WO1999021536A1 - Controlled release formulations - Google Patents
Controlled release formulations Download PDFInfo
- Publication number
- WO1999021536A1 WO1999021536A1 PCT/GB1998/003178 GB9803178W WO9921536A1 WO 1999021536 A1 WO1999021536 A1 WO 1999021536A1 GB 9803178 W GB9803178 W GB 9803178W WO 9921536 A1 WO9921536 A1 WO 9921536A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- film
- amylose
- polymer
- forming
- water
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
-
- 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
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
Definitions
- the present invention relates to controlled, usually delayed release formulations, where the release characteristics are controlled by a polymer.
- the present invention provides a method for producing a controlled release composition comprising an active ingredient and a film formed from a film-forming composition comprising a mixture of a substantially water-insoluble film-forming polymer and amylose, the method comprising contacting the active ingredient with a solution of the film-forming composition in a solvent system comprising (1) water and (2) a water-miscible organic solvent which on its own is capable of dissolving the film- forming polymer and removing the water and organic solvent, wherein the weight ratio of amylose to film-forming polymer is in the range 1 :2 to 3:2 and the solvent system contains at least 50% w/w organic solvent.
- the temperature used in the process generally need be no higher than 60°C and may often be ambient. Preferably the temperature is in the range 20 to 40°C.
- the controlled release composition formed according to the method of the present invention finds particular application in the delivery of an active material to the colon.
- the composition has been found to be substantially resistant to the conditions present in the stomach and the small intestine but is susceptible to attack by the microorganisms of the colon.
- the present invention should generally be accompanied by solvent recovery.
- the vapour which generally comprises a mixture of water vapour and solvent vapour, should be recovered, condensed and the solvent preferably recycled in the process.
- the condensed solvent mixture may be separated to render the solvent substantially free of water, or a mixture of water and solvent of known solvent concentration may be reused in the process.
- Suitable condenser equipment for solvent removal and recovery from an active ingredient coating station is known and is available, for instance from the manufacturers Glatt.
- the organic solvent which is used in the invention is selected for its miscibility with water. It is preferably sufficiently water-miscible such that a homogeneous blend containing 10 to 90% of an organic solvent at room temperature and pressure can be formed.
- the solvent should also be selected for its ability to solubilise the film-forming polymer and the amylose. Thus those components should be soluble in the organic solvent (in the absence of water) at a concentration of at least 5 or 6%, preferably at least 10%, at a temperature of 40°C.
- Suitable solvents are C 2 _, 0 -alkanols, ethers, alcohol ethers and esters of mono or higher base carboxylic acids, generally with mono alkanols, which are liquid at room temperature and miscible with water in the stated amounts.
- Suitable esters are, for instance, esters of lactic acid, such as ethyl lactate.
- the solvent is a C 2 . 4 alkanol, and is most preferably selected from ethanol and propanol.
- the relative amounts of solvent and water required for use in the solvent system of the present invention have been found to depend upon the nature of both the organic solvent used and the water-insoluble polymer.
- the organic solvent may comprise at least 50% by weight (w/w) of the solvent system, preferably between 60 and 90% of the solvent system.
- the organic solvent system used in the preparation of the film-forming composition preferably contains at least 60% by weight organic solvent when propanol is used and at least 70% by weight organic solvent when ethanol is used.
- the film-forming compositions of choice used in the method of the present invention are those which give rise to films in which the amylose is present in the glassy state. Films comprising glassy amylose have been found to be resistant to degradation by both the stomach and the amylase enzymes of the small intestine, but have been found to be susceptible to attack by the micro-organisms present in the colon.
- Glassy amylose is one of the two forms of predominantly amorphous amylose, the other being a rubbery form.
- the theoretical Tg for pure, dry amylose may be predicted to be 210°C but the presence of water depresses this figure: with 10% w/w of water the Tg is 80°C and at 20% w/w of water it is 7°C.
- ⁇ - amylolytic enzymes such as those present in the small intestine do not readily degrade glassy amylose and this effect is still apparent at up to 20°C above the Tg.
- Such materials have been found to be sufficiently insoluble in aqueous media over the pH range 1-9 at 37°C to be resistant to degradation in the stomach or intestine. They are, however, degraded by faecal micro-organisms present in the colon.
- the ability of glassy amylose to provide the required delayed release characteristics is not lost immediately the glassy amylose passes through the Tg and films containing amylose which has been produced in the glassy condition at temperatures less than the Tg may therefore then be utilized at the Tg or at temperatures slightly higher than the Tg as well as at temperatures less than the Tg, whilst still retaining its glassy properties.
- the glassy amylose present in the films formed from the film-forming compositions used according to the method of the present invention preferably has a Tg of no more than 20°C below the temperature at which use of the composition is envisaged, i.e. at body temperature of about 37°C, i.e.
- the Tg can be predetermined by controlling the amount of water in it. This can be achieved by varying the concentration of the amylose in the film-forming composition.
- the ultimate test of the suitability of a particular sample of amylose in a film formed under any given conditions is of course its ability to resist hydrolytic degradation under aqueous conditions, particularly at a pH of 1-9 and a temperature of 37°C, and conveniently also to resist enzymatic degradation in the presence of the digestive enzymes such as normally occur in the stomach and the small intestine, but to o undergo enzymatic degradation in the presence of amylose-cleaving enzymes such as are provided by the microbial flora normally present in the large intestine.
- Films comprising amylose in the glassy state may conveniently be prepared from the film-forming compositions used in the method of the present invention by forming a gel by casting or spraying and drying that gel.
- the gel forms by a phase separation 5 which produces a concentrated polymer-rich phase and a polymer-poor phase.
- the polymer-rich phase may have only, say 10% w/w water and hence be glassy at room temperature, even though the whole gel may contain up to 50% of water.
- the whole preparation may be dried if necessary or desirable at between 20 to 80°C, and more preferably between 20 to 40°C in air or in an inert atmosphere such as nitrogen.
- the amylose used in the film-forming composition may be prepared from any suitable source although it is preferably prepared from starch, for example cereal starch or tuber starch or starch from pulses, for example smooth-seeded pea starch, conveniently by precipitation from aqueous solution as a complex with an alcohol, for example 1-butanol, methanol, ethanol, propan-1-ol, propan-2-ol, pentanol, 2- 5 methylbutan-2-ol or 2-methylbutan-l-ol as described by Ring et al., Macromolecules, 1985, 1_8, 182.
- the alcohol may conveniently then be removed from an aqueous dispersion of that complex by blowing through a suitable heated inert gas, for example nitrogen.
- the glassy amylose in the film formed will detract from the selective nature of the degradation of this material as between the stomach and small intestine and the large intestine. It is preferred therefore that the glassy amylose in the film is substantially free (i.e. contains no more than 20% by weight and preferably no more than 10% or 5% by weight) of any material which is susceptible to digestion in the stomach or small intestine.
- the glassy amylose preferably contains no more than 10% or 5% by weight of amylopectin, for example 1 or 2% or less, and conveniently also of any material containing glucoside linkages of the type found in amylopectin.
- the glassy amylose in the film formed from the film-forming composition does not contain hydroxy groups in derivative form and, if any derivatization is present that this is conveniently to an extent of no more than 10% of the hydroxy groups present, in particular no more than 4 or 5% and particularly 1 or 2% less.
- amylose A convenient test for the purity of the amylose is provided by its iodine binding ability in a standard assay procedure such as is described by Banks et al, Starke, 1971. 23, 1 18.
- a standard assay procedure such as is described by Banks et al, Starke, 1971. 23, 1 18.
- iodine binds with iodine to a level of about 19.5% w/w (i.e. 19.5 + 0.5% w/w) whereas the other main starch polysaccharide, amylopectin, binds less than 2.0% w/w and derivatization of the amylose will also reduce this binding ability.
- amylose used in the present intention binds with iodine to a level of 15.0% + 0.5% w/w, or above, preferably to a level of 18.0% + 0.5% w/w or above, and particularly to a level of 19.5 + 0.5% w/w.
- the molecular weight of the amylose used in the invention may conveniently be at least 20000 g/mol (or daltons) and is preferably higher so that it is advantageous to use amylose with a molecular weight of at least 100000, 200000, 300000, 400000 or 500000 g/mol depending on the particular circumstances.
- film-forming compositions that can be used to form films containing glassy amylose in the controlled release compositions of the present invention it is also possible to use film-forming compositions that give rise to films containing rubbery amylose.
- Preparation of films containing rubbery amylose may be conveniently be brought about by the addition of a plasticiser to the film-forming composition.
- the addition of a plasticiser conveniently leads to the formation of films containing amylose which is rubbery rather than glassy at ambient temperature since the plasticiser can depress the Tg of amylose in the film which would otherwise be glassy to some tens of degrees, i.e. 10°, 20°, 30°C or more, below ambient temperature.
- the amylose in the film may well then be rubbery at physiological temperature if not also at ambient temperature.
- Films containing rubbery amylose are however also of value, particularly when prepared with a water soluble plasticiser since such plasticisers will tend to be leached out in an aqueous environment to produce a porous amylose material. It will be appreciated, therefore, that it may be appropriate for reasons of aiding the coating procedure, controlling permeability or otherwise to add a plasticiser to the film-forming composition.
- the film-forming compositions used in the method of the present invention are prepared by admixing a solution of the water-insoluble polymer in an organic solvent with an aqueous dispersion of an amylose-butanol complex.
- the relative amounts in which the two component systems are mixed will depend upon the solid ratios of amylose and the insoluble polymer required in the final film.
- solutions containing between 2 and 25% w/w insoluble polymer, preferably between 2 and 8% w/w and especially between 3 and 5% w/w insoluble polymer in an organic solvent are mixed with an aqueous dispersion containing between 3 and 12% w/w of an amylose- butanol complex, preferably between 3 and 8% w/w and especially between 3 and 6% w/w. It may be necessary to concentrate the amylose-butanol dispersion to an appropriate concentration before mixing.
- the solutions are mixed and stirred until fully blended.
- the resultant solution is then passed through a sieve to remove agglomerates.
- the film-forming composition thus prepared typically comprises between 2 and 8% w/w of film-forming solids in the solvent system, preferably between 3 and 6% w/w and especially between 4 and 5% w/w.
- the films can be prepared by casting or spraying the film-forming composition at a temperature of between 20 and 60°C.
- the films are formed by spraying the compositions onto the active material, the active material being maintained at a temperature of between 20 and 40°C, preferably between 30 and 40°C and especially between 35 and 40°C during the spraying process.
- the substantially water-insoluble film-forming polymer should be water- insoluble, as well as insoluble in aqueous acidic and alkaline environments.
- solubility of the film- forming polymer in water at room temperature should be less than 10%.
- the level of solubility in aqueous acidic medium at a pH 1 should be less than about 1% and in aqueous alkaline medium at a pH of 7.2 should be less than about 1%.
- the polymer should, on the other hand, be sufficiently soluble in the coating composition such that suitable coating/protective film formation can be achieved.
- the polymer should thus have a solubility of at least 5% in the organic solvent (in the absence of water) selected for the liquid composition.
- Suitable film-forming materials are preferably water-insoluble cellulosic or acrylic polymer materials. Mixtures of different cellulosic or acrylic polymer materials may be used. The use of ethyl cellulose as a film-forming polymer is especially preferred.
- cellulose materials are the preferred film-forming materials for use as the outer coating
- acrylic polymer materials may also be employed in the compositions of the present invention either alone or in admixture with a cellulose material.
- both acrylate and methacrylate polymers may be used and especially copolymers thereof, the esterifying groups in these polymers being of various types, for example of C 8 alkyl groups.
- a preferred molecular weight range for the film- forming cellulose materials is
- the film-forming acrylic polymer materials is 150,000 to 250,000 g/mol (or daltons) but materials with molecular weights outside these ranges, for example of a higher molecular weight, can be used where appropriate.
- the degradation of the cellulose materials in vivo is in general not pH dependent and it is preferred that this is also true for the acrylate materials. This may be achieved by the selection of appropriate forms of side chain on the main polymer chain, in particular of side chains which have a low negative charge or preferably which are uncharged, as opposed to those having a positive charge.
- Preferred forms of acrylate materials are those marketed by Dumas (UK) Limited of Tunbridge Wells under the Trade Mark Eudragit, particularly the materials Eudragit L whose degradation is independent of pH.
- the preferred cellulose materials, ethyl cellulose, is marketed by the Dow Chemical Company and Shinetsu Chemical Products under the Trade Mark Ethocel.
- the ratio of the amylose to the film-forming polymer in the process should be in the range 1 :2 to 3:2, preferably in the range 2:3 to 3:2, for instance about 1 :1. Where the level of amylose is higher than the upper limit, it is found that the films mechanical characteristics may be inadequate. Where the amount of amylose is lower, the degradation of the amylose in the desired location for release (for instance the colon) l o may be inadequate.
- plasticiser As indicated above it may be desirable to incorporate a plasticiser into the blend of amylose and film-forming polymer in order to facilitate formation of the film, control the porosity and improve the mechanical properties of the film.
- the amount of plasticiser used will depend upon the nature of the insoluble polymer. 15 Examples of suitable plasticiser, particularly in the case of the cellulose materials, are dicarboxy-acid and tricarboxy-acid esters such as triethylcitrate, glycerol triacetate, acetyl tributylcitrate, tributylcitrate, triacetin and dibutyl sebacate.
- substantially insoluble polymer, amylose and plasticiser can be varied according to the nature of the materials used to give a coating with the required delayed 20 and controlled release and porosity characteristics.
- Ethylcellulose can be plasticised with both hydrophobic and hydrophilic plasticisers.
- the thickness of the film also influences the rate at which an active material is released from a dosage form. Depending upon the solubility of the active material in the dosage form, release is generally slower when thicker films are 25 employed. Thicker films are also required when highly soluble active materials are employed in order to prepare a dosage form in which the release of active material in the colon can be adequately controlled.
- TWG total weight gain
- the nature of the amylose in the film is important in providing a slow release barrier and controlling the degradation thereof by micro-organisms (microbial flora) thereby to control release of the active material once the composition reaches the colon.
- micro-organisms microbial flora
- Control can therefore be exercised over release of the active ingredient with respect to time by varying one or more of the parameters controlling release, e.g. coat thickness, method of coating and ratio of coating ingredients. It is also possible to employ a mixture of, for example, spherules having coatings designed to provide differing release times so as to allow pulsed release of the active ingredient.
- active ingredient includes any material which is or may be sensitive to temperatures above low ambient, for example 20 to 40°C, but also includes materials that are not degraded at temperatures outside this range.
- the active ingredient could, for example, be a foodstuff, pharmaceutical, electrically conducting component, without limitation. However, it particularly includes any compound or composition useful in human or veterinary medicine in therapy or diagnosis.
- Therapeutic agents of particular interest have been referred to hereinbefore.
- the compositions of the invention are also of interest in a diagnostic context, for example in delivering agents such as contrast media to the colon in connection with X-ray and NMR imaging techniques.
- An alternative diagnostic area lies in the delivery of potentially allergenic foodstuff components to the colon for the diagnosis of allergies.
- the active compound may be mixed with other carrier materials suitable to its particular use.
- the active compound will often be mixed with one or more of a bulking agent and a lubricant, for example lactose and magnesium stearate, respectively.
- a bulking agent and a lubricant for example lactose and magnesium stearate, respectively.
- Dosages of active compounds for therapeutic use will be as disclosed in the literature, for example in the ABPI Data Sheet Compendium, or may sometimes be less owing to the more efficient delivery of the compound.
- 5-aminosalicylic acid a drug 5 which is used orally in the treatment of colonic disorders.
- the present invention provides a composition comprising 5-ASA which can be administered orally with delayed release of a substantial amount of the active ingredient in the colon.
- the 5-ASA is preferably l o provided in the form of spherules, suitably spheronized in admixture with microcrystalline cellulose and a minor proportion of an inorganic binder such as bentonite.
- suitable active materials include ephedrine and paracetamol.
- the organic system was developed using mixture of aqueous dispersion of amylose-butanol complex and organic solutions of ethyl cellulose.
- Three 20 solvents were selected to form ethyl cellulose solutions. They were ethyl lactate, ethanol and propanol.
- the mixture systems were investigated for solvent aqueous compatibility, polymer miscibility and possible influencing factors such as solvent ratio, sold ratio and temperature effect.
- the study was carried out using free films. The free films formed were subsequently subjected 25 to acid permeability test and in vitro fermentation tests.
- Amylose-butanol complex dispersion prepared at Institute of Food Research, 30 Norwich, UK
- Example 1.3 After drying, samples of the film were cut and incubated with a predetermined quantity of faecal slurry (same quantity of the same slurry used for each experiment). Following incubation for 24 hours at 37°C, the films are washed with water and dried at 20C and 44%RH for 7 days in an incubator and reweighed.
- Figure 1 shows the percentage film loss after 24 hours incubation of film cast from ethanokwater solutions of amylose/ethyl cellulose based on the level of amylose in the mixture.
- Figure 2 shows the film loss values based on the level of amylose in the amylose/ethyl cellulose mixture for films cast from propanol: water mixtures.
- Figure 3 shows the percentage film loss for similar films cast from ethylactate.
- 5-ASSA 5-aminosalicyclic acid
- the spheres obtained above were coated using mixed water/solvent amylose/ethyl cellulose coating composition prepared at a total polymer concentration of 5% by spraying the spheres in a fluidised bed coater at a bed temperature of 35-40°C to prepare products with varying coating thicknesses (expressed as total weight gain, TWG).
- the release of 5 ASA from the spheres was measured using a quantity of spheres containing a known level of 5 AS A into 100 ml dissolution fluid at a temperature of 37°C and under agitation.
- the dissolution fluids used were phosphate buffer at pH 7.2 and faecal slurry (10-15%). Samples were taken at 2 hour intervals up to 8 hours and subsequently after 12 hours and 24 hours and analysed by HPLC. For control purposes, uncoated pellets were subjected to the same release tests.
- Figure 4 shows the release profile of spheres which are uncoated and spheres which are coated with a 4:1 ethylcellulose:amylose mixture from an ethyl lactate:water (about 4:1) mixture to a coating level of 3% TWG, in each case into phosphate buffer and faecal slurry.
- Figure 5 shows results similar to those in Figure 4 but using a 2:1 mixture of ethylcellulose:amylose to a total coating level of 6% TWG.
- Figure 6 shows similar results as those in Figure 4 but using ethyl cellulose:amylose in a ratio 3 :2 and to a TWG of 10%.
- Figure 7 shows similar results as for Figure 4, but using ethyl cellulose:amylose 1 :1 to a TWG of 15%.
- Figure 8 shows similar results to Figure 4 but using ethanol in place of ethyl lactate.
- Figure 9 shows results similar to those of 6 but using ethanol in place of ethyl lactate.
- Figure 10 shows results similar to those of Figure 7 but using ethanol in place of ethyl lactate.
- Figure 11 shows results similar to those of Figure 5 but using propanol in place of ethyl lactate.
- Figure 12 shows results similar to those of Figure 7 but using propanol in place of ethyl lactate.
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2000517696A JP2001520986A (en) | 1997-10-23 | 1998-10-23 | Controlled release formulation |
AT98950189T ATE221773T1 (en) | 1997-10-23 | 1998-10-23 | CONTROLLED RELEASE FORMULATIONS |
DE69807104T DE69807104T2 (en) | 1997-10-23 | 1998-10-23 | CONTROLLED RELEASE FORMULATIONS |
CA002302585A CA2302585C (en) | 1997-10-23 | 1998-10-23 | Controlled release formulations |
EP98950189A EP1024795B1 (en) | 1997-10-23 | 1998-10-23 | Controlled release formulations |
DK98950189T DK1024795T3 (en) | 1997-10-23 | 1998-10-23 | Controlled release formulations |
US09/516,253 US6534549B1 (en) | 1997-10-23 | 2000-03-01 | Controlled release formulations |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9722426.5 | 1997-10-23 | ||
GBGB9722426.5A GB9722426D0 (en) | 1997-10-23 | 1997-10-23 | Controlled release formulations |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/516,253 Continuation US6534549B1 (en) | 1997-10-23 | 2000-03-01 | Controlled release formulations |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1999021536A1 true WO1999021536A1 (en) | 1999-05-06 |
Family
ID=10820995
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB1998/003178 WO1999021536A1 (en) | 1997-10-23 | 1998-10-23 | Controlled release formulations |
Country Status (10)
Country | Link |
---|---|
US (1) | US6534549B1 (en) |
EP (1) | EP1024795B1 (en) |
JP (2) | JP2001520986A (en) |
AT (1) | ATE221773T1 (en) |
CA (1) | CA2302585C (en) |
DE (1) | DE69807104T2 (en) |
DK (1) | DK1024795T3 (en) |
ES (1) | ES2178268T3 (en) |
GB (1) | GB9722426D0 (en) |
WO (1) | WO1999021536A1 (en) |
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WO2003068196A1 (en) * | 2002-02-13 | 2003-08-21 | Alizyme Therapeutics Limited | Colonic release composition |
FR2862654A1 (en) * | 2003-11-20 | 2005-05-27 | Roquette Freres | Amylaceous film-forming composition useful e.g. for coating pharmaceuticals, foods and agricultural materials, contains a stabilized starch and has controlled viscosity |
EP1547601A1 (en) * | 2003-12-23 | 2005-06-29 | Ferring B.V. | Coating method |
CN100347879C (en) * | 2002-09-18 | 2007-11-07 | 锌矩阵动力公司 | Method for manufacture of films containing insoluble solids embedded in cellulose-based films |
FR2934467A1 (en) * | 2008-07-31 | 2010-02-05 | Roquette Freres | Coated solid form composed of coated center in laminating layer, useful for tablets, capsules, pellets, and granules, comprises hydrophilic film forming agent, where the hydrophilic film-forming agent is non-grafted film-forming agent |
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US8858992B2 (en) | 2003-04-23 | 2014-10-14 | Ferring B.V. | High drug load mesalazine sachet |
US9006288B2 (en) | 2009-01-12 | 2015-04-14 | Biokier, Inc. | Composition and method for treatment of diabetes |
US9023368B2 (en) | 2006-04-13 | 2015-05-05 | University College London | Colonic drug delivery formulation |
US9301938B2 (en) | 2009-09-23 | 2016-04-05 | Biokier, Inc. | Composition and method for treatment of diabetes |
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EP3542791A1 (en) | 2013-10-29 | 2019-09-25 | Tillotts Pharma AG | A delayed release drug formulation |
EP3662902A1 (en) | 2018-12-07 | 2020-06-10 | Tillotts Pharma AG | Colonic drug delivery formulation |
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US8048919B2 (en) * | 2004-06-28 | 2011-11-01 | Archer Daniels Midland Company | Use of ethyl lactate as an excipient for pharmaceutical compositions |
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WO2009120382A1 (en) | 2008-03-27 | 2009-10-01 | Zpower, Inc. | Electrode separator |
GB0808537D0 (en) | 2008-05-12 | 2008-06-18 | Archimedes Dev Ltd | Compositions |
ES2425762T3 (en) | 2008-10-27 | 2013-10-17 | Roquette Freres | Water insoluble polymer: film coatings based on modified starch derivatives for colon-directed release |
DK3403654T3 (en) | 2009-10-01 | 2019-08-26 | Adare Dev I L P | ORAL ADMINISTRATED CORTIC COSTEROIDS COMPOSITIONS |
WO2012068105A2 (en) | 2010-11-15 | 2012-05-24 | Archer Daniels Midland Company | Compositions and uses thereof in converting contaminants |
US20140271931A1 (en) * | 2013-03-12 | 2014-09-18 | Perosphere Inc. | Anti-Acne Topical Films |
US11896719B2 (en) | 2022-01-24 | 2024-02-13 | Calliditas Therapeutics Ab | Pharmaceutical compositions |
Citations (1)
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WO1991007949A1 (en) * | 1989-11-24 | 1991-06-13 | British Technology Group Ltd. | Delayed release formulations |
-
1997
- 1997-10-23 GB GBGB9722426.5A patent/GB9722426D0/en not_active Ceased
-
1998
- 1998-10-23 ES ES98950189T patent/ES2178268T3/en not_active Expired - Lifetime
- 1998-10-23 DE DE69807104T patent/DE69807104T2/en not_active Expired - Lifetime
- 1998-10-23 WO PCT/GB1998/003178 patent/WO1999021536A1/en active IP Right Grant
- 1998-10-23 DK DK98950189T patent/DK1024795T3/en active
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Also Published As
Publication number | Publication date |
---|---|
JP2010270335A (en) | 2010-12-02 |
DK1024795T3 (en) | 2002-12-02 |
EP1024795A1 (en) | 2000-08-09 |
ATE221773T1 (en) | 2002-08-15 |
CA2302585C (en) | 2007-09-25 |
JP2001520986A (en) | 2001-11-06 |
CA2302585A1 (en) | 1999-05-06 |
ES2178268T3 (en) | 2002-12-16 |
EP1024795B1 (en) | 2002-08-07 |
GB9722426D0 (en) | 1997-12-24 |
US6534549B1 (en) | 2003-03-18 |
DE69807104T2 (en) | 2002-12-05 |
DE69807104D1 (en) | 2002-09-12 |
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