Controlled release tacrine dosage form

FIELD OF THE INVENTION

The invention relates to a controlled release tacrine dosage form and the preparation process thereof.

BACKGROUND OF THE INVENTION

Alzheimer's Disease (AD) is a progressive form of presenile neuropathy which causes chronic symptoms of serious neurodegeneration, and which is prone to progress to dementia. The recognition and intelligence functions of AD patients are seriously destroyed. The disease is the main cause of adult dementia and it is estimated that about 2.5 million individuals are infected with such disease in the United States and Canada. With the growth of senile population, it is expected that the impact of AD on public health will continuously increase. Accordingly, the development of effective medicines for AD therapy is in urgent need.

Tacrine, also known as 1,2,3,4-tetrahydro-9-acridinamine hydrochloride (THA), is a reversible acetyl cholinesterase inhibitor which may increase cerebral acetyl choline concentration, in particular in the cerebral cortex, by counteracting the destruction of acetyl choline by acetyl cholinesterase. Tacrine has been approved by U.S. Food and Drug Administration (FDA) for use in AD therapy in 1993, and is the only agent for treating mild to medium AD. It can significantly improve the memory and recognition of patients.

Tacrine has also been used as the analgesic for end-staged cancers, myasthenia gravis, tricyclic anti-depressive agent toxication and tardive dyskinesia.

It is known that tacrine may cause reversible hepatoxicity and many adverse effects, e.g. gastro-intestinal side effects, such as nausea, vomiting, diarrhea, dyspepsia and loss of appetite; kinetic ataxia of voluntary muscles and myalgia; sweating and bradycardia induced by overexcitement of vagus nerues.

The conventional preparations of tacrine should be administered four times a day. The compliance to senile people is therefore poor. Moreover, the pharmacokinetics of tacrine reveal that the oral bioavailability of tacrine may significantly vary in different individuals, and patients should experience a dosage adjustment period.

Accordingly, it is desired in the art to develop controlled release dosage forms of tacrine in order for maintaining stable concentration of the medicine in blood and brain to lower side effects, and for reducing the administration frequency to increase the compliance of the medicine, in particular to senile people.

U.S. Pat. No. 5,576,022 discloses a controlled release tacrine drug delivery system comprising immediate release pellets and sustained release pellets. The immediate release pellets are formed by coating non-pareil seeds with a coating comprising tacrine and a binder, and then with a coating comprising a sealing agent and a plasticizing agent. The sustained release pellets are formed by coating the immediate release pellets with a sustained release coating comprising a water insoluble polymer, a water soluble polymer and a second plasticizing agent.

The delivery system of the above patent may control the release of tacrine. However, as the sustained release pellets are multilayered, the preparation procedures are complex. In addition, as the size of the immediate pellets and the sustained release pellets are different, it would be inconvenient to fill them into capsules.

SUMMARY OF THE INVENTION

Accordingly, the object of the invention is to provide a controlled release tacrine dosage form comprising a single type of pellets.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1

depicts the dissolution curves of release-controlling-film coated pellets F-1 in H

2

O.

FIG. 2

depicts the dissolution curves of release-controlling-film coated pellets F-3 (240.8 mg, —♦—), F-8 (235 mg, —▪—), and F-9 (240.8 mg, —▴—) in H

2

O.

FIG. 3

depicts the dissolution curves of release-controlling-film coated pellets F-10 (240.8 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

FIG. 4

depicts the dissolution curves of release-controlling-film coated pellets F-11 (235 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

FIG. 5

depicts the dissolution curves of release-controlling-film coated pellets F-12 (235 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

FIG. 6

depicts the dissolution curves of release-controlling-film coated pellets F-13 (232 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

FIG. 7

depicts the dissolution curves of release-controlling-film coated pellets F-14 (233 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

FIG. 8

depicts the dissolution curves of release-controlling-film coated pellets F-18 (252.2 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

FIG. 9

depicts the dissolution curves of release-controlling-film coated pellets F-20 (265 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

FIG. 10

depicts the dissolution curves of release-controlling-film coated pellets F-24 (265 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

FIG. 11

depicts the dissolution curves of release-controlling-film coated pellets F-28 (274.5 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

FIG. 12

depicts the dissolution curves of release-controlling-film coated pellets F-29 (270.4 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

FIG. 13

depicts the dissolution curves of release-controlling-film coated pellets F-30 (289 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

FIG. 14

depicts the dissolution curves of release-controlling-film coated pellets F-31 (237.5 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

FIG. 15

depicts the dissolution curves of release-controlling-film coated pellets F-32 (271 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

FIG. 16

depicts the dissolution curves of release-controlling-film coated pellets F-33 (270 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

FIG. 17

depicts the dissolution curves of release-controlling-film coated pellets F-36 (250.8 mg) at pH 1.2 (—♦—),4.5(—▪—) and 6.88 (—▴—).

FIG. 18

depicts the dissolution curves of release-controlling-film coated pellets F-37 (253.3 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

FIG. 19

depicts the dissolution curves of release-controlling-film coated pellets F-39 (310.7 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

FIG. 20

depicts the dissolution curves of release-controlling-film coated pellets F-40 (263.85 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

FIG. 21

depicts the dissolution curves of release-controlling-film coated pellets F-41 (252.7 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

FIG. 22

depicts the dissolution curves of release-controlling-film coated pellets F-42 (253.33 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

FIG. 23

depicts the dissolution curves of release-controlling-film coated pellets F-43 (267.22 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

FIG. 24

depicts the dissolution curves of release-controlling-film coated pellets F-45 (254.18 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

FIG. 25

depicts the dissolution curves of release-controlling-film coated pellets F-46 (253.33 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

FIG. 26

depicts the dissolution curves of release-controlling-film coated pellets F-48 (249 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

FIG. 27

depicts the dissolution curves of release-controlling-film coated pellets F-49 (253.33 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

FIG. 28

depicts the dissolution curves of release-controlling-film coated pellets F-50 (250 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

FIG. 29

depicts the dissolution curves of release-controlling-film coated pellets F-51 (250 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

FIG. 30

depicts the dissolution curves of release-controlling-film coated pellets F-52 (250 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

FIG. 31

depicts the dissolution curves of release-controlling-film coated pellets F-53 (250 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

FIG. 32

depicts the dissolution curves of release-controlling-film coated pellets F-54 (250 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

FIG. 33

depicts the dissolution curves of release-controlling-film coated pellets F-3 (—♦—) and F-17 (—▴—), and controlled release dosage form O-1 (—▪—).

FIG. 34

depicts the dissolution curves of controlled release dosage form O-1 (215 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

FIG. 35

depicts the dissolution curves of controlled release dosage form O-2 (218.77 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

FIG. 36

depicts the dissolution curves of controlled release dosage form O-3 (233.8 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

FIG. 37

depicts the dissolution curves of controlled release dosage form O-4 (232.7 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

FIG. 38

depicts the dissolution curves of controlled release dosage form O-5 (230.3 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

FIG. 39

depicts the dissolution curves of controlled release dosage form O-6 (230.3 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

FIG. 40

depicts the dissolution curves of controlled release dosage form O-7 (230 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

FIG. 41

depicts the dissolution curves of controlled release dosage form O-8 (230 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

FIG. 42

depicts the dissolution curves of controlled release dosage form O-9 (230 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

FIG. 43

depicts the dissolution curves of controlled release dosage form O-10 (230 mg) at pH 1.2 (—♦—), 4.5 (—▪—) and 6.88 (—▴—).

DETAILED DESCRIPTION OF THE INVENTION

It has been surprisingly found that pellets which release controlled amount of tacrine can be prepared by forming a release-controlling film on tacrine-coated pellets, and then coating thereon a second tacrine coating.

Accordingly, in the first aspect of the invention, there is provided a controlled release tacrine dosage form composed of single type of pellets, said dosage form comprising:

(a) a core;

(b) an inner active layer comprising tacrine and a binder;

(c) a release-controlling layer comprising one or more release-controlling film-forming polymer; and

(d) an active overcoat comprising tacrine and a binder.

The first part of the controlled release dosage form of the invention is a core which serves as the basis for proceeding layer-coatings.

The term “core” used herein refers to any inner cores which are known in the art to be suitable for use in pharmaceutical coating technology, e.g. granules or beads made of sugars, sugar alcohols (such as sucrose, lactose, mannitol and xylitol), celluloses and starch which do not chemically react with pharmacologically active substances. For instance, Nu-pareil seeds available from Ingrient Technology, U.S.A. can be conveniently used in the invention.

The second part of the controlled release dosage form in accordance with the invention is an active inner layer coated on the core. The layer comprising the active ingredient, i.e. tacrine, and a binder serves as the reservoir for continuously releasing tacrine.

The term “tacrine” used herein refers to any tacrine forms known in the art that provide pharmacologically active 1,2,3,4-tetrahydro-9-acridinamine. It may be in the form of a free tacrine or the pharmaceutically acceptable salts, solvates or hydrates thereof. In one embodiment of the invention, the tacrine form used is tacrine hydrochloride monohydrate.

The amount of tacrine contained in the inner active layer of the controlled release dosage form of the invention may vary depending on the subject to apply the dosage form to, the recommended dosage amount and the rest components in the controlled release dosage form of the invention. The amount should be sufficient to allow the controlled release dosage form of the invention to continuously release therapeutically effective amount of tacrine for at least 24 hours. In general, tacrine comprises about 10 to 70% by weight of the inner active layer and core of the controlled release dosage form of the invention, preferably about 20 to 60%, more preferably 25 to 45%, and most preferably 28 to 38%.

The term “binder” used herein refers to a compound that exerts a physicochemical attractive force between molecules. Binders suitable for use in the invention include, but not limited to, polyvinylpyrrolidone, acacia, gelatin, glucose, guar gum, pregelatinized starch, sodium alginate, cellulose derivatives, and the like, and mixtures thereof. Preferably, the binder used in the invention is a cellulose derivative, e.g. ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, sodium carboxymethylcellulose, and the like, and mixtures thereof. Most preferably, the binder is hydroxypropylmethylcellulose.

The amount of the binder in the inner active layer of the invention should be sufficient to effectively bind tacrine to the core. The amount may vary depending on the desired release effect, and the species of the core, the binder, and the rest components in the inner active layer and the components of the release-controlling layer. In general, the binder comprises about 0.1 to 30% by weight of the active inner layer, preferably about 1 to 25%, more preferably about 2 to 20%, and most preferably 3 to 15%.

Typically, the weight ratio of the core to the inner active layer of the controlled release dosage form of the invention is in the range from about 3:7 to about 9:1, preferably about 4:6 to about 8:2, and most preferably about 5:5 to about 7:3.

The third part of the controlled release dosage form of the invention is a release-controlling layer comprising one or more release-controlling-film forming polymer. The layer is coated on the active inner layer to control the active ingredient contained therein, i.e. tacrine, to release in an desired amount.

The “release-controlling-film-forming polymer” used herein refers to a polymer that forms a film on the inner active layer comprising tacrine to control said active ingredient to be released in a suitable amount. The polymer may be any film-forming polymer that is conventionally used in the art for preparing controlled release dosage forms. Examples of the polymer include, but not limited to, water insoluble polymers, water soluble polymers, enteric polymers, and the like, and mixtures thereof.

Water insoluble polymers suitable for use in the invention include, but not limited to, cellulose derivatives, such as ethylcellulose; acrylic polymers, such as polyacrylamide, polyacrylic dextrin, polyalkylcyanoacrylates, polymethyl-methacrylates and methacrylic resins; polyvinyl acetate; polyvinyl chloride; polyethylene; and the like; and mixtures thereof. Preferably, the water insoluble polymer used in the invention is ethylcellulose.

In the invention, the water insoluble polymer comprises about 40 to 95% by weight of the release-controlling layer, preferably about 50 to 85%, and most preferably about 65 to 80%.

Water soluble polymers suitable for use in the invention include, but not limited to, hydroxycellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, and the like, and mixtures thereof. Preferably, the water soluble polymer used in the invention is hydroxypropylcellulose or hydroxypropylmethylcellulose. More preferably, the polymer is hydroxypropylmethylcellulose.

In the invention, the water soluble polymer comprises about 0 to 50% by weight of the release-controlling layer, preferably about 10 to 40%, and most preferably about 15 to 30%.

Enteric polymers suitable for use in the invention include, but not limited to, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, styrene acrylic copolymers, methacrylic copolymers, maleic anhydride copolymers, shellac, and the like, and mixtures thereof. Preferably, the enteric polymer used in the invention is shellac.

In accordance with the invention, the release-controlling layer may comprise one or more the above described film-forming polymer. For instance, the water soluble polymer may be used alone. In one embodiment of the invention, ethylcellulose is used alone. The water soluble polymer may also be used in combination with a water insoluble polymer. In other embodiments of the invention, ethylcellulose is used in combination with hydroxypropylcellulose or hydroxypropylmethylcellulose. In addition, the enteric polymer may also be used alone. In a firer embodiment of the invention, shellac is used alone. Furthermore, it is possible to use two polyacrylates. A still further embodiment of the invention uses the combination of acrylic acid and a methacrylate polymer.

The amount of release-controlling-film-forming polymer in the controlled release dosage form of the invention should be sufficient to effectively control tacrine to be released in a desired amount. Preferably, the amount is effective to allow the controlled release dosage form of the invention to release therapeutically effective amount of tacrine for at least 24 hours after administration.

The release-controlling layer of the controlled release dosage form of the invention may further comprise one or more plasticizing agent.

The “plasticizing agent” used herein refers to any organic molecule capable of increasing the flexibility and toughness of final products by internally modifying or solvating polymer molecules. Plasticizing agents suitable for use in the invention include, but not limited to, phthalates, such as dibutyl phthalate; adipates; sebacates, such as dibutyl sebacate; ethylene glycol; polyethylene glycol and their derivatives; tricresyl phosphate; castor oil; citrates, such as triethyl citrate, tributyl citrate, acetyl tributyl citrate; triacetin; acetylated mono-, di- and triglycerides; and the like; and mixtures thereof. Preferably, the plasticizing agent used in the invention is selected from the group consisting of dibutyl phthalate, dibutyl sebacate and triethyl citrate.

In general, the plasticizing agent used in the invention comprises about 1 to 15% by weight of the release-controlling layer of the invention, preferably about 1.5 to 20%, and more preferably about 2 to 15%.

The fourth part of the controlled release dosage form of the invention is an active overcoat coated on the release-controlling layer. Said overcoat comprises tacrine and a binder, and provides an impulse of tacrine upon administration of the dosage form.

The amount of tacrine contained in the active overcoat of the controlled release dosage form of the invention may vary depending on the subject to apply the dosage form to, the recommended dosage amount and the rest components in the controlled release dosage form of the invention. The amount should be sufficient to allow the controlled release dosage form of the invention to release therapeutically effective amount of tacrine upon administration. In general, tacrine comprises about 55 to 99% by weight of the active overcoat, preferably about 60 to 98%, more preferably 65 to 97%, and most preferably 70-95%.

Any binder that is suitable for use in the active inner layer of the controlled release dosage form of the invention is suitable for use in the active overcoat. The amount of the binder in the active overcoat should be sufficient to bind tacrine to the release-controlling layer and may vary depending on the desired release effect, the species of the binder and the components in the release-controlling layer and the rest components in the active overcoat. In general, the binder comprises about 1 to 45% by weight of the active overcoat, preferably about 2 to 40%, more preferably 3 to 35%, and most preferably 5 to 30%.

The controlled release dosage form of the invention is constituted as stated above and can effectively release therapeutically effective amount of tacrine upon administration and continue the release for at least 24 hours. In general, to achieve the effect of immediate and continuous release of therapeutically effective amount of tacrine, the weight ratio of the tacrine component in the active inner layer to the active overcoat is in the range about 12:1 to about 1:1, preferably about 10:1 to about 3:1, and most preferably about 8:1 to 5:1.

The weight percentage of the core, the active inner layer, the release-controlling layer and the active overcoat in the controlled release dosage form of the invention may vary depending on the desired release effect. Typically, the four parts may comprise 42-62%, 25-45%, 3.5-13.5% and 2.5-6.5% by weight of the dosage form, respectively. In one embodiment of the invention, the four parts comprise 52%, 35%, 8.5% and 4.5% by weight of the dosage form, respectively.

In another aspect of the invention, there is provided a process for preparing a controlled release tacrine dosage form, which comprises:

(a) coating a suitable core with a mixture of tacrine and a binder to obtain a coated pellet;

(b) further coating the pellet obtained in step (a) with a release-controlling-film-forming polymer or a mixture thereof; and

(c) further coating the pellet obtained in step (b) with a mixture of tacrine and a binder.

The components in each layer of the controlled release dosage form of the invention can be formulated to coating solutions with a suitable solvent or solvent system and then used to coat the core or the resultant pellets. For instance, the coating solutions can be formulated with water, an organic solvent or a mixture of organic solvents. Suitable organic solvents are those customarily used in the art, e.g. alcohols, such as ethanol, propanol or isopropanol; ketones such as acetone; and hydrocarbon chloride, such as methylene chloride. A mixture of water and an organic solvent of suitable ratios may also be used, e.g. a 3:7 to 7:3 mixture.

To facilitate the processing, one or more conventional pharmaceutically acceptable excipient and additive can be added to the coating solutions of active inner layer, release-controlling layer, and active overcoat, e.g. anti-foam agents, fillers, coloring agents, flavoring agents, perfumes, sweetening agents, surface active agents, lubricants, stabilizing agents, anti-tacking agents, and the like, and mixtures thereof.

For instance, one or more anti-tacking agent can be used in the coating solution to uniformly disperse the components. Anti-tacking agents suitable for use in the invention are those customarily used in the art, which include, but not limited to, polymeric electrolytes, condensed silicates, polyphosphates, xylin derivatives, such as aluminum stearate, aluminum laurate, magnesium stearate, calcium stearate, zinc stearate, talc, kaolin, fumed silica, and the like, and mixtures thereof. Preferably, the anti-tacking agent is talc or silica, which also acts as a light-barrier.

The dosage form of the present invention may be prepared using standard techniques and equipment known to those skilled in the art. The core may be prepared by suspension layering, powder layering, or extrusion/spheronization techniques, or other standard procedures, using standard techniques and equipment known to those skilled in the art. The core and pellets may be coated by fluid-bed coating, pan coating, or other standard coating procedures using standard techniques and equipment known to those skilled in the art. The exact conditions for forming and coating pellets will vary with the particular apparatus selected and are readily determined by those skilled in the art without the need for undue experimentation. Fluid-bed coating and pan coating are well known in the arts and therefore the selection of the specific apparatus will be apparent to the artisan.

The invention is further illustrated in the following examples, which, however, are not limitations of the invention.

In the following examples, the tacrine form used is tacrine hydrochloride monohydrate commercially available from Effechem Co. Italy; Pharmacoat 645 comprising hydroxypropylmethylcellulose is from Shin-Etsu Co., Japan; EC N-10 and EC D-30 comprising 27% ethylcellulose are from Aqualon Co., U.S.A.; methylene chloride HPLC grade is from Merck Co., German; Nu-pareil PG is from Ingrient Technology Co., U.S.A.; talc is from Nakarai Tesque Co., Japan; Surelease comprising ethylcellulose and fractionally distilled coconut oil is from Colorcon Co., U.S.A.; Aerosil comprises silica; triethyl citrate (TEC) is form Pfizer Co., Japan; hydroxypropylcellulose is form Shin-Etsu Co.; dibutyl phthalate (DBP) is from Nacalai Tesque Co.; Eudragit RS 30D, Eudragit RL 30D, Eudragit RS PO and Eudragit RL PO comprising acrylic acid/methacrylate copolymers are from Rohm Pharma Co., German; and Tween 80 comprising polysorbitol is from Merck Co., Germany.

EXAMPLE 1

Preparation of Inner Active Layer-Coated Pellets

The coating solution of active inner layer is of the following composition:

Tacrine HCl

36

g

Pharmacoat 645

24

g

Ethanol (EtOH)

265

ml

H

2

O

265

ml

Ethanol and water were mixed first. Pharmacoat 645 was dissolved in the mixture, and thereafter Tacrine HCl was added. The resultant mixture was heated to 50° C. to dissolve the components.

Nu-pareil seeds (60 g, 25-30 mesh) were coated with the above coating solution on Aerocoater Model Strea-1 (Aeromatic AG, Swiss) under the following conditions:

Inlet:

50° C.

Outlet:

40° C.

Air:

1.2 Bar

Air volume:

100 M

3

/hr

Spray:

4 ml/min

The seeds coated to a suitable diameter were dried at 50° C. for 30 min. to obtain inner active layer-coated pellets P-1 (yield: 109.8 g; efficiency: 83%).

Following the similar procedures, inner active layer-coated pellets P-2 to P-38 were prepared on Aerocoater Model Stea-1 or Model GPC G-3 (Glatt GmbH, Germany) fluid-bed granulator with the cores and coating solutions shown in Table 1 below:

TABLE 1

No.

core

coating solution

result

conditions

P-2

50 g

Tacrine Hcl

40 g

efficiency

82.9%

Aeromatic

Nupareil

Pharmacoat 645

12 g

yield

93.1 g

inlet

48° C.

(25-30 mesh)

EtOH

210 ml

outlet

38° C.

H

2

O

105 ml

spray

4 ml/min

air

1.2 bar

air volume

100 m

3

/hr

P-3

1000 g

Tacrine Hcl

36 g

acceptable

Glatt

Nupareil

Pharmacoat 645

24 g

inlet

52° C.

(25-30 mesh)

EtOH

300 ml

outlet

40° C.

H

2

O

300 ml

spray

20 ml/min

air

1.8 bar

air volume

0.35 bar

P-4

1000 g

Tacrine Hcl

40 g

acceptable

Glatt

Nupareil

Pharmacoat 645

40 g

inlet

52° C.

(25-30 mesh)

Talc

15 g

outlet

38° C.

EtOH

300 ml

spray

25 ml/min

H

2

O

300 ml

air

1.8 bar

air volume

95 m

3

/hr

P-5

1000 g

Tacrine Hcl

40 g

acceptable

Glatt

Nupareil

Pharmacoat 645

20 g

inlet

52° C.

(25-30 mesh)

Talc

20 g

outlet

36° C.

EtOH

250 ml

spray

30 ml/min

H

2

O

250 ml

air

1.8 bar

air volume

2.35 bar

P-6

1000 g

Tacrine Hcl

40 g

acceptable

Glatt

Nupareil

Pharmacoat 645

20 g

inlet

52° C.

(25-30 mesh)

Talc

20 g

outlet

36° C.

EtOH

200 ml

spray

30 ml/min

H

2

O

200 ml

air

1.8 bar

air volume

0.35 bar

P-7

1000 g

Tacrine Hcl

40 g

acceptable

Glatt

Nupareil

EtOH

200 ml

inlet

50° C.

(25-30 mesh)

H

2

O

100 ml

outlet

36° C.

spray

35 ml/min

air

1.8 bar

air volume

0.35 bar

P-8

1000 g

Tacrine Hcl

40 g

acceptable

Glatt

Nupareil

Pharmacoat 645

10 g

inlet

50° C.

(25-30 mesh)

EtOH

200 ml

outlet

36° C.

H

2

O

100 ml

spray

35 ml/min

air

1.8 bar

air volume

0.35 bar

P-9

1000 g

Tacrine Hcl

40 g

acceptable

Glatt

Nupareil

Pharmacoat 645

12 g

inlet

50° C.

(25-30 mesh)

EtOH

200 ml

outlet

37° C.

H

2

O

100 ml

spray

30 ml/min

air

1.8 bar

air volume

0.34 bar

P-10

50 g

Tacrine Hcl

40 g

efficiency

82.9%

Aeromatic

Nupareil

Pharmacoat 645

12 g

yield

93.1 g

inlet

48° C.

(25-30 mesh)

EtOH

210 ml

outlet

38° C.

H

2

O

105 ml

spray

4 ml/min

air

1.2 bar

air volume

100 m

3

/hr

P-11

60 g

Tacrine Hcl

48 g

efficiency

85.3%

Aeromatic

Nupareil

Pharmacoat 645

14.4 g

yield

113.2 g

inlet

48° C.

(25-30 mesh)

EtOH

252 ml

outlet

34° C.

H

2

O

126 ml

spray

30 ml/min

air

1.2 bar

air volume

100 m

3

/hr

P-12

630 g

Tacrine Hcl

480 g

efficiency

95.81%

Glatt

Nupareil

Pharmacoat 645

144 g

yield

1227.88 g

inlet

30° C.

(25-30 mesh)

EtOH

2520 ml

outlet

34° C.

H

2

O

1260 ml

spray

30 ml/min

air

1.8 bar

air volume

0.35 bar

P-13

650 g

Tacrine Hcl

480 g

efficiency

92.06%

Glatt

Nupareil

Pharmacoat 645

150 g

yield

1230 g

inlet

50° C.

(25-30 mesh)

EtOH

2500 ml

outlet

34° C.

H

2

O

1250 ml

spray

30 ml/min

air

1.8 bar

air volume

0.35 bar

P-14

60 g

Tacrine Hcl

48 g

efficiency

90.5%

Aeromatic

Nupareil

Pharmacoat 645

15 g

yield

117 g

inlet

55° C.

(25-30 mesh)

H

2

O

250 ml

outlet

45° C.

spray

3 ml/min

air

1.2 bar

air volume

100 m

3

/hr

P-15

60 g

Tacrine Hcl

48 g

efficiency

92%

Aeromatic

Nupareil

Pharmacoat 645

15 g

yield

118.71 g

inlet

55° C.

(25-30 mesh)

Talc

1 g

outlet

45° C.

H

2

O

250 ml

spray

3 ml/min

air

1.2 bar

air volume

100 m

3

/hr

P-16

70 g

Tacrine Hcl

48 g

efficiency

91.2%

Aeromatic

Nupareil

Pharmacoat 645

12 g

yield

124.7 g

inlet

60° C.

(25-30 mesh)

H

2

O

250 ml

outlet

44° C.

spray

3.3 ml/ min

air

1.3 bar

air volume

100 m

3

/hr

P-17

85.4 g

Tacrine Hcl

60 g

efficiency

85.5%

Aeromatic

Nupareil

Pharmacoat 645

12 g

yield

147 g

inlet

55° C.

(25-30 mesh)

EtOH

180 ml

outlet

43° C.

H

2

O

120 ml

spray

3.3 ml/min

air

1.2 bar

air volume

100 m

3

/hr

P-18

85 g

Tacrine Hcl

60 g

efficiency

86.4%

Aeromatic

Nupareil

Pharmacoat 645

12 g

yield

147.2 g

inlet

55° C.

(25-30 mesh)

EtOH

150 ml

outlet

43° C.

H

2

O

150 ml

spray

3-3.5 ml/min

air

1.2 bar

air volume

100 m

3

/hr

P-19

700 g

Tacrine Hcl

480 g

efficiency

93.5%

Glatt

Nupareil

Pharmacoat 645

96 g

yield

1238.5 g

inlet

55° C.

(25-30 mesh)

EtOH

1200 ml

outlet

38° C.

H

2

O

1200 ml

spray

30-33 ml/min

air

1.8 bar

air volume

0.35 bar

P-20

85 g

Tacrine Hcl

60 g

efficiency

87.16%

Aeromatic

Nupareil

Pharmacoat 645

11.25 g

yield

147.1 g

inlet

50° C.

(25-30 mesh)

EtOH

150 ml

outlet

40° C.

H

2

O

150 ml

spray

3 ml/min

air

1.2 bar

air volume

100 m

3

/hr

P-21

86 g

Tacrine Hcl

60 g

efficiency

85.71%

Aeromatic

Nupareil

Pharmacoat 645

10 g

yield

146 g

inlet

50° C.

(25-30 mesh)

EtOH

130 ml

outlet

40° C.

H

2

O

130 ml

spray

3 ml/min

air

1.2 bar

air volume

100 m

3

/hr

P-22

1210.5 g

Tacrine Hcl

816 g

efficiency

98.16%

Glatt

Nupareil

Pharmacoat 645

161.5 g

yield

2170 g

inlet

55° C.

(25-30 mesh)

EtOH

2125 ml

outlet

33° C.

H

2

O

2125 ml

spray

30-36 ml/min

air

1.8 bar

air volume

0.35 bar

P-23

1250.7 g

Tacrine Hcl

816 g

efficiency

95.58%

Glatt

Nupareil

Pharmacoat 645

161.5 g

yield

2185 g

inlet

55° C.

(25-30 mesh)

EtOH

2125 ml

outlet

36° C.

H

2

O

2125 ml

spray

30-36 ml/min

air

1.8 bar

air volume

0.35 bar

P-24

1450 g

Tacrine Hcl

816 g

efficiency

98.63%

Glatt

Nupareil

Pharmacoat 645

161.5 g

yield

2414.1 g

inlet

54° C.

(25-30 mesh)

EtOH

2125 ml

outlet

34° C.

H

2

O

2125 ml

spray

30-36 ml/min

air

1.8 bar

air volume

0.35 bar

P-25

1300 g

Tacrine Hcl

816 g

efficiency

99.0%

Glatt

Nupareil

Pharmacoat 645

161.5 g

yield

2270 g

inlet

54° C.

(25-30 mesh)

EtOH

2125 ml

outlet

34° C.

H

2

O

2125 ml

spray

30-36 ml/min

air

1.8 bar

air volume

0.35 bar

P-26

1399 g

Tacrine Hcl

816 g

efficiency

96.256%

Glatt

Nupareil

Pharmacoat 645

161.5 g

yield

2339.9 g

inlet

54° C.

(25-30 mesh)

EtOH

2125 ml

outlet

34° C.

H

2

O

2125 ml

spray

30-36 ml/min

air

1.8 bar

air volume

0.35 bar

P-27

820 g

Tacrine Hcl

480 g

efficiency

99.0%

Glatt

Nupareil

Pharmacoat 645

95 g

yield

1389 g

inlet

60° C.

(25-30 mesh)

H

2

O

2500 ml

outlet

36° C.

spray

30 ml/min

air

1.8 bar

air volume

0.35 bar

P-28

820 g

Tacrine Hcl

480 g

efficiency

99.0%

Glatt

Nupareil

Pharmacoat 645

95 g

yield

1338.9 g

inlet

60° C.

(25-30 mesh)

H

2

O

2500 ml

outlet

36° C.

spray

30 ml/min

air

1.8 bar

air volume

0.35 bar

P-29

1399 g

Tacrine Hcl

816 g

efficiency

95.13%

Glatt

Nupareil

Pharmacoat 645

161.5 g

yield

2328.9 g

inlet

54° C.

(25-30 mesh)

EtOH

2125 ml

outlet

34° C.

H

2

O

2125 ml

spray

30-36 ml/min

air

1.8 bar

air volume

0.35 bar

P-30

1399 g

Tacrine Hcl

816 g

efficiency

95.33%

Glatt

Nupareil

Pharmacoat 645

161.5 g

yield

2330.8 g

inlet

54° C.

(25-30 mesh)

EtOH

2125 ml

outlet

34° C.

H

2

O

2125 ml

spray

30-36 ml/min

air

1.5 bar

air volume

0.35 bar

P-31

93 g

Tacrine Hcl

61.5 g

efficiency

86.46%

Aeromatic

Nupareil

Pharmacoat 645

11.875 g

yield

159.9 g

inlet

53° C.

(25-30 mesh)

Tween 80

4 g

outlet

41° C.

EtOH

166 ml

spray

3-3.3 ml/min

H

2

O

156 ml

air

1.2 bar

air volume

90 m

3

/hr

P-32

90 g

Tacrine Hcl

60 g

efficiency

86.94%

Aeromatic

Nupareil

Pharmacoat 645

11.875 g

yield

154.23 g

inlet

53° C.

(25-30 mesh)

Tween 80

2 g

outlet

41° C.

EtOH

156 ml

spray

3-3.3 ml/min

H

2

O

156 ml

air

1.2 bar

air volume

90 m

3

/hr

P-33

80 g

Tacrine Hcl

60 g

efficiency

86.94%

Glatt

Nupareil

Pharmacoat 645

11.875 g

yield

142.7 g

inlet

53° C.

(25-30 mesh)

Tween 80

0.2 g

outlet

41° C.

EtOH

156 ml

spray

3-3.3 ml/min

H

2

O

156 ml

air

1.2 bar

air volume

90 m

3

/hr

P-34

1399 g

Tacrine Hcl

816 g

efficiency

95.95%

Glatt

Nupareil

Pharmacoat 645

161.5 g

yield

2336.9 g

inlet

54° C.

(25-30 mesh)

EtOH

2125 ml

outlet

33° C.

H

2

O

2125 ml

spray

30-36 ml/min

air

1.5 bar

air volume

0.35 bar

P-35

1399 g

Tacrine Hcl

816 g

efficiency

95%

Glatt

Nupareil

Pharmcoat 645

161.5 g

yield

2325.7 g

inlet

54° C.

(25-30 mesh)

EtOH

2125 ml

outlet

33° C.

H

2

O

2125 ml

spray

30-36 ml/min

air

1.8 bar

air volume

0.35 bar

P-36

685 g

Tacrine Hcl

408 g

efficiency

93%

Glatt

Nupareil

Pharmacoat 645

80.75 g

yield

1140 g

inlet

54° C.

(25-30 mesh)

EtOH

1062.5 ml

outlet

33° C.

H

2

O

1062.5 ml

spray

30-36 ml/min

air

1.8 bar

air volume

0.35 bar

P-37

1399 g

Tacrine Hcl

816 g

efficiency

95%

Glatt

Nupareil

Pharmacoat 645

161.5 g

yield

2325.7 g

inlet

54° C.

(25-30 mesh)

EtOH

2125 ml

outlet

33° C.

H

2

O

2125 ml

spray

30-36 ml/min

air

1.8 bar

air volume

0.35 bar

P-38

1399 g

Tacrine Hcl

816 g

efficiency

95%

Glatt

Nupareil

Pharmacoat 645

161.5 g

yield

2327.5 g

inlet

54° C.

(25-30 mesh)

EtOH

2125 ml

outlet

33° C.

H

2

O

2125 ml

spray

30-36 ml/min

air

1.8 bar

air volume

0.35 bar

EXAMPLE 2

Preparation of Release-Controlling-Film-Coated Pellets

The coating solution of release controlling film is of the following composition:

ECN-1O

5

g

Pharmacoat 645

1.25

g

DBS

1

g

EtOH

60

ml

Methylene Chloride

60

ml

EC N-10 was dissolved in ethanol. Pharmacoat 645, DBS and water were then added. After the mixture was uniformly nixed, methylene chloride was added. The mixture was stirred to be thoroughly uniform.

Inner active layer-coated pellets P-1 prepared in Example 1 (50 g) were coated on Aerocoater Model Strea-1 fluid-bed granulator under the following conditions:

Inlet:

40° C.

Outlet:

30° C.

Air:

1.2 Bar

Air volume:

100 M

3

/hr

Spray:

4 ml/min

The pellets coated to a suitable diameter were dried at 35° C. for 30 min. to obtain release-controlling-film-coated pellets F-1 (yield: 55.72 g; efficiency: 97%).

EXAMPLE 3

Preparation of Release-Controlling-Film-Coated Pellets

The coating solution of release-controlling-film is of the following composition:

ECN-30

5

g

DBS

1

g

H

2

O

50

ml

EC N-30, DBS and water were uniformly mixed. Inner active layer-coated pellets P-2 prepared in Example 1 (40 g) were coated on Aerocoater Model Strea-1 fluid-bed granulator under the following conditions:

Inlet:

50° C.

Outlet:

35° C.

Air:

1.2 Bar

Air volume:

100 M

3

/hr

Spray:

4 ml/min

The pellets coated to a suitable diameter were dried at 50° C. for 30 min. to obtain release-controlling-film-coated pellets F-2 (yield: 44.74 g; efficiency: 79%).

Following the similar procedures to Example 2 or 3, release-controlling-film-coated pellets F-3 to F-58 were prepared on Aerocoater Model Stea-1 or Model GPC G-3 with the cores and coating solutions shown in Table 2 below:

TABLE 2

No.

core

coating solution

result

conditions

F-3

50 g

EC N-10

5 g

efficiency

81.4%

Aeromatic

P-2

Pharmacoat 645

1.25 g

yield

55.9 g

inlet

37° C.

DBS

1 g

outlet

30° C.

EtOH

60 ml

spray

5 ml/min

M.C

60 ml

air

1.2 bar

air volume

100 m

3

/hr

F-4

P-10

Surelease

40 g

efficiency

80%

Aeromatic

40 g

H

2

O

50 ml

yield

48 g

inlet

40° C.

outlet

32° C.

spray

4 ml/min

air

1.2 bar

air volume

103 m

3

/hr

F-5

P-10

Surelease

30 g

efficiency

88.53%

Aeromatic

50 g

H

2

O

50 ml

yield

56.6 g

inlet

40° C.

outlet

32° C.

spray

4 ml/min

air

1.2 bar

air volume

103 m

3

/hr

F-6

P-10

Surelease

20 g

efficiency

86.4%

Aeromatic

60 g

H

2

O

50 ml

yield

54.3 g

inlet

40° C.

outlet

32° C.

spray

4 ml/min

air

1.2 bar

air volume

103 m

3

/hr

F-7

P-10

Surelease

16 g

efficiency

84.52%

Aeromatic

40 g

Pharmacoat 645

0.2 g

yield

43.55 g

inlet

40° C.

H

2

O

40 ml

outlet

32° C.

spray

4 ml/min

air

1.2 bar

air volume

103 m

3

/hr

F-8

P-11

Surelease

6 g(24 g)

efficiency

87.58%

Aeromatic

50 g

Pharmacoat 645

0.12 g

yield

55.36 g

inlet

40° C.

H

2

O

40 ml

outlet

32° C.

spray

4 ml/min

air

1.2 bar

air volume

103 m

3

/hr

F-9

P-11

ECN-10

5 g

efficiency

79.17%

Aeromatic

50 g

Pharmacoat 645

1.25 g

yield

55.74 g

inlet

38° C.

DBS

1.0 g

outlet

32° C.

EtOH

60 ml

spray

4 ml/min

M.C

60 ml

air

1.2 bar

air volume

100 m

3

/hr

F-10

600 g

EC N-10

50 g

efficiency

78.21%

Glatt

P-12

Pharmacoat 645

12.5 g

yield

655.6 g

inlet

44° C.

DBS

10 g

outlet

30° C.

EtOH

600 ml

spray

30 ml/min

M.C

600 ml

air

1.8 bar

air volume

0.35 bar

F-11

600 g

Surelease

264 g

efficiency

90%

Glatt

P-12

Pharmacoat 645

1.32 g

yield

660.6 g

inlet

50° C.

H

2

O

440 ml

outlet

32° C.

spray

18 ml/min

air

1.8 bar

air volume

0.35 bar

F-12

600 g

Surelease

264 g

efficiency

92.73%

Glatt

P-13

Pharmacoat 645

1.4 g

yield

662.5 g

inlet

50° C.

H

2

O

300 ml

outlet

33° C.

spray

24 ml/min

air

1.8 bar

air volume

0.33 bar

F-13

600 g

Surelease

264 g

efficiency

90.8%

Glatt

P-19

Pharmacoat 645

1.4 g

yield

661.2 g

inlet

50.C

H

2

O

400 ml

outlet

34° C.

spray

24 ml/min

air

1.8 bar

air volume

0.34 bar

F-14

1903 g

Surelease

792 g

efficiency

94.11%

Glatt

P-23

Pharmacoat 645

4.2 g

yield

2093.3 g

inlet

50° C.

H

2

O

1200 ml

outlet

34° C.

spray

24 ml/min

air

1.8 bar

air volume

0.35 bar

F-15

2205.45 g

Surelease

924 g

yield

2395.5 g

Glatt

P-24

Pharmacoat 645

4.9 g

inlet

50° C.

H

2

O

1400 ml

outlet

34° C.

spray

24 ml/min

air

1.8 bar

air volume

0.35 bar

F-16

2240 g

Surelease

924 g

efficiency

90.28%

Glatt

P-25

Pharmacoat 645

4.9 g

yield

2453.2 g

inlet

50° C.

H

2

O

1400 ml

outlet

34° C.

spray

24 ml/min

air

1.8 bar

air volume

0.35 bar

F-17

600 g

Surelease

264 g

yield

659.4 g

Glatt

P-26

Pharmacoat 645

2.64 g

efficiency

86.54%

inlet

50° C.

H

2

O

400 ml

outlet

34° C.

spray

24 ml/min

air

1.8 bar

air volume

0.35 bar

F-18

600 g

Surelease

264 g

yield

661.6 g

Glatt

P-26

Pharmacoat 645

2.64 g

inlet

50° C.

H

2

O

400 ml

outlet

34° C.

spray

24 ml/min

air

1.8 bar

air volume

0.35 bar

F-19

50 g

Surelease

24 g

efficiency

81.4%

Aeromatic

P-26

Pharmacoat 645

0.24 g

yield

59.15 g

inlet

50° C.

Talc

5 g

outlet

38° C.

H

2

O

40 ml

spray

4 ml/min

air

1.2 bar

air volume

95 m

3

/hr

F-20

50 g

Surelease

24 g

efficiency

80%

Aeromatic

P-26

Pharmacoat 645

0.18 g

yield

57.54 g

inlet

50° C.

Talc

3 g

outlet

38° C.

H

2

O

40 ml

spray

4 ml/min

air

1.2 bar

air volume

95 m

3

/hr

F-21

75 g

Shellac

9 g

efficiency

80%

Aeromatic

P-26

PVP

1 g

yield

87 g

inlet

40° C.

Talc

5 g

outlet

32° C.

EtOH

65 ml

spray

4 ml/min

air

1.2 bar

air volume

95 m

3

/hr

F-22

50 g

Surelease

24 g

efficiency

85.57%

Aeromatic

P-26

Pharmacoat 645

0.18 g

yield

57.0 g

inlet

50° C.

Aerosil

2 g

outlet

38° C.

H

2

O

40 ml

spray

4 ml/min

air

1.2 bar

air volume

95 m

3

/hr

F-23

50 g

EC-N10

8 g

efficiency

80%

Aeromatic

P-26

HPC

1.6 g

yield

59.7 g

inlet

45° C.

Talc

2 g

outlet

35° C.

EtOH

130 ml

spray

4 ml/min

air

1.2 bar

air volume

95 m

3

/hr

F-24

65 g

EC-N10

8 g

efficiency

80%

Aeromatic

P-26

HPC

1.6 g

yield

75 g

inlet

45° C.

TEC

0.8 g

outlet

35° C.

Talc

2 g

spray

4 ml/min

EtOH

180 ml

air

1.2 bar

air volume

95 m

3

/hr

F-25

65 g

EudragitRS 30D

32 g

efficiency

84.9%

Aeromatic

P-26

EudragitRL 30D

8 g

yield

80.5 g

inlet

48° C.

DBP

1.25 g

outlet

36° C.

Talc

5 g

spray

4 ml/min

H

2

O

70 ml

air

1.2 bar

air volume

95 m

3

/hr

F-26

60 g

EudragitRS 30D

39 g

efficiency

84.62%

Aeromatic

P-26

EudragitRL 30D

1 g

yield

75.4 g

inlet

48° C.

DBP

1.2 g

outlet

36° C.

Talc

5 g

spray

4 ml/min

H

2

O

70 ml

air

1.2 bar

air volume

95 m

3

/hr

F-27

63.5 g

EudragitRS 30D

50 g

efficiency

87.64%

Aeromatic

P-26

DBP

1.5 g

yield

83 g

inlet

48° C.

Talc

6.25 g

outlet

36° C.

H

2

O

87.5 ml

spray

4 ml/min

air

1.2 bar

air volume

95 m

3

/hr

F-28

50 g

Surelease

36 g

efficiency

81.4%

Aeromatic

P-26

Pharmacoat 645

0.45 g

yield

57.5 g

inlet

50° C.

H

2

O

60 ml

outlet

38° C.

spray

4 ml/min

air

1.2 bar

air volume

95 m

3

/hr

F-29

50 g

Surelease

40 g

efficiency

85%

Aeromatic

P-26

Pharmacoat 645

0.6 g

yield

59.1 g

inlet

50° C.

H

2

O

60 ml

outlet

38° C.

spray

4 ml/min

air

1.2 bar

air volume

95 m

3

/hr

F-30

50 g

EudragitRS PO

7.5 g

efficiency

67.7%

Aeromatic

P-26

EudragitRL PO

0.2 g

yield

63 g

inlet

40° C.

DBP

1.5 g

outlet

34° C.

Talc

10 g

spray

4 ml/min

Acetone

50 ml

air

1.2 bar

isopropanol

75 ml

air volume

90 m

3

/hr

F-31

50 g

Surelease

40 g

efficiency

85%

Aeromatic

P-26

Pharmacoat 645

1 g

yield

59.8 g

inlet

50° C.

H

2

O

60 ml

outlet

36° C.

spray

4 ml/min

air

1.2 bar

air volume

95 m

3

/hr

F-32

65 g

EC-N10

8 g

efficiency

80.48%

Aeromatic

P-26

HPC

1.8 g

yield

77.05 g

inlet

43° C.

TEC

0.8 g

outlet

35° C.

Talc

4 g

spray

4 ml/min

EtOH

150 ml

air

1.2 bar

air volume

95 m

3

/hr

F-33

65 g

EC-N10

8 g

efficiency

80.0%

Aeromatic

P-26

HPC

1.8 g

yield

76.66 g

inlet

43° C.

DBS

0.8 g

outlet

35° C.

Talc

4 g

spray

4 ml/min

EtOH

150 ml

air

1.2 bar

air volume

95 m

3

/hr

F-34

66 g

EC-N10

8 g

efficiency

80.0%

Aeromatic

P-26

HPC

1.8 g

yield

77.9 g

inlet

43° C.

DBS

0.8 g

outlet

35° C.

Talc

4 g

spray

4 ml/min

isopropanol

150 ml

air

1.2 bar

air volume

95 m

3

/hr

F-35

80 g

EC-N10

8 g

efficiency

85.0%

Aeromatic

P-26

HPC

2 g

yield

93.1 g

inlet

43° C.

Talc

5 g

outlet

35° C.

isopropanol

160 ml

spray

4 ml/min

air

1.2 bar

air volume

95 m

3

/hr

F-36

600 g

EC-N10

50 g

efficiency

83.5%

Aeromatic

P-29

Pharmacoat 645

12.5 g

yield

656.35 g

inlet

44° C.

DBS

5 g

outlet

36° C.

EtOH

600 ml

spray

30 ml/min

M.C

600 ml

air

1.5 bar

air volume

0.34 m

3

/hr

F-37

600 g

EC-N10

60 g

efficiency

84.32%

Aeromatic

P-29

Pharmacoat 645

15 g

yield

668.3 g

inlet

44° C.

TEC

6 g

outlet

36° C.

EtOH

600 ml

spray

30 ml/min

M.C

600 ml

air

1.8 bar

air volume

0.34 m

3

hr

F-38

100 g

EudragitRS 30D

32 g

efficiency

84.9%

Aeromatic

P-26

EudragitRL 30D

8 g

yield

115.5 g

inlet

48° C.

DBP

1.25 g

outlet

35° C.

Talc

5 g

spray

4-5 ml/min

H

2

O

70 ml

air

1.2 bar

air volume

95 m

3

/hr

F-39

65 g

EudragitRS 30D

32 g

efficiency

85%

Aeromatic

P-26

EudragitRL 30D

8 g

yield

80.75 g

inlet

48° C.

DBP

1.25 g

outlet

35° C.

Talc

5 g

spray

4-5 ml/min

H

2

O

70 ml

air

1.2 bar

air volume

95 m

3

/hr

F-40

70 g

EC-N10

8 g

efficiency

80%

Aeromatic

P-29

Pharmacoat 645

1.8 g

yield

80.8 g

inlet

44° C.

TEC

0.8 g

outlet

36° C.

Talc

3 g

spray

4-5 ml/min

EtOH

130 ml

air

1.2 bar

M.C

30 ml

air volume

95 m

3

/hr

F-41

600 g

Surelease

264 g

efficiency

94.7%

Glatt

P-29

Pharmacoat 645

2.64 g

yield

665 g

inlet

50° C.

H

2

O

400 ml

outlet

34° C.

spray

24 ml/min

air

1.5 bar

air volume

0.35 bar

F-42

600 g

Surelease

264 g

efficiency

91.8%

Glatt

P-29

Pharmacoat 645

2.64 g

yield

663.2 g

inlet

50° C.

H

2

O

400 ml

outlet

34° C.

spray

24 ml/min

air

1.8 bar

air volume

0.35 bar

F-43

65 g

EC-N10

8 g

efficiency

80%

Glatt

P-31

Pharmacoat 645

1.8 g

yield

75.8 g

inlet

44° C.

TEC

0.8 g

outlet

36° C.

Talc

3 g

spray

3.5 ml/min

EtOH

130 ml

air

1.2 bar

M.C

50 ml

air volume

95 bar

F-44

60 g

EC-N10

8 g

efficiency

79.45%

Aeromatic

P-32

Pharmacoat 645

1.8 g

yield

71.6 g

inlet

44° C.

TEC

0.8 g

outlet

36° C.

Talc

4 g

spray

3.5 ml/min

EtOH

110 ml

air

1.2 bar

M.C

50 ml

air volume

95 m

3

/hr

F-45

53 g

EC-N10

8 g

efficiency

80.14%

Aeromatic

P-33

Pharmacoat 645

1.8 g

yield

64.7 g

inlet

44° C.

TEC

0.8 g

outlet

36° C.

Talc

4 g

spray

3.5 ml/min

EtOH

110 ml

air

1.2 bar

M.C

50 ml

air volume

95 m

3

/hr

F-46

600 g

EC-N10

60 g

efficiency

80.23%

Glatt

P-30

Pharmacoat 645

18 g

yield

667.4 g

inlet

44° C.

TEC

6 g

outlet

34° C.

EtOH

600 ml

spray

33 ml/min

M.C

600 ml

air

1.8 bar

air volume

0.35 bar

F-47

600 g

EC-N10

60 g

acceptable

Glatt

P-30

Pharmacoat 645

17 g

inlet

44° C.

TEC

6 g

outlet

36° C.

EtOH

600 ml

spray

33 ml/min

M.C

600 ml

air

1.8 bar

air volume

0.35 bar

F-48

600 g

EC-N10

50 g

efficiency

80.3%

Glatt

P-30

Pharmacoat 645

15 g

yield

656.2 g

inlet

44° C.

DBS

5 g

outlet

36° C.

EtOH

600 ml

spray

33 ml/min

M.C

600 ml

air

1.8 bar

air volume

0.35 bar

F-49

600 g

Surelease

262 g

efficiency

95.5%

Glatt

P-35

Pharmacoat 645

2.64 g

yield

665.6 g

inlet

50° C.

H

2

O

400 ml

outlet

34° C.

spray

24 ml/min

air

1.8 bar

air volume

0.35 bar

F-50

600 g

Surelease

262 g

efficiency

93.82%

Glatt

P-34

Pharmacoat 645

2.64 g

yield

664.4 g

inlet

50° C.

H

2

O

400 ml

outlet

34° C.

spray

24 ml/min

air

1.8 bar

air volume

0.35 bar

F-51

600 g

EC-N10

50 g

efficiency

82%

Glatt

P-35

Pharmacoat 645

15 g

yield

657.6 g

inlet

44° C.

DBS

5 g

outlet

36° C.

EtOH

600 ml

spray

33 ml/min

M.C

600 ml

air

1.8 bar

air volume

0.35 bar

F-52

1115 g

EC-N10

92.5 g

efficiency

85%

Glatt

P-36

Pharmacoat 645

27.75 g

yield

1225.1 g

inlet

44° C.

DBS

9.25 g

outlet

36° C.

EtOH

925 ml

spray

33 ml/min

M.C

925 ml

air

1.8 bar

air volume

0.35 bar

F-53

2330 g

EC-N10

175 g

efficiency

85.6%

Glatt

P-34

Pharmacoat 645

52.5 g

yield

2539.45 g

inlet

44° C.

DBS

17.5 g

outlet

36° C.

EtOH

1750 ml

spray

36 ml/min

M.C

1750 ml

air

1.8 bar

air volume

0.35 bar

F-54

2320 g

EC-N10

190 g

efficiency

85.7%

Glatt

P-37

Pharmcoat 645

57 g

° yield

2547.96 g

inlet

44° C.

DBS

19 g

outlet

36° C.

EtOH

1900 ml

spray

33 ml/min

M.C

1900 ml

air

1.8 bar

air volume

0.35 bar

F-55

2322.5 g

EC-N10

190 g

efficiency

85.7%

Glatt

P-38

Pharmacoat 645

57 g

yield

2550.5 g

inlet

44° C.

DBS

19 g

outlet

36° C.

EtOH

1900 ml

spray

33 ml/min

M.C

1900 ml

air

1.8 bar

air volume

0.35 bar

EXAMPLE 4

Preparation of Active Over-Coated Pellets

The coating solution of active overcoat layer is of the following composition:

Tacrine HCl

5.506

g

Pharmacoat 645

1.1012

g

EtOH

30

ml

H

2

O

30

ml

Ethanol and water were mixed first. Pharmacoat 645 was dissolved in the mixture, and thereafter Tacrine HCl was added. The resultant mixture was heated to 50° C. to dissolve the components.

Release-controlling-film-coated pellets F-13 prepared in Example 3 were coated on Aerocoater Model Strea-1 under the following conditions:

Inlet:

50° C.

Outlet:

40° C.

Air:

1.2 Bar

Air volume:

100 M

3

/hr

Spray:

3 ml/min

The pellets coated to a suitable diameter were dried at 50° C. for 30 min. to obtain active overcoat-coated pellets O-1 (yield: 105.5 g; efficiency: 83%).

Following the similar procedures, active overcoat-coated pellets O-2 to O-10 were prepared on Aerocoater Model Stea-1 or Glatt Model GPC G-3 fluid-bed granulator with the cores and coating solutions shown in Table 3 below:

TABLE 3

No.

core

coating solution

result

conditions

O-1

100 g

Tacrine Hcl

5.506 g

efficiency

83%

Aeromatic

F-13

Pharmacoat 645

1.1012 g

yield

105.5 g

inlet

50° C.

EtOH

30 ml

outlet

40° C.

H

2

O

30 ml

spray

3 ml/min

air

1.2 bar

air volume

100 m

3

/hr

O-2

2070 g

Tacrine Hcl

100 g

efficiency

98.0%

Glatt

F-14

Pharmacoat 645

19.8 g

yield

2197.2 g

inlet

50° C.

+Talc 10 g

H

2

O

700 ml

outlet

36° C.

spray

24 ml/min

air

1.8 bar

air volume

0.35 bar

O-3

52 g

Tacrine Hcl

2.5 g

efficiency

86.7%

Aeromatic

F-45

Pharmacoat 645

0.5 g

yield

54.6 g

inlet

50° C.

H

2

O

50 ml

outlet

40° C.

spray

3 ml/min

air

1.2 bar

air volume

95 m

3

/hr

O-4

F-47

Tacrine Hcl

29 g

efficiency

86.7%

Glatt

Pharmacoat 645

5.8 g

yield

54.6 g

inlet

50° C.

H

2

O

300 ml

outlet

38° C.

spray

18 ml/min

air

1.8 bar

air volume

0.35 bar

O-5

600 g

Tacrine Hcl

25.5 g

efficiency

92%

Glatt

F-48

Pharmacoat 645

5.1 g

yield

627.85 g

inlet

50° C.

H

2

O

300 ml

outlet

38° C.

spray

18 ml/min

air

1.8 bar

air volume

0.35 bar

O-6

600 g

Tacrine Hcl

27 g

efficiency

90%

Glatt

F-36

Pharmacoat 645

5.4 g

yield

628.8 g

inlet

50° C.

H

2

O

300 ml

outlet

38° C.

spray

18 ml/min

air

1.8 bar

air volume

0.35 bar

O-7

600 g

Tacrine Hcl

26 g

efficiency

93%

G1att

F-51

Pharmacoat 645

5.2 g

yield

628.9 g

inlet

50° C.

H

2

O

300 ml

outlet

38° C.

spray

18 ml/min

air

1.8 bar

air volume

0.35 bar

O-8

1200 g

Tacrine Hcl

52 g

efficiency

96%

Glatt

F-52

Pharmacoat 645

10.4 g

yield

1260 g

inlet

50° C.

H

2

O

450 ml

outlet

40° C.

spray

18 ml/min

air

1.8 bar

air volume

0.35 bar

O-9

2540 g

Tacrine Hcl

111.8 g

efficiency

98%

Glatt

F-53

Pharmacoat 645

22.36 g

yield

2674.16 g

inlet

50° C.

H

2

O

967.5 ml

outlet

38° C.

spray

18 ml/min

air

1.8 bar

air volume

0.35 bar

O-10

2540 g

Tacrine Hcl

111.8 g

efficiency

98%

Glatt

F-55

Pharmacoat 645

22.36 g

yield

2671.2 g

inlet

50° C.

H

2

O

970 ml

outlet

38° C.

spray

20 ml/min

air

1.8 bar

air volume

0.35 bar

EXAMPLE 5

Encapsulation

Active overcoat-coated pellets O-10 were encapsulated in #2 capsules on MG2 automatic encapsulator (Mgfutura Co, Italy). The ingredients and their ratios, on the basis of 10,000 capsules, are shown below:

Active Inner Layer-Coated Pellets

Nu-Pareil (25-30 mesh)

1201.7

g

Tacrine HCl Monohydrate

665.86

g

Hydroxypropyl Methylcellulose 2910 USP

131.78

g

Ethanol (95%)

1825

ml

Water

1825

ml

Release-Controlling-Film-Coated Pellets

Ethyl Cellulose

139.86

g

Hydroxypropyl Methylcellulose 2910 USP

41.96

g

Dibutyl Sebacate

13.986

g

Ethanol (95%)

1632

ml

Methylene Chloride

1632

ml

Active Overcoat-Coated Pellets

Tacrine HCl Monohydrate

94.1

g

Hydroxypropyl Methylcellulose 2910 USP

18.82

g

Water

859

ml

Total

2308.1

g

Each capsule contains 230.8 mg of pellets, with a label claim of 76 mg of Tacrine.HCl:H

2

O.

EXAMPLE 6

Dissolution Test

The dissolution test on release-controlling-film-coated pellets and the release controlled dosage forms according to the invention was tested on standard USP No. 1 Dissolution Tester (Toyama, Sangoyo Co. Ltd., Japan). The tested pellets were stirred, 50 rpm, at 37° C. in deionized water or in HCl media (pH 1.2, 4.5 and 6.8). One ml of samples were diluted. filtered (PTFE, 13 mm, 0.45 μm), and quantitatively analyzed with UV-visible spectrophotometer (UV-160A, Shimadzu, Japan) at 240 nm at 0, 1, 2, 4, 6, 9, 12 and 24 hr. The accumulative percentages of dissolved Tacrine HCl were calculated. The results are shown in

FIGS. 1

to

43

.

The release-controlling layer in the controlled release dosage forms of the invention effectively controls the inner active layer to release suitable amount of tacrine for at least 24 hours. In addition, the controlled release dosage forms of the invention immediately release suitable amount of tacrine upon administration and continue the release for at least 24 hours.

EXAMPLE 7

Bioavailability Test

Dogs (weighed 17 to 20 Kg and aged 18 months) are kept in a temperature-and-humidity controlled animal room, and fasted overnight. On the day of test, the dogs are given the tested dosage forms (60 mg tacrine/capsule), and then water (30 ml). Blood samples are withdrawn immediately before and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 15, 16, 18, 21 and 24 hours after administration. Parameters such as apparent volume of distribution divided by bioavailability (Vd/F), first order absorption rate constant (Ka), first order elimination rate constant (kel), area under the blood concentration versus time curve (AUC), half-life (t

½

) clearance, maximum concentration (C

max

) and time to peak concentration (T

peak

) are determined in accordance with Bourne, D. W. A., “Boomer, a Simulation and Modeling Program for Pharmacokinetic and Pharmacodynamic Data Analysis,” Computer Method Prog. Biomed, 29, 191-195 (1989).

Number	Date	Country
0 327 086	Aug 1989	EP
9503052	Feb 1995	WO
9514460	Jun 1995	WO

Controlled release tacrine dosage form

Information

Patent Number

Date Filed

Date Issued

Inventors

Original Assignees

Examiners

Agents

CPC

US Classifications

Field of Search

US

International Classifications

Abstract

Description

Claims

Priority Claims (1)

US Referenced Citations (1)

Foreign Referenced Citations (3)