Containing ondansetron formulations for oral administration
(57) Abstract:The invention relates to chemical-pharmaceutical industry and relates to a liquid composition for oral administration. The invention consists in that the composition contains the ondansetron or pharmaceutically acceptable derivative, sweetener and one or more pharmaceutically acceptable excipients, and the sweetener is one or more polyhydric alcohols, and the pH of the composition is in the range from 2.0 to 5.0. Also describes how the use of such compositions in the treatment of conditions mediated by the action of 5-hydroxytryptamine (NT) NT3the receptors. The invention provides fast action combined with continued activity and good bioavailability. 2 C. and 10 C.p. f-crystals, 2 tab. The present invention describes a pharmaceutical composition containing as an active start 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl - 1H-imidazol-1-yl)-methyl] -4H-carbazole-4-one, in particular a liquid composition for oral administration.Described (patent UK N 2153821B) 1,2,3,9-tetrahydro-9-methyl-3-[(2 - methyl-1H-imidazol-1-yl)-methyl] -4H-carbazole-4-one, currently known as ondansetron, which may be represented by forms of the s.In the above-mentioned source of these compounds are described as potent and selective antagonists of 5-hydroxytryptamine (5HT) on "neuronal" 5HT receptors subspecies, localized on the endings of primary afferent nerves, and is also present in the Central nervous system. The receptors of this subspecies now known as 5HT3the receptors. Describes the use of these compounds for the treatment of human or animal suffering from a condition caused by a disorder of neuronal 5HT transmission, for example in the treatment of migraine or of such mental disorders such as schizophrenia. It is also claimed that these compounds may be useful in the treatment of such conditions as anxiety, obesity and mania.It is also known (publication of a European patent application N 226266) that these compounds are antiemetic drugs and can be used in the treatment or prevention of nausea and vomiting. Described (European patent N 201165) the use of these compounds for the treatment of vomiting, as well as their use for the treatment of intestinal dyskinesia.Numerous clinical studies have demonstrated the effectiveness of ondansetron in the treatment of vomiting, especially nausea and vomiting due to chemo - the x drug always used either in injectable form, or oral.Oral administration in the form of conventional tablets, pills or capsules is usually a preferred way of application of medicines, because this method is usually convenient and acceptable to patients. Unfortunately, such compounds may have some drawbacks, in particular in the treatment of patients of children and elderly who may not like or which may be difficult to swallow such compositions, and also in those cases where the application of conventional tablets, pills or capsules impossible. It is highly desirable, particularly when treating acute conditions, to pharmaceutical compositions were characterized by a rapid and predictable onset of action combined with continued activity and good bioavailability. Rapid absorption can be achieved by parenteral injection, but this is unacceptable for some patients, especially in those cases where the medicine is applied without direct medical supervision, it is applied by the patient.Proposed (GB 2153821) alternative use of ondansetron, including liquid formulations for oral administration. Described (GB 2153821) multiple farmatsevticheskii and nesadurai sugar syrups, contains ondansetron hydrochloride dihydrate.The present invention is described particularly useful pharmaceutical composition, which has not previously been separately described, and which is a liquid medication ondansetron suitable for oral administration.Thus, the first aspect of the present invention is a liquid composition for oral administration containing the ondansetron or pharmaceutically acceptable derivative, sweetener and one or more pharmaceutically acceptable excipients, and sweetener contains one or more polyhydric alcohols, and the pH of the composition is in the range from 2.0 to 5.0.Under the pharmaceutically acceptable derivative is meant any pharmaceutically acceptable salt or MES ondansetron, or any other compound which upon application by the recipient is able to form (directly or indirectly) ondansetron, or its active metabolite or residue.Most preferred is that described in the present invention the compositions contain ondansetron in the form of the hydrochloride, in particular the hydrochloride dihydrate. Specialists know that ondansetron contains one chiral CE is on there enantiomers). This invention includes all isomers of ondansetron and its pharmaceutically acceptable derivatives, including all tautomeric and optical form, or any mixture of ondansetron, including racemic mixtures.In contrast to previously known compositions, the sweetener composition described in this invention contains one or more polyhydric alcohols. Applicants have discovered that the use of one or more polyhydric alcohols allows to obtain a surprisingly high-quality pharmaceutical composition due to their good stability and acceptable taste.Specialists it is obvious that the above-mentioned polyhydric alcohols should be a pharmaceutically acceptable polyhydric alcohols or mixtures thereof, for example sorbitol, mannitol, xylitol and ▫ maltitol. Preferably, the sweetener for use in accordance with this invention include sorbitol; more preferred is a sweetener, representing sorbitol and xylitol; however, the most preferred sweetener is sorbitol.Convenient to the total content of the polyhydric alcohols in the liquid composition, expressed in terms of polyhydric alcohols in solid sustaninable, about 40% of m/O.Each polyhydric alcohol may be used in solid form or in the form of a solution. Preferred is the use in the form of a solution such as an aqueous solution. For example, sorbitol is conveniently used in the form of an aqueous solution in which the concentration of solids in the solution is in the range from 64 to 72% m/m (mass).Convenient to the concentration of ondansetron in the liquid composition in terms of free base was in the range of 0.005 to 1% m/o, for example from 0.01 to 0.5% m/o, and preferably from 0.02 to 0.2% m/o, for example around 0.08% m/O.It is convenient that the pH of the liquid compositions described in this invention were in the range from 2.5 to 4.5, preferably from 3 to 4, for example about 3.5.Described in this invention, the compounds may be presented in the form of liquids, suspensions or syrups. Preferably, these compositions are presented in the form of liquids.Conventional components that may be used is described in this invention, the compounds include preservatives, buffer systems, increasing viscosity, flavorings, dyes, additional sweeteners, and mixtures thereof.Praml is/or butylperoxybenzoate; sorbic acid or its salt; benzoic acid or its salt; and mixtures thereof. The most preferred composition according to the invention contains sodium benzoate.Acceptable buffer systems include combinations of citric acid and its salts and solvate, for example citric acid (anhydrous and monohydrate) in combination with dihydrate sodium citrate). Preferably the compositions according to the invention contain a buffer system consisting of anhydrous citric acid and sodium citrate.Acceptable substances that increase the viscosity include resins (for example, xanthan gum resin), glycerin, polyvinyl alcohol, polyvinylpyrrolidine, cellulose derivatives such as carboxymethylcellulose and its salt, C1-4is an alkyl and/or hydroxy-C2-4is an alkyl cellulose ether such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose and hypromellose and mixtures thereof.Convenient to the viscosity of the liquid compositions described in this invention were in the range from 20 to 100 centipoise (CP), for example from 10 to 75 centipoise, in particular from 15 to 50 centipoise.Acceptable flavors include strawberry, cherry, plastically include, for example, sugars such as glucose; cyclamate and its salts. Preferably the compositions according to the invention practically does not contain fructose or fructosidase of sugars (e.g. sucrose), for example, contain less than 5% fructose, and preferably less than 1% of fructose.In a further preferred aspect according to this invention proposed a liquid composition for oral administration containing hydrochloride dihydrate ondansetron and sorbitol.According to the following preferred aspect of the proposed liquid composition for oral administration containing hydrochloride dihydrate ondansetron, sorbitol, sodium benzoate, anhydrous citric acid, dihydrate sodium citrate and strawberry flavoring.In accordance with the foregoing preferred aspects of the invention, a liquid composition with a concentration of ondansetron (in terms of free base) from 0.02 to 0.2% m/o, for example around 0.08% of the content of sorbitol (in terms of solid sorbitol) from 30 to 50% m/o, for example about 40% m/o, and pH from 3.0 to 4.0, for example about 3.5, is particularly preferred.Liquid compositions for oral administration can be suitably prepared in the usual way, aprimary of excipients.In a further aspect of the invention, a method for treating mammals, including humans, suffering from conditions, the indirect effect on 5HT 5HT3receptors, consisting in applying a liquid composition for oral administration containing the ondansetron or pharmaceutically acceptable derivative, sweetener and one or more pharmaceutically acceptable carriers or excipients, and sweetener contains one or more polyhydric alcohols, and the pH of the composition is in the range from 2.0 to 5.0. Assumes that under treatment is understood as the prevention and alleviation of established symptoms.State, the indirect effect on 5HT 5HT3receptors include vomiting; disorders of cognitive function, such as dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, a disease of the Peak horey of Huntington, Parkinson's disease Creutzfeldt-Jakob disease) and vascular dementia (including multifocal dementia), as well as dementia associated with intracranial volume lesions, trauma, infections and such conditions (including HIV infection), metabolism, toxins, anoxia and deficit vitengeni memory; mental disorders such as schizophrenia and mania; anxiety disorders, including panic disorder, agoraphobia, social phobia, simple phobia, binding disorder, posttraumatic stress disorder, mixed anxiety-depressivnii disorder and generalized anxiety; syndrome, intestinal dyskinesia, as well as drugs and drug addiction. Other conditions mediated in the same way, include itching, especially caused by cholestasis; gastroparesis; symptoms of gastrointestinal dysfunction characteristic of peptic ulcers, reflux esophagitis, flatulence and dyspepsia; migraine; obesity and conditions such as bulimia, pain, and depression.Emesis, i.e. nausea, hiccups and vomiting, are divided into acute, delayed and expected. Ondansetron useful in the treatment of vomiting of any nature. For example, vomiting can be caused by drugs such as agents for cancer chemotherapy, namely alkylating agents (e.g. cyclophosphamide, carmustin, lomustin, and chlorambucil); cytotoxic antibiotics (e.g. dactinomycin, doxorubicin, mitomycin-C and bleomycin); antimetabolites drugs (e.g., cytarabine, methotrexat and 5-formazin, procarbazine, hydroxyurea, and their various combinations; radiation sickness; radiotherapy, for example by irradiation of the thorax or abdomen in the treatment of cancer; poisons; toxins such as toxins formed by metabolic disorders or by infection, such as gastritis, or released by bacterial or viral gastrointestinal infection; pregnancy; vestibular disorders, such as air, Maritime and transport sickness, vertigo, dizziness and trouble Miniera; postoperative weakness, obstruction of the gastrointestinal tract; paralysis of the gastrointestinal tract; visceral pain (e.g. myocardial infarction or peritonitis); migraine; increased intracranial pressure; low intracranial pressure (for example, when altitude sickness); opioid analgesics, such as morphine; gastroesophageal reflux; indigestion; the abuse of food or alcohol; high acidity, belching/regurgitation; heartburn (such as episodic heartburn, nocturnal heartburn, heartburn after a meal), and dyspepsia.The pharmaceutical compositions described in this invention are useful in the treatment of vomiting, especially in the o what precise therapeutic dose of the beginning of the current will depend on the age and condition of the patient and the nature of the disease and to be determined solely by the treating physician.In General, however, the effective dose for treating conditions mediated by the action on 5HT 5HT3receptors, such as vomiting, are in the range from 0.05 to 100 mg, for example from 0.1 to 50 mg, and preferably from 0.5 to 25 mg, for example, 1, 2, 4, or 8 mg per reception, which can be applied once or several times a day, for example from 1 to 4 times.Convenient to the volume of liquid composition per unit intake was in the range from 1 to 15 ml, for example from 2.5 to 10 ml, in particular about 5 ml.The following examples illustrate the invention but are not restrictive.Example 1. The composition shown in table. 1.The solution of sorbitol was mixed with water and the resulting mixture was added anhydrous citric acid. To the hydrochloride dihydrate ondansetron added water to the formation of aqueous suspension and this mixture added to the above mixture, and then added the dihydrate of sodium citrate. Sodium benzoate dissolved in water and added this solution to the mixture, and then added strawberry aromatised the holding of 2.5 mg of the hydrochloride dihydrate ondansetron (2 mg of ondansetron in the form of free base) in 5 ml was prepared by the method described in example 1.Example 3. The composition shown in table. 2.Anhydrous citric acid dissolved in water, then added the hydrochloride dihydrate ondansetron, and then sodium citrate. Sodium benzoate dissolved in water and added the solution to the above mixture. To the mixture was added xylitol, then sorbitol and finally strawberry flavoring. The mixture is added to the desired volume with water, filtered and bottled.Examples 4, 5. Compositions containing 1.25 and 10 mg of the hydrochloride dihydrate ondansetron (1 and 8 mg of ondansetron in free base form, respectively) in 5 ml were prepared by the method described in example 1. 1. A liquid composition for oral administration containing the ondansetron or pharmaceutically acceptable derivative, sweetener and one or more pharmaceutically acceptable excipients, characterized in that the sweetener contains sorbitol, and the pH of the composition is in the range from 2.0 to 5.0.2. Composition under item 1, characterized in that it contains ondansetron in the form of hydrochloride.3. Composition under item 1, characterized in that it contains ondansetron in the form of the hydrochloride dihydrate.4. The composition according to any one of paragraphs.1 to 3, characterized in that the>5. The composition according to any one of paragraphs.1 to 4, characterized in that the concentration of ondansetron in terms of free base is 0.005 to 1% weight/volume.6. The composition according to any one of paragraphs.1 to 5, characterized in that the total content of sorbitol in the specified composition in terms of solid sorbitol is from 20 to 85% weight/volume.7. The composition according to any one of paragraphs.1 - 6, characterized in that the pH is from 2.5 to 4.5.8. The composition according to any one of paragraphs.1 to 7, characterized in that the concentration of ondansetron in the specified composition in terms of free base is from 0.02 to 0.2% weight/volume; the total content of sorbitol in the specified composition in terms of solid sorbitol is from 30 to 50% weight/volume, and the pH is in the range from 3.0 to 4.0.9. The composition according to any one of paragraphs.1 to 8, characterized in that its viscosity is from 1 to 100 centipoise (CP).10. The composition according to any one of paragraphs.1 to 9, characterized in that it contains almost no fructose or fructosidase saccharides.11. A method of treating mammals, including humans, suffering from conditions mediated by the action NT on T3receptors, which affect the composition according to any one of paragraphs.1 - 10.12. The method according to p. 1
FIELD: medicine, cardiology.
SUBSTANCE: the suggested method should be performed at the background of medicinal therapy with preparations out of statins group, tevetene, polyoxidonium and conducting seances of plasmapheresis by removing 800 ml plasma twice weekly with N 5 due to additional intramuscular injection of immunophan 0.005%-1.0 with N 10 and fluimucyl 300 mg intravenously daily with N 5-10, total course of therapy lasts for 2 mo. The method provides modulation of leukocytic functional activity, moreover, due to altered cytokine profile and, thus, through disintegration of protein-lipid complexes participating in the development of atherosclerotic platelets.
EFFECT: higher efficiency of therapy.
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to a prophylactic or therapeutic agent used against hyperlipidemia and comprising as an active component the heterocyclic compound of the formula :
or its pharmaceutically acceptable salt wherein R1 represents aryl optionally substituted with similar or different one-three groups taken among alkyl, halogenalkyl, trihalogen alkyl, alkoxy-group and halogen atom; Het represents bivalent aromatic heterocyclic group of the formula :
wherein X represents oxygen, sulfur atom or NR6 wherein R6 represents hydrogen atom or alkyl; R2 represents hydrogen atom, alkyl or trihalogenalkyl; D represents alkylene and alkenylene; E represents group of the formulae  or  wherein Y represents oxygen or sulfur atom; R3 and R4 are similar or different and each represents hydrogen atom or alkyl; p = 1; Z represents carboxy-group, alkoxycarbonyl, cyano-group or 1H-5-tetrazolyl. Also, invention relates to new compounds belonging to group of above enumerated heterocyclic compounds of the formula  that show effect reducing blood triglycerides level, low density lipoprotein cholesterol, glucose and insulin or effect enhancing high density lipoprotein cholesterol and effect reducing the atherogenic effect. Therefore, these compounds can be used in prophylaxis or treatment of hyperlipidemia, arteriosclerosis, heart ischemic disease, brain infarction, rheocclusion after percutaneous intraluminal coronary angioplasty, diabetes mellitus and obesity.
EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.
29 cl, 1 tbl, 170 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to a pharmaceutical composition used in treatment or prophylaxis of hypertension, heart diseases, vascular disorders and kidney diseases. The composition comprises compound of the formula (1) as antagonist of angiotensin II receptors and one or some diuretics. The composition shows enhanced effectiveness.
EFFECT: valuable medicinal properties of composition.
23 cl, 2 tbl, 1 ex
FIELD: organic chemistry, medicine, hormones.
SUBSTANCE: invention describes imidazole derivatives of the formula (I) , racemic-diastereomeric mixtures and optical isomers, pharmaceutical salts wherein ---- represents an optional bond; R1 represents hydrogen atom (H), -(CH2)m-C(O)-(CH2)m-Z1, -(CH2)m-Z1; R2 represents hydrogen atom (H), or R1 and R2 are joined with nitrogen atoms to which they are bound forming compounds represented by formulae (Ia), (Ib) or (Ic) wherein R3 represents -(CH2)m-E-(CH2)m-Z2; R4 represents hydrogen atom (H) or -(CH2)m-A1; R5 represents (C1-C12)-alkyl, (C0-C6)-alkyl-C(O)-NH-(CH2)m-Z3 and optionally substituted phenyl; R6 represents hydrogen atom (H); R7 represents (C1-C12)-alkyl or -(CH2)m-Z4; m = 0 or a whole number from 1 to 6; n is a whole number from 1 to 5. Proposed compounds bind with subtypes of somatostatin receptors selectively.
EFFECT: valuable properties of compounds.
20 cl, 13776 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to derivatives of imidazole of the formula (I):
or its pharmaceutically acceptable salts wherein X represents -CH2-(CH2)p-, -O-; R1 represents phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, (C3-C7)-cycloalkyl wherein indicated phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, (C3-C7)-cycloalkyl are substituted optionally with 1-3 substitutes taken independently among halogen atom, -OH, halogen-(C1-C6)-alkyl, (C1-C6)-alkyl, (C1-C6)-alkoxy group and OH-(C1-C6)-alkyl; R2 represents hydrogen atom (H) or (C1-C6)-alkyl; R3 represents H or (C1-C6)-alkyl; R4 represents H or (C1-C6)-alkyl; R5 represents H, or R5 and R7 form in common a bond; each R6 represents independently halogen atom, -OH, halogen-(C1-C6)-alkyl, (C1-C6)-alkyl, (C1-C6)-alkoxy group or OH-(C1-C6)-alkyl; R7 represents H, or R7 and R5 form in common a bond; each R8 represents independently -OH, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl or (C1-C6)-alkoxy group; m = 0, 1, 2 or 3; n = 0 or 1; p = 0 or 1; r = 0 or 1; t = 0. Also, invention relates to a method for preparing compounds of the formula (I) and to a pharmaceutical composition showing affinity to alpha-2-adrenoceptors based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof used in aims for treatment of neurological disturbances, psychiatric disorders or disturbances in cognitive ability, diabetes mellitus, lipolytic diseases, orthostatic hypotension or sexual dysfunction.
EFFECT: improved preparing method, valuable medicinal properties of compounds and compositions.
25 cl, 1 tbl, 14 ex
FIELD: medicine, pharmacy.
SUBSTANCE: invention proposes a pharmaceutical preparation based on angiotensin-converting enzyme inhibitor, its using in prophylaxis of insult, diabetes and/or congestive cardiac insufficiency and corresponding methods for its using in patient with maintenance heart function and subjected for risk of cardiovascular attack due to previous history of ischemic disease, insult or peripheral arterial disease. In particular, inhibitor of angiotensin-converting enzyme can be chosen from ramipril, ramiprilat, lisinopril, enalapril and enalaprilat. Invention promotes to reducing the total lethality of patients group in case of cardiovascular diseases, cardiac attacks and insults, the necessity for carrying out procedures for revascularization (such as surgery operation for coronary shunt, angioplasty with using balloon and so on) and diabetic complication are diminished.
EFFECT: improved and valuable medicinal properties of preparations.
19 cl, 1 ex
FIELD: medicine, cardiology.
SUBSTANCE: invention proposes an agent for correction of abdominal complications in acute period in myocardium infarction. Proposed agent represents ondansetron or domperidone. Agent reduces frequency of hyperemia occurring, improved indices of intestine contractions, promotes to declining lethality in acute period in myocardium infarction.
EFFECT: improved and valuable medicinal properties of agent.
4 tbl, 6 dwg
FIELD: organic chemistry, chemical technology, medicine, veterinary science.
SUBSTANCE: invention describes the compound R-(-)-1-[2-(7-chlorobenzo[b]thiophene-3-ylmethoxy)-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole of the formula (I) and its salts, in particular, its mononitrate. Also, invention relates to a method for preparing compound of the formula (I) possessing antifungal effect based on compound of the formula (I), and using compound of the formula (I) as an active component of the antifungal composition. Compound of the formula (I) can be used in compositions for treatment of fungal infections in humans or animals and against diseases of agricultural crops.
EFFECT: improved preparing method, valuable properties of compound and composition.
15 cl, 1 tbl, 10 ex
SUBSTANCE: method involves administering required dose of renin-angiotensin inhibitor Ramipryl or its salt combined with a hypotensive drug, means for reducing cholesterol content, diuretic or aspirin to patients showing no signs of left ventricle dysfunction or cardiac insufficiency.
EFFECT: prevented cardiovascular attacks, angina pectoris, diabetes manifestations.
18 cl, 5 tbl
FIELD: organic chemistry, pharmacy.
SUBSTANCE: invention relates to new compounds of the general formula (I) in racemic form, enantiomer form or in any combinations of these forms possessing affinity to somatostatin receptors. In the general formula (I): R1 means phenyl; R2 means hydrogen atom (H) or -(CH2)p-Z3 or one of the following radicals: and Z3 means (C3-C8)-cycloalkyl, possibly substituted carbocyclic or heterocyclic aryl wherein carbocyclic aryl is chosen from phenyl, naphthyl and fluorenyl being it can be substituted, and heterocyclic aryl is chosen from indolyl, thienyl, thiazolyl, carbazolyl, or radicals of the formulae and and it can be substituted with one or some substitutes, or also radical of the formula: R4 means -(CH2)p-Z4 or wherein Z4 means amino-group, (C1-C12)-alkyl, (C3-C8)-cycloalkyl substituted with -CH2-NH-C(O)O-(C1-C6)-alkyl, radical (C1-C6)-alkylamino-, N,N-di-(C1-C12)-alkylamino-, amino-(C3-C6)-cycloalkyl, amino-(C1-C6)-alkyl-(C3-C6)-cycloalkyl-(C1-C6)-alkyl, (C1-C12)-alkoxy-, (C1-C12)-alkenyl, -NH-C(O)O-(C1-C6)-alkyl, possibly substituted carbocyclic or heterocyclic aryl; p = 0 or a whole number from 1 to 6 if it presents; q = a whole number from 1 to 5 if it presents; X means oxygen (O) or sulfur (S) atom n = 0 or 1. Also, invention relates to methods for preparing compounds of the general formula (I), intermediate compounds and a pharmaceutical composition. Proposed compounds can be used in treatment of pathological states or diseases, for example, acromegaly, hypophysis adenomas, Cushing's syndrome and others.
EFFECT: improved preparing method, valuable medicinal properties of compounds and composition.
11 cl, 2 tbl