IL94516A - Injectable clarithromycin composition containing a triglyceride oil, stabilizing agent and optionally an emulsifier - Google Patents

Description

Injectable Clarithromycin Composition Abbott Laboratories INJECTABLE CLARITHROMYCIN COMPOSITION TECHNICAL FIELD This invention relates to injectable compositions of clarithromycin.

BACKGROUND ART Lipophilic drugs such as erythromycin and clarithromycin are not administered by intramuscular injection or intravenously because these drugs cause severe pain at the injection site. A variety of approaches have been taken to address this problem, including attempts to derivatize the lipophilic drugs themselves. Nevertheless, there is a continuing need for injectable compositions of lipophilic drugs that do not cause severe pain.

It has been found that erythromycin fat emulsions are locally non-irritative. The antibiotic clarithromycin, however, has a low solubility in fat emulsions even in the presence of oils, and will precipitate out of such emulsions. It has heretofore not been possible to solubilize clarithromycin so as to achieve stable injectable compositions at concentrations which are high enough for therapeutically effective pharmaceutical purposes. For example, Japanese patent application No. 61291520 (published December 22, 1986) suggests the addition of benzyl benzoate to increase the concentration of erythromycin in vegetable oils.

However, when clarithromycin is prepared as suggested by the Japanese patent, therapeutically acceptable concentrations (for example, 5 mg/ml) are not achieved.

Therefore, administration of the desired total daily dose of clarithromycin would require the administration of either larger individual injections or more numerous injections. Accordingly, there is a continuing need for stable injectable compositions of clarithromycin at therapeutically acceptable concentrations that do not cause severe pain at the injection site.

SUMMARY OF THE INVENTION The present invention relates to pharmaceutical compositions of clarithromycin for injection. The composition can be delivered by intramuscular or central or peripheral venous routes.

More particularly, the present invention relates to an injectable fat emulsion having a therapeutically effective concentration of clarithromycin which includes a triglyceride oil and a stabilizing agent.

DETAILED DESCRIPTION OF THE INVENTION The pharmaceutical compositions of the present invention include compositions comprising an injectable fat emulsion having a therapeutically effective concentration of clarithromycin, a triglyceride oil and a stabilizing agent. The invention also includes compositions which additionally comprise an emulsifier, as well as those containing a tonicity-adjusting agent.

The compositions of the invention are specifically those containing the antibiotic clarithromycin. By "clarithromycin" as used herein is meant e^O-methyl-erythromycin (see U.S. 4,331,803) and semisynthetic derivatives of clarithromycin known to the art as well as their pharmaceutically acceptable salts and esters. By "pharmaceutically acceptable salts and esters" as used herein is meant those salts and esters which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use in the chemotherapy and prophylaxis of antimicrobial infections. Among the more common pharmaceutically acceptable salts and esters of macrolide antibiotics are the acetate, estolate (lauryl sulfate salt of the propionate ester), ethyl succinate, gluceptate (glucoheptonate), lactobionate, stearate, and hydrochloride forms. Other acid salts used in the pharmaceutical arts are the following: adipate, alginate, aspartate, benzoate, benzene-sulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, gluconate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide , hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalene-sulfonate, nicotinate, oxalate, pamoate, pantothenate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. Basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.

Because the compositions of the invention offer improved solubilization of clarithromycin, higher concentrations are achieved than have previously been attainable. By "therapeutically effective concentration" as used herein is meant the concentration of clarithromycin that is effective to treat or prevent susceptible bacterial or other microbial infections, at a reasonable benefit/risk ratio applicable to any medical treatment, for example 5 mg/ml. Of course, the total daily dose of the compositions herein will be decided by the attending physician within the scope of sound medical judgment. The specific total daily dose level for any particular patient will depend upon a variety of factors including age, body weight, general health, sex, diet, time of administration, route of administration (i.e., intramuscular or central or peripheral venous routes), rate of excretion, the severity of the particular disease undergoing therapy, and like factors well known in the medical arts. The preferred therapeutically effective concentration of cla ithromycin is from about 2.5 mg/ml to about 10 mg/ml. The most preferred concentration is about 5 mg/ml .

The lipid phase of the injectable emulsious of the invention is provided by a triglyceride oil. By "triglyceride oil" as used herein is meant a triglyceride composition which is liquid at room temperature (22° C) , and which consists primarily of triglycerides of C, to C1B fatty acids. The triglyceride oil can be short chain (Cg to C12) or long chain (C14 to C18) and preferably C& to C12 aliphatic fatty acids. These triglyceride oils are generally present in a range of from about 2 to about 40%.

One preferred class of triglyceride oils of short chain fatty acids is represented by those oils which consist predominantly of glycerol triesters of C6 to C10 fatty acids. Such oils can be prepared synthetically by well known techniques, or can be obtained from natural sources by known techniques of thermal or solvent fractionation of suitable natural oils, such as palm oil, to yield fractions rich in the desired low-melting triglycerides. A preferred low-melting, low molecular weight triglyceride oil is a low molecular weight fraction of palm oil which is rich in mixed esters of caprylic (octanoic) and capric (decanoic) acids. Such an oil is commercially available as Neobee® M-5 oil from PVO International, Inc., of Boonton, New Jersey. Other low-melting cuts of palm oil are also suitable.

Another preferred class of triglyceride oil consists of triglyceride oils having a high percentage of glycerol triesters of unsaturated or polyunsaturated Cg to C18 fatty acids. A preferred example of such an oil is safflower oil, which typically has a fatty acid composition of over 90% oleic and linoleic acids. Triglycerides of these acids are liquid at 20°C, while the corresponding saturated triglyceride tristearin is a waxy solid at room temperature and melts at about 72°C. A further preferred example of such an oil is soybean oil. Other low-melting vegetable oils or low-melting fractions of oils, which can be obtained by conyentional thermal or solvent fractionation, are also suitable. While such unsaturated or polyunsaturated vegetable oils may offer a cost advantage in formulating compositions according to this invention, they also exhibit a greater tendency to oxidative deterioration, and may require the addition of oil soluble antioxidants, such as tocopherols.

Also preferred are intravenous fat emulsions which are generally prepared from either soybean or safflower oil and provide a mixture of neutral triglycerides containing predominantly unsaturated fatty acids. An example of such an emulsion is Liposyn II, a commercially available triglyceride oil and water emulsion. The major component fatty acids are linoleic, oleic, palmitic, stearic, and linolenic acids. In addition, these products can contain egg yolk phospholipids as an emulsifier, and glycerol to adjust tonicity. The emulsified fat particles are generally 0.33 to 0.5 microns in diameter, similar to naturally occurring chylomicrons.

In some compositions according to this invention, the triglyceride oil may contain small amounts of mono- and/or diglycerides to enhance solubility of the components or to enhance emulsification. In other compositions of this invention, it will be preferable that the oil have a low polarity. In such a case, the preferred triglyceride oils will be low in the content of mono- and diglycerides, as well as phospholipids, all of which have significant polarity.

The compositions of the present invention also include at least one stabilizing agent. By "stabilizing agent" as used herein is meant an additive that increases the solubility of the clarithromycin in the triglyceride oil phase such that a therapeutically acceptable concentration of clarithromycin can be achieved. Stabilizing agents include fatty acids (Cg to C12 saturated fatty acids, or unsaturated Clg to C18 fatty acids), N-methyl pyrrolidone (NMP), and benzyl alcohol. Preferred fatty acids are oleic, decanoic, octanoic and hexanoic acids. Methylene chloride can be utilized, but it must be evaporated off to achieve the final product. It has been found that, in the absence of the stabilizer, the emulsion is not stable and the clarithromycin tends to precipitate out of the emulsion within a short period of time, i.e., within one month. The stabilizing agent acts to increase the stability of the emulsion and maintain the suspension for at least six months.

The present invention also includes compositions containing an amulsifier. By "emulsif ier" as used herein is meant a compound which prevents the separation of the injectable emulsion into individual lipid and aqueous phases. Suitable emulsifiers include, but are not restricted to, egg yolk phospholipids (approximately 0.5 to 5%); glycodeoxycholic or glycocholic acids or a combination thereof; and non-ionic surfactants (as for example polysorbate, sorbitan monostea ate and combinations thereof).

The compositions of the present invention may also contain minor additives such as compounds to adjust tonicity, as for example glycerol (1-5%) and propylene glycol (1-10%).

The following examples are intended to illustrate the invention without limiting the practice thereof .

EXAMPLE 1 A representative composition of the present invention was prepared as follows: Compound Amount clarithromycin solution in NMP 167 mg/ml x 3 ml Liposyn® II 20% 100 ml Clarithromycin base (500 mg, available from Abbott Laboratories, Illinois) was dissolved in 3 ml NMP (N-methyl pyrrolidone, available from GAF Corp., Wayne N.J.). This ® solution was then added to 97 ml of Liposyn II 20% (20% oil/80% water emulsion) and the mixture shaken. The clarithromycin concentration was calculated to be approximately 5 mg/ml.

EXAMPLE 2 The compositions of EXAMPLE 2 can generally contain the following relative amounts of ingredients.

Compound Amount* Neobee® oil 10-40% decanoic acid 0.5-3% clarithromycin base 0.5-3% egg phosphatide 0.5-3% glycerol 1-4% water q.s.** * = percent of composition ** q.s. = adjust volume to desired value Solution A was prepared by adding 2.5 gm clarithromycin and 5.6 gm decanoic acid to 100 gm of ® Neobee oil (a medium chain triglyceride). The solution was then stirred with heating (approximately 40°C) until dissolved.

Solution B was prepared by stirring 6 gm egg phosphatide and 12 gm glycerol into 200 ml of water .

Solution B was passed through a Microfluidizer M-110 (Microfluidics Corp.) 3 times. Solution A was then added via a syringe pump at 1 ml/min while the mixture was passed through the microfluidizer . After the addition was completed, the mixture was passed 5 more times through the microfluidizer , adjusted to pH 7.5 with NaOH and diluted to 500 ml with water. The clarithromycin concentration was calculated to be approximately 5 mg/ml.

EXAMPLE 3 A methylene chloride-containing example of the compositions of the present invention was prepared as follows : Compound Amount clarithromycin base 1-20 mg/ml final concentration egg phosphatide in methylene 0.5-3% chloride Neobee® oil 10-40% water q.s.

Clarithromycin (2.5 gm) and 6 gm egg phosphatide were dissolved in 150 ml methylene chloride. The solution was evaporated to dryness in a rotary evaporator and the residue thin film was taken up, with vortexing, into 200 ml ® of water. Neobee oil (100 gm) was then added via a syringe pump and microfluidizer to the drug-phosphatide mixture as in EXAMPLE 2. The final emulsion was adjusted to pH 7.5 with NaOH and diluted to 500 ml with water.

EXAMPLE 4 EXAMPLE 2 can be repeated using the solubilizer octanoic acid. Solution A is prepared by adding 2.5 gm clarithromycin base and 4.7 gm octanoic acid to 100 gm of ® Neobee oil. The solution is then stirred with heating until dissolved.

Solution B is prepared by stirring 6 gm egg phosphatide and 12 gm glycerol into 200 ml of water.

Solution B is passed through a microfluidizer 3 times. Solution A is then added via a syringe pump while the mixture is passed through the microfluidizer . After the addition is completed, the mixture is passed 5 more times through the microfluidizer , adjusted to pH 7.5 with NaOH and diluted to 500 ml with water. The clarithromycin concentration is calculated to be approximately 5 mg/ml .

EXAMPLE 5 A further example of the compositions of the present invention was prepared as follows: Clarithromycin base (5 gm) and soybean oil (20 gm) were mixed to a smooth suspension. Oleic and hexanoic acids (6 gm and 3gm, respectively) were added while stirring and the oil phase mixture heated to 45°C or until clear.

Separately, egg lecithin (50 gm) was dissolved in preheated water (500 ml) and the solution stirred without heat as 12.2. gm NaOH is 50 ml water was added. Glycerin (25 gm) was then stirred in and the mixture circulated without cooling (approx. 10-15 min.) through a Gaulin M-15 homogenizer until 60-65°C and semi-transparent. After transfer of the dispersion to a beaker, and while cooling if necessary to less than 40°C, the above oil phase was gradually blended in using a Silverson mixer at the highest speed possible. Keeping the temperature below 40°C, the mixture was blended an additional 30 minutes.

The resulting mixture was then homogenized (30 passes at 6000-7000 p.s.i. at 35-40°C) and the homogenizer rinsed with 450 ml water, the rinse being stirred into the emulsion. After adjusting the pH to 7.7-7.9 with 7% NaOH, the volume was adjusted to 1 liter with water and the emulsion filtered through a 0.2 micron nylon membrane under 2 gas at about 30 p.s.i.

SCRATCH TEST A scratch test was conducted in mice to measure the response to the sensation of irritation, i.e., the pain associated with an injection. A composition containing ® clarithromycin, MP, and Liposyn II (see EXAMPLE 1) was administered subcutaneously at a dose of 5 ml/kg to groups of mice (10/group) weighing 16 to 30 g each. A second inventive composition containing the oleic acid/hexanoic acid system of EXAMPLE 5 and a clarithromycin lactobionate standard were similarly tested. The number of times that each mouse scratched the injection site was then counted for exactly five minutes. The results indicate a low scratch response associated with the compounds of the present invention and are summarized in Table 1 below.

TABLE 1 Composition No. of Scratches Mean S.D. * 1. 0.9% Saline Solution 2. cla ithromycin base (2mg/ml) in Liposyn II plus NMP 3. clarithromycin base (5mg/ml) in Liposyn II plus NMP 4. clarithromycin base (5mg/ml) 11 in oleic/hexanoic system 5. clarithromycin lactobionate 52 ( 5mg/ml ) * S.D. = standard deviation ** = extrapolated from 1-4 mg/ml VEIN IRRITATION TEST Clarithromycin in Liposyn II (5 mg/ml) was evaluated for acute vein irritation in rabbits. The test composition was infused into two male and two female rabbits at a rate of 1 ml/minute via the marginal ear vein at a dose volume of 8 ml/kg. The rabbits were observed frequently during and after treatment for signs of local irritation. The injection site appearance at 1 hour, 3 hours and 21 hours was normal with no apparent redness, thus indicating that the composition did not cause local irritation.

ANTIBACTERIAL ACTIVITY The antibacterial activity of 5mg/ml compositions of clarithromycin base in Liposyn II for intravenous administration (composition A) was compared to the activity of clarithromycin base lactobionate (composition B) in mouse protection tests. Mice were infected intraper toneally with 100 LI50 doses of Staphylococcus aureus , Streptococcus pyogenes , or Streptococcus pneumoniae (Groups 1, 2 and 3, respectively) and treated one hour after infection by injecting either (A) or (B) intravenously via the tail vein. ED5o was calculated from cumulative mortalities on the sixth day after infection. The results indicate that the composition has antibacterial activity as shown in Table 2 below.

TABLE 2 ED50 (mg/kq/day) Composition Group 1* Group 2** Group 3*** A 16.8 2.5 0.6 B 40.0 2.1 1.3 * = innoculum size 5.01 x 106 colony-forming units (CFU's) ** = innoculum size 1995 CFU's *** = innoculum size 6310 CFU's Similar mouse protection tests comparing the oleic/hexanoic system of EXAMPLE 5 with clarithromycin lactobionate showed no significant differences in antibacterial activity.

PHARMACOKINETIC ACTIVITY Six beagle dogs were allowed to fast overnight. The dogs were administered an intravenous infusion of clarithromycin (100 mg) in 20% Liposyn II (5 mg/ml). Blood samples were obtained periodically for 24 hours and the concentration of clarithromycin in the plasma samples was determined using a high-performance liquid chromatographic assay with electrochemical detection. The results indicate good plasma levels of clarithromycin and are shown in Table 3 below.

Table 3 Dog No. 24-hr AUC (hrs x ug/ml) 38.59 19.62 42.04 36.64 32.40 21.04 AUC = area under curve Mean 31.72 Standard Deviation 9.37 S.E.M. 3.82 A separate pharmacokinetic study likewise confirmed that plasma levels obtained using the oleic/hexanoic system of EXAMPLE 5 are comparable to those obtained with clarithromycin lactobionate. Four beagle dogs were treated as before with these compositions; blood samples were drawn and analyzed using standard microassay techniques. The results, shown in Table 4 below, demonstrate the bioavailability of the compounds of the present invention.

TABLE 4 Oleic/hexanoic system 41.07 36 33 Clarithromycin 37.16 84 67 lactobionate This invention has been described in terms of specific embodiments set forth in detail. It should be understood, however, that these embodiments are presented by way of illustration only, and that the invention is not necessarily limited thereto. It is contemplated that equivalent lipophilic drugs are those drugs which have solubility parameters similar to clarithromycin, such as roxithromycin. Modifications and variations within the spirit and scope of the claims that follow will be readily apparent from this disclosure, as those skilled in the art will appreciate. -16- 94516/2

Claims (13)

1. A pharmaceutical composition containing an injectable fat emulsion comprising a therapeutically effective concentration of clarithromycin of 2.5 mg/ml or greater, a triglyceride oil and at least one stabilizing agent.

2. A composition according to claim 1 additionally comprising an emulsifier.

3. A composition according to claim 2 wherein the emulsifier is an egg phosphatide.

4. A composition according to any of claims 1 to 3 wherein the triglyceride oil is an oil having C6 to C18 aliphatic fatty acids.

5. A composition according to any of claims 1 to 4, wherein the stabilizing agent is selected from C6 to C12 saturated fatty acid or C16 to C18 unsaturated fatty acid.

6. A composition according to any of claims 1 to 4 wherein the stabilizing agent is selected from decanoic acid, actanoic acid, oleic acid, hexanoic acid, N-methyl pyrrolidone, benzyl alcohol, and methylene chloride.

7. A composition according to claim 6 wherein the stabilizing agent is decanoic acid.

8. A composition according to claim 6 wherein the stabilizing agent is N-methyl pyrrolidone.

9. A composition according to claim 6 wherein the stabilizing agent is a combination of oleic and hexanoic acids.

10. A composition according to any of claims 1 to 9 wherein the therapeutically effective concentration is from about 2.5 mg/ml to about 10 mg/ml.

11. A composition according to claim 10 wherein the therapeutically effective concentration is about 5 mg/ml.

12. A composition according to any of claims 1 to 11 additionally comprising a tonicity-adjusting agent.

13. A pharmaceutical composition containing an injectable fat emulsion comprising a therapeutically effective concentration of clarithromycin, as defined in claim 1, soybean oil, an egg phosphatide, oleic acid, hexanoic acid and glycerin.