CA2117351C - Preparation of tablets of increased strength - Google Patents
Preparation of tablets of increased strengthInfo
- Publication number
- CA2117351C CA2117351C CA002117351A CA2117351A CA2117351C CA 2117351 C CA2117351 C CA 2117351C CA 002117351 A CA002117351 A CA 002117351A CA 2117351 A CA2117351 A CA 2117351A CA 2117351 C CA2117351 C CA 2117351C
- Authority
- CA
- Canada
- Prior art keywords
- tablet
- tablets
- binder
- pharmaceutically active
- active agent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
Abstract
Tablets of increased strength are manufactured by combining and compressing a meltable binder, excipients and a pharmaceutically active agent into a tablet, melting the binder in the tablet, and then solidifying the binder.
Description
C~ 21 1 7~5 3 . ,~ , 1 PREPARATION OF TABLETS OF INCREASED STRENGTH
This invention relates to a method for the preparation of a tablet of increased strength, and to tablets when made by said method. The method is particularly useful in the manufacture of tablets, that contain pharmaceutically active agents which are difficult to cG",press; that are soft and chewable; and that are fast-disintegrating and porous.
Pharmaceuticals are often administered orally in the form of a tablet. The tablet is usually manufactured by combining tablet ing~ nls and compressing the combined ingredients in a mold. Due to the compression, tablets of mechanical stability are formed capable of withstanding disintegration during handling including removal from the mold, packing and transport. Mechanical stability depends on many factors, one of which is the compressibility of the pharmaceutically active agent in the tablet, particularly when large amounts of the agent are contained in a single tablet, and another one of which is the porosity of the tablet.
The porosity of a tablet relates to ease of tablet disintegration not only during handling but also during administration whether orally or rectally, and whether disintegration takes place in the mouth, or in the stomach. An increase in the disintegration rate in the mouth facilitates adl"inisl.alion to patients in general, and to the very young, the elderly, and non-human animals, in particular. Ad,.,ini~llation is also facilitated by use of soft chewable tablets. Since such tablets are soft, having a hardness of less than about 6 kp, tablet friability is often a problem.
Tablets of increased porosity and disintegration rates are disclosed in United States Patent Nos. 3,885,026,4,134,943 and 4,305,502. These patents suggest various ways of dealing with the problems associated with the handling of such highly porous tablets. U.S. Patent No. 4,305,502 suggests reducing the amount of handling of the tablets by forming them in situ in a substrate having depressions for deposition of tablets. However, removal of tablets from these depressions is more difficult than simple removal from a bottle or tube.
U.S. Patent Nos. 3,885,026 and 4, 134,943 suggest increasing tablet strength of porous tablets by first compressing the tablet and then volatilizing a readily vol~ti~ hle solid adjuvant incorporated in the tablet to attain desired porosity. The maximum porosity obtained according to U.S. Patent No. 3,885,026 is 50% and preferably 10 to 30%.
French patent 2,231,365 and Belgian patent 668121 disclose water insoluble meltable binders used in the manufacture of sustained release tablets.
The invention provides a method for the preparation of a tablet of increased strength by including the steps of (a) combining and compressing a meltable binder, at least one excipient, and a pharmaceutically active agent into a tablet, (b) melting said binder in said tablet, and (c) solidifying said binder.
Figure 1 shows surface views of a tablet of the invention and a comparison tablet under a scanning electron microscope at 100X magnification.
Figure 2 shows a friability comparison between Tablet F according to the invention and comparison Tablet E.
In the context of the invention, a tablet of increased strength refers to a tablet having a higher tablet strength than one made by blending the same tablet ingredients followed by compressing in a conventional tablet compressor.
The tablet ingredients of use in the present invention include a meltable binder, at least one excipient, and a pharmaceutically active agent.
The meltable binder increases the strength of the final tablet when processed according to the method of-the invention. The binder has a melting point generally ranging from about 20~C to about 100~C, preferably from about 40~C to about 70~C.
The melting point of the binder is usually at least about 20~C since the mixing of the ingredients is usually carried out at about 20~C and the binder is solid at the mixing temperature. Of course, if mixing is carried out at lower temperatures, a lower melting binder may be used which is solid at that temperature.
The melting point of the binder is usually not higher than about 100~C since themelting of the binder should be at a temperature at which the activity of the pharmaceutically active agent is not adversely affected. For instance, the melting of the binder should be at a temperature lower than the decomposition temperature of the pharmaceutically active agent as well as any one of the excipients present.
The amount of the meltable binder in the tablet ranges from about 5% to about 40% by weight, preferably from about 8% to about 25% by weight, based on the weight of the tablet. The specific amount depends on several factors, e.g., on use of SU~6Tl~ E S~T
WO 93JI3758 PCI'/US92/07497 -3- a~ ~ 7351 excessiYe amounts of the meltable binder the tablet may deform during melting whereas on use of insu~ficient arnounts the desired i"crease in strength may not be attained.
The meltable binders of the inYention may be nonwatersoluble or water soluble.
Suitable nonwatersoluble meltable binders include natural fats such as cocoa~butter, monoglycerides such as 1-monolaurin (m.p. 63~C), 2-monolaurin (m.p. 51~C), 1-monopalmitin (m.p.77~C), and 2~monopalmitin (m.p.68.5~C), diglycerides such as 1,2-dipalmitin (m.p. 63.5~C), 1,3 dipalmitin (m.p. 74~C), 1,2~istearin (m.p. 71~C), 1,~
distearin (m.p.80~C) and 1,3-dioleostearin (m.p.49~C), triglycerides such as tripalmitin (m.p.56~C)andtrimyristin(m.p.46.5~C),ethoxylatedfattyesterssuchaspolyethylene (12) distearate and polyoxyethylene (20) sorbitan tristearate, and natural waxes such as carnauba wax (m.p. 83-86~C), beeswax (m.p.62~C), and paraffins (m.p. 52-74~C).
Suitable water soluble meltable binders of use in the invention include polyethylene glycols (PEG) having molecular weights ranging from about 1,500 to about 20,000 such as PEG 3350 (m.p. 58~C) and PEG 8000 (m.p. 62~C), sucrose esters such as sucrosemonostearate (m.p.49-56~C), and sucrose monopalmitate (m.p.4048~C), ethoxylated fatty acids such as polyoxyethylene (40) stearate (m.p. 47~C) (Myrj -52S), and ethoxylated alcohols such as polyoxyethylene (23) lauryl ester (m.p.3840~C). Specitic meltable water-soluble binders are PEG 3350 and polyoxyethylene (40) stearate. The rneltable water-soluble binders of use in the invention are of particular use in the preparation of tablets having increased disintegration rates in the mouth, e.g., rapid disintegration rates of less than ten seconds, for instance 1 to 5 seconds.
The meltable binder may be combined with the excipient or excipients and the pharmaceutically active agent in ~ny sequence. The binder may be combined in dryform or in a suitable solvent such as alcohol, isopropanol or water. The dissolved binder on addition to the remaining tablet ingredients forms a wet granulation. If desired, the pharmaceutically act~ve agent is added after drying of the wet granulation.
Usually, the combined tablet ingredients are milled and mixed with a tabletting lubricant before the dry granules are compressed into tablets.
The excipients of use in the invention are generally known in the art, e.g., as described in Remington's Pharmaceutical Sciences, 18th Edition (1990), particularly pages 1633 to 1638. They impart necessary processing and compression characteristics either to the tablet tormulation before tabletting, or to the finished tablet.
~Trademark ~' WO g3/13758 PCI/US92/07497 CA2] 17351 Examples of excipients are diluents, binders, lubricants, flavors, and sweetening agents.
Specific diluents of use in the invention are water soluble diluents such as mannitol, xylitol, sucrose, lactose, and sodium chloride. Suitable binders of use in the invention.
in addition to the meltable binder of use in the invention, impart cohesive properties 5 and include starch, gelatin, microcrystalline cellulose and sugars such as sucrose, glucose, dextrose, and lactose. As is clear from the above, the same excipient may be used for different purposes within the same tablet formulation.
In one embodiment of the invention, a disintegrating agent is present to increase the disintegration rate of the tablet after oral intake. Examples of disintegrating agents 10 are cellulose such as carboxymethylcellulose, starches, clay, algins, gums and crosslinked polymers, such as crosslinked polyvinylpyrrolidone (PVP-XL).
In another embodiment of the invention, a volatilizable component is present in the tablet formation to manufacture porous tablets. After combination and compression of the tablet ingredients, the volatilizable component is removed from the tablets by 15 heating at atmospheric or reduced pressure to form porous tablets. Suitable volatilizable components include sublimable materials such as menthol, camphor, urea, and vanillin, and materials that decompose at or below the melting point of the binder such as ammonium bicarbonate. The amount of volatilizable material ranges from about 1% to about 95% by weight, based on the weight of the combined tablet 20 ingredients. For instance, when using ammonium bicarbonate, the amount is usually from about 50% to about 90% by weight, and when using menthol, the amount rangesfrom about 30% to about 55% by weight. Preferably, the volatilizable material isremoved during melting step (b) according to the invention when the compressed tablets are heated above the melting point of the meltable binder for a period of time 25 sufficient to melt the meltable binder and to remove the volatilizable material. When using menthol, removal thereof is by heating to about 40~C under vacuum.
The terms "porosity" and "% porous" of a tablet as used herein refer to the voidspaces created by the removal of the volatilizable component of the tablet. Since removal of the volatilizable component does not affect the inner or outer dimensions 30 of the tablet, the porosity as defined above is the percentage by weight of the vols~tili7~hle component in the original tablet formation.
In general, the melting step (b) to melt the binder in the tablet is for a period of time sufficient to melt the meltable binder. The binder solidifies after the tablets are WO 93/137~8 PCI/US92/07497 ~,~21 1 7351 cooled to ambient temperature. The melting and solidifying of the meltable binder in the tablet strengthens the bonding among the tablet particles by filling of the minor cracks in the tablet matrix, as shown in the scanning electron micrographs of Figure 1.
The tablets prepared by the method of the invention may be coated with a thin 5 layer of a coating material to improve the surface integrity of the tablet. Suitable coating materials include disaccharides such as sucrose, polysaccharides such asmaltodextrins and pectin, and cellulose derivatives such as hydroxypropylmethylcellulose and hydroxypropylcellulose.
The pharmaceutically active agent of use in the invention may be any compound 10 that is pharmaceutically active on oral intake or on rectal administration. Examples of such agents include antifungal agents such as flucon~ole, pain relievers such asacetaminophen and acetylsalicylic acid, antihistamines such as diphenhydramine, doxylamine succinate and meclizine, decongestants such as pseudoephedrine hydrochloride, antibiotics such as ~ithromycin and erythromycin, penicillins such as 15 sultamicillin tosylate and amoxicillin trihydrate, enzyme inhibitors such as sulbactam sodium, antihypertensives such as nifedipine, dox~osin mesylate and amlodipine besylate, antidiabetics such as glipizide, bronchodilators such as pirbuterol hydrochloride and theophylline, anti-inflammatory agents such as piroxicam and tenidap, anti-dep~-essants such as sertraline hydrochloride, antacids such as calcium 20 carbonate and magnesium oxide, and non-sedative antihistamines such as cetirizine.
It is understood that the pharmaceutically active agents of use in the invention include nutritional and dietary supplements, for example, vitamins.
The following examples illustrate the invention. The strength of the tablets wasmeasured with a tablet hardness tester, particularly the Schleuniger Hardness Tester, 25 and a friability tester, particularly the Vanderkamp Friabilator. The hardness of the tablet is the force in kp (kilopond) required to break a tablet. The higher the kp value, the stronger the tablet is. Friability is the percentage of the tablet weight loss after a certain number of revolutions in the Vanderkamp Friabilator. The lower the percentage is, the stronger the tablet. As used in the Examples, the term Ufailedu refers to tablets 30 which break during friability testing.
W O 93/13758 PC~r/US92/07497 54.5% Porous Tablets Tablet A: The following ingredients were blended and compressed into tablets of 0.5 inch diameter and 0.130 inch thickness . These tablets were then heated at 72 ~ C
5 under vacuum for 18 hours. This temperature is above the melting point of PEG 3350, 58~C. A 54.5% porous structure was formed after the ammonium bicarbonate was removed by thermal decomposition.
INGREDIENTS OF TABLET A MG/TABLET
1 Ammonium bicarbonate (pore former)(300.00) later removed 2 Mannitol 168.00 3 Bananaflavor 8.00 4 Aspartame 4.00 PEG 3350 20.00 6 PVP-XL 40.00 7 Sodium stearyl fumarate 10.00 TOTAL 250.00 Tablet B: Tablets of 0.5 inch diameter and 0.125 inch thickness were made 20 based on the following formulation which contained no PEG 3350. The tablet size, weight, and the relative amounts (weight to weight ratios) of the non-volatilizable components (ingredients 2 to 6) remained the same as in Tablet A in order to make a fair comparison between the two tablets. The porosity of the comparative tablet was therefore maintained at 54.5%.
WO g3/13758 PCI'~US92/07497 CA21 l 7351 INGREDIENTS OF TABLET B MG/TABLET
Ammonium bicarbonate (pore former)(300.00) later removed 2 Mannitol 183.27 3 Bananaflavor 8.73 4 Aspartame 4.36 6 PVP-XL 43.64 7 Sodium stearyl fumarate 10.00 ~ TOTAL 250.00 10 The physical characterization of these two tablets is shown in Table 1.
.DiameterThickness Hardness Friability (%) (inch) (inch) (kp) 100 revolutions Tablet A 0.5 0.130 4.0 0.8 Tablet B 0.5 0.125 2.4 6.8 The tablet strength of Tablet A is much better than that of Tablet B because of the presence of melted and solidified PEG 3350.
38% Porous Tablets Tablet C: The following ingredients were blended and compressed into tablets of 0.5 inch diameter and 0.114 inch thickness. These tablets were then heated at 42~C
under vacuum. A 38% porous structure was formed after the menthol was removed bysublimation.
Tablet D: These tablets were made by further heating Tablet C at 72~C under vacuum for one hour.
WO 93/13758 PCr/US92/07497 INGREDIENTS OF TABLETS C AND D MG/rABLET
Menthol (pore former) (150) later removed 2 Mannitol 150 3 Banana flavor 8 4 Aspartame - 4 7 Sodium stearyl fumarate 8 ~ TOTAL (395) 245 The physical characterization of these two tablets is shown in Table 2.
, . , ., ~, . . .
: ':.',~/'''!~:/..: 't;. Diameter Thickness Hardness Friability (%) .,,,,t,,''~ (inch) (inch) (kp) 100 revolutions Tablet C 0.5 0.114 below scale Failed Tablet D 0.5 ~ 0.114 2.7 0.4 The improvement in both hardness and friability was dramatic with the tablets (Tablet D) that were heated above the melting point of PEG 3350 (58~C). The amount of void space in Tablet D was not compromised by further heating and melting of PEG
3350. This is demonstrated by the microscopic views of both tablets in Figure 1. In comparing the photographs of the two tablets, it is evident that the melted PEG 3350 had filled and connected the hairline cracks of the type visible in Tablet C.
54.5% Porous Tablets Tablet E: The following ingredients were blended and compressed into tablets of 0.5 inch diameter and 0.168 inch thickness. These tablets were then heated at 40~ C
under vacuum for 18 hours. A 54.5% porous structure was formed after the mentholwas removed by sublimation.
Tablet F: These tablets were made by further heating Tablet E at 70OC under vacuum for 16 hours.
WO 93/13758 PCr/US92/07497 INGREDIENTS OF TABLETS E AND F MG/TABLET
Menthol (pore former) (300) later removed 2 Mannitol 168 3 Banana flavor 8 4 As~. artame 4 7 Sodium stearyl fumarate 10 ~ TOTAL (550) 250 The physical characterization of these two tablets is shown in Table 3.
,. . .............
' ~Diameter ThicknessHardnessFriability (%) .~ (inch) (inch) (kp) 25 revolutions ...............
Tablet E 0.5 0.168below scale failed Tablet F 0.5 0.168below scale 8.5 The difference in friability of both tablets due to the melting and solidifying of PEG 3350 is demonstrated in Figure 2, which is a plot of the tablet weight loss as a function of the number of revolutions in the Vanderkamp friabilator.
75% Porous Tablets Tablet G: The following ingredients 1, 2, 3, 5, 6, and 7 were blended and then wet-granulated with a solution of PEG 3350 (ingredient 4) in ethanol. The dry granulates were milled and blended with sodium stearyl fumarate (ingredient 8). The 25 final blend was compressed into tablets of 0.625 inch diameter. These tablets were then heated at 70~C under vacuum. A 75% porous structure was formed after the ammonium bicarbonate was removed during the heating by thermal decomposition.
-10- 2~ 35~
INGREDIENTS OF TABLET G MGITABLET
Ammonium bicarbonate (pore former) (600) later removed 2 Mànnitol 90 3 Avicel- PH101 (microcrystalline cellulose) 35 6 Aspartame 15 7 Bananaflavor 15 8 Sodium stearyl fumarate 15 ~ TOTAL (880~ 200 The friability of the tablets after 10 revolutions in the Vanderkamp friabilator was 4%.
Tablets Not Containinq Volatilizable Component Tablet H: The following ingredients were blended and compressed into tablets of 0.625 inch diameter and 0.2 inch thickness.
Tablet l: These tablets were made by heating tablet H at 70~C for 3 hours.
These tablets remained non-porous in the absence of a volatilizable component.
INGREDIENTS OF TABLETS H AND I MG/TABLET
Lactose 733.33 2 PEG 3350 129.4 3 Sodium stearyl fumarate 17.27 ~ TOTAL 880 The physical characterization of these two tablets is shown in Table 4.
Trademark ~' WO g3/13758 PCI/US92/07497 -1 1 - 21 ~
Diameter Thickness HardnessFriability (%) (inch) (inch) (kP)100 revolutions Tablet H 5/8 0.2 3.5 failed after 20~rev.
Tablet 1 5/8 0.2 3.5 0.5 The friability of Tablet I was improved because of the melting and then solidifying of PEG 3350.
36% Porous Tablets Tablet J: The following ingredients were blended and compressed into tablets of 0.5 inch diameter and 0.125 inch thickness. These tablets were then heated at 40~C
under vacuum for 18 hours. A 36% porous structure was formed after the menthol was removed by sublimation.
Tablet K: These tablets were made by further heating Tablet J at 70~C under 15 vacuum for 4 hours.
INGREDIENTS OF TABLETS J AND K MG/TABLET
Menthol (pore former) (150) later removed 2 Mannitol 150 3 PVP-XL .- 15 4 MyrJ--52S 60 Piroxicam 20 6 Bananaflavor 8 7 Aspartame 4 8 Sodium stearyl fumarate 8 25 t~ -X~ ' ' ' TOTAL (415) 265 The physical characterization of these two tablets is shown in Table 5.
Trademark WO 93/13758 PCr~US92/07497 .~
~ ~73~ ~
~_Diameter Thickness Hardness Friability (%) ~_ (inch) (inch) (kp) 80 revolutions Tablet J 0.5 0.125 below scaleFailed after 20 rev.
Table K 0.5 0.125 2 kp 0.0 Both hardness and friability of Tablet K were improved because of the metting and solidifying of Myrj-52S.
75% Porous Tablets Tablet L: The Sollowing ingredients 1, 2, 3, 4, 8 and 9 were blended and then wet-granulated with a solution of ingredients 5 and 6 in isopropanol. The dry granules were milled and blended with ingredient 7. Finally, ingredient 10 was mixed with the blend. The final blend was compressed into tablets of 0.625 inch diameter. Thesetablets were then heated at 65~C under vacuum for 18 hours to remove ammonium 15 bicarbonate by thermal decomposition. A 75% porous structure was formed.
INGREDIENTS OF TABLET L MGITABLET
- 1 Ammonium bicarbonate (pore former) (600) later removed 2 Mannitol 29 4 Avicel PH 105 35 6 Klucel EF 5 7 Microencapsulated fluconazole 71 8 Bananaflavor 15 9 Aspartame 15 10 Sodium stearyl fumarate 15 TOTAL (800) 200 The friability of Tablet L was 0.0% after 10 revolutions in the Vanderkamp 30 friab~ilator.
~Trad~m~rk WO 93/137~8 PCI'/US92/07497 ~A2 1 1 7 351 Example 8 Tablets Not Containing Volatilizable Component Tablet M: The following ingredients were blended and compressed into tablets of 0.5 inch diameter and 0.104 inch thickness.
Tablet N: These tablets were made by further heating Tablet M at 83~C for one hour.
INGREDIENTS OF TABLETS M AND N MG/TABLET
Xylitol 322 2 Carnauba wax 40 3 Doxylamine succinate 25 4 Grapeflavor 5 Magnesium stearate 8 ~,~ TOTAL 400 15The physical characterization of these two tablets is shown in Table 6.
_~ Diameter Thickness HardnessFriability (%) (inch) (inch) (kp)100 revolutions Tablet M 0.5 0.104 3 kp 0.96 20Tablet N 0.5 0.104 8 kp 0.00 Both hardness and friability of Tablet N were improved because of the melting and solidifying of carnauba wax.
Example 9 25Tablets Not Containinq Volatilizable Component Tablet O: The following ingredients were blended and compressed into tablets of 0.5 inch diameter and 0.090 inch thickness Tablet P: These tablets were made further heating Tablet M at 60~C for one hour.
WO 93/13758 PCI'/US9V07497 -14~ 3 7 ~
INGREDIENTS OF TABLETS M AND N MG/TABLET
Lactose 241.4 3 Tenidap~ 90.6 4 Explotab (sodium starch glycolate) 20 Magnesium stearate 8 The physical characterization of these two tablets is shown in Table 7.
............. .......
Diameter Thickness Hardness Friability (%) ... ,.~*~ (inch) (inch) (kp) 100 revolutions Tablet 0 0.5 0.104 3 kp failed at 10 rev Tablet P 0.5 0.104 8 kp 0.02 Both hardness and friability of Tablet K were improved because of the melting and solidifying of PEG 3350.
*TradP.n~rk ~'
This invention relates to a method for the preparation of a tablet of increased strength, and to tablets when made by said method. The method is particularly useful in the manufacture of tablets, that contain pharmaceutically active agents which are difficult to cG",press; that are soft and chewable; and that are fast-disintegrating and porous.
Pharmaceuticals are often administered orally in the form of a tablet. The tablet is usually manufactured by combining tablet ing~ nls and compressing the combined ingredients in a mold. Due to the compression, tablets of mechanical stability are formed capable of withstanding disintegration during handling including removal from the mold, packing and transport. Mechanical stability depends on many factors, one of which is the compressibility of the pharmaceutically active agent in the tablet, particularly when large amounts of the agent are contained in a single tablet, and another one of which is the porosity of the tablet.
The porosity of a tablet relates to ease of tablet disintegration not only during handling but also during administration whether orally or rectally, and whether disintegration takes place in the mouth, or in the stomach. An increase in the disintegration rate in the mouth facilitates adl"inisl.alion to patients in general, and to the very young, the elderly, and non-human animals, in particular. Ad,.,ini~llation is also facilitated by use of soft chewable tablets. Since such tablets are soft, having a hardness of less than about 6 kp, tablet friability is often a problem.
Tablets of increased porosity and disintegration rates are disclosed in United States Patent Nos. 3,885,026,4,134,943 and 4,305,502. These patents suggest various ways of dealing with the problems associated with the handling of such highly porous tablets. U.S. Patent No. 4,305,502 suggests reducing the amount of handling of the tablets by forming them in situ in a substrate having depressions for deposition of tablets. However, removal of tablets from these depressions is more difficult than simple removal from a bottle or tube.
U.S. Patent Nos. 3,885,026 and 4, 134,943 suggest increasing tablet strength of porous tablets by first compressing the tablet and then volatilizing a readily vol~ti~ hle solid adjuvant incorporated in the tablet to attain desired porosity. The maximum porosity obtained according to U.S. Patent No. 3,885,026 is 50% and preferably 10 to 30%.
French patent 2,231,365 and Belgian patent 668121 disclose water insoluble meltable binders used in the manufacture of sustained release tablets.
The invention provides a method for the preparation of a tablet of increased strength by including the steps of (a) combining and compressing a meltable binder, at least one excipient, and a pharmaceutically active agent into a tablet, (b) melting said binder in said tablet, and (c) solidifying said binder.
Figure 1 shows surface views of a tablet of the invention and a comparison tablet under a scanning electron microscope at 100X magnification.
Figure 2 shows a friability comparison between Tablet F according to the invention and comparison Tablet E.
In the context of the invention, a tablet of increased strength refers to a tablet having a higher tablet strength than one made by blending the same tablet ingredients followed by compressing in a conventional tablet compressor.
The tablet ingredients of use in the present invention include a meltable binder, at least one excipient, and a pharmaceutically active agent.
The meltable binder increases the strength of the final tablet when processed according to the method of-the invention. The binder has a melting point generally ranging from about 20~C to about 100~C, preferably from about 40~C to about 70~C.
The melting point of the binder is usually at least about 20~C since the mixing of the ingredients is usually carried out at about 20~C and the binder is solid at the mixing temperature. Of course, if mixing is carried out at lower temperatures, a lower melting binder may be used which is solid at that temperature.
The melting point of the binder is usually not higher than about 100~C since themelting of the binder should be at a temperature at which the activity of the pharmaceutically active agent is not adversely affected. For instance, the melting of the binder should be at a temperature lower than the decomposition temperature of the pharmaceutically active agent as well as any one of the excipients present.
The amount of the meltable binder in the tablet ranges from about 5% to about 40% by weight, preferably from about 8% to about 25% by weight, based on the weight of the tablet. The specific amount depends on several factors, e.g., on use of SU~6Tl~ E S~T
WO 93JI3758 PCI'/US92/07497 -3- a~ ~ 7351 excessiYe amounts of the meltable binder the tablet may deform during melting whereas on use of insu~ficient arnounts the desired i"crease in strength may not be attained.
The meltable binders of the inYention may be nonwatersoluble or water soluble.
Suitable nonwatersoluble meltable binders include natural fats such as cocoa~butter, monoglycerides such as 1-monolaurin (m.p. 63~C), 2-monolaurin (m.p. 51~C), 1-monopalmitin (m.p.77~C), and 2~monopalmitin (m.p.68.5~C), diglycerides such as 1,2-dipalmitin (m.p. 63.5~C), 1,3 dipalmitin (m.p. 74~C), 1,2~istearin (m.p. 71~C), 1,~
distearin (m.p.80~C) and 1,3-dioleostearin (m.p.49~C), triglycerides such as tripalmitin (m.p.56~C)andtrimyristin(m.p.46.5~C),ethoxylatedfattyesterssuchaspolyethylene (12) distearate and polyoxyethylene (20) sorbitan tristearate, and natural waxes such as carnauba wax (m.p. 83-86~C), beeswax (m.p.62~C), and paraffins (m.p. 52-74~C).
Suitable water soluble meltable binders of use in the invention include polyethylene glycols (PEG) having molecular weights ranging from about 1,500 to about 20,000 such as PEG 3350 (m.p. 58~C) and PEG 8000 (m.p. 62~C), sucrose esters such as sucrosemonostearate (m.p.49-56~C), and sucrose monopalmitate (m.p.4048~C), ethoxylated fatty acids such as polyoxyethylene (40) stearate (m.p. 47~C) (Myrj -52S), and ethoxylated alcohols such as polyoxyethylene (23) lauryl ester (m.p.3840~C). Specitic meltable water-soluble binders are PEG 3350 and polyoxyethylene (40) stearate. The rneltable water-soluble binders of use in the invention are of particular use in the preparation of tablets having increased disintegration rates in the mouth, e.g., rapid disintegration rates of less than ten seconds, for instance 1 to 5 seconds.
The meltable binder may be combined with the excipient or excipients and the pharmaceutically active agent in ~ny sequence. The binder may be combined in dryform or in a suitable solvent such as alcohol, isopropanol or water. The dissolved binder on addition to the remaining tablet ingredients forms a wet granulation. If desired, the pharmaceutically act~ve agent is added after drying of the wet granulation.
Usually, the combined tablet ingredients are milled and mixed with a tabletting lubricant before the dry granules are compressed into tablets.
The excipients of use in the invention are generally known in the art, e.g., as described in Remington's Pharmaceutical Sciences, 18th Edition (1990), particularly pages 1633 to 1638. They impart necessary processing and compression characteristics either to the tablet tormulation before tabletting, or to the finished tablet.
~Trademark ~' WO g3/13758 PCI/US92/07497 CA2] 17351 Examples of excipients are diluents, binders, lubricants, flavors, and sweetening agents.
Specific diluents of use in the invention are water soluble diluents such as mannitol, xylitol, sucrose, lactose, and sodium chloride. Suitable binders of use in the invention.
in addition to the meltable binder of use in the invention, impart cohesive properties 5 and include starch, gelatin, microcrystalline cellulose and sugars such as sucrose, glucose, dextrose, and lactose. As is clear from the above, the same excipient may be used for different purposes within the same tablet formulation.
In one embodiment of the invention, a disintegrating agent is present to increase the disintegration rate of the tablet after oral intake. Examples of disintegrating agents 10 are cellulose such as carboxymethylcellulose, starches, clay, algins, gums and crosslinked polymers, such as crosslinked polyvinylpyrrolidone (PVP-XL).
In another embodiment of the invention, a volatilizable component is present in the tablet formation to manufacture porous tablets. After combination and compression of the tablet ingredients, the volatilizable component is removed from the tablets by 15 heating at atmospheric or reduced pressure to form porous tablets. Suitable volatilizable components include sublimable materials such as menthol, camphor, urea, and vanillin, and materials that decompose at or below the melting point of the binder such as ammonium bicarbonate. The amount of volatilizable material ranges from about 1% to about 95% by weight, based on the weight of the combined tablet 20 ingredients. For instance, when using ammonium bicarbonate, the amount is usually from about 50% to about 90% by weight, and when using menthol, the amount rangesfrom about 30% to about 55% by weight. Preferably, the volatilizable material isremoved during melting step (b) according to the invention when the compressed tablets are heated above the melting point of the meltable binder for a period of time 25 sufficient to melt the meltable binder and to remove the volatilizable material. When using menthol, removal thereof is by heating to about 40~C under vacuum.
The terms "porosity" and "% porous" of a tablet as used herein refer to the voidspaces created by the removal of the volatilizable component of the tablet. Since removal of the volatilizable component does not affect the inner or outer dimensions 30 of the tablet, the porosity as defined above is the percentage by weight of the vols~tili7~hle component in the original tablet formation.
In general, the melting step (b) to melt the binder in the tablet is for a period of time sufficient to melt the meltable binder. The binder solidifies after the tablets are WO 93/137~8 PCI/US92/07497 ~,~21 1 7351 cooled to ambient temperature. The melting and solidifying of the meltable binder in the tablet strengthens the bonding among the tablet particles by filling of the minor cracks in the tablet matrix, as shown in the scanning electron micrographs of Figure 1.
The tablets prepared by the method of the invention may be coated with a thin 5 layer of a coating material to improve the surface integrity of the tablet. Suitable coating materials include disaccharides such as sucrose, polysaccharides such asmaltodextrins and pectin, and cellulose derivatives such as hydroxypropylmethylcellulose and hydroxypropylcellulose.
The pharmaceutically active agent of use in the invention may be any compound 10 that is pharmaceutically active on oral intake or on rectal administration. Examples of such agents include antifungal agents such as flucon~ole, pain relievers such asacetaminophen and acetylsalicylic acid, antihistamines such as diphenhydramine, doxylamine succinate and meclizine, decongestants such as pseudoephedrine hydrochloride, antibiotics such as ~ithromycin and erythromycin, penicillins such as 15 sultamicillin tosylate and amoxicillin trihydrate, enzyme inhibitors such as sulbactam sodium, antihypertensives such as nifedipine, dox~osin mesylate and amlodipine besylate, antidiabetics such as glipizide, bronchodilators such as pirbuterol hydrochloride and theophylline, anti-inflammatory agents such as piroxicam and tenidap, anti-dep~-essants such as sertraline hydrochloride, antacids such as calcium 20 carbonate and magnesium oxide, and non-sedative antihistamines such as cetirizine.
It is understood that the pharmaceutically active agents of use in the invention include nutritional and dietary supplements, for example, vitamins.
The following examples illustrate the invention. The strength of the tablets wasmeasured with a tablet hardness tester, particularly the Schleuniger Hardness Tester, 25 and a friability tester, particularly the Vanderkamp Friabilator. The hardness of the tablet is the force in kp (kilopond) required to break a tablet. The higher the kp value, the stronger the tablet is. Friability is the percentage of the tablet weight loss after a certain number of revolutions in the Vanderkamp Friabilator. The lower the percentage is, the stronger the tablet. As used in the Examples, the term Ufailedu refers to tablets 30 which break during friability testing.
W O 93/13758 PC~r/US92/07497 54.5% Porous Tablets Tablet A: The following ingredients were blended and compressed into tablets of 0.5 inch diameter and 0.130 inch thickness . These tablets were then heated at 72 ~ C
5 under vacuum for 18 hours. This temperature is above the melting point of PEG 3350, 58~C. A 54.5% porous structure was formed after the ammonium bicarbonate was removed by thermal decomposition.
INGREDIENTS OF TABLET A MG/TABLET
1 Ammonium bicarbonate (pore former)(300.00) later removed 2 Mannitol 168.00 3 Bananaflavor 8.00 4 Aspartame 4.00 PEG 3350 20.00 6 PVP-XL 40.00 7 Sodium stearyl fumarate 10.00 TOTAL 250.00 Tablet B: Tablets of 0.5 inch diameter and 0.125 inch thickness were made 20 based on the following formulation which contained no PEG 3350. The tablet size, weight, and the relative amounts (weight to weight ratios) of the non-volatilizable components (ingredients 2 to 6) remained the same as in Tablet A in order to make a fair comparison between the two tablets. The porosity of the comparative tablet was therefore maintained at 54.5%.
WO g3/13758 PCI'~US92/07497 CA21 l 7351 INGREDIENTS OF TABLET B MG/TABLET
Ammonium bicarbonate (pore former)(300.00) later removed 2 Mannitol 183.27 3 Bananaflavor 8.73 4 Aspartame 4.36 6 PVP-XL 43.64 7 Sodium stearyl fumarate 10.00 ~ TOTAL 250.00 10 The physical characterization of these two tablets is shown in Table 1.
.DiameterThickness Hardness Friability (%) (inch) (inch) (kp) 100 revolutions Tablet A 0.5 0.130 4.0 0.8 Tablet B 0.5 0.125 2.4 6.8 The tablet strength of Tablet A is much better than that of Tablet B because of the presence of melted and solidified PEG 3350.
38% Porous Tablets Tablet C: The following ingredients were blended and compressed into tablets of 0.5 inch diameter and 0.114 inch thickness. These tablets were then heated at 42~C
under vacuum. A 38% porous structure was formed after the menthol was removed bysublimation.
Tablet D: These tablets were made by further heating Tablet C at 72~C under vacuum for one hour.
WO 93/13758 PCr/US92/07497 INGREDIENTS OF TABLETS C AND D MG/rABLET
Menthol (pore former) (150) later removed 2 Mannitol 150 3 Banana flavor 8 4 Aspartame - 4 7 Sodium stearyl fumarate 8 ~ TOTAL (395) 245 The physical characterization of these two tablets is shown in Table 2.
, . , ., ~, . . .
: ':.',~/'''!~:/..: 't;. Diameter Thickness Hardness Friability (%) .,,,,t,,''~ (inch) (inch) (kp) 100 revolutions Tablet C 0.5 0.114 below scale Failed Tablet D 0.5 ~ 0.114 2.7 0.4 The improvement in both hardness and friability was dramatic with the tablets (Tablet D) that were heated above the melting point of PEG 3350 (58~C). The amount of void space in Tablet D was not compromised by further heating and melting of PEG
3350. This is demonstrated by the microscopic views of both tablets in Figure 1. In comparing the photographs of the two tablets, it is evident that the melted PEG 3350 had filled and connected the hairline cracks of the type visible in Tablet C.
54.5% Porous Tablets Tablet E: The following ingredients were blended and compressed into tablets of 0.5 inch diameter and 0.168 inch thickness. These tablets were then heated at 40~ C
under vacuum for 18 hours. A 54.5% porous structure was formed after the mentholwas removed by sublimation.
Tablet F: These tablets were made by further heating Tablet E at 70OC under vacuum for 16 hours.
WO 93/13758 PCr/US92/07497 INGREDIENTS OF TABLETS E AND F MG/TABLET
Menthol (pore former) (300) later removed 2 Mannitol 168 3 Banana flavor 8 4 As~. artame 4 7 Sodium stearyl fumarate 10 ~ TOTAL (550) 250 The physical characterization of these two tablets is shown in Table 3.
,. . .............
' ~Diameter ThicknessHardnessFriability (%) .~ (inch) (inch) (kp) 25 revolutions ...............
Tablet E 0.5 0.168below scale failed Tablet F 0.5 0.168below scale 8.5 The difference in friability of both tablets due to the melting and solidifying of PEG 3350 is demonstrated in Figure 2, which is a plot of the tablet weight loss as a function of the number of revolutions in the Vanderkamp friabilator.
75% Porous Tablets Tablet G: The following ingredients 1, 2, 3, 5, 6, and 7 were blended and then wet-granulated with a solution of PEG 3350 (ingredient 4) in ethanol. The dry granulates were milled and blended with sodium stearyl fumarate (ingredient 8). The 25 final blend was compressed into tablets of 0.625 inch diameter. These tablets were then heated at 70~C under vacuum. A 75% porous structure was formed after the ammonium bicarbonate was removed during the heating by thermal decomposition.
-10- 2~ 35~
INGREDIENTS OF TABLET G MGITABLET
Ammonium bicarbonate (pore former) (600) later removed 2 Mànnitol 90 3 Avicel- PH101 (microcrystalline cellulose) 35 6 Aspartame 15 7 Bananaflavor 15 8 Sodium stearyl fumarate 15 ~ TOTAL (880~ 200 The friability of the tablets after 10 revolutions in the Vanderkamp friabilator was 4%.
Tablets Not Containinq Volatilizable Component Tablet H: The following ingredients were blended and compressed into tablets of 0.625 inch diameter and 0.2 inch thickness.
Tablet l: These tablets were made by heating tablet H at 70~C for 3 hours.
These tablets remained non-porous in the absence of a volatilizable component.
INGREDIENTS OF TABLETS H AND I MG/TABLET
Lactose 733.33 2 PEG 3350 129.4 3 Sodium stearyl fumarate 17.27 ~ TOTAL 880 The physical characterization of these two tablets is shown in Table 4.
Trademark ~' WO g3/13758 PCI/US92/07497 -1 1 - 21 ~
Diameter Thickness HardnessFriability (%) (inch) (inch) (kP)100 revolutions Tablet H 5/8 0.2 3.5 failed after 20~rev.
Tablet 1 5/8 0.2 3.5 0.5 The friability of Tablet I was improved because of the melting and then solidifying of PEG 3350.
36% Porous Tablets Tablet J: The following ingredients were blended and compressed into tablets of 0.5 inch diameter and 0.125 inch thickness. These tablets were then heated at 40~C
under vacuum for 18 hours. A 36% porous structure was formed after the menthol was removed by sublimation.
Tablet K: These tablets were made by further heating Tablet J at 70~C under 15 vacuum for 4 hours.
INGREDIENTS OF TABLETS J AND K MG/TABLET
Menthol (pore former) (150) later removed 2 Mannitol 150 3 PVP-XL .- 15 4 MyrJ--52S 60 Piroxicam 20 6 Bananaflavor 8 7 Aspartame 4 8 Sodium stearyl fumarate 8 25 t~ -X~ ' ' ' TOTAL (415) 265 The physical characterization of these two tablets is shown in Table 5.
Trademark WO 93/13758 PCr~US92/07497 .~
~ ~73~ ~
~_Diameter Thickness Hardness Friability (%) ~_ (inch) (inch) (kp) 80 revolutions Tablet J 0.5 0.125 below scaleFailed after 20 rev.
Table K 0.5 0.125 2 kp 0.0 Both hardness and friability of Tablet K were improved because of the metting and solidifying of Myrj-52S.
75% Porous Tablets Tablet L: The Sollowing ingredients 1, 2, 3, 4, 8 and 9 were blended and then wet-granulated with a solution of ingredients 5 and 6 in isopropanol. The dry granules were milled and blended with ingredient 7. Finally, ingredient 10 was mixed with the blend. The final blend was compressed into tablets of 0.625 inch diameter. Thesetablets were then heated at 65~C under vacuum for 18 hours to remove ammonium 15 bicarbonate by thermal decomposition. A 75% porous structure was formed.
INGREDIENTS OF TABLET L MGITABLET
- 1 Ammonium bicarbonate (pore former) (600) later removed 2 Mannitol 29 4 Avicel PH 105 35 6 Klucel EF 5 7 Microencapsulated fluconazole 71 8 Bananaflavor 15 9 Aspartame 15 10 Sodium stearyl fumarate 15 TOTAL (800) 200 The friability of Tablet L was 0.0% after 10 revolutions in the Vanderkamp 30 friab~ilator.
~Trad~m~rk WO 93/137~8 PCI'/US92/07497 ~A2 1 1 7 351 Example 8 Tablets Not Containing Volatilizable Component Tablet M: The following ingredients were blended and compressed into tablets of 0.5 inch diameter and 0.104 inch thickness.
Tablet N: These tablets were made by further heating Tablet M at 83~C for one hour.
INGREDIENTS OF TABLETS M AND N MG/TABLET
Xylitol 322 2 Carnauba wax 40 3 Doxylamine succinate 25 4 Grapeflavor 5 Magnesium stearate 8 ~,~ TOTAL 400 15The physical characterization of these two tablets is shown in Table 6.
_~ Diameter Thickness HardnessFriability (%) (inch) (inch) (kp)100 revolutions Tablet M 0.5 0.104 3 kp 0.96 20Tablet N 0.5 0.104 8 kp 0.00 Both hardness and friability of Tablet N were improved because of the melting and solidifying of carnauba wax.
Example 9 25Tablets Not Containinq Volatilizable Component Tablet O: The following ingredients were blended and compressed into tablets of 0.5 inch diameter and 0.090 inch thickness Tablet P: These tablets were made further heating Tablet M at 60~C for one hour.
WO 93/13758 PCI'/US9V07497 -14~ 3 7 ~
INGREDIENTS OF TABLETS M AND N MG/TABLET
Lactose 241.4 3 Tenidap~ 90.6 4 Explotab (sodium starch glycolate) 20 Magnesium stearate 8 The physical characterization of these two tablets is shown in Table 7.
............. .......
Diameter Thickness Hardness Friability (%) ... ,.~*~ (inch) (inch) (kp) 100 revolutions Tablet 0 0.5 0.104 3 kp failed at 10 rev Tablet P 0.5 0.104 8 kp 0.02 Both hardness and friability of Tablet K were improved because of the melting and solidifying of PEG 3350.
*TradP.n~rk ~'
Claims (7)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A method for the preparation of a tablet of increased strength which comprises the steps of:
(a) combining and compressing from about 5% to about 40% by weight, based on the weight of the tablet, of a water soluble meltable binder, at least one excipient and a pharmaceutically active agent into a tablet, wherein the binder is at a temperature at which the activity of the pharmaceutically active agent is not adversely affected;
(b) melting said binder in said tablet; and (c) solidifying said binder.
(a) combining and compressing from about 5% to about 40% by weight, based on the weight of the tablet, of a water soluble meltable binder, at least one excipient and a pharmaceutically active agent into a tablet, wherein the binder is at a temperature at which the activity of the pharmaceutically active agent is not adversely affected;
(b) melting said binder in said tablet; and (c) solidifying said binder.
2. A method according to Claim 1 wherein said binder is polyethylene glycol, a sucrose ester, an ethoxylated fatty acid, or an ethoxylated alcohol.
3. A method according to Claim 1 or 2 wherein said binder has a melting point ranging from about 20°C to about 100°C.
4. A method according to Claim 1 or 2 wherein step (a) includes combining with a volatilizable material which is removed after said compressing step.
5. A method according to Claim 4 wherein said volatilizable material is ammonium bicarbonate.
6. A tablet of increased strength made according to a method for the preparation thereof which comprises the steps of:
(a) combining and compressing from about 5% to about 40% by weight, based on the weight of the tablet, of a water soluble meltable binder, at least one excipient and a pharmaceutically active agent into a tablet wherein said pharmaceutically active agent is fluconazole, piroxicam, tenidap or doxylamine succinate;
and wherein the binder is at a temperature at which the activity of the pharmaceutically active agent is not adversely affected;
(b) melting said binder in said tablet, and (c) solidifying said binder.
(a) combining and compressing from about 5% to about 40% by weight, based on the weight of the tablet, of a water soluble meltable binder, at least one excipient and a pharmaceutically active agent into a tablet wherein said pharmaceutically active agent is fluconazole, piroxicam, tenidap or doxylamine succinate;
and wherein the binder is at a temperature at which the activity of the pharmaceutically active agent is not adversely affected;
(b) melting said binder in said tablet, and (c) solidifying said binder.
7. A tablet according to Claim 6 having a porosity of 50% to 90%.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US81955392A | 1992-01-13 | 1992-01-13 | |
| US07/819,553 | 1992-01-13 |
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|---|---|
| CA2117351A1 CA2117351A1 (en) | 1993-07-22 |
| CA2117351C true CA2117351C (en) | 1998-03-03 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002117351A Expired - Fee Related CA2117351C (en) | 1992-01-13 | 1992-09-10 | Preparation of tablets of increased strength |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US5853758A (en) |
| EP (1) | EP0620728B1 (en) |
| JP (1) | JP2640570B2 (en) |
| AT (1) | ATE147261T1 (en) |
| CA (1) | CA2117351C (en) |
| DE (1) | DE69216642T2 (en) |
| DK (1) | DK0620728T3 (en) |
| ES (1) | ES2096103T3 (en) |
| FI (1) | FI109086B (en) |
| GR (1) | GR3022458T3 (en) |
| PT (1) | PT101175B (en) |
| WO (1) | WO1993013758A1 (en) |
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| CN108159019A (en) | 2009-12-02 | 2018-06-15 | 阿黛尔药物有限公司 | Fexofenadine microcapsules and the composition containing fexofenadine microcapsules |
| EP2701532B1 (en) | 2011-04-29 | 2017-11-15 | Intercontinental Great Brands LLC | Encapsulated acid, method for the preparation thereof, and chewing gum comprising same |
| US9445971B2 (en) | 2012-05-01 | 2016-09-20 | Johnson & Johnson Consumer Inc. | Method of manufacturing solid dosage form |
| US9511028B2 (en) | 2012-05-01 | 2016-12-06 | Johnson & Johnson Consumer Inc. | Orally disintegrating tablet |
| CN103432091A (en) * | 2013-09-13 | 2013-12-11 | 钟术光 | Improved-performance tablet and preparation method thereof |
| ES2750323T3 (en) | 2014-01-10 | 2020-03-25 | Johnson & Johnson Consumer Inc | Method for manufacturing a tablet using radio frequency and loss coated particles |
| CN105769887B (en) * | 2014-12-23 | 2019-04-30 | 上海复星星泰医药科技有限公司 | A kind of compound fructose diphosphate sodium fructose oral disintegrating tablet and preparation method thereof |
| US20190022013A1 (en) | 2015-12-19 | 2019-01-24 | First Time Us Generics Llc | Soft-chew tablet pharmaceutical formulations |
| WO2017106812A1 (en) | 2015-12-19 | 2017-06-22 | First Time Us Generics Llc | Soft-chew tablet pharmaceutical formulations |
| EA039362B1 (en) * | 2017-02-01 | 2022-01-18 | Джонсон энд Джонсон Консьюмер Инк. | Lozenge |
| US10493026B2 (en) | 2017-03-20 | 2019-12-03 | Johnson & Johnson Consumer Inc. | Process for making tablet using radiofrequency and lossy coated particles |
| JP7145121B2 (en) | 2019-05-31 | 2022-09-30 | 信越化学工業株式会社 | Tablet manufacturing method |
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| US2987445A (en) * | 1958-10-10 | 1961-06-06 | Rohm & Haas | Drug composition |
| NL297357A (en) * | 1962-08-31 | |||
| US4132753A (en) * | 1965-02-12 | 1979-01-02 | American Cyanamid Company | Process for preparing oral sustained release granules |
| DE1617593A1 (en) * | 1965-10-12 | 1971-04-29 | Leo Pharm Prod Ltd | Method of making tablets or pills |
| US3487138A (en) * | 1966-11-23 | 1969-12-30 | Merck & Co Inc | Process for preparing a delayed release medicinal tablet |
| US3653914A (en) * | 1970-03-20 | 1972-04-04 | Alberto Culver Co | Production of tablets |
| ES403326A1 (en) * | 1971-06-04 | 1975-05-01 | Boehringer Mannheim Gmbh | Procedure for the granulation of masses for tablets in the form of dust. (Machine-translation by Google Translate, not legally binding) |
| DE2246013A1 (en) * | 1972-09-20 | 1974-03-28 | Boehringer Mannheim Gmbh | PROCESS FOR THE MANUFACTURING OF POROUS TABLETS |
| JPS5031022A (en) * | 1973-05-29 | 1975-03-27 | ||
| US3961004A (en) * | 1974-04-11 | 1976-06-01 | Auburn Research Foundation | Method of tabletting using gluconolactone as the direct compression diluent |
| US3923939A (en) * | 1974-06-07 | 1975-12-02 | Alza Corp | Process for improving release kinetics of a monolithic drug delivery device |
| JPS58403B2 (en) * | 1975-07-24 | 1983-01-06 | 武田薬品工業株式会社 | L- Ascorbine Sanseizaino Seizouhou |
| DE2556561C2 (en) * | 1975-12-16 | 1983-04-14 | Boehringer Mannheim Gmbh, 6800 Mannheim | Process for the production of porous tablets |
| CA1097233A (en) * | 1977-07-20 | 1981-03-10 | George K. E. Gregory | Packages |
| US4166107A (en) * | 1978-07-25 | 1979-08-28 | The United States Of America As Represented By The Secretary Of Agriculture | Sustained release bolus formulations containing insect growth regulators for control of livestock pests |
| US4994227A (en) * | 1986-03-10 | 1991-02-19 | American Cyanamid Company | Method for the preparation of sustained released bolus formulation |
| US4760094A (en) * | 1986-10-21 | 1988-07-26 | American Home Products Corporation (Del.) | Spray dried acetaminophen |
| US5137669A (en) * | 1988-03-02 | 1992-08-11 | Endocon, Inc. | Manufacture of partially fused peptide pellet |
| DE3812567A1 (en) * | 1988-04-15 | 1989-10-26 | Basf Ag | METHOD FOR PRODUCING PHARMACEUTICAL MIXTURES |
| LU87233A1 (en) * | 1988-06-07 | 1990-02-28 | Pharlyse Sa | PHARMACEUTICAL COMPOSITION BASED ON A NON-STEROIDAL ANTI-INFLAMMATORY, PREPARATION METHOD AND USE THEREOF |
| US5036097A (en) * | 1989-10-17 | 1991-07-30 | Oklahoma Medical Research Foundation | Phenylbutyl nitrone compositions and methods for prevention of gastric ulceration |
| EP0565560B1 (en) * | 1991-01-03 | 1994-09-28 | Glaxo Canada Inc. | Method for production of solid pharmaceutical preparation |
-
1992
- 1992-09-10 WO PCT/US1992/007497 patent/WO1993013758A1/en active IP Right Grant
- 1992-09-10 ES ES92920132T patent/ES2096103T3/en not_active Expired - Lifetime
- 1992-09-10 DE DE69216642T patent/DE69216642T2/en not_active Expired - Fee Related
- 1992-09-10 DK DK92920132.5T patent/DK0620728T3/en active
- 1992-09-10 CA CA002117351A patent/CA2117351C/en not_active Expired - Fee Related
- 1992-09-10 AT AT92920132T patent/ATE147261T1/en not_active IP Right Cessation
- 1992-09-10 EP EP92920132A patent/EP0620728B1/en not_active Expired - Lifetime
- 1992-09-10 JP JP5512404A patent/JP2640570B2/en not_active Expired - Fee Related
-
1993
- 1993-01-11 PT PT101175A patent/PT101175B/en active IP Right Grant
-
1994
- 1994-07-12 FI FI943327A patent/FI109086B/en not_active IP Right Cessation
-
1996
- 1996-07-10 US US08/677,992 patent/US5853758A/en not_active Expired - Fee Related
-
1997
- 1997-01-31 GR GR970400169T patent/GR3022458T3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| WO1993013758A1 (en) | 1993-07-22 |
| PT101175B (en) | 1999-09-30 |
| DK0620728T3 (en) | 1997-07-07 |
| FI943327A (en) | 1994-07-12 |
| DE69216642T2 (en) | 1997-05-07 |
| DE69216642D1 (en) | 1997-02-20 |
| GR3022458T3 (en) | 1997-04-30 |
| JP2640570B2 (en) | 1997-08-13 |
| US5853758A (en) | 1998-12-29 |
| EP0620728A1 (en) | 1994-10-26 |
| FI943327A0 (en) | 1994-07-12 |
| EP0620728B1 (en) | 1997-01-08 |
| FI109086B (en) | 2002-05-31 |
| JPH07503237A (en) | 1995-04-06 |
| PT101175A (en) | 1994-03-31 |
| CA2117351A1 (en) | 1993-07-22 |
| ATE147261T1 (en) | 1997-01-15 |
| ES2096103T3 (en) | 1997-03-01 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |