CA1248452A - Cylindrical microtablets - Google Patents
Cylindrical microtabletsInfo
- Publication number
- CA1248452A CA1248452A CA000484346A CA484346A CA1248452A CA 1248452 A CA1248452 A CA 1248452A CA 000484346 A CA000484346 A CA 000484346A CA 484346 A CA484346 A CA 484346A CA 1248452 A CA1248452 A CA 1248452A
- Authority
- CA
- Canada
- Prior art keywords
- pharmaceutical
- microtablet
- microtablets
- coating
- diameter
- 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
Links
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B30—PRESSES
- B30B—PRESSES IN GENERAL
- B30B15/00—Details of, or accessories for, presses; Auxiliary measures in connection with pressing
- B30B15/0094—Press load monitoring means
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
- A61J3/10—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of compressed tablets
-
- 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
-
- 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
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B30—PRESSES
- B30B—PRESSES IN GENERAL
- B30B11/00—Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses
- B30B11/005—Control arrangements
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B30—PRESSES
- B30B—PRESSES IN GENERAL
- B30B11/00—Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses
- B30B11/02—Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses using a ram exerting pressure on the material in a moulding space
- B30B11/08—Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses using a ram exerting pressure on the material in a moulding space co-operating with moulds carried by a turntable
Abstract
Abstract of the Disclosure: Cylindrical microtablets which have a convex upper face and a convex lower face and whose cylinder diameter and height independ-ently of one another are each from 1.0 to 2.5 mm and the ratio of the said diameter to said height is from 1:0.5 to 1:1.5, and a process for their preparation.
Description
~2'~ ~5;~
- 1 - O.Z. 0050/37177/178 Cylindrical Microtablets For many purposes, it is desirable to have par-ticles of 1 - 2.5 mm diameter which possess a very uniform particle size a nd regular shape, high weight 5 uniformity, very low poros;ty, 3 reproducible surface structure and a high content of active substance. For example, the administration of drugs in the form of pellets which can be introduced into, for example, capsules ;s generally preferred to the administration 10 of compact tablets because very high local concentrations of active compound in the gastrointestinal tract are avoided with multi-unit-dose-system pellets, in contrast to single-unit-dose-system tablets. However, uniform fiLling of capsules necessitates uniform size and shape 15 of the pellets. Moreover, the very steady release of active compound per unit time generally desired in the case of sustained-release pellets is only possible ;f the pellets are of uniform size and shape. The same appli~s to pellets which are provided with a coating re-20 sistant to gastric juice. Only regularly shaped particlespermit uniform coating with a very small amount of coating agent.
It is also des;rabLe to prepare pellets which have the stated properties and are of such uniformity that 25 single-unit doses are possible. This means that each individual pellet particle must meet the requirements set by the European pharmacopeia with regard to the single-un;t dose forms described there. The necessary weight uniformity for tablets is specified in the European pharma-30 copeia, vol. III, page 77.
The specifications regarding the disintegrationtimes for uncoated tablets (loc.cit page 235), of coated tablets which are soluble in gastric juice (loc.cit page 237) and of tablets which are provided with a coating re-35 sistant to gastric juice (loc.cit page 237) must be met byeach pellet particle.
F~ellets are usuaLly produced by a pelletizing ~2~
- 1 - O.Z. 0050/37177/178 Cylindrical Microtablets For many purposes, it is desirable to have par-ticles of 1 - 2.5 mm diameter which possess a very uniform particle size a nd regular shape, high weight 5 uniformity, very low poros;ty, 3 reproducible surface structure and a high content of active substance. For example, the administration of drugs in the form of pellets which can be introduced into, for example, capsules ;s generally preferred to the administration 10 of compact tablets because very high local concentrations of active compound in the gastrointestinal tract are avoided with multi-unit-dose-system pellets, in contrast to single-unit-dose-system tablets. However, uniform fiLling of capsules necessitates uniform size and shape 15 of the pellets. Moreover, the very steady release of active compound per unit time generally desired in the case of sustained-release pellets is only possible ;f the pellets are of uniform size and shape. The same appli~s to pellets which are provided with a coating re-20 sistant to gastric juice. Only regularly shaped particlespermit uniform coating with a very small amount of coating agent.
It is also des;rabLe to prepare pellets which have the stated properties and are of such uniformity that 25 single-unit doses are possible. This means that each individual pellet particle must meet the requirements set by the European pharmacopeia with regard to the single-un;t dose forms described there. The necessary weight uniformity for tablets is specified in the European pharma-30 copeia, vol. III, page 77.
The specifications regarding the disintegrationtimes for uncoated tablets (loc.cit page 235), of coated tablets which are soluble in gastric juice (loc.cit page 237) and of tablets which are provided with a coating re-35 sistant to gastric juice (loc.cit page 237) must be met byeach pellet particle.
F~ellets are usuaLly produced by a pelletizing ~2~
- 2 - O.Z. OOS0/37177/178 process, for example using 3 disk or drum pelletizer, in a coating pan or with the aid of other apparatuses for agglomerative granulation, or by extrusion, cutting of the extrudates and rounding off the resulting cylin-drical particles on appropriate conventional apparatuses.These processes are descr;bed, for example, by R. Voigt, in Lehrbuch der pharmazeutischen Technologie, 2nd edition, VEB Verlag Volk und Gesundheit, Berlin 1975, 153-169, and in Hagers Handbuch der pharmazeutischen Praxis, 4th edition, Springer-Verlag, aerlin - Heidelberg - New York, 1971, VII A, 312 - 318.
All of these processes have the disadvantage that they give a broad particle size distribution, so that oversize and undersize particles have to be separated off.
Moreover, the shape andlor the surface structure are fre-quently non-uniform. In all of these processes, a solvent is incorporated and then evaporated, so that a porous structure ;s produced. The weight of the individual particles fluctuates greatly. Single-un;t doses are im-possible s;nce the requirements of the European pharmacopeia are not met.
These disadvantages are overcome if tablets are produced by pressing, but tablets having a diameter of less than 3 mm are unknown to date.
Sk;lled workers from the manufacturing sector for tableting presses and tools, ie. dies and punches, are unanimous in the opinion that it is impossible to produce smaller tablets. The reasons for this are the sensit;vity of the thin punches, which are compressed and break off when used ;n conventional presses, the required precis;onof the tablet;ng presses, and the requirements w;th re-spect to the free-flow;ng propert;es, particle s;ze and particle size distribution of the tableting material.
It is an object of the present invention to pro-duce particles having the properties described at theoutset.
We have found that this object ;s achieved by a ~ 3 ~ ~ 52 cylindrical pharmaceutical microtablet having a convex upper face and convex lower face, wherein the cylinder diameter and the height independently of one another are each from 1.0 to 2.5 mm, the ratio from the said diameter to the said height being from 1:0.5 to 1:1.5, which tablet contains pancreatin as the active compound.
The preferred cylinder diameter and height are independently each from 2.0 to 2.3mm, while the preferred ratio of the diameter to the height is from 1:09 to 1:1.1.
A free-flowing tableting material having a maximum particle diameter of 30%, preferably 20~, of the tablet diameter and containing less than 10, preferably less than 5, per cent by weight of dust (with particle diameters of less than 50~m) can be pressed into the microtablet with a force of from 0.4 to 3, preferably from 1 to 2, kN.
The reguired tableting materials having the stated particle size and the stated low dust content are advantageously obtained by milling larger particles, preferred mills being those which have a low shearing action. The process furthermore requires novel tablet-ing presses unlike those available commercially to date. Not only must they possess correspondingly small dies and punches, but the measuring range for the ap-plied compressive force must be adapted to the smaller dimensions of the microtablet. The tools must be controlled in a particularly precise manner. Sensitive control of the metering is required in order to avoid deviations of the mean tablet weight during the pressing procedure, since overfilling the dies leads to overloading of the tools. Finally, it is necessary to provide a very efficiently functioning scraper, which conveys the microtablets carefully and without damage, but also reliably without leaving a residue, from the die into 1~84~
the discharge device.
The radius of curvature r of the convex upper and lower faces of the cylindrical microtablet is from 0.6 to 1.5 times, preferably from 0.7 to 0.9 times, the diameter~of the cylinder. With smaller radii of curvature (a spherical shape), the tools do not withstand the pressure required, while with larger radii flat upper and lower faces (infinite radius of curvature) are approached, with the disadvantage that the edges present problems during coating and are susceptible to mechanical damage.
The height of the tablet is the maximum dimen-sion along the cylinder axis.
The phrase "free-flowing" is intended to mean that the cotangent ~ of the angle of slope deter-mined in accordance with DIN 53916 is greater than 1.2, preferably greater than 1.4.
The term dust content embraces the product fractions having particle diameters of less than 50 ~m.
The am~unt of such fractions in the material being pressed should be less than 10, preferably less than 5, per cent by weight.
Pharmaceutical microtablets contain one or more active pharmaceutical compounds in an effective amount, in addition to conventional pharmaceutical auxiliaries.
The novel microtablets weigh from 1 to 20, preferably from 5 to 10, mg. The relative standard deviations of the mean weights of 50 (=n;cf. claims
All of these processes have the disadvantage that they give a broad particle size distribution, so that oversize and undersize particles have to be separated off.
Moreover, the shape andlor the surface structure are fre-quently non-uniform. In all of these processes, a solvent is incorporated and then evaporated, so that a porous structure ;s produced. The weight of the individual particles fluctuates greatly. Single-un;t doses are im-possible s;nce the requirements of the European pharmacopeia are not met.
These disadvantages are overcome if tablets are produced by pressing, but tablets having a diameter of less than 3 mm are unknown to date.
Sk;lled workers from the manufacturing sector for tableting presses and tools, ie. dies and punches, are unanimous in the opinion that it is impossible to produce smaller tablets. The reasons for this are the sensit;vity of the thin punches, which are compressed and break off when used ;n conventional presses, the required precis;onof the tablet;ng presses, and the requirements w;th re-spect to the free-flow;ng propert;es, particle s;ze and particle size distribution of the tableting material.
It is an object of the present invention to pro-duce particles having the properties described at theoutset.
We have found that this object ;s achieved by a ~ 3 ~ ~ 52 cylindrical pharmaceutical microtablet having a convex upper face and convex lower face, wherein the cylinder diameter and the height independently of one another are each from 1.0 to 2.5 mm, the ratio from the said diameter to the said height being from 1:0.5 to 1:1.5, which tablet contains pancreatin as the active compound.
The preferred cylinder diameter and height are independently each from 2.0 to 2.3mm, while the preferred ratio of the diameter to the height is from 1:09 to 1:1.1.
A free-flowing tableting material having a maximum particle diameter of 30%, preferably 20~, of the tablet diameter and containing less than 10, preferably less than 5, per cent by weight of dust (with particle diameters of less than 50~m) can be pressed into the microtablet with a force of from 0.4 to 3, preferably from 1 to 2, kN.
The reguired tableting materials having the stated particle size and the stated low dust content are advantageously obtained by milling larger particles, preferred mills being those which have a low shearing action. The process furthermore requires novel tablet-ing presses unlike those available commercially to date. Not only must they possess correspondingly small dies and punches, but the measuring range for the ap-plied compressive force must be adapted to the smaller dimensions of the microtablet. The tools must be controlled in a particularly precise manner. Sensitive control of the metering is required in order to avoid deviations of the mean tablet weight during the pressing procedure, since overfilling the dies leads to overloading of the tools. Finally, it is necessary to provide a very efficiently functioning scraper, which conveys the microtablets carefully and without damage, but also reliably without leaving a residue, from the die into 1~84~
the discharge device.
The radius of curvature r of the convex upper and lower faces of the cylindrical microtablet is from 0.6 to 1.5 times, preferably from 0.7 to 0.9 times, the diameter~of the cylinder. With smaller radii of curvature (a spherical shape), the tools do not withstand the pressure required, while with larger radii flat upper and lower faces (infinite radius of curvature) are approached, with the disadvantage that the edges present problems during coating and are susceptible to mechanical damage.
The height of the tablet is the maximum dimen-sion along the cylinder axis.
The phrase "free-flowing" is intended to mean that the cotangent ~ of the angle of slope deter-mined in accordance with DIN 53916 is greater than 1.2, preferably greater than 1.4.
The term dust content embraces the product fractions having particle diameters of less than 50 ~m.
The am~unt of such fractions in the material being pressed should be less than 10, preferably less than 5, per cent by weight.
Pharmaceutical microtablets contain one or more active pharmaceutical compounds in an effective amount, in addition to conventional pharmaceutical auxiliaries.
The novel microtablets weigh from 1 to 20, preferably from 5 to 10, mg. The relative standard deviations of the mean weights of 50 (=n;cf. claims
3 and 11) weighed microtablets prepared by this process are less than 4%, in general even less than 2.5~. They meet the requirements of the European pharmacopeia in respectof weight uniformity of tablets. For a defini-tion of the standard deviation, see textbooks of sta-tistics, eg. Siegfried Noack, Auswertung von Mess-undVersuchsdaten mit Taschenrechner und Tischkomputer, 1~8~
~ ~ 4a Walter de Gruyter Verlag, Berlin, New York 1980, pages 192 - 201.
After having been provided with a retarding lacquer coating, conventional pellets of non-uniform size and shape give characteristics for the release of active compound which exhibit pronounced scatter in in-dividual cases. This is attributable to the different surface areæ of pellets which have different diameters.
Smaller pellets which have a large surface 345;~
- 5 - O.Z. 0050/37177/178 area per unit weight require a larger amount of coat-ing material than larger pellets with a smaller surface area per unit weight, in order to produce a coating which has the same thickness and is thus equally effective. This broad distribution of release rates is reinforced by the effects of shape factors, since parti-cles with edges and corners or raised surface structures require a larger amount of coating material in order to cover these irregularities.
1û When an average amount of surface coating mat-erial is applied during the coating procedure, only a few pellets will achieve the desired average release characteristics. Release from large and flat particles will be slower, and that from small and irregular particles will be faster.
Mixing these different particles leads to ad-dition of the individual release characteristics and hence to pronounced deviation from the desired linear characteristics. 0-order release is not possible in the case of a large number of simultaneously releasing pellets, as are present, for example, after a hard gelatine capsule has been dissolved.
If the novel microtablets are provided with a retarding coating by a conventional method, for example by fluidized-bed coating or by coating in a perforated drum coater with coating solutions based on, for example, ethylcellulose or acrylic resins, the uniformity of size, shape and surface structure of the microtablets leads to coatings which ensure that each retard pellet 3û releases the active compound present at a steady rate.
A pellet ensemble, eg. the contents of a hard gelatine capsule, has the same narrow-band release chara teristics, ie. linear variation with time.
The skilled worker is familiar with the problem of using coatings which are soluble in intestinal juice - to formulate conventional pellets resistant to gastric juice so that the active compound present in the pellets lZ~
- 6 - O.Z. 0050/37177/178 is rel;ably protected from the action of the acidic medium in the stomach. Protection from gastric acid is necessary particularly for acid-sensitive substances, eg. the enzyme lipase. In the case of pellets of this type, a coating which is resistant to gastric juice usually requires a very large amount of coating material, which accounts for as much as 50% of the total weight of the coated pellets. Nevertheless, such resistant pellets too are generally only resistant to gastric juice in the sense that the active compound does not diffuse through the coating and into the gastric acid, but not in the required way whereby the gastric acid is not diffused in the opposite direction through the coating and into the interior o~ the pellet.
With the novel microtablets, pellets which are completely resistant to gastric juice can be produced without particular expense. With the aid of the above-mentioned coating procedures, pellets which are homo-geneously resistant to gastric juice can be obtained by apply;ng coatings based on conventional coating systems, such as cellulose acetate phthalate or hydroxy-propylmethylcellulose phthalate. The consumption of coating material is not more than 25% (w/w), depending on the pellet size; in many cases 10X (w/w) is sufficient.
The novel microtablets can consist of a very wide range of materials and accordingly can be used for a very large variety of purposes. For example, they can be employed as catalysts in the petroleum and chemi-cal industries, or as readily meterable startingmaterials or additives for solutions as used in a very wide variety of industrial processes, for example for finishing and dyeing textiles, tanning, impregnation, etc.
However, the most important and very particularly pre-3; ferred field of use is in the pharmaceutical sector.Their advan~ages are particularly utilized when they are provided with a retarding or gastric juice-resistant ~2'~
- - 7 - O.Z. 0050/37177/178 coating. Retardation can be effected by the matrix principle or, preferably~ by means of a coating. The very particularly preferred novel microtablets pro-vided with a coating resistant to gastric juice are 5 those which contain pancreatin as the active compound.
Surprisingly, not only is ;t possible to produce microtablets having a diameter of less than 2.5 mm by pressing, but these microtablets furthermore possess unexpectedly good pressing characteristics, and the press-10 ability of materials intended for pressing is, surpris-ingly, better in the case of such small tablets.
For example, it is possible to produce micro-tablets having a high content of substances which are difficult to press.
Paracetamol can be pressed, via PVP granules, to give mechanically stable microtablets containing 95% of active compound. These are so stable that they can be coated in a Wurster apparatus.
1û mm tablets prepared from the same granules by 20 way of comparison cannot be coated since they undergo laminar cleavage under mechanical load.
This cannot be prevented by means of a higher com-pressive pressure, this resulting, on the contrary, in direct capping~
The mold release agent talc can likewise be pressed via PVP granules to give firm microtablets having a content of 95%. These microtablets, too, are so stable that they can be coated without difficulty in a Wurster appa ratus.
10 mm tablets prepared from the same granules by way of comparison possess only little strength. When they are fluidized ;n the Wurster apparatus, the mechanical abrasion is sufficient to cause the tablets to lose their shape.
Pancreatin can be pressed to give tablets having a content of 99.5X.
If these granules are pressed using conventional lZ~8~5~
- 8 - O.Z. 0050/37177/178 round tools of 10 mm diameter, either capping is observed or the strength of the resulting tablets is insufficient to permit them to be further processed.
In the Examples, parts and percentages are by 5 weight.
Commercial coarse-particled ascorbic acid which met the requirements of the pharmacopeia was commin-uted on a roll mill so that 1.2% remained on a sieve 10 having a mesh size of 0.4 mm. The fraction belou 50 jum was 7.5%
1,940 9 of this milled vitamin C were mixed with 50 9 of microcrystalline cellulose and 10 9 of mag-nesium sterate in a 5 liter mixer. The mixture, having 15 free-flow characteristics according to DIN 53916 which corresponded to cotangent ~p = 1.45, was pressed on an eccentric press equipped with instrumentation and having precise punch control to give microtablets having a diameter of 1.5 mm and a height of 1.8 mm, the compres-20 s;ve force used being 0.9 kN. The rad;us of curvature was 1.0 mm.
The mean weight of 50 microtablets was 3.56 mg, the relative standard deviation be;ng 2.9X. The microtablets met the pharmacopeia requirements ;n re-25 spect of weight uni~ormity for tablets.
After 300,000 microtablets had been prepared,the press tool still remained completely undamaged.
The oversize was removed from commercial potas-30 sium chloride which met the pharmacopeia requirementsby means of a 0.5 mm sieve. The fine fraction con-tained 2.7X of dust having a size of less than 50 jum.
After 11,940 9 of th;s potassium chloride fraction has been mixed with 60 9 of magnesium stearate in a 50 35 liter mixer, the mixture had free-flow characteristics according to DIN 53916 which corresponded to cotangent y = 1.49.
- 9 - O.Z. 0050/37177/178 This material for pressing was converted to pellet-like microtablets having a diameter of 2.0 mm and a height of 2.0 mm on a Z4-punch rotary press with sensitive monitoring of the compressive force and control S of metering, and with a very precisely operating scraper, the compressive force used being 1.5 kN. The radius of curvature was 1.4 mm, the mean weight of 50 microtablets was 11.2 mg and the relative standard deviation was 1.8X.
The microtablets met the oharmacopeia require-ments for weight uniformity for tablets. After the preparation of 100,00û microtablets, the press tool was still undamaged~
The potassium chloride microtablets were coated continuously in a fluidized-bed spray granulator with an ethanolic ethylcellulose solution whose concentration was 5.5% (w/w). The specific viscosity of the ethyl-cellulose was 10 mPas. The polymer solution con-tained 2û%, based on the weight of the polymer, of dibutyl phthalate as a p~asticizer.
Talc was suspended in this solution, as a filler, in an amount of 50% (w/w), based on the weight of the polymer. The total amount of coating material was SX
(w/w), based on the coated potassium chloride micro-tablets. The fluidized-bed coating procedure was controlled so that the product temperature was from 23 to 25C.
Filling of the retarded potassium chloride micro-tablets produced in this manner into hard gelat;ne capsules could be carried out very easily and precisely in conventional apparatuses.
Potassium chloride release as determined by the paddle method according to U.S. pharmacopeia XX showed the following behavior:
~2~52 - 10 - O.Z. 0050/371771178 Time (h) _Amount liberated in
~ ~ 4a Walter de Gruyter Verlag, Berlin, New York 1980, pages 192 - 201.
After having been provided with a retarding lacquer coating, conventional pellets of non-uniform size and shape give characteristics for the release of active compound which exhibit pronounced scatter in in-dividual cases. This is attributable to the different surface areæ of pellets which have different diameters.
Smaller pellets which have a large surface 345;~
- 5 - O.Z. 0050/37177/178 area per unit weight require a larger amount of coat-ing material than larger pellets with a smaller surface area per unit weight, in order to produce a coating which has the same thickness and is thus equally effective. This broad distribution of release rates is reinforced by the effects of shape factors, since parti-cles with edges and corners or raised surface structures require a larger amount of coating material in order to cover these irregularities.
1û When an average amount of surface coating mat-erial is applied during the coating procedure, only a few pellets will achieve the desired average release characteristics. Release from large and flat particles will be slower, and that from small and irregular particles will be faster.
Mixing these different particles leads to ad-dition of the individual release characteristics and hence to pronounced deviation from the desired linear characteristics. 0-order release is not possible in the case of a large number of simultaneously releasing pellets, as are present, for example, after a hard gelatine capsule has been dissolved.
If the novel microtablets are provided with a retarding coating by a conventional method, for example by fluidized-bed coating or by coating in a perforated drum coater with coating solutions based on, for example, ethylcellulose or acrylic resins, the uniformity of size, shape and surface structure of the microtablets leads to coatings which ensure that each retard pellet 3û releases the active compound present at a steady rate.
A pellet ensemble, eg. the contents of a hard gelatine capsule, has the same narrow-band release chara teristics, ie. linear variation with time.
The skilled worker is familiar with the problem of using coatings which are soluble in intestinal juice - to formulate conventional pellets resistant to gastric juice so that the active compound present in the pellets lZ~
- 6 - O.Z. 0050/37177/178 is rel;ably protected from the action of the acidic medium in the stomach. Protection from gastric acid is necessary particularly for acid-sensitive substances, eg. the enzyme lipase. In the case of pellets of this type, a coating which is resistant to gastric juice usually requires a very large amount of coating material, which accounts for as much as 50% of the total weight of the coated pellets. Nevertheless, such resistant pellets too are generally only resistant to gastric juice in the sense that the active compound does not diffuse through the coating and into the gastric acid, but not in the required way whereby the gastric acid is not diffused in the opposite direction through the coating and into the interior o~ the pellet.
With the novel microtablets, pellets which are completely resistant to gastric juice can be produced without particular expense. With the aid of the above-mentioned coating procedures, pellets which are homo-geneously resistant to gastric juice can be obtained by apply;ng coatings based on conventional coating systems, such as cellulose acetate phthalate or hydroxy-propylmethylcellulose phthalate. The consumption of coating material is not more than 25% (w/w), depending on the pellet size; in many cases 10X (w/w) is sufficient.
The novel microtablets can consist of a very wide range of materials and accordingly can be used for a very large variety of purposes. For example, they can be employed as catalysts in the petroleum and chemi-cal industries, or as readily meterable startingmaterials or additives for solutions as used in a very wide variety of industrial processes, for example for finishing and dyeing textiles, tanning, impregnation, etc.
However, the most important and very particularly pre-3; ferred field of use is in the pharmaceutical sector.Their advan~ages are particularly utilized when they are provided with a retarding or gastric juice-resistant ~2'~
- - 7 - O.Z. 0050/37177/178 coating. Retardation can be effected by the matrix principle or, preferably~ by means of a coating. The very particularly preferred novel microtablets pro-vided with a coating resistant to gastric juice are 5 those which contain pancreatin as the active compound.
Surprisingly, not only is ;t possible to produce microtablets having a diameter of less than 2.5 mm by pressing, but these microtablets furthermore possess unexpectedly good pressing characteristics, and the press-10 ability of materials intended for pressing is, surpris-ingly, better in the case of such small tablets.
For example, it is possible to produce micro-tablets having a high content of substances which are difficult to press.
Paracetamol can be pressed, via PVP granules, to give mechanically stable microtablets containing 95% of active compound. These are so stable that they can be coated in a Wurster apparatus.
1û mm tablets prepared from the same granules by 20 way of comparison cannot be coated since they undergo laminar cleavage under mechanical load.
This cannot be prevented by means of a higher com-pressive pressure, this resulting, on the contrary, in direct capping~
The mold release agent talc can likewise be pressed via PVP granules to give firm microtablets having a content of 95%. These microtablets, too, are so stable that they can be coated without difficulty in a Wurster appa ratus.
10 mm tablets prepared from the same granules by way of comparison possess only little strength. When they are fluidized ;n the Wurster apparatus, the mechanical abrasion is sufficient to cause the tablets to lose their shape.
Pancreatin can be pressed to give tablets having a content of 99.5X.
If these granules are pressed using conventional lZ~8~5~
- 8 - O.Z. 0050/37177/178 round tools of 10 mm diameter, either capping is observed or the strength of the resulting tablets is insufficient to permit them to be further processed.
In the Examples, parts and percentages are by 5 weight.
Commercial coarse-particled ascorbic acid which met the requirements of the pharmacopeia was commin-uted on a roll mill so that 1.2% remained on a sieve 10 having a mesh size of 0.4 mm. The fraction belou 50 jum was 7.5%
1,940 9 of this milled vitamin C were mixed with 50 9 of microcrystalline cellulose and 10 9 of mag-nesium sterate in a 5 liter mixer. The mixture, having 15 free-flow characteristics according to DIN 53916 which corresponded to cotangent ~p = 1.45, was pressed on an eccentric press equipped with instrumentation and having precise punch control to give microtablets having a diameter of 1.5 mm and a height of 1.8 mm, the compres-20 s;ve force used being 0.9 kN. The rad;us of curvature was 1.0 mm.
The mean weight of 50 microtablets was 3.56 mg, the relative standard deviation be;ng 2.9X. The microtablets met the pharmacopeia requirements ;n re-25 spect of weight uni~ormity for tablets.
After 300,000 microtablets had been prepared,the press tool still remained completely undamaged.
The oversize was removed from commercial potas-30 sium chloride which met the pharmacopeia requirementsby means of a 0.5 mm sieve. The fine fraction con-tained 2.7X of dust having a size of less than 50 jum.
After 11,940 9 of th;s potassium chloride fraction has been mixed with 60 9 of magnesium stearate in a 50 35 liter mixer, the mixture had free-flow characteristics according to DIN 53916 which corresponded to cotangent y = 1.49.
- 9 - O.Z. 0050/37177/178 This material for pressing was converted to pellet-like microtablets having a diameter of 2.0 mm and a height of 2.0 mm on a Z4-punch rotary press with sensitive monitoring of the compressive force and control S of metering, and with a very precisely operating scraper, the compressive force used being 1.5 kN. The radius of curvature was 1.4 mm, the mean weight of 50 microtablets was 11.2 mg and the relative standard deviation was 1.8X.
The microtablets met the oharmacopeia require-ments for weight uniformity for tablets. After the preparation of 100,00û microtablets, the press tool was still undamaged~
The potassium chloride microtablets were coated continuously in a fluidized-bed spray granulator with an ethanolic ethylcellulose solution whose concentration was 5.5% (w/w). The specific viscosity of the ethyl-cellulose was 10 mPas. The polymer solution con-tained 2û%, based on the weight of the polymer, of dibutyl phthalate as a p~asticizer.
Talc was suspended in this solution, as a filler, in an amount of 50% (w/w), based on the weight of the polymer. The total amount of coating material was SX
(w/w), based on the coated potassium chloride micro-tablets. The fluidized-bed coating procedure was controlled so that the product temperature was from 23 to 25C.
Filling of the retarded potassium chloride micro-tablets produced in this manner into hard gelat;ne capsules could be carried out very easily and precisely in conventional apparatuses.
Potassium chloride release as determined by the paddle method according to U.S. pharmacopeia XX showed the following behavior:
~2~52 - 10 - O.Z. 0050/371771178 Time (h) _Amount liberated in
4 62 COMPARATIVE EXPERIMENT
For comparison, potassium chloride pellets were prepared on a disk pelletizer, 4% (w/w) of hydroxy-propylmethylcellulose being incorporated as a binder, and undersize particles smaller than 1.6 mm and over-size particles larger than 2.0 mm were separated off by means of a sieve. The useful fract;on was retarded by a similar process, the total amount of coating material being 5.5% (w/w) based on the coated potassium chloride pellets.
Release of potassium chloride gave the following values:
Time (h?Amount liberated in X
Comparison of the two products showed that the retarded potassium chloride microtablets used according to the invention approach ideal behavior, ie. O-order release, whereas the conventionally prepared potassium chloride exhibits substantial deviations.
Pancreatin prepared by the extraction method was comminuted on a roll mill so that the fraction above 0.5 mm was 0.8X, and the dust fraction below 50 ~m was 3.5%.
After 1,990 9 of this pancreatin had been mixed with 10 9 of magnesium stearate in a 5 liter laboratory mixer, the mixture had free-flow characteristics accord-ing to DIN 53916 which corresponded to cotangent ~ = 1.35.
4~2 ~ O.Z. 0050/37177/178 This material for pressing was converted to microtablets having a diameter of 2.25 mm and a height of 2.2 mm on an eccentric press equipped with instru-mentation, and having precise punch control, the compressive force used being 2 kN. The radius of curva~
ture was 1.7 mm. The Mean weight of 50 microtablets was 8.5 mg and the relative standard deviation was 2.4%.
The microtablets met the pharmacopeia require-ments in respect of weight uniformity for tablets.
The pancreatin microtablets were coated in a rotating perforated drum (Accela Cota 24" from Manesty, Liverpool having a drum with 0.3 mm perforations pro-duced by laser beam) with a solution of hydroxypropyl-methylcellulose phthalate in a 3: 7 isopropanol/
methylenechloride mixture with the aid of a two-material nozzle. The concentration of the solution was 7% ~w/w).
The total amount of the coating polymer was 14% (w/w), based on the coated pancreatin microtablets. 20X (w/w), based on the polymer mater;al, of dibutyl phthalate was added to the polymer solution, as a plastic;zer.
The coating procedure was controlled so that when the coating solut;on was metered at a rate of 40 ml/min, the product temperature remained at 24-26C.
The pancreatin microtablets resistant to gastric juice could be introduced into hard gelatine capsules very easily and precisely using conventional apparatuses.
The resistance to gastric juice was tested by the method described in Ph. Eur. Furthermore, the pene-tration of synthetic gastric acid into the pellets wasdetermined by measuring the content of lipase after the acid had been allowed to act for 2 hours, and comparing this content with the init;al value.
In the m;crotablets res;stant to gastric juice and produced according to the invention, no decrease in the lipase activity could be detected.
For comparison a commercial product containing 12~5~
- 12 - O.Z. OOS0/37177/178 pellets resistant to gastric juice was investigated.
Although this product was resistant to gastric juice according to the pharmacopeia specification, the lipase activity was found to decrease by 60,' after S exposure to synthetic gastric acid for 2 hours. The amount of coating in this product was determined as 38% (w/w).
To compare the tabletting behavior, circular 10 mm tablets were prepared from the same material for pressing, 1û containing 99~5X of pancreatin.
These tablets possess only a low breaking strength and exhibit high abrasion. An attempt to coat them in a Wurster apparatus had to be terminated because frag-ments and particles produced by abrasion did not permit 5 useful coating to be carried out.
Finely powdered active carbon was granulated in an intensive mixer, together with starch paste, pre-pared by heat;ng 10X of corn starch in water. The amount of starch paste was 15% (w/w). The moist granules were passed through a sieve of 1.6 mm mesh size, dried in a dry;ng oven and then comminuted in a suitable mill so that the fraction above 0.5 mm was 2.8X and the dust fraction below 50 jum was 1.4X.
These granules were mixed with 3% of talc to give a mixture having free-flow characteristics accord-ing to DIN 53916 which corresponded to cotangent = 1.6.
This material for pressing was converted to microtablets having a diameter of 2.0 mm and a height of 2.5 mm on a 24-punch rotary press with sensitive moni.oring of the compressive force and control of metering and with a precisely operated scraper, the compressive force used being 1.5 kN. The radius of curvature was 1.4 mm, the mean weight of 50 micro tablets was ~.2 mg and the relative standard deviation was 2.5% the microtablets met the pharmacopeia re-- 13 - O.Z. OOS0/37177/178 qu;rements in respect of weight uniformity for tablets.
Coarse-particled propafenone was comminuted using a roll mill so that the fraction above 0.6 mm was 0.2%
and the dust fraction below 50 ~m was 0.9%.
When 1,600 9 of this propafenone had been mixed w;th 250 9 of m;crocrystalline cellulose, 100 9 of lactose, 40 9 of talc and 10 9 of magnesium stearate in a
For comparison, potassium chloride pellets were prepared on a disk pelletizer, 4% (w/w) of hydroxy-propylmethylcellulose being incorporated as a binder, and undersize particles smaller than 1.6 mm and over-size particles larger than 2.0 mm were separated off by means of a sieve. The useful fract;on was retarded by a similar process, the total amount of coating material being 5.5% (w/w) based on the coated potassium chloride pellets.
Release of potassium chloride gave the following values:
Time (h?Amount liberated in X
Comparison of the two products showed that the retarded potassium chloride microtablets used according to the invention approach ideal behavior, ie. O-order release, whereas the conventionally prepared potassium chloride exhibits substantial deviations.
Pancreatin prepared by the extraction method was comminuted on a roll mill so that the fraction above 0.5 mm was 0.8X, and the dust fraction below 50 ~m was 3.5%.
After 1,990 9 of this pancreatin had been mixed with 10 9 of magnesium stearate in a 5 liter laboratory mixer, the mixture had free-flow characteristics accord-ing to DIN 53916 which corresponded to cotangent ~ = 1.35.
4~2 ~ O.Z. 0050/37177/178 This material for pressing was converted to microtablets having a diameter of 2.25 mm and a height of 2.2 mm on an eccentric press equipped with instru-mentation, and having precise punch control, the compressive force used being 2 kN. The radius of curva~
ture was 1.7 mm. The Mean weight of 50 microtablets was 8.5 mg and the relative standard deviation was 2.4%.
The microtablets met the pharmacopeia require-ments in respect of weight uniformity for tablets.
The pancreatin microtablets were coated in a rotating perforated drum (Accela Cota 24" from Manesty, Liverpool having a drum with 0.3 mm perforations pro-duced by laser beam) with a solution of hydroxypropyl-methylcellulose phthalate in a 3: 7 isopropanol/
methylenechloride mixture with the aid of a two-material nozzle. The concentration of the solution was 7% ~w/w).
The total amount of the coating polymer was 14% (w/w), based on the coated pancreatin microtablets. 20X (w/w), based on the polymer mater;al, of dibutyl phthalate was added to the polymer solution, as a plastic;zer.
The coating procedure was controlled so that when the coating solut;on was metered at a rate of 40 ml/min, the product temperature remained at 24-26C.
The pancreatin microtablets resistant to gastric juice could be introduced into hard gelatine capsules very easily and precisely using conventional apparatuses.
The resistance to gastric juice was tested by the method described in Ph. Eur. Furthermore, the pene-tration of synthetic gastric acid into the pellets wasdetermined by measuring the content of lipase after the acid had been allowed to act for 2 hours, and comparing this content with the init;al value.
In the m;crotablets res;stant to gastric juice and produced according to the invention, no decrease in the lipase activity could be detected.
For comparison a commercial product containing 12~5~
- 12 - O.Z. OOS0/37177/178 pellets resistant to gastric juice was investigated.
Although this product was resistant to gastric juice according to the pharmacopeia specification, the lipase activity was found to decrease by 60,' after S exposure to synthetic gastric acid for 2 hours. The amount of coating in this product was determined as 38% (w/w).
To compare the tabletting behavior, circular 10 mm tablets were prepared from the same material for pressing, 1û containing 99~5X of pancreatin.
These tablets possess only a low breaking strength and exhibit high abrasion. An attempt to coat them in a Wurster apparatus had to be terminated because frag-ments and particles produced by abrasion did not permit 5 useful coating to be carried out.
Finely powdered active carbon was granulated in an intensive mixer, together with starch paste, pre-pared by heat;ng 10X of corn starch in water. The amount of starch paste was 15% (w/w). The moist granules were passed through a sieve of 1.6 mm mesh size, dried in a dry;ng oven and then comminuted in a suitable mill so that the fraction above 0.5 mm was 2.8X and the dust fraction below 50 jum was 1.4X.
These granules were mixed with 3% of talc to give a mixture having free-flow characteristics accord-ing to DIN 53916 which corresponded to cotangent = 1.6.
This material for pressing was converted to microtablets having a diameter of 2.0 mm and a height of 2.5 mm on a 24-punch rotary press with sensitive moni.oring of the compressive force and control of metering and with a precisely operated scraper, the compressive force used being 1.5 kN. The radius of curvature was 1.4 mm, the mean weight of 50 micro tablets was ~.2 mg and the relative standard deviation was 2.5% the microtablets met the pharmacopeia re-- 13 - O.Z. OOS0/37177/178 qu;rements in respect of weight uniformity for tablets.
Coarse-particled propafenone was comminuted using a roll mill so that the fraction above 0.6 mm was 0.2%
and the dust fraction below 50 ~m was 0.9%.
When 1,600 9 of this propafenone had been mixed w;th 250 9 of m;crocrystalline cellulose, 100 9 of lactose, 40 9 of talc and 10 9 of magnesium stearate in a
5 liter laboratory mixer, the resulting mixture had free-flow characteristics according to DIN 53916 which corresponded to cotangent ~ = 1.5.
This material for pressing was converted to microtablets having a diameter of 2.1 mm and a he;ght of 2.0 mm on an eccentr;c press equipped with instru-mentat;on, and having precise punch control, the compres-sive force used being 1.5 kN. The radius of curvature was 1.5 mm. The mean weight of 50 microtablets was 7.0 mg and the relat;ve standard deviat;on was 1.5X.
The propafenone microtablets were coated continuously, in a fluidized-bed spray granulator having a Wurster insert, with a 20X strength ~w/w) aqueous solution of hydroxypropylmethylcellulose (specific vis-cosity 3 mPas). The total amount of the coating polymer was 5X based on the coated propafenone micro-tablets. The coating procedure was controlled so thatthe product temperature remained at 31 - 34C.
Iron(III) oxide powder for catalytic purposes was granulated with a 20% strength (w/w) aqueous solution of polyvinylpyrrolidone (specif;c v;scos;ty K = 25) in an intensive mixer. The moist granules were passed through a sieve of 2 mm mesh size, dried in a drying oven and then comminuted using a roll mill so that the fraction above O.S mm was 3.4% and the dust fraction below 50~m was 5.8%. The amount of polyvinylpyrrolidone was 2%
(w/w) .
12~
- 14 - O.Z. 0050/37177/178 These granules were mixed with 2X of graphite to give a mixture having free-flow characteristics according to DIN 53916 which corresponded to cotangent ~ = 1.4.
This material for pressing was converted to microtablets having a diameter of 2.25 mm and a height of 2.25 mm on an eccentric press equipped with instru-mentation, and having precise punch control, the comoressive forced used being 1.2 kN. The radius of curvature was 2.0 mm. The mean weight of 50 micro-tablets was 15.8 mg and the relative standard deviation was 3.5X. The catalyst microtablets could be fluidized in a fluidized bed without any notice-able mechanical abrasion.
This material for pressing was converted to microtablets having a diameter of 2.1 mm and a he;ght of 2.0 mm on an eccentr;c press equipped with instru-mentat;on, and having precise punch control, the compres-sive force used being 1.5 kN. The radius of curvature was 1.5 mm. The mean weight of 50 microtablets was 7.0 mg and the relat;ve standard deviat;on was 1.5X.
The propafenone microtablets were coated continuously, in a fluidized-bed spray granulator having a Wurster insert, with a 20X strength ~w/w) aqueous solution of hydroxypropylmethylcellulose (specific vis-cosity 3 mPas). The total amount of the coating polymer was 5X based on the coated propafenone micro-tablets. The coating procedure was controlled so thatthe product temperature remained at 31 - 34C.
Iron(III) oxide powder for catalytic purposes was granulated with a 20% strength (w/w) aqueous solution of polyvinylpyrrolidone (specif;c v;scos;ty K = 25) in an intensive mixer. The moist granules were passed through a sieve of 2 mm mesh size, dried in a drying oven and then comminuted using a roll mill so that the fraction above O.S mm was 3.4% and the dust fraction below 50~m was 5.8%. The amount of polyvinylpyrrolidone was 2%
(w/w) .
12~
- 14 - O.Z. 0050/37177/178 These granules were mixed with 2X of graphite to give a mixture having free-flow characteristics according to DIN 53916 which corresponded to cotangent ~ = 1.4.
This material for pressing was converted to microtablets having a diameter of 2.25 mm and a height of 2.25 mm on an eccentric press equipped with instru-mentation, and having precise punch control, the comoressive forced used being 1.2 kN. The radius of curvature was 2.0 mm. The mean weight of 50 micro-tablets was 15.8 mg and the relative standard deviation was 3.5X. The catalyst microtablets could be fluidized in a fluidized bed without any notice-able mechanical abrasion.
Claims (12)
1. A cylindrical pharmaceutical microtablet having a convex upper face and convex lower face, wherein the cylinder diameter and the height independently of one another are each from 1.0 to 2.5 mm, the ratio from the said diameter to the said height being from 1:0.5 to 1:1.5, which tablet contains pancreatin as the active compound.
2. A cylindrical microtablet as defined in claim 1, wherein the diameter and the height are each from 1.5 to 2.3 mm.
3. A pharmaceutical capsule containing cylin-drical microtablets as defined in claim 1, wherein the weight of the individual tablet is from 1 to 20 mg and the relative standard deviation of the mean weight is less than 4%
(n = 50).
(n = 50).
4. A pharmaceutical capsule as defined in claim 3, wherein the weight uniformity and the disintegration of each individual tablet meet the requirements of the Euro-pean pharmacopeia for tablets.
5. A pharmaceutical microtablet as defined in claim 1, which is provided with a coating which is solu-ble in gastric juice.
6. A retarded pharmaceutical microtablet as defined in claim 1.
7. A pharmaceutical microtablet as defined in claim 6, which has been retarded by coating.
8. A pharmaceutical microtablet as defined in claim 6, which has been provided with a coating which is resistant to gastric juice.
9. A pharmaceutical microtablet as defined in claim 1, wherein the tablet consists of substantially pure pancreatin.
10. A pharmaceutical microtablet as defined in claim 1, wherein the radius of curvature, r, of said convex upper and lower faces is from 0.6 to 1.5 times the diameter of the cylinder.
11. A pharmaceutical capsule as defined in claim 3 wherein the weight of the individual tablet is from 5 to 10mg and the relative standard deviation of the mean weight is less than 4% (n=50).
12. A pharmaceutical microtablet as defined in claim 1 wherein the cylinder diameter and the height independently of one another are each from 2.0 to 2.3mm, the ratio from the said diameter to the said height being from 1:0.9 to 1:11.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEG8418439.6 | 1984-06-19 | ||
| DE19848418439 DE8418439U1 (en) | 1984-06-19 | 1984-06-19 | Cylindrical micro-tablet |
| DEP3422619.2 | 1984-06-19 | ||
| DE19843422619 DE3422619A1 (en) | 1984-06-19 | 1984-06-19 | Cylindrical microtablets |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1248452A true CA1248452A (en) | 1989-01-10 |
Family
ID=25822242
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000484346A Expired CA1248452A (en) | 1984-06-19 | 1985-06-18 | Cylindrical microtablets |
Country Status (5)
| Country | Link |
|---|---|
| US (2) | US4797287A (en) |
| EP (1) | EP0166315B1 (en) |
| JP (1) | JPH06694B2 (en) |
| CA (1) | CA1248452A (en) |
| DE (1) | DE3572440D1 (en) |
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| NZ233403A (en) * | 1989-04-28 | 1992-09-25 | Mcneil Ppc Inc | Simulated capsule-like medicament |
| IL95574A (en) | 1989-09-09 | 1994-11-11 | Knoll Ag | Colestyramine preparation |
| DE3937455A1 (en) * | 1989-11-10 | 1991-05-16 | Nordmark Arzneimittel Gmbh | ANTACIDATE TABLETS |
| PH30058A (en) * | 1989-11-24 | 1996-11-08 | Biochemie Gmbh | Pancreation preparations |
| IT1246382B (en) * | 1990-04-17 | 1994-11-18 | Eurand Int | METHOD FOR THE TARGETED AND CONTROLLED DELIVERY OF DRUGS IN THE INTESTINE AND PARTICULARLY IN THE COLON |
| US5204162A (en) * | 1991-10-03 | 1993-04-20 | Corning Incorporated | Non-spherical bodies |
| US5262172A (en) * | 1992-06-19 | 1993-11-16 | Digestive Care Inc. | Compositions of gastric acid-resistant microspheres containing buffered bile acids |
| US5460812A (en) * | 1992-06-22 | 1995-10-24 | Digestive Care Inc. | Compositions of digestive enzymes and salts of bile acids and process for preparation thereof |
| US5578304A (en) * | 1992-06-22 | 1996-11-26 | Digestive Care Inc. | Compositions of digestive enzymes and salts of bile acids and process for preparation thereof |
| US5234697A (en) * | 1992-06-22 | 1993-08-10 | Digestive Care Inc. | Compositions of gastric acid-resistant microspheres containing salts of bile acids |
| US5260074A (en) * | 1992-06-22 | 1993-11-09 | Digestive Care Inc. | Compositions of digestive enzymes and salts of bile acids and process for preparation thereof |
| US5415872A (en) * | 1992-06-22 | 1995-05-16 | Digestive Care Inc. | Compositions of gastric acid-resistant microspheres containing salts of bile acids |
| US5302400A (en) * | 1992-06-22 | 1994-04-12 | Digestive Care Inc. | Preparation of gastric acid-resistant microspheres containing digestive enzymes and buffered-bile acids |
| DE4239442C2 (en) * | 1992-11-24 | 2001-09-13 | Sebo Gmbh | Use of an adsorbent material modified with polynuclear metal oxide hydroxides for the selective elimination of inorganic phosphate from protein-containing liquids |
| US5352682A (en) * | 1993-03-08 | 1994-10-04 | Digestive Care Inc. | Compositions containing salts of bile acid-aminosalicylate conjugates |
| US5750104A (en) * | 1996-05-29 | 1998-05-12 | Digestive Care Inc. | High buffer-containing enteric coating digestive enzyme bile acid compositions and method of treating digestive disorders therewith |
| DE19739746A1 (en) | 1997-09-10 | 1999-03-11 | Basf Ag | Tablet catalyst |
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| AR034813A1 (en) * | 2001-07-20 | 2004-03-17 | Novartis Ag | PHARMACEUTICAL COMPOSITIONS AND USE OF THE SAME |
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| US20060222705A1 (en) * | 2005-03-31 | 2006-10-05 | Flanner Henry H | Pharmaceutical tablet and apparatus and method for making |
| US9044049B2 (en) * | 2005-04-29 | 2015-06-02 | Philip Morris Usa Inc. | Tobacco pouch product |
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| US20070009591A1 (en) * | 2005-07-07 | 2007-01-11 | Trivedi Jay S | ACE inhibitor formulation |
| PT1762231E (en) * | 2005-08-19 | 2010-12-13 | Verla Pharm | Sustained release magnesium microtablets |
| US8685478B2 (en) | 2005-11-21 | 2014-04-01 | Philip Morris Usa Inc. | Flavor pouch |
| US8865743B2 (en) | 2006-01-06 | 2014-10-21 | Acelrx Pharmaceuticals, Inc. | Small volume oral transmucosal dosage forms containing sufentanil for treatment of pain |
| US8202535B2 (en) * | 2006-01-06 | 2012-06-19 | Acelrx Pharmaceuticals, Inc. | Small-volume oral transmucosal dosage forms |
| DE102006006532B4 (en) * | 2006-02-10 | 2007-11-08 | Biogenerics Pharma Gmbh | Pharmaceutical preparation |
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| PT2319804E (en) * | 2006-12-14 | 2014-11-24 | Novartis Ag | Iron(iii)-carbohydrate based phosphate adsorbent |
| US8616221B2 (en) | 2007-02-28 | 2013-12-31 | Philip Morris Usa Inc. | Oral pouch product with flavored wrapper |
| US9888712B2 (en) * | 2007-06-08 | 2018-02-13 | Philip Morris Usa Inc. | Oral pouch products including a liner and tobacco beads |
| WO2009010881A2 (en) | 2007-07-16 | 2009-01-22 | Philip Morris Products S.A. | Oral pouch products with immobilized flavorant particles |
| US8424541B2 (en) | 2007-07-16 | 2013-04-23 | Philip Morris Usa Inc. | Tobacco-free oral flavor delivery pouch product |
| US8119173B2 (en) * | 2007-07-16 | 2012-02-21 | Philip Morris Usa Inc. | Method of flavor encapsulation through the use of a drum coater |
| WO2009010876A2 (en) | 2007-07-16 | 2009-01-22 | Philip Morris Products S.A. | Oral pouch product having soft edge and method of making |
| WO2010043950A2 (en) | 2008-10-15 | 2010-04-22 | Aizant Drug Research Solutions Private Limited | Propafenone extended release composition |
| US8377215B2 (en) | 2008-12-18 | 2013-02-19 | Philip Morris Usa Inc. | Moist botanical pouch processing |
| US8863755B2 (en) * | 2009-02-27 | 2014-10-21 | Philip Morris Usa Inc. | Controlled flavor release tobacco pouch products and methods of making |
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| US8747562B2 (en) | 2009-10-09 | 2014-06-10 | Philip Morris Usa Inc. | Tobacco-free pouched product containing flavor beads providing immediate and long lasting flavor release |
| ITBO20110732A1 (en) * | 2011-12-19 | 2013-06-20 | I M A Ind Macchine Automatic He S P A | DRUM AND RELATIVE METHOD OF REALIZATION |
| WO2014043553A1 (en) * | 2012-09-15 | 2014-03-20 | Slaboden Jeffery K | Dissolvable tablet |
| TWI608849B (en) * | 2014-06-16 | 2017-12-21 | 國邑藥品科技股份有限公司 | High drug load pharmaceutical compositions with controllable release rate and production methods thereof |
| GB201520007D0 (en) | 2015-11-12 | 2015-12-30 | Sensidose Ab | Compacted powder |
| JP6430679B2 (en) * | 2016-04-01 | 2018-11-28 | 株式会社クレハ | Tablet containing spherical adsorption charcoal for oral administration |
| TWI701055B (en) * | 2016-04-01 | 2020-08-11 | 吳羽股份有限公司 | Tablet containing spherical adsorption carbon for oral administration and its manufacturing method |
| CN107441051B (en) * | 2016-05-30 | 2022-09-16 | 北京科信必成医药科技发展有限公司 | Propafenone hydrochloride micro-tablet and preparation method thereof |
| CN114392240B (en) * | 2022-01-20 | 2023-12-19 | 北京微智瑞医药科技有限公司 | Vitamin C orally disintegrating micro-tablet and preparation method thereof |
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|---|---|---|---|---|
| US3175521A (en) * | 1961-02-23 | 1965-03-30 | Schering Corp | Apparatus for punching miniature tablets |
| NL297357A (en) * | 1962-08-31 | |||
| US3473490A (en) * | 1966-01-17 | 1969-10-21 | Camillo Corvi Mora | Producing chronoactive pharmaceutical granules |
| GB1204580A (en) * | 1968-10-05 | 1970-09-09 | Aspro Nicholas Ltd | Pharmaceutical dosage forms |
| DE2033121A1 (en) * | 1970-07-03 | 1972-03-16 | Institutul Pentrü Controlul de Stat al Medicamentului si Cercetari Farmaceutice, Bukarest | Microtablets for antibiogrammes - contg an adsorbent to retain excess moisture |
| IE48715B1 (en) * | 1978-12-22 | 1985-05-01 | Elan Corp Plc | New galencial forms for administration of medicaments by oral route,with programmed release and processes for preparing same |
| US4294819A (en) * | 1980-08-18 | 1981-10-13 | Bristol-Myers Company | Alkaline analgesic capsule |
| US4339428A (en) * | 1980-08-18 | 1982-07-13 | Bristol-Myers Company | Capsule product containing high dosage of aspirin in powder or granulated form and alkaline tablet or pellet comprising magnesium carbonate, calcium carbonate and a magnesium dry component |
| GB2091554B (en) * | 1981-01-13 | 1984-09-12 | Mitsui Toatsu Chemicals | Rod like moulded drug |
-
1985
- 1985-06-13 EP EP85107311A patent/EP0166315B1/en not_active Expired
- 1985-06-13 DE DE8585107311T patent/DE3572440D1/en not_active Expired
- 1985-06-18 CA CA000484346A patent/CA1248452A/en not_active Expired
- 1985-06-19 JP JP60132106A patent/JPH06694B2/en not_active Expired - Lifetime
-
1987
- 1987-04-30 US US07/045,194 patent/US4797287A/en not_active Expired - Lifetime
-
1988
- 1988-06-24 US US07/210,852 patent/US4828843A/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| EP0166315A3 (en) | 1987-03-25 |
| JPS6140212A (en) | 1986-02-26 |
| EP0166315A2 (en) | 1986-01-02 |
| DE3572440D1 (en) | 1989-09-28 |
| US4797287A (en) | 1989-01-10 |
| EP0166315B1 (en) | 1989-08-23 |
| JPH06694B2 (en) | 1994-01-05 |
| US4828843A (en) | 1989-05-09 |
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