Use of prodrugs of 3-hydroxymorphinans to prevent bitter taste upon buccal, nasal or sublingual administration

• US 4,673,679 A
• Filed: 05/14/1986
• Issued: 06/16/1987
• Est. Priority Date: 05/14/1986
• Status: Expired due to Term

• Current Assignee: Bristol-Myers Squibb Pharma Company (Bristol-Myers Squibb Company)
• Original Assignee: E. I. du Pont de Nemours and Company (Corteva, Inc.)
• Inventors: Hussain, Munir A., Aungst, Bruce J.
• Primary Examiner(s): Friedman, Stanley J.
• Application Number:
  US06/863,045
• Time in Patent Office: 398 Days
• Field of Search: 514/969, 514/282, 514/812
• US Class Current: 514/282
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents

Abstract

Aliphatic, aromatic, carbonate, carbamate, or sulfonate ester prodrugs of 3-hydroxymorphinans lack the bitter taste of the parent compounds and provide enhanced bioavailability of 3-hydroxymorphinans from buccal, nasal, and sublingual dosage forms.

Claims

1. A pharmaceutical composition consisting essentially of (i) a therapeutically effective amount of a 3-hydroxymorphinan analgesic, agonist-antagonist, or narcotic antagonist of the formula:

##STR32## or a pharmaceutically acceptable acid addition salt thereof, wherein;

a is a single bond, or double bond;

R is methyl, allyl, methylallyl, cyclopropylmethyl, or cyclobutylmethyl;

R¹ is H, or OH;

R² is H, OH, ═

O, or ═

CH₂ ;

R³ and R⁴ are hydrogen, or taken together are ----O------;

R⁵ is alkanoyl of 2-18 carbon atoms;

alkenoyl of 2-18 carbon atoms;

mono- or dialkylcarbamoyl where each alkyl group contains 1-18 carbon atoms;

alkylsulfonyl of 1-18 carbon atoms;

alkylcarbonates where the alkyl group contains 1-18 carbon atoms;

benzoyl, phenylsulfonyl;

phenylcarbamoyl;

substituted benzoyl;

where the benzene ring contains 1-2 substituents individually selected from alkyl of 1-12 carbon atoms, OR⁷, NHR⁷ and NR⁷ R⁸, Cl, F, Br, I, trifluoromethyl;

substituted phenylsulfonyl or phenylcarbamoyl, where the benzene ring contains 1-2 substituents individually selected from alkyl of 1-12 carbon atoms, alkoxy of 1-12 carbon atoms, Cl, F, Br, I, CF₃ ;

R⁶ is t-butyl or n-propyl;

R⁷ is H, alkyl of 1-4 carbon atoms or COR⁹ ;

R⁸ is alkyl of 1-4 carbon atoms or COR⁹ ; and

R⁹ is H, or alkyl of 1-4 carbon atoms;

and (ii) a pharmaceutically acceptable carrier suitable for buccal, nasal, or sublingual administration.

2. A pharmaceutical composition according to claim 1, wherein the 3-hydroxymorphinan analgesic, agonist-antagonist, or narcotic antagonist is selected from the group consisting of nalbuphine, naltrexone, naloxone, nalmefene, morphine, butorphanol, oxymorphone, hydromorphone, levorphanol, levallorphan, buprenorphine, and etorphine.

3. A pharmaceutical composition according to claim 2, wherein the 3-hydroxymorphinan agonist-antagonist or narcotic antagonist is nalbuphine, naltrexone, or naloxone.

4. A pharmaceutical composition according to claim 1, wherein the carrier for buccal administration of the 3-hydroxymorphinan consists essentially of hydroxypropyl cellulose, carboxypolymethylene and polyethylene glycol.

5. A method of treating pain, controlling appetite, or reversing the effects of a narcotic drug in a mammal requiring such treatment, comprising administering to the mammal buccally, nasally, or sublingually a therapeutically effective amount of a pharmaceutical composition of claim 1.

6. A method of treating pain, controlling appetite, or reversing the effects of a narcotic drug in a mammal requiring such treatment, comprising administering to the mammal buccally, nasally, or sublingually a therapeutically effective amount of a pharmaceutical composition of claim 2.

7. A method of treating pain, controlling appetite, or reversing the effects of a narcotic drug in a mammal requiring such treatment, comprising administering to the mammal buccally, nasally, or sublingually a therapeutically effective amount of a pharmaceutical composition of claim 3.

8. A method of treating pain, controlling appetite, or reversing the effects of a narcotic drug in a mammal requiring such treatment, comprising administering buccally a pharmaceutical composition of claim 4.