WO2004093884A2 - High drug load mesalazine sachet - Google Patents

High drug load mesalazine sachet Download PDF

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Publication number
WO2004093884A2
WO2004093884A2 PCT/EP2004/004297 EP2004004297W WO2004093884A2 WO 2004093884 A2 WO2004093884 A2 WO 2004093884A2 EP 2004004297 W EP2004004297 W EP 2004004297W WO 2004093884 A2 WO2004093884 A2 WO 2004093884A2
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WO
WIPO (PCT)
Prior art keywords
mesalazine
pharmaceutical formulation
granulate
coating
released
Prior art date
Application number
PCT/EP2004/004297
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French (fr)
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WO2004093884A3 (en
Inventor
Svenn Klüver JEPSEN
Original Assignee
Ferring B.V.
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Priority claimed from EP20030388023 external-priority patent/EP1470819A1/en
Priority to PL04729050T priority Critical patent/PL1615648T3/en
Priority to NZ542591A priority patent/NZ542591A/en
Priority to ES04729050.7T priority patent/ES2486245T3/en
Priority to EP04729050.7A priority patent/EP1615648B1/en
Priority to SI200432177T priority patent/SI1615648T1/en
Priority to AU2004231316A priority patent/AU2004231316B2/en
Priority to JP2006505237A priority patent/JP4753864B2/en
Priority to DK04729050.7T priority patent/DK1615648T3/en
Application filed by Ferring B.V. filed Critical Ferring B.V.
Priority to CN2004800107906A priority patent/CN1777430B/en
Priority to CA2520026A priority patent/CA2520026C/en
Priority to US10/553,629 priority patent/US8858992B2/en
Priority to MXPA05011308A priority patent/MXPA05011308A/en
Publication of WO2004093884A2 publication Critical patent/WO2004093884A2/en
Publication of WO2004093884A3 publication Critical patent/WO2004093884A3/en
Priority to IL170978A priority patent/IL170978A/en
Priority to NO20055534A priority patent/NO335375B1/en
Priority to HK06104975.5A priority patent/HK1083312A1/en
Priority to US14/483,695 priority patent/US9402815B2/en

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    • B32B15/04—Layered products comprising a layer of metal comprising metal as the main or only constituent of a layer, which is next to another layer of the same or of a different material
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    • A61K31/60—Salicylic acid; Derivatives thereof
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    • A61K31/606—Salicylic acid; Derivatives thereof having amino groups
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Abstract

The present invention is directed to a high drug formulation having desirable properties in terms of ease of manufacture and visual appearance as well as a sachet for the formulation.

Description

HIGH DRUG LOAD MESALAZINE SACHET
Field of the Invention
The present invention concerns a pharmaceutical formulation comprising a high load of active drug.
In particular, it concerns a particulate pharmaceutical formulation comprising a high load (i.e. with high weight % active drug) of 5-aminosalicylic acid (5-ASA, mesalamine, mesalazine) for oral administration as well as a method for producing it and a sachet for the formulation.
The present writ claims priority from the Danish patent application PA 2003 00612, The European patent application EP 03388023, and the US provisional patent application 60/464649.
Technical Background
Oral pharmaceutical formulations comprising mesalazine are known, which are either tablets or granulate. The granulate may be packed in sachets. For the purposes of the present invention a "sachet" will refer to an envelope or bag for a granulate, while "granulate" refers to particles, granulate or spheronised particles.
Presently, tablets containing 250 or 500 mg mesalazine are known. Tablets of 250 mg typically weigh about 540 mg, i.e. they have a drug load of (250/540)% by weight = 46% by weight. Tablets containing up to 84 % by weight mesalazine have been described in the patent application WO 00/44353 with the title "Pharmazeutische Zusammensetzungen" . For sachets, Dr. Falk Pharma has launched a product which claims to contain 500 mg mesalazine in a 930 mg sachet, corresponding to a drug load of 54% by weight.
Presently up to 4 g of mesalazine are often prescribed for the daily treatment of intestinal bowel diseases, such as Crohn's disease and Ulcerative Colitis.
If 4 g of mesalazine is administered in 250 mg tablets, the patient needs to swallow 16 tablets a day.
Alternatively, 500 mg tablets may be administered, but with a drug load in the 50% range, the tablets will weigh about 1 g each, which many patients find rather large to swallow.
There exists a need to provide a product which allows administering large daily doses of drug without adversely affecting patient compliance.
Methods for manufacturing oral pharmaceutical formulations comprising mesalazine on an industrial scale are known. However, known methods of manufacture necessitate a high number of production steps to achieve a product having desirable release characteristics. This leads to cumbersome and expensive manufacture.
Disclosure of the Invention
These problems and others mentioned below are addressed by aspects of the invention.
According to an aspect, the present invention concerns an oral pharmaceutical formulation, preferably for a sachet, comprising an amount of mesalazine selected among the group consisting of 55; 60; 65; 70; 75; 80; 85; 90; 92; 94 and 96 % by weight. According to a preferred aspect, the formulation comprises 92 - 98, preferably 94 - 96, % by weight mesalazine. These aspects provide a high load pharmaceutical composition.
For the purposes of the present invention "mesalazine" also encompasses pharmaceutically acceptable salts and esters thereof, such as those mentioned in WO 97/23199 p. 15, 1. 17 - p. 6, 1. 12, as well as prodrugs, such as balsalazide .
The formulation is preferably in the form of a particulate material, e.g. granulate, spheres, pellets, particles, preferably granulate.
According to an aspect, the present invention concerns a pharmaceutical formulation further comprising a pharmaceutically acceptable binder, preferably Povidone, in an amount selected among the group consisting of 1; 2; 3; 4; 5; 6; 7; 8; 9; 10; and 12 % by weight. According to a preferred aspect, the formulation comprises 1 - 10, preferably 2 - 8; more preferred 3 - 7; preferably 4 - 6; most preferred 5 % by weight Povidone.
The pharmaceutically acceptable binder may comprise any acceptable binder such as Acacia, Gelatin, Hydroxypropyl cellulose, Hydroxypropylmethyl cellulose, Methylcellulose, Polyetylene glycol (PEG) , Povidone, Sucrose, Starch or a mixture of any of these. Povidone (Polyvinylpyrrolidone, PVP) is preferred.
According to an aspect, the present invention concerns a pharmaceutical formulation further comprising a coating.
The coating should preferably comprise a release modifying agent, such as ethylcellulose, carnauba wax, shellac or a mixture of any of these. Ethylcellulose is preferred. The selected coating depends inter alia on the desired release pattern. It may be chosen from rate limiting barrier materials, e.g. enteric or delayed coating material, such as polymethacrylate, commercially available in the form of Eudragits, e.g. Eudragit NE 40 D or Eudragit L 100. When a semi-permeable polymer is used, ethyl cellulose is the most preferred coating.
According to an aspect, the formulation is a modified release formulation, preferably an extended release formulation.
According to an aspect, the formulation comprises a coating, the ratio of the weight of said coating to the weight of said mesalazine or said pharmaceutically acceptable salt being selected among 0.1-10%; 0.3-7%; 0.5-5%; 0.7-3%; 0.8-2%; and 0.9-1.5%. The amount of coating may be adjusted to reach the desired release profile. Very high amount of coating may impede the release of active ingredient.
According to an aspect, the present invention concerns a pharmaceutical formulation essentially consisting of mesalazine, a pharmaceutically acceptable binder and a coating .
According to an aspect, the present invention concerns a pharmaceutical formulation having in vitro release characteristics of mesalazine of at least 40, 50, 60, 70, 80, or 90 % released after 240 min, of the total amount of mesalazine in the formulation, measured in a model system using a USP Paddle System 2 operated at 37°C with stirring at 100 rpm. Usually a higher release is preferred in order to ensure effective release in the intestines . According to an aspect, the present invention concerns a pharmaceutical formulation having in vitro release characteristics of mesalazine of a) 5 - 25 % released after 15 min; b) 30 - 70 %, preferably 40 - 60 %, released after 90 min; and c) 75 - 100 % released after 240 min; of the total amount of mesalazine in the formulation, measured in a model system using a USP Paddle System 2 operated at 37°C with stirring at 100 rpm.
The dissolution parameters for the model system were: Dissolution medium: 1000 ml deaerated 0.1 M sodium phosphate buffer pH 7.5. Apparatus: USP 23 Paddle method (Apparatus 2)
Shaft rotation speed: 100 rpm. 1 g sachets were used for experiments .
According to a first preferred aspect, the present invention concerns a pharmaceutical formulation having a similarity factor f2 above a number selected from 25, 30, 35, 40, 45, 50, 55, 60, 65, and 70, as compared to a standard having the in vitro release characteristics of mesalazine of a) 12 % released after 15 min; b) 50 % released after 90 min; and c) 85 % released after 240 min; as measured under the conditions listed above.
The similarity factor f2 is defined as
/2 -r,)2]"α5 *ιooj
Figure imgf000006_0001
wherein n is the number of time points, R (t) is the mean percent active ingredient dissolved of the standard, and T (t) is mean percent active ingredient dissolved of the formulation according to the invention. The similarity factor is usually considered satisfactory if in the range 50 - 100, but may for the purposes of the present invention be even smaller.
According to a second preferred aspect, the present invention concerns a pharmaceutical formulation having a similarity factor f2 above a number selected from 25, 30, 35, 40, 45, 50, 55, 60, 65, and 70, as compared to a standard having the in vitro release characteristics of mesalazine of d) 21 % released after 15 min; e) 68 % released after 90 min; and f) 94 % released after 240 min; as measured under the conditions listed above.
According to an aspect, the present invention concerns a pharmaceutical formulation, wherein said pharmaceutical formulation is packed in a sachet.
According to an aspect, the present invention concerns a method for manufacturing a granulate comprising the steps: a) mixing mesalazine with granulation liquid; b) obtaining granulate by granulating, compacting or extruding; c) drying the granulate; d) adjusting the size of the granulate as necessary; and e) sieving the granulate as necessary; characterised in the additional step of: f) coating the granulate; and optionally further: g) sieving the coated granulate; h) air purging the coated granulate. According to an aspect, the present invention concerns a method, wherein the coated granulate are packed in sachets .
Other suitable package forms are containers usually used for oral formulations.
This method provides a simple manufacturing method for pharmaceutical formulations.
According to an aspect of the invention a pharmaceutical composition is provided being produced without spheronization. The composition is thus obtainable without spheronization. Thereby the need for a spheronization aid is eliminated, allowing the pharmaceutical composition to have a high drug load.
Spheronization has been used to obtain a reproducible product on an industrial scale, the product being visually appealing and easy to administer, leading to high patient compliance.
It has until the present invention been considered neccessary to spheronise mesalazine drugs in order to obtain a visually appealing and easily administrable sachet product. Spheronisation implies the use of a spheronization aid or enhancer, such as microcrystalline cellulose. The presence of a spheronization aid leads to drug loads lower than obtainable with the present invention.
There exists a demand for a dust-free high load pharmaceutical composition. A pharmaceutical formulation meeting these criteria is achieved according to an aspect of the invention without spheronization. Such composition may be provided by obtaining a granulate. A granulate may be obtained by granulating, compacting or extruding, in order to achieve a product which is visually appealing to a person to whom said pharmaceutical formulation is administered. Compacting may be performed e.g. by roll compacting. The granulate is preferably obtained by extruding.
According to a certain preferred aspect of the present invention, the pharmaceutical composition is obtained according to co-pending patent application PCT/DK01/00677 with the title "Method for the preparation of a pharmaceutical composition comprising 5-aminosalicylic acid for use in treatment of Ulcerative Colitis and Crohn's Disease", with modifications. The modifications comprise that the coating should be adapted according to the present invention, and that after coating, sieving and nitrogen purging, the obtained granulate are packed in sachets, without the need for further excipients (cf. Example 3 and Fig. 4 of said application) . It is especially preferred that the granulation liquid comprises at least 50%, more preferred 60%, preferably 70%, more preferred 80%, preferably 85%, more preferred 90%, w/w water.
According to an aspect, the present invention concerns the method, wherein the granulation liquid consists of Povidone dissolved in water.
According to an aspect, the present invention concerns the method, wherein said drying step c) is performed in a fluid bed dryer.
According to an aspect, the present invention concerns the method, wherein said adjusting of size step d) is performed by milling.
According to an aspect, the present invention concerns the method, wherein the sieving step e) is performed by selecting granulate passing a 1.8 mm sieve, but not passing a 0.5 mm sieve.
Other suitable sieves may be used, e.g. having sizes selected among the group consisting of 4.0; 3.15; 2.5;
2.0; 1.8; 1.6; 1.4; 1.25; 1.18; 1.0; 0.9; 0.8; 0.71; 0.6; 0.5 and 0.4 mm for selecting desired granulate. The sieves may be chosen to determine upper and/or lower limits of particle sizes.
According to another aspect, the resulting granules, after being milled, have a particle size distribution measured by sieve analysis where the main fraction is from 850 μm to 1000 μm. The holes in an extruder may be varied in order to obtain the desired particle size.
According to an aspect, more than 75 %, preferably more than 85 % and most preferably more than 90 % of the granules have a particle size from 850 μm to 1000 μm.
According to an aspect, the present invention concerns the method, wherein the coating step f) is performed with ethylcellulose .
According to an aspect, the present invention concerns the method, wherein the coating step f) is performed by spraying with an amount of coating material, adjusted according to the specific surface area, to be in the range 0.09 - 0.17 mg/cm2, preferably 0.11 - 0.15 mg/cm2, more preferred 0,12 - 0,14 mg/cm2, followed by drying. These amounts have been found suitable for coating with ethylcellulose .
It has been discovered that the desired release profile may be obtained by adjusting the amount of coating material used according to the specific surface area. The specific surface area may be measured by permeametry according to "Evaluation of a permeametry technique for surface area measurement of coarse particulate materials, International Journal of Pharmaceutics, Eriksson et al . , 1990, 63, p. 189-199".
Granulate obtained according to co-pending patent application PCT/DK01/00677, preferably with modifications according to the present invention, is especially preferred, as is has a smooth surface facilitating measurement of specific surface area as well as subsequent coating.
In order to be able to determine the amount of coating that has to be applied to the granules the surface area is measured. Based on the measured correlation between the amount of coating per surface area and the dissolution rate profile, the amount of coating needed can be predicted from the measured surface area of the granules. The amount is adjusted by trial and error, as it depends on the exact conditions used, e.g. apparatus and excipients.
According to an aspect, the present invention concerns the method, wherein the sieving step g) is performed on a rotation sieve, preferably with a mesh size of 2.5 mm, in order to obtain coated granulate of a size smaller than or equal to 2.5 mm.
Other suitable sieves may be used, e.g. having sizes selected among the group consisting of 4.0; 3.15; 2.5; 2.0; 1.8; 1.6; 1.4; 1.25; 1.18; 1.0; 0.9; 0.8; 0.71; 0.6; 0.5 and 0.4 mm for selecting desired size of coated granulate.
According to an aspect, the present invention concerns a pharmaceutical formulation, preferably according to any of the aspects mentioned above, obtainable according to the method.
According to an aspect, the invention concerns pharmaceutical formulations for medical use.
According to an aspect, the present invention concerns the use of mesalazine for the manufacture of a pharmaceutical formulation according to the invention, comprising a total amount of mesalazine chosen among the group consisting of 0,5 g; 1,0 g; 1,5 g; 2 g; 3 g; 4 g; 5 g; 6 g; 8 g; and 10 g.
According to an aspect, the present invention concerns the use, wherein the medicament is for the treatment of intestinal bowel disease (IBD) , preferably Crohns's Disease or Ulcerative Colitis.
The formulations according to the invention are suitable for the treatment of IBD.
According to an aspect the invention concerns a method for treatment of IBD, wherein the formulation according to the invention is administered to the patient, preferably 1, 2, 3 or 4 times daily.
The formulations according to the invention may be packed in different containers which allow administering to patients, such as capsules, blister packages, dispensers, glass or plastic containers, and sachets.
According to an aspect, the present invention concerns a sachet for a pharmaceutical formulation, preferably according to the invention.
The present sachet may be used for any pharmaceutical formulation, but is especially suitable for storing pharmaceuticals comprising sensitive compounds such as mesalazine .
According to an aspect, the present invention concerns a sachet, comprising the layers: i) paper; ii) bonding layer, preferably an adhesive such as polyethylene ; iii) barrier layer, preferably aluminium foil; and iv) sealing layer, preferably low density polyethylene.
Mesalazine is sensitive to humidity, atmospheric air and/or light. A sachet for a product containing mesalazine should therefore preferably provide a barrier to humidity, atmospheric air and light. The sachet should also be easy to open for a patient, preferably without the use of additional tools, such as scissors. It has been a problem to provide a sachet with the necessary barrier properties without sacrificing the possibility of tearing open the sachet with human fingers. Further, existing sachets tend to suffer from the build up of static electricity. Preferably, a sachet should be easy to manufacture, easy to fill, easy to empty, and have an appealing look to improve patient compliance.
This aspect provides a sachet giving long storage stability for a pharmaceutical composition contained therein, e.g. where the active pharmaceutical ingredient is mesalazine. Further, the sachet is easy to tear and static electricity is eliminated, providing for a sachet which may be emptied completely for its contents. The combination of the sachet and the oral formulation according to the present invention provides for little build up of static electricity.
According to an aspect, the present invention concerns the sachet, wherein the bonding layer ii) preferably has a weight per unit area of 6-20 g/m2, preferably 9-15 g/m2, more preferred 12 g/m2,- the barrier layer iii) preferably has a thickness of 6-30 μm, more preferred 7-25 μm, preferably 9-25 μm, more preferred 8-20 μm, preferably 9- 15 μm, more preferred 12 μm; and/or the sealing layer iv) preferably has a weight per unit area of 10-100 g/m2, more preferred 15-75 g/m2, preferably 20-50 g/m2, more preferably 30-40 g/m2, most preferred 35 g/m2.
The outer paper i) has in a preferred embodiment a weight per unit area of 10-100 g/m2, preferably 30-70 g/m2, most preferred 50 g/m2.
According to an aspect, the present invention concerns the use of the sachet for a pharmaceutical composition according to the invention.
The sachet has proven suitable for storing the pharmaceutical compositions according to the invention.
According to an aspect, the present invention concerns the use of the sachet for medical purposes.
According to an aspect of the present invention it is not limited to the use of mesalazine as the active ingredient, but also relates to other active ingredients, such as the ingredients mentioned in WO 00/44353, p. 12- 16. Other low potent active ingredients are suitable for the present invention. Especially ibuprofen is envisioned as replacing mesalazine.
According to an aspect of the present invention further excipients may be comprised in the composition according to the invention, such as fillers, disintegrants, pH adjusters, or surfactants. Such excipients are well known from the literature, see e.g. WO 00/44353, p. 16-20, for a number of suitable excipients. Examples
Unless otherwise stated, all percentages are in % by weight .
Example 1
A batch for the production of 180,000 sachets of prolonged release granules was provided as follows.
Constituents Quantity Specification
Mesalazine 180 kg Ferring
Povidone 9 kg Ph. Eur.
Water, purified 33,3 kg** Ph. Eur. Ethylcellulose 1,9 kg*** Ph. Eur. Acetone 188 kg** Ph. Eur.
** Evaporates during production.
*** The amount of ethylcellulose was adjusted to ensure the desired dissolution profile of the finished product. Ph. Eur. refers to the current edition at the time of filing of the present application.
The manufacturing method follows closely the manufacturing method described in co-pending patent application PCT/DKOl/00677, with some exceptions. The amount and type of ingredients is adjusted, and in particular the amount of ethylcellulose is reduced to obtain the desired dissolution profile. In this example no tablets were made, so excipients for this purpose are not included, no dry blending is performed after the air purging, and no tableting performed. The granulate product resulting from the present process is therefore different from the tablet of said application.
The manufacturing process for the formulation can be divided into 9 steps: 1. Preparation of granulation liquid
2. Granulation of Mesalazine with water and PVP
3. Extrusion
4. Fluid bed drying
5. Milling
6. Sieving
7. Coating
8. Sieving
9. Air purging
Equipment for the production Function
NICA Extruder E220 Extrusion
Rotostat T05 Blending NIRO Fluid bed dryer Drying
Quadro Comil U10 Milling
Mogensen sieve Sieving
Hϋttlin Kugelcoater HKC 400 Coating
Prodima rotation sieve Sieving Purging unit Air purge
Step 1:
For one batch of granulation liquid water is filled into a Mϋller drum. The mixer is put into position and started. Polyvinylpyrrolidone (PVP) is slowly sprinkled onto the water and the mixer is allowed to run a fixed time until all PVP is dissolved.
Step 2 and 3 : Mesalazine is placed in a vibrating Prodima hopper and by the use of a conveyor the mesalazine is transported up to a weight belt feeder dosing the mesalazine into the continuous Niro line. In the first part of the Niro line the mesalazine and the water solution of PVP are mixed to a wet mass before being transported into the extruder. After extrusion of the wet mass of mesalazine and PVP/water through a screen mesh 0.9 mm, the granules fall directly into the fluid bed dryer.
Step 4 : The fluid bed dryer is divided into two main sections. In the first section, the granules are dried on the surface to prevent them from sticking together. In this section of the fluid bed, a random mixing of the granules takes place. After a certain residence time, the granules are moved into the second part of the dryer where the actual drying takes place. In the second part of the dryer the granules are guided by the use of the drying air through the dryer (special pattern of holes in the gill plate) . When the granules are dry they are allowed to fall into a drum placed under the fluid bed. The fluid bed is constructed in such a way that the overall dwelling time in the fluid bed is approximately 2% hours.
Step 5: The drums containing the dry granules are placed upside down on top of the mill and the granules are gently milled using a screen, which will only break the granules that are too long. After passing the mill, the granules are allowed to fall into a drum.
Step 6:
Due to the fact that the milling process generates a small amount of undersized granules, the granules are sieved using a Mogensen vibration sieve. Granules, which pass the screen 0.8 mm, are discarded or can be collected for reprocessing stored in airtight, labelled containers.
Step 7:
200 kg of sieved granules are coated in a Kugel coater (fluid bed system) with a coating liquid consisting of ethyl cellulose dissolved in acetone. In order to be able to determine the right amount of ethylcellulose necessary to apply on the granules to get the desirable dissolution rate profile, the surface area of the granules is measured prior to the coating process. The prediction of the quantity of coating that is necessary to apply on the granules has been developed based on the fact that there is a correlation between the amount of coating per surface area and the dissolution rate of the granules.
When the coating step was performed in a HKC 400 Hϋttlin Kugel coater and followed by production scale sieving, release characteristics according to the invention, as measured as released % of total amount of mesalazine or according to the first preferred aspect as defined by the similarity factor, was achieved when the amount of ethylcellulose was adjusted to 0.13 mg/cm2.
After finishing the coating process, the coated granules are loaded into a drum for further processing.
Step 8 :
After the coating process, the coated granules are sieved in a Prodima rotation sieve. Large lumps are discarded.
Step 9:
After sieving the batch of coated granules, they are divided into two drums for purging with compressed air or nitrogen. The granules are purged for 6 - 14 hours. This purging process is necessary to reduce the amount of residual solvent (acetone) in the coated granules.
This batch gave granulate with the following approximate composition: mesalazine 94,3%
Povidone 4,7%
Ethylcellulose 1,0% The granulate was subsequently filled into sachets.
The material of the sachets had the following composition:
Paper, claycoated 50 g/m2
Polyethylene, low density 12 g/m2 Aluminium foil 12 μm
Polyethylene, low density 35 g/m2 For the present example 12 g/m2 PE corresponds to 13 μm, and 35 g/m2 PE corresponds to 38 μm. The material had a grammage of 129 g/m2. The permeability to water vapour was <0.05 g/m2, 24 h, 25°C, 75% RH, and to 02 <0.05 ml/m2, 24 h, atm, 23°C, 75% RH.
The sachets were folded around the filling tube of a filling/sealing station, such that the paper was on the outside of the sachet, and then sealed lengthwise, with a low density polyethylene as a sealing layer. After forming the cross seal at the bottom the sachet is filled with granulates, and then sealed again at the top and finally cut.
All citations are incorporated in their entirety by reference .

Claims

1. Oral pharmaceutical formulation in the form of a granulate comprising more than 60% by weight of mesalazine or a pharmaceutically acceptable salt thereof.
2. Pharmaceutical formulation according to claim 1 comprising more than 70% by weight of mesalazine or a pharmaceutically acceptable salt thereof.
3. Pharmaceutical formulation according to claim 1 comprising more than 80% by weight of mesalazine or a pharmaceutically acceptable salt thereof.
4. Pharmaceutical formulation according to any of the preceding claims, having in vitro release characteristics of mesalazine of at least 40% released after 240 min, of the total amount of mesalazine in the formulation, measured in a model system using a USP Paddle System 2 operated at 37°C with stirring at 100 rpm.
5. Pharmaceutical formulation according to any of the preceding claims, having in vitro release characteristics of mesalazine of a) 5 - 25 % released after 15 min; b) 30 - 70 %, preferably 40 - 60 %, released after 90 min; and c) 75 - 100 % released after 240 min; of the total amount of mesalazine in the formulation measured in a model system using a USP Paddle System 2 operated at 37°C with stirring at 100 rpm.
6. Pharmaceutical formulation according to any of the preceding claims, having a similarity factor f2 above 30, preferably above 40, more preferred above 50, as compared to a standard having the in vitro release characteristics of mesalazine of a) 12 % released after 15 min; b) 50 % released after 90 min; and c) 85 % released after 240 min; as measured under the conditions of claim 5.
7. Pharmaceutical formulation according to any of the preceding claims, further comprising a pharmaceutically acceptable binder, preferably Povidone, in an amount less than or equal to an amount selected among the group consisting of 1; 2; 3; 4; 5; 6; 7; 8; 9; 10 and 12 % by weight .
8. Pharmaceutical formulation according to any of the preceding claims, further comprising a coating, preferably comprising or consisting of ethylcellulose .
9. Pharmaceutical formulation according to any of the preceding claims, comprising a coating, the ratio of the weight of said coating to the weight of said mesalazine or said pharmaceutically acceptable salt being selected among 0.1-10%; 0.3-7%; 0.5-5%; 0.7-3%; 0.8-2%; and 0.9-1.5%.
10. Pharmaceutical formulation according to any of the preceding claims, essentially consisting of mesalazine, a pharmaceutically acceptable binder and a coating.
11. Pharmaceutical formulation according to any of the preceding claims, wherein said pharmaceutical formulation is packed in a sachet .
12. Method for manufacturing a pharmaceutical formulation according to any of the preceding claims, comprising the steps: a) mixing mesalazine with granulation liquid; b) obtaining granulate by granulating, compacting or extruding; c) drying the granulate; d) adjusting the size of the granulate as necessary; and e) sieving the granulate as necessary; characterised in the additional step of: f) coating the granulate; and optionally further: g) sieving the coated granulate; h) air purging the coated granulate.
13. Method according to claim 12, wherein said coated granulate are packed in a sachet .
14. Method according to claim 12 or 13, wherein said granulation liquid consists of Povidone dissolved in water.
15. Method according to any of the claims 12 - 14, wherein said drying step c) is performed in a fluid bed dryer.
16. Method according to any of the claims 12 - 15, wherein said adjusting of size step d) is performed by milling.
17. Method according to any of the claims 12 - 16, wherein said sieving step e) is performed by selecting granulate passing a 1.8 mm sieve, but not passing a 0.5 mm sieve.
18. Method according to any of the claims 12 - 17, wherein said coating step f) is performed with ethylcellulose .
19. Method according to any of the claims 12 - 18, wherein said coating step f) is performed by applying an amount of coating material adjusted, according to the specific surface area, to be in the range 0.09 - 0.17 mg/cm2, preferably 0.11 - 0.15 mg/cm2, followed by drying .
20. Method according to any of the claims 12 - 19, wherein said sieving step g) is performed on a rotation sieve, preferably with a mesh size of
2.5 mm.
21. Use of mesalazine for the manufacture of a pharmaceutical formulation according to any of the claims 1 - 11, comprising a total dosage amount of mesalazine chosen among the group consisting of 0,5 g; 1,0 g; 1,5 g; 2 g; 3 g; 4 g; 5 g; 6 g; 8 g; and 10 g; preferably packed in a sachet .
22. Use according to the preceding claim, wherein the medicament is for the treatment of intestinal bowel disease, preferably Crohns's Disease or Ulcerative Colitis.
PCT/EP2004/004297 2003-04-23 2004-04-23 High drug load mesalazine sachet WO2004093884A2 (en)

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US10/553,629 US8858992B2 (en) 2003-04-23 2004-04-23 High drug load mesalazine sachet
MXPA05011308A MXPA05011308A (en) 2003-04-23 2004-04-23 High drug load mesalazine sachet.
CN2004800107906A CN1777430B (en) 2003-04-23 2004-04-23 High drug load mesalazine sachet
ES04729050.7T ES2486245T3 (en) 2003-04-23 2004-04-23 Mesalazine envelope with high drug load
EP04729050.7A EP1615648B1 (en) 2003-04-23 2004-04-23 High drug load mesalazine sachet
SI200432177T SI1615648T1 (en) 2003-04-23 2004-04-23 High drug load mesalazine sachet
AU2004231316A AU2004231316B2 (en) 2003-04-23 2004-04-23 High drug load mesalazine sachet
JP2006505237A JP4753864B2 (en) 2003-04-23 2004-04-23 Mesalazine sachet with a high content of medicinal drugs
DK04729050.7T DK1615648T3 (en) 2003-04-23 2004-04-23 Sachet with high load of mesalazine
PL04729050T PL1615648T3 (en) 2003-04-23 2004-04-23 High drug load mesalazine sachet
NZ542591A NZ542591A (en) 2003-04-23 2004-04-23 High drug load sachet containing 5-aminosalicylic acid
CA2520026A CA2520026C (en) 2003-04-23 2004-04-23 High drug load mesalazine sachet
IL170978A IL170978A (en) 2003-04-23 2005-09-19 High drug load mesalazine sachet
NO20055534A NO335375B1 (en) 2003-04-23 2005-11-23 High drug-loaded mesalazine bag
HK06104975.5A HK1083312A1 (en) 2003-04-23 2006-04-26 High drug load mesalazine sachet
US14/483,695 US9402815B2 (en) 2003-04-23 2014-09-11 High drug load mesalazine sachet

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US46464903P 2003-04-23 2003-04-23
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US60/464,649 2003-04-23
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EP20030388023 EP1470819A1 (en) 2003-04-23 2003-04-23 High drug load mesalazine sachet

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011073245A2 (en) 2009-12-18 2011-06-23 Ferring B.V. Granules for pharmaceutical preparations, methods and apparatus for their production
WO2012032185A1 (en) * 2010-09-10 2012-03-15 Pharmazell Gmbh Method for producing crystalline 5-aminosalicylic acid
EP3162362A1 (en) 2015-10-30 2017-05-03 Dr. Falk Pharma Gmbh Optimized high-dose tablet of mesalazine
WO2019240700A2 (en) 2017-12-29 2019-12-19 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Oral pharmaceutical compositions of mesalazine
US11602513B1 (en) 2016-07-22 2023-03-14 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11602512B1 (en) 2016-07-22 2023-03-14 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11779557B1 (en) 2022-02-07 2023-10-10 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11839597B2 (en) 2016-07-22 2023-12-12 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics

Families Citing this family (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6632429B1 (en) 1999-12-17 2003-10-14 Joan M. Fallon Methods for treating pervasive development disorders
US8030002B2 (en) 2000-11-16 2011-10-04 Curemark Llc Methods for diagnosing pervasive development disorders, dysautonomia and other neurological conditions
US8282955B2 (en) 2001-10-15 2012-10-09 Ferring B.V. Method for the preparation of a pharmaceutical composition comprising 5-aminosalicylic acid for use in treatment of ulcerative colitis and Crohn's disease
JP2007523664A (en) 2003-04-23 2007-08-23 フェリング ベスローテン フェンノートシャップ Sachet for pharmaceutical composition
US20080058282A1 (en) 2005-08-30 2008-03-06 Fallon Joan M Use of lactulose in the treatment of autism
US7951436B2 (en) 2006-08-14 2011-05-31 Frito-Lay North America, Inc. Environmentally-friendly multi-layer flexible film having barrier properties
US7943218B2 (en) * 2006-08-14 2011-05-17 Frito-Lay North America, Inc. Environmentally-friendly multi-layer flexible film having barrier properties
US7645801B2 (en) * 2007-01-29 2010-01-12 Alaven Pharmaceutical Llc Reduced irritant enema for treatment of inflammatory bowel disease (IBD)
US20090169622A1 (en) * 2007-12-27 2009-07-02 Roxane Laboratories, Inc. Delayed-release oral pharmaceutical composition for treatment of colonic disorders
US8658163B2 (en) 2008-03-13 2014-02-25 Curemark Llc Compositions and use thereof for treating symptoms of preeclampsia
WO2009118761A2 (en) * 2008-03-24 2009-10-01 Bhandari Mohan Harakchand Metallized paper based lidding material for blister packaging & process thereof
US8084025B2 (en) 2008-04-18 2011-12-27 Curemark Llc Method for the treatment of the symptoms of drug and alcohol addiction
US9320780B2 (en) 2008-06-26 2016-04-26 Curemark Llc Methods and compositions for the treatment of symptoms of Williams Syndrome
PL2318035T3 (en) 2008-07-01 2019-10-31 Curemark Llc Methods and compositions for the treatment of symptoms of neurological and mental health disorders
US10776453B2 (en) 2008-08-04 2020-09-15 Galenagen, Llc Systems and methods employing remote data gathering and monitoring for diagnosing, staging, and treatment of Parkinsons disease, movement and neurological disorders, and chronic pain
US20100092447A1 (en) 2008-10-03 2010-04-15 Fallon Joan M Methods and compositions for the treatment of symptoms of prion diseases
AU2009298139B2 (en) * 2008-10-03 2015-02-19 Dr. Falk Pharma Gmbh Compositions and methods for the treatment of bowel diseases with granulated mesalamine
CN105031628B (en) 2009-01-06 2020-10-02 加尔纳根有限责任公司 Compositions and methods for treating or preventing oral infections caused by E.coli
KR20170005192A (en) 2009-01-06 2017-01-11 큐어론 엘엘씨 Compositions and methods for the treatment or prevention of staphylococcus aureus infections and for the eradication or reduction of staphylococcus aureus on surfaces
US9056050B2 (en) 2009-04-13 2015-06-16 Curemark Llc Enzyme delivery systems and methods of preparation and use
WO2011050135A1 (en) 2009-10-21 2011-04-28 Curemark Llc Methods and compositions for the prevention and treatment of influenza
AU2012245287B2 (en) 2011-04-21 2017-04-13 Curemark, Llc Compounds for the treatment of neuropsychiatric disorders
US9040120B2 (en) 2011-08-05 2015-05-26 Frito-Lay North America, Inc. Inorganic nanocoating primed organic film
US9267011B2 (en) 2012-03-20 2016-02-23 Frito-Lay North America, Inc. Composition and method for making a cavitated bio-based film
US9162421B2 (en) 2012-04-25 2015-10-20 Frito-Lay North America, Inc. Film with compostable heat seal layer
US10350278B2 (en) 2012-05-30 2019-07-16 Curemark, Llc Methods of treating Celiac disease
CN104395493B (en) 2012-06-23 2017-08-25 福瑞托-雷北美有限公司 Deposition of the ultra-thin inorganic oxide coating in packaging
US9090021B2 (en) 2012-08-02 2015-07-28 Frito-Lay North America, Inc. Ultrasonic sealing of packages
US9149980B2 (en) 2012-08-02 2015-10-06 Frito-Lay North America, Inc. Ultrasonic sealing of packages
CN102784154B (en) * 2012-09-01 2013-10-09 朱文军 Mesalazine enteric coated tablet and preparation method thereof
ES2799888T3 (en) * 2014-04-17 2020-12-22 Athena Pharmaceutiques Sas Procedure for preparing mesalamine composition and mesalamine composition thereof
EP3154523B1 (en) * 2014-06-16 2018-11-21 Valpharma International S.P.A. Formulation for oral administration containing mesalazine
WO2019123269A1 (en) * 2017-12-20 2019-06-27 Flamel Ireland Limited Packaged modified release gamma-hydroxybutyrate formulations having improved stability
US11541009B2 (en) 2020-09-10 2023-01-03 Curemark, Llc Methods of prophylaxis of coronavirus infection and treatment of coronaviruses
WO2022129003A1 (en) 2020-12-15 2022-06-23 Dsm Ip Assets B.V. Multiparticulate solid oral dosage form comprising statin and vitamin e

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000044353A1 (en) 1999-01-29 2000-08-03 Losan Pharma Gmbh Pharmaceutical compositions

Family Cites Families (67)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4638131B1 (en) 1966-06-22 1971-11-10
US4085244A (en) * 1976-02-10 1978-04-18 Champion International Corporation Balanced orientated flexible packaging composite
US4360550A (en) * 1979-09-12 1982-11-23 Toyo Kagaku Kabushiki Kaisha Composite packing film and packing bag made of the same
WO1981002671A1 (en) * 1980-03-20 1981-10-01 Ferring Farma Lab Pharmaceutical composition and method for the treatment of colitis ulcerosa and crohn's disease by oral administration
US4960765A (en) 1980-03-20 1990-10-02 Farmaceutisk Laboratorium Ferring A/S Pharmaceutical composition and method for the treatment of colitis ulcerosa and Crohn's disease by oral administration
JPS6048484B2 (en) 1980-05-20 1985-10-28 アルザ・コ−ポレ−シヨン Diffusable activator dispenser
JPS5758631A (en) 1980-09-24 1982-04-08 Toyo Jozo Co Ltd Coating composition
ZA825384B (en) 1981-07-31 1983-05-25 Tillott J B Ltd Orally administrable pharmaceutical compositions
US4418841A (en) * 1982-11-23 1983-12-06 American Can Company Multiple layer flexible sheet structure
DE3151196A1 (en) 1981-12-23 1983-06-30 Kurt Heinz Prof. Dr. 7800 Freiburg Bauer METHOD FOR PRODUCING EASILY SOLUBLE 5-AMINOSALICYL ACID MEDICAL PREPARATIONS
US4629657A (en) * 1982-12-13 1986-12-16 Enron Chemical Company Biaxially oriented polypropylene film construction for special lamination
US4489112A (en) * 1983-03-28 1984-12-18 Ex-Cell-O Corporation Laminated paperboard container with absorption resistance means, and blank for constructing same
SE457505B (en) 1984-01-10 1989-01-09 Lejus Medical Ab LAMINATED ORAL PHARMACEUTICAL COMPOSITION AND PROCEDURES FOR ITS PREPARATION
NL8502178A (en) 1984-08-16 1986-03-17 Sandoz Ag NEW PHARMACEUTICAL PREPARATIONS.
US4693395A (en) * 1984-12-28 1987-09-15 Colgate-Palmolive Company Ethylene propylene copolymer in a substrate and collapsible dispensing container made therefrom
US4702905A (en) * 1985-08-30 1987-10-27 Colgate-Palmolive Company Packaged dental cream
US4705680A (en) * 1986-01-22 1987-11-10 Colgate-Palmolive Company Stable dental cream in polyethylene or polypropylene container
US4720473A (en) 1986-03-10 1988-01-19 Cri International, Inc. Production of improved catalyst-type particles using length and density grading
FR2600893B1 (en) * 1986-07-01 1990-01-12 Sandoz Lab NEW PHARMACEUTICAL COMPOSITIONS BASED ON CALCIUM SALTS
US5254347A (en) 1988-03-31 1993-10-19 Tanabe Seiyaku Co., Ltd. Controlled release pharmaceutical preparation and method for producing the same
US5194464A (en) * 1988-09-27 1993-03-16 Takeda Chemical Industries, Ltd. Enteric film and preparatoin thereof
US5484605A (en) 1988-11-25 1996-01-16 Henning Berlin Gmbh Chemie-Und Pharmawerk Agent for treating chronically inflammatory intestinal diseases
GB8828349D0 (en) * 1988-12-05 1989-01-05 Du Pont Canada Film laminate with easy to td tear
GB8913889D0 (en) 1989-06-16 1989-08-02 May & Baker Ltd New compositions of matter
IT1246382B (en) 1990-04-17 1994-11-18 Eurand Int METHOD FOR THE TARGETED AND CONTROLLED DELIVERY OF DRUGS IN THE INTESTINE AND PARTICULARLY IN THE COLON
GB2253346A (en) * 1991-02-22 1992-09-09 John Rhodes Delayed release oral dosage forms for treatment of intestinal disorders
US5433982A (en) * 1990-11-14 1995-07-18 Dai Nippon Printing Co., Ltd. Composite container having barrier property
US5316772A (en) 1990-12-19 1994-05-31 Solvay & Cie, S.A. (Societe Anonyme) Bilayered oral pharmaceutical composition with pH dependent release
GB2256587A (en) 1991-06-11 1992-12-16 American Cyanamid Co Acetazolamide in sustained release form
US5472712A (en) 1991-12-24 1995-12-05 Euroceltique, S.A. Controlled-release formulations coated with aqueous dispersions of ethylcellulose
US5474818A (en) * 1992-05-15 1995-12-12 International Paper Flexible container with nonstick interior
JP2607422B2 (en) * 1992-09-08 1997-05-07 呉羽化学工業株式会社 Packaging for adsorbent for internal use and method for producing the same
JPH0827133B2 (en) 1993-07-13 1996-03-21 不二パウダル株式会社 Wet powder processing equipment
US5482718A (en) 1994-03-23 1996-01-09 Hoffmann-La Roche Inc. Colon-targeted delivery system
JPH0880597A (en) * 1994-07-14 1996-03-26 Kyodo Printing Co Ltd Anti-fungus laminate, and bag, container and formed cup using the same
JPH0826977A (en) 1994-07-19 1996-01-30 Tanabe Seiyaku Co Ltd Elution-controlled type oral preparation
IT1277663B1 (en) * 1995-09-28 1997-11-11 Crinos Industria Farmaco STABLE AQUEOUS SUSPENSIONS OF MESALAZINE FOR TOPICAL USE
US6004581A (en) 1995-12-21 1999-12-21 Farmaceutisk Laboratorium Ferring A/S Modified release oral pharmaceutical composition and method for the treatment of bowel diseases
PL186790B1 (en) * 1995-12-21 2004-02-27 Ferring Farma Lab Orally administered 5-asa containing pharmaceutic composition of modified active substance release and method of treating intestinal diseases
US6245351B1 (en) 1996-03-07 2001-06-12 Takeda Chemical Industries, Ltd. Controlled-release composition
IL118932A0 (en) 1996-07-24 1996-10-31 Dexcel Ltd Controlled release tablets
DE69725596T2 (en) 1996-07-28 2004-08-05 Biosense Inc. ELECTROMAGNETIC HEART BIOSTIMULATION
WO1998026767A2 (en) 1996-12-17 1998-06-25 Poli Industria Chimica S.P.A. Site-specific controlled release dosage formulation for mesalamine
GB9722426D0 (en) 1997-10-23 1997-12-24 Univ London Pharmacy Controlled release formulations
EP0939037A1 (en) * 1998-02-26 1999-09-01 Alusuisse Technology &amp; Management AG Packaging material
EP1079820A1 (en) 1998-05-19 2001-03-07 Centaur Pharmaceuticals, Inc. Benzamide therapeutics for the treatment of inflammatory bowel disease
EP1117869B1 (en) * 1998-09-03 2012-04-18 Stora Enso Aktiebolag Paper or paperboard laminate and method to produce such a laminate
CO5140079A1 (en) * 1998-10-14 2002-03-22 Novartis Ag PHARMACEUTICAL COMPOSITION OF SUSTAINED LIBERATION AND METHOD TO RELEASE A PHARMACEUTICALLY ACTIVE AGENT FROM SUSTAINED LIBERATION AND METHOD TO RELEASE A PHARMACEUTICALLY ACTIVE AGENT
IT1303753B1 (en) 1998-11-13 2001-02-23 Ct Lab Farm Srl ORAL ADMINISTRABLE PHARMACEUTICAL COMPOSITIONS CONTAINING A RESISTANT COATING BASED ON ACRYLIC POLYMERS.
ITMI991316A1 (en) * 1999-06-14 2000-12-14 Cip Ninety Two 92 S A ORAL PHARMACEUTICAL COMPOSITIONS WITH MODIFIED RELEASE OF MESALAZINE
JP2001055322A (en) 1999-08-18 2001-02-27 Tanabe Seiyaku Co Ltd Pulse release type preparation
JP4439629B2 (en) * 1999-09-14 2010-03-24 久光製薬株式会社 Packaging bag
US6199698B1 (en) * 1999-12-03 2001-03-13 Alusuisse Technology & Management, Ltd. Pharmaceutical packaging with separation means
US6627223B2 (en) 2000-02-11 2003-09-30 Eurand Pharmaceuticals Ltd. Timed pulsatile drug delivery systems
IT1318376B1 (en) 2000-03-07 2003-08-25 Pharmatec Internat S R L ORAL SOLID FORMS WITH CONTROLLED RELEASE CONTAINING MESALAZINE AS AN ACTIVE PRINCIPLE.
DE10013030A1 (en) 2000-03-17 2001-09-20 Roehm Gmbh Formulation for treating ulcerative colitis, comprising active agent, e.g. 5-aminosalicylic acid or prednisone, coated with acrylic copolymer to provide delayed release at high pH in the colon
IT1318625B1 (en) * 2000-07-14 2003-08-27 Roberto Valducci ORAL SOLID PHARMACEUTICAL FORMULATIONS WITH MULTI-PHASE RELEASE - EMPLOYEE.
JP2004507487A (en) * 2000-08-29 2004-03-11 メファ・アクチェンゲゼルシャフト Intestinal disease drug
US20020177579A1 (en) * 2000-11-06 2002-11-28 Larry Augsburger Extended release formulation of water-soluble drugs
US8282955B2 (en) 2001-10-15 2012-10-09 Ferring B.V. Method for the preparation of a pharmaceutical composition comprising 5-aminosalicylic acid for use in treatment of ulcerative colitis and Crohn's disease
MXPA04003506A (en) * 2001-10-15 2004-07-23 Ferring Bv Method for the preparation of a pharmaceutical composition comprising 5-aminosalicyclic acid for use in treatment of ulcerative colitis and crohn's disease.
US7025205B2 (en) * 2002-06-26 2006-04-11 Aventis Pharma Limited Method and packaging for pressurized containers
SI1565258T1 (en) 2002-11-26 2012-04-30 Univ Gent Process and apparatus for continuous wet granulation of powder material
JP2007523664A (en) 2003-04-23 2007-08-23 フェリング ベスローテン フェンノートシャップ Sachet for pharmaceutical composition
EP1547601A1 (en) 2003-12-23 2005-06-29 Ferring B.V. Coating method
WO2008102671A1 (en) * 2007-02-22 2008-08-28 Ajinomoto Co., Inc. Method for purifying 4-hydroxyisoleucine
EP2340812A1 (en) 2009-12-18 2011-07-06 Ferring International Center S.A. Granules for pharmaceutical preparations, methods and apparatus for their production

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000044353A1 (en) 1999-01-29 2000-08-03 Losan Pharma Gmbh Pharmaceutical compositions

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ERIKSSON ET AL.: "Evaluation of a permeametry technique for surface area measurement of coarse particulate materials", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 63, 1990, pages 189 - 199

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011073245A2 (en) 2009-12-18 2011-06-23 Ferring B.V. Granules for pharmaceutical preparations, methods and apparatus for their production
EP2340812A1 (en) 2009-12-18 2011-07-06 Ferring International Center S.A. Granules for pharmaceutical preparations, methods and apparatus for their production
EP2512453B1 (en) 2009-12-18 2016-11-09 Ferring B.V. Granules for pharmaceutical preparations, methods and apparatus for their production
WO2012032185A1 (en) * 2010-09-10 2012-03-15 Pharmazell Gmbh Method for producing crystalline 5-aminosalicylic acid
CN103153944A (en) * 2010-09-10 2013-06-12 法莫再尔公司 Method for producing crystalline 5-aminosalicylic acid
AU2011300642B2 (en) * 2010-09-10 2015-02-26 Pharmazell Gmbh Process for producing crystalline 5-aminosalicylic acid
US11135159B2 (en) 2015-10-30 2021-10-05 Dr. Falk Pharma Gmbh Optimized high-dose mesalazine-containing tablet
EP3162362A1 (en) 2015-10-30 2017-05-03 Dr. Falk Pharma Gmbh Optimized high-dose tablet of mesalazine
US11602513B1 (en) 2016-07-22 2023-03-14 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11602512B1 (en) 2016-07-22 2023-03-14 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
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US11826335B2 (en) 2016-07-22 2023-11-28 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11839597B2 (en) 2016-07-22 2023-12-12 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11896572B2 (en) 2016-07-22 2024-02-13 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
WO2019240700A2 (en) 2017-12-29 2019-12-19 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Oral pharmaceutical compositions of mesalazine
US11779557B1 (en) 2022-02-07 2023-10-10 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics

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