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    • 专利摘要:
    There is provided a composition comprising an aminoalkylglucosaminide phosphate compound or a pharmaceutically acceptable salt thereof and a buffer for use as an immunomodulator.
    公开号:BE1021939B1
    申请号:E2014/0160
    申请日:2014-03-13
    公开日:2016-01-27
    发明作者:David A. Johnson；David Burkhart；Nupur Dutta
    申请人:Glaxosmithkline Biologicals S.A.；
    IPC主号:
    专利说明:

    COMPOSITION FOR AMINOALKYLGLUCOSAMINIDE TAMPONED PHOSPHATE COMPOUNDS AND USE THEREOF
    Field of the invention
    The present invention relates to a composition comprising aminoalkylglucosaminide phosphate (AGP) compounds and the use of the composition in or as a vaccine adjuvant or in prophylactic or therapeutic treatments. Methods of using the compositions are also disclosed. Statements regarding research conducted with federal support
    Aspects of the present invention have been made with the support of the United States Government in accordance with NIH Contract No. HHSN272200900008C, the United States Government having certain rights in the invention.
    Context of the invention
    Aminoalkylglucosaminide phosphates (AGP) are synthesis ligands of the Toll 4 receptor (TLR4). AGPs and their immunomodulatory effects via TLR4 are disclosed in patent publications such as WO 2006/016997, WO 2001/090129 and / or U.S. Patent No. 6,113,918 and have been reported in the literature. Additional AGP derivatives are disclosed in U.S. No. 7,129,219, the US Pat. No. 6,525,028 and U.S. Patent No. 6,911,434. Some PFAs act as TLR4 agonists, while others are known as TLR4 antagonists. AGPs are known to be useful as vaccine adjuvants and immunomodulators to stimulate cytokine production, activate macrophages, promote an innate immune response, and increase antibody production in immunized animals. Previously, AGPs as adjuvants and / or immunomodulators have mainly been used in the form of an oil-in-water emulsion, typically using sterilized water and glycerol (approximately 2%). There is a continuing need to identify buffers that can be used with these AGPs in pharmaceutical and / or adjuvant compositions. Summary of the invention
    Accordingly, the present invention provides a pharmaceutical composition comprising one or more AGPs and a buffer. The pharmaceutical composition disclosed in the present invention can result in one or more of the following benefits: maximum or increased or improved stability of AGP in a buffered solution and / or maximum or increased or enhanced activity of AGP in a solution buffered compared to other aqueous AGP formulations.
    There is also provided a buffered AGP composition having improved stability and / or activity at about pH 7 or a physiologically normal pH, or a pharmaceutically acceptable pH.
    There is also provided a method of treating a subject (or a patient such as a human or other mammal) with the composition of the invention.
    In accordance with the invention, there is provided a composition comprising (i) an aminoalkylglucosaminide phosphate or a pharmaceutically acceptable salt thereof, and (ii) a buffer. The buffered solution and the AGP compound are combined to form a composition having utility as an immunomodulator.
    There is further provided a method of modulating the immune response of a subject, preferably a human, comprising administering to said subject an effective amount of the pharmaceutical composition.
    There is also provided a method for substantially improving or preventing an infectious disease, an autoimmune disease, a neurological disease, or an allergic or inflammatory condition in a subject, preferably a human, comprising administering to said subject an effective amount of the pharmaceutical composition.
    Brief description of the drawings
    Figure 1 shows the structure of CRX-601 and the degradation product of CRX-601 from the examples.
    Figure 2 shows the accelerated rate of degradation for buffers formulated with CRX-601 at a neutral or near-physiological pH.
    Figure 3 shows the accelerated rate of degradation for three buffers formulated with CRX-601 at near optimal pH for each buffer.
    Figure 4 shows the structure of CRX-527 and CRX-527 degradation product from the examples.
    Figure 5 shows the accelerated degradation rate using phosphate and HEPES buffers in CRX-527 and CRX-601, respectively.
    Figure 6 shows the long-term stability of CRX-601 formulated in three buffers.
    Figures 7 to 9 show the relative activity among the three buffers (HEPES, acetate, citrate) formulated with CRX-601 at near optimal pH for each buffer.
    Detailed description of the invention
    Aminoalkyl glucosaminide phosphate compounds
    AGPs are modulators of the Toll 4 receptor (TLR4). The Toll 4 receptor recognizes bacterial LPS (lipopolysaccharide) and, when activated, initiates an innate immune response. AGPs are a monosaccharide mimetic substance of the bacterial LPS lipid A protein and were developed with ether and ester linkages on the "acyl chains" of the compound. Processes for the preparation of these compounds are known and disclosed, for example, in WO 2006/016997, US Pat. Nos. 7,288,640 and 6,113,918, and WO 01/90129, which are incorporated herein. in reference in their entirety. Other AGPs and related processes are disclosed in US Pat. No. 7,129,219, US Pat. No. 6,525,028 and US Patent No. 6,911,434. AGPs with ether linkages on acyl chains employed in the US Pat. composition of the invention are known and disclosed in WO 2006/016997 which is incorporated herein by reference in its entirety. Of particular interest are the aminoalkylglucosaminide phosphate compounds specified and described according to formula (III) in paragraphs [0019] to [0021] in WO 2006/016997.
    Aminoalkylglucosaminide phosphate compounds employed in the present invention have the structure specified in formula (I) as follows
    (Formula 1) wherein m is 0 to 6 n is 0 to 4; X is 0 or S, preferably O; Y is O or NH; Z is O or H; each R1, R2, R3 is independently selected from the group consisting of C1-20 acyl and C1-20 alkyl; R4 is H or Me; R5 is independently selected from the group consisting of -H, -OH, -alkoxy (C1-C4), -PO3R8R9, -OPO3R8R9, -SO3R8, -OSO3R8, -NR8R9, -SRs, -CN, -NO2, -CHO , -CO2R8 and -CONR8R9, wherein Rs and R9 are each independently selected from H and (C1-C4) alkyl; and each R6 and R7 is independently H or PO3H2.
    In formula 1, the configuration of the 3 'stereogenic centers to which normal fatty acyl residues (i.e., acyloxy or secondary alkoxy residues, eg, RiO, R 2 O and R 3 O) are attached is R or S, preferably R (as designated by the Cahn-Ingold-Prelog priority rules). The configuration of the aglycone stereogenic centers to which R4 and R5 are attached may be R or S. All stereoisomers, both enantiomers and diastereoisomers, and mixtures thereof are considered within the scope of the present invention.
    The number of carbon atoms between the X heteroatom and the aglycone nitrogen atom is determined by the variable "n", which can be an integer of 0 to 4, preferably an integer of 0 to 2.
    The chain length of normal fatty acids R 1, R 2 and R 3 may be from about 6 to about 16 carbons, preferably from about 9 to about 14 carbons. The chain lengths may be the same or different. Some preferred embodiments include chain lengths where R 1, R 2 and R 3 are 6 or 10 or 12 or 14.
    Formula 1 includes L / D-seryl, -treonyl, -cysteinyl ether and ester lipid AGP, both agonists and antagonists and their homologs (n = 1 to 4), as well as various carboxylic acid bioisosteres. (ie, R5 is an acid group capable of salt formation, the phosphate may be in position 4 or 6 of the glucosamine unit, but is preferably in the 4 position).
    In a preferred embodiment of the invention employing an AGP compound of formula 1, n is 0, R5 is CO2H, R6 is PO3H2 and R7 is H. This preferred AGP compound is specified as the structure of formula la as follows:
    (Formula la) wherein X is O or S; Y is O or NH; Z is O or H; each of R 1, R 2, R 3 is independently selected from the group consisting of C 1 -C 20 acyl and C 1 -C 20 alkyl; and R4 is H or methyl.
    In formula la, the configuration of the 3 'stereogenic centers to which normal fatty acyl residues (i.e., acyloxy or secondary alkoxy residues, eg, RiO, R 2 O and R 3 O) are attached is R or S, preferably R (as designated by the Cahn-Ingold-Prelog priority rules). The configuration of the aglycone stereogenic centers to which R4 and CO2H are attached may be R or S. All stereoisomers, both enantiomers and diastereoisomers, and mixtures thereof are considered within the scope of the present invention.
    Formula la includes L / D-seryl, -treonyl, -cysteinyl ether lipid AGP, and both agonists and antagonists. In both Formula 1 and Formula Ia, Z is attached to 0 by a double bond or two hydrogen atoms each attached by a single bond. Namely, the compound forms an ester bond when Z = Y = O, an amide bond when Z = O and Y = NH; and an ether linkage when Z = H / H and Y = 0.
    Especially preferred compounds of Formula 1 are designated CRX-601 and CRX-527. Their structures are specified as follows: (CRX-601) (CRX-527).
    In addition, another preferred embodiment employs CRX-547 having the structure shown. CRX-547
    Still other embodiments include AGPs such as CRX-602 and CRX-526 imparting increased stability to AGPs having shorter secondary or secondary alkyl chains.
    CRX-602
    CRX-526
    tampons
    In one embodiment of the present invention, the composition comprising an AGP is buffered using a zwitterionic buffer. Suitably, the zwitterionic buffer is an aminoalkanesulfonic acid or a suitable salt. Examples of aminoalkanesulfonic buffers include, but are not limited to, HEPES, HEPPS / EPPS, MOPS, MOBS, and PIPES. Preferably, the buffer is a pharmaceutically acceptable buffer, suitable for use in humans, such as for use in a commercial injection product. Most preferably, the buffer is HEPES.
    In suitable embodiments of the present invention, the AGPs are buffered with a buffer selected from the group consisting of: i) HEPES having a pH of about 7, ii) citrate (by example, sodium citrate) having a pH of about 5, and iii) acetate (eg, ammonium acetate) having a pH of about 5.
    In a preferred embodiment of the present invention, the AGP CRX-601, CRX-527 and CRX-547 are buffered using HEPES having a pH of about 7. The buffers can be used with an appropriate amount of saline or other excipient to achieve a desired isotonicity. In a preferred embodiment, a 0.9% saline solution is used.
    HEPES: CAS Registry Number 7365-45-9 C8H18N2O4S 1-Piperazine-Ethanesulfonic Acid, 4- (2-hydroxyethyl) -HEPES is a zwitterionic buffer designed to buffer in the physiological pH range of about 6 to about 8 (by for example, 6.15-8.35) and more specifically a more useful range of about 6.8 to about 8.2 and, as in the present invention, between about 7 and about 8 or between 7 and 8, and preferably between about 7 and less than 8. HEPES is typically a white crystalline powder having the molecular formula: C8H18N2O4S of the following structure:
    HEPES is well known and commercially available (see, for example, Good et al., Biochemistry 1966.)
    The buffers of citrate (e.g., sodium citrate) and acetate when used as a buffer in the composition of the invention both have a pH of about 5. In one embodiment, the concentration of buffer is about 10 mM, but in some embodiments, an increased buffer concentration may be required. The citrate and acetate buffers may be employed in the compositions of the invention with AGPs that require an acidic or slightly acidic pH. Acetate buffer works well in environments or compositions in which citrate buffers may not be used, such as in the presence of alum. Citrate and acetate buffers are commercially available. Melanqe / nanoparticle solution
    Once formed, the composition of the invention may be a dispersion or a solution. Adequately, the composition is a solution of nanoparticles with particle sizes <200 nm. In a suitable embodiment, the composition is a solution of nanoparticles with particle sizes <200 nm displaying micellar or liposomal characteristics. In one embodiment, the solution or dispersion is suitable for pharmaceutical use as an immunomodulator. Particle size in solution is determined in part by the time during which the composition in the solution or dispersion is sonicated.
    Process of treatment and administration
    The present invention provides a method for enhancing an immune response of a subject comprising administering to an effective amount of the pharmaceutical composition.
    The compositions of the present invention can be used to protect or treat a mammal by means of administration via the systemic or mucosal route. These administrations may include intramuscular, intraperitoneal, intradermal or subcutaneous injection; or via mucosal administration to the oral / alimentary, respiratory, genitourinary tract. The composition of the invention may be administered as a single dose or as multiple doses. In addition, the compositions of the invention may be administered by different routes for primary vaccination and boosting, for example, IM primary doses and IN booster doses.
    The composition of the present invention may be administered alone or with suitable pharmaceutical vectors, and may be used in manufacture in solid or liquid form, such as tablets, capsules, powders, solutions, suspensions or emulsions. The composition may be formulated into a "vaccine" and administered as a free solution, or formulated with an adjuvant, or an excipient. The vaccine preparation is generally described in Vaccine Design ("The Subunit and Adjuvant Approach" (Powell M.F. & Newman M.J.) (1995) Plenum Press New York). The encapsulation within liposomes is described by Fullerton, US Pat. No. 4,235,877. Vaccines can be stored in solution or lyophilized.
    Effective doses of treatments that incorporate the compositions of the present invention for the treatment of a subject will vary depending on many different factors, including the means of administration, the target site, the physiological condition of the patient, other medications administered, the physical condition of the patient in relation to other medical complications, and whether the treatment is prophylactic or therapeutic. Treatment dosages must be adapted to optimize safety and efficacy. The doses described herein typically range from about 0.1 μg to 50 mg per administration which, depending on the application, may be given daily, weekly or monthly or any other time between them. More generally, mucosal or local doses range from about 10 μg to 10 mg per administration, and optionally from about 100 μg to 1 mg, with 2 to 4 administrations being a few days or weeks apart. More typically, immunostimulant doses range from 1 μg to 10 mg per administration, most typically from 10 μg to 1 mg, with daily or weekly administrations. Dosages according to the invention described here for parenteral administration, for example to induce an innate immune response, or in vehicles of specialized administrations typically vary from about 0.1 μg to 10 mg per administration which according to the application , may be given daily, weekly or monthly or any other period between them. More typically, parenteral doses for these purposes range from about 10 μg to 5 mg per administration, and most typically from about 100 μg to 1 mg, with 2 to 4 administrations being several days or weeks apart. In some embodiments, however, parenteral doses for these purposes may be used in a range of 5 to 10,000 times higher than the typical doses described above.
    There is also provided a method for substantially improving or preventing an infectious disease, an autoimmune disease, a neurological disorder or an allergic or inflammatory condition in a subject comprising administering to an effective amount of the pharmaceutical composition. In some cases, an exogenous antigen may be administered to the subject together with the pharmaceutical composition. In compositions for triggering or enhancing an immune response, the compositions of the subject invention are administered to a warm-blooded animal, such as a human or other mammal, with an antigen such as a protein antigen or polypeptide or a polynucleotide that expresses a protein or polypeptide antigen. The amount of antigen administered to elicit a desired response can be readily determined by those skilled in the art and will vary with the type of antigen administered, the route of administration, and the immunization schedule. The compositions of the present invention may also be administered without exogenous antigen, to elicit immediate protection via a nonspecific resistance effect. Compositions having the ability to stimulate nonspecific resistance and / or elicit an adjuvant effect can be used in rapid-acting vaccine formulations.
    Terms / definitions
    As mentioned herein, the term "aliphatic" in itself or as part of another substituent means, unless otherwise indicated, a straight or branched chain, or a cyclic hydrocarbon radical, or a combination thereof, which may be fully saturated, mono- or poly-unsaturated and may include di- and multi-valent radicals, having the designated carbon number (i.e., Ci to Cio or Ci to 10 means one to ten carbons). Examples of saturated hydrocarbon radicals include such groups as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl, homologues and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated aliphatic group is a group having one or more double bonds or triple bonds. Examples of unsaturated aliphatic groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2,4-pentadienyl, 3- (1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and homologs and higher isomers. Typically, an aliphatic group will have from 1 to 24 carbon atoms. A "lower aliphatic" group is a shorter chain aliphatic group, generally having eight carbon atoms or less.
    The term "acyl" refers to a group derived from an organic acid by removal of the hydroxy group. Examples of acyl groups include acetyl, propionyl, dodecanoyl, tetradecanoyl, isobutyryl, and the like. Accordingly, the term "acyl" as used herein is meant to include a group otherwise defined as -C (O) -aliphatic, where the aliphatic group is preferably a saturated aliphatic group. The term "pharmaceutically acceptable salts" is intended to include salts of the active compounds that are prepared with relatively nontoxic acids or bases according to particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acid functionalities, the base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either undiluted or in a solvent. inert suitable. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts, or a similar salt. In one embodiment, the salt is an ethanolamine salt, such as monoethanolamine (MEA) or triethanolamine (TEA). When compounds used in the composition of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either diluted, either in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogenocarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogenosulfuric, hydroiodophoric or phosphorous acids and the like, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and Similar. Also included are amino acid salts such as arginate and the like, and salts of organic acids such as glucuronic or galacturonic acids and the like (see, for example, Berge, SM, et al., "Pharmaceutical Salts" Journal of Pharmaceutical Science, 66, 1-19, 1977). Certain specific compounds used in the composition of the present invention contain both basic and acid functionalities which make it possible to convert the compounds into addition salts of either bases or acids.
    As used herein "pharmaceutically acceptable carrier" means a medium that does not interfere with the immunomodulatory activity of the active ingredient and is not toxic to the patient to whom it is administered.
    The pharmaceutically acceptable vectors include oil-in-water or water-in-oil emulsions, multiple emulsions (for example, water in oil in water), microemulsions, liposomes, microbeads, microspheres , microsomes and the like. For example, the vector may be a microsphere or preferably a nanosphere, or may be a microparticle or preferably a nanoparticle, having a compound of the present invention in the matrix of the sphere or particle or adsorbed on the surface of the sphere. or particle. The vector may also be an aqueous solution or a micellar dispersion containing triethylamine, triethanolamine or another agent which renders the formulation alkaline in nature, or a suspension containing aluminum hydroxide, calcium hydroxide , calcium phosphate or tyrosine adsorbate. Vectors can also include all solvents, dispersion media, vehicles, coatings, diluents, antibacterial and antifungal agents, isotonic and absorption delay agents, buffers, vector solutions, suspensions , colloids, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except to the extent that any conventional medium or agent is incompatible with the active ingredient, its use in therapeutic compositions is contemplated.
    In some embodiments, liposomes, nanocapsules, microparticles, lipid particles, vesicles and the like are used to introduce the compositions of the present invention into suitable host cells / organisms. In particular, the compositions of the present invention may be formulated for encapsulated delivery into a lipid particle, liposome, vesicle, nanosphere or nanoparticle or the like.
    The formation and use of liposome and liposome preparations as potential drug vectors are generally known to those skilled in the art (see, for example, Lasic, Trends Biotechnol July 1998; 16 (7): 307-21). Takakura, Nippon Rinsho March 1998, 56 (3): 691-695, Chandran et al., Indian J Exp Biol, August 1997, 35 (8): 801-809, Margalit, Crit Rev Ther Drug Carrier System, 1995; 12 (2 to 3): 233 to 261, US Patent 5,567,434, US Patent 5,552,157, US Patent 5,565,213, US Patent 5,738,868 and US Patent 5,795,587).
    Liposomes have been successfully used with a number of cell types that are normally difficult to transfect by other procedures, including T cell suspensions, primary hepatocyte cultures, and PC12 cells (Renneisen et al. Biol Chem, 25 Sept. 1990, 265 (27): 16337-16342, Muller et al., DNA Cell Biol, April 1990, 9 (3): 221-229). In addition, liposomes are free of DNA length constraints that are typical of virus-based delivery systems. Liposomes have been used effectively to introduce genes, various drugs, radiotherapeutic agents, enzymes, viruses, transcription factors, allosteric effectors and the like into a variety of cultured cell lines and animals. In addition, the use of liposomes does not appear to be associated with autoimmune responses or unacceptable toxicity after systemic intake.
    In some embodiments, liposomes are formed from phospholipids that are dispersed in an aqueous medium and spontaneously form multilamellar concentric bilayer vesicles (also referred to as multilamellar vesicles (MLVs)).
    Alternatively, in other embodiments, the invention provides pharmaceutically acceptable nanocapsule formulations of the compositions of the present invention. Nanocapsules can typically entrap compounds in a stable and reproducible manner (see, for example, Quintanar-Guerrero et al., Drug Dev Ind Pharm, Dec. 1998; 24 (12): 1113-1128). To avoid side effects due to intracellular polymeric overload, such ultrafine particles (about 0.1 μm in size) can be designed using in vivo degradable polymers. Such particles may be prepared as described, for example, by Couvreur et al., Crit Rev Ther Drug Carrier Syst. 1988; 5 (1): 1 to 20; Mühlen et al., Eur J Pharm Biopharm. March 1998; 45 (2): 149 to 155; Zambaux et al. J Controlled Release. January 2, 1998; 50 (1-3): 31-40; and U.S. Patent 5,145,684.
    The term "immunomodulator" as used herein means a substance that modifies the immune response in a subject, such as by increasing, reducing, changing, or otherwise affecting the subject's immune response.
    Routes of administration
    Compositions of the subject invention that can be administered parenterally, i.e., intraperitoneally, subcutaneously, or intramuscularly, include the following preferred vectors. Examples of suitable vectors for subcutaneous use include, but are not limited to, phosphate buffered saline (PBS) solution, or 0.9% sodium chloride in USP water for injection. , and 0.01 to 0.1% triethanolamine in USP water for injection. Suitable vectors for intramuscular injection include, but are not limited to, 10% ethanol USP, 40% propylene glycol, and the balance being an acceptable isotonic solution such as 5% dextrose, or sodium chloride. 0.9% in USP water for injection. Examples of suitable vectors for intravenous use include, but are not limited to, 10% USP ethanol, 40% propylene glycol and the remainder USP water for injection, or 0% sodium chloride. , 9% in USP water for injection. In one embodiment, the vector includes 10% ethanol USP and USP water for injection; for yet another embodiment, the acceptable vector is 0.01 to 0.1% triethanolamine in USP water for injection. Pharmaceutically acceptable parenteral solvents are such as to provide a solution or dispersion which can be filtered on a 5 micron filter, or preferably a 0.2 micron filter, without removing the active ingredient.
    Another route of administration of the compositions of the present invention is mucosal administration, particularly intranasal administration or in some cases administration by inhalation (pulmonary administration). The pulmonary delivery of a drug can be accomplished by several different approaches, including liquid nebulizers, aerosol MDIs, and dry powder dispersing devices. Compositions for use in such administrations are typically dry powders or aerosols.
    The dry powders contain, in addition to the composition of the invention, a vector, an absorption enhancer and optionally other ingredients. The vector is, for example, a mono-, di- or polysaccharide, sugar alcohol or other polyol.
    Suitable vectors include lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol; and starch. Lactose is particularly preferred, especially in the form of its monohydrate. Absorption enhancers such as polypeptides, surfactants, alkyl glycosides, fatty acid amine salts or phospholipids are also included. The ingredients of the formulation should typically be in finely divided form, i.e. their median volume diameter should generally be from about 30 to about 200 microns, as measured by a laser diffraction instrument or Coulter counter. The desired particle size can be produced using methods known in the art, for example milling, micronization or direct precipitation.
    The intranasal route of administration provides many advantages over other forms of administration for the compounds of the present invention. For example, an advantage of intranasal administration is convenience. An injectable system requires sterilization of the hypodermic syringe and, in the institutional setting, leads to concerns about medical personnel about the risk of contracting the disease by being accidentally bitten by a contaminated needle. Strict requirements for the safe disposal of the used needle and syringe must also be imposed in the institutional establishment. In contrast, intranasal administration requires little time from the patient and the attendant medical staff, and is much less burdensome than injectables for the institution.
    A second important benefit of intranasal administration is the patient's acceptance of the drug delivery system. Intranasal administration is perceived as non-invasive, does not involve pain, has no significant side effects, and provides relief from rapid relief in the symptomatic patient. This is particularly advantageous when the patient is a child. Another important consideration is that the patient may be able to self-administer the prescribed dosage (s) of nasal spray.
    For intranasal administration, the compositions of the present invention may be formulated as liquids or as solids. Such formulations may contain one or more additional adjuvants, agents to enhance the absorption of the active ingredients by permeation through the nasal membrane, and (for liquid compositions) an additional aqueous buffer or other pharmaceutically acceptable carriers. The composition may optionally further include one or more polyhydric alcohols and one or more preservatives. Suitable preservatives include, for example, gentamicin, bacitracin (0.005%) or cresol. The compositions may be administered to the nasal cavity in the form of a spray using an atomizer, nebulizer, spray, drip or other device that provides contact of the solution with the nasal mucous membrane. The device can be a simple device such as a simple nasal spray that can be used by the patient, or can be a more elaborate instrument for more accurate distribution of the compositions, which can be used in a doctor's office or in a doctor's office. a medical facility.
    The nasal powder compositions can be prepared by freeze-drying the composition of the present invention or by adsorbing the composition onto suitable nasal powders (eg, lactose) and milling if necessary to the desired particle size. Alternatively, a solution of the cyclodextrin composition and excipients can be prepared, followed by precipitation, filtration and spraying. It is also possible to remove the solvent by freeze drying, followed by spraying the powder into the desired particle size using conventional techniques known in the pharmaceutical literature. The final step is the size classification, for example by sieving, to obtain particles which are preferably between 30 and 200 microns in diameter. The powders may be administered by means of a nasal insufflator, or they may be placed in a capsule disposed in an inhalation or insufflation device. A needle penetrates the capsule to make pores at the top and bottom of the capsule and air is sent to blow the powder particles outward. The powder formulation may also be administered in an inert gas jet spray or suspended in liquid organic fluids.
    The compositions of the subject invention are administered to an individual in an effective amount or a pharmaceutically effective amount to effect or enhance the immune response of the individual. As used herein, "effective amount" or "pharmaceutically effective amount" is the amount that has a response above and above that of the vehicle or negative controls. An "effective amount of adjuvant" is the amount of the compound in question which, when administered together with an antigen, has a response above and above that produced by the antigen alone. The precise dosage of the composition of the subject invention to be administered to a patient will depend on the particular compound used, the route of administration, the pharmaceutical composition and the patient.
    MM6 activity assay
    The MonoMaco activity assay is used to quantitatively measure the relative activity between two different batches of a biological product. A range of doses of test and reference compounds are co-located with MonoMac6 cells, a human monocyte cell line, and cell supernatants are harvested for further testing. A chemokine marker (MIP-1β), measured from cell supernatants by nested ELISA, serves as an output. An activity analysis model has been constructed in which the raw optical densities are joined, and the analysis is automatically performed. Based on the slope and parallelism between the test and reference response curves, setpoint criteria in the defined metrics determine whether a successful activity determination may or may not occur. If these criteria are met successfully, the analysis will give a relative activity value of the test product relative to the reference product.
    The present invention is further described with the aid of the following non-limiting examples and test examples which are given for purposes of illustration only. All references cited herein are incorporated by reference in their entirety.
    Experimental part
    Example 1: Formulation of HEPES at pH = 7.0
    The molecular weight of HEPES is 238.3 g / mol. Thus, 6.044 g of HEPES was weighed and 200 ml of sterile water was added and the mixture was stirred with a magnetic stirrer. The pH of the solution was measured at 5.2. Then, 5 N NaOH was added dropwise to reach a final pH of 7.0. The volume of the solution was supplemented to 250 mL, resulting in a 100 mM HEPES buffer at pH = 7.0. This buffer was sterile filtered for future use. To prepare the 10 mM HEPES buffer, 10 mL of the 100 mM HEPES buffer was diluted in 90 mL of sterile water (total volume = 100 mL). The resulting 10 mM HEPES buffer was also sterile filtered to pH = 7.0 for use with CRX-601 obtained from GSK Vaccines Hamilton, Montana.
    Example 2 (Comparative): HEPES formulation at pH = 8.0 The molecular weight of HEPES is 238.3 g / mol. Thus, 6.044 g of HEPES was weighed and 200 ml of sterile water was added and the mixture was stirred with a magnetic stirrer. The pH of the solution was measured at 5.2. Then, 5N NaOH was added dropwise to reach a final pH of 8.0. The volume of the solution was supplemented to 250 mL, resulting in a 100 mM HEPES buffer at pH = 8.0. This buffer was sterile filtered for future use. To prepare the 10 mM HEPES buffer, 10 mL of the 100 mM HEPES buffer was diluted in 90 mL of sterile water (total volume = 100 mL). The resulting 10 mM HEPES buffer was also sterile filtered at pH = 8.0 for use with CRX-601.
    Example 3: Formulation of AGP and HEPES at pH = 7.0
    CRX-601 in 10 mM HEPES buffered at pH = 7.0 was formulated at a target concentration of 2 mg / mL by weighing 3.99 mg CRX-601 and adding 1.877 mL of 10% HEPES. mM followed by ultrasonication in a water bath sonicator. After 25 minutes, the solution was visibly clear, but sonication was continued since the other formulations of CRX-601 with the other buffers employed here had not yet achieved a similar visual appearance. This was achieved because the goal was to subject each CRX-601 buffered formulation to the same amount of process energy.
    Example 4 (Comparative): AGP and HEPES formulation at pH = 8
    CRX-601 in 10 mM HEPES buffered at pH = 8.0 was formulated at a target concentration of 2 mg / mL by weighing 3.99 mg CRX-601 and adding 1.877 mL of 10% HEPES. mM followed by ultrasonication in a water bath sonicator. After 25 minutes, the solution was visibly clear, but sonication was continued since the other formulations of CRX-601 with the other buffers employed here had not yet achieved a similar visual appearance. This was achieved because the goal was to subject each CRX-601 buffered formulation to the same amount of process energy.
    Formulation of non-HEPES buffers
    The pH for each buffer was in the buffering capacity of the respective buffer. The preparation recipe for each buffer is described below.
    Example 5: acetate buffer at pH = 5.0
    The molecular weight of the ammonium acetate is 77.08 g / mol. Thus 1.927 g of ammonium acetate was weighed and 200 ml of sterile water was added and the mixture was stirred with a magnetic stirrer. The pH of the solution was measured at 6.6. Then, acetic acid was added dropwise to reach a final pH of 5.0. The volume of the solution was supplemented to 250 mL resulting in a 100 mM acetate buffer at pH = 5.0. This buffer was sterile filtered for future use. To prepare the 10 mM acetate buffer, 10 ml of the 100 mM acetate buffer was diluted in 90 ml of sterile water (total volume = 100 ml). The resulting 10 mM acetate buffer was then sterile filtered to pH = 5.0 for use with CRX-601.
    Example 6 (Comparative) acetate buffer at pH = 5.5
    The molecular weight of the ammonium acetate is 77.08 g / mol. Thus 1.927 g of ammonium acetate was weighed and 200 ml of sterile water was added and the mixture was stirred with a magnetic stirrer. The pH of the solution was measured at 6.6. Then, acetic acid was added dropwise to reach a final pH of 5.5. The volume of the solution was supplemented to 250 mL resulting in a 100 mM acetate buffer at pH = 5.5. This buffer was sterile filtered for future use. To prepare the 10 mM acetate buffer, 10 ml of the 100 mM acetate buffer was diluted in 90 ml of sterile water (total volume = 100 ml). The resulting 10 mM acetate buffer was also sterile filtered at pH = 5.5 for use with CRX-601.
    Example 7: citrate buffer at pH = 5.0
    The molecular mass of trisodium citrate (dehydrated) is 294.1 g / mol and that of acetic acid (monohydrate) is 210.14 g / mol. Thus, 3,670 g of trisodium citrate and 2,627 g of acetic acid were weighed and 200 ml of sterile water were added and the mixture was stirred with a magnetic stirrer. The pH of the solution was measured at 4.1. Then, 5N NaOH was added dropwise to reach a final pH of 5.0. The volume of the solution was supplemented to 250 mL, resulting in a 100 mM citrate buffer at pH = 5.0. This buffer was sterile filtered for future use. To prepare the 10 mM citrate buffer, 10 ml of the 100 mM citrate buffer was diluted in 90 ml of sterile water (total volume = 100 ml). The resulting 10 mM citrate buffer was sterile filtered to pH = 5.0 for use with CRX-601.
    Example 8 (Comparative): citrate buffer at pH = 6.0
    The molecular mass of trisodium citrate (dehydrated) is 294.1 g / mol and that of citric acid (monohydrate) is 210.14 g / mol. Thus, 3,670 g of trisodium citrate and 2,627 g of citric acid were weighed and 200 ml of sterile water were added and the mixture was stirred with a magnetic stirrer. The pH of the solution was measured at 4.1. Then, 5N NaOH was added dropwise to reach a final pH of 6.0. The volume of the solution was supplemented to 250 mL, resulting in a 100 mM citrate buffer at pH = 6.0. This buffer was sterile filtered for future use. To prepare the 10 mM citrate buffer, 10 ml of the 100 mM citrate buffer was diluted in 90 ml of sterile water (total volume = 100 ml). The resulting 10 mM citrate buffer at pH = 6.0 was sterile filtered for use with CRX-601.
    Example 9 (comparative): citrate buffer at pH = 6.1
    The molecular mass of trisodium citrate (dehydrated) is 294.1 g / mol and that of citric acid (monohydrate) is 210.14 g / mol. Thus, 3,670 g of trisodium citrate and 2,627 g of citric acid were weighed and 200 ml of sterile water were added and the mixture was stirred with a magnetic stirrer. The pH of the solution was measured at 4.1. Then, 5N NaOH was added dropwise to reach a final pH of 6.1. The volume of the solution was supplemented to 250 mL resulting in a 100 mM citrate buffer at pH = 6.1. This buffer was sterile filtered for future use. To prepare the 10 mM citrate buffer, 10 ml of the 100 mM citrate buffer was diluted in 90 ml of sterile water (total volume = 100 ml). The resulting 10 mM citrate buffer at pH = 6.1 was sterile filtered for use with CRX-601.
    Example 10 (Comparative): citrate buffer at pH = 7.0 The molecular weight of trisodium citrate (dehydrated) is 294.1 g / mol and that of citric acid (monohydrate) is 210.14 g / mol . Thus, 3,670 g of trisodium citrate and 2,627 g of citric acid were weighed and 200 ml of sterile water were added and the mixture was stirred with a magnetic stirrer. The pH of the solution was measured at 4.1. Then, 5 N NaOH was added dropwise to reach a final pH of 7.0. The volume of the solution was supplemented to 250 mL, resulting in a 100 mM citrate buffer at pH = 7.0. This buffer was sterile filtered for future use. To prepare the 10 mM citrate buffer, 10 ml of the 100 mM citrate buffer was diluted in 90 ml of sterile water (total volume = 100 ml). The resulting 10 mM citrate buffer at pH = 7.0 was sterile filtered for use with CRX-601.
    Example 11 (comparative): TRIS buffer at pH = 7.0
    The molecular weight of TRIS is 121.14 g / mol. Thus, 3.029 g of TRIS was weighed and 200 ml of sterile water was added and the mixture was stirred with a magnetic stirrer. The pH of the solution was measured at 10.5. Then, 6N HCl was added dropwise to reach a final pH of 7.0. The volume of the solution was supplemented to 250 mL, resulting in a 100 mM TRIS buffer at pH = 7.0. This buffer was sterile filtered for future use. To prepare the 10 mM TRIS buffer, 10 ml of the 100 mM citrate buffer was diluted in 90 ml of sterile water (total volume = 100 ml). The resulting 10 mM TRIS buffer was also sterile filtered at pH = 7.0 for use with CRX-601.
    Example 12 (comparative): buffer of succinate at pH-7.0
    The molecular weight of the succinic anhydride is 100.07 g / mol. Thus, 2.502 g of succinic anhydride was weighed and 200 mL of sterile water was added and the mixture was stirred with a magnetic stirrer. The pH of the solution was measured at 2.5. Then, 5 N NaOH was added dropwise to reach a final pH of 7.0. The volume of the solution was supplemented to 250 mL, resulting in a 100 mM succinate buffer at pH = 7.0. This buffer was sterile filtered for future use. To prepare the 10 mM succinate buffer, 10 ml of the 100 mM succinate buffer was diluted in 90 ml of sterile water (total volume = 100 ml). The resulting 10 mM succinate buffer was also sterile filtered at pH = 7.0 for use with CRX-601.
    Example 13 (comparative): phosphate buffer at pH = 7.0
    The molecular weight of sodium phosphate (monobasic) is 137.99 g / mol and that of sodium phosphate (dibasic) is 141.96 g / mol. Thus, 0.059 g of sodium phosphate (monobasic) and 0.082 g of sodium phosphate (dibasic) were weighed and 80 ml of sterile water were added and the mixture was stirred with a magnetic stirrer. The pH of the solution was measured at 7.0. The volume of the solution was supplemented to 100 mL, resulting in a 10 mM phosphate buffer at pH = 7.0. This buffer was sterile filtered for future use with CRX-601.
    Example 14 (comparative): sodium phosphate buffer at pH = 6.1
    The molecular weight of sodium phosphate (dibasic) is 141.96 g / mol and that of sodium chloride is 58.5 g / mol. Thus, 7.098 g of sodium phosphate (dibasic) and 5.844 g of sodium chloride were weighed and 900 ml of sterile water were added and the mixture was stirred with a magnetic stirrer. The pH of the solution was measured at 9.0. Then, 6N HCl was added dropwise to reach a final pH of 6.1. The volume of the solution was supplemented to 1000 mL, resulting in 100 mM NaCl and 50 mM sodium phosphate buffer (dibasic) at pH = 6.1. This buffer was sterile filtered for future use with CRX-601.
    Example 15
    Formulation of AGP and buffers
    Table 1 lists seven common buffers considered useful in the pharmaceutical art. CRX-601 was formulated in each of the buffers summarized in Table 1 at a target concentration of 2 mg / mL. Buffers were formulated at or near their optimum reported pH shown in Table 1.
    All samples were processed under the same conditions to quantify CRX-601 degradation caused by the specific buffer and not due to treatment except for CRX-601 in acetate buffer which took longer to be processed. treaty.
    Table 1
    Each of the buffer solutions was then sonicated to reduce the particle size to allow sterile filtration. Table 2 shows the treatment time to reach a partially clear solution (i.e., reach a particle size of approximately 200 nm) by sonication for each of the CRX-601 buffered formulations.
    Table 2
    Degradation
    The stability of Buffers 1-7 of Table 1 was tested at the concentrations shown in Table 1 using an accelerated stability test. The buffer compositions were held for 14 days at 40 ° C. The stability of CRX-601 in each composition was determined by measuring the percentage of CRX-601 in the composition relative to a common CRX-601 degradation product (structures shown in Figure 1). The plot in Figure 2 shows the data from the first set of buffers that were screened with CRX-601. The slope of the trend lines adjusted to each data series is a measure of the degradation rate of the CRX-601. Interestingly, it was found that HEPES (pH = 7.00), acetate (pH = 5.50) and citrate (pH = 6.10) resulted in less degradation of CRX-601 in solution after 14 days at 40 ° C. Sodium phosphate (pH = 7.15), succinate (pH = 7.00), TRIS (pH = 7.10) and sodium phosphate (pH = 6.10) showed reduced stability, and reduced surprisingly stability compared to HEPES (pH = 7). No significant changes in pH were observed during the study. The particle size of all formulations remained stable except for CRX-601 in the liposome hydration buffer (LHB) and acetate buffer which aggregated.
    Example 16 Stability / purity
    Buffers were evaluated to identify the effect of pH on the degradation rate of CRX-601; especially, the stability of CRX-601 formulated in acetate at pH = 5.0, HEPES at pH 7.0, 8.0, and citrate at pH 5.0, 6.0, and 7.0. For this purpose, the following buffers were prepared: HEPES at pH 7.0, 8.0, citrate at pH 5.0, 6.0, 7.0 and acetate at pH = 5.0 according to Examples 1, 2 , 5, 7, 8 and 10 and CRX-601 was formulated in each of them and subjected to forced degradation for 14 days at 40 ° C.
    Purity for each buffered solution was determined by measuring the percentage of CRX-601 in the composition relative to the common CRX-601 degradation product. The purity data are plotted in Figure 3 and indicate that HEPES at pH = 7.0 leads to minimal degradation, while at a different pH (pH = 5), both citrate and acetate lead to one. minimal degradation of CRX-601.
    No significant changes in particle size were observed except for CRX-601 in citrate buffer at pH = 5.0, which showed an increase in particle size. No significant changes in pH were observed for any of the formulations in this study.
    Example 17
    Buffer testing with another AGP
    Another CRX-527 PFA (obtained from GSK Vaccines, Hamilton, Montana) was screened in the accelerated stability study for 14 days at 40 ° C with phosphate buffer and HEPES at pH = 7.0. The stability of CRX-527 in each composition was determined by measuring the percentage of CRX-527 in the composition relative to the common CRX-527 degradation product (structures shown in Figure 4). Similarly, the purity of the buffered solution was determined by measuring the percentage of CRX-601 in the composition relative to the common CRX-601 degradation product as explained above. The plot in Figure 5 shows the degradation profile of CRX-527 in both buffers along with CRX-601. HEPES conferred increased stability to AGP compared to phosphate buffer at the same pH (pH = 7.0).
    Example 18
    Long-term stability / purity of CRX-601
    Buffers were evaluated to identify the effect of pH on the long-term stability of CRX-601; especially, the stability of CRX-601 formulated in acetate at pH = 5.0, HEPES at pH 7.0 and citrate at pH 5.0 were evaluated. For this purpose, the following buffers were prepared: HEPES pH 7.0, citrate pH 5.0 and acetate pH 5.0 according to Examples 1, 5 and 7 and CRX-601 was formulated in each of between them and stored for> 1 year at 2-8 ° C. Purity for each buffered solution was determined by measuring the percentage of CRX-601 in the composition relative to the common CRX-601 degradation product. Purity data are plotted in Figure 6 and indicate that there is no significant degradation in any of the buffers tested over a ~ 1 year period. Thus, the HEPES buffer gives AGP compounds of desired stability at a significantly different pH value compared to acetate and citrate buffers.
    Example 19
    Testing the activity of CRX-601
    A MonoMac 6 cell activity assay was used to measure the relative activity of CRX-527 in different buffers at an optimal pH and a relative activity of CRX-501 in different buffers at an optimal pH. Initial experiments comparing the activity of CRX-527 in HEPES and CRX-527 IN showed no significant difference in activity (data not shown). However, significant differences in activity were observed when CRX-601 was screened in HEPES at pH = 7.0, citrate at pH = 5.0 and acetate at pH = 5, In the MM 6 cell activity assay against a reference formulation CRX-601 IN (aqueous solution in 2% glycerol). The activity results given in Figures 7 to 9 show that CRX-601 acetate and CRX-601 citrate had less than 50% activity compared to CRX-601 IN. No significant cell death was observed in the acetate or citrate buffered formulations when stained with trypan blue. In comparison, HEPES CRX-601 had a double increase in CRX-601 activity compared to CRX-601 IN.
    权利要求:
    Claims (49)
    [1]
    A composition comprising (i) an aminoalkylglucosaminide phosphate or a pharmaceutically acceptable salt thereof and (ii) an effective amount of a HEPES buffer sufficient to provide a pharmaceutically acceptable pH range.
    [2]
    The composition of claim 1, wherein said buffer is selected from the group consisting of HEPES having a pH which is in a pharmaceutically acceptable pH range.
    [3]
    The composition of claim 2 wherein said buffer is HEPES having a pH of from about 7 to about 8.
    [4]
    The composition of claim 2 having a pH of about 7.0.
    [5]
    The composition of claim 2 having a pH = 7.0.
    [6]
    The composition of claim 1, wherein said aminoalkylglucosaminide phosphate has a structure

    wherein m is 0 to 6 n is 0 to 4; X is 0 or S; Y is O or NH; Z is O or H; each R1, R2, R3 is independently selected from the group consisting of C1-20 acyl and C1-20 alkyl; R4 is H or methyl; R5 is independently selected from the group consisting of -H, -OH, -alkoxy (C1-C4), -PO3R8R9, -OPO3R8R9, -SO3R8, -OSO3R8, -NR8R9, -SRe, -CN, -NO2, -CHO , -CO2R8 and -CONR8R9, wherein Rs and Rg are each independently selected from H and (C1-C4) alkyl; and each R6 and R7 is independently H or PO3H2.
    [7]
    The composition of claim 6, wherein n is an integer from 0 to 2 inclusive.
    [8]
    The composition of claim 6 wherein R 1, R 2 and R 3 each independently contain from about 7 to about 16 carbon atoms.
    [9]
    The composition of claim 6, wherein R 1, R 2 and R 3 each independently contain from about 9 to about 14 carbon atoms.
    [10]
    The composition of claim 6 wherein n is 0.
    [11]
    11. The composition of claim 6 wherein R5 is CO2H.
    [12]
    The composition of claim 6 wherein R6 is PO3H2.
    [13]
    13. The composition of claim 6, wherein R7 is H.
    [14]
    The composition of claim 1, wherein said aminoalkylglucosaminide phosphate has a structure

    (Formula la) wherein X is O or S; Y is O or NH; Z is O or H; each of R1, R2 and R3 is independently selected from the group consisting of C1-C20 acyl and C1-C20 alkyl; and FU is H or methyl.
    [15]
    The composition of claim 1, wherein said aminoalkylglucosaminide phosphate has a structure


    [16]
    The composition of claim 1, wherein said aminoalkylglucosaminide phosphate has a structure


    [17]
    17. The composition of claim 6 wherein R6 is a phosphate group and the counterion is selected from the group consisting of monoethanolamine, diethanolamine and triethanolamine.
    [18]
    18. The composition of claim 17 wherein the counterion is monoethanolamine.
    [19]
    The composition of claim 14, wherein the counterion is monoethanolamine.
    [20]
    20. Composition according to claim 1, in the form of a dispersion.
    [21]
    21. Composition according to claim 1, in the form of a solution.
    [22]
    22. The composition of claim 20 or 21, in the form of a clear solution.
    [23]
    The composition of claim 22, wherein the mixture, the solution and the clear solution are a nanoparticle composition having a particle size <200 μm.
    [24]
    The composition of claim 23, wherein said solution is used as an immunomodulator.
    [25]
    The composition of claim 1, wherein said composition has a particle size after sterile filtration, as measured by dynamic light scattering (DLS) over a period of 14 days at 40 degrees centigrade, <200 nanometers.
    [26]
    The composition of claim 1, wherein said composition has a percent loss of purity after 14 days at 40 degrees centigrade, as measured by reverse phase high performance liquid chromatography (RP-HPLC), of 4.46%. at 5.93%.
    [27]
    27. The composition of claim 1, wherein said solution is used as an immunomodulator.
    [28]
    28. The composition of claim 27, wherein said solution is used as a vaccine adjuvant.
    [29]
    29. The composition of claim 28, further comprising an antigen.
    [30]
    30. Composition according to claim 27, suitable for mucosal administration.
    [31]
    31. The composition of claim 30, suitable for intranasal administration.
    [32]
    32. The composition of claim 27 administered to a subject in the absence of an exogenous antigen.
    [33]
    33. A method for enhancing an immune response in a subject comprising administering to said subject an effective amount of the pharmaceutical composition of claim 1.
    [34]
    34. The method of claim 33, wherein said subject is a mammal.
    [35]
    The method of claim 34, wherein said mammal is a human.
    [36]
    The method of claim 35, further comprising administering an exogenous antigen to said subject.
    [37]
    37. The method of claim 36, wherein said subject is a mammal.
    [38]
    38. The method of claim 37, wherein said mammal is a human.
    [39]
    A method for substantially improving or preventing an infectious disease, an autoimmune disease, or an allergic condition in a subject comprising administering to said subject an effective amount of the pharmaceutical composition of claim 1.
    [40]
    40. The method of claim 39, wherein said subject is a mammal.
    [41]
    41. The method of claim 40, wherein said mammal is a human.
    [42]
    42. The method of claim 41, further comprising administering an exogenous antigen to said subject.
    [43]
    43. The method of claim 42, wherein said subject is a mammal.
    [44]
    44. The method of claim 43, wherein said mammal is a human.
    [45]
    45. The composition of claim 1, wherein said water is sterile.
    [46]
    46. A composition comprising (i) an aminoalkylglucosaminide phosphate or a pharmaceutically acceptable salt thereof and (ii) an effective amount of a citrate or acetate buffer sufficient to provide a pharmaceutically acceptable pH.
    [47]
    47. The composition of claim 46, wherein the pH is not greater than 6.5.
    [48]
    48. The composition of claim 46 wherein the pH is between about 4.0 and about 6.0.
    [49]
    49. The composition of claim 48 wherein the pH is about 5.0.
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    法律状态:
    优先权:
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    US201361791165P| true| 2013-03-15|2013-03-15|
    US61/791165|2013-03-15|
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