CA2769046A1 - Coating agent for the dip coating of capsule halves - Google Patents
Coating agent for the dip coating of capsule halves Download PDFInfo
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- CA2769046A1 CA2769046A1 CA2769046A CA2769046A CA2769046A1 CA 2769046 A1 CA2769046 A1 CA 2769046A1 CA 2769046 A CA2769046 A CA 2769046A CA 2769046 A CA2769046 A CA 2769046A CA 2769046 A1 CA2769046 A1 CA 2769046A1
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- 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
- A61K9/4891—Coated capsules; Multilayered drug free capsule shells
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
Abstract
The invention relates to a coating agent for the gastric juice-resistant coating of capsule halves, which are made of a water-soluble or water-swellable polymer material, in a dip coating process, in the form of an aqueous dispersion or solution, containing a polymer mixture of at least an initial (meth)acrylate copolymer that is gastric juice-resistant, as well as auxiliary materials that influence the viscosity of the dispersion and the elasticity of the dried polymer film, characterized in that the solids content of the dispersion or solution is more than 25 percent by weight and the viscosity is 150 to 1,500 mPas, wherein a film generated by the dispersion or solution and dried has an ultimate elongation of at least 200 percent and a capsule composed of two capsule halves coated with the dispersion or solution in the dip coating process does not dissolve in 0.1 N HCl at a pH of 1.2 after two hours, but does completely dissolve subsequently in a buffer at a pH of 6.8 in less than 30 minutes.
Description
Coating agent for the dip coating of capsule halves Field of the invention According to the claims, the invention relates to a coating composition for the enteric coating of capsule halves made of water-soluble or water-swellable polymer material in the dipping process.
Prior art Huyghebaert et al., European Journal of Pharmaceutical Sciences 21 (2004) 617-623, describe an alternative method for the enteric coating of capsules made of hydroxypropylmethylcellulose (HPMC) in which ready-to-use enteric capsule parts are obtained.
In the introductory section, it is reported that enteric coated HPMC capsules have for a long time been used in the dietetic food supplement industry as vegetarian alternatives to gelatine. It is also mentioned that although the enteric coating of hard gelatine capsules made of organic solutions is possible, it is difficult to execute and may lead to embrittlement of the capsules, which can result in poor adhesion of the coating. This can be overcome by applying an intermediate layer, although this is lengthy and complicated. Moreover, coating processes from aqueous preparations have the advantage over coating processes from organic solutions on account of the toxicological and safety aspects. The coating of gelatine capsules from aqueous preparations, however, is very demanding and requires long processing times on account of the solubility of the gelatine in water, which overall leads to high costs.
It is furthermore reported that, in, contrast to gelatine capsules, HPMC capsules can be enteric coated relatively easily from aqueous preparations. However, it is necessary to additionally apply a sealing between the capsule halves, e.g. through a gelatine solution to be applied manually, in order to avoid an untightness of the capsule and an uncontrolled escape of the contents in the stomach. Another technique is to apply water/ethanol mixtures between the capsule halves and to weld the parts together at 40-60 C.
Using aqueous preparations (EUDRAGIT FS 30 D, EUDRAGIT L 30 D-55, Aquoat AS-HF or Sureteric ) based on (meth)acrylate copolymers or polyvinyl acetate phthalate, plasticizers such as triethyl citrate and further auxiliaries, such as, for example, talc, it is possible to provide HPMC capsules with an enteric film.
A separate sealing step can be dispensed with in the case of this coating technology. In particular, HPMC
capsules which have been coated with (meth)acrylate copolymers are depicted as particularly advantageous in the sum of their properties.
It is furthermore mentioned that the dipping process for the enteric coating of capsules is very time-consuming and can bring with it a multitude of practical problems. In particular, the problems consist in an uneven coating and unsatisfactory enteric properties.
Problem and solution Capsules filled with active ingredients or food constituents, in particular made of gelatine or hydroxypropylmethylcellulose, have been used for a long time in the fields of pharmacy, food supplements and cosmetics. Active ingredients are to be understood as meaning in particular pharmaceutical active ingredients, food supplements or active ingredients with an assumed cosmetic effect, so-called cosmeceuticals. Enteric coatings which are intended to prevent the capsule contents from being released in the stomach have likewise been known for a long time.
Whereas capsule halves e.g. made of gelatine are produced with high precision in the dipping process, the enteric coatings for such capsules are produced almost exclusively in the spraying process. Attempts to apply enteric coatings in the dipping process have hitherto proven unsatisfactory.
It was seen as an object to provide a coating composition for the enteric coating of capsule halves which can be applied in the dipping process.
Furthermore, the coating composition should comprise no organic solvents. The coating composition should ensure the tightness of the closed capsules in the gastric juice without the capsules having to be provided to this end with an additional sealing. The coating composition should have adequate flowability in order to be able to be applied in the dipping process, but at the same time permit short drying times. The dried coating should be sufficiently elastic and have a uniform coating thickness. In the milieu of the intestine, rapid dissolution of the capsules should take place.
The object is achieved by a coating composition for the enteric coating of capsule halves made of water-soluble or water-swellable polymer material in the dipping process, in the form of an aqueous dispersion or solution, comprising a polymer mixture of at least one first (meth)acrylate copolymer, which is enteric, and at least one further (meth)acrylate copolymer which is enteric or water-insoluble, and also auxiliaries which influence the viscosity of the dispersion and the elasticity of the dried polymer film, characterized in that the solids content of the dispersion or solution is more than 25%
by weight and the viscosity is 150 to 1500 mPa=s, where a dried film produced from the dispersion or solution has an elongation at break of at least 200% and a capsule composed of two capsule halves coated with the dispersion or solution in the dipping process does not dissolve in 0.1 N HC1 at pH 1.2 after two hours, but then dissolves completely in buffer at pH 6.8 in less than 30 minutes.
Explanation of the invention According to the claims, the invention relates to a coating composition for the enteric coating of capsule halves made of water-soluble or water-swellable polymer material in the dipping process.
Capsule halves and capsules Capsule halves may be upper or lower parts of a capsule. Upper and lower part fit together such that they can be engaged in one another in a locking manner and form a closed capsule. A capsule thus consists of an upper and a lower half which can be filled as required as a container with an active ingredient and then is firmly closed by engaging with the upper part.
Filled capsules are provided in particular for oral application. Capsules e.g. made of gelatine without an enteric coating dissolve in the stomach.
Capsule halves, upper or lower parts, consist in particular of a water-soluble or water-swellable polymer material. Both capsule halves preferably consist of gelatine or of hydroxypropylmethylcellulose.
Preference is given to gelatine. Less customary, but also possible material for capsule halves are polymers such as, for example, starch, pectin or agar.
As a rule, a capsule consists of a uniform, in particular of the same or identical material.
Consequently, preferably both capsule halves, upper and lower halves, consist e.g. uniformly of gelatine, in -particular of the same or identical gelatine.
Capsules and capsule halves made of water-soluble or water-swellable polymer material are used widely for 5 administering pharmaceutical active ingredients or food supplements. In particular, mention may be made of the fields of pharmacy and food supplements (nutraceuticals), where the field of cosmetics, as far as food supplements or potential active ingredients (cosmeceuticals) are concerned, may be included.
The capsule halves are enteric coated. "Enteric coated"
means that the capsule halves have been enteric coated on their exterior. A closed capsule is therefore protected externally from dissolution in gastric juice, pH 1 to about 5. The enteric coating rapidly dissolves in the area of the intestinal fluid, above pH 5, meaning that the underlying capsule material likewise dissolves and releases the contents.
A capsule composed of two capsule halves enteric coated with the dispersion or solution in the dipping process does not dissolve in 0.1 N HC1 (artificial gastric fluid according to USP without the addition of enzyme) at pH 1.2 after 2 hours, then dissolve completely in buffer at pH 6.8 according to USP, either after rebuffering the pH 1.2 medium to pH 6.8 or by transferring the capsule to the pH 6.8 buffer. Suitable testing methods are known to the person skilled in the art and can be found, for example, in USP 32. The capsules are held under the surface of the liquid using sinkers.
Dimension of capsules Within the context of the invention, a closed capsule can have a total length in the range from about 5 to 50 mm. The diameter of the upper part can be in the range from about 4 to 12 mm. The diameter of the lower part can be in the range from about 2 to 10 mm. The length of the upper part can be in the range from about 4 to 20 mm and that of the lower part in the range from 8 to 30 mm. The fill volume can be between about 0.1 and 2 ml.
Capsules can be divided, for example, into standardized sizes from 000 to 5 (see in this context e.g.:
Fahrig W. and Hofer U. (1983): Die Kapsel, Grundlagen, Technologie and Biopharmazie einer modernen Arzneiform [Capsules, Principles, Technology and Biopharmacy of a Modern Drug Form], Wissenschaftliche Verlagsgesellschaft mbH Stuttgart).
A closed capsule of size 000 has, for example, a total length of about 28 mm for a diameter of the upper part of about 9.9 mm and a diameter of the lower part of about 9.5 mm. The length of the upper part is about 14 mm, that of the lower part 22 mm. The fill volume is about 1.4 ml.
A closed capsule of size 5 has, for example, a total length of about 10 mm for a diameter of the upper part of about 4.8 mm and a diameter of the lower part of about 4.6 mm. The length of the upper part is about 5.6 mm, that of the lower part 9.4 mm. The fill volume is about 0.13 ml.
Layer thicknesses The coating composition according to the invention is preferably adjusted so that, in the dried state, coating films with layer thicknesses in the range from 20 to 100, in particular 40 to 80 pm, are produced. In this connection, the capsule halves can already be produced such that the wall thicknesses on the outside are in each case reduced by the layer thickness of the enteric coating to be expected, such that standard wall thicknesses arise again following the dip coating. If, for example, a customary standard capsule upper part and lower part made of gelatine has a wall thickness of 100 pm, then the wall thicknesses for enteric coated capsules are reduced in the preparation to e.g. ca.
60 gm. Then, in the dipping process, an enteric coating with a layer thickness in the dried state of ca. 40 pm is applied. The resulting upper and lower parts then again have wall thicknesses of 100 m and can be further processed in the same way as standard capsules without altering the machine settings.
Sealing function of the enteric coating As a result of the preparation in dipping processes, the lower capsule half, the lower part, receives a continuous enteric coating which, in the closed state, is partly overlapped by the upper part. Favoured by the elasticity of the film and its uniformity, the overlapped part of the enteric coating assumes here a sealing function which effectively prevents the penetration of gastric fluid through a possible gap between the lower part and the upper part. The dipping process thus offers an advantage over the coating of closed capsules in a spraying process in which no overlapping occurs, as a result of which the abutment point on the edge of the upper part always brings with it the potential risk of untightness. In many cases, therefore, prior to the enteric coating of closed capsules in a spraying process, a sealing band is applied or another measure is undertaken for sealing the abutment point. Measures of this kind can be dispensed with when applying the coating composition according to the invention in the dipping process, which represents a further advantage.
The tightness of the capsule material can be demonstrated, for example, by pouring a marker, e.g. a dye or an active ingredient that is easy to detect and readily soluble in water, into the coated capsule halves or into the capsule and observing its escape into the medium or its retention in the capsule during the incubation for 2 hours in 0.1 N HCl or in artificial gastric fluid pH 1.2 in accordance with USP.
Here, no or only a very small part of the marker should be detectable in the medium, less than 10%.
Aqueous dispersion or solution The coating composition according to the invention is in the form of an aqueous dispersion or solution. The term "aqueous dispersion or solution" is understood in the broad sense and is intended to include all transition states, in particular also so-called polymer/colloidal solutions. The aqueous dispersion consists of a solid phase and a liquid phase. The solids phase and the liquid phase add up to 100% by weight.
The liquid phase of the aqueous dispersion or solution is based essentially or completely on the dispersant or solvent water. The liquid phase thus consists of at least 95% by weight, preferably at least 98% by weight, in particular 100% by weight, of water. Organic solvents, such as, for example, ethanol, isopropanol or acetone, may be present up to 5% by weight, preferably up to 2% by weight. This may be of use in individual cases for lowering the surface tension or for preventing microbiological contamination. Preferably, however, no organic solvents are present.
The term "dispersion or solution" refers to the fact that the substances present can in their totality be present either in dispersed form, dissolved form or else partly dispersed or dissolved in an intermediate state. The aqueous dispersion or solution preferably has a pH of from 6.0 to 10.0, in particular from 6.5 to 9Ø In this pH range, the (meth)acrylate copolymers present are predominantly in dispersed or at least partly dissolved form. Plasticizers are generally present in dissolved form. Other additives or auxiliaries, such as, for example, talc, may be present in dispersed form.
Solids content The solids content of the aqueous dispersion or solution is more than 25% by weight, preferably more than 30% by weight, in particular 32 - 36% by weight.
For comparison, the solids contents of dispersions or solutions which are used in spraying processes are generally only around 20% by weight.
The solids content is used in particular together with the viscosity for controlling the balance between good wettability of the as yet uncoated capsule halves in the dipping process and acceptable drying time of the coated capsule halves after the dipping process. If the solids content is too low, the drying times become too long, and, moreover, as a rule no adequate viscosity can be built up. If the solids content is too high, this may lead to drop formations on the dipsticks and to overall uneven coatings. Consequently, no exact adjustment of the layer thickness is possible.
Viscosity The viscosity of the aqueous dispersion or solution is 150 to 1500, preferably 180 to 1000, in particular 200 to 350 mPa=s. The viscosity can be determined, for example, using a Brookfield rotary viscometer. The determination method is known to the person skilled in the art (see e.g. ISO 3219:1993).
Elongation at break The elasticity of the dried polymer film can essentially be characterized by its elongation at break. A dried film produced from the dispersion or solution according to the invention, e.g. by pouring, has an elongation at break of at least 200, preferably at least 250%. The elongation at break in [%] can be determined on sample films in accordance with DIN 53 455.
(Meth)acrylate copolymers The aqueous dispersion or solution comprises a polymer mixture of at least one first (meth)acrylate copolymer, which is enteric, and at least one further (meth)acrylate copolymer, which is enteric or water-insoluble.
At least one first (meth)acrylate copolymer means one or more first (meth)acrylate copolymers.
At least one further (meth)acrylate copolymer means one or more further (meth)acrylate copolymers.
The polymer mixture comprises or consists of at least two (meth)acrylate copolymers. Preferably, the polymer mixture comprises or consists of two (meth)acrylate copolymers.
The first (meth)acrylate copolymer, which is enteric, and the further (meth)acrylate copolymer, which is enteric or water-insoluble, are preferably present in a ratio of from 2:1 to 1:2.
The first (meth)acrylate copolymer, which is enteric, and the further (meth)acrylate copolymer, which is enteric or water-insoluble, constitute preferably at least 45% by weight, particularly preferably at least 60% by weight, in particular at least 70% by weight, of the solid present in the dispersion.
An enteric (meth)acrylate copolymer is understood as meaning those (meth)acrylate copolymers which are insoluble in the pH range of gastric fluid, pH 1.0 to 5.0, but dissolve in the pH range of the intestinal fluid, above pH 5.0, in particular pH 5.5 to 8Ø In particular, enteric coated drug forms in 0.1 N HC1 release at most 10% of the active ingredient present over the course of 2 hours. Enteric (meth)acrylate copolymers are synonymous with (meth)acrylate copolymers which are composed of C1- to C4-alkyl esters of acrylic acid or methacrylic acid and have at least 5%, preferably 5 to 70%, in particular 8 to 60%, of monomer radicals with anionic groups, as a rule methacrylic acid radicals. Cl- to C4-alkyl esters of acrylic acid or methacrylic acid are in particular methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate and butyl acrylate.
First enteric (meth)acrylate copolymer Preferably, the first enteric (meth)acrylate copolymer is an anionic (meth)acrylate copolymer. Preferably, the glass transition temperature of the first (meth)acrylate copolymer in accordance with ISO 11357-2, point 3.3.3, is more than 70 C.
Preferably, the first enteric (meth)acrylate copolymer is a polymer of 40 to 60% by weight of methacrylic acid and 60 to 40% by weight of methyl methacrylate or 60 to 40% by weight of ethyl acrylate (grade EUDRAGIT L100 or EUDRAGIT L100-55).
Of suitability in particular is EUDRAGIT L100-55, which is a copolymer of 50% by weight of ethyl acrylate and 50% by weight of methacrylic acid.
Likewise suitable are anionic (meth)acrylate copolymers of 20 to 40% by weight of methacrylic acid and 80 to 60% by weight of methyl methacrylate (grade EUDRAGIT S).
Further (meth)acrylate copolymer The further (meth)acrylate copolymer may be enteric or water-insoluble. If the further (meth)acrylate copolymer is an enteric polymer, it is different from the first enteric (meth)acrylate copolymer.
Further anionic (meth)acrylate copolymer Preferably, the further (meth)acrylate copolymer may be an enteric, anionic polymer which is different from the first enteric (meth)acrylate copolymer. Preferably, the glass transition temperature of the further (meth)acrylate copolymer in accordance with ISO 11357-2, point 3.3.3, is at most 70, preferably at most 60, in particular at most 50 C, e.g. 40 to 60 C.
Of particular suitability is, for example, a polymer of 10 to 30% by weight of methyl methacrylate, 50 to 70%
by weight of methyl acrylate and 5 to 15% by weight of methacrylic acid (grade EUDRAGIT FS).
Specifically, for example EUDRAGIT FS, which is a copolymer of 25% by weight of methyl methacrylate, 65%
by weight of methyl acrylate and 10% by weight of methacrylic acid, is suitable. EUDRAGIT FS 30 D is a dispersion comprising 30% by weight of EUDRAGIT FS.
Also suitable for the purposes of the invention is a (meth)acrylate copolymer (see WO 2003/072087), which is composed of 20 to 34% by weight of methacrylic acid and/or acrylic acid, 20 to 69% by weight of methyl acrylate and 0 to 40% by weight of ethyl acrylate and/or optionally 0 to 10% by weight of further vinylically copolymerizable monomers, with the proviso that the glass transition temperature of the (meth)acrylate copolymer in accordance with ISO 11357-2, point 3.3.3, is at most 60 C. This (meth)acrylate copolymer has in particular very good elongation at break properties.
The copolymer is composed in particular of radically polymerized units of to 34, preferably 25 to 33, particularly preferably 28 to 32% by weight of methacrylic acid or acrylic 15 acid, preferably methacrylic acid, 20 to 69, preferably 35 to 65, particularly preferably 35 to 55% by weight of methyl acrylate and optionally 20 0 to 40, preferably 5 to 35, particularly preferably 15 to 35% by weight of ethyl acrylate, with the proviso that the glass transition temperature of the copolymer (measurement without the addition of plasticizer at a residual monomer content (REMO) of less than 100 ppm, heating rate 10 C/min, nitrogen atmosphere) in accordance with ISO 11357-2, point 3.3.3 (Tmg), is at most 60, preferably 40 to 60, particularly preferably 45 to 55 C.
The copolymer preferably consists essentially to exclusively of the monomers methacrylic acid, methyl acrylate and ethyl acrylate in the quantitative fractions given above.
However, it is additionally possible, without leading to an impairment of the essential properties, for small amounts in the range from 0 to 10, e.g. 1 to 5% by weight of further vinylically copolymerizable monomers, such as, for example, methyl methacrylate, butyl methacrylate, butyl acrylate or hydroxyethyl methacrylate, to be present.
Glass transition temperature here is to be understood in particular as meaning the midpoint temperature Tmg in accordance with ISO 11357-2, point 3.3.3. Measurement takes place without the addition of plasticizer, at residual monomer contents (REMO) of less than 100 ppm, at a heating rate of 10 C/min and under a nitrogen atmosphere.
Also suitable for the purposes of the invention are (meth)acrylate copolymers (see WO 2004/096185) comprising 20 to 33% by weight of methacrylic acid and/or acrylic acid, 5 to 30% by weight of methyl acrylate and to 40% by weight of ethyl acrylate and 20 greater than 10 to 30% by weight of butyl methacrylate and optionally 0 to 10% by weight of further vinylically copolymerizable monomers, where the fractions of the monomers add up to 100% by weight, with the proviso that the glass transition temperature of the copolymer in accordance with ISO 11357-2, point 3.3.3 (midpoint temperature Tmg) is 55 to 70 C. On account of their good mechanical properties, copolymers of this type are particularly suitable for compressing pellets to give tablets.
The aforementioned copolymer is composed in particular of radically polymerized units of 20 to 33% by weight, preferably 25 to 32% by weight, particularly preferably 28 to 31% by weight, of methacrylic acid or acrylic acid, preferably methacrylic acid, to 30% by weight, preferably 10 to 28% by weight, particularly preferably 15 to 25% by 5 weight, of methyl acrylate, 20 to 40% by weight, preferably 25 to 35% by weight, particularly preferably 28 to 32% by weight, of ethyl acrylate, and greater than 10 to 30% by weight, preferably 15 to 25% by weight, particularly preferably 18 to 22%
by weight, of butyl methacrylate, where the monomer composition is selected so that the glass transition temperature of the copolymer is 55 to 70 C, preferably 59 to 66 C, particularly preferably 60 to 65 C.
The copolymer preferably consists essentially to exclusively, to 90, 95 or 99 to 100% by weight, of the monomers methacrylic acid, methyl acrylate, ethyl acrylate and butyl methacrylate in the quantitative ranges stated above.
However, it is also possible, without having to lead to an impairment of the essential properties, for small amounts in the range from 0 to 10, e.g. 1 to 53 by weight of further vinylically copolymerizable monomers, such as, for example, methyl methacrylate, butyl acrylate, hydroxyethyl methacrylate, vinylpyrrolidone, vinylmalonic acid, styrene, vinyl alcohol, vinyl acetate and/or derivatives thereof, to be present.
Water-insoluble (meth)acrylate copolymers Within the context of the invention, a water-insoluble (meth)acrylate copolymer is to be understood as meaning those (meth)acrylate copolymers which are water-insoluble or merely water-swellable over the entire pH
range from 1 to 14. These are preferably "neutral"
(meth)acrylate copolymers. Neutral is understood as meaning that the (meth)acrylate copolymers are composed predominantly or completely of neutral monomers, e.g.
to more than 95% by weight, to more than 98% by weight, to more than 99% by weight or to 100% by weight.
Accordingly, the term "neutral" does not entirely rule out the presence of ionic groups in the polymer.
(Meth)acrylate copolymers with a content of less than 5% by weight, preferably less than 2% by weight, preferably less than 1% by weight, of ionic, in particular anionic groups, are referred to as "neutral"
within the context of the invention or as "essentially neutral". These neutral or essentially neutral, or optionally only to a small extent, ionic polymers are water-insoluble or merely water-swellable and have no enteric properties.
The further (meth)acrylate copolymer may preferably be a water-insoluble polymer which is a polymer of 20 to 40% by weight of ethyl acrylate, 60 to 80% by weight of methyl methacrylate and less than 5% by weight, preferably less than 2% by weight, preferably less than 1% by weight, of methacrylic acid (grade EUDRAGIT NE
or EUDRAGIT NM).
For example, EUDRAGIT NE, which is a copolymer of 30%
by weight of ethyl acrylate and 70% by weight of methyl methacrylate, is suitable.
Auxiliaries which influence the viscosity of the dispersion or solution and the elasticity of the dried polymer film The viscosity of the dispersion and the elasticity or the elongation at break of the dried polymer film can usually not be brought into the required ranges by the polymer mixture alone. Consequently, the aqueous dispersion or solution additionally comprises auxiliaries which, together with the polymer mixture, influence or increase and steer into the required ranges the viscosity of the dispersion and the elasticity of the dried polymer film.
A comparatively strong influencing of said parameters can be achieved in particular through the addition of plasticizers or basic substances. These auxiliaries preferably constitute at most 30% by weight, in particular at most 20% by weight, of the solid present in the dispersion. The content of these auxiliaries can be, for example, 5 to 30% by weight, preferably 10 to 20% by weight, of the solid present in the dispersion.
Plasticizers Plasticizers can contribute to influencing and/or increasing the viscosity of the dispersion and the elasticity of the dried polymer film.
Substances suitable as plasticizers generally have a molecular weight (MW) between 100 and 20 000 and contain one or more hydrophilic groups in the molecule, e.g. hydroxyl, ester or amino groups. Citrates, phthalates, sebacates, castor oil are suitable.
Examples of suitable plasticizers are alkyl esters of citric acid, propylene glycol, glycerol esters, alkyl esters of phthalic acid, alkyl esters of sebacic acid, sucrose esters, sorbitan esters, diethyl sebacate, dibutyl sebacate and polyethylene glycol 300 to 35 000.
Preferred plasticizers are tributyl citrate, triethyl citrate, acetyltriethyl citrate, dibutyl sebacate and diethyl sebacate. The use amounts of plasticizers may be in the range from 1 to 30, preferably 5 to 25% by weight, based on the polymer mixture. Preference is given to polyethylene glycols with a high molecular weight, in particular polyethylene glycol 20 000 or polyethylene glycol 35 000, which can greatly increase the viscosity of the dispersion or solution.
Preferably, the use amounts for polyethylene glycol 20 000 or polyethylene glycol 35 000 are 5 to 25, in particular 10 to 20% by weight, based on the polymer mixture. Additionally, other plasticizers, such as, for example, triethyl citrate, in amounts of from 5 to 15%
by weight based on the polymer mixture, can be combined with polyethylene glycol 20 000 or polyethylene glycol 35 000.
Basic substances Basic substances can contribute to influencing or increasing the viscosity of the dispersion and the elasticity of the dried polymer film.
In order to prepare an aqueous solution of the enteric (meth)acrylate copolymer, a partial or complete neutralization of the acid groups is generally necessary. The first or optionally also a further enteric (meth)acrylate copolymer can, for example, be gradually stirred into water and in so doing be partially or completely neutralized by adding a basic substance, such as, for example, NaOH, KOH, ammonium hydroxide or organic bases, such as, for example, triethanolamine. It is also possible to use a powder of the copolymer to which a base, e.g. NaOH, has already been added during its preparation for the purpose of (partial) neutralization, meaning that the powder is an already (partially) neutralized polymer. Particular preference is given to sodium hydroxide solution or NaOH.
Further suitable basic substances are, for example:
sodium carbonate, potassium carbonate, sodium bicarbonate, trisodium phosphate, trisodium citrate or ammonia or physiologically compatible amines, such as triethanolamine or tris(hydroxymethyl)aminomethane, the cationic, basic amino acids histidine, arginine and/or lysine, natural or synthetic oligomers or polymers, e.g. of 3 to 100, preferably 5 to 25, units, of histidine, arginine or lysine, polyhistidines, polyarginines, polylysines, cationic or zwitterionic phospholipids, such as, for example, phosphatidylcholine, ribonucleosides, condensation products of the hydroxyl function on carbon atom 1 of ribose with the heterocyclic amino function of the bases adenine, guanine, cytosine, thymine or uracil, corresponding to the occurrence in RNA, or deoxyribonucleosides, condensation products of the hydroxyl function on carbon atom 1 of deoxyribose with the heterocyclic amino function of the bases adenine, guanine, cytosine, thymine or uracil, corresponding to the occurrence in DNA.
Preference is given to a degree of neutralization of from 3 to 12 mol% of the anionic groups at least of the (meth)acrylate copolymer. Preferably, the neutralization takes place with sodium hydroxide in the form of 1.5 to 2 normal sodium hydroxide solution. The relatively high concentration of the sodium hydroxide solution prevents too great a reduction in the solids content. The partial neutralization is accompanied by a thickening of the dispersion or solution, i.e. an increase in the viscosity.
The quantitative fraction of basic substances of the total content of the auxiliaries which influence or increase the viscosity of the dispersion and the elasticity of the dried polymer film is more likely to be low compared to plasticizers. The influence of the basic substances in particular on the viscosity, however, is relatively great, meaning that even these comparatively small amounts bring about significant effects. Preference is given to using a combination of plasticizers and basic substances.
Prior art Huyghebaert et al., European Journal of Pharmaceutical Sciences 21 (2004) 617-623, describe an alternative method for the enteric coating of capsules made of hydroxypropylmethylcellulose (HPMC) in which ready-to-use enteric capsule parts are obtained.
In the introductory section, it is reported that enteric coated HPMC capsules have for a long time been used in the dietetic food supplement industry as vegetarian alternatives to gelatine. It is also mentioned that although the enteric coating of hard gelatine capsules made of organic solutions is possible, it is difficult to execute and may lead to embrittlement of the capsules, which can result in poor adhesion of the coating. This can be overcome by applying an intermediate layer, although this is lengthy and complicated. Moreover, coating processes from aqueous preparations have the advantage over coating processes from organic solutions on account of the toxicological and safety aspects. The coating of gelatine capsules from aqueous preparations, however, is very demanding and requires long processing times on account of the solubility of the gelatine in water, which overall leads to high costs.
It is furthermore reported that, in, contrast to gelatine capsules, HPMC capsules can be enteric coated relatively easily from aqueous preparations. However, it is necessary to additionally apply a sealing between the capsule halves, e.g. through a gelatine solution to be applied manually, in order to avoid an untightness of the capsule and an uncontrolled escape of the contents in the stomach. Another technique is to apply water/ethanol mixtures between the capsule halves and to weld the parts together at 40-60 C.
Using aqueous preparations (EUDRAGIT FS 30 D, EUDRAGIT L 30 D-55, Aquoat AS-HF or Sureteric ) based on (meth)acrylate copolymers or polyvinyl acetate phthalate, plasticizers such as triethyl citrate and further auxiliaries, such as, for example, talc, it is possible to provide HPMC capsules with an enteric film.
A separate sealing step can be dispensed with in the case of this coating technology. In particular, HPMC
capsules which have been coated with (meth)acrylate copolymers are depicted as particularly advantageous in the sum of their properties.
It is furthermore mentioned that the dipping process for the enteric coating of capsules is very time-consuming and can bring with it a multitude of practical problems. In particular, the problems consist in an uneven coating and unsatisfactory enteric properties.
Problem and solution Capsules filled with active ingredients or food constituents, in particular made of gelatine or hydroxypropylmethylcellulose, have been used for a long time in the fields of pharmacy, food supplements and cosmetics. Active ingredients are to be understood as meaning in particular pharmaceutical active ingredients, food supplements or active ingredients with an assumed cosmetic effect, so-called cosmeceuticals. Enteric coatings which are intended to prevent the capsule contents from being released in the stomach have likewise been known for a long time.
Whereas capsule halves e.g. made of gelatine are produced with high precision in the dipping process, the enteric coatings for such capsules are produced almost exclusively in the spraying process. Attempts to apply enteric coatings in the dipping process have hitherto proven unsatisfactory.
It was seen as an object to provide a coating composition for the enteric coating of capsule halves which can be applied in the dipping process.
Furthermore, the coating composition should comprise no organic solvents. The coating composition should ensure the tightness of the closed capsules in the gastric juice without the capsules having to be provided to this end with an additional sealing. The coating composition should have adequate flowability in order to be able to be applied in the dipping process, but at the same time permit short drying times. The dried coating should be sufficiently elastic and have a uniform coating thickness. In the milieu of the intestine, rapid dissolution of the capsules should take place.
The object is achieved by a coating composition for the enteric coating of capsule halves made of water-soluble or water-swellable polymer material in the dipping process, in the form of an aqueous dispersion or solution, comprising a polymer mixture of at least one first (meth)acrylate copolymer, which is enteric, and at least one further (meth)acrylate copolymer which is enteric or water-insoluble, and also auxiliaries which influence the viscosity of the dispersion and the elasticity of the dried polymer film, characterized in that the solids content of the dispersion or solution is more than 25%
by weight and the viscosity is 150 to 1500 mPa=s, where a dried film produced from the dispersion or solution has an elongation at break of at least 200% and a capsule composed of two capsule halves coated with the dispersion or solution in the dipping process does not dissolve in 0.1 N HC1 at pH 1.2 after two hours, but then dissolves completely in buffer at pH 6.8 in less than 30 minutes.
Explanation of the invention According to the claims, the invention relates to a coating composition for the enteric coating of capsule halves made of water-soluble or water-swellable polymer material in the dipping process.
Capsule halves and capsules Capsule halves may be upper or lower parts of a capsule. Upper and lower part fit together such that they can be engaged in one another in a locking manner and form a closed capsule. A capsule thus consists of an upper and a lower half which can be filled as required as a container with an active ingredient and then is firmly closed by engaging with the upper part.
Filled capsules are provided in particular for oral application. Capsules e.g. made of gelatine without an enteric coating dissolve in the stomach.
Capsule halves, upper or lower parts, consist in particular of a water-soluble or water-swellable polymer material. Both capsule halves preferably consist of gelatine or of hydroxypropylmethylcellulose.
Preference is given to gelatine. Less customary, but also possible material for capsule halves are polymers such as, for example, starch, pectin or agar.
As a rule, a capsule consists of a uniform, in particular of the same or identical material.
Consequently, preferably both capsule halves, upper and lower halves, consist e.g. uniformly of gelatine, in -particular of the same or identical gelatine.
Capsules and capsule halves made of water-soluble or water-swellable polymer material are used widely for 5 administering pharmaceutical active ingredients or food supplements. In particular, mention may be made of the fields of pharmacy and food supplements (nutraceuticals), where the field of cosmetics, as far as food supplements or potential active ingredients (cosmeceuticals) are concerned, may be included.
The capsule halves are enteric coated. "Enteric coated"
means that the capsule halves have been enteric coated on their exterior. A closed capsule is therefore protected externally from dissolution in gastric juice, pH 1 to about 5. The enteric coating rapidly dissolves in the area of the intestinal fluid, above pH 5, meaning that the underlying capsule material likewise dissolves and releases the contents.
A capsule composed of two capsule halves enteric coated with the dispersion or solution in the dipping process does not dissolve in 0.1 N HC1 (artificial gastric fluid according to USP without the addition of enzyme) at pH 1.2 after 2 hours, then dissolve completely in buffer at pH 6.8 according to USP, either after rebuffering the pH 1.2 medium to pH 6.8 or by transferring the capsule to the pH 6.8 buffer. Suitable testing methods are known to the person skilled in the art and can be found, for example, in USP 32. The capsules are held under the surface of the liquid using sinkers.
Dimension of capsules Within the context of the invention, a closed capsule can have a total length in the range from about 5 to 50 mm. The diameter of the upper part can be in the range from about 4 to 12 mm. The diameter of the lower part can be in the range from about 2 to 10 mm. The length of the upper part can be in the range from about 4 to 20 mm and that of the lower part in the range from 8 to 30 mm. The fill volume can be between about 0.1 and 2 ml.
Capsules can be divided, for example, into standardized sizes from 000 to 5 (see in this context e.g.:
Fahrig W. and Hofer U. (1983): Die Kapsel, Grundlagen, Technologie and Biopharmazie einer modernen Arzneiform [Capsules, Principles, Technology and Biopharmacy of a Modern Drug Form], Wissenschaftliche Verlagsgesellschaft mbH Stuttgart).
A closed capsule of size 000 has, for example, a total length of about 28 mm for a diameter of the upper part of about 9.9 mm and a diameter of the lower part of about 9.5 mm. The length of the upper part is about 14 mm, that of the lower part 22 mm. The fill volume is about 1.4 ml.
A closed capsule of size 5 has, for example, a total length of about 10 mm for a diameter of the upper part of about 4.8 mm and a diameter of the lower part of about 4.6 mm. The length of the upper part is about 5.6 mm, that of the lower part 9.4 mm. The fill volume is about 0.13 ml.
Layer thicknesses The coating composition according to the invention is preferably adjusted so that, in the dried state, coating films with layer thicknesses in the range from 20 to 100, in particular 40 to 80 pm, are produced. In this connection, the capsule halves can already be produced such that the wall thicknesses on the outside are in each case reduced by the layer thickness of the enteric coating to be expected, such that standard wall thicknesses arise again following the dip coating. If, for example, a customary standard capsule upper part and lower part made of gelatine has a wall thickness of 100 pm, then the wall thicknesses for enteric coated capsules are reduced in the preparation to e.g. ca.
60 gm. Then, in the dipping process, an enteric coating with a layer thickness in the dried state of ca. 40 pm is applied. The resulting upper and lower parts then again have wall thicknesses of 100 m and can be further processed in the same way as standard capsules without altering the machine settings.
Sealing function of the enteric coating As a result of the preparation in dipping processes, the lower capsule half, the lower part, receives a continuous enteric coating which, in the closed state, is partly overlapped by the upper part. Favoured by the elasticity of the film and its uniformity, the overlapped part of the enteric coating assumes here a sealing function which effectively prevents the penetration of gastric fluid through a possible gap between the lower part and the upper part. The dipping process thus offers an advantage over the coating of closed capsules in a spraying process in which no overlapping occurs, as a result of which the abutment point on the edge of the upper part always brings with it the potential risk of untightness. In many cases, therefore, prior to the enteric coating of closed capsules in a spraying process, a sealing band is applied or another measure is undertaken for sealing the abutment point. Measures of this kind can be dispensed with when applying the coating composition according to the invention in the dipping process, which represents a further advantage.
The tightness of the capsule material can be demonstrated, for example, by pouring a marker, e.g. a dye or an active ingredient that is easy to detect and readily soluble in water, into the coated capsule halves or into the capsule and observing its escape into the medium or its retention in the capsule during the incubation for 2 hours in 0.1 N HCl or in artificial gastric fluid pH 1.2 in accordance with USP.
Here, no or only a very small part of the marker should be detectable in the medium, less than 10%.
Aqueous dispersion or solution The coating composition according to the invention is in the form of an aqueous dispersion or solution. The term "aqueous dispersion or solution" is understood in the broad sense and is intended to include all transition states, in particular also so-called polymer/colloidal solutions. The aqueous dispersion consists of a solid phase and a liquid phase. The solids phase and the liquid phase add up to 100% by weight.
The liquid phase of the aqueous dispersion or solution is based essentially or completely on the dispersant or solvent water. The liquid phase thus consists of at least 95% by weight, preferably at least 98% by weight, in particular 100% by weight, of water. Organic solvents, such as, for example, ethanol, isopropanol or acetone, may be present up to 5% by weight, preferably up to 2% by weight. This may be of use in individual cases for lowering the surface tension or for preventing microbiological contamination. Preferably, however, no organic solvents are present.
The term "dispersion or solution" refers to the fact that the substances present can in their totality be present either in dispersed form, dissolved form or else partly dispersed or dissolved in an intermediate state. The aqueous dispersion or solution preferably has a pH of from 6.0 to 10.0, in particular from 6.5 to 9Ø In this pH range, the (meth)acrylate copolymers present are predominantly in dispersed or at least partly dissolved form. Plasticizers are generally present in dissolved form. Other additives or auxiliaries, such as, for example, talc, may be present in dispersed form.
Solids content The solids content of the aqueous dispersion or solution is more than 25% by weight, preferably more than 30% by weight, in particular 32 - 36% by weight.
For comparison, the solids contents of dispersions or solutions which are used in spraying processes are generally only around 20% by weight.
The solids content is used in particular together with the viscosity for controlling the balance between good wettability of the as yet uncoated capsule halves in the dipping process and acceptable drying time of the coated capsule halves after the dipping process. If the solids content is too low, the drying times become too long, and, moreover, as a rule no adequate viscosity can be built up. If the solids content is too high, this may lead to drop formations on the dipsticks and to overall uneven coatings. Consequently, no exact adjustment of the layer thickness is possible.
Viscosity The viscosity of the aqueous dispersion or solution is 150 to 1500, preferably 180 to 1000, in particular 200 to 350 mPa=s. The viscosity can be determined, for example, using a Brookfield rotary viscometer. The determination method is known to the person skilled in the art (see e.g. ISO 3219:1993).
Elongation at break The elasticity of the dried polymer film can essentially be characterized by its elongation at break. A dried film produced from the dispersion or solution according to the invention, e.g. by pouring, has an elongation at break of at least 200, preferably at least 250%. The elongation at break in [%] can be determined on sample films in accordance with DIN 53 455.
(Meth)acrylate copolymers The aqueous dispersion or solution comprises a polymer mixture of at least one first (meth)acrylate copolymer, which is enteric, and at least one further (meth)acrylate copolymer, which is enteric or water-insoluble.
At least one first (meth)acrylate copolymer means one or more first (meth)acrylate copolymers.
At least one further (meth)acrylate copolymer means one or more further (meth)acrylate copolymers.
The polymer mixture comprises or consists of at least two (meth)acrylate copolymers. Preferably, the polymer mixture comprises or consists of two (meth)acrylate copolymers.
The first (meth)acrylate copolymer, which is enteric, and the further (meth)acrylate copolymer, which is enteric or water-insoluble, are preferably present in a ratio of from 2:1 to 1:2.
The first (meth)acrylate copolymer, which is enteric, and the further (meth)acrylate copolymer, which is enteric or water-insoluble, constitute preferably at least 45% by weight, particularly preferably at least 60% by weight, in particular at least 70% by weight, of the solid present in the dispersion.
An enteric (meth)acrylate copolymer is understood as meaning those (meth)acrylate copolymers which are insoluble in the pH range of gastric fluid, pH 1.0 to 5.0, but dissolve in the pH range of the intestinal fluid, above pH 5.0, in particular pH 5.5 to 8Ø In particular, enteric coated drug forms in 0.1 N HC1 release at most 10% of the active ingredient present over the course of 2 hours. Enteric (meth)acrylate copolymers are synonymous with (meth)acrylate copolymers which are composed of C1- to C4-alkyl esters of acrylic acid or methacrylic acid and have at least 5%, preferably 5 to 70%, in particular 8 to 60%, of monomer radicals with anionic groups, as a rule methacrylic acid radicals. Cl- to C4-alkyl esters of acrylic acid or methacrylic acid are in particular methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate and butyl acrylate.
First enteric (meth)acrylate copolymer Preferably, the first enteric (meth)acrylate copolymer is an anionic (meth)acrylate copolymer. Preferably, the glass transition temperature of the first (meth)acrylate copolymer in accordance with ISO 11357-2, point 3.3.3, is more than 70 C.
Preferably, the first enteric (meth)acrylate copolymer is a polymer of 40 to 60% by weight of methacrylic acid and 60 to 40% by weight of methyl methacrylate or 60 to 40% by weight of ethyl acrylate (grade EUDRAGIT L100 or EUDRAGIT L100-55).
Of suitability in particular is EUDRAGIT L100-55, which is a copolymer of 50% by weight of ethyl acrylate and 50% by weight of methacrylic acid.
Likewise suitable are anionic (meth)acrylate copolymers of 20 to 40% by weight of methacrylic acid and 80 to 60% by weight of methyl methacrylate (grade EUDRAGIT S).
Further (meth)acrylate copolymer The further (meth)acrylate copolymer may be enteric or water-insoluble. If the further (meth)acrylate copolymer is an enteric polymer, it is different from the first enteric (meth)acrylate copolymer.
Further anionic (meth)acrylate copolymer Preferably, the further (meth)acrylate copolymer may be an enteric, anionic polymer which is different from the first enteric (meth)acrylate copolymer. Preferably, the glass transition temperature of the further (meth)acrylate copolymer in accordance with ISO 11357-2, point 3.3.3, is at most 70, preferably at most 60, in particular at most 50 C, e.g. 40 to 60 C.
Of particular suitability is, for example, a polymer of 10 to 30% by weight of methyl methacrylate, 50 to 70%
by weight of methyl acrylate and 5 to 15% by weight of methacrylic acid (grade EUDRAGIT FS).
Specifically, for example EUDRAGIT FS, which is a copolymer of 25% by weight of methyl methacrylate, 65%
by weight of methyl acrylate and 10% by weight of methacrylic acid, is suitable. EUDRAGIT FS 30 D is a dispersion comprising 30% by weight of EUDRAGIT FS.
Also suitable for the purposes of the invention is a (meth)acrylate copolymer (see WO 2003/072087), which is composed of 20 to 34% by weight of methacrylic acid and/or acrylic acid, 20 to 69% by weight of methyl acrylate and 0 to 40% by weight of ethyl acrylate and/or optionally 0 to 10% by weight of further vinylically copolymerizable monomers, with the proviso that the glass transition temperature of the (meth)acrylate copolymer in accordance with ISO 11357-2, point 3.3.3, is at most 60 C. This (meth)acrylate copolymer has in particular very good elongation at break properties.
The copolymer is composed in particular of radically polymerized units of to 34, preferably 25 to 33, particularly preferably 28 to 32% by weight of methacrylic acid or acrylic 15 acid, preferably methacrylic acid, 20 to 69, preferably 35 to 65, particularly preferably 35 to 55% by weight of methyl acrylate and optionally 20 0 to 40, preferably 5 to 35, particularly preferably 15 to 35% by weight of ethyl acrylate, with the proviso that the glass transition temperature of the copolymer (measurement without the addition of plasticizer at a residual monomer content (REMO) of less than 100 ppm, heating rate 10 C/min, nitrogen atmosphere) in accordance with ISO 11357-2, point 3.3.3 (Tmg), is at most 60, preferably 40 to 60, particularly preferably 45 to 55 C.
The copolymer preferably consists essentially to exclusively of the monomers methacrylic acid, methyl acrylate and ethyl acrylate in the quantitative fractions given above.
However, it is additionally possible, without leading to an impairment of the essential properties, for small amounts in the range from 0 to 10, e.g. 1 to 5% by weight of further vinylically copolymerizable monomers, such as, for example, methyl methacrylate, butyl methacrylate, butyl acrylate or hydroxyethyl methacrylate, to be present.
Glass transition temperature here is to be understood in particular as meaning the midpoint temperature Tmg in accordance with ISO 11357-2, point 3.3.3. Measurement takes place without the addition of plasticizer, at residual monomer contents (REMO) of less than 100 ppm, at a heating rate of 10 C/min and under a nitrogen atmosphere.
Also suitable for the purposes of the invention are (meth)acrylate copolymers (see WO 2004/096185) comprising 20 to 33% by weight of methacrylic acid and/or acrylic acid, 5 to 30% by weight of methyl acrylate and to 40% by weight of ethyl acrylate and 20 greater than 10 to 30% by weight of butyl methacrylate and optionally 0 to 10% by weight of further vinylically copolymerizable monomers, where the fractions of the monomers add up to 100% by weight, with the proviso that the glass transition temperature of the copolymer in accordance with ISO 11357-2, point 3.3.3 (midpoint temperature Tmg) is 55 to 70 C. On account of their good mechanical properties, copolymers of this type are particularly suitable for compressing pellets to give tablets.
The aforementioned copolymer is composed in particular of radically polymerized units of 20 to 33% by weight, preferably 25 to 32% by weight, particularly preferably 28 to 31% by weight, of methacrylic acid or acrylic acid, preferably methacrylic acid, to 30% by weight, preferably 10 to 28% by weight, particularly preferably 15 to 25% by 5 weight, of methyl acrylate, 20 to 40% by weight, preferably 25 to 35% by weight, particularly preferably 28 to 32% by weight, of ethyl acrylate, and greater than 10 to 30% by weight, preferably 15 to 25% by weight, particularly preferably 18 to 22%
by weight, of butyl methacrylate, where the monomer composition is selected so that the glass transition temperature of the copolymer is 55 to 70 C, preferably 59 to 66 C, particularly preferably 60 to 65 C.
The copolymer preferably consists essentially to exclusively, to 90, 95 or 99 to 100% by weight, of the monomers methacrylic acid, methyl acrylate, ethyl acrylate and butyl methacrylate in the quantitative ranges stated above.
However, it is also possible, without having to lead to an impairment of the essential properties, for small amounts in the range from 0 to 10, e.g. 1 to 53 by weight of further vinylically copolymerizable monomers, such as, for example, methyl methacrylate, butyl acrylate, hydroxyethyl methacrylate, vinylpyrrolidone, vinylmalonic acid, styrene, vinyl alcohol, vinyl acetate and/or derivatives thereof, to be present.
Water-insoluble (meth)acrylate copolymers Within the context of the invention, a water-insoluble (meth)acrylate copolymer is to be understood as meaning those (meth)acrylate copolymers which are water-insoluble or merely water-swellable over the entire pH
range from 1 to 14. These are preferably "neutral"
(meth)acrylate copolymers. Neutral is understood as meaning that the (meth)acrylate copolymers are composed predominantly or completely of neutral monomers, e.g.
to more than 95% by weight, to more than 98% by weight, to more than 99% by weight or to 100% by weight.
Accordingly, the term "neutral" does not entirely rule out the presence of ionic groups in the polymer.
(Meth)acrylate copolymers with a content of less than 5% by weight, preferably less than 2% by weight, preferably less than 1% by weight, of ionic, in particular anionic groups, are referred to as "neutral"
within the context of the invention or as "essentially neutral". These neutral or essentially neutral, or optionally only to a small extent, ionic polymers are water-insoluble or merely water-swellable and have no enteric properties.
The further (meth)acrylate copolymer may preferably be a water-insoluble polymer which is a polymer of 20 to 40% by weight of ethyl acrylate, 60 to 80% by weight of methyl methacrylate and less than 5% by weight, preferably less than 2% by weight, preferably less than 1% by weight, of methacrylic acid (grade EUDRAGIT NE
or EUDRAGIT NM).
For example, EUDRAGIT NE, which is a copolymer of 30%
by weight of ethyl acrylate and 70% by weight of methyl methacrylate, is suitable.
Auxiliaries which influence the viscosity of the dispersion or solution and the elasticity of the dried polymer film The viscosity of the dispersion and the elasticity or the elongation at break of the dried polymer film can usually not be brought into the required ranges by the polymer mixture alone. Consequently, the aqueous dispersion or solution additionally comprises auxiliaries which, together with the polymer mixture, influence or increase and steer into the required ranges the viscosity of the dispersion and the elasticity of the dried polymer film.
A comparatively strong influencing of said parameters can be achieved in particular through the addition of plasticizers or basic substances. These auxiliaries preferably constitute at most 30% by weight, in particular at most 20% by weight, of the solid present in the dispersion. The content of these auxiliaries can be, for example, 5 to 30% by weight, preferably 10 to 20% by weight, of the solid present in the dispersion.
Plasticizers Plasticizers can contribute to influencing and/or increasing the viscosity of the dispersion and the elasticity of the dried polymer film.
Substances suitable as plasticizers generally have a molecular weight (MW) between 100 and 20 000 and contain one or more hydrophilic groups in the molecule, e.g. hydroxyl, ester or amino groups. Citrates, phthalates, sebacates, castor oil are suitable.
Examples of suitable plasticizers are alkyl esters of citric acid, propylene glycol, glycerol esters, alkyl esters of phthalic acid, alkyl esters of sebacic acid, sucrose esters, sorbitan esters, diethyl sebacate, dibutyl sebacate and polyethylene glycol 300 to 35 000.
Preferred plasticizers are tributyl citrate, triethyl citrate, acetyltriethyl citrate, dibutyl sebacate and diethyl sebacate. The use amounts of plasticizers may be in the range from 1 to 30, preferably 5 to 25% by weight, based on the polymer mixture. Preference is given to polyethylene glycols with a high molecular weight, in particular polyethylene glycol 20 000 or polyethylene glycol 35 000, which can greatly increase the viscosity of the dispersion or solution.
Preferably, the use amounts for polyethylene glycol 20 000 or polyethylene glycol 35 000 are 5 to 25, in particular 10 to 20% by weight, based on the polymer mixture. Additionally, other plasticizers, such as, for example, triethyl citrate, in amounts of from 5 to 15%
by weight based on the polymer mixture, can be combined with polyethylene glycol 20 000 or polyethylene glycol 35 000.
Basic substances Basic substances can contribute to influencing or increasing the viscosity of the dispersion and the elasticity of the dried polymer film.
In order to prepare an aqueous solution of the enteric (meth)acrylate copolymer, a partial or complete neutralization of the acid groups is generally necessary. The first or optionally also a further enteric (meth)acrylate copolymer can, for example, be gradually stirred into water and in so doing be partially or completely neutralized by adding a basic substance, such as, for example, NaOH, KOH, ammonium hydroxide or organic bases, such as, for example, triethanolamine. It is also possible to use a powder of the copolymer to which a base, e.g. NaOH, has already been added during its preparation for the purpose of (partial) neutralization, meaning that the powder is an already (partially) neutralized polymer. Particular preference is given to sodium hydroxide solution or NaOH.
Further suitable basic substances are, for example:
sodium carbonate, potassium carbonate, sodium bicarbonate, trisodium phosphate, trisodium citrate or ammonia or physiologically compatible amines, such as triethanolamine or tris(hydroxymethyl)aminomethane, the cationic, basic amino acids histidine, arginine and/or lysine, natural or synthetic oligomers or polymers, e.g. of 3 to 100, preferably 5 to 25, units, of histidine, arginine or lysine, polyhistidines, polyarginines, polylysines, cationic or zwitterionic phospholipids, such as, for example, phosphatidylcholine, ribonucleosides, condensation products of the hydroxyl function on carbon atom 1 of ribose with the heterocyclic amino function of the bases adenine, guanine, cytosine, thymine or uracil, corresponding to the occurrence in RNA, or deoxyribonucleosides, condensation products of the hydroxyl function on carbon atom 1 of deoxyribose with the heterocyclic amino function of the bases adenine, guanine, cytosine, thymine or uracil, corresponding to the occurrence in DNA.
Preference is given to a degree of neutralization of from 3 to 12 mol% of the anionic groups at least of the (meth)acrylate copolymer. Preferably, the neutralization takes place with sodium hydroxide in the form of 1.5 to 2 normal sodium hydroxide solution. The relatively high concentration of the sodium hydroxide solution prevents too great a reduction in the solids content. The partial neutralization is accompanied by a thickening of the dispersion or solution, i.e. an increase in the viscosity.
The quantitative fraction of basic substances of the total content of the auxiliaries which influence or increase the viscosity of the dispersion and the elasticity of the dried polymer film is more likely to be low compared to plasticizers. The influence of the basic substances in particular on the viscosity, however, is relatively great, meaning that even these comparatively small amounts bring about significant effects. Preference is given to using a combination of plasticizers and basic substances.
Further pharmaceutically customary auxiliaries which are not plasticizers or bases If appropriate, further pharmaceutically customary auxiliaries, which are not plasticizers or bases, but which are also used in the fields of food supplements and cosmetics, may be present in amounts of, for example, at most 25% by weight, at most 10% by weight, or at most 5% by weight, based on the total solids content of the dispersion or solution. Compared to the plasticizers or the bases, these further pharmaceutically customary auxiliaries only influence the viscosity of the dispersion or solution and the elasticity of the dried polymer film to a low degree, if at all.
Here, mention is to be made, for example, of antioxidants, dyes, flavourings, lustre agents, lubricants, such as, for example, talc, wetting agents, pigments, stabilizers, sweeteners etc. These serve primarily as processing auxiliaries and are intended primarily to ensure, for example, a safe and reproducible production process, good long-term storage stabilities, a pleasant appearance or the identifiability.
In particular, pigments require particular mention. In order to be covering, pigments have to be added, for example, in relatively high concentrations, for example in amounts of from 10 to 25% by weight, based on the total solids content of the dispersion or solution. In this large amount and depending on the pigment used, an at least slight, measurable influence on the viscosity of the dispersion or the elasticity of the dried polymer film is usually observed. When adding large amounts, of pigments, the viscosity will possibly increase whereas the elasticity of the dried polymer film generally ought to decrease. However, this can be compensated through a slight shift in the type and quantitative ratios of the other components which, for their part, have a relatively great influence on the viscosity of the dispersion or the elasticity of the dried polymer film, the polymer mixture, and, if appropriate, plasticizers or bases.
Further auxiliaries which are not plasticizers or bases and which are also not pigments are, if present at all, generally present in much lower concentrations, e.g.
less than 10% by weight, less than 5% by weight or less than 2% by weight, based on the total solids content of the dispersion or solution. Consequently, these further auxiliaries merely influence the viscosity of the dispersion or the elasticity of the dried polymer film in a negligible manner or only to a very slight extent.
Preferably, only plasticizers and/or bases and also optionally pigments are present as auxiliaries.
Dipping process The dipping processes or dip coating processes for producing capsule halves and for the enteric coating of capsule halves are known to the person skilled in the art (see in this regard e.g.: Fahrig W. and Hofer U.
(1983): Die Kapsel, Grundlagen, Technologie and Biopharmazie einer modernen Arzneiform [Capsules, Principles, Technology and Biopharmacy of a Modern Drug Form], Wissenschaftliche Verlagsgesellschaft mbH
Stuttgart).
Capsule halves are produced by dipping sticks into viscous solutions, e.g. gelatine solutions. The sticks are then removed from the viscous solution. The viscous solution dries on the sticks. The capsule halves are cut off straight from the sticks using a cutting tool and then removed from the sticks. Since matching upper and lower parts of capsules have different sizes and geometries, they are produced separately.
Here, mention is to be made, for example, of antioxidants, dyes, flavourings, lustre agents, lubricants, such as, for example, talc, wetting agents, pigments, stabilizers, sweeteners etc. These serve primarily as processing auxiliaries and are intended primarily to ensure, for example, a safe and reproducible production process, good long-term storage stabilities, a pleasant appearance or the identifiability.
In particular, pigments require particular mention. In order to be covering, pigments have to be added, for example, in relatively high concentrations, for example in amounts of from 10 to 25% by weight, based on the total solids content of the dispersion or solution. In this large amount and depending on the pigment used, an at least slight, measurable influence on the viscosity of the dispersion or the elasticity of the dried polymer film is usually observed. When adding large amounts, of pigments, the viscosity will possibly increase whereas the elasticity of the dried polymer film generally ought to decrease. However, this can be compensated through a slight shift in the type and quantitative ratios of the other components which, for their part, have a relatively great influence on the viscosity of the dispersion or the elasticity of the dried polymer film, the polymer mixture, and, if appropriate, plasticizers or bases.
Further auxiliaries which are not plasticizers or bases and which are also not pigments are, if present at all, generally present in much lower concentrations, e.g.
less than 10% by weight, less than 5% by weight or less than 2% by weight, based on the total solids content of the dispersion or solution. Consequently, these further auxiliaries merely influence the viscosity of the dispersion or the elasticity of the dried polymer film in a negligible manner or only to a very slight extent.
Preferably, only plasticizers and/or bases and also optionally pigments are present as auxiliaries.
Dipping process The dipping processes or dip coating processes for producing capsule halves and for the enteric coating of capsule halves are known to the person skilled in the art (see in this regard e.g.: Fahrig W. and Hofer U.
(1983): Die Kapsel, Grundlagen, Technologie and Biopharmazie einer modernen Arzneiform [Capsules, Principles, Technology and Biopharmacy of a Modern Drug Form], Wissenschaftliche Verlagsgesellschaft mbH
Stuttgart).
Capsule halves are produced by dipping sticks into viscous solutions, e.g. gelatine solutions. The sticks are then removed from the viscous solution. The viscous solution dries on the sticks. The capsule halves are cut off straight from the sticks using a cutting tool and then removed from the sticks. Since matching upper and lower parts of capsules have different sizes and geometries, they are produced separately.
The process for the enteric coating of capsule halves can be integrated into the dipping process for producing capsule halves by, in an additional step, dipping the capsule halves dried on the dipsticks into the coating composition according to the invention. In an analogous manner, the enteric coated capsule halves are cut off straight from the sticks using a cutting tool and are then removed from the sticks.
Process The invention furthermore relates to a process for producing enteric coated capsule halves in the dipping process by means of the steps:
= Dipping uncoated capsule halves on dipsticks into a coating composition according to one or more of Claims 1 to 10, = Removing the sticks with the enteric coated capsule halves, = Drying the coating composition, = Cutting off the coated capsule halves on the sticks by means of a cutting tool and = Removing the enteric coated capsule halves from the sticks.
Use The invention relates to the use of a coating composition according to the invention for the enteric coating of capsule halves in the dipping process. The enteric coated capsule halves can be used for producing capsules filled with active ingredients or food supplements for oral applications in the fields of pharmacy, food supplements or cosmetics.
Examples First (meth)acrylate copolymer:
EUDRAGIT L100-55 is a copolymer of 50% by weight of ethyl acrylate and 50% by weight of methacrylic acid.
Further (meth)acrylate copolymers EUDRAGIT FS is a copolymer of 25% by weight of methyl methacrylate, 65% by weight of methyl acrylate and 10% by weight of methacrylic acid.
EUDRAGIT FS 30 D is a dispersion comprising 30%
by weight of EUDRAGIT FS.
EUDRAGIT NE is a copolymer of 30% by weight of ethyl acrylate and 70% by weight of methyl methacrylate.
Auxiliaries which influence the viscosity of the dispersion and the elasticity of the dried polymer film:
Polyethylene glycol 35 000 (PEG 35 000) and triethyl citrate (TEC), and NaOH (for the partial neutralization of EUDRAGIT L100-55 / EUDRAGIT
L 30 D55).
Formulations:
A partially neutralized redispersion of EUDRAGIT L 100 - 55 served as the basis for all examples and as comparative examples. This has the purpose of achieving a somewhat higher solids concentration than with standard commercial EUDRAGIT L 30 D - 55.
For this, 300 g of EUDRAGIT L 100 - 55 were incorporated into 650 g of demineralized water through slow addition by means of a propeller stirrer. After stirring for 30 minutes, 50 g of 2 N NaOH solution were then slowly added in order to produce a dispersion with a solids content of 30.4%. The degree of partial neutralization corresponds to about 6 mol% of the anionic groups present in the copolymer. The following final mixtures were prepared using this base formulation. Standard commercial hard gelatine capsule shells were coated therewith by dipping with subsequent drying.
The results of Examples 1 to 3 and Comparative Examples C4 to C7 are summarized in the table below.
Table Example 1 2 3 C4 C5 C6 C7 EUDRAGIT
dispersion with 30.4%
solids (% of polymer) (% of polymer) TEC (% of / 5 10 / / 10 20 polymer) Viscosity 801 316 290 70 8700 70 70 [mPa=s ]
Elongation at break [%] 430 261 398 34 225 394 1236 Dissolution of 25-30 15-20 15-20 15-20 15-20 > 60 > 60 sample capsule min min min min min min min at pH 6.8 ISolids content 33.2 34.2 35.1 34.3 36.1 32.0 34.0 [% by wt.) Brittleness of +++ + ++ --- - ++ +++
the sample capsule of polymer = o by weight, based on the polymer or polymers +++ = ideal, ++ = good, + = just acceptable, - = too thick and nonuniform, --- = very brittle
Process The invention furthermore relates to a process for producing enteric coated capsule halves in the dipping process by means of the steps:
= Dipping uncoated capsule halves on dipsticks into a coating composition according to one or more of Claims 1 to 10, = Removing the sticks with the enteric coated capsule halves, = Drying the coating composition, = Cutting off the coated capsule halves on the sticks by means of a cutting tool and = Removing the enteric coated capsule halves from the sticks.
Use The invention relates to the use of a coating composition according to the invention for the enteric coating of capsule halves in the dipping process. The enteric coated capsule halves can be used for producing capsules filled with active ingredients or food supplements for oral applications in the fields of pharmacy, food supplements or cosmetics.
Examples First (meth)acrylate copolymer:
EUDRAGIT L100-55 is a copolymer of 50% by weight of ethyl acrylate and 50% by weight of methacrylic acid.
Further (meth)acrylate copolymers EUDRAGIT FS is a copolymer of 25% by weight of methyl methacrylate, 65% by weight of methyl acrylate and 10% by weight of methacrylic acid.
EUDRAGIT FS 30 D is a dispersion comprising 30%
by weight of EUDRAGIT FS.
EUDRAGIT NE is a copolymer of 30% by weight of ethyl acrylate and 70% by weight of methyl methacrylate.
Auxiliaries which influence the viscosity of the dispersion and the elasticity of the dried polymer film:
Polyethylene glycol 35 000 (PEG 35 000) and triethyl citrate (TEC), and NaOH (for the partial neutralization of EUDRAGIT L100-55 / EUDRAGIT
L 30 D55).
Formulations:
A partially neutralized redispersion of EUDRAGIT L 100 - 55 served as the basis for all examples and as comparative examples. This has the purpose of achieving a somewhat higher solids concentration than with standard commercial EUDRAGIT L 30 D - 55.
For this, 300 g of EUDRAGIT L 100 - 55 were incorporated into 650 g of demineralized water through slow addition by means of a propeller stirrer. After stirring for 30 minutes, 50 g of 2 N NaOH solution were then slowly added in order to produce a dispersion with a solids content of 30.4%. The degree of partial neutralization corresponds to about 6 mol% of the anionic groups present in the copolymer. The following final mixtures were prepared using this base formulation. Standard commercial hard gelatine capsule shells were coated therewith by dipping with subsequent drying.
The results of Examples 1 to 3 and Comparative Examples C4 to C7 are summarized in the table below.
Table Example 1 2 3 C4 C5 C6 C7 EUDRAGIT
dispersion with 30.4%
solids (% of polymer) (% of polymer) TEC (% of / 5 10 / / 10 20 polymer) Viscosity 801 316 290 70 8700 70 70 [mPa=s ]
Elongation at break [%] 430 261 398 34 225 394 1236 Dissolution of 25-30 15-20 15-20 15-20 15-20 > 60 > 60 sample capsule min min min min min min min at pH 6.8 ISolids content 33.2 34.2 35.1 34.3 36.1 32.0 34.0 [% by wt.) Brittleness of +++ + ++ --- - ++ +++
the sample capsule of polymer = o by weight, based on the polymer or polymers +++ = ideal, ++ = good, + = just acceptable, - = too thick and nonuniform, --- = very brittle
Claims (12)
1. Coating composition for the enteric coating of capsule halves made of water-soluble or water-swellable polymer material in the dipping process, in the form of an aqueous dispersion or solution, comprising a polymer mixture of at least one first (meth)acrylate copolymer, which is enteric, and at least one further (meth)acrylate copolymer which is enteric or water-insoluble, and also auxiliaries which influence the viscosity of the dispersion and the elasticity of the dried polymer film, characterized in that the solids content of the dispersion or solution is more than 25% by weight and the viscosity is 150 to 1500 mPa.cndot.s, where a dried film produced from the dispersion or solution has an elongation at break of at least 200% and a capsule composed of two capsule halves coated with the dispersion or solution in the dipping process does not dissolve in 0.1 N HCl at pH 1.2 after two hours, but then dissolves completely in buffer at pH 6.8 in less than 30 minutes.
2. Coating composition according to Claim 1, characterized in that the capsule halves consist of gelatine or of hydroxypropylmethylcellulose.
3. Coating composition according to Claim 1 or 2, characterized in that the first, enteric (meth)acrylate copolymer is a polymer of 40 to 60%
by weight of methacrylic acid and 60 to 40% by weight of methyl methacrylate or 60 to 40% by weight of ethyl acrylate.
by weight of methacrylic acid and 60 to 40% by weight of methyl methacrylate or 60 to 40% by weight of ethyl acrylate.
4. Coating composition according to one or more of Claims 1 to 3, characterized in that the further (meth)acrylate copolymer is an enteric polymer which is a polymer of 10 to 30% by weight of methyl methacrylate, 50 to 70% by weight of methyl acrylate and 5 to 15% by weight of methacrylic acid.
5. Coating composition according to one or more of Claims 1 to 4, characterized in that the further (meth)acrylate copolymer is a water-insoluble polymer which is a polymer of 20 to 40% by weight of ethyl acrylate, 60 to 80% by weight of methyl methacrylate and less than 5% methacrylic acid.
6. Coating composition according to one or more of Claims 1 to 5, characterized in that the auxiliaries which influence the viscosity of the dispersion and the elasticity of the dried polymer film are plasticizers or basic substances or mixtures thereof.
7. Coating composition according to Claim 6, characterized in that the plasticizer is a polyethylene glycol.
8. Coating composition according to Claim 6, characterized in that the basic substance is sodium hydroxide or sodium hydroxide solution.
9. Coating composition according to one or more of Claims 1 to 8, characterized in that the first (meth)acrylate copolymer, which is enteric, and the further (meth)acrylate copolymer, which is enteric or water-insoluble, are present in a ratio of from 2:1 to 1:2.
10. Coating composition according to one or more of Claims 1 to 9, characterized in that the first (meth)acrylate copolymer, which is enteric, and the further (meth)acrylate copolymer, which is enteric or water-insoluble, constitute at least 45% by weight of the solid present in the dispersion.
11. Use of a coating composition according to one or more of Claims 1 to 10 for the enteric coating of capsule halves in the dipping process.
12. Use according to Claim 11, characterized in that the coating has a layer thickness in the range from 20 to 100 µm.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102009028076A DE102009028076A1 (en) | 2009-07-29 | 2009-07-29 | Coating composition for dip coating of capsule halves |
| DE102009028076.6 | 2009-07-29 | ||
| PCT/EP2010/058370 WO2011012369A2 (en) | 2009-07-29 | 2010-06-15 | Coating agent for the dip coating of capsule halves |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2769046A1 true CA2769046A1 (en) | 2011-02-03 |
Family
ID=42635497
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2769046A Abandoned CA2769046A1 (en) | 2009-07-29 | 2010-06-15 | Coating agent for the dip coating of capsule halves |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP2459178A2 (en) |
| JP (1) | JP5686802B2 (en) |
| CN (1) | CN102448446B (en) |
| CA (1) | CA2769046A1 (en) |
| DE (1) | DE102009028076A1 (en) |
| HK (1) | HK1164726A1 (en) |
| WO (1) | WO2011012369A2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020229192A1 (en) * | 2019-05-15 | 2020-11-19 | Evonik Operations Gmbh | Process for preparing filled hard-shell capsules with cellulose or starch-based coatings with a capsule-filling machine |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2905365C (en) * | 2013-03-15 | 2021-03-23 | Banner Life Sciences Llc | Silk-based capsules |
| US10413507B2 (en) * | 2014-06-11 | 2019-09-17 | Massachusetts Institute Of Technology | Enteric elastomers |
| CN108472249A (en) | 2015-10-23 | 2018-08-31 | 林德拉有限公司 | Stomach resident system and its application method for therapeutic agent sustained release |
| US11576866B2 (en) | 2016-09-30 | 2023-02-14 | Lyndra Therapeutics, Inc. | Gastric residence systems for sustained delivery of adamantane-class drugs |
| CA3069396A1 (en) | 2017-07-11 | 2019-01-17 | Qualicaps Co., Ltd. | Enteric hard capsule |
| MX2020005012A (en) | 2017-11-17 | 2020-08-27 | Evonik Operations Gmbh | Process for preparing a coated hard shell capsule. |
| US20210228491A1 (en) | 2018-06-22 | 2021-07-29 | Qualicaps Co., Ltd. | Enteric hard capsule |
| KR20210139263A (en) | 2019-03-14 | 2021-11-22 | 에보닉 오퍼레이션스 게엠베하 | Capsule shell comprising core-shell polymer and cellulose |
| JP2022533610A (en) | 2019-05-15 | 2022-07-25 | エボニック オペレーションズ ゲーエムベーハー | Method for producing filled hard-shell capsules having a (meth)acrylate copolymer-based coating using a capsule filling machine |
| IL308701A (en) * | 2021-05-25 | 2024-01-01 | Evonik Operations Gmbh | Hard shell capsules with modified release coating |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59155325A (en) * | 1983-02-25 | 1984-09-04 | Kohjin Co Ltd | Preparation of water-based enteric coating agent |
| PT93637A (en) * | 1989-04-20 | 1990-11-20 | Procter & Gamble | METHOD FOR THE TREATMENT OF INTESTINAL / COLONIC FUNCTIONAL DISORDERS, ESPECIALLY THE INTESTINAL IRRITATION SYNDROME |
| ES2130056B1 (en) * | 1997-01-16 | 2000-02-01 | Lipotec Sa | A NEW PHARMACEUTICAL PREPARATION TO IMPROVE THE ORAL BIOAVAILABILITY OF DRUGS WITH HARD ABSORPTION. |
| ATE429210T1 (en) * | 1998-01-20 | 2009-05-15 | Applied Analytical Ind Inc | ORAL LIQUID COMPOSITIONS |
| DE10208335A1 (en) | 2002-02-27 | 2003-09-04 | Roehm Gmbh | Pharmaceutical form and process for its preparation |
| CA2514879C (en) * | 2003-01-03 | 2014-09-16 | Shire Laboratories Inc. | Two or more enteric materials to regulate drug release |
| MXPA04010956A (en) | 2003-01-30 | 2005-01-25 | Roehm Gmbh | Pharmaceutical dosage form and method for the production thereof. |
| EP2187876B1 (en) * | 2007-09-21 | 2012-08-22 | Evonik Röhm GmbH | Ph-dependent controlled release pharmaceutical opioid composition with resistance against the influence of ethanol |
| GB0724279D0 (en) * | 2007-12-12 | 2008-01-23 | Photocure Asa | Use |
-
2009
- 2009-07-29 DE DE102009028076A patent/DE102009028076A1/en not_active Withdrawn
-
2010
- 2010-06-15 WO PCT/EP2010/058370 patent/WO2011012369A2/en active Application Filing
- 2010-06-15 CN CN201080022662.9A patent/CN102448446B/en active Active
- 2010-06-15 JP JP2012522057A patent/JP5686802B2/en active Active
- 2010-06-15 CA CA2769046A patent/CA2769046A1/en not_active Abandoned
- 2010-06-15 EP EP10724857A patent/EP2459178A2/en not_active Ceased
-
2012
- 2012-06-07 HK HK12105568.7A patent/HK1164726A1/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020229192A1 (en) * | 2019-05-15 | 2020-11-19 | Evonik Operations Gmbh | Process for preparing filled hard-shell capsules with cellulose or starch-based coatings with a capsule-filling machine |
Also Published As
| Publication number | Publication date |
|---|---|
| JP5686802B2 (en) | 2015-03-18 |
| HK1164726A1 (en) | 2012-09-28 |
| CN102448446B (en) | 2015-04-01 |
| JP2013500293A (en) | 2013-01-07 |
| DE102009028076A1 (en) | 2011-02-03 |
| WO2011012369A3 (en) | 2011-09-15 |
| WO2011012369A2 (en) | 2011-02-03 |
| CN102448446A (en) | 2012-05-09 |
| EP2459178A2 (en) | 2012-06-06 |
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