BR9702231B1 - pharmaceutical composition, compound, and process for stabilizing a carbapenem - Google Patents

Abstract

"compound pharmaceutical composition and process for stabilizing a carbapenem". A pharmaceutical composition is described which contains a compound of formula (I) or a pharmaceutically acceptable salt, prodrug or hydrate thereof, in stabilized form and / or in combination with a carbon dioxide source.

Description

"PHARMACEUTICAL COMPOSITION, COMPOUND, AND, PROCESS TO STABILIZE A CARBAPENEM". : ·. :. ·. · ;:. ·. . ·. . ·. · ;:

BACKGROUND OF THE INVENTION ^Γ '' ·· ”'·» · -

The present invention relates to a carbapenem antibiotic composition, a stabilized form of antibiotic and processes for preparing it. The composition can be used to treat infectious diseases, including gram positive and negative, aerobic and anaerobic bacteria. The composition provides good stability against beta-lactamases, and a favorable duration of action.

SUMMARY OF THE INVENTION

A compound composition of formula I:

pharmaceutical is described that contains a

or a pharmaceutically acceptable salt, stabilized form, prodrug or hydrate thereof in combination with a carbon dioxide source.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term stabilized form refers to compounds that have a carbamate group formed on the nitrogen atom pyrrolidine as shown in compounds of formula II. This carbamate is obtainable by combining a compound of formula I or a salt, prodrug or hydrate thereof with a source of carbon dioxide, such as sodium carbonate or sodium bicarbonate. Examples are shown as formula II and ΙΙ-a through II-g.

The term prodrug refers to compounds with a removable group attached to the hydroxyl side chain hydroxyethyl (position 6 in the carbapenem nucleus), the carboxylic acid in position 3 of the carbapenem nucleus or the ncr.anel.-phenib meta-carboxylic acid group. chain: lateral. The ·· · ·· · ··· · ·· groups that are usable in the formation of urródrbgas should be apparent to the medical chemist from the teachings here. Examples include allyl, acetyl, benzyloxycarbonyl, methoxymethyl, t-butoxycarbonyl, trimethylsilyl and others.

The term hydrate is used in the conventional sense to include compounds of formula I and II in physical association with water.

The present invention relates to pharmaceutical compositions containing the antibiotic compound carbapenem:

C (O) NH2 ^ z ^ ^c ° ^2H

as well as salts, stabilized forms, prodrugs and hydrates thereof. The compound is a carbapenem antibiotic that is particularly useful for intravenous and intramuscular administration.

In one aspect of the invention, the pharmaceutical composition is formulated with a pharmaceutically acceptable buffer that will provide a pH of about 6.0 to about 9.0 upon dissolution. For example sodium bicarbonate is a preferred pharmaceutically acceptable buffer. Preferably, the pH of the composition upon dissolution is about 6.2 to about 8.5.

In another aspect of the invention, a stabilized form of compound, shown below as formula II is included. In general, any compound will provide carbon dioxide upon dissolution can be used with a compound of formula I to form a compound of formula II./

--------- ¹ ~ ¹ - - / /

OH

The compositions of the present invention are generally formulated using a carbon dioxide source. Preferred sources of carbon dioxide are carbon dioxide (liquid or solid gas), carbonates and bicarbonates, and more preferably sodium carbonate and sodium bicarbonate, which can be incorporated into the formulation, as an appropriate pH, for example about 6 , 2-8.5, is obtained upon dissolution. The native pH of the monosodium salt of compound I is approximately 5.4.

The compounds of formula I can be synthesized according to US patent 5,478,820 issued to Betts et al, on December 26, 1995, the teachings of which are incorporated herein by reference. The compound of formula I in lyophilized or non-lyophilized form · combined with the compound that produces carbon dioxide, such as sodium carbonate or sodium bicarbonate, is converted into a compound of formula II.

In general, compounds of formula II can be synthesized by combining the compound of formula I with the carbon dioxide source, and then dissolving the mixture in an appropriate solvent. The compound of formula I can be mixed with fónTéZêc ^> Tdo ”Hêcarbono, and the dissolved mixture, which generally produces the · compound of formula II.

. In many cases, it is preferred to dissolve the compound of formula

I with the compound producing carbon dioxide, in an aqueous solvent, and then lyophilizing the resulting composition, thus providing a mixture containing compounds of formula II.

Upon dissolution, compounds of formula II (II and ΙΙ-a to II25 g) convert to a compound of formula I (I, I-a, I-b and I-c) over time.

IO

The compound of formula I can be mixed in powder with a ·· · «« ·· · · · ··· · compound producing carbon dioxide <j, · 'of «cèQdki jqjffe · © .dó ^ · · · · · · ♦ ··· ··· · ··· Formula II, I am the salt, prodrug or hydrate of it is produced when dissolved or reconstituted.

Alternatively, the compound of formula I and the compound producing carbon dioxide can be combined in solution to form compound II,. after which the composition is lyophilized to provide a composition containing a compound of formula II, salt, prodrug or. hydrate of it.

The amount of sodium carbonate or sodium bicarbonate used in the composition can be varied over wide limits. For example, the amount of sodium carbonate in the formulation can be varied from as low as about 0.025 g of sodium carbonate / gram of drug to as high as about 0.25 g of sodium carbonate / gram of drug. Likewise, the amount of sodium bicarbonate in the formulation can be varied from as low as about 0.025 g / gram of drug, to as high as about 0.7 g / gram of drug. Other compounds can be included to adjust the pH of the composition upon dilution or reconstitution. Examples include potassium hydroxide, sodium hydroxide, N-methyl glucamine and others.

A formulation that is of particular interest is composed of about 3-6 parts by weight, and preferably about 4.5 parts by weight, of compound I or the pharmaceutically acceptable salt, stabilized form, prodrug or hydrate thereof, and 1 part by weight of sodium bicarbonate. Preferably, carbapenem is in the form of monosodium salt. The pH that results from dissolution ,. of this formulation ... is approximately 6.5. The drug formulation. this. way, it can prolong the stability of the product in solution.

Another formulation that is of particular interest is composed of about 4-10 parts by weight and preferably about 6.7 parts by weight of the compound of formula I or the pharmaceutically acceptable salt, stabilized form, prodrug or hydrate of the same ^: and jl £ aríè · jf jpêtto '<d? sodium carbonate. Preferably, carbapenem is in the form of monosodium salt. The pH resulting from the dissolution of this formulation is approximately 7.5. The drug formulation in this way can extend the stability of the product in solution.

As mentioned above, the compound of formula I. or II can be presented in lyophilized or non-lyophilized form. The lyophilized form is produced using standard freeze-drying techniques.

Additional components can be included in the compositions of the present invention as well. Because the composition is preferably administered by injection, various diluents, buffers, preservatives, local anesthetics, tonicity control agents, and other components can be included.

Representative examples of diluents include sterile water for injection, normal saline, dextrose solution, 5% (D5W), lactated Ringer's solution, and others. Preferably the diluent is normal saline or sterile water for injection.

Representative examples of buffers include phosphate buffer, such as sodium dihydrogen phosphate, citrate buffer, such as sodium citrate, meglumine and tri (hydroxymethyl) aminomethane.

Representative examples of preservatives include butyl hydroxyacetone (BHA), butyl hydroxytoluene (BHT) and benzalkonium chloride.

Representative examples of local anesthetics include benzocaine, lidocaine, novacaine, pontocaine and others.

Representative examples of tonicity modifying agents include sodium chloride, mannitol, dextrose, glucose, lactose and sucrose.

Representative examples of pharmaceutical excipients include water, mannitol, sorbitol, dextrose, lactose, glucose, dextran, sucrose, maltose, gelatin, sofq boYVO ^ BAVgiiíina, mannose, · * ······· <·· ·· · ··· ··· · ·· ribose, polyvinyl pyrrolidone (PVP), derivâdüs * ^: from '' deulútóSè, '''glutamma, inositol, potassium glutamate, erythritol, serine and other amino acids.

When the compound of formula I is formulated in a pharmaceutical composition with an appropriate amount of sodium carbonate or sodium bicarbonate, any or all of the species described herein can be contained in the formulation upon dilution or reconstitution. Compound I represents the unstabilized form of free acid. Thus, various forms of salt of formula I such as I-a to I-c are included herein.

The X + species represents a charge-balance cation, which is present in association with the compound as necessary to maintain global charge neutrality, typically, the charged species must be a pharmaceutically acceptable salt-forming ion, such as sodium, potassium, magnesium and others. A divalent species such as Ca ²⁺ can likewise be present, as when two anion-carboxylate. .are found in the ·· «··· ··· ·« · compound, as in formula Ia, or when a * níeiá'qtrârítf (nary * age is present in relation to the compound as in formula Ib or Ic. When the counterion includes a bis-cationic species, for example Ca ⁺² , an appropriate amount is typically present with respect to the carbapenem portion to provide overall charge neutrality, so the half molar equivalent of Ca + 2 can be included with a mono-carboxylate to maintain overall charge neutrality All of these embodiments are included in the present invention.

Numerous salt-forming ions are recited in Berge, S.M., et al, J. Pharm. Know. 66 1), 1977) whose teachings are hereby incorporated by reference.

A preferred group of salt-forming cations represented by 'X + is an ion selected from the group consisting of sodium, potassium, calcium and magnesium.

More preferably, X + represents an element selected from the group consisting of Na +, Ca * and K +.

Upon inclusion of an appropriate amount of carbon dioxide-producing compound, preferably sodium bicarbonate or sodium carbonate, one or more of the following stabilized structures is formed

The above compound II is referred to as the stabilized compound-free acid form. Compounds ΙΙ-a to ΙΙ-g are examples of stabilized compound salt forms.

O (X ⁺ ) ₂ ll-c

'Z3L

The amount of carbon dioxide-producing compound, for example sodium bicarbonate or sodium carbonate that is included in the composition is that which is sufficient to form compounds of formula II up to II-g, 1 and which optionally provides the desired pH of the composition. upon 'dissolution or reconstitution.

To provide · electronic balance and · global charge neutrality, zero to three positively charged counterions are present. Many different . counterions can be included in the composition. So, for example,. calcium and 'sodium' can be. included together in the pharmaceutical composition to provide overall charge neutrality. The counterions can thus be varied. within wide limits. · In general, the counterion or counterions are pharmaceutically acceptable cationic species.

The carbapenem compound of the present invention is usable for the treatment of bacterial infections in animal and human subjects. ·. The term 'pharmaceutically acceptable salt' refers to the forms of salt they can. . be · evident · to the chemist · pharmaceutical, that is · those who are substantially. · · Non-toxic and that provide · the desired pharmacokinetic properties, palatability, absorption, 'distribution, metabolism or excretion. · Other · factors, more practical. in nature, which are also important in selection, are raw material costs, ease of crystallization, yield, stability, hygroscopicity and flowability of the resulting raw drug. Conveniently, pharmaceutical compositions can be prepared from the active ingredients in combination with pharmaceutically acceptable carriers. Thus, the present invention is concerned with pharmaceutical compositions and processes for treating bacterial infection using the carbapenem compound. *: · *: · * ^:: » ^: ·:

-U *:: c: ·: «•«: ♦ *: :::: · *: · «>

Carbapenem can be used in various pharmaceutical preparations. Compositions for injection, the preferred route of release, can be prepared in unit dosage form or in multi-dose containers. The compositions can take forms as suspensions, solutions or emulsions, of an oily or aqueous nature, and can contain various formulation agents, such as diluents, buffers, preservatives and others. Thus, the compound is present in combination with these pharmaceutically acceptable vehicles.

Alternatively, the active ingredient can be in the form of a powder, which can be reconstituted with a liquid such as sterile water, normal saline and others at the time of administration. The powder can be in lyophilized and non-lyophilized form.

Representative oral compositions are typically in the form of tablets, capsules, solutions or suspensions. These compositions can likewise be packaged in multi-dose or unitary containers. In these oral compositions, pharmaceutically acceptable carriers can be composed of diluents, tablets, and granulation aids, lubricants, disintegrants, buffers, sweeteners, preservatives and the like.

Topical compositions can be formulated with pharmaceutically acceptable carriers in the form of hydrophobic or hydrophilic ointments, creams, lotions, solutions, paints or powders.

The dosage to be administered depends largely on the condition and size of the mammalian patient being treated as well as the route of release and frequency of administration. The parenteral route (by injection) is preferred.

Compositions for human release by unit dosage, whether liquid or solid, can contain from about 0.01% to about 99% of active material, the preferred range being about 10-60%. The composition will generally contain from about 10 mg to about 3000 mg of active ingredient, however, it is generally preferred to employ a dosage amount in the range of about 100 mg to about 1,000 mg. In parenteral administration, the unit dosage is usually the compound in saline or sterile water or in the form of a powder intended for dissolution or reconstitution.

The preferred method of administering the compound of formula I is parenteral by intravenous infusion. (i.v.). Alternatively, the compound can be administered by intramuscular injection (i.m.).

For adults, a dose of about 5 to about 50 mg of compound of anti-bacterial formula I per kg of body weight is administered 1 to 6 times a day. The preferred dosage is in the range of about 100 mg to about 1,000 mg of compound given one to four times a day, preferably 1-2 times a day, and more preferably once a day.

More specifically, for mild infections, a dose of about 100 mg to about 1,000 mg one to four times daily is preferred, more preferably once a day. For moderate infections, a dose of about 500 mg to about 1,000 mg one to four times daily is preferred. For severe, life-threatening infections, a dose of about 1000-2000 mg one to six times daily is preferred.

For children, a dose of 5-25 mg / kg of body weight given 1 to 4 times a day is preferred, a dose of 10 mg / kg one to four times daily is preferred.

The compound of formula I is a broad class known as carbapenem. Naturally occurring carbapenems are susceptible to attack by a renal enzyme known as dehydropeptidase (DHP). This attack or degradation can reduce the effectiveness of carbapenem antibacterial agent.

The compound used in the present invention is significantly less subject to this attack, and thus may not require the use of a DHP inhibitor. However, the use of a DHP inhibitor is optional and is contemplated as being included in the present invention. DHP inhibitors and their use with carbapenem antibacterial agents are described in European patent applications 79102616.4, filed on June 24, 1979, patent no. 0 007 614, and no. 82107174.3, filed on August 9, 1982 (publication no. 0 072 014).

The compound of the present invention can, where DHP inhibition is desired or necessary, be combined or used with the appropriate dHP inhibitor as described in the aforementioned patents and published application. The aforementioned European patent application defines the procedure for determining DHP susceptibility of the present carbapenems and describes appropriate inhibitors, combination compositions and treatment processes.

A preferred weight ratio of compound of formula I: DHP inhibitor in combination compositions is about 1: 1. A preferred DHP inhibitor is 7- (L-2-amino-2-carboxyethylthio) -2- (2,2-dimethylcyclopropane carboxmide), 2-heptenoic acid, or a salt thereof, also known as cilastatin.

Carbapenem is active against several gram-positive bacteria and to a lesser extent gram-negative bacteria, and consequently finds use in veterinary and human medicine.

The pharmacokinetic profile for the composition described here is surprisingly better than that of the related compounds.

Representative examples of pharmaceutical compositions containing the compounds described here are shown below.

Composition 1

Compound I 4.5 g Sodium bicarbonate 1.0 g

The powder mixture of the ingredients noted above. Compound I is in the form of monosodium salt. The pH resulting from an aqueous solution (225 ml) is approximately 6.5.

Composition 2

Compound I 6.7 g Sodium carbonate 1.0 g

The powder mixture of the ingredients noted above. Compound I is in the form of monosodium salt. The resulting pH of the solution (335 ml) is approximately 7.5.

EXAMPLE

Compound I 45.4 mg / ml (equivalent to 36 mg of anhydrous free acid) Sodium bicarbonate, USP 8.0 mg / ml Sodium chloride, USP 4.0 mg / ml

The powder mixture of the above ingredients as in the composition

1, and combine with water (q.s. 1.0 ml). The final pH of the solution is shown below.

The solution stability of this intravenous formulation was determined at 25 ° C with the following results:

ã0% Remaining in the solution at:

Cone. (mg / ml) pH initial pH Final Ih 2 am 4 am 6am: : 8: h: ► · · • • · · • · · · : · · ·, : · < *: 90? Ώ> · ·· ví) '- ^: 36 mg / ml 6.7 7.3 96.7 95.7 94.1 91.8 89.9 0.0104 38 7.3 '12 mg / ml 7.0 7.4 98.6 98.0 97.2 96.5 95.0 0.0049 94 21.0

Although some preferred embodiments of the invention have been described in detail here, numerous alternative embodiments are contemplated to be within the scope of the appended claims. Consequently, the invention is not limited to them.

Claims (9)

1. Compound, characterized by the fact that it is represented by formula II or a pharmaceutically acceptable salt or hydrate thereof. 2. Pharmaceutical composition, characterized by the fact that it is composed of a compound represented by the formula (1) or a pharmaceutically acceptable salt or hydrate thereof, in combination with a pharmaceutically acceptable carrier. A compound according to claim 1, characterized by the fact that the pharmaceutically acceptable salt is selected from the group consisting of: Π-a, (X ⁺ ) z Hd, ο .Π-g, where X ^4- represents a pharmaceutically acceptable cationic group. 4. Process for stabilizing a formula I carbapenem: 5 or a pharmaceutically acceptable salt or hydrate thereof, characterized in that it comprises adding a sufficient amount of a carbon dioxide source to the compound to form a compound of formula II Ο π 10 or a pharmaceutically acceptable salt or hydrate thereof. 5. Process according to claim 4, characterized by the fact that the carbon dioxide source is selected from carbon dioxide, sodium carbonate and sodium bicarbonate. 6. Process according to claim 5, characterized by the fact that the source of carbon dioxide is selected from sodium carbonate and sodium bicarbonate. Process according to claim 4, characterized in that the addition comprises mixing the carbapenem of formula I, or a pharmaceutically acceptable salt or hydrate thereof, with sufficient quantity of the carbon dioxide source so that the mix shape 5 compound of formula Π during dissolution. ' 8. Process according to claim 4, characterized in that the addition comprises combining the carbapenem of formula I, or a pharmaceutically acceptable salt or hydrate thereof, with the sufficient amount of the carbon dioxide source in solution to provide a solution 10 containing the compound of formula II. Process according to claim 8, characterized in that the solution containing the compound of formula II is lyophilized to provide a stabilized composition containing the compound of formula II or a pharmaceutically acceptable salt or hydrate thereof.