MXPA98002026A - Pharmaceutical formulations containing darifenac - Google Patents

Abstract

A pharmaceutical dosage form for administration to the gastrointestinal tract of a patient is provided, comprising darifenacin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable auxiliary, diluent or carrier, characterized in that the dosage form is adapted to release by at least 10% by weight of darifenacin, or the pharmaceutically acceptable salt thereof, to the lower gastrointestinal tract of the patient, the formulation minimizes unwanted side effects and increases the bioavailability of darifenaci

Description

PHARMACEUTICAL FORMULATIONS CONTAINING DARIFENACINE DESCRIPTIVE MEMORY This invention relates to pharmaceutical dosage forms of darifenacin and its pharmaceutically acceptable salts. Darifenacin is (S) -2-. { l- [2- (2,3-Dihydrobenzofuran-5-yl) ethyl] -3-pi rrolidinyl} -2, 2-diphenyl acetamide and is disclosed in European Patent No. 0388054, Examples IB and 8 and is mentioned there as 3- (S) - (-) - (1-carbamoy1-1-, 1-diphenyl- methyl) -l- [2- (2, 3-dihydro-benzofuran-5-yl) ethyl] pyrrolidine. It is indicated for the treatment of urinary incontinence and irritable bowel syndrome and has the following structure: Clinical investigations showed that an important metabolite of darifenacin is the following 3 '-hydroxy derivative: It appears that etabolite is 6 times less selective with respect to M3 muslin receptors than on Ml receptors and therefore is more likely to produce unwanted side effects such as dry mouth, confusion and blurred vision. It has now been found that the supply of darifenacin and its pharmaceutically acceptable salts to the lower gastrointestinal tract results in a greater relationship between darifenacin and the metabolites in the systemic circulation and thus is likely to minimize any side effects and increase the bioavailability of darifenacin. This is surprising since a slower release rate normally leads to a slower release to liver enzymes and a higher degree of metabolism of a drug administered. Therefore, according to the present invention, there is provided a pharmaceutically adapted dosage form for administration to the gastrointestinal tract of a patient, comprising darifenacin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically adjuvant, diluent or carrier. acceptable; characterized in that the dosage form is adapted to release at least 10% by weight of the darifenacin or pharmaceutically acceptable salt thereof, to the lower gastrointestinal tract of the patient. The dosage forms of the invention can be of the sustained or delayed release type and in this way darifenacin, or the pharmaceutically acceptable salt thereof, is released to the gastrointestinal tract of the patient during or after a sustained period of time following the administration of the dosage form to the patient . However, when the dosage forms are administered rectally, conventional rectal formulations can be used. By "lower gastrointestinal tract" is meant the portion of the gastrointestinal tract between the ileo-cecal junction and the rectum inclusive. accordingly, the dosage forms of the invention are adapted to deliver at least 25%, and more preferably 50% by weight of darifenacin, or the pharmaceutically acceptable salt thereof, to the lower gastrointestinal tract. Preferably, no more than 90% by weight of darifenacin, or the pharmaceutically acceptable salt thereof, is released 4 hours after dosing: more preferably not more than 90% by weight of darifenacin, or the pharmaceutically acceptable salt thereof. , it is released 8 hours after dosing; and more preferably not more than 90% by weight of darifenacin, or the pharmaceutically acceptable salt thereof, is released 16 hours after dosing. Conditions in the gastrointestinal tract are believed to be reproduced in vitro using Apparatus 1 described in USP XXII on page 1578, which has 40 mesh containers (381 μm openings), a rotation speed of 100 rpm and a water dissolution medium at 37 ° C. Therefore, the sustained release formulations of the invention can be alternatively defined as a pharmaceutical dosage form adapted for administration to the gastrointestinal tract of a patient, comprising darifenacin, or a pharmaceutically acceptable salt thereof, and an adjuvant, diluent or pharmaceutically acceptable vehicle; characterized in that the dosage form is adapted to release darifenacin, or the pharmaceutically acceptable salt thereof in Apparatus 1 described in USP XXII on page 1578, which has 40 mesh containers (381 μm openings), one speed of rotation of 100 rpm and a medium of dissolution of water at 37 ° C, during a sustained period of time. Particular dosage forms include: (a) those wherein the darifenacin, or the pharmaceutically acceptable salt thereof, is inserted into a matrix from which it is released by diffusion or erosion; (b) those wherein the darifenacin, or the pharmaceutically acceptable salt thereof, is present in a multi-particle core; (c) those in which there is an impermeable coating provided with an opening through which darifenacin, or the pharmaceutically acceptable salt thereof, is liberated; (d) those where there is a coating of low aqueous solubility; (e) those where there is a semipermeable coating; (f) those in which darifenacin is present as a complex of ion exchange resin; (g) pulsatile devices from which darifenacin is released at specific points in the gastrointestinal tract; and (h) rectal suppositories. It will be apparent to those skilled in the art that some of the means indicated above for achieving sustained release can be combined: for example, a matrix containing the active compound can be formed with multiple particles and / or coated with an impermeable coating provided of an opening. Considering each category in turn: (a) In matrix systems, the active compound is inserted or dispersed in a matrix of another material that serves to retard the release of the active compound in an aqueous environment. Suitable matrix materials include hydroxypropylmethylcellulose ethers and hydroxypropyl cellulose.

The matrix formulations according to the present invention preferably comprise high molecular weight hydroxypropylmethylcellulose ethers (ie, 85. 000-95,000 mass units). (b) In multi-particle cores, the compound is present in a number of particles that also contain adjuvants, diluents or vehicles. Suitable adjuvants, diluents and carriers include microcrystalline celluloses (preferably having a particle size of 50 μm) and lactose (preferably having a particle size equivalent to 110 mesh (137.5 μm aperture) Typically, the mixed ingredients are shaped to a wet mass that is extruded and spheroid to form beads that are then dried (c) The waterproof coatings are applied to tablets containing the active compound. "Waterproof" means that no significant transport of the active compound through the coating during the release period of the intended formulation Suitable materials include polymers and film forming waxes [eg, thermoplastic polymers such as poly (ethylene-covinyl acetate), poly (vinyl chloride), ethylcellulose and cellulose acetate] and the thickness of the coating is preferably greater than 100 μm.The opening can be formed by perforation, if the coated formulation is conical, cutting the tip. (d) Coatings of low solubility in water include polymers. The solubility of such polymers can be pH-dependent, for example substantially insoluble at pH < 5 (so that dissolution is not carried out in the stomach) and soluble in water at pH > 5. pH sensitive polymers preferably include shellac, phthalate derivatives (including cellulose acetate phthalate, polyvinyl acetate phthalate), polyacrylic acid and vinyl acetate derivatives and crotonic acid copolymer. (e) Semipermeable membrane coatings allow the active compound to diffuse through the membrane or through the pores filled with liquid within the membrane. Suitable coating materials include polymers such as cellulose ester or ether and acrylic polymers. Preferred materials include ethyl cellulose, cellulose acetate and cellulose butyrate acetate. (f) Darifenacin resinates can be prepared by treating the anionic ion exchange resin beads (e.g., sodium polystyrene sulfonate) with an acid addition salt of darifenacin. (g) Pulsed devices have the ability to release drugs at various points of gastrointestinal touch. It may depend on the osmotic potential to activate the release (see US Patent No. 3,952,741) or on the erosion of polymer material due to changes in pH or microbial degradation. Suitable polymeric materials include pectin [Rubinstein et al. 1991, pectic salt as a release system in the colon, Proceed. Intern. Symp. Control. I laughed Bioact. Mater.], Methacrylate-galactomannan [Lehman et al., 1991, Coating with methacrylate galactomannan for specific drug release in the colon, ibid.], Substance containing azo bonds [Kopeckova et al., 1991, Bioadhesive polymers for specific drug release in the colon, ibid. .], chondroitin [Sintov et al., 191, Administration of indomethacin in the colon using modified chondroitin in a channeled dog model, ibid], dextran hydrogels [Bronsted et al., 1993, A new hydrogel system designed for controlled drug release in the colon, ibid.], methacrylic acid copolymers [Siefke et al., 1993, ß-cyclodextrin matrix films for specific drug release in the colon, ibid.], and amylose [Milojevik et al. , In vitro and in vivo evaluation of pellets coated with amylose for specific drug release in the colon, ibid.]. Release at specific points in the gastrointestinal tract can also be achieved using multilayer tablets [Gazzaniga et al, 1993, Time-dependent oral delivery system for specific release in the colon, ibid.], Or hydrogel plugs in a capsule [Binns et al. col .. Application of a PEG-based hydrogel independent of pH to achieve a pulsatile drug release]. (h) Formulations of rectal suppositories can be prepared by dispersing the active ingredient in hydrogenated oils or waxes using conventional methods. Preferably, in the dosage forms of the present invention, darifenacin is in the form of its salt hydrobromide (except when darifenacin is present as a complex of ion exchange resin). Preferably, the dosage forms of the present invention are adapted for oral administration, but may also be adapted for rectal administration. According to another aspect of the invention, there is provided a method of treating irritable bowel syndrome or urinary incontinence, which comprises supplying darifenacin, or a pharmaceutically acceptable salt thereof, to the lower gastrointestinal tract of a patient requiring such treatment. . The method can be accomplished by administering a dosage form of the invention to the gastrointestinal tract of a patient who requires such treatment. The invention is illustrated by the following examples wherein the following materials are used: Methocel ™ K4M - a high molecular weight hydroxypropylmethylcellulose ether with number average molecular weight of 90,000. It is classified in the USP (Pharmacopoeia of the United States) as 2208 and a 2% solution in water has a nominal viscosity of 4000 cps. It has a methoxy content of 19-24% and a hydroxypropoxy content of 7-12%; Methocel ™ E4M - a high molecular weight hydroxypropylmethylcellulose ether with a number average molecular weight of 93,000. It is classified in the USP (Pharmacopoeia of the United States) as 2910 and a 2% solution in water has a nominal viscosity of 4000 cps. It has a methoxy content of 28-30% and a hydroxypropoxy content of 7-12%; Methocel ™ K100LV - a low molecular weight hydroxypropylmethyl cellulose ether. It is classified in the USP (Pharmacopoeia of the United States) as 2208 and a 2% solution in water has a nominal viscosity of 100 cps. It has a methoxy content of 19-24% and a hydroxy-propoxy content of 7-12%; Klucel EFMR -hydroxypropylcellulose with a number average molecular weight of 60,000; Ethocel ™ - methylcellulose; Avicel ™ PH101 - microcrystalline cellulose with an average particle size of 50 μm; Regular lactose -lactose with a particle size equivalent to 110 mesh (openings of 137.5 μm); Lactose Fast FloMR - spray-dried lactose; and EncomPressM - dibasic calcium phosphate (anhydrous) Aerosil 200 - colloidal anhydrous silica EXAMPLE 1 (Comparative) Quick release matrix tablet Methocel K4M, premium K100LV, darifenacin and Fast-flo lactose were mixed in a Turbula mixer for 10 minutes. The mixture was filtered using a 30 mesh screen (50 μm openings) and mixed again for another 10 minutes. The magnesium stearate was filtered through a 30 mesh screen (500 μm openings) and added to the mixture before mixing for another 5 minutes. The mixture was compressed in a tabletting machine using 8 mm round normal convex tooling to prepare 1250 tablets.

EXAMPLE 2 Medium Release Matrix Tablet Methocel K4M, E4M, darifenacin and Fastflo lactose were mixed in a suitable mixer for 10 minutes. The mixture was then filtered using a 30 mesh screen (500 μm openings) and mixed again for another 10 minutes. The magnesium stearate was filtered through a 30 mesh screen (500 μm openings) and added to the mixture before mixing for another 5 minutes. The mixture was then subjected to compression in a tabletting machine using a standard 8 mm round convex tooling to prepare 1250 tablets.

EXAMPLE 3 Slow-release matrix tablet Methocel K4M, darifenacin and anhydrous dibasic calcium phosphate were mixed in a Turbula mixer for 10 minutes. The mixture was then filtered using a 30 mesh screen (500 μm openings) and mixed again for another 10 minutes. The magnesium stearate was filtered through a 30 mesh screen (500 μm openings) and added to the mixture before mixing for another 5 minutes. The mixture was then subjected to compression in a tabletting machine using a standard 8 mm round convex tooling to prepare 1250 tablets.

EXAMPLE 4 The Avicel PH101, the regular lactose, the darifenacin and the fumaric acid were mixed in an Apex 2L cone Y for 10 minutes. The mixture was then filtered using a 30 mesh screen (500 μm openings) and mixed again for another 10 minutes. Purified water was added to form a wet mass that could be extruded. The resulting wet mass was extruded using a Nica E 140 extruder (1 mm screen) and then spheried using a Caleva spheronizer to form multi-particle beads. The beads were then dried using a bed temperature of 50 ° C for 1 hour to remove excess moisture. (b) Preparation of the final formulation.

Filling in size 2 white gelatin capsules. Ethyl acetate and isopropyl alcohol were stirred in a suitable container to ensure good mixing. Klucel EF and ethyl cellulose NIO were added to this mixture and the solution was stirred until complete dissolution was carried out. The uncoated beads were added to a fluidized bed coater and using an inlet temperature of 40 ° C the beads were coated with the solution containing the Klucel EF and the ethyl cellulose NIO. Upon completion of the coating the beads were dried for 10 minutes using a bed temperature of about 50 ° C. The coated beads were filled into capsules before administration.

EXAMPLE 5 Formulation of ion exchange resin Ingredient g / lot Darifenacin Bromhydrate 60.39 Sodium polystyrene sulfonate 187, 00 Disodium edetate, dihydrate 1.53 Water 2000, 00 Disodium edetate and sodium polystyrene sulfonate were suspended in water. This suspension was then heated to 50 ° C while stirring. Darifenacin hydrobromide was then added to the suspension and the suspension was stirred for another 2 hours at 50 ° C. The darifenacin polystyrene sulfonate was then filtered and washed until free of bromide ions. The darifenacin resinate was then dried under vacuum at 25 ° C for about 16 hours.

EXAMPLE 6 (Comparative) Immediate-release capsule 7.5 mg 1467.2 g of the lactose were added to all the darifenacin hydrobromide and mixed in an Apex 8L double cone drum mixer for 20 minutes. This was then ground using a Fitzmill (hammers forward, high speed) through a 1 mm sieve and the mill was washed with the remaining lactose (4800.0 g). This lactose, Aerosil 200 and corn starch were then added to the darifenacin / lactose hydrobromide premix initially prepared and mixed for 20 minutes in a Gardner 28L double cone drum mixer. This mixture was then passed through a 1 mm sieve using a Fitzmill (blades forward, low speed) and then mixed for another 20 minutes using the 28L mixer. Magnesium stearate (88.88 g) was then added and mixing was continued using the 28L mixer for 5 minutes. The final mixture was then encapsulated in size 2 hard gelatin capsules using a Zanasi capsule filling machine.

EXAMPLE 7 Measurement of in vitro release rates Dissolution methods Dissolution of the formulas of Examples 1-4 were performed using a rotary vessel apparatus (Apparatus 1, USPXXII, page 1578). The formulations were placed in containers (40 mesh, 381 μm openings) using a rotation speed of 100 rpm in 900 ml of water at 37 ° C +/- 0.5 * 0 At specified time intervals, 10 ml aliquots were removed from the dissolution container from an intermediate zone between the surface of the dissolution medium and the upper part of the container not less than 1 cm from the wall of the container. The first 7 ml were discarded and the remaining solution was transferred to an HPLC ampule for subsequent analysis. The release of darifenacin from the formulation of Example 5 was determined in accordance with USP XXIII Apparatus 4 (page 1794). Using a flow rate of 250 ml / hour, solutions at 37 ° C of the following pH were used to evaluate the release: 0-1 h pH 1.5; 1-2 hrs pH 2.5; 2-3.5 hrs pH 4.5; 3.5-5 hrs pH 6.9; 5-24 hrs pH 7.2. The solution of the formulation of Example 6 was made using a rotary vessel apparatus (Apparatus 1, USPXXII, page 1578). The formulations were placed in containers (40 mesh, 381 μm openings) using a rotation speed of 100 rpm in 900 ml of water at 37 ° C +/- 0.5 ° C. At specified time intervals, 20 ml aliquots of the dissolution medium were removed from an intermediate zone between the surface of the dissolution medium and the top of the container no less than 1 cm from the wall of the container. The aliquots were filtered (0.45 μm, Acrodisc) and the first 5 ml of filtrate were discarded. Then 5 ml of the remaining filtrate were diluted to 25 ml using a solution 1: 1 (v / v) water / methanol before HPLC analysis. Analysis For the formulations of Example 1-5, high performance liquid chromatography (HPLC) was performed using a BDS Hypersil C18 column. The mobile phase used was a 0.03 M aqueous potassium dihydrogen orthophosphate at pH 3.5 / methanol (1000: 800 v / v) using a flow rate of 1.5 ml / min at 37 ° C and a sample size of 20 μl. The detection was by fluorescence operating at an excitation wavelength of 288 nm (slot width 18 nm) and an emission wavelength of 320 nm (slot width 18 nm). For the formulation of Example 6, high performance liquid chromatography (HPLC) was performed using a Novapack C18 column. The mobile phase was aqueous 0.01M sodium acetate containing 0.2% v / v triethylamine at pH 6.0 / methanol / acetonitrile (45: 54: 1, v / v / v) using a flow rate of 1, 0 ml / min and a sample size of 50 μl. The detection was made by ultraviolet spectroscopy at 230 nm.

Results Formulation of Example 1 (comparative) Time (hs)% release (range) 1 65 (52-81) 2 80 (72-92) 4 91 (87-96) Formulation of Example 2 Time (hs)% release 1 41 (38-64) 4 77 (73-81) 8 95 (94-96) Formulation of Example 3 Time (hs)% release 1 6 (5-7) 8 42 (36-44) 16 67 (59-70) Formulation of Example 4 Time (hs)% release 1 11 (9-15) 4 58 (50-70) 8 98 (95-103) Formulation of Example 5 Time (hs)% release 1 11 (10-12) 2 25 (24-27) 6 55 (51-59) 12 79 (77-82) 18 90 (89-91) 24 94 (93-95) Formulation of Example 6 (comparative) Time (hs)% release 21 0.25 94 0.5 99 0.75 98 EXAMPLE 8 Pharmacokinetic clinical study A four-way multiple dose cross-over study was conducted to investigate the bioavailability of darifenacin and its 3'-hydroxy metabolite when administered as a sustained release formulation compared to an immediate release formulation. Thirty normal men received the formulations of Examples 1-3 or each for 6 days as well as the formulation of Example 6 three times per day. The plasma samples for the test of the drug and the metabolite were taken during 24 hours to the last day of the dosage for each period of the study. The pharmacokinetic parameters (area under the concentration-time curve for 24 hours, AUC, maximum concentration and concentration at 24 hours post dose) were obtained for the drug and the metabolite. The table below shows the relationship between the AUC values for darifenacin the metabolite (AUCdar i f in ac ina: AUCmßtabo i ito) and the relative bioavailability of darifenacin (F-rßi darifen cina) and of the metabolite (Freí metabolite).

AUC ratio of darifenacin: metabolite and relative bioavailability Fr «?) Formulac. Formulac. Formulac. Formulac. Example 6 Example 1 Example 2 Example 3 AUCdarif enacina: 0,66 0,58 0,82 1,03 AUC etabolite ito Freí darifenacin na 0,88 1,10 1,17 Freito metabolite na 0.98 0.82 0.70 na = not applicable These data indicate that the relative bioavailability of darifenacin with respect to the metabolite is increased when darifenacin is administered in a sustained release formulation according to the invention.

Claims (23)

NOVELTY OF THE INVENTION CLAIMS

1. - A pharmaceutical dosage form adapted for administration to the gastrointestinal tract of a patient, comprising darifenacin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier thereof, characterized in that the dosage form is adapted to release at least 10% by weight of darifenacin, or the pharmaceutically acceptable salt thereof, into the patient's gastrointestinal tract.

2. A dosage form according to claim 1, adapted to release at least 50% by weight of darifenacin, or pharmaceutically acceptable salt thereof, to the lower gastrointestinal tract.

3. A dosage form according to claim 1 or claim 2, adapted to deliver the darifenacin, or the pharmaceutically acceptable salt thereof, to the gastrointestinal tract of the patient during or after a sustained period of time after the administration of the dosage form of the patient.

4. A dosage form according to claim 3, characterized in that not more than 90% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, is released 4 hours after dosing.

5. A dosage form according to claim 4, characterized in that no more than 90% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, is released 8 hours after dosing.

6. A dosage form according to claim 4, characterized in that no more than 90% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, is released 16 hours after dosing.

7. A pharmaceutical dosage form adapted for administration to the gastrointestinal tract of a patient, comprising darifenacin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier, characterized in that the dosage form is adapted to release darifenacin, or the pharmaceutically acceptable salt thereof, in Apparatus 1 described in USP XXII on page 1578, which has 40 mesh containers (381 μm openings), a rotation speed of 100 rpm and a means of dissolving water at 37 ° C, for a prolonged period of time.

8. A dosage form according to claim 7, characterized in that not more than 90% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, is released after 4 hours.

9. A dosage form according to claim 7, characterized in that no more than 90% by weight of the darifenacin, or the pharmaceutically acceptable salt of the It is released after 8 hours.

10. A dosage form according to claim 7, characterized in that not more than 90% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, is released after 16 hours.

11. A dosage form according to any of the preceding claims, characterized in that the darifenacin, or pharmaceutically acceptable salt thereof, is inserted into a matrix from which it is released by diffusion.

12. A dosage form according to any of claims 1-10, characterized in that the darifenacin, or the pharmaceutically acceptable salt thereof, is present in a multi-particle core.

13. A dosage form according to any of claims 1-10, characterized in that darifenacin is present as an ion exchange resin complex.

14. A dosage form according to any of claims 1-10, having an impermeable coating provided with an opening through which darifenacin is released, or the pharmaceutically acceptable salt thereof.

15. A dosage form according to any of claims 1-10, which has a coating of low water solubility.

16. - A dosage form according to any of claims 1-10, which has a semipermeable coating.

17. A dosage form according to any of claims 1-10, which is a pulsatile device.

18. A dosage form according to any of claims 1-10, characterized in that darifenacin is in the form of its hydrobromide salt.

19. A dosage form according to any of the preceding claims, which is adapted for oral administration.

20. A form according to any of claims 1-18, which is adapted for rectal administration.

21. A dosage form according to claim 20, which is a suppository.

22. A method of treating irritable bowel syndrome or urinary incontinence, comprising administering darifenacin, or a pharmaceutically acceptable salt thereof, to the gastrointestinal tract of a patient in need of such treatment.

23. A method according to claim 22, which comprises administering a dosage form as defined in any of claims 1-21 to the gastrointestinal tract of a patient requiring such treatment.