KR20140030156A - Modified release pharmaceutical compositions of desvenlafaxine - Google Patents

Abstract

The present invention relates to a modified release pharmaceutical composition comprising Desvenlafaxine, one or more release modifier (s) and one or more pharmaceutically acceptable excipient (s). More particularly, the present invention relates to release-controlled pharmaceutical compositions comprising desvenlafaxine benzoate, and methods of making the same. The invention also relates to a release-controlled pharmaceutical composition comprising desvenlafaxine benzoate, one or more release modifier (s) thereof and one or more pharmaceutically acceptable excipient (s), wherein C _max and AUC are independent of food effect.

Description

Release-controlled desvenlafaxine pharmaceutical composition {MODIFIED RELEASE PHARMACEUTICAL COMPOSITIONS OF DESVENLAFAXINE}

The present invention relates to a modified release pharmaceutical composition comprising Desvenlafaxine, and a method for preparing the same.

Serotonin-norepinephrine reuptake inhibitors (SNRIs) are a type of antidepressant used in the treatment of major depression and other mood disorders. They are also used to treat anxiety disorders, obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), chronic neuropathic pain, fibromyalgia syndrome (FMS), and alleviation of menopausal syndrome.

Serotonin-norepinephrine reuptake inhibitors (SNRI) include venlafaxine, desvenlafaxine, milnacipran, duloxetine, sibutramine, levomilnacipran and sibutramine. It is not limited to this.

Desvenlafaxine is chemically serotonin-norepinephrine reuptake inhibitor, the chemical name of desvenlafaxine is (±) -1- [2- (dimethylamino) -1- (4-hydroxyphenyl) ethyl] cyclohexanol, As a major metabolite of venlafaxine, it has been shown to inhibit norepinephrine and serotonin uptake. Desvenlafaxine, which may also be referred to as O-desmethylvenlafaxine or desmethylvenlafaxine, is represented by the formula:

O-desmethyl venlafaxine is the main metabolite of venlafaxine and has been shown to inhibit norepinephrine and serotonin uptake.

Desvenlafaxine is exemplified as fumarate salt in US Pat. No. 4,535,186. However, the fumarate salt of O-desmethyl-venlafaxine has inadequate physicochemical and permeability characteristics. O-desmethyl-venlafaxine is also exemplified as free base in WO 00/32555.

U. S. Patent No. 6,673, 838 discloses desvenlafaxine succinate in different crystalline forms, primarily of Forms I, II, III and IV. Also disclosed is desvenlafaxine succinate in amorphous form. US Pat. No. 7,820,716 discloses desvenlafaxine succinates of type V and F.

Different salts of desvenlafaxine have been disclosed in the literature. Succinate salts (US Pat. No. 6,673,838 and US Patent Application No. 20040106576); Formate (US Pat. No. 7,001,920); Hydrochloride (Australian Patent Application No. 20080218997); Citrate, maleate, mesylate, mandelate, quinic acid salt and tartrate (WO 2010008735); Phosphate (WO 2009136756); D-glucononate and orotate (WO 2009095431); Oxalate, benzoate and lactate (WO 2009053840); Sacharinate (WO 2009017813).

Salt formation provides a means of changing physicochemical characteristics and consequently changing their biological characteristics without altering the chemical structure of the drug. The salt form can have a big impact on the properties of the drug. The selection of the appropriate salt depends in part on the yield, speed and amount of the crystalline structure. In addition, the hygroscopicity, stability, solubility and process profile of the salt form are important considerations. Identification of salt forms that exhibit the proper combination of properties can be difficult.

Desvenlafaxine in the form of succinate monohydrate is incorporated into extended release hydrogel tablets to reduce side effects such as nausea, vomiting, diarrhea, and abdominal pain. Formulations describing the use of hydroxypropyl methylcellulose (HPMC) as a hydrogel matrix are described in US Pat. No. 7,291,347.

U.S. Patent Application No. 20050175698 provides desvenlafaxine in enteric coated multiparticulate form, which reduces inadequate features associated with desvenlafaxine and its hydrogel formulations. These desvenlafaxine polygranules consist of desvenlafaxine succinate, desvenlafaxine formate, or a combination thereof. Advantageously, such formulations also provide more convenient dosing for patients who have difficulty swallowing solid food.

U.S. Patent Application No. 20100210719 describes a stable amorphous O-desmethylvenlafaxine succinate solid dispersion comprising one or more pharmaceutically acceptable carriers.

US patent application 20100330172 discloses a matrix controlled-release pharmaceutical formulation comprising desvenlafaxine succinate having an MMD of about 5 μm to about 100 μm and a matrix rate-controlled pharmaceutically acceptable polymer.

US patent application 20110046231 provides a pharmaceutical composition comprising an O-desmethylvenlafaxine salt in solid state form and one or more pharmaceutically acceptable excipients, wherein the salts of O-desmethylvenlafaxine are oxalate salts, benzo Acid salts or lactate salts.

U.S. Patent Application No. 20070014859 discloses at least DVS and water in an oral dosage unit having a delayed release of at least about 1 hour and sustained release over several hours with a total release greater than about 85% within about 12 hours to about 14 hours. A superbioavailable DVS (O-desmethylvenlafaxine succinate) sustained release composition comprising a core comprising an insoluble filler is disclosed.

While there are many compositions that can be used to reduce the side effects of conventional dosage forms, there is still a need to develop controlled release compositions of desvenlafaxine.

It is a primary object of the present invention to provide a release-modulated desvenlafaxine pharmaceutical composition.

Another object of the present invention is a release-controlled pharmaceutical composition comprising desvenlafaxine, one or more release controlling agent (s) thereof and one or more pharmaceutically acceptable excipient (s).

Another object of the present invention is a release-controlled pharmaceutical composition comprising desvenlafaxine, one or more release controlling agent (s) thereof, and one or more pharmaceutically acceptable excipient (s), wherein the d ₅₀ particle size of desvenlafaxine is about 80 microns or less.

Another object of the invention is a release-controlled pharmaceutical composition comprising desvenlafaxine, one or more release modifier (s) and one or more pharmaceutically acceptable excipient (s), wherein the composition is 0.9 rpm in water at 100 rpm. Desvenlafaxine releases about 75% within 16 hours when measured using a USP Type I dissolution apparatus in 900 mL% NaCl.

Another object of the present invention is a release-controlled pharmaceutical composition comprising desvenlafaxine, one or more release controlling agent (s) thereof and one or more pharmaceutically acceptable excipient (s), wherein the d ₅₀ particle size of desvenlafaxine is about 80 Up to micron, the composition releases about 75% of desvenlafaxine within 16 hours when measured using a USP Type I dissolution device at 100 rpm, 900 ml of 0.9% NaCl in water.

Another object of the present invention is a release-controlled pharmaceutical composition comprising a matrix core comprising desvenlafaxine, one or more release modifier (s) and one or more pharmaceutically acceptable excipient (s), wherein the matrix core is one Further coated with one or more release controlling agent (s) and one or more pharmaceutically acceptable excipient (s).

Another object of the present invention is a release-controlled pharmaceutical composition comprising a matrix core comprising desvenlafaxine, one or more release modifier (s) and one or more pharmaceutically acceptable excipient (s), wherein the matrix core is one Further coated with one or more of the release controlling agent (s) and one or more pharmaceutically acceptable excipient (s), such that the d ₅₀ particle size of desvenlafaxine is about 80 microns or less.

Another object of the present invention is a release-controlled pharmaceutical composition comprising a matrix core comprising desvenlafaxine, one or more release modifier (s) and one or more pharmaceutically acceptable excipient (s), wherein the matrix core is one Further coated with one or more release controlling agent (s) and one or more pharmaceutically acceptable excipient (s), wherein the composition is measured using a USP Type I dissolution device at 100 rpm and 900 ml of 0.9% NaCl in water, It releases about 75% of desvenlafaxine within 16 hours.

Another object of the present invention is a release-controlled pharmaceutical composition comprising a matrix core comprising desvenlafaxine, one or more release modifier (s) and one or more pharmaceutically acceptable excipient (s), wherein the matrix core is one Further coated with one or more release controlling agent (s) and one or more pharmaceutically acceptable excipient (s) and having a d ₅₀ particle size of desvenlafaxine of about 80 microns or less, such that the composition is at 100 rpm, 0.9% NaCl in water. When measured using a USP Type I dissolution apparatus at 900 ml, it releases about 75% of desvenlafaxine within 16 hours.

The present invention provides release-controlled pharmaceutical compositions comprising desvenlafaxine, methods for their preparation, and their use in medicine. The present invention is directed to a release-controlled pharmaceutical composition comprising desvenlafaxine benzoate, one or more release modifier (s) thereof and one or more pharmaceutically acceptable excipient (s), wherein desvenlafaxine is used in bioavailability studies in humans. Bioequivalent with extended release compositions of succinate. In addition, the C _max and AUC of the release-controlled composition comprising desvenlafaxine benzoate is independent of the food effect.

The present invention is directed to providing a release-controlled pharmaceutical composition comprising desvenlafaxine and a method of making the same.

For the purposes of the present invention, it will be understood that desvenlafaxine may be used as its base, pharmaceutically acceptable salt (s) or enantiomer (s) or polymorph (s).

The term “pharmaceutically acceptable salts” refers to salts including, but not limited to, salts prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Suitable non-toxic acids are acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethensulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isthionic acid, lactic acid, maleic acid, malic acid, Inorganic and organic acids such as mandelic acid, methane-sulfonic acid, slime acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid and the like. Preferably, desvenlafaxine is in salt form. More preferably the desvenlafaxine salt is benzoate, succinate, glutarate and palmitate.

In another embodiment, desvenlafaxine benzoate is present in crystalline or amorphous form or a mixture thereof. For the purposes of the present invention, it is understood that desvenlafaxine benzoate may exist in the form of solvates or hydrates or enantiomers such as monohydrates, dihydrates in organic solvents such as ethanol, isopropanol.

For the purposes of the present invention, desvenlafaxine benzoate may be prepared by the method disclosed in Indian Patent Application No. 0761 / KOL / 2011, which is incorporated by reference in its entirety.

In another embodiment, desvenlafaxine benzoate is characterized by a powder X-ray diffraction pattern having one or more peaks substantially at about 5.4, 10.75, 16.6, 18.0, 19.2, 23.32 ± 0.2 ° 2θ, as shown in FIG. 1. It exists in crystalline form that is built.

In another embodiment, desvenlafaxine benzoate is characterized by a powder X-ray diffraction pattern having peaks at substantially about 5.4, 10.75, 16.6, 18.0, 19.2, 23.32 ± 0.2 ° 2θ, as shown in FIG. 1. Present in crystalline form.

In another embodiment, desvenlafaxine benzoate is powder X- having peaks at substantially about 5.4, 9.5, 10.75, 16.1, 16.6, 17.3, 18.0, 19.2, 20.4, 23.32 ± 0.2 ° 2θ, as shown in FIG. Present in crystalline form characterized by a line diffraction pattern.

In another embodiment, desvenlafaxine benzoate is present in crystalline form characterized by a powder X-ray diffraction pattern substantially in accordance with FIG. 1.

More preferably, desvenlafaxine benzoate has a powder X-ray with peaks at about 5.4, 9.5, 10.7, 16.1, 16.6, 17.3, 18.0, 19.2, 20.4, 21.5, 23.3, 24.9, 28.3, 29.9 ± 0.2 ° 2θ It is present in crystalline form characterized by the diffraction pattern.

Desvenlafaxine benzoate has a solubility in water of more than 30 mg / ml, preferably the aqueous solubility of desvenlafaxine benzoate is at least about 50 mg / ml at 25 ° C., more preferably, the aqueous of desvenlafaxine benzoate Solubility is about 60 mg / ml at 25 ° C.

Desvenlafaxine succinate has a solubility in water of greater than 30 mg / ml, preferably the aqueous solubility of desvenlafaxine benzoate is about 35 mg / ml at 25 ° C.

Desvenlafaxine used in the pharmaceutical compositions of the present invention in safe and well tolerated amounts in patients with an acceptable side effect profile are those that are commonly practiced and are known to those skilled in the art.

Depression (including but not limited to major depressive disorders, bipolar disorders and mood alterations), fibromyalgia syndrome, anxiety disorders, airport disorders, agoraphobia, post-traumatic stress disorder, premenstrual (also known as physiological syndrome) Dysphoric disorder, attention deficit disorder (with and without hyperactivity), obsessive compulsive disorder (including trichotillomania), social anxiety disorder, general anxiety disorder, autism, schizophrenia, obesity, anorexia nervosa (anorexia nervosa), anorexia nervosa, Gilles de la Tourette Syndrome, vasomotor redness, cocaine and alcoholism, sexual dysfunction (including premature ejaculation), borderline personality disorder, chronic fatigue syndrome (Including, but not limited to, stool incontinence, overflow incontinence, passive incontinence, reflex incontinence, stress incontinence, urge incontinence, urinary exertional incontinence, and urinary incontinence Incontinence, pain (including but not limited to) pains (including but not limited to migraine, chronic low back pain, ring pain, central pain, diabetic neuropathy, and post shingles neuropathy), Shy Drager Desvenlafaxine, which is used to treat or prevent central nervous system disorders, includes, but is not limited to: preventing the recurrence or recurrence of depression; Treatment of cognitive impairment; It can also be used to treat inducement syndrome, Raynaud's syndrome, Parkinson's disease, epilepsy, and other. The compounds and compositions of the present invention can improve cognition in patients suffering from senile dementia, Alzheimer's disease, memory impairment, amnesia and amnesia syndrome; And regimens for stopping smoking or other tobacco use.

Dosages useful for treating, preventing, inhibiting or alleviating each of the foregoing symptoms will vary depending on the severity of the condition to be treated and the route of administration. Dosage and frequency of administration will also depend on the age, weight, reactivity and past history of the individual patient.

Dosages are described in the form of free base and adjusted according to pharmaceutically acceptable salts. In terms of managing the patient, it is generally desirable to start treatment at a lower dose and increase as needed. Dosages for non-human patients can be adjusted as appropriate by those skilled in the art.

The release-controlled pharmaceutical compositions according to the invention are tablets (monolayer tablets, multilayer tablets, mini tablets, bioadhesive tablets, dragees, matrix tablets, tablets within a tablet, mucoadhesive tablets, release-modulated tablets). Tablets, pulsatile release tablets, and timed release tablets, pellets, beads, granules, sustained release formulations, capsules, microcapsules, tablets in capsules, microspheres, Matrix formulations, including but not limited to microencapsulation.

The term "modified release" as used in the pharmaceutical compositions of the present invention means controlled release, extended release, sustained release, delayed release or a combination of these techniques. That is, the release-controlled pharmaceutical composition of the present invention may be any formulation technique, modified such that release of the active ingredient from the composition occurs at a slower rate than release from the immediate release composition.

In one embodiment, the release-controlled pharmaceutical composition comprises desvenlafaxine, one or more release modifier (s) thereof and one or more pharmaceutically acceptable excipient (s).

In another embodiment, the release-controlled pharmaceutical composition comprises desvenlafaxine succinate, one or more release modifier (s) thereof and one or more pharmaceutically acceptable excipient (s).

In another embodiment, the release-controlled pharmaceutical composition comprises desvenlafaxine benzoate, one or more release modifier (s) thereof and one or more pharmaceutically acceptable excipient (s).

In other embodiments, the release-controlled pharmaceutical composition comprises desvenlafaxine benzoate in crystalline form, one or more release modifier (s) thereof and one or more pharmaceutically acceptable excipient (s).

In another embodiment, the release-controlled pharmaceutical composition is formed by a powder X-ray diffraction pattern having one or more peaks substantially at about 5.4, 10.75, 16.6, 18.0, 19.2, 23.32 ± 0.2 ° 2θ as shown in FIG. 1. Desvenlafaxine benzoate in crystalline form characterized by one or more release controlling agent (s) thereof and one or more pharmaceutically acceptable excipient (s).

In another embodiment, the release-controlled pharmaceutical composition is characterized by a powder X-ray diffraction pattern having peaks at substantially about 5.4, 10.75, 16.6, 18.0, 19.2, 23.32 ± 0.2 ° 2θ as shown in FIG. Paper includes desvenlafaxine benzoate in crystalline form, one or more release controlling agent (s) thereof and one or more pharmaceutically acceptable excipient (s).

In another embodiment, the release-controlled pharmaceutical composition comprises a powder X having peaks at substantially about 5.4, 9.5, 10.75, 16.1, 16.6, 17.3, 18.0, 19.2, 20.4, 23.32 ± 0.2 ° 2θ as shown in FIG. Desvenlafaxine benzoate in crystalline form characterized by a line diffraction pattern, one or more release controlling agent (s) thereof and one or more pharmaceutically acceptable excipient (s).

In another embodiment, the release-controlled pharmaceutical composition comprises desvenlafaxine benzoate in crystalline form substantially characterized by a powder X-ray diffraction pattern according to FIG. 1, one or more release modulator (s) thereof and one or more pharmaceutical agents. Acceptable excipient (s).

In another embodiment, the release-controlled pharmaceutical composition comprises a powder X having peaks at about 5.4, 9.5, 10.7, 16.1, 16.6, 17.3, 18.0, 19.2, 20.4, 21.5, 23.3, 24.9, 28.3, 29.9 ± 0.2 ° 2θ Desvenlafaxine benzoate in crystalline form characterized by a line diffraction pattern, one or more release controlling agent (s) thereof and one or more pharmaceutically acceptable excipient (s).

In another embodiment, the release-controlled pharmaceutical composition comprises desvenlafaxine benzoate in amorphous form, one or more release modifier (s) thereof and one or more pharmaceutically acceptable excipient (s).

In another embodiment, the release-controlled pharmaceutical composition comprises desvenlafaxine glutarate, one or more release modifier (s) thereof and one or more pharmaceutically acceptable excipient (s).

In another embodiment, the release-controlled pharmaceutical composition comprises desvenlafaxine palmitate, one or more release modifier (s) thereof and one or more pharmaceutically acceptable excipient (s).

The release modifier (s) is hydrophilic, hydrophobic or a combination thereof.

In another embodiment, the release-controlled pharmaceutical composition comprises desvenlafaxine, one or more release controlling agent (s) thereof and one or more pharmaceutically acceptable excipient (s), wherein the release controlling agent (s) is the total weight of the composition. From about 1% to about 95%.

In another embodiment, the release-controlled pharmaceutical composition comprises desvenlafaxine succinate, one or more release controlling agent (s) thereof and one or more pharmaceutically acceptable excipient (s), wherein the release controlling agent (s) of the composition It is present in an amount of less than about 55% based on the total weight.

In another embodiment, the release-controlled pharmaceutical composition comprises desvenlafaxine benzoate, one or more release controlling agent (s) thereof and one or more pharmaceutically acceptable excipient (s), wherein the release controlling agent (s) From about 1% to about 95% by total weight.

Hydrophilic release controlling agent (s) according to the present invention include, but are not limited to, cellulose derivatives, alginic acid derivatives, polysaccharides, alkylene oxides or mixtures thereof.

Preferably, the hydrophilic release controlling agent (s) is cellulose or a salt or derivative thereof, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), sodium carboxymethyl cellulose, Alginic acid or salts thereof and derivatives thereof, carbomer (Carbopol ™), polyethylene oxide, xanthan gum, guar gum, locust bean gum, polyvinyl acetate, polyvinyl alcohol, lactose It includes.

Hydrophobic release controlling agent (s) according to the present invention include, but are not limited to, hydrogenated vegetable oils, polymethacrylates, ethyl cellulose or mixtures thereof.

Preferably, the hydrophobic release modifier (s) is ammonio methacrylate copolymers A and B described in USP, methacrylic acid copolymers A, B and C described in USP, Ph. 30% polyacrylate dispersion described in Eur., Polyvinyl acetate dispersion, ethylcellulose, cellulose acetate, cellulose propionate (low molecular weight, medium or high molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate Phthalates, cellulose triacetate, poly (methyl methacrylate), poly (ethyl methacrylate), poly (butyl methacrylate), poly (isobutyl methacrylate), and poly (hexyl methacrylate). . Poly (isodecyl methacrylate), poly (lauryl methacrylate), poly (phenyl methacrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl acrylate), poly Waxes such as (octadecyl acrylate), beeswax, carnauba wax, microcrystalline wax, and ground wax; Fatty alcohols such as cetostearyl alcohol, stearyl alcohol, cetyl alcohol and myristyl alcohol; And glyceryl monostearate, glycerol distearate; Fatty acid esters such as glycerol monooleate, acetylated monoglycerides, tristearin, tripalmitin, cetyl ester wax, glyceryl palmitostearate, glyceryl behenate, and hydrogenated castor oil.

In the release-controlled pharmaceutical compositions of the invention, the average particle size of the particles of desvenlafaxine or a pharmaceutically acceptable salt thereof is from about 5 microns to about 120 microns, preferably from about 7 microns to about 100 microns, more preferably. From about 10 microns to about 80 microns. The terms "average particle size", "d ₅₀ " and "mass average diameter" can be used interchangeably.

The average particle size, i.e. average equivalent diameter, is defined as the diameter when 50 mass% of the particles of desvenlafaxine have a larger equivalent diameter and the remaining 50 mass% have a smaller equivalent diameter.

“Average particle size” also refers to the median particle diameter by mass (ie, half of the mass of the particle is occupied by particles with smaller diameters, and half of the mass of particles is represented by particles with larger diameters). Particle diameter when occupied).

Particle size can be measured using light (e.g., light scattering or turbidity), sedimentation (e.g., pipette analysis using an andracene pipette, sedimentation scale, photo-sedimentometer or centrifugal force). Heavy sedimentation), pulsed methods (e.g. Coulter counters), or sorting using gravity or centrifugal forces, can be measured using a variety of methods currently available.

To determine the particle size of desvenlafaxine or pharmaceutically acceptable salts such as succinate or benzoate in pharmaceutical compositions, methods commonly used include, but are not limited to, isolation, crushing, extraction, separation and precipitation. It is understood that it can be. Determining the particle size of desvenlafaxine or a pharmaceutically acceptable salt such as succinate or benzoate in the pharmaceutical composition is within the scope of the present invention.

In another embodiment, the release-controlled pharmaceutical composition comprises desvenlafaxine benzoate, one or more release modifier (s) thereof and one or more pharmaceutically acceptable excipient (s), wherein the d ₅₀ particle size of desvenlafaxine is about 80 microns or less.

In another embodiment, the release-controlled pharmaceutical composition comprises desvenlafaxine benzoate, one or more of its release controlling agent (s) and one or more pharmaceutically acceptable excipient (s), the d ₅₀ particle size of desvenlafaxine benzoate Is from about 10 microns to about 80 microns.

In another embodiment, the release-controlled pharmaceutical composition comprises desvenlafaxine succinate, one or more release modifier (s) thereof and one or more pharmaceutically acceptable excipient (s), wherein the d ₅₀ particle size of desvenlafaxine succinate Is about 80 microns or less.

In another embodiment, the release-controlled pharmaceutical composition comprises desvenlafaxine succinate, one or more release modifier (s) thereof and one or more pharmaceutically acceptable excipient (s), wherein the d ₅₀ particle size of desvenlafaxine succinate Is about 50 microns or less.

In another embodiment, the release-controlled pharmaceutical composition comprises a matrix core comprising desvenlafaxine, one or more release modifier (s) and one or more pharmaceutically acceptable excipient (s), wherein the matrix core is one or more Further coated with release controlling agent (s) and one or more pharmaceutically acceptable excipient (s).

In another embodiment, the release-controlled pharmaceutical composition comprises a matrix core comprising desvenlafaxine, one or more release modifier (s) and one or more pharmaceutically acceptable excipient (s), wherein the matrix core is one or more Further coated with release modifier (s) and one or more pharmaceutically acceptable excipient (s), the d ₅₀ particle size of desvenlafaxine is less than or equal to about 80 microns.

In another embodiment, the release-controlled pharmaceutical composition comprises a matrix core comprising desvenlafaxine, one or more release modifier (s) and one or more pharmaceutically acceptable excipient (s), wherein the matrix core is one or more Further coating with release controlling agent (s) and one or more pharmaceutically acceptable excipient (s), the release of desvenlafaxine is mainly controlled by the coating.

In another embodiment, the release-controlled pharmaceutical composition, which releases desvenlafaxine at two or more stages at different release rates, is a) desvenlafaxine, one or more release modifier (s) thereof and one or more pharmaceutically acceptable excipients. Release-controlled Part A comprising (s), and b) desvenlafaxine, one or more release controlling agent (s) thereof and one or more pharmaceutically acceptable excipient (s) comprising do.

In another embodiment, the release-controlled pharmaceutical composition, which releases desvenlafaxine at two or more stages at different release rates, is a) desvenlafaxine, one or more release modifier (s) thereof and one or more pharmaceutically acceptable excipients. Release-controlled Part A comprising (s), and b) desvenlafaxine, one or more release controlling agent (s) thereof and one or more pharmaceutically acceptable excipient (s) comprising Part A is coated with Part B.

In another embodiment, the release-controlled pharmaceutical composition is a bi-layer tablet tablet, comprising: sustained release comprising desvenlafaxine, one or more release modifier (s) thereof and one or more pharmaceutically acceptable excipient (s). Strata; And an immediate release layer comprising desvenlafaxine and one or more pharmaceutically acceptable excipient (s).

In another embodiment, the release-controlled pharmaceutical composition is a multi-layered tablet.

In another embodiment, the release-controlled pharmaceutical composition is loaded with a drug layer comprising desvenlafaxine benzoate, one or more release control agent (s) thereof and one or more pharmaceutically acceptable excipient (s). wherein the desvenlafaxine benzoate layer is further coated with at least one release controlling layer comprising a release controlling agent (s) and one or more pharmaceutically acceptable excipient (s).

In another embodiment, the release-controlled pharmaceutical composition comprises an inert core loaded with a drug layer comprising desvenlafaxine succinate, one or more release control agent (s) thereof and one or more pharmaceutically acceptable excipient (s). The desvenlafaxine succinate layer is further coated with one or more release controlling layer comprising a release controlling agent (s) and one or more pharmaceutically acceptable excipient (s).

The inert cores include, but are not limited to, sugar spheres or pellets, microcrystalline cellulose spheres, sugar / starch cores or any suitable material.

In other embodiments, the drug layer and release controlling layer may be separated by one or more separation layers.

The separation layer comprises one or more pharmaceutically acceptable excipients and one or more hydrophilic agent (s), hydrophobic agent (s) or a combination thereof.

Hydrophilic agent (s) according to the present invention include, but are not limited to, cellulose derivatives, alginic acid derivatives, polysaccharides, alkylene oxides or mixtures thereof.

Preferably, the hydrophilic agent (s) are cellulose or salts or derivatives thereof, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), sodium carboxymethyl cellulose, alginic acid or Salts and derivatives thereof, carbomer (carbopol (TM)), polyethyleneoxide, xanthan gum, guar gum, locust bean gum, polyvinyl acetate, polyvinyl alcohol, lactose.

Hydrophobic agent (s) according to the present invention include, but are not limited to, hydrogenated vegetable oils, polymethacrylates, ethyl cellulose or mixtures thereof.

Preferably, the hydrophobic agent (s) are ammonia methacrylate copolymer type A and B described in USP, methacrylic acid copolymer type A, B and C described in USP, Ph. 30% polyacrylate dispersion described in Eur., Polyvinyl acetate dispersion, ethylcellulose, cellulose acetate, cellulose propionate (low, medium or high molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, Cellulose triacetate, poly (methyl methacrylate), poly (ethyl methacrylate), poly (butyl methacrylate), poly (isobutyl methacrylate), and poly (hexyl methacrylate). Poly (isodecyl methacrylate), poly (lauryl methacrylate), poly (phenyl methacrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl acrylate), poly Waxes such as (octadecyl acrylate), beeswax, carnauba wax, microcrystalline wax, and ground wax; Fatty alcohols such as cetostearyl alcohol, stearyl alcohol, cetyl alcohol and myristyl alcohol; And glyceryl monostearate, glycerol distearate, glycerol monooleate, acetylated monoglycerides, tristearin, tripalmitin, cetyl ester wax, glyceryl palmitostearate, glyceryl behenate and hydrogenated castor oil Fatty acid esters such as;

The term 'pharmaceutically acceptable excipient (s)' as used in the pharmaceutical compositions of the present invention includes, but is not limited to, diluents, binders, pH stabilizers, disintegrants, surfactants, glidants and lubricants. .

The amount of excipient (s) used will depend on how much of the active agent is used. Some excipient (s) may perform one or more functions.

The binder used in the present invention may be a starch such as potato starch, wheat starch, corn starch; Microcrystalline cellulose, such as a product known by Avicel, Filtrak, Heweten or Pharmacel; Celluloses such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose (HPMC), ethyl cellulose, sodium carboxy methyl cellulose; Natural rubbers such as acacia, alginic acid, guar gum; Liquid glucose, dextrin, povidone, syrup, polyethylene oxide, polyvinyl pyrrolidone, poly-N-vinyl amide, polyethylene glycol, gelatin, poly propylene glycol, tragacanth, combinations thereof, and known to those skilled in the art Other materials and mixtures thereof, including but not limited to.

The fillers or diluents used in the present invention are confectioner's sugar, compressible sugar, dexrate, dextrin, dextrose, fructose, lactitol, mannitol, sucrose, starch, lactose , Xylitol, sorbitol, talc, microcrystalline cellulose, calcium carbonate, calcium phosphate dibasic or tribasic, calcium sulfate, and the like, but may be used without limitation.

Lubricants used in the present invention include, but are not limited to, Mg, Al, Ca or Zn stearate, polyethylene glycol, glyceryl behenate, mineral oil, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oils and talc.

Glidants include silicon dioxide; Magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogels and other materials known to those skilled in the art. .

Disintegrants include starch; Clay; cellulose; Alginate; Rubber; Crosslinked polymers such as crosslinked polyvinyl pyrrolidone or crospovidone such as POLYPLASDONE XL, crosslinked sodium carboxymethylcellulose or croscarmellose sodium, such as AC-DI from FMC -SOL; And crosslinked calcium carboxymethylcellulose; Soy polysaccharides; And guar gum. The use of a disintegrant according to the invention facilitates the release of the drug in a later step, allowing the drug to be completely released from the dosage form.

The pharmaceutical composition may optionally comprise a surfactant. Preferred formulations are copolymers consisting of central hydrophobic chains of polyoxypropylene (poly (propylene oxide)) and polyoxyethylene (poly (ethylene oxide)), well known as poloxamers. However, dioctyl sodium sulfosuccinate (DSS), triethanolamine, sodium lauryl sulfate (SLS), polyoxyethylene sorbitan and poloxalkol derivatives, quaternary ammonium salts or those known to those skilled in the art Other agents, such as other pharmaceutically acceptable surfactants, can also be used.

The pharmaceutical compositions may be prepared in a variety of ways known in the art, such as, but not limited to, dry granulation, wet granulation, melt granulation, direct compression, double compression, extrusion spheronization, layering, and the like. It can be formed by a process. Solvent (s) used in wet granulation include both solvents or mixtures well known in the art.

In another embodiment, the controlled pharmaceutical composition of the present invention is a release-controlled coating, sustained release coating, extended release coating, enteric coating, partial enteric coating or leaky enteric coating, bioadhesive coating, and the like. One or more coatings, including but not limited to similar coatings known in the art. These coatings can help the pharmaceutical composition release the drug for the required time and at the required time.

These coatings include coating (s) selected from hydrophilic or hydrophobic agent (s) or combinations thereof.

The hydrophobic agent (s) of the coating include ammonio methacrylate copolymer type A and B described in USP, methacrylic acid copolymer type A, type B and C described in USP, pH. 30% polyacrylate dispersion described in Eur., Polyvinyl acetate dispersion, ethylcellulose, cellulose acetate, cellulose propionate (low, medium or high molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, Cellulose triacetate, poly (methyl methacrylate), poly (ethyl methacrylate), poly (butyl methacrylate), poly (isobutyl methacrylate), and poly (hexyl methacrylate). Poly (isodecyl methacrylate), poly (lauryl methacrylate), poly (phenyl methacrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl acrylate), poly Waxes such as (octadecyl acrylate), beeswax, carnauba wax, microcrystalline wax, and ground wax; Fatty alcohols such as cetostearyl alcohol, stearyl alcohol, cetyl alcohol and myristyl alcohol; And glyceryl monostearate, glycerol distearate; Fatty acid esters such as glycerol monooleate, acetylated monoglycerides, tristearin, tripalmitin, cetyl ester wax, glyceryl palmitostearate, glyceryl behenate, and hydrogenated castor oil .

The hydrophilic agent (s) of the coating may be cellulose or a salt or derivative thereof, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), sodium carboxymethyl cellulose, alginic acid or salts thereof And derivatives thereof, carbomer (carbopol (TM)), polyethyleneoxide, xanthan gum, guar gum, locust bean gum, polyvinyl acetate, polyvinyl alcohol, lactose, PVA, and these hydrophilic polymers also include It also acts as a pore forming agent.

These coatings may be one or more excipients selected from the group consisting of coatings, opacifiers, taste-masking agents, fillers, polishing agents, colorants, antitacking agents, and the like. It includes.

The pharmaceutical composition can be coated in a wide variety of ways. Suitable methods include compression coating, coating in a fluidized bed or pan and hot melt (extrusion) coating. Such methods are well known to those skilled in the art.

In another embodiment, the stable release-controlled pharmaceutical composition comprises desvenlafaxine, one or more release modifier (s) thereof and one or more pharmaceutically acceptable excipient (s).

In another embodiment, the release-controlled pharmaceutical composition comprises desvenlafaxine, one or more release controlling agent (s) thereof and one or more pharmaceutically acceptable excipient (s), wherein the composition is 0.9% in water at 100 rpm. Desvenlafaxine releases about 75% within 16 hours when measured using USP Type I dissolution apparatus in 900 mL NaCl.

In another embodiment, the release-controlled pharmaceutical composition comprises desvenlafaxine succinate, one or more release controlling agent (s) thereof and one or more pharmaceutically acceptable excipient (s), wherein the composition is in water at 100 rpm. Desvenlafaxine succinate releases about 75% within 16 hours when measured using a USP Type I dissolution apparatus in 900 ml of 0.9% NaCl.

In another embodiment, the release-controlled pharmaceutical composition comprises desvenlafaxine, one or more release modifier (s) thereof and one or more pharmaceutically acceptable excipient (s), wherein the d ₅₀ particle size of desvenlafaxine is about 80 microns. The composition then releases about 75% of desvenlafaxine within 16 hours when measured using a USP Type I dissolution apparatus at 900 rpm, 0.9% NaCl in water at 100 rpm.

In another embodiment, the release-controlled pharmaceutical composition comprises desvenlafaxine benzoate, one or more of its release controlling agent (s) and one or more pharmaceutically acceptable excipient (s), the d ₅₀ particle size of desvenlafaxine benzoate Is from about 5 microns to about 80 microns, the composition releases about 75% of desvenlafaxine within 16 hours when measured using a USP Type I dissolution device at 100 rpm and 900 ml of 0.9% NaCl in water.

In another embodiment, the release-controlled pharmaceutical composition comprises from about 10% to about 50% by weight of desvenlafaxine succinate and less than about 60% by weight of release modifier (s), based on the total weight of the composition, Since the d ₅₀ particle size of desvenlafaxine succinate is about 50 microns or less, the composition is capable of about 75 desvenlafaxine within 16 hours when measured using a USP Type I dissolution device at 100 rpm and 900 ml of 0.9% NaCl in water. Emits%.

In another embodiment, the release-controlled pharmaceutical composition comprises a matrix core comprising desvenlafaxine, one or more release modifier (s) and one or more pharmaceutically acceptable excipient (s), wherein the matrix core is one or more Further coated with release controlling agent (s) and one or more pharmaceutically acceptable excipient (s), said composition being measured using a USP Type I dissolution device at 100 rpm, at 900 mL of 0.9% NaCl in water, Releases about 75% of desvenlafaxine within hours.

In another embodiment, the release-controlled pharmaceutical composition comprises a matrix core comprising desvenlafaxine, one or more release modifier (s) and one or more pharmaceutically acceptable excipient (s), wherein the matrix core is one or more Further coated with a release controlling agent (s) and one or more pharmaceutically acceptable excipient (s) and having a d ₅₀ particle size of desvenlafaxine of about 80 microns or less, such that the composition is at 100 rpm, 0.9% NaCl 900 in water When measured using a USP Type I dissolution apparatus in ml, approximately 75% of desvenlafaxine is released within 16 hours.

In another embodiment, the present invention provides nausea, vomiting, diarrhea, abdominal pain, headache, vaso-vagal sensation caused by oral administration of a salt of desvenlafaxine other than venlafaxine, desvenlafaxine, or desvenlafaxine benzoate to a patient. malaise, and / or trismus. The method comprises orally administering desvenlafaxine benzoate to a patient in need thereof in a therapeutically effective amount.

In another embodiment, the invention is a method of lowering the incidence of nausea, vomiting, diarrhea, abdominal pain, headache, vasospasm, and / or opening disorder caused by oral administration of desvenlafaxine benzoate to a patient. The method comprises orally administering a sustained release oral dosage form comprising desvenlafaxine benzoate having a peak plasma concentration of less than about 225 ng / ml to a patient in need thereof.

Desvenlafaxine benzoate may also be provided with venlafaxine. The dose of venlafaxine is preferably from about 75 mg / day to about 350 mg / day, more preferably from about 75 mg / day to about 225 mg / day. Even more preferably, the dose of venlafaxine is about 75 mg / day to about 150 mg / day. The ratio of desvenlafaxine to venlafaxine will vary from patient to patient depending on the patient's response rate, but in general the ratio of desvenlafaxine to venlafaxine will be at least 6: 1.

Desvenlafaxine benzoate is less fluffy than desvenlafaxine succinate. Thus, less dusting in the manufacture of the drug allows for easier handling of the drug component compared to succinate, and provides a advantage over the succinate salt, with minimal chance of drug loss during the manufacturing process. In addition, the particle size distribution of the desvenlafaxine benzoate drug component is smaller compared to the desvenlafaxine succinate drug component. Thus, the distribution of drug components in the drug is uniform and there is no opportunity for a change in the uniformity of the contents of the final drug / dose form.

Due to these advantageous properties, in order to achieve a similar drug release profile and also to produce products that are biocompatible with Pristiq ^® , a rate controlling polymer or a release controlling polymer at a lower concentration in desvenlafaxine benzoate than desvenlafaxine succinate in matrix tablet formulations Is required.

Pristiq ^® is Wyeth Pharmaceuticals Inc. of Philadelphia, PA 19101. 50 mg and 100 mg of the extended release composition of desvenlafaxine succinate sold by Now Pfizer.

In another embodiment, the release-controlled pharmaceutical composition comprises desvenlafaxine benzoate, one or more release control agent (s) thereof and one or more pharmaceutically acceptable excipient (s), wherein the release-controlled composition comprises C _max (Peak plasma concentration) is provided at about 225 ng / ml or less.

In another embodiment, the release-controlled pharmaceutical composition comprises desvenlafaxine benzoate, one or more release control agent (s) thereof and one or more pharmaceutically acceptable excipient (s), wherein the release-controlled composition comprises C _max (Peak plasma concentration) is provided at about 300 ng / ml or less.

In another embodiment, the release-controlled pharmaceutical composition comprises desvenlafaxine benzoate, one or more release modifier (s) thereof and one or more pharmaceutically acceptable excipient (s), wherein the C _max of the release-controlled composition And AUC are within the 80% to 125% limit of the C _max and AUC of the extended release composition of desvenlafaxine succinate.

The term “C _max ” as used herein means the maximum plasma concentration of desvenlafaxine produced by the degradation of a release-controlled composition or a commercially available Pristiq® composition (extended release composition of desvenlafaxine succinate). C _max or peak plasma concentrations may be used interchangeably.

As used herein, the term "AUC" refers to the area under the plasma concentration-time curve of desvenlafaxine produced by degradation of the release-controlled composition or commercially available Pristiq® (extended release composition of desvenlafaxine succinate) of the present invention. do.

In another embodiment, the release-controlled pharmaceutical composition comprises desvenlafaxine benzoate, one or more release modifier (s) thereof and one or more pharmaceutically acceptable excipient (s), wherein the T _max of the release-controlled composition is Is similar to the T _max of the extended release composition of desvenlafaxine succinate.

As used herein, the term “T _max ” refers to the maximum observed plasma of desvenlafaxine produced by degradation of the release-controlled composition or commercially available Pristiq® (extended release composition of desvenlafaxine succinate) of the present invention. time for concentration).

In another embodiment, the release-controlled pharmaceutical composition comprises desvenlafaxine benzoate, one or more release modifier (s) thereof and one or more pharmaceutically acceptable excipient (s), wherein the T _max of the release-controlled composition is Is less than about 8 hours.

In another embodiment, for the release-controlled composition of desvenlafaxine benzoate, C _max and AUC were similar in ratios of 80% to 125% when administered after high-fat diet and under fasting conditions.

In another embodiment, the release-controlled pharmaceutical composition comprises desvenlafaxine benzoate, one or more release modifier (s) thereof and one or more pharmaceutically acceptable excipient (s), wherein the C _max of the release-controlled composition And AUC is independent of dietary efficacy.

In another embodiment, the release-controlled pharmaceutical composition comprises desvenlafaxine benzoate, one or more release modifier (s) thereof and one or more pharmaceutically acceptable excipient (s), and in a bioavailability study in humans, Pristiq ^® Tablets and bioactivity.

The release-controlled pharmaceutical compositions of the present invention include depression, fibromyalgia syndrome, anxiety disorder, airport disorder, agoraphobia, posttraumatic stress disorder, (including but not limited to major depressive disorder, bipolar disorder and mood modulation) ( Premenstrual dysphoric disorder (also known as premenstrual syndrome), attention deficit disorder (with and without hyperactivity), obsessive-compulsive disorder (including hair growth walls), social anxiety disorder, generalized anxiety disorder, autism, schizophrenia Obesity, anorexia nervosa, anorexia nervosa, zidra Tourette syndrome, vasomotor flushing, cocaine and alcoholism, sexual dysfunction (including premature ejaculation), borderline personality disorder, chronic fatigue syndrome, incontinence, stool incontinence, Incontinence, including but not limited to passive incontinence, reflex incontinence, stress incontinence, urge incontinence, stress incontinence, and incontinence; Treating or preventing central nervous system disorders, including but not limited to pain, Shire Dragger, including but not limited to painful pain, central pain, diabetic neuropathy, and postherpetic neuropathy Can also be used for the prevention of relapse or recurrence of depression; Treatment of cognitive impairment; It can also be used to treat indussion syndrome, Raynaud's syndrome, Parkinson's disease, epilepsy, and other. The compounds and compositions of the present invention can improve cognition in patients suffering from senile dementia, Alzheimer's disease, memory impairment, amnesia and amnesia syndrome; And regimens for stopping smoking or other tobacco use.

Additionally, the compounds and compositions of the present invention can be used to treat hypothalamic amenorrhea in women with and without depression.

The following examples are illustrative of the invention and the examples are not intended to limit the scope of the invention in any way, and these examples and other equivalents thereof are considered in the art in view of the disclosure and the appended claims. It will be apparent to those skilled in the art.

X- RD  Stability study

X-ray diffraction patterns for desvenlafaxine benzoate were measured using an X-ray diffractometer.

The X-RD pattern for desvenlafaxine benzoate is shown in FIG. 1.

Example  One:

step:

1. Aqueous / non-aqueous granulate desvenlafaxine benzoate, hypromellose and dibasic calcium phosphate / MCC using povidone as binder.

2. Dry the granules at 50 ± 5 ° C. until the desired LOD is achieved.

3. Add extragranular part and mix well.

4. Compress the granules using suitable punch tooling.

5. Aqueous / non-aqueous film coating.

Example  2:

step:

1. Aqueous / non-aqueous granulate desvenlafaxine benzoate, hypromellose and dibasic calcium phosphate / MCC using povidone as binder.

2. Dry the granules at 50 ± 5 ° C. until the desired LOD is achieved.

3. Add extragranular parts and mix well.

4. Compress the granules using suitable punch tooling.

5. Non-aqueous coating while constructing 1-10% w / w.

6. Apply aqueous / non-aqueous film coating.

Example  3:

step:

1. Aqueous / non-aqueous granulate desvenlafaxine glutarate / palmitate, hypromellose and dibasic calcium phosphate / MCC using povidone as binder.

2. Dry the granules at 50 ± 5 ° C. until the desired LOD is achieved.

3. Add extragranular parts and mix well.

4. Compress the granules using suitable punch tooling.

5. Aqueous / non-aqueous film coating.

Example  4:

step:

Immediately Emission layer

1. Aqueous / non-aqueous granulate desvenlafaxine benzoate and dibasic calcium phosphate / MCC using povidone as binder.

2. Dry the granules at 50 ± 5 ° C. until the desired LOD is achieved.

3. Add colloidal silicon dioxide and magnesium stearate and mix well.

Sue castle  layer

1. Aqueous / non-aqueous granulation of desvenlafaxine benzoate, dibasic calcium phosphate / MCC using methacrylic acid or ethylcellulose as a sustained release polymer.

2. Dry the granules at 50 ± 5 ° C. until the desired LOD is achieved.

3. Add colloidal silicon dioxide and magnesium stearate and mix well.

4. Compress both layers of immediate release and sustained release parts using suitable punch tooling.

5. Aqueous / non-aqueous film coating.

Example  5:

step:

1. Dry mix desvenlafaxine succinate and hypromellose or xanthan gum.

2. Add the microcrystalline cellulose / dibasic calcium phosphate from step 1 and mix well.

3. Add colloidal silicon dioxide to step 3 and mix well.

4. Lubricate the blend with stearic acid or magnesium stearate.

5. Compress the granules using suitable punch tooling.

6. Apply aqueous / non-aqueous film coating.

Example  6:

step:

1. Aqueous / non-aqueous granulation of desvenlafaxine succinate, hypromellose and dibasic calcium phosphate / MCC using povidone as binder.

2. Dry the granules at 50 ± 5 ° C. until the desired LOD is achieved.

3. Add extragranular parts and mix well.

4. Compress the granules using suitable punch tooling.

5. Non-aqueous coating while constructing 1-10% w / w.

6. Apply aqueous / non-aqueous film coating.

Example  7:

step:

part  A

1. Aqueous / non-aqueous granulate desvenlafaxine succinate and dibasic calcium phosphate / MCC using povidone as binder.

2. Dry the granules at 50 ± 5 ° C. until the desired LOD is achieved.

3. Add colloidal silicon dioxide and magnesium stearate and mix well.

part  B

4. Aqueous / non-aqueous granulation of desvenlafaxine succinate, dibasic calcium phosphate / MCC using methacrylic acid or ethylcellulose as a sustained release polymer.

5. Dry the granules at 50 ± 5 ° C. until the desired LOD is achieved.

6. Add colloidal silicon dioxide and magnesium stearate and mix well.

7. Compress both layers of Part A and Part B parts with appropriate punch tooling.

8. Apply aqueous / non-aqueous film coating.

Example  8:

step:

1. Dry mix desvenlafaxine succinate and ethyl cellulose.

2. Add microcrystalline cellulose / dibasic calcium phosphate to step 1 and mix well.

3. Add colloidal silicon dioxide to step 3 and mix well.

4. Lubricate the blend with stearic acid or magnesium stearate.

5. Compress the granules using suitable punch tooling.

6. Apply aqueous / non-aqueous film coating.

Example  9:

step:

1. Hardening of the sugar spheres is carried out.

2. Mix desvenlafaxine succinate, HPMC, talc & aerosil.

3. Coat the mixture of step 2 on the sugar sphere of step 1 using a DCM / IPA solution to form a drug layer.

4. Release controlled coating of HPMC, ethyl cellulose, talc and triethyl citrate loaded in the drug layer of step 3.

Example  10:

step:

1. Non-aqueous granulate desvenlafaxine benzoate and hypromellose using povidone as binder.

2. Dry the granules at 55 ± 5 ° C. until the desired LOD is achieved.

3. Add extragranular parts and mix well.

4. Compress the granules using suitable punch tooling.

5. Apply aqueous film coating.

Example  11:

step:

1. Non-aqueous granulate desvenlafaxine succinate and hypromellose using povidone as binder.

2. Dry the granules at 55 ± 5 ° C. until the desired LOD is achieved.

3. Add extragranular parts and mix well.

4. Compress the granules using suitable punch tooling.

5. Apply aqueous film coating.

Example  12:

step:

1. Desvenlafaxine succinate, hypromellose, colloidal silicon dioxide, talc and magnesium stearate are compressed in a roller compactor.

2. The granules are sifted and sized to the desired granule size using a comminuting mill.

3. Add extragranular parts and mix well.

4. Compress the granules using suitable punch tooling.

5. Apply aqueous film coating.

Example  13:

step:

1. Desvenlafaxine benzoate, hypromellose, talc and stearic acid are compressed in a roller compactor.

2. Sift the granules to the desired granule size using a committing mill.

3. Add extragranular parts and mix well.

4. Compress the granules using suitable punch tooling.

5. Apply aqueous film coating.

In vitro  Dissolution Research:

Table 1 given below shows the desvenlafaxine benzoate release-controlled tablets of Example 1 of the present invention, which were carried out in 900 ml of 0.9% NaCl in water for 24 hours using a USP-I (Basket) apparatus at a rate of 100 rpm. Dissolution profile is shown. The release profile (cumulative percent of drug released) is shown in Table 1 below.

Time (hours hr )) Example  Cumulative Drug Release for 1% One 20% less than 4 30-50% 8 50-70% 16 More than 75%

Table 2 given below shows the desvenlafaxine succinate release-controlled tablets of Example 5 of the present invention which were carried out in 900 ml of 0.9% NaCl in water for 24 hours using a USP-I (Basket) apparatus at a speed of 100 rpm. Dissolution profile is shown. The release profile (cumulative percent of drug released) is shown in Table 2 below.

Time (hour) Example  Cumulative Drug Release for 5% One 20% less than 4 30-50% 8 50-70% 16 More than 75%

In vivo  Bioavailability Study:

Under fasting conditions, the control product of Example 13 (treatment A) of Philadelphia, PA 19101 of material Wyeth Pharmaceuticals Inc.'s PRISTIQ ^® (des venlafaxine succinate extended release composition of the carbonate) 100 ㎎, and test product (treatment B) Desvenlafaxine benzoate release-controlled tablets formulated according to the open label, balanced, randomized, single-dose, 3-treatment, 3-sequence, 3-period crossover oral bioactivity study (Open Label, Balanced Example 13, administered under fasting (treatment B) and nourishment (treatment C), in a randomized, single-dose, three-treatment, three-sequence, three-period crossover oral bioequivalence study, and healthy adult male subjects Efficacy study of 100 mg of desvenlafaxine benzoate release-controlled tablets formulated according to the invention.

This study was designed to show similar clinical efficacy compared to Pristiq ^® . In vivo bioavailability studies in the fasted state are shown in Table 3 below:

Comparison of pharmacokinetic parameters of Example 13 vs Pristiq ^® 100 mg in the fasted state product name AUC  (0-t)
ng . hr / ml AUC  (0-∞)
ng . hr / ml C _max
ng / Ml T _{max ( hrs )} Desvenlafaxine Benzoate MR Tablets 100 mg 5429.332 6140.836 249.504 5.943 Pristiq 100 mg 5762.351 6096.586 263.630 6.257

conclusion:

Between Treatments A and B, administered under a fasted state Bioactivity :

The 90% confidence interval for the relative geometric mean of C _max , AUC _(0-t) and AUC _(0-∞) was found to be within the limits of 80% to 125%. The formulations according to the basis of the obtained results, Example 13 Des venlafaxine benzoate release-controlled tablet 1OO ㎎ and Philadelphia, PA 19101 of material Wyeth Pharmaceuticals Inc.'s PRISTIQ ^® is (Des venlafaxine succinate extended release composition) 100 mg was shown to be bioactive in healthy human adult male subjects with fasting.

Desvenlafaxine Benzoate  Release-controlled tablets 1 OO  About mg Food  (Treatment B large ( vs C):

When 100 mg of desvenlafaxine benzoate release-controlled tablet was administered with food, it had a slight effect on drug absorption, causing T _max to be postponed approximately 2 hours. For 100 mg of desvenlafaxine benzoate release-controlled tablets, C _max and AUC were similar at 80% to 125% when administered after fasting and fasting. Food is expected to have no significant clinical effect on the uptake of desvenlafaxine from 100 mg of desvenlafaxine benzoate release-controlled tablets (C _max and AUC). Desvenlafaxine benzoate release-controlled tablets 100 mg may be administered regardless of food.

Claims (11)

A modified release pharmaceutical composition comprising Desvenlafaxine Benzoate, one or more release modifier (s) thereof and one or more pharmaceutically acceptable excipient (s). The method of claim 1,
A release-controlled pharmaceutical composition wherein desvenlafaxine benzoate is crystalline. 3. The method of claim 2,
A release-controlled pharmaceutical composition wherein desvenlafaxine benzoate is characterized by a powder X-ray diffraction pattern having at least one peak at about 5.4, 10.75, 16.6, 18.0, 19.2, 23.32 ± 0.2 ° 2θ. 3. The method of claim 2,
A release-controlled pharmaceutical composition wherein desvenlafaxine benzoate is characterized by a powder X-ray diffraction pattern substantially in accordance with FIG. 1. 3. The method of claim 2,
A release-controlled pharmaceutical composition wherein desvenlafaxine benzoate is characterized by a powder X-ray diffraction pattern having peaks at about 5.4, 10.75, 16.6, 18.0, 19.2, 23.32 ± 0.2 ° 2θ. 6. The method of claim 5,
Desvenlafaxine benzoate is characterized by a powder X-ray diffraction pattern with peaks at about 5.4, 9.5, 10.7, 16.1, 16.6, 17.3, 18.0, 19.2, 20.4, 21.5, 23.3, 24.9, 28.3, 29.9 ± 0.2 ° 2θ A tailored, release-controlled pharmaceutical composition. The method of claim 1,
Wherein the d ₅₀ particle size of desvenlafaxine benzoate is from about 5 microns to about 80 microns. The method of claim 1,
A release-controlled pharmaceutical composition that releases about 75% of desvenlafaxine benzoate within 16 hours when the composition is measured using a USP Type I dissolution device at 900 rpm with 0.9% NaCl in water at 100 rpm. The method of claim 1,
A release-controlled pharmaceutical composition wherein desvenlafaxine benzoate is amorphous. A release-controlled pharmaceutical composition comprising desvenlafaxine benzoate, one or more release control agent (s) and one or more pharmaceutically acceptable excipient (s), wherein the C _max and AUC of the release-controlled composition is desvenlafaxine. A release-controlled pharmaceutical composition, which is within the limits of 80% to 125% of the C _max and AUC of the extended release composition of succinate. A release-controlled pharmaceutical composition comprising desvenlafaxine benzoate, one or more release control agent (s) thereof and one or more pharmaceutically acceptable excipient (s), wherein the C _max and AUC of the release-controlled composition are release-controlled pharmaceutical composition, irrespective of food effect).

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