Peroral liquid compositions

FIELD: pharmaceutics.

SUBSTANCE: the present innovation deals with peroral liquid compositions which could be designed into gelatinous capsules. The suggested pharmaceutical composition includes a pharmaceutically active agent, a solubilizing agent and, not obligatory, a surface-active substance and a plastifying agent. The pharmaceutically active agent has got, at least, one acidic fragment, preferrably, that of carbonic acid being chosen out of the group of non steroid antiphlogistic preparations being acid-soluble at acid : dissolved substance ratio being from 3:1 to 10000:1. New compositions provide increased rates and degrees of absorption of pharmaceutically active agent and minimize side effects caused by such active substances.

EFFECT: higher efficiency of application.

42 cl, 39 ex

 

This application is a partial continuation of application serial No. 09/232354, filed January 15, 1999, the description of which is included in this text, which has priority over previously filed application No. 60/071865, registered January 20, 1998, the description of which is included in this text.

The technical field to which the invention relates.

The present invention relates to pharmaceutically acceptable compositions for oral administration and to methods of applying such compositions to improve the speed and extent of absorption of pharmaceutically active ingredient contained in such compositions, and to reduce to a minimum irritation of the stomach, induced or caused by the ingestion of such pharmaceutically active components. Pharmaceutically active component of the compositions according to the present invention includes at least one pharmaceutically active agent having at least one acid fragment preferably is a fragment of a carboxylic acid, especially of the class of agents known as nonsteroidal anti-inflammatory drugs (NSAIDs), which are soluble in the acid at a ratio of approximately 30 : 1 (acid to the dissolved substance) to 10000 : 1 (acid to the dissolved substance).

Prior art

In the pharmaceutical field composed of pharmaceutically active compounds in the form of usable dosage forms, in which the absorption of the active ingredient is perfect and the degree controlled side effects are reduced to a minimum, is for scientists working in the field of preparation of pharmaceutical compositions, challenging and often with unexpected results. In particular, pharmaceutical compositions for pharmaceutical agents having at least one acid fragment preferably is a fragment of a carboxylic acid, and which is soluble in the acid at a ratio of approximately 30 : 1 (acid to the dissolved substance) to 10,000 to 1 [acid to the dissolved substance; moderately soluble to practically insoluble or insoluble state (see, for example, Sokoloski, T.D., Remingtons Pharmaceutical Sciences, 16:208, 1990)], known in this field mainly as having a less than ideal absorption and in some cases cause adjustable side effects with the introduction of mammals. Representatives of such compounds include, for example, pharmaceutical agents, well known in this area as non-steroidal anti-inflammatory drugs (NSAIDs), acetylcholinesterase inhibitors (“ACE”), represented by the family is the bycatch”, inhibitors of HMG-CoA reductase, presents a collection of “statins”, antagonists histamine H1receptors, such as, for example, fexofenadin, inhibitors of secretion of gastric acid, such as omeprazole, agents, stabilizing mast cells, agents against hyperlipidemia, penicillins, protivougrevoe agents, cephalosporins, including, for example, β-lactam, salicylates, and individual pharmaceutical agents.

For example, in U.S. patent No 4880835 describes the preparation of oral liquid compositions containing calcium sulindac, using pharmaceutical carrier, representing a glycol, a polyol and potential alcohol. In addition, in the patent discussed widely known problem of absorption of pharmaceutical agents, as described above, in particular NSAIDs from the intestines.

K.Chan, et al., Pharma Research, 7:1027 (1990) showed that diclofenac sodium (NSAID) was more biologically available in oral use of covered intersolubility shell tablet than from the aqueous solution. The results were contrary to expectations from this experiment and confirmed the fact that the problem in this issue still exists. In U.S. patent No. 4704405 also discussed the problem of absorption of the above compounds, in particular NSAIDs, such as sulindac, from the gastrointestinal tract.

N.M.Najib, et al., International Journal of Pharmaceutics, 45:139 (1988) reported that ibuprofen-polyvinylpyrrolidone can form complex type weak acid - weak base in the solid state or in solution. In this publication are not informed of any research in respect of the environment and fillers used in the present invention.

In the United Kingdom patent No 2059768 described results in the formation of more soluble derivatives of NSAIDs with Tris-group connections.

Furthermore, in U.S. patent No. 5183829 describes the preparation of compositions containing NSAID, which, apparently, was partially improved absorption of pharmaceutically active agent, at the same time they had a positive impact on the aforementioned gastric side effects caused by taking NSAIDs. In the patent specified medium containing glycol polyol, which can be efficiently used for soft gelatin capsules. In more detail, it was found that polyols, and the concentration of polyols used in this case was the reason that soft gelatin capsules have become sticky and stuck together with the adjacent soft capsules. The results showed that the pharmaceutical composition described in patent No 5183829, it is unsustainable when it is used in soft gelatin capsules.

Thus, pharmaceutical compositions according infusion is he to the invention are solving problems, which arise in the manufacture of compositions according to the patent No 5183829, and have been successful in the preparation of compositions of pharmaceutically active substances in the form of more suitable medicines.

A brief description of the invention

The present invention relates to oral compositions which are used as an oral liquid medicines, which can also be enclosed in hard capsules or subjected to hardening, as shown herein, for use in hard capsules, in particular soft gelatin capsules and hard gelatin capsules, respectively containing one or more pharmaceutically active agent, and the above-mentioned pharmaceutically active agent is chosen from the group consisting of the above-mentioned agents, where at least one of the above agents has at least one acid fragment and at least one of the above agents is at least one ester group or other reactive fragment and the agent terminal fragment in relation to the above ether group or other reactive fragment hydrolyzed or otherwise removed in situ or in vivo, forming at least one acid fragment; and where the above-mentioned pharmaceutically active agent is Astori acid at a ratio of approximately 3:1 (acid to the dissolved substance) to 10000:1 (acid to the dissolved substance), or its pharmaceutically acceptable salt (hereinafter the "active ingredient/at least one dispersing agent; and at least one solubilizers agent; and optionally,

at least one surfactant; and, in addition, optional

at least one plasticizing agent.

In addition, the present invention concerns the application of the compositions according to the present invention for improving the absorption of active ingredients and to reduce to the minimum adjustable side effects caused by such active ingredients, in particular NSAIDs where it is needed. The invention relates to methods of applying the compositions according to the present invention, where the above composition contains as active ingredient, at least one NSAID and optional agent, promoting, and/or antiemetic agent for the treatment of paroxysmal headaches, particularly migraine headaches.

Detailed description of the invention

One aspect of the present invention relates to compositions which are used as an oral liquid medicines, which can also be enclosed in soft capsules, or subjected to hardening, as shown herein, for use in hard capsules, in particular soft gelatin ka is the Sulam and hard gelatin capsules, accordingly contains

one or more pharmaceutically active agent, and the above-mentioned pharmaceutically active agent is chosen from the group consisting of the above-mentioned agents, where at least one of the above agents has at least one acid fragment and at least one of the above agents is at least one ester group or other reactive fragment and the agent terminal fragment in relation to the above ether group or other reactive fragment hydrolyzed or otherwise removed in situ or in vivo, forming at least one acidic fragment; and where the above-mentioned pharmaceutically active agent is soluble in the acid at a ratio of approximately 3:1 (acid to the dissolved substance) to 10000:1 (acid to the dissolved substance), or its pharmaceutically acceptable salt (hereinafter the "active ingredient");

at least one dispersing agent; and at least one solubilizers agent; and optionally a

at least one surfactant; and, in addition, optional

at least one plasticizing agent.

Active ingredients used in these compositions are well known in the pharmaceutical field, get them through methods well known in x the chemical and pharmaceutical sectors, and include, for example, pharmaceutically active compounds, described above, having at least one acid fragment, and the most preferable when such acid fragment is a carboxylic acid. Other acid fragments are well known to the person skilled in the art. Representatives of active ingredients include, for example, non-steroidal anti-inflammatory drugs (NSAIDs), examples of which are aralkylamines acids such as diclofenac, fenoprofen, flurbiprofen, ibuprofen, indometacin, Ketoprofen, Ketorolac, naproxen, sulindac, etodolac and Tomatin, and arylcarbamoyl acid, such as diflunisal, mefenamovaya acid, meclofenamic acid and floranova acid. This list NSAIDs are presented solely for the purpose of illustration and does not seek to limit these tools.

Other NSAIDs, as well as other active ingredients, which are used in the compositions according to the present invention, are described in addition to the schemes taking these drugs in well-known publications, such as the Physicians Desk Reference and the Merck Index. For example, the following family of compounds, individual compounds included in this text, without limitation, as active ingredients for the compositions of this izaberete the Oia:

inhibitors “ACE”, which includes, for example, inapril, ramipril, captopril, benazepril, trandolapril, fosinopril, lisinopril, moexipril and enalapril;

inhibitors of HMG-CoA reductase, which includes, for example, fluvastatin, lovastatin, pravastatin, cervistatin, atorvastatin and simvastatin;

antagonists histamine H1receptors, which include, for example, Phenoperidine;

agents, stabilizing mast cells, including, for example, kromolin;

inhibitors of secretion of stomach acid, including, for example, omeprazole;

antihyperlipidemic agents, including, for example, gemfibrozil;

gipolipidemicheskie agents, including, for example, ciprofibrate;

fluorinated quinolones, including, for example, ciprofloxacin, lomefloxacin and ofloxacin;

peripheral decarboxylase inhibitors, including, for example, carbidopa and levodopa;

protivougrevoe agents, including, for example, retinoic acid;

analogs of the prostaglandins, including, for example, carboprost;

various well known penicillins (including, for example, amoxicillin and ampicillin), P-lactams and cephalosporins, and

various compounds such as, for example, liotironin, probenecid, and the like.

Of course, the above list and the active ingredients are presented only for illustration purposes and does not seek to limit in any respect the volume of the present invention and should not be so interpreted.

As shown above, the compounds included in this invention also include pharmaceutically active substances, which are used to obtain pharmaceutical compositions contain at least one ester group or other reactive fragment whose terminal fragment of such ether group or other reactive fragment hydrolyzed or otherwise removed in situ or in vivo, and is formed, at least one acid fragment, such as, for example, lovastatin, simvastatin (for example, the lactone → -COOH). Such other chemically active fragments are well known in this field. As used herein the term “active ingredients” includes pharmaceutically acceptable salts of all compounds described in this text. Obtaining the above-described active ingredients, including obtaining appropriate pharmaceutically acceptable salts are well documented in the chemical, medical, patent and pharmaceutical literature.

In the compositions according to the present invention using non-toxic pharmaceutically number of active ingredients. Thus, the concentration of each active ingredient are known or can be determined by standard methods that are well known in this region the STI. More precisely, the concentration of active ingredient in the compositions according to the present invention can range from about less than one percent to about ninety-nine percent (wt/wt), preferably, from about less than one percent (1%) to less than twenty percent (20%) and, in addition, preferably, from about one percent (1%) to less than or equal to fifteen percent (15%). Mainly the concentration of NSAIDs used in the present compositions ranges from about 5 percent to 25 percent (wt/wt), preferably from about less than one percent (1%) to less than twenty percent (20%) and, in addition, preferably from about one percent (1%) to less than or equal to fifteen percent (15%).

Also in the composition according to the present invention is enabled, at least one pharmaceutically acceptable, non-toxic dispersing agent. As used herein, the term “pharmaceutically acceptable”, when referring to any of the components or all the components of the present compositions, means that the component or components similar or similar with other components mentioned in this text, and is harmless to the person (s) receives. Such dispersing agents are well known in this field and include for example, based on the polymer dispersing agents, which include, for example, polyvinylpyrrolidone (PVP; commercially known as Plasdone®), and is based on the carbohydrate dispersing agents, such as, for example, hypromellose (receiver array), hydroxypropylcellulose (LDCs) and cyclodextrins. Preferred dispersing agents include PVP K29-32, dextrins, starch, derivatives of starch and dextrans, while from dextrins particularly preferred are the derivatives of cyclodextrins. Especially preferred of these cyclodextrin is hydroxypropyl-β-cyclodextrin and γ-cyclodextrin. Numbers refer to the molecular weight of the polymer, such as PVP K-30 has an average molecular weight of approximately 30,000 with concomitant viscosity characteristics. Usually dispersing polymer is chosen in such a way as to achieve appropriate homogeneity using viscosity, at the same time to buy to get the suitable solution.

The ratio of the active ingredient or active ingredients based polymer dispersing agent is from about 3 : 1 (wt/wt) to 1 : 50 (wt/wt). The preferred ratio is from about 2 : 1 (wt/wt) to 1 : 20 (wt/wt). For the compositions according to the present invention, sod is rzasa, at least one NSAID as an active ingredient, the preferred ratio of NSAID-based polymer dispersing agent is from about 1 : 1 (wt/wt) to 1 : 5 (wt/wt).

The ratio of active ingredient to based on carbohydrate dispersing agent is from about 3 : 1 (wt/wt) to 1 to 30 (wt/wt), with a preference to range from approximately 2 : 1 (wt/wt) to 1 : 10 (wt/wt). For the compositions according to the present invention, containing at least one NSAID as an active ingredient, the preferred ratio of NSAID-based carbohydrate dispersing agent is from about 1 : 1 (wt/wt) to 1 : 3 (wt/wt).

For these compositions can be used one or more dispersing agent, to obtain the ratio of active ingredient to a dispersing agent such as described above.

Another required component of the compositions according to the present invention is at least one pharmaceutically acceptable non-toxic solubilizers agent. Such easily accessible solubilizing agents well-known in this field and is usually represented by a family of compounds known as polyethylene glycol (PEG)having a molecular weight from about 200 to 8000. For the compositions according to the present and the finding, when the liquid is desired for the final composition, or the liquid may be used for the conclusion of her soft capsules, preferably soft gelatin capsules, the preferred molecular weight ranging from about 200 to 600, and PEG 400 is particularly preferred. For the composition according to the present invention, when it is preferable to semi-solid composition, especially for filling hard capsules, preferably hard gelatin capsules, the preferred molecular weight of PEG is approximately 3350, while especially preferred molecular weight is 3350 plus sufficient PEG with a molecular weight of 400 to improve the properties of the filler capsule.

Other solubilizers agent, which can be used in the compositions according to the present invention is water, especially purified, and most preferably deionized. For such compositions, the concentration of water is from about zero percent to ninety-nine percent (wt/wt). In private cases, the compositions according to the present invention, which conclude in soft capsules, the preferred maximum concentration of water is from about 0% to 5%, although the concentration of total solubilizing agent may be present is a whole area of concentration, specified in this text.

When used in these compositions, the concentration of the amount applied solubilizing agent which can be used for more than one solubilizing agent is from about 0 percent (barely above zero) to 99% (wt/wt). The preferred concentration solubilizing agent in the present compositions is from about 60 percent to 90 percent (wt/wt).

One possible component of the compositions according to the present invention, but which should be used in those cases when such compositions should be placed in soft gelatin capsules is at least one pharmaceutically acceptable non-toxic plasticizing agent. Such plasticizing agents, which are well known in the field of pharmaceutical technology include, for example, glycerol, propylene glycol and sorbitol. Such commercially available plasticizers can be obtained, which include more than one plasticizing component, but the preferred plasticizing agent for the present compositions is glycerin. Propylene glycol, in addition to using it as a plasticizing agent, may serve as solubilizing agent, when used him alone or in combination with other solubilis the dominant agent, specified in this text.

When used in the present invention plasticizing agent concentration the amount of plasticizing agent which can be used for more than one plasticizing agent is from about zero percent (barely above zero) to 75 percent (wt/wt). The preferred concentration of the plasticizing agent is approximately zero percent (0%) to fifty (50%) percent, and particularly preferred concentration is in the area of approximately one percent (1%) to thirty percent (30%). When the compositions according to the present invention is used for filling soft gelatin capsules, the preferred concentration of such plasticizing agent is from about 5 percent to 10 percent (wt/wt). Such plasticizers are particularly suitable for soft gelatin capsules, because without them these capsules become hard and lose their favorable properties, possibly with the cracking or brittleness.

Another possible component of the present compositions, which is a preferred component represents at least one pharmaceutically acceptable non-toxic surfactant, preferably a nonionic surfactant. Such behavior is Resto-active agents are well known in the field of pharmaceutical compositions and include readily available surfactants, having a concentration of from about zero percent to 90 percent, such as, for example, macroporous gel-esters (Labrafils), Tandem 522®, Span 80®, Gelucieres®, as, for example, tocopherol polyethylene glycol 1000 succinate, Polysorbate 20 and Polysorbate 80. Of them Polysorbate 20 and Polysorbate 80 are preferred.

When used in the present invention the nonionic surfactant concentration is the amount of non-ionic surfactants which can be used more than one such surfactant is from about zero percent to 10 percent (wt/wt) with a preference in the area from about 1 percent to 5 percent (wt/wt). Especially preferred concentration is about 3% (wt/wt).

Typically, the order of addition of the various components included in the present invention, should not affect the formation of the solution according to the present invention, when this is desirable. However, when using such surface-active substance, it may be better to add a surfactant or surfactant after adding the active ingredient and dispersing agent, as described in the text. The order of adding these components is probably more critical for the cooking the compositions according to the present invention with NSAID, in particular with diclofenac, which is used as such an NSAID.

It should be understood that each component included in the composition according to the present invention should be pharmaceutically acceptable and used in non-toxic concentrations.

In addition, it is known that when the desired active ingredient used in the compositions according to the present invention, degrades in acidic medium (for example, labile in acidic compounds, including, for example, proton pump inhibitors, including, for example, those represented by chemical class that includes lanzoprazol and omeprazole), it is preferable dissolving an active ingredient in a solution of a strong base having a pH of at least 9.0 and maintaining a pH of at least 9.0 in the course of obtaining the composition according to the present invention. However, pH of 9.0 or higher can prevent the filling soft gelatin capsules. Thus, compositions according to the present invention that require high pH (for example, higher than about pH 7.5 to pH 9,0), should be used to fill them, when desirable, hard capsules, described in the text.

Typically, for such labile in acidic compound, at least one dispersing agent and the edge is her least one solubilizers agent and, optionally, one or more plasticizing agent and low (C1-C4) alkanol mixed and stirred under heating, if necessary to dissolve the dispersing agent. Mainly for transferring these fillers in the solution is sufficient to maintain a constant temperature of approximately 40 to 50°With stirring for 30 minutes. To the specified solution is added a base, preferably a strong base, which includes, for example, sodium hydroxide, ammonium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide and the like, in sufficient quantity to raise the pH of the solution to a pH of at least 9.0 in. To the resulting solution add one or more active ingredient, including labile in acidic environment the active ingredient. This active ingredient should be added slowly and intermittently, at the same time, it is necessary to control the pH of the resulting solution and to maintain its pH at least at 9.0 by adding, if necessary, an extension Foundation, which is described above. Once the desired concentration of active ingredient will be achieved and the pH will be maintained at a pH of at least 9.0 in, you can add one or more possible surfactant, preferably a nonionic surface-active ve is estvo, and/or one or more possible plasticizing agent. After preparation of the composition according to the present invention, the solution can be transferred to semi-solid state by methods well known to the person skilled in the art, or can be placed in capsules, hard or soft, as it is more suitable. The concentration of the active ingredient or active ingredients and each filler specified in this description. The preferred active ingredient for use in the specified method is one or more proton pump inhibitors, which are known to experts in this field, of which particularly preferred is omeprazole.

In addition, capsules, filled with the pharmaceutical compositions obtained above, or any capsule containing a pharmaceutical composition according to the present invention, can be coated with a layer when it is necessary, for example, omeprazole, any non-toxic pharmaceutically acceptable coating. Such coatings include, for example, intersolubility membrane masking the taste sensation of cover layers, colored coating layers, with prolonged or delayed release coatings without the taste and the like, and receive and apply by methods well what about the well-known specialist in this field. Preferably the capsules containing the composition according to the present invention, in which the active ingredient is omeprazole, cover intersolubility shell.

This method gives an amazing result saving the active ingredient in solution during the whole way, leading to a stable pharmaceutical composition according to the present invention with a concomitant beneficial effects, as described in the text.

Thus, another aspect of the present invention concerns a method for obtaining a pharmaceutical composition according to the present invention, in which indicated at least one acid fragment above one or more pharmaceutically active agent is cyclotourism, including:

education solution, at least one dispersing agent and at least one solubilizing agent and optionally one or more low (C1-C4) alkanol,

add sufficient grounds for establishing the pH of the above solution, at least at pH 9.0 and

adding to the above one or more pharmaceutically active agent and maintaining the pH of the above solution, at least at pH 9.0 and optional

one or more surface-Akti the substance and, in addition, optional

one or more plasticizing agent.

Another aspect of the present invention concerns a pharmaceutical composition, which is obtained according to the above method.

Other pharmaceutically acceptable, non-toxic pharmaceutical additives can be included in compositions according to the present invention, and they are, for example, sweeteners, mestnoanesteziruyuschie tools, Antibacterials, lower alkyl alcohols, such as ethanol and the like.

Commonly used pharmaceutical agents, such as, for example, hydrochloric acid in a concentration of from about 0.1 G. to 2., used to regulate the pH of the composition and/or when at least one active ingredient is in the form of salts, usually alkali metal salt, to turn the active ingredient in free-acid. The preferred region pH of the present compositions, which are used for filling them soft gelatin capsules, extends approximately from 4.0 to 9.0.

Thus, the new compositions according to the present invention have favorable pharmaceutical properties, this includes a minimum number of components.

Typical that the oral solution containing one or more active ingredient, is mixed with the gastric acid, to glomerulopathy and form a precipitate in a short period of time, which makes the active ingredient is less biologically available. Compositions according to the present invention with a minimum number of ingredients, at least one of each ingredient listed below: active ingredient, dispersing agent and solubilizing agent and optionally a surfactant and, in addition, optional plasticizing agent, which are described above, preferably represent a new liquid pharmaceutical composition, when the present composition is used to fill their non-toxic, pharmaceutically acceptable capsules, of which particularly preferred are soft gelatin capsules and hard gelatin capsules. Such compositions improve the dispersing properties of the active ingredient upon contact with gastric acid, which promote more rapid, reproducible and uniform rate of absorption than the pharmaceutical compositions outside the scope of the present invention. Usually even faster absorption of the active ingredients leads to more rapid onset of therapeutic effect, respectively provided for each active ingredient.

It is known that NSAIDs cause irritation of the gastrointestinal tract, the usual expressed in the form of peptic ulcers, bleeding and perforation. Due to the improved dispersion and absorption properties of the compositions according to the present invention such compositions suppress this stomach irritation induced by prolonged administration of these NSAIDs. The term “suppress”used in this text is used in the accepted for value, and it includes without limitation, reduction, maintaining in a state of latency and/or minimize the irritation of the stomach of a mammal, induced and/or resulting from the introduction of one or more NSAID to a mammal, in comparison with such irritation of the stomach, which is induced and/or is the result of the introduction of the standard pharmaceutical compositions with NSAIDs.

Surprisingly, in light of the discussion described in the above U.S. patent No 5183829, it was found that the addition of at least one of surfactants, in particular nonionic surfactants described above, the compositions according to the present invention improves the dispersion properties of the active ingredients in the compositions according to the present invention do not contain such non-ionic surfactant. Thus, compositions according to the present invention, which include such surface-active substance, in particular the hat, which contain one or more NSAIDs as the active ingredient, also contribute to a more rapid onset of therapeutic effect, respectively generated by each active ingredient. Such compositions containing such surface-active substance, also inhibit irritation of the stomach of a mammal, induced and/or resulting from the introduction of the compositions according to the present invention, where the active ingredient is at least one NSAID, in comparison with such irritation of the stomach, which is induced and/or is the result of the introduction of the standard pharmaceutical compositions with NSAIDs.

Essentially another aspect of the present invention relates to a method of improving the rate of absorption of the active ingredients in mammals, in particular humans, which consists in the introduction to a mammal in need of treatment of such active ingredient, the compositions according to the present invention.

An additional aspect of the present invention relates to a method for accelerating the onset of therapeutic action on mammals, in particular humans, respectively provided for each active ingredient, which consists in the introduction to a mammal in need of treatment of such active ingredient, the compositions according to the present invention.

Compositions according to the present invention are usually so daily to deliver a standard, non-toxic dosage amount of the active ingredient from about 0.25 mg to 400 mg per day. Preferred doses for each active ingredient used in the compositions according to the present invention, will be determined by individual circumstances in which there is a patient, including, for example, evaluation of the patient by the physician and the severity of the pathological condition that requires treatment. The preferred daily dose of the composition where the active ingredient is a NSAID or pharmaceutically acceptable salt will be from about 10 mg to 2000 mg per day. Usually oral composition according to the present invention are to deliver from about 10 mg to 500 mg per teaspoon of liquid product.

Liquid or semi-solid composition according to the present invention is also used to fill their capsules, in particular of hard gelatin capsules and especially soft gelatin capsules, where the amount of active ingredient in each capsule is from about 10 mg to 250 mg of the Receipt of such capsules are well known in the pharmaceutical field [see, e.g., Modern Pharmaceutics, Third Edition (G.S.Banker and C.T.Rhodes, ed.; 1966); and theory and Practice of Indutrial Pharmacy, Third Edition, (L.Lachman, H.A.Lieberman, and J.L.Kanig, ed.; 1986)].

Thus, another aspect of the present invention relates to a method of treating mammals in need of treatment, by using one or more active ingredients or their pharmaceutically acceptable salts, which consists in the introduction of the above to a mammal, particularly a human, the compositions according to the present invention, with the above composition contains at least one active ingredient. Preferred active ingredients include one or more NSAID, in particular diclofenac, sulindac or indomethacin for the treatment of a mammal in need of treatment an anti-inflammatory and/or analgesic agents, omeprazole to suppress secretion of gastric acid and antihistaminic agent, fexofenadin. A further aspect of the present invention relates to such a method of treatment, which are described in this section, where the composition according to the present invention is orally administered to such mammal in liquid form or in the form of soft or hard gelatin capsules, filled with the composition.

Due to exceptional in vivo pharmacodynamics of compositions according to the present invention such compositions, in particular, in which at least one active ingredient is a NSAID, preferably diclofenac,indomethacin, or sulindac, are active, and one that is otherwise unattainable clinical results are achieved. For example, NSAIDs are usually not distinguish, in order to achieve relief of acute paroxysmal headache, in particular migraine. However, compositions according to the present invention, in which the active ingredient is at least one NSAID, contribute to a more rapid weakening of migraine when administered orally a single dose of approximately 10 mg to 2000 mg, preferably from about 50 mg to 250 mg, repeated at intervals of approximately 2 to 4 hours, on demand, in comparison with existing compositions containing the same pharmaceutically active ingredient. This weakening of migraine also achieved with the acceptance of such compositions, introduced in combination with an agent promoting, such as, for example, metoclopramide, the introduction of which is simultaneous or sequential. When the introduction is carried out simultaneously with respect to the introduction of such compositions according to the present invention, such as promoting agent may be included as a possible ingredient in such compositions according to the present invention. Usually metoclopramide is effective as a promoting agent, it is when it is administered at a dose in the region of from about 5 mg to 15 mg for each such composition according to the present invention.

Thus, another aspect of the present invention relates to a method of treatment of paroxysmal headache, in particular migraine, which consists in the introduction of the mammal, usually a person in need of such treatment, a composition according to the present invention, preferably in the form of capsules and especially in the form of soft gelatin capsules in which the above-mentioned active ingredient is at least one NSAID in an effective amount, or its pharmaceutically acceptable salt, preferably diclofenac, sulindac or indomethacin and not necessarily promoting agent, preferably metoclopramide in effective amounts.

In addition, compositions according to the present invention, in which the active ingredient is at least one NSAID, preferably injected in combination with an agent that promotes the advancement, the introduction of which is simultaneous or sequential in relation to the introduction of the composition, as described above, contribute to a more rapid decrease in pain as the primary analgesic agent, and, in particular, pain from trauma or surgical procedures such as dental surgery, hysterectomy and arthroscopy. In addition to the analgesic actions such compositions in which the active ingredient is, at the ore, one NSAID, also contribute to the more rapid attenuation of inflammation caused by injury, stress, surgical procedures and the like. The dosage and dosage amount for applying such compositions according to the present invention as anti-inflammatory and analgesic for the treatment of paroxysmal headache installed above.

Thus, another aspect of the present invention relates to a method of treatment of pain and treatment of inflammation in a mammal, preferably human, which consists in the introduction to a mammal in need of treatment a composition according to the present invention, preferably in the form of capsules and especially in the form of soft gelatin capsules in which the active ingredient is at least one NSAID in an effective amount, or its pharmaceutically acceptable salt, preferably diclofenac, sulindac or indomethacin, and optional agent promoting, preferably metoclopramide, in an effective amount.

Used in this text, the term “treatment” or derived from it involves the partial or total suppression installed painful conditions, such as pain when the composition according to the present invention is administered for the prevention or after the occurrence of more than the United States.

Another aspect of the present invention relates to a method of inhibition of secretion of gastric acid, which consists in the introduction of the mammal, usually a person in need of such treatment, a composition according to the present invention, preferably in the form of capsules, in which the above-mentioned active ingredient is a proton pump inhibitor in an effective amount, preferably omeprazole or its pharmaceutically acceptable salt.

An additional aspect of the present invention relates to a method of achieving antihistamine effect in mammals, preferably humans, which consists in the introduction of this mammal in need of treatment a composition according to the present invention, preferably in liquid form, in which the above-mentioned active ingredient is Fexofenadine effective amount or its pharmaceutically acceptable salt.

Compositions according to the present invention, in which the active ingredient is omeprazole or its pharmaceutically acceptable salt, typically carry non-toxic dosage amount of from about 5 mg to 40 mg per day, and especially preferred dosage is about 20 mg.

Compositions according to the present invention, in which the active ingredient is Fexofenadine or FA is matemticas acceptable salt, usually take non-toxic dosage amount of from about 30 mg to 120 mg per day, and especially preferred dosage is about 60 mg

Also the present invention relates to compositions according to the present invention includes at least the first active ingredient in an effective amount, which is a NSAID or pharmaceutically acceptable salt, preferably diclofenac, sulindac or indomethacin, and at least a second ingredient in an effective amount, which is the agent, promoting, or its pharmaceutically acceptable salt, in particular metoclopramide.

The following analytical procedures used to verify the behavior of the active ingredients in contact with the acidic environment that is considered in this area as a model of gastric fluid (SGF)without enzyme:

A. Visual variance

In a clean glass beaker with a volume of 400 ml was added to 100 ml or 150 ml of 0.1 G. of hydrochloric acid. The acid was added 1 ml of the composition according to the present invention, the mixture is vigorously stirred and observed the behavior of the variance. Visual observations included observations of homogeneity and agglomeration, the relative time of sintering, and the like. Visual observation confirmed that the compositions according to the SNO present invention showed improved dispersion properties and had less tendency to agglomerate.

Century of Light

In a clean glass beaker with a volume of 400 ml was added 150 ml of 0.1 G. of hydrochloric acid. The acid was added 1 ml of the composition according to the present invention, and the mixture was stirred at a constant speed. In the process of mixing the resulting solution was passed through a pump through a Hewlett-Packard (Roseville, CA) spectrophotometer, equipped with a 1 cm cell is installed to measure the percent transmittance at a wavelength of 530 nm. The results showed that the percentage of light transmission with the compositions according to the present invention, in particular, those compositions which include at least one non-ionic surfactant, was less than with compositions outside the scope of the present invention. Data suggests that the compositions according to the present invention have a higher dispersion of the active ingredients than the reference composition.

C. the Turbidity of

In a glass bottle with pump dispenser is equipped with a turbidimeter model 2100AN sold Hach (Loveland, Colorado), was added 30 ml of 0.1 G. of hydrochloric acid. The acid was added 0.1 g of the composition according to the present invention. The mixture was vigorously shaken, and the turbidity of the mixture was measured in Nephelometric Turbidity Units (NTU). The turbidity of the mixture was measured at various time intervals using, for example, one of the following modes: (i) 30, 45, 60, 75, 90 and 120 minutes; (ii) 0, 20, 30, or 45 seconds and once every minute from 1 to 15 minutes; and (iii) 10 and 30 seconds, and 3, 5, 10, 15, 20, 30 and 60 minutes.

The results showed that the compositions according to the present invention are more dispersed and less subject to agglomeration in a model of gastric fluid than compositions outside the scope of the present invention.

The following aspects of the invention, to illustrate and to offer a specific application of the invention, but they do not seek to limit the invention in any respect and should not be construed so.

Example 1

Obtaining a liquid composition containing diclofenac sodium

In glass chemical glass with a volume of 100 ml was added 35,95 g of polyethylene glycol 400 (PEG 400 and PEG 400 was stirred using a magnetic stirrer with heating, maintaining the temperature between about 45-55°C. the glass was slowly added 3,15 g PVP K29-32. After complete dissolution (visual observation) PVP K29-32 added 3,15 g of diclofenac sodium, and the mixture was left to cool to ambient temperature, then added 1.5 g of Polysorbate 80. This mixture was stirred for approximately two minutes, then added 5.0 g of glycerol, at the same time, the mixture was stirred for an additional approximately two minutes, then was added to 1.25 g of hydrochloric acid, thus formed slightly the cozy solution. This mixture was stirred for an additional approximately 10-15 minutes. The resulting composition is administered as an oral solution or used for filling soft gelatin capsules using standard methods.

Example 2

The following composition was obtained using the method of preparation of the compositions of example 1:

 % wt/wt
Diclofenac sodium6,3
The polyethylene glycol 40071,9
2 n hydrochloric acid2,5
Glycerin10,0
Polysorbate 803,0
PVP K29-326/3
 100,0%

Example 3

Obtaining a liquid composition containing kromolin sodium

In glass chemical glass with a volume of 100 ml was added 37,0 g of polyethylene glycol 400 (PEG 400 and PEG 400 was stirred using a magnetic stirrer with heating, maintaining the temperature between about 45-55°C. the beaker was added 5.0 g of glycerol, at the same time, the stirring was continued for about 2 minutes, then was added 2.5 g of purified water and the mixture was stirred for an additional approximately 2-3 minutes. Then to the mixture was added 2.0 g of PVP K29-32 when re is eshiwani until while PVP K29-32 is not completely dissolved (visual observation). Then added 2.0 g cromolyn sodium and the mixture was stirred until until kromolin sodium is not completely dissolved (visual observation). The mixture was left to cool to ambient temperature before adding 1.5 g of Polysorbate 80. The resulting mixture was stirred for about 10-15 minutes, it was formed slightly turbid solution. The resulting composition is administered as an oral solution or used for filling soft gelatin capsules using standard methods.

Example 4

The following composition was obtained using the method of preparation of the compositions of example 3:

 % wt/wt
Kromolin sodium4,0
The polyethylene glycol 40074,0
Purified water5,0
Glycerin10,0
Polysorbate 803,0
PVP K29-324,0
 100,0%

Example 5

Obtaining a liquid composition comprising sulindac

In glass chemical glass with a volume of 100 ml was added 31.0 g of polyethylene glycol 400 (PEG 400 and PEG 400 was stirred with a magnetic stirrer at the grove, maintaining the temperature between about 55-65°C. the beaker was added 5.0 g of glycerol, at the same time, the stirring was continued for about 2 minutes, then was added 2.5 g of purified water and the mixture was stirred for an additional approximately 2-3 minutes. Then to the mixture was slowly added 5.0 g of PVP K29-32 under stirring until until PVP K29-32 is not completely dissolved (visual observation). Then added 5.0 g sulindaka and the mixture was stirred until such time as sulindac is not completely dissolved (visual observation). The mixture was left to cool to ambient temperature before adding 1.5 g of Polysorbate 80. The resulting mixture was stirred for about 10-15 minutes, it was formed slightly turbid solution. The resulting composition is administered as an oral solution or used for filling soft gelatin capsules using standard methods.

Example 6

The following composition was obtained using the technique of preparation of the composition of example 5:

 %wt/wt.
Sulindac10,0
The polyethylene glycol 40062,0
Purified water5,0
Glycerin10,0
Polisorb the t 80

PVP K29-32
3,0

10,0
 100,0%

Example 7

Obtaining a liquid composition containing gemfibrozil

In glass chemical glass with a volume of 100 ml was added 27,25 g of polyethylene glycol 400 (PEG 400 and PEG 400 was stirred using a magnetic stirrer with heating, maintaining the temperature between about 45-55°C. the glass was slowly added 7.5 g of PVP K29-32. After the complete dissolution of PVP K29-32 (visual observation) to the mixture was slowly added to 7.5 g of gemfibrozil with stirring until until gemfibrozil is not completely dissolved (visual observation). The mixture was left to cool to ambient temperature, then added 1.5 g of Polysorbate 80. The resulting mixture was stirred for approximately two minutes, when it was formed slightly turbid solution. Then to the mixture was added 5.0 g of glycerol, at the same time continuing the stirring for approximately two minutes, and then added to 1.25 g of purified water, and the solution was stirred for an additional 10-15 minutes. The resulting composition is administered as an oral solution or used for filling soft gelatin capsules using standard methods.

Example 8

The following composition was obtained using the method of preparation of the compositions of example 7:

 % wt/wt
Gemfibrozil15,0
The polyethylene glycol 40054,5
Purified water2,5
Glycerin10,0
Polysorbate 803,0
PVP K29-3215,0
 100,0%

Example 9

A composition containing diclofenac sodium

In glass chemical glass with a volume of 100 ml was added 37,45 g of polyethylene glycol 400 (PEG 400 and PEG 400 was stirred using a magnetic stirrer with heating, maintaining the temperature between about 45-55°C. the glass was slowly added 3,15 g PVP K29-32. After the complete dissolution of PVP K29-32 (visual observation) to the mixture was slowly added a 3.15 g of diclofenac sodium with stirring until then, until the diclofenac sodium was dissolved (visual observation). The mixture was left to cool to ambient temperature. The resulting mixture was stirred for approximately two minutes, when it was formed slightly turbid solution. Then to the mixture was added 5.0 g of glycerol, at the same time continuing the stirring for approximately two minutes, then was added to 1.25 g of 2.0 N. hydrochloric acid and the solution was stirred for an additional 10-15 mine is. The resulting composition is administered as an oral solution or used for filling soft gelatin capsules using standard methods.

Example 10

The following composition was obtained using the method of preparation of the compositions of example 9:

 % wt/wt
Diclofenac sodium6,3
The polyethylene glycol 40074,9
2 n hydrochloric acid2,5
Glycerin10,0
PVP K29-326,3
 100,0%

Example 11

Obtaining a liquid composition containing gemfibrozil

In glass chemical glass with a volume of 100 ml was added 28,75 g of polyethylene glycol 400 (PEG 400 and PEG 400 was stirred using a magnetic stirrer with heating, maintaining the temperature between about 45-55°C. the glass was slowly added 7.5 g of PVP K29-32 under stirring, which was continued up until PVP K29-32 is not completely dissolved (visual observation). Then to the mixture was slowly added to 7.5 g of gemfibrozil and the mixture was stirred until until gemfibrozil is not completely dissolved (visual observation). The mixture was left to cool to ambient temperature before adding the 5.0 is glycerin. The mixture was stirred for approximately two minutes and then was added to 1.25 g of purified water, at the same time continuing the stirring for about 10-15 minutes. The resulting composition is administered as an oral solution or used for filling soft gelatin capsules using standard methods.

Example 12

The following composition was obtained using the method of preparation of the compositions of example 11:

% wt/wt
Gemfibrozil15,0
The polyethylene glycol 400of 57.5
Purified water2,5
Glycerin10,0
PVP K29-3215,0
 100,0%

Example 13

Obtaining a liquid composition containing gemfibrozil

In glass chemical glass with a volume of 100 ml was added 35 mg of polyethylene glycol 400 (PEG 400 and PEG 400 was stirred using a magnetic stirrer with heating, maintaining the temperature between about 45-55°C. the glass was slowly added 7.5 g of PVP K29-32 under stirring, which was continued up until PVP K29-32 is not completely dissolved (visual observation). Then to the mixture was slowly added to 7.5 g of gemfibrozil and a mixture of premesis the do until while gemfibrozil is not completely dissolved (visual observation). The mixture was left to cool to ambient temperature. The resulting composition is administered as an oral solution or used for filling soft gelatin capsules using standard methods.

Example 14

The following composition was obtained using the method of preparation of the compositions of example 13:

 % wt/wt
Gemfibrozil15,0
The polyethylene glycol 40070,0
PVP K29-3215,0
 100,0%

Example 15

Obtaining a liquid composition containing diclofenac

In glass chemical glass with a volume of 100 ml was added 43,7 mg of polyethylene glycol 400 (PEG 400 and PEG 400 was stirred using a magnetic stirrer with heating, maintaining the temperature between about 45-55°C. To the mixture was slowly added 3,15 g PVP K29-32 under stirring, which was continued up until PVP K29-32 is not completely dissolved (visual observation). Then to the mixture was slowly added a 3.15 g of diclofenac and the mixture was stirred until then, while diclofenac is not completely dissolved (visual observation). The mixture was left to cool down to a temperature environment is environment. The resulting composition wodatch oral solution or used for filling soft gelatin capsules using standard methods.

Example 16

The following composition was obtained using the method of preparation of the compositions of example 15:

 % wt/wt
Diclofenac6,3
The polyethylene glycol 40087,4
PVP K29-326,3
 100,0%

Example 17

Obtaining a liquid composition containing kromolin sodium

In glass chemical glass with a volume of 100 ml was added 46 mg of polyethylene glycol 400 (PEG 400 and PEG 400 was stirred using a magnetic stirrer with heating, maintaining the temperature between about 45-55°C. To the mixture was slowly added 2.0 g of PVP K29-32 under stirring, which was continued up until PVP K29-32 is not completely dissolved (visual observation). Then to the mixture was slowly added 2.0 g cromolyn sodium and the mixture was stirred until until kromolin sodium is not completely dissolved (visual observation). The mixture was left to cool to ambient temperature. The resulting composition is administered as an oral solution or used for filling soft gelatin capsules, is using standard methods.

Example 18

The following composition was obtained using the method of preparation of the compositions of example 17:

 % wt/wt.
Kromolin sodium4,0
The polyethylene glycol 40092,0
PVP K29-324,0
 100,0%

Example 19

Obtaining a liquid composition comprising sulindac

In glass chemical glass with a volume of 100 ml was added 40 mg of polyethylene glycol 400 (PEG 400 and PEG 400 was stirred using a magnetic stirrer with heating, maintaining the temperature between about 45-55°C. To the mixture was slowly added 5.0 g of PVP K29-32 under stirring, which was continued up until PVP K29-32 is not completely dissolved (visual observation). Then to the mixture was slowly added 5.0 g sulindaka and the mixture was stirred until such time as sulindac is not completely dissolved (visual observation). The mixture was left to cool to ambient temperature. The resulting composition is administered as an oral solution or used for filling soft gelatin capsules using standard methods.

Example 20

The following composition was obtained using the method of preparation of the composition of example 19:

 % wt/wt
Sulindac10,0
The polyethylene glycol 40080,0
PVP K29-3210,0
 100,0%

Examples 21-37

The following method was used to obtain the compositions of examples 21-37:

In a suitable stainless steel container was added polyethylene glycol (PEG) and, where necessary, ethanol. The mixture was stirred using an agitator Lightnin low speed for 3 minutes. To the resulting mixture, which was maintained at a constant temperature (40°C to 50° (C)using a heated plate, added polyvinylpyrrolidone and mixed using a Lightnin agitator for at least 30 minutes. To the resulting solution was added to the selected active ingredient and the mixture was stirred for at least 20 minutes with Lightnin agitator, at the same time maintaining a constant temperature, but not more than 50°With, before, until this active ingredient is not fully dissolved. To this solution was added to the nonionic surfactant, when it was necessary, and the solution was mixed using a Lightnin agitator for about 10 minutes. The obtained liquid composition according to the present invention is administered according to the methods described in this paper is whether further receive for placing them in non-toxic, pharmaceutically acceptable capsule.

In the second suitable stainless steel container was added an excess of PEG 4600, which was heated at a temperature of from about 55°C to 60°C. as soon As the PEG 4600 melted, its melt was left to mix with Lightnin agitator. The first stainless steel container was added the appropriate amount of PEG 4600 from the second container made of stainless steel. The solution from the first container stainless steel maintained at a temperature of from about 45°C to 50°to add and for adding PEG 4600. The resulting mixture was stirred for at least 30 minutes.

Compositions containing indomethacin: the ingredients are given in percent of the whole composition (wt/wt).

 Number example
 21222324
Indometacin8,95,08,78,3
PEG 40025,024,024,323,3
PEG 460050,056,048,746,8
PVP K29-321,81,74,38,3
T is in 80 10,710,010,410,0
Ethanol    
fortress 1903,63,33,63,3
 100,0100,0100,0100,0

 Number example
 252627
Indometacin9,08,98,9
PEG 40025,241,182,2
PEG 4600a 50.541,1-0,0
PVP K29-3210,88,98,9
Tween 800,90,00,0
Ethanol   
Fortress 1903,60,00,0
 100100100

*PEG 4600 was replaced with PEG 3350

Compositions containing alprenolol acid: the ingredients are given in percent of the whole composition (wt/wt)

 Number example
 28293031
Valparola    
acidof 40.3to 25.325,823,2
PEG 4000,00,00,00,0
PEG 460045,256,657,751,9
PVP K29-321/62,00,00,0
Tween 80the 9.712,112,411,1
Ethanol    
fortress 1903,24,04,1the 3.8
 100,0100,0100,0100,0

 Number example
 323334
Valparola   
acid20,612,5 12,5
PEG 4000,037,575,0
PEG 460046,237,5*0,0
PVP K29-3220,012,512,5
Tween 809,90,00,0
Ethanol   
fortress 1903,30,00,0
 100,0100,0100,0

*PEG 4600 was replaced with PEG 3350

Compositions containing diclofenac sodium: the ingredients are given in percent of the whole composition (wt/wt)

  Number example 
 353637
Diclofenac   
sodium5,15,15,1
PEG 40024,444,989,8
PEG 460057,0to 49.9*0,0
PVP K29-320,05,15,1
Tween 8010,200 0,0
Ethanol   
fortress 1903,30,00,0
 100,0100,0100,0

*PEG 4600 was replaced with PEG 3350

Example 38

For the compositions listed above, you should replace the installed active ingredient on fexofenadin.

Example 39

A method of obtaining a composition in which omeprazole is the active ingredient preparation of the solution

In suitable first vessel was added 264,0 g of polyethylene glycol (PEG) 400, NF and 38.0 g of ethanol, fortress 190, USP. To the resulting solution, which is continuously mixed using a Lightnin agitator, was added 19,0 g PVP K29-32. Fillers was stirred for at least 30 minutes and to maintain a constant temperature between 40°s and 50°used With a water bath. the pH of the resulting solution brought to a pH of 13.5 with 8 M of sodium hydroxide. To the obtained solution containing the buffer slowly and periodically added 38.0 g of omeprazole, and at the same time constantly monitored and regulated pH, to maintain pH at least when at 9.0 by adding dropwise 8 M of sodium hydroxide. To the resulting solution was added level 113.0 g of Polysorbate 80, NF and the resulting solution was moderately paramesh the Wali for 10 minutes using a mixer Lightnin.

Manufacturing capsules

In suitable second vessel was added excess (600 g) of the required number of PEG 3350. PEG 3350 was heated on a water bath to maintain a temperature of approximately 55°C to 60°and mixed using a Lightnin agitator up until PEG 3350 was not melted. In the first vessel was added 528,0 g PEG 3350 from the second vessel, and the temperature of the mixture in the first vessel is maintained at a temperature of from 40°C to 50°With, at the same time stirring the mixture for at least 30 minutes. the pH of the resulting solution was maintained at approximately pH of 10.0 (pH 9,8-10,2) by adding 8 M solution of sodium hydroxide. Body capsules number one was filled, at the same time, the solution was constantly stirred and maintained at a temperature of from 45°C to 55°during the filling process. After corking the obtained capsules were weighed 575 g to 635 g (gross weight). Then each capsule of size one was placed in the capsule size to zero for cover.

In addition, these drugs were manufactured using 1.9 grams of omeprazole, of 15.4 g of PEG 400, 30,8 g PEG 3350 and 1.9 g of PVP K29-32 instead of those numbers, which are for the active ingredient and excipients, as described in the example 39.

Floor capsules

In the first glass vessel was added 440,0 g of acetone, NF, which was stirred to maintain moderate peremeci the project with Lightnin agitator. The acetone was added 10.0 g of triethylcitrate, NF, and was stirred for 2 minutes, followed by slow addition of 50.0 g of Eudragit® L100 with constant stirring for 10 minutes, or until until a homogeneous dispersion. The second glass vessel was added an aliquot of the mixture from the first vessel.

Under moderate stirring using a magnetic stirrer capsules zero size then manually partially dipped, left to dry and uncovered portion of such capsules are then manually dipped and left to dry. Each capsule was applied 3 complete coverage using the procedure described above. Otherwise apply other coatings known to the experts in this field, including, for example, coating by dipping, coating, spraying and the like.

1. Pharmaceutical oral liquid composition containing

one or more pharmaceutically active agent selected from the group consisting of those agents where,

at least one of these agents has at least one acid fragment, and at least one of these agents has at least one ester or other chemically active fragment, where terminal fragment to the specified ester or other chemically active fragment hydrolyzed or otherwise UDA is aetsa in situ or in vivo, forming at least one acid fragment; and where specified pharmaceutically active agent is soluble in the acid at a ratio of approximately 3:1 (acid to the dissolved substance) to 10000:1 (acid to the dissolved substance), or its pharmaceutically acceptable salt, with the specified one or more pharmaceutically active agent selected from the group consisting of nonsteroidal anti-inflammatory drugs, inapril, fluvastatin, lovastatin, pravastatin, cervistatin, atorvastatin, simvastatin, Fexofenadine, cromolyn, omeprazole, gemfibrozil, ciprofibrate, ciprofloxacin, lomefloxacin, ofloxacin, carbidopa, levodopa, retinoic acid, carboprost, penicillins, beta-lactams, cephalosporins, liothryonine and probenecid, and

at least one dispersing agent; and

at least one solubilizers agent; and, optionally,

at least one surfactant; and, in addition, optional

at least one plasticizing agent.

2. The pharmaceutical composition according to claim 1, in which the above-mentioned dispersing agent selected from the group consisting of dispersing agents, based on the polymer, and dispersing agents based on carbohydrate.

3. The pharmaceutical composition according to claim 2, to the second ratio above one or more pharmaceutical agent to the above-mentioned one or more dispersing agent, based on the polymer, is from about 3:1 (wt./wt.) to 1:50 (wt./wt.).

4. The pharmaceutical composition according to claim 3, in which the above-mentioned one or more dispersing agent, based on the polymer is polyvinylpyrrolidone.

5. The pharmaceutical composition according to claim 4, in which the above polyvinylpyrrolidone is polyvinylpyrrolidone having a molecular weight of 32,000.

6. The pharmaceutical composition according to claim 2, in which the ratio is above one or more pharmaceutically active agent to the above-mentioned one or more dispersing agent, based on the carbohydrate is from about 3:1 (wt./wt.) to 1:20 (wt./wt.).

7. The pharmaceutical composition according to claim 6, in which the above-mentioned one or more dispersing agent, based on the carbohydrate selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose and cyclodextrin.

8. The pharmaceutical composition according to claim 1, in which the concentration of the above-mentioned one or more solubilizing agent is about to 99% (wt./wt.) from the whole composition.

9. The pharmaceutical composition of claim 8 in which the above-mentioned one or more solubilizers agent selected from the group consisting of water and glycol.

10. The pharmaceutical composition according to claim 9, in which forefront of the lar weight of the above polyethylene glycol is from about 200 to 8000.

11. The pharmaceutical composition according to claim 9, in which the concentration of the above-mentioned polyethylene glycol is from about 20 to 99% (wt./wt.) from the whole composition.

12. The pharmaceutical composition of claim 8 in which the concentration is above the water is about to 99% (wt./wt.) from the whole composition.

13. The pharmaceutical composition according to claim 3, in which the concentration of the above-mentioned one or more solubilizing agent is about to 99% (wt./wt.) from the whole composition.

14. The pharmaceutical composition according to claim 6, in which the concentration of the above-mentioned one or more solubilizing agent is about to 99% (wt./wt.) from the whole composition.

15. The pharmaceutical composition according to claim 1, in which the above non-steroidal anti-inflammatory drugs are selected from the group consisting of aralkylamines acids and arylcarboxylic acids.

16. The pharmaceutical composition according to item 15, in which aralkylamines acid selected from the group consisting of diclofenac, fenoprofen, flurbiprofen, ibuprofen, indometacin, Ketoprofen, Ketorolac, naproxen, sulindaka, etodolac and Tomatina.

17. The pharmaceutical composition according to item 15, in which the above arylcarbamoyl acid selected from the group consisting of diflunisal, mefenamovoy acid, Melo is anamovie acid and flufenamic acid.

18. The pharmaceutical composition according to claim 1, in which the above penicillins are selected from the group consisting of amoxicillina and ampicillin.

19. The pharmaceutical composition according to item 13, in which the above-mentioned one or more pharmaceutically active agent selected from the group consisting of nonsteroidal anti-inflammatory drugs, inapril, fluvastatin, lovastatin, pravastatin, cervistatin, atorvastatin, simvastatin, Fexofenadine, cromolyn, omeprazole, gemfibrozil, ciprofibrate, ciprofloxacin, lomefloxacin, ofloxacin, carbidopa, levodopa, retinoic acid, carboprost, penicillins, beta-lactams, cephalosporins, liothryonine and probenecid.

20. The pharmaceutical composition according to 14, in which the above-mentioned one or more pharmaceutically active agent selected from the group consisting of nonsteroidal anti-inflammatory drugs, inapril, fluvastatin, lovastatin, pravastatin, cervistatin, atorvastatin, simvastatin, Fexofenadine, cromolyn, omeprazole, gemfibrozil, ciprofibrate, ciprofloxacin, lomefloxacin, ofloxacin, carbidopa, levodopa, retinoic acid, carboprost, penicillins, beta-lactams, cephalosporins, liothryonine and probenecid.

21. The pharmaceutical composition according to item 13, in which the concentration videocasino is possible, at least one plasticizing agent is approximately 75% (wt./wt.) from the whole composition.

22. The pharmaceutical composition according to item 21, in which the above-mentioned plasticizing agent selected from the group consisting of glycerin, propylene glycol and sorbitol.

23. The pharmaceutical composition according to 14, in which the concentration of the above possible, at least one or more plasticizing agent is approximately 75% (wt./wt.) from the whole composition.

24. The pharmaceutical composition according to item 23, in which the above-mentioned plasticizing agent selected from the group consisting of glycerin, propylene glycol and sorbitol.

25. The pharmaceutical composition according to item 21, in which the concentration of the above optional, at least one surfactant is approximately 10% (wt./wt.) from the whole composition.

26. The pharmaceutical composition according to item 23, in which the concentration of the above optional, at least one surfactant is approximately 10% (wt./wt.) from the whole composition.

27. Pharmaceutical dosage form, which is a capsule filled with a composition according to claim 1.

28. The pharmaceutical dosage form according to item 27, where the above-mentioned capsule is selected from the group consisting of soft the x gelatin capsules and hard gelatin capsules.

29. Pharmaceutical dosage form, which is a capsule filled with a composition according to p. 25 or 26, and need not be coated.

30. The pharmaceutical dosage form according to clause 29, where the above-mentioned capsule is selected from the group consisting of soft gelatin capsules and hard gelatin capsules.

31. The pharmaceutical dosage form according to clause 29, in which the above-mentioned one or more pharmaceutically active agent selected from the group consisting of nonsteroidal anti-inflammatory drugs, inapril, fluvastatin, lovastatin, pravastatin, cervistatin, atorvastatin, simvastatin, Fexofenadine, cromolyn, omeprazole, gemfibrozil, ciprofibrate, ciprofloxacin, lomefloxacin, ofloxacin, carbidopa, levodopa, retinoic acid, carboprost, penicillins, beta-lactams, cephalosporins, liothryonine and probenecid.

32. The way to increase the rate of absorption of one or more pharmaceutically active agent in mammals, in which the above-mentioned pharmaceutically active agent is chosen from the group consisting of the above agent, where

at least one of the above agents has at least one acid fragment, and

at least one of the above agents is at least one ester or friend is th chemically active fragment, where terminal fragment to the specified ether group or other reactive fragment hydrolyzed or otherwise removed in situ or in vivo, forming at least one acid fragment;

and where the above-mentioned pharmaceutically active agent is soluble in the acid at a ratio of approximately 3:1 (acid to the dissolved substance) to 10000:1 (acid to the dissolved substance), or its pharmaceutically acceptable salts, which consists in the introduction to a mammal in need of treatment of such pharmaceutically active agent, an effective amount of a composition according to claim 1, provided that the composition contains the above-mentioned possible surface-active substance.

33. A method of obtaining a pharmaceutical composition according to claim 1, wherein said at least one or more acidic fragment of the specified one or more pharmaceutically active agent is cyclotourism, including

education solution, at least one dispersing agent and at least one solubilizing agent and, optionally, one or more lower (1-C4)alkanol; adding a sufficient basis for establishing the pH of the solution, at least 9,0; and

add the specified one or more pharmaceutically active agent, at the same time supporting R is specified solution, at least 9,0; and, optionally,

one or more surfactants; and, in addition, optional

one or more plasticizing agents.

34. The method according to p, wherein said dispersing agent is selected from the group consisting of dispersing agents, based on the polymer, and dispersing agents based on carbohydrate.

35. The method according to clause 34, in which the ratio of the specified one or more pharmaceutically active agent to the dispersing agent selected from the group consisting of ratios of approximately 3:1 (wt./wt.) to 1:50 (wt./wt.) for these dispersing agents, based on the polymer, and from about 3:1 (wt./wt.) to 1:20 (wt./wt.) for these dispersing agents based on the carbohydrate, and the concentration of the specified one or more solubilizing agent is about to 99% (wt./wt.) from the whole composition.

36. The method according to p, wherein said at least one dispersing agent, based on the polymer is a polyvinylpyrrolidone specified, at least one dispersing agent, based on the carbohydrate selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose and cyclodextrin, and the specified at least one or more solubilizers agent chosen by the group, consisting of glycol and water.

37. The method according to p or 36, comprising the additional step of filling capsules pharmaceutical composition.

38. The method according to clause 37, in which the specified capsule is selected from the group consisting of soft gelatin capsules and hard gelatin capsules.

39. The method according to p or 38, wherein said one or more pharmaceutically active agent is a proton pump inhibitor.

40. The method according to § 39, in which the specified proton pump inhibitor is omeprazole.

41. The method according to clause 37, or 40, comprising the additional step of coating specified capsules are non-toxic, pharmaceutically acceptable coating.

42. The method according to paragraph 41, in which the specified floor is intersolubility coating layer.



 

Same patents:

FIELD: medicine, pharmaceutics, pharmacology.

SUBSTANCE: one should apply mammalian anti-HBP-antibodies. The ways are being suggested to identify monoclonal antibody bound, at least, with one epitope upon native HBP (heparin-binding protein) and methods to detect whether a mammal produces HBR being bound with a monoclonal antibody and, also, the kits for the above-mentioned purpose. The present innovation provides the opportunity to apply the mentioned antibodies in preventing and treating disorders associated with bradykinin releasing.

EFFECT: higher efficiency of application.

25 cl, 11 dwg, 3 ex, 1 tbl

FIELD: veterinary science.

SUBSTANCE: the suggested preparation for parturient activity, prophylaxis and therapy of afterbirth delay and puerperal endometritis in cows includes 0.05 g carbacholine, 70 g ichthyol, 5 g crystalline glucose and 1 g phenol/1000 ml distilled water. The method for treating acute puerperal endometritis in cows deals with injection of the above-mentioned preparation at the quantity of 20 ml preheated up to animal's body temperature deeply into gluteal muscles 4-8 times at interval of 24-28 h. The preparation suggested is considered to be of high curative and prophylactic efficiency.

EFFECT: higher efficiency.

2 cl

FIELD: organic chemistry and drugs.

SUBSTANCE: New class of compounds of general formula 1, where R has formula 2 or 3; other residues are as described in claim of invention is disclosed. Said compounds are interleikyn-1β converting enzyme (ICE) inhibitors and have specific structural and physicochemical properties. Invention also relates to pharmaceutical composition containing said compounds. Compounds and composition of present invention are particularly useful in ICE activity inhibition and thereby can be used as drug for treating of diseases mediated by IL-1, apoptosis, IGIF and IFN-γ, as well as inflammations, autoimmune diseases, bone-destructive disorder, infections, disorder associated with cell proliferation, degenerative and necrotic disorders. Uses of claimed compounds and compositions as well as methods for production of N-acylamino compounds also are disclosed.

EFFECT: effective interleikyn-1beta converting enzyme inhibitors.

64 cl, 35 ex, 35 tbl, 21 dwg

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: 5-aryl-1H-1,2,4-triazole derivatives of general formula I

, pharmaceutically acceptable salts thereof or pharmaceutical composition containing the same are described. In formula R1 is C1-C6-alkyl, C1-C6-haloalkyl or phenyl; R2 is C3-C8-cycloalkyl; phenyl optionally substituted with one or more substituents selected from C1-C4-alkyl; halogen, hydroxyl, C1-C4-alkoxy, nitro, di-(C1-C4)-alkylamino, C1-C4-alkylsulphonyl, C1-C4- alkylsulphonylamino, and methylenedioxy; phenyl-(C1-C4)-alkyl, wherein phenyl is substituted with C1-C4-alkoxy; or pyridil. New compounds are effective and selective cyclooxygenase-2 (COX-2) inhibitors and useful in treatment of inflammations.

EFFECT: new compounds for inflammation treatment.

10 cl, 36 ex, 1 tbl

FIELD: organic chemistry, heterocyclic compounds, biochemistry.

SUBSTANCE: invention relates to new compounds - purine derivatives of the general formula (I): in free form or salt wherein X means oxygen or sulfur atom or group NR5; R1 means alkyl, alkenyl, cycloalkyl, benzocycloalkyl, cycloalkylalkyl or aralkyl group that can be substituted optionally with hydroxy-, carboxy-group or alkoxycarbonyl; or if X means NR5 then R1 can mean alternatively heterocyclic group taken among benzylpiperidyl or the formula: ; or group of the formula (II): ; R2 means hydrogen atom, alkyl or alkoxy-group; R3 means hydrogen atom, alkoxy-, carboxy-group, carboxyalkyl, alkoxycarbonyl, -N(R9)R10, (C1-C4)-alkylene-SO2N(R11)R12 or -CON(R13)R14; or if two substitutes R2 and R3 are joined to adjacent carbon atoms in indicated benzene ring then in common with carbon atoms to which they are joined they mean heterocyclic group comprising 5-10 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen, oxygen and sulfur atom; R4 means hydrogen atom, alkoxy-, carboxy-group, carboxyalkyl, -SO2N(R11)R12, -N(R9)R10 or -CON(R13)R14; or if two substitutes R3 and R4 are joined to adjacent carbon atoms in indicated benzene ring then in common with carbon atoms to which they are joined they mean heterocyclic group comprising 5-6 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen, oxygen or sulfur atom; R5 means hydrogen atom or alkyl; R6, R7 and R8 mean hydrogen atom, or one of these radicals means -SO2NH2, -N(CH3)COCH3, -CONH2 and two others mean hydrogen atom; R9 means hydrogen atom or alkyl; R10 means hydrogen atom, -COR15 wherein R15 means alkyl, alkoxy-group; or R9 and R10 in common with nitrogen atom to which they are joined mean heterocyclic group comprising 5 or 6 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen and oxygen atom; R11 means hydrogen atom or alkyl; R12 means hydrogen atom, alkyl, hydroxyalkyl, carboxyalkyl or alkoxycarbonylalkyl; or R11 and R12 in common with nitrogen atom to which they are joined mean heterocyclic group comprising 5 or 6 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen and oxygen atom; R13 and R14 each and independently of one another means hydrogen atom or alkyl with exception of 2-(para-n-butylanilino)-6-methoxypurine, 2-(para-n-butylanilino)-6-(methylthio)purine, 2,6-di-(phenylamino)-purine, 2,6-di-(para-tolylamino)-purine and 2-(para-tolylamino)-6-(phenylamino)-purine.

EFFECT: valuable biochemical properties of compounds.

11 cl, 4 tbl, 221 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a method for preparing a pharmaceutical composition eliciting anti-inflammatory and analgetic activity for oral administration and containing compound of the formula (I): A-X1-NO2 wherein A and X1 are given in cl. 1 of the invention claim and representing in the amorphous state or partially amorphous state. Method involves the following steps: stirring compound of the formula (I) with at least one filling agent that is able to confer the amorphous state to obtained mixture wherein this filling agent is taken among group consisting of (C5-C6)-polyalcohols, mono- and disaccharides and their derivatives, oligosaccharides comprising from 3 to 10 monosaccharide units, polysaccharides, their derivatives involving their salts, cyclodextrins and their derivatives, noncyclic derivatives of β-cyclodextrin, polymers and copolymers based on vinyl monomeric links, and/or comprising the carboxyl function, or methacrylic monomers wherein the mass ratio between amount of compound of the formula (I) and the amount of at least one filling agent is in the range = (1:20)-(1:0.5), and providing the amorphous state of obtained mixture by combined grinding, stirring, spraying drying and lyophilization. Also, invention relates to a pharmaceutical composition eliciting an anti-inflammatory and analgetic activity. Invention provides preparing a pharmaceutical composition for oral administration and medicinal agents based on thereof for treatment of inflammatory diseases.

EFFECT: improved preparing method, valuable medicinal properties of composition.

10 cl, 1 tbl, 10 ex

FIELD: medicine, phytotherapy, pharmaceutical industry and technology, pharmacy.

SUBSTANCE: invention relates to a method for preparing agent eliciting immunocorrecting and anti-inflammatory activity. Method for preparing the phytopreparation eliciting immunocorrecting and anti-inflammatory activity involves milling common horse radish fresh roots, extraction of raw by maceration method in the definite ratio of ratio raw : extractant for definite time at room temperature, at periodic stirring, clarification of extract under definite conditions and filtration. Method provides preparing the phytopreparation from common horse radish roots for carrying out pharmacotherapy of immune deficient states and inflammatory diseases.

EFFECT: improved preparing method, valuable medicinal properties of preparation.

4 tbl, 3 ex

FIELD: medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to the agent comprising the following components: lidazum (16-32 U), proserinum 0.05% solution, 0.00025-0.0005 g; methylprednisolone succinate sodium, 0.02-0.04 g; lidocaine 10% solution, 0.05-0.1 g, and glucose 40% solution, 3-4 ml. Also, invention relates to a method for administration of agent and a method for treatment of inflammatory diseases. Invention provides expanding assortment of medicinal agents and improving the regional transport of medicinal preparations.

EFFECT: improved and valuable properties of agent.

6 cl, 5 ex

FIELD: pharmaceutical industry.

SUBSTANCE: rectal- and vaginal-administration suppositories contain 1,3-diethylbenzimidazolium triiodide as active principal, polyvinylpyrrolidone as solubilizer and stabilizer, and lipophilic base with specified proportions of components.

EFFECT: extended therapeutical activity and reduced occurrence of side effects.

4 cl, 2 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with curative ointments of antiphlogistic and wound-healing action and could be applied for treating hemorrhoid, burns, bruises, fractures, wounds, chronic bronchitis, polyarthritis, periarthritis, radiculitis, trophic ulcer and psoriasis. Three variants of ointments have been suggested. They contain oily extract of plant components and, also, honey, mumiye, propolis and bear oil. This innovation enables to widen the assortment of ointments of antiphlogistic and wound-healing and the range of curative action upon a body.

EFFECT: higher efficiency of application.

3 cl, 11 ex

The invention relates to the field of medicine and surgery and it can be used in extreme conditions with severe injuries, evacuation, field

The invention relates to medicine, therapy, and can be used for treatment of pain
The invention relates to medicine, namely to Oncology, and can be used for the treatment of pain in cancer patients in the postoperative period, incurable patients

The invention relates to possess analgesic activity of new substituted Cycloheptane General formula I

in which R1IT denotes, O-C1-C6alkyl, R2represents C1-C6alkyl, (CH2)(1-2)-aryl, and R3means (CH2)(0-1)-C5-C7cycloalkyl, (CH2)(0-2)-aryl, and the rest of the aryl can be substituted one or more times, HE, F, Cl, CF3C1-C6the alkyl, in the form of their racemate or enantiomer, in the form of bases, and salts physiological acceptable acids

The invention relates to medicine, in particular to the treatment of pain

The invention relates to a peptide, which is derived prosaposin containing from 14 to 50 amino acids and including the sequence Thr-XAA-Leu-Ilе-Asp-Asn-Asn-Ala-Thr-Glu-Glu-Ile-Leu-Tight

The invention relates to a synthetic amide of opioid peptide or its pharmaceutically acceptable salt having affinity against-opioid receptor, which is at least 1000 times greater than its affinity in relation to-opioid receptor, and which reveals long-term effect when introduced in vivo, and this peptide has the following formula:

H-Xaa1-Xaa2-Xaa3-Xaa4-Q

where Xaa1shown are (A)D-Phe,D-Tyr, D-Tic, or D-Ala (cyclopentyl or thienyl), and A - N, NO2, F, Cl or CH3; Xaa2(A')D-Phe, D-1Nal, D-2Nal, D-Tyr or D-Trp, where A' - or 3,4 Cl2; XAA3- D-Nle, (B)D-Leu, D-Hle, D-Met, D-Val, D-Phe or D-Ala (cyclopentyl), and In - N or CMe; XAA4represents the D-Arg, D-Har, D-nArg, D-Lys, D-i.l.y bit, D-Arg (Et2), D-Har(Et2), D-Amf, D-Gmf, D-Dbu, D-Orn or D-Ior; a Q - NR1R2morpholinyl, thiomorpholine, (C)piperidinyl, piperazinil, 4-one or 4,4-disubstituted piperazinil or-lysyl, where R1is lower alkyl, substituted lower alkyl, benzyl, substituted benzyl, and the laminitis)-polymethene or 4-polyoxyethylene group, a R2is H or lower alkyl; C - H, 4-hydroxy or 4-oxo

The invention relates to medicine, specifically to the creation of oral compositions, consisting of many subunits, which are granules prolonged action and containing tramadol or its physiologically tolerated salt and at least one pharmaceutically acceptable compound that slows the release of the active substance, as well as to a method for producing such compositions

FIELD: medicine.

SUBSTANCE: method involves applying eradicative anti-helicobacterial therapy comprising Omeprazol administration at a dose of 20 mg twice a day and Ximedone at a dose of 500 mg twice a day in 12 days long course.

EFFECT: enhanced effectiveness of eradication; reduced adverse side effects risk.

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