DESC:FIELD OF THE INVENTION
The present invention relates to a pharmaceutical immediate release oral liquid formulation of tramadol. In particular, the present invention provides a pharmaceutical oral solution of tramadol. It also relates to the process for the preparation of said liquid formulation. It further relates to the use of pharmaceutical liquid formulation of tramadol for the treatment of pain.
BACKGROUND OF THE INVENTION
Tramadol is an opioid pain medication widely used to treat moderate to severe pain. Although the mode of action is not completely understood, the analgesic effect of tramadol is believed to be due to both binding to µ-opioid receptors and weak inhibition of re-uptake of norepinephrine and serotonin.
Tramadol hydrochloride is chemically known as (±) cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride and is represented by the following formula:

Tramadol hydrochloride is marketed in the United States as (i) immediate release tablets in 50 mg and 100 mg strengths under the brand name Ultram® by Janssen Pharmaceuticals, (ii) extended release capsules in 100 mg, 200 mg and 300 mg strengths under the brand name Conzip® by Cipher Pharmaceuticals, (iii) oral solution in 5 mg/mL strength under the brand name Qdolo® by Athena Biosciences and (iv) extended release tablets in 100 mg, 200 mg, and 300 mg strengths.
The marketed tramadol oral solution (Qdolo®) is indicated in adults for the management of pain severe enough to require an opioid analgesic. It contains the following inactive ingredients: citric acid, sodium citrate dihydrate, propylene glycol, glycerin, sucralose, grape flavor, sodium benzoate, and purified water.
In the prior art, attempts have been made to reduce the bitter taste of tramadol hydrochloride in the oral liquid formulations.
U.S. Publication No. 2021/0137835, assigned to Athena Bioscience, discloses oral solution of tramadol comprising propylene glycol, glycerin, sucralose, sodium benzoate, flavoring agent, buffer and water.
U.S. Publication No. 2018/0140566, assigned to Bora Pharmaceuticals, discloses acetaminophen and tramadol oral solution in a solvent system comprising polyethylene glycol.
PCT Publication No. 2019/161938, assigned to Laboserve Pharmaceuticals, discloses oral solution of tramadol in a high concentration of 10 mg/ml to 40 mg/ml. It teaches the drawbacks of preparing low concentration (less than 10 mg/ml) of oral solution of tramadol. It highlighted that at low concentration of tramadol (less than 10 mg/ml), a larger volume of solution is required which gives rise to a bitter aftertaste in the mouth that lasts longer. To mask the bitterness of tramadol relatively high concentration of taste masking agent is required which causes a negative effect on solubility, resulting in the formation of a suspension, with the presence of visible particles that become apparent upon production.
Tramadol has an intense bitter taste and liquid formulation with dissolved tramadol may found little acceptability by the patients, particularly the children. It is a challenging task to mask the intensely bitter taste of tramadol after administration of a liquid formulation. There is a need in the art for novel pharmaceutical oral liquid compositions of tramadol with improved palatability and patient acceptability. The present invention is directed to an oral solution of tramadol, which is palatable, easy to administer, easy to manufacture, functionally reproducible, and stable. The novel taste masked oral solution of tramadol as per the present invention is expected to provide improved patient acceptability and thereby enhanced patient compliance. The oral solution of tramadol is particularly useful for pediatric and older patients with moderate to severe pain. Further, the oral solution of tramadol is expected to exhibit desirable technical attributes such as appearance, pH, assay, specific gravity/density, physical stability, microbiological stability, and storage stability.
SUMMARY OF THE INVENTION
It is a principal object of the present invention to provide a stable immediate release pharmaceutical oral liquid formulation of tramadol comprising tramadol, at least one or more pharmaceutically acceptable excipients, and a pharmaceutically acceptable carrier, and a process for its preparation.
It is another object of the present invention to provide an oral solution of tramadol comprising tramadol, at least one or more pharmaceutically acceptable excipients, and a pharmaceutically acceptable carrier; wherein the one or more pharmaceutically acceptable excipients are selected from the group comprising sweeteners, flavoring agents, preservatives, buffering agents/pH adjusting agents, surfactants/solubilizer/wetting agents, cosolvents, antioxidant, coloring agent, antifoaming agent, taste-masking agents, and combinations thereof.
It is another object of the present invention to provide an oral solution of tramadol, wherein the solution exhibits desirable technical attributes like appearance, pH, assay, physical stability, microbiological stability and storage stability, and a process for preparing the same.
It is another object of the present invention to provide an oral solution of tramadol for use in the treatment of pain.

DETAILED DESCRIPTION OF THE INVENTION
The present invention can be more readily understood by following detailed description of the invention and study of the included examples.
As used herein, the term “composition or “formulation” or “dosage form”, as in pharmaceutical composition, is intended to encompass a drug product comprising tramadol and other inert ingredient(s) (pharmaceutically acceptable excipients and carrier). Such pharmaceutical compositions are synonymous with “formulation” and “dosage form”. The pharmaceutical composition of the invention includes a liquid formulation. Preferably, the composition of the invention is an oral solution.
As used herein, the term “tramadol” is used in a broad sense to include not only “tramadol” per se but also its pharmaceutically acceptable salts, solvates, hydrates, enantiomers, derivatives, isomers, polymorphs, stereoisomers, diastereoisomers, metabolites, prodrugs thereof, also its various crystalline and amorphous forms or mixtures thereof. Particularly, the pharmaceutically acceptable salt of tramadol is tramadol hydrochloride. Tramadol is present in the oral solution in an amount from 0.01 mg/ml to 200 mg/ml, particularly from 0.01 mg/ml to 100 mg/ml, particularly from 0.01 mg/ml to 70 mg/ml, particularly from 0.01 mg/ml to 50 mg/ml, particularly from 0.01 mg/ml to 40 mg/ml, particularly from 0.01 mg/ml to 20 mg/ml, particularly from 0.01 mg/ml to 9.9 mg/ml, particularly from 4.5 to 5.5 mg/ml. Particularly, tramadol is present in the oral solution in an amount of about 5 mg/ml.
The term “excipient” means a pharmacologically inactive component such as a sweetener, flavoring agent, preservative, buffer agents/pH adjusting agent, surfactant/solubilizer/wetting agent, cosolvent, antioxidant, coloring agent, antifoaming agent, taste-masking agent, and the like. Reference to an excipient includes both one and more than one such excipient. Co-processed excipients are also covered under the scope of the present invention. Combination of excipients performing the same function may also be used to achieve desired formulation characteristics.
As used herein, the term “about” means ± approximately 10% of the indicated value, such that “about 10 percent” indicates approximately 08 to 12 percent.
As used in this specification, the singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to “a process” includes one or more processes, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.
The term “stable,” as used herein, refers to chemical stability, wherein not more than 5% w/w of total related substances are formed on storage at 40±2°C and 75±5% relative humidity (R.H.) or at 25±2°C °C and 60±5% R.H. or at 25±2°C and 40±5% relative humidity for a period of at least 1 week, for a period of at least one month, for a period of two months, particularly for a period of at least three months, and more particularly for a period of at least six months.
The term “therapeutically effective amount” or “effective amount’ as used herein, refers to the amount of active ingredient that elicits a biological response to prevent, inhibit, ameliorate or mitigate a disease.
The concentration unit “% w/v” as used herein, is a measure of the weight amount of a specified ingredient based on the total volume of the composition.
The term “polyol” (polyhydric alcohol) as used herein, refers to pharmaceutical excipients containing multiple hydroxyl groups, which however are not sugars.
The term “taste-masking agents”, as used herein, refers to taste receptor blockers, compounds that mask the chalkiness, grittiness, dryness, and/or astringent or bitter taste properties of an active compound.
The following aspects and embodiments further describe the objects of the present invention in accordance with the best mode of practice, however, disclosed invention is not restricted to the particular embodiments hereinafter described.
In accordance with one embodiment of the present invention, there is provided an oral solution of tramadol comprising:
a) tramadol,
b) at least one or more pharmaceutically acceptable excipients, and
c) pharmaceutically acceptable carrier.
In accordance with one embodiment of the present invention, there is provided an oral solution of tramadol comprising:
a) tramadol,
b) at least one or more pharmaceutically acceptable excipients, and
c) a pharmaceutically acceptable carrier,
wherein the solution is free of propylene glycol.
In accordance with one embodiment of the present invention, there is provided an oral solution of tramadol comprising:
a) tramadol,
b) at least one or more pharmaceutically acceptable excipients, and
c) a pharmaceutically acceptable carrier,
wherein the solution is free of propylene glycol or polyethylene glycol or both.
In accordance with one embodiment of the present invention, there is provided an oral solution of tramadol comprising:
a) tramadol from 0.01 mg/ml to 9.9 mg/ml,
b) at least one or more pharmaceutically acceptable excipients, and
c) a pharmaceutically acceptable carrier,
wherein the solution is free of propylene glycol.
In accordance with one embodiment of the present invention, there is provided an oral solution of tramadol comprising:
a) tramadol from 0.01 mg/ml to 9.9 mg/ml,
b) surfactant,
c) at least one or more pharmaceutically acceptable excipients, and
d) a pharmaceutically acceptable carrier.
In accordance with one embodiment of the present invention, there is provided an oral solution of tramadol comprising:
a) tramadol from 0.01 mg/ml to 9.9 mg/ml,
b) at least one or more pharmaceutically acceptable excipients, and
c) a pharmaceutically acceptable carrier,
wherein the pH of the solution is from about 2 to about 8.
In accordance with one embodiment of the present invention, there is provided an oral solution of tramadol comprising:
a) tramadol from 0.01 mg/ml to 9.9 mg/ml,
b) at least one or more pharmaceutically acceptable excipients, and
c) a pharmaceutically acceptable carrier,
wherein the pH of the solution is from about 2 to about 4.
In accordance with one embodiment of the present invention, there is provided an oral solution of tramadol comprising:
a) tramadol from 0.01 mg/ml to 9.9 mg/ml,
b) at least one or more pharmaceutically acceptable excipients, and
c) a pharmaceutically acceptable carrier,
wherein the pH of the solution is from 6.1 to 8.
In accordance with one embodiment of the present invention, there is provided an oral solution of tramadol comprising:
a) tramadol from 0.01 mg/ml to 9.9 mg/ml,
b) at least one or more pharmaceutically acceptable excipients, and
c) a pharmaceutically acceptable carrier,
wherein the solution is free of buffering agent/pH adjusting agent.
In accordance with one embodiment of the present invention, there is provided an oral solution of tramadol comprising:
a) tramadol from 0.01 mg/ml to 9.9 mg/ml,
b) polyethylene glycol,
c) at least one or more pharmaceutically acceptable excipients, and
d) a pharmaceutically acceptable carrier.
In accordance with one embodiment of the present invention, there is provided an oral solution of tramadol, wherein the oral solution comprises:
a) tramadol,
b) at least one or more pharmaceutically acceptable excipients, and
c) a pharmaceutically acceptable carrier,
wherein the solution is stable.
In accordance with one embodiment of the present invention, there is provided an oral solution of tramadol, wherein the pharmaceutically acceptable excipients are selected from the group comprising sweeteners, flavoring agents, preservatives, buffering agents/pH adjusting agents, surfactants, cosolvents, antioxidants, taste-masking agents, and combinations thereof.
In accordance with one embodiment of the present invention, there is provided an oral solution of tramadol, wherein the pharmaceutically acceptable carrier is an aqueous carrier.
In accordance with one embodiment of the present invention, there is provided an oral solution of tramadol, wherein the pharmaceutically acceptable carrier is water, glycerin, a combination of glycerin and water, or a combination of water with a water-miscible solvent.
In accordance with one embodiment of the present invention, there is provided an oral solution of tramadol, wherein the oral solution comprises:
a) tramadol,
b) sweetener,
c) flavoring agent,
d) preservative, and
e) pharmaceutically acceptable carrier.
In accordance with one embodiment of the present invention, there is provided an oral solution of tramadol, wherein the oral solution comprises:
a) tramadol,
b) buffering agent/ pH adjusting agent,
c) sweetener,
d) flavoring agent,
e) preservative, and
f) water.
In accordance with one embodiment of the present invention, there is provided an oral solution of tramadol, wherein the oral solution comprises:
a) tramadol,
b) buffering agent/pH adjusting agent,
c) sweetener,
d) flavoring agent,
e) preservative,
f) glycerin, and
g) water.
In accordance with one embodiment of the present invention, there is provided an oral solution of tramadol, wherein the oral solution comprises:
a) tramadol,
b) buffering agent/pH adjusting agent,
c) sweetener,
d) flavoring agent,
e) preservative,
f) glycerin,
g) polyethylene glycol, and
h) water.
In accordance with one embodiment of the present invention, there is provided an oral solution of tramadol, wherein the oral solution comprises:
a) tramadol in an amount from 0.1 mg/ml to 100 mg/ml,
b) buffering agent/pH adjusting agent in an amount from about 0.01% to about 8% w/v,
c) sweetener in an amount from about 0.01% w/v to about 80% w/v,
d) flavoring agent in an amount from about 0.01% to about 5% w/v,
e) preservative in an amount from about 0.001% to about 5% w/v, and
f) carrier in an amount from about 5% w/v to about 99.5% w/v.
In accordance with one embodiment of the present invention, there is provided an oral solution of tramadol, wherein the oral solution comprises:
a) tramadol in an amount from 0.1 mg/ml to 9.9 mg/ml,
b) buffering agent/pH adjusting agent in an amount from about 0.01% to about 8% w/v,
c) sweetener in an amount from about 0.01% w/v to about 80% w/v,
d) flavoring agent in an amount from about 0.01% to about 5% w/v,
e) preservative in an amount from about 0.001% to about 5% w/v,
f) carrier in an amount from about 5% w/v to about 99.5% w/v.
In accordance with one embodiment of the present invention, there is provided an oral solution of tramadol, wherein the oral solution comprises:
a) tramadol,
b) at least one or more pharmaceutically acceptable excipients, and
c) a pharmaceutically acceptable carrier,
wherein the solution is bioequivalent to the marketed oral solution of tramadol (Qdolo®).
Another aspect of the present invention provides a process for preparing an oral solution of tramadol comprising:
i) dissolving one or more pharmaceutical excipients and tramadol in a portion of a pharmaceutically acceptable carrier, and
ii) adding the remaining portion of the pharmaceutically acceptable carrier with stirring to the solution of step i) to form the oral solution of tramadol.
Another aspect of the present invention provides a method of treating pain in a subject in need thereof, which comprises administering to the subject an effective amount of the aqueous oral solution of tramadol comprising:
a) tramadol,
b) at least one or more pharmaceutically acceptable excipients, and
c) a pharmaceutically acceptable carrier.
In accordance with one embodiment of the present invention, there is provided an oral solution of tramadol, wherein the tramadol is present in the solution from about 0.1 mg/ml to about 100 mg/ml.
In accordance with one embodiment of the present invention, there is provided an oral solution of tramadol, wherein the tramadol is present in the solution from 0.1 mg/ml to 9.9 mg/ml.
In accordance with one embodiment of the present invention, there is provided an oral solution of tramadol, wherein the tramadol is present in the solution from 40.1 mg/ml to 100 mg/ml.
In accordance with another embodiment of the present invention, the oral solution contains tramadol as the sole active ingredient.
In accordance with one embodiment of the present invention, there is provided an oral solution of tramadol, wherein the preservative is paraben and/or a mixture of one or more parabens.
In accordance with another embodiment of the present invention, the oral solution of tramadol is free of sodium benzoate.
In accordance with another embodiment of the present invention, the oral solution comprises tramadol and at least an analgesic drug.
In accordance with another embodiment of the present invention, the oral solution comprises tramadol and acetaminophen.
In accordance with another embodiment of the present invention, the oral solution of tramadol is free of any sugar. In another preferred embodiment, the oral solution of the present invention can be given to diabetic patients also.
In accordance with another embodiment of the present invention, the oral solution of tramadol is free of any sugar alcohol.
In accordance with another embodiment of the present invention, the oral solution of tramadol is free of sucralose.
In accordance with another embodiment of the present invention, the oral solution of tramadol is free of any sugar and/or sugar alcohol.
In accordance with another embodiment of the present invention, the oral solution of tramadol solution is free of alcohol. In an preferred embodiment, the oral solution of tramadol is free of ethanol.
In accordance with another embodiment of the present invention, there is provided a method of treating pain by administering an oral solution of tramadol to a subject in need thereof.
In accordance with another embodiment of the present invention, the oral solution comprises propylene glycol.
In accordance with another embodiment of the present invention, the oral solution of tramadol is free of polyethylene glycol.
In accordance with another embodiment of the present invention, the oral solution of tramadol comprises polyethylene glycol in an amount from 0.2% to 16.9% w/v.
In accordance with another embodiment of the present invention, the oral solution of tramadol comprises glycerin in an amount from 0.1% to 9% w/v.
In accordance with another embodiment of the present invention, the oral solution of tramadol comprises glycerin in an amount from 34% to 90% w/v.
In accordance with another embodiment of the present invention, the oral solution of tramadol comprises a surfactant in an amount from 0.2% to 5% w/v.
In accordance with another embodiment of the present invention, the total concentration of polyols is from 200 mg/ml to 300 mg/ml.
In accordance with another embodiment of the present invention, the oral solution is expected to exhibit an amount of tramadol hydrochloride having a purity of at least 98% by HPLC after storage at 25±2°C and 40±5% relative humidity in a container for at least 3 months.
In accordance with still another embodiment of the present invention, there is provided a kit comprising:
a) an immediate release oral solution comprising tramadol with one or more pharmaceutically acceptable excipients and a pharmaceutically acceptable carrier,
b) a dispensing and/or dosing syringe for administering the composition, and
c) optionally, instructions for preparation and use.
In accordance with still another embodiment of the present invention, there is provided a kit comprising:
a) an immediate release oral solution comprising tramadol with one or more pharmaceutically acceptable excipients and a pharmaceutically acceptable carrier,
b) a dispensing and/or dosing syringe or a measuring cup for administering the composition, and
c) optionally, instructions for preparation and use.
In accordance with still another embodiment of the present invention, there is provided a kit comprising:
a) an immediate release oral solution comprising tramadol with one or more pharmaceutically acceptable excipients and a pharmaceutically acceptable carrier;
b) a measuring cup for administering the composition, and
c) optionally, instructions for preparation and use.
In another embodiment, the oral solution of tramadol includes particle size of tramadol, having a particle size distribution such that D90 is less than about 200 µm, D50 is less than about 100 µm and D10 is less than about 50 µm. Particularly, D90 is between about 5 µm to about 200 µm. The particle size of tramadol can be measured by suitable techniques such as Laser light scattering (e.g. Malvern Light Scattering), Coulter counter, microscopy, Fraunhofer diffraction, and any other technique known in the art.
Carrier/vehicle used in the oral solution of tramadol is selected from an aqueous and a non-aqueous carrier, but are not limited to, water, glycerin, alcohol, polyethylene glycol and its derivatives (such as PEG 400, PEG 200), propylene glycol, oil, or combinations thereof. By “aqueous carrier” is meant a solution comprising water, or a combination of water and a water-miscible organic solvent or solvents. Water-miscible solvents include but are not limited to glycerin, propylene glycol, polyethylene glycol, and ethanol. The carrier is present in an amount from about 5% w/v to about 99.9% w/v, particularly from about 10% w/v to about 99% w/v of the solution, particularly from about 20% w/v to about 99% w/v of the solution, particularly from about 30% w/v to about 99% w/v of the solution, particularly from about 40% w/v to about 99% w/v of the solution, particularly from about 50% w/v to about 99% w/v of the solution, particularly from about 10% w/v to about 95% w/v of the solution, particularly from about 20% w/v to about 95% w/v of the solution.
Various useful buffering agents or pH adjusting agents include, but are not limited to, citrate buffers, phosphate buffers, or any other suitable buffer known in the art including monosodium dibasic phosphate, gluconic acid, lactic acid, citric acid, trisodium citrate, acetic acid, maleic acid, tartaric acid, fumaric acid, sodium phosphate, sodium gluconate, sodium lactate, sodium citrate, sodium acetate potassium citrate, sodium bicarbonate, potassium bicarbonate, sodium dihydrogen phosphate and potassium dihydrogen phosphate, and combinations thereof. They also include combination of acidic and basic substances. Strong acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and the like can be used alone or in combination with basic substances such as inorganic bases (e.g., sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, magnesium carbonate, calcium carbonate, magnesium oxide, ammonia, synthetic hydrotalcite), organic bases (e.g., basic amino acids such as lysine, arginine, etc., meglumine, and the like).
The buffering agents or pH adjusting agents are present in an amount of about 0.001% to about 15% w/v of the composition, particularly from about 0.01% to about 10% w/v of the composition, and particularly from about 0.01% to about 5% w/v of the composition.
Various useful sweeteners include, but are not limited to, sugars such as sucrose, dextrose, fructose, lactose, maltose, invert sugar, sugar alcohols such as sorbitol, mannitol, xylitol, lactitol, erythritol, maltodextrin, maltitol, isomaltitol, isomalt, maltulose, isomaltulose, lactulose, threitol, arabitol, ribitol, galactitol, and sugar substitutes such as thaumatin, saccharin sodium, aspartame, acesulfame, and sucralose, and combinations thereof. The sweeteners are present in an amount of 0.01% w/v to about 95% w/v of the composition, particularly in an amount of about 0.01% w/v to about 90% w/v of the composition, particularly in an amount of about 0.01% w/v to about 70% w/v of the composition, particularly in an amount of about 0.01% w/v to about 60% w/v of the composition, particularly in an amount of about 0.01% w/v to about 50% w/v of the composition, particularly in an amount of about 0.01% w/v to about 40% w/v of the composition and more particularly in an amount of about 0.01% w/v to about 30% w/v of the composition.
Various useful flavoring agents, include, but are not limited to, flavors such as banana, lemon, orange, grape, lime and grapefruit, vanilla, bubble gum, peppermint, fantasy fruit flavor, tutti-frutti, and fruit essence, including apple, banana, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plant leaves, flowers, fruits such as cinnamon oil, oil of wintergreen, peppermint oils, clove oil, citrus oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, oil of bitter almonds, and cassia oil; maltol, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid and combinations thereof. The flavoring agents are present in an amount of about 0.01% to about 8% w/v of the composition. Particularly, the flavoring agents are present in an amount of about 0.01% to about 5% w/v of the composition, about 0.01% to about 3% w/v of the composition about 0.01% to about 2% w/v of the composition, and particularly from about 0.01% to about 1% w/v of the composition.
Suitable surfactant or wetting agents are selected from the group comprising non-ionic, anionic, cationic, or zwitterionic surfactants, and combinations thereof. Suitable examples of surfactants are sodium lauryl sulphate; cetrimide; polyethylene glycols; polyglycerin fatty acid esters such as decaglyceryl monolaurate and decaglyceryl monomyristate; sorbitan fatty acid esters such as sorbitan monostearate; polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monooleate (Polysorbate® 80); polyoxyethylene alkyl ether such as polyoxyethylene lauryl ether; polyoxyethylene castor oil; polyoxyethylene-polyoxypropylene block copolymers such as poloxamers (e.g. Poloxamer® 188); and combinations thereof. Particularly, surfactant or wetting agents are non-ionic. The surfactant or wetting agents are present in an amount of about 0.01% to about 8% w/v of the composition. Particularly, the surfactant or wetting agents are present in an amount of about 0.01% to about 3% w/v, and more particularly from about 0.01% to about 1% w/v of the composition.
Various useful preservatives include, but are not limited to, parabens such as methylparaben, propylparaben, butylparaben, and their salts, sorbic acid, sodium sorbate, potassium sorbate, calcium sorbate, benzoic acid, sodium benzoate, potassium benzoate, calcium benzoate, methyl hydroxybenzoate, ethyl para-hydroxybenzoate, sodium ethyl para-hydroxybenzoate, sodium metabisulphite, chlorhexidine, diazolidinyl urea, sodium citrate, butylated hydroxyl toluene (BHT), butylated hydroxyl anisole (BHA), tocopherol, ethylenediamine tetraacetic acid, propyl gallate, quaternary compounds, e.g. benzalkonium chloride and cetylpyridinium chloride, phenyl ethyl alcohol and combinations thereof. The preservative is present in an amount of about 0.001% w/v to about 5% w/v of the composition, particularly in an amount of about 0.001% w/v to about 4% w/v of the composition, particularly in an amount of about 0.001% w/v to about 3% w/v of the composition.
Various useful antioxidants include, but are not limited to, ascorbic acid, tert-butylhydroquinone, sodium pyrosulfite, glutathione, sodium bisulfite, sodium sulfite, a-tocopherol, a-tocopherol acetate, monothioglycerol, cysteine, ascorbyl palmitate, acetylcysteine, dithiothreitol, sodium metabisulfite, thiourea, sodium thiosulfate, butylated hydroxy anisole (BHA), butylated hydroxytoluene (BHT) and propyl gallate The antioxidant is present in an amount from 0% to about 20% w/v, from about 0.001% w/v to about 5% w/v.
Various useful taste masking agents include, but are not limited to, water soluble and/or insoluble polymeric excipient, water insoluble non-polymeric excipient, adsorbent, ion exchange resins such as Amberlite, Amberlite® CG 50, Amberlite® IRP-64, Amberlite® IRP-69, Indion® 204, Indion®214, Indion® 234, Indion® CRP 244, Indion® CRP 254, carbomers such as Carbomer 934, Carbomer 974, Carbomer 971, PEG-5M, Carbopol®934P NF, Carbopol®971P, Carbopol® 974P NF, alkali metal chlorides or an alkaline earth metal chloride or a derivative thereof, Opadry AMB, sodium starch glycolate, bitter masker, PEG-5M, sodium acetate, ethylcellulose, cyclodextrin, beta-cyclodextrin, polyvinyl acetate dispersion, trehalose, vinylacetate, polystyrene, cellulose acetate butyrate, methacrylic acid, and methyl methacrylates such as Eudragit R) L100, polymethacrylates (such as Eudragit(R) L100), sodium chloride, polyethoxylated castor oil, Kolliphor® RH 40, Sentry® Polyox® WSR N80 NF, natural or synthetic fatty type or other flavorant such as cocoa, chocolate (especially mint chocolate), cocoa butter, peppermint oil, wintergreen oil, spearmint oil, and similar oils. Compounds which reduce throat catch include for example high solubility acids include amino acids (eg alanine, arginine, etc), glutaric, ascorbic, malic, oxalic, tartaric, malonic, acetic, citric acids, low solubility acids include oleic, stearic, and aspartic acids plus certain amino acids such as glutamic acid, glutamine, histidine, isoleucine, leucine, methionine, phenylalanine, serine, tryptophan, tyrosine, valine, and fumaric acid. The taste-masking agents are present in an amount of about 0.01% to about 50% w/v of the composition, particularly from about 0.01% to about 30% w/v of the composition, particularly from about 0.01% to about 20% w/v of the composition, and particularly from about 0.01% to about 10% w/v of the composition.
Various useful antifoaming agents include, but are not limited to simethicone and dimethicone.
Suitable coloring agents are selected from the group comprising FD&C (Federal Food, Drug and Cosmetic Act) approved coloring agents; natural coloring agents; natural juice concentrates; pigments such as iron oxide, titanium dioxide, and zinc oxide; and combinations thereof.
The pharmaceutical oral solution of tramadol can be packaged in a suitable pack/container such as amber-colored polyethylene terephthalate (PET) bottle, glass bottle, vials, high-density polyethylene (HDPE) bottle, low-density polyethylene (LDPE) bottle, polypropylene (PP) bottle, vial, packets, pouches, sachets and the like. The glass or plastic bottle is provided with a child-proof closure. The package can include a syringe (marked in mL) or cup for ease of dosing. A cup having a volume of about 8 ml may be used for a dosage volume of 5 ml, while a cup having a volume of about 16 ml may be used for a dosage volume of 10 ml.
The pharmaceutical oral solutions of tramadol of the present invention is expected to have suitable organoleptic properties in terms of taste, after taste, odor, flavor, and acceptability.
The invention may be further illustrated by the following examples, which are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.
EXAMPLES
Examples 1-8. Oral Solution of Tramadol
Ingredients Function Quantity (%/w/v)
Example 1 2 3 4 5 6 7 8
Tramadol hydrochloride Active ingredient 0.01- 50 0.50 0.50 0.50 0.50 0.50 0.50 0.50
Citric acid or trisodium citrate or fumaric acid or combinations thereof Buffering agent/ pH adjusting agent 0.01-5 0.3 0.4 - 0.25 - 0.3 0.4
Hydrochloric acid or malic acid or sodium phosphate or potassium bicarbonate or sodium hydroxide or combinations thereof Buffering agent/ pH adjusting agent 0.01-5 - - - - 0.3 - -
Sorbitol/ Xylitol Sweetener 0.01-80 15 11 13 - 15 11 14
Sucralose Sweetener 0.01-80 - - - 0.08 - - -
Thaumatin Sweetener 0-4 - 0.2 0.1 - - 0.2 0.1
Strawberry flavour or peppermint flavour or bubble gum flavour or vanilla flavour or fantasy fruit masking flavour or combinations thereof Flavoring agent 0.01-3 0.4 0.4 0.5 0.4 0.4 0.5 0.48
Polysorbate or Poloxamer orPolyethylene Glycol Monostearte (Gelucire 48/16) or combinations thereof Surfactant 0-5 - 0.05 - - - 0-5 -
Methyl paraben or propyl paraben or combination thereof or potassium sorbate Preservative 0.01-5 - - 0.3 - - - 0.3
Sodium benzoate or benzoic acid or combination thereof Preservative 0.01-5 0.4 0.3 - 0.4 0.4 0.4 -
Polyethylene glycol Carrier 0-16.9 - - - - 0.5 - 5
Glycerin Carrier 1-50 9 20 20 20 9 7 8
Water Carrier q.s. q.s q.s q.s q.s. q.s q.s q.s

Examples 9-11. Oral Solution of Tramadol
Ingredients Function Quantity (%/w/v)
Example - 9 10 11
Tramadol hydrochloride Active ingredient 0.70 0.90 0.99
Citric acid or trisodium citrate or fumaric acid or combination thereof Buffering agent/ pH adjusting agent - 0.3 0.3
Hydrochloric acid or malic acid or sodium phosphate or potassium bicarbonate or sodium hydroxide or combination thereof Buffering agent/ pH adjusting agent 0.3 - -
Sorbitol or Xylitol Sweetener 13 15 -
Sucralose Sweetener - - 0.08
Thaumatin Sweetener 0.1 - -
Strawberry flavour or peppermint flavour or bubble gum flavour or vanilla flavour or fantasy fruit masking flavour or combinations thereof Flavoring agent 0.5 0.4 0.4
Methyl paraben or propyl paraben or combination thereof or potassium sorbate Preservative 0.3 - -
Sodium benzoate or benzoic acid Preservative - 0.4 0.4
Polyethylene glycol Carrier 5 - -
Glycerin Carrier 20 - 9
Water Carrier q.s. q.s q.s

CLAIMS:

We Claim:

1. An oral solution of tramadol comprising:
a) tramadol from 0.01 mg/ml to 9.9 mg/ml,
b) at least one or more pharmaceutically acceptable excipients, and
c) a pharmaceutically acceptable carrier,
wherein the solution is free of propylene glycol or polyethylene glycol or both.
2. An oral solution of tramadol comprising:
a) tramadol from 0.01 mg/ml to 9.9 mg/ml,
b) surfactant,
c) at least one or more pharmaceutically acceptable excipients, and
d) a pharmaceutically acceptable carrier.
3. An oral solution of tramadol comprising:
a) tramadol from 0.01 mg/ml to 9.9 mg/ml,
b) at least one or more pharmaceutically acceptable excipients, and
c) a pharmaceutically acceptable carrier,
wherein the solution is free of pH adjusting agent.
4. An oral solution of tramadol comprising:
a) tramadol from 0.01 mg/ml to 9.9 mg/ml,
b) polyethylene glycol,
c) at least one or more pharmaceutically acceptable excipients, and
d) a pharmaceutically acceptable carrier.
5. The oral solution as claimed in claim 1, wherein the pharmaceutically acceptable excipients are selected from the group comprising sweeteners, flavoring agents, preservatives, pH adjusting agents, surfactants, cosolvents, antioxidants, and combinations thereof.
6. The oral solution as claimed in 1, wherein the pharmaceutically acceptable carrier is an aqueous carrier.
7. The oral solution as claimed in 1, wherein the solution is free of any sugar.
8. The oral solution as claimed in claim 1, wherein the pH of the solution is from about 2 to about 8.
9. The oral solution as claimed in claim 1, wherein the solution is free of ethanol.
10. A process for preparing an oral solution of tramadol as claimed in claim 1, wherein the process comprises:
i) dissolving one or more pharmaceutical excipients and tramadol in a portion of a pharmaceutically acceptable carrier, and
ii) adding the remaining portion of the pharmaceutically acceptable carrier with stirring to the solution of step i) to form the oral solution of tramadol.