Tablet with controlled release of alfuzosine chlorhydrate

• US 6,149,940 A
• Filed: 04/26/1999
• Issued: 11/21/2000
• Est. Priority Date: 08/29/1996
• Status: Expired due to Term

• Current Assignee: 2-Jagotec AB, Sanofi , Jagotec Ag (Vectura Group Ltd.)
• Original Assignee: Synthelabo (Paris Cedex, FR) (Sanofi-Synthélabo SA), Jagotec Ag (Vectura Group Ltd.)
• Inventors: Grenier, Pascal, Conte, Ubaldo, Jarreau, Fran.cedilla.ois Xavier, Rauch-Desanti, Clemence, Dufour, Alain, Vergnault, Guy, Maggi, Lauretta
• Primary Examiner(s): Spear, James M.
• Application Number:
  US09/147,581
• Time in Patent Office: 575 Days
• Field of Search: 424/468, 424/469, 424/470, 424/472, 424/474, 424/465
• US Class Current: 424/472
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 9/2086 Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat active cores with a complete drug-free outer coat A61K9/28
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system

Abstract

Pharmaceutical tablet which consists of:

a) a first layer having the property of swelling considerably and quickly on contact with aqueous biological fluids, the first layer being produced by compression of a mixture or of a granulate comprising hydrophilic polymers, and

b) a second layer adjacent to the first layer being formulated with hydrophilic polymers and with other auxiliary substances in order to give the preparation suitable properties of compressibility and in order to allow the release of alfuzosin hydrochloride within a predetermined time period.

Claims

1. A pharmaceutical tablet for oral administration and for the controlled release of alfuzosin hydrochloride into the proximal segments of the gastrointestinal tract, the tablet comprising:

a) a first layer having the property of swelling considerably and quickly on contact with aqueous biological fluids, the first layer being produced by compression of a mixture or of a granulate comprising a hydrophilic polymer constituting from 5.0 to 90% of the weight of the first layer,

b) a second layer adjacent to the first layer containing the alfuzosin hydrochloride, the second layer being formulated with a hydrophilic polymer and with an auxiliary substance to give the preparation suitable properties of compressibility and in order to allow the release of alfuzosin hydrochloride within a predetermined time period,

c) and optionally a third layer adjacent to the second layer comprising a hydrophilic polymer which gels and/or swells and which may optionally be broken down and has a barrier function which modifies the release of the alfuzosin hydrochloride from the second layer, the third layer being primarily highly impervious to passage of the active substance.

2. The tablet according to claim 1, wherein at least one of the layers comprises an hydrophilic product and/or an excipient.

3. The tablet according to claim 2, wherein the hydrophilic excipient is crosslinked polyvinylpyrrolidone, hydroxypropylcellulose or hydroxypropylmethylcellulose having a molecular weight from 1,000 to 100,000, crosslinked sodium carboxymethylcellulose, carboxymethyl starch or its salts, or divinylbenzene/potassium methyacrylate copolymer.

4. The tablet according to claim 2, wherein the hydrophilic excipient constitutes from 1 to 50% of the weight of the layer.

5. The tablet according to claim 1, wherein the third layer has an identical composition to that of the first layer and the same functional properties.

6. The tablet according to claim 5, wherein the first and third layers differ in the amount applied to the second layer and their thickness.

7. The tablet according to claim 1, wherein, on contact with an aqueous liquid, at least one of the layers of the tablet increases by at least 1.5 times relative to the initial volume after two hours.

8. Tablet according to claim 1, wherein the hydrophilic polymer is hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose having a molecular weight of from 1000 to 4,000,000, hydroxypropylcellulose having a molecular weight of from 2000 to 2,000,000, a carboxyvinyl polymer, a chitosan, a mannan, a galactomannan, a xanthan, a carrageenan, an amylose, an alginic acid, a pectin, an acrylate, a methacrylate, an acrylic/methacrylic copolymer, a polyanhydride, a polyamino acid, a poly(methyl vinyl ether/maleic anhydride) polymer, a polyvinyl alcohol, a glucan, a scleroglucan, a carboxymethylcellulose, an ethylcellulose, or a methylcellulose.

9. The tablet according to claim 1, wherein the second layer containing the active substance comprises 5 to 90% by weight of the hydrophilic polymer.

10. The tablet according to claim 1, wherein the third layer contains alfuzosin hydrochloride.

11. The tablet according to claim 1, wherein the amount of alfuzosin hydrochloride in the tablet ranges from 2.5 to 50 mg.

12. The tablet according to claim 1, further comprising a surfactant which is sodium lauryl, sulphate, sodium ricinoleate, sodium tetradecyl sulphate, sodium dioctyl, sulphosuccinate, cetomacrogol, poloxamer, glyceryl monostearate, a polysorbate, sorbitan monolaurate, or a lecithin.

13. The tablet according to claim 1, further comprising an hydrophilic diluent which is mannitol, lactose, a starch, sorbitol, xylitol, microcrystalline cellulose or a substance which promotes the penetration of water and/or an aqueous fluid into the layers.

14. The tablet according to claim 1, further comprising an hydrophobic diluent which is glyceryl monostearate, a palmitate, an hydrogenated plant oil or a wax used for slowing down the penetration of water and/or of aqueous fluids into the second layer containing the active substance and into the first and third layers.

15. The tablet according to claim 1, wherein the layers of the tablet have different thicknesses ranging from 0.2 mm to 8 mm.

16. The tablet according to claim 1, wherein the tablet is compressed at a pressure that ranges from 7 to 50 KN.

17. The tablet according to claim 1, wherein the tablet is covered with a coating which may optionally contain alfuzosin hydrochloride.

18. A pharmaceutical composition comprising one or more tablets according to claim 1.

19. The tablet according to claim 1, wherein the hydrophilic polymer constitutes from 10 to 85% of the weight of the first layer.

20. The tablet according to claim 2, wherein the hydrophilic excipient constitutes from 10 to 30% of the weight of the layer.

21. The tablet according to claim 1, wherein, on contact with an aqueous liquid, at least one of the layers of the tablet increases by at least 3 times relative to the initial volume after two hours.

22. The tablet according to claim 1, wherein the second layer comprises 10 to 85% by weight of the hydrophilic polymer.

23. The tablet according to claim 1, wherein

a) the first layer consists of by weight:

space="preserve" listing-type="tabular">______________________________________ hydroxypropylmethylcellulose 79.75% hydrogenated castor oil 13.50% yellow iron oxide 0.25% ethylcellulose 5.00% magnesium stearate 1.00% silica gel 0.50% ______________________________________

b) the second layer consists of by weight;

space="preserve" listing-type="tabular">______________________________________ alfuzosin hydrochloride 10.00 mg mannitol 10.00 mg hydroxypropylmethylcellulose 10.00 mg polyvinylpyrrolidone 3.20 mg microcrystalline cellulose 65.00 mg magnesium stearate 1.00 mg colloidal silica 1.25 mg ______________________________________

c) and the third layer consists of by weight;

space="preserve" listing-type="tabular">______________________________________ hydroxypropylmethylcellulose 76.00% hydrogenated castor oil 18.60% polyvinylpyrrolidone 3.15% yellow iron oxide 0.10% magnesium stearate 0.70% colloidal silica 1.45%. ______________________________________