WO2018154395A2 - Controlled release pharmaceutical composition of varenicline - Google Patents

Controlled release pharmaceutical composition of varenicline Download PDF

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Publication number
WO2018154395A2
WO2018154395A2 PCT/IB2018/000635 IB2018000635W WO2018154395A2 WO 2018154395 A2 WO2018154395 A2 WO 2018154395A2 IB 2018000635 W IB2018000635 W IB 2018000635W WO 2018154395 A2 WO2018154395 A2 WO 2018154395A2
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Prior art keywords
varenicline
tablet
controlled release
magnesium stearate
layer
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PCT/IB2018/000635
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French (fr)
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WO2018154395A3 (en
Inventor
Jaya Abraham
Tae Kyung Kim
Tae Hee Han
Ji Eun Ahn
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Alvogen Malta Operations (Row) Ltd
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Priority to PCT/IB2018/000635 priority Critical patent/WO2018154395A2/en
Publication of WO2018154395A2 publication Critical patent/WO2018154395A2/en
Publication of WO2018154395A3 publication Critical patent/WO2018154395A3/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806Coating materials
    • A61K9/2833Organic macromolecular compounds
    • A61K9/284Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone

Abstract

The invention refers to tablet form with controlled release of Varenicline, which is used in the pharmacy and medicine and especially to reduce the nicotine addiction, to support the suspension and limit the use of tobacco products. The tablet can be with one-layer or two-layer core which is formed from the active substance Varenicline free base and the excipients mannitol, cellulose powder, magnesium stearate and hydroxypropyl methylcellulose with molecular weight from 100 000 to 200 000. The advantage of the tablet form with controlled release, according to the invention, is its good stability, uniformity of content and good bioavailability, with low amplitude of Cmax and Cmjn and possibility to overcome the side effects from the rapid release of Varenicline as nausea and headache.

Description

CONTROLLED RELEASE PHARMACEUTICAL COMPOSITION OF VARENICLINE

Technical Field

The invention refers to tablet form with controlled release of Varenicline, which is used in the pharmacy and medicine and especially to reduce the nicotine addiction, to support the suspension and limit the use of tobacco products.

Background Art

Varenicline is benzazepine derivative and it is also known as 7, 8, 9, 10- tetrahydro-6,10-methano-6H-pyrazino[2.3-h][3]-benzazepine. It is partial cholinergic agonist. Varenicline and its pharmaceutically acceptable added acidic salts, especially its hydrochloride salt, are described in W09935131. The tartarate, citrate and succinate salt of Varenicline as well as their polymorphic, anhydrous and hydrate forms (WO2002092089, WO02092597 WO03045394) are protected in separate patents. These are actually the pharmaceutically acceptable salts of Varenicline that are used to formulate the market products.

The studies indicates that Varenicline can bind to some of the α4β2 nicotine acetylcholine receptors, acting on the one hand as the nicotine (partial agonist), that alleviated the symptoms of overwhelming desire for smoking and at the same time against the nicotine (as an antagonist), taking its place and thus reduces the feeling of satisfaction from the smoking. (Tashkin, Donald P. (2015). "Smoking Cessation in Chronic Obstructive Pulmonary Disease", Seminars In Respiratory & Critical Care Medicine. 36: 491-507).

The Varenicline is a compound with high efficiency that allows low dosages of use. Such medicinal substances are often formulated with high degree of dilution, which may allow the excipients or even the impurities of excipients to cause significant degradation of the drug during storage ( J.T. Cartestensen, Drug Stability: Principles and Practices, 2 "Ed, Marcel Dekker, NY, 1995, 4449-452; Waterman et al., Pharm Dev. Tech., 2002, 7 (2), 113-146) or variability of the efficacy due to segregation and traction with the equipment during production. Varenicline also has high solubility and low thermal, photo- and oxidative stability, which also create problems in the process of formulating of the pharmaceutical ingredients. Therefore, in formulating, it is necessary to select such combination of excipients that can provide mixture homogeneity for tabletting and appropriate stability of the finished dosage form.

The market product of Varenicline with trade name Chantix® or Champix® is a medicine, which is used for treatment of nicotine addiction. It is presented as film- coated tablets with immediate release, containing of 0.5 mg or 1 mg Varenicline as tartarate salt. The tablet core includes the excepients - microcrystal cellulose, anhydrous calcium hydrogen phosphate, croscarmellose sodium, anhydrous colloidal silicon dioxide and magnesium stearate but its film coating contains hypromellose, titanium dioxide, macrogol and coloring agent. The film coated tablets indicates dissolution profile, where almost 100% of the Varenicline is dissolved after 5 minutes. (Summary of product characteristics and Scientific discussion, EMA)

Patent application WO2006072832 refers to rapidly disintegrating tablet, that falls apart in the oral cavity for less than 3 minutes, in the composition of which the active substance Varenicline is in the form of L-tartaric or succinate salt. The excipients are from 70 to 95 weight parts % and are selected from the group mannitol, xylitol, sorbitol, microcrystal cellulose, silicified microcrystal cellulose, cellulosic polymer, HPMC and HPC, pupulan and rapidly solubilising carbohydrates.

The disadvantage of these dosage forms is the accelerated release of the active substance, because it is found that the application of dosage forms with immediate release, consisting of the active substance Varenicline cause, in their application to a high degree, side effects as nausea and vomiting (WO03045437).

WO2009034431 describes the pharmaceutical composition, in which the controlled release of Varenicline tartrate from the tablet core, including excipients as mannitol, microcrystal cellulose and magnesium stearate, is achieved by the osmotic or enteric coating of the tablet core, which coating includes antioxidant, too in quantity from 0,1% to 5%. European patent EP1448235 describes the pharmaceutical compositions with controlled and immediate release, containing tartarate or citrate salt of Varenicline,as well as method for their use to treat the nicotine addiction. The method includes oral use for a period of 1 to 30 days of the dosage form of Varenicline with controlled release, followed by use of the dosage form with immediate release, containing the same active substance. The Varenicline is in quantity of 0,1 to 10 mg in the oral drug forms with immediate and controlled release. The tablet forms with controlled release are matrix, multiparticulates or coated multiparticulates, but their tablet core contains Varenicline L-tartarate salt and the excipients: mannitol, microcrystalline cellulose, dicalcium phosphate and magnesium stearate. The preferred coating consists of a mixture of hydroxypropyl methyl cellulose, titanium dioxide, polyethylene glycol or triacetin, and optionally a colorant. While the dosage form with immediate release contains core, composed of Varenicline and its pharmaceutically acceptable salts and pharmaceutically acceptable excipients in quantity from 77 to 91 %, and the total quantity of the diluting carbs is less than 20 weight %, as its coating is polymeric and contains hydroxypropyl methyl-cellulose (HPMC), titanium dioxide, triacetin or PEG.

WO2009027786 describes the matrix tablet with controlled release, where the release of Varenicline from the tablet form is controlled by combination of the erosion and diffusion processes. The matrix tablet includes from 0,1 to 10 weigh % Varenicline tartarate and from 35 to 70 weigh % water insoluble hydrophilic excipient as microcrystal cellulose, pregelatinized starch or starch for direct compression, from 30 to 60 weigh % water-soluble polymer with high molecular weight as HPMC with molecular weight higher than 10000, from 0-10 weigh % slide-substance, selected from colloidal silicon dioxide and talcum, and from 0,2 to 2 weigh% magnesium stearate. The tablet cores can be prepared by direct extrusion, extrusion or dry granulation.

Possibility to form two-layer tablet is mentioned in the patent, in which one layer is with immediate release but the other - with controlled release, but there is no described particular composition of such tablet form. Assignment of the invention is getting a tablet form with controlled release with good stability, uniformity of content and good bioavailability, with low amplitude of Cmax and Cmin to overcome the side effects from the rapid release of Varenicline as nausea and headache. Disclosure of Invention

The assignment is solved by composition of the tablet form with controlled release, containing Varenicline, where the tablet core is formed from the active substance Varenicline free base and the excipients mannitol, cellulose powder, magnesium stearate and hydroxypropyl methylcellulose with molecular weight from 100 000 to 200 000, and the components of the formed tablet core are in the following quantitative ratios in mg: from 0,5 to 3,0 Varenicline free base, from 87 to 130 mannitol, from 42 to 86 powder cellulose, from 88 to 114 hydroxypropyl methylcellulose and 4,9 magnesium stearate.

The tablet core can be coated with first film - coating layer in quantity 4 mg, consisting hydroxypropyl methylcellulose, triacetin and talcum and second layer film - coating Opadry white 88a180040 in quantity 10 mg.

The hydroxypropyl methylcellulose in the composition of the tablet core manifested predominantly gelling properties and its addition gives the opportunity to maintain the firmness and the uniformity of the pharmaceutical composition. 70% of the magnesium stearate quantity in the composition of the tablet core plays the role of inside ingredient, but the other quantity performs the function of outside ingredient.

In one variant of the execution the core of the tablet form with controlled release with the described above composition of the tablet core, is formed by layer with immediate release and layer with prolonged release, located above it, each of them includes Varenicline free base, mannitol, powder cellulose and 70% of the quantity of the magnesium stearate, and the layer with prolonged release includes also hydroxypropyl methylcellulose and the other part of the magnesium stearate, and the ratio between the layer with immediate release and the layer with prolonged release is from 0,5 : 1 ,5 to 1 ,5: 0,5. The proportion between the layer for immediate release and the layer for prolonged release in the composition of the two-layer core provides an opportunity to control the Dissolution rate of the active component.

A controlled release tablet has the dissolution rate in water between 10% and 50% at 1 hour, between 30% and 85% at 3 hours, and between 50% and 95% at 8 hours when tested according to USP dissolution method apparatus 2.

The tablet form with controlled release according to the invention is obtained according to the dry granulation method. The necessary quantities of Varenicline free base, mannitol and powder cellulose shall be mixed to obtain granule. After that 70% of the necessary quantity magnesium stearate shall be added and the obtained dry mixture is granulated by roller compactor. The obtained granule is transferred to mixer unit where first the necessary quantity hydroxypropyl methylcellulose is added, after that the other quantity magnesium stearate for final mix is added. The obtained mixture is preformed at tablet press. The tablet core is covered by film-coating, containing first film coating layer, consisting hydroxypropyl methylcellulose, triacetin and talcum and second layer film coating Opadry® white 88a180040.

In one variant of the execution, when the tablet core is two-layer, one of the layers is formed from 0,5 to 1 ,5 weight parts from the granule and it builds up the layer for immediate release of the tablet core but the other part of the granule is put into the mixer unit, where it is mixed with the necessary quantity of hydroxypropyl methylcellulose and with the other quantity of magnesium stearate to obtain granule mixture, which forms the layer with prolonged release of the two-layer tablet core. The dry granule and the granule mixture are submitted for preforming at tablet press to obtain two-layer tablet.

The advantage of the tablet form with controlled release, according to the invention, is the obtaining of tablet with good stability, uniformity of content and good bioavailability, with low amplitude of Cmax and Cmin to overcome the side effects from the rapid release of Varenicline as nausea and headache.

Best Mode for Carrying Out the Invention The pharmaceutical composition of the tablet form of Varenicline according to the invention is illustrated with the following examples:

Example 1. Obtaining a monolayer tablet form with controlled release, containing Varenicline free base. Granules with the following composition shall be prepared to obtain tablet form with controlled release:

Figure imgf000007_0001

The granules are obtained by dry mixture of particular quantities Varenicline free base, mannitol and powder cellulose after that magnesium stearate is added to the obtained dry mixture and the mixture is submitted for dry granulation at "Roller compactor". The obtained dry granules are mixed with 88 mg HPMC with molecular weight 100 000, running the function of polymer gelling agent, after that 1 ,5 mg magnesium stearate is added to the mixture. The obtained granule mixture is tabletting at tablet press.

The obtained tablet is covered with film coat, containing first film coating layer of 4 mg Opadry clear 03k19229 and second layer film coat of 10 mg Opadry white 88a180040.

Example 2. Obtaining a monolayer tablet form with controlled release, containing Varenicline free base.

Granules with the following composition shall be prepared to obtain tablet form: Component and Quality Function Quantity in mg Standard per unit

Varenicline free base API 2,0

Mannitol Diluent 130,0

Powder cellulose Filler 42,6

Magnesium Stearate Lubricant 3,4

The granules are obtained according to the method described in Sample 1. The obtained dry granules with immediate release are mixed with 114 mg of HPMC with molecular weight 100 000 after that magnesium stearate is added to the mixture. The obtained granule mixture is preformed at tablet press.

Example 3. Determination of the dissolution profile of the tablets from Sample 1 and Sample 2.

The dissolution profile of film coated tablets from Example 1 and Example 2 is determined according to method II from USP under the following conditions: Dissolution test media - distilled water , 900ml_

Test temperature - 37.0 ± 0.5 °C

Dissolution method - USP Method II (Paddle), 50rpm

The obtained results are listed in Table .

Table 1. Dissolution rate (%) of Varenicline free base

Figure imgf000008_0001
10 90.6 79.7

16 98.4 91.6

22 101.1 96.7

Example 4. Assay of the uniformity and degradation products and impurities in the granules of Example 2.

The obtained granule mixture with composition, described in Sample 2 was tested before submission to the tablet press for preforming, to set the uniformity of the mixture and the samples that are suggested for test were taken in three different points from the total weight of the granule mixture. The results are given in Table 2.

Table 2. Test results for uniformity and presence of degradation products and impurities

Figure imgf000009_0001

*NMV- is specific impurity N-methylvarenicline; **NFV-is specific impurity N-formylvarenicline

Example 5. Obtaining a two-layer tablet form with controlled release, containing Varenicline free base.

The following dry granule and granule mixture have to be prepared to receive two- layer tablet form with controlled release:

A. The dry granules with immediate release are obtained during the use of the following components: Component and Quality Function Quantity in mg Standard per unit

Varenicline free base API 1.0

Mannitol Diluent 43,7

Powder cellulose Filler 42,7

Magnesium Stearate Lubricant 1,7

The granules are obtained by dry mixture of particular quantities Varenicline free base, mannitol and powder cellulose after that magnesium stearate is added to the obtained dry mixture. The mixture is submitted for dry granulation at "Roller compactor" The obtained granule is sifted and used to form the layer with immediate release.

B. The dry granule mixture with prolonged release is obtained during the use of the following components:

Figure imgf000010_0001

The granules are obtained by dry mixture of particular quantities Varenicline free base, mannitol and powder cellulose after that magnesium stearate is added to the obtained dry mixture. The mixture is submitted for dry granulation at "Roller compactor" The obtained granule is sifted and mixed with 88 mg of HPMC with molecular weight 100 000 after that 1 ,5 mg magnesium stearate is added to the mixture. The granule mixture is used to form the layer with prolonged release.

The obtained dry granule and dry granule mixture are submitted for preforming at tablet press to prepare two-layer tablet, where tablet with weight 281 ,7 mg is obtained. The obtained two-layer tablet is covered with Paddry 03K19229 Clear in quantity 4 mg and 10 mg Opadry AMB 88A180040.

Example 6. Obtaining two-layer tablet form with controlled release, containing Varenicline free base.

The following is prepared to obtain tablet form with controlled release:

A. Dry granule to form the layer with immediate release of two-layer tablet with the following composition:

Figure imgf000011_0001

The granules are obtained according to the method described in Example 5, A.

B. Dry granule mixture to form the layer with prolonged release has the following composition:

Figure imgf000011_0002
Powder cellulose Filler 32.0

Magnesium Stearate Lubricant 1.3

The granule is obtained according to the method described in example 5, B. The obtained dry granule is mixed with 88 mg of HPMC with molecular weight 100 000 after that magnesium stearate 1 ,5 mg is added to the mixture. The granule mixture is used to form the layer with prolonged release.

The obtained dry granule and granule mixture are submitted for preforming at tablet press to prepare two-layer tablet, where tablet with weight 281 ,7 mg is obtained. The obtained two-layer tablet is covered with Paddry 03K19229 Clear in quantity 4 mg and 10 mg Opadry AMB 88A180040. Sample 7. Determination of the dissolution profile of the film coated tablets from Example 5 and Example 6.

The dissolution profile of film coated tablets from Example 5 and Example 6 is analyzed according to method II from USP under the following conditions:

Dissolution test media - distilled water, 900mL

Test temperature - 37.0 ± 0.5 °C

Dissolution method - USP Method II (Paddle), 50rpm

The obtained results are listed in Table 2.

Table 3. Dissolution rate (%) of Varenicline free base

Figure imgf000012_0001
10 93,7 95,6

16 98,2 99,4

22 101 ,0 101 ,3

Example 8. Test for stability in the conditions of accelerated aging of the film coated two-layer tablet form with controlled release, containing Varenicline free base.

Firmness test was performed for film coated two-layer tablet form with controlled release, described in Example 5. The accelerated aging in the following conditions: 40°C, 75.0% RH. The test results are listed in Table 4.

Table 4. Accelerated Condition, 40° C/ 75% RH, for 2 month

Figure imgf000013_0001

Claims

Claims
1. Tablet form with controlled release of Varenicline, with tablet core containing water insoluble hydrophilic excipient, HPMC with high molecular weight and magnesium stearate, characterized by the fact that the tablet core contains also mannitol, Varenicline is in the form of free base, the water insoluble hydrophilic excipient is powder cellulose, molecular weight of the HPMC is in the limits from 100 000 to 200 000, and the components of the tablet core are with the following quantitative ratios in mg: from 0,5 to 3,0 Varenicline free base, from 87 to 130 mannitol, from 42 to 86 powder cellulose , from 88 to 114 hydroxypropyl methylcellulose and 4,9 magnesium stearate.
2. Tablet form with controlled release of Varenicline according to Claim 1 , characterized by the fact that the tablet core is formed by immediate release layer and prolonged release layer, located above it, each of them includes Varenicline free base, mannitol, powder cellulose and 70 w/w% from the magnesium stearate, and the prolonged release layer includes also the HPMC and the rest part of the magnesium stearate, and the ratio between the immediate release layer and the prolonged release layer in the tablet core is from 0,5: 1 ,5 to 1 ,5: 0,5.
PCT/IB2018/000635 2018-06-11 2018-06-11 Controlled release pharmaceutical composition of varenicline WO2018154395A2 (en)

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Publication number Priority date Publication date Assignee Title
WO1999035131A1 (en) 1997-12-31 1999-07-15 Pfizer Products Inc. Aryl fused azapolycyclic compounds
WO2002092597A1 (en) 2001-05-14 2002-11-21 Pfizer Products Inc. The citrate salt of 5, 8, 14-triazatetracyclo(10.3.1.0?2,11.04.9¿)-hexadeca-2.(11),3,5,7,9-pentaene and pharmaceutical compositions thereof
WO2002092089A1 (en) 2001-05-14 2002-11-21 Pfizer Products Inc. Tartrate salts of 5,8,14-triazatetracyclo {10.3.1.0?2,11.04,9¿}-hexadeca-2(11),3,5,7,9-pentaene and pharmaceutical compositions thereof
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WO2006072832A1 (en) 2005-01-07 2006-07-13 Pfizer Products Inc. Fast-disintegrating dosage forms of 5,8,14-triazatetracyclo[10.3.1.02,11.04,9]-hexadeca-2(11),3,5,7,9-pentaene
WO2009027786A2 (en) 2007-08-29 2009-03-05 Pfizer Inc. Matrix dosage forms of varenicline
WO2009034431A2 (en) 2007-09-10 2009-03-19 Pfizer Inc. Controlled-release dosage forms for varenicline

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999035131A1 (en) 1997-12-31 1999-07-15 Pfizer Products Inc. Aryl fused azapolycyclic compounds
WO2002092597A1 (en) 2001-05-14 2002-11-21 Pfizer Products Inc. The citrate salt of 5, 8, 14-triazatetracyclo(10.3.1.0?2,11.04.9¿)-hexadeca-2.(11),3,5,7,9-pentaene and pharmaceutical compositions thereof
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WO2009027786A2 (en) 2007-08-29 2009-03-05 Pfizer Inc. Matrix dosage forms of varenicline
WO2009034431A2 (en) 2007-09-10 2009-03-19 Pfizer Inc. Controlled-release dosage forms for varenicline

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Title
J.T. CARTESTENSEN: "Drug Stability: Principles and Practices", 1995, MARCEL DEKKER, pages: 4449 - 452
TASHKIN, DONALD P.: "Smoking Cessation in Chronic Obstructive Pulmonary Disease''", SEMINARS IN RESPIRATORY & CRITICAL CARE MEDICINE, vol. 36, 2015, pages 491 - 507
WATERMAN ET AL., PHARM DEV. TECH., vol. 7, no. 2, 2002, pages 113 - 146

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