JP2012107058A - Pharmaceutical dosage form with multiple coatings - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutical composition which maintains the delivery of a therapeutic active agent to a desired site in the gastrointestinal tract by the administration to a human or low animal and a method of administering the same to the lower animal.SOLUTION: The pharmaceutical composition in a solid unit dosage form for peroral administration in a human or lower animal includes a. a safe and effective amount of a therapeutic active agent; b. an inner coating layer selected from the group consisting of poly(methacrylic acid, methyl methacrylate) 1:2; poly(methacrylic acid, methyl methacrylate) 1:1; and a mixture thereof, and c. an outer coating layer having an enteric polymer or film coating material and the inner coating layer is not the same as the outer coating layer, and when the inner coating layer is poly(methacrylic acid, methyl methacrylate) of 1:1, the outer coating layer is poly(methacrylic acid, methyl methacrylate) 1:2 or not the mixture of poly(methacrylic acid, methyl methacrylate) 1:1 and poly(methacrylic acid, methyl methacrylate) 1:2, and the inner coating layer and the outer coating layer do not include any therapeutic active agent.

Description

  The present invention relates to new unit dosage forms containing therapeutically active agents with improved durability against coating breakage during dispensing, manufacturing or packaging.

  Many prior art references teach the benefits of delivering therapeutic agents to the lower gastrointestinal tract, particularly the large intestine or colon. These references explain the difficulty of formulating dosage forms that achieve this delivery effect. For example, US Pat. Nos. 5,541,170 and 5,541,171, both issued July 30, 1996 to Rhodes et al. For the treatment of pharmacologically active substances, particularly the delivery of 5-aminosalicylic acid to the large intestine, which is described in US Pat. No. 5,686,105) describes the delivery of a therapeutically active agent to the colon comprising a coating system having at least one inner coating layer and one outer coating layer, the inner coating layer having a pH of about 5 to 5. An enteric polymer that begins to dissolve in an aqueous medium at about 6.3, and the outer coating layer is an enteric polymer that begins to dissolve in an aqueous medium at a pH of about 6.8 to 7.2. In US Pat. No. 5,171,580 issued December 15, 1992 to Iamartino et al., Active substances released into the lower gastrointestinal tract, the large intestine, and in particular the colon are described. A pharmaceutical comprising an active agent core coated with three protective layers having different solubilities is disclosed, which makes the therapeutic active substance more specific and reliable in the lower gastrointestinal tract, especially the colon. This provision is achieved by the benefit of having a selective effect on the colon in addition to the three layers of protective layers. Focusing on the delivery benefit of therapeutically active agents, these references include US Pat. No. 5,686,106, issued November 11, 1997 to Kelm et al. 1 to Kelm et al. U.S. Pat. No. 5,914,132 issued Jun. 22, 999; U.S. Pat. No. 4,914,132 issued U.S. Pat. No. 4,914,132 issued Mar. 20, 1990 to Davis et al. 910,021); Patent Document 8 (U.S. Pat. No. 4,432,966) issued to Zeitoun et al. On February 21, 1984; Okayama et al. On August 5, 1997 Issued US Pat. No. 5,654,004; US Pat. No. 5,900,252 issued May 4, 1999 to Calcanchi et al. (US Pat. No. 5,900,252); US Pat. No. 5,482,718 issued Jan. 9, 1996 to Shah et al. (US Pat. No. 5,482,718); US Pat. No. 5,482,718 issued May 31, 1994 to Jurgens et al. (US Pat. No. 5,316,7 No. 2); Patent Document 13 (European Patent No. 225,189) published on June 10, 1987 to Davies et al .; and Drug Development and Occupational Pharmacy of Khan et al. (Drug Development and Industrial Pharmacy) 26 (5), 549-554, (2000)).

US Pat. No. 5,541,170 US Pat. No. 5,541,171 US Pat. No. 5,686,105 US Pat. No. 5,171,580 US Pat. No. 5,686,106 US Pat. No. 5,914,132 US Pat. No. 4,910,021 U.S. Pat. No. 4,432,966 US Pat. No. 5,654,004 US Pat. No. 5,900,252 US Pat. No. 5,482,718 US Pat. No. 5,316,772 European Patent No. 225,189 US Pat. No. 4,412,992 US Pat. No. 4,552,899

Drug Development and Industrial Pharmacy) 26 (5), 549-54, (2000) Colonic Drug Absorption and Metabolism, by M. Mackay and E. Tomlinson, edited by P. R. Bieck, Marcel Dekker, Inc., New York, Basel, Hong Kong, 137-158 (1993) Remington's Pharmaceutical Sciences; Mack Publishing Co. (19th edition, 1995) Modern Pharmaceutics; Volume 7, Chapters 9 and 10, Banker & Rhodes (1979) Pharmaceutical Dosage Forms); Tablets (1981) Introduction to Pharmaceutical Dosage Forms; 2nd edition (1976)

  However, the above prior art references do not describe the problem or possibility of coating breakage that may occur during the preparation, manufacture, or packaging of oral unit dosage forms. If the coating breaks, the therapeutically active agent may not be reliably or stably delivered to the desired area of the gastrointestinal tract. These breaks may be related to premature cleavage or release of the unit dosage form. Indeed, coating failure can be particularly problematic in unit dosage forms that are larger or heavier than average as a result of using larger volumes or concentrations of therapeutically active agent.

  Thus, the present invention relates to solid unit dosage forms for oral administration of humans or lower animals that minimize the effects of coating breakage or negative effects, especially for large or heavy unit dosage forms. By reducing these negative effects, such compositions maintain desired site delivery of therapeutically active agents in the gastrointestinal tract.

The present invention relates to a pharmaceutical composition in solid unit dosage form for oral administration in humans or lower animals, the composition comprising:
a. A safe and effective amount of a therapeutically active substance;
b. An inner coating layer selected from the group consisting of poly (methacrylic acid, methyl methacrylate) 1: 2, poly (methacrylic acid, methyl methacrylate) 1: 1, and mixtures thereof; and c. An outer coating layer comprising an enteric polymer or film coating material;
Including
The inner coating layer is not the same as the outer coating layer; when the inner coating layer is poly (methacrylic acid, methyl methacrylate) 1: 1, the outer coating layer is poly (methacrylic acid, methyl methacrylate) 1: 2, or poly ( Not a mixture of methacrylic acid, methyl methacrylate) 1: 1 and poly (methacrylic acid, methyl methacrylate) 1: 2; the inner coating layer and the outer coating layer do not contain a therapeutically active substance.

In another embodiment, the invention relates to a solid unit dosage form pharmaceutical composition for oral administration in humans or lower animals, the pharmaceutical composition comprising:
a. A safe and effective amount of a therapeutically active substance;
b. An inner coating layer comprising poly (methacrylic acid, methyl methacrylate) 1: 2; and c. An outer coating layer comprising an enteric polymer or film coating material;
Including
The inner coating layer is not the same as the outer coating layer. The invention further relates to a method of maintaining the desired site delivery of a therapeutically active agent by reducing the effects of coating breakage in the gastrointestinal tract through administration of the above composition to a human or lower animal.

  As used herein, the term “safe and effective amount” is sufficient to cause a markedly good change in treatment status within the scope of appropriate medical wisdom, but does not Means an amount of the therapeutically active substance or other component of the composition that is small enough to avoid (with a significant benefit / risk). The safe and effective amount of the therapeutically active substance or other component of the composition is selected based on the particular treatment condition, the age and physical condition of the patient being treated, the extent of the condition, the duration of treatment, the nature of the current treatment. Depends on the active agent and factors.

(Therapeutic active substance)
The methods and compositions of the present invention comprise a safe and effective amount of a therapeutically active substance. In certain embodiments, therapeutically active agents suitable for incorporation into the dosage forms of the invention are active agents that have a therapeutic benefit in the treatment of the colon. These active agents include therapeutic active agents useful in the treatment of colonic diseases, such as constipation, diarrhea, irritable bowel syndrome (IBS), Crohn's disease, colitis, ulcerative colon Inflammation, cancer, idiopathic proctitis, infections that do not require and undesirable systemic absorption of therapeutically active agents, and other colon or rectal diseases or abnormalities. These therapeutic active agents include active substances for the treatment of constipation such as picosulfate and sennaside and laxatives, antidiarrheals such as loperamide, salicylates, indomethacin, ibuprofen, flurbiprofen, naproxen, piroxicam 5-amino US Pat. No. 4,412,992 issued on November 1, 1983 to Chan, a non-steroidal anti-inflammatory drug such as salicylic acid (or pharmaceutically acceptable salts or esters thereof). Balsalazide and its dosage form as disclosed in US Pat. No. 4,552,899, issued November 12, 1985 to Sunshine et al. NSAIDS, hydrocortisone, prednisone, prednisolone, prephosphate Steroids such as nizolone, sodium prednisolone metasulfobenzoate, sodium prednisolone phosphate, beclomethasone dipropionate and beclomethasone valerate, glucocorticoids such as dextramethazone, antibacterial or antiparasitic agents (especially methotrexate) Effective anaerobic microorganisms), 5-aminosalicyl compounds, 4-aminosalicyl compounds, sulfasalazine, benzalazine, erythromycin, chloroquine, iodochlorhydroxyquine, diiodohydroxyquine, neomycin and tetracycline, cyclosporine Gastrointestinal stimulants and exercise promoters such as immunosuppressive agents such as A, chemotherapeutic agents for cancer treatment, cisapride, mint oil, and other futuristic essential oils, excessive bile such as cholestyramine Active substances that remove sap acid are included. The above references are hereby incorporated in their entirety by reference.

  Certain therapeutically active agents, particularly peptides and proteins, undergo luminal degradation in the stomach and small intestine. The colon may be a preferred site of absorption for such compounds because of low luminal enzyme activity in the colon. Absorption and Metabolism of Colonic Drugs (Non-Patent Document 2 (Colonic Drug Absorption and Metabolism, M. Mackay and E. Tomlinson, edited by PR Bieck, Marcel Dekker, Inc., New York, Basel, Hong Kong, 137-158 (1993)) Peptides and proteins that can exhibit improved systemic biological benefits when released in the colon include calcitonin, insulin, and human growth hormone, in some cases, peptides or proteins May be formulated with a system that enhances macromolecule absorption (colon drug absorption and metabolism (Colonic Drug Absorption and Metabolism, by M. Mackay and E. Tomlinson, edited by PR Bieck, Marcel Dekker, Inc., New York, Basel, Hong Kong, 137-158, (1993))).

The therapeutically active substance is present in the solid dosage form in a suitable unit dose. These doses will be known to those skilled in the art. In certain embodiments, the active agent is 5-aminosalicylic acid or a pharmaceutically acceptable salt or ester thereof in a dosage range of about 400 mg to about 1.5 g / tablet, and in another embodiment, a dosage range of about 700 mg / tablet. ~ 900 mg / tablet.
The therapeutically active agent is incorporated into one of the substrates described herein in a manner consistent with the physicochemical properties of the drug and its pharmacodynamics using techniques known to those skilled in the art. There is.

(Internal and external coating layers)
In certain embodiments, the coating layer of the present invention does not include any of the therapeutically active substances of the present invention. Further, as used herein, “coating layer” means complete inclusion or coating of the entire solid unit dosage form (coated microcrystalline spheres, coated pellets, coated with therapeutic active agent) No globules, coated microparticles or particles, or coated granules).

(Inner coating layer)
The inner coating layer is selected from the group consisting of poly (methacrylic acid, methyl methacrylate) 1: 2, poly (methacrylic acid, methyl methacrylate) 1: 1, and mixtures thereof. In general, the inner coating layer is selected based on the preferred delivery site desired and is applied to the core of the unit dosage form to obtain a minimum coating thickness of about 20 μm to about 120 μm. Although the coating thickness depends on the actual size of the unit dosage form, in certain embodiments, the minimum coating thickness of the inner coating layer is from about 20 μm to about 50 μm.

  In some embodiments, the inner coating layer is the same as poly (methacrylic acid, methyl methacrylate) 1: 2 (Eudragit® S), or Eudragit® S in an aqueous medium. Includes other enteric polymer materials with pH release characteristics. Eudragit (R) S from Rohm Tech is derived from methacrylic acid and methyl methacrylate having an average molecular weight of about 135,000 and a ratio of free carboxyl groups to ester groups of about 1: 2. Anionic copolymer. In certain embodiments, the inner coating layer is any other polymer that has the same aqueous pH release properties as Eudragit® S.

(External coating layer)
The outer coating layer includes an enteric polymer or film coating material, and the outer coating layer is different from the inner coating layer. Generally, when the inner coating layer is poly (methacrylic acid, methyl methacrylate) 1: 1 (Eudragit® L), the outer coating layer is poly (methacrylic acid, methyl methacrylate) 1: 2 (Eudra Not Eudragit® S) or a mixture of poly (methacrylic acid, methyl methacrylate) 1: 1 and poly (methacrylic acid, methyl methacrylate) 1: 2. The outer coating material can be any coating material that protects the inner coating layer from shipping damage and is dissolved or removed in the gastrointestinal tract prior to the inner coating layer. The outer coating layer is a single layer coating or a multilayer coating of an enteric polymer material or a film coating material. In another embodiment, the unit dosage form has a single outer coating layer. In yet another embodiment, the outer coating layer is an anionic copolymer. In certain embodiments, the outer coating cannot comprise an enteric polymer or mixture thereof having the same release pH as Eudragit® S in an aqueous medium. When the inner coating layer is poly (methacrylic acid, methyl methacrylate) 1: 2, poly (methacrylic acid, methyl methacrylate) 1: 2 is mixed with another enteric polymer or film coating material and the release pH of the mixture Is lower than the release pH of poly (methacrylic acid, methyl methacrylate) 1: 2 (Eudragit® S) alone in an aqueous medium, the outer coating layer is poly (methacrylic acid, methyl methacrylate) 1: 2. (Eudragit (R) S).

  In another embodiment, the outer coating layer is an enteric polymer material that begins to dissolve in an aqueous medium having a pH of less than about 7, and in yet another embodiment, the enteric polymer that begins to dissolve in an aqueous medium having a pH of less than about 6.8. It is a material. Generally, the outer coating layer is applied to the unit dosage form core to obtain a minimum thickness of about 10 μm to about 200 μm, and in another embodiment the outer coating layer is about 30 μm to about 150 μm.

  In certain embodiments, the outer coating layer comprises a film coating, a cellulose derivative, cellulose ether, methyl cellulose, ethyl cellulose, carboxymethyl cellulose, carboxymethyl ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, low viscosity hydroxypropyl cellulose, low viscosity hydroxy Wax or waxy substances such as propylmethylcellulose, carnauba wax, aliphatic alcohol, hydrogenated vegetable oil, zein, shellac, sucrose, gum arabic, polyethylene glycol, polyvinylpyrrolidone, gelatin, sodium alginate, dextrin, psyllium husk powder, polymethacrylate, shade Ionic polymethacrylate, poly (methacrylic acid, methyl (Crylate) 1: 1, poly (methacrylic acid, methyl methacrylate) 1: 2 and poly (methacrylic acid, methyl methacrylate) 1: 1 mixture, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate (HPMCP) , Cellulose propionate phthalate, cellulose acetate maleate, polyvinyl alcohol phthalate, hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropylmethylcellulose hexahydrophthalate, polyvinyl acetate phthalate, poly (methacrylic acid, ethyl acrylate) 1: 1, And selected from the group consisting of compatible mixtures thereof.

  In another embodiment, the outer coating layer comprises a cellulose derivative, cellulose ether, methyl cellulose, ethyl cellulose, carboxymethyl cellulose, carboxymethyl ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, low viscosity hydroxypropyl cellulose, low viscosity hydroxypropyl methyl cellulose. , Fatty alcohol, hydrogenated vegetable oil, zein, shellac, sucrose, gum arabic, polyethylene glycol, polyvinylpyrrolidone, gelatin, sodium alginate, dextrin, psyllium husk powder, polymethacrylate, anionic polymethacrylate, poly (methacrylic acid, methyl methacrylate ) 1: 1, poly (methacrylic acid, methyl methacrylate) G) A mixture of 1: 2 and poly (methacrylic acid, methyl methacrylate) 1: 1, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose propionate phthalate, cellulose acetate maleate, From the group consisting of polyvinyl alcohol phthalate, hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropylmethylcellulose hexahydrophthalate, polyvinyl acetate phthalate, poly (methacrylic acid, ethyl acrylate) 1: 1, and compatible mixtures thereof. Selected.

  In yet another embodiment, the outer coating layer comprises anionic polymethacrylate, poly (methacrylic acid, methyl methacrylate) 1: 1, poly (methacrylic acid, methyl methacrylate) 1: 2 and poly (methacrylic acid, methyl methacrylate). Mixture with 1: 1, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose propionate phthalate, cellulose acetate maleate, polyvinyl alcohol phthalate, hydroxypropyl methylcellulose acetate succinate (HPMCAS) , Hydroxypropylmethylcellulose hexahydrophthalate, polyvinyl acetate phthalate, poly (methacrylic acid, ethyl acrylate) 1 1, and is selected from the group consisting of mixtures of these compatible.

  In another embodiment, the outer coating layer comprises poly (methacrylic acid, methyl methacrylate) 1: 1 (Eudragit® L) and poly (methacrylic acid, methyl methacrylate) 1: 2 (eudragit ( Eudragit) (R) S), the mixing ratio of about 1:10 to about 1:10, preferably about 1: 5 to about 1: 3, more preferably about 2: 3. It is. The coating thickness depends on the actual size of the unit dosage form, but in some embodiments the minimum coating thickness of the outer coating layer is about 10 to about 50 μm, and in another embodiment about 20 to about 40 μm.

  In another embodiment, the outer coating layer is a single layer coating of an enteric polymer that begins to dissolve in an aqueous medium having a pH of about 5 to about 6.3, and in yet another embodiment a pH of about 5 to about 6, In an embodiment of the present invention is a single layer coating of an enteric polymer that begins to dissolve in an aqueous medium having a pH of about 5 to about 5.5.

  In certain embodiments, the function of the outer coating layer is to prevent or minimize breakage of the inner coating layer during formulation, manufacture, and packaging, and the function of the inner coating layer is the therapeutically active substance in the gastrointestinal tract. Maintaining the release to the desired site. For example, when the inner coating is poly (methacrylic acid, methyl methacrylate) 1: 2 (Eudragit® S), US Pat. Nos. 5,541,170 and 5 , 541, 171 (Rhodes et al.), Etc., maintain the desired release site. These patents are hereby incorporated in their entirety by reference.

In some embodiments, the total coating thickness (sum of the inner and outer coating layers) is from about 5 mg / cm ² to about 40 mg / cm ² , and in another embodiment from about 10 mg / cm ² to about 15 mg / cm ² . .

Specific examples of the outer coating layer are as follows.
Rohm Tech's Eudragit® L is derived from methacrylic acid and methyl methacrylate having an average molecular weight of about 135,000 and a ratio of free carboxyl groups to ester groups of about 1: 1. An anionic copolymer;
Eudragit® L30D is derived from a dispersion of aqueous acrylic resin, ie, methacrylic acid and ethyl acrylate having an average molecular weight of about 250,000 and a free carboxyl to ester group ratio of about 1: 1. An anionic copolymer (supplied as an aqueous dispersion with 30% w / w dry lacquer material);
Eudragit® L100-55 is an anionic copolymer derived from methacrylic acid and ethyl acrylate having an average molecular weight of about 100,000 or more and a ratio of free carboxyl groups to ester groups of about 1: 1. is there;
Cellulose acetate phthalate (CAP®) is available from Eastman Chemical;
Cellulose acetate trimellitate (CAT®) is available from Eastman Chemical;
Hydroxypropyl methylcellulose phthalate (USP / NF type 220824) HPMCP50® and (USP / NF type 2000073) HPMCP55® are available from Shin Etsu Chemical;
Polyvinyl acetate phthalate (PVAP®) is available from Colorcon;
Hydroxypropyl methylcellulose acetate succinate (HPMCAS®) is from Shin Etsu Chemical; hydroxypropylcellulose (Klucel®).

  In order to increase the elasticity of the coating material, the coating material of the present invention preferably also contains a plasticizer. Suitable plasticizers include polyethylene glycol, propylene glycol, 1,2-propylene glycol, dibutyl phthalate, diethyl phthalate, tributyl citrate, tributyrin, butyl phthalyl butyl glycolate (Monsanto, St. MO). Louis, Missouri) Sanicizer (R) B-16), triacetin, castor oil, and citrate; in another embodiment, the plasticizer is dibutyl phthalate, tributyl citrate, or Triethyl citrate. The content of these plasticizers is such that the coating process is facilitated and a uniform coating film with better physical stability can be obtained. Generally, the coating material comprises from about 0% to about 50%, preferably from about 2% to about 25%, more preferably from about 10% to about 20% plasticizer by weight of the enteric polymer. In addition, the coating material can also include inert solid particulates to facilitate the coating process. Preferred inert solid particulates include talc and titanium dioxide.

  Any plasticizer, any inert solid particulates, and their concentrations, the type of coating formulation (solvent, aqueous ammonia solution, or aqueous dispersion), and the method are specific to the particular one used according to criteria known to those skilled in the art It is selected based on the enteric polymer or film coating and the type of dosage form used. The solvent used for the coating layer can be an organic solvent or an aqueous solvent. In some embodiments, an aqueous dispersion of coating material is used to obtain the coating layer.

(Dosage form and production method thereof)
Solid unit dosage forms contain a safe and effective amount of the therapeutically active substance. The term “solid unit dosage form” means any dosage form that is preferably not liquid but intended to be swallowed and has a well-defined form to be coated. The solid unit dosage form can also be selected from the group consisting of hard capsules, soft capsules, or compressed tablets. In certain embodiments, the solid dosage form of the present invention is selected from the group consisting of soft gelatin capsules of any size or shape, hard gelatin capsules, and compressed tablets. In certain embodiments, the unit dosage form of the present invention comprises a unit dosage form having a total weight of about 550 mg to about 1.5 g, in another embodiment the total weight is about 600 mg to about 1.2 g, yet another embodiment. In a unit dosage form of about 750 mg to about 1 g in total weight.

In certain embodiments, the unit dosage form is a spherical or elliptical soft elastic gelatin capsule. Soft elastic gelatin capsules are filled with a therapeutically active substance suspended in a suitable dispersion medium compatible with soft gelatin capsules.
In yet another embodiment, the unit dosage form is a hard capsule (ie, a hard capsule made of starch or gelatin), such as from Capsulgel (Greenwood, SC). Starch capsules such as Capill®. The capsule has a major axis length of less than about 10 mm and no more than about 1.5 times the minor axis diameter of the capsule. Capsules can be filled with a solid therapeutic active as described above, or with a therapeutic active dissolved or suspended in a suitable dispersion medium compatible with the capsule wall.
In another embodiment, the unit dosage form is a spherical or oval compressed tablet. Tablets contain the solid therapeutic active and are compressed using conventional equipment and methods.

  In addition to the therapeutically active substance, the compositions of the present invention generally also include a pharmaceutically acceptable excipient. As used herein, the term “excipient” means one or more compatible solid or liquid filling diluents or capsule filling materials suitable for administration to a patient. As used herein, the term “compatible” means that there is no interaction that substantially reduces the pharmaceutical effectiveness of the composition under normal use conditions, and that the components of the composition are active substance and It means that they can be mixed with each other. A pharmaceutically acceptable excipient should, of course, be sufficiently pure, sufficiently low in toxicity and suitable for administration to a treated patient. Excipients facilitate the incorporation of the therapeutically active substance into the dosage form, moderate the release of the therapeutically active substance from the dosage form, stabilize the therapeutically active substance, or absorb the therapeutically active substance. It can function to enhance. Excipients must be safe at the concentrations used in the formulation for the intended purpose. The formulation of the therapeutically active substance and excipients is selected according to criteria known to those skilled in the art to achieve the desired release rate, stability, absorbability and facilitate the manufacture of dosage forms.

  Examples of pharmaceutically acceptable excipients or components thereof include sugars such as lactose, glucose, and sucrose; from about 1% to about 8% by weight, in another embodiment from about 2% to about 4% by weight. % Corn starch, potato starch, and starch such as sodium glycolate starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate; powdered tragacanth; malt; gelatin; talc; stearic acid and magnesium stearate Solid lubricants; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; arginic acid; Emulsifiers such as Tweens®; wetting agents such as sodium lauryl sulfate; colorants; fragrances; excipients; tableting tablets; stabilizers; antioxidants; preservatives; Isotonic saline; and phosphate buffer. The excipient is Remington's Pharmaceutical Sciences (Remington's Pharmaceutical Sciences; Mack Publishing Co. (19th Edition, 1995)); Modern Pharmaceutical Sciences (Modern Pharmaceutics; Vol. 7, Chapters 9 and 10, Banker & Rhodes (1979)); Pharmaceutical dosage forms of Lieberman et al. (Pharmaceutical Dosage Forms); Tablets (1981) And Ansel's introduction to pharmaceutical dosage forms (Introduction to Pharmaceutical Dosage Forms; 2nd edition (1976)). , And secondary considerations such as storability, which are not important for the purposes of the present invention and can be readily determined by one skilled in the art.

  In certain embodiments, the dosage forms of the present invention prior to coating with a coating layer are all the same size. If the size is the same, the coating thickness can be made uniform, and the elution of the coating layer can be made more constant.

The enteric polymer is generally applied to the unit dosage form as a solution in an organic or aqueous solvent. The solvent used as the dispersion medium is usually water, methylene chloride, ethanol, methanol, isopropyl alcohol, acetone, ethyl acetate, and combinations thereof. The solvent is selected primarily based on polymer solubility, ease of evaporation, and solution viscosity.
Certain polymers can also be used as aqueous systems. These polymers include Eudragit® L30D (methacrylic acid-ethyl acrylate ester copolymer commercially available from Rohm-Haas GmBH (West Germany)); Aquateric ( Registered trademark (a product containing cellulose acetate phthalate commercially available from FMC Corporation); and Coateric® (commercially available from Colorcon, Inc., West Point, Pa.). Polyvinyl acetate phthalate base product). Unlike organic solvents, these aqueous systems can be prepared at high concentrations without increasing viscosity. Also, these aqueous systems do not cause problems associated with organic systems such as flammability and toxicity of residual solvents in dosage forms.

  Coating can be performed by methods known to those skilled in the art, such as, for example, fluid bed apparatus, perforated dishes, standard pharmaceutical dishes, compression coating, use of continuous or short-term spray methods, or dipping methods. For example, the plasticized dispersion of the coating polymer can be applied to the core tablet containing the therapeutically active agent by spraying using any suitable spray device known in the art. In certain embodiments, the solid unit dosage form is coated by a continuous spray process. In certain embodiments, after the inner coating layer, the outer coating layer is applied before the inner coating layer is dried or cured. In another embodiment, the outer coating layer is applied immediately (eg, within a few seconds) after application of the inner coating layer. If a glossy finish coat is desired in the solid dosage form of the present invention, a small amount of polyethylene glycol can be applied to the final dosage form.

  The following examples illustrate typical formulations of the compositions of the present invention, but are not limited thereto.

Example 1
Wet granules of 5-ASA (active ingredient), lactose, and povidone are mixed with talc, magnesium stearate, sodium starch glycolate, and colloidal silicon dioxide. The mixture is compressed into about 1034 mg tablets containing 800 mg of active ingredient on a standard pharmaceutical rotary tablet press.

First, a portion of the pigment-free coating formulation is poured onto the core tablet, and then the tablet is sprayed with a coating so that the dried coating is 9.2 mg / cm ² (about 62 microns). An inner coating layer of (EUDRAGIT) ® S is applied. The coating suspension sprayed onto the tablets is based on isopropyl alcohol and acetone containing about 62% EUDRAGIT® S by dry weight, with dibutyl phthalate as a temporary plasticizer.

The outer coating is applied immediately after application of the inner coating or after curing of the inner coating. The outer coating layer is sprayed onto the tablets so that the dried coating is 4.1 mg / cm ² (about 28 microns). This coating suspension contains about 61% EUDRAGIT® S and L in a ratio of 3: 2 by dry weight. This suspension is based on isopropyl alcohol and acetone containing dibutyl phthalate as a temporary plasticizer.

(Example 2)
Wet granules of 5-ASA (active ingredient), lactose, and povidone are mixed with talc, magnesium stearate, sodium starch glycolate, and colloidal silicon dioxide. The mixture is compressed into about 1570 mg tablets containing 1200 mg of active ingredient on a standard pharmaceutical rotary tablet press.

First, a portion of the pigment-free coating formulation is poured onto the core tablet, and then the tablet is sprayed with a coating so that the dried coating is 8.8 mg / cm ² (about 60 microns). Apply an inner layer of a mixture of (EUDRAGIT) ® S and L. The coating suspension sprayed onto the tablets comprises isopropyl alcohol containing about 61% EUDRAGIT® S and L in a dry weight ratio of 3: 2 with dibutyl phthalate as a temporary plasticizer. Based on acetone.

The outer coating is applied immediately after application of the inner coating or after curing of the inner coating. The outer coating layer is sprayed onto the tablets so that the dried coating is 11.9 mg / cm ² (about 80 microns). This suspension contains about 38% EUDRAGIT® L by dry weight and is based on isopropyl alcohol and acetone containing triethyl citrate as a temporary plasticizer.

(Example 3)
Wet granules of 5-ASA (active ingredient), lactose, and povidone are mixed with talc, magnesium stearate, sodium starch glycolate, and colloidal silicon dioxide. The mixture is compressed into about 690 mg tablets containing 500 mg of active ingredient on a standard pharmaceutical rotary tablet press.

First, a portion of the pigment-free coating formulation is poured onto the core tablet, and then the tablet is sprayed with a coating so that the dried coating is 15.6 mg / cm ² (about 105 microns). An inner coating layer of (EUDRAGIT) ® S is applied. The coating suspension sprayed onto the tablets is based on isopropyl alcohol and acetone containing about 62% EUDRAGIT® S by dry weight, with dibutyl phthalate as a temporary plasticizer.

  The outer coating is applied immediately after application of the inner coating or after curing of the inner coating. An outer coating layer of hydroxypropylmethylcellulose is applied according to the following formulation so that the coating thickness after drying is about 100 microns.

¹ドリクレア（Dri-Klear）は、ヒドロキシプロピルメチルセルロース、ポリエチレングリコール、ヒドロキシプロピルセルロース、及び二酸化珪素の混合物であり、ＣＨＲハンセン（CHR Hansen）により製造されている。
²白色彩度トーン（White Chroma-Tone）は、二酸化チタン及びヒドロキシプロピルメチルセルロースの混合物であり、ＣＨＲハンセン（CHR Hansen）により製造されている。

¹ Dri-Klear is a mixture of hydroxypropylmethylcellulose, polyethylene glycol, hydroxypropylcellulose, and silicon dioxide, manufactured by CHR Hansen.
² White Chroma-Tone is a mixture of titanium dioxide and hydroxypropyl methylcellulose, manufactured by CHR Hansen.

Example 4
The core tablet is manufactured with the following formulation.

次の処方のコーティングをスプレーして、約２０ミクロンのユードラジット（EUDRAGIT）（登録商標）Ｓの内部コーティング層をコア錠剤に適用する。

A coating of the following formulation is sprayed to apply an inner coating layer of about 20 microns EUDRAGIT® S to the core tablet.

外部コーティング層をコア錠剤と内部コーティング層に適用する。乾燥後のコーティング厚が約１５０ミクロンになるように、ヒドロキシプロピルメチルセルロースの外部コーティング層を次の処方に従って適用する。

An outer coating layer is applied to the core tablet and the inner coating layer. An outer coating layer of hydroxypropylmethylcellulose is applied according to the following formulation so that the coating thickness after drying is about 150 microns.

³ドリクレア（Dri-Klear）は、ヒドロキシプロピルメチルセルロース、ポリエチレングリコール、ヒドロキシプロピルセルロース、及び二酸化珪素の混合物であり、ＣＨＲハンセン（CHR Hansen）により製造されている。
⁴白色彩度トーン（White Chroma-Tone）は、二酸化チタン及びヒドロキシプロピルメチルセルロースの混合物であり、ＣＨＲハンセン（CHR Hansen）により製造されている。

³ Dri-Klear is a mixture of hydroxypropylmethylcellulose, polyethylene glycol, hydroxypropylcellulose, and silicon dioxide, manufactured by CHR Hansen.
⁴ White Chroma-Tone is a mixture of titanium dioxide and hydroxypropyl methylcellulose, manufactured by CHR Hansen.

(Example 5)
To the core tablet described in Example 4, an inner layer of an aqueous coating of EUDRAGIT® L30D-55 is applied according to the following formulation so that the coating after drying is about 70 microns.

次に、乾燥後のコーティング厚が約５０ミクロンになるように、ヒドロキシプロピルメチルセルロースの外部コーティング層を次の処方に従って適用する。

Next, an outer coating layer of hydroxypropylmethylcellulose is applied according to the following formulation such that the coating thickness after drying is about 50 microns.

⁵ドリクレア（Dri-Klear）は、ヒドロキシプロピルメチルセルロース、ポリエチレングリコール、ヒドロキシプロピルセルロース、及び二酸化珪素の混合物であり、ＣＨＲハンセン（CHR Hansen）により製造されている。
⁶白色彩度トーン（White Chroma-Tone）は、二酸化チタン及びヒドロキシプロピルメチルセルロースの混合物であり、ＣＨＲハンセン（CHR Hansen）により製造されている。

⁵ Dri-Klear is a mixture of hydroxypropylmethylcellulose, polyethylene glycol, hydroxypropylcellulose, and silicon dioxide, manufactured by CHR Hansen.
⁶ White Chroma-Tone is a mixture of titanium dioxide and hydroxypropyl methylcellulose, manufactured by CHR Hansen.

(Example 6)
The following formulation is filled into soft or hard gelatin capsules.

次に、カプセルをコーティングする。乾燥後のコーティング厚が約１００ミクロンになるように、次の処方のコーティングをスプレーして、ユードラジット（EUDRAGIT）（登録商標）Ｓの内部コーティング層をカプセルに適用する。

Next, the capsule is coated. The coating of the following formulation is sprayed so that the coating thickness after drying is about 100 microns and an inner coating layer of EUDRAGIT® S is applied to the capsule.

内部コーティングの適用後、次の処方のコーティングをスプレーして、ユードラジット（EUDRAGIT）（登録商標）Ｓ及びＬの混合物の割合が２：３の外部コーティング層を約２０ミクロンになるように錠剤に適用する。

After applying the inner coating, spray the coating of the following formulation into the tablets so that the outer coating layer with a mixture ratio of EUDRAGIT® S and L of 2: 3 is about 20 microns. Apply.

本発明の特定の実施形態を記載したが、本発明の趣旨及び範囲から逸脱することなく、本発明の様々な変更及び修正が可能であることは、当業者には明らかである。本発明の範囲内にあるこのようなすべての修正形態については、添付の特許請求の範囲で扱うものとする。

While particular embodiments of the present invention have been described, it will be apparent to those skilled in the art that various changes and modifications can be made to the present invention without departing from the spirit and scope of the invention. All such modifications that come within the scope of the invention are intended to be covered by the appended claims.

Claims (14)

A pharmaceutical composition in solid unit dosage form for oral administration of humans or lower animals, said pharmaceutical composition comprising:
a. A safe and effective amount of a therapeutically active substance;
b. An inner coating layer selected from the group consisting of poly (methacrylic acid, methyl methacrylate) 1: 2, poly (methacrylic acid, methyl methacrylate) 1: 1, and mixtures thereof; and c. An outer coating layer comprising an enteric polymer or film coating material applied directly to the inner coating layer and starting to dissolve in an aqueous medium at a pH of less than about 7;
Including
The inner coating layer is not the same as the outer coating layer;
When the inner coating layer is poly (methacrylic acid, methyl methacrylate) 1: 1, the outer coating layer is poly (methacrylic acid, methyl methacrylate) 1: 2, or poly (methacrylic acid, methyl methacrylate) 1: 1 and poly (Not a mixture with (methacrylic acid, methyl methacrylate) 1: 2; and
A pharmaceutical composition wherein the inner coating layer and the outer coating layer do not contain a therapeutically active substance.   The composition of claim 1, wherein the inner coating layer is poly (methacrylic acid, methyl methacrylate) 1: 2. A pharmaceutical composition in a solid unit dosage form for oral administration of humans or lower animals, the pharmaceutical composition comprising:
a. A safe and effective amount of a therapeutically active substance;
b. An inner coating layer comprising poly (methacrylic acid, methyl methacrylate) 1: 2; and c. An outer coating layer comprising an enteric polymer or film coating material applied directly to the inner coating layer and starting to dissolve in an aqueous medium at a pH of less than about 7;
Including
A pharmaceutical composition wherein the inner coating layer is not the same as the outer coating layer.   The outer coating layer comprises polymethacrylate, anionic polymethacrylate, poly (methacrylic acid, methyl methacrylate) 1: 1, poly (methacrylic acid, methyl methacrylate) 1: 2 and poly (methacrylic acid, methyl methacrylate) 1: 1. An enteric polymer selected from the group consisting of a mixture of and a polyvinyl acetate phthalate, poly (methacrylic acid, ethyl acrylate) 1: 1, and compatible mixtures thereof; preferably poly (methacrylic acid, methyl The composition according to claim 1, which is a mixture of (methacrylate) 1: 2 and poly (methacrylic acid, methyl methacrylate) 1: 1.   The outer coating layer is composed of cellulose ether, methylcellulose, ethylcellulose, carboxymethylcellulose, carboxymethylethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, low viscosity hydroxypropylcellulose, low viscosity hydroxypropylmethylcellulose, wax, carnauba wax, aliphatic Alcohol, hydrogenated vegetable oil, zein, shellac, sucrose, gum arabic, polyethylene glycol, polyvinylpyrrolidone, gelatin, sodium alginate, dextrin, psyllium husk powder, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose Propio A film coating material selected from the group consisting of phthalate, cellulose acetate maleate, polyvinyl alcohol phthalate, hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropylmethylcellulose hexahydrophthalate, and compatible mixtures thereof. The composition according to claim 1 or 3.   The therapeutic active substance is laxative, antipruritic agent, non-steroidal anti-inflammatory agent, 5-aminosalicylic acid, glucocorticoid, antibacterial agent, immunosuppressive agent, chemotherapeutic agent or anticancer agent, peptide, protein, cardiovascular agent, The psychotropic drug, H2 blocker, anti-asthma drug, and antihistamine are selected from the group, preferably the therapeutically active substance is a non-steroidal anti-inflammatory drug according to any one of claims 1-5. Composition.   The composition according to claim 6, wherein the therapeutically active substance is 5-aminosalicylic acid.   8. The composition of claim 7, wherein the 5-aminosalicylic acid is present in an amount of about 700 mg to about 900 mg per solid unit dosage form. Total coating thickness the combined and the outer coating layer and the inner coating ^{layer, 5mg / cm 2 ~40mg / cm} 2, preferably from ^{10mg / cm 2 ~15mg / cm 2} , any one of claims 1 to 8 The composition according to one item.   10. The composition according to claim 1, wherein the outer coating layer has a minimum thickness of 10 μm to 200 μm, preferably 10 μm to 50 μm, more preferably 20 μm to 40 μm.   The composition according to any one of claims 1 to 10, wherein the total weight of the solid unit dosage form is 600 mg to 1200 mg.   12. The composition according to any one of claims 1 to 11, wherein the solid dosage form is a compressed tablet.   13. The solid dosage form is coated by a continuous spray process, and the outer coating layer is applied after the inner coating layer but before the inner coating layer is dried or cured. A composition according to 1.   A method for stably and reliably delivering and releasing a therapeutically active substance to a desired delivery site by orally administering the composition of any one of claims 1-13.