# US 2019/0167591 A1 · Taste-Masked Formulations of Raltegravir

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- Number: US 2019/0167591 A1
- Document ID: US20190167591A1
- Status: Published application
- Kind: A1
- Application number: 16/220,064
- Filed: 2018-12-14
- Published: 2019-06-06
- Earliest claimed: 2011-04-22
- Assignees: Merck Sharp & Dohme Corp.
- Applicants: Merck Sharp & Dohme Corp.
- Inventors: Karen Cassidy Thompson; Kimberly Nicole Kaighn; Indra Neil Mukherjee; Catherine Elizabeth Diimmler; Hedy Teppler Weiser; Christopher Mancinelli
- Web page: https://patentgrep.com/patent/US20190167591A1

## CPC

- A61K 9/1652: {Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin (homeopathic globules A61K9/1623)}
- A61K 9/0056: {Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals}
- A61K 9/2081: {with microcapsules or coated microparticles according to A61K9/50}
- A61K 9/5047: {Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose}
- A61K 31/41: having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K 31/513: having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 31/18: for HIV
- 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

Disclosed are taste-masked pharmaceutical formulations of raltegravir comprising coated API granules mixed with a screened powder excipient blend in either tablet or sachet form. The core and coated granules are produced using a Wurster process for enhanced control of particle size. Also disclosed are methods of treating HIV, e.g., in pediatric populations.

## Claims

### Claim 1

A pharmaceutical composition for oral administration wherein the active agent consists of raltegravir potassium and which comprises a plurality of taste-masked granules, each of which comprises:
a core granule comprising raltegravir potassium and a binder, and
(ii) a taste-masking polymer composition that forms a coating on the core granule, wherein said taste-masking polymer composition comprises an ethyl cellulose dispersion,
wherein said pharmaceutical composition is in the form of a chewable tablet or sachet.

### Claim 2

(canceled)

### Claim 3

(canceled)

### Claim 4 (depends on 1)

The composition according to claim 1, wherein said raltegravir potassium is anhydrous, and in crystalline Form 1, which is characterized by an X-ray powder diffraction pattern obtained using copper Kα radiation which comprises 2θ values in degrees of about 5.9, about 12.5, about 20.0, about 20.6 and about 25.6.

### Claim 5

(canceled)

### Claim 6 (depends on 1)

The composition according to claim 1, wherein said raltegravir potassium is anhydrous, and in crystalline Form 1, which is characterized by a differential scanning calorimetry curve, obtained at a heating rate of 10° C./min in a closed cup under nitrogen, exhibiting a single endotherm with a peak temperature of about 279° C.

### Claim at position 7

-8. (canceled)

### Claim 9 (depends on 1)

The composition according to claim 1, wherein said raltegravir potassium is anhydrous, and in crystalline Form 2, which is characterized by an X-ray powder diffraction pattern obtained using copper Kα radiation which comprises 2θ values in degrees of about 7.9, about 13.8, about 15.7, about 24.5 and about 31.5.

### Claim at position 9

-13. (canceled)

### Claim 14 (depends on 1)

The composition according to claim 1, wherein said raltegravir potassium is anhydrous, and in crystalline Form 3, which is characterized by an X-ray powder diffraction pattern obtained using copper Kα radiation which comprises 2θ values in degrees of about 7.4, about 7.8, about 12.3, about 21.6 and about 24.7.

### Claim at position 11

-17. (canceled)

### Claim 18 (depends on 1)

The composition according to claim 1, wherein said binder is hydroxypropyl cellulose.

### Claim 19 (depends on 1)

The composition according to claim 1, wherein the weight ratio of said binder to said raltegravir potassium is between about 0.06 and about 0.08.

### Claim 20

(canceled)

### Claim 21 (depends on 1)

The composition according to claim 1, wherein the amount of raltegravir in the composition is about 25 mg, about 50 mg, or about 100 mg, or the salt-equivalent thereof.

### Claim 22 (depends on 1)

The composition according to claim 1, further comprising an extragranular matrix, said matrix comprising at least one flavoring agent, a disintegrant, a filler and a lubricant.

### Claim 23 (depends on 1)

The composition according to claim 1, wherein said composition is a tablet or capsule.

### Claim 24 (depends on 1)

A composition according to claim 1 selected from Compositions A, B and C, wherein said compositions are comprised of the following:
Composition
A (mg)
B (mg)
C (mg)
Raltegravir
27
54
109
Hydroxypropyl cellulose
2
5
9
Ethyl cellulose dispersion
3
5
11
Film coating blend, clear Opadry
2
4
7
Total Coated Raltegravir Granule
34
68
136
Extragranular
Saccharin sodium
7
7
14
Sucralose
2
2
5
Banana Flavor
5
5
9
Orange Flavor
7
7
14
Monoammonium Glycyrrhizinate
2
2
5
Flavor Masking Neutral
5
5
9
Sodium Citrate Dihydrate
1
1
2
Mannitol
154
120
240
Crospovidone
12
12
23
Ferric Oxide, yellow
1
1
2
Sodium Stearyl Fumarate
2
2
5
Magnesium Stearate
1
1
2

### Claim 25 (depends on 1)

The composition according to claim 1, wherein said composition is a sachet for aqueous suspension prior to administration, further comprising at least one flavoring agent, a disintegrant, a suspending agent, a lubricant and a diluent.

### Claim 26 (depends on 25)

The composition according to claim 25 comprising the following:
Ingredient
Composition per sachet (mg)
Raltegravir
109
Hydroxypropyl cellulose
9
Ethycellulose
11
Opadry I Clear
7
Crospovidone
23
Mannitol
194
Sucralose
2
MagnaSweet
2
Banana Flavor
9
Avicel CL-611
9
Magnesium Stearate
7

### Claim 27 (depends on 1)

The pharmaceutical composition according to claim 1, wherein said core granules have a D50 of between about 130 and about 330 μm.

### Claim 28

(canceled)

### Claim 29 (depends on 1)

The pharmaceutical composition according to claim 1, wherein said coated granules have a D50 of between about 180 and about 340 μm.

### Claim 30

(canceled)

### Claim 31 (depends on 1)

The pharmaceutical composition according to claim 1, wherein administration of said composition to a person results in a mean blood plasma concentration of raltegravir displaying a Cmax of about 3.4 μm and an AUC of about 8 μm·hr.

### Claim 32

(canceled)

### Claim 33 (depends on 1)

A method of treating HIV in a person in need of such treatment comprising to said person a pharmaceutical composition according to claim 1, wherein said dose of raltegravir is determined as follows:
Patient Body Weight
(kg)
(lbs)
Dose
7 through 10
15 through 22
50 mg twice daily
10 through 14
22 through 31
75 mg twice daily
14 through 20
31 through 44
100 mg twice daily
20 through 28
44 through 62
150 mg twice daily
28 through 40
62 through 88
200 mg twice daily
at least 40
at least 88
300 mg twice daily

### Claim 34

(canceled)

### Claim 35

(canceled)

### Claim 36

A process for preparing a pharmaceutical composition comprising the steps of:
a) granulating raltegravir and a binder into granules by a Wurster granulating process;
b) coating said granules with a taste-masking agent by a Wurster coating process;
c) preparing an extragranular matrix comprising a binder, a disintegrant, a flavoring agent and a lubricant; and,
d) compressing said granules and said matrix into a tablet.

### Claim 37

(canceled)

### Claim 38 (depends on 1)

The composition according to claim 1 comprising 27.16 mg of raltegravir potassium, hydroxypropyl cellulose, an ethyl cellulose dispersion, a film coating blend, saccharin sodium, sucralose, banana flavor, orange flavor, monoammonium glycyrrhizinate, flavor masking neutral, sodium citrate dehydrate, mannitol, crospovidone, ferric oxide yellow, ferric oxide red, sodium stearyl fumarate and magnesium stearate.

### Claim 39 (depends on 1)

The composition according to claim 1 comprising 108.6 mg of raltegravir potassium, hydroxypropyl cellulose, an ethyl cellulose dispersion, a film coating blend, saccharin sodium, sucralose, banana flavor, orange flavor, monoammonium glycyrrhizinate, flavor masking neutral, sodium citrate dehydrate, mannitol, crospovidone, ferric oxide yellow, ferric oxide red, sodium stearyl fumarate and magnesium stearate.