 minutes after to be moistened dose of addition, II fast stirring is pelletized 3 minutes, goes out after granulation
Material.
Agitating paddle: I speed 150rpm, II speed 180rpm
Shredder bar: I speed 1500rpm, II speed 2000rpm
D. it dries: wet granular being fitted into GPCG15 boiling coating of pellets machine, sets 50 DEG C of inlet air temperature, starting boiling is micro-
Ball seed-coating machine starts drying, and control temperature of charge is 40 ± 10 DEG C, and pellet moisture is controlled 3.00%~6.00%.
E. whole grain: confirm that multi-functional pelletizing machine has installed the intact sieve of 1.5mm, set multi-functional pelletizing machine flying knife speed
It is 300~500rpm, whole grain for revolving speed.
F. total mix: the dry particl of whole grain, hydroxypropyl methylcellulose K100M (additional), talcum powder and magnesium stearate are added
Into stationary hopper mixing machine, setting speed 10rpm mixes 20min, sample detection granule content and moisture.
G. 50mg specification tablet is suppressed using P2020 rotary pelleting machine, tabletting weight, setting pressure is answered according to granule content calculating
Piece relevant parameter: tabletting speed: 30~120,000 tablets hs, sizer revolving speed: 20~100rpm, filler depth 9.50~
13.50mm, tablet main pressure 0.50~3.00mm of thickness, tablet precompressed 1.30~3.00mm of thickness, principal pressure average value: 8.0~
20.0KN, formed punch is having a size of Φ 10.5mm dimple form.Control weight differential should be ± 5%, and hardness is 5.00~18.00kg/
cm2, friability≤1%, and the piece of fracture, cracking and crushing must not be detected.
H. it is coated:
1. preparing coating solution: recipe quantity ethyl alcohol and purified water being added in pneumatic stirring bucket, stirring is opened, is added with stirring
Recipe quantity film coating pre-mix dose (stomach dissolution type, 85G68918), starts timing, mixing time is not less than after the entry to be completely
60min is sieved with 100 mesh sieve until being uniformly dispersed, spare.
2. coating parameter: taking label to be placed in high-efficiency coating pot, setting coating relevant parameter: setting inlet air temperature 55~65
DEG C, coating pan 6~12rpm of revolving speed, 6~20rpm of wriggling revolution speed, control sheet bed tempertaure is 35~45 DEG C in coating process, until
When coating weight gain 2.0%~3.0%, stop coating.
(d) evaluation index: production process whether smoothly and f2The factor is that inspection target is evaluated.
Table 8: technology assessment result
Table 9: release evaluation result
| Time | Reference preparation (D16404) | Embodiment 15 | Embodiment 16 |
| 2h | 27 | 37 | 29 |
| 4h | 42 | 56 | 43 |
| 8h | 64 | 75 | 62 |
| 12h | 77 | 88 | 73 |
| 24h | 100 | 102 | 98 |
| Similar factors | / | 49 | 79 |
| Conclusion | / | It is dissimilar | It is similar |
Table 10: 16 sample of embodiment accelerates (40 DEG C ± 2 DEG C, RH75% ± 5%) 6 months release stability results
Table 11: the release stability result of 16 sample of embodiment 24 months long-term (30 DEG C ± 2 DEG C, RH65% ± 5%).
| Time | 0 month | March | June | September | December | 18 months | 24 months |
| 2h | 29 | 31 | 31 | 30 | 30 | 29 | 31 |
| 4h | 43 | 47 | 45 | 46 | 45 | 43 | 42 |
| 8h | 62 | 65 | 67 | 65 | 66 | 66 | 65 |
| 12h | 73 | 76 | 79 | 75 | 81 | 80 | 81 |
| 24h | 98 | 96 | 99 | 96 | 97 | 98 | 97 |
Table 12: the related material stability result of 16 sample of embodiment 24 months long-term (30 DEG C ± 2 DEG C, RH65% ± 5%).
Embodiment 17
According to the prescription of embodiment 16, manual mixing, drying, whole grain, total mix, tabletting, is coated obtained sample at granulation,
Middle wetting agent is added at one time, and manual preparation process is more smooth.Sample made from embodiment 17, release stability have
It is almost the same to close the sample that material stability is prepared with embodiment 16.
Claims (10)
1. desmethylvenlafaxine hydrochloride drug composition, which is characterized in that contain desmethylvenlafaxine hydrochloride, gel skeleton
Material, filler, lubricant and antitackiness agent.
2. pharmaceutical composition according to claim 1, which is characterized in that desmethylvenlafaxine hydrochloride accounts for composition weight
Than being 10%~45%, it is 50%~80% that gelatum skeleton material, which accounts for composition weight ratio, and filler accounts for composition weight ratio and is
0.5%~10%, antitackiness agent account for composition weight ratio be 0.5%~3%, lubricant account for composition weight ratio be 0.1%~
2%；Can also be that desmethylvenlafaxine hydrochloride accounts for composition weight ratio is 10%~40%, and gelatum skeleton material accounts for composition
Weight ratio be 50%~80%, filler account for composition weight ratio be 2%~6%, antitackiness agent account for composition weight ratio be 1%~
3%, it is 0.5%~2% that lubricant, which accounts for composition weight ratio,.
3. pharmaceutical composition according to claim 1, which is characterized in that gelatum skeleton material be selected from hydroxypropyl methylcellulose,
Sodium carboxymethylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyethylene glycol oxide, sodium alginate or xanthan gum, can be
Hydroxypropyl methylcellulose.
4. pharmaceutical composition according to claim 1, which is characterized in that filler is selected from microcrystalline cellulose, lactose or sugarcane
Sugar can be microcrystalline cellulose.
5. pharmaceutical composition according to claim 1, which is characterized in that antitackiness agent is selected from talcum powder or colloidal silica
Silicon can be talcum powder.
6. pharmaceutical composition according to claim 1, which is characterized in that lubricant be selected from magnesium stearate, hydrogenated vegetable oil,
Polyethylene glycols or sldium lauryl sulfate, can be magnesium stearate.
7. a kind of preparation method of pharmaceutical composition described in claim 1, includes the following steps,
A, desmethylvenlafaxine hydrochloride, partial gel framework material and filler are uniformly mixed；
B, wetting agent granulation is added by spraying, wet granular obtained is dried, obtains dry particl after whole grain；
C, tabletting after addition remainder gelatum skeleton material, lubricant and antitackiness agent total mix.
8. the method according to the description of claim 7 is characterized in that the addition speed of wetting agent is 5 Grams Per Seconds~40 Grams Per Seconds.
9. the method according to the description of claim 7 is characterized in that wetting agent is selected from ethyl alcohol or ethanol water.
10. according to the method described in claim 9, it is characterized in that, the volume ratio of ethyl alcohol is more than or equal in ethanol water
60%.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112545894A (en) * | 2020-12-05 | 2021-03-26 | 钱汉云 | Full-automatic intelligent tablet processing technology |
| CN113842364A (en) * | 2021-11-19 | 2021-12-28 | 福建瑞泰来医药科技有限公司 | Oral solid preparation and preparation method thereof |
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| CN101663263A (en) * | 2007-02-21 | 2010-03-03 | 塞普拉柯公司 | Solid forms comprising (-) o-desmethylvenlafaxine and uses thereof |
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| CN112545894A (en) * | 2020-12-05 | 2021-03-26 | 钱汉云 | Full-automatic intelligent tablet processing technology |
| CN113842364A (en) * | 2021-11-19 | 2021-12-28 | 福建瑞泰来医药科技有限公司 | Oral solid preparation and preparation method thereof |
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Application publication date: 20190521 |