JP2001522794A - New oral dosage form of carvedilol - Google Patents

Abstract

  (57) [Summary] The present invention describes a matrix formulation comprising carvedilol.

Description

DETAILED DESCRIPTION OF THE INVENTION

FIELD OF THE INVENTION [0001] The present invention relates to novel formulations comprising carvedilol or a pharmaceutically acceptable salt thereof, and its use in treating and / or preventing certain disorders.

BACKGROUND OF THE INVENTION US Pat. No. 4,503,067 describes a compound known as carvedilol. This compound is a novel multi-agent useful in the treatment of mild to moderate hypertension. Carvedilol is also a competitive non-selective β-adrenergic receptor antagonist and is also known to be a vasodilator. The vasodilator effect of carvedilol is mainly obtained from α ₁ -adrenergic receptor blockers, while the β-adrenergic receptor blocking activity of the drug prevents reflex tachycardia when used in the treatment of hypertension. I do. These multiple actions of carvedilol are due to the antihypertensive action of the drug. Carvedilol is also useful for organ protection, especially cardioprotection, as a result of its antioxidant action in attenuating lipid peroxidation initiated by oxygen free radicals. In addition, carvedilol is useful for treating congestive heart failure.

[0003] Current carvedilol formulations are conventional swallow tablets that are administered twice daily.
The formulation is in immediate release form; that is, the formulation is in the form of a solution or a suspension of fine particles, by the time carvedilol leaves the stomach, ie, a form in which carvedilol can be readily absorbed. It has the property of becoming

[0004] Recently, a controlled-release and slow-release preparation containing carvedilol has been used once a day.
It has been found that a single dose preparation can be obtained. These formulations can extend the duration of action of carvedilol and thus improve the bioavailability of the drug.

SUMMARY OF THE INVENTION [0005] The present invention provides controlled release or slow release formulations comprising carvedilol or a pharmaceutically acceptable salt thereof.

Detailed Description of the Invention The present invention relates to oral unit dosage forms of the formula (I):

Embedded image A controlled release containing carvedilol which is 1- (carbazol-4-yloxy-3-[[2- (o-methoxyphenoxy) ethyl] amino] -2-propanol or a pharmaceutically acceptable salt thereof represented by Provide a slow release formulation.

The present invention also provides a matrix formulation comprising carvedilol in oral unit dosage form,
And an enteric formulation comprising carvedilol in oral unit dosage form.

[0008] Carvedilol can be conveniently prepared as described in US Patent No. 4,503,067. The patent should be cited for its full description, the entire content of which is incorporated herein by reference.

In the formulations of the present invention, carvedilol is preferably in the form of the free base or a pharmaceutically acceptable salt thereof. Preferably, carvedilol is in free base form.

The term controlled release refers to a formulation that provides a slow release of drug over an extended period of time. In the controlled release formulation of the present invention, a part of carvedilol in the formulation,
It becomes available as an initial dose and the rest is released continuously. One example of a controlled release system is a matrix formulation.

The term slow release refers to a formulation that utilizes carvedilol repeatedly and intermittently from one or more immediate release units incorporated into a dosage form. Examples of slow release systems include repetitive acting tablets and capsules, and enteric coated tablets, where release is achieved after a period of time by the barrier coating.

Examples of controlled release formulations suitable for containing carvedilol include: Sustained Release Medications, Chemical Technology, Review No. 177, Ed.
JC Johnson, Noyes Data Corporation (1980); and Controlled Drug Delivery, Fundamentals and Applications, 2nd Edition,
Eds. JR Robinson, VHL Lee, Mercel Dekkes Inc., New York (1987).

Examples of suitable slow release formulations containing carvedilol include Remington's Pharmaceutical Sciences, 16th Edition, Ed. A. Osol, Mack P.
ublishing Company (1980).

Other examples of controlled release formulations suitable for containing carvedilol are US Pat. No. 4,839,177 issued June 13, 1989 and US Pat. No. 4,839,177 issued June 6, 1995. No. 5,422,123. A controlled release matrix formulation of carvedilol is disclosed in U.S. Pat.No. 4,389,393 issued June 21, 1983 and in November 1990.
No. 4,968,508, issued on Jun. 6, 2016.

[0015] Further, the controlled-release preparation containing carvedilol may be in the form of an uncompressed pellet having an enteric coating or sustained-release coating which is permeable to gastrointestinal fluids. These controlled release formulations are prepared, for example, as described in US Pat. No. 4,524,060 issued June 18, 1985 and US Pat. No. 4,983,401 issued Jan. 8, 1991. Other controlled release formulations are U.S. Pat.No. 4,880,830 issued Nov. 14, 1989 and U.S. Pat.No. 5,068,1 issued Nov. 26, 1991.
It is described in No. 12.

Such controlled release formulations are preferably formulated so that the release of carvedilol occurs predominantly during passage through the stomach and small intestine, while slow release formulations are preferably formulated such that the release of carvedilol is gastric It is formulated so that it is avoided in the interior and predominantly takes place during its passage through the small intestine.

The formulation is preferably formulated such that the release of carvedilol is predominantly 1.5 to 3 hours after ingestion.

[0018] The small intestine is preferably the duodenum, ileum or jejunum.

The formulations of the present invention allow for once daily dosing.

Preferred formulations of carvedilol are enteric coated tablets or caplets, wax or polymer coated tablets or caplets, or time release matrixes, or combinations thereof. The oral route of administration of the formulations of the present invention is preferred.

In the present invention, the controlled release preparation may be a matrix preparation. The formulation may include a plurality of matrix cores comprising carvedilol, wherein the matrix cores have different release rates of the drug. Preferred formulations include an immediate release phase and a sustained release phase of carvedilol. The sustained release phase matrix core may or may not be coated with a release retardant. Preferably, when the matrix core is coated with a release retardant, the release retardant is present in an amount of 2 to 30% (w / w) relative to the matrix core. More preferably, the release retardant is present in an amount from 5 to 25% (w / w).

The release retardant of the present invention is a coating or blend of coatings that prevents carvedilol from immediately degrading in the stomach. The overcoating allows for continuous, slow or slow release, depending on the desired release rate. A preferred release retardant is an enteric coating, ie, a pharmaceutical preparation that disintegrates in the intestine, which has been treated to pass through the stomach unchanged.

The matrix formulation of the present invention can be prepared using three types of substances: insoluble plastics, hydrophilic polymers or aliphatic compounds. Plastic matrices include methyl acrylate-methacrylate, polyvinyl chloride and polyethylene. Hydrophilic polymers include methylcellulose, hydroxypropylmethylcellulose (HMPC) and sodium carboxymethylcellulose. Aliphatic compounds include various waxes such as carnauba wax and glycerin tristearate. The most common preparation method is to mix carvedilol with a matrix material and then tablet the mixture. In the case of a wax matrix, the carvedilol is generally dispersed in molten wax, then coagulated, granulated and compressed into a core. In such matrix formulations containing carvedilol, the initial dose (a portion of the carvedilol that is readily available in the formulation) is located in the tablet coating. The coating can be applied by press coating or conventional pan or air suspension coating.

In one embodiment of the invention, the carvedilol matrix tablet formulation comprises H
Includes a mixture of MPC and Carbopol. In another embodiment of the present invention, the carvedilol matrix tablet formulation comprises a mixture of HMPC, carbopol and mannitol. The following flow diagram illustrates the manufacturing process for preparing a controlled release tablet containing carvedilol.

[0025]

[Table 1]

In the present invention, carvedilol, mannitol and HPMC are granulated using purified water, subjected to wet sieving, and then dried. The dried granules are sieved.
The resulting internal granulation is blended with the pre-sieved Carbomer 941 until homogeneous. Pre-sieved magnesium stearate is mixed with the blend to form a compressed mixture. The tablets are compressed as round cores, coated with a white Opadry® solution to about 3% weight gain, and then about 0.5% weight gained with a clear Opadry® solution. Coat until done.

The present invention also provides various combinations of immediate release and controlled release forms. For example, an uncoated sustained release matrix core may be combined with an immediate release form of carvedilol and / or a coated matrix form. The matrix core may be composed of a plurality of pellets separately coated with different release retardants, all of which may be combined with an uncoated or immediate release form of carvedilol.

[0028] Slow release formulations containing carvedilol can be prepared either by coating the particles or granules of carvedilol with a slowly dissolving polymer while changing its thickness or by microencapsulation. In formulations using microencapsulation, the hydrophilic substance acts as a coating substance around the microcapsules. The hydrophilic substance can be selected from a variety of natural and synthetic polymers including shellac, wax, starch, cellulose phthalate or butyrate, polyvinylpyrrolidone and polyvinyl chloride. As soon as the coating substance dissolves, all the carvedilol in the microcapsules is immediately available for dissolution and absorption. Thus, the release of carvedilol can be controlled by adjusting the coating thickness and dissolution rate. The thickness can be varied from less than 1 micromolar to 200 micromolar by varying the amount of coating material from 3% to 30% of the total weight. With several, usually three or four, thicknesses, the carvedilol is released at various predetermined points in time, resulting in a delayed, or repetitive, effect. Using spectra of various thicknesses, more uniform carvedilol blood levels can be obtained. The coated particles can be compressed directly into tablets or placed in a capsule.

[0029] Carvedilol in the form of controlled or slow release formulations can be used to treat hypertension, angina and congestive heart failure. The formulations of the present invention also include
It can be used for organ defense, for example, heart defense.

The present invention is a method of treating hypertension, angina and congestive heart failure, comprising a controlled release or a slow release comprising an effective amount of carvedilol or a pharmaceutically acceptable salt thereof in a patient in need of such treatment. A method of treatment by administering a formulation is provided.

The present invention further provides the use of a controlled or slow release formulation comprising carvedilol or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of hypertension, angina and congestive heart failure.

The present invention also provides a pharmaceutical composition for the treatment of hypertension, angina and congestive heart failure, comprising a controlled release or slow release formulation comprising carvedilol or a pharmaceutically acceptable salt thereof, preferably a matrix formulation. I will provide a.

It is believed that there is no unacceptable toxic effect when carvedilol is used according to the present invention.

The following examples do not limit the scope of the invention, but are provided to illustrate the invention. Many other embodiments will be readily apparent to those skilled in the art.

EXAMPLES Description of the Manufacturing Process Blend Step 1 Weigh out the exact amounts of carvedilol, mannitol, hydroxypropyl methylcellulose and purified water. Step 2 Transfer carvedilol, mannitol and hydroxypropyl methylcellulose to a high shear mixer product bowl. Step 3 Pre-blend ingredients for 2 minutes with impeller and chopper at low speed setting.

Granulation Step 4 Granulate with purified water at low speed until desired granules appear Step 5 Fill the granules in a stainless steel container for wet milling process. Step 6 Slowly add the wet granulation into a stainless steel container via a Quadro Comil (with screen). Step 7 Transfer the milled granules to a preheated fluidized bed product bowl. Step 8 Approximately 70 ° C (65 ° C) until the product temperature reaches the target temperature (40-47 ° C).
The granules are dried by maintaining the desired internal temperature of (.degree. C.-75.degree. C.) (loss on drying is within the desired range (0.5-1.8%)). Step 9 Set up a Quadro Comil (variable speed) and wear a screen for attrition. Step 10 Add the dry granules to a pre-tared polyethylene bag via a Quadro Comil (with screen).

Ungranulated granulation mixture Step 11 Excess carbomer 941 (Carbopol 971) by hand through a # 20 mesh stainless steel screen for deagglomeration
P) is sieved. Step 12 Precise amount of pre-sieved carbomer 941 (Carbopol 971P
) Is weighed on weighing paper. Step 13 Weigh the correct amount of carvedilol internal granulation into a suitably labeled polyethylene bag. Step 14 Install a suitable sized V-blender. Step 15 Transfer one third of the carvedilol internal granulation to a V-blender. Step 16 Add one third of Carbomer 941 (Carbopol 971P) to the V-blender. Step 17 All internal granules and carbomer 941 (Carbopol 971P)
Steps 15 and 16 are repeated until has been placed in the V-blender. Step 18 Mix for 30 minutes or until homogeneous. Step 19 Take a sample for inter-process testing.

Lubricated Granulated Mixture Step 20 Excess magnesium stearate is manually sieved (to deagglomerate) by passing through a # 40 mesh stainless steel screen. Step 21 The correct amount of pre-sieved magnesium stearate is weighed out on weighing paper. Step 22 Place magnesium stearate in a blender (including non-lubricated granules) and mix for 3 minutes.

Compression Step 23 Transfer the compressed mixture to the hopper of a rotary tablet press using a 7/16 "× 5/8" round standard instrument. Step 24 Compress the tablets to suit the desired physical properties. Step 25 Remove samples for interprocess testing throughout this process.

Coating Step 26 The exact amount of round active core of carvedilol, white Opadry® and clear Opadry® are weighed separately into polyethylene bags. If necessary, the round active core may be augmented with an oval placebo core to the required batch size to fill the coating pan. Step 27 Transfer the required amount of purified water to produce 12% solids white Opadry® into a suitable freshly tared container. Step 28 Slowly add white Opadry® to purified water with vortex mixing. Continue mixing until no solid components are visible to the naked eye. Use this solution within 24 hours of manufacture. Step 29 Transfer to a suitable freshly tared container the amount of purified water required to produce a clear Opadry® at 5% solids. Step 30 Slowly add clear Opadry® to purified water with vortex mixing. Continue mixing until no solid components are visible to the naked eye. Use this solution within 24 hours of manufacture. Step 31 Install an Accela Coater coating pan. The pump is set to deliver the white and clear coating solution and spray at a rate of about 35 g / min. Step 32 Transfer core to coating pan. Preheat the core. The internal temperature is adjusted to 55 ° C (40 ° C to 70 ° C) while rocking the pan periodically.
When the product temperature reaches about 42 ° C (37 ° C to 45 ° C), start spraying. Spray the entire volume of the white coating solution to obtain an approximately 3% weight gain coating. An about 0.5% weight gain coating is then obtained using the clear coating solution. Step 33 Transfer the coated tablets from the coating pan to the double polyethylene lining drum. If the coating batch size is increased using a placebo core, a classification / inspection step is performed after the completion of the coating operation to separate the oval placebo core from the round active core.

Embodiment 1

[Table 2]

Embodiment 2

[Table 3]

Example 3 (pH Sensitive Coating on Immediate Release Core) Tablet Core % w / w Carvedilol 11.45 Lactose 64.05 Microcrystalline Cellulose 20.0 Sodium Starch Glycolate 4.0 Magnesium Stearate 0.5 Total 100.0

Tablet coating (applying about 6-10% of tablet core weight) % w / w hydroxypropyl methylcellulose phthalate 90.0 Triacetin 10.0

Example 4 (pH Sensitive Coating on Immediate Release Core) Tablet core as in Example 3 Tablet coating (applying about 6 to 10% of tablet core weight) % w / w cellulose acetate phthalate 90 2.0 Diethyl phthalate 10.0

Example 5 Controlled Release Coating on Immediate Release Core Tablet core as in Example 3 Tablet coating (applying about 5-12% of tablet core weight) % w / w Eudragit RS 100 86.0 Dibutyl phthalate 10.0 Talc 4.0 FD & C Yellow No. 0.01 0.01

Example 6 (pH sensitive coating on controlled release core) Tablet core as in Example 3 Tablet coating as in Example 3

Example 7 (Encapsulated Controlled Release Coated Beads) Pellet % w / w (approx.) Non Pareil Seed 30 Carvedilol 40 Gelatin 8 Lactose 20 Talc 2

Coating % w / w Glycerin monostearate 36.6 Glycerin distearate 53.4 White wax 10.0

The preceding is an explanation of the invention. However, the invention is not limited to the specific embodiments described herein, but covers all modifications within the scope of the following claims. Various references to periodicals, patents and other publications cited herein constitute prior art and are hereby incorporated by reference as if fully set forth.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 9/00 A61P 9/00 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM ), AL, AU, BA, BB, BG, BR, CA, CN, CZ, EE, GE, HU, ID, IL, IS, JP, KP, KR, LC, LK, LR, L , LV, MG, MK, MN, MX, NO, NZ, PL, RO, SG, SI, SK, SL, TR, TT, UA, US, UZ, VN, YU (71) Applicant Boehringer Mannheim Pharmaceuticals Corporation-Smith Klein Beckman Corporation Limited Partnership Number 1 Boehringer Mannheim Pharmaceuticals Corporation-SmithKline Beckman Corporation. 1 Orchard Ridge Drive 101, Gaithersburg, MD 20878, United States of America (72) Inventor Tune Kaew United States 19425 Harshad Drive, Chester Springs, PA 1942 F-term (reference) 4C076 AA37 AA45 AA53 BB05 CC11 EE06J EE32J EE33J FF25 FF31 4C086 AA01 BC12 MA01 MA05 MA35 MA36 MA37 MA52 NA12 ZA36 ZA39

Claims (8)

[Claims] 1. A matrix formulation comprising carvedilol in an oral unit dosage form. 2. The preparation according to claim 1, which comprises a hydrophilic polymer. 3. The method according to claim 1, wherein the hydrophilic polymer is hydroxypropyl methylcellulose (H
The preparation according to claim 2, which is MPC). 4. The formulation according to claim 1, comprising a mixture of HMPC and Carbopol. 5. The formulation according to claim 1, comprising a mixture of HMPC, carbopol and mannitol. 6. An enteric formulation comprising carvedilol in oral unit dosage form. 7. A method for treating hypertension, angina or congestive heart failure, comprising administering carvedilol in a matrix formulation. 8. A method for treating hypertension, angina or congestive heart failure, comprising administering carvedilol in an enteric formulation.