The pharmaceutical composition of cefuroxime aksetila masked with a bitter taste
The invention relates to pharmaceutical compositions cefuroxime aksetila in the form of particles. The particles have a continuous coating of the lipid or mixture of lipids, which are insoluble in water and disperse or dissolve upon contact with gastric juice. The composition comprises a bulk sweetener and binder, and optionally includes a system sweeteners and modifier structure. The modifier is a thickener, or a combination of thickeners and is used in quantities sufficient to mask the bitter taste of cefuroxime aksetila oral. The invention provides an improvement of the General “feeling” in the mouth from suspension cefuroxime aksetila than promotes respect for patients schema and mode of treatment. 11 C.p. f-crystals, 11 PL.
The scope of the invention
The present invention relates to compositions, in particular pharmaceutical compositions containing complex 1-ecotoxicology ester of cefuroxime, which was called “cefuroxime aksetil”.
Background of invention
Cefuroxime, as described in British patent application No. 1453049, is an antibiotic Shiro and gram-negative microorganisms. This property is enhanced due to the high stability against-lactamase produced near gram-negative microorganisms. Cefuroxime and its salts are mainly valued as antibiotics for injections because they are poorly absorbed from the gastrointestinal tract.
The esterification of the carboxyl group of cefuroxime to complex 1-ecotoxicologie ether, giving cefuroxime aksetil, improves the effectiveness of oral administration, as described in British patent application No. 1571683. 1-acetoxyethyl esterified groups leads to a significant absorption from the gastrointestinal tract, and then esterified group is hydrolyzed under the influence of enzymes, e.g. in serum and tissues of the body, giving the acid activity of the antibiotic. Particularly useful cefuroxime aksetil in amorphous form, as described in British patent application No. 2127401.
Traditionally, antibiotics for oral administration is used in the form of granules, which can be taken in the form of a solution or suspension, or drinking a SIP of water. A solution or suspension of the granules, for example in the form of syrup, especially convenient for oral is aneesa and cannot be adequately masked by the addition of sweeteners and corrigentov to usually manufactured granular preparations.
Another problem arises from the tendency cefuroxime aksetila, as in crystalline form or in amorphous form, to the formation of gel-like mass upon contact with an aqueous medium. This effect gelation depends on the temperature, but occurs at temperatures around 37°C, i.e., at physiological temperatures, in which there is a disintegration of the oral input granules. Even when using a relatively low dispersion cefuroxime aksetila in the aquatic environment, after ingestion, there is still a risk that is present in the composition cefuroxime aksetil can form gel. Such gelation leads to poor dissolution cefuroxime aksetila and, consequently, poor absorption from the gastrointestinal tract, i.e. low biological availability. In the case of granular formulations, in order to avoid gelation, it is desirable to use particles of a small diameter and high surface area.
In the manufacture of granules cefuroxime aksetila it is important to avoid release of the medicinal product in any liquid medium in which it suspendered, even in the mouth during the reception. Such problems can be minimized by making pravide particles, where solved the above problem. This patent describes a composition including cefuroxime aksetil in the form of particles, the particles have a continuous coating of the lipid or mixture of lipids, which is insoluble in water and is used for masking the bitter taste of cefuroxime aksetila when administered orally, but which is dispersed or dissolved upon contact with gastric juice. Particles obtained by coating dissolved upon contact with gastric juice, thereby allowing the particles to quickly dispergirujutsja or dissolve in the gastric juice.
WO 94/25006 describes the method for taste masking of bitter drugs in the form of particles by mixing the drug with the lipid at a temperature below the temperature at which significant decomposition of the drug. To obtain a stable pharmaceutical composition with masked taste to the mixture of drug and lipid type emulsifier and surfactant, polymer solution and the diluent.
WO 00/076479 describes compositions with masked taste, including bitter taste of the active ingredient, such as cefuroxime aksetil, and two intersolubility polymer, namely a copolymer of methacrylate is of the matrix of “solid solution”, where the drug is contained in a thin dispergirovannom state inside the polymer, which prevents the detection of bitter taste gustatory papillae.
Applicants recently released on the market oral composition in the form of a suspension comprising cefuroxime aksetil where the particles have a continuous shell of lipid in the United Kingdom under the trademark Zinnat and in the USA under the brand name Ceftin. This oral composition in the form of a suspension includes, in addition to cefuroxime to aksetilom, inactive ingredients: stearic acid, flavoring sweeties (tutti frutti - tutti Frutti), binding agent (Povidone K30) and sucrose as a bulk sweetener.
Although the lipid coating to some extent allows to mask the bitter taste of cefuroxime aksetila in oral administration, cefuroxime aksetil so bitter that these suspensions and the songs still have a bitter taste, and especially is a problem when it is received by the children. In addition, the suspension can create a feeling of “sand” in the mouth, which makes them less enjoyable than the suspension of other antibiotics. Both of these factors can badly affect patient compliance with the regimen of medicines,ient will feel better than to continue the prescribed course. In light of the above, there is a need for improved suspension cefuroxime aksetila enough to reduce the bitter taste and improve the “feeling” in his mouth.
The authors of the present invention was unexpectedly discovered a way to further improve the taste of cefuroxime aksetila used to obtain the suspension, so that it unpleasant bitter taste was more acceptable. Conveniently, that the General “feel” in the mouth from the composition in the form of a suspension cefuroxime aksetila also improved, in the sense that it becomes less feeling of sand and easier to swallow.
Brief description of the invention
According to the present invention includes a composition comprising cefuroxime aksetil in the form of particles, which particles have a continuous coating of the lipid or mixture of lipids, they are insoluble in water and disperse or dissolve upon contact with gastric juice, characterized in that the composition additionally includes a system sweeteners and modifier patterns in quantities sufficient to mask the bitter taste of cefuroxime aksetila.
In particular, the present invention relates to a composition comprising tsefa storymy in water and disperse or dissolve upon contact with gastric juice, bulk sweetener and binder, characterized in that the composition additionally includes a system sweeteners and modifier patterns in quantities sufficient to mask the bitter taste of cefuroxime aksetila.
It has been unexpectedly discovered that the system sweeteners and modifier structures act synergistically reducing bitter taste and improving the “feel” in the mouth, and thereby ensure that patients schema and mode of treatment. As indicated above, the system sweeteners reduces the bitter taste due to the initial sweet taste in the mouth. However, the simultaneous use of modifier structure helps to ensure that the structure of the cream, improving the “feel” in the mouth and in addition reducing the number of particles with a lipid coating remaining in the mouth after swallowing the drug, further reducing bitter taste. Use only the individual sweeteners or only modifier structure does not give such a significant simultaneous improvement in masking the taste and sensation in your mouth. Applicants found that such positive effects are manifested when sweeteners are mixed, and additionally improve when modificationtime lipid or mixture of lipids for particles cefuroxime aksetila along with ways of obtaining particles of cefuroxime aksetila with the lipid coating is described, for example, in GB 2204792, the content of which is incorporated in its entirety by reference. Particularly preferred lipid coating is stearic acid in a mixture of palmitic acid in the ratio ranging from 3:7 to 7:3 by weight, more preferably 1:1 by weight.
The composition according to the invention may contain cefuroxime aksetil in crystalline and amorphous forms, and more preferably in crystalline form, for example as described in GB 2127401.
As described in GB 2204792, particles cefuroxime aksetila can be covered with an intermediate layer of a substance with the properties of the coating material to protect cefuroxime aksetila in cases where cefuroxime aksetil can be chemically-sensitive lipid, which it is covered. As described in GB 2204792 covered by an intermediate layer of particles, in which cefuroxime aksetil is present at a concentration of 10-30%, for example about 20%, usually can be used for coating the lipid.
Suitable methods of coating particles cefuroxime aksetila a lipid or mixture of lipids is described in GB 2204792. The patent also indicates the preferred dimensions covered by the lipid particles. When cefuroxime aksetil to disperse the lipid cover pranevich % by weight of coated particles.
Covered with lipid particles according to the present invention preferably contain from 5 to 90%, more preferably from 5 to 50% and even more preferably from 5 or 10 to 30 mass % cefuroxime aksetila. When cefuroxime aksetil first intermediate cover layer, the particles with the lipid coating is most preferably contain from 5 to 15 mass % cefuroxime aksetila, when the intermediate layer is not used, the particles with the lipid coating is most preferably contain from 10 to 30 mass % cefuroxime aksetila.
Under “system sweeteners” understand the sweetener or combination of sweeteners that are added in addition to the bulk sweetener used in the granulation process, described below, and in particular intended to create an acceptable level of sweetness of the drug. System sweeteners of the present invention causes a reduction of the bitter taste. Preferably sweeteners, artificial or natural origin used either individually or in a mixture. Suitable sweeteners include, but are not in the order restrictions, saccharin, Nachrichten, nutritional, Acesulfame, thaumatin, neohesperidoside, thaumatin, neohesperidoside, ammonium salt licorice root and aspartame.
System sweeteners is approximately in the range of 0.1-10 mass % of the final granulated composition, more preferably about 0.3 to 5 mass %. When two of sweetener used in the mixture, the mass ratio between the two sweeteners is from about 1:10 to 10:1.
The preferred system sweetener is a mixture of Acesulfame and aspartame, preferably in a mass ratio of about 1:1.
The composition further includes a modifier structure comprising one or more thickeners. Modifier patterns add in addition to any thickeners and binders tools, which can optionally be part of the composition, and therefore it is an essential characteristic of the invention. Under “modifier patterns” understand thickener, or a combination of thickeners, which help to improve the structure of cefuroxime aksetila at its location in the mouth, because they create the desired “feel” in the mouth.
Used the modifier structure has an effect to reduce the bitter taste, suspending and more easily swallowed. Suitable modifiers patterns chosen from the group comprising polyvinylpyrrolidone (povidone, for example Povidone K30 or Povidone K90, nutricosmetics, hydroxyethyl cellulose, hydroxypropylcellulose, guar gum or xanthan gum.
Alternative modifiers patterns chosen from the group comprising polyvinylpyrrolidone (povidone, for example Povidone K30 or Povidone K90, sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, guar gum, alginates, carageenan or xanthan gum.
Preferably the modifier structure is xanthan gum.
Most preferably, the system sweetener is a mixture of Acesulfame and aspartame and modifier structure is xanthan gum.
Modifier structure preferably is present in a mass ratio modifier:particles with a lipid coating in the range from about 1:300 to 1:3000, more preferably in the range from 1:500 to 1:1500. The modifier is from about 0.01 to 5 mass % of the final granulated composition, more preferably, from about 0.01 to 1 mass %.
The mass ratio m is sustained fashion, in the range from 1:10 to 1:100.
The mass ratio of particles with a lipid coating system sweeteners:modifier patterns in the final granulated composition is in the range from about 300:10:1 to 3000:100:1, preferably approximately in the range from 500:10:1 to 1500:100:1.
The composition of the fractions sweetener/modifier composition can also optionally contain other excipients, such as suspendresume and binding agents, fillers, thickeners, corrigentov and bulk sweeteners.
Suitable suspendresume and binding agents include, but are not in the order restrictions, alkylaryl, such as methylcellulose, hydroxyethylcellulose, such as hydroxypropylcellulose and hypromellose, sodium carboxymethyl cellulose, or mixtures thereof, pre-gelatinizing starch or polyvinylpyrrolidone.
Suitable excipients include sucrose, starch, lactose and microcrystalline cellulose.
Bulk sweeteners suitable for the present invention include sorbitol, sucrose, or artificial sweeteners, such as Nachrichten or nutritional.
Alternatively, surround the treatment tip can the RAM, sucrose or artificial sweeteners, such as Nachrichten or nutritional.
Thickeners that are appropriate to the purposes of the present invention include, but are not in the order restrictions, lecithin or aluminum stearate.
Suitable corrigentov, such as mint, peppermint, strawberry or tutti Frutti may optionally be present in the composition.
In a preferred embodiment, the granules cefuroxime aksetila with lipid coating granularit with sucrose using an aqueous solution of polyvinylpyrrolidone (povidone) as a binder to obtain pellets. Add a suitable corrigent, such as a flavoring tutti Frutti, and the composition is stirred. Sweetener and modifier structure according to the present invention can be mixed with granulated particles in the form of a dry mixture using conventional methods prior to, after or at the time of adding corrigenda to obtain the final granulated composition. Alternatively, the sweetener and the modifier patterns can be mixed with lipid particles during granulation. During the mixing process, you must ensure that the system sweeteners S2">The product in the form of particles according to the present invention can be used in pharmaceutical compositions for oral administration and can be represented in the form of a suspension for use in the form of a dry product for dissolution (recreation) water or other suitable diluent for suspension or for direct reception of the product and then drinking after water or other suitable liquid.
The present invention is also a pharmaceutical composition for oral administration comprising the composition according to the present invention together with one or more pharmaceutical carriers or excipients.
The pharmaceutical compositions of the present invention, manufactured for oral administration in the form of suspensions may be formulated with a suitable amount of water to apply cefuroxime aksetila for oral administration. Particles are usually present in such quantity to obtain a suspension multiple doses, containing the equivalent of 125 mg - 5 g cefuroxime aksetila, or suspension with a single dose containing the equivalent of 125-500 mg cefuroxime aksetila.
Doses used for treatment of humans, are typically in the range from CNA dose depends including, and frequency of administration.
The present invention is additionally illustrated by the following examples which are not considered as limiting.
Used in the examples cefuroxime aksetil consists of the dried spray dried amorphous material of high purity, obtained as described in GB 2127401. System sweeteners and modifier patterns evenly mixed with granules cefuroxime aksetila in the form of a dry mix.
Suspension cefuroxime aksetila 125 mg/5 ml (see table. 1).
Suspension cefuroxime aksetila 125 mg/5 ml (see table. 2).
Suspension cefuroxime aksetila 125 mg/5 ml (see table. 3).
Suspension cefuroxime aksetila 125 mg/5 ml (see table. 4).
Suspension cefuroxime aksetila 125 mg/5 ml (see table. 5).
Suspension cefuroxime aksetila 250 mg/5 ml (see table. 6).
Suspension cefuroxime aksetila 250 mg/5 ml (see table. 7).
Suspensibility 250 mg/5 ml (see table. 9).
Test is carried out on the taste, with 5 volunteers appreciate the slurry composition of example 1, reconstituted with drinking water, according to the following categories:
Initial taste: sweet or bitter
Remaining in the mouth after administration of the composition: present or absent residual bitter taste
Mouth feel: cream or sand
Flavoring: pleasant or unpleasant
The test results on the taste are shown in table 10.
Conducted additional tests on the taste on the number of adult healthy patients to compare the slurry composition of example 1 (125 mg/5 ml) and example 6 (250 mg/5 ml) suspension of identical compositions cefuroxime aksetila, with the exception that there is no system of sweeteners and modifier structure. The compounds at the indicated concentrations of active substances assessed in the “fresh”, i.e. were evaluated svezhesobrannye compositions.
In the preferred testing suspension compare on sweets, Horikoshi, the sensation in the mouth and preference in General. The results are shown in table 11, showing the percentage of patients who preferred about the Sabbath. The results clearly show what suspension according to the present invention, optionally containing sweeteners and modifier patterns represent the most preferred form, both in taste and mouth feel.
1. Pharmaceutical composition with masked taste, including cefuroxime aksetil in the form of particles, which particles have a continuous coating of the lipid or mixture of lipids, which are insoluble in water and disperse or dissolve upon contact with gastric juice, bulk sweetener and binder, characterized in that the composition additionally includes a system sweeteners and modifier structure representing a thickener, or a combination of thickeners in amounts sufficient to mask the bitter taste of cefuroxime aksetila.
2. The pharmaceutical composition under item 1, in which the system of sweeteners includes at least one sweetener, artificial or natural origin selected from saccharin, sodium saccharin, sodium cyclamate, Acesulfame potassium, thaumatin, neohesperidoside, ammonium salt licorice root and aspartame.
3. The pharmaceutical composition under item 1 or 2, in which the system sweeteners vqlue under item 2, which sweeteners are Acesulfame potassium and aspartame.
5. The pharmaceutical composition according to p. 4, in which Acesulfame potassium and aspartame are present in a mass ratio of 1:1.
6. The pharmaceutical composition under item 1, in which the modifier structure selected from polyvinylpyrrolidone, sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, the guar gum, alginates, carageenan or xanthan gum.
7. The pharmaceutical composition according to p. 6, in which the modifier structure is xanthan gum.
8. The pharmaceutical composition under item 1, in which the mass ratio of modifier structure:the system of sweetener is in the range from about 1:1 to 1:1000.
9. The pharmaceutical composition under item 1, in which the mass ratio of particles with a lipid coating system sweeteners:modifier structure is in the range from about 300:10:1 to 3000:100:1.
10. The pharmaceutical composition under item 1, characterized in that it further comprises one or more pharmaceutically acceptable carriers or excipients.
11. The pharmaceutical composition under item 10 in the form of a water suspension.
in which Y denotes a hydrogen atom or fluorine; n denotes an integer from 1 to 8; Z represents a hydrogen atom or a residue of carboxylic acid, and in which pyrazol cycle substituted heteroaryl radical, which contains one nitrogen atom; and their salt adducts with tilotama