CN1162263A - Cisapride extended release oral compositions - Google Patents
Cisapride extended release oral compositions Download PDFInfo
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- CN1162263A CN1162263A CN 95195951 CN95195951A CN1162263A CN 1162263 A CN1162263 A CN 1162263A CN 95195951 CN95195951 CN 95195951 CN 95195951 A CN95195951 A CN 95195951A CN 1162263 A CN1162263 A CN 1162263A
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- cisapride
- preparation
- slow releasing
- tartrate
- releasing preparation
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Abstract
The present invention concerns extended release formulations comprising cisapride-(L)-tartrate, in particular an oral formulation, the use thereof as a medicine, especially in treating gastrokinetic disorders.
Description
The present invention relates to be specially adapted to the slow releasing preparation (extended release formulation) that contains cisapride-(L)-tartrate of oral administration and as the application of medicine, particularly as in the application aspect the medicine of treatment gastroenteropathy.
European patent number 0,076 discloses medicine for stomach dynamic cisapride and conventional compositions thereof in 530, and cisapride has following structural:
The chemical system name of cisapride is called cis-4-amino-5-chloro-N-' (1-(3-(4-fluorophenoxy) propyl group)-3-methoxyl group-4-piperidyl)-2-methoxy benzamide.Cisapride is the racemic mixture of two kinds of enantiomer.Cisapride has fabulous digestive tract power stimulus quality and it is reported, cisapride does not have the activity of dopamine antagonist.Wide coverage the application of cisapride in the treatment of various gastrointestinal disease.
Effectively the cisapride oral slow-releasing preparation should discharge active component in 15-24 hour, i.e. cisapride, and along with the change of pH value, it is by whole gastrointestinal tract.Yet the dissolubility of cisapride depends on the pH of surrounding to a great extent.
In the highly acid medium such as gastric juice of pH1-2, the dissolubility of cisapride is maximum.As in intestinal, dissolubility reduces rapidly when the pH of (physiology) medium increases.Therefore, effectively slow release cisapride preparation should not only all play a role at highly acid but also in faintly acid or neutral medium.In addition, slow releasing preparation should just discharge active component immediately and should discharge active component in a continuous manner when giving preparation, preferably follow zero level to first order kinetics.Needing such preparation, is because it just can alleviate patient's symptom soon after administration, and avoid because of successive administration may cause excessive.
Use (+)-cis-4-amino-5-chloro-N-(1-(3-(4-fluorophenoxy) propyl group)-3-methoxyl group-4-piperidyl)-2-methoxy benzamide (R (R in the described hereinafter matrix formulations
*, R
*))-2,3 dihydroxybutanedioic acid salt (1: 1) found the solution at this problem when (hereinafter being called " cisapride-(L) tartrate ").Cisapride-(L)-tartrate be the raceme cisapride with the tartaric salt of (+)-L-and at european patent number 0,076, be illustrated as chemical compound 241 in 530.
Shown in hereinafter embodiment, the present invention is that the production method of slow releasing preparation is very simple on the other hand.The production method of this and preparation slow releasing preparation known in the art forms contrast.
Compare with other salt of cisapride, with (R (R
*, R
*))-2,3 dihydroxybutanedioic acid, i.e. the salt that (+)-L-tartaric acid (being tartaric native form) forms shows good especially water-soluble.The salt that the cisapride of racemic mixture form and the tartaric acid of single enantiomeric form produce is mainly two kinds of diastereoisomeric salts: the mixture of (+)-cisapride-(L)-tartrate and (-)-cisapride-(L)-tartrate.
Be surprised to find that cisapride-L-tartrate is the mixture of diastereomer ((3R4S) (2R3R)) and ((3S4R) (2R3R)), its crystallization is 1: 1 a double salt, (determining by the X-line).(3R4S) and (3S4R) be respectively the enantiomer of cisapride and (2R3R) be optical voidness L-tartrate anion.
Be surprised to find that, the preparation that contains cisapride-(L)-tartrate discharges the cisapride of racemic form, be (+)-cisapride of equivalent and (-)-cisapride or in other words, be surprised to find that diastereomer salt form (+)-cisapride-(L)-tartrate and (-)-cisapride-(L)-tartrate has identical dissolution rate.
Find in addition, in preparation cisapride-(L)-tartrate process, do not find the phenomenon a kind of on the high side in two kinds of diastereomer salt forms.
The present composition comprises pharmaceutically suitable carrier and excipient, as filler, and for example lactose, sucrose, mannitol, corn starch, preferred lactose; Lubricant, for example stearic acid, magnesium stearate, Pulvis Talci or silicon dioxide or its mixture; Preferred magnesium stearate, Pulvis Talci and colloidal silica (Aerosil
) mixture.Also can there be other pharmaceutically acceptable adjuvant such as coloring agent or correctives etc.
" delay " effect or " slow release " effect are owing to cisapride-(L)-tartrate is embedded in the mixture of two kinds of sticky polymers and produces.Therefore, comprise the mixture of bigger hydrophilic polymer of viscosity and viscosity hydrophilic polymer in the said preparation, it discharges active component gradually from preparation.With regard to active component of the present invention, cisapride-(L)-tartrate, usually can utilize plain derivant of hydroxypropyl emthylcellulose and another kind of viscous fiber such as hydroxypropyl cellulose, ethyl cellulose, hydroxyethyl-cellulose, hydroxyethylmethyl-cellulose, methylcellulose, the mixture of preferred hydroxypropyl cellulose obtains said preparation.
When contacting with water, these two kinds of hydrophilic polymeies expand and therefore produce porous sample substrate, and by these holes, cisapride discharges gradually.Described polymer itself also slowly is dissolved in the aqueous medium.Then, therefore dosage surface also dissolving constantly makes that also aqueous medium arrives the more nexine of polymeric blends, and conversely, polymer begins swelling and discharges active component, therefore, provides the active component of continuous release to make it follow zero level-first order kinetics.
Preferably, the viscosity of the hydroxypropyl emthylcellulose that uses in said mixture is approximately 15,000mPa.s, for example hydroxypropyl emthylcellulose (hypromellose) 2208.
Employed hydroxypropyl cellulose should preferably have 150 to the range of viscosities of 700mPa.s in the said mixture, preferably from 200 to 600mPa.s, as Klucel EF
Preferably, the scope of the relative quantity of the hydrophilic cellulosic polymers of viscosity described in preparation mixture is the 15%-35% of total composition weight.The time correlation that the relative quantity of viscosity hydrophilic cellulosic polymers mixture and active component discharge.Minimum, promptly the 15% suitable slow-release time that is provided is approximately 900 minutes.The highest limit promptly 35% provides long release time, the whole active components in discharging preparation.Estimate that it is incomplete that relative quantity be higher than at 35% o'clock to discharge active component.
The weight ratio of hydroxypropyl emthylcellulose and other cellulosic polymer is 0.33-3.Especially the weight ratio of hydroxypropyl emthylcellulose and hydroxypropyl cellulose is 0.33-3.Preferred ratio is 1, and promptly contained hydroxypropyl emthylcellulose is identical with the amount of hydroxypropyl cellulose.
Preferred oral formulations of the present invention is a tablet.
Described tablet can have different shapes, and is for example oval or circular.The shape of tablet influences release time, because different shapes has different surface area/volume ratio.
One skilled in the art will know that the volume of tablet is other parameter such as actual compositions, the function of shape, pre-release time and predose.The compositions example that is provided is a circular tablet, and diameter is approximately 11.5mm and thickness is approximately 5.2mm.
Suitable tablet can have stria or indentation and can have symbol or other sign.
Suitable tablet can be with known coated composition coating in field or coating not.The tablet of coating is the preferred preparation of the present invention.Usually, said components and ratio are applied to especially be applied in " tablet core " in " preparation core ".Hereinafter the compositions with these " preparation cores " is called core component.
Suitable coated preparation comprises film and forms polymer such as hydroxypropyl emthylcellulose, for example hydroxypropyl methylcellulose 2910 (5mPa.s); Plasticizer such as ethylene glycol, for example propylene glycol; Opacifier such as titanium dioxide; Film smoothing preparation such as Pulvis Talci.Add entry as solvent.
：- ( L )-： 2-15％ ( ) ： 50-70％ ( ) ： 15-35％ ( ) ： 0.5-10％ ( ) ：- ( L )-： 5-15％ ( ) ： 50-70％ ( ) ： 15-35％ ( ) ： 0.5-10％ ( ) ：- ( L )-： 8-12％ ( ) ： 55-65％ ( ) ： 20-25％ ( ) ： 2.5-8％ ( ) ：- ( L )-： 9％ ( ) ： 61％ ( ) ： 23.5％ ( ) ： 6.5％ ( ) ：- ( L )-： 9％ ( ) ： 61％ ( ) ： 5.5-18％ (*) hydroxypropyl cellulose: 5.5-18% (
*) lubricant: 6.5% (weight)
(
*) the cellulose derivative overall weight percent is approximately 23.5%.
Because cisapride has gastrointestinal motility stimulus quality, the present invention utilizes preparation of the present invention as medicine, is particularly useful for treating stomach-intestinal diseases.Embodiment part embodiment 1
In ethanol (81ml) solution of cis-4-amino-5-chloro-N-(1-(3-(4-fluorophenoxy) propyl group)-3-methoxyl group-4-piperidyl)-2-methoxy benzamide (4g) that stirs, add (R (R
*, R
*))-2, ethanol (20ml) solution of 3-dyhydrobutanedioic acid (1.4g) also allows the product crystallization, filter and drying, obtain 4.8g (89%) (+)-cis-4-amino-5-chloro-N-(1-(3-(4-fluorophenoxy) propyl group)-3-methoxyl group-4-piperidyl)-2-methoxy benzamide (R (R
*, R
*))-2,3 dihydroxybutanedioic acid salt (1: 1), i.e. cisapride-(L)-tartrate.Fusing point: 197.1 ℃, and [α]
D 20=6.7 (c=0.1% methanol).Embodiment 2
The component for preparing 1000 (570mg) preparations 1:
The % cisapride of group component tablet weight-(L)-tartrate 52.92g 9.3% lactose 346.08g 60.7% hydroxypropyl methylcellulose 2208 66g 11.6%Klucel EF
67.95g 11.9% water (
*) the 60g isopropyl alcohol (
*) 140g magnesium stearate 2.85g 0.5%Aerosil
5.7g 1.0% Pulvis Talci 28.5g 5.0%
(
*) in the final composition of tablet, do not comprise these components.
Preparation:
With the cisapride of above-mentioned amount-(L)-tartrate, lactose, hydroxypropyl emthylcellulose, Klucel EF
In rustless steel frame sieve (sieve mesh: sieve 0.95mm) and in planetary powder blenders, mixed 5 minutes.With isopropyl alcohol and water-wet mixture.Moistening mixture is sieved (sieve mesh: sieve 1.8mm) at frame once more.With mixture 45 ℃ of following dried overnight.Dried granules is sieved (sieve mesh: sieve 0.95mm) at frame.With drying and the granule that sieved and the magnesium stearate of sieving, Aerosil
Mixed 5 minutes in planetary powder blenders with Pulvis Talci.The preparation of tablet:
Utilize said mixture, extrude 1000.Embodiment 3
Be used to prepare the component of 1000 (every 570mg) preparations 2:
Group component tablet weight % cisapride-(L)-tartrate 52.92g 9.3% lactose 346.08g 60.7% hydroxypropyl methylcellulose 2208 40g 7.0%Klucel EF
93.95g 16.5% water (
*) the 45g isopropyl alcohol (
*) 105g magnesium stearate 2.85g 0.5%Aerosil
5.7g 1.0% Pulvis Talci 28.5g 5.0%
(
*) in the final composition of tablet, do not comprise these components.
Preparation is quite analogous to preparation 1 described preparation method.Embodiment 4
Be used to prepare the component of 1000 tablet preparations: cisapride-(L)-tartrate 52.92mg lactose-hydrate 346.08mg hydroxypropyl methylcellulose 2208 15000mPa.s 66mg hydroxypropyl cellulose 67.95mg water (
*) isopropyl alcohol (
*) magnesium stearate 2.85mgAerosil
5.7mg Pulvis Talci 28.5mg
Coated composition: hydroxypropyl methylcellulose 2910 5mPa.s 12mg propylene glycol 3mg titanium dioxide 3mg Pulvis Talci 2mg water (
*) 120mg
Preparation:
With cisapride-(L)-tartrate, lactose, hydroxypropyl emthylcellulose and Klucel
Mixing and moistening in high shear mixing-granulating machine with the mixture of isopropyl alcohol and water.Vacuum and heating drying and obtain granule.After the dried granules calibration, add aerosil, Pulvis Talci and magnesium stearate and mixing are up to obtaining uniform mixture.Mixture is pressed into the double-convex tablet, and its diameter is that 11.5mm and weight are approximately 570mg.
In suitable coating container, use the coating suspension of forming by hydroxypropyl emthylcellulose (5mPa.s), propylene glycol, titanium dioxide, Pulvis Talci and water to come coated tablet.
Claims (10)
1. one kind is used for oral administration, comprises the slow releasing preparation of cisapride-(L)-tartrate.
2. the slow releasing preparation of claim 1, it comprises hydroxypropyl emthylcellulose and the plain mixture of polymers of another kind of viscous fiber.
3. the slow releasing preparation of claim 2, it comprises the mixture of hydroxypropyl emthylcellulose and hydroxypropyl cellulose.
4. the slow releasing preparation of claim 2, wherein the core of preparation comprises 15%-35% hydroxypropyl emthylcellulose and the plain mixture of polymers of another kind of viscous fiber.
5. the slow releasing preparation of claim 4, wherein the weight ratio of hydroxypropyl emthylcellulose and hydroxypropyl cellulose is approximately 0.33-3.
6. the slow releasing preparation of claim 5, wherein the weight ratio of hydroxypropyl emthylcellulose and hydroxypropyl cellulose is approximately 1.
7. the slow releasing preparation of arbitrary claim among the claim 1-4, it comprises: cisapride-(L)-and tartrate: about 9% (weight ratio) lactose: about 61% (weight ratio) hydroxypropyl emthylcellulose: 5.5%-18% hydroxypropyl cellulose: 5.5%-18% lubricant: the gross weight of about 6.5% (weight ratio) cellulose derivative is approximately 23.5%.
8. the cisapride of crystal type-(L)-tartrate, wherein diastereomer ((3R4S) (2R3R)) and ((3S4R) (2R3R)) with 1: 1 ratio with the crystallization of double salt form.
9. the method for the slow releasing preparation of arbitrary claim among the preparation claim 1-7 is characterized in that the pharmaceutically acceptable component of active component and other fully mixes.
10. the compositions of utilizing arbitrary claim among the claim 1-7 is as medicine, and is special in the application that is used for the treatment of the medicine of gastroenteropathy.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 95195951 CN1162263A (en) | 1994-11-02 | 1995-10-25 | Cisapride extended release oral compositions |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP94203184.0 | 1994-11-02 | ||
| CN 95195951 CN1162263A (en) | 1994-11-02 | 1995-10-25 | Cisapride extended release oral compositions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1162263A true CN1162263A (en) | 1997-10-15 |
Family
ID=5083052
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 95195951 Pending CN1162263A (en) | 1994-11-02 | 1995-10-25 | Cisapride extended release oral compositions |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1162263A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1466451B (en) * | 2000-09-29 | 2010-05-12 | 索尔瓦药物有限公司 | Ion-strength independent sustained release pharmacetuical formulation |
| CN109394711A (en) * | 2018-11-06 | 2019-03-01 | 威海贯标信息科技有限公司 | A kind of cinbitrate tartrate tablet composition |
| CN111110645A (en) * | 2020-02-14 | 2020-05-08 | 齐齐哈尔医学院 | Mosapride citrate sustained release tablet and preparation method thereof |
-
1995
- 1995-10-25 CN CN 95195951 patent/CN1162263A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1466451B (en) * | 2000-09-29 | 2010-05-12 | 索尔瓦药物有限公司 | Ion-strength independent sustained release pharmacetuical formulation |
| CN109394711A (en) * | 2018-11-06 | 2019-03-01 | 威海贯标信息科技有限公司 | A kind of cinbitrate tartrate tablet composition |
| CN111110645A (en) * | 2020-02-14 | 2020-05-08 | 齐齐哈尔医学院 | Mosapride citrate sustained release tablet and preparation method thereof |
| CN111110645B (en) * | 2020-02-14 | 2022-02-22 | 齐齐哈尔医学院 | Mosapride citrate sustained release tablet and preparation method thereof |
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