Pharmaceutical preparation for oral administration containing ibandronate
(57) Abstract:The invention relates to medicine, namely to pharmaceutical drugs ibandronate or its physiologically acceptable salts for oral administration, and is a drug for the treatment of hypercalcemia, osteoporosis, tumor osteolysis, Paget's disease. The invention is not to be resistant to gastric juice film-coated tablets ibandronate, which releases at least 30% of the contained dose activitiesthese substances upon contact with an aqueous medium at a pH of from 1 to 7.4 for 2 hours, the Proposed tool allows to reduce side effects, in particular to prevent esophagitis. 8 C.p. f-crystals, 6 PL. The invention relates to pharmaceutical preparations of ibandronate or its physiologically acceptable salts for oral administration and the way they are received.Activetestsuite substance ibandronic acid (1-hydroxy-3-(N-methyl-N-pentyl)aminopropyl-1,1-diphosphonic acid), its salts, respectively (ibandronate) belong to the class of diphosphonic acids, which are of interest primarily in the treatment of bone disease and certain violations of the balance of calcium, the diseases these active substances should be given frequently and for a long time, along with the intravenous use are mainly for oral use, which many patients agree faster.However, oral treatment method, in General, complicated known, in principle, the problems of oral tolerance diphosphonic acids. It is known that diphosphonic acids or their physiologically not calling the salvation of salt, and especially iminodiethanol acid causes irritation to the upper part of the gastrointestinal tract (Fleisch H, Bisphosphonates in GP Disease, Herbert Fleisch, Bern 1993, pages 126 - 131). This also applies to diphosphonates, which are also in relatively small doses, for example, less than 50 mg per form introduction.In WO 93/09785 indicate that, for example, the active substance is Risedronate ([1-hydroxy-2-(3-pyridinyl)-ethylidene] bis-phosphonate) can lead to erosions and ulcerations in the upper parts of the digestive tract. Various literary sources indicate then on gastrointestinal intolerance active substances of Pamidronate (Dodwell D, etc., Biochemical Effects, Antitumor Activity and Pharmacokinetics of Oral and Intravenous Pamidronate (APD) in the Treatment of Skeletal Breast Cancer, Br. J. Cancer 62, 496 (1990)) and Tiludronat (Reginster. J. Y, Efficacy and Tolerability of a New Formulation of Oral Tiludronate (Tablet) in the Treatment of Paget's Disease of Bone, J. Bone Miner. Bes. 9, 615 - my tablets because of the anatomical accidents stuck in the esophagus. This may occur odynophagia and esophageal narrowing. Often this occurs in the case of older patients, or patients who, due to his illness can take the necessary tablets preferably in the supine condition.Accordingly, to solve these problems, the specialists were delivered to the requirement to cover prescribed for oral purpose of the form of acceptance resistant to gastric juice film, so that the active substance was released only after passing through the stomach, and therefore, to avoid irritation of the stomach and esophagus. For example, in WO 95/08331 describe the forms of introduction, which can reduce potential irritation alendronate and other diphosphonates for oral use.Based on the described oral neperenosimosti of diphosphonates for a number of these active substances were looking for the most portable form of introduction. Were designed in such oral forms of administration, which are resistant to gastric juice shells. Such membranes are selectable means to protect the upper part of the gastrointestinal tract, especially the esophagus other forms introduction dissolve only at higher pH-value of from about 5.5, so in the acidic environment of the stomach, the pH-value is significantly lower than 5,5, no active substance is not released from the forms of introduction, and, therefore, the stomach is protected from irritation as active substance. As activetestsuite substance is not released in the stomach, at the same time can be prevented that due to reflux, containing the active substance of gastric contents may cause inflammation or other irritation of the digestive tract. Further, in the patent Germany 59005517 (European patent EP 0421921) describes resistant to gastric juice oral introduction, which is suitable to reduce the risk of stomach ulcers. International application WO 93/09785 describes this form of introduction to Risedronate, WO 95/08331 for Alendronate and other diphosphonates.A possible advantage resistant to gastric juice forms opposes the introduction of a number of shortcomings. So, in such dosage forms can be reduced resorption compared with pH-independent fast release forms, or resorption compared with conventional forms has much greater variability and, consequently, impairs, or questions the reliability therapy. There is therefore a need for al the resultant juice forms, but nevertheless offer sufficient protection against these aggressive acting on the mucous membrane of the stomach aminobisphosphonates.It has been unexpectedly found that in the case of activitiesthese matter ibandronate achieve improved oral tolerance even then, if the oral form of the introduction of the cover layer excipients or film so that activetestsuite substance dissolves in a short time and consequently achieve high local concentrations of active substance in the stomach. Dissolving upon contact with digestive juices film is preferably a coating that dissolves regardless of the value of pH. The application of this layer excipients can be accomplished using conventional pharmaceutically-technological methods. Although this layer does not prevent the dissolution of ibandronate in the stomach, in clinical studies unexpectedly even with high doses of ibandronate observed no typical side effects. Despite the fact that the form of the introduction of covered quickly releasing activetestsuite substance film, swallowing pills, there was no irritation in the esophagus and no vocal is fostered in bed patients.According to the invention placed at the disposal of solid oral dosage forms, which consist of containing the active substance core covered not containing the active substance layer excipients, the latter dissolves upon contact with digestive juices or independent from the value of pH or from solid oral dosage forms. This ensures that the dosage form dissolves relatively quickly, and activetestsuite substance is released in a short time and, therefore, achieve high local concentrations activitiesthese substances. The coating can be applied by means of a coating film, the coating under pressure, drazhirovanie, kapsulirovanie or microcapsular. Release activitiesthese substances from respectively coated solid forms of introduction for oral administration, such as tablets film tablets, coated tablet, capsule or microcapsule occurs more quickly in comparison with resistant to gastric juice forms the introduction. According to the invention at least 30% containing ibandronate dose, and preferably 75% and especially at least about 85% quickly released in teeth% release is preferably less than 2 hours, preferably less than 1 h, particularly preferably about 1-30 minutes Release activitiesthese substances can be identified as part of the experience in vitro using well-known standard method.Quick release activitiesthese substances, despite formed as a consequence of the high local concentration of the active substance (i.e., despite the high gradient of the active substance), not unexpectedly results in the stomach it is usually known for diphosphonic acid side effects as described above. On the contrary, it was found that despite the rapid release of the active substance suddenly completely avoid a problem of occurrence of gastrointestinal disorders. In addition, it was observed that patients who were treated with these quickly released forms of introduction, was found significantly fewer cases of nausea, vomiting, pain or direi, which are usually observed in the appointment of aminobisphosphonates.Quickly releasing activetestsuite substance in the sense of the present invention, the coating can be applied to all suitable oral form of introduction such as tablets, capsules, pills, beads, pologitelnui substances or of pure active substances. The coating can be accomplished using various conventional pharmaceutical methods. Suitable methods use, for example, a pelleting plant, to cover film tablet press press to cover under pressure machines for encapsulation or installation for microencapsulation, as for example, the device to obtain the freezing spray and injection drug spray device for producing simple or complex koatservatov it.As film-forming agents in the sense of the invention use conventional pharmaceutically or physiologically not cause fear polymers. The binders in the sense of the invention occur, for example, from the group of cellulose derivatives, dextrin, starch and derivatives of starch, polymers based on other carbohydrates and their derivatives, natural rubbers such as gum Arabic, xanthan gum alginate, polyacrylic acid, polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone, polymethacrylate and derivatives thereof (Eudragit), chitosan and its derivatives, shellac and its derivatives. Along with these binders for coatings according to the invention can also serve substances from the class of waxes and fats.In the case of polymethacrylates take into account the cationic copolymers of dimethylaminoethylmethacrylate neutral esters of methacrylic acid EudragitE, copolymers of esters of acrylic and methacrylic acid with a low content of Quaternary ammonium groups (described in "Ammonio Methacrylate Copolymer Type a or Type b USP/NF, EudragitRL or RS) and copolymers of acrylate and methacrylate with a neutral nature (in the form of aqueous dispersions described in "the polyacrylate Dispersion 30%" Ph. Eur., Eudragit
Dose ibandronate [mg] 400 mg of granulate: 20 mg and 50 mgDoes not contain ibandronate shell [mg]: capsule shell made of hard gelatin size 0, white opal.Encapsulation mass medicines perform on the machine for encapsulation type Karro-Hafliger.Pressing is carried out using the hand pump in the usual ways. 1. Drug for the treatment of hypercalcemia, osteoporosis, tumor osteolysis, Paget's disease, characterized in that carisopodol at least 30% of the contained dose activitiesthese substances upon contact with an aqueous medium at a pH of from 1 to 7.4 for 2 h2. Drug under item 1, characterized in that the tablets release at least 75% of the contained dose activitiesthese substance within 2 hours, preferably for 1 h, particularly preferably within 30 minutes3. Drug on PP.1 and 2, characterized in that the containing activetestsuite substance the inner part of the tablet is a tablet, a granulate, a ball or powder in a mixture with excipients or without excipients.4. Drug on PP.1-3, characterized in that the covering pill, the film contains at least one component selected from one of the following groups of substances: cellulose, cellulose derivatives, dextrin, starch and starch derivatives, polymers based on other carbohydrates and their derivatives, natural rubber, as gum Arabic, xanthan gum, alginate, polyacrylic acid, polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone, polymethacrylates and derivatives thereof (Eudragit), chitosan and its derivatives, shellac and its derivatives, fats, wax.5. The drug in one of the paragraphs.1-4, characterized in that the covering pill, the film contains at least one of kailalerose, methylhydroxyethylcellulose, methylhydroxypropylcellulose, sodium carboxymethyl cellulose, ethylcellulose, preferably methylhydroxypropylcellulose.6. The drug in one of the paragraphs.1-4, characterized in that the covering pill, the film contains at least one polymethacrylate, preferably chosen from cationic copolymer dimethylaminoethylmethacrylate neutral esters of methacrylic acid; a copolymer of esters of acrylic and methacrylic acid, copolymer of acrylate and methacrylate.7. The drug in one of the paragraphs.1-4, characterized in that the covering pill, the film contains at least one of the following components: anionic copolymer of methacrylic acid and methylmethacrylate, calculateoffset, cellulosimicrobium and methylhydroxypropylcellulose, polyvinylacetate.8. The drug in one of the paragraphs.1-7, characterized in that the covering pill, the film contains at least one additive selected from plasticizers, pore-formers, fillers, dyes, pigments, antispyware, anti-bonding.m cover, pressing, film coating or drazhirovanie.
FIELD: experimental medicine.
SUBSTANCE: on should introduce solution into fracture area at the following ratio of ingredients, g/l: 1-hydroxyethylidenediphosphonic acid 1.80 - 2.06, water-free calcium chloride 1.44 - 2.22, gadolinium (III) nitrate hexahydrate 0.30 - 0.40, dysprosium (III) chloride hexahydrate 0.038 - 0.076, moreover, solution's pH corresponds to 7.3 - 7.8. The present innovation enables to shorten the process of bony tissue regeneration in the site of its lesion or defect and, also, shorten the period for restoring normal physiological function of traumatized bone.
EFFECT: higher efficiency of regeneration.
22 ex, 1 tbl
FIELD: medicine, pharmacy, pharmaceutical technology.
SUBSTANCE: invention relates to pharmaceutical compositions as tablets, namely, to a tablet preparing by direct pressing and comprising 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or its pharmaceutically acceptable salts as an active component taken in the amount from 5 to 140 mg as measured for a pure acid, an excipient, a dry binding agent, a disintegrating agent and a lubricating substance, and to a method for its preparing. As an excipient the claimed composition comprises the combination of at least two recipients but with exception of lactose, and it comprises 20-80 weight% of excipient chosen from group comprising microcrystalline or powder-like cellulose and calcium hydrophosphate, and 0.001-50 weight% of one or more recipients chosen from group comprising mannitol and phosphates or hydrophosphates of alkaline or alkaline-earth metals. As a disintegrating agent the composition comprises maize starch taken in the amount 7-15%. The content of lubricating agent is 1%.
EFFECT: improved preparing method of tablet.
3 cl, 19 tbl, 7 ex
SUBSTANCE: the present innovation deals with applying biphosphonate for treating osteonecrosis and/or osteonecrosis dissecans. This medicinal preparation could be additionally applied for preventing the development of osteonecrosis and/or osteonecrosis dissecans and any complications associated with both diseases. Biphosphonate acts for the decrease or prevention of severe degree of deformation and/or destruction of a bone or a cartilage and provides the chance to form new bony tissue in a patient.
EFFECT: higher efficiency of therapy.
38 cl, 7 dwg, 1 tbl
FIELD: medicine, pharmaceutics.
SUBSTANCE: the present innovation deals with rectal suppositories that contain biphosphonic acids and their pharmacologically acceptable salts applied for preventing and treating diseases caused by affected calcium and magnesium balance in the body. The suggested new suppositories contain 0.1-10 weight% xydiphone and 0.5-10 weight emulsifiers, the rest - the foundation for one suppository of 1.125-2.5 g weight. Rectal xydiphone-containing suppositories could additionally contain medicinal and/or biologically active supplements, for example 0.1-1.0 weight% trisodium salt of phosphonoformic acid as medicinal additive, and, also, biologically active additive chosen out of the group of vitamin B6, B12 or carbon dioxide solution of common camomile, olive oil. The innovation provides the chance to avoid some complications occurred at applying this preparation in known forms and, also, in some cases leads to its increased efficiency.
EFFECT: higher efficiency of application.
4 cl, 4 ex, 1 tbl
SUBSTANCE: method involves applying N-bisphosphonates like Zoledronic acid and its derivatives for prolonged inhibiting bone tissue resorption in states distinguished by increased bone tissue renewal like it occurs in osteoporosis cases by periodically administering the drug at a dose of 2 to 10 mg. Pauses between drug introductions have become longer when compared to periodicity considered to be required in earlier times, while being greater than 6 months.
EFFECT: enhanced effectiveness of treatment.
10 cl, 1 tbl
SUBSTANCE: invention relates to a method for increasing osseous mass in osteoporosis disease. Method involves using sets containing standard doses of bisphosphonates in the amount sufficient for using in "impact" period from 7 to 180 days, and standard doses of bisphosphonate for the following using in supporting period. Bisphosphonate is chosen from group consisting of risedronate, alendronic acid, pamidronate, tiludronate, clodronate, cimadronate, ibandronate, zoledronate and their salts and esters. Standard doses of bisphosphonate in "impact" period are by 3-6 times higher as compared with standard doses of bisphosphonate in supporting period. Using sets of bisphosphonates in the given ratio of doses in "impact" and supporting periods provides increasing the osseous mass in osteoporosis of different genesis.
EFFECT: improved treatment method.
6 cl, 4 ex
SUBSTANCE: method involves applying biphosphonates for producing preparations and treating osteoblastic (osteosclerotic) metastases connected with prostate cancer.
EFFECT: enhanced effectiveness in inhibiting abnormal osteoblast proliferation.
5 cl, 3 tbl