US3220925A - Tetracycline-novobiocin compositions and method of use - Google Patents

Description

United States Patent Office 3,220,925 Patented Nov. 30, 1965 3,220,925 TETRACYCLINE-NOVOBIOCIN COMPOSITIONS AND METHOD OF USE Louis C. Schroeter, Kalamazoo, Mich., assignor to The Upjohn Company, Kalamazoo, Mich, a corporation of Delaware No Drawing. Fiied Nov. 15, 1962, Ser. No. 238,051 12 Claims. (Cl. 167-82) This invention relates to antibiotic compositions and, more particularly, to a combination of tetracycline and novobiocin with which higher antibiotic blood levels can be obtained.

Tetracycline and novobiocin in combination have been widely used in the treatment of a number of bacterial infections with outstanding success. The combination has been reported to be particularly useful in delaying the onset of antibiotic resistance by initially susceptible pathogens. Despite the efiicacy of this combination, it has been recognized that in some instances lower blood levels of novobiocin are obtained when the two antibiotics in powder form are administered in the same dosage unit as compared with blood levels resulting from the administration of novobiocin alone. This problem has been studied by various groups, but no satisfactory explanation or solution to the problem has heretofore been available.

It has now been found that the administration of a solid oral dosage unit comprising tetracycline and novobiocin as the essential active ingredients can be prepared which gives optimum novobiocin and tetracycline blood levels. This is accomplished by providing the novobiocin in the form of from about 5 to about 2000 pellets, preferably coated with a pharmaceutically acceptable material which will delay release on the novobiocin from about to about 20 minutes after reaching the stomach. During this period the tetracycline will dissolve and be diluted by gastric contents and the novobiocin pellets dispersed beyond the site of tetracycline release and dissolution.

The term tetracycline as employed herein embraces all forms of tetracycline, including specifically the bases tetracycline, chlortetracycline, oxytetracycline and demethylchlortetracycline, and in particular the pharmaceutically acceptable acid addition salts of these bases, such as the hydrochloride, hydrobromide, phosphate, phosphate complexes (e.g., as described in US. Patent No. 2,791,609), and the like.

The term novobiocin includes all forms of novobiocin absorbable from the intestinal tract and employed in therapy, specifically, novobiocin, amorphous (but not crystalline) novobiocin acid, and the pharmaceutically acceptable alkali metal and alkaline earth metal salts of novobiocin such as sodium novobiocin and calcium novobiocin.

As employed herein the term pellets describes discrete particles, such as granules, compressed powders, pilules, spheres and the like, having an integrity suflicient to withstand formulation into a single dosage unit such as a hard gelatin capsule, soft gelatin capsule or tablet. These pellets, prepared in conventional manner, can range in size from about 0.3 mm. to about 6.0 mm. in diameter, or in their longest dimension if not round, depending on the number to be incorporated in each dosage unit and the limitations on size of the dosage unit. The shape of the pellets is unimportant except insofar as coating considerations are concerned, but they should be essentially uniform in size (for example, between 16 and 20 mesh and free from powders finer than about 50 mesh). Pellets comprising granules can be prepared, for example, by conventional wet or dry (slugging) techniques.

Studies have indicated that a portion of the novobiocin, when incorporated as a powder with tetracycline powder in a single capsule, is converted to crystalline novobiocin acid when the capsule is ingested and reaches the acidic fluids of the stomach. Although novobiocin itself, even as an amorphous acid, is normally absorbed without difficulty from the intestinal tract, crystalline novobiocin acid is relatively insoluble and is not absorbed in significant amounts. The surfaces of novobiocin particles exposed to gastric juices, and especially to high concentrations of tetracycline solution, are converted to crystalline novobiocin acid. The purpose of the pellets of novobiocin is therefore to render the novobiocin in a form more readily transportable through peristaltic movement to various parts of the stomach away from the vicinity of tetracycline release and dissolution. The optional provision of these pellets with a coating which will delay release of the novobiocin in the stomach for about 10 to 20 minutes after reaching the stomach assures that the surfaces of these pellets will not, in the course of dispersing, be exposed to locally high concentrations of tetracycline solution and develop the insoluble crystalline novobiocin acid coating. A further advantage of the coating is to thwart the tendency of these pellets to be enveloped by the crystalline coating, which otherwise would interfere with the dispersive process.

The provision of novobiocin in pellet form accomplishes also the objective of achieving a steady, statistically predictable release of novobiocin to the intestinal tract in absorbable form whereby optimum and dependable blood levels of novobiocin can be obtained, In general, from about 50 to about 500 pellets of novobiocin provides a distribution in the stomach sufficient to give a favorable discharge rate into the intestinal tract through normal stomach emptying. A broader range of from about 5 to about 2000 pellets, while embracing marginal regions, nevertheless alfords a distribution and rate of discharge into the absorption regions which satisfies the requirements of this invention.

Styrene maleic acid copolym'er, utilized as described in US. Patent No. 2,897,121, is admirably suited as a coating material in the present instance. In general, coating thickness should be sufficient to provide protection to the pellets or granules against disintegration in simulated gastric fluid (0.05 N hydrochloric acid at 37 C.) for 10 to 20 minutes. Other pharmaceutically acceptable coating materials can be employed to delay release of the novobiocin in the stomach. Such coatings include, for example, fatty or waxy materials (mono-, di? or triglycerides, beeswax and the like) and hydrophobic polymers (ethyl cellulose and the like) in thicknesses calculated to give the desired release delay. Suitable coatings include, in addition, those described in Remingtons Practice of Pharmacy, 12th Edition, 1961, pages 483-485.

Advantageously, but not necessarily, the novobiocin pellet formulation can include a surfactant of the anionic or non-ionic type in order to facilitate the dissolution of novobiocin on breakdown of the pellets. Pharmaceutically acceptable anionic surfactants such as dioctyl sodium sulfosuccinate, sodium 'lauryl sulfate and the like are prefered for use with sodium novobiocin. The nonionic surfactants, such as polysorbate 80, are likewise acceptable. Cationic surfactants are not suitable because of their tendency to interact with sodium novobiocin to form insoluble novobiocin salts or crystalline novobiocin acid.

Combinations of tetracycline and novobiocin preferably contain from about 50 to about 500 mg. of tetracyline and from about 50 to about 500 mg. of novobiocin for the treatment of bacterial infections in mammals. Such combinations, formulated in accord with this invention and administered on the usual schedule for the combination, give blood levels of tetracyline and novobiocin in humans and animals approximating EXAMPLE l.HARD GELATIN CAPSULES One kilogram of sodium novobiocin is prepared in pellet form by first mixing with 20 gm. of magnesium stearate and gm. of a mixture of 85 dioctyl sodium sulfosuccinate and sodium benzoate.- The. resulting mixture is screened through a No. 40 screen and blended for 30 minutes. Pellets are then formed by slugging. Approximate size of the resulting pellets is 0.03l-inch thick and 0.045-inch diameter.

The pellets above are coated by air suspension with an alcoholic solution of 1.5% styrene maleic acid copolymer and 0.3% n-dibutyl phthalate to a thickness of 0.5 mm.

Hard gelatin No. 0 capsules are then filled with 125 mg. of sodium novobiocin as pellets (approximately 150 pellets) and 250 mg. of tetracycline hydrochloride powder.

EXAMPLE 2.SOFT GELATIN CAPSULES Granules are prepared from the following materials:

Sodium novobiocin 125 Spray dried lactose 85% dioctyl sodium sulfosuccinate and 15% sodium benzoate 2 Silicon dioxide 1 Magnesium stearate 1 After slugging, the large tablets or slugs are broken down to the correct size by forcing them through a 14-20 mesh screen using an oscillating granulator. Granules are classified according to size by screening so that all granules pass through a No. 20 screen (0.84 mm.) but not through a No. screen (0.59 mm.). The granules are coated as in Example 1. Soft gelatin capsules are then filled with a mixture of 125 mg. of sodium novobiocin as coated granules and 250 mg. of tetracycline hydrochloride.

EXAMPLE 3.--HARD GELATIN CAPSULES Fifty million coated pilules containing sodium novobiocin are prepared from the following ingredients:

Pill starters 50,000,000

An unmeasured quantity of bolted sucrose (30-40 mesh per square inch screen) is placed in a revolving pill tub and moistened with a spray of deionized or distilled water until uniformly moistened. Uniformity in size of the bolted sucrose is more important at this stage that is the relative size of the sucrose granules. A small amount of a homogeneous mixture of bolted talc, starch and sucrose (100 mesh per square inch screen) in a ratio of 20:5:1 is dusted on the moistened sucrose. The talc-starch-sucrose mixture rolls onto the moistened sucrose. The contents of the pill tub are alternately water-sprayed and powder-dusted until spherical masses (pill starters), having a diameter between 0.020 and 0.021 inch, are produced. The smaller spheres are separated from the larger ones by screening during processing. They are returned to the pill tub and brought up to the proper size by the above described method. Those spheres which are out of shape at this point are discarded. Only round, smooth starters are used to form pilules.

4 Medicinal agent mixture Sodium novobiocin kg. 44.6 Starch, bolted kg. 3.4 Sucrose, powdered kg. 1.7 Talc kg. 6.2 Dioctyl sodium sulfosuccinate gm. 400

The sodium novobiocin and an equal amount of the starch are uniformly mixed and the mixture is micronized. 'The mixture is then blended with the remaining starch and other ingredients and bolted through No. 11 cloth.

Coating solution Kg. Hydrolysed styrene-maleic acid copolymer 5.4 White mineral oil, 180 viscosity 0.9 Denatured ethanol, anhydrous 28 The copolymer is dissolved in the alcohol and the mineral oil is added.- It is preferred to use 0.5 kg. of n-dibutylphthalate as plasticizer in the coating solution.

Directions: (a) The pill starters are sprayed in a revolving pill tub with deionized water until uniformly moistened.

(b) The medicinal agent mixture is dusted on the moistened starters. The spraying and dusting are repeated until the average diameter of the pilules is from 0.035-0.038 inch. The pilules are air dried and assayed for sodium novobiocin content.

(c) The assayed pilules are coated with the coating solution by the air suspension technique until the average diameter is increased by 0.00050.0008 inch. The coated pilules are assayed for sodium novobiocin content.

(d) The coated pilules are encapsulated into twopiece hard gelatin capsules each containing mg. of sodium novobiocin in the form of delayed-coated pilules and 250 mg. of powdered tetracycline hydrochloride.

What is claimed is:

1. A solid oral dosage unit comprising, as essential active ingredients, powdered tetracycline and novobiocin, said novobiocin being separated from said tetracycline by being in the form of from about 5 to about 2000 pellets.

2. A solid oral dosage unit comprising: as essential active ingredients, powdered tetracycline and novobiocin, said novobiocin being in the form of from about 5 to about 2000 pellets coated with a pharmaceutically acceptable material which will delay release of the novobiocin from about 10 to about 20 minutes after reaching the stomach to permit the tetracycline to dissolve and be diluted by gastric contents and novobiocin pellets to disperse beyond the site of tetracycline release and dissolution.

3. A solid oral dosage unit comprising: as essential active ingredients, powdered tetracycline and novobiocin, said novobiocin being in the form of from about 50 to about 500 pellets containing novobiocin admixed with a surfactant selected from the group consisting of anionic and non-ionic surfactants and coated with a pharmaceutically acceptable material which will delay release of the novobiocin from about 10 to about 20 minutes after reaching the stomach to permit the tetracycline to dissolve and be diluted by gastric contents and novobiocin pellets to disperse beyond the site of tetracycline release and dissolution.

4. A capsule for therapeutic use comprising: as essential active ingredients, from about 50 to about 500 mg. of powdered tetracycline and from about 50 to about 500 mg. of novobiocin, said novobiocin being in the form of from about 50 to about 500 pellets containing novobiocin admixed with a surfactant selected from the group consisting of anionic and non-ionic surfactants and coated with styrene maleic acid copolymer.

5. A capsule for therapeutic use comprising: as essential active ingredients, about 250 mg. of powdered tetracycline and about 125 mg. of novobiocin, said novobiocin being present in the form of pellets containing novobiocin admixed with diocytyl sodium sulfosuccinate and coated with styrene maleic acid copolymer.

6. A method for obtaining higher novobiocin blood levels from a single dosage unit containing tetracycline and novobiocin than results from administering powdered tetracycline and powdered novobiocin together in a single dosage unit, which method comprises: administering to mammals a single dosage unit containing powdered tetracycline and novobiocin, said novobiocin being in the form of from about 5 to about 2000 pellets.

7. A method for obtaining higher novobiocin blood levels from a single dosage unit containing tetracycline and novobiocin than results from administering powdered tetracycline and powdered novobiocin together in a single dosage unit, which method comprises: administering to mammals a single dosage unit containing powdered tetracycline and novobiocin, said novobiocin being in the form of from about 50 to about 500 pellets coated with a pharmaceutically acceptable material which will delay release of the novobiocin from about to about minutes after reaching the stomach to permit the tetracycline to dissolve and be diluted by gastric contents and novobiocin pellets to disperse beyond the site of tetracycline release and dissolution.

8. A method for obtaining higher novobiocin blood levels from a single dosage unit containing tetracycline and novobiocin than results from administering powdered tetracycline and powdered novobiocin together in a single dosage unit, which method comprises: administering to mammals a single dosage unit containing powdered tetracycline and novobiocin, said novobiocin being in the form of from about 50 to about 500 pellets containing novobiocin admixed with a surfactant selected from the group consisting of anionic and non-ionic surfactants and coated with a pharmaceutically acceptable material which will delay release of the novobiocin from about 10 to about 20 minutes after reaching the stomach to permit the tetracycline to dissolve and be diluted by gastric contents and novobiocin pellets to disperse beyond the site of tetracycline release and dissolution.

9. A method for obtaining higher novobiocin blood levels from a single dosage unit containing tetracycline and novobiocin that results from administering powdered tetracycline and powdered novobiocin together in a single dosage unit, which method comprises: administering to mammals a single dosage unit containing from about to about 500 mg. of powdered tetracycline hydrochloride and from about 50 to about 500 mg. of sodium novobiocin, said sodium novobiocin being in the form of from about 50 to about 500 pellets containing sodium novobiocin admixed with surfactant selected from the group consisting of anionic and non-ionic surfactants and coated with styrene maleic acid copolymer.

10. A method for obtaining higher novobiocin blood levels from a single dosage unit containing tetracycline and novobiocin than results from administering powdered tetracycline and powdered novobiocin together in a single dosage unit, which method comprises: administering to humans and animals a single dosage unit containing about 250 mg. of powdered tetracycline hydrochloride and about mg. of sodium novobiocin, said sodium novobiocin being present in the form of pellets containing sodium novobiocin admixed with dioctyl sodium sulfosuccinate and coated with styrene maleic acid copolymer.

11. A solid oral dosage unit comprising: as essential active ingredients, about 250 mg. of powdered tetracycline and about 125 mg. of novobiocin, said novobiocin being in the form of from about 50 to about 500 pellets.

12. A method for obtaining higher novobiocin blood levels from a single dosage unit containing tetracycline and novobiocin than results from administering powdered tetracycline and powdered novobiocin together in a single dosage unit, which method comprises: administering to mammals a single dosage unit containing about 250 mg. of powdered tetracycline and about 125 mg of novobiocin, said novobiocin being in the form of from about 50 to about 500 pellets.

References Cited by the Examiner UNITED STATES PATENTS 2,928,770 3/1960 Bardani 167-82 2,954,323 12/1960 Endicott et al. 16782 2,994,639 8/1961 Carper et al. 167-65 3,070,501 12/1962 Mullins et al. 16765 JULIAN S. LEVITT, Primary Examiner.

Claims (1)

1. 8. A METHOD FOR OBTAINING HIGHER NOVOBIOCIN BLOOD LEVELS FROM A SINGLE DOSAGE UNIT CONTAINING TETRACYCLINE AND NOVOBIOCIN THAN RESULTS FROM ADMINISTERING POWDERED TETRACYCLINE AND POWDERED NOVOBIOCIN TOGETHER IN A SINGLE DOSAGE UNIT, WHICH METHOD COMPRISES: ADMINISTERING TO MAMMALS A SINGLE DOSAGE UNIT CONTAINING POWDERED TETRACYCLINE AND NOVOBIOCIN, SAID NOVOBIOCIN BEING IN THE FORM OF FROM ABOUT 50 TO ABOUT 500 PELLETS CONTAINING NOVOBIOCIN ADMIXED WITH A SURFACTANT SELECTED FROM THE GROUP CONSISTING OF ANIONIC AND NON-IONIC SURFACTANTS AND COATED WITH A PHARMACEUTICALLY ACCEPTABLE MATERIAL WHICH WILL DELAY RELEASE OF THE NOVOBIOCIN FROM ABOUT 10 TO ABOUT 20 MINUTES AFTER REACHING THE STOMACH TO PERMIT THE TETRACYCLINE TO DISSOLVE AND BE DILUTED BY GASTRIC CONTENTS AND NOVOBIOCIN PELLETS TO DISPERSE BEYOND THE SITE OF TETRACYCLINE RELEASE AND DISSOLUTION.