Composition with controlled release

FIELD: medicine.

SUBSTANCE: invention discovers improved composition for profile control of active compound release through the digestive tract, including particles, especially granules, containing the active compounds. They are covered with coating material, solution of which depends on pH value, or polymethacrylate material, solution of which, for preference, depends on pH value, the definite thickness, desirable place and speed of the active compound release. In preferable compositions two or more particles, in which particles of each multitude are covered with the coating material, the solution which depends on pH value, or polymethacrylate material, of different thickness in comparison with the particles of each other multitude, are contained in capsules with enterosoluble coating and provide the active substance release in different desirable places of the digestive tract.

EFFECT: provision of active substance release in desirable places of digestive tract.

28 cl, 7 dwg, 9 ex

 

The invention relates to the use of polymethacrylate materials, especially those whose dissolution is dependent on pH, and other coating materials, the dissolution of which depends on pH, to control release of the active compound in the gut. The present invention relates also to the use of prednisolone metasulphobenzoate (11,17-dihydroxy-21-[(3-sulfobenzoic)oxy]pregna-1,4-diene-3-20-dione) and pharmacologically acceptable salts, especially sodium salts, for the treatment of inflammatory bowel disease, especially Crohn's disease.

In particular, the invention discloses a solid pharmaceutical composition having two or more sets containing the active compound particles coated with polymethacrylate material of the desired thickness, or other covering material, the dissolution of which depends on pH, to control the release profile of the active compound, such as prednisolone metasulphobenzoate. It also reveals the coating thickness of polymethacrylate material or other covering material, the dissolution of which depends on pH, to control the release profile of the active compounds in the intestinal tract.

Unless the context clearly that you are using the free ester, the term "prednisolone metasulphobenzoate" is used in the us is oasam the description to denote the pharmacologically acceptable salts prednisolone metasulphobenzoate, as well as free of ester.

The ability to control release of the active compounds in the gastrointestinal tract is desirable. Some States require local treatment of the bowel, and if medicines are used for the purpose indicated, are absorbed systemically, may be problematic side effects. In other situations, acidic conditions in the stomach can destroy some active compounds, especially peptides and proteins, and it would be advantageous provision of the media for their delivery in the areas of the intestine, from which they can be absorbed systemically, or in which they can provide their therapeutic effect. Can also be advantageous in the case of some active compounds, especially peptides and proteins, introduction to specific areas of the intestine to the systemic absorption, which may be carried out in two or more different areas. Examples are compounds of systemic absorption which depends on the location of M-cells, or Meyerovich plaques.

In other situations, it is desirable only to the introduction of active compounds to a patient continuously for a certain period of time to maintain the desired concentration of active compound in the blood plasma, and composition with controlled release for oral administration to provide the provides a convenient and efficient way to achieve this goal.

Some ways of controlling release of the active compounds is known. For example, providing Intercollege coating on the tablet or capsule to ensure its passage through the stomach to the destruction in the small intestine is well known. Also known introduction to the patient active compounds in the matrix with a slow release. Another known method consists in the manufacture of derived active compounds, for example, a derivative of glucuronic acid, which will not be split until then, until you come in contact with the corresponding intestinal enzyme, for example, glucuronidases, thus releasing the active connection.

Particularly aimed at providing compositions with controlled release of active compounds in diseases of the bowel, especially those for which will benefit local impact, and a suitable example is inflammatory bowel disease (IBD).

Inflammatory bowel disease includes chronic nonspecific inflammatory condition of the gastrointestinal tract, the two major forms of which are Crohn's disease and ulcerative colitis.

Crohn's disease can affect any part of the gastrointestinal tract, although it often affects the small intestine, especially odvzdusneni intestine, and can also affect the gut and skinny any part of the colon, including the rectum and, especially, blind intestine. It is characterized by thickened patches of the walls of the gastrointestinal tract, inflammation, covering all layers, deep pitting and cracking of the mucosa. The affected area often alternate with areas of relatively normal tissue.

To treat cases of Crohn's disease affecting the colon, is used sulfasalazin, because it contains 5-aminosalicylic acid in intersolubility the shell or in the form of delayed release. Steroids are widely used to treat severe cases of inflammation of the colon, particularly ulcerative colitis and Crohn's disease. They are usually administered orally or parenterally to obtain a systemic effect, or rectally by enema, to obtain a local effect. Relatively high doses of steroids are required to treat severe cases of inflammatory bowel disease. However, systemic absorption causes serious side effects, although systemic absorption less with the introduction of rectal enemas treat only the lower parts of the colon and rectum, and it creates discomfort.

The steroid most commonly used oral treatment vospalitelno the bowel disease, is prednisolone (17,21-dihydroxypregna-1,4-diene-3,11,20-Trion) in the form of the free alcohol or of ester, typically acetate. Daily doses of 15 to 60 mg (calculated as the free alcohol) are required to treat severe cases of inflammatory bowel disease, but the absorption of these doses is harmful. Accordingly, the existing treatment prednisolone is limited as the dose and duration of therapy.

It was suggested several methods and compositions for targeting or control the release of active compound in the gut, often for the treatment of inflammatory bowel disease and Crohn's disease.

US-A-4496553 relates to oral pharmaceutical composition comprising 5-aminosalicylic acid (5-ASA), for the treatment of ulcerative colitis or Crohn's disease. The patent describes a tablet delayed release, consisting of granules 5-ASA coated ethylcellulose and pressed to pellets, microcrystalline cellulose, talc and sodium stearate. Tests on patients with ileostomy showed that 50% of the active ingredient from the tablets released in the small intestine. In the patent approved (column 6, lines 15-22)that the release can be controlled by varying one or more of the particle size of the granulated active ingredient, thickness and pronic is a resistant coating, the active ingredient and pH conditions inside the particles is coated.

EP-IN-0097651 describes a composition for selective administration of 5-aminosalicylic acid in the large intestine, including solid dosage form for oral administration containing an active compound, coated in a layer thickness of from 60 to 150 micrometers of the anionic polymer, which is insoluble in gastric juice and in intestinal juice at pH below 7, but soluble in the content of the large intestine, so that the dosage form remains intact until it reaches the colon.

EP-IN-0572486 describes a pharmaceutical dosage form for oral administration, which includes many of the granule drugs such as 5-aminosalicylic acid, is covered with a material which dissolves in the intestine and is contained in a capsule, which is also covered with a material which dissolves in the intestine. The composition is intended for the selective introduction of the drug in the intestine. It is argued that the granules are preferably contained in a capsule with intersolubility coating that releases the granules in the small intestine, and that the granules have a coating that remains essentially intact up until they reach at least the ileum, and, preferably,after which provide slow release of the drug in the colon.

EP-A-0772443 describes netintegrity solid intersolubility pharmaceutical composition comprising prednisolone metasulphobenzoate, relatively fast dissolving at pH 6.5 of the matrix-excipients, and dosage forms containing pellets of this composition. Rapid dissolution is enhanced in the presence of rheological modifier of superdisintegrants in the amount of at least 5 wt.%, but insufficient to cause disintegration of the composition. It is argued that the composition may include a number of such granules, which may have intersolubility floor, such as acatitla cellulose, or, preferably, partially methylethylamine polymers of methacrylic acid having a ratio of free acid groups and ester groups of approximately 1:2, contained in a capsule with intersolubility coating of a suitable covering material. The covering material on the granules preferably is a material that is not soluble in gastric juice and intestinal juice at pH below 7, but soluble in intestinal juice more distal bowel. Intersolubility covering the capsule material is chosen in such a way as to protect the capsule during passage through the stomach. The composition is intended for the treatment of Crohn's disease.

EP-IN-0502032 describes a composition for the release of the active compound in a specific area - in the colon, for the treatment of diseases of the colon such as ulcerative colitis and Crohn's disease. Among others, the active ingredient may be, for example, prednisolone or 5-aminosalicylic acid. The composition comprises an active compound and amorphous amylose, with an outer coating of cellulose or acrylic polymer material. The active compound is preferably covered with a vitreous aminosol, which tends not to degradirovali until then, until you reach the large intestine, where it is attacked by splitting amylose enzymes provided by the microbial flora present in the norm in the colon. The composition optionally coated with cellulose or acrylic polymer material, which enhances the property delayed release composition coated aminosol. The rate of release of active compound from the composition after it reaches the large intestine can be controlled by varying the thickness of the internal coating of amylose. It is argued that is also possible to vary the release in the colon coating of amylose different thickness on different parts of the active compounds. Features of release can be varied additionally the drying, which affects the pore size and permeability, or the addition of a fatty or waxy substances to slow the penetration of water. Preferably, the outer covering material of cellulose or acrylic polymer showed a pH-independent degradation.

WO-A-9921536 relates to compositions with controlled release formulation suitable for delivery of the active ingredient in the colon. Describes the composition, which includes balls 5-aminosalicylic acid, also contains microcrystalline cellulose and having diameters in the range from 1.00 to 1.40 mm; these balls cover composition of amylose/ethyl cellulose in a mixed solvent (water and miscible with water, an organic solvent), although instead of the ethyl cellulose may be an acrylic polymer. The release profiles were studied for a range of ratios amylose/ethylcellulose and the thickness of the coating. It was found that coatings with a high proportion of ethyl cellulose was provided by a very small release of drugs, due to the absence of end-to-end channels in amylose through the surface to the core of the granules, while coating with a high proportion of amylose created a film whose structure was balanced. Accordingly, when the coatings had higher concentrations of amylose was used thicker pok the eve ENT, and the results showed that in these circumstances, the release of the active compounds should not take place before reaching the colon.

EP-A-0264989 describes pharmaceutical compositions derived Reina with a slow release. In particular, describes compositions designed to provide levels of the drug in the blood over a period of time up to 24 hours from the moment of introduction. As you can see from the example 2 of this reference, describes the General concept of coating particles of material of different thickness (in the example - acatitla pulp) in order to release drugs at different speeds, therefore, to provide a slow release over a predetermined period of time.

US-A-5529790 describes pharmaceutical compositions, which provide a delayed and slow release of drug from the composition through Gidrodinamika diffusion barrier coating. The delay is a consequence of the speed of hydration and thickness of the coating, and slow release depends on the permeability and thickness of the coating. The diffusion barrier preferably comprises a film-forming material which is not soluble in the conditions of the intestine, and at least one additional additive, which controls the duty to regulate the rate of hydration and permeability of the diffusion barrier. Preferred film-forming polymers are aqueous dispersions of fully esterified acrylic resins (e.g., Eudragit NE30D), a fully esterified acrylic resins containing side chains of Quaternary amines (for example, Eudragit RS30D), or aqueous dispersions of ethyl cellulose. The preferred additive for controlling the rate of hydration and permeability is magnesium stearate. Drug (e.g., diltiazem hydrochloride) may be made in the form of spherical particles having a diameter in the range of 500-1500 μm, and preferably made in the form of two groups of particles, the group's long-delayed release, with a low rate of hydration and low permeability, and groups with a short delay release, with a relatively high rate of hydration and high permeability, so that the slow release of drugs can be influenced over a long period of time. Conducted research dissolving the particles with different coating thickness.

US-A-4728512 describes a pharmaceutical composition, comprising three groups of releasing the drug pellet, placed, for example, in a capsule, of which each group of pellets releases the drug at a different time in the digestive systems of the patient. In particular, describes a composition in which one group of granules has no coating and releases the drug immediately after the release of pellets from the capsule, the second group of granules, which has a pH-dependent coating (e.g., 20-30 wt.% Eudragit S), and the third group of granules, which has a pH-independent coating, such as a double cover, which is dependent on time of the lower layer (e.g. hypromellose) additionally covered gidratirutmi diffusion barrier coating (e.g., Eudragit E30D and metal stearate). The composition, therefore, consists of three release drug systems that provide the maximum release of the drug over a time period 0-2 hours after administration, 2-6 hours after dosing and 4-10 hours after administration, respectively. The composition provides three doses of the medicinal product during the period of time, for example, 12 hours, by release of the drug in three installments in an amount corresponding to the relative number of each group of particles. Groups of particles covered with the covering materials of different thickness, and thus, the document describes the General concept of the application of different groups of particles with different properties release to release of the active compounds in R is slichnih the sections of the intestinal tract (through various delays in the release of drug from the second and third group of granules).

So far there is no effective method or composition for the controlled release of active compounds in the intestine, which overcomes or responds to changes in pH and the rate of passage that occur throughout the gastrointestinal tract.

Desirable would be an improved method and composition for controlled release of active compounds, such as prednisolone metasulphobenzoate in the intestines.

The authors currently have installed that application polymethacrylate material of different thickness, the dissolution of which depends on pH, particle prednisolone metasulphobenzoate, unexpectedly led to the release of prednisolone metasulphobenzoate with different speeds at the same pH and controlled manner within a range of pH. The thickness of the applied polymethacrylates coverage you can choose depending on pH and the desired speed and location of release, to provide a controlled release profile prednisolone metasulphobenzoate. Covering materials, the dissolution of which depends on the pH, such as the polymethacrylates are typically used to provide release of the active compound in one place gastrointestinal tract. To the authors ' knowledge, the use of varying thickness covering m is materials, the dissolution of which depends on the pH, is not practiced to provide continuous or slow-release.

Accordingly, in a first aspect the present invention relates to pharmaceutical compositions for oral administration, comprising two or more sets of particles; these particles include prednisolone metasulphobenzoate where the particles of each of the specified set is covered polymethacrylate material of different thickness as compared with particles of a given set or every other set, whereby prednisolone metasulphobenzoate released in different parts of the intestinal tract.

The authors also found that the application of this technology can be extended to compositions comprising other active compounds.

Accordingly, also in the first aspect of the present invention relates to pharmaceutical compositions for oral administration, comprising two or more sets of particles; these particles comprise the active compound, in which the particles of each of the specified set is covered polymethacrylate material of different thickness as compared with particles of a given set or every other variety, the dissolution of which depends on the pH, whereby the active compound is released in different sections of the intestinal tra is the same.

Not wanting to be limited to any particular theory, the authors suggest that the type of release of the active compounds of the compositions may occur due soon altered permeability of the coating than the destruction of coatings of various thickness. Observations show that the active connection seems to be separated from the composition before degradation of the composition.

The following characteristics can be applied to a variant implementation of the first aspect of the present invention, uses of prednisolone metasulphobenzoate, or to a more General variant of implementation of the present invention.

The covering material may be any material that is used or is suitable in coating of oral pharmaceutical dosage forms for delivery of active compounds in the intestine, and, preferably, is a derivative of cellulose, the dissolution of which depends on pH, such as acatitla pulp and acatitla hydroxypropylmethylcellulose, or polymethacrylate material, the dissolution of which, preferably, is dependent on the pH value.

Derived cellulose is preferably selected from acatitla cellulose, hydroxypropylmethylcellulose, phthalate of hydroxypropylmethylcellulose, acatitla hydro is dipropylthiocarbamate and other mono - or polyclonality and/or ether derivatives of cellulose, the dissolution of which depends on the pH value.

Under the covering material, the dissolution of which depends on pH, refers to such materials, which, according to the prior art, are insoluble in gastric media up until not achieved a certain pH value, and such materials that provide dependent on the pH of the release of drugs when they are used as a covering material for pharmaceutical dosage forms for oral administration.

The polymethacrylates which are particularly suitable for the purposes of the present invention are anionic polymers dimethylaminoethylmethacrylate, methacrylic acid and esters of methacrylic acid in different ratios.

The polymethacrylates can be a copolymer of acrylic acid (such as methacrylic acid) and esters of acrylic acid (such as metilmetakrilat or tilatequila). Preferably, polymethacrylates, used for the purposes of the present invention are copolymers of methacrylic acid, based on methacrylic acid, and various esters of acrylic acid (such as acrylate or methacrylate), or mixtures thereof. More preferably, use one or more with the polymers of methacrylic acid and methyl methacrylate, preferably having a ratio of free carboxyl groups and ester groups, for example, about 1:2 (sold under the registered trademark EUDRAGIT S Röhm Pharma GmbH, Darmstadt, Germany), and having a molecular weight of 135,000, or about 1:1 (sold by the company Röhm Pharma GmbH under the registered trademark EUDRAGIT L), or a mixture thereof.

Preferably, in the present invention using such polymethacrylates, the dissolution of which depends on the pH. Under polymethacrylates, the dissolution of which depends on the pH, refers to such polymethacrylates, which, according to the prior art, are insoluble in gastric media up until not achieved a certain pH value, and such polymethacrylates that provide dependent on the pH of the release of drugs when they are used as a covering material, for example, see The Handbook of Pharmaceutical Excipients, 3rd ed., published by Arthur H. Kibbe (American Pharmaceutical Society and the Pharmaceutical Press, 2000). Preferably, polymethacrylate material includes polymethacrylate, which is insoluble in the gastric environment up until not achieved a certain pH value, and/or provides dependent on the pH of the release of the medicinal product, when used as a covering material is material, according to The Handbook of Pharmaceutical Excipients, the contents of which are on pages 401-406 included in the present description by reference.

These include polymethacrylates and copolymers of methacrylic acid and methyl methacrylate having a ratio of free carboxyl groups and ester groups of approximately 1:2 (sold as EUDRAGIT S Röhm Pharma GmbH), or about 1:1 (sold as EUDRAGIT L by the company Röhm Pharma GmbH), and a copolymer of methacrylic acid and ethyl acrylate with a ratio of free carboxyl groups and ester groups of approximately 1:1 (sold under the registered trademark EUDRAGIT L 30 D-55 or EUDRAGIT L 100-55 company Röhm Pharma GmbH). More preferably, polymethacrylate is polymethacrylate, which is soluble at pH above 5.5, and even more preferably above 6.

Preferably, the material covering the particles of each set of particles is the same, which covers the particles of a given set or every other set of particles.

In one embodiment of the present invention, the particles of each of the sets can be coated covering material, the increment of the thickness which is selected so as to provide a uniform release profile of the active compound during at least one selected part of the gastrointestinal tract or throughout the intestinal is rakta. The selected portion may be positioned around, but preferably, before and after ileocecal valve.

Preferably, the thickness of the covering material and the size of its increment is chosen so to ensure release of the active compounds in many areas, so the release is uniform throughout the intestine. It may be desirable, for example, with the introduction of active compounds for the treatment of Crohn's disease, to provide a uniform release of the active compounds over the ileum and colon and, more specifically, the ascending colon.

In this embodiment, the present invention can provide a uniform release of the active compound that has advantages compared with conventional drugs with a slow release that the magnitude of the increment of the thickness of the covering material, especially polymethacrylate material can be chosen in such a way as to overcome the change of pH and varying the rate of passage or transit of the capsule or tablet through the intestines.

In the case of conventional drugs with a slow release changes the rate of passage through the intestinal tract can lead to the delivery of active compounds in certain parts of the intestine at the lower concentration than in the other is x parts. Similarly, changes in pH in different parts of the intestine tends to lead to different rates of release of regular medications with a slow release. This can lead to loss of effect.

In patients with inflammatory bowel disease, especially with active inflammation, the rate of passage through the gut and pH within the gut often do not correspond to the norm. Conventional compositions with delayed release, which provide release of the active agent in a time-dependent or pH, may not provide a predictable or effective delivery of active agent to the target areas of the intestine. Such compositions can lead to the delivery of insufficient doses in some areas or to the delivery of an excessive dose "dose dumping", in other places.

In this embodiment of the present invention, these changes can be taken into account, for example, coating the particles of each set of particles covering material of a selected thickness to provide a release in many areas throughout the gut; and the value of increment of thickness of the coating for each set can vary. For example, in order to obtain a homogeneous release in parts of the bowel, in which the speed is higher, and in those parts where the speed etc is going lower the value of increment of thickness of the coating sets of particles delivered to the part of the intestine with a higher speed will be less than that of the particles delivered to the part of the intestine with lower speed and/or number of particles in the set of particles delivered to the part of the intestine with a higher speed, there will be more. Similarly, in order to provide a uniform release in parts of the intestine with a higher pH and a lower pH value, the thicker the coating should be applied to particles that are designed to release the active compound in the part of the intestine where the pH is higher, although this will depend on its location in the intestine. In this way, the rate of release of active compound can be controlled for changes in pH or the rate of passage through the gut, independently from specific attained pH or specific time that passed before the release of the active connection.

Alternatively, the coating thickness for each of the sets can be chosen in such a way as to affect the release of the active compounds in specific areas of the intestine. For example, each of the sets of particles can be coated covering material of different thickness, making active the connection is released, for example, in places around, but preferably, before and after, ileocecal valve.

Preferably, there are two sets of particles; one set in which the particles are covered with a covering material of such thickness to release the active compound in the distal part of the ileum to the ileocecal valve, and another set in which the particles are covered with a covering material of a different thickness to release the active compound in the proximal part of the caecum, after ileocecal valve. Preferably, the covering material is polymethacrylate material, more preferably, a copolymer of methacrylic acid and, more preferably, a copolymer of methacrylic acid and of methyl methacrylate, preferably having a ratio of free carboxyl groups and ester groups of approximately 1:2.

The coating on the particles may have a thickness corresponding to a theoretical weight gain on coating 15% for one of the sets, and 20% weight gain for the other, and, preferably, the number of particles in each set has a ratio of coated particles with a 15% weight gain and coated particles with a 20% weight gain 1:3.

In order to further control the release profile of the active compound during bowel particles from one of the many frequent is t possible to cover other covering material relative to the particles of another set of particles. Particles of the same variety can also be of a size different from a size of another set.

The present invention can be used, for example, for the introduction of active compounds that exert local therapeutic effects in the gut, for the introduction of active compounds with high molecular weight for local or systemic effect and for the introduction of any active compound, which has the advantages of controlled release throughout the gastrointestinal tract, for example, active compounds that have systemic absorption depends on the location and speed of release in the intestine.

It is especially suitable for the delivery of active connections for local effects on one or more sections of the intestinal tract. For example, in the treatment of inflammatory bowel disease, particularly Crohn's disease, when the affected area can have a different location in the intestinal tract, and controlled delivery of active compounds in the specified area without entering in unaffected areas to minimize systemic absorption of the active compounds and, consequently, any adverse effect that may occur due to systemic absorption.

In the case of the introduction of high-molecular compounds, for example, proteins or peptides, the present izaberete the s can be used to protect the active compound from degradation in the acidic conditions of the stomach, and it may, for example, to ensure the delivery of compounds in such areas of the intestine, from which it can be absorbed, or which are necessary M-cells or Peyer's plaques.

The present invention is particularly suitable for the delivery of macromolecular compounds, for which the integrity of the tertiary structure is critical to the efficiency and security of the connection. A special advantage of the present invention is that the pharmaceutical composition for oral administration can be produced in gentle conditions compared with most pharmaceutical processes, at the same time providing the desired release profile of the compounds in the intestinal tract.

An example of a high-molecular compounds, which will be beneficial when used in compositions of the present invention, is erythropoietin, a glycosylated protein hormone and hematopoietic growth factor, which is considered suitable for the treatment of anemia in chronic renal failure, among other conditions, and has been studied in the treatment of anemia in inflammatory bowel disease, and other normocytic/normochromic anemia. Erythropoietin is usually injected subcutaneously or intravenously, although described tableted form of erythropoietin (EN-A-2152206).

Other classes of high molecular weight with the joining, who can benefit when using the present invention include interferons, TNF antagonists and specific protein and polypeptide agonists and antagonists of the immune system, hormones such as human growth hormone and cytokines and antagonists of cytokines.

Other compounds and classes of compounds, the introduction of which can benefit when using the present invention include analgesics and antipyretics; antibacterial and Antiprotozoal agents, such as metronidazole and other nitroimidazole antibiotics, and antibiotics, active against anaerobic bacteria, clarithromycin and other macrolide antibiotics, gentamicin, ciprofloxacin, rifabutin and other similar antibiotics, active against pathogens commonly associated with or causing bowel disease; anti-inflammatory agents such as salicylates, for example, 5-aminosalicylic acid, 4-aminosalicylic acid and derivatives, such as balsalazide, steroids, especially prednisone metasulphobenzoate; probiotics and prebiotics, which has been shown to affect the symptoms of inflammatory bowel disease and irritable bowel syndrome and recovery from associated with antibiotics diarrhea, and pharmacologically active drug substances, know the IDT, they affect the symptoms of irritable bowel syndrome, for example, those that affect the serotonergic system, and those that are active in the field of opiate receptors. α-amylase and paracetamol can also be entered by using the composition according to the present invention.

Other compounds that can benefit when using the present invention include certain compounds with toxic effects, which limits their clinical application, especially cause local toxicity in specific areas of the gastrointestinal tract. These compounds include, among others, examples of antibiotics, bisphosphonates and anti-inflammatory medicines. A concrete example is Metformin, which many patients cannot tolerate due to adverse effects on the gastrointestinal tract. The present invention can be used to minimize the concentration of the compound at certain sites of toxicity and, thus, allow to introduce an effective therapeutic dose while reducing adverse effects.

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

In a preferred embodiment of the present invention, the composition further includes a capsule, preferably a capsule with intersolubility coating, which contains many particles. Capsule usually will be a soft or, preferably, hard gelatin capsule, although you can use other capsules that will dissolve in the small intestine. Intersolubility coating will protect the capsule during its passage through the stomach. You can use any suitable material for Intercollege coating, which dissolves in the small intestine. For example, you can use acatitla cellulose, acatitla hydroxypropylmethylcellulose or first ethylcellulose, and then polyvinylacetate, but it is preferable to use anionic polymer having a suitable dissolution profile. Presently preferred polymers are anionic carboxylic polymers, i.e. polymers in which the anionic groups are at least mostly free carboxyl and/or esterified carboxyl group. Particularly preferably, the polymers represented acrylic polymers, and preferably in the present polymers are copolymers of methacrylic acid and methyl methacrylate, in the which is the ratio of free acid groups and ester groups is about 1:1 (i.e. Eudragit L).

Alternatively, the particles can be pressed into a tablet, which can be applied intersolubility floor.

The coating of the capsule or other dosage forms) can and usually will contain a plasticizer and, optionally, other additives for coatings, such as coloring agents, agents which impart gloss, talc and/or magnesium stearate, which are well known to specialists in this field. In particular, anionic carboxylic acrylic polymer coatings usually contain from 10 to 25 wt.% plasticizer, especially diethylphthalate.

In a second aspect the present invention relates to a coating thickness of cover material, the dissolution of which depends on pH, the particles containing the active compound, to control the release profile of the active compounds in the intestinal tract. Under the covering material, the dissolution of which depends on pH, refers to the covering material, the dissolution of which depends on the pH. For example, polymethacrylate material, which is insoluble at pH 2, but essentially soluble at pH above 5.5, is polymethacrylate material, the dissolution of which depends on the pH value.

In the third aspect of the present invention relates to the use of a covering material selected from the

A. polymethacrylate material and

C. a covering material, the dissolution of which depends on pH,

for the manufacture of a medicinal product, described above, for the treatment of diseases of the intestinal tract. In a typical case, the drug will be used in the treatment of Crohn's disease.

In the fourth aspect of the present invention relates to a method of treating diseases of the intestinal tract of the patient; this method includes the introduction to the patient an effective amount of an active compound for the treatment of this disease in the composition of at least two sets of particles, covered, each covering material of different thickness, selected from

A. polymethacrylate material and

C. a covering material, the dissolution of which depends on pH,

for release of the active compound in those areas of the intestinal tract, in which symptoms, and/or in which is located the receptor substrate for the active connection.

The disease may be any disease of the intestinal tract, and the active compound can be any compound that is effective in the treatment of specified diseases, but, preferably, the disease is any disease mentioned above, and, preferably also, an active connection is giving represents any of the active compounds, mentioned above for the treatment of the disease. Most preferably, the disease is an inflammatory bowel disease, especially Crohn's disease or anemia associated with disease irritable bowel, and even more preferably, the active compound is a prednisolone metasulphobenzoate, 5-aminosalicylic acid, metronidazole, clarithromycin, Metformin, or erythropoietin.

Antibiotics 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 used for introducing them place their actions in the intestine, reaching sufficient local concentrations while minimizing systemic absorption. Especially the present invention is applicable to toxic antibiotics, such as gentamicin, especially in patients susceptible to the toxic effects of these drugs, such as patients with impaired renal function. Patients with chronic diseases of the bowel, such as Crohn's disease and inflammation pockets that require continuous administration of certain antibiotics, such as metronidazole, over long periods of time, in all probability, will especially benefit from this is subramania.

Other possible active agents include cytotoxic agents such as cyclophosphamide, cisplatin and other drugs based on platinum, vincristine and other Vinca alkaloids; immunomodulators such as methotrexate, azathioprine and cyclosporine; and antiparasitic agents such as albendazole.

The particles used in the present invention, are usually beads or granules.

Particles according to the present invention can be present in the form of granules having a diameter in the range from 500 to 2500 μm, preferably from 800 to 1700 μm, more preferably from 800 to 1500 μm and, more preferably, 1,000 to 1,500 μm. However, it should be understood that the particles may have a diameter in the above-mentioned limits or beyond these limits, and that the unit dosage form of the present invention may contain particles of one or more diameters or diameter range.

It should be understood that the true coating thickness for any particular weight gain on coating depends on the size and mass of the particles.

Preferably, the thickness of the coating of the present invention is in the range from 5% to 30%, more preferably from 10% to 25%, and most preferably approximately 15% and approximately 20%.

Dosage forms in accordance with the present invention may contain particles, to the which contain different active compounds. For example, one set of particles may contain a first active connection, and another set of particles may contain a second, different from the first active connection. Particles can be deposited coating to provide different release profiles for each of the active compounds in dosage form. Coverage for each of the sets of particles will usually be polymethacrylate materials such composition and thickness that provides the desired release profile for each of the active compounds. Alternatively, one set of particles may be covered with a covering material that is different from the coating material of another variety, in order to take advantage of the different characteristics of the release coating material, non-polymethacrylate.

Many particles in any such dosage form will generally be administered in a capsule with intersolubility the floor.

The present invention is further illustrated by the following non-limiting examples with reference to the accompanying figures.

Fig. 1 is a graph of percent release (% release) prednisolone metasulphobenzoate from granules coated with a copolymer of methacrylic acid and methyl methacrylate having a ratio slobodnakrajina groups and ester groups of 1:2, up to a theoretical weight gain of 5%, 15% and 25%, from time to time;

Fig. 2 is a graph of percent release (% release) prednisolone metasulphobenzoate from granules coated with a copolymer of methacrylic acid and methyl methacrylate having a ratio of free carboxyl groups and ester groups of 1:2, up to a theoretical weight gain of 15%from the time, at pH 6.0 and 6.2, and 6.6 and 7.2;

Fig. 3 is a graph of percent release (% release) prednisolone metasulphobenzoate from granules coated with a copolymer of methacrylic acid and methyl methacrylate having a ratio of free carboxyl groups and ester groups of 1:2, up to a theoretical weight gain of 15% and a particle size of up to 1500 microns and 2000 microns, and from pellets coated with mixed polymethacrylate coating of 5% of a copolymer of methacrylic acid and ethyl acrylate with a ratio of free carboxyl groups and ester groups of 1:1 and 95% of a copolymer of methacrylic acid and methyl methacrylate having a ratio of free carboxyl groups and ester groups of 1:2, up to a theoretical weight gain of 15%, from time to time;

Fig. 4 is a graph of percent release (% release) of paracetamol granules coated with a copolymer of methacrylic acid and methyl methacrylate having a ratio of St the free carboxyl groups and ester groups of 1:2, up to a theoretical weight gain of 20%from the time when the pH of 6.2, and 6.6 and 7.2;

Fig. 5 is a graph of percent release (% release) metronidazole from granules coated with a copolymer of methacrylic acid and methyl methacrylate having a ratio of free carboxyl groups and ester groups of 1:2, up to a theoretical weight gain of 20%from the time, at pH 6.0, 6.6 and 7,2;

Fig. 6 is a graph of percent release (% release) metronidazole from granules coated with a copolymer of methacrylic acid and methyl methacrylate having a ratio of free carboxyl groups and ester groups of 1:2, up to a theoretical weight gain of 15%, 20% and 25%of the time, at pH 6.6; and

Fig. 7 is a graph depicting how the activity of amylase released from granules α-amylase, covered with a copolymer of methacrylic acid and methyl methacrylate having a ratio of free carboxyl groups and ester groups of 1:2, up to a theoretical weight gain of 15%, 20% and 25%, varies with time at pH 6.0.

Example 1

Granules prednisolone metasulphobenzoate produced by obtaining a dry mixture of 5 wt.% prednisolone sodium-metasulphobenzoate, 40 wt.% microcrystalline cellulose (AvicelTMPH 101), 35 wt.% monohydrate lactose (D80 200 Mesh) and 30 wt. sodium croscarmellose (Ac-Di-Sol TM). Added purified water (185 wt.%) and the resulting mixture was stirred for 10 minutes to formation suitable for paste extrusion, which then was extrudible from the tank with a diameter of 25 mm tube diameter of 1 mm and a length of approximately 5 mm, with a speed of approximately 100 mm/min, using an extruder Niro Fielder Type E140, and spirolateral (shape area) at Nica Systems Spheroniser S700 20 cm plate, rotating with a speed of approximately 33 rpm Granules are then dried in the granulator, fluidized bed and were screened to ensure that the particle size in the range from 800 to 1500 μm.

The pellets were then coated with a dispersion of a copolymer of methacrylic acid and methyl methacrylate having a ratio of free carboxyl groups and ester groups of 1:2, to obtain the three parties, with a theoretical weight gain on coating (the weight gain) 5%, 15% and 25%.

Studied the rate of release of prednisolone metasulphobenzoate from pellets coated with different thickness at different pH values.

Example 2

The effect on the rate of release of prednisolone metasulphobenzoate of granules having a coating of up to 5%, 15% and 25% weight gain, produced as described in example 1, was studied on the apparatus for dissolving by mixing the granules in the environment trehosnovnogo phosphate in the N-6 and the sampling intervals of 15 minutes for measuring by HPLC the number prednisolone metasulphobenzoate in solution. The results are presented in Fig. 1.

As can be seen from Fig. 1, increasing the thickness of the coating significantly reduces the rate of release of the drug. Pellets coated to a 5% weight gain, provide full (100%) release of drug within 15 minutes. However, granules covering up to 15% weight gain contributed to 50% release of drug through approximately 45 minutes and 100% release of drug through approximately 100 minutes, and the pellets coated to 25% weight gain contributed to 50% release of drug after 120 minutes and 100% release of drug through approximately 300 minutes.

Particularly surprising is that the particles covered with the same covering material, the dissolution of which depends on pH, but with different thicknesses, provide for the release of drugs with essentially different speeds at the same pH value.

Example 3

Studied the effect of pH on the rate of release of drug from the coated pellets, coated with 15% weight gain, produced as described in example 1. Granules was studied on the subject of release of the medicinal product, as described in example 2, using only pH 6.0 and 6.2, and 6.6 and 7.2. Fig. 2 shows the pH-dependent ha the actor release of drug from the coated granules, with coverage of up to 15% weight gain.

As can be seen from Fig. 2, at pH 6 full release of drug was observed after approximately 120 minutes, and 50% release of drug through approximately 45 minutes. At higher pH values, the rate of release of drug is increased to a pH of 7.2, a complete release of the drug is observed in approximately 30 minutes.

Example 4

In order to study the influence of the exact composition of the coating on the release of drugs, two batches of granules prednisolone metasulphobenzoate with 15% weight gain due to one of the two selected polymethacrylate covering materials produced by the method described in example 1. Granules of the first batch inflicted mixed polymethacrylate floor, consisting of 5% of a copolymer of methacrylic acid and ethyl acrylate with a ratio of free carboxyl groups and ester groups of 1:1 and 95% of a copolymer of methacrylic acid and methyl methacrylate having a ratio of free carboxyl groups and ester groups of 1:2, to a weight gain of 15%. The granules of the second lot were covered with a copolymer of methacrylic acid and methyl methacrylate having a ratio of free carboxyl groups and ester groups of 1:2, to a weight gain of 15%.

She is Ali the effect of coating composition on the release of drugs from two batches of pellets, as described in example 2. The results are illustrated in Fig. 3.

As can be seen from Fig. 3, part 1, pellets were coated with a mixture of polymethacrylates - one, which dissolves at pH 6.0, and the other, which dissolves at pH 5.5 was released the drug faster than batch 2, the granules of which were covered with polymethacrylates, which dissolves at a pH of from 6.0 to 7.0.

Example 5

In order to study the effect of granule size on the release of drugs, granules prednisolone metasulphobenzoate were made in two batches, using the method of example 1; the first batch had a diameter of up to 2000 μm, and the second to 1500 μm, and both had a coating of a copolymer of methacrylic acid and methyl methacrylate having a ratio of free carboxyl groups and ester groups of 1:2, to a weight gain of 15%. Granules was studied on the subject of release of the medicinal product, as described in example 4. The results are also shown in Fig. 3.

As is shown in Fig. 3, the increase in the size of the granules was reduced speed of release of the drug. It is possible that this is because the larger granule size, having a specific percentage weight gain, due to the cover, has a thicker coating than the grains of a smaller size so W is the percent weight gain due to the cover, because the ratio of surface area and mass below the granules of larger size.

Example 6

Granules containing paracetamol instead prednisolone metasulphobenzoate, produced by the method described in example 1, and inflicted on them a coating of a copolymer of methacrylic acid and methyl methacrylate having a ratio of free carboxyl groups and ester groups of 1:2, to weight gain, 20%, and studied on the subject of release of the medicinal product, as described in example 3, only when the pH of 6.2, and 6.6 and 7.2. The results are shown in Fig. 4.

As can be seen from Fig. 4, the rate of release of drug was found to be pH dependent; at pH 6,2 50% of drug is released after 120 minutes, and the complete release of drug was observed after approximately 300 minutes, while at pH 7.2 for a complete release of drug was observed after 15 minutes.

Accordingly, the ability to control the delay and the rate of release of drugs is not limited to prednisolone by metasulphobenzoate, but, obviously, can be used more widely.

Example 7

Granules metronidazole produced as described in example 1, except that 20 wt.% metronidazole used instead of 5 wt.% prednisolone metasulphobenzoate. Por the portions other components brought up to 40 wt.% microcrystalline cellulose (Avicel TMPH 101), 20 wt.% monohydrate lactose and 20 wt.% sodium croscarmellose (Ac-Di-SolTM).

Granules metronidazole then covered by dispersion of a copolymer of methacrylic acid and methyl methacrylate having a ratio of free carboxyl groups and ester groups of 1:2, to obtain coated granules having a theoretical weight gain due to the coating (the weight gain) 20%.

Studied the effect of pH on the rate of release of metronidazole from granules metronidazole apparatus for dissolving by mixing the granules in the environment trehosnovnogo of sodium phosphate at pH 6.0, pH 6.6, and then at pH 7.2 and sampling at intervals of 15 minutes for measuring by HPLC the number of metronidazole in solution. The results are presented in Fig. 5.

As can be seen from Fig. 5, at pH 6.0 full release of drug was observed in approximately 240 minutes, and 50% release of drug was observed in approximately 145 minutes. At higher pH the rate of release of drugs increases until, while at pH of 7.2 does not fully release drugs through approximately 180 minutes.

Example 8

Granules metronidazole produced as described in example 7. The granules were then coated by spraying the copolymer of methacrylic acid is methyl methacrylate, having a ratio of free carboxyl groups and ester groups of 1:2, to obtain the three parties, with a theoretical weight gain due to the coating (the weight gain) 15%, 20% and 25%.

Studied the effect of coating thickness on the rate of release of metronidazole from coated pellets metronidazole apparatus for dissolving by mixing the granules in the environment trehosnovnogo of sodium phosphate at pH 6.6 and sampling at intervals of 15 minutes for measuring by HPLC the number of metronidazole in solution. The results are presented in Fig. 6.

As can be seen from Fig. 6, increasing the thickness of the coating significantly reduces the rate of release of the drug. Pellets coated to a 15% weight gain, provide full (100%) release of drug through approximately 120 minutes. However, pellets coated with 20% weight gain, provided 50% release of drug through approximately 120 minutes and 100% release of drug through approximately 240 minutes, and pellets coated to 25% weight gain contributed to 50% release of drug after approximately 200 minutes and 100% release of drug through approximately 300 minutes.

Example 9

Granules α-amylase produced as described in example 1, so the claim is ucheniem, that α-amylase was dissolved in fluid granulation (water). The proportions of the remaining components was 40 wt.% microcrystalline cellulose (AvicelTMPH 101), 20 wt.% monohydrate lactose and 40 wt.% sodium croscarmellose (Ac-Di-SolTM).

The granules were then coated by spraying the copolymer of methacrylic acid and methyl methacrylate having a ratio of free carboxyl groups and ester groups of 1:2, to obtain the three parties, with a theoretical weight gain due to the coating (the weight gain) 15%, 20% and 25%.

Studied the effect of coating thickness on the rate of release of α-amylase from coated granules α-amylase at pH 6.0 by colorimetry, using analysis α-amylase Sigma Enzymatic Assay (EC 3.2.1.1) (Sigma-Aldrich Company Ltd., The Old Brickyard, New Road, Gillingham, Dorset, SP8 4XT, UK), and the results are presented in Fig. 7.

As can be seen from Fig. 7, as in the case of granules prednisolone metasulphobenzoate and pellets of metronidazole, an increase in the thickness of the coating significantly reduces the rate of release of the drug. The number of released α-amylase is directly proportional to the observed activity. Pellets coated to a 15% weight gain, provided the maximum activity α-amylase through approximately 240 minutes. However, pellets coated with 20% weight gain, contributed about 50% of total is aktivnosti α -amylase through approximately 180 minutes and 100% of the total activity through approximately 300 minutes. Granules covering up to 25% weight gain, provided 25% of the total activity through approximately 180 minutes, but after 300 minutes was observed less than 50% of the total activity.

The results of examples 6-9 show that the present invention is applicable to active compounds, non-prednisolone-metasulphobenzoate. Scope of application of the present invention, therefore, is surprisingly wide.

It should be understood that the present invention is not limited to the details described above with reference to the preferred options for its implementation, and that numerous modifications and variations can be made without deviation from the idea or scope of the present invention, as defined by the following claims.

1. Pharmaceutical composition for oral administration comprising two or more sets of particles; these particles comprise the active compound, where the particles of each of the specified set is covered with a covering material of different thickness, the dissolution of which depends on pH, as compared with particles of a given set or every other variety, thanks to which the active compound is released in different parts of the intestinal tract.

2. The composition according to claim 1, in which dormancy is yuushi material is polymethacrylate material.

3. The composition according to claim 1, in which the particles of each set is covered with the same covering material, and particles of a given set or every other set.

4. The composition according to claim 2, in which polymethacrylate material includes a copolymer of methacrylic acid.

5. The composition according to claim 2, in which polymethacrylate material includes a copolymer of methacrylic acid and methyl methacrylate.

6. The composition according to claim 2, in which polymethacrylate material selected from a copolymer of methacrylic acid and methyl methacrylate having a ratio of free carboxyl groups and ester groups of about 1:2, copolymer of methacrylic acid and methyl methacrylate having a ratio of free carboxyl groups and ester groups of about 1:1, or mixtures thereof.

7. The composition according to claim 1, in which the particles are covered with a copolymer of methacrylic acid and methyl methacrylate having a ratio of free carboxyl groups and ester groups of approximately 1:2.

8. The composition according to claim 1, in which the particle has a diameter in the range from 800 to 1500 μm.

9. The composition according to claim 1, in which the particles are covered with polymethacrylate material to theoretical mass increase due to the coating in the range from 5 to 30%.

10. The composition of claim 1 in which the particles are covered with polymethacrylate material to theoretical mass increase due to the coverage limit is from 10 to 25%.

11. The composition according to claim 1, in which the active compound is released in the plots before and after ileocecal valve.

12. The composition according to claim 1, in which the thickness polymethacrylate material covering the particles of each set of particles has an increment selected so as to provide a uniform release profile of the active compound during at least one selected part of the gastrointestinal tract.

13. The composition according to claim 1, further comprising a capsule with intersolubility coating inside which contains many particles.

14. The composition according to claim 1, in which there are two sets of particles.

15. The composition according to claim 1, in which the first set of particles covered thereby, to provide a theoretical weight gain of 15%, and the second set of particles covered thereby, to provide a theoretical weight gain of 20%.

16. The composition according to item 15, in which the first and second set of particles are present in a ratio of about 1:3.

17. The composition according to claim 1, in which the active compound is selected from the group consisting of a peptide, polypeptide agonists and antagonists of the immune system, proteins, interferons, TNF antagonists, hormones, cytokines, antagonists of cytokines, analgesics, antipyretic agents, antibacterial agents, Antiprotozoal agents, protivovesa is sustained fashion agents steroids, probiotics, prebiotics, antibiotics and bisphosphonates.

18. The composition according to claim 1, in which the active compound is selected from the group consisting of cytotoxic agents, immunomodulators, and anti-parasitic agents.

19. The composition according to claim 1, in which the active compound is selected from the group consisting of erythropoietin, human growth hormone, metronidazole, clarithromycin, gentamicin, ciprofloxacin, rifabutin, 5-aminosalicylic acid, 4-aminosalicylic acid, balsalazide, Metformin, prednisolone metasulphobenzoate.

20. The composition according to claim 1, in which the active compound is selected from the group consisting of α-amylase, paracetamol, cyclophosphamide, cisplatin, vincristine, methotrexate, azathioprine, cyclosporine and albendazole.

21. The composition according to claim 1, in which the active compound is selected from the group consisting of prednisolone metasulphobenzoate, paracetamol, metronidazole and α-amylase.

22. Composition for oral administration according to claim 1 for use in therapy or diagnosis of human or animal.

23. A method of treating diseases of the intestinal tract in a patient, comprising the administration to a patient an effective amount of an active compound for the treatment of this disease in the composition of at least two sets of particles, each covered with a covering material according to the offered thickness, the dissolution of which depends on the pH, to release the active compounds in places intestinal tract, in which symptoms.

24. The method according to item 23, in which the disease is a Crohn's disease.

25. The method according to item 23, in which there are two sets of particles.

26. The method according to paragraph 24, in which the active compound is a prednisolone metasulphobenzoate.

27. The method according to item 23, in which the covering material is polymethacrylate material.

28. The method according to item 23, in which the active compound is released in the plots before and after ileocecal valve.

Priority items:

05.07.2002 according to claims 1 to 25, 27 and 28;

05.07.2002 on p.



 

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