GB2367002A - Coating composition - Google Patents

Coating composition Download PDF

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Publication number
GB2367002A
GB2367002A GB0023449A GB0023449A GB2367002A GB 2367002 A GB2367002 A GB 2367002A GB 0023449 A GB0023449 A GB 0023449A GB 0023449 A GB0023449 A GB 0023449A GB 2367002 A GB2367002 A GB 2367002A
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United Kingdom
Prior art keywords
dosage form
delayed release
release dosage
form according
starch
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GB0023449A
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GB0023449D0 (en
Inventor
Wei Tian
Louise Botham
David Hopkins
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British Sugar PLC
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British Sugar PLC
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Publication date
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Priority to GB0023449A priority Critical patent/GB2367002A/en
Publication of GB0023449D0 publication Critical patent/GB0023449D0/en
Publication of GB2367002A publication Critical patent/GB2367002A/en
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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806Coating materials
    • A61K9/2833Organic macromolecular compounds
    • A61K9/286Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1652Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin

Abstract

A delayed release dosage form comprising: a core containing an active agent; and a coating which comprises a water-insoluble film-forming polymer matrix and microparticles dispersed in the polymer matrix, wherein the microparticles comprise a major fraction of a dietary fibre other than amorphous amylose. Preferred dietary fibres for the microparticles include crystalline resistant starches and modified cellulose. The dosage form provides targeted delivery of the active agent to the large intestine by oral administration. The water-insoluble film forming polymer may be a cellulose acrylate or lignin derivative. The dietary fibre may be a plant cell wall material or derivative or a complex polysaccharide such as guar gum xanthan gum gum arabic a carageenan pectin or starch. The active agent may be a pharmaceutical a dietary supplement or diagnostic agent.

Description

COATING COMPOSITIONS
The present invention relates to delayed release dosage products, in particular to compositions for oral administration that provide targeted release of an active agent in the colon.
Generally systems for the delivery of substances selectively to the colon by oral administration are formulated based on the sensitivity to gastrointestinal pH, gastrointestinal transit time, or sensitivity to bacterial enzymes of colonic region.
Gastrointestinal pH sensitive coatings have been widely used to deliver drugs to the lower gastrointestinal tract. For example, polymer coating based on methylacrylic acid and methylacrylic acid esters (such as EUDRAGIT (Registered Trade Mark of Lands Rohm Pharma) will dissolve and release between pH 5 and 7 depending on the formulation and coating thickness. However, these systems may be susceptible to variable release as the pH of the gut can be influenced by a number of factors such as disease conditions, types and amounts of food ingested, etc.
Systems operating on gastrointestinal transit time principles usually utilise the water permeability of certain polymer coatings. This allows the ingress of water into the core of the solid dosage form. The core substances then swell up and lead to the rupture of the dosage form and release the active. However, the applicability of these systems is limited by the variable transit times among individuals.
Colon delivery can also be achieved with systems that utilise materials that are degraded by bacterial enzymes within the colon, but are less sensitive to the conditions of the upper gastrointestinal tract.
US 5,811, 388 discloses a method of delivering drugs to the lower G ! tract by admixing polysaccharide gums with the active. The mixture is then compressed to form tablets, these tablets may be optionally coated by an enteric
coating. The loading capacity of the dosage form is limited as no more than 10% of active can be incorporated into the system. Furthermore, it is well known that polysaccharide gums are very prone to swelling when in contact with water, thereby releasing the actives. Presumably the optional enteric coating is designed to limit this swelling. Nevertheless, the efficacy of the delivery system is again not guaranteed because of the variation in the intestinal pH of patients as discussed previously.
W097/25980 and W097/27843 describe conventional solid dosage forms such as tablets and capsules and other delivery vehicles such as microspheres, microcapsules and liposomes that may be first coated by a polysaccharide gum, i. e. pectin, followed by a second enteric coating to achieve targeted delivery to the colon. These systems again depend on the intestinal pH of patients, which can lead to inconsistency in the bioavailability of the actives.
W091/07949 describes medicaments for oral administration, wherein the medicaments have a delayed release coating that provides targeted delivery to the colon. According to one of the described aspects, the coating may comprise a mixture of an amorphous, high molecular weight amylose and a film-forming cellulose or acrylic polymer material. The selected amylose is said to be resistant to intestinal amylase, but to be broken down by microbial action in the large intestine, thereby making it suitable for colonic targeting. The film-forming material is said to reduce swelling of the amylose in the digestive fluids. Unfortunately, coating of the medicaments has to be carried out at temperatures above 60 C in order to prevent retrogradation of the amorphous amylose.
WO99/21536 describes applying mixed coatings of amorphous amylose and a film forming polymer by dissolving both the amylose and the polymer in an aqueous solvent containing at least 50% of a water-miscible organic solvent for the film-forming polymer. The solution is coated onto a core.
WO99/25325 describes an alternative method of applying mixed coatings of amorphous amylose and a film forming polymer. The method comprises
dispersing an amylose-butanol complex, a dry powder of the film-forming polymer and a plasticiser in water, followed by coating the dispersion onto a solid core and drying.
One of the key requirements of the above coating systems is that the amylose is present in the amorphous state, i. e. glassy or rubbery. Hence, it is stated that crystallisation of amylose should be avoided and the crystallinity is less than 20% and preferably less than 10%.
The resistance of these coating systems is thought to correlate in part to the glass transition temperature of amylose. Generally, the glass transition temperature of amylose depends on its molecular weight, i. e. the higher the molecular weight, the higher the glass transition temperature, which would in turn produce a more resistant product. Hence, it is stated that the molecular weight of the amylose for this application is at least 20000 g/mol (or daltons) and is preferably higher with a molecular weight of at least 100000,200000, 300000, 400000 or 500000 g/mol.
The glass transition temperature also depends on the amount of impurities/contaminants such as smaller molecular weight oligosaccharides or water. These substances are generally referred to as plasticisers. Their presence reduces the glass transition temperature of a glassy amylose and reduce its resistance.
The presence of branched points in the amylose molecules is another factor affecting the resistance of the film, which reduces the density of the glassy film and acts as the weak point for enzymatic attack. Hence, amylose used for this coating system need to be molecularly uniform, i. e. essentially free of amylopectin (branched a-glucans normally present in starch granules).
Therefore, in order to maintain the integrity of the coating system through the passage of upper gastrointestinal tract and to minimise inconsistency associated with extracted material from natural products, amylose for these
applications must be extensively purified to minimise the amounts of the oligosaccharides and branched molecules and lead to increased process cost.
The above coating systems also require the presence of a film forming water insoluble polymer such as ethylcellulose. A key function of this polymer is to limit the ingress of water to the glassy amylose, which would otherwise result in the transition of the glassy film to its rubbery state. This transition would cause an excessive swelling of the film and lead to the premature release of the actives. On the other hand, an essential requirement of the coating system is that amylose is phase separated from the insoluble polymer to allow the access of the bacterial enzyme for its digestion and to ensure the eventual release of the actives in the colon. The compatibility of these polymers (phase separation) may be affected by a number of factors such as ratio of the insoluble polymer to amylose, quantity and types of plasticizers, spray coating and curing conditions etc. If the polymers are not phase separated, or the phase separated domain is not sufficiently large, little or no release of active at the targeted site will occur.
To overcome the possible problems identified with the earlier compositions, the present invention provides a delayed release dosage form comprising: a core containing an active agent; and a coating which comprises a water-insoluble filmforming polymer matrix and microparticles dispersed in the polymer matrix, wherein the microparticles comprise a major fraction of a dietary fibre other than amorphous amylose.
The water-insoluble film-forming polymer matrix limits the swelling of the microparticles dispersed therein, and thereby limits the degradation of the particles by acids and enzymes in the gastrointestinal tract. The film-forming polymer matrix should normally be non-toxic and preferably itself is resistant to the endogenous secretions of the GI tract as hereinafter discussed. Preferably, the water-insoluble film-forming polymer is a pharmaceutically acceptable polymer, such as a cellulose derivative, an acrylic polymer, lignin, or a lignin derivative.
More preferably, the cellulose derivative comprises or consists essentially of 2-cyanoethyl cellulose, ethyl 2-hydroxycellulose, and most preferably ethyl cellulose and mixtures thereof. More preferably, the acrylic polymer comprises or consists essentially of a polymer of a Ci-C1o acrylate or Ci-C1o methylacrylate or mixtures thereof.
The microparticles dispersed in the polymer matrix comprise a major fraction, i. e. at least 25% by weight on a dry weight basis, preferably 50% and more preferably at least 75%, of a dietary fibre. The term"dietary fibre"is used in its usual sense of any dietary polysaccharide (including a resistant dietary starch) or lignin that is resistant to degradation by the endogenous secretions of the gastrointestinal tract. However, the dietary fibre may be degradable by microflora normally present in the large intestine. That is to say, the microparticles are not broken down rapidly by the acid and enzymes present in the human stomach, nor are they broken down rapidly by the enzymes such as amylase that are present in the duodenum or ileum.
However, the dietary fibre preferably has the characteristic that it is broken down by microbial flora present in the large intestine. This enables the coated products according to the present invention to release the contents of the core selectively into the large intestine, even when the product has been ingested orally.
Preferably, the dietary fibre comprises plant cell wall materials (including non-starch polysaccharides and lignin), polysaccharide gums or other fermentable carbohydrates, a resistant starch other than amorphous amylose, or mixtures thereof.
Plant cell wall materials can be derived from fruits, vegetables, cereal products and other seeds. The cell wall composition depends on the maturity of the plant organ on harvesting and also, in part, on its postharvest storage conditions. The principal chemical constituents include complex polysaccharides such as pectic polysaccharides, hemicellulose, cellulose, some of which are
associated with polyphenolics (i. e. lignin) and proteins. Both the intact plant cell wall materials or extracts thereof can be used for the present coating composition.
In general, parenchymatous tissues of dicotyledonous plants (fruits and vegetables) and parenchymatous tissues of cereal grains are preferred as lignified tissues tend to have a limited degree of degradability. However, lignified tissues such as wheat bran can also be used provided degradability is improved by certain pre-treatment (Table 1). For example, wheat bran can be pre-treated by 1M potassium hydroxide. The degradability of plant cell wall materials by faecal bacteria is shown in Table I (Adopted from Selvendran R. et al. (1988) in Dietary fibres, eds Kritchevsky, D. et al. pages 1-13. Plennum Press, New York) Table 1
Substrate Incubation time (h) % Degradability* Apple cell wall material 0 14. 6 Apple cell wall material 24 88. 3 Apple cell wall material 72 92. 3 Bran cell wall material 0 11. 5 Bran cell wall material 24 29. 7 Bran cell wall material 72 34. 7 1 M KOH-treated material 40 70. 2 1 M KOH-soluble material 40 85. 8 *% material solubilise In certain embodiments, plant cell wall materials can be isolated and size reduced to be incorporated into the present invention. For example, sugar beet roots may be cleaned, cut open and sucrose removed by an extraction process such as counter current diffusion. The remaining beet pulp is either dried and milled to the required particle sizes, or the wet pulp is size reduced by a high speed homogeniser then dried. The latter technique may lead to improved fermentability of the microparticles prepared from sugar beet pulp.
In other embodiments, the plant cell wall materials, in particular those that contain lignin may be chemically or enzymatically treated prior to be incorporated into the present composition. For example, wheat bran may be physically treated with 1 M KOH at 1 C for 2 hours, dialysed and freeze dried. The treated bran can be further classified/milled to appropriate particle sizes.
The term"resistant starch"signifies starch that is digested only slowly or not at all by amylase in the upper Gt tract.
The following factors may contribute to the incomplete digestion. First of all, starch is contained within undisrupted plant structures such as whole or partly milled grains and seeds. Here, the cell walls trap starch and prevent its gelatinisation (cooking), thereby delaying or inhibiting its absorption in the small intestine.
Secondly, in the plant, starch is contained within granular structures where it exists in a closely packed, partially crystalline form. The crystalline structures vary from starch to starch, but can be broadly classified into three categories i. e.
A, B and C types by X-ray diffraction. Typically Band C starches are more resistant than A starches and have a characteristic peak between 4 and 100 (2 theta) on the X-ray diffractogram. Examples of B starches are raw potato starch, green banana starch and high amylomaize starch. The relative crystallinity of these semi-crystalline materials are between 35-50% for potato and banana starches and 25-35% for amylomaize starch.
Crystallinity can be determined by wide angle X-ray diffraction (WAXD) techniques such as a Philips PW 1730 X-ray diffractometer where the X-ray generator is equipped with a copper tube operating at 40kV and 50mA producing Cu Ka radiation of approximately 1.54 A. Data can be recorded over an angular range between 40 to 500 2 theta at an angular interval of 0. 050. Several methods can be used to determine the relative crystallinity for example, by calculating the ratio of the intensities of the maximum to trough for a particular peak, typically the 170 angle (0.516 nm).
A third category of resistant starch is that prepared from processed starch by controlled recrystallisation. For example, under low temperature and high water content, the cooked starch will recrystallise to B type crystallites whereas the less resistant A type crystallites are prepared under high temperature and low water content conditions. According to WO91/07949, glassy amylose prepared from high molecular weight amylose can also offer resistance. The molecular weight of this amylose will need to be a minimum of 20,000 and preferably above 100,000 and the degree of crystallinity should be less than 20%, in particular less than 10%. However, the present inventor has found that it is not necessary to have such high molecular weight or such low crystallinity in order to achieve the desired colon selectivity.
In certain embodiments of the present invention, the resistant starch can be prepared by gelatinising a native starch, then allowing the starch to retrograde, in particular to the B type crystallites. Gelatinisation may be effected by any heat treatment such as steam jacket cooking, pressure cooking and extrusion cooking.
For example, wheat starch can be admixed with water (70%), then subjected to cooker extrusion to fully gelatinise the starch. The gelatinised starch is then stored in an air tight container at 20 C for at least two days to allow the development of crystallinity. The retrograded starch is then freeze dried and size reduced for inclusion in the current composition. This material has a B or C type crystal morphology and with a relative crystallinity of at least 30% as determined by wide angle X-ray diffraction measurement.
A further embodiment of the present invention is to subject the retrograded starch from the previous embodiment to enzyme and acid pre-treatment to remove any non-resistant material. For example, the retrograded starch is size reduced and suspended in 1 M HCI for 1 hour, then washed with water and re-suspended in a buffered a-amylase (pH 6.0) solution for 6 hours. The residual solid starch is then washed with plenty of water and freeze dried to produce the enzyme resistant starch microparticles. This material retains the B or C type crystalline structure but with an increased crystallinity to at least 40%, preferably about 50%.
In another embodiment, the resistant starch can be prepared by a process comprising enzymatically debranching a native starch such as a potato starch, a high amylose starch such as HYLON Vil (Registered Trade Mark of National Starch and Chemicals Inc.), wheat starch or maize starch. For example, the native starch may be gelatinized, enzymatically debranched to produce a large number of short amylose chains (up to 70% with degree of polymerisation in the range 10 to 35), and the resulting slurry allowed to retrograde to produce resistant starch particles having high crystallinity, at least 30%, preferably 40% or greater as determined by wide angle X-ray diffraction. A native starch especially that with B or C-type crystallinity such as raw potato starch, wrinkled pea starch, high amylose starch and green banana starch as characterised by wide angle X-ray diffraction may be directly incorporated to the present composition. The starch has a semicrystalline structure with a crystallinity of least 20%, preferably 25% or above.
In a further embodiment, the resistant starch may be prepared by treating a native starch with an amylase, such as an alpha-amylase in a buffered solution at pH 5 to 7, to remove non-resistant starch fractions. The resistant fraction can then be further comminuted to the desired microparticle sizes. These microparticles are also characterized by high crystallinity, preferably at least 30% and more preferably at least 40% as determined by wide-angle X-ray diffraction.
It will be appreciated that microparticles of resistant starch may be prepared by a variety of other ways including controlled crystallisation of a-glucan of various degrees of polymerisation, spraying drying an amylose solution/suspension or microparticles formed in the presence of supercritical fluid.
In an alternative embodiment, the dietary fibre is selected from resistant polysaccharides e. g. guar gum, gum tragacanth, locust bean gum, karaya gum, gum arabic, algal polysaccharides e. g. alginic acid, carageenans, fermentation gums e. g. xanthan gums and modified polysaccharide thereof.
Microparticles of calcium alginate may be especially suitable for the present application. When in contact with gastric juice, some exchange between the calcium ion of the solid dosage form coated by the present composition and proton in the gastic juice may take place to convert calcium alginate to alginic acid. As alginic acid is water insoluble, the integrity of the microparticles will be preserved.
It is particularly advantageous that sufficient calcium ion is retained within the microparticles to ensure that the integrity of the microparticles is maintained during the passage through the small intestines.
Microparticles of calcium alginate may be prepared by numerous ways.
One example is to prepare a sodium alginate solution, then carefully introduce a solution of calcium chloride. Calcium alginate can be collected either by centrifugation or filtration. After extensive washings, the calcium alginate microparticles can be freeze dried or dehydrated by absolute alcohol. The release profiles of the actives can be manipulated by the size of the micro particles and the amount of calcium incorporated, which is in turn controlled by its molecular structure (i. e. the ratio of guluronic acid and mannuronic acid and their sequence in the polymeric chain).
Microparticle polysaccharide gums may also be prepared by precipitation, cocrystallisation, spray drying, or any other relevant size reduction technology or particle formation technology.
It is known that there exist a large number of oligosaccharides which pass through the upper G) tract intact and can be fermented in the large bowel, for example, some fructo-oligosaccharides and galacto-oligosaccharides, which are collectively known as prebiotics. Microparticles incorporating prebiotics can be included in the present invention. Indeed, biodegradable synthetic polymers may also be incorporated into the present composition.
Preferably, the matrix comprises a plasticiser in addition to the water insoluble polymer. It will be appreciated that the presence of plasticizer is beneficial for homogeneity of coating, the mechanical strength and flexibility and
the integrity of the coating during storage. Therefore, the choice and quantity of plasticiser depends on the polymer selected for this application. For example, if ethyl cellulose is used as the insoluble film former, the plasticiser is present in an amount of from 0 to 50% by weight based on the weight of the water-insoluble polymer, and more preferably in an amount of from 20 to 40 % by weight. Preferably, the plasticiser is selected from the group consisting of dibutyl sebacate, triethyl citrate, triacetin, acetyl tributyl citrate, tributyl citrate and hydrogenated coconut oil, and mixtures thereof.
Preferably, the thickness of the coating in the dosage forms according to the present invention is from 0. 0111m to 2mm, more preferably from 0. 1 p. m to 200 m and most preferably from 1m to 100m.
Preferably, in the delayed release dosage form according to the present invention, the weight average particle size of the microparticles is 0.01 to 1mm, more preferably from 0.1 m to 200 m and most preferably from 1 m to 100 m. In general the size of microparticles depends on the coating thickness. These particles should not be too big as to hinder the application of the coat and shall not be too small as to limit the access of bacterial enzymes in the colon.
Preferably the weight ratio of the matrix material to the microparticles on a dry weight basis is from 1: 5 to 20: 1, more preferably from 1: 3 to 10: 1, and most preferably from 1: 2 to 5: 1. The ratio will depend on the nature of the microparticles, and is selected to give the desired dissolution rate of the coating in the large intestine.
Preferably, the core of the dosage form according to the present invention comprises a human or animal medicament, a diagnostic agent or a dietary supplement. Preferably, the medicament is a medicament for the treatment of a disorder of the colon, or a medicament that is advantageously absorbed by the colonic route. Preferred medicaments include 5-aminosalicylic acid, hydrocortisone, prednisolone, hormones, insulins and cholesterol sequencing agents. Preferred dietary supplements include probiotic organisms, prebiotic
substrates, calcium, and short chain fatty acids. The active agent in the core may be combined with pharmaceutical excipients such as diluents, granulating agents, binders, disintegrants and mixtures thereof, in the usual way.
The dosage forms according to the present invention may be prepared in any conventional means known in the art. Preferably, the core is prepared by any one of the conventional solid dosage forming methods, or the core is a capsule containing the active ingredient, and the coating is then applied to the core. The coating may be applied, for example by spray coating, rotating pan coating or dip coating.
Preferably, the coating is applied from a dispersion of the matrix materials and the microparticles in a solvent. Preferably, the matrix materials are dissolved in the solvent and the microparticles are in the form of a colloidal dispersion (preferably a sol), in which case it will be appreciated that the solvent is preferably partially or completely non-aqueous. The colloidal dispersion of the microparticles may also be prepared separately from that of the matrix material using a different solvent system.
Suitable matrix materials, solvent systems and coating methods are described, for example, in WO99/21536.

Claims (20)

1. A delayed release dosage form comprising : a core containing an active agent; and a coating which comprises a water-insoluble film-forming polymer matrix and microparticles dispersed in the polymer matrix, wherein the microparticles comprise a major fraction of a dietary fibre other than amorphous amylose.
2. A delayed release dosage form according to claim 1, wherein the water insoluble film-forming polymer matrix comprises a cellulose derivative or an acrylic polymer, lignin or a lignin derivative.
3. A delayed release dosage form according to claim 2, wherein the water insoluble film-forming polymer matrix comprises 2-cyanoethyl cellulose, ethyl 2-hydroxycellulose, ethyl cellulose, or a polymer of a C1-C10 acrylate or methacrylate.
4. A delayed release dosage form according to any preceding claim, wherein the microparticles comprise a polysaccharide gum, an alginate, a pectin, a resistant starch, a degradable synthetic polymer, plant cell wall materials or prebiotic oligosaccharides or mixtures thereof.
5. A delayed release dosage form according to claim 4, wherein the microparticles comprise a crystalline starch having a crystallinity of at least 20% as determined by wide-angle X-ray diffraction.
6. A delayed release dosage form according to claim 5, where the crystalline starch has a B or C type morphology with a characteristic peak between 4 and 100 (2 theta) as determined by wide angle X-ray diffraction.
7. A delayed release dosage form according to claim 4 or 5, wherein the microparticles comprise a starch fraction having a number average degree
of polymerisation of from about 10 to about 50, or a molecular weight between 2, 000 and 10, 000 daltons.
8. A delayed release dosage form according to claim 4, where the microparticles are prepared from plant cell wall materials.
9. A delayed release dosage form according to claim 8, wherein the plant cell wall materials have been pre-treated physically, chemically or enzymatically to modify their degradability by the colonic microorganisms.
10. A delayed release dosage form according to claim 4, wherein the microparticles comprise a storage polysaccharide (. e. g. guar gum, gum tragacanth, locust bean gum, karaya gum, gum arabic), an algal polysaccharides (e. g. alginic acid, carageenans), a fermentation gum (e. g. xanthan gums), calcium alginate, araban or a pectin.
11. A delayed release dosage form according to claim 4 or 5, wherein the starch has been prepared by a process comprising gelatinizing and the controlled crystallisation of said starch, followed by enzymatically debranching a native starch.
12. A delayed release dosage form according to claim 4, where the microparticles comprise a resistant starch is prepared from purified amylose by crystallisation or other ways of particle formation such as spray drying.
13. A delayed release dosage form according to claim 4 or 5, wherein the starch has been prepared by treating a native starch with an amylase to remove non-resistant starch fractions.
14. A delayed release dosage form according to any preceding claim, wherein the matrix further comprises a plasticiser.
15. A delayed release dosage form according to claim 14, wherein the plasticiser is present in an amount of up to 50% by weight based on the weight of the water-insoluble polymer.
16. A delayed release dosage form according to claim 14 or 15, wherein the plasticiser is selected from the group consisting of dibutyl sebacate, triethyl citrate, triacetin, acetyl tributyl citrate, tributyl citrate and hydrogenated coconut oil.
17. A delayed release dosage form according to any preceding claim, wherein the thickness of the coating is from 0.01 urn to 2 mm.
18. A delayed release dosage form according to any preceding claim, wherein the particle size of the microparticles is from 10 nm to 100 gm.
19. A delayed release dosage form according to claim 18, wherein the particle size of the microparticles is from 0. 1 m to 1 mm.
20. A delayed release dosage form according to any preceding claim, wherein the core comprises a medicament, a dietary supplement or a diagnostic agent.
GB0023449A 2000-09-25 2000-09-25 Coating composition Withdrawn GB2367002A (en)

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CN104304245A (en) * 2014-09-19 2015-01-28 仲恺农业工程学院 Pesticide controlled release microcapsule and preparation method thereof
US9023368B2 (en) 2006-04-13 2015-05-05 University College London Colonic drug delivery formulation
EP1916995B1 (en) 2005-07-29 2015-10-28 Stichting Groningen Centre for Drug Research Ph-controlled pulsatile delivery system, methods for preparation and use thereof
AU2012247013B2 (en) * 2006-04-13 2016-01-14 University College London Colonic drug delivery formulation
EP3409688A1 (en) 2017-05-31 2018-12-05 Tillotts Pharma Ag Topical treatment of inflammatory bowel disease using anti-tnf-alpha antibodies and fragments thereof
EP3459529A1 (en) 2017-09-20 2019-03-27 Tillotts Pharma Ag Preparation of sustained release solid dosage forms comprising antibodies by spray drying
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EP3662898A1 (en) 2018-12-07 2020-06-10 Tillotts Pharma AG Solid composition comprising mesalazine
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EP3662901A1 (en) 2018-12-07 2020-06-10 Tillotts Pharma AG Delayed release drug formulation comprising an outerlayer with an enzymaticyaaly degradable polymer, its composition and its method of manufacturing
WO2020115277A1 (en) 2018-12-07 2020-06-11 Tillotts Pharma Ag Topical treatment of immune checkpoint inhibitor induced diarrhoea, colitis or enterocolitis using antibodies and fragments thereof
US11173116B2 (en) * 2018-07-11 2021-11-16 Industry-Academic Cooperation Foundation, Yonsei University Drug delivery system kit comprising an enzyme

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