HU176305B - Process for producing stabil tetracyclic compositions - Google Patents

Description

FIELD OF THE INVENTION The present invention relates to a process for the preparation of a pharmaceutical composition containing antibiotics for therapeutic use. More particularly, the present invention relates to a process for preparing aqueous solutions of oxytetracycline, doxycycline, tetracycline and chlorotetracycline containing 2-pyrrolidone.

Previous attempts to produce stable, highly concentrated solutions of these tetracycline-type compounds have been unsuccessful, although such solutions are essential in veterinary medicine for parenteral treatment of large animals.

Japanese Patent Publication No. Sho 47-303 discloses stable 2.5% aqueous solutions of p-biphenylylmethyl (dl-tropyl space tropinium) bromide containing 2-pyrrolidone at a concentration of 20%. It also describes the use of polyvinylpyrrolidone at a concentration of 30%. The pH of these solutions is less than 7, preferably between 3 and 4.

Japanese Patent Publication No. Sho 43-1758 discloses the preparation of insecticidal solutions of hexachlorocyclohexane in alcohol and 2-pyrrolidone as solvents. The use of N-methylpyrrolidone as a co-solvent is also described herein.

British Patent No. 802,111 discloses the use of 2-pyrrolidone and N-methylpyrrolidone as a solvent for solutions of DDT, Dieldrin, Aldrin and the like. The examples contain between 67% and 82% of 2-pyrrolidone.

British Patent No. 805,026 discloses that 40% of various formulations for parenteral administration, such as chloramphenicol, Ν, Ν'-dibenzylethylenediamine penicillin G and procaine penicillin, N-methylpyrrolidone was used as a solvent in concentrated concentrations.

In U.S. Patent No. 2,987,437, a solution of 3,4-dichloro-tetrahydrothiophene-1,1-dioxide in 2-pyrrolidone can be used as an anti-metallic agent.

German Patent No. 1,091,287 discloses the preparation of stable, concentrated aqueous solutions of thyrotricin 0.25% and subtiline 0.2% by the nose or ear, using pyrrolidone and / or as a solubilizer for these solutions. or polyvinylpyrrolidone. Accordingly, pyrrolidone may be used in a concentration of 0.5% and polyvinylpyrrolidone in a concentration of up to 10%.

U.S. Patent No. 3,957,980 discloses the preparation of aqueous injectable doxycycline solutions containing from 1% to 10% by weight of doxycycline, the latter being about 10% by weight. 3 to 8 moles of a phosphate, which is less than about seven moles of phosphoric acid, sodium or potassium orthophosphate, metaphosphate, pyrophosphate, tripolyphosphate or hexametaphosphate, and about 3 to 8 moles of an acceptable pharmaceutical magnesium salt and having a pH between 1 and 3.5.

U.S. Patent No. 3,674,859 discloses the preparation of aqueous doxycycline solutions in which 1 to 15% of doxycycline and ca. Polyvinylpyrrolidone is present in an amount ranging from 5% to 40%, having an average molecular weight of 10,000 to 60,000, and the pH of the composition is between 5 and 8.

J. Pharm. Sci., 46, 458 (1957), describes that oxytetracycline in aqueous solution forms a stable complex with N-methylpyrrolidone. The degree of interaction is determined by the pH of the solution and the solubility conditions.

In U.S. Patent No. 2,980,584, 25-80% of acetic acid or lactic acid amide derivative of aqueous complexes of oxytetracycline, such as Ν, Ν-dimethylacetamide or N - (N-hydroxyethyl), are prepared for aqueous parenteral administration. ) -lactamide-containing solutions. The specification refers to solutions having a concentration of 10-100 mg / ml.

U.S. Pat. No. 2,990,331 discloses oxytetracycline hydrochloride and tetracycline hydrochloride in a concentration of ca. He describes the preparation of solutions for parenteral administration containing 50 mg / ml, the pH of which is between 5 and 7, and magnesium ions, an alkali metal bisulfite and a carboxylic acid such as lactic acid hydroxyethyl. amide.

U.S. Patent No. 3,062,717 discloses an acetic acid or lactic acid amide derivative such as Ν, imet-dimethylacetamide or N- (3-hydroxyethyl) lactic acid amide in an amount of 35% to 80%. containing aqueous solutions of tetracycline calcium complex for parenteral administration at pH 7 to 9.5. Solutions of between 10 mg / ml and 100 mg / ml are mentioned.

U.S. Patent 3,557,280 discloses the preparation of aqueous solutions having a pH of 8.0 to 9.5 containing 1-20% oxytetracycline, a magnesium compound and 7.5-25% polyvinylpyrrolidone.

Belgian Patent 825,656 discloses the preparation of aqueous solutions of oxytetracycline comprising 4-11% oxytetracycline, 20-50% polyethylene glycol, such as polyethylene glycol 400, a magnesium compound, and 0.10-0.35% amount of a buffer such as tris (hydroxymethyl) aminomethane and the pH of the solution is 8-9.

French Patent No. 2,258,187 discloses the preparation of aqueous oxytetracycline solutions containing 50 mg / ml oxytetracycline, 5-7.4% polyvinylpyrrolidone and up to 24.9% of a C 1-6 acid amide, e.g. containing dimethylacetamide and having a pH of 8-9.5.

FIELD OF THE INVENTION The present invention relates to a process for the preparation of stable antibiotic pharmaceutical compositions which require an aqueous solution of 2-pyrrolidone and a pharmaceutically acceptable acid addition salt of a tetracycline, e.g.

According to a preferred embodiment of the process of the present invention, stable antibiotic formulations are prepared by dissolving a tetracycline-type antibiotic, a pharmaceutically acceptable alkaline earth metal compound and, if desired, polyvinylpyrrolidone in aqueous 2-pyrrolidone solution and then dissolving it, if desired. adjust the pH of the mixture.

2-pyrrolidone, 2-pyrrolidinone, 2-oxo-pyrrolidone, space pyrrolidone and 2-oxo-pyrrolidone are also known. The oral LD _{50 is} 800 mg / kg in the rat and 3800 mg / kg in the mouse by intraperitoneal injection. Its use minimizes the volume of dose to be administered and is easy to inject due to the low viscosity of the formulation.

As an optional additive, polyvinylpyrrolidone having a molecular weight of from 5,000 to 100,000 (K-12 to 30) may be present in the composition, e.g. 1-7% by weight. Polyvinylpyrrolidone having an average molecular weight (K-value = 17) of between 10,000 and 17,000 is preferably used in the pharmaceutical composition of the invention. This part is present as a co-solubility mediator in the formulation and may improve the drug tolerance of the tissues.

The addition of 0.01% to 1.0% by weight of an antioxidant such as dehyde sulfoxylate in the form of sodium or magnesium or monothioglycerol can further increase the stability of these pharmaceutical solutions.

Previous attempts to produce topical or parenteral formulations containing oxytetracycline in concentrations greater than 200 mg / ml have failed, although such solutions are particularly important for parenteral formulations for veterinary use where high doses are required.

According to a preferred embodiment of the process of the invention, stable, high-potency solutions of oxytetracycline can be obtained by preparing new pharmaceutical compositions containing from 1 to 40% by weight of the active ingredient in an aqueous solution of oxytetracycline or a pharmaceutically acceptable acid addition salt thereof. from about 0.8 to about 1.3 mol., of a pharmaceutically acceptable magnesium compound soluble in the above solution and ca. It contains 10-50% by weight of 2-pyrrolidone and the pH of the total solution is between 7.5 and 9.5.

Oxytetracycline is a widely used antibiotic of the tetracycline type. For a detailed description, see U.S. Patent 2,516,080. In the solutions of the present invention, the actual concentration of oxytetracycline free base or a pharmaceutically acceptable acid addition salt thereof is between 1% and 40% by weight. Preferably the free base is used, having a preferred concentration of between 10% and 30% by weight. Suitable acid addition salts of oxytetracycline include, for example, the following pharmaceutically acceptable salts: hydrochloride, hydrobromide, sulfate, nitrate, ascorbate, citrate, gluconate, lactate, isonicotinate, gentizinate, pantothenate, salicylate, glucuronate, formate. However, oxytetracycline hydrochloride is preferably used.

Magnesium ions in solution form magnesium oxytetracycline chelates with oxytetracycline. A convenient and preferred source of magnesium ion is magnesium 176305, but other magnesium compounds such as magnesium chloride, magnesium acetate, magnesium sulfate, magnesium ascorbate, magnesium lactate or magnesium gluconate may be used. The molar amount of magnesium compound per oxytetracycline in these formulations is between 0.8 and 1.3. This relative amount is required to obtain clear and stable solutions. If less than 0.8 molar or more than 1.3 molar magnesium compounds per oxytetracycline are used, solids remain insoluble in the solution and form a suspension in the solution.

2-Pyrrolidone is used as a co-solvent to dissolve oxytetracycline and is present in an amount of between 10% and 50% by weight of the total composition.

If necessary, adjust the pH of the solution to 7.5 to 9.5. The preferred pH range is between 8.5 and 9.0. Organic bases such as 2-aminoethanol, dimethylaminoethanol, dimethylamine and the like. adjust the pH to the desired value. Preferred of these compounds is 1-aminoethanol.

According to a preferred embodiment of the process of the invention, the preparation of oxytetracycline-containing pharmaceutical compositions is carried out by firstly applying ca. At 75 ° C, the magnesium compound and the 2-pyrrolidone are mixed with water, and oxytetracycline is slowly added with stirring and the mixture is stirred until completely dissolved. The pH is then adjusted to the desired value. If the composition also contains polyvinylpyrrolidone, it is added to the mixture of 2-pyrrolidone and water before the addition of the magnesium compound and oxytetracycline as described above.

Oxytetracycline is currently used as a 50 mg / ml solution for parenteral administration. Therefore, for example, in the case of a bull of 500 kg body weight, 200 ml of a 50 mg / ml solution would need to be injected into the animal's body at 5 to 10 different sites to deliver an effective dose. The solutions of the present invention can overcome this difficulty by providing high solutions, e.g., 200 mg / ml.

The oxytetracycline formulations of the present invention are easily injected over a wide range of temperatures, are well tolerated by animal tissues, can be used to achieve the therapeutic concentration of the active ingredient in the blood, and are satisfactory in physical and chemical stability.

The primary uses of the oxytetracycline-containing compositions of the invention are parenteral administration, but they can also be used for topical or oral administration.

According to the present invention, stable, high-potency solutions of doxycycline may be prepared by the preparation of novel pharmaceutical compositions comprising 1.8 to 2% by weight of the active ingredient in aqueous solution of doxycycline or a pharmaceutically acceptable acid addition salt thereof in an amount of 1.8 to 25% by weight. 2 moles of a pharmaceutically acceptable magnesium compound soluble in the above solution and ca. It contains 10-70% by weight of 2-pyrrolidone and the pH of the total solution is between 3 and 7.5.

Doxycycline is a tetracycline-type, widely used, high potency antibiotic with a very favorable half-life. For a detailed description, see U.S. Patent 3,200,149, designated α-6-deoxy-5-oxytetracycline. In solutions prepared by the process of the present invention, the actual concentration of the free base of doxycycline or a pharmaceutically acceptable acid addition salt thereof is generally between 1% and 25% by weight. Preferably the free base is used, having a preferred concentration of between 5% by weight and 20% by weight and most preferably between 10% and 20% by weight.

Suitable acid addition salts of doxycycline include, for example, the following pharmaceutically acceptable salts: hydrochloride, hydrobromide or sulfate. However, doxycycline hydrochloride is preferably used, for example in the form of "doxycycline hyclate", which is the semi-ethanolate half-hydrate of doxycycline hydrochloride.

Magnesium ions in solution form magnesium doxycycline chelates with doxycycline. A convenient and preferred source of magnesium ion is magnesium oxide, but other magnesium compounds such as magnesium chloride, magnesium acetate or magnesium sulfate may be used. The molar amount of magnesium compound per doxycycline in these formulations is about. It is between 1.8 and 2.2. This relative amount is required to swallow clean and stable solutions.

2-Pyrrolidone is used as a co-solvent for dissolving doxycycline and is present in an amount of between 10% and 70%, preferably between 30% and 50% by weight of the total composition.

If necessary, adjust the pH of the solution to between 3 and 7.5. A preferred pH range is from 5 to 7. The pH can be adjusted to the desired value using pharmaceutically acceptable acids such as hydrochloric acid or an organic base such as 2-aminoethanol.

According to a preferred embodiment of the process according to the invention, the preparation of pharmaceutical compositions containing doxycycline is carried out by firstly applying ca. At 50 ° C, the magnesium compound is mixed with the 2-pyrrolidone / water mixture, and the doxycycline antibiotic is added slowly, with constant stirring, until complete dissolution, and finally the pH is adjusted to the desired value.

The compositions of the invention containing doxycycline are readily injected over a wide range of temperatures and are satisfactory in terms of physical and chemical stability.

The use of the high-active doxycycline formulations of the present invention may reduce the number of injections required to achieve effective dosage levels in large animals such as bulls.

The novel compositions of the present invention containing doxycycline are primarily intended for parenteral administration, but may also be used for topical or oral administration.

According to the present invention, stable, high-potency tetracycline oils can be prepared by preparing novel pharmaceutical compositions comprising a 1 to 15% aqueous solution of tetracycline or a pharmaceutically acceptable salt thereof in an amount of about 1% to about 5% by weight of this antibiotic. 0.8-1.3 moles of a pharmaceutically acceptable magnesium compound soluble in the above aqueous solution and ca. It contains 10-70% by weight of 2-pyrrolidone and the pH of the total solution is between 7.5 and 9.5.

Tetracycline is a widely used antibiotic. It is described in detail in U.S. Patent No. 2,699,054. In solutions prepared by the process of the invention, the actual concentration of the free base of tetracycline or a pharmaceutically acceptable salt thereof is generally between 1% and 15% by weight. Preferably the free base is used, having a preferred concentration generally between 5% and 15% by weight, and more preferably between 5% and 10% by weight.

Suitable acid addition salts of tetracycline include, for example, the following pharmaceutically acceptable acid addition salts: hydrochloride, hydrobromide or sulfate, but tetracycline hydrochloride is preferred.

Magnesium ions in solution form magnesium tetracycline chelates with tetracycline. A convenient and preferred source of magnesium ion is magnesium oxide, but other magnesium compounds such as magnesium chloride, magnesium acetate or magnesium sulfate may be used. The molar amount of magnesium compound per tetracycline in these formulations is about. It is between 0.8 and 1.3. This relative amount is required to obtain clear and stable solutions.

2-Pyrrolidone is used as a co-solvent for complete dissolution of tetracycline and is present in an amount of from 10% to 70% by weight of the total composition and preferably from 60% to 70%.

If necessary, adjust the pH of the solution to 7.5 to 9.5. The preferred pH range is between 8 and 9. The pH of the solution is adjusted with an organic base such as 2-aminoethanol or a pharmaceutically acceptable acid such as hydrochloric acid.

According to a preferred embodiment of the process according to the invention, the preparation of tetracycline-containing compositions is carried out by firstly applying ca. The magnesium compound is mixed with a mixture of 2-pyrrolidone and water at 50 ° C, and tetracycline antibiotic is added slowly with constant stirring, then stirred until complete dissolution and finally adjusted to the desired pH. If polyvinylpyrrolidone is also required, it is mixed with a mixture of 2-pyrrolidone and water before the addition of magnesium compound and tetracycline as described above.

The tetracycline formulations of the present invention are readily injected over a wide range of temperatures and are also suitable for physical and chemical stability.

The use of high-tetracycline-containing compositions of the present invention can reduce the number of injections required to achieve an effective dosage level in large animals such as bulls.

The novel compositions of the present invention containing tetracycline are primarily intended for parenteral administration, but may also be used for topical or oral administration.

It has now been found that stable, high-potency solutions of chlorotetracycline can be prepared by the preparation of novel pharmaceutical compositions comprising 5 to 20% by weight of an aqueous solution of clotetetracycline or a pharmaceutically acceptable acid addition salt thereof, based on the amount of this antibiotic. approx. 2 to 4 moles of a pharmaceutically acceptable calcium compound soluble in the above aqueous solution and ca. It contains 50-70% by weight of 2-pyrrolidone and the pH of the total solution is between 8 and 10.

Chlorotetracycline is a widely used antibiotic of the tetracycline type. For a detailed description, see U.S. Patent No. 2,482,055. In solutions prepared by the process of the invention, the actual concentration of the free base of chlorotetracycline or a pharmaceutically acceptable acid addition salt thereof is generally between 5% and 20% by weight. Preferably an acid addition salt is used which has a preferred concentration of between 10% by weight and 20% by weight, and in particular between 10% by weight and 15% by weight.

Suitable acid addition salts of chlorotetracycline include, for example, the following pharmaceutically acceptable acid addition salts: hydrochloride, hydrobromide or sulfate. However, it is preferred to use chlorotetracycline hydrochloride.

Calcium ions in solution form calcium chlorotetracycline chelates with chlorotetracycline. A convenient and preferred source of calcium ion is calcium chloride, but other calcium compounds such as calcium oxide, calcium acetate, or calcium sulfate may be used. The molar amount of calcium compound in these formulations, based on chloro-tetracycline, is approx. It is between 2 and 4. It is advisable to choose this relative amount in order to obtain clear and stable solutions.

2-Pyrrolidone is used as a co-solvent and is present in an amount of from 50% to 70% and preferably from 60% to 70% by weight of the total composition.

If necessary, adjust the pH of the solution to between 8 and 10. The preferred pH range is 8.5 and

It's between 9.5. An organic base such as 2-aminoethanol or a pharmaceutically acceptable acid such as hydrochloric acid may be used to adjust the pH of the solution.

According to a preferred embodiment of the process of the invention, the preparation of the compositions containing chlorotetracycline is first carried out with ca. The calcium compound is mixed with a mixture of 2-pyrrolidone and water at 50 ° C, and the chlorotetracycline antibiotic is added slowly with constant stirring and stirred until complete dissolution, and finally the pH is adjusted to the desired value. If polyvinylpyrrolidone is required for the formulation, it is added to the mixture of 2-pyrrolidone and water before the calcium compound is added as described above.

The chlorotetracycline compositions of the present invention are also readily injected over a wide range of temperatures and are of suitable quality for physical and chemical stability.

The use of the high-active ingredient chlorotetracycline compositions of the present invention may reduce the number of injections required to achieve an effective dosage level in large animals such as cattle.

The novel compositions of the present invention containing chlorotetracycline are primarily intended for parenteral administration, but may also be used for topical or oral administration.

The invention is further illustrated by the following non-limiting examples.

Example 1 g / 100 ml

Oxytetracycline (927 γ / mg specific activity, 5% overdose) 22.65

Magnesium oxide 1.9 21

2-Pyrrolidone 40.00

Magnesium formaldehyde sulfoxylate 0.44

2-Amino-ethanol 0.10

Make up to 100.0 ml with water

A solution of the above composition is prepared as follows: 2-Pyrrolidone is mixed with water, ca. The solution is heated to 75 ° C, magnesium formaldehyde sulfoxylate is added and the mixture is stirred until the latter is dissolved. Magnesium oxide was added to the solution and oxytetracycline was added slowly with stirring and stirred until a clear solution was obtained. Allow to cool to room temperature and adjust the pH of the solution to 8.5 with 2-aminoethanol. The solution is then made up to 100 ml with water.

The above solution, containing 200 mg of oxytetracycline active ingredient per milliliter, has a viscosity of 13.0 cSt (centi-Stoke) at 25 ° C.

Administration of the above solution by subcutaneous injection to cattle allowed the animal tissues to tolerate the formulation well and to obtain satisfactory blood levels.

By adding 1.0 g of sodium formaldehyde sulfoxylate instead of magnesium formaldehyde sulfoxylate, a similar product is obtained.

Example 2 g / 100 ml

Oxytetracycline (927 γ / mg specific activity, 5% overdose) 22.65

Magnesium oxide 1.9 21

2-Pyrrolidone 40.00

Polyvinylpyrrolidone, K-17 5.00

Magnesium formaldehyde sulfoxylate 0.44

2-Amino-ethanol 0.17

Make up to 100.0 ml with water.

A solution of the above composition is prepared as follows: 2-Pyrrolidone is mixed with water, then polyvinylpyrrolidone is added and stirred until the latter is dissolved. The procedure of Example 1 is then followed.

The above solution, containing 200 mg of oxytetracycline active ingredient per ml, has a viscosity of 25.0 ° C and 23.0 cSt.

Administration of the above solution to cattle by subcutaneous and intramuscular injection allowed the animal tissues to tolerate the product well and to obtain satisfactory blood levels.

By adding 1.0 g of sodium formaldehyde sulfoxylate instead of magnesium formaldehyde sulfoxylate, a similar product is obtained.

Example 3

A solution containing 25 mg of oxytetracycline per ml was prepared as described in Example 1:

g / 100 ml

Oxytetracycline (927 γ / mg specific activity, 5% overdose) 2,831

Magnesium oxide 0.245

2-Pyrrolidone 10.00

Sodium formaldehyde sulfoxylate 1.00

2-Amino-ethanol 0.012

Make up to 100.0 ml with water.

The solution has a viscosity of 2 cSt at 25 ° C.

Example 4

A solution of 50 mg of oxytetracycline active ingredient per ml was prepared as described in Example 1:

g / 100 ml

Oxytetracycline (927 γ / mg specific activity, 5% overdose) 5,662

Magnesium oxide 0.490

2-Pyrrolidone 20.00

Sodium formaldehyde sulfoxylate 1.00

2-Amino-ethanol 0.065

Make up to 100.0 ml with water.

The solution has a viscosity of 2.5 cSt at 25 ° C.

Example 5

A solution of 100 mg of oxytetracycline compound per ml was prepared as described in Example 1:

g / 100 ml

Oxytetracycline (927 γ / mg specific activity, 5% overdose) 11,325

Magnesium oxide 0.480

2-Pyrrolidone 35.00

Sodium formaldehyde sulfoxylate 1.00

Make up to 100.0 ml with water.

The solution has a viscosity of 3.0 cSt at 25 ° C.

Example 6

In the same manner as in Example 2, 200 mg of oxytetracycline per ml was prepared

Sodium formaldehyde sulfoxylate 1.00

2-Amino-ethanol 0.76

Make up to 100.0 ml with water.

The solution has a viscosity of 33 cSt at 25 ° C.

solution containing the active substance:

g / lOOml

Oxytetracycline (927 γ / mg specific activity, 5% overdose) 22.65

Magnesium oxide 1.421

2-Pyrrolidone 40.00

Polyvinylpyrrolidone, K-30 5.00

Magnesium formaldehyde sulfoxylate 0.44

2-Amino-ethanol 0.50

Make up to 100.0 ml with water,

Example 10

A solution containing 300 mg of oxytetracycline compound per ml was prepared as described in Example 1:

g / 100 ml

Oxytetracycline (927 γ / mg specific

The solution has a viscosity of 5.0 cSt at 25 ° C.

Example 7

A solution of 200 mg of oxytetracycline compound per ml was prepared as described in Example 2:

g / 100 ml

Oxytetracycline hydrochloride (based on 905 γ / mg specific activity, calculated as 5% activity, 5% overdose)

Magnesium oxide 2.94

2-Pyrrolidone 50.00

Sodium formaldehyde sulfoxylate 1.00

Make up to 100.0 ml with water.

The solution has a viscosity of 70 cSt at 25 ° C.

overdose)

Magnesium oxide 1.921

2-Pyrrolidone 40.00

Polyvinylpyrrolidone, K-17 5.00

Magnesium formaldehyde sulfoxylate 0.44

2-Amino-ethanol 3.84

Make up to 100.0 ml with water.

Example 11

A solution of 350 mg of oxytetracycline compound per ml was prepared as described in Example 1:

g / 100 ml

Oxytetracycline (927 γ / mg specific

The solution has a viscosity of 45 cSt at 25 ° C.

Example 8 Calculated with activity at 5% overdose) 39,597

Magnesium oxide 3.43

2-Pyrrolidone 50.00

Sodium formaldehyde sulfoxylate 1.00

Make up to 100.0 ml with water.

The solution has a viscosity of 200 cSt at 25 ° C.

Example 2 was prepared as follows

of 200 mg per milliliter oxytetracycline 40 Example 12 solution containing the active substance: g / 100 ml The following Example 1 was prepared as follows Oxytetracycline (927 γ / mg specific of a composition of 400 ml mg oxytetracycline activity, 5% solution containing the active substance: overdose) 22.65 45 g / 100 ml Magnesium chloride hexahydrate 9.668 Oxytetracycline (927 γ / mg specific 2-Pyrrolidone 40.00 activity, 5% Polyvinylpyrrolidone, K-17 5.00 overdose) 45.30 Magnesium formaldehyde sulfoxylate 0.44 Magnesium oxide 3.92 2-aminoethanol 0.88 50 2-Pyrrolidone 50.00 Make up with water To 100.0 ml. Sodium formaldehyde sulfoxylate 1.00 The solution has a viscosity of 35 cSt at 25 ° C. Make up with water To 100.0 ml.

The solution has a viscosity of 785 cSt at 25 ° C.

Example 9 55

A solution of 200 mg of oxytetracycline active ingredient in the following Example 13 was prepared in the same manner as in Example 1:

Oxytetracycline (927 γ / mg specific g / 100 ml 60 solution containing 100 mg doxycycline: g / lOOml activity, 5% Doxycycline (930 γ / mg specific overdose) 22.65 activity, 5% Magnesium acetate tetrahydrate 10.021 overdose) 11.29 2-Pyrrolidone 40.00 65 Magnesium oxide 1.921

2-Pyrrolidone 50.00

Sodium formaldehyde sulfoxylate 1.00

Concentrated hydrochloric acid to adjust the pH to 7.3

Make up to 100.0 ml with water.

A solution of the above composition is prepared as follows: 2-Pyrrolidone is mixed with water. Approx.

The solution is warmed to 0 ° C and then added with stirring and dissolved in sodium formaldehyde sulfoxylate. Magnesium oxide is added to the solution and the mixture is slowly added with stirring to the doxycycline and adjusted to pH with concentrated hydrochloric acid. Allow the resulting solution to cool to room temperature and adjust the pH of the solution to 7.3 with concentrated hydrochloric acid. Finally, make up to 100 ml with water,

Similar to the above, but with 5.0 and. Solutions of pH 6.5 can also be prepared as described above.

Example 14

A solution containing 100 mg of doxycycline active ingredient per ml was prepared as described in Example 13:

g / 100 ml

Doxycycline (based on 930 γ / mg specific activity, 5% overdose)

Magnesium oxide 1.9 21

2-Pyrrolidone 40.00

Sodium formaldehyde sulfoxylate 1.00

Concentrated hydrochloric acid to adjust the pH to 7.2

Make up to 100.0 ml with water.

A solution similar to the one above but having a pH of 5.2 can also be prepared as described above.

Example 15

A solution of 200 mg of doxycycline active ingredient per ml was prepared as described in Example 13:

g / 100 ml

Doxycycline (based on 930 γ / mg specific activity, 5% overdose)

Magnesium oxide 3,828

2-Pyrrolidone 50.00

Sodium formaldehyde sulfoxylate 1.00

Concentrated hydrochloric acid to adjust the pH to 7.2

Make up to 100.0 ml with water.

A solution similar to the one above but having a pH of 5.2 can also be prepared as described above.

Example 16

A solution containing 200 ml of doxycycline active ingredient per ml was prepared as described in Example 13:

g / 100 ml

Doxycycline (based on 930 γ / mg specific activity, 5% overdose)

Magnesium oxide 3,828

2-Pyrrolidone 40.00

Sodium formaldehyde sulfoxylate 1.00

Concentrated hydrochloric acid to adjust pH to 7

Make up to 100.0 ml with water.

Example 17

A solution of 200 mg of doxycycline active ingredient per ml was prepared as described in Example 13:

g / 100 ml

Doxycycline (based on 930 γ / mg specific activity, 5% overdose)

Magnesium oxide 3,828

2-Pyrrolidone 30.00

Sodium formaldehyde sulfoxylate 1.00

Concentrated hydrochloric acid to adjust the pH to 5.8

Make up to 100.0 ml with water.

Example 18

Prepare a solution of 200 mg doxycycline, per ml, of the following composition:

g / 100 ml

Doxycycline (based on 930 γ / mg specific activity, 5% overdose)

Magnesium oxide 3.8 28

2-Pyrrolidone 40.00

Sodium formaldehyde sulfoxylate 1.00

Polyvinylpyrrolidone, K-17 7.00

Concentrated hydrochloric acid to adjust pH to 6.6

Make up to 100.0 ml with water.

The 2-pyrrolidone is mixed with water. Polyvinylpyrrolidone is added and the mixture is stirred until a homogeneous solution is obtained. The additional ingredients are then added as in Example 13.

A solution of the same composition as above, but containing only 30 g of 2-pyrrolidone instead of 40 g, can also be prepared as described above.

Example 19

A solution of 100 mg of doxycycline active ingredient per ml was prepared as described in Example 13:

g / 100 ml

Doxycycline hydrochloride (based on 850 γ / mg specific activity, 5% overdose)

Magnesium oxide 2.02

2-Pyrrolidone 60.00

Sodium formaldehyde sulfoxylate 1.00

Concentrated hydrochloric acid to adjust the pH to 7.2

Make up to 100.0ml with water,

Similar to the above, but with a 6.5 and a. Solutions at pH 5.0 can also be prepared as described above.

Example 20

A solution of 100 mg of doxycycline active ingredient per ml was prepared as described in Example 13:

g / 100 ml

Doxycycline (based on 930 γ / mg specific activity, 5% overdose)

Magnesium oxide 0.059

Sodium formaldehyde sulfoxylate 1.00

2-Pyrrolidone 70.00

Concentrated hydrochloric acid to adjust the pH to 7.2

Make up to 100.0 ml with water.

Similar to the above, but with a 6.5 and a. Solutions of pH 5.2 can also be prepared as described above.

Example 21

A solution of 10 mg of doxycycline active ingredient per ml was prepared as described in Example 13:

g / 100 ml

Doxycycline (based on 930 γ / mg specific activity, 5% overdose) 1,129

Magnesium oxide 0.206

2-Pyrrolidone 10.00

Sodium formaldehyde sulfoxylate 1.00

Concentrated hydrochloric acid to adjust the pH to 6.7

Make up to 100.0 ml with water.

A solution similar to the one above but having a pH of 5 can also be prepared as described above.

Example 22

Prepare a solution of 100 mg tetracycline hydrochloride per ml in the following composition:

g / 100 ml

Tetracycline (based on 955 γ / mg specific tetracycline hydrochloride activity, 5% overdose)

Magnesium oxide 0.958

2-Pyrrolidone 70.00

Sodium formaldehyde sulfoxylate 1.00

Polyvinylpyrrolidone, K-17 5.00

2-Amino-ethanol to adjust the pH to 8.5

Make up to 100.0 ml with water.

2-Pyrrolidone is mixed with water, then polyvinylpyrrolidone is added and the mixture is stirred until a homogeneous solution is obtained. Heat the solution to ca. At 50 ° C, sodium formaldehyde sulfoxylate is added and dissolved with stirring. Magnesium oxide is then added to the solution, and tetracycline is added slowly with stirring and the mixture is stirred until a clear solution is obtained. Allow the solution to cool to room temperature and then with 2-aminoethanol

Adjust the pH of the solution to 8.5. Finally, make up to 100 ml with water.

A solution of the same composition, but containing 60.00 g of 2-pyrrolidone per 100 ml of solution, may also be prepared as described above.

Example 23

A solution of 50 mg of tetracycline hydrochloride active ingredient per ml was prepared as described in Example 22:

g / 100 ml

Tetracycline (based on 955 γ / mg specific tetracycline hydrochloride activity, 5% overdose)

Magnesium oxide 0.479

2-Pyrrolidone 70.00

Sodium formaldehyde sulfoxylate 1.00

Polyvinylpyrrolidone, K-17 5.00

2-Aminoethanol to adjust the pH to 8.5

Make up to 100.0 ml with water.

A solution of the same composition, but containing 50.00 g of 2-pyrrolidone per 100 ml of solution, may be prepared as described above.

Example 24

A solution of 50 mg of tetracycline hydrochloride active ingredient per ml was prepared as described in Example 22:

g / 100 ml

Tetracycline (based on 955 γ / mg specific tetracycline hydrochloride activity, 5% overdose)

Magnesium oxide 0.479

2-Pyrrolidone 60.00

Magnesium formaldehyde sulfoxylate 0.44

Polyvinylpyrrolidone, K-17 5.00

2-Aminoethanol to adjust the pH to 8.5

Make up to 100.0 ml with water,

Example 25

A solution containing 100 mg of tetracycline hydrochloride per milliliter of active ingredient was prepared as described in Example 22, except that polyvinylpyrrolidone was not added:

g / 100 ml

Tetracycline (based on 955 γ / mg specific tetracycline hydrochloride activity, 5% overdose)

0.958

60.00

0.44

To 100.0 ml.

Magnesium oxide 2-Pyrrolidone

Magnesium Formaldehyde Sulfoxylate 2-Amino-Ethanol for Adjustment to pH 8.9

Make up with water

A solution of the same composition containing 70.00 g of 2-pyrrolidone at pH 8.8 can also be prepared as described above.

Example 26

A solution containing 50 mg of tetracycline hydrochloride per ml was prepared as described in Example 25:

g / 100 ml

Tetracycline (based on 955 7 / mg specific tetracycline hydrochloride activity, 5% overdose)

Magnesium oxide 0.479

2-Pyrrolidone 60.00

Magnesium formaldehyde sulfoxylate 0.44

2-Amino-ethanol to adjust pH to 8.8

Make up to 100.0 ml with water.

A solution of the same composition containing 70.00 g of 2-pyrrolidone at pH 8.7 can also be prepared as described above.

Example 27

A solution of 100 mg of tetracycline hydrochloride active ingredient per ml was prepared as described in Example 25:

g / 100 ml

Tetracycline Hydrochloride (based on 980 y / mg specific tetracycline hydrochloride activity, 5% overdose)

Magnesium oxide 0.939

2-Pyrrolidone 60.00

Sodium formaldehyde sulfoxylate 1.00

2-Amino-ethanol to adjust the pH to 8.5

Make up to 100.0 ml with water.

Example 28

A solution of the following formulation, containing 10 mg of tetracycline hydrochloride active ingredient per milliliter, was prepared as described in Example 25, except that the pH was adjusted to the desired value with concentrated hydrochloric acid:

g / 100 ml

Tetracycline (based on 955 7 / mg specific tetracycline hydrochloride activity, 5% overdose)

Magnesium oxide 0.096

2-Pyrrolidone 30.00

Sodium formaldehyde sulfoxylate 1.00

Concentrated hydrochloric acid to adjust pH to 7.5

Make up to 100.0 ml with water.

Similar to the above, but with a 6.5 and a. Solutions of pH 5.2 can also be prepared as described above.

Example 29

Prepare a solution of 100 mg chlorotetracycline per ml in the following composition:

g / 100 ml

Chloro-tetracycline hydrochloride (based on 950 7 / mg specific activity of chloro-tetracycline hydrochloride, 5% overdose)

Calcium chloride 4.96

2-Pyrrolidone 60.00

Monothio-glycerol 1.00

2-Amino-ethanol to adjust pH to 8.8

Make up to 100.0 ml with water.

2-Pyrrolidone is mixed with water, ca. The solution is heated to 50 ° C, the monothioglycerol is added and the mixture is stirred until dissolved. The solution is then mixed with calcium chloride. Chloro-tetracycline hydrochloride is added slowly with stirring and the pH of the mixture is increased by addition of 2-aminoethanol until a homogeneous solution is obtained. Allow the solution to cool to room temperature and adjust the pH of the solution by adding 2-aminoethanol. Finally, make up to 100 ml with water.

Similar to the one above, but with 8.0 and 8.0 respectively. Solutions of pH 9.5 can also be prepared as described above.

Example 30

A solution containing 100 mg of chlorotetracycline hydrochloride per ml was prepared as described in Example 29:

Chloro-tetracycline hydrochloride (based on 950 7 / mg specific activity of chloro-tetracycline-hydrochloride, 5% overdose) Calcium chloride

2-Pyrrolidone

Monothioglycerol

2-Amino-ethanol to adjust pH to 8.8

Make up with water

Similar to the above but 8.0 dl.

g / 100 ml

11.053

9.92

60.00

1.00

To 100.0 ml. Solutions of pH 9.5 can also be prepared as described above.

Example 31

Prepare a solution of 50 mg of chlorotetracycline hydrochloride per ml in the following composition:

17 g 3 x 5 g / 100 ml

Chloro-tetracycline hydrochloride (based on 950 7 / mg specific activity of chloro-tetracycline hydrochloride,

5% overdose) 5,527

Calcium chloride 2.48

2-Pyrrolidone 50.00

Polyvinylpyrrolidone 5.00

Monothio-glycerol 1.00

2-Amino-ethanol to adjust the pH to 8.8

Make up to 100.0 ml with water.

The 2-pyrrolidone is mixed with water, the polyvinylpyrrolidone is added and stirred until the latter is dissolved. The other ingredients are then added in the same manner as in Example 29.

Similar to the one above, but with 8.0 and 8.0 respectively. Solutions of pH 9.5 can also be prepared as described above.

Example 32

A solution containing 200 mg of chlorotetracycline hydrochloride per ml was prepared as described in Example 29:

gflOO ml

Chloro-tetracycline hydrochloride (based on 950 7 / mg specific activity of chloro-tetracycline hydrochloride,

With 5% overdose) 22.106

Klacium chloride 9.92

2-Pyrrolidone 60.00

Monothio-glycerol 1.00

2-Amino-ethanol to adjust pH to 8.8

Make up to 100.0 ml with water.

Solutions similar to the above, but with pHs of 8.0 and 9.5, can also be prepared as described above.

Example 33

A solution containing 100 mg of chlorotetracycline hydrochloride per ml was prepared as described in Example 29:

g / 100 ml

Chlorotetracycline hydrochloride (based on 950 γ / mg specific chlorotetracycline hydrochloride activity).

5% overdose) 11,053

Calcium chloride 4.96

2-Pyrrolidone 70.00

Monothio-glycerol 1.00

2-Amino-ethanol to adjust pH to 8.8

Make up to 100.0 ml with water.

Similar to the one above, but with 8.0 and 8.0 respectively. Solutions of pH 9.5 can also be prepared as described above.

Example 34

A solution containing 100 mg of chlorotetracycline hydrochloride per ml was prepared as described in Example 31:

g / lOOml

Chlorine r-tetracycline hydrochloride (based on 950 7 / mg specific chlorotetracycline hydrochloride activity,

5% overdose) 11,053

Calcium chloride 4.96

2-Pyrrolidone 60.00

Polyvinylpyrrolidone 5.00

Monothio-glycerol 1.00

2-Amino-ethanol to adjust pH to 8.8

Make up to 100.0 ml with water.

Similar to the one above, but with 8.0 and 8.0 respectively. Solutions of pH 9.5 can also be prepared as described above.

Claims (10)

Patent claims CLAIMS 1. A process for the preparation of a stable pharmaceutical composition comprising an antibiotic in chelated form comprising oxytetracycline, doxycycline, tetracycline, chlorotetracycline or a pharmaceutically acceptable acid addition salt thereof in an aqueous solution of 2-pyrrolidone, and a pharmaceutically acceptable alkali metal, if necessary, dissolve polyvinylpyrrolidone and, if desired, adjust the pH of the solution to complete dissolution, with the proviso that when the antibiotic is chlorotetracycline, it is an alkaline earth metal compound which is soluble in the solution and a tetracycline antibiotic other than chloro-tetracycline, the alkali earth metal compound is a soluble magnesium compound. (Priority: December 28, 1976) 2. The process of claim 1, wherein the aqueous solution of 2-pyrrolidone used in an amount of 10% to 50% by weight of the composition comprises dissolving 1% to 40% by weight of oxytetracycline or a pharmaceutically acceptable acid addition thereof. and 0.8 to 1.3 molar soluble pharmaceutically acceptable magnesium compounds per oxytetracycline, and the pH of the solution is preferably adjusted to 7.5 to 9.5. (Priority: January 2, 1976) 3. A process according to claim 1, wherein the aqueous solution of 2-pyrrolidone used in an amount of 10% to 70% by weight of the composition is dissolved in 1% to 25% by weight of doxycycline or a pharmaceutically acceptable acid addition thereof. and about 1.8 to 2.2 moles of soluble, pharmaceutically acceptable magnesium compound per doxycycline, and the solution is preferably adjusted to a pH of between 3 and 7.5. (Priority: December 28, 1976) The method of claim 1, which is an embodiment. characterized in that 1% to 15% by weight of tetracycline or a pharmaceutically acceptable acid addition salt thereof is dissolved in an aqueous solution of 10% to 70% by weight of 2-pyrrolidone, and 0.8% by weight of tetradcline. -13 moles of pharmaceutically acceptable seed10 The lithium compound and the pH of the solution are preferably adjusted to 7.5 to 9.5. (Priority: December 28, 1976) 5. The process of claim 2 wherein the magnesium compound is magnesium oxide. (Priority: January 2, 1976) A process according to any one of claims 3 or 4 wherein the magnesium compound is magnesium oxide. (Priority: December 28, 1976) 7. The process of claim 1 wherein the aqueous solution of 2-pyrrolidone used in an amount of 50% to 70% by weight of the composition comprises dissolving 5% to 15% by weight of chlorotetracycline or a pharmaceutically acceptable salt thereof. and a 2-4 molar amount of the pharmaceutically acceptable calcium compound per chlorotetracycline, and preferably the pH of the solution is between 8 and 10. (Priority: December 28, 1976) 8. A process according to claim 7, wherein the calcium compound is chloride. (Priority: December 28, 1976) 9. The method of claim 2, wherein the composition is complete Polyvinylpyrrolidone having an average molecular weight of 5000 to 100,000 is also added to the solution in an amount of 1% to 7% by weight. (Priority: January 2, 1976) 10. Figures 1, 3, 4 and 6-8. A process according to any one of claims 1 to 6, wherein polyvinylpyrrolidone having an average molecular weight of 5000 to 10000 is also added to the solution in an amount of 1% to 7% by weight of the total composition. (Priority: December 28, 1976)