DESC:FIELD OF THE INVENTION
The present invention relates to stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate (APC) and one or more pharmaceutically acceptable excipients.
BACKGROUND OF INVENTION
APC is a norepinephrine–dopamine reuptake inhibitor and is derived from phenylalanine. The structure of (R)-2-amino-3-phenylpropyl carbamate (APC) has been disclosed generically and specifically in US patent no. US5705640 and US5955499 respectively. The structure of the free base of APC is as follows:

It has been disclosed by many inventors that it can be used for the treatment of various disorders like including excessive daytime sleepiness, cataplexy, narcolepsy, fatigue, depression, bipolar disorder, fibromyalgia, and others.
US8440715 B2 discloses method of using APC to treat excessive daytime sleepiness.
US8877806 B2, US10351517 B2 discloses method of using the compound to increase wakefulness or alertness in a patient suffering from certain CNS disorders or sleep deficiencies.
US9604917 B2 discloses methods of using APC to treat excessive daytime sleepiness.
US9359290 B2, US10259780 B2 and US9585863 B2 discloses methods of using APC to treat cataplexy.
US9464041 B2, US9999609 B2 and US8741950 B2 discloses methods of using (R)-2-amino-3-phenylpropyl carbamate to treat or prevent fatigue.
US8552060 B2 discloses method of treating sexual dysfunction using APC
US9226910 B2 discloses method of treating obesity using APC
US8623913 B2 discloses method of using APC for the treatment of restless leg syndrome.
US9610274 B2, US9907777 B2 discloses method of using APC for the treatment of manic symptoms in a mammal suffering from bipolar disorder.
US9663455 B2, US8895609 B2, US10202335 B2 discloses method of using APC for the treatment of diminishing symptoms associated with attention deficit hyperactivity disorder.
US8927602 B2, US9688620 B2 discloses method of treating fibromyalgia syndrome.
US8232315 B2 discloses method of treating drug addiction.
US10105341 A1 discloses method of treating or preventing body weight gain using APC
US9649291 B2 discloses method of treating pathological eating in a subject using (R)-2-amino-3-phenylpropyl carbamate
US8729120 B2 discloses method of treating depression using APC
Inventors of different inventions have further put down various efforts to develop a stable pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate. However, chemical composition, physio-chemical properties, quantity of excipients can affect the stability and dissolution of pharmaceutical composition.
US10195151 B2 discloses immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate and methods of using the same to treat disorders. It has been further disclosed that increasing the concentration of binder in the pharmaceutical composition improves the hardness but reduces the rate of dissolution of composition. Also, it is disclosed that APC is a highly water soluble compound but in a pH dependent manner. On comparing the dissolution at pH 1.2, 4.5 and 6.8, there is about 20-fold drop in solubility around pH 7. The skilled artisan might expect such a large drop in solubility would result in a change in dissolution as solubility drives the gradient which typically determines dissolution.
It is therefore an object of the present invention to provide a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate and one/more pharmaceutically acceptable excipients; wherein the composition exhibits substantially identical dissolution rates of the APC or a pharmaceutically acceptable salt thereof at pH 1.2, pH 4.5 and pH 6.8. Specifically, the present invention relates to stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder in a concentration range of about 5 % w/w to about 30% w/w and one/more pharmaceutically acceptable excipients; wherein the composition exhibits substantially identical dissolution rates of the APC or a pharmaceutically acceptable salt thereof at pH 1.2, pH 4.5 and pH 6.8.

SUMMARY OF THE INVENTION
In one aspect of the present invention, there is provided a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate (APC) with or without binder and one/more pharmaceutically acceptable excipients.
In another aspect of the present invention, there is provided a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate (APC), stabilizing agent and pharmaceutically acceptable excipients.
In another aspect of the present invention, there is provided a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, wherein an amount of (R)-2-amino-3-phenylpropyl carbamate is less than 90 % w/w of the total composition.
In another aspect of the present invention, there is provided a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder and one/more pharmaceutically acceptable excipients.
In another aspect of the present invention, there is provided a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder in a concentration range of about 5 % w/w to about 30% w/w and one/more pharmaceutically acceptable excipients.
In another aspect of the present invention, there is provided a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder in a concentration range of about 5 % w/w to about 30% w/w; wherein binder is selected from but not limited to hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), microcrystalline cellulose (MCC), Polyvinylpyrrolidone (PVP), starch, StarTab and one/more pharmaceutically acceptable excipients.
In another aspect of the present invention, there is provided a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder in a concentration range of about 5 % w/w to about 30% w/w, lubricant in a concentration range of about 0.1 % w/w to about 3.0 % w/w and one/more pharmaceutically acceptable excipients.
In another aspect of the present invention, there is provided a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder in a concentration range of about 5.4 % w/w to about 10 % w/w, lubricant in a concentration range of about 1.0 % w/w to about 1.75 % w/w and one/more pharmaceutically acceptable excipients.
In another aspect of the present invention, there is provided a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder in a concentration range of about 5.4 % w/w to about 10 % w/w, stabilizing agent in a concentration range of about 2 % w/w to about 5 % w/w, diluent in a concentration range of about 2 % w/w to about 10 % w/w, glidant in a concentration range of about 1.0 % w/w to about 1.75 % w/w and lubricant in a concentration range of about 1.0 % w/w to about 1.75 % w/w.
In another aspect of the present invention, there is provided a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder in a concentration range of about 5.4 % w/w to about 10 % w/w, diluent in a concentration range of about 2 % w/w to about 10 % w/w, glidant in a concentration range of about 1.0 % w/w to about 1.75 % w/w and lubricant in a concentration range of about 1.0 % w/w to about 1.75 % w/w.
In another aspect of the present invention, there is provided a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, HPC in a concentration range of about 5.4 % w/w to about 10 % w/w, citric acid in a concentration range of about 2 % w/w to about 3.5 % w/w, MCC in a concentration range of about 2 % w/w to about 10 % w/w, colloidal silicon dioxide in a concentration range of about 1.0 % w/w to about 1.75 % w/w and magnesium stearate in a concentration range of about 1.0 % w/w to about 1.75 % w/w.
In another aspect of the present invention, there is provided a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, HPC in a concentration range of about 5.4 % w/w to about 10 % w/w, MCC in a concentration range of about 2 % w/w to about 10 % w/w, colloidal silicon dioxide in a concentration range of about 1.0 % w/w to about 1.75 % w/w and magnesium stearate in a concentration range of about 1.0 % w/w to about 1.75 % w/w.
In another aspect of the present invention, there is provided a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, HPC in an amount of about 5.4 % w/w, citric acid in an amount of about 2.9 % w/w, MCC in an amount of about 5.4 % w/w, colloidal silicon dioxide in an amount of about 1.6 % w/w and magnesium stearate in an amount of about 1.6 % w/w.
In another aspect of the present invention, there is provided a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, HPC in an amount of about 5.4 % w/w, MCC in an amount of about 8.3 % w/w, colloidal silicon dioxide in an amount of about 1.6 % w/w and magnesium stearate in an amount of about 1.6 % w/w.

DETAILED DESCRIPTION OF THE INVENTION
Provided is the stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder and one/more pharmaceutically acceptable excipients. Further provided is the stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder in a concentration range of about 5 % w/w to about 30% w/w and one/more pharmaceutically acceptable excipients wherein the formulations described herein are useful for the treatment of disorder amenable to treatment with APC.
Binders, commonly used in solid oral dosage form holds the active pharmaceutical ingredient and inactive ingredients together in a cohesive mix. However, it has been previously reported that increasing the concentration of binder in the pharmaceutical composition comprising APC can lead to reduction in the rate of dissolution of immediate release pharmaceutical composition.
However, the inventors of the present invention have surprisingly found that a stable immediate release pharmaceutical composition comprising APC can be prepared without binder or in the presence of high concentration of binder with one or more pharmaceutically acceptable excipient; wherein there is no reduction in the rate of dissolution of pharmaceutical composition.
Further, the inventors of the present invention have surprisingly found that a stable immediate release pharmaceutical composition comprising APC can be prepared in the presence of binder; wherein binder is present in the concentration range of about 5 % w/w to about 30% w/w with one or more pharmaceutically acceptable excipients; wherein the composition exhibits substantially identical dissolution rates of the APC or a pharmaceutically acceptable salt thereof at pH 1.2, pH 4.5 and pH 6.8.
Further, the inventors of the present invention have surprisingly found that a stable immediate release pharmaceutical composition comprising APC can be prepared in the presence of binder which is present in the concentration range of about 5 % w/w to about 30% w/w with one or more pharmaceutically acceptable excipients; wherein the composition exhibits substantially identical dissolution rates of the APC or a pharmaceutically acceptable salt thereof at pH 1.2, pH 4.5 and pH 6.8; wherein it can be used for the treatment of disorders which are amenable to treatment with APC.
As used herein, a stable immediate release APC compositions described herein comprise a therapeutically effective amount of APC or an alternative salt thereof.
As used herein, "a," "an," or "the" can mean one or more than one. For example, "a" cell can mean a single cell or a multiplicity of cells.
Also as used herein, "and/or" refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative ("or").
Furthermore, the term "about," as used herein when referring to a measurable value such as an amount of a compound or agent of this invention, dose, time, temperature, and the like, is meant to encompass variations of ±10%, ±5%, ± 1%, ±0.5%, or even ± 0.1% of the specified amount.
As used herein, “APC”, “Solriamfetol” and “(R)-2-amino-3-phenylpropyl carbamate” are same and can be interchangeable.
The term "stable" as used herein refers to chemical stability in solid dosage forms wherein there is no change in assay values and dissolution and/or the total impurity remains less than 2 %, when the dosage form is kept at 40°C/75% RH for 6 months.
The term “composition” as used herein is intended to encompass a product comprising the specified ingredients (and in the specified amounts, if indicated), as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By “pharmaceutically acceptable” it is meant that the diluent, excipient or carrier must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The term “pharmaceutical composition” refers to a composition comprising at least one active ingredient, whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human). Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan.
The term “pharmaceutically acceptable” refers to carrier, diluent or excipient compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The term “therapeutically effective amount" or "effective amount" as used herein refers to the amount of active compound or pharmaceutical agent that elicits a biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease, (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology), and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology). As such, a non-limiting example of a "therapeutically effective amount" or "effective amount" of a formulation of the present disclosure may be used to inhibit, block, or reverse the activation, migration, or proliferation of cells or to effectively treat hypertension or ameliorate the symptoms of hypertension.
As used herein "excipient" refers to but not limited to binders, fillers, compression aids, diluents, disintegrants, colorants, flavouring agents, buffering agents, coatings, glidants, stabilizing agent, granulating solvent, isotonic agent or other suitable excipients, which is non-toxic, and inert, which does not have undesirable effects on a subject to whom it is administered and is suitable for delivering a therapeutically active agent to the target site without affecting the therapeutic activity of the said agent. Diluents are selected from but not limited to diluent is selected from lactose, dextrose, glucose, sucrose, microcrystalline cellulose, maize starch, pregelatinized starch, modified corn starch, cellulose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium carbonates, magnesium carbonates combinations thereof, and the like. Disintegrants are selected from but not limited to cellulose derivatives, including microcrystalline cellulose, starches, including potato starch; croscarmellose sodium, crospovidone, alginic acid or alginates, insoluble polyvinylpyrrolidone, sodium carboxymethyl starch, sodium starch glycolate and the like.
As used herein “isotonic agent” refers to a compound commonly used for such purposes at known concentrations. Isotonicity agents are selected but not limited to the group comprising glycerol, mannitol, sorbitol, lactose, dextrose, trehalose, sodium chloride, propylene glycol, dimethyl sulfone or mixture thereof.
As used herein “binder” refers to a compound used in solid oral dosage form that holds the active pharmaceutical ingredient and inactive ingredients together in a cohesive mix and is selected from but not limited to hydroxypropyl cellulose (HPC), ethylcellulose, hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol, hydroxyethyl cellulose (HEC), Polyvinylpyrrolidone (PVP), copovidone, pregelatinized starch, dextrin, gelatin, maltodextrin, starch, zein, acacia, alginic acid, carbomers (cross-linked polyacrylates), polymethacrylates, sodium carboxymethylcellulose, guar gum, hydrogenated vegetable oil (type 1), methylcellulose, magnesium aluminium silicate, microcrystalline cellulose, silicified microcrystalline cellulose (S-MCC), StarTab (dispersion product comprising pregelatinized corn starch and colloidal silicon dioxide), partially pregelatinized maize starch, sodium alginate and or its derivatives or any combination thereof.
In certain embodiments, the at least one binder is present in an amount of about 5 % w/w to about 30% w/w of the pharmaceutical composition or any value or range therein. In certain embodiments, the at least one binder is present in an amount of about 5.1 % w/w to about 25% w/w, about 5.2 % w/w to about 20% w/w, about 5.3 % w/w to about 15% w/w, more preferably about 5.4 % w/w to about 10% w/w.
In some embodiments, amount of binder is about 5.4 % w/w.
In some embodiments, amount of binder is about 5.5 % w/w.
In some embodiments, a stable preferable pharmaceutical composition releases at least 70-79%, 80%-89%, 90-99% of APC or a pharmaceutically acceptable salt thereof contained therein within a period of less than 15 minutes after administration of the composition to a subject, e.g., less than 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5 minutes. In some embodiments, a stable preferable composition releases at least 80 %, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of APC or a pharmaceutically acceptable salt thereof contained therein within a period of less than 30 minutes after administration of the composition to a subject.
In some embodiments, a stable preferable composition releases at least 80 %, of APC or a pharmaceutically acceptable salt thereof contained therein within a period of less than 30 minutes after administration of the composition to a subject.
In certain embodiments, APC or a pharmaceutically acceptable salt thereof is present in an amount of about 60% w/w to about 85% w/w of the pharmaceutical composition or any value or range therein. In certain embodiments, APC or a pharmaceutically acceptable salt thereof is present in an amount of about 65% w/w to about 82% w/w, about 70% to about 81% w/w or about 75% w/w to about 80.50% w/w. In certain embodiments, APC or a pharmaceutically acceptable salt thereof is present in an amount of less than 90 % w/w of the total composition.
In certain embodiments, at least one lubricant is selected from the group comprising but not limited to magnesium stearate, stearic acid, calcium stearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate, sodium stearyl fumarate, and zinc stearate or any combination thereof. In some embodiments, the at least one lubricant is magnesium stearate.
In certain embodiments, the at least one lubricant is present in an amount of about 0.1% w/w to about 3.0% w/w, about 0.5% w/w to about 2.0% w/w, more preferably about 1.0% w/w to about 1.75 % w/w, more preferably about 1.25% w/w to about 1.65% w/w.
In some embodiments, amount of lubricant is about 1.5 % w/w.
In some embodiments, amount of lubricant is about 1.6 % w/w.
As used herein “glidant” refers to a compound used in solid oral dosage form added to improve the powder flow is selected from but not limited to Colloidal Silicon dioxide (Aerosil), Corn starch, Talc, or any combination thereof.
In certain embodiments, the at least one glidant is present in an amount of about 0.1% w/w to about 3.0% w/w, about 0.5% w/w to about 2.0% w/w, more preferably about 1.0% w/w to about 1.75 % w/w, more preferably about 1.25% w/w to about 1.65% w/w.
In some embodiments, amount of glidant is about 1.5 % w/w.
In some embodiments, amount of glidant is about 1.6 % w/w.
As used herein “stabilizing agent” refers to a compound used in solid oral dosage form, added to stabilize the API, is selected from but not limited to acetic acid, succinic acid, citric acid, tartaric acid, acrylic acid, benzoic acid, malic acid, maleic acid, oxalic acid and sorbic acid; and mixtures thereof. Preferred stabilizing agents are selected from the group consisting of oxalic acid, tartaric acid and citric acid. More preferably, stabilizing agent is citric acid.
In certain embodiments, the at least one stabilizing agent is present in an amount of about 0.1% w/w to about 5.0% w/w, about 0.5% w/w to about 4.5% w/w, more preferably about 1.0% w/w to about 4.0 % w/w, more preferably about 2% w/w to about 3.5% w/w.
In some embodiments, amount of stabilizing agent is about 2.9 % w/w.
In some embodiments, amount of stabilizing agent is about 3.0 % w/w.
As used herein “granulating solvent” refers to a solvent used in solid oral dosage form, added to assist the granulation process, is selected from but not limited to alcohol i.e. ethanol, propanol; water; dichloromethane and mixture thereof.
In some embodiments, at least one binder is hydroxypropyl methyl cellulose. In some embodiments, at least one lubricant is magnesium stearate. In some embodiments, at least one binder is microcrystalline cellulose and at least one lubricant is magnesium stearate.
In certain embodiments, the tablet is coated. The coating may be, without limitation, a colour overcoat.
"Immediate release" as used herein, refers to a composition that releases APC or a pharmaceutically acceptable salt, hydrate, isomer, tautomer, solvate or complex thereof substantially completely into the gastrointestinal tract of the user within a period of less than about 15 minutes, usually between about 1 minute and about 15 minutes from ingestion. Such a delivery rate allows the drug to be absorbed by the gastrointestinal tract in a manner that is bioequivalent to an oral solution. Such rapid absorption will typically occur for an immediate release unit dosage form, such as a tablet, caplet or capsule, if the drug included in such dosage form dissolves in the upper portion the gastrointestinal tract.
Release rates can be measured using standard dissolution test methods. For example, the standard conditions may be those described in FDA guidance (e.g., 50 rpm, 37 oC, USP 2 paddles, pH 1.2, pH 4.5 and pH 6.8 media, 900 ml, 1 test article per vessel).
"Dissolution rate," as used herein, refers to the quantity of drug released in vitro from a dosage form per unit time into a release medium.
In some embodiments, a stable preferable composition releases at least 80 %, of APC or a pharmaceutically acceptable salt thereof contained therein within a period of less than 30 minutes in all dissolution media i.e. pH 1.2, pH 4.5 and pH 6.6 measured in 900 mL media using USP 2 paddles apparatus.
“Disintegration time” as used herein, refers to the time needed for the drug to break into fragments under certain conditions. Disintegration time is measured by placing 6 tablets in disintegration time tester and disintegration time is considered as the time at which the last tablet disintegrated out of a set of 6 tablets.
"Bioavailability," as used herein, refers to the estimated area under the curve, or AUC of the active drug in systemic circulation after oral administration with a dosage form as disclosed herein when compared with the AUC of the active drug in systemic circulation after intravenous administration of the active drug. The AUC is affected by the extent to which the drug is absorbed in the GI tract.
Products are considered to be "bioequivalent" if the relative mean Cmax, AUC(0-t) and AUC(0-.infin.) of the test product to reference product is within 80% to 125%.
The term "AUC(0-t)" mean the area under the plasma concentration curve from time 0 to time t.
The term "AUC(0-.infin.)" or "AUC0-inf" means the area under the plasma concentration time curve from time 0 to infinity.
"Cmax" refers to the maximum plasma concentration of APC.
"Tmax" refers to the time to maximum plasma concentration for a given drug.
"t1/2" refers to the time to reduce the plasma concentration by 50% during the terminal elimination phase of the drug.
Immediate release pharmaceutical composition suitable for oral administration may comprise unit dosage forms, such as tablets, caplets or filled capsules, which can deliver a therapeutically effective dose of APC upon ingestion thereof by the patient of one or more of said dosage forms, each of which can provide a dosage of, for example, about 1 to about 1000 mg of APC.
Where desired or necessary, the outer surface of stable immediate release dosage form as disclosed herein may be coated with a moisture barrier layer using materials and methods known in the art. For example, where the APC delivered by the unit dosage form is highly hygroscopic, providing a moisture barrier layer over the immediate release dosage form as disclosed herein may be desirable. For example, protection of an immediate release dosage form as disclosed herein from water during storage may be provided or enhanced by coating the tablet with a coating of a substantially water soluble or insoluble polymer. Useful water-insoluble or water-resistant coating polymers include ethyl cellulose and polyvinyl acetates. Further water-insoluble or water resistant coating polymers include polyacrylates, polymethacrylates or the like. Suitable water-soluble polymers include polyvinyl alcohol and HPMC. Further suitable water-soluble polymers include PVP, HPC, HPEC, PEG, HEC and the like.
Where desired or necessary, the outer surface of a stable immediate release dosage form as disclosed herein may be coated with a seal coat, colour overcoat or other aesthetic or functional layer using materials and methods known in the art.
In some embodiments, the coating is present from about l %w/w to about 50 % w/w of the total composition weight, preferably from about l.5 % w/w to about 15 % w/w, more preferably from about 2 % w/w to about 5 % w/w. In addition to coating ingredients, sometimes commercially available pre-mixed coating materials such as Opadry® Clear 03K19229 (contains hydroxypropylmethyl cellulose, triacetin and talc), Opadry® Clear YS-1 R-7006 (contains hydroxypropylmethyl cellulose, PEG 400 and PEG 6000), Opadry® White OY 58900 (contains hydroxypropylmethyl cellulose, PEG 400, and titanium dioxide), Opadry® Yellow (Contains hydroxypropylmethyl cellulose, PEG 400, and titanium dioxide) and Lusterclear®, etc. will be used. These typically require only mixing with a liquid before use. These coating comprises one or more excipients selected from the group comprising plasticizers, coating agents, opacifiers, fillers, polishing agents, colouring agents, anti-tacking agents and the like.
Methods are disclosed herein to treat conditions amenable to treatment by APC, by administering an effective amount of one or more dosage forms as described herein. For example, the present dosage forms can be administered to treat a subject in need of treatment for narcolepsy, cataplexy, excessive daytime sleepiness, drug addiction, sexual dysfunction, fatigue, fibromyalgia, attention deficit/hyperactivity disorder, restless legs syndrome, depression, bipolar disorder, or obesity, or to promoting smoking cessation in a subject in need thereof.
A daily dose of about 1 to about 2000 mg of APC or a pharmaceutically acceptable salt thereof may be administered to accomplish the therapeutic results disclosed herein. For example, a daily dosage of about 10 mg to about 1000 mg, e.g., about 20mg to about 500 mg, in single or divided doses, is administered. In some embodiments, the daily dose may be about 0.01 mg/kg to about 150 mg/kg body weight, e.g., about 0.2 mg/kg to about 18 mg/kg body weight.
In one embodiment, the present disclosure provides a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder and one/more pharmaceutically acceptable excipients.
In another embodiment, the present disclosure provides a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder in a concentration range of about 5 % w/w to about 30% w/w and one/more pharmaceutically acceptable excipients.
In another embodiment, the present disclosure provides a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder in a concentration range of about 5 % w/w to about 30% w/w, lubricant in a concentration range of about 0.1 % w/w to about 3.0 % w/w and one/more pharmaceutically acceptable excipients.
In still another embodiment, the present disclosure provides a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder in a concentration range of about 5.4 % w/w to about 10 % w/w, lubricant in a concentration range of about 1.0 % w/w to about 1.75 % w/w and one/more pharmaceutically acceptable excipients.
In some embodiments, the stable immediate release pharmaceutical composition optionally comprises stabilizing agent.
In still another embodiment, the present disclosure provides a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder in a concentration range of about 5.4 % w/w to about 10 % w/w, stabilizing agent in a concentration range of about 2 % w/w to about 5 % w/w, diluent in a concentration range of about 2 % w/w to about 10 % w/w, glidant in a concentration range of about 1.0 % w/w to about 1.75 % w/w and lubricant in a concentration range of about 1.0 % w/w to about 1.75 % w/w.
In still another embodiment, the present disclosure provides a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder in a concentration range of about 5.4 % w/w to about 10 % w/w, diluent in a concentration range of about 2 % w/w to about 10 % w/w, glidant in a concentration range of about 1.0 % w/w to about 1.75 % w/w and lubricant in a concentration range of about 1.0 % w/w to about 1.75 % w/w.
In another embodiment, the present disclosure provides a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder is HPMC in a concentration range of about 5 % w/w to about 30% w/w and one/more pharmaceutically acceptable excipients.
In another embodiment, the present disclosure provides a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder is HPC in a concentration range of about 5 % w/w to about 30% w/w and one/more pharmaceutically acceptable excipients.
In another embodiment, the present disclosure provides a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder is HPMC in a concentration range of about 5 % w/w to about 30% w/w, lubricant is magnesium stearate in a concentration range of about 0.1 % w/w to about 2% w/w and one/more pharmaceutically acceptable excipients; wherein the preferable composition releases at least 70% of the pharmaceutically salt of (R)-2- amino-3-phenylpropyl carbamate contained therein within a period of less than 15 minutes after administration of the composition to a subject.
In another embodiment, the present disclosure provides a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder is PVP in a concentration range of about 5 % w/w to about 30% w/w, lubricant is magnesium stearate in a concentration range of about 0.1 % w/w to about 2% w/w and one/more pharmaceutically acceptable excipients; wherein the preferable composition releases at least 70% of the pharmaceutically salt of (R)-2- amino-3-phenylpropyl carbamate contained therein within a period of less than 15 minutes after administration of the composition to a subject; wherein the composition exhibits substantially identical dissolution rates of the pharmaceutically acceptable salt of (R)-2- amino-3-phenylpropyl carbamate at pH 1.2, pH 4.5 and pH 6.8.
In another embodiment, the present disclosure provides a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder is HPC in a concentration range of about 5 % w/w to about 30% w/w and one/more pharmaceutically acceptable excipients.
In another embodiment, the present disclosure provides a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder is HPC in a concentration range of about 5 % w/w to about 30% w/w, lubricant is magnesium stearate in a concentration range of about 0.1 % w/w to about 2% w/w and one/more pharmaceutically acceptable excipients; wherein the preferable composition releases at least 70% of the pharmaceutically salt of (R)-2- amino-3-phenylpropyl carbamate contained therein within a period of less than 15 minutes after administration of the composition to a subject.
In another embodiment, the present disclosure provides a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder is HPC in a concentration range of about 5 % w/w to about 30% w/w, lubricant is magnesium stearate in a concentration range of about 0.1 % w/w to about 2% w/w and one/more pharmaceutically acceptable excipients; wherein the preferable composition releases at least 70% of the pharmaceutically salt of (R)-2- amino-3-phenylpropyl carbamate contained therein within a period of less than 15 minutes after administration of the composition to a subject; wherein the composition exhibits substantially identical dissolution rates of the pharmaceutically acceptable salt of (R)-2- amino-3-phenylpropyl carbamate at pH 1.2, pH 4.5 and pH 6.8.
In another embodiment, the present disclosure provides a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, HPC in a concentration range of about 5 % w/w to about 30% w/w, magnesium stearate in a concentration range of about 0.1 % w/w to about 3.0 % w/w and one/more pharmaceutically acceptable excipients.

In still another embodiment, the present disclosure provides a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, HPC in a concentration range of about 5.4 % w/w to about 10 % w/w, magnesium stearate in a concentration range of about 1.0 % w/w to about 1.75 % w/w and one/more pharmaceutically acceptable excipients.
In some embodiments, the stable immediate release pharmaceutical composition optionally comprises stabilizing agent.
In still another embodiment, the present disclosure provides a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, HPC in a concentration range of about 5.4 % w/w to about 10 % w/w, citric acid in a concentration range of about 2 % w/w to about 3.5 % w/w, MCC in a concentration range of about 2 % w/w to about 10 % w/w, colloidal silicon dioxide in a concentration range of about 1.0 % w/w to about 1.75 % w/w and magnesium stearate in a concentration range of about 1.0 % w/w to about 1.75 % w/w.
In still another embodiment, the present disclosure provides a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, HPC in a concentration range of about 5.4 % w/w to about 10 % w/w, succinic acid in a concentration range of about 2 % w/w to about 5 % w/w, MCC in a concentration range of about 2 % w/w to about 10 % w/w, colloidal silicon dioxide in a concentration range of about 1.0 % w/w to about 1.75 % w/w and magnesium stearate in a concentration range of about 1.0 % w/w to about 1.75 % w/w.
In still another embodiment, the present disclosure provides a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, HPC in a concentration range of about 5.4 % w/w to about 10 % w/w, MCC in a concentration range of about 2 % w/w to about 10 % w/w, colloidal silicon dioxide in a concentration range of about 1.0 % w/w to about 1.75 % w/w and magnesium stearate in a concentration range of about 1.0 % w/w to about 1.75 % w/w.
In still another embodiment, the present disclosure provides a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, HPC in an amount of about 5.4 % w/w, citric acid in an amount of about 2.9 % w/w, MCC in an amount of about 5.4 % w/w, colloidal silicon dioxide in an amount of about 1.6 % w/w, magnesium stearate in an amount of about 1.6 % w/w and optionally coating.

In still another embodiment, the present disclosure provides a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, HPC in an amount of about 5.4 % w/w, citric acid in an amount of about 2.9 % w/w, MCC in an amount of about 5.4 % w/w, colloidal silicon dioxide in an amount of about 1.6 % w/w, magnesium stearate in an amount of about 1.6 % w/w and opadry yellow in an amount of about 2.70 % w/w.
In still another embodiment, the present disclosure provides a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, HPC in an amount of about 6.50 % w/w, succinic acid in an amount of about 4.7 % w/w, MCC in an amount of about 5.2 % w/w, colloidal silicon dioxide in an amount of about 1.8 % w/w, magnesium stearate in an amount of about 1.5 % w/w and optionally coating.
In still another embodiment, the present disclosure provides a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, HPC in an amount of about 6.50 % w/w, succinic acid in an amount of about 4.7 % w/w, MCC in an amount of about 5.2 % w/w, colloidal silicon dioxide in an amount of about 1.8 % w/w, magnesium stearate in an amount of about 1.5 % w/w and opadry yellow in an amount of about 2.90 % w/w.
In still another embodiment, the present disclosure provides a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, HPC in an amount of about 5.4 % w/w, MCC in an amount of about 8.3 % w/w, colloidal silicon dioxide in an amount of about 1.6 % w/w and magnesium stearate in an amount of about 1.6 % w/w.
In another embodiment, the present disclosure provides a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, diluent is partially pregelatinized starch, lubricant is sodium stearyl fumarate in a concentration range of about 0.1 % w/w to about 2% w/w and one/more pharmaceutically acceptable excipients; and wherein the composition does not comprise binder; wherein the preferable composition releases at least 70% of the pharmaceutically salt of (R)-2- amino-3-phenylpropyl carbamate contained therein within a period of less than 15 minutes after administration of the composition to a subject.

In another embodiment, the present disclosure provides a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate in a concentration range of about 60 % w/w to about 85 % w/w, binder is HPC, diluent is partially pregelatinized starch, lubricant is sodium stearyl fumarate and one/more pharmaceutically acceptable excipients; wherein the preferable composition releases at least 70% of the pharmaceutically salt of (R)-2- amino-3-phenylpropyl carbamate contained therein within a period of less than 15 minutes after administration of the composition to a subject.
In another aspect of the present invention, there is provided a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate in a concentration range of about 60 % w/w to about 85 % w/w, binder is HPC, diluent is microcrystalline cellulose, lubricant is magnesium stearate and one/more pharmaceutically acceptable excipients; wherein the preferable composition releases at least 70% of the pharmaceutically salt of (R)-2- amino-3-phenylpropyl carbamate contained therein within a period of less than 15 minutes after administration of the composition to a subject.
Fillers or diluents for use in the formulations of the present invention include fillers or diluents typically used in the formulation of pharmaceuticals. Examples of fillers or diluents for use in accordance with the present invention include but are not limited to lactose, dextrose, glucose, sucrose, microcrystalline cellulose, maize starch, pregelatinized starch, modified corn starch, cellulose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium carbonates, magnesium carbonates combinations thereof, and the like.
In another embodiment, the present disclosure provides a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder is S-MCC in a concentration range of about 5 % w/w to about 30% w/w and one/more pharmaceutically acceptable excipients.
In another embodiment, the present disclosure provides a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder is S-MCC in a concentration range of about 5 % w/w to about 30% w/w, lubricant is magnesium stearate in a concentration range of about 0.1 % w/w to about 2 % w/w and one/more pharmaceutically acceptable excipients; wherein the preferable composition releases at least 70% of the pharmaceutically salt of (R)-2- amino-3-phenylpropyl carbamate contained therein within a period of less than 15 minutes after administration of the composition to a subject.
In another embodiment, the present disclosure provides a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder is S-MCC in a concentration range of about 5 % w/w to about 30% w/w, lubricant is magnesium stearate in a concentration range of about 0.1 % w/w to about 2 % w/w and one/more pharmaceutically acceptable excipients; wherein the preferable composition releases at least 70% of the pharmaceutically salt of (R)-2- amino-3-phenylpropyl carbamate contained therein within a period of less than 15 minutes after administration of the composition to a subject; wherein the composition exhibits substantially identical dissolution rates of the pharmaceutically acceptable salt of (R)-2- amino-3-phenylpropyl carbamate at pH 1.2, pH 4.5 and pH 6.8.
In another embodiment, the present disclosure provides a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder is partially pregelatinized maize starch in a concentration range of about 5 % w/w to about 30% w/w and one/more pharmaceutically acceptable excipients.
In another embodiment, the present disclosure provides a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder is partially pregelatinized maize starch in a concentration range of about 5 % w/w to about 30% w/w, lubricant is magnesium stearate in a concentration range of about 0.1 % w/w to about 2 % w/w and one/more pharmaceutically acceptable excipients; wherein the preferable composition releases at least 70% of the pharmaceutically salt of (R)-2- amino-3-phenylpropyl carbamate contained therein within a period of less than 15 minutes after administration of the composition to a subject.
In another embodiment, the present disclosure provides a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder is partially pregelatinized maize starch in a concentration range of about 5 % w/w to about 30% w/w, lubricant is magnesium stearate in a concentration range of about 0.1 % w/w to about 2 % w/w and one/more pharmaceutically acceptable excipients; wherein the preferable composition releases at least 70% of the pharmaceutically salt of (R)-2- amino-3-phenylpropyl carbamate contained therein within a period of less than 15 minutes after administration of the composition to a subject; wherein the composition exhibits substantially identical dissolution rates of the pharmaceutically acceptable salt of (R)-2- amino-3-phenylpropyl carbamate at pH 1.2, pH 4.5 and pH 6.8.
In another embodiment, the present disclosure provides a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder is StarTab in a concentration range of about 5 % w/w to about 30% w/w and one/more pharmaceutically acceptable excipients
In another embodiment, the present disclosure provides a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder is StarTab in a concentration range of about 5 % w/w to about 30% w/w, lubricant is magnesium stearate in a concentration range of about 0.1 % w/w to about 2 % w/w and one/more pharmaceutically acceptable excipients; wherein the preferable composition releases at least 70% of the pharmaceutically salt of (R)-2- amino-3-phenylpropyl carbamate contained therein within a period of less than 15 minutes after administration of the composition to a subject.
In another embodiment, the present disclosure provides a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder is StarTab in a concentration range of about 5 % w/w to about 30% w/w, lubricant is magnesium stearate in a concentration range of about 0.1 % w/w to about 2 % w/w and one/more pharmaceutically acceptable excipients; wherein the preferable composition releases at least 70% of the pharmaceutically salt of (R)-2- amino-3-phenylpropyl carbamate contained therein within a period of less than 15 minutes after administration of the composition to a subject; wherein the composition exhibits substantially identical dissolution rates of the pharmaceutically acceptable salt of (R)-2- amino-3-phenylpropyl carbamate at pH 1.2, pH 4.5 and pH 6.8.
In still another embodiment, the present disclosure provides a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, wherein the composition is packed in High Density Polyethylene (HDPE) bottle.
In still another embodiment, the present disclosure provides a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, wherein the composition remains stable after storing at different stability conditions for at least 24 hours, i.e. 25 oC / 60 % RH and 40 oC / 75 % RH.
In still another embodiment, the present disclosure provides a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, wherein there is no impurity generated upon storage at different stability conditions, i.e. 25 oC / 60 % RH and 40 oC / 75 % RH for at least 24 hours.
In still another embodiment, the present disclosure provides a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, wherein N-Acetyl solriamfetol based impurity is generated in an amount not more than 0.2 % upon storage at different stability conditions, i.e. 25 oC / 60 % RH and 40 oC / 75 % RH, for at least 24 hours.
In another embodiment, the present disclosure provides a method of manufacturing a solid formulation comprising a (R)-2-amino-3-phenylpropyl carbamate, wherein the method comprises the following steps: (a) mixing suitable amounts of APC, a diluent, disintegrating agent and optionally a binder, in an aqueous solvent, (b) granulating the mixture produced in step (a), preferably by wet granulation, (c) blend the dried granules produced in step (b) with extra-granular ingredients, (d) pressing the blend produced in step (c) to tablets, and (e) optionally applying a coating to the tablets obtained in step (d).
In another embodiment, the present disclosure provides a method of manufacturing a solid formulation comprising a (R)-2-amino-3-phenylpropyl carbamate, wherein the method comprises the following steps: (a) mixing suitable amounts of APC, a diluent, disintegrating agent and optionally a binder by suitable machine to form dry slugs (b) blend the dried granules produced in step (a) with extra-granular ingredients (c) pressing the blend produced in step (b) to tablets, and (e) optionally applying a coating to the tablets obtained in step (c).
In another embodiment, the present disclosure provides a method of manufacturing a solid formulation comprising a (R)-2-amino-3-phenylpropyl carbamate, wherein the method comprises the following steps: (a) mixing suitable amounts of APC, binder and optionally stabilizing agent, in an aqueous solvent, (b) granulating the mixture produced in step (a), preferably by wet granulation, (c) blend the dried granules produced in step (b) with extra-granular ingredients, (d) pressing the blend produced in step (c) to tablets, and (e) optionally applying a coating to the tablets obtained in step (d).
EXAMPLE
Example 1: Stable oral solid pharmaceutical composition (%w/w) of (R)-2-amino-3-phenylpropyl carbamate at varying concentrations of excipients and dissolution profile
Table 1
Component Concentration (in %w/w) of excipients
C1 C2 C3 C4 C5 C6
(R)-2-amino-3-phenylpropyl carbamate 60-85 70-80 70-80 70-80 60-85 60-85
HPMC 3 cps 5-30 - - - - -
HPC - - - - 5-30 5-30
Starch 1500 - 10-30 - - - -
StarTab - - 10-30 - - -
S-MCC - - - 10-30 - -
Purified water q.s q.s q.s q.s q.s -
Organic solvent - - - - - q.s
Lubrication
Magnesium stearate 0.1-0.5 0.5-0.9 0.1-0.7 0.1-0.7 0.1-0.5 -
Sodium stearyl fumarate (SSF) - - - - - 0.1-2
Core Tablet Weight 95-98 95-98 95-98 95-98 95-98 95-98
Opadry Yellow 1-3 1-3 1-3 1-3 1-3 1-3
Purified water q.s q.s q.s q.s q.s q.s
Film Coated Tablet Weight 100.000 100.000 100.000 100.000 100.000 100.000

Table 2 shows the dissolution profile of composition in Table 1 at different pH 1.2, 4.5 and 6.8.
Table 2
C1
Time 0 5 10 15 30 45 60
pH 1.2 0 91 102 102 102 102 102
pH 4.5 0 64 95 95 96 96 97
pH 6.8 0 66 97 98 99 99 100
C2
pH 1.2 0 29 64 86 102 102 102
pH 4.5 0 16 37 61 94 95 96
pH 6.8 0 20 54 83 104 106 107
C3
pH 1.2 0 97 103 103 104 104 104
pH 4.5 0 40 88 96 96 96 97
pH 6.8 0 77 98 98 98 98 98
C4
pH 1.2 0 25 43 62 96 98 98
pH 4.5 0 23 37 48 88 98 100
pH 6.8 0 37 72 100 102 103 103
C5
pH 1.2 0 43 78 95 98 98 98
pH 4.5 0 40 76 95 99 99 99
pH 6.8 0 38 73 92 96 96 96
C6
pH 1.2 0 47 78 96 101 101 -
pH 4.5 0 16 47 71 89 104 -
pH 6.8 0 16 51 75 89 99 -

Example 2: Stable oral solid pharmaceutical composition (%w/w) of (R)-2-amino-3-phenylpropyl carbamate.
Table 3
Component Concentration (in %w/w) of excipients
A1 A2 A3 A4 A5
Intragranular
(R)-2-amino-3-phenylpropyl carbamate 80.41 77.37 80.00 80.41 80.41
Citric acid anhydrous 0.00 0.00 0.00 2.93 3.50
Succinic acid 0.00 4.68 4.0 0.00 0.00
Hydroxypropyl cellulose 5.41 6.50 6.00 5.41 5.41
Binder
Dichloromethane q.s q.s q.s q.s q.s
Extra Granular
Microcrystalline cellulose 8.33 5.20 4.14 5.41 4.84
Colloidal Silicon dioxide 1.58 1.82 1.58 1.58 1.58
Magnesium stearate 1.58 1.52 1.58 1.58 1.58
Film coat
Opadry Yellow 2.70 2.91 2.70 2.70 2.70
Isopropyl alcohol q.s q.s q.s q.s q.s
Dichloromethane q.s q.s q.s q.s q.s
Film Coated Tablet Weight 100.000 100.000 100.000 100.000 100.000

Manufacturing process:
a. Drug substance and excipients were sifted through suitable sieve.
b. Hydroxypropyl cellulose and optionally organic acid i.e. citric acid and Succinic acid were mixed with (R)-2-amino-3-phenylpropyl carbamate in rapid mixer granulator.
c. Dichloromethane was sprayed on mixture of step b. to prepare the wet granules.
d. Wet granules prepared in step c. were dried in fluidized bed dryer till desired LOD was achieved.
e. Separately, microcrystalline cellulose and colloidal silicon dioxide were passed through suitable sieve and mixed with dry granules prepared in step d.
f. Magnesium stearate was mixed with blend prepared in step e. and mixed for proper mixing.
g. Lubricated blend of step f. was compressed into tablet using rotary press tablet machine with suitable punch size.
h. Film coat:
Preparation of film coating dispersion: Opadry yellow was dispersed in isopropyl alcohol and dichloromethane and stirred for not less than 30 minutes to get uniform dispersion.
i. Tablets prepared in step g. were coated using coating dispersing of step h. in perforated coating pan using film coating dispersion till desired weight gain was achieved.
Table 4 shows the disintegration time of compositions referenced in Table 3
Table 4
A1 A2 A3 A4 A5
Disintegration time (Minutes) 8.50 7.58 7.66 7.66 7.50
Formulations A2-A5 provided satisfactory disintegration time results, while formulation A1 was having higher disintegration time of about 8.50 minutes.
Table 5 shows the dissolution profile of composition in Table 3 at different pH 1.2, 4.5 and 6.8.
Table 5
A1
Time 0 5 10 15 20 30
pH 1.2 0 39 75 94 98 99
pH 4.5 0 36 67 88 98 100
pH 6.8 0 22 37 47 55 66
A2
pH 1.2 0 32 66 89 97 100
pH 4.5 0 32 72 87 96 99
pH 6.8 0 29 64 83 92 97
A3
pH 1.2 0 34 70 90 99 100
pH 4.5 0 32 73 88 97 99
pH 6.8 0 30 65 84 93 98
A4
pH 1.2 0 33 68 91 100 100
pH 4.5 0 34 69 90 99 99
pH 6.8 0 31 62 84 94 98
A5
pH 1.2 0 34 67 89 98 99
pH 4.5 0 33 69 90 98 99
pH 6.8 0 32 60 85 95 98

Based on above dissolution data in various pH conditions i.e. 1.2, 4.5 and 6.8, formulations A2-A5 provided satisfactory dissolution with nearly 100 % drug dissolution within 30-minute time period in all pH conditions, while formulation A1 provided less than 80 % drug release in pH 6.8.
Based on dissolution at various pH conditions as well as disintegration time parameters, formulations A2-A5 found satisfactory and considered for further evaluation.
Example 3: Stable oral solid pharmaceutical composition (%w/w) of (R)-2-amino-3-phenylpropyl carbamate with stabilising agent(s).
Table 6
Component Concentration (in %w/w) of excipients
B1 B2
Intragranular
(R)-2-amino-3-phenylpropyl carbamate 77.37 80.41
Citric acid anhydrous 0.00 2.93
Succinic acid 4.68 0.00
Hydroxypropyl cellulose 6.50 5.41
Binder
Dichloromethane q.s q.s
Extra Granular
Microcrystalline cellulose 5.20 5.41
Colloidal Silicon dioxide 1.82 1.58
Magnesium stearate 1.52 1.58
Film coat
Opadry Yellow 2.91 2.70
Isopropyl alcohol q.s q.s
Dichloromethane q.s q.s
Film Coated Tablet Weight 100.000 100.000
Formulations of example 3 were prepared using same manufacturing process as used in example 2.
Table 7 shows the impurity profile of compositions referenced in Table 6 as below
Table 7
N Acetyl Solriamfetol impurity (%)
Condition B1 B2
Initial 0.007 0.001
3M 25 oC /60 % RH 0.042 Not detected
3M 40 oC/75 % RH 0.132 Not detected
6M 25 oC /60 % RH 0.068 0.017
6M 40 oC/75 % RH 0.183 0.017
Based on the above results, Impurity profile of Formulation B1 was not found to be satisfactory in comparison to Formulation B2.
Although the inventions herein have been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and application of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described.
All publications, patents, and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference.
,CLAIMS:We claim:
1. A stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate (APC), stabilizing agent and pharmaceutically acceptable excipients.

2. The stable composition of claim 1, wherein stabilizing agent comprises about 2 % w/w to about 5 % w/w of the composition.

3. The stable composition of claim 1 or 2, wherein stabilizing agent is selected from the group consisting of acetic acid, succinic acid, citric acid, tartaric acid, acrylic acid, benzoic acid, malic acid, maleic acid, oxalic acid and sorbic acid; and mixtures thereof.

4. The stable composition of claim 1, wherein pharmaceutically acceptable excipients are selected from the group consisting of binder, diluent, glidant lubricant and mixture thereof.

5. The stable composition of claim 1, wherein (R)-2-amino-3-phenylpropyl carbamate (APC) is less than 90 % w/w of the total composition.

6. A stable immediate release pharmaceutical composition comprising (a) about 80% w/w (R)-2-amino-3-phenylpropyl carbamate, (b) about 5.4 % w/w to about 10 % w/w of hydroxypropyl cellulose, (c) about 2 % w/w to about 3.5 % w/w of citric acid, (d) about 2 % w/w to about 10 % w/w microcrystalline cellulose, (e) about 1.0 % w/w to about 1.75 % w/w colloidal silicon dioxide and (f) about 1.0 % w/w to about 1.75 % w/w magnesium stearate.

7. The stable composition of claim 6, wherein the composition contains less than 0.2 % of N-acetyl solriamfetol when stored for at least 24 hours at 25°C and 60% relative humidity.

8. The stable composition of claim 6, wherein the composition exhibits substantially identical dissolution rates at pH 1.2, pH 4.5 and pH 6.8.

9. A stable immediate release pharmaceutical composition comprising a core containing (a) (R)-2-amino-3-phenylpropyl carbamate, (b) hydroxypropyl cellulose in an amount of about 5.4 % w/w, (c) citric acid in an amount of about 2.9 % w/w, (d) microcrystalline cellulose in an amount of about 5.4 % w/w, (e) colloidal silicon dioxide in an amount of about 1.6 % w/w and (f) magnesium stearate in an amount of about 1.6 % w/w.
10. The stable composition of claim 9, wherein the composition is further coated with opadry based composition in an amount of about 2.7 % w/w of the composition.