KR20000053326A - Pharmaceutical dosage form with multiple enteric polymer coatings for colonic delivery - Google Patents

Abstract

PURPOSE: A pharmaceutical composition in a unit dosage form for peroral administration in a human or lower animal, is provided which has a gastrointestinal tract comprising a small intestine and a colon with a lumen therethrough having an inlet to the colon from the small intestine CONSTITUTION: A present invention comprises: a) a safe and effective amount of a therapeutically active agent incorporated into or coated on the surface of a dosage form selected from the group consisting of a spherical substrate, an elliptical substrate, a hard capsule, or a compressed tablet, with a maximum diameter of about 3 mm to about 10 mm; and b) an enteric polymer coating material comprising at least one inner coating layer and one outer coating layer; wherein the dosage form has a smooth surface free from edges or sharp curves; the elliptical substrate and the hard capsule have a ratio of the long to short diameters of no greater than about 1.5; the therapeutically active agent is released at a point near the inlet to, or within the colon; each of the inner coating layer(s) is an enteric polymer that begins to dissolve in an aqueous media at a pH between about 5 to about 6.3; and the outer coating layer is an enteric polymer that begins to dissolve in an aqueous media at a pH between about 6.8 to about 7.2.

Description

PHARMACEUTICAL DOSAGE FORM WITH MULTIPLE ENTERIC POLYMER COATINGS FOR COLONIC DELIVERY}

The release of therapeutically active agents from orally administered formulations in the colon may include (1) infections that do not require or undesirable systemic absorption of constipation, irritable bowel syndrome (IBS), Crohn's disease, ulcerative colitis, cancer and therapeutic agents. Topical treatment of colon diseases such as; (2) systemic absorption of therapeutic agents such as peptides and proteins that undergo lumenal degradation in the stomach and small intestine; And (3) systemic absorption of the therapeutic agent required when the systemic concentration of the climax (ie, the plasma concentration of the climax from the oral formulation ingested at bedtime in the early morning just before waking up) and the pharmacological activity is significantly delayed from the time of oral administration. It is desirable in many situations, including. Release of the therapeutically active agent from the orally administered formulation into the colon requires that the release of the agent for local activity or systemic absorption is prohibited in the stomach or small intestine but must be allowed in the colon. This, in turn, requires that the formulation's design accept advantages over the features of the gastrointestinal tract, which indicate that the formulation has arrived in the colon compared to other sites of the gastrointestinal tract (M. Ashford and JT Fell, J. Drug Targeting). , 1994, 2: 241-258). Various features include the pH, ionic strength, appearance rate and bacterial content of the lumen contents at various anatomical sites of the gastrointestinal tract as well as the retention time of the pharmaceutical unit formulation therein (M. Ashford and JT Fell, J. Drug Targeting, 1994, 2: 241-258; SS Davis, J. Contr.Rel., 1985, 2: 27-38).

The residence time of the above pharmaceutical unit dosage forms can be particularly variable (M. Ashfold and J. T. Fell, J. Drug Targeting, 1994, 2: 241-258). However, the small intestine transit time of the pharmaceutical unit dosage form has proven to be relatively constant, on average about 3 hours (M. Ashfold and J. T. Fell, J. Drug Targeting, 1994, 2: 241-258). The residence time in the colon is usually longer than in other parts of the gastrointestinal tract, but the time in the various parts can be significantly variable (M. Ashfold and J. T. Fell, J. Drug Targeting, 1994, 2: 241-258).

The pH profile of the luminal contents of the gastrointestinal tract is also characterized and known to be relatively consistent (D. F. Evans, G. Pye, R. Bramley, A. G. Clark, and T. J. Dyson, Gut, 1988, 29: 1035-1041). The pH above may vary temporarily depending on the condition of the meal, but is generally below about pH 2. The pH of the small intestine gradually increases from about 5 to about 5.5 in the duodenum and about 7.2 at the distal end of the small intestine (ileum). At the junction of the zygote, the pH drops considerably to about 6.3 and increases very gradually to about 7 in the left or descending colon.

A prominent feature of the colon compared to other parts of the gastrointestinal tract is the presence of exogenous bacteria. They are capable of enzymatic catalysis that the host animal cannot.

In general, it has been recognized that formulations designed for release into the colon can use one of the following properties to indicate that the formulation has been reached in the colon compared to other sites of the gastrointestinal tract: (1) generally increasing gradually to the junction of the parliament; PH profile of the lumen contents; (2) relatively constant small intestine transit time of the pharmaceutical unit dosage form (offsets high variable gastric retention time); And (3) the presence of exogenous bacteria in the colon (M. Ashfold and J. T. Fell, J Drug Targeting, 1994, 2: 241-258).

Formulations using an increasingly pH profile of the lumen contents of the gastrointestinal tract as a design feature to indicate arrival in the colon typically use a membrane coating of an enteric polymer. These enteric polymers are next-ionic polymers that are insoluble in water and low pH but begin to elute at a pH of about 5. Commercially available enteric polymers begin to dissolve within a pH range of about 5-7.

An example using this kind of basis for designing a formulation for delivery to the colon teaches a formulation for delivery in the colon and in particular the colon, containing a core containing active coated with a coating of three protective layers of different solubility. US Patent No. 5,171,580 to Boehringer Ingelheim Italia, issued December 15, 1992, which is hereby incorporated by reference in its entirety. The inner layer is Eudragit® S with a coating thickness of about 40 to 120 microns, the middle coating layer is a swellable polymer with a coating thickness of about 40-120 microns and the outer layer is cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate , Polyvinyl acetate phthalate, hydroxyethyl cellulose phthalate, cellulose acetate tetrahydrophthalate or Eudragit® L. In the formulation of the present invention, only Eudragit® S is used as the outer layer.

In US Patent No. 4,910,021 to Scherer Corp., issued March 20, 1990, the composition teaches a targeted delivery system comprising hard or soft gelatin capsules containing an active ingredient such as insulin and an absorption enhancer. do. The capsule is coated with a film forming composition that is sufficiently soluble at a pH of 7 or higher so that the capsule can corrode or elute. The film forming composition is preferably a mixture of Eudragit® L, Eudragit® RS, and Eudragit® S in a specific proportion to provide solubility at a pH of 7 or higher.

US Patent No. 4,432,966 to Russel-UCLAF, issued February 21, 1984, contains a mixture of microcrystalline cellulose and lower alkyl ethers of cellulose film forming organic polymers such as ethyl cellulose. 1 coating layer and copolymer of cellulose acetylphthalate, hydroxypropyl methylcellulose phthalate, benzophenyl salicylate, cellulose acetosuccinate, styrene and maleic acid, formulated gelatin, salol, keratin, stearic acid, myristic acid, gluten , Compressed tablets having an activator coated with a second coating layer selected from acrylic acid and methacrylic acid resins, and copolymers of maleic acid and phthalic acid derivatives.

There are some difficulties with using pH as an indicator of colon arrival of the formulation. Although the pH of the lumen content gradually increases from above through the small intestine, the pH of the lumen content in the proximal portion of the colon is lower than the distal end of the small intestine. This is because in the colon, short-chain fatty acids produced by the action of exogenous bacteria are present. Thus, a given pH value does not distinguish the colon from several parts of the small intestine. Formulations designed to release a therapeutic agent at a pH near the colon may also release the therapeutic at a site of the small intestine adjacent to the zygotes whose pH is similar to the pH of the adjacent colon. Thus, the effectiveness of using enteric coatings to achieve intracolonal release has been questioned (M. Ashfold and JT Fell, J. Drug Targeting, 1994, 2: 241-258; M. Ashfold, JT Fell, D Attwood, and PJ Woodhead, Int. J. Pharm., 1993, 91: 241-245; M. Ashford, JT Fell, D. Attwood, HL Sharma, and PJ Woodhead, Int. J. Pharm., 1993, 95 : 193-199).

Although the pH of the lumen contents alone does not distinguish the colon from many other areas of the small intestine, the pH distinguishes the stomach from the small intestine and the colon. Enteric polymer coatings have been extensively used in the prior art to distinguish the stomach from the small intestine and to prevent release of the therapeutic until the formulation is empty. This use has confirmed the stability of these polymers over a long history, and many documents describe suitable methods for applying these polymers as coatings for formulations and the commercial utility of many suitable enteric polymers.

It has been recognized that formulations that delay release of therapeutic agents for periods corresponding to stomach and small intestine residence time will provide intracolonical delivery (S. S. Davis, J. Contr. Rel., 1985, 2: 27-28). This is basically based on a fairly constant residence time in the small intestine, and the additional use of an enteric polymer coating counteracts the variable gastric retention time by preventing activation of the time-based delay mechanism until the formulation reaches the small intestine. I guess. The proposed time delay mechanisms include slow dissolution of pH independent coatings (A. Gazzaniga, P. lamartino, G. Maffione, and ME Sangalli, Proceed. 6th Int. Conf. On Pharm. Techn. (Paris) 305-313, 1992 ), By osmotic pressure (F. Theeuwes, PL Wong, TL Burkoth, and DA Fox, in Colonic Drug Absorption and Metabolism, PR Bieck, ed., Marcel Dekker, Inc., New York, Basel, Hong Kong, 137-158 (1993)) or by physical swelling (R. Ishino, H. Yoshino, Y. Kirakawa, and K. Noda, Chem. Pharm. Bull., 1992, 40: 3036-3041) to activate the disintegration of the formulation. Controlled pH-independent permeation of water through and swelling and discharge of the plug by pH-independent hydration (IR Wilding, SS Davis, M. Bakhshaee, HNE Stevens, RA Sparrow, and J. Brennan, Pharm. Res. , 1992, 9: 654-657). This approach was not completely satisfactory for reasons of size, reproducibility of release time, complexity and cost.

Although the commercial use of enteric polymers has a long history and essentially supplements the variable gastric residence time, it has not been supported to use them to provide a delay in the release of a therapeutic based on the dissolution of the enteric polymer coating. . This is probably due to the change in enteric polymer dissolution, as a function of changing pH and the rate of contents of the lumen of the small intestine and colon. However, formulations using enteric polymers to achieve colon release based on the dissolution time of the enteric polymer coating have advantages in that the stability of these polymers has been demonstrated and is a commercially viable application method.

It is an object of the present invention to use a unique, multiple coating or multilayer enteric polymer as a means of delaying release of a therapeutic agent until the formulation reaches the proximal colon, thereby releasing the therapeutic agent from the unit dosage form in the colon.

Summary of the Invention

The present invention relates to a pharmaceutical composition of a unit dosage form for oral administration to a human or lower animal having a gastrointestinal tract comprising a colon and the small intestine having an inlet from the small intestine to the colon, and including:

a. A safe effective amount of a therapeutically active agent incorporated into or coated on a formulation selected from the group consisting of spherical substrates, elliptical substrates, hard capsules, or compressed tablets having a maximum diameter of about 3 mm to about 10 mm. ; And

b. An enteric polymer coating material comprising at least one inner coating layer and at least one outer coating layer;

Wherein the formulation has a smooth surface without edges or sharp curves; Elliptical substrates and hard capsules have a long diameter to short diameter ratio of less than about 1.5; The therapeutically active agent is released in the colon or at a point near the entrance of the colon; Each inner coating layer (s) is an enteric polymer that begins to dissolve in an aqueous medium at a pH of about 5 to about 6.3; The outer coating layer is an enteric polymer that begins to dissolve in the aqueous medium at a pH of about 6.8 to about 7.2.

Detailed description of the invention

The use of enteric polymers to delay release of the therapeutic agent from the pharmaceutical unit dosage form until the formulation reaches the colon has not been entirely successful. Reasons for not being successful include:

a. A decrease in the pH of the lumen contents of the proximal colon compared to the terminal small intestine (the intestine), which prevents the use of pH as a cognitive factor for colon transport as described above;

b. difficulty in designing enteric polymer coatings for unit dosage forms that will dissolve completely during the time the formulation remains in the small intestine due to changes in pH and the rate of the lumen contents of the small and small intestine; And

c. Thin spots in an enteric polymer coating that show edges and sharp curves in typical unit dosage forms that cause premature rupture of the enteric polymer coating and release of the therapeutic agent.

The formulations of the invention coated with an enteric polymer are designed to delay the release of the therapeutic agent for a time approximately corresponding to the retention time in the small intestine rather than using a given pH value as a recognition factor for colonic attainment. This eliminates the problems caused by decreased pH in the proximal colon compared to the ileum.

The inventors have found that the amount and type of enteric polymer required to delay the release of a therapeutic agent for a time approximately corresponding to the retention time in the small intestine can be determined by the following: 1. Size and pH of the formulation and of the aqueous medium Knowledge of the dissolution mode of the selected enteric polymer, such as a function of velocity, and 2. evaluation of the pH and apparent velocity of the lumen contents of successive anatomical sections of the small intestine and colon. Since final dissolution of the enteric coating is desired in the colon, the enteric polymer or polymers comprising the coating of the unit dosage form may be formulated such that the coating dissolves when the formulation is in the proximal portion of the colon, or at a maximum pH of about 6.3. Should be chosen and administered. If a single enteric polymer coating is used, the amount of enteric polymer required to achieve the necessary delay in release of the therapeutic agent is relatively higher and much higher than that found in the prior art (filed by Kelm and Manring on May 17, 1995). See also pending P & G patent application no. 5673). However, if a unique, multilayer enteric polymer coating layer is used, the total amount of enteric polymer coating required to release in the colon may be reduced. The outermost layer consists of an enteric polymer that begins to dissolve at a pH of about 6.8 to 7.2, in an amount such that this coating layer is completely dissolved in the distal portion of the small intestine (ileum). The inner coating layer or layers consist of an enteric polymer that begins to dissolve at pH about 5.0 to 6.3 in an amount such that complete dissolution substantially occurs in the proximal colon. Thus, the function of the outermost coating layer is to prevent the release of the therapeutic agent when the formulation moves from the gastrointestinal tract to the distal small intestine, and the function of the inner coating layer adds that the therapeutic agent releases until the formulation reaches the proximal colon. To delay.

In the formulations of the present invention, it is desirable to completely dissolve the enteric polymer coating prior to release of the therapeutic agent to confirm that the expected dissolution time for a given amount of enteric polymer coating corresponds to the time delayed release of the therapeutic agent. This requires a uniform enteric polymer film coating thickness throughout the formulation. Thin spots in the enteric polymer coating may appear over the edges and sharp curves of conventional formulations and cause premature rupture of the enteric polymer coating and release of the therapeutic agent. Therefore, the formulations of the present invention are spherical or elliptical in shape, having a nearly uniform particle size and a smooth surface that is essentially free of edges or sharp curves to facilitate the application of a uniform thickness of the enteric polymer coating in each unit dosage form. .

The present invention relates to a pharmaceutical composition of unit dosage form for oral administration to a human or lower animal having a gastrointestinal tract comprising a colon and the small intestine having an inlet from the small intestine to the colon, and including:

a. A therapeutically active agent incorporated into or coated on a formulation selected from the group consisting of spheres, oval substrates, hard capsules, or compressed tablets having a maximum diameter of about 3 mm to about 10 mm. Safe effective amount of;

b. An enteric polymer coating material containing at least one inner coating layer and at least one outer coating layer;

Wherein the formulation has a smooth surface without edges or sharp curves; Elliptical substrates and hard capsules have a long diameter to short diameter ratio of less than about 1.5; The therapeutically active agent is released in the colon or at a point near the inlet of the colon; Each inner coating layer (s) is an enteric polymer that begins to dissolve in an aqueous medium at a pH of about 5 to about 6.3; The outer coating layer is an enteric polymer that begins to dissolve in the aqueous medium at a pH of about 6.8 to about 7.2.

The formulations of the present invention are distinguished from controlled release (sustained release) compositions which slowly release the therapeutic agent over a long period of time and prolong the duration of the therapeutic action achieved by normal transportation. The formulation of the invention prevents release of the active agent until the formulation reaches the colon. Subsequent release rates of the therapeutic agent then vary from fast to slow depending on the pharmacokinetic requirements of the particular therapeutic agent.

Preferably, the enteric polymer coating material has one inner coating layer and one outer coating layer.

Therapeutically active agent

The methods and compositions of the present invention include a safe effective amount of a therapeutically active agent. As used herein, the term "safely effective amount" means an amount of therapeutically active agent that is high enough to provide significant positive relief of the condition to be treated, but low enough to avoid dangerous side effects within safe medical judgment ( Reasonable benefit / risk ratio). The safe effective amount of a therapeutically active agent will vary depending on factors such as each condition to be treated, the age and physiological condition of the patient to be treated, the severity of the condition, the duration of the treatment, the nature of the treatment involved, the drug selected and the like.

Therapeutic agents suitable for incorporation into the formulations of the invention are those that are released in the colon or those in which delayed release is therapeutically advantageous. These include therapeutic agents useful for the local treatment of colon diseases such as constipation, diarrhea, irritable syndrome (IBS), Crohn's disease, ulcerative colitis, cancer, and infections that do not require or undesirable systemic absorption. These include laxatives such as phycosulfate and senasides, antidiarrheal agents such as loperamide, nonsteroidal anti-inflammatory drugs such as 5-amino salicylic acid, glucocorticoids such as dextrametazone, antimicrobial agents, especially anaerobic microorganisms such as methotrexate. Effective antimicrobial agents, immunosuppressants such as cyclosporin A, and chemotherapeutic agents for cancer treatment.

Certain therapeutic agents, particularly peptides and proteins, undergo lumenous degradation in the stomach and small intestine. Because of the low lumenogenic activity in the colon, the colon may be a preferred site for absorption of these compounds (M. Mackay and E. Tomlinson, in Colonic Drug Absorption and Metabolism, PR Bieck, ed., Marcel Dekker, Inc., New). York, Basel, Hong Kong, 137-158 (1993). Peptides and proteins that may exhibit improved systemic bioavailability when released in the colon include calcitonin, insulin, and human growth hormone. In certain cases, the peptides and proteins can be formulated using systems that enhance the uptake of macromolecules (M. Mackay and E. Tomlinson, in Colonic Drug Absorption and Metabolism, PR Bieck, ed., Marcel Dekker, Inc.). , New York, Basel, Hong Kong, 137-158 (1993).

Colon release is also desirable for systemic absorption of therapeutic agents that require maximum systemic concentrations and pharmacological activity at significant delays from the time of oral administration (i.e., the maximum plasma concentration at dawn just before taking place from the oral formulation ingested at bedtime). . This is particularly advantageous for conditions such as asthma, arthritis, inflammation, coronary infarction, and angina pectoris susceptible to daytime rhythm (B. Lemmer, in Pulsatile Drug Delivery, R. Gumy, HE Junginger, and NA Pepas, eds, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 11-24 (1993)). Drugs that have been reported to change their effects daily in clinical studies include cardiovascular active agents such as beta-blockers (acebutolol, propranolol), calcium channel blockers (verapramyl), and ACE inhibitors (enalapril). , Anticancer agents such as cisplatin and duxorubicin, anti-asthmatic agents such as theophylline, psychotropic agents such as diazepam, H ₁ -antihistamines such as terfenadine, nonsteroidal anti-inflammatory agents such as flurbiprofen, naproxen, and pyroxicam, And H ₂ -blockers such as cimetidine and ranitidine.

A therapeutically active medicament can be applied to or on the surface of one of several substrates described herein in a manner consistent with the physicochemical properties of the medicament and its pharmacokinetics using techniques known to those skilled in the art. Can be incorporated. The rate of release of a therapeutically active agent in the colon depends on the manner of incorporation of the therapeutically active agent and the nature and concentration of any excipient. The release rate should be such that the therapeutic activity of the agent is maximized.

As used herein, "excipient" means any ingredient that is admixed with or incorporated together with a therapeutically active agent on or within the substrate. Excipients facilitate the incorporation of the therapeutically active agent into or on the surface of the substrate, control the release of the therapeutically active agent from the substrate, stabilize the therapeutically active agent, or It can act to enhance the absorption of the active drug. Excipients must be compatible with the safe and therapeutically active agents for their intended use at the concentrations used in the formulation. Formulations of therapeutically active agents and excipients are selected according to criteria already known to those skilled in the art to achieve the desired release rates, stability, absorbency, and convenience of formulation formulation.

Formulation

Incorporating or coating on the surface thereof a safe effective amount of a therapeutically active agent in a formulation selected from the group consisting of spherical substrates, elliptical substrates, hard capsules, or compressed tablets having a maximum particle diameter of about 3 mm to about 10 mm; The formulation has a smooth surface without edges or sharp curves, and the ratio of the long diameter to the short diameter of the oval substrate and the hard capsule is less than about 1.5.

Preferably, the formulation of the present invention is a soft gelatin capsule; Molded spheres or ellipsoids made of any pharmaceutically acceptable excipient that can be melted or molded; Spheres prepared by coating a substrate on seed crystals made of any inert and pharmaceutically acceptable excipient; Hard capsules with flat seals without edges; And compressed tablets, wherein the formulation has a smooth surface without edges or sharp curves, and the ratio of the long diameter to the short diameter of the oval substrate and the hard capsule is less than about 1.5.

As used herein, the ″ elliptical substrate ″ is an ellipsoid, where all flat surfaces have the formula x ² / a ² + y ² / b ² + z ² / c ² (where b = c, a / b <1.5, and ″ a ″ Is 3 to 10 mm).

As used herein, ″ smooth surface without edges or sharp curves ″ means that there are not enough edges on the formulation relative to the average coating thickness to make a thin stain on the enteric coating. Particularly preferred formulations range from about 3 mm to about 8 mm in diameter; More preferably from about 4 mm to about 7 mm. It is desirable for all formulations to have a uniform size before coating with a polymeric coating. It is preferred that substantially all of the spheres have a diameter of about 5%, more preferably about 2% of the average particle diameter. Smooth surface and uniform size allow for uniform coating thickness and uniform dissolution of the polymer coating material.

The formulation is preferably composed of NF, which is an inert spherical substrate prepared by coating and / or lamination methods such as sugar spheres. The substrates are separated by size, ie using a gravimetric meter, by sieving and / or weighing to have a desired uniform diameter before coating. It is preferred that substantially all of the spheres have a diameter of about 5%, more preferably about 2% of the average particle diameter. Thereafter, they are coated with a therapeutically active agent. The therapeutically active agent is preferably bound to the sugar spherical substrate using a water soluble inert polymer, preferably low viscosity hydroxypropyl cellulose or hydroxypropyl methylcellulose. The ratio of binding polymer to therapeutically active agent is about 1:10 to 10: 1; Preferably from about 1: 5 to 5: 1; More preferably about 1: 4 to 1: 1.

Coating the therapeutically active agent on the sugar spheres optionally comprises from about 10 μm to about 50 μm using an inert water soluble polymer; Preferably, the coating may be overcoated to a thickness of about 20 μm to about 40 μm. The overcoat is referred to herein as a barrier coating. The barrier coating is preferably composed of low viscosity hydroxypropyl methylcellulose. If the substrate is a sugar sphere and the deepest inner enteric polymer coating is cellulose acetate phthalate, it is preferred that the formulation includes a barrier coating between the therapeutically active agent and cellulose acetate phthalate. Coating and barrier coating of the active agent may be performed on commercially available inert spherical substrates by any number of processes already known to those skilled in the art, including but not limited to perforated pan coating and fluid bed coating.

The formulation may also preferably comprise an inert spherical or elliptical substrate. As used herein, the term &quot; molding &quot; refers to the process of injecting and solidifying a molten or semi-solid inert, pharmaceutically acceptable material into the mold cavity. Therefore, the size of the mold cavity determines the size of the substrate. Suitable materials include ingestible and pharmaceutically acceptable waxes such as beeswax, paraffin and carnova wax, triglycerides having a melting point of about 50 ° C. or higher, such as tristearin, and polymer polyethylene glycols having a melting point of about 50 ° C. or higher. It is not limited to. The therapeutically active agent may be incorporated into the substrate during the molding process or coated on the molded substrate, and may optionally be overcoated with a water soluble, inert polymer as described above.

Preferred unit dosage forms are also spherical or elliptical soft elastic gelatin capsules. Soft elastic gelatin capsules are filled with a therapeutically active agent suspended in a suitable carrier compatible with the soft gelatin capsules.

More preferred unit dosage forms are edgeless, hard capsules that are flat sealed to a short diameter to long diameter of less than about 1.5 (ie starch or gelatin hard capsules). Examples include starch capsules available under the trade name Capill (registered trademark of Capsulgel, Greenwood, SC) with no surface edges, less than about 10 mm in length of the capsule long axis, and less than about 1.5 times the diameter of the capsule short axis. Starch capsules may be filled in solid form with a therapeutically active agent as described above, or optionally with a therapeutically active agent dissolved or suspended in a suitable carrier compatible with the capsule wall.

Additionally preferred unit dosage forms are compressed spherical or oval tablets with a maximum diameter of about 3 to about 10 mm without surface edges and sharp curves. The tablets consist of therapeutically active agents in solid form and are compressed using conventional equipment and processes.

Enteric Polymer Coating Materials

In the compositions of the present invention, the polymeric coating material is therapeutically active until the formulation is located through the upper gastrointestinal tract, including the mouth, esophagus, stomach and small intestine, near the junction between the small intestine and the colon or in the colon. Inhibit release of the drug; This prevents systemic absorption of the therapeutically active agent from the upper gastrointestinal tract and / or dilution of the therapeutically active agent released in the contents of the upper gastrointestinal tract. Therefore, polymeric coating materials in combination with spherical or elliptical substrates with flat surfaces provide a method of delivering a concentrated active therapeutically active agent to the colon.

As used herein, the term "enteric polymer coating material" is a substance that completely encloses a therapeutically active agent in a unit dosage form prior to oral administration. The polymer coating material of the present invention does not contain any active compound of the present invention. That is, the polymer coating material of the present invention does not contain any therapeutically active agent of the present invention. The invention also does not contain enteric coated microcrystalline spheres or particles of the active compound, or enteric coated granules of the active compound. Preferably, to delay dissolution of the therapeutically active agent, substantial amounts or all of the enteric polymer coating material is dissolved before the therapeutically active agent is released from the formulation.

The polymeric coating material is selected such that the therapeutically active agent is released at a time when the formulation reaches the inlet between the small intestine and the colon or subsequent colon. The choice above depends on the pH profile of the small intestine and colon. The pH of the small intestine gradually increases from about 5 to 5.5 in the duodenum bulb and up to about 7.2 in the distant part of the small intestine (ileum). The pH drops significantly to about 6.3 at the synaptic junction and increases very slowly to about 7 in the left or descending colon. The coating begins to dissolve within the pH range of the small intestine in order to provide a predictable dissolution time corresponding to a small intestine residence time of about 3 hours and to reproducibly release the drug at the inlet between the small intestine and the colon or thereafter. Continue to dissolve at the pH of the proximal colon. This means that a single coating of a single enteric polymer coating material should begin to dissolve in the pH range of about 5 to 6.3, which requires a minimum coating thickness of 250 μm (in Kelm and Manring, dated May 17, 1995). And P-G Patent Application No. 5673, filed and pending. Monolayer coatings of enteric polymer coating materials that begin to dissolve at higher pH, such as about 7, require a thinner coating thickness of the formulation that reaches the inlet or colon between the small intestine and the colon. However, when the formulation reaches the colon, any remaining coating will not dissolve in the proximal portion of the colon with a pH of less than 7, and therefore, until the formulation reaches the portion of the colon where the pH of the lumen exceeds 7, Delay release.

In order to release in the proximal colon while minimizing the total thickness of the enteric polymer coating, the enteric polymer coating material of the present invention consists of a plurality of, preferably two, serial coatings of the material. The outer coating layer consists of an enteric polymer coating material that begins to dissolve at a pH of about 6.8 to about 7.2, and the amount of layer is such that it is completely dissolved when the formulation is in the distal small intestine. The inner layer (s) consists of an enteric polymer coating material that begins to dissolve at a pH of about 5 to about 6.3, preferably at a pH of about 5 to about 6, more preferably at a pH of about 5 to about 5.5. The amount of inner layer (s) is such that the release of the drug is delayed until the formulation reaches the inlet or colon between the small intestine and the colon. Therefore, the function of the outer coating layer of the enteric polymer coating material is to prevent the release of the drug from the stomach until it passes through the distant part of the small intestine, and the function of the inner coating layer (s) is from the distant part of the small intestine (the outer layer dissolves). To prevent the release of the drug into the small intestine and colon or into the colon.

Preferred coating materials for the outer coating layer of the enteric polymer coating material include pH sensitive materials which remain intact in the low pH environment of the stomach and small intestine, but begin to dissolve in aqueous solutions at a pH of about 6.8 to about 7.2. The coating thickness depends on the size of the unit dosage form but is in the range of about 20 μm to about 50 μm. Preferred materials for the outer coating of the enteric polymer coating material are poly (methacrylic acid, methyl methacrylate) 1: 2 (Eudragit ) S), and poly (methacrylic acid, methyl methacrylate) 1: 1 (eudragit L) and poly (methacrylic acid, methyl methacrylate) 1: 2 (eudragit S) with a mixture in a ratio of about 1:10 to about 1: 2, preferably about 1: 5 to about 1: 3. Especially preferred is Eudragit S is.

Eudragit L is an anionic copolymer derived from methacrylic acid and methyl methacrylate, sold by Rohm Tech, with a ratio of free carboxyl groups to ester groups of approximately 1: 1 and an average molecular weight of approximately 135,000. ego; Eudragit S is an anionic copolymer derived from methacrylic acid and methyl methacrylate having a ratio of free carboxyl to ester groups of approximately 1: 2 and an average molecular weight of approximately 135,000, sold by Romtech.

Preferred coating materials for the inner coating layer (s) include pH sensitive materials that remain intact in the low pH environment of the stomach and small intestine, but decompose or dissolve at the pH commonly found in the distant parts of the small intestine, particularly the proximal colon. The inner coating layer polymer has a low apparent pKa range in order to minimize the impact of a sharp drop in pH upon passing through the slab. The inner coating layer enteric polymer (s) begins to dissolve in aqueous solution at a pH of about 5 to about 6.3. The enteric polymer should be able to dissolve in the proximal portion of the colon, which usually has a lower lumenal pH than in the distant part of the small intestine due to the presence of short chain fatty acids produced by the metabolic activity of the bacteria residing in the colon. It is especially important.

Enteric polymer coating materials for the inner layer (s) include cellulose acetate phthalate; Cellulose acetate trimelliate; Hydroxypropyl methylcellulose phthalate; Hydroxypropyl methylcellulose acetate succinate; Polyvinyl acetate phthalate; Poly (methacrylic acid, methyl methacrylate) 1: 1; Poly (methacrylic acid, ethyl acrylate) 1: 1; And their compatible mixtures, preferably poly (methacrylic acid, methyl methacrylate) 1: 1; And poly (methacrylic acid, ethyl acrylate) 1: 1, and compatible mixtures thereof, more preferably poly (methacrylic acid, ethyl acrylate) 1: 1.

Specific examples of the polymer coating material include the following:

Eudragit ) L; Anionic copolymers derived from methacrylic acid and methyl methacrylate, wherein the ratio of free carboxyl groups to ester groups is approximately 1: 1 and the average molecular weight is approximately 135,000;

Eudragit L 30 D; Anionic copolymer derived from methacrylic acid and ethyl acrylate (containing 30% w / w dry lacquer base) having an aqueous acrylic resin dispersion, a ratio of free carboxyl groups to ester groups of approximately 1: 1 and an average molecular weight of approximately 250,000 As an aqueous dispersion);

Eudragit L 100-55; Anionic copolymers derived from methacrylic acid and ethyl acrylate, wherein the ratio of free carboxyl groups to ester groups is approximately 1: 1 and the average molecular weight is greater than approximately 100,000;

Cellulose Acetate Phthalate (CAP ) (Available from Eastman Chemical); Cellulose Acetate Trimelliate (CAT ) (Available from Eastman Chemical); Hydroxypropyl Methylcellulose Phthalate (USP / NF Form 220824) HPMCP 50 available from Shin Etsu Chemical. And (USP / NF type 200731) HPMCP 55 ; Polyvinyl acetate phthalate, PVAP, available from Colorcon ; Hydroxypropyl Methylcellulose Acetate Succinate, available from Shin-Etsu Chemical Co., Ltd., HPMCAS .

Preferred polymer coating materials are poly (methacrylic acid, ethyl acrylate) 1: 1 (eudragit L 100-55), wherein the preferred coating thicknesses are about 120 to 350 μm and about 100 to 300 μm, respectively, for a diameter of about 4 to about 7 mm.

Another preferred polymer is poly (methacrylic acid, methyl methacrylate) 1: 1 (eudragit L) and the preferred coating thicknesses are about 110 to about 300 μm and about 90 to about 250 μm, respectively, for a diameter of about 4 to about 7 mm.

The total amount of enteric polymer above the formulation should be sufficient to allow complete dissolution of the coating until the formulation is located in the gastrointestinal tract, or in the colon near the colon inlet, to release the therapeutically active agent into the colon. do. This requires the requirement of a spherical or ellipsoidal formulation without surface edges or sharp curves creating a thin flaw in the coating. The coating on these thin blemishes dissolves before the formulation reaches the colon, resulting in the release of the therapeutically active agent too early.

Gastrointestinal transit of pharmaceutical formulations is described in M. Ashford and J. T. Fell, J. Drug Targeting, 1994, 2, 241-258. Pharmaceutical gastric emptying can be very variable, but the small intestine passage has a relatively constant mean residence time of about 3 hours. The pH-solubility action of the enteric polymer of the present invention is such that significant dissolution of the enteric polymer coating does not occur until the dosage form is released from the stomach, thereby resulting in a coating required to release a therapeutically active agent in the colon. It is enough to eliminate the variability of gastric emptying as a factor in determining the amount of water. Therefore, the amount of enteric polymer coating should be such that it substantially dissolves during the residence time of the small intestine of approximately 3 hours.

Dissolution of the enteric polymer of the invention is influenced by the size of the formulation and the pH, ionic strength and rate of the surrounding aqueous medium. The three factors of pH, ionic strength and velocity of the surrounding aqueous medium differ throughout the length of the small intestine and colon. In addition, the influence of these factors on the dissolution rate is different for each enteric polymer. However, the amount of a single coating layer of enteric polymer is significant, wherein the enteric polymer is dissolved in the proximal portion of the colon, as described in pending P & G patent application 5673 filed by Kelm and Manring on May 17, 1995. Can be. An important aspect of the present invention is the use of a multi-layer coating of enteric polymers consisting of an enteric polymer or an enteric polymer combination wherein the outermost layer is insoluble at a pH of less than about 6.8. The inner layer (s) consists of an enteric polymer that begins to dissolve at a pH of about 5 to about 6.3 so that it can dissolve in the proximal portion of the colon. The use of multiple layers in the manner described herein reduces the total amount of enteric polymer coating compared to using a single coating of enteric polymer that can dissolve in the proximal portion of the colon.

A more important factor for determining the amount of enteric polymer required to delay drug release until the formulation reaches the colon is to include the pH solubility profile of the enteric polymer applied to the outermost and inner coating layers and the size of the formulation. Found. The approximate minimum amounts of enteric polymer and formulation size as a role of pH at which the enteric polymer begins to dissolve are shown in Table 1. Also included are examples of enteric polymers.

Diameter (mm) layer pH Thickness (μm) Examples of enteric polymers 3 inside 5.0 150 HPMCP 50 3 Out 7.0 40 Eudragit S 5 inside 5.0 130 HPMCP 50 5 Out 7.0 30 Eudragit S 10 inside 5.0 100 HPMCP 50 10 Out 7.0 20 Eudragit S 3 inside 5.5 140 Eudragit L100-55 3 Out 7.0 40 Eudragit S 5 inside 5.5 120 Eudragit L100-55 5 Out 7.0 30 Eudragit S 10 inside 5.5 90 Eudragit L100-55 10 Out 7.0 20 Eudragit S 3 inside 6.0 130 Eudragit L 3 Out 7.0 40 Eudragit S 5 inside 6.0 110 Eudragit L 5 Out 7.0 30 Eudragit S 10 inside 6.0 80 Eudragit L 10 Out 7.0 20 Eudragit S

The enteric polymer coating materials can be prepared using any process known to those skilled in the art, including but not limited to perforated pan coating and fluidized bed coating, such as ethanol, acetone, isopropanol, ethyl acetate, or their As a solution in a mixture; As an aqueous solution buffered with ammonium hydroxide; Or as spherical or ellipsoidal substrates in water.

In order to improve the elasticity of the coating material, preferably the coating material of the present invention further contains a plasticizer. Suitable plasticizers include polyethylene glycol, propylene glycol, dibutyl phthalate, diethyl phthalate, tributyl citrate, tributyrin, butyl phthalyl butyl glycolate (Santicizer B-16, Monsanto, St .. Louis, Missouri), triacetin, castor oil and citric acid esters, and preferred plasticizers are dibutyl phthalate or triethyl citrate. These plasticizers are present in amounts to facilitate the coating process and to obtain a flat coating film with improved physical stability. Typically the coating material contains about 0% to about 50% by weight of a plasticizer, preferably about 0% to about 25% by weight, more preferably about 10% to about 20% by weight of the enteric polymer.

In addition, to facilitate the coating process, the coating material may also contain inert solid particles. Preferred inert solid particles include talc and titanium dioxide.

The choice of any plasticizer, any inert solid particles, and their concentrations, coating formulation forms (solvents, aqueous ammonia or aqueous dispersions), and procedures depends on the particular enteric polymer used and the formulation used according to the categories known to those skilled in the art. Based.

Manufacturing method

Enteric polymers are usually applied on spherical or elliptical substrates as solutions in organic solvents. Solvents commonly used as excipients are methylene chloride, ethanol, methanol, isopropyl alcohol, acetone, ethyl acetate and combinations thereof. The choice of solvent is mainly based on the solubility of the polymer, the ease of evaporation, and the viscosity of the solution.

Some polymers can be used as aqueous systems. In general, three aqueous enteric polymer coatings are in commercial use in the United States. These are Eudragit L30D (methacrylic acid-ethyl acrylate ester copolymer, Rohm-Haas GmBH, West Germany); Aquateric (Cellulose acetate phthalate containing product, FMC Corporation, Philadelphia, Pa.); And Coateric (Polyvinyl acetate phthalate based product, sold by Colorcon, Inc., West Point, Pa.). Unlike organic solutions, these aqueous based systems can be prepared in high concentrations without high viscosity. In addition, these aqueous systems have no problems with organic systems such as flammability, toxicity of residual solvents in formulations, and the like.

Coating can be accomplished by methods known to those skilled in the art (eg using fluid bed apparatus, perforation pans, regular pharmaceutical pans, compression coatings, etc.), continuous or short spraying methods or drenching.

The following non-limiting examples provide typical formulations for the compositions of the present invention.

Example 1

Formulations of the following formulations are prepared as described below:

materials Barrier coating ingredient Wt. (mg) ingredient Wt. (mg) Sugar Sphere, USP 212 HPMC, USP ¹ 5 Dextramethasone 3 HPMC, USP ¹ One 1: hydroxypropyl methylcellulose, USP, Methocel E15LV, Dow Chemical.

Internal enteric coating Outermost enteric coating ingredient Wt. (Mg) ingredient Wt. (Mg) Eudragit L100-55 ² 18 Eudragit S ³ 5 Dibutyl phthalate 4 Dibutyl phthalate One Talc, USP 8 Red ferric oxide One Talc, USP 2 2: poly (methacrylic acid, ethyl acrylate) 1: 1, Eudragit L100-55, Rohm Tech. 3: Poly (methacrylic acid, methyl methacrylate) 1: 2, Eudragit S, Rohm Tech.

materials

Dextramethasone is a conjugated polymer dispersed in water at a concentration of 2.7 weight% with 0.9 weight% HPMC and on sugar spheres (diameter 6.53-6.63 mm) in a perforated pan coater maintaining an outlet air / bed temperature of about 40 ° Is sprayed on.

Barrier coating

HPMC is dissolved in water to produce a 4% by weight solution coated on the substrate of the substrate in a perforated pan coater maintaining an outlet air / bed temperature of about 40 ° C.

Internal enteric coating

Eudragit L100-55 and dibutyl phthalate are dissolved in solutions of isopropanol, acetone and water (37: 9: 1) at concentrations of 8.0% and 1.6% (total weight%), respectively. Talc is then suspended in solution at a concentration of 3.3% by weight. The resulting mixture is coated on the barrier coated substrate above in a perforated pan coater maintaining an outlet air / bed temperature of about 30 ° C.

Outermost enteric coating

Eudragit S and dibutyl phthalate are dissolved in solutions of isopropanol, acetone and water (37: 9: 1), respectively, at concentrations of 8.0% and 1.6% (total weight%). The red ferric oxide and talc are then suspended in solution at concentrations of 1.2% and 2.1% by weight, respectively. The resulting mixture is coated on the barrier coated substrate above in a perforated pan coater maintaining an outlet air / bed temperature of about 30 ° C.

Example 2

Formulations of the following formulations are prepared as described below:

materials ingredient Wt. (mg) Medium Chain Triglycerides ¹ 63 Polyoxyl 35 Castor Oil, NF 2 Poloxamer 182 20 Propanolol base 15 # 3 Spherical Soft Enteric Gelatin Capsules N / A Internal enteric coating Outermost enteric coating ingredient Wt. (mg) ingredient Wt. (mg) Eudragit® L100-55 ² 18 Eudragit® S ³ 5 Dibutyl phthalate 4 Dibutyl phthalate One Talc, USP 8 Ferric oxide One Talc, USP 2

1 Captex (registered trademark) 300, Avitek Co., Ltd.

2 poly (methacrylic acid, ethyl acrylate) 1: 1, Eudragit® L100-55, Rom Tech.

3 poly (methacrylic acid, methyl methacrylate) 1: 2, Eudragit® S, Rom Tech.

materials

Heavy chain triglycerides, polyoxyl 35 castor oil, and poloxamer 182 are mixed to produce self-emulsifying lipids. The propanolock substrate is then dissolved in a self-emulsifying lipid carrier and then 100 mg is filled into # 3 soft elastic gelatin capsules using conventional equipment.

Internal enteric coating

Eudragit (registered trademark) L100-55 and dibutylphthalate are dissolved in solutions of isopropanol, acetone, and water (37: 9: 1) at concentrations of 8.0% and 1.6% (total weight percent), respectively. Talc is then suspended in the solution at a 3.3% by weight concentration. The resulting mixture is coated onto the barrier coated substrate in a perforated pan coater maintaining an outlet air / bed temperature of about 30 ° C.

Outer layer enteric coating

Eudragit (registered trademark) S and dibutylphthalate are dissolved in solutions of isopropanol, acetone, and water (37: 9: 1) at concentrations of 8.0% and 1.6% (total weight percent), respectively. The ferric red oxide and talc are then suspended in the solution at 1.2 wt% and 2.1 wt% concentrations, respectively. The resulting mixture is coated onto the barrier coated substrate in a perforated pan coater maintaining an outlet air / bed temperature of about 30 ° C.

Example 3

Formulations of the following formulations are prepared as described below:

materials ingredient Wt. (mg) Sugar Sphere, USP 50 Mesalamine 200 HPMC, USP ¹ 50 Internal enteric coating Outermost enteric coating ingredient Wt. (mg) ingredient Wt. (mg) Eudragit (registered trademark) L² 8 Eudragit (registered trademark) S³ 3 Dibutyl phthalate 1.6 Dibutyl phthalate 0.6 Talc, USP 3 Ferric oxide 0.5 Talc, USP One

1 hydroxypropyl methylcellulose, USP. Methocel® E15LV, Dow Chemical.

2 poly (methacrylic acid, methyl methacrylate) 1: 1, Eudragit (registered trademark) L, rom tech.

3 poly (methacrylic acid, methyl methacrylate) 1: 2, Eudragit® S, Rom Tech.

materials

In a CF granulator (Vector), mesalamin is coated onto a sugar sphere (diameter 2.9-3.1 mm) using a binding solution of HPMC 10% by weight aqueous solution.

Internal enteric coating

Eudragit (registered trademark) L and dibutylphthalate are dissolved in solutions of isopropanol, acetone, and water (37: 9: 1) at concentrations of 8.0% and 1.6% (total weight percent), respectively. Talc is then suspended in the solution at a 3.3% by weight concentration. The resulting mixture is coated onto the barrier coated substrate in a perforated pan coater maintaining an outlet air / bed temperature of about 30 ° C.

Outer layer enteric coating

Eudragit (registered trademark) S and dibutylphthalate are dissolved in solutions of isopropanol, acetone, and water (37: 9: 1) at concentrations of 8.0% and 1.6% (total weight percent), respectively. Ferric red oxide and talc are then suspended in the solution at concentrations of 1.2 and 2.1% by weight, respectively. The resulting mixture is coated onto the barrier coated substrate in a perforated pan coater maintaining an outlet air / bed temperature of about 30 ° C.

Example 4

Formulations of the following formulations are prepared as described below:

materials ingredient Wt. (mg) Oleic acid 30 Polyoxyl 60 Hydrogenated Castor Oil, NF 69.5 Salmon Calcitonin 0.5 # 3 Spherical Soft Elastic Gelatin Capsules N / A Internal enteric coating Outermost enteric coating ingredient Wt. (mg) ingredient Wt. (mg) Eudragit® L100-55 ¹ 18 Eudragit® S ² 5 Dibutyl phthalate 4 Dibutyl phthalate One Talc, USP 8 Ferric oxide One Talc, USP 2

1 poly (methacrylic acid, ethyl acrylate) 1: 1, Eudragit® L100-55, Rom Tech.

2 poly (methacrylic acid, methyl methacrylate) 1: 2, Eudragit (registered trademark) S, rom tech.

materials

The solution is prepared by mixing oleic acid and polyoxyl 60 hydrogenated castor oil. Salmon calcitonin is then dispersed in a self-emulsifying lipid carrier and then 100 mg is filled into # 3 soft elastic gelatin capsules using conventional equipment.

Internal enteric coating

Eudragit (registered trademark) L100-55 and dibutylphthalate are dissolved in solutions of isopropanol, acetone, and water (37: 9: 1) at concentrations of 8.0% and 1.6% (total weight percent), respectively. Talc is then suspended in the solution at a 3.3% by weight concentration. The resulting mixture is coated onto the barrier coated substrate in a perforated pan coater maintaining an outlet air / bed temperature of about 30 ° C.

Outer layer enteric coating

Eudragit (registered trademark) S and dibutylphthalate are dissolved in solutions of isopropanol, acetone, and water (37: 9: 1) at concentrations of 8.0% and 1.6% (total weight percent), respectively. Ferric red oxide and talc are then suspended in the solution at concentrations of 1.2 and 2.1% by weight, respectively. The resulting mixture is coated onto the barrier coated substrate in a perforated pan coater maintaining an outlet air / bed temperature of about 30 ° C.

While specific embodiments of the invention have been described, it will be apparent to those skilled in the art that various changes and modifications of the invention can be made without departing from the spirit and scope of the invention. The present invention includes all such modifications within the scope of the invention in the appended claims.

The present invention relates to a novel spherical unit dosage form for releasing a therapeutic agent at a point near the inlet of the colon or in the colon.

Claims (10)

A unit dosage form pharmaceutical composition for oral administration of a human or lower animal having an entrance from the small intestine to the colon and a lumen through the colon and the gastrointestinal tract comprising the small intestine: a. A safe effective amount of a therapeutically active agent incorporated into or coated on a formulation selected from the group consisting of spherical substrates, elliptical substrates, hard capsules, or compressed tablets having a maximum diameter of 3 mm to 10 mm; And b. An enteric polymer coating material comprising at least one inner coating layer and at least one outer coating layer; Wherein the formulation has a smooth surface without edges or sharp curves; Elliptical substrates and hard capsules have a long diameter to short diameter ratio of less than 1.5; The therapeutically active agent is released in the colon or at a point near the inlet of the colon; Each inner coating layer (s) is an enteric polymer that begins to dissolve in an aqueous medium at a pH of 5 to 6.3; The outer coating layer is an enteric polymer that begins to dissolve in the aqueous medium at a pH of 6.8 to 7.2. The composition of claim 1, wherein the formulation is a soft elastic gelatin capsule; Molded spherical or oval substrates made of pharmaceutically acceptable excipients that can be melted or molded; Spherical or oval substrates prepared by coating or laminating substrates on seed crystals made of inert and pharmaceutically acceptable excipients; Preferably the composition is selected from the group consisting of soft elastic gelatin capsules or sugar spheres. The method of claim 1, wherein the enteric polymer coating material comprises cellulose acetate phthalate; Cellulose acetate trimelliate; Hydroxypropyl methylcellulose phthalate; Hydroxypropyl methylcellulose acetate succinate; Polyvinyl acetate phthalate; Poly (methacrylic acid, methyl methacrylate) 1: 1; Poly (methacrylic acid, ethyl acrylate) 1: 1; And an inner coating layer selected from the group consisting of compatible mixtures thereof. The method of claim 1 wherein the outer coating layer is poly (methacrylic acid, methyl methacrylate) 1: 2, and poly (methacrylic acid, methylmethacrylate) 1: 1 and poly (methacrylic acid, methyl methacrylate 1) a mixture of 1:10 to 1: 2 ratio of 1: 2; Preferably the outer coating layer having a coating thickness of 20 μm to 50 μm is poly (methacrylic acid, methyl methacrylate). A unit dosage form pharmaceutical composition for oral administration of a human or lower animal having an intestine through the small intestine to the colon and a lumen through the colon and the gastrointestinal tract comprising the small intestine: a. Safe and effective amounts of therapeutically active agents incorporated into soft elastic gelatin capsules with a maximum diameter of 3 mm to 10 mm; And b. Inner coating layer of poly (methacrylic acid, ethyl acrylate) 1: 1 or poly (methacrylic acid, methyl methacrylate) 1: 1, and outer coating layer of poly (methacrylic acid, methyl methacrylate) 1: 2 An enteric polymer coating material comprising; Wherein the soft elastic gelatin capsule has a smooth surface without edges or sharp curves; The therapeutically active agent is released in the colon or at a point near the inlet of the colon. A unit dosage form pharmaceutical composition for oral administration of a human or lower animal having an intestine through the small intestine to the colon and a lumen through the colon and the gastrointestinal tract comprising the small intestine: a. A safe effective amount of a therapeutically active agent coated on the surface of a sugar sphere substrate having a maximum diameter of 3 mm to 10 mm (preferably all of the sugar sphere substrates are within an average diameter of about 5%); b. Inner coating layer of poly (methacrylic acid, ethyl acrylate) 1: 1 or poly (methacrylic acid, methyl methacrylate) 1: 1, and outer coating layer of poly (methacrylic acid, methyl methacrylate) 1: 2 An enteric polymer coating material comprising; And c. If desired, a barrier coating, preferably hydroxypropyl methylcellulose, which is coated with a therapeutically active agent followed by coating a sugar sphere substrate; Wherein the sugar sphere substrate has a smooth surface without edges or sharp curves; The therapeutically active agent is released in the colon or at a point near the inlet of the colon. The therapeutically active agent according to any one of claims 1, 5 or 6, wherein the therapeutically active agent is a picosulfate, a senoside, an anti-diabetic agent, a nonsteroidal anti-inflammatory agent, a glucocorticoid, an antimicrobial agent, an immunosuppressive agent, a chemotherapeutic agent , Peptides, proteins, beta blockers, calcium channel blockers, ACE inhibitors, H2-blockers, anti-asthma drugs, and antihistamines. The inner coating layer according to any one of claims 3, 5 or 6, wherein the coating thickness is 120 μm to 350 μm when the diameter is 4 mm and the coating thickness is 100 μm to 300 μm when the diameter is 7 mm. Krylic acid, ethyl acrylate) 1: 1 composition. The inner coating layer according to any one of claims 3, 5, or 6, wherein the coating thickness is about 110 mm to 300 m when the diameter is about 4 mm, and the coating thickness is about 90 mm to about 250 m when the diameter is 7 mm. Methacrylic acid, methyl methacrylate) 1: 1. A method of orally administering a safe effective amount of the composition of claim 1, 5 or 6 to provide release of a therapeutically active agent in the colon of a human or lower animal.