Solid pharmaceutical composition for oral administration

 

(57) Abstract:

The invention relates to pharmaceutical industry and relates to a solid pharmaceutical composition risedronate for oral administration. The essence of the invention lies in the fact that it contains as the active ingredient risedronate and covered intersolubility shell consisting of anionic carboxylic polymer of a thickness of 20 to 100 μm. The invention provides the ability to reduce the risk of esophagitis or irritation of the esophagus, sometimes accompanying oral introduction of risedronate. 7 C.p. f-crystals.

The present invention relates to novel oral dosage forms diphosphonates derived, namely 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonate acid, hereinafter called the "risedronate".

New dosage forms have enterocoelous shell and delay the allocation risedronate before falling into the lower part of the intestine with the protection of the epithelial tissues and mucous membranes of the mouth and the threshold of the mouth, pharynx, larynx and esophagus from erosion, ulceration and other skin irritations arising from direct contact of the tissue with the active component risedronate to a method of treatment or prevention of diseases, characterized by an abnormal metabolism of calcium and phosphate, the use of new dosage forms with intersolubility shell disclosed below.

Polyphosphonate acids and their pharmaceutically acceptable salts are proposed for the treatment and prevention of a number of pathological conditions that can affect humans or other mammals, including the metabolism of calcium and phosphate. Such States can be divided into two large groups.

1. Condition characterized by abnormal mobilization of calcium and phosphate leading to General or specific reduction of bone tissue, or excessively high content of calcium and phosphate in biological fluids. This condition is sometimes called pathological demineralization of hard tissues.

2. Condition, cause or result of which is the abnormal deposition of calcium and phosphate in the body. Such States are sometimes referred to as pathological calcification.

The first group consists of osteoporosis, i.e. a condition in which loss of solid bone occurs disproportionately to the development of new hard tissue.

Cavity of the bone and bone marrow become ballerstein on menopause, senile caused by medication (e.g. , adrenocorticoids that can occur during treatment with steroids), caused by disease (e.g.; arthritic or tumor), and so on, but manifestations in all cases the same.

Other sostoyanii the first group refers Paget's disease (deforming ostos). During the course of this disease is the dissolution of normal bone, which then steadily replaced by soft, weakly mineralized tissue, resulting in bone is deformed under pressure acting on her weight, in particular in the area of the tibia and femur.

The first group included also hyperparathyroidism, malignant hypercalcemia and istericheskie bone metastases.

The second group, including the state, manifested in abnormal deposition of calcium and phosphate, includes: myositis ossificans progressiva, calcinosis universalis, and such afflictions as arthritis, neuritis, bursitis, tendant and other inflammatory conditions which predispose to the deposition in the tissues of calcium phosphates.

Diphosphonates, such as ethane-1-hydroxy-1,1-diphosphonic acid (EGDF), propane-3-amino-1-hydroxy-1,1-diphosphonic acid (APD) and dichlorothiophene is ejeta and heterotopic ossification now successfully treatable EGDF. Diphosphonates have a tendency to inhibition of resorbtive bone that has a beneficial effect on patients suffering from excessive loss of bone tissue.

However AGFD, AAA and many other diphosphonates of the prior art tend to inhibit the mineralization of bones when administered in higher doses.

Risedronate is more biologically active diphosphonates derived, which can be administered at low dosage levels, and low dosages lead to wider limits of security and little or no inhibition of mineralization.

I believe that the reduction in the inhibition of bone mineralization at low dosage levels is due to the fact that the inhibition of mineralization mainly refers to the physical-chemical process related to the mass, while inhibition of resorbtive occurs when biological interaction with cells.

In addition, the low dosage desirable because they allow to avoid discomfort in the gastrointestinal tract, such as vomiting, diarrhea, pain in the abdomen, which sometimes occur with a dose of diphosphonates.

I believe that these phenomena are caused by esophagitis or irritation of the esophagus caused by erosion, ulceration and other similar stimulation of epithelial tissues and mucous membranes of the upper part of the gastrointestinal tract, usually from the mouth to the esophagus, more usually of the esophagus.

The hypothesis that such stimuli are the result of direct contact of risedronate as the active component of epithelial tissue and mucous these areas, leading to their local irritation.

Accordingly, it is desirable to create new oral dosage forms of risedronate capable of preventing allocation risendronate in the area of these tissues.

These new dosed oral forms have intersolubility shell and delay the onset of allocation risedronate before, until you reach a certain point of the small intestine or the colon, resulting in protection of tissues of the mouth, pharynx and esophagus.

These nknow shell, starch or gelatin capsules containing beads or particles with intersolubility shell.

The present invention is directed to new oral dosage forms of risedronate as an active ingredient, having intersolubility shell and containing a safe and effective amount of a pharmaceutical preparation containing as an active ingredient risedronate and pharmaceutically acceptable excipients.

Such dosage forms prevent the selection of risedronate in the oral cavity, pharynx, esophagus and stomach and protect their epithelial tissues and mucous membranes from erosion, ulceration and other similar stimuli.

Accordingly, the new disclosed here dosage forms to deliver in the lower part of the intestines of humans and other mammals a safe and effective amount of risedronate as an active ingredient and to facilitate the esophagitis or irritation of the esophagus, sometimes accompanying oral introduction of risedronate as an active ingredient.

The invention also is directed to a method of treating diseases characterized by abnormal calcium metabolism is observed new oral dosage forms.

The present invention relates to novel oral dosage forms of risedronate as an active ingredient, having intersolubility shell and containing a safe and effective amount of a pharmaceutical preparation comprising as an active ingredient risedronate and pharmaceutically acceptable excipients.

This dosage form prevents the allocation of risedronate mouth, throat and esophagus and protects as a result of their epithelial tissue mucosal erosion, ulceration and other irritation.

In addition, such dosage forms inhibit the secretion of risedronate as an active ingredient in the stomach and the anterior part of the duodenum.

These dosage forms affect the flow in the lower part of the intestines of man or other mammal a safe and effective amount of risedronate as an active ingredient and thereby significantly reduce the risk of esophagitis or irritation of the esophagus, sometimes accompanying oral introduction of risedronate.

The invention also includes a method of treating Soboleva another mammal, suffering from such a disease disclosed here is a new oral dosage forms.

The name "risedronate" as used here, the value applies to diphosphonates derived, namely 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonate acid of the following formula:

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Risedronate described in the following publications, each of which is introduced here as a reference: EPO Patent application 0186405 on the name Benedict and others, published July 2, 1986, "International conference on bisphosphonates. Current status and prospects." Royal College of physicians, London, England, 21 - 22 may 1990, organized by the technical service of the company JBC.

The expression "risedronate as an active ingredient" includes risedronate, salt risedronate, esters of risedronate and any mixture.

New oral dosage forms of the present invention as an active ingredient can be used any pharmaceutical acceptable salts or esters of risedronate.

Salt risedronate can be represented by the salts formed by addition of acids, in particular the hydrochloride, but can be used with any other pharmaceutically acceptable non-toxic salt of the s reaction with karboksilnoj group, including, but without limitation only by them: salts of alkali metals (K, Na) and salts of alkaline earth metals (Ca, Mg), of which the preferred Ca - and Na-salt.

To esters of risedronate applicable as active components include, in particular, alkalemia C1-C18-esters with normal or branched chain, including, but without limitation only by them: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, hexyl, p, oktilovom, monolopy, decroly, lauric, ministerului, cetyl and stearyl; alkenilovyh C2-C18-esters with normal or branched chain, including but without limitation only by them: vinyl, alkilany undertray and linalilovy; cycloalkyl C3-C8-esters, including, but without limitation only by them: cyclopropylamine, cyclobutylamine, cyclopentylamine, cyclohexylamine, cycloheptylamine and collectively; arrouye esters, including, but without limitation only by them: phenyl, tallowy, Kilroy, nattily; alicyclic esters, including, but not limited, metalowy and Uralkaliy esters, including, but without limitation only by them: benzyl and finitely.

In addition, physical and chemical characteristics of the active component should be taken into account when selecting an acceptable pharmaceutical excipients intended for use in new dosage forms containing risedronate as an active ingredient.

Effective oral dose of risedronate as an active ingredient depends on the depth of the disease and for adults usually ranges from 1 to 40 grams per day, preferably from 1 to 30 grams per day.

When continuous dose the recommended dose is 1 to 15 mg/day, preferably 1 to 10 mg/day. Circular dose the recommended dose is 5 to 40 mg/day, preferably 10 to 30 mg/day.

Man or other mammal, suffering from diseases or disorders, including the metabolism of calcium and phosphate, may be successfully submitted to treatment when risedronate as the active component in the lower part of the intestine of a human or mammal, preferably in the small intestine.

The new disclosed here oral dosage forms with intersolubility shell ASU is entering risedronate in the mouth, pharynx and/or esophagus, as well as inhibit the secretion of risedronate as an active ingredient in the stomach and thereby prevent erosion, or other similar expressions of irritation of the epithelial tissue or mucous membrane in these areas.

Although admission only in the small intestine generally preferred, in some cases, however, it may be desirable to flow risedronate as an active ingredient in all the lower part of the intestine, from entering the small intestine with the continuation of the entrance to the colon, and in some cases be desirable receipt risedronate as an active ingredient only in the colon.

In the manufacture of new disclosed here oral dosage forms having intersolubility shell, a specialist can easily vary pharmaceutically acceptable carriers, create a shell composition and/or thickness of the shell.

The term "gastrointestinal tract" as used here, the value applies to the digestive channel, i.e., musculo-membranous tube with a length of about thirty pounds (9 m) that passes from the mouth to the anus.

The term "the upper part of the CLASS="ptx2">

The term "lower part" "gastrointestinal tract" as used herein is meant the small intestine and the colon.

The term "vestibule of mouth" means mouth or oral cavity, covered with mucous membrane, passing continuously from the outer cover lip to the mucous membrane of the pharynx.

The term "SIP" refers to the portion of the gastrointestinal tract, which is located behind the nose, mouth and larynx. SIP is a membrane-mucous tube length of about 4 in (10 cm) inches adjacent to the mouth and ending with the esophagus; it consists of a mucous membrane, fiber shell and a muscular sheath.

The term "esophagus" used here is the mean muscle channel length of about nine inches (23 cm), passing from the pharynx to the stomach. SIP has three membranes: the inner mucous membrane surrounding the lumen, the average areola and external muscular sheath.

The term "stomach" used here, the value applies to the portion of the gastrointestinal tract, which is located between the esophagus and the small intestine.

The term "small intestine" as used here, the value means that part of the gastrointestinal tract, which includes dwenadzatiperstnuu the fundus of the stomach and proximal to the colon.

The term "colon" as used here includes the portion of the gastrointestinal tract, which directly distal to the small intestine, begins with the cecum, including the ascending colon the colon, transverse colon the colon, the descending colon rectum, sigmoid colon the colon and rectum.

As indicated above, the present invention is directed to new oral dosage forms of risedronate as an active ingredient, having intersolubility shell, intended for delivery in the lower part of the intestine of a human or other mammal, preferably in the small intestine of a pharmaceutical preparation containing as an active ingredient risedronate and pharmaceutically acceptable excipients.

New oral dosage forms can be either drugs with delayed allocation, or drugs long separation, and such oral dosage forms prevent the admission of risedronate as an active ingredient until you hit dosage forms in the lower part of the intestine of the individual.

Accordingly, eliminates direct contact of the tissue of the upper part of the gastro-kesederhanaan as an active ingredient.

Thus, these oral dosage forms significantly reduce the risk of esophagitis or irritation of the esophagus that occurs sometimes when orally administered pharmaceutical preparations containing as an active ingredient risedronate.

Accordingly, the oral dosage forms suitable for use in the present invention, are drugs with intersolubility shell and delayed allocation or drugs with intersolubility shell and durable selection.

Dosage forms can be in the form of tablets or capsules, comprising a pharmaceutical acceptable excipients well known in the art, and disclosed below.

The term "pharmaceutical composition" means oral dosage form comprising as active ingredient a safe and effective amount of risedronate mixed with pharmaceutical excipients.

Disclosed here is pharmaceutical compositions containing as an active ingredient 0.15 to 40%, preferably 0.5 to 30% risedronate and 60 of 99.75%, preferably 70 to 99.5% of pharmaceutically acceptable fillers.

The phrase "safe and effective amount the MOU and/or conditions, be treated, but low enough to avoid serious side effects (at a reasonable ratio benefit/risk) within common with medically sense.

Safe and effective amount of the active component, intended for use in the method of the present invention will vary depending on the particular condition to be treated, the age and physical condition of the subject to treatment of the patient, the severity of the condition, the duration of treatment, the nature of the concurrent treatment, specific applied active ingredient, the pharmaceutically acceptable fillers and similar factors determined by the knowledge and experience of the treating physician.

The term "pharmaceutically acceptable excipients" as used herein includes any physiologically inert, pharmacologically inactive substances known in the art and compatible with the physical and chemical characteristics of risedronate used as the active component.

Pharmaceutically acceptable excipients include, but without limitation only by them): polymers, resins, plasticizers, carriers, lubricants is e substances, the corrigentov, pharmaceutical dyes or pigments, and viscosity additives.

All or part of pharmaceutically acceptable fillers contained in the disclosed here pharmaceutical preparations used to create intersolubility shell, intended for use in new disclosed here oral dosage forms.

The term "oral dosage form" as used here, the value applies to any pharmaceutical composition intended for introduction into the gastrointestinal tract of the individual through his mouth, and for the purposes of the present invention, the insertion can be made in the form of tablets (preferably with intersolubility shell), containing as an active ingredient particles or granules risedronate, or capsules (intersolubility shell or not), containing as an active ingredient balls with intersolubility shell or granules with intersolubility sheath risedronate.

The term "oral dosage form with intersolubility shell" refers to an oral dosage form containing disclose here a pharmaceutical preparation in which to implement videolock.

Oral dosage forms with intersolubility sheath can be in the form of compressed tablets (with shell or without) containing granules or particles of risedronate as an active ingredient, which in turn have or do not have a shell.

Oral dosage forms with intersolubility shell can be a gelatin capsule (with shell or without) containing beads or granules risedronate as an active ingredient, which in turn have or do not have a shell.

The term "intersolubility shell" as used here, the value applies to a mixture of pharmaceutically acceptable fillers, which is applied to combine, mix, or some other way to add to risedronate as an active ingredient.

This shell can be put on the pressed tablet, a gelatin capsule and/or beads, granules or particles of risedronate as an active ingredient, which capsulebuy in starch or gelatin capsules or pressed into tablets.

Accordingly, such intersolubility shell put on the pressed tablet containing particles or granules of the active component, Odie, the application of this coating on the pressed tablet is optional.

Intersolubility shell can be deposited on the beads or small particles of the active component, which can then be encapsulated in a starch or gelatin capsules.

After that, if desired, the capsules can be applied intersolubility shell. Due to its intersolubility shell such new dosage forms prevent unwanted ingress of risedronate as the active component on the mucous and epithelial tissue of the upper part of the gastrointestinal tract, especially of the mouth, pharynx and esophagus.

This shell also helps to deliver the active ingredient in the lower part of the gastrointestinal tract in the point, which can be selected by specialist recruitment forming a shell fillers, type shell and/or its thickness.

The term "delayed release" as used here, the value applies to the delivery of risedronate as an active ingredient, which is carried by the introduction of the active component in the pharmaceutical composition of the drug so that the selection of the active component will be in some, Teleki would not have changed the method of delivery of the active component.

The preferred method of slowing down the selection of the active component is applied to the active component of the coating (or kapsulirovanie in some other way) of a substance that is not absorbed or destroyed in some other way gastro-intestinal juice with the release of the active ingredient until, until you reach a certain target point intestine.

The most recommended type of drug delayed allocation, intended for use in the present invention, they are applied on the tablets, capsules or particles, granules or pellets of the active substance coating of pH-dependent substances, i.e. substances collapsing at pH values common to the small intestine, but not collapsing at pH values typical of the mouth, pharynx, esophagus and stomach.

However, when orally administered pharmaceutical preparation containing as an active ingredient risedronate, want to deliver locally and only in the colon or the entire length of the intestine, starting with the small intestine, in this case, selection of the material of the shell and/or the method of coating or connection in any other way risedronate as the active component is or modified as proposed herein, or otherwise known to the specialist way.

The term "delayed release" refers to the allocation mechanism, which is designed for delivery of the active ingredient over an extended period of time, which is different from the dose delivered with delayed allocation.

Most preferred for use in the present invention the type of ways to extend the selection is applied to the granules risedronate as an active ingredient pH-independent coating selected from the group including (but without limitation only by them): ethylcellulose, hypromellose, methylcellulose, hydroxymethylcellulose, hydroxyethyl cellulose, and sodium carboxymethyl cellulose.

A variety of dosage forms with prolonged selection can be easily modeled by a specialist, which can be achieved delivery risedronate as an active ingredient in the small intestine and in the colon, only in the small intestine or only in the colon, depending on the shell material and/or thickness of the shell.

As indicated above, the exact location and/or speed of delivery double what their factors:

(a) selecting a suitable active ingredient;

(b) type membrane and simultaneously the target thickness and permeability (the ability to swell) shell;

(c) dependent on the time the state of the membrane and/or within which shell pellets, particles, beads or granules;

(d) the particle size of the granulated active ingredient and

(e) dependent on the pH condition of the membranes and/or within the coated tablets, particles, beads or granules.

In particular, solubility, acidity, and susceptibility to hydrolysis of various derivatives risedronate as an active ingredient, such as salts with acids, salts formed with a carboxyl group, for example salts of alkali metals, salts of alkaline earth metals, etc., and esters, e.g.: alkalemia, alkenilovyh, arrouye, Arakelova can serve as a guide for the proper selection derived.

In addition, in accordance with the agreed way of allocating addition to the active ingredient acceptable buffer coated tablet, particle, granule or bead must be created suitable conditions of pH.

In addition to the above variations, with the goal of achieving the intended path you what component derived risedronate.

As described above, pharmaceutically acceptable excipients include, but without limitation only by them): polymers, resins, plasticizers, carriers, lubricants, solvents, co-solvents, surfactants, preservatives, sweetening agents, corrigentov, buffer systems, pharmaceutical dyes or pigments, and viscosity additives.

As a solvent it is recommended that water.

Applicable in the present invention corrigentov include corrigentov shown in Remington's Tharmaceutical Sciences, 18th edition, Mack publishing Company, 1990, pp. 1288-1300, which is introduced here as a reference.

It is applicable in the present invention the dyes or pigments include dyes and pigments listed in the Handbook of pharmaceutical excipients, pages 81-90, 1986, published by American pharmaceutical Association and the Pharmaceutical society of great Britain, which is introduced here as a reference.

Recommended co-solvents include, but without limitation only by them): ethanol, glycerol, propylene glycol, polyethylene glycol.

Recommended buffer systems include (but without limitation only by them): kalyanamitra, boric, carbonic, posthorn Glukhovo. It is especially recommended phosphoric, tartaric, citric and kalyanamitra buffer systems.

Preferred surfactants include, but without limitation only by them): esters of polyoxyethylenesorbitan with fatty acids, simple monoalkyl ethers of polyoxyethylene, complex monetary sucrose, ethers and esters of lanoline.

Preferred preservatives include, but without limitation only by them): phenol, alkalemia esters of p-hydroxybenzoic acid, benzoic acid and its salts, boric acid and its salts, sorbic acid and its salts, chlorbutanol, benzyl alcohol, thimerosal, acetate finalstate, nitrate of finalstate, nitromersol, chloride benzalconia, chloride of cetylpyridinium, methylparaben, propylparaben.

Especially recommended salt of benzoic acid, chloride of cetylpyridinium, methylparaben and propylparaben.

Preferred sweeteners include, but without limitation only by them): sucrose, glucose, saccharin and aspartame. Especially recommended sucrose and saccharin.

The preferred viscosity of the additive include (but without limitation only by them): methylcellulose, nutricosmetics, hydroxypropylmethylcellulose recommended methylcellulose, carbomer, xanthan gum, carob bean gum, povidone and sodium carboxymethyl cellulose.

Preferred carriers include (but without limitation only by them): lactose, sucrose, malodextrin and microcrystalline cellulose.

Preferred plasticizers include (but without limitation only them): polyethylene glycol, propylene glycol, castor oil, dibutyl phthalate, acetylated monoglycerides, and triacetin.

Preferred polymers include (but without limitation only by them): ethylcellulose, phthalate of hydroxypropylmethylcellulose, acetated cellulose, polyvinylacetate, Eudragit L-30 DEudragit L-100 - 55production room Pharma GmbH, Weiterstadt, Germany, Catterick production Colorcon, Inc., West point, units PA.

Preferred lubricants include (but without limitation only by them): magnesium stearate, stearic acid and talc.

The use of new oral dosage forms of the present invention risedronate as an active ingredient can be guaranteed to be delivered anywhere in the lower part of the gastrointestinal tract, preferably in the small intestine, thus preventing undesired hair is a division in the stomach.

These dosage forms give risedronate as an active ingredient the ability to easily be absorbed in the lower part of the gastrointestinal tract, without any contact of the active component with epitelial tissue and mucous membrane of the mouth, pharynx, esophagus or stomach.

Accordingly, a new oral dosage forms with intersolubility shell significantly improve the symptoms of esophagitis or irritation of the esophagus that may occur with orally administered pharmaceutical preparation containing as an active ingredient risedronate.

The most preferred oral dosage form, allowing delivery to the small intestine, contains as an active ingredient risedronate, and it uses a pH-dependent intersolubility sheath material made of partially esterified polymer methyl ester of methacrylic acid.

Such solid oral dosage form can be in the form of pressed tablets with intersolubility shell made of granules or particles of the active component, or gelatin capsules containing beads or small particles of the active is the way to create a shell preferred however, in the practice of the present invention can be used any intersolubility floor, insoluble at pH below 5.5 (i.e., at pH values common to the mouth, throat, esophagus and stomach), but soluble at a pH of 5.5 or higher (i.e. characteristic of the small intestine and colon pH values).

Accordingly, if it is desirable to deliver local risedronate as an active ingredient in the small intestine, apply any intersolubility floor, fully or partially insoluble at pH below 5.5 and soluble at a pH of 5.5 or higher.

Partially esterified polymer of methyl methacrylic acid, featured as intersolubility membrane must be applied to the pressed tablet, a gelatin capsule and/or beads, particles or granules of the active component layer of sufficient thickness so that the whole shell was not dissolved in the gastro-intestinal juice at pH below 5.5, but dissolved at a pH of 5.5 or higher.

The dissolution or destruction of the shell of the filler, as a rule, does not occur until the dosage form in the shell will not fall into the small intestine.

In particular, no allocation risedronate essentially Etaseco of the invention to achieve the delivery of risedronate as an active ingredient in the small intestine can be used any anionic polymer, possessing the requisite pH-dependent solubility and forming intersolubility shell.

Selected, the membrane must be compatible with concrete, used as an active ingredient derived risedronate. It is recommended for use in the present invention polymers include anionic carboxylic polymers.

Especially recommended acrylic polymers, of which the most preferred partially methylethylamine polymers of methacrylic acid, with the ratio of anionic free carboxyl groups to ester groups is approximately 1:1.

It is especially suitable for the copolymers of methacrylic acid is Eudragit Lin particular, Eudragit L-30-Dand Eudragit 100-55production room Pharma GmbH, Weiterstadt.

In Eudragit L-30-Dthe ratio of free carboxyl groups to ester groups is approximately 1:1.

In addition, it is known that this copolymer is insoluble in gastrointestinal fluids having a pH below 5.5, typically in the range of 1.5 to 5.5, i.e. at pH values common to the liquid in the upper part of the gastrointestinal tract, but easily soluble at pH above 5.5,measures of methacrylic acid, suitable for wrapping oral dosage forms and/or granules, particles or beads of the active component, which can be used with the method of treatment of the present invention represented by Eudragit Sproduction room Pharma GmbH, Weiterstadt, Germany.

Eudragit Sused both in pure form and in combination with other coatings. Eudragit Sdifferent from Eudragit L-30-Donly the fact that it is the ratio of free carboxyl groups to ester groups is approximately 1:2.

Eudragit Salso, as Eudragit L-30-Dinsoluble at pH below 5.5, typically in the range of 1.5 to 5.5, i.e. at pH values typical of gastric juice, and in contrast to Eudragit L-30-Dpoorly soluble in gastrointestinal fluids having a pH in the range of 55.5-7,0 for example, at pH, typical of the juice of the small intestine. The specified polymer soluble at pH 7 and above, i.e. at pH values typical of the colon.

Eudragit Sas the coating can be used in pure form, which provides for the delivery of risedronate as an active ingredient, starting with a colon (, Eudragit Spoorly soluble in intestinal juice with a pH below 7, can be used with Eudragit L-30 - Dsoluble in intestinal juice with a pH above 5.5, with the purpose of preparation of the drug delayed allocation, capable of delivering the active ingredient in different parts of the intestine, while the more applied Eudragit L-30-Dthe closer starts the selection and delivery of the drug, and the more used Eudragit Sthe far begins the selection and delivery of the drug.

The shell can contain and usually contains a plasticizer and possibly other fillers shell, for example a dye, talc and/or magnesium stearate, the application of which is to create a wrapper is well known.

In particular, anionic acrylic polymers with carboxyl groups usually contain 10-25% by weight of plasticizer, in particular dibutyl phthalate, polyethylene glycol, triethylcitrate and triacetin.

The coating used conventional technology, for example by spraying or coating in the bath. As mentioned above, the thickness of the shell must be sufficient to ensure that p is it part of the intestine.

As indicated above, the solid oral dosage form may be molded coated tablet containing as an active ingredient particles or granules risedronate, or gelatin capsules (with shell or without), containing as an active ingredient bulbs risedronate, which in turn have intersolubility shell.

A. Tablets in intersolubility shell

One of the featured new oral dosage forms is represented in compressed tablets in intersolubility shell.

Tablets make the connection, mixing or adding some other way of risedronate as an active ingredient to an acceptable pharmaceutical excipients, including (but without limitation only by them): sucrose, maltodextrins, lactose, microcrystalline cellulose, talc, magnesium stearate, crosspovidone and glycolate natricinae.

The resulting mixture was then pressed using a variety of techniques tabletting available to the specialist. Pressed tablets and then sign in intersolubility shell of material made with an acceptable pharmaceutical excipients, including (but without limiting the t Sthe phthalate of hydroxypropylmethylcellulose, acetated cellulose, polyvinylacetate, acatarinella cellulose, polyethylene glycol 400-8000, triacetin, dibutyl phthalate, acetylated monoglycerides, triethylcitrate, talc and iron oxide.

The material is then intersolubility shell using the many available specialist sputtering techniques applied on the extruded tablets.

Intersolubility shell tablet insoluble in the fluids of the mouth, pharynx, esophagus and stomach, which prevents the selection of risedronate, until it reaches the lower part of the intestine, preferably the small intestine

One acceptable dosage forms (less preferred), allowing to deliver risedronate as the active component in the lower part of the gastrointestinal tract with the protection of the mucous membranes of the mouth, esophagus and stomach are not having a sheath extruded tablets containing as an active ingredient, granules or particles risedronate enclosed in intersolubility shell.

However, from the standpoint of ease and cheapness of manufacture recommended a new dosage form of predstavnicki.

In addition, some derivatives of the active component sensitive to moisture, and the effect is better when the delivery tablet dosage form.

When the preferred way to create a shell with the use of methacrylate copolymers, and if the delivery location is the small intestine, it is found that the thickness of the shell should be in the range of 20 to 100 μm. The recommended thickness of the shell 30 - 75 μm, most preferably 30 to 50 μm.

Way that is acceptable to create a shell of compressed tablets containing as an active ingredient risedronate and able to deliver the active ingredient in the small intestine, see examples I and II.

Another type of CT with delayed allocation, suitable for delivery risedronate locally in the colon as an active ingredient, obtained by use of the material (most preferably resin), the dissolution of which depends on time, in contrast to the pH-dependent type shell of a copolymer of methacrylic acid, mentioned earlier.

Delivery of the active ingredient in the small intestine carry out the sealing of the individual particles of the active component in a slowly collapsing or slow the element remains protected during the movement of particles through the mouth, throat, esophagus and stomach, and at the time of entering into the small intestine particles of the active component to be fully released.

In particular, the recommended resin applicable to the filling material of this type is high-viscosity modified vinyl acetate resin, such as Gelva C3 - V30produced by Monsanto Co., San Louis, Missouri.

Other acceptable resins include karboksilirovanie the polyvinyl acetate, copolymers of polyvinyl with maleic anhydride, ethylcellulose, polymers, cellulose, copolymers of methacrylic acid with methyl methacrylate, wax mixtures thereof, including mixtures with shellac.

Although the recommended oral dosage form are tablets with delayed release in the shell, containing as an active ingredient risedronate, and most preferably, if the selection starts in the small intestine, may certainly be used in other ways, guarantee delivery into the intestine of risedronate with shell tablet long separation, and as the shell material is applied to the polymer, and the polymer is chosen from the group comprising ethylcellulose, hypromellose, hydroxymethyl CLASS="ptx2">

Another oral dosage form with prolonged isolation, suitable for delivery risedronate as an active ingredient in the intestine, is a tablet, characterized by the presence of the nucleus, consisting of risedronate as an active ingredient, and this core is enclosed in the first inner layer diffusion membrane consisting of ethyl cellulose and/or copolymers of polarisability, methacrylate, chloride trimethylammoniumchloride or mixtures thereof.

In addition, the inner layer has a second layer of filler material, preferably anionic polymer, fatty acids or mixtures thereof having a pKa of 4.5 - 7.0 and preferably from 6.0 to 6.5.

After the outer layer is removed by dissolution with the passage of the drug in the small intestine with a higher value of pH is very low, but adjustable discharge from the core of risedronate as an active ingredient due to the diffusion through the membrane due to the difference in concentration on both sides of the membrane.

C. the Beads or granules in intersolubility shell

Another new dosage form for oral administration of risedronate as an active ingredient predstavlennoi shell.

Optionally, gelatin or starch capsules can also be enclosed in the shell. The use of capsules containing balls in intersolubility shell because of the difficulty and cost of manufacture is generally not recommended.

However, some derivatives of the active component, which must be entered in relatively high doses, can hardly be pressed into tablets.

In addition, especially if the active component can have an irritating effect on the mucous membrane, it may be preferred shipping drug in gelatin or starch capsules containing smaller particles, beads or granules in intersolubility shell, not coated tablet.

In addition, the assimilation of dietary pills often get stuck in the stomach until digestion is not compelled to open the pyloric sphincter pushing the tablet into the duodenum.

When using do not have shell gelatin or starch capsules gelatin or starch in the stomach is destroyed emitting balls in intersolubility shell.

The balls can pass through the pylorus, regardless of their uncertain time in direct contact with epithelial tissue and mucous membranes.

As used here, the meaning of "balls" refers to the particles containing the active ingredient and prepared applying risedronate as the active component into spheres or balls are inert substrate, preferably using a polymer film.

Accordingly, as the substrate used balls, to which the active component is applied risedronate.

Beads can be made of one substance or mixture of substances selected from the group including (but without limitation only by them): sucrose, mannitol, lactose, destrose, sorbitol, cellulose and starch, of which the most preferred sucrose and starch. The recommended size of the balls are inert substrate is in the range of 0.25 - 2 mm, preferably 4 to 7 mm

Additionally, there may be used the finished balls are inert substrate, such as excellent PG balls production Crompton & NOELs, Mahway, pc. new York or Edward Mendel CO., Patterson, pieces of new York.

Risedronate as the active component must be fixed on the balls of inert substrate. The most preferred method of fixation of the active component on the balls of the substrate is to use the and serves to prevent absorption of the active component moisture.

If the selected active ingredient unstable in certain conditions, the polymer film can give him some stability.

The polymeric film preferably consists of a mixture of hydroxypropylmethylcellulose, ethyl cellulose, polyvinylpyrrolidone, hydroxypropylcellulose and/or ethyl cellulose, preferably hydroxypropylmethylcellulose and ethyl cellulose and acceptable plasticizer.

Examples applicable in the film of the plasticizer include (but without limitation only by them) polyethylene glycol, propylene glycol, triacetin, acetylated triglycerides, esters of phthalic acid, castor oil, dibutylsebacate, triethylcitrate and their chosen mixture.

The recommended amount of plasticizer is in the range 5% to 40%, more preferably 20 to 40% by the polymer film.

Besides risedronate as an active ingredient a polymer film may contain fillers, pigments and dyes mentioned above.

It is recommended that the polymer or polymer mixture consisted of any combination that provides protection against absorption of moisture and/or oxygen transport and intended for immediate allocation actionet, applied to the balls inert substrate may vary depending on the concentration in the final product.

However, the weight applied to the balls of the substrate film is in the range of 5 - 50% of body weight, preferably 5 to 25% of body weight and most preferably 5 to 10% weight gain.

After the deposition of the balls are inert substrate coating of the active component, they can be enclosed in intersolubility shell.

This intersolubility shell can be created using various well-known specialist by spraying. Shell create around the balls with the active component with a thickness of 20 to 100 μm, preferably 30 to 75 μm, most preferably 30 to 50 μm.

It may be desirable conclusion to the shell granules risedronate as active instead of spraying balls inert substrate of the active component.

Granules are used here, the mean value of the particles of the active component in a mixture with acceptable pharmaceutical carriers mentioned above.

Although introduction as oral dosage forms, it is recommended to capsulerebel granules with intersolubility shell in starch sludge is to be obtained by extrusion wet kneaded mass with subsequent molding areas and drying. Recommended pellets streamlined forms, for example in the form of rods, a cylindrical shape, in particular a spherical shape. It is recommended that the spherical granules with a diameter of 0.3 to 15 mm, preferably from 0.5 to 1.25 mm

Acceptable pharmaceutical components used for the preparation of granules for use in new dosage forms of the present invention include (but without limitation only by them) lactose, cellulose, mannitol, sucrose and starch.

The obtained pellets of the active component and then sign into the shell of Intercollege material prepared from pharmaceutically acceptable excipients.

To create a wrapper using various methods known in the art of coating. The thickness of the shell around the granules of the active component of 20-100 μm, preferably 30 to 75 μm, most preferably 30 to 50 μm.

The following not limiting the invention examples serve to further illustrate the new oral dosage forms of the present invention.

Example I Tablets risedronate in intersolubility shell

Tablets risedronate in intersolubility shell is produced by preparing the composition is iciu shell put on pills.

The composition intersolubility shell get in the form of a varnish containing the following excipients (per tablet):

A. Suspension intersolubility shell

Fillers, mg:

Eudragit L-30-D(production room Pharma GmbH, Weiterstadt, Germany) and 33.4

Polietilenglikol - 1,00

Talc - 2,500

Yellow iron oxide - 0,034

The emulsion simethicone - 0.800 to

Purified water - 75,000

Intersolubility shell receive the following way.

Part of purified water add talc and yellow iron oxide and mix until smooth. With continuous stirring, add the polyethylene glycol 8000 and simeticone emulsion.

The resulting pigment suspension is then passed through a sieve, or a mill with the destruction of agglomerates. Eudragit L-30-Dsift and then in an appropriate vessel is diluted with a part of purified water.

Then to dilute suspension of Eudragit add a suspension of pigment and mix until smooth.

Acceptable bath for coating tablets risedronate sodium obtained by the following method, heated to 35-40oC.

Tabled the Sri cycle of spraying temperature decrease, the tablets are then removed from the bath and dried for approximately 1 h at 30-40oC.

Spraying tablets risedronate as an active ingredient, obtained by the method following part B, above composition are shell 4 mg/cm2dried substance varnish (i.e., thickness of about 45 μm).

B. Pressing tablets risedronate sodium

On the tablet risedronate (30 mg) round shape, each of which weighs 250 mg and contains:

The active ingredient

Risedronate 30,00 mg

Fillers, mg:

Lactose - 156,00*

Microcrystalline cellulose is 60.5

Crosspovidone - 7,40

Magnesium stearate - 1,10

*A specified number of risedronate sodium is determined by analysis, after adjusting with the required dose level of risedronate sodium on the anhydrous basis.

Tablets of the above composition was prepared as follows.

Tablets obtained by mixing double chamber mixer risedronate as an active ingredient with microcrystalline cellulose.

The mixture is passed through a rocking chair, equipped with a sieve of 60 mesh. Milled mixture with lactose and crosspovidone return to the mixer with rotating is achieved the necessary lubrication. Then in rotary tabletirujut press pressed tablets.

Example II. Capsules containing the balls in intersolubility shell

Capsules containing the balls in intersolubility shell, get cooking balls in intersolubility shell with their subsequent kapsulirovaniem in gelatin capsules.

The balls are spheres inert sugar, which are coated with a polymeric film containing risedronate sodium and obtained using the methods described in the following part A. After this, the beads using methods following part B conclude in intersolubility shell.

A. Bulbs risedronate sodium in the shell

Component (mg/capsule:

Risedronate sodium - 30*< / BR>
Areas of sugar, 20-25 mesh - 115,6

The hypromellose - 12

Polyethylene glycol 3350 - 2,4

Purified water - 155,6

*The specified number of risedronate sodium is determined by analysis, after adjusting with the required dose level of risedronate sodium on the anhydrous basis.

Bulbs risedronate in the shell was prepared as follows.

Heat the purified water and medlens add the polyethylene glycol and the solution is allowed to cool to 30oC or below.

Risedronate sodium is cooled, and then optionally passed through a mill to break up the agglomerates and mixed with the polymer solution to a homogeneous condition.

In the right column for coating the sugar spheres are heated to 25oC, after which the beads are sprayed vysheperechislennoe opaque suspension risedronate with the coating 5 mg/cm2dried substance coat thickness of about 50 μm. At the end of the cycle of spraying the air supply is stopped and the beads are cooled to room temperature.

B. Balls in intersolubility shell

Component (mg/capsule:

Bulbs risedronate sodium in the shell (obtained by the method of part (A) - 160,0

Eudragit L-30 - D(on wet basis) - to 106.0

Talc USP - 16,90

Triethylcitrate NF - 3,20

Simeticone emulsion USP - 2,10

Yellow iron oxide (III) N - 0.04

Purified water - 225,00

Part of purified water add talc and yellow iron oxide (III) and mix until smooth. Under continuous stirring, triethylcitrate and simeticone emulsion.

The resulting pigment suspension is passed through a sieve or acceptable mill part of purified water. For dilute suspensions of Eudragit add the pigment suspension and stirring is continued.

A suspension of talc is produced by dispersing talc in parts of purified water and stirring until it reaches a homogenous state of talc.

In the appropriate column for coating the balls risedronate sodium is heated to the required temperature. Then the beads are sprayed with the suspension of the sheath material, the composition of which is given in part B. the Balls in intersolubility shell sprayed with a suspension of talc.

At the end of the cycle of spraying the air supply is stopped. Before kapsulirovaniem balls in the shell stand at least 12 h at 40-50oC. Balls capsulebuy in gelatin capsules, hard shell by using the appropriate device for filling capsules.

Example III. Tablets risedronate in intersolubility shell

According to the method shown in the example , get nieoprocentowana tablet risedronate in the shell.

Covering composition is obtained from the varnish containing the following components (mg/tablet:

Coutaric(production Colorcon, Inc., West point, units PA, USA) - 24

Triacetin - 3

the party in the tub enclosed in a shell of laquer-like substance in an amount of 10 wt./wt.% dry matter (shell thickness of about 75 μm) and the result is tablets are oval, each weighing 300 mg Tablets have the following composition:

The active ingredient

Risedronate sodium 10 mg

Fillers, mg:

Sorbitol - 142

Starch 1500 - 142

Silicon dioxide - 1

Stearic acid - 15

Example IV. Capsules containing particles in intersolubility shell

Capsules containing particles in intersolubility shell, get cooking particles risedronate sodium as an active ingredient, followed by kapsulirovaniem in gelatin capsules. Particles have the following composition:

Active ingredient (mg/capsule:

Risedronate sodium - 25

Fillers, mg:

Lactose - 50

Microcrystalline cellulose - 50

A mixture of risedronate sodium, lactose and microcrystalline cellulose hydrate with water, knead, ekstragiruyut and formed into spheres. The dried particles and then sign in intersolubility membrane as described in example III.

Intersolubility shell has the following composition:

Component

Eudragit L-30 - Dto 90.0

Triethylcitrate - 21

The non AF - 2

Talc - 7

Water - 275

Particles of the above composition will conclude in nakivale in the shell Viseu appropriate column for coating particles is heated to 25oC and particles by spraying the solution is applied to the material intersolubility shell in an amount of 5 mg/cm2dry laquer-like substance when the shell thickness is about 50 microns.

At the end of the cycle of spraying the air supply is stopped and the particles are cooled to room temperature.

Particles in the lacquer shell pripudrivayut talc and capsulebuy in capsules (size capsules 0) with industrial installation for filling capsules (Hofliger & Karg).

1. Solid pharmaceutical composition for oral administration comprising 0.25 to 40.0 wt.% risedronate as the active ingredient and 60.0-of 99.75 wt. % of pharmaceutically acceptable excipients, characterized in that it is covered intersolubility shell consisting of anionic carboxylic polymer with a thickness of 20-100 μm to achieve slow release of the active ingredient.

2. The composition according to p. 1, characterized in that intersolubility shell is pH-dependent membrane, and this membrane is insoluble at pH below 5.5, but soluble at a pH of 5.5 or higher.

3. Composition under item 1 or 2, characterized in that intersolubility shell insoluble in gastrointestinal fluid intestine.

4. Composition according to any one of paragraphs.1-3, characterized in that the membrane consists of anionic carboxylic polymers, preferably anionic carboxylic polymer that is partially methylethylamine polymer of methacrylic acid, and the ratio of anionic free carboxyl groups to ester groups is approximately 1:1.

5. The composition according to p. 1, characterized in that intersolubility shell is pH-dependent membrane, and this membrane is insoluble at pH below 7 and soluble at pH 7 or above.

6. The composition according to p. 5, characterized in that intersolubility shell insoluble in gastrointestinal fluids vestibule of the mouth, pharynx, stomach, esophagus and small intestine, but soluble in gastrointestinal fluids of the colon.

7. Composition under item 5 or 6, characterized in that the membrane consists of anionic carboxylic polymers and preferably anionic carboxylic polymer is partially methylethylamine polymer of methacrylic acid in which the ratio of anionic free carboxyl groups to ester groups is approximately 1:2.

8. Composition according to any one of paragraphs.1-7, characterized in that it has the appearance of pressie fillers.

 

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