KR20140032450A - Dry powder vancomycin compositions and associated methods - Google Patents

Abstract

The present invention relates to dry powder vancomycin compositions and methods of administering and preparing such compositions. The composition of the present invention can be administered via pulmonary administration in an effective amount to treat the subject and / or prevent bacterial infection. Administration of an effective amount of a composition of the present invention may be particularly useful for treating Gram-positive bacteria infection in a subject's suffering from pneumonia, cystic fibrosis, bronchiectasis or other chronic lung disease with bacterial infection of the subject's airways and / or lungs. have.

Description

Dry powder vancomycin composition and related methods {DRY POWDER VANCOMYCIN COMPOSITIONS AND ASSOCIATED METHODS}

This application is incorporated herein by reference in its entirety based on US Patent No. 61 / 487,971, filed May 19, 2011.

Vancomycin is a glycopeptide antibiotic used for the prevention and treatment of infection by Gram-positive bacteria. Vancomycin is the international generic name (INN) corresponding to a compound having the general formula:

Vancomycin is proposed to function to inhibit the synthesis of certain cell walls in Gram-positive bacteria. More specifically, vancomycin is thought to inhibit the binding of N-acetylmuramic acid (NAM) and N-acetylglucosamine (NAG) glycan subunits to the peptidoglycan matrix that forms the major structural component of the gram positive cell wall. The binding of the terminal D-alanyl-D-alanine moiety to vancomycin of the NAM / NAG-peptide inhibits their binding to the peptidoglycan matrix.

Vancomycin is administered intravenously for oral as well as systemic treatments for mastitis. Vancomycin is used in the form of nebulized aerosol off labels for the treatment of various infections of the upper and lower respiratory tracts. However, because safety and efficacy are not provided for studies and / or appropriate dosages, the use of drugs approved in an off-label manner can put the patient at risk. In addition, delivery by nebulization can take up to 20 minutes, which is a significant burden on the patient. At present, no commercially available dry powder aspirated phase form of vancomycin is known.

The present invention generally relates to dry powder compositions and methods of administering and preparing such compositions.

In one embodiment, the present invention provides a composition comprising vancomycin or a pharmaceutically acceptable salt thereof, wherein the composition is a dry powder.

In another embodiment, the present invention provides a method comprising administering to a subject a dry powder composition comprising vancomycin or a pharmaceutically acceptable salt thereof via pulmonary administration.

In yet another embodiment, the present invention provides a method comprising spray drying an aqueous composition comprising vancomycin or a pharmaceutically acceptable salt thereof and a hydrophobic amino acid to form a dry powder composition.

Features and advantages of the invention will be apparent to those skilled in the art. Many modifications may be made by one skilled in the art, but such modifications include the spirit of the present invention.

Specific embodiments of the present specification may be understood with reference to the following description and the accompanying drawings in part.
1 is a graph showing the aerodynamic particle size distribution of a dry powder vancomycin composition (lot SA010) measured using an Anderson Cascade Impactor and a Monodose RS01 Model 7 Inhaler.
FIG. 2 is a graph showing the effect of leucine content on delivery efficiency of dry powder vancomycin compositions (lots SA002, SA006, SA007, SA008 and SA009) measured using a Fast Screening Amp and Monodoses RS01 Model 7 Inhaler. Emission% is the amount of drug in the dry powder exiting the inhaler as a percentage of the initial amount of drug in the dry powder present in the capsule. The fine particle fraction (%) is the amount of drug in the dry powder having an aerodynamic size of less than 5 μm as a percentage of the emissions. Delivery efficiency (%) is the amount of drug in the dry powder having an aerodynamic diameter of less than 5 μm as a percentage of the initial amount in the capsule.
3 is an image of lab scale dry powder vancomycin particles (lot SA010) obtained using a scanning electron microscope.
FIG. 4 shows the aerodynamic particle size distribution of dry powder vancomycin composition (lot SA010) stored at 25 ° C. and 60% relative humidity (RH) for up to 6 months measured using the Anderson Cascade Impactor and Monodose RS01 Model 7 inhaler. It is a graph.
FIG. 5 shows uniform emission content under three different stable conditions for six months of ten continuous operations through a monodose RS01 Model 7 inhaler compared to FDA draft guidance specification limits of ± 20% (lot SA010). A graph representing.
FIG. 6 shows the dry powder vancomycin composition of the invention (lot G-11-26-1) measured from three monodose RS01 Model 7 inhalers tested at 100 L / min (equivalent to 4 L) for 2.4 seconds using a next-generation impactor. It is a graph showing the aerodynamic particle size distribution of.
7 is a graph showing emissions content uniformity through 10 monodose RS01 Model 7 inhalers tested at lot L-11-26-1 at 100 L / min (equivalent to 4 L) for 2.4 seconds. ± 20% and ± 25% above represent the FDA draft guidelines limit.
8 is a graph showing the effect of trehalose concentration on the chemical stability of the dry powder vancomycin composition of the present invention at 50 ° C. for 4 weeks.
9 is a graph showing comparison with two lots of dry powder vancomycin composition containing 10% leucine. One that does not contain API or process modifications (lot SA010) and the other with a purer API source is treated under nitrogen, taking precautions to lower the moisture content in the powder composition and protect it from light (lot G -11-026-1).
Fig. 10 is an image of pilot scale dry powder vancomycin particles (lot 19SA01.HQ00005) obtained using a scanning electron microscope.
11 shows single dose administration of vancomycin dry powder composition (lot G-11-026-1) or intravenous administration of vancomycin (inhaled vancomycin dose 16 mg, round; inhaled vancomycin dose 32 mg, triangle; inhaled vancomycin dose 80 mg, A graph showing blood concentration as a function of time (semi-log) after square injection; 250 mg intravenous infusion over 60 minutes (circle with a line).
Although the present invention is sensitive to various modifications and alternative forms, specific embodiments are shown in the figures and described in more detail herein. However, the description of specific embodiments does not limit the invention to the specific forms, but the invention includes all modifications and equivalents in part by the appended claims.

The present invention generally relates to dry powder vancomycin compositions and methods of administering and preparing such compositions. In any of the embodiments, the compositions of the present invention may be administered via pulmonary administration in an effective amount to treat a subject and / or prevent bacterial infection. Administration of an effective amount of a composition of the present invention may be particularly useful for treating Gram-positive bacteria infection in a subject's suffering from pneumonia, cystic fibrosis, bronchiectasis or other chronic lung disease due to bacterial infection of the subject's airways and / or lungs. Can be.

In one embodiment, the composition of the present invention is a dry powder comprising vancomycin or a pharmaceutically acceptable salt thereof. The term vancomycin, as used herein, includes analogs and derivatives of vancomycin. As used herein, the term "drying" means that the composition has a water content to easily disperse the particles in the inhaler to form an aerosol. In certain embodiments, this moisture content may be up to about 10 weight percent, up to about 7 weight percent, up to about 5 weight percent, up to about 3 weight percent. In addition, the term "powder" as used herein consists of finely dispersed solid particles that can be easily inhaled by a subject after being readily dispersed in an inhalation device, allowing the particles to penetrate the upper and lower airways Can reach the lungs. Thus, the powder is referred to as "breathable". In certain embodiments, the dry powder compositions of the present invention may have a tap density greater than about 0.4 g / cm 3, greater than about 0.45 g / cm 3 or greater than about 0.5 g / cm 3. Vancomycin can be primarily used in the description contained in the present invention, but the present invention is directed to other glycopeptide antibiotics (e.g., vancomycin, teicoplanin, theravancin, bleomycin, lamoplanin and decaplanin), and It can be done with derivatives and analogs, and most of all, it can treat certain Gram-positive infections.

In certain embodiments, the dry powder composition of the present invention comprises vancomycin or a pharmaceutically acceptable salt thereof present in an amount of about 90% by weight of the composition, wherein the powder has a tap density greater than about 0.4 g / cm 3. And further comprise leucine in an amount of about 10% by weight of the composition.

In certain embodiments, the dry powder compositions of the present invention have an average particle size of about 10 microns (μm) or less at a diameter defined by aerodynamic median particle diameter (MMAD) (measured using cascade impact). It includes particles having. In certain embodiments, at least 95% of the particles have an MMAD of less than about 10 μm. In certain embodiments, the diameter may be about 7 μm or less. In another embodiment, the diameter may be about 5 μm or less. In other embodiments, the diameter may be between about 0.5 μm and about 5 μm in diameter, particularly between about 1 μm and about 3 μm. Dry powder compositions of the present invention comprising particles having an average particle size of about 10 μm or less in diameter may be particularly useful for delivery via oral inhalation devices.

In another embodiment, the dry powder composition of the present invention may comprise particles having an average particle size of about 10 μm or more in a diameter defined by MMAD (measured using cascade impact). In certain embodiments, at least 95% of the particles have a MMAD greater than about 10 μm. In certain embodiments, the particle size may be between about 10 μm and about 50 μm in diameter, particularly between about 20 μm and about 40 μm. Dry powder compositions of the invention comprising particles having an average particle size of 10 μm or more in diameter may be particularly useful for nasal delivery.

In certain embodiments, the particles may be empty. In certain embodiments, the particles may be porous. In another embodiment, the particles may have a distribution of a spheroidal shape that may be relatively uniform. In certain embodiments, the vancomycin efficacy measured by microbial activity does not change effectively when compared to unprescribed drugs (eg, within 5% of the drug).

Suitable vancomycins or pharmaceutically acceptable salts thereof that can be used in the present invention can generally be used through various commercial vendors. Examples of suitable pharmaceutically acceptable salts of vancomycin are not limited to vancomycin hydrochloride, vancomycin sulfate, and the like.

In certain embodiments, in addition to vancomycin or a pharmaceutically acceptable salt thereof, the compositions of the present invention may further comprise one or more additives. Examples of suitable additives include hydrophobic amino acids. Such hydrophobic amino acids may include, but are not limited to, tryptophan, tyrosine, leucine, trileucine and phenylalanine. In certain embodiments, it is desirable to include hydrophobic amino acids in the compositions of the present invention to enhance the physical stability and / or dispersibility of the compositions, to enhance the chemical stability of vancomycin or its pharmaceutically acceptable salts, And / or to prepare the bitter taste of vancomycin and its salts to alter the taste of the composition and / or to alter the rate (eg, increase or slow rate) of the composition absorbed from the lungs into the body circulation. While not being bound by any theory, it is presently believed that the hydrophobic amino acid additives remain on the surface of the particles to protect them from moisture and light, thus increasing the stability of the formulation.

Other examples of suitable additives include carbohydrate bulking agents. Such carbohydrate bulking agents may include, but are not limited to, lactose, mannitol, trehalose, raffinose and maltodextrin. In another embodiment, it is preferred to include a carbohydrate bulking agent in the composition of the present invention to improve the physical stability of the composition. In another embodiment, the carbohydrate bulking agent can enhance the chemical stability of vancomycin or a pharmaceutically acceptable salt thereof. Other additives known to those skilled in the art may be included.

Generally, additives that can be used in the compositions of the present invention include up to about 50% by weight of the composition, up to 30% by weight of the composition, up to 10% by weight of the composition. In another embodiment, suitable additives that may be used in the compositions of the present invention may include an amount from about 10% to about 30% by weight of the composition. In another embodiment, suitable additives that may be used in the compositions of the present invention may comprise from about 10% to about 20% by weight of the composition.

The compositions of the present invention are not limited to including pH adjusters and buffers and / or isotonic agents, for example sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, and the like, and include pharmaceutically acceptable auxiliary substances or You may further include an adjuvant. Leucine has the dual advantage of modifying pH. Likewise, the compositions of the present invention may contain pharmaceutically acceptable carriers and excipients, including microspares, microcapsules, nanoparticles and the like.

In certain embodiments, the dry powder composition may be reduced and the obtained reduced powder may have a pH of greater than 3.0, preferably greater than 3.5 and most preferably greater than 4.0.

As mentioned above, administration of an effective amount of a dry powder vancomycin composition may relieve symptoms and / or treat a painful subject from a disease that includes, but is not limited to, pneumonia and cystic fibrosis with Gram-positive bacteria infection and / or vancomycin Or particularly useful for airway and / or lung tissue by bacteria or other pathogens sensitive to the derivatives. Other diseases include, but are not limited to, bronchitis, bronchiectasis, diffuse pancreatitis, capillary bronchitis, bronchial obstruction, idiopathic stratified pneumonia (BOOP), pneumonia caused by any cause, and include, but are not limited to, community pneumonia, pathogenic pneumonia, and artificial Respiratory related pneumonia (VAP) also includes, but is not limited to. Examples of Gram-positive bacteria infections include, but are not limited to, bacterial infections by pneumococci including methicillin resistant Staphylococcus aureus and Staphylococcus aureus.

As will be appreciated by those skilled in the art, the effective amount necessary to treat a particular condition or disease state will vary depending on the pathogen, individual, condition, duration of treatment, treatment regime, type of vancomycin used, and other factors, but will be readily determined by the skilled person. Can be. The patient can inhale the appropriate amount of the composition to achieve the desired dosage.

The dry powder composition of the present invention may be delivered to the subject in any manner so long as the solid particles of the dry powder composition can be inhaled by the subject so that the particles penetrate into the upper and lower airways and reach the lungs. In certain embodiments, the dry powder compositions of the present invention may be delivered to a subject in a sufficient amount by placing the dry powder in a suitable metered receptacle. Suitable quantitative receptacles may be stored in either a storage device (e.g., a device comprising one or more quantifications, itself as a metering device) or a factory metered metering device (e.g., a single unit or multiple units). Device for which each quantitative is contained). In one embodiment, a suitable storage device is dispersed in a gas stream to allow aerosolization of the dry powder composition to form an aerosol, followed by aerosols produced from a mouthpiece attached for subsequent inhalation by a subject in need of treatment. Appropriate quantitative receptacles may be provided in suitable inhalation devices for delivering these. Such quantitative receptacles include any container surrounding known compositions such as gelatin, hydroxypropylmethyl cellulose or plastic capsules having a removable portion or body capable of cutting or piercing to allow dispersion of the dry powder composition ( For example, via gas and centrifugal force dispersed directly into the vessel). Such containers are disclosed in US Pat. No. 4,227,522, filed October 14, 1980; US Patent No. 4,192,309, filed March 11, 1980; And US Pat. No. 4,105,027, filed August 8, 1978. Suitable containers include those used with the GlaxoSmithKline Ventolin Rotahaler brand powder inhaler or Fisons Spinhaler brand powder inhaler. Another suitable unit dose container that provides a good moisture barrier is formed from an aluminum foil plastic laminate. The powder composition is sealed to be sealable with a foil plastic laminate filled and covered with recesses by weight or volume in the formable foil. Such containers that can be used with powder inhalation devices are described in US Pat. No. 4,778,054 and used by GlaxoSmithKline's Diskhaler (US Pat. Nos. 4,627,432; 4,811,731; and 5,035,237). All of these references are incorporated herein by reference. In another embodiment, the dry powder composition of the present invention may be delivered to a subject via an tracheal tube.

In certain embodiments, the compositions of the present invention may be prepared by spray drying an aqueous composition of vancomycin or a salt thereof and a pharmaceutically acceptable carrier under conditions sufficient to provide a respirable dry powder composition. In another embodiment, the dry powder composition is substantially amorphous.

Generally speaking, spray drying is a process in which a homogeneous aqueous mixture of vancomycin or its salts and carrier is introduced through a nozzle (e.g. two fluid nozzles), rotating the disk or equivalent device in a hot gas stream and rotating the solution. By subdividing to form fine droplets which are then mixed with the hot gas stream. The aqueous mixture may be a solution, a suspension, a slurry, or the like, but must be uniform in order to ensure a uniform distribution of the composition in the mixture and, in turn, the powder composition. Preferably the aqueous mixture is a solution. In certain embodiments, the aqueous mixture may have at least 1 weight percent solids. In another embodiment, the aqueous mixture may have at least 2% by weight solids. In another embodiment, the aqueous mixture may have at least 4% by weight solids. The solvent, general water, evaporates rapidly from the droplets which produce fine powder having particles of 1 to 5 탆 in diameter.

In certain embodiments, the spray drying is performed under conditions to result in a substantially amorphous powder of uniform configuration with properties that allow for respirable particle size, low water content and pre-aerosolization. In certain embodiments, the particle size of the obtained powder is such that at least about 95% of the mass is particles having a diameter of about 10 μm or less.

For the spraying process, this rotation method can be used as rotation atomization, pressurization atomization and difluid atomization. Examples of suitable devices are described in US Pat. No. 6,372,258, the contents of which are incorporated herein by reference.

In addition, the dry powder composition may be prepared by other processes such as freeze drying and jet milling described in WO 91/16038, the contents of which are incorporated herein by reference.

Among these, the number of formulations and process steps may be useful to improve the shelf life and stability of the dry powder vancomycin composition of the present invention. In certain embodiments, the vancomycin used may be selected in high purity. In another embodiment, the step can be taken to prevent oxidation of vancomycin. For example, the process and packaging of the composition can be carried out under nitrogen. Likewise, in other embodiments, the process and packaging can be done to minimize exposure to direct sunlight. This step can reduce the light mediated degradation of vancomycin. In certain embodiments, steps may be taken to reduce the amount of moisture in the composition. This step may be useful to prevent hydrolysis, deamidation and oxidation of vancomycin. As mentioned above, carbohydrate bulking agents may be added to the composition in order to improve chemical stability.

In addition, while the dry powder vancomycin composition of the present invention has a number of advantageous properties in certain embodiments, one particularly advantageous property is that the composition has a desirable pharmacokinetic profile for the antimicrobial effect of bactericidal antibiotics over time such as vancomycin. And by providing a prolonged high concentration of vancomycin in the lung, it is possible to increase the time when the minimum inhibitory concentration of the subject pathogen is exceeded.

For example, in certain embodiments, upon administration of a dry powder vancomycin composition to a subject, the median time required for the plasma concentration of the subject to reach a maximum concentration (T _max ) of vancomycin is about 30 minutes or more, about 1 hour or more. Or about 6 hours or less. In some embodiments, T _max may be between about 1 hour and 3 hours. Similarly, the median of the time (t _1/2) required for the plasma concentration of the subjects to be reduced to half of the total maximum concentration of vancomycin in a particular embodiment may be more than 6 hours. In another embodiment, t _1/2 each may be about 8 hours.

In certain embodiments, upon administration of a dry powder vancomycin composition to a subject, the mean maximum plasma concentration (C _max ) of vancomycin may be in the range of about 50% to about 150% of about n × 620 ng / mL, wherein n is It shows the factor to multiply and the value of 0.01-10 may be sufficient, and when n = 1, a dose is 80 mg.

In one particular embodiment, wherein the vancomycin or a pharmaceutically acceptable salt thereof is present in an amount of about 80 mg and the dry powder composition is from about 50% to about 620 ng / mL as measured after a single lung administration about 150% within the range of the average maximum plasma concentration of vancomycin in, 6,250nghr / mL of about 50% to about 150% in the range of average AUC _{0 -24h} value, and the center in the range of about 0.75 sigan ~3 time T You can provide _max . As confirmed by those skilled in the art, for dry powder compositions containing a concentration of vancomycin lower than or higher than 80 mg, the range can be directly proportional to the dose. Thus, in certain embodiments the present invention provides a composition, wherein vancomycin or a pharmaceutically acceptable salt thereof is present in the dry powder composition in an amount of about n × 80 mg, and the dry powder composition is about n × 620 ng. mean maximum plasma concentration (C _max ) of vancomycin in the range of about 50% to about 150% of / mL; About n × 6,250nghr / mL of about 50% ~ in the range of about 150% average AUC _{0 -24h} value; And provides a central T _max value in the range of about 0.5 hour to about 6 hours, up to plasma concentrations of the vancomycin, the AUC _{0 -24h} value, and wherein the T _max value is measured after a single pulmonary administration of the dry powder composition ; N represents the factor to multiply here, and the value of 0.01-10 may be sufficient.

In certain embodiments, the dry powder vancomycin composition of the present invention can provide a delivery efficiency of at least 40%. In another embodiment, the dry powder vancomycin composition of the present invention may provide a delivery efficiency of at least 60%. Delivery efficiency (%) is the amount of powder with an aerodynamic diameter of less than 5 μm as a percentage of the initial amount of dry powder in the capsule. Delivery efficiency is the percentage of emissions (i.e., multiplied by the fine particle fraction (%) (i.e. the amount of dry powder or respirable amount having an aerodynamic median particle diameter (MMAD) of 5 µm or less as a percentage of emissions) (i.e. The amount of dry powder discharged to the inhaler as a percentage of the initial amount of dry powder in the capsule.

In certain embodiments, the dry powder vancomycin compositions of the present invention may provide at least 40% absolute bioavailability. Absolute bioavailability is calculated as AUC _{0 - inf} of vancomycin after administration of the vancomycin composition divided by AUC _{0 - inf} of vancomycin after intravenous administration and adjusted for dose.

To assist in the understanding of the present invention, the following examples of certain forms of certain embodiments are provided. The following examples should not limit or define the full scope of the invention.

Example 1

Dry powder vancomycin compositions were prepared with a Buchi lab scale spray dryer in two different batch sizes (1 g and 20 g) without loss of high yield (75-95%) and purity. These powders exhibited very high transfer efficiency and consistency over the lot.

The overall aerodynamic particle size distribution for the 20 g batch shows that most of the particle size distribution is less than 5 μm and a substantial portion (about 59%) is within the ultrafine particle fraction (3 μm) that is a precursor to deep lung delivery. 1 is shown.

Initial studies have shown that the emission content uniformity of vancomycin powders readily meets FDA's draft guidance on aerosol dose content uniformity. This has been one of the biggest challenges facing the pulmonary drug delivery industry over the last decade. The foregoing has explained that one or less of the ten actions may be other than ± 20% of the displayed amount without having an operation other than ± 25% of the displayed amount.

In certain embodiments, the delivery efficiency of the dry powder vancomycin composition could be improved through the addition of small amounts of leucine (FIG. 2). The addition of leucine to the vancomycin powder significantly reduced the water content and aerodynamic median particle diameter of the powder. It also resulted in the addition of leucine to the powder having a more physiologically acceptable pH value. The effect of leucine concentration on powder water content, particle size and reducing pH is shown in Table 1 below.

Protocol for preparing an example of dry powder vancomycin composition

Solution Preparation

Examples of batch prescriptions are included in Table 2. The target mass of leucine was weighed in a beaker. The required mass of deionized water was added and mixed using a magnetic stirrer. Vancomycin hydrochloride was then added and stirred for 1.0-1.5 hours until the solution became clear. The feedstock solution was prepared immediately before spray drying. The solution concentration was about 4% w / w total dissolved solids.

Manufacturing process

A benchtop spray drying system (Buchi Model 191) with a high efficiency cyclone was used to generate and collect the powder. For a 19 g batch size, the powder was more conveniently withdrawn from the process stream via a four cyclone powder collection event. The equilibrium drying conditions were set using deionized water. When stable operation was obtained, the nozzle input was switched to the feedstock solution. After 1/4 of the solution was used, the solution was fed to the dryer until the nozzle was switched back to water for about 5 minutes to make the system clear. The dryer was then paused to allow collector change-out and immediately lined out to water before restarting to resume the feed solution.

The filled collector was quickly capped to minimize exposure to room humidity. Thereafter, each collector was transferred to each glass sample vial in a low humidity dry glovebox, and a complete set of vials was packaged in a desiccant and heat-sealed aluminum pouch.

Figure 3 shows a scanning electron microscope (SEM) image of vancomycin leucine powder formulation from lot SA010.

Stability of Dry Powder Vancomycin Composition

The results of a six month stability study conducted on lot SA010 showed that the aerosol particle size distribution did not change over time (FIG. 4). Similarly, emissions were not altered and kept within the limits of the draft FDA guidance of ± 20% of the mean (Figure 5). The chemical stability of this initial study was predicted to be a composition requiring refrigeration.

Example 2

As mentioned previously, in any embodiment the dry powder vancomycin composition of the present invention could be prepared using a spray drying method. This method has proven to be very efficient and exhibit excellent batch consistency.

Table 3 below shows yield, primary particle size and moisture content data for batch sizes ranging from 25 g to 100 g prepared using the spray drying method. The smaller the mass diameters X ₁₀ , X ₅₀ and X ₉₀ of the respective particles for 10%, 50% and 90% of the distribution, the less ND = determined.

In addition, the overall aerodynamic particle size distribution for lot G-11-26-1 is included in FIG. 6, with the majority of the particle size distribution being less than 5 μm (85%) and a significant portion (about 70%) being deep. It was shown that it was the ultra-fine particle fraction (<3 micrometer) of prediction of lung delivery.

FIG. 7 shows that the emission content for lot G-11-26-1 meets FDA's draft draft specification for aerosol dose content uniformity (ie, one or less of ten actions may be in addition to ± 25% of the indicated amount). ± 20% of display amount without operation).

stability

A summary of the six month stability study for lot G-11-026-1 is included in Table 4.

Example 3

Carbohydrate bulking agents have been included in the vancomycin leucine preparations. The chemical stability of this formulation was studied at 50 ° C. for 4 weeks. 8 shows that addition of carbohydrate bulking agents (eg trehalose) can improve the chemical stability of the dry powder vancomycin composition of the present invention.

Two lots of vancomycin compositions containing 10% leucine were compared. One of the lots that did not contain process changes processed under nitrogen (lot SA010) or the like was protected from light and moisture (lot G-11-026-1). As shown in FIG. 9, these changes significantly delayed the degradation of vancomycin. Indeed, extrapolation of the data suggested the composition at stable room temperature for at least two years.

Example 4

The powder production process was successfully scaled up from lab scale to pilot scale equipment. The process was able to produce 1,000 g of powder per day without loss of purity in high yield (75%).

FIG. 10 shows SEM images of particles from 1,000 g lot (lot 19SA01.HQ00005) made in a Niro Mobile Minor “2000” spray dryer.

Table 5 below shows powder testing data from two scale-up lots. Table 6 shows the test results of the corresponding final product for lot 19SA01.HQ00002.

Example 5

After a single dose of the dry powder vancomycin composition (lot G-11-062-1) in 18 healthy volunteers, an absorption step was observed slowly after the removal step. The main pharmacokinetic parameters are shown in Table 7 after a single dose administration of the inhaled vancomycin composition and intravenous vancomycin. The corresponding mean plasma concentration curves over 24 hours are shown in FIG. 11. AUC _{0- t} refers to the lower region of the plasma concentration-time curve calculated by the linear trapezoidal formula at the last measurement time point (24 hours). AUC _{0 - inf} refers to the lower region of the infinite concentration-time curve. C _max refers to the maximum plasma concentration of vancomycin, T _max is to say the amount of time required to reach the maximum plasma concentration of vancomycin, t _1/2 is opposite to be the drug concentration was determined by 0.693 / K _el - end of the time curve The elimination half-life associated with the slope (Kel).

Median T _max values are more than 1 hour in the total dose, suggesting slow absorption of vancomycin from the lungs. There was a slight trend towards short T _max with increased dose (16 mg: 2 hours (range of 1-3 hours); 32 mg: 1.5 hours (range of 1-3 hours); 80 mg: 1.25 hours (range of 1-2 hours). The observed T _max values were significantly higher than expected based on previously issued results with TOBI Podhaler prescription information, 1 hour T _max at all test doses ranging from 28 mg to 112 mg, with inhaled antibiotic powder. C of vancomycin _max was a very close dose proportional between 16 mg and 80 mg (R> 0.95) Similarly, very good dose linearity was observed for AUC values between different inhaled vancomycin doses (R> 0.95). The absolute bioavailability of vancomycin afterwards was on average 49% ± 8% based on results from subjects in each group receiving both vancomycin composition and IV infusion (after intravenous administration and dosage Calculated by dividing the AUC _{0 -inf} of vancomycin after administration of the vancomycin composition by the AUC _{0 - inf} of vancomycin adjusted as described above.

Of T _1/2 other vancomycin dosage level is very consistent, intravenous injection, and after the 8 hours observation longer than T _1/2. The apparent extension of the T _1/2 was further proposed a long-term lung absorption sustained to supply the systemic vancomycin during the removal phase of the concentration curve.

The pharmacokinetic profile is highly desirable for the antimicrobial effects of bactericidal antibiotics, such as time dependent (regardless of concentration at concentrations greater than about 1 μg / mL), such as vancomycin, providing a prolonged high concentration of vancomycin in the lungs. The time beyond the minimum inhibitory concentration of the target pathogen was increased.

Thus, the present invention has been adopted to achieve the objects and advantages mentioned as well as those inherent therein. The specific embodiments described above are merely examples, and may be modified as the present invention, and may be equivalently obvious to those skilled in the art having the advantages of the present specification. In addition, details of the structure or design shown in this specification are not restrict | limited except what is described in the following claims. It is apparent that the specific embodiments described above can be modified and modified, and all such changes are considered within the scope and spirit of the invention. While the compositions and methods describe the various components or steps in terms of "comprising", "containing" or "comprising," the various components and steps may be "consisting essentially of" or "constituting". All values and ranges described above may be changed by any amount. Whenever a numerical range having a lower limit and an upper limit is described, any numerical value and any range included in the range are specifically described. In particular, all ranges of values described herein (in the form of "about a to about b" or equivalently "about a to b" or equivalently "about ab") are intended to encompass all numerical values and ranges falling within a broad range of values. I think to enumerate. In addition, the terms of the claims have the general meaning unless explicitly stated or explicitly defined by the patentee. In addition, the indefinite articles used in the claims mean "one" or "one" to mean one or more of the introducing elements. Conflicts in the use of a word or term, and one or more patents or other documents herein, are incorporated herein by reference and should adopt a definition consistent with this specification.

Claims (67)

A composition comprising vancomycin or a pharmaceutically acceptable salt thereof,
The composition is a dry powder. The method of claim 1,
Said pharmaceutically acceptable salt comprises vancomycin hydrochloride. The method of claim 1,
A composition comprising a hydrophobic amino acid further. The method of claim 3, wherein
Wherein said hydrophobic amino acid is selected from the group consisting of tryptophan, tyrosine, leucine, trileucine and phenylalanine. The method of claim 3, wherein
Wherein said hydrophobic amino acid is leucine. The method of claim 3, wherein
Wherein said hydrophobic amino acid is present in an amount of less than 50% by weight of the composition. The method of claim 3, wherein
Wherein said hydrophobic amino acid is present in an amount of less than 30% by weight of the composition. The method of claim 3, wherein
Wherein said hydrophobic amino acid is present in an amount from about 10% to about 20% by weight of the composition. The method of claim 1,
A composition comprising a carbohydrate bulking agent. The method of claim 9,
The carbohydrate bulking agent is selected from the group consisting of lactose, mannitol, trehalose, raffinose and maltodextrin. The method of claim 9,
Wherein said carbohydrate bulking agent is trehalose. The method of claim 1,
Wherein said dry powder comprises particles having an aerodynamic median particle diameter of about 10 μm or less. The method of claim 1,
Wherein said dry powder comprises particles having an aerodynamic median particle diameter of at least about 10 μm. 13. The method of claim 12,
Wherein at least 95% of the particles have an aerodynamic median particle diameter of less than about 10 μm. The method of claim 1,
Wherein said dry powder comprises particles having an aerodynamic median particle diameter of at least about 1 μm and at most 5 μm. The method of claim 1,
Wherein said dry powder is wrapped in a capsule. 17. The method of claim 16,
The capsule is characterized in that it comprises hydropropylmethylcellulose. The method of claim 1,
Wherein said dry powder has a water content of about 10% by weight or less. The method of claim 1,
Wherein said dry powder has a water content of about 7% by weight or less. The method of claim 1,
Wherein said dry powder is substantially amorphous. The method of claim 1,
The pH of the reducing powder is greater than 3.0, greater than 3.5 or greater than 4.0. The method of claim 1,
Said dry powder having a tap density of greater than 0.4 g / cm 3. The method of claim 1,
The dry powder has a tap density greater than about 0.4 g / cm 3;
The vancomycin or a pharmaceutically acceptable salt thereof is present in an amount of about 90% by weight of the composition;
Further comprising leucine in an amount of about 10% by weight of the composition. 24. The method of claim 23,
Providing a median T _max value of 1 hour to 3 hours. 24. The method of claim 23,
Providing a median T _max value of at least 1 hour. 24. The method of claim 23,
Providing a median T _max value of at least 30 minutes. 24. The method of claim 23,
Providing a median T _max value of 6 hours or less. 24. The method of claim 23,
Providing an average maximum plasma concentration (C _max ) of vancoamicin in the range of about 50% to about 150% of about n × 620 ng / mL, where n is a value of 0.01 to 10 and the amount of vancomycin is 80 mg N is 1, wherein the composition. 24. The method of claim 23,
Composition characterized by providing a central t _1/2 values of greater than 6 hours. 24. The method of claim 23,
Composition characterized by providing a central t _1/2 value of about 8 hours. 24. The method of claim 23,
The dry powder composition is characterized in that it provides a delivery efficiency of at least 40%. 23. The method of claim 22,
The dry powder composition is characterized in that it provides a transfer efficiency of at least 60%. 24. The method of claim 23,
The dry powder composition is characterized by providing at least 40% absolute bioavailability. 24. The method of claim 23,
The vancomycin or a pharmaceutically acceptable salt thereof is present in the dry powder composition in an amount of about 80 mg,
The dry powder composition may have an average maximum plasma concentration (C _max ) of vancomycin in the range of about 50% to about 150% of about 620 ng / mL;
From about 50% to about 150% in the range of average AUC _{0 -24h} value of about 6,250nghr / mL; And
Providing a median T _max value in the range of about 0.75 hours to about 3 hours,
Maximum plasma concentrations of vancomycin, AUC _{0 -24h} value and T _max values are compositions characterized in that the measurement after a single pulmonary administration of a dry powder composition. 24. The method of claim 23,
The vancomycin or a pharmaceutically acceptable salt thereof is present in the dry powder composition in an amount of about n × 80 mg,
The dry powder composition may have an average maximum plasma concentration (C _max ) of vancomycin in the range of about 50% to about 150% of about n × 620 ng / mL;
About n × 6,250nghr / mL of about 50% ~ in the range of about 150% average AUC _{0 -24h} value; And
Providing a median T _max value in the range of about 0.5 hours to about 6 hours,
Maximum plasma concentrations of vancomycin, AUC _{0 -24h} value and T _max value is measured after a single pulmonary administration of a dry powder composition, wherein n is a composition, wherein a value of 0.01. A method comprising administering to a subject a dry powder composition comprising vancomycin or a pharmaceutically acceptable salt thereof via pulmonary administration. 33. The method of claim 32,
The subject is a mammal having a lung or airway infection. 34. The method of claim 33,
Said pulmonary or airway infection is caused by a bacterium or other pathogen sensitive to vancomycin or a pharmaceutically acceptable salt thereof. 34. The method of claim 33,
Said lung or airway infection is caused by Gram-positive bacteria. 36. The method of claim 35,
The Gram-positive bacteria is a methicillin resistant Staphylococcus aureus. 34. The method of claim 33,
The subject has cystic fibrosis, bronchiectasis or pneumonia. 34. The method of claim 33,
A dry powder inhaler is used to administer the dry powder composition. The method of claim 38,
And said dry powder inhaler is a capsule-based dry powder inhaler. 40. The method of claim 39,
And said capsule based dry powder inhaler is a monodose inhaler. 33. The method of claim 32,
Wherein said composition provides a median T _max value between 1 hour and 3 hours. 33. The method of claim 32,
Wherein said composition provides a median T _max value of at least 30 minutes. 33. The method of claim 32,
Wherein the composition provides a median T _max value of 6 hours or less. 33. The method of claim 32,
The composition provides an average maximum plasma concentration (C _max ) of vancomycin in the range of about 50% to about 150% of about n × 620 ng / mL, wherein n is a value of 0.01 to 10 and the amount of vancomycin is 80 mg. And n is 1 when. 33. The method of claim 32,
The composition is characterized in that to provide a central t _1/2 values of greater than 6 hours. 33. The method of claim 32,
The composition is characterized in that to provide a central t _1/2 value of about 8 hours. 33. The method of claim 32,
Said dry powder composition provides a delivery efficiency of at least 40%. 33. The method of claim 32,
Wherein said dry powder composition provides a delivery efficiency of at least 60%. 33. The method of claim 32,
The dry powder composition provides at least 40% absolute bioavailability. 24. The method of claim 23,
Vancomycin or a pharmaceutically acceptable salt thereof is present in the dry powder composition in an amount of about n × 80 mg,
The dry powder composition may have an average maximum plasma concentration (C _max ) of vancomycin in the range of about 50% to about 150% of about n × 620 ng / mL;
About n × 6,250nghr / mL of about 50% ~ in the range of about 150% average AUC _{0 -24h} value; And
Providing a median T _max value in the range of about 0.5 hours to about 6 hours,
Maximum plasma concentrations of vancomycin, AUC _{0 -24h} value and T _max value is measured after a single pulmonary administration of a dry powder composition,
N is a value of 0.01 to 10, characterized in that the composition. Spray drying the aqueous composition comprising hydrophobic amino acids and vancomycin or a pharmaceutically acceptable salt thereof to form a dry powder composition. 56. The method of claim 55,
The dry powder composition is substantially amorphous. 56. The method of claim 55,
The aqueous composition comprising vancomycin or a pharmaceutically acceptable salt thereof has a solids content of at least 1% by weight. 56. The method of claim 55,
Wherein said aqueous composition comprising vancomycin or a pharmaceutically acceptable salt thereof has a solids content of at least 2% by weight. 56. The method of claim 55,
An aqueous composition comprising vancomycin or a pharmaceutically acceptable salt thereof has a solids content of at least 4% by weight. A composition comprising vancomycin or a pharmaceutically acceptable salt thereof,
The composition is a dry powder. 64. The method of claim 60,
Providing a median T _max value of at least 30 minutes. 64. The method of claim 60,
Providing a median T _max value of 6 hours or less. 64. The method of claim 60,
Providing an average maximum plasma concentration (C _max ) of vancomycin within the range of about 50% to about 150% of about n x 620 ng / mL, where n is a value of 0.01 to 10 and n when the amount of vancomycin is 80 mg Silver is a composition, characterized in that 1. 64. The method of claim 60,
Composition characterized by providing a central t _1/2 values of greater than 6 hours. 64. The method of claim 60,
The dry powder composition is characterized in that it provides a delivery efficiency of at least 40%. 64. The method of claim 60,
The dry powder composition is characterized by providing at least 40% absolute bioavailability. 64. The method of claim 60,
The vancomycin or a pharmaceutically acceptable salt thereof is present in the dry powder composition in an amount of about n × 80 mg,
The dry powder composition may have an average maximum plasma concentration (C _max ) of vancomycin in the range of about 50% to about 150% of about n × 620 ng / mL;
About n × 6,250nghr / mL of about 50% ~ in the range of about 150% average AUC _{0 -24h} value; And
Providing a median T _max value in the range of about 0.5 hours to about 6 hours,
Maximum plasma concentrations of vancomycin, AUC _{0 -24h} value and T _max value is measured after a single pulmonary administration of a dry powder composition,
N is a value of 0.01 to 10, composition comprising vancomycin or a pharmaceutically acceptable salt thereof.

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