WO1994002177A1 - Method of preparation of inclusion compounds of nimesulide with cyclodextrins - Google Patents
Method of preparation of inclusion compounds of nimesulide with cyclodextrins Download PDFInfo
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- WO1994002177A1 WO1994002177A1 PCT/EP1993/001560 EP9301560W WO9402177A1 WO 1994002177 A1 WO1994002177 A1 WO 1994002177A1 EP 9301560 W EP9301560 W EP 9301560W WO 9402177 A1 WO9402177 A1 WO 9402177A1
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- nimesulide
- cyclodextrins
- preparation
- water
- soluble
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
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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
- A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
Definitions
- the present invention relates to a new method fo the preparation of inclusion compounds of nimesulid with cyclodextrins.
- the methods of preparation of the inclusion compound of nimesulide with cyclodextrins include the coprecipitation of the inclusion compound from an organic solution of nimesulide mixed with an aqueous solution of cyclodextrin, or the neutralization of the aqueous solution of cyclodextrins, the solubilization of nimesulide and isolation of the inclusion compound, or the isolation from saturated aqueous solution of the inclusion compound of nimesulide with cyclodextrins.
- the inclusion compound can be isolated by filtration, freeze-drying or evaporation under reduced pressure.
- the present invention relates to an one-step process for the preparation of the inclusion compounds of nimesulide with water-soluble cyclodextrins.
- the method of the invention consists in subjecting a solid mixture, an aqueous solution or an homogeneous slurry of nimesulide and water-soluble cyclodextrins to co-milling, to spray-drying or to kneading respectively.
- Water-soluble cyclodextrins which may be used according to the present invention are unsubstituted or substituted 0*1, ⁇ or ⁇ "-cyclodextrins or hydrates thereof, preferably unsubstitued ⁇ -cyclodextrins.
- nimesulide with water- soluble cyclodextrins show a great improvement of dissolution and wettability properties of nimesulide in aqueous or biological media, due to the following factors: - amorphous state of the obtained product; surfactant-like properties of cyclodextrins which can reduce the interfacial tension between water- insoluble drugs and the solvent; the smaller particle size produced by the co- milling, spray-drying and kneading processes; reduction of the dissolution energy of nimesulide brought by its complete or partial amorphization or by the transition of its original crystalline state into a higher energy state.
- the methods of the invention show furthermore a significant versatility over the other known methods.
- micromeritic properties of the spray- dried, co-milled and kneaded products can be checked in order to facilitate the next formulation steps, necessary for the preparation of the conventional solid oral dosage form, as granules, capsules, tablets.
- the method involves a particularly simply and safe procedure and it is generally applicable in the preparation of other complexes of cyclodextrins with different drugs.
- a dry mixture of nimesulide and water-soluble cyclodextrins is laced in a rotating ball mill, in a vibrational ball mill, in an automatic rotor speed mill or any other suitable comminution, crushing, milling, micronization apparatus until an amorphization of the crystalline nimesulide is achieved.
- the amorphization degree is checked by the absence in the Differential Scanning Calorimetry thermogram of the obtained compound of the endothermic peak relative to the solid/liquid transition of the crystalline nimesulide.
- the milling of the inclusion compound can be stopped when an amorphization degree of nimesulide (measured by the reduction of enthalpy value of melting of the crystalline nimesulide) sufficient to sensibly increase the dissolution rate, is achieved.
- Molar ratios between nimesulide and water-soluble cyclodextrins, in the mixture to be milled can vary from 1 : 0.5 and 1 : 10 moles/moles respectively, preferably between 1 : 0.8 and 1 : 4 moles/moles.
- the resulting milled mixture can be forced through a sieve to eliminate possible aggregates and then mixed in any mixing device to guarantee the most homogeneity and fluidity of the product.
- the resulting powdered milled inclusion compound of nimesulide and cyclodextrins can be subsequently used to prepare any desired solid dosage form (granules, tablets, capsules) with or without the addition of any excipients conventionally used in the pharmaceutical compositions.
- any desired solid dosage form granules, tablets, capsules
- any excipients conventionally used in the pharmaceutical compositions b. Spray-drying
- Nimesulide and water-soluble cyclodextrins are co- mixed in distilled water and the pH of the solution is adjusted to the desired value by adding 0.1 NaOH or
- the solutions and the homogeneous suspensions are atomized into a drying chamber with a spray nozzle.
- the spray atomized typically works under the following conditions: inlet temperature: 140°C outlet temperature: 70°C
- the resulting powdered inclusion compound of nimesulide and cyclodextrins can be subsequently used to prepare any desired solid dosage form (granules, tablets, capsules) with or without the addition of any excipients of common use in the pharmaceutical compositions.
- Kneading Nimesulide is solubilized or suspended in an alkaline aqueous solution (pH > 7.0) and then water- soluble cyclodextrins are added.
- the preparation is homogenized by mixer-homogenizer, like Silverson, for the time period needed to achieve the desired degree of amorphization of the crystalline nimesulide.
- the preparation is dried in a forced ventilation oven at 40-50 ⁇ C overnight.
- Molar ratios between nimesulide and water-soluble cyclodextrins in the preparation of their alkaline aqueous solution can vary from 1 : 0.5 and 1 : 10 moles/moles respectively, preferably between 1 : 0.8 and 1 : 4 moles/moles.
- the resulting mixture can be forced through a sieve to eliminate possible aggregates and subsequently mixed in any mixing device to guarantee the most homogeneity and fluidity of the product.
- the resulting powdered inclusion compound of nimesulide and cyclodextrins can be subsequently use to prepare any desired solid dosage form (granules, tablets, capsules) with or without the addition of an of the common excipients used in the pharmaceutica compositions.
- Example 1 Nimesulide (200 g) and the suitable amount of ⁇ cyclodextrin (about 205 g) were dry-mixed and the milled by a rotating ball mill. This working, being i function with the capacity and potency of the mill, ca be repeated more time until nimesulide- ⁇ -cyclodextri compound of the desired crystallinety was obtained.
- Example 2 210 g of nimesulide were partially solubilized i 800 ml of ammoniacal solution (pH 8.2). The obtaine suspension was homogenized and dispersed by means of mixer-homogenizer like Silverson for 2 hours. Th suitable amount of ⁇ -cyclodextrin was added in order t obtain a nimesulide- ⁇ -cyclodextrin compound 1 : 2. After dispersion, ⁇ -cyclodextrins were solubilize under stirring by Silverson until the suspensio homogenization and solid particle reduction were achieved. The compound was dried in an oven at 45° overnight putting it in a thin layer. Before sendin the compound for the formulations, it was milled by 200 ⁇ m sieve.
- Example 3 Nimesulide was dissolved in alkaline solution (5 1/for the addition of NH 4 OH (pH 8.2). The required amount of ⁇ -cyclodextrin was then added to the alkaline solution on ⁇ -cyclodextrin, in order to have a molar ratio 1 : 1 in the final compound. The mixture was kept under stirring until a complete dissolution. The solution was feeded (spray-drier BUCUI 190 M) with the following operative conditions: feeding speed: 720 ml/h air temperature: 150 e C air flow: 400 1/h
- Example 4 Granules Inclusion compound of nimesulide with ⁇ -cyclodextrins 468 mg sorbitol 2472 mg
- solubility (saturation concentration) of the inclusion compound of nimesulide with cyclodextrins was measured by placing an excess amount of the powdered compound in a flask containing 50 ml of pH 7.4 phosphate buffer at 25°C; the flasks were placed in a shaking apparatus and aliquots of sample solutions were taken and filtered through a Millipore membrane filter; the concentration of nimesulide in the filtered aliquot was determined by spectrophotometer VARIAM DMS 100 at 369.9 nm.
- nimesulide solubility values were achieved by preparing the inclusion compound of nimesul ide and cyclodextrins , according to the present invention . It is particularly interesting to observe that nimesul ide concentrations resulting from the inclusion compound of nimesulide with cyclodextrins are about 20 times higher than from crystall ine pure nimesulide . 4 . Dis solution data Dissolution profiles of the inclusion compound of nimesulide with cyc lodextrins were measured applying the USP XXII dissolution method. The withdrawn sample solutions are checked for the nimesulide concentration by UV.Vis spectrophotometric analysis. These results stress the advantages of the inclusion compound of nimesulide with cyclodextrins obtained by any of the three techniques (table 2), described in this application.
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Abstract
A method for the preparation of inclusion compounds of nimesulide with cyclodextrins, which consists in subjecting a solid mixture, an aqueous solution or a homogeneous slurry of nimesulide and water-soluble cyclodextrins to co-milling, to spray-drying or to kneading respectively, is described.
Description
METHOD OF PREPARATION OF INCLUSION COMPOUNDS O NIMESULIDE WITH CYCLODEXTRINS
The present invention relates to a new method fo the preparation of inclusion compounds of nimesulid with cyclodextrins.
The inclusion compound of nimesulide wit cyclodextrins and the relevant methods of preparation are already described in the Italian patent application No. 20393 A/90 as compound endowed with analgesic and antiinflammatory activity, having a good water solubility and a more efficient and rapid absorption in comparison with the uncomplexed nimesulide.
The methods of preparation of the inclusion compound of nimesulide with cyclodextrins, described in the above mentioned Italian patent application, include the coprecipitation of the inclusion compound from an organic solution of nimesulide mixed with an aqueous solution of cyclodextrin, or the neutralization of the aqueous solution of cyclodextrins, the solubilization of nimesulide and isolation of the inclusion compound, or the isolation from saturated aqueous solution of the inclusion compound of nimesulide with cyclodextrins.
By these methods, the inclusion compound can be isolated by filtration, freeze-drying or evaporation under reduced pressure.
These methods are industrially not much applicable for great amounts of aqueous or organic solution to be used, requiring a considerable expenditure of time an expensive processes when they must be removed, besides showing obvious implications at environmental level.
These procedures require long time and multistage processing including solubilization, initial reaction, recrystallization, filtration, washing and drying. Some of these methods foresee the use of an organic solvent whose residues in the inclusion compound may be difficult to eliminate completely or may cause environmental problems.
The present invention relates to an one-step process for the preparation of the inclusion compounds of nimesulide with water-soluble cyclodextrins.
The method of the invention consists in subjecting a solid mixture, an aqueous solution or an homogeneous slurry of nimesulide and water-soluble cyclodextrins to co-milling, to spray-drying or to kneading respectively.
Water-soluble cyclodextrins which may be used according to the present invention are unsubstituted or substituted 0*1, β or ^"-cyclodextrins or hydrates thereof, preferably unsubstitued β-cyclodextrins. The resulting forms of nimesulide with water- soluble cyclodextrins show a great improvement of dissolution and wettability properties of nimesulide in aqueous or biological media, due to the following factors: - amorphous state of the obtained product; surfactant-like properties of cyclodextrins which can reduce the interfacial tension between water- insoluble drugs and the solvent; the smaller particle size produced by the co- milling, spray-drying and kneading processes; reduction of the dissolution energy of nimesulide
brought by its complete or partial amorphization or by the transition of its original crystalline state into a higher energy state.
The methods of the invention show furthermore a significant versatility over the other known methods.
They offer, in particular, an one-step process with the advantage of reducing the preparation steps saving time and cost, as well as better process control.
Also, the micromeritic properties of the spray- dried, co-milled and kneaded products can be checked in order to facilitate the next formulation steps, necessary for the preparation of the conventional solid oral dosage form, as granules, capsules, tablets.
The method, according to the present invention, involves a particularly simply and safe procedure and it is generally applicable in the preparation of other complexes of cyclodextrins with different drugs.
The different realization forms, according to the method of the invention, are now described in detail: a. Co-milling
A dry mixture of nimesulide and water-soluble cyclodextrins is laced in a rotating ball mill, in a vibrational ball mill, in an automatic rotor speed mill or any other suitable comminution, crushing, milling, micronization apparatus until an amorphization of the crystalline nimesulide is achieved. The amorphization degree is checked by the absence in the Differential Scanning Calorimetry thermogram of the obtained compound of the endothermic peak relative to the solid/liquid transition of the crystalline nimesulide. The milling of the inclusion compound can be stopped
when an amorphization degree of nimesulide (measured by the reduction of enthalpy value of melting of the crystalline nimesulide) sufficient to sensibly increase the dissolution rate, is achieved. Molar ratios between nimesulide and water-soluble cyclodextrins, in the mixture to be milled can vary from 1 : 0.5 and 1 : 10 moles/moles respectively, preferably between 1 : 0.8 and 1 : 4 moles/moles. The resulting milled mixture can be forced through a sieve to eliminate possible aggregates and then mixed in any mixing device to guarantee the most homogeneity and fluidity of the product. The resulting powdered milled inclusion compound of nimesulide and cyclodextrins can be subsequently used to prepare any desired solid dosage form (granules, tablets, capsules) with or without the addition of any excipients conventionally used in the pharmaceutical compositions. b. Spray-drying
Nimesulide and water-soluble cyclodextrins are co- mixed in distilled water and the pH of the solution is adjusted to the desired value by adding 0.1 NaOH or
NH4OH.
The solutions and the homogeneous suspensions are atomized into a drying chamber with a spray nozzle. The spray atomized typically works under the following conditions: inlet temperature: 140°C outlet temperature: 70°C
3 drying air flow rate: 0.35 m /min atomizing air pressure: 1 Kg./cm liquid phase feeding speed: 4 ml/min.
Molar ratios between nimesulide and water-soluble cyclodextrins in the preparation of their alkaline solution can vary from 1 : 0.5 and 1 : 10 moles/moles respectively, preferably between 1 : 0.8 and 1 : 4 moles/moles. The resulting mixture can be forced through a sieve to eliminate possible aggregates and subsequently mixed in any mixing device to guarantee the most homogeneity and fluidity of the product. The resulting powdered inclusion compound of nimesulide and cyclodextrins can be subsequently used to prepare any desired solid dosage form (granules, tablets, capsules) with or without the addition of any excipients of common use in the pharmaceutical compositions. c. Kneading Nimesulide is solubilized or suspended in an alkaline aqueous solution (pH > 7.0) and then water- soluble cyclodextrins are added. The preparation is homogenized by mixer-homogenizer, like Silverson, for the time period needed to achieve the desired degree of amorphization of the crystalline nimesulide. The preparation is dried in a forced ventilation oven at 40-50βC overnight.
Molar ratios between nimesulide and water-soluble cyclodextrins in the preparation of their alkaline aqueous solution can vary from 1 : 0.5 and 1 : 10 moles/moles respectively, preferably between 1 : 0.8 and 1 : 4 moles/moles. The resulting mixture can be forced through a sieve to eliminate possible aggregates and subsequently mixed in any mixing device to guarantee the most homogeneity and fluidity of the product. The resulting powdered inclusion compound of
nimesulide and cyclodextrins can be subsequently use to prepare any desired solid dosage form (granules, tablets, capsules) with or without the addition of an of the common excipients used in the pharmaceutica compositions.
The following examples illustrate the invention:
Example 1 Nimesulide (200 g) and the suitable amount of β cyclodextrin (about 205 g) were dry-mixed and the milled by a rotating ball mill. This working, being i function with the capacity and potency of the mill, ca be repeated more time until nimesulide-β-cyclodextri compound of the desired crystallinety was obtained.
Yield : 95%. After milling the compound was again mixe and forced through a 0.038 mm sieve to guarantee th homogeneity and to eliminate possible aggregates befor using it for the formulations.
Example 2 210 g of nimesulide were partially solubilized i 800 ml of ammoniacal solution (pH 8.2). The obtaine suspension was homogenized and dispersed by means of mixer-homogenizer like Silverson for 2 hours. Th suitable amount of β-cyclodextrin was added in order t obtain a nimesulide-β-cyclodextrin compound 1 : 2. After dispersion, β-cyclodextrins were solubilize under stirring by Silverson until the suspensio homogenization and solid particle reduction wer achieved. The compound was dried in an oven at 45° overnight putting it in a thin layer. Before sendin the compound for the formulations, it was milled by 200 μm sieve.
Example 3 Nimesulide was dissolved in alkaline solution (5 1/for the addition of NH4OH (pH 8.2). The required amount of β-cyclodextrin was then added to the alkaline solution on β-cyclodextrin, in order to have a molar ratio 1 : 1 in the final compound. The mixture was kept under stirring until a complete dissolution. The solution was feeded (spray-drier BUCUI 190 M) with the following operative conditions: feeding speed: 720 ml/h air temperature: 150eC air flow: 400 1/h
Example 4 Granules Inclusion compound of nimesulide with β-cyclodextrins 468 mg sorbitol 2472 mg
Saccharin sodium 10 mg
Orange flavour powder 50 mg Characteristics of inclusion compound of nimesulide with cyclodextrins 1. Differential scanning calorimetry data
The- differential scanning calorimetry data (using Mettler TA 3000 at a rate of 10°C/min. under N2 gas in the range of heating temperature from 30° to 200eC) are shown in figure 1. By comparing these data with differential scanning calorimetry of pure nimesulide (a), it is possible to observe a complete amorphization in the case of kneaded mixture (c) and spray-dried one (d), and a partial amorphization for the co-milled one (b).
2. Infrared spectroscopy
The infrared spectra are reported in figure 2. By comparing the spectrum of nimesulide (a) with that of spry-dried (b), kneaded (c) and co-milled (d) there are evident modifications in the bands around 1520 cm-1, due to the asymmetric stretching of nitro group, and especially in the region 1300-1200 cm-1, giving proof of the significant differences existing between nimesulide and the above mentioned mixture. 3. Solubility data
The solubility (saturation concentration) of the inclusion compound of nimesulide with cyclodextrins was measured by placing an excess amount of the powdered compound in a flask containing 50 ml of pH 7.4 phosphate buffer at 25°C; the flasks were placed in a shaking apparatus and aliquots of sample solutions were taken and filtered through a Millipore membrane filter; the concentration of nimesulide in the filtered aliquot was determined by spectrophotometer VARIAM DMS 100 at 369.9 nm.
As shown in table 1 , a relevant increase of the nimesulide solubility values was achieved by preparing the inclusion compound of nimesul ide and cyclodextrins , according to the present invention . It is particularly interesting to observe that nimesul ide concentrations resulting from the inclusion compound of nimesulide with cyclodextrins are about 20 times higher than from crystall ine pure nimesulide . 4 . Dis solution data Dissolution profiles of the inclusion compound of nimesulide with cyc lodextrins were measured applying
the USP XXII dissolution method. The withdrawn sample solutions are checked for the nimesulide concentration by UV.Vis spectrophotometric analysis. These results stress the advantages of the inclusion compound of nimesulide with cyclodextrins obtained by any of the three techniques (table 2), described in this application.
TABLE I
EQUILIBRIUM SOLUBILITY
Claims
1. A method for the preparation of the inclusion compounds of nimesulide with cyclodextrins which consists in subjecting a solid mixture, an aqueous solution or a homogeneous slurry of nimesulide and water-soluble cyclodextrins to co-milling, to spray- drying or to kneading respectively.
2. A method according to claim 1, in which the molar ratio of nimesulide to water-soluble cyclodextrins is comprised between 1 : 0.5 and 1 : 10.
3. A method according to claims 1 or 2, in which the water-soluble cyclodextrins are selected from unsubstituted, substituted 0*1, β and Jr-cyclodextrins, or a hydrates thereof.
4. A method according to claim 3 in which the water- soluble cyclodextrin is the unsubstituted β- cyclodextrin.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI921833A IT1255462B (en) | 1992-07-28 | 1992-07-28 | METHOD OF PREPARATION OF NIMESULIDE INCLUSION COMPOUNDS WITH CYCLODESTRINE |
| ITMI92A001833 | 1992-07-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1994002177A1 true WO1994002177A1 (en) | 1994-02-03 |
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ID=11363762
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1993/001560 WO1994002177A1 (en) | 1992-07-28 | 1993-06-18 | Method of preparation of inclusion compounds of nimesulide with cyclodextrins |
Country Status (2)
| Country | Link |
|---|---|
| IT (1) | IT1255462B (en) |
| WO (1) | WO1994002177A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999047172A2 (en) * | 1998-03-13 | 1999-09-23 | Recordati S.A. Chemical And Pharmaceutical Company | Oral pharmaceutical compositions to be taken without liquids, which contain inclusion complexes |
| US6232304B1 (en) | 1996-05-07 | 2001-05-15 | Pfizer Inc. | Inclusion complexes of aryl-heterocyclic salts |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0371431A2 (en) * | 1988-11-28 | 1990-06-06 | Vectorpharma International S.P.A. | Supported drugs with increased dissolution rate, and a process for their preparation |
| WO1991017774A1 (en) * | 1990-05-22 | 1991-11-28 | Boehringer Ingelheim Italia S.P.A. | Inclusion compounds of nimesulide with cyclodextrins |
| FR2662360A1 (en) * | 1990-05-22 | 1991-11-29 | Leetrim Ltd | INCLUSION COMPOUNDS OF NIMESULIDE WITH CYCLODEXTRIN, PROCESSES FOR THE PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITIONS WITH ANALGESIC AND ANTI-INFLAMMATORY ACTIVITY CONTAINING SAME |
-
1992
- 1992-07-28 IT ITMI921833A patent/IT1255462B/en active IP Right Grant
-
1993
- 1993-06-18 WO PCT/EP1993/001560 patent/WO1994002177A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0371431A2 (en) * | 1988-11-28 | 1990-06-06 | Vectorpharma International S.P.A. | Supported drugs with increased dissolution rate, and a process for their preparation |
| WO1991017774A1 (en) * | 1990-05-22 | 1991-11-28 | Boehringer Ingelheim Italia S.P.A. | Inclusion compounds of nimesulide with cyclodextrins |
| FR2662360A1 (en) * | 1990-05-22 | 1991-11-29 | Leetrim Ltd | INCLUSION COMPOUNDS OF NIMESULIDE WITH CYCLODEXTRIN, PROCESSES FOR THE PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITIONS WITH ANALGESIC AND ANTI-INFLAMMATORY ACTIVITY CONTAINING SAME |
Non-Patent Citations (2)
| Title |
|---|
| CHEMICAL ABSTRACTS, vol. 118, no. 22, 1992, Columbus, Ohio, US; abstract no. 219627y * |
| L. OWAIS ET AL.: "A NOVEL METHOD FOR THE PREPARATION OF SOME BETA CYCLODEXTRIN COMPLEXES USING A COLLOIDAL MILL.", CONGR. INT. TECHNOL. PHARM. 6TH, vol. 5, pages 339 - 348 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6232304B1 (en) | 1996-05-07 | 2001-05-15 | Pfizer Inc. | Inclusion complexes of aryl-heterocyclic salts |
| US6399777B2 (en) | 1996-05-07 | 2002-06-04 | Pfizer Inc. | Inclusion complexes of aryl-heterocyclic salts |
| WO1999047172A2 (en) * | 1998-03-13 | 1999-09-23 | Recordati S.A. Chemical And Pharmaceutical Company | Oral pharmaceutical compositions to be taken without liquids, which contain inclusion complexes |
| WO1999047172A3 (en) * | 1998-03-13 | 1999-11-11 | Recordati Chem Pharm | Oral pharmaceutical compositions to be taken without liquids, which contain inclusion complexes |
Also Published As
| Publication number | Publication date |
|---|---|
| ITMI921833A0 (en) | 1992-07-28 |
| IT1255462B (en) | 1995-11-02 |
| ITMI921833A1 (en) | 1994-01-28 |
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