CA1200494A - Process of producing composition for long acting nicardipine preparation - Google Patents
Process of producing composition for long acting nicardipine preparationInfo
- Publication number
- CA1200494A CA1200494A CA000418228A CA418228A CA1200494A CA 1200494 A CA1200494 A CA 1200494A CA 000418228 A CA000418228 A CA 000418228A CA 418228 A CA418228 A CA 418228A CA 1200494 A CA1200494 A CA 1200494A
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- composition
- nicardipine
- mixture
- water
- organic solvent
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Hydrogenated Pyridines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
A spherical pellet like composition of nicardipine showing long acting activity is produced by dissolving (a) nicardipine or a salt thereof (b) a pH-dependent additive and/or a water-soluble polymer, and, if necessary, a surface active agent in an organic solvent, a mixture of organic solvents or a mixture of water and an organic solvent and spray-coating small granular nuclei such as, for example, sugar particle with the solution.
The spherical pellet like composition of nicardipine may be further spray-coated with an organic solution of a medicament permeating material for further prolonging the long acting activity. Moreover, the spherical pellet like composition may be mixed with the spherical pellet like composition coated with the medicament permeating material.
A spherical pellet like composition of nicardipine showing long acting activity is produced by dissolving (a) nicardipine or a salt thereof (b) a pH-dependent additive and/or a water-soluble polymer, and, if necessary, a surface active agent in an organic solvent, a mixture of organic solvents or a mixture of water and an organic solvent and spray-coating small granular nuclei such as, for example, sugar particle with the solution.
The spherical pellet like composition of nicardipine may be further spray-coated with an organic solution of a medicament permeating material for further prolonging the long acting activity. Moreover, the spherical pellet like composition may be mixed with the spherical pellet like composition coated with the medicament permeating material.
Description
~2~
A PROCESS OF PRODUCING COMPOSITION FOR LONG ACTING
NICARDIPINE PREPARATION
FIELD OF TH~ INVENTION
_ This invention relates -to a process of producing of a composition for a long acting or long lasting prepara-tion of nicardipine (chemical name: 2,6-dimethyl-4-(3'-nitro-phenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-~-(N-benzyl-N-methylamino)-e-thyl ester) or a salt thereof.
BACKGROUND OF THE INVENTION
Nicardipine possesses a coronary dilator activity and a cerebral vascular di]ator activity, and is a medicament useful for curing cerebral vascular disease, hypertension, and angina pectoris. Since nicardipine or its salt has a good solubili-ty in the first fluid of Japanese Pharmacopeia IX (a fluid of about pH 1.2 prepared by adding 24.0 ml of diluted hydrochloric acid and water to 2.0 g of sodium chloride to make 1,000 ml of the solution), it exhibits sufficiently the medical activity in usual preparations but since nicardipine is sparingly soluble in the second fluid of Japanese Pharmacopeia IX (a fluid of about pH 7.5 prepared by addin~ 6.0 ml of diluted hydrochloric acid and water to 35.8 g oE disodium hydrogenphosphate to make 1,000 ml of the solu-tion) and is poor in solubility in intestinal juice, it is di.fficult to realize a long acting prepara-tion of nicardipine.
Since a long acting preparation has many therapeutic advantages c~
~2~3~
Erequency such as the reduction in dosing/of the medicament~
long acting effective concentration of medicament in blood, etc.~, various general long acting preparations have hithe~to been developed. For example, there are a prepara-tion having compo~nded therewith a large amount of a material which is reluctant to collapse in stomach or intestines, a preparation formed by coating pellets or tablets with a water repellent, and a preparation formed by mixing a medicament with a sparingly soluble or hydrophilic high molecular compound or by adsorbing the high molecular compound onto a medicament, thereby the medicament is gradually released. Howe~er, in t~e case of a medicament having a low solubility in an intestinal juice, such as nicardipine or a salt thereof, a long acting effect cannot be expected by such conventional long acting preparations. That is, the appli-cation of the foregoing conventional long acting technique to such a medicament may cause only the reduction of bio-availability and hence in the case of such a medicament it is necessary to compound therewith an additive for improving the solubility thereof in an intestinal juice to improve the solubility of the medicament.
Therefore, various processes of producing long acting preparations of nicardipine have been proposed. For example, there are a process of producing a long acting preparation o~
nicardipine by dissolving nicardipine in water or organic solvent~together with (a) hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), methyl cellulose (MC), etc., and further, if desired, (b) polyethylene glycol, a sur~ace active agent1 etc., removing water or the organic solvent to form solid material, pulverizing, if necessary, the solid mate~ial, and then adding thereto polyethylene oxide (PEO); or by adding PEO to nicardipine and the components (a) and (b), dissolving the mixture in water or organic solvent~S) removing the water or the organic solvent(S)to form a solid material, pulverizing, if necessary, the solid material, and then forming the preparation using the solid material or the pulverized solid material (Japanese Patent Application ~OPI) No. 49,314/'81) and a process of producing a long acting preparation of nicardipine by, if necessary, riction~:pulverizing nicardipine crystals pH~
and adding a/ ~dependent additive, diluents , etc~, to the nicardipine crystals be~ore or after pulverizing them (Japanese Patent Application (OPI) No.
133,217/'81). However,-the preparations obtained by these processes have such demerits that the concentration of the medic~nent ~oes not reach to an effective plasma level in a short period of time after the adminstration of it, clinically the / effective ~lasma level is not sufficiently ~ nterstibject variation of plasma maintained, the /of concentration, etc.
SUMMARY OF THE INVENTION
~ .
Under these circumst~nces /as the result o~- varlous investigations on long actlng preparations of nicardipine~
the inventors have discovered that a spherical pellet like composition (Composition A) formed by coating small granular nuclei with ta) amorphous nicardipine or a salt thereof, (b) ~2~
a pH-dependent additive and/or a water-soluble polymer and, if desired, a surface active agent an~ a spherical pellet like'composition (Composition B) formed by ~urther (Composition A) coating the ~oregoing composition/with a medicament-permeating material have an excellent long acting effect. Furthermore, t has been discovered that by mixing Composition A and B appropriate Composition/at an /ratio, a composition having a desired long acting effect is obtained. Based on these discoveries, the invention has been attained.
Thus, the invention provides a spherical pellet like long acting composition comprising small granular nuclei coated with (a) amorphous nicardipine or a salt thereof and (b) a pH-dependent additive and/or a water-soluble polymer.
The foregoing c~mposition may have further been coated with (c) a medica~ent-permeating material.
By the composition of this invention, the solubility ot`
icardipine in an intestinal juice can be remarkabl~ improved plasma the intersubject variation of /concentra-significant extent tion can be reduced to a /and the clinically effective plasma level can be maintaine~for a long period of time as compared to conventional preparations of nicardipine.
DESCRIPTION OF THE PREFERED EMBODIMENT
Composition A of this lnvention can be produced ~y dissolv-ing (a) nicardipine or a salt thereof, (b) a pH-dependent additive and/or a water-soluble polymer, and further. if desired, a surface active agent in an organic solvent or a mixture of water and an organic solvent and coating small granular nuclei with the solution by, e. g., spray coating.
~31~
Also~ composi~ion B can be produced by further spray-coating composition A with a solution of a medicament permeating material dissolved in an organic solvent.
More practically~ composition A can be obtained by dissolving (a) nioardipine or a salt thereo~, (b) a pH-reliability additive and/or a water-soluble polymer, and, if desired, a surface active agen~ in an organic solvent such as methanol, ethanol, isopropanol, chloroform, acetone1 1nethylene chloride, etc.~ a mixture of them, or a mixture of water and the foregoing organic solvent and coating small granular nuclei composed of crystalline cellulose, a mix~ure oF sugar and corn starch~ a mixture of crystalline cel7ulose and lactose etc.~
(e.g., Nonpareil*, made by Freund Industrial Co. Ltd~) by a spray coating method~ such as, a centrifugal fluidized coating method, a fluidized bed coating me~hod, etc. Also~ Composi~ion B of this invention can be obtained by further coating the composition A
thus obtained with a solution of a medicament permeating material dissolved in the foregoing organic solvent by, for example, a spray coating method to form, thereby~ a layer of ~he medicament permeating ma~erial on the composi~tion. In such a production process of the preparation~ nicardipine or a salt thereof is converted into the amorphous form.
I n addition, regarding composition A, the long acting property considerably changes according to the k~nd and nature of additives used. For example, when a pH dependent additive is used, a composition having a high l~ong acting property is obtained but when a pH-dependent additive is not used~ a *trade mark composition having a low acting property is obtained.
Examples of the foregoing pH-dependent additive are hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate7 Eudragit-L* and -S* (made by Ro~m and Haas Co., components: a methylme~hacrylatemethacrylic acid copolymer), etc.
Examples of the surface active agent used in this invention are Tween 80* (made by Kao Atlas Co., component: polyoxyethylene sorbitan mono-olèate~, Renex 30* (made by ICI Co., component:
polyoxyethylene alkyl ether), Nikkol HC0-60* (made by Nikko Chemicals Co., Ltd., componen~: polyoxyethylene-hydrogenated castor oil), etc. Also, examples of the water~-soluble polymer are HPC* (made by Shin-Etsu Chemical Co., Ltd~, composition: hydroxy propyl cellulosel, macrogol 400, 1500 and 6000 (Jap~ Pharmacopeia X, component: polyoxyethylene glycol), Metholose* (made by Shin-Etsu Chemical Co., Ltd., composition: methyl cellulose), TC-5* (made by Shin-Etsu Chemical Co., Ltd., compsnent:
hydroxypropylmethyl cellulose), etc. Furthermore, examples of ~he medicament permeating material are Eudragit* RL and RS (made by Rohm and Haas Co., component: ethylmethacrylate-trimethylammonio-e~hylmethacrylatechloride copolymer3, Ethocel* (made by Dow Chemical Co., component: ethyl cellulose), and mixture thereof with foregoing water-soluble polymers.
In composition A, the ratio of the coating to the srnall granular nucleus is L: 0~1 to 1 : 10 and in composition B, the ratio of the medicament permeating material to the composi~ion A
is 15 : 85 to 1 : 99.
Also, in the mixture of composition A and composi~ion B
.
*trade mark the effective concentration o* nicardipine in blood can be maintained for a longer period of time than the case of using each composition solely since there is a difference in the rate of dissolution between both the compositions. Furthermore, if a composition of nicardipine showing a high concentration in bloodim~ediatelyxafter administration and also maintaining the concentration for a long time is desired, the object can be attained by using composition A having low lasting property (or almost no lasting property) and composition B having a long lasting property. Such a composition can be obtained by blendingcomposition A and Composition B at a ratio o~ O.S {
to 1 : 19 by a conventional method~
The composition of this invention can be adminstered as the form of itself or may be filled in a capsule by a conventional method and administered as the capsulated composition.
Compositions of this invention are tested on long acting effect and the results are shown in tables 1 and ~.
W ` ~ X ~h O X l-h O 3 . . . ~ ~ 3 O ~ . .. __ ~ ,,(D,__ ~ _1~ ,,__ 1~ p) 15~ ~ ~ ~ I-h O ~ ~ ~ QJ O !Z
pJ ~ . O ' ~ ~1 CO O ~h O
_____ _ _ ~ 11 4 ~
O~ 3 3 3 O P , ~ 7~ ~ ~ ~ _ O _ .. _ ~ O ~ ~ , ~ o o. ~ _ _ _ .. _ O
~ 00 00 ~ 3 ~ 00 -00 ~0 O
_ _L~ l Oh ~i _ _ It . I-h . . _ __ . ~ _ _ ._ ., _ ~ ~D ~ I_ o ~D
c ~ ?al ~ o ~ ~
~ ~ U~ ~ ~ . ~ ,. ~
O .~ _ ~ ~ ~ a~ ~ O .
co t~ ~_ w : ~n n o~ ~ _ _ ~ g ~
t ~ ~ ~ _~ ~ ~ ~ ~ ~ ~
:~- - ---- --' -t -_ - ~ __ _ 1~ ~
31- ~ ~ -~n ~ I 1- ~5 U~ g ~D
~:: _ ~ l ~ (D ~ o M (D O
Ul ~ ~ ~ _ h ,~ a~ ~ _ h (D . _ ~__ ~t w ~ o u~ 3 P
O ~ 1~ ~ ~ ~ :~ ~ ~Q, ~2 ~to~ 3 1 w~ ~ ~ :~- ,w U3 ~ :~
___ _ IJ. , Ul ~, U~
_~ _ __ ~t î~ ~
~ ' 1- ~ ~ ~' O
~ I ::~ rt ~ I W~ ~
~ ~ ~ I O W ~ n _ W
W N 1_. 3 1-- t~ ~t ._ ~ _ _.__ --tO~- ~ ._~ _ o t~ _~ , 1_ ~ ~ ~
,o i,-l- ~ ~ ~ _ Then, the invention will be Fur~her explained in detail by ~he following examples but the inven~ion is not limited to them.
Example 1.
I n a 5 1 i ter centri Fugal f`l ui di zed bed coati ng apparatus was placed 728.6 9 of Nonpareil 103* (made by Freund Indus~rial Co., L~d~ main component: sugar) and 1.2 kg of a solution of 80 g of nicardipine hydrochl ori de, 80 9. of hydroxypropyl methyl cellulose phthalate, HP-55* ~made by Shin-Etsu Chemical Co., Ltd.~ and 20 9 of Tween-80* completely dissolved in a mixkure of methanol and methylene chloride (1: 1 by weight ratio) was spray-coated onto Nonpareil 103* by a conventional method to form a s pheri cal pel 1 et 1 i ke composi ti on (continue) ' ' .
*trade mark If necessary, a proper amount o~ talc may be added thereto to prevent the spherical pellet like compositions from sticking with each other. After drying the composition for 4 hours at 40 C, the composition was filled in capsules by a conventional method to provide capsulated composltion.
Example 5, After drying the spherical pellet like composition produced in Example 4 for 4 hours at 40 C, 200 g of an acetone isopropanol ~1 : 1 by weight ratio) solution having completely dissolved therein 10 g of Eudragit RL-100 was applied to 500 g of the spherical pellet like composition as in Example 1 to form a medicament permeating coating on the composition.
If necessary, a proper amount of talc may be added to prevent the sp~erical pellet like compositions from sticking with each other. The resultant composition was dried as in Example 4 and filled in capsules by a conventional methcd to provide capsulated composition.
Example 6.
The spherical pellet like composition produced in Example blended well 4 was /with the spherical pellet like composition produced in Example 5 at a ratio of 3 : '7 by weight ratio by acvnventional method. The resultant mixture was filled in capsules by aConv~n~ional methc~ to provide capsulated composition.
Example 7.
In a fluidized bed type granulator (GL~TT WSG 15) was placed 12 kg of Nonpareil 103 ~24-32 mesh) and 53~3 kg of a methanol-methylene chl~,oride (l 1 by weight ratio) solution having completely dissolved therein 4 kg of nicardipine _ 1~--If necessary, a proper amount or talc may be added to the mixture for preventing the spherical pellet like compositions from sticking with each other~ After drying the composi~ion or 4 hours at 40C, the composition was filled in capsules method composition.
by a conventional to provide capsulated/~ nn~
Example 2.
After drying the spherical pellet like composition produced p~pa~e~ as in Example 1 for 4 hours at 40 C, 90 g of an acetone-isopropanol solution of 8% Eudragi~ RL-100 per 500 g ~ oated of the compositio~was spray~ onto the composition as in Example 1 to apply a medicament permeating coating on the composition. If necessary, a small amount of talc may be added for preventing the spherical pellet like compositions from forming lumps o~ them. After drying the coated composi-ion for 4 hours at 40C~ the composition was filled inmethod capsules by a conventional ¦to provide capsulted composition.
~xal~cxs~P~x Example 3.
The spherical pellet like composition produced in Example blended 1 was /with the spherical pellet like composition produced in ~xample 2 at a ratio of 3 : 7 by weight ratio and the resultant mixture was filled in casules by a conventional method to provide capsulated composition.
Example 4.
682g of Nonpareil 103r 8y following the same procedure as in Example 1 using~
kg oY a me~hanol-methylene chloride ~1 : 1 by weight ratio) solution having completely dissolved t~ereln, 80g of Eudragit L-100 80 g of nicardipine hydrochloride,/and 20 g of Tween-80, a spherical pellet like composition was obtained.
- rl-hydrochloride /and 4 kg of hydropropylmethyl cellulsoe (TC-5) was sprayed thereto to provide a spherical pellet like compo~
sition. T~e composition thus obtained was dried for 4 hours at 40C.
Example 8.
In a fluidized bed type granulator (GL~TT WSG 15) was placed 60 kg of 9.5 kg of ~onpareil 103 (24-32 mesh) and then/a methanol-ethylene chloride (1 : 1 by weight ratio) solution havinghydrochloride, completely dissolved therein 4 kg of nicardipine/
4 kg of Eudragit L-100, and 2 kg of Tween 80 was sprayed thereto by a conventional method to provide a spherical pellet like composition. The composition thus obtained was dried for one hour at 40C.
Then, 18.5 kg of the spherical pellet like composition was spray~coatad with 7,4 kg of a methanol-methylene chloride (1 : 1 by weight ratio~ solution having completely dissolved therein 670 g of Eudragi~ L-100 and 70 g of Macrogol 400 by a o~nventicnal method to provide a spherical pellet like composition coated with the medicament permeating material.
Exa~ple 9.
In a V type mixer were placed 2 kg of the spherical pellet like composition produced in Example 7 and 8 kg of the coated spherical pellet like cornposition produced in Example 8 and after adding thereto ?00 g of talc, the resultant mixture was ccmpoun~ until the mixture became sufficiently uniform. The mixture thus obtained was filled in capsules to provide capsulated composition.
Example 10.
In a fluidized bed type granulator (UNIGRATT) was placed 950 g o~ Nonpareil 103 (less than 32 mesh) and then a 20%
water-containing methanol solution having dispersed and hydrochloride, dissolved therein 400 g of nicardipine/ 400 g of Eudragi~ L-100, and 100 g of T~een ao was sprayed thereto by a conventional method to provide a spherical pellet like composi-tion. The composition thus obtained was dried for about 4 t hours at 40C. Then, 1,850 g of the spherical pellet like composition was spray-coated with 740 g of a methanol-methylene chloride (1 : 1 by weight ratio) solution having dissolved therein 50 g of Et~cell CP-10, 50 g of hydroxy-propylmethyl cellulose (TC-5) ~ and 11 g of Macrogol 400 by a conventional method to apply medicament permeat-ing coating.
Then, 800 g of the coated spherical pellet like composi-tion thus produced was uniformly mixed with 200 g of the spherical pellet like composition produced in Example 7 by the same manner as in Example 9 and the resultant mixture was f`illed in capsules to provide capsulated composition.
Example 11.
By spray-coating 200 g of Nonpareil 103 (32-42 mesh) with 1.8 kg of a methanol-methylene chloride (1 : 1 by weight ratio) solution having completely dissolved therein 80 g of nicaridipine hydrochloride, 80 g of Eudragit L 100, and 40 g of Macrogoal 1500 in aCcnventional metho~, a spherical pellet like composition was obtained.
~ 13 -Example 12.
By spray-coating 500 g of the spherical pellet like composition obtained in Example 11 with 200 g o~ a methanol-dichloromethane (1 : 1 by weight ratio) solution having completely dissolved therein 20 g of Eudragit RL-100, medicamant permeating coating was applied thereon.
Example 13.
The spherical pellet like composi.tions obtained in uniformly Example 7, Example 11, and Example 12 were/mixed with eacn other at a weight ratio of 1.5 : 5.0 : 3.5 and after adding thereto 2~ talc, the resultant mixture was filled in capsules to provide capsulated compositionO
- 1.4 -
A PROCESS OF PRODUCING COMPOSITION FOR LONG ACTING
NICARDIPINE PREPARATION
FIELD OF TH~ INVENTION
_ This invention relates -to a process of producing of a composition for a long acting or long lasting prepara-tion of nicardipine (chemical name: 2,6-dimethyl-4-(3'-nitro-phenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-~-(N-benzyl-N-methylamino)-e-thyl ester) or a salt thereof.
BACKGROUND OF THE INVENTION
Nicardipine possesses a coronary dilator activity and a cerebral vascular di]ator activity, and is a medicament useful for curing cerebral vascular disease, hypertension, and angina pectoris. Since nicardipine or its salt has a good solubili-ty in the first fluid of Japanese Pharmacopeia IX (a fluid of about pH 1.2 prepared by adding 24.0 ml of diluted hydrochloric acid and water to 2.0 g of sodium chloride to make 1,000 ml of the solution), it exhibits sufficiently the medical activity in usual preparations but since nicardipine is sparingly soluble in the second fluid of Japanese Pharmacopeia IX (a fluid of about pH 7.5 prepared by addin~ 6.0 ml of diluted hydrochloric acid and water to 35.8 g oE disodium hydrogenphosphate to make 1,000 ml of the solu-tion) and is poor in solubility in intestinal juice, it is di.fficult to realize a long acting prepara-tion of nicardipine.
Since a long acting preparation has many therapeutic advantages c~
~2~3~
Erequency such as the reduction in dosing/of the medicament~
long acting effective concentration of medicament in blood, etc.~, various general long acting preparations have hithe~to been developed. For example, there are a prepara-tion having compo~nded therewith a large amount of a material which is reluctant to collapse in stomach or intestines, a preparation formed by coating pellets or tablets with a water repellent, and a preparation formed by mixing a medicament with a sparingly soluble or hydrophilic high molecular compound or by adsorbing the high molecular compound onto a medicament, thereby the medicament is gradually released. Howe~er, in t~e case of a medicament having a low solubility in an intestinal juice, such as nicardipine or a salt thereof, a long acting effect cannot be expected by such conventional long acting preparations. That is, the appli-cation of the foregoing conventional long acting technique to such a medicament may cause only the reduction of bio-availability and hence in the case of such a medicament it is necessary to compound therewith an additive for improving the solubility thereof in an intestinal juice to improve the solubility of the medicament.
Therefore, various processes of producing long acting preparations of nicardipine have been proposed. For example, there are a process of producing a long acting preparation o~
nicardipine by dissolving nicardipine in water or organic solvent~together with (a) hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), methyl cellulose (MC), etc., and further, if desired, (b) polyethylene glycol, a sur~ace active agent1 etc., removing water or the organic solvent to form solid material, pulverizing, if necessary, the solid mate~ial, and then adding thereto polyethylene oxide (PEO); or by adding PEO to nicardipine and the components (a) and (b), dissolving the mixture in water or organic solvent~S) removing the water or the organic solvent(S)to form a solid material, pulverizing, if necessary, the solid material, and then forming the preparation using the solid material or the pulverized solid material (Japanese Patent Application ~OPI) No. 49,314/'81) and a process of producing a long acting preparation of nicardipine by, if necessary, riction~:pulverizing nicardipine crystals pH~
and adding a/ ~dependent additive, diluents , etc~, to the nicardipine crystals be~ore or after pulverizing them (Japanese Patent Application (OPI) No.
133,217/'81). However,-the preparations obtained by these processes have such demerits that the concentration of the medic~nent ~oes not reach to an effective plasma level in a short period of time after the adminstration of it, clinically the / effective ~lasma level is not sufficiently ~ nterstibject variation of plasma maintained, the /of concentration, etc.
SUMMARY OF THE INVENTION
~ .
Under these circumst~nces /as the result o~- varlous investigations on long actlng preparations of nicardipine~
the inventors have discovered that a spherical pellet like composition (Composition A) formed by coating small granular nuclei with ta) amorphous nicardipine or a salt thereof, (b) ~2~
a pH-dependent additive and/or a water-soluble polymer and, if desired, a surface active agent an~ a spherical pellet like'composition (Composition B) formed by ~urther (Composition A) coating the ~oregoing composition/with a medicament-permeating material have an excellent long acting effect. Furthermore, t has been discovered that by mixing Composition A and B appropriate Composition/at an /ratio, a composition having a desired long acting effect is obtained. Based on these discoveries, the invention has been attained.
Thus, the invention provides a spherical pellet like long acting composition comprising small granular nuclei coated with (a) amorphous nicardipine or a salt thereof and (b) a pH-dependent additive and/or a water-soluble polymer.
The foregoing c~mposition may have further been coated with (c) a medica~ent-permeating material.
By the composition of this invention, the solubility ot`
icardipine in an intestinal juice can be remarkabl~ improved plasma the intersubject variation of /concentra-significant extent tion can be reduced to a /and the clinically effective plasma level can be maintaine~for a long period of time as compared to conventional preparations of nicardipine.
DESCRIPTION OF THE PREFERED EMBODIMENT
Composition A of this lnvention can be produced ~y dissolv-ing (a) nicardipine or a salt thereof, (b) a pH-dependent additive and/or a water-soluble polymer, and further. if desired, a surface active agent in an organic solvent or a mixture of water and an organic solvent and coating small granular nuclei with the solution by, e. g., spray coating.
~31~
Also~ composi~ion B can be produced by further spray-coating composition A with a solution of a medicament permeating material dissolved in an organic solvent.
More practically~ composition A can be obtained by dissolving (a) nioardipine or a salt thereo~, (b) a pH-reliability additive and/or a water-soluble polymer, and, if desired, a surface active agen~ in an organic solvent such as methanol, ethanol, isopropanol, chloroform, acetone1 1nethylene chloride, etc.~ a mixture of them, or a mixture of water and the foregoing organic solvent and coating small granular nuclei composed of crystalline cellulose, a mix~ure oF sugar and corn starch~ a mixture of crystalline cel7ulose and lactose etc.~
(e.g., Nonpareil*, made by Freund Industrial Co. Ltd~) by a spray coating method~ such as, a centrifugal fluidized coating method, a fluidized bed coating me~hod, etc. Also~ Composi~ion B of this invention can be obtained by further coating the composition A
thus obtained with a solution of a medicament permeating material dissolved in the foregoing organic solvent by, for example, a spray coating method to form, thereby~ a layer of ~he medicament permeating ma~erial on the composi~tion. In such a production process of the preparation~ nicardipine or a salt thereof is converted into the amorphous form.
I n addition, regarding composition A, the long acting property considerably changes according to the k~nd and nature of additives used. For example, when a pH dependent additive is used, a composition having a high l~ong acting property is obtained but when a pH-dependent additive is not used~ a *trade mark composition having a low acting property is obtained.
Examples of the foregoing pH-dependent additive are hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate7 Eudragit-L* and -S* (made by Ro~m and Haas Co., components: a methylme~hacrylatemethacrylic acid copolymer), etc.
Examples of the surface active agent used in this invention are Tween 80* (made by Kao Atlas Co., component: polyoxyethylene sorbitan mono-olèate~, Renex 30* (made by ICI Co., component:
polyoxyethylene alkyl ether), Nikkol HC0-60* (made by Nikko Chemicals Co., Ltd., componen~: polyoxyethylene-hydrogenated castor oil), etc. Also, examples of the water~-soluble polymer are HPC* (made by Shin-Etsu Chemical Co., Ltd~, composition: hydroxy propyl cellulosel, macrogol 400, 1500 and 6000 (Jap~ Pharmacopeia X, component: polyoxyethylene glycol), Metholose* (made by Shin-Etsu Chemical Co., Ltd., composition: methyl cellulose), TC-5* (made by Shin-Etsu Chemical Co., Ltd., compsnent:
hydroxypropylmethyl cellulose), etc. Furthermore, examples of ~he medicament permeating material are Eudragit* RL and RS (made by Rohm and Haas Co., component: ethylmethacrylate-trimethylammonio-e~hylmethacrylatechloride copolymer3, Ethocel* (made by Dow Chemical Co., component: ethyl cellulose), and mixture thereof with foregoing water-soluble polymers.
In composition A, the ratio of the coating to the srnall granular nucleus is L: 0~1 to 1 : 10 and in composition B, the ratio of the medicament permeating material to the composi~ion A
is 15 : 85 to 1 : 99.
Also, in the mixture of composition A and composi~ion B
.
*trade mark the effective concentration o* nicardipine in blood can be maintained for a longer period of time than the case of using each composition solely since there is a difference in the rate of dissolution between both the compositions. Furthermore, if a composition of nicardipine showing a high concentration in bloodim~ediatelyxafter administration and also maintaining the concentration for a long time is desired, the object can be attained by using composition A having low lasting property (or almost no lasting property) and composition B having a long lasting property. Such a composition can be obtained by blendingcomposition A and Composition B at a ratio o~ O.S {
to 1 : 19 by a conventional method~
The composition of this invention can be adminstered as the form of itself or may be filled in a capsule by a conventional method and administered as the capsulated composition.
Compositions of this invention are tested on long acting effect and the results are shown in tables 1 and ~.
W ` ~ X ~h O X l-h O 3 . . . ~ ~ 3 O ~ . .. __ ~ ,,(D,__ ~ _1~ ,,__ 1~ p) 15~ ~ ~ ~ I-h O ~ ~ ~ QJ O !Z
pJ ~ . O ' ~ ~1 CO O ~h O
_____ _ _ ~ 11 4 ~
O~ 3 3 3 O P , ~ 7~ ~ ~ ~ _ O _ .. _ ~ O ~ ~ , ~ o o. ~ _ _ _ .. _ O
~ 00 00 ~ 3 ~ 00 -00 ~0 O
_ _L~ l Oh ~i _ _ It . I-h . . _ __ . ~ _ _ ._ ., _ ~ ~D ~ I_ o ~D
c ~ ?al ~ o ~ ~
~ ~ U~ ~ ~ . ~ ,. ~
O .~ _ ~ ~ ~ a~ ~ O .
co t~ ~_ w : ~n n o~ ~ _ _ ~ g ~
t ~ ~ ~ _~ ~ ~ ~ ~ ~ ~
:~- - ---- --' -t -_ - ~ __ _ 1~ ~
31- ~ ~ -~n ~ I 1- ~5 U~ g ~D
~:: _ ~ l ~ (D ~ o M (D O
Ul ~ ~ ~ _ h ,~ a~ ~ _ h (D . _ ~__ ~t w ~ o u~ 3 P
O ~ 1~ ~ ~ ~ :~ ~ ~Q, ~2 ~to~ 3 1 w~ ~ ~ :~- ,w U3 ~ :~
___ _ IJ. , Ul ~, U~
_~ _ __ ~t î~ ~
~ ' 1- ~ ~ ~' O
~ I ::~ rt ~ I W~ ~
~ ~ ~ I O W ~ n _ W
W N 1_. 3 1-- t~ ~t ._ ~ _ _.__ --tO~- ~ ._~ _ o t~ _~ , 1_ ~ ~ ~
,o i,-l- ~ ~ ~ _ Then, the invention will be Fur~her explained in detail by ~he following examples but the inven~ion is not limited to them.
Example 1.
I n a 5 1 i ter centri Fugal f`l ui di zed bed coati ng apparatus was placed 728.6 9 of Nonpareil 103* (made by Freund Indus~rial Co., L~d~ main component: sugar) and 1.2 kg of a solution of 80 g of nicardipine hydrochl ori de, 80 9. of hydroxypropyl methyl cellulose phthalate, HP-55* ~made by Shin-Etsu Chemical Co., Ltd.~ and 20 9 of Tween-80* completely dissolved in a mixkure of methanol and methylene chloride (1: 1 by weight ratio) was spray-coated onto Nonpareil 103* by a conventional method to form a s pheri cal pel 1 et 1 i ke composi ti on (continue) ' ' .
*trade mark If necessary, a proper amount o~ talc may be added thereto to prevent the spherical pellet like compositions from sticking with each other. After drying the composition for 4 hours at 40 C, the composition was filled in capsules by a conventional method to provide capsulated composltion.
Example 5, After drying the spherical pellet like composition produced in Example 4 for 4 hours at 40 C, 200 g of an acetone isopropanol ~1 : 1 by weight ratio) solution having completely dissolved therein 10 g of Eudragit RL-100 was applied to 500 g of the spherical pellet like composition as in Example 1 to form a medicament permeating coating on the composition.
If necessary, a proper amount of talc may be added to prevent the sp~erical pellet like compositions from sticking with each other. The resultant composition was dried as in Example 4 and filled in capsules by a conventional methcd to provide capsulated composition.
Example 6.
The spherical pellet like composition produced in Example blended well 4 was /with the spherical pellet like composition produced in Example 5 at a ratio of 3 : '7 by weight ratio by acvnventional method. The resultant mixture was filled in capsules by aConv~n~ional methc~ to provide capsulated composition.
Example 7.
In a fluidized bed type granulator (GL~TT WSG 15) was placed 12 kg of Nonpareil 103 ~24-32 mesh) and 53~3 kg of a methanol-methylene chl~,oride (l 1 by weight ratio) solution having completely dissolved therein 4 kg of nicardipine _ 1~--If necessary, a proper amount or talc may be added to the mixture for preventing the spherical pellet like compositions from sticking with each other~ After drying the composi~ion or 4 hours at 40C, the composition was filled in capsules method composition.
by a conventional to provide capsulated/~ nn~
Example 2.
After drying the spherical pellet like composition produced p~pa~e~ as in Example 1 for 4 hours at 40 C, 90 g of an acetone-isopropanol solution of 8% Eudragi~ RL-100 per 500 g ~ oated of the compositio~was spray~ onto the composition as in Example 1 to apply a medicament permeating coating on the composition. If necessary, a small amount of talc may be added for preventing the spherical pellet like compositions from forming lumps o~ them. After drying the coated composi-ion for 4 hours at 40C~ the composition was filled inmethod capsules by a conventional ¦to provide capsulted composition.
~xal~cxs~P~x Example 3.
The spherical pellet like composition produced in Example blended 1 was /with the spherical pellet like composition produced in ~xample 2 at a ratio of 3 : 7 by weight ratio and the resultant mixture was filled in casules by a conventional method to provide capsulated composition.
Example 4.
682g of Nonpareil 103r 8y following the same procedure as in Example 1 using~
kg oY a me~hanol-methylene chloride ~1 : 1 by weight ratio) solution having completely dissolved t~ereln, 80g of Eudragit L-100 80 g of nicardipine hydrochloride,/and 20 g of Tween-80, a spherical pellet like composition was obtained.
- rl-hydrochloride /and 4 kg of hydropropylmethyl cellulsoe (TC-5) was sprayed thereto to provide a spherical pellet like compo~
sition. T~e composition thus obtained was dried for 4 hours at 40C.
Example 8.
In a fluidized bed type granulator (GL~TT WSG 15) was placed 60 kg of 9.5 kg of ~onpareil 103 (24-32 mesh) and then/a methanol-ethylene chloride (1 : 1 by weight ratio) solution havinghydrochloride, completely dissolved therein 4 kg of nicardipine/
4 kg of Eudragit L-100, and 2 kg of Tween 80 was sprayed thereto by a conventional method to provide a spherical pellet like composition. The composition thus obtained was dried for one hour at 40C.
Then, 18.5 kg of the spherical pellet like composition was spray~coatad with 7,4 kg of a methanol-methylene chloride (1 : 1 by weight ratio~ solution having completely dissolved therein 670 g of Eudragi~ L-100 and 70 g of Macrogol 400 by a o~nventicnal method to provide a spherical pellet like composition coated with the medicament permeating material.
Exa~ple 9.
In a V type mixer were placed 2 kg of the spherical pellet like composition produced in Example 7 and 8 kg of the coated spherical pellet like cornposition produced in Example 8 and after adding thereto ?00 g of talc, the resultant mixture was ccmpoun~ until the mixture became sufficiently uniform. The mixture thus obtained was filled in capsules to provide capsulated composition.
Example 10.
In a fluidized bed type granulator (UNIGRATT) was placed 950 g o~ Nonpareil 103 (less than 32 mesh) and then a 20%
water-containing methanol solution having dispersed and hydrochloride, dissolved therein 400 g of nicardipine/ 400 g of Eudragi~ L-100, and 100 g of T~een ao was sprayed thereto by a conventional method to provide a spherical pellet like composi-tion. The composition thus obtained was dried for about 4 t hours at 40C. Then, 1,850 g of the spherical pellet like composition was spray-coated with 740 g of a methanol-methylene chloride (1 : 1 by weight ratio) solution having dissolved therein 50 g of Et~cell CP-10, 50 g of hydroxy-propylmethyl cellulose (TC-5) ~ and 11 g of Macrogol 400 by a conventional method to apply medicament permeat-ing coating.
Then, 800 g of the coated spherical pellet like composi-tion thus produced was uniformly mixed with 200 g of the spherical pellet like composition produced in Example 7 by the same manner as in Example 9 and the resultant mixture was f`illed in capsules to provide capsulated composition.
Example 11.
By spray-coating 200 g of Nonpareil 103 (32-42 mesh) with 1.8 kg of a methanol-methylene chloride (1 : 1 by weight ratio) solution having completely dissolved therein 80 g of nicaridipine hydrochloride, 80 g of Eudragit L 100, and 40 g of Macrogoal 1500 in aCcnventional metho~, a spherical pellet like composition was obtained.
~ 13 -Example 12.
By spray-coating 500 g of the spherical pellet like composition obtained in Example 11 with 200 g o~ a methanol-dichloromethane (1 : 1 by weight ratio) solution having completely dissolved therein 20 g of Eudragit RL-100, medicamant permeating coating was applied thereon.
Example 13.
The spherical pellet like composi.tions obtained in uniformly Example 7, Example 11, and Example 12 were/mixed with eacn other at a weight ratio of 1.5 : 5.0 : 3.5 and after adding thereto 2~ talc, the resultant mixture was filled in capsules to provide capsulated compositionO
- 1.4 -
Claims (8)
PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A long acting spherical pellet like nicardipine composition comprising small granular nuclei spray-coated with a solution comprising:
(a) nicardipine or a salt thereof; and (b) a pH-dependent additive and/or a water-soluble polymer in an organic solvent, a mixture of organic solvents or a mixture of water and an organic solvent,
(a) nicardipine or a salt thereof; and (b) a pH-dependent additive and/or a water-soluble polymer in an organic solvent, a mixture of organic solvents or a mixture of water and an organic solvent,
2. A composition according to claim 1, wherein said spray-coated nuclei are further spray-coated with an organic solution of a medicament permeating material.
3. A long acting spherical pellet like nicardipine composition comprising small granular nuclei spray coated with a solution comprising:
(a) nicardipine or a salt thereof; and (b) a pH-dependent additive and/or a water-soluble polymer, and a surface active agent in an organic solvent, a mixture of organic solvents, or a mixture of water and an organic solvent.
(a) nicardipine or a salt thereof; and (b) a pH-dependent additive and/or a water-soluble polymer, and a surface active agent in an organic solvent, a mixture of organic solvents, or a mixture of water and an organic solvent.
4. A composition according to claim 31 wherein said spray-coated nuclei are further spray-coated with an organic solution of a medicament permeating material.
5. A process of producing a composition for spherical pellet like nicardipine long acting preparation which comprises dissolving:
(a) nicardipine or a salt thereof; and (b) a pH-dependent additive and/or a water-soluble polymer in an organic solvent, a mixture of organic solvents or a mixture of water and an organic solvent; and spray-coating small granular nuclei with the solution.
(a) nicardipine or a salt thereof; and (b) a pH-dependent additive and/or a water-soluble polymer in an organic solvent, a mixture of organic solvents or a mixture of water and an organic solvent; and spray-coating small granular nuclei with the solution.
6. A process of producing a composition for spherical pellet like nicardipine long acting preparation which comprises dissolving:
(a) nicardipine or a salt thereof; and (b) a pH-dependent additive and/or a water-soluble polymer in an organic solvent, a mixture of organic solvents or a mixture of water and an organic solvent;
spray-coating small granular nuclei with the solution, and further spray-coating the product with an organic solution of;
(c) a medicament permeating material.
(a) nicardipine or a salt thereof; and (b) a pH-dependent additive and/or a water-soluble polymer in an organic solvent, a mixture of organic solvents or a mixture of water and an organic solvent;
spray-coating small granular nuclei with the solution, and further spray-coating the product with an organic solution of;
(c) a medicament permeating material.
7. A process of producing a composition for spherical pellet like nicardipine long acting preparation which comprises dissolving:
(a) nicardipine or a salt thereof; and (b) a pH-dependent additive and/or a water-soluble polymer, and a surface active agent in an organic solvent, a mixture of organic solvents or a mixture of water and an organic solvent; and spray-coating small granular nuclei with the solution.
(a) nicardipine or a salt thereof; and (b) a pH-dependent additive and/or a water-soluble polymer, and a surface active agent in an organic solvent, a mixture of organic solvents or a mixture of water and an organic solvent; and spray-coating small granular nuclei with the solution.
8. A process of producing a composition for spherical pellet like nicardipine long acting preparation which comprises dissolving:
(a) nicardipine or a salt thereof;
(b) a pH-dependent additive and/or a water soluble polymer, and a surface active agent in an organic solvent, a mixture of organic solvents or a mixture of water and an organic solvent;
spray-coating small granular nuclei with the solution, and further spray-coating the product with fan organic solution of (c) a medicament permeating material.
(a) nicardipine or a salt thereof;
(b) a pH-dependent additive and/or a water soluble polymer, and a surface active agent in an organic solvent, a mixture of organic solvents or a mixture of water and an organic solvent;
spray-coating small granular nuclei with the solution, and further spray-coating the product with fan organic solution of (c) a medicament permeating material.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JPSN108608/81 | 1981-12-23 | ||
| JP56208608A JPS58116414A (en) | 1981-12-23 | 1981-12-23 | Composition for pharmaceutical of prolonged release containing nicardipine and preparation thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1200494A true CA1200494A (en) | 1986-02-11 |
Family
ID=16559022
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000418228A Expired CA1200494A (en) | 1981-12-23 | 1982-12-21 | Process of producing composition for long acting nicardipine preparation |
Country Status (8)
| Country | Link |
|---|---|
| KR (1) | KR860001147B1 (en) |
| AT (1) | AT386743B (en) |
| CA (1) | CA1200494A (en) |
| ES (1) | ES518487A0 (en) |
| GR (1) | GR77096B (en) |
| IT (1) | IT1200966B (en) |
| MX (1) | MX7567E (en) |
| PT (1) | PT76023B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0164959A2 (en) * | 1984-06-04 | 1985-12-18 | Sterwin Ag. | Pharmaceutical composition in sustained release unit dose form and process for its preparation |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2117571C3 (en) * | 1971-04-10 | 1979-10-11 | Bayer Ag, 5090 Leverkusen | Asymmetrical 1,4-dihydropyridine-33-dicarboxylic acid esters, process for their preparation and their use as pharmaceuticals |
| EP0001247A1 (en) * | 1977-09-14 | 1979-04-04 | Kanebo, Ltd. | Pharmaceutical preparation containing nifedipine and a method for producing the same. |
| CA1146866A (en) * | 1979-07-05 | 1983-05-24 | Yamanouchi Pharmaceutical Co. Ltd. | Process for the production of sustained release pharmaceutical composition of solid medical material |
-
1982
- 1982-12-16 MX MX82101116U patent/MX7567E/en unknown
- 1982-12-20 AT AT0460682A patent/AT386743B/en not_active IP Right Cessation
- 1982-12-21 CA CA000418228A patent/CA1200494A/en not_active Expired
- 1982-12-21 GR GR70132A patent/GR77096B/el unknown
- 1982-12-22 ES ES518487A patent/ES518487A0/en active Granted
- 1982-12-22 PT PT76023A patent/PT76023B/en unknown
- 1982-12-22 IT IT68503/82A patent/IT1200966B/en active Protection Beyond IP Right Term
- 1982-12-23 KR KR8205782A patent/KR860001147B1/en active
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0164959A2 (en) * | 1984-06-04 | 1985-12-18 | Sterwin Ag. | Pharmaceutical composition in sustained release unit dose form and process for its preparation |
| US4806361A (en) * | 1984-06-04 | 1989-02-21 | Sterling Drug Inc. | Medicaments in sustained release unit dose form |
| EP0164959B1 (en) * | 1984-06-04 | 1992-03-11 | Sterwin Ag. | Pharmaceutical composition in sustained release unit dose form and process for its preparation |
Also Published As
| Publication number | Publication date |
|---|---|
| ATA460682A (en) | 1988-03-15 |
| PT76023A (en) | 1983-01-01 |
| PT76023B (en) | 1986-02-12 |
| ES8402156A1 (en) | 1984-02-01 |
| IT1200966B (en) | 1989-01-27 |
| IT8268503A0 (en) | 1982-12-22 |
| AT386743B (en) | 1988-10-10 |
| ES518487A0 (en) | 1984-02-01 |
| MX7567E (en) | 1989-10-27 |
| GR77096B (en) | 1984-09-06 |
| KR840002652A (en) | 1984-07-16 |
| KR860001147B1 (en) | 1986-08-18 |
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