SI20058A - Pharmaceutical forms - Google Patents

Abstract

New stable pharmaceutical forms for peroral applications containing amoxycillin trihydrate and potassium clavanulate are described. The invention refers to water suspensions and dispersions obtained after reconstitution of powder or granulate by addition of the prescribed quantity of water. The new forms contain cellulose as the main filler and show a pleasant taste and slight side effects on gastrointestinal tract.

Description

PHARMACEUTICAL FORM

FIELD OF THE INVENTION

A 61K 31/43

The invention relates to the field of pharmaceutical technology and relates to stable pharmaceutical forms of amoxicillin and clavulanic acid for oral administration. The invention relates to aqueous suspensions and dispersions obtained after reconstitution of a powder or granulate with the addition of a prescribed amount of water. The invention also relates to a powder for preparing a stable aqueous suspension and a granulate for preparing an aqueous dispersion.

A technical problem

Amoxicillin is a well-known broad-spectrum antibiotic that, in combination with clavulanic acid, which acts as an inhibitor of β-lactamases, also acts on bacterial strains that are resistant to β-lactamases. Antibiotic therapy is known to be a common side effect of gastrointestinal disorders, particularly pronounced in susceptible persons and young children. Therefore, there is an ongoing need to develop pharmaceutical formulations that are stable, acceptable in taste and that have as little adverse effects on the gastrointestinal tract as possible.

The state of the art

Conventional formulations in the form of a powder for powder or dispersion granulate contain sugars such as glucose, fructose, lactose, maltose or polyols such as e.g. mannitol, sorbitol, xylitol. Sugars and polyols have this poor property of having a laxative effect on oral administration, in large quantities, and of producing a palatable pharmaceutical product, which is especially important in therapy in young children.

To make suspensions of amoxicillin and clavulanic acid less gastrointestinal, sugar or mannitol have been replaced, for example. with silica. In doing so, the taste of the suspension deteriorated.

The side effects on the gastrointestinal tract caused by treatment with drugs containing amoxicillin and clavulanic acid have also been tried to reduce various supplements. WO 96/07408 discloses pharmaceutical formulations containing amoxicillin and clavulanic acid and the addition of pharmaceutically acceptable organic acids or their salts, which reduce side effects on the gastrointestinal tract. WO 97/06798 discloses pharmaceutical forms with clavulanate containing pharmaceutically acceptable salts of alkaline earth metals and inorganic acids to reduce gastrointestinal intolerance.

The addition of various metallic salts, especially with the predominant amount of silica, increases the taste discomfort and such formulations are difficult to accept.

Description of solution to a technical problem

The main purpose of the invention is to provide a powder for suspension or granulate for dispersion with amoxicillin trihydrate and potassium clavulanate, which in oral administration has reduced gastrointestinal intolerance and has a pleasant taste. The taste of suspension is particularly important in therapy in young children. This objective is achieved by using cellulose, which may be microcrystalline or powdered, as a filler. For this purpose, different types of cellulose can be used which give stable suspensions depending on their properties such as swelling ability or different particle size. Cellulose is a natural polysaccharide derived from vegetable fibers. It is available in two forms: the colloidal form, used in combination with other fillers as a suspending agent, and the non-water dispersible formulation, which is suitable as a filler for tablet manufacture. Typically, other types of cellulose with higher swelling capacity are used in suspensions, which act as thickeners in suspensions and at lower concentrations (0.2 - 5%).

By using cellulose as a filler, which simultaneously acts as a thickening agent and a stabilizing agent of the suspension and which is previously dried to reduce the amount of free water which adversely affects the stability of clavulanic acid, good stability of the reconstituted suspension is achieved during use 7 to 10 days. The amount of cellulose as the main filler in the formulation may range from 5 to 60% by weight. The percentage of active ingredients is 20 to 70%.

Microcrystalline cellulose (Avicel, Emcocel, Vitacel) with an average particle size of 50μηι, more preferably microcrystalline cellulose with finer particles, e.g. with an average particle size of 20μηη.

Powdered cellulose (Vivacel, Elcema, Solka-Flok) with different particle sizes or as granulated powder may be used.

Cellulose in combination with sugars or polyols may also be used in such an amount that no action is taken.

Excipients commonly used in the pharmaceutical industry for the manufacture of such preparations are included as excipients. To improve the taste, suitable flavors and sweeteners are added, preferably saccharin, its sodium salt or aspartame in a concentration authorized for use in oral pharmaceutical forms. One flavor or even better combination of two or more flavors such as e.g. berry aroma, cherry aroma, wild cherry, lemon, banana, raspberry, orange, caramel and other fruit aromas and other aromas that, in combination with antibiotics, have a pleasant aroma and taste.

As other additives, pH adjusting agents such as various acids can be used. citric acid, succinic acid, swelling and thickening agents such as e.g. alginates, xanthan gum, cellulose, silica slides, preservatives, suspension stabilizers and other additives.

The formulation is intended for oral therapy at a dosage of 2x daily or 3x daily at the prescribed dose. It is intended for pediatric treatment, treatment for adults and the elderly, and those who have difficulty swallowing.

The formulation refers to a combination of clavulanic acid and amoxicillin trihydrate in a ratio of 1: 1 to 1:20 expressed in free acid, preferably 4: 1 to 8: 1. Covers powder for suspension or granulate for dispersion for oral administration in doses of:

amoxicillin: clavulanic acid: 125 mg / 5ml 31.25 mg / 5ml 250 mg / 5ml 62.5 mg / 5ml 200 mg / 5ml 28.5 mg / 5ml 400 mg / 5ml 57 mg / 5ml 600 mg / 5ml 42.9 mg / 5ml 300 mg / 5ml 21.45 mg / 5ml

Other doses are also possible.

The powder or granulate is packaged in an airtight container such as bottles or bottles with a suitable thread or sachets for the preparation of the suspension or sachets. dispersions just before use.

For the preparation of a powder or granulate, conventional procedures such as homogenization, sieving and milling are used. Part of the constituents may be pre-granulated or pre-granulated ingredients may be used. This results in better absorption of the powder, which is especially important when packing in bags.

The ingredients used in the formulation should also be pre-dried or use an anhydrous form. The cellulose and cellulose combination are thus dried with sodium carboxymethylcellulose to a drying loss of less than 1%. Drying can be done on a tray dryer or in a vacuum dryer. By additionally drying the ingredients, it is possible to have a powder or a powder. low moisture granulate, eg below 6%. Namely, clavulanic acid is known. its salts are extremely sensitive to the presence of moisture and free water and subject to rapid hydrolytic degradation. The formulation is therefore carried out in properly air-conditioned production rooms with relative humidity below 30% and temperature below 25 ° C.

Implementing examples:

Example 1:

Four formulations with different content of amoxicillin trihydrate and potassium clavulanate were prepared. Their composition and the role of each of the excipients is given in the table:

composition: mg / 5ml mg / 5ml mg / 5ml mg / 5ml amoxicillin (as trihydrate) -Active substance 400.00 200.00 600.00 300.00 acid (as K-salt) -Active substance 57.00 28.50 42.90 21.45 citric acid -to adjust the pH 2.69 2.69 2.69 2.69 To citrate -to adjust the pH 8.33 8.33 8.33 8.33 cellulose microcryst. and carboxymethylcell. On - means for increase in viscosity 28.10 28.10 28.10 28.10 xanthan gum - means for increase in viscosity 10.00 10.00 10.00 10.00 coll. silica 16.67 16.67 16.67 16.17 sil. dioxide - thickener 216.60 216.60 216.60 216.60 aromas: -good 13.30 13.30 13.30 13.30 -Caramel 15.00 15.00 15.00 15.00 sweetener e.g. sodium saccharinate 6.70 6.70 6.70 6.70 cellulose to to to to (microcrystalline or powdered) - Filler 1250.00 1000.00 1250.00 1000.00

For the preparation, we used techniques that are common in pharmaceutical technology for the preparation of powders and granules for reconstitution.

The quantities of pharmaceutical excipients can be varied in the formulation so that the most favorable formulation is obtained according to taste and stability.

The results of a three-month stability test at 40 ° C and 75% relative humidity indicate that the formulations in which the cellulose is the main filler are stable.

Lek, a pharmaceutical and chemical factoryr d.d.

Claims (1)

PATENT APPLICATIONS A pharmaceutical formulation in the form of an aqueous suspension or aqueous dispersion containing amoxicillin trihydrate and potassium clavulanate as active substances, cellulose as the main filler and other pharmaceutical excipients. Pharmaceutical formulation according to claim 1, characterized in that it contains microcrystalline cellulose, powdered cellulose or a mixture of both as a cellulose. Pharmaceutical formulation according to claims 1 and 2, characterized in that it contains from 5 to 60% by weight of cellulose. The pharmaceutical formulation according to the preceding claims, characterized in that the microcrystalline cellulose has a particle size of 20 to 100 µm, preferably 20 to 50 µm. Pharmaceutical formulation according to the preceding claims, characterized in that the weight fraction of the active ingredients is from 20 to 70% by weight %. Powder and granulate for use in reconstitution with water for the preparation of a pharmaceutical formulation according to the preceding claims.