WO2006094736A2 - Alfuzosin controlled-release formulations - Google Patents

Alfuzosin controlled-release formulations Download PDF

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Publication number
WO2006094736A2
WO2006094736A2 PCT/EP2006/002021 EP2006002021W WO2006094736A2 WO 2006094736 A2 WO2006094736 A2 WO 2006094736A2 EP 2006002021 W EP2006002021 W EP 2006002021W WO 2006094736 A2 WO2006094736 A2 WO 2006094736A2
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WO
WIPO (PCT)
Prior art keywords
hpmc
composition
alfuzosin
mixture
tablet
Prior art date
Application number
PCT/EP2006/002021
Other languages
French (fr)
Other versions
WO2006094736A3 (en
Inventor
Vittorino Ravelli
Fabrizio Niccolai
Original Assignee
Ph & T S.P.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ph & T S.P.A. filed Critical Ph & T S.P.A.
Publication of WO2006094736A2 publication Critical patent/WO2006094736A2/en
Publication of WO2006094736A3 publication Critical patent/WO2006094736A3/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, 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
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate

Definitions

  • the present invention relates to solid formulations in the form of controlled-release tablets containing alfuzosin, the process for its preparation and use thereof in the treatment of prostate hypertrophy.
  • Alfuzosin hydrochloride
  • alfuzosin and its salts are known to be potent blockers of ⁇ -adrenergic receptors and act selectively on the urinary tract. Since Alfuzosin has a short duration of action, it would be desirable to provide oral pharmaceutical forms allowing for a single daily administration ensuring an effective plasma concentration of active ingredient over 24 hours.
  • Geomatrix ® technology consisting of a three layer- tablet in which alfuzosin is distributed in two layers.
  • a ready-release layer contains a portion of the total alfuzosin
  • a second layer contains the drug residual amount providing a protracted release
  • the third layer acts as a barrier preventing alfuzosin release (EP 938318).
  • This technology which allows to flexibly modulate the kinetics release, has however problems such as high production costs and difficulty in reproducing the release kinetics and therefore the drug plasma levels, which are the result of different mechanisms determined by single sub-components of the formulation.
  • WO 2004/037228 relates to alfuzosin protracted-release formulations in which one or more layers are present, only one of which containing alfuzosin.
  • Other patent applications deal with alfuzosin solid controlled-release formulations which, in most cases, include multiple layers with differential release and various spatial dispositions (see for instance EP 673650 and HU 9903428). DISCLOSURE OF THE INVENTION
  • hydrophilic polymers are hydroxypropyl methylcellulose mixtures. Said compounds form, in the presence of water, a gel whose dissolution/erosion rate decreases with the increase in viscosity. Mixtures of these polymers having different viscosity degrees make it possible to modulate the drug release rate, which is determined by mechanisms of diffusion through the hydrated matrix and progressive dissolution/erosion of the matrix.
  • the tablet of the present invention may contain ingredients which contribute to modulating the active ingredient release, preferably polyvinylpyrrolidone in amounts from 1 to 4% and lactose in amounts from 15 to 25% on the tablet total weight.
  • Polyvinylpyrrolidone allows to maintain a high gradient of drug concentration in solution inside the hydrated matrix. Lactose, thanks to its high water solubility, promotes the rapid entry of water or digestive liquids inside the tablet, providing the rapid hydration of the core and therefore the formation of a gradient of drug concentration among non-hydrated matrix, hydrated matrix and surrounding environment.
  • the tablets are coated with a water-insoluble, film-forming polymer, preferably ethylcellulose (e.g. NlO and NlOO) and poly-methylmethacrylates (e.g. Eudragit RS) in a quantity ranging from 0.5% to 10% of the weight of the tablet.
  • a water-insoluble, film-forming polymer preferably ethylcellulose (e.g. NlO and NlOO) and poly-methylmethacrylates (e.g. Eudragit RS) in a quantity ranging from 0.5% to 10% of the weight of the tablet.
  • the solid formulation according to the invention is preferably prepared by a process that comprises the steps of:
  • the tablet of the invention shows a dissolution profile independent of the pH of the dissolution medium. Moreover, the tablet of the invention is easy to manufacture, by means of easily-available and non-expensive apparatuses.
  • a further aspect of the invention relates to the use of said tablet in the treatment of benign prostate hypertrophy.
  • EXAMPLE 100 g alfuzosin hydrochloride are mixed with 200 g hydroxypropyl methylcellulose KlOO, 700 g hydroxypropyl methylcellulose Kl 5M and 500 g hydroxypropyl methylcellulose KlOOM.
  • the resulting mixture is kneaded with a povidone solution, granulated through a calibrated wire extruder and dried.
  • the resulting granulate is mixed with 500 g lactose monohydrate, 500 g microcrystalline cellulose, 4 g colloidal silica and 6 g magnesium stearate.
  • the resulting mixture is pressed with 10 mm diameter round dies into tablets containing 10 mg of alfuzosin hydrochloride each.
  • Tablets can optionally be coated with an insoluble polymer in quantities ranging from 0.5% to 10% of the weight of the tablet, to further modulate the in vitro dissolution pattern.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Urology & Nephrology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A solid controlled-release pharmaceutical formulation containing alfuzosin hydrochloride and the use thereof in the treatment of prostate hypertrophy.

Description

ALFUZOSIN CONTROLLED-RELEASE FORMULATIONS
The present invention relates to solid formulations in the form of controlled-release tablets containing alfuzosin, the process for its preparation and use thereof in the treatment of prostate hypertrophy.
Alfuzosin (hydrochloride) is a molecule able to contrast α-adrenergic contractions. In particular, alfuzosin and its salts are known to be potent blockers of α-adrenergic receptors and act selectively on the urinary tract. Since Alfuzosin has a short duration of action, it would be desirable to provide oral pharmaceutical forms allowing for a single daily administration ensuring an effective plasma concentration of active ingredient over 24 hours. PRIOR ART
Different technical solutions have been proposed to solve this problem, one of which is the Geomatrix® technology, consisting of a three layer- tablet in which alfuzosin is distributed in two layers. A ready-release layer contains a portion of the total alfuzosin, a second layer contains the drug residual amount providing a protracted release, while the third layer acts as a barrier preventing alfuzosin release (EP 938318). This technology, which allows to flexibly modulate the kinetics release, has however problems such as high production costs and difficulty in reproducing the release kinetics and therefore the drug plasma levels, which are the result of different mechanisms determined by single sub-components of the formulation.
Alfuzosin protracted-release formulations exhibiting "fluctuating" properties are reported in WO 02/06231; said properties would allow longer gastric permanence and therefore the possibility to obtain in vivo the absorption of the released drug for prolonged times. This approach has been known for some time, but it does not ensure reproducibility of plasmatic levels, prejudicing the effectiveness and safety of the drug. This is due to the fact that gastric emptying is highly erratic and depends on physio-pathological conditions that may vary even in the same patient.
WO 2004/037228 relates to alfuzosin protracted-release formulations in which one or more layers are present, only one of which containing alfuzosin. Other patent applications deal with alfuzosin solid controlled-release formulations which, in most cases, include multiple layers with differential release and various spatial dispositions (see for instance EP 673650 and HU 9903428). DISCLOSURE OF THE INVENTION
It has now been found that a daily-constant release of alfuzosin, in pharmacologically active amounts, can be obtained by means of a tablet containing the active ingredient together with a mixture of hydrophilic polymers, polyvinylpyrrolidone and lactose. Hydrophilic polymers according to the invention are hydroxypropyl methylcellulose mixtures. Said compounds form, in the presence of water, a gel whose dissolution/erosion rate decreases with the increase in viscosity. Mixtures of these polymers having different viscosity degrees make it possible to modulate the drug release rate, which is determined by mechanisms of diffusion through the hydrated matrix and progressive dissolution/erosion of the matrix.
According to a preferred embodiment, hydroxypropyl methylcellulose (HPMC) mixtures having different viscosity degrees comprise 5 to 10% (w/w) HPMC KlOO (USP definition: Hypromellose type 2208; nominal viscosity: 100,000 cP), 20 to 35% HPMC Kl 5M (USP definition: Hypromellose type 2208; nominal viscosity: 15,000 cP) and 15 to 25% HPMC KlOOM (Hypromellose type 2910; nominal viscosity: lOOcP) on the tablet final weight. A formulation containing 7.87% HPMC KlOO, 19.68% HPMC KlOOM and 27.56% HPMC Kl 5M, is particularly preferred.
In addition to the hydiOxypropyl methylcellulose mixture and alfuzosin, the tablet of the present invention may contain ingredients which contribute to modulating the active ingredient release, preferably polyvinylpyrrolidone in amounts from 1 to 4% and lactose in amounts from 15 to 25% on the tablet total weight.
Polyvinylpyrrolidone allows to maintain a high gradient of drug concentration in solution inside the hydrated matrix. Lactose, thanks to its high water solubility, promotes the rapid entry of water or digestive liquids inside the tablet, providing the rapid hydration of the core and therefore the formation of a gradient of drug concentration among non-hydrated matrix, hydrated matrix and surrounding environment.
Further ingredients can be added to the formulation during the work up steps, such as diluents, lubricants and film-forming agents. In another embodiment of the invention, the tablets are coated with a water-insoluble, film-forming polymer, preferably ethylcellulose (e.g. NlO and NlOO) and poly-methylmethacrylates (e.g. Eudragit RS) in a quantity ranging from 0.5% to 10% of the weight of the tablet.
The solid formulation according to the invention is preferably prepared by a process that comprises the steps of:
(a) mixing the hydrophilic polymers, alfuzosin and polyvinylpyrrolidone;
(b) wet- granulating the mixture from (a), through a 14 wire mesh extruder; (c) adding lactose and any other excipients, in particular diluents and lubricants, to the granular mixture from (b);
(d) compressing the product from (c); and, optionally, (e) film-coating the obtained tablets with a water-insoluble polymer in a quantity ranging from 0.5% to 10% of the weight of the tablet.
The use of granules with calibrated size enables the generation of an alfuzosin concentration gradient within the matrix, whereby a difference in the osmotic pressure is generated for the whole duration of the dissolution process.
Although alfuzosin hydrochloride solubility is pH-dependent, the tablet of the invention shows a dissolution profile independent of the pH of the dissolution medium. Moreover, the tablet of the invention is easy to manufacture, by means of easily-available and non-expensive apparatuses.
A further aspect of the invention relates to the use of said tablet in the treatment of benign prostate hypertrophy.
EXAMPLE 100 g alfuzosin hydrochloride are mixed with 200 g hydroxypropyl methylcellulose KlOO, 700 g hydroxypropyl methylcellulose Kl 5M and 500 g hydroxypropyl methylcellulose KlOOM.
The resulting mixture is kneaded with a povidone solution, granulated through a calibrated wire extruder and dried. The resulting granulate is mixed with 500 g lactose monohydrate, 500 g microcrystalline cellulose, 4 g colloidal silica and 6 g magnesium stearate.
The resulting mixture is pressed with 10 mm diameter round dies into tablets containing 10 mg of alfuzosin hydrochloride each.
Tablets can optionally be coated with film-forming agents of various type to improve friability and flowability.
Tablets can optionally be coated with an insoluble polymer in quantities ranging from 0.5% to 10% of the weight of the tablet, to further modulate the in vitro dissolution pattern.

Claims

1. A solid pharmaceutical composition in the form of tablet containing alfuzosin hydrochloride, hydrophilic polymers, polyvinylpyrrolidone and lactose.
2. A pharmaceutical composition according to claim I5 wherein the tablet is coated with with an insoluble, film- forming polymer.
3. A composition according to claim 2, wherein the insoluble, film- forming polymer is present in a quantity ranging from 0.5% to 10% of the weight of the tablet.
4. A composition as claimed in claim 1, in which said hydrophilic polymers are hydroxypropyl methylcelluloses (HPMC) with different viscosity degrees.
5. A composition as claimed in claim 4, containing a mixture of HPMC KlOO, HPMC KlOOM and HPMC K15M.
6. A composition as claimed in claim 5, in which said mixture consists of 5 to 10% HPMC KlOO, 15 to 25% HPMC KlOOM and 20 to 35% HPMC K15M.
7. A composition as claimed in claim 6, in which said mixture consists of 7.87% HPMC KlOO, 19.68% HPMC KlOOM and 27.56% HPMC K15M.
8. A composition as claimed in claim 1, containing 1 to 4% polyvinylpyrrolidone .
9. A composition as claimed in claim I5 containing 15 to 25% lactose.
10. A composition as claimed in claim I5 further containing an excipient selected from diluents, lubricants and film-forming agents.
11. A process for the preparation of a solid composition according to the above claims, which comprises the steps of:
(a) preparing a mixture containing hydrophilic polymers, alfuzosin and polyvinylpyrrolidone;
(b) wet-granulating- the mixture from *(a) through a 14 wire mesh extruder;
(c) adding lactose and any other excipients, in particular diluents and lubricants, to the granular mixture from (b);
(d) compressing the product from (c) and, optionally,
(e) film-coating the obtained tablets with a water-insoluble, water-permeable polymer.
12. The use of a solid formulation as claimed in claims 1-10 for the preparation of a medicament for the treatment of prostate hypertrophy.
PCT/EP2006/002021 2005-03-11 2006-03-06 Alfuzosin controlled-release formulations WO2006094736A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI2005A000391 2005-03-11
IT000391A ITMI20050391A1 (en) 2005-03-11 2005-03-11 CONTROLLED RELEASE FORMULATIONS OF ALFUZOSIN

Publications (2)

Publication Number Publication Date
WO2006094736A2 true WO2006094736A2 (en) 2006-09-14
WO2006094736A3 WO2006094736A3 (en) 2007-01-04

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KR (1) KR20070110068A (en)
CN (1) CN101137351A (en)
IT (1) ITMI20050391A1 (en)
RU (1) RU2423107C2 (en)
TR (1) TR200706209T1 (en)
WO (1) WO2006094736A2 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008050188A2 (en) * 2006-10-23 2008-05-02 Torrent Pharmaceuticals Limited Sustained release pharmaceutical compositions of alfuzosin and process for preparation thereof
WO2008073388A2 (en) * 2006-12-11 2008-06-19 Mutual Pharmaceutical Company, Inc. Alfuzosin formulations, methods of making and methods of use
CN101095681B (en) * 2007-07-13 2011-04-20 沈阳药大制剂新技术有限公司 Alfuzosin Hydrochloride permeating pump type controlled-release preparation and method for preparing the same
CN105287422A (en) * 2015-12-07 2016-02-03 黑龙江省智诚医药科技有限公司 Alfuzosin hydrochloride sustained release tablets and preparation method thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2752737A1 (en) * 1996-08-29 1998-03-06 Synthelabo Tablet for controlled release of alfuzosin hydrochloride
US6149940A (en) * 1996-08-29 2000-11-21 Synthelabo Tablet with controlled release of alfuzosine chlorhydrate
US20040115259A1 (en) * 2001-02-08 2004-06-17 Frederique Bordes Method for producing a floating tablet containing an active principle and the tablet obtained

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2752737A1 (en) * 1996-08-29 1998-03-06 Synthelabo Tablet for controlled release of alfuzosin hydrochloride
US6149940A (en) * 1996-08-29 2000-11-21 Synthelabo Tablet with controlled release of alfuzosine chlorhydrate
US20040115259A1 (en) * 2001-02-08 2004-06-17 Frederique Bordes Method for producing a floating tablet containing an active principle and the tablet obtained

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008050188A2 (en) * 2006-10-23 2008-05-02 Torrent Pharmaceuticals Limited Sustained release pharmaceutical compositions of alfuzosin and process for preparation thereof
WO2008050188A3 (en) * 2006-10-23 2008-09-12 Torrent Pharmaceuticals Ltd Sustained release pharmaceutical compositions of alfuzosin and process for preparation thereof
WO2008073388A2 (en) * 2006-12-11 2008-06-19 Mutual Pharmaceutical Company, Inc. Alfuzosin formulations, methods of making and methods of use
WO2008073388A3 (en) * 2006-12-11 2008-12-31 Mutual Pharmaceutical Co Alfuzosin formulations, methods of making and methods of use
CN101095681B (en) * 2007-07-13 2011-04-20 沈阳药大制剂新技术有限公司 Alfuzosin Hydrochloride permeating pump type controlled-release preparation and method for preparing the same
CN105287422A (en) * 2015-12-07 2016-02-03 黑龙江省智诚医药科技有限公司 Alfuzosin hydrochloride sustained release tablets and preparation method thereof

Also Published As

Publication number Publication date
RU2007133793A (en) 2009-03-20
KR20070110068A (en) 2007-11-15
WO2006094736A3 (en) 2007-01-04
RU2423107C2 (en) 2011-07-10
TR200706209T1 (en) 2007-12-24
CN101137351A (en) 2008-03-05
ITMI20050391A1 (en) 2006-09-12

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