Pharmaceutical compositions comprising 5,8,14-triazatetracyclo[10,3,1,0(2,11),0(4,9)hexadeca-2( 11),3,5,7,9-pentaene

FIELD: organic chemistry, medicine, narcology, pharmacy.

SUBSTANCE: invention relates to a sustained-release medicinal formulation designated for reducing abuse to nicotine. The medicinal formulation comprises 5,8,14-triazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaene or its pharmaceutically acceptable salt that is administrated in patient at the rate less 6 mg/h that corresponds to at least 0.1 mg of indicated compound for 24 h. Also, invention relates to the sustained-release medicinal formulation comprising low dose of indicated medicinal substance. Method for using involves oral administration of the sustained-release medicinal formulation at the first stage for period from about 1 day to about 30 days followed by administration the sustained-release medicinal formulation at the second stage. Invention provides reducing abuse for nicotine and simultaneous decreasing appearance of nausea frequency as adverse effect.

EFFECT: valuable medicinal properties of composition.

10 cl, 13 ex

 

The present invention relates to dosage forms of a pharmaceutical product on the basis of compounds 1, 5,8,14-triazinetrione[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaen, controlled release oral introduction and related compounds, and methods of use thereof for reducing the addiction to nicotine or to facilitate the cessation or reduction of its consumption while reducing nausea, manifested as undesirable actions of the drug. The present invention also relates to compositions with a low dose of medicinal substance immediate release with a stable composition with a uniform distribution of the drug substance and effectiveness.

Prior art

Compound 1, also known as 7,8,9,10-tetrahydro-6,10-methane-6N-pyrazin[2,3-h][3]benzazepin, binds to nicotinic acetylcholine receptors on neurons and is used when the modulation of cholinergic function. Accordingly, this connection is applicable in the treatment of inflammatory bowel disease (including, but not limited to ulcerative colitis, pyoderma pyodermia and Crohn's disease), irritable bowel syndrome, spastic dis is onii, chronic pain, acute pain, abdominal sprue, pouchitis, narrowing of the blood vessels, anxiety, panic, depression, bipolar disorder, autism, sleep disorders, disorders of the normal circadian rhythm, manifested by fatigue, amyotrophic lateral sclerosis (ALS), disorders of cognitive abilities, hypertension, bulimia, anorexia, obesity, cardiac arrhythmias, increased secretion of gastric juice, ulcers, pheochromocytoma, progressive nanolearning paralysis, drug dependency and previsani (for example, nicotine addiction or habituation to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbiturates, opioids or cocaine), headache, migraine, stroke, traumatic brain injury (TBI), obsessive-compulsive condition (OCD), psychosis, horii's chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, dementia caused by repeated heart attacks, reduced cognitive ability, age, epilepsy, including status epilepticus, senile dementia type Alzheimer's disease (AD), Parkinson's disease (PD), increased activity due to lack of attention (ADHD), and Tourette syndrome.

Compound 1 and its pharmaceutically acceptable additive salts with an acid are described in the international application on p the tent WO 99/35131, published July 15, 1999, which is incorporated in its entirety in the present description by reference.

Since the dosage forms of the above compounds immediate release (IR), i.e. the dosage form, intended to ensure the availability of the drug in dissolved form ingestion within about 30 minutes, provide therapeutically useful levels of drug substances in the blood and brain, it has been observed that patients often suffer from nausea, especially at high enough doses that are therapeutically necessary for some patients. Because nausea can cause regimens for patients medicines, there is a need to obtain compound 1 in the form of reducing the frequency of occurrence of nausea.

Accordingly, the present invention relates to dosage forms of compound 1 CR that reduce or eliminate nausea while maintaining therapeutic drug levels in the blood and the Central nervous system (CNS). Although in this area there are examples suggesting that CR dosage forms may in some cases to provide a means of reducing such side effects as nausea (for example, oxycodone (J.R.Caldwell et al., J. of Rheumatology 1999, 26, 862-869), venlafaxine (REntsuah and R.Chitra, Psychopharmacology Bulletin, 1997, 33, 671-676) and paroxetine (R.N.Golden et al., J. Clin. Psychiatry, 2002, 63, 577-584), there are also opposite examples, which show that CR dosage forms sometimes reduce nausea no better than the dosage form immediate release, and therefore they are not indicated on the usefulness of the dosage form CR as a means of reducing side effects. Opposite examples include the use of martinslife (T.D.Walsh et al., J. Clin. Oncology, 1992, 15, 268-272), hydromorphone (H. Hays et al., Cancer, 1994, 74, 1808-1816), tartrate of Dihydrocodeine (G. Xu et al., Zhongguo Yaowu Yilaixing Zazhi, 1999, 8, 52-57) and carbidopa/levodopa (G. Block et al., European Neurology, 1997, 37, 23-27). In addition, in many cases, the dosage form CR cause a reduction in bioavailability compared with IR dosage forms, which entails an increase in the dose or even makes use of the dosage form CR impossible. Consequently, it is impossible to predict a priori what drugs cause nausea, are actually beneficial when used in the form of dosage forms CR. In addition, the rate at which the drug becomes available, that is, the rate of dissolution can vary considerably from slightly lower than the rate of the dosage form IR, to delivery over an extended period BP is the seed (approximately 24 hours). The authors found that the dosage form of compound 1 CR with a certain speed range of drug delivery will provide therapeutic levels of drug substances in the blood and the Central nervous system while simultaneously reducing the frequency of occurrence of nausea compared with the IR dosage form. The authors also found a specific preferred ways of formulating the compounds 1 to achieve the required speed of the injection medicines. The authors also found preferable schemes medicines that provide therapeutic levels of drug substances, while maintaining low levels of probability of occurrence of nausea.

High efficiency compound 1 as a ligand nicotinic receptor provides the possibility of using low doses for injection. To facilitate manipulation, manufacturing and facilities for patient's medicines with a low dose of the active substance often get with a substantial dilution of the excipients. However, during preparation and storage of such diluted drugs can have unwanted processes. First, high dilution can enable excipients or even contained in excipient impurities to cause significant decomposition lekarstvennoj the substance during storage. Examples of properties excipient, which may affect the decomposition of medicinal substances include moisture content and mobility of moisture (see J.T.Carstensen, Drug Stability: Principles and Practices, 2ndEd. Marcel Dekker, NY, 1995, 449-452) and acidity excipient adverse effect on the pH of the local microcred (see K.Waterman et al., Pharm. Dev. Tech., 2002, 7 (2), 113-146). Examples of the excipients contained in the impurities that affect the decomposition of medicines include trace amounts of metals, peroxides and formic acid (see K.Waterman et al., Pharm. Dev. Tech., 2002, 7 (1), 1-32). Although the interpretation of the possible ways of decomposition are taken into account in chemical structure and identification of chemically active groups, predict a priori whether a particular excipient form acceptable stable medication with this drug substance is impossible. In addition, it was observed that compound 1 interacts with many conventional excipients and excipients contained in the impurities. Therefore, there remains a need in finding excipient and combinations of excipients that can provide acceptable compositions (for properties such as the ability to form tablets) while ensuring appropriate stability 1. The authors also found a specific preferred ways of formulating compounds the Oia 1 to achieve the required stability. More specifically, the authors found the specific formulations and techniques to achieve the required stability of the film-coated tablets.

The second subject for discussion, sometimes discussed in relation to effective drugs obtained at high dilution, includes the variability in effectiveness due to segregation and sticking to the equipment during production. It was found that this phenomenon is also a problem of getting drugs on the basis of the connection 1. One method of achieving uniform distribution of medicinal substance in a mixture containing a low dose of medicinal substance reported recently, involves the use of excipient carrier (lactose) to form an ordered mixture containing micronized drug substance (L. Wu et al., AAPS PharmSciTech, 2000, 1 (3), article 26). Although it is possible to effectively carry out the stage of manual cleaning brush to extract the active ingredient, segregated by fluidization or adhering to metal surfaces in small-scale equipment, stage manual cleaning is both inefficient and undesirable in the environment of the production scale. The processes carried out in a liquid medium, can minimize the loss of medicinal substances during production ready is karstenii form; however, compounds that undergo a change of form (for example, due to the formation of polymorph, hydrate or solvate form), significantly complicate the processes in the liquid medium while maintaining the stability of drug substances (chemical and physical). Although to solve these common problems have been used many methods, the prediction of what specific methods will be effective for the selection of drug substances and excipients, remains impossible. Therefore, due to the high dilution required for connection 1, there remains a need for a method suitable for the commercialization of compounds 1, through which can be saved adequate uniformity effectiveness from the dosage form (e.g. tablets) dosage form and from batch to batch. The authors also found the preferred methods of obtaining drugs, compounds 1 to achieve the required uniform of the efficacy of medicinal substances and homogeneous distribution of the drug substance.

The invention

The present invention relates to certain dosage forms of a pharmaceutical product on the basis of compound 1 or its pharmaceutically acceptable salts controlled release (CR) for oral administration to a needy patient p and this dosage form CR contains the specified compound or its pharmaceutically acceptable salt and a means for delivery of the compound or its pharmaceutically acceptable salt to a specified patient with a speed less than approximately 6 mga/HR (where MHA refers to the milligrams of active drug in the calculation of the free base), resulting in the introduction of at least about 0.1 mga compound or its pharmaceutically acceptable salt for 24 hours. For some patients it may be beneficial introduction disclosed in this description of the dosage form immediate release (IR)containing the compound or its pharmaceutically acceptable salt, after administration of the dosage form CR consecutive doses.

The present invention particularly relates to methods of treatment using CR dosage forms of a pharmaceutical product on the basis of compound 1, which leads to reduction of nausea, manifested as undesirable actions of the drug. Such dosage forms of CR are characterized by receipt of medical substances in the gastro-intestinal tract (GIT) in dissolved form with a speed in the range from about 0.03 mga/HR to about 6 mga/HR, more preferably from about 0.06 mga/HR to about 3 mga/HR, and most preferably from about 0.10 mga/HR to about 1 mga/HR. The present invention also relates to medicinal forms of CR, which ensure the achievement of reducing the proportion of the drug concentration (Cmax) in the blood at first the second dose the patient on the value of from 10 to 80% of the average maxrelative to the initial introduction of the dosage form immediate release; more preferably in an amount of from 30 to 70%. The present invention also provides dosage forms that provide an increase in the time required to achieve the specified maximum concentration level in the blood TmaxIn particular, it was found that the increase in the average Tmax50% compared with the average obtained for boles immediate release, reduces nausea. The present invention also features pharmaceutical form, by means of which the rate of release of compound 1, as determined by the method of dissolving type II Pharmacopoeia of the United States, less than 6 mga/HR, and the time of dissolution to 50 wt./wt.% specified medicinal substance is in the range from 1 to 15 hours, more preferably in the range of from 2 to 10 hours.

The present invention also relates to pharmaceutical compositions that are designed to achieve the specified speed of drug delivery. The present invention particularly relates to dosage forms of compound 1, which include such means of delivery as hydrophilic matrices, hydrophobic matrix tablets CR coated and multicystic, transbukkalno system, percutaneous system is neither, suppositories and depot. From tablets coated in a particularly preferred dosage form is obtained asymmetric membrane technology which is disclosed in U.S. patent No. 5612059 and 5698220, the contents of which are included in this description as a reference).

The present invention also features such dosage form controlled release, which is a form with a combination of delayed and prolonged release showing the slowdown to 8 hours before prolonged release of which pentaen is released with a speed of no more than about 0.1 mga/HR during the period of deceleration and where the slowdown is regulated in time or space position in the gastrointestinal tract.

The present invention is providing reduce nausea in the case where the compound 1 is administered to patients starting treatment with the introduction of the dosage form CR, and then carrying out the treatment using IR dosage forms.

Used in this description, the term "controlled release" (CR) refers to dosage forms that slowly release the drug substance or deliver a drug to a patient with such speed, that at least the art of medicinal substances was not available in the first hour. The CR system can release the drug at a constant speed (zero order), with a uniform reduction rate (first order) or even with irregular or pulsating speed. Delivery of medicinal substance may also include latent period in the initial release of drug substance. The latent period may be temporary or may depend on the provisions of the drug in the patient's body. For example, the dosage form CR can be obtained using Intercollege coverage, with the medicinal substance is released from it upon reaching the pH of the intestine after oral administration.

Suitable dosage form of compound 1 CR can be identified in the present invention one or two of the following methods.

(1) the First method involves determining the conduct of drug substance in the dosage form by sampling and analysis of blood after the initial introduction of the drug (creation pharmacokinetic profile). The initial introduction is to put the patient to a medicinal product or for the first time, or at least four days after the previous introduction of any form of compound 1. It was found that of particular importance to reduce nausea when using the connection 1 has a maximum connection level 1 in the blood, made after the initial introduction of the drug (Cmax), and the time required to achieve the maximum (Tmax). In the measurement Withmaxand Tmaxspecialists in this field was recognized the existence of significant variability depending on doses and patients. To achieve adequate comparison Withmaxand Tmaxand, consequently, to determine whether this dosage form to achieve the desired reduction of nausea, it is necessary to measure these parameters for at least 10 patients in the experiment carried out double-blind (i.e., each patient receives both dosage forms IR and CR), for at least 7 days between experimental latent periods. In particular, it was found that to decrease nausea is required, the average reduction With initialmaxto achieve value from 10 to 80% of the values achieved with an average initial administration of the dosage form IR; more preferably to achieve value from 30 to 70%. As for Tmaxthe increase in the average initial Tmaxfor CR dosage forms in comparison with the IR dosage form should be at least 50% (i.e. the number of hours for the average dose of the drug is the result of the form CR, compared with an average dose of the dosage form IR 1.5 times more).

(2) the Second method of analysis of the dosage form CR to determine whether there will be a reduction in nausea, comprises a test in vitro. The authors found that the construction of the graphical dependence of the percentage of dissolved compounds 1 from the time it is best to use to determine the time required for dissolution of 50% of the drug substance. The data required to build the specified graphics dependence is obtained using a standard device for dissolving type II (50 rpm, 500 ml of 0.01 N. hydrochloric acid, 37° (C)used in the USP (United States Pharmacopeia), such as the device Hanson model SR8. Analysis of samples carried out using HPLC with reversed phase. It was found that nausea is decreased when the dosage form shows the dissolution of 50 wt./wt.% of the total dose over time from about 1 to about 15 hours, more preferably for a time from 2 to 10 hours.

Accordingly, the present invention additionally relates to dosage forms for immediate release, suitable for administration to a patient, which are resistant dosage forms with a uniform distribution of the drug substance and effectiveness, including a core containing the compound of formula 1 or its pharmaceutically acceptable salt, and f is rmaceuticals acceptable diluent, essentially containing no reducing carbohydrate. The invention particularly relates to such a dosage form immediate release, where IR dosage form contains L-tartrate or citrate salt of 5,8,14-triazinetrione[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaen.

Used in this description, the expression "essentially containing no reducing carbohydrate" means the reducing sugar content of less than about 20 wt./wt.% (including, but without limitation, lactose). The dosage form obtained in accordance with the present invention, preferably will contain less than 10 wt./wt.% reducing sugar and more preferably less than 5 wt./wt.%.

Dosage form immediate release according to the invention may further comprise means for sliding the tool promoting raspadaemosti dosage form, and/or grease. The present invention also relates to a method of obtaining the above dosage forms for immediate release.

Dosage form immediate release according to the invention may additionally include film coating. The present invention also relates to a method of obtaining the above dosage forms for immediate release coated film.

This izopet the tion also relates to the composition, suitable for coating film dosage forms of compound 1 immediate-release, in which the polymeric binder for such coating consists essentially of a polymer of cellulose. Particularly preferred polymer cellulose is a hypromellose (receiver array). The said coating further comprises a muffler (especially titanium dioxide), a plasticizer and/or a means for slide, all of which contain less than about 20 wt./wt.% reducing carbohydrates. Particularly preferred compositions for coatings contain a receiver array, titanium dioxide and triacetin or PEG (PEG).

The present invention also relates to methods that provide high efficiency and uniformity of the content of the above mixtures. Such methods include a method of geometric dilution of drug substances excipients prior to the implementation of tableting. Such methods also include the use of mixing components a moderate shift efforts. In a preferred method of mixing is used "bunker mixer", however, also applicable to other mixers that give such shifts.

Disclosed methods of treatment using the pharmaceutical dosage forms of the drug on the basis of the connection 1 CR, which leads to reduction of nausea, have the suwasa as a unwanted drug action, characterized by the provision of medicinal substances in the gastrointestinal tract (GIT) in dissolved form with a speed in the range from about 0.03 mga/HR to about 8 mga/HR, more preferably from about 0.06 mga/HR to about 3 mga/HR, and most preferably from 0.10 mga/HR to about 1 mga/HR.

The present invention particularly relates to a method for reducing the addiction to nicotine or encourage cessation or reduction of its use by a patient, comprising the administration to a patient of a certain amount or dosage forms of compound 1 of supervised release, or dosage forms of compound 1 for immediate release, which is effective for reducing the addiction to nicotine or to facilitate the cessation or reduction of its use. The invention particularly relates to such method, in which dosage form CR or IR or contains L-tartrate, or citrate salt of 5,8,14-triazinetrione[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaen.

The present invention also relates to a method of treatment of a disorder or condition selected from inflammatory bowel disease, ulcerative colitis, pyoderma pyodermia, Crohn's disease, irritable bowel syndrome, spastic di is tonii, chronic pain, acute pain, abdominal sprue, pouchitis, narrowing of the blood vessels, anxiety, panic, depression, bipolar disorder, autism, sleep disorders, disorders of the normal circadian rhythm, manifested by fatigue, amyotrophic lateral sclerosis (ALS), disorders of cognitive abilities, hypertension, bulimia, anorexia, obesity, cardiac arrhythmias, increased secretion of gastric juice, ulcers, pheochromocytoma, progressive nanolearning paralysis, drug dependency and previsani; nicotine dependence or addiction to nicotine, tobacco products, alcohol, benzodiazepines, barbiturates, opioids or cocaine; head pain, stroke, traumatic brain injury, obsessive-compulsive condition (OCD), psychosis, horii's chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, dementia caused by repeated heart attacks, reduced cognitive ability, age, epilepsy, including status epilepticus, senile dementia type Alzheimer's disease (AD), Parkinson's disease (PD), increased activity due to lack of attention (ADHD), and Tourette's syndrome, comprising the administration to the patient of an amount or dosage forms of compound 1 of supervised release or dosage forms soy is inania 1 for immediate release which is effective in treating such disorder or condition. The invention particularly relates to such method, in which dosage form CR or IR or contains L-tartrate, or citrate salt of 5,8,14-triazinetrione[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaen.

The present invention also relates to pharmaceutical compositions that are designed to achieve these speeds the introduction. The present invention particularly relates to dosage forms of compound 1, which include administration, as hydrophilic matrices, hydrophobic matrix, osmotic systems, multicystic, dosage form controlled release, having a permeable coating, suppositories, transbukkalno system, percutaneous systems and implantable systems. From osmotic systems particularly preferred dosage form is obtained asymmetric membrane technology which is disclosed in U.S. patent No. 5612059 and 5698220, the contents of which are included in this description as a reference).

The present invention also relates to methods of introducing drugs that reduce nausea, which is manifested as undesirable actions, when compound 1 is administered to patients starting treatment with an introd the drug form CR and then carrying out the treatment using IR dosage forms.

Used in this description, the expression dosage form "instant release" (IR) refers to a dosage form that when administered orally provides essentially the medicinal substance in the form available for absorption, for about one hour.

The expression "matrix" system refers to a special dosage form CR, in which the medicinal substance is mixed with excipients, often molded or extruded form, so that the release of drug substance from the dosage form was regulated by a combination of erosion and diffusion. Erosion control of drug delivery involves the slow removal of the matrix material liquid blood for gradual exposure and releasing the drug from the matrix. Diffusion control of drug delivery involves the diffusion of soluble medicinal substance through a grid matrix of excipients regulated by. In practice, many of the matrix dosage form include, to some extent, the combination of two mechanisms.

"Hydrophilic matrix" is a matrix CR dosage forms in which water-soluble or vodosnabzhenie polymers form a grid containing the medicinal substance. The speed with which the drug diffuses the surface of the dosage form, and the speed with which the matrix is removed, adjust the speed, which makes the drug available to the digestive system.

"Hydrophobic matrix" is a matrix CR dosage forms in which water-soluble or partially water-soluble materials slow down the rate at which the drug is exposed to a fluid environment of the digestive system, due to which it becomes possible to regulate the rate of absorption of drug substances.

"Permeable coating system CR refers to different coatings on tablets or particles, which act as barriers for drug substances released from the tablets, or water, reaching medicinal substance. Such coatings include intersolubility coatings which are permeable, as the pH is increased when the dosage form enters the stomach. Examples of such coatings include Eudragits™manufactured by Rohm Pharma GmbH Polymers (Darmstadt, Germany), and acid phthalate cellulose acetate (CAP)manufactured by Eastman Chemical (Kingsport, TN). One group of such coatings systems CR osmotic system. Such dosage forms include CR semipermeable membrane surrounding the core medicinal substances that have an osmotic pressure sufficient to propel the water through the membrane in which the system of the digestive tract. The osmotic pressure can then push the medicinal substance from the core through pre-formed or formed in situ holes or pores in the coating. Such systems often include adding means (osmotic funds)designed to increase the osmotic pressure in the core. An overview describing these systems are found in G.Santus and R.W.Baker, J. Control. Rel., 1995, 35, 1-21.

"Asymmetric membrane technology" AMT describes specific osmotic system CR, where the porous coating is performed by the phase separation process during the operation of the coating, as described in U.S. patent No. 5612059 and 5698220, the contents of which are included in this description as a reference.

"Percutaneous delivery system" is a device for delivering medicines for system security medicinal substance to the patient through the skin. Such systems typically include a layer of material containing the medicinal substance in the lining with adhesive designed to attach material to the patient's skin.

"Transbukkalno delivery system" are dosage forms that provide a suction process of drug substances through the buccal tissue (the inner surface of the cheeks).

"Depot" is a medicinal fo the mu medicinal substance controlled release, while the medicinal substance and the appropriate excipients injected or subcutaneously, or intramuscularly, and thus form a mass (matrix), which provides a slow intake of drug in the systemic circulation.

The medicinal substance 1 for the purposes of the present invention relates to the original medicinal substance and all of its pharmaceutically acceptable salts and prodrugs.

The term "mga" refers to the number of milligrams of active drug in the calculation of the free basic form of the medicinal substance.

The expression "pharmaceutically acceptable" indicates that the substance or composition must be chemically, physically and/or toxicologically compatible with the other ingredients that make up the drug, and/or the treated mammal.

The term "active ingredient" refers to a therapeutically active compound, and any prodrugs, and pharmaceutically acceptable salts, hydrate and solvate compounds and prodrugs.

The expression "the relevant time" or "suitable period of time" refers to the period of time necessary to achieve the desired effect or result. For example, the mixture can be mixed to achieve an efficient allocation, which is acceptable to the local range for a given application or use mixed mixture.

Used in this description, the term "standard dose" or "standard dosage" refers to physically discrete unit that contains a specified quantity of active ingredient calculated to obtain the desired therapeutic effect. The standard dose or standard dose may be in the form of tablets, capsules, sachets, etc. that in this description referred to "the standard dosage form".

Detailed description of the invention

Methods for obtaining compounds 1 are described in U.S. patent No. 6410550, the contents of which are included in this description as a reference, and the splitting of racemic mixtures is described in WO 01/62736. In accordance with the present invention the pharmaceutical compositions of compound 1 CR may be, if necessary, introduced by doses in the range of from about 0.1 to about 6 MHA per day, more preferably from about 0.5 to 4 mga / day and most preferably from about 1 to 4 MHA day in a single dose or fractional doses, although depending on the body weight of the patient and his condition is inevitable deviations from the indicated doses. Depending on the individual reactions may be more adequate doses that are less than the lower limit of the above range, whereas in other cases, there may be used a higher dose levels not causing harmful n the adverse action.

Although the present invention can be used in any pharmaceutically acceptable form of compound 1, it is preferable to use a salt form of a drug substance. Particularly preferred salt form of a drug substance is L-tartrate salt.

To combat nausea using dosage forms of compound 1 CR rate of release of the drug substance should be such that the medicinal substance was desirables in the digestive system in the form available for absorption at a rate considerably slower than the rate of absorption IR dosage forms. When used in clinical trials of fractional doses of IR was found that if the drug substance is released with a speed corresponding approximately 12 mga/HR (total dose 3 MHA), the frequency of nausea in subjects patients exceeded 50%. Conversely, when the speed of dosing, corresponding to about 8 MHA/hour (total dose 2 MHA) is the frequency of occurrence of nausea fell to a value of about 13%. Therefore, the upper limit of the speed of introduction of the drug, needed to reduce nausea when using the dosage form CR is 8 mga/HR. Whereas the present invention can be predicted that when using a slower speed visual the statement of the medicinal product will be achieved even greater decrease nausea. It is expected that CR dosage forms for oral administration can usually be approximately no more than 18 hours of absorption of drug substances, depending on the mobility of the dosage form in the patient's body. Based on the levels of drug substances in the blood of the patient is necessary for its effectiveness, it is expected that the required total dose of medicinal substance is from about 0.5 to 6 MHA in the day. With this in mind, the lower limit of the speed of introduction of the drug is approximately 0.03 mga/HR. Although these limits will undoubtedly provide the benefits specified in the present invention, the authors found that to achieve the required therapeutic levels of drug substance in blood of a patient while maintaining a reducing nausea, drug is introduced at a rate from about 0.06 to 3 mga/HR, and more preferably from 0.1 to 1 mga/HR.

To achieve the required rate of administration of the medicinal product was found several tools that provide such a system CR. One such tool is the matrix. In accordance with the present invention can be, in particular, received the tablets of compound 1 with the matrix or multicystic connection 1 with the matrix. In the case of multicystic final dosage form m which may be particles in the capsule or sachet, or other such form. These matrix dosage forms can be formed using conventional techniques such as extrusion using tabletiruemogo press, or by processes such as extrusion or solidification of the melt. For compound 1 are suitable two types of matrix dosage forms: hydrophilic and hydrophobic. Hydrophilic matrix of the matrix composition generally consists of mixtures of water-soluble polymers with high and low molecular weight. These matrix materials in particular consist of combinations of hydroxypropylmethylcellulose (receiver array), polyethylene oxide (REO), hydroxypropylcellulose (LDCs), polyacrylates, alginate, xanthan resins and other polymers with different molecular weights. Particularly preferred polymers include a receiver array and REO. Particularly preferred composition consists of a mixture of a receiver array, manufactured under the trade name Methocel™ CM (Dow Corp., Midland, MI), and secondary acidic calcium phosphate, sold under the trade name D-tab™ (Rhodia Inc., Cranbury, NJ). Hydrophobic matrix preparations of compound 1 can be obtained with the use of hydrophobic materials, inhibiting, respectively, the speed with which the water comes into contact with the connection 1. Particularly preferred hydrophobic material is include Carnauba wax, glycerinated and stearic acid. However, experts in this field it is clear that other waxy materials will function equivalently.

Required level speed of release of compound 1 can also provide an osmotic dosage form. Examples of such dosage forms are described in G.Santus and R.W.Baker, J. Control. Rel., 1995, 35, 1-21 included in this description by reference. Particularly preferred osmotic dosage form of compound 1 is in the form of a system obtained AMT, which is described, for example, in U.S. patent No. 5612059 and 5698220 (see, for example, S.M.Herbig, J. Control. Rel., 1995, 35, 127-136). Such systems provide high control releasing the drug in the gastrointestinal system. The authors also found that the preferred drugs consist of a core comprising L-tartrate salt drug substances, mannitol, microcrystalline cellulose, secondary acidic calcium phosphate and magnesium stearate. Such a core can be obtained by direct compression, wet granulation (wet granulator with high or low shift effort or granulator, fluidized bed), the granulation by extrusion, rotary granulation or compaction using rollers. Compaction using rollers is particularly pre is respectful due to its ability to prevent segregation of medicinal substance, while maintaining the stability of the drug substance (unlike aqueous wet granulation, which can lead to the formation of hydrate medicinal substances). Tablets can be obtained on the standard tabletiruemyh presses (rotary). Core tablets then cover using a machine with a bowl to coat. The coating preferably consists of a mixture of cellulose acetate (CA) and polyethylene glycol (PEG), applied from acetone and water. The ratio of the components is chosen so that the combination of CA/PEG gave a porous, semi-permeable coating, which introduces the medicinal substance through pores in the digestive tract with the required speed. Most preferably the ratio of SA to PEG is chosen so that the PEG was in the same phase with SA because it was found that PEG in a separate phase, leads to the decomposition of the drug in the final dosage form at elevated temperatures. For the purpose of the present invention, the compatibility of the phases can be determined using standard differential scanning calorimeter when the desired ratio of SA to PEG in the mixture. No transition of the melt PEG at a temperature of between 30 and 50°With an indicator single phase and, hence, an indication that this attitude will give your preferred film. Therefore, it is most preferable that the ratio of CA/PEG remained above about 4./p>

The CR system for refererlog introduction can also provide reduction of nausea while maintaining efficiency with the introduction of compound 1. Such systems include suppositories, percutaneous systems, transbukkalno system, depot and implantable devices. For the operation to reduce nausea such devices should provide controlled release, as described above. Particularly preferred dosage form for refererlog introduction is percutaneous dosage form.

When using all dosage forms CR drug substance is preferably delivered at a speed ranging from about 0.06 to 3 mga/HR, and more preferably from 0.1 to 1 mga/HR. Suitability for the present invention can be determined by testing or in vivo, or in vitro. Particularly preferably, the average initialmaxdecreased to reach the value of 10 to 80% from smaxachieved with an average initial administration of the dosage form IR, more preferably to reach the value of 30 to 70%. As for Tmaxthe increase in the average initial Tmaxfor dosage forms CR compared to the average initial Tmaxfor IR dosage forms should preferably be on m is Nisha least 50%. Preferred dosage forms according to the invention provides in a solution of 50 wt./wt.% total dose over time from about 1 to 15 hours, more preferably for a time from 2 to 10 hours.

The CR system according to the invention may include a delay period or the latent period between dose and period of availability of medicinal substance for absorption. Such delays can be temporary or can depend on the position of the drug in the gastrointestinal tract. These systems will be effective for the purposes of the present invention, provided that since the beginning of the suction medicinal substances speed falls within a specified range. Particularly preferred system delayed actions are tablets or multicystic covered intersolubility coating. The preferred system intersolubility coating, disintegrating in the intestine, can be obtained by coating tablets or multicystic materials such as phthalate cellulose acetate, or intersolubility polyacrylic compounds, such that available under the trademark Eudragit (Rohm Pharmaceuticals).

Formulations suitable for the present invention can be obtained using a wide range of materials and methods known in annoyable. However, the authors found that the presence of reducing carbohydrates is unfavorable for the stability of the drug during storage. Particularly preferred preparations CR containing less than 20 wt./wt.% reducing carbohydrates, more preferred are CR drugs, containing less than 10 wt./wt.% reducing carbohydrates, and the most preferred drugs CR containing less than 5 wt./wt.% reducing carbohydrates. Special reducing sugar, which preferably should be avoided, is the lactose.

For the preparation of dosage forms for controlled release and immediate release of the active ingredient can be used as such or in the form of its pharmaceutically acceptable salts, MES and/or hydrate. The active ingredient can be used as such or in the form of its pharmaceutically acceptable salts, MES and/or hydrate. The term "pharmaceutically acceptable salt" refers to non-toxic additive to the acid salts derived from inorganic and organic acids. Suitable salt derivatives include halides, thiocyanates, sulphates, bisulfate, sulfites, bisulfite, arylsulfonate, alkyl sulphates, phosphonates, secondary acid phosphate, monopotassium phosphate, metaphosphate, pyrophosphate, alkanoate cycloalkylcarbonyl, arylalkenes, adipate, alginates, aspartate, benzoate, fumarate, glucoheptonate, glycerophosphate, lactates, maleate, nicotinate, oxalates, palmitate, pectinate, picrate, pivalate, succinate, tartratami, citrates, camphorate, camphorsulfonate, digluconate, triptoreline and similar salts.

The final pharmaceutical composition is processed in a standard dosage form (e.g. tablet, capsule or sachet) and then packaged for sale. Stage of processing depends on the specific standard dosage forms. For example, the pill usually pressed under pressure to give it the required shape and to obtain a capsule or sachet use the normal filling operation. Professionals in this field are familiar techniques used to manufacture a variety of standard dosage forms.

The active mixture dosage form immediate release typically includes one or more pharmaceutically acceptable excipients, carriers or diluents. The specific choice of carrier, diluent or excipient to use will depend upon the means and purpose for which the applied active ingredient. Usually preformed drug immediate release includes tools such as diluents, binders, lubricants, means for sliding means is a, contributing raspadaemosti dosage forms, and mixtures thereof. Although specialists in this field there are many such excipients, the authors found that only a subset of these substances provides the most stable structures. The authors in particular have found that the preferred compositions contain less than about 20 wt./wt.% reducing carbohydrates. Reducing carbohydrates are sugars and their derivatives, which contain a free aldehyde or ketone group capable of interacting as a reductant through the transfer of electrons. Examples of reducing carbohydrates include the monosaccharides and disaccharides, and more specifically, include lactose, glucose, fructose, maltose and other sugars. The authors also found that compositions containing secondary acidic calcium phosphate, are particularly stable. More specifically, a stable composition is obtained using more than about 20 wt./wt.% secondary acidic calcium phosphate. Other acceptable excipients include starch, mannitol, kaolin, calcium sulfate, inorganic salts (e.g. sodium chloride), powdered cellulose derivatives, calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, poloxamer, such as polyethylene oxide and hydroxypropyl icellulse. To ensure uniformity of content of the mixture particularly preferably used particles of drug substance with an average volume diameter less than or equal to 30 microns. Preferred diluents are microcrystalline cellulose (such as Avicel® PH200, PH102 or PH101, FMC Pharmaceutical, Philadelphia, PA) and secondary acidic calcium phosphate or dicalcium phosphate (e.g., A-Tab®, Rhodia, Chicago Heights, IL). The average particle size of the microcrystalline cellulose is typically in the range from about 90 μm to about 200 μm. Suitable varieties secondary acidic calcium phosphate include anhydrous (average particle size from 135 to 180 μm, PenWest Pharmaceuticals Co., Patterson, NY, or Rhodia, Cranbury, NJ) and dihydrate (particle size of about 180 microns, PenWest Pharmaceuticals Co., Patterson, NY, or Rhodia, Cranbury, NJ). Typically, the microcrystalline cellulose is present in an amount of from about 10 wt.% to about 70 wt.% and secondary acidic calcium phosphate is present in amount from about 10 wt.% to about 50 wt.%, more preferably microcrystalline cellulose is present in an amount of about 30-70 wt.% and secondary acidic calcium phosphate is present in an amount of about 20-40 wt.%.

If necessary can be added binder. Suitable binders include such substances as cellulose (e.g., cellulose, methylcellulose, ethylcellulose, hydroxypropylcellulose the memory and hydroxymethylcellulose), polipropilenglicol, polyvinylpyrrolidone, gelatin, gum Arabic, polyethylene glycol, starch, natural and synthetic gums (such as acacia, alginates and gum Arabic) and waxes.

To prevent sticking of tablets and punches in the stamp teletrauma machine in the composition for the manufacture of tablets typically use a lubricating substance. Suitable lubricants include calcium stearate, glycerylmonostearate, glycerylmonostearate, gidrirovannoe vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium fumarate, stearic acid, talc and zinc stearate. Preferred lubricating substance is a stearate. Magnesium stearate is typically present in an amount of from about 0.25 wt.% to about 4.0 wt.%.

For disintegration of the dosage form and release of the active compound to the composition can be added to contribute raspadaemosti dosage forms. Suitable means contributing raspadaemosti dosage forms include sodium glycolate starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, nitrocresols, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, poroscopy the bacterial cellulose, lower-alkyl-substituted hydroxypropylcellulose, calibration, starch, pre-gelatinising starch and sodium alginate. Of these funds are preferred nitrocresols and sodium glycolate starch, the most preferred is nitrocresols. Nitrocresols usually present in amount from about 0.5 wt.% to about 6 wt.%. A number of tools to help raspadaemosti included in the dosage form, depends on several factors, including dispersion properties, the properties of the pore-forming (discussed below) and the properties of the selected tools to help raspadaemosti dosage forms. Usually a means of facilitating raspadaemosti dosage form ranges from 1 to 15 wt.%, preferably from 1 to 10 wt.% by weight of the dosage form.

Examples of means for sliding include silicon dioxide, talc and corn starch.

Film coating on the dosage form immediate action can provide ease of ingestion, reducing unpleasant taste or odor during injection, high photochemical stability during use of the muffler, great elegance, reduced friction during high speed packaging or it can serve as a barrier between overestimate substances (G.Cole, J.Hogan and M.Aulton, Pharmaceutical Coating Technology, Taylor and Francis Ltd, Ch.1, 1995). The authors found that when using a coverage that contains most of the polymers cellulose, provide high chemical stability of the drug. Derivatives of cellulose are polymers derived from cellulose. Examples of polymers include such compounds cellulose, as hypromellose, hydroxypropylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, methyl cellulose and sodium carboxymethyl cellulose. The preferred polymer is hypromellose. Coatings according to the invention include a polymer, a muffler, a plasticizer, a pharmaceutically acceptable diluent/filler, and optionally a colorant. The muffler is excipients, helping to reduce light transmission through the coating to the core tablet. Examples of silencers include titanium dioxide and talc. The preferred muffler is titanium dioxide. A plasticizer is a material that lowers the glass transition temperature of the polymer, resulting in generally improved physical properties. Examples of plasticizers include polyhydric alcohols such as glycerol and glycols, and esters of acetic acid such as glyceryltrinitrate (triacetin) and triethylcitrate. Compositions solenoidality optionally may include a dye. Such dyes are available from a number of suppliers and well-known specialists in this field. Particularly preferred coating formulations contain a receiver array, triacetin and titanium dioxide or a receiver array, PEG and titanium dioxide.

To achieve uniform distribution of medicinal substance in the mixture before manufacture of tablets or capsules invented two ways. The first method uses a geometric dilution. In this way prepare a pre-mixture of a drug and part of excipients and the mixture is then further diluted with the remaining excipients during 2-5 additional stages. At the first stage of dilution of the medicinal substance is mixed with 10-30 wt.% excipient(s). In the second stage of dilution of the first pre-prepared mixture is further diluted with 10-40 wt.% excipient(s). On the third to fifth stages of dilution of the mixture obtained after the second stage of dilution, further diluted with 10-75 wt.% excipient(s) with the formation of the final mixture. The preferred dilution scheme includes the first dilution of the drug by the dicalcium phosphate with two increments and then combining it with the remaining mixture(s) excipient(s).

The second method of achieving uniform distribution of the drug substance consists of a mixture which their compositions at a certain level shifting efforts. The authors found that the required shear load is achieved with the use or hopper mixer, or a mixer with a high shear force, operating at low shear rate (less than 200 rpm). Typical mixing time for mixing in bunker mixer is from about 20 minutes to about 30 minutes. Although it may be used while stirring over 30 minutes, you should take care that the mixture is separated into its component parts. After the initial stage of mixing the active mixture may be sieved using a conical mill (Comil 197, Quadro Engineering Inc., Waterloo, Ontario, Canada)equipped with a sieve with a mesh size of 0.8 mm and Then to the active mixture grease and before the dry granulation is stirred for about 3 minutes in the mixer with dual stators "V" or in bunker mixer.

The above methods provide effective mixing and a more uniform distribution of the active ingredient without substantial decomposition of the active ingredient; however, the loss of the active ingredient, due to segregation or adhesion compounds to metal surfaces of equipment (such as screens and surfaces of containers)represents an additional obstacle, particularly for compositions containing a lower dose of active substances is (for example, less than 4 mg standard dose). The authors found a third way to achieve acceptable efficiency of the mixture, which includes the use of abrasive excipient, such as dicalcium phosphate. More specifically, the preferred composition contains 10-50 wt.% the dicalcium phosphate.

The pharmaceutical composition can be used to obtain a standard dosage forms containing from about 0.1 mg to about 10.0 mg of the active ingredient in a single dose, preferably from about 0.2 mg to about 5.0 mg of the active ingredient in a single dose. The weight of the tablet (i.e. the standard dosage forms) typically ranges from about 100 mg to 600 mg

Tablets usually get by pressing on the rotary press. However, the specific method used for forming tablets, is not restrictive and is well known to specialists in this field. After the formation of the tablets are often coated with one or more coatings. The tablet may be coated with the coating for taste masking, as a sealant and/or surface quality when printing of a logo or trademark on the surface of the tablet. Alternative tablet may be coated with film-forming and protective(s) agent(s) for modifying the solubility of the tablets. For example, a tablet may be coated with film-forming coating that p is patstat dissolution within a specified period of time, that leads to an anemic or prolonged release of the active ingredient. Suitable film-forming protective equipment include cellulose (e.g., hypromellose, hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone and copolymers of acrylate and methacrylate. Compositions for coating may also include additives such as plasticizers (e.g., polyethylene glycol or triacetin), preservatives, sweeteners, korrigentami taste, dyes and other known additives to provide elegance medicines. The preferred composition for the coating contains 40-70 wt.% polymer(s) of the cellulose. Aqueous coating of the dosage form immediate release according to the invention contains Opadry® (YS-1-18202-A) and Opadry Clear® (YS-2-19114-A)produced by the use, West Point, Pennsylvania. Opadry®applicable as an opaque coating contains hypromellose, titanium dioxide and polyethylene glycol or triacetin. Opadry Clear®applicable as polishing coating contains hypromellose and triacetin.

The authors also found that the preferred compositions consist of a core comprising L-tartrate salt drug substances, mannitol, microcrystalline cellulose, secondary acid phosphate ka is ice and magnesium stearate. More preferred compositions consist of a core comprising L-tartrate salt drug substances, microcrystalline cellulose, secondary acidic calcium phosphate and magnesium stearate. More preferred compositions consist of a core comprising L-tartrate salt drug substances, microcrystalline cellulose, secondary acidic calcium phosphate, nitrocresols, silicon dioxide and magnesium stearate. These core can be obtained by direct compression, wet granulation (wet granulator with high or low shift effort or granulator, fluidized bed), the granulation by extrusion, rotary granulation or compaction using rollers. Compaction using rollers is particularly preferred due to its ability to prevent segregation of medicinal substance, while maintaining the stability of the drug substance (unlike aqueous wet granulation, which can lead to the formation of hydrate medicinal substances). Tablets can be obtained on the standard tabletiruemyh presses (rotary). Core tablets are then coated using a machine with a bowl to coat. The preferred coating consists of a mixture of hydroxypropylmethyl is cellulose, titanium dioxide, polyethylene glycol or triacetin and optional dye.

Alternative active pharmaceutical mixture may be enclosed in hard shell capsules, which are referred to in this description of capsules filled with a mixture of dry (DFC). The capsules and method of their production is similar to the foregoing composition for the core tablet and the way it was received. Hard shell capsule may consist of gelatin and water or hydroxypropylmethylcellulose, the water and the gel (the gel-forming resin or carrageenan).

The pharmaceutical composition (or product) may be packaged in a variety of ways. Usually the product distribution of the dosage form includes a container that contains a pharmaceutical composition in an appropriate form. Suitable containers are well known to specialists in this field and include materials such as bottles (plastic and glass), Sasha, exhaust packing foil and the like. The container may also include structure to prevent inadvertent access to the contents of the package. In addition, the container usually has attached to it a label that describes the contents of the container and the appropriate warnings or instructions.

Pharmaceutical compositions containing specified in this opisaniemopyta 1, are applicable for the treatment or prevention, among other diseases, bowel disease (including, but not limited to ulcerative colitis, pyoderma pyodermia and Crohn's disease), irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, abdominal sprue, pouchitis, narrowing of the blood vessels, anxiety, panic, depression, bipolar disorder, autism, sleep disorders, disorders of the normal circadian rhythm, manifested by fatigue, amyotrophic lateral sclerosis (ALS), disorders of cognitive abilities, hypertension, bulimia, anorexia, obesity, cardiac arrhythmias, increased secretion of gastric juice, ulcers, pheochromocytoma, progressive nanolearning paralysis, drug dependency and previsani (for example, nicotine addiction or habituation to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbiturates, opioids or cocaine), headache, migraine, stroke, traumatic brain injury, obsessive-compulsive condition (OCD), psychosis, horii's chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, dementia caused by repeated heart attacks, reduced cognitive ability, age, epilepsy, including epilepsy status, with areskog dementia type Alzheimer's disease (AD), Parkinson's disease (PD), increased activity due to lack of attention (ADHD) and Tourette's syndrome.

Accordingly, pharmaceutical compositions containing compound 1, and methods for their preparation disclosed herein, can be used in the manufacture of a medicinal product for the above therapeutic applications.

Therapeutically effective amount is made of a medicinal product can be administered to the person in case of need of such treatment or prevention. Used in this description, the term "therapeutically effective amount" refers to the amount of the active ingredient, is able to inhibit or prevent various pathological conditions or their symptoms and complications. The terms "inhibit" or "inhibition" refers to the prevention, treatment, mitigation, intensity reduction, suspension, restriction, slowing or reversal of the progression of the disease or to reduce the severity of the pathological condition or symptom associated with the respective condition of the patient under treatment, or resulting from this condition. Pharmaceutical products as such can be used for conservative drug (acute or chronic) and/or preventive (pre aktivnogo) introduction accordingly. The dose, frequency of administration and duration of treatment depends on factors such as the origin and severity of the condition being treated, the age and General health of the host, and the tolerability of the owner of the active ingredient. The pharmaceutical composition or the medicinal drug can be prescribed as a single daily dose, multiple doses during the day or even weekly dose. Drug treatment may continue over time from 2-3 days to several weeks or more. Usually the drug is administered to the patient once or twice daily dose of from about 0.25 mg to about 10.0 mg, but the above dosage may be properly changed depending on the age, body weight, General condition of the patient and the type of injection drugs.

The following examples are provided for illustrative purposes and should not be construed as examples, the bounding volume of the present invention.

The following list of materials used in the examples can be obtained or purchased from the appropriate source.

Connection 1 (L-tartrate salt) can be obtained by the methods described in patent applications WO 9935131 A1 or WO 162736 A1 included in this description as a reference.

Microcrystalline cellulose (Avicel™ PH200)supplied by FMC Pharmaceutical (Philadelphia, PA).

the annite (granular 2080), supplied SPI Polyols, Inc. (New Castle, DE).

Secondary calcium phosphate anhydrous (A-tab™)supplied by Rhodia Inc. (Chicago Heights, IL).

Nitrocresols (Ac-Di-Sol™)supplied by FMC BioPolymer (Philadelphia, PA).

The sodium glycolate starch (Explotab™)supplied Penwest (Patterson, NJ).

The colloidal silicon dioxide (Cab-O-Sil™)supplied by Cabot Corporation (Boston, MA).

Selectiona microcrystalline cellulose (ProSolv™)supplied Penwest (Patterson, NJ).

Hydroxypropylcellulose (Klucel™)supplied by Hercules, Inc. (Hopewell, VA).

Lactose anhydrous, supplied by Quest International (Norwich, NY).

The stearate of animal or vegetable origin, supplied by Mallinckrodt (St. Louis, MO).

Film coating, Opadry™supplied (use, West Point, PA).

Cellulose acetate (398-10NF)supplied by Eastman Chemicals (Kingsport, TN).

Polyethylene glycol (PEG 3350), supplied by Union Carbide Corp. (subsidized Dow Chemical Co., Midland, MI).

The hypromellose (receiver array, CM, methocel™)supplied by Dow Chemical Co., Midland, MI.

Example 1

Getting the dosage form L-tartrate salt of compound 1 CR using AMT

Download 3 kg tableting granulometric composition was prepared as follows: 450 g of microcrystalline cellulose and 1602 g secondary acidic calcium phosphate was mixed in a V-mixer with a capacity of 8 quarts for 10 minutes. Half of the mixture was unloaded in poly is terenowy bag, leaving half the mixture in the mixer. In a glass vessel with a capacity of 1250 cm3added 450 g of mannitol and 10.3 g of the medicinal substance. The mixture was stirred using the turbula mixer™ (available from Geln Mills Inc., Clifton, NJ). The resulting mixture was added to the V-mixer containing the above materials. In a glass bottle was additionally added 450 g of mannitol and then within 5 minutes mixed in the turbula mixer for leaching from bottles of medicinal substance. The resulting mixture was also added in the V-mixer and the mixture was stirred for 20 minutes. The mixture, which was unloaded in a plastic bag, then added to the V-mixer and the mixture was stirred for another 20 minutes. Then in the V-mixer was added to 22.5 g (aliquot) of magnesium stearate and the mixture was stirred for 5 min. and the Mixture was condensed using a roll compactor TF-Mini (available from Vector Corp., Marion IA) with rollers DSP when the pressure rolls 30 kg/cm2the speed of rotation of the rolls to 4.0 rpm and the rotation speed of the screw of 15.6 rpm Educated ribbon was crushed using M5A mill (available from Fitzpatrick Corp., Elmhurst, IL) with Serkalem a sieve, Conidur with cell size 18 mesh, rotating at 300 rpm and Then the powder was again placed in a V-mixer, was added 15 g of magnesium stearate, and then was carried out by stirring for 5 minutes.

The grain is amerykaski the composition of the alloy preformed using tabletiruemogo press Kilian T100 (available from Kilian & Co. Inc., Horsham, PA) with a cutting tool SRC 9/32 inch (11 mm), were obtained tablets weighing 250 mg (0.5 MHA). Used pre-compressive force 2,8 kN main compression force of 8 kN by passing through the rolls with a speed of 74 rpm, the rotation speed of the blade 20 rpm the resulting tablets showed a hardness of 7-9 KP, this fragility was immeasurable.

Tablets were coated with cooking first solution for coating, consisting of 538 g of cellulose acetate and 134,5 g PEG in 4506 g of acetone and 1547 water. The coating was performed using Hicoater HCT-30EX (available from Vector Corp., Marion, IA). The deposition rate equal to 20.0 g/min, was supported by the outlet temperature of 28°to achieve weight gain target coverage of 27.5%. Then the tablets were dried on a tray in an oven at 40°With within 24 hours.

Tablets showed a pH independent dissolution in vitro when using type II dissolution United States Pharmacopeia (37°, propeller rotation speed of 50 rpm, the analysis of the effectiveness of drug substances using HPLC). The percentage of dissolved drug in solvent environment as a function of time was: 2 hours, 1%; after 5 h 8%; in 8 hours 35%; after 10 h 52%; after 12 hours, 65%; after 16 h 81%; after 24 h 95%. Thus, the composition delivers 0.03 mg/hour Lakers the public of the substance after a delay, equal to 5 hours.

Example 2

The results of clinical trials of medicinal forms AMT of example 1 on the occurrence of nausea.

When using connection 1 in a clinical trial of a single dose of the dosage form IR input persistent naturalista, nausea occurred in 50% of patients (2/4) at the dose of 1 MHA and 75% of patients (3/4) at the dose of 3 MHA. With the introduction of multiple doses of 1 MHA in the day, had a high tolerance to the drug; however, the constant nausea was strong enough (7/12 patients) at a dose of 2 mga/day, so the study was stopped. With the introduction of a single dose of healthy smokers nausea or complaints arise from 2/16 patients received a maximum dose of 2 mga IR. Conversely, doses 3 and 4 MHA of the above dosage forms AMT resulted in the same levels of nausea, which was observed with the introduction of low-dose dosage form IR (2/16 for each case). In studies conducted with the introduction of multiple doses, the levels of nausea caused by introduction 3 mga tablets AMT, were comparable to levels nausea caused by introduction of 1 MHA of IR tablets twice a day, and significantly exceeded the levels of nausea caused by introduction 2 mga IR tablets once a day.

Example 3

Obtaining the preferred dosage form L-tartrate salt of compound 1 CR AMT

Load 7 kg tableting granulometric composition was prepared as follows: 1050 g of microcrystalline cellulose and 3340 g secondary acidic calcium phosphate was mixed in a V-mixer with a capacity of 16 quarts for 20 minutes. In the V-mixer with a capacity of 8 quarts were added 2450 g of mannitol and 71,8 g medicinal substance. The mixture was stirred for 30 minutes. The resulting mixture was added to the V-mixer with a capacity of 16 quart (to the mixture from the first mixing process) and the mixture was stirred for 30 minutes (the mixture can be used for rinsing mixer to ensure reliable full transfers). Then in the V-mixer was added 52,5 g aliquot of magnesium stearate and the mixture was stirred for 5 minutes. The mixture was condensed using a roll compactor TF-Mini roller DSP when the pressure rolls 30 kg/cm2the speed of rotation of the rolls to 4.0 rpm and the speed of rotation of the auger 15 rpm, which resulted in the receipt of tapes with a thickness of 0.06 to 0.08 inches. The ribbons were crushed using a mill MA (available from Fitzpatrick Corp., Elmhurst, IL) with Serkalem a sieve, Conidur with cell size 18 mesh, rotating at 300 rpm and Then the powder was again placed in a V-mixer, was added 35 g of magnesium stearate, and then was carried out by stirring for 5 minutes.

Granulometric composition of the alloy preformed using tabletiruemogo press Kiian T100 with a cutting tool SRC 9/32 inch (11 mm), when this was received tablets weighing 250 mg (1.5 MHA). Used pre-compressive force was 1.2 kN, the main force of 8 kN by passing through the rolls with a speed of 74 rpm, the rotation speed of the blade 20 rpm the resulting tablets showed hardness 5-8 KP, this fragility was immeasurable.

Tablets were coated with cooking first solution for coating, consisting of 4095 g of cellulose acetate and 405 g of PEG 30.6 kg of acetone and 9.9 kg of water. The coating on the tablet in an amount of from 40,000 to 48,000 pieces in the batch was performed using Hicoater HCT-60 (available from Vector Corp., Marion, IA). The deposition rate equal to 180 g/min, was supported by the outlet temperature of 27°to achieve weight gain target coverage of 13%. Then the tablets were dried on a tray in an oven at 40°C for 16 hours.

Tablets showed a pH independent dissolution in vitro when using type II dissolution United States Pharmacopeia (37°With the rotation of the blades with a speed of 50 rpm, the analysis of the effectiveness of drug substances using HPLC). The percentage of dissolved drug in solvent environment as a function of time was: 2 hours 5%; after 5 h 30%; after 7 hours 50%; after 10 hours 70%; after 12 hours, 80%; after 24 hours 97%. Thus, the composition delivers 0.1 mg/hour drug substance after detention is key, equal to 2 hours.

Example 4

Getting the dosage form L-tartrate salt of compound 1 CR with hydrophilic matrix

A receiver array KM (45,000 g) and 50,575 g secondary acidic calcium phosphate was mixed in a bottle in the turbula mixer for 10 minutes. About 10 g of the obtained mixture was combined with 3,425 g L-tartrate salt compounds 1 and mixed in the turbula mixer for 10 minutes Remaining from the first mixture powder was then added to the mixture containing the medicinal substance and the resulting combined mixture was mixed in the turbula mixer for 20 minutes. Then was added magnesium stearate (1,000 g) and the combined mixture was stirred for a further 3 minutes. Tablets were obtained using an F-press, Manesty™ (teletrauma machine with one punch, available from Manesty Corporation, Liverpool, UK), with a cutting instrument SRC 1/4 inch. Average weight of tablet was 102 mg, which corresponded to 0.5 MHA, and the hardness of the tablets was equal to 5-7 KP. Experiments with in vitro dissolution was carried out using simulating intestinal fluid (pH 6.8) at 37°using baskets and tablets with the weights and blades, rotating at 50 rpm, the Number of drug substances dissolved over time, measured by analysis of the efficacy of medicinal substances HPLC as follows: after 2 h 59%; after 4 hours 85%; che the ez 8 hour 94%; after 16 h 97%. Thus, the composition is delivered to 0.10 mg/hour of medicinal substance.

Example 5

Getting the dosage form L-tartrate salt of compound 1 CR with a hydrophobic matrix

The mixture 0,86 g of compound 1 and 42,25 g of mannitol was passed through sieve No. 36 and then mixed in the turbula mixer for 2 minutes. In chemical beaker was added Carnauba wax (6,04 g) and stearic acid (0,61 g) and melted using a water bath at 90°C. To the molten mixture of wax and stearic acid with stirring was added mannitol and the medicinal substance. Then warm the mixture was sieved through sieve No. 20 and then left to cool over night. The mixture was combined with 0.09 g of silicon dioxide and mixed in the turbula mixer for 2 minutes. Added magnesium stearate (0.17 g) and then mixed in the turbula mixer for 0.5 minutes With the use of cutting tools SRC 5/16 inch and F-press received a tablet weight of 200 mg (2 MHA).

Example 6

The choice of production method based on the stability of tablets and performance properties

This example compares traditional methods of direct compression and wet granulation dry granulation as the preferred method of production. Method of dry granulation represented using double, triple composition p is zbawiciela.

Dry granulation

In bunker mixer were added the following ingredients, listed in table 1, with the medicinal substance was placed layers between the excipients.

Table 1

The composition of the diluent
IngredientBinaryThree
L-Tartrate of compound 10,87%0,57%
Mannitol0%to 26.02%
Microcrystalline cellulose (PH 200)62,55%33,33%
Secondary acidic calcium phosphate33,33%33,33%
Nitrocresols2,00%to 5.00%
Silicon dioxide (colloidal)0,50%0,50%
Magnesium stearate0,25%0,75%
Magnesium stearate0,50%0,50%

The mixture was stirred for 30 minutes. To the mixture was added magnesium stearate and then was stirred for 3 minutes. The lubricated mixture is then condensed with rolls of tape with pressure rolls 30 kg/cm2the speed of rotation of the rolls 4 rpm and the speed of rotation of the auger 15 rpm (using a roller PR is SSA TF-Mini, available from Vector Corp., Marion, IA). The ribbons were crushed through a sieve with a mesh size of 20 mesh (rotating granulator from Vector) to obtain the particle size distribution. Granulometric composition was stirred for 10 minutes. To granulometric composition was added to the second portion of magnesium stearate and mixed for 3 minutes. The final mixture was pressed into tablets weighing 200 mg using tabletiruemogo press Kilian T100 (Kilian & Co., Inc., Horsham, PA), equipped with standard krugovorote the punches size 5/16 in.

Direct pressing (comparative method)

Double the composition of the diluent (i.e. microcrystalline cellulose and secondary calcium phosphate) was obtained with the concentrations of the compounds listed below:

L-Tartrate of compound 18,68 g
Microcrystalline cellulose621,27 g
Secondary acidic calcium phosphate333,30 g
Nitrocresols20,00 g
Silicon dioxide (colloidal)5,00 g

Prepare two different mixtures, called "preliminary mixture excipient" and "active pre-mix". "Preliminary mixture excipient" consisted of microcrystalline cellulose dioxide is silicon and nitrocresols. The ingredients were added in the V-mixer and mixed for 20 minutes. Active pre-mixture consisted of medicinal substances and one half of the secondary of calcium hydrogen phosphate. Ingredients active pre-mix was added to the V-mixer and mixed for 30 minutes and was unloaded. One half of the "preliminary mixture excipient" was added to the mixer of a suitable size and then added all active pre-mixture and was stirred for 20 minutes. In the empty mixer used for mixing active pre-mix", added the second part of the secondary acid calcium phosphate and was stirred for 5 minutes. Its the second half of "pre-mixture excipient" was added to the mixer containing the active pre-blend. The mixture was stirred for 20 minutes. To the mixture was added magnesium stearate (5,00 g) and then was stirred for 5 minutes. The final mixture was pressed into tablets weighing 200 g using tabletiruemogo press Kilian T100 (Kilian & Co., Inc., Horsham, PA), equipped with standard krugovorote the punches size 5/16 in.

Wet granulation (comparative compositions and methods)

The method of wet granulation was estimated using two different granulating means, comprising water and isopropyl Speer is. Compositions prepared from each of the granulating means, are listed in table 2.

Table 2

IngredientGranulating tool
Isopropyl alcohol
L-Tartrate of compound 15,70 g5,70 g
Mannitol255,20 g260,20 g
Selectiona microcrystalline cellulose333,30 g-
Microcrystalline cellulose (PH 200)-333,30 g
Secondary acidic calcium phosphate333,30333,30 g
Hydroxypropylcellulose10,00 g-
Nitrocresols50,00 g50,00 g
Water533,30 g-
Isopropyl alcohol-533,30 g
Silicon dioxide (colloidal)5,00 g5,00 g
Magnesium stearate7.50 g12,50

Chemically inactive ingredients listed above granulating agent (water or isopropyl alcohol) in table 2 composition, were added to the mixer with a high shear force and mixed in the dry state for 1 minute at a speed of rotation of the impeller 100 rpm One half of the mixture excipient removed from the container and the mixer was added the whole amount of the L-tartrate of compound 1 and covered by the remote mixture. The resulting mixture was stirred for 1 minute at a speed of 100 rpm With continued stirring the mixture for 1 minute was added granulating means with the speed of rotation of the chipping machine 1000 rpm and the speed of rotation of the impeller 300 rpm Wet granulation was stirred for another 15 seconds and then add the water or isopropyl alcohol. The wet mass was dried in an oven to a temperature of 50°With up to a moisture content of 1% relative to the initial values before pelleting. The dried granulation was crushed in a conical mill (Comil, Quadro Engineering, Inc., Waterloo, Ontario, Canada)equipped with a sieve with mesh size 0,050 inch impeller with rounded edges, rotating at 1770 rpm To the specified particle size distribution of the added colloidal silicon dioxide and mixed in a V-mixer for 20 minutes. To the mixer was added magnesium stearate and was stirred for 5 minutes. The final mixture was pressed into tablets weighing 300 mg using tabletiruemogo press Kilian T100 (Kilian & Co., Inc. Horsham, PA), equipped with standard krugovorote the punches size 11/32 inch.

The homogeneity of the mixture, direct p is escolania and dry granulation compared below. To download used the same incoming bulk batch of medicinal substances, a load of drug substances (0,868%) and the same weight of the tablets (200 mg). The data of the efficacy of medicines and variability are summarized in table 3 for methods, direct compression and dry granulation. The influence of the dry granulation of the composition on the homogeneity of the mixture is illustrated by the reduction in variability of a mixture of RSD from 8% to 1.8%.

The method of productionTable 3
Dry granulation (binary)Direct pressing
The percentage loading of the medicinal product0,8680,868
The weight of tablets (mg)200200
The effectiveness of the final mixture (average)99,299,4
The effectiveness of a finite mixture

(% RSD)
1,88

High variability (8% RSD) effectiveness in the final mixture before direct pressing of tablets was the basis for choosing a dry granulation as the preferred method.

Methods of wet and dry granulation was compared with performance properties from the point of view of lastwednesday and changing the values of granular mixtures and pills (percent relative standard deviation or %RSD). To download used the same incoming bulk batch of medicinal substances, a load of drug substances (0,57%) and the same weight of the tablets (300 mg). Data validity and variability are summarized in table 4 for the three evaluated methods of granulation.

Table 4
The method of productionDrygranulation (three-part diluent)Wet granulation with waterWet granulation with isopropyl alcohol
The percentage of the utilization of medicinal substance0,570,570,57
The weight of tablets (mg)300300300
The effectiveness of particle size distribution (secondary)for 91.3101,393,6
The effectiveness of particle size distribution (% RSD)4,24,01,8
The effectiveness of particle size distribution (secondary)

In the beginning
94,599,093,7
In the middle95,0100,896,1
At the end of96,099,894,8
Tab is EDI (% RSD)

In the beginning
1,22,52,3
In the middle0,40,90,4
At the end of1,22,61,0

Values of the effective particle size distribution and tablets are closest to the desired 100% in the method of wet granulation, in which the granulating means used water. How dry granulation and wet granulation with isopropyl alcohol resulted in obtaining similar results in relation to operating properties.

In the presented table 5 shows the results of stability of the tablets stored under accelerated ageing conditions for 6 weeks and subjected to HPLC analysis in the methods of wet and dry granulation.

The total content of impurities in 6 weeks
Table 5
The method of productionDry granulation (triplethinnerWet granulation with waterWet granulation with isopropyl alcohol
The percentage of the utilization of medicinal substance0,570,570,57
The weight of tablets(mg)300300300
At 5°ND0,080,30
At 25°C/60% RHNDNANA
At 30°C/60% RHNA0,100,35
At 40°C/75% RH00,120,40
At 50°C/20% RHNA0,200,35
Dosage form during processingAnhydrousHydrateAnhydrous

It was found that the wet granulation using as a granulating means water is physically unstable due to the conversion state of the L-tartrate of compound 1 from anhydrous to hydrate. Subsequently hydrated form were lost during the stages of drying and formed anhydrous dosage form. These changes physical resistance during the process of wet granulation with water and drying helped to decide when choosing your preferred method. Dry granulation and wet granulation with isopropyl alcohol are the preferred methods of obtaining the tablets on the basis of the L-tartrate of compound 1. By the way, ensuring the lowest common level of impurities, was the manual dry granulation, after which followed a wet granulation with water and then wet granulation with isopropyl alcohol.

Therefore, the most preferred method of granulation manufacturing tablets L-tartrate of compound 1, from the viewpoint of stability, the homogeneity of the mixture and operational properties, is a dry granulation.

Example 7

The choice of diluent based on sustainability tablets

The diluents used in the manufacture of tablets based on the L-tartrate of compound 1, was chosen on the basis of chemical resistance and performance characteristics. Evaluated three diluent (secondary acidic calcium phosphate, microcrystalline cellulose and mannitol) using your preferred method of dry granulation and composition included two (binary diluent) or three (three-part diluent) diluent (see table 6).

Table 6

IngredientThinners
Dical/MCC/mannitolMCC/mannitol
L-Tartrate of compound 10,57%0,57%
Mannitolto 26.02%42,68%
Microcrystalline cellulose (PH 200)33,33%50,00%
Secondary sour F. the SFAT calcium 33,33%0,0%
Nitrocresolsto 5.00%to 5.00%
Silicon dioxide (colloidal)0,50%0,50%
Magnesium stearate0,75%0,75%
Magnesium stearate0,50%0,50%

The following table 7 shows the results of stability of tablets prepared by dry granulating method using, or ternary, or binary (with and without the secondary acidic calcium phosphate) composition of the diluent stored for 3 months under accelerated ageing conditions and analyzed HPLC.

Table 7
The method of productionDry granulation (three-part diluent)Dry granulation, binary diluent (MCC/mannitol) without Dical (secondary acidic calcium phosphate)
The percentage of the utilization of medicinal substance0,570,57
The weight of tablets (mg)300300
The total content of impurities in 6 weeks/3 months
At 5°ND/00/0,05
At 25°C/60% RH/td> ND/0NA
At 30°C/60% RHNA0,13/0,12
At 40°C/75% RH0/0,100,28/0,34
At 50°C/20% RHNA0,23/0,58
NA indicates inapplicability.
ND indicates a non-detection.

The composition obtained by dry granulation, providing the lowest total level of impurities, used secondary acidic calcium phosphate. The preferred composition obtained by dry granulation, contain binary or ternary thinners, including secondary acidic calcium phosphate, microcrystalline cellulose and mannitol. The most preferred composition obtained by dry granulation, contain secondary acidic calcium phosphate as one of the main thinners.

The following table 8 shows the results of the stability of the tablets stored under accelerated ageing conditions within 6-12 weeks and analizowanych HPLC, and the tablets obtained the preferred method of dry granulation using or three binary compounds of a diluent, or a three-component composition of the diluent.

Table 8
Binary thinnersMCC/DicalMannitol/DicalLactose/DicalThree-part diluent (Dical/MCC/mannitol
The percentage of drug substance0,860,860,860,86
The weight of tablets (mg)200200200300
The total content of impurities after 6 and 12 weeks
At 5°C/75% RH0/00/00/NA0/0
At 30°C/60% RH0,1/0,10/00,2/NA0,1/0,1
At 40°C/75% RH0,1/0,30,1/0,22,6/NA0,1/0,3
At 50°C/20% RH0,2/0,30,1/0,21,3/NA0,2/0,3

It was found that the binary composition of the diluent containing lactose/secondary acidic calcium phosphate is less stable under accelerated ageing conditions, including temperature/humidity. As shown in table 8 tablets with binary diluent microcrystalline cellulose/secondary acidic calcium phosphate and mannitol/secondary acidic calcium phosphate showed the overall level of content primes the th, such such tablets with a three-part composition of the diluent. Therefore, a three-component structures and component structures MCC (microcrystalline cellulose)/Dical (secondary acidic calcium phosphate and mannitol/Dical are the preferred variants of the invention.

Example 8

The choice of diluent based on the operational properties and the content uniformity of tablets

If based only on chemical resistance, suitable compositions L-tartrate of compound 1 are compositions containing two binary composition of the diluent (MCC/Dical and mannitol/Dical), described in example 7. To select the most preferred compositions was carried out by production assessment at the press Kilian T100 at three positions of the cutting tool SRC 5/16 inch. Tablets were pressed at a force of 4, 8, 12, 16 and 20 kN and conducted testing to determine mass, thickness, hardness, time raspadaemosti and % fragility in each state. These data are listed in table 9.

Table 9
no partyThe pressing force (kN)Mass (mg)Thickness (inches)Hardness (KP)Time raspadaemosti (min:sec)Friability (%)
Mannitol/Dical 4,53199,80,150<100:1735,48%(a)
to $ 7.91200,70,1461,8100:210,59%
11,65200,10,1412,7300:190,34%
16,32200,8was 0.1382,7100:161,20%(b)
19,69201,00,1362,8800:20100%(c)
MCC/Dical3,94201,50,156<100:04100%(d)
7,89201,8 thousand cub.0,1463,0500:090,21%
11,51202,00,1394,8400:120,11%
16,08202,70,1367,1700:230,14%
17,56201,5is 0.135to $ 7.9100:130,067%
(a) Two tablets is completely destroyed after the test.
(b) Two tablets were covered during the test.
(C) All tablets were covered during the test.
(d) All the tablets were destroyed during the test.

For binary composition of mannitol/secondary acidic calcium phosphate was required harsh conditions of coating and it could not be preformed to the hardness of greater than 3 CP, whereas the target range for the size of the tool is 6-9 KP. When the specified hardness of the tablets had poor mechanical integrity, taking into account the high % of fragility (required value of less than 0.2%). Alternative pills containing binary diluent MSS/secondary acidic calcium phosphate, had values of hardness and fragility within the target ranges. Therefore, a more preferred binary composition of the diluent on the basis of production estimates is the composition of microcrystalline cellulose/secondary acidic calcium phosphate. Three-component composition is a preferred composition based on stability and production estimates, and also is a variant of the present invention.

Example 9

The choice of tools to help raspadaemosti dosage forms, based on sustainability tablets

Tablets containing sodium glycolate starch (SSG) as a means of promoting raspadaemosti dosage forms were analyzed on a flat surface is clean and compared with pills, containing nitrocresols (CS). Tablets were placed in vessels with a capacity of 60 cm3made of HDPE (HDPE)/HIS, at 5°C/RH 75%, 40°C/RH 75% and 50°C/RH 20% for analysis after 6 and 12 weeks. The results of determining the purity after 6 and 12 weeks are shown in table 10.

Table 10
The condition of stabilityThe time of extractionNitrocresolsThe glycolate sodium starch
5°C/75% RHAfter 6 weeks0%0,3%
After 12 weeks0%0,3%
40°C/75% RHAfter 6 weeks0,1%0,6%
After 12 weeks0,3%0,9%
50°C/20% RHAfter 6 weeks0,2%0,9%
After 12 weeks0,3%1,1%

Decomposition of tablets containing SSG (from 0.3 to 1.1%)is higher than the decomposition observed for tablets containing as a means of promoting raspadaemosti dosage form CS. The overall degree of decomposition of tablets containing CS, never exceed the value of 0.3% at Otsu is in accordance tablets lactose in any state after 6 or 12 weeks. For this reason nitrocresols selected as a more desirable means of facilitating raspadaemosti tablets based on the L-tartrate of compound 1, which was established on the basis of an increased chemical resistance in comparison with sodium glycolate starch.

Example 10

Means for sliding included in the composition to reduce the cohesive ability of the mixture

Effect adding means for sliding, in this case, colloidal silicon dioxide in the composition to obtain the tablets were assessed using tests shedding standard powder for okharakterizovanie of flow characteristics. For this assessment used the binary composition of the placebo, because downloading medicinal substances was less than 1%. The compositions are listed in table 11. These tablets were obtained by dry granulating method described in example 6.

Table 11
IngredientThe contents of the means for sliding
0%0,5%
Microcrystalline cellulose (PH 200)63,42%62,92%
Secondary acidic calcium phosphate33,33%33,33%
Nachrichtenkanal is and 2,0%2,0%
Silicon dioxide (colloidal)0,0%0,50%
Magnesium stearate0,75%0,75%
Magnesium stearate0,50%0,50%

Immediately before each of the stages of lubrication samples were taken of the mixture and particle size distribution analysis. Estimated cohesive ability, the variability of yield and particle size, the results obtained are presented in table 12. The particle size of the two parties particle size distribution was very similar and therefore should not influence the results shedding powder. Cohesive capacity and the variability of the yield was improved due to the presence of silicon dioxide. Add reduced cohesive ability to level from "low" to "very low" for mixtures and to the extent from "high" to "low" for granulometric compositions. The presence of 0.50% silicon dioxide is also reduced degree of variability of the yield strength of particle size distribution from moderate to low.

Table 12
Property0.5% silicon dioxide in the mixture0.5% silicon dioxide in particle size with which tave 0% of silicon dioxide in the mixture0% silica in the particle size distribution
Cohesive capacity ()a 3.9Very low cohesive ability4,5Low cohesive ability4,5Low cohesive ability6,1High cohesive capacity
Variability of yield40,7Moderate variability of yield31,1Low variability of yield41,0Moderate variability of yield41,1Moderate variability of yield
D[4,3]191,5 mcm161,0 mcm155,5 mcm160,5 mcm

During tabletting force demolding regulated as a function of the tonnage. Table 13 lists the efforts of demolding, the resulting effort of pressing in the range of 5-20 kN compositions containing silicon dioxide in the range from 0 to 0.5%.

Table 13

The pressing force (kN)0%0,5%
The force of buoyancy (N)The force of buoyancy (N)
6,3

8,9
29,56

27,47
12,225,88
14,3

18,6
21,08

21,56
5,7

9,1
16,64

25,40
11,422,58
15,0

18,6
19,97

23,56

Tablets containing 0,50% Cab-O-Sil, showed slightly lower extraction force from the mold in a larger part of the specified range of pressing. On the basis of the desired properties (reduced cohesive ability, variability of yield and effort demolding), it was found that tablets containing means for sliding are the preferred drug.

Example 11

The choice of film coating on the basis of sustainability tablets

Preferred white film coating for tablets L-tartrate of compound 1 was chosen based on the chemical stability using accelerated ageing conditions. Four composition for applying white film coating Opadry inflicted on one of the more preferred dry granular tablet compositions.

The core tablets were obtained using mixing schemes, including geom the electrical dilution, before compaction using rollers contained in the core components are listed below:

L-Tartrate of compound 1to 10.62 g
Microcrystalline cellulose744,42 g
Secondary acidic calcium phosphate399,96 g
Nitrocresols24,00
Silicon dioxide (colloidal)6,00 g
Magnesium stearate9.00 g
Magnesium stearate6,00 g

Prepare two different mixtures, known as "pre-mix excipient" and "active pre-mix". "Preliminary mixture excipient" consisted of microcrystalline cellulose, silicon dioxide and nitrocresols. The ingredients were added in the V-mixer and mixed for 20 minutes. Active pre-mix" consisted of a medicinal substance and one half of the secondary of calcium hydrogen phosphate. Ingredients active pre-mix" was added to the V-mixer and mixed for 30 minutes and was unloaded. One half of the "preliminary mixture excipient" was added to the V-mixer suitable size and then added all active pre-mixture and was stirred over their 20 minutes. In the empty mixer used for mixing active pre-mix", added the second part of the secondary acid calcium phosphate and was stirred for 5 minutes. Its the second half of "pre-mixture excipient" was added to the mixer containing the active pre-blend. The mixture was stirred for 20 minutes. To the mixture was added to the first portion of magnesium stearate and then was stirred for 5 minutes. The lubricated mixture was condensed using rolls of tape with the use of pressure rolls 30 kg/cm2the speed of rotation of the rolls 4 rpm and the speed of rotation of the auger 15 rpm (roll seal TF-Mini from Vector). Ribbons were crushed to pass through a sieve with a mesh size of 20 mesh (rotating granulator from Vector) to obtain the particle size distribution. Granulometric composition was stirred for 10 minutes. To granulometric composition was added the second part of the stearate and was stirred for 5 minutes. The final mixture was pressed into tablets weighing 200 mg using tabletiruemogo press Kilian T100 (Kilian & Co., Inc., Horsham, PA), equipped with standard krugovorote the punches size 5/16 in.

The qualitative composition of the four compositions for coating are listed in table 14. Composition for coating, specified as the party room And consisted of lactose,hydroxypropylmethylcellulose or a receiver array, titanium dioxide and triacetin. The main difference between the compositions for coating In D that do not contain lactose, was the type of polymer (hypromellose or a receiver array in comparison with polyvinyl alcohol or PVA) and the type of plasticizer (polyethylene glycol or PEG, and triacetin). PVA coating also contained talc. The final dosage form was covered with 4 wt.% the white coating and 0.5 wt.% transparent cover. Film-coated tablets were placed for 10 days in vessels with a capacity of 60 cm3made of HDPE (HDPE)/HIS, and caused aging at 5°s and 70°C/RH 75% and then evaluated the degree of purity. For comparison also evaluated uncoated core tablets. Received placebo tablets and analyzed for purity in the initial moment of time as a control. The set values of the purity shown in table 15.

tr>
Table 14
no party coverageComponents cover
AndThe lactose monohydrate
The hypromellose
Titanium dioxide
Triacetin
InThe hypromellose
Titanium dioxide
Triacetin
The hypromellose
Titanium dioxide
The polyethylene glycol
DPolyvinyl alcohol :
Titanium dioxide
The polyethylene glycol
Talc

It was found that the receiver array containing tablets (b and C), covered with a film that does not contain lactose, are more chemical resistant than the tablets covered with a film of lactose/receiver array (A) or PVA (D). It was found that the overall degree of decomposition of the parties tablets with a coating containing a receiver array, and coated tablets containing PEG and triacetine plasticizer, were 0.4 to 1.2% and 0.5-1.0%. Meanwhile, the total degree of decomposition of inspection lots with lactose and parties with PVA was high, respectively, 3.5 and 2.9 percent. On the basis of an increased chemical resistance determined that the preferred film coating consisted of a receiver array, titanium dioxide and or triacetin, or PEG in compositions b and C, respectively.

Table 15
Identification of film coatingPlaceboTablet without coatingAndInD
At 5 0,0*0,000,440,410,520,06
At 70°C/75% RHNA1,073,541,290,962,95
* indicates that the analysis was performed only in the initial moment of time.

Example 12

The choice of method, providing uniformity of content of the dry particle size distribution

This example illustrates the preferred method of mixing to ensure the effectiveness and uniformity of the mixture and tablets. Estimated V-mixing (with geometric dilution and without it), bunker blending (with reflective walls and without them and with direct rotation in comparison with the angular rotation) and mixing with high shear force. The composition contained the binary composition of the diluent containing the secondary acidic calcium phosphate and microcrystalline cellulose, the components of the composition are listed below.

ComponentWt.%
L-Tartrate of compound 10,885
Microcrystalline cellulose62,035
Secondary acidic calcium phosphate (Tab)33,330
Sodium is crosscarmellose 2,00
Silicon dioxide (colloidal)0,50
Magnesium stearate0,75
Magnesium stearate0,50

V-Mixing with geometric dilution

Description of the composition for the core tablets and method of reception shown in example 11.

V-Mixing for one stage

The mixture (without lubricant) was stirred for 30 minutes. To the mixture was added to the first portion of magnesium stearate and then was stirred for 5 minutes. The lubricated mixture was condensed rollers in the tape when the pressure rolls 30 kg/cm2the speed of rotation of the rolls 4 rpm and the speed of rotation of the auger 15 rpm (roll seal TF-Mini from Vector). The ribbons were crushed through a sieve with a mesh size of 20 mesh (rotating granulator from Vector) to obtain the particle size distribution. Granulometric composition was stirred for 10 minutes. To granulometric composition was added to the second portion of magnesium stearate and was stirred for 5 minutes. The final mixture was pressed into tablets weighing 200 mg using tabletiruemogo press Kilian T100 (Kilian & Co., Horsham, PA), equipped with standard krugovorote the punches.

Bunker blending

In bunker mixer with the medicinal substance layers located in the middle of added ingredients (without lubricant what about the matter). Set the configuration of the mixer (with reflective walls or without them and with straight or angular rotation). The mixture was stirred for 30 minutes, was added to the first portion of the lubricant and was stirred for 5 minutes. The lubricated mixture was condensed rollers in the tape when the pressure rolls 30 kg/cm2the speed of rotation of the rolls 4 rpm and the speed of rotation of the auger 15 rpm (roll seal TF-Mini from Vector). The ribbons were crushed through a sieve with a mesh size of 20 mesh (rotating granulator from Vector) to obtain the particle size distribution. Granulometric composition was stirred hopper concrete mixer for 10 minutes. To granulometric composition was added to the second portion of magnesium stearate and was stirred for 5 minutes. The final mixture was pressed into tablets weighing 200 mg using tabletiruemogo press Kilian T100 (Kilian & Co., Horsham, PA), equipped with standard krugovorote the punches size 5/16 in.

Mixing with high shearing force

In a mixer with a high shear force with the medicinal substance layers located in the middle of added ingredients (without lubricant). The mixture was stirred for 10 minutes at a speed of rotation of the impeller at 200 rpm and speed chippers 0 rpm was Added to the first portion of the lubricant and was stirred for 5 minuten the mixture was condensed rollers in the tape when the pressure rolls 30 kg/cm 2the speed of rotation of the rolls 4 rpm and the speed of rotation of the auger 15 rpm (roll seal TF-Mini from Vector). The ribbons were crushed through a sieve with a mesh size of 20 mesh (rotating granulator from Vector) to obtain the particle size distribution. Granulometric composition was mixed in a V-mixer for 10 minutes. To granulometric composition was added to the second portion of magnesium stearate and was stirred for 5 minutes. The final mixture was pressed into tablets weighing 200 mg using tabletiruemogo press Kilian T100 (Kilian & Co., Horsham, PA), equipped with standard krugovorote the punches size 5/16 in.

The results of the effectiveness and uniformity of particle size distribution and tablets are presented in table 16. How V-mixing for one phase and mixing with high shear force resulted in obtaining the lowest values of the effective particle size distribution. The preferred method of mixing, as has been established on the basis of the results of the effectiveness and uniformity of particle size distribution and tablets, is mixing with geometric dilution and bunker blending with any configuration of the reflective walls and any rotation. Mixer with high shear force, operating at low speeds of rotation of the impeller (low to moderate shear in question is the mixer), is also the preferred option of the present invention.

Table 16
The method of mixingGranulationTablet
Effectiveness% RSDEffectiveness% RSD
V-Mixing with geometric dilution98,30,398,80,8
V-Mixing for one stage94,57,3103,41,2
Bunker blending; without reflective walls, forward rotationof 99.11,2101,70,8
Bunker blending; reflective walls, forward rotation100,30,7102,71,4
Bunker blending; reflective walls, the angular rotation98,31,0102,10,6
Mixing with high shearing forceto 91.10,496,22,3

Example 13

The choice of diluent based on the content uniformity of particle size distribution

Pre is respectful diluent, used in active pre-mix" in the way of mixing with geometric dilution was chosen on the basis of the effectiveness and uniformity of particle size distribution and tablets. Investigated two main diluent (secondary acidic calcium phosphate and mannitol) on their ability to be excipient carrier to facilitate mixing of the L-tartrate of compound 1 in the composition. The ingredients used in tablet compositions containing a three component solvent (the same composition as in example 7), were mixed in accordance with the scheme of the geometric dilution described in example 11. In active pre-mix" used or one half of mannitol (13A), or secondary acidic calcium phosphate (13C). In this example, the medicinal substance was ground in a jet mill to approximately half the initial average particle size before mixing with excipients.

Table 17

IngredientThe diluent in active pre-mix"
Mannitol(13A)Secondary acidic calcium phosphate (13C)
L-Tartrate of compound 1 (crushed in a mill)0,86%0,86%
Mannitol25,95% 25,95%
Microcrystalline cellulose (PH 200)33,22%33,22%
Secondary acidic calcium phosphate (Tab)33,22%33,22%
Nitrocresolsto 5.00%to 5.00%
Silicon dioxide (colloidal)0,50%0,50%
Magnesium stearate0,75%0,75%
Magnesium stearate0,50%0,50%

For each tablet compositions were prepared two different mixtures, referred to in this description as "pre-mix excipient" and "active pre-mix". "Preliminary mixture excipient" consisted of microcrystalline cellulose, silicon dioxide, nitrocresols and secondary acidic calcium phosphate or mannitol. The ingredients were added in the V-mixer and mixed for 20 minutes. Active pre-mix" consisted of a medicinal substance and about one-half or mannitol (12A), or secondary acidic calcium phosphate (12V). Ingredients active pre-mix" was added to the V-mixer, mixed for 30 minutes and was unloaded. One half of the "preliminary mixture excipient" was added to the V-mixer suitable size, then added the Xiu "active pre-mixture and was stirred for 20 minutes. In the empty mixer used for mixing active pre-mix", added the second part mannitol or secondary acidic calcium phosphate and was stirred for 5 minutes. Its the second half of "pre-mixture excipient" was added to the mixer containing the active pre-blend. The mixture was stirred for 20 minutes. To the mixture was added to the first portion of magnesium stearate and then was stirred for 5 minutes. The lubricated mixture was condensed rollers in the tape when the pressure rolls 30 kg/cm2the speed of rotation of the rolls 4 rpm and the speed of rotation of the auger 15 rpm (roll seal TF-Mini Vector). The ribbons were crushed through a sieve with a mesh size of 20 mesh (rotating granulator from Vector) to obtain the particle size distribution. To granulometric composition was added to the second portion of magnesium stearate and was stirred for 5 minutes. The final mixture was pressed into tablets weighing 300 mg using tabletiruemogo press Kilian T100 (Kilian & Co., Horsham, PA), equipped with standard krugovorote the punches size 11/32 inch. The values of effectiveness and variability (% RSD) of the final particle size distribution and tablets are listed in table 18.

13B
Table 18
Excipient-media13A
Mannitol 2080, granulatedSecondary acidic calcium phosphate, anhydrous
The effectiveness of particle size distributionGeneral: 95,9%, RSD: 0,2%General: 96,3%, RSD: 1,0%
The effectiveness of the pillGeneral: 95,1%, RSD: 2,4%General: 97,2%, RSD: 0,8%

Values of the effective particle size distribution of formulations with mannitol and secondary acidic calcium phosphate, which are thinner active pre-mix", like that. However, the values of the effectiveness of the tablets was increased from 95,1 to 97,2%, when as a diluent active pre-mixture used in the method of mixing with geometric dilution, instead of mannitol used secondary acidic calcium phosphate. Therefore, the preferred diluent used in active pre-mix" method of mixing with geometric dilution is secondary acidic calcium phosphate.

1. Dosage form controlled release, intended to reduce the addiction to nicotine, suitable for administration to a patient, containing 5,8,14-triazinetrione[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaen or its pharmaceutically acceptable salt and a means for introducing a specified connection or gasoli patient with a speed of at least about 6 mg/hour, consequence of which is introduced at least about 0.1 mg of the compound or its pharmaceutically acceptable salt for 24 hours, the dosage form upon initial introduction of the patient leads to maximum concentration (Cmax) specified pentene in the plasma, which ranged from 10 to 80% from the correspondingmaxdefined to equal doses of pentene in the form of a bolus immediate release, and to increase the time of establishing the maximum concentration in plasma (Tmax) an initial introduction to the patient an average of 50% relative to the corresponding Tmaxdefined to equal doses of pentene in the form of a bolus immediate release, also dosage form releases pentaen in vitro with a speed of less than 6 mg/h when tested for dissolution in the device USP-2 (Pharmacopoeia-2 USA), so that the time of dissolution to 50 wt.% medicinal substances ranged from approximately 1 to 15 hours

2. Dosage form controlled release according to claim 1, where the means for introducing the compound or its pharmaceutically acceptable salts include the tablet matrix, multicystic or covered multicystic.

3. Dosage form controlled release according to claim 2, where the tablet matrix or multicystic contain hydrophilic matrix.

4. Lekarstvo the I form of a controlled release according to claim 1, where the means for introducing the compound or its pharmaceutically acceptable salts include coated tablets.

5. Dosage form controlled release according to claim 1 where the pharmaceutically acceptable salt is an L-tartrate or citrate salt.

6. Dosage form controlled release according to claim 1, where the patient is the man.

7. Dosage form immediate release designed to reduce habituation to nicotine, suitable for administration to a patient, comprising a core containing 5,8,14-triazinetrione[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaen or its pharmaceutically acceptable salt and pharmaceutically acceptable excipient, where the share of excipient is from about 77 wt.% to about 91 wt.%, and reducing the overall level of carbohydrates is less than 20 wt.%.

8. Dosage form immediate release according to claim 7, where the pharmaceutically acceptable excipient selected from the group consisting of mannitol, xylitol, sorbitol, microcrystalline cellulose, powdered cellulose,starch, pre-gelatinizing starch, calcium carbonate, secondary acidic calcium phosphate, calcium phosphate, calcium sulphate, magnesium carbonate, magnesium oxide, poloxamers, such as polyethylene oxide and hypromellose.

9. Les is artena form immediate release according to claim 7, where excipients are mannitol, secondary acidic calcium phosphate and microcrystalline cellulose.

10. The method of introducing the patient to reduce the addiction to nicotine 5,8,14-triazinetrione[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaen or its pharmaceutically acceptable salts, and the method comprises oral introduction in the first stage of the dosage form controlled release, described in any one of claims 1 to 6, and oral introduction in the second stage of the dosage form immediate release described in any of claims 7 to 9, where the first stage includes the period of time from about 1 day to about 30 days, and the second stage begins after the first stage.



 

Same patents:

FIELD: medicine.

SUBSTANCE: method involves delivering nicotine to patient organism and administering medicament by smearing internal surface of superior and inferior nasal passage part. Treatment is carried out with cigarette consumption being retained. Smell receptor canal blocker like rapid sodium canal blocker lidocaine is used as the medicament. Its aerosol is introduced immediately before smoking action as single jet in each nasal passage. Medicament introduction is localized with epithelial smell receptor cells arrangement.

EFFECT: enhanced effectiveness of treatment.

2 cl, 2 tbl

FIELD: medicine, narcology, pharmacy.

SUBSTANCE: invention proposes applying the following agonists of gamma-aminobutyric acid receptors of B-type: β-(4-chlorophenyl)-GABA (Baclofen), 3-aminopropyl(methyl)-phosphinic acid, 3-aminopropylphosphinic acid, Y-amino-β-4-(4-chlorophenyl)-nitropropane or their salts, esters, ethers, complexes and their corresponding isomers used in treatment of nicotine dependence. Invention provides the selective suppression of smoking addiction and effect on behavior indices causing the abuse relapse and with absence of symptoms typical in nicotine dependence.

EFFECT: valuable properties of compounds.

9 cl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes applying N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazol-3-carboxamide or its salt for manufacturing a medicinal agent used for treatment of nicotine dependence and/or symptoms of nicotine withdrawal syndrome and a method for help in ceasing using tobacco. The claimed compound is known as antagonist of central cannabinoid receptors and agent used for treatment of disorders associated with using psychoactive substances. Indicated compounds are effective with respect to complete or partial tobacco abstinence with elimination of attenuation of nicotine withdrawal syndrome and patients show reduced weight loss or its absence.

EFFECT: valuable medicinal properties of antagonist.

3 cl, 5 ex

The invention relates to medicine, namely to section narcology, and can be used for the treatment of tobacco

The invention relates to the field of medicine and relates to new N-pinakamaraming tryptophanase of dipeptides of the formula

C6H5-(CH2)n-CO-NH-(CH2)m-CO-X-Trp-R,

where n=1-5;

m=1-3;

X=L or D-configuration;

R=OH, OCH3OC2H5, NH2, NHCH3,

as well as pharmaceutical compositions containing them

The invention relates to medicine, to compositions containing polar lipid composition on the basis of nicotine in liquid crystals and colloidal dispersions and their predecessors or secondary products, which are in contact with fluid body and/or under the influence of body temperature into liquid crystals, or a mixture of liquid crystals, which acts as a matrix with controlled release of nicotine, suitable for Smoking cessation and/or replacement area
The invention relates to medicine, in particular, pharmacology, and can be used to treat nikotinizma, including for the treatment of the syndrome of nicotine and psychosomatic consequences of tobacco use

The invention relates to medicine, in particular to the prevention and treatment of alcoholism, nicotinamine and addiction in General

FIELD: medicine, pharmacology.

SUBSTANCE: the suggested preparation contains ethacyzine, interpolymeric complex of polymetacrylic or polyacrylic acid and polyethylene glycol, lactose and/or microcrystalline cellulose and a slipper, and, also, method to obtain the mentioned preparation has been suggested due to mixing the components followed by dry granulation. The preparation provides prolonged maintenance of concentration of active substance at therapeutically efficient level.

EFFECT: higher efficiency of application.

7 cl, 5 ex, 2 tbl

FIELD: medicine, pharmacology.

SUBSTANCE: the suggested preparation contains ethmozine, interpolymeric complex of polymetacrylic or polyacrylic acid and polyethylene glycol, lactose and/or microcrystalline cellulose and a slipper, and, also, method to obtain the mentioned preparation has been suggested due to mixing the components followed by dry granulation. The preparation provides prolonged maintenance of concentration of active substance at therapeutically efficient level.

EFFECT: higher efficiency of application.

7 cl, 1 dwg, 7 ex, 2 tbl

FIELD: medicine, pharmacology.

SUBSTANCE: the suggested preparation contains isosorbide dinitrate, interpolymeric complex of polymetacrylic or polyacrylic acid and polyethylene glycol, lactose and/or microcrystalline cellulose and a slipper, and, also, method to obtain the mentioned preparation has been suggested due to mixing the components followed by dry granulation. The preparation provides prolonged maintenance of concentration of active substance at therapeutically efficient level.

EFFECT: higher efficiency of application.

9 cl, 8 ex, 3 tbl

FIELD: chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to manufacturing solid medicinal formulations of preparations. Invention proposes a medicinal formulation consisting of a core comprising the following components: indometacin, lactose, calcium phosphate, hydroxypropylcellulose, magnesium stearate, sodium croscarmellose and envelope comprising collicute MAE 100P, propylene glycol, pigment titanium dioxide, talc, collidon-30, brown sycovite-70. Also, invention discloses a method for preparing the formulation. Invention provides enhancing stability of envelope to effect of stomach juice, rapid and complete release of active substance, simultaneous simplifying the process of applying the envelope for a single step.

EFFECT: improved and valuable pharmaceutical properties of formulation.

3 cl, 1 tbl

FIELD: pharmaceutics.

SUBSTANCE: the suggested pharmaceutical composition at delayed release contains fluvastatin or its pharmaceutically acceptable salt hydroxypropylmethylcellulose and nonionic hydrophilic polymer. The latter is being hydroxyethylcellulose at average molecular weight ranged 90000-1300000 or hydroxypropylcellulose at average molecular weight ranged 370000-1500000 or polyethylenoxide at average molecular weight ranged 100000-500000. The suggested pharmaceutical composition is necessary to obtain peroral medicinal remedy for decreasing cholesterol level in plasma, it, also, provides the supply of fluvastatin into the body during prolonged period of time, for example, for more than 6 h and enables to minimize the possibility for premature release or "discharge" of considerable fluvastatin quantities.

EFFECT: higher efficiency.

21 cl, 6 dwg, 5 ex, 5 tbl

FIELD: pharmaceutical industry.

SUBSTANCE: invention discloses solid oral dozed pharmaceutical form of hydrocodon with controlled release. Pharmaceutical form comprises analgetically effective amount of hydrocodon or pharmaceutically acceptable salt thereof and controlled-release material. Pharmaceutical forms of hydrocodon are suitable to be administered once a day and provides early commencement of therapeutical effect, which lasts at least about 24 h.

EFFECT: enhanced analgetic action.

44 cl, 3 tbl, 3 ex

FIELD: pharmaceutics, medicine.

SUBSTANCE: the present innovation deals with cardiotherapy for treating and preventing coronary deficiency. The preparation is designed as a plate (film) consisted of three layers, each of them is manufactured out of co-polymer of vinyl pyrrolidone, acrylamide and nitroglycerin-containing ethylacrylate; moreover, internal layer additionally contains solid fat - cacao oil, and weight ratio for the sum of external layers to internal corresponds to 1 : 1. The suggested preparation could additionally contain brilliant green dyestuff. The preparation should be manufactured out of pre-obtained mixture of nitroglycerin and copolymer in solution of alcohol and water followed by layer-by-layer forming three-layer film due to spreading the mixture onto solid bottom plate and drying at 30-50 C. The innovation provides higher adhesion to gingival mucosal surface, decreased side action, improved bioavailability and stability of therapeutic effect.

EFFECT: higher efficiency of therapy.

3 cl, 3 ex

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to human insulin drug of durable action. Drug contains human insulin substance of high purity, protamine sulfate, zinc chloride, glycerol, m-cresol, phenol, sodium dihydrogenphosphate dihydrate or disodium hydrogenphosphate heptahydrate, sodium chloride, and water and has residual proteolysis activity not more than 0.005 adsorption units.

EFFECT: human insulin drug of durable action with increased physiological activity and physical and chemical storage stability.

4 ex, 1 tbl

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to human insulin drug with activity of 100 IU/ml, including cartridge forms. Drug contains active ingredient, glycerol as isotonic agent, conserving agent and water, wherein it contains human insulin substance of high purity with residual proteolysis activity not more than 0.005 adsorption units, sodium chloride as additional isotonic agent, m-cresol as conserving agent, and additionally sodium dihydrogenphosphate dihydrate or disodium hydrogenphosphate heptahydrate as substance with buffer capacity and pH 6.9-7.8.

EFFECT: human insulin drug of short action with increased physiological activity and physical and chemical storage stability.

6 ex, 1 tbl

FIELD: pharmaceutics.

SUBSTANCE: the present innovation deals with pharmaceutical composition of bactericidal action. The composition suggested contains ciprofloxacin in the form of hydrochloride monohydrate, maltodextrin as a binding substance, sodium carboxymethyl starch as a disintegrating agent, silica gel, a lubricant at quantities mentioned in its formula. Ciprofloxacin tablets should be obtained due to pressing technique by applying the stage of moisture granulation. If necessary, the surface of tablets should be covered with a hydroxypropylmethylcellulose-based water-soluble membrane. Simultaneous application of maltodextrin as a binding substance and sodium carboxymethyl starch as a disintegrating agent enables to obtain ciprofloxacin-containing tablets of sufficient strength and quick release of active ingredient.

EFFECT: higher efficiency of application.

6 cl, 6 ex, 9 tbl

FIELD: medicine.

SUBSTANCE: invention proposes using percutaneous therapeutic system inducing high plasma levels of rotigotin for producing anti-parkinsonic medicinal agent and a method for treatment of Parkinson's disease. Proposed system involves rotigotin in the concentration from 0.1 to 3.15 mg/cm2 in form of free base and silicone representing a mixture of at least one pressure-sensitive stick silicone adhesive (Q7-4301) and at least one pressure-sensitive silicone adhesive with mean stickness (Q7-4201). This provides an average plasma concentration of rotigotin from 0.4 to 2.0 ng/ml for 24 h after its applying.

EFFECT: enhanced medicinal effectiveness of system.

10 cl, 2 tbl, 1 ex

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