MXPA97001873A - Prolong release formulation - Google Patents

Abstract

The present invention relates to a dosage formula and unit dose thereof, venlafaxine hydrochloride, an antidepressant agent, prolonged release in 24 hours that offers a control of plasma concentrations better than conventional formulas in tablets that should administered two or more times a day, and that is also associated with a lower incidence of nausea and vomiting than conventional tablets

Description

FORMULATION OF PROLONGED RELEASE BACKGROUND OF THE INVENTION Conventional sustained release pharmaceutical formulas are produced in the form of compressed tablets using the hydrogel tablet technology. In the conventional production of these sustained release pharmaceutical dosage formulas, the active ingredient is mixed with cellulose ethers such as methylcellulose, ethylcellulose or hydroxypropylmethylcellulose with or without other excipients and the resulting mixture is compressed into tablets. After oral administration of these tablets, the cellulose ethers in the tablets will swell due to hydration by the moisture present in the digestive system, thus limiting the exposure of the active ingredient to moisture. As moisture slowly absorbs the cellulose ethers, water penetrates deeper into the gel matrix and the active ingredient dissolves and diffuses slowly through the gel, making it available for it to be absorbed by the body. U.S. Pat. N ° 4. No. 966,768 discloses an example of this sustained release dosage form of the analgesic / antiinflammatory drug etodolac (Lodine *). REF: 24223 When production in tablets is not feasible, the conventional practice of the pharmaceutical industry is the preparation of encapsulated pharmaceutical formulas that offer prolonged or sustained release properties. In this situation, the dosage forms in prolonged release capsules may be prepared by mixing the drug with one or more binding agents to form a uniform mixture which is then moistened with water or a solvent such as ethanol to form an extrudable plastic mass of which They extrude small diameter cylinders, typically 1 mm, of the drug / matrix that are cut into appropriate lengths and transformed into spheroids using standard spheroidization equipment. After drying, the spheroids may be coated with a film to delay dissolution. The gelatin capsules are filled with the coated spheroids in the amount necessary to obtain the desired therapeutic effect. They can be combined in a gelatin capsule spheroids that release the drug at different speeds in order to obtain the desired blood levels and release levels. U.S. Pat. No. 4,138,475 discloses a sustained release pharmaceutical formula consisting of a hard gelatin capsule filled with spheroids coated with propranolol compounds in a mixture with microcrystalline cellulose, in which the coating is composed of ethylcellulose, optionally with hydroxypropylmethylcellulose and / or a plasticizer . Venlafaxine, 1- [2 - (dimethylamino) -1- (4-methoxyphenyl) ethyl] cyclohexanol is an important drug in the neuropharmacological arsenal used for the treatment of depression. Venlafaxine and the acid addition salts thereof are disclosed in U.S. Pat. 4,535,186. Currently, venlafaxine hydrochloride is administered to adults in the form of compressed tablets at dosage regimens ranging from 75 to 350 mg / day, administered in divided doses two or three times a day. In the therapeutic dosing with venlafaxine hydrochloride tablets, rapid dissolution causes an abrupt increase in the plasma concentrations of the active compound shortly after administration, followed by a decrease in such concentrations over several hours, as it is eliminated. or the active compound is metabolized, until approaching subtherapeutic plasma concentrations after about twelve hours after administration, for which additional doses of the drug are required. With the regimen of multiple daily doses, the most common side effect is nausea, which is experienced by approximately forty-five percent of patients under treatment with venlafaxine hydrochloride. Vomiting also occurs in about seventeen percent of patients.

BRIEF DESCRIPTION OF THE INVENTION According to the present invention, there is provided an encapsulated sustained release (LP) formula containing venlafaxine hydrochloride as an active pharmaceutical compound, which, after a single dose, generates a therapeutic serum concentration over a twenty-four hour period. The administration of the venlafaxine formula of the present invention offers a method to obtain a uniform profile of plasma concentration of the drug as a function of time, thus allowing a better control of the therapeutic range compared to what can be obtained with multiple daily doses. . In other words, this invention offers a method for removing pronounced peaks and valleys (slopes and valleys) from blood concentrations of drugs induced by the daily administration of multiple doses with conventional, immediate-release venlafaxine hydrochloride tablets. In essence, after administration of the sustained release formulas of this invention, the plasma concentrations of venlafaxine hydrochloride increase for about five to about eight hours (optimally, about six hours) and then begin to decay into a decrease. prolonged substantially linear prolongation of the maximum serum concentration for the remainder of the twenty-four hour period, maintaining at least a therapeutic threshold level of the drug throughout the twenty-four hour period. In contrast, conventional venlafaxine hydrochloride tablets of immediate release reach peak serum concentrations within 2 to 4 hours. Accordingly, according to the aspect of use of this invention, a method is offered for moderating the multiple peaks and valleys of the serum concentrations involved in the pharmacokinetic therapy of the multiple daily doses of venlafaxine hydrochloride tablets, which method consists of administration to a patient in need of treatment with venlafaxine hydrochloride of an extended-release venlafaxine hydrochloride formula once a day. The use of the venlafaxine hydrochloride formula once a day of the present invention reduces by adaptation the incidence of nausea and emesis that involves the administration of multiple daily doses. In clinical trials of venlafaxine hydrochloride LP, the likelihood of developing nausea during the course of trials was markedly reduced after the first week.

Venlafaxine LP exhibited a statistically significant improvement over conventional venlafaxine hydrochloride tablets in two eight-week and one 12-week clinical studies. Accordingly, according to this aspect of use of the invention, a method is offered to reduce the level of nausea and the incidence of emesis that leads to the administration of venlafaxine hydrochloride, whose method consists of administration to a patient in need of treatment. with venlafaxine hydrochloride, of a prolonged release formula of venlafaxine hydrochloride once a day in a therapeutically effective amount.

PBfí RTF ^^ ragfflj, tAn * ™ INVENTION 1- [2- (Dimethylamino) -1- (4-methoxyphenyl) ethyl] cyclohexanol hydrochloride is a polymorph compound. Of the forms isolated and characterized to date, Form I is considered the kinetic product of crystallization that can be converted to Form II by heating in the crystallization solvent. Forms I and II can not be distinguished based on their melting points, but they do exhibit certain differences in their infrared spectra and radiographic diffraction patterns. Any of the polymorphic forms such as Form I or Form II may be used in the formulas of the present invention. The extended release formulas of the present invention are composed of 1- [2- (dimethylamino) -1- (4-methoxyphenyl) ethyl] cyclohexanol hydrochloride mixed with microcrystalline cellulose and hydroxypropyl methylcellulose. The formula that contains the drug, formed into beads or spheroids, is coated with a mixture of ethylcellulose and hydroxypropylmethylcellulose to provide the desired level of coating, generally between about two and about twelve percent based on weight / weight of the final product, or more preferably between about five and about ten percent (w / w), with the best results being between about 6 and about 8 percent (w / w). More specifically, the extended release spheroidal formulations of the present invention consist of about 30 to 40 percent venlafaxine hydrochloride, between about 50 and about 70 percent microcrystalline cellulose, FN, between about 0.25. and about 1 percent hydroxypropylmethylcellulose, FEU, and between about 5 and about 10 percent coating film, all based on weight / weight. Also, preferably, spheroidal formulations contain about 35 percent venlafaxine hydrochloride, between about 55 and 60 percent microcrystalline cellulose, FN (Avicel * PH101), about one-half percent hydroxypropylmethylcellulose. 2208, FEU (K3, Dow, which has a viscosity of 3 cps for aqueous solutions at 2%, a methoxy content of 19 to 24% and a hydroxypropoxy content of 4 to 13%) and between about 6 and 8 percent coating film. The coating film consists of 80 to 90 percent ethylcellulose, FN, and 10 to 20 percent hydroxypropyl methylcellulose (2910), FEU, on a weight / weight basis. Preferably, the ethylcellulose has an ethoxy content of 44.0 to 51% and a viscosity of 50 cps for a 5% aqueous solution and the hydroxy-propyl methylcellulose used is FEU 2910, with a viscosity of 6 cps for a solution 2% aqueous, with a methoxy content of 28 to 30% and a hydroxy-propoxy content of 7 to 12%. The ethylcellulose used in this invention is Aqualon HG 2834. Other equivalents of the hydroxy-propyl-methylcelluloses 2208 and 2910, FEU, and ethylcellulose, FN, with the same chemical and physical characteristics as the patented products mentioned above can be substituted in the formula. without altering the concept of the invention.

The possibility of obtaining a prolonged-release formula containing venlafaxine hydrochloride was totally unexpected because venlafaxine hydrochloride is highly soluble in water. Numerous attempts to produce extended release tablets with hydrogel technology have failed because the compressed tablets were physically unstable (poor compressibility or overlapping problems) or dissolves too quickly in dissolution studies. Typically, tablets made as sustained release hydrogel formulations recorded a 40 to 50% solution at 2 hours, 60 to 70% at 4 hours and 85 to 100% at 8 hours. Numerous spheroidal formulas were made using different grades of microcrystalline cellulose and hydroxypropyl methylcellulose, different proportions of venlafaxine hydrochloride and excipient, different binders such as polyvinyl pyrrolidone, methylcellulose, water and polyethylene glycol of different molecular weight ranges to obtain a formula that would provide an appropriate granulation mixture for a satisfactory extrusion. In the extrusion process, an accumulation of heat occurred that dried out both the extruded material and it was difficult to convert the extruded cylinders into spheroids. With the addition of hydroxypropyl methylcellulose 2208 to the mixture of venlafaxine hydrochloride microcrystalline cellulose, the production of spheroids was feasible. The following examples are presented in order to illustrate the applicant's solution to the problem of making the extended-release pharmaceutical formulas of this invention.

Example 1.

CAPSULES DP rrnTCTTTTRATQ DB VENTAFAXIN OF PROLONGED LIBERATON A mixture of 44.8 parts (88.4% free base) of venlafaxine hydrochloride, 74.6 parts of microcrystalline cellulose, FN, and 0.60 parts of hydroxypropyl methylcellulose 2208, FEU is combined with the addition of 41.0 parts of water. The plastic mass of material is extruded, spheroidized and dried to obtain uncoated spheroids containing the drug. 38.25 parts of ethylcellulose, FN, HG are stirred 2834 and 6.75 parts of hydroxypropyl methylcellulose 2910, FEU, in a 1: 1 v / v mixture of methylene chloride and anhydrous methanol until the solution of the coating material is complete.

In a fluidized bed of uncoated spheroids, 0.667 parts of coating solution are applied by uncoated spheroids in order to obtain extended release coated spheroids with a coating degree of 3%. The spheroids are screened to retain the coated spheroids with a particle size between 0.85 mm and 1.76 mm in diameter. These selected coated spheroids are loaded into hard gelatin capsules in the conventional manner.

Example 2 Same as Example 1, except that 1.11 parts of coating solution are applied by uncoated spheroids to obtain a coating degree of 5%.

Example 3 Same as Example 1, except that 1.33 parts of coating solution are applied by uncoated spheroids to obtain a coating degree of 6%.

Example 4 Same as Example 1, except that 1.55 parts of coating solution are applied by uncoated spheroids to obtain a coating degree of 7%. The acceptability test of the degree of coating is determined by analysis of the dissolution rate of the finished coated spheroids before encapsulation. The dissolution procedure used uses FEU Apparatus 1 (basket) at 100 rpm in purified water at 37 ° C. Compliance with the dissolution regimen indicated in Table 1 provides the twenty-four hour therapeutic blood concentrations of the pharmacological component of the extended release capsules of this invention in the form of capsules. When a specific batch of spheroids releases the drug too slowly to comply with the desired dissolution regimen of the studyA portion of uncoated spheroids or spheroids with a lower degree of coating may be added to the batch in order to obtain, after thorough mixing, a loading dose for rapid increase in blood concentrations of the drug. A batch of coated spheroids that release the drug too quickly may receive an additional coating to obtain the desired dissolution profile.

Table 1 Acceptable dissolution rates of coated ssfsroiHpa Time (hours) mean% of venlafaxine HCl released 2 < 30 4 30-55 8 55-80 12 65-90 24 > 80 The batches of venlafaxine hydrochloride-coated spheroids having a dissolution rate corresponding to the regimen indicated in Table 1 are loaded into hard gelatin capsules in an amount sufficient to provide the desired unit dosage level. The standard tablet of immediate-release unit dose (LI) currently used provides amounts of venlafaxine hydrochloride equivalent to 25 mg, 37.5 mg, 50 mg, 75 mg and 100 mg of venlafaxine. The capsules of this invention are loaded to provide an amount of venlafaxine hydrochloride equivalent to that currently used in the form of a tablet, and also up to about 150 mg of venlafaxine hydrochloride.

The dissolution of the venlafaxine LP hydrochloride capsules is determined in accordance with that indicated in the US Pharmacopoeia. (FEU) using the apparatus 1 at 100 rpm in 0.9 L of water. A filtered sample is taken from the dissolution medium at the specified intervals. The absorbance of the clear solution is determined from 240 to 450 nanometers (nm) as a function of the dissolution medium. A baseline value is plotted from 450 nm to 400 nm and extended to 240 nm. Absorbance at the maximum absorbance wavelength (around 274 nm) is determined with respect to this baseline value. Six hard gelatine capsules are loaded with the theoretical amount of venlafaxine hydrochloride spheroids and their dissolution is measured. The standard samples consist of standard solutions of venlafaxine hydrochloride plus a correction solution of the gelatin capsule. The percentage of venlafaxine released is determined using the following equation: % d-venlafaxine hydrochloride released - IAsHWr) < SHV1l (0.888H100) (Ar) (V2). { C) where As is the absorbance of the sample composition, Wr is the weight of the reference standard, in mg; S is the power of the reference standard, in decimal; VI is the volume of the dissolution medium used to dissolve the dosage form, in me; 0.884 is the percentage of free base; Ar is the absorbance of the standard preparation; V2 is the volume of the standard reference solution, in me, and C is the concentration of the capsule in mg. Table 2 shows the plasma concentration of venlafaxine as a function of time for a conventional immediate-release tablet (L1) of 75 mg administered every 12 hours, two prolonged-release (LP) capsules of 75 mg administered simultaneously every 24 hours and one capsule prolonged release (LP) of 150 mg administered once every 24 hours to male subjects. The subjects were already receiving venlafaxine hydrochloride according to the dosage protocol, and therefore the plasma concentration at zero hour of dose administration is not zero.

Table 2 Plasma concentration of venlafaxine (ng / ml) as a function of time, conventional tablet (not prolonged release) compared to the LP capsule.

Time (hours) Tablet (I) 2 capsules (LP) 1 capsule (LP) of 75 mg of 75 mg of 150 mg (c / 12 h) (w / 24 h) (w / 24 h) 0 62 3 55.0 55.8 0. 5 76.3 1 135.6 53.3 53.2 2 212.1 69.8 70.9 4 162.0 138.6 133.3 6 114.6 149.0 143.5 8 86.7 129.3 129.5 118.4 114.4 12 51.9 105.1 105.8 12. 5 74.7 13 127.5 14 161.3 90.5 91.3 16 134.6 78.2 78.5 18 106.2 20 83.6 62.7 63.3 24 57.6 56.0 57.3 Table 2 shows that the plasma concentrations of the two capsules of venlafaxine LP 75 mg / capsule and 150 mg venlafaxine LP hydrochloride capsule achieve very similar plasma concentrations. The data also reveal that the plasma concentration after 24 hours for the two prolonged-release regimens is very similar to that obtained with the two tablets of immediate-release venlafaxine hydrochloride., 75 mg, administered at 12-hour intervals. Additionally, venlafaxine plasma concentrations, obtained with the prolonged-release formula, do not rise to the maximum concentrations obtained with conventional immediate-release tablets administered at 12-hour intervals. The maximum concentration of venlafaxine (LP), slightly lower than 150 ng / ml, is reached within approximately six hours, plus or minus two hours, based on this specific dose administered to patients currently under treatment with venlafaxine hydrochloride (LI ). The maximum plasma concentration of venlafaxine, slightly higher than 200 ng / ml after the administration of the form (Ll), is reached within two hours, after which it decays rapidly.

Table 3 shows the plasma concentrations of venlafaxine in male subjects with an initial blood concentration of zero. Again, the maximum plasma concentration of venlafaxine is observed about 6 hours after the administration of the prolonged-release venlafaxine hydrochloride capsules in the indicated amounts. Subjects receiving the 50 mg immediate release capsule exhibited a maximum plasma concentration at approximately 4 hours. For comparative purposes, venlafaxine plasma concentrations for subjects who received the conventional tablet can be multiplied by a factor of three to approximate the expected plasma concentrations of a single 150 mg dose of the conventional formula.

Table 3. Plasma concentrations in male subjects without previous venlafaxine plasma concentration Time (hours) Tablet Ll 2 capsules LP 1 capsule LP of 50 mg of 75 mg of 150 mg 0 0 0 0 27.87 1.3 0. 1. 5 44.12 6.0 2.2 2 54.83 20.6 12.8 4 66.38 77.0 81.0 6 49.36 96.5 94.4 8 30.06 93.3 86.9 10 21.84 73.2 72.8 12 15.91 61.3 61.4 14 13.73 52.9 51.9 16 10.67 47.5 41.1 20 5.52 35.2 34.0 24 3.56 29.3 28.5 28 2.53 23.4 22.9 36 1.44 11.9 13.5 48 0.66 5.8 5.2 The venlafaxine plasma concentrations were measured according to the following procedure. Blood samples were collected from the subjects in heparinized evacuated blood tubes and the tubes were gently inverted several times. As quickly as possible, the tubes were centrifuged at 2500 rpm for 15 minutes. The plasma was pipetted into plastic tubes and stored at -20 ° C until the tests were completed.

To 1 ml of each plasma sample in a plastic tube was added 150 μl of a standard internal mother solution (150 μg / ml). To each tube was added a solution of saturated sodium borate (0.2 ml) and vortexed. To each tube 5 ml of ethyl ether was added and then capped and stirred for 10 minutes at high speed. The tubes were centrifuged at 3000 rpm for 5 minutes. The aqueous layer was frozen in dry ice and the organic layer was transferred to a clean tube with a screw cap. An aliquot of 0.3 ml of 0.01 N HCl was added to each tube and stirred at high speed for 10 minutes. The aqueous layer was frozen and the organic layer was removed and discarded.

To each tube was added a 50 μl aliquot of the mobile phase (23:77 of acetonitrile: 0.1 M monobasic ammonium phosphate buffer, pH 4.4), the tubes were vortexed and 50 μl samples were injected onto a Supelco Supelcoil LC-8-DB column of 5 cm x 4.6 mm, 5 μ, in a high pressure liquid chromatography apparatus equipped with a Waters Lambda Max 481 detector or its equivalent, at 229 nm. As a standard, solutions of venlafaxine hydrochloride at various concentrations were employed. In this way, with the spheroidal coated formulations of the present invention, the desired dissolution rate of a sustained release dosage form of venlafaxine hydrochloride, which is impossible to obtain with the hydrogel tablet technology, has been achieved. It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it relates. Having described the invention as above, property is claimed as contained in the following:

Claims (8)

1. An encapsulated formula of prolonged release of venlafaxine hydrochloride, characterized in that it is composed of a hard gelatin capsule containing a therapeutically effective amount of spheroids composed of venlafaxine hydrochloride, microcrystalline cellulose and hydroxypropyl methylcellulose coated with ethylcellulose and hydroxypropyl -methylcellulose.

2. A prolonged-release formula according to claim 1, characterized in that the spheroids are composed of about 37.3% by weight of venlafaxine hydrochloride, about 0.5% by weight of hydroxypropyl-methylcellulose 2208 and about dl. 62.17% by weight of microcrystalline cellulose.

3. The formula according to claim 1, characterized in that the coating film is composed of ethylcellulose (4.81% of the total weight) and hydroxypropylmethylcellulose (0.85% of the total weight).

4. The formula according to claim 1, characterized in that the coating film is composed of ethylcellulose (4.04% of the total weight) and hydroxypropylmethylcellulose (0.714% of the total weight).

5. The formula according to claim 1, characterized in that the coating film is composed of ethylcellulose (2.48% of the total weight) and hydroxypropylmethylcellulose (0.437% of the total weight).

6. A coating film formula, characterized in that it is composed of ethylcellulose (15% of total weight), with a content of 44.0 to 51.0% of ethoxy groups, and hydroxypropyl methylcellulose (85% of total weight) , with a methoxy content of 28.0 to 30.0% and a hydroxypropoxy group content of 7.0 to 12.0%.

7. A prolonged release formula of venlafaxine hydrochloride for administration once a day, characterized because it is composed of spheroids containing 37.3% of venlafaxine, 62.17% of microcrystalline cellulose and 0.5% of hydroxy-propyl-methylcellulose type 2208, coated with an amount of a mixture composed of 15% ethylcellulose type HG 2834 and 85% hydroxypropylmethylcellulose type 2910 sufficient to generate coated spheroids with a dissolution profile that complies with the desired release regime during a 24 hour period.

8. The prolonged release formula of venlafaxine hydrochloride according to claim 7, characterized in that it offers lower peak serum concentrations of up to 150 ng / ml and prolonged therapeutically effective plasma concentrations over a twenty-four hour period.