Compositions with modified release, containing complexes medication-ion-exchanging resin

FIELD: medicine.

SUBSTANCE: invention relates to composition for peroral introduction, which possesses properties of modified release. According to invention composition includes pharmaceutically acceptable excipients and complex medication-ion-exchanging resin with coating with modified release, which contains pharmaceutically active medication, combined with pharmaceutically acceptable ion-exchanging resin. Complex has solidified barrier coating with high rupture strength, water-permeable, water-insoluble, which contains polyvinyl acetate polymer, stabiliser and efficient amount of plastifier. Said coating is in fact non-sticky, when applied onto complex in absence of anti-adhesive preparation, if composition presents tablet, complex medication-ion-exchanging resin with coating additionally contains release-retarding substance in matrix together with complex medication-ion-exchanging resin. Invention also relates to product with modified release, including package which contains composition described above.

EFFECT: invention ensures regulated prolonged active agent release without breaking coating integrity, without application of water-soluble impregnating substances and without agglomeration of complex particles during application of coating.

27 cl, 22 ex

 

Background of invention

This invention relates to pharmaceutical preparations containing complex drug-ion exchange resin, which is processed with software programmable release characteristics in the gastrointestinal tract.

One of the important aspects of drug therapy is the action of medicinal substance in the long term, and in many cases, the longer the term, the more important the beneficial effect.

The use of ion exchange resins for the formation of complex drug-ion exchange resin are well known and are described, for example, in U.S. patent No. 2990332. This patent describes the use of ion-exchange resin for the formation of a complex with the ionic drug and thereby slowing down the release of these complexes medicinal substance. This slow release of medicinal substance, considered to have a relatively short duration. Later had additional publications and patents (for example, U.S. patent No. 3138525; 3499960; 3594470; Belgian patent 729827; German patent 2246037), which describes the use of such complexes ion-exchange resin with a water-permeable diffusion barrier coating of complex drug-ion exchange resin coated, n is wearable for to modify the release of drugs from complex drug-ion exchange resin.

Known and commercially available dosage forms of various drugs with long or slow release. However, there are only a few products available that provide prolonged release of drug substance from very finely ground particles coated complexes of the drug-ion exchange resin. In a recently published patent application U.S. 2005/0181050 A1, published August 18, 2005, mentions that several commercially available liquid preparations containing particles of ion exchange resin loaded with the drug. In addition, it was found that such products require several time-consuming steps and require the use of potentially dangerous stage coating from a solution-based solvent. Regulatory authorities require that these solvents were carefully removed from pharmaceutical products before ingestion.

Raghunathan in U.S. patent No. 4221778; 4847077 and Raghunathan et al. in J. Pharm. Sci. Vol. 70, pp. 379-384, April 1981, describe the processing complexes of the drug-ion exchange resin water-soluble, hydrophilic, impregnating (collaterality) means, such as polyethylene glycol and others, so h is ordinary to make it possible to cover the complexes of the drug-ion exchange resin water-permeable diffusion barrier coating. These publications show that drug-ion exchange resin tend to swell upon contact with water, causing the destruction of the covering layer and premature drug release, thereby adversely affecting the purpose of the coating (i.e. modified release). Attempts were made to minimize this destruction of the coating layer using a sealing (Salvaterra) means to combat swelling of complex drug-ion exchange resin. Other patents which describe variations of this type of product described in published patent application U.S. 2003/0099711 A1, section 0006.

In addition, Kelleher et al. in U.S. patent No. 4996047 describe the use of the contents of medicinal substances above guideline values in the complex drug-ion exchange resin in order to avoid swelling of the complex drug-ion exchange resin and thereby reduce to a minimum the destruction of the coating. Umemoto et al. describe in U.S. patent No. 5368852 that despite the use of a sealing means, some preservatives used in liquid preparations, tend to cause the destruction of the diffusion barrier coating of complex drug-ion exchange resin. Umemoto et al. reported overcoming the destruction of the covering is blocki through the use of a preservative, which does not cause destruction.

In another patent, U.S. patent No. 6001392, filed December 14, 1999, describes some of the polymers based on acrylate (for example, the polymer system EUDRAGIT and ethyl cellulose (e.g., SURELEASE, AQUACOAT) to cover the complex drug-ion exchange resin using a coating or solvent-based or water-based to achieve prolonged release of drug substances from complex drug-ion exchange resin. Not presents significant data regarding the integrity of the covering film. In addition, there is no data or evidence of prolonged release of drug substances from complex drug-ion exchange resin coated for more than 12 hours. Recently published patent application US 2003/0099711 A1, which describes the use of ethylcellulose polymer in the cover system water-based. In this publication additionally describes the use of Intercollege coverage as an optional additional coverage to slow the release of drug substance. In the literature it was reported disadvantages of using aqueous dispersions based on ethyl cellulose as a coating for drug-ion exchange resin.

Similarly,there were disadvantages, associated with the previously used water-dispersion covering systems based on acrylate and methacrylate polymers for coating the complex drug-ion exchange resin. Among these observed shortcomings there is stickiness in the coating process and during solidification, which complicates the coating process on complexes of the drug-ion exchange resin and/or require the addition of additional components, such as substance against stickiness, to counteract this undesirable property.

Brief description of the invention

This invention provides pharmaceutical preparations containing the drug(s) substance(s), bound(s) with ion exchange resin to obtain a complex drug-ion exchange resin, the mixing of such a complex with a slow release of water-insoluble polymer and applying as a coating a mixture of a highly elastic, essentially non-sticky, non-ionic, water-insoluble, water-permeable diffusion membrane, which preferably is water-based and provides a covering membrane, which retains the integrity of their films, and additionally provides adjustable modified release of the active(s) pharmaceutical(their) substances which(a) in the gastrointestinal tract for up to about 24 hours.

In one aspect of this invention is swallow pharmaceutical compositions containing essentially non-sticky, non-ionic, water-permeable diffusion barrier coating for drug-ion exchange resin, which do not require the basics of organic solvents to dissolve the covering composition, which do not use polymeric compositions based on or ethyl cellulose or acrylate, or other standard coatings previously used to cover the complexes of the drug-ion exchange resin does not require the use of a sealing (relative exchange constants) substances, provide excellent holistic film coating and can provide prolonged programmable release of drug substances from the complexes of the drug-ion exchange resin for up to about 24 hours.

In another aspect, the invention is a pharmaceutical composition containing a water-permeable diffusion barrier coatings for complex drug-ion exchange resin, which are water-based, provide a highly elastic coating, which is applied in essentially non-sticky form that facilitates the process of applying such coatings, in the presence of acceptable levels of plasticizers and with ranaut the integrity of the covering film and minimize the destruction of the coating layer even after exposure to the floor in a strong physical effort, including the stage of the pressing operation tableting.

In another aspect of this invention is highly elastic coating, which has a great advantage in reducing dependence on drugs or drugs that must be accounted for. Elastic coating can reduce the ability of patients to get "maximum", making it so that it was difficult to break the barrier coating chewing or other mechanical means due to the increased resistance of such elastic coating for easy destruction.

In an additional aspect this invention is an oral pharmaceutical composition containing the complex of the drug-ion exchange resin, which does not need intersolubility the floor to provide sustained release for up to about 24 hours.

In another aspect, the invention is an oral pharmaceutical composition containing the complex of the drug-ion exchange resin which can be prepared in dosage form with obtaining satisfying the requirements, programmable release of one or more medicinal substances of such complexes by combining the use of slow release means in combination with grease is m water-permeable diffusion barrier coating, which is water based, and which are believed not previously used in covering films for complexes of the drug-ion exchange resin.

Additional desirable advantage, which was previously reported in relation to the use of ion exchange resins, is to reduce unwanted taste, sometimes associated with the received oral drug, where unbearable or bad taste of the active drug substance may be a hindrance to the recommended regimen of the drug.

Another aspect of the present invention is to provide a method of producing complexes of the drug-ion exchange resin, which ensures flexibility, higher efficiency of binding of a drug and favorable action against the drug load and processing upon receipt of such complexes.

It has been observed that the use of previously known film coating of polymer systems based on acrylate EUDRAGIT can lead to agglomeration of the particles during the coating process and/or solidification, in particular high-temperature solidification. In addition, such polymer systems based on acrylate, as was observed, causing agglomeration and moving color in the presence of dyes in the received oral liquid the second suspension during storage for more than about one month. In addition, it was observed that the covering system based on ethyl cellulose cause flocculation in liquid suspension, thereby covering defective system.

Thus, this invention applies to both conventional in this field and, as suggested, it is not considered the problems associated with the previous complexes of the drug-ion exchange resin. These and other advantages of this invention will be apparent from the following detailed description of the invention.

Detailed description of the invention

This invention is a composition of the drug-ion exchange resin coated for further use in the dosage form with the usual pharmaceutically acceptable components to obtain compositions for oral administration. The final dosage of the compositions can be given the form of liquid preparations such as suspensions, or solid preparations such as tablets, capsules, liquids, gels, powders, wafers, plates, etc. In one of the preferred embodiments of the invention the coating is coated on a water basis. However, in this invention it is possible to use only non-aqueous-based solvent (because the excess solvent is removed) or in combination with coating water-based.

Can the be obtained particles, containing a pharmaceutically active drug substance, with adjustable release, which is covered by a system of water-based and are safe products. Describe the use of water-based coatings, the use of slow release nutrients and the ways to get.

Discovered that through the use of medicinal substances-ion-exchange resin having a water-permeable diffusion barrier coating described in this document, receive the number of drug-ion exchange resin with a prolonged release of drug substance without the use of water-soluble impregnating (relative exchange constants) substances, as those terms are defined in U.S. patent No. 4221778.

The nature of releasing the drug from the compositions of this invention can further adjust or modify the combination of medicinal substances and resin forming a matrix of complex drug-ion exchange resin before application of the water-permeable diffusion barrier coating. Water-insoluble polymers used in the barrier coating include a single polymer or mixture of polymers, which can be selected from polymers, ethyl cellulose, polyvinyl acetate, cellulose acetate, such polymers as ftal the pulp, polymers and copolymers based on acrylic (such as, for example, known under the trade name EUDRAGIT), or any combination of such insoluble polymers or polymer systems defined in this description as "inhibiting the release of substance". The system water-permeable diffusion barrier coating with "slow-release substance" or without it can be prepared in dosage form to achieve the desirable norm duration of time of releasing the drug from the complexes of the drug-ion exchange resin. Such covering system could additionally be modified accordingly by including a separate plasticizer, or a combination of hydrophilic or lipophilic plasticizers with dispersion or suspension containing the polymer for the deposition of barrier coatings. Such plasticizers include, for example, propylene glycol, polyethylene glycol, triacetin, triethylcitrate, dibutylsebacate, vegetable oil, lipids, etc.

The polyvinyl acetate, due to the high tensile strength in the presence of plasticizer(s), provides a flexible covering film for use as a water-permeable diffusion barrier coating that preserves the integrity of the film, even when subjected to extreme physical the attack and stroke, such as during the stage of extrusion in teletrauma machine or grind in a coffee grinder, mill, etc. These coatings even with the addition of plasticizer remain essentially non-sticky and supportive for the process during the operation of the coating in the fluidized bed by Wurster or other operation of the coating and does not cause agglomeration during the coating of very fine particles of drug substance-ion-exchange resin. Agglomeration (sometimes referred to as "sintering" or "the formation of clinker) during the operation of the coating may otherwise impede the flow of air, to violate the nature of the flow and/or clog the spray nozzle, thereby increasing the possibility of defective or uneven coating of the particles of drug substance-ion-exchange resin.

Found that using the above described compositions can be obtained compositions with controlled release, which is highly elastic, and use essentially non-sticky cover system in the process of applying and hardening of the coating. In addition, the compositions of this invention do not require the use of a sealing (solvotrode) means for limiting swelling or counteract the destruction of the covering shell. Thus, the compositions of this izaberete the Oia can provide programmable and prolonged release of drug substances from the complexes of the drug-ion exchange resin, using the system described here the diffusion barrier coating is water-based.

The term "programmable release" is used to describe a pre-established profile of releasing the drug from the complex drug-ion exchange resin for up to about 24 hours.

Thanks to the extension of time releasing the drug up to 24 hours for the compositions of this invention have concomitant advantages: instead of taking two or three doses a day, you can take the medication once per day, which will provide a more uniform flow (discharge) medicinal substances, which otherwise may need to take many times a day. This is especially beneficial in the case of young children, the elderly or other persons who find it difficult to swallow large solid dosage forms such as tablets or capsules.

Drugs drugs-ion exchange resins coated according to this invention is made in view of the final dosage forms for internal use, such as liquid suspension or rapidly disintegrating tablet, which does not need to swallow. It has been observed that for use in the liquid compositions forming the film coating according to this invention for complex medication is substance-ion exchange resin in the manufacture of a liquid suspension does not give undesirable agglomerations and move the color with the suspended liquid particles in the presence of the dye, desirable for use in medical preparations that need to take children. Therefore, such compositions slow release may contribute to adherence.

As used herein, the term "modified release" refers to compositions according to this invention, which are characterized by release of drug substance from a complex drug-ion exchange resin according to this invention for a period of more than at least about 8 hours and preferably about 24 hours. As for the product with a 24-hour release, in one aspect less than 50% of the drug substance is released from the complex drug-ion exchange resin according to this invention, approximately 12 hours after injection. In another aspect less than 60% of the drug substance is released from the complex drug-ion exchange resin according to this invention, approximately 12 hours after injection. In another aspect less than 70% of the drug substance is released from the complex drug-ion exchange resin after about 12 hours. In some embodiments, the implementation is less than approximately 80% or more medicinal substances released from the complex drug-ion exchange resin cher the C for about 12 hours. The term "modified-release" may include, for example, compositions that represent drugs with prolonged-release preparations with protracted release or preparations with delayed release.

As used in connection with numerical values given in this description, the term "about" can mean variability as much as 10%. The term "contains, comprises", "comprising," and its variants include other components, parts and stages. The term "comprises", "comprising" and its variants include other components, parts and stages.

Detailed description of the components of compositions according to this invention follows.

The ion-exchange resin

In the framework of the present invention presents pharmaceutically active compounds that are safe for internal use, which form a complex with an ion exchange resin and obtained in accordance with Good Manufacturing Practices (GMP) for large amounts of pharmaceutical chemicals. Usually these connections are intended for oral administration and the introduction of a nasogastric tube.

Ion exchange resins suitable for use in these preparations, insoluble in water and preferably include pharmacologically inert organic and/or inorganic matrix containing functional the group, which are ionic or capable to ionize in terms of the respective pH. The organic matrix may be synthetic (e.g., polymers or copolymers of acrylic acid, methacrylic acid, from sulphonated styrene, from sulphonated polystyrene) or partially synthetic (e.g., modified cellulose and dextrans). Inorganic matrix preferably includes silica gel, modified by the addition of ionic groups. Covalently linked ionic groups can be groups of strong acids (e.g., sulfonic acid, phosphoric acid), weak acids (e.g., carboxylic acid), strong bases (e.g., primary amine), weak bases (e.g., Quaternary ammonium), or a combination of acid and base groups. Typically, the types of ion-exchange substances suitable for use in ion-exchange chromatography and for such applications as deionization of water, suitable for use in formulations with controlled release. Such ion-exchange substances described H. F. Walton in “Principles of Ion Exchange” (pp: 312-343) and “Techniques and Applications of Ion-Exchange Chromatography” (pp: 344-361) in Chromatography (E. Heftmann, editor), van Nostrand Reinhold Company, New York (1975). Ion-exchange resins that can be used in this invention possess exchange capacity equal to approximately 6 Millikin the tapes (mEq)/g and preferably of about 5.5 mEq/g or lower.

Typically, the particle size of the ion exchange resin is from about 5 microns to about 750 microns, preferably the particle size is in the range from about 40 microns to about 250 microns for liquid dosage forms, although particles up to about 1000 microns can be used in solid dosage forms such as tablets and capsules. The particle size essentially below the lower limit is usually hard to manipulate at all stages of the process. Usually uncoated particles of drug substance-ion exchange resin according to this invention will have a tendency to be at the lower end of this interval, while the coated particles of drug substance-ion exchange resin according to this invention will have a tendency to be at the upper end of this interval. However, both uncoated and coated particles of drug substance-ion exchange resin can be created in this interval sizes.

Commercially available ion exchange resin particles having a spherical form and a diameter of up to about 1000 microns, granular to liquid dosage forms and more prone to breaking, when there are cycles of drying and hydration. In addition, I believe that the increased distance that the roaming ion must pass during its diffusion in these large particles, and velicanstveni, which moved the medicinal substance must be in its diffusion of these large particles cause measurable but not easily adjustable magnification time of release, even when the complexes of the drug-ion exchange resin are uncovered. Drug release from uncoated complexes of the drug-ion exchange resin with a particle size in the approximate range of from 40 microns to 250 microns is relatively fast. Satisfactory regulation of the release of medicinal substance from such complexes reach due to the applied diffusion barrier coating, and it can be modified by the inclusion of inhibiting the release of substance, as described in this document.

As the resins can be used particles as the correct shape and irregular shape. Particles of regular shape are those particles that are essentially consistent with such geometric forms, such as spherical, elliptical, cylindrical and the like, examples of which are Dow XYS-40010.00 and Dow XYS-40013.00 (The Dow Chemical Company). Irregular-shaped particles are particles whose shape is not correct, such as particles of amorphous forms and particles with increased surface area due to the channels or curvatures on the surface. An example of the mi ion exchange resins with irregular-shaped particles of this type are Amberlite IRP-69 (Rhom and Haas). Two preferred resins for this invention are Amberlite IRP-69 and Dow XYS-40010.00. Both are from sulphonated polymers formed by polystyrene, structured around 8% of divinylbenzene, with ion exchange capacity of about 4.5 to 5.5 mEq/g dry resin (N+-form). Their essential difference is in the physical form. Amberlite IRP-69 consists of irregular-shaped particles with sizes in the range of from about 5 microns to about 149 microns, obtained by grinding the source areas of large Amberlite IRP-120. Product Dow XYS-40010.00 consists of spherical particles with sizes in the range from 45 microns to 150 microns.

Other suitable ion exchange resins include anion exchange resins, such as described in the literature in this field and commercially available. These resins are particularly well suited for use with drugs-acids, including, for example, nicotinic acid, mefenamico acid, indomethacin, diclofenac, Repaglinide, Ketoprofen, ibuprofen, valproate acid, lansoprazole, Ambroxol, omeprazole, acetaminophen, topiramate and carbamazepine, phenobarbital, warfarin, triameterene and prednisolone, and their prodrugs, salts, isomers, polymorphs and a solvate, as well as other drugs, specified herein and known in this field.

Example anyoneon is authorized resin is holesterinova resin, powder anion exchange resin strong base type 1 with a polystyrene matrix and functional groups of the Quaternary ammonium. Exchangeable anion is usually the chloride, which can be exchanged for almost any kinds of anions or replaced them. Commercially available cholestyramine resin represented by the resin PUROLITE™ A430MR. As described by the manufacturer, this resin has an average particle size in the range of less than 150 microns, a pH in the range of 4-6 and the exchange capacity of 1.8-2.2 mEq/g of dry matter. Another holesterinova resin pharmaceutical brand in the form of DUOLITE™ AP143/1094 [Rohm and Haas], described by the manufacturer as having a particle size in the range up to 95% less than 100 microns and 40% less than 50 microns. Commercial literature from suppliers on these and other resins included in this description by reference (PUROLITE A-430MR; DOW Cholestyramine USP, Form No. 177-01877-204, Dow Chemical Company; DUOLITE AP143/1083, Rohm and Haas Company IE-566EDS-Feb 06).

Cation-exchange resin, for example, AMBERLITE IRP-69, is particularly well suited for use with medicinal substances and other molecules with cationic functionality, including, for example, acycloguanosine, tinidazole, deferiprone, cimetidine, oxycodone, remacemide, nicotine, morphine, hydrocodone, rivastigmine, dextromethorphan, propranolol, betaxolol, 4-aminopyridine, chlorpheniramine, paroxetine, DULOXETINE HCl, Atomoxetine is as HCl, risperidone, atovaquone, esmolol, naloxone, phenylpropanolamine, gemifloxacin, Oxymorphone, hydromorphone, Albuferon and O-desmethylvenlafaxine, and their prodrugs, salts, isomers, polymorphs and a solvate, as well as other drugs, specified herein and known in the field. You can easily choose cation exchange resin for use with these alkaline drugs or other drugs, specified herein, and/or those known to specialists in this field.

Selected ion-exchange resin can be further processed by the manufacturer or the buyer for maximum safety in pharmaceutical use or for enhanced action songs. Impurities present in the resin can be removed or neutralized by the use of conventional chelating agents, antioxidants, preservatives, such as edetate disodium, sodium bisulfite, etc. including them at any stage, or before formation of the complex, or during the formation of the complex, or after it. These impurities together with a chelating agent with which they are associated, can be removed before further processing of the ion-exchange resin is a substance that slows the release and application of the diffusion barrier coating.

Drug what s the matter

Medicinal substances which are suitable for use in these drugs by their chemical nature, represented by the molecules of acids, bases, amphoteric and zwitterionic molecules. Such medicinal substances include substances with small molecules, as well as selected substances with large molecules, including chemical and biological agents, such as, for example, protein or its fragments (e.g., peptide, polypeptide, etc.), enzyme, antibody or antibody fragment.

Medicinal substances which are suitable for use in these drugs include drugs for the treatment of respiratory diseases, such as, for example, antitussive expectorants, such as Dihydrocodeine phosphate, codeine phosphate, noscapine hydrochloride, phenylpropanolamine hydrochloride, guaiacolsulfonate potassium, cloperastine fendizoate, dextromethorphan hydrobromide and cloperastine hydrochloride; bronchodilating agents, such as D,L-methylephedrine hydrochloride and D,L-methylephedrine saccharinate; and antihistamines such as Fexofenadine HCl - or D,L-chlorpheniramine maleate. Other medicines that are applicable to this invention include drugs for the treatment of diseases of the digestive tract, such as, for example, antispasmodics for peshawaria inogo tract, including scopolamine hydrobromide, meteksan hydrochloride and dicyclomine hydrochloride, drugs for treatment of disorders of the Central nervous system, such as, for example, antipsychotic drugs, including phenothiazine derivatives (chlorpromazine hydrochloride, etc.) and phenothiazinetake connection (chlorprothixene hydrochloride etc.), sedative drugs, such as benzodiazepine derivatives (hlordiazepoksida hydrochloride, diazepam etc.), alprazolam etc., antidepressants, such as imipramine connection (imipramine hydrochloride, etc.), respiration, an SSRI, like sertraline HCl, paroxetine HCl, venlafaxine HCl, etc., antipyretic analgesics, such as sodium salicylate, and hypnotics, such as sodium phenobarbital; opioid analgesic drugs, such as Alfentanil, eliprodil, Alphaprodine, Anileridine, benzylmorphine, Bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desmartin, dextromoramide, dexion, diampromide, Dihydrocodeine, dihydromorphine, dimensionsal, dimepheptanol, dimethylthiambutene, dioxaphetyl, Dipipanone, eptazocine, attepting, ethylmethylthiambutene, Ethylmorphine, etonitazene, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, Ketobemidone, levallorphan, Levorphanol, levie azilsartan, lofentanil, meperidine, machinelocation, methadone, metopon, morphine, morphine sulfate, mirfin, nalbuphine, narceine, Nicomorphine, norlevorphanol, nomeadamente, normorphine, norpipanone, opium, oxycodone, Oxymorphone, papaveretum, pentazocine, phenadoxone, penmorfa, phenazocine, Phenoperidine, piminodine, perfumed, proheptazine, promedol, properidine, propiram, proposition, Sufentanil, tramadol, tilin, their salts, and mixtures of any of the above, mixed mu-agonists/antagonists, combinations of mu-antagonists, and the like; and medicines for the treatment of respiratory diseases such as, for example, koronarorasshiryayuschee means comprising athenon hydrochloride, calcium antagonists such as verapamil hydrochloride, antihypertensives, such as hydrazine hydrochloride, propranolol hydrochloride and clonidine hydrochloride, peripheral vasodilator/vasoconstrictor agents such as tolazoline hydrochloride, respiration, other means for treatment of the respiratory tract, such as prednisolone, prednisolone sodium phosphate, albuterol, albuterol sulfate, terbutaline, etc. Can be also applicable antibiotics, including macrolides, such as oleandomitsina phosphate, tetracyclines, such as tetracycline hydrochloride, streptomycin, such as prodiamesinae sulfate, and penicillin drug with whom estva, such as amoxicillin, dicloxacillin sodium salt, pivmecillinam hydrochloride and carbenicillin-indanyl-sodium; can Also be used chemotherapeutic drugs, including selfprepared, such as sulfisomidine-sodium, TB drugs, such as kanamycin sulfate, and antibacterial drugs, such as amodiaquine hydrochloride. Excellent effect of prolonged release obtained from alkaline medicines for the treatment of respiratory diseases, such as Dihydrocodeine phosphate, D,L-methyl-ephedrine hydrochloride and phenylpropanolamine hydrochloride. Drugs-acid, which can be used in this invention include, for example, dehydrocholic acid, diflunisal, etakrinova acid, fenoprofen, furosemide, gemfibrozil, ibuprofen, naproxen, phenytoin, Provence, sulindac, theophylline, salicylic acid and acetylsalicylic acid. Alkaline medicinal substance that can be used in this invention include, for example, acetophenazine, amitriptyline, amphetamine, benztropine, biperiden, bromodiphenhydramine, brompheniramine, carbinoxamine, cloperastine, chlorcyclizine, chlorpheniramine, chlorphenoxamine, chlorpromazine, clemastin, clomiphene, clonidine, codeine, cyclizine, cyclobenzaprin cyproheptadine at, the desipramine, dexbrompheniramine, dexchlorpheniramine, dextroamphetamine, dextromethorphan, dicyclomine, diphemanil, diphenhydramine, doxepin, doxylamine, ergotamine, fluphenazine, haloperidol, hydrocodone, hydroxychloroquin, hydroxyzine, giostsiamin, imipramine, levopropoxyphene, maprotiline, meclizine, mepenzolate, meperidine, mephentermine, mesoridazine, Metformin, methadone, methylephedrine, methdilazine, methscopolamine, methysergide, metoprolol, nortriptyline, noscapine, nylidrin, oxybutinin, oxycodone, Oxymorphone, orphenadrine, papaverine, pentazocine, phendimetrazine, phentermine, phenylephrine, phenylpropanolamine, pyrilamine, tripelennamine, triprolidine, promazine, propoksifen, propanolol, pseudoephedrine, pyrilamine, quinidine, scopolamine, dextromethorphan, chlorpheniramine, and codeine. Amphoteric drugs that can be used in this invention include, for example, aminocaproic acid, aminosalicylic acid, hydromorphone, isoxaben, Levorphanol, melphalan, morphine, nalidixic acid and paraaminosalicilovaya acid.

Other drugs that are provided include methylphenidate, dexmethylphenidate, Oxymorphone, codeine, hydrocodone, chlorpheniramine, Niacin, aspirin, their salts and combinations thereof. Salts include, but are not limited to, methylphenidate HCl, dexmethylphenidate HCl, Oxymorphone HCl, the code is in the phosphate, hydrocodone bitartrate, albuterol sulfate, albuterol phosphate, chlorpheniramine maleate, dexchlorpheniramine maleate, Metformin HCl, oxybutynine HCl, albuterol sulfate, saligenina hydrochloride, cetirizine hydrochloride, ranitidine HCl, all separately or in combination.

Typical examples of other suitable classes of drugs and specific drugs that may not be mentioned in this description, can be found in U.S. patent 5900882 (columns 7-11), the disclosure of which is incorporated herein by reference. In addition, pharmaceutically acceptable prodrugs, salts, isomers, polymorphs, and a solvate of the medicines listed above, are applicable in this invention. In addition, specifically listed salt of the free base can be replaced with other pharmaceutically acceptable salts or used in the form of free base or in the form of prodrugs.

Complexes of drug-ion exchange resin

Linking the selected drug or combination of drugs with ion exchange resins can be made using methods known in this field. Specialist in this field with little experimentation or without it can easily determine the appropriate method depending on the drug substance. Usually used in the t are four main reactions for binding of alkaline medicines, these reactions are (a) resin (Na+-form) plus drug (salt form); (b) resin (Na+-form) plus drug (as free base); (C) resin (H+-form) plus drug (salt form) and (d) resin (H+-form) plus drug (as free base). All of these reactions except (d)are cationic by-products, and these by-products by competing with cationic drug for binding sites on the resin reduces the amount of medicinal substance associated with equilibrium. For alkaline drugs stoichiometric binding of the drug substance from the resin shall be administered solely by the reaction of (d).

Four similar binding assays carried out for the binding of drugs-acids from the anion-exchange resin. These reactions are (a) resin (Cl--form) plus drug (salt form); (b) resin (Cl--form) plus drug (as free acid); (C) resin (OH--form) plus drug (salt form); (d) resin (OH--form) plus drug (in the form of the free acid). All of these reactions except (d)are ionic by-products and anions generated when reactions occur competitive with anionic Leka is the only substance for binding sites on the resin with the result in the equilibrium state associated lower levels of drug substances. For drug substances-acids stoichiometric binding of the drug substance from the resin is performed only by the reaction of (d). The binding may be performed, for example, on a periodic or column process, which is known in this field.

Usually complex drug-ion exchange resin formed thereby is collected by filtration and washed with suitable solvents to remove any unbound drug substances or by-products. These complexes can be dried in the air on the tray, fluidized bed, or other suitable drying at room temperature or at elevated temperature.

To obtain complex data establishment of equilibrium in a periodic process is the preferred practice, when you boot medicinal substance in finely ground powders ion-exchange resin. Due to the very small size of the particles of ion exchange resin itself is not suitable for a regular column operations applied with ion exchange resins. The total ion-exchange capacity is the maximum attainable capacity to exchange cations or anions measured under ideal laboratory conditions. On the ability, the which will be implemented when loading medicinal substances on ion exchange resin, will be affected by such factors as the inherent ion-exchange resin selectivity in respect of the medicinal substance, the concentration of the medicinal substance in the loading solution and the concentration of competing ions also present in the loading solution. The download speed will be affected by the activity of a drug and the size of its molecules, and the degree to which the polymer phase swells during boot.

If you use a periodic process or a process with the establishment of the equilibrium state for loading medicinal substances on ion exchange resin, it is often desirable to load the ion-exchange resin as a large number of valuable substances. Full migration of medicinal substance from the loading solution is probably impossible for one stage of the establishment of the equilibrium state. Accordingly, it may be necessary for more than one stage of establishment of the equilibrium state, in order to achieve the desired load on the ion exchange resin. The use of two or more stages of loading, separation of the resin from the liquid phase between stages are the means to achieve maximum load medicinal substances on ion exchange resin, although there is a loss of medicinal substance from a liquid phase at a final stage.

Although carefully controlled laboratory is Torno experiments are necessary to establish the precise conditions of loading and elution, you can use a few General principles. High loading capacity will be conducive to the high charge density in the drug substance. Higher loading favors lower molecular weight. Higher concentration in the loading solution with a minimum of competing ions will also be conducive to a higher adsorption capacity.

The amount of medicinal substance, which can be loaded on the resin will typically be in the range of from about 1% to about 75% by weight of particles of drug substance-ion-exchange resin. A qualified technician using a small number of experiments will be able to determine the optimal loading for any complex drug-resin. In one of the embodiments can be used to download constituting from about 10% to about 40% by weight, more preferably from about 15% to about 30% by weight of particles of drug substance-ion-exchange resin. Can be advantageously used normal load, comprising about 25% by weight of particles of drug substance-ion-exchange resin.

Thus, in one aspect of this invention is the complexes of the drug-ion exchange resin containing the medicinal substance, loaded the TES on ion exchange resin, as described in this document. Drug and ion-exchange resin can be easily selected from those medicinal substances and resins, which are described in this document. This invention additionally provides a matrix of medicinal substance-ion exchange resin as defined below.

Substances that slow release

Indicators releasing the drug from the compositions of this invention can be improved or modified by processing complex drug-ion exchange resin before application of the water-permeable diffusion barrier coating described herein, inhibiting the release of substance is a water-insoluble polymer, or a combination of water-insoluble polymers.

Mainly inhibiting the release of substance does not form a separate layer on the complex drug-ion exchange resin, but forms a matrix. Examples of suitable slow release of substances include, for example, polyvinyl acetate polymer or mixture of polymers containing such a substance (e.g., KOLLICOAT SR 30D), polymers based on cellulose acetate, ethyl cellulose (e.g., AQUACOAT™ ECD-30 or SURELEASE™), polymers and copolymers based on acrylic acid (for example, presents the SEMA is STV EUDRAGIT acrylic resins), phthalate cellulose, or any combination of such water-insoluble polymers or systems of polymers, all defined here as "inhibiting the release of substance". These slow release of substances, when used, can extend or modify the drug release from the complex drug-ion exchange resin and to ensure maximum achievement of the desired release profile. In addition, the use of slow release of substances in some cases can reduce the amount of the coating thickness required to achieve prolonged release of drug substances up to 24 hours. These slow release of substances can be used or the substance in pure form or in a commercial product received from a supplier. Preferred slow release substance is polyvinyl acetate polymer, which is described in this document, or acrylic polymer of the EUDRAGIT family. Examples of suitable acrylic polymers of the EUDRAGIT family may include, for example, a copolymer containing acrylate and methyl methacrylate (e.g., EUDRAGIT NE-30D) or EUDRAGIT RS, RL30D, RL100 or NE, which are mostly independent from the pH of the polymer; and although less desirable, it is possible to choose some pH-dependent the representatives of the family of polymers EUDRAGIT, for example, L, S, and E.

The amount of polymer, which is added as inhibiting the release of substance, is usually in the range from about 3% to about 30% or more by weight from uncoated particles of drug substance-ion-exchange resin. More preferably the amount of retarding the release of the substance, if it is used, is in the range from about 5% to about 20% and most preferably in the range from about 10% to about 15% by weight from uncoated particles of drug substance-ion-exchange resin, depending on the nature of the complex drug-ion exchange resin and the desired release profile of drug(s) substance (s).

These slow release of substances can be added during the formation of the complex drug-ion exchange resin or in the beginning, during the middle period of the complex formation or after resulted in a significant number of complex. In a more preferred embodiment, inhibiting the release of substance is added after the formation of the complex drug-ion exchange resin. After mixing, the mixture of particles of complex drug-ion exchange resin with a slow release substance is dried and, accordingly, grind. is some cases, the grinding can be performed before complete drying of the complex, and then optionally drying followed by grinding, getting the desirable characteristics of the complex.

Another variant implementation is to use a sealing (solvotrode) as the slow release of substances included in the pharmaceutically acceptable complex drug-ion exchange resin before adding the coating is water-based. This impregnating (colatitude) tool is hydrophilic (water soluble) substance, its examples are those compounds which are described, for example, in U.S. patent No. 4221778 and published patent application, publication number US 2003/009971 A1, descriptions of which are incorporated herein by reference. Specific examples of suitable sealing means include propylene glycol, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone (e.g., KOLLIDON™ K30), mannitol, methylcellulose, hypromellose, hydroxypropylcellulose and sorbitol.

Covering system

Covering system used in this invention offers several advantages in the manufacture of complex drug-ion exchange resin with a coating. More specifically, the polymers used in the coating according to this invention are insoluble in water and usually non-ionic in nature. Pok is Yausa polymers fix the issues, associated with a relatively high viscosity faced during application and hardening still covering systems (including, for example, ionic polymers and polymers known polymer systems EUDRAGIT™). These problems associated with the stickiness of the previous systems, as found, lead to undesirable formation of conglomerates of coated particles and require additional processing to separate particles coated with these polymers. There have been previous attempts to solve the problem, including, for example, the addition of anti-sticking to the old covering systems. However, such tools are not provided satisfactory solutions to these problems. In addition, well-known prior to covering the system based on the use of many polymers known trademark EUDRAGIT™ (and ionic polymers) and was found to have additional disadvantages for other reasons, as they cause problems related to physical stability, including agglomeration and moving colors when using the dye liquid suspension ready-made forms.

Covering system according to this invention can be applied in the form of essentially non-sticky dispersion without aggregation problems associated with some of the previous covering systems, during the coating process and in EMA curing at high temperature. In addition, the covering system according to this invention provides barrier coverage with high tensile strength.

In one embodiment, the barrier covering layer is from about 5% to about 200% by weight of non-complex drug-ion exchange resin. In another embodiment, the barrier covering layer is from about 25% to about 50% by weight of non-complex drug-ion exchange resin, from about 30% to about 45% by weight of non-complex or from about 35% to about 40% by weight of non-complex drug-ion exchange resin.

Accordingly, this invention represents a barrier coating containing water-insoluble polymer comprising polyvinyl acetate polymer or mixture of polymers containing polyvinyl acetate polymer. In one embodiment, the barrier coating further comprises a plasticizer, which facilitates obtaining a uniform coating of complex drug-ion exchange resin and increases the tensile strength of the layer of barrier coating.

Covering the dispersions according to this invention, water-based, which is used for the diffusion barrier coatings, characterized by the fact that you have consider is Ino low stickiness or in the absence or in the presence of plasticizer(s) and provide a high percent elongation of the polymer film (elasticity) at break in the presence or in the absence of plasticizer(s). More specifically, the polymer film coating is characterized by the fact that exhibits stickiness, as measured by the method Hössel described P. Hössel, Cosmetics and Toiletries, 111 (8) 73 (1996), at 20°C/80% RH (relative humidity) and 30°C/75% RH, equal to about 2 or less in the presence or in the absence of plasticizer, and preferably about 0.5 or less.

Application of the barrier film c is relatively low viscosity in this invention using polyvinyl acetate (PVA) polymer facilitates the manufacturing process of the composition of the coating, making it faster and easier, and allows the use of low quantities of plasticizer. This provides increased elongation (elasticity) and the flexibility of the film coating, the desired property of the polymer film, without significantly increasing the adhesion of the film to an undesirable level due to the use of plasticizer.

Covering system used in this invention preferably contains a polyvinyl acetate polymer, characterized by the fact that it has film-forming ability at a relatively low temperature, i.e. about 20°C or less, without the plasticized the RA. The combination of plasticizer from polyvinyl acetate polymer system may further reduce the film forming temperature of the polyvinyl acetate system.

Thus, the selection criteria in respect of the plasticizer included in the dispersion polymer is water-based, consist in improving high ductility or elongation (elasticity) film coating at break, measured by the analyzer structure TA-HT HiR (Stable Microsystems) and the method presented by the manufacturer in the literature [i.e., Jan-Peter Mittwollen, Evaluation of Mechanical Behavior of Different Sustained Release Polymers, Business Briefing: Pharmagenerics, 2003, pp. 1-3, BASF], is equal to at least about 100%, at least about 125%, and preferably in the range of from about 150% to about 400%, at the same time essentially without increasing the stickiness of the polymer film more than about 2 (and the film evaluated by the method Hössel above, regardless of any composition to which it was applied). Higher limits of elasticity typically reach coatings according to this invention through the use of a relatively small amount of plasticizer. When using relatively small amounts of plasticizer are not achieved relatively high levels of plasticizer to have a negative effect on the properties of the coating. Discovered that these goals on tigalda by using a relatively low percentage by weight of the selected(s), plasticizer(s) in per cent by weight of solids in the composition of film-forming polymer is water-based.

Typically, the plasticizer or mixture of plasticizers, taken as a whole, is used in a percentage range of from 2 to about 50% by weight from the coating layer, more preferably from about 2.5 to about 20% by weight of the layer of the coating on the coated complex drug-ion exchange resin. Preferably the content of the plasticizer in the range of from about 5% to about 10% by weight of the layer of the coating on the coated complex provides the most desirable properties.

Suitable plasticizers are water-soluble and water-insoluble plasticizers. Examples of suitable plasticizers include, for example, dibutylsebacate, propylene glycol, polyethylene glycol, polyvinyl alcohol, triethylcitrate, acetyltributyl, acetyltributyl, tributyltin, triacetin and Soluphor® P (2-pyrrolidone), and mixtures thereof. Other plasticizers described in the published patent application US 2003/0099711 A1, 29-may-2003, page. 4 (0041), the description of which is incorporated herein by reference.

Covering the composition according to this invention is preferably applied in the form of water covering dispersions based on polyvinyl acetate (PVA) polymer. PVA is insoluble in water at room temperature. PVA can be used or the substance in pure form or in the form of a mixture. Commercial mixture contains mainly polivinilatsetatny polymer, the stabilizer and the minimum amount of surfactant, such as sodium lauryl sulfate. More specifically, the preferred solution for coating water-based is KOLLICOAT SR 30 D (BASF Corporation), which represented approximately 27% PVA polymer, about 2.7% polyvinylpyrrolidone (PVP), 0.3% sodium lauryl (solids content of 30% wt./wt.). Cm. also U.S. patent 6066334, which is included in this description by reference. PVP and surfactant helps to stabilize the aqueous dispersion. Typically, these stabilizing components are present in amounts generally less than about 10% wt./wt. and preferably less than about 5% wt./wt. In one of the embodiments, when using PVA essentially in its pure form, it can be dissolved in a suitable nonaqueous solvent to obtain the coating solution for complex drug-ion exchange resin.

In a particularly desirable embodiment, discovered that the optimal modified-release get when utverjdayut aqueous dispersion KOLLICOAT™ SR-30D. Preferably the coating utverjdayut for about from 1 hour to 24 hours. In alternative embodiments, the implementation of the floor utverjdayut for from about 4 to about 16 hours, and preferably each is about 5 hours at an elevated temperature, for example, from about 50°to about 65°C. and preferably at about 60°C.

If the barrier coating contains PVA polymer, PVA polymer is present in amount from about 70% to about 90% by weight from the final barrier layer covering at least about 75%, at least about 80%, about 85 wt.%./wt. from the end of the layer of barrier coating.

If the barrier coating also includes PVP as a stabilizing component (for example, which is present in KOLLICOAT™ SR 30D), then the final layer of barrier coating typically contains from about 5 to about 10% wt./wt. polyvinylpyrrolidone.

The rate of release of these polymeric water-based coatings of the present invention, which is designed to provide end-dosed taken oral pharmaceutical compositions, such as liquid suspensions, tablets, etc. are set so as to provide the desired release profile of the medicinal product during the period from approximately 8 hours to 24 hours, and preferably from 12 to 24 hours. This programmable rate of release can be adjusted mainly by two variables, i.e. the thickness of the diffusion barrier shell polymer film coating and an optional, but preferred the use of "slowing down the release of substances which, as described above, added to the complex drug-ion exchange resin, with the formation of finely dispersed in the matrix at the stage of application of a polymeric film coating. Inhibiting the release of substance is preferably water-insoluble polymer described previously, such as dispersion, which has the same or similar composition solids, in the form of preferred covering film-forming polymer dispersion, water-based, described in this document used at the stage of coating or polymer, acrylic-based, commercially available under the trademark EUDRAGIT™, produced by Rohm Pharma Polymers. The properties of the various compositions EUDRAGIT™, commercially available, described in the literature from Rohm Pharma, and also described in U.S. patent 6419960 (columns 10-11), the description of which is incorporated herein by reference. Other water-insoluble polymers include those listed in column 10, lines 41-53 in U.S. patent 6419960, the description of which is incorporated herein by reference.

END-DOSED COMPOSITION

Complexes of drug-ion exchange resin according to this invention can be easily obtained by using pharmaceutically acceptable excipients in accordance with methods well known to specialists in this field. In od the ohms of the embodiments these compositions contain essentially complex drug-ion exchange resin coated according to this invention, not necessarily slow down the release of the substance. In another embodiment, such compositions may also contain a selected number of uncovered complex drug-ion exchange resin, optionally with slow-release substance, as described in this document. Some tracks are a mixture of covered and uncovered complexes of the drug-ion exchange resin. These compositions may contain the coated and uncoated product in any suitable ratio.

For example, the composition of this invention containing the active ingredient dextromethorphan, preferably contains a mixture of coated complex drug-ion exchange resin according to this invention and uncovered complex drug-ion exchange resin according to this invention in order to achieve optimum release profile. Uncovered complex dextromethorphan-ion exchange resin and covered with complex dextromethorphan-ion exchange resin may be present in a ratio of from 100:1 to 1:100 by weight. In some embodiments, the implementation ratio may be about 30:70, from about 10:1 to about 1:10, or from about 2:1 to about 1:2, by weight.

In another embodiment, the compositions of this invention can contain more than one sports the component. For example, the composition may contain more than one drug substance, loaded on ion exchange resin with the formation of the complex according to this invention. In another example, the composition may contain a first set of drug-ion exchange resin according to this invention in combination with another active ingredient (drug substance), which may be in the second complex drug-ion exchange resin according to this invention. In another example, the composition may contain the complex of the drug-ion exchange resin according to this invention in combination with one or more active ingredients that are not in the complex drug-ion exchange resin.

Covered with complex drug-ion exchange resin according to this invention can be prepared in dosage form for delivery by any suitable means, including, for example, oral, topical, intraperitoneal, transdermal, sublingual, intramuscular, rectal, cheek, intranasally, via liposomes, by inhalation, vaginally, in the eye, by local delivery (for example, through a catheter or stent), subcutaneously, in adipose tissue, or intrathecal. Preferably the complex is in a dosage form for oral delivery.

Composition lekarstvennym substance-ion exchange resin, thus obtained can be stored for future use or immediately be in the dosage form with the usual pharmaceutically acceptable carriers to obtain the final accepted into compositions for delivery by oral, nasogastric tube or by other means. The compositions in accordance with this invention can, for example, take the form of liquid preparations such as suspensions, solid preparations such as capsules, tablets, caplet, sublingual preparations, powders, plates, strips, gels, including liquid gels, etc. In one of the embodiments tablet according to this invention is made in view of the disintegrating in the mouth tablets. Such dissolving in the mouth pill may disintegrate in the mouth in less than about 60 seconds.

The composition of the drug-ion exchange resin can be prepared in dosage form using conventional pharmaceutically acceptable carriers or excipients, as well as conventional methods. Without these restrictions, such conventional carriers or excipients include diluents, binders and adhesive substances (i.e. derivatives of cellulose and acrylic derivatives), lubricants (i.e. magnesium stearate or calcium stearate, or vegetable oil, propylene glycols, talc, lauryl soda is I, polyoxyethylenated), thickeners, soljubilizatory, humidifiers, dezintegriruetsja, dyes, improves the taste and odor substances (corrigentov), stabilizers, sweeteners and miscellaneous materials such as buffers and adsorbents for specific pharmaceutical composition. The stabilizers may include preservatives and antioxidants, among other components that will be absolutely obvious to a person skilled in this field.

Suitable thickeners include, for example, tragacanth gum, xanthan gum, bentonite, starch, gum Arabic and simple lower alkalemia cellulose ethers (including hydroxy - and carboxyprimaquine ethers of cellulose). Examples of cellulose include, for example, hydroxypropylcellulose, hypromellose, sodium carboxymethyl cellulose, microcrystalline cellulose (MCC) and MCC with natrocarbonatite. In one of the embodiments use tragakant and it is included in an amount of from about 0.1 to about 1.0% weight per volume (V/o) from the composition and more preferably from about 0.5% V/o of the total composition. Xanthan gum is used in an amount of from about 0.025 to about 0.5% and preferably about 0.25% in/O.

Compositions with ion exchange resin with a prolonged release may include the composition of the humidifier for the doctrine of the greater viscosity and stability of the liquid. Suitable moisturizers, applicable in the final compositions, include glycerin, polyethylene glycol, propylene glycol and mixtures thereof.

Oral liquid compositions of this invention may also contain one or more surfactants in an amount up to 5% and preferably from about 0.02 to about 3.0 per cent V/o of the total composition. Surface-active substances, applicable in the final compositions of this invention are typically organic compounds that contribute to the stabilization and dispersion of the ingredients in water systems to obtain a suitable homogeneous composition. Preferred surfactants for selection are non-ionic surfactants, such as monooleate poly(oksietilenom)(20)sorbitane and monooleate sorbitan. These substances are known in the market as the twins and spiny, and they are produced with a wide variety of structures and molecular weights.

Since you can use any of a number of surface-active substances, preferably used as a compound from the group comprising Polysorbate copolymers (sorbitan-mono-9-octadecenoate-poly(oxy-1,2-ethandiyl)). This connection also adds the function to hold any flavorings and sweeteners, homogeneous dissolved and dispersed in races is a thief.

Suitable polysorbates include Polysorbate 20, Polysorbate 40, Polysorbate 80 and mixtures thereof. Most preferably Polysorbate 80. Surface-active component will be from about 0.01 to about 2.0%/o of the total composition and preferably will be about 0.1% to about by weight of the entire composition.

You can use the second emulsifier/surfactant, applicable in combination with Polysorbate, and preferably it is poloxamers, such as poloxamer 407. Poloxamer 407 has an HLB (hydrophilic-lipophilic balance) of approximately 22 and is sold under the trade name Pluronic-127 (BASF-NJ). Two surfactants can be used essentially in equivalent quantities. For example, poloxamer 407 and Polysorbate 80, each can be used together at levels approximately from about 0.02 to about 4.0% of the total weight of the composition.

Aqueous suspensions can be obtained by dispersion compositions of the drug-ion exchange resin in a suitable aqueous medium, optionally with the addition of a suitable increase of the viscosity of the substance (s) (for example, cellulose derivatives, xanthan gum and so on). Non-aqueous suspensions can be obtained by dispersing the above compositions in a suitable non-aqueous medium, optionally with doba is of the suitable increase of the viscosity of the substance (s) (for example, hydrogenated edible fats, aluminum compounds and so on). Suitable non-aqueous carriers include, for example, almond oil, peanut oil, soybean oil or fractionated vegetable oils such as fractionated coconut oil.

Applicable preservatives include, but are not limited to, sodium benzoate, benzoic acid, potassium sorbate, edetate salt (also known as salts of ethylenediaminetetraacetic acid, or EDTA, such as disodium salt of EDTA), parabens (such as methyl, ethyl, propyl or butylperoxybenzoate etc) and sorbic acid. Applicable preservatives include chelating agents, some of which are listed above, and other chelating agents, for example, nitryltriacetic acid (NTA); ethylenediaminetetraacetic acid (EDTA), hydroxyethylenediaminetriacetate acid (HEDTA), diethylenetriaminepentaacetic acid (DPTA), 1,2-diaminodiphenylsulfone acid (1,2-the pdta); 1,3-diaminodiphenylsulfone acid (1,3-the pdta); 2,2-ethylendiamine[ethylimino(acetic acid)] (EGTA); 1,10-bis(2-pyridylmethyl)-1,4,7,10-teresadeca (BPTETA); Ethylenediamine (EDAMINE); TRANS-1,2-diaminocyclohexane-N,N,N',N'-tetraoxane acid (CDTA); Ethylenediamine-N,N'-diacetate (EDDA); finishingtouches (PMS); 2,6-dichloroindophenol (DCPIP); bis(carboxymethyl)diaza-18-crown-6 (CROWN); porphin; chlorophyll; dimercaprol (2,3-dimercapto-1-about anal); citric acid; tartaric acid; fumaric acid; malic acid and their salts. The preservatives listed above are typical examples, but each preservative must be assessed in relation to each composition, to ensure compatibility and effectiveness of the preservative. Methods of evaluating the effectiveness of preservatives in pharmaceutical compositions is well-known specialists in this field. Preferred preservatives are Barabanova preservatives, which include methyl-, ethyl-, propyl -, and butylparaben. Methyl - and propylparaben are the most preferred. Preferably as methylparaben and propylparaben are present in the composition in respect of methylparaben to propyl paraben from about 2.5:1 to about 16:1, preferably 9:1.

In the example where use additional sweeteners, this invention involves the incorporation of those sweeteners, which are well known in this area, including both natural and artificial sweeteners. Thus, additional sweeteners may be chosen from the following non-limiting list: water-soluble sweeteners such as monosaccharides, disaccharides and polysaccharides such as xylose, ribose, glucose, mannose, galactose, fructose, corn syrup high fructose, dextrose, sucrose, sugar, maltose, partially hydrolyzed starch or solids corn syrup, and sugar alcohols such as sorbitol, xylitol, mannitol and mixtures thereof.

Typically, the amount of sweetener will vary depending on the desired amount of sweetener is selected for a particular liquid composition. This amount will typically be from about 0.001 to about 90% by weight on the volume of the final liquid composition, if used easily extractable sweetener. Water-soluble sweeteners described above, preferably used in amounts from about 5 to about 70% by weight by volume and most preferably from about 10 to about 50% by weight on the volume of the final liquid composition. In contrast, the artificial sweeteners [e.g., Sucralose, Acesulfame K and sweeteners-based dipeptides] is used in amounts from about 0.005-about 5.0% and most preferably from about 0.01 to about 2.5% by weight on the volume of the final liquid composition. These quantities are usually required to achieve the desired level of sweetness, regardless of the level of flavor achieved by using aromatic oils.

Suitable corrigentov (substances that improve the taste and smell) include both natural and artificial corrigentov, and discusses the various types of mint, on the example peppermint, menthol, artificial vanilla, cinnamon, various fruit flavors, both individual and mixed, essential oils (i.e. thymol, eucalyptol, menthol and methyl salicylate), and the like. The amount used corrigent is usually a matter of preference on such factors as the type of corrigenda, specific corrigent and desired intensity. Thus, the number may vary in obtaining the desired result in the final product. Such changes are within the competence of specialists in the field without the need for unnecessary experimentation. The corrigentov usually used in amounts that will vary depending on the specific corrigenda and may, for example, range from about 0.01 to about 3% by weight on the amount of the weight of the final composition.

Colorants used in this invention include pigments such as titanium dioxide that can be included in amounts up to 1% by weight by volume, and preferably up to about 0.6% by weight to volume. Also colorants can include dyes suitable for use in food, drugs and cosmetics and is known as the dye D&C and F.D.& C, and the like. Substance acceptable to the above range of applications, are preferably vodorastvorimami. Illustrative examples include indigency the dye known as F.D.&C. Blue No. 2, which is the disodium salt of 5,5'-indigotindisulfonate acid. Similarly, the dye known as F.D.&C. Green No. 1, contains triphenylmethane dye and is a monosodium salt of 4-[4-N-ethyl-p-sulfanilamide)diphenylmethylene]-[1-(N-ethyl-N-p-califonians)-2,5-cyclohexadienone]. A complete list of all F.D.&C. and D. & C. and their corresponding chemical structures may be found in Kirk-Othmer Encyclopedia of Chemical Technology, in Volume 5 at Pages 857-884, which text is accordingly incorporated in this description by reference.

Suitable oils and fats that can be used include partially hydrogenated vegetable or animal fats, such as coconut oil, stone fruit, palm oil, fat cattle, pork fat and the like. These ingredients are usually used in amounts relative to take the product to about 7.0 percent by weight, and preferably up to about 3.5% by weight from the final product.

Moisturizing agents can be used in the compositions of this invention to facilitate the dispersion of hydrophobic ingredients. The concentration of moisturizing agents in the composition should be chosen so as to achieve optimum dispersion of the ingredient in the composition with the lowest (say what th) concentration of moisturizing substances. It should be clear that excessive concentration of moisturizing agents may be the cause flocculation of the composition in suspension. Specialists in this field are well aware of the relevant empirical methods for determining suitable moisturizing agents and concentrations to achieve optimal dispersion and flocculation. Suitable moisturizing agents listed in the US Pharmacopoeia 29.

In another aspect, the invention is a product containing a complex drug-ion exchange resin according to this invention.

In some embodiments, implementation of the covered complexes of drug-ion exchange resin according to this invention are packaged in a form ready for use, for example in a blister pack, bottle, syringes, packaging foil, bags or other suitable containers. In other embodiments, implementation of the compositions of this invention are provided in a concentrated form in packs not necessarily together with the solvent needed to obtain the final solution for injection. In some embodiments, the implementation of the product contains a compound used in this invention in solid form and, optionally, in a separate container with a suitable basis for suspension or other media to set the KSA drug-ion exchange resin, used in this invention.

In some embodiments, the implementation of the above packaging/sets include other components, for example a device for measuring the dose, instructions for thinning, mixing and/or application of the product, other containers, nasogastric tubes, etc. Other such components packaging/set will be obvious to a person skilled in this field.

Were described devices, and many of them are commercially available that provide measured the administration of a medicinal product, including devices for the controlled infusion (for example, for an adjustable patient analgesia), inhalers with measuring dose and implantable pumps. For example, have been described various measuring fluid device for compressible bottles [U.S. patent No. 6997358, U.S. patent No. 3146919 registered in 1960, U.S. patent No. 3567079 registered in 1968, and GB 2201395 registered in 1986]. Device for dispensing multiple compositions are presented in U.S. patent No. 6997219.

Methods and apparatus for drug delivery through the nasogastric tube is well known to specialists in this field. See, for example, E. Bryson, “Drug Administration via Nasogastric Tube”, Nurs Times, 2001, Apr 19-25, 97(16):51. The preparation according to this invention can be easily delivered using the Aceh devices. Suitable nasogastric tube commercially available and/or were described. See, for example, U.S. patent No. 5334166; U.S. patent No. 5332073; U.S. patent No. 4619673; U.S. patent No. 4363323.

The following examples are presented to more particularly illustrate the composition with modified release according to this invention, and are not intended to be limiting. They are presented for illustrative purposes only, and implies that there may be changes to exist and their variants, without departing from the essence and scope of this invention.

Examples 1-17 are illustrations of obtaining typical complexes of the drug-ion exchange resin with a coating according to this invention. Some samples of the compositions described in these examples were further processed into final dosage forms, while others kept to obtain compositions in the future and testing for stability under acceleration decomposition and room temperature conditions.

Example 18 illustrates the composition of the disintegrating in the mouth tablets using the compositions of the present invention.

Examples 19 and 20 are compositions containing EUDRAGIT and AQUACOAT as coating compositions, which have resulted in the movement of the colors and led to flocculation/agglomeration.

Examples 21 e illustrate compositions according to this invention, to reduce the possibility of abuse of drugs when using complexes of the drug-ion exchange resin with a coating according to the present invention.

Obtaining complex drug-resin coated

Example 1

Obtaining complex morphine-resin coated

IngredientNumber
Complex morphine-resin
Morphine sulfate450 g
Purified water5 l
Resin AMBERLITE IRP-69807 g
Polymer system KOLLICOAT SR-30D501 g
Complex morphine-resin coated
Polymer system KOLLICOAT SR-30D952 g
Triacetin14 g
Purified water533 g
Complex morphine-resin600 g

Complex morphine-resin was obtained, first dissolving 450 g of morphine sulfate in 5 l of purified water, and then slowly adding 807 g resin AMBERLITE™ IR-69 with continuous stirring. This dispersion was stirred for 4 hours and at the end was allowed to settle before decanting the supernatant. The process of obtaining a dense suspension/desantirovaniya was repeated twice, with a sufficient quantity of purified water. Wet with resin and then dried in a convection oven VWR™supported at 50°C, up until the moisture content does not become equal to approximately 25%. Then wet the complex resin was slowly added 501 g KOLLICOAT™ SR-30D in a Hobart type mixer (Kitchen Aid) until a homogeneous mass. The wet mass was again dried at 50°C in a convection oven VWR™ to a moisture content of about 20%. The moist granules are then grinded through a sieve of 40 mesh using mill brand CO-MIL™ and continued drying at 50°C until the moisture content does not become equal to 4-6%. Dry granules are then grinded through a sieve of 40 mesh, using the mill brand CO-MIL™ [QUADRO].

Covering solution was obtained by dispersing 952 g of KOLLICOAT™ SR-30D, 14 g of triacetin in 533 g of purified water and mixing for 1 hour. The process nanese the Oia coating was performed in the processor with the fluidized bed VECTOR™ FLM-1, causing 1350 g of coating solution to 600 g of the complex morphine-resin using the method WURSTER, which resulted in a gain of 45%. Conditions coating regulated, keeping the temperature at the inlet 77-82°C, product temperature 26-33°C, airflow 17-18 ft3/min, pressure in the nozzle 2.5 kg/cm2the pressure in the accelerator air flow of 1.0 kg/cm2and the spray rate of 5-8 g/min so as to achieve a uniform coating. Complex morphine-resin coated and then subjected to temperatures of 60°C for 5 hours for hardening.

Example 2

Obtaining complex oxycodone-resin coated

IngredientNumber
Complex oxycodone-resin
Oxycodone HCl450 g
Purified water8 l
Resin AMBERLITE IRP-691427
Polymer system KOLLICOAT SR-30D500 g
Complex oxycodo the-resin coated
Polymer system KOLLICOAT SR-30D825 g
Triacetin12 g
Purified water462 g
Complex oxycodone-resin600 g

Complex oxycodone-resin was obtained, first dissolving 450 g of oxycodone Hcl in 8 liters of purified water, and then slowly adding 1427 resin AMBERLITE™ IR-69 with continuous stirring. This dispersion was stirred for 4 hours and at the end was allowed to settle before decanting the supernatant. The process of obtaining a dense suspension/desantirovaniya was repeated twice, with a sufficient quantity of purified water. Wet with resin and then dried in a convection oven VWR™supported at 50°C, up until the moisture content does not become equal to approximately 15%. Then wet the complex resin was slowly added to 500 g of KOLLICOAT™ SR-30D in a Hobart type mixer (Kitchen Aid) until a homogeneous mass. The wet mass was again dried at 50°C in a convection oven VWR™ to a moisture content of about 12%. The moist granules are then grinded through a sieve of 40 mesh using mill brand CO-MIL™ and continued drying n and 50°C as long while the moisture content does not become equal to 4-6%. Dry granules are then grinded through a sieve of 40 mesh, using the mill brand CO-MIL™.

Covering solution was obtained by dispersing 825 g of KOLLICOAT™ SR-30D, 12 g of triacetin 462 g of purified water and mixing for 1 hour. The coating process was performed in the processor with the fluidized bed VECTOR™ FLM-1, causing 1200 g of coating solution to 600 g of the complex oxycodone-resin using the method Wurster, which resulted in a gain of 40%. Conditions of the coating was adjusted, while maintaining the inlet temperature of 70-80°C, product temperature 25-31°C, airflow 16-17 ft3/min, pressure in the nozzle of 2.5-3.0 kg/cm2the pressure in the accelerator air flow of 1.0 kg/cm2and the spray rate of 3-5 g/min so as to achieve a uniform coating. Complex oxycodone-resin coated then kept at 60°C for 5 hours for hardening.

Example 3

Obtaining complex albuterol-resin coated

Purified water
IngredientNumber
Complex albuterol-resin
Sulfate albuterol286 g
8 l
Resin AMBERLITE IRP-691837
Polymer system KOLLICOAT SR-30D640 g
Complex albuterol-resin coated
Polymer system KOLLICOAT SR-30D952 g
Triacetin14 g
Purified water533 g
Complex albuterol-resin600 g

Complex albuterol-resin was obtained, first dissolving 286 g of sulfate albuterol in 8 liters of purified water, and then slowly adding 1837 resin AMBERLITE™ IR-69 with continuous stirring. This dispersion was stirred for 4 hours and at the end was allowed to settle before decanting the supernatant. The process of obtaining a dense suspension/desantirovaniya was repeated twice, with a sufficient quantity of purified water. Wet with resin and then dried in a convection oven VWR ™supported at 50°C, up until the moisture content does not become equal to the ome 30%. Then wet the complex resin was slowly added 640 g KOLLICOAT™ SR-30D in a Hobart type mixer (Kitchen Aid) until a homogeneous mass. The wet mass was again dried at 50°C in a convection oven VWR™ to a moisture content of about 25%. The moist granules are then grinded through a sieve of 40 mesh using mill brand CO-MIL™ and continued drying at 50°C until the moisture content does not become equal to 4-6%. Dry granules are then grinded through a sieve of 40 mesh, using the mill brand CO-MIL™.

Covering solution was obtained by dispersing 952 g of KOLLICOAT™ SR-30D, 14 g of triacetin in 533 g of purified water and mixing for 1 hour. The coating process was performed in the processor with the fluidized bed VECTOR™ FLM-1, causing 1350 g of coating solution to 600 g of the complex albuterol-resin using the method Wurster, which resulted in a gain of 45%. Conditions of the coating was adjusted, while maintaining the inlet temperature 60°C, product temperature 31-34°C, airflow 18-19 ft3/min, pressure in the nozzle 2.5 kg/cm2the pressure in the accelerator air flow of 1.0 kg/cm2and the spray rate of 3-6 g/min so as to achieve a uniform coating. Complex albuterol-resin coated then kept at 60°C for 5 hours for hardening.

Example 4

Obtaining complex methylphenidate-resin coated

IngredientNumber
Complex methylphenidate-resin
Methylphenidate HCl500 g
Purified water8 l
Resin AMBERLITE IRP-691306 g
Polymer system EUDRAGIT NE-30D467 g
Complex methylphenidate-resin coated
Polymer system KOLLICOAT SR-30D635 g
Triacetin9.5 g
Purified water356 g
Complex methylphenidate-resin600 g

Complex methylphenidate-resin was obtained, first dissolving 500 g of methylphenidate HCl in 8 liters of purified water, and then slowly adding 1306 g resin AMBERLITE™ IR-69 when continuous is m stirring. This dispersion was stirred for 4 hours and at the end was allowed to settle before decanting the supernatant. The process of obtaining a dense suspension/desantirovaniya was repeated twice, with a sufficient quantity of purified water. Wet with resin and then dried in a convection oven VWR™supported at 50°C, up until the moisture content does not become equal to about 20-30%. Then wet the complex resin was slowly added 467 g EUDRAGIT™ NE-30D in a Hobart type mixer (Kitchen Aid) until a homogeneous mass. The wet mass was then passed through a 10 mesh sieve and again dried at 50°C in a convection oven VWR™ to a moisture content of about 4-6%. Dry granules are then grinded through a sieve of 40 mesh, using the mill brand CO-MIL™.

Covering solution was obtained by dispersing 635 g of KOLLICOAT™ SR-30D, 9.5 g of triacetin in 356 g of purified water and mixing for 1 hour. The coating process was performed in the processor with the fluidized bed VECTOR™ FLM-1, causing 900 g of coating solution to 600 g of the complex methylphenidate-resin using the method Wurster, which resulted in a gain of 30%. Conditions coating regulated, keeping the temperature at the inlet 55-62°C, product temperature of 29-31°C, airflow 20-24 ft3/min, pressure in the nozzle 2.5 kg/cm2pressure is scarytale air flow of 1.0 kg/cm 2and the spray rate of 4-6 g/min so as to achieve a uniform coating. Complex methylphenidate-resin coated and then subjected to temperatures of 60°C for 5 hours for hardening.

Example 5

Obtaining complex dextromethorphan-resin coated

IngredientNumber
Complex dextromethorphan-resin
Dextromethorphan HBr954 g
Purified water8 l
Resin AMBERLITE IRP-691758
The polymer KOLLIDON K-30116 g
Purified water1150 g
Complex dextromethorphan-resin coated
Polymer system KOLLICOAT SR-30D762 g
Triacetin11 g
The eyes of the military water 427 g
Complex dextromethorphan-resin600 g

Complex dextromethorphan-resin was obtained, first dissolving 954 g of dextromethorphan HBr in 8 liters of purified water heated to 75-80°C and then slowly adding 1758 resin AMBERLITE™ IR-69 under continuous stirring with cooling to room temperature. This dispersion was stirred for 4 hours and at the end was allowed to settle before decanting the supernatant. The process of obtaining a dense suspension/desantirovaniya was repeated twice, with a sufficient quantity of purified water. Wet with resin and then dried in a convection oven VWR ™supported at 50°C, up until the moisture content does not become equal to about 20-25%. In a separate container polymer KOLLIDON K-30 (116 g) was dissolved in 1150 g of purified water and slowly put on wet with resin in a Hobart type mixer (Kitchen Aid) until a homogeneous mass. The wet mass was then dried at 50°C in a convection oven VWR™ to a moisture content of about 4-6%. Dry granules are then grinded through a sieve of 40 mesh, using the mill brand CO-MIL™.

Covering solution was obtained by dispersing 762 g of polymer KOLLICOAT™ SR-30D, 11 g of triacetin in 427 g of purified water and mixing in techenie hours. The coating process was performed in the processor with the fluidized bed VECTOR™ FLM-1, causing 1050 g of coating solution to 600 g of the complex dextromethorphan-resin using the method Wurster, which resulted in a gain of 35%. Conditions coating regulated, keeping the temperature at the inlet 64-71°C, product temperature 27-35°C air flow (15-20 ft3/min, pressure in the nozzle 2.5 kg/cm2the pressure in the accelerator air flow of 1.0 kg/cm2and the spray rate of 4-6 g/min so as to achieve a uniform coating. Complex dextromethorphan-resin coated then kept at 60°C for 5 hours for hardening.

Example 6

Obtaining complex codeine-resin coated

IngredientNumber
Complex codeine-resin
Codeine phosphate500 g
Purified water5 kg
Resin AMBERLITE IRP-691856
Polymer system EUDRAGIT NE-30D668 g
Purified water1150 g
Complex codeine-resin coated
The polymer KOLLICOAT SR-30D635 g
Triacetin9.5 g
Purified water356 g
Complex codeine-resin600 g

Complex codeine-resin was obtained, first dissolving 500 g of codeine phosphate in 5 kg of purified water, and then slowly adding 1856 resin AMBERLITE™ IR-69 with continuous stirring. This dispersion was stirred for 4 hours and at the end was allowed to settle before decanting the supernatant. The process of obtaining a dense suspension/desantirovaniya was repeated twice, with a sufficient quantity of purified water. Wet with resin and then dried in a convection oven VWR™supported at 50°C, up until the moisture content does not become equal to about 20-30%. Polymer system EUDRAGIT™ NE-30D (668 g) were mixed with 1150 g of purified water and then slowly add to wet the complex with the resin in a Hobart type mixer (Kitchen Aid) until a homogeneous mass. In the most important mass was then dried at 50°C in a convection oven VWR™ to a moisture content of about 3-7%. Dry granules are then grinded through a sieve of 40 mesh, using the mill brand CO-MIL™.

Covering solution was obtained by dispersing 635 g of polymer KOLLICOAT™ SR-30D, 9.5 g of triacetin in 356 g of purified water and mixing for 1 hour. The coating process was performed in the processor with the fluidized bed VECTOR™ FLM-1, causing 900 g of coating solution to 600 g of the complex codeine-resin using the method Wurster, which resulted in a gain of 30%. Conditions coating regulated, keeping the temperature at the inlet 54 to 68°C, product temperature 30-35°C, airflow 19-23 ft3/min, pressure in the nozzle 2.5 kg/cm2the pressure in the accelerator air flow of 1.0 kg/cm2and the spray rate of 4-6 g/min so as to achieve a uniform coating. Complex codeine-resin coated then kept at 60°C for 5 hours for hardening.

Example 7

Obtaining complex tramadol-resin coated

IngredientNumber
The complex tramadol-resin
Tramadol HCl500 g
Purified water 8 l
Resin AMBERLITE IRP-691345
The polymer KOLLICOAT SR-30D467 g
The complex tramadol-resin coated
The polymer KOLLICOAT SR-30D762 g
Triacetin11 g
Purified water427 g
The complex tramadol-resin600 g

The complex tramadol-resin was obtained, first dissolving 500 g of tramadol HCl in 8 liters of purified water, and then slowly adding 1345 resin AMBERLITE™ IR-69 with continuous stirring. This dispersion was stirred for 4 hours and at the end was allowed to settle before decanting the supernatant. The process of obtaining a dense suspension/desantirovaniya was repeated twice, with a sufficient quantity of purified water. Wet with resin and then dried in a convection oven VWR™supported at 50°C, up until the moisture content does not become equal to approximately 25%. Then wet the complex resin was slowly added to the polymer KOLLICOAT the SR-30D (467 g) in a Hobart type mixer (Kitchen Aid) until a homogeneous mass. The wet mass was again dried at 50°C in a convection oven VWR™ to a moisture content of about 20%. The moist granules are then grinded through a sieve of 40 mesh using mill brand CO-MIL™ and continued drying at 50°C until the moisture content does not become equal to 4-6%. Dry granules are then grinded through a sieve of 40 mesh, using the mill brand CO-MIL™.

Covering solution was obtained by dispersing 762 g of polymer KOLLICOAT™ SR-30D, 11 g of triacetin in 427 g of purified water and mixing for 1 hour. The coating process was performed in the processor with the fluidized bed VECTOR™ FLM-1, causing 1050 g of coating solution to 600 g of the complex tramadol-resin using the method Wurster, which resulted in a gain of 35%. Conditions coating regulated, keeping the temperature at the inlet 60-66°C, product temperature 25-33°C, airflow 16-19 ft3/min, pressure in the nozzle 2.5 kg/cm2the pressure in the accelerator air flow of 1.0 kg/cm2and the spray rate of 4-5 g/min so as to achieve a uniform coating. The complex tramadol-resin coated then kept at 60°C for 5 hours for hardening.

Example 8

Obtaining complex pseudoephedrine-resin coated

IngredientNumber
Complex pseudoephedrine-resin
Pseudoephedrine HCl857 g
Purified water5 l
Resin AMBERLITE IRP-691589
Polymer system KOLLICOAT SR-30D668 g
IngredientNumber
Complex pseudoephedrine-resin coated
Polymer system KOLLICOAT SR-30D825 g
Triacetin12 g
Purified water462 g
Complex pseudoephedrine-resin600 g

Complex pseudoephedrine-resin was obtained, first dissolving 857 g of pseudoephedrine HCl in 5 l of purified water, and then slowly adding 1589 resin AMBERLITE™ IR-69 with continuous stirring. This dispersion was stirred for 4 hours and at the end gave utstats is before decanting the supernatant. The thick suspension was filtered and washed 3 times with a sufficient amount of purified water. Wet with resin and then dried in a convection oven VWR™supported at 50°C, up until the moisture content does not become equal to approximately 25%. Then wet the complex resin was slowly added to the polymer KOLLICOAT™ SR-30D (668 g) in a Hobart type mixer (Kitchen Aid) until a homogeneous mass. The wet mass was again dried at 50°C in a convection oven VWR™ to a moisture content of about 30%. The moist granules are then grinded through a sieve of 40 mesh using mill brand CO-MIL™ and continued drying at 50°C until the moisture content does not become equal to 4-6%. Dry granules are then grinded through a sieve of 40 mesh, using the mill brand CO-MIL™.

Covering solution was obtained by dispersing 825 g of polymer KOLLICOAT™ SR-30D, 12 g of triacetin 462 g of purified water and mixing for 1 hour. The coating process was performed in the processor with the fluidized bed VECTOR™ FLM-1, causing 1200 g of coating solution to 600 g of the complex pseudoephedrine-resin using the method Wurster, which resulted in a gain of 40%. Conditions coating regulated, keeping the temperature at the inlet 68-72°C. product temperature 26-32°C, airflow 16-19 ft3/min, pressure in the nozzle of 2.5 to the/cm 2the pressure in the accelerator air flow of 1.0 kg/cm2and the spray rate of 4-6 g/min so as to achieve a uniform coating. Complex pseudoephedrine-resin coated then kept at 60°C for 5 hours for hardening.

Example 9

Obtaining complex phenylephrine-resin coated

IngredientNumber
Complex phenylephrine-resin
Phenylephrine HCl400 g
Purified water8 l
Resin AMBERLITE IRP-691165
Polymer system KOLLICOAT SR-30D467 g
Complex phenylephrine-resin coated
Polymer system KOLLICOAT SR-30D825 g
Triacetin12 g
Purified water46 g
Complex phenylephrine-resin600 g

Complex phenylephrine-resin was obtained, first dissolving 400 g of phenylephrine HCl in 8 liters of purified water, and then slowly adding 1165 resin AMBERLITE™ IR-69 with continuous stirring. This dispersion was stirred for 4 hours and at the end was allowed to settle before decanting the supernatant. The process of obtaining a dense suspension/desantirovaniya was repeated twice, with a sufficient quantity of purified water. Wet with resin and then dried in a convection oven VWR™supported at 50°C, up until the moisture content does not become equal to approximately 25%. Then wet the complex resin was slowly added to the polymer system KOLLICOAT™ SR-30D (467 g) in a Hobart type mixer (Kitchen Aid) until a homogeneous mass. The wet mass was again dried at 50°C in a convection oven VWR™ to a moisture content of about 30%. The moist granules are then grinded through a sieve of 40 mesh using mill brand CO-MIL™ and continued drying at 50°C until the moisture content does not become equal to 4-6%. Dry granules are then grinded through a sieve of 40 mesh, using the mill brand CO-MIL™.

Covering solution was obtained by dispersing 825 g of polymer systems KOLLICOAT™ SR-30D, 12 g three the Cetina 462 g of purified water and mixing for 1 hour. The coating process was performed in the processor with the fluidized bed VECTOR™ FLM-1, causing 1200 g of coating solution to 600 g of the complex phenylephrine-resin using the method Wurster, which resulted in a gain of 40%. Conditions coating regulated, keeping the temperature at the inlet 60-72°C, product temperature 25-34°C, airflow 16-19 ft3/min, pressure in the nozzle 2.5 kg/cm2the pressure in the accelerator air flow of 1.0 kg/cm2and the spray rate of 4-6 g/min so as to achieve a uniform coating. Complex phenylephrine-resin coated then kept at 60°C for 5 hours for hardening.

Example 10

Obtaining complex hydrocodone-resin coated

IngredientNumber
Complex hydrocodone-resin
Hydrocodone bitartrate450 g
Purified water8 kg
Resin AMBERLITE IRP-691407
Polymer system KOLLICOAT SR-30D500 g
Complex hydrocodone-resin coated
Polymer system KOLLICOAT SR-30D952 g
Triacetin14 g
Purified water533 g
Complex hydrocodone-resin600 g

Complex hydrocodone-resin was obtained, first dissolving 450 g of hydrocodone bitartrate in 8 kg of purified water, and then slowly adding 1407 resin AMBERLITE™ IR-69 with continuous stirring. This dispersion was stirred for 4 hours and at the end was allowed to settle before decanting the supernatant. The process of obtaining a dense suspension/desantirovaniya was repeated twice, with a sufficient quantity of purified water. Wet with resin and then dried in a convection oven VWR™supported at 50°C, up until the moisture content does not become equal to about 20-25%. Then wet the complex resin was slowly added to the polymer KOLLICOAT™ SR-30D (500 g) in a Hobart type mixer (Kitchen Aid) until a homogeneous mass. The wet mass was again dried at 50°C in a convection oven VWR™ until the moisture content is approximately 15-20%. The moist granules are then grinded through a sieve of 40 mesh using mill brand CO-MIL™ and continued drying at 50°C until the moisture content does not become equal to 3-7%. Dry granules are then grinded through a sieve of 40 mesh, using the mill brand CO-MIL™.

Covering solution was obtained by dispersing 952 g of polymer KOLLICOAT™ SR-30D, 14 g of triacetin in 533 g of purified water and mixing for 1 hour. The coating process was performed in the processor with the fluidized bed VECTOR™ FLM-1, causing 1050 g of coating solution to 600 g of the complex hydrocodone-resin using the method Wurster, which resulted in a gain of 35%. Conditions coating regulated, keeping the temperature at the inlet 55-66°C, product temperature 26-32°C, airflow 16-20 ft3/min, pressure in the nozzle 2.5 kg/cm2the pressure in the accelerator air flow of 1.0 kg/cm2and the spray rate of 4-5 g/min so as to achieve a uniform coating. Complex hydrocodone-resin coated then kept at 60°C for 5 hours for hardening.

Example 11

Obtaining complex venlafaxine-resin coated

IngredientNumber
Complex venlafaxine-resin
Venlafaxine HCl500 g
Purified water5 l
Resin AMBERLITE IRP-691000 g
Polymer system EUDRAGIT NE-30D467 g
Complex venlafaxine-resin coated
Polymer system KOLLICOAT SR-30D635 g
Triacetin9.5 g
Purified water356 g
Complex venlafaxine-resin600 g

Complex venlafaxine-resin was obtained, first dissolving 500 g of venlafaxine HCl in 5 l of purified water, and then slowly adding 1000 g of the resin AMBERLITE™ IR-69 with continuous stirring. This dispersion was stirred for 4 hours and at the end was allowed to settle before decanting the supernatant. The process of obtaining a dense suspension/desantirovaniya was repeated twice with a sufficient quantity of the eyes of the military of water. Wet with resin and then dried in a convection oven VWR™supported at 50°C, up until the moisture content does not become equal to approximately 25%. Then wet the complex resin was slowly added 467 g of polymer EUDRAGIT™ NE-30D in a Hobart type mixer (Kitchen Aid) until a homogeneous mass. The wet mass was dried at 50°C in a convection oven VWR™ to a moisture content of about 4-6%. Dry granules are then grinded through a sieve of 40 mesh, using the mill brand CO-MIL™.

Covering solution was obtained by dispersing 635 g of polymer systems KOLLICOAT™ SR-30D, 9.5 g of triacetin in 356 g of purified water and mixing for 1 hour. The coating process was performed in the processor with the fluidized bed VECTOR™ FLM-1, causing 900 g of coating solution to 600 g of the complex venlafaxine-resin using the method Wurster, which resulted in a gain of 30%. Conditions of the coating was adjusted, while maintaining the inlet temperature 40-45°C, product temperature of 29-33°C, the air flow 40 ft3/min, pressure in the nozzle 2.5 kg/cm2the pressure in the accelerator air flow of 1.0 kg/cm2and spraying speed of 4-7 g/min so as to achieve a uniform coating. Complex venlafaxine-resin coated then kept at 60°C for 5 hours for hardening.

When is EP 12

Obtaining complex oxybutynin-resin coated

IngredientNumber
The complex oxybutynin-resin
Oxybutynin hydrochloride300 g
Purified water8 l
Resin AMBERLITE IRP-69 (anhydrous)1586
Polymer system KOLLICOAT SR-30D540 g
The complex oxybutynin-resin coated
Polymer system KOLLICOAT SR-30D761,9 g
Triacetin11.4 g
Purified water426,7 g
The complex oxybutynin-resin600 g

The complex oxybutynin-resin was obtained, first dissolving 300 g of the hydrochloride of oxibutinina in 8 liters of purified water, and then slowly adding 1586 the resin AMBERLITE™ IR-69 with continuous stirring. The pH was brought to 3.9. This dispersion was stirred for 4 hours and at the end was allowed to settle before decanting the supernatant. The process of obtaining a dense suspension/desantirovaniya was repeated twice, with a sufficient quantity of purified water. Wet with resin and then dried in a convection oven VWR™supported at 50°C, up until the moisture content does not become equal to approximately 25%. Then wet the complex resin was slowly added to the polymer system KOLLICOAT™ SR-30D (540 g) in a Hobart type mixer (Kitchen Aid) until a homogeneous mass. The wet mass was again dried at 50°C in a convection oven VWR™ to a moisture content of about 25%. The moist granules are then grinded through a sieve of 40 mesh using mill brand CO-MIL™ and continued drying at 50°C until the moisture content does not become equal to 3-7%. Dry granules are then grinded through a sieve of 40 mesh, using the mill brand CO-MIL™.

Covering solution was obtained by dispersing 761,9 g of polymer KOLLICOAT™ SR-30D, 11.4 g of triacetin in 426,7 g of purified water and mixing for 1 hour. The coating process was performed in the processor with the fluidized bed VECTOR™ FLM-1, causing 1050 g of coating solution to 600 g of the complex oxybutynin-resin using the method Wurster, giving in is the result of a gain of 35%. Conditions coating regulated, keeping the temperature at the inlet 58-72°C, product temperature 26-32°C, airflow 16-20 ft3/min, pressure in the nozzle 2.5 kg/cm2the pressure in the accelerator air flow of 1.0 kg/cm2and the spray rate of 4-6 g/min so as to achieve a uniform coating. The complex oxybutynin-resin coated then kept at 60°C for 5 hours for hardening.

Example 13

Obtaining complex Metformin-resin coated

IngredientNumber
Complex Metformin-resin
Metformin HCl225 g
Purified water4 l
Resin AMBERLITE IRP-69 (anhydrous)735 g
Polymer system KOLLICOAT SR-30D250 g
Purified water150 g
IngredientNumber
Complex Metformin-resin with the opening
Polymer system KOLLICOAT SR-30D761,9 g
Triacetin11.4 g
Purified water426,7 g
Complex Metformin-resin600 g

Complex Metformin-resin was obtained, first dissolving 225 g of Metformin HCl in 4 l of purified water, and then slowly adding 735 g of resin AMBERLITE™ IR-69 with continuous stirring. This dispersion was stirred for 4 hours and at the end was allowed to settle before decanting the supernatant. The process of obtaining a dense suspension/desantirovaniya was repeated twice, with a sufficient quantity of purified water. Wet with resin and then dried in a convection oven VWR™supported at 50°C, up until the moisture content does not become equal to approximately 25%. KOLLICOAT SR-30D (250 g) were first mixed with 150 g of purified water and the mixture is then slowly added to the wet-complex with the resin in a Hobart type mixer (Kitchen Aid) until a homogeneous mass. The wet mass was again dried at 50°C in a convection oven VWR™ to a moisture content of about 20%. The moist granules are then grinded through a sieve of 40 mesh using m is linity brand CO-MIL™ and continued drying at 50°C until while the moisture content does not become equal to 3-7%. Dry granules are then grinded through a sieve of 40 mesh, using the mill brand CO-MIL™.

Covering solution was obtained by dispersing 761,9 g of polymer KOLLICOAT™ SR-30D, 11.4 g of triacetin in 426,7 g of purified water and mixing for 1 hour. The coating process was performed in the processor with the fluidized bed VECTOR™ FLM-1, causing 1050 g of coating solution to 600 g of the complex Metformin-resin using the method Wurster, which resulted in a gain of 35%. Conditions coating regulated, keeping the temperature at the inlet 68-72°C. product temperature 28-38°C, airflow 16-24 ft3/min, pressure in the nozzle 2.5 kg/cm2the pressure in the accelerator air flow of 1.0 kg/cm2and the spray rate of 5-7 g/min so as to achieve a uniform coating. Complex Metformin-resin coated and then subjected to temperatures of 60°C for 5 hours for hardening.

Example 14

Obtaining complex ibuprofen-resin coated

IngredientNumber
Complex ibuprofen-resin
Ibuprofen 400 g
Purified water8 l
Resin PUROLITE A430MR800 g
Polymer system KOLLICOAT SR-30D250 g
IngredientNumber
Complex ibuprofen-resin coated
Polymer system KOLLICOAT SR-30D761,9 g
Triacetin11.4 g
Purified water426,7 g
Complex ibuprofen-resin600 g

Complex ibuprofen-resin was obtained, first dissolving 400 g of ibuprofen in 8 liters of purified water (brought to pH>8 10N NaOH), and then slowly adding 800 g of resin PUROLITE™ A430MR with continuous stirring. This dispersion was stirred for 4 hours and at the end was allowed to settle before decanting the supernatant. The process of obtaining a dense suspension/desantirovaniya was repeated twice, with a sufficient quantity of purified water. Wet with resin and then dried in a convection oven VWR™, p is derivagem at 50°C, up until the moisture content does not become equal to approximately 25%. Then wet the complex resin was slowly added KOLLICOAT™ SR-30D (250 g) in a Hobart type mixer (Kitchen Aid) until a homogeneous mass. The wet mass was again dried at 50°C in a convection oven VWR™ to a moisture content of about 20%. The moist granules are then grinded through a sieve of 40 mesh using mill brand CO-MIL™ and continued drying at 50°C until the moisture content does not become equal to 4-6%. Dry granules are then grinded through a sieve of 40 mesh, using the mill brand CO-MIL™.

Covering solution was obtained by dispersing 761,9 g of polymer KOLLICOAT™ SR-30D, 11.4 g of triacetin in 426,7 g of purified water and mixing for 1 hour. The coating process was performed in the processor with the fluidized bed VECTOR™ FLM-1, causing 1050 g of coating solution to 600 g of the complex ibuprofen-resin using the method Wurster, which resulted in a gain of 35%. Conditions coating regulated, keeping the temperature at the inlet 55-70°C, product temperature 28-33°C, airflow 16-21 ft3/min, pressure in the nozzle 2.5 kg/cm2the pressure in the accelerator air flow of 1.0 kg/cm2and spraying speed of 4-7 g/min so as to achieve a uniform coating. Complex ibuprofen-resin coated then in the wide at 60°C for 5 hours for hardening.

Getting suspension

Example 15

Getting suspension albuterol

IngredientNumber
Placebo, the base suspension
Purified water500 g
Citric acid, anhydrous4 g
FD&C yellow #6to 0.032 g
FD&C red #400,072 g
Corn syrup with high fructose 42600 g
Methylparaben3.6 g
Propylparaben0.4 g
Glycerin200 g
Sucrose300 g
Starch50,13 g
Xanthan gum4.35 g
Strawberry/banana flavoring of 22.44 g
Purified water to1742,45 g
Suspension of albuterol ER
Purified water100 g
Polysorbate 800.55 g
Complex albuterol-resin coated (from example 3)5,54 g
The basis for the suspension, placebo435,6 g
Purified waterto 500 ml

The basis for the suspension, placebo, received first dissolving 4 g of citric acid in 500 g of purified water in the main container, then adding 600 g of corn syrup with high fructose and 300 g of sucrose to achieve complete dissolution. In a separate container was dissolved to 0.032 g, FD&C yellow #6 and 0,072 g FD&C red #40 in sufficient quantity of purified water, and then transferred into the main container. Then in the main container was slowly introduced starch (50,13 g) in terms of mixing with high speed and high shear to obtain a homogeneous dispersion. In another container add recipients who do 200 g of glycerol and heated to 45-50°C before adding 3.6 g of methylparaben and 0.4 g of propyl paraben. After both paraben were dissolved, the solution was cooled to room temperature and the solution was slowly introduced 4.35 g xanthan gum with the formation of a homogeneous dispersion. The dispersion of the gum is then transferred into the main container in terms of mixing with high speed and high shear to obtain a homogeneous dispersion. Added of 22.44 g strawberry/banana flavoring and has been the basis for suspension, placebo, leading to the final weight 1742,45 g of purified water, and mixed to homogeneity. To obtain a final suspension of 0.55 g of Polysorbate 80 was dissolved in 100 g of purified water and then adding 435,6 g basis suspensions placebo. Complex albuterol-resin coated, obtained as described in example 3 (5,54 g), then slowly introduced into the dispersion obtained above in smooth mixing. The final suspension was received, bringing the volume up to 500 ml of an appropriate amount of purified water and mixed until smooth.

Example 16

Obtaining a suspension of morphine

IngredientNumber
Placebo, the base suspension
Tartaric acid 8 g
FD&C red #400,144 g
Cherry flavoringof 2.06 g
Corn syrup with high fructose 421200 g
Methylparaben7.2 g
Propylparaben0.8 g
Glycerin400 g
Sucrose600 g
Microcrystalline cellulose AVICEL RC-59148 g
Xanthan gumof 7.68 g
Purified waterto 3484,91 g
IngredientNumber
Suspension of morphine ER
Purified water20 g
Metabisulphite sodium0.1 g
Surfactant Polysorbate 80 0.11 g
Complex morphine-resin coated (example 1)3.2 g
The basis for the suspension, placebo87,12 g
Purified waterto 100 ml

The basis for the suspension, placebo, received first dissolving 8 g of tartaric acid in an appropriate amount of purified water in the main container, followed by the addition of 1200 g of corn syrup with high fructose and 600 g of sucrose to achieve complete dissolution. In a separate container was dissolved 0,144 g FD&C red #40 in sufficient quantity of purified water, and then transferred into the main container. In the main container and then slowly introduced microcrystalline cellulose AVICEL RC-591 (48 g) in terms of mixing with high shearing force to obtain a homogeneous dispersion. In another container was added 400 g of glycerol and heated to 45-50°C before adding 7.2 g of methylparaben and 0.8 g of propyl paraben. After both paraben were dissolved, the solution was cooled to room temperature and the solution was slowly introduced to 7.68 g of xanthan gum with the formation of a homogeneous dispersion. The dispersion of the gum is then transferred into the main container in terms of mixing with high speed and high condition is Liem shift to obtain a homogeneous suspension. Added to 2.06 g cherry flavoring and has been the basis for suspension, placebo, leading to the final weight 3484,91 g of purified water, and mixed to homogeneity. To obtain a final suspension of 0.1 g of sodium metabisulfite and 0.11 g of surfactant, Polysorbate 80 were dissolved in 20 g of purified water and then adding 87,12 g basis suspensions placebo. Complex morphine-resin coated, obtained as described in example 1 (3.2 g), then slowly introduced into the dispersion obtained above in smooth mixing. The final suspension was received, bringing the volume to 100 ml of an appropriate amount of purified water and mixed until smooth.

Example 17

Obtaining a suspension of oxycodone

The basis for the suspension, placebo, received first dissolving 8 g of tartaric acid in an appropriate amount of purified water in the main container, followed by the addition of 1200 g of corn syrup with high fructose and 600 g of sucrose to achieve complete dissolution. In a separate container was dissolved 0,144 g FD&C red #40 in sufficient quantity of purified water, and then transferred into the main container. In the main container and then slowly introduced microcrystalline cellulose AVICEL RC-591 (48 g) in terms of mixing with high shearing force to obtain a homogeneous dispersion. In another container was added 400 g of glycerol and heated to 45-50°C before adding 7.2 g of methylparaben and 0.8 g of propyl paraben. After both paraben were dissolved, the solution was cooled to room temperature and the solution was slowly introduced to 7.68 g of xanthan gum with the formation of a homogeneous dispersion. The dispersion of the gum is then transferred into the main container in terms of mixing with high speed and high shear to obtain a homogeneous dispersion. Added to 2.06 g strawberry flavour and has been the basis for suspension, placebo, leading to the final weight 3484,91 g of purified water, and mixed to homogeneity. To obtain a final suspension of 0.5 g of sodium metabisulfite and 0.55 g of surface-active ve is esta, Polysorbate 80 was dissolved in 100 g of purified water and then adding 435,6 g basis suspensions placebo. Complex oxycodone-resin coating obtained in accordance with example 2 (5,66 g), then slowly introduced into the dispersion obtained above in smooth mixing. The final suspension was received, bringing the volume up to 500 ml of an appropriate amount of purified water and mixed until smooth.

Example 18

Getting disintegrating in the mouth tablets

Obtaining complex dextromethorphan-resin coated

IngredientNumber
Placebo, the base suspension
Tartaric acid8 g
FD&C red #400,144 g
Strawberry flavoringof 2.06 g
Corn syrup with high fructose 42Methylparaben7.2 g
Propylparaben0.8 g
Glycerin400 g
Sucrose600 g
Microcrystalline cellulose AVICEL RC-59148 g
Xanthan gumof 7.68 g
Purified waterto 3484,91 g
Suspension of oxycodone ER
Purified water100 g
Metabisulphite sodium0.5 g
Surfactant, Polysorbate 800.55 g
Complex oxycodone-resin coated (from example 2)to 5.66 g
The basis for the suspension, placebo435,6 g
Purified waterto 500 ml
IngredientNumber
Complex dextromethorphan-resin
Dextromethorphan HBr USP954 g
Purified water8 l
Resin AMBERLITE IRP-69 (anhydrous)1758
PVP trademark KOLLIDON K-30116 g
Purified water1151 g
Complex dextromethorphan-resin coatedthe
Polymer system KOLLICOAT SR-30D635 g
Triacetin9.5 g
Purified water356 g
Complex dextromethorphan-resin600 g

Complex dextromethorphan-resin was obtained, first dissolving 954 g of dextromethorphan HBr in 8 liters of purified water heated to 75-80°C., and then adding 1758 resin AMBERLITE™ IRP-69 calm stirring for 4 hours. After the suspension was allowed to settle, decantation, washed twice with purified water and dried in a drying Cabinet, supported at 50°C, up until the moisture content does not become equal to approximately 5%. The PVP solution was obtained by dissolving 116 g PVP trademark KOLLIDON K-30 in 1151 g of purified water, this solution was slowly added to the complex dextromethorphan-resin in a Hobart type mixer (Kitchen Aid) until a homogeneous mass was dried at 50°C until the moisture content of 3-7%. Dry granules are then grinded through a sieve of 40 mesh, using the mill brand CO-MIL™.

Covering solution was obtained, first calmly mixing 635 g of polymer systems KOLLICOAT™ SR-30D, 9.5 g of triacetin and 356 g of purified water for 1 hour. The coating process issue is lnai processor fluidized bed VECTOR™ FLM-1, dealing 900 g of coating solution to 600 g of the complex dextromethorphan-resin using the method Wurster, which resulted in a gain of 30%. Conditions coating regulated, keeping the temperature at the inlet 62-76°C, product temperature 28-35°C, airflow 16-20 ft3/min, pressure in the nozzle 2.5 kg/cm2the pressure in the accelerator air flow of 1.0 kg/cm2and the spray rate of 4-6 g/min so as to achieve a uniform coating. Complex dextromethorphan-resin coated then kept at 60°C for 5 hours for hardening.

Getting uncovered complex dextromethorphan-resin

Uncovered complex dextromethorphan-resin was obtained, as described below.

IngredientNumber
Uncovered complex dextromethorphan-resin
Dextromethorphan HBr US119,28 g
Purified water1 l
Resin AMBERLITE IRP-69 (anhydrous)223,01 g

Uncovered complex dextromethorphan-resin was obtained, first dissolving 119,28 where is tromethane HBr in 1 l of purified water, heated to 75-80°C., and then adding 223,01 g resin AMBERLITE IRP-69 calm stirring for 4 hours. After the suspension was allowed to settle, and then decantation, washed twice with purified water and dried in a drying Cabinet, supported at 50°C to a moisture content of about 5%. The dried complex with the resin manually sieved through a sieve of 40 mesh.

Getting pills

Dextromethorphan-resin coated and dextromethorphan-resin without the coating of this example was used to obtain tablets, as presented below.

IngredientThe number on pillNumber
Dextromethorphan-resin uncoated23,78 mg4,76 g
Dextromethorphan-resin coated72,70 mg14,54 g
The calcium silicate49 mg9,8 g
Seafarm3.5 mg0.7 g
Silicon dioxide5.0 mg 1.0 g
Microcrystalline cellulose24 mg4.8 g
Acesulfame K sweetener2 mg0.4 g
Aspartame5 mg1.0 g
Peppermint2.5 mg0.5 g
Crosspovidone15 mg3.0 g
Mannitol124 mg24.8 g
Stearate Mg5 mg1.0 g
Just331,48 mgto 66.30 g

Small batch of tablets received, first by adding it to the mixer shown in the above formula the number of dextromethorphan-resin uncoated and coated calcium silicate, teofarma, silicon dioxide, microcrystalline cellulose, crospovidon, sweetener Acesulfame K, aspartame and mannitol, and stirring for 10 minutes. To the powder mixture was added to the article the Arat magnesium (1.0 g) and stirred for a further 3 minutes. The final mixture was unloaded in tablet press RIMEK™, equipped with 3/8" standard concave tooling, and extruded tablets moderate hardness (3-6 CP test device to determine the strength tablets VANDERKAMP™).

Dissolution to determine the speed of release from disintegrating in the mouth tablets with prolonged-release dextromethorphan according to this invention was carried out in 900 ml of 0,4M KN2RHO4mixing paddle stirrer at 50 rpm, and the results for the tablets was comparable to results for the ER suspension.

Example 19

Migration staining water-soluble dyes in the final compositions containing the complexes of the drug-ion exchange resin, coated with a polymer shell of the polymer of the trade mark EUDRAGIT comparative example

Suspension of dextromethorphan obtained from complex dextromethorphan-resin uncoated and coated with EUDRAGIT, as was observed, is moving staining; this movement of the staining was more pronounced at 40°C/75% RH compared with 25°C/60% RH.

Getting uncovered and covered complex dextromethorphan-resin

IngredientNumber
Uncovered complex dextromethorphan-resin
Dextromethorphan HBr USP119,28
Purified water1 l
Resin AMBERLITE IRP-69 (anhydrous)223,01 g

Uncovered complex dextromethorphan-resin was obtained, first dissolving 119,28 g of dextromethorphan HBr in 1 l of purified water heated to 75-80°C., and then adding 223,01 g resin AMBERLITE IRP-69 under mild stirring for 4 hours. After the suspension was allowed to settle, and then decantation, washed twice with purified water and dried in a drying Cabinet, supported at 50°C, up until the moisture content does not become equal to approximately 5%. The dried complex was manually sieved through a sieve of 40 mesh.

1784,0 g
IngredientNumber
Complex dextromethorphan-resin
Dextromethorphan HBr USP954,2 g
Purified water8 l
Resin AMBERLITE IRP-69 (anhydrous)
Polyvinylpyrrolidone KOLLIDON K-30116 g
Purified water528,4 g
Complex dextromethorphan-resin coated
Polymer system EUDRAGIT RS-30D334,89 g
Triethylcitrate20,25 g
Talc50,19 g
Surfactant Polysorbate 800.29 grams
Purified water292,2 g
Complex dextromethorphan-resin600 g

Complex dextromethorphan-resin was obtained, first dissolving 954,2 g of dextromethorphan HBr in 8 liters of purified water heated to 75-80°C., and then adding 1784 resin AMBERLITE IR-69 calm stirring for 4 hours. After the suspension was allowed to settle, decantation, washed twice with purified water and dried in a drying Cabinet, supported at 50°C to a moisture content of about 5%. The PVP solution obtained by dissolving 116 g KOLLIDON K-30 in 582,4 g of purified water, slow is added to the complex dextromethorphan-resin in a Hobart type mixer (Kitchen Aid) until a homogeneous mass was dried at 50°C until while the moisture content does not become equal to 3-7%. Dry granules are then grinded through a sieve of 40 mesh, using CO-MIL.

Covering solution has been relaxed by mixing 334,89 g polymer systems EUDRAGIT RS-30D, 0.29 grams surfactant, Polysorbate 80, 20,25 g triethylcitrate and 292,2 g of purified water for 45 minutes, then add 50,19 g of talc and continuous stirring for 1 hour. The coating process was performed in the processor with the fluidized bed Glatt GPCG-1, causing 698 g of coating solution to 600 g of the complex dextromethorphan-resin using the method Wurster, which resulted in a gain of 28.5%. Complex dextromethorphan-resin coated then kept at 60°C for 5 hours for hardening.

Obtaining a suspension of dextromethorphan

IngredientNumber
Placebo, the base suspension
Citric acid6 g
FD&C yellow #60,03278 g
Orange flavoring2,01 g
Corn syrup with high fructose 42600 g
Methylparaben3.6 g
Propylparaben0.6 g
Propylene glycol100 g
Sucrose300 g
Tragacanth gum10,51
Xanthan gum3,59 g
Purified water1015 g
Suspension of dextromethorphan
Purified water10 g
Surfactant Polysorbate 800,22 g
Complex dextromethorphan-resin uncoated2,68 g
Complex dextromethorphan-resin coated1,00 g
The basis for the suspension, placebo203,15 g
Purified water to 200 ml

The basis for the suspension, placebo, received first dissolving 6 g of citric acid in an appropriate amount of purified water from the total number 1015 g in the main container, then adding 300 g of sucrose and 600 g of corn syrup with high fructose to achieve complete dissolution. In a separate container was dissolved 0,03278 g FD&C yellow #6 in sufficient quantity of purified water, and then transferred into the main container. In another container was added 100 g of propylene glycol and heated to 45-50°C before adding 3.6 g of methylparaben and 0.6 g of propyl paraben. After both paraben were dissolved, the solution was cooled to room temperature and the solution was slowly introduced 10,51 g tragacanth gums and 3,59 g xanthan gum with the formation of a homogeneous dispersion. The dispersion of the gum is then transferred into the main container in terms of mixing with high speed and high shear to obtain a homogeneous suspension. Added 2,01 g orange flavour and has been the basis for suspension, placebo adding the remaining purified water and stirring until smooth. To obtain a final suspension and 0.22 g of surfactant, Polysorbate 80 were dissolved in 10 g of purified water and then adding 203,15 g basis suspensions placebo. Uncovered whom the Lex dextromethorphan-resin (2,68 g) and complex dextromethorphan-resin coated (1 g) was then slowly introduced into the above dispersion under conditions of mild agitation. The final suspension was received, bringing the volume up to 200 ml of an appropriate amount of purified water and mixed until smooth.

If the complexes of the drug-ion exchange resin obtained in accordance with this invention and covered by the copolymers of methacrylic acid, such as a polymer coating of the trade mark EUDRAGIT, mixed with the dye in a liquid suspension, the dye had a tendency to move on the surface of the polymer, and this led to non-uniform color distribution in the liquid. The use of polymer trademark EUDRAGIT end a liquid suspension containing a water-soluble dyes, leads to uneven coloring due to moving color. In addition, the nature of the polymer trademark EUDRAGIT this polymer was also caused by flocculation of the resin, leading to the formation of flocculent agglomerates in a liquid suspension.

Example 20

Drug-ion exchange resin-coated ethylcellulose in the composition of the liquid suspension -

comparative example

Suspension of dextromethorphan obtained with uncoated and coated with AQUACOAT™ complex dextromethorphan-resin, as was observed, formed of loose and dense cereals. This is more pronounced at 40°C/75% RH than at 25°C/60% RH.

Getting covered complex dextromethorphan-resin/u>

IngredientNumber
Complex dextromethorphan-resin coated
Polymer system AQUACOAT ECD-30460,08 g
Dibutylsebacate33,56 g
Purified water115,97
Complex dextromethorphan-resin (from example 18)600g

Covering solution was obtained, first calmly stirring 460,08 g AQUACOAT ECD-30 and 33,56 g dibutylsebacate for 45 minutes, then add 115,97 g of purified water and kept stirring for 30 minutes. The coating process was performed in the processor with the fluidized bed Glatt GPCG-1, causing 615 g of coating solution to 600 g of the complex dextromethorphan-resin using the method Wurster, which resulted in a gain of 28.9%. Complex dextromethorphan-resin coated then kept at 60°C for 5 hours for hardening.

Obtaining a suspension of dextromethorphan

IngredientNumber
Suspension of dextromethorphan ER
Purified water10 g
Surfactant Polysorbate 800,22 g
Uncovered complex dextromethorphan-resin (from example 18)1.50 g
Complex dextromethorphan-resin coated2,68 g
The basis for the suspension, placebo (from example 18)203,14 g
Purified waterto 200 ml

To obtain a final suspension and 0.22 g of surfactant, Polysorbate 80 were dissolved in 10 g of purified water and then adding 203,14 g basis suspensions placebo. Uncovered complex dextromethorphan-resin (1.50 g) and complex dextromethorphan-resin coated (2,68 g) was then slowly introduced into the dispersion obtained above in smooth mixing. The final suspension was received, bringing the volume up to 200 ml of an appropriate amount of purified water and mixed until smooth.

If a liquid suspension floor is Ali from covered ethylcellulose particles, these coated particles formed flakes, swollen and large, the index weakened adhesion ethylcellulose coating to the surface of the particles. These covered ethylcellulose particles did not show a reduction in the speed of release of the medicinal substance, or if it was negligible.

Resistant to abuse the characteristics of the products of this invention

Example 21 - Getting uncovered and covered complex dextromethorphan-resin

IngredientNumber
Uncovered complex dextromethorphan-resin
Dextromethorphan HBr USP95,42 g
Purified water0.8 l
Resin AMBERLITE IRP-69 (anhydrous)175,82 g

Uncovered complex dextromethorphan-resin was obtained, first dissolving 95,42 g of dextromethorphan HBr in 0.8 l of purified water heated to 75-80°C., and then adding 175,82 g resin AMBERLITE IRP-69 (anhydrous) at a calm stirring for 4 hours. After the suspension was allowed to settle, decantation, washed twice in water and dried in a drying cupboard supported at 50°C, up until the moisture content does not become equal to approximately 5%. The dried complex with the resin manually sieved through a sieve of 40 mesh.

IngredientNumber
Complex dextromethorphan-resin
Dextromethorphan HBr USP954 g
Purified water8 l
Resin AMBERLITE IRP-69 (anhydrous)1758
Polyvinylpyrrolidone KOLLIDON K-30116 g
Purified water1151 g
Complex dextromethorphan-resin coated
Polymer system KOLLICOAT SR 30D761 g
Triacetin11.4 g
Purified water427 g
Complex dextromethorphan-resin1200 g

Complex dextrose the orthanes-resin was obtained, first dissolving 954 g of dextromethorphan HBr in 8 liters of purified water heated to 75-80°C., and then adding 1758 resin AMBERLITE IRP-69 calm stirring for 4 hours. After the suspension was allowed to settle, decantation, washed twice with purified water and dried in a drying Cabinet, supported at 50°C, up until the moisture content does not become equal to approximately 5%. The solution of polyvinylpyrrolidone (PVP) was obtained by dissolving 116 g PVP, KOLLIDON K-30 in 1151 g of purified water, this solution was slowly added to the complex dextromethorphan-resin in a Hobart type mixer (Kitchen Aid) until a homogeneous mass was dried at 50°C until the moisture content of 3-7%. Dry granules are then grinded through a sieve of 40 mesh, using the mill brand CO-MIL™.

Covering solution was obtained, first calmly stirring 761 g of the polymer system KOLLICOAT SR-30D, 11.4 g of triacetin and 427 g of purified water for 1 hour. The coating process was performed in the processor with the fluidized bed VECTOR™ FLM-1, causing 1050 g of coating solution to 600 g of the complex dextromethorphan-resin using the method Wurster, which resulted in a gain of 35%. Conditions coating regulated, keeping the temperature at the inlet 59-75°C, product temperature 27-35°C air flow (15-20 ft3/min, pressure in the nozzle 2.5 kg/cm2the pressure in the accelerator d is to achieve air 1.0 kg/cm 2and the spray rate of 4-6 g/min so as to achieve a uniform coating. Complex dextromethorphan-resin coated then kept at 60°C for 5 hours for hardening.

Obtaining a suspension of dextromethorphan ER

IngredientNumber
Suspension of dextromethorphan ER
Purified water20 g
Polysorbate 800.11 g
Complex dextromethorphan-resin uncoated0,476 g
Complex dextromethorphan-resin coated1,596
Metabisulphite sodium0.1 g
The basis for the suspension, placebo (from example 18)87,12 g
Purified waterto 100 ml

To obtain a suspension of dextromethorphan ER, a mixture of resin were prepared by mixing 0,476 g of dextromethorphan-resin uncoated and 1,596 g of dextromethorphan-resin is coated. The mixture is then passed through a mill brand CO-MIL™, equipped with a sieve of 40 mesh. Suspension of dextromethorphan was obtained by dissolving 0.11 g of surfactant, Polysorbate 80, and 0.1 g of sodium metabisulfite in 20 g of purified water and then adding 87,12 g basis suspensions placebo. A mixture of covered and uncovered complex dextromethorphan-resin is then slowly introduced into the dispersion obtained above in smooth mixing. The final suspension was received, bringing the volume to 100 ml of an appropriate amount of purified water and mixed until smooth.

Another suspension was obtained using the same ingredients and methods, except that the mixture of resin was crushed with mill trade mark CO-MIL™.

Compared the dissolution of both suspensions in 500 ml 0,1N HCl for 1 hour followed by the addition of 900 ml of buffer with pH 6.8, and stirring for up to 24 hours paddle stirrer, 50 rpm, and the results showed no significant differences. Strong external force during grinding, applied to covered and uncovered complex with the resin, did not change the nature of the dissolution of their suspensions compared to the suspension obtained is not milled mixture with the resin, which indicates that the elastic film is not torn.

Complex drug-resin, dormancy is ity polymer film, showed increased resistance against the possibility of abuse. The particle coating is subjected to mechanical grinding force, as described above, did not change the nature of dissolution, which indicates that the combination of the formed complex and highly elastic film makes extremely difficult the selection of medicinal substance from the coated particles using conventional mechanical means.

Example 22

Obtaining pseudoephedrine suspension

IngredientNumber
Placebo, the base suspension
Citric acid8 g
FD&C yellow #60,064 g
FD&C red #400,144 g
Strawberry/banana flavoring44,88 g
Corn syrup with high fructose 421200 g
Methylparaben7.2 g
Propylparaben 0.8 g
Glycerin400 g
Sucrose600 g
Starch100,26 g
Xanthan gum8.7 g
Purified waterto 3484,91 g
Suspension pseudoephedrine ER
Purified water20 g
Surfactant Polysorbate 800.11 g
Complex pseudoephedrine-resin coated (from example 8)3.11 g
The basis for the suspension, placebo87,12 g
Purified waterto 100 ml

The basis for the suspension, placebo, received first dissolving 8 g of citric acid in an appropriate amount of purified water, followed by addition of 600 g of sucrose and 1200 g of corn syrup with high fructose to achieve complete dissolution. In a separate container was dissolved 0,064 g FD&C yellow #6 and 0,144 g FD&C to the ACLs #40 in sufficient quantity of purified water, and then transferred into the main container. Then in the main container was slowly introduced starch (100,26 g) in terms of mixing with high shearing force to obtain a homogeneous dispersion. In another container was added 400 g of glycerol and heated to 45-50°C before adding 7.2 g of methylparaben and 0.8 g of propyl paraben. After both paraben were dissolved, the solution was cooled to room temperature and the solution was slowly introduced to 8.7 g of xanthan gum with the formation of a homogeneous dispersion. The dispersion of the gum is then transferred into the main container in terms of mixing with high speed and high shear to obtain a homogeneous suspension. Added 44,88 g strawberry/banana flavoring and has been the basis for suspension, placebo, the addition of the balance of purified water and stirring until smooth.

To obtain a suspension of pseudoephedrine ER, covered with complex pseudoephedrine-resin (3.11 g) was passed through a CO-MIL™, equipped with a sieve of 40 mesh. The pseudoephedrine suspension was obtained by dissolving 0.11 g of surfactant, Polysorbate 80, 20 g of purified water and then adding 87,12 g basis suspensions placebo. Complex pseudoephedrine-resin coated then slowly introduced into the dispersion obtained above in smooth mixing. The final suspension was received, bringing the volume up to 10 ml of an appropriate amount of purified water, and stirred until smooth.

Another suspension was obtained with the same ingredients and the same methods, except that the complex pseudoephedrine-resin coated not crushed on CO-MIL™.

Compared the dissolution of both suspensions in 500 ml 0,1N HCl for one hour followed by the addition of 900 ml of buffer with pH 6.8 for up to 24 hours, stirring paddle stirrer at 50 rpm, and the results showed no significant differences. Strong external grinding force applied to the grinding covered complex with the resin, did not change the nature of the dissolution of his suspension when compared to the suspension obtained is not crushed coated with resin.

All patents, patent publications and other publications listed in this description, incorporated herein by reference. Although this invention has been described with reference to particularly preferred embodiments of, it should be clear that can be produced modifications not departing from the essence of the present invention. Such modifications, as implied fall in the scope of the attached claims.

1. Composition for oral administration having the properties of modified release comprising pharmaceutically acceptable excipients and at least one complex drug - ion exchange resin with aircraft is receiving with modified-release containing at least one pharmaceutically active drug substance, associated with a pharmaceutically acceptable ion exchange resin, and having a curable barrier coating of non-ionic polymer with high tensile strength, water permeable, water insoluble, where the aforementioned polymeric barrier coating is cured and contains polyvinyl acetate polymer, a stabilizer and an effective amount of plasticizer and additionally characterized by the fact that it is essentially non-sticky when applied to the complex in the absence of anti-adhesive means, and, if the composition is a tablet, complex drug - ion exchange resin with a coating further comprises inhibiting the release of substance in matrix with complex drug - ion exchange resin.

2. The composition according to claim 1, in which the plasticizer is from about 2.5 to about 20 wt.% the solids in the coating.

3. The composition according to claim 1, wherein the stabilizer is polyvinylpyrrolidone.

4. The composition according to claim 1, and complex drug - ionoobmennaya resin further includes inhibiting the release of substance in the matrix with complex drug - ionoobmennaya resin.

5. The composition according to claim 1, with the specified C is Malaysia the release of a substance selected from at least one representative, selected from the group consisting of polyvinyl acetate polymer, cellulose acetate, polymers, ethyl cellulose, cellulose phthalate, and polyvinylpyrrolidone.

6. The composition according to claim 1, and a barrier coating is a measure of the stickiness of approximately 2 or less, as measured by the method Hössel at 20°C/80% relative humidity and 30°C/75% relative humidity.

7. The composition according to claim 6, with the barrier coating is a measure of the stickiness of approximately 0.5 or less.

8. The composition according to claim 1, and a barrier coating has a rate of elongation of at least about 100%, or from about 150 to 400%.

9. The composition according to claim 1, and a barrier coating comprises from 5 to 200% by weight of the complex uncoated, from 25 to 50% by weight of the complex without coating or from 30 to 45% by weight of the complex without coverage.

10. The composition according to claim 1, in which the stabilizer in the barrier coating is contained in an amount of from about 5% to 10% by weight, curing of the barrier layer.

11. The composition according to claim 1, and polyvinyl acetate polymer is from about 70 to about 95 wt.% the coating layer.

12. The composition according to claim 1, in which the barrier coating containing polyvinyl acetate polymer, further comprises a surfactant.

13. The composition according to item 12, and surface-active agent is one who by sodium lauryl sulphate.

14. Composition according to any one of PP-13, in which the barrier coating, the ratio of polyvinyl acetate and polyvinylpyrrolidone is about 10:1 by weight solids in coating and plasticizer is contained in an amount of from about 5% to 10% by weight in the coating.

15. The composition according to claim 1, and a plasticizer selected from the group consisting of dibutylsebacate, propylene glycol, polyethylene glycol, polyvinyl alcohol, triethylcitrate, acetylsalicylate, acetyltributyl, tributyltin, triacetin, solupor R and mixtures thereof.

16. The composition according to claim 1, where the composition includes two or more pharmaceutically active drugs.

17. The composition according to claim 1, in which the complete form for oral administration is a liquid suspension containing pharmaceutically acceptable basis for suspension.

18. The composition according to 17, further comprising sodium metabisulfite.

19. The composition according to 17, in which the specified curable polymeric barrier coating contains a polyvinyl acetate polymer, a stabilizer, containing polyvinylpyrrolidone, a surfactant and a plasticizer.

20. The composition according to claim 19, in which the barrier covering layer is from about 30 to about 45% by weight of non-complex.

21. The composition according to 17 containing mA is ritsu, includes the specified complex drug - ion exchange resin in a mixture with slow release substance and a specified barrier coating applied over said matrix including complex drug - ion exchange resin.

22. The composition according to item 21, in which the number of slow release polymer is from about 5 to about 20% by weight from uncoated particles of drug substance - ion-exchange resin.

23. The composition according to item 21 or 22, which is a substance that slows the release includes a polymer selected from polyvinyl acetate, polymers based on acrylate or copolymers, polyvinylpyrrolidone and mixtures thereof.

24. Composition according to any one of p-23, in which the specified barrier coating contains at least about 75% by weight polyvinyl acetate polymer, from 5 to 10% by weight polyvinylpyrrolidone, a surfactant and from 2.5 to 20% plasticizer by weight from the cured layer of the barrier coating.

25. The composition according to paragraph 24, in which the plasticizer is a triacetin.

26. The composition according to claim 1 or 24, and the medicinal substance selected from the group consisting of morphine, oxycodone, albuterol, methylphenidate, dexmethylphenidate, dextromethorphan, codeine, tramadol, dicyclomine, pseudoephedrine, phenylephrine, hydrocodone, venlafaxine, IB is profane, oxibutinina, Metformin, clonidine, dexchlorpheniramine, Fexofenadine, diphenhydramine, chlorpheniramine, amphetamine, naproxen, diclofenac, paroxetine, amoxicillin, and their pharmaceutically acceptable salts.

27. Product with modified drug release, and specified product includes a package containing the composition for oral administration according to any one of claims 1 to 26.



 

Same patents:

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

FIELD: medicine.

SUBSTANCE: invention refers to a carrier for drugs, biologically active substances, biological objects used in medicine for diagnostics and treatment in pharmaceutical industry. The carrier represents a material sensitive to external magnetic or electric fields and consisting of magnetic or ferroelectric material filmed with biocompatible thermosensitive, biodegradable polymer and/or dispersed in thermosensitive medium properties of which change with varying temperature relative to that of human body within 15.9 to 42°C. The magnetic or ferroelectric materials are made of substance with great magnetocaloric or electrocaloric component effect 1 to 13 K, have temperature of magnetic or ferroelectric phase transition within temperature range 33 to 37°C, and are chosen from the group including rare-earth, transition and precious metals, their alloys and compounds.

EFFECT: invention also concerns methods of controlled drug delivery by means of such carrier with enabling release thereof (regulated desorption) in the preset point.

32 cl, 9 ex

FIELD: medicine; pharmacology.

SUBSTANCE: minitablets have a kernel and an external cover which makes 2-15% of gross weight of minitablets, the kernel of the specified minitablets, includes a venlafaxine hydrochloride, microcrystallic cellulose and a polyvinylpyrolidone, and the specified cover includes polymer, insoluble in water, and a polymer, soluble in water.

EFFECT: provision of levels of concentration in a blood plasma above the minimum therapeutic concentration during the long period of time.

10 cl, 1 dwg, 1 tbl, 5 ex

FIELD: medicine.

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

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

28 cl, 7 dwg, 9 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to sustained-release medicinal formulation composition comprising venlafaxin hydrochloride as an active component. In this formulation venlafaxin hydrochloride in common with a binding agent is applied on inert core as lozenge form (nonpareil) followed applying with a cover-insulating polymeric layer for providing stability and additional cover with external polymeric layer providing the sustained-release of venlafaxin hydrochloride.

EFFECT: improved and valuable properties of composition.

18 cl, 1 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: the [present innovation deals with manufacturing intestinally soluble capsular forms of medicinal preparations, particularly, to the technology for creating capsular membranes of improved protective properties. The innovation deals with the method for obtaining capsular membrane out of calcium alginate due to successive keeping capsular nuclei in solutions of sodium alginate and calcium chloride, in which sodium alginate solution at concentration of 1.5-2.0% (weight/volume) should be pre-treated with ultrasound for about 8-10 at the power of 400-450 W/sq. cm. Calcium chloride solution should be applied at concentration of 2.0-2.5%, moreover, the terms for keeping capsular nuclei in solutions of sodium alginate and calcium chloride corresponds to 5 min in every solution.

EFFECT: higher efficiency.

1 dwg, 3 ex, 1 tbl

The invention relates to medicine and can be used for the treatment of venous leg ulcers
The invention relates to soft gelatin capsules filled with granules that contain at least one beneficial agent

FIELD: medicine.

SUBSTANCE: pH-controlled pulse delivery system according to the invention, contains a nucleus enclosed by an external coating. Said nucleus contains an active substance which is preferentially a pharmaceutically active substance. Said external coating contains a pH-sensitive coating material embedding a swelling ingredient of water swell equal to at least 1.1 in relation to own weight. Said swelling ingredient is present in aforesaid coating in an amount which depending on particle size and structure of the coating forms a coating with a leakless system. The pH-controlled pulse delivery system aims at pH-related place-specific delivery of an active substance preferentially to a large intestine or a duodenum.

EFFECT: invention allows fast release of the active substance owing to the presence of the swelling ingredient in the external coating.

15 cl, 6 dwg, 8 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: solid dosage form consists of a core containing, wt %: bisacodyl - 1.5-12; potato starch - 0.5-10; pregelatinised starch - 2-15; croscarmellose sodium - 0.5-4; colloidal silicon dioxide - 0.2-5; stearic acid and/or its salts - 0.3-1.07; lactose - the rest; and a coating containing, wt %: polyethylene glycol - 0.05-0.2; staining agent - 0.05-0.25; titanium dioxide - 5-25; talc - 20-54; triethyl citrate - 1-7; colloidal silicon dioxide 0.5-2; sodium hydrocarbonate - 0.5-2; sodium lauryl sulphate - 0.1-1 and copolymer of methacrylic acid and ethyl acrylate - the rest.

EFFECT: invention ensures good strength and disintegration of a tablet in the neutral or alkalescent intestinal environment.

8 cl, 4 tbl

FIELD: medicine.

SUBSTANCE: invention relates to protected against unadministered application peroral medication form with controlled release from it of opioid for single intake per day which is different in that it contains opioid (A), which potentially is a subject of its non-medicinal applicatuion, synthetic or natural polymer (C), which forms retarding opioid release matrix material or retarding opioid release coating, optionally physiologically compatible auxiliary substances (B), optionally wax (D), component (C), respectively component (D) possess resistance to destruction 500 H and component (C) and possibly applied component (D) are present in amounts at which resistance of medication form to destruction constitutes 500 H.

EFFECT: invention also relates to methods of obtaining protected against unadministered application coompositions, which include stages of component mixing, formation by force applicatuion and/or thermal influence and, if necessary, providing retarding opioid release coating.

36 cl, 1 dwg, 1 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: claimed invention relates to field of medications, in particular to tablet, manufactured by method of building-up coating, in composition of which included are core, containing medication, and core-surrounding coat from non-soluble or badly water-soluble material, core being located inside said coat in such way that coat on axis (X-Y) has greater thickness and lower density than on axis (A-B), orthogonal to axis (X-Y), coat porosity on axis (X-Y) being sufficient for ensuring penetration of water medium, so that when immersed into water medium after period from 2 to 6 hours destruction of coat and release of medication takes place. Invention also relates to method of said tablet manufacturing, pharmaceutical package containing it and treatment method. Said tablet form ensures fast release and delivery of active component after period of delay, which can be set with great accuracy.

EFFECT: system will ensure directed delivery of active component to place of absorption or action.

19 cl, 2 dwg, 3 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: dosed (medicinal) form of immediate release contains at least one active ingredient, has hard core and coat. Coat surrounds at least part of core. Core has density of about 0.9 g/cm3 and porosity less than 40%. Coat of dosed form contains one or more holes and is easily soluble in gastro-intestinal fluids.

EFFECT: dosed form according to the invention ensures immediate release of active ingredient after contact with liquid medium of gastro-intestinal tract, minimises impact of environment on core in oral cavity and increases impact of solving medium on core.

17 cl, 17 dwg, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: oral controlled-release dosage form includes granules of therapeutically effective amount of pharmacologically high water-soluble active substance, and at least one nonpolymeric release inhibitor. Said granules are combined at least with one pH-independent nonswelling release inhibitor representing a polymer. Nonpolymeric release inhibitor represents glyceryl behenate. Polymeric pH-independent release inhibitor preferentially represents mixed polyvinyl acetate and polyvinyl pyrrolidone (Collidone SR). The active substance preferentially represents vitamin C.

EFFECT: dosage form provides controlled release of an active component with the reduced initial "explosive" release.

34 cl, 4 dwg, 19 tbl, 10 ex

FIELD: medicine.

SUBSTANCE: pharmaceutical composition contains alimemazine as an active component, and target adjuvants: lactose, potato starch, microcrystalline cellulose, kollidon, magnesium stearate in the following ratio. The composition is made in the form of coated tablets with the coating containing polyvinyl alcohol, talc, polyethylene glycol, titanium dioxide, acceptable dying agents.

EFFECT: pharmaceutical composition extends range of medical products, meets all of the standard requirements and has shelf-life of 2 years.

5 cl, 2 ex

FIELD: medicine.

SUBSTANCE: as additional components, a new medicinal form contains stearic acid or its pharmaceutically acceptable salt, succinic acid or its pharmaceutically acceptable salt, microcrystalline cellulose, magnesium carbonate, starch and hydroxypropyl cellulose.

EFFECT: extended range of storage-stable preparations of 3-oxy-6-methyl-2-ethylpyridine as solid oral dosage forms without by-effects of existing preparations.

14 cl, 2 tbl

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

FIELD: medicine.

SUBSTANCE: present invention concerns coated tableted form containing a tablet centre coated with a medical agent as inhibitor DPP4 sacsaglipitin, and the method for preparing such coated tableted form. The layers that coat the tablet centre are applied as a coating polymer suspension.

EFFECT: according to the invention, coated tablets are characterised with improved chemical stability as compared to the conventional tablets.

17 cl, 2 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: pharmaceutical composition of prolonged release in form of pill includes metformin or its pharmaceutically acceptable salt; agent, which generates gas, selected from carbonates or bicarbonates; hydrophilic or hydrophobic polymer as release moderator; disintegration-causing agent; hydrophilic polymer for ensuring system stability; additional hydrophilic polymer or gum as release moderator, binding substance and other pharmaceutical additional substances.

EFFECT: composition by invention ensures increased term of device holding in stomach and release of metformin by regulated method, in addition, it is simple and cheap in production.

19 cl, 1 dwg, 11 tbl, 8 ex

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