DESC:TECHNICAL FIELD OF THE INVENTION

The invention relates to a solid oral pharmaceutical compositions comprising novel fixed dose combination of pharmaceutically effective amounts of pregabalin and nortriptyline or pharmaceutically acceptable salt thereof. This novel pharmaceutical composition is useful for the treatment of neuropathic pain and related disorders. The present invention also discloses methods of preparing such pharmaceutical compositions.

BACKGROUND OF THE INVENTION
Neuropathic pain results from damage to or dysfunction of the peripheral or central nervous system, rather than stimulation of pain receptors. Neuropathic pain is a complex, chronic pain state that usually is accompanied by tissue injury. Anything that leads to loss of function within the sensory nervous system can cause neuropathic pain. With neuropathic pain, the nerve fibers themselves may be damaged, dysfunctional, or injured.
Neuropathic pain may have continuous and/or episodic (paroxysmal) components. The latter are likened to an electric shock. Common qualities include burning or coldness, "pins and needles" sensations, numbness and itching. Neuropathic pain may result from disorders of the peripheral nervous system or the central nervous system (brain and spinal cord). Thus, neuropathic pain may be divided into peripheral neuropathic pain, central neuropathic pain, or mixed (peripheral and central) neuropathic pain.

Neuropathic pain can be very difficult to treat with only some 40-60% of people achieving partial relief from pain. Currently there is no proven treatment to prevent or cure neuropathic pain (neuropathy or nerve pain). Instead, the primary goals of treatment are to reduce the pain as much as possible, balance the negative side effects of the treatment, and help patients manage any unresolved pain. Hence, various treatment options for neuropathic pain includes use of antidepressants e.g. tricyclics and selective serotonin-norepinephrine reuptake inhibitors, anticonvulsants, especially pregabalin and gabapentin, and topical lidocaine.

Pregabalin is an anticonvulsant drug used for neuropathic pain and as an adjunct therapy for partial seizures with or without secondary generalization in adults. It is also used in neuropathic pain associated with diabetic peripheral neuropathy (DPN); postherpetic neuralgia (PHN); adjunctive therapy for adult patients with partial onset seizures; fibromyalgia; neuropathic pain associated with spinal cord injury.

Pregabalin is described chemically as (S)-3-(aminomethyl)-5-methylhexanoic acid. The molecular formula is C8H17NO2 and the molecular weight is 159.23 gm/mole. The chemical structure of pregabalin is:

Pregabalin binds to the alpha-2-delta (a-2-d) subunit of a calcium channel and is related to the endogenous inhibitory neurotransmitter amino butyric acid (GABA), which is involved in the regulation of brain neuronal activity.

Pregabalin is currently marketed in the United States by PF Prism CV under the trade name Lyrica®, available as 25, 50, 75, 100, 150, 200, 225, and 300 mg hard shell capsules and 20mg/ml oral solution and is administered in patients two or three times daily (BID or TID).

Nortriptyline is a second-generation tricyclic antidepressant (TCA) marketed worldwide as the hydrochloride salt under the trade names Sensoval, Aventyl, Pamelor, Norpress, Allegron, Noritren and Nortrilen. It is used in the treatment of major depression and childhood nocturnal enuresis (bedwetting). In addition, it is sometimes used for chronic illnesses such as chronic fatigue syndrome, chronic pain and migraine, and labile affect in some neurological conditions.

Nortriptyline, the N-demethylated active metabolite of amitriptyline, is a dibenzocycloheptene-derivative and chemically defined as 3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-1-propanamine. Its empirical formula is C19H21N and molecular weight is 263.38 gm/mole and it is represented by the following structural formula:

It is believed that nortriptyline either inhibits the reuptake of the neurotransmitter serotonin at the neuronal membrane or acts at beta-adrenergic receptors.
Nortriptyline is currently marketed in the United States by Mallinckrodt LLC under the trade name PamelorTM, available as Eq 10, 25, 50, and 75 mg base hard shell capsules and is administered in patients as 25 mg three or four times daily.
U.S. Patent No. 6,001,876 and U.S. Patent No. RE 41,920 discloses method of using certain analogs (including pregabalin) of glutamic acid in pain therapy.
U.S. Patent No. 6,197,819 discloses pregabalin and its salt thereof; which is useful in the treatment of seizure disorders.
U.S. Patent No. 5,563,175 and 6,117,906 describes the use of pregabalin in the treatment of seizure disorders and use of pregabalin in treatment of anxiety.
U.S. Patent No. 8,916,610 discloses an acid addition salt of a nortriptyline-GABA conjugate.

U.S. Patent Application No. 20130116215 discloses novel pharmaceutical combinations useful for the treatment of neurological diseases.
PCT Publication No. WO 2011053003 discloses a gastric-retentive sustained release formulation that can be administrated once a day containing pregabalin (50-900mg).
PCT Publication No. WO 2013054285 discloses novel gastro-retentive dosage systems.
PCT Publication No. WO 2010143052 discloses a gastro-retentive tablet comprising pregabalin and one or more water insoluble component.
PCT Publication No. WO 2013114281 discloses a gastro-retentive tablet comprising pregabalin, an acrylic acid polymer, one or more swellable polymers.
PCT Publication No. WO 2013114283 discloses a gastro retentive tablet comprising pregabalin, at least one swellable polymer.
PCT Publication No. WO 2011151708 discloses gastro retentive dosage forms comprising GABA analog, at least one swelling agent.
PCT Publication No. WO 2012035559 discloses stable once daily SR pharmaceutical compositions comprising pregabalin or pharmaceutically acceptable salt thereof.
There are numerous literatures available which suggest gastro-retentive dosage form of pregabalin in sustained release form for the treatment of neuropathic pain, however, there still exists a need to find better options for treating neuropathic pain which may eliminate or reduce side effects that are associated with current monotherapy.
Literature suggests that combining agents acting at the a2d1 subunit of voltage gated calcium channel (gabapentin or pregabalin) with nortriptyline provided better pain relief than monotherapy. (Ref: J. Pain 2011, 12(2): 157-166 and Lancet 2009; 974: 1252-1261).
This invention is related to combined use of gastro-retentive pregabalin in sustained release form and nortriptyline in immediate release form which is not disclosed in the prior art. Hence, there exists a dire need to develop dosage forms of pregabalin and nortriptyline which will provide rapid release of nortriptyline, while rate of release of pregabalin is sustained release with gastro-retentive mechanism.
Hence it is an object of the invention to provide a novel fixed dose combination dosage form of pregabalin and nortriptyline or pharmaceutically acceptable salt thereof, which will be useful for the treatment of neuropathic pain of various types as mentioned above.
It is an object of the invention to provide an improved solid pharmaceutical composition comprising gastro-retentive pregabalin or pharmaceutically acceptable salts thereof in sustained release dosage form and nortriptyline in immediate release form which will provide better therapeutic effect.
The invention also provides process for preparing fixed dose pharmaceutical composition comprising pharmaceutically effective amounts of nortriptyline or pharmaceutically acceptable salt thereof and pregabalin or pharmaceutically acceptable salt thereof.
The inventors of this invention have surprisingly found that by formulating the fixed dose combination of nortriptyline and pregabalin in particular structure, a composition providing coordinated drug release can be obtained.
In particular, the inventors have found that when the composition comprises one or multiple pregabalin compartments exhibiting immediate and/or sustained release, and nortriptyline compartment exhibiting immediate release, the aforesaid objective can be achieved.
SUMMARY OF THE INVENTION
In one general aspect, there is provided a pharmaceutical composition comprising combination of nortriptyline and pregabalin or pharmaceutically acceptable salt or solvate thereof.

In another general aspect, there is provided a pharmaceutical composition comprising combination of
(a) nortriptyline or pharmaceutically acceptable salt thereof;
(b) pregabalin or pharmaceutically acceptable salt thereof; and
(c) at least one or more pharmaceutically acceptable excipients.

In another general aspect, there is provided a solid oral pharmaceutical composition comprising nortriptyline or pharmaceutically acceptable salt thereof and pregabalin or pharmaceutically acceptable salt thereof, wherein pregabalin is in sustained release form and nortriptyline is in immediate release form.

In another general aspect there is provided a pharmaceutical composition comprising:
a) first component comprising nortriptyline or pharmaceutically acceptable salt thereof and one or more pharmaceutical excipients;
b) second component comprising pregabalin or pharmaceutically acceptable salt thereof and one or more pharmaceutical excipients;
c) Optionally first and second components are coated with suitable coating material, wherein first component exhibits immediate release of active and second component exhibits sustained release

In another general aspect, the solid oral pharmaceutical composition is in the form of a bilayer tablet or a trilayer tablet or a multilayer tablet.

In another general aspect, there is provided a bilayer tablet comprising at least one layer of nortriptyline or pharmaceutically acceptable salt thereof exhibiting immediate release, at least one layer of pregabalin or pharmaceutically acceptable salt thereof exhibiting gastro-retentive sustained release, wherein the tablet is coated with moisture barrier coating.

In another general aspect there is provided an oral pharmaceutical composition comprising nortriptyline and pregabalin or pharmaceutically acceptable salt thereof, wherein the amount of pregabalin or pharmaceutically acceptable salt thereof present in the composition is from about 2% w/w to about 30% w/w of the total weight of the composition and amount of nortriptyline or pharmaceutically acceptable salt thereof present in the composition is from about 0.5% w/w to about 15% w/w of the total weight of the composition.

In another general aspect there is provided a pharmaceutical composition comprising:
a) first component comprising 11.46mg of nortriptyline or pharmaceutically acceptable salt thereof;
b) second component comprising 50mg of pregabalin or pharmaceutically acceptable salt thereof;
c) Optionally first and second components are coated with suitable coating material, wherein first component exhibits immediate release of active and second component exhibits gastro-retentive sustained release of active.

In another general aspect, there is provided a pharmaceutical composition comprising:
a) first component comprising 11.46mg of nortriptyline or pharmaceutically acceptable salt thereof;
b) second component comprising 50mg of pregabalin or pharmaceutically acceptable salt thereof; 85mg of sodium bicarbonate;
c) Optionally first and second components are coated with suitable coating material, wherein first component exhibits immediate release of active and second component exhibits gastro-retentive sustained release of active.

In another general aspect, there is provided a pharmaceutical composition comprising:
a) first component comprising 11.46mg of nortriptyline or pharmaceutically acceptable salt thereof; 10mg crosspovidone;
b) second component comprising 50mg of pregabalin or pharmaceutically acceptable salt thereof; 85mg of sodium bicarbonate;
c) Optionally first and second components are coated with suitable coating material, wherein first component exhibits immediate release of active and second component exhibits gastro-retentive sustained release of active.

In another general aspect, there is provided a pharmaceutical composition comprising:
a) 11.46mg of nortriptyline or pharmaceutically acceptable salt thereof in immediate release part;
b) 50mg of pregabalin or pharmaceutically acceptable salt thereof in gastro-retentive sustained release part;
c) 85mg of sodium bicarbonate;
d Optionally one or more coating layer.

In another general aspect, there is provided a process for the preparation of pharmaceutical composition comprising:
a) first component comprising nortriptyline or pharmaceutically acceptable salt thereof and one or more pharmaceutical excipients;
b) second component comprising pregabalin or pharmaceutically acceptable salt thereof and one or more pharmaceutical excipients;
c) Optionally first and second components are coated with suitable coating material.

In another general aspect, there is provided a process of preparing solid pharmaceutical composition comprising steps of:
a) mixing of nortriptyline or pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients;
b) mixing of Polyvinyl Pyrrolidine in to suitable solvent;
c) granulation of material obtained in step (a) with binder solution obtained in step
(b); and drying, sifting and lubrication;
d) compression of material obtained in step (c) to get immediate release component;
e) mixing of pregabalin or pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients;
f) granulation of material obtained in step (e) with binder solution obtained in step
(b); and then drying, sifting and lubrication;
g) compression of material obtained in step (f) to get sustained release component;
h) compression of component obtained in step (d) or step (g) to get bilayer tablet dosage form.
In another general aspect, there is provided a process of preparing solid pharmaceutical composition comprising steps of:
a) mixing of nortriptyline or pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients;
b) mixing of Polyvinyl Pyrrolidine in to suitable solvent;
c) granulation of material obtained in step (a) with binder solution obtained in step
(b); and drying, sifting and lubrication;
d) compression of material obtained in step (c) to get immediate release component;
e) mixing of pregabalin or pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients;
f) granulation of material obtained in step (e) with binder solution obtained in step
(b); and then drying, sifting and lubrication;
g) compression of material obtained in step (f) to get sustained release component;
h) compression of component obtained in step (d) or step (g) to get bilayer tablet dosage form;
i) optionally one or more coating layer applied over bilayer tablet obtained in step (h)

In another general aspect, there is provided a process of preparing solid pharmaceutical composition comprising steps of:
a) mixing of nortriptyline or pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients;
b) mixing of Polyvinyl Pyrrolidine in to suitable solvent;
c) granulation of material obtained in step (a) with binder solution obtained in step (b); and drying, sifting and lubrication;
d) compression of material obtained in step (c) to get immediate release component;
e) mixing of pregabalin or pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients;
f) granulation of material obtained in step (e) with binder solution obtained in step (b); and then drying, sifting and lubrication;
g) compression of material obtained in step (f) to get sustained release component;
h) coating of component obtained in step (d) or step (g) which further filled in to capsule to get capsule dosage form.

The compositions of the invention can be prepared together with at least one pharmaceutically acceptable excipient or as oral, parental, inhalation dosage forms comprising the active agent(s).

In another general aspect there is provided a solid oral pharmaceutical composition is in the form of a bilayer tablet or a trilayer tablet or a multilayer tablet.

In another general aspect, there is provided a method of treating neuropathic pain and related disorders which method comprises of administering the pharmaceutical composition comprising nortriptyline and pregabalin or pharmaceutically acceptable salt thereof, to a patient in need thereof.

A characteristic of the invention is that said composition is prepared in a gastro-retentive solid oral dosage form. The preferred solid oral dosage forms of the invention can be tablet, film-coated tablet, controlled-release tablet, bilayer tablet; effervescent tablet, moisture coated tablet, enteric-coated tablet forms or combinations thereof.

DETAILED DESCRIPTION OF THE INVENTION
The term “nortriptyline” and “pregabalin” used throughout the specification refers to not only their base per se, but also their other pharmaceutically acceptable salt, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof.

As used herein, the term “immediate release” refers to the release of more than 80% drug within a short time period following administration, e.g., generally within a few minutes to about 1 hour.

As used herein, the term “sustained release” refers to a pharmaceutical composition which release active over a specific period of time that conforms to a particular pattern of release to effect a therapeutic outcome. The period of time may include, but is not limited to, hours, days.

As used herein, the term “gastro-retentive” refers to dosage forms with delayed gastric emptying as compared to food (or retention in the stomach beyond the retention of food).

As used herein, the term "treatment" refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder.

Pharmaceutical excipients that can be used in the pharmaceutical composition of the present invention can be selected from a group comprising one or more binding agents (binders), disintegrants, lubricants, one or more diluents, glidants, wetting agents, coating agents, anti-adhesive agents, swelling agent, viscosity enhancing agents, filling agents, drying agents, rate controlling polymer agent, surfactants, co-solvents, acidifier, alkaliser, stabilizing agents, pH regulators, flavouring agent, sweeteners, emulgators, antifoaming agents, antioxidants, protective agents, solvents or solvent combinations, colouring agents and complexing agents or the combinations thereof.

The disintegrants that can be used in the pharmaceutical compositions of the present invention can be selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch, sodium starch glycolate or combinations thereof.

The binders that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminum silicate, maltodextrin, methyl cellulose, povidone, co-povidone, starch or combinations thereof.

The diluents that can be used in the pharmaceutical compositions according to the present invention can be selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch and starch derivatives, sodium chloride, sucrose, talc, xylitol or the combinations thereof.

The lubricants that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulphate, talc, stearic acid, zinc stearate or combinations thereof.

The glidants that can be used in the pharmaceutical compositions according to the present invention can be selected from but not limited to colloidal silicon dioxide, calcium silicate, magnesium silicate, silicon hydrogel, magnesium trisilicate, corn starch, talc and the like or combinations thereof.

The alkaliser that can be used in the pharmaceutical compositions according to the present invention can be selected from but not limited to sodium silicate, sodium metasilicate, sodium bicarbonate, potassium hydrogen carbonate, ammonium carbonate, ammonium hydrogen carbonate and sodium hydrogen carbonate and mixtures thereof.

The acidifier that can be used in the pharmaceutical compositions according to the present invention can be selected from but not limited to hydrochloric acid, sodium citrate, citric acid, ascorbic acid, lactic acid, acetic acid, malic acid, tartaric acid, gluconic acid and mixtures thereof.

The swelling agent that can be used in the pharmaceutical compositions according to the present invention can be selected from but not limited to cross-linked polyvinylpyrrolidone, sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, croscarmellose sodium (e.g., Ac-Di-Sol), starches and derivatives, cellulose and derivatives, microcrystalline celluloses, such as AvicelTM PH 101 or AvicelTM CE-15 (a microcrystalline modified with guar gum), methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose (Pharmacoat, Methocel E (propylene glycol ether of methyl cellulose)), alginic acid and their salts (Na--, Ca-- salt, also mixtures of sodium alginate and calcium salts such as CaHPO4), starch, carboxymethyl starch, carboxymethyl cellulose and their salts (e.g. Na-- salts), galactomannan, gum arabic, karaya rubber, ghatti gum, agar-agar, carrageen, xanthan rubber, guar rubber and its derivatives, carob bean flour, propylene glycol alginate, pectin, tragacanth and mixtures thereof.

The rate controlling polymer that can be used in the pharmaceutical compositions according to the present invention can be selected from but not limited to POLYOX 303, polymer derived from acrylic or methacrylic acid and esters or copolymers derived from acrylic or methacrylic acid, hydroxypropylcellulose and hydroxypropylmethylcellulose; poly(ethylene) oxide; alkyl cellulose such as ethyl cellulose and methyl cellulose; carboxymethyl cellulose, hydrophilic cellulose derivatives; polyethylene glycol; polyvinylpyrrolidone; cellulose acetate; cellulose acetate butyrate; cellulose acetate phthalate; cellulose acetate trimellitate; polyvinyl acetate phthalate; hydroxypropylmethylcellulose phthalate; hydroxypropylmethylcellulose acetate succinate; polyvinyl acetaldiethylamino acetate; poly(alkylmethacrylate) and poly (vinyl acetate). Other suitable hydrophobic polymers include polymers and/or copolymers derived from acrylic or methacrylic acid and their respective esters, zein, waxes, shellac and hydrogenated vegetable oils and mixtures thereof.

The coloring agent that can be used in the pharmaceutical compositions according to the present invention can be selected from but not limited to tar dye, caramel, red iron oxide, titanium oxide, riboflavins, iron oxide yellow, edible pigments such as edible Yellow No. 5, edible Red No. 2, and edible Blue No. 2; edible lake pigments and mixtures thereof.

The solid dosage forms of the invention can be coated with coatings such as protective coating, enteric-coating, moisture barrier coating, film-coating and/or those designed to provide various release properties (such as fast-release, slow-release, controlled-release) afterwards. In the case that active agents are prepared in separate dosage forms, coatings with the same or different properties can be used in said dosage forms.

The film-coating agents that can be used within the scope of the invention can be selected from a group comprising cellulose derivatives such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose or a mixture of hydroxypropylcellulose and/or hydroxypropylmethylcellulose containing titanium dioxide and/or other coloring agents, such as iron oxides, dyes, and lakes; a mixture of polyvinyl alcohol (PVA) and polyethylene glycol (PEG) containing titanium dioxide and/or other coloring agents, such as iron oxides, dyes, and lakes; or any other suitable immediate-release film-coating agent(s). The film coating may also further contain non-aqueous solvent such as alcohol and dichloromethane or combinations thereof. A commercial film-coat is Insta Moist shield, which is a HPMC based ready-to-use tablet coating system with dual choice of organic and hydro alcoholic solvent system.
The pharmaceutical compositions of the invention are prepared by wet or dry processing methods. In general aspect of the invention the pharmaceutical compositions are prepared by wet processing methods. In a class of this aspect the pharmaceutical compositions are prepared by wet granulation methods. With wet granulation either high-shear granulation or fluid-bed granulation may be used. In this aspect fluid-bed granulation is employed which has the advantage of affording tablets with higher diametric strength.

In one embodiment, the pharmaceutical compositions are prepared by dry processing methods. In a class of this aspect the pharmaceutical compositions are prepared by direct compression or dry granulation methods. Dry granulation is done by using roller compaction.

The pharmaceutical compositions obtained by the dry or wet processing methods may be compressed into tablets, encapsulated, or metered into sachets.

The pharmaceutical tablet compositions of the invention may also contain one or more additional formulation ingredients selected from a wide variety of excipients known in the pharmaceutical formulation art. According to the desired properties of the pharmaceutical composition, any number of ingredients may be selected, alone or in combination, based upon their known uses in preparing tablet compositions. Such ingredients include, but are not limited to diluents, compression aids, glidants, disintegrants, lubricants, flavors, flavor enhancers, sweeteners, and preservatives.

The term "tablet" as used herein is intended to encompass compressed pharmaceutical dosage formulations of all shapes and sizes, whether coated or uncoated.

In one embodiment, a pharmaceutical composition comprises combination of nortriptyline or pharmaceutically acceptable salt thereof in amount ranging from about 2 mg to 50 mg and pregabalin or pharmaceutically acceptable salt thereof in amount ranging from about 10 mg to 400 mg.

In another embodiment the pharmaceutical compositions of the present invention are in the dosage form of a tablet, and in particular, moisture coated bilayer tablet.

In another embodiment the amount of nortriptyline present in the pharmaceutical composition may ranges from about 0.5% w/w to about 15% w/w of the total weight of the composition and the amount of pregabalin present in the pharmaceutical composition may ranges from about 2% w/w to about 30 % w/w of the total weight of the composition.

In another embodiment there is provided a pharmaceutical composition; wherein the ratio of the amount of nortriptyline or pharmaceutically acceptable salt thereof to pregabalin or pharmaceutically acceptable salt thereof ranges from about 1:1 to about 1:10.

In another embodiment the pharmaceutical composition comprising combination of nortriptyline or pharmaceutically acceptable salt thereof and pregabalin or pharmaceutically acceptable salt thereof which composition retains at least 90% by weight of the total content of nortriptyline or pharmaceutically acceptable salt thereof and pregabalin or pharmaceutically acceptable salt thereof when stored at 40°C and 75% relative humidity over a period of at least 6 months.

In another embodiment, there is provided a method of treating neuropathic pain and related disorders which method comprises of administering the pharmaceutical composition comprising fixed dose combination of the invention.

Suitable pharmacologically acceptable salt of active are in particular water-soluble and water-insoluble acid addition salt with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)-benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 1-hydroxy-2-naphthoic acid, the acids being employed in salt preparation - depending on whether it is a mono- or polybasic acid and depending on which salt is desired -in an equimolar quantitative ratio or one differing therefrom.

The term ‘combination’ as used throughout the specification refers to a single dosage form comprising nortriptyline and pregabalin together. The term also encompasses kit comprising separate dosage forms of nortriptyline and pregabalin which are intended to be administered together, simultaneously or sequentially for the purpose of prophylaxis or treatment.

The dose of each of nortriptyline and pregabalin in the combination composition in accordance with the invention may be selected based on particular patient need, however, particularly preferred dose of nortriptyline and pregabalin in the composition ranges from about 2 mg to about 50 mg and about 10 mg to about 400 mg respectively.

In a further embodiment, the amount of nortriptyline present in the composition ranges from about 0.5% w/w to about 15% w/w of the total weight of the composition, and the amount of pregabalin present in the composition may ranges from about 2% w/w to about 30% w/w of the total weight of the composition.

In one embodiment of the invention, the pharmaceutical compositions contain about 1% w/w to about 5% w/w by weight of a nortriptyline as one of the two pharmaceutically active ingredients; about 5% w/w to about 25% w/w by weight of pregabalin the second pharmaceutically active ingredient; about 0.5 to 10% by weight of a binding agent; and about 0.25 to 5% by weight of a lubricant.

In another embodiment, a pharmaceutical composition comprising:
a) first component comprising nortriptyline or pharmaceutically acceptable salt thereof and one or more pharmaceutical excipients;
b) second component comprising pregabalin or pharmaceutically acceptable salt thereof and one or more pharmaceutical excipients;
c) Optionally first and second components are coated with suitable coating material.

In another embodiment a pharmaceutical composition comprising:
a) first component comprising nortriptyline or pharmaceutically acceptable salt thereof and one or more pharmaceutical excipients;
b) second component comprising pregabalin or pharmaceutically acceptable salt thereof and one or more pharmaceutical excipients;
c) Optionally first and second components are coated with suitable coating material, wherein first component exhibits immediate release of active and second component exhibits sustained release.

In another embodiment a process for the preparation of pharmaceutical composition comprising:
a) first component comprising nortriptyline or pharmaceutically acceptable salt thereof and one or more pharmaceutical excipients;
b) second component comprising pregabalin or pharmaceutically acceptable salt thereof and one or more pharmaceutical excipients;
c) Optionally first and second components are coated with suitable coating material, wherein first component exhibits immediate release of active and second component exhibits sustained release.

In another embodiment a process of preparing solid pharmaceutical composition comprising steps of:
a) mixing of nortriptyline or pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients;
b) mixing of Polyvinyl Pyrrolidine in to suitable solvent;
c) granulation of material obtained in step (a) with binder solution obtained in step
(b); and drying, sifting and lubrication;
d) compression of material obtained in step (c) to get immediate release component;
e) mixing of pregabalin or pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients;
f) granulation of material obtained in step (e) with binder solution obtained in step (b); and then drying, sifting and lubrication;
g) compression of material obtained in step (f) to get sustained release component;
h) compression of component obtained in step (d) or step (g) to get bilayer tablet dosage form.

In another embodiment a process of preparing solid pharmaceutical composition comprising steps of:
a) mixing of nortriptyline or pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients;
b) mixing of Polyvinyl Pyrrolidine in to suitable solvent;
c) granulation of material obtained in step (a) with binder solution obtained in step (b); and drying, sifting and lubrication;
d) compression of material obtained in step (c) to get immediate release component;
e) mixing of pregabalin or pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients;
f) granulation of material obtained in step (e) with binder solution obtained in step (b); and then drying, sifting and lubrication;
g) compression of material obtained in step (f) to get sustained release component;
h) compression of component obtained in step (d) or step (g) to get bilayer tablet dosage form;
i) optionally one or more coating layer applied over bilayer tablet obtained in step (h)

In another embodiment a process of preparing solid pharmaceutical composition comprising steps of:
a) mixing of nortriptyline or pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients;
b) mixing of Polyvinyl Pyrrolidine in to suitable solvent;
c) granulation of material obtained in step (a) with binder solution obtained in step
(b); and drying, sifting and lubrication;
d) compression of material obtained in step (c) to get immediate release component;
e) mixing of pregabalin or pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients;
f) granulation of material obtained in step (e) with binder solution obtained in step (b); and then drying, sifting and lubrication;
g) compression of material obtained in step (f) to get sustained release component;
h) coating of component obtained in step (d) or step (g) which further filled in to capsule to get capsule dosage form.

In another embodiment a pharmaceutical composition comprising:
a) first component comprising 11.46mg of nortriptyline or pharmaceutically acceptable salt thereof;
b) second component comprising 50mg of pregabalin or pharmaceutically acceptable salt thereof;
c) Optionally first and second components are coated with suitable coating material, wherein first component exhibits immediate release of active and second component exhibits gastro-retentive sustained release of active.

In another embodiment a pharmaceutical composition comprising:
a) first component comprising 11.46mg of nortriptyline or pharmaceutically acceptable salt thereof;
b) second component comprising 50mg of pregabalin or pharmaceutically acceptable salt thereof; 85mg of sodium bicarbonate;
c) Optionally first and second components are coated with suitable coating material, wherein first component exhibits immediate release of active and second component exhibits gastro-retentive sustained release of active.

In another embodiment a pharmaceutical composition comprising:
a) first component comprising 11.46mg of nortriptyline or pharmaceutically acceptable salt thereof; 10mg crosspovidone;
b) second component comprising 50mg of pregabalin or pharmaceutically acceptable salt thereof; 85mg of sodium bicarbonate;
c) Optionally first and second components are coated with suitable coating material, wherein first component exhibits immediate release of active and second component exhibits gastro-retentive sustained release of active.

In another embodiment a pharmaceutical composition comprising:
a) 11.46mg of nortriptyline or pharmaceutically acceptable salt thereof in immediate release part;
b) 50mg of pregabalin or pharmaceutically acceptable salt thereof in gastro-retentive sustained release part;
c) 85mg of sodium bicarbonate;
d) Optionally one or more coating layer.

In another embodiment, the pharmaceutical compositions of the invention may be prepared in the form of a tablet; layered tablet; capsule; enterically coated or modified release tablets; controlled release tablet; prolonged release tablet; delayed release tablet; slow or fast release tablet; fast soluble tablet; fast soluble powder mixture; water soluble powder, tablet, or granule; granule; pellet; mini tablet; micro tablet; granule in capsule; pellet in capsule; mini tablet in capsule; micro tablet in capsule or dry powder mixture to prepare syrup; film coated tablet or a combination thereof.

The present invention is further illustrated by the following example which is provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES
Example 1: Pharmaceutical composition comprising Nortriptyline 10mg and Pregabalin 50mg
Table 1
Sr. No. Ingredients % Mg/tab
Nortriptyline 10mg IR layer
Intragranular
1 Nortryptyline HCl 2.25 11.46
2 Microcrystalline Cellulose 18.30 93.34
3 Crosspovidone 1.96 10.00
4 Colloidal Silicone Dioxide 0.29 1.50
Binder
5 Polyvinyl Pyrrolidine 1.37 7.00
6 IPA
Extragranular
7 Micro crystalline Cellulose 2.94 15.00
8 Crosspovidone 1.57 8.00
9 Iron oxide yellow 0.04 0.20
10 Colloidal Silicone Dioxide 0.29 1.50
11 Magnesium Stearate 0.39 2.00
Total weight of IR layer 150.00
Pregabalin 50mg SR layer
Intragranular
12 Pregabalin 9.80 50.00
13 Microcrystalline Cellulose 3.9 20.00
14 Hydroxypropyl methylcellulose NF (Methocel K15M Premium CR) 6.66 34.00
15 Hydroxypropyl methyl cellulose NF (Methocel K100M Premium CR) 1.94 10.00
Binder
16 Polyvinyl Pyrrolidine 3.1 16.00
17 IPA q.s
Extragranular
18 Hydroxypropyl methylcellulose NF (Methocel K15M Premium CR) 6.66 34.00
19 Hydroxypropyl methyl cellulose NF (Methocel K100M Premium CR) 1.94 10.00
20 Sodium Bicarbonate IP 16.5 85.00
21 Microcrystalline Cellulose IP
(Chemicel PH-112) 16.5 85.00
22 Iron Oxide Yellow IH 0.12 0.62
24 Magnesium Stearate 0.97 5.00
Total weight of SR layer 350.00
25 Instamoist Shield Yellow IH (A21D00908) 2.91 15.00
26 Isopropyl Alcohol q.s q.s
27 Dichloromethane q.s q.s
Total weight of tablet 100.00 515.00

Example 2: Pharmaceutical composition comprising Nortriptyline and Pregabalin
Table 2
Sr. No. Ingredients Quantity
Mg/tab
Nortriptyline IR layer
Intragranular
1 Nortryptyline HCl 8-15
2 Microcrystalline Cellulose 80-110
3 Crosspovidone 8-12
4 Colloidal Silicone Dioxide 0.8-2.3
Binder
5 Polyvinyl Pyrrolidine 5-10
6 IPA q.s.
Extragranular
7 Micro crystalline Cellulose 13-18
8 Crosspovidone 6-10
9 Iron oxide yellow 0.1-0.4
10 Colloidal Silicone Dioxide 1.2-2
11 Magnesium Stearate 1.5
Total weight of IR layer 120-180
Pregabalin SR layer
Intragranular
12 Pregabalin 40-60
13 Microcrystalline Cellulose 10-30
14 Hydroxypropyl methylcellulose NF (Methocel K15M Premium CR) 25-50
15 Hydroxypropyl methyl cellulose NF (Methocel K100M Premium CR) 5-15
Binder
16 Polyvinyl Pyrrolidine 10-20
17 IPA q.s.
Extragranular
18 Hydroxypropyl methylcellulose NF (Methocel K15M Premium CR) 25-50
19 Hydroxypropyl methyl cellulose NF (Methocel K100M Premium CR) 5-15
20 Sodium Bicarbonate IP 75-90
21 Microcrystalline Cellulose IP
(Chemicel PH-112) 75-90
22 Iron Oxide Yellow IH 0.2-1
24 Magnesium Stearate 1-8
Total weight of SR layer
25 Instamoist Shield Yellow IH (A21D00908) 7-20
26 Isopropyl Alcohol q.s.
27 Dichloromethane q.s.
Total weight of tablet 450-550

Procedure:
I. Nortriptyline IR Layer 10mg:
1. All ingredients were dispensed as per formula
2. All Intragranular materials were sifted through sieve ASTM No. 40 and transferred to a suitable RMG bowl.
3. Binder prepared by addition of Povidone to IPA under stirring.
4. Step 2 material is granulated using Step 3 material.
5. Above granulated material is dried using FBD.
6. Dried material is passed through sieve ASTM No. 25.
7. Extragranular material compensated as per practical yield.
8. Except magnesium Stearate all Extragranular materials were sifted through sieve ASTM No.40
9. Step 8.0 and 6.0 materials were mixed and blended for 10mins using double cone blender.
10. Magnesium Stearate is passed through sieve ASTM No. 60 lubricated for 3.0mins.
II. Pregabalin SR layer 50mg:
11. All ingredients were dispensed as per formula
12. All Intragranular materials were sifted through sieve ASTM No. 40 and transferred to a suitable RMG bowl.
13. Binder prepared by addition of Povidone to IPA under stirring.
14. Step 12 material is granulated using Step 13 material.
15. Above granulated material is dried using FBD.
16. Dried material is passed through sieve ASTM No. 25.
17. Extragranular material compensated as per practical yield.
18. Except magnesium Stearate all Extragranular materials were sifted through sieve ASTM No.40
19. While mixing of the Sodium bicarbonate care should be taken that the Relative humidity of the area should be NMT35%
20. Step 18 and 16 materials were mixed and blended for 10mins using double cone blender.
21. Magnesium Stearate is passed through sieve ASTM No. 60 lubricated for 3.0mins.
Compression:
22. Step 21 & Step 10 derived materials were compressed by using a suitable bilayer compression machine for desired thickness and hardness.
23. Necessary care should be taken to avoid layer mixing.
Coating:
24. Instacoat Moist shield white was added to IPA under stirring, to it add Dichloromethane continue stirring for 30mins
25. Core tablets were coated using a suitable Autocoater till 2.0% weight gain achieves.

Table 3: Dissolution profile of Nortriptyline of example-1

Time (Min) % Drug Dissolved
10 95
20 98
30 98
45 98
60 99

Table 4: Dissolution Profile of Pregabalin of example-1

Time (hr) % Drug Dissolved
1 35
2 46
4 62
6 73
8 82
10 89
12 93

,CLAIMS:1. A pharmaceutical composition comprising:
a) first component comprising nortriptyline or pharmaceutically acceptable salt thereof and one or more pharmaceutical excipients;
b) second component comprising pregabalin or pharmaceutically acceptable salt thereof and one or more pharmaceutical excipients;
c) Optionally first and second components are coated with suitable coating material.

2. A pharmaceutical composition comprising:
a) first component comprising nortriptyline or pharmaceutically acceptable salt thereof and one or more pharmaceutical excipients;
b) second component comprising pregabalin or pharmaceutically acceptable salt thereof and one or more pharmaceutical excipients;
c) Optionally first and second components are coated with suitable coating material, wherein first component exhibits immediate release of active and second component exhibits sustained release;

3. A pharmaceutical composition comprising:
a) first component comprising 11.46mg of nortriptyline or pharmaceutically acceptable salt thereof;
b) second component comprising 50mg of pregabalin or pharmaceutically acceptable salt thereof;
c) Optionally first and second components are coated with suitable coating material, wherein first component exhibits immediate release of active and second component exhibits gastro-retentive sustained release of active.

4. A pharmaceutical composition comprising:
a) first component comprising 11.46mg of nortriptyline or pharmaceutically acceptable salt thereof;
b) second component comprising 50mg of pregabalin or pharmaceutically acceptable salt thereof; 85mg of sodium bicarbonate;
c) Optionally first and second components are coated with suitable coating material, wherein first component exhibits immediate release of active and second component exhibits gastro-retentive sustained release of active.

5. A pharmaceutical composition comprising:
a) first component comprising 11.46mg of nortriptyline or pharmaceutically acceptable salt thereof; 10mg crosspovidone;
b) second component comprising 50mg of pregabalin or pharmaceutically acceptable salt thereof; 85mg of sodium bicarbonate;
c) Optionally first and second components are coated with suitable coating material, wherein first component exhibits immediate release of active and second component exhibits gastro-retentive sustained release of active.

6. A pharmaceutical composition comprising:
a) 11.46mg of nortriptyline or pharmaceutically acceptable salt thereof in immediate release part;
b) 50mg of pregabalin or pharmaceutically acceptable salt thereof in gastro-retentive sustained release part;
c) 85mg of sodium bicarbonate;
d) Optionally one or more coating layer.

7. The pharmaceutical composition of claim 1 or 2; wherein the amount of nortriptyline present in the composition ranges from about 0.5% w/w to about 15% w/w of the total weight of the composition, and the amount of pregabalin present in the composition ranges from about 2% w/w to about 30% w/w of the total weight of the composition.

8. The pharmaceutical composition of claim 1 or 2, wherein the solid oral pharmaceutical composition is in the form of a bilayer tablet or a trilayer tablet or a multilayer tablet.

9. A method of treating neuropathic pain and related disorders which method comprises of administering the pharmaceutical composition of the preceding claim to a patient in need thereof.