MXPA99007204A - Pain reducing parenteral liposome formulation - Google Patents

Abstract

Disclosed is an invention directed towards pain-reducing parenteral formulations comprising a macrolide drug entrapped in a liposome vesicle. The macrolide drug is selected from the group consisting of derivatives of erythromycins A, B, C and D;clarithromycin;azithromycin;dirithromycin;josamycin;midecamycin;kitasamycin;roxithromycin;rokitamycin;oleandomycin;miocamycin;flurithromycin;rosaramicin;8,9-anhydro-4''-deoxy-3'-N-desmethyl-3'-N-ethylerythromycin B 6,9-hemiacetal;8,9-anhydro-4''-deoxy-3'-N-desmethyl-3'-N-ethylerythromycin A 6,9-hemiacetal;and 11-amino-11-deoxy-3-oxo-5-O-desosaminyl-6-O-[1'-3'-quinolyl-2'-propenyl]-erythronolide A 11, 12-cyclic carbamate. The formulations of the invention are effective in substantially reducing the pain at the injection site typically associated with the injection of macrolide antibiotics.

Description

FORMU LATION OF LI POSOMA PARENTERAL REDUCTOR OF PAIN ICO TECHNICAL FIELD The present invention relates to parenteral pain reducing formulation in liposome system. More particularly, it relates to a parenteral formulation comprising a macrolide drug entrapped in a liposome vesicle. The formulations of the invention are effective in substantially reducing the pain typically associated with the injection of macrolide antibiotics.

BACKGROUND OF THE INVENTION Pain in the place of an injection following a parenteral administration is usually caused by pharmacological / physiological reactions between drug molecules and the local tissue.

Formulations to reduce pain in the form of either micelles or emulsions for intravenous administration of macrolide antibiotics have been disclosed by Lovell, et al. , International Journal of Pharmaceuticals, 109, 45-57, (1994); Cannon and collaborators. , International Journal of Pharmaceutics, 14, 65-74, (1995); Klement et al., British Journal of Anesthesia, 67, 281-284, (1991). For emulsion systems, the drugs are trapped in small droplets of oil. The emulsions are generally stabilized by some surfactants which create an interfacial layer to separate the oil phase and the aqueous phase. This interfacial layer is a barrier to reduce direct contact of the drug molecules with the local tissue around the site of the injection. However, this barrier is very dynamic. Drug molecules travel to and out of the contact surface very frequently. This property limits the effectiveness of the emulsion in the reduction of pain by injection. For micellar systems, the drugs are trapped in micelles that consist of surfactants. The polar head groups of the surfactant molecules face the bulk aqueous solution and the lipofilic tails face the core to form spherical or cylindrical structures. The packing of the bedside groups is not usually crowded and is very dynamic allowing rapid release of the drug following an injection. Similarly, the effectiveness of micelles to reduce pain at the site of injection is limited. Currently, some of these antibiotics, for example clarithromycin, are sold only in the oral form in the United States due to their highly painful and irritating nature at the site of the injection. Therefore, there is a need for formulations that can be used for drugs that produce pain at the site of injection and that are more effective in reducing such pain than emulsions and micelles known in the art.

BRIEF DESCRIPTION OF THE DICHES Figure 1 compares the response to pain by successive infusion of saline solution, clarithromycin solution and saline solution using Rat Tail Infusion Pain Model. Figure 2 compares the pain response by successive infusion of the saline liposome, placebo, liposome, saline, clarithromycin formulation of the invention containing phosphatidylglycerol solution, saline and clarithromycin using Vein Infusion Pain Model.

Tail of rat. Figure 3 compares the pain response by successive infusion of saline liposome formulation, placebo liposome, saline, clarithromycin of the invention containing dimiristoi acid solution; phosphatidic, saline, clarithromycin and saline using Model I nfusion Pain by Rat Vein. Figure 4 compares the pain response by successive infusion of saline ABT-229 liposome formulation, placebo liposome, saline of Example 3 of the invention, IV solution ABT-229, saline, placebo IV (lactobionic acid solution), and saline using Infusion Pain Model by Rattail Vein. Figure 5 compares the pain response by successive infusion of saline ABT-773 liposome formulation, placebo liposome, saline, Example 4 of the invention, saline solution V ABT-773, placebo V (lactobionic acid solution) , saline, and saline using Rat Vein Infusion Pain Model.

BRIEF DESCRIPTION OF THE INVENTION In one aspect, the present invention is directed toward a pain reducing parenteral formulation comprising a macrolide drug entrapped in a liposome vesicle comprising a lipid. The formulations of the invention are effective in reducing pain at the site of injection caused by drug macrolide molecules. In another aspect, the present invention is directed to a method for reducing injection pain site caused by a macrolide drug comprising administering a parenteral formulation comprising a macrolide drug trapped in a liposome vesicle.

DETAILED DESCRIPTION OF THE INVENTION The term "liposome vesicle" as used herein refers to single layer or multiple bilayer vesicles consisting of phospholipids or other lipids in which an aqueous volume is completely enclosed by a membrane composed of lipid molecules. Parenteral formulations of the invention comprise a macrolide drug entrapped in liposome vesicles which comprise a lipid. Macrolide drugs can be selected from erythromycin derivatives A, B, C, and D; clarithromycin; azithromycin; dirithromycin; josamycin; midecamycin; kitasamycin; roxithromycin; rokitamycin; oleandomycin; myokamycin; fluritromycin; rosaramycin; 8,9-anhydro-4"-deoxy-3 '- N - desmethyl - 3' - N - etylethroetin icine B, 6,9 - hemiacetal (ABT - 229); 8,9 - anhydro - 4" - deoxy - 3 '-N-desmethyl-3'-N-ethylerythromycin A, 6,9-hemiacetal (ABT-269); 11-amino-11-deoxy-3-oxo-5-O-desosaminyl-6-O- [1 '-3'-quinolyl-2, -propenyl] -erithronolide A 1 1, 12-cyclic carbamate (ABT-773 ); and the similar ones. Preferably, the macrolide drug used in the formulation is clarithromycin, ABT-229 and ABT-773. More preferably, the macrolide drug used in the formulation is clarithromycin. The liposome vesicle is formed when the lipids are dispersed in an aqueous medium. By way of example, but not limiting, the lipids that can be used to form the liposomes are naturally occurring lipids, synthetic lipids and semi-synthetic lipids. Naturally occurring lipids include phospholipids, phosphatidyl choline, fatty acids, secondary double-chain amines and cholesterol derivatives, and the like. Lipids synthetically obtained include, but are not limited to, phosphatidyl choline bound to ether, dimyristyl lecithin, dipalmitoyl lecithin, distearoyl lecithin. Preferably, the lipids are phospholipids which include phosphatidyl choline, phosphatidyl ethanolamine, phosphatidyl inositol, fsofatidyl serine, sphingomyelin, phosphatidyl choline bound with ether, dimyristoyl phosphatidyl choline, dimyristoyl phosphatidic acid, dimyristoyl phosphatidyl glycerol, phosphatidic acid and the like. The molar ratio of the drug molecules to the lipid may be as low as 1: 2 or may contain a higher proportion of lipid such as 1: 100. Preferably, this molar ratio varies from 1: 8 to 1: 20. The molar ratio depends on the drug used but will ensure the presence of a sufficient number of neutral and / or negatively charged lipids and the drug to form a stable complex with most drugs. Preferably, the liposome vesicles comprise both the neutral and negatively charged lipids. Illustrative neutral lipids include phosphatidyl serine and phosphatidyl ethanolamine. In the most preferred embodiment of the invention, the molar ratio of a negatively charged phospholipid to the drug ranges from about 0.5 to about 3.0 with a drug to a neutral phospholipid ratio that is from about 10 to about 7.0. The pH of the formulation can fluctuate from pH 3 to pH 11.

The pH of the formulation is adjusted by adding an alkali or an acid as needed. The required pH of the formulation is determined by the type of drug to be trapped and its solubility in water at ambient temperatures. The liposome formulation may contain other optional ingredients, which include minor amounts of auxiliary, non-toxic substances; such as antioxidants, v. g. , butylated hydroxytoluene, alpha-tocopherol and ascorbyl palmitate, ascorbic acid, butylated hydroxyanisole, fumaric acid, malic acid, propyl gallate, sodium ascorbate, and sodium metabisulfite; and pH buffering agents; such as phosphates, glycine and the like. When using naturally occurring phospholipids, it is recommended that the liposome formulation contains antioxidant to prevent oxidation of the unsaturated ligatures present in the fatty acid chains in the phospholipid.

The liposome formulation can contain cryoprotective agent known to be useful in the art of preparing dry-frozen formulations, such as di- or polysaccharides or other bulking agent such as lysine. In addition, isotonic agents aggregated typically can be used to maintain isomolarity with body fluids. In a preferred embodiment, a di-saccharide or poly-saccharide is used and functions as both a cryoprotective agent and an isotonic agent. The addition of a di-saccharide or poly-saccharide provides instantaneous hydration and the largest surface area to deposit a thin film of the drug-lipid complex. This thin film provides more rapid hydration so that, when the liposome is initially formed by adding the aqueous phase, the liposomes formed are of a smaller and more uniform particle size. This provides significant advantages in terms of ease of manufacture. Accordingly, the preferred liposome composition of the present invention comprises a di-saccharide or poly-saccharide, in addition to the phospholipids. When present, the di-saccharide or poly-saccharide is preferably selected from the group consisting of lactose, trehalose, maltose, maltotriose, palatinose, lactulose, or sucrose, with lactose or trehalose being preferred. Even more preferable, the liposomes comprise lactose or trehalose. When present, the di- or poly-sao aride is formulated in a preferred mixing ratio of about 10-20 of saccharide to 0.5-0.6 of phospholipid, respectively, even more preferred in the ratio of about 10 to 1.5-4.0. The presence of the di-saccharide or poly-saccharide in the composition not only tends to give liposomes having extremely small and narrow particle size ranges, but it also provides a liposome composition in which the drug, in particular, can be incorporated in an efficient way, that is, with an encapsulation efficiency approaching 80-100%. In addition, liposomes made with a saccharide typically exhibit improved chemical and physical stability, such that they can retain an incorporated compound without prolonged storage leakage, either as a reconstituted liposome suspension or as a cryo-dried powder. Liposomes can be prepared by any of the methods known in the art. (See for example, "Liposomes, a Practical Approach," RRC New, pp 1-161, IRL Press, (1990).) In one of the liposome preparation methods, a solution of a macrolide drug, excipients and lipid is formed. in an organic solvent and introduced into a round bottom flask Suitable solvents include any volatile organic solvent, such as diethyl ether, acetone, methylene chloride, chloroform, piperidine, piperidine-water mixtures, methanol, tert-butanol, sulfoxide dimethyl, N-methyl-2-pyrrolidone, and mixtures thereof Preferably, the organic solvent is immiscible with water, such as methylene chloride, but immiscibility in water is not a requirement, In any case, the chosen solvent must not only be able to dissolve all the components of the lipid film, but also must not react with, or otherwise detrimentally affect, these components to any significant degree.The organic solvent is then removed from the resulting solution to form a dry lipid film by any known laboratory technique that is not detrimental to the dried lipid film. Preferably, the solvent is removed under vacuum until all of the organic solvent is evaporated. A rotary evaporator is immersed in a water bath with a thermostat at 40 ° C, evacuated, and rotated at 60 rpm. The evacuation and rotation is continued until all the solvent has evaporated from the solution and a dry lipid film has been deposited on the walls of the flask. The residual solvent is removed by a vacuum pump for a minimum period of twenty-four hours. The dried lipid film is then dispersed in an aqueous solution, preferably containing a disaccharide or polysaccharide, or a saline solution. Examples of the useful aqueous solutions used during hydration of the film include sterile water, a sodium chloride solution buffered with phosphate (pH 7.2-7.4), free of calcium- and magnesium-, a 5% dextrose solution, or any other physiologically acceptable aqueous solution of one or more electrolytes. Preferably, however, the aqueous solution is sterile. The volume of the aqueous solution used during hydration can vary greatly, but should be greater than about 35% and less than about 95% of the total volume. The flask is rotated at 60 rpm at room temperature until the entire lipid film has been removed from the wall of the flask. The dispersion of the lipid is then allowed to stand for two additional hours at room temperature in order to complete the growth process. The thick liposome thus formed incorporates a drug-lipid complex. The hydration step should take place at a temperature not exceeding about 40 ° C, preferably at room temperature or lower. The particle size of the thick liposome obtained is homogenized by passing the dispersion through high-speed stirring devices; such as "Microfluidizer", for example, a Microfluidics ™ Model 1 10F; a sonicator; a high cut mixer; a homogenizer; or a normal laboratory agitator. Preferably, a high pressure device such as a Microfluidizer ™ is used for agitation. In microfluidization, a large amount of heat is generated during the short period of time during which the fluid passes through a high pressure interaction chamber. For this reason, the homogenization temperature is cooled to a temperature no higher than 40 ° C after the composition passes through the maximum agitation zone, e.g. , the interaction camera of a Microfluidizer ™ device. The homogenization temperature would preferably be room temperature or lower. Although the pressure used in such high pressure devices is not critical, pressures from about 703.7 to about 1.126 kg / cm2 are not uncommon. It is crucial that one obtain vesicles that are of the correct size and structure, and trap materials with high efficiency and in such a way that the materials do not leak out of the liposome once formed. The pH of the formulation is adjusted to a desired level by the addition of an alkali or an acid as the case may be. The dispersion of the liposome thus obtained is aseptically filtered through a 0.2 μm filter using a syringe pump and the heavy postfiltrate to determine filterability. The filtering power of pre-filtering and post-filtering can be determined using High Performance Liquid Chromatography (HPLC). The particle size distribution of the vesicles can be determined using a NICOMP submicron particle analyzer (Model 370) or other conventional particle size measurement techniques. The liposomal compositions of the invention provide liposomes of sufficiently small particle size such that aseptic filtration of the composition through a 0.2 μm hydrophilic filter can be performed efficiently. The particle size of the liposome can vary from about 10 nm to about 25 μm. A particularly preferred size range is below about 300 nm, more preferably below about 250 nm. Most preferred, the particle size is below about 220 nm. The particles of the liposome can be uniform in size or can be bimodal or in multiple ways. The filtration ability can be tested by passing a liposome composition through a Microfluidizer ™ 5 times and extracting a sample with a syringe. The syringe is connected to a 0.2 μm hydrophilic filter and then placed in a syringe pump. The constant rate of piston movement is set at 10 ml / min, and the filtrate is collected until the filter is blocked by large aggregates of liposome. The volume or weight of the filtrate is then measured and recorded in terms of ml / cm2 or g / cm2, with one square centimeter being the effective filtration area. Thus, the filtering ability for the purpose of the invention is defined as the maximum volume or weight of liposome composition that can be filtered through a 0.2 μm filter. The liposome compositions of the invention are typically administered parenterally. The injection may be intravenous, subcutaneous, intramuscular, intrathecal, intraperitoneal, and any other parenteral administrations. The amount of liposome formulation to be administered depends on the selection of active drug, the condition to be treated, the mode of administration, the individual subject, and the judgment of the practitioner. Generally speaking, however, doses of active drug in the range of 0.05-50 mg / kg may be necessary. The above range is, of course, merely suggested, since the number of variables with respect to an individual treatment regimen is large. Therefore, considerable inroads are expected from these recommended values. Packing of bilayers in the liposome vesicle is very tight with glass transition temperature higher than that of micelles and emulsion, and, therefore, the liposome vesicle is more rigid and less dynamic than micelles and emulsions. The physical barriers created by the liposome of the invention especially multi-layer liposome vesicles are effective against rapid movement of the drug from there to the site of injection after such infusion, thereby reducing pain with comitant.

EVALUATION OF PAIN USING INFUSION PAIN MODEL OF RAT TAIL VENUE The effectiveness of the formulation to reduce pain is tested using a rat tail vein infusion engine response model. This model is based on the assumption that the movement of a rat during intravenous infusion will be proportional to the pain caused by the infusion. The rat (Spargue Dawley male, 325 to 375 g) is placed in a restricted cage mounted on springs. Multiple test substances are successively infused in a desired sequence, through a butterfly needle inserted into the tail lateral vein of a rat. The movement of the cage is monitored by an accelerometer mounted at the base of the cage. The signal from the accelerometer is transmitted to a computer for display and storage of information. The following examples illustrate the invention and should not be considered as limiting the invention.

Example 1 The formulations of Example 1 (a) through 1 (f), containing various ingredients in the amounts set forth below in Table 1, were prepared by the following general method.

Table 1 amount of PG varied, see Table 2.

An organic drug-lipid solution was prepared by dissolving PG, DMPC, clarithromycin, and BHT in 25 ml of methylene chloride. The lipid solution is introduced into a round bottom flask. The flask is attached to a rotary evaporator, and immersed in a water bath with thermostat at 4o C. The flask is rotated at 60 rpm and vacuum is applied until all the solvent has evaporated from the solution and a film has been deposited dry lipid in the walls of the flask. The residual trace solvent is removed by applying a vacuum for a minimum period of 24 hours. The flask is then washed with an added solution of nitrogen and lactose. The flask is rotated (60 rpm) at room temperature until all the lipid film has been removed from the wall of the flask. The lipid dispersion is allowed to stand for an additional 2 hours at room temperature in order to complete the swelling process. The particle size of the coarse liposome is reduced by passing the liposome solution through a Microfluidizer ™ five times. The pH is adjusted to an appropriate value by adding an alkali or an acid. The liposome dispersion is filtered through a 0.2 μm hydrophilic filter using a syringe pump and the post filtered is weighed to determine the filtration ability. The filtering power of pre-filtering and postfiltering is determined using a CLAR method. The particle size distribution is measured using a NICOMP submicron particle analyzer (Model 370). Table 2 below sets forth the various parameters for the formulations of Example 1 (a) to 1 (f). The amount of clarithromycin contained in the formulation is 5 mg / ml of the dispersion. The liposome particle size distribution is bimodal.

Table 2 Example 1 PH PG (MR *) Filterability Power Filtration Size (%) (g / cm2) Particle Mean nm ** 0.5 45.9 1 .28 1 10/1 1 70.3 0.46 37/10 97.8 2.78 77/5 10 0.5 19.5 0.24 92/14 e 10 17.5 0.24 104/17 f 10 39.7 0.12 41/6 * means the molar ratio of PG to clarithromycin ** means Nicomp distribution: 2 modes From Table 2 it can be seen that at pH 8, the post-filtration power was increased with increasing PG MR. Nearly 100% of the liposomes with 3 PG MR passed through a 0.2 micron filter. In contrast, about 50% of the 0.5 PG MR liposomes and about 70% of the 1 PG MR liposomes passed through the 0.2 micron filter. These results indicate that PG5 effectively increases the entrapment of clarithromycin in the bilayer lipid at pH 8. Without being limited by theory, it is believed that this effect may be caused by the electrostatic attraction of the positively charged clarithromycin and the negatively charged PG. At pH 10, the post-filtration powers were lower than those corresponding to the pH 8 values for all PG M Rs. Increases in MR did not show a significant increase in post-filtration power. To a PG M R of 3, only about 40% of the clarithromycin liposomes passed through the 0.2 micron filter. The negatively charged PG does not have a significant effect on the entrapment of clarithromycin in the two-layer lipid. The diminished effect of PG in entrapment may be due to the lack of electrostatic attraction between PG and clarithromycin-free base at pH 10. Unclogged clarithromycin may cause aggregation of liposomes and / or precipitate due to its insoluble nature. Consequently, these large particles can clog the filter and result in low power.

Example 2 A liposomal formulation was prepared according to the method described in Example 1. Table 3 sets forth the amounts of the ingredients used to prepare the formulation. The amount of clarithromycin in the formulation is 3.5 mg / ml of the dispersion. The concentration (3.5 mg / ml) was determined using a CLAR method. The pH of the suspension is 8.0 with the filtration power of 100% and filterability of 0.31 g / cm2. The liposome particle size distribution is bimodal having a particle size of 83.4 / 19.9 nm.

Table 3 means not applicable.

Example 3 A liposomal formulation comprising ABT-229 was prepared according to the method described in Example 1. Table 4 sets forth the amounts of the ingredients used to prepare the formulation. The amount of ABT-229 in the formulation is 2.5 mg / ml of the dispersion. The concentration (2.5 mg / ml) was determined using a CLAR method. The pH of the suspension is 8.0 with the filtering power of 97.9% and filterability of > 4.0 g / cm2. The liposome particle size distribution is trimodal having a particle size of 7.9 / 62.5 / 296.4 nm.

Table 4 means not applicable.

Example 4 A liposomal formulation comprising ABT-773 was prepared according to the method described in Example 1. Table 5 sets out the amounts of the ingredients used to prepare the formulation. The amount of ABT-773 in the formulation is 5.0 mg / ml of the dispersion. The concentration (5.0 mg / ml) was determined using a CLAR method. The pH of the suspension is 9.0 with the filtering power of 103.4% and filterability of > 4.0 g / cm2. The liposome particle size distribution is unimodal having a particle size of 15.4 nm.

Table 5 means not applicable.

Example 5 This example illustrates the evaluation of pain reducing properties of liposomal formulations using Rat Tail Infusion Pain Model. The rats are initially acclimated to the restricted cage for a period of thirty minutes, 1 to 5 days before the infusion of the test formulation. The formulations of the above examples are then infused by the insertion of a 23 gauge butterfly needle into the tail lateral vein of the rats. The needle is connected by tubing to a syringe pump and the formulations are infused at 0.1 ml / minute. The infusion of each formulation is continued and followed by saline. The movement of the cage is monitored by an accelerometer mounted at the base of the cage. The signal from the accelerometer is transmitted to a computer for display and storage of information.

Figure 1 illustrates the results of the infusion of 5 mg / ml of clarithromycin lactobionic acid solution continued and followed by saline. At this concentration, the clarithromycin solution leads to a definite pain response. Figure 2 illustrates the results of the pain-producing property of the formulation of the invention of Example 1 compared to placebo liposomes, saline, and clarithromycin solution (5 mg / ml). The results are obtained by sequentially infusing saline, placebo liposomes, saline, clarithromycin liposomes of Example 1, saline and clarithromycin using the same individual rat throughout the experiment, thereby eliminating the uncertainty caused by the variability between animals. The results clearly indicate that the rat showed no response to the placebo liposomes or the liposomes loaded with clarithromycin. The pain response to the clarithromycin solution is typical for 5 mg / ml and similar to the results shown in Figure 1. Figure 3 illustrates the results of an experiment designed to compare the pain-producing property of the formulation of Example 2 and free clarithromycin at 3.5 mg / ml. The results are obtained by sequentially infusing saline, placebo liposomes, saline, clarithromycin liposomes of Example 2, saline solution, clarithromycin, and saline using the same individual rat throughout the experiment, thereby eliminating the uncertainty caused by the variability between animals. The results clearly indicate that the rat showed no response to the placebo liposomes or the liposomes loaded with clarithromycin. The pain response to the clarithromycin solution is typical for 3.5 mg / ml and similar to the results obtained in Figure 1. Figure 4 illustrates the results of the pain-producing property of the formulation of the invention of Example 3. results are obtained by sequentially infusing saline, placebo liposome, saline, ABT-229 liposome formulation of Example 3, saline, IV placebo (lactobionic acid solution), saline, ABT-229 IV solution, and saline using Infusion Pain Model by Rat Tail Vein using the same individual rat throughout the experiment, thereby eliminating the uncertainty caused by the variability between animals. The results clearly indicate that the rat showed no response to the placebo liposomes, placebo IV or the liposomes loaded with ABT-229, but showed the pain response to solution IV of ABT-229. In this Example, placebo IV was infused to demonstrate that the pain response is associated with ABT-229 and not with lactobionic acid alone. Figure 5 illustrates the results of the pain-producing property of the formulation of the invention of Example 4. The results are obtained by sequentially infusing saline, placebo liposome, saline, ABT-773 liposome formulation of Example 4, saline, placebo V ( lactobionic acid solution), saline, solution V of ABT-773, and saline using the same individual rat throughout the experiment, thereby eliminating the uncertainty caused by the variability between animals. The results clearly indicate that the rat showed no response to the placebo liposomes, placebo V or the liposomes loaded with ABT-773, but showed the pain response to the ABT-773 solution. In this Example, placebo V was infused to show that the pain response is associated with ABT-773 and not with lactobionic acid alone. These Figures clearly illustrate that trapping a macrolide in the liposomes effectively reduces the painful nature of clarithromycin in injection to a level that was not detectable using the Rat Tail Infusion Pain Model.

Claims (24)

1. REIVI NDICATIONS 1. A reduced pain parenteral formulation comprising a macrolide drug selected from the group consisting of erythromycin derivatives A, B, C and D; clarithromycin; azithromycin; dirithromycin; josamycin; midecamycin; kitasamycin; roxithromycin; rokitamycin; oleandomycin; myokamycin; fluritromycin; rosaramycin; 8,9-anhydro-4"-deoxy-3'-N-desmethyl-3'-N-ethylerythromycin B 6,9-hemiacetal; 8,9-anhydro-4" -deoxi-3'-N-desmethyl-3 '-N-ethylerythromycin A 6,9-hemiacetal; and 11-amino-1 1-deoxy-3-oxo-5-O-desosaminyl-6-O- [1 '-3, -quinolyl-2'-propenyl] -eritronolide A1 1, 12-cyclic carbamate trapped in a liposome vesicle comprising a lipid, wherein at least one lipid is negatively charged, and the molar ratio of the drug to the lipid ranges from about 1: 2 to about 1: 100.
2. 2. The formulation of claim 1 , wherein the lipid is selected from the group consisting of phospholipids, fatty acids, secondary double-chain amines and cholesterol.
3. The formulation of claim 2, wherein the lipid is selected from the group consisting of phosphatidyl choline, sphingomyelin, phosphatidyl ethanolamine, phosphatidyl-inositol, phosphatidyl serine, phosphatidyl choline bound with ether, dimyristoyl phosphatidyl choline, egg phosphatidyl glycerol, dimiristoil phosphatidic acid, and distearoyl lecithin.
4. The formulation of claim 3, wherein the molar ratio of the lipid negatively charged to the drug in the vesicle ranges from about 0.5 to about 3.0, and the molar ratio of the drug to the neutral lipid ranges from 1.0 to 7.0.
5. 5. The formulation of claim 1, wherein the pH of the formulation ranges from about 3.0 to about 1.0.
6. The formulation of claim 1, wherein the average size of the liposome vesicles ranges from approximately 10 nm to about 25 μm.
7. The formulation of claim 1, further comprising antioxidants.
8. The formulation of claim 1, wherein the antioxidant is selected from the group consisting of butylated hydroxytoluene, alpha-tocopherol, ascorbyl palmitate, ascorbic acid, butylated hydroxyanisole, fumaric acid, malic acid, propyl gallate, sodium ascorbate , and sodium metabisulfite.
9. The formulation of claim 8, wherein the macrolide is selected from the group consisting of erythromycin derivatives A, B, C, and D; clarithromycin; azithromycin; roxithromycin; 8,9-anhydro-4"-deoxy-3'-N-desmethyl-3'-N-ethylerythromycin B 6,9-hemiacetal; 8,9-anhydro-4" -deoxi-3'-N-desmethyl-3 '-N-ethylerythromycin A 6,9-hemiacetal; and 1 1-amino-11-deoxy-3-oxo-5-O-desosaminyl-6-O- [1 '-3, -quinolyl-2, -propenyl] -eritronolide A 1 1, 12-cyclic carbamate.
10. The formulation of claim 9, further comprising a disaccharide or polysaccharide.
11. The formulation of claim 10, wherein the disaccharide or polysaccharide is selected from the group consisting of lactose, trehalose, maltose, maltotriose, palatinose, lactulose, and sucrose.
12. 12. The formulation of claim 1, wherein the macrolide is clarithromycin.
13. 13. A method for reducing pain at the site of injection caused by a macrolide drug comprising administering a parenteral formulation comprising the macrolide drug trapped in a liposome vesicle.
14. The method according to claim 13, wherein the liposome vesicle comprises lipids selected from the group consisting of phospholipids, fatty acids, secondary double-chain amines and cholesterol.
15. The method according to claim 14, wherein the lipid is selected from the group consisting of phosphatidyl choline, sphingomyelin, phosphatidyl ethanolamine, phosphatidyl-inositol, phosphatidyl serine, phosphatidyl choline bound with ether, dimyristoyl phosphatidyl choline, phosphatidyl glycerol egg, dimyristoyl phosphatidic acid, dipalmitoyl lecithin, and distearoyl lecithin.
16. The method according to claim 15, wherein the molar ratio of a lipid negatively charged to the drug in the vesicle ranges from about 0.5 to about 3.0, and the molar ratio of the drug to a neutral lipid varies from about 1.0. up to about 7.0.
17. 17. The method according to claim 16, wherein the pH of the formulation ranges from about 3.0 to about 1.0.
18. 18. The method according to claim 13, wherein the average size of the vesicles of the iiposome varies from about 10 nm to about 25 μm.
19. 19. The method according to claim 13, wherein the formulation further comprises antioxidants.
20. The method according to claim 19, wherein the antioxidant is selected from the group consisting of butylated hydroxytoluene, alpha-tocopherol, ascorbyl palmitate, ascorbic acid, butylated hydroxyanisole, fumaric acid, malic acid, propyl gallate, ascorbate of sodium, and sodium metabisulfite.
21. The method according to claim 20, wherein the macrolide drug is selected from the group consisting of erythromycin derivatives A, B, C, and D; clarithromycin; azithromycin; roxithromycin; 8,9-anhydro-4"-deoxy-3'-N-desmethyl-3'-N-ethylerythromycin B6,9-hemiacetal; 8,9-anhydro-4" -deoxi-3'-N-desmethyl-3 ' -N-ethylerythromycin A6,9-hemiacetal; and 1 1-amino-11-deoxy-3-oxo-5-O-desosaminyl-6-O - [1'-3'-quinolyl-2'-propenyl] -eritronolide A 11,12-cyclic carbamate.
22. 22. The method according to claim 21, wherein the formulation further comprises a disaccharide or polysaccharide.
23. The method according to claim 22, wherein the disaccharide or polysaccharide is selected from the group consisting of lactose, trehalose, maltose, maltotriose, palatinose, lactulose, and sucrose.
24. 24. The method according to claim 23, wherein the macrolide is clarithromycin.