Dosage forms of risedronate

FIELD: medicine.

SUBSTANCE: there are described oral dosage forms of risedronate containing safe and effective amount of a pharmaceutical composition containing risedronate, a chelating agent and an agent for effective delayed release of risedronate and the chelating agent in small intestine. The pharmaceutical composition is directly released in a small intestine of a mammal with ensuring pharmaceutically effective absorption of bisphosphonate together with or without food or drinks. Present invention essentially reduces interaction between risedronate and food or drinks which leads to that the active component of bisphosphonate becomes inaccessible to absorption. Thus, the final oral dosage form can be taken with and without food. Further, present invention covers delivery of risedronate and the chelating agent in a small intestine, essentially reducing irritation of upper gastrointestinal tract associated with bisphosphonate therapy. These advantages simplify previous, complicated regimens and can lead to more complete observance of the bisphosphonate therapy regimen.

EFFECT: present invention essentially reduces interaction between risedronate and food or drinks which leads to that the active component of bisphosphonate becomes inaccessible to absorption.

23 cl, 12 ex

Cross-reference to related application

This application is a partial continuation of application for U.S. patent No. 11/106 .816, filed April 15, 2005, which claims the benefits of provisional application No. 60/573 .881 from may 24, 2004

The technical field to which the invention relates.

The invention relates to oral dosage forms of risedronate containing a safe and effective amount of a pharmaceutical composition comprising a bisphosphonate, a chelating agent for the possible introduction of risedronate with food or drink, a means for effective delayed release risedronate and chelating agent in the small intestine and one or more pharmaceutically acceptable excipients. Oral dosage forms of the present invention provide a release pharmaceutical composition in the small intestine of a mammal and a pharmaceutically effective absorption of risedronate when taken together with food or drinks, or without them. The present invention also relates to a method of treatment or prevention of diseases characterized by abnormal calcium and phosphate metabolism, and contain oral administration to a human or other mammal required number described here dosage forms.

Art

Bisphosphonates first became widespread in the form of the calcium complex to improve the action of detergents in hard water. Over time, it was also found that bisphosphonates suitable for the treatment and prevention of diseases or conditions characterized by abnormal calcium and phosphate metabolism. Such States can be divided into two main categories:

1. Condition characterized by anomalous mobilization of calcium and phosphate, leading to General or specific destruction of bones, or excessively high levels of calcium and phosphate in the body fluids. Such States are sometimes referred to here as pathological demineralization of hard tissues.

2. Conditions that are caused by or result from abnormal deposits of calcium and phosphate in the body. These States are sometimes referred to here as pathological calcification.

The first category includes osteoporosis - a condition in which solid bone tissue is destroyed disproportionate growth of new bone tissue. The main part of the spongy bone is destroyed and the bone marrow and bone space become larger, which reduces the strength of the trabecular bone. The bone becomes brittle and less dense. Osteoporosis can be podolskyrosen on senile, medicines (for example, Adra is cortically, as a result of steroid therapy), caused by disease (such as arthritis and tumor) and so on, but its manifestations are similar. Another state of the first category - Paget's disease (distortive ostit). This disease is the destruction of normal bone, which then haphazardly replaced by brackish soft tissue, resulting in bone is deformed under the pressure of the weight of the load, especially in the tibia and the femur. In the first category also includes such conditions as hyperparathyroidism, hypercalcemia malignant tumors and osteolytic bone metastasis.

The second category includes state, manifested in the abnormal deposition of calcium and phosphate, namely references for additional information progressive myositis, systemic calcification and such afflictions as arthritis, neuritis, bursitis, tendonitis and other inflammatory conditions, which promote the deposition of calcium phosphates on the affected tissues.

Bisphosphonates have a tendency to inhibition of bone resorption, which is useful for patients suffering from excessive bone destruction. However, many of the previously known bisphosphonates, such as ethane-1,1-diphosphonate acid (EHDP), propane-3-amino-1-hydroxy-1,1-diphosphonate acid (APD) and dichlorothiophene acid (Cl₂MDP), tend to ingibirovany the mineralization of the bone with the introduction of high levels of dosage. Although there are more biologically active bisphosphonates that can be applied at low dosage levels (such as 1-hydroxy-2-(3-pyridyl)-ethylidene-1,1-bisphosphonate acid (risedronate, alendronate, ibandronate and zoledronate), oral administration of bisphosphonates sometimes leads to the sickness of the patient soon after taking the dose. These ailments are usually characterized by the patient as heartburn, a burning sensation in the esophagus, pain and / or difficulty swallowing, and (or) pain and (or) in the centre of the sternum. Based on this we can assume that such irritation are the result of a build-up of tablets with bisphosphonates in epithelial tissue and mucous, causing local irritation. In order to avoid more gastro-intestinal irritation, the patient taking bisphosphonates for instructions, squeezed medicine full glass of water and remain upright for at least thirty minutes after administration of the oral dosage forms based on bisphophonates.

It is known that the oral dosage forms of bisphosphonates are poorly absorbed (less than 1% of the oral dosage form in the gastrointestinal (LCD) tract (see Ezra et al., Adv. Drug Del. Rev.42: 175-95 (2000)). Some methods cause an increase in absorption of oral bisphosphonates via the LCD tract. These methods include the tificatio penetrating properties of the intestinal mucosa (e.g., through the use of amplifiers absorption) or changes in physical or chemical properties of bisphosphonates (for example, using prodrugs).

Although the use of amplifiers absorption, such as ethylenediaminetetraacetic acid (EDTA), which increase the permeability of the intestine at high doses, suggests them as a means of increasing the absorption of oral bisphosphonates, the use of EDTA as an agent in pharmacotherapy person was considered "impossible" in the light of the influence of EDTA on the integrity of the mucosa (see Ezra et al., Adv. Drug Del. Rev.42: 185 (2000)). However, other researchers concluded that the high content of EDTA required for the manifestation of increased gastrointestinal absorption, eliminates this agent as a candidate for use in oral bisphosphonate therapies (Janner at al., Calcif. Tissue Int. 49; 280-83 (1991)).

Although the primary area of absorption of bisphosphonates is the small intestine, bisphosphonates, such as risedronate, have similar absorption throughout the small intestine, regardless of what place they were delivered (Mitchell et al., Pharm Res., vol.15, No.2: 228-232 (1998)). Thus, targeted delivery in the small intestine only bisphosphonates could not increase its absorption or effectiveness. However, other authors tried to increase the absorption of bisphosphonates potamogalidae permeability of the intestinal mucosa using the release of microparticles chelating agents and bisphosphonates in this region absorption (BR2001-006601).

Such bisphosphonates, as risedronate and alendronate were backed up by several regulatory agencies as an effective tool in the treatment of various bone pathologies. However, the interaction between bisphosphonates and food and minerals (especially magnesium cations, calcium and aluminum, food or supplements containing iron) leads to less absorption of bisphosphonates. For example, Mitchell et al., Br. J. Clin. Pharmacol. 48: 536-542 (1999)showed that the introduction of risedronate with food within 30 minutes reduces the absorbed amount to 50% compared with the introduction of on an empty stomach. In order to reduce such impact of food labeling, oral bisphosphonate forms encourages the patient to take the medicine at least thirty minutes or, in the case of ibandronate, sixty minutes prior to the first day of the meal, and to take calcium supplements at a different time, or in the day when oral dosage forms based bisphosphonates are not accepted. These instructions for use may seem to the patient and uncomfortable, which can lead to non-compliance of the patient mode and treatment.

There is still a need to develop oral dosage forms on the basis of bisphosphonates, which can be taken together with food or drinks, or without them(i.e. having a pharmaceutically effective absorption irrespective accept food or drinks)that is preferred for patients, and which do not cause irritation of the upper gastrointestinal tract.

Discovered that a pharmaceutical composition comprising risedronate required for binding of ions and minerals of food the amount of chelating agent and a means for effective delayed release risedronate and chelating agent in the small intestine, suitable for the manufacture of oral dosage form that provides immediate release of risedronate in the small intestine, as well as pharmaceutically effective absorption of risedronate with the introduction together with food or without, or drinks. Oral dosage forms of the present invention may be taken together with food or drinks, or without them, making it easier bisphosphonate medical therapy and leads to enhanced susceptibility of their patient. In addition, the oral dosage forms according to the invention provide a delayed release of risedronate and chelating agent in the small intestine, which may reduce irritation to the upper digestive tract, when tested with other dosage forms of bisphosphonates, and you shall be staying in a vertical position within thirty minutes after taking the dose.

The invention

The present invention relates to an oral dosage form, based on risedronate containing a safe and effective amount of a pharmaceutical composition containing:

(a) from about 1 to about 250 mg of risedronate;

(b) from about 10 mg to about 970 mg of the chelating agent and

(C) the mechanism of delayed release for immediate supply risedronate and chelating agent in the small intestine; however, such a composition is a tablet weighing not more than 1 year

Dosage forms of the present invention provides immediate release of risedronate and chelating agent in the small intestine of a mammal and a pharmaceutically effective absorption of risedronate with the introduction together with food or drinks, or without them.

The present invention essentially reduces the interaction between risedronate and food, resulting in reduced absorption of risedronate. Received a new oral dosage form may be administered together with food or drinks, or without them, which makes it easier prior to complex treatment regimens and may lead to rapid consent of a patient with bisphosphonate therapies, and, if the patient agrees, the illness can be treated faster. In addition, the invention reduces the potential section shall agenie upper digestive tract, associated with immediate release bisphosphonate oral dosage forms in the delayed release bisphosphonate active ingredient as long as the bisphosphonate and the chelating agent does not reach the small intestine.

The present invention further relates to a method of treating or preventing diseases characterized by abnormal calcium-phosphate metabolism, containing an introduction to the human or other mammal, the necessary number of dosage forms described herein.

The invention further relates to a kit containing one or more oral dosage forms of the present invention and a means to facilitate reception of the accounting methods of the present invention.

Detailed description of the invention

Definitions and terms used

The term "immediate release"as used in this application means the dissolution of the core tablets in less than 60 minutes for measurements under standard conditions USP (United States Pharmacopoeia). For example, the USP establishes that all tablets and capsules are consistent with the overall standard of dissolution, namely, that not less than 75% of the content of the core was dissolved in 900 ml of water for 45 minutes, using the devices, methods and explanations presented on SCR, in the Chapter "R is stvaranje" "Pharmacopoeia of the United States". To do this, 75% is taken for Q, and respectively show the apparatus 1 at 100 rpm or apparatus 2 at 50 rpm

The terms "continuous" or "continuously"used here means a regular, defined intervals. For example, continuous mode corresponding to the mode of taking the medicine once a week, means that the active substance take once a week for an unlimited period of time or up until there is a need for treatment.

The term "delayed release" or "delayed delivery", as used in this application, refers to a formulation of a pharmaceutical composition containing risedronate and the chelating agent in which their release is carried out entirely in some predetermined region of the small intestine.

The term "nutrient"as used here means any food or dietary Supplement, including but not limited to, vitamins, minerals, amino acids, herbs or other botanicals, or concentrates, metabolites, components, extracts or mixtures thereof.

The term "pharmaceutical composition", as used here, means an oral dosage form, containing a safe and effective amount of risedronate and one or more pharmaceutically acceptable fillers, enabling the x at least one chelating agent. Described herein, the pharmaceutical compositions contain from 0.5% to 75%, preferably from 1% to 40% of risedronate and from 25% to 99.5%, preferably from 60% to 99% of pharmaceutically acceptable excipients comprising at least one chelating agent.

The term "safe and effective amount", as used here, means the number of compounds or compositions that are large enough to significantly positively modify the symptoms and / or condition treated, but low enough to avoid serious side effects (ratio of justified risk and benefit), in the framework adopted in medicine. Used in the method according to the invention is safe and effective amount of active ingredient will vary depending on the particular condition being treated, the age and physical condition of the patient, the severity of the condition, the duration of treatment, the nature of competitive therapies, specific type of the active ingredient, a specific type of pharmaceutically acceptable carrier and the like factors within the knowledge and experience of the treating physician.

The term "pharmaceutically effective absorption"as used here, means the amount of chelating agent that is large enough to ensure that the s largely to bind metal ions and minerals in food but low enough to significantly alter the absorption of risedronate compared to absorption on an empty stomach. Thus, the absorption proceeds in a similar manner as with food or without it. It is expected that giving high variability of absorption risedronate, bringing exposure time approximately 50% of the exposure time when taking on an empty stomach will lead to a pharmaceutically effective absorption.

The term "oral dosage form"as used here means any pharmaceutical composition intended for insertion into the small intestine of a human or other mammal through the mouth of this person or other mammal. For the purposes of the present invention deliver the form may be in the form of compressed tablets containing granules or particles risedronate and chelat forming agent.

The term "unit dose" or "unit dosage"as used in the application means a dosage form containing necessary for the introduction of a number of pharmaceutically active or nutrients in one single dose in accordance with the basics of medical practice. The present invention is particularly useful for the introduction of unit doses in the form of tablets or capsules.

The term "gastrointestinal tract" or "LCD tract"as used here, refers to the digestive Tr is KTU, i.e. musculo-membranous tube with approximately thirty feet in length and extends from your mouth to the anus. The term "upper gastrointestinal tract", as used here, means the mouth, throat, esophagus and stomach. The term "lower gastrointestinal tract", as used here, means the small intestine and the large intestine.

The term "small intestine"used here means a portion of the small intestine, which includes everything that is not related to the stomach, including the duodenum, skinny intestine and terminal ileum, i.e. the part of the gastrointestinal tract, which is distant from the duodenal sphincter of the fundus of the stomach and is located closer to a thick gut. The term "colon", as used here, means the part of the lower gastrointestinal tract, which includes the vertical (upward) the colon, transverse colon the colon, the descending colon rectum, sigmoid colon and rectum.

Risedronate

The terms "bisphosphonate" and "diphosphonate", as used here, include acids, salts, esters, hydrates, polymorphs, palpitate, solvate and their derivatives. The bisphosphonates of the present invention include: 1-hydroxy-2-(3-pyridinyl)-ethylidene-1,1-bisphosphonate acid (risedronate), described Benedict et al. in U.S. patent No. 5.583.122, publ. 10.12.1996; Caser et al. in U.S. patent No. 6.410.520 B2, publ. 25.06.2002.

Not limiting primarialy, suitable in accordance with the present invention include salts selected from the group consisting of alkali metals, alkaline earth metals, ammonium and mono-, di-, tri - or Tetra-C₁-C₃₀-alkyl substituted ammonium. Preferred salts are selected from the group consisting of sodium, potassium and ammonium salts.

The number of risedronate contained in the oral dosage forms of the present invention, will depend on the specific form selected risedronate and the scheme of continuous reception, which risedronate is dosed to the patient. Non-limiting examples of modes suitable for oral administration dosage forms of the present invention, are the schemes of continuous reception times a day, once a week, twice a month, three times per month once a month. The terms "three times a month" or "three month" means that the dosage form is entered three times, i.e. three times in a calendar month. Under the scheme "three times a month" oral dosage forms can be entered for three consecutive days, or once every nine or eleven days. The terms "twice a month" or "twice a month" means that the dosage form is entered twice, i.e. two times in a calendar month. For rhythm is e "twice a month" oral dosage forms can be entered for two consecutive days, or once every fourteen to sixteen days. The terms "monthly" or "once a month" means that the dosage form is introduced at a time, i.e. once during the calendar month, i.e. every 28-31 days.

Currently, specialists use a mixed item, for example an indication of the proportion or percentage bisphosphonate active ingredient is given in the calculation of anhydrous monosodium salt basis of risedronate. According to the present invention, the phrase "about 35 mg risedronate, its pharmaceutically acceptable salts and mixtures thereof, based on the anhydrous monosodium salt" means that the number of selected risedronate compounds calculated on the basis of 35 mg of anhydrous monosodium salt of risedronate.

Typically, the oral dosage forms of the present invention will contain from about 1 mg to about 250 mg of risedronate calculated on the anhydrous monosodium salt basis of risedronate. Daily oral dosage form contains from about 1 mg to about 10 mg risedronate calculated on the anhydrous salt. With weekly oral dosage form contains from about 10 mg to about 70 mg risedronate, calculated on the anhydrous salt risedronate, preferably from about 15 to about 55 mg, more preferably from about 35 to about 50 mg risedro the TA. When risedronate is dosed twice a month, the oral dosage form contains from about 20 mg to about 120 mg of risedronate, preferably from about 75 mg to about 90 mg risedronate, calculated on the anhydrous salt risedronate. When risedronate is dosed three times a month, the oral dosage form contains from about 15 mg to about 90 mg risedronate, preferably from about 50 to about 75 mg risedronate, calculated on the anhydrous salt risedronate. When risedronate dosed monthly, oral dosage form contains from about 50 mg to about 280 mg, preferably from about 100 to about 250 mg, and more preferably from about 150 mg to about 200 mg of risedronate, calculated on the anhydrous salt risedronate. In one embodiment of the invention, the dosage form contains about 100% effective amount of risedronate as the equivalent of a chelating agent contained in the tablets risedronate with immediate, not delayed, release. In accordance with another embodiment of the invention, the dosage form is about 145% effective amount of risedronate as equivalent degelatinised agent contained in the tablets risedronate with immediate, not delayed, visualaid the assemblies.

Chelating agent

The term "chelating agent"used herein means a molecule that contains two or more atom donors of electrons that can form coordination with one metal ion. It is implied that the term "chelating agent" includes both the chelating agent and its salts. For example, the term "chelating agent comprises citric acid and its salts.

The most commonly and widely used chelating agents form a coordination bond with metal atoms through an oxygen or nitrogen donor atoms, or through both. Other, less common chelating agents form a coordination bond through sulfur in the form of - SH (tylenol or mercaptanes groups). After the formation of the first coordination each subsequent donor atom, forming a connection, creates a ring containing a metal atom. Chelating agent may be bidentate, tridentate, tetradentate, etc., depending on whether it contains two, three, four or more donor atoms that can bond to the metal atom (see Kirk-Othmer Encyclopedia of Chemical Technology, 4^thed. 2001).

In homogeneous dilute solutions the equilibrium constant of complex formation of solvated metal ion (e.g. calcium) and chelating agent in its fully dissociate the Anna form is called constant To education, or stability. Practical importance of constant education is such that a high value of log K means great value chelated and neklinovskogo (or free) metal ion when equivalent amounts of metal ion and chelating agent. To almost all metal ions form a complex with a chelating agent instead of bisphosphonates, preferred are the higher the ratio (or difference, if It is expressed in log) constant of the chelating complexing agent and bisphosphonates. For example, in the case of equimolar amounts of bisphosphonates and a chelating agent to 99% of the metal ions formed a complex with a chelating agent, the chelating agent should have a log For that at least 4 units higher than that of the complex of bisphosphonate - metal ion. Another method that can be used for the preferred formation of the complex of the chelating agent - metal ion compared to the complex of bisphosphonate - metal ion is added a molar excess chelating agent, calculated on the basis of the law of actions of the masses with the preferred formation of the complex chelating agent - metal ion.

Although the pH and the concentration of the solution can affect the constant of education, in General, To log chelating agent preferably m is Nisha least equal To log bisphosphonates. In other cases, log on To chelating agent for 2-5 units more log To bisphosphonates. In other cases, the chelating agent is present in a molar excess relative to the bisphosphonates. In such cases, the chelating agent is present in a molar ratio to the bisphosphonates at least 2:1.

Chelating agent and the form in which it is introduced, constitute at least 50% when dissolved in water, and risedronate. In other cases, the chelating agent and the form in which it is administered, can have a solubility that is comparable or exceeds the solubility of risedronate.

In one embodiment of the invention the chelating agent is selected from the group consisting of sodium or disodium salts of EDTA, citric acid, malic acid, tartaric acid, lactic acid, adipic acid, succinic acid, lysine, sodium hexametaphosphate, and combinations thereof. In another embodiment of the invention the chelating agent is sodium or disodium salt of EDTA, citric acid or sodium hexametaphosphate.

The amount of chelating agent present in the oral dosage form of the present invention, will depend on the selected specific chelating agent or agents (i.e. mixtures of chelating agents), the amount of the active ingredient - bisphosphonate, p is outstayed in oral dosage form, and from a certain area of the small intestine, in which it is desirable to provide delivery and release of chelating agent and / or active ingredient - bisphosphonates. As was shown in the previous prior art, after taking milk decreases the concentration of calcium along the entire length of the lower digestive tract, from the beginning to the end of the small intestine (see Mahe, J. et al., Gastroileal nitrogen and electrolyte movements after bovine milk ingestion in humans. Am. J. Clin. Nutr. 56: 410-16 (1992).

The concentration of calcium in the stomach about 10 times higher than in the jejunum, and about 40 times higher than in the intestine. Therefore, if the risedronate and the chelating agent are released in the stomach (along with food), the amount of chelating agent according to the present invention will be enough to overcome the effect of the absorption of calcium or drugs. Calcium concentration in the jejunum and lower intestine, and by directional release dosage forms in these areas, where the calcium content is lower chelating agent is most effective when the binding of calcium than with the release of his stomach. It is also desirable not only to obtain targeted release tablets in the small intestine, but also to achieve the immediate release of risedronate and chelating agent from the core tablets after coating will dissolve. This will increase the local concentration gelatinous what about the agent in relation to the concentration of calcium in the small intestine. Slow or prolonged, the release of chelating agent in the small intestine will not provide the desired local concentration of the chelating agent and such liberation would not overcome the influence of food.

Typically, the oral dosage forms of the present invention will contain a safe and effective amount of chelating agent needed to achieve the desired chelating effect to the chelation of residual metal ions emerging from food in the gastrointestinal tract, in place of the release was carried out without a significant effect on the absorption of bisphosphonates in the absence of food. In one embodiment, the oral dosage form contains from about 10 mg to about 1000 mg of the chelating agent in a single dose. In another embodiment, oral dosage forms contain from about 10 mg to about 500 mg of the chelating agent in a single dose. When the chelating agent is a disodium salt of EDTA, preferred is the range from about 55 mg to about 500 mg, preferably from about 75 mg to about 250 mg per dose. When the chelating agent is a citric acid, preferred is the range from about 100 mg to about 970 mg, preferably from approx the RNO 250 mg to about 500 mg per dose.

Delayed delivery in the small intestine

The specialist is able to satisfactorily adjust the speed and (or) the best release in the small intestine, by altering one or more of the following options:

(a) the appropriate active ingredient;

(b) the type and the content of substances that facilitate the breakup;

(c) type of coverage, type and content of media added to the floor, and desirable concomitant thickness and permeability (swelling properties) cover;

(d) time-dependent parameters of the coating and / or coated tablet, particle, bead or granule;

(e) the particle size of the granulated active ingredient;

(f) depending on the pH condition of the coating and / or coated tablet, particle, bead or granule;

(g) the size of the particles or the solubility of the chelating agent;

(h) the dissolution rate of the coating;

(j) the size or shape of the pill.

In addition, the pharmacodynamic effect of the tablets in the multiple use must be at least 75% in comparison with the tablet immediate release.

Delayed release in the small intestine

Man or other mammal, suffering from diseases or disorders associated with calcium-phosphate metabolism, can be treated successfully through the receipt of risedronate in tonco the intestine mentioned person or other mammal. Described here is a new dosage form is released directly into the small intestine and prevent unwanted release of risedronate mouth, throat, esophagus and / or stomach, thus preventing the formation of erosions, ulcers or other such stimuli kapitelnyh or mucous covers these tissues.

Chelating agent and risedronate are released quickly and, if possible, at the same time. In such cases, the local concentration of chelating agent is higher with respect to the concentration of metal ions in food. High local concentration of chelating agent in the environment, where the active principle is released, can efficiently bind to metal ions in food and to promote the absorption of bisphosphonates. This can be achieved using a single pill.

A variety of tools for targeted release of bisphosphonates and chelating agent in the lower digestive tract are suitable for use in the present invention. Non-limiting examples of means for delivery to the lower gastrointestinal tract include pH-triggered delivery systems and time-dependent delivery system.

pH-triggered delivery systems

One variant of implementation of the present invention includes a coating (or encapsulating) risedronate and chelating Agay the TA(s) substance which is not destroyed in the gastro-intestinal fluids, with the release of risedronate and chelating agent in the gastrointestinal tract to achieve a certain desired point. In one embodiment, the delayed release pharmaceutical composition is achieved by coating tablets, capsules, particles, or granules risedronate and chelating agent is a substance that is sensitive to pH, i.e. erodible or soluble at pH, which predominantly affects the small intestine, but not typical for the upper (i.e. for the mouth, cheek space, pharynx, esophagus or stomach) or lower digestive tract.

In some cases it is desirable that the risedronate and the chelating agent would be released in a particular place in the small intestine. In other cases, it is desirable independent release of risedronate and chelating agent in various places of the small intestine, for Example, it may be desirable to secure the release of chelating agent in the ascending colon, and risedronate in the transverse colon. When it is desirable joint or separate target release risedronate and chelating agent in specific areas of the small intestine, the choice of coating material and (or) method of coating or otherwise the Association risedronate and chelating agent with a selected coating material, or another pharmacist who Cesky acceptable carrier may be varied or amended, as described herein, or by any method known to the expert from the prior art.

As guidance for selecting an appropriate coating can be used solubility, acidity and sensitivity to hydrolysis of various active ingredients risedronate, for example, salts of acidic additives, salts formed by postnasal group (for example, salts of alkali metals, salts of alkaline earth metals, and so forth), and esters (e.g., alkyl, alkenyl, aryl, arylalkyl). In addition, inside coated tablets, particles or granules suitable pH values can be set by adding a suitable buffer to the active component, in accordance with the desired model release.

In one embodiment of the present invention, the delivery to the small intestine is manufactured using a material with pH-dependent intersolubility coating made of polymer partially methylated methacrylic acid. Oral dosage form can be in the form of pressed tablets with intersolubility coating made of granules or particles of the active ingredient.

Any intersolubility coating that is insoluble at pH below 5.5 (i.e. which mainly exists in the mouth, throat, esophagus and stomach), but soluble at pH PR is about 5.5 to 6.5 (i.e. which exists in the small intestine) can be practically used in the present invention. In addition, desirable for the effective delivery of bisphosphonates or chelating agent in the small intestine fit any intersolubility floor, which is completely or partially insoluble at pH below 5.5 and soluble at a pH of from about 5.5 to 6.5.

Intersolubility coating should be applied to the pressed tablet or capsule (e.g., gelatin, starch or hypromellose) in a thick enough layer so that the solid coating does not dissolve in the gastrointestinal environment at pH below 5.5, but was dissolved in pH from about 5.5 to 6.5. Generally, dissolution or destruction of the coating media is not going to hit coated dosage forms in the small intestine.

It is expected that any anionic polymer exhibiting the desired profile of the dependence of solubility on pH, can be practically used as Intercollege coating in the present invention, ensuring the delivery of bisphosphonates and chelating agent in the small intestine. The selected coating must be compatible with specifically selected risedronate the active ingredient. The preferred polymers used in the present invention are anionic carboxyl p is the materials. Especially preferred polymers are acrylic polymers, preferred partially methylated polymers of methacrylic acid in which the ratio of free anionic carboxyl groups to ester groups is approximately 1:1.

In particular, the appropriate methacrylic acid copolymer is Eudragit L®, especially Eudragit L 30 D-55® and Eudragit L 100-55®, manufactured by Röhm Pharma GmBH & Co.KG Darmstadt, Germany. In Eudragit L 30 D-55® regarding free of anionic carboxyl groups to ester groups is approximately 1:1. Further, it is known that the above-mentioned copolymer is not soluble in the environment of an LCD having a pH below 5.5, mostly 1.5 to 5.5, i.e. which mainly exists in the environment of the upper LCD tract, but easily soluble at pH above 5.5, i.e. mainly in the environment of the small intestine.

The coating may and usually will contain a plasticizer and possibly other coating media, such as colorants, surfactants, talc and / or magnesium stearate, many of which are well known from the field of coatings. In particular, anionic carboxylic acrylic polymers usually contain 10-25 wt.% plasticizer, especially triethylcitrate, tributyltin, activitiesare, dibutyl phthalate, diethylphthalate, polyethylene glycol, acetylated monoglycerides propylene glycol and triacetin. For coating use still the traditional methods of coating, as applying in the liquefied layer or lubrication forms. The coating thickness should be sufficient to ensure the release oral dosage form upon reaching the area of the small intestine.

Solid oral dosage form may be in the form of compressed tablets with a coating, which contains particles or granules bisphosphonate active ingredient and a chelating agent, or soft or hard capsules (for example, gelatin, starch or hydroxypropylmethylcellulose), with coating or without it, which contains beads or particles bisphosphonate active ingredient and a chelating agent, who themselves have intersolubility floor. In the embodiment of the invention, the tablets are compressed and covered intersolubility the floor.

Suitable intersolubility coatings include Eudragit L-100®, acetated cellulose, shellac, or any other intersolubility coatings that dissolve at a pH of from about 5.5 to about 6.5. Intersolubility coating is applied using various evaporation methods known to the expert from the prior art. In addition, intersolubility coating can contain one or more pharmaceutically acceptable carriers, including, but not limited to, talc, triethylcitrate, poly is trangleball, Tween 80® (polyoxyethylene sorbitan monooleate, available from Sigma Chemical Co., St. Louis, MO), castor oil. Intersolubility coating is applied to the tablet core, providing the increase in weight from 2.5 to 40%.

Preformed core includes bisphosphonate active ingredient, a chelating agent, and may contain one or more pharmaceutically acceptable carriers. Suitable carrier materials include, but are not limited to, crystalline cellulose, calcium phosphate, polyvinylpyrrolidone, magnesium stearate, sucrose, starch, magnesium oxide and sodium lauryl sulfate.

Breathability delivery system

In another embodiment of the invention the delivery risedronate and chelating agent in the small intestine is accomplished by applying breathability delivery systems. After a certain transit time after emptying of the stomach, the drug and (or) release of chelating agent can be directed at different segments of the small intestine. Approaches to time-dependent systems of delivery, suitable for use in the present invention include, but are not limited to such means, as Pulsincap™ (Scherer DDS, Strathclyde, U.K.), Time Clock™ (Zambon Group, Milan, Italy) and SyncroDose™ (Penwest, Patterson, NY), as well as various coatings, which over time are destroyed, releasing composition is shining pills, such as hypromellose, hydroxypropylcellulose, and any suitable hydrogels.

In one embodiment of the invention the time-dependent system Pulsincap™ is used to target delivery of the active ingredient and a chelating agent in the small intestine. The active ingredient and other media, including chelating agent is contained within a water-insoluble capsule Pulsincap™ through hydrogel ligament, which is surrounded by a water-soluble shell. All dosage form optionally covered intersolubility coating for protection from damage during the progress of the upper LCD tract. When the patient ingests dosage form Pulsincap™, a water-soluble coating dissolves and allocates hydrogel mass in the gastric and (or) the gastro-intestinal environment. Then hydrogel mass swells, resulting stands out the contents of the capsule and thereby emits an integral part of the capsule. The release of parts of the capsule can be initiated in specific areas of the small intestine by modifying the properties of the hydrogel mass (see Watts, Peter J. & Illum, Lisbeth, Drug Dev. and Indus. Pharm., 23(9): 893-917 (1997)).

In one embodiment of the invention the time-dependent coating is applied to a compressed tablet, and then intersolubility the coating is applied to the head is reported from time coverage. It is used to target delivery of the active ingredient and a chelating agent in the small intestine. The active ingredient and other media, including chelating agent contained in the core tablets. Intersolubility dosage form cover time-dependent coating and then intersolubility coating. Intersolubility coating material protects the dosage form from decomposition when moving through the upper LCD tract. When the patient ingests dosage form, intersolubility coating dissolves, after which the dosage form leaves the stomach and then the core of the tablet begins to swell. Ultimately, in a pre-specified point in the environment of the small intestine is dependent on the time the coating will break down and release an integral part of the core tablet into the small intestine. The release of parts of the core tablet may be aimed at certain parts of the small intestine by modification of core tablets, time-dependent coatings, and (or) Intercollege coverage.

Pharmaceutically acceptable carriers

Pharmaceutically acceptable carriers include, but are not limited to, polymers, resins, plasticizers, fillers, lubricants, diluents, binders, substances that facilitate the dissolution, the solution is teli, the co-solvents, surfactants, buffer systems, preservatives, sweeteners, flavouring agents, pharmaceutically acceptable dyes or pigments, chelating agents, viscosity regulators and their combinations. Pharmaceutically acceptable carriers can be used in any component in the production of oral dosage forms, i.e. core tablets or coatings.

Suitable perfumes and dyes, and pigments, among others, include, but are not limited to - such as those described in Handbook of Pharmaceutical Excipients (4^thEd., Pharmaceutical Press, 2003).

Suitable co-solvents include, but are not limited to, ethanol, isopropanol and acetone.

Suitable surfactants include, but are not limited to - fatty acid esters of polyoxyethylenesorbitan, monoalkyl ethers of polyoxyethylene, monetary sucrose, simeticone emulsion, sodium lauryl sulfate, Tween 80®, simple and complex esters of lanolin.

Suitable preservatives include, but are not limited to, phenol, alkalemia esters by parahydroxybenzoic acid, benzoic acid and its salts, boric acid and its salts, sorbic acid and its salts, chlorbutanol, benzyl alcohol, thimerosal, acetate and nitrate of finalstate, nitromersol, benzalconi chloride, pyridinium chloride, methylparaben and propylparaben.

Suitable fillers include, but are not limited to - starch, lactose, sucrose, maltodextrin and microcrystalline cellulose.

Suitable plasticizers include, but are not limited to - triethylcitrate, polyethylene glycol, propylene glycol, dibutyl phthalate, castor oil, acetylated monoglycerides, and triacetin.

Suitable polymers include, but are not limited to - ethylcellulose, acetatetreated cellulose phthalate of hydroxypropylmethylcellulose, acetated cellulose, polyvinylacetate, Eudragit® L 30 D, Eudragit® L 100-55 (Röhm Pharma Gmbh and Co. KG, Darmstadt, Germany), Acryl-EZE® and Sureteric® (use, Inc., West Point, Pa.).

Suitable lubricants include, but are not limited to - stearate, stearic acid and talc.

Applications

The present invention relates further to a method of treatment or prevention of diseases characterized by abnormal calcium-phosphate metabolism, containing an introduction to the human or other mammal, the necessary, safe and effective amount of pharmaceutically acceptable compositions, delivered mentioned person or mammal described here by oral dosage forms.

Diseases characterized by abnormal calcium-phosphate metabolism, include, but are not ogran who receive them - the osteoporosis, Paget's disease (distortive ostit), hyperparathyroidism, hypercalcemia malignant tumors, osteolytic bone metastasis, references for additional information progressive myositis, systemic calcification and such ailments as arthritis, neuritis, bursitis, tendonitis and other inflammatory condition that causes the affected tissue to deposition of calcium phosphates.

Oral dosage forms of the present invention are suitable for administration to a patient in accordance with continuous dosing once per day, once per week, three times per month, twice a month and once a month.

Sets

The present invention further provides kits, especially suitable for introduction described here oral dosage forms in accordance with the continuous regimen once a day, once a week, three times per month, twice a month and once a month. Such kits include one or more oral dosage forms containing risedronate and the chelating agent, and a means of facilitating the combination with the methods of the present invention. These kits provide a convenient and effective means to ensure that the subject will take the appropriate oral dosage form in suitable doses and appropriate way. Convenient means such nab the ditch includes any means, which facilitates the introduction of the active ingredient in accordance with the method of the present invention. Such convenient means include instructions, packaging and dosing means, and a combination of both. The kits may also contain a means to facilitate memorization, including - but not limited to, print the days of the week, numbers, illustrations, signs, Braille, calendar stickers, reminiscent of cards and other means, individually selected by the patient. Examples of packaging and dispensing means well known in the art and described Flora et al. in U.S. patent No. 4.761.406, publ. 02.08.1988 and Uchtman in U.S. patent No. 4.812.311, publ. 14.03.1989.

Optionally, the kit may include at least one oral dosage form, containing risedronate and the chelating agent, and at least one oral dosage form accompanying nutrients. Preferred nutrients are calcium and / or vitamin D. Oral formulations based on calcium, suitable for use in the present invention include capsules, compressed tablets, chewable tablets, and the like. Typical salt form of calcium suitable for use in the present invention include, but are not limited to - calcium carbonate, calcium citrate, small is calcium, citramalate calcium, glubionate calcium, gluceptate calcium, calcium gluconate, calcium lactate, dibasic calcium phosphate and rejonowy calcium phosphate. In one embodiment, the kits of the present invention may include tablets containing 400 mg to 1500 mg of calcium.

The term "vitamin D", as used here, refers to any form of vitamin D, which can be administered to the mammal as nutrients. Vitamin D is absorbed in the body, producing what is often referred to as "activated forms of vitamin D. the Term "vitamin D" may include activated and non-activated forms of vitamin D, as well as precursors and metabolites of such forms. Predecessors such activated forms include vitamin D₂(ergocalciferol produced by plants) and vitamin D₃(cholecalciferol produced in the skin, found in animal organisms and used for vitaminizirovanniy food). Vitamin D₂and D₃have similar biological effects on humans. The inactive metabolites of vitamin D₂and D₃include gidroksilirovanii form of vitamin D₂and D₃. Analogues of activated vitamin D can not be set in high doses in the transient regime because of their toxic who is actvie on mammals. However, the non-activated vitamin D₂and D₃and their metabolites can be introduced in large doses in comparison with the active forms of vitamin D on an interim basis without toxic effects. In one embodiment, the kits of the present invention may contain tablets containing from 100 IU to 10,000 IU of vitamin D.

In another embodiment, the kits of the present invention may contain one or more nutrient tablets containing calcium and vitamin D. In another embodiment, a single dose of nutrients includes approximately 600 mg of calcium and 400 IU of vitamin D.

The following non-limiting examples illustrate the compositions, processes and methods of application of the present invention.

EXAMPLES

Example I

Tablets with intersolubility coating containing risedronate and EDTA

Tablets with intersolubility coating containing risedronate and EDTA, manufactured by preparing coating compositions and extruded tablets containing risedronate and EDTA, and then applying this coating composition on these tablets.

Intersolubility coating composition is presented in the form of a glaze that contains the following media in one tablet:

A. Intersolubility coating suspension

Intersolubility coating obtained using the following method:

The pigment suspension is prepared by adding with stirring Polysorbate 80, milled iron oxide and talc to approximately two-thirds of purified water. The suspension is stirred for at least two hours. To the pigment suspension add 30% simeticone emulsion and the remaining water and mix for at least 45 minutes. Combine a solution of Eudragit L 30 D-55® and triethylcitrate and stirred in t the value of at least 45 minutes. Then the pigment suspension is added to a solution of Eudragit and stirred for 30 to 60 minutes. The obtained coating suspension is taken and is mixed throughout the coating process. The core tablet was placed in a tank (vessel) for coating and heated with occasional shaking. The tablets are coated using conventional lubrication process forms up until the required number of coating solution will not be applied. Then the tablet is cooled and collected in special containers.

Coating having a weight gain of 30% (total solids), is applied by spraying the above composition for extruded tablets containing risedronate and EDTA obtained below in part C.

C. Extruded tablets containing risedronate and EDTA

Intersolubility coating composition is obtained, as shown in section a, is deposited on 35 mg tablets risedronate, with each tablet weighs 240 mg and contains:

Active ingredients:

Chelating agent:

Media:

* This number is calculated on the anhydrous monosodium salt risedronate.

Tablets containing the above-mentioned composition, obtained in the following way:

Risedronate sodium, disodium edetate, nitroglycol starch and microcrystalline cellulose are passed through a mill and placed in a mixer equipped with intensifier. The mixture is stirred for approximately 10 minutes with the intensifier. Select stearic acid and magnesium stearate and add to the mixer. The mixture is stirred for approximately 3 minutes off the intensifier. The mixture is pressed into tablets by means of a suitable press.

Example II

Tablets with intersolubility coating containing risedronate and EDTA

Tablets with intersolubility coating containing risedronate sodium, receive, as described below, using the method outlined in example I.

Coating composition obtained from a glaze that contains the following media in one tablet:

Ingr dirty:

Coating having a weight of 40% weight gain, applied to the tablets containing 150 mg of risedronate and 75 mg EDTA, using the continuous lubrication of the forms so that each oval tablet in the result has a weight of 500 mg of the Composition of each tablet is as follows:

Active ingredients:

Chelating agent:

Media:

Example III

Tablets with intersolubility coating containing risedronate and EDTA

Tablets with intersolubility coating containing risedronate and EDTA, manufactured by preparing coating compositions and extruded tablets containing risedronate and EDTA, and then applying this coating composition on these tablets.

Intersolubility coating composition obtained in the form of a glaze that contains the following media in one tablet:

A. Intersolubility coating suspension

Ingredients:

Intersolubility coating obtained using the following method:

The pigment suspension get by adding under stirring Polysorbate 80, milled iron oxide and talc to approximately two-thirds of purified water. The suspension is stirred for at least two hours. 30%simeticone emulsion and the remaining water is added to the pigment suspension is stirred for at least 45 minutes. Combine a solution of Eudragit L 30 D-55® and triethylcitrate and stirred for at least 45 minutes. Then the pigment suspension is added to a solution of Eudragit and stirred for 30 to 60 minutes. The resulting suspension is taken and is mixed throughout the coating process. The core tablet was placed in a tank (vessel) for coating and heated with occasional shaking. The tablets are coated using conventional process lubricate molds until then, until you applied the desired amount of coating solution. Then the tablet is cooled and collected in special containers.

Coating having a weight gain of 10% (total solids), is applied by spraying the above composition for extruded tablets containing risedronate and EDTA obtained below in part C.

C. Extruded tablets containing Reese is dronet and EDTA

Intersolubility coating suspension obtained, as shown above in part a, is deposited on the pill containing 35 mg of risedronate, with each tablet weighs 290 mg and contains:

Active ingredients:

Chelating agent:

Media:

*This amount is calculated on the anhydrous monosodium salt risedronate.

Tablets containing the above-mentioned composition, obtained in the following way:

Risedronate sodium, edetate disodium, nitroglycol starch,¹/₂rSolvSMCC90,¹/₂stearic acid and¹/₂the magnesium stearate is passed through a mill and add to the mixer, equipped with intensifier. The mixture was stirred at listello 20 minutes when the intensifier, and then cool and grind. Add the rest ProSolvSMCC90 and stearic acid and is stirred for another 10 minutes. The remaining magnesium stearate is screened and added to the blender with the granulation. The mixture is stirred for about 3 minutes when the intensifier. The mixture is pressed into tablets using a suitable tablet press.

Example IV

Tablets with intersolubility coating containing risedronate and EDTA

Tablets with intersolubility coating containing risedronate and EDTA, manufactured by preparing coating compositions and extruded tablets containing risedronate and EDTA, and then applying this coating composition on these tablets.

Intersolubility coating composition obtained in the form of a glaze that contains the following media in one tablet:

A. Intersolubility coating suspension

Ingredients:

Intersolubility coating obtained using the following method:

The pigment suspension obtained by adding Polysorbate 80, primary iron oxide, white chromatone and talc to approximately 2/3 of purified water under stirring. The suspension is stirred for at least 2 hours. 30%simeticone emulsion and the residue water is added to the pigment suspension and stirred for at least 45 minutes. A solution of Eudragit L 30 D-55 and triethylcitrate are combined and stirred for at least 45 minutes. Then add the suspension of the pigment to a solution of Eudragit and stirred for 30 to 60 minutes. The resulting coating, the suspension is sieved and mixed in the coating process.

Core tablets are transferred into the tank coating and pre-heated with periodic shaking. For coating tablets used conventional method for coating using eat the spine of the coating; the coating is applied until such time until it is applied the desired amount of coating solution. Then the tablet is cooled and collected in suitable containers.

By spraying the above composition for extruded tablets containing risedronate and EDTA obtained in part C below, was obtained weight gain cover about 9% (of total solids).

C. Extruded tablets containing EDTA and risedronate

Intersolubility covered suspension obtained in part a previously sprayed on the tablets with 50 mg of risedronate, and each tablet weighs 414,3 mg each tablet contains:

Active ingredients:

Chelating agent:

Media:

*This amount is calculated in anhydrous monosodium salt risedronate. Tablets containing the above-mentioned composition, obtained in the following way:

Risedronate sodium, edetate disodium, nitroglycol starch,¹/₂rSolvSMCC90,¹/₂stearic acid and¹/₂the magnesium stearate is passed through a mill and add to the mixer, equipped with intensifier mixing. The mixture is stirred for approximately 20 minutes when the intensifier, and then cool and grind. Add the rest ProSolvSMCC90 and stearic acid and is stirred for another 10 minutes. The remaining magnesium stearate is screened and added to the blender with the granulation. The mixture is stirred for about 3 minutes when the intensifier. The mixture is pressed into tablets using a suitable tablet press.

Example V

Tablets with intersolubility coating containing risedronate and EDTA

Tablets with intersolubility coating containing risedronate and EDTA, manufactured by preparing coating compositions and extruded tablets containing risedronate and EDTA, and then applying this coating composition on these tablets.

Intersolubility coating composition obtained in the form of a glaze that contains the following media in one tablet:

A. Intersolubility coating suspension

Ingredients:

Intersolubility coating obtained in the following way:

Talc and black iron oxide is added to parts of purified water and mixed until homogeneous. Under continuous stirring, triethylcitrate. The obtained pigment suspension is then passed through a sieve or a suitable mill for grinding the agglomerates. Eudragit L 30 D-55 sift, and then transferred into a suitable container, and dilute a portion of the purified water. Then the pigment suspension is added to a dilute suspension of Eudragit and stirred to obtain a homogeneous mass.

In a suitable pan for coating heated to about 30-35°C extruded tablets (10 kg)containing risedronate and EDTA, as described next. Intersolubility WM is enzio sprayed on the tablets with an intensity of about 30 grams per minute. When spraying is finished, the temperature is lowered and the tablets are taken out and dried at 30-35°C for approximately 1 hour.

By spraying the above composition for extruded tablets containing risedronate and EDTA obtained in part C below, was obtained weight gain cover approximately 35% (of total solids).

C. Extruded tablets containing risedronate and EDTA

Intersolubility coating composition obtained as above in part a, is deposited on the tablets containing 5 mg of risedronate, with each tablet weighs 240 mg and contains:

Active ingredients:

Chelating agent:

Media:

*This amount is calculated on the anhydrous monosodium salt risedronate. Tablets containing vishey the above composition, obtained in the following way:

Tablets get through sifting risedronate active ingredient and EDTA with¹/₂part of microcrystalline cellulose in a mixer with double casing. The mixture is stirred until homogeneous. Then add¹/₂part of stearic acid and continue stirring. The mixture is then compressed with a roller and crushed. Add the remaining monocrystalline cellulose and nitroglycol starch and mix until smooth. Then add the remaining stearic acid and mix to achieve sufficient lubrication. Then the tablets are compressed on a rotary press.

Example VI

Tablets, time-dependent and has intersolubility coating containing risedronate and citrate

Tablets, time-dependent and has intersolubility coating containing risedronate and sodium citrate, manufactured by preparing a two-layer coating composition and compressed tablets containing risedronate and sodium citrate, and then applying the aforementioned coating composition on these tablets.

The first (breathability) layer coating composition is obtained in the form of a polymer containing the following media in one tablet:

A. acid-Soluble coating layer

Ingredients:

Acid-soluble coating is obtained using the following method:

The solution is produced by adding ethyl cellulose to approximately two-thirds of a mixture of toluene: ethyl alcohol with stirring. The solution is stirred for at least two hours. Dibutylsebacate added and stirred for another two hours. The resulting solution to cover the pick and mix at the time of coating.

C. Suspension with intersolubility coating

Ingredients:

Intersolubility coating is obtained using the following method:

The pigment suspension get by adding under stirring milled iron oxide and talc to approximately two-thirds of purified water. The suspension is stirred for at least two hours. Combine a solution of Eudragit L 30 D-55® and triethylcitrate and stirred for at least 45 minutes. Then the pigment suspension is added to a solution of Eudragit and stirred for 30 to 60 minutes. The resulting suspension is taken and is mixed throughout the coating process.

Molded tablets are placed in the VAT to cover and heated with occasional shaking. Pressed tablet cover time-dependent coating and then intersolubility coating suspension, using a standard process form smearing until then, until you applied the desired amount of coating solution. Then the tablet is cooled and collected in special containers.

Coating having a weight gain of 10% for the time-dependent coverage and 13% for Intercollege coverage (total solids compared with the weight of the core tablet), is applied by spraying the above-mentioned compositions (a and b) on presova the s tablet, containing risedronate and sodium citrate, obtained below in part C.

C. Extruded tablets containing risedronate and citrate

Water-soluble coating and intersolubility coating suspension obtained in the above parts a and b, sprayed on the tablets of 5 mg risedronate, with each tablet has a weight of 500 mg and contains:

Active ingredients:

Chelating agent:

Media:

*This amount is calculated on the anhydrous monosodium salt risedronate.

Tablets, content is the following of the above composition, obtained in the following way:

Of risedronate sodium, sodium citrate, microcrystalline cellulose, croscarmellose sodium, mannitol and polyvinylpyrrolidone is passed through the mill and placed in a mixer with the included intensifier. The mixture is stirred for approximately 10 minutes with the use of the intensifier and granularit in the presence of purified water for 15 minutes. The mixture is dried overnight at 30°C, passing through the mill. Magnesium stearate is selected and added to the mixer. The mixture is stirred for approximately 3 minutes. The mixture is pressed into tablets by means of a suitable press.

Example VII

Tablet with time-dependent delivery containing risedronate and EDTA

Tablets with gramasevaka delivery containing risedronate and EDTA, manufactured by preparing coating compositions and extruded tablets containing risedronate and EDTA, and then applying this coating composition on these tablets.

The obtained coating composition contains the following media in one tablet:

A. Coating suspension

Media:

Floor receive the following method:

Carnauba wax, beeswax, polyoxyethylenated sorbitan and hypromellose added to purified water at 60°C and stirred for 3 hours. The obtained coating mixture are selected and mixed during the coating process. Core tablets placed in the VAT to cover and warm up with periodic shaking. Tablet cover using conventional methods of lubrication forms until, until you applied the desired amount of coating solution (at 60°C). Then the tablet is cooled and collected in appropriate containers.

Coating having a weight gain of 30% (total solids), is applied by spraying the above composition for extruded tablets containing risedronate and EDTA obtained below in part C.

C. Extruded tablets containing risedronate and EDTA

Coating suspension obtained, as shown above in part a, is deposited on tablets 35 mg risedronate, each tablet weighing 500 mg and contains:

Active ingredients:

Chelating agent:

Media:

*This amount is calculated on the anhydrous monosodium salt risedronate.

Tablets containing the above-mentioned composition, obtained in the following way:

Sodium risedronate, disodium EDTA, microcrystalline cellulose, spray-dried lactose and nitroglycol starch is passed through a crusher and placed into a mixer equipped with intensifier. The mixture is stirred for approximately 10 minutes when the intensifier. Magnesium stearate is selected and added to the mixer. The mixture is stirred for approximately 3 minutes off the intensifier. The mixture is pressed into tablets by means of a suitable press.

Example VIII

Tablets with EN is resolubilized coating, containing risedronate and EDTA

Tablets with intersolubility coating containing risedronate and EDTA, manufactured by preparing coating compositions and extruded tablets containing risedronate and EDTA, and then applying this coating composition on these tablets.

Intersolubility coating composition obtained in the form of a glaze that contains the following fillers in one tablet:

A. Intersolubility coating suspension

Ingredients:

Intersolubility the coating obtained the following way:

The pigment suspension get by adding under stirring milled iron oxide, Polysorbate 80 and talc to approximately two-thirds of purified water. The suspension is stirred for at least two hours. 30%simeticone emulsion and the remaining water added to the pigment suspension and stirred for at least 45 minutes. Combine the solutions of Eudragit L 30 D-55® and triethylcitrate and stirred for at least 45 minutes. Then the pigment suspension is added to a solution of Eudragit and stirred for 30 to 60 minutes. The obtained coating suspension is taken and is mixed throughout the coating process. Core tablets placed in the VAT to cover and heated with occasional shaking. The tablets are coated using conventional methods of lubrication forms until, until you applied the desired amount of coating solution. Further, the tablet is cooled and collected in special containers.

Intersolubility coating suspension obtained in part a, is applied by spraying on extruded tablets containing 35 mg of risedronate, with each tablet has a weight of 240 mg and obtained in accordance with example IB.

Example IX

Intersolubility soft gelatin capsules containing risedronate and the disodium salt of EDTA

Intersolubility capsules containing risedronate and EDTA, obtained by applying the coating composition on soft gelatin capsules containing risedronate and EDTA.

Intersolubility coating composition was prepared in the form of a glaze that contains the following fillers in one tablet:

A. Intersolubility coating suspension

Fillers:

Intersolubility coating obtained in the following way:

The pigment suspension get by adding under stirring milled iron oxide, Polysorbate 80 and talc to approximately two-thirds purified in the waters. The suspension is stirred for at least two hours. 30%simeticone emulsion and the remaining water added to the pigment suspension and stirred for at least 45 minutes. Combine the solutions of Eudragit L 30 D-55® and triethylcitrate and stirred for at least 45 minutes. Then the pigment suspension is added to a solution of Eudragit and stirred for 30 to 60 minutes. The obtained coating suspension is taken and stirred throughout the coating process. Soft gelatin capsules are placed in the VAT to cover and heated with occasional shaking. Soft gelatin capsules are coated using conventional methods of lubrication forms until, until you applied the desired amount of coating solution. Next, the capsule is cooled and collected in special containers.

Coating having a weight gain of 13% (total solids), is applied by spraying the above composition for soft gelatin capsules containing risedronate and EDTA obtained below in part C.

Century Soft gelatin capsules containing risedronate and EDTA

Intersolubility coating suspension obtained above in part a, sprayed on soft gelatin capsules containing 50 mg of risedronate, each has a weight of 764 mg and contains:

Soft gelatin capsules having the above composition was prepared as follows:

Real Macrogol-6 glycerides placed in the tank for slurry preparation, provided in the upper part of the agitator. Risedronate sodium, disodium EDTA, colloidal silicon dioxide are passed through a mill and under continuous stirring, to Real Macrogol-6 glycerides. The mixture is stirred for approximately 60 minutes. The mixture is then dearyou and prepare for filling capsules. Glycerin, special sorbitol and purified water with the mixture together in a heated vessel under vacuum. Heating continued until until the temperature reaches at least 80°C, then add gelatin and stirred for 75 minutes. The gel mass is examined for the complete dissolution of the particles. If necessary, continue heating and stirring until the disappearance of undissolved particles. Gel mass dearyou, and then with constant stirring add titanium dioxide, FD & C Red No. 40 and FD & C Blue No. 1. The gel mass is placed in a heated storage capacity of the gel for further processing. The filler material then encapsulate the medium is filling soft gelatin capsules.

Example X

Woman (65 kg) with a diagnosis of postmenopausal osteoporosis" appointed reception of the oral form of the drug with intersolubility coating according to Example I once a week, which includes 35 mg risedronate and 100 mg disubstituted sodium salt of EDTA. Absorbed amount of risedronate equivalent to taking prandial pill containing 35 mg immediate release.

Example XI

Man (70 kg) with a diagnosis of prostate cancer" and "bone remodeling" appointed reception intersolubility forms of oral dosing in the Example I once a week, which includes 35 mg risedronate and 150 mg of citric acid. The patient takes the form of oral dosing immediately before bedtime once a week. The patient does not have irritation or discomfort in the upper stomach.

Example XII

The group of women diagnosed with postmenopausal osteoporosis have an appointment forms of oral drug with intersolubility coating according to Example IV once a week, which includes 50 mg of risedronate. Patients received oral dosage form for Breakfast once a week. Absorbed amount of risedronate equivalent to a pill containing 35 mg immediate release, 30 minutes before eating or drinking.

All the mentioned documents in relevant part including the us here by reference; the citation of any document is not to be regarded as recognition of his known from the prior art, in accordance with the present invention.

Although described and illustrated a partial embodiments of the present invention, it is obvious to a person skilled that can be done other variations and modifications without departing from the scope and essence of the present invention. In the following claims reflect all such alterations and modifications not beyond the scope of the present invention.

1. Oral dosage form risedronate containing safe
and an effective amount of a pharmaceutical composition containing:
(a) from 1 to 250 mg risedronate;
(b) from 10 to 970 mg of a chelating agent; and
(c) means delayed release for immediate release risedronate and chelating agent in the small intestine, while the risedronate and the chelating agent is contained in a ratio of from about 1:15 to about 2:1, and the said oral dosage form is a tablet weighing not more than 1 year

2. Oral dosage form according to claim 1, characterized in that the pharmaceutical composition contains 35 mg of risedronate and 100 mg chelating agent.

3. Oral dosage form according to claim 1, characterized in that the chelating agent is at least 50% so W is soluble in water, as risedronate.

4. Oral dosage form according to claim 3, characterized in that the chelating agent is selected from the group consisting of sodium or disodium ethylenediaminetetraacetate, citric acid, malic acid, tartaric acid, lactic acid, lysine, sodium hexametaphosphate, their salts and their combinations.

5. Oral dosage form according to claim 4, characterized in that the chelating agent is selected from the group consisting of sodium and disodium ethylenediaminetetraacetate, citric acid, sodium hexametaphosphate, and combinations thereof.

6. Oral dosage form according to claim 5, characterized in that the chelating agent is a disodium EDTA.

7. Oral dosage form according to claim 1, characterized in that the means for the delayed release of risedronate and chelating agent in the small intestine selected from the group consisting of pH-triggered delivery systems, breathability delivery systems and mixtures thereof.

8. Oral dosage form according to claim 7, characterized in that the means for delayed release is a pH-triggered delivery system.

9. Oral dosage form of claim 8, wherein the pH-triggered delivery system contains enteric coating which delivers the risedronate and the chelating agent in the small intestine.

10. Peroral what I dosage form according to claim 9, wherein the enteric coating is decomposed between about pH 5.5 and about pH 6.5.

11. Oral dosage form according to claim 1, characterized in that the pharmaceutical composition contains from about 0.5% to about 75% of risedronate and from about 25% to about 99.5% of the pharmaceutically acceptable carrier.

12. Oral dosage form according to claim 11, characterized in that the chelating agent is present in amount from about 10 mg to about 500 mg

13. Oral dosage form containing a safe and effective amount of a pharmaceutical composition containing:
(a) from about 5 mg to about 70 mg risedronate;
(b) from about 25 mg to about 500 mg, and disodium salt of EDTA; and
(C) enteric coating that provides release of risedronate and EDTA in the small intestine of a mammal, with risedronate and disodium salt of EDTA contained in a ratio of about 1:3.

14. Oral dosage form according to item 13, wherein the pharmaceutical composition contains from about 35 mg to about 50 mg risedronate.

15. Oral dosage form according to 14, characterized in that the pharmaceutical composition contains an enteric coating that dissolves at about pH 5.5.

16. Method for the treatment or prevention of diseases characterized by abnormal calcium is ievo-phosphate metabolism, which is administered to a human or other mammal in need this, necessary and effective amount of the pharmaceutical composition is delivered to said human or other mammal by oral dosage form according to claim 1.

17. The method according to item 16, wherein the disease is selected from the group consisting of osteoporosis, Paget's disease, hyperparathyroidism, hypercalcemia malignant tumors and osteolytic bone metastasis.

18. The method according to 17, wherein the disease is osteoporosis.

19. The method according to p, wherein the oral dosage form is administered in accordance with the scheme of continuous reception, having a dosing interval selected from the group consisting of techniques once a day, once a week, three times per month, twice a month and once a month.

20. The method according to claim 19, wherein the oral dosage form is administered weekly.

21. The method according to claim 20, characterized in that the oral risedronate is administered to the patient with food or without food by dispensing a safe and effective amount of the pharmaceutical composition according to 14.

22. Set contains:
(a) one or more oral dosage forms containing risedronate and the chelating agent; and
(b) a means to facilitate adherence to treatment, is about a method according to item 16.

23. Set by article 22, characterized in that it further contains at least the next one or more unit doses of nutrients.