BR112017013598B1 - ENTERIC FILM COATING COMPOSITIONS, COATING METHOD, AND COATED FORMS - Google Patents

Abstract

ENTERIC FILM COATING COMPOSITIONS, METHOD OF COATING, AND COATED FORMS. A safe, water-soluble, vegetable-based, dry powder formulation and an aqueous enteric coating solution prepared therefrom, which is used to provide an enteric film coating on oral dosage forms including capsules, tablets, and the like; and methods for preparing the dry powder formulation, preparing the aqueous coating solution, and coating oral dosage forms including capsules, tablets, and the like.

Description

CROSS-REFERENCE TO RELATED ORDERS

[0001] This application claims the benefit of U.S. Provisional Application No. 62/124,590, filed December 23, 2014, which is incorporated by reference in its entirety.

FIELD OF INVENTION

[0002] This invention relates to the field of enteric film coatings, including dry powder formulations and aqueous solutions used in the manufacture of enteric film coatings; enteric coated oral dosage forms of orally ingestible active ingredients, including capsules, tablets and the like, for preventing the release of the active ingredient ingredients into the gastric juices of the stomach, and for releasing the ingredients after passing through the stomach, e.g., into the intestines; and methods for preparing the dry powder formulations, aqueous solutions and enteric coated oral dosage forms. The invention provides a water-soluble, herbal dry powder formulation and aqueous enteric coating solutions made therefrom that can be used in oral dosage forms coated with an intestinal-soluble coating that is insoluble in the gastric juices of the stomach, and methods for preparing the dry powder formulations and aqueous enteric coating solutions. The invention also provides various oral dosage forms that are coated with an enteric film coating using aqueous enteric coating solutions and methods of coating oral dosage forms.

FUNDAMENTALS OF THE INVENTION

[0003] Enteric coating materials are types of materials that are acid resistant, protect and prevent the coated oral dosage form from releasing its contents into the stomach. However, these coatings dissolve or disintegrate in the neutral or slightly alkaline conditions found beyond the stomach. Enteric coatings can also be used to prevent irritation or damage to the mucous membrane of the stomach caused by substances contained in the oral dosage form, and to neutralize or prevent the formation or release of substances that have an unpleasant odor or taste in the stomach. Finally, such coatings can be used to prevent nausea or vomiting upon ingestion of the coated oral dosage form. Many enteric coatings have been approved for pharmaceutical use, but few are approved for food use. Many dietary supplements and health foods are available in oral dosage forms that may benefit from enteric coatings. However, without approval for food use, enteric coating compositions cannot be used in oral dosage forms in nutraceutical applications. It would be useful to provide an enteric composition made from materials that have been approved for pharmaceutical, nutritional, veterinary and food use, so that such coatings can also be used in non-pharmaceutical dosage forms.

[0004] Many of the previously available enteric coating materials required the use of organic solvents. The use of organic solvents presents numerous problems, including increased pollution with increased fire and explosion hazards. Expensive equipment and training of workers handling organic solvents are required to mitigate these risks. Aqueous enteric coating materials have also been proposed, but many do not have adequate enteric performance. Therefore, it would be beneficial to provide an aqueous enteric composition that is capable of providing adequate enteric coating performance.

[0005] Many of the previously available enteric materials included phthalates. Enteric coating utilizing phthalates include hydroxypropylmethyl cellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), and polyvinyl acetate phthalate (PVAP). However, phthalates have disadvantages in that they require undesirable additional processing steps. HPMCP, for example, generally requires neutralization with a base such as ammonia to increase solubility and must also undergo acid treatment after spraying in order to provide enteric functionality. The addition of ammonia results in an unpleasant odor. Furthermore, the acid treatment step requires the use of a strong acid with a pH in the range of 1 to 3. Therefore, it is desirable and there is a need for enteric film coating compositions having enteric polymers other than phthalates.

[0006] Alginates, derived, among others, from brown seaweed (Phaeophyceae sp.) are linear unbranched chemical polymers containing (1-4)-linked β-D-mannuronic acid residues (M) and C-5 epimer α-L-guloronic acid (G). Alginates consist of homopolymeric blocks of consecutive G residues, consecutive M residues or alternating M and G residues, e.g. MMMM, GGGG and GMGM. Alginates are widely used in the food industry to increase viscosity, form hydrogels and also to be used as emulsifiers. Alginates have also been used in capsules. Alginates are generally useful in the form of alginic acid or salts thereof. The number of G residues relative to the sum of G and M residues is known as the G content. Similarly, the percentage content of M residues is known as the M content, so that the G content and the M content represent 100%. The content of G and M residues can also be expressed as an M/G ratio. M/G ratios can be determined by NMR or IR spectroscopy using methods known in the art. The G content in major alginates from algae is generally between approximately 30% and 70%. However, different algae produce alginates that differ in monomer composition. A wide range of alginates are commercially available, including, for example, the PROTANAL and MANUCOL alginate lines (FMC BioPolymer, Philadelphia, PA). Gels and films made from alginate having a relatively high amount of G blocks are mechanically stronger than those made from alginate having a relatively high amount of M blocks. Consequently, gels and films made from high-M alginates generally have poor mechanical strength compared to gels and films made from high-G alginates. Furthermore, increasing the concentration of a high-M alginate in the film coating is expected to unacceptably increase the process viscosity and create very difficult processing conditions, while at the same time undesirably decreasing the molecular weight of such alginate, resulting in further weakening of the (already very weak) film even at high concentrations. While sodium alginate is water-soluble at neutral pH but insoluble at low pH, it has failed to demonstrate adequate enteric performance when used as the sole enteric polymer.

[0007] Therefore, there is a need for a phthalate-free, water-soluble, plant-based, food-safe dry powder formulation and aqueous enteric coating solutions made therefrom that can provide adequate enteric coating performance that is suitable for pharmaceutical, nutraceutical, veterinary, and food use.

SUMMARY OF THE INVENTION

[0008] An object of this invention is to provide a food-safe, water-soluble, dry powder formulation that is useful for preparing an aqueous enteric coating and/or enteric film coating solution comprising a water-soluble enteric polymer and a water-soluble film-forming polymer having a 10:1 to 1:3 ratio of enteric polymer to film-forming polymer by weight, whereby when the enteric film coating dry powder formulation is used for an enteric coating of an oral dosage form containing an active ingredient, the active ingredient is not released in a 0.1 N HCl medium at about 37°C for up to one hour, and then about 90% or more of the active ingredient is released within two hours in a phosphate buffer medium having pH 7.2 at about 37°C. Preferably, the active ingredient is not released in a 0.1 N HCl medium at about 37°C for up to one hour and then about 90% or more of the active ingredient is released in less than one hour or, more preferably, less than 30 minutes in a phosphate buffer medium having pH 7.2 at about 37°C.

[0009] Preferably, the dry powder formulation is substantially free of phthalates. Preferably, the dry powder formulation is water-soluble at 10% solids. Preferably, the enteric polymer has a viscosity of 3 to 200 centipoises (3 mPa.s to 200 mPa.s) at 1% solids, and more preferably 3 to 20 cps (3 to 20 mPa.s) at 1% solids. Preferably, the enteric polymer and/or the film-forming polymer is/are made from a plant-based material. More preferably, the enteric polymer is an alginate. Even more preferably, the enteric polymer is the monovalent salt form of alginate, e.g., sodium alginate or potassium alginate. Most preferably, the enteric polymer is sodium alginate. Preferably, the alginate has a G content that is from 20% to 55%, and more preferably from 20% to 40%. Preferably, the film-forming polymer is made from one or more plant-based materials. Most preferably, the film-forming polymer is polyvinyl alcohol-polyethylene glycol graft copolymer (commercially available from BASF as KOLLICOAT IR), low viscosity carrageenan (FMC BioPolymer, Philadelphia, PA), hydroxypropyl methyl cellulose (HPMC), gum acacia or a low viscosity modified starch. Even more preferably, the film-forming polymer is HPMC, gum acacia or a low viscosity modified starch. Low viscosity modified starches can be made from tapioca starch, corn starch, pea starch or other suitable food starches. Preferably, the viscosity of the film-forming polymer is 100 to 1000 cps (100 to 1000 mPa.s) at 10% solids, and more preferably 100 to 500 cps (100 to 500 mPa.s) at 10% solids.

[0010] It is an object of this invention to provide aqueous enteric coating solutions using any of the above-mentioned dry powder formulations for use in providing an enteric film coating with enteric performance suitable for pharmaceutical, nutraceutical, veterinary and food applications. The aqueous enteric coating solution comprises any of the above-mentioned dry powder formulations dissolved in water and optionally a plasticizer, an antifoaming agent, an adhesion enhancing agent, a coloring and antitack agent.

[0011] Preferably, the plasticizer is glycerin. Preferably, the antifoaming agent is simethicone. Preferably, the aqueous enteric coating solution has a viscosity of 50 to 2,000 cps (50 to 2,000 mPa.s), more preferably 200 to 1,000 cps (200 to 1,000 mPa.s), most preferably 400 to 600 cps (400 to 600 mPa.s). The percent solids of the aqueous enteric coating solution is preferably 2% to 30%, more preferably 3% to 20%, even more preferably 5% to 20%, and most preferably 10% to 20%.

[0012] It is also an object of this invention to provide oral dosage forms containing an active ingredient coated using any of the above-mentioned aqueous enteric coating solutions to provide an enteric film coating having suitable enteric performance in the oral dosage form.

[0013] Preferably, after the enteric coated oral dosage form is stored at 20 degrees Celsius for six weeks, the active ingredient contained in the enteric film coated oral dosage form is not released when placed in a 0.1 N HCl medium at about 30 degrees Celsius for up to one hour and then about 90% or more of the active ingredient is released within two hours in a phosphate buffer medium having pH 7.2 at about 37 degrees Celsius (the phosphate buffer may be 0.05 M potassium phosphate monobasic adjusted to pH 7.2 by addition of sodium hydroxide). Preferably, the oral dosage form is a tablet or capsule, and more preferably, a tablet or soft capsule, and most preferably a soft capsule. Preferably, the active ingredient is a pharmaceutical, nutraceutical, veterinary or food product. Most preferably, the active ingredient is fish oil, garlic, probiotic, Lumbrokinase, S-Adenosyl Methionine (SAM-e), Nattokinase, a non-steroidal anti-inflammatory drug or iron supplement. Most preferably, the active ingredient is fish oil.

[0014] Additional aspects of the invention include methods for preparing dry powder formulation, aqueous enteric coating solutions, and methods of coating pharmaceutical, nutraceutical, veterinary, and food products in particular oral dosage forms with the aqueous enteric coating solutions of the invention. Preferred methods of applying the enteric film coating include spray coating, dipping, and tumbling.

DETAILED DESCRIPTION

[0015] It has been found that certain combinations of film-forming polymers and alginates are capable of providing a dry powder formulation that is food safe, plant-based, phthalate-free, and water soluble and when dissolved in water can be used to coat oral dosage forms to provide an enteric film coating. In particular, it has been found that combinations of certain film-forming polymers and alginates with low to medium G content are capable of providing the coating with adequate enteric properties whereas film-forming polymers alone, alginate alone, or combinations using a high G content alginate cannot match the same level of enteric performance or is too viscous to be commercially applicable. In addition, combinations of film-forming polymers and alginates have been identified that have viscosities that allow for use in spray coating as well as other coating methods. An advantage of this system is that the water solubility of the dry powder formulations makes them easier to process and does not require additional steps or components to enhance solubility. In particular, the products and methods of the invention do not require the use of ammonia or strong acids. Another advantage is that these combinations can be used with plasticizers without destroying their enteric performance.

[0016] According to one embodiment of the present invention, there is provided a dry powder formulation comprising a water-soluble film-forming polymer and a water-soluble enteric polymer. Preferably, the ratio of enteric polymer to film-forming polymer is 10:1 to 1:3 by weight. Acceptable film-forming polymers are water-soluble at 10% solids and are capable of providing sufficient mechanical strength to permit film formation. An acceptable viscosity range of the film-forming polymer is 100 to 1,000 centipoises (cps) (100 mPa.s to 1,000 mPa.s) at 10% solids. Preferably, the viscosity range is 100 to 500 cps (100 to 500 mPa.s) at 10% solids. Examples of suitable water-soluble film-forming polymers include polyvinyl alcohol-polyethylene glycol graft copolymer (commercially available from BASF as KOLLICOAT IR), low-viscosity carrageenan (FMC BioPolymer, Philadelphia, PA), HPMC, gum acacia, and low-viscosity modified starch. Low-viscosity modified starches can be made from tapioca starch, cornstarch, pea starch, or other suitable food starches. Examples of suitable low-viscosity modified starch include CRYSTAL TEX 627M (Ingredion Inc., Bridgewater, NJ), Instant PURE-COTE B792 (Grain Process Corp., Muscatine, IA), LYCOAT RS720 and RS780 (Roquette, Lestrem, France). Examples of commercially available gum acacia include ENCAPSIA (Nexira, Somerville, NJ). Examples of water-soluble enteric polymers include alginates. Preferably, the alginate salts are monovalent salts and more preferably the alginate is in the form of sodium alginate or potassium alginate. Most preferably, it is sodium alginate, for example, MANUCOL LD, MANUCOL DH, PROTANAL CR 8133 and PROTANAL GP3350 (FMC BioPolymer). A preferred G content for alginates is from about 20% to about 55%, and more preferably the G content is from about 20% to about 40%. Accordingly, the M content is preferably from about 45% to about 80%, and most preferably from about 60% to about 80%. Each of the components of the dry powder formulation is preferably mixed together in a dry powder form.

[0017] According to one embodiment of the present invention, the water-soluble film-forming polymer is a low viscosity modified vegetable starch. In these embodiments, little or no foaming was observed when the formulations were processed. This provides an advantage over other film-forming polymers that include HPMC in that fewer anti-foaming agents are required and preferably no anti-foaming agent is used. Furthermore, the combination of vegetable starch and low viscosity modified alginate resulted in a homogeneous clear film with a wider range of plasticizers compared to the combination of alginate and HPMC. Finally, the combination of alginate and low viscosity modified vegetable starch provided improved adhesion properties of the resulting coating compared to HPMC and alginate.

[0018] According to another embodiment of the present invention, there is provided an aqueous enteric coating solution for use in providing an enteric film coating comprising any of the above-mentioned dry powder formulations, and water, and optionally an anti-foaming agent. Suitable anti-foaming agents include, without limitation, silicones, silanes, polydimethylsiloxane (PDMS), hydrophobic silica, dimethicones, and simethicones. A preferred anti-foaming agent is Simethicone USP 30%, e.g., DOW CORNING Q7-2587. Preferably, the water is deionized water. The enteric coating aqueous solution has a viscosity of 50 to 2,000 cps (50 to 2,000 mPa.s), preferably the viscosity is 100 to 1,000 cps (100 to 1,000 mPa.s), and most preferably the viscosity is 100 to 800 cps (100 to 800 mPa.s).

[0019] According to another embodiment of the present invention, the aqueous enteric coating solution further comprises a plasticizer. Suitable plasticizers include, without limitation, glycerol, sorbitol, maltitol, triethyl citrate, and polyethylene glycols. A preferred plasticizer is glycerol.

[0020] According to another embodiment of the present invention, there is provided an enteric film coated oral dosage form, wherein an active ingredient is provided as an oral dosage form and is coated using any of the aforementioned aqueous enteric coating solutions. Preferred oral dosage forms include an encapsulated powder, tablet, dragee, microcapsule, or capsule. More preferably, the oral dosage form is a gelatin capsule or tablet. Most preferably, the oral dosage is a gelcap. The oral dosage form may contain any components that are commonly used in such dosage forms, such as active pharmaceutical agents, nutraceuticals, veterinary products, food products, and additional excipients. Suitable pharmaceutical agents include, without limitation, an oil-soluble, oil-insoluble, water-soluble, and water-insoluble drug. For oral tablet and gel capsule dosage forms, suitable pharmaceutical active agents include oil-soluble, oil-insoluble, and water-insoluble drugs. A preferred pharmaceutical active agent is an omega-3 fatty acid. Suitable nutraceuticals include oils, probiotics, proteins, enzymes, herbs, roots, leaves, fruits, flowers, grasses, barks, fruit peels, minerals or trace minerals in ionic or elemental form, such as calcium, magnesium, zinc, selenium, and iron, and combinations thereof. For example, the nutraceutical product is lumbrokinase, S-adenosyl methionine (SAM-e), or Nattokinase. Preferred nutraceuticals are oils; most preferably an oil that is high in omega-3 fatty acids; and most preferably fish oil. The enteric film coating provided in the oral dosage form has a thickness of 500 microns or less. Prior to being coated, the oral dosage form may have immediate release, controlled release, delayed release capabilities or may be released upon activation by a known event, condition or process. Preferably, the oral dosage form has an immediate release profile prior to being coated. Preferably, it is beneficial after ingestion of the oral dosage form to prevent the release of at least one component in the stomach containing the component(s). More preferably, at least one component in the enteric coated oral dosage form is likely to cause irritation or damage to the stomach lining or to form or release substances having an unpleasant odor or taste in the stomach. Most preferably, at least one component tends to form or release substances having an unpleasant odor in the stomach when ingested without an enteric coating, e.g., garlic or fish oil. Preferably, the thickness of the enteric film coating is 20 to 200 microns. Most preferably, the thickness of the enteric film coating is 30 to 90 microns. An appropriate amount of weight gain due to coating with the enteric film coating is 2% to 50%. Preferably, the weight gain is 2 to 15%.

[0021] The processes are well known in the industry as methods for preparing oral dosage forms. The fill materials for the soft capsules can be any fill materials commonly used in such dosage forms. Generally, the fill materials can be liquids (including emulsions) or solids, such as powders. The fill materials can be a pharmaceutical ingredient, nutraceutical ingredient, veterinary ingredient, food, etc. For the oral dosage forms of tablets and gel capsules, the fill materials are insoluble in water.

[0022] The definitions of “disintegration”, “disintegrate”, “rupture”, “dissolution”, “immediate release”, “delayed release”, “enteric” and “enteric coated” can be found in US Pharmacopeia 32 (USP32) and are incorporated herein by reference. Likewise, methods for measuring disintegration and dissolution are described in the examples and in USP 32, chapter <2040>, including the chapter on ‘delayed release (enteric coated) tablets’ (incorporated herein by reference). As used herein, the term “phthalate-free” means that the composition contains no more than trace amounts of phthalates. As used herein, the term “substantially phthalate-free” means that the composition contains less than 10% phthalates by weight. In embodiments of the present invention, the dry powder formulation contains less than 10%, 5%, or 1% phthalates by weight. In embodiments of the present invention, the amount of phthalates contained in the dry powder formulation is 0% by weight. In embodiments of the present invention, the aqueous enteric coating solution contains less than 10%, 5%, or 1% phthalates by weight. In embodiments of the present invention, the amount of phthalates contained in the aqueous enteric coating solution is 0% by weight.

[0023] As used herein, the term “enteric film coating” means an enteric coating having a thickness of 500 microns or less. According to the definition found in USP32, the term enteric coating is used herein as an acid-resistant layer or covering of an oral dosage form containing an active ingredient, which is capable of protecting and preventing the coated oral dosage for a period of time from the release of the contents of the active ingredient into the stomach and is thereafter capable of dissolving or disintegrating under neutral or slightly alkaline conditions, thereby releasing the contents of the active ingredient into a portion of the gastrointestinal tract other than the stomach. In this way, an enteric coating allows transit through the stomach into the small intestine before the active ingredient is released.

[0024] According to another embodiment of the present invention, there is provided a method for preparing the above-mentioned aqueous enteric coating solutions comprising dissolving a plasticizer and optionally an anti-foaming agent in water by mixing under agitation, adding an amount of film-forming polymer and an amount of an enteric polymer to the mixture under agitation, and mixing the resulting mixture under high agitation. Optionally, the film-forming polymer and the enteric polymer are mixed together to prepare a dry powder formulation before being added to the mixture of plasticizer, anti-foaming agent and water.

[0025] According to another embodiment of the present invention, there is provided a method for coating an oral dosage form using the aqueous enteric coating solutions of the invention to provide an enteric film coating for the oral dosage form comprising spraying, dipping, tumbling coating using a coating pan, or coating using a fluid bed coater. Such devices and their configurations are well known to one skilled in the art and can be used to coat oral dosage forms using the aqueous enteric coating solutions of the invention.

[0026] In one embodiment of the present invention, oral dosage forms were spray coated using a Thomas Accela-Cota Compu-Lab spray coater under the settings listed in Table 1. One of ordinary skill in the art will understand how to adjust the spray coating settings to suit the coating batch size or the oral dosage form to be coated. Table 1. Spray Coating Settings

[0027] All viscosities referred to herein can be measured using a Brookfield viscometer at appropriate spindle speeds in water at room temperature such as 18-25°C or at 20°C+/-2°C. For example, all viscosities referred to herein can be measured using a Brookfield viscometer, #62 spindle, 12 rpm, at 20°C+/-2°C.

[0028] Non-limiting embodiments of the present invention also include other suitable components in the formulation, solutions or oral dosage form. Other suitable components include, without limitation, conventional excipients such as binders (such as microcrystalline cellulose), disintegrants, diluents, lubricants, glidants, matrix formers, emulsifying solubilizing agents, sweetening agents, antimicrobial preservatives, dyes; colorants and pigments such as titanium dioxide and calcium carbonate; stabilizing polymers such as chitosan; cellulose gums, carrageenan, additional forms of alginates, propylene glycol alginate, gellan, xanthan gum, locust bean gum, guar, pectins, gum arabic, gum tragacanth, sodium carboxymethyl cellulose, alkyl cellulose ethers other than HPMC, hydroxypropyl cellulose, hydroxyethyl cellulose and methyl cellulose and agar-agar; preservatives such as lower alkylparabens, sorbic acid, potassium sorbate, benzoic acid, sodium benzoate or esters of hydroxybenzoic acid and benzyl alcohol; antioxidants such as ascorbic acid, ascorbyl palmitate, sulphites, L-tocopherol, butylated hydroxyanisole and propyl gallate; disintegrating compounds and other components. The quantity required for these other suitable components will depend on the component, the composition of the product, the storage conditions and is known to those having the necessary skill in the art.

[0029] The present invention is now described in greater detail by reference to the following examples, but it is to be understood that the invention is not to be construed as limited thereto. Unless otherwise indicated herein, all parts, percentages, proportions and the like are by weight. Method for Preparing Aqueous Enteric Coating Solutions

[0030] A plasticizer (glycerol) and optionally an anti-foaming agent (30% Simethicone, DOW Q7-2587, Dow) were added to deionized water according to the amounts set forth in Table 2 under stirring at about 300 RPM using a mixer (Heidolph RZR 2021). Once the plasticizer and optional anti-foaming agent were completely dissolved or dispersed, the enteric polymer (low viscosity alginate, Manucol LD, FMC BioPolymer) and film-forming polymer (low viscosity HPMC, HPMC E3 LV, FMC BioPolymer) were slowly added according to the amounts set forth in Table 2 while maintaining stirring at about 300 RPM in the vortex created by the stirred water to avoid agglomeration. Premixing the enteric polymer and film-forming polymer is optional and may help to enhance dissolution. Once all enteric polymers and film-forming polymers were added, the agitation speed was increased to approximately 450 RPM and mixed for an additional 2 hours to ensure complete hydration. The solution was then filtered through a 106 micron screen (140 mesh sieve) prior to coating. After coating, the coatings are not crosslinked. Alginate-based coatings are usually crosslinked using a treatment step, e.g., by spraying, dipping, or washing with calcium salt. As described in the examples below, the coatings of the present invention were able to provide adequate enteric coating performance even without crosslinking step(s). Table 2. Solution Formulation

Method for Testing Enteric Performance

[0031] In accordance with aspects of this invention, the enteric coating has adequate enteric coating performance if the coating remains substantially insoluble in Simulated Gastric Fluid (SGF) at 37±2°C for at least one hour and then disintegrates or ruptures within two hours in Simulated Intestinal Fluid (SIF) at 37±2°C. SGF is a 0.1 N HCl medium. SIF is a phosphate buffer medium with a pH of 7.2. It is manufactured by dissolving 136.0 g of KH2PO4 (Merck, Lot A585477) in 5 L of deionized water, adding 61.6 mL of 5N NaOH in 10 mL of deionized water, and diluting to a final volume of 20 L. More specifically, enteric-coated gel capsule oral dosage forms were tested for rupture using a Dr. Schleuniger Pharmatron Tablet Disintegration Tester according to USP Standard Method 32 Chapter <2040>. A similar method can be used for disintegration testing of enteric-coated tablets. One (1) gel capsule was placed in each of the six basket tubes. The apparatus was then operated using SGF maintained at 37°C as the immersion fluid. After 1 hour of operation in the SGF, the basket was removed from the fluid, and the observation gel capsules were observed for evidence of disintegration, fracture, rupture, leakage, or softening. The apparatus was then operated using SIF, maintained at 37°C, as the immersion fluid until all gel capsules were completely empty and the enteric film coating had completely dissolved. The times taken for each capsule to completely empty and dissolve were recorded. If 1 or 2 capsules did not close completely within 2 hours, repeat the test on 12 additional capsules. Not less than 16 of the total 18 tablets tested should be completely empty within 2 hours.

EXAMPLE 1 Enteric Performance of Enteric Film-Coated Gel Capsules

[0032] An aqueous enteric coating solution was prepared according to the formulation in Table 3. The formulation had a viscosity of 795 cps (795 mPa.s) at 9.9% solids. S19 SeaGel® gels (0.5” x 0.375” (1.27 cm x 0.95 cm) diameter), available from FMC Corp., Philadelphia, PA) were filled with oil and spray coated. The resulting coating had a thickness of 69 microns to 74 microns and the coated capsules were 7.4% heavier. After coating, the capsules were tested for enteric performance according to the method described above. After 1 hour in SGF, 6/6 of the coated capsules remained intact. The coated soft gels were then placed in SIF. After 1 minute, all coated capsules began to ooze oil and all were completely emptied within 5 minutes. All capsule shells were completely dissolved within 11 minutes. These results suggest that the combination of low viscosity, low G alginate and a film-forming polymer when used with a plasticizer and an antifoaming agent is capable of providing an enteric film coating with adequate enteric performance. In contrast, when similar coatings were prepared without film-forming polymers, the coatings failed to remain intact in SGF for 1 hour (see, Comparative Examples 8). In another alternative coating formulation, high G alginate was used with and without a film-forming polymer. In both cases, coatings made with high G alginate did not remain intact for more than 15 minutes in SGF (see, Comparative Examples 9, 10, and 11). Table 3. Enteric Film Coating Formulation of Gel Capsule

EXAMPLE 2 Enteric Performance of Enteric Film Coating using KOLLICOAT IR

[0033] An aqueous enteric coating solution was prepared using a 2:1 ratio of Manucol LD to KOLLICOAT IR according to the formulation in Table 4. The formulation had a viscosity of 1.182 cps (1,182 mPa.s) at 9% solids and coated into S23 soft gelatin capsules (1.0” x 0.33” (2.4 cm x 0.84 cm) diameter). The resulting coated capsules had a weight gain of 10.9%. After coating, the capsules were tested for enteric performance according to the method described above. 5 capsules spent 2 hours in SGF and 1 ruptured within 60 minutes. The intact coated soft gels were placed in SIF. After 7 minutes, the remaining 5 coated capsules were completely emptied and completely dissolved within 15 minutes. In another experiment, a 1:1 ratio of Manucol LD to KOLLICOAT IR was used to coat capsules, 5/6 of these coated capsules remained intact with 1 coated capsule rupturing after 45 minutes. These results show that the combination of low viscosity, low G alginate and KOLLICOAT IR when used as an antifoaming agent is capable of providing an enteric film coating with adequate enteric performance and adjusting the ratio of Manucol LD to KOLLICOAT IR can improve the enteric performance. Table 4. Enteric Film Coating Formulation of Softgel Capsule

EXAMPLE 3 Enteric Performance of Enteric Film Coating with a Plasticizer

[0034] An aqueous enteric coating solution similar to the formulation of Example 2 but with a higher solids content was prepared (see Table 5). The formulation had a viscosity of 597 cps (597 mPa.s) at 9.9% solids. It was coated into S19 gelatin capsules (0.5” x 0.375” (1.27 cm x 0.95 cm) diameter). The resulting coating had a thickness of 54 microns and 5.4% weight gain. After coating, the capsules were tested for enteric performance according to the method described above. After 1 hour in SGF, 6/6 of the coated capsules remained intact. These results suggest that the combination of low viscosity, low G alginate and film-forming polymer when used with suitable plasticizer is also capable of providing an enteric film coating with adequate enteric performance.Table 5. Softgel Capsule Enteric Film Coating Formulation

EXAMPLE 4 Enteric Performance of Enteric Film Coating Using Low G, Medium Viscosity Alginate

[0035] An aqueous enteric coating solution was prepared according to the formulation in Table 6. Manucol DH is a medium viscosity alginate with low G content. The formulation had a viscosity of 847 cps (847 mPa.s) at 5.0% solids. S19 gelatin capsules (0.5” x 0.375” (1.27 cm x 0.95 cm) diameter) were coated with the formulation. The resulting coating had a thickness of 40 microns at 2.5% weight gain. After coating, the capsules were tested for enteric performance according to the method described above. All 6 coated capsules remained intact for 1 hour and 4/6 remained intact for 2 hours. These results suggest that the combination of low G medium viscosity alginate and film forming polymer is capable of providing an enteric film coating with adequate enteric performance. Furthermore, the amount of alginate used was able to decrease due to the increased viscosity of alginate. Table 6. Gel Capsule Enteric Film Coating Formulation

EXAMPLE 5 Enteric Performance of Enteric Film Coating Using PEG8 Plasticizer after 6 Weeks of Storage

[0036] An aqueous enteric coating solution was prepared according to the formulation in Table 7 and coated onto Spring Valley S23 gelatin fish oil capsules (1” x 0.33” diameter (2.54 cm x 0.84 cm) at a gain of 8.3%. The capsules were then stored at room temperature for 6 weeks and tested for enteric performance according to the method described above. After 2 hours in SGF, 6/6 of the coated capsules remained intact. The coated soft gels were then placed in SIF. All capsules were completely emptied after 8 minutes. The capsule shells were completely dissolved within 18 minutes. These results suggest that the enteric performance of the enteric film coating is stable after storage for 6 weeks. Table 7. Gel Capsule Enteric Film Coating Formulation

EXAMPLE 6 Enteric Performance of Enteric Film Coating Using Low Viscosity Modified Starch

[0037] An aqueous enteric coating solution was prepared according to the formulation in Table 8 and resulted in a solution with a viscosity of 907 cps (907 mPa.s). PURE-COTE B792 is a modified food starch specifically designed to produce translucent, flexible films. The formulation was coated onto size S22 fish oil capsules resulting in a 3% weight gain. The film coating is homogeneous and translucent with excellent adhesion. These coated capsules with 3% weight gain passed the 1 hour disintegration time in SGF at 37°C well. These results suggest that the combination of low viscosity alginate with low G content and a low viscosity modified vegetable starch when used with a plasticizer is capable of providing an enteric film coating with adequate enteric performance without the use of an antifoaming agent. Table 8. Softgel Capsule Enteric Film Coating Formulation

EXAMPLE 7 Enteric Performance of Enteric Film Coating Using Low Viscosity Modified Pea Starch

[0038] An aqueous enteric coating solution was prepared according to the formulation in Table 9. LyCoat RS780 is a modified pea starch specifically developed for aqueous film coating for immediate release. The formulation had a viscosity of 780 cps (780 mPa.s). Size S22 fish oil capsules were coated resulting in a 3% weight gain. The film coating was clear and homogeneous with excellent adhesion to the gelatin capsule surfaces. Six of these capsules were tested for the USP disintegration test. All 6 capsules passed 1 hour in SGF at 37°C. Similar results were obtained with the LyCoat RS 720 material with slightly higher formulation viscosity (867 cps (867 mPa.s)). These results suggest that the combination of low viscosity, low G alginate and a low viscosity modified pea starch when used with a plasticizer is capable of providing an enteric film coating with adequate enteric performance without the use of an antifoaming agent. Table 9. Gel Capsule Enteric Film Coating Formulation

COMPARATIVE EXAMPLE 8 Enteric Performance of an Enteric Coating Using Low-G Alginate without a Film-Forming Polymer

[0039] An aqueous coating solution was prepared according to the formulation in Table 10 and resulted in a formulation with 735 cps (735 mPa.s). S23 fish oil capsules were coated with the formulation resulting in a weight gain of 10.9%. In the standard USP disintegration test, 2/6 of the coated capsules ruptured after only 30 minutes and 4/6 of the coated capsules ruptured by 1 hour in SGF. Only 2/6 of the coated capsules remained intact at the 1 hour mark. These results suggest that low viscosity alginate with a low G content when used without a film forming polymer is incapable of providing an enteric film coating with adequate enteric performance. Careful formulation with other ingredients is required to achieve adequate functionalities. Table 10. Softgel Film Coating Formulation

COMPARATIVE EXAMPLE 9 Enteric Performance of an Enteric Coating Using High G Alginate without a Film-Forming Polymer

[0040] An aqueous coating solution was prepared according to the formulation in Table 10. Protonal GP1740 is a high G alginate used for specific gelling, thickening and stabilizing applications. The formulation was coated onto fish oil capsules resulting in a weight gain of 10.8%. After coating, the capsules were tested for enteric performance according to the method described above. After 15 minutes in SGF, 6/6 of the coated capsules were completely deflated. These results suggest that low viscosity high G alginate when used without a film forming polymer is incapable of providing an enteric film coating with adequate enteric performance. Table 11. Gel Capsule Enteric Film Coating Formulation

COMPARATIVE EXAMPLE 10 Enteric Performance of High G Alginate Polymer with Film-Forming Polymer

[0041] An aqueous coating solution was prepared according to the formulation in Table 12. High G alginate Protonal GP1740 was used in combination with film forming polymer HPMC E15. The formulation had a viscosity of 95 cps (9 mPa.s). The capsules, when coated, resulted in a weight gain of 11.6%, 6/6 of the coated capsules were completely fractured at 4 minutes in SGF. These results suggest that the combination of a high G low viscosity alginate and a film forming polymer is incapable of providing an enteric film coating with adequate enteric performance even at very thick coating. Table 12. Softgel Capsule Enteric Film Coating Formulation

COMPARATIVE EXAMPLE 11 Enteric Performance of High G Alginate Polymer Formulation

[0042] An aqueous coating solution was prepared according to the formulation in Table 13. High G alginate Manugel FB was used in combination with film-forming polymer HPMC E3LV. This formulation had a viscosity of 557 cps (557 mPa.s) and coated onto S19 gelatin gels (diameter 0.5” x 0.375” (1.27 cm x 0.95 cm)), resulting in a weight gain of 8.0%. Using the standard USP disintegration test, 6/6 of the coated capsules were completely emptied after 32 minutes in SGF. These results again suggest that the combination of a high G low viscosity alginate and a film-forming polymer is incapable of providing an enteric film coating with adequate enteric performance. Table 13. Gelatin Capsule Enteric Film Coating Formulation

Claims (13)

1. A water-soluble dry powder formulation useful for forming an aqueous enteric coating solution comprising an alginate and a film-forming polymer, wherein: the ratio of alginate to film-forming polymer is 10:1 to 1:3 by weight, the alginate is soluble in water at 10% solids and has an α-L-guloronic acid C-5 epimer (G) content of 20% to 40%, and a viscosity of 3 to 20 cps (3 mPa.s to 20 mPa.s) at 1% solids, measured at 20°C +/- 2°C using a Brookfield viscometer, spindle #62, the film-forming polymer is soluble in water at 10% solids, and whereby when the aqueous enteric coating solution comprising the water-soluble dry powder formulation is applied to an oral dosage form containing an ingredient active, the active ingredient is not released in a medium of 0.1 N HCl at about 37°C for up to one hour, and thereafter, about 90% or more of the active ingredient is released within two hours in a phosphate buffer medium having pH 7.2 at about 37°C. 2. Water-soluble dry powder formulation according to claim 1, characterized in that the alginate is in the form of a monovalent salt. 3. The water-soluble dry powder formulation of any one of claims 1 to 2, wherein the film-forming polymer is hydroxypropyl methyl cellulose (HPMC) or a modified vegetable starch having a viscosity of 100 to 1000 cps (100 to 1,000 mPa.s) at 10% solids, measured at 20°C +/- 2°C using a Brookfield viscometer, spindle #62. 4. The water-soluble dry powder formulation of any one of claims 1 to 3, wherein the film-forming polymer is modified cornstarch having a viscosity of 100 to 1000 cps (100 to 1,000 mPa.s) at 10% solids, measured at 20°C +/- 2°C using a Brookfield viscometer, spindle #62. 5. The water-soluble dry powder formulation of any one of claims 1 to 4, wherein the water-soluble dry powder formulation is substantially phthalate-free. 6. Water-soluble dry powder formulation according to any one of claims 1 to 5, characterized in that the alginate is sodium alginate or potassium alginate. 7. The water-soluble dry powder formulation of claims 1 to 6, wherein said enteric polymer comprises alginate and said film-forming polymer comprises at least one of a modified cornstarch or pea starch having a viscosity of 100 to 1000 cps (100 to 1,000 mPa.s) at 10% solids, measured at 20°C +/- 2°C using a Brookfield viscometer, spindle #62. 8. An aqueous enteric coating solution useful for forming an enteric film coating, comprising the water-soluble dry powder formulation as defined in any one of claims 1 to 7 dissolved in the aqueous enteric coating solution. 9. The aqueous enteric coating solution of claim 8, further comprising a plasticizer and, optionally, an anti-foaming agent, optionally the plasticizer is glycerin and, optionally, the anti-foaming agent is simethicone. 10. The aqueous enteric coating solution of any one of claims 8 to 9, wherein the aqueous enteric coating solution has a viscosity of 50 to 2,000 cps (50 to 2,000 mPa.s) and, optionally, a viscosity of 100 to 1,000 cps (100 to 1,000 mPa.s) or 100 to 800 cps (100 to 800 mPa.s), measured at 20oC +/- 2oC using a Brookfield viscometer, spindle #62. 11. An enteric film coated oral dosage form comprising an active ingredient, wherein: the oral dosage form is coated with the aqueous enteric coating solution as defined in any one of claims 8 to 10. 12. The enteric film-coated oral dosage form of claim 11, wherein: the active ingredient contained in the enteric film-coated oral dosage form is not released in the 0.1 N HCl medium at about 37°C for up to one hour, and thereafter, about 90% or more of the active ingredient is released within two hours in a phosphate buffer medium having pH 7.2 at about 37°C after six weeks of storage at 20 degrees Celsius. 13. The enteric film coated oral dosage form of any one of claims 11 to 12, wherein the oral dosage form is a tablet or a soft capsule, optionally the active ingredient is a pharmaceutical, nutraceutical, veterinary or food product, and optionally the active ingredient is fish oil, garlic, probiotic, lumbrokinase, S-adenosyl methionine (SAM-e), Nattokinase, a non-steroidal anti-inflammatory drug or iron supplement.