WO2019162756A2 - Compositions pharmaceutiques liquides de médicaments anticancéreux - Google Patents

Compositions pharmaceutiques liquides de médicaments anticancéreux Download PDF

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WO2019162756A2
WO2019162756A2 PCT/IB2019/000068 IB2019000068W WO2019162756A2 WO 2019162756 A2 WO2019162756 A2 WO 2019162756A2 IB 2019000068 W IB2019000068 W IB 2019000068W WO 2019162756 A2 WO2019162756 A2 WO 2019162756A2
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agents
pharmaceutically acceptable
solvents
patients
liquid
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PCT/IB2019/000068
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WO2019162756A3 (fr
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Swati NAGAR
Vijay Patel
Sandeep Pal
Sandip Mehta
Manish UMRETHIA
Jayanta Kumar Mandal
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Ftf Pharma Private Limited
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Publication of WO2019162756A2 publication Critical patent/WO2019162756A2/fr
Publication of WO2019162756A3 publication Critical patent/WO2019162756A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions

Definitions

  • 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.
  • 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
  • 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.
  • oral liquid dosage forms including solutions, syrups, suspensions, elixirs, and concentrates offer unique advantages to many patients.
  • liquids may provide better patient compliance for those0 with swallowing difficulties and better dosage control versus a fixed tablet dose.
  • liquid dosage forms are generally formulated for use in geriatric and pediatric patients.
  • “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.
  • 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.
  • solubility 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.
  • large proportions of new drug candidates that are emerging are predominantly water insoluble and, therefore, demonstrate poor bioavailability in the solution dosage form.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • a solution dosage form e.g. a simple mixture
  • drugs are sufficiently soluble to allow suitable strength solution medicines to be developed and manufactured with an acceptable shelf-life.
  • 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.
  • 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.
  • the drug should not have a quick sedimentation rate. Furthermore, it should re suspend easily upon shaking and it must not cake.
  • 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.
  • solubilizers are required in case of clear liquids, suspending agents are needed for suspensions and emulsifying agents for emulsions.
  • the present invention provides liquid pharmaceutical compositions comprising anticancer drugs and one or more pharmaceutically acceptable excipients.
  • pharmaceutically acceptable excipients 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.
  • 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.
  • the liquid compositions of the invention may be administered orally.
  • liquid compositions of the invention are suitable for administration to all types of patients’ population.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the present invention provides concentrate liquid compositions which may be diluted using suitable diluent before administering to the patient.
  • 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.
  • 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).
  • 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.
  • 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, beesw
  • 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.
  • alcohol, glycerin, and PG are frequently used to facilitate the removal of adsorbed air from the surface of particles.
  • 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.
  • 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.
  • 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.
  • the solution pH such as temperature, ionic strength, dilution, and the amount and type of co-solvents present.
  • the pH of acetate buffers is known to increase with temperature, whereas the pH of boric acid buffers decreases with temperature.
  • 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.
  • 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
  • preservatives are bacteriostatic rather than bacteriocidal, and consists of both acid and nonacid types.
  • 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.
  • 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.
  • 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.
  • 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.
  • BHT Butylated hydroxytoluene
  • 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.
  • Surfactant is a general name for materials that possess surface activity; in solution they tend to orient at the surface of the liquid.
  • 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.
  • surfactants are Sodium lauryl sulfate, Docusate sodium, Cocamidopropyl amino betaine, Polyoxyethylene sorbitan fatty acid esters (Polysorbate, Tween®), Polyoxyethylene 15 hydroxystearate (Macrogol 15 hydroxystearate, Solu
  • 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. Mg 2+ 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.
  • sweetening agents are sugar alcohols (also known as polyhydric alcohols, polyols and hydrogenated sugars).
  • sugar alcohols also known as polyhydric alcohols, polyols and hydrogenated sugars.
  • 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.
  • 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.
  • 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.
  • 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.
  • anticancer drugs 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
  • 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
  • the present invention provides a liquid composition
  • 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.
  • a 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
  • the present invention provides a liquid composition
  • 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.
  • 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-
  • the present invention provides a liquid composition
  • 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.
  • 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-
  • the present invention provides a liquid composition
  • 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.
  • liquid compositions according to the invention are suitable for administration to a subject to treat or prevent a disease or condition.
  • the subject is a mammal. In some of the other aspects, the mammal is a human.

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Abstract

Le cancer est l'une des maladies dont l'émergence est rapide à travers le globe et la population affectée comprend des patients provenant de tous les groupes d'âges. Les médicaments anticancéreux ont un goût amer et deviennent donc parfois inacceptables pour les patients en raison de leur odeur, de leur goût, de leur arrière-goût et de la sensation dans la bouche. Par conséquent, il y aura toujours un risque de rejet pour les formes posologiques anticancéreuses orales solides par les patients. De plus, des formes posologiques orales solides peuvent ne pas être appropriées pour des patients pédiatriques et gériatriques ou pour les patients ayant des difficultés de déglutition. La présente invention concerne donc des compositions liquides de médicaments anticancéreux qui sont agréables au goût et acceptables pour tous les types de populations de patients.
PCT/IB2019/000068 2018-02-20 2019-02-20 Compositions pharmaceutiques liquides de médicaments anticancéreux WO2019162756A2 (fr)

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