# US 9,750,702 B2 · Pharmaceutical composition for treating parkinson's disease and preparation method thereof

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- Number: US 9,750,702 B2
- Document ID: US9750702B2
- Status: Granted
- Kind: B2
- Application number: 13/518,767
- Filed: 2009-12-25
- Published: 2012-11-01
- Granted: 2017-09-05
- Earliest claimed: 2009-12-25
- Assignees: Innopharmax, Inc.
- Applicants: Weihua Hao; Jongjing Wang; Huiyun Chen
- Inventors: Weihua Hao; Jongjing Wang; Huiyun Chen
- Web page: https://patentgrep.com/patent/US9750702B2

## CPC

- A61K 9/2077: {Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets}
- A61K 31/195: having an amino group
- A61K 31/198: Alpha-amino acids, e.g. alanine or edetic acid [EDTA] (betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00)
- A61K 31/277: having a ring, e.g. verapamil
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 25/16: Anti-Parkinson drugs
- A61K 9/5084: {Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs (tablets containing such a mixture A61K9/2077)}
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

A pharmaceutical composition used to treat Parkinson's disease contains levodopa, carbidopa and entacapone or pharmaceutically acceptable salt thereof, and at least one kind of pharmaceutically acceptable excipients. Entacapone is not mixed with levodopa or carbidopa in the pharmaceutical composition. The preparation method of the pharmaceutical composition includes making the first particles with levodopa and carbidopa, making the second particles with entacapone, and then pressing the two kinds of particles into tablets.

## Claims

### Claim 1

An oral solid pharmaceutical composition for treating Parkinson's disease, comprising first granules that comprise 25-300 milligrams of levodopa and 5-75 milligrams of carbidopa but that do not comprise entacapone, and
second granules that comprise a binder that binds particles
which comprise sodium dodecyl sulfate (SDS) and 25-300 milligrams of entacapone,
which do not comprise levodopa or carbidopa, and
which comprise entacapone particles having a diameter of at least about 150 micrometers,
wherein
the size of the particles,
the identity of the binder, and
the amounts of the binder, entacapone, and SDS in the second granules are selected such that when the composition is assessed using a modification of USP levodopa/carbidopa/entacapone dissolution method USP 32, NF27 (1791) in which the USP standard basket with a rotation speed of 125 rotations per minute and 900 milliliters of pH 5.5 phosphate buffer solution are used, the time required for 90% of the entacapone to dissolve in the buffer solution is greater than about 25 minutes, but not more than about 80 minutes.

### Claim 2 (depends on 1)

The composition of claim 1, being in the form of a tablet.

### Claim 3 (depends on 1)

The composition of claim 1, being in the form of a double-layer tablet.

### Claim 4

A method for preparing an oral solid pharmaceutical composition for treating Parkinson's disease, the method comprising
(a) mixing levodopa, carbidopa and a first excipient to obtain a first mixture;
(b) granulating the first mixture to obtain first granules that do not contain entacapone;
(c) mixing entacapone, a binder, and SDS to obtain a second mixture;
(d) granulating the second mixture to obtain second granules in which the binder binds particles
which comprise entacapone and SDS,
which do not comprise levodopa or carbidopa, and
which comprises entacapone particles having a diameter of at least about 150 micrometers;
wherein
the size of the particles,
the identity of the binder, and
the amounts of the binder, entacapone, and SDS in the second granules
are selected such that when the composition is assessed using a modification of USP levodopa/carbidopa/entacapone dissolution method USP 32, NF27 (1791) in which the USP standard basket with a rotation speed of 125 rotations per minute and 900 milliliters of pH 5.5 phosphate buffer solution are used, the time required for 90% of the entacapone to dissolve in the buffer solution is greater than about 25 minutes, but not greater than about 80 minutes and
(e) compressing first and second granules into a tablet.

### Claim 5 (depends on 4)

The method of claim 4, wherein said step (e) is compressing the first granules into one layer and the second granules into the other layer of a double-layer tablet.

### Claim 6 (depends on 4)

The method of claim 4,
wherein the first granules comprise an excipient selected from the group consisting of mannitol, a sugar, a starch, and a hydroxypropyl methylcellulose, and
wherein the binder is selected from the group consisting of polyvinyl pyrrolidone (PVP), a starch, and a microcrystalline cellulose.

### Claim 7 (depends on 4)

The method of claim 4, wherein each of the first and second mixtures is wet granulated.

### Claim 8 (depends on 4)

The method of claim 4, further comprising coating the tablet with a film.

### Claim 9 (depends on 3)

The composition of claim 3, wherein the first and second granules are present in different layers of the double-layer tablet.

### Claim 10 (depends on 1)

The composition of claim 1, wherein the first granules comprise a combination of one or more excipients
that are mixed with the levodopa and the carbidopa and
that are selected such that when the composition is assessed using a modification of USP levodopa/carbidopalentacapone dissolution method USP 32, NF27 (1791) in which the USP standard basket with a rotation speed of 50 rotations per minute and 750 milliliters of 0.1 normal hydrochloric acid are used, the dissolution rates of the levodopa and the carbidopa are such that
the time required for 90% of the levodopa to dissolve in the acid is greater than about 10 minutes, but not greater than about 65 minutes and
the time required for 90% of the carbidopa to dissolve in the acid is greater than about 10 minutes, but not greater than about 65 minutes.

### Claim 11 (depends on 10)

The composition of claim 10, wherein
the time required for 90% of the entacapone to dissolve in the buffer solution is about 45 minutes,
the time required for 90% of the levodopa to dissolve in the acid is about 35 minutes, and
the time required for 90% of the carbidopa to dissolve in the acid is about 35 minutes.

### Claim 12 (depends on 1)

The composition of claim 1, wherein the binder is povidone.

### Claim 13 (depends on 12)

The composition of claim 12, wherein the second granules further comprise microcrystalline cellulose and mannitol.

### Claim 14 (depends on 12)

The composition of claim 12, wherein the second granules further comprise microcrystalline cellulose and lactose.

### Claim 15 (depends on 14)

The composition of claim 14, wherein the relative proportions, by weight, of entacapone:SDS:povidone:microcrystalline cellulose:mannitol in the second granules are about 200:12:40:0.5:168.

### Claim 16 (depends on 1)

The composition of claim 1, wherein the first granules further comprise an excipient selected from the group consisting of binders, diluents, disintegrants, lubricants, compression aid agents, preservatives, coating agents, flavors, colors, and sweeteners.

### Claim 17 (depends on 1)

The composition of claim 1, wherein the first granules further comprise a binder and a diluent.

### Claim 18 (depends on 16)

The composition of claim 16, wherein the binder is hydroxypropyl methylcellulose (HPMC) and the diluent is mannitol.

### Claim 19 (depends on 18)

The composition of claim of claim 18, wherein the carbidopa is present in the form of carbidopa monohydrate and the relative proportions, by weight, of levodopa:carbidopa monohydrate:mannitol:HPMC in the first granules are about 100:27:88:16.4.

### Claim 20 (depends on 1)

The composition of claim 1, wherein, in addition to the first and second granules, the composition further comprises an excipient independently selected from the group consisting of binders, diluents, disintegrants, lubricants, compression aid agents, preservatives, coating agents, flavors, colors, and sweeteners.

### Claim 21 (depends on 20)

The composition of claim 20, being in the form of a tablet and comprising the first granules, the second granules, a disintegrant, and a lubricant.

### Claim 22 (depends on 20)

The composition of claim 20, being in the form of a tablet and comprising the first granules, the second granules, crospovidone, and magnesium stearate.