Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4891—Coated capsules; Multilayered drug free capsule shells
• • 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

Definitions

• the invention relates, as claimed, to a coating composition for
• enteric-coated HPMC capsules have long been used in the dietary supplement industry as a vegetarian alternative to gelatin. It is also mentioned that the enteric coating of hard gelatin capsules from organic solutions is possible, but difficult to carry out and embrittles the capsule, which may result in poor adhesion of the coating. This can be overcome by the application of an intermediate layer, but this is tedious and complicated.
• coating methods from aqueous preparations are preferred over coating methods from organic solutions due to the toxicological and safety-relevant aspects.
• coating gelatin capsules from aqueous preparations is very demanding and requires long processing times due to the water solubility of the gelatin, resulting in high overall costs.
• HPMC capsules can be coated enteric-coated relatively easily from aqueous preparations.
• a seal between the capsule halves, z As by a manually applied gelatin solution, apply to prevent leakage of the capsule and an uncontrolled leakage of the contents in the stomach.
• Another technique is to apply between the capsule halves water-ethanol mixtures and the parts at 40 - 60 0 C to weld together.
• HPMC capsules can be enteric-coated. A separate sealing step is dispensable in this coating technique.
• HPMC capsules coated with (meth) acrylate copolymers are shown to be particularly advantageous in the sum of their properties.
• Active ingredients are, in particular, pharmaceutical active substances,
• Coatings are sometimes referred to in technical jargon as enteric
• Coating agent should continue to contain no organic solvents.
• the coating agent is to ensure the tightness of the closed capsules in gastric juice, without the capsule must be provided with an additional seal.
• the coating agent should have sufficient
• the dried coating should be sufficiently elastic and have a uniform layer thickness. In the environment of the intestine, a rapid dissolution of the capsule should take place.
• Coating composition for the enteric coating of capsule halves of water-soluble or water-swellable polymer material in the dipping process in the form of an aqueous dispersion or solution containing a polymer mixture of at least one first (meth) acrylate copolymer which is enteric-coated, and at least one further (meth) acrylate copolymer which
• the invention relates, as claimed, to a coating composition for
• Capsule halves may be upper or lower parts of a capsule.
• the upper and lower parts fit together in such a way that they can be plugged into each other and form a closed capsule.
• a capsule thus consists of an upper and a lower half, which can be filled as intended container with an active ingredient and is then firmly closed by nesting with the upper part. Filled capsules are especially intended for oral administration.
• both capsule halves consist of gelatin or of hydroxypropylmethylcellulose. Preference is gelatin. Less common, but also as a possible material for
• capsule halves polymers such. As starch, pectin or agar.
• a capsule consists of a uniform, in particular of the same or identical material.
• both capsule halves, upper and lower half, z. B. uniformly from gelatin, in particular from the same or identical gelatin.
• Polymeric material is widely used for the administration of pharmaceutical agents or nutritional supplements.
• the areas of pharmacy and dietary supplements (nutraceuticals), where the field of cosmetics, as far as dietary supplements or potential agents (cosmeceuticals) are concerned, can be included.
• the capsule halves are enteric-coated "gastroresistant coated” means that the capsule halves on their outside
• enteric coated A closed capsule is therefore protected from the outside against dissolution in the gastric juice, pH 1 to about 5.
• the enteric coating dissolves quickly in the area of the intestinal juice, above pH 5, so that the underlying capsule material also dissolves and releases the contents.
• a capsule composed of two capsule halves enterically coated with the dispersion or solution in the immersion process does not dissolve in 0.1 N HCl (artificial gastric juice according to USP without enzyme addition) at pH 1.2 after two hours, then dissolves in buffer at pH 6 8 after USP, either after buffering the pH 1, 2 medium to pH 6.8 or by transferring the capsule to the pH 6.8 buffer.
• a suitable test method is familiar to the expert and can, for. B. the USP 32 are removed. The capsules are held with sinkers below the liquid surface.
• a closed capsule a total length in
• the diameter of the top may be in the range of about 4 to 12 mm.
• the diameter of the base may be in the range of about 2 to 10 mm.
• the length of the upper part may be in the range of about 4 to 20 mm that of the lower part in the range of 8 to 30 mm.
• Filling volume can range between about 0.1 and 2 ml.
• Capsules can z. B. in normalized sizes from 000 to 5 are divided (see, for example: Fahrig W. and Hofer U. (1983): The capsule, fundamentals, technology and
• a closed capsule of size 000 has a total length of about 28 mm with a diameter of the top of about 9.9 mm and a diameter of the bottom of about 9.5 mm.
• the length of the top is about 14 mm, the bottom of the 22 mm.
• the filling volume is about 1, 4 ml.
• a closed capsule of size 5 has an overall length of about 10 mm with a diameter of the top of about 4.8 mm and a diameter of the bottom of about 4.6 mm.
• the length of the upper part is about 5.6 mm, the bottom of the 9.4 mm.
• the filling volume is about 0.13 ml.
• the coating composition of the invention is preferably adjusted so that coating films in the dried state with layer thicknesses in the range from 20 to 100, in particular 40 to 80 microns.
• the capsule halves can already be produced in such a way that the wall thicknesses on the outside are each reduced by the expected layer thickness of the enteric coating, so that again standard wall thicknesses result after the dip coating.
• the wall thicknesses for enteric-coated capsules in the production of z. B. reduced about 60 microns.
• a continuous enteric coating which is partially covered in the closed state of the upper part.
• the covered part of the enteric coating takes over, favored by the elasticity of the film and its uniformity, while a sealing function, the penetration of gastric juice through a possible gap between the lower part and upper part effectively prevented.
• the dipping method thus offers an advantage over the coating of closed capsules in the spraying process, in which there is no overlap, whereby the joint at the edge of the upper part always brings the potential risk of leakage with it. In many cases, therefore, before the
• enteric coating of closed capsules by spraying a sealing band applied or made some other measure to seal the joint.
• Such measures are dispensable in the application of the coating composition according to the invention in the dipping process, which represents a further advantage.
• the tightness of the capsule material can be detected, for example, by inserting into the coated capsule halves or into the capsule a marker substance, e.g. B. a dye or a readily soluble in water, easily detectable drug is filled and its escape into the medium or its retention in the capsule during incubation for 2 hours in 0.1 N HCl or in artificial gastric juice pH 1, 2 according to USP is observed. It should be no or only a very small part of the marker substance, e.g. B. a dye or a readily soluble in water, easily detectable drug is filled and its escape into the medium or its retention in the capsule during incubation for 2 hours in 0.1 N HCl or in artificial gastric juice pH 1, 2 according to USP is observed. It should be no or only a very small part of the marker substance, e.g. B. a dye or a readily soluble in water, easily detectable drug is filled and its escape into the medium or its retention in the capsule during incubation for 2 hours in 0.1 N HCl or in artificial gastric
• Marker substance in the medium less than 10%, be detectable.
• the coating composition according to the invention is in the form of an aqueous dispersion or solution.
• aqueous dispersion or solution is understood in a broad sense and is intended to include all transition states, in particular so-called
• the aqueous dispersion consists of a solid phase and a liquid phase.
• the solid phase and the liquid phase complement each other to 100 wt .-%.
• the liquid phase of the aqueous dispersion or solution is based substantially or completely on the dispersing or solvent water.
• the liquid phase thus consists of at least 95, preferably at least 98, in particular 100 wt .-% of water.
• Organic solvents such as ethanol, isopropanol or acetone may be up to 5, preferably up to 2 wt .-%. This can in individual cases to reduce the surface tension or to prevent be useful against microbiological contamination. Preferably, however, no organic solvents are included.
• the term "dispersion or solution” refers to the fact that the substances contained in their entirety can either be dispersed, dissolved or partially dispersed or dissolved in an intermediate state,
• the aqueous dispersion or solution preferably has a pH of 6.0 to 10.0, in particular from 6.5 to 9.0
• the (meth) acrylate copolymers present are present predominantly in dispersed or at least partially dissolved form in this pH range.
• Plasticizers are generally present in dissolved form. or adjuvants such as talc may be in dispersed form.
• the solids content of the aqueous dispersion or solution is more than 25, preferably more than 30, in particular 32-36 wt .-%.
• the solids contents of dispersions or solutions used in spraying processes are generally only about 20% by weight.
• the solids content is used in particular together with the viscosity to control the balance between good wettability of the still 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 are too long, it can also usually not sufficient
• Viscosity be built up. If the solids content is too high, this may be too
• the viscosity of the aqueous dispersion or solution is 150 to 1500, preferably 180 to 1000, in particular 200 to 350 mPas.
• the viscosity can, for. B. be determined with a Brookfield rotary viscometer. The expert is the
• the elasticity of the dried polymer film can be characterized essentially by its elongation at break.
• B. produced by pouring, dried film has a
• Elongation at break in [%] can be determined on test films according to DIN 53 455.
• the aqueous dispersion or solution contains a polymer mixture of at least one first (meth) acrylate copolymer which is enteric-coated and at least one further (meth) acrylate copolymer which is enteric-coated 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 contains or consists of at least two (meth) acrylate copolymers.
• the polymer mixture preferably contains or consists of two (meth) acrylate copolymers.
• the first (meth) acrylate copolymer which is gastroresistant and the further (meth) acrylate copolymer which is enteric or water-insoluble are preferably present in a ratio of 2 to 1 to 1 to 2.
• the first (meth) acrylate copolymer which is gastroresistant and the further (meth) acrylate copolymer which is enteric or water-insoluble make preferably at least 45, particularly preferably at least 60% by weight. in particular at least 70 wt .-% of the solid contained in the dispersion.
• an enteric (meth) acrylate copolymer are those
• Enteric-coated (meth) acrylate copolymers are synonymous with (meth) acrylate copolymers which are composed of C 1 - to C 4 -alkyl esters of acrylic or methacrylic acid and at least 5%, preferably 5 to 70, in particular 8 to 60%, monomer residues with anionic groups , usually methacrylic acid radicals, C 1 - to C 4 -alkyl esters of acrylic or methacrylic acid are in particular methyl methacrylate, ethyl methacrylate,
• the first enteric (meth) acrylate copolymer is a
• the glass transition temperature of the first (meth) acrylate copolymer according to ISO 11357-2, item 3.3.3 is, more than 70 0 C.
• the first enteric (meth) acrylate copolymer is a
• EUDRAGIT® L100-55 which is a copolymer of 50% by weight of ethyl acrylate and 50% by weight of methacrylic acid.
• anionic (meth) acrylate copolymers of from 20 to 40% by weight of methacrylic acid and from 80 to 60% by weight of methyl methacrylate (type 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.
• the further (meth) acrylate copolymer may preferably be an enteric, anionic polymer which is different from the first enteric (meth) acrylate copolymer.
• the glass transition temperature of the further (meth) acrylate copolymer according to ISO 11357-2, item 3.3.3 is at most 70, preferably at most 60, especially at most 50 0 C, z. B. 40 to 60 0 C.
• Particularly suitable z. B a polymer of 10 to 30 wt .-%,
• Methyl methacrylate 50 to 70% by weight of methyl acrylate and 5 to 15% by weight
• EUDRAGIT® FS which is a copolymer of 25 wt .-%, methyl methacrylate, 65 wt .-% methyl acrylate and 10 wt .-% methacrylic acid.
• EUDRAGIT® FS 30 D is a dispersion containing 30% by weight EUDRAGIT® FS.
• a (meth) acrylate copolymer (see WO 2003/072087), which is composed of
• Methacrylic acid or acrylic acid preferably methacrylic acid
• the glass transition temperature of the copolymer (measurement without addition of plasticizer at a residual monomer content (REMO) of less than 100 ppm, heating rate 10 ° C. / min, nitrogen atmosphere) according to ISO 11357-2, point 3.3.3 (T mg ), at most 60, preferably 40 to 60, particularly preferably 45 to 55 0 C.
• REMO residual monomer content
• the copolymer preferably consists essentially to exclusively of the
• glass temperature is meant in particular the midpoint temperature T mg according to ISO 11357-2, point 3.3.3.
• the measurement is carried out without addition of plasticizer, with residual monomer contents (REMO) of less than 100 ppm, at a heating rate of 10 ° C / min and under a nitrogen atmosphere.
• REMO residual monomer contents
• (meth) acrylate copolymers From 20 to 33% by weight of methacrylic acid and / or acrylic acid,
• the above-mentioned copolymer is composed, in particular, of free-radically polymerized units of
• From 20 to 33 preferably from 25 to 32, particularly preferably from 28 to 31,% by weight of methacrylic acid or acrylic acid, preference is given to methacrylic acid,
• the monomer composition is selected such that the glass transition temperature of the copolymer is 55 to 70 ° C., preferably 59 to 66, particularly preferably 60 to 65 ° C.
• the copolymer is preferably substantially to exclusively, at 90, 95 or 99 to 100 wt .-%, of the monomers methacrylic acid, methyl acrylate, ethyl acrylate and butyl methacrylate in the quantitative ranges given above.
• Vinylmalonic acid, styrene, vinyl alcohol, vinyl acetate and / or derivatives thereof may be included.
• a water-insoluble (meth) acrylate copolymer in the context of the invention is understood to mean those (meth) acrylate copolymers which are water-insoluble over the entire pH range from 1 to 14 or only swellable in water.
• neutral is understood to mean that the (meth) acrylate copolymer consists predominantly or entirely of neutral monomers, for example to more than 95, to more than 98% more than 99 or 100% by weight.
• neutral thus excludes the term
• (Meth) acrylate Copolymers having a content of less than 5, preferably less than 2, preferably less than 1 wt .-% of ionic, in particular anionic groups are considered "neutral” in the context of the invention or as “substantially neutral”.
• These neutral or substantially neutral, or possibly only slightly ionic, polymers are water-insoluble or swellable only in water and have no enteric properties.
• the further (meth) acrylate copolymer may preferably be a water-insoluble polymer which comprises a polymer of from 20 to 40% by weight of ethyl acrylate, from 60 to 80% by weight of methyl methacrylate and less than 5, preferably less than 2, preferably less than 1% by weight .-% methacrylic acid is (type EUDRAGIT® NE or EUDRAGIT® NM).
• Suitable is z. B, EUDRAGIT® NE, which is a copolymer of 30% by weight
• Ethyl acrylate and 70 wt .-% methyl methacrylate Adjuvants that affect the viscosity of the dispersion or solution and the elasticity of the dried polymer film.
• the viscosity of the dispersion and the elasticity or elongation at break of the dried polymer film can not be brought into the required ranges by the polymer mixture alone. Therefore, the aqueous dispersion or solution additionally contains auxiliaries, which together with the
• auxiliaries preferably make up at most 30, in particular at most 20% by weight of the solid contained in the dispersion.
• the content of these auxiliaries may, for. B. 5 to 30, preferably 10 to 20 wt .-% of the solid contained in the dispersion.
• Plasticizers can contribute to the viscosity of the dispersion and the
• Plasticizers generally have a molecular weight (M w ) between 100 and 20,000 and contain one or more hydrophilic groups in the molecule, eg. B. hydroxyl, ester or amino groups. Suitable are citrates, phthalates, sebacates, castor oil. Examples of suitable plasticizers are
• Citric acid alkyl esters propylene glycol, glycerol esters, alkyl phthalates, sebacic acid alkyl esters, sucrose esters, sorbitan esters, diethyl sebacate, dibutyl sebacate and polyethylene glycols 300 to 35,000.
• Preferred plasticizers are tributyl citrate, ethyl citrate, acetyl triethyl citrate, dibutyl sebacate and diethyl sebacate.
• plasticizers may be in the range of 1 and 30, preferably 5 to 25 wt .-%, based on the polymer mixture. Preferred are
• High molecular weight polyethylene glycols especially polyethylene glycol 20,000 or polyethylene glycol 35,000, which can greatly increase the viscosity of the dispersion or solution.
• other plasticizers such.
• Polyethylene glycol 20,000 or polyethylene glycol 35,000 are combined.
• Basic substances can help to increase or increase the viscosity of the dispersion and the elasticity of the dried polymer film.
• enteric-coated (meth) acrylate copolymers can, for. B. are gradually stirred into water and thereby partially or completely neutralized by adding a basic substance such. As NaOH, KOH, ammonium hydroxide or organic bases such. B. triethanolamine. It is also possible to use a powder of the copolymer, which already in its preparation for the purpose of (partial) neutralization of a base z. B. NaOH was added, so that the powder already (partially) neutralized polymer. Particular preference is given to sodium hydroxide solution or NaOH.
• a degree of neutralization of from 3 to 12 mol% of the anionic groups of at least the (meth) acrylate copolymer is preferred.
• the neutralization with sodium hydroxide in the form of 1, 5 to 2 normal sodium hydroxide solution is preferred.
• the relatively high concentration of caustic soda prevents too high a reduction of the
• Solids content With the partial neutralization is a thickening of the dispersion or solution i. an increase in viscosity associated.
• the quantitative proportion of basic substances in the total content of the excipients which influence or increase the viscosity of the dispersion and the elasticity of the dried polymer film is rather low in comparison to plasticizers.
• the influence of the basic substances, in particular on the viscosity is relatively high, so that these comparatively small amounts already bring about significant effects.
• a combination of plasticizers and basic substances is used.
• z. B. at most 25, at most 10 wt .-% or at most 5 wt .-% based on the total solids content of the dispersion or solution may optionally further pharmaceutically customary excipients that are no plasticizers or bases, but also in the fields of dietary supplements and cosmetics Find application be included.
• These other pharmaceutically acceptable auxiliaries have little or no effect on the viscosity of the dispersion or solution and the elasticity of the dried polymer film in comparison with the plasticizers or the bases.
• antioxidants dyes, flavors, brighteners, lubricants such. Talc, wetting agents, pigments, stabilizers, sweeteners, etc. These serve primarily as a processing aid and should primarily z. B. ensure a safe and reproducible manufacturing process, good long-term storage stabilities, a pleasing appearance or the identifiability.
• Pigments have to be opaque z. B. be added in relatively high concentrations, for. B. in amounts of 10 to 25 wt .-% based on the total solids content of
• Dispersion or solution In this high quantities and depending on the pigment used, it is generally possible to observe at least a slight, measurable influence on the viscosity of the dispersion or the elasticity of the dried polymer film.
• the viscosity may increase, while the elasticity of the dried polymer film tends to decrease. However, this can be caused by a slight shift in the type and the
• excipients that are not plasticizers or bases, and that are not pigments are generally far smaller, if any Contain concentrations, eg. B. less than 10, less than 5 or less than 2 wt .-% based on the total solids content of the dispersion or solution. For this reason, these further auxiliaries influence the viscosity of the dispersion or the elasticity of the dried polymer film negligibly or only to a very small extent.
• plasticizers and / or bases and optionally pigments are preferably included.
• Capsule halves are made by dipping sticks in viscous solutions, e.g. Gelatin solutions, prepared. The pins are then removed from the viscous solution. The viscous solution dries on the pins.
• viscous solutions e.g. Gelatin solutions
• Capsule halves are cut straight on the pins by means of a cutting tool and then removed from the pins. Since associated upper and lower parts of capsules have different sizes and geometries, they are manufactured separately.
• the process for the enteric coating of capsule halves can be integrated into the dipping process for producing capsule halves by immersing the capsule halves dried on the dip sticks in an additional working step in the coating composition according to the invention.
• the enteric coated capsule halves by means of a
• the invention further relates to a
• the invention relates to the use of an inventive
• the enteric coated capsule halves may be used for the preparation of active ingredient or dietary supplement capsules for oral use in the pharmaceutical, pharmaceutical, and pharmaceutical fields
• EUDRAGIT® L100-55 is a copolymer of 50% by weight of ethyl acrylate and 50% by weight of methacrylic acid.
• EUDRAGIT® FS is a copolymer of 25% by weight, methyl methacrylate, 65% by weight of methyl acrylate and 10% by weight of methacrylic acid.
• EUDRAGIT® FS 30 D is a dispersion containing 30% by weight EUDRAGIT® FS.
• EUDRAGIT® NE is a copolymer of 30% by weight of ethyl acrylate and 70% by weight of methyl methacrylate.
• Adjuvants that influence the viscosity of the dispersion and the elasticity of the dried polymer film Adjuvants that influence the viscosity of the dispersion and the elasticity of the dried polymer film:
• % of polymer wt .-%, based on the or the polymers

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• 2009
  • 2009-07-29 DE DE102009028076A patent/DE102009028076A1/de not_active Withdrawn
• 2010
  • 2010-06-15 WO PCT/EP2010/058370 patent/WO2011012369A2/de active Application Filing
  • 2010-06-15 CN CN201080022662.9A patent/CN102448446B/zh active Active
  • 2010-06-15 EP EP10724857A patent/EP2459178A2/de not_active Ceased
  • 2010-06-15 JP JP2012522057A patent/JP5686802B2/ja active Active
  • 2010-06-15 CA CA2769046A patent/CA2769046A1/en not_active Abandoned
• 2012
  • 2012-06-07 HK HK12105568.7A patent/HK1164726A1/zh unknown

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