WO2019162756A2

WO2019162756A2 - Liquid pharmaceutical compositions of anticancer drugs

Info

Publication number: WO2019162756A2
Application number: PCT/IB2019/000068
Authority: WO
Inventors: Swati NAGAR; Vijay Patel; Sandeep Pal; Sandip Mehta; Manish UMRETHIA; Jayanta Kumar Mandal
Original assignee: Ftf Pharma Private Limited
Priority date: 2018-02-20
Filing date: 2019-02-20
Publication date: 2019-08-29
Also published as: WO2019162756A3

Abstract

Cancer is one of the fast emerging diseases across the globe and the affected population includes patients from all age groups. Anticancer drugs are bitter in taste and therefore sometimes become unacceptable to patients because of its smell, taste, aftertaste and feeling in the mouth. Therefore there will always be a threat of rejection for the anticancer solid oral dosage forms by the patients. Additionally, solid oral dosage forms may not be suitable option for pediatric and geriatric patients or for the patients having swallowing difficulties. The present invention therefore describes liquid compositions of anticancer drugs which are palatable and acceptable to all types of patients' population.

Description

LIQUID PHARMACEUTICAL COMPOSITIONS OF ANTICANCER DRUGS

FILED OF THE INVENTION

The present invention relates, in general to the pharmaceutical field, and more precisely it relates to the liquid pharmaceutical compositions of an active pharmaceutical ingredient. In particular, the present invention relates to the liquid compositions 5 comprising anticancer drugs, suitable for oral administration. Disclosed liquid compositions may be advantageous for the patients having swallowing difficulties such as pediatric or geriatric patients or when the patients are unable to take solid oral dosage forms. 0 BACKGROUND OF THE INVENTION

Children generally reject taking medicine which does not have a favorable shape, taste, flavor, etc. However, if a child who needs to take a medicine, rejects taking it, he might never recover from his condition. When a child is unable to take medicine orally, it is intravenously administered, and he and his caregivers then may experience stress.5 Syrups and suspensions are considered as favorable types of dosage forms in which to orally administer medicine to infants and children. However, they may have disadvantages such as solubility, a bad taste, portability problems or required refrigerator storage. World Health Organization (WHO) currently favors that infants and children be treated with oral solid medicines. New oral solid tablets, such as a mini-0 tablet, instead of liquid medicines are proposed for this group, however, there are a few reports that mini-tablets are suitable for infants and children. Palatability is one of the main elements of patient acceptability of an oral pediatric medicine. Palatability is defined as the overall appreciation of an oral medicinal product in relation to its smell, taste, aftertaste and feeling in the mouth. Design of the formulation of an oral pediatric5 medicine should be considered together with its palatability.

Compared to conventional tablets and capsules, oral liquid dosage forms including solutions, syrups, suspensions, elixirs, and concentrates offer unique advantages to many patients. For example, liquids may provide better patient compliance for those0 with swallowing difficulties and better dosage control versus a fixed tablet dose. Hence, liquid dosage forms are generally formulated for use in geriatric and pediatric patients. However, there are also a number of“challenges” surrounding the formulation and development of these forms. Oral liquids are formulated as solutions, suspensions and emulsions depending on the nature of the active ingredient particularly solubility and stability. They are also designed as ready to use liquids and powders for reconstitution into liquid orals like syrups, solutions, suspensions and emulsions. Liquid formulation needs various excipients including vehicle, solubilizer, stabilizer, and viscosity builder, preservative and off course sweeteners, color and flavor. The selection of these excipients is of major concern to design stable, effective and palatable oral liquid formulation.

Characteristics of active drug are of major concern in developing an oral liquid dosage formulation. The major challenges in developing oral liquid dosage forms are (i) the stability of a drug in solution, (ii) the solubility of a drug at the required level, and (iii) an acceptable taste. It is the effective use of excipients, which allows formulators overcome these challenges. Additionally, an excipient’s compatibility with a drug in the solid state cannot infer the same compatibility in solution.

The decision to develop a solution, syrup or a suspension of a drug is influenced by many factors like solubility and the desired release profile of the drug and properties of the base vehicle like surface tension, viscosity, boiling point, and specific heat of solution, all of which may be affected in various ways. In case of clear liquids, lack of solubility of the drug in the base vehicle may demand the need for miscible co-solvents. Similarly, a miscible solvent may be needed to decrease the solubility of the drug in a primary vehicle in formulating a suspension.

The therapeutic utility of drugs involves the application of dosage forms/delivery systems, which serve as carrier systems together with several excipients to deliver the active therapeutic agent to the site of action. Suspensions are an important class of pharmaceutical dosage forms that may be given by many routes, including oral, topical, parenteral, and also used in the eye for ophthalmic purposes. Surprisingly, large proportions of new drug candidates that are emerging are predominantly water insoluble and, therefore, demonstrate poor bioavailability in the solution dosage form. While suspensions present a viable formulation option for many drugs, particularly for water insoluble, hydrophobic drug substances, there are certain criteria that a well- formulated suspension should meet. The suspension dosage form has long been used for poorly soluble active ingredients for various therapeutic indications. Development of stable suspensions over the shelf life of the drug product continues to be a challenge on many fronts. Drugs from suspension formulations typically exhibit an improved bioavailability when compared to the same drug formulated as a tablet or capsule.

A good understanding of the fundamentals of disperse systems is essential in the development of a suitable pharmaceutical suspension. The development of a suspension dosage form follows a very complicated path. The selection of the proper excipients (surfactants, viscosity imparting agents etc.) is important. The particle size distribution in the finished drug product dosage form is a critical parameter that significantly impacts the bioavailability and pharmacokinetics of the product.

Suspensions are an important class of pharmaceutical dosage forms. The advantages of suspension dosage forms include effective dispensing of hydrophobic drugs; avoidance of the use of co-solvents; masking of unpleasant taste of certain ingredients; offering resistance to degradation of drugs due to hydrolysis, oxidation or microbial activity; easy swallowing for young or elderly patients; and efficient intramuscular depot therapy. In addition, when compared to solution dosage forms, relatively higher concentration of drugs can be incorporated into suspension products. To date, numerous theories have been introduced and successfully used to explain the unique behavior of suspension preparations.

Anticancer drugs represent a very important therapeutic class among others. Anticancer agents are known to have bitter taste and therefore are unacceptable to some patient populations. Further, in many cases, surgery of cancer patients becomes necessary. It is very difficult for such patients who have under gone surgery to swallow oral medicines for few days or weeks ln such a situation, medicine can be administered using a tube. Therefore, if finished dosage form is in liquid, it will be easier to administer dose as compared to any other type of dosage forms.

Though liquid pharmaceutical compositions of anticancer drugs are advantageous and much more required, they are not much explored by the formulation scientists. Therefore, looking at the need existing in the art for the preparation of liquid pharmaceutical compositions of anticancer drugs to mask its bitter taste and make them overall acceptable to all types of patient population, the present inventors have formulated anticancer drugs in liquid pharmaceutical compositions having palatability and acceptability along with prolonged stability. These properties of the liquid compositions of the present invention make them favorable for use in the pharmaceutical industry.

OBJECTS OF THE INVENTION

Cancer is one of the fast growing diseases across the globe and cancer patients’ population is increasing day by day. Anticancer drugs are very bitter in taste and are therefore not acceptable to some patients’ population such as pediatric patients’ population. Bitter taste of such anticancer drugs can be masked by preparing liquid dosage forms such as solutions or suspensions which comprise sweeteners as well as flavors. Acceptability of anticancer dosage forms can thus be increased by increasing its palatability. Therefore in its one of the principal objects, the present invention provides pharmaceutical compositions of anticancer drugs having palatability.

Liquid dosage forms represent one of the most favorable dosage forms as compared to solid dosage forms especially when patients are unable to take oral therapy or have swallowing difficulties, e.g. pediatric and geriatric patients. A yet another object of the present invention is therefore to provide liquid pharmaceutical compositions of anticancer drugs. The liquid compositions of the present invention are suitable for oral administration.

A yet another object of the present invention is to provide liquid pharmaceutical compositions of anticancer drugs comprising one or more pharmaceutically acceptable excipients selected from the group comprising of vehicles, solvents/cosolvents/solubilizers, preservatives, pH adjusting agents/pH modifying agents/buffering agents, surfactants, anti-foaming agents, suspending agents/thickening agents/viscosity modifying agents, bulking agents/auxiliary suspending agents, wetting agents, anti-oxidants, chelating agents, anti-caking agents, sweetening agents, flavoring agents, coloring agents and the like or any combination thereof. In one of the further objects, an anticancer drug is Capacitabine, Erlotinib, Sunitinib, or Sorafenib or its pharmaceutically acceptable salts and chemical derivatives such as polymorphs, solvates, hydrates, anhydrous forms, prodrugs, chelates, and complexes thereof.

A yet another object of the present invention is to provide liquid pharmaceutical compositions of anticancer drugs having stability over prolonged time when stored under storage conditions.

A yet another object of the present invention is to provide processes for the preparation of liquid pharmaceutical compositions of anticancer drugs prepared according to the present invention.

DESCRIPTION OF THE INVENTION

An important consideration in any treatment regime is to ensure that the patient receives the correct dose of medicine. For many patients and many drugs there is an acceptable dose window that allows fixed-dose medicines to be used to treat patients with a wide range of body weights without the need to precisely adjust the dose. However, there are other groups of patients where the“fixed-unit-dose” model may not be appropriate, depending on the drug’s therapeutic index and pharmacokinetics, e.g. pediatric patients, geriatric patients, patients with severe renal insufficiency and patients with severe hepatic insufficiency. Oral solid unit dose forms, e.g. tablets and capsules, are not convenient under such circumstances since they are fixed strength unit dose forms. In contrast, oral liquid dose forms do have the in-built flexibility that allows the dose to be tailored to the patients’ needs.

Where the drug is sufficiently soluble, a solution dosage form, e.g. a simple mixture, may be used. But not all drugs are sufficiently soluble to allow suitable strength solution medicines to be developed and manufactured with an acceptable shelf-life. In such cases, an alternative approach could be to develop a stable aqueous suspension that will allow consistent dosing of the patient. Pharmaceutical suspensions have several advantages and disadvantages when compared to other dosage forms. Since suspensions are liquids, dose adjustment for patients with renal or hepatic impairment, or for pediatric or geriatric patients, may be more straightforward. This is an oversimplification of the development of a dosing strategy for a drug candidate. There are many other details that must be considered for a formulation development project to be successful, but it does provide a simple overview of some of the issues.

The suspension must be physically stable (no appreciable settling) for a sufficient time, chemically stable over the required time (shelf-life), possess a viscosity that allows it to be used for its intended purpose, be easily reconstituted by shaking, and be acceptable in use to the patient, care-giver or other user.

Some materials may possess a combination of properties useful in the formulation and manufacture of stable, elegant pharmaceutical suspensions. Formulation scientists need to consider the totality of properties possessed by a particular excipient. Even though it is being added for one particular characteristic, the other properties will still be present, and will still influence the formulation.

Many of the recently discovered active pharmaceutical ingredients are quite hydrophobic with limited solubility. They may also be quite distasteful. Other drugs may also have quite a high chemical degradation precluding them to be administered as aqueous solutions, and in this case, it may be possible to synthesize an insoluble derivative. In other cases, some drugs are required to be present in the gastrointestinal tract or in the pre-corneal pocket with long residence time. For such drugs, a suspension is an ideal delivery system as it provides better chemical stability and larger surface area and is often more bioavailable than aqueous solutions, tablets, and capsules.

Formulation of an elegant, stable, preserved, safe, and effective suspension is a technically challenging task compared aqueous solutions, tablets, and capsules. Pharmaceutical suspensions are thermodynamically unstable systems. Thus, preparation of such systems is often associated with problems of physical stability, content uniformity, sedimentation, caking, re-suspendibility, and crystal growth. Furthermore, issues related to the masking of bitter taste and undesirable odor of the pharmaceutical ingredient must be taken into consideration. Some desirable attributes of a suspension are described as follows,

1. It should be safe, effective, stable, and pharmaceutically elegant during the shelf life of the product.

2. The drug should not have a quick sedimentation rate. Furthermore, it should re suspend easily upon shaking and it must not cake.

3. Physical attributes such as particle size, particle size distribution, viscosity should remain fairly uniform throughout the shelf life of the product.

4. Its viscosity must promote free and uniform flow from the container. The product must have appropriate substantivity that it spreads freely over the affected area.

5. Re-suspension should produce a homogeneous mix of drug particles such that there is a content uniformity with each dose.

A quick means to identify whether or not a drug may be more suitable for solution or suspension is to overlap the pH-stability profile with the pH-solubility profile. This overlap creates a window, which may suggest which dosage form might be most desirable and subsequently the type of excipients needed.

Oral liquid formulation needs a meticulous blend of ingredients to perform various functions like wetting and solubilization, stabilization and to impart suitable color, taste and viscosity. The blend should be compatible, non-reactive and stable. The common excipients generally required for any liquid formulation are vehicles (base), viscosity builders, stabilizers, preservatives, colors and flavors. In addition, solubilizers are required in case of clear liquids, suspending agents are needed for suspensions and emulsifying agents for emulsions.

In one of the principal aspects, the present invention provides liquid pharmaceutical compositions comprising anticancer drugs and one or more pharmaceutically acceptable excipients.

The term“pharmaceutically acceptable excipients” as used herein refers to such pharmaceutically acceptable excipients which are known to those skilled in the art for the purposes of preparing liquid pharmaceutical compositions as described in the present invention. Such pharmaceutically acceptable excipients without limitation include aqueous/non-aqueous vehicles, aqueous/non-aqueous solvents/co-solvents or solubilizers, suspending agents/thickening agents/viscosity modifying agents, anti- foaming agents, stabilizing agents, anti-oxidants, pH adjusting/pH modifying/buffering agents, wetting agents, bulking agents/auxiliary suspending agents, chelating agents, surfactants, preservatives, sweetening agents, coloring agents, flavoring agents and the like or any combination thereof. Such pharmaceutically acceptable excipients can be used in an amount which provides the liquid dosage forms of the present invention desired property for which they are intended to use.

In one of the further aspects, the present invention provides liquid pharmaceutical compositions such as liquids, liquid dispersions, suspensions, solutions, emulsions, sprays, spot-on, syrups, elixirs or concentrates comprising anticancer drugs and suitable excipients to prepare such compositions. In some of the aspects, the liquid compositions of the invention may be administered orally.

In one of the further aspects, the liquid compositions of the invention are suitable for administration to all types of patients’ population. In particular, liquid compositions of the invention are suitable for pediatric and geriatric patients. The liquid compositions of the invention are also useful for the patients having swallowing difficulties.

In one of the further aspects, the liquid compositions of the invention are palatable. In one of the further aspects, the liquid compositions of the invention are stable for prolonged time when stored under storage conditions.

As used herein, terms“stable” or“stability” encompass any characteristic of the liquid compositions which may be affected by storage conditions including, without limitation, potency, total impurities, degradation products, specific optical rotation, optical purity, water content, appearance, viscosity, sterility, and colour and clarity. The storage conditions which may affect stability include, for example, duration of storage, temperature, humidity, and/or light exposure.

In certain aspects of the present invention, stable liquid compositions refer to compositions which retain at least about 90%, or about least about 95%, or at least about 96%, or at least about 98%, of the labelled concentration of an active pharmaceutical ingredient contained in the said composition after storage under typical and/or accelerated conditions. In further aspects, stable liquid dosage forms refer to less than about 15% (area percent), or less than about 10% (area percent), or less than about 7% (area percent), or less than about 5% (area percent), or less than about 2% (area percent) of active pharmaceutical ingredient-related impurities are present after storage under typical and/or accelerated conditions.

Typical storage conditions include but not limited to 2°C-8°C, 40°C±2°C/75±5% RH, 30°C±2°C/65±5% RH, 25°C±2°C/40±5% RH. The liquid compositions of the present invention are stable at above mentioned conditions for at least 1 month, at least 3 months, at least 6 months or at least 12 months.

Methods for determining the stability of the liquid dosage forms of the present invention with respect to a given parameter are well-known to those of skill in the art. For example, individual impurities and total impurities can be assessed by high- performance liquid chromatography (HPLC) or thin layer chromatography (TLC). Unless otherwise indicated to the contrary, a percentage amount of any individual impurities (known/unknown), or total impurities reported herein in the liquid dosage forms are determined by a peak area percent method using HPLC.

In some of the further aspects, the present invention provides concentrate liquid compositions which may be diluted using suitable diluent before administering to the patient. In some of the aspects, the liquid compositions of the invention are ready-to- use liquid compositions. Such ready-to-use compositions of the invention are administered directly to the patients in required doses without any prior preparation e.g. reconstitution in suitable diluent such as water.

The term“comprise/comprises/comprising” as used herein mean that other ingredients, steps, etc. are optionally present. When reference is made herein to a method comprising two or more defined steps, the steps can be carried in any order or simultaneously (except where the context excludes that possibility), and the method can include one or more steps which are carried out before any of the defined steps, between two of the defined steps, or after all of the defined steps (except where the context excludes that possibility). In one of the further aspects, the pH of the liquid compositions of the present invention is between about 3.0 and about 9.0. In some of the aspects, the pH of the composition is between about 4.0 and about 8.0. In some of the aspects, the pH of the composition is between about 5.0 and about 7.0.

The term“about,” as used herein, refers to any value which lies within the range defined by a variation of up to ±10% of the value.

The use of the terms“a” and“an” and“the” and similar referents in the context of describing the invention (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

All percentages mentioned herein, unless otherwise indicated, are on a w/v basis, i.e. percentage ingredient (active/inactive) present in the total volume of the liquid dosage form.

Following embodiments of the invention describe suitable excipients which may be used to prepare liquid compositions of the present invention. It is in no way the intention of the present inventors to limit the scope of the liquid compositions of the present invention by description of following embodiments. Described embodiments are for illustrative purpose only and a skilled person may use other excipients from the same or different classes as well which may provide liquid compositions of the present invention improved physico-chemical properties, palatability, stability and the like or increase patients’ acceptability towards the therapy. Such other excipients, classes of excipients and compositions resulted therefrom are also covered within the scope of the present invention.

Vehicles may be used in the liquid compositions of the present invention. Vehicles are the liquid bases that carry drugs and other excipients in dissolved or dispersed state. Vehicles may be aqueous or non-aqueous or mixture thereof. Non-aqueous solvents may be added in the liquid compositions of the present invention to increase the solubility of poorly soluble substances and enhance the chemical stability of a drug. Suitable solvents/co-solvents, solubilizer or vehicles, that may be employed, in the liquid compositions of the invention include, but are not limited to, dichloromethane, acetonitrile, ethyl acetate, acetone, propylene carbonate, water, glycerine, coconut fatty acid diethanolamide, medium and/or long chain fatty acids or glycerides, monoglycerides, diglycerides, triglycerides, structured triglycerides, soyabean oil, peanut oil, corn oil, corn oil mono glycerides, corn oil di glycerides, com oil triglycerides, polyethylene glycol, caprylocaproylmacroglycerides, caproyl 90, propylene glycol, polyoxyethylenesorbitan fatty acid esters, polyoxyethylene castor oil derivatives, castor oil, cottonseed oil, olive oil, safflower oil, peppermint oil, coconut oil, palm seed oil, beeswax, oleic acid, methanol, ethanol, isopropyl alcohol, butanol, acetone, methyl isobutyl ketone, methyl ethyl ketone or combinations thereof.

Wetting agents as used herein are routinely used in pharmaceutical formulations, especially in liquid dosage forms to create a homogeneous dispersion of solid particles in a liquid vehicle. This process can be challenging due to a layer of adsorbed air on the particle’s surface. Hence, even particles with a high density may float on the surface of the liquid until the air phase is displaced completely. The use of a wetting agent allows removal of adsorbed air and easy penetration of the liquid vehicle into pores of the particle in a short period of time. For an aqueous vehicle, alcohol, glycerin, and PG are frequently used to facilitate the removal of adsorbed air from the surface of particles. Whereas for a non-aqueous liquid vehicle, mineral oil is commonly used as a wetting agent. Non-limiting examples of wetting agents are Benzalkonium chloride, Benzethonium chloride, Cetylpyridinium chloride, Docusate sodium, Nonoxynol 9, Octoxynol, Poloxamer, Poloxamer 124, Poloxamer 188, 237, 338, 407, Polyoxyl 35 castor oil, Polyoxyl 40 hydrogenated castor oil, Polyoxyl 10 oleyl ether, Polyoxyl 20 cetylstearyl ether, Polyoxyl 40 stearate, Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 80, Sodium lauryl sulfate, Sorbitan monolaurate, Sorbitan monooleate, Sorbitan monopalmitate, Sorbitan monostearate, Tyloxapol and the like.

The pH of an oral liquid formulation is a key point in many regards. Control of the formulation pH, could prevent large changes during storage. Therefore, most formulations utilize a buffer to control potential changes in the solution pH. The amount of buffer capacity needed is generally between 0.01 and 0.1 M, and a concentration between 0.05 and 0.5 M is usually sufficient. The selection of a suitable buffer should be based on (i) Whether the acid-base forms are listed for use in oral liquids, (ii) The stability of the drug and excipients in the buffer, and (iii) The compatibility between the buffer and container. A combination of buffers can also be used to gain a wider range of pH compared to the individual buffer alone. However, not all buffers are suitable for use in oral liquids. For example, a boric acid buffer may be used for optical and IV delivery but not in oral liquids because of its toxicity. The stabilizing effect of buffers that have multiple charged species in solution could also determine the potential reaction between excipients and API. For example, buffers that use carbonates, citrate, tartrate, and various phosphate salts may precipitate with calcium ions by forming sparingly soluble salts. However, this precipitation is dependent upon the solution pH. The activity of phosphate ions may be lowered due to interactions with other solution components.

There are a number of factors that may also affect the solution pH such as temperature, ionic strength, dilution, and the amount and type of co-solvents present. For example, the pH of acetate buffers is known to increase with temperature, whereas the pH of boric acid buffers decreases with temperature. Finally, the drug in solution may itself act as a buffer. If the drug is a weak electrolyte, such as salicylic acid or ephedrine, the addition of base or acid, respectively, will create a system in which the drug can act as a buffer.

One of the most crucial factors involved in formulating a pharmaceutical suspension is the selection of an appropriate suspending agent. Suspending agents impart viscosity, and thus retard particle sedimentation. Other factors considered in the selection of the appropriate agent include desired rheological property, suspending ability in the system, chemical compatibility with other excipients, pH stability, length of time to hydrate, batch-to-batch reproducibility, and cost. Non-limiting examples of pH modifiers and buffers are Acetic acid, Adipic acid, Ammonium carbonate, Ammonium hydroxide, Ammonium phosphate, Boric acid, Citric acid, Diethanolamine, Fumaric acid, Hydrochloric acid, Malic acid, Nitric acid, Propionic acid, Potassium acetate, Potassium bicarbonate, Potassium chloride, Potassium citrate, Potassium metaphosphate, Potassium phosphate, Sodium acetate, Sodium bicarbonate, Sodium borate, Sodium carbonate, Sodium chloride, Sodium citrate, Sodium glycolate, Sodium hydroxide, Sodium lactate, Sodium phosphate, Sodium proprionate, Succinic acid, Sulfuric acid, Tartaric acid, Triethylamine, Triethanolamine, Tromethamine, Trolamine and the like.

Suspending agents can be classified into cellulose derivatives, clays, natural gums, and synthetic gums. In many cases, these excipients are used in combination. There are many water soluble hydrocolloids that can act as suspending agents in the formulation of pharmaceutical suspensions. They can be of natural, semi-synthetic or synthetic origin. Non-limiting examples of suspending agents are Acacia, Agar, Alginic acid, Carbomer, Carmellose sodium, Dextrin, Gelatin, Veegum or Gel white, Gellan gum, Sodium alginate, Methylcellulose, Hydroxyethyl cellulose, Hydroxypropyl cellulose, Hydroxypropylmethyl cellulose, Hydroxypropyl starch, Hypromellose, Maltodextrin, Methylcellulose, Modified starch, Pectin, Poloxamer, Polycarbophil, Polyethylene glycol, Polyvinyl acetate, Poly (vinyl alcohol), Potassium alginate, Polyvinyl pyrrolidone, Pregelatinized starch, Propylene glycol alginate, Sodium alginate, Carboxymethyl cellulose or an alkali metal salt thereof, Microcrystalline cellulose, gum Arabic, Karaya gum, Sterculia gum, Tragacanth, Xanthangum, Bentonite, Carageenan, Guar gum, Colloidal silicon dioxide and the like.

Microbiological contamination presents a significant health hazard in oral liquids. Therefore, the use of preservatives become inevitable to prevent the growth of microorganisms during the product’s manufacture and shelf life, although it may be most desirable to develop a“preservative-free” formulation to address the increasing concerns about the biological activity of these compounds. Most formulations require some kind of preservative to ensure no microbial growth.

The majority of preservatives are bacteriostatic rather than bacteriocidal, and consists of both acid and nonacid types. Among the acidic types are phenol, chloro-cresol, 9- phenyl phenol, alkyl esters of para-hydroxybenzoic acid, benzoic acid, boric acid, and sorbic acid, and their respective salts. Therefore, the pH of solution, and the pKa of the preservative need to be carefully evaluated prior to selecting a preservative for a formulation. Neutral preservatives include chlorobutanol, benzyl alcohol, and beta- phenylethyl alcohol. Under alkaline conditions, it is generally regarded that microbial growth is insignificant and at these pH values, the need for a preservative is not generally recommended. Many preservatives listed in the FDA inactive ingredient guide for liquid dosage forms. Unfortunately, many of them are not recommended for use in oral liquids and hence the choice of an acceptable preservative for an oral liquid formulation is limited. In addition, the solubility of many preservatives in aqueous system may not be high enough for effective antimicrobial activity. Additionally, it is essential to understand that bacteriostatic agents like para hydroxyl benzoic acids can partition between organic and aqueous phases in a heterogenous liquid formulations in such a way that their activity is significantly reduced. Non-limiting examples of preservatives are Alcohol, Ethanol, Chlorobutanol, Phenoxyethanol, Potassium benzoate, Benzyl alcohol, Benzoic acid, Potassium sorbate, Sorbic acid, Benzalkonium chloride, Benzethonium chloride, Cetrimonium bromide, Cetylpyridinium chloride, Bronopol, Chlorbutol, Chlorocresol, Cresol, Butylparaben, Methylparaben, Propylparaben, Ethylparaben, Phenol, Thymol, Phenylethanol, Sodium benzoate, Antimicrobial solvents like Propylene glycol, Glycerin, Chloroform and the like. In addition, some formulation ingredients like nonionic surfactants, quaternary ammonium compounds, gelatin, ferric salts, calcium salts and salts of heavy metals, including silver, lead, and mercury prevent microbial growth.

Antioxidants can be compounds that can reduce a drug that has been oxidized, or compounds that are more readily oxidized than the agents they are to protect (oxygen scavengers). Many of the lipid-soluble antioxidants act as scavengers. Antioxidants can also act as chain terminators, reacting with free radicals in solution to stop the free- radical propagation cycle. Mixtures of chelating agents and antioxidants are often used because there appears to be a synergistic effect. This occurs because many of the agents act at differing steps in the oxidative process.

Some substances prone to oxidation include unsaturated oils/fats, compounds with aldehyde or phenolic groups, colors, flavors, sweeteners, plastics and rubbers, the latter being used in containers for products. Oxidation may manifest as products with an unpleasant odour, taste, appearance, precipitation, discoloration or even a slight loss of activity. The term rancidity refers to many typical off-flavors that result from autoxidation of unsaturated fatty acids that are present in oils and fats, and it affects many oils and fats. The distinct rancid odour may result from short-chain, volatile monomers resulting from the cleavage of the longer chain, less volatile oils and fats. Non-limiting examples of anti-oxidants are a-Tocopherol acetate, Ascorbic acid, Erythorbic acid, Butylated hydroxytoluene (BHT), d-a-Tocopherol natural, Monothioglycerol, Sodium bisulfite, Sodium sulfite, Sodium metabisulfite, Potassium metabisulfite, Acetone sodium bisulfite, Ascorbyl palmitate, Cysteine, d-a-tocopherol synthetic, Nordihydroguaiaretic acid, Sodium formaldehyde sulfoxylate, Sodium thiosulfate, Acetylcysteine, Ascorbyl palmitate, Butylated hydroxyanisole (BHA), Cysteine hydrochloride, Dithiothreitol, Propyl gallate, Thiourea and the like.

In some instances, there are insufficient drug particles in a unit dose of suspension to make a pharmaceutically elegant suspension. This is particularly true for the more highly active drugs, where the unit dose is small. Under such circumstances, the formulator will need to add more particles to improve the appearance of the final product, and also to help stabilize the suspension. To serve this purpose, bulking agents, also known as auxiliary suspending agents are used. Non-limiting examples of bulking agents are Calcium carbonate, Calcium hydroxide, Cellulose, Crospovidone, Dibasic calcium phosphate, Magnesium carbonate, Magnesium hydroxide, Microcrystalline cellulose, Silica (silicon dioxide), Titanium dioxide and the like.

Many different materials are capable of adsorbing onto the suspended particles, e.g. natural gums, cellulosics and non-ionic surfactants. However, not all of them are able to act as protective colloids and provide steric hindrance to caking at a sufficiently low concentration. High levels of surfactants, for example, can increase gastro-intestinal motility. Higher molecular weight gums and cellulosics may also cause an unacceptable increase in the viscosity of the system. There are, however, certain polymers, or grades of polymers, that are capable of acting as protective colloids at concentrations that do not markedly increase the viscosity of the system, or increase gut motility, etc. Such materials include poloxamers, lower molecular weight grades of povidone, and low molecular weight grades of some other hydrophilic colloids.

Surfactant is a general name for materials that possess surface activity; in solution they tend to orient at the surface of the liquid. There are several general classes of surfactants: anionic, cationic, amphoteric and non-ionic. Surfactants are amphiphilic molecules, i.e. part of the molecule is hydrophilic, and part is lipophilic. This combination of the two opposite affinities in the same molecule causes them to orient to the interface and thereby reduce the interfacial tension between the continuous and disperse phases, such as in emulsions and suspensions, Ionic surfactants work primarily through electrostatic forces, whereas non-ionic surfactants work primarily through steric forces. Non-limiting examples of surfactants are Sodium lauryl sulfate, Docusate sodium, Cocamidopropyl amino betaine, Polyoxyethylene sorbitan fatty acid esters (Polysorbate, Tween®), Polyoxyethylene 15 hydroxystearate (Macrogol 15 hydroxystearate, Solutol HS15®), Polyoxyethylene castor oil derivatives (Cremophor® EL, ELP, RH 40), Polyoxyethylene stearates (Myrj®), Sorbitan fatty acid esters (Span®), Polyoxyethylene alkyl ethers (Brij®), Polyoxyethylene nonylphenol ether (Nonoxynol®) and the like.

Anti-foaming agents may be used in the preparation of the liquid pharmaceutical compositions of the present invention to lower the surface tension and cohesive binding of liquid phase. Non-limiting examples of anti-foaming agents are simethicone, organic phosphates, alcohols, paraffin oils, stearates, glycols and the like.

Chelating agents, also known as sequestrants, are molecules that have the ability to form stable complexes with metal ions, particularly di-valent and tri-valent metal ions including trace metals and heavy metals. These metal ions are often implicated in API degradation by acting as catalysts, e.g. Mg²⁺ will catalyze both ester hydrolysis and the Maillard interaction between primary or secondary amines and reducing sugars. Oxidative degradation is also often catalyzed by heavy metals. In addition, certain trace metals are required for microbial growth, and chelation (sequestration) to form complexes can help prevent microbial growth and spoilage, and thus allow lower levels of microbiocidal agents to be used. Non-limiting examples of chelating agents are Calcium disodium edetate, Disodium edetate, Edetic acid (also known as ethylenediaminetetraacetic acid/EDTA), Citric acid and the like.

Palatability of oral medicines is an important factor in compliance. There are several components to palatability including flavor, mouth-feel and sweetness. Most patients prefer medicines that are not too bitter but may be slightly“tart” (acidic). Most APIs are bitter. However, for bitterness to develop, the drug must be sufficiently soluble to interact with taste receptors on the tongue. For insoluble APIs in the form of suspensions, components of the suspension are also bitter, e.g. preservatives, or very salty, e.g. buffer systems. However, a slight saltiness and a slight bitterness are desirable for palatability.

Traditionally, oral medicines were sweetened using Syrup (concentrated sucrose solution) or honey (contains fructose). However, these materials are inadequate for the formulation of many products because they simply are not able to adequately mask the very bitter taste of many pharmaceutical materials, including APIs and excipients. Several alternative sweetening agents have been developed over the years to better mask unpleasant tastes in both processed foods and pharmaceuticals.

Several of the materials classified as sweetening agents are sugar alcohols (also known as polyhydric alcohols, polyols and hydrogenated sugars). Several of the commonly used sweetening agents are ionic and have the potential to interact with other components of the suspension. Some sweetening agents are more stable than others in aqueous solution. These will be important factors in the final selection of the sweetening agent. Non-limiting examples of sweetening agents are Glucose, Sucralose, Trehalose, Fructose, Xylose, Dextrose, Galactose, Tagatose, Maltose, Sucrose, Glycerol, Dulcitol, Mannitol, Lactitol, Sorbitol, Xylitol, Saccharine or the corresponding sodium, potassium or calcium salt, Cyclamate or the corresponding sodium or calcium salt, Aspartame, or Acesulfame or the potassium salt thereof, Dulcin or Ammonium glycyrrhizinate, Alitame, Inulin, Isomalt, Neohesperidin dihydrochalcone, Thaumatin and the like.

Flavors are used to improve the palatability of oral medicines. One problem that can arise with oral suspensions is that the suspension may produce a“cloying” sensation in the mouth. While this is not the same as a bitter taste, it can nevertheless cause problems for the patient and affect compliance. This can be a particular problem with high levels of inorganic components. Flavors can help reduce this“cloying” taste and thereby improve palatability, and ultimately patient compliance.

There are many different flavors, and most flavors are complex mixtures of many components. Today most flavors are developed by specialist flavor houses, and typically the flavor is formulated for each individual application. Since flavor will be part of the suspension continuous phase, it has the maximum potential for interaction, and some flavor components may cause stability issues (physical or chemical) for the suspension. Flavor development and compounding is a specialist discipline. When deciding on which particular flavor is appropriate, the flavor specialist would benefit from knowledge of the other likely components in the suspension, just as the formulation scientist would benefit from knowledge of the components of the flavor. Flavors can adsorb onto finely divided solids, thus reducing their effectiveness. They can also be absorbed by packaging. Flavor preferences vary with age, but the citrus flavors appear generally acceptable to most age groups. Non-limiting examples of flavoring agents are synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plants leaves, flowers, fruits, and so forth and combinations thereof. These may include cinnamon oil, oil of wintergreen, peppermint oils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, oil of bitter almonds, and cassia oil. Also useful as flavors are vanilla, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, banana, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, and so forth. Solid forms, such as spray dried forms of flavoring agents, may also be useful in the liquid dosage forms disclosed herein. Preferred flavoring agent is tutti fruity flavor.

Coloring agents may also be used in the preparation of the liquid compositions of the present invention. Pharmaceutical colors come in two types; soluble dyes and insoluble pigments. For pharmaceutical suspensions intended for oral use, soluble dyes are often used; however, pigments may also be used and would be part of the disperse phase. Soluble dyes have the potential to interact with other components of the formulation.

In one of the further aspects, anticancer drugs according to the present invention include, but are not limited to alkylating agents, antitumor antibiotics, anti-microtubule agents, DNA linking agents, bisphosphonates, topoisomerase inhibitors, antimetabolites, biological agents and nucleoside analogues, or any combinations thereof.

In one of the further aspects, anticancer drugs according to the present invention include, but are not limited to azidine, actinomycin, asparaginase, alemtuzumab, atezolizumab, avelumab, axitinib, acalabrutinib, alectinib, afatinib, acyclovir, abacavir, anastrozole, amifostine, busulfan, blinatumomab, bosutinib, brentuximab vedotin, brigatinib, belinostat, bendamustine, bleomycin, bevacizumab, bexarotene, bicalutamide, buserelin, cabozantinib, copanlisib, ceritinib, cobimetinib, cyclophosphamide, chlorambucil, carmustine, cisplatin, carboplatin, capecitabine, cladribine, clofarabine, cetuximab, crizotinib, cytarabine, cyproterone, dacarbazine, daratumumab, dexamethasone, dinutuximab, durvalumab, daunorubicin, doxorubicin, decitabine, dabrafenib, dasatinib, denosumab, degarelix, didanosine, everolimus, elotuzumab, enasidenib, epirubicin, erlotinib, entecavir, emtricitabine, exemestane, fotemustine, fluorouracil, flutamide, filgrastim, folinic acid, fulvestrant, gefitinib, goserelin, gemtuzumab ozogamicin, ifosfamide, idarubicin, inotuzumab, ibrutinib, imatinib, ipilimumab, idoxuridine, imiquimod, ibritumomab tiuxetan, idelalisib, ixazomib, lomustine, lapatinib, lamivudine, lanreotide, letrozole, lenalidomide, lenvatinib, leucovorin, leuprolide, mechlorethamine, methylnaltrexone, mustine, melphalan, mitomycin, mitozolomide, mitoxantrone, mitomycin, methotrexate, mercaptopurine, esna, medroxyprogesterone, megestrol, necitumumab, neratinib, niraparib, nivolumab, nitrosoureas, nedaplatin, nelarabine, nilotinib, obinutuzumab, olaratumab, olaparib, osimertinib, oxaliplatin, octreotide, palonosetron, panobinostat, palbociclib, pembrolizumab, pegfilgrastim, pazopanib, peginterferon alfa-2b, pertuzumab, pomalidomide, procarbazine, pirarubicin, pentostatin, pemetrexed, ponatinib, panitumumab, romiplostim, ramucirumab, recombinant interferon alfa-2b, ribociclib, rolapitant, rucaparib, raltitrexed, regorafenib, ruxolitinib, rituximab, siltuximab, sonidegib, sirolimus, semustine, streptozotocin, satraplatin, sorafenib, sunitinib, stavudine, stilbestrol, tetrazine, thiotepa, temozolomide, thioguanine, trametinib, temsirolimus, trastuzumab, thalidomide, telbivudine, trifluridine, tamoxifen, trifluridine and tipiracil, uridine, uramustine, vandetanib, vemurafenib, venetoclax, vinblastine, vincristine, vismodegib, vorinostat, vidarabine, zidovudine and the like or its pharmaceutically acceptable salts and chemical derivatives such as polymorphs, solvates, hydrates, anhydrous forms, prodrugs, chelates, and complexes thereof.

In one of the aspects, general formula of the liquid compositions according to the present invention may be provided as follows. Table- 1 : General formula of liquid compositions of the present invention

Those who are skilled in the art will appreciate that one or more above mentioned excipients can be omitted from the liquid compositions for preparing solutions, say for example suspending agents, bulking agents, anti-foaming agents etc. Table- 1 is provided herein for the illustration purpose only and should not be construed as the exact or only scope of the present invention.

In one of the aspects, the present invention provides a liquid composition comprising Capacitabine or its pharmaceutically acceptable salts and chemical derivatives such as polymorphs, solvates, hydrates, anhydrous forms, prodrugs, chelates, and complexes thereof and one or more pharmaceutically acceptable excipients selected from the group comprising of vehicles, solvents or co-solvents or solubilizers, suspending agents or thickening agents or viscosity modifying agents, anti-foaming agents, stabilizing agents, anti-oxidants, pH adjusting agents or pH modifying agents or buffering agents, wetting agents, bulking agents or auxiliary suspending agents, chelating agents, surfactants, preservatives, sweetening agents, coloring agents, flavoring agents or combinations thereof.

In one of the aspects, the present invention provides a liquid composition comprising Erlotinib or its pharmaceutically acceptable salts and chemical derivatives such as polymorphs, solvates, hydrates, anhydrous forms, prodrugs, chelates, and complexes thereof and one or more pharmaceutically acceptable excipients selected from the group comprising of vehicles, solvents or co-solvents or solubilizers, suspending agents or thickening agents or viscosity modifying agents, anti-foaming agents, stabilizing agents, anti-oxidants, pH adjusting agents or pH modifying agents or buffering agents, wetting agents, bulking agents or auxiliary suspending agents, chelating agents, surfactants, preservatives, sweetening agents, coloring agents, flavoring agents or combinations thereof.

In one of the aspects, the present invention provides a liquid composition comprising Sunitinib or its pharmaceutically acceptable salts and chemical derivatives such as polymorphs, solvates, hydrates, anhydrous forms, prodrugs, chelates, and complexes thereof and one or more pharmaceutically acceptable excipients selected from the group comprising of vehicles, solvents or co-solvents or solubilizers, suspending agents or thickening agents or viscosity modifying agents, anti-foaming agents, stabilizing agents, anti-oxidants, pH adjusting agents or pH modifying agents or buffering agents, wetting agents, bulking agents or auxiliary suspending agents, chelating agents, surfactants, preservatives, sweetening agents, coloring agents, flavoring agents or combinations thereof.

In one of the further aspects, the present invention provides a liquid composition comprising Sorafenib or its pharmaceutically acceptable salts and chemical derivatives such as polymorphs, solvates, hydrates, anhydrous forms, prodrugs, chelates, and complexes thereof and one or more pharmaceutically acceptable excipients selected from the group comprising of vehicles, solvents or co-solvents or solubilizers, suspending agents or thickening agents or viscosity modifying agents, anti-foaming agents, stabilizing agents, anti-oxidants, pH adjusting agents or pH modifying agents or buffering agents, wetting agents, bulking agents or auxiliary suspending agents, chelating agents, surfactants, preservatives, sweetening agents, coloring agents, flavoring agents or combinations thereof. The liquid compositions of the invention may be prepared using processes generally known to those skilled in the art.

The liquid compositions according to the invention are suitable for administration to a subject to treat or prevent a disease or condition. In some of the aspects, the subject is a mammal. In some of the other aspects, the mammal is a human.

It should be understood that various changes and modifications to the herein described embodiments will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the subject matter of the present invention and without diminishing its intended advantages. It is therefore intended that such changes and modifications be covered within the scope of the present invention.

Claims

WE CLAIM,

1. A liquid composition comprising an anticancer drug and one or more pharmaceutically acceptable excipients.

2. A liquid composition as claimed in claim 1 , wherein the composition is selected from the group comprising of liquids, liquid dispersions, suspensions, solutions, emulsions, sprays, spot-on, syrups, elixirs or concentrates.

3. A liquid composition as claimed in claim 1 or claim 2, wherein one or more pharmaceutically acceptable excipients are selected from the group comprising of vehicles, solvents or co-solvents or solubilizers, suspending agents or thickening agents or viscosity modifying agents, anti-foaming agents, stabilizing agents, anti-oxidants, pH adjusting agents or pH modifying agents or buffering agents, wetting agents, bulking agents or auxiliary suspending agents, chelating agents, surfactants, preservatives, sweetening agents, coloring agents, flavoring agents or combinations thereof.

4. A liquid composition as claimed in any one of claims 1-3, wherein the composition is suitable for oral administration.

5. A liquid composition as claimed in any one of claims l to 4, wherein an anticancer drug is selected from the group comprising of azidine, actinomycin, asparaginase, alemtuzumab, atezolizumab, avelumab, axitinib, acalabrutinib, alectinib, afatinib, acyclovir, abacavir, anastrozole amifostine, busulfan, blinatumomab, bosutinib, brentuximab vedotin, brigatinib, belinostat, bendamustine, bleomycin, bevacizumab, bexarotene, bicalutamide, buserelin, cabozantinib, copanlisib, ceritinib, cobimetinib, cyclophosphamide, chlorambucil, carmustine, cisplatin, carboplatin, capecitabine, cladribine, clofarabine, cetuximab, crizotinib, cytarabine, cyproterone, dacarbazine, daratumumab, dexamethasone, dinutuximab, durvalumab, daunorubicin, doxorubicin, decitabine, dabrafenib, dasatinib, denosumab, degarelix, didanosine, everolimus, elotuzumab, enasidenib, epirubicin, erlotinib, entecavir, emtricitabine, exemestane, fotemustine, fluorouracil, flutamide, filgrastim, folinic acid, fulvestrant, gefitinib, goserelin, gemtuzumab ozogamicin, ifosfamide, idarubicin, inotuzumab, ibrutinib, ima mib, ipilimumab, idoxuridine, imiquimod, ibritumomab tiuxetan, idelalisib, ixazomib, lomustine, lapatinib, lamivudine, lanreotide, letrozole, lenalidomide, lenvatinib, leucovorin, leuprolide, mechlorethamine, methylnaltrexone, mustine, melphalan, mitomycin, mitozolomide, mitoxantrone, mitomycin, methotrexate, mercaptopurine, mesna, medroxyprogesterone, megestrol, necitumumab, neratinib, niraparib, nivolumab nitrosoureas, nedaplatin, nelarabine, nilotinib, obinutuzumab, olaratumab, olaparib, osimertinib, oxaliplatin, octreotide, palonosetron, panobinostat, palbociclib, pembrolizumab, pegfilgrastim, pazopanib, peginterferon alfa-2b, pertuzumab, pomalidomide, procarbazine, pirarubicin, pentostatin, pemetrexed, ponatinib, panitumumab, romiplostim, ramucirumab, recombinant interferon alfa-2b, ribociclib, rolapitant, rucaparib, raltitrexed, regorafenib, ruxolitinib, rituximab, siltuximab, sonidegib, sirolimus, semustine, streptozotocin, satraplatin, sorafenib, sunitinib, stavudine, stilbestrol, tetrazine, thiotepa, temozolomide, thioguanine, trametinib, temsirolimus, trastuzumab, thalidomide, telbivudine, trifluridine, tamoxifen, trifluridine and tipiracil, uridine, uramustine, vandetanib, vemurafenib, venetoclax, vinblastine, vincristine, vismodegib, vorinostat, vidarabine, zidovudine or its pharmaceutically acceptable salts and chemical derivatives such as polymorphs, solvates, hydrates, anhydrous forms, prodrugs, chelates, and complexes thereof.

6. A liquid composition as claimed in any one of claims 1 to 4 comprising Capacitabine or its pharmaceutically acceptable salts and chemical derivatives such as polymorphs, solvates, hydrates, anhydrous forms, prodrugs, chelates, and complexes thereof and one or more pharmaceutically acceptable excipients selected from the group comprising of vehicles, solvents or co-solvents or solubilizers, suspending agents or thickening agents or viscosity modifying agents, anti-foaming agents, stabilizing agents, anti-oxidants, pH adjusting agents or pH modifying agents or buffering agents, wetting agents, bulking agents or auxiliary suspending agents, chelating agents, surfactants, preservatives, sweetening agents, coloring agents, flavoring agents or combinations thereof.

7. A liquid composition as claimed in any one of claims 1 to 4 comprising Erlotinib or its pharmaceutically acceptable salts and chemical derivatives such as polymorphs, solvates, hydrates, anhydrous forms, prodrugs, chelates, and complexes thereof and one or more pharmaceutically acceptable excipients selected from the group comprising of vehicles, solvents or co-solvents or solubilizers, suspending agents or thickening agents or viscosity modifying agents, anti-foaming agents, stabilizing agents, anti-oxidants, pH adjusting agents or pH modifying agents or buffering agents, wetting agents, bulking agents or auxiliary suspending agents, chelating agents, surfactants, preservatives, sweetening agents, coloring agents, flavoring agents or combinations thereof.

8. A liquid composition as claimed in any one of claims 1 to 4 comprising Sunitinib or its pharmaceutically acceptable salts and chemical derivatives such as polymorphs, solvates, hydrates, anhydrous forms, prodrugs, chelates, and complexes thereof and one or more pharmaceutically acceptable excipients selected from the group comprising of vehicles, solvents or co-solvents or solubilizers, suspending agents or thickening agents or viscosity modifying agents, anti-foaming agents, stabilizing agents, anti-oxidants, pH adjusting agents or pH modifying agents or buffering agents, wetting agents, bulking agents or auxiliary suspending agents, chelating agents, surfactants, preservatives, sweetening agents, coloring agents, flavoring agents or combinations thereof.

9. A liquid composition as claimed in any one of claims 1 to 4 comprising Sorafenib or its pharmaceutically acceptable salts and chemical derivatives such as polymorphs, solvates, hydrates, anhydrous forms, prodrugs, chelates, and complexes thereof and one or more pharmaceutically acceptable excipients selected from the group comprising of vehicles, solvents or co-solvents or solubilizers, suspending agents or thickening agents or viscosity modifying agents, anti-foaming agents, stabilizing agents, anti-oxidants, pH adjusting agents or pH modifying agents or buffering agents, wetting agents, bulking agents or auxiliary suspending agents, chelating agents, surfactants, preservatives, sweetening agents, coloring agents, flavoring agents or combinations thereof.