Non-aqueous liquid formulations of tetracycline antibiotics

Abstract

The present disclosure generally relates to liquid formulations of pharmaceutical compounds. In particular, the present disclosure relates to non-aqueous liquid formulations of tetracycline antibiotics. More specifically, the present disclosure relates to a non-aqueous liquid formulation comprising a tetracycline antibiotic, a magnesium or a calcium ion, and a non-aqueous vehicle. The present disclosure also relates to a process for preparing non-aqueous liquid formulations of tetracycline antibiotics, a kit comprising it, and its method of use in preparing medicaments for treatment, prevention, or management of conditions responsive to tetracycline antibiotics.

Description

[0001] NON-AQUEOUS LIQUID FORMULATIONS OF TETRACYCLINE ANTIBIOTICS TECHNICAL FIELD

[0002] The present disclosure generally relates to liquid formulations of pharmaceutical compounds. In particular, the present disclosure relates to non-aqueous liquid formulations of tetracycline antibiotics. More specifically, the present disclosure relates to a non-aqueous liquid formulation comprising a tetracycline antibiotic, a magnesium or a calcium ion, and a non-aqueous vehicle. The present disclosure also relates to a process for preparing non-aqueous liquid formulations of tetracycline antibiotics, a kit comprising it, and its method of use in preparing medicaments for treatment, prevention, or management of conditions responsive to tetracycline antibiotics.

[0003] BACKGROUND

[0004] Tetracycline antibiotics, such as doxycycline, are widely employed in both human and veterinary medicine due to their broad-spectrum antimicrobial activity. These antibiotics are effective against a wide range of gram-positive and gram-negative bacteria, making them essential for treating various infections, including respiratory tract infections and certain resistant infections. However, their clinical application, particularly via parenteral routes, is significantly hampered by their poor stability in aqueous formulations.

[0005] Injectable formulations of tetracyclines including doxycycline have traditionally been developed as lyophilized powders, requiring reconstitution before use. These formulations address the inherent instability of actives in aqueous systems but pose practical challenges during storage, handling, and administration.

[0006] Challenges in existing formulations are reconstitution complexity due to which lyophilized products require aseptic preparation, which increases the risk of human error, contamination, and variability in drug concentration. They also face stability issues since aqueous solutions of doxycycline are prone to degradation due to oxidation and pH fluctuations, necessitating stringent control measures; and operational inefficiencies such as reconstitution delays and handling errors which impact patient care.

[0007] Lyophilized injections offer a solution to stability concerns, however, there is a lack of a ready -to-dilute liquid formulation that provides comparable or improved stability while simplifying the preparation process. Addressing this gap requires overcoming challenges related to active's aqueous stability.

[0008] Tetracyclines, including doxycycline, are inherently unstable in aqueous environments due to hydrolysis and epimerization. Hydrolysis predominantly affects the amide functional group, leading to inactive degradation products, such as 4-epidoxycycline. Oxidation further compromises stability, particularly in formulations exposed to light and oxygen, necessitating stringent stabilization strategies.

[0009] Current liquid formulations of tetracycline antibiotics often rely on co-solvents and / or solubilizers to enhance their solubility and / or stability. Polyvinylpyrrolidone (PVP) is one such widely used solubilizer however, is associated with safety issues at higher concentrations. PVP at higher concentrations or high molecular weight grades, can accumulate in the kidneys, potentially causing nephropathy. Typical liquid formulations may contain PVP, often in combination with magnesium complexes of the tetracycline antibiotics.

[0010] Other water-miscible solvents, such as 1,2-propanediol and N,N-dimethylacetamide, have also been employed in tetracycline formulations to enhance solubility. However, both of these solvents are known to cause significant irritation, further limiting their clinical applicability. Pyrrolidone derivatives, including 2-pyrrolidone and N-methylpyrrolidone, have emerged as alternatives to traditional solvents. While these compounds offer improved tolerance compared to propanediol and dimethylacetamide, they still pose risks of tissue irritation and other side effects, particularly when administered in high concentrations.

[0011] Given the aforementioned challenges, there is a growing need for non-aqueous liquid formulations of tetracycline antibiotics. Such formulations may potentially enhance stability by reducing the risk of hydrolysis and degradation, thereby prolonging shelf life and maintaining efficacy. Furthermore, there is a need for formulations that can be readily reconstituted prior to administration, allowing for convenient preparation, accurate dosing, and improved patient compliance without compromising the stability or potency of the antibiotic.

[0012] OBJECT

[0013] Object of the present disclosure is to provide a non-aqueous liquid formulation of tetracycline antibiotics and methods for preparing and using the same. Another object of the present disclosure is to provide a non-aqueous liquid formulation of a tetracycline antibiotic that is stable at room temperature and more stable than the aqueous formulations of the same tetracycline antibiotic.

[0014] Another object of the present disclosure is to provide a formulation that can be readily diluted prior to administration, enabling convenient preparation, accurate dosing, and improved patient compliance while maintaining the stability and efficacy of the antibiotic.

[0015] Yet another object of the present disclosure is to provide a kit comprising the non-aqueous liquid formulation of a tetracycline antibiotic, optionally together with one or more diluents, delivery devices, or instructions for use, to facilitate proper preparation and administration of the formulation.

[0016] Still another object of the present disclosure is to provide methods of using the non-aqueous liquid formulation or the kit described herein for the treatment, prevention, or management of conditions responsive to tetracycline antibiotics.

[0017] SUMMARY

[0018] In one aspect, the present disclosure provides a non-aqueous liquid formulation comprising a tetracycline antibiotic, a magnesium or a calcium ion and a non-aqueous vehicle.

[0019] In an embodiment, the non-aqueous liquid formulation comprises:

[0020] • at least one tetracycline antibiotic selected from the group consisting of doxycycline, aminomethylcycline, chlortetracycline, chlorocycline, demeclocycline, tigecycline, lymecycline, meclocycline, methacycline, minocycline, oxytetracycline, rolitetracycline, tetracycline, eravacy cline, sarecy cline, and omadacy cline, in an amount from 10 mg / mL to 50 mg / mL;

[0021] • a magnesium or a calcium ion in an amount amount from 1.0 mg / mL to 5 mg / mL; and • a sufficient quantity of non-aqueous vehicle to constitute the remainder of the formulation volume.

[0022] In an embodiment, the non-aqueous liquid formulation essentially consists of: • at least one tetracycline antibiotic selected from the group consisting of doxycycline, aminomethylcycline (such as TP434, and PTK796 (also known as BAY 73-7388 and MK2764)), chlortetracycline, chlorocycline, demeclocycline, glycylcycline (such as tigecycline), lymecycline, meclocycline, methacycline, minocycline, oxytetracycline, rolitetracy cline, tetracycline, eravacy cline, sarecy cline, omadacy cline and tigecycline, in an amount from 10 mg / mL to 50 mg / mL;

[0023] • a magnesium or a calcium ion in an amount amount from 1.0 mg / mL to 5 mg / mL; and • a sufficient quantity of non-aqueous vehicle to constitute the remainder of the formulation volume.

[0024] In a further specific embodiment, the non-aqueous liquid formulation of the present disclosure comprises doxycycline hy elate, magnesium ion, and polyethylene glycol.

[0025] In an embodiment, the non-aqueous liquid formulation of the foregoing embodiment comprising tetracycline antibiotic, a magnesium or a calcium ion and a non-aqueous vehicle, additionally comprises a base.

[0026] In an embodiment, the non-aqueous liquid formulation comprises:

[0027] • at least one tetracycline antibiotic selected from the group consisting of doxycycline, aminomethylcycline, chlortetracycline, chlorocycline, demeclocycline, tigecycline, lymecycline, meclocycline, methacycline, minocycline, oxytetracycline, rolitetracycline, tetracycline, eravacy cline, sarecy cline, and omadacy cline, in an amount from 10 mg / mL to 50 mg / mL;

[0028] • a magnesium or a calcium ion in an amount amount from 1.0 mg / mL to 5 mg / mL;

[0029] • a sufficient quantity of non-aqueous vehicle to constitute the remainder of the formulation volume; and

[0030] • a base.

[0031] In a specific embodiment, the non-aqueous liquid formulation essentially consists of:

[0032] • at least one tetracycline antibiotic selected from the group consisting of doxycycline, aminomethylcycline (such as TP434, and PTK796 (also known as BAY 73-7388 and MK2764)), chlortetracycline, chlorocycline, demeclocycline, glycylcycline (such as tigecycline), lymecycline, meclocycline, methacycline, minocycline, oxytetracycline, rolitetracy cline, tetracycline, eravacy cline, sarecy cline, omadacy cline and tigecy cline, in an amount from 10 mg / mL to 50 mg / mL;

[0033] • a magnesium or a calcium ion in an amount amount from 1.0 mg / mL to 5 mg / mL; and • a sufficient quantity of non-aqueous vehicle to constitute the remainder of the formulation volume; and

[0034] • a base.

[0035] In a further specific embodiment, the non-aqueous liquid formulation of the present disclosure comprises doxycycline hyclate, magnesium ion, polyethylene glycol, and sodium hydroxide.

[0036] In another aspect, the present disclosure provides a process for preparing a non-aqueous liquid formulation comprising a tetracycline antibiotic, a magnesium or a calcium ion, and a nonaqueous vehicle. The process comprises:

[0037] a) dissolving a source of magnesium or calcium ion in a non-aqueous vehicle; and

[0038] b) adding a tetracycline antibiotic compound to the solution obtained in step a).

[0039] In an embodiment, the process of the foregoing embodiment for preparing a non-aqueous liquid formulation additionally comprises a step c) comprising adding a base to the solution obtained in step b).

[0040] In a specific embodiment, the process for preparing a non-aqueous liquid formulation comprises:

[0041] a) dissolving magnesium chloride in polyethylene glycol;

[0042] b) adding doxycycline hyclate to the solution of step a); and

[0043] c) optionally, heating the solution to fasten solubilization of ingredients.

[0044] In a further specific embodiment, the process for preparing a non-aqueous liquid formulation comprises:

[0045] a) dissolving magnesium chloride in polyethylene glycol;

[0046] b) adding doxycycline hyclate to the solution of step a);

[0047] c) optionally, heating the solution to fasten solubilization of ingredients; and

[0048] d) adding sodium hydroxide to the solution of step b) or step c). In yet another aspect the present disclosure provides a kit comprising the non-aqueous liquid formulation of any one of the preceding aspects.

[0049] In an embodiment, the kit is for oral and parenteral administration, and comprises:

[0050] • a liquid formulation comprising a tetracycline antibiotic, a magnesium or a calcium ion, and a non-aqueous vehicle; and

[0051] • optionally a diluent.

[0052] Still another aspect of the present disclosure provides a non-aqueous liquid formulation of tetracycline antibiotics defined in any of the previous embodiments for use in the manufacture of a medicament.

[0053] In an embodiment, the non-aqueous liquid formulation of doxycycline is for use in the manufacture of a medicament for the treatment of bacterial infections, acne or other dermatological inflammatory conditions, respiratory tract infections, ocular infections and the like.

[0054] Still another aspect of the present disclosure provides a method for the treatment or prophylaxis of a condition or disorder in a subject in need thereof by administering a therapeutically effective amount of the formulation of any one of the preceding aspects.

[0055] DETAILED DESCRIPTION

[0056] The present disclosure relates to a non-aqueous liquid formulation of tetracycline antibiotic. The formulation is stable and / or has total impurities not more than 5.0 %, or not more than 3.0%, or not more than 1.5 % or not more than 1.0 % as determined by high performance liquid chromatography (HPLC). The formulation also results in reduction of irritation at the site of ingestion / inj ection, improving patient comfort and compliance.

[0057] At the very outset of the detailed description, it may be understood that the ensuing description only illustrates a particular form of this invention. However, such a particular form is only exemplary embodiment, and without intending to imply any limitation on the scope of this invention. Accordingly, the description is to be understood as an exemplary embodiment and teaching of invention and not intended to be taken restrictively. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the present invention.

[0058] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the methods. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the methods, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the methods.

[0059] Certain ranges are presented herein with numerical values being preceded by the term “about.” The term “about” is used herein to provide literal support for the exact number that it precedes, as well as a number that is near to or approximately the number that the term precedes. In determining whether a number is near to or approximately a specifically recited number, the near or approximating unrecited number may be a number which, in the context in which it is presented, provides the substantial equivalent of the specifically recited number. In an embodiment, “about” can mean within one or more standard deviations, or within ± 30%, 25%, 20%, 15%, 10% or 5% of the stated value.

[0060] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred methods and materials are described. For the purposes of the present invention, the following terms are defined below.

[0061] The articles "a" and "an" are used herein to refer to one or to more than one (i.e. to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0062] As used herein, the term “comprises” or “comprising” is generally used in the sense of include, that is to say permitting the presence of one or more features or components. Reference throughout this specification to “certain embodiments”, “further embodiments”, “specific embodiments”, “further specific embodiment”, “one embodiment”, “a non-limiting embodiment”, “an exemplary embodiment”, “some instances”, or “further instances”, means that a particular feature, structure or characteristic described in connection with the embodiment may be included in at least one embodiment of the present disclosure. As used herein, the terms ‘include’, ‘have’, ‘comprise’, ‘contain’ etc. or any form of said terms such as ‘having’, ‘including’, ‘containing’, ‘comprising’ or ‘comprises’ are inclusive and will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

[0063] The term “excipient(s)” is used to describe an inert substance that is added to a pharmaceutical composition to make it easier to administer the active ingredient. This can include a range of substances, such as a surfactants, an antioxidants, an isotonicity agents, a pH adjusters, a buffers, a preservatives, and vegetable oils.

[0064] The term “formulation” or “composition” refers to a pharmaceutical formulation comprising a tetracycline antibiotic, including any pharmaceutically acceptable salt, solvate, hydrate, derivative, chelate, or complex thereof, together with one or more pharmaceutically acceptable carriers, excipients, or diluents as described herein.

[0065] The term “subject” includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).

[0066] The term, "vehicle" refers to a solvent or carrier fluid in a pharmaceutical product that does not have any pharmacological function. For instance, in an embodiment, polyalkylene glycol is used as the vehicle in the non-aqueous formulation of the present disclosure.

[0067] The term “magnesium ion” or “calcium ion” refers to divalent magnesium (Mg2+), or calcium (Ca+2) present in the composition, whether in free ionic form or coordinated / chelated with the tetracycline antibiotic compound. The ions may be supplied by any pharmaceutically acceptable salts of magnesium or calcium. As used herein, the term ‘diluent’ refers to any pharmaceutically acceptable fluid suitable for diluting the formulation prior to administration.

[0068] Before the present invention is described in greater detail, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. Each embodiment is provided by way of explanation of the invention and not by way of limitation of the invention. In fact, it will be apparent to those skilled in the art that various modifications and variations can be made to the compounds, compositions and / or methods described herein without departing from the scope or spirit of the invention. For instance, features illustrated or described as part of one embodiment can be applied to another embodiment to yield a still further embodiment. Thus, it is intended that the present invention includes such modifications and variations and their equivalents.

[0069] Other objects, feature, and aspects of the present invention are disclosed in or are obvious from, the following detailed description. It is to be understood by one of ordinary skill in the art that the present discussion is a description of exemplary embodiments only and is not to be construed as limiting the broader aspects of the present invention.

[0070] In one aspect, the present disclosure provides a non-aqueous formulation of tetracycline antibiotics comprising a tetracycline antibiotic, magnesium or calcium ion, and a non-aqueous vehicle.

[0071] The non-aqueous formulation of the present invention possesses advantages over the known aqueous injectable formulation of tetracycline antibiotic(s). In certain embodiments, the present disclosure provides a non-aqueous injectable formulation of a tetracycline antibiotic that is more stable than an aqueous injectable formulation of the same tetracycline antibiotic.

[0072] Examples of tetracycline antibiotics include, but are not limited to, doxycycline, aminomethylcycline (such as TP434, and PTK796 (also known as BAY 73-7388 and MK2764)), chlortetracycline, chlorocycline, demeclocycline, glycylcycline (such as tigecycline), lymecycline, meclocycline, methacycline, minocycline, oxytetracycline, rolitetracycline, tetracycline, eravacycline, sarecycline, and omadacycline. The tetracycline antibiotic may be present in the formulation in any suitable form, including a free base, a pharmaceutically acceptable salt, a stereoisomer, a polymorph, a crystal, a solvate, a hydrate, a prodrug, a metabolite, or a complex. In certain embodiments, the tetracycline antibiotic is present as a complex, such as a coordination or chelate complex. In a preferred embodiment, the tetracycline antibiotic is present as a chelate complex, which has been found to provide advantageous stability and compatibility within the formulation.

[0073] In certain embodiment, the tetracycline antibiotic may undergo a change in form in-situ upon preparation of the formulation, particularly in the presence of divalent metal ions such as magnesium or calcium. For instance, they may form coordination complexes such as chelates.

[0074] In a specific embodiment, the tetracycline antibiotic is doxycycline. Doxycycline may be present in the formulation in the form of a free base, a pharmaceutically acceptable salt, a stereoisomer, a polymorph, a crystal, a solvate, a hydrate, a prodrug, a metabolite, or a complex. In certain embodiments, source of doxycycline in the formulation can be a pharmaceutically acceptable salt. The pharmaceutically acceptable salts may include acid addition salts. Examples of doxycycline acid addition salts that may be utilized include pharmaceutically acceptable salts like hydrochloride, hydrobromide, and sulfate. In some instances, the salt is doxycycline hydrochloride, such as doxycycline hyclate, which is the hemi ethanol ate hemihydrate form of doxycycline hydrochloride.

[0075] In certain embodiments, the pharmaceutically acceptable salt added to the formulation is doxycycline hyclate. Doxycycline hyclate forms a chelate complex upon addition to a formulation comprising magnesium and / or calcium salts. Without being bound by theory, it is believed that the interaction of doxycycline with Mg2+and Ca2+ions promotes chelation, thereby contributing to enhanced stability, reduced impurity formation, and improved compatibility with the formulation components.

[0076] The non-aqueous formulation of the present disclosure may comprise the tetracycline antibiotic in an amount ranging from about 10.0 mg / mL to about 100.0 mg / mL, preferably, about 10 to about 50.0 mg / mL including about 11.0 mg / mL, about 12.0 mg / mL, about 13.0 mg / mL, about 14.0 mg / mL, about 15.0 mg / mL, about 16.0 mg / mL, about 17.0 mg / mL, about 18.0 mg / mL, about 19.0 mg / mL, about 20.0 mg / mL, about 21.0 mg / mL, about 22.0 mg / mL, about 23.0 mg / mL, about 24.0 mg / mL, 25.0 mg / mL 26.0 mg / mL, about 27.0 mg / mL %, about 28.0 mg / mL, about 29.0 mg / mL, about 30.0 mg / mL, about 31.0 mg / mL, about 32.0 mg / mL, about 33.0 mg / mL, about 34.0 mg / mL, about 35.0 mg / mL, about 36.0 mg / mL, about 37.0 mg / mL, about 38.0 mg / mL, about 39.0 mg / mL, about 40.0 mg / mL, about 41.0 mg / mL, about 42.0 mg / mL, about 43.0 mg / mL, about 44.0 mg / mL, about 45.0 mg / mL, about 46.0 mg / mL, about 48.0 mg / mL, and about 49.0 mg / mL.

[0077] In certain embodiments, the magnesium and calcium ions are generated in situ within the pharmaceutical formulation by incorporating pharmaceutically acceptable salts of magnesium and calcium. In certain embodiments, the magnesium and calcium ions comprised in the nonaqueous formulation can form chelates with the tetracycline antibiotic and chelation can significantly improve the stability. Without being bound by theory, it is believed that chelation of the tetracycline antibiotic by divalent metal ions such as Mg2+and Ca2+can stabilize the antibiotic’s molecular structure, thereby reducing degradation pathways including epimerization, oxidation, and hydrolysis. Such chelate formation can significantly improve the chemical and physical stability of the formulation during storage, enhance resistance to thermal and photolytic stress, and maintain potency over extended periods. In some embodiments, the chelation interaction contributes to improved shelf-life, reduced formation of degradation products, and enhanced robustness of the pharmaceutical formulation under non-aqueous conditions.

[0078] In certain embodiments, source of magnesium ions can be any magnesium compound which effectively reacts with the tetracycline antibiotic to form magnesium-tetracycline antibiotic chelates. In certain embodiments, the magnesium compound is a magnesium salt. Examples include, but are not limited to, magnesium chloride, magnesium ascorbate, magnesium lactate, magnesium gluconate, magnesium sulfate, magnesium oxide, magnesium acetate, magnesium bromide, magnesium malate, magnesium hydroxide, and magnesium citrate. In a specific embodiment, the magnesium salt is magnesium chloride.

[0079] In certain embodiments, source of calcium ions can be any calcium compound that serves as a source of calcium ions, which effectively reacts with the tetracycline antibiotic to form calcium-tetracycline antibiotic chelates, may be used in the present invention. In certain embodiments, the calcium compound is a calcium salt. Examples include, but are not limited to, calcium chloride, calcium carbonate, calcium citrate, calcium phosphate, calcium gluconate, calcium lactate, and calcium hydroxide. In an embodiment, the non-aqueous liquid formulation of the foregoing embodiment comprising tetracycline antibiotic, a magnesium or a calcium ion and a non-aqueous vehicle, additionally comprises a base.

[0080] In certain embodiments, the base can be selected from inorganic base, such as a bicarbonate, a carbonate, or a hydroxide, including a hydroxide of an alkali or alkaline earth metal, as well as a hydroxide of a transition metal, or an organic base, such as ammonium hydroxide (NH4OH), aminomethane, 2-aminoethanol, dimethylaminomethanol, diethylaminoethanol, dimethylamine, diethylamine, trimethylamine, or triethylamine. The base in the formulation serves to adjust and maintain the pH of the formulation within a predetermined range, in particular between about 1 and about 6, and in some embodiments between about 2 and about 5. Maintaining the pH within this range can provide improved stability of active pharmaceutical ingredients, including pH-sensitive compounds such as tetracycline antibiotics.

[0081] In certain embodiments, the base is present in the formulation in an amount sufficient to provide buffering capacity to maintain and resist pH changes during storage, handling, or upon dilution. The amount of base employed in the formulation ranges from about 0.1 mg / mL to about 10.0 mg / mL, about 0.5 to about 6.0 mg / mL, about 2.0 to about 4.0 mg / mL, or from about 2.0 to 3.0 mg / mL of the total volume liquid formulation. In particular embodiments, the range of about 2.0 to 3.0 mg / mL provides an optimal balance between buffering capacity and minimizing potential irritation or undesired interactions with other formulation components. The term “total volume of the liquid formulation” as used herein encompasses the volume of the formulation either prior to or after dilution with a suitable diluent.

[0082] In a specific embodiment, the base employed is including a hydroxide of an alkali or alkaline earth metal, as well as a hydroxide of a transition metal, or a strong base selected from ammonium hydroxide. In a more specific embodiment, the base is an alkali hydroxide selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, and cesium hydroxide.

[0083] In a further specific embodiment, the base is sodium hydroxide (NaOH) or ammonium hydroxide (NH4OH) in an amount of about 2.0 to 4.0 mg / mL, or about 2.0 to 3.0 mg / mL relative to the total volume of the liquid formulation. In a specific embodiment, the tetracycline antibiotic is doxycycline hyclate, and the divalent metal ion is a magnesium ion supplied by a magnesium salt, such as magnesium chloride hexahydrate. Upon incorporation into the non-aqueous formulation, the magnesium chloride hexahydrate dissociates to provide Mg2+, which can interact with and form chelates or coordination complexes with doxycycline hyclate.

[0084] The molar ratio of the tetracycline antibiotic to the magnesium or calcium ion ranges from about 1:0.5 to about 1:5. In certain embodiments, the molar ratio of tetracycline antibiotic to the magnesium or calcium ion ranges from about 1 : 1 to about 1 :2, which equates to 1.0 to 10.0 mg / mL of the ion, or from about 1.0 to 5.0 mg / mL, or more preferably, about 2.0 to about 3.0 mg / mL.

[0085] The non-aqueous liquid formulations of the present disclosure can comprise one or more nonaqueous vehicles. The non-aqueous vehicles can be selected from, but not limited to glycerin, polyethylene glycol derivatives, vegetable oils, fatty acid esters, and mixtures thereof

[0086] In certain embodiments, the non-aqueous vehicle consists solely of a single non-aqueous vehicle. The non-aqueous vehicle comprises (or consists of) only a polyalkylene glycol. In some embodiments, the polyalkylene glycol may be a polyC2-C3 alkylene glycol, such as polyethylene glycol (PEG) and polypropylene glycol (PPG). As polymeric ethers, polyalkylene glycols exist in various molecular weights, often indicated by a number that reflects their approximate molecular weight. In certain instances, the polyalkylene glycol solvent PEG may have a molecular weight of 700 or lower, or a mixture thereof; particularly, a polyalkylene glycol with a molecular weight ranging from 100 to 700 or a mixture thereof; or one with a molecular weight between 200 and 600, or a mixture thereof; and more specifically, a polyalkylene glycol with a molecular weight from 300 to 500, or a mixture thereof.

[0087] In a specific embodiment, the non-aqueous vehicle comprises (or consists of) only a PEG 300. When PEG is utilized as the non-aqueous vehicle, the remaining formulation components may be expressed in weight per milliliter (mg / mL), and the PEG is added in a quantity sufficient (QS) to bring the total volume of the formulation to 1 mL.

[0088] In certain embodiments, the non-aqueous liquid formulation comprises: • at least one tetracycline antibiotic selected from the group consisting of doxycycline, aminomethylcycline, chlortetracycline, chlorocycline, demeclocycline, tigecycline, lymecycline, meclocycline, methacycline, minocycline, oxytetracycline, rolitetracycline, tetracycline, eravacy cline, sarecy cline, and omadacy cline, in an amount from 10 mg / mL to 50 mg / mL;

[0089] • a magnesium or a calcium ion in an amount amount from 1.0 mg / mL to 5 mg / mL; and • a sufficient quantity of non-aqueous vehicle to constitute the remainder of the formulation volume.

[0090] In certain embodiments, the non-aqueous liquid formulation essentially consists of:

[0091] • at least one tetracycline antibiotic selected from the group consisting of doxycycline, aminomethylcycline, chlortetracycline, chlorocycline, demeclocycline, tigecycline, lymecycline, meclocycline, methacycline, minocycline, oxytetracycline, rolitetracycline, tetracycline, eravacy cline, sarecy cline, and omadacy cline, in an amount from 10 mg / mL to 50 mg / mL;

[0092] • a magnesium or a calcium ion in an amount amount from 1.0 mg / mL to 5 mg / mL; and • a sufficient quantity of non-aqueous vehicle to constitute the remainder of the formulation volume.

[0093] In an embodiment, the non-aqueous liquid formulation comprises:

[0094] • at least one tetracycline antibiotic selected from the group consisting of doxycycline, aminomethylcycline, chlortetracycline, chlorocycline, demeclocycline, tigecycline, lymecycline, meclocycline, methacycline, minocycline, oxytetracycline, rolitetracycline, tetracycline, eravacy cline, sarecy cline, and omadacy cline, in an amount from 10 mg / mL to 50 mg / mL;

[0095] • a magnesium or a calcium ion in an amount amount from 1.0 mg / mL to 5 mg / mL;

[0096] • a sufficient quantity of non-aqueous vehicle to constitute the remainder of the formulation volume; and

[0097] • a base.

[0098] In certain embodiments, the non-aqueous liquid formulation essentially consists of:

[0099] • at least one tetracycline antibiotic selected from the group consisting of doxycycline, aminomethylcycline, chlortetracycline, chlorocycline, demeclocycline, tigecycline, lymecycline, meclocycline, methacycline, minocycline, oxytetracycline, rolitetracycline, tetracycline, eravacy cline, sarecy cline, and omadacy cline, in an amount from 10 mg / mL to 50 mg / mL;

[0100] • a magnesium or a calcium ion in an amount amount from 1.0 mg / mL to 5 mg / mL;

[0101] • a sufficient quantity of non-aqueous vehicle to constitute the remainder of the formulation volume; and

[0102] • a base.

[0103] In a specific embodiment, the present disclosure provides a non-aqueous liquid formulation of a tetracycline antibiotic comprising about 10.0 mg / mL to about 50.0 mg / mL of tetracycline antibiotic, a magnesium or a calcium ion, and a non-aqueous vehicle comprising a polyalkylene glycol; wherein the molar ratio of the tetracycline antibiotic to the magnesium or calcium ion ranges from about 1:0.5 to about 1:5.

[0104] In another specific embodiment, the present disclosure provides a non-aqueous liquid formulation of a tetracycline antibiotic comprising about 10.0 mg / mL to about 50.0 mg / mL of tetracycline antibiotic, a magnesium or a calcium ion, and non-aqueous vehicle comprising PEG 300; wherein the molar ratio of the tetracycline antibiotic to the magnesium or calcium ion ranges from about 1: 0.5 to about 1:5.

[0105] In yet another specific embodiment, the present disclosure provides a non-aqueous liquid formulation of doxycycline comprising about 10.0 mg / mL to about 50.0 mg / mL of doxycycline hyclate, a magnesium or a calcium ion and a non-aqueous vehicle comprising PEG 300; wherein the molar ratio of the tetracycline antibiotic to the magnesium or calcium ion ranges from about 1:0.5 to about 1:5.

[0106] In still another specific embodiment, the present disclosure provides a non-aqueous liquid formulation of doxycycline comprising about 10.0 mg / mL to about 50.0 mg / mL of doxycycline hyclate, magnesium ion obtained from magnesium chloride, and a non-aqueous vehicle comprising PEG 300; wherein the molar ratio of tetracycline antibiotic to the magnesium or calcium ion ranges from about 1 :0.5 to about 1:5, and the formulation has a pH of about 1.5 to about 6. In still another specific embodiment, the non-aqueous liquid formulation of the present disclosure comprises doxycycline hyclate, magnesium ion, and polyethylene glycol, wherein it comprises:

[0107] • about 10.0 mg / mL to about 50.0 mg / mL of doxycycline hyclate;

[0108] • about 1.0 mg / mL to about 5 mg / mL of magnesium ions supplied by magnesium chloride;

[0109] and

[0110] • a sufficient quantity of PEG 300 to constitute the remainder of the formulation volume.

[0111] In still another specific embodiment, the present disclosure provides a non-aqueous liquid formulation of doxycycline comprising about 10.0 mg / mL to about 50.0 mg / mL of doxycycline hyclate, magnesium chloride, a base, and a non-aqueous vehicle; wherein the molar ratio of tetracycline antibiotic to the magnesium or calcium ion ranges from about 1:0.5 to about 1:5, and the formulation has a pH of about 1.5 to 6.

[0112] In still another specific embodiment, the present disclosure provides a non-aqueous liquid formulation of a tetracycline antibiotic comprising about 10.0 mg / mL to about 50.0 mg / mL of tetracycline antibiotic, a magnesium or a calcium ion, a base, and a non-aqueous vehicle comprising a polyalkylene glycol; wherein the molar ratio of tetracycline antibiotic to the magnesium or calcium compound ranges from about 1:0.5 to about 1:5.

[0113] In still another specific embodiment, the present disclosure provides a non-aqueous liquid formulation of a tetracycline antibiotic comprising about 10.0 mg / mL to about 50.0 mg / mL of tetracycline antibiotic, a magnesium or a calcium compound, a base, and non-aqueous vehicle comprising PEG 300; wherein the molar ratio of tetracycline antibiotic to the magnesium or calcium compound ranges from about 1:0.5 to about 1:5.

[0114] In still another specific embodiment, the present disclosure provides a non-aqueous liquid formulation of doxycycline comprising about 10.0 mg / mL to about 50.0 mg / mL of doxycycline hyclate, a magnesium or calcium compound, a base and a non-aqueous vehicle comprising PEG 300; wherein the molar ratio of tetracycline antibiotic to the magnesium or calcium compound ranges from about 1:0.5 to about 1:5. In still another specific embodiment, the present disclosure provides a non-aqueous liquid formulation of doxycycline comprising about 10.0 mg / mLto about 50.0 mg / mL of doxycycline hyclate, magnesium chloride, sodium hydroxide and a non-aqueous vehicle comprising PEG 300; wherein the molar ratio of tetracycline antibiotic to the magnesium or calcium ion ranges from about 1 : 1.5 to about 1 :2; and the formulation has a pH of about 1.5 to 3.

[0115] In still another specific embodiment, the non-aqueous liquid formulation of the present disclosure comprises doxycycline hyclate, magnesium ion, polyethylene glycol, and sodium hydroxide, wherein it comprises:

[0116] • about 10.0 mg / mL to about 50.0 mg / mL of doxycycline hyclate;

[0117] • about 1.0 mg / mL to about 5.0 mg / mL magnesium ions supplied by magnesium chloride;

[0118] • about 2.0 mg / mL to about 3.0 mg / mL of sodium hydroxide; and

[0119] • a sufficient quantity of PEG 300 to constitute the remainder of the formulation volume.

[0120] The formulation provided by the present invention has a pH of about 1.5 to 6, or from about 1.5 to 5.

[0121] In certain embodiments, the non-aqueous liquid formulation of the present disclosure comprising a tetracycline antibiotic, a magnesium or a calcium ion and a non-aqueous vehicle, and optionally a base is devoid of water, preferably containing less than about 4% water content.

[0122] In certain embodiments, the non-aqueous liquid formulation of the present disclosure comprising tetracycline antibiotic, a magnesium or a calcium ion and a non-aqueous vehicle, and optionally a base is devoid of a stabilizer.

[0123] In certain embodiments, the non-aqueous liquid formulation of the present disclosure comprising a tetracycline antibiotic, a magnesium or a calcium ion and a non-aqueous vehicle, and optionally a base is devoid of a co-solvent.

[0124] In certain embodiments, the non-aqueous liquid formulation of the present disclosure may further comprise at least another active agent. In some embodiments, another active agent may be a mucolytic, an expectorant, an antitussive, an anti-inflammatory, an antipyretic, a bronchodilator, an antihistamine, and / or a beta-blocker and an antibiotic.

[0125] In certain embodiments, the non-aqueous liquid formulation of the present disclosure comprises a tetracycline antibiotic, a magnesium or calcium ion, and a non-aqueous vehicle, and optionally a base. In these embodiments, the formulation is substantially free of polyvinylpyrrolidone (PVP), 2-propanediol, N,N-dimethylacetamide (DMA), 2-pyrrolidone, N-methylpyrrolidone (NMP), and / or dehydrating agent.

[0126] In some embodiments, the formulation does not comprise PVP.

[0127] In other embodiments, the formulation does not comprise 2-propanediol.

[0128] In further embodiments, the formulation does not comprise DMA.

[0129] In further embodiments, the formulation does not comprise 2-pyrrolidone.

[0130] In further embodiments, the formulation does not comprise NMP.

[0131] In some embodiments, the formulation does not comprise a dehydrating agent selected from the group consisting of absolute ethanol, ethyl acetate and acetic anhydride.

[0132] In an embodiment, the composition of the present invention is considered "substantially nonaqueous". This means that the composition contains very little water - below 10%, 5%, or 4%. In other embodiments, the composition is completely non-aqueous, meaning that it contains no or very little free, unassociated, or absorbed water. It's important to note that just because a composition is non-aqueous doesn't mean it can't contain substances that are hydrophilic or able to absorb water in an associated or unfree form. The ability to do so is measured by its hygroscopic water capacity. Essentially non-aqueous compositions or formulations may include a small amount of water, but it's intended that the water content be minimal. In some instances, the ingredients in the composition may be pre-treated to remove any residual or associated water. The liquid formulations of the present invention may be designed for various pharmaceutical applications, including both injectable and oral administration.

[0133] In an embodiment, the liquid formulations are oral liquid formulations and are commonly used for children, elderly patients, or those who have difficulty swallowing pills. These can be solutions, suspensions, or syrups, depending on the solubility of the tetracycline and the desired release profile. Suitable further excipients which may be employed to prepare oral liquid formulations are suspending agents, sweeteners, flavours, preservatives, vehicles, antioxidants, chelating agents, pH adjusting agents buffers, thickeners, etc.

[0134] In another embodiment, the formulations of the present invention are parenteral liquid formulations, viz. injections. Injectable formulations can be administered through different routes, including intramuscular, intravenous, or subcutaneous methods. Suitable further excipients which may be employed to prepare the injections solvents, vehicles, antioxidants, chelating agents, pH adjusting agents buffers, preservatives, suspending agents, oil vehicles, viscosity enhancers etc.

[0135] In a specific embodiment, the oral liquid formulations are provided as a single dose formulation that is ready for direct infusion without any further dilution. In some instances, the single dose formulations of tetracycline antibiotics are ready for direct introduction into an infusion bag or for direct dilution with a diluent.

[0136] In a further specific embodiment, formulations of tetracycline antibiotics are ready for direct introduction into an infusion bag or for direct dilution with a diluent. Immediately prior to administration to a patient, the non-aqueous liquid formulation is diluted with a pharmaceutically acceptable aqueous diluent to yield a solution suitable for parenteral or other routes of administration. The dilution step ensures that the therapeutic composition achieves the desired concentration, osmolality, and physiological compatibility for safe use in humans or animals.

[0137] The liquid concentrate of the invention may be diluted with any sterile, isotonic aqueous medium that is chemically compatible with tetracycline compounds. Suitable diluents include, but are not limited to, 0.9% sodium chloride (normal saline), 5% dextrose (D5W), , lactated Ringer’s solution, Ringer’s solution, invert sugar (10% in water), 5% dextrose in Lactated Ringers, 5% dextrose in 0.45% sodium chloride solution, sterile water for injection, glucosesodium citrate solution, sorbitol (5-10%), mannitol (5%), Normosol-M® in D5-W (5% Dextrose), normosol-R® in D5-W (5% Dextrose), plasma-Lyte® 56 in 5% Dextrose, and plasma-Lyte® 148 in 5% Dextrose.

[0138] In practice, the selected diluent is added aseptically to the non-aqueous formulation under gentle mixing to ensure complete and uniform blending. The order of addition is important; preferably, the aqueous diluent is introduced slowly into the non-aqueous phase to avoid localized supersaturation or precipitation of the tetracycline. The process results in a clear, homogeneous, single-phase solution that remains physically stable for the time required to complete the administration.

[0139] The concentration of the tetracycline antibiotic in the final diluted preparation may be adjusted depending on the intended route and rate of administration. Typically, the concentration ranges from 0.05 mg / mL to 50 mg / mL, with a preferred range of 0.1 mg / mL to 10 mg / mL, or from 0.1 mg / mL to 1 mg / mL. Upon dilution, the osmolality of the diluted solution is controlled to remain within a physiologically acceptable range, typically between 300 and 600 mOsm / kg. Maintaining osmolality within this range is critical for parenteral safety, as it ensures nearisotonicity with blood plasma, thereby minimizing pain, hemolysis, or irritation at the injection site.

[0140] In certain embodiments, the non-aqueous liquid formulation essentially consists of:

[0141] • at least one tetracycline antibiotic selected from the group consisting of doxycycline, aminomethylcycline, chlortetracycline, chlorocycline, demeclocycline, tigecycline, lymecycline, meclocycline, methacycline, minocycline, oxytetracycline, rolitetracycline, tetracycline, eravacy cline, sarecy cline, and omadacy cline, in an amount from 10 mg / mL to 50 mg / mL;

[0142] • a magnesium or a calcium ion in an amount amount from 1.0 mg / mL to 5 mg / mL; and • a sufficient quantity of non-aqueous vehicle to constitute the remainder of the formulation volume;

[0143] • a base; and

[0144] • a diluent. The non-aqueous tetracycline formulations of the invention demonstrate excellent stability under both normal and accelerated storage conditions.

[0145] In certain embodiments, the formulations of the present invention are stable and can be stored for shelf life at room temperature (25°C ± 2°C with relative humidity (RH) of 60% ± 5%) short term at accelerated storage conditions (40°C ± 2°C, relative humidity of 75% ± 5%) without any substantial physical and / or chemical changes.

[0146] In another aspect, the present disclosure provides a process for the preparation of non-aqueous liquid formulation comprising a tetracycline antibiotic. In an embodiment, the process comprises:

[0147] a) dissolving a source of magnesium or calcium ion in a non-aqueous vehicle; and

[0148] b) adding a tetracycline antibiotic compound to the solution obtained in step a).

[0149] In certain embodiments of the process, the source of magnesium or the calcium ions, the nonaqueous vehicle, and the tetracycline antibiotic and their quantities are the same as defined in the preceding embodiments.

[0150] The non-aqueous vehicle can be optionally purged with an inert gas such as nitrogen or argon to remove oxygen before it is employed in step a). This is to prevent oxidative degradation of the tetracycline antibiotic during formulation. The purging may be carried out using flowing nitrogen or in a controlled environment in a nitrogen purged hood or glove box.

[0151] The non-aqueous vehicle in step a) is suitably heated to a temperature of about 30 to about 100 °C, or from about 50 to 90 °C or from about 60 to about 70 °C before addition of the magnesium or calcium compound.

[0152] Addition of the tetracycline antibiotic in step b) to the solution of step a) is carried out at temperatures of about 20 °C to about 100 °C, or from about 50 to 30 °C or from about 20 to about 30 °C. The mixture can then be heated to a temperature of about 30 to about 100 °C, or from about 50 to 90 °C or from about 60 to about 70 °C.

[0153] In a specific embodiment, the process for preparing a non-aqueous liquid formulation comprises: a) dissolving magnesium chloride in polyethylene glycol;

[0154] b) adding doxycycline hyclate to the solution of step a); and

[0155] c) optionally, heating the solution to fasten solubilization of ingredients.

[0156] In an embodiment, the process of the foregoing embodiment for preparing a non-aqueous liquid formulation additionally comprises a step c) comprising adding a base to the solution obtained in step b).

[0157] Optionally, pH of the solution can be adjusted to about 1.5 to about 4 using a base. The base may be an inorganic base, such as a bicarbonate, a carbonate, or a hydroxide, including a hydroxide of an alkali or alkaline earth metal, as well as a hydroxide of a transition metal, or an organic base, such as ammonium hydroxide, aminomethane, 2-aminoethanol, dimethylaminomethanol, diethylaminoethanol, dimethylamine, diethylamine, trimethylamine, or triethylamine.

[0158] In a specific embodiment, the base is sodium hydroxide.

[0159] After adjusting the pH, the solution may be cooled to room temperature.

[0160] In a specific embodiment, the process for preparing a non-aqueous liquid formulation comprises:

[0161] a) dissolving magnesium chloride in polyethylene glycol;

[0162] b) adding doxycycline hyclate to the solution of step a);

[0163] c) optionally, heating the solution to fasten solubilization of ingredients; and

[0164] d) adding sodium hydroxide to the solution of step b) or step c).

[0165] In certain embodiments of the process, the non-aqueous vehicle, temperatures at each stage of the process, and the molar ratios of magnesium or calcium compound, the non-aqueous vehicle, and the tetracycline antibiotic and their quantities are the same as defined in the preceding embodiments.

[0166] In another aspect the present invention provides a kit comprising one or more liquid formulations comprising a tetracycline antibiotic, a magnesium or calcium ion, a base, and a non-aqueous vehicle. The kit is designed to facilitate storage, handling, dilution, and administration of the pharmaceutical product in a manner that preserves stability and ensures accurate dosing.

[0167] In an embodiment, the kit is for oral or parenteral administration, and comprises:

[0168] • a liquid formulation comprising a tetracycline antibiotic, a magnesium or a calcium compound, a base, and a non-aqueous vehicle; and

[0169] • optionally, a diluent.

[0170] In certain embodiments, the kit may further include additional components for formulation, dilution, preparation, or administration of the drug product. Such components may include diluents, excipients, delivery devices, or detailed instructions for use, enabling reproducible preparation of the final dosage form. Diluents may correspond to those described in preceding embodiments and can include buffered aqueous solutions, isotonic solutions, or palatable vehicles. In oral formulations, the diluent may optionally contain sweeteners, flavors, viscosity -modifying agents, or other organoleptic enhancers to improve patient acceptability.

[0171] For kits intended for oral administration, the system may further comprise measuring and delivery devices such as calibrated oral syringes, droppers, dosing spoons, or graduated cups. Additional components may include closed or semi-closed mixing containers designed to prevent contamination, reduce dosing error, and enable accurate dilution for pediatric or adult use.

[0172] For kits intended for parenteral administration, the system may include a vial, ampoule, prefilled syringe, cartridge, or multi-chamber infusion bag configured to safely contain the tetracycline formulation and segregate components until dilution. Additional accessories may include sterile needles, syringes, transfer devices, or connectors designed to support aseptic technique, maintain sterility during handling, and ensure accurate parenteral delivery of the final preparation.

[0173] In a specific embodiment, the kit is for parenteral administration and comprises:

[0174] • a liquid formulation comprising a tetracycline antibiotic, a magnesium or a calcium compound, and a non-aqueous vehicle;

[0175] • vial or ampoule or pre-filled syringe or multi chamber infusion bag or container for injections; needles and / or syringes; and

[0176] a diluent.

[0177] The vial or ampoule or pre-filled syringe or multi chamber infusion bag or container is designed to safely hold the tetracycline and the vehicle for dilution. Needles and syringes are included to ensure safe, accurate, and sterile injection of the diluted drug.

[0178] Yet another aspect of the present invention provides a method for the treatment or prophylaxis of a condition or disorder in a subject in need thereof by administering an effective amount of a ready-to-use and / or ready-to-dilute formulation of teracycline antibiotics comprising a magnesium or a calcium compound, and a non-aqueous vehicle.

[0179] In certain embodiments, the method includes administering a formulation that is pre-formed and supplied in a ready-to-use state, requiring no further manipulation prior to administration. In other embodiments, the formulation is provided in a concentrated or partially concentrated form that is ready to dilute, such that the user combines the formulation with a suitable diluent (e.g., water or a buffered solution) immediately before administration.

[0180] The method is applicable to the treatment, prevention or management of any condition for which tetracycline antibiotics are indicated, including bacterial infections or other disorders responsive to tetracycline therapy. The subject may be a human or a non -human animal, and the formulation may be administered by any suitable route, including oral administration.

[0181] In some embodiments, the method further includes diluting the ready-to-dilute formulation with a diluent immediately prior to administration. In other embodiments, adjunct components such as sweeteners, flavors, or stabilizing excipients may be co-administered or included in the formulation or diluent to improve palatability and compliance.

[0182] In an embodiment, the present invention provides the use of formulation of teracycline antibiotics of the present disclosure for the prophylaxis and / or treatment of diseases.

[0183] In an embodiment, the present disclosure provides a non-aqueous liquid formulation of tetracycline antibiotics defined in any of the previous embodiments for use in the manufacture of a medicament. In certain embodiment, the non-aqueous liquid formulation of doxycycline is for use in the manufacture of a medicament for the treatment of bacterial infections, acne or other dermatological inflammatory conditions, respiratory tract infections, ocular infections and the like.

[0184] EXAMPLES

[0185] Although the content of the present invention is further specifically explained using Examples, the present invention is not limited to the following Examples as long as the gist of the present invention is not exceeded. Values of various manufacturing conditions and evaluation results in the following Examples mean preferable values of an upper limit or a lower limit in the embodiments of the present invention, and a preferable range may be a range defined by a combination of the above-described upper limit or the above-described lower limit and the values of the following Examples or a combination of the values of Examples.

[0186] Inventive Examples (IE1 to IE5), and comparative Example (CE1):

[0187] Non-aqueous formulations IE1 to IE5 and CE1 were prepared using a process described below:

[0188] Bulk Solution Preparation:

[0189] 90% batch size of polyethylene glycol 300 (PEG 300) was collected and purged with nitrogen gas to get DO level less than 2 ppm. The PEG 300 was heated to 65 ± 5°C temperature. Magnesium chloride hexahydrate was added & dissolved in PEG 300 under stirring and continued the stirring to get clear solution. The solution was cooled to 25 ± 2°C temperature. Dispensed quantity of doxycycline hyclate was added and dissolved under stirring and the stirring was continued to get clear solution. Dispensed quantity of sodium hydroxide was added under stirring and continued to get clear solution. The batch volume was made up to 100% with nitrogen purged PEG 300. The temperature was maintained at 25 ± 2°C.

[0190] Filtration and filling:

[0191] The solution was aseptically filtered through 0.2 micron PVDF membrane filter and filled into Type-I USP amber glass vials with headspace oxygen level control (below 5%), stoppered coated butylated rubber stopper and sealed with aluminum flip-off seal. Compositions IE1 to IE5 were prepared with various combinations of PEG 300 & different molar ratios of MgCh. CE1 was a comparative Example, without MgCh, and NaOH. The details of formulations are provided in Table-1.

[0192] Table 1:

[0193]

[0194] Q.S.: Quantity Sufficient

[0195] Analytical results: The analytical results of the samples CE1, and IE1 to IE5 are provided in Tables 2-8 given below.

[0196] Table 2: Stability data for formulation of Example CE1.

[0197]

[0198] Table 3: Stability data for formulation of Example CE1

[0199]

[0200] NP: Not Performed

[0201] Table 4: Stability data for formulation of Example IE1.

[0202]

[0203] Table 5: Stability data for formulation of Example IE2.

[0204]

[0205] Table 6: Stability data for formulation of Example IE3 under normal conditions.

[0206]

[0207] Table 7: Stability data for formulation of Example IE4 under normal conditions.

[0208]

[0209] Table 8: Stability data for formulation of Example IE5 under normal conditions.

[0210]

[0211] The stability data provided above proves that Mg ions in non-aqueous environment provides much better stability with very low 4-Epidoxycycline impurity levels than prior art where Mg ions disclosed in aqueous vehicle. Data clearly establishes that combination of Mg ions and non-aqueous vehicle (PEG 300) surprisingly improves the stability compared with Mg ions or non-aqueous vehicle alone. In this regard, reference is made to the fact that the currently approved European aqueous based formulations containing MgCh Doxycyclin-ratiopharm® SF 100 mg / 5 ml Injection Solution and VIBRAVEINEUSE, injectable solution for IV use and infusion are labelled with a mandatory storage condition of 2 °C-8 °C (refrigerated storage). These products demonstrate insufficient stability at controlled room-temperature (CRT) conditions, necessitating cold-chain handling throughout their lifecycle, though they contain MgCh, but have showed stability at only refrigerated condition.

[0212] In contrast, the proposed invention exhibits a significantly enhanced stability profile, enabling long-term storage under controlled room-temperature conditions without degradation of the active ingredient. This differentiating attribute effectively eliminates cold-chain dependency and provides a technical advantage over the existing aqueous based formulations.

[0213] Comparative Examples CE2 to CE7:

[0214] Non-aqueous formulations were prepared using a process similar to that described for inventive examples IE1 to IE5. The details of formulations are provided in Table-9.

[0215] In the comparative formulations L-Cysteine Hydrochloride Monohydrate was employed instead of a magnesium compound.

[0216] Table 9:

[0217]

[0218] Q.S: Quantity Sufficient; — : Not in Composition

[0219] Stability data: The results of initial and stability data for the samples CE2 to CE7 are provided in Tables 10 and 11.

[0220] Table 10: Initial data for Examples CE2, CE3, CE4, CE5, CE6 & CE7

[0221]

[0222] ND: Not Detected

[0223] Table 11: Results of one-month stability data for Examples CE2, CE3, CE4, CE5, CE6 & CE7

[0224]

[0225] ND: Not Detected

[0226] Conclusion: The non-aqueous formulations from Examples CE2 to CE7 showed significant increase in 4-Epidoxycycline impurity (hydrolysis impurity).

[0227] Comparative Examples CE8 to CE12: Non-aqueous formulations were prepared using a process similar to that described for inventive Examples IE1 to IE5. The details of formulations are provided in Table-12.

[0228] In the comparative formulations Combination of different vehicles (polypropylene glycol) & chelating Agent (L-Cysteine Hydrochloride Monohydrate) were employed which do not fall in the definition of the inventive formulations.

[0229] Table-12:

[0230]

[0231] Q.S: Quantity Sufficient; — : Not in Composition

[0232] Stability results: The results of stability data are provided in Tables 13 to 16. Table 13: Results of one-and three-month stability data for Example CE8

[0233]

[0234] Table 14: Results of one-and three-month stability data for Example CE9.

[0235]

[0236] Table 15: Results of initial analysis for Example CE10 & CE11

[0237]

[0238] ND: Not Detected

[0239] Table 16: Results of one month stability for Example CE12.

[0240]

[0241] Conclusion: The formulations from comparative Examples showed significant increase in total impurity content.

[0242] Inventive Example IE6:

[0243] An inventive formulation IE6 was checked for diluent compatibility with 0.9% Sodium Chloride Injection as diluent

[0244] The composition of IE6 used for Diluent Compatibility Study is provided in Table 17:

[0245] Table 17:

[0246]

[0247]

[0248] Q.S: Quantity Sufficient

[0249] Diluent compatibility study data is provided in below Tables.

[0250] Table 18: Results of Dilution Study at 0.1 mg / mL Concentration with 0.9% Sodium Chloride Injection for IE6

[0251]

[0252] * After 72 hours exposure at refrigerate (2 - 8°C) condition followed by 12 hours at room temperature.

[0253] Inventive Example IE7: Diluent compatibility study for sample without sodium hydroxide: A composition without sodium hydroxide was evaluated for the stability and diluent compatibility. Composition used for Diluent Compatibility Study is provided in Table 19: Table 19:

[0254]

[0255] Q.S: Quantity Sufficient

[0256] The stability results are provided in the below table 20 .

[0257] Table 20: Stability Data of the Liquid Doxycycline Injection 25 mg / mL of IE7

[0258]

[0259] NP: Not Performed The analytical results of the diluent compatibility study samples with the Example IE7.

[0260] Table 21: Results of Dilution Study at 0.1 mg / mL Concentration with 0.9% Sodium Chloride Injection

[0261]

[0262] Conclusion: In the absence of sodium hydroxide, the drug product composition demonstrated slightly reduced stability due to higher 4-epidoxycycline impurity levels, while exhibiting improved diluent compatibility with respect to the unknown impurity profile. Conclusions are provided in Table 22. Nevertheless, the sample still has better performance when compared with the aqueous formulations.

[0263] Table 22:

[0264]

[0265] Inventive Examples IE8 to IE 14 with different molar ratios of sodium hydroxide: Samples were taken with similar molar ratio of Doxycycline and Magnesium complex and different Sodium Hydroxide Concentrations were evaluated.

[0266] Table 23: Compositions with Combination of PEG 300, same Molar Ratio of Chelating Agent (MgCh) and different Sodium Hydroxide Concentrations

[0267]

[0268] Q.S.: Quantity Sufficient

[0269] *28.85 mg of Doxycycline Hyclate is equivalent to 25 mg of Doxycycline

[0270] The analytical results of the samples are provided in Tables 24 & 25 given below.

[0271] Table 24: Impurity Profile of the Batches with Different Sodium Hydroxide Concentrations at Initial

[0272]

[0273] Table 25: Impurity Profile of the Batches with Different Sodium Hydroxide Concentrations at 60°C

[0274]

[0275] Conclusion: When sodium hydroxide concentration was increased 4-Epidoxycycline impurity level was slightly decreased.

[0276] Inventive Examples IE8 to IE14: Diluent compatibility studies for sample with different concentrations of sodium hydroxide:

[0277] Diluent compatibility studies were conducted using drug product formulations containing varying concentrations of sodium hydroxide (2.5 mg / mL, 3.0 mg / mL, and 3.5 mg / mL) upon dilution with 0.9% sodium chloride injection.

[0278] The analytical results of the dilution samples are provided in Tables 26 - 28 given below. Table 26: Results of Dilution Study at 0.1 mg / mL Concentration with 0.9% Sodium Chloride Injection

[0279]

[0280]

[0281] Table 27: Results of Dilution Study at 0.1 mg / mL Concentration with 0.9% Sodium Chloride Injection

[0282]

[0283] Table 28: Results of Dilution Study at 0.1 mg / mL Concentration with 0.9% Sodium Chloride Injection

[0284]

[0285] Conclusion: Based on the dilution study results, it was observed that drug product formulations containing sodium hydroxide concentrations in the range of 2.5 mg / mL to 3.0 mg / mL demonstrated highest stability upon dilution with 0.9% sodium chloride injection.

Claims

We Claim:

1. A non-aqueous liquid formulation comprising a tetracycline antibiotic, a magnesium or a calcium ion and a non-aqueous vehicle.

2. The non-aqueous liquid formulation as claimed in claim 1, wherein, the tetracycline antibiotic is doxycycline, aminomethylcycline, chlortetracycline, chlorocycline, demeclocycline, tigecycline, lymecycline, meclocycline, methacycline, minocycline, oxytetracycline, rolitetracycline, tetracycline, eravacycline, sarecycline, and omadacycline or their salts or hydrates or solvates thereof.

3. The non-aqueous liquid formulation as claimed in claim 1, wherein, the tetracycline antibiotic is doxycycline or doxycycline hyclate.

4. The non-aqueous liquid formulation as claimed in claim 1, wherein the formulation comprises magnesium ion.

5. The non-aqueous liquid formulation as claimed in claim 1, wherein the non-aqueous vehicle is poly alkylene glycol.

6. The non-aqueous liquid formulation as claimed in claim 1, wherein the non-aqueous vehicle is polyethylene glycol.

7. The non-aqueous liquid formulation as claimed in claim 1, comprising:• at least one tetracycline antibiotic selected from the group consisting of doxycycline, aminomethylcycline, chlortetracycline, chlorocycline, demeclocycline, tigecycline, lymecycline, meclocycline, methacycline, minocycline, oxytetracycline, rolitetracycline, tetracycline, eravacycline, sarecycline, and omadacycline, in an amount from 10 mg / mLto 50 mg / mL;• a magnesium or a calcium ion in an amount amount from 1.0 mg / mL to 5 mg / mL; and • a sufficient quantity of non-aqueous vehicle to constitute the remainder of the formulation volume.

8. The non-aqueous liquid formulation of doxycycline as claimed in claim 1, comprising• about 10.0 mg / mL to about 50.0 mg / mL of doxycycline hyclate;• about 1.0 mg / mL to about 5 mg / mL of magnesium ions supplied by magnesium chloride;and• a sufficient quantity of PEG 300 to constitute the remainder of the formulation volume;wherein the molar ratio of tetracycline antibiotic to the magnesium or calcium ion ranges from about 1 :0.5 to about 1:5, and the formulation has a pH of about 1.5 to about 6.

9. The non-aqueous liquid formulation as claimed in claim 1, further comprising a base.

10. The non-aqueous liquid formulation as claimed in claim 9, wherein the base is present in an amount of about 1.0 mg / mL to about 4.0 mg / mL of the liquid formulation.

11. The non-aqueous liquid formulation as claimed in claim 9, wherein the base is present in an amount of about 2.0 mg / mL to about 3.0 mg / mL of the liquid formulation.

12. The non-aqueous liquid formulation as claimed in claim 9, wherein the base is an inorganic base.

13. The non-aqueous liquid formulation as claimed in claim 12, wherein the inorganic base, is an alkali hydroxide.

14. The non-aqueous liquid formulation as claimed in claim 13, wherein the alkali hydroxide is sodium hydroxide.

15. The non-aqueous liquid formulation as claimed in claim 12, comprising:• at least one tetracycline antibiotic selected from the group consisting of doxycycline, aminomethylcycline, chlortetracycline, chlorocycline, demeclocycline, tigecycline, lymecycline, meclocycline, methacycline, minocycline, oxytetracycline, rolitetracycline, tetracycline, eravacy cline, sarecy cline, and omadacy cline, in an amount from 10 mg / mL to 50 mg / mL;• a magnesium or a calcium ion in an amount amount from 1.0 mg / mL to 5 mg / mL;• a sufficient quantity of non-aqueous vehicle to constitute the remainder of the formulation volume; anda base.

16. The non-aqueous liquid formulation of doxycycline as claimed in claim 15, comprising:• about 10.0 mg / mL to about 50.0 mg / mL of doxycycline hyclate;• about 1.0 mg / mL to about 5.0 mg / mL magnesium ions supplied by magnesium chloride;• about 2.0 mg / mL to about 3.0 mg / mL of sodium hydroxide; and• a sufficient quantity of PEG 300 to constitute the remainder of the formulation volume, wherein the molar ratio of tetracycline antibiotic to the magnesium or calcium ion ranges from about 1 :0.5 to about 1:5, and the formulation has a pH of about 1.5 to about 6.

17. The non-aqueous liquid formulation of doxycycline as claimed in claims 1-16, wherein the formulation is diluted with diluents selected from 0.9% sodium chloride, 5% dextrose, , lactated Ringer’s solution, Ringer’s solution, invert sugar (10% in water), 5% dextrose in Lactated Ringers, 5% dextrose in 0.45% sodium chloride solution, sterile water for injection, glucosesodium citrate solution, sorbitol (5-10%), mannitol (5%), Normosol-M® in D5-W (5% Dextrose), Normosol-R® in D5-W (5% Dextrose), plasma-Lyte® 56 in 5% Dextrose, and plasma-Lyte® 148 in 5% Dextrose.

18. A process for the preparation of non-aqueous liquid formulations comprising a tetracycline antibiotic comprising:a) dissolving a source of magnesium or calcium ion in a non-aqueous vehicle; andb) adding a tetracycline antibiotic compound to the solution obtained in step a).

19. The process as claimed in claim 18, wherein the non-aqueous vehicle is polyalkylene glycol.

20. The process as claimed in claim 18, wherein the non-aqueous vehicle is polyethylene glycol.

21. The process as claimed in claim 18, wherein the source of magnesium ions in the formulation is any magnesium salt selected from magnesium chloride, magnesium ascorbate, magnesium lactate, magnesium gluconate, magnesium sulfate, magnesium oxide, magnesium acetate, magnesium bromide, magnesium malate, magnesium hydroxide, and magnesiumcitrate; and the source of calcium salt is calcium chloride, calcium carbonate, calcium citrate, calcium phosphate, calcium gluconate, calcium lactate, and calcium hydroxide.

22. The process as claimed in claim 18, wherein the tetracycline antibiotic is doxycycline hyclate.

23. The process as claimed in claim 18, wherein, the process comprises a step c) of optionally, heating the solution to fasten the solubilization of above ingredients.

24. The process as claimed in claim 18, wherein, the process comprises a step c) comprising adding a base to the solution obtained in step b).

25. The process as claimed in claim 24, wherein the base is added in an amount of about 1 to about 4 mg / mL of the total volume of the liquid formulation.

26. The process as claimed in claim 25, wherein, the base is sodium hydroxide.

27. The process for preparing a non-aqueous liquid formulation as claimed in claim 26, wherein the process comprises:a) dissolving magnesium chloride in polyethylene glycol;b) adding doxycycline hyclate to the solution of step a);c) optionally, heating the solution to fasten the solubilization of above ingredients; and d) adding sodium hydroxide to the solution of step b) or step c).

28. A kit for parenteral and oral administration comprising:• a liquid formulation comprising a tetracycline antibiotic, a magnesium or a calcium compound, a base, and a non-aqueous vehicle; and• optionally a diluent.

29. A method for the treatment or prophylaxis of a condition or disorder in a subject in need thereof by administering a non-aqueous liquid formulation of doxycycline as claimed in any of claims 1 to 17.

30. Anon-aqueous liquid formulation of doxycycline as claimed in any of claims 1 to 17 for use in the manufacture of a medicament.

31. The non-aqueous liquid formulation of doxycycline as claimed in claims 1 to 17 for use in the manufacture of a medicament for the treatment of bacterial infections, acne or other dermatological inflammatory conditions, respiratory tract infections, and ocular infections.

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