Title:  Aqueous enteric coating composition and low gastric permeability enteric coating

United States Patent:  6,139,875

Assignee:  Eastman Chemical Company (Kingsport, TN)

Filed:  September 29, 1998

Disclosed herein is an aqueous enteric coating composition comprised of a solution of a water-soluble salt of an enteric coating polymer, with a hydrophobic compound containing 12 to 20 carbon atoms and a water-insoluble solid flake material dispersed in the aqueous solution. The enteric coating formed from the present composition has good mechanical strength and shows superior resistance to attack by atmospheric moisture and simulated gastric fluid, while being readily broken down under the alkaline conditions which exist in the intestine.

DETAILED DESCRIPTION OF THE INVENTION

The applicants discovered that, while maintaining good mechanical strength, the water and acid resistance of an enteric polymer film coating is increased beyond that which was previously achievable via solids loading by way of loading an aqueous solution of enteric polymer salt with a dispersion of a particular concentration of solid flake filler material and a hydrophobic compound containing aliphatic carbon atoms. Enteric coating compositions have not previously been loaded with a combination of solid flake material and hydrophobic aliphatic compound.

It was found that the present combination of flake material and hydrophobic aliphatic compound, within a particular concentration range, adds a "shingle effect" to the enteric coating. This shingle effect is evidenced by the fact that the moisture resistance provided is equivalent to that which would be provided by a coating containing a much higher percentage of solid filler. Since mechanical strength decreases with an increased concentration of solid filler, the present invention is beneficial in providing an increased water resistance without decreasing the mechanical strength of the coating. Additionally, the water resistant composition of the present invention can usefully be applied to a tablet as a relatively thin coat for the purpose of quick intestinal disintegration.

The aqueous enteric coating composition of the present invention comprises an aqueous dispersion of about 5 to 45 weight percent of a hydrophobic compound having between 12 to 20 aliphatic carbons and about 5 to 50 weight percent of a water-insoluble flake, dispersed in an aqueous solution comprising about 35 to 70 weight percent of a water soluble salt of an enteric polymer which dissolves only at a pH above about 5.0. The above listed weight percentages are based on the total weight of solids in the composition. The composition preferably contains a sufficient amount of water to provide a total solids content between about 5 to 20 weight percent, preferably between about 10 to 15 weight percent, based on the total weight of the composition.

The present composition comprises about 35 to 70 weight percent enteric polymer salt. The presence of more than about 70 weight percent polymer salt would provide a coating with insufficient resistance to water permeation in a gastric environment. But at least 35 weight percent enteric polymer is needed in order for a sufficient protective film to be formed around the tablet core and to hold the flake material and hydrophobic compound onto the core. The preferred concentration range of the soluble enteric polymer salt is about 40 to 55 weight percent.

An "enteric polymer" is herein defined as a polymer having a polystyrene equivalent weight average molecular weight (Mw) of about 50,000 to 150,000, and containing carboxyl groups which remain insoluble at a pH below about 4 (gastric pH range), but which ionize, and thus cause the polymer to dissolve, at a pH above about 5.0 (intestinal pH range). The enteric polymer used in the present composition is preferably a film-forming polymer. The most useful film-forming enteric polymers are cellulose acetate phthalate (C-A-P), cellulose acetate trimellitate (C-A-T), hydroxypropylmethylcellulose phthalate (HPMCP), copolymer of methacrylic acid and ethyl acrylate, hydroxypropylmethylcellulose acetate succinate (HPMCAS), and polyvinyl acetate phthalate (PVAP). The preferred Mw for HPMCP is between about 80,000 and 110,000, most preferably between 95,000 and 100,000. The preferred Mw for C-A-P is between about 55,000 and 75,000, with a Mw between 68,000 and 80,000 being more preferred.

A concentration of about 5 to 45 weight percent of a hydrophobic compound is dispersed throughout the present aqueous composition. The hydrophobic compound is a compound having 12 to 20 aliphatic carbon atoms. This hydrophobic component chemically repels aqueous, acidic medium away from the enteric polymer. At least 5 weight percent is needed to provide the shingle effect. The presence of more than 45 weight percent hydrophobic aliphatic compound causes agglomeration in the coating process. A concentration of about 20 to 35 weight percent hydrophobic compound is preferable.

The hydrophobic compound used may be any linear or branched chain compound having less than 1 percent solubility in water, a hydrophile-lipophile balance (HLB) value less than about 6, and which does not interfere chemically with the other components of the composition. The hydrophobic compound may contain non-aliphatic groups. Examples of such useful C₁₂ to C₂₀ hydrophobic compounds include alcohols, fatty acids and salts thereof, fatty amides and salts thereof, and lipids. A C₁₂ to C₂₀ alcohol is preferred, with stearyl alcohol being most preferred because of it's low toxicity.

The insoluble solid flake material dispersed throughout the aqueous composition of the present invention is present at a concentration of about 5 to 50 weight percent. More than about 50 weight percent solid flake material reduces the mechanical strength too much. A concentration of about 25 to 40 weight percent flake material is preferred.

The flake material (sheet-like) is water-insoluble, preferably an inorganic mineral. The more preferred flake material is one of the inert hydrous magnesium silicate materials referred to commonly as "talc" or pyrophyllite, which is essentially aluminum silicate having similar crystal structure and other properties to the talc materials. Other inert, powders whose crystals have a sheet-like or flake structure include materials such as aluminum flake, TiO₂ flakes, and silicate flakes.

It is a critical aspect of the present invention that the solid filler material has a flake or sheet-like shape. The shingle effect is most enhanced when the solid filler material is a flake material.

The average particle size of the flake material is preferably less than about 50 micrometers, with the average particle size being measured in equivalent circular diameters. It was a surprising aspect of the present invention to find that the water permeation barrier is further improved as the particle size of the solid flake material is decreased, using the same concentration of flake material. The preferred particle size of the flake material is less than about 10 micrometers, with a size less than about 1 micrometer (1,000 nanometers) being more preferable.

An exemplary embodiment of the preferred composition of the present invention is an approximately 10 percent solids content aqueous composition containing about 40 to 55 weight percent ammoniated HPMCP, with about 20 to 35 weight percent stearyl alcohol and about 25 to 40 weight percent talc dispersed therein, based on the total weight of solids.

Besides the insoluble flake material and hydrophobic compound of the present composition, the composition may also contain additive materials within the size range of about 0.1 to 100 micrometers. Additives used should be relatively hydrophobic. Plasticizers are especially useful for forming a flexible soft coating. Examples of suitable plasticizers include triacetin, diethyl phthalate (DEP), triethyl citrate (TEC), and dibutyl sebacate (DBS). Solid pigments may also be used. The weight percent of such additives should be less than about 15 weight percent, more preferably less than about 5 weight percent, based on the total weight of solids in the composition.

The present invention further includes a process of making an aqueous enteric coating composition comprising reacting about 35 to 70 weight percent of a enteric polymer with a solubilizing amount of a water-soluble base to provide an aqueous solution or dispersion of a salt of the enteric polymer and, dispersing about 5 to 45 weight percent of a hydrophobic compound having from about 12 to 20 aliphatic carbon atoms and about 5 to 50 weight percent of a water insoluble flake material in the aqueous polymer solution. The present process is preferably conducted under conditions providing a total solids content of about 5 to 20 weight percent solids. The water-insoluble components are preferably dispersed throughout the solution through high shear mixing using a homogenizer or a colloid mill.

The enteric polymer salt of the aqueous coating composition is preferably formed in situ by adding the non-ionized enteric polymer and a water-soluble base to the aqueous solution separately for reaction. Suitable water-soluble bases for neutralization of the polymer include NH₄+ OH^-, and alkali metal hydroxides, with ammonium hydroxide being the preferred neutralizing agent.

The aqueous enteric coating solution of the present invention is applied to a core substrate by any traditional coating means such as by spray coating. Suitable core substrates to which the aqueous enteric coating solution of the present invention can be applied includes pharmaceutically active tablets, pellets, granules, and beads. A coating weighing about 5 to 15 weight percent of the total coated core is preferable so that the core is fully coated, yet the coating is thin enough so that it dissolves quickly in the intestines. In order to protect the tablet cores from reacting with the basic coating solution, it is often preferable to apply a subcoat of polymer prior to applying the basic aqueous enteric coating solution of the present invention. For example, a polymer subcoat film weighing about 2 percent of the core table weight is useful.

In order for the polymer to demonstrate enteric properties in the gastric and intestinal media, a sufficient amount of ionized carboxyl salt groups must be converted back to the non-ionized free acid form. This can be done via different routes, depending on the exact polymer salt used. Heat may be applied to the coated tablets to convert the carboxylic acid groups into the free acid form upon evaporation of ammonia or water. Alternatively, the polymer carboxylic acid groups of the coated tablets can be reprotonated by treatment with an acid during production or by the gastric acid upon entry into the stomach environment.

The present invention further includes the enteric coating formed from the composition of the present invention. The coating of the present invention is preferably a film coating formed from a film-forming enteric polymer. The present coating dissolves only at a pH above about 5.0. The coating of the present invention may contain enteric polymer in the ionized salt form, enteric polymer in the protonated non-ionized enteric polymer form, or a combination thereof. The coating is formed upon evaporation of the water and other volatiles of the present aqueous composition. The components of the coating should be dispersed evenly throughout the coating in order to provide the maximum benefit.

The present invention further includes an enterically active dosage form, meaning that the active ingredient is released according to an enteric profile. The active dosage form of the present invention is a pharmaceutically active core enveloped by the enteric coating of the present invention. The core will typically contain an active ingredient and various excipients. Examples of useful pharmaceutically active ingredients for use in the present invention include aspirin, ibuprofen, ivermectin, acetaminophen, naproxen sodium, indomethacin, theophylline, propanolol, sucrose, erythromycin, pharmaceuticals such as diclofenac sodium, and the like. It is necessary that the tablet core is hard enough to resist attack by the coating solution and that it does not react with the components of the coating. Application of a sub-coating between the core and the enteric coating is useful in some situations so that the core does not react with the coating. The enterically active solid dosage form of the present invention preferably has a coating weighing between about 5 to 15 weight percent of the total coated dosage form so that the active core is adequately protected from water permeation, yet the active ingredient is released quickly enough in the intestines.

Claim 1 of 16 Claims

We claim:

1. An aqueous enteric coating composition comprising: a dispersion of about 5 to 45 weight percent of a hydrophobic compound having from about 12 to 20 carbon atoms selected from the group consisting of alcohols, fatty acids and salts thereof, fatty amides and salts thereof, and lipids and about 5 to 50 weight percent of a water-insoluble flake material, dispersed in an aqueous solution of about 35 to 70 weight percent of a water-soluble salt of an enteric polymer selected from the group consisting of cellulose acetate phthalate (C-A-P), cellulose acetate trimellitate (C-A-T), hydroxypropyl methylcellulose phthalate (HPMCP), methacrylic acid/ethyl acrylate copolymer, hydroxypropyl methylcellulose acetate succinate (HPMCAS), and polyvinyl acetate phthalate (PVAP), wherein said weight percentages are based on a total solids weight.

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