TW581679B - Water miscible macrolide solutions - Google Patents

Abstract

Water miscible pharmaceutical compositions containing up to about 40% of a macrolide such as an azalide antibiotic are prepared by reaction of the macrolide with acid in a non-aqueous water miscible organic solvent system. A stable water miscible macrolide antibiotic composition comprising: (a) a macrolide antibiotic at a concentration of between about 10% and about 40% by weight, based on the volume of the composition; (b) an acid present in an amount about equimolar to the number of available nitrogen groups present in the macrolide and forming a water soluble salt compound of the macrolide; and (c) a water miscible non-aqueous vehicle composed of a veterinary or pharmaceutically acceptable organic solvent or mixture of solvents, wherein the macrolide antibiotic is erythromycin, an azalide, carbomycin, clarithromycin, josamycin, leucomycins, midecamycins, mikamycin, miokamycin, oleandomycin, pristinamycin, rokitamycin, rosaramicin, roxithromycin, spiramycin, tylosin, troleandomycin or virginiamycin or a derivative of these antibiotics.

Description

581679 A7 __B7___ _ 5. Description of the invention (〇 related applications (please read the notes on the back before filling out this page) This application is US application Serial No. 09/1 1 2,690 (Application date is July 9, 1 998, which has been approved so far, and part of the US · patent application (with an application date of July 1, 999), which is a continuation of all applications. All documents cited herein and documents cited in all cited documents are hereby incorporated herein in their entirety. References. Scope of the Invention The present invention relates to an antibiotic composition suitable for medical use, especially a macrolide antibiotic (eg, azalide) solution that can be mixed with water. BACKGROUND OF THE INVENTION Consumption by employees of the Bureau of Intellectual Property, Ministry of Economic Affairs Cooperatives print macrolides, such as azalides, which are a family of antibiotics that contain multiple member lactone rings linked to one or more deoxysaccharides. Macrolides are generally bacteriostatic, but in It has a bactericidal effect on susceptible organisms at high concentrations. Although macrolides can fight some Gram negative bacteria, they are most effective against Gram-positive cocci and Bacillus. Macrolides Its antibacterial activity inhibits bacterial protein synthesis through reversible binding to 50 S ribosomal subunits. (', Goodman & Gillman's the Pharmacological Basis of Therapeutics' " 9th ed., JG Hadman & LE Limbird, eds ., ch. 47, pp. 1 1 35- 1 140, McGraw-Hill, New York (1996) ° Macrolides are generally colorless crystals. Macrolides such as azalide paper are applicable to China National Standard (CNS) A4 specification (210X297 mm) -4- 581679 A7 B7 V. Description of the invention (2) Ester is generally known as stable in near neutral solution, and its stability is limited in acid or alkali solution. Because glycosidic bonds can be hydrolyzed in acids, lactone rings can be converted in bases (* Principles of Medicinal Chemistry, " 2nd ed., WF Foye, ed ·, ch · 31, ρ · 782-785, Lea & Febiger, Philadelphia (1981)). Therefore it is necessary to prepare stable parenteral (eg intravenous, intramuscular, subcutaneous) that is miscible with water. Pharmaceutical or veterinary administration of macrolide antibiotics Medical composition. Macrolides, including azalides It is soluble in many organic solvents' but only sparingly soluble in water. Macrolide dissolved in a solution of organic solvent systems may be used in human and veterinary intramuscular administration and subcutaneous route. However, such solutions should not be used for intravenous administration, as the macrolide will precipitate when the solution is introduced into a water-soluble medium of body fluids. Although a salt solution of macrolides can be prepared, the stability of this solution is limited, so its use is limited. It can only be used shortly after preparation. A solution of macrolides (including azalides) that can be mixed with water, If it can extend its stable period, it will certainly increase its price in medicine and veterinary medicine. It can be used for intravenous administration to quickly provide therapeutic content in blood, which can effectively treat infectious diseases. Water-miscible solutions can also be absorbed more rapidly from intramuscular and subcutaneous injection sites, resulting in higher concentrations in body fluids and more effective control of infectious diseases. This solution can also be administered orally in poultry and swine water. Summary of the Invention The present invention provides a stable, high-efficiency, water-miscible large ring. The paper size is applicable to the Chinese National Standard (CNS) A4 (210X25) 7 mm.) (Please read the precautions on the back before filling in this Page) Order m! Printed by the Consumer Cooperatives of the Intellectual Property Office of the Ministry of Economic Affairs -5- 581679 A7 ____B7_ V. Description of the invention (3) Esters (such as azalide) preparations. Macrolides contain at least one basic nitrogen group, which can be converted into a stable water-miscible composition by adding an acid to a non-aqueous solution. The resulting composition has a stable growth period and does not cause the precipitation of macrolides (such as azalactones) when introduced into a water-soluble environment. The amount of this acid added is about the same as the nitrogen in the solution. This method can prepare 40% of macrolides (such as azalactones). Such and other specific embodiments are disclosed in or are apparently included in the detailed description below. Detailed description Macrolides, including erythromycin and its derivatives and other derivatives such as azalactone. Erythromycin (MW 733 · 94 ear swallows) is a common name for macrolide antibiotics, produced by the erythromycin Streptomyces strain. It is a mixture of three erythromycins A, B, and C, mainly composed of erythromycin, and its molecular formula is: (Please read the precautions on the back before filling this page), -ιτο System

The chemical name is (3R *, 4S *, 5S *, 6R *, 7R *, 9R *, 11R *, 12R *, 13S *, 14R *) The paper size is in accordance with China National Standard (CNS) A4 specification (210X297 (Mm) 'a-6-581679 A7 B7 V. Description of the invention (4) —4— [, 6 —Dideoxy 1 — 3 — C —Methyl 3 — 〇1 (Please read the precautions on the back before (Fill in this page) Methyl-a — L — Ribose — Hexanosyl) —oxy] — 14 —Ethyl 7, 12, 13 — Trihydroxy — 3, 5, 7, 9, 11, 11 — Hexamethyl-6 [[3,4,6 -Trideoxy-3-(dimethylamino) -p-D-xylose-heptylhexosyl] oxy] oxetradecane 1,2,10-dione, (C37H67N〇13) 〇 Erythromycin has extensive and necessary antibacterial effect against many Gram-positive and certain Gram-negative bacteria and other organisms, including bacteroids Body, Borrelia, Chlamydia and Rickettsia. It is used in humans to treat many infections. Veterinary medicine can treat infectious diseases, such as pneumonia, mastitis, metritis, rhinitis, and bronchitis of cattle, pigs and sheep. Other derivatives of erythromycin printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, including: carbonomycin, Clarithromycin, josamycin, and leucomycin , Medecamycin, mikamycin, miokamycin, oleandomycin, prisomymycin, rocamycin (Rokitamycin)), rosaramicin, roxithromycin, spiramycin, tylosin, troleandomycin, and veriliomycin素 (virginiamycin). Many derivatives of erythromycin exist as a mixture. For example, carbonomycin is a mixture of carbonomycin A and carbonomycin B. Leucomycin exists as a mixture of Ai, A2, A3, A9, B1-B4, U and V in various proportions. Ingredient A 3 is also known as josamycin (this paper size is applicable to Chinese National Standard (CNS) A4 specifications (210X29 < 7 mm)) — 581679 A7 ____ B7 5. Description of the invention (5)) Leucomycin V is also called miokomycin. The main component of medecamycin is medecamycin A, and the minor component is midecamycin A 2, A 3 and A ′ 1. Similarly, mikamycin is a mixture of many ingredients mikamycin A and B. Mikamycin A is also known as virginiamycin M 1. Pristinamycin consists of Pristinamycin I a, IB, and I c, which are the same as Virginiamycin B 2, B! 3, and B 2 respectively. Primostomycin (Pristinamycin) II a and II b are the same as virginiamycin M1 and 2 6 '2 7 —monohydrovirimycin (virginiamycin) M1. Spiramycin consists of three components (spiramycin I, Π, and H). Viriminiarnycin is composed of Virginiamycin S 1 and Viriminiarnycin M 1. All such ingredients can be used in the present invention. The sources of such macrolides are known and described in references, e.g., The Merck Index / 12th ed., S. BudalTri, ed., Merck & Co., Inc., Whitehouse Station, NTU (1 996). Azalactone is a semisynthetic macrolide antibiotic related to erythromycin A and has similar solubility characteristics. Such compounds include the following general structure. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) — (Please read the precautions on the back before filling this page). Printing-8- 581679 A7 B7 V. Description of Invention (6

Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs and its pharmaceutically acceptable _ and esters, and its pharmaceutically acceptable metal complexes, where R 1 is hydrogen; hydroxyl; C 1 4 oxygen Base; formamyl; C 1 1. Alkylcarbonyl, Ci i. Alkoxycarbonyl, aryloxycarbonyl 'C 1 1Q aralkyloxycarbonyl, (:!:. Alkylsulfonyl, or arylsulfonyl wherein the C 1 i D alkyl or aryl is unsubstituted Or substituted with χ-3 halogen (F'Ci'Br), hydroxyl, amine, c_amino, or Ci.1 alkyl; or unsubstituted or substituted with ci 0 yl, C 2 i D ene Or c 2 i. Alkynyl substitution, in which the substituent is independently 1 to 3 / N (a) aryl or heteroaryl, depending on the choice of 1 ~ 3 exposure element (F, c 1, B r , &Quot;, c 1 " octyl, Cl 3 alkoxy, amine, C 1 4 alkylamino, bis (ci 4 alkyl) amino or hydroxy substituted, (b) heterocyclic group depending on choice The hydroxyl, amine, and paper sizes of this paper are suitable for Nakae County (CNS) A4 specifications (21GX297). (Please read the precautions on the back before filling this page) k. Order ~ 9-581679 A7 --- ----- B7 V. Description of the invention (7) C 1 1 alkylamino group, di (C! Alkyl) amino group (please read the precautions on the back before filling this page) '^: ^ alkylcarbonyl Oxygen or Cl! Alkylcarbonylamino substitution, (c) halogen (; p, Ci, Bi · or I), (d) Selected by the group acylated 0 0 '0 Ji h W //

RaC or S where

Ra is hydrogen, Ci 6 alkyl, aryl, heteroaryl'aralkyl, or heteroaralkyl and R b is C 1 6 alkyl or aryl, (e) C 1 i Q alkoxy, ( f) aryloxy or isoyloxy is optionally selected and substituted by 1-3 halogen, hydroxyl, amine or C i 4 alkyl, (g) fl female or C 1 1 D alkylamino is optional Deuterated by

RaC, RaOC Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs or a Rh S〇2, where R a and R b are as defined above, (h) Di (Ci iq-based) amine '(i) arylamine Group, heteroarylamino group, aralkylamino group or heteroaralkylamino group, where the aryl or heteroaryl group is selected as required. This paper size is applicable to the Chinese National Standard (CNS) A4 specification (2 丨 〇 > <; 297 mm) 10-

V. Description of the invention (8) Optional substitution by 1-3 halogen, hydroxy, amine or C it alkyl (Please read the notes on the back before filling this page) (j) Hydrothio, (k) C 1 1 D alkylthio, alkylsulfinyl or alkylsulfonyl, arylsulfur, arylsulfinyl or arylsulfonyl ', where the aryl group is selected by 1 to 3 Halogen, hydroxy, amine or C! .4 alkyl substitution, (1) formamyl, (m) Cl-1Q alkylcarbonyl, (η) arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl or hetero Square radical, carbonyl, wherein the aryl or heteroaryl is optionally substituted with 1 to 3 halogen, hydroxyl, amine or C: 4 alkyl, ... (〇) carboxyl, (P) C 1 1D alkoxy Carbonyl, printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs (q) aryloxymine, heteroaryloxycarbonyl, aralkyloxyfluorenyl, or heteroaralkyloxycarbonyl, where the aryl or heteroaryl The base depends on the choice of 1 to 3 halogen, hydroxy, amine or C i 4 alkyl substitution, (r) formamidine or sulfamoyl 'where N-atom depends on the choice of 1 to 2 C i 6 alkyl or C 4 6 e Basic bond substitution, (s) cyano, (t) isonitrogen basic paper size applies Chinese National Standard (CNS) A4 specification (21〇297 public envy) • 11-581679 A7 — ^ __! Z____ 5. Description of the invention (9 ) (u) nitro, (V) azido, (Please read the notes on the back before filling out this page) (W) Imino group is selected as nitrogen or carbon via C ii. Alkyl substitution, (X) keto or (y) sulfur bridge; if the length of the alkyl chain is not more than two carbon atoms, it may be selected by 1-2 oxygen, sulfur or nitrogen (NR-where r For hydrogen or C] L3 alkyl). R] L 0 is hydrogen or R] 1 and R 1 0 are both C 1-C 3 and are optionally substituted by keto groups; R 1 and R 4 are C 1--C 3 The keto-substituted R: 2 and R 3 are gas, Cl 1 0 alkyl, aryl R 2 and R 3 are selected to print keto and sulfur for the consumer cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs; R 1 and R 5 is independently hydrogen and alkyl carbonyl; R 1 and R 5 together apply the Chinese National Standard (CNS) A4 specification (210X297 mm) for this paper size -12- «1Ό / ^ V. Description of the invention (j A7 B7 carbonyl ;

R6 and R7 are both hydrogen or R printed by the Industrial and Commercial Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs and one of R7 is hydrogen and the other is hydroxyl and oxy-oxygenated. Group, alkoxy group, arylcarbonyloxy group and aralkylcarbonyloxy group, or -n HR 1 2 'where R12 is hydrogen, arylsulfonyl or heteroarylsulfonyl. 3 halides or c 1 3 alkyl substituted, alkyl sulfonyl, $ 0-C,, A, R13 where X is a bonding bond, 0_NH, A is a bonding bond or C 1 -C 3 alkylene RU is hydrogen, ei 1 () alkyl, aryl, aralkyl, heteroaryl, heterocyclyl, or C3-C7 cycloalkyl, and any R 1 3 except hydrogen may be subjected to one or more halogen, hydroxyl , C! -C3 alkoxy, cyano, isonitro, nitro, amine, mono

C —or di- (Ci — c alkylamino, hydrogenthio)

Cl-C3 alkylsulfide, Cl-C3 alkylsulfinylsulfenyl group, C1-C3 alkylsulfinylsulfenyl group, arylsulfide, arylsulfinyl group, aminesulfinyl group, arylsulfinyl group, Carboxyl, carbamate, Ci-c3 alkylcarbonyl, or C c3 alkoxycarbonyl substitution; This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) (Please read the precautions on the back first Fill in this page) 13- 581679 A7 B7 V. Description of the invention (〇6 and R7 _ together are keto, hydroxyimine, alkoxyimine, aralkyloxyimine or aminoimine; R 8 is a methyl group, an aralkyloxycarbonyl group, and an arylsulfonyl group; R is a gas group, a methyl group, a Cl 10 alkyl group, a Cl 10 alkyl carbonyl group, and an aryl alkoxycarbonyl group; And η are independent integers of 0 or 1. The metal complexes are copper, zinc, cobalt, nickel, and cadmium. Such compounds are disclosed in EP 5 6 8 6 9 and are incorporated herein by reference in their entirety. The components of azalactone are technically known and further derivatives are described in, for example: US Patent Nos. 5,869,629; 5,629,296; 5,434,140; 5,332,807; US 5,2501518; 5,215 , 890: and 5,2 1 0,235, the entire text of which is incorporated herein by reference. The most preferred is azithromycin. The structure of azithromycin is (please read the precautions on the back first) (Fill in this page again) Printed by the Consumer Cooperative of the Intellectual Property Office of the Ministry of Economic Affairs h3c

The structure of the compound of formula I and formula Π in this paper is as follows: The paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) -14- 581679 A7 B7 V. Description of the invention (j

〇 where De s is desosomine, C 1 a d is red plum sugar (formula I) and (Please read the precautions on the back before filling this page)

Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs (Form Π). The compound of formula II is also called 8a-azalactone. Such compounds are disclosed in EP 5 0 6 9 9 which is hereby incorporated by reference in its entirety. Macrolides corresponding to basic and acid addition salts and ester derivatives' include azalactone compounds, and can also be considered for use. Such salts are formed from corresponding organic or inorganic acids or bases. Such derivatives include general hydrogen chloride and phosphate salts as well as acetate, propionate and butyrate esters. Such derivatives have different names. For example, the phosphonate salts of oleandomycin are called matromycin and its triethyl derivative is called trioleamycin (oleolemycin). Rocco's large paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) ^ -15- 581679 A7 B7 V. Description of the invention (^ Rokitamycin is called leucomycin V 4 -B-butyrate, 3B-propionate. When the composition of the present invention is prepared in this form, an appropriate amount of acid can be added to make the molar number of the acid in the solution approximately equal to the nitrogen atom of the molecule. All pharmaceutically or veterinarily acceptable inorganic or organic acids. Organic acids include mineral acids such as hydrohalic acids, such as hydrogen bromide and hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid. Organic acids include all pharmaceutically or veterinary acceptable Accepted aliphatic, aliphatic cyclic and aromatic carboxylic acids, dicarboxylic acids, tricarboxylic acids and fatty acids. Preferred acids are linear or branched, saturated or unsaturated Ci-C2 〇 Aliphatic carboxylic acid, optionally substituted with halogen or hydroxyl, or C 6 -C i 2 aromatic carboxylic acid. Examples of such acids are carbonic acid, formic acid, fumaric acid, acetic acid, propylene Acids, isopropanoic acid, valeric acid, α-hydroxy acids, such as ethanol And lactic acid, chloroacetic acid, benzoic acid, methanesulfonic acid, and salicylic acid. Examples of dicarboxylic acids include: oxalic acid, malic acid, succinic acid, tartaric acid, and anhydrous malic acid. Examples of tricarboxylic acids are lemons Acids. Fatty acids include all pharmaceutically or veterinarily acceptable saturated or unsaturated aliphatic or aromatic carboxylic acids having 4 to 24 carbon atoms. Examples include butyric acid, isobutyric acid, second -Butyric acid, lauric acid, hexadecanoic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, and phenyl stearic acid. Other acids include gluconic acid, glucoheptanoic acid, and lactobionic acid. Various organic solvents Or a solvent mixture can be used as a composition carrier. The solvent includes an organic solvent that can be mixed with water, wherein the macrolide can be dissolved and is a pharmaceutically or veterinarily acceptable solvent. Such compounds include: alcohols, Alcohols, triols, esters, amines, and ethers. Suitable for solvents. Paper size applies to China National Standard (CNS) A4 specifications (210X29 * 7 mm 1 ~~ '-16- (please first (Read the notes on the back and fill out this page) Order- Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 581679 A7 B7 V. Description of the invention ((Please read the notes on the back before filling this page) Examples, including 'methanol, ethanol, propanol, butanol, glycerin, propylene glycol; Polyethylene glycols, such as polyethylene glycol 200, polyethylene glycol 300, and polyethylene glycol 4 0; pyrrolidone, such as: N-methylpyrrolidone and 2-pyrrolidone; glycol ethers, such as: propylene glycol mono Methyl ether, dipropylene glycol monomethyl ether, and diethylene glycol ether. Other solvents include: di (ethylene glycol) ether (transcutol), di (ethylene glycol) ether acetate, and dimethyl isosorbide. Ether (Arlasolve DMI), bis (propylene glycol) methyl ether (DowanolDPM), bis (propylene glycol) methyl ether acetate, glyceryl formate, glycofurol, isoketyl glycerol (Solketal), isopropyl myristate, N, N, dimethylacetamide, PEG 300, propylene glycol, and glyceryl triacetate. Ester can also be used. It is also possible to use polar aprotic solvents such as DM S0. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Antioxidants may be added to the composition of the present invention. Preferred antioxidants contain sodium. Particularly preferred antioxidants include sodium bisulfite, monothioglycerol, and sodium formyl sulfonate. The composition of the present invention can be easily prepared by adding a molar acid equivalent to the nitrogen group of the macrolide. For example, if there are three nitrogen groups, about 2.7 to 3.3 moles of acid is added. If there are two nitrogen groups, approximately 1.8 to 2.2 · of acid are added. Erythromycin contains a nitrogen group and approximately 0.9 to 1.1 moles of acid is added. For example, when preparing a composition of erythromycin or 8 a-azalide as a macrolide, first add a mol acid such as acetic acid or the number of macrolide nitrogens to the selected organic solvent or solvent. (Hu Pao). Then add erythromycin or 8a-azalactone and stir the mixture until it is completely dissolved. It is also possible to add all the dry ingredients to a container and then stir to add the solvent or solvent mixture. Other macrolides use similar methods. The paper size is in accordance with Chinese National Standard (CNS) A4 (210X29 * 7). -17- 581679 A7 B7 ___ V. Description of the invention (^ Preparation. _ (Please read the back first) Note: Please fill in this page again.) In the same way, the present invention relates to stable macrolide antibiotic compositions which can be mixed with water, including: a) macrolides, such as azalide 'or its derivatives, Concentrations ranging from about 10% to about 40% by weight, based on the volume of the composition; b) Modified with a molar acid such as a nitrogen group of a macrolide (eg, azalactone) to form water-soluble A macrolide acetate compound; and c) a water-miscible water-insoluble carrier consisting of a suitable organic solvent or solvent mixture. Macrolides, such as azalactone or erythromycin, are more advantageous in their basic form. Particularly preferred macrolides are 8a-azalides in the form of their bases. The composition can be provided in the form of an advantageous sterilized injection composition. Macrolides preferably have a concentration of about 7.5 to about 30%, more preferably greater than 7.5 to about 25%, and most preferably about 10 to about 20% by weight of the composition. The volume shall prevail). Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economics The carrier is advantageously composed of propylene glycol monomethyl ether, or dipropylene glycol monomethyl ether, or diethylene glycol ether, or a mixture thereof. The carrier is advantageously composed of N-methylpyrrolidone, or glyceryl formate or benzamyl benzoate, at a concentration of about 30% to about 50% by volume and equilibrated with propylene glycol. The carrier may also consist of N-methylpyrrolidone or glyceryl formate at a concentration of about 30% to about 50% by volume and using polyethylene glycol 200, polyethylene glycol 300, or polyethylene glycol. Alcohol 4 0 0 equilibrium. In particular, the present invention relates to a stable 8 a-azalide composition that can be mixed with water, including: a) 8 a-azalactone, with a concentration of about 10% to the paper standard applicable to the Chinese National Standard (CNS) A4 specifications (210X297) -18-581679 A7 B7 V. Description of the invention (y about 20% by weight, based on the volume of the composition; b) succinic acid, about 1.1 to about 1.5% and formed Water-soluble azalide succinate compounds; and c) a water-miscible water-insoluble carrier consisting of a suitable organic solvent or solvent mixture. The invention further relates to a method for preparing a stable, highly effective macrolide antibiotic composition which can be mixed with water, comprising the steps of: a) preparing an organic solvent or a solvent-insoluble carrier which can be mixed with water; b) Macrolides, such as azalides, are added with acids, and the total total acid concentration is approximately equal to the mole number of the free nitrogen group of the macrolides within the required macrolide concentration; and c) the combined acid solution and Macrolide, the final concentration of macrolide is about 7.5% to 40% by weight. In addition, the method for preparing the composition of the present invention includes the steps of: a) adding an acid to the macrolide (such as azalactone), and the total total concentration of the acid is about the required macrolide concentration Molar numbers such as free nitrogen groups; b) preparing organic solvents or solvent-insoluble carriers that can be mixed with water, and c) combining the acid solution and the macrolide, the final concentration of the macrolide is about 7 5% to 40% by weight. A better understanding of the present invention can be obtained by the following description of the embodiments. (Please read the notes on the back before filling this page)

1T t Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Example 1 Prepare a liter of a 20% erythromycin solution of erythromycin (9 10 micrograms / mg efficacy) according to the following procedure: 20 g _-丨· 丨 丨 丨 丨 丨 One — — 0 * 910 N-methylpyrrolidone 2 19 8 6 4 0 0.0

gg L The size of this paper applies to Chinese National Standard (CNS) A4 (210X297 mm) -19- 581679 A7 B7 V. Description of the invention (j propylene glycol-qs 1000.0 ml, (Please read the precautions on the back before filling this page) Add glacial acetic acid to the mixture of N-methylpyrrolidone and 300 mL of propylene glycol and mix. Add erythromycin slowly. When the erythromycin is completely dissolved, the solution is adjusted to the proper volume with propylene glycol. Example 2 Short-term stability The nature of the study Put the dry ingredients into a suitable container and stir, add the liquid to prepare the following 8a-azalide formulations. Continue stirring until the solution is clear. The formula of the composition is as follows: 8a-azalide 12.5 % w / v Succinic acid 1.3% w / v Sodium bisulfite 0.5% w / v 40/6 〇% v / v qsAD 1 0 0% w / v Glyceryl formate / propylene glycol mixture Ministry of Economy Wisdom The formulation of the short-term stability test printed by the Property Cooperative Consumer Cooperative was stored at 80 ° C for eight weeks. No significant change in the formulation was observed, and it remained clear. The foregoing description of the invention is intended to be illustrative, not limiting. The scope of the invention. For cooked Those skilled in the art can make various changes or modifications as described in the specific embodiments. Such modifications do not depart from the scope or essence of the present invention. Therefore, describing the detailed and preferred specific embodiments of the present invention does not limit the present invention. The following is the scope of the patent application, and the obvious changes after the above description do not depart from the scope or essence of the present invention. This paper size applies to the Chinese national standard (CNS) A4 specification (210x297 mm) • 20-

Claims (1)

581679 8 888 ABCD 々Appendix II: Patent Application No. 88111724 Amendment Chinese Application without Patent Application Scope Replaced by the Republic of China on January 9, 1993 1. A stable and water-soluble macrocycle A lactone antibiotic composition comprising: a) a macrolide antibiotic having a concentration of about 10% to about 40% by weight based on the volume of the composition; b) an acid whose content is about equal The number of nitrogen groups in the macrolide and can form water-soluble salt compounds with the macrolide; and c) a non-aqueous vehicle miscible with water, acceptable by veterinary or pharmacologically Organic solvents or solvent mixtures, wherein the macrolide antibiotics are erythromycin, azalide, carbomycin, clarithromycin, j. Josamycin, leucomycins, medecamycins, mikamycin, miokamycin, oleandomycin, and pristinamycin Luo Keda Rokitamycin, rosaramicin, rosamycin (r ο X ithr 〇myci η), spiramycin, tylosin, triandandomycin ), Or virginiamycin or derivatives of these antibiotics. 2. If the composition of the scope of patent application item 1, in which the size of the macrolide is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm)-IΦ-I (Please read the precautions on the back before reading (Fill this page) Order printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 581679 A8 B8 C8 D8 VI. Patent Application Scope The antibiotic is selected from erythromycin and its derivatives. 3. The composition according to item 1 of the application, wherein the erythromycin is in the form of erythromycin base. 4. The composition according to item 1 of the patent application range, wherein the composition is in the form of a sterilizable injectable composition. 5. The composition according to item 1 of the patent application range, wherein the concentration of the macrolide antibiotic is from about 20% to about 30% by weight based on the volume of the composition. 6. The composition according to item 1 of the application, wherein the carrier is composed of propylene glycol monomethyl ether, dipropylene glycol monomethyl ether, or diethylene glycol ethyl ether, or a mixture thereof. 7. The composition as claimed in claim 1, wherein the carrier is composed of N-methylpyrrolidone at a concentration of about 30% by volume to about 50% by volume, and the balance is propylene glycol. 8. The composition according to item 1 of the patent application range, wherein the carrier is N-methylpyrrolidone having a concentration of about 30% by volume to about 50% by volume and the balance is polyethylene glycol 200, or polyethylene glycol 3 00 or polyethylene glycol 400. 9. The composition according to item 1 of the patent application scope, wherein the acid is selected from the following acids: acetic acid, propionic acid, isopropyl acid, butyric acid, isobutyric acid, dibutyric acid, and valeric acid. 10. The composition of claim 1 in which the solvent is N-methylpyrrolidone. Π. — A method for preparing a stable, highly efficient, and water-miscible macrolide antibiotic composition, including the following steps: This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) ---- -: I — IAW —— (Please read the notes on the back before filling this page) Order printed by the Intellectual Property Bureau Employee Consumer Cooperative of the Ministry of Economic Affairs 581679 A8 B8 C8 D8 VI. Application for patent scope a) Preparation contains one or more Non-aqueous carrier of water-mixed organic solvents; b) Add acid at a concentration relative to the desired macrolide content so that the total amount of acid is approximately equal to the number of free nitrogen groups contained in the macrolide And 0; combining the acid solution with the macrolide to achieve a final macrolide concentration of about 10% to about 40% by weight; wherein the macrolide antibiotic is erythromycin (Erythromymycin), azalide, carbomycin, clarithromycin, josamycin, leucomycins, medicamycin (Midecamycins), mikamycin Miokamycin, Oleandomycin, Pristinamycin, Rokitaniycin, Rosar amici, Roxithromycin , Spiramycin, tylosin, triorandomycin, or virginiamycin or derivatives of these antibiotics. 12. —Azalide lactone macrolide antibiotic composition that is stable and miscible with water, comprising: a) —Azalactone, the concentration of which is approximately by volume of the composition! 〇 Weight ° /. To about 40% by weight; b) an acid whose content is approximately equal to the number of nitrogen groups in the azalide and can form a water-soluble salt compound with the azalactone; and c) A non-aqueous vehicle that is miscible with water and consists of a veterinary or pharmaceutically acceptable organic solvent or solvent mixture. This paper size applies the Chinese national standard "CNS" A4 specification (210X297 mm) ——i — IIΙΦΙ — (Please read the precautions on the back before filling this page) Order printed by the Intellectual Property Bureau of the Ministry of Economic Affairs Consumer Cooperatives 581679 A8 B8 C8 D8 _ 6. Scope of patent application 1 3 · For the composition of the scope of patent application No. 12 wherein the azalide is azithromycin or the formula Where Des is desosomine and Clad is cladinose or —, —, II (Please read the notes on the back before filling out this page) Order printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 1. If the composition of the scope of patent application No. 12 is applied, the azalide for Among them, Des is desosomine, and Clad is Cladin (this paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 581679 A8 B8 C8 D8 Ⅵ. Patent scope cladinose) or (Π) --------— I (Please read the notes on the reverse side before filling out this page) 1 5 · If the composition of the scope of patent application No. 12 is used, the concentration of the azalactone is based on the combination And the carrier is composed of propylene glycol monomethyl ether, or dipropylene glycol monomethyl ether, or diethylene glycol ethyl ether, or a mixture thereof. . 16. The composition according to item 12 of the scope of patent application, wherein the carrier is N-methylpyrrolidone with a concentration of about 30 vol% to about 50 vol% and the rest is polyethylene glycol 200 or polyethylene glycol. Alcohol 300 or polyethylene glycol 400. 17 · The composition according to item 12 of the scope of patent application, wherein the acid is selected from the following acids: acetic acid, propionic acid, isopropyl acid, butyric acid, isobutyric acid, second butyric acid, and valeric acid . Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 1 8. —Azalide lactone macrolide antibiotic composition that is stable and miscible with water * Contains: a) azithromycin or the following formula Azalactone This paper is sized to the Chinese National Standard (CNS) A4 (2I0X297 mm) 581679 A8 B8 C8 D8 VI. Patent Application Scope (!) Where Des is desosomine cladinose or ’and Clad is cladidine ( (Please read the notes on the back before filling out this page) The Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs has printed its concentration from about 10% by weight to about 40% by weight of the composition; b) acetic acid, Its content is at least equal to the number of free nitrogen atoms in the azalide macrolide and can form a water-soluble acetate compound with the azalactone macrolide; and c) a water-soluble acetate compound that can be mixed with water A non-aqueous vehicle is composed of a suitable organic solvent or solvent mixture. This paper size applies to China National Standard (CNS) A4 (210X297 mm) -6-