Formulations of alfaxin and methods of making the same

Abstract

This invention relates to afarubicin formulations and methods for their preparation. The invention provides solid pharmaceutical compositions containing afarubicin that exhibit excellent solubility properties, comprising afarubicin or a pharmaceutically acceptable salt thereof, histidine or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. This beneficial effect is achieved through the presence of a histidine compound used in the manufacture of the composition. The invention also provides methods for manufacturing these compositions and their uses.

Description

[0001] This application is a divisional application of 202080014005.3 (Chinese National Application No.). The original international application number was PCT / EP2020 / 053882, the filing date was February 14, 2020, and the invention title was "Alfabecin Formulation and Preparation Method Thereof". Technical Field

[0002] This invention relates to pharmaceutical compositions containing afabicin, and particularly to afabicin formulations containing histidine compounds. The invention also relates to methods for manufacturing such formulations and their uses, particularly for treating bacterial infections. Background Technology

[0003] Alfarubicin is described in WO2013 / 190384A, either in its free acid form or in various salt forms, as a prodrug of the active agent known from Example 99 of WO03 / 088897A. Alfarubicin has the following structure (described in its free acid form):

[0004]

[0005] For oral administration, afabicin must be provided in a formulation capable of decomposing at the pH of gastric juice and releasing the drug. WO2013 / 190384A describes methods for manufacturing afabicin and formulations containing afabicin. This document describes various materials suitable as excipients for formulating afabicin.

[0006] However, when attempting to develop afabicin formulations based on commonly used excipient materials, incomplete disintegration of the drug form and poor dissolution of afabicin were observed.

[0007] Purpose of the invention

[0008] The object of this invention is to provide pharmaceutical compositions comprising alfarubicin, preferably alfarubicin ethanolamine (i.e., the bis-2-ethanolamine salt of alfarubicin, sometimes also referred to as the diethanolamine salt of alfarubicin), which allow for disintegration exhibiting excellent solubility properties. Another object of this invention is to provide such compositions that also exhibit satisfactory solubility stability. Another object of this invention is to provide such compositions that also exhibit satisfactory chemical stability. Another object of this invention is to provide such compositions that exhibit satisfactory oral bioavailability and therapeutic effect. Another object of this invention is to provide such compositions that are easy to manufacture at low cost. Summary of the Invention

[0009] The above-mentioned objectives are achieved by pharmaceutical compositions comprising alfabecin as disclosed herein and as specified in the appended claims. In particular, the following pharmaceutical compositions are provided:

[0010] 1. A solid pharmaceutical composition in unit dosage form, said composition comprising afabicin or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, characterized in that said composition comprises a histidine compound.

[0011] 2. The solid pharmaceutical composition as described in item 1, wherein the pharmaceutical composition comprises an amount of 20 mg to 480 mg of afabicin or a pharmaceutically acceptable salt thereof.

[0012] 3. A solid pharmaceutical composition as described in item 1 or 2, wherein the pharmaceutical composition comprises histidine.

[0013] 4. A solid pharmaceutical composition as described in any one of items 1 to 3, wherein the composition is in tablet form, the tablet preferably comprising an internal phase and an external phase, wherein alfabecin or a pharmaceutically acceptable salt thereof is preferably contained only in the internal phase.

[0014] 5. The solid pharmaceutical composition as described in item 4, wherein the composition contains the histidine compound only in the inner phase.

[0015] 6. A solid pharmaceutical composition as described in any one of items 1 to 5, said composition comprising a binder selected from the group consisting of povidone, copovidone, poloxamer, polyethylene glycol, magnesium aluminosilicate, gelatin, gum arabic, dextrin, glucose binder, dextrose, polydextrose, guar gum, hydrogenated vegetable oil, liquid glucose, wax, maltose, sucrose, lactose, waxes and mixtures thereof.

[0016] 7. A solid pharmaceutical composition as described in any one of items 1 to 6, said composition comprising a diluent selected from mannitol, isomaltitol, lactose, calcium phosphate, calcium carbonate, calcium sulfate, sucrose, fructose, maltose, xylitol, maltitol, lactitol, trehalose, aluminum silicate, cyclodextrin, dextran, polydextrin, glucose, dextrin, glucose binders, magnesium carbonate, and mixtures thereof.

[0017] 8. A solid pharmaceutical composition as described in any one of items 1 to 7, said composition comprising a surfactant selected from the group consisting of sodium dodecyl sulfate, poloxamer, sodium docusate, sodium deoxycholate, sorbitan esters, sucrose esters of fatty acids, tyloxapine, lecithin, and polysorbate esters and mixtures thereof.

[0018] 9. A solid pharmaceutical composition as described in any one of items 1 to 8, said composition comprising a disintegrant selected from the group consisting of cross-linked povidone, magnesium aluminosilicate, colloidal silica, guar gum, and mixtures thereof.

[0019] 10. A solid pharmaceutical composition as described in any one of items 1 to 3 and 6 to 9, wherein the composition is in capsule form, the capsule comprising alfabecin or a pharmaceutically acceptable salt thereof in powder or granule form and one or more pharmaceutically acceptable excipients.

[0020] In addition to the above, the present invention also provides methods for manufacturing the pharmaceutical compositions of the present invention. Such methods of the present invention are disclosed below. These methods particularly include the following:

[0021] 11. A method for manufacturing a solid pharmaceutical composition according to any one of items 1 to 9, said method comprising the following steps in a specified order:

[0022] (i) Dry mixing one or all of the components of the composition;

[0023] (ii) Granulate the resulting mixture to obtain particles;

[0024] (iii) Mix any remaining ingredients of the composition into the granules;

[0025] (iv) Compress the resulting mixture to obtain compressed tablets; and

[0026] (v) Optionally, the resulting compressed tablets may be coated.

[0027] 12. The method of Item 11, wherein the granulation step is performed by wet granulation or dry granulation.

[0028] 13. The method as described in item 11 or 12, wherein a portion of the diluent (if present) and / or a portion of the disintegrant (if present) and a portion or all of the cosolvent and lubricant (if present) are mixed into the particles of step (ii).

[0029] Finally, the present invention provides for the use of the pharmaceutical compositions of the present invention. These uses are also described below. They particularly include the following uses:

[0030] 14. The solid pharmaceutical composition as described in any one of items 1 to 10, used in a method of treating bacterial infections in mammals.

[0031] 15. A solid pharmaceutical composition as described in Item 14, wherein the mammal is a human.

[0032] 16. A solid pharmaceutical composition as described in Item 14 or 15, wherein the bacterial infection is caused by a species of Staphylococcus aureus, namely acute bacterial skin and skin structure infection (ABSSI) or bacterial infection associated with diabetic foot syndrome.

[0033] This invention also relates to methods for treating bacterial infections in mammals in need using the solid pharmaceutical compositions of this invention (e.g., those described in any one of items 1 to 10 above). Specifically, this invention relates to such methods, wherein the mammal is a human. In preferred embodiments of these treatment methods of the invention, the bacterial infection is caused by a bacterial strain selected from Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus. Attached Figure Description

[0034] Figure 1 In vitro dissolution curves of Examples 1 to 8 after manufacturing (T0)

[0035] Figure 2 In vitro dissolution curves of Comparative Examples 1 to 11 after manufacturing (T0)

[0036] Figure 3 In vitro dissolution curves of Examples 1 to 8 after accelerated storage conditions (15 days in an open bottle at 40°C / 75% RH).

[0037] Figure 4 In vitro dissolution curves of Comparative Examples 1, 2, 4, 5, 7, 8, 9, and 10 after accelerated storage conditions (15 days in an opened bottle at 40°C / 75% RH). Detailed Implementation

[0038] definition

[0039] The open lists introduced by the verbs "comprise" and "contain" allow for the presence of additional ingredients not included in the list. In contrast, the closed lists introduced by the verb "compose of" do not allow for the presence of other unmentioned ingredients. Wherever the verbs "comprise" or "compose of" are used in this application, it means that the option "compose of" is included as a preferred implementation.

[0040] Unless the context otherwise requires, the terms "a" or "an" refer to a substance or component, but do not limit the number or quantity of such components. For example, reference to "adhesive" should be understood as referring to a single adhesive or a combination of two or more adhesives.

[0041] The term "histidine compound" is used to characterize histidine itself and its pharmaceutically acceptable salts. Histidine or its pharmaceutically acceptable salts may be used as racemic forms of histidine compounds, such as L-enantiomers, D-enantiomers, or any mixture thereof. L-enantiomers are preferred. Any reference to histidine compounds should also be understood as (only) a reference to histidine itself, which is the most preferred embodiment of histidine compounds.

[0042] The term "cellulose material" describes a material that contains at least 10 continuously repeating units of the following general structure:

[0043]

[0044] Where n is 10 or more, and R is independently hydrogen or a substituent. Specifically, each R in the repeating unit is independently chosen from H and C. 1-6 Alkyl, hydroxy-C 1-6 Alkyl, carboxyl-C 1-6 Alkyl, -(C=O)-C 1-6 A group composed of alkyl groups.

[0045] The term "starch material" is used to characterize any material having at least 10 consecutive repeating units of amylose or amylopectin structure. Starch materials also include materials having at least 10 consecutive repeating units of amylose or amylopectin structure, wherein one or more substituents are connected to the amylose and / or amylopectin structural elements via hydroxyl-derived oxygen atoms in the same manner as described in cellulose materials. Such starch materials may optionally be pregelatinized.

[0046] As used herein, the term "polysaccharide" refers to any material having at least 10 monosaccharide units linked by glycosidic bonds. The range of monosaccharides is not particularly limited. Furthermore, two or more different types of monosaccharides may coexist in a polysaccharide. Polysaccharides can be linear or branched.

[0047] The term "modified release agent" is used to characterize a group of materials used in the pharmaceutical industry to control, delay, or prolong the release of active pharmaceutical ingredients. Modified release agents include polymethacrylates (including methyl acrylate-methacrylate copolymers and / or methyl methacrylate-methacrylate copolymers), polyvinyl acetate phthalates, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose (high molecular weight), methylcellulose (high molecular weight), microcrystalline waxes, carbomer, guar gum, shellac, carrageenan, chitosan, glyceryl monostearate, glyceryl behenate, glyceryl monooleate, glyceryl monostearate, glyceryl palmitate stearate, polycrylene potassium, polycarbofil, polyethylene oxide (high molecular weight), alginate, sodium alginate, and zein.

[0048] The term "solution stability" characterizes a formulation exhibiting an average dissolution curve after short-term storage under accelerated conditions, preferably after 15 days of storage in an opened vial at 40°C / 75% RH, where the deviation from the average dissolution curve of the same formulation before storage is preferably reduced by no more than 30%, preferably no more than 25%, more preferably no more than 20%, and even more preferably no more than 15%. The deviation is determined at time points of 45 minutes and 60 minutes. The formulation is considered "solution-stable" in the sense of this invention only when the deviation (preferably reduced) at both time points is less than 30%, preferably less than 25%, more preferably less than 20%, and even more preferably less than 15%. The relative deviation is calculated using the dissolution value before storage as a standard. That is, the relative deviation can be calculated using the following formula:

[0049] deviation, T＝x (%) = 100% × | [Diss] T＝x (After saving) - Diss T＝x (Before saving)│ / Diss T＝x (Before storage)

[0050] Among them Diss T＝x The percentage of alphabetic acid dissolved at time x.

[0051] The term "alkyl" refers to the general formula C n H 2n+1 The alkyl group is a monovalent saturated hydrocarbon group. The alkyl residue can be straight-chain or branched. Preferred alkyl groups have 1 to 6 carbon atoms.

[0052] The term "alkoxy" refers to a monovalent group of the general formula -O-alkyl, wherein the alkyl group is as defined above.

[0053] In this application, the term "ingredient" in the pharmaceutical composition of the present invention refers to any material present in the final product, including excipients and the active pharmaceutical ingredient. The term "ingredient" also includes tablet coatings (if present) or capsule shells (if present). "Excipients" are all components in the pharmaceutical composition that do not produce a pharmaceutical effect on their own, i.e., all components other than the active pharmaceutical ingredient.

[0054] Unless otherwise specified, all absolute amount indications in this application are given in mg. Unless otherwise specified, all relative amount indications are given in weight % (wt%) based on the total weight of the pharmaceutical composition. If the pharmaceutical composition is in the form of coated tablets, the coating weight is not included in the total weight. If the pharmaceutical composition is in the form of capsules, the weight of the capsule shell is also not included in the total weight. The weight of any liquid that may be temporarily present during wet granulation but is removed by a subsequent drying process is not included in the total weight.

[0055] Unless otherwise specified, all absolute amount indications (e.g., daily doses) of the active substance afabicin are based on the molecular weight in its free acid form. Therefore, if afabicin in its salt form is used, the relative molecular weight must be considered to convert the specified absolute amount. This can be done using the following formula (1):

[0056] M(salt) = m(free acid) * M(salt) / M(free acid) (1)

[0057] Where m specifies the absolute amount, and M specifies the molecular weight in various forms.

[0058] Unless otherwise specified, all relative quantity indications (e.g., compositional ranges) of the active substance alfabicin are based on the molecular weight of the diethanolamine salt of alfabicin (alfabicin ethanolamine). Therefore, if alfabicin is used in a different salt form or free acid form, the specified absolute quantity needs to be converted with respect to the relative molecular weight. This can be done using the following formula (2):

[0059] w(s2) = 100*w(s1)*M(s2) / (M(s1)*(100+w(s1)*(M(s2)-M(s1)) / M(s1))) (2)

[0060] Where w(s2) is the relative amount of the second salt form or free acid form (based on the total weight of the composition containing the salt form as a percentage by weight); w(s1) is the relative amount of the diethanolamine salt form (based on the total weight of the composition containing the diethanolamine salt form as a percentage by weight); M(s2) is the molecular weight of the second salt form or free acid form; and M(s1) is the molecular weight of the diethanolamine salt form.

[0061] In this application, indications that the pharmaceutical composition of the present invention "does not contain" a specific substance, indications that such a substance is absent, and statements regarding the absence or omission of said substance, should be understood to mean that the relative amount of said substance in the pharmaceutical composition is less than 0.1% by weight, and preferably less than 0.01% by weight. According to a particularly preferred embodiment, the substance is completely absent or present in such a small amount that it is undetectable based on analytical techniques available at the date of application. According to another embodiment, the pharmaceutical composition contains such a small amount of the corresponding substance that it has no measurable effect on the solubility properties of the active ingredient, afabicin.

[0062] The relative amounts of ingredients expressed as ranges should be understood so that, in the case of "comprising," any amount within the specified range may be present, provided that the total amount of the mentioned ingredient must be less than 100% by weight, to allow for the optional presence of other unmentioned ingredients. In the case of "consisting of," any amount within the specified range may be present, provided that the total amount of the mentioned ingredient must be 100% by weight. In this respect, the term "mentioned ingredient" refers to any ingredient for which a relative amount is specified in the same technical context.

[0063] Some of the excipients mentioned below may have two or more functions. For example, poloxamer can be used as a surfactant, but also as an adhesive component. Using these components to benefit from two or more functions of the respective component is entirely in accordance with the present invention. If such components having two or more functions are used, it is obvious that the amount of any other component having one of these functions can be reduced or completely omitted. Regarding the indication of amount, the following should be considered:

[0064] Histidine compounds are considered only for their function as agents that improve solubility, regardless of whether they may also perform any other function. For example, if the formulation contains diluents such as mannitol and / or isomaltitol in addition to the histidine compound, the amount of dilution is the same as the amount of mannitol and / or isomaltitol. This means that the amount of histidine compound in the diluent is not calculated regardless of whether the histidine compound functions as a diluent.

[0065] • The quantity indications provided below should be understood as taking into account each function that this multifunctional component can perform in a pharmaceutical composition. For example, if poloxamer is present in an amount of 5% by weight, then this component should be counted as 5% by weight of surfactant, and also as 5% by weight of binder.

[0066] • It is possible and consistent with the present invention that the amount of multifunctional ingredient used is consistent with the indicated amount given for one type of ingredient, but higher than the indicated amount given for one or more other types of ingredients.

[0067] In this case, only the portion of the component that meets the upper limit of the lower amount indication is considered present to assess consistency with the lower amount indication in this invention, while the total amount is considered to assess consistency with the higher amount indication. For example, if 50% by weight of starch (which can be used as a diluent or as a binder) is used, the question is whether this amount meets the indication specified below. According to one embodiment described below, the diluent can be present in an amount of 50% to 75% by weight, and the binder can be present in an amount of 4% to 7% by weight. Using 50% by weight of starch is consistent with this embodiment: for the binder function, 7% by weight of starch is considered to be used as the binder, while 50% by weight of the total amount is used for the diluent function.

[0068] Furthermore, and consistent with the present invention, it is possible that the amount of the multifunctional component used is consistent with the indicated amount given for one type of component, but less than the indicated amount given for one or more other types of components. In this case, an additional component with the same function must be used in sufficient quantity to conform to the indicated amount specified for these other types of components. For example, if, similar to the example above, there is a quantity of 7% by weight of starch, this would conform to the amount of binder specified for the above embodiment. To conform to the dosage specifications of the diluent component, at least 43% by weight of another diluent must be used in addition to the starch component.

[0069] • If there is any doubt about the function performed by a particular ingredient, the information provided below should be considered decisive. In the absence of the following information, this information may be supplemented by the information contained in the Handbook of Pharmaceutical Excipients, 8th edition, PJ Sheskey, Pharmaceutical Press, 2017.

[0070] Overview

[0071] This invention is based on a surprising discovery that adding histidine compounds to formulations can significantly improve the release characteristics of alfabecin-containing formulations.

[0072] Histidine is a well-known pharmaceutical component commonly used in lyophilized protein formulations (for parenteral administration) and acts as a buffer (see Excipient Development for Pharmaceutical, Biotechnology, and Drug Delivery Systems, ed. Ashok Katdare, Mahesh Chaubal, CRC Press, 2006, pp. 299-300). Histidine has been shown to protect monoclonal antibodies against heat stress in both liquid and lyophilized states (see Arakawa et al., Biotechnology Applications of Amino Acids in Protein Purification and Formulations. Amino Acids. 33, 587–605).

[0073] Not wishing to be bound by this theory, it is presumed that histidine compounds are advantageous because they stabilize alfabicin through molecular interactions. In particular, this allows for formulations that readily release alfabicin without disintegration problems. This overall inventive concept can be implemented in any kind of solid dosage form, particularly including tablets and capsules. The advantages of the invention are most pronounced in tablets, especially those having an internal and an external phase. It is particularly advantageous to use specified excipient materials to manufacture such tablets having an internal phase containing alfabicin and an external phase not containing alfabicin. In this case, it is preferable to provide the histidine compound at least in the internal phase.

[0074] Better results can be obtained by adding histidine itself to the formulation. Therefore, conjugation of histidine is a preferred embodiment of the present invention. The present invention further provides solid pharmaceutical compositions containing one or more excipient materials that are well-suited for manufacturing solid dosage forms of alfabracin that exhibit excellent solubility and stability characteristics. In a preferred embodiment, the present invention also provides solid pharmaceutical compositions characterized by the absence of other excipient materials specified in the next section as alternative methods for improving solubility and stability characteristics.

[0075] Preferred substances to avoid

[0076] The pharmaceutical compositions of the present invention are preferably free of cellulose materials. This specifically means the absence of the following materials: microcrystalline cellulose, silanized microcrystalline cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, methylcellulose, carboxymethyl cellulose and their salts, as well as any other polymeric substances based on the above-mentioned cellulose repeating units.

[0077] In a more preferred embodiment, the pharmaceutical composition of the present invention further contains no starch material. In particular, the pharmaceutical composition of the present invention does not contain pregelatinized starch. According to yet another preferred embodiment of the present invention, the pharmaceutical composition of the present invention contains absolutely no polysaccharide material.

[0078] The above general rules for preferred embodiments that do not contain cellulose materials and / or starch materials or even polysaccharides apply in general, regardless of the intended function of the ingredient and its positioning in the solid dosage form. For example, in tablets containing an internal phase, an external phase, and a coating, there is no cellulose material in the internal phase, no cellulose material in the external phase, and no cellulose material in the coating.

[0079] It is also preferable not to include the modified release agent in the pharmaceutical composition. This also applies to its coating (if present).

[0080] Active substances

[0081] Unless the context otherwise requires, the term “alfabisin” is used herein to characterize the above-mentioned compounds and any pharmaceutically acceptable salts thereof.

[0082] Alfarubicin can be used in its free acid form and / or in its pharmaceutically acceptable salt form. The free acid form of alfarubicin has been attributed to the following CAS RN 1518800-35-5. The most favorable salt form currently known is the diethanolamine salt, as shown below.

[0083]

[0084] Alfabecin, in this diethanolamine salt form, is also known as alfabecin ethanolamine, with CAS RN 1518800-36-6.

[0085] A mixture of the free acid form of alfarubicin and its diethanolamine salt is also advantageously used. According to a particularly preferred embodiment of the invention, all references to alfarubicin should be understood as references to the alfarubicin diethanolamine salt (optionally in combination with the free acid form of alfarubicin). In the most preferred embodiment, a combination of the alfarubicin diethanolamine salt and the free acid form of alfarubicin is used, wherein the molar ratio of the free acid to the diethanolamine salt is 0.7 to 0.9, and even more preferably 0.75 to 0.85.

[0086] In addition to the particularly preferred embodiments described above, alternative salt forms of alfabracin, such as dipotassium salts or monodialkylammonium salts, may also be used, but are less preferred, wherein the alkyl group is selected from methyl and ethyl groups. In principle, the type of salt form is not particularly limited, and any pharmaceutically acceptable salt form of alfabracin may be used, including but not limited to the salts disclosed in WO 2013 / 190384.

[0087] The above-mentioned forms, including both the free acid form and the less preferred salt form, can of course be used in combination. The dosage indication provided for alfabicin refers to the amount in the free acid form. If a salt of alfabicin is used, the dosage must be adjusted accordingly, taking into account the higher molecular weight of the alfabicin salt. This is easiest to do with an absolute dosage indication in mg. If necessary, the adjusted value can be converted to a relative amount.

[0088] Alfabecin may be present in the pharmaceutical compositions of the present invention in amounts from 20 mg to 480 mg, preferably from 40 mg to 240 mg, and most preferably 120 mg or 240 mg (by weight).

[0089] The relative amount of alfarubicin salt in the compositions of the present invention can be from 10% to 90% by weight, preferably from 30% to 85% by weight, and most preferably from 40% to 60% by weight. As mentioned above, such relative amount indications apply to alfarubicin ethanolamine. If another alfarubicin salt or a free acid form of alfarubicin is used, the relative amounts must be converted to take into account the molecular weight of alfarubicin ethanolamine and the molecular weight of the alfarubicin form of interest. The above definition section provides formulas applicable to this calculation.

[0090] According to the present invention, the active substance of alfabecin can also be combined with another active pharmaceutical substance. Paragraphs

[0132] to

[0140] of WO2013 / 190384A describe pharmaceutical substances suitable for such combinations, which are incorporated herein by reference.

[0091] Histidine compounds

[0092] Histidine compounds are used as agents that allow the composition to disintegrate and alfabicin to be released. In a preferred embodiment, the histidine compound is histidine itself. Instead of the free form of the histidine compound, a pharmaceutically acceptable salt thereof, such as a citrate, may also be used. Histidine or a pharmaceutically acceptable salt thereof may be used in racemic forms other than L-enantiomers, D-enantiomers, or any mixture thereof. L-enantiomers are preferred. Another possibility according to the invention is the use of a combination of two or more histidine compounds, such as a combination of histidine and a histidine salt. The histidine compound may also be used with one or more other compounds that exhibit molecular interactions with alfabicin or alfabicin salts.

[0093] If the histidine compound is used as the sole reagent of this type, it may be present in a molar ratio of (histidine compound) / (alfarubicin (salt)) relative to alfarubicin or alfarubicin salt of 0.5 to 5, preferably 0.6 to 4.5, 0.7 to 4, 0.75 to 4, or 0.8 to 3.5, or 1 to 3, or more preferably 1 to 2. If the histidine compound is used with another stabilizer that exhibits molecular interaction with alfarubicin or alfarubicin salt, it may be present with the other stabilizer in a molar ratio of (histidine compound + other stabilizer) / (alfarubicin (salt)) relative to alfarubicin or alfarubicin salt of 0.5 to 10, preferably 0.6 to 9, 0.7 to 8, 0.75 to 8, or 0.8 to 7, or 1 to 6, more preferably 1 to 3.

[0094] If the relative amounts of alfabicin or alfabicin salt and histidine compound are known, the molar ratio can be calculated using the following formula, shown in an exemplary manner with respect to alfabicin. A similar formula can be used if alfabicin is used in its free form:

[0095] Molar ratio (histidine compound / alfabicin salt) = ((histidine compound) / M(histidine compound) weight %) / (alfabicin salt) / M(alfabicin salt) weight %)

[0096] Where M (histidine compound) is the molecular weight of the histidine compound; M (alfabisin salt) is the molecular weight of the alfabisin salt (or alfabisin itself if the free form is used instead of the salt).

[0097] adhesives

[0098] Adhesives are advantageously used to increase the particle size of active components, either alone or in combination with excipients, and to improve their processability. There are no particular limitations on the adhesive materials that can be used in this invention. According to a preferred embodiment, cellulose materials are not used. According to another preferred embodiment, starch materials are not used.

[0099] Suitable adhesive materials include polyvinylpyrrolidone (PVP), copolyvinylpyrrolidone (1-vinylpyrrolidone-vinyl acetate copolymer), hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, methylcellulose, microcrystalline cellulose, poloxamer (block copolymer with a first poly(ethylene oxide) block, a second and a central poly(propylene oxide) block, and a third poly(ethylene oxide) block), polyethylene glycol, magnesium aluminosilicate, gelatin, gum arabic, alginate, carbomer (such as carbopol), and carboxylic acid. Gum, dextrin, glucose binder (a purified mixture of sugars produced by controlled enzymatic hydrolysis of starch), dextrose, polydextrose, guar gum, hydrogenated vegetable oil, liquid glucose, maltose, sucrose, lactose, wax, maltodextrin, starch (pregelatinized and regular starch), hydroxypropyl starch, glyceryl behenate, glyceryl palmitate stearate, polyethylene oxide, sodium alginate, ethyl cellulose, cellulose acetate phthalate, polymethyl methacrylate, sodium carboxymethyl cellulose, polycarboxymethyl cellulose, chitosan, and mixtures thereof.

[0100] Povidone and copovidone are preferred.

[0101] The adhesive may be present in a relative amount of 0.5% to 15% by weight, preferably 2% to 10% by weight, for example 2% to 8% by weight, more preferably 3% to 8% by weight, for example 3% to 6% by weight.

[0102] diluent

[0103] Diluents can be optionally, but advantageously, used to increase the volume of the pharmaceutical composition and facilitate its processing. There are no particular limitations on the diluent materials that can be used in this invention. Similar to the case of the binders described above, it is preferable not to use cellulose materials and / or starch materials and / or modified release agents.

[0104] Suitable diluent materials include mannitol, isomaltitol, lactose (including anhydrous or monohydrate forms), calcium phosphate (including dibasic and tribasic calcium phosphates), calcium carbonate, magnesium carbonate, magnesium oxide, calcium sulfate, sucrose, fructose, maltose, xylitol, sorbitol, maltitol, lactitol, trehalose, aluminum silicate, dextran, cyclodextrin (natural or modified cyclodextrin), starch (pregelatinized or ordinary starch), maltodextrin, cellulose (microcrystalline, silicified microcrystalline), glucose, dextrin, glucose binders (purified mixtures of sugars produced by controlled enzymatic hydrolysis of starch), dextran, polydextrin, ammonium alginate, glyceryl behenate, glyceryl palmitate stearate, sodium alginate, ethyl cellulose, cellulose acetate, cellulose phthalate acetate, polymethyl methacrylate, chitosan, and mixtures thereof.

[0105] Mannitol, xylitol, sorbitol and / or isomaltitol are preferred, with mannitol and / or isomaltitol being the most preferred.

[0106] The diluent (if present) may be present in a relative amount without particular limitation. Suitable amounts may be from 2% to 85% by weight, preferably from 8% to 80% by weight, more preferably from 10% to 30% by weight.

[0107] surfactants

[0108] In one embodiment, the composition comprises a surfactant. The surfactant can advantageously be used to enhance the wetting properties of the tablet and the active ingredient. The surfactant is an optional but preferred component. There are no particular limitations on the surfactant materials that can be used in this invention. Similar to the case of the binders described above, it is preferable not to use cellulose materials and / or starch materials and / or modified release agents.

[0109] Suitable surfactant materials include sodium dodecyl sulfate, poloxamer, sodium docusate, sodium deoxycholate, sorbitan ester, polyethylene oxide, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 (an ethoxylated sorbitan ester ester of fatty acids, where the number indicates the number of repeating polyethylene glycol units), sucrose esters of fatty acids, tyloxapine, lecithin, and mixtures thereof.

[0110] Sodium dodecyl sulfate is preferred.

[0111] Surfactants can be present in a relative amount without particular limitation. Suitable amounts can be from more than 0% by weight to 7% by weight, preferably from 0.1% by weight to 6.5% by weight, and more preferably from 1% by weight to 6% by weight. In one specific embodiment, the surfactant is preferably present in an amount within the above range, with the molar ratio of alfabracin or alfabracin salt to histidine compound (and other stabilizers (if present)) set to fall within one of the ranges described above. For example, the surfactant can be present in an amount from 0.1% by weight to 6.5% by weight, while the above molar ratio can be greater than 0.5, and if no other stabilizers are present, it can be, for example, from 0.6 to 4.5, or if other stabilizers are present, it can be from 0.6 to 9.

[0112] Disintegrant

[0113] Disintegrants are advantageously used to accelerate the disintegration of pharmaceutical compositions, thereby facilitating the dissolution of the active ingredient. There are no particular limitations on the disintegrant materials that can be used in this invention. Similar to the case of binders described above, it is preferable not to use cellulose materials and / or starch materials and / or modified release agents.

[0114] Suitable disintegrant materials include homopolymers and copolymers and mixtures thereof of crospovidone, sodium starch glycolate, croscarmellose sodium, magnesium aluminum silicate, colloidal silica, sodium alginate, calcium alginate, pregelatinized starch, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, alginate, guar gum, (meth)acrylic acid and its salts (such as potassium polacrine).

[0115] Crosspovidone is preferred.

[0116] The disintegrant can be present in a relative amount without particular limitation. Suitable amounts can be from more than 0% by weight to 20% by weight, preferably from 1% by weight to 15% by weight, and more preferably from 2% by weight to 10% by weight.

[0117] Flow aid

[0118] Gliders are advantageously used to improve the flowability of pharmaceutical compositions, thereby enhancing their processability. Gliders are optional but preferred components. There are no particular limitations on the glider materials that can be used in this invention. Similar to the case of adhesives described above, it is preferable not to use cellulose materials and / or starch materials and / or modified release agents.

[0119] Suitable flow aid materials include colloidal silica, magnesium oxide, magnesium silicate, calcium silicate, calcium triphosphate, talc, and mixtures thereof.

[0120] Colloidal silica is preferred.

[0121] The gliding agent can be present in a relative amount without particular limitation. Suitable amounts can be from more than 0% by weight to 5% by weight, preferably from 0.1% by weight to 4% by weight, and more preferably from 0.2% by weight to 1% by weight.

[0122] lubricant

[0123] Lubricants are advantageously used to facilitate tableting, particularly by preventing tablets from adhering to the tableting machine. Lubricants are optional but preferred components. There are no particular limitations on the lubricant materials that can be used in this invention. Similar to the case of adhesives described above, it is preferable not to use cellulose materials and / or starch materials and / or modified release agents.

[0124] Suitable lubricant materials include magnesium stearate, sodium stearoyl fumarate, talc, stearic acid, leucine, poloxamer, polyethylene glycol, glyceryl behenate, glyceryl monostearate, magnesium dodecyl sulfate, sucrose esters of fatty acids, calcium stearate, aluminum stearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, sodium benzoate, zinc stearate, palmitic acid, carnauba wax, magnesium dodecyl sulfate, sodium dodecyl sulfate, sodium dodecyl sulfate, polyoxyethylene monostearate, calcium silicate, and mixtures thereof.

[0125] Lubricants selected from magnesium stearate and sodium stearoyl fumarate and combinations thereof are preferred.

[0126] The lubricant can be present in a relative amount without particular restriction. Suitable amounts can be from more than 0% by weight to 7% by weight, preferably from 0.1% by weight to 5% by weight, such as from 0.1% by weight to 4% by weight, and more preferably from 0.25% by weight to 4% by weight, such as from 0.5% by weight to 3.5% by weight.

[0127] Other types of excipients

[0128] The compositions of the present invention may contain other excipients commonly used in the art. Such other excipients may include plasticizers, film-forming agents, colorants, anti-sticking agents, and / or pigments for coating the compositions of the present invention. Other types of excipients that may be present include buffers, flavoring agents, sweeteners, antioxidants, and / or absorption promoters. Similar to the case of the adhesives described above, it is preferable not to use cellulose materials and / or not to use starch materials and / or not to use modified release agents.

[0129] The relative amount of such excipients is not particularly limited. It can be determined by a technician based on common sense and standard procedures.

[0130] Film-forming agents are advantageously used to provide a coherent coating for the tablets of the present invention. Suitable film-forming agents include isomaltitol, polyvinyl alcohol, polyethylene glycol, maltodextrin, sucrose, xylitol, and maltitol. Enteric coating agents can be used, for example, materials selected from the group consisting of methyl acrylate-methacrylic acid copolymer, polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymer, shellac, sodium alginate, and zein, but these are not preferred. Similar to the case of the binders described above, it is preferable not to use cellulose materials and / or not to use starch materials. It is preferable to use a combination of film-forming agents comprising polyvinyl alcohol and one or more second agents selected from isomaltitol, sucrose, xylitol, and maltitol.

[0131] Suitable plasticizers include sorbitol, triacetin, poloxamer, polyethylene glycol, glycerin, propylene glycol, polyethylene glycol monomethyl ether, tributyl acetylacetonate, triethyl acetylacetonate, castor oil, glyceryl monostearate, diacetylated monoglyceride, dibutyl sebacate, diethyl phthalate, triethyl citrate, and tributyl citrate.

[0132] tablet

[0133] The pharmaceutical compositions of the present invention are preferably in tablet form. The tablets can be monolayer monolithic tablets, they can be layered structures having two or more layers, or they can have a structure containing an internal phase (obtained through a granulation step) and an external phase. Variations having both internal and external phases are particularly preferred. In this variation, it is also particularly preferred that the active pharmaceutical ingredient, afabicin, is present only in the internal phase. In this variation, it is further particularly preferred that at least a portion (e.g., greater than 50%, and preferably greater than 80%) of the histidine compound is also present in the internal phase. It is also preferred that at least a portion (e.g., greater than 50%, and preferably greater than 55%) of the disintegrant is also present in the internal phase. If the tablet has an internal and an external phase, the weight ratio of the internal to the external phase is preferably 50:50 or more, and more preferably 80:20 to 95:5.

[0134] If the tablet is a single-layer tablet, the above-mentioned amount indications are applicable without limitation. In the case of a bilayer tablet, the components are separated from each other by incorporating some of them into separate layers. For tablets with two or more layers, it is preferred that at least a portion (e.g., greater than 50% and preferably greater than 80%) of the histidine compound is present in the same layer as alfarubicin. In the case of tablets with two or more layers, it is preferred that at least a portion (e.g., greater than 50% and preferably greater than 55%) of the disintegrant is also present in the same layer as alfarubicin. Apart from this, there are no particular limitations on the distribution of excipients in different layers. In the case of multilayer tablets with three or more layers, it is preferred that the active substance alfarubicin and, ideally, the histidine compound are separately incorporated into the outer layer. For this preferred embodiment, the above limitations apply together with the limitations provided below for tablets having an inner phase and an outer phase (such that the indication of the inner phase applies to at least one of one or more inner layers, while the indication of the outer phase applies to the outer layer and any inner layer that may be present other than the alfarubicin-containing layer).

[0135] internal phase

[0136] The internal phase (if present) preferably contains the following components:

[0137] • Alfabicin or Alfabicin salt (50% to 100% by weight of the total amount of Alfabicin or Alfabicin salt, preferably 100% by weight);

[0138] • Histidine compounds (50% to 100% by weight of the total amount of histidine compounds, preferably 100% by weight);

[0139] • Adhesive (50% to 100% by weight of the total adhesive, preferably 100% by weight);

[0140] • Optional diluent (0% to 100% by weight of the total diluent, preferably 0% to 20% by weight); these amounts do not include the amount of the histidine compound mentioned above;

[0141] • Optional surfactant (50% to 100% by weight of the total surfactant, preferably 100% by weight);

[0142] • Optional disintegrant (40% to 100% by weight of the total amount of disintegrant, preferably 60% to 100% by weight);

[0143] • Optional flow aids (0% to 100% by weight of the total flow aid, preferably 0% to 50% by weight); and

[0144] • Optional lubricant (0% to 100% by weight of the total lubricant, preferably 0% to 50% by weight).

[0145] Additional ingredients such as release rate modifiers, colorants, buffers, flavoring agents, and / or sweeteners may also be present in the internal phase.

[0146] foreign minister

[0147] The external phase (if present) preferably contains the following components:

[0148] • Alfabisin or Alfabisin salt (0% to 50% by weight of total Alfabisin or Alfabisin salt)

[0149] Preferred weight percentage (0%)

[0150] • Histidine compounds (0% to 50% by weight of the total amount of histidine compounds, preferably 0% by weight);

[0151] • Adhesive (0% to 50% by weight of the total adhesive, preferably 0% by weight);

[0152] • Optional diluent (0% to 100% by weight of the total diluent, preferably 80% to 100% by weight); these amounts do not include the amount of the histidine compound mentioned above;

[0153] • Optional surfactant (0% to 50% by weight of the total surfactant, preferably 0% by weight);

[0154] • Optional disintegrant (0% to 60% by weight of the total amount of disintegrant, preferably 0% to 40% by weight);

[0155] • Optional flow aids (0% to 100% by weight of the total flow aid, preferably 50% to 100% by weight); and

[0156] • Optional lubricant (0% to 100% by weight of the total lubricant, preferably 50% to 100% by weight).

[0157] The above weight percentages are calculated for the total weight of the corresponding compound in 100% by weight of a tablet. For example, according to the above instructions, a tablet containing 240 mg of alfabicin is prepared, with 200 mg of alfabicin in the internal phase and 40 mg of alfabicin in the external phase. This distribution corresponds to 83% by weight of alfabicin in the internal phase and 17% by weight in the external phase. Therefore, it conforms to the range specified above.

[0158] Additional ingredients such as release rate regulators, buffers, colorants, pigments, flavorings and / or sweeteners may also be present in the external phase.

[0159] Coating

[0160] The tablets of the present invention may optionally be coated, regardless of whether they are single-layer tablets, multi-layer tablets, or tablets having internal and external phases. Such coatings can be used for aesthetic purposes and can also facilitate the tracking, handling, and swallowing of tablets and / or provide protection.

[0161] The materials suitable for coating are not particularly limited. Typically, the coating contains the film-forming agents described above, with a preferred or more preferred combination of these agents preferred. Additional components such as plasticizers, colorants and / or pigments, and anti-sticking agents may also be present in the coating.

[0162] capsule

[0163] In another embodiment, the pharmaceutical composition may be in capsule form. In this embodiment, the ingredients of this application preferably include the above-described materials:

[0164] • Alphabeus Star;

[0165] Histidine compounds;

[0166] • Optional adhesives;

[0167] • Optional diluent;

[0168] • Optional but preferred surfactants;

[0169] • Optional but preferred disintegrants;

[0170] • Optional lubricants; and

[0171] • Optional glialization agents

[0172] The relative amounts of these components are preferably the same as specified above. The components of the capsule composition can be provided and introduced into the capsule shell in powder or granule form.

[0173] The capsule shell can be made of gelatin or any other material, such as polyvinyl alcohol and polyvinyl alcohol-based polymers, alginate, or amylopectin (pullulan). Similar to the case of adhesives described above, capsules containing starch materials and / or modified release agents are preferred. However, unlike the above, cellulose materials should be completely avoided as capsule materials. Gelatin is preferred. There are no particular limitations regarding capsule size and / or the amount of composition to be filled into the capsule shell.

[0174] Manufacturing method

[0175] The tablets of the present invention can be manufactured using conventional equipment and techniques. Such manufacturing methods may particularly include a first step of dry mixing and granulating a portion or all of the components of the composition, followed by a step of mixing any remaining components of the composition, then compressing the resulting mixture, and finally an optional coating step.

[0176] In this method, the granulation type can be selected from wet granulation, dry granulation, and melt granulation. In another method of the invention, the granulation step can be completely omitted (i.e., direct compression). After granulation but before compression into tablets, the resulting particles are preferably screened and / or ground to obtain the desired particle size. In the case of wet granulation, the particles are further dried before or after sieving and / or grinding. The preferred granulation solution for wet granulation is water, which may optionally contain a binder.

[0177] In the composition of the present invention, it is preferable to mix a portion or all of the cosolvent, lubricant, disintegrant and diluent after the granulation step, while granulating the remaining components (excluding, of course, components for selective coating).

[0178] Tablets having internal and external phases can, in principle, be manufactured in the same manner as described above, but with the following modifications: Separate compositions for the internal and external phases are prepared, and the composition for the internal phase is granulated. Then, the granulated composition for the internal phase is blended with the composition for the external phase, and the resulting blend is compressed in a tableting machine to obtain the final tablet having both internal and external phases.

[0179] The capsules of the present invention can be prepared by: dry mixing a portion or all of the components of the composition, optionally granulating the mixture, mixing any remaining components, and finally introducing the resulting composition into a capsule shell.

[0180] use

[0181] The pharmaceutical compositions of the present invention are suitable for treating bacterial infections in patients in need. In particular, they are suitable for treating infections caused especially by Staphylococcus aureus (including methicillin-resistant Staphylococcus aureus), such as acute bacterial skin and skin structure infections (ABSSI) or diabetic foot-related bacterial infections.

[0182] The pharmaceutical compositions of the present invention are administered to patients orally. Typically, a single unit dose of the pharmaceutical composition of the present invention is administered at least once daily, and preferably twice daily. The daily dose is determined by a physician based on the severity of the infection, the patient's sex, weight, age, and general condition. The typical daily dose range for humans is 120 mg to 480 mg. A typical daily dose of 120 mg or 240 mg twice daily results in a total daily dose of 240 mg to 480 mg. Therefore, the preferred unit dose strength of the pharmaceutical compositions of the present invention is 120 mg or 240 mg of the active pharmaceutical component (calculated in terms of afarubicin; for example, if afarubicin ethanolamine is used, the preferred unit dose strength based on the total weight of afarubicin ethanolamine is 150 mg or 300 mg, respectively).

[0183] The patients to be treated are mammals, typically selected from humans, companion animals, and food animals, with humans being the preferred choice.

[0184] Preferred Implementation

[0185] The invention is particularly preferred to be carried out by combining two or more embodiments characterized as preferred in the foregoing description or the appended claims. Similarly, it is preferred to combine embodiments with different degrees of preference, for example, combining a preferred adhesive material with a particularly preferred tablet type.

[0186] The following preferred embodiments are important and are therefore specifically mentioned:

[0187] (A) According to a set of preferred embodiments, two or more components of the pharmaceutical composition containing alfabecin and a histidine compound are selected from a preferred list of ingredients. That is, preferably, for two or more of the following component types (A1) to (A6), the corresponding components are selected from the following preferred list of ingredients:

[0188] (A1) An adhesive selected from polyvinylpyrrolidone and copolyvinylpyrrolidone and combinations thereof;

[0189] (A2) The diluent is selected from mannitol, xylitol, sorbitol, isomaltitol and combinations thereof, with mannitol, isomaltitol and combinations thereof being the most preferred.

[0190] (A3) Sodium dodecyl sulfate as a surfactant;

[0191] (A4) Crosspovidone as a disintegrant;

[0192] (A5) Colloidal silica as a flow aid; and

[0193] (A6) Lubricant selected from magnesium stearate and sodium stearoyl fumarate and combinations thereof.

[0194] More preferably, all of the above-mentioned component types are selected from the above-mentioned preferred component list.

[0195] (B) A particularly preferred embodiment of the invention relates to a solid pharmaceutical composition in the optional form of a coated tablet (having an internal phase and an external phase), (B1) wherein the internal phase comprises:

[0196] 40% to 60% by weight of alfabracin or its salt (calculated as alfabracin ethanolamine), with a histidine compound in a molar ratio of 1 to 2 relative to alfabracin or its salt.

[0197] 0% to 10% by weight of diluent (these amounts do not include the histidine compounds mentioned above).

[0198] 3% to 6% by weight of adhesive,

[0199] 1% to 6% by weight of surfactant, and

[0200] 1.2% to 10% by weight of disintegrant,

[0201] 0% to 0.5% by weight of gliding agent,

[0202] Lubricant ranging from 0% to 1.75% by weight,

[0203] And / or (B2) wherein the external phase includes:

[0204] 8% to 50% by weight of diluent (these amounts do not include the histidine compounds mentioned above),

[0205] 0% to 4% by weight of disintegrant

[0206] 0.1% to 1% by weight of a gliding agent, and

[0207] 0.25% to 3.5% by weight of lubricant,

[0208] And / or (B3) wherein the tablets are coated with a coating containing the following substances:

[0209] 0.5% to 6% by weight of film-forming agent, and

[0210] 0.1% to 1.5% by weight of plasticizer.

[0211] All of the above relative amount indications are based on the total weight of the tablets.

[0212] A particularly preferred formulation is an uncoated tablet, characterized by the following components and their relative amounts.

[0213] Internal appearance:

[0214] 55% to 59% by weight of alfabicin ethanolamine,

[0215] 19% to 23% by weight histidine,

[0216] 5.75% to 7.75% by weight of adhesive,

[0217] 5.0% to 7.0% by weight of surfactant, and

[0218] 2.0% to 4.0% by weight of disintegrant,

[0219] and Foreign Secretary:

[0220] 1.0% to 3.0% by weight of disintegrant,

[0221] 0.1% to 0.9% by weight of a gliding agent, and

[0222] 2.0% to 5.0% by weight of lubricant.

[0223] The tablet is preferably manufactured by mixing and wet granulating the inward-facing components, then mixing the outward-facing components, and then compressing.

[0224] A more particularly preferred embodiment is characterized by the following composition and amounts (in mg / tablet):

[0225] Internal appearance:

[0226] Alfarubicin ethanolamine: 300.41 (equivalent to 240.00 mg alfarubicin)

[0227] Povidone: 34.65

[0228] L-histidine: 112.65

[0229] Sodium dodecyl sulfate: 30.00

[0230] Chloroprene: 15.75

[0231] Foreign Minister:

[0232] Chloroprene: 10.51

[0233] Colloidal silica: 2.40

[0234] Magnesium stearate: 18.00

[0235] Of course, tablets are more preferred, wherein the characteristics of groups (B1) and (B2) are satisfied. Tablets that simultaneously satisfy the characteristics of groups (B1), (B2) and (B3) are particularly preferred.

[0236] (C) According to another particularly preferred embodiment, the pharmaceutical composition is in the form of an uncoated tablet, or in the form of a coated tablet wherein the coating comprises polyvinyl alcohol and a second film-forming agent, or in the form of a gelatin capsule.

[0237] (D) According to a more preferred embodiment, the tablets described above, especially the tablets described in any one of embodiments (A), (B) or (C) described above, contain alfabicin in the form of a diethanolamine salt.

[0238] The most preferred tablets are those that simultaneously satisfy the preferred characteristics of groups (A), (B), (C), and (D). Ideally, this includes combinations of all preferred subgroups (including (A1) to (A6) and (B1) to (B3)).

[0239] Another particularly preferred formulation is an uncoated tablet, characterized by the ingredients and their relative amounts as described below.

[0240] Internal appearance:

[0241] 48% to 52% by weight of alfabicin ethanolamine,

[0242] 17% to 21% histidine

[0243] 4.75% to 6.75% by weight of adhesive,

[0244] 4.0% to 6.0% by weight of surfactant, and

[0245] 1.6% to 3.6% by weight of disintegrant,

[0246] and Foreign Secretary:

[0247] 10.5% to 14.5% by weight of diluent (this amount does not include the histidine compound mentioned above).

[0248] 0.75% to 2.75% by weight of disintegrant,

[0249] 0.1% to 0.7% by weight of a gliding agent, and

[0250] 2.0% to 4.0% by weight of lubricant.

[0251] The tablet is preferably manufactured by mixing and wet granulating the inward-facing components, then mixing the outward-facing components, and then compressing.

[0252] The particularly advantageous formulation according to the above preferred embodiments is characterized by the presence of the following specific components:

[0253] Polyvinyl ketone as an adhesive

[0254] Sodium dodecyl sulfate as a surfactant

[0255] Crosspovidone as a disintegrant

[0256] Isomaltitol or mannitol, other than histidine, can be used as diluents.

[0257] Colloidal silica as a flow aid, and

[0258] Magnesium stearate as a lubricant.

[0259] By using these particularly preferred specific ingredients and their particularly preferred relative amounts, the following particularly preferred formulations are obtained:

[0260] Internal appearance:

[0261] 48% to 52% by weight of alfabecin ethanolamine,

[0262] 17% to 21% histidine

[0263] 4.75% to 6.75% by weight of povidone,

[0264] 4.0% to 6.0% by weight of sodium dodecyl sulfate, and

[0265] 1.6% to 3.6% by weight of cropovidone,

[0266] and Foreign Secretary:

[0267] 10.5% to 14.5% by weight of isomaltitol and / or mannitol,

[0268] 0.75% to 2.75% by weight of cropovidone,

[0269] 0.1% to 0.7% by weight of colloidal silica, and

[0270] 2.0% to 4.0% by weight magnesium stearate.

[0271] The tablet is preferably manufactured by mixing and wet granulating the inward-facing components, then mixing the outward-facing components, and then compressing.

[0272] The particularly preferred embodiments are characterized by the following composition and amounts (in mg / tablet):

[0273] Internal appearance:

[0274] Alfarubicin ethanolamine: 300.41 (equivalent to 240.00 mg alfarubicin)

[0275] Povidone: 34.65

[0276] L-histidine: 112.65

[0277] Sodium dodecyl sulfate: 30.00

[0278] Chloroprene: 15.75

[0279] Foreign Minister:

[0280] Isomaltitol: 75.63

[0281] Chloroprene: 10.51

[0282] Colloidal silica: 2.40

[0283] Magnesium stearate: 18.00

[0284] Another particularly preferred embodiment is characterized by the following composition and amounts (in mg / tablet):

[0285] Internal appearance:

[0286] Alfarubicin ethanolamine: 300.41 (equivalent to 240.00 mg alfarubicin)

[0287] Povidone: 34.65

[0288] L-histidine: 112.65

[0289] Sodium dodecyl sulfate: 30.00

[0290] Chloroprene: 15.75

[0291] Foreign Minister:

[0292] Mannitol: 75.63

[0293] Chloroprene: 10.51

[0294] Colloidal silica: 2.40

[0295] Magnesium stearate: 18.00

[0296] The specific preferred embodiments described above describe pharmaceutical compositions in tablet form. These tablets can be used in an uncoated form as described above, or they can be further coated to, for example, improve their chemical stability or aesthetic appearance. For example, the tablets can be coated with a coating composition comprising 2 to 9 parts by weight relative to 100 parts by weight of an uncoated tablet, the composition comprising a combination of polyvinyl alcohol with a second film-forming agent, a colorant and / or pigment, and an anti-adhesive and a plasticizer.

[0297] Of course, such particularly preferred embodiments may additionally implement other features as preferably described elsewhere in this specification or as described in the appended claims.

[0298] Example

[0299] Examples 1 to 8 and Comparative Examples 1 to 11

[0300] Tablets having an internal and external phase are manufactured by wet granulation using the materials and methods specified in Tables 1, 2, 3 and 4 below.

[0301]

[0302]

[0303]

[0304]

[0305] The solubility properties of the aforementioned drug components were determined through in vitro experiments using fasting-state simulated gastric juice (FaSSGF) over a period of 60 minutes. Due to the limited solubility of the active drug components, this identification method is best suited for testing compositions containing up to 40 mg of afarubicin. Therefore, even if there is an intention to develop a drug composition containing more afarubicin, it is recommended to proportionally reduce the amounts of all components (to keep the relative amounts constant and the afarubicin content no higher than 40 mg), test the drug composition, and then infer the drug composition of interest from the obtained test results.

[0306] A dissolution test was conducted in basket apparatus 1 under the following conditions:

[0307] Temperature: 37.0℃±0.5℃

[0308] Speed: 100 rpm for the first 45 minutes, then 250 rpm for 15 minutes.

[0309] Dissolution medium and volume: 1000 mL FaSSGF

[0310] Number of units tested: 3 or 6

[0311] The results of the experiment showed that... Figure 1 , 2 , 3 and 4. Figure 1 and Figure 2 The dissolution characteristics of the sample before storage under forced conditions are shown. Figure 2 and Figure 3 The dissolution characteristics of those samples that showed satisfactory solubility before storage were displayed after storage under forced conditions. These results confirmed the minor differences in the in vitro dissolution profiles among the eight inventive compositions: Examples 1 to 8 exhibited rapid dissolution over time (initially and after 15 days under forced conditions at 40°C / 75% RH). These results were evaluated as satisfactory. In contrast, Figure 2 The initial dissolution of Comparative Examples 3, 6, and 11 was slow, but the initial dissolution of the remaining Comparative Examples 1, 2, 4, 5, 7, 8, 9, and 10 was relatively rapid. However, all Comparative Examples 1, 2, 4, 5, 7, 8, 9, and 10 showed slow dissolution after storage under forced conditions, such as... Figure 4 As shown. These slow dissolution characteristics were evaluated as unsatisfactory.

Claims

1. A solid pharmaceutical composition in unit dose form, said composition comprising afabicin or a pharmaceutically acceptable salt thereof, histidine or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

2. The solid pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises 20 mg to 480 mg of afabicin or a pharmaceutically acceptable salt thereof.

3. The solid pharmaceutical composition of claim 1 or 2, wherein the composition is in tablet form, the tablet comprising an internal phase and an external phase, wherein afabicin or a pharmaceutically acceptable salt thereof is contained only in the internal phase.

4. The solid pharmaceutical composition of claim 1 or 2, wherein the composition comprises a binder selected from the group consisting of povidone, copovidone, poloxamer, polyethylene glycol, magnesium aluminosilicate, gelatin, gum arabic, dextrin, glucose binder, dextrose, polydextrose, guar gum, hydrogenated vegetable oil, liquid glucose, wax, maltose, sucrose, lactose, and mixtures thereof.

5. The solid pharmaceutical composition of claim 1 or 2, wherein the composition comprises a diluent selected from the group consisting of mannitol, isomaltitol, lactose, calcium phosphate, calcium carbonate, calcium sulfate, sucrose, fructose, maltose, xylitol, maltitol, lactitol, trehalose, aluminum silicate, cyclodextrin, dextran, polydextrin, glucose, dextrin, glucose binders, magnesium carbonate, and mixtures thereof.

6. The solid pharmaceutical composition of claim 1 or 2, wherein the composition comprises a surfactant selected from the group consisting of sodium dodecyl sulfate, poloxamer, sodium docusate, sodium deoxycholate, sorbitan esters, sucrose esters of fatty acids, tyloxapine, lecithin, and polysorbate esters and mixtures thereof.

7. The solid pharmaceutical composition of claim 1 or 2, wherein the composition comprises a disintegrant selected from the group consisting of cross-linked povidone, magnesium aluminosilicate, colloidal silica, guar gum, and mixtures thereof.

8. The solid pharmaceutical composition of claim 1 or 2, wherein the composition is in capsule form, the capsule comprising alfabecin or a pharmaceutically acceptable salt thereof in powder or granule form and one or more pharmaceutically acceptable excipients.

9. The solid pharmaceutical composition of claim 1 or 2, wherein the composition is in tablet form, the tablet comprising an internal phase and an external phase, wherein the histidine is contained only in the internal phase.

10. A method for manufacturing a solid pharmaceutical composition according to any one of claims 1 to 7, said method comprising the following steps in a specified sequence: (i) Dry mixing one or all of the components of the composition; (ii) Granulate the resulting mixture to obtain particles; (iii) Mixing any remaining components of the composition into the particles; and (iv) Compress the resulting mixture to obtain compressed tablets.

11. The method of claim 10, further comprising the step of: (v) Coating the compressed tablets obtained in step (iv).

12. The method of claim 10 or 11, wherein the granulation step is performed by wet granulation or dry granulation.

13. The method of claim 10 or 11, wherein at least one of the following conditions is satisfied: (a) A diluent is present, and a portion of the diluent is mixed into the particles of step (ii); (b) A disintegrant is present, and a portion of the disintegrant is mixed into the particles of step (ii); (c) A flow aid is present, and some or all of the flow aid is mixed into the particles of step (ii); and / or (d) A lubricant is present, and some or all of the lubricant is mixed into the particles of step (ii).

14. Use of the solid pharmaceutical composition of any one of claims 1 to 9 in the preparation of a medicament for treating bacterial infections in mammals, wherein the bacterial infection is caused by a species of Staphylococcus aureus.

15. The use as claimed in claim 14, wherein the infection is an acute bacterial infection of the skin and skin structures or a bacterial infection associated with diabetic foot syndrome.

16. The use as described in claim 14 or 15, wherein the mammal is a human.

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