CA2001673C - Pharmaceutical composition containing piroxicam - Google Patents
Pharmaceutical composition containing piroxicamInfo
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- CA2001673C CA2001673C CA002001673A CA2001673A CA2001673C CA 2001673 C CA2001673 C CA 2001673C CA 002001673 A CA002001673 A CA 002001673A CA 2001673 A CA2001673 A CA 2001673A CA 2001673 C CA2001673 C CA 2001673C
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Abstract
The present invention relates to a pharmaceutical composition comprising N-(2-piridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide as active ingredient and a process for preparing the same.
The composition is composed of 1 part by weight of N-(2-piridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide as active ingredient which at least in 90% by mass has a particle size of at most 30 /um, preferably 10 /um, if desired, 0.1 to 5.0 parts by mass, preferably 1 part by mass, of mannitol optionally of the same particle size, if desired, 0.005 to 0.15 parts by mass, preferably 0.06 to 0.1 parts by mass of silica optionally of the same particle size, 5 to 25 parts by mass, preferably 8 to 18 parts by mass, of spray-dried lactose which at least in 80% by mass has a particle size of 80 to 200 /um, if desired, 0.5 to 6.0 parts by mass, preferably 1.5 to 4.0 parts by mass, of a disintegrant, preferably corn starch, if desired, 0.005 to 0.05 parts by mass, preferably 0.01 to 0.02 parts by mass, of a surface active agent, preferably sodium lauryl sulfate, and if desired, 0.05 to 0.5 parts by mass, preferably 0.1 to 0.2 parts by mass of a lubricant, preferably magnesium stearate.
The composition is composed of 1 part by weight of N-(2-piridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide as active ingredient which at least in 90% by mass has a particle size of at most 30 /um, preferably 10 /um, if desired, 0.1 to 5.0 parts by mass, preferably 1 part by mass, of mannitol optionally of the same particle size, if desired, 0.005 to 0.15 parts by mass, preferably 0.06 to 0.1 parts by mass of silica optionally of the same particle size, 5 to 25 parts by mass, preferably 8 to 18 parts by mass, of spray-dried lactose which at least in 80% by mass has a particle size of 80 to 200 /um, if desired, 0.5 to 6.0 parts by mass, preferably 1.5 to 4.0 parts by mass, of a disintegrant, preferably corn starch, if desired, 0.005 to 0.05 parts by mass, preferably 0.01 to 0.02 parts by mass, of a surface active agent, preferably sodium lauryl sulfate, and if desired, 0.05 to 0.5 parts by mass, preferably 0.1 to 0.2 parts by mass of a lubricant, preferably magnesium stearate.
Description
~0~7 I
PHARMACEUTICAL COMPOSITION AND PROCESS FOR PREPARING THE
SAME
The present invention relates to a homogenizate comprising piroxicam as active ingredient, to a process for preparing the same and a process for the preparation of capsule or tablet from the said homogenizate.
More particularly, the invention relates to a powder homogenizate comprising N-(2-piridyl)-2-methyl-4-hydroxy--2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide (further on piroxicam) as active ingredient together with carriers, further to capsules or tablets prepared from the said homogenizate.
Piroxicam has been described first by US patent specification No. 3,591,584, the examples of which suggest the following compounds to incorporate into tablets or capsules:
tablets: piroxicam, sodium citrate, alginic acid, polyvinyl pyrrolidone, magnesium stearate;
capsules: piroxicam, calcium carbonate, polyethylene glycol.
The said patent specification does not disclose any specific data, e.g. breaking rigidity, resistance to abrasion, fluidity, disintegration time, mass density, active ingredient dissolution, being characteristic for - 2 ~ 7 the tablets or the capsules.
European patent specification No. 66,459 relates to the preparation of piroxicam ethylenediamine and mono-or diethanaolamine salts having enhanced dissolving ability. The examples of this reference describe the following compositions of tablets and capsules, but the qualitative properties and dissolution curves are not taught:
Tablet:
piroxicam ethylenediamine salt 5.88 mg corn starch USP 34.00 mg magnesium stearate 1.04 mg Tablets with 10, 25 and 50 mg active ingredient content can be prepared similarly, taking the proportional amounts of the ingredients.
Capsule:
piroxicam monoethanolamine salt 59.21 mg anhydrous dicalcium phosphate 230.10 mg corn starch 32.50 mg sodium lauryl sulfate 0.32 mg magnesium stearate 2.07 mg _ - 3 - ~ ~0~3 Tablet:
piroxicam monoethanolamine salt 23.92 mg microcrystalline cellulose 311.03 mg modified, pregelatinized starch 84.00 mg 5 magnesium stearate , 0.945 mg sodium lauryl sulfate 0.105 mg Tablet:
piroxicam monoethanolamine salt 23.69 mg anhydrous dicalcium phosphate 113.37 mg polyvinyl pyrrolidone 50.00 mg modified, pregelatinized starch 10.0 mg magnesium stearate 2.65 mg sodium lauryl sulfate 0.294 mg When a pharmaceutical composition comprising piroxicam as active ingredient is prepared, the following problems arise:
a) Piroxicam is poorly soluble in aqueous medium, therefore in order to eliminate this disadvantage European patent specification No. 66,459 suggests the use of a salt of piroxicam.
b) In the course of a wet granulation process the composition gets coloured due to the effect of the aqueous or hydroxyl-group-containing granulating liquid, thus the composition does not meet the international standard.
c) The adsorption of the active ingredient from the pharmaceutical formulation is a very important characteristic, which can be measured by expensive biological tests; thus - 4 - ~ 3 it is preferred if the different dosage forms have the same composition.
d) When the composition is formulated by wet granulation technique, the homogeneous distribution of the ingredients is assured, while when dry homogenization is applied, in case of non-properly selected excipients, especially in the course of tabletting, sorting owing to the gravitational filling uneven distribution of the active agent may occur which may result in non-admitted scatter-ing of the active ingredient.
The aim of the invention was to prepare a homogenizate 1) which is suitable for preparing tablets and capsules of the same composition, - 2) in which, independently from the crystal form of the 15active ingredient, the dissolution values and qualitative parameters of the capsule and tablet are suitable, 3) in which the scattering of the active ingredient content is in accordance with the standards, 4) which can be in dry medium.
20No composition meeting the above requirements can be found in the prior art.
In the course of our experiments it was found that with the composition comprising piroxicam as active ingredient according to USP XXI the desired in vitro dis-solution level could not be achieved. This dissolutionrate would be obtained if at least 75% by mass of the active ingredient content were dissolved out from the composition within 45 minutes.
_ 5 - ~ ~ ~1673 According to our measurements, from the standard composition comprising piroxicam as active ingredient 42 to 45% by mass of the active ingredient content were dissolved out within 45 minutes at a temperature of 37 C, at a stirring rate of 50 revolution/minute, by using artificial gastric juice under the prescriptions of USP XXI
in a rotating dissolving equipment.
The scattering of the active ingredient content in pharmaceutical formulations comprising piroxicam as active ingredient may be RSD = 6.0% according to USP XXI.
Now it has been found that if piroxicam crystals are micronized below a particle size of 30 /um, preferably below 10 /um, and if possibly mannitol and silica are added, the composition comprising the micronized piroxicam crystals assures the desired dissolution values and these values can safely be maintained.
Based on the above, the homogenizate according to the invention is composed of 1 part by weight of N-(2-piridyl)-2-methyl-4-hydroxy-2H--1,2-benzothiazine-3-carboxamide-1,1-dioxide as active ingredient which at least in 90% by mass has a particle size of at most 30 /um, preferably 10 /um, if desired, 0.1 to 5.0 parts by mass, preferably 1 part by mass, of mannitol optionally of the same particle size, if desired, 0.005 to 0.15 parts by mass, preferably 0.06 to 0.1 parts by mass, of silica optionally of the same particle size, - 6 - ~ai 673 5 to 25 parts by mass, preferably 8 to 18 parts by mass, of spray-dried lactose which at least in 80% by mass has a particle size of 80 to 200 /um, if desired, 0.5 to 6.0 parts by mass, preferably 1.5 to 4.0 parts by mass, of a disintegrant, preferably corn starch, if desired, 0.005 to 0.05 parts by mass, preferably 0.01 to 0.02 parts by mass,of a surface active agent, preferably sodium lauryl sulfate, and if desired, 0.05 to 0.5 parts by mass, preferably 0.1 to 0.2 parts by mass,of a lubricant, preferably magnesium stearate.
The lactose has preferably a surface pore size of 10 to 20 /um.
The homogenizate according to the invention is prepared by micronizing 1 part by mass of N-(2-piridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide as active ingredient with or without 0.1 to 5.0 parts by mass, preferably 1 part by mass of mannitol and 0.005 to 0.15 parts by mass, preferably 0.06 to 0.1 parts by mass, of silica in such a manner that at least 90% by mass of the mixture have a particle size of at most 30 /um, preferably at most 10 /um, or if mannitol and silica have not been micronized together with the active ingredient, if desired, adding mannitol and/or silica in the above amounts to the mixture after micronization, then homogenizing the mixture thus obtained with - 7 - 20~ 3 the partial or complete mixture of 5 to 25 parts by mass, preferably 8 to 18 parts by mass of spray-dried lactose which at least in 80% by mass has a particle size of 80 to 200 /um, a disintegrant such as corn starch in an amount of 0.5 to 6.0 parts by mass, preferably 1.5 to 4.0 parts by mass, a surface active agent such as sodium lauryl sulfate in an amount of 0.005 to 0.05 parts by mass, prefer-ably 0.01 to 0.02 parts by mass, a lubricant such as magnesium stearate in an amount of 0.05 to 0.5 parts by mass, preferably 0.1 to 0.2 parts by mass, and if desired, filling the thus-obtained homogenizate into capsules or pressing it into tablets.
The composition according to the invention has anti-rheumatic and antiinflammatory activity.
The piroxicam capsules according to the invention show the following dissolution data:
Dissolution of the active ingredient 5 minutes 15 minutes 45 minutes 69% 86% 92%
The suitably low scattering of the active ingredient content of the tablet or capsule and the high and safe dilution of the homogenizate could be achieved by mixing the piroxicam with spray-dried lactose of a surface pore size of 10 to 20 /um which at least in 80% by weight has a particle size of 80 to 200 /um. Thus a so-called "arranged"
mixture could be achieved, in which the micronized piroxicam particles are adhered into the pores of the lactose, while the preferable flowing characteristics of lactose are maintained, enabling the easy preparation of the homogenizate and the easy formulation of tablets or capsules from the homogenizate.
The scattering of the active ingredient content in the capsules is about RS0 = 2.0%, while in the tablets is about RSD = 2.5%.
The invention is further illustrated by the follow-ing, non-limiting examples.
Example 1 Micronizing The particle size distribution of piroxicam of a quality according to USP XXI measured by microscope:
maximal size:500 /um above 100 /um:15 %
below 100 /um:85 %
below 50 /um:50 %
20 below 20 /um: 30 %
below 10 /um:10 %
below 5 /um: 5 %.
The micronizing is carried out in a Fryma JM-80 air-jet mill.
300 9 of piroxicam, 300 9 of mannitol and 18 9 of ~erosil 200 (SiO2) are charged into the mixer and the components are mixed. The powdering is carried out by adjust-ing the charger and the air valve to 6 bar.
* trade-mark 9 - 20~ 3 The particle size of the micronized powder mixture is as follows:
90% by weight under 10 /um, 10% by weight between 10 and 30 /um.
The bulk density of the micronized powder mixture is as follows:
loose 3.12 ml/g compacted 2.81 ml/g.
Example 2 Trituration 1800 9 of lactose (DCL 11) and 3.6 9 of sodium lauryl sulfate are homogenized according to the rules of triturate preparation. A bronze sieve cloth of 250 /ummesh size is used in the course of the process. The triturate is prepared in 40 minutes.
Example 3 Homogenization The homogenization is carried out in a homogenizator of Lodige FM-50 type. 3582 9 of lactose (DCL 11) and 1160.4 9 of corn starch are charged into the equipment and the micronizate and triturate prepared according to Examples 1 and 2 are added. The equipment is closed and the powder mixture is homogenized for 19 minutes by moving the plough arms. Then 0.3 9 of magnesium stearate is added and the mixture is further homogenized for 1 minute. The complete homogenization time is one hour.
- l o - 2001673 The bulk density of the homogenized powder mixture is as follows:
loose 1.56 ml/g compacted 1.20 ml/g Mass density: 0.72 g/ml.
Flowability: 2.85 ml/sec.
The sieve analysis of the homogenized powder mixture is as follows:
between 0.32 to 0.20 mm:6 to 15%, between 0.20 to 0.10 mm:35 to 45%, below 0.10 mm: 45 to 55%.
Example 4 Capsulation and tabletting Preparation of capsules and tablets of 10 mg From the homogenizate according to Example 3 capsules and tablets of 10 mg are prepared with the following composi-tion:
Capsule Tablet piroxicam USP XXI 10.00 mg 10.00 mg mannitol 10.00 mg 10.00 mg aerosil 200 (colloidal SiO2)0.60 mg0.60 mg sodium lauryl sulfate 0.12 mg 0.12 mg lactose (DCL 11) 179.40 mg 179.40 mg corn starch 38.68 mg 38.68 mg magnesium stearate 1.20 mg 1.20 m~
240.00 mg 240.00 mg - 1 1 - 2~Q1673 The capsulation is carried out in a capsule filling machine of Zanasi LZ-64 type.
Mass of the capsule filling: 240 mg Type and size of the capsule: Capsugel Coni-snap, 2-s Maroon op/Buff op, 33/35 or White L 500-Pink L 770 The homogenizate according to Example 3 is directly tabletted. The tabletting is carried out on a tabletting machine of Erweka E XI by using a flat, flanged pressing tool of 9 mm.
The characteristic properties of the capsules are as follows:
Disintegration time: 3 minutes Dissolution of the active ingredient from the capsule:
5 minutes 15 minutes 45 minutes 69% 86% 92%
Scattering of the active ingredient: RSD = 1.8%.
The characteristic properties of the tablets are 20 as follows:
Tabletting Pressing power 10 kN 15 kN 20 kN
breaking resistance 43.2 N 67.7 N 86.5 N
abrasion loss at a 0.43 % 0.44 % 0.74 %
25 rate of 4 minutes/100 revolution disintegration time 1.6 min. 1.5 min. 2.6 min.
- 12 ~ 2~01~7~
Dissolution of the active ingredient from the tablet prepared with 20 kN pressing power:
15 minutes 30 minutes 45 minutes 83% 87.5% 88.5%
Scattering of the active ingredient: RSD = 2.5 %.
Preparation of capsules and tablets of 20 mg Tablets and capsules containing 20 mg of piroxicam are similarly prepared. The composition of the tablets and capsules is as follows:' Capsule Tablet piroxicam USP XXI 20.00 mg 20.00 mg mannitol 20.00 mg 20.00 mg aerosil 200 (colloidal SiO2) 1.20 mg 1.20 mg sodium lauryl sulfate0.24 mg 0.24 mg lactose (DCL 11) 162.00 mg 162.00 mg corn starch 36.36 mg 36.36 mg magnesium stearate 1.20 m~ 1.20 mg 240.00 mg 240.00 mg The characteristics of the capsule are as follows:
Active ingredient dissolution: 100% within 45 minutes.
Scattering of the active ingredient: RSD = 2.1 %.
The characteristics of the tablet are as follows:
Active ingredient dissolution: 100% within 10 minutes.
Scattering of the active ingredient: RSD = 2.5 %.
- 13 - 200~673 Example 5 Preparation of capsules and tablets of 10 mg or 20 mg mass The process of Examples 1 to 4 is followed except that the micronizing of piroxicam according to Example 1 is carried out without mannitol or without mannitol and silica.
The composition of capsules and tablets of 10 mg without mannitol and silica is as follows:
Capsule Tablet piroxicam USP XXI 10.00 mg10.00 mg sodium lauryl sulfate 0.12 mg 0.12 mg lactose (DCL 11) -190.00 mg190.00 mg corn starch 38.68 mg38.68 mg magnesium stearate 1.20 mg 1.20 mg 240.00 mg240.00 mg The composition of capsules and tablets of 20 mg without mannitol is as follows:
Capsule Tablet piroxicam USP XXI 20.00 mg20.00 mg aerosil 200 (colloidal SiO2)1.20 mg1.20 mg sodium lauryl sulfate 0.24 mg 0.24 mg lactose (DCL 11) 162.00 mg 162.00 mg corn starch 36.36 mg 36.36 mg magnesium stearate 1.20 mg 1.20 mg 220.00 mg 220.00 mg
PHARMACEUTICAL COMPOSITION AND PROCESS FOR PREPARING THE
SAME
The present invention relates to a homogenizate comprising piroxicam as active ingredient, to a process for preparing the same and a process for the preparation of capsule or tablet from the said homogenizate.
More particularly, the invention relates to a powder homogenizate comprising N-(2-piridyl)-2-methyl-4-hydroxy--2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide (further on piroxicam) as active ingredient together with carriers, further to capsules or tablets prepared from the said homogenizate.
Piroxicam has been described first by US patent specification No. 3,591,584, the examples of which suggest the following compounds to incorporate into tablets or capsules:
tablets: piroxicam, sodium citrate, alginic acid, polyvinyl pyrrolidone, magnesium stearate;
capsules: piroxicam, calcium carbonate, polyethylene glycol.
The said patent specification does not disclose any specific data, e.g. breaking rigidity, resistance to abrasion, fluidity, disintegration time, mass density, active ingredient dissolution, being characteristic for - 2 ~ 7 the tablets or the capsules.
European patent specification No. 66,459 relates to the preparation of piroxicam ethylenediamine and mono-or diethanaolamine salts having enhanced dissolving ability. The examples of this reference describe the following compositions of tablets and capsules, but the qualitative properties and dissolution curves are not taught:
Tablet:
piroxicam ethylenediamine salt 5.88 mg corn starch USP 34.00 mg magnesium stearate 1.04 mg Tablets with 10, 25 and 50 mg active ingredient content can be prepared similarly, taking the proportional amounts of the ingredients.
Capsule:
piroxicam monoethanolamine salt 59.21 mg anhydrous dicalcium phosphate 230.10 mg corn starch 32.50 mg sodium lauryl sulfate 0.32 mg magnesium stearate 2.07 mg _ - 3 - ~ ~0~3 Tablet:
piroxicam monoethanolamine salt 23.92 mg microcrystalline cellulose 311.03 mg modified, pregelatinized starch 84.00 mg 5 magnesium stearate , 0.945 mg sodium lauryl sulfate 0.105 mg Tablet:
piroxicam monoethanolamine salt 23.69 mg anhydrous dicalcium phosphate 113.37 mg polyvinyl pyrrolidone 50.00 mg modified, pregelatinized starch 10.0 mg magnesium stearate 2.65 mg sodium lauryl sulfate 0.294 mg When a pharmaceutical composition comprising piroxicam as active ingredient is prepared, the following problems arise:
a) Piroxicam is poorly soluble in aqueous medium, therefore in order to eliminate this disadvantage European patent specification No. 66,459 suggests the use of a salt of piroxicam.
b) In the course of a wet granulation process the composition gets coloured due to the effect of the aqueous or hydroxyl-group-containing granulating liquid, thus the composition does not meet the international standard.
c) The adsorption of the active ingredient from the pharmaceutical formulation is a very important characteristic, which can be measured by expensive biological tests; thus - 4 - ~ 3 it is preferred if the different dosage forms have the same composition.
d) When the composition is formulated by wet granulation technique, the homogeneous distribution of the ingredients is assured, while when dry homogenization is applied, in case of non-properly selected excipients, especially in the course of tabletting, sorting owing to the gravitational filling uneven distribution of the active agent may occur which may result in non-admitted scatter-ing of the active ingredient.
The aim of the invention was to prepare a homogenizate 1) which is suitable for preparing tablets and capsules of the same composition, - 2) in which, independently from the crystal form of the 15active ingredient, the dissolution values and qualitative parameters of the capsule and tablet are suitable, 3) in which the scattering of the active ingredient content is in accordance with the standards, 4) which can be in dry medium.
20No composition meeting the above requirements can be found in the prior art.
In the course of our experiments it was found that with the composition comprising piroxicam as active ingredient according to USP XXI the desired in vitro dis-solution level could not be achieved. This dissolutionrate would be obtained if at least 75% by mass of the active ingredient content were dissolved out from the composition within 45 minutes.
_ 5 - ~ ~ ~1673 According to our measurements, from the standard composition comprising piroxicam as active ingredient 42 to 45% by mass of the active ingredient content were dissolved out within 45 minutes at a temperature of 37 C, at a stirring rate of 50 revolution/minute, by using artificial gastric juice under the prescriptions of USP XXI
in a rotating dissolving equipment.
The scattering of the active ingredient content in pharmaceutical formulations comprising piroxicam as active ingredient may be RSD = 6.0% according to USP XXI.
Now it has been found that if piroxicam crystals are micronized below a particle size of 30 /um, preferably below 10 /um, and if possibly mannitol and silica are added, the composition comprising the micronized piroxicam crystals assures the desired dissolution values and these values can safely be maintained.
Based on the above, the homogenizate according to the invention is composed of 1 part by weight of N-(2-piridyl)-2-methyl-4-hydroxy-2H--1,2-benzothiazine-3-carboxamide-1,1-dioxide as active ingredient which at least in 90% by mass has a particle size of at most 30 /um, preferably 10 /um, if desired, 0.1 to 5.0 parts by mass, preferably 1 part by mass, of mannitol optionally of the same particle size, if desired, 0.005 to 0.15 parts by mass, preferably 0.06 to 0.1 parts by mass, of silica optionally of the same particle size, - 6 - ~ai 673 5 to 25 parts by mass, preferably 8 to 18 parts by mass, of spray-dried lactose which at least in 80% by mass has a particle size of 80 to 200 /um, if desired, 0.5 to 6.0 parts by mass, preferably 1.5 to 4.0 parts by mass, of a disintegrant, preferably corn starch, if desired, 0.005 to 0.05 parts by mass, preferably 0.01 to 0.02 parts by mass,of a surface active agent, preferably sodium lauryl sulfate, and if desired, 0.05 to 0.5 parts by mass, preferably 0.1 to 0.2 parts by mass,of a lubricant, preferably magnesium stearate.
The lactose has preferably a surface pore size of 10 to 20 /um.
The homogenizate according to the invention is prepared by micronizing 1 part by mass of N-(2-piridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide as active ingredient with or without 0.1 to 5.0 parts by mass, preferably 1 part by mass of mannitol and 0.005 to 0.15 parts by mass, preferably 0.06 to 0.1 parts by mass, of silica in such a manner that at least 90% by mass of the mixture have a particle size of at most 30 /um, preferably at most 10 /um, or if mannitol and silica have not been micronized together with the active ingredient, if desired, adding mannitol and/or silica in the above amounts to the mixture after micronization, then homogenizing the mixture thus obtained with - 7 - 20~ 3 the partial or complete mixture of 5 to 25 parts by mass, preferably 8 to 18 parts by mass of spray-dried lactose which at least in 80% by mass has a particle size of 80 to 200 /um, a disintegrant such as corn starch in an amount of 0.5 to 6.0 parts by mass, preferably 1.5 to 4.0 parts by mass, a surface active agent such as sodium lauryl sulfate in an amount of 0.005 to 0.05 parts by mass, prefer-ably 0.01 to 0.02 parts by mass, a lubricant such as magnesium stearate in an amount of 0.05 to 0.5 parts by mass, preferably 0.1 to 0.2 parts by mass, and if desired, filling the thus-obtained homogenizate into capsules or pressing it into tablets.
The composition according to the invention has anti-rheumatic and antiinflammatory activity.
The piroxicam capsules according to the invention show the following dissolution data:
Dissolution of the active ingredient 5 minutes 15 minutes 45 minutes 69% 86% 92%
The suitably low scattering of the active ingredient content of the tablet or capsule and the high and safe dilution of the homogenizate could be achieved by mixing the piroxicam with spray-dried lactose of a surface pore size of 10 to 20 /um which at least in 80% by weight has a particle size of 80 to 200 /um. Thus a so-called "arranged"
mixture could be achieved, in which the micronized piroxicam particles are adhered into the pores of the lactose, while the preferable flowing characteristics of lactose are maintained, enabling the easy preparation of the homogenizate and the easy formulation of tablets or capsules from the homogenizate.
The scattering of the active ingredient content in the capsules is about RS0 = 2.0%, while in the tablets is about RSD = 2.5%.
The invention is further illustrated by the follow-ing, non-limiting examples.
Example 1 Micronizing The particle size distribution of piroxicam of a quality according to USP XXI measured by microscope:
maximal size:500 /um above 100 /um:15 %
below 100 /um:85 %
below 50 /um:50 %
20 below 20 /um: 30 %
below 10 /um:10 %
below 5 /um: 5 %.
The micronizing is carried out in a Fryma JM-80 air-jet mill.
300 9 of piroxicam, 300 9 of mannitol and 18 9 of ~erosil 200 (SiO2) are charged into the mixer and the components are mixed. The powdering is carried out by adjust-ing the charger and the air valve to 6 bar.
* trade-mark 9 - 20~ 3 The particle size of the micronized powder mixture is as follows:
90% by weight under 10 /um, 10% by weight between 10 and 30 /um.
The bulk density of the micronized powder mixture is as follows:
loose 3.12 ml/g compacted 2.81 ml/g.
Example 2 Trituration 1800 9 of lactose (DCL 11) and 3.6 9 of sodium lauryl sulfate are homogenized according to the rules of triturate preparation. A bronze sieve cloth of 250 /ummesh size is used in the course of the process. The triturate is prepared in 40 minutes.
Example 3 Homogenization The homogenization is carried out in a homogenizator of Lodige FM-50 type. 3582 9 of lactose (DCL 11) and 1160.4 9 of corn starch are charged into the equipment and the micronizate and triturate prepared according to Examples 1 and 2 are added. The equipment is closed and the powder mixture is homogenized for 19 minutes by moving the plough arms. Then 0.3 9 of magnesium stearate is added and the mixture is further homogenized for 1 minute. The complete homogenization time is one hour.
- l o - 2001673 The bulk density of the homogenized powder mixture is as follows:
loose 1.56 ml/g compacted 1.20 ml/g Mass density: 0.72 g/ml.
Flowability: 2.85 ml/sec.
The sieve analysis of the homogenized powder mixture is as follows:
between 0.32 to 0.20 mm:6 to 15%, between 0.20 to 0.10 mm:35 to 45%, below 0.10 mm: 45 to 55%.
Example 4 Capsulation and tabletting Preparation of capsules and tablets of 10 mg From the homogenizate according to Example 3 capsules and tablets of 10 mg are prepared with the following composi-tion:
Capsule Tablet piroxicam USP XXI 10.00 mg 10.00 mg mannitol 10.00 mg 10.00 mg aerosil 200 (colloidal SiO2)0.60 mg0.60 mg sodium lauryl sulfate 0.12 mg 0.12 mg lactose (DCL 11) 179.40 mg 179.40 mg corn starch 38.68 mg 38.68 mg magnesium stearate 1.20 mg 1.20 m~
240.00 mg 240.00 mg - 1 1 - 2~Q1673 The capsulation is carried out in a capsule filling machine of Zanasi LZ-64 type.
Mass of the capsule filling: 240 mg Type and size of the capsule: Capsugel Coni-snap, 2-s Maroon op/Buff op, 33/35 or White L 500-Pink L 770 The homogenizate according to Example 3 is directly tabletted. The tabletting is carried out on a tabletting machine of Erweka E XI by using a flat, flanged pressing tool of 9 mm.
The characteristic properties of the capsules are as follows:
Disintegration time: 3 minutes Dissolution of the active ingredient from the capsule:
5 minutes 15 minutes 45 minutes 69% 86% 92%
Scattering of the active ingredient: RSD = 1.8%.
The characteristic properties of the tablets are 20 as follows:
Tabletting Pressing power 10 kN 15 kN 20 kN
breaking resistance 43.2 N 67.7 N 86.5 N
abrasion loss at a 0.43 % 0.44 % 0.74 %
25 rate of 4 minutes/100 revolution disintegration time 1.6 min. 1.5 min. 2.6 min.
- 12 ~ 2~01~7~
Dissolution of the active ingredient from the tablet prepared with 20 kN pressing power:
15 minutes 30 minutes 45 minutes 83% 87.5% 88.5%
Scattering of the active ingredient: RSD = 2.5 %.
Preparation of capsules and tablets of 20 mg Tablets and capsules containing 20 mg of piroxicam are similarly prepared. The composition of the tablets and capsules is as follows:' Capsule Tablet piroxicam USP XXI 20.00 mg 20.00 mg mannitol 20.00 mg 20.00 mg aerosil 200 (colloidal SiO2) 1.20 mg 1.20 mg sodium lauryl sulfate0.24 mg 0.24 mg lactose (DCL 11) 162.00 mg 162.00 mg corn starch 36.36 mg 36.36 mg magnesium stearate 1.20 m~ 1.20 mg 240.00 mg 240.00 mg The characteristics of the capsule are as follows:
Active ingredient dissolution: 100% within 45 minutes.
Scattering of the active ingredient: RSD = 2.1 %.
The characteristics of the tablet are as follows:
Active ingredient dissolution: 100% within 10 minutes.
Scattering of the active ingredient: RSD = 2.5 %.
- 13 - 200~673 Example 5 Preparation of capsules and tablets of 10 mg or 20 mg mass The process of Examples 1 to 4 is followed except that the micronizing of piroxicam according to Example 1 is carried out without mannitol or without mannitol and silica.
The composition of capsules and tablets of 10 mg without mannitol and silica is as follows:
Capsule Tablet piroxicam USP XXI 10.00 mg10.00 mg sodium lauryl sulfate 0.12 mg 0.12 mg lactose (DCL 11) -190.00 mg190.00 mg corn starch 38.68 mg38.68 mg magnesium stearate 1.20 mg 1.20 mg 240.00 mg240.00 mg The composition of capsules and tablets of 20 mg without mannitol is as follows:
Capsule Tablet piroxicam USP XXI 20.00 mg20.00 mg aerosil 200 (colloidal SiO2)1.20 mg1.20 mg sodium lauryl sulfate 0.24 mg 0.24 mg lactose (DCL 11) 162.00 mg 162.00 mg corn starch 36.36 mg 36.36 mg magnesium stearate 1.20 mg 1.20 mg 220.00 mg 220.00 mg
Claims (35)
1. A pharmaceutical composition comprising N-(2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide as active ingredient, which comprises:
(i) 1 part by weight of N-(2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide as active ingredient such that at least 90% by mass has a particle size of at most 30 µm; and (ii) 5 to 25 parts by mass of spray-dried lactose of which at least 80% by mass has a particle size of 80 to 200 µm.
(i) 1 part by weight of N-(2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide as active ingredient such that at least 90% by mass has a particle size of at most 30 µm; and (ii) 5 to 25 parts by mass of spray-dried lactose of which at least 80% by mass has a particle size of 80 to 200 µm.
2. A pharmaceutical composition according to claim 1, wherein at least 90% by mass of the N-(2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide has a maximum particle size of 10 µm.
3. A pharmaceutical composition according to claim 1 or 2, further comprising 0.1 to 5.0 parts by mass of mannitol optionally of the same particle size.
4. A pharmaceutical composition according to claim 3, wherein the mannitol is used in an amount of 1 part by mass.
5. A pharmaceutical composition according to claim 1 or 2, further comprising 0.005 to 0.15 parts by mass of silica optionally of the same particle size.
6. A pharmaceutical composition according to claim 5, wherein the silica is used in an amount of 0.06 to 0.1 part by mass.
7. A pharmaceutical composition according to claim 1, 2, 4 or 6, wherein the spray-dried lactose is used in an amount of 8 to 18 parts by mass.
8. A pharmaceutical composition according to claim 1, 2, 4 or 6, further comprising 0.5 to 6.0 parts by mass of a disintegrant.
9. A pharmaceutical composition according to claim 8, wherein the disintegrant is used in an amount of 1.5 to 4.0 parts by mass.
10. A pharmaceutical composition according to claim 8, wherein corn starch is used as the disintegrant.
11. A pharmaceutical composition according to claim 1, 2, 4, 6, 9 or 10, further comprising 0.005 to 0.05 part by mass of a surface active agent.
12. A pharmaceutical composition according to claim 11, wherein the surface active agent is used in an amount of 0.01 to 0.02 part by mass.
13. A pharmaceutical composition according to claim 11, wherein sodium lauryl sulfate is used as the surface active agent.
14. A pharmaceutical composition according to claim 1, 2, 4, 6, 9, 10, 12 or 13, further comprising 0.005 to 0.5 parts by mass of a lubricant.
15. A pharmaceutical composition according to claim 14, wherein the lubricant is used in an amount of 0.1 to 0.2 part by mass.
16. A pharmaceutical composition according to claim 14, wherein magnesium stearate is used as the lubricant.
17. A process for the preparation of a pharmaceutical composition comprising N-(2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide as active ingredient, which comprises:
(i) micronizing 1 part by weight of N-(2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide as active ingredient such that at least 90% by mass has a maximum particle size of 30 µm; and (ii) homogenizing the mixture thus obtained with:
(a) the partial or complete mixture of 5 to 25 parts by mass of spray-dried lactose of which at least 80%
by mass has a particle size of 80 to 200 µm;
(b) a disintegrant in an amount of 0.5 to 6.0 parts by mass;
(c) a surface active agent in an amount of 0.005 to 0.05 part by mass; and (d) a lubricant in an amount of 0.05 to 0.5 part by mass.
(i) micronizing 1 part by weight of N-(2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide as active ingredient such that at least 90% by mass has a maximum particle size of 30 µm; and (ii) homogenizing the mixture thus obtained with:
(a) the partial or complete mixture of 5 to 25 parts by mass of spray-dried lactose of which at least 80%
by mass has a particle size of 80 to 200 µm;
(b) a disintegrant in an amount of 0.5 to 6.0 parts by mass;
(c) a surface active agent in an amount of 0.005 to 0.05 part by mass; and (d) a lubricant in an amount of 0.05 to 0.5 part by mass.
18. A process according to claim 17, wherein at least 90% by mass of the N-(2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide has a maximum particle size of 10 µm.
19. A process according to claim 17 or 18, wherein 0.1 to 5.0 parts by mass of mannitol, optionally of the same particle size, is micronized together with the active ingredient.
20. A process according to claim 19, wherein 1 part by mass of mannitol is employed.
21. A process according to claim 17, 18 or 20, wherein 0.005 to 0.15 part by mass of silica, optionally of the same particle size, is micronized together with the active ingredient.
22. A process according to claim 21, wherein 0.06 to 0.1 part by mass of silica is employed.
23. A process according to claim 17, 18, 20 or 22, wherein mannitol and/or silica is added to the active ingredient after micronization.
24. A process according to claim 23, wherein the mannitol is used in an amount of 0.1 to 5.0 parts by mass.
25. A process according to claim 24, wherein 1 part by mass of mannitol is employed.
26. A process according to claim 23, wherein the silica is used in an amount of 0.005 to 0.15 part by mass.
27. A process according to claim 26, wherein the silica is used in an amount of 0.06 to 0.1 part by mass.
28. A process according to claim 17, 18, 20, 22, 24, 25, 26 or 27, wherein the spray-dried lactose is used in an amount of 8 to 18 parts by mass.
29. A process according to claim 17, 18, 20, 22, 24, 25, 26 or 27, wherein the disintegrant is used in an amount of 1.5 to 4.0 parts by mass.
30. A process according to claim 29, wherein corn starch is used as the disintegrant.
31. A process according to claim 17, 18, 20, 22, 24, 25, 26, 27 or 30, wherein the surface active agent is used in an amount of 0.01 to 0.02 part by mass.
32. A process according to claim 31, wherein sodium lauryl sulfate is used as the surface active agent.
33. A process according to claim 17, 18, 20, 22, 24, 25, 26, 27, 30 or 32, wherein the lubricant is used in an amount of 0.1 to 0.2 part by mass.
34. A process according to claim 33, wherein magnesium stearate is used as the lubricant.
35. A process according to claim 17, 18, 20, 22, 24, 25, 26, 27, 30, 32 or 34, wherein the thus-obtained homogenizate is filled into capsules or pressed into tablets.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU885621A HU200926B (en) | 1988-10-28 | 1988-10-28 | Pharmaceutical composition comprising piroxicam and lactose for use in making tablets or capsules |
| HU5621/88 | 1988-10-28 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2001673A1 CA2001673A1 (en) | 1990-04-28 |
| CA2001673C true CA2001673C (en) | 1996-08-27 |
Family
ID=10970484
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002001673A Expired - Fee Related CA2001673C (en) | 1988-10-28 | 1989-10-27 | Pharmaceutical composition containing piroxicam |
Country Status (9)
| Country | Link |
|---|---|
| JP (1) | JPH02172918A (en) |
| AT (1) | AT399277B (en) |
| CA (1) | CA2001673C (en) |
| DE (1) | DE3936112C2 (en) |
| FR (1) | FR2638357B1 (en) |
| GB (1) | GB2224207B (en) |
| HU (1) | HU200926B (en) |
| IL (1) | IL92138A (en) |
| IT (1) | IT1239542B (en) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2642486B2 (en) * | 1989-08-04 | 1997-08-20 | 田辺製薬株式会社 | Ultrafine particle method for poorly soluble drugs |
| JP2964195B2 (en) * | 1992-04-28 | 1999-10-18 | エスエス製薬株式会社 | Piroxicam tablets and method for producing the same |
| DE19603402A1 (en) * | 1995-02-24 | 1996-08-29 | Basf Ag | Soft gelatin capsules |
| DE69739967D1 (en) | 1996-06-14 | 2010-09-30 | Kyowa Hakko Kirin Co Ltd | A rapidly disintegrating tablet in the mouth |
| US8071128B2 (en) | 1996-06-14 | 2011-12-06 | Kyowa Hakko Kirin Co., Ltd. | Intrabuccally rapidly disintegrating tablet and a production method of the tablets |
| US6964779B1 (en) * | 1998-04-08 | 2005-11-15 | Kyowa Hakko Kogyo Co., Ltd. | Tablet manufacturing method and tablet |
| JP2000095674A (en) * | 1998-09-22 | 2000-04-04 | Sato Pharmaceutical Co Ltd | Production of tablet having shortened intraoral disintegration time and apparatus therefor |
| US9358214B2 (en) | 2001-10-04 | 2016-06-07 | Adare Pharmaceuticals, Inc. | Timed, sustained release systems for propranolol |
| BR0317349A (en) * | 2002-12-16 | 2005-11-16 | Kissei Pharmaceutical | Solid drug for oral use |
| US8367111B2 (en) | 2002-12-31 | 2013-02-05 | Aptalis Pharmatech, Inc. | Extended release dosage forms of propranolol hydrochloride |
| US8747895B2 (en) | 2004-09-13 | 2014-06-10 | Aptalis Pharmatech, Inc. | Orally disintegrating tablets of atomoxetine |
| US9884014B2 (en) | 2004-10-12 | 2018-02-06 | Adare Pharmaceuticals, Inc. | Taste-masked pharmaceutical compositions |
| NZ589750A (en) | 2004-10-21 | 2012-07-27 | Aptalis Pharmatech Inc | Taste-masked pharmaceutical compositions with gastrosoluble pore-formers |
| US9161918B2 (en) | 2005-05-02 | 2015-10-20 | Adare Pharmaceuticals, Inc. | Timed, pulsatile release systems |
| CN101232905B (en) * | 2005-07-25 | 2013-01-09 | 大塚制药株式会社 | Oral preparation useful in measuring capacity to metabolize pyridine |
| JP5309262B2 (en) | 2009-12-02 | 2013-10-09 | アプタリス ファーマ リミテッド | Fexofenadine microcapsule and composition containing the same |
| KR102105354B1 (en) | 2012-08-20 | 2020-04-29 | 오츠카 세이야쿠 가부시키가이샤 | Method for measuring carbohydrate metabolism ability, and composition for use in said method |
| JP6305392B2 (en) | 2013-03-15 | 2018-04-04 | 大塚製薬株式会社 | Method for measuring insulin resistance by fatty acid combustion, and composition used therefor |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3591584A (en) * | 1968-08-27 | 1971-07-06 | Pfizer | Benzothiazine dioxides |
| GB1308533A (en) * | 1969-06-02 | 1973-02-21 | Pfizer | Benzothiazine dioxides as anti-thombotic agents |
| JPS55129221A (en) * | 1979-03-29 | 1980-10-06 | Kaken Pharmaceut Co Ltd | Preparation of oral preparation containing hardly soluble medicine |
| US4350689A (en) * | 1980-02-15 | 1982-09-21 | American Cyanamid Company | Combinations of agents which give enhanced anti-inflammatory activity |
| US4434164A (en) * | 1981-06-01 | 1984-02-28 | Pfizer Inc. | Crystalline benzothiazine dioxide salts |
| RO88420A (en) * | 1983-04-25 | 1986-01-30 | Pfizer Inc,Us | PROCEDURE FOR THE PREPARATION OF PIROXICAN BASIC BATCHES EMPTY ON PHARMACEUTICAL SUPPORTS |
| DE3419128A1 (en) * | 1984-05-23 | 1985-11-28 | Bayer Ag, 5090 Leverkusen | DIHYDROPYRIDINE PREPARATIONS AND METHOD FOR THE PRODUCTION THEREOF |
| CH663899A5 (en) * | 1985-03-20 | 1988-01-29 | Nestle Sa | PROCESS FOR THE PREPARATION OF A COMPOSITION BASED ON A FINELY DIVIDED LOW HYDROSOLUBILITY ACTIVE INGREDIENT. |
| ES545221A0 (en) * | 1985-07-02 | 1986-01-01 | Ferrer Int | PROCEDURE FOR OBTAINING PARTICLES OF 4-HYDROXY-2-METHYL-N-2-PIRIDIL-2H-1,2-BENZOTIAZINE-3-CARBOXAMIDE-1,1-DIOXI-DO (PIROXICAM) COATED |
-
1988
- 1988-10-28 HU HU885621A patent/HU200926B/en unknown
-
1989
- 1989-10-19 JP JP1270514A patent/JPH02172918A/en active Pending
- 1989-10-27 AT AT0247489A patent/AT399277B/en not_active IP Right Cessation
- 1989-10-27 FR FR8914117A patent/FR2638357B1/en not_active Expired - Fee Related
- 1989-10-27 IT IT22164A patent/IT1239542B/en active IP Right Grant
- 1989-10-27 IL IL9213889A patent/IL92138A/en not_active IP Right Cessation
- 1989-10-27 CA CA002001673A patent/CA2001673C/en not_active Expired - Fee Related
- 1989-10-27 GB GB8924286A patent/GB2224207B/en not_active Expired - Lifetime
- 1989-10-30 DE DE3936112A patent/DE3936112C2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| IL92138A (en) | 1994-08-26 |
| GB2224207B (en) | 1992-06-10 |
| JPH02172918A (en) | 1990-07-04 |
| HU200926B (en) | 1990-09-28 |
| FR2638357B1 (en) | 1993-10-22 |
| DE3936112A1 (en) | 1990-05-31 |
| CA2001673A1 (en) | 1990-04-28 |
| IT8922164A0 (en) | 1989-10-27 |
| GB8924286D0 (en) | 1989-12-13 |
| HUT51143A (en) | 1990-04-28 |
| FR2638357A1 (en) | 1990-05-04 |
| ATA247489A (en) | 1994-09-15 |
| GB2224207A (en) | 1990-05-02 |
| IL92138A0 (en) | 1990-07-12 |
| IT8922164A1 (en) | 1991-04-27 |
| DE3936112C2 (en) | 1999-02-18 |
| AT399277B (en) | 1995-04-25 |
| IT1239542B (en) | 1993-11-05 |
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