US3703511A - Alpha-aminobenzyl penicillins - Google Patents

Alpha-aminobenzyl penicillins Download PDF

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US3703511A
US3703511A US831225A US3703511DA US3703511A US 3703511 A US3703511 A US 3703511A US 831225 A US831225 A US 831225A US 3703511D A US3703511D A US 3703511DA US 3703511 A US3703511 A US 3703511A
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microns
sterile
ampicillin
particle size
ampicillin trihydrate
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US831225A
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Charles Riffkin
Carl B Rifino
Gilman N Cyr
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ER Squibb and Sons LLC
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ER Squibb and Sons LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring

Definitions

  • ampicillin a-Aminobenzyl penicillin, hereafter called ampicillin, which has antibacterial activity against both gram-positive and gram-negative bacteria upon both parenteral or oral administration and which also exhibits resistance to destruction by acid
  • U.S-. Patent 2,985,648 While ampicillin possesses a broad spectrum of activity, the only sterile injectable form available has been the soluble sodium salt. The solution of this salt, however, has an extremely short shelf-life, about one hour, and the solution is irritating on injection. The irritation appears to be due to its high pH (8.5-9.0) and even buffered solutions are irritating.
  • an object of the present invention to provide ampicillin which does not have the disadvantage of extremely short shelf-life. Another object is to provide ampicillin in a form which is substantially nonirritating. A further object is to provide ampicillin in such a form that elfective blood levels are produced in the patient for prolonged periods of time. Still another object is to provide a sterile powder of ampicillin trihydrate from which stable, non-irritating and long-acting suspensions may be prepared. Yet another object is to prepare concentrated suspensions of ampicillin.
  • ampicillin trihydrate having a particle size range from about 5 microns to about 50 microns may be used to form suspensions which are stable, non-irritating, longer acting, and may be administered in more highly concentrated form.
  • the ampicillin trihydrate crystals are next reduced to a useful particle size in the range of from about 5 microns 3,73,511 Patented Nov. 21, 1972 to about 50 microns by, for example, aseptic micropulverization.
  • Micropulverization or mechanical grinding produces a product which has larger particle size range than that made by either attrition mills or fluid energy mills.
  • This particle size material yields a more manageable suspension which can be formulated to higher potencies. This is desirable from the standpoint of medical practice since it reduces the size of the injection and still provides an adequate dosage regimen.
  • the sterile ampicillin trihydrate of the present invention may be stored as the powder, or as a dry mixture containing other sterile excipients such as, for example, suspending agents and dispersing agents.
  • a suitable dispersing agent is lecithin, and a suitable suspending agent is sodium carboxymethylcellulose.
  • the ampicillin trihydrate having a particle size in the range of from about 5 microns to about 50 microns is combined with water for injection to form a suspension having from about 250 to about 550 mg. of ampicillin activity (as determined by biological assay) per ml.
  • the suspensions of the present invention may be butfered to maintain the pH in the range of from about 4.0 encountered in preparing suspensions from micronized material. Even at low potency levels of about 200 mg./ ml., the suspension is very viscous, foamy and difficult to handle.
  • the ampicillin starting material for the present invention may be prepared as described in US. Patent 2,985,- 648. At temperatures below about 40 C. the ampicillin is present as ampicillin trihydrate.
  • the ampicillin trihydrate is dissolved in water by reducing the pH to about 1.2, for example, by addition of concentrated HCl. After the ampicillin trihydrate is solubilized, it is sterilized, for example by passing through a millipore filter. The filtrate is collected in "a sterile vessel. The pH is then raised to from about 4.0 to about 5.0 by the addition of sterile 20% NaOH. in this pH range, substantially all of .the ampicillin trihydrate is crystallized. The sterile crystals are separated, washed and dried aseptically.
  • the ampicillin trihydrate crystals so produced have a particle size range of from about 5 microns to about microns. Only a very small percentage of the crystals have a particle size below about 10 microns. The majority of to about 7.0, preferably from about 4.5 to about 5.0.
  • An example of a suitable buffer is an acetate buffer.
  • sterile ampicillin trihydrate suspensions of the present invention are less irritating on injection in contrast to the only other injectable form, sodium ampicillin.
  • a further advantage of sterile aqueous suspensions of the present invention is their prolonged shelf-like. Pre-formed aqueous suspensions of sterile ampicillin trihydrate, prepared according to the present invention, are stable for at least one year when stored under refrigeration.
  • suspensions of the present invention are long acting and produce effective blood levels of ampicillin for prolonged periods of time. This prolonged efiectiveness reduces the number of injections required in therapeutic treatment.
  • the sterile suspensions of the present invention are intended to be applied parentcrally, for example, by subcutaneous or intramuscular injection.
  • Example 1 Ampicillin trihydrate (1.2 kg.) is dissolved in Water 12 liters) by reducing the pH to about 1.2 by addition of concentrated HCl, passed through a millipore filter, type GS, and the filtrate collected in a 20 liter sterile bottle. Ampicillin trihydrate is precipitated by raising the pH to about 4.3 by addition of sterile 20% NaOH. The sterile crystalline precipitate is separated, washed with sterile water for injection (2-3 liters), then with sterile acetone (12 liters) and vacuum dried. The yield is approximately 83% of ampicillin trihydrate needle-like crystals having a particle size range of from about to about 100 microns, the majority of the crystals having a particle size above 50 microns.
  • Example 2 One thousand parts by weight of sterile needle crystals of ampicillin trihydrate are ground in a micropulverizer, type CF (American Marietta Co.) fitted with an 027 round screen. Alternatively a tornado mill or hammer mill may be used, equipped with appropriate size mesh screen. The resulting sterile micropulverized ampicillin trihydrate is aseptically blended with 89 parts of sterile lecithin which has been micropulverized in the same manner, and 1.35 parts of sterile sodium carboxymethylcellulose. 'Ihe sterile powder blend is then aseptically filled into sterile vials for use as an intramuscular injection, after reconstitution with sterile Water or saline.
  • a micropulverizer type CF (American Marietta Co.) fitted with an 027 round screen.
  • a tornado mill or hammer mill may be used, equipped with appropriate size mesh screen.
  • the resulting sterile micropulverized ampicillin trihydrate is aseptically blended with 89 parts of sterile lecithin which has
  • Example 3 When approximately 1.1 gm. of the sterile powder blend of Example 2 is filled into sterile glass vials and reconstituted by adding 1.6 cc. of water for injection, a sterile suspension is obtained which upon intramuscular injection provides high and sustained blood levels of ampicillin. This was demonstrated as follows:
  • Example 2 Four hundred parts by weight of sterile ampicillin trihydrate which has been micropulverized in the manner described in Example 2 are combined with parts by weight of sterile lecithin and one part of sodium carboxymethylcellulose. 1.3 parts by weight of methyl paraben and 0.2 part by weight of propyl paraben are added as presenvatives. 0.1 part by weight of acetate buffer having a pH of 5.0 and sufficient water to make 1000 parts by Weight are then added. The suspension is aseptically homogenized and filled into sterile vials for use as a multiple dose injection. Full potency is retained for at least one year when stored in the refrigerator.
  • Sterile ampicillin trihydrate having a particle size in the range of from about 5 microns to about 100 microns, the majority of the ampicillin trihydrate having a particle size above about 20 microns.

Abstract

AMPICILLIN TRIHYDRATE HAVING A PARTICLE SIZE RANGE FROM ABOUT 5 MICRONS TO ABOUT 50 MICRONS MAY BE USED TO FORM SUSPENSIONS WHICH ARE STABLE, NON-IRRITATING, LONGERACTING, AND MAY BE ADMINISTERED IN MORE HIGHLY CONCENTRATED FORM.

Description

United States Patent 3,703,511 u-AMINOBENZYL PENICILLINS Charles Rifikin, Highland Park, Carl B. Rifino, East Brunswick, and Gilman N. Cyr, Piscataway, N.J., assignors to E. R. Squibb & Sons, Inc., Princeton, NJ. No Drawing. Filed June 6, 1969, Ser. No. 831,225 Int. Cl. C07d 91/16 US. Cl. ZED-439.1 3 Claims ABSTRACT OF THE DISCLOSURE Ampicillin trihydrate having a particle size range from about 5 microns to about 50 microns may be used to form suspensions which are stable, non-irritating, longeracting, and may be administered in more highly concentrated form.
BACKGROUND OF THE [INVENTION a-Aminobenzyl penicillin, hereafter called ampicillin, which has antibacterial activity against both gram-positive and gram-negative bacteria upon both parenteral or oral administration and which also exhibits resistance to destruction by acid, is disclosed in U.S-. Patent 2,985,648. While ampicillin possesses a broad spectrum of activity, the only sterile injectable form available has been the soluble sodium salt. The solution of this salt, however, has an extremely short shelf-life, about one hour, and the solution is irritating on injection. The irritation appears to be due to its high pH (8.5-9.0) and even buffered solutions are irritating.
It is, accordingly, an object of the present invention to provide ampicillin which does not have the disadvantage of extremely short shelf-life. Another object is to provide ampicillin in a form which is substantially nonirritating. A further object is to provide ampicillin in such a form that elfective blood levels are produced in the patient for prolonged periods of time. Still another object is to provide a sterile powder of ampicillin trihydrate from which stable, non-irritating and long-acting suspensions may be prepared. Yet another object is to prepare concentrated suspensions of ampicillin. These and other objects of the present invention will be apparent from the following descrpition.
SUMMARY OF THE INVENTION It has now been found that ampicillin trihydrate having a particle size range from about 5 microns to about 50 microns may be used to form suspensions which are stable, non-irritating, longer acting, and may be administered in more highly concentrated form.
DETAILED DESCRIPTION Sterile crystals of ampicillin trihydrate usually occur in the form of long needles. In this form the ampicillin is dilatant and unuseable for preparing suspensions which are to be injected. Traditionally, insoluble solids have been micronized, for example, by air attrition mills or fluid energy mills, to reduce the particle size to from 5 to microns. Typical examples are procaine penicillin G, various steroids, etc. Due to the amphoteric nature of ampicillin, however, extreme difiiculties are the crystals, about 85%, have a particle size above about microns, and within the range of from about 20 microns to about 100 microns. The yield is approximately 80% or higher.
The ampicillin trihydrate crystals are next reduced to a useful particle size in the range of from about 5 microns 3,73,511 Patented Nov. 21, 1972 to about 50 microns by, for example, aseptic micropulverization. Micropulverization or mechanical grinding produces a product which has larger particle size range than that made by either attrition mills or fluid energy mills. At least 50% of the material, and preferably at least should have a particle size in the raneg of from about 20 microns to about 50 microns. This particle size material yields a more manageable suspension which can be formulated to higher potencies. This is desirable from the standpoint of medical practice since it reduces the size of the injection and still provides an adequate dosage regimen.
The sterile ampicillin trihydrate of the present invention may be stored as the powder, or as a dry mixture containing other sterile excipients such as, for example, suspending agents and dispersing agents. A suitable dispersing agent is lecithin, and a suitable suspending agent is sodium carboxymethylcellulose.
The ampicillin trihydrate having a particle size in the range of from about 5 microns to about 50 microns is combined With water for injection to form a suspension having from about 250 to about 550 mg. of ampicillin activity (as determined by biological assay) per ml.
The suspensions of the present invention may be butfered to maintain the pH in the range of from about 4.0 encountered in preparing suspensions from micronized material. Even at low potency levels of about 200 mg./ ml., the suspension is very viscous, foamy and difficult to handle.
It has been found, according to the present invention, that when crystals of ampicillin trihydrate are reduced to an optimum particle size in the range of from about 5 microns to about 50 microns, the crystals no longer behave in a dilatant manner when suspended in Water. Surprisingly, the suspensions are stable for up to a year when stored under refrigeration, and, when administered to patients, provide effective ampicillin levels for more than twice as long as solutions of sodium ampicillin. It has also been found that highly concentrated suspensions may be prepared.
The ampicillin starting material for the present invention may be prepared as described in US. Patent 2,985,- 648. At temperatures below about 40 C. the ampicillin is present as ampicillin trihydrate. The ampicillin trihydrate is dissolved in water by reducing the pH to about 1.2, for example, by addition of concentrated HCl. After the ampicillin trihydrate is solubilized, it is sterilized, for example by passing through a millipore filter. The filtrate is collected in "a sterile vessel. The pH is then raised to from about 4.0 to about 5.0 by the addition of sterile 20% NaOH. in this pH range, substantially all of .the ampicillin trihydrate is crystallized. The sterile crystals are separated, washed and dried aseptically. The ampicillin trihydrate crystals so produced have a particle size range of from about 5 microns to about microns. Only a very small percentage of the crystals have a particle size below about 10 microns. The majority of to about 7.0, preferably from about 4.5 to about 5.0. An example of a suitable buffer is an acetate buffer.
The sterile ampicillin trihydrate suspensions of the present invention are less irritating on injection in contrast to the only other injectable form, sodium ampicillin. A further advantage of sterile aqueous suspensions of the present invention is their prolonged shelf-like. Pre-formed aqueous suspensions of sterile ampicillin trihydrate, prepared according to the present invention, are stable for at least one year when stored under refrigeration. In
addition, the suspensions of the present invention are long acting and produce effective blood levels of ampicillin for prolonged periods of time. This prolonged efiectiveness reduces the number of injections required in therapeutic treatment.
The sterile suspensions of the present invention are intended to be applied parentcrally, for example, by subcutaneous or intramuscular injection.
The following examples illustrate the present invention without, however, limiting the same thereto.
Example 1 Ampicillin trihydrate (1.2 kg.) is dissolved in Water 12 liters) by reducing the pH to about 1.2 by addition of concentrated HCl, passed through a millipore filter, type GS, and the filtrate collected in a 20 liter sterile bottle. Ampicillin trihydrate is precipitated by raising the pH to about 4.3 by addition of sterile 20% NaOH. The sterile crystalline precipitate is separated, washed with sterile water for injection (2-3 liters), then with sterile acetone (12 liters) and vacuum dried. The yield is approximately 83% of ampicillin trihydrate needle-like crystals having a particle size range of from about to about 100 microns, the majority of the crystals having a particle size above 50 microns.
Example 2 One thousand parts by weight of sterile needle crystals of ampicillin trihydrate are ground in a micropulverizer, type CF (American Marietta Co.) fitted with an 027 round screen. Alternatively a tornado mill or hammer mill may be used, equipped with appropriate size mesh screen. The resulting sterile micropulverized ampicillin trihydrate is aseptically blended with 89 parts of sterile lecithin which has been micropulverized in the same manner, and 1.35 parts of sterile sodium carboxymethylcellulose. 'Ihe sterile powder blend is then aseptically filled into sterile vials for use as an intramuscular injection, after reconstitution with sterile Water or saline.
Example 3 When approximately 1.1 gm. of the sterile powder blend of Example 2 is filled into sterile glass vials and reconstituted by adding 1.6 cc. of water for injection, a sterile suspension is obtained which upon intramuscular injection provides high and sustained blood levels of ampicillin. This was demonstrated as follows:
INTRAMUSCULAR INJECTION OF 400 MGJML. AMPICILLIN ACTIVITY IN DOGS BLOOD LEVEL IN MOGJML. l
Intramuscular Injection of 400 mgJml. Ampicillin Activity in Dogs Blood Levels in meg/ml. 1
Four hundred parts by weight of sterile ampicillin trihydrate which has been micropulverized in the manner described in Example 2 are combined with parts by weight of sterile lecithin and one part of sodium carboxymethylcellulose. 1.3 parts by weight of methyl paraben and 0.2 part by weight of propyl paraben are added as presenvatives. 0.1 part by weight of acetate buffer having a pH of 5.0 and sufficient water to make 1000 parts by Weight are then added. The suspension is aseptically homogenized and filled into sterile vials for use as a multiple dose injection. Full potency is retained for at least one year when stored in the refrigerator.
What is claimed is:
1. Sterile ampicillin trihydrate having a particle size in the range of from about 5 microns to about 100 microns, the majority of the ampicillin trihydrate having a particle size above about 20 microns.
2. Sterile, substantially non-dilatant ampicillin trihydrate having a particle size in the range of from about 5 microns to about 50 microns, at least 50% of the ampicillin trihydrate having a particle size in the range of from about 20 microns to about 50 microns.
3. Ampicillin trihydrate according to claim 2 wherein at least of the ampicillin trihydrate has a particle size in the range from about 20 microns to about 50 microns.
References Cited UNITED STATES PATENTS 3,157,640 11/1964 Johnson et al 260239.1
NICHOLAS S. RIZZO, Primary Examiner US. Cl. X.R.
22 3 UNITED STATES PATENT OFFICE CERTIFICATE OF CORECTKN Patent N0, 3:7O3,5ll D t d November 2]., 1972 I e to Charles Riffkin et a1.
It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:
Column 1, line 45, the word "descrpition" should read -description--. Column 2, line 26 to the word "of" in line 57 of column 2 should be inserted following the word "are" in column 1, line 62. Column 2, line 6, the word "raneg" should read range-. Column 4, line 2,' "level" should read -levels-. Column 4, line 18, "presenvatives" should read -preservatives-.
Signed and sealed this 10th day of Apri1 l973.
(SEAL) Attest:
V EDWARD M.FLETCHER,JR. ROBERT GOTTSCHALK ,Attesting Officer Commissioner of Patents
US831225A 1969-06-06 1969-06-06 Alpha-aminobenzyl penicillins Expired - Lifetime US3703511A (en)

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DE (1) DE2027044C3 (en)
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ES (1) ES380448A1 (en)
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ZA703565B (en) 1971-01-27
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JPS4913963B1 (en) 1974-04-04
ES380448A1 (en) 1972-09-01
DE2027044C3 (en) 1980-09-11
NL7008083A (en) 1970-12-08
FR2052937B1 (en) 1974-08-30
DK126835B (en) 1973-08-27
IE34226B1 (en) 1975-03-05
CA946285A (en) 1974-04-30
FR2052937A1 (en) 1971-04-16
DE2027044B2 (en) 1980-01-17
BR6915337D0 (en) 1973-03-13
CH525240A (en) 1972-07-15

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