KR20050023396A - Controlled release composition - Google Patents

Abstract

An improved composition for controlling the release profile through the intestinal tract of the active compound comprises particles containing the active compound, specifically pellets, which have a pH dissolution dependent coating having a certain thickness depending on the desired release location and release rate of the active compound. The material or polymethacrylate material, preferably a pH dissolution dependent polymethacrylate material, is coated. In a preferred composition, two or more of the plurality of particles in which each of the plurality of particles is coated with a pH dissolution dependent coating material or a polymethacrylate material at a different thickness than the other plurality of particles are contained in the enteric coated capsule. It is possible to release the active compound at various desired locations in the intestine.

Description

Controlled Release Composition {CONTROLLED RELEASE COMPOSITION}

The present invention relates to the use of polymethacrylate materials, in particular polymethacrylate materials exhibiting pH dissolution dependence and other coating materials exhibiting pH dissolution dependence, in controlling the release of active compounds in the intestine. The invention also relates to prednisolone metasulfobenzoate (11,17-dihydroxy-21-[(3-sulfobenzoyl) oxy] pregna-1, useful for the treatment of inflammatory bowel disease and specifically Crohn's disease. 4-diene-3,20-dione) and pharmacologically acceptable salts, specifically sodium salts.

More specifically, the present invention provides for the purpose of controlling the release profile of an active compound such as prednisolone metasulfobenzoate, which contains particles coated with a polymethacrylate material or other pH dissolution dependent coating material of a desired thickness. Provided are solid pharmaceutical compositions having at least one active compound. The present invention also provides the use of the coating thickness of polymethacrylate material or other pH dissolution dependent coating material, which is used to control the release profile of the active compound through the intestine.

As used herein, the term "prednisolone metasulfobenzoate" as used herein includes pharmacologically acceptable salts of prednisolone metasulfobenzoate as well as free ester.

It is desirable to be able to control the release of the active compound in the gastrointestinal tract. Serious side effects can occur when systemic absorbent drugs are used for some diseases that require topical treatment in the intestine. In addition, acidic conditions of the stomach can degrade some active compounds, especially peptides and proteins, so vehicles that deliver these active compounds as part of the intestine to be systemically absorbed or provide therapeutic effects have a beneficial effect. Will go crazy. In addition, some active compounds, specifically peptides and proteins, may be advantageously administered to specific sites within the intestinal tract for systemic absorption, and administration may be at two or more different locations. In embodiments, there are compounds in which systemic uptake is different depending on whether the location is M cells or fire measures.

In addition, it is sometimes desirable to continuously administer the active compound to a patient over a period of time simply to maintain the active compound at the desired plasma concentration, and controlled release oral compositions have been provided as a convenient and effective way of doing this.

Several methods are known for controlling the release of the active compound. For example, methods of providing enteric coatings on tablets or capsules for passage through the stomach and for degradation in the small intestine are well known. Also known are methods of administering the active compound to a patient in a sustained release substrate. Another known method is the preparation of derivatives of active compounds, such as glucuronic acid derivatives, in which such compounds are cleaved only after contact with a suitable enteric enzyme, such as glucuronidase, to release the active compounds.

The provision of controlled release formulations of the active compounds is of particular relevance to intestinal diseases, especially those with favorable local effects, with inflammatory bowel disease (IBD) as a specific example.

Inflammatory bowel disease is a chronic nonspecific inflammatory disease of the gastrointestinal tract, with two major forms being Crohn's disease and ulcerative colitis.

Crohn's disease often affects the small intestine, specifically the vocal tract, but also any part of the gastrointestinal tract, and also any part of the jejunum and colon, such as the rectum and especially the intestinal tract. The disease is characterized by inflammation occurring throughout all layers and thickening of the gastrointestinal wall, severe ulcers and mucosal fissures. These lesions are often scattered in relatively normal tissue areas.

Sulfasalazine has been used to treat cases of Crohn's disease in the colon, such as 5-aminosalicylic acid, in the form of enteric coatings or sustained release. Steroids are widely used to treat serious cases of colon inflammation, specifically ulcerative colitis and Crohn's disease. Steroids are usually in oral or parenteral forms that provide systemic effects or rectal dosage forms by enemas that provide local effects. Treatment of serious cases of inflammatory bowel disease requires relatively large amounts of steroids. However, systemic absorption causes serious side effects, and rectal administration reduces systemic absorption, but the enema treats only the lower colon and rectum and is inconvenient to use.

The most commonly used steroids for oral treatment of inflammatory bowel disease are prednisolone (17,21-di-hydroxypregna-1,4-diene-3,11,20 in free alcohol or ester form thereof, usually in acetate form. -Trion). Treatment of serious cases of inflammatory bowel disease requires a daily dose of 15 to 60 mg (calculated as free alcohol), but absorption of such doses is dangerous. Thus, treatment with prednisolone is currently limited in both dosage and duration of treatment.

Often, for the purpose of treating inflammatory bowel disease and Crohn's disease, several methods and compositions have been proposed for targeting or controlling the release of active compounds in the intestine.

US-A-4496553 relates to oral pharmaceutical compositions containing 5-aminosalicylic acid (5-ASA) for the treatment of ulcerative colitis or Crohn's disease. This patent discloses sustained-release tablets consisting of 5-ASA granules coated with ethyl cellulose and pressed together with microcrystalline cellulose granules, talc and sodium stearate. Examination on dorsumone patients confirmed that 50% active ingredient was released from the small intestine from the tablet. This patent suggests that this release can be controlled by changing one or more of the particle size, coating thickness and permeability of the granulated active ingredient, the pH conditions in the coated particles and the appropriate active ingredient (Columns 6, 15-22). line).

EP-B-0097651 is a composition for the selective administration of 5-aminosalicylic acid to the large intestine, which is insoluble in gastric and intestinal fluids below pH 7, but soluble in colonic intestinal fluid, so that the original formulation is maintained until reaching the colon. A composition comprising a solid oral formulation containing an active compound coated with a thick anionic polymer layer is disclosed.

EP-B-0572486 discloses an orally administrable pharmaceutical formulation containing a plurality of granules of a drug, such as 5-aminosalicylic acid, in a capsule coated with a substance that is intestinal soluble and also coated with a substance that is intestinal soluble. have. This composition is for selective administration of the drug to the intestine. This patent preferably contains the granules in an enteric coated capsule which releases the granules from the small intestine, which is coated with a coating which remains substantially intact before the granules reach at least the pulmonary tract, and thereafter the drug via the colon It is stated that it is desirable to sustain release.

EP-A-0772443 discloses non-disintegrating solid enteric pharmaceutical compositions comprising prednisolone metasulfobenzoate, which dissolves relatively quickly from excipient substrates at pH 6.5, and formulations containing pellets of the composition. Rapid dissolution is increased by at least 5% by weight superdisintegrant for flow modification, but insufficient to cause disintegration of the composition. The compositions disclosed in this patent are capsules coated with an enteric coating and suitably coated with a suitable coating material such as cellulose acetate phthalate or a partially methyl esterified methacrylic acid polymer, preferably having a ratio of free acid groups to ester groups of about 1: 2. It may contain a plurality of the pellets contained in. The coating material on the pellets is preferably insoluble in gastric juices and intestinal fluids below pH 7 and soluble in lower intestinal fluids. The enteric coating material of the capsule is chosen to protect the capsule during passage through the stomach. The compositions of this patent are for use in treating Crohn's disease.

EP-B-0502032 discloses agents for the site-specific release of active compounds in the colon for the treatment of colon diseases such as ulcerative colitis and Crohn's disease. The active compound here may in particular be prednisolone or 5-aminosalicylic acid or the like. Such formulations contain the active compound and amorphous amylose and are coated on the outside with a cellulose or acrylic acid polymer material. It is preferred that the active compound is coated with free amylose, and this free amylose tends not to degrade until it is attacked by the amylose degrading enzyme provided by the microflora normally present in the colon. Such compositions are further coated with cellulose or acrylic acid polymer materials, which serve to improve the delayed release of the amylose coating composition. Once such a composition reaches the colon, the rate of release of the active compound from the composition can be controlled through the change in thickness of the amylose coating provided therein. As such, the patent discloses that the release in the colon can be varied by coating several particles of the active compound with amylose of different thickness. Release properties can also be altered through the addition of fat or wax components that retard drying or permeability, which affects pore size and permeability. Preferably, the outer coating material of the cellulose or acrylic acid polymer exhibits pH dependent degradation.

WO-A-9921536 relates to controlled release compositions suitable for delivering the active ingredient to the colon. This patent includes 5-aminosalicylic acid spheres containing microcrystalline cellulose and having diameters ranging from 1.00 to 1.40 mm, wherein the spheres contain amylose / ethyl cellulose compositions contained in mixed solvents (water and water miscible organic solvents). Discloses a composition coated with acrylic acid polymer in place of cellulose. The release profile was investigated here for a range of amylose / ethyl cellulose ratios and coating thicknesses. As a result, coatings with high proportions of ethyl cellulose rarely release the drug due to loss of continuous amylose channels through the coating surface and into the pellet cores, whereas coatings with high proportions of amylose prevent membranes with poor quality structures. It was found to form. Thus, it has been shown that when amylose is provided to the coating in high concentrations and the coating thickness is thick, it is possible to prevent the release of the active compound prior to the colon.

EP-A-0264989 discloses sustained release pharmaceutical formulations of rhein derivatives. In particular, this patent discloses formulations for maintaining blood levels of the drug for up to 24 hours after administration. As can be seen in Example 2 of this patent specification, the general concept of coating a particle with a material of different thickness (cellulose in this example cellulose acetophthalate) in order to release the drug compound at different rates to sustain release for a predetermined time is disclosed. have.

US-A-5529790 discloses a pharmaceutical formulation which utilizes a water hydratable diffusion barrier coating to facilitate delayed and sustained release of the drug from the formulation. The delay comes from the hydration rate and the coating thickness, and the sustained release comes from the permeability and the coating thickness. The diffusion barrier is preferably comprised of a film forming material that is insoluble at intestinal conditions and one or more additional additives that control the rate of hydration and permeability of the diffusion barrier. Preferred film forming polymers include aqueous dispersions of fully esterified acrylic acid resins (eg Eudragit NE300), aqueous dispersions of fully esterified acrylic acid resins (eg Eudragit RS30D) containing quaternary amine side chains or ethyl cellulose There is an aqueous dispersion of. A preferred additive that controls the rate of hydration and permeability is magnesium stearate. Drugs (eg, diltiazem hydrochloride) can be prepared from spherical microparticles with a diameter in the range from 500 to 1500 μm, preferably with low hydration rate and permeability, so that delayed release of the drug can be effected for a long period of time. It is preferable to prepare two-part particles consisting of a long-term delayed fraction and a short-term delayed fraction having a relatively fast and permeable rate of hydration. Dissolution studies were conducted with particles with different coating thicknesses.

US-A-4728512 discloses pharmaceutical formulations containing, for example, capsules of three groups of drug release pellets that release the drug at different times in the patient's digestive system. Specifically, the patent relates to a first group in which the drug is released as soon as the pellet is released from the capsule without coating, the second group having a pH dependent coating (e.g. 20-30 wt% Eudragit S) and a third independent coating system such as a pH independent coating, such as a time dependent subcoating (eg hydroxypropyl methyl cellulose), further coated with a hydrating diffusion barrier coating (eg Eudragit E30D and metallic stearate) A formulation consisting of a group of pellets is disclosed. Thus, such formulations consist of a triple drug release system in which the maximum drug release occurs, respectively, for 0 to 2 hours after administration, for 2 to 6 hours after administration and for 4 to 10 hours after administration. This formulation provides three doses of the drug for a period of time, such as 12 hours, by releasing the drug three times in an amount that depends on the relative amount of particles belonging to each group. The particles of the group are coated with coating materials of different thickness, so the present patent discloses different release properties (via different release delays of the drug from the pellets of the second and third groups) to release the active compounds at various positions in the intestinal tract. The general concept of using different groups of particles with is disclosed.

However, there is no literature presenting an effective method or composition for overcoming or resolving changes in delivery rate and pH throughout the intestine to control the release of active compounds in the intestine.

There is a need in the art for improved methods and compositions that can control the intestinal release of active compounds such as prednisolone metasulfobenzoate.

The inventors of the present invention have shown that the use of different pH dissolving dependent polymethacrylate materials on prednisolone metasulfobenzoate particles releases prednisolone metasulfobenzoate at different rates at the same pH and in a controllable manner over a range of pH. Found. The thickness of the polymethacrylate coating used can be selected according to the pH and the desired release rate and location to provide a release control profile of prednisolone metasulfobenzoate. PH dissolution dependent coating materials such as polymethacrylates have generally been used to release the active compound at a single location in the intestinal tract. To the best of our knowledge, different coating thicknesses of such pH dissolution dependent coating materials have never been used to provide continuous or sustained release.

1 is a prednisolone metasulfo wherein methacrylic acid copolymers of methacrylic acid and methyl methacrylate with a ratio of free carboxyl groups to ester groups are released in pellets coated with theoretical weight increments of 5%, 15% and 25%. It is a graph which shows the release rate (%) of benzoate with time elapsed.

FIG. 2 shows that methacrylic acid copolymers of methacrylic acid and methyl methacrylate with a ratio of free carboxyl groups to ester groups are released at pH 6.0, 6.2, 6.6 and 7.2 in pellets coated with a theoretical weight increment of 15%. It is a graph which shows the release rate (%) of prednisolone metasulfobenzoate with time elapsed.

3 is pellets having a methacrylic acid copolymer of methacrylic acid and methyl methacrylate having a ratio of free carboxyl to ester groups of 1: 2 coated in a theoretical weight increment of 15% and particle sizes up to 1500 μm and up to 2000 μm, And a mixed poly with 5% methacrylic acid ethyl acetate copolymer having a ratio of free carboxyl group to ester group of 1: 1 and a copolymer of methacrylic acid and methyl methacrylate having a ratio of 1: 2 of free carboxyl group to ester group The percent release of prednisolone metasulfobenzoate released in pellets coated with methacrylate in a theoretical weight increment of 15% is plotted over time.

Figure 4 shows the paracetamol release of methacrylic acid copolymers of methacrylic acid and methyl methacrylate with a ratio of free carboxyl groups to ester groups of 1: 2 at pH 6.2, 6.6 and 7.2 in pellets coated with a 20% theoretical weight increment. It is a graph showing the release rate (%) over time.

FIG. 5 shows the metronidazole release of methacrylic acid copolymers of methacrylic acid and methyl methacrylate with a ratio of free carboxyl groups to ester groups of 1: 2 at pH 6.0, 6.6 and 7.2 in pellets coated with a 20% theoretical weight increment. It is a graph showing the release rate (%) over time.

FIG. 6 shows that methacrylic acid copolymers of methacrylic acid and methyl methacrylate with a ratio of free carboxyl groups to ester groups are released at pH 6.6 in pellets coated with theoretical weight increments of 15%, 20% and 25%. The graph shows the percent release of metronidazole over time.

FIG. 7 shows that the methacrylic acid copolymers of methacrylic acid and methyl methacrylate with a ratio of free carboxyl groups to ester groups are released in α-amylase pellets coated with theoretical weight increments of 15%, 20% and 25%. It is a graph showing how the activity of amylase varies with elapsed time under pH 6.0.

Accordingly, in a first aspect the present invention provides an oral pharmaceutical composition comprising two or more particles, wherein the particles comprise prednisolone metasulfobenzoate and each of the plurality of particles differs from each other of the plurality of particles. The coating of thick polymethacrylate material provides an oral pharmaceutical composition in which prednisolone metasulfobenzoate is released to various positions in the intestinal tract.

In addition, the inventors have surprisingly found that this technique can be extended to compositions containing other active compounds.

Thus, as another embodiment of the first aspect, the present invention is an oral pharmaceutical composition comprising two or more types of a plurality of particles, each of the plurality of particles wherein the particles comprise the active compound and each of the plurality of particles is different A pH dissolution dependent polymethacrylate material of different thickness is coated to provide an oral pharmaceutical composition in which the active compound is released to various positions in the intestinal tract.

The graded release of the active compounds from such pharmaceutical compositions is not intended to be limited to a particular theory, but is believed to be due to the change in permeability of the coatings rather than breakdown of coatings of different thicknesses. This is because the active compound that is permeated from the composition is observed before disintegration of the composition occurs.

The features described below can be applied to the prednisolone metasulfobenzoate embodiment as well as to the more general embodiment according to the first aspect of the invention.

The coating material may be any material used or useful for coating oral pharmaceutical dosage forms that deliver the active compound to the intestine, and preferably is a pH dissolution dependent cellulose derivative (eg, cellulose acetate phthalate and hydroxypropyl methylcellulose acetate phthalate). Or a polymethacrylate material, preferably a pH dissolution dependent polymethphthalate material.

The cellulose derivative is selected from cellulose acetate phthalate, hydroxypropyl metacellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate phthalate, alone or multiple esters and / or ether derivatives of cellulose exhibiting other pH solubility dependencies. desirable.

pH dissolution dependent coating materials include those which, in the present state of the art, include substances which are insoluble in gastric juice until reaching a specific pH and which release the drug according to pH when used as a coating material in oral pharmaceutical dosage forms. it means.

Polymethacrylates exhibiting particular utility in the present invention are anionic polymers of varying proportions of dimethylaminoethylmethacrylate, methacrylic acid and methacrylic acid esters.

The polymethacrylate may be a copolymer of acrylic acid (eg methacrylic acid) and acrylic acid esters (eg methyl methacrylate or ethyl acrylate). Preferably, the polymethacrylates used according to the invention are methacrylic acid copolymers based on methacrylic acid and various acrylic acid esters (such as ethyl acrylate or methyl methacrylate), or mixtures thereof. More preferably, at least one copolymer of methacrylic acid and methyl methacrylate, preferably a copolymer having a ratio of free carboxyl groups to ester groups, for example of about 1: 2 (Lom Parma Cage, Darmstadt, Germany) EMBAR, sold under the trademark EUDRAGIT S) and a copolymer having a molecular weight of 135,000 or about 1: 1 (available under the trademark EUDRAGIT L), or mixtures thereof.

Preferably, the present invention utilizes polymethacrylates that exhibit pH dissolution dependence. Polymethacrylates exhibiting pH dissolution dependence include polymethacrylates that are insoluble in gastric fluid until they reach a particular pH in the state of the art and polymethacrylates that release the drug according to pH when used as a coating material. (See, eg, The Handbook of Pharmaceutical Excipients, 3rd Edn., Edited by Arthur H. Kibbe (American Pharmaceutical Society and Pharmaceutical Press, 2000)). Preferably, the polymethacrylate material is insoluble (or insoluble) in gastric juice until a specific pH is reached, and The Handbook of Pharmaceutical Excipients (published articles on pages 401-406), which is incorporated herein by reference. ], When used as a coating material, it is preferable to include a polymethacrylate to release the drug according to the pH.

Such polymethacrylates include copolymers of methacrylic acid and methyl methacrylate (EUDRAGIT S available from Lom Parma GmbH) or ratio of free carboxyl groups to ester groups having a ratio of free carboxyl groups to ester groups of about 1: 2. Copolymer of methacrylic acid with methyl methacrylate (EUDRAGIT S available from Rohm Parma GmbH) and copolymer of methacrylic acid with ethyl acrylate having a ratio of free carboxyl group to ester group of about 1: 1 Commercially available trademarks EUDRAGIT L 30 D-55 or EUDRAGIT L 100-55. More preferably, the polymethacrylate has a pH higher than 5.5, even more preferably higher than pH 6.

Preferably, the coating material coating the particles of each of the plurality of particles is the same as the coating material coating the other respective plurality of particles.

In one embodiment of the present invention, each of the plurality of particles may be coated with a coating material of different thickness selected in increments that provide a uniform release profile of the active compound along one or more sites selected from the intestine or along the entire intestine. . The selected site may be around the stony valve, but preferably before and after.

It is desirable to select the difference in thickness and increment of the coating material to provide multi-site release of the active compound so that uniform release throughout the intestine is achieved. For example, upon administration of an active compound for treating Crohn's disease, it may be necessary to ensure that the active compound is released uniformly along the dorsum and colon, particularly the ascending colon.

In this embodiment, the present invention selects the difference in the thickness increments of the coating material, in particular the polymethacrylate material, in order to overcome the change in pH or the rate of progression or delivery through the intestine of the capsule or tablet. It is possible to provide homogeneous release of the active compound, which is advantageous over conventional sustained release formulations.

Changes in the rate of progression through the intestine seen in conventional sustained release formulations can deliver the active compound to a specific site of the intestine at a lower concentration than other sites. Likewise, pH changes appearing in different parts of the intestine are likely to induce different release rates from conventional sustained release formulations. This change can cause the effect to be lost.

In patients with inflammatory bowel disease, especially active inflammation, the rate of delivery through the intestine and the pH in the intestine are often abnormal. Conventional sustained release formulations that release the active agent in a time or pH dependent manner are not easy to predict or effectively deliver the active agent to the target site of the intestine. That is, such formulations may provide under-dosing at certain sites, and over-dosing, “dose delivery” at other sites.

In such embodiments, the change is achieved by, for example, coating the particles of each of the plurality of particles with a selected thickness of the coating material but varying the incremental difference in coating thickness between each of the plurality of particles to be released to multiple sites throughout the intestine. I can solve it. For example, if you want to have a uniform release in the intestine section with a faster pass rate and a slower pass rate, the coating thickness of the plurality of particles delivered to the intestine section with a faster pass rate will result in a higher pass rate. The incremental difference should be less than the coating thickness of the plurality of particles delivered to the slow bowel section and / or the number of particles in the plurality of particles delivered to the bowel section with faster passage speed. Likewise, if uniform release is to be made to the higher or lower pH intestine, then a thicker coating should be provided to the particles for releasing the active compound into the higher pH. However, this will also depend on your position in the intestine. In this way the release rate of the active compound can be controlled in terms of the change in pH or the change in rate delivered through the intestine, so that it will not depend only on whether the release of the active compound has reached a certain pH or a certain time has elapsed. .

In addition, the coating thickness on each of the plurality of particles may be selected to release the active compound at a particular location in the intestine. For example, each of a plurality of particles is coated with a different thickness of the coating material so that the active compound is released, for example before and after, at a position around the intestinal valve.

Preferably, there are two plural particles present, wherein one plural particles are coated with a coating material of a thickness that causes the active compound to release in the distal bolus prior to the mitral valve and the other plural particles It is coated with a coating material of different thickness that causes the active compound to release in the proximal intestine after the intestinal valve. The coating material is preferably a polymethacrylate material, more preferably a methacrylic acid copolymer, even more preferably a copolymer of methacrylic acid and methyl methacrylate, preferably of free carboxyl group to ester group Particularly good ratio is about 1: 2.

The coating on the particles may be a thickness corresponding to a theoretical weight increment on 15% of the coating on one of the plurality of particles and a theoretical weight increment on 20% of the coating on the other plurality of particles, preferably each The ratio of the plurality of particles to the coating particles coated with 15% weight increments to the particles coated with 20% weight increments is present as 1: 3.

Further, in order to control the release profile of the active compound passing through the intestine, particles derived from one plurality of particles may be coated with particles derived from another plurality of particles and a different coating material. In addition, one plurality of particles may have a different size than another plurality of particles.

The present invention relates to all active compounds, for example systemic, which may be advantageous, for example, in the administration of an active compound having a local therapeutic effect in the intestine, administration of a high molecular weight active compound useful for local or systemic action, and control of release through the intestine. Absorption may be utilized for the administration of the active compound, which depends on location and rate of release in the intestine.

In particular, it is very useful when it is desired to provide an active compound for local action at one or more sites in the intestine. For example, in the treatment of inflammatory bowel disease, particularly Crohn's disease, in which there may be sites of infection at various sites in the intestine, controlled delivery of the active compound to the site of infection without administration to the uninfected site results in systemic absorption of the active compound. And all side effects that can be caused by this systemic absorption are minimized.

When administering high molecular weight compounds such as proteins or peptides, the present invention can be utilized to protect the active compound from degradation in acidic conditions of the stomach, for example in the intestinal region or M- which can be absorbed. The compound can be delivered to an intestinal site at a suitable location, such as a cell or fire passage.

The present invention is particularly applicable to delivering high molecular weight compounds where the integrity of tertiary structures is important for the efficacy and safety of the compounds. A unique advantage of the present invention is that it can be prepared under mild conditions compared to most pharmaceutical processes while providing the desired release profile of the compound in the intestine.

One example of a high molecular weight compound that may be advantageously formulated in a composition of the present invention is considered particularly useful for treating anemia in chronic renal failure and studies in the treatment of inflammatory bowel disease as well as other normal erythrocyte-normal pigment anemia. Erythropoietin, glycosylated protein hormones, and hematopoietic growth factors. Erythropoietin has been disclosed in its tablet form (RU-A-2152206), but usually subcutaneous or intravenous administration is customary.

Another class of high molecular weight compounds in which the present invention may be helpful include interferons, TNF antagonists and certain protein and polypeptide agonists and antagonists of the immune system, hormones such as human growth hormone, and cytokine and cytokine antagonists.

Other compounds and classes of compounds in which the present invention may be helpful in administration include analgesics and antipyretics; Antibacterial and antiprotozoal agents such as metronidazole and other nitroimidazole antibiotics and antibiotics active against anaerobes; Clarithromycin and other macrolide antibiotics; Antibiotics that cause or are generally associated with or active against infectious organisms, such as gentamycin, ciprofloxacin, rifabutin and other intestinal diseases; Anti-inflammatory agents such as salicylates (eg 5-aminosalicylic acid, 4-aminosalicylic acid and derivatives), valsalazides, steroids, specifically prednisolone metasulfobenzoate; Probiotics and prebiotics found to affect the syndromes of inflammatory bowel disease and irritable bowel symptoms; And pharmacologically active drugs known to affect the irritable bowel syndrome, such as drugs that affect serotonergic systems and drugs that are active at the anesthetic receptor site. α-amylase and paracetamol can also be administered using the compositions of the present invention.

Other compounds in which the present invention may be helpful include certain compounds that have toxic effects that limit clinical utility, particularly those that cause local toxicity in certain areas of the gastrointestinal tract. Such compounds include those belonging to antibiotics, bisphosphonates and anti-inflammatory agents. Specific examples are metformin, which is difficult for many patients to suffer due to side effects on the gastrointestinal tract. In addition, the present invention can be used to minimize the concentration of a compound at a toxic site, thereby allowing a therapeutically effective dose to be administered through the reduction of side effects.

Preferred compounds for use in the present invention are prednisolone metasulfobenzoate, 5-aminosalicylic acid, metronidazole, clarithromycin, metformin and erythropoietin.

In a preferred embodiment of the invention, such compositions further comprise a capsule containing a plurality of particles, preferably an enteric coated capsule. The capsules may generally be soft capsules or preferably hard gelatin capsules. Of course, other capsules that dissolve in the small intestine can also be used. The enteric coating will protect the capsule when it passes through the stomach. Enteric coating materials can be any suitable enteric coating materials that are soluble in the small intestine. By way of example, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate or primarily ethyl cellulose, followed by polyvinyl acetate phthalate may be used, but it is preferred to use anionic polymers which exhibit a suitable dissolution profile. Presently preferred polymers include anionic carboxylic acid polymers, ie polymers wherein the anionic groups are at least primarily free carboxyl groups and / or esterified carboxyl groups. In particular, it is preferred that the polymer is an acrylic acid polymer and the presently preferred polymer is a copolymer of methacrylic acid and methyl methacrylate (ie Eudragit L) having a ratio of free acid groups to ester groups of about 1: 1.

Alternatively, the particles can be compressed into tablets, which can be applied an enteric coating.

Capsule (or other formulation) coatings may include and generally include emollients, and may include other coating additives, such as colorants, gloss producers, talc and / or magnesium stearate, perhaps as known in the coating art. will be. In particular, the anionic carboxylic acid acrylic acid polymer coating generally comprises 10 to 25% by weight softener, specifically diethyl phthalate.

In a second aspect, the present invention provides the use of a coating thickness of a pH dissolution dependent coating material on particles containing the active compound, useful for controlling the release profile of the active compound in the intestine. By pH dissolution dependent coating material is meant a coating material in which dissolution is pH dependent. For example, a polymethacrylate material that is insoluble at pH is a pH dissolution dependent polymethacrylate material that substantially dissolves when the pH is higher than 5.5.

In a third aspect, the invention is used in the manufacture of a medicament as described above for use in the treatment of intestinal diseases.

A. polymethacrylate material; And

B. pH Dissolution Dependent Coating Materials

It provides the use of the coating material selected from. In general, the drug will be a drug useful for treating Crohn's disease.

In a fourth aspect, the present invention provides a method of treating intestinal disease in a patient, wherein the active compound effective for intestinal disease is released at the intestinal tract in which the syndrome of the disease is expressed and / or in the intestinal tract where the receptor substrate of the active compound is located To let

A. polymethacrylate material; And

B. pH Dissolution Dependent Coating Materials

Provided is a method comprising administering to a patient an amount of an active compound effective for the treatment of the disease contained in at least two plurality of particles each coated with a different thickness with a coating material selected from among the two.

Such diseases may include all diseases of the intestinal tract, and active compounds may include all compounds effective for the treatment of such diseases, but preferably the disease is a disease as mentioned above, and the active compound is used to treat each disease. For the active compound as mentioned above. Most preferably the disease is an inflammatory bowel disease, in particular anemia associated with Crohn's disease or irritable bowel disease, more preferably the active compound is prednisolone metasulfobenzoate, 5-aminosalicylic acid, metronidazole, clarithromycin, metformin or It is erythropoietin.

Antibiotics that are effective in the treatment of inflammatory bowel disease or infectious diseases of the intestine are often toxic when absorbed, and the present invention can be adapted to be administered to the site of action in the intestine to reach sufficient local concentrations with minimal systemic absorption. In particular, antibiotics to which the present invention can be applied include toxic antibiotics such as gentamicin, which are used in patients particularly susceptible to the toxic effects of such drugs, such as patients with renal failure. In particular, the present invention is believed to be particularly effective for patients suffering from chronic intestinal diseases such as Crohn's disease and cystitis, which require long-term continuous administration of certain antibiotics such as metronidazole.

Other active agents that can be used include cytotoxic agents such as cyclophosphamide, cisplatin and other platinum drugs, vincristine and other vinca alkaloids; Immunomodulators such as metrotrexate, azathiaprine and cyclosporin; And antiparasitic agents such as albenazole.

Particles used in the present invention are generally pellets or granules.

The particles according to the invention may be pellets having a diameter in the range from 500 to 2500 μm, preferably in the range from 800 to 1700 μm, more preferably in the range from 800 to 1500 μm, even more preferably in the range from 1000 to 1500 μm. However, the particles may be any diameter within the above-mentioned range as well as a diameter outside the above range, and it should be understood that a single formulation according to the present invention may have particles having one or more diameters or particles having a range of diameters. do.

In addition, it should be understood that the actual coating thickness providing the coating in any particular weight increment depends on the size and weight of the particles.

The coating thickness according to the invention is preferably in the range of 5% to 30%, particularly preferably in the range of 10% to 25%, most preferably in the range of about 15% to about 20%.

Formulations according to the invention may comprise particles containing several active compounds. For example, one plurality of particles may contain a first active compound and another plurality of particles may contain a second other active compound. In addition, the particles in such formulations may be coated to provide different release profiles for each active compound. The coating for each of the plurality of particles will generally be a polymethacrylate material of thickness and composition that provides the desired release profile for each active compound. Alternatively, in order to take advantage of different release properties of coating materials other than polymethacrylate, one plurality of particles may be coated with a different coating material than the other plurality of particles.

The plurality of particles contained in any of these formulations is generally contained in and administered in an enteric coated capsule.

Hereinafter, the present invention will be described in more detail with reference to the accompanying drawings, the present invention is not limited by these embodiments.

Example 1

5% by weight of sodium prednisolone metasulfobenzoate, 40% by weight microcrystalline cellulose (Avicel ™ PH 101), 35% by weight lactose monohydrate (D80 200 Mesh) and 30% by weight croscarmellose sodium (Ac-Di-Sol ™) Anhydrous mixtures were prepared to prepare prednisolone metasulfobenzoate pellets. The mixture obtained by adding purified water (185% by weight) was mixed for 10 minutes to form an extrudable paste, and then a tube of 1 mm in diameter and about 5 mm in length from a 25 mm diameter intestine using a Nika fielder type E140 extruder. Extruded through at a rate of about 100mm / min and spheronized on a 20cm plate rotating at about 33rpm using the Nikka system spheronizer S700. The pellets obtained were dried in a fluidized granulator and screened to yield particles having a particle size in the range from 800 to 1500 μm.

These pellets were then spray coated with methacrylic acid and methyl methacrylate copolymers of methacrylic acid having a ratio of free carboxyl groups to ester groups of 1: 2 to give a theoretical weight increment (coating weight increment) of 5%, 15% and Three batches of 25% were obtained.

The release rate of prednisolone metasulfobenzoate released at a range of pH from pellets having these different coating thicknesses was investigated.

Example 2

The effect on the release of prednisolone metasulfobenzoate released from pellets to which coatings of 5%, 15% and 25% weight increments, prepared as described in Example 1, was applied was determined in the dissolution apparatus. Stir in sodium triphosphate solution and investigate the amount of prednisolone metasulfobenzoate in the solution by HPLC. The result is shown in FIG.

As can be seen in FIG. 1, the increase in coating thickness significantly reduced drug release rate. The 5% weight increment coated pellets released the drug completely (100%) within 15 minutes. However, pellets coated with 15% weight increments showed 50% drug release after about 45 minutes and 100% drug release after about 100 minutes, and 25% weight increments coated pellets after 50% drug release. , 100% drug release was seen after about 300 minutes.

Particularly surprising is that particles coated with coating materials of the same pH dissolution dependence only at different thicknesses release the drug at significantly different rates at the same pH.

Example 3

The effect of pH on the rate of drug release in coated pellets with a 15% weight increment coating prepared according to Example 1 was investigated. Drug release experiments of the pellets were conducted as described in Example 2, except that pH 6.0, 6.2, 6.6 and 7.2 were used. FIG. 2 shows the pH dependent properties of the drug released from coated pellets with 15% weight increments of the coating.

As can be seen in Figure 2, at pH 6, complete drug release appeared after about 120 minutes and 50% drug release appeared after about 45 minutes. Drug release rates increased at pH higher than pH 6, resulting in complete drug release after about 30 minutes at pH 7.2.

Example 4

In order to investigate the effect of the specific coating composition on drug release, two prednisolone metasulfobenzoate pellet batches, each coated with 15 selected weight increments of two selected polymethacrylate coating materials, were prepared according to the method of Example 1. Prepared. The pellets of the first batch had a copolymer of 5% methacrylic acid ethyl acrylate copolymer having a ratio of free carboxyl groups to ester groups 1: 1 and methacrylic acid and methyl methacrylate having a ratio of free carboxyl groups to ester groups 1: 2. A mixed polymethacrylate coating containing% was applied in 15% weight increments. The pellets of the second batch were coated in 15% weight increments with a copolymer of methacrylic acid and methyl methacrylate with a ratio of free carboxyl groups to ester groups of 1: 2.

The two pellet batches thus obtained were subjected to a drug release experiment in the manner described in Example 2 to investigate the effect of the coating composition on drug release. The result is shown in FIG.

As can be seen in FIG. 3, batch 1 in which the pellets are coated with a polymethacrylate mixture (ie, one is dissolved at pH 6.0 and the other is dissolved at pH 5.5) is a polymer in which the pellets are dissolved at pH 6.0 to 7.0. The drug was released at a faster rate than batch 2 coated with methacrylate.

Example 5

To investigate the effect of pellet size on drug release, prednisolone metasulfobenzoate pellets were prepared in two batches according to the method of Example 1. The first batch is up to 2000 μm in diameter and the second batch is up to 1500 μm in diameter and both have a 15% weight increment of a copolymer of methacrylic acid and methyl methacrylate with a ratio of free carboxyl to ester groups of 1: 2. It is coated with. This pellet was used to perform drug release experiments in accordance with Example 4. The result is also shown in FIG.

As can be seen in Figure 3, the drug release rate decreased with increasing pellet size. This is because the larger the pellet size, the smaller the surface area-to-weight ratio, so that pellets with larger pellet sizes to which a certain percentage of the coating weight increment is applied will have a thicker coating thickness than smaller pellets through the same percentage of coating weight increments. It is feed.

Example 6

A pellet containing paracetamol instead of prednisolone metasulfobenzoate was prepared according to the method of Example 1, and a copolymer of methacrylic acid and methyl methacrylate having a ratio of free carboxyl group to ester group of 1: 2 in 20% weight increments. After coating, a similar drug release experiment was performed as in Example 3 except that the pH was 6.2, 6.6 and 7.2. The result is shown in FIG.

As can be seen in Figure 4, the drug release rate was found to be pH dependent, with pH 6.2 at 50% drug release at about 120 minutes and complete drug release at about 300 minutes, while at pH 7.2 complete drug release was within 15 minutes. appear.

Thus, it was evident that this delay and rate control ability of drug release is not limited to prednisolone metasulfobenzoate but could be applied to a wider range of drugs.

Example 7

Metronidazole pellets were prepared according to the method as described in Example 1 except that 20% by weight of metronidazole was used instead of 5% by weight of prednisolone metasulfobenzoate. The proportion of the remaining components was adjusted to 40% by weight microcrystalline cellulose (Avicel ™ PH 101), 20% by weight lactose monohydrate and 20% by weight croscarmellose sodium (Ac-Di-Sol ™).

These metronidazole pellets are then spray coated with a methacrylic acid copolymer of methacrylic acid and methyl methacrylate having a ratio of free carboxyl groups to ester groups of 1: 2 to give the coating a 20% theoretical weight increment (coating weight increment). Coated pellets were obtained.

In order to investigate the effect of pH on the release rate of metronidazole released from metronidazole pellets, the pellets obtained above were placed in a sodium triphosphate solution (pH 6.0, 6.6 and 7.2) in a dissolution apparatus and stirred, followed by 15 minute intervals. Samples were taken and the metronidazole content in the solution was measured by HPLC. The results are shown in FIG.

As can be seen in Figure 5, the complete drug release appears at about 240 minutes at pH 6.0, 50% drug release appears at about 145 minutes, while the drug release rate increases at higher pH, resulting in about 180 minutes at pH 7.2. Appeared after.

Example 8

Metronidazole pellets were prepared as described in Example 7. The pellet was then spray coated with methacrylic acid copolymer of methacrylic acid and methyl methacrylate with a ratio of free carboxyl groups to ester groups of 1: 2 to give the coating (weight increments) a theoretical weight increment of 15%, 20%. And 25 batches of 25% were obtained.

The effect of coating thickness on the release rate of metronidazole released from coated metronidazole pellets was determined by dissolving the pellets of each batch in a trisodium phosphate solution (pH 6.6) and taking samples every 15 minutes with stirring to determine the content of metronidazole in the solution. Was determined by HPLC. The result is shown in FIG.

As can be seen in Figure 6, as the coating thickness increased drug release rate significantly decreased. Pellets coated with 15% weight increments showed complete (100%) drug release at about 120 minutes. However, pellets coated with 20% weight increments showed 50% drug release after about 120 minutes and 100% drug release after about 240 minutes, and pellets coated with 25% weight increments showed 50% drug release after about 200 minutes. And about 300 minutes, 100% drug release.

Example 9

Α-amylase pellets were prepared using the method described in Example 1 except that the α-amylase was dissolved in the granulation fluid (water). The proportions of the other components were adjusted to 40% by weight microcrystalline cellulose (Avicel ™ PH 101), 20% by weight lactose monohydrate and 40% by weight croscarmellose sodium (Ac-Di-Sol ™).

These pellets were then coated with a methacrylic acid copolymer of methacrylic acid and methyl methacrylate having a ratio of free carboxyl groups to ester groups of 1: 2 in the theoretical weight increments (coating weight increments) of 15%, 20% and 25 Spray coated to%.

The effect of coating thickness on the release rate of α-amylase released from α-amylase pellets coated at pH 6.0 was determined by the sigma enzyme assay (Sigma-Aldrich Company Ltd., The Old Brickyard, New). Road, Gillingham, Dorset, SP8 4XT, UK) was used to colorimetrically investigate and the results are shown in FIG.

As can be seen in FIG. 7, the drug release rate decreased with increasing coating thickness, as in prednisolone metasulfobenzoate pellets and metronidazole pellets. The amount of α-amylase released was directly proportional to the activity observed. Pellets coated in 15% weight increment showed maximum amylase activity at about 240 minutes. However, pellets coated with 20% weight increments showed about 50% total activity after about 180 minutes and 100% total activity after about 300 minutes. Pellets coated with 25% weight increments exhibited 25% total activity after about 180 minutes but less than 50% after 300 minutes.

The results of Examples 6-9 demonstrate that the present invention is applicable to other active compounds besides prednisolone metasulfobenzoate. Therefore, the scope of application of the present invention is surprisingly wide.

The present invention is not limited to the details described above with reference to the preferred embodiments, and various modifications and changes can be made without departing from the spirit or scope of the invention as defined in the following claims. Is obvious.

Claims (39)

An oral pharmaceutical composition comprising two or two or more types of particles, wherein the particles comprise prednisolone metasulfobenzoate, and each of the plurality of particles is a polymethacrylate having a different thickness from each of the other plurality of particles. An oral pharmaceutical composition coated with a substance such that prednisolone metasulfobenzoate is released at different positions in the intestinal tract. The oral pharmaceutical composition according to claim 1, wherein the polymethacrylate material is a pH dissolution dependent polymethacrylate material. The oral pharmaceutical composition according to claim 1 or 2, wherein each of the plurality of particles is coated with a polymethacrylate material of different thickness such that the prednisolone metasulfobenzoate is released at positions before and after the intestinal valve. The method according to claim 1, wherein the thickness of the polymethacrylate material coating particles of each of the plurality of particles provides a uniform release profile of prednisolone metasulfobenzoate along one or more selected sites of the intestinal tract. Oral pharmaceutical composition selected and increasing. An oral pharmaceutical composition comprising two or more types of particles, wherein the particles comprise an active compound, and each of the plurality of particles has a different pH dissolution dependent polymethacrylate with a different thickness of each of the plurality of particles. An oral pharmaceutical composition coated with a substance such that the active compound is released at different positions in the intestinal tract. 6. The oral pharmaceutical composition according to claim 5, wherein the active compound is selected from the group consisting of prednisolone metasulfobenzoate, metronidazole and alpha-amylase. The oral pharmaceutical composition according to any one of claims 1 to 6, wherein each of the plurality of particles is coated with the same coating material as each of the other plurality of particles. 8. The oral pharmaceutical composition according to any one of claims 1 to 7, wherein the polymethacrylate material comprises methacrylic acid copolymer. The oral pharmaceutical composition according to any one of claims 1 to 8, wherein the polymethacrylate material comprises a copolymer of methacrylic acid and methyl methacrylate. 10. The copolymer of free carboxyl group to ester group according to claim 1, wherein the polymethacrylate material is a copolymer of methacrylic acid and methyl methacrylate having a ratio of free carboxyl groups to ester groups of about 1: 2. 11. Oral pharmaceutical composition selected from copolymers of methacrylic acid and methyl methacrylate or mixtures thereof having a ratio of about 1: 1. The oral pharmaceutical agent according to any one of claims 1 to 10, wherein the particles are coated with methacrylic acid copolymer of methacrylic acid and methyl methacrylate having a ratio of free carboxyl groups to ester groups of about 1: 2. Composition. The oral pharmaceutical composition according to claim 1, wherein the particles have a diameter in the range of 800 to 1500 μm. 13. The oral pharmaceutical composition according to any one of claims 1 to 12, wherein the particles are coated with the polymethacrylate material in a theoretical theoretical weight increment in the range of 5% to 30%. 14. An oral pharmaceutical composition according to any one of claims 1 to 13, wherein the particles are coated with the polymethacrylate material in a theoretical theoretical weight increment in the range of 10% to 25%. The method according to claim 1, wherein the thickness of the polymethacrylate material coated particles of each of the plurality of particles is selected and increased to provide a uniform release profile of the active compound along one or more selected sites of the intestine. Oral pharmaceutical composition. 16. The oral pharmaceutical composition according to any one of claims 1 to 15, further comprising an enteric coated capsule containing a plurality of particles. The oral pharmaceutical composition according to any one of claims 1 to 16, wherein two or more kinds of particles are present. 18. The oral cavity of claim 1 wherein the first plurality of particles is coated to provide a 15% theoretical weight increment and the second plurality of particles is coated to provide a 20% theoretical weight increment. Type pharmaceutical composition. 19. The oral pharmaceutical composition according to claim 17 or 18, wherein the first plurality of particles and the second plurality of particles are present in a ratio of about 1: 3. Use of the coating thickness of the pH dissolution dependent coating material on particles comprising the active compound to control the release profile of the active compound in the intestine. The use of claim 20, wherein the coating material is a polymethacrylate material. 22. The use of claim 21, wherein the polymethacrylate material comprises methacrylic acid copolymer. Use according to claim 22 or 23, wherein the polymethacrylate material comprises a copolymer of methacrylic acid and methyl methacrylate. 24. The copolymer of any of claims 20 to 23 wherein the polymethacrylate material is a copolymer of methacrylic acid and methyl methacrylate, free carboxyl group to ester group, wherein the ratio of free carboxyl group to ester group is about 1: 2. And a copolymer of methacrylic acid and methyl methacrylate or a mixture thereof having a ratio of about 1: 1. The use according to any one of claims 20 to 24, wherein the active compound is selected from the group consisting of prednisolone metasulfobenzoate, metronidazole and alpha-amylase. 20. An oral pharmaceutical composition according to any one of claims 1 to 19 for use in the treatment or diagnosis performed in the human or animal body. 20. Used for the preparation of the pharmaceutical composition according to any one of claims 1 to 19 for treating intestinal diseases. A. polymethacrylate material; And B. Use of a coating material selected from pH dissolution dependent coating materials. 28. The use of claim 27, wherein the coating material is a polymethacrylate material. Use according to claim 27 or 28, wherein the coating material is a pH dissolution dependent polymethacrylate material. Use of a polymethacrylate material for the preparation of a pharmaceutical composition according to any one of claims 1 to 19 for the treatment of Crohn's disease. A method of treating intestinal disease in a patient, the method of releasing an active compound at the intestinal location at which symptoms of the intestinal disease have occurred, A. polymethacrylate material; And B. A method comprising administering to a patient an effective amount of an active compound for treating intestinal diseases contained in at least two plurality of particles each coated with a coating material of different thickness selected from a pH dissolution dependent coating material. 32. The method of claim 31, wherein the disease is Crohn's disease. 33. The method of claim 31 or 32, wherein there are two plurality of particles. 34. The method of any one of claims 31-33, wherein the active compound is prednisolone metasulfobenzoate. 35. The method of any one of claims 31-34, wherein the coating material is a polymethacrylate material. 36. The method of any one of claims 31-35, wherein the active compound is released at locations before and after the intestinal valve. A composition as substantially described above with reference to the Examples appended hereto. Use of the coating thickness of the pH dissolution dependent coating material as substantially described above with reference to the Examples appended hereto. Use of a coating material as substantially described above with reference to the examples appended hereto.