KR101285103B1 - Sustained release venlafaxine hydrochloride formulations - Google Patents

Abstract

The present invention relates to a sustained-release preparation containing venlafaxine hydrochloride, and more particularly, using a predetermined amount of venlafaxine hydrochloride as an effective drug, and mixing a wax-like thermoplastic material at a predetermined ratio as a base to control elution from the inside and from the outside. The present invention relates to venlafaxine hydrochloride-containing sustained-release preparations capable of controlling elution more consistently than conventional venlafaxine hydrochloride-containing sustained-release preparations through double control of the coating layer.

Venlafaxine Hydrochloride, Sustained Release Formulations

Description

Sustained release venlafaxine hydrochloride formulations             

Figure 1 shows the sustained release formulation dissolution rate of Comparative Examples 2 to 5 and Example 1 over time

Figure 2 is a comparison of the dissolution rate of the sustained release capsule of Example 1 with commercially available IPAX XAL [Wires Corporation] over time.

The present invention relates to a sustained-release preparation containing venlafaxine hydrochloride, and more particularly, by using a predetermined amount of venlafaxine hydrochloride as an effective drug, and mixing and melting a wax-like thermoplastic material at a predetermined ratio as a base, and then formulating it. The present invention relates to venlafaxine hydrochloride-containing sustained-release preparations capable of more uniform elution control than venlafaxine hydrochloride-containing sustained-release preparations.

The advantages of sustained release preparations in the pharmaceutical art are generally well known. Among these advantages, the blood concentration of the drug can be maintained at a desirable level for a relatively long period of time, which can reduce the number of administrations required to achieve the same purpose as a conventional method, and consequently, can improve drug adaptability to patients.

Sustained-release drugs are generally administered orally. An important feature of sustained-release drugs is that the active drug should be released slowly over an extended period of effective blood concentration, contain no toxic or irritant components, and be a high dose drug. It should also be suitable.

Conventionally, sustained release has been achieved using a method using a sustained release carrier such as a hydrophilic polymer, a method using a sustained release carrier of a hydrophobic polymer such as a wax-like material, and a film coating.

In the case of the matrix preparation in which the drug is dispersed in the matrix of the sustained release carrier of the hydrophilic polymer, the dissolution rate of the drug in the sustained release preparation is determined by the viscosity of the hydrophilic polymer (2%, 20 ° C), hydrophilicity. Although it is influenced by the ratio of polymer and drug content, tableting pressure, tablet shape and thickness, excipient, drug particle size, tablet surface area, etc., the viscosity of hydrophilic polymer and the content ratio of hydrophilic polymer and drug and the physical properties of drug It is determined by chemical properties.

There are many reports on sustained-release preparations, and various polymer materials are used for most of these preparations. For example, hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, flulan, gelatin, collagen, casein, agar, gum arabic, dextrin, ethylcellulose, methylcellulose, chitin, chitosan, mannan , Carboxymethylethylcellulose, sodium carboxymethylcellulose, polyethyleneglycols, sodium alginate, polyvinylalcohol, cellulose acetate, polyvinylpyrrolidone, silicone, polyvinylacetaldiethylamino acetate, albumin and the like [Sustained and controlled Release Drug Delivery Systems (1978) MARCEL DEKKER, INC.].

Melt granulation techniques in sustained release formulations have also been used for years in Europe and the like. This melt granulation technique has several advantages, cost and stability compared to alcohol granulation technique. No solvents, associated fire protection equipment and solvent recovery equipment are required. The control of drug release from conventional melt granulation matrices, Drug development and industrial pharmacy, 13 (6), 1001-1022 (1987).

Many melt granulation techniques have been reported in this regard, and various polymer materials are used for most of these formulations. For example natural fats (e.g. coconut, soy, cocoa) itself or partly or wholly hydrogenated, beeswax, polyethoxylated beeswax, single, double or triple substituted glycerides, glyceryl palmitostearate, glycerol Reel behenate, diethylene glycol palmitostearate, polyethylene glycol stearate, polyoxyethylene glycol palmitostearate, glyceryl monopalmitostearate, cetyl palmitate, polyethylene glycol palmitostearate, mono- or di- Glyceryl behenate, polyethoxylate fatty alcohols, fatty alcohols, cetyl alcohols, stearic acid, saturated or unsaturated fatty acids or hydrogenated derivatives thereof, and / or hydrogenated casta oils and the like.

Conventionally, sustained release has been achieved by coating drug formulations, and the development of such sustained release formulations has relied on highly chemically modified coatings and the like, leading to the production of formulations of reliable quality. In addition, significant advances have been made in the coating technology with advances in the coating equipment technology, in particular with the invention of a warster film coating machine.

Many coating technologies have been reported, and for these sustained release coatings, non-enteric coating materials include ethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, carboxymethylcellulose, and carnauba. Waxes, castor oils, cetyl alcohols, ethylene vinyl acetate copolymers, hydrogenated vegetable oils, polyvinyl alcohols, silicone based polymers and enteric coating materials, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, methacrylic acid polymers, poly Vinyl acetate phthalate and shellac.

Sustained release preparations are effectively used in a group of drugs that act as antihypertensive agents and anti-inflammatory drugs that have a constant concentration in the blood. Examples of such drugs are felodipine (felodipine), nicardipine (nicardipine), nifedipine (nifedipine), diclofenac (diclofenac), ibuprofen (ibuprofen), indomethacin (indomethacin) and the like.

Meanwhile, venlafaxine hydrochloride is used as an antidepressant, and studies on sustained release formulations of venlafaxine hydrochloride are as follows.

Venlafaxine, 1- [2- (dimethylamino) -1- (4-methoxyphenyl) ethyl] cyclohexanol, is an important drug among neuropharmacological agents used in the treatment of depression. Venlafaxine and acid addition salts thereof are described in US Pat. No. 4,535,186. At present, venlafaxine hydrochloride is administered to adults in compressed tablet form divided into two or three times daily doses ranging from 70 to 350 mg / day. In the case of therapy with venlafaxine hydrochloride tablets, rapid dissolution rapidly increases the plasma level of the active compound immediately after administration, and then decreases the plasma level over several hours as the active compound is removed or metabolized. It is therefore required to additionally administer the medicament, since plasma levels are reached which do not have a therapeutic effect about 12 hours after administration. For multiple daily regimens, the most common side effect is nausea experienced in about 45% of patients treated with venlafaxine hydrochloride. Vomiting also occurs in about 17% of patients.

Korean Patent Application No. 1997-8590 describes a sustained release capsule comprising venlafaxine hydrochloride, microcrystalline cellulose and hydroxypropylmethylcellulose and containing a therapeutically effective amount of spheroid coated with ethylcellulose and hydroxypropylmethylcellulose However, there is a problem that a large variation in dissolution rate between formulations is emerging.

International patent publication WO 00/71099 A1 discloses a multiple of beads or pellets of a drug coated with a rate-controlling membrane that allows sustained release of selective serotonin reuptake inhibitors (SSRIs) for at least 12 hours after oral administration. Particle sustained release formulations are described. In addition, there is a problem that the variation in dissolution rate between formulations is great.

Korean Patent Application No. 1993-001899 discloses a sustained-release powder containing one or two or more selected from oily components and water-insoluble polymers, and containing a pharmacologically active substance, and a sustained-release powder containing a water-soluble polymer and a pharmacological activity. Although slow-release tablets containing a sieve are described, there is a problem of excessive initial dissolution in water-soluble drugs.

Such excessive initial release results in the release of the drug at the initial stage of administration in a sustained release formulation that requires a constant blood profile, making it impossible to control the long-term dose of the drug. There is a problem in that the variation between the objects in the effect appears.

Therefore, the present inventors have studied to solve the above problems, using a predetermined amount of venlafaxine hydrochloride as an effective drug, by mixing the wax-like thermoplastic material in a constant ratio as a base for sustained release and formulated it to the conventional venlafaxine hydrochloride The present invention has been completed by enabling a constant dissolution control (the coefficient of variation of dissolution rate of 3% or less) through dual control of the wax from the inside and double coating of the coating layer from the outside.

Accordingly, an object of the present invention is to provide a venlafaxine hydrochloride-containing sustained-release preparation having a coefficient of variation of dissolution rate of 3% or less.

In the present invention, venlafaxine hydrochloride and one or more wax-like thermoplastics are melted to form a carrier and composed of one or more coating agents and have a CV (Coefficient of Variation) coefficient of dissolution rate of 3% or less. The formulation is characterized by that.

Hereinafter, the present invention will be described in detail.

The present invention uses a certain amount of venlafaxine hydrochloride as an effective drug, and by mixing and melting a wax-like thermoplastic material at a predetermined ratio as a base, then coating and sustained release, and formulated it, more uniform dissolution control than conventional venlafaxine hydrochloride-containing sustained-release formulation It relates to a venlafaxine hydrochloride-containing sustained-release preparation that can be.

The venlafaxine hydrochloride-containing sustained-release preparation of the present invention will be described in more detail according to the composition of the composition as follows.

Venlafaxine hydrochloride, an active ingredient of the sustained-release preparation according to the present invention, has been used as an antidepressant, and it has been difficult to sustain release due to a problem in which venlafaxine hydrochloride is soluble in water. Coating solved the problem.

In addition, a wax-like thermoplastic is used as a sustained release carrier which is the most important component for sustaining the effective drug, and a preferable content thereof is 20 to 500 parts by weight based on 100 parts by weight of the venlafaxine hydrochloride. If the content of the wax-like thermoplastic is less than 20 parts by weight, there is a problem of excessive initial release, and if it exceeds 500 parts by weight, there is a problem that the dosage unit becomes large and difficult to take. More preferably 100 to 400 parts by weight based on 100 parts by weight of the venlafaxine hydrochloride. The wax-like thermoplastic material serves as a sustained release carrier, and the hydrophobic thermoplastic material may be a natural fat (eg coconut, soybean, cocoa) itself or partly or wholly hydrogenated, beeswax, polyethoxylated beeswax, single , Double or triple substituted glycerides, glyceryl palmitostearate, diglyceryl behenate, glyceryl behenate, diethylene glycol palmitostearate, polyethylene glycol stearate, polyoxyethylene glycol palmitostearate, glycerol Reel monopalmitostearate, cetyl palmitate, polyethylene glycol palmitostearate, fatty alcohols associated with polyethoxylate fatty alcohols, cetyl alcohol, stearic acid, saturated fatty acids, unsaturated fatty acids or hydrogenated derivatives thereof, and hydrogenated cations At least one selected from star oils is preferred.

In addition, in the sustained-release preparation according to the present invention, talc, magnesium stearate, and the like are used within the range of a pharmaceutical formulation in an amount of 100 parts by weight of the active drug as an excipient, in addition to the above-described active drug and sustained-release carrier.

In addition, it is preferable to use 5 to 100 parts by weight of a pharmaceutically usable coating material with respect to 100 parts by weight of the effective drug as a coating agent, and particularly preferably 10 to 75 parts by weight. As the coating agent, when the content of the coating agent is less than 5 parts by weight, there is a problem of initial release, and when it exceeds 100 parts by weight, there is a problem of release delay. The coating material may be ethyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, carboxymethyl cellulose, carnauba wax, castor oil, cetyl alcohol, ethylene vinyl acetate copolymer, hydrogenated vegetable oil, polyvinyl At least one selected from alcohols, silicone-based polymers, cellulose acetate phthalates, hydroxypropylmethylcellulose phthalates, methacrylic acid polymers, polyvinylacetate phthalates and shellac is preferred.

Referring to the process of producing a sustained release formulation as the composition component in detail as follows.

The dissolution rate criteria of the sustained release formulation thus obtained are shown in Table 1 below.

Time (h) Average Dissolution Rate of Venlafaxine Chloride (%) 2 〈30 4 30 to 55 8 55 to 80 12 65 to 90 24 80 〈

Therefore, the venlafaxine hydrochloride-containing sustained-release capsule according to the present invention can obtain a constant blood profile by controlling elution with wax in the inside than the conventional sustained-release formulation and enabling constant elution control through double control to the coating layer on the outside. Can be.

As a manufacturing method, there are a manufacturing method by a melting method for producing an internal dissolution control layer and a manufacturing method for double control through an external coating layer. As a manufacturing method through the melting method, it is possible to manufacture granules that can prepare pellets and hard capsules, mini tablets and general tablets by pharmaceutically applicable methods such as high speed mixer, hot melt extrusion method and hot melt fluidized bed method. In order to apply the coating layer by using this coating is carried out using a pharmaceutically applicable coating tool such as a high coater, fluidized bed coater or CF coater.

Hereinafter, the present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

Example 1 and Comparative Examples 1-5

Cutina HR was dissolved at 85 ° C. with venlafaxine hydrochloride and hydrogenated casta oil. The resulting melt was transferred to a metal container, cooled to 42 ° C., and granules were prepared using a high speed mixer. The granules were mixed with talc, magnesium stearate and hit directly into 3 mm mini tablets. Eudragit RS and dibutyl sebacade were stirred in isopropyl alcohol to prepare a solution for coating. The mini-tablet was coated with the coating solution to obtain a sustained-release coating mini-tablet. The sustained release mini tablets were filled into hard gelatin capsules according to a conventional method to finally obtain a capsule.

division Weight (mg) / Capsule Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Example 1 Effective drug Venlafaxine Hydrochloride 100 100 100 100 100 100 carrier Hydrogenated castor oil 420 270 10 10 320 300 Elution
For control
Excipient Talc 7 4 One One 6 5 Magnesium stearate 7 4 One One 6 5 Coating Eudragit RS 150 0 0 25 140 50 DBS 8 0 0 One 7 3

Examples 2-6

Glyceryl Behenate, Glyceryl Palmitostearate, Carnauba Wax Instead of Hydrogenated Castor Oil, Compritol 888, Precirol ATO, Caranda wax in various sizes, prepared in minitablets, tablets and pellets with ethylcellulose The experiment was carried out in the same manner as in Example 1 except that it was used.

division Weight (mg) / Capsule Example 2 Example 3 Example 4 Example 5 Example 6 Effective drug Venlafaxine Hydrochloride 100 100 100 100 100 carrier Glyceryl behenate 330 Glyceryl Palmitostearate 290 220 Carnauba wax 250 320 Elution
For control
Excipient Talc 6 One 7 4 One Magnesium stearate 6 One 7 4 One Coating Ethyl cellulose 80 60 30 20 30 DBS 4 3 1.5 One 1.5 Tablet size 3 mm 4 mm 5 mm 9mm - Formulation Type Mini Tablet Mini Tablet Mini Tablet refine Pellets

Experimental Example 1: Confirm the dissolution effect

The capsule was subjected to the dissolution test in the following manner.

1. Apparatus-USP Type I (Basket), 100 rpm

2. Eluent-Purified Water 900ml

3. Sampling time-2, 3, 8, 12 hours and 24 hours

4. Analysis-Measure the absorbance at wavelength 274 nm by testing according to the absorbance method

5. The elution criteria are shown in Table 1 above and were in accordance with Korean Patent Application No. 1997-8590.

division Dissolution rate (%) Comparative Example 2 Comparative Example 4 Comparative Example 5 Example 1 Example 2 Dissolution Criteria Dissolution Criteria time
(h) 2 46 80 69 14 13 0 30 4 67 95 82 38 36 30 50 8 78 100 93 63 61 55 80 12 89 99 98 73 70 65 90 24 98 100 100 90 89 80 100

As shown in Table 4, the sustained-release capsules of Examples 1 and 2 are lower than the general formulation initial dissolution rate than the general formulation initial dissolution rate (20 ~ 30%) and gradually the drug at a constant rate for 24 hours The release was confirmed to be a very suitable formulation as a sustained release formulation.

Experimental Example 2: Comparison of Dissolution Rates

The results of comparing the dissolution rate of IPAX XAL, which is a sustained-release capsule containing Wila's venlafaxine hydrochloride, and the sustained-release capsule of Example 1 are shown in the following Table 5, Table 6 and FIG.                     

The capsule was subjected to the dissolution test in the following manner.

1. Apparatus-USP Type I (Basket), 100 rpm

2. Eluate-900 ml of purified water

3. Sampling time-2, 3, 8, 12 hours and 24 hours

4. Analysis-Measure the absorbance at wavelength 274 nm by testing according to the absorbance method

5. The elution criteria are shown in Table 1 above and were in accordance with Korean Patent Application No. 1997-8590.

Elution Effect of Ifax XAL with Time division Dissolution rate (mean ± standard deviation,%) C.V (%) time
(h) 2 11 ± 0.90 7.87 4 37 ± 3.30 8.96 8 60 ± 3.84 6.37 12 70 ± 3.56 5.06 24 85 ± 2.43 3.10

Elution Effect of Sustained-release Capsule of Example 1 with Time division Dissolution rate (mean ± standard deviation,%) C.V (%) time
(h) 2 14 ± 0.41 2.46 4 38 ± 0.71 1.89 8 63 ± 0.53 0.84 12 73 ± 1.54 2.10 24 90 ± 1.35 1.50

As shown in Table 5 and Table 6, the sustained release formulation of Example 1 has a better dissolution rate with time compared to the IPAX XAL, and the CV is more constant, indicating that the drug is constantly eluted for 24 hours. Confirmed.

As described above, the venlafaxine hydrochloride-containing sustained-release capsule according to the present invention can control the dissolution with wax in the inside and more precise dissolution control through the double control to the coating layer from the outside than the conventional sustained release formulation. have.

Claims (6)

One or more wax-like selected from hydrogenated castor oil, glyceryl behenate, diglyceryl behenate, glyceryl palmitostearate, glyceryl monopalmitostearate, carnauba wax, relative to 100 parts by weight of venlafaxine hydrochloride 20 to 500 parts by weight of the thermoplastic polymer as a carrier and granules obtained by melting the same, at least one coating agent selected from ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, carboxymethyl cellulose and methacrylic acid polymer Venlafaxine hydrochloride-containing sustained-release preparation, characterized in that the coating layer is formed from 20 to 75 parts by weight, and the CV (Coefficient of Variation) value of the dissolution rate is 3% or less. delete delete delete A sustained release preparation comprising 100 to 400 parts by weight of a wax-like thermoplastic polymer and 20 to 75 parts by weight of a coating agent based on 100 parts by weight of venlafaxine hydrochloride. The sustained-release preparation according to claim 1, wherein the sustained-release preparation is a pellet, a mini tablet, a capsule, or a tablet.

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