SK194A3 - Tables of medicines mixtures of colestipol hydrochloride - Google Patents

Abstract

Pharmaceutical capsule based on ionite resins contains 1000 mg of fine-ground colestipole hydrochloride, 10 to 200 mg providone, 1 to 50 mg colloidal sillicon oxide and 1 to 30 mg magnesia stearan and with following physical characteristics, hardness 40 to 75 SCU and brittleness the most 0.1%/15 minutes. The weight of capsule is 1017 to 1079 mg, time of decomposition of capsule is shorter than 5 minutes and the thickness of capsule is 5.08 to 8.64. Method for production of capsules of colestipole hy drochloride consists of that to the suspension of fine-ground colestipole hydrochloride is added 10 to 200 mg providone, the obtained mixture is dried and dried material is subsequently deagregated. Then 1 to 50 mg colloidal sillicon oxide and 1 to 30 mg magnesia stearan are added and resulting mixture is shaped into capsules.

Description

Tableting of colestipol hydrochloride drug mixtures.

Technical field

The present invention relates to a new type of tablet and a novel process for the manufacture thereof. In particular, the present invention provides unique and highly effective (i.e., 1000 mg) colestipol hydrochloride tablets having advantageous properties such as hardness, friability and thickness, and a novel method of making such tablets.

BACKGROUND OF THE INVENTION

Colestipol is a basic ion exchange resin, described as a copolymer of diethylenetriamine and 1-chloro-2,3-epoxypropane (hydrochloride) with a high molecular weight and with about one in five nitrogen atoms protonated. It can also be called diethylenetriamine-epichlorohydrin copolymer hydrochloride. It is a light yellow, hygroscopic resin which swells when immersed in water or water-containing liquids. See Merck Index (Tenth Edition), Number 2440, page 2438.

Colestipol hydrochloride is commercially available in the form of granules, such as COLESTIO ^R granules. See Physicians Desk Reference (PDR) 42nd Edition, page 2119 (1988).

COLESTID ^R granules are tasteless and odorless, although they may act explicitly as semolina when taken orally, suspended in liquids.

Cholesterol is the major and perhaps the only bile acid precursor.

In normal digestion, bile acids are excreted via the bile from the liver and gall bladder into the intestines. The emulsion bile acids and lipids present in the diet thus facilitate digestion.

The major part of the excreted bile acids is reabsorbed from the intestines and returned via the portal circulation to the liver, completing the enterohepatic cycle. In normal serum, there is only a very small amount of bile acids. Physicians Desk Reference (PDR) 42nd Edition, page 2115 (1988).

Colestipol hydrochloride, marketed, for example, as COLESTID ^R Granules, is considered to be a supportive therapy for a diet to reduce serum cholesterol levels in patients with primary hypercholesterolaemia (increased low-density lipoprotein content). These granules must be consumed orally and generally require the addition of a pleasant flavor when swallowed. The usual daily dose of COLESTID ^R granules for the treatment of hypercholesterolemia is between 15 and 30 grams per day. Patients taking this medicine usually need to take anticholesterolemic medicines throughout their lives to keep their serum cholesterol levels low.

However, patients do not tolerate the COLESTID ^R granules well because of their semolinainess, which is disgusting and significantly violates the pharmaceutical elegance and patient acceptability. Granular use also means that the product must be mixed with the liquid when swallowed, which is uncomfortable for many patients. For example, patients have to take a powder, disperse it in a liquid, and drink the entire volume when receiving the medicine. Tablets are therefore a more elegant and convenient pharmaceutical form of colestipol hydrochloride.

U.S. Patent Application Serial No. 07 / 623,904, filed December 19, 1990 (also International Publication No. WO 89/12452, published Dec. 28, 1989) discloses finely divided colestipol hydrochloride and tablets prepared therefrom. Some differences between these tablets and the tablets of the present invention are shown in Table 1. Table 2 shows some differences between the methods used to prepare both different tablets.

According to Table 1, the tablets of the present invention are much harder than the prior art tablets, but they disintegrate readily. The tablets of the present invention are also preferably smaller than prior art tablets. Other advantageous properties of the tablets according to the invention, such as friability and disintegration time, are also shown in the table.

According to Table 2, the production method of the present invention uses wet granulation of the raw drug instead of direct compression, which makes the repeated drying of the material unnecessary. The described process uses a single stage drying. This and other differences are explained in more detail below.

Pharmaceutical Dosage Forms: Tablets, Volume 1, Editors HALieberman and L.Lachman (1980), Marcel Oekker, Inc., New York and Basel, pages 114-116, 122-129, 184-185, describe a wet granulation method, which is a well known method of preparing granules for tabletting. It is noted that this is a convenient method for tabletting many drugs used in high doses. Also disclosed are a variety of excipients, such as binders, used in wet granulation: starch, pregelatinized starch, gelatin, polyvinylpyrrolidone, methylcellulose, ethylcellulose, polyacrylamides, and polyvinyl alcohols. It is noted that the binder is the basis for homogeneous granule size, suitable hardness, easy compression and overall tablet quality.

Polyvinylpyrrolidone, also known as PVP or Povidone, is a well known tablet binder and granulating excipient. USP XXII (1990) Povidone on page 1118.

Published European Patent Application 0 347 748 discloses a drug granule coating composition comprising a polymer such as Povidone and microcrystalline cellulose. It is believed that the polymeric material serves as a binder and carrier for microcrystalline cellulose, while microcrystalline cellulose provides excellent granular compressibility.

Remington's Pharmaceutical Sciences, RPS XIV, Editor-in-Chief John E. Hoover, 14th Edition, (1970) Mack Publishing Company, Pa, pages 1655-1659, describes various steps and various devices that can be used in wet granulation to prepare tablets. .

Colestipol hydrochloride is known in the form of spherical beads, of which at least 75% by weight or by volume of the particles have a diameter greater than 100 microns and 30% by weight or by volume of the particles having a diameter greater than 80 microns. See PDR supra, page 2115. Oral use of the colestipol hydrochloride dosage form in the form of spherical beads for the treatment of hypercholesterolemia is also known. See U.S. Patent 3,692,895.

Colestipol hydrochloride in the form of fine beads is described in International Publication No. WO 90/02148, published March 8, 1990.

U.S. Pat. No. 4,404,346 describes and protects a process for preparing particles of reduced size antihypercholesterolemic cholestyramine resins. The pulverulent cholestyramine resin is produced by swelling or shrinking the resin particles in water or in an organic solvent, causing internal stresses in the particles and subsequent grinding of the swollen or shrinked particles in a rotary mill. In a wet swollen state, 90% by weight or by volume of the particles are said to have an average particle size of less than 30 microns.

EP-B-0026574 protects a method of reducing the particle size of synthetic polymeric ion exchange or absorbent resins in general, and in particular cholestyramine. Also protected is a process for preparing the ground synthetic polymeric ion exchange or absorbent resin obtained by this process and the resin itself in pharmaceutical compositions.

U.S. Patent 3,692,895 protects a method of using colestipol hydrochloride to reduce hypercholesterolemia in humans. It describes compositions (including tablets and capsules) and methods for reducing hypercholesterolemia in affected mammals and birds. These compositions and methods use oral uptake of an effective amount of a non-toxic polymer prepared from polyethylene polyamine, such as tetraethylenepentamine, and a bifunctional compound such as epichlorohydrin or 1,2: 3,4-di-epoxybutane.

U.S. Patent 4,439,419 discloses a method of using colestipol hydrochloride to neutralize gastric acid, to treat hyperacidity in humans with excess gastric acid, and to treat ulcers.

A preferred process for the preparation of colestipol hydrochloride for medical use is described in US Patent 3,803,237 and is known as the bead process. U.S. Patent 4,631,305 protects compressed tablets comprising a polymeric material such as colestipol hydrochloride as a tablet disintegrating agent.

Summary of the invention .......

The present invention relates to pharmaceutical tablets comprising:

and (b) an amount of colestipol hydrochloride effective to treat or prevent hypercholesterolemia in a patient receiving one or more tablets having the following physical characteristics:

Hardness: 40-75 SCU

Thickness: 5.08-8.64 mm

Friability: 0-0.1% / 15 minutes.

Further, the present invention relates to a process for the preparation of a 1000 mg tablet of colestipol hydrochloride which comprises adding povidone to a suspension of finely ground colestipol hydrochloride.

By hardness, it is meant the amount of force required to break a tablet when the tablet is placed longitudinally in the hardness tester. Measured in SCUs (Strong Cobb Units).

Friability is a measure of the stability of a tablet required to maintain the tablet during shaping on the coating pan and during packaging. They are measured at specified time intervals, such as 15 minutes, in a Roche micrometer.

Thickness is the size of the tablet height in millimeters, measured by micrometer.

The disintegration time is the time required to disintegrate the tablet in pure water (37 ° C). Measured in minutesSuspension of finely ground colestipol hydrochloride is understood to mean a mixture of 5 to 1 (water to seed) hydrochloride beads (water to seed) that has been milled in colestipol and water to a ratio of 12 to 1 precisely adjustable chopper such as a mill Comitrol, according to the method described in International Publication No. WO 89/12452, published

On December 28, 1989, which is incorporated herein by reference. Colestipol hydrochloride beads are prepared by the bead method described in U.S. Patent 3,803,237, which is incorporated herein by reference. It can be used in suspension or in a dry state (e.g., material of formula B-3 in Scheme B) or in a wet state (e.g., material of formula A-3 in Scheme A), with a wet state being preferred. Beads can also be prepared by a fine bead method as described in International Publication No. WO 90/02148, published March 8, 1990, which is incorporated herein by reference.

Finely ground means substantially the spherical form of colestipol hydrochloride (more than 95% non-spherical crumb particles, most preferably more than 99% non-spherical crumb particles), wherein more than 75% by weight or by volume of the particles have a diameter of less than 100 microns, preferably when more than 75% by weight or by volume of the particles have a diameter of less than 65 microns and more than 30% of the particles (by weight or by volume) have a diameter of less than 30 microns. These particle diameter measurements can be made using standard light scattering techniques. The finely ground form of colestipol hydrochloride is also described, as already mentioned, in International Publication No. WO 89/12452, published December 28, 1989.

Dewatered means that water has been removed from the suspension in a conventional manner up to a moisture content of 74-85%, preferably 80%.

The preferred amount of colestipol hydrochloride per tablet of the present invention is 1000 mg. In hypercholesterolemic patients with serum cholesterol levels above 200 mg per 100 ml, tablets of the present invention have been shown to effectively lower serum cholesterol levels. Conventional clinical data show that two 1000 mg tablets administered twice daily to cholesterol patients by approximately 12% and eight 1000 mg tablets administered twice daily to cholesterol patients by approximately 24%.

Tablets according to the invention also generally have the following physical characteristics: tablet weight 1017-1079 mg and disintegration time of less than 5 minutes. The tablets may be compressed and preferably have a weight of about 1048 mg and a hardness of from 40 to 50 SCU and a thickness of 8.13-8.64 mm.

Preferred excipients for use in the tablets of the present invention are povidone, colloidal silica and magnesium stearate. The amounts of these excipients in the tablets of the present invention are from about 10 to about 200 mg of povidone, from about 1 to about 50 mg of colloidal silica and from about 1 to about 30 mg of magnesium stearate. Preferably the amounts of these excipients used are in the range of 40 to 50 mg povidone, from 5 to 10 mg colloidal silica and from 2.5 to 3.5 mg magnesium stearate, or most preferably about 40 mg povidone, about 5 mg colloidal silica and about 3 mg of magnesium stearate.

The tablets of the present invention may have a coating comprising acetate phthalate The amount of ingredients in cellulose sealing phthalate and about 15.6 mg triacetin.

from 0.5 acetate coating to 20 phthalate this further have sealing cellulose and triacetin.

from 2 to 200 mg of triacetin acetate, preferably cellulose and about 3.12 mg is mg of transparent triacetin may also be of the invention.

coating have also know to

100

USP

USP which contains an amount of these mg hydroxypropyl CPS, from 5 to 100 CPS and from 2 to 80

The tablets according to the hydroxypropyl methylcellulose sealing coating and the additives in the transparent coating are from 5 methylcellulose type 2910 E5 Premium hydroxypropyl methylcellulose type 2910 mg triacetin, preferably approximately 30 methylcellulose type 2910-E5 Premium hydroxypropyl methylcellulose type triacetin.

2910

USP mg

CPS

USP 15 CPS and hydroxypropyl about 30 mg about 12 mg

The coating of the tablets should maintain their shape when exposed to prolong their disintegration time. Such character is a stable dosage form.

Tablets according to the invention with a surface film generally follow the tablet in moist air and do not have substantially

1100-1230 hardness greater than rng,

0-0.1% mg, hardness from 70-80 / 15 minutes.

/15 minutes.

of the invention with physical characteristics: disintegration time less than SCU, thickness 5.08-10.16 preferably have a tablet weight of about 1138 SCU, a thickness of 9.52 mm and a friability of about 0% have a weight of mm, minutes, friability

The binder of povidone according to the invention is usually added during wet granulation and not in the preparation of a drug suspension. This solution eliminates the soaking / drying cycle, saving time and money. Without wishing to be limited, it is believed that the addition of povidone in the method of the invention may increase the cohesion of colestipol, which is intermolecular.

According to this hydrochloride inside the trihydrochloride the cohesion of the polymer structure, can be used from about theory, the preparation of molecules have two basic bonds, The addition of povidone to its production can increase the bonds due to colestipol during and intermolecular

In the production process of the present invention up to about 200 mg povidone is used, preferably 40 mg.

Other pharmaceutical binders that are effective according to the invention include hydroxymethylcellulose, hydroxyethylcellulose and starch. However, povidone is preferred.

Scheme A shows a production method according to the present invention which uses a one-stage drying method involving wet granulation of a bulk drug. Scheme B a method of wet granulation of tablets that a drying method, similar to those shown by an alternative two-stage used are used in the pharmaceutical production of granular tablets. Tablets of the present invention were made using both methods, and Scheme A was found to be much more effective than Scheme B.

Scheme A

Scheme A describes a preferred method of preparing 1000 mg colestipol hydrochloride surface film tablets. Compounds A-1 and A-2 are prepared by polymerization and crosslinking according to the method described in U.S. Patent 3,803,237, which is incorporated herein by reference. Water is added to the material in a ratio of 5 parts water to 1 part material up to a ratio of 12 parts water to 1 part material resulting in a colestipol hydrochloride suspension (A-3). Preferably, a ratio of 12 parts of USP purified water to 1 part of the resulting material is used. The suspension is ground in a precision adjustable chopper, such as a Comitrol mill, to give a milled suspension of colestipol hydrochloride (A-4) having a moisture content of about 92%. The milled suspension is dewatered to form a milled dewatered suspension of colestipol hydrochloride (A-5) having a moisture content of about 80%. To the milled dewatered colestipol hydrochloride, a povidone USP K = 30 binder is added at a concentration of 4% to form a mixture of milled dewatered colestipol hydrochloride with povidone (A-6). The wet granulated material is passed through a drying oven, such as a Wyssmont dryer, as it vacuums the Inox dryer until the loss on drying (LOD) is below 1% moisture to obtain aggregates of dry ground colestipol hydrochloride with povidone (A-7). The Inox vacuum dryer is more preferred. This material is disintegrated by m i to a sieve mill 046, or other suitable mill, such as Comil, to break up any aggregate particles formed during drying. Add colloidal NF-type silica as a glidant and anti-caking agent and magnesium stearate as a lubricant. The resulting material is compressed into tablets using a D die press (8000-10000 pounds of compressive force) to give compressed tablets (A-8).

The tablets are coated with a sealing coating containing cellulose acetate phthalate NF (CAF), which is dissolved in a mixture of methyl ethyl ketone (MEK) with anhydrous alcohol S.0. A3 to give sealed tablets (A-9). Triacetin USP is used as a plasticizer for CAP. This seal coating provides a barrier to allow the application of an aqueous clear coating solution without causing the tablet core to disintegrate upon contact with each other.

An aqueous clear coating solution composed of hydroxypropyl methylcellulose type E5 Premium 2910 USP 5 CPS and type 15 CPS was applied to the tablets to obtain clear coated tablets (A-10). The solids required to prepare the clear coat are dissolved in purified USP water using triacetin USP as plasticizer. This clear coating makes the tablets resistant to swelling when exposed to a humid environment.

Finally, the tablets are waxed with Carnauba Wax NF No. 120 wax to facilitate packaging. A 1000 mg film-coated tablet of colestipol hydrochloride (A-11) is obtained.

Scheme B

Scheme B describes, according to the present invention, an alternative process for preparing 1000 mg colestipol hydrochloride film-coated tablets.

Compounds B-1 and B-2 are prepared by polymerization and crosslinking according to the method described in U.S. Patent 3,803,237, which is incorporated herein by reference. The resulting material was washed with water in a ratio of 8 parts of purified water USP to 1 part of the resulting material and then dried to a water content of less than 1% to obtain colestipol hydrochloride USP (8-3). (See, for example, the bead process described in U.S. Patent 3,803,237). Water of 5 parts water to 1 part of colestipol USP hydrochloride is added to up to 12 parts water to 1 part of colestipol hydrochloride USP to 1 colestipol hydrochloride hydrochloride. Preferably a ratio of 12 parts purified USP water to 1 part colestipol hydrochloride USP is used. Colestipol hydrochloride USP and water are then mixed to give a colestipol hydrochloride suspension (8-4). The suspension is ground with a Comitrol mill to obtain a milled suspension of colestipol hydrochloride (B-5). This suspension was filtered on a Buchner funnel to give a milled dewatered suspension of colestipol hydrochloride (B-6). This material is then dried to 20% humidity to form semi-dry ground colestipol hydrochloride (B-7). (See, for example, the method described in International Publication No. WO 89/12452, published December 28, 1989). This material is placed in the product chamber in a GLATT fluidized bed reactor. The povidone solution is injected into the GLATT-type reactor to give the granules of colestipol hydrochloride with povidone (8-8). These granules are dried in a GLATT reactor until the outlet temperature reaches about 60 ° C to obtain dry milled granular aggregates of colestipol hydrochloride with povidone (B-9). This material is disintegrated by means of a microspheres with a sieve 046, or other suitable mill, such as Comil, to break up any aggregate particles formed during drying. Colloidal silica NF, as a glidant and anti-caking agent, and magnesium stearate are added as a lubricant. The resulting material is compressed into tablets using a Manesty Express D-head press to give compressed tablets (B-10).

The compressed tablets were coated with a sealing coating (B-11), a clear coating (B-12), and waxed as described in Scheme A. A 1000 mg colestipol hydrochloride tablet coated (B-13) was formed.

Colestipol hydrochloride is a crosslinked polymer. The compound swells three to four times the volume in the aqueous phase. If colestipol hydrochloride is compressed into a binder-free tablet, the tablet will not achieve the hardness required for coating and transport. The tablet has to be less than 0.1% in 15 minutes and less than 8.64 mm thick. Surprisingly and unexpectedly, the tablets of the invention have these desirable properties as illustrated in the examples below.

Examples

Example 1

1000 mg colestipol hydrochloride tablet (See Scheme A)

1. Process A: Preparation of the suspension (mixing, grinding, dewatering)

Suspension preparation:

Colestipol hydrochloride beads 300 kg

Purified water USP 3600 kg

Mixing: In a suitable container, the ingredients are mixed for about 30 minutes to 1 hour or until the mixture is hydrated.

Grinding: The above mixture is ground in a Comitrol 1700 mill.

Drainage: ... The ground material is centrifuged with a Sharple centrifuge. The total yield after dewatering is about 1620 kg (82% moisture content).

2. Process B: Adding PVP

Preparation of the solution:

Povidone (PVP) 12 kg

Purified water USP 36 kg

Preparation: In a suitable container, mix both components until a clear solution is obtained.

Mixing: 405 kg of ground dewatered colestipol and 12 kg of povidone solution (25%) are added to the Pony mixer. The mixture was stirred for 5 minutes.

3. Process C: Drying

When using a Wyssmont dryer, the material is pre-dried with

using the following parameters: D Inlet temperature Mp 110 ° C 2) Total addition time 12 hours 3) Outlet temperature neodčítaná 4) Stay in the drying room 3 1/2 hours 5) Final humidity 20%

The material is then screened using No. 8 screen and dried under the following conditions:

1) Inlet temperature 2) Total addition time 3) Stay in the oven 4) Final humidity 5) Water-soluble fraction 88 ° C 5 hours 1 1/2 hour 0.2% 0.1% At application vacuum dryer I.nox the material is dried

using the following parameters: D input temperature 120-160 “C 2) vacuum 22-25 kPa 3) T eplota of the product is maintained lower 50 ° C 4) final loss on drying (LOD) lower than 1%.

4. Process D: Deagregation (micromilling)

The material is disintegrated and screened with a diagonal sieve having a mesh size of 046 (or other suitable disintegrator).

5. Process E: Mixing

The following is added to the PK 5 cu ft mixer:

Dry ground colestipol hydrochloride 50 kg

Cab-o-sil

Magnesium stearate

250 g

150 g

The mixture was stirred for 10 minutes and 3 minutes, respectively.

6. Process F: Pressing

The blend from process 5 is compressed on a Manesty Express press with Motrin 800 mg D heads (18.91 * 9.60 mm special elliptical capsule) using a compressive force of 8000-10000 pounds.

Physical characteristics measured for compressed tablets typically have the following values: (Data are approximate)

Disintegration time (for 6 tablets) 4 minutes 53 seconds

Tablet thickness 8.30 mm

Tablet hardness 43.7 SCU

Tablet weight 1046 mg

Orobivosí 0-0,1% / 15 minutes

Í3 -

7. Process G: Sealing Coating

Per 1 tablet

Per 100 kg of handle

1048 mg Compressed tablet cores 103 kg 6.15 mg Cellulose acetate phthalate NF 1,544 kg 120 mg Methyl ethyl ketone 11.88 kg 120 mg Anhydrous S.D. alcohol A3 11.88 kg 3.12 mg Triacetin USP 308.9 g

The above ingredients are mixed in a suitable container until the solution is clear and free of particulate matter. The solution is sprayed onto the shaft using a 48-inch Accela-Cota using the following parameters:

Inlet temperature

Outlet temperature

(a) initial

(b) continuous

Spray Speed Nozzle Pressure (Graco) Plate speed

15-30 ° C

Room temperature

Room temperature

430 g / min

9-18 kg rpm

8. Process H: Clear coating Per 1 tablet Per 100 kg of handle 1066 mg Tablets of colestide p 105 kg sealing coating 30 mg hydroxypropyl methylcellulose 2.97 kg ES Premium 5 CPS 30 mg Hydroxypropylmethylcellulose 15 CPS 2.97 kg 12 mg Triacetin USP 1,188 kg 860 mg Purified Water USP 85,14 kg

The above ingredients are mixed until the solution is clear. The solution is sprayed onto tablets using an Accela-Cota 48 inch device using the following parameters:

1, Inlet temperature 30-85 ° C

2. Outlet temperature

(a) initial 45 ° C

(b) continuous

3. Air spraying

(a) nozzle

(b) cylinder

4. Spray rate

5. Binks Spray System

6. Disintegration time

40-45 ° C

0.35 MPa

0.50 MPa

660 g / min nozzle

NMT 10 minutes

The physical characteristics measured by deposition typically had the following values:

Weight of tablets:

for tablets (Data are

Disintegration time

Tablet hardness:

Thickness of tablets with final approximate 1138 mg less than 10 minutes

60-80 SCU

Minority:

9.52 mm% / 15 minutes.

Example 2

Colestid 1000 mg tablet (See Diagram B)

Mix 7 kg of purified USP water with a slurry. Using a wet mill, the suspension is drained onto a pan to mix colestipol hydrochloride material in a suitable container until Comitrol is formed and colestipol hydrochloride is reduced in size.

USP and 84 liters of particles. Ground tablets,

Buchner funnel and placed on

Trays and dried according to the following regulations that can be covered with film:

Colestipol hydrochloride, ground, moisture content 20% with moisture content

%. Obtained and methods pressed into kg

Preparation of granulation

PVP resource:

280 g

Water / ethanol,

1100 g

The PVP is dissolved in the Product con tainer reactor with stirring

It is granulated with a water / ethanol solution. Colestipol hydrochloride (PVP) is added to it using the following parameters:

Inlet temperature

Outlet temperature

Low: 14 ° C

Low: 14 ° C

Spray rate 8-70 g / min

Finally, it is dried to an outlet temperature of at least 50 ° C.

Final mixing:

Granules of colestipol from previous steps

Cab-o-si1 kg g

Magnesium stearate

Instructions: Mix the above ingredients in a Hobart mixer for 5 minutes. The blend is compressed into tablets on a Manesty Express press with D heads (18.91 * 9.60 mm, special elliptical capsule) using 8000-10000 pounds of compressive force.

The physical characteristics measured for compressed tablets typically had the following values: (Data are approximate)

Disintegration time (for 6 tablets): 5 minutes

Tablet weight: 1056mg

Tablet hardness: 43.7SCU

Tablet thickness: 8.36mm

friability:

% / 4 min., Below 0.1% / 15 minutes

The ingredients in Table 3 below were used to coat the tablets. The following parameters (Accela-Cota 24 inches):

Inlet temperature

Outlet temperature

Spray rate

Air spraying

(a) nozzle

(b) cylinder

Spray rate

Plate speeds were used for the seal coating

15-30 ° C

15-30 ° C

430 g / min

0.21 MPa

0.42 MPa

20-35 rpm

12-20 rpm

The following parameters were used to prepare a clear coating (Accela-Cota 24 inches):

Inlet temperature

Adjust to maintain the flow temperature

Outlet temperature

40-50 ° C

Air spraying

(a) nozzle

(b) cylinder

Plate speed

Binks Spray System

0.21 M P a

0.42 MPa

12-20 rpm air jet

To facilitate handling. the tablets are waxed with Carnauba Wax NF No. 120. The physical characteristics of the final film tablets are shown in Example 1.

Examples 3-18 Failures in other preparation procedures

The following examples demonstrate attempts to prepare 1000 mg tablets of Colestid that have failed either in the preparation of the tablets or in the preparation of the coating. These failures show how surprising and unexpected the results obtained in preparing the tablets of the present invention.

Example 3

Tablets were prepared according to the following procedure: Ground Colestipol hydrochloride 1 kg

Magnesium stearate 5 g

The components are weighed and mixed in a Hobart mixer.

Physical characteristics were as follows: (Lis Kilian)

Weight of tablets:

Disintegration time:

Tablet hardness:

Tablet thickness:

friability:

pressure:

Prepressure:

1005 mg minutes 55 seconds

41,2-44,1 SCU

8.68-9.45 mm

4.92814%

1996 kg

181 kg

These tablets had friability problems. In this method of preparation, the desired tablet weight could not be achieved.

Example 4

The ingredients for granulation were as follows:

Povidone K = 30 (PVP) 300 g anhydrous S.O. alcohol A3 The composition was as follows: 2000 ml Ground Colestipol Hydrochloride 6 kg Silicon dioxide - Magnesium stearate 30 g All ingredients are weighed and ingredients and colestipol granules

are mixed using a high shear mixer and a T.K type granulator, Fielder. The wet granules are placed in an oven at 49 ° C for 12-16 hours until they dry. Magnesium stearate is used as a lubricant. Pressed on Kilian's press.

These tablets had friability and fluidity problems. In this method of preparation, the desired tablet weight could not be achieved.

Example 5

The composition of the mixture was as follows:

Ground Colestipol Hydrochloride 1 kg Magnesium stearate 3 g Avicel PH 102 30 g

Physical characteristics were as follows: (Lis Kilian)

Weight of tablets: 1030 mg friability: 0.149% (bad)

These soft tablets had poor friability and fluidity.

Example 6

The composition of the mixture was as follows:

Ground Colestipol Hydrochloride 1 kg Magnesium stearate 2.5 g

Physical characteristics were as follows: (Lis Kilian)

Weight of tablets: 1002.5 mg friability: 0,97%

These tablets were not hard enough due to high friability.

Example 7

The composition of the mixture was as follows:

Ground Colestipol Hydrochloride

Additives for granulation:

povidone

Purified water USP for application pan kg

300 g

2000 ml

The PVP and water are mixed to form a clear solution. Weigh 5 kg of colestipol hydrochloride. The GLATT fluid bed dryer is heated up to. reaches 50 degrees (from left to right panel). (Shaking intervals every 30 seconds for 5 seconds).

Inlet temperature 70 ° C

Outlet temperature 32 ° C

Outlet air damper 40%

The spray ratio is adjusted so that the product does not stick to the walls unless alcohol and filter are used.

The granules were difficult to dry as a granulating agent.

Example 8

The composition of the mixture was as follows: Colestipol ground magnesium magnesium stearate

Avicel PH 102

Physical characteristics were Theoretical tablet weight: Actual tablet weight: Tablet hardness:

Tablet thickness:

Pressure:

Prepressure:

r obi in os:

With these tablets there was no tablet weight.

kg g

100 g the following: (Kilian press)

1100 mg

650 mg

42,5 SCU

8.68-9.45 mm

1814 kg

227 kg has not been determined possible to achieve the desired

P. example 9

The composition of the mixture was as follows:

Ground Colestipol Hydrochloride 1 kg Magnesium stearate 6 g Avicel PH 102 10 g All ingredients are screened and mixed in a Hobart mixer.

Physical characteristics had the following values:

Weight of tablets: 1016 mg Tablet hardness: 26-29 SCU friability: 0.128% (bad) pressure: 907-1860 kg Prepressure: 136-363 kg

Friability was a problem with these tablets because the tablets were too soft.

Example 10

The composition of the mixture was as follows:

Ground Colestipol Hydrochloride 1 kg Magnesium stearate 2.5 g Avicel PH 102 50 g

Mix all ingredients.

Physical characteristics had the following values:

Weight of tablets: 1052.5 mg Tablet hardness: 33-34 SCU friability: 0.118% (bad) Pressure: 1814 kg Prepressure: 227 kg

The friability of these tablets was not good because the tablets were too soft.

P r.i k. la d 11

The composition of the mixture was as follows:

Colestipol hydrochloride ground 800 g

Magnesium stearate. 5 g

Avicel PH 10276 g

Physical characteristics had the following values:

Weight of tablets: 1105 mg friability: immeasurable

These tablets were too soft as a sponge due to the moisture content of the 1 or 2 colestipol.

Example 12

The composition of the mixture was as follows:

Ground Colestipol Hydrochloride 1 kg Magnesium stearate, 6 g Avicel PH 102 150 g

The physical characteristics had the following values: (Lis

Kilian). ......... Weight of tablets: 1156 mg Tablet hardness: 36-44 SCU friability: bad pressure: 1996 kg Prepressure: 249 kg Friability of these tablets was not good enough to

withstand the conditions in the coating pan.

Example 13

The composition of the mixture was as follows:

Ground Colestipol Hydrochloride 700 g Magnesium stearate 4 g ňvicel PH 102 70 g

Physical characteristics had the following values:

Weight of tablets: 1050 mg Tablet hardness: 33,2 SCU friability: bad

Example 14

The composition of the mixture was as follows:

Ground Colestipol Hydrochloride 1 kg Magnesium stearate 6 g Avicel PH 102 100 g

Physical characteristics had the following values:

Weight of tablets:

Tablet hardness:

D r obi os os:

110 0 m g

42,2-42,7 SCU bad

Example 15

The composition of the mixture was as follows: (Lis Kilian)

Colestipol milled hydrochloride

Povidone (PVP)

Magnesium stearate

940 g

2.5 g

Cab-o-sil 4 g

Physical, characteristics have the following values Tablet weight: 1006 mg

The flowability of these tablets was poor.

Example 16

The composition of the mixture was as follows:

Ground Colestipol Hydrochloride

Povidone (PVP)

Magnesium stearate

Cab-o-sil

Physical Characteristics (Kilian):

Weight of tablets:

Disintegration time:

Tablet hardness:

Tablet thickness:

D robivosť:

Example 17 kg g

g g

the following values (Lis

1058 mg minutes

SCU

8.81 mm diameter

The composition of the mixture was as follows:

Ground Colestipol Hydrochloride

HPMC 5 CPS

Magnesium stearate

Avicel PH 102

The physical characteristics were as follows

Tablet weight: 1103

Tablet thickness: 9.04

Frenzy: bad

1000 g g

g g

values:

mg mm

Example 18

The composition of the mixture was as follows:

Colestipol hydrochloride ground 1000 g

Povidone (PVP)

Chilsonator at 1000 pounds pressure with screen # 8.

The mixture is processed in a Chilsonator and mill. It is compressed into tablets.

Physical characteristics have the following values: Tablet weight:

1040 mg

Tablet hardness:

37-40 SCU

Tablet thickness:

friability:

9,04 mm bad

Table 1

Compressed tablets according to the invention Compressed tablets are known to date Dimensions of tablets 19.13 * 9.70 * 8.38 mm 19.30 * 9.83 * 9.47 mm Tablet hardness greater than 40 SCU less than 40 SCU shortness 0-0.1% / 15 minutes 0.4% Disintegration time less than 5 minutes 6 minutes 50 seconds

Table 2

The method of the present invention is the prior art method

The wet granulation used in the manufacture of the drug mixture with the addition of Povidone

Single-stage drying with Wyssmont or Inox vacuum dryer

Direct compression of tablet components

Two-stage drying using a plate dryer

Table 3

Ingredients used in tablet coating (Example 2)

Per 1 tablet For 10 kg tablets 15.6 mg Cellulose acetate phthalate 163 g 120 mg Acetone or methyl ethyl ketone 1.26 kg 3.12 mg Triacetin USP 32,7 g 120 mg Anhydrous S.D. alcohol 3A 1.26 kg 30 mg Hydroxypropyl methylcellulose 314 g ES Premium 5 CPS 30 mg Hydroxypropyl methylcellulose 314 g 15 CPs 12 mg Triacetin USP 125.8 g 860 mg Purified Water USP 9 kg

- 24 Scheme A diethylenetriamine A-1 +

1-chloro-2,3-epoxypropane A-2 (hydrochloride) colestipol polymerization colestipol crosslinking colestipol hydrochloride washing with water (+ water to 12/1 ratio) colestipol hydrochloride suspension

A-3 grinding Comitrol ground colestipol hydrochloride A-4 suspension (moisture content 92%) dewatering ground dewatered colestipol hydrochloride suspension A-5 (moisture content 80%) adding povidone ground dewatered colestipol hydrochloride with Povidone A-6 Wyssmont dryer or vacuum dryer Inox aggregates of dry ground colestipol hydrochloride with povidone A-7 (moisture content less than 1%) compressed tablets tablets

Scheme A (continued) Deggregation of granules (micron or Comil) blending with Cab-o-sil and magnesium stearate tableting in a press with D matrices (8000-10000 pounds of compressive force) Tablets Applying Sealing Coating (CAP / SD, Alcohol, MEK) Sealing coating clear coating (aqueous HPMC solution) clear coating waxing (Carnauba Wax)

A-9

A-10 colestipol hydrochloride tablets coated with A-11

Scheme B diethylenetriamine B-1 +

1-chloro-2,3-epoxypropane (hydrochloride) B-2 colestipol polymerization crosslinking colestipol washing colestipol hydrochloride with water (+ water to 8/1) drying to moisture content less than 1% colestipol hydrochloride USPB-3 water addition (12: 1) and mixing the colestipol hydrochloride B-4 suspension grinding in a Comitrol mill colestipol hydrochloride B-5 ground suspension dewatering the milled dewatered colestipol hydrochloride B-6 suspension tenier drying semi-dry ground colestipol hydrochloride B-7 adding povidone in GL.ATT

Scheme 2 (continued) Pellets of Colestipol hydrochloride with povidone After-drying in the GLATT Dry ground granulated aggregates of Colestipol hydrochloride with povidone Pellet deagregation (Micromill or Comil) Mixing with Cab-o-sil and Magnesium Stearate Tableting (Manesty Express) Compressed Tablets Applying Sealing Coating CAP / SO, alcohol 3A perfect, MEK) sealed tablets clear coating (aqueous HPMC solution) clear coated tablets waxing (Carnauba Wax) colestipol hydrochloride coated tablets

B-8

B-9

B-10

B-II

B-12

B-13

Claims (20)

A pharmaceutical tablet comprising: (a) one or more pharmaceutically acceptable excipients; and (b) an amount of colestipol hydrochloride effective to treat or prevent hypercholemia in a patient receiving one or more tablets, characterized by the following physical characteristics: hardness: 40-75 SCU thickness: 5,08-8,64 mm friability: 0-0.1% / 15 minutes Tablet according to claim 1, characterized in that the colestipol hydrochloride is finely ground colestipol hydrochloride. A tablet according to claim 1, characterized by the following additional characteristic: tablet weight 1017-1079 mg disintegration time less than 5 minutes A tablet according to claim 3, characterized by a content of about 1000 mg colestipol hydrochloride, a weight of about 1048 mg, a hardness of 40 to 50 SCU and a thickness of 8.13-8.64 mm. Tablet according to claim 1, characterized in that the excipients are povidone, colloidal silicon dioxide and magnesium stearate. A tablet according to claim 5, comprising about 1000 mg colestipol hydrochloride, from 10 to 200 mg povidone, from 1 to 50 mg colloidal silica and from 1 to 30 mg magnesium stearate. A tablet according to claim 6, characterized in that it contains 40 to 50 mg povidone, 5 to 10 mg colloidal silica and 2.5 to 3.5 mg magnesium stearate. A tablet according to claim 7, comprising about 40 mg povidone, about 5 mg colloidal silica and about 3 mg magnesium stearate. A tablet according to claim 8, characterized by a sealing coating comprising cellulose acetate phthalate and triacetin. Tablet according to claim 9, characterized in that it contains 2 to 100 mg cellulose acetate phthalate and 0.5 to 20 mg triacetin. The tablet of claim 10 comprising about 15.6 mg cellulose acetate phthalate and about 3.12 mg triacetin. A tablet according to claim 11, characterized by a clear coating comprising hydroxypropyl methylcellulose and triacetin. Tablet according to claim 12, characterized in that it contains 5 to 100 mg of hydroxypropyl methylcellulose type 2910 E5 Premium USP 5 CPS, 5 to 100 mg of hydroxypropyl methylcellulose type 2910 USP 15 CPS and 2 to 80 mg of triacetin. The tablet of claim 13, comprising about 30 mg of hydroxypropyl methylcellulose type 2910 E5 Premium USP 5 CPS, about 30 mg of hydroxypropyl methylcellulose type 2910 USP 15 CPS, and about 12 mg of triacetin. Tablet according to claim 14, characterized by the following physical characteristics: Tablet weight 1100-1230 mg Disintegration time T vrdosf thickness Friability less than 30 minutes greater than 60 SCU 5.08-10.16 mm 0-0.1 t / 15 minutes. A tablet according to claim 15, characterized by a weight of about 1138 mg, a hardness of 70-80 SD, a thickness of 9.52 mm and a friability of about 0% / 15 minutes. A process for producing colestipol hydrochloride tablets, characterized by adding povidone to the finely ground colestipol hydrochloride suspension. A process for the manufacture of tablets according to claim 17, characterized in that 10 to 200 mg povidone is added. A method for producing tablets according to claim 18, wherein about 40 mg of povidone is added. A method for producing tablets according to claim 17, characterized in that the suspension is dewatered before the addition of povidone.