CA2045358C - Controlled release pharmaceutical preparation - Google Patents
Controlled release pharmaceutical preparationInfo
- Publication number
- CA2045358C CA2045358C CA002045358A CA2045358A CA2045358C CA 2045358 C CA2045358 C CA 2045358C CA 002045358 A CA002045358 A CA 002045358A CA 2045358 A CA2045358 A CA 2045358A CA 2045358 C CA2045358 C CA 2045358C
- Authority
- CA
- Canada
- Prior art keywords
- water
- pharmaceutical preparation
- coating layer
- controlled release
- cont
- 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.)
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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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
- A61K9/2846—Poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
Abstract
A controlled release pharmaceutical preparation comprising a core containing a medicinal compound and a coating layer containing a water-repellent salt and a water-insoluble and slightly water-permeable acrylic polymer having trimethylammoniumethyl group. Said preparation releases a medicinal compound in a sigmoid type dissolution pattern irrespective of the PH of a dissolution medium.
Description
Q ~ 3 ~ 8 CONTROLLED RELEASE PHARMACEUTICAL PREPARATION
BACKGROUND OF THE INVENTION
The present invention relates to a controlled release pharmaceutical preparation, and more particularly to a so-called sigmoid type controlled 5 release pharmaceutical preparation (Sigmoidal-Releasing System) from which a medicinalcompound rapidly dissolves after a certain lag time.
Hitherto, concerningpharmaceutical preparations cont~inin~ medicinal compounds, there have 10 been various attempts to maintain their effects after the ~clministration. For example, following two pharmaceutical preparations have been known. One is a sustained release pharmaceutical preparation (see Japanese Un~mined Patent Publication No. 156617/1985) 15 in which a core is alterately coated with two compositions, namely, with a coating composition comprising a water-soluble polymer such as a polyvinyl alcohol or polyvinylpyrrolidone and a water-insoluble polymer such as ethylcellulose, polyvinyl chloride or 20 Eudragit RS (trade mark, from Rohm Pharma, Germany), and a c-omposition comprising diltiazem hydrochloride, an organic acid and a lubricant to form multi coating layers. And the other is a sustained release pharmaceutical preparation- (see Japanese Un~min~-l 25 Patent Publication No. 193913/1985) in which a core cont~ining a medicinal active ingredient and an organic acid is spray-coated with an ethanol solution of an acrylic polymer having ~ trimethylammoniumethyl group.
However, although these pharmaceutical preparations are suitable for releasing medicinal active ingredients gradually after the ~-1ministration~ they have a problem that the starting of the dissolution of their medicinal active ingredients can hardly be controlled.
On the other hand, it is known in the field of the pharmaceutical preparation that an increase in the ~ ~ =
BACKGROUND OF THE INVENTION
The present invention relates to a controlled release pharmaceutical preparation, and more particularly to a so-called sigmoid type controlled 5 release pharmaceutical preparation (Sigmoidal-Releasing System) from which a medicinalcompound rapidly dissolves after a certain lag time.
Hitherto, concerningpharmaceutical preparations cont~inin~ medicinal compounds, there have 10 been various attempts to maintain their effects after the ~clministration. For example, following two pharmaceutical preparations have been known. One is a sustained release pharmaceutical preparation (see Japanese Un~mined Patent Publication No. 156617/1985) 15 in which a core is alterately coated with two compositions, namely, with a coating composition comprising a water-soluble polymer such as a polyvinyl alcohol or polyvinylpyrrolidone and a water-insoluble polymer such as ethylcellulose, polyvinyl chloride or 20 Eudragit RS (trade mark, from Rohm Pharma, Germany), and a c-omposition comprising diltiazem hydrochloride, an organic acid and a lubricant to form multi coating layers. And the other is a sustained release pharmaceutical preparation- (see Japanese Un~min~-l 25 Patent Publication No. 193913/1985) in which a core cont~ining a medicinal active ingredient and an organic acid is spray-coated with an ethanol solution of an acrylic polymer having ~ trimethylammoniumethyl group.
However, although these pharmaceutical preparations are suitable for releasing medicinal active ingredients gradually after the ~-1ministration~ they have a problem that the starting of the dissolution of their medicinal active ingredients can hardly be controlled.
On the other hand, it is known in the field of the pharmaceutical preparation that an increase in the ~ ~ =
2 ~ 3 ~ ~
thickness of the coating layer results a delay of the starting of the dissolution of a medicinal active ingredient. However, it is also known that in this case the thick coat layer hinders rapid dissolution of a medicinal active ingredient after the starting of the dissolution and therefore an effective blood concentration can not be obtained rapidly.
An object of this invention is to provide a controlled release pharmaceutical preparation giving a so-called sigmoid type dissolution pattern wherein a lag time until the starting of the dissolution of a medicinal compound and the rate of the following dissolution can be controlled and the rate of the dissolution of the medicinal compound does not depend on the pH of a medium for the dissolution.
This and other o~jects of the present invention will be come apparent from the description hereinafter.
SUMMARY OF THE INVENTION
It has been found that in case of coating a medicinal active ingredient with a water-insoluble and slightly water-permeable acrylic polymer having trimethylammoniumethyl group and a water-repellent salt such as magnecium stearate or calcium sterarate, Q the time until the starting of the dissolution of a medicinal active ingredient from the pharmaceutical preparation lengthens, (~) the time until the starting of the dissolution can be controlled by the amount of the coating layer and (~) once the dissolution starts, almost 100 % of the medicinal active ingredient dissolves irrespective of the a~ount of the coating layer.
The present invention provides a controlled release pharmaceutical preparation comprising a core cont~ining a medicinal co~pound and a coating layer 35 cont~ining a water-repellent salt and a water-insoluble and slightly water-perm~eable acrylic polymer having trimethylammoniumethyl group.
~ - 3 - 2 ~ B, 5 ~ 5 ~
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is a graph showing the result of the dissolution test with water as to various controlled release granules (a) to (e) obtained in Test Example 1 5 which differ from each other in the amount of coating layer. Fig. 2 is a graph showing the result of the dissolution test with water, first fluid and second fluid as to the controlled release granule (d) obtained in Test F~mple 1. Fig. 3 is a graph showing the change 10 in blood concentration of a medicinal compound in case that the granule (d) was ~lministered to dogs in Test F~r~mple 2. Fig. 4 is a graph showing the result of the dissolution test as to a capsule cont~ining various controlled release granules obtained in Test Example 3 15 which differ from each other in the amount of the coating layer.
DETAILED DESCRIPTION
The controlled release pharmaceutical 20 preparation of the present invention comprises a core cont~ining a medicinal compound and a coating layer cont~inin~ a water-repellent salt and a water-insoluble and slightly water-permeable acrylic polymer having trimethylammoniumethyl group, which surrounds said core.
2 5 If desired, another coating layer of at least one material selected from the group consisting of ethylcellulose, hydroxypropylcellulose and a medicinal compound may be provided around said coating layer in the constrolled release pharmaceutical preparation of 30 the present invention.
In the present invention, a polymer of acrylic acid, methyl acrylate, ethyl acrylate, methacrylic acid, methyl methacrylate, ethyl methacrylate or the like, which has trimethylammoniumetyl group in the molecule, 3 5 may be used as a water-insoluble and slightly water-permeable acrylic polymer constituting the coating layer. For instance, a copolymer of ethyl acrylate, me thyl methacrylate and ~-methacryloyloxyethyl-~ ~ 4 - 2045~5~
trimethylammonium chloride in which about 0. 0 2 5 to about 0 . 0 3 3 mole of ~-methacryloyloxyethyltrimethylammonium chloride is contained per mole of the other neutral acrylic monomers is preferably used. Such copolymer is, 5 for example, commercially available under trade mark " Eudragit RS" from Rohm Pharma, Germany or the like.
The above-mentioned polymer may contain, for instance, a small quantity of a water-permeable polymer. Such copolymer is, for example, commercially 10 available under trade mark " Eudragit RL" from Rohm Pharma, Germany or the like.
As ethylcellulose or hydroxypropylcellulose which is a material of another coating layer provided around the coating layer of an acrylic polymer, for 15 instance, ethylcellulose cont~ining about 46.5 to about 51. 0 % of ethoxy group, hydroxypropylcellulose cont~ining about 53.4 to about 77.5 % of hydroxypropoxy group or the like can be suitably used.
As a water-repellent salt which constitute the 20 coating layer with an acrylic polymer, a salt of higher fatty acid and an ~lk~line earth metal is preferably used. Concretely, examples of the salts are calcium stearate, magnecium stearate and the like.
In the present invention, as the ratio of the 25 above-mentioned acrylic polymer and the water-repellent salt in the coating layer, it is adequate that about 0. 5 to about 5 parts by weight, preferably about 1. 5 to about 4. 5 parts by weight and more preferably about 2 to about 4 parts by weight of the acrylic polymer is 3 0 contained per part by weight of the water-repellent salt.
The amount of the coating layer for the core is variable a little dep~n-ling on the form or the size of the core. However, it is preferable that the amount of 35 the coating layer to be used tends to increase a bit dep~n-ling on the increase of the surface area per unit weight, that is, the decrease of the particle size of the core. For example, in case of spherical particles ~ 2~ 3~8 having mean particle size of about 500 to about 1000 ,(1 m, the amount of the coating layer is about 5 to about 80 %, preferably about 7 to about 50 %, in particular, preferably about 8 to about 3 0 %, based on the weight of 5 the core.
In the present invention, the form of the core to be coated is not particularly limited and various forms such as plain tablet, pill, granule and fine granule may be suitably used. Above all, the granulated 10 cores having mean particle size of about 300 to about 5000 ,u m, in particular, about 500 to about 1500 ,u m may be preferably used.
The medicinal compound to be contained in the core is not particularly limited. For instance, calcium 15 antagonists such as diltiazem hydrochloride, verapamil hydrochloride, nicardipine, nitrendipine and nimodipine, antiasthmatic agents such as theophylline and trimetaquinol, water soluble vit~min.~, antibiotics, antimalignantumor agents, antipyretic analgesics, 20 antihyperglycemic agents and the like may be used.
In addition, various additives such as an excipient, a binder, a lubricant, an aggregation-preventing agent and a solubilizer for a medicinal compound which are usually used in this field may be 25 contained in the core.
F~mr)les of excipients are sugars such as sucrose, lactose, mannitol and glucose, starch, crystalline cellulose, calcium phosphate, calcium sulfate, calcium lactate and the like. Examples of carriers for reg~ ting particle sizes are sucrose, lactose, starch, crystalline cellulose and the like.
F~mples of binders are polyvinylalcohol, polyacrylic acid, polymethacrylic acid, polyvinylpyrrolidone, glucose, sucrose, lactose, maltose, sorbitol, mannitol, 3 5 hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, macrogols, arabic gum, gelatin, agar, starch and the like. Examples of lubricants are stearic acid, talc and the like. F~mples of 3 ~ 8 aggregation-preventing agents are the above-mentioned lubricants, silicone dioxide, colloidal silicone dioxide and the like. Examples of solubilizers for medicinal compounds are organic acids such as fumaric 5 acid, succinic acid and malic acid and the like.
The pharmaceutical preparation of the present invention can be prepared by coating cores cont~ining a medicinal compound with a dispersion of a water-insoluble and slightly water-permeable acrylïc polymer 10 having trimethylammoniumethyl group and a water-repellent salt. The preparation of the cores can be carried out according to the usual procedure for the preparation, for example, as described in Lemingtons Pharmaceutical Sciences 17, 1603-1632, 1633-1643 (Mack 15 Publishing Company, published in 1985). For F~r~mple, the cores can be prepared by gr~n~ ting the composition of a medicinal compound, a binder and, as occasion dem~n-ls, other additives such as an exicipent according to the method of wet oscillating granulation, rotating 20 granulation, fluidizing bed granulation or the like to obtain granules. Alternatively, for example, the cores may be prepared using carriers for regulating particle sizes. That is, spherically granulated carriers may be coated with a medicinal compound according to the usual 25 method such as powder coating method to obtain the cores. Powder coating can be carried out, for instance, by gradually ~l(lin~ a medicinal compound or a mixture of the medicinal compound and suitable additives such as an excipient with spraying a solution obtained by 30 dissolving a binder in a suitable solvent such as water, a lower alcohol such as methanol, ethanol, propanol, isopropanol or butanol, a lower alkanone such as acetone or methylethylketone, chloroform, dichloromethane, dichloroethane or a mixture thereof, on carrier 35 particles to be cores, according to the method of rotating granulation, pan coating, fluidizing bed coating or the like.
The coating for thus obtained cores can be carried out by adhering a dispersion of a water-repellent salt and an acrylic polymer to the cores followed by drying.
As a dispersion medium for the above-mentioned 5 component of the coating layer, water, an alcohol such as methanol, ethanol or propanol, a ketone such as acetone, a halogenated hydrocarbon such as methylene-chloride or chloroform, a mixture thereof or the like is exemprified. Water, an alcohol or a mixture thereof is 10 preferable, and ethanol or a mixture of ethanol and water is particularly preferable.
The coating can be carried out according to a method generally used in the art for preparation such as the method of fluidizing bed coating or pan coating.
15 For example, in case of the method of fluidizing bed coating, the coating can be carried out as follows.
That is, while the cores are fluidized in an apparatus by means of air pressure, they are spray-coated with an aqueous dispersion of a water-repellent salt and an 20 acrylic acid polymer at an adequate rate from the nozzle of the spray-gun.
The concentration of a water-repellent salt and an acrylic polymer in the dispersion is not particularly limited, but it is preferable that these components are 25 added within the above-mentioned scope of the preferable proportion of both components, to be the concentration of about 5 to about 40 % by weight. In addition, a plasticizer, a coloring agent and the like may be cont~ine~ in the dispersion. As a plasticizer, for instance,triacetin,triethyl citrate, acetyltributyl citrate, diethylphthalate, polyethyleneglycol, polysorbate or the like can be suitably used. The amount of the plasticizer to be used is preferably about 5 to about 4 0 % by weight based on the weight of an 35 acrylic polymer.
The drying of thus obtained coating layer can be easily carried out, for example, by heating at about 35 to about 100~C, particularly about 40 to about 70~C.
- 8 - 2~
The other form of the pharmaceutical preparation of the present invention wherein another coating layer made of at least one material selected from the group consisting of ethylcellulose, 5 hydroxypropylcellulose and a medicinal compound is provided around the coating layer cont~ining a water-repellent salt and a water-insoluble and slightly water-permeable acrylic polymer having trimethyl-ammoniumethyl group, can be easily prepared by further 10 coating the above-mentioned pharmaceutical preparation having the coating layer of an acrylic polymer with these components according to the usual method.
For example, in case of coating with ethyl-cellulose or hydroxypropylcellulose, the solution 15 prepared by dissolving ethylcellulose or hydroxypropyl-cellulose in water, methanol, ethanol, acetone or a mixed solvent thereof to be the conc~ alion of about 0.5 to about 10 %, may be sprayed for coating. In case of coating with a medicinal compound, the solution or 20 dispersion cont~ining said medicinal compound or a mixture of the medicinal compound and suitable additives such as an excipient and a binder may be sprayed for coating according to the usual method. As the additives, for instance, the above-mentioned binders and 25 excipients may be suitably used.
Thus obtained controlled release pharmaceutical preparation of the present invention may be ~iministered as it is or in a form filled in capsules.
The pharmaceutical preparation of the present 30 invention has the following characteristics because of its coating layer of a slightly water-permeable acrylic polymer. That is, a medicinal active ingredient rapidly dissolves from the preparation after a certain period which depends upon the amount of the coating layer 35 although it never dissolves after ~(lministration until the certain time passes. Besides, the time until the start of the dissolution of a medicinal active ingredient is optionally adjustable by changing the 9 ~O=~ 8 amount of the coating layer.
Therefore, the pharmaceutical preparation of the present invention is useful as a pharmaceutical preparation wherein the starting of the dissolution of a 5 pharmaceutical compound can be adjusted by itself.
And it is further useful that the pharmaceutical preparation which can rçtain an effective blood concentration for many hours can be obtained by combining various pharmaceutical preparations which 10 differ from each other in the amount of the coating layer or in a kind of a component of the coating layer, according to the present invention.
The pharmaceutical preparation of the present invention wherein the coating layer of a slightly 15 water-permeable acrylic polymer is further coated with ethylcellulose, hydroxypropylcellulose or the like, has a following advantage. That is, because the dissolution rate of a medicinal compound after a lag time in such pharmaceutical preparation is sm~ r than that in a 20 pharmaceutical preparation whose coating layer of an acrylic polymer and a water-repellent salt is not further coated, the most suitable dissolution pattern can be obtained by employing the above-mentioned coating layer in accordance with a kind of medicinal active 25 ingredient. In addition, these pharmaceutical preparations also have an advantage of being useful for preventing the aggregation of the preparations, which occurs during preparing them.
Further the pharmaceutical preparation wherein 30 the layer of a medicinal compound is provided around the coating layer of an acrylic polymer can start the dissolution of the inside medicinal compound when the blood concentration originated in the outside medicinal compound has lowered after its dissolution followed by 35 the rise of its concentration, by adjusting the amounts of the medicinal compound layer and an acrylic polymer layer or providing an another coating layer of hydroxy-propylcellulose or the like around the layer of a , ~ - 10 - ~ 5 3 5 8 medicinal compound. Therefore, the pharmaceutical preparation of the present invention has an advantage that it can be ~rlministered as a pharmaceutical preparation suitable for once ~-lministration a day.
The present invention is more specifically described and explained by means of the following Test Examples and F~mples in which all percents and parts are by weight unless otherwise noted. It is to be understood that the present invention is not limited to the ~mples, and various changes and modifications may be made in the invention without departing from the spirit and scope thereof.
Test Example 1 (1) Preparation Nonpareil (granulated sucrose, from Freund Industrial Co. Ltd., Japan) having the diameter of 350 to 500 u m (80 g) was put into the centrifugal fluidizing type granulating and coating apparatus 20 (CF-360EX Type, made by Freund Industrial Co. Ltd., Japan) and rolled in it.
Thereto was gradually added fine powder of diltiazem hydrochloride (900 g) with spraying a solution of polyvinylpyrrolidone (20 g) dissolved in a mixture of 25 water and ethanol (3: 2) (640 g). Nonpareil was thus coated around its surface with diltiazem hydrochloride to obtain plain granule cont~ining diltiazem hydrochloride in the amount of 90 % .
Then this plain granule was spray-co~ated with a 30 solution cont~ining 30 parts of Eudragit RS, 10 parts of calcium stearate and 3 parts of triethyl citrate to obtain various controlled release pharmaceutical preparations (a) to (e) cont~ining diltiazem hydrochloride, which differ from each other in the 35 amount of the coating layer on the plain granule as shown in Table 1.
* T~ade~ rk B
~ 2 ~ ~' J ~ 5 8 Table 1 Controlled release pharmaceutical Amount of coating layer~
preparation (a) 12 (b) 14 (c) 16 (d) 20 (e) 22 Amount of coating layer (g) per 10 0 g of plain granule (2) Comparison of dissolution patterns The dissolution test according to the puddle method (37~C, water, 100 rpm) based on the specification of the dissolution test under 11th revised Japanese 20 Pharmacopoeia (JPXI) was carried out with respect to each pharmaceutical preparation obtained in the above.
Plain granule cont~ining diltiazem hydro-chloride which was not yet coated was used as a control preparation.
25 ~ The dissolution test according to the same condition as in (~) was carried out with respect to the pharmaceutical preparation (d) in Table 1, with first fluid (JPXI), second fluid (JPXI) and water.
30 (3) Result The result of the dissolution test in (~) is shown in Fig. 1. It is recognized that according to the pharmaceutical preparation of the present invention, the medicinal compounds are completely released and their 35 dissolution patterns shows sigmoid type in water, although the lag time until the start of the dissolution is prolonged according as the increase of the amount of the coating layer in the pharmaceutical preparation.
12 -- ~ c 3 5 8 The result of the dissolution test in (~) is shown in Fig. 2. It is shown that the pharmaceutical preparation of the present invention shows the same dissolution patterns both with first fluid and second 5 fluid as that with water. This result shows that the pharmaceutical preparation of the present invention has the pH-independent dissolution property. Therefore, it is recognized that according to the pharmaceutical preparation of the present invention, a medicinal 10 compound dissolves immediately after a lag time irrespective of the pH change in the digestive tract.
Test Example 2 The controlled release pharmaceutical 15 preparation (d) obtained in Test Example 1 was orally ~1mini~stered (dose: 100 mg as the amount of diltiazem hydrochloride) to dogs. After ~-lministration, the blood was collected from vein at fixed times. The pl~m~
concentration of diltiazem hydrochloride was measured by 20 high performance liquid chromatography.
The result is shown in Fig. 3. It is recognized that the plasma concentration level is still high 30 hours later after the lag time of 8 hours.
Test Fsc~mple 3 The controlled release pharmaceutical preparations (a) (373 g) and (d) (800 g) obtained in the Test F~c~mr)le 1 and the plain granule ( 111 g) cont~ining diltiazem hydrochloride were mixed. The mixture ( 128 30 mg) cont~ining 100 mg of diltiazem hydrochloride was filled into a gelatin capsule to obtain a controlled release capsule.
Then the dissolution test according to the puddle method (37~C, water, 100 rpm) under JPXI was 35 carried out in the same m~nn~r as in Test F~r~mI le 1 with respect to the controlled release capsule obtained in the above.
The result of the dissolution test shows the ~ - 13 - ~ 5 :~ ~ 8 durative dissolution pattern for 24 hours as shown in Fig. 4. Therefore, it is clear that a preparation can be designed to release a drug continuously for long hours by combining various pharmaceutical preparations 5 of the present invention.
F~r~mple 1 Nonpareil 103 (granulated sucrose, from Freund Industrial Co. Ltd., Japan) which was a spherically 10 granulated sucrose having the diameter of 350 to 500 ,u m (800 g) was put into the centrifugal fluidizing type granulating and coating apparatus (made by Freund Industrial Co. Ltd., Japan hereinafter referred to as CF
apparatus) and rolled in it. Thereto was gradually 15 spread fine powder of diltiazem hydrochloride (9 kg) with spraying a solution of polyvinylpyrrolidone (200 g) in a mixture of ethanol and water (2: 3) (6.4 kg).
Plain granule having the diameter of 12 to 20 mesh (1400 to 840 ,u m) cont~ining diltiazem hydrochloride, wherein 20 Nonpareil was coated around its surface with diltiazem hydrochloride, was thus prepared. Then the obtained plain granule (1 kg) cont~inin~ diltiazem hydrochloride was put into CF apparatus and spray-coated with a solution consisting of Eudragit RS (a copolymer of ethyl 25 acrylate, methyl methacrylate and ~-methacryloyloxyethyl-trimethylammonium chloride, from Rohm Pharma, Germany) (84 g), calcium stearate (28 g), triethyl citrate (8 g), ethanol (160 g) and water (320 g). After coating, the glanule was dried by heating at 60~C for 16 hours to 30 obtain a controlled release pharmaceutical preparation cont~ining diltiazem hydrochloride (yield: 1.12 kg).
F~mple 2 The procedure was carried out in the same 35 m~nn~r as in F~mple 1 except that a mixture of Eudragit RS (112 g), calcium stearate (37 g), triethyl citrate (11 g), ethanol (210 g) and water (430 g) was used as a coating solution to obtain a controlled release B
14 2 ~ r 3 ~ ~
pharmaceutical preparation cont~iningdiltiazem hydrochloride (yield: 1.16 kg).
Fx~mI-le 3 The procedure was carried out in the same m~nn~r as in Example 1 except that a mixture of Eudragit RS (140 g), calcium stearate (47 g), triethyl citrate (14 g), ethanol (267 g) and water (533 g) was used as a coating solution to obtain a controlled release pharmaceutical preparation cont~iningdiltiazem hydrochloride (yield: 1. 2 kg).
Fx~mple 4 The procedure was carried out in the same 15 m~nn~r as in Example 3 except that magnesium stearate (47 g) was used instead of calcium stearate to obtain a controlled release pharmaceutical preparation cont~ining diltiazem hydrochloride (yield: 1.2 kg).
Fx~mr)le 5 The procedure was carried out in the same ni~nn~r as in F,x~mple 3 except that tributyl acetylcitrate ( 14 g) was used instead of triethyl citrate as a plasticizer toobtain a controlled release pharmaceutical preparationcont~ining diltiazem hydrochloride (yield: 1. 2 kg).
Fx~mple 6 The procedure was carried out in the same 30 m~nn~r as in F,~mple 3 except that both Eudragit RS (126 g) and Eudragit RL (14 g) were used instead of Eudragit RS ( 140 g) to obtain a controlled release pharmaceutical preparation cont~ining diltiazem hydrochloride (yield:
1.2 kg).
F,~r~mple 7 Thecontrolled release pharmaceutical preparation (0.56 kg) cont~inin~ diltiazem hydrochloride ~ 2 0 ~ 8 obtained in the same m~nn~r as in Example 3 was put into CF apparatus and spray-coated with a coating solution consisting of ethylcellulose (9.5 g), hydroxypropylcellulose (0.$ g), ethanol (59 g) and water 5 (32 g). Then the preparation was dried at 60~C for 16 hours to obtain a controlled release pharmaceutical preparation cont~ining diltiazem hydrochloride (yield:
0.57 kg)-Example 8 The controlled release pharmaceutical preparation (1.12 kg) cont~ining diltiazem hydrochloride obtained in the same m~nn~r as in Example 3 was put into CF apparatus and spray-coated with a coating solution 15 consisting of diltiazem hydrochloride (151 g), poly-vinylpyrrolidone (12 g), ethanol (87 g) and water (203 g). Then the preparation was dried at 60~C for 16 hours to obtain a controlled release pharmaceutical preparation cont~ining diltiazem hydrochloride, wherein 20 the part which rapidly released diltiazem hydrochloride was provided in its surface layer.
Example 9 To diltiazem chloride (4.8 kg) was added a 25 solution of polyvinylpyrrolidone (K30) (0.15 kg) dissolved in water (0.3 kg). The mixture was kne~d, dried at 45~C for 4 hours and granulated by sieving with 32 mesh sieve. To the obtained granule (4.5 kg) was added magnesium stearate (45 g) and the mixed powder 30 thereof was tabletted to give plain tablets cont~ining diltiazem hydrochloride, which have the diameter of 5 mm and the weight of 50 mg per tablet.
Then plain tablets (4.0 kg) were put into the coating apparatus (Hi-coater, made by Freund Industrial 35 Co. Ltd., Japan) and spray-coated with a solution consisting of Eudragit RS (224 g), calcium stearate (74 g), triethyl citrate (22 g), ethanol (420 g) and water (860 g). Then the tablets were dried by heating at 60~C
- 16 - ?J~ .3~8 for 16 hours to obtain controlled release tablets cont~ining diltiazem hydrochloride (yield: 4.3 kg).
Example 10 Nonpareil 103 which was a spherically granulated sucrose having the diameter af 350 to 500 ,u m (1500 g) was put into CF apparatus and rolled in it.
Thereto was gradually spread fine powder of nicotinamide (NA) ~900 g) with spraying a solution of sucrose (135 g) in a mixture (465 g) of ethanol and water (1: 3). The plain granule having the diameter of 12 to 20 mesh (1400 to 840 ,u m) cont~ining NA, wherein Nonpareil was coated around its surface with NA, was thus prepared.
Then the obtained plain granule (0.5 kg) cont~ining NA was put into CF apparatus and spray-coated with a solution consisiting of Eudragit RS - (105 g), calcium stearate (35 g), triethyl citrate (11 g), ethanol (200 g) and water (400 g). Then the granule was dried by heating at 60~C for 16 hours to obtain a 20 controlled release pharmaceutical preparation cont~ining NA (yield: 0.56 kg).
F,~mple 11 The procedure was carried out in the same 25 m~nn~r as in F,~mple 10 except that phenylpropanol~mine hydrochloride was used instead of NA to obtain a controlled release pharmaceutical preparation cont~ining phenylpropanol~mine hydrochloride (yield: 0.56 kg).
Example 12 The procedure was carried out in the same m~nner as in F,~mple 10 except that bisoprolol fumarate was used instead of NA to obtain a controlled release pharmaceutical preparation cont~ining bisoprolol fumarate (yield: 0.56 kg).
F,~mple 13 The procedure was carried out in the same 17 -- ~ ~ L!~ 8 m~nn~r as in F~mple 10 except that ascorbic acid was used instead of NA to obtain a controlled release pharmaceutical preparation cont~ining ascorbic acid (yield: 0.56 kg).
F~mple 14 The procedure was carried out in the same m~nn~r as in F.~mple 10 except that thi~mine hydro-chloride was used instead of NA to obtain a controlled 10 release pharmaceutical preparation cont~ining thi~mine hydrochloride (yield: 0.56 kg).
Example 15 The procedure was carried out in the same 15 m~nn~r as in Example 10 except that pyridoxine hydrochloride was used instead of NA to obtain a controlled release pharmaceutical preparation cont~ining pyridoxine hydrochloride (yield: 0.56 kg).
~mple 16 Nonpareil 103 which was a spherically granulated sucrose having the diameter of 500 to 710 ,u m (1.04 kg) was put into CF apparatus and rolled in it. Thereto was gradually spread a mixed powder of fine 25 powder of (+)-(2S,3S)-3-acetoxy-8-chloro-5-[2-(dimethyl-amino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one- maleate (hereinafter referred to as Clentiazem) (1.176 kg) and succinic acid (1.96 kg) with spraying a solution of sucrose (0.78 kg) in the 30 mixture of ethanol and water (1: 3) (2.22 kg). The plain granule having the diameter of 12 to 24 mesh (1400 to 710 ,~ m) cont~ining aentiazem, wherein Nonpareil was coated around its surface with Clentiazem, was thus prepared.
Then the obtained plain granule (1 kg) cont~ining Clentiazem was put into CF apparatus and spray-coated with a solution consisiting of Eudragit RS
(279 g), calcium stearate (93 g), triethyl citrate (28 - =
~ 18 - ~ ~Of~ 3~i~
g), ethanol (533 g) and water (1067 g). After coating, the granule was dried by heating at 60~C for 16 hours to obtain a controlled release pharmaceutical preparation cont~ining Clentiazem (yield: 1.38 kg).
In addition to the ingredients used in the Fx~mples, other ingredients can be used in the F,~mples as set forth in the specification to obtain substantially the same results.
thickness of the coating layer results a delay of the starting of the dissolution of a medicinal active ingredient. However, it is also known that in this case the thick coat layer hinders rapid dissolution of a medicinal active ingredient after the starting of the dissolution and therefore an effective blood concentration can not be obtained rapidly.
An object of this invention is to provide a controlled release pharmaceutical preparation giving a so-called sigmoid type dissolution pattern wherein a lag time until the starting of the dissolution of a medicinal compound and the rate of the following dissolution can be controlled and the rate of the dissolution of the medicinal compound does not depend on the pH of a medium for the dissolution.
This and other o~jects of the present invention will be come apparent from the description hereinafter.
SUMMARY OF THE INVENTION
It has been found that in case of coating a medicinal active ingredient with a water-insoluble and slightly water-permeable acrylic polymer having trimethylammoniumethyl group and a water-repellent salt such as magnecium stearate or calcium sterarate, Q the time until the starting of the dissolution of a medicinal active ingredient from the pharmaceutical preparation lengthens, (~) the time until the starting of the dissolution can be controlled by the amount of the coating layer and (~) once the dissolution starts, almost 100 % of the medicinal active ingredient dissolves irrespective of the a~ount of the coating layer.
The present invention provides a controlled release pharmaceutical preparation comprising a core cont~ining a medicinal co~pound and a coating layer 35 cont~ining a water-repellent salt and a water-insoluble and slightly water-perm~eable acrylic polymer having trimethylammoniumethyl group.
~ - 3 - 2 ~ B, 5 ~ 5 ~
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is a graph showing the result of the dissolution test with water as to various controlled release granules (a) to (e) obtained in Test Example 1 5 which differ from each other in the amount of coating layer. Fig. 2 is a graph showing the result of the dissolution test with water, first fluid and second fluid as to the controlled release granule (d) obtained in Test F~mple 1. Fig. 3 is a graph showing the change 10 in blood concentration of a medicinal compound in case that the granule (d) was ~lministered to dogs in Test F~r~mple 2. Fig. 4 is a graph showing the result of the dissolution test as to a capsule cont~ining various controlled release granules obtained in Test Example 3 15 which differ from each other in the amount of the coating layer.
DETAILED DESCRIPTION
The controlled release pharmaceutical 20 preparation of the present invention comprises a core cont~ining a medicinal compound and a coating layer cont~inin~ a water-repellent salt and a water-insoluble and slightly water-permeable acrylic polymer having trimethylammoniumethyl group, which surrounds said core.
2 5 If desired, another coating layer of at least one material selected from the group consisting of ethylcellulose, hydroxypropylcellulose and a medicinal compound may be provided around said coating layer in the constrolled release pharmaceutical preparation of 30 the present invention.
In the present invention, a polymer of acrylic acid, methyl acrylate, ethyl acrylate, methacrylic acid, methyl methacrylate, ethyl methacrylate or the like, which has trimethylammoniumetyl group in the molecule, 3 5 may be used as a water-insoluble and slightly water-permeable acrylic polymer constituting the coating layer. For instance, a copolymer of ethyl acrylate, me thyl methacrylate and ~-methacryloyloxyethyl-~ ~ 4 - 2045~5~
trimethylammonium chloride in which about 0. 0 2 5 to about 0 . 0 3 3 mole of ~-methacryloyloxyethyltrimethylammonium chloride is contained per mole of the other neutral acrylic monomers is preferably used. Such copolymer is, 5 for example, commercially available under trade mark " Eudragit RS" from Rohm Pharma, Germany or the like.
The above-mentioned polymer may contain, for instance, a small quantity of a water-permeable polymer. Such copolymer is, for example, commercially 10 available under trade mark " Eudragit RL" from Rohm Pharma, Germany or the like.
As ethylcellulose or hydroxypropylcellulose which is a material of another coating layer provided around the coating layer of an acrylic polymer, for 15 instance, ethylcellulose cont~ining about 46.5 to about 51. 0 % of ethoxy group, hydroxypropylcellulose cont~ining about 53.4 to about 77.5 % of hydroxypropoxy group or the like can be suitably used.
As a water-repellent salt which constitute the 20 coating layer with an acrylic polymer, a salt of higher fatty acid and an ~lk~line earth metal is preferably used. Concretely, examples of the salts are calcium stearate, magnecium stearate and the like.
In the present invention, as the ratio of the 25 above-mentioned acrylic polymer and the water-repellent salt in the coating layer, it is adequate that about 0. 5 to about 5 parts by weight, preferably about 1. 5 to about 4. 5 parts by weight and more preferably about 2 to about 4 parts by weight of the acrylic polymer is 3 0 contained per part by weight of the water-repellent salt.
The amount of the coating layer for the core is variable a little dep~n-ling on the form or the size of the core. However, it is preferable that the amount of 35 the coating layer to be used tends to increase a bit dep~n-ling on the increase of the surface area per unit weight, that is, the decrease of the particle size of the core. For example, in case of spherical particles ~ 2~ 3~8 having mean particle size of about 500 to about 1000 ,(1 m, the amount of the coating layer is about 5 to about 80 %, preferably about 7 to about 50 %, in particular, preferably about 8 to about 3 0 %, based on the weight of 5 the core.
In the present invention, the form of the core to be coated is not particularly limited and various forms such as plain tablet, pill, granule and fine granule may be suitably used. Above all, the granulated 10 cores having mean particle size of about 300 to about 5000 ,u m, in particular, about 500 to about 1500 ,u m may be preferably used.
The medicinal compound to be contained in the core is not particularly limited. For instance, calcium 15 antagonists such as diltiazem hydrochloride, verapamil hydrochloride, nicardipine, nitrendipine and nimodipine, antiasthmatic agents such as theophylline and trimetaquinol, water soluble vit~min.~, antibiotics, antimalignantumor agents, antipyretic analgesics, 20 antihyperglycemic agents and the like may be used.
In addition, various additives such as an excipient, a binder, a lubricant, an aggregation-preventing agent and a solubilizer for a medicinal compound which are usually used in this field may be 25 contained in the core.
F~mr)les of excipients are sugars such as sucrose, lactose, mannitol and glucose, starch, crystalline cellulose, calcium phosphate, calcium sulfate, calcium lactate and the like. Examples of carriers for reg~ ting particle sizes are sucrose, lactose, starch, crystalline cellulose and the like.
F~mples of binders are polyvinylalcohol, polyacrylic acid, polymethacrylic acid, polyvinylpyrrolidone, glucose, sucrose, lactose, maltose, sorbitol, mannitol, 3 5 hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, macrogols, arabic gum, gelatin, agar, starch and the like. Examples of lubricants are stearic acid, talc and the like. F~mples of 3 ~ 8 aggregation-preventing agents are the above-mentioned lubricants, silicone dioxide, colloidal silicone dioxide and the like. Examples of solubilizers for medicinal compounds are organic acids such as fumaric 5 acid, succinic acid and malic acid and the like.
The pharmaceutical preparation of the present invention can be prepared by coating cores cont~ining a medicinal compound with a dispersion of a water-insoluble and slightly water-permeable acrylïc polymer 10 having trimethylammoniumethyl group and a water-repellent salt. The preparation of the cores can be carried out according to the usual procedure for the preparation, for example, as described in Lemingtons Pharmaceutical Sciences 17, 1603-1632, 1633-1643 (Mack 15 Publishing Company, published in 1985). For F~r~mple, the cores can be prepared by gr~n~ ting the composition of a medicinal compound, a binder and, as occasion dem~n-ls, other additives such as an exicipent according to the method of wet oscillating granulation, rotating 20 granulation, fluidizing bed granulation or the like to obtain granules. Alternatively, for example, the cores may be prepared using carriers for regulating particle sizes. That is, spherically granulated carriers may be coated with a medicinal compound according to the usual 25 method such as powder coating method to obtain the cores. Powder coating can be carried out, for instance, by gradually ~l(lin~ a medicinal compound or a mixture of the medicinal compound and suitable additives such as an excipient with spraying a solution obtained by 30 dissolving a binder in a suitable solvent such as water, a lower alcohol such as methanol, ethanol, propanol, isopropanol or butanol, a lower alkanone such as acetone or methylethylketone, chloroform, dichloromethane, dichloroethane or a mixture thereof, on carrier 35 particles to be cores, according to the method of rotating granulation, pan coating, fluidizing bed coating or the like.
The coating for thus obtained cores can be carried out by adhering a dispersion of a water-repellent salt and an acrylic polymer to the cores followed by drying.
As a dispersion medium for the above-mentioned 5 component of the coating layer, water, an alcohol such as methanol, ethanol or propanol, a ketone such as acetone, a halogenated hydrocarbon such as methylene-chloride or chloroform, a mixture thereof or the like is exemprified. Water, an alcohol or a mixture thereof is 10 preferable, and ethanol or a mixture of ethanol and water is particularly preferable.
The coating can be carried out according to a method generally used in the art for preparation such as the method of fluidizing bed coating or pan coating.
15 For example, in case of the method of fluidizing bed coating, the coating can be carried out as follows.
That is, while the cores are fluidized in an apparatus by means of air pressure, they are spray-coated with an aqueous dispersion of a water-repellent salt and an 20 acrylic acid polymer at an adequate rate from the nozzle of the spray-gun.
The concentration of a water-repellent salt and an acrylic polymer in the dispersion is not particularly limited, but it is preferable that these components are 25 added within the above-mentioned scope of the preferable proportion of both components, to be the concentration of about 5 to about 40 % by weight. In addition, a plasticizer, a coloring agent and the like may be cont~ine~ in the dispersion. As a plasticizer, for instance,triacetin,triethyl citrate, acetyltributyl citrate, diethylphthalate, polyethyleneglycol, polysorbate or the like can be suitably used. The amount of the plasticizer to be used is preferably about 5 to about 4 0 % by weight based on the weight of an 35 acrylic polymer.
The drying of thus obtained coating layer can be easily carried out, for example, by heating at about 35 to about 100~C, particularly about 40 to about 70~C.
- 8 - 2~
The other form of the pharmaceutical preparation of the present invention wherein another coating layer made of at least one material selected from the group consisting of ethylcellulose, 5 hydroxypropylcellulose and a medicinal compound is provided around the coating layer cont~ining a water-repellent salt and a water-insoluble and slightly water-permeable acrylic polymer having trimethyl-ammoniumethyl group, can be easily prepared by further 10 coating the above-mentioned pharmaceutical preparation having the coating layer of an acrylic polymer with these components according to the usual method.
For example, in case of coating with ethyl-cellulose or hydroxypropylcellulose, the solution 15 prepared by dissolving ethylcellulose or hydroxypropyl-cellulose in water, methanol, ethanol, acetone or a mixed solvent thereof to be the conc~ alion of about 0.5 to about 10 %, may be sprayed for coating. In case of coating with a medicinal compound, the solution or 20 dispersion cont~ining said medicinal compound or a mixture of the medicinal compound and suitable additives such as an excipient and a binder may be sprayed for coating according to the usual method. As the additives, for instance, the above-mentioned binders and 25 excipients may be suitably used.
Thus obtained controlled release pharmaceutical preparation of the present invention may be ~iministered as it is or in a form filled in capsules.
The pharmaceutical preparation of the present 30 invention has the following characteristics because of its coating layer of a slightly water-permeable acrylic polymer. That is, a medicinal active ingredient rapidly dissolves from the preparation after a certain period which depends upon the amount of the coating layer 35 although it never dissolves after ~(lministration until the certain time passes. Besides, the time until the start of the dissolution of a medicinal active ingredient is optionally adjustable by changing the 9 ~O=~ 8 amount of the coating layer.
Therefore, the pharmaceutical preparation of the present invention is useful as a pharmaceutical preparation wherein the starting of the dissolution of a 5 pharmaceutical compound can be adjusted by itself.
And it is further useful that the pharmaceutical preparation which can rçtain an effective blood concentration for many hours can be obtained by combining various pharmaceutical preparations which 10 differ from each other in the amount of the coating layer or in a kind of a component of the coating layer, according to the present invention.
The pharmaceutical preparation of the present invention wherein the coating layer of a slightly 15 water-permeable acrylic polymer is further coated with ethylcellulose, hydroxypropylcellulose or the like, has a following advantage. That is, because the dissolution rate of a medicinal compound after a lag time in such pharmaceutical preparation is sm~ r than that in a 20 pharmaceutical preparation whose coating layer of an acrylic polymer and a water-repellent salt is not further coated, the most suitable dissolution pattern can be obtained by employing the above-mentioned coating layer in accordance with a kind of medicinal active 25 ingredient. In addition, these pharmaceutical preparations also have an advantage of being useful for preventing the aggregation of the preparations, which occurs during preparing them.
Further the pharmaceutical preparation wherein 30 the layer of a medicinal compound is provided around the coating layer of an acrylic polymer can start the dissolution of the inside medicinal compound when the blood concentration originated in the outside medicinal compound has lowered after its dissolution followed by 35 the rise of its concentration, by adjusting the amounts of the medicinal compound layer and an acrylic polymer layer or providing an another coating layer of hydroxy-propylcellulose or the like around the layer of a , ~ - 10 - ~ 5 3 5 8 medicinal compound. Therefore, the pharmaceutical preparation of the present invention has an advantage that it can be ~rlministered as a pharmaceutical preparation suitable for once ~-lministration a day.
The present invention is more specifically described and explained by means of the following Test Examples and F~mples in which all percents and parts are by weight unless otherwise noted. It is to be understood that the present invention is not limited to the ~mples, and various changes and modifications may be made in the invention without departing from the spirit and scope thereof.
Test Example 1 (1) Preparation Nonpareil (granulated sucrose, from Freund Industrial Co. Ltd., Japan) having the diameter of 350 to 500 u m (80 g) was put into the centrifugal fluidizing type granulating and coating apparatus 20 (CF-360EX Type, made by Freund Industrial Co. Ltd., Japan) and rolled in it.
Thereto was gradually added fine powder of diltiazem hydrochloride (900 g) with spraying a solution of polyvinylpyrrolidone (20 g) dissolved in a mixture of 25 water and ethanol (3: 2) (640 g). Nonpareil was thus coated around its surface with diltiazem hydrochloride to obtain plain granule cont~ining diltiazem hydrochloride in the amount of 90 % .
Then this plain granule was spray-co~ated with a 30 solution cont~ining 30 parts of Eudragit RS, 10 parts of calcium stearate and 3 parts of triethyl citrate to obtain various controlled release pharmaceutical preparations (a) to (e) cont~ining diltiazem hydrochloride, which differ from each other in the 35 amount of the coating layer on the plain granule as shown in Table 1.
* T~ade~ rk B
~ 2 ~ ~' J ~ 5 8 Table 1 Controlled release pharmaceutical Amount of coating layer~
preparation (a) 12 (b) 14 (c) 16 (d) 20 (e) 22 Amount of coating layer (g) per 10 0 g of plain granule (2) Comparison of dissolution patterns The dissolution test according to the puddle method (37~C, water, 100 rpm) based on the specification of the dissolution test under 11th revised Japanese 20 Pharmacopoeia (JPXI) was carried out with respect to each pharmaceutical preparation obtained in the above.
Plain granule cont~ining diltiazem hydro-chloride which was not yet coated was used as a control preparation.
25 ~ The dissolution test according to the same condition as in (~) was carried out with respect to the pharmaceutical preparation (d) in Table 1, with first fluid (JPXI), second fluid (JPXI) and water.
30 (3) Result The result of the dissolution test in (~) is shown in Fig. 1. It is recognized that according to the pharmaceutical preparation of the present invention, the medicinal compounds are completely released and their 35 dissolution patterns shows sigmoid type in water, although the lag time until the start of the dissolution is prolonged according as the increase of the amount of the coating layer in the pharmaceutical preparation.
12 -- ~ c 3 5 8 The result of the dissolution test in (~) is shown in Fig. 2. It is shown that the pharmaceutical preparation of the present invention shows the same dissolution patterns both with first fluid and second 5 fluid as that with water. This result shows that the pharmaceutical preparation of the present invention has the pH-independent dissolution property. Therefore, it is recognized that according to the pharmaceutical preparation of the present invention, a medicinal 10 compound dissolves immediately after a lag time irrespective of the pH change in the digestive tract.
Test Example 2 The controlled release pharmaceutical 15 preparation (d) obtained in Test Example 1 was orally ~1mini~stered (dose: 100 mg as the amount of diltiazem hydrochloride) to dogs. After ~-lministration, the blood was collected from vein at fixed times. The pl~m~
concentration of diltiazem hydrochloride was measured by 20 high performance liquid chromatography.
The result is shown in Fig. 3. It is recognized that the plasma concentration level is still high 30 hours later after the lag time of 8 hours.
Test Fsc~mple 3 The controlled release pharmaceutical preparations (a) (373 g) and (d) (800 g) obtained in the Test F~c~mr)le 1 and the plain granule ( 111 g) cont~ining diltiazem hydrochloride were mixed. The mixture ( 128 30 mg) cont~ining 100 mg of diltiazem hydrochloride was filled into a gelatin capsule to obtain a controlled release capsule.
Then the dissolution test according to the puddle method (37~C, water, 100 rpm) under JPXI was 35 carried out in the same m~nn~r as in Test F~r~mI le 1 with respect to the controlled release capsule obtained in the above.
The result of the dissolution test shows the ~ - 13 - ~ 5 :~ ~ 8 durative dissolution pattern for 24 hours as shown in Fig. 4. Therefore, it is clear that a preparation can be designed to release a drug continuously for long hours by combining various pharmaceutical preparations 5 of the present invention.
F~r~mple 1 Nonpareil 103 (granulated sucrose, from Freund Industrial Co. Ltd., Japan) which was a spherically 10 granulated sucrose having the diameter of 350 to 500 ,u m (800 g) was put into the centrifugal fluidizing type granulating and coating apparatus (made by Freund Industrial Co. Ltd., Japan hereinafter referred to as CF
apparatus) and rolled in it. Thereto was gradually 15 spread fine powder of diltiazem hydrochloride (9 kg) with spraying a solution of polyvinylpyrrolidone (200 g) in a mixture of ethanol and water (2: 3) (6.4 kg).
Plain granule having the diameter of 12 to 20 mesh (1400 to 840 ,u m) cont~ining diltiazem hydrochloride, wherein 20 Nonpareil was coated around its surface with diltiazem hydrochloride, was thus prepared. Then the obtained plain granule (1 kg) cont~inin~ diltiazem hydrochloride was put into CF apparatus and spray-coated with a solution consisting of Eudragit RS (a copolymer of ethyl 25 acrylate, methyl methacrylate and ~-methacryloyloxyethyl-trimethylammonium chloride, from Rohm Pharma, Germany) (84 g), calcium stearate (28 g), triethyl citrate (8 g), ethanol (160 g) and water (320 g). After coating, the glanule was dried by heating at 60~C for 16 hours to 30 obtain a controlled release pharmaceutical preparation cont~ining diltiazem hydrochloride (yield: 1.12 kg).
F~mple 2 The procedure was carried out in the same 35 m~nn~r as in F~mple 1 except that a mixture of Eudragit RS (112 g), calcium stearate (37 g), triethyl citrate (11 g), ethanol (210 g) and water (430 g) was used as a coating solution to obtain a controlled release B
14 2 ~ r 3 ~ ~
pharmaceutical preparation cont~iningdiltiazem hydrochloride (yield: 1.16 kg).
Fx~mI-le 3 The procedure was carried out in the same m~nn~r as in Example 1 except that a mixture of Eudragit RS (140 g), calcium stearate (47 g), triethyl citrate (14 g), ethanol (267 g) and water (533 g) was used as a coating solution to obtain a controlled release pharmaceutical preparation cont~iningdiltiazem hydrochloride (yield: 1. 2 kg).
Fx~mple 4 The procedure was carried out in the same 15 m~nn~r as in Example 3 except that magnesium stearate (47 g) was used instead of calcium stearate to obtain a controlled release pharmaceutical preparation cont~ining diltiazem hydrochloride (yield: 1.2 kg).
Fx~mr)le 5 The procedure was carried out in the same ni~nn~r as in F,x~mple 3 except that tributyl acetylcitrate ( 14 g) was used instead of triethyl citrate as a plasticizer toobtain a controlled release pharmaceutical preparationcont~ining diltiazem hydrochloride (yield: 1. 2 kg).
Fx~mple 6 The procedure was carried out in the same 30 m~nn~r as in F,~mple 3 except that both Eudragit RS (126 g) and Eudragit RL (14 g) were used instead of Eudragit RS ( 140 g) to obtain a controlled release pharmaceutical preparation cont~ining diltiazem hydrochloride (yield:
1.2 kg).
F,~r~mple 7 Thecontrolled release pharmaceutical preparation (0.56 kg) cont~inin~ diltiazem hydrochloride ~ 2 0 ~ 8 obtained in the same m~nn~r as in Example 3 was put into CF apparatus and spray-coated with a coating solution consisting of ethylcellulose (9.5 g), hydroxypropylcellulose (0.$ g), ethanol (59 g) and water 5 (32 g). Then the preparation was dried at 60~C for 16 hours to obtain a controlled release pharmaceutical preparation cont~ining diltiazem hydrochloride (yield:
0.57 kg)-Example 8 The controlled release pharmaceutical preparation (1.12 kg) cont~ining diltiazem hydrochloride obtained in the same m~nn~r as in Example 3 was put into CF apparatus and spray-coated with a coating solution 15 consisting of diltiazem hydrochloride (151 g), poly-vinylpyrrolidone (12 g), ethanol (87 g) and water (203 g). Then the preparation was dried at 60~C for 16 hours to obtain a controlled release pharmaceutical preparation cont~ining diltiazem hydrochloride, wherein 20 the part which rapidly released diltiazem hydrochloride was provided in its surface layer.
Example 9 To diltiazem chloride (4.8 kg) was added a 25 solution of polyvinylpyrrolidone (K30) (0.15 kg) dissolved in water (0.3 kg). The mixture was kne~d, dried at 45~C for 4 hours and granulated by sieving with 32 mesh sieve. To the obtained granule (4.5 kg) was added magnesium stearate (45 g) and the mixed powder 30 thereof was tabletted to give plain tablets cont~ining diltiazem hydrochloride, which have the diameter of 5 mm and the weight of 50 mg per tablet.
Then plain tablets (4.0 kg) were put into the coating apparatus (Hi-coater, made by Freund Industrial 35 Co. Ltd., Japan) and spray-coated with a solution consisting of Eudragit RS (224 g), calcium stearate (74 g), triethyl citrate (22 g), ethanol (420 g) and water (860 g). Then the tablets were dried by heating at 60~C
- 16 - ?J~ .3~8 for 16 hours to obtain controlled release tablets cont~ining diltiazem hydrochloride (yield: 4.3 kg).
Example 10 Nonpareil 103 which was a spherically granulated sucrose having the diameter af 350 to 500 ,u m (1500 g) was put into CF apparatus and rolled in it.
Thereto was gradually spread fine powder of nicotinamide (NA) ~900 g) with spraying a solution of sucrose (135 g) in a mixture (465 g) of ethanol and water (1: 3). The plain granule having the diameter of 12 to 20 mesh (1400 to 840 ,u m) cont~ining NA, wherein Nonpareil was coated around its surface with NA, was thus prepared.
Then the obtained plain granule (0.5 kg) cont~ining NA was put into CF apparatus and spray-coated with a solution consisiting of Eudragit RS - (105 g), calcium stearate (35 g), triethyl citrate (11 g), ethanol (200 g) and water (400 g). Then the granule was dried by heating at 60~C for 16 hours to obtain a 20 controlled release pharmaceutical preparation cont~ining NA (yield: 0.56 kg).
F,~mple 11 The procedure was carried out in the same 25 m~nn~r as in F,~mple 10 except that phenylpropanol~mine hydrochloride was used instead of NA to obtain a controlled release pharmaceutical preparation cont~ining phenylpropanol~mine hydrochloride (yield: 0.56 kg).
Example 12 The procedure was carried out in the same m~nner as in F,~mple 10 except that bisoprolol fumarate was used instead of NA to obtain a controlled release pharmaceutical preparation cont~ining bisoprolol fumarate (yield: 0.56 kg).
F,~mple 13 The procedure was carried out in the same 17 -- ~ ~ L!~ 8 m~nn~r as in F~mple 10 except that ascorbic acid was used instead of NA to obtain a controlled release pharmaceutical preparation cont~ining ascorbic acid (yield: 0.56 kg).
F~mple 14 The procedure was carried out in the same m~nn~r as in F.~mple 10 except that thi~mine hydro-chloride was used instead of NA to obtain a controlled 10 release pharmaceutical preparation cont~ining thi~mine hydrochloride (yield: 0.56 kg).
Example 15 The procedure was carried out in the same 15 m~nn~r as in Example 10 except that pyridoxine hydrochloride was used instead of NA to obtain a controlled release pharmaceutical preparation cont~ining pyridoxine hydrochloride (yield: 0.56 kg).
~mple 16 Nonpareil 103 which was a spherically granulated sucrose having the diameter of 500 to 710 ,u m (1.04 kg) was put into CF apparatus and rolled in it. Thereto was gradually spread a mixed powder of fine 25 powder of (+)-(2S,3S)-3-acetoxy-8-chloro-5-[2-(dimethyl-amino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one- maleate (hereinafter referred to as Clentiazem) (1.176 kg) and succinic acid (1.96 kg) with spraying a solution of sucrose (0.78 kg) in the 30 mixture of ethanol and water (1: 3) (2.22 kg). The plain granule having the diameter of 12 to 24 mesh (1400 to 710 ,~ m) cont~ining aentiazem, wherein Nonpareil was coated around its surface with Clentiazem, was thus prepared.
Then the obtained plain granule (1 kg) cont~ining Clentiazem was put into CF apparatus and spray-coated with a solution consisiting of Eudragit RS
(279 g), calcium stearate (93 g), triethyl citrate (28 - =
~ 18 - ~ ~Of~ 3~i~
g), ethanol (533 g) and water (1067 g). After coating, the granule was dried by heating at 60~C for 16 hours to obtain a controlled release pharmaceutical preparation cont~ining Clentiazem (yield: 1.38 kg).
In addition to the ingredients used in the Fx~mples, other ingredients can be used in the F,~mples as set forth in the specification to obtain substantially the same results.
Claims (3)
1. A controlled release pharmaceutical preparation comprising a core containing a medicinal compound; and a single coating layer containing (i) a water-repellent salt selected from the group consisting of calcium stearate and magnesium stearate, and (ii) a water-insoluble and slightly water-permeable acrylic polymer having trimethylammoniumethyl group;
wherein 0.5 to 5 parts by weight of the acrylic polymer is contained per part byweight of the water-repellent salt in the coating layer.
wherein 0.5 to 5 parts by weight of the acrylic polymer is contained per part byweight of the water-repellent salt in the coating layer.
2. The pharmaceutical preparation of claim 1, wherein the acrylic polymer is a water-insoluble and slightly water-permeable copolymer of ethyl acrylate, methyl methacrylate and .beta.-methacryloyloxyethyltrimethyl-ammonium chloride.
3. The pharmaceutical preparation of claim 1, wherein another coating layer made of at least one material selected from the group consisting of ethylcellulose, hydroxypropylcellulose and a medicinal compound is provided around the coating layer containing a water-repellent salt and a water-insoluble and slightly water-permeable acrylic polymer having trimethylammoniumethyl group.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP171762/1990 | 1990-06-28 | ||
| JP17176290 | 1990-06-28 | ||
| SG4995A SG4995G (en) | 1990-06-28 | 1995-01-13 | Controlled release pharmaceutical preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2045358A1 CA2045358A1 (en) | 1991-12-29 |
| CA2045358C true CA2045358C (en) | 1998-04-28 |
Family
ID=26494375
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002045358A Expired - Lifetime CA2045358C (en) | 1990-06-28 | 1991-06-25 | Controlled release pharmaceutical preparation |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US5137733A (en) |
| EP (1) | EP0463877B2 (en) |
| JP (1) | JP2558396B2 (en) |
| KR (1) | KR0133511B1 (en) |
| CN (1) | CN1040061C (en) |
| AT (1) | ATE106241T1 (en) |
| CA (1) | CA2045358C (en) |
| DE (1) | DE69102211T3 (en) |
| DK (1) | DK0463877T3 (en) |
| ES (1) | ES2055962T5 (en) |
| FI (1) | FI103476B1 (en) |
| GR (1) | GR3024471T3 (en) |
| HK (1) | HK33895A (en) |
| HU (1) | HU214590B (en) |
| IE (1) | IE64629B1 (en) |
| IL (1) | IL98611A (en) |
| SG (1) | SG4995G (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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| JPS5944311A (en) * | 1982-09-07 | 1984-03-12 | Santen Pharmaceut Co Ltd | Slow-releasing granule and its preparation |
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| JPH0674206B2 (en) * | 1989-12-28 | 1994-09-21 | 田辺製薬株式会社 | Controlled release formulation and process for producing |
-
1991
- 1991-06-11 JP JP3138998A patent/JP2558396B2/en not_active Expired - Lifetime
- 1991-06-18 FI FI912952A patent/FI103476B1/en not_active IP Right Cessation
- 1991-06-21 IE IE216691A patent/IE64629B1/en not_active IP Right Cessation
- 1991-06-25 CA CA002045358A patent/CA2045358C/en not_active Expired - Lifetime
- 1991-06-25 IL IL9861191A patent/IL98611A/en not_active IP Right Cessation
- 1991-06-27 AT AT91305834T patent/ATE106241T1/en not_active IP Right Cessation
- 1991-06-27 DK DK91305834.3T patent/DK0463877T3/en active
- 1991-06-27 EP EP91305834A patent/EP0463877B2/en not_active Expired - Lifetime
- 1991-06-27 DE DE69102211T patent/DE69102211T3/en not_active Expired - Lifetime
- 1991-06-27 ES ES91305834T patent/ES2055962T5/en not_active Expired - Lifetime
- 1991-06-27 HU HU912170A patent/HU214590B/en unknown
- 1991-06-28 KR KR1019910010955A patent/KR0133511B1/en not_active IP Right Cessation
- 1991-06-28 CN CN91105399A patent/CN1040061C/en not_active Expired - Lifetime
- 1991-06-28 US US07/723,031 patent/US5137733A/en not_active Expired - Lifetime
-
1995
- 1995-01-13 SG SG4995A patent/SG4995G/en unknown
- 1995-03-09 HK HK33895A patent/HK33895A/en not_active IP Right Cessation
-
1997
- 1997-08-14 GR GR970402109T patent/GR3024471T3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| FI103476B (en) | 1999-07-15 |
| IL98611A0 (en) | 1992-07-15 |
| IE64629B1 (en) | 1995-08-23 |
| CA2045358A1 (en) | 1991-12-29 |
| KR920000313A (en) | 1992-01-29 |
| FI912952A0 (en) | 1991-06-18 |
| DE69102211D1 (en) | 1994-07-07 |
| CN1058533A (en) | 1992-02-12 |
| ES2055962T5 (en) | 1997-09-16 |
| FI103476B1 (en) | 1999-07-15 |
| JP2558396B2 (en) | 1996-11-27 |
| IE912166A1 (en) | 1992-01-01 |
| CN1040061C (en) | 1998-10-07 |
| AU634400B2 (en) | 1993-02-18 |
| KR0133511B1 (en) | 1998-04-23 |
| SG4995G (en) | 1995-06-16 |
| US5137733A (en) | 1992-08-11 |
| ATE106241T1 (en) | 1994-06-15 |
| DE69102211T2 (en) | 1994-09-15 |
| HUT59321A (en) | 1992-05-28 |
| GR3024471T3 (en) | 1997-11-28 |
| DK0463877T3 (en) | 1994-06-27 |
| HU912170D0 (en) | 1991-12-30 |
| DE69102211T3 (en) | 1997-08-28 |
| HU214590B (en) | 1998-04-28 |
| AU7924391A (en) | 1992-01-02 |
| JPH04235123A (en) | 1992-08-24 |
| EP0463877B1 (en) | 1994-06-01 |
| EP0463877B2 (en) | 1997-07-02 |
| EP0463877A1 (en) | 1992-01-02 |
| ES2055962T3 (en) | 1994-09-01 |
| FI912952A (en) | 1991-12-29 |
| HK33895A (en) | 1995-03-17 |
| IL98611A (en) | 1998-10-30 |
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