CA1309951C - Press coated dhp tablets - Google Patents
Press coated dhp tabletsInfo
- Publication number
- CA1309951C CA1309951C CA000570069A CA570069A CA1309951C CA 1309951 C CA1309951 C CA 1309951C CA 000570069 A CA000570069 A CA 000570069A CA 570069 A CA570069 A CA 570069A CA 1309951 C CA1309951 C CA 1309951C
- Authority
- CA
- Canada
- Prior art keywords
- core
- coat
- active compound
- dihydropyridine
- preparation according
- 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 - Lifetime
Links
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
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Abstract
Press coated DHP tablets ABSTRACT
A solid medicament preparation having a long-lasting action in the form of a press coated tablet which contains a sparingly soluble dihydropyridine, the tablet comprising a) a core which contains a dihydropyridine in rapid-release form, and b) a coat around the core, the coat containing a di-hydropyridine in slow-release form. The tablet has a long-lasting action.
A solid medicament preparation having a long-lasting action in the form of a press coated tablet which contains a sparingly soluble dihydropyridine, the tablet comprising a) a core which contains a dihydropyridine in rapid-release form, and b) a coat around the core, the coat containing a di-hydropyridine in slow-release form. The tablet has a long-lasting action.
Description
~ 3 ~ 23189-6742 The invention relates to solid pharmaceutical prepara-tions which have a long-lasting action and are for dihydro pyridines in the form of a press coated tablet, and a process for their preparation.
Active compounds Erom the dihydropyridine class of sub-stances and their use as cardiac and circulatory agents have already been disclosed (compare Brit. Pat. 1,173,862, Brit. Pat.
1,358,951, US-Pat. 4,256,749, German Offenlegungsschrift 3,311,003 and US Pat. 4,264,611). Difficu]ties frequently appear in the galenical preparation of these potent active compounds, in that the substances possess only a very low solubility, are frequently light-sensitive and their absorbability in biological systems frequently leads to problems. Numerous experiments have been undertaken to produce galenical preparations which improve the bioavailability of these potent active compounds. Thus, for example, some active compounds have been dissolved in specific organic solvent systems and filled into gelatine capsules in order to ensure a rapid and effective commencement of action (compare Brit. Pat. 1,362,627). The conversion of dihydropyridines such as nifedipine into co-precipitates or into "solid solutions" has also been attempted using water-soluble polymers, in order to improve the bioavailability (compare Bri-t. Pat. 1,579,818).
For the treatment of illnesses which must be treated over relatively long periods of time, such as, for example, hyper-tension, it is desirable to keep the frequency of administration ; of medicaments as low as possible. This is not only more agree-:
able for the patient, but also increases the safety of the -, ~ 3 ~ 23189-~742 treatment by diminlshing the disadvantages of irregular adminis-tration and leads to a uniform active compound concentration/time profile in the body. The risk of under- or overdosing is thereby minimi~ed at the same time.
~ oth for the physician and also for the patient, there is a demand, for example for the continuous therapy of circulatory diseases, to have available the highly active dihydropyridines in a form in which a once daily application suffices for treatment of the disease. Medicament preparations having delayed release of active compound (retard forms) have already been described for dihydropyridines. Thus, for example, the production of a slow-release preparation has been attempted by specific particle size distribution of the crystalline active compound or by a selected specific surface area of the crystals of the active compound tcompare German Offenlegungsschrift 3,033,919). Furthermore, specific tablet preparations have been proposed which, according to the principle of the osmotic pump, release the active compound from the interior of a tablet which is provided with a semi-permeable coating layer through a given opening over a relatively ~20 long period of time and thus to achieve a retard effect (compare US-PS 3j916,899).
The prev1ously known forms of preparation having retard-ed release of active compound, in particular those for dihydro-pyridines, exhib1t a number of disadvantages. Their retard action isj for example, only limited to a few hours in some forms, so that the patient must, as a rule, administer them two or more times daily as before. After a few hours, the rate of release of :
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-the active compound decreases markedly, so that the blood level can also drop beneath the necessary efficacy limit.
In Ger~an Offenlegungsschrift 2~65:L,176, pellets having controlled release of active compound are described. The formula-tions described there differ fundamentally from the coated tablets according to the invention, since these pellets can only be ob-tained in complex processes by continuous application of many layers, whereas the tablet according to the invention is prepared by simple :
~:
2a -.... ....... ~ ~
: ~ :
~ 5~ 23189-6742 compression. An additional substantial difference is that the spherical pelleks according to this Offenlegungsschrift even when they are produced in tablet dimensions, show a terminally decreasing release rats as oppo.sed to the stepwise ~erminally increasing release rate of the coated tablets according to the invention. In the embodiment examples described there, only readily soluble active compounds are employed and all the examples describe the preparation of the pellet layers using lipophilic retarding agents. The use according to the invention of hydrophillic polymers, in particular hydroxypropylcellulose, cannot be carried out practically by the embodiment examples of this Offenlegungsschrift.
In the abovementioned osmotic system, local irritation of the ~issue can occur in the stomach or gastro-intestinal tract, depending on the capsule filling employed, owing to excessive concentration. Furthermore, a flattening of the release curve in tbe terminal region is also to be observed in the case of this osmotic retardation principle, which should ensure a linear course of release over a relatively long period of time. Due to the nature of the osmotic system, some of the active compound remains ln the medicament form and is thus not available for the desired absorption. An additlonal disadvantage of this system is the delayed seteing in of active compound release after adminlstration, whlch in some cases only begins after about 2 hours. In addition, the production of this medicament form is very expensive, since organic solvents must be employed in the preparation process here and the coating layer of each tablet must ::
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.
.
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be perfora~ed separately with khe aid of a laser beam.
This invention relates to a solid medicament preparation having a long-las~ing action in the form of a press coated tablet which contains a sparingly soluble dihydropyridine, the press coa~ed tablet comprising (a~ a core which contains a dihydropyridine in rapid-release form, and (b) a coat around tha core, the coat contalning a dihydropyridine in slow-release ~orm.
These preparations show surprising long-las~ing e~icacy. Preferably the dihydropyridine compound is of the formula I Rl R O~C ~ R2 I, in whi h R represents a phenyl radical which is substituted by one or two identical or dif~erent sub~tituents from the group comprising nitro, halogen and tri~luoromethyl, or represents a radical ~rom the group comprising ~f~o :~: ~ N~
and J
R2 represents a nitro group or the radical COOR6, ~, ~ , ~L 3 0 ~ ~ I
23189-67~2 in which R6 denotes alkyl having 1 to 10 C atoms which is optionally subs~ituted by alkoxy having 1 to 4 C atoms or by one or more halogens, or in which R , toge~her with R5, represents the lactone group -Co-0-CH2, R3 represents alkyl having 1 to 10 C atoms, which is optionally substituted by alkoxy having 1 to 4 C ato~s or by one or more fluorine atoms and R4 and R5 are identical or different and in each case represent alkyl having 1 to ~ C atoms, which is optionally substituted by hydroxyl.
Coated tablets may be preferably mentioned which contain 5% to 50~, preferably 10% to 40~, of ~he total dthydropyridine active compound in the core and which contain 50% to 95~, in particular 60% to 90%, of the total dihydropyridine active compound in the coating.
Particularly preferred active compounds which may be mentioned are nifedipine, nitrendipine, nimodipiner nisoldipine and felodipine.
According to the type of active co~pound, the coated tablets accordlng to the invention preferably contain 1 to 200 mg ~n total, in particular 10 to lS0 mg, of at least one activa compound ~ro~ the dihydropyridine class.
The rapid-release core of the coated tablet preferably ~;~ contains the active compound in amorphous form or in finely grounded or micronized crystalline form. When using crystallina '"
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active eompound, the release rate is preferably influenced by the addition of auxiliaries with good water solubility and by alteration of the particle ~ize distribution of the active compound.
Tablet cores having rapid release are prePerably those cores which release 75~ of the dihydropyxidine active compound in one hour, preferably in 30 minutes, under the following conditions:
Active compounds Erom the dihydropyridine class of sub-stances and their use as cardiac and circulatory agents have already been disclosed (compare Brit. Pat. 1,173,862, Brit. Pat.
1,358,951, US-Pat. 4,256,749, German Offenlegungsschrift 3,311,003 and US Pat. 4,264,611). Difficu]ties frequently appear in the galenical preparation of these potent active compounds, in that the substances possess only a very low solubility, are frequently light-sensitive and their absorbability in biological systems frequently leads to problems. Numerous experiments have been undertaken to produce galenical preparations which improve the bioavailability of these potent active compounds. Thus, for example, some active compounds have been dissolved in specific organic solvent systems and filled into gelatine capsules in order to ensure a rapid and effective commencement of action (compare Brit. Pat. 1,362,627). The conversion of dihydropyridines such as nifedipine into co-precipitates or into "solid solutions" has also been attempted using water-soluble polymers, in order to improve the bioavailability (compare Bri-t. Pat. 1,579,818).
For the treatment of illnesses which must be treated over relatively long periods of time, such as, for example, hyper-tension, it is desirable to keep the frequency of administration ; of medicaments as low as possible. This is not only more agree-:
able for the patient, but also increases the safety of the -, ~ 3 ~ 23189-~742 treatment by diminlshing the disadvantages of irregular adminis-tration and leads to a uniform active compound concentration/time profile in the body. The risk of under- or overdosing is thereby minimi~ed at the same time.
~ oth for the physician and also for the patient, there is a demand, for example for the continuous therapy of circulatory diseases, to have available the highly active dihydropyridines in a form in which a once daily application suffices for treatment of the disease. Medicament preparations having delayed release of active compound (retard forms) have already been described for dihydropyridines. Thus, for example, the production of a slow-release preparation has been attempted by specific particle size distribution of the crystalline active compound or by a selected specific surface area of the crystals of the active compound tcompare German Offenlegungsschrift 3,033,919). Furthermore, specific tablet preparations have been proposed which, according to the principle of the osmotic pump, release the active compound from the interior of a tablet which is provided with a semi-permeable coating layer through a given opening over a relatively ~20 long period of time and thus to achieve a retard effect (compare US-PS 3j916,899).
The prev1ously known forms of preparation having retard-ed release of active compound, in particular those for dihydro-pyridines, exhib1t a number of disadvantages. Their retard action isj for example, only limited to a few hours in some forms, so that the patient must, as a rule, administer them two or more times daily as before. After a few hours, the rate of release of :
~:
~ - 2 -:: :
::
-the active compound decreases markedly, so that the blood level can also drop beneath the necessary efficacy limit.
In Ger~an Offenlegungsschrift 2~65:L,176, pellets having controlled release of active compound are described. The formula-tions described there differ fundamentally from the coated tablets according to the invention, since these pellets can only be ob-tained in complex processes by continuous application of many layers, whereas the tablet according to the invention is prepared by simple :
~:
2a -.... ....... ~ ~
: ~ :
~ 5~ 23189-6742 compression. An additional substantial difference is that the spherical pelleks according to this Offenlegungsschrift even when they are produced in tablet dimensions, show a terminally decreasing release rats as oppo.sed to the stepwise ~erminally increasing release rate of the coated tablets according to the invention. In the embodiment examples described there, only readily soluble active compounds are employed and all the examples describe the preparation of the pellet layers using lipophilic retarding agents. The use according to the invention of hydrophillic polymers, in particular hydroxypropylcellulose, cannot be carried out practically by the embodiment examples of this Offenlegungsschrift.
In the abovementioned osmotic system, local irritation of the ~issue can occur in the stomach or gastro-intestinal tract, depending on the capsule filling employed, owing to excessive concentration. Furthermore, a flattening of the release curve in tbe terminal region is also to be observed in the case of this osmotic retardation principle, which should ensure a linear course of release over a relatively long period of time. Due to the nature of the osmotic system, some of the active compound remains ln the medicament form and is thus not available for the desired absorption. An additlonal disadvantage of this system is the delayed seteing in of active compound release after adminlstration, whlch in some cases only begins after about 2 hours. In addition, the production of this medicament form is very expensive, since organic solvents must be employed in the preparation process here and the coating layer of each tablet must ::
~ 3 :
A
.
.
~: ~ . -:
be perfora~ed separately with khe aid of a laser beam.
This invention relates to a solid medicament preparation having a long-las~ing action in the form of a press coated tablet which contains a sparingly soluble dihydropyridine, the press coa~ed tablet comprising (a~ a core which contains a dihydropyridine in rapid-release form, and (b) a coat around tha core, the coat contalning a dihydropyridine in slow-release ~orm.
These preparations show surprising long-las~ing e~icacy. Preferably the dihydropyridine compound is of the formula I Rl R O~C ~ R2 I, in whi h R represents a phenyl radical which is substituted by one or two identical or dif~erent sub~tituents from the group comprising nitro, halogen and tri~luoromethyl, or represents a radical ~rom the group comprising ~f~o :~: ~ N~
and J
R2 represents a nitro group or the radical COOR6, ~, ~ , ~L 3 0 ~ ~ I
23189-67~2 in which R6 denotes alkyl having 1 to 10 C atoms which is optionally subs~ituted by alkoxy having 1 to 4 C atoms or by one or more halogens, or in which R , toge~her with R5, represents the lactone group -Co-0-CH2, R3 represents alkyl having 1 to 10 C atoms, which is optionally substituted by alkoxy having 1 to 4 C ato~s or by one or more fluorine atoms and R4 and R5 are identical or different and in each case represent alkyl having 1 to ~ C atoms, which is optionally substituted by hydroxyl.
Coated tablets may be preferably mentioned which contain 5% to 50~, preferably 10% to 40~, of ~he total dthydropyridine active compound in the core and which contain 50% to 95~, in particular 60% to 90%, of the total dihydropyridine active compound in the coating.
Particularly preferred active compounds which may be mentioned are nifedipine, nitrendipine, nimodipiner nisoldipine and felodipine.
According to the type of active co~pound, the coated tablets accordlng to the invention preferably contain 1 to 200 mg ~n total, in particular 10 to lS0 mg, of at least one activa compound ~ro~ the dihydropyridine class.
The rapid-release core of the coated tablet preferably ~;~ contains the active compound in amorphous form or in finely grounded or micronized crystalline form. When using crystallina '"
' 3 ~
active eompound, the release rate is preferably influenced by the addition of auxiliaries with good water solubility and by alteration of the particle ~ize distribution of the active compound.
Tablet cores having rapid release are prePerably those cores which release 75~ of the dihydropyxidine active compound in one hour, preferably in 30 minutes, under the following conditions:
4 liters of 0,1 N hydrochloric acld and 0,1-0,5 ~ of weight of surfactant e.g. TWEEN* 80 or sodiumlaurylsulphate; 37C; 100 Rpm;
USP-Paddle method.
I~ the rapid-release core contains amorphous dihydropyridine, the latter is preferably dissolved in an organic solvent together wi~h water-soluble polymers such as polyvinylpyrrolidone, methylcellulose, hydroxypropylcellulose or hydroxypropylmethylcellulose. It i5 expedient here to employ 2 to 10 parts by weiyht, in particular 3 to 8 parts by weight, o~ the water-soluble polymers to 1 part by welght of dihydropyridine and to prepare suitable co-precipitates $rom this.
If the rapid-release core contains dihydropyri-*Trade-mark 5a ~ ~"
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dines in crystalline form, dihydropyridine crystals having a maxi-mum mean particle size of about 25 ~m, in particular a maximum mean particle size of about 15 ~m, are preferably employed. The particle size is determined by the Cilas method (Lit.: A.
Buerkholz et al, Part. Charact. 1, 1984, 153-160, I'Laser defrac-tion spectrometers/experience in particle size analysis").
When using crystalline dihydropyridine in the core, the addition of readily water-soluble auxiliaries such as, for example, lactose is expedient. Likewise, the release rate can be accelerated by the use of disintegrants, such as, for example, crosslinked polyvinylpyrrolidone ~PVP), or surface-active sub-stances, such as, for example, sodium lauryl sulphate.
The preparation of this rapid-release core takes place by customary methods (compare German Offenlegungsschrift 3,415,128 and German Offenlegungsschrift 3,142,853 or Brit. Pat.
1,579,818).
The granules for the coat of the tablet contain 10 to ; 99 %, preferably 20 to 90 %, of the total coating weight of hyd~o-philic gel-forming polymers.
Suitable hydrophilic gel-forming polymers are, for :: , example, modifled starch or cellulose-like substances such as, for example, methylcellulose, hydroxypropylmethylcellulose, hydroxy-propylcellulose and sodium carboxymethylcellulose. Hydroxypropyl-cel~lulose (HPC) may be mentioned as being particularly preferred ~compare: Hagers Handbuch der pharmazeutischen Praxis (Hager's Handbook of Pharmaceutical Practice), volume 7, part B, (1977) 130-I41).
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Various types of HPC can be used according to the inven-tion, in each case differing in their viscosity, for example HPC-L
(low viscosity of about 6-10 mPa.s), ElPC-M (medium viscosity of about 150 mPa.s) and HPC-H (high viscosity of about 1000-4000 mPa.s). The release rate can be controlled through the different viscosity grades, the release rate increasing when lower viscosity grades are employed and slowing when using higher viscosity types.
In some cases, it is expedient to apply some of the active compound as the initial dose in the form of an outer layer of the coated tablet using the known techniques and auxiliariesO
Customary known galenical measures, such as, for exam-ple, the coating of the core with a gastric juice-resistant layer, the use of flavorings and aromas and lubricants and customary auxiliaries which are familiar to the galenical expert, can of course also be employed and used in the press coated tablets according to the invention.
It should be expressly pointed out that the coated tab let according to the invention differs from the previously known coated tablets due to the fact that the coating contains the active compound in slow release form and the core contains the active compound in rapid-release form.
Multi-layer tablets based on casein matrices, which contain two or three layers which in each case can in turn contain active compounds (compare US-Pat. 3,184,386), have already been described in the prior art. The tablets described there contain a :
rapid-release preparation in the outer coating, the core primarily ~; having the function of not allowing the surface of the outer `~
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` 23189-6742 active compound-containing layer relevant for the release to be-come too small. This patent specification contains no indication, however, that the core of the preparation contains a sparely sol-uble active compound in rapid-release form. On the contrary, both the central coat and also the core are described in the examples as slow-release-forms of highly soluble active compounds.
Coated tablets which contain active compounds in slow-release form both in the core and in the coating are also describ-ed in US-Pat. 3,558,768~ The release rates according to this US
patent specification may be different, but the specification refers only to slow-release forms.
Through the principle of the coated tablet according to the invention, the hitherto customary disadvantages of normal retard tablets and also of previously known multi-layer or coated tablets or of preparation forms which depend upon the osmotic principle are avoided. In particular, the situation where the release rate of the active compound becomes smaller and smaller towards the end of the dissolution of the tablets and the plasma levels thus sink is avoided. The decreasing release rate of normal retard tablets due to a reduction in the volume of the tablet is more than compensated for by the rapid-release action of the core of the press coated tablet according to the invention.
Complete release of the active compound is achieved at the same time, in contrast to osmotic systems~
The formulation according to the inven-tion differs from all previously known retardation principles for solid medicament forms through the accelerated release rate in the terminal region.
~ 23189-6742 Any reduced absorption of the administered medicament substance in deeper intestinal sections, for example limited by hindrance of diffusion, may thus be better equalized. Further advantages which may be mentioned are the rapid influx of the active compound after administration with the avoidance of a re-tardation phase and also the simple preparation technology. A
further advantage of the inventive formulations is, that they are specially useful for those drugs, which show a higher resorption in the lower parts of the gastro intestinal tracts e.g. in the colon. This may lead to an increase of the bioavailability of those drugs.
Inventive composition can be manufactured by the follow-ing procedure~
A) Core:
In accordance with usual techniques the active substance and the other ingredients are mixed and granulated by adding an aqueous solution of binders, e.g~ in a planatory mixer or in a high speed mixer or by fluidized bed granulation. The granulate is dried, preferably in a fluidized bed dryer. The dried granulate is 20 ~ sieved and mixed with magnesiumstearate and afterwards pressed to tablets. Alternatively the manufacture of the core can be made by direct compression of the ingredients or by roller compaction plus compression. Optionally the core can be coated by usual methods, preferably in a coating pan or by other usual means.
Granules for the coat:
:: ~
The granulate is produced preferably in a fluidized bed granulator by spraying an aqueous suspension containing the active substance ,, .
:: ~
~: : ,.
, ~ 23189-6742 and a binder on the solid ingredients, the obtained granules are dried, sieved and mixed with a lubricant, e.g. magnesiumstearate.
The production of the granules can also be made by other usual techniques.
Press coa-ting:
The press coating of the core is carried out on usual press coat-ers (e.g. machines of the company Kilian or Manesty).
Optionally the press coated tablets can be film coated with usual laquers. In certain cases it may be recommendable to incorporate a small amount of the active substance into this film coating layer, the maximum amount of the active substance in the film coating layer should be 20 % of the total amount oE the active substance.
~ ith regard to the long existing requirement for medica-ment preparation forms having a long-lasting action, it is more than surprising that hitherto nobody has described or produced the coated tablets according to the invention having a rapid-release core which are simple to produce and very effective. Through the ; ~ present invention, the patient is placed in the position of only having to take the medicament once dai;ly, which in continuous therapy, in particular, represents a safer and more agreeable type of treatment.
The curves in Figure 1 show for several examples accord-ng to the invention the;princlple of the coat of the tablet which is slowly released over several hours and the core which is re-leased rapidly.
, ~ .
Illustrative embodiments Example 1 A) Core 50 g of crystalline nifedipine (mean particle size 5 m) are mixed with 388 g of lactose and 150 g of corn starch, and the mixture is granulated in a paste of 10 g of starch and 140 g of hot water and then dried. The granules are sieved and mixed with 50 g of microcrystalline cellulose and 2 g of magnesium stearate.
This mixture is compressed to 65 mg weight tablets having a di-ameter of 6 mm. The cores are coated for resistance to gastricjuice using an organic solution of hydroxypropylmethylcellulose phthalate. The coated tablets weigh 72 mg.
B) Granules for the coat 250 g of nifedipine are mixed with 400 g of lactose, 16 g of colloidal silica, 700 g of type M hydroxypropylcellulose, 1747 g of type L hydroxypropylcellulose (~PC) and 320 g of citric acid, and the mixture is granulated in a fluidized bed granulator with a solution of 20 g of type L hydroxypropylcellulose. The dried and sieved granules are mixed with 27 g of magnesium stear-ate.
These granules and the cores described under A) arepressed to 420 mg weight press coated tablets having a diameter of 10 mm in a press coater. The tablets are then coated using an aqueous dispersion of hydroxypropylmethylcellulose, polyethylene glycol, titanium dioxide and iron oxide red.
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~ 3 ~ ~ jr~ 23189-6742 Example 2 A) Core Preparation as in Example 1.
B) Granules for the coat: 400 g of lactose are mixed with 17 g of colloidal silical 2196 g of type L hydroxypropylcellulose, 250 g of type M hydroxypropylcellulose and 320 g of citric acid, and the mixture is granulated with an aqueous suspension of 250 g nifedipine and 20 g of type L hydroxypropylcellulose in a fluid-ized bed granulator. The dried granules are sieved and mixed with 27 g of magnesium stearate.
These granules and the cores described under A) are pressed to 420 mg weight press coated tablets having a diameter of 10 mm in a press coater. The tablets are then coated using an ; aqueous dispersion of hydroxypropylmethylcellulose, polyethylene glycol, titanium dioxide and iron oxide red.
Example 3 A) Core 50 g of crystalline nifedipine (mean particle size 8 ~m) are mixed with 291 g of lactose and 162.5 g of corn starch, and ~20 the mixture is granulated using a paste oE 7.5 g of corn starch in 100 g of hot water. The granules are dried, sieved and then mixed with 1.5 g of magnesium stearate and 37.5 g of microcrystalline cellulose. This mixture is compressed to 55 mg weight cores hav-ing a diameter of 5.5 mm.
B) Granules for the coat ; 400 g of lactose are mixed with 17 g of colloidal sili-ca, 1105 g of type L HPC, 443 g of type M HPC and 202 g of citric ~; ~ :
~3~ ~1t~ 23189-67~2 acid, and the mixture is granulated using an aqueous s~spension consisting of 250 g of nifedipine and 16 g of type L HPC. The granules are dried and sieved and mixed with 17 g of magnesium stearate.
Press coated tablets having a weight of 300 rng and a diameter of 9 mm are produced from these granules and the cores.
The tablets are then coated as in Example 1.
Example 4 A) Core Preparation as in Example 3O
The cores are coated for resistance to gastric juice using an organic solution of hydroxypropylmethylcellulose phtha-late. The coated tablets weigh 60 mg~
B) Granules for the coat 250 g of nifedipine are mixed with 400 g of lactose, 17 g of colloidal silica, 1155 g of type L HPC, 343 g of type M
HPC and 202 g of citric acid, and the mixture is granulated using an aqueous solution of 16 g of type L HPC . The granules are dried, sieved and mixed with 17 g of magnesium stearate.
~20 Press Coated tablets having a weight of 300 mg and a ; ~ diameter of 9 mm are prepared from these granules and the cores.
The tablets are then coated as in Example 1.
Example_5 A) Core 250 g of crosslinked polyvinylpyrrolidone and 197 g of .
m~icrocrystalline cellulose are mixed and granulated using a solu~
tlon of 30 g of nifedipine and 150 g of polyvinylpyrxolidone 25 in : .
: ~, '' :
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~ J~3~ 23189-6742 350 g of acetone. The granules are dried and sieved and pressed with 3 g of magnesium stearate. This mixture is pressed to 65 mg weight tablets having a diameter of 6 mm. The cores are coated using an organic solution of hydroxypropylmethylcellulose phtha-late. The coated cores weigh 72 mg.
B) Granules for the coat The granules are prepared analogously to Example 1.
The additional processing is as in Example 1.
Example _ A) Core Preparation as in Example 3.
B) Granules for the coat 200 g of nifedipine are mixed with 350 g of lactose, 17 g of colloidal silica, 1105 g of type L HPC, 443 g of type M HPC and 202 g of citric acid, and the mixture is granulated using an aqueous solution of 16 g of type L HPC. The granules are dried and sieved and mixed with 12 g of magnesium stearate.
Press Coated tablets having a weight of 290 mg are pressed from these granules and the cores.
USP-Paddle method.
I~ the rapid-release core contains amorphous dihydropyridine, the latter is preferably dissolved in an organic solvent together wi~h water-soluble polymers such as polyvinylpyrrolidone, methylcellulose, hydroxypropylcellulose or hydroxypropylmethylcellulose. It i5 expedient here to employ 2 to 10 parts by weiyht, in particular 3 to 8 parts by weight, o~ the water-soluble polymers to 1 part by welght of dihydropyridine and to prepare suitable co-precipitates $rom this.
If the rapid-release core contains dihydropyri-*Trade-mark 5a ~ ~"
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dines in crystalline form, dihydropyridine crystals having a maxi-mum mean particle size of about 25 ~m, in particular a maximum mean particle size of about 15 ~m, are preferably employed. The particle size is determined by the Cilas method (Lit.: A.
Buerkholz et al, Part. Charact. 1, 1984, 153-160, I'Laser defrac-tion spectrometers/experience in particle size analysis").
When using crystalline dihydropyridine in the core, the addition of readily water-soluble auxiliaries such as, for example, lactose is expedient. Likewise, the release rate can be accelerated by the use of disintegrants, such as, for example, crosslinked polyvinylpyrrolidone ~PVP), or surface-active sub-stances, such as, for example, sodium lauryl sulphate.
The preparation of this rapid-release core takes place by customary methods (compare German Offenlegungsschrift 3,415,128 and German Offenlegungsschrift 3,142,853 or Brit. Pat.
1,579,818).
The granules for the coat of the tablet contain 10 to ; 99 %, preferably 20 to 90 %, of the total coating weight of hyd~o-philic gel-forming polymers.
Suitable hydrophilic gel-forming polymers are, for :: , example, modifled starch or cellulose-like substances such as, for example, methylcellulose, hydroxypropylmethylcellulose, hydroxy-propylcellulose and sodium carboxymethylcellulose. Hydroxypropyl-cel~lulose (HPC) may be mentioned as being particularly preferred ~compare: Hagers Handbuch der pharmazeutischen Praxis (Hager's Handbook of Pharmaceutical Practice), volume 7, part B, (1977) 130-I41).
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Various types of HPC can be used according to the inven-tion, in each case differing in their viscosity, for example HPC-L
(low viscosity of about 6-10 mPa.s), ElPC-M (medium viscosity of about 150 mPa.s) and HPC-H (high viscosity of about 1000-4000 mPa.s). The release rate can be controlled through the different viscosity grades, the release rate increasing when lower viscosity grades are employed and slowing when using higher viscosity types.
In some cases, it is expedient to apply some of the active compound as the initial dose in the form of an outer layer of the coated tablet using the known techniques and auxiliariesO
Customary known galenical measures, such as, for exam-ple, the coating of the core with a gastric juice-resistant layer, the use of flavorings and aromas and lubricants and customary auxiliaries which are familiar to the galenical expert, can of course also be employed and used in the press coated tablets according to the invention.
It should be expressly pointed out that the coated tab let according to the invention differs from the previously known coated tablets due to the fact that the coating contains the active compound in slow release form and the core contains the active compound in rapid-release form.
Multi-layer tablets based on casein matrices, which contain two or three layers which in each case can in turn contain active compounds (compare US-Pat. 3,184,386), have already been described in the prior art. The tablets described there contain a :
rapid-release preparation in the outer coating, the core primarily ~; having the function of not allowing the surface of the outer `~
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` 23189-6742 active compound-containing layer relevant for the release to be-come too small. This patent specification contains no indication, however, that the core of the preparation contains a sparely sol-uble active compound in rapid-release form. On the contrary, both the central coat and also the core are described in the examples as slow-release-forms of highly soluble active compounds.
Coated tablets which contain active compounds in slow-release form both in the core and in the coating are also describ-ed in US-Pat. 3,558,768~ The release rates according to this US
patent specification may be different, but the specification refers only to slow-release forms.
Through the principle of the coated tablet according to the invention, the hitherto customary disadvantages of normal retard tablets and also of previously known multi-layer or coated tablets or of preparation forms which depend upon the osmotic principle are avoided. In particular, the situation where the release rate of the active compound becomes smaller and smaller towards the end of the dissolution of the tablets and the plasma levels thus sink is avoided. The decreasing release rate of normal retard tablets due to a reduction in the volume of the tablet is more than compensated for by the rapid-release action of the core of the press coated tablet according to the invention.
Complete release of the active compound is achieved at the same time, in contrast to osmotic systems~
The formulation according to the inven-tion differs from all previously known retardation principles for solid medicament forms through the accelerated release rate in the terminal region.
~ 23189-6742 Any reduced absorption of the administered medicament substance in deeper intestinal sections, for example limited by hindrance of diffusion, may thus be better equalized. Further advantages which may be mentioned are the rapid influx of the active compound after administration with the avoidance of a re-tardation phase and also the simple preparation technology. A
further advantage of the inventive formulations is, that they are specially useful for those drugs, which show a higher resorption in the lower parts of the gastro intestinal tracts e.g. in the colon. This may lead to an increase of the bioavailability of those drugs.
Inventive composition can be manufactured by the follow-ing procedure~
A) Core:
In accordance with usual techniques the active substance and the other ingredients are mixed and granulated by adding an aqueous solution of binders, e.g~ in a planatory mixer or in a high speed mixer or by fluidized bed granulation. The granulate is dried, preferably in a fluidized bed dryer. The dried granulate is 20 ~ sieved and mixed with magnesiumstearate and afterwards pressed to tablets. Alternatively the manufacture of the core can be made by direct compression of the ingredients or by roller compaction plus compression. Optionally the core can be coated by usual methods, preferably in a coating pan or by other usual means.
Granules for the coat:
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The granulate is produced preferably in a fluidized bed granulator by spraying an aqueous suspension containing the active substance ,, .
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, ~ 23189-6742 and a binder on the solid ingredients, the obtained granules are dried, sieved and mixed with a lubricant, e.g. magnesiumstearate.
The production of the granules can also be made by other usual techniques.
Press coa-ting:
The press coating of the core is carried out on usual press coat-ers (e.g. machines of the company Kilian or Manesty).
Optionally the press coated tablets can be film coated with usual laquers. In certain cases it may be recommendable to incorporate a small amount of the active substance into this film coating layer, the maximum amount of the active substance in the film coating layer should be 20 % of the total amount oE the active substance.
~ ith regard to the long existing requirement for medica-ment preparation forms having a long-lasting action, it is more than surprising that hitherto nobody has described or produced the coated tablets according to the invention having a rapid-release core which are simple to produce and very effective. Through the ; ~ present invention, the patient is placed in the position of only having to take the medicament once dai;ly, which in continuous therapy, in particular, represents a safer and more agreeable type of treatment.
The curves in Figure 1 show for several examples accord-ng to the invention the;princlple of the coat of the tablet which is slowly released over several hours and the core which is re-leased rapidly.
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Illustrative embodiments Example 1 A) Core 50 g of crystalline nifedipine (mean particle size 5 m) are mixed with 388 g of lactose and 150 g of corn starch, and the mixture is granulated in a paste of 10 g of starch and 140 g of hot water and then dried. The granules are sieved and mixed with 50 g of microcrystalline cellulose and 2 g of magnesium stearate.
This mixture is compressed to 65 mg weight tablets having a di-ameter of 6 mm. The cores are coated for resistance to gastricjuice using an organic solution of hydroxypropylmethylcellulose phthalate. The coated tablets weigh 72 mg.
B) Granules for the coat 250 g of nifedipine are mixed with 400 g of lactose, 16 g of colloidal silica, 700 g of type M hydroxypropylcellulose, 1747 g of type L hydroxypropylcellulose (~PC) and 320 g of citric acid, and the mixture is granulated in a fluidized bed granulator with a solution of 20 g of type L hydroxypropylcellulose. The dried and sieved granules are mixed with 27 g of magnesium stear-ate.
These granules and the cores described under A) arepressed to 420 mg weight press coated tablets having a diameter of 10 mm in a press coater. The tablets are then coated using an aqueous dispersion of hydroxypropylmethylcellulose, polyethylene glycol, titanium dioxide and iron oxide red.
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~ 3 ~ ~ jr~ 23189-6742 Example 2 A) Core Preparation as in Example 1.
B) Granules for the coat: 400 g of lactose are mixed with 17 g of colloidal silical 2196 g of type L hydroxypropylcellulose, 250 g of type M hydroxypropylcellulose and 320 g of citric acid, and the mixture is granulated with an aqueous suspension of 250 g nifedipine and 20 g of type L hydroxypropylcellulose in a fluid-ized bed granulator. The dried granules are sieved and mixed with 27 g of magnesium stearate.
These granules and the cores described under A) are pressed to 420 mg weight press coated tablets having a diameter of 10 mm in a press coater. The tablets are then coated using an ; aqueous dispersion of hydroxypropylmethylcellulose, polyethylene glycol, titanium dioxide and iron oxide red.
Example 3 A) Core 50 g of crystalline nifedipine (mean particle size 8 ~m) are mixed with 291 g of lactose and 162.5 g of corn starch, and ~20 the mixture is granulated using a paste oE 7.5 g of corn starch in 100 g of hot water. The granules are dried, sieved and then mixed with 1.5 g of magnesium stearate and 37.5 g of microcrystalline cellulose. This mixture is compressed to 55 mg weight cores hav-ing a diameter of 5.5 mm.
B) Granules for the coat ; 400 g of lactose are mixed with 17 g of colloidal sili-ca, 1105 g of type L HPC, 443 g of type M HPC and 202 g of citric ~; ~ :
~3~ ~1t~ 23189-67~2 acid, and the mixture is granulated using an aqueous s~spension consisting of 250 g of nifedipine and 16 g of type L HPC. The granules are dried and sieved and mixed with 17 g of magnesium stearate.
Press coated tablets having a weight of 300 rng and a diameter of 9 mm are produced from these granules and the cores.
The tablets are then coated as in Example 1.
Example 4 A) Core Preparation as in Example 3O
The cores are coated for resistance to gastric juice using an organic solution of hydroxypropylmethylcellulose phtha-late. The coated tablets weigh 60 mg~
B) Granules for the coat 250 g of nifedipine are mixed with 400 g of lactose, 17 g of colloidal silica, 1155 g of type L HPC, 343 g of type M
HPC and 202 g of citric acid, and the mixture is granulated using an aqueous solution of 16 g of type L HPC . The granules are dried, sieved and mixed with 17 g of magnesium stearate.
~20 Press Coated tablets having a weight of 300 mg and a ; ~ diameter of 9 mm are prepared from these granules and the cores.
The tablets are then coated as in Example 1.
Example_5 A) Core 250 g of crosslinked polyvinylpyrrolidone and 197 g of .
m~icrocrystalline cellulose are mixed and granulated using a solu~
tlon of 30 g of nifedipine and 150 g of polyvinylpyrxolidone 25 in : .
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~ J~3~ 23189-6742 350 g of acetone. The granules are dried and sieved and pressed with 3 g of magnesium stearate. This mixture is pressed to 65 mg weight tablets having a diameter of 6 mm. The cores are coated using an organic solution of hydroxypropylmethylcellulose phtha-late. The coated cores weigh 72 mg.
B) Granules for the coat The granules are prepared analogously to Example 1.
The additional processing is as in Example 1.
Example _ A) Core Preparation as in Example 3.
B) Granules for the coat 200 g of nifedipine are mixed with 350 g of lactose, 17 g of colloidal silica, 1105 g of type L HPC, 443 g of type M HPC and 202 g of citric acid, and the mixture is granulated using an aqueous solution of 16 g of type L HPC. The granules are dried and sieved and mixed with 12 g of magnesium stearate.
Press Coated tablets having a weight of 290 mg are pressed from these granules and the cores.
5 mg of nifedipine per tablet are coated onto these tablets from an aqueous dispersion containing hydroxypropylmethyl-cellulose and polyethylene glycol. These tablets are then covered with a light protecting coating analogously to Example 1.
Example 7 A) Core ~; 50 g of crystalline nifedipine (mean particle size 10 ~m) are mixed with 600 g of lactose and 228 g of corn starch, , .
~ 23189-6742 and the mixture is granulated using a paste of 20 g of starch and 320 g of water and then dried The granules are sieved and mixed with 2 g of magnesium stearate, and the mixture is pressed to 90 mg weight tablets having a diameter of 7 mm. The cores are coated using an organic solution of hydroxypropylmethylcellulose phthalate. The coated cores weigh 97 mg.
B) Granules for the coat 250 g of nifedipine are mixed with 400 g of lactose and 16 g of colloidal silica, and the mixture is granulated using a solution of 16 g of type L hydroxypropylcellulose in water. The dried and sieved granules are mixed with 900 g of type M hydroxy-propylcellulose, 2387 g of type L hydroxypropylcellulose, 400 g of citric acid and 61 g of magnesium stearate.
These granules and the cores described under A) are pressed to 540 mg weight tablets having a diameter of 11 mm in a press coater. The tablets are then coated using an aqueous dis-perslon of hydroxypropylmethylcellulose, polyethylene glycol, titanium dioxide and iron oxide red.
Example 8 A) Core ~;~ 100 g of crystalline nifedipine (mean particle size 4 ~m) are mixed with 241 g of lactose and 162.5 g of corn starch, and the mixture is granulated with a paste of 7.5 g of corn starch in 100 g of water. The dried granules are sieved and mixed with 1.5 g of magnesium stearate and 37.5 g of Avicel and this mixture is pressed to 55 mg weight tablets having a diameter of 5.5 mm.
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.
~ 23189-6742 B) Granules for the coat 500 g of nifedipine are mixed wi-th 335 g of lactose and 16 g of colloidal silica, and the mixture is granulated using a solution of 33 g of type L hydroxypropylcellulose in water. The dried granules are sieved and mixed with 443 g of type M hydroxy-propylcellulose, 1105 g of type L hydroxypropylcellulose and 18 g of magnesium stearate.
These granules and the cores described under A) are pressed -to 300 mg weight tablets having a diameter of 9 mm in a press coater. The tablets are then coated using an aqueous dis-persion of hydroxypropylmethylcellulose, polyethylene glycol, titanium dioxide and iron oxide red.
Examples 9 and 10 were prepared in an analogous manner.
Example 9 Core: nitrendipine mean particle size 6 ~m 5.0 mg corn starch 27.8 mg microcrystalline cellulose20.0 mg lactose 21.49 mg are mixed and then granula-ted with:
~20 polyvinylpyrrolidone 25 5.0 mg sodium lauryl sulphate 0.5 mg FD + C blue lake No. 2 0.01 mg in agueous suspension by means of customary granulation processes after drying, magnesium stearate 0.2 mg . :..:~ : :
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.
23l89-6742 is admixed. The mixture is pressed to cores in a tablet press:
weight: 80 mg, size: ~ 6 mm Granules :Eor the coat:
type L hydroxypropylcellulose210.0 mg type M hydroxypropylcellulose82.0 mg citric acid 146.0 mg are mixed and granulated with an aqueous suspension of nitrendipine (mean particle size 5 ~m) 25.0 mg hydroxypropylcellulose type L 2.0 mg after drying admixing of magnesium stearate 5.0 mg Press Coated tablets are prepared with the aid of a press coater Total weight: 550 mg Size: ~ 10 mm Example 10 Core: nitrendipine mean particle size 5 ~m 5.0 mg microcrystalline cellulose17.5 mg lactose 6.4 mg corn starch 7.5 mg : ~ !
mixing and granulation with : ~ polyvinylpyrrolidone 25 3.0 mg : sodium lauryl sulphate 0.5 mg in aqueous solution by means of customary granu-lation processes : _ _ : - 17 -`~ . , ~ , ~; ` ' ' '' ' . ' .. : .
after drying, magnesium stearate 0.1 mg .
is admixed and the mixture ls pressed to cores in a tablet press:
weight: 40 mg, size: ~ 5.5 mm Granules for the coat:
micronized nitrendipine 25.0 mg type L hydroxypropylcellulose221.0 mg -are mixed and granulated (if desired a part of the hydroxypropylcellulose can be removed for processing in : the granulation liquid) admixing of magnesium stearate 7.0 mg Press Coated tablets are prepared with the aid of a press coater~
Total weight: 293 mg Size: 9 mm Example 11 ;~ ~ Core: nitrendipine (mean particle size 10 ~-m) 2.5 mg corn starch 23.0 mg microcrystalline cellulose 20.0 mg lactose 21~5 mg Plasdone XL: 7.3 mg ' ~ ~ :
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are granulated using an aqueous solution of:
polyvinylpyrrolidone 25 5 mg sodium lauryl sulphate0.5 mg -after drying, magnesium stearate 0.2 mg is admixed and the mixture pressed to cores in a tablet press.
Gran ~eight: 80 mg, size: 6 mm foers micronized nisoldipine12.5 mg 10 coat type L hydroxypropylcellulose212 mg type M hydroxypropylcellulose 82 mg lactose 158.5 mg are mixed and granulated with water admixing of magnesium stearate 12 mg Press Coated tablets are prepared with the aid of a press coater Total weight: 557 mg Size: 10 mm 20 Example 12 : A) Core ; : The preparation is as in Example 8, 200 g of nimodipine and 141 g of lactose now being employed instead of 100 g of nifedipine and 241 g of lactose.
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B) Granules for the coat Preparation by analogy with Example 8, 600 g of nimodipine and 235 g of lactose now being employed instead of 500 g of nifedipine and 335 g of lactose. The aqueous coating is likewise analogous to Example 8, but without the use of red iron oxide.
Example 13 A) Core The preparation is analogous to Example 8, 50 g of nifedipine, 150 g of nisoldipine and 141 g of lactose now being employed instead of 100 g of nifedipine and 241 g of lactose.
B) Granules for the coat The preparation is analogous to Example 8, 200 g of nifedipine and nisoldipine now being employed instead of 500 g of nifedipine.
At the same time, 518 g of HPC-M and 1030 g of HPC-L are now used instead of 443 g of HPC-M and 1105 g of HPC-L.
Example 14 Core: nitrendipine of mean particle size 5 ~m 8.0 mg ~20 microcrystalline cellulose 12.0 mg lactose 4.0 mg Plasdone XL 15.0 mg mixing and granulation with polyvinylpyrrolidone 25 2.0 mg - 17c -. ~ ~: . .
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sodium lauryL sulphat~ 0.8 mg in aqueous solution by ~eans of cust~mary granulation processes ... .. _ S after drying, magnesiu~ stearate 0 2 15 admixed and the ~ixture is pressed to cores in a tablet press:
weight: 4? ~9~ size: 5 mm Granules for the coat:
micronlze~ nitrendipine 32.0 mg type L hydroxypropylcel~ulose77~0 mg type M hydroxypropy~cellulose 77.0 mg lac.ose 92.5 mg are ~ixed and granulated (if des;red a part of ~he hydro.xypropyLcellulose can be removed for pro~ess-ing in the granu~ation liquid) admi~ing of magnesiu~ stearate 1.5 ~9 Press Coated tablets are prepared ~ith the aid of a press coa,er.
Tota~ ~e~ght: 322.0 mg; size~ 9 mm Exam~le 15 A. Core: .
50 g Nifedipine (mean particle size 5 ~m) are mixed with : l70 g lactose and 173,5 g corn starch. This mixture is granu-lated wlth an aqueous paste of S g corn starch. After ~rying and sieving l,5 g magnesium stearate, S0 g plasdone XL
: : and 50 g Avicel are added. The granules are compressed to tablets with a size of 5 ~m and a weight of 50 mg.
B. granules for the:coat llOl g hydroxypropylcellulose type L, 755 g hydroxypropylcellu-lose type M,:341 g lactose and 16 g of colloidal silica are mixed. This mixture is granulated using an aqueous suspension of 250 g nifedipine and 20 g HPC type L. The granules are dried , . .
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and sieved and mixed with 17 g of magnesium stearate. Press coated tablets having a weight of 300 mg and a diameter of 9 mm are pressed from these granules and the cores.
C. Coating The tablets are then coated with an aqueous suspension of hydroxypropylmethylcellulose, polyethylene glycol, tita-nium dioxide and iron oxide red in order to give light protection.
Exam~e 16 A. Core 100 g nifedipine (mean particle size 5 ~m) are mixed with 160 g lactose, 148,8 corn starch. This mixture is granulated with an aqueous paste of S g corn starch. After drying and sieving 1,3 g magnesium stearate, 50 q plasdone XL
and 34,9 g Avicel are added. The granules are compressed to tablets with a size of 5 mm and a weight of 50 mg.
,~
B. granules for the coat 1010 g hydroxypropylcellulose type L, 628 g hydroxypropyl-20 cellulose type M, 289 g lactose and 16 g of colloidal silica are mixed. This mixture is granulated using an aqueous suspension of 500 g nifedipine and 40 g ~PC type L. The granules are dried and sieved and mixed with 17 g of mag-nesium stearate. Press coated tablets having a weight of ~5 300 mg and a diameter of 9 mm are pressed from these granules and the cores.
C. Coating The tablets are then coated with an aqueous suspension of hydroxypropylmethylcellulose,,polyethylene glycol, tita-nium dioxide and iron oxide red in order to give lightprotection.
Le A 25 204 - 19 -~,: . . .
Example l_ A. Core 150 g nifedipine (mean particle si~e 5 ~m) are mixed with 130 g lactose, 124 g corn starch. This mixture is granulated S with an aqueous paste of 5 g corn starch. After drying and sieving 1 g magnesium stearate, 50 g plasdone XL and 40 g Avicel are added. The granules are compressed to tablets with a size of 5 mm and a weight of 50 mg.
B. granules for the coat 780 g hydroxypropylcellulose type L, 588 g hydroxypropyl-cellulose type M, 289 g lactose and 16 g of colloidal silica are mixed. This mixture is granulated using an aqueous suspension of 750 g nifedipine and 60 g HPC type L. The granules are dried and sie~ed and mixed with 17 g of mag-nesium stearate. Press coated tablets having a weight of300 mg and a diameter of 9 mm are pressed from these granules and the cores.
C. Coating The tablets are then coated with an aqueous suspension of hydroxypropylmethylcellulose, polyethylene glycol, tita-nium dioxide and iron oxide red in order to give light protection.
xample 18 A. Core 8 g nitrendipine (mean particle size 5 ~m) are mixed with 4 g lactose, 15 g crosslinked PVPPand 12,3 g microcrystalline cellulose. This mixture is granu}ated with an aqueous solu-tion of 1,8 g PVP and 0,8 g sodium laurylsulfate. After drying and sieving 0l1 g ma~nesium ste~rate are added.
The granules are compressed t~ tablets with a size of 5 mm ` and a weight of 42;mg.
B. granules for the coat 104,5 g hydroxypropylcellulose type L, 40 g hydroxypropyl-cellulose type M and B8,~ g lac~ose are mixed. This mixture Le A 25 204 --- 20 -:
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is granulated using an aqueous suspension of 32 g nitrendi-pine and 1,5 g HPC type L. The granules are dried and sieved and mixed with 1,5 g of magnesium stearateO Press coated ~ablets having a weight of 310 mg and a diameter of 9 mm are pressed from these granules and the cores.
C. Coating The tablets are then coated with an aqueous suspension of hydroxypropylmethylcellulose, polyethylene glycol and titanium dio~ide.
Example 19 A. Core 20 g nitrendipine (mean particle size 5 ~m) are mixed with 15 g crosslinked PVP and 7,2 g microcrystalline cellulose.
This mixture is granula~ed with an aqueous solution of 1,8 g PVP and 0,9 g sodium lauryl sulfate. After drying and sieving 0,1 g magnesium stearate are added. ~he granules are compressed to tablets with a size of 5 mm and a weight of 45 mg.
B. granule for the coat 144.5 g hydroxypropylcellulose type L and 97,5 g lactose are mixed. This mixture is granulated using an aqueous suspension of 20 g nitrendipine and L,5 g ~PC type L. The granules are dried and sieved and mi~ed with 1,5 ~ of mag-nesium stearate. Press coated tablets having a weight of 310 mg and a diameter of 9 mm are pressed from ~hese granules and the cores.
C. Coating The tablets ar~ then coated with an aqueous suspension of hydroxypropylmethylcellulose, polyethylene glycol and titanium dioxide.
;~ Le A 25 204 - 21 -::
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Example 20 A. Core 4 g nisoldipine (mean particle size 5 ~m) are mixed with 8 g lactose, 15 g crosslinked PVPPand 12 3 g microcrystalline cellulose. This mixture is granulated ~ith an aqueous solu-tion of 1,8 g PVP and 0 8 g sodium laurylsulfate. After drying and sieving 0,1 g maynesium stearate are added.
The granules are compressed to tablets with a size of S mm and a weight of 42 mg.
B. granule for the coat 46 5 g hydroxypropylcellulose type L 100 g hydroxypropyl-cellulose type M and 103 g lactose are mi~:ed. This mixture is granulated using an aqueous suspension of 16 g nisoldipine and 1,5 g HPC typ~ L. The granules are dried and sieved and mixed with 1 g of magnesium stearate. Press coated tablets having a weight of 310 mg and a diameter of 9 mm are pressed from ~hese granules and the cores.
I
C. Coating The tablets are then coated with an aqueous suspension of hydroxypropylmethylcellulose polyethylene glycol ti~a-nium dioxide and iron oxide red in order to give light protection.
Exam~le 21 A. Core 4 g nisoldipine (mean particle size 5 ~m) are mixed with 8 g lactose, lS g crosslinked Pvppand 12,3 g microcrystalline cellulose. This mixture is granula~ed with an aqueous svlu-tion of 1,8 g PVP and 0,8 g sodium laurylsulfate. ~fter drying and sieving 0~1 g magnesium stearate are added.
The granules are compressed to tablets with a size of 5 mm and a weight of 42 mg.
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B. granule for the coat 92,5 g hydroxypropylcellulose type L, 54 g hydroxypropyl-cellulose type M and 103 g lactose are mi~ed. This miY~ture is granulated using an aqueous suspension of 16 g nisoldi-pine and 1,5 g HPC type L. The granules are dried and sievedand mi ed with 1 g of maanesium s~earate. Press coated tablets having a weight of 310 mg and a diameter of 9 mm are pressed from these granules and the cores.
C. Coating The tablets are then coated with an aqueous suspension of hydroxypropylcellulose, polyethylene glycol, titanium dioxide and iron o~ide red in order to give light protection.
Example 22 A. Core 4 g nisoldipine (mean particle size 5 ~m) are mixed with 8 g lactose, 15 g crosslinked PVP and 12,3 g microcrystalline cellulose. This mixture is granulated with an aqeous solution of 1,8 g PVP and 0,8 g sodium laurylsulfate. After dryiny and sieving 0,1 g magnesium stearate are added. The granules are compressed to tablets with a size of 5 mm and~a weight of 42 mg.
B. granule for the coat 175 g hydroxypropylcellulose~type M and 74,5 g lactose are mixed. This mixture is granulated using an aqueous suspension of 16 g nisoldipine and 1,5 g HPC type L. The granules are dried and sieved and mixed with 1 g of mag-nesium stearate. Press coated tablets having a weight of 310 mg and a diameter of 9 mm are pressed from these granules and the cores.
C. Coating The tablets are then coated with an aqueous suspension of hydro~ypropylmethylcellulose, polyethylene glycol, tita-nium dioxide and iron oxide red in order ~o give light protection.
Le A 25 204 - - 23 -It will be unders~ood that the specification and examples are illustrative but not limitative of the presen~ inven~ion and that other embodiments within the spirit and scope of the invention will suggest ~hemselves to those skilled in the art~
:: Le A 25 204 - 24 -.
-
Example 7 A) Core ~; 50 g of crystalline nifedipine (mean particle size 10 ~m) are mixed with 600 g of lactose and 228 g of corn starch, , .
~ 23189-6742 and the mixture is granulated using a paste of 20 g of starch and 320 g of water and then dried The granules are sieved and mixed with 2 g of magnesium stearate, and the mixture is pressed to 90 mg weight tablets having a diameter of 7 mm. The cores are coated using an organic solution of hydroxypropylmethylcellulose phthalate. The coated cores weigh 97 mg.
B) Granules for the coat 250 g of nifedipine are mixed with 400 g of lactose and 16 g of colloidal silica, and the mixture is granulated using a solution of 16 g of type L hydroxypropylcellulose in water. The dried and sieved granules are mixed with 900 g of type M hydroxy-propylcellulose, 2387 g of type L hydroxypropylcellulose, 400 g of citric acid and 61 g of magnesium stearate.
These granules and the cores described under A) are pressed to 540 mg weight tablets having a diameter of 11 mm in a press coater. The tablets are then coated using an aqueous dis-perslon of hydroxypropylmethylcellulose, polyethylene glycol, titanium dioxide and iron oxide red.
Example 8 A) Core ~;~ 100 g of crystalline nifedipine (mean particle size 4 ~m) are mixed with 241 g of lactose and 162.5 g of corn starch, and the mixture is granulated with a paste of 7.5 g of corn starch in 100 g of water. The dried granules are sieved and mixed with 1.5 g of magnesium stearate and 37.5 g of Avicel and this mixture is pressed to 55 mg weight tablets having a diameter of 5.5 mm.
., ~. . : .
.
~ 23189-6742 B) Granules for the coat 500 g of nifedipine are mixed wi-th 335 g of lactose and 16 g of colloidal silica, and the mixture is granulated using a solution of 33 g of type L hydroxypropylcellulose in water. The dried granules are sieved and mixed with 443 g of type M hydroxy-propylcellulose, 1105 g of type L hydroxypropylcellulose and 18 g of magnesium stearate.
These granules and the cores described under A) are pressed -to 300 mg weight tablets having a diameter of 9 mm in a press coater. The tablets are then coated using an aqueous dis-persion of hydroxypropylmethylcellulose, polyethylene glycol, titanium dioxide and iron oxide red.
Examples 9 and 10 were prepared in an analogous manner.
Example 9 Core: nitrendipine mean particle size 6 ~m 5.0 mg corn starch 27.8 mg microcrystalline cellulose20.0 mg lactose 21.49 mg are mixed and then granula-ted with:
~20 polyvinylpyrrolidone 25 5.0 mg sodium lauryl sulphate 0.5 mg FD + C blue lake No. 2 0.01 mg in agueous suspension by means of customary granulation processes after drying, magnesium stearate 0.2 mg . :..:~ : :
~;
;
.
23l89-6742 is admixed. The mixture is pressed to cores in a tablet press:
weight: 80 mg, size: ~ 6 mm Granules :Eor the coat:
type L hydroxypropylcellulose210.0 mg type M hydroxypropylcellulose82.0 mg citric acid 146.0 mg are mixed and granulated with an aqueous suspension of nitrendipine (mean particle size 5 ~m) 25.0 mg hydroxypropylcellulose type L 2.0 mg after drying admixing of magnesium stearate 5.0 mg Press Coated tablets are prepared with the aid of a press coater Total weight: 550 mg Size: ~ 10 mm Example 10 Core: nitrendipine mean particle size 5 ~m 5.0 mg microcrystalline cellulose17.5 mg lactose 6.4 mg corn starch 7.5 mg : ~ !
mixing and granulation with : ~ polyvinylpyrrolidone 25 3.0 mg : sodium lauryl sulphate 0.5 mg in aqueous solution by means of customary granu-lation processes : _ _ : - 17 -`~ . , ~ , ~; ` ' ' '' ' . ' .. : .
after drying, magnesium stearate 0.1 mg .
is admixed and the mixture ls pressed to cores in a tablet press:
weight: 40 mg, size: ~ 5.5 mm Granules for the coat:
micronized nitrendipine 25.0 mg type L hydroxypropylcellulose221.0 mg -are mixed and granulated (if desired a part of the hydroxypropylcellulose can be removed for processing in : the granulation liquid) admixing of magnesium stearate 7.0 mg Press Coated tablets are prepared with the aid of a press coater~
Total weight: 293 mg Size: 9 mm Example 11 ;~ ~ Core: nitrendipine (mean particle size 10 ~-m) 2.5 mg corn starch 23.0 mg microcrystalline cellulose 20.0 mg lactose 21~5 mg Plasdone XL: 7.3 mg ' ~ ~ :
~ ~ - 17a -:, .
~ 3 ~
are granulated using an aqueous solution of:
polyvinylpyrrolidone 25 5 mg sodium lauryl sulphate0.5 mg -after drying, magnesium stearate 0.2 mg is admixed and the mixture pressed to cores in a tablet press.
Gran ~eight: 80 mg, size: 6 mm foers micronized nisoldipine12.5 mg 10 coat type L hydroxypropylcellulose212 mg type M hydroxypropylcellulose 82 mg lactose 158.5 mg are mixed and granulated with water admixing of magnesium stearate 12 mg Press Coated tablets are prepared with the aid of a press coater Total weight: 557 mg Size: 10 mm 20 Example 12 : A) Core ; : The preparation is as in Example 8, 200 g of nimodipine and 141 g of lactose now being employed instead of 100 g of nifedipine and 241 g of lactose.
17b -,. ~ , . . : : .
. .
. ~ .
~ : .
~ 3 ~
B) Granules for the coat Preparation by analogy with Example 8, 600 g of nimodipine and 235 g of lactose now being employed instead of 500 g of nifedipine and 335 g of lactose. The aqueous coating is likewise analogous to Example 8, but without the use of red iron oxide.
Example 13 A) Core The preparation is analogous to Example 8, 50 g of nifedipine, 150 g of nisoldipine and 141 g of lactose now being employed instead of 100 g of nifedipine and 241 g of lactose.
B) Granules for the coat The preparation is analogous to Example 8, 200 g of nifedipine and nisoldipine now being employed instead of 500 g of nifedipine.
At the same time, 518 g of HPC-M and 1030 g of HPC-L are now used instead of 443 g of HPC-M and 1105 g of HPC-L.
Example 14 Core: nitrendipine of mean particle size 5 ~m 8.0 mg ~20 microcrystalline cellulose 12.0 mg lactose 4.0 mg Plasdone XL 15.0 mg mixing and granulation with polyvinylpyrrolidone 25 2.0 mg - 17c -. ~ ~: . .
~: " ~ " '' ~ ~ .
sodium lauryL sulphat~ 0.8 mg in aqueous solution by ~eans of cust~mary granulation processes ... .. _ S after drying, magnesiu~ stearate 0 2 15 admixed and the ~ixture is pressed to cores in a tablet press:
weight: 4? ~9~ size: 5 mm Granules for the coat:
micronlze~ nitrendipine 32.0 mg type L hydroxypropylcel~ulose77~0 mg type M hydroxypropy~cellulose 77.0 mg lac.ose 92.5 mg are ~ixed and granulated (if des;red a part of ~he hydro.xypropyLcellulose can be removed for pro~ess-ing in the granu~ation liquid) admi~ing of magnesiu~ stearate 1.5 ~9 Press Coated tablets are prepared ~ith the aid of a press coa,er.
Tota~ ~e~ght: 322.0 mg; size~ 9 mm Exam~le 15 A. Core: .
50 g Nifedipine (mean particle size 5 ~m) are mixed with : l70 g lactose and 173,5 g corn starch. This mixture is granu-lated wlth an aqueous paste of S g corn starch. After ~rying and sieving l,5 g magnesium stearate, S0 g plasdone XL
: : and 50 g Avicel are added. The granules are compressed to tablets with a size of 5 ~m and a weight of 50 mg.
B. granules for the:coat llOl g hydroxypropylcellulose type L, 755 g hydroxypropylcellu-lose type M,:341 g lactose and 16 g of colloidal silica are mixed. This mixture is granulated using an aqueous suspension of 250 g nifedipine and 20 g HPC type L. The granules are dried , . .
: ~ ' ' ' , :
- , .
, ~ , , .
1 3 ~
and sieved and mixed with 17 g of magnesium stearate. Press coated tablets having a weight of 300 mg and a diameter of 9 mm are pressed from these granules and the cores.
C. Coating The tablets are then coated with an aqueous suspension of hydroxypropylmethylcellulose, polyethylene glycol, tita-nium dioxide and iron oxide red in order to give light protection.
Exam~e 16 A. Core 100 g nifedipine (mean particle size 5 ~m) are mixed with 160 g lactose, 148,8 corn starch. This mixture is granulated with an aqueous paste of S g corn starch. After drying and sieving 1,3 g magnesium stearate, 50 q plasdone XL
and 34,9 g Avicel are added. The granules are compressed to tablets with a size of 5 mm and a weight of 50 mg.
,~
B. granules for the coat 1010 g hydroxypropylcellulose type L, 628 g hydroxypropyl-20 cellulose type M, 289 g lactose and 16 g of colloidal silica are mixed. This mixture is granulated using an aqueous suspension of 500 g nifedipine and 40 g ~PC type L. The granules are dried and sieved and mixed with 17 g of mag-nesium stearate. Press coated tablets having a weight of ~5 300 mg and a diameter of 9 mm are pressed from these granules and the cores.
C. Coating The tablets are then coated with an aqueous suspension of hydroxypropylmethylcellulose,,polyethylene glycol, tita-nium dioxide and iron oxide red in order to give lightprotection.
Le A 25 204 - 19 -~,: . . .
Example l_ A. Core 150 g nifedipine (mean particle si~e 5 ~m) are mixed with 130 g lactose, 124 g corn starch. This mixture is granulated S with an aqueous paste of 5 g corn starch. After drying and sieving 1 g magnesium stearate, 50 g plasdone XL and 40 g Avicel are added. The granules are compressed to tablets with a size of 5 mm and a weight of 50 mg.
B. granules for the coat 780 g hydroxypropylcellulose type L, 588 g hydroxypropyl-cellulose type M, 289 g lactose and 16 g of colloidal silica are mixed. This mixture is granulated using an aqueous suspension of 750 g nifedipine and 60 g HPC type L. The granules are dried and sie~ed and mixed with 17 g of mag-nesium stearate. Press coated tablets having a weight of300 mg and a diameter of 9 mm are pressed from these granules and the cores.
C. Coating The tablets are then coated with an aqueous suspension of hydroxypropylmethylcellulose, polyethylene glycol, tita-nium dioxide and iron oxide red in order to give light protection.
xample 18 A. Core 8 g nitrendipine (mean particle size 5 ~m) are mixed with 4 g lactose, 15 g crosslinked PVPPand 12,3 g microcrystalline cellulose. This mixture is granu}ated with an aqueous solu-tion of 1,8 g PVP and 0,8 g sodium laurylsulfate. After drying and sieving 0l1 g ma~nesium ste~rate are added.
The granules are compressed t~ tablets with a size of 5 mm ` and a weight of 42;mg.
B. granules for the coat 104,5 g hydroxypropylcellulose type L, 40 g hydroxypropyl-cellulose type M and B8,~ g lac~ose are mixed. This mixture Le A 25 204 --- 20 -:
:
.
-.
.
J .'.~ ~
is granulated using an aqueous suspension of 32 g nitrendi-pine and 1,5 g HPC type L. The granules are dried and sieved and mixed with 1,5 g of magnesium stearateO Press coated ~ablets having a weight of 310 mg and a diameter of 9 mm are pressed from these granules and the cores.
C. Coating The tablets are then coated with an aqueous suspension of hydroxypropylmethylcellulose, polyethylene glycol and titanium dio~ide.
Example 19 A. Core 20 g nitrendipine (mean particle size 5 ~m) are mixed with 15 g crosslinked PVP and 7,2 g microcrystalline cellulose.
This mixture is granula~ed with an aqueous solution of 1,8 g PVP and 0,9 g sodium lauryl sulfate. After drying and sieving 0,1 g magnesium stearate are added. ~he granules are compressed to tablets with a size of 5 mm and a weight of 45 mg.
B. granule for the coat 144.5 g hydroxypropylcellulose type L and 97,5 g lactose are mixed. This mixture is granulated using an aqueous suspension of 20 g nitrendipine and L,5 g ~PC type L. The granules are dried and sieved and mi~ed with 1,5 ~ of mag-nesium stearate. Press coated tablets having a weight of 310 mg and a diameter of 9 mm are pressed from ~hese granules and the cores.
C. Coating The tablets ar~ then coated with an aqueous suspension of hydroxypropylmethylcellulose, polyethylene glycol and titanium dioxide.
;~ Le A 25 204 - 21 -::
r ,~
Example 20 A. Core 4 g nisoldipine (mean particle size 5 ~m) are mixed with 8 g lactose, 15 g crosslinked PVPPand 12 3 g microcrystalline cellulose. This mixture is granulated ~ith an aqueous solu-tion of 1,8 g PVP and 0 8 g sodium laurylsulfate. After drying and sieving 0,1 g maynesium stearate are added.
The granules are compressed to tablets with a size of S mm and a weight of 42 mg.
B. granule for the coat 46 5 g hydroxypropylcellulose type L 100 g hydroxypropyl-cellulose type M and 103 g lactose are mi~:ed. This mixture is granulated using an aqueous suspension of 16 g nisoldipine and 1,5 g HPC typ~ L. The granules are dried and sieved and mixed with 1 g of magnesium stearate. Press coated tablets having a weight of 310 mg and a diameter of 9 mm are pressed from ~hese granules and the cores.
I
C. Coating The tablets are then coated with an aqueous suspension of hydroxypropylmethylcellulose polyethylene glycol ti~a-nium dioxide and iron oxide red in order to give light protection.
Exam~le 21 A. Core 4 g nisoldipine (mean particle size 5 ~m) are mixed with 8 g lactose, lS g crosslinked Pvppand 12,3 g microcrystalline cellulose. This mixture is granula~ed with an aqueous svlu-tion of 1,8 g PVP and 0,8 g sodium laurylsulfate. ~fter drying and sieving 0~1 g magnesium stearate are added.
The granules are compressed to tablets with a size of 5 mm and a weight of 42 mg.
::
: ~:
Le A 25 204 - 22 ' ::
~ ::
, .
. ' .
', .
.
'IL 3 ~ ~ r ~L
B. granule for the coat 92,5 g hydroxypropylcellulose type L, 54 g hydroxypropyl-cellulose type M and 103 g lactose are mi~ed. This miY~ture is granulated using an aqueous suspension of 16 g nisoldi-pine and 1,5 g HPC type L. The granules are dried and sievedand mi ed with 1 g of maanesium s~earate. Press coated tablets having a weight of 310 mg and a diameter of 9 mm are pressed from these granules and the cores.
C. Coating The tablets are then coated with an aqueous suspension of hydroxypropylcellulose, polyethylene glycol, titanium dioxide and iron o~ide red in order to give light protection.
Example 22 A. Core 4 g nisoldipine (mean particle size 5 ~m) are mixed with 8 g lactose, 15 g crosslinked PVP and 12,3 g microcrystalline cellulose. This mixture is granulated with an aqeous solution of 1,8 g PVP and 0,8 g sodium laurylsulfate. After dryiny and sieving 0,1 g magnesium stearate are added. The granules are compressed to tablets with a size of 5 mm and~a weight of 42 mg.
B. granule for the coat 175 g hydroxypropylcellulose~type M and 74,5 g lactose are mixed. This mixture is granulated using an aqueous suspension of 16 g nisoldipine and 1,5 g HPC type L. The granules are dried and sieved and mixed with 1 g of mag-nesium stearate. Press coated tablets having a weight of 310 mg and a diameter of 9 mm are pressed from these granules and the cores.
C. Coating The tablets are then coated with an aqueous suspension of hydro~ypropylmethylcellulose, polyethylene glycol, tita-nium dioxide and iron oxide red in order ~o give light protection.
Le A 25 204 - - 23 -It will be unders~ood that the specification and examples are illustrative but not limitative of the presen~ inven~ion and that other embodiments within the spirit and scope of the invention will suggest ~hemselves to those skilled in the art~
:: Le A 25 204 - 24 -.
-
Claims (21)
1. A solid medicament preparation having a long-lasting action in the form of a press coated tablet which contains a sparingly soluble dihydropyridine, the press coated tablet comprising (a) a core which contains a dihydropyridine in rapid-release form, and (b) a coat around the core, the coat containing a dihydropyridine in slow-release form.
2. A medicament preparation according to claim 1 wherein the dihydropyridine is of the formula I
I, in which R1 represents a phenyl radical which is substituted by one or two identical or different substituents from the group comprising nitro, halogen and trifluoromethyl, or represents a radical from the group comprising and R2 represents a nitro group or the radical COOR6 in which R6 denotes alkyl having 1 to 10 C atoms which is optionally substituted by alkoxy having 1 to 4 C atoms or by one or more halogens, or in which R2, together with R5, represents the lactone group -CO-O-CH2, R3 represents alkyl having 1 to 10 C atoms, which is optionally substituted by alkoxy havlng 1 to 4 C atoms or by one or more fluorine atoms and R4 and R5 are identical or different and in each case represent alkyl having 1 to 4 C atoms, which is optionally substituted by hydroxyl.
I, in which R1 represents a phenyl radical which is substituted by one or two identical or different substituents from the group comprising nitro, halogen and trifluoromethyl, or represents a radical from the group comprising and R2 represents a nitro group or the radical COOR6 in which R6 denotes alkyl having 1 to 10 C atoms which is optionally substituted by alkoxy having 1 to 4 C atoms or by one or more halogens, or in which R2, together with R5, represents the lactone group -CO-O-CH2, R3 represents alkyl having 1 to 10 C atoms, which is optionally substituted by alkoxy havlng 1 to 4 C atoms or by one or more fluorine atoms and R4 and R5 are identical or different and in each case represent alkyl having 1 to 4 C atoms, which is optionally substituted by hydroxyl.
3. A medicament preparation according to Claim 1, wherein 5 to 50% of the dihydropyridine active compound is present in the core and 50 to 95% of the total dihydropyridine active compound is present in the coat.
4. A medicament preparation according to Claim 1, wherein 10 to 40% of the total dihydropyridine active compound is present n the core and 60 to 90% of the dihydropyridine active compound is present in the coat.
5. A medicament preparation according to Claim 1, 2, 3 or 4 wherein the core contains the active compound in amorphous form or in a crystalline form having a maximum mean particle size of 25 µm.
6. A medicament preparation according to Claim 1, 2, 3 or 4 wherein the core contains the active compound in amorphous form as a component of a coprecipitate with a water-soluble polymer the coprecipitate containing from 2 to 10 parts by weight of water-soluble polymer per part of active compound.
7. A medicament preparation according to Claim 1, 2, 3 or 4 wherein the core contains the active compound in amorphous form as a component of a coprecipitate with a water-soluble polymer selected from polyvinylpyrrolidone, methylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose, the coprecipitate containing from 2 to 10 parts by weight of water-soluble polymer per part of active compound.
8. A medicament preparation according to Claim 1, 2, 3 or 4 wherein the core contains the active compound in crystalline form having a maximum mean particle size of about 25 µm and the core also contains a readily water-soluble auxiliary substance, a disintegrant or a wetting agent.
9. A medicament preparation according to Claim 1, 2, 3 or 4 wherein the core contains the active compound in crystalline form having a maximum mean particle size of about 25 µm and the core also contains lactose as a readily water-soluble auxiliary substance, crosslinked polyvinylpyrrolidone as a disintegrant or sodium lauryl sulphate as a surface active agent.
10. A medicament preparation according to Claim 1, 2, 3 or 4 wherein 10 to 99% of the total coat weight is a hydrophillic gel-forming polymer.
11. A medicament preparation according to Claim 1, 2, 3 or 4 wherein 10 to 99% of the total coat weight is a hydrophillic gel-forming polymer selected from the group consisting of methyl-cellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose and sodium carboxymethylcellulose.
12. A medicament preparation according to Claim 1, 2, 3 or 4 wherein 10 to 99% of the total coat weight is hydroxy-propylcellulose.
13. A medicament preparation according to Claim 1, 2, 3 or 4 wherein in the coat containing the active compound in slow-release form the active compound is present in crystalline form.
14. A medicament preparation according to Claim 1, 2, 3 or 4 wherein the dihydropyridine comprises at least one compound selected from the group comprising nifedipine, nitrendipine, nimodipine, nisoldipine and felodipine.
15. A medicament preparation according to Claim 1, 2, 3 or 4 wherein the dihydropyridine comprises at least one compound selected from the group consisting of nifedipine, nitrendipine, nimodipine and nisoldipine.
16. A medicament preparation according to Claim 1, 2, 3 or 4 wherein the core contains the dihydropyridine in crystalline form and further contains at least one of a readily water-soluble auxiliary, disintegrant and wetting agent.
17. A medicament preparation according to Claim 1, 2, 3 or 4 wherein the coating is itself coated with a layer of dihydropyridine in rapid-release form.
18. A process for manufacturing solid medicament preparations having a long lasting action containing a sparingly soluble dihydropyridine in form of a press coated tablet comprising, (a) a core which contains a dihydropyridine in rapid-release form, and (b) a coat around the core, the coat containing a dihydropyridine in slow-release form, the core having been produced by mixing the active substance and a filler, granulating this mixture by adding an aqueous solution of binder, drying and sieving the granulate, adding a lubricant and pressing to form the core, or forming the core by direct compression or by roller compaction plus compression, producing the granule for the coat by spraying an aqueous suspension containing the active substance and a binder on the solid ingredients, drying and sieving, mixing with a lubricant, press coating the granules for the coat upon the core, and optionally film coating the obtained press coated tablet with lacquers which optionally contain a small amount of the active substance up to a maximum of 20% of the total amount of the active substance in the whole composition.
19. A process for the preparation of solid medicament preparations which have a long-lasting action in the form of a coated tablet and which contain a sparingly soluble dihydropyridine active compound of the general formula I, in which R1 represents a phenyl radical which is substituted by one or two identical or different substituents from the group comprising nitro, halogen and trifluoromethyl, or represents a radical from the group comprising and R2 represents a nitro group or the radical COOR6, in which R6 denotes alkyl having 1 to 10 C atoms, which is optionally substituted by alkoxy having 1 to 4 C atoms or by one or more halogens, or in which R2, together with R5, represents the lactone group -CO-O-CH2, R3 represents alkyl having 1 to 10 C atoms, which is optionally substituted by alkoxy having 1 to 4 C atoms or by one or more fluorine atoms and R4 and R5 are identical or different and in each case represent alkyl having 1 to 4 C atoms, which is optionally sub-stituted by hydroxyl, where the coated tablet has a) a core which contains at least one of the above-mentioned dihydropyridines in rapld-rele~ase form, and b) a coat around the core, this coat containing at least one of the above mentioned dihydropyridines in slow-release form, which process comprises:
(i) preparing a core containing the active compound in rapid-release form, the active compound being (a) in amorphous form and present as a coprecipitate with a water-soluble polymer, or (b) in crystalline form and present with a water-soluble auxiliary a disintegrant or a surface active agent;
(ii) preparing a coat of slow-release active compound and hydrophilic gel-forming polymer; and (iii) pressing the core and the coat in a coated-tablet press to form the required solid medicament.
(i) preparing a core containing the active compound in rapid-release form, the active compound being (a) in amorphous form and present as a coprecipitate with a water-soluble polymer, or (b) in crystalline form and present with a water-soluble auxiliary a disintegrant or a surface active agent;
(ii) preparing a coat of slow-release active compound and hydrophilic gel-forming polymer; and (iii) pressing the core and the coat in a coated-tablet press to form the required solid medicament.
20. A process according to Claim 19 wherein the core is coated with a gastric juice-resistant layer.
21. A process according to Claim 19 wherein the solid medicament is given a further coat which contains the active compound in rapid-release form.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19873720757 DE3720757A1 (en) | 1987-06-24 | 1987-06-24 | DHP COAT TABLET |
| DEP3720757.1 | 1987-06-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1309951C true CA1309951C (en) | 1992-11-10 |
Family
ID=6330136
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000570069A Expired - Lifetime CA1309951C (en) | 1987-06-24 | 1988-06-22 | Press coated dhp tablets |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US4892741A (en) |
| EP (1) | EP0299211B1 (en) |
| JP (2) | JPH0611699B2 (en) |
| AT (1) | ATE75142T1 (en) |
| CA (1) | CA1309951C (en) |
| DE (2) | DE3720757A1 (en) |
| ES (1) | ES2051800T3 (en) |
| GR (1) | GR3004448T3 (en) |
| IE (1) | IE60352B1 (en) |
| IL (1) | IL86827A (en) |
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| GB906422A (en) * | 1958-05-02 | 1962-09-19 | Wellcome Found | Improvements in and relating to prolonged acting pharmaceutical preparations |
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| IT1198386B (en) * | 1982-07-06 | 1988-12-21 | Lepetit Spa | A PROTRACTED RELEASE PRODUCT CONTAINING SULOCTIDYL |
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| GB8322007D0 (en) * | 1983-08-16 | 1983-09-21 | Wellcome Found | Pharmaceutical delivery system |
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| SE8404467D0 (en) * | 1984-09-06 | 1984-09-06 | Ferrosan Ab | CONTROLLED-RELEASE MEDICAL PREPARATIONS |
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| SE8601624D0 (en) * | 1986-04-11 | 1986-04-11 | Haessle Ab | NEW PHARMACEUTICAL PREPARATIONS |
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-
1987
- 1987-06-24 DE DE19873720757 patent/DE3720757A1/en not_active Withdrawn
-
1988
- 1988-06-08 US US07/204,056 patent/US4892741A/en not_active Expired - Lifetime
- 1988-06-14 DE DE8888109420T patent/DE3870338D1/en not_active Expired - Lifetime
- 1988-06-14 ES ES88109420T patent/ES2051800T3/en not_active Expired - Lifetime
- 1988-06-14 EP EP88109420A patent/EP0299211B1/en not_active Expired - Lifetime
- 1988-06-14 AT AT88109420T patent/ATE75142T1/en not_active IP Right Cessation
- 1988-06-22 CA CA000570069A patent/CA1309951C/en not_active Expired - Lifetime
- 1988-06-22 IL IL86827A patent/IL86827A/en not_active IP Right Cessation
- 1988-06-23 JP JP63153676A patent/JPH0611699B2/en not_active Expired - Lifetime
- 1988-06-23 IE IE191688A patent/IE60352B1/en not_active IP Right Cessation
-
1992
- 1992-04-23 GR GR920400734T patent/GR3004448T3/el unknown
-
1996
- 1996-11-18 JP JP8321158A patent/JP2955524B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| GR3004448T3 (en) | 1993-03-31 |
| US4892741A (en) | 1990-01-09 |
| JPH09183728A (en) | 1997-07-15 |
| IE60352B1 (en) | 1994-06-29 |
| IL86827A (en) | 1993-02-21 |
| EP0299211B1 (en) | 1992-04-22 |
| JPH0611699B2 (en) | 1994-02-16 |
| IE881916L (en) | 1988-12-24 |
| DE3870338D1 (en) | 1992-05-27 |
| IL86827A0 (en) | 1988-11-30 |
| ATE75142T1 (en) | 1992-05-15 |
| JP2955524B2 (en) | 1999-10-04 |
| EP0299211A1 (en) | 1989-01-18 |
| ES2051800T3 (en) | 1994-07-01 |
| JPS6422822A (en) | 1989-01-25 |
| DE3720757A1 (en) | 1989-01-05 |
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