FORM – 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION (See section 10 and rule 13)
Title:
PHARMACEUTICAL COMPOSITION COMPRISING (R)-2-AMINO-3-PHENYLPROPYL CARBAMATE”
Applicant:
ALKEM LABORATORIES LIMITED
An INDIAN Company of
ALKEM HOUSE, SENAPATI BAPAT MARG, LOWER PAREL, MUMBAI-400013
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER, IN WHICH IT IS TO BE PERFORMED.

FIELD OF THE INVENTION
The present invention relates to stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate (APC) with or without binder 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, US20170158622 A1 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 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 of about 5-30% w/w and one/more pharmaceutically acceptable excipients; wherein the

composition exhibits 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 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, 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 of about 5-30% 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 of about 5-30% w/w; wherein binder is selected from but not limited to hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), microcrystalline cellulose (MCC), povidone, starch, StarTab and one/more pharmaceutically acceptable excipients.
In one aspect of the present invention, there is provided a stable immediate release pharmaceutical composition comprising:
a. about 60 to 85% w/w amount of (R)-2-amino-3-phenylpropyl carbamate
b. about 5 to 30% w/w of binder
c. about 0.1 to 1 % w/w of magnesium stearate
and one/more pharmaceutically acceptable excipients.
In another aspect of the present invention, there is provided a stable immediate release
pharmaceutical composition comprising:
a. about 60 to 75% w/w amount of (R)-2-amino-3-phenylpropyl carbamate

b. about 6 to 25 % w/w of binder
c. about 0.1 to 1 % w/w of magnesium stearate
and one/more pharmaceutically acceptable excipients.
In one aspect of the present invention, there is provided a stable immediate release pharmaceutical composition comprising:
a. about 60 to 85% w/w amount of (R)-2-amino-3-phenylpropyl carbamate
b. about 0.1 to 1 % w/w of magnesium stearate
c. one/more pharmaceutically acceptable excipients and wherein the composition does not
comprise a binder
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 of about 5-30% 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 of about 5-30% w/w with one or more pharmaceutically acceptable excipients; wherein the composition exhibits 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 of about 5-30% w/w with one or more pharmaceutically acceptable excipients; wherein the composition exhibits 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.
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, flavorants, buffering agents, coatings, glidants, 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), povidone, 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 aluminum 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 – 30% by weight 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 6% to about 25% w/w, about 6 to about 20% w/w, about 6 to about 15% w/w, more preferably about 6 to about 14% w/w, more preferably about 6 to about 13% w/w, more preferably about 6 to about 12% w/w, more preferably about 6 to about 11% w/w. The composition may comprise one or more binders.

In some embodiments, if the binder is present in an amount of about 0-5% by weight of the pharmaceutical composition or any value or range therein. In certain embodiments, the binder is present in an amount in the range of about 0-4% w/w, preferably in the range of about 0-3% w/w, preferably in the range of about 0-2% w/w, preferably in the range of about 0-1 %w/w, preferably about 0% 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 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 certain embodiments, APC or a pharmaceutically acceptable salt thereof is present in an amount of about 60% to 85% by weight 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 60% to about 80% w/w, about 60% to about 75% w/w or about 60% to about 70% w/w.
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, at least one lubricant is present in an amount of about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, or 2.0% by weight of the tablet or any value or range therein. In certain embodiments, the at least one lubricant is present in an amount of about 0.1% to about 2.0% w/w, about 0.5% to about 2.0% w/w, about 1.0% to about 2.0% w/w, about 1.5% to about 2.0% w/w, about 0.1% to about 0.5% w/w, about 0.1% to about 1.0% w/w, about 0.1% to about 1.5% w/w, about 0.5% to about 1.0% w/w, about 0.5% to about 1.5% w/w, or about 1.0% to about 1.5% w/w.

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 color 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.degree. C., 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.
"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 C.sub.max, AUC.sub.(0-t) and AUC.sub.(0-.infin.) of the test product to reference product is within 80% to 125%.

The term "AUC.sub.(0-t)" means the area under the plasma concentration curve from time 0 to time t.
The term "AUC.sub.(0-.infin.)" or "AUC.sub.0-inf" means the area under the plasma concentration time curve from time 0 to infinity.
"C.sub.max" refers to the maximum plasma concentration of APC.
"T.sub.max" refers to the time to maximum plasma concentration for a given drug.
"t.sub.1/2" 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, color overcoat or other aesthetic or functional layer using materials and methods known in the art.

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 10-1000 mg, e.g., about 20-500 mg, in single or divided doses, is administered. In some embodiments, the daily dose may be about 0.01 to about 150 mg/kg body weight, e.g., about 0.2 to about 18 mg/kg body weight.
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 5-30% 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 is HPMC in a concentration of about 5-30% 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 is HPMC in a concentration of about 5-30% w/w, lubricant is magnesium stearate in a concentration of about 0.1-2% 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 aspect of the present invention, there is provided a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder is

PVP in a concentration of about 5-30% w/w, lubricant is magnesium stearate in a concentration of about 0.1-2% 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 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 aspect of the present invention, there is provided a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder is HPC in a concentration of about 5-30% 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 is HPC in a concentration of about 5-30% w/w, lubricant is magnesium stearate in a concentration of about 0.1-2% 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 aspect of the present invention, there is provided a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder is HPC in a concentration of about 5-30% w/w, lubricant is magnesium stearate in a concentration of about 0.1-2% 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 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 aspect of the present invention, there is provided 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 of about

0.1-2% 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 aspect of the present invention, there is provided a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate in a concentration of about 60-85% 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.
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 aspect of the present invention, there is provided a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder is S-MCC in a concentration of about 5-30% 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 in a concentration of about 60-85% w/w, binder is HPC or its derivative in a concentration of about 0- 5% 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 is S-MCC in a concentration of about 5-30% w/w, lubricant is magnesium stearate in a concentration of about 0.1-2% 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 aspect of the present invention, there is provided a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder is S-MCC in a concentration of about 5-30% w/w, lubricant is magnesium stearate in a concentration of about 0.1-2% 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 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 aspect of the present invention, there is provided a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder is partially pregelatinized maize starch in a concentration range of 5-30% 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 is partially pregelatinized maize starch in a concentration of about 5-30% w/w, lubricant is magnesium stearate in a concentration of about 0.1-2% 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 aspect of the present invention, there is provided a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder is partially pregelatinized maize starch in a concentration of about 5-30% w/w, lubricant is magnesium stearate in a concentration of about 0.1-2% 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 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 aspect of the present invention, there is provided a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder is StarTab in a concentration of about 5-30% 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 is StarTab in a concentration of about 5-30% w/w, lubricant is magnesium stearate in a concentration of about 0.1-2% 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 aspect of the present invention, there is provided a stable immediate release pharmaceutical composition comprising (R)-2-amino-3-phenylpropyl carbamate, binder is StarTab in a concentration of about 5-30% w/w, lubricant is magnesium stearate in a concentration of about 0.1-2% 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 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.
One aspect of the present invention relates to 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).
Another aspect of the present invention relates to 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).
Figures
Figure 1 shows the dissolution rate of composition C1 as disclosed in Table 1 Figure 2 shows the dissolution rate of composition C2 as disclosed in Table 1 Figure 3 shows the dissolution rate of composition C3 as disclosed in Table 1 Figure 4 shows the dissolution rate of composition C4 as disclosed in Table 1 Figure 5 shows the dissolution rate of composition C5 as disclosed in Table 1 Figure 6 shows the dissolution rate of composition C6 as disclosed in Table 1
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
Stable oral solid formulation comprising (R)-2-amino-3-phenylpropyl carbamate was prepared
according to the table 1.
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 -

Claims:
What is claimed is:
Claim 1: A solid oral formulation of (R)-2-amino-3-phenylpropyl carbamate, the formulation
comprising:
a) (R)-2-amino-3-phenylpropyl carbamate in a concentration of about 60-85% w/w,
b) binder in a concentration of about 5-30% w/w and
c) one/more pharmaceutically acceptable excipients.
Claim 2: The solid oral dosage form of claim 1, wherein the (R)-2-amino-3-phenylpropyl carbamate is present in an amount in the range of about 60-80% w/w, preferably in the range of about 60-75% w/w, preferably in the range of about 60-70% w/w.
Claim 3: The solid oral dosage form of claim 1, wherein the binder is selected from HPMC, HPC, polyvinyl alcohol, HEC, povidone, 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 aluminum 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 the like.
Claim 4: The solid oral dosage form of claim 1, wherein the binder is present in an amount in the range of about 6-25% w/w, preferably in the range of about 6-20% w/w, preferably in the range of about 6-15% w/w, more preferably in the range of about 6-14 % w/w, more preferably in the range of about 6-13 % w/w, more preferably in the range of about 6-12 % w/w, more preferably in the range of about 6-11% w/w.
Claim 5: The solid oral dosage form of claim 1, wherein the one or more acceptable excipients are selected from diluent, disintegrating agent, glidant, lubricant and/or coating agent

Claim 6: The solid oral dosage form of claim 5, wherein the 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
Claim 7: The solid oral dosage form of claim 5, wherein the disintegrating agent is selected from 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.
Claim 8: A solid oral formulation of (R)-2-amino-3-phenylpropyl carbamate, the formulation comprising:
a) (R)-2-amino-3-phenylpropyl carbamate in a concentration of about 60-85% w/w,
b) binder in a concentration of about 0-5% w/w and
c) one/more pharmaceutically acceptable excipients.
Claim 9: The solid oral dosage form of claim 8, wherein the (R)-2-amino-3-phenylpropyl carbamate is present in an amount in the range of about 60-80% w/w, preferably in the range of about 60-75% w/w, preferably in the range of about 60-70% w/w.
Claim 10: The solid oral dosage form of claim 8, wherein if the binder is present it is selected from HPMC, HPC, polyvinyl alcohol, HEC, povidone, 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 aluminum 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 the like.
Claim 11: The solid oral dosage form of claim 8, wherein the binder is present in an amount in the range of about 0-5% w/w, preferably in the range of about 0-4% w/w, preferably in the range of about 0-3% w/w, preferably in the range of about 0-2% w/w, preferably in the range of about 0-1 %w/w, preferably about 0% w/w.

Claim 12: The solid oral dosage form of claim 8, wherein the one or more acceptable excipients are selected from diluent, disintegrating agent, glidant, lubricant and/or coating agent
Claim 13: The solid oral dosage form of claim 12, wherein the 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
Claim 14: The solid oral dosage form of claim 12, wherein the disintegrating agent is selected from 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.