Pharmaceutical preparations containing amoxicillin and clavunalate

FIELD: medicine; pharmacology.

SUBSTANCE: invention is used for treatment of bacteriemic infections, it is prepared as composition in the form of dry powder, adapted for delution by water with reception of the suspension important pH in a range from approximately 5.0 to approximately 5.5 at initial delution and which in addition contains the stabilizer pH which represents sodium-carboxymethyl cellulose. Besides, the invention concerns application sodium-carboxymethyl cellulose for reduction of degree of degradation clavunalate and for stabilisation pH the received suspension.

EFFECT: stability improvement in preparation.

7 cl, 1 dwg, 1 tbl

 

The present invention relates to adapted for pediatric introduction to pharmaceutical preparations that contain amoxicillin and clavulanate.

The combination of amoxicillin and application (co-Amoxiclav) is an effective and practical treatment of bacterial infections and can be administered orally by, for example, in tablet form and, in the case of paediatric medicines in the form of an aqueous solution or suspension, which usually add corrigent. A variety of drugs co-Amoxiclav sold by GlaxoSmithKline produced sign Augmentin.

Pediatric drugs containing amoxicillin and clavulanate, usually offered in the form of powder or granules in the container, for example in the vial. Before the first use, they are bred in a certain volume of water to provide a suspension with a certain concentration, usually the suspension for repeated administration, which is enough for the entire course of treatment.

It is well known that clavulanate susceptible to degradation in the form of dry powder, and in the dissolved state. Stability in the dry state is important because it can limit the shelf life of the product. When the product is prepared in the form of liquid suspensions, stability is also important, since it is necessary to provide the product in a liquid state, which remains stable in the bushes period of 7 or 10 days when stored in proper conditions, for example at a temperature of approximately 5°C (in the refrigerator).

Usually include excess clavulanate components in order after 7 or 10 days of storage was maintained at least 90% of its nominal amount, thereby maintaining optimal efficiency. Even if such excess is necessary to carefully control the pH of the product to minimize the degradation rate of application in a liquid state.

Clavulanate in aqueous solution has a U-shaped profile, pH stability with optimal stability in pH values from 5.0 to 5.5. However, it is difficult to maintain the solution at the optimum pH value, as the degradation causes an increase in pH due to the formation of the main degradation products. If the pH is increased greatly, the degradation increases even within the period length of 7 or 10 days (as shown in the drawing).

Maintaining good stability clavulanate components in the liquid state using pH control is complicated by the fact that in aqueous solution amoxicillin generates acidic degradation products. In addition, amoxicillin and clavulanate, as a result of the fermentation process, through which they receive, initially after receipt contain low levels of degradation products. These levels can increase during storage is, product manufacture and storage of the product in the form of a dry powder prior to breeding. Such variability may lead to an unstable pH of the product and changing stability in diluted conditions; therefore, there is a need to control.

Additionally, this problem is further exacerbated obtained by dilution of the suspensions, which have higher concentrations of amoxicillin. Amoxicillin has a tendency to lower the pH dependent concentration. Since it is required increasingly to use higher doses of amoxicillin to cope with the increasing resistance of bacteria to have to increase the levels included in the medication. Thus, the suspension drugs amoxicillin/application that was originally 125/32,5 mg/5 ml and 250/62 .5 mg/5 ml, were increased to 400/57 mg/5 ml and 100/12 .5 mg/5 ml and, most recently, in late 2001, with the introduction in the USA product Augmentin ES 600®to 600/43 mg/5 ml. moreover, there is a probability that in the future may require drugs, containing 800 mg/5 ml and 1000 mg/5 ml As specified higher levels of inclusion of amoxicillin tend to lower the pH in the region where the product is less stable, such changes are essential for periods of stability.

At the same time, the pH of the product is increased ka is during storage in the form of a dry powder, and during storage in the liquid state due to increased formation of the main degradation products of the application. If this increase is excessive, the product will move into the region of the low stability of the application.

Thus, fluctuations in pH, due to the concentrations of these drugs, the variability of the input substances or changes, when the product is diluted conditions, can lead to unstable stability and unreliable product.

In light of such limitations, complications and trends there is a great need to identify a substance which can have a stabilizing effect on clavulanate to amoxicillin/clavulanate suspensions.

Medication in the form of a dry powder contains a mixture of different excipients included for various reasons, for example, to facilitate the production process, to keep the product dry to promote the formation of a suitable suspension and to enhance the aesthetic properties such as taste and mouth feel. Of the different types of commonly used excipients is necessary to choose those that do not have an adverse effect on the stability. Under the condition of pH-sensitive application one would expect that to optimize stability should we use the ingredients which sautereau pH of the product. However, it is known that the degradation of application increases the buffer salts and other ions (Haginaka. J; Nakagawa. T; Uno. T: Chem Pharm Bull (1981) 29 (11) 3334-3341 Stability of Clavulanic Acid in Aqueous Solutions). Normally, therefore, should be avoided useful pH modifiers, such citrate salts. Other pH modifiers may also be unsuitable, for example, because of the salty taste, bitterness or other unpleasant taste properties that are undesirable in a liquid product that is administered to children. Thus, the choice of excipients is limited to such considerations, therefore, to minimize adverse effects on the stability in the liquid state, the preparations contain as little as possible of the excipients.

Traditionally in drugs amoxicillin and application for preparation in the form of liquid oral suspensions included the diluent for application of potassium, desiccant, typically silicon dioxide, a moving substance, usually colloidal silicon dioxide, suspension additive, usually a combination of xanthan gum and hydroxypropylmethylcellulose, sweetener, usually an artificial sweetener, such as aspartame, and corrigentov, usually a combination corrigentov like fruit or candy, such as orange, raspberry and light syrup. Typical drugs, close tragoudi the existing commercial products, described in WO 96/34605 (SmithKline Beecham), 400/57 suspension and 200/28 mg/5 ml, and in WO 97/09042 (SmithKline Beecham), suspension 600/43 mg/5 ml. in Addition, these drugs also includes a pH modifier, such as succinic acid, for pH modification obtained by dilution of the suspension to a pH value remained within the stability range of the application. The drugs described in WO 00/03695 (Lek), contain a buffer system of citric acid/sodium citrate. On the contrary, in WO 98/35672 and WO 01/13883 (which is the closest analogue of the present invention) (SmithKline Beecham Laboratoires Pharmaceutiques) described the preparations in the form of dry powders intended for cultivation with suspensions, which are prepared from granules of amoxicillin and application in the ratio 2:1, while the remainder of the amoxicillin is caused by granules of amoxicillin and drugs do not contain identifiable pH modifier.

Now unexpectedly discovered that when the suspension is prepared in the form of liquids, low levels of sodium-carboxymethylcellulose have a favorable effect on the stability clavulanate components.

Sodium carboxymethylcellulose is a pharmaceutical excipient, which is widely used for a number of purposes, for example as a covering agent, baking powder for tablets and capsules, containing substances in tablets or in liquid product is tah, as a stabilizer, suspending agent, the agent that increases the viscosity, or water-absorbing agent (Handbook of Pharmaceutical Excipients, third edition, 2000, American Pharmaceutical Association and Pharmaceutical Press, 87). The use of sodium carboxymethylcellulose in the resulting dilution of the suspension amoxicillin and application, containing 100/12 .5 mg/5 ml and 400/57 mg/5 ml, is described in WO 98/35672 and WO 01/13883 (SmithKline Beecham Laboratoires Pharmaceutique). However, it is clear that it is included as a conventional suspending agent or thickener, without the discovery of the beneficial effect, discovered in the present invention, through the use of relatively low levels of amoxicillin.

Thus, according to the present invention is proposed pharmaceutical preparat amoxicillin and application, prepared as a composition in the form of a dry powder, adapted for dilution with water to form a suspension for repeated administration, which contains from about 400 to about 1250 mg of amoxicillin and from about 40 to about 90 mg application on a standard quantity of the drug, so that the ratio of amoxicillin to clavulanate is at least 10:1, and which further comprises a pH stabilizer, which is sodium carboxymethylcellulose. Found that the inclusion of sodium-carboxymethylcellulose both the provides not only the optimal pH value at initial breeding, but also minimizes the change in pH during storage within ten days, without any harmful catalytic effect on the degradation of the application. The surprise of this effect is that the sodium-carboxymethyl cellulose in nature is ionic, and one would expect that as such it catalyzes the degradation of the application. This can be compared with earlier application derived neutral cellulose, hydroxypropylmethylcellulose, for example, in a product containing 600/43 mg/5 ml (WO 97/09042), where a similar favorable effect on pH was not observed.

In an additional aspect according to the present invention offered a pharmaceutical drug amoxicillin and application, prepared in the form obtained by dilution of the suspension, which has a concentration of amoxicillin in the range of from about 400 to about 1250 mg and the concentration of application in the range from approximately 40 to approximately 90 mg per 5 ml obtained by dilution of the suspension, so that the ratio of amoxicillin to clavulanate is at least 10:1, and which further comprises a pH stabilizer, which is a sodium carboxymethylcellulose.

In an additional aspect according to the present invention proposed the use of sodium carboxymethylcellulose in stabilizing the pH is received by dilution of the suspension, containing from about 400 to about 1250 mg of amoxicillin and from about 40 to about 90 mg application of 5 ml obtained by dilution of the suspension, so that the ratio of amoxicillin to clavulanate is at least 10:1, which reduces the degree of degradation of the application.

In one embodiment, the pH is in the range from approximately 5.0 to approximately 5.5 during the initial breeding. Preferably the change in pH (increase) during storage is less than about 1 pH units, preferably less than 0.9 pH units, more preferably less than 0.8 pH units, after 10 days at 4°C. Preferably the final pH after 10 days of storage at 4°C is from about 5.8 to approximately 5.9. This can be compared with an initial value of approximately pH from 4.1 to 4.6, the subsequent shift in pH by at least 1.5 units and a final pH of from about 5.8 to 6.1 comparable drugs in the absence of sodium-carboxymethylcellulose and in the same conditions. Currently marketed product 600/43 mg/5 ml has an initial pH value of approximately 4.7.

In an additional aspect according to the present invention offered a pharmaceutical drug amoxicillin and application, prepared as a composition in the form of dry powder, hell is pteramanna for dilution with water to form a suspension for repeated administration, which contains from about 400 to about 1250 mg of amoxicillin and from about 40 to about 90 mg application on a standard quantity of the drug, so that the ratio of amoxicillin to clavulanate is at least 10:1, and which, after dilution with water has an initial pH value of from approximately 5.0 to approximately 5.5. Preferably the final pH after 10 days of storage at 4°C is from about 5.8 to approximately 5.9. In an additional aspect according to the present invention proposed the use of sodium carboxymethylcellulose in a decrease in the degree of degradation of the application in the resulting dilution of the suspension containing from about 400 to about 1250 mg of amoxicillin and from about 40 to about 90 mg application on a standard quantity of the drug. Preferably the loss of application 10 days of storage at 4°reduced by at least 15%; more preferably, obtained by dilution of the suspension, which has a concentration of amoxicillin in the range from about 750 to about 1250 mg and the concentration of application in the range from approximately 40 to approximately 90 mg per standard amount, at least 20%, compared with the same suspension, but without sodium carboxyl is etilzellulozy.

In an additional aspect according to the above inventions this suspension contains from about 500 to about 1250 mg of amoxicillin and from about 40 to about 90 mg application on a standard quantity of the drug, so that the ratio of amoxicillin to clavulanate is at least 12:1.

In an additional aspect according to the above inventions this suspension contains from about 550 to about 1250 mg of amoxicillin and from about 40 to about 90 mg application on a standard quantity of the drug, so that the ratio of amoxicillin to clavulanate is at least 14:1.

In an additional aspect of the present invention, the amoxicillin is present in the range from about 700 to about 1250 mg per standard amount, and the standard amount of drug is present from about 40 to about 90 mg of the application, so that the ratio of amoxicillin to clavulanate is at least 14:1.

In an additional aspect of the present invention clavulanate is present in the range of from about 40 to about 60 mg per standard amount, so that the ratio of amoxicillin to clavulanate is at least 14:1.

The ratio of amoxicillin to clavula the ATU is in the range from about 10:1 to 30:1, preferably from 12:1 to about 30:1 (mass of the corresponding free acids). Typical relations of amoxicillin to clavulanate include approximately 14:1, about 15:1, about 16:1 and approximately 20:1, preferably about 14:1 or about 16:1. However, the specialist will be clear that the critical parameters are essentially individual absolute number amoxicillin and application, and not their relationship.

Typical compositions contain approximately 600, 750, 800, 1000 and 1200 mg of amoxicillin per 5 ml obtained by dilution of the suspension, in particular approximately 600/43 and approximately 800/57 (ratio 14:1), approximately 750/50 (ratio 15:1), approximately 800/50 and approximately 1000/62,5 (16:1) and approximately 800/40 and approximately 1000/50 (ratio 20:1) mg/5 ml (amoxicillin/clavulanate).

To minimize the change in pH during storage, for example less than about 1 pH units, preferably less than about 0.9 pH units, more preferably less than about 0.8 pH units, after 10 days of storage at 4°C, sodium carboxymethylcellulose is present in an amount that after the initial cultivation and subsequently is effective to provide a pH value in the range from approximately 5.0 to approximately 5.5. Prefer the LNO after 10 days of storage at 4° With a final pH value is from about 5.8 to approximately 5.9. It was unexpectedly discovered that the sodium carboxymethylcellulose is effective at relatively low levels. Typically, the sodium carboxymethylcellulose is present in an amount of from about 10 to about 60 mg, preferably from about 20 to about 50 mg, more preferably from about 20 to about 40 mg, more preferably from about 25 to about 35 mg, at the standard amount. These quantities are favorable because it does not have a harmful impact on the ease of cultivation or properties associated with viscosity, such as fluidity. Many hydrophilic resin does not disperse quickly, because each particle is enveloped in a "sticky" layer, obstructing further hydration. In contrast, sodium carboxymethylcellulose used in levels quickly dispersed. Moreover, the level of its inclusion has no significant impact on its effect on the pH, changing its value only within 0.5 pH units in the concentration range from 10 to 50 mg per standard amount of the drug.

Various grades of sodium carboxymethylcellulose, suitable for use in the preparations according to the present invention, are commercially detachment various suppliers. These brands may vary in particle size, degree of polymerization, degree of substitution and clean. Preferred are pharmaceutically acceptable brand. In addition, according to the monograph USP (US Pharmacopeia 25, 2002) the pH value of their 1-percentage (wt./about.) solutions can vary from 6.5 to 8.5. Preferred brand of sodium-carboxymethylcellulose for use in the preparations according to the present invention are those brands that have a pH value of from about 7.0 to about 7.5 (for 1.0% (wt./about.) solution). Suitable brand sodium carboxymethylcellulose available from such suppliers as Hercules Incorporated (Wilmington, Delaware, USA), for example products Such as® Blanose CMC and® CMC, and Akzo Nobel Functional Chemicals (3800 AE Amersfoort, The Netherlands).

One of the embodiments contains approximately 600/43 mg amoxicillin/application and from about 25 to 35 mg, usually about 30 mg, sodium-carboxymethylcellulose on a standard quantity of the drug. In one of the typical examples, this corresponds to from about 2.5 to about 3.5% by weight of the drug, usually about 3%.

In an additional embodiment of the specified preparation additionally contains xanthan gum in addition to the sodium-carboxymethylcellulose. Xanthan gum has an immediate onset of action. Preferably xanthan gum is present inthe number of from about 1 to about 10 mg, preferably from about 1 to about 5 mg, more preferably from about 1 to about 4 mg, typically from about 2.5 to about 3.5 mg per standard amount of the drug. A typical ratio of sodium carboxymethylcellulose to xanthan gum is from about 12:1 to about 8:1, more typically about 10:1 by weight, for example approximately 30 mg of sodium-carboxymethylcellulose and about 3 mg of xanthan gum to the standard amount.

Additional excipients include diluents (for application), a desiccant, a moving substance, corrigent and sweetener.

Usually silicon dioxide include as a diluent and desiccant present in a total amount of from about 140 to about 190 mg (taking into account any contribution from silicon dioxide in the use of a mixture of application of potassium and silicon dioxide, for example a mixture of 1:1) of the standard quantity of the drug.

Usually moving the substance is colloidal silicon dioxide is present in an amount of from about 30 to about 50 mg, preferably from about 30 to about 40 mg, usually about 35 mg per standard amount of drug for a drug with a number of AIOC is icillin to 900 mg. In the case of drugs with a higher level of amoxicillin for maintaining the flowability of the product is considered useful to include higher levels, for example from about 60 to about 80 mg, preferably from about 65 to about 80 mg per standard amount of the drug.

Typically the sweetener is an artificial sweetener, such as aspartame present in the range from about 10 to about 15 mg, usually in the amount of about 12.5 mg to the standard amount.

Usually corrigent is a fruit corrigent, for example creamy strawberry corrigent described in WO 01/13883.

An additional embodiment includes the amoxicillin is present in an amount of from about 700 mg to about 1250 mg, for example about 800, 1000 or 1200 mg, clavulanate potassium is present in an amount of from about 40 to 90 mg, for example about 800/50, 800/57, 1000/62,5 and 1200/43 mg; sodium carboxymethylcellulose present in an amount of from about 20 to about 50 mg, preferably from about 20 to about 40 mg, more preferably from about 25 to about 35 mg, usually about 30 mg, and xanthan gum present in an amount of from about 1 to priblizitel is but 10 mg, preferably from about 1 to about 5 mg, more preferably from about 1 to about 4 mg, usually about 3 mg; more preferably about 30 mg of sodium-carboxymethylcellulose and about 3 mg of xanthan gum to the standard amount.

An additional embodiment includes the amoxicillin is present in amount of about 600 mg, clavulanate potassium is present in the amount of approximately 43 mg; sodium carboxymethylcellulose present in an amount of from about 20 to about 40 mg, preferably from about 25 to about 35 mg; usually about 30 mg, and xanthan gum present in an amount of from about 1 to about 10 mg, preferably from about 1 to about 5 mg, more preferably from about 1 to about 4 mg, usually about 3 mg per standard number of the drug; more preferably about 30 mg sodium-carboxymethylcellulose and about 3 mg of xanthan gum to the standard amount.

In additional embodiments of the present invention excipients consist essentially of silicon dioxide, sodium carboxymethylcellulose, xanthan gum, colloidal silicon dioxide, the claim is stannage sweetener and corrigenda, as specified above.

Used herein, the term "standard number of drug" refers to the amount of the drug in dry form, which is diluted with water to obtain 5 ml of suspension.

In the preparations according to the invention, the amoxicillin is in the form of three-hydrate amoxicillin. Preferably the trihydrate amoxicillin use in pellet form, for example in the form described in WO 02/49618 (SmithKline Beecham). Preferably the equilibrium relative humidity (ERH) of three-hydrate amoxicillin used as the raw material, carefully regulate by means of a suitable drying so that it had no adverse effects on other aspects of the drug. Preferably ERH tea is less than 30%, more preferably from 10 to 20%.

Preferably clavulanate is in the form of application of potassium. Clavulanate potassium is normally supplied in a mixture with silicon dioxide as a diluent, usually in the form of a mixture of 1:1. Clavulanate potassium is very sensitive to moisture and should be stored and handled under conditions of 30%or less, ideally as low as possible, relative humidity (RH).

Mass ratio of amoxicillin:clavulanate here are expressed in free acid equivalents.

Active ingredients : amoxicillin trihydrate and clavulanate potassium are usually present in amounts of from approx is Ino 70 to about 85% by weight of the original product (if you use an absolute mass of three-hydrate amoxicillin and application of potassium).

Excipients are preferably present in an amount of from about 15 to about 30% by weight of the original drug.

The preparations according to the present invention can be fabricated using methods that are conventional in the manufacture of drugs in the form of dry powders intended for dilution with the receiving water suspensions. Usually, to obtain a homogeneous mixture, these dry powdered ingredients are mixed together in the mixer for one stage. Then this mixture fill suitable containers so that each had a specific weight of the product. In another aspect, this process may include a preliminary stage of formation of granules of subgroups of ingredients, for example from some or all of the contents of amoxicillin and application.

Preferably, the preparations according to the present invention provide a container that is impermeable to atmospheric moisture, for example in a glass or plastic vial, intended for dilution with water or other suitable aqueous medium immediately before use. Preferably the preparation is in the form of a dry powder provide in a bottle with leakproof lid.

The preparations according to the present invention are intended primarily for administration to paediatric patients and therefore presupposes the equipment adapted accordingly.

For ease of dispensing the amount of powder provided in a vial, and the amount of water used for cultivation of this powder, determined so that the standard dose was provided in a convenient volume, for example from 2.5 to 10 ml, usually about the amount of 5 ml, obtained by dilution of the suspension. Typically, the bottle is designed for the full course of treatment, so that the resulting breeding suspension is a suspension for repeated administration. Such introduction can be carried out by the spoon, such as a calibrated spoon or a calibrated measuring Cup, blunt syringe or calibrated metering pump.

It should be understood that, when the above-mentioned specific amount of application, such as 43 mg, 50 mg, 57 mg, 62.5 mg, and so forth, they reflect the nominal amount and that in practice it may be necessary to include an excess of up to 10%, preferably up to 8%, more preferably up to 5%, based on the nominal mass application to consider a controlled and acceptable level of degradation. The present invention includes any such excess.

It should also be understood that, in practice, to conform with industry practice, it may be necessary to take into account the excess fall asleep mass to the amount specified above on the standard kolichestvoparkov, you can change by up to 10%, usually by means of appropriate changes all ingredients of this drug. The present invention includes any such modification.

The person skilled in the art it will be clear that, when the above-mentioned relationship of amoxicillin to clavulanate, for example 14:1, this ratio represents the nominal target ratio and that in practice the ratio in the product may deviate from the specified nominal value, for example, by up to approximately ±10%, preferably up to ±8%, the number of amoxicillin to align with the need to ensure a surplus, which should take into account the degradation and also display any subsequent degradation of one or both active ingredients. Thus, for example, the ratio of the masses of amoxicillin and application in drug, which falls within the range from 13:1 to 15:1, corresponds to the nominal ratio of 14:1. The present invention includes any such modification.

Preparations according to this invention may be suggested to treat a bacterial infection, usually in children, among other things, for example, one or more infections of the upper respiratory tract, lower respiratory tract infections, urinary tract infections and skin infections and soft tissue infections. Drugs in this izopet who were suitable for treatment of infections of the upper respiratory tract in children, such as otitis media and sinusitis, in particular of acute otitis media when infections are often caused by N. influenzae, M. catarrhalis and S. pneumoniae, including S. pneumoniae, insensitive to penicillin and penicillin-resistant S. pneumoniae. It should be understood that these patients are usually treated with doses adjusted for body weight. So, as an example, the dosage 90/6,4 (14:1) mg/kg/day in divided doses every 12 hours (BID (twice a day)may be provided with a suspension according to the present invention, containing 600/43 mg/5 ml or 800/57 mg/5 ml, if you prefer less standard dose. The dosage 135/6,75 (ratio 20:1) mg/kg/day in divided doses every 12 hours (BID) may be provided with a suspension according to the present invention, containing 800/40 mg/5 ml or 1000/50 mg/5 ml dosage regimen 150/10 (ratio 15:1) mg/kg/day in divided doses every 8 or 12 hours (TID (three times daily) or BID) may be provided with a suspension according to the present invention, containing 750/50 mg/5 ml dosage regimen 160/10 (ratio 16:1) mg/kg/day in divided doses every 8 or 12 hours (TID or BID) may be provided with a suspension according to the present invention, containing 800/50 mg/5 ml or 1000/62 .5 mg/5 ml, Respectively suspension for repeated administration provide in sufficient quantity to cover the course of treatment, usually 7 to 10 days.

ISOE is ishemia here the terms "pediatric" and "children's" cover the age range from newborn to teenager, for example, approximately 40 kg of body weight, when it would better fit the use of the drug for adults, such as tablets.

Hereinafter the present invention will be described using examples.

Example 1A - suspension drug 600/43 mg/5 ml

Ingredient(mg/5 ml
* Amoxicillin trihydrate (corresponding to 600 mg

free acid)
697,67
* Potassium clavulanate/silica mixture 1:1

(corresponding to 42.9 mg of the free acid)
113,00

(includes 8%-

cent excess)
Xanthan gum, NF (national

pharmaceutical form)
3,00
Aspartame NF12,50
**Silicon dioxide, NF92,82
Colloidal silicon dioxide, NF35,00
Sodium carboxymethyl cellulose, NF30,00
Strawberry corrigent26,00
Total fall asleep the dry weight of the powder on the standard number1010
*On the basis that the trihydrate amoxicillin contains 86% of the amoxicillin (free acid) and a mixture of potassium clavulanate/silicon dioxide 1:1 contains 41% clavulan the howling acid.

**The amount of silicon dioxide adjusted on the active content of the three-hydrate amoxicillin mixture and clavulanate potassium/silicon dioxide in order to maintain a constant mass dose.

It should be understood that in the above example, the amount of sodium carboxymethylcellulose on a standard quantity of the drug is 30.00 mg

It should be understood that in practice may be included excess sleeps mass on the standard number, so that the total sleeps the dry weight of the powder on the standard number may increase to 10%, for example, in relation to the total poured weight of dry powder per standard amount of about 2000 mg

Suspension in example 1A has an initial pH of approximately 5.2, for comparison, product Augmentin ES 600 has an initial pH value of approximately 4.7. In addition, for a ten-day period of storage at 4°With the number of application is reduced by approximately 10%, for comparison, the loss for the product Augmentin ES 600 is approximately 15%.

Example 1B - suspension drug 800/57 mg/5 ml

Ingredient(mg/5 ml
* Amoxicillin trihydrate (corresponding to 600 mg

free acid)
930,23
* Clavulanate Kali is/silica mixture 1:1

(corresponding to 42.9 mg of the free acid)
150,15

(includes 8%-

cent excess)
Xanthan gum, NF3,00
Aspartame NF12,50
**Silicon dioxide, NF98,12
Colloidal silicon dioxide, NF50,00
Sodium carboxymethyl cellulose, NF30,00
Strawberry corrigent26,00
Total fall asleep the dry weight of the powder on the standard

Number
1300
*On the basis that the trihydrate amoxicillin contains 86% of the amoxicillin (free acid) and a mixture of potassium clavulanate/silicon dioxide 1:1 contains 41% of clavulanic acid.

**The amount of silicon dioxide adjusted on the active content of the three-hydrate amoxicillin mixture and clavulanate potassium/silicon dioxide in order to maintain a constant mass dose.

It should be understood that in the above example, the amount of sodium carboxymethylcellulose on a standard quantity of the drug is 30.00 mg

It should also be understood that the above-mentioned drugs in examples 1A and 1B contain amoxicillin trihydrate and potassium clavulanate in a ratio that the equivalent ratio of 14:1 (based on the mass equivalent is x free acids).

Examples 2-4 - preparations containing 800/43,1000/43 and 1200/43 mg/5 ml amoxicillin and application

IngredientProduct ′800′ (mg/5 mlProduct ′1000′ (mg/5 mlProduct ′1200′ (mg/5 ml
Trihydrate amoxicillin

(corresponding to

free acid)
930,23

(800)
1162,79

(1000)
1395,35

(1200)
The mixture clavulanate

potassium/silicon dioxide

(Syloid) (corresponding to

free acid)
113,00

(43)
113,00

(43)
113,00

(43)
Xanthan gum3,003,003,00
Aspartame12,5012,5012,50
Fine

silica gel, 9 m
100,27107,71105,15
Colloidal dioxide

silicon
35,0035,0035,00
Sodium

carboxymethylcellulose
30,0030,0030,00
Strawberry corrigent26,0026,0026,00
The final weight dose

(the standard number

preparation)
1490 mg1720 mg
Initial pH value5,205,11of 5.05
pH in 10 daysof 5.83of 5.82of 5.82

On the basis of 86,0%content of active ingredient amoxicillin (pfa) and 41,0%content of active substance of the application.

Example 5

On a series of typical drugs containing amoxicillin and clavulanate, investigated the impact of adding sodium carboxymethylcellulose in the loss of application in the resulting dilution of the suspension for a period of 10 days. Priced drugs-prototypes met the preparations in examples 1A and 2-4, with the contents of amoxicillin from 600 to 1200 mg/5 ml and constant level of application, amounting to 43 mg/5 ml. in Addition, for comparison, also included an additional drug with a similar number of excipients containing 400 mg/5 ml, and a control preparation containing 200 mg/5 ml

Drugs were diluted with water to the given concentrations. Samples were collected at the beginning and after 10 days storage (at 4°). The concentration of the application in the samples were analyzed using HPLC (high performance liquid chromatography and UV detection (UV - UV). In addition, at the same time measured the pH of the suspension.

The results of pH and loss application for 10 days is redstavleny in the table below.

Table
Medication0 dayspH 10 daysThe differenceLoss application within 10 days (%)Decrease/(%)
′200′

′200′ w/CMC
4,60

5,48
6,13

5,91
1,53

0,43
9,4

8,6
0,8/8,5
′400′

′400′ w/CMC
4,46

of 5.40
6,05

by 5.87
1,59

0,47
12,0

9,1
2,9/24,2
′600′

′600′ w/CMC
4,35

and 5.30
6,00

of 5.84
1,65

0,54
11,8

9,5
2,3/19,5
′800′

′800′ w/CMC
4,25

5,20
5,90

of 5.83
1,65

0,63
13,7

10,2
3,5/25,5
′1000′

′1000′ w/CMC
4,17

5,11
5,86

of 5.82
1,69

0,71
15,0

9,6
5,4/36
′1200′

′1200′ w/CMC
4,11

of 5.05
of 5.82

of 5.82
1,71

0,77
16,2

11,4
4,8/29,6
w/CMC - a drug with sodium carbox what metilzellulosa

The above results show that in the range of concentrations of amoxicillin from 200 to 1200 mg/5 ml) add sodium carboxymethylcellulose reduces the percentage of loss application. While for preparation containing 200 mg/5 ml amoxicillin, less waste application within 10 days from the addition of sodium-carboxymethylcellulose is only minor, it is becoming more and more significant for drugs with higher concentrations, in particular at concentrations of 600, 800, 1000 and 1200 mg/5 ml

Moreover, found that drugs with sodium carboxymethyl cellulose pH value, first in the field of optimal stability (pH 5.0 to 5.5), is changed to a final pH of 5.8 to 5.9. For comparison, the corresponding drugs without sodium-carboxymethylcellulose had an initial pH value of 4.1 to 4.6 and the final value of pH from about 5.8 to 6.1,

1. Pharmaceutical drug amoxicillin and application for treatment of bacterial infections, prepared as a composition in the form of a dry powder, adapted for dilution with water to form a suspension having a pH value in the range from approximately 5.0 to approximately 5.5 at initial breeding for multiple reception, which contains approximately 600 mg amoxicillin and approximately 43 mg clavulan is and the standard quantity of the drug, so that the ratio of amoxicillin to clavulanate is approximately 14:1, and which further comprises a pH stabilizer, which is a sodium carboxymethylcellulose present in an amount of from 25 to 35 mg per standard amount, and pharmaceutically acceptable excipients.

2. The preparation according to claim 1, which further comprises xanthan gum present in an amount of from about 1 to about 10 mg per standard amount of the drug.

3. The preparation according to claim 1, which further comprises xanthan gum present in an amount of from about 1 to about 5 mg per standard amount of the drug.

4. The pharmaceutical preparation according to claim 1, in which the excipients consist essentially of silicon dioxide, xanthan gum, colloidal silicon dioxide, artificial sweetener and corrigenda.

5. Pharmaceutical drug amoxicillin and application for treatment of bacterial infections, prepared in the form obtained by dilution of a suspension having a pH value in the range from approximately 5.0 to approximately 5.5 at initial dilution, which has a concentration of about amoxicillin 600 mg and the concentration of application approximately 43 mg per 5 ml obtained by dilution of the suspension, so that the ratio of Amax is Zilina to clavulanate is approximately 14:1, and which further comprises a pH stabilizer, which is a sodium carboxymethylcellulose present in an amount of from 25 to 35 mg per 5 ml obtained by dilution of the suspension.

6. The use of sodium carboxymethylcellulose in an amount of from 25 to 35 mg to reduce the degree of degradation of the application in the resulting dilution of the suspension having a pH value in the range from approximately 5.0 to approximately 5.5 at initial dilution containing approximately 600 mg amoxicillin and approximately 43 mg of application of 5 ml obtained by dilution of the suspension, so that the ratio of amoxicillin to clavulanate is approximately 14:1.

7. The use of sodium carboxymethylcellulose in an amount of from 25 to 35 mg to stabilize the pH obtained by dilution of a suspension having a pH value in the range from approximately 5.0 to approximately 5.5 at initial dilution containing approximately 600 mg amoxicillin and approximately 43 mg of application of 5 ml obtained by dilution of the suspension, so that the ratio of amoxicillin to clavulanate is approximately 14:1, which reduces the degree of degradation of the application.



 

Same patents:

FIELD: medicine.

SUBSTANCE: method is implemented as follows: bacterial-enzymatic probiotic "Balance-narine-f" is introduced locally and orally in combination with inhalation of negative air ions.

EFFECT: allows for decrease of complications and higher efficiency of treatment.

1 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: sterile aqueous inhalation solution containing active substance Tobramycine. Preparation of invention is offered with high content of active substance (approximately 80 to 120 mg/ml Tobramycine). Preparation also contains acid adjuvant and has low content of sodium chloride (maximum approximately 2 mg/ml). Preparation can be injected or introduced as aerosol with e.g. common sprays.

EFFECT: suitable for application in combination with recent sprays with vibrating membrane and gives the chance for application of an individual therapeutic dose.

24 cl, 1 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: antibacterial and rehydration therapies are combined with prescribed sorbents, symptomatic therapy. From first day of disease prescribed is infusion herb collection consisting of silverweed rhizome, salvia leaves, milfoil herb, St. John's wort herb, inula rhizomes with roots, tickseed herbs, mint leaves, fennel fruits and buckthorn bark at ratio of components 2:2:2:2:2:2:2:2:1. Infusion is taken up dosed 1\3 glass 3 times a day, 30 min before meal within 10 days. Then within three weeks after basic therapy appoint infusion from silverweed rhizome, salvia leaves, milfoil herb.

EFFECT: provides accelerated normalisation of clinical-laboratory indicators, and prevention of infectious complications without by-effects.

2 cl, 1 tbl, 1 ex

FIELD: medicine; biotechnologies.

SUBSTANCE: strain Lactobacillus casei FERM BP-100059 (FERM P-19443), possessing probiotic properties; grow up in the presence of any from one to four amino acids as a source of the nitrogen necessary for growth. At planting in suitable cultural to medium, the final value pH makes 4.0 or lower, and the highest acidity makes 1.5% or above. The strain resistable is to 5% salts of cholic acids. The strain produces an antibiotic. On the basis of the strain as the active beginning, the lactobacillus preparation of probiotic action for humans, animals and plants and the preventive or therapeutic agent against human, animal and plant infections.

EFFECT: ability to colonise and breed in the centres chronic the infections, steady against treatment, strong clearing action and destruction causing a bacterium infection.

12 cl, 5 dwg, 56 tbl, 34 ex

FIELD: medicine; pharmacology.

SUBSTANCE: peroral pharmaceutical dosed out form for treatment of the conditions bound to secretion of acid in a stomach, includes an acid-sensible inhibitor of the proton pump and antagonist of H2-molecular switchers, with the delayed and-or prolonged liberation of the proton pump acid-sensible inhibitor, and fast liberation of antagonist of H2-molecular switchers.

EFFECT: maximum suppression of acid in a stomach after the first dose and throughout all course of treatment.

69 cl, 4 dwg, 7 ex

FIELD: medicine; veterinary science.

SUBSTANCE: vaccine includes inactivated adhesive antigens E.coli K88, E.coli K99, E.coli F-41, E.coli 987P and an adjuvant - aluminum hydrate. As the inactivated adhesive antigens E.coli use inactivated filamentous adhesive antigens E.coli K88 ab, E.coli K88 ad, E.coli K88 ad, E.coli K99, E.coli F-41, E.coli Att-25, E.coli 987P with activity level in reaction of the passive hemagglutination peer as 1:2048-4096; 1:1024-2048; 1:256-512; 1:1024-2056; 1:1024-2056; 1:32-64; 1:256-512, accordingly, at a following parity of components, wt. %: inactivated filamentous adhesive antigens E.coli K88 ab, E.coli K88 ad, E.coli K88 ad, E.coli K99, E.coli F-41, E.coli Att-25, E.coli 987P, taken in mass parities 1:(0.8-1.2:(0.8-1.2:(0.8-1.2:(0.8-1.2:(0.8-1.2:(0.8-1.2, accordingly - 55-65, 5.8-6.2%-s' aluminium hydrate the rest.

EFFECT: rising of safety of livestock of agricultural animals.

2 cl, 1 tbl, 8 ex

FIELD: medicine; pharmacology.

SUBSTANCE: perform processing of an elevated part and roots of the primrose plant (Primula macrocalyx Bge.) with an organic dissolvent - ligroin or hexane with the subsequent extraction with acetone and allocation of a target product using chromatography.

EFFECT: increase of output of the product.

4 ex, 2 dwg

FIELD: medicine; pharmacology.

SUBSTANCE: system of delivery of medicinal substance includes one department consisting from (i) of a kernel from thermoplastic polymer, filled with medicinal substance, (ii) an intermediate layer from the thermoplastic polymer filled with medicinal substance, and (iii) covers from the thermoplastic polymer, covering an intermediate layer and not containing medicinal substance, where the specified intermediate layer is filled (a) with crystals of the first pharmacologically active substance, and (b) the second pharmacologically active substance in the dissolved form and where the kernel is filled specified to the second pharmacologically active substance in the dissolved form. The delivery system is intended for vaginal introduction of the medicinal substance.

EFFECT: possibility of adjustment of rate of liberation of two or more active ingredients irrespective of others, at maintenance of long physical stability of system at room temperature.

51 cl, 21 dwg, 10 tbl, 4 ex

FIELD: chemistry, immonology.

SUBSTANCE: hybrid protein includes 936 protein sequence from Neisseria meningitides or protein with sequence identical to the mentioned protein sequence by 90% or more, and 741 protein sequence from Neisseria meningitides or protein with sequence identical to the mentioned protein sequence by 90% or more. The sequences can be linked by N- and/or C-end to histidine labels, with or without a linker. Linker is selected out of group of polyglycine linker, histidine labels and GSGGGG linker. A nucleic acid encoding this protein is displayed. Invention also claims composition for treatment and/or prevention of disease caused by Neisseria meningitides bacterium, based on hybrid protein and one or more proteins of the following group: 287, 741, ORF46.1, 961, NH2-A-[X-L-]n-B-COOH, where n=2, X1=287, and X2 is selected out group of: 953, 919, 961, 741. Invention claims application of composition in production of medicine for treatment of disease caused by Neisseria.

EFFECT: efficient treatment and prevention of disease.

13 cl, 5 dwg, 28 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of formula (I) and their pharmaceutically acceptable salts as β-lactamase inhibitors, method of their production, pharmaceutical composition based on them, and methods of treatment involving the claimed compounds. In the general formula (I) one of A and B is hydrogen, while the other is optionally substituted condensed bicyclic heteroaryl group; if aromatic ring part of bicyclic heteroaryl group is imidazole, non-aromatic ring part does not include S atom adjacent to head carbon atom of bridge group; X is S; R5 is H, C1-C6-alkyl or C5-C6-cycloalkyl; or its pharmaceutically acceptable salt where bicyclic heteroaryl group is (1-A) , where one of Z1, Z2 and Z3 is independently S, while the others are CR2 or S, if one of Z1-Z3 is carbon and is linked to the rest of molecule; W1, W2 and W3 are independently CR4R4, S, O or N-R1, if it does not form S-S, O-O, or S-O link with saturated ring system; t=1-4; R1 is H, C1-C6-alkyl, C5-C7-cycloalkyl, -C=O-aryl, -C=O(C1-C6)-alkyl, -C=O(C5-C6)-cycloalkyl, aryl-C1-C6-alkyl, optionally substituted C1-C6-alkoxy; heteroalkyl- C1-C6-alkyl or C=O(heteroaryl), where heteroaryl is 6-member ring containing 1 nitrogen atom, R2 is hydrogen, C1-C6-alkyl, R4 ir H, C1-C6-alkyl.

EFFECT: efficient application in bacterial infection treatment.

29 cl, 3 tbl, 58 ex

FIELD: medicine; pharmacology.

SUBSTANCE: pharmaceutical composition includes an anthelminthic agent chosen from the group, consisting of macroleads, benzimidazoles, isoquinolones, pyrantel or their mixes, and the first inert material, masking taste. The inert material has porous structure with an internal surface approximately of 500-1500 m2/g and the surface area according to VET is approximately 5000 m2/g. As an inert material, usually use charcoal.

EFFECT: improved masking of taste and the prolonged liberation of the anthelminthic agent.

16 cl, 1 dwg

FIELD: medicine.

SUBSTANCE: mare's milk concentrate which has been dried up at temperature from 10 to 50°C at pressure from 1 to 50 mb, on biologically inert, highly dispersive matrix being a highly dispersive dioxide of silicon, apply for obtaining of a preparation for oral ingestion at treatment of diseases of neurodermite and psoriasis. The preparation additionally contains irreplaceable amino acids, hydrocarbonate, potassium, carbonate, citrate, calcium, magnesium, vitamin C, vitamin E, niacin, zinc, iron, beta carotin, pantothenic acid, manganese, vitamin B6, B2, B1, B12, copper, sodium, a biotin, Acidum folicum, molybdenum, selenium, xanthan, fructose, lemon acid, or from both such substances.

EFFECT: application of mare's milk concentrate is oral for neurodermite and psoriasis treatment, firmness at storage and maintenance of high-quality components in the concentrated form.

6 cl, 7 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: according to novel method liquid medium, containing at least one dissolved organic or inorganic compound, which is subject to solidification, is forced through membrane into one or several anti-solvents, or one or few anti-solvents are forced through membrane into liquid medium, which contains at least one organic or inorganic compound. Membrane is located in membrane module, has pores with size to 3mcm, membrane form is selected from pipe, fibre or spiral winding. Method is realised as continuous process. Method ensures obtaining solid particles, which include organic or inorganic compound, which are non - agglomerated. Method can be used for large volumes and allows controlling particle size.

EFFECT: obtaining possibility of application for large volumes and ensuring control of particle size.

15 cl, 2 dwg, 2 tbl, 5 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention represents a composition including micronised particles of biologically active substance of respirable size in a combination with coarsely dispersed, unrespirable particles of the inert carrier where glutarilhistamine is used as biologically active substance. The composition contains biologically active substance, namely glutarilhistamine, and possesses with expressed antiinflammatory, antiallergic, antiasthmatic and antiviral action.

EFFECT: invention provides the maximum value of size respirable fraction at inhalation.

8 ex, 2 dwg

FIELD: medicine, pharmacology.

SUBSTANCE: pharmaceutical preparation is placed in sealed packing that is essentially waterproof and hermetic. In this volume there are pharmaceutical preparation and adsorbent. The pharmaceutical preparation consists of pharmaceutical composition that includes formotherol, reducing sugar, and effective quantity of adsorbent. The proportion of cyclesonide, included in the pharmaceutical composition as stabiliser, to formotherol being minimum 5:1; and the adsorbent effective quantity must be sufficient to prevent or lower generation of Meillard reaction products.

EFFECT: preservation of formotherol superfine fraction in permanent state.

18 cl, 3 dwg, 2 tbl, 2 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention concerns medical product for metabolic regulation associated with magnesium deficiency in organism. Medical product is solid dosage form containing magnesium di-(L-asparaginate) in amount 200 to 1000 mg and pyridoxine hydrochloride in amount 2 to 20 mg per unit dose (magnesium di-(L-asparaginate) and pyridoxine hydrochloride in weight ratio 50:1 to 200:1).

EFFECT: medical product provides high ion bioavailability and decreased excretory system burden.

8 cl, 5 ex, 3 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: composition displays tuberculostatic activity in respect of isoniazid-resistant M. Tuberculosis and amplifies specific pharmacological effect of isoniazid and ethambuthol hydrochloride due to its synergism. The composition is made in the form of granules with the components in the following quantities, g: isoniazid - 0.3000, ethambuthol hydrochloride - 0.3000, pectin - 0.3000.

EFFECT: high tuberculostatic activity; low toxicity and reduced side effects of the components.

2 cl, 4 tbl

FIELD: medicine.

SUBSTANCE: invention describes pharmaceutical atorvastatin composition granulated by humid method with at least ca. 5% (mass) addition of alkali-earth metal salt containing: (a) atorvastatin, where atorvastatin is at least partly disordered form or mix of crystal and disordered atorvastatin forms, or its pharmaceutically acceptable salt; and (b) fluffer or combination of fluffers selected out of a group including sodium starch glycolate, starch, corn starch, preliminarily gelatinised starch, sodium alginate, cellulose powder, hydroxypropyl cellulose, magnesium aluminosilicate and potassium polacrylin, where the claimed atorvastatin composition granulated by humid method contains not more than ca. 3% of atorvastatin lactone, on the basis of ratio of lactone peak to the combined peak areas of total formulation, defined by high-efficiency liquid chromatography. Also the invention describes method of obtaining the claimed composition and assays of the composition content.

EFFECT: high purity grade; stable formulation of atorvastatin and good decomposition and bioavailability rate.

23 cl, 4 tbl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: method consists in as follows: initial organic drug substance and auxiliary low-molecular organic ingredient, serving as a matrix to prolongate the release of the former substance into aqueous solution, are simultaneously and separately vaporised in rarefied neutral gas medium. The simultaneously obtained vapours of the mentioned substance and the matrix ingredient are then co-condensed on deposition surface. The angle between deposition velocity vectors of the mentioned drug substance and the matrix-forming ingredient, and inclination of the angle bisector to deposition surface are 5-170° and 10-90° respectively. Microcapsulation is effected or at positive temperatures of deposition surface during co-condensation process, or at negative temperatures of deposition surface during the co-condensate obtained warming to positive temperatures.

EFFECT: production of micronised powder of encapsulated organic drug substance with prolonged dissolution in aqueous medium during single-stage process.

5 cl, 4 dwg, 5 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to medicinal agents and concerns pharmaceutical formulation for nasal absorption containing biologically active acidic polypeptide with isoelectric point 7 and lower; carrier which is water-insoluble or weak-soluble and contains particles of average size 100 mcm and less; and adjuvant for dispersion and consolidation of polypeptide on carrier surface, which is water-insoluble or weak-soluble, where average size of particle contained in specified adjuvant is lower than average size of carrier and is within the range 1 mcm to 20 mcm.

EFFECT: improved biological acceptability of biologically active polypeptide.

6 cl, 4 dwg, 11 tbl, 47 ex

FIELD: chemistry.

SUBSTANCE: nano-sized highly-pure hydroxylapatite (HAP) is obtained in form of alcohol colloid solution (gel), which can be used for production of medicinal preventive preparations in stomatology, for applying bioactive coating on bone implants. Method includes hydroxylapatite synthesis by adding solution of orthophosphoric acid to calcium hydroxide solution and exposure to ultrasound impact, and ethyl or isopropyl alcohol is added to colloid of highly-pure nano-sized hydroxylapatite with concentration from 5% to 40±2% in order to obtain concentration of hydrooxylapatite in alcohol from 0.2 to 20%. After that alcohol mixture is processed with ultrasound with frequency 10-50 kHz during 1-2 hours.

EFFECT: alcohol colloid of nano-sized hydroxylapatite with high stability.

2 cl, 3 ex

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