Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/65—Tetracyclines

Definitions

• This invention relates to improved antibiotic compositions of the tetracycline type.
• antibiotic therapy has been very widespread. Normally a single antibiotic, chosen for its known effectiveness against a diognosed or suspected microorganism, has been used; and for most antibiotics recommended daily dosage has been determined. Proposals have been made to use different types of antibiotic in a combined dose. In a few cases, such as enterococcal endocarditis and some resistant strains of Staphylococcus, combinations of antibiotics of different types have proven effective. Also in some cases combinations of an antibacterial and an antifungal have been used. Many if not most of the proposed compositions have either been no more effective than a single antibioctic or in some cases there has been serious antogonism.
• the bacteriostatic antibiotics of which the tetracyclines with which the present invention deals are members, have either shown antogonism, for example in combinations of the tetracyclines and penicillin, or lack of useful improved results. It should be noted that the distinction between bactericidal and bacteriostatic antibiotics is one which is only of significance in tests made in vitro. When tests are made in living animals or men, all that can be determined is whether or not a drug shows good antibacterial activity. It cannot be determined Whether the test animals or man recovered because the antibiotic actually killed bacteria on contact with them, that is to say was bactericidal, or whether it was merely bacteriostatic and inhibited or very greatly reduced the rate at which the bacteria reproduced themselves.
• the present invention is directed to a combination of tetracyclines, all of them of course being bacteriostatic antibiotics which have been considered unsuitable for combination antibiotic therapy.
• the compositions of the present invention use three tetracyclines in doses which are much smaller for each tetracycline than those normally used with the tetracycline alone. Results are obtained which show as high antibacterial activity in the blood of patients to whom the tripleantibiotic has been given, but the side effects which are often very undesirable, such as nausea, gastrointestinal disturbances, and the like, are eliminated or drastically reduced over thoseof comparable doses of a single antibiotics. As a result, the problems of side effects with most patients are not significant with the preferred doses which will be set out below.
• tetracyclines which are preferred are a mixture of tetracycline itself, hereinafter abbreviated TC; chlortetracycline, abbreviated CT C, and demethylchlortetracycline, abbreviated DMCT.
• TC tetracycline
• CT C chlortetracycline
• DMCT demethylchlortetracycline
• the triple combinations may also include oxytetracycline in place of part or all of the TC, or methacycline in place of .part or all of the DMCT.
• Such combined antibiotic compositions are therefore included in the broader aspects of the present invention.
• the minimum single dose to produce a concentra tion sufficient to show effective antibacterial activity is about 50 mg. TC, 25 mg. CTC, and 25 mg. DMCT, or a total of about 100 mg. If oxytetracycline or methacycline replaces TC or DMCT, the same amounts apply, which will be true in the other dosage limits to follow.
• the maximum single dose is about 500 mg. TC, 250 mg. CTC, and 300 mg. DMCT.
• the preferred dosage for a day is about one third the daily dose of each antibiotic alone, i.e. 333 mg. TC, 333 mg. CTC, and 200 mg. DMCT, or a total of 866 mg.
• the maximum daily dosage under the present invention may be up to twice as great for each ingredient, with a total of 1732 mg. It should be noted that this maximum dose depends on the sensitivity of the organism and tolerance of the patient.
• compositions of the present invention produce antibacterial activities in blood serum at all times during twenty-four hours after administration in excess of a dose of TC equal to the total weight of the composition.
• the composition is, therefore, more efifective than the same amount of TC and gives considerably better antibacterial activities in blood serum over the total period.
• undesirable side effects such as nausea, gastrointestinal disturbances and the like, are either eliminated entirely or so drastically reduced that they do not involve any significant problems with most patients with the preferred daily doses.
• the improved antibacterial activities in the blood of patients as determined by antimicrobial microbiological assay are obtained not only Without offsetting side elfects but with a great reduction and, in the case of most patients, complete elimination of the side eifects which were encountered before. It is not desired to limit the present invention to any theory of the mechanism by which this desirable result is obtained. It is possible that the three tetracyclines have synergistic properties without any comparable eifect on side effects, but the invention is in no sense limited to this particular theory, which is advance as only one of a number of possible explanations. What is known is that improved antibacterial activities with greatly reduced or eliminated undesirable side effects are obtained as compared with the same total dose of each antibiotic when taken alone.
• a powdered mixture of the three tetracyclines with a suitable excipient may be filled into a gelatin capsule for oral use.
• Tablets may be made with a suitable binder such as acacia gum, cornstarch, gelatin and the like, with suitable disintegrating agents such as cornstarch, potato starch, alginic acid and the like, and the customary lubricant such as stearic acid, magnesium stearate, talc, etc.; or syrups or drops may be prepared with suitable sweetening agents, flavoring agents and the like.
• the tetracyclines need not be in the form of the free bases and, in fact, it is generally desirable to use the antibiotics in the form of the hydrochloride salt.
• the active ingredients and lactose are blended together thoroughly to form a homogeneous mixture.
• the powder is used to fill hard gelatin capsules of a suitable size at a gross filled weight of 360 milligrams. Each capsule then contains a total of 250 milligrams of antibiotics in the proportion of one part each of TC HCl and CTC HCl and 0.6 part of DMCT HCl.
• composition described above was tested clinically on twelve subjects, six of whom first received TC HCl in the quantity above, namely 250 mg, and six of whom received a capsule of the three antibiotics. Blood samples were taken at regular intervals during twenty-four hours and antibacterial activities were determined. One week later the subjects who were given the TC HCl were given a capsule of the three antibiotics and the subjects who were given a capsule of three antibiotics the first week were given a capsule of TC HCl. Antibacterial activity was determined by microbiological assay procedures using a standard test for tetracycline antibiotics as given by Grove and Randall (Grove, D. C., and Randall, W.
• the above syrup or pediatric drops has a pH of about 4.0-6.0.
• various agents can be used in place of those shown in the above formulation.
• suspending agents such as Vegum magma (complex colloidal magnesium-aluminum silicate) can be replaced with bentonite magma, tragacanth, carboxymethyl cellulose, methyl cellulose, carbopol 934 (carboxyvinyl polymer of high molecular weight), etc.
• the phosphates used as buffers in the above formulation can be replaced with citrates or tartrates.
• preservatives such as parabens others can be used such as alkali metal benzoates, sorbic acid, etc.
• the sugar and sorbital can be replaced as a whole or in part with corn syrup, glycerol, invert sugars, etc.
• the adjuvants, such as dyes and flavors can be replaced in whole or in part with sequesterene, bisulfites, etc.
• EXAMPLE 4 Oral syrup or drop preparation An oral preparation of syrup or pediatric drops may be formulated substantially as in Example 3 above, substituting the calcium salts of the tetracyclines in place of the neutral tetracyclines. The pH of the preparations should be adjusted to 8.0-9.0 by suitable bufier adjustments.
• Example 5 The procedure of Example 1 was repeated replacing the DMCT with an equal weight of methacycline. A product was produced which exhibited improved antibacterial activity in blood serum and decreased side effects.
• Example 6 The procedure of Example 2 was repeated replacing the DMCT with an equal weight of methacycline. Products were produced which showed improved antibacterial activity in blood serum and the same desirable lack of side effects.

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Cited By (66)

• 1965
  • 1965-06-08 US US462407A patent/US3454697A/en not_active Expired - Lifetime
• 1966
  • 1966-06-07 GB GB25291/66A patent/GB1080617A/en not_active Expired
  • 1966-06-08 BE BE682244D patent/BE682244A/xx unknown
  • 1966-06-08 BR BR180268/66A patent/BR6680268D0/pt unknown
  • 1966-06-08 NL NL6607935A patent/NL6607935A/xx unknown
  • 1966-06-08 FR FR64592A patent/FR5503M/fr not_active Expired
  • 1966-06-08 ES ES0327705A patent/ES327705A1/es not_active Expired
• 1970
  • 1970-08-04 CY CY55070A patent/CY550A/xx unknown

Non-Patent Citations (1)

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