IE48096B1 - A penicillin salt,process for its preparation and pharmaceutical compositions containing it - Google Patents
A penicillin salt,process for its preparation and pharmaceutical compositions containing itInfo
- Publication number
- IE48096B1 IE48096B1 IE66379A IE66379A IE48096B1 IE 48096 B1 IE48096 B1 IE 48096B1 IE 66379 A IE66379 A IE 66379A IE 66379 A IE66379 A IE 66379A IE 48096 B1 IE48096 B1 IE 48096B1
- Authority
- IE
- Ireland
- Prior art keywords
- talampicillin
- sulphonate
- group
- napsylate
- ampicillin
- Prior art date
Links
Landscapes
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
This invention relates to a penicillin salt. More specifically this invention relates to the naphthalene 2-sulphonate salt of ampicillin phthalidyl ester, its preparation, and,its use in the therapy of disease.
Parent/ NoV °Π 36461 described, and claimed the phthalidyl ester of 6-[D(-)-o-aminophenylacetamido] penicillanic acid, of formula (I) : and pharmaceutically acceptable acid addifcon salts thereof This penicillin, hereinafter referred to as talampicillin, and its acid addition salts produce high serum concentrations of the parent penicillin, ampicillin, when administered orally.
Due to its ready solubility and ease of preparation, talampicillin is normally used in the form of its hydrochloride salt. However, in this form the ester has an unpleasant taste which makes formulations thereof such as syrups and uncoated tablets unpalatable.
It is an object of this invention to provide a form of talampicillin which has a greatly improved taste relative to talampicillin hydrochloride whilst retaining therapeutically effective bioavailability.
The object has been achieved by the provision of ampicillin phthalidyl ester naphthalene 2-sulphonate.
Specification It should be noted that Patent/ No. 36461. discloses that talampicillin can form salts with inorganic and organic acids (especially those which have been employed to form salts with ampicillin). However in this U.K. Patent the only salt specifically exemplified is the hydrochloride salt, and there is no suggestion that the specific salt of this invention should be prepared or that very advantageous properties could be obtained therewith.
Accordingly, the present invention provides ampicillin phthalidyl ester naphthalene 2-sulphonate.
Ampicillin phthalidyl ester naphthalene 2-sulphonate, hereinafter referred to as talampicillin napsylate, has the structure (A) : The invention also provides a process for the preparation of talampicillin napsylate, which process comprises reacting together a source of ampicillin, a source of napsylate ions and a souce of the 3-phthalidyl group.
It will be appreciated that talampicillin will conveniently act as both a source of ampicillin and a source of the phthalidyl group.
Thus one preferred process of the reaction comprises 10 contacting talampicillin, or a salt thereof, with naphthalene 2-sulphonic acid, or a salt thereof.
Normally this reaction is carried out in an aqueous solvent, such as water or an aqueous organic solvent mixture such as aqueous methylene dichloride. In such cases the talampicillin is used in the form of a water soluble salt, such as the hydrochloride salt. Similarly, in such cases the naphthalene 2-sulphonic acid is used in the form of a water soluble salt, such as the sodium salt.
The product of the reaction can be isolated in any suitable manner. Suitable methods include precipitation from an essentially water solvent, followed by filtration; dissolution of a precipitated product in an organic solvent, such as methylene dichloride, and then spray drying this solution; and carrying out the process in an aqueous organic solvent mixture, isolating the organic phase after the reaction is complete, and then spray drying this organic phase.
In one such preferred reaction system, a solution in water of sodium naphthalene-2-sulphonate is added to a solution in water of talampicillin hydrochloride. In such cases we have found that the concentration of the talampicillin hydrochloride solution can be increased (at a given reaction temperature) if a gel inhibitor is included in the solution.
Suitable gel inhibitors for this use include secondary butanol (for example at 3% v/v); urea (for example at 6% w/v); acetic acid (for example at 1% v/v); polyvinylpyrrolidone, suitably of molecular weight 20003500 or 10,000 (for example at 10% w/v); polyethylene glycol, suitably of molecular weight 600 (for example at 10% v/v); and ethylene glycol (for example at 10% v/v).
By way of example we have found that suitably concentrations of talampicillin hydrochloride solutions for use in the reaction can be increased from about 4 to 5% at 20 to 25°C to about 7.5 to 10% at the same temperature using a gel inhibitor as described.
In a further useful process modification the talampicillin hydrochloride for reaction with the naphthalene2-sulphonie acid salt can be produced by means of phase transfer catalysis, in the manner described in West German Offenlegungsschrift No.2656062.3 or U.S. Patent No. 4072677. In this way isolation of the talampicillin hydrochloride can be avoided.
It will also be appreciated that talampicillin having its amino group protected with an acid-sensitive protecting group can act as the source of ampicillin and phthalidyl group in the process of the invention. In such cases of course acid hydrolysis of the N-protecting group, for example an enamine group, will generate the corresponding talampicillin acid addition salt, and then this salt can be reacted in the usual way with a source of napsylate ions. Alternatively however the N-protected talampicillin can be reacted with naphthalene 2-sulphonic acid to effect both the acid hydrolysis of the N-protecting group and the subsequent formation of the napsylate salt of talampicillin.
In a further modification, ampicillin napsylate can act as the source of ampicillin and also as the source of napsylate ion. In this modification the ampicillin napsylate may be reacted with a suitable source of the phthalidyl group, such as phthalidyl bromide, suitably under neutral conditions, to yield the desired product.
In an alternative reaction sequence, phthalidyl 6-APA of formula (B) : S ch3 wherein the amino group is optionally substituted with a group which permits acylation to take place, is reacted with a N-acylating derivative of phenylglycine napsylate of (C) Suitably this reaction is carried out under neutral conditions.
Suitable groups which permit acylation to take place and which are optionally present on the amino group of the starting material of the formula (B) include N-silyl, N-stannyl and N-phosphorus groups, for example trialkylsilyl groups such as trimethylsilyl, trialkyltin groups such as tri-n-butyltin, groups of formula -P.RaRb wherein Ra io an alkyl, haloalkyl, aryl, aralkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy or dialkylamino group, R^ is the same as Ra or is halogen or Ra and R^3 together form a ring; suitable such phosphorus groups being -PiO^Hg^, -P(C2H5)2, -P A reactive N-acylating derivative of the acid is employed in the above process.
Suitable N-acylating derivatives include an acid halide, preferably the acid chloride or bromide.
The acid halide may be prepared by reacting the acid (C) or a salt thereof with a halogenating (e.g. chlorinating or brominating) agent such as phosphorus pentachloride, thionyl chloride or oxalyl chloride.
Alternatively, the N-acylating derivative of the acid (C) may be symmetrical or mixed anhydride. Suitable mixed anhydrides are alkoxyformic anhydrides, or anhydrides with, for example carbonic acid monoesters.
Other reactive N-acylating derivatives of the acid (C) include the reactive intermediate formed by reaction in situ with a condensing agent such as a carbodiimide.
A further alternative reaction sequence comprises ; (a) reacting a conpound of formula (D) Ιό wherein the group R is an organic acyl group (preferably of a naturally-occuixin-q.penicillin)^ with an agent forming an imino halide on the 6-amino atom; (b) reacting the resulting compound to introduce a group QRg on the imino carbon atom, wherein Q is oxygen, sulphur or nitrogen and R^ is an alkyl group of from 1 to 12 carbon atoms, or an aralkyl group of up to 14 carbon atoms, to form an iminoether, iminothioether or amidine (when Q is 0, S or N respectively); (c) reacting with a reactive derivative of an acid of formula (C) above and (d) treating with water or an alcohol.
The invention also provides a pharmaceutical composition, which composition comprises talampicillin napsylate and a pharmaceutically acceptable carrier.
The invention further provides a process for the preparation of this composition, which process comprises bringing the ingredients thereof into association.
The pharmaceutical compositions of this invention may be presented in single dose, multi-dose, or fractional dose form as convenient and appropriate. Single dose compositions will suitably contain a weight of talampicillin napsylate equivalent to an effective dose of talampicillin hydrochloride, such as 10 to 500 mg. of talampicillin hydrochloride, for example 125 or 250 mg. Multi-dose and fractional dose compositions will suitably contain proportionate amounts of talampicillin napsylate.
A particularly preferred composition of the invention is a powder for reconstitution into a syrup (suspension), as it is in this presentation form that talampicillin napsylate's advantageous properties of improved taste and effective bioavailability are best employed.
Thus the invention provides a pharmaceutical composition in the form of a powder which may be reconstituted with water to form a syrup, which powder comprises talampicillin napsylate and a syrup additive.
The powder may be prepared by simple mixing of the ingredients, for example using a planetary mixer, Y-cone blender or similar apparatus conventionally used in the preparation of penicillin syrup powders.
In this powder the talampicillin napsylate is suitably of low particle size, as of course is conventional for syrup powders.
Syrup additives are present to improve the stability, appearance and palatability of the resultant made up syrup. Examples of such additives include flavours, sugar, dyes, anti-foaming agents, thickeners.
S buffering agents and the like.
One particularly preferred additive for inclusion in the powder is sugar. Often sugar will represent 30 to 95% of the powder, more suitably 60 to 90% of the powder.
The powder may be presented for use for example in single dose sachets or in multi-dose bottles.
A single dose of the powder will suitably contain the weight of talampicillin napsylate equivalent to an j_q effective dose of talampicillin hydrochloride, such as for example 125 mg. or 250 mg. of talampicillin hydrochloride. However it will be appreciated that smaller quantities of active ingredient may be used for therapy of infants. Thus while a single dose of the powder will often contain a weight of talampicillin napsylate equivalent to 125 or 250 mg. of talampicillin hydrochloride, it may also contain lesser weights such as for example weights equivalent to 31.25 or 62.5 mg. of talampicillin hydrochloride for therapy of infants 2Q or young children.
Talampicillin napsylate may also be formulated into tablets (when used herein tablet* includes dispersible tablet). Thus in a further aspect, the invention provides a tablet, which tablet comprises talampicillin napsylate.
Such tablets will also of course comprise one or more tablet additives. Suitable examples of such additives include diluents, disintegrants, lubricants, binders and the like, and in addition for dispersible tablets, flavours, sweeteners and buffering agents and the like. Normally such tablets will comprise 15 to 80% talampicillin napsylate and 20 to 85% additives,more suitably 20 to 60% and 40 to 80% respectively.
The tablets of the invention may be prepared in conventional manner, for example by direct compression.
Usually the tablets of the invention will weigh 100 to 2500 mg., suitably 100 to 2000 mg., more suitably 300 to 1700 mg. Normally dispersible tablets will have a weight toward the higher end of these weight ranges.
Talampicillin napsylate may also be formulated into capsules. Such capsules will suitably of course also contain conventional additives such as diluents, disintegrants, lubricants and the like. In such capsules the talan$>icillin napsylate will suitably represent 40 to 99% of the capsule contents.
The capsules may be prepared in normal manner, for example by filling the mixed ingredients into empty capsule shells.
Suitably the tablets and capsules of the invention will contain the weight of talampicillin napsylate equivalent to an effective dose of talampicillin hydrochloride. Thus they will often contain a weight of talampicillin napsylate equivalent to 125 or 250 mg. of talampicillin hydrochloride. It will be appreciated however that the tablets and capsules could quite easily contain fractional doses of active ingredient, but then of course two or more such tablets or capsules would have to be taken at one time to yield the desired effective dose.
Talampicillin napsylate, and syrups, tablets and capsules prepared therefrom as hereinbefore described, have useful stability.
The invention also provides a method of treatment of infection, which method comprises administering to the other than a human being . . sufferer/an effective amount of talampicillin napsylate.
Normally of course the talampicillin napsylate will be administered in the form of a composition of the invention, and so in this case sufficient of the chosen composition must be administered to give the effective amount of talampicillin napsylate.
The 'effective amount' of talampicillin napsylate will be, as hereinbefore discussed, the weight thereof equivalent to an effective dose of talampicillin hydrochloride. This effective dose of talampicillin hydrochloride will, as hereinbefore discussed, normally be 125 or 250 mg., but as pointed out (especially with syrups) lesser amounts may be used with infants and young children.
The administration will normally be repeated, for 10 example following the dosage regime conventionally used for talampicillin hydrochloride.
The following Examples illustrate the invention.
EXAMPLES 1 to 7 These Examples illustrate the preparation of talampicillin napsylate.
EXAMPLE 1 Sodium naphthalene-2-sulphonate 12.5 g. (0.054 moles) was dissolved in water (300 ml) at 35-40°, filtered and cooled to 20°. This was added with stirring to a solution of talampicillin HCl (25 g. activity weight, 0.048 moles) in water (500 ml) at 22-25° over 15 minutes.
The solution was cooled to ca 5-10° and the product isolated by filtration, reslurried in water (250 ml) for 30 minutes and the product isolated and dried in a fluid bed dryer at 20-25° initially, then increasing the temperature gradually to 50°. Yield 30 g. of talampicillin napsylate.
EXAMPLE 2 Identical to Example 1 except that naphthalene sulphonic acid (12.5 g.) was used.
EXAMPLE 3 Identical to Example 1 except that the sodium-2naphthalene sulphonate solution was acidified with concentrated hydrochloric acid (5.0 ml.) before addition to the talampicillin solution.
In Examples 1 to 3 the order of addition can be reversed if desired.
EXAMPLE 4 Sodium naphthalene-2-sulphonate (150 gj was dissolved in water (4 litres) at 35-40°, filtered, cooled to 20° and acidified with concentrated hydrochloric acid (60 ml.).
This was added with stirring to a solution, of talampicillin HC] (300 g. actiyity weight) in water (6.5 litres) at 22-25° over 15 minutes then cooled to 5-10°.
Precipitated product was isolated, reslurried in water (3.5 litres)re-isolated, dissolved in methylene dichloride (3.0 litres), separated from water and desiccated over molecular sieve (200 g. type 4A). The filtered solution was spray dried to give 320 g. of talampicillin napsylate.
EXAMPLE 5 Sodium nap hthalene-2-sulphonate (150 g.) and water (6.0 litres) were stirred for ca 15 minutes at 20-25°. Hydrochloric acid (60 ml.) , methylene dichloride (3.5 litres) and talampicillin HCI (300 g. activity weight) were then added, and stirring was continued for 15 minutes.
The talampicillin napsylate produced was located entirely in the organic phase. After washing with water (4 x 5.0 litres) this was desiccated over molecular sieve prior to spray drying to give 350 g. of talampicillin napsylate.
EXAMPLE 6 A solution of sodium naphthalene-2-sulphonate was prepaired by adding sodium naphthalene-2-sulphonate (12.5 g.) to a stirred solution of PVP (12.5 g.) in water (125 ml) at 35-40°C. After dissolution the solution was filtered, acidified with concentrated hydrochloric acid (5.0 ml.) and cooled to 20-25°C.
Talampicillin hydrochloride (25 g.) was added to a stirred solution of PVP (25 g.) in water (250 ml.) at 20-25°c. When dissolved the solution was filtered into the precipitation vessel.
The temperature was adjusted to 25-27°c and the sodium naphthalene-2-sulphonate solution was added with stirring over ca 30 minutes. The slurry was cooled to 5-10°C and filtered. The product was reslurried in water (250 ml.) and dried in a fluid bed drier to give 30 g. of talampicillin napsylate.[PVP m.wt;10,000j.
EXAMPLE 7 1. Preparation of Sodium-[p-N-(1-methoxycarbonylpropen2-yl)a-aminophenyl-acetamido1-penicillinate A slurry of 6-aminopenicillanic acid (77 g.) in a mixture of water (85 ml.) and acetone (125 ml.) at 0-5°C was treated with 15% potassium hydroxide solution to give a clear solution at pH 9.0, then cooled to -22°C.
At the same time a mixed anhydride was prepared by adding sodium D-N-(l-methoxycarbonyl-propen-2-yl)a-aminophenyl acetate (100.5 g.) to a mixture of ethylchloroformate (37.4 ml.) and dimethylaminopropanol (1.22 ml.) in acetone (300 ml.) at -50°C. After ca 20 minutes this was added to the 6-aminopenicillanio acid solution, and stirring was continued for 20 minutes. 2. Esterification of Product from (1).
To the reaction product solution were added water (250 ml.), sodium bicarbonate (70 g.), tributylethylammonium ethosulphate (48 ml of 80% aqueous solution) and bromophthalide (100 g.) in methylene dichloride (400 ml.).
The temperature was raised to 28-29°C, stirring was continued for 1.5 hours and water (650 ml.) was added.
The lower methylene dichloride phase containing the required phthalidyl ester of (1) was isolated and washed with water (1350 ml,, 1500 ml.). 3. Hydrolysis of Product from (2) To the methylene dichloride solution was added water (1100 ml.) and concentrated hydrochloric acid (54 ml. of 31% w/w). The mixture was stirred for 15 minutes at 20°C.
Heptane (400 ml) was added and stirring was continued for 45 minutes.
The lower aqueous layer containing talampicillin was isolated, diluted with water (385 ml.) and warmed to 30°C. The solution was washed with heptane (2 x 770 ml.). 4. Precipitation of Talampicillin Napsylate A solution of sodium naphthalene sulphonate (77 g.) in water (1540 ml.) was prepared at 35-40°C, filtered, acidified with concentrated hydrochloric acid (30 ml.) and cooled to 20°C.
To this solution was added the talampicillin solution from (3) over ca 30 minutes, maintaining the temperature at 20-22°C. The slurry was cooled to -10°C, filtered and washed with cold water (2 litres).
The product was dried in a fluid bed drier to give 185 g. of talampicillin napsylate.
EXAMPLE 8 The N-(1-methoxy carbonyl propen-2-yl) derivative of talampic Ulin (20 g.) was dissolved in methylene dichloride (100 ml). Naphthalene-2-sulphonxc acid (10 g) dissolved in water (100 mis.) was added, and the mixture was stirred for one hour at 5 to 10°C. The organic phase was separated, and added dropwise to isopropyl ether (450 mis.), to precipitate the talampicillin napsylate (20 g.).
EXAMPLE 9 This Example illustrates the preparation of powder containing talampicillin napsylate, for reconstitution into syrups.
The following formulations were prepared by mixing 5 together the stated ingredients in the appropriate proportions in a Y-cone blender, and then filling the stated weight of powder into the unidose sachet and 20 ml., 60 ml., 75 ml., and 100 ml., bottles.
The talampicillin napsylate was used after sieving 10 with a 750 μιη (20 mesh) sieve.
Ingredients (Jnidose Sachet mg. 20 ml. bottle g- 60 ml. bottle g· 75 ml. bottle g. 100 ml. bottle g. ............1 % w/w j Disodium Edetate 2.834 0.012 0.036 0.045 0.060 0.0800 Sodium Benzoate 4.723 0.020 0.060 0.075 0.100 0.1333 Sodium methyl hydr oxybenznte 2.834 0.012 0.036 0.045 0.060 0.0800 Xanthan gum 7.795 0.033 0.099 0.124 0.165 0.2200 Anti-foam agent 3.780 0.016 0.048 0.060 0.080 0.1067 Erythrosine 0.567 0.002 0.007 0.009 0.012 0.0160 Flavours 136.858 0.579 1.738 2.174 2.897 3.8627 Talampicillin napsylate (pure basis) 176.445 0.747 2.241 2.801 3.735 4.9800 Sucrose to 3543 .072 15.000 45.000 56.250 75.000 100.0000 These formulations provided a nominal 167 mg. talampicillin napsylate per dose, equivalent to 125 mg. talampicillin hydrochloride per dose, and also provided the usual overage (i.e excess) of approximately 10%.
Corresponding formulations providing an equivalent of 250 mg. talampicillin hydrochloride per dose can be made in analogous manner.
EXAMPLE 10 This Example illustrates the preparation of talampicillin napsylate syrups.
Syrups were prepared from the formulations of Example 9 by adding thereto 15 ml (unidose sachet), 11 ml. (20 ml. bottle), 32 ml. (60 ml. bottle), 40 ml. (75 ml. bottle) and 55 ml. (100 ml. bottle)of purified water, to give approximately 17 mL, 20ml., 60 ml., 80 ml., and 100 ml., of syrup respectively.
EXAMPLE 11 Bioavailability In a blood level study in volunteers, similar 10 biological availability of ampicillin was demonstrated after oral administration of equivalent dosages of talampicillin hydrochloride in tablet form and talampicilin napsylate in syrup form.
EXAMPLE 12 Stability (a) Our stability tests have demonstrated that powders prepared as in Example 9 have a shelf life of at least 18 months at 20°C. (b) Similarly, stability tests on reconstituted syrups of four different strengths (talampicillin napsylate equivalent to 250 mg., 125 mg., 62.5 mg., and 31.25 mg., of talampicillin hydrochloride in 5 ml. of water) have shown these syrups to have a shelf life of at least 7 days in a cool place.
Claims (5)
1. Ampicillin phthalidyl ester naphthalene 2-sulphonate
2. A process for preparing ampicillin phthalidyl ester naphthalene 2-sulphonate, which process 5 comprises either: (i) reacting together a source of ampicillin, a source of napsylate ions, and a source of the
3. -phthalidyl group; or (ii) reacting phthalidyl 6-APA of formula (B): lo wherein the amino group is optionally substituted with a group which permits acylation to take place, with a N-acylating derivative of phenylgycine napsylate of formula (C) : oCH - CO„H l 2 R so7 (C) : or (iii) (a) reacting a compound of formula (D): wherein the group R is an organic acyl group (preferably of a naturally-occurring penicillin) with an agent forming an imino halide on the 6-amino atom; 5 b) reacting the resulting compound to introduce a group QR^ on the imino carbon atom, wherein Q is oxygen, sulphur or nitrogen and R^ is an alkyl group of from 1 to 12 carbon atoms, or an aralkyl group of up to 14 carbon atoms, to form an 10 iminoether, iminothioether or amidine (when Q is 0, S, or N respectively); c) reacting with a reactive derivative of an acid of formula (C) above and d) treating with water or an alcohol. 15 3. A process according to claim 2 wherein process variant (i) is carried out by contacting talampicillin, or a salt thereof, with naphthalene-2-sulphonic acid, or a salt thereof.
4. A process according to claim 3, which comprises 20 adding an aqueous solution of sodium naphthalene2-sulphonate to an aqueous solution of talampicillin hydrochloride. 5. A pharmaceutical composition, which composition comprises ampicillin phthalidyl ester naphthalene2-sulphonate and a pharmaceutically acceptable carrier, 6. A composition according to claim 5, in the 5 form of a powder which may be reconstituted with water to form a syrup, which powder comprises ampicillin phthalidyl ester naphthalene-2-sulphonate, and a syrup additive. 7. A composition according to claim 6, wherein 10 the powder contains sugar. 8. A unit dose composition according to any one of claims 5 to 7, containing a weight of ampicillin phthalidyl ester naphthalene-2-sulphonate equivalent to 250 mg of talampicillin hydrochloride. 15 9- A unit dose composition according to any one of claims
5. To 7, containing a weight of ampicillin phthalidyl ester naphthalene-2-sulphonate equivalent to 125 mg of talampicillin hydrochloride.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB1282378 | 1978-04-01 | ||
EP79300495A EP0004740B1 (en) | 1978-04-01 | 1979-03-27 | A penicillin salt, process for its preparation and pharmaceutical compositions containing it |
Publications (2)
Publication Number | Publication Date |
---|---|
IE790663L IE790663L (en) | 1979-10-01 |
IE48096B1 true IE48096B1 (en) | 1984-09-19 |
Family
ID=26077996
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE66379A IE48096B1 (en) | 1978-04-01 | 1979-08-08 | A penicillin salt,process for its preparation and pharmaceutical compositions containing it |
Country Status (1)
Country | Link |
---|---|
IE (1) | IE48096B1 (en) |
-
1979
- 1979-08-08 IE IE66379A patent/IE48096B1/en not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
IE790663L (en) | 1979-10-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP2568401B2 (en) | Water-soluble meglumine salt and glucamine salt, production method thereof and pharmaceutical composition containing the same | |
KR0180798B1 (en) | Crystalline penicillin derivative, and its production and use | |
US4485033A (en) | Adjuvant for promoting absorption of pharmacologically active substances through the rectum | |
US3939270A (en) | Pharmaceutical preparations containing α-aminopenicillins | |
SK403191A3 (en) | 1-acetoxyethylester of cefuroxim, method of its production and pharmaceutical agents containing it | |
CA2227994C (en) | Carbapenem antibiotic, composition and method of preparation | |
EP0004740B1 (en) | A penicillin salt, process for its preparation and pharmaceutical compositions containing it | |
US3655658A (en) | 7(alpha-amino-alpha-phenylacetamido)-cephalosporanate esters | |
IE48096B1 (en) | A penicillin salt,process for its preparation and pharmaceutical compositions containing it | |
US4215120A (en) | Penicillin esters and their preparation | |
US4285960A (en) | Penicillin compositions | |
US4377583A (en) | N-Methyl-D-glucamine salt of with 3,4-dihydro-5-methyl-6-(2-methylpropyl)-4-oxothieno[2,3-d]pyrimidine-2-carboxylic acid | |
US4150157A (en) | Penicillin compositions | |
AU760934B2 (en) | Process for preparing crystalline salts of amoxycillin | |
JPH06503805A (en) | Penem compounds | |
US20020137926A1 (en) | Process for preparing crystalline salts of amoxycillin | |
KR0177844B1 (en) | Antibacterial penem compounds | |
AU4867799A (en) | Injectable sodium acetylsalicylate composition and method | |
US3917590A (en) | Cephalosporanic acid esters | |
JPS58192889A (en) | Penicillins, manufacture and composition | |
MXPA00011833A (en) | Process for preparing crystalline salts of amoxycillin | |
JPH11512730A (en) | Penicilling recollate | |
JPH04247031A (en) | Antimicrobial composition | |
JPH04247030A (en) | Antimicrobial composition | |
IT8922055A1 (en) | ESTERS OF CEFAMANDOL NAFATO, PROCEDURE FOR THEIR PREPARATION AND RELATED PHARMACEUTICAL COMPOSITIONS. |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MM4A | Patent lapsed |