US3454697A - Tetracycline antibiotic compositions for oral use - Google Patents
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- 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
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- 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.
Description
United States Patent 3,454,697 TETRACYCLINE ANTIBIOTIC COMPOSITIONS FOR ORAL USE Austin Joyner, River Edge, N.J., and Charles Knoefel Piercy, Sulfern, N.Y., assignors to American Cyanamid Company, Stamford, Conn., a corporation of Maine No Drawing. Filed June 8, 1965, Ser. No. 462,407 Int. Cl. A61k 21/00 US. Cl. 424-227 2 Claims ABSTRACT OF THE DISCLOSURE A new composition of tetracycline antibiotics in dosage unit form is provided comprising chlortetracycline, tetracycline and demethylchlortetracycline in the ratio of 1:1:0.6 in combination with a suitable pharmaceutical carrier.
This invention relates to improved antibiotic compositions of the tetracycline type.
In the past years 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. In every case where two different types of antibiotics have been used there has been the very serious risk of sensitizing a patient to two types of antibiotic instead of only one. The best discussion of antibiotic combinations are given in the Hatfield Lecture by Dr. Harry F. Dowling, published in Transactions & Studies of the College of Physicians of Philadelphia, volume 31, number I (July 1963), pages 1-9. Dr. Dowling points out that there is a vital distinction between medical rather than chemical types of antibiotics, namely those which in vitro are bactericidal rather than bacteriostatic. Only on the case of bactericidal antibiotics have there been useful combination compositions. 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. In the case of such bacteriostatic activity the ordinary defenses of the body may be the ones which showed an antibiotic as being of satisfactory antibacterial efiicacy. Even in tests made in vitro there is not always an absolutely hard and fast qualitative difference between a bacteriostatic antibiotic and a bactericidal one. In many cases an antibiotic in one concentration shows bacteriostatic activity but if the concentration is enormously increased may actually kill the bac- 3,454,697 Patented July 8, 1969 teria with which it comes in contact. Nevertheless, the differences are sufficiently great so that the distinction between the types of antibiotics is one which is made in practice, and it is this practical interpretation which is to be put on the terms used in the present application.
Even in the case of combinations of bactericidal antibiotics there is only one instance cited by Dr. Dowling where the antibiotics were chemically of similar nature. This is a combination of streptomycin and dithydrostreptomycin. This combination was proposed and has been used in the hopes that it would reduce the serious side effect of nerve deafness of streptomycin alone. As Dr. Dowling points out, there is strong controversy as to Whether this improved result has been obtained and, in any event, it should be emphasized that here as in the case of the few medically accepted combined antibiotics, we are dealing with two bactericidal products.
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. It should be noted that in certain very severe infections, it is not unusual to give a greatly increased antibiotic dose even at the risk of some side effects. After all, a patient with a dangerous infection presenting a serious risk of death will accept a considerable amount of discomfort which may be involved with extremely large doses. Even here, as will be shown below, the maximum dose for extremely sereve cases is still markedly reduced and so, while side effects are not completely eliminated in such cases, they are quite substantially reduced. The tetracyclines which are preferred are a mixture of tetracycline itself, hereinafter abbreviated TC; chlortetracycline, abbreviated CT C, and demethylchlortetracycline, abbreviated DMCT. 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.
An absolutely exact numerical dosage is of no meaning because we are dealing with a mixture of three antibiotics and not materials which react in fixed proportions to form a single new chemical compound. Also, the reactions of patients vary, and there is no such thing as an absolutely precise quantitative dose figure which has any meaning in antibiotic therapy. Nevertheless, it is accepted practice to use minimum daily doses of 1,000 mg. for TC, CTC and oxytetracycline, and 600 mg. for DMTC and methacycline. The corresponding maximum doses recommended for extreme cases are double the figures given above.
It should be noted that side effects are not determined solely by the total intake during a day but are greatly affected by the amount of anibiotics in any single close. For this reason it is customary to give the antibiotics in two or more doses during twenty-four hours. This will be reflected in the data given for minimum preferred and maximum dosages below.
Depending on the sensitivity of the microorganisms involved, 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.
In the composition of the present invention we are dealing with very closely related antibiotics of the bacteriostatic type which have not been considered accept able or practically useful in combination antibiotic therapy. The 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. At the same time, as stated above, 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.
It is an advantage of the invention that the improved results are obtained when the composition is used in any of the customary forms for therapy; thus for example 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. In each form the improved results of the present invention are obtained. It should be noted that 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 invention will be described in greater detail in conjunction with the following specific examples in which Lactose, U.S.P. 43.0
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.
The 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. A., Assay Methods of Antibiotics: A Laboratory Manual, Medical Encyclopedia, Inc., New York, N.Y. 1955, p. 63). The results appear in the following table, which also gives the percentage increase of antibacterial activities in the serum as compared to TC HCl. The study indicates that higher and more sustained antibacterial activity in blood serum is produced by the capsules containing the combination of antibiotics as compared to the tetracycline capsules. It is well known that certain patients are exceptions in that the absorption of a particular antibiotic is not satisfactory. In the case of the patients tested as described above all of the patients showed adequate antibacterial activity by the above test. It is a further advantage of the present invention that it is much less likely that any one patient would fail to acquire adequate antibacterial activity for all of the drugs than would be the case where only a single antibiotic was used. In the test above described, none of the patients showed any undesirable side effects.
TABLE [Antibiotic activity as TO 1301 in blood serum (mcg./m.l.)]
Hours after dose The data in the table are expressed as geometric averages in accordance with standard investigating procedure.
EXAMPLE 2 Table TC HCl 960 CT HCl 960 DMCT HCl 580 Lactose, U.S.P. 410 Cornstarch (for mix) 50 Cornstarch (for paste) 40 Magnesium stearate, U.S.P. (1%) 30 The three antibiotics, lactose and cornstarch (for mix) are blended together. The cornstarch (for paste) is suspended in 35 parts of water and heated with stirring, to form a paste. This paste is then used to granulate the mixed powders. Additional water is used, if needed. The wet granules are passed through a No. 8 hand screen and dried at 20 F. The dry granules are passed through a No. 16 screen. The mixture is lubricated with 1% magnesium stearate and compressed into tablets (tablet weight 303 mg), giving a total of 250 mg. of antibiotics per tablet.
EXAMPLE 3 Oral syrup or drop preparation Percent w./v.
CTC neutral, TC neutral, DMCT neutral 2.0l2.0 Complex colloidal magnesiumaluminum silicate 0.31.0 Sodium phosphate monobasic 0.070.7 Sodium phosphate dibasic 0.02-0.2 Methylparabens 0.08 Propylparabens 0.02 Sucrose 0.030.0 Red dye ED. and C. No. 2 0.0030.15 Cherry fiavor 0.06 Distilled water 25.060.0
Sorbitol solution to make 600-1000.
The above syrup or pediatric drops has a pH of about 4.0-6.0. In formulating syrup or pediatric drops various agents can be used in place of those shown in the above formulation. For example, 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. In place of preservatives such as parabens others can be used such as alkali metal benzoates, sorbic acid, etc. Also in the above formulation, the sugar and sorbital can be replaced as a whole or in part with corn syrup, glycerol, invert sugars, etc. Also 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.
EXAMPLE 7 References Cited The Merck Index, seventh edition, Merck and Co., Inc., Rahway, N.J., 1960, pages 250, 251, 322, 765, 766 and 1021.
Chemical Abstracts 58: 8326c (1963).
ALBERT T. MEYERS, Primary Examiner.
I. A. GOLDBERG, Assistant Examiner.
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US46240765A | 1965-06-08 | 1965-06-08 |
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BR (1) | BR6680268D0 (en) |
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Also Published As
Publication number | Publication date |
---|---|
BR6680268D0 (en) | 1973-12-26 |
ES327705A1 (en) | 1967-08-01 |
NL6607935A (en) | 1966-12-09 |
BE682244A (en) | 1966-12-08 |
FR5503M (en) | 1967-10-30 |
GB1080617A (en) | 1967-08-23 |
CY550A (en) | 1970-08-04 |
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