# US 9,433,625 B2 · Pharmaceutical compositions for treating or preventing pain

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- Number: US 9,433,625 B2
- Document ID: US9433625B2
- Status: Granted
- Kind: B2
- Application number: 14/244,455
- Filed: 2014-04-03
- Published: 2014-10-16
- Granted: 2016-09-06
- Earliest claimed: 2009-07-08
- Assignees: Locl Pharma, Inc.
- Applicants: LOCL Pharma, Inc.
- Inventors: Paul Bosse; John Ameling; Bernard Schachtel; Ray Takigiku
- Web page: https://patentgrep.com/patent/US9433625B2

## CPC

- A61K 9/209: {containing drug in at least two layers or in the core and in at least one outer layer}
- A61K 9/2013: {Organic compounds, e.g. phospholipids, fats}
- A61K 9/2054: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61K 31/167: having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
- A61K 31/485: Morphinan derivatives, e.g. morphine, codeine
- A61K 31/5415: ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
- A61P 25/06: Antimigraine agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- 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

Methods and compositions are provided which comprise effective amounts of one or more analgesics, such as hydrocodone or acetaminophen, and an antiemetic, such as promethazine, to treat or prevent pain in a subject, and to reduce or prevent an adverse effect associated with the analgesics.

## Claims

### Claim 1

A pharmaceutical composition in the form of a tablet comprising two layers, wherein the tablet comprises
(1) a layer formulated for immediate release comprising:
(a) 5 mgs to 30 mgs of an antiemetic;
(b) about 75 mgs to about 150 mgs of silicified microcrystalline cellulose;
(c) about 10 mgs to about 20 mgs of croscarmellose sodium; and
(d) about 0.5 mgs to about 2 mgs of magnesium stearate; and
(2) a layer formulated for controlled release comprising:
(a) about 200 mgs to about 1000 mgs of a non-opioid analgesic;
(b) about 0.5 mgs to about 20 mgs of an opioid analgesic;
(c) about 75 mgs to about 250 mgs of silicified microcrystalline cellulose;
(d) about 10 mgs to about 40 mgs of hydroxypropyl methylcellulose;
(e) about 0.5 mgs to 5 mgs of magnesium stearate; and
(f) about 0.5 mgs to about 5 mgs of stearic acid.

### Claim 2 (depends on 1)

The pharmaceutical composition of claim 1, wherein the tablet has a hardness of about 7, 8, 9, 10, 11, 12, 13, 14, or 15 kilaponds (kp).

### Claim 3 (depends on 1)

The pharmaceutical composition of claim 1, wherein the tablet has a hardness of about 15 kp.

### Claim 4 (depends on 1)

The pharmaceutical composition of claim 1, wherein the antiemetic is promethazine, aprepitant, dronabinol, perphenazine, palonosetron, metoclopromide, domperidone, prochlorperazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron, benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone, oxyperndyl, pipamazine, scopolamine, sulpiride, thiethylperazine, thioproperazine, tropisetron, droperidol, haloperidol, diphenhydramine, midazolam, lorazepam, hyoscine, dexamethasone, emetrol, or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

The pharmaceutical composition of claim 1, wherein the antiemetic is promethazine or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

The pharmaceutical composition of claim 1, wherein the antiemetic is promethazine hydrochloride.

### Claim 7 (depends on 1)

The pharmaceutical composition of claim 1, wherein the antiemetic is present in an amount of about: 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, or 25 mgs.

### Claim 8 (depends on 1)

The pharmaceutical composition of claim 1, wherein the antiemetic is present in the amount of about 12.5 mgs.

### Claim 9 (depends on 1)

The pharmaceutical composition of claim 1, wherein the opioid analgesic is hydrocodone, oxycodone, acetyldihydrocodeinone, diamorphine, codeine, pethidine, alfentanil, buprenorphine, butorphanol, codeine, dezocine, fentanyl, hydromorphone, levomethadyl acetate, levorphanol, meperidine, methadone, morphine, nalbuphine, oxymorphone, pentazocine, propoxyphene, remifentanil, sufentanil, tramadol, or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 1)

The pharmaceutical composition of claim 1, wherein the opioid analgesic is hydrocodone or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 1)

The pharmaceutical composition of claim 1, wherein the opioid analgesic is hydrocodone bitartrate.

### Claim 12 (depends on 1)

The pharmaceutical composition of claim 1, wherein the opioid analgesic is oxycodone or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 1)

The pharmaceutical composition of claim 1, wherein the opioid analgesic is oxycodone hydrochloride.

### Claim 14 (depends on 1)

The pharmaceutical composition of claim 1, wherein the opioid analgesic is present in an amount of about: 1, 1.5, 2.5, 3, 4, 5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, or 15 mgs.

### Claim 15 (depends on 1)

The pharmaceutical composition of claim 1, wherein the opioid analgesic is present in an amount of about 7.5 mgs.

### Claim 16 (depends on 1)

The pharmaceutical composition of claim 1, wherein the non-opioid analgesic is acetaminophen, aspirin, ibuprofen, carprofen, fenbuprofen, flubiprofen, ketaprofen, ketorolac, loxoprofen, naproxen, suprofen, or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 1)

The pharmaceutical composition of claim 1, wherein the non-opioid analgesic is acetaminophen.

### Claim 18 (depends on 1)

The pharmaceutical composition of claim 1, wherein the non-opioid analgesic is present in an amount of : 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, or 350 mgs.

### Claim 19 (depends on 1)

The pharmaceutical composition of claim 1, wherein the non-opioid analgesic is acetaminophen and is present in an amount of about 325 mgs.

### Claim 20 (depends on 1)

The pharmaceutical composition of claim 1, wherein the antiemetic is promethazine or a pharmaceutically acceptable salt thereof, the opioid analgesic is hydrocodone or a pharmaceutically acceptable salt thereof, and the non-opioid analgesic is acetaminophen or a pharmaceutically acceptable salt thereof.

### Claim 21 (depends on 20)

The pharmaceutical composition of claim 20, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg or about 25 mg, wherein the hydrocodone or the pharmaceutically acceptable salt thereof is present in an amount of about 5 mg, about 7.5 mg, or about 10 mg, and wherein the acetaminophen or the pharmaceutically acceptable salt thereof is present in an amount of about 250 mg to about 402 mg.

### Claim 22 (depends on 20)

The pharmaceutical composition of claim 20, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg or about 25 mg, wherein the hydrocodone or the pharmaceutically acceptable salt thereof is present in an amount of about 5 mg, and wherein the acetaminophen or the pharmaceutically acceptable salt thereof is present in an amount of about 325 mg.

### Claim 23 (depends on 20)

The pharmaceutical composition of claim 20, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg or about 25 mg, wherein the hydrocodone or the pharmaceutically acceptable salt thereof is present in an amount of about 7.5 mg, and wherein the acetaminophen or the pharmaceutically acceptable salt thereof is present in an amount of about 325 mg.

### Claim 24 (depends on 20)

The pharmaceutical composition of claim 20 wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg or about 25 mg, wherein the hydrocodone or the pharmaceutically acceptable salt thereof is present in an amount of about 10 mg, and wherein the acetaminophen or the pharmaceutically acceptable salt thereof is present in an amount of about 325 mg.

### Claim 25 (depends on 22, 23, 24)

The pharmaceutical composition of any one of claims 22-24, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg.

### Claim 26 (depends on 1)

The pharmaceutical composition of claim 1, wherein the antiemetic is promethazine or a pharmaceutically acceptable salt thereof, the opioid analgesic is oxycodone or a pharmaceutically acceptable salt thereof, and the non-opioid analgesic is acetaminophen or a pharmaceutically acceptable salt thereof.

### Claim 27 (depends on 26)

The pharmaceutical composition of claim 26, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg or about 25 mg, wherein the oxycodone or the pharmaceutically acceptable salt thereof is present in an amount of about 5 mg, about 7.5 mg, or about 10 mg, and wherein the acetaminophen or the pharmaceutically acceptable salt thereof is present in an amount of about 250 mg to about 402 mg.

### Claim 28 (depends on 26)

The pharmaceutical composition of claim 26, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg or about 25 mg, wherein the oxycodone or the pharmaceutically acceptable salt thereof is present in an amount of about 5 mg, and wherein the acetaminophen or the pharmaceutically acceptable salt thereof is present in an amount of about 325 mg.

### Claim 29 (depends on 26)

The pharmaceutical composition of claim 26, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg or about 25 mg, wherein the oxycodone or the pharmaceutically acceptable salt thereof is present in an amount of about 7.5 mg, and wherein the acetaminophen or the pharmaceutically acceptable salt thereof is present in an amount of about 325 mg.

### Claim 30 (depends on 26)

The pharmaceutical composition of claim 26, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg or about 25 mg, wherein the oxycodone or the pharmaceutically acceptable salt thereof is present in an amount of about 10 mg, and wherein the acetaminophen or the pharmaceutically acceptable salt thereof is present in an amount of about 325 mg.

### Claim 31 (depends on 28, 29, 30)

The pharmaceutical composition of any one of claims 28-30, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg.

### Claim 32 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24)

The pharmaceutical composition of any one of claims 1, 2, 3, 4-19, 20-24, and 26-30, wherein the layer formulated for controlled release further comprises about 5 mgs to about 25 mgs of croscarmellose sodium.

### Claim 33 (depends on 31)

The pharmaceutical composition of claim 31, wherein the layer formulated for controlled release comprises from about 8 mgs to about 12 mgs of croscarmellose sodium.

### Claim 34

A method of treating or preventing pain in a subject in need thereof, comprising:
orally administering to a subject in need thereof in a dosing interval of 4 to 6 hours, as needed, a pharmaceutical composition in the form of a tablet comprising two layers, wherein the tablet comprises:
(1) a layer formulated for immediate release comprising:
(a) 5 mgs to 30 mgs of an antiemetic;
(b) about 75 mgs to about 150 mgs of silicified microcrystalline cellulose;
(c) about 10 mgs to about 20 mgs of croscarmellose sodium; and
(d) about 0.5 mgs to about 2 mgs of magnesium stearate; and
(2) a layer formulated for controlled release comprising:
(a) about 200 mgs to about 1000 mgs of a non-opioid analgesic;
(b) about 0.5 mgs to about 20 mgs of an opioid analgesic;
(c) about 75 mgs to about 250 mgs of silicified microcrystalline cellulose;
(d) about 10 mgs to about 40 mgs of hydroxypropyl methylcellulose;
(e) about 0.50 mgs to 5 mgs of magnesium stearate; and
(f) about 0.5 mgs to about 5 mgs of stearic acid,
wherein the pharmaceutical composition provides an effective amount of the opioid analgesic and the non-opioid analgesic to treat or prevent pain in the subject in need thereof, and an effective amount of the antiemetic to reduce or prevent an adverse effect associated with the opioid analgesic in the subject in need thereof.

### Claim 35 (depends on 34)

The method of claim 34, wherein the subject has a reduction in the adverse effect associated with the opioid analgesic.

### Claim 36 (depends on 34)

The method of claim 34, wherein the adverse effect associated with the opioid analgesic is nausea, vomiting, constipation, itching, gastric upset, or skin rash.

### Claim 37 (depends on 34)

The method of claim 34, wherein the subject is about age 65 or older.

### Claim 38 (depends on 34)

The method of claim 34, wherein the pain is associated with a headache.

### Claim 39 (depends on 38)

The method of claim 38, wherein the headache is a migraine headache, cluster headache, hemicrania continua headache, chronic headache, tension headache or chronic tension headache.

### Claim 40 (depends on 34)

The method of claim 34, wherein the pain is associated with photophobia.

### Claim 41 (depends on 34)

The method of claim 34, wherein the antiemetic is promethazine, aprepitant, dronabinol, perphenazine, palonosetron, metoclopromide, domperidone, prochlorperazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron, benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone, oxyperndyl, pipamazine, scopolamine, sulpiride, thiethylperazine, thioproperazine, tropisetron, droperidol, haloperidol, diphenhydramine, midazolam, lorazepam, hyoscine, dexamethasone, emetrol, or a pharmaceutically acceptable salt thereof.

### Claim 42 (depends on 34)

The method of claim 34, wherein the antiemetic is promethazine or a pharmaceutically acceptable salt thereof.

### Claim 43 (depends on 34)

The method of claim 34, wherein the antiemetic is promethazine hydrochloride.

### Claim 44 (depends on 34)

The method of claim 34, wherein the antiemetic is present in an amount of about: 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5 or 20 mgs.

### Claim 45 (depends on 34)

The method of claim 34, wherein the antiemetic is present in an amount of about 12.5 mgs.

### Claim 46 (depends on 34)

The method of claim 34, wherein the opioid analgesic is hydrocodone, oxycodone, acetyldihydrocodeinone, diamorphine, codeine, pethidine, alfentanil, buprenorphine, butorphanol, codeine, dezocine, fentanyl, hydromorphone, levomethadyl acetate, levorphanol, meperidine, methadone, morphine, nalbuphine, oxymorphone, pentazocine, propoxyphene, remifentanil, sufentanil, tramadol, or a pharmaceutically acceptable salt thereof.

### Claim 47 (depends on 34)

The method of claim 34, wherein the opioid analgesic is hydrocodone or a pharmaceutically acceptable salt thereof.

### Claim 48 (depends on 34)

The method of claim 34, wherein the opioid analgesic is hydrocodone bitartrate.

### Claim 49 (depends on 34)

The method of claim 34, wherein the opioid analgesic is oxycodone or a pharmaceutically acceptable salt thereof.

### Claim 50 (depends on 34)

The method of claim 34, wherein the opioid analgesic is oxycodone hydrochloride.

### Claim 51 (depends on 34)

The method of claim 34, wherein the opioid analgesic is present in an amount of about: 1, 1.5, 2.5, 3, 4, 5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, or 15 mgs.

### Claim 52 (depends on 34)

The method of claim 34, wherein the opioid analgesic is present in an amount of about 7.5 mgs.

### Claim 53 (depends on 34)

The method of claim 34, wherein the non-opioid analgesic is acetaminophen, aspirin, ibuprofen, carprofen, fenbuprofen, flubiprofen, ketaprofen, ketorolac, loxoprofen, naproxen, suprofen, or a pharmaceutically acceptable salt thereof.

### Claim 54 (depends on 34)

The method of claim 34, wherein the non-opioid analgesic is acetaminophen.

### Claim 55 (depends on 34)

The method of claim 34, wherein the non-opioid analgesic is present in an amount of: 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, or 350 mgs.

### Claim 56 (depends on 34)

The method of claim 34, wherein the non-opioid analgesic is acetaminophen and is present in an amount of about 325 mgs.

### Claim 57 (depends on 34)

The method of claim 34, wherein the adverse effect is nausea or vomiting.

### Claim 58 (depends on 34)

The method of claim 34, wherein the subject has a reduction in incidence of nausea or vomiting.

### Claim 59 (depends on 34)

The method of claim 34, wherein the subject has a reduction in intensity of nausea or vomiting.

### Claim 60 (depends on 34)

The method of claim 34, wherein the antiemetic is promethazine or a pharmaceutically acceptable salt thereof, the opioid analgesic is hydrocodone or a pharmaceutically acceptable salt thereof, and the non-opioid analgesic is acetaminophen or a pharmaceutically acceptable salt thereof.

### Claim 61 (depends on 60)

The method of claim 60, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg or about 25 mg, wherein the hydrocodone or the pharmaceutically acceptable salt thereof is present in an amount of about 5 mg, about 7.5 mg, or about 10 mg, and wherein the acetaminophen or the pharmaceutically acceptable salt thereof is present in an amount of about 250 mg to about 402 mg.

### Claim 62 (depends on 60)

The method of claim 60, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg or about 25 mg, wherein the hydrocodone or the pharmaceutically acceptable salt thereof is present in an amount of about 5 mg, and wherein the acetaminophen or the pharmaceutically acceptable salt thereof is present in an amount of about 325 mg.

### Claim 63 (depends on 60)

The method of claim 60, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg or about 25 mg, wherein the hydrocodone or the pharmaceutically acceptable salt thereof is present in an amount of about 7.5 mg, and wherein the acetaminophen or the pharmaceutically acceptable salt thereof is present in an amount of about 325 mg.

### Claim 64 (depends on 60)

The method of claim 60, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg or about 25 mg, wherein the hydrocodone or the pharmaceutically acceptable salt thereof is present in an amount of about 10 mg, and wherein the acetaminophen or the pharmaceutically acceptable salt thereof is present in an amount of about 325 mg.

### Claim 65 (depends on 62, 63, 64)

The method of any one of claims 62-64, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg.

### Claim 66 (depends on 34)

The method of claim 34, wherein the antiemetic is promethazine or a pharmaceutically acceptable salt thereof, the opioid analgesic is oxycodone or a pharmaceutically acceptable salt thereof, and the non-opioid analgesic is acetaminophen or a pharmaceutically acceptable salt thereof.

### Claim 67 (depends on 66)

The method of claim 66, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg or about 25 mg, wherein the oxycodone or the pharmaceutically acceptable salt thereof is present in an amount of about 5 mg, about 7.5 mg or about 10 mg, and wherein the acetaminophen or the pharmaceutically acceptable salt thereof is present in an amount of about 250 mg to about 402 mg.

### Claim 68 (depends on 66)

The method of claim 66, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg or about 25 mg, wherein the oxycodone or the pharmaceutically acceptable salt thereof is present in an amount of about 5 mg, and wherein the acetaminophen or the pharmaceutically acceptable salt thereof is present in an amount of about 325 mg.

### Claim 69 (depends on 66)

The method of claim 66, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg or about 25 mg, wherein the oxycodone or the pharmaceutically acceptable salt thereof is present in an amount of about 7.5 mg, and wherein the acetaminophen or the pharmaceutically acceptable salt thereof is present in an amount of about 325 mg.

### Claim 70 (depends on 66)

The method of claim 66, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg or about 25 mg, wherein the oxycodone or the pharmaceutically acceptable salt thereof is present in an amount of about 10 mg, and wherein the acetaminophen or the pharmaceutically acceptable salt thereof is present in an amount of about 325 mg.

### Claim 71 (depends on 68, 69, 70)

The method of any one of claims 68-70, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg.

### Claim 72 (depends on 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64)

The method of any one of claims 34-36, 37-40, 41-59, 60-64, and 66-70, wherein the layer formulated for controlled release of the tablet further comprises about 5 mgs to about 25 mgs of croscarmellose sodium.

### Claim 73 (depends on 72)

The method of claim 72, wherein the layer formulated for controlled release of the tablet comprises from about 8 mgs to about 12 mgs of croscarmellose sodium.

### Claim 74 (depends on 1)

The pharmaceutical composition of claim 1, wherein the tablet further comprises an effective amount of an abuse deterrent agent.

### Claim 75 (depends on 34)

The method of claim 34, wherein the tablet further comprises an effective amount of an abuse deterrent agent.