Pharmaceutical tablet characterized by a showing high volume increase when coming into contact with biological fluids

• US 5,780,057 A
• Filed: 02/14/1997
• Issued: 07/14/1998
• Est. Priority Date: 02/19/1996
• Status: Expired due to Term

• Current Assignee: Jagotec Ag (Vectura Group Ltd.)
• Original Assignee: Jagotec Ag (Vectura Group Ltd.)
• Inventors: Maggi, Lauretta, Conte, Ubaldo
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Shelborne, Kathryne E.
• Application Number:
  US08/799,313
• Time in Patent Office: 515 Days
• Field of Search: 424/472, 424/466, 424/474, 424/475, 424/468, 424/482
• US Class Current: 424/468
• 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

Abstract

A description is given of a pharmaceutical form for oral administration consisting of a two- or three-layers tablet, wherein at least one layer can rapidly swell by contact with biological and/or aqueous fluids, said swelling resulting in a considerable increase in the tablet volume. Said phenomenon determines a prolonged residence of the pharmaceutical form at the gastric level and therefore allows a slow release of the active ingredient from said pharmaceutical form to the stomach and/or the first tract of the intestine.

Claims

1. A pharmaceutical tablet wherein the active ingredients are released at a controlled rate selectively in the first portion of the gastrointestinal tract, said tablet having a multi-layer structure and comprising:

a) a first layer, which considerably and rapidly swells in the presence of biological aqueous fluids, said swelling resulting in an increase by at least 50% of the total volume of the tablet when coming into contact with the gastric juice, said layer being formed by a compressed granular mixture of biocompatible hydrophilic polymers and at least one highly swellable (superdisintegrating) polymer selected from the group consisting of cross-linked polyvinylpyrrolidone, hydroxypropylcellulose and hydroxypropyl methylcellulose having molecular weight up to 150,000, cross-linked sodium carboxymethylcellulose, carboxymethyl starch, sodium carboxymethyl starch, potassium methacrylate-divinylbenzene copolymer, polyvinyl alcohols, amylose, cross-linked amylose, starch derivatives, microcrystalline cellulose and cellulose derivatives, alpha-, beta-and gamma-cyclodextrin and dextrin derivatives in general, said substances amounting to 1% to 90% of the layer weight

b) a second layer, adjacent to the first and containing the active ingredient, made out of biodegradable and biocompatible polymeric materials and other adjuvants whereby the formulation can be formed by compression and the active ingredient may be released within a time interval that may be predetermined by preliminary tests in vitro;

c) an optional third layer, formed by compression and applied to the second layer, comsprising erodible and/or gellable and/or swellable hydrophilic polymers and, being initially impermeable to the active ingredient, acting as a barrier modulating the release of the active ingredient contained in the adjacent 2nd layer, said third layer optionally being identical with the first layer in composition and functional characteristics.

2. The pharmaceutical tablet as claimed in claim 1, wherein the first layer besides increasing rapidly in volume exhibits bioadhesion properties whereby the pharmaceutical tablet is maintained in contact with the epithelium of the first portion of the gastroduodenal tract for a long time.

3. The pharmaceutical tablet as claimed in claim 1, wherein the active ingredients may be contained not only in said first layer, but also in said second layer and or/said third layer so that said active ingredients may be released at different times.

4. The pharmaceutical tablet as claimed in claim 1, wherein the active ingredients exhibit a small absorption window in the gastrointestinal tract, i.e. are more effectively absorbed in the stomach, duodenum and in the first portion of the small intestine.

5. The pharmaceutical tablet as claimed in claim 1, wherein the active ingredients contained in the system exert their action mostly at the gastroduodenal level and in the first portion of the small intestine.

6. The pharmaceutical tablet as claimed in claim 1, wherein the active ingredients are selected from the group consisting of prazosin, ketanserin, guanabenz acetate, captopril, captopril hydrochloride, enalapril, enalapril maleate, lysinopril, hydralazide, methyldopa, methyldopa hydrochloride, levodopa, carbidopa, benserazide, amlodipine, nitrendipine, nifedipine, nicardipine, verapamil, acyclovir, inosine, pranobex, tribavirine, vidarabine, zidovudine or AZT.

7. The pharmaceutical tablet as claimed in claim 1, wherein the active ingredients contained in the systems are those exerting a medicinal action at the gastric level, selected from the group consisting of aluminum hydroxide, magnesium carbonate, magnesium oxide, sucralphate, sodium carbenoxolone, pirenzepin, loperamide, cimetidine, ranitidine, famotidine, misoprostol, omeprazol.

8. The pharmaceutical tablet as claimed in claim 1, wherein the polymeric substances used to prepare the 2nd layer, which contains the active ingredient, are hydrophilic and soluble and/or gellable and/or erodible and/or swellable at a different rate in aqueous fluids, and are selected from the group consisting of hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose having molecular weight of from 1,000 to 4,000,000, hydroxypropyl cellulose having molecular weight of from 2,000 to 2,000,000, carboxyvinyl polymers, chitosans, mannans, galactomannans, xanthan gums, carrageenin and carrageenans, amylose, alginic acid, salts and derivatives thereof, pectins, acrylates, methacrylates, acrylic/methacrylic copolymers, polyanhydrides, polyamino acids, methyl vinyl ethers/maleic anhydride copolymers, polyvinyl alcohols, glucans, scleroglucans, carboxymethylcellulose and derivatives thereof, ethylcellulose, methylcellulose and polyvinylpyrrolidone.

9. The pharmaceutical tablet as claimed in claim 8, wherein said polymeric substances amount to 5% to 90% by wt. of the layer containing the active ingredient to 85%.

10. The pharmaceutical compressed tablet as claimed in claim 1, wherein a rapid swelling of the swellable layer is favoured by the use of adjuvants classifiable as anionic, cationic and non-ionic surfactants, selected from the group consisting of sodium lauryl sulphate, sodium ricinoleate, sodium tetradecyl sulphate, dioctyl sulphosuccinate, cetomacrogol, poloxamer, glyceryl monostearate, polysorbates, sorbitan monolaurate, lecithins.

11. The pharmaceutical tablet as claimed in claim 1, wherein a rapid swelling of the swellable layer is favoured by the use of adjuvants, classified as effervescent mixtures selected from the group consisting of carbonates and bicarbonates of sodium and of other alkali or alkaline-earth metals, glycocoll sodium carbonate and other salts, either alone or in combination with pharmaceutically acceptable acids, such as citric, tartaric, adipic, ascorbic acids, capable of causing effervescence in an aqueous medium.

12. The pharmaceutical tablet as claimed in claim 1, wherein the thickness of the layers of said tablet may range from 0.2 mm to 8 mm.

13. The pharmaceutical tablet as claimed in claim 1, wherein the layer containing the active ingredient and the barrier layers further contain diluents, binding agents, gliding agents, disgregating agents, colouring agents, lubricants currently used in the pharmaceutical field.

14. The pharmaceutical compressed tablet as claimed in claim 1, wherein water and/or aqueous fluids penetration into the various layers is favoured by including in the formulation hydrophilic diluents, selected from the group consisting of mannitol, lactose, starch of various origin, sorbitol, xylitol, microcrystalline cellulose, colloidal silica.

15. The pharmaceutical tablet as claimed in claim 1, wherein hydrophobic diluents, such as glyceryl monostearate, glyceryl behenate, hydrogenated castor oil, waxes and mono-, bi-, and trisubstituted glycerides, are used when water and/or aqueous fluids penetration into the medicated or barrier layers has to be slowed down.

16. The pharmaceutical tablet as claimed in claim 1, wherein the adjuvants used for the preparation of said barrier layers are selected from the group consisting of glyceryl monostearate and derivative thereof, semisynthetic triglycerides, semisynthetic glycerides, hydrogenated castor oil, glycerylpalmitostearate, glyceryl behenate, cetyl alcohol, polyvinylpyrrolidone, glycerin, ethylcellulose, methylcellulose, sodium carboxymethylcellulose, magnesium stearate, stearic acid, talc, sodium benzoate, boric acid, polyoxyethylene glycols, colloidal silica.

17. The pharmaceutical tablet as claimed in claim 1, wherein the plasticizers used to provide said barrier layers with the elasticity required and to improve their compressibility, adhesion and cohesion, are selected from the group consisting of hydrogenated castor oil, cetyl alcohol, cetylstearyl alcohol, fatty acids, glycerides and triglycerides as are or variously substituted, polyoxyethylene glycols and derivatives thereof having a molecular weight ranging from 400 to 60,000.