Containing hydrated ceftibuten powder antibacterial composition intended for oral use in the form of a suspension

 

(57) Abstract:

Powder antibacterial composition comprises the following components, mg/g: hydrated ceftibuten 65-150, including 7-14 wt.% water; nonionic surfactant 0,30-0,50; protivovspenivayushchie agent 0,6-1,0; thickener selected from the group comprising silicon dioxide, a silicate of magnesium, a mixture of microcrystalline cellulose and carboxymethyl cellulose mass ratio of 6:1 to 10:1 xanthan resin and mixtures thereof; giving the opacity of the substance 14-22 and the rest is at least one sweetener. The new composition is stable. When suspendirovanie powder composition in water, the resulting suspension is stable to sedimentation and decomposition during storage in air containing about 20 vol. % oxygen. 8 C.p. f-crystals, 1 Il., table 4.

The invention relates to a stable solid pharmaceutical compositions of derivatives of cyclosporine, in particular containing hydrated ceftibuten powder antibacterial compositions intended for oral use in the form of a suspension.

Known antibacterial powder composition intended for oral use the ia-1-azabicyclo [4.2.0] -Oct-2-ene-2-carboxylic acid, representing the containing cephalosporin antimicrobial agent] in an effective amount and at least one additive from the group comprising sweeteners, fillers, thickeners and lubrication, and the composition is enclosed in a hermetically-sealed capsules of hard gelatin (see U.S. patent No. 4 812561, MKI A 61 K 31/545, 1989).

Due to the instability of suspension known antibacterial powder composition is not suitable for application in the form intended for oral use of a suspension, for example, in the water.

The objective of the invention is to create a stable powder antibacterial compositions containing a derivative of hydrated cephalosporin, in particular hydrated ceftibuten, containing approximately 7-14 wt. % water, making the composition suitable for suspension in water for oral use.

The problem is solved powder antibacterial composition intended for oral use, containing hydrated ceftibuten, including approximately 7-14 wt.% water, giving the opacity of the substance, at least one sweetener and thickener, due to the fact that ispolnyayushiy agent, a thickener selected from the group comprising silicon dioxide, a silicate of magnesium, a mixture of microcrystalline cellulose and carboxylmethylcellulose mass ratio of 6 : 1 to 10 : 1, xanthan resin and mixtures thereof, and the composition contains components in the following amounts (mg/g):

65 - 150 ceftibuten, including 7-14 wt.% water,

0,30 - 0,50 nonionic surfactants,

of 0.60 to 1.0 protivovspenivayushchie agent,

20 - 40 specified thickener,

14 - 22 gives the opacity of the substance, and the rest is at least one sweetener.

According to the first preferred form of execution of the invention offer antibacterial powder composition contains (mg/g):

65 - 150 hydrated ceftibuten, including 7-14 wt.% water,

0,3 - 0,5 nonionic surfactants, preferably Polysorbate 80,

0,6 - 1,0 protivovspenivayushchie agent, preferably simeticone,

12 - 20 xanthan gum as a thickener,

8 - 12 of silicon dioxide as an additional thickener,

14 - 22 gives the opacity of the substance, preferably titanium dioxide, and the rest is at least one sweetening substances is redlagaemaya powder antibacterial composition contains (mg/g):

72 - 144 hydrated ceftibuten, including 7-14 wt.% water, preferably di -, or three hydrate ceftibuten,

0,4 nonionic surfactants,

0,8 protivovspenivayushchie agent,

16 xanthan gum as a thickener,

10 of silicon dioxide as an additional thickener,

18 gives the opacity of the substance and the rest is at least one sweetener.

In the case of powder antibacterial composition is intended for oral application in the form of an aqueous suspension, it additionally contains 3 to 9, in particular approximately 4-8 water-soluble preservative, and 3 to 5, in particular about 3-4 fruit flavoring substance, preferably enclosed in microcapsules fruit flavourings.

We offer powder antibacterial composition, which preferably contains ceftibuten in the form of di - or three-hydrate, should preferably be stored in an atmosphere having a maximum oxygen content, comprising about 5 to about. %.

Nonionic surfactant that may be present in compositions according to the invention can be polyaxial interaction of fatty acids and polyhydric alcohols, or the anhydrides of such alcohols, esterified polyalkylene oxides. Preferred are addition products monoterpenovogo ester of lauric acid to 20 mol of ethylene oxide, similar compounds containing palmitic or oleic acid, and the product of the interaction of a complex of propylene glycol ester of stearic acid with 25 mol of ethylene oxide. There are a number of various other pharmaceutically acceptable nonionic surfactants and other media listed below. The most preferred nonionic surface-active agent is Polysorbate 80, sold by ICI Americas under the trade name Tween 80 and representing a mixture of complex sorbitolovy esters of oleic acid and their anhydrides, consisting mainly of complex monoether to which precondensation about 20 mol of ethylene oxide.

If used as a thickener mixture of microcrystalline cellulose and carboxymethylcellulose, their preferred mass ratio is 1:1.3 to 1: 2, in particular 1,6.

As water-soluble preservatives according to the invention can be used sodium benzoate, sodium citrate, chlorine is as preservative use sodium benzoate.

As protivovspenivayushchie agent you can use any commercially available agent suitable for this purpose, for example, methylated linear siloxane polymers end trimethylsiloxy links, for example, Dimethicone and simethicone, as well as mixtures of Dimethicone with an average chain length, part 200 - 250 dimethylsiloxane units and silica gel.

Suitable, giving the opacity of the substances in the framework of the present invention are pharmaceutically acceptable metallic oxides, in particular titanium dioxide.

As sweeteners in the framework of the present invention can be used sugar substances, such as fructose, sucrose, glucose, maltose or lactose, and no-calorie sweeteners, such as aspartame, which can be used separately or in combination with other no-calorie or low-calorie sweetening matter, with a synergistic sweetening effect with aspartane, for example, saccharin, Acesulfame, thaumatin, Halcon (benzylideneacetophenone), cyclamate, stevioside, etc. Data combinations of sweeteners can be used in smaller quantities, and they give good kadotettua. Because they are more sweet than aspartame, can be applied in fewer than aspartame, for example, in the frozen dietary desserts.

The filler in apartamentai combinations of sweeteners used in the framework of the present invention consists of nematoblastic beskosova hydrocarbons, and suitable hydrocarbon is, for example, Polydextrose, which may be in liquid or solid form and contains one calorie per gram. It can be used separately or in combination with a small amount of sugar alcohols, such as mannitol, xylitol etc. These sugar alcohols contribute sweets, and usually they are metabolisme. According to the invention sorbitol can be used in combination with Polydextrose, if, as a combination of sweeteners used a combination of aspartame and synergy with him on the sweetness of the above substances. In addition, you may also have smaller amounts of sugar substances as, for example, corn syrup, fructose, dextrose or glucose, which also contributes to the sweetness.

Fillers are used to improve the structure and mouth feel, what those oils, or honey.

Other substances that can be used either as filler or in the composition of the fillers are carboxymethylcellulose, or karboksimetilcelljuloza as, for example, microcrystalline cellulose Avicel (trade product of the company FMC Corporation, Philadelphia, USA).

Although the above fillers are preferably used in combination with Polydextrose, they can also be applied in dry powder compositions according to the invention or separately, or in a mixture with each other.

Sweetening agent and filler can be added to the drug in available form, in particular in solid form, or in an enclosed capsule form to obtain a flowable powder.

In the framework of the present invention is suitable fruit flavoring substance enclosed in microcapsules, in which the flavouring substance is protected from decomposition and/or oxidation, as well as from the interaction with other components of the dry powder composition according to the invention. Preferably use fruit flavoring substance enclosed in the microcapsules containing maltodextrin.

According to a preferred form of the invention offer paraskevopoulou composition according to the invention can be submitted in bottles of 60 ml as aliquots 5, of 7.5 or 15 g, or in bottles of 120 ml as aliquots 25 or 30, With the addition of an appropriate amount of sterilized water receive pharmaceutical composition comprising or 18 mg/ml, or 36 mg/ml of three-hydrate ceftibuten.

The number of hydrated ceftibuten varies depending on its water content and effectiveness of party and used appropriately regulate the amount of sweeteners, such as sucrose. The number of hydrated ceftibuten may exceed the specified value by 8 %.

Antibacterial effective amount preferably used of the three-hydrate ceftibuten is usually about 4.0 - 13 mg per kg of body weight per day, preferably about 9 mg per kg of body weight per day. Needless to say that the exact dose is determined by the doctor depending on the patient's weight, age, sex and physical condition, and the severity of bacterial destruction. Preferred pharmaceutical composition in the form of aqueous suspensions intended for oral application, preferably given once or twice a day.

We offer powder antibacterial composition was prepared way is or in the form of dry solid powder with mainly dry pharmaceutically portable media group, including thickeners, giving opacity substances and sweeteners, to obtain the dry mixture, and feeding the resulting dry mixture in a hermetically sealable container, impervious to rays of the visible spectrum, while the hydrated ceftibuten optionally mixed with at least one surface-active substance, at least one protivovspenivayushchie agent and at least one preservative, and thus obtained dry mixture served in a tightly sealable container in the atmosphere with a maximum oxygen content constituting about 5% vol.

Intended for oral use suspension obtained by mixing the powder composition according to the invention with water, preferably sterile water, is resistant to settling in for an unexpectedly long period. For example, the suspension, including the preferred trihydrate containing ceftibuten powder composition according to the invention is resistant to sedimentation for at least 3 hours, preferably 24 hours, and decay-resistant for at least two weeks in the presence of the drug atmetimas powder served in the capacity impervious to radiation, with the presence of a nitrogen atmosphere on a drug, the maximum oxygen content which is about 5 vol.%, at a temperature of 2 - 25oC.

The method of obtaining the above preferred powder compositions containing 18 mg/ml (72 mg/g) respectively 36 mg/ml (144 mg/g) of three-hydrate ceftibuten, preferably contains the following methods:

1. Sucrose is crushed, passed through a sieve with a suitable amount of cells and loaded in a suitable mixer.

2. In a separate suitable mixer serves xanthan resin, or during mixing slowly add the Polysorbate 80 and simethicone. Also add part of the sugar and continue to stir for about 5 minutes.

3. Silicon dioxide, sodium benzoate and titanium dioxide are passed through a sieve of the size of the cells 30 mesh (or other appropriate sieve, and mixed with the other part of the powdered sugar.

4. The substances according to the reception 3 add to the mixture obtained according to technique 2, and mixed with part of the sugar for about 10 minutes.

5. Received according to the reception 4 mixture to the sugar according to 1, then add the trihydrate of ceftibuten and peremeci is N 2 (or the corresponding crusher/corresponding sieve), and served back to the mixer.

7. Prepare the mixture with the taste of cherry, which is added in the mixer the mixture, and stirred for at least 20 minutes.

8. Certain quantity of powder served in a relevant capacity in the atmosphere with a maximum oxygen content, comprising about 5 to about. %.

9. Tightly closed containers store before placing in containers.

Choose packaging that protects the product from moisture and radiation, for example, light, and oxygen.

On the basis of data on physical and chemical stability of the drug as containers under dry, containing hydrated ceftibuten powder drugs choose yellow glass bottle fitted with a suitable shut-off site, including 1) rubber stopper and floor, equipped with aluminum foil, and 2) the shutter with teams of two parts plastic screw-on cap with soft plastic lining (with a waxy coating) and at a pressure sensitive samanlaisuuksia internal closing element, made for example from vinyl, as aluminum foil or paper. According to preferred forms of execution nastoiasciaia tanks fitted with a suitable shut-off site, and the space above the powder-filled inert atmosphere, e.g. nitrogen, with a maximum oxygen content, comprising about 5 to about. %, preferably of 0.5 vol.%, when closed containers are impervious to rays, for example, the visible spectrum, and stored at a temperature of 2 - 25oC in a dark place. Preferably, the storage temperature is 2 - 8oC.

According to the method, the techniques described above can be obtained, for example, a composition having specified in table 2 composition.

To determine the homogeneous distribution of the three-hydrate ceftibuten in water suspension after receiving a suspension spend experience on the deposition. The slurry obtained by adding water to placed in the bottle of powder preparation containing the trihydrate of ceftibuten, and intensive shaking for 5 minutes or less. At certain intervals from the bottle by pouring without shaking take samples weighing 10, Determine the concentration of ceftibuten in the samples. Table 2 shows that ceftibuten evenly dispersed throughout the suspension even after 180 minutes (3 hours) in the presence of ambient air, sod is the ATA ceftibuten in the presence of ambient air, containing 20 vol.% oxygen was minimal and amounted to only 2% (table 3).

There is only a very minor loss of activity ceftibuten when storing the dry powder compositions according to the invention in the form of an aqueous suspension in the atmosphere, the maximum oxygen content which is about 5 vol.%, at a temperature of 2 - 8oC for two weeks.

After storage for two weeks at room temperature using a statistical model Plackett/Burman determine the influence of each component on the chemical stability of the prepared suspension. Table 4 shows that in the presence of simeticone and/or titanium dioxide in the composition of the average values obtained from experience and expressed in mg/g, in the case of compositions with the corresponding component were significantly higher than in the case of compositions without this component. In addition, averages decomposition were significantly lower in the case of compositions with the corresponding component than in the case of compositions that do not contain this component.

The drawing shows the effect of changes in the oxygen content (volume%) in the atmosphere over the drug in the yellow bottle is the temperature 25oC. Chose a bottle of yellow color for the protection of three-hydrate ceftibuten from decomposition when possible light. The horizontal axis shows time in months, and the vertical axis stability ceftibuten in percent of the original number of three-hydrate ceftibuten at 25oC. the Bottles were partially filled trihydrate containing ceftibuten composition according to table 2 and different numbers of oxygen and screeny rubber tube and cover, provided with aluminum foil.

The drawing shows three curves. The curve with triangles shows the stability trihydrate containing ceftibuten composition according to table 2, filled in a yellow bottle, and the drug has an ambient air containing about 20 vol.% oxygen, at a temperature of 25oC; the curve with thick circles shows the stability trihydrate containing ceftibuten composition according to table 2, filled in a yellow bottle, and the drug has a mixture of 5 vol.% oxygen and 95 vol.% nitrogen, at a temperature of 25oC, and the curve with thin circles shows the stability trihydrate containing ceftibuten composition according to table 2, filled in yellow is the understanding of the fact, that contains the trihydrate of ceftibuten composition according to table 2 in the presence of the drug nitrogen to oxygen content of 5 vol.% or less shows significantly lower decomposition ceftibuten than in the presence of the drug of ambient air with oxygen, amounting to 25 vol.%.

1. Powder antibacterial composition intended for oral use, containing hydrated ceftibuten, including 7-14 wt.% water, giving the opacity of the substance, at least one sweetener and thickener, characterized in that for use in suspension it further comprises a nonionic surfactant and protivovspenivayushchie agent, a thickener selected from the group comprising silicon dioxide, a silicate of magnesium, a mixture of microcrystalline cellulose and carboxymethyl cellulose mass ratio of 6:1 to 10:1, xanthan resin and mixtures thereof, and the composition contains components in the following number, mg/g:

Hydrated ceftibuten, including 7-14 wt.% water - 65-150

Nonionic surfactant - 0,30-0,50

Protivovspenivayushchie agent - 0,60-1,0

Specified thickener - 20-40
/BR>2. The composition according to p. 1, characterized in that it contains, mg/g:

Hydrated ceftibuten, including 7-14 wt.% water - 65-150

Nonionic surfactant - 0,30-0,50

Protivovspenivayushchie agent - 0,60-1,0

Xanthan gum as a thickener - 12-20

Silicon dioxide as an additional thickener - 8-12

Giving the opacity of the substance - 14-22

At least one sweetener - Rest

3. The composition according to p. 1, characterized in that it contains, mg/g:

Hydrated ceftibuten, including 7-14 wt.% water - 72-144

Nonionic surfactant - 0,4

Protivovspenivayushchie agent - 0,8

Xanthan gum as a thickener - 16,0

Silicon dioxide as an additional thickener - 10,0

Giving the opacity of the substance - 18,0

At least one sweetener - Rest

4. Composition according to any one of paragraphs.1-3, characterized in that for use in a water suspension it further comprises 3-9 mg/g of water-soluble preservative and 3-5 mg/g fruit flavourings.

5. The composition according to p. 4, characterized in that as the fruity taste of vases is made of PP.1-5, characterized in that as a nonionic surface-active substances it contains Polysorbate 80, as protivovspenivayushchie agent is simethicone, as giving the opacity of a substance is titanium dioxide, and as sweeteners - sucrose.

7. Composition according to any one of paragraphs.1-6, characterized in that it contains the trihydrate of ceftibuten.

8. Composition according to any one of paragraphs.1-6, characterized in that it contains the dihydrate of ceftibuten.

9. Composition according to any one of paragraphs.1-8, characterized in that it is stored in the atmosphere with a maximum oxygen content of about 5 vol.%.

 

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