CN100506222C - Preparing method for controlled released type tablet tamsulosin hcl and the tablet thereof - Google Patents
Preparing method for controlled released type tablet tamsulosin hcl and the tablet thereof Download PDFInfo
- Publication number
- CN100506222C CN100506222C CNB2004800231231A CN200480023123A CN100506222C CN 100506222 C CN100506222 C CN 100506222C CN B2004800231231 A CNB2004800231231 A CN B2004800231231A CN 200480023123 A CN200480023123 A CN 200480023123A CN 100506222 C CN100506222 C CN 100506222C
- Authority
- CN
- China
- Prior art keywords
- weight portion
- tamsulosin hydrochloride
- tablet
- hydroxypropyl methylcellulose
- methylcellulose phathalate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
Abstract
The present invention relates to a simple and effective method for preparing a tamsulosin HCl sustained-release tablet and a tamsulosin HCl sustained-release tablet produced thereby. The method comprises the steps of: dissolving tamsulosin HCl as an active ingredient in an organic solvent; dissolving the tamsulosin HCl solution in hydroxypropylmethylcellulose phthalate to prepare a binder solution; and kneading the binder solution with a hydroxypropylmethylcellulose phthalate/glyceryl dibehenate mixture as an excipient and allows tamsulosin HCl to be released at uniformly controlled amounts in a subtained-release manner in vivo by controlling drug release rate according to different pH environments in vivo, so that it shows improved bioavailability and minimized side effects.
Description
Technical field
The present invention relates to the preparation method of tamsulosin hydrochloride (tamsulosin hydrochloride (HCl)) slow releasing tablet, reach tamsulosin hydrochloride slow releasing tablet with its preparation.More particularly, the present invention relates to prepare the method for tamsulosin hydrochloride slow releasing tablet, it comprises the steps: tamsulosin hydrochloride is dissolved in the organic solvent as active component; Gained tamsulosin hydrochloride solution is dissolved in prepares bonding agent (binder) solution in the Hydroxypropyl Methylcellulose Phathalate; This bonding agent solution and Hydroxypropyl Methylcellulose Phathalate/Glyceryl dibehenate (glyceryl dibehenate) mixture as excipient are mediated (kneading).Tamsulosin hydrochloride slow releasing tablet prepared in accordance with the present invention passes through according to pH environment control drug release speed in the different bodies, the tamsulosin hydrochloride as active medicine than low dosage is discharged with the amount of even control in vivo in the slow release mode, thereby demonstrate the bioavailability and the minimum side effect of improvement.
Background technology
Tamsulosin hydrochloride ((-)-(R)-5-[2-((2-(O-ethoxyl oxygen base) ethyl) amino) propyl group]-2-methoxyl group-benzsulfamide hydrochlorate), promptly with the left-handed optical isomer of following formula (I), it is the active medicine that improves or alleviate urinary dysfunction, this urinary dysfunction is to block the structural or mechanical obstruction of urinary tract cause by neck of bladder to cause, or by matter (stroma) between neck of bladder, prostate be distributed in that functional urinary tract obstruction that the excess shrinkage of the hypertrophy smooth muscle in the urethra causes causes.Its mechanism of action is under autonomous orthosympathetic control, and it has optionally blocked alpha 1 adrenergic receptor, thereby suppressed the contraction of neck of bladder, prostate smooth muscle and urethral smooth muscle, and then diastole neck of bladder, prostate and urethra, thereby improve or alleviated the urinary dysfunction symptom.At present, its form with capsule preparations is sold, and said preparation was administered once in one day.
[formula I]
Usually, the medicine of administration has been given play to maximum effect in order to make, and need make the bulk concentration of described medicine keep constant in a long time.For this reason, need the rate of release of the described medicine of control from the preparation that contains this medicine, so broad research has been carried out for the multiple slow releasing preparation of exploitation in this area.
In this class slow releasing preparation, the main compatibility that can improve patient and Drug therapy at the oral slow-releasing preparation of gastrointestinal tract inner control drug release reduces and treats the number of times of administration and avoid the drug level in the blood too high.Therefore, this pharmaceutical preparation not only can reduce side effect, can also make medicine maintain best treatment concentration in a long time, thereby improves therapeutic effect.
The exemplary of this class oral slow-releasing preparation comprises the diffused controlled release preparation, especially has the controlled release capsule preparation of insoluble coating.In this class capsule preparations, the outer surface that contains the core (tablet or granule) of medicine is coated with insoluble coating.When the medicine in the capsule was dissolved by the Digestive system that infiltrates from the outside, institute's dissolved drug was by the pore diffusion and the release of described insoluble coating.Because its preparation is simple, these capsule preparations have obtained the wide range of commercial application.
United States Patent (USP) the 4th, 772, No. 475 (corresponding Korean Patent Publication No. is 93-7245, and Yamanouchi Pharmaceutical Co. Ltd.) discloses preparation and contained the method for tamsulosin hydrochloride as the oral controlled-release pharmaceutical preparation of active component.In order to make tamsulosin hydrochloride bring into play continuous action behind oral administration, described disclosed method comprises: tamsulosin hydrochloride and the unit that is difficult for decomposing in gastrointestinal tract are formed (units-forming) material (being that crystalline cellulose is as excipient) mix; Add release control agent/aqueous mixtures in this tamsulosin hydrochloride/crystalline cellulose mixture, described release control agent is selected from acrylate copolymer, acrylic copolymer, and with the mixture of cellulose derivative; With the gained mixture pelleting; And the gained granule formed independently unit (microcapsule and microsphere).
As oral controlled-release tamsulosin hydrochloride preparation, Harnal
Capsule (by YamanouchiPharmaceutical Co., Ltd. sells) is by above-mentioned existing method preparation, and this method comprises: tamsulosin hydrochloride is mixed with crystalline cellulose; The aqueous emulsion that in this mixture, adds methacrylic acid copolymer; With gained mixture pelleting and dry; With the spraying of the aqueous solution of methacrylic acid copolymer and bag by the gained granule; Dry and sieve the granule of described bag quilt.Should existing method be applied to prepare the tamsulosin hydrochloride slow releasing preparation., rely on its lower water solublity herein, described crystalline cellulose not only serves as excipient to obtain given volume, also serves as release control agent, and it assists the slow release of tamsulosin hydrochloride when keeping the particulate structure and intensity that contains methacrylic acid copolymer.Yet, in this existing method, if other usual excipients outside the crystalline cellulose (as lactose and starch) is used from the preparation granule but not final preparation, then because rising is quickened in the infiltration of water in time, use the release of the tamsulosin hydrochloride of usual excipients to increase sharply, cause described particulate physical strength to descend rapidly.This feasible slow release that is difficult to realize tamsulosin hydrochloride.
In addition, in this existing method, owing at first carry out the mixing of very a small amount of tamsulosin hydrochloride and relative a large amount of crystalline cellulose, so be difficult to they uniform mixing.And, in order to improve the integrity of preparation, need to use expensive special equipment, as the ultrahigh speed blender be used for centrifugal fluidized bed pelletizer.In addition, in order to control all even continuous release of medicine, only screen granule and prepare microcapsule or microsphere, and, need to add other component for the granule of tablet or capsule form is provided with intended size.Therefore, the prior art needs complicated preparation process, and must cause production cost to rise and productive rate decline.In addition, if the active component unit dose such as tamsulosin hydrochloride lower (0.1-0.2mg/ tablet or capsule), the uneven distribution that medicine in the mixed process of described active component and excipient (being called " unit formation material "), can occur, the probability that causes the serious non-uniform phenomenon of medicament contg to occur rises, and rises thereby make body inner blood drug level can not keep uniform probability.
Simultaneously, mention another prior art that is widely used in useful in preparing drug formulations, this method adopts the solid dispersion effect.According to fusing or solvent method, use solid dispersion usually.
In this melting method, by heating the mixture of relatively poor medicine of dissolving and carrier is dissolved, cooling then.Yet, can degeneration and medicinal property (as the dissolubility) problem that can change with cooldown rate owing to exist medicine to be heated, the application of this method can be restricted.
Simultaneously, in described solvent method, medicine that dissolving is relatively poor and carrier are dissolved in and can dissolve simultaneously in the solvent of these two kinds of components, and drying is removed described solvent then.Yet, if use cellulose or other polymer or its copolymer, because the high viscosity of this carrier is difficult to evenly stir as carrier.And if fully do not remove organic solvent, residual solvent can influence the physics and the chemical stability of solid dispersion.Because this class problem, described solvent method is considered to not be suitable for large-scale industrial production.
Therefore, researcheres think that being difficult to the tamsulosin hydrochloride prescription is the tablet with satisfied medicament slow release characteristic.Based on this reason, still untappedly go out the tamsulosin hydrochloride slow releasing tablet.
Summary of the invention
Summary of the invention
The inventor has carried out the method that big quantity research is developed the sustained release tablet for oral use of the hydrochloric tamsulosin of preparation, this method can solve effectively preparation with tamsulosin hydrochloride as the variety of issue that exists in the capsular prior art of the oral sustained release of active component, these problems comprise owing to adopt the rapid rising of the special equipment and the production cost that complicated preparation technology causes of costliness, low-yield, the uneven distribution that reaches by active component causes the uneven probability of medicament contg, and the probability of organic solvent residual.As a result, the present invention's discovery can be effectively by the improved solid dispersion method of employing (solvent method) and is prepared the tamsulosin hydrochloride slow releasing tablet easily, and this method adopts conventional equipment to carry out under conventional preparation condition and need not to use complicated technology or special equipment.On the basis of this discovery, the inventor has carried out numerous researchs, thereby has finished the present invention.
First purpose of the present invention provides the method for preparing the tamsulosin hydrochloride slow releasing tablet with simple and effective way, this method need not to adopt complicated technology or expensive special equipment, wherein by controlling release rate of drugs according to the different pH environment in the gastrointestinal tract, the tamsulosin hydrochloride as active drug composition of science of low unit dose can the slow release mode discharge in gastrointestinal tract with controlled amounts, thereby improves its bioavailability and make its side effect minimum.
Second purpose of the present invention provides the economic method for preparing the tamsulosin hydrochloride slow releasing tablet, and this method makes production cost reduce and productive rate significantly rises.
The 3rd purpose of the present invention provides the method for preparing the tamsulosin hydrochloride slow releasing tablet, and this method can effectively eliminate because the uneven probability of medicament contg that the uneven distribution of the low dosage tamsulosin hydrochloride in the tablet causes.
The 4th purpose of the present invention provides the tamsulosin hydrochloride slow releasing tablet by of the present invention first to the 3rd purpose preparation.
To achieve these goals, the invention provides by behind dissolving step, carrying out the method that blend step prepares the tamsulosin hydrochloride slow releasing tablet, this method comprises the steps: tamsulosin hydrochloride is dissolved in the organic solvent, first Hydroxypropyl Methylcellulose Phathalate (A) is dissolved in this tamsulosin hydrochloride solution with preparation bonding agent solution, described bonding agent solution and the excipient mixture that comprises second Hydroxypropyl Methylcellulose Phathalate (B) and Glyceryl dibehenate are mediated.
Preparation in accordance with the present invention will be dissolved in as the tamsulosin hydrochloride of active component in the described bonding agent solution.This can eliminate the probability of medicine uneven components in the tablet that the uneven distribution by medicine causes effectively, and very small amount of active component can be caused the uneven distribution of this medicine during with relative a large amount of mixed with excipients.
The Hydroxypropyl Methylcellulose Phathalate that adopts among the present invention demonstrates the dissolubility that changes with pH, thereby can control the dissolution characteristics of tamsulosin hydrochloride according to the variation of gastrointestinal fluid.With respect to a tamsulosin hydrochloride, the content of the Hydroxypropyl Methylcellulose Phathalate in the described bonding agent solution is the 10-150 weight portion, preferred 25-120 weight portion, more preferably 35-100 weight portion.According to the inventive method, a spot of abundant water-soluble tamsulosin hydrochloride is dispersed in the Hydroxypropyl Methylcellulose Phathalate, therefore can prepare solid dispersion, by controlling rate of dissolution according to pH, this solid dispersion demonstrates different dissolution characteristics between gastric juice and intestinal juice.
Except that needs can dissolve tamsulosin hydrochloride and the Hydroxypropyl Methylcellulose Phathalate simultaneously, the adoptable organic solvent of the present invention does not have particular restriction.The preferred example of described organic solvent comprises ethanol, dichloromethane, and composition thereof, and the mixture of any and water in this kind solvent.This organic solvent is used in the described bonding agent solution with suitable amount, and for example every part of tamsulosin hydrochloride relatively is the 100-500 weight portion, preferred 180-300 weight portion.
In addition, Hydroxypropyl Methylcellulose Phathalate also is used in kneading and the granulation step, is the 50-500 weight portion with respect to its consumption in kneading and granulation step of every part of tamsulosin hydrochloride, preferred 100-350 weight portion, more preferably 200-350 weight portion.
Selectively, Hydroxypropyl Methylcellulose Phathalate also can be used for additional excipient and adds step, and its consumption is the 5-80 weight portion in this case, preferred 5-50 weight portion, more preferably 15-35 weight portion.
Above-mentioned Hydroxypropyl Methylcellulose Phathalate can not fully be dissolved in the gastric juice, but it mainly is dissolved in the intestinal juice.Because this reason, it has caused the slow release of tamsulosin hydrochloride by interacting with other excipient such as Glyceryl dibehenate or hydroxypropyl emthylcellulose, simultaneously by controlling rate of dissolution according to pH, make it between gastric juice and intestinal juice, demonstrate different dissolution characteristics, thus the release of control or adjusting tamsulosin hydrochloride.
Adding can be used for Glyceryl dibehenate of the present invention and hydroxypropyl emthylcellulose prepares slow releasing tablet.Glyceryl dibehenate itself is hydrophobic, so it has formed the interface between tamsulosin hydrochloride and the Digestive system (juice), and no matter the kind of Digestive system, thereby make that the rate of dissolution of described active component is lower.Glyceryl dibehenate is Compretol 888 for example
Trade mark buy.Its consumption is the 10-200 weight portion, is preferably the 25-150 weight portion, more preferably the 50-100 weight portion.In addition, hydroxypropyl emthylcellulose has the performance of cellulosic polymer.Be that it demonstrates intrinsic viscosity in aqueous solution, and wetted and expansion in aqueous solution.Because this character, it has stoped the rapid decomposition of solid dispersion tablet, thereby makes this tablet form keep the sufficiently long time in gastro-intestinal Fluid and dissolving liquid, thereby the surface area of tablet is maintained constant level.Therefore, hydroxypropyl emthylcellulose can guarantee that tablet has lasting dissolution characteristics in the long time period, and reduces the difference between the tablet.It is Metolose for example
Trade mark buy.With respect to every part of tamsulosin hydrochloride, the hydroxypropyl emthylcellulose consumption is the 10-300 weight portion, is preferably the 25-200 weight portion.
In the methods of the invention, can use routine to be used to prepare the additive of slow releasing tablet.The example of additive comprises excipient, and (as hydroxypropyl emthylcellulose, for example the ShinEtsu Co. of Japan sells as lactose, cereal starch, cellulosic polymer
60SH-4000 or
60SH-50; Hydroxypropyl cellulose, a kind of modified cellulose as hydrophilic polymer is sold as the ShinEtsu Co. of Japan
And the phthalic acid hydroxypropyl cellulose, the HPMCP that sells as the ShinEtsu Co. of Japan), mannitol, laolin, starch, powdery white sugar and calcium phosphate; And lubricant, as magnesium stearate, Talcum, calcium stearate and smoked (fumed) silicon dioxide.The preferred example of excipient includes but not limited to lactose, cereal starch and cellulosic polymer, and the preferred example of lubricant includes but not limited to magnesium stearate.
The method that the present invention prepares the tamsulosin hydrochloride slow releasing tablet comprises the steps:
(A) provide the step of bonding agent solution
The tamsulosin hydrochloride of portion as active drug composition of science is dissolved in ethanol, dichloromethane, water or its mixture of the preferred 180-300 weight portion of 150-500 weight portion.Subsequently with 10-150 weight portion, preferred 25-120 weight portion, more preferably first Hydroxypropyl Methylcellulose Phathalate (A) of 35-100 weight portion is dissolved in the tamsulosin hydrochloride solution, prepares bonding agent solution.
(B) kneading and granulation step
The bonding agent solution of step (A) gained and excipient mixture are mediated, and this excipient mixture comprises 50-500 weight portion, preferred 100-350 weight portion, more preferably second Hydroxypropyl Methylcellulose Phathalate (B) of 200-350 weight portion and the Glyceryl dibehenate of 10-200 weight portion, 25-150 weight portion and 50-100 weight portion.The material pelletize that to mediate then.This excipient mixture also can comprise the lactose of 300-700 weight portion, preferred 400-550 weight portion.
(C) screening step
Mixture drying after the pelletize is sieved then.
(D) additional excipient adds step
Then, the 3rd Hydroxypropyl Methylcellulose Phathalate (C), hydroxypropyl emthylcellulose, hydroxypropyl cellulose and/or cereal starch are added in the granule after the described screening as excipient.In this step, added lubricant such as magnesium stearate.
If adopt, the addition of then described the 3rd Hydroxypropyl Methylcellulose Phathalate (C) is the 5-80 weight portion, preferred 5-50 weight portion, more preferably 15-35 weight portion.If adopt, then the addition of hydroxypropyl emthylcellulose is the 10-300 weight portion, preferred 25-200 weight portion.If adopt, then the addition of hydroxypropyl cellulose is the 5-120 weight portion, is preferably the 15-100 weight portion, and if adopt, then the addition of cereal starch is the 10-300 weight portion, is preferably the 50-150 weight portion.
In addition, the addition of lubricant is arbitrarily, but is generally the 3-40 weight portion, is preferably the 5-20 weight portion.
(E) tabletting step
Described granule is pressed into tablet.
Therefore, in tablet of the present invention, continue and the controllable release of tamsulosin hydrochloride realize by Hydroxypropyl Methylcellulose Phathalate, Glyceryl dibehenate and solid dispersion system thereof.Therefore, satisfy purpose of the present invention, then these materials and various conventional excipients can be comprised lactose and starch, be used in combination if can control the addition of this class material.
The method that the present invention prepares the tamsulosin hydrochloride slow releasing tablet can prepare equipment and simple technology is implemented with conventional tablet, and has high yield, therefore has very high economic factor from industrial point of view.Simultaneously, it makes being evenly distributed of tamsulosin hydrochloride, and can be (like this according to the release of the variation of pH control tamsulosin hydrochloride, dissolution characteristics can change with pH, wherein tamsulosin hydrochloride is to a certain degree to be dissolved in gastric juice, and mainly be dissolved in intestinal juice, but the maintenance of the rate of release of tamsulosin hydrochloride is constant).Based on this reason, the tamsulosin hydrochloride in the tablet prepared in accordance with the present invention can the slow release mode discharge in the harmonization of the stomach small intestinal with uniform controlled amounts.
Can suitably select the dosage of contained tamsulosin hydrochloride as active component in the tamsulosin hydrochloride slow releasing tablet according to various parameters, these parameters are patient's age, sex, health status, disease to be treated and the order of severity of disease for example, and absorption rate, deactivation rate and discharge rate in the body of tamsulosin hydrochloride.Yet because tablet of the present invention has good slow release characteristic and stability, the tamsulosin hydrochloride in the tablet of the present invention is preferably with the dosed administration of 0.1mg/ days (a day to multi-disc) or 0.2mg/ days (a day to multi-disc).
Description of drawings
Figure 1 shows that the time dependent average dissolution rate figure of tamsulosin hydrochloride of the tamsulosin hydrochloride tablet of embodiment of the invention preparation, detect in the dissolving test that wherein said rate of dissolution carries out under anthropomorphic dummy's gastrointestinal conditions and obtain.
Fig. 2 has shown the time dependent blood tamsulosin hydrochloride concentration comparison diagram than Ge Er dog than the contrast tablet of Ge Er dog (Beagle dog) and 1 preparation of oral administration comparing embodiment of the tamsulosin hydrochloride tablet of oral administration embodiment 4 preparations.
Figure 3 shows that the tamsulosin hydrochloride tablet of the embodiment of the invention 4 preparations and particulate existing tamsulosin hydrochloride slow releasing capsule (the Harnal capsule of use bag quilt in contrast; By Yamanouchi Pharmaceutical Co., Ltd. sells) time dependent average dissolution rate figure, detect in the dissolving test that wherein said rate of dissolution carries out under anthropomorphic dummy's gastrointestinal conditions and obtain.
Figure 4 shows that the volunteer of the tamsulosin hydrochloride that oral administration embodiment 4 prepares and particulate existing tamsulosin hydrochloride slow releasing capsule (the Harnal capsule of oral administration use bag quilt in contrast; By YamanouchiPharmaceutical Co., Ltd. sells) volunteer's time dependent blood tamsulosin hydrochloride concentration comparison diagram, tablet wherein of the present invention and existing capsule carry out administration in cross matching.
The preferred forms of invention
Below will the present invention is described in detail by embodiment.Yet, will be understood by those skilled in the art that the present invention is not limited to these embodiment.
Preparation contains the slow releasing tablet of following component as follows:
Tamsulosin hydrochloride 0.2g
Hydroxypropyl Methylcellulose Phathalate (A) 10g
Hydroxypropyl Methylcellulose Phathalate (B) 65g
Lactose 99.8g
Glyceryl dibehenate 15g
Metolose?60SH-4000(A)15g
Metolose?60SH-4000(B)20g
Magnesium stearate 2g
Tamsulosin hydrochloride is dissolved in 60ml mixed organic solvents (ethanol: water=8: 2), dissolve Hydroxypropyl Methylcellulose Phathalate (A) subsequently therein and prepare bonding agent solution fully.Simultaneously, lactose, Hydroxypropyl Methylcellulose Phathalate (B), Metolose 60SH-4000 (A) and Glyceryl dibehenate are mixed mutually, to bonding agent solution that wherein adds gained and kneading.With the material pelletize and the drying of mediating.With dried granules screening, and with mix as the Metolose 60SH-4000 (B) of excipient with as the magnesium stearate of lubricant, be pressed into tablet with tablet machine subsequently.Contain the 0.2mg tamsulosin hydrochloride in each tablet.
Preparation contains the slow releasing tablet of following component as follows:
Tamsulosin hydrochloride 0.2g
Hydroxypropyl Methylcellulose Phathalate (A) 10g
Hydroxypropyl Methylcellulose Phathalate (B) 60g
Lactose 94.8g
Glyceryl dibehenate 15g
Cereal starch 20g
Magnesium stearate 2g
Tamsulosin hydrochloride is dissolved in 50ml mixed organic solvents (ethanol: in the water=8:2), dissolve Hydroxypropyl Methylcellulose Phathalate (A) subsequently therein and prepare bonding agent solution fully.Simultaneously, lactose, Hydroxypropyl Methylcellulose Phathalate (B) and Glyceryl dibehenate are mixed mutually, to bonding agent solution that wherein adds gained and kneading.With the material pelletize and the drying of mediating.With dried granules screening, and with mix as the cereal starch of excipient with as the magnesium stearate of lubricant, be pressed into tablet with tablet machine subsequently.Contain the 0.2mg tamsulosin hydrochloride in each tablet.
-hydroxypropyl cellulose 11 of replacing rudimentary except adding, adopt with embodiment 1 in identical mode prepare the slow releasing tablet that contains following component:
Tamsulosin hydrochloride 0.2g
Hydroxypropyl Methylcellulose Phathalate (A) 20g
Hydroxypropyl Methylcellulose Phathalate (B) 70g
Lactose 104.8g
Glyceryl dibehenate 15g
The hydroxypropyl cellulose 1115g of rudimentary-replacement
Metolose?60SH-4000(B)30g
Magnesium stearate 2g
Except the consumption of described mixed organic solvents is 40ml, and add in the step at additional excipient and in the gained dried particles, to add outside the Hydroxypropyl Methylcellulose Phathalate, adopt with embodiment 2 in identical mode prepare the slow releasing tablet that contains following component:
Tamsulosin hydrochloride 0.2g
Hydroxypropyl Methylcellulose Phathalate (A) 10g
Hydroxypropyl Methylcellulose Phathalate (B) 55g
Hydroxypropyl Methylcellulose Phathalate (C) 5g
Lactose 89.8g
Glyceryl dibehenate 15g
Cereal starch 20g
Magnesium stearate 2g
In the gained dried particles, add the hydroxypropyl cellulose (Metolose 60SH4000) except adding in the step at additional excipient, adopt with embodiment 4 in identical mode prepare the slow releasing tablet that contains following component:
Tamsulosin hydrochloride 0.2g
Hydroxypropyl Methylcellulose Phathalate (A) 10g
Hydroxypropyl Methylcellulose Phathalate (B) 55g
Metolose?60SH40005g
Lactose 89.8g
Glyceryl dibehenate 15g
Cereal starch 20g
Magnesium stearate 2g
Except the consumption of cereal starch is the 28g, adopt with embodiment 2 in identical mode prepare slow releasing tablet.
Embodiment 7-10
Except the consumption of Hydroxypropyl Methylcellulose Phathalate (B) is 20g, 30g, 40g and the 50g, adopt with embodiment 1 in identical mode prepare slow releasing tablet.
Embodiment 11-13
Except the consumption of Hydroxypropyl Methylcellulose Phathalate (A) is 5g, 10g and the 15g, adopt with embodiment 3 in identical mode prepare slow releasing tablet.
Embodiment 14-16
Except the consumption of Glyceryl dibehenate is 5g, 10g and the 30g, adopt with embodiment 4 in identical mode prepare slow releasing tablet.
Embodiment 17
Except mixture (5:5) 40ml that adopts methanol and dichloromethane as the described mixed organic solvents, mode identical among employing and the embodiment 4 prepares slow releasing tablet.
Comparing embodiment 1
Prepared conventional tablet with following component:
Tamsulosin hydrochloride 0.2g
Lactose 150g
Starch gluconic acid sodium salt (sodium starch glyconate) 5g
Polyvinylpyrrolidone 10g
Magnesium stearate 2g
Test implementation example 1
Under mimic gastrointestinal conditions, the tablet to embodiment 2,4,5,11,14 and 16 preparations dissolves test as follows.
1) preparation of test solution
Carry out described test according to the dissolution test method 2 described in the Pharmacopoeia Coreana (Korea Pharmacopeia).In order to prepare test solution, 1ml polysorbate80 solution (3 → 200) is added 500ml decompose in first solution described in the detection method.Dissolving test beginning is after two hours, with (37 ± 0.5 ℃ of 500ml phosphate buffered solution; PH7.2) substitute described test solution.
2) operation
Adopt high performance liquid chromatography (HPLC) to carry out described test under the following conditions:
Detector: UV absorption spectrophotometer (detection wavelength: 225nm)
Spectrum post: Capcell
3mm * 150mm, 5 μ m C
18(ODS)
Column temperature: 40 ℃
Mobile phase: the mixture of 0.05N perchloric acid and acetonitrile (7:3)
Injection: 50 μ l
(test result)
Test result as shown in Figure 1.In Fig. 1, symbol-D-represents among the embodiment 2 average dissolution rate of the tamsulosin hydrochloride in the tablet of preparation, the tablet of and symbol-◇-represent embodiment 4 to prepare, and symbol-
-represent the tablet of embodiment 5 preparation, symbol-+-tablet of represent tablet of embodiment 11 preparations, symbol-X-represents embodiment 14 to prepare, and symbol-O-tablet of representing embodiment 16 to prepare.
Test implementation example 2
The tablet of embodiment 4 preparations is used as specimen of the present invention, and the conventional tablet of comparing embodiment 1 preparation in contrast.In cross-over experiment, every kind of tablet is carried out oral administration to three than Ge Er dog.Detect blood tamsulosin hydrochloride concentration subsequently and be used for comparison over time.
(test result)
Test result such as following table 1 and shown in Figure 2.In Fig. 2, symbol-O-and-●-represent in the tablet of comparing embodiment 1 and embodiment 4 preparations the average blood concentration of tamsulosin hydrochloride over time respectively.
Confirm ground as test result, the tablet of embodiment 4 preparations shows the feature of tangible slow releasing tablet, and it demonstrates long term.
Table 1: the haemoconcentration of tamsulosin hydrochloride and time relation (ng/ml)
Test implementation example 3
With the slow releasing tablet that contains the 0.2mg tamsulosin hydrochloride of preparation among the embodiment 4 as specimen of the present invention, and with existing tamsulosin hydrochloride capsule (
Capsule, by Yamanouchi Pharmaceutical Co., Ltd. sells) in contrast.Under simulated person's gastrointestinal conditions, with above-mentioned test implementation example 1 in identical mode described tablet and capsule are dissolved test.
(test result)
The result of the dissolving test of carrying out under simulated person's gastrointestinal conditions as shown in Figure 3.In Fig. 3, symbol-O-and-(represent respectively the tablet of embodiment 4 preparation and existing capsule (
Capsule) test result.Confirm ground as test result, tamsulosin hydrochloride tablet of the present invention demonstrates and has now the essentially identical dissolution characteristics of tamsulosin hydrochloride capsule.
Test implementation example 4
The tablet that contains the 0.2mg tamsulosin hydrochloride of preparation among the embodiment 4 is used as specimen of the present invention, and with the existing tamsulosin hydrochloride capsule (Harnal that contains the 0.2mg tamsulosin hydrochloride
Capsule, by Yamanouchi Pharmaceutical Co., Ltd. sells) in contrast.In 2 * 2 contrast cross-over experiment, described tablet and capsule are carried out oral administration to 32 volunteers of NAM respectively.Detect each volunteer's time dependent blood substance concentration subsequently.
(test result)
With sample of the present invention and the contrast to after 32 volunteer's administrations, the average blood drug level of detection and time relation are as shown in Figure 4.In Fig. 4 symbol-O-and-(represent respectively the tablet of embodiment 4 preparation and existing capsule (
Capsule) average blood tamsulosin hydrochloride concentration and time relation.
Test implementation example 5
Every slow releasing tablet that contains the 0.2mg tamsulosin hydrochloride of preparation among the embodiment 4 is stored 6 months under the condition of room temperature and 40 ℃ and 75%RH.Subsequently, under simulated person's gastrointestinal conditions with test implementation example 1 in identical mode described tablet is dissolved test, and estimate its time dependent stability.
(test result)
Evaluation result as shown in the following Table 2.As demonstrated in Table 2, the dissolubility of described tablet changes very little in time, shows its stable fine to the time.
Table 2
Test implementation example 6
Use the tablet of preparation among the embodiment 4, prepare three kinds of samples of different batches in identical mode described in the above-mentioned test implementation example 1.Subsequently, under simulated person's gastrointestinal conditions, all batches are dissolved test, and estimate the difference between each batch.
(test result)
Evaluation result is as shown in table 3 below.As demonstrated in Table 3, the difference between each batch is very little, within the acceptable range.
Table 3
| 0 | 2 |
3 |
5 hours | |
| A | 0.0 | 25.6％ | 55.7％ | 90.1％ |
| B | 0.0 | 24.8％ | 55.1％ | 90.4％ |
| C | 0.0 | 26.2％ | 56.3％ | 89.7％ |
Embodiment 7
Tablet to embodiment 4 and 17 preparations carries out the residual solvent test.
(test result)
Test result is as shown in table 4 below, and shows effective organic solvent of having removed.
Table 4
| Solvent | The ICH standard * | Detected | |
| Embodiment | |||
| 4 | Ethanol | Be lower than 5,000ppm | 288ppm |
| Embodiment 17 | Ethanol | Be lower than 5,000ppm | 96ppm |
| Dichloromethane | Be lower than 600ppm | 29ppm |
*ICH: human body uses the international coordination meeting of drug legislation specification requirement
Industrial applicibility
As mentioned above, in the method for the present invention for the preparation of the tamsulosin hydrochloride sustained-release tablet, will be by at first being dissolved in the tamsulosin hydrochloride of dissolving in the mixed organic solvents, subsequently Hydroxypropyl Methylcellulose Phathalate is dissolved in the mixture that obtains in this tamsulosin hydrochloride solution and is used as bond, and need not independent dry run. This can effectively eliminate variety of issue, and such as the stirring difficulty that residual organic solvent and dry latter stage cause owing to high viscosity, this phenomenon occurs in active component and carrier and prepares in the process of solid dispersions. And, according to the present invention, because bond solution and the excipient of hydrochloric tamsulosin are mediated equably, can obtain at an easy rate uniform active component content, the raising of drying efficiency makes it possible to remove at an easy rate organic solvent, thereby has eliminated because the problem that residual organic solvent causes. In addition, according to the present invention, can effectively prepare the equally distributed solid dispersions of active component by conventional steps, and need not to use expensive equipment and extra complicated technology, described conventional steps for example to mix, mediate, sieve, add and mix and compressing tablet. This can realize preparation method's simplification, the significantly reduction of production cost, the rising of productive rate and uniform medicament contg. In addition, tamsulosin hydrochloride sustained-release tablet prepared in accordance with the present invention can be according to pH environment control drug release rate in the different bodies, thereby so that tamsulosin hydrochloride can the slowly-releasing mode discharge with the amount of even control in vivo, thereby demonstrate bioavilability and the minimum side effect of improvement.
Claims (13)
1. prepare the method for tamsulosin hydrochloride slow releasing tablet, comprise the steps:
(A) tamsulosin hydrochloride is dissolved in the organic solvent, then first Hydroxypropyl Methylcellulose Phathalate is dissolved in the described tamsulosin hydrochloride with preparation bonding agent solution; And
(B) described bonding agent solution and the excipient mixture that comprises second Hydroxypropyl Methylcellulose Phathalate and Glyceryl dibehenate are mediated, and with the material pelletize of described kneading;
Wherein in step (A), the tamsulosin hydrochloride of a relative weight portion, the amount of described first Hydroxypropyl Methylcellulose Phathalate is the 10-150 weight portion, and described solvent is selected from least a in ethanol, dichloromethane and the water; And
In step (B), the tamsulosin hydrochloride of a relative weight portion, amount at second Hydroxypropyl Methylcellulose Phathalate described in the described excipient mixture is the 50-500 weight portion, and the tamsulosin hydrochloride of a relative weight portion, be the 10-200 weight portion in the amount of Glyceryl dibehenate described in the described excipient mixture.
2. the method for claim 1 also comprises step (C): in described kneading and granulation step (B) back the material of described pelletize is carried out drying and sieve then.
3. the method for claim 1, comprise that also additional excipient adds step (D): after described kneading and granulation step (B), in described granule, add at least a material that is selected from the 3rd Hydroxypropyl Methylcellulose Phathalate, hydroxypropyl emthylcellulose and cereal starch.
4. method as claimed in claim 2, comprise that also additional excipient adds step (D): after described screening step (C), in described granule, add at least a material that is selected from the 3rd Hydroxypropyl Methylcellulose Phathalate, hydroxypropyl emthylcellulose and cereal starch.
5. method as claimed in claim 1 or 2, wherein in described bonding agent formulations prepared from solutions step (A), the tamsulosin hydrochloride of a relative weight portion, the addition of described first Hydroxypropyl Methylcellulose Phathalate is the 25-120 weight portion, and in described kneading and granulation step (B), the tamsulosin hydrochloride of a relative weight portion, the addition of described second Hydroxypropyl Methylcellulose Phathalate are the 100-350 weight portion.
6. method as claimed in claim 1 or 2, wherein in described kneading and granulation step (B), the tamsulosin hydrochloride of a relative weight portion, the addition of described Glyceryl dibehenate is the 25-150 weight portion.
7. method as claimed in claim 1 or 2, the tamsulosin hydrochloride of a wherein relative weight portion, the addition of described solvent is the 100-500 weight portion.
8. method as claimed in claim 7, the tamsulosin hydrochloride of a wherein relative weight portion, the addition of described solvent is the 180-300 weight portion.
9. as claim 3 or 4 described methods, wherein add in the step (D) at described excipient, described material is a Hydroxypropyl Methylcellulose Phathalate, the tamsulosin hydrochloride of a relative weight portion, and the addition of described Hydroxypropyl Methylcellulose Phathalate is the 5-80 weight portion.
10. as claim 3 or 4 described methods, wherein add in the step (D) at described excipient, described material is a hydroxypropyl emthylcellulose, the tamsulosin hydrochloride of a relative weight portion, and the addition of described hydroxypropyl emthylcellulose is the 10-300 weight portion.
11. as claim 3 or 4 described methods, wherein add in the step (D) at described excipient, described material is a cereal starch, the tamsulosin hydrochloride of a relative weight portion, and the addition of described cereal starch is the 10-300 weight portion.
12. method as claimed in claim 1 or 2, wherein said excipient mixture also comprises lactose, the tamsulosin hydrochloride of a relative weight portion, and the addition of described lactose is the 300-700 weight portion.
13. by claim 1,2 and 8-11 in the tamsulosin hydrochloride slow releasing tablet of the described method of arbitrary claim preparation.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR20030055579 | 2003-08-12 | ||
| KR1020030055579 | 2003-08-12 | ||
| KR1020040023668 | 2004-04-07 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1835742A CN1835742A (en) | 2006-09-20 |
| CN100506222C true CN100506222C (en) | 2009-07-01 |
Family
ID=37003247
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004800231231A Expired - Fee Related CN100506222C (en) | 2003-08-12 | 2004-06-15 | Preparing method for controlled released type tablet tamsulosin hcl and the tablet thereof |
Country Status (3)
| Country | Link |
|---|---|
| KR (1) | KR100531612B1 (en) |
| CN (1) | CN100506222C (en) |
| AT (1) | ATE519483T1 (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100706036B1 (en) * | 2005-04-04 | 2007-04-11 | 대화제약 주식회사 | A controlled release tamsulosine hydrochloride tablet and improved manufacturing method thereof |
| CN104666257B (en) * | 2013-12-03 | 2017-09-15 | 长春海悦药业股份有限公司 | A kind of pharmaceutical composition containing terbinafine HCl |
| KR101879133B1 (en) | 2017-07-11 | 2018-07-17 | (주)동구바이오제약 | Agents for preventing or treating urinary disease and preparing the same |
| KR101957694B1 (en) | 2018-05-28 | 2019-03-13 | (주)동구바이오제약 | Agents for preventing or treating urinary disease and preparing the same |
| KR102389339B1 (en) * | 2018-12-26 | 2022-04-22 | (주)휴온스 | Controlled release high-dose tamsulosin hydrochloride tablet and its preparing method |
| CN110214711A (en) * | 2019-06-28 | 2019-09-10 | 昱庆塑胶五金制品（惠州）有限公司 | Intelligent pet feeder |
| CN111773192A (en) * | 2020-08-18 | 2020-10-16 | 福建广生堂药业股份有限公司 | Sofosbuvir tablet and preparation method thereof |
-
2004
- 2004-04-07 KR KR10-2004-0023668A patent/KR100531612B1/en active IP Right Grant
- 2004-06-15 AT AT04773926T patent/ATE519483T1/en not_active IP Right Cessation
- 2004-06-15 CN CNB2004800231231A patent/CN100506222C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| KR20050020575A (en) | 2005-03-04 |
| CN1835742A (en) | 2006-09-20 |
| ATE519483T1 (en) | 2011-08-15 |
| KR100531612B1 (en) | 2005-11-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP1976489B1 (en) | Multiple unit type sustained release oral formulation comprising zaltoprofen and process for the preparation thereof | |
| CN1298317C (en) | Tamsulosin tablets | |
| CN1104891C (en) | Controlled release preparation containing a salt of morphine | |
| EP0533297A1 (en) | Controlled-release pharmaceutical formulations | |
| CN101977593B (en) | Drug delivery systems comprising weakly basic drugs and organic acids | |
| CN1630513A (en) | Hydrodynamically balancing oral drug delivery system with biphasic release | |
| FI94094C (en) | Carrier composition for delayed action drug preparations | |
| CN101312716A (en) | Pharmaceutical dosage forms having immediate release and/or controlled release properties | |
| CZ2001215A3 (en) | Enteric coated pharmaceutical tablet and process for preparing thereof | |
| CN102105136A (en) | Gastric retentive extended-release dosage forms comprising combinations of a non-opioid analgesic and an opioid analgesic | |
| TW200301139A (en) | Zero-order sustained release dosage forms and method of making same | |
| CN109562072B (en) | Pharmaceutical preparation for oral administration with controlled dissolution comprising sustained release pellets containing tamsulosin hydrochloride | |
| US20030157169A1 (en) | Controlled release dosage form of [R-(Z)]-alpha-(methoxyimino)-alpha-(1-azabicyclo[2.2.2]oct-3-yl)acetonitrile monohydrochloride | |
| KR20060118452A (en) | Pantoprazole multiparticulate formulations | |
| EP2380563A1 (en) | A enteric formulation of duloxetine and its core and prepration method | |
| CN1988884B (en) | Controlled release matrix pharmaceutical dosage formulation | |
| US20030129236A1 (en) | Multiple pulse extended release formulations of clindamycin | |
| WO2008068731A1 (en) | Extended release formulations of carvedilol | |
| CN108201534A (en) | A kind of Rui Kapabu takes orally sustained and controlled release medicament composition and application thereof | |
| CN100506222C (en) | Preparing method for controlled released type tablet tamsulosin hcl and the tablet thereof | |
| WO1998010762A2 (en) | Controlled release dosage form of r-(z)-alpha-methoxyimino-alpha-(1-azabicyclo2.2oct-c-yl)acetonitrile monohydrochloride | |
| JP4614139B2 (en) | Method for producing tamsulosin hydrochloride sustained release tablet and tamsulosin hydrochloride sustained release tablet comprising the same | |
| JP2006507298A (en) | Oral sustained-release tablets and methods for making and using the same | |
| JP2018508501A (en) | Oral pharmaceutical formulation containing tamsulosin hydrochloride-containing sustained release granules | |
| KR20170001545A (en) | Mosapride sustained-release formulation and Composite formulation comprising mosapride and rabeprazole |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CI02 | Correction of invention patent application |
Correction item: Priority Correct: 2004.04.07 KR 10-2004-0023668 False: Lack of priority second Number: 38 Page: The title page Volume: 22 |
|
| COR | Change of bibliographic data |
Free format text: CORRECT: PRIORITY; FROM: MISSING THE SECOND ARTICLE OF PRIORITY TO: 2004.4.7 KR 10-2004-0023668 |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20090701 Termination date: 20190615 |