US3703511A - Alpha-aminobenzyl penicillins - Google Patents
Alpha-aminobenzyl penicillins Download PDFInfo
- Publication number
- 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
- Authority
- US
- United States
- Prior art keywords
- microns
- sterile
- ampicillin
- particle size
- ampicillin trihydrate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- -1 Alpha-aminobenzyl penicillins Chemical class 0.000 title description 2
- 229930182555 Penicillin Natural products 0.000 title description 2
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 abstract description 44
- 229960003311 ampicillin trihydrate Drugs 0.000 abstract description 28
- 239000002245 particle Substances 0.000 abstract description 20
- 239000000725 suspension Substances 0.000 abstract description 18
- 231100000344 non-irritating Toxicity 0.000 abstract description 5
- 229960000723 ampicillin Drugs 0.000 description 16
- 239000013078 crystal Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000036765 blood level Effects 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000010255 intramuscular injection Methods 0.000 description 5
- 239000007927 intramuscular injection Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical group CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical group [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 235000010445 lecithin Nutrition 0.000 description 3
- 239000000787 lecithin Substances 0.000 description 3
- 229940067606 lecithin Drugs 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000036515 potency Effects 0.000 description 3
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 3
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 239000008351 acetate buffer Substances 0.000 description 2
- KLOHDWPABZXLGI-YWUHCJSESA-M ampicillin sodium Chemical compound [Na+].C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C([O-])=O)(C)C)=CC=CC=C1 KLOHDWPABZXLGI-YWUHCJSESA-M 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 238000005057 refrigeration Methods 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- WHRVRSCEWKLAHX-LQDWTQKMSA-N benzylpenicillin procaine Chemical compound [H+].CCN(CC)CCOC(=O)C1=CC=C(N)C=C1.N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)CC1=CC=CC=C1 WHRVRSCEWKLAHX-LQDWTQKMSA-N 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008221 sterile excipient Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
-
- 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.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US83122569A | 1969-06-06 | 1969-06-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3703511A true US3703511A (en) | 1972-11-21 |
Family
ID=25258589
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US831225A Expired - Lifetime US3703511A (en) | 1969-06-06 | 1969-06-06 | Alpha-aminobenzyl penicillins |
Country Status (14)
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1532993A (en) * | 1975-03-07 | 1978-11-22 | Beecham Group Ltd | Injectable antibiotic compositions |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL6705789A (enrdf_load_stackoverflow) * | 1967-03-08 | 1968-09-09 |
-
1969
- 1969-06-06 US US831225A patent/US3703511A/en not_active Expired - Lifetime
- 1969-12-19 BR BR215337/69A patent/BR6915337D0/pt unknown
-
1970
- 1970-05-26 CA CA083,754A patent/CA946285A/en not_active Expired
- 1970-05-26 IE IE681/70A patent/IE34226B1/xx unknown
- 1970-05-26 ZA ZA703565A patent/ZA703565B/xx unknown
- 1970-06-01 BE BE751261D patent/BE751261A/xx not_active IP Right Cessation
- 1970-06-02 DE DE2027044A patent/DE2027044C3/de not_active Expired
- 1970-06-02 FR FR7020146A patent/FR2052937B1/fr not_active Expired
- 1970-06-03 NL NL7008083A patent/NL7008083A/xx unknown
- 1970-06-04 DK DK291670AA patent/DK126835B/da not_active IP Right Cessation
- 1970-06-04 CH CH839970A patent/CH525240A/fr not_active IP Right Cessation
- 1970-06-05 ES ES380448A patent/ES380448A1/es not_active Expired
- 1970-06-05 JP JP45048627A patent/JPS4913963B1/ja active Pending
- 1970-06-05 GB GB2612470A patent/GB1316625A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| ES380448A1 (es) | 1972-09-01 |
| CA946285A (en) | 1974-04-30 |
| NL7008083A (enrdf_load_stackoverflow) | 1970-12-08 |
| DE2027044B2 (de) | 1980-01-17 |
| IE34226B1 (en) | 1975-03-05 |
| BR6915337D0 (pt) | 1973-03-13 |
| ZA703565B (en) | 1971-01-27 |
| FR2052937B1 (enrdf_load_stackoverflow) | 1974-08-30 |
| DK126835B (da) | 1973-08-27 |
| CH525240A (fr) | 1972-07-15 |
| DE2027044C3 (de) | 1980-09-11 |
| IE34226L (en) | 1970-12-06 |
| DE2027044A1 (de) | 1970-12-17 |
| JPS4913963B1 (enrdf_load_stackoverflow) | 1974-04-04 |
| GB1316625A (en) | 1973-05-09 |
| BE751261A (fr) | 1970-12-01 |
| FR2052937A1 (enrdf_load_stackoverflow) | 1971-04-16 |
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