NO168375B - PROCEDURE FOR DELIGNIFICATION OF CELLULOSE-CONTAINING MATERIAL - Google Patents

Abstract

1. Process for the delignification of cellulosic materials characterized in that in a first step the cellulosic materials are treated with an acid under regulated conditions to effect a decontamination of the cellulosic material of the metals which they contain, in a second step the cellulosic materials of the first step are treated with hydrogen peroxyde under alcaline conditions and in a third step the cellulosic materials of the second step are boiled in the presence of sulphite or sulphate.

Description

Process for the production of stable aqueous solutions

solutions of oxytetracycline suitable for parenteral

ral, oral and local administration.

The present invention relates to a method for

position of stable aqueous solutions of oxytetracycline which are particularly well suited for parenteral, oral and local administration of this therapeutically important antibiotic, but which can also be made suitable for other therapeutic administration methods.

It is known that oxytetracycline is poorly soluble in water.

Salts of this compound with mineral acids are, however, more soluble, but at the pH level that prevails in such salt solutions (pH = 2.0 - 3.0), these aqueous solutions are not sufficiently stable and are thus not particularly well suited for the production of injection fluids with a good shelf life. Furthermore, an intramuscular injection of such solutions is very painful and is often followed by significant necrotic reactions at the injection site itself. To some extent, attempts have been made to reduce the pain by adding a local anesthetic. Nevertheless, these solutions have not found much use due to the above-mentioned serious disadvantages.

It is also known e.g. from British patent no. 742 157 that the solubility of tetracycline derivatives can be significantly increased by the presence of calcium or magnesium ions, which results in the formation of relatively well soluble complexes. The solubility of these complexes is, despite this, insufficient, and it has not been possible to prepare water-soluble complexes with Mg or Ca salts of sufficiently high concentration and stability and at a physiologically suitable pH level, which can be used as injection fluids. \

This can be achieved if, instead of water, an essentially organic solvent is used, e.g. propylene glycol e.g. as discussed in British patent no. 894 619, or a concentrated solution of certain carbonamides, such as e.g. dimethylacetamide or 3-hydroxy-acetylacetamide as indicated in US patent no. 2,980,584.

However, injections with these high concentrations of organic solvent, due to their markedly hypertonic nature, will also cause pain at the injection site, in addition to the relatively undesirable injection of large amounts of unphysiological organic compounds.

Attempts have been made to produce water-soluble compounds which satisfy the requirements for a good injection composition by reacting tetracycline (or its derivatives) with formaldehyde and certain amino compounds, such as e.g. dialkylamine, piperazine, morpholine, piperidine and amino acids such as lysine. These so-called Mannich bases are quite soluble in water, but are often not very stable, and with prolonged storage there will always be the risk that the relatively poorly soluble tetracycline (or its derivatives) will precipitate again. Furthermore, these compounds, which in reality must be regarded as new therapeutic products with properties that are not completely identical to those found in the starting products, namely in the tetracycline antibiotic as such, must be specially manufactured for this purpose.

It is also previously known, e.g. from French patent no.

1439M and Australian Patent No. 205,892, to add polyvinylpyrrolidone to aqueous suspensions of tetracyclines. The solutions thus obtained have very poor storage capacity and stability.

With the present invention, on the other hand, stable, concentrated, aqueous solutions of oxytetracycline are obtained, which are particularly well suited for parenteral administration of this antibiotic. The invention relates in particular to the preparation of oxytetracycline solutions which are suitable for intramuscular or intravenous use. The solutions obtained by applying the present invention are extremely stable and are essentially aqueous solutions with regard to their composition. Besides the above-mentioned purposes, the solutions are also suitable, or can be made suitable, for other therapeutic administration methods, such as .eg in the form of a syrup for oral administration, eg in paediatrics, or as a solution or as an ointment for intramammary administration in connection with veterinary practice.

An intramuscular injection of therapeutic doses of these solutions does not cause pain at the injection site itself, so that the addition of a local anesthetic is superfluous. One also achieves a very high tetracycline level in the blood shortly after the injection.

According to the present invention, a method is provided for the production of stable aqueous solutions of oxytetracycline suitable for parenteral, oral and local administration, characterized in that oxytetracycline is suspended or dissolved, either as a salt or as a base, in water containing polyvinylpyrrolidone with an average molecular weight in the range 10,000 - 60,000, in a concentration of 2.5 - 25%, a magnesium compound is added in an amount of between 2/3 and 3/2 mol magnesium per mol oxytetracycline, and the solution is adjusted to a pH value in the range 8.0 - 9.5.

When carrying out the method, a physiologically harmless inorganic or organic base is suitably used, and suitable bases for this purpose are sodium hydroxide, ammonium hydroxide, ethanolamine, ethylenediamine, etc.

Depending on the chosen concentrations of oxytetracycline, polyvinylpyrrolidone and the magnesium compound, the solutions obtained are completely clear. Even dilutions of such solutions with water or serum remain clear, so that these solutions are very well suited for intravenous administration of this antibiotic. By using the present invention, solutions of this antibiotic can easily be prepared in concentrations e.g. varying from 2.5

to 15%, i.e. the concentration range that is particularly well suited for medical use.

Polyvinylpyrrolidone, which is, among other things, used as a blood plasma thinner (Norwegian patent no. 66 319) and as such is medically acceptable, even when administered in relatively large quantities, is a con- . densation product with an average molecular weight varying from approx. 10,000 to .1 million. Both high-molecular and low-molecular polyvinylpyrrolidone have an unexpectedly strong solubility-improving effect. Because solutions of the high molecular weight product have a high viscosity, low molecular weight polyvinylpyrrolidone is used, i.e. with a molecular weight varying from 10,000 to 60,000. For the preparation of solutions according to the present invention, a polyvinylpyrrolidone with an average molecular weight varying from 10,000 is preferably used to 12,000 (K value = 17). Solutions of 10 to 15% of this product in water do not increase the viscosity to any great extent, a property which is very favorable in the production of injection fluids.

Due to the relatively high molecular weight, the polyvinyl pyrrolidone has no or very little effect on the isotonicity of the injection fluid.

When carrying out the present invention, solutions are prepared which preferably contain from 10 to 15% PVP.

For the preparation of solutions according to the present invention, it is essential to use a given amount of a magnesium compound, preferably the chloride or the oxide. The amount to be used is in a given relationship to the concentration of oxytetracycline, and preferably amounts to from 1 to 1.5 mol of the magnesium compound to 1 mol of oxytetracycline. If one wants to ensure extended stability for the solutions, it is furthermore also advantageous that, after small bottles or ampoules have been filled with the solutions produced according to the present invention, to replace the air above the liquid with an inert gas, preferably with nitrogen.

The stability is also favored by adding the solutions

a relatively small amount of a reducing compound, such as sodium metabisulphite, sodium sulphite or sodium formaldehyde sulphoxylate.

Unlike many other injection forms of oxytetracycline, an intramuscular injection of a medically adjusted dose of this antibiotic in its new form will not cause any pain reaction or necrosis at the injection site.

Solutions prepared according to the present invention can also be made suitable for oral administration (e.g. in paediatrics) in a very effective way by adding flavor and color additives.

Solutions prepared according to the invention can further be made suitable, e.g. for intramammary administration in connection with veterinary practice, by adding a harmless thickening agent.

Example 1

In 82.5 ml of distilled, sterile and pyrogen-free water, 0.5 g of sodium formaldehyde sulphoxylate and 15 g of polyvinylpyrrolidone (K-value = 17) were dissolved. In the solution obtained, 0.5 g of magnesium oxide was suspended, after which 5.5 g of oxytetracycline hydrochloride was added and the pH adjusted to 8.5 to 9.0 using ethanolamine, which resulted in a clear solution containing 50 mg of oxytetracycline per ml. The solution was sterilized by filtering it through a sterilizing and pyrogen-absorbing asbestos filter, after which the solution was dispensed into suitable injection bottles or ampoules.

Example 2

In 84 ml of distilled, sterile and pyrogen-free water, 0.5 g of sodium formaldehyde sulphoxylate and 7.5 g of polyvinylpyrrolidone (k-value = 25) were dissolved. 0.5 g of magnesium oxide was then suspended in the resulting solution. 5.5 g of oxytetracycline hydrochloride was added to the suspension, after which the pH was adjusted to 8.5 - 9.0 with 10% ammonium hydroxide, whereby a clear solution containing 50 mg of oxytetracycline per ml was obtained. This solution was sterilized and filled into bottles or ampoules which described in example 1.

Example 3

In 83 ml of distilled, sterile and pyrogen-free water, 0.5 g of sodium formaldehyde sulphoxylate and 15 g of polyvinylpyrrolidone (K-value = 17) were dissolved. In this solution, 0.83 g of magnesium oxide was suspended, after which 9.2 g of oxytetracycline hydrochloride was added and the pH adjusted to 8.5 - 9.0 using ethylene hydramine. The obtained solution contains approx. 83 mg oxytetracycline per ml. The solution was sterilized and poured into bottles or ampoules as described in example 1.

Example 4

In 80 ml of distilled, sterile and pyrogen-free water, 0.5 g of sodium formaldehyde sulfoxylate, 15 g of polyvinylpyrrolidone (K-value = 17), 2.5 g of magnesium chloride 6 aq., and 5.5 g of oxytetracycline hydrochloride were successively dissolved. The pH of the solution was adjusted to 8.5 - 9.0 using ethanolamine, whereby a clear solution containing 50 mg of oxytetracycline per ml was obtained. The solution was sterilized and poured into bottles or ampoules as described in example 1.

Example 5

In 80 ml of distilled, sterile and pyrogen-free water, 0.5 g of sodium formaldehyde sulphoxylate, 15 g of polyvinylpyrrolidone (K-value = 17) and 2.5 g of magnesium chloride 6 aq were dissolved. 5.5 g of oxytetracycline dihydrate was added to this solution, after which the pH was adjusted to 8.5 - 9.0 using ethanolamine, whereby a clear solution containing 50 mg of oxytetracycline per ml was obtained. The solution was sterilized and poured into bottles or ampoules as described in example 1.

Example 6

In 78 ml of distilled, sterile and pyrogen-free water, 0.5 g of sodium formaldehyde sulphoxylate and 15 g of polyvinylpyrrolidone (K value = 17) were dissolved, after which 0.5 g of magnesium oxide was suspended in the solution. 5.5 g of oxytetracycline hydrochloride was added to the resulting suspension, after which the pH was adjusted to 8.5 - 9.0 using 10% ammonium hydroxide. The obtained clear solution containing 50 mg of oxytetracycline per ml was sterilized and filled into bottles or ampoules as described in Example 1.

Example 7

In 86 ml of distilled, sterile and pyrogen-free water, 0.5 g of sodium formaldehyde sulphoxylate and 10 g of polyvinylpyrrolidone (K value = 17) were dissolved. In this solution, 0.5 g of magnesium oxide was then suspended, after which 6.0 g of oxytetracycline citrate was added. Finally, the pH was adjusted to 8.5 - 9.0 using ethanolamine, whereby a clear solution containing 50 mg of oxytetracycline per ml was obtained. This solution was sterilized and poured into bottles or ampoules as described in example 1.

Example 8

In 55 ml of water, the following compounds were successively dissolved:

0.09 g methyl 1-p-hydroxybenzoate

XW WC VU

0.01 g propyl-p-hydroxybenzoate

0.5 g sodium sulphite 7 aq.

1.6 g magnesium sulfate 7 aq.

10 g polyvinylpyrrolidone (K-value = 30)

1 g sodium cyclamate

40 g crystallized sugar

2.75 g of oxytetracycline hydrochloride

The pH of the solution was then adjusted to 8.5 - 9.0 using ammonium hydroxide and the volume was increased to 100 ml using water.

In this way, a solution with a good taste was produced, which contained 25 mg of oxytetracycline per ml and which is well suited for oral administration.

simple 9

In 40 ml of water, the following compounds were successively dissolved:

0.09 g methyl p-hydroxybenzoate

0.01 g propyl-p-hydroxybenzoate

0.2 g of sodium bisulphite

1 g sodium cyclamate

25 g polyvinylpyrrolidone (K-value = 17)

40 g crystallized sugar

10 g glycerin

2.8 g of oxytetracycline phosphate

The liquid was then mixed with 0.25 g of magnesium oxide, and the pH adjusted to 8.5 - 9.0 using 4 N sodium hydroxide, after which the Lumet was elevated to 100 ml with water.

A solution with a good taste was prepared, which contained 25 mg of oxytetracycline per ml and which is well suited for oral administration.

simple 10

In 73 ml of distilled, sterile and pyrogen-free water, 0.5 g of sodium formaldehyde sulphoxylate and 15 g of polyvinylpyrrolidone (value = 17) were added. In this solution, 1.5 g of magnesium syd was suspended, after which 16.5 g of oxytetracycline hydrochloride was added. The box's pH was then adjusted to 8.5 - 9.0 with the help of ethanolamine. As a result, a clear viscous liquid containing approx. 150 mg oxytracycline per ml, and which e.g. is well suited for intramammary administration with a view to combating mastitis.

Example li

In 93 ml of distilled, sterile and pyrogen-free water, 0.5 g of sodium formaldehyde sulfoxylate and 5 g of polyvinylpyrrolidone (K-value = 17) were dissolved. Then 0.25 g of magnesium oxide was suspended in this solution, after which 2.75 g of oxytetracycline hydrochloride was added to the thus obtained suspension, and the pH adjusted to 8.5 - 9.0 with ethanolamine. This gave a clear solution containing 25 mg of oxytetracycline per ml. This solution was sterilized by filtering through a sterilizing and pyrogen-absorbing asbestos filter and then distributed into suitable ampoules.

Example 12

In 95 ml of distilled, sterile and pyrogen-free water, 0.5 g of sodium formaldehyde sulphoxylate and 5 g of polyvinylpyrrolidone (K-value = 27) were dissolved. Then 0.1 g of magnesium oxide was suspended in this solution, and 1.1 g of oxytetracycline hydrochloride was added to the thus obtained suspension, and the pH value adjusted to 8.5 - 9.0 with ethanolamine. This gave a clear solution containing 10 mg of oxytetracycline per ml. This solution was finally sterilized and distributed among ampoules as described in example 1.

Example 13

In 96 ml of distilled, sterile and pyrogen-free water, 0.5 g of sodium formaldehyde sulphoxylate and 3 g of polyvinylpyrrolidone (K-value = 17) were dissolved. Then 0.1 g of magnesium oxide was suspended in this solution, and 1.1 g of oxytetracycline hydrochloride was added and the pH adjusted to 8.5 - 9.0 with ethanolamine. The solution thus obtained then contained about 10 mg of oxytetracycline per ml. The solution was sterilized and distributed into bottles as described in example 1.

Example 14

In 84 ml of distilled, sterile and pyrogen-free water, 0.5 g of sodium formaldehyde sulphoxylate and 7-5 g of polyvinylpyrrolidone (K-value = 25) were successively dissolved. Then 0.5 g of magnesium oxide was suspended in this solution, and 5.5 g of oxytetracycline hydrochloride was added to the thus obtained suspension and the pH adjusted to 8.5 - 9.0 with 10% ammonia. This gave a clear solution containing 50 mg of oxytetracycline per ml. This solution was finally sterilized and distributed among ampoules as described in example 1.

Example 15

In 55 ml of sterile water, the following compounds were dissolved successively:

The pH of the solution was then adjusted to 8.5 - 9.0 with ammonia and the volume of the solution was supplemented with 100 ml of water, if this was considered necessary.

In this way, a solution with a good taste was obtained, which contained 25 mg of oxytetracycline per ml and was suitable for oral administration.

Claims (2)

1. Process for producing stable aqueous solutions of oxytetracycline suitable for parenteral, oral and local administration, characterized in that oxytetracycline is suspended or dissolved, either as a salt or as a base, in water containing polyvinylpyrrolidone with an average molecular weight in the range of 10 000 - 60,000, in a concentration of 2.5 - 25%, a magnesium compound is added in an amount of between 2/3 and 3/2 mol magnesium per mol oxytetracycline, and the solution is adjusted to a pH value in the range 8.0 - 9.5. 2. Method according to claim 1, characterized in that magnesium salts or magnesium oxide are used as magnesium compounds.